Tetracyclic-macrocycles and their use

Abstract

The present disclosure relates to heterocyclic tetracyclic macrocyclic compounds comprising in the condensed ring system both rings having oxygen atoms as the only ring hetero atoms and rings having nitrogen atoms as the only ring hetero atoms, as multistargeted kinase inhibitors that are potent against emerging and established resistances mutations, and / or emerging resistance targets for tolerant / persistent cancers. Further disclosed are pharmaceutical compositions and methods of utilization thereof for treating disease, such as cancer.

Description

TETRACYCLIC-MACROCYCLES AND THEIR USE RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 696,123, filed September 18, 2024, the entire disclosure of which is incorporated herein by reference. TECHNICAL FIELD

[0002] The present disclosure relates to 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 therelease of negative feedback loops, transcriptional rewiring mediated by chromatin remodeling and autocrine / paracrine communication among tumor cells and within the tumor microenvironment (Swayden M, et al. Tolerant / Persister Cancer Cells and the Path to Resistance to Targeted Therapy. Cells 2020, 9, 2601). Therefore, it is necessary to invent kinase inhibitors that can target not only the kinase oncogenic drivers, overcome most frequent resistance mutations, but also tolerant persister cancer cells for overcoming resistance, achieving better efficacy and longer disease control.

[0004] 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, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof,

[0006] wherein R1, R2, R3, R4, R11, R15, A, B, C, D, L, X, X1, X2, X3, X4, X5, X6, X7, Y, Y1,m, n, p, q, r, and “ ” are as described herein.

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

[0008] wherein R1, R2, R3, R4, R11, R15, A, B, C, D, L, X, X1, X2, X3, X4, X5, X6, X7, m, n, p,q, r, and “ ” are as described herein.

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

[0010] wherein R1, R2, R3, R4, R11, R15, A, B, C, D, L, X, X1, X2, X3, X4, X5, X7, m, n, and p, are as described herein.

[0011] In some embodiments, the disclosure provides a compound of the formula IV, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof,

[0012] wherein R1, R2, R3, R4, R8, R9, R11, R15, A, B, C, D, L, X7, m, n, and p, are as described herein.

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

[0014] wherein R1, R2, R3, R4, R11, R15, A, B, C, D, L1, L2, X, X1, X2, X3, X4, X5, X6, X7, Y2,Y3, m, n, q, r, t, and “ ” are as described herein.

[0015] In some embodiments, the disclosure provides a compound of the formula VI, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof,

[0016] wherein R1, R2, R3, R4, R11, R15, A, B, C, D, L1, L2, X, X1, X2, X3, X4, X5, X7, Y2, Y3,m, n, q, r, t, and “ ” are as described herein.

[0017] In some embodiments, the disclosure provides a compound of the formula VII, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof,

[0018] wherein R1, R2, R3, R4, R11, R15, A, B, C, D, L1, L2, X, X1, X2, X3, X4, X5, X7, Y2, Y3, m, n, and t are as described herein.

[0019] In some embodiments, the disclosure provides a compound of the formula VIII, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof,

[0020] wherein R1, R2, R3, R4, R8, R9, R11, R15, A, B, C, D, L1, L2, X7, Y2, Y3, m, n, and t are as described herein.

[0021] In some embodiments, the disclosure provides a compound of the formula IX, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof,

[0022] wherein R1, R2, R3, R4, R11, R15, A, B, C, D, L, X1, X2, X5, X7, m, n, p, q, r, and “ ” are as described herein.

[0023] In some embodiments, the disclosure provides a compound of the formula X, or a pharmaceutically acceptable salt thereof,

[0024] wherein R1, R2, R3, R4, R11, R15, A, B, C, D, L, X1, X2, X5, X7, m, n, and p are as described herein.

[0025] In some embodiments, the disclosure provides a compound of the formula XI, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof,

[0026] wherein R1, R2, R3, R4, R9, R10, R11, R15, A, B, C, D, L, m, n, and p are as described herein.

[0027] In some embodiments, the disclosure provides a compound of the formula XII, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof,

[0028] wherein R1, R2, R3, R4, R11, R15, A, B, C, D, L1, L2, X1, X2, X5, X7, Y2, Y3, m, n, q, r,t, and “ ”are as described herein.

[0029] In some embodiments, the disclosure provides a compound of the formula XIII, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof,

[0030] wherein R1, R2, R3, R4, R11, R15, A, B, C, D, L1, L2, X1, X2, X5, X7, Y2, Y3, m, n, and t, are as described herein.

[0031] In some embodiments, the disclosure provides a compound of the formula XIV, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof,(XIV

[0032] wherein R1, R2, R3, R4, R9, R10, R11, R15, A, B, C, D, L1, L2, Y2, Y3, m, n, and t, are as described herein.

[0033] In further aspects, the disclosure relates to a pharmaceutical composition comprising at least one compound of Formula (I)-(XIV), an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof. Pharmaceutical compositions according to the disclosure may further comprise a pharmaceutically acceptable excipient.

[0034] In further aspects, the disclosure relates to a compound of Formula (I)-(XIV), an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0035] 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)-(XIV), an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof.

[0036] In further aspects, the disclosure relates to use of a compound of Formula (I)-(XIV), an isotopically labeled form thereof, 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.

[0037] In further aspects, the disclosure relates to a method of inhibiting a protein kinase, comprising contacting a cell comprising one or more of the protein kinase with an effective amount of at least one compound of Formula (I)-(XIV), an isotopically labeled form thereof, 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.

[0038] Additional embodiments, features, and advantages of the disclosure will be apparent from the following detailed description and through practice of the disclosure. The compounds of the present disclosure can be described as embodiments in any of the following enumerated clauses. It will be understood that any of the embodiments described herein can be used in connection with any other embodiments described herein to the extent that the embodiments do not contradict one another.

[0039] 1. A compound of the formula I

[0040] wherein

[0041] A is a 5- to 10-membered heteroarylene or C6-C10arylene;

[0042] B is a 5- to 10-membered heteroarylene or C6-C10 arylene;

[0043] C / D is a 9-membered bicyclic heteroarylene, wherein

[0044] X is C or N;

[0045] X1is C(R5), N(R6), or N;

[0046] X2is C(R7), N(R8), or N;

[0047] X3is C or N;

[0048] X4is C or N;

[0049] X5is C(R9) or N; and

[0050] X6is C or N;

[0051] X7is C(R10) or N; provided that at least one of X1to X7is a nitrogen atom;

[0052] each of Y and Y1is independently C, O, N, or S; provided that X, Y, and Y1do not comprise an -O-O-, -O-S-, -O-N-, -S-S-, or -N-N- bond;

[0053] each L is independently a bond, -C(R12)(R13)-, -O-, -N(R14)C(O)-, -C(O)N(R14)-, -N(R14)-, -N(R14)S(O)-, -S(O)N(R14)-, -N(R14)S(O)2-, -S(O)2N(R14)-, -S-, -S(O)-, or -S(O)2-, provided that (L)p does not comprise an -O-O-, -O-S-, -O-N-, -S-S-, or -N-N- bond;

[0054] each R1and R2, 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 R1and R2, when present and bonded to a nitrogen atom, is independently deuterium, C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, 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;

[0055] each of R3and R4is independently 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, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, or 5- to 10- membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;

[0056] each of R5, R7, R9, and R10, when present, is independently H, deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -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-C10aryl, 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;

[0057] each R6and R8, when present, is independently 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;

[0058] R11and R15, taken together with the atoms to which they are attached, combine to form a fused C6-C8cycloalkyl, fused 6- to 8-membered heterocycloalkyl, fused C6aryl, or fused 5- or 6-membered heteroaryl, wherein each hydrogen atom in fused C6-C8 cycloalkyl, fused 6- to 8-membered heterocycloalkyl, fused C6aryl, and fused 5- or 6-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;

[0059] each R12and R13, 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, -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-C6cycloalkyl or 3- to 7-membered heterocycloalkyl; wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 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, -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;

[0060] each R14, when present, is independently H, deuterium, -C(O)Rc, C1-C6 alkyl, C2-C6 alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-C10aryl, 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;

[0061] each Ra, Rb, Rc, Rd, Re, and Rfis independently selected from the group consisting of H, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, C1-C6 alkylene-C6-C10 aryl, 5- to 10-membered heteroaryl, C1-C6 alkylene-5- to 10-membered heteroaryl, and C1-C6alkylene-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-C10aryl, C1-C6alkylene-C6-C10aryl, 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-C6alkyl), -OS(O)N(H or C1-C6alkyl)2, -OS(O)N(C2-C6alkylene), -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-C6alkyl), -S(O)2(H or C1-C6alkyl), -S(O)N(H or C1-C6alkyl)2, -S(O)N(C2-C6alkylene), -S(O)2N(H or C1-C6 alkyl)2, -S(O)2N(C2-C6 alkylene), -N(H or C1-C6 alkyl)2, -N(C2-C6 alkylene), -N(H or C1-C6alkyl)C(O)-(H or C1-C6alkyl), -N(H or C1-C6alkyl)C(O)O(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)C(O)N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)C(O)N(C2-C6alkylene), -N(H or C1-C6alkyl)S(O)-(H or C1-C6alkyl), -N(H or C1-C6alkyl)S(O)2(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)S(O)N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)S(O)N(C2-C6alkylene), -N(H or C1-C6alkyl)S(O)2N(H or C1-C6alkyl)2, -N(H or C1-C6alkyl)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-C6alkylene), -P(H or C1-C6alkyl)2, -P(C2-C6alkylene), -P(O)(H or C1-C6alkyl)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-C6alkylene), -P(O)2N(H or C1-C6alkyl)2, -P(O)2N(C2-C6alkylene), -P(O)O(H or C1-C6 alkyl), -P(O)2O(H or C1-C6 alkyl), -CN, or -NO2;

[0062] m is 0, 1, 2, 3, or 4;

[0063] n is 1, 2, 3, or 4; and

[0064] p is 3, 4, 5, 6, 7, or 8;

[0065] q is 0, 1, or 2, as valency allows;

[0066] r is 0, 1, or 2, as valency allows; and

[0067] “ ” is a single bond or a double bond;

[0068] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof.

[0069] 2. The compound of clause 1, having the formula II

[0070] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof,

[0071] wherein

[0072] when “ ” is a single bond, then q is 2 and r is 2, and

[0073] when “ ” is a double bond, then q is 1 and r is 1.

[0074] 3. The compound of clause 1 or 2, having the formula III

[0075] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof.

[0076] 4. The compound of any of the preceding clauses, having the formula IV

[0077] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof.

[0078] 5. The compound of clause 1 or 2, having the formula VV

[0079] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein

[0080] each of Y2and Y3is independently a bond, -O-, -N(R14)C(O)-, -C(O)N(R14)-, -N(R14)-, -N(R14)S(O)-, -S(O)N(R14)-, -N(R14)S(O)2-, -S(O)2N(R14)-, -S-, -S(O)-, or -S(O)2-;

[0081] each L1is independently -C(R12)(R13)-, -C(R12)(R13)-C(R12)(R13)-, -C(R12)(R13)- C(R12)(R13)-C(R12)(R13)-, or -C(R12)(R13)-C(R12)(R13)-C(R12)(R13)-C(R12)(R13)-;

[0082] L2is a bond, -C(R12)(R13)-, -C(R12)(R13)-C(R12)(R13)-, or -C(R12)(R13)-C(R12)(R13)- C(R12)(R13)-; and

[0083] t is 0, 1, or 2,

[0084] wherein

[0085] when “ ” is a single bond, then q is 2 and r is 2, and

[0086] when “ ” is a double bond, then q is 1 and r is 1.

[0087] 6. The compound of any one of clauses 1, 2, or 5, having the formula VI

[0088] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein

[0089] each of Y2and Y3is independently a bond, -O-, -N(R14)C(O)-, -C(O)N(R14)-, -N(R14)-, -N(R14)S(O)-, -S(O)N(R14)-, -N(R14)S(O)2-, -S(O)2N(R14)-, -S-, -S(O)-, or -S(O)2-;

[0090] each L1is independently -C(R12)(R13)-, -C(R12)(R13)-C(R12)(R13)-, -C(R12)(R13)- C(R12)(R13)-C(R12)(R13)-, or -C(R12)(R13)-C(R12)(R13)-C(R12)(R13)-C(R12)(R13)-;

[0091] L2is a bond, -C(R12)(R13)-, -C(R12)(R13)-C(R12)(R13)-, or -C(R12)(R13)-C(R12)(R13)- C(R12)(R13)-; and

[0092] t is 0, 1, or 2,

[0093] wherein

[0094] when “ ” is a single bond, then q is 2 and r is 2, and

[0095] when “ ” is a double bond, then q is 1 and r is 1.

[0096] 7. The compound of any one of clauses 1 to 3, 5, or 6, having the formula VI

[0097] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein

[0098] each of Y2and Y3is independently a bond, -O-, -N(R14)C(O)-, -C(O)N(R14)-, -N(R14)-, -N(R14)S(O)-, -S(O)N(R14)-, -N(R14)S(O)2-, -S(O)2N(R14)-, -S-, -S(O)-, or -S(O)2-;

[0099] each L1is independently -C(R12)(R13)-, -C(R12)(R13)-C(R12)(R13)-, -C(R12)(R13)- C(R12)(R13)-C(R12)(R13)-, or -C(R12)(R13)-C(R12)(R13)-C(R12)(R13)-C(R12)(R13)-;

[0100] L2is a bond, -C(R12)(R13)-, -C(R12)(R13)-C(R12)(R13)-, or -C(R12)(R13)-C(R12)(R13)- C(R12)(R13)-; and

[0101] t is 0, 1, or 2.

[0102] 8. The compound of any of the preceding clauses, having the formula VIII

[0103] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein

[0104] each of Y2and Y3is independently a bond, -O-, -N(R14)C(O)-, -C(O)N(R14)-, -N(R14)-, -N(R14)S(O)-, -S(O)N(R14)-, -N(R14)S(O)2-, -S(O)2N(R14)-, -S-, -S(O)-, or -S(O)2-;

[0105] each L1is independently -C(R12)(R13)-, -C(R12)(R13)-C(R12)(R13)-, -C(R12)(R13)- C(R12)(R13)-C(R12)(R13)-, or -C(R12)(R13)-C(R12)(R13)-C(R12)(R13)-C(R12)(R13)-;

[0106] L2is a bond, -C(R12)(R13)-, -C(R12)(R13)-C(R12)(R13)-, or -C(R12)(R13)-C(R12)(R13)- C(R12)(R13)-; and

[0107] t is 0, 1, or 2.

[0108] 9. The compound of clause 1 or 2, having the formula IX,

[0109] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein

[0110] when “ ” is a single bond, then q is 2 and r is 2, and

[0111] when “ ” is a double bond, then q is 1 and r is 1.

[0112] 10. The compound of any one of clauses 1, 2, or 9, having the formula X

[0113] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof.

[0114] 11. The compound of any one of clauses 1, 2, 9, or 10, having the formula XI

[0115] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof.

[0116] 12. The compound of clause 1, 2, or 9, having the formula XII

[0117] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein

[0118] each of Y2and Y3is independently a bond, -O-, -N(R14)C(O)-, -C(O)N(R14)-, -N(R14)-, -N(R14)S(O)-, -S(O)N(R14)-, -N(R14)S(O)2-, -S(O)2N(R14)-, -S-, -S(O)-, or -S(O)2-;

[0119] each L1is independently -C(R12)(R13)-, -C(R12)(R13)-C(R12)(R13)-, -C(R12)(R13)- C(R12)(R13)-C(R12)(R13)-, or -C(R12)(R13)-C(R12)(R13)-C(R12)(R13)-C(R12)(R13)-;

[0120] L2is a bond, -C(R12)(R13)-, -C(R12)(R13)-C(R12)(R13)-, or -C(R12)(R13)-C(R12)(R13)- C(R12)(R13)-; and

[0121] t is 0, 1, or 2,

[0122] wherein

[0123] when “ ” is a single bond, then q is 2 and r is 2, and

[0124] when “ ” is a double bond, then q is 1 and r is 1.

[0125] 13. The compound of any one of clauses 1, 2, 9, 10, or 12, having the formula XIII

[0126] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein

[0127] each of Y2and Y3is independently a bond, -O-, -N(R14)C(O)-, -C(O)N(R14)-, -N(R14)-, -N(R14)S(O)-, -S(O)N(R14)-, -N(R14)S(O)2-, -S(O)2N(R14)-, -S-, -S(O)-, or -S(O)2-;

[0128] each L1is independently -C(R12)(R13)-, -C(R12)(R13)-C(R12)(R13)-, -C(R12)(R13)- C(R12)(R13)-C(R12)(R13)-, or -C(R12)(R13)-C(R12)(R13)-C(R12)(R13)-C(R12)(R13)-;

[0129] L2is a bond, -C(R12)(R13)-, -C(R12)(R13)-C(R12)(R13)-, or -C(R12)(R13)-C(R12)(R13)- C(R12)(R13)-; and

[0130] t is 0, 1, or 2.

[0131] 14. The compound of any one of clauses 1, 2, or 9 to 13, having the formula XIV (

[0132] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein

[0133] each of Y2and Y3is independently a bond, -O-, -N(R14)C(O)-, -C(O)N(R14)-, -N(R14)-,-N(R14)S(O)-, -S(O)N(R14)-, -N(R14)S(O)2-, -S(O)2N(R14)-, -S-, -S(O)-, or -S(O)2-;

[0134] each L1is independently -C(R12)(R13)-, -C(R12)(R13)-C(R12)(R13)-, -C(R12)(R13)- C(R12)(R13)-C(R12)(R13)-, or -C(R12)(R13)-C(R12)(R13)-C(R12)(R13)-C(R12)(R13)-;

[0135] L2is a bond, -C(R12)(R13)-, -C(R12)(R13)-C(R12)(R13)-, or -C(R12)(R13)-C(R12)(R13)- C(R12)(R13)-; and

[0136] t is 0, 1, or 2.

[0137] 15. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring C / D is of the formula

[0138] wherein each “ ” represents a point of covalent attachment.

[0139] 16. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring A in the portion

[0140] is a 5- or 6-membered heteroarylene, and each “ ” represents a point of covalentattachment.

[0141] 17. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring A in the portion[

[0143] wherein m is 0, 1, or 2, and each “” represents a point of covalent attachment.

[0144] 18. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein m is 1 or 2.

[0145] 19. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each R1, when present and bonded to carbon, is independently fluoro, chloro, methyl, ethyl, propyl, 2-hydroxyeth-1-yl, 1- hydroxyprop-2-yl, 2-hydroxyprop-1-yl, methoxy, ethoxy, isopropoxy, -C(O)ORa, -C(O)NRaRb, -CN, -CH2CN, or 4-piperidinyl.

[0146] 20. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each R1, when present and bonded to nitrogen, is independently methyl, ethyl, propyl, 2-hydroxyeth-1-yl, 1-hydroxyprop- 2-yl, 2-hydroxyprop-1-yl, 4-piperidinyl, or -CH2CN.

[0147] 21. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring A in the portion [

[0149] wherein each “ ” represents a point of covalent attachment.

[0150] 22. The compound of any one of clauses 1 to 7, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring A in the portion

[0151] is a C6-C10 arylene, m is 0, 1, 2, or 3, and each “ ” represents a point of covalentattachment.

[0152] 23. The compound of any one of clauses 1 to 7, or 14, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring A in the portion

[0153] is a phenylene, m is 0, 1, 2, or 3, and each “ ” represents a point of covalentattachment.

[0154] 24. The compound of any one of clauses 1 to 7, 14, or 15, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2.

[0155] 25. The compound of any one of clauses 1 to 7, or 14 to 16, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each R1, when present, is independently fluoro, chloro, methyl, ethyl, methoxy, ethoxy, -C(O)ORa, -C(O)NRaRb, -CN, or 4-piperidinyl.

[0156] 26. The compound of any one of clauses 1 to 7, or 14 to 17, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring A in the portion

[0157] is selected from the group consisting of

[0158] wherein each “ ” represents a point of covalent attachment.

[0159] 27. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring B in the portion

[0160] is a 5- or 6-membered heteroarylene, n is 0, 1, or 2, and each “ ” represents apoint of covalent attachment.

[0161] 28. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring B in the portion

[0162] is a 5- or 6-membered heteroarylene selected from the group consisting of,

[0163] wherein n is 0, 1, or 2, and each “” represents a point of covalent attachment.

[0164] 29. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each R2, when present and bonded to carbon, is independently fluoro, chloro, methyl, ethyl, methoxy, ethoxy, or methoxymethyl.

[0165] 30. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each R2, when present and bonded to nitrogen, is independently methyl or ethyl.

[0166] 31. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring B in the portion

[0167] is selected from the group consisting of

[0168] wherein each “ ” represents a point of covalent attachment.

[0169] 32. The compound of any one of clauses 1 to 18, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring B in the portion

[0170] is a C6-C10 arylene, m is 0, 1, 2, or 3, and each “” represents a point of covalentattachment.

[0171] 33. The compound of any one of clauses 1 to 18, or 24, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring B in the portion

[0172] is a phenylene, m is 0, 1, 2, or 3, and each “ ” represents a point of covalentattachment.

[0173] 34. The compound of any one of clauses 4 to 8, 12 to 14, or 15 to 33, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each L1, when present, is independently -C(R12)(R13)-, -C(R12)(R13)-C(R12)(R13)- or -C(R12)(R13)- C(R12)(R13)-C(R12)(R13)-.

[0174] 35. The compound of any one of clauses 4 to 8, 12 to 14, or 15 to 34, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each L1, when present, is independently -C(R12)(R13)-, -C(R12)(R13)-C(R12)(R13)- or -C(R12)(R13)- C(R12)(R13)-C(R12)(R13)-, wherein one or two of R12is a C1-C6alkyl.

[0175] 36. The compound of any one of clauses 4 to 8, 12 to 14, or 15 to 35, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each L1, when present, is independently -C(R12)(R13)-, -C(R12)(R13)-C(R12)(R13)- or -C(R12)(R13)- C(R12)(R13)-C(R12)(R13)-, wherein one or two of R12is a C1-C6 alkyl, and the remaining R12and R13are H or deuterium.

[0176] 37. The compound of any one of clauses 4 to 8, 12 to 14, or 15 to 36, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein q, when present, is 1.

[0177] 38. The compound of any one of clauses 4 to 8, 12 to 14, or 15 to 37, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein L1, when present, is -C(R12)(R13)-C(R12)(R13)-.

[0178] 39. The compound of any one of clauses 4 to 8, 12 to 14, or 15 to 38, an isotopicallylabeled form thereof, or a pharmaceutically acceptable salt thereof, wherein q, when present, is 2.

[0179] 40. The compound of any one of clauses 4 to 8, 12 to 14, or 15 to 39, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein one of L1, when present, is -C(R12)(R13)- and one of L1, when present, is -C(R12)(R13)-C(R12)(R13)-.

[0180] 41. The compound of any one of clauses 4 to 8, 12 to 14, or 15 to 40, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein Y, when present, is -O-.

[0181] 42. The compound of any one of clauses 4 to 8, 12 to 14, or 15 to 41, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein Y, when present, is -N(R14)C(O)-.

[0182] 43. The compound of any one of clauses 4 to 8, 12 to 14, or 15 to 42, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein Y, when present, is a bond.

[0183] 44. The compound of any one of clauses 4 to 8, 12 to 14, or 15 to 43, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each Y1, when present, is independently -O- or -N(R14)-.

[0184] 45. The compound of any one of clauses 4 to 8, 12 to 14, or 15 to 44, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each L2, when present, is a bond.

[0185] 46. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein -(L)p- or -L2-(Y1-L1)q-Y is of the formula,

[0186] wherein each “” represents a point of covalent attachment.

[0187] 47. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each R3is H or deuterium.

[0188] 48. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each R4is H or deuterium.

[0189] 49. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein R5, when present, is H or deuterium.

[0190] 50. The compound of any one of the preceding clauses, an isotopically labeled formthereof, or a pharmaceutically acceptable salt thereof, wherein R6, when present, is H, deuterium, or C1-C6 alkyl.

[0191] 51. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein R7, when present, is H or deuterium.

[0192] 52. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein R8, when present, is H, deuterium, or C1-C6 alkyl.

[0193] 53. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein R9, when present, is H or deuterium.

[0194] 54. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein R10, when present, is H, deuterium, halogen, C1-C6 alkyl, or -NRaRb.

[0195] 55. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein R14, when present, is H or C1- C6 alkyl.

[0196] 56. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein R11and R15, taken together with the atoms to which they are attached, combine to form a fused 6-membered heterocycloalkyl.

[0197] 57. The compound of any one of clauses 1 to 55, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein R11and R15, taken together with the atoms to which they are attached, combine to form a fused C6 aryl.

[0198] 58. The compound of any one of clauses 1 to 55, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein R11and R15, taken together with the atoms to which they are attached, combine to form a fused 5- or 6-membered heteroaryl.

[0199] 59. The compound of clause 1, selected from the group consisting of

[0200] (2S)-2-[(7S,14E)-13-ethoxy-5,7,9-trimethyl-5,7,8,9,10,17-hexahydro-18,1-(metheno)- 2,6-dioxa-4,5,9,11,12,16,17-heptaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3-cd]inden- 11(3H)-yl]propan-1-ol;

[0201] (2S)-2-[(7S,14E)-13-ethoxy-20-fluoro-5,7,9-trimethyl-5,7,8,9,10,17-hexahydro-18,1- (metheno)-2,6-dioxa-4,5,9,11,12,16,17-heptaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3- cd]inden-11(3H)-yl]propan-1-ol;

[0202] (2S)-2-[(7S,14E)-20-chloro-13-ethoxy-5,7,9-trimethyl-5,7,8,9,10,17-hexahydro-18,1- (metheno)-2,6-dioxa-4,5,9,11,12,16,17-heptaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3-cd]inden-11(3H)-yl]propan-1-ol;

[0203] (2S)-2-[(7S,14E)-13-ethoxy-5,7,9-trimethyl-5,7,8,9,10,17-hexahydro-18,1-(azeno)- 2,6-dioxa-4,5,9,11,12,16,17-heptaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3-cd]inden- 11(3H)-yl]propan-1-ol;

[0204] (2S)-1-[(7S,14E)-9-ethyl-5,7-dimethyl-13-[(propan-2-yl)oxy]-5,7,8,9,10,17- hexahydro-18,1-(azeno)-2,6-dioxa-4,5,9,11,12,16,17- heptaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3-cd]inden-11(3H)-yl]propan-2-ol;

[0205] (7S,14E)-13-ethoxy-11-[(2S)-1-hydroxypropan-2-yl]-5,7,9-trimethyl-3,5,8,9,11,17- hexahydro-18,1-(metheno)-2,6-dioxa-4,5,9,11,12,16,17- heptaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3-cd]inden-10(7H)-one;

[0206] (2S)-2-[(7S,14E)-13-ethoxy-5,7,9-trimethyl-7,8,9,10-tetrahydro-1,18-(metheno)-6- oxa-1,4,5,9,11,12,16,17-octaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3-cd]inden- 11(5H)-yl]propan-1-ol;

[0207] 2-[(7S,14E)-13-ethoxy-5,7,9-trimethyl-7,8,9,10-tetrahydro-1,18-(metheno)-6-oxa- 1,4,5,9,11,12,16,17-octaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3-cd]inden-11(5H)- yl]ethan-1-ol; and

[0208] (2S)-1-[(7S,14E)-5,7,9-trimethyl-13-[(propan-2-yl)oxy]-5,7,8,9,10,17-hexahydro- 18,1-(azeno)-2,6-dioxa-4,5,9,11,12,16,17- heptaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3-cd]inden-11(3H)-yl]propan-2-ol;

[0209] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof.

[0210] 60. A pharmaceutical composition comprising a compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, and optionally one or more excipients.

[0211] 61. A method of treating disease in a subject comprising, administering a therapeutically effective amount of a compound of any one of clauses 1 to 59, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of clause 60.

[0212] 62. A compound according to any one of clauses 1 to 59, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, for use in a method of treating disease in a subject.

[0213] 63. Use of a compound according to any one of clauses 1 to 59, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of disease in a subject.DETAILED DESCRIPTION

[0214] Before the present disclosure is further described, it is to be understood that this disclosure is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.

[0215] 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.

[0216] 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.

[0217] As used herein, the terms “including,” “containing,” and “comprising” are used in their open, non-limiting sense.

[0218] 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.

[0219] 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 disclosurebelongs. 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.

[0220] 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.

[0221] 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.).

[0222] 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

[0223] 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 atomswithin 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 oxygen atom covalently attached to ring B, where the atoms counted in the macrocycle includes the shortest path through ring B, followed by the shortest path of atoms through the bicycloheteroarylene portion, followed by the atoms in the ethenylene portion, followed by the shortest path of atoms through ring A, and finally the shortest path of atoms through the linker portion and terminating at the atom along the shortest chain that is attached to the oxygen that served as the starting point.

[0224] The term “alkyl” refers to a straight- or branched-chain monovalent hydrocarbon group. The term “alkylene” refers to a straight- or branched-chain divalent hydrocarbon group. In some embodiments, it can be advantageous to limit the number of atoms in an “alkyl” or “alkylene” to a specific range of atoms, such as C1-C20 alkyl or C1-C20 alkylene, C1-C12 alkyl or C1-C12alkylene, or C1-C6alkyl or C1-C6alkylene. Examples of alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples. Examples of alkylene groups include methylene (-CH2-), ethylene ((-CH2-)2), n- propylene ((-CH2-)3), iso-propylene ((-C(H)(CH3)CH2-)), n-butylene ((-CH2-)4), and the like. It will be appreciated that an alkyl or alkylene group can be unsubstituted or 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.

[0225] 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-C20alkenyl or C2-C20alkenylene, C2-C12alkenyl 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.

[0226] 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-C20alkynyl or C2-C20alkynylene, C2-C12alkynyl or C2-C12alkynylene, or C2-C6 alkynyl or C2-C6 alkynylene. 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.

[0227] 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 formulaparticular, a cyclopropylene moiety can be depicted by the structural formula. It will be appreciated that a cycloalkyl or cycloalkylene group can be unsubstituted or substituted as described herein. A cycloalkyl or cycloalkylene group can be substituted withany of the substituents in the various embodiments described herein, including one or more of such substituents.

[0228] The term “halogen” or “halo” represents chlorine, fluorine, bromine, or iodine.

[0229] 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)-.

[0230] 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-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-C10 aryl), 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-C10 arylene). 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.

[0231] 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. Thering 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:

[0232] A three-membered heterocycle may contain at least one heteroatom ring atom, where the heteroatom ring atom is a sulfur, oxygen, or nitrogen. Non-limiting examples of three- membered heterocycle groups include monovalent and divalent radicals of oxirane, azetidine, and thiirane. A four-membered heterocycle may contain at least one heteroatom ring atom, where the heteroatom ring atom is a sulfur, oxygen, or nitrogen. Non-limiting examples of four-membered heterocycle groups include monovalent and divalent radicals of azitidine, oxtenane, and thietane. A five-membered heterocycle can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of five-membered heterocyle groups include mono-valent and divalent radicals of pyrrolidine, tetrahydrofuran, 2, 5-dihydro-1H- pyrrole, pyrazolidine, thiazolidine, 4,5-dihydro-1H-imidazole, dihydrothiophen-2(3H)-one, tetrahydrothiophene 1,1-dioxide, imidazolidin-2-one, pyrrolidin-2-one, dihydrofuran-2(3H)-one, 1,3-dioxolan-2- one, and oxazolidin-2-one. A six-membered heterocycle can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of six-membered heterocycle groups include mono- valent or divalent radicals of piperidine, morpholine, 4H-1,4-thiazine, 1,2,3,4-tetrahydropyridine, piperazine, 1,3-oxazinan-2-one, piperazin-2-one, thiomorpholine, and thiomorpholine 1,1-dioxide. A “heterobicycle” is a fused bicyclic system comprising one heterocycle ring fused to a cycloalkyl or another heterocycle ring.

[0233] 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.

[0234] The term “heteroaryl” refers to a mono-valent monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms or members selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) that is fully unsaturated and having from 3 to 12 ring atoms per heterocycle. The term “heteroarylene” refers to a divalent monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms or members selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms per heterocycle. In some embodiments, it can be advantageous to limit the number of ring atoms in a “heteroaryl” or “heteroarylene” to a specific range of atom members, such as 5- to 10-membered heteroaryl or 5- to 10-membered heteroarylene. In some instances, a 5- to 10- membered heteroaryl can be a monocyclic ring or fused bicyclic rings having 5- to 10-ring atoms wherein at least one ring atom is a heteroatom, such as N, O, or S. In some instances, a 5- to 10-membered heteroarylene can be a monocyclic ring or fused bicyclic rings having 5- to 10-ring atoms wherein at least one ring atom is a heteroatom, such as N, O, or S. The ring structure may optionally contain an oxo group or an imino group on a carbon ring member or up to two oxo groups on sulfur ring members. Illustrative examples of 5- to 10-membered heteroaryl groups include monovalent radicals of the following entities, while examples of 5- to 10-membered heteroarylene groups include divalent radicals of the following entities, in the form of properly bonded moieties:

[0235] In some embodiments, a “monocyclic” heteroaryl can be an aromatic five- or six- membered heterocycle. A five-membered heteroaryl or heteroarylene can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of five-membered heteroaryl groups include mono-valent radicals of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole. Non-limiting examples of five-membered heteroarylene groups include di-valent radicals of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole. A six-membered heteroaryl or heteroarylene can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of six-membered heteroaryl groups include monovalent radicals of pyridine, pyrazine, pyrimidine, pyridazine, or triazine. Non-limiting examples of six-membered heteroarylene groups include divalent radicals of pyridine, pyrazine, pyrimidine, pyridazine, or triazine. A “bicyclic heteroaryl” or “bicyclic heteroarylene” is a fused bicyclic system comprising one heteroaryl ring fused to a phenyl or another heteroaryl ring. Non-limiting examples of bicyclic heteroaryl groups include monovalent radicals of quinoline, isoquinoline, quinazoline, quinoxaline, 1,5-naphthyridine, 1,8-naphthyridine, isoquinolin-3(2H)-one, thieno[3,2-b]thiophene, 1H-pyrrolo[2,3-b]pyridine, 1H- benzo[d]imidazole, benzo[d]oxazole, and benzo[d]thiazole. Non-limiting examples of bicyclic heteroarylene groups include divalent radicals of 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 formula.

[0236] It will be appreciated that a heteroaryl or heteroarylene group can be unsubstituted or substituted as described herein. A heteroaryl or heteroarylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0237] The term “oxo” represents a carbonyl oxygen. For example, a cyclopentyl substituted with oxo is cyclopentanone.

[0238] 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.

[0239] 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.

[0240] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as2H,3H,11C,13C,14C,15N,18O,17O,31P,32P,35S,18F,36Cl, and125I, respectively. Such isotopically labelled compounds are useful in metabolic studies (preferably with14C), reaction kinetic studies (with, for example2H or3H), detection or imaging techniques [such as positron emission tomography (PET) or single- photon emission computed tomography (SPECT)] including drug or substrate tissuedistribution 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.

[0241] As described herein, a compound may be of a particular formula (e.g., of Formula (I)- (XIV)), an isotopically labeled form thereof (e.g., an isotopically labeled form of the compound of Formula (I)-(XIV)), or a pharmaceutically acceptable salt thereof (e.g., a pharmaceutically acceptable salt of the compound of Formula (I)-(XIV) or a pharmaceutically acceptable salt of the isotopically labeled form of the compound of Formula (I)-(XIV)).

[0242] Certain chemical entities of Formula (I)-(XIV) 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.

[0243] The nomenclature “(ATOM)i-(ATOM)j” with j > i, when applied herein to 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), embodiments that have two carbon members (C2), and embodiments that have three carbon members (C3).

[0244] 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.

[0245] 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.

[0246] 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 chemical structure in which the identifier is shown to an adjacent chemical group or chemical structure. For example, in a hypothetical chemical structure A-B, where A and B are joined by a covalent bond, in some embodiments, the portion of A-B defined by the group or chemical structure A can be represented by,represents a bond to A andthe point of covalent bond attachment to B. Alternatively, in some embodiments, the portion of A-B defined by the group or chemical structure B can be represented by,represents a bond to B andthe point of covalent bond attachment to A.

[0247] As used herein and in connection with chemical structures depicting the variousembodiments described herein “ ” represents a σ-bond with an optional π-bond eithernot present, in the case of “ ̶̶ ̶̶̶̶̶̶̶̶ “, or present, in the case of “”. It will be appreciatedthat the “ ” symbol can be used in the context of a chain of atoms or a cyclic group. Itwill be understood that a "” used in connection with a cyclic structure indicates thatthe bonds between the atoms within which the “” symbol is located can be either“̶̶̶ ̶ ̶̶̶̶̶̶ “ or “ ” bonds, and the “” represents the delocalized electrons of π-bondswithin the ring structure. In particular, a 9-membered heteroarylene described by the structure

[0248] where X1is a carbon, X2is and nitrogen, and X3-X7are all carbons, can be depicted as either

[0249] where each of R5, R8, R9, R10, and R11are as described herein.

[0250] The disclosure also includes pharmaceutically acceptable salts of the compounds represented by Formula (I)-(XIV), preferably of those described above and of the specific compounds exemplified herein, and pharmaceutical compositions comprising such salts, and methods of using such salts.

[0251] A “pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of a compound represented herein that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S.M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977, 66, 1-19. Preferred pharmaceutically acceptablesalts 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.

[0252] 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.

[0253] For a compound of Formula (I)-(XIV) 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.

[0254] The disclosure also relates to pharmaceutically acceptable prodrugs of the compounds of Formula (I)-(XIV), and treatment methods employing such pharmaceutically acceptable prodrugs. The term “prodrug” means a precursor of a designated compound that, followingadministration 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)-(XIV)). 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.

[0255] The present disclosure also relates to pharmaceutically active metabolites of compounds of Formula (I)-(XIV), 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)-(XIV) 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

[0256] In some embodiments, the disclosure provides a compound of the formula I, or a pharmaceutically acceptable salt thereof,

[0257] wherein R1, R2, R3, R4, R11, R15, A, B, C, D, L, X, X1, X2, X3, X4, X5, X6, X7, Y, Y1,m, n, p, q, r, and “ ” are as described herein.

[0258] In some embodiments, the disclosure provides a compound of the formula II, or a pharmaceutically acceptable salt thereof,

[0259] wherein R1, R2, R3, R4, R11, R15, A, B, C, D, L, X, X1, X2, X3, X4, X5, X6, X7, m, n, p,q, r, and “ ” are as described herein.

[0260] In some embodiments, the disclosure provides a compound of the formula III, or a pharmaceutically acceptable salt thereof,

[0261] wherein R1, R2, R3, R4, R11, R15, A, B, C, D, L, X, X1, X2, X3, X4, X5, X7, m, n, and p are as described herein.

[0262] In some embodiments, the disclosure provides a compound of the formula IV, or a pharmaceutically acceptable salt thereof,

[0263] wherein R1, R2, R3, R4, R8, R9, R11, R15, A, B, C, D, L, X7, m, n, and p are as described herein.

[0264] In some embodiments, the disclosure provides a compound of the formula V, or a pharmaceutically acceptable salt thereof,

[0265] wherein R1, R2, R3, R4, R11, R15, A, B, C, D, L1, L2, X, X1, X2, X3, X4, X5, X6, X7, Y2,Y3, m, n, q, r, t, and “ ” are as described herein.

[0266] In some embodiments, the disclosure provides a compound of the formula VI, or a pharmaceutically acceptable salt thereof,VI

[0267] wherein R1, R2, R3, R4, R11, R15, A, B, C, D, L1, L2, X, X1, X2, X3, X4, X5, X7, Y2, Y3, m, n, q, r, t, and“ ” are as described herein.

[0268] In some embodiments, the disclosure provides a compound of the formula VII, or a pharmaceutically acceptable salt thereof,

[0269] wherein R1, R2, R3, R4, R11, R15, A, B, C, D, L1, L2, X, X1, X2, X3, X4, X5, X7, Y2, Y3,m, n, t, and “ ” are as described herein.

[0270] In some embodiments, the disclosure provides a compound of the formula VIII, or a pharmaceutically acceptable salt thereof,

[0271] wherein R1, R2, R3, R4, R8, R9, R11, R15, A, B, C, D, L1, L2, X7, Y2, Y3, m, n, and t are as described herein.

[0272] In some embodiments, the disclosure provides a compound of the formula IX, or a pharmaceutically acceptable salt thereof,

[0273] wherein R1, R2, R3, R4, R11, R15, A, B, C, D, L, X1, X2, X5, X7, m, n, p, q, r, and“ ” are as described herein.

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

[0275] wherein R1, R2, R3, R4, R11, R15, A, B, C, D, L, X1, X2, X5, X7, m, n, and p are as described herein.

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

[0277] wherein R1, R2, R3, R4, R9, R10, R11, R15, A, B, C, D, L, m, n, and p are as described herein.

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

[0279] wherein R1, R2, R3, R4, R11, R15, A, B, C, D, L1, L2, X1, X2, X5, X7, Y2, Y3, m, n, q, r,t, and “ ” are as described herein.

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

[0281] wherein R1, R2, R3, R4, R11, R15, A, B, C, D, L1, L2, X1, X2, X5, X7, Y2, Y3, m, n, t are as described herein.

[0282] In some embodiments, the disclosure provides a compound of the formula XIV, or a pharmaceutically acceptable salt thereof,(XIV

[0283] wherein R1, R2, R3, R4, R9, R10, R11, R15, A, B, C, D, L1, L2, Y2, Y3, m, n, and t are as described herein.

[0284] In some embodiments, at least one hydrogen atom in the compound of the Formula (I)- (XIV) is substituted by a deuterium. In some embodiments, at least one hydrogen atom in ring A, ring B, ring C, ring D, or any of R1-R15in the compound of the Formula (I)-(XIV) is substituted by a deuterium.

[0285] In some embodiments, ring A is a 5- to 10-membered heteroarylene. In some embodiments, ring A is a 5- or 6-membered heteroarylene. In some embodiments, ring A is a 5-membered heteroarylene. In some embodiments, ring A is a 6-membered heteroarylene.

[0286] In some embodiments, ring A is a 5- to 10-membered heteroarylene, wherein each R1, when present and bonded to a carbon, is independently 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, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, or each R1, when present and bonded to a nitrogen atom, is independently deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6cycloalkyl, 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.

[0287] In some embodiments, ring A is a 5- or 6-membered heteroarylene, wherein each R1, when present and bonded to a carbon, is independently 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, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, or 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-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.

[0288] In some embodiments, ring A in the portionis a 5- or 6-membered heteroarylene selected from the group consisting of

[0289] wherein each R1is independently as described herein, m is 0, 1, or 2, and each“ ” represents a point of covalent attachment.

[0290] In some embodiments, ring A is a 6-membered heteroarylene, wherein each R1, when present and bonded to a carbon, is independently 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, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, or each R1, when present and bonded to a nitrogen atom, is independently deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6 cycloalkyl, 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.

[0291] In some embodiments, ring A in the portionis a 6-membered heteroarylene selected from the group consisting of,

[0292] wherein each R1is independently as described herein, m is 0, 1, or 2, and each“ ” represents a point of covalent attachment.

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

[0294] wherein “ ” is optionally a carbon-carbon single bond or a carbon-carbon doublebond, each “ ” represents a point of covalent attachment, ring A is a 5-memberedheteroarylene, and R1and m are as described herein.

[0295] In some embodiments, ring A is a 5-membered heteroarylene, wherein each R1, when present and bonded to a carbon, is independently 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, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, or each R1, when present and bonded to a nitrogen atom, is independently deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6 cycloalkyl, 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.

[0296] In some embodiments, ring A in the portionis a 5-membered heteroarylene selected from the group consisting ofwherein each R1 is independently as described herein, m is 0, 1, or 2, and each “”represents a point of covalent attachment. For example, the hydrogen on NH may be s.

[0297] In some embodiments, ring A is pyrazolylene, isoxazolylene, isothiazolylene, imidazolylene wherein each is independently optionally substituted by 1, 2, or 3 R1(m of R1), wherein each R1, when present and bonded to a carbon, is independently deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, or 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-C10aryl, or 5- to 10-membered heteroaryl is independentlyoptionally 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, m is 0, 1, 2, 3, or 4. In some embodiments, m is 1, 2, 3, or 4. In some embodiments, m is 2, 3, or 4. In some embodiments, m is 3 or 4. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 2 or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 1 or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0299] In some embodiments, ring A is a 5-membered heteroarylene selected from the group consisting of,

[0300] wherein each “ ” represents a point of covalent attachment, and each R1 isindependently as described herein.

[0301] In some embodiments, ring A is a 5-membered heteroarylene selected from the group consisting of

[0302] wherein each “ ” represents a point of covalent attachment, and each R1 isindependently as described herein.

[0303] In some embodiments, ring A is a 5-membered heteroarylene selected from the group consisting of

[0304] wherein each“ ” represents a point of covalent attachment, and each R1 isindependently as described herein.

[0305] In some embodiments, each R1, when present and bonded to a carbon atom, is independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 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, and / or 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, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORc, -OC(O)Rc,-OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2.

[0306] In some embodiments, each R1, when present and bonded to a carbon atom, is independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 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-C10aryl, 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.

[0307] In some embodiments, 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-C10aryl, 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.

[0308] In some embodiments, each R1, when present and bonded to a nitrogen atom, is independently a 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.

[0309] In some embodiments, each R1, when present and bonded to a carbon atom, is independently a C1-C6alkyl, -ORa, or a -NRaRb, 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.

[0310] In some embodiments, each R1, when present and bonded to carbon, is independently fluoro, chloro, methyl, ethyl, propyl, methyl-cyclopropan-1-ol, 2-hydroxyeth-1-yl, 1- hydroxyprop-2-yl, 2-hydroxyprop-1-yl, methoxy, ethoxy, isopropoxy, aminomethyl, aminoethyl, aminomethyl(ethyl), -OCD2CD3, -C(O)ORa, -C(O)NRaRb, -CH2CH2NRcRd, -CH(CH3)CH2NRcRd, -OCH2CN, -OCH(CH3)CN, -CN, or 4-piperidinyl, and / or each R1, when present and bonded to nitrogen, is independently methyl, ethyl, propyl, methyl-cyclopropan- 1-ol, 2-hydroxyeth-1-yl, 1-hydroxyprop-2-yl, 2-hydroxyprop-1-yl, 4-piperidinyl, -CH2CH2NRcRd, -CH(CH3)CH2NRcRd, or -CH2CN. In some embodiments, each R1, when present and bonded to carbon, is independently fluoro, chloro, methyl, ethyl, propyl, methyl- cyclopropan-1-ol, 2-hydroxyeth-1-yl, 1-hydroxyprop-2-yl, 2-hydroxyprop-1-yl, methoxy, ethoxy, isopropoxy, aminomethyl, aminoethyl, aminomethyl(ethyl), -OCD2CD3, -C(O)ORa, -C(O)NRaRb, -CH2CH2NRcRd, -CH(CH3)CH2NRcRd, -OCH2CN, -OCH(CH3)CN, -CN, or 4- piperidinyl. In some embodiments, each R1, when present and bonded to nitrogen, is independently methyl, ethyl, propyl, methyl-cyclopropan-1-ol, 2-hydroxyeth-1-yl, 1- hydroxyprop-2-yl, 2-hydroxyprop-1-yl, 4-piperidinyl, -CH2CH2NRcRd, -CH(CH3)CH2NRcRd, or -CH2CN. In some embodiments, each R1, when present, is independently fluoro, chloro, methyl, ethyl, methoxy, ethoxy, -C(O)ORa, -C(O)NRaRb, -CN, or 4-piperidinyl.

[0311] In some embodiments, each R1, when present and bonded to carbon, is independently fluoro, chloro, methyl, ethyl, propyl, 2-hydroxyeth-1-yl, 1-hydroxyprop-2-yl, 2-hydroxyprop- 1-yl, methoxy, ethoxy, isopropoxy, -C(O)ORa, -C(O)NRaRb, -CN, -CH2CN, or 4-piperidinyl, and / or each R1, when present and bonded to nitrogen, is independently methyl, ethyl, propyl, 2-hydroxyeth-1-yl, 1-hydroxyprop-2-yl, 2-hydroxyprop-1-yl, 4-piperidinyl, or -CH2CN. In some embodiments, each R1, when present and bonded to carbon, is independently fluoro, chloro, methyl, ethyl, propyl, 2-hydroxyeth-1-yl, 1-hydroxyprop-2-yl, 2-hydroxyprop-1-yl, methoxy, ethoxy, isopropoxy, -C(O)ORa, -C(O)NRaRb, -CN, -CH2CN, or 4-piperidinyl. In some embodiments, each R1, when present and bonded to nitrogen, is independently methyl, ethyl, propyl, 2-hydroxyeth-1-yl, 1-hydroxyprop-2-yl, 2-hydroxyprop-1-yl, 4-piperidinyl, or -CH2CN.

[0312] In some embodiments, ring A is a 5-membered heteroarylene selected from the group consisting of

[0313] wherein each “ ” represents a point of covalent attachment.

[0314] In some embodiments, ring A is a 5-membered heteroarylene selected from the group consisting of

[0315] wherein each “ ” represents a point of covalent attachment.

[0316] In some embodiments, ring A in the portionis a 5- or 6-membered heteroarylene selected from the group consisting of

[0317] wherein each “” represents a point of covalent attachment.

[0318] In some embodiments, ring A is C6-C10arylene. In some embodiments, ring A in the portion

[0319] is a C6-C10 arylene, each R1is independently as described herein, m is 0, 1, 2, or 3, andeach “ ” represents a point of covalent attachment.

[0320] In some embodiments, ring A is a phenylene. In some embodiments, ring A in the portion

[0321] is a phenylene, m is 0, 1, 2, or 3, and each “ ” represents a point of covalentattachment.

[0322] In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, m is 1, 2, 3, or 4. In some embodiments, m is 2, 3, or 4. In some embodiments, m is 3 or 4. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 2 or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 1 or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0323] In some embodiments, each R1, when present, is independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 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-C6alkynyl, C3-C6cycloalkyl, 3- to 7- membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2. In some embodiments, each R1, when present, is independently fluoro, chloro, methyl, ethyl, methoxy, ethoxy, -C(O)ORa, -C(O)NRaRb, -CN, or 4-piperidinyl.

[0324] In some embodiments, ring A in the portionis selected from the group consisting of

[0325] wherein each “ ” represents a point of covalent attachment.

[0326] In some embodiments, ring B is 5- to 10-membered heteroarylene. In some embodiments, ring B is a 5- or 6-membered heteroarylene. In some embodiments, ring B is a 5-membered heteroarylene. In some embodiments, ring B is a 6-membered heteroarylene.

[0327] In some embodiments, ring B 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, -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- to7-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.

[0328] In some embodiments, ring B 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-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 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-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.

[0329] In some embodiments, ring B in the portion

[0330] is a 5- or 6-membered heteroarylene, n is 0, 1, or 2, and each “ ” represents apoint of covalent attachment.

[0331] In some embodiments, ring B is of the formula

[0332] wherein “ ” is optionally a carbon-carbon single bond or a carbon-carbon doublebond, each “ ” represents a point of covalent attachment, and R2, R15, and n are asdescribed herein.

[0333] In some embodiments, ring B is of the formula

[0334] wherein “ ” is optionally a carbon-carbon single bond or a carbon-carbon doublebond, each “ ” represents a point of covalent attachment, ring A is a 5-memberedheteroarylene, and R2, R15, and n are as described herein.

[0335] In some embodiments, ring B is pyrazolylene, isoxazolylene, isothiazolylene, imidazolylene wherein each is optionally substituted with 1, 2, or 3 R2(n of R2), wherein each R2, when present and bonded to a carbon atom, is independently deuterium, halogen, C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 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 R2, when present and bonded to a nitrogen atom, is independently deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 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-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, or 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.

[0336] In some embodiments, ring B in the portionis a 5- or 6-membered heteroarylene selected from the group consisting of

[0337] wherein n is 0, 1, or 2, and each “” represents a point of covalent attachment.

[0338] 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.

[0339] In some embodiments, ring B is a 5-membered heteroarylene selected from the group consisting of

[0340] wherein each “ ” represents a point of covalent attachment, and R15 and each R2is independently as described herein. For example, ring B is a 5-membered heteroarylene selected from the group consisting of

[0341] wherein each “” represents a point of covalent attachment, and R15 and each R2is independently as described herein.

[0342] In some embodiments, ring B is a 6-membered heteroarylene selected from the group consisting of

[0343] wherein each “ ” represents a point of covalent attachment, and R15 and each R2is independently as described herein.

[0344] In some embodiments, each R2, when present and bonded to a carbon atom, is independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 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-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. In some embodiments, each R2, when present and bonded to carbon,is independently fluoro, chloro, methyl, ethyl, methoxy, ethoxy, or methoxymethyl.

[0345] In some embodiments, 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-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 R2, when present and bonded to nitrogen, is independently methyl or ethyl.

[0346] In some embodiments, ring B in the portionis selected from the group consisting of

[0347] wherein each “ ” represents a point of covalent attachment, and R15 is asdescribed herein.

[0348] In some embodiments, ring B is a 5-membered heteroarylene selected from the group consisting of

[0349] wherein each “ ” represents a point of covalent attachment, and R15 is asdescribed herein.

[0350] In some embodiments, ring B is a 6-membered heteroarylene selected from the group consisting of

[0351] wherein each “ ” represents a point of covalent attachment, and R15 is asdescribed herein.

[0352] In some embodiments, ring B in the portion

[0353] is a C6-C10 arylene, n is 0, 1, 2, or 3, and each “ ” represents a point of covalentattachment, and R2, R15, and n are as described herein.

[0354] In some embodiments, ring B in the portion

[0355] is a phenylene, n is 0, 1, 2, or 3, and each “ ” represents a point of covalentattachment.

[0356] In some embodiments, each of R3and R4is independently H, deuterium, halogen, C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 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, -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.

[0357] In some embodiments, each of Y and Y1is independently C, O, N, or S; provided thatX, Y, and Y1do not comprise an -O-O-, -O-S-, -O-N-, -S-S-, or -N-N- bond. In some embodiments, each of Y and Y1is C. In some embodiments, Y, when present, is -O-. In some embodiments, Y, when present, is -N(R14)C(O)-. In some embodiments, Y, when present, is a bond. In some embodiments, each Y1, when present, is independently -O- or -N(R14)-.

[0358] In some embodiments, each of R3and R4is independently H, deuterium, or C1-C6alkyl. In some embodiments, each R3is H or deuterium. In some embodiments, each R4is H or deuterium. In some embodiments, each R3and each R4are H.

[0359] In some embodiments, q is 0, 1, or 2, as valency allows. In some embodiments, q is 0 or 1. In some embodiments, q is 1 or 2. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2.

[0360] In some embodiments, r is 0, 1, or 2, as valency allows. In some embodiments, r is 0 or 1. In some embodiments, r is 1 or 2. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2.

[0361] In some embodiments, when “ ” is a single bond between two carbon atoms, thenq is 2 and r is 2, and when “ ” is a double bond between two carbon atoms, then q is 1and r is 1. In some embodiments, when “ ” is a single bond between a carbon atoms anda heteroatom, then one of q and r is 2 and the other one of q and r is 1 (e.g., if the heteroatom is nitrogen) or 0 (e.g., if the heteroatom is oxygen or sulfur).

[0362] In some embodiments, ring C / D is a 9-membered bicyclic heteroarylene wherein X is C or N, X1is C(R5), N(R6), or N; X2is C(R7), N(R8), or N; X3is C or N; X4is C or N; X5is C(R9) or N; X6is C or N; and X7is C(R10) or N; provided that at least one of X1to X7is a nitrogen atom (e.g., N or NR6or NR8). In some embodiments, X is C. In some embodiments, X is N. In some embodiments, X1is C(R5). In some embodiments, X1is N(R6) or N. In some embodiments, X1is N(R6). In some embodiments, X1is N. In some embodiments, X2is C(R7). In some embodiments, X2is N(R8) or N. In some embodiments, X2is N. In some embodiments, one or both of X1and X2is N. In some embodiments, X is C, X1is N(R6) or N, and X2is N(R8) or N. In some embodiments, X is C, X1is N, and X2is N(R8). In some embodiments, X is C, X1is N, and X2is N. In some embodiments, X1is N and X2is N(R8). In some embodiments, X1is N and X2is N.

[0363] 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, one of X3and X4is C. In some embodiments, each of X3and X4is C. In some embodiments, X5is C(R9) or N. In some embodiments, X5is C(R9). In some embodiments, X5is N. In some embodiments, X6is C or N. In some embodiments, X6is C. In some embodiments, X6is N. In some embodiments, X7is C(R10) or N. In some embodiments, X7is C(R10). In some embodiments, X7is N.

[0364] In some embodiments, X3is C, X4is C, X5is C(R9), X6is C, and X7is C(R10). In some embodiments, X3is C, X4is C, X5is C(R9), X6is C, and X7is N. In some embodiments, X3is C, X4is C, X5is C(R9), X6is N, and X7is C(R10).

[0365] In some embodiments, ring C / D is of the formula

[0366] wherein each “, ”represents a point of covalent attachment.

[0367] In some embodiments, each of R5, R7, R9, R10, or R11, 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-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-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-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.

[0368] In some embodiments, each R6and R8, when present, is independently H, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, -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 and C3-C6 cycloalkyl 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.

[0369] In some embodiments, each R6and R8, when present, is independently H, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, -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, each R6and R8, when present, is independently H or deuterium.

[0370] In some embodiments, R5, 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-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, 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, R5, when present, is H, deuterium, halogen, or C1-C6 alkyl. 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.

[0371] In some embodiments, R6, when present, is H, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, -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 and C3- C6 cycloalkyl 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, R6, when present, is H, deuterium, C1-C6alkyl, or C3-C6 cycloalkyl wherein each hydrogen atom in C1-C6 alkyl and C3-C6 cycloalkyl 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.

[0372] In some embodiments, R6, 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, R6, 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-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, R6, when present, is H, deuterium, C1-C6alkyl, or C3-C6 cycloalkyl. In some embodiments, R6, when present, is H or C1-C6 alkyl. In some embodiments, R6, when present, is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec- butyl, cyclopropyl, and the like. In some embodiments, R6, when present, is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, and the like. 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.

[0373] In some embodiments, R7, 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-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, 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-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, R7, when present, is H, deuterium, halogen, or C1-C6alkyl. 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.

[0374] In some embodiments, R8, when present, is H, deuterium, C1-C6alkyl, C3-C6cycloalkyl, -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 and C3-C6 cycloalkyl 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, R8, when present, is H, deuterium, C1-C6 alkyl, or C3-C6cycloalkyl wherein each hydrogen atom in C1-C6alkyl and C3-C6cycloalkyl 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.

[0375] In some embodiments, R8, 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, R8, 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, R8, when present, is H, deuterium, C1-C6 alkyl, or C3-C6cycloalkyl. In some embodiments, R8, when present, is H or C1-C6alkyl. In some embodiments, R8, when present, is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec- butyl, cyclopropyl, and the like. In some embodiments, R8, when present, is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, and the like. 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.

[0376] In some embodiments, R9, 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-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-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, 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, 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.

[0377] In some embodiments, R10, 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-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, R10, 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, R10, when present, is H, deuterium, halogen, or C1-C6alkyl. In some embodiments, R10, when present, is H, deuterium, or halogen. In some embodiments, R10, when present, is H or deuterium. In some embodiments, R10, when present, is H. In some embodiments, R10, when present, is deuterium. In some embodiments, R10, when present, is halogen.

[0378] In some embodiments, R11and R15, taken together with the atoms to which they are attached, combine to form a fused C6-C8 cycloalkyl, fused 6- to 8-membered heterocycloalkyl, fused C6 aryl, or fused 5- or 6-membered heteroaryl, wherein each hydrogen atom in fused C6- C8 cycloalkyl, fused 6- to 8-membered heterocycloalkyl, fused C6 aryl, and fused 5- or 6-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, R11and R15, taken together with the atoms to which they are attached, combine to form an optionally substituted fused C6-C8cycloalkyl, optionally substituted fused 6- to 8-membered heterocycloalkyl, optionally substituted fused C6 aryl, or optionally substituted fused 5- or 6- xample in the following formula,and R15taken together with the atoms to which they are attached, combine to form a fused C6-C8 cycloalkyl, fused 6- to 8-membered heterocycloalkyl, fused C6 aryl, or fused 5- or 6-membered heteroaryl, each of which is optionally substituted, such as the following

[0379] In some embodiments, ring C / D is of the formula ,

[0380] wherein each “ ” represents a point of covalent attachment.

[0381] In some embodiments, each L in (L)p is independently a bond, -C(R12)(R13)-, -O-, -N(R14)C(O)-, -C(O)N(R14)-, -N(R14)-, -N(R14)S(O)-, -S(O)N(R14)-, -N(R14)S(O)2-, -S(O)2N(R14)-, -S-, -S(O)-, or -S(O)2-, provided that (L)p does not comprise an -O-O-, -O-S-, -O-N-, -S-S-, or -N-N- bond. In some embodiments, each L in (L)p is independently a bond, -C(R12)(R13)-, -O-, -N(R14)C(O)-, -C(O)N(R14)-, or -N(R14)-, provided that (L)p does not comprise an -O-O-, -O-N-, or -N-N- bond.

[0382] In some embodiments, p is 3, 4, 5, 6, 7, or 8. In some embodiments, p is 3, 4, 5, 6, or 7. In some embodiments, p is 3, 4, 5, or 6. In some embodiments, p is 3, 4, or 5. In some embodiments, p is 4, 5, 6, or 7. In some embodiments, p is 4, 5, 6, or 7. In some embodiments, p is 5, 6, or 7. In some embodiments, p is 4, 5, 6, or 7. In some embodiments, p is 4, 5, or 6. In some embodiments, p is 5 or 6. In some embodiments, p is 4 or 5. In some embodiments, p is 3 or 4. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6. In some embodiments, p is 7. In some embodiments, p is 8.

[0383] In some embodiments, (L)p comprises the moieties Y2, Y3, L1, and L2. In some embodiments, each of Y2and Y3is independently a bond, -O-, -N(R14)C(O)-, -C(O)N(R14)-,-N(R14)-, -N(R14)S(O)-, -S(O)N(R14)-, -N(R14)S(O)2-, -S(O)2N(R14)-, -S-, -S(O)-, or -S(O)2-. In some embodiments, each L1is independently -C(R12)(R13)-, -C(R12)(R13)-C(R12)(R13)-, -C(R12)(R13)-C(R12)(R13)-C(R12)(R13)-, or -C(R12)(R13)-C(R12)(R13)-C(R12)(R13)-C(R12)(R13)-. In some embodiments, each L1is independently -C(R12)(R13)-, -C(R12)(R13)-C(R12)(R13)- or -C(R12)(R13)-C(R12)(R13)-C(R12)(R13)-. In some embodiments, each L1, when present, is independently -C(R12)(R13)-, -C(R12)(R13)-C(R12)(R13)- or -C(R12)(R13)-C(R12)(R13)- C(R12)(R13)-, wherein one or two of R12is a C1-C6alkyl. In some embodiments, each L1, when present, is independently -C(R12)(R13)-, -C(R12)(R13)-C(R12)(R13)- or -C(R12)(R13)- C(R12)(R13)-C(R12)(R13)-, wherein one or two of R12is a C1-C6alkyl, and the remaining R12and R13are H or deuterium.

[0384] In some embodiments, L1, when present, is -C(R12)(R13)-C(R12)(R13)-. In some embodiments, one of L1, when present, is -C(R12)(R13)- and one of L1, when present, is -C(R12)(R13)-C(R12)(R13)-.

[0385] In some embodiments, each L2is independently a bond, -C(R12)(R13)-, -C(R12)(R13)- C(R12)(R13)-, or -C(R12)(R13)-C(R12)(R13)-C(R12)(R13)-. In some embodiments, each L2is independently a bond, or -C(R12)(R13)-. In some embodiments, each L2is independently a bond.

[0386] In some embodiments, each of Y2and Y3is independently a bond, -O-, -N(R14)C(O)-, -C(O)N(R14)-, -N(R14)-. In some embodiments, Y2is a bond, -O-, -N(R14)C(O)-, -C(O)N(R14)-, -N(R14)-. In some embodiments, Y2is a bond, -O-, -N(R14)C(O)-, or -C(O)N(R14)-. In some embodiments, Y2is -O- or -N(R14)C(O)-. In some embodiments, Y2is -O-. In some embodiments, Y2is -N(R14)C(O)-. In some embodiments, Y2is -C(O)N(R14)-. In some embodiments, Y2is -N(R14)-. In some embodiments, each Y3is independently a bond, -O-, -N(R14)C(O)-, -C(O)N(R14)-, -N(R14)-. In some embodiments, each Y3is independently -O- or -N(R14)-. In some embodiments, each Y3is -O-. In some embodiments, each Y3is -N(R14)-.

[0387] In some embodiments, (L)pis of the formula -L2-(Y3-L1)t-Y2-, -L2-(Y3-L1)t-, -(Y3-L1)t- Y2-, (Y3-L1)t- or -L2-Y2-. In some embodiments, (L)p is of the formula -L2-(Y3-L1)t-Y2-. In some embodiments, t is 0, 1, or 2. In some embodiments, t is 0 or 1. In some embodiments, t is 1 or 2. In some embodiments, t is 0. In some embodiments, t is 1. In some embodiments, t is 2.

[0388] In some embodiments, each R12and R13, when present, is independently H, deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -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-C6cycloalkyl or 3- to 7-membered heterocycloalkyl; wherein each hydrogen atom in C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 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, -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.

[0389] In some embodiments, one of R12or R13and an R14, 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.

[0390] In some embodiments, each R12and R13, when present, is independently H, deuterium, halogen, or C1-C6 alkyl, or two of R12and R13, taken together with the carbon or carbons to which they are attached, combine to form C3-C6cycloalkyl or 3- to 7-membered heterocycloalkyl; wherein each hydrogen atom in 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 R12or R13and an R14, 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.

[0391] In some embodiments, each R12and R13, when present, is independently H, deuterium, halogen, or C1-C6alkyl, 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, C3-C6cycloalkyl, and 3- to 7- membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, or -ORe,; or one of R12or R13and an R14, 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.

[0392] In some embodiments, each R14, 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-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-C10 aryl, 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 R14and one of R12or 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 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.

[0393] In some embodiments, each R14, 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-C6alkenyl, C2-C6alkynyl, and C3-C6cycloalkyl 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.

[0394] In some embodiments, each R14, when present, is independently C1-C6 alkyl or C3-C6 cycloalkyl, wherein each hydrogen atom in C1-C6alkyl and C3-C6cycloalkyl 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.

[0395] In some embodiments, each R14is independently H, deuterium, C1-C6alkyl, or C3-C6cycloalkyl. In some embodiments, each R14, when present, is independently H, C1-C6 alkyl, or C3-C6cycloalkyl. In some embodiments, R14, when present, is H or C1-C6alkyl. In some embodiments, an R14and an R12or R13, taken together with the atoms to which they are attached, combine to form 4- to 7-membered heterocycloalkyl. In some embodiments, each R14is independently H, deuterium, methyl, ethyl, propyl, iso-propyl, or cyclopropyl. In some embodiments, each R14, when present, is independently H, methyl, or ethyl.

[0396] In some embodiments, -(L)p- or -L2-(Y3-L1)t-Y2is of the formula

[0397] wherein each “ ” represents a point of covalent attachment, and each hydrogenis independently optionally substituted with deuterium..

[0398] In some embodiments, the portion -L1-Y2- is of the formula

[0399] wherein each “” represents a point of covalent attachment, and each hydrogenis independently optionally substituted with deuterium.

[0400] In some embodiments, each Ra, Rb, Rc, Rd, Re, and Rfis independently selected from the group consisting of H, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, C1-C6alkylene-C6-C10aryl, 5- to 10-membered heteroaryl, 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-C6alkylene-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-C6alkyl), -OC(O)N(H or C1-C6alkyl)2, -OC(O)N(C2-C6alkylene), -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-C6alkyl)2, -OS(O)2N(C2-C6alkylene), -S(H or C1-C6alkyl), -S(O)(H or C1-C6 alkyl), -S(O)2(H or C1-C6 alkyl), -S(O)N(H or C1-C6 alkyl)2, -S(O)N(C2-C6 alkylene), -S(O)2N(H or C1-C6alkyl)2, -S(O)2N(C2-C6alkylene), -N(H or C1-C6alkyl)2, -N(C2-C6 alkylene), -N(H or C1-C6 alkyl)C(O)-(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)C(O)O(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)C(O)N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)C(O)N(C2-C6alkylene), -N(H or C1-C6alkyl)S(O)-(H or C1-C6alkyl), -N(H or C1-C6alkyl)S(O)2(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)S(O)N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)S(O)N(C2-C6alkylene), -N(H or C1-C6alkyl)S(O)2N(H or C1-C6alkyl)2, -N(H or C1-C6alkyl)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-C6alkylene), -P(H or C1-C6alkyl)2, -P(C2-C6alkylene), -P(O)(H or C1-C6alkyl)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-C6alkylene), -P(O)2N(H or C1-C6alkyl)2, -P(O)2N(C2-C6alkylene), -P(O)O(H or C1-C6 alkyl), -P(O)2O(H or C1-C6 alkyl), -CN, or -NO2.

[0401] In certain aspects, the compounds of the present disclosure are macrocycles. For example, in the compounds of Formula I, it will be appreciated that ring A and ring B are connected by a linker portion as described herein, wherein the linker portion comprises a chain of atoms, including but not limited to C, N, O, and S to provide a macrocycle.

[0402] In some embodiments, the disclosure provides a compound selected from the group consisting of

[0403] (2S)-2-[(7S,14E)-13-ethoxy-5,7,9-trimethyl-5,7,8,9,10,17-hexahydro-18,1- (metheno)-2,6-dioxa-4,5,9,11,12,16,17-heptaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3- cd]inden-11(3H)-yl]propan-1-ol;

[0404] (2S)-2-[(7S,14E)-13-ethoxy-20-fluoro-5,7,9-trimethyl-5,7,8,9,10,17-hexahydro-18,1- (metheno)-2,6-dioxa-4,5,9,11,12,16,17-heptaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3- cd]inden-11(3H)-yl]propan-1-ol;

[0405] (2S)-2-[(7S,14E)-20-chloro-13-ethoxy-5,7,9-trimethyl-5,7,8,9,10,17-hexahydro-18,1- (metheno)-2,6-dioxa-4,5,9,11,12,16,17-heptaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3- cd]inden-11(3H)-yl]propan-1-ol;

[0406] (2S)-2-[(7S,14E)-13-ethoxy-5,7,9-trimethyl-5,7,8,9,10,17-hexahydro-18,1-(azeno)- 2,6-dioxa-4,5,9,11,12,16,17-heptaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3-cd]inden- 11(3H)-yl]propan-1-ol;

[0407] (2S)-1-[(7S,14E)-9-ethyl-5,7-dimethyl-13-[(propan-2-yl)oxy]-5,7,8,9,10,17- hexahydro-18,1-(azeno)-2,6-dioxa-4,5,9,11,12,16,17- heptaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3-cd]inden-11(3H)-yl]propan-2-ol;

[0408] (7S,14E)-13-ethoxy-11-[(2S)-1-hydroxypropan-2-yl]-5,7,9-trimethyl-3,5,8,9,11,17- hexahydro-18,1-(metheno)-2,6-dioxa-4,5,9,11,12,16,17- heptaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3-cd]inden-10(7H)-one;

[0409] (2S)-2-[(7S,14E)-13-ethoxy-5,7,9-trimethyl-7,8,9,10-tetrahydro-1,18-(metheno)-6- oxa-1,4,5,9,11,12,16,17-octaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3-cd]inden- 11(5H)-yl]propan-1-ol; and

[0410] 2-[(7S,14E)-13-ethoxy-5,7,9-trimethyl-7,8,9,10-tetrahydro-1,18-(metheno)-6-oxa- 1,4,5,9,11,12,16,17-octaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3-cd]inden-11(5H)- yl]ethan-1-ol;

[0411] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof.

[0412] The following represent illustrative embodiments of compounds of Formula (I)- (XIV):

[0413] an isotopically labeled form thereof, and pharmaceutically acceptable salts thereof.

[0414] 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

[0415] 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.

[0416] Sterile compositions are also contemplated by the disclosure, including compositions that are in accord with national and local regulations governing such compositions.

[0417] 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.

[0418] 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.

[0419] 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.

[0420] 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.

[0421] For parenteral use, including intravenous, intramuscular, intraperitoneal, intranasal, or subcutaneous routes, the agents of the disclosure may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms may be presented in unit-dose form such as ampoules or disposable injection devices, in multi-dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation. Illustrative infusion doses range from about 1 to 1000 μg / kg / minute of agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.

[0422] 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.

[0423] 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.

[0424] 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.

[0425] The term “subject” refers to a mammalian patient in need of such treatment, such as a human.

[0426] 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, skin cutaneous melanoma, head and neck squamous cell carcinoma, pediatric glioma CML, prostate cancer, lung squamous carcinoma, ovarian serous cystadenocarcinoma, skin cutaneous melanoma, castrate-resistant prostate cancer, Hodgkin lymphoma, and serous and clear cell endometrial cancer. In some embodiments, cancer includes, lung cancer, colon cancer, breast cancer, prostate cancer, hepatocellular carcinoma, renal cell carcinoma, gastric and esophago-gastric cancers, glioblastoma, head and neck cancers, inflammatory myofibroblastic tumors, and anaplastic large cell lymphoma.

[0427] 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.

[0428] 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).

[0429] Once improvement of the patient’s disease has occurred, the dose may be adjusted for preventative or maintenance treatment. For example, the dosage or the frequency of administration, or both, may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained. Of course, if symptoms have been alleviated to an appropriate level, treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms. Patients may also require chronic treatment on a long-term basis.DRUG COMBINATIONS

[0430] 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.

[0431] 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

[0432] 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)-(XIV).

[0433] 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:

[0434] 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 tert-butyl (R)-(2-hydroxypropyl)carbamate, methyl 5-hydroxy-1- methyl-1H-pyrazole-3-carboxylate, ethynyltriisopropylsilane, methyl 3-chloro-3- oxopropanoate, 2-bromo-4-methyl-5-nitrophenol, dimethyl but-2-ynedioate, iodoethane, (R)- propane-1,2-diol, (2-bromoethoxy)(tert-butyl)dimethylsilane, 5-bromo-1H-pyrazolo[3,4- c]pyridine, potassium vinyltrifluoroborate, and (R)-2-methyloxirane. Those skilled in the art will recognize that the commercially available materials listed or illustrated herein are not exhaustive, and that additional commercially available materials may also be selected.

[0435] Intermediate synthesis

[0436] Preparation of tert-butyl (S)-(2-((3-(hydroxymethyl)-1-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazol-5-yl)oxy)propyl)(methyl)carbamate (I-1-1):

[0437] Step 1. To a solution of tert-butyl (R)-(2-hydroxypropyl)carbamate (22.4 g, 127 mmol, 1 eq) in DCM (300 mL) was added Ms2O (66.8 g, 383 mmol, 3 eq) and TEA (38.8 g, 383 mmol, 3 eq). The mixture was stirred at 0 °C for 2 hours. On completion, the reaction mixture was partitioned between dichloromethane (500 mL × 3) and water (500 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give (R)- 1-((tert-butoxycarbonyl)amino)propan-2-yl methanesulfonate (32.0 g, 126 mmol, 98% yield) as a yellow oil.

[0438] Step 2. To a solution of methyl 5-hydroxy-1-methyl-1H-pyrazole-3-carboxylate (14.0 g, 89.6 mmol, 1 eq) in DMF (200 mL) was added Cs2CO3(58.4 g, 179 mmol, 2 eq) and (R)- 1-((tert-butoxycarbonyl)amino)propan-2-yl methanesulfonate (29.5 g, 116 mmol, 1.3 eq). The mixture was stirred at 80 °C for 12 hours. On completion, the reaction mixture was partitioned between ethyl acetate (200 mL × 3) and water (200 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 1:0 to 0:1) to give methyl (S)-5-((1-((tert-butoxycarbonyl)amino)propan-2-yl)oxy)-1-methyl-1H-pyrazole- 3-carboxylate (23.5 g, 75.0 mmol, 83% yield) as a yellow oil. LCMS: m / z 314.0 (M+1).

[0439] Step 3. To a solution of methyl (S)-5-((1-((tert-butoxycarbonyl)amino)propan-2- yl)oxy)-1-methyl-1H-pyrazole-3-carboxylate (23.0 g, 73.4 mmol, 1 eq) and MeI (15.6 g, 110 mmol, 1.5 eq) in DMF (200 mL) was added NaH (4.40 g, 110 mmol, 60% purity, 1.5 eq). The mixture was stirred at 0 °C for 1 hour. On completion, the mixture was quenched with asaturated solution of NH4Cl (20 mL) and extracted with ethyl acetate (600 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, Petroleum ether / Ethyl acetate= 1:0 to 0:1) to give methyl (S)-5-((1-((tert- butoxycarbonyl)(methyl)amino)propan-2-yl)oxy)-1-methyl-1H-pyrazole-3-carboxylate (22.6 g, 69.0 mmol, 94% yield) as a yellow oil. LCMS: m / z 328.0 (M+1).

[0440] Step 4. To a solution of methyl (S)-5-((1-((tert-butoxycarbonyl)(methyl)amino)propan- 2-yl)oxy)-1-methyl-1H-pyrazole-3-carboxylate (17.6 g, 53.7 mmol, 1 eq) in THF (150 mL) was added LAH (2.5 M in THF, 32 mL, 1.5 eq). The mixture was stirred at 0 °C for 1 hour. On completion, the mixture was quenched with water (3 mL), 15% NaOH (3 mL) and water (9 mL) sequentially, and extracted with ethyl acetate (150 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give tert-butyl (S)-(2-((3-(hydroxymethyl)-1-methyl-1H-pyrazol-5-yl)oxy)propyl)(methyl)carbamate (14.8 g, 49.4 mmol, 91% yield) as a yellow oil. LCMS: m / z 300.0 (M+1).

[0441] Step 5. To a solution of tert-butyl (S)-(2-((3-(hydroxymethyl)-1-methyl-1H-pyrazol-5- yl)oxy)propyl)(methyl)carbamate (14.8 g, 49.4 mmol, 1 eq) in ACN (200 mL) was added NBS (13.2 g, 74.1 mmol, 1.5 eq). The mixture was stirred at 0 °C for 1 hour. On completion, the mixture was quenched with a saturated solution of Na2SO3(50 mL) and extracted with ethyl acetate (200 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, Petroleum ether / Ethyl acetate= 1:0 to 0:1) to give tert-butyl (S)-(2-((4- bromo-3-(hydroxymethyl)-1-methyl-1H-pyrazol-5-yl)oxy)propyl)(methyl)carbamate (14.2 g, 37.5 mmol, 75% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ = 5.00 (t, J = 5.6 Hz, 1H), 4.68 (s, 1H), 4.26 (d, J = 5.6 Hz, 2H), 3.60 (s, 3H), 3.48 - 3.39(m, 2H), 2.89 (s, 3H), 1.39 (d, J = 6.0 Hz, 9H), 1.21 (d, J = 6.4 Hz, 3H).

[0442] Step 6. A mixture of tert-butyl (S)-(2-((4-bromo-3-(hydroxymethyl)-1-methyl-1H- pyrazol-5-yl)oxy)propyl)(methyl)carbamate (5.00 g, 13.2 mmol, 1 eq), 4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (5.07 g, 39.6 mmol, 3 eq), XPhos (630 mg, 1.32 mmol, 0.1 eq), PdCl2(MeCN)2 (342 mg, 1.32 mmol, 0.1 eq) and TEA (2.01 g, 19.8 mmol, 1.5 eq) in dioxane (80 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 110 °C for 2 hours under N2 atmosphere. On completion, the reaction mixture was partitioned between ethyl acetate (80 mL × 3) and water (80 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF= 1:0 to 0:1) to give tert- butyl (S)-(2-((3-(hydroxymethyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-5-yl)oxy)propyl)(methyl)carbamate (4.90 g, 11.5 mmol, 87% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ = 4.99 - 4.75 (m, 1H), 4.47 - 4.40 (m, 1H), 4.39 - 4.31 (m, 2H), 3.48 - 3.36 (m, 2H), 3.33 (s, 3H), 2.85 (s, 3H), 2.51 (td, J = 1.6, 3.6 Hz, 3H), 1.38 (s, 9H), 1.25 (s, 12H).

[0443] Preparation of 1-methyl-3-((triisopropylsilyl)ethynyl)-1H-pyrazol-5-ol (I-1-2):

[0444] Step 1. To a solution of ethynyltriisopropylsilane (33.4 g, 183 mmol, 41.1 mL, 2.5 eq) in THF (200 mL) at −78 °C was added n-BuLi (2.5 M, 87.9 mL, 3 eq) under N2. The mixture was stirred at -78 °C for 1 h, and then BF3.Et2O (26.0 g, 183 mmol, 22.5 mL, 2.5 eq) was added. After 0.2 h, methyl 3-chloro-3-oxopropanoate (10.0 g, 73.2 mmol, 7.82 mL, 1 eq) in THF (50 mL) was added. The mixture was stirred at -78 °C for 2 h. On completion, the mixture was quenched with sat. NH4Cl ( 500 mL) and water (500 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 330g SepaFlash® Silica Flash Column, Eluent of 0~2% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to give methyl 3-oxo-5-(triisopropylsilyl)pent-4-ynoate (7.05 g, 25.0 mmol, 34% yield) as a yellow liquid.1H NMR (400 MHz, CDCl3) δ = 3.77 (s, 3H), 3.62 (s, 1H), 1.11 (s, 21H).

[0445] Step 2. To a solution of methyl 3-oxo-5-(triisopropylsilyl)pent-4-ynoate (5.00 g, 17.7 mmol, 1 eq) in MeOH (50 mL) was added methylhydrazine (2.57 g, 22.3 mmol, 2.94 mL, 1.26 eq) at 0 °C. The mixture was stirred at 25 °C for 2 h. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~4% DCM / MeOH gradient @ 100 mL / min). The residue was further purified by flash silica gel chromatography (ISCO®;40 g SepaFlash® Silica Flash Column, Eluent of 0~20% THF / Petroleum ether gradient @ 80 mL / min) to give 1-methyl-3-((triisopropylsilyl)ethynyl)-1H-pyrazol-5-ol (3.40 g, 12.2 mmol, 69% yield, 100% purity) as an orange solid.1H NMR (400 MHz, DMSO-d6) δ = 11.21 (s, 1H),5.49 (s, 1H), 3.53 - 3.48 (m, 3H), 3.30 - 3.25 (m, 1H), 1.07 (s, 21H). LCMS: m / z 279.1 (M+1).

[0446] Preparation of methyl (S)-5-((1-((tert-butoxycarbonyl)(methyl)amino)propan-2- yl)oxy)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-3-carboxylate (I-1-3):

[0447] Step 1. To a solution of methyl (S)-5-((1-((tert-butoxycarbonyl)(methyl)amino)propan- 2-yl)oxy)-1-methyl-1H-pyrazole-3-carboxylate (6.00 g, 18.3 mmol, 1 eq) in ACN (60 mL) was added NBS (4.40 g, 24.7 mmol, 1.35 eq). The mixture was stirred at 0 °C for 1 hour. On completion, the mixture was quenched with a saturated solution of Na2SO3 (50 mL) and extracted with ethyl acetate (200 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, Hexanes: Ethyl acetate= 100 / 1 to 2 / 1) to give methyl (S)- 4-bromo-5-((1-((tert-butoxycarbonyl)(methyl)amino)propan-2-yl)oxy)-1-methyl-1H- pyrazole-3-carboxylate (6.50 g, 15.2 mmol, 83% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 4.74 (d, J = 4.4 Hz, 1H), 3.78 (s, 3H), 3.72 (s, 3H), 3.49 - 3.39 (m, 2H), 2.88 (s, 3H), 1.37 (s, 9H), 1.22 (d, J = 6.4 Hz, 3H); LCMS: m / z 406.1 (M+1)

[0448] Step 2. A mixture of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.84 g, 22.1 mmol, 3 eq), methyl (S)-4-bromo-5-((1-((tert-butoxycarbonyl)(methyl)amino)propan-2-yl)oxy)-1- methyl-1H-pyrazole-3-carboxylate (3.00 g, 7.38 mmol, 1 eq), XPhos (352 mg, 738 μmol, 0.1 eq), TEA (1.12 g, 11.0 mmol, 1.5 eq) and PdCl2(MeCN)2(191 mg, 738 μmol, 0.1 eq) in dioxane (30 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110 °C for 2 hours under N2atmosphere. On completion, the reaction mixture was partitioned between ethyl acetate (80 mL × 3) and water (80 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Commercial hexanes: Ethyl acetate= 100 / 1 to 2 / 1) to give methyl (S)-5-((1-((tert-butoxycarbonyl)(methyl)amino)propan-2-yl)oxy)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-3- carboxylate (3.00 g, 6.09 mmol, 82% yield) as a yellow oil. LCMS: m / z 454.2 (M+1).

[0449] Preparation of tert-butyl (S)-(2-((3-(hydroxymethyl)-1-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazol-5-yl)oxy)propyl)(methyl)carbamate (I-1-4):

[0450] I-1-4 was synthesized using the procedure of intermediate I-1-1 (steps 3-6) and substituting MeI for EtI in step 1 to give tert-butyl (S)-(2-((3-(hydroxymethyl)-1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-5- yl)oxy)propyl)(methyl)carbamate. LCMS: m / z 440.2 (M+1).

[0451] Preparation of (2-bromo-4-methyl-5-nitrophenoxy)triisopropylsilane (I-2-1):

[0452] Step 1. To a solution of 2-bromo-4-methyl-5-nitrophenol (7.70 g, 33.1 mmol, 1 eq) in DCM (80 mL) was added TIPSCl (9.60 g, 49.7 mmol, 1.5 eq) and TEA (6.72 g, 66.3 mmol, 2 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 column chromatography (SiO2, Petroleum ether / Ethyl acetate= 1:0 to 0:1) to give (2-bromo-4-methyl-5- nitrophenoxy)triisopropylsilane (12.8 g, 32.9 mmol, 99% yield) as a yellow oil.1H NMR (400MHz, CDCl3) δ = 7.47 (s, 1H), 7.44 (s, 1H), 2.45 (s, 3H), 1.07 (d, J = 7.6 Hz, 21H).

[0453] Preparation of 5-bromo-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-6- ((triisopropylsilyl)oxy)-3-vinyl-1H-indazole (I-2-2):

[0454] Step 1. To a solution of 5-bromo-6-methoxy-1H-indazole (1.00 g, 4.40 mmol, 1 eq) in ACN (20 mL) was added Select F (3.12 g, 8.81 mmol, 2 eq). The mixture was stirred at 20 °C for 1 hour. On completion, the mixture was quenched with H2O (50 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 100 / 0 to 10 / 1) to give 5-bromo-7- fluoro-6-methoxy-1H-indazole (80.0 mg, 7% yield) as a white solid.

[0455] Step 2. To a solution of 5-bromo-7-fluoro-6-methoxy-1H-indazole (6.90 g, 28.2 mmol, 1 eq) in DMF (70 mL) was added t-BuOK (9.48 g, 84.6 mmol, 3 eq) and I2(14.3 g, 56.3 mmol, 2 eq). The mixture was stirred at 20 °C for 2 hours. The mixture was poured into a solution of sodium sulfite in H2O (300 mL) and filtered to give 5-bromo-7-fluoro-3-iodo-6-methoxy-1H- indazole (7.30 g, 69% yield) as a white solid. LCMS: m / z 370.7 (M+1).

[0456] Step 3. To a solution of 5-bromo-7-fluoro-3-iodo-6-methoxy-1H-indazole (7.20 g, 19.4 mmol, 1 eq) in DCM (75 mL) was added BBr3 (2 M in DCM, 19.4 mL, 2 eq). The mixture was stirred at 0 °C for 1 hour. The mixture was quenched with a saturated solution of NaHCO3(150 mL), and filtered to give 5-bromo-7-fluoro-3-iodo-1H-indazol-6-ol (5.90 g, 16.5 mmol,85% yield) as a brown solid. LCMS: m / z 356.8 (M+1).

[0457] Step 4. To a solution of 5-bromo-7-fluoro-3-iodo-1H-indazol-6-ol (5.90 g, 16.5 mmol, 1 eq) in DCM (60 mL) was added TIPSCl (4.78 g, 24.8 mmol, 1.5 eq) and DIEA (6.41 g, 49.6 mmol, 3 eq). The mixture was stirred at 0 °C for 0.5 hours. On completion, the mixture was poured into H2O (50 mL), and extracted with DCM (50 mL × 2). The combined organic layers were washed with brine (40 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give 5-bromo-7-fluoro-3-iodo-6-((triisopropylsilyl)oxy)-1H-indazole (8.20 g, 96% yield) as a brown oil. LCMS: m / z 512.9 (M+1).

[0458] Step 5. To a solution of 5-bromo-7-fluoro-3-iodo-6-((triisopropylsilyl)oxy)-1H- indazole (8.00 g, 15.5 mmol, 1 eq) in THF (80 mL) was added PTSA (536 mg, 3.12 mmol, 0.2 eq) and DHP (3.93 g, 46.7 mmol, 3 eq). The mixture was stirred at 70 °C for 1 hour. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 10 / 1 to 5 / 1) to give 5-bromo- 7-fluoro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-6-((triisopropylsilyl)oxy)-1H-indazole (9.00 g, 15.0 mmol, 96% yield) as a brown oil. LCMS: m / z 597.0 (M+1).

[0459] Step 6. To a solution of 5-bromo-7-fluoro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-6- ((triisopropylsilyl)oxy)-1H-indazole (9.00 g, 15.0 mmol, 1 eq), potassium trifluoro(vinyl)boranuide (2.02 g, 15.0 mmol, 1 eq) in dioxane (140 mL) and H2O (30 mL) was added Pd(dppf)Cl2 (1.10 g, 1.50 mmol, 0.1 eq) and Cs2CO3 (9.82 g, 30.0 mmol, 2 eq). The mixture was stirred at 80 °C for 1 hour under N2atmosphere. On completion, the mixture was poured into H2O (200 mL), and extracted with EA (100 mL × 3). The combined organic layers were washed with brine (100 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a reside. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 5 / 1 to 0 / 1) to give 5-bromo-7-fluoro-1-(tetrahydro-2H-pyran- 2-yl)-3-vinyl-1H-indazol-6-ol (5.05 g, 97% yield) as a brown oil. LCMS: m / z 362.9 (M+1).

[0460] Step 7. To a solution of 5-bromo-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H- indazol-6-ol (5.00 g, 14.6 mmol, 1 eq) in DCM (50 mL) was added TIPSCl (4.24 g, 22.0 mmol, 1.5 eq) and TEA (4.45 g, 43.8 mmol, 3 eq). The mixture was stirred at 0 °C for 0.5 hours. On completion, the mixture was poured into H2O (50 mL), and extracted with DCM (50 mL × 2). The combined organic layers were washed with brine (40 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 1:0) to give 5-bromo-7-fluoro-1- (tetrahydro-2H-pyran-2-yl)-6-((triisopropylsilyl)oxy)-3-vinyl-1H-indazole (4.30 g, 8.64 mmol, 58% yield) as a brown oil. LCMS: m / z 497.2 (M+1).

[0461] Preparation of 5-bromo-7-chloro-6-(methoxymethoxy)-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazole (I-2-3):

[0462] Step 1. To a solution of 5-bromo-6-methoxy-1H-indazole (10.0 g, 44.0 mmol, 1 eq) in ACN (50 mL) and AcOH (5.25 g, 87.3 mmol, 1.98 eq) was added NCS (6.47 g, 48.4 mmol, 1.1 eq). The mixture was stirred at 25 °C for 16 hours. On completion, the mixture was quenched with Na2S2O3 (20 mL) and extracted with ethyl acetate (20 mL× 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 5- bromo-7-chloro-6-methoxy-1H-indazole (11.0 g, 39.9 mmol, 90% yield) as a yellow solid. LCMS: m / z 261.0 (M+1).

[0463] Step 2. To a solution of 5-bromo-7-chloro-6-methoxy-1H-indazole (11.0 g, 42.0 mmol, 1 eq) in DMF (150 mL) was added I2 (21.3 g, 84.1 mmol, 2 eq) and t-BuOK (18.8 g, 168 mmol, 4 eq). The mixture was stirred at 25 °C for 16 hours. On completion, the reaction mixture was quenched by addition of Na2S2O3 (100 mL) at 25 °C, and then filtered. The cake was rinsed with water and dried. The crude product was triturated with water at 25 °C for 10 minutes to give 5-bromo-7-chloro-3-iodo-6-methoxy-1H-indazole (16.0 g, 37.1 mmol, 88% yield) as a yellow solid. LCMS: m / z 386.9 (M+1).

[0464] Step 3. To a solution of 5-bromo-7-chloro-3-iodo-6-methoxy-1H-indazole (15.0 g, 38.7 mmol, 1 eq) in DCM (150 mL) was added BBr3(2 M in DCM, 38 mL, 2 eq). The mixture was stirred at 25 °C for 16 hours. On completion, the reaction mixture was quenched with NaHCO3 (300 mL) and extracted with DCM (50 mL × 3). The combined organic phase was dried overanhydrous sodium sulfate, filtered and concentrated to give 5-bromo-7-chloro-3-iodo-1H- indazol-6-ol (14.0 g, 37.5 mmol, 96% yield) as a yellow solid. LCMS: m / z 372.7 (M+1).

[0465] Step 4. To a solution of 5-bromo-7-chloro-3-iodo-1H-indazol-6-ol (14.0 g, 37.5 mmol, 1 eq) in DCM (100 mL) was added MOMCl (5.66 g, 56.2 mmol, 80% purity, 1.5 eq) and TEA (11.3 g, 112 mmol, 3 eq). The mixture was stirred at 25 °C for 16 hours. On completion, the reaction mixture was quenched with NaHCO3 (100 mL) and extracted with DCM (50 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, Commercial hexanes: Ethyl acetate= 100 / 1 to 2 / 1) to give 5-bromo-7-chloro-3-iodo-6- (methoxymethoxy)-1H-indazole (12.0 g, 20.1 mmol, 54% yield) as a white solid. LCMS: m / z 416.8 (M+1).

[0466] Step 5. To a solution of 5-bromo-7-chloro-3-iodo-6-(methoxymethoxy)-1H-indazole (10.0 g, 23.9 mmol, 1 eq) in DCM (70 mL) was added DHP (5.04 g, 59.8 mmol, 2.5 eq) and PPTS (602 mg, 2.40 mmol, 0.1 eq). The mixture was stirred at 70 °C for 1 hour. On completion, the mixture was concentrated to give 5-bromo-7-chloro-3-iodo-6-(methoxymethoxy)-1- (tetrahydro-2H-pyran-2-yl)-1H-indazole (6.00 g, 8.37 mmol, 35% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ = 7.79 (s, 1H), 5.82 - 5.75 (m, 1H), 5.20 (s, 2H), 3.97 (d, J = 11.2 Hz, 1H), 3.75 - 3.67 (m, 1H), 3.65 - 3.56 (m, 3H), 3.45 - 3.34 (m, 1H), 2.48 - 2.39 (m, 2H), 2.13 - 1.98 (m, 2H), 1.84 - 1.71 (m, 1H), 1.68 - 1.42 (m, 3H); LCMS: m / z 522.9 (M+1).

[0467] Step 6. A mixture of 5-bromo-7-chloro-3-iodo-6-(methoxymethoxy)-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazole (3.26 g, 6.50 mmol, 1 eq), potassium trifluoro(vinyl)boranuide (870 mg, 6.50 mmol, 1 eq), Pd(dppf)Cl2(475 mg, 650 μmol, 0.1 eq), Cs2CO3(6.35 g, 19.5 mmol, 3 eq) in dioxane (30 mL) and H2O (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 1 hour under N2atmosphere. On completion, the mixture was poured into H2O (100 mL), and extracted with EA (100 mL × 3). The combined organic layers were washed with brine (100 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a reside. The residue was purified by column chromatography (SiO2, Hexanes: Ethyl acetate= 100 / 1 to 2 / 1) to give 5-bromo-7-chloro-6- (methoxymethoxy)-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazole (2.38 g, 5.45 mmol, 84% yield) as a yellow oil. LCMS: m / z 423.0 (M+1).

[0468] Preparation of 5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H- pyrazolo[3,4-b]pyridine (I-2-4):

[0469] Step 1. To a solution of 5-bromo-6-chloro-1H-pyrazolo[3,4-b]pyridine (2.00 g, 8.60 mmol, 1 eq) in THF (30 mL) was added I2(3.28 g, 12.9 mmol, 2.60 mL, 1.5 eq) and t-BuOK (2.90 g, 25.8 mmol, 3 eq). The mixture was stirred at 25 °C for 1 hour. On completion, the mixture was quenched with saturated solution of Na2SO3(30 mL) and extracted with ethyl acetate (30 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF= 1:0 to 0:1) to give 5-bromo-6-chloro-3-iodo- 1H-pyrazolo[3,4-b]pyridine (2.50 g, 6.98 mmol, 81% yield) as a yellow solid. LCMS: m / z 357.7 (M-1).

[0470] Step 2. To a solution of 5-bromo-6-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine (2.40 g, 6.70 mmol, 1 eq) in THF (20 mL) was added DHP (1.13 g, 13.3 mmol, 2 eq) and 4- methylbenzenesulfonic acid hydrate (127 mg, 0.669 mmol, 0.1 eq). The mixture was stirred at 70 °C for 1 hour. 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 5-bromo-6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazolo[3,4-b]pyridine (1.80 g, 4.07 mmol, 60% yield) as a yellow solid.1H NMR (400 MHz, CDCl3-d) δ = 7.98 (d, J = 1.2 Hz, 1H), 5.91 (d, J = 10.4 Hz, 1H), 4.10 - 4.00 (m, 1H), 3.86 - 3.78 (m, 2H),3.77 - 3.68 (m, 1H), 3.51 - 3.40 (m, 2H), 1.83 - 1.76 (m, 2H).

[0471] Step 3. A mixture of 5-bromo-6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazolo[3,4-b]pyridine (1.70 g, 3.84 mmol, 1 eq), potassium;trifluoro(vinyl)boranuide (463 mg, 3.46 mmol, 0.9 eq), Pd(dppf)Cl2(281 mg, 0.384 mmol, 0.1 eq), K2CO3(1.59 g, 11.5 mmol, 3 eq) in dioxane (20 mL) and H2O (4 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 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 give5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-pyrazolo[3,4-b]pyridine (960 mg, 2.80 mmol, 72% yield) as a yellow oil. LCMS: m / z 260.0 (M-82).

[0472] Preparation of (S)-1-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo-5- (iodomethyl)-1H-pyrazole (I-3-1)

[0473] Step 1. The solution of dimethyl but-2-ynedioate (100 g, 703 mmol, 1 eq) in toluene (500 mL) was added hydrazine hydrate (46.7 g, 914 mmol, 45.2 mL, 98% purity, 1.3 eq). The mixture was stirred at 25 °C for 4 h. On completion, the mixture was concentrated in vacuo to give a residue. The crude product was triturated with EA (100 mL) at 25 °C for 30 min to give methyl 3-hydroxy-1H-pyrazole-5-carboxylate (92.0 g, 647 mmol, 92% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 5.74 (s, 1H), 3.75 (s, 3H).

[0474] Step 2. To a solution of methyl 3-hydroxy-1H-pyrazole-5-carboxylate (30.0 g, 211 mmol, 1 eq) in DMF (300 mL) was added K2CO3 (43.7 g, 316 mmol, 1.5 eq) and iodoethane (32.9 g, 211 mmol, 1 eq). The mixture was stirred at 80 °C for 2 h. On completion, the mixture was poured into H2O (1000 mL) and extracted with EA (300 mL x 4). The combined organic phase was washed with H2O (300 mL x 3) and dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF= 10:1 to 5:1) to give methyl 3-ethoxy-1H-pyrazole-5-carboxylate (7.19 g, 42.2 mmol, 20% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 13.11 (s, 1H),6.23 (s, 1H), 4.12 (q, J = 7.2 Hz, 2H), 3.86 - 3.79 (m, 3H), 1.33 - 1.26 (m, 3H). LCMS: m / z 171.1 (M+1).

[0475] Step 3. To a solution of (R)-propane-1,2-diol (50.0 g, 657 mmol, 1 eq) in DCM (500 mL) was added TBSCl (99.0 g, 657 mmol, 1 eq) and imidazole (44.7 g, 657 mmol, 1 eq). The mixture was stirred at 0 °C for 2 h and then heated to 25 °C for 10 hr. On completion, the mixture was filtered and concentrated to give (R)-1-((tert-butyldimethylsilyl)oxy)propan-2-ol (120 g, 630 mmol, 95% yield) as a colorless oil.1H NMR (400 MHz, DMSO-d6) δ = 4.75 - 4.22 (m, 1H), 3.64 - 3.53 (m, 1H), 3.47 (dd, J = 5.6, 9.6 Hz, 1H), 3.31 - 3.23 (m, 1H), 1.06 - 0.97 (m, 3H), 0.92 - 0.84 (m, 9H), 0.02 (s, 6H).

[0476] Step 4. A mixture of methyl 3-ethoxy-1H-pyrazole-5-carboxylate (22.0 g, 129 mmol, 1 eq), (R)-1-((tert-butyldimethylsilyl)oxy)propan-2-ol (49.2 g, 258 mmol, 2 eq), and PPh3(74.6 g, 284 mmol, 2.2 eq) in THF (250 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 0.5 h. Then DIAD (57.5 g, 284 mmol, 55.1 mL, 2.2 eq) was added at 0 °C, and then the mixture was stirred at 25 °C for 2 h. On completion, the mixture was concentrated in vacuum to give a residue, then to the residue was added Petroleum ether / Ethyl acetate= 5:1 (200 mL) and was stirred at 25 °C for 10 min, 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 5:1) to give methyl (S)-1-(1- ((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-1H-pyrazole-5-carboxylate (36.0 g, 105 mmol, 81% yield) as transparent oil.1H NMR (400 MHz, CDCl3-d) δ = 6.15 (s, 1H), 5.47 - 5.33 (m, 1H), 4.15 (dq, J = 1.2, 7.2 Hz, 2H), 3.87 - 3.71 (m, 5H), 1.44 - 1.36 (m, 6H), 0.80 (s, 9H), -0.03 - -0.12 (m, 6H). LCMS: m / z 343.3 (M+1).

[0477] Step 5. To a solution of methyl (S)-1-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3- ethoxy-1H-pyrazole-5-carboxylate (36.0 g, 105 mmol, 1 eq) in THF (300 mL) was added LAH (2.5 M, 63.0 mL, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 2 h. On completion, the reaction mixture was quenched with H2O (6 mL) and adjusted with 15% NaOH (6 mL). The combined organic layers were dried over Na2SO4 with stirring 10 min at 25 °C, filtered and concentrated under reduced pressure to give (S)-(1-(1-((tert-butyldimethylsilyl)oxy)propan-2- yl)-3-ethoxy-1H-pyrazol-5-yl)methanol (30.0 g, crude) as a transparent oil. LCMS: m / z 315.3 (M+1).

[0478] Step 6. To a solution of (S)-(1-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy- 1H-pyrazol-5-yl)methanol (29.5 g, 93.8 mmol, 1 eq) in ACN (400 mL) was added NIS (21.1 g, 93.8 mmol, 1 eq). The mixture was stirred at 0 °C for 2 h. On completion, the reaction mixture was quenched dropwise with a sodium sulfite aqueous solution (300 mL), and then was extracted with EA (200 mL × 3). The combined organic layer was washed with brine (200mL), dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 5:1 to 3:1) to give (S)-(1- (1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo-1H-pyrazol-5-yl)methanol (25.6 g, 58.1 mmol, 61.9% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 5.28 (dd, J = 4.4, 6.0 Hz, 1H), 4.56 - 4.43 (m, 2H), 4.34 (dd, J = 4.4, 13.2 Hz, 1H), 4.20 - 4.09 (m, 2H), 3.67 (d, J = 6.8 Hz, 2H), 1.33 - 1.25 (m, 6H), 0.75 (s, 9H), -0.07 (s, 3H), -0.17 (s, 3H). LCMS: m / z 440.9 (M+1).

[0479] Step 7. To a solution of (S)-(1-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy- 4-iodo-1H-pyrazol-5-yl)methanol (1.00 kg, 2.27 mol, 1 eq), and NIS (1.02 kg, 4.54 mol, 2 eq) in DCM (7 L) was degassed and purged with N2 for 3 times. PPh3 (893 g, 3.41 mol, 1.5 eq) was dissolved in DCM (800 mL) and slowly added to the reaction solution at 0 °C, and the mixture was stirred at 25 °C for 1 h under N2 atmosphere. On completion, the mixture was poured into a saturated sodium sulfite (7000 mL) aqueous solution, and the aqueous phase was extracted with DCM (2000 mL × 3). The combined organic phase was washed with brine (2000 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100- 200 mesh silica gel, Petroleum ether / Ethyl acetate= 1 / 0 to 10 / 1) to give (S)-1-(1-((tert- butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo-5-(iodomethyl)-1H-pyrazole (950 g, 1.62 mol, 71% yield, 94% purity) as a yellow oil. LCMS: m / z 551.1 (M+1).

[0480] Preparation of 5-(bromomethyl)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-ethoxy-4- iodo-1H-pyrazole (I-3-2)

[0481] Step 1. To a solution of methyl 3-ethoxy-1H-pyrazole-5-carboxylate (10.0 g, 58.7 mmol, 1 eq) and (2-bromoethoxy)(tert-butyl)dimethylsilane (21.0 g, 88.1 mmol, 1.5 eq) in DMF (100 mL) was added NaI (8.81 g, 58.7 mmol, 1 eq) and K2CO3 (24.3 g, 176 mmol, 3 eq).The mixture was stirred at 60 °C for 16 hr. On completion, the mixture was diluted with H2O (100 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic phase was washed with a saturated NaCl solution (80 mL × 2), dried over Na2SO4, filtered, and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 1:0 to 17:83) to give methyl 1-(2-((tert- butyldimethylsilyl)oxy)ethyl)-3-ethoxy-1H-pyrazole-5-carboxylate (12.7 g, 38.6 mmol, 66% yield) as a yellow liquid. LCMS: m / z 329.5 (M+1).

[0482] Step 2. To a solution of methyl 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-ethoxy-1H- pyrazole-5-carboxylate (12.0 g, 36.5 mmol, 1 eq) in THF (120 mL) was added LiAlH4(1.39 g, 36.5 mmol, 1 eq) at 0 °C. The mixture was stirred at 0 °C for 2 hr. On completion, the mixture was quenched with MeOH (150 mL) at 0 °C, and the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 1:0 to 75:25) to give (1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-ethoxy-1H-pyrazol- 5-yl)methanol (12.7 g, 38.6 mmol, 66% yield) as a yellow liquid. LCMS: m / z 301.1 (M+1).

[0483] Step 3. To a solution of (1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-ethoxy-1H- pyrazol-5-yl)methanol (7.00 g, 23.3 mmol, 1 eq) in ACN (70 mL) was added NIS (4.72 g, 20.9 mmol, 0.9 eq) at 0 °C. The mixture was stirred at 25 °C for 2 hr. On completion, the mixture was quenched with sat. Na2SO3(200 mL) at 0oC and extracted with ethyl acetate (50 mL × 3). The combined organic phase was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 1:0 to 80:20) to give (1-(2-((tert-butyldimethylsilyl)oxy)ethyl)- 3-ethoxy-4-iodo-1H-pyrazol-5-yl)methanol (7.70 g, 18.0 mmol, 66% yield) as a yellow liquid.1H NMR (400 MHz, CDCl3) δ = 4.60 (d, J = 2.0 Hz, 2H), 4.30 - 4.25 (m, 2H), 4.23 (dt, J = 2.4, 4.8 Hz, 2H), 3.95 -3.90 (m, 2H), 3.33 (br s, 1H), 1.45 - 1.39 (m, 3H), 0.84 (d, J = 2.0 Hz, 9H), 0.02 - 0.01 (m, 6H). LCMS: m / z 427.0 (M+1).

[0484] Step 4. To a solution of (1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-ethoxy-4-iodo-1H- pyrazol-5-yl)methanol (3.50 g, 8.21 mmol, 1 eq) and PPh3 (2.58 g, 9.85 mmol, 1.2 eq) in DCM (35 mL) was added CBr4(3.27 g, 9.85 mmol, 1.2 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was diluted with water (50 mL) and extracted with DCM (30 mL × 3). The combined organic phase was dried over Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 1:0 to 80:20) to give 5-(bromomethyl)-1-(2-((tert- butyldimethylsilyl)oxy)ethyl)-3-ethoxy-4-iodo-1H-pyrazole (2.90 g, 5.93 mmol, 72% yield) as a yellow oil. LCMS: m / z 490.8 (M+1).

[0485] Preparation of (S)-5-(bromomethyl)-1-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)- 3-ethoxy-4-iodo-1H-pyrazole (I-3-3)

[0486] To a solution of (S)-(1-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo- 1H-pyrazol-5-yl)methanol (2.00 g, 4.54 mmol, 1 eq) in DCM (20 mL) was added PPh3 (1.43 g, 5.45 mmol, 1.2 eq), and then CBr4(1.81 g, 5.45 mmol, 1.2 eq) was added at 0°C under N2. The mixture was stirred at 25 °C for 1 h. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:THF= 1:0 to 5:1) to give (S)-5-(bromomethyl)-1-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo- 1H-pyrazole (1.7 g, 3.38 mmol, 74% yield) as a yellow oil. LCMS: m / z 504.7 (M+1).

[0487] Preparation of (S)-1-(2-((tert-butyldimethylsilyl)oxy)propyl)-4-iodo-5-(iodomethyl)- 3-isopropoxy-1H-pyrazole (I-3-4):

[0488] Step 1. To a solution of ethyl (S)-2-hydroxypropanoate (1.20 kg, 10.1 mol, 1.16 L, 1 eq), and imidazole (1.38 kg, 20.3 mol, 2 eq) in DCM (9 L) at 0 °C was added TBSCl (1.61 kg, 10.6 mol, 1.31 L, 1.05 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated in vacuum. The residue was purified by combi flash chromatography (5 kg silica gel column, THF in PE from 0% to 5%) to give ethyl (S)-2-((tert- butyldimethylsilyl)oxy)propanoate (2.45 kg, 10.0 mol, 98% yield, 95% purity) as a yellow oil.1H NMR (400 MHz, CDCl3) δ = 4.21 (q, J = 6.8 Hz, 1H), 4.13 - 3.99 (m, 2H), 1.29 (d, J = 6.8 Hz, 3H), 1.17 (t, J = 7.2 Hz, 3H), 0.80 (s, 9H), -0.01 (d, J = 11.8 Hz, 6H); Chiral GC: 98.39% ee).

[0489] Step 2. A solution of ethyl (S)-2-((tert-butyldimethylsilyl)oxy)propanoate (1.00 kg, 4.30 mol, 1 eq) was dissolved in THF (3 L) and slowly added to LiBH4(2 M in THF, 5.38 L, 2.5 eq) in THF (3 L) solution at 15 °C. The reaction was stirred at 25 °C for 16 h. The reaction mixture was quenched by a saturated NH4Cl aqueous solution (12 L ), the temperature was maintained at 5 - 10 °C under N2, then the reaction mixture was diluted with H2O (2 L) and extracted with EtOAc 8 L (4 L * 2). The combined organic layers were washed with brine (4 L), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether / Ethyl acetate= 1 / 0, 10 / 1) to give (S)-2-((tert-butyldimethylsilyl)oxy)propan-1-ol (830 g, 3.92 mol, 91% yield, 90% purity) as a yellow oil.1H NMR (400 MHz, CDCl3) δ = 3.92 (dq, J = 2.4, 6.4 Hz, 1H), 3.51 (dd, J = 3.6, 10.8 Hz, 1H), 3.37 (dd, J = 6.4, 10.8 Hz, 1H), 1.93 (s, 1H), 1.13 (d, J = 6.4 Hz, 3H), 0.91 (s, 12H), 0.10 (s, 3H).

[0490] Step 3. To a solution of ethyl 3-isopropoxy-1H-pyrazole-5-carboxylate (1.00 kg, 5.04 mol, 1 eq), and (S)-2-((tert-butyldimethylsilyl)oxy)propan-1-ol (1.15 kg, 6.05 mol, 1.2 eq) in THF (10 L) was added PPh3 (2.65 kg, 10.0 mol, 2 eq) and DIAD (1.53 kg, 7.57 mol, 1.47 L, 1.5 eq) at 0 °C under N2. The mixture was stirred at 25 °C for 16 h. On completion, the reaction mixture was concentrated in vacuum and triturated with EtOAc: MTBE= 1:1 (2000 mL) for 3 times to remove PPh3O. The filtrate was filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 1:0 to 10:1) to give ethyl (S)-1-(2-((tert-butyldimethylsilyl)oxy)propyl)-3-isopropoxy-1H- pyrazole-5-carboxylate (1.80 kg, 3.59 mol, 71% yield, 74% purity) as a yellow oil. LCMS: m / z 371.4 (M+1).

[0491] Steps 4 to 6 were performed following the procedure outlined in steps 5 to 7 for the preparation of intermediate I-3-1 to give (S)-1-(2-((tert-butyldimethylsilyl)oxy)propyl)-4- iodo-5-(iodomethyl)-3-isopropoxy-1H-pyrazole.1H NMR (400 MHz, CDCl3) δ = 4.81 (td, J= 6.4, 12.4 Hz, 1H), 4.47 - 4.41 (m, 1H), 4.35 - 4.30 (m, 1H), 4.19 - 4.12 (m, 1H), 3.99 - 3.93 (m, 1H), 3.92 - 3.84 (m, 1H), 1.35 (t, J = 5.6 Hz, 6H), 1.21 (d, J = 6.4 Hz, 3H), 0.79 (s, 9H), - 0.06 (s, 3H), -0.25 (s, 3H); LCMS: m / z 565.0 (M+1).

[0492] Preparation of 1-methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-pyrazolo[3,4- c]pyridin-5-yl)-3-((triisopropylsilyl)ethynyl)-1H-pyrazol-5-ol (I-4-1)

[0493] Step 1. To a solution of 5-bromo-1H-pyrazolo[3,4-c]pyridine (23.0 g, 116 mmol, 1 eq), and t-BuOK (26.0 g, 232 mmol, 2 eq) in THF (300 mL) was added a solution of I2 (32.4 g, 127 mmol, 1.1 eq) in THF (100 mL) dropwise at 0 °C. The mixture was stirred at 0 °C for 3 hrs. On completion, the mixture was quenched with sat. NaHSO3 (100 mL) and diluted with H2O (300 mL), extracted with EA (3 × 300 mL), and 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 a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 8.80 (s, 1H), 7.55 (s, 1H). LCMS: m / z 323.6 (M+1).

[0494] 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 a NH4Cl solution (2 × 100 mL), washed with brine (2 × 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.1H NMR (400 MHz, DMSO-d6) δ = 9.08 (s, 1H), 7.72 (s, 1H), 6.00 (dd, J = 1.6, 8.8 Hz, 1H), 3.92 - 3.84 (m, 1H), 3.80 - 3.72 (m, 1H), 2.35 - 2.26 (m, 1H), 2.06 - 1.96 (m, 2H), 1.79 - 1.66 (m, 1H), 1.63 - 1.55 (m, 2H). LCMS: m / z 409.8 (M+1).

[0495] Step 3. To a solution of 5-bromo-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazolo[3,4-c]pyridine (12.0 g, 29.4 mmol, 1 eq), and potassium vinyltrifluoroborate (19.7 g,147 mmol, 5 eq) in a mixture solvent of dioxane (120 mL) and H2O (24 mL) was added Pd(dppf)Cl2 (2.15 g, 2.94 mmol, 0.1 eq) and Na2CO3 (9.35 g, 88.2 mmol, 3 eq). The mixture was stirred at 40 °C for 72 hrs under N2. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE / EA= 50 / 1) to give 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-pyrazolo[3,4- c]pyridine (8.6 g, 27.9 mmol, 95% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 9.06 (s, 1H), 8.30 (s, 1H), 7.01 (dd, J = 11.6, 18.0 Hz, 1H), 6.21 (d, J = 18.0 Hz, 1H), 6.03 - 5.93 (m, 1H), 5.59 (d, J = 11.6 Hz, 1H), 3.93 - 3.84 (m, 1H), 3.81 - 3.72 (m, 1H), 2.39 - 2.27 (m, 1H), 2.05 - 1.97 (m, 2H), 1.78 - 1.69 (m, 1H), 1.63 - 1.55 (m, 2H). LCMS: m / z 309.8 (M+1).

[0496] Step 4. A mixture of 1-methyl-3-((triisopropylsilyl)ethynyl)-1H-pyrazol-5-ol (2.00 g, 7.18 mmol, 1 eq), 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-pyrazolo[3,4-c]pyridine (2.66 g, 8.62 mmol, 1.2 eq), tBuBrettPhosPdG3(614 mg, 718 μmol, 0.1 eq), and K2CO3(2.98 g, 21.6 mmol, 3 eq) in dioxane (40 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 130 °C for 16 h under N2 atmosphere. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, MeOH / DCM= 1 / 0 to 20 / 1) to give 1-methyl-4-(1- (tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-pyrazolo[3,4-c]pyridin-5-yl)-3- ((triisopropylsilyl)ethynyl)-1H-pyrazol-5-ol (1.20 g, 2.37 mmol, 33% yield) as a brown solid. LCMS: m / z 506.3 (M+1).

[0497] General Procedures

[0498] Preparation of (2S)-2-[(7S,14E)-13-ethoxy-5,7,9-trimethyl-5,7,8,9,10,17-hexahydro- 18,1-(metheno)-2,6-dioxa-4,5,9,11,12,16,17- heptaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3-cd]inden-11(3H)-yl]propan-1-ol (Ex.1)

[0499] Step 1. A mixture of (2-bromo-4-methyl-5-nitrophenoxy)triisopropylsilane (5.50 g, 14.1 mmol, 1 eq), tert-butyl (S)-(2-((3-(hydroxymethyl)-1-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazol-5-yl)oxy)propyl)(methyl)carbamate (7.23 g, 16.9 mmol, 1.2 eq), Cs2CO3 (13.8 g, 42.4 mmol, 3 eq), and Pd(dtbpf)Cl2 (922 mg, 1.42 mmol, 0.1 eq) in dioxane (80 mL) and H2O (16 mL) was degassed and purged with N2for 3 times, and then themixture was stirred at 80 °C for 12 hours under N2atmosphere. On completion, the reaction mixture was partitioned between ethyl acetate (60 mL × 3) and water (80 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 1:0 to 0:1) to give tert-butyl (S)-(2-((4-(2-hydroxy-5-methyl-4- nitrophenyl)-3-(hydroxymethyl)-1-methyl-1H-pyrazol-5-yl)oxy)propyl)(methyl)carbamate (3.47 g, 7.70 mmol, 54% yield) as a yellow oil. LCMS: m / z 451.3 (M+1).

[0500] Step 2. A mixture of tert-butyl (S)-(2-((4-(2-hydroxy-5-methyl-4-nitrophenyl)-3- (hydroxymethyl)-1-methyl-1H-pyrazol-5-yl)oxy)propyl)(methyl)carbamate (3.47 g, 7.70 mmol, 1 eq), PPh3 (4.04 g, 15.4 mmol, 2 eq), and DBAD (2.66 g, 11.5 mmol, 1.5 eq) in THF (40 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 0 °C for 1 hour under N2 atmosphere. On completion, the mixture was concentrated to give the residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 1:0 to 0:1) to give tert-butyl (S)-(2-((2,8-dimethyl-7-nitro-2,4-dihydrochromeno[3,4- c]pyrazol-1-yl)oxy)propyl)(methyl)carbamate (1.76 g, 4.07 mmol, 52% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ = 7.59 (s, 1H), 7.19 (s, 1H), 5.09 (d, J = 2.0 Hz, 2H), 4.41 - 4.28 (m, 1H), 3.65 (s, 3H), 3.51 (s,3H), 2.98 (d, J = 16.8 Hz, 2H), 2.52 (s, 3H), 1.40 (s, 9H), 1.19 (d, J = 6.0 Hz, 3H).

[0501] Step 3. To a solution of tert-butyl (S)-(2-((2,8-dimethyl-7-nitro-2,4- dihydrochromeno[3,4-c]pyrazol-1-yl)oxy)propyl)(methyl)carbamate (1.76 g, 4.07 mmol, 1 eq) in EtOH (20 mL) and H2O (5 mL) was added Fe (2.27 g, 40.7 mmol, 10 eq), HOAc (488 mg, 8.14 mmol, 2 eq) and NH4Cl (108 mg, 2.03 mmol, 0.5 eq). The mixture was stirred at 40 °C for 12 hours. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF= 1:0 to 0:1) to give tert-butyl (S)-(2-((7-amino-2,8-dimethyl-2,4-dihydrochromeno[3,4-c]pyrazol-1- yl)oxy)propyl)(methyl)carbamate (860 mg, 2.14 mmol, 52% yield) as a yellow solid. LCMS: m / z 425.2 (M+23).

[0502] Step 4. A mixture of tert-butyl (S)-(2-((7-amino-2,8-dimethyl-2,4- dihydrochromeno[3,4-c]pyrazol-1-yl)oxy)propyl)(methyl)carbamate (860 mg, 2.14 mmol, 1 eq), KOAc (419 mg, 4.27 mmol, 2 eq), and HOAc (898 mg, 14.9 mmol, 7 eq) in toluene (10 mL) was degassed and purged with N2 for 3 times. Then was added isopentyl nitrite (375 mg, 3.21 mmol, 1.5 eq) at 0 °C, and the mixture was stirred at 25 °C for 1 hour under N2atmosphere. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF= 1:0 to 0:1) to give tert-butyl (S)-methyl(2-((2-methyl-2,7-dihydro-4H-pyrazolo[4',3':4,5]pyrano[3,2-f]indazol-1-yl)oxy)propyl)carbamate (200 mg, 0.483 mmol, 22% yield) as a yellow oil. LCMS: m / z 414.2 (M+1).

[0503] Step 5. To a solution of tert-butyl (S)-methyl(2-((2-methyl-2,7-dihydro-4H- pyrazolo[4',3':4,5]pyrano[3,2-f]indazol-1-yl)oxy)propyl)carbamate (200 mg, 0.483 mmol, 1 eq) in DMF (3 mL) was added I2(184 mg, 725 μmol, 1.5 eq) and K2CO3(200 mg, 1.45 mmol, 3 eq). The mixture was stirred at 25 °C for 1 hour. On completion, the mixture was quenched with a saturated solution of Na2SO3and extracted with ethyl acetate (5 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF= 1:0 to 0:1) to give tert-butyl (S)-(2-((9-iodo-2-methyl-2,7-dihydro-4H- pyrazolo[4',3':4,5]pyrano[3,2-f]indazol-1-yl)oxy)propyl)(methyl)carbamate (200 mg, 0.37 mmol, 76% yield) as a yellow oil. LCMS: m / z 540.0 (M+1).

[0504] Step 6. To a solution of tert-butyl (S)-(2-((9-iodo-2-methyl-2,7-dihydro-4H- pyrazolo[4',3':4,5]pyrano[3,2-f]indazol-1-yl)oxy)propyl)(methyl)carbamate (200 mg, 0.37 mmol, 1 eq) in THF (4 mL) was added DHP (77.9 mg, 927 μmol, 2.5 eq) and PTSA (12.7 mg, 74.1 μmol, 0.2 eq). The mixture was stirred at 70 °C for 6 hours. On completion, the mixture was quenched with a saturated solution of NaHCO3 (2 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF= 1:0 to 0:1) to give tert-butyl ((2S)-2-((9-iodo-2-methyl-7-(tetrahydro- 2H-pyran-2-yl)-2,7-dihydro-4H-pyrazolo[4',3':4,5]pyrano[3,2-f]indazol-1- yl)oxy)propyl)(methyl)carbamate (133 mg, 0.213 mmol, 57% yield) as a yellow oil. LCMS: m / z 624.0 (M+1).

[0505] Step 7. A mixture of tert-butyl ((2S)-2-((9-iodo-2-methyl-7-(tetrahydro-2H-pyran-2- yl)-2,7-dihydro-4H-pyrazolo[4',3':4,5]pyrano[3,2-f]indazol-1- yl)oxy)propyl)(methyl)carbamate (133 mg, 0.213 mmol, 1 eq), potassium vinyltrifluoroborate (57.1 mg, 426 μmol, 2 eq), Pd(dppf)Cl2 (15.6 mg, 21.3 μmol, 0.1 eq), and Na2CO3 (67.8 mg, 639 μmol, 3 eq) in dioxane (2 mL) and H2O (0.4 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 80 °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 / THF= 1:0 to 0:1) to give tert-butyl methyl((2S)-2-((2-methyl-7-(tetrahydro-2H-pyran-2-yl)-9-vinyl-2,7-dihydro-4H- pyrazolo[4',3':4,5]pyrano[3,2-f]indazol-1-yl)oxy)propyl)carbamate (50.0 mg, 0.095 mmol, 44% yield) as a yellow oil. LCMS: m / z 524.1 (M+1).

[0506] Step 8. To a solution of tert-butyl methyl((2S)-2-((2-methyl-7-(tetrahydro-2H-pyran- 2-yl)-9-vinyl-2,7-dihydro-4H-pyrazolo[4',3':4,5]pyrano[3,2-f]indazol-1- yl)oxy)propyl)carbamate (40.0 mg, 0.076 mmol, 1 eq) in DCM (2 mL) was added TMSOTf (33.9 mg, 0.152 mmol, 2 eq). The mixture was stirred at 0 °C for 1 hour. On completion, the mixture was quenched with a saturated solution of K3PO4(2 mL) and extracted with dichloromethane (5 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give (2S)-N-methyl-2-((2-methyl-7-(tetrahydro-2H-pyran- 2-yl)-9-vinyl-2,7-dihydro-4H-pyrazolo[4',3':4,5]pyrano[3,2-f]indazol-1-yl)oxy)propan-1- amine (32.0 mg, 0.075 mmol, 98% yield) as a yellow oil. LCMS: m / z 424.1 (M+1).

[0507] Step 9. To a solution of (2S)-N-methyl-2-((2-methyl-7-(tetrahydro-2H-pyran-2-yl)-9- vinyl-2,7-dihydro-4H-pyrazolo[4',3':4,5]pyrano[3,2-f]indazol-1-yl)oxy)propan-1-amine (32.0 mg, 0.075 mmol, 1 eq) in DMF (2 mL) was added K3PO4 (48.1 mg, 226 μmol, 3 eq) and (S)- 1-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo-5-(iodomethyl)-1H-pyrazole (83.1 mg, 151μmol, 2 eq). The mixture was stirred at 60 °C for 1 hour. On completion, the reaction mixture was partitioned between dichloromethane (3 mL × 3) and water (5 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 1:0 to 0:1) to give (2S)-N-((1-((S)-1-((tert- butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo-1H-pyrazol-5-yl)methyl)-N-methyl-2- ((2-methyl-7-(tetrahydro-2H-pyran-2-yl)-9-vinyl-2,7-dihydro-4H- pyrazolo[4',3':4,5]pyrano[3,2-f]indazol-1-yl)oxy)propan-1-amine (60.0 mg, 0.071 mmol, 93% yield) as a yellow oil. LCMS: m / z 846.5 (M+1).

[0508] Step 10. A mixture of (2S)-N-((1-((S)-1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3- ethoxy-4-iodo-1H-pyrazol-5-yl)methyl)-N-methyl-2-((2-methyl-7-(tetrahydro-2H-pyran-2- yl)-9-vinyl-2,7-dihydro-4H-pyrazolo[4',3':4,5]pyrano[3,2-f]indazol-1-yl)oxy)propan-1-amine (50.0 mg, 0.059 mmol, 1 eq), Pd(OAc)2(1.33 mg, 5.91 μmol, 0.1 eq), NaHCO3(12.4 mg, 147 μmol, 2.5 eq) and TBAC (24.6 mg, 88.6 μmol, 1.5 eq) in DMF (2 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 130 °C for 1 hour under N2atmosphere. On completion, the reaction mixture was partitioned between dichloromethane (3 mL × 3) and water (5 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF= 1:0 to 0:1) to give (7S,14E)-11-[(2S)-1-{[tert- butyl(dimethyl)silyl]oxy}propan-2-yl]-13-ethoxy-5,7,9-trimethyl-17-(oxan-2-yl)- 3,5,7,8,9,10,11,17-octahydro-18,1-(metheno)-2,6-dioxa-4,5,9,11,12,16,17-heptaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3-cd]indene (40.0 mg, 0.056 mmol, 94% yield) as a yellow oil. LCMS: m / z 718.3 (M+1).

[0509] Step 11. To a solution of (7S,14E)-11-[(2S)-1-{[tert-butyl(dimethyl)silyl]oxy}propan- 2-yl]-13-ethoxy-5,7,9-trimethyl-17-(oxan-2-yl)-3,5,7,8,9,10,11,17-octahydro-18,1- (metheno)-2,6-dioxa-4,5,9,11,12,16,17-heptaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3- cd]indene (40.0 mg, 0.056 mmol, 1 eq) in DCM (2 mL) was added HCl / dioxane (2 M, 27.8 μL, 1 eq). The mixture was stirred at 25 °C for 5 hours. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by prep-HPLC purification (column: CD24-XPT C18150*25*7um;mobile phase: [water(FA)-ACN]; gradient: 20%-50% B over 13 min) to give (2S)-2-[(7S,14E)-13-ethoxy-5,7,9-trimethyl-5,7,8,9,10,17-hexahydro- 18,1-(metheno)-2,6-dioxa-4,5,9,11,12,16,17- heptaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3-cd]inden-11(3H)-yl]propan-1-ol (3.17 mg, 0.005 mmol, 9.4% yield, 93% purity, FA) as a yellow solid. Analytical data are shown in the table below.

[0510] Preparation of (2S)-2-[(7S,14E)-13-ethoxy-20-fluoro-5,7,9-trimethyl-5,7,8,9,10,17- hexahydro-18,1-(metheno)-2,6-dioxa-4,5,9,11,12,16,17-heptaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3-cd]inden-11(3H)-yl]propan-1-ol (Ex.2):

[0511] Step 1. To a solution of 5-bromo-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-6- ((triisopropylsilyl)oxy)-3-vinyl-1H-indazole (4.00 g, 8.04 mmol, 1 eq), and tert-butyl (S)-(2- ((3-(hydroxymethyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol- 5-yl)oxy)propyl)(methyl)carbamate (3.42 g, 8.04 mmol, 1 eq) in dioxane (80 mL) and H2O (10mL) was added Pd(dtbpf)Cl2(524 mg, 0.1 eq) and Cs2CO3(7.86 g, 24.1 mmol, 3 eq). The mixture was stirred at 80 °C for 3 hours under N2 atmosphere. On completion, the mixture was poured into H2O (200 × mL), and extracted with EA (100 mL × 3). The combined organic layers were washed with brine (100 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a reside. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 5 / 1 to 0 / 1) to give tert-butyl ((2S)-2-((4-(7-fluoro-6- hydroxy-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazol-5-yl)-3-(hydroxymethyl)-1- methyl-1H-pyrazol-5-yl)oxy)propyl)(methyl)carbamate (1.35 g, 30% yield) as a brown oil. LCMS: m / z 582.4 (M+1).

[0512] Step 2. To a solution of tert-butyl ((2S)-2-((4-(7-fluoro-6-hydroxy-1-(tetrahydro-2H- pyran-2-yl)-3-vinyl-1H-indazol-5-yl)-3-(hydroxymethyl)-1-methyl-1H-pyrazol-5- yl)oxy)propyl)(methyl)carbamate (1.30 g, 2.32 mmol, 1 eq) and PPh3 (913 mg, 3.48 mmol, 1.5 eq) in THF (10 mL) was added DBAD (802 mg, 3.48 mmol, 1.5 eq) at 0 °C. The mixture was stirred at 0 °C for 1 hour. On completion, the mixture was poured into H2O (20 mL), and extracted with EA (10 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a reside. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 5 / 1 to 0 / 1) to give tert-butyl ((2S)-2-((6-fluoro-2-methyl-7-(tetrahydro-2H-pyran-2-yl)-9-vinyl-2,7- dihydro-4H-pyrazolo[4',3':4,5]pyrano[3,2-f]indazol-1-yl)oxy)propyl)(methyl)carbamate (1.05 g, 79% yield) as a brown oil. LCMS: m / z 542.2 (M+1).

[0513] Step 3. To a solution of tert-butyl ((2S)-2-((6-fluoro-2-methyl-7-(tetrahydro-2H-pyran- 2-yl)-9-vinyl-2,7-dihydro-4H-pyrazolo[4',3':4,5]pyrano[3,2-f]indazol-1- yl)oxy)propyl)(methyl)carbamate (1.05 g, 1.85 mmol, 1 eq) in DCM (10 mL) was added ZnBr2 (1.25 g, 5.54 mmol, 3 eq). The mixture was stirred at 25 °C for 2 hours. On completion, the mixture was quenched by H2O (50 mL), and extracted with DCM (20 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a reside. The residue was purified by column chromatography (SiO2, Petroleum ether / THF= 10 / 1 to 0 / 1) to give (2S)-2-((6-fluoro-2-methyl- 7-(tetrahydro-2H-pyran-2-yl)-9-vinyl-2,7-dihydro-4H-pyrazolo[4',3':4,5]pyrano[3,2- f]indazol-1-yl)oxy)-N-methylpropan-1-amine (290 mg, 35% yield) as a brown oil. LCMS: m / z 442.2 (M+1).

[0514] Step 4. To a solution of (2S)-2-((6-fluoro-2-methyl-7-(tetrahydro-2H-pyran-2-yl)-9- vinyl-2,7-dihydro-4H-pyrazolo[4',3':4,5]pyrano[3,2-f]indazol-1-yl)oxy)-N-methylpropan-1- amine (290 mg, 656 μmol, 1 eq), and (S)-1-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3- ethoxy-4-iodo-5-(iodomethyl)-1H-pyrazole (661 mg, 1.31 mmol, 2 eq) in DMF (2 mL) wasadded K3PO4(557 mg, 2.63 mmol, 4 eq). The mixture was stirred at 60 °C for 1 hour. On completion, the mixture was poured into H2O (20 mL), and extracted with EA (10 mL × 3). The combined organic layers were washed with brine (100 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a reside. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 5 / 1 to 0 / 1) to give (2S)-N-((1-((S)-1- ((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo-1H-pyrazol-5-yl)methyl)-2-((6- fluoro-2-methyl-7-(tetrahydro-2H-pyran-2-yl)-9-vinyl-2,7-dihydro-4H- pyrazolo[4',3':4,5]pyrano[3,2-f]indazol-1-yl)oxy)-N-methylpropan-1-amine (165 mg, 29% yield) as a brown oil. LCMS: m / z 864.3 (M+1).

[0515] Step 5. A mixture of (2S)-N-((1-((S)-1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3- ethoxy-4-iodo-1H-pyrazol-5-yl)methyl)-2-((6-fluoro-2-methyl-7-(tetrahydro-2H-pyran-2-yl)- 9-vinyl-2,7-dihydro-4H-pyrazolo[4',3':4,5]pyrano[3,2-f]indazol-1-yl)oxy)-N-methylpropan- 1-amine (70.0 mg, 0.081mmol, 1 eq), TBAC (22.5 mg, 0.081 mmol, 1 eq), NaHCO3(20.4 mg, 0.243 mmol, 3 eq) and Pd(OAc)2 (1.82 mg, 0.0081 mmol, 0.1 eq) in DMF (0.5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 0.5 hours under N2atmosphere. On completion, the mixture was poured into H2O (20 mL), and extracted with EA (10 mL × 3). The combined organic layers were washed with brine (100 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a reside. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 5 / 1 to 0 / 1) to give (7S,14E)-11-[(2S)-1-{[tert-butyldi(methyl)silyl]oxy}propan-2-yl]-13-ethoxy-20- fluoro-5,7,9-trimethyl-17-(oxan-2-yl)-3,5,7,8,9,10,11,17-octahydro-18,1-(metheno)-2,6- dioxa-4,5,9,11,12,16,17-heptaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3-cd]indene (12.0 mg, 0.0163 mmol, 20% yield) as a brown oil. LCMS: m / z 736.2 (M+1).

[0516] Step 6. To a solution of (7S,14E)-11-[(2S)-1-{[tert-butyldi(methyl)silyl]oxy}propan- 2-yl]-13-ethoxy-20-fluoro-5,7,9-trimethyl-17-(oxan-2-yl)-3,5,7,8,9,10,11,17-octahydro-18,1- (metheno)-2,6-dioxa-4,5,9,11,12,16,17-heptaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3- cd]indene (12.0 mg, 0.0163 mmol, 1 eq) in DCM (0.5 mL) was added HCl / dioxane (2 M, 0.2 mL). The mixture was stirred at 25 °C for 0.5 hours. On completion, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give (2S)-2-[(7S,14E)-13-ethoxy-20-fluoro-5,7,9-trimethyl-5,7,8,9,10,17-hexahydro-18,1- (metheno)-2,6-dioxa-4,5,9,11,12,16,17-heptaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3- cd]inden-11(3H)-yl]propan-1-ol (0.67 mg, 0.00115 mmol, 7.04% yield, 91.623% purity, FA) as a grey solid. Analytical data are found in the example table below.

[0517] Preparation of (2S)-2-[(7S,14E)-20-chloro-13-ethoxy-5,7,9-trimethyl-5,7,8,9,10,17- hexahydro-18,1-(metheno)-2,6-dioxa-4,5,9,11,12,16,17- heptaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3-cd]inden-11(3H)-yl]propan-1-ol (Ex.3):

[0518] Step 1. A mixture of 5-bromo-7-chloro-6-(methoxymethoxy)-1-(tetrahydro-2H-pyran- 2-yl)-3-vinyl-1H-indazole (2.20 g, 5.48 mmol, 1 eq), methyl (S)-5-((1-((tert- butoxycarbonyl)(methyl)amino)propan-2-yl)oxy)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole-3-carboxylate (2.98 g, 6.57 mmol, 1.2 eq), Cs2CO3 (5.35 g, 16.4 mmol, 3 eq), and Sphos Pd G4(481 mg, 0.547 mmol, 0.1 eq) in dioxane (20 mL) and H2O (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 16 hours under N2atmosphere. On completion, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Commercial hexanes: Ethyl acetate= 100 / 1 to 0 / 1) to give methyl 5-(((S)-1-((tert- butoxycarbonyl)(methyl)amino)propan-2-yl)oxy)-4-(7-chloro-6-(methoxymethoxy)-1- (tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazol-5-yl)-1-methyl-1H-pyrazole-3-carboxylate (3.20 g, 4.05 mmol, 74% yield) as a yellow oil. LCMS: m / z 648.6 (M+1).

[0519] Step 2. A mixture of methyl 5-(((S)-1-((tert-butoxycarbonyl)(methyl)amino)propan-2- yl)oxy)-4-(7-chloro-6-(methoxymethoxy)-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazol- 5-yl)-1-methyl-1H-pyrazole-3-carboxylate (3.00 g, 4.63 mmol, 1 eq), and LiBH4 (2 M in THF, 2.5 mL, 1.05 eq) in THF (20 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 0 °C for 16 hours under N2 atmosphere. On completion, the mixture was poured into H2O (20 × mL), and extracted with EA (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a reside. The residue was purified by column chromatography (SiO2, Commercial hexanes: Ethyl acetate= 100 / 1 to 0 / 1) to give tert-butyl ((2S)-2-((4-(7-chloro-6- (methoxymethoxy)-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazol-5-yl)-3- (hydroxymethyl)-1-methyl-1H-pyrazol-5-yl)oxy)propyl)(methyl)carbamate (1.50 g, 1.79 mmol, 39% yield) as a yellow oil. LCMS: m / z 620.4 (M+1).

[0520] Step 3. To a solution of tert-butyl ((2S)-2-((4-(7-chloro-6-(methoxymethoxy)-1- (tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazol-5-yl)-3-(hydroxymethyl)-1-methyl-1H- pyrazol-5-yl)oxy)propyl)(methyl)carbamate (2.00 g, 3.23 mmol, 1 eq) in DCM (10 mL) was added HCl / dioxane (2 M, 3.5 mL, 2 eq). The mixture was stirred at 25 °C for 1 hour. On completion, the mixture was concentrated under reduced pressure to give 7-chloro-5-(3- (hydroxymethyl)-1-methyl-5-(((S)-1-(methylamino)propan-2-yl)oxy)-1H-pyrazol-4-yl)-3- vinyl-1H-indazol-6-ol (1.26 g, 3.22 mmol, 100% yield, HCl) as a white solid. LCMS: m / z 392.1 (M+1).

[0521] Step 4. A mixture of 7-chloro-5-(3-(hydroxymethyl)-1-methyl-5-(((S)-1- (methylamino)propan-2-yl)oxy)-1H-pyrazol-4-yl)-3-vinyl-1H-indazol-6-ol (1.26 g, 3.22 mmol, 1 eq, HCl), 2-(tributyl-phosphanylidene)acetonitrile (1.55 g, 6.43 mmol, 2 eq) intoluene (20 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 90 °C for 16 hours under N2 atmosphere. On completion, the mixture was concentrated under reduced pressure to give (S)-2-((6-chloro-2-methyl-9-vinyl-2,7-dihydro-4H- pyrazolo[4',3':4,5]pyrano[3,2-f]indazol-1-yl)oxy)-N-methylpropan-1-amine (600 mg, 1.60 mmol, 50% yield) as a yellow oil. LCMS: m / z 374.1 (M+1).

[0522] Step 5. To a solution of (S)-2-((6-chloro-2-methyl-9-vinyl-2,7-dihydro-4H- pyrazolo[4',3':4,5]pyrano[3,2-f]indazol-1-yl)oxy)-N-methylpropan-1-amine (600 mg, 1.60 mmol, 1 eq) in DMF (10 mL) was added K3PO4 (1.02 g, 4.81 mmol, 3 eq) and (S)-1-(1-((tert- butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo-5-(iodomethyl)-1H-pyrazole (971 mg, 1.77 mmol, 1.1 eq). The mixture was stirred at 60 °C for 2 hours. On completion, the mixture was poured into H2O (30 mL), and extracted with EA (20 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a reside. The residue was purified by column chromatography (SiO2, Commercial hexanes : Ethyl acetate= 100 / 1 to 0 / 1) to give (S)-N-((1-((S)-1-((tert- butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo-1H-pyrazol-5-yl)methyl)-2-((6-chloro- 2-methyl-9-vinyl-2,7-dihydro-4H-pyrazolo[4',3':4,5]pyrano[3,2-f]indazol-1-yl)oxy)-N- methylpropan-1-amine (500 mg, 0.427 mmol, 27% yield) as a yellow oil. LCMS: m / z 796.1 (M+1).

[0523] Step 6. To a solution of (S)-N-((1-((S)-1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3- ethoxy-4-iodo-1H-pyrazol-5-yl)methyl)-2-((6-chloro-2-methyl-9-vinyl-2,7-dihydro-4H- pyrazolo[4',3':4,5]pyrano[3,2-f]indazol-1-yl)oxy)-N-methylpropan-1-amine (314 mg, 0.394 mmol, 1 eq) in DCM (3 mL) was added DHP (99.5 mg, 1.18 mmol, 3 eq) and PPTS (9.91 mg, 0.0394 mmol, 0.1 eq). The mixture was stirred at 40 °C for 16 hours. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, Commercial hexanes : Ethyl acetate= 100 / 1 to 2 / 1) to give (2S)-N-((1- ((S)-1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo-1H-pyrazol-5-yl)methyl)- 2-((6-chloro-2-methyl-7-(tetrahydro-2H-pyran-2-yl)-9-vinyl-2,7-dihydro-4H- pyrazolo[4',3':4,5]pyrano[3,2-f]indazol-1-yl)oxy)-N-methylpropan-1-amine (250 mg, 0.195 mmol, 50% yield) as a yellow oil. LCMS: m / z 880.2 (M+1).

[0524] Step 7. A mixture of (2S)-N-((1-((S)-1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3- ethoxy-4-iodo-1H-pyrazol-5-yl)methyl)-2-((6-chloro-2-methyl-7-(tetrahydro-2H-pyran-2-yl)- 9-vinyl-2,7-dihydro-4H-pyrazolo[4',3':4,5]pyrano[3,2-f]indazol-1-yl)oxy)-N-methylpropan- 1-amine (200 mg, 0.227 mmol, 1 eq), Pd(OAc)2 (10.2 mg, 0.0454 mmol, 0.2 eq), NaHCO3 (57.2 mg, 0.681 mmol, 3 eq) and TBAC (63.1 mg, 0.227 mmol, 1 eq) in DMF (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 120 °C for 0.2hours under N2atmosphere. On completion, the mixture was poured into H2O (10 mL), and extracted with EA (10 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a reside. The residue was purified by column chromatography (SiO2, Commercial hexanes : Ethyl acetate= 100 / 1 to 0 / 1) to give tert-butyl-[(2S)-2-[(8E,18S)-28-chloro-11-ethoxy-16,18,21-trimethyl-5- tetrahydropyran-2-yl -19,25-dioxa-5,6,12,13,16,21,22-heptazahexacyclo [18.6.1.14,26.03,7.010,14.023,27] octacosa-1,3,6,8,10(14),11,20(27),22,26(28)-nonaen-13- yl]propoxy]-dimethyl-silane (60.0 mg, 0.0598 mmol, 26% yield) as a yellow oil. LCMS: m / z 752.4 (M+1).

[0525] Step 8. To a solution of tert-butyl-[(2S)-2-[(8E,18S)-28-chloro-11-ethoxy-16,18,21- trimethyl-5-tetrahydropyran-2-yl- 19,25-dioxa-5,6,12,13,16,21,22-heptazahexacyclo [18.6.1.14,26.03,7.010,14.023,27] octacosa-1,3,6,8,10(14),11,20(27),22,26(28)-nonaen-13- yl]propoxy]-dimethyl-silane (50.0 mg, 0.0664 mmol, 1 eq) in DCM (0.5 mL) was added HCl / dioxane (2 M, 2.50 mL). The mixture was stirred at 25 °C for 0.5 hour. On completion, the mixture was concentrated under reduced pressure to give the residue. The residue was purified by prep-HPLC to give (2S)-2-[(7S,14E)-20-chloro-13-ethoxy-5,7,9-trimethyl- 5,7,8,9,10,17-hexahydro-18,1-(metheno)-2,6-dioxa-4,5,9,11,12,16,17- heptaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3-cd]inden-11(3H)-yl]propan-1-ol (12.09 mg, 0.027 mmol, 32.63% yield, 99.37% purity) as an off-white solid. Analytical data for Ex. 3 can be found in the table below.

[0526] Preparation of (2S)-1-[(7S,14E)-9-ethyl-5,7-dimethyl-13-[(propan-2-yl)oxy]- 5,7,8,9,10,17-hexahydro-18,1-(azeno)-2,6-dioxa-4,5,9,11,12,16,17- heptaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3-cd]inden-11(3H)-yl]propan-2-ol (Ex.5):

[0527] Step 1. A mixture of tert-butyl (S)-ethyl(2-((3-(hydroxymethyl)-1-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-5-yl)oxy)propyl)carbamate (1.80 g, 4.10 mmol, 1 eq), 5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-pyrazolo[3,4- b]pyridine (1.40 g, 4.10 mmol, 1 eq), Sphos Pd G4 (360 mg, 0.409 mmol, 0.1 eq), and Cs2CO3(4.00 g, 12.2 mmol, 3 eq) in dioxane (20 mL) and H2O (4 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 partitioned between ethyl acetate (20 mL × 3) and water (15 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF= 1:0 to 0:1) to give tert-butyl ((2S)-2-((4-(6-chloro-1-(tetrahydro-2H- pyran-2-yl)-3-vinyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(hydroxymethyl)-1-methyl-1H- pyrazol-5-yl)oxy)propyl)(ethyl)carbamate (1.40 g, 2.43 mmol, 59% yield) as a yellow solid. LCMS: m / z 597.1 (M+1).

[0528] Step 2. To a solution of tert-butyl ((2S)-2-((4-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)- 3-vinyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(hydroxymethyl)-1-methyl-1H-pyrazol-5- yl)oxy)propyl)(ethyl)carbamate (1.35 g, 2.35 mmol, 1 eq) in DMF (12 mL) was added Cs2CO3 (2.29 g, 7.04 mmol, 3 eq). The mixture was stirred at 80 °C for 1 hour. On completion, the reaction mixture was quenched by addition of H2O (40 mL) and extracted with EA (20 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF= 1:0 to 0:1) to give tert-butyl ethyl((2S)-2-((2- methyl-7-(tetrahydro-2H-pyran-2-yl)-9-vinyl-2,7-dihydro-4H-pyrazolo[3,4- b]pyrazolo[4',3':4,5]pyrano[3,2-e]pyridin-1-yl)oxy)propyl)carbamate (870 mg, 1.62 mmol, 68% yield) as a yellow oil. LCMS: m / z 539.3 (M+1).

[0529] Step 3. To a solution of tert-butyl ethyl((2S)-2-((2-methyl-7-(tetrahydro-2H-pyran-2- yl)-9-vinyl-2,7-dihydro-4H-pyrazolo[3,4-b]pyrazolo[4',3':4,5]pyrano[3,2-e]pyridin-1- yl)oxy)propyl)carbamate (400 mg, 0.742 mmol, 1 eq) in DCM (8 mL) was added ZnBr2 (1.00 g, 4.46 mmol, 6 eq). The mixture was stirred at 25 °C for 12 hours. On completion, the reaction mixture was partitioned between dichloromethane (15 mL × 3) and water (15 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give (2S)-N-ethyl-2-((2-methyl-7-(tetrahydro-2H-pyran-2-yl)-9-vinyl-2,7-dihydro-4H- pyrazolo[3,4-b]pyrazolo[4',3':4,5]pyrano[3,2-e]pyridin-1-yl)oxy)propan-1-amine (180 mg, 0.410 mmol, 55% yield) as a yellow solid. LCMS: m / z 439.3 (M+1).

[0530] Step 4. To a solution of (2S)-N-ethyl-2-((2-methyl-7-(tetrahydro-2H-pyran-2-yl)-9- vinyl-2,7-dihydro-4H-pyrazolo[3,4-b]pyrazolo[4',3':4,5]pyrano[3,2-e]pyridin-1- yl)oxy)propan-1-amine (180 mg, 0.410 mmol, 1 eq) in DMF (3 mL) was added K3PO4(261 mg, 1.23 mmol, 3 eq) and (S)-1-(2-((tert-butyldimethylsilyl)oxy)propyl)-4-iodo-5- (iodomethyl)-3-isopropoxy-1H-pyrazole (231 mg, 0.410 mmol, 1 eq). The mixture was stirred at 60 °C for 1 hour. On completion, the reaction mixture was partitioned between ethyl acetate(5 mL × 3) and water (10 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 / THF= 1:0 to 0:1) to give (2S)-N-((1-((S)-2-((tert- butyldimethylsilyl)oxy)propyl)-4-iodo-3-isopropoxy-1H-pyrazol-5-yl)methyl)-N-ethyl-2-((2- methyl-7-(tetrahydro-2H-pyran-2-yl)-9-vinyl-2,7-dihydro-4H-pyrazolo[3,4- b]pyrazolo[4',3':4,5]pyrano[3,2-e]pyridin-1-yl)oxy)propan-1-amine (80.0 mg, 0.0914 mmol, 22% yield) as a yellow oil. LCMS: m / z 897.2 (M+23).

[0531] Step 5. A mixture of (2S)-N-((1-((S)-2-((tert-butyldimethylsilyl)oxy)propyl)-4-iodo-3- isopropoxy-1H-pyrazol-5-yl)methyl)-N-ethyl-2-((2-methyl-7-(tetrahydro-2H-pyran-2-yl)-9- vinyl-2,7-dihydro-4H-pyrazolo[3,4-b]pyrazolo[4',3':4,5]pyrano[3,2-e]pyridin-1- yl)oxy)propan-1-amine (80.0 mg, 0.0914 mmol, 1 eq), Pd(OAc)2(2.05 mg, 0.00914 mmol, 0.1 eq), TBAC (38.1 mg, 0.137 mmol, 1.5 eq) and NaHCO3 (19.2 mg, 0.228 mmol, 2.5 eq) in DMF (2 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 130 °C for 1 hour under N2 atmosphere. On completion, the reaction mixture was partitioned between ethyl acetate (5 mL × 3) and water (5 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF= 1:0 to 0:1) to give (7S,14E)- 11-[(2S)-2-{[tert-butyldi(methyl)silyl]oxy}propyl]-9-ethyl-5,7-dimethyl-17-(oxan-2-yl)-13- [(propan-2-yl)oxy]-3,5,7,8,9,10,11,17-octahydro-18,1-(azeno)-2,6-dioxa-4,5,9,11,12,16,17- heptaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3-cd]indene (65.0 mg, 0.0870 mmol, 95% yield) as a yellow solid. LCMS: m / z 747.5 (M+1)

[0532] Step 6. To a solution of (7S,14E)-11-[(2S)-2-{[tert-butyldi(methyl)silyl]oxy}propyl]- 9-ethyl-5,7-dimethyl-17-(oxan-2-yl)-13-[(propan-2-yl)oxy]-3,5,7,8,9,10,11,17-octahydro- 18,1-(azeno)-2,6-dioxa-4,5,9,11,12,16,17- heptaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3-cd]indene (60.0 mg, 0.0803 mmol, 1 eq) in DCM (1 mL) was added HCl / dioxane (2 M, 0.4 mL, 10 eq). The mixture was stirred at 25 °C for 1 hour. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by prep-HPLC to give (2S)-1-[(7S,14E)-9-ethyl-5,7-dimethyl-13- [(propan-2-yl)oxy]-5,7,8,9,10,17-hexahydro-18,1-(azeno)-2,6-dioxa-4,5,9,11,12,16,17- heptaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3-cd]inden-11(3H)-yl]propan-2-ol (5.29 mg, 0.00964 mmol, 12% yield, 93.278% purity) as a yellow solid. Analytical data are shown in the table below.

[0533] Preparation of (2S)-2-[(7S,14E)-13-ethoxy-5,7,9-trimethyl-7,8,9,10-tetrahydro-1,18- (metheno)-6-oxa-1,4,5,9,11,12,16,17-octaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3- cd]inden-11(5H)-yl]propan-1-ol (Ex.7)

[0534] Step 1. To a solution of (R)-2-methyloxirane (20.0 g, 344 mmol, 1 eq) in MeOH (150 mL) was added methylamine (2 M, 516 mL, 3 eq). The mixture was stirred at 25 °C for 16 hours. On completion, the mixture was concentrated in vacuo to give the compound (R)-1-(methylamino)propan-2-ol (25.0 g, 280 mmol, 81% yield) as a white solid.1H NMR (400 MHz, CDCl3) δ = 3.67 - 3.48 (m, 3H), 3.30 (dt, J = 3.2, 5.6 Hz, 1H), 2.86 - 2.78 (m, 1H), 1.91 - 1.83 (m, 2H), 0.69 (tdd, J = 2.4, 4.8, 7.2 Hz, 3H).

[0535] Step 2. To a solution of (R)-1-(methylamino)propan-2-ol (20.0 g, 224 mmol, 1 eq) in DCM (200 mL) was added (2,2,2-trifluoroacetyl) 2,2,2-trifluoroacetate (70.6 g, 336 mmol, 1.5 eq) and TEA (113 g, 1.12 mol, 5 eq).The mixture was stirred at 0 °C for 18 hours. On completion, the reaction mixture was quenched by addition of H2O (500 mL) and extracted with DCM (200mL × 3). The combined organic layers were washed with saturated solution of NaCl (500 mL), filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF= 1:1) to give (R)-2,2,2- trifluoro-N-(2-hydroxypropyl)-N-methylacetamide (9.80 g, 52.9 mmol, 23% yield) as a white solid.1H NMR (400 MHz, CDCl3) δ = 4.05 - 3.96 (m, 1H), 3.38 (d, J = 3.6 Hz, 1H), 3.34 - 3.24 (m, 2H), 3.16 (d, J =1.6 Hz, 3H), 1.12 (d, J = 6.4 Hz, 3H).

[0536] Step 3. A mixture of 1-methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H- pyrazolo[3,4-c]pyridin-5-yl)-3-((triisopropylsilyl)ethynyl)-1H-pyrazol-5-ol (1.00 g, 1.98 mmol, 1 eq), (R)-2,2,2-trifluoro-N-(2-hydroxypropyl)-N-methylacetamide (513 mg, 2.77 mmol, 1.4 eq), PPh3 (1.04 g, 3.95 mmol, 2 eq), and DBAD (683 mg, 2.97 mmol, 1.5 eq) in THF (10 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 25 °C for 1 h under N2 atmosphere. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® Silica Flash Column, Eluent of 0~20% THF / Petroleum ether gradient @ 80mL / min) to give 2,2,2-trifluoro-N-methyl-N-((2S)-2-((1- methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-pyrazolo[3,4-c]pyridin-5-yl)-3- ((triisopropylsilyl)ethynyl)-1H-pyrazol-5-yl)oxy)propyl)acetamide (1.12 g, 1.57 mmol, 80 % yield, 95% purity) as an orange oil. LCMS: m / z 673.3 (M+1).

[0537] Step 4. To a mixture of 2,2,2-trifluoro-N-methyl-N-((2S)-2-((1-methyl-4-(1- (tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-pyrazolo[3,4-c]pyridin-5-yl)-3- ((triisopropylsilyl)ethynyl)-1H-pyrazol-5-yl)oxy)propyl)acetamide (1.02 g, 1.52 mmol, 1 eq) in THF (10 mL) and H2O (2 mL) was added LiOH^H2O (318 mg, 7.58 mmol, 5 eq). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was diluted with water (50 mL), extracted with ethyl acetate (3 × 20 mL), and washed with brine (3 × 20 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give (2S)-N-methyl-2-((1-methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-pyrazolo[3,4- c]pyridin-5-yl)-3-((triisopropylsilyl)ethynyl)-1H-pyrazol-5-yl)oxy)propan-1-amine (940 mg, crude) as a yellow oil. LCMS: m / z 577.4 (M+1).

[0538] Step 5. To a solution of (2S)-N-methyl-2-((1-methyl-4-(1-(tetrahydro-2H-pyran-2-yl)- 3-vinyl-1H-pyrazolo[3,4-c]pyridin-5-yl)-3-((triisopropylsilyl)ethynyl)-1H-pyrazol-5- yl)oxy)propan-1-amine (450 mg, 0.78 mmol, 1 eq), and (S)-5-(bromomethyl)-1-(1-((tert- butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo-1H-pyrazole (432 mg, 0.86 mmol, 1.1 eq) in DMF (5 mL) was added K2CO3(323 mg, 2.34 mmol, 3 eq). The mixture was stirred at 80 °C for 1 h. On completion, the mixture was poured into water (20 mL), and the aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phase was washed with brine (20 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~8% THF / Petroleum ether gradient @ 50 mL / min). (2S)-N-((1-((S)- 1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo-1H-pyrazol-5-yl)methyl)-N- methyl-2-((1-methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-pyrazolo[3,4-c]pyridin-5- yl)-3-((triisopropylsilyl)ethynyl)-1H-pyrazol-5-yl)oxy)propan-1-amine (635 mg, 0.635 mmol, 81% yield) was obtained as a light yellow oil.1H NMR (400 MHz, CDCl3) δ = 9.12 (d, J = 3.2 Hz, 1H), 8.19 (s, 1H), 7.00 (dd, J = 11.2, 18.0 Hz, 1H), 6.13 (d, J =17.6 Hz, 1H), 5.81 (td, J = 3.2, 6.4 Hz, 1H), 5.54 (d, J = 11.6 Hz, 1H), 4.54 - 4.40 (m, 2H), 4.12 - 3.99 (m, 1H), 3.86 - 3.78 (m,1H), 3.75 (s, 3H), 3.72 - 3.57 (m, 3H), 3.32 (br d, J = 13.2 Hz, 1H), 2.69 - 2.41 (m, 3H), 2.22 - 2.07 (m, 2H), 1.85 - 1.53 (m,7H), 1.39 (t, J = 7.2 Hz, 3H), 1.28 (br d, J = 6.4 Hz, 3H), 1.14 (dd, J = 3.2, 6.0 Hz, 3H), 1.10 (d, J = 3.2 Hz, 2H), 1.07 (br d, J =3.6 Hz, 2H), 1.04 (s, 12H), 1.03 (br s, 6H), 0.75 (d, J = 2.0 Hz, 9H), -0.10 (d, J = 1.2 Hz, 3H), -0.20 (d, J = 2.0 Hz, 3H). LCMS: m / z 999.4 (M+1).

[0539] Step 6. A mixture of (2S)-N-((1-((S)-1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3- ethoxy-4-iodo-1H-pyrazol-5-yl)methyl)-N-methyl-2-((1-methyl-4-(1-(tetrahydro-2H-pyran- 2-yl)-3-vinyl-1H-pyrazolo[3,4-c]pyridin-5-yl)-3-((triisopropylsilyl)ethynyl)-1H-pyrazol-5- yl)oxy)propan-1-amine (500 mg, 0.500 mmol, 1 eq), Pd(dppf)Cl2^CH2Cl2 (40.9 mg, 0.05 mmol, 0.1 eq), Na2CO3(159 mg, 1.50 mmol, 3 eq) in DMF (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 16 h under N2 atmosphere. On completion, the mixture was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (20 mL × 2). The combined organic phase was washed with brine (30 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~18% THF / Petroleum ether gradient @ 50 mL / min) to give (10S,17E)- 14-[(2S)-1-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl]-16-ethoxy-8,10,12-trimethyl-2- (oxan-2-yl)-6-{[tri(propan-2-yl)silyl]ethynyl}-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine (132 mg, 0.152 mmol, 30% yield) as a yellow solid. LCMS: m / z 871.5 (M+1).

[0540] Step 7. To a solution of (10S,17E)-14-[(2S)-1-{[tert-butyl(dimethyl)silyl]oxy}propan- 2-yl]-16-ethoxy-8,10,12-trimethyl-2-(oxan-2-yl)-6-{[tri(propan-2-yl)silyl]ethynyl}- 2,10,11,12,13,14-hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecine (122 mg, 0.140 mmol, 1 eq) in DCM (1.2 mL) was added TFA (0.4 mL, 38.5 eq). The mixture was stirred at 25 °C for 2 h. On completion, the reaction mixture was concentrated under reduced pressure to give (2S)-2-[(10S,17E)-16-ethoxy-8,10,12- trimethyl-6-{[tri(propan-2-yl)silyl]ethynyl}-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol (130 mg, crude) as a yellow oil. LCMS: m / z 673.3 (M+1).

[0541] Step 8. To a solution of (2S)-2-[(10S,17E)-16-ethoxy-8,10,12-trimethyl-6-{[tri(propan- 2-yl)silyl]ethynyl}-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4- f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol (130 mg, 0.193 mmol, 1 eq) in DMSO (1 mL) was added CsF (587 mg, 3.86 mmol, 20 eq). The mixture was stirred at 25 °C for 32 h. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Ultimate C18 150*25mm*5um;mobile phase: [water(FA)-ACN];gradient:15%-45% B over 10 min) to give (2S)-2-[(7S,14E)-13-ethoxy-5,7,9-trimethyl-7,8,9,10-tetrahydro-1,18-(metheno)-6-oxa- 1,4,5,9,11,12,16,17-octaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3-cd]inden-11(5H)- yl]propan-1-ol (4.58 mg, 0.008 mmol, 4.2% yield, 100% purity, FA) as a red solid. Analytical data are shown in the table below.

[0542] Ex.8 was synthesized using the procedure of Ex.7 and substituting I-3-2 for I-3-3 in step 5. Analytical data are shown in the table below.

[0543] Preparation of (2S)-1-[(7S,14E)-5,7,9-trimethyl-13-[(propan-2-yl)oxy]-5,7,8,9,10,17- hexahydro-18,1-(azeno)-2,6-dioxa-4,5,9,11,12,16,17- heptaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3-cd]inden-11(3H)-yl]propan-2-ol (Ex.9):

[0544] Step 1. A mixture of tert-butyl (S)-(2-((3-(hydroxymethyl)-1-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-5-yl)oxy)propyl)(methyl)carbamate (1.15 g, 2.70 mmol, 1 eq), 5-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-pyrazolo[3,4- b]pyridine (926 mg, 2.70 mmol, 1 eq), Sphos Pd G4(237 mg, 0.270 mmol, 0.1 eq), Cs2CO3(2.64 g, 8.11 mmol, 3 eq) in dioxane (10 mL) and H2O (2 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 80 °C for 1 hour under N2atmosphere. On completion, the reaction mixture was partitioned between ethyl acetate (15 mL × 3) and water (15 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF= 1:0 to 0:1) to give tert-butyl ((2S)-2-((4-(6-chloro-1-(tetrahydro-2H- pyran-2-yl)-3-vinyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(hydroxymethyl)-1-methyl-1H- pyrazol-5-yl)oxy)propyl)(methyl)carbamate (860 mg, 1.53 mmol, 56% yield) as a yellow solid. LCMS: m / z 561.3 (M+1).

[0545] Step 2. To a solution of tert-butyl ((2S)-2-((4-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)- 3-vinyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(hydroxymethyl)-1-methyl-1H-pyrazol-5- yl)oxy)propyl)(methyl)carbamate (840 mg, 1.50 mmol, 1 eq) in DMF (8 mL) was added Cs2CO3(1.46 g, 4.49 mmol, 3 eq). The mixture was stirred at 80 °C for 1 hour. On completion, the reaction mixture was partitioned between ethyl acetate (20 mL × 3) and water (10 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF= 1:0 to 0:1) to give tert-butyl methyl((2S)-2-((2-methyl-7-(tetrahydro-2H-pyran-2-yl)-9-vinyl-2,7-dihydro-4H-pyrazolo[3,4-b]pyrazolo[4',3':4,5]pyrano[3,2- e]pyridin-1-yl)oxy)propyl)carbamate (450 mg, 0.857 mmol, 57% yield) as a yellow solid.1H NMR (400 MHz, CDCl3) δ = 8.10 (s, 1H), 6.95 (dd, J = 11.6, 18.4 Hz, 1H), 5.95 (d, J = 2.4 Hz, 1H), 5.93 - 5.90 (m, 1H), 5.49 (d, J = 11.6 Hz, 1H), 5.38 - 5.33 (m, 2H), 4.06 (d, J = 11.6 Hz, 1H), 3.65 (s, 3H), 3.49 - 3.40 (m, 1H), 2.93 (s, 3H), 2.58 -2.45 (m, 1H), 2.08 - 2.00 (m, 1H), 1.85 (d, J = 13.2 Hz, 1H), 1.78 (td, J = 3.2, 6.8 Hz, 1H), 1.74 - 1.68 (m, 2H), 1.66 (d, J = 3.6 Hz, 2H), 1.52 (d, J = 10.8 Hz, 1H), 1.38 (d, J = 11.2 Hz, 9H), 1.23 - 1.19 (m, 3H).

[0546] Step 3. To a solution of tert-butyl methyl((2S)-2-((2-methyl-7-(tetrahydro-2H-pyran- 2-yl)-9-vinyl-2,7-dihydro-4H-pyrazolo[3,4-b]pyrazolo[4',3':4,5]pyrano[3,2-e]pyridin-1- yl)oxy)propyl)carbamate (430 mg, 0.819 mmol, 1 eq) in DCM (5 mL) was added TMSOTf (255 mg, 1.15 mmol, 1.4 eq) and 2,6-dimethylpyridine (105 mg, 0.983 mmol, 1.2 eq). The mixture was stirred at 0 °C for 0.5 hours. On completion, the mixture was filtered and concentrated to give (S)-N-methyl-2-((2-methyl-9-vinyl-2,7-dihydro-4H-pyrazolo[3,4- b]pyrazolo[4',3':4,5]pyrano[3,2-e]pyridin-1-yl)oxy)propan-1-amine (270 mg, 0.793 mmol, 96% yield) as a yellow oil. LCMS: m / z 341.1 (M+1).

[0547] Step 4. To a solution of (S)-N-methyl-2-((2-methyl-9-vinyl-2,7-dihydro-4H- pyrazolo[3,4-b]pyrazolo[4',3':4,5]pyrano[3,2-e]pyridin-1-yl)oxy)propan-1-amine (270 mg, 0.793 mmol, 1 eq) in THF (5 mL) was added DIEA (307 mg, 2.38 mmol, 3 eq) and (S)-1-(2- ((tert-butyldimethylsilyl)oxy)propyl)-4-iodo-5-(iodomethyl)-3-isopropoxy-1H-pyrazole (447 mg, 0.793 mmol, 1 eq). The mixture was stirred at 25 °C for 12 hours. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF= 1:0 to 0:1) to give (S)-N-((1-((S)-2-((tert- butyldimethylsilyl)oxy)propyl)-4-iodo-3-isopropoxy-1H-pyrazol-5-yl)methyl)-N-methyl-2- ((2-methyl-9-vinyl-2,7-dihydro-4H-pyrazolo[3,4-b]pyrazolo[4',3':4,5]pyrano[3,2-e]pyridin- 1-yl)oxy)propan-1-amine (330 mg, 0.424 mmol, 53% yield) as a yellow oil. LCMS: m / z 777.3 (M+1)

[0548] Step 5. To a solution of (S)-N-((1-((S)-2-((tert-butyldimethylsilyl)oxy)propyl)-4-iodo- 3-isopropoxy-1H-pyrazol-5-yl)methyl)-N-methyl-2-((2-methyl-9-vinyl-2,7-dihydro-4H- pyrazolo[3,4-b]pyrazolo[4',3':4,5]pyrano[3,2-e]pyridin-1-yl)oxy)propan-1-amine (310 mg, 0.399 mmol, 1 eq) in DCM (4 mL) was added DHP (100 mg, 1.20 mmol, 3 eq) and PPTS (20.0 mg, 0.0798 mmol, 0.2 eq). The mixture was stirred at 40 °C for 12 hours. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF= 1:0 to 0:1) to give (2S)-N-((1-((S)-2-((tert- butyldimethylsilyl)oxy)propyl)-4-iodo-3-isopropoxy-1H-pyrazol-5-yl)methyl)-N-methyl-2- ((2-methyl-7-(tetrahydro-2H-pyran-2-yl)-9-vinyl-2,7-dihydro-4H-pyrazolo[3,4-b]pyrazolo[4',3':4,5]pyrano[3,2-e]pyridin-1-yl)oxy)propan-1-amine (220 mg, 0.255 mmol, 64% yield) as a yellow solid. LCMS: m / z 861.5 (M+1).

[0549] Step 6. A mixture of (2S)-N-((1-((S)-2-((tert-butyldimethylsilyl)oxy)propyl)-4-iodo-3- isopropoxy-1H-pyrazol-5-yl)methyl)-N-methyl-2-((2-methyl-7-(tetrahydro-2H-pyran-2-yl)- 9-vinyl-2,7-dihydro-4H-pyrazolo[3,4-b]pyrazolo[4',3':4,5]pyrano[3,2-e]pyridin-1- yl)oxy)propan-1-amine (200 mg, 0.232 mmol, 1 eq), Pd(OAc)2 (5.22 mg, 0.0232 mmol, 0.1 eq), TBAC (96.8 mg, 0.348 mmol, 1.5 eq) and NaHCO3(48.7 mg, 0.580 mmol, 2.5 eq) in DMF (4 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 130 °C for 1 hour under N2atmosphere. On completion, the reaction mixture was partitioned between ethyl acetate (5 mL × 3) and water (5 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF= 1:0 to 0:1) to give (7S,14E)- 11-[(2S)-2-{[tert-butyldi(methyl)silyl]oxy}propyl]-5,7,9-trimethyl-17-(oxan-2-yl)-13- [(propan-2-yl)oxy]-3,5,7,8,9,10,11,17-octahydro-18,1-(azeno)-2,6-dioxa-4,5,9,11,12,16,17- heptaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3-cd]indene (140 mg, 0.191 mmol, 82% yield) as a yellow solid. LCMS: m / z 733.5 (M+1).

[0550] Step 7. To a solution of (7S,14E)-11-[(2S)-2-{[tert-butyldi(methyl)silyl]oxy}propyl]- 5,7,9-trimethyl-17-(oxan-2-yl)-13-[(propan-2-yl)oxy]-3,5,7,8,9,10,11,17-octahydro-18,1- (azeno)-2,6-dioxa-4,5,9,11,12,16,17-heptaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3- cd]indene (120 mg, 0.163 mmol, 1 eq) in DCM (2 mL) was added HCl / EA (2 M, 59.7 mg, 1.64 mmol, 10 eq). The mixture was stirred at 25 °C for 0.5 hours. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by prep-HPLC to give (2S)-1-[(7S,14E)-5,7,9-trimethyl-13-[(propan-2-yl)oxy]-5,7,8,9,10,17-hexahydro-18,1- (azeno)-2,6-dioxa-4,5,9,11,12,16,17-heptaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3- cd]inden-11(3H)-yl]propan-2-ol (6.68 mg, 0.0125 mmol, 7.63% yield) as a yellow solid. Analytical data are shown in the table below.

[0551] Example Table 1.CELLULAR ASSAYS Generation of Engineered Ba / F3 Cell Lines with EML4-ALK Fusion Genes

[0552] 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 andconfirmed 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.

[0553] Cellular Assays

[0554] 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.).

[0555] Bioassay Table 1.

Claims

1. WHAT IS CLAIMED IS:

1. A compound of the formula Iwherein A is a 5- to 10-membered heteroarylene or C6-C10 arylene; B is a 5- to 10-membered heteroarylene or C6-C10arylene; C / D is a 9-membered bicyclic heteroarylene, wherein X is C or N; X1is C(R5), N(R6), or N; X2is C(R7), N(R8), or N; X3is C or N; X4is C or N; X5is C(R9) or N; and X6is C or N; X7is C(R10) or N; provided that at least one of X1to X7is a nitrogen atom; each of Y and Y1is independently C, O, N, or S; provided that X, Y, and Y1do not comprise an -O-O-, -O-S-, -O-N-, -S-S-, or -N-N- bond; each L is independently a bond, -C(R12)(R13)-, -O-, -N(R14)C(O)-, -C(O)N(R14)-, -N(R14)-, -N(R14)S(O)-, -S(O)N(R14)-, -N(R14)S(O)2-, -S(O)2N(R14)-, -S-, -S(O)-, or -S(O)2-, provided that (L)p does not comprise an -O-O-, -O-S-, -O-N-, -S-S-, or -N-N- bond; each R1and R2, when present and bonded to a carbon atom, is independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 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, and each R1and R2, when present and bonded to a nitrogen atom, is independently deuterium, C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, 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; each of R3and R4is 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, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, 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; each of R5, R7, R9, and R10, 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-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-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-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 R6and R8, when present, is independently 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; R11and R15, taken together with the atoms to which they are attached, combine to form a fused C6-C8 cycloalkyl, fused 6- to 8-membered heterocycloalkyl, fused C6 aryl, or fused 5- or 6-membered heteroaryl, wherein each hydrogen atom in fused C6-C8cycloalkyl, fused 6- to 8-membered heterocycloalkyl, fused C6 aryl, and fused 5- or 6-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, - ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, - OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2; each R12and R13, when present, is independently 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; 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-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-memberedheteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; each R14, 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-C10aryl, C1-C6alkylene-C6-C10aryl, 5- to 10-membered heteroaryl, C1-C6alkylene-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-C6alkylene-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-C6alkyl)2, -OC(O)N(C2-C6alkylene), -OS(O)-(H or C1-C6alkyl), -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-C6alkyl)2, -OS(O)2N(C2-C6alkylene), -S(H or C1-C6alkyl), -S(O)(H or C1-C6 alkyl), -S(O)2(H or C1-C6 alkyl), -S(O)N(H or C1-C6 alkyl)2, -S(O)N(C2-C6 alkylene), -S(O)2N(H or C1-C6 alkyl)2, -S(O)2N(C2-C6 alkylene), -N(H or C1-C6 alkyl)2, -N(C2-C6 alkylene), -N(H or C1-C6 alkyl)C(O)-(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)C(O)O(H orC1-C6alkyl), -N(H or C1-C6alkyl)C(O)N(H or C1-C6alkyl)2, -N(H or C1-C6alkyl)C(O)N(C2-C6 alkylene), -N(H or C1-C6 alkyl)S(O)-(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)S(O)2(H or C1-C6alkyl), -N(H or C1-C6alkyl)S(O)N(H or C1-C6alkyl)2, -N(H or C1-C6alkyl)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-C6alkylene), -C(O)-(H or C1-C6alkyl), -C(O)O(H or C1-C6alkyl), -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-C6alkylene), -P(O)2(H or C1-C6alkyl)2, -P(O)2(C2-C6alkylene), -P(O)N(H or C1-C6alkyl)2, -P(O)N(C2-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 0, 1, 2, 3, or 4; n is 1, 2, 3, or 4; and p is 3, 4, 5, 6, 7, or 8; q is 0, 1, or 2, as valency allows; r is 0, 1, or 2, as valency allows; and “” is a single bond or a double bond;an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, having the formula IIan isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein when “ ” is a single bond, then q is 2 and r is 2, andwhen “ ” is a double bond, then q is 1 and r is 1.

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

4. The compound of any of the preceding claims, having the formula IVan isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 or 2, having the formula VV an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each of Y2and Y3is independently a bond, -O-, -N(R14)C(O)-, -C(O)N(R14)-, -N(R14)-, -N(R14)S(O)-, -S(O)N(R14)-, -N(R14)S(O)2-, -S(O)2N(R14)-, -S-, -S(O)-, or -S(O)2-; each L1is independently -C(R12)(R13)-, -C(R12)(R13)-C(R12)(R13)-, -C(R12)(R13)- C(R12)(R13)-C(R12)(R13)-, or -C(R12)(R13)-C(R12)(R13)-C(R12)(R13)-C(R12)(R13)-; L2is a bond, -C(R12)(R13)-, -C(R12)(R13)-C(R12)(R13)-, or -C(R12)(R13)-C(R12)(R13)- C(R12)(R13)-; and t is 0, 1, or 2, wherein when “ ” is a single bond, then q is 2 and r is 2, andwhen “ ” is a double bond, then q is 1 and r is 1.

6. The compound of any one of claims 1, 2, or 5, having the formula VIan isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each of Y2and Y3is independently a bond, -O-, -N(R14)C(O)-, -C(O)N(R14)-, -N(R14)-, -N(R14)S(O)-, -S(O)N(R14)-, -N(R14)S(O)2-, -S(O)2N(R14)-, -S-, -S(O)-, or -S(O)2-; each L1is independently -C(R12)(R13)-, -C(R12)(R13)-C(R12)(R13)-, -C(R12)(R13)- C(R12)(R13)-C(R12)(R13)-, or -C(R12)(R13)-C(R12)(R13)-C(R12)(R13)-C(R12)(R13)-; L2is a bond, -C(R12)(R13)-, -C(R12)(R13)-C(R12)(R13)-, or -C(R12)(R13)-C(R12)(R13)- C(R12)(R13)-; and t is 0, 1, or 2, wherein when “ ” is a single bond, then q is 2 and r is 2, andwhen “ ” is a double bond, then q is 1 and r is 1.

7. The compound of any one of claims 1 to 3, 5, or 6, having the formula VIan isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each of Y2and Y3is independently a bond, -O-, -N(R14)C(O)-, -C(O)N(R14)-, -N(R14)-, -N(R14)S(O)-, -S(O)N(R14)-, -N(R14)S(O)2-, -S(O)2N(R14)-, -S-, -S(O)-, or -S(O)2-; each L1is independently -C(R12)(R13)-, -C(R12)(R13)-C(R12)(R13)-, -C(R12)(R13)- C(R12)(R13)-C(R12)(R13)-, or -C(R12)(R13)-C(R12)(R13)-C(R12)(R13)-C(R12)(R13)-; L2is a bond, -C(R12)(R13)-, -C(R12)(R13)-C(R12)(R13)-, or -C(R12)(R13)-C(R12)(R13)- C(R12)(R13)-; and t is 0, 1, or 2.

8. The compound of any of the preceding claims, having the formula VIIIan isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each of Y2and Y3is independently a bond, -O-, -N(R14)C(O)-, -C(O)N(R14)-, -N(R14)-,-N(R14)S(O)-, -S(O)N(R14)-, -N(R14)S(O)2-, -S(O)2N(R14)-, -S-, -S(O)-, or -S(O)2-; each L1is independently -C(R12)(R13)-, -C(R12)(R13)-C(R12)(R13)-, -C(R12)(R13)- C(R12)(R13)-C(R12)(R13)-, or -C(R12)(R13)-C(R12)(R13)-C(R12)(R13)-C(R12)(R13)-; L2is a bond, -C(R12)(R13)-, -C(R12)(R13)-C(R12)(R13)-, or -C(R12)(R13)-C(R12)(R13)- C(R12)(R13)-; and t is 0, 1, or 2.

9. The compound of claim 1 or 2, having the formula IX,an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein when “ ” is a single bond, then q is 2 and r is 2, andwhen “ ” is a double bond, then q is 1 and r is 1.

10. The compound of any one of claims 1, 2, or 9, having the formula Xan isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof.

11. The compound of any one of claims 1, 2, 9, or 10, having the formula XIan isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1, 2, or 9, having the formula XIIan isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each of Y2and Y3is independently a bond, -O-, -N(R14)C(O)-, -C(O)N(R14)-, -N(R14)-, -N(R14)S(O)-, -S(O)N(R14)-, -N(R14)S(O)2-, -S(O)2N(R14)-, -S-, -S(O)-, or -S(O)2-; each L1is independently -C(R12)(R13)-, -C(R12)(R13)-C(R12)(R13)-, -C(R12)(R13)- C(R12)(R13)-C(R12)(R13)-, or -C(R12)(R13)-C(R12)(R13)-C(R12)(R13)-C(R12)(R13)-; L2is a bond, -C(R12)(R13)-, -C(R12)(R13)-C(R12)(R13)-, or -C(R12)(R13)-C(R12)(R13)- C(R12)(R13)-; and t is 0, 1, or 2, wherein when “ ” is a single bond, then q is 2 and r is 2, andwhen “ ” is a double bond, then q is 1 and r is 1.

13. The compound of any one of claims 1, 2, 9, 10, or 12, having the formula XIIIan isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each of Y2and Y3is independently a bond, -O-, -N(R14)C(O)-, -C(O)N(R14)-, -N(R14)-, -N(R14)S(O)-, -S(O)N(R14)-, -N(R14)S(O)2-, -S(O)2N(R14)-, -S-, -S(O)-, or -S(O)2-; each L1is independently -C(R12)(R13)-, -C(R12)(R13)-C(R12)(R13)-, -C(R12)(R13)- C(R12)(R13)-C(R12)(R13)-, or -C(R12)(R13)-C(R12)(R13)-C(R12)(R13)-C(R12)(R13)-; L2is a bond, -C(R12)(R13)-, -C(R12)(R13)-C(R12)(R13)-, or -C(R12)(R13)-C(R12)(R13)- C(R12)(R13)-; and t is 0, 1, or 2.

14. The compound of any one of claims 1, 2, or 9 to 13, having the formula XIVan isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, whereineach of Y2and Y3is independently a bond, -O-, -N(R14)C(O)-, -C(O)N(R14)-, -N(R14)-, -N(R14)S(O)-, -S(O)N(R14)-, -N(R14)S(O)2-, -S(O)2N(R14)-, -S-, -S(O)-, or -S(O)2-; each L1is independently -C(R12)(R13)-, -C(R12)(R13)-C(R12)(R13)-, -C(R12)(R13)- C(R12)(R13)-C(R12)(R13)-, or -C(R12)(R13)-C(R12)(R13)-C(R12)(R13)-C(R12)(R13)-; L2is a bond, -C(R12)(R13)-, -C(R12)(R13)-C(R12)(R13)-, or -C(R12)(R13)-C(R12)(R13)- C(R12)(R13)-; and t is 0, 1, or 2.

15. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring C / D is of the formulawherein each “” represents a point of covalent attachment.

16. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring A in the portionis a 5- or 6-membered heteroarylene, and each “ ” represents a point of covalentattachment.

17. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring A in the portionis a 5- or 6-membered heteroarylene selected from the group consisting ofwherein m is 0, 1, or 2, and each “” represents a point of covalent attachment.

18. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein m is 1 or 2.

19. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each R1, when present and bonded to carbon, is independently fluoro, chloro, methyl, ethyl, propyl, 2-hydroxyeth-1-yl, 1- hydroxyprop-2-yl, 2-hydroxyprop-1-yl, methoxy, ethoxy, isopropoxy, -C(O)ORa, -C(O)NRaRb, -CN, -CH2CN, or 4-piperidinyl.

20. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each R1, when present and bonded to nitrogen, is independently methyl, ethyl, propyl, 2-hydroxyeth-1-yl, 1-hydroxyprop-2-yl, 2- hydroxyprop-1-yl, 4-piperidinyl, or -CH2CN.

21. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring A in the portionis a 5- or 6-membered heteroarylene selected from the group consisting ofwherein each “ ” represents a point of covalent attachment.

22. The compound of any one of claims 1 to 7, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring A in the portionis a C6-C10 arylene, m is 0, 1, 2, or 3, and each “” represents a point of covalentattachment.

23. The compound of any one of claims 1 to 7, or 14, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring A in the portionis a phenylene, m is 0, 1, 2, or 3, and each “ ” represents a point of covalent attachment.

24. The compound of any one of claims 1 to 7, 14, or 15, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2.

25. The compound of any one of claims 1 to 7, or 14 to 16, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each R1, when present, is independently fluoro, chloro, methyl, ethyl, methoxy, ethoxy, -C(O)ORa, -C(O)NRaRb, -CN, or 4-piperidinyl.

26. The compound of any one of claims 1 to 7, or 14 to 17, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring A in the portionis selected from the group consisting ofwherein each “” represents a point of covalent attachment.

27. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring B in the portionis a 5- or 6-membered heteroarylene, n is 0, 1, or 2, and each “ ” represents a point ofcovalent attachment.

28. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring B in the portionis a 5- or 6-membered heteroarylene selected from the group consisting of,wherein n is 0, 1, or 2, and each “” represents a point of covalent attachment.

29. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each R2, when present and bonded to carbon, is independently fluoro, chloro, methyl, ethyl, methoxy, ethoxy, or methoxymethyl.

30. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each R2, when present and bonded to nitrogen, is independently methyl or ethyl.

31. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring B in the portionis selected from the group consisting ofwherein each “” represents a point of covalent attachment.

32. The compound of any one of claims 1 to 18, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring B in the portionis a C6-C10 arylene, m is 0, 1, 2, or 3, and each “ ” represents a point of covalentattachment.

33. The compound of any one of claims 1 to 18, or 24, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring B in the portionis a phenylene, m is 0, 1, 2, or 3, and each “ ” represents a point of covalent attachment.

34. The compound of any one of claims 4 to 8, 12 to 14, or 15 to 33, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each L1, when present, is independently -C(R12)(R13)-, -C(R12)(R13)-C(R12)(R13)- or -C(R12)(R13)-C(R12)(R13)-C(R12)(R13)-.

35. The compound of any one of claims 4 to 8, 12 to 14, or 15 to 34, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each L1, when present, is independently -C(R12)(R13)-, -C(R12)(R13)-C(R12)(R13)- or -C(R12)(R13)-C(R12)(R13)- C(R12)(R13)-, wherein one or two of R12is a C1-C6 alkyl.

36. The compound of any one of claims 4 to 8, 12 to 14, or 15 to 35, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each L1, when present, is independently -C(R12)(R13)-, -C(R12)(R13)-C(R12)(R13)- or -C(R12)(R13)-C(R12)(R13)- C(R12)(R13)-, wherein one or two of R12is a C1-C6alkyl, and the remaining R12and R13are H or deuterium.

37. The compound of any one of claims 4 to 8, 12 to 14, or 15 to 36, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein q, when present, is 1.

38. The compound of any one of claims 4 to 8, 12 to 14, or 15 to 37, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein L1, when present, is - C(R12)(R13)-C(R12)(R13)-.

39. The compound of any one of claims 4 to 8, 12 to 14, or 15 to 38, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein q, when present, is 2.

40. The compound of any one of claims 4 to 8, 12 to 14, or 15 to 39, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein one of L1, when present, is -C(R12)(R13)- and one of L1, when present, is -C(R12)(R13)-C(R12)(R13)-.

41. The compound of any one of claims 4 to 8, 12 to 14, or 15 to 40, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein Y, when present, is -O-.

42. The compound of any one of claims 4 to 8, 12 to 14, or 15 to 41, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein Y, when present, is - N(R14)C(O)-.

43. The compound of any one of claims 4 to 8, 12 to 14, or 15 to 42, an isotopically labeledform thereof, or a pharmaceutically acceptable salt thereof, wherein Y, when present, is a bond.

44. The compound of any one of claims 4 to 8, 12 to 14, or 15 to 43, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each Y1, when present, is independently -O- or -N(R14)-.

45. The compound of any one of claims 4 to 8, 12 to 14, or 15 to 44, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each L2, when present, is a bond.

46. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein -(L)p- or -L2-(Y1-L1)q-Y is of the formula,,wherein each “ ” represents a point of covalent attachment.

47. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each R3is H or deuterium.

48. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each R4is H or deuterium.

49. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein R5, when present, is H or deuterium.

50. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein R6, when present, is H, deuterium, or C1- C6 alkyl.

51. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein R7, when present, is H or deuterium.

52. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein R8, when present, is H, deuterium, or C1- C6 alkyl.

53. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein R9, when present, is H or deuterium.

54. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein R10, when present, is H, deuterium, halogen, C1-C6 alkyl, or -NRaRb.

55. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein R14, when present, is H or C1-C6alkyl.

56. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein R11and R15, taken together with the atoms to which they are attached, combine to form a fused 6-membered heterocycloalkyl.

57. The compound of any one of claims 1 to 55, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein R11and R15, taken together with the atoms to which they are attached, combine to form a fused C6 aryl.

58. The compound of any one of claims 1 to 55, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein R11and R15, taken together with the atoms to which they are attached, combine to form a fused 5- or 6-membered heteroaryl.

59. The compound of claim 1, selected from the group consisting of (2S)-2-[(7S,14E)-13-ethoxy-5,7,9-trimethyl-5,7,8,9,10,17-hexahydro-18,1-(metheno)-2,6- dioxa-4,5,9,11,12,16,17-heptaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3-cd]inden- 11(3H)-yl]propan-1-ol; (2S)-2-[(7S,14E)-13-ethoxy-20-fluoro-5,7,9-trimethyl-5,7,8,9,10,17-hexahydro-18,1- (metheno)-2,6-dioxa-4,5,9,11,12,16,17-heptaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3- cd]inden-11(3H)-yl]propan-1-ol; (2S)-2-[(7S,14E)-20-chloro-13-ethoxy-5,7,9-trimethyl-5,7,8,9,10,17-hexahydro-18,1- (metheno)-2,6-dioxa-4,5,9,11,12,16,17-heptaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3- cd]inden-11(3H)-yl]propan-1-ol; (2S)-2-[(7S,14E)-13-ethoxy-5,7,9-trimethyl-5,7,8,9,10,17-hexahydro-18,1-(azeno)-2,6-dioxa- 4,5,9,11,12,16,17-heptaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3-cd]inden-11(3H)- yl]propan-1-ol;(2S)-1-[(7S,14E)-9-ethyl-5,7-dimethyl-13-[(propan-2-yl)oxy]-5,7,8,9,10,17-hexahydro-18,1- (azeno)-2,6-dioxa-4,5,9,11,12,16,17-heptaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3- cd]inden-11(3H)-yl]propan-2-ol; (7S,14E)-13-ethoxy-11-[(2S)-1-hydroxypropan-2-yl]-5,7,9-trimethyl-3,5,8,9,11,17- hexahydro-18,1-(metheno)-2,6-dioxa-4,5,9,11,12,16,17- heptaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3-cd]inden-10(7H)-one; (2S)-2-[(7S,14E)-13-ethoxy-5,7,9-trimethyl-7,8,9,10-tetrahydro-1,18-(metheno)-6-oxa- 1,4,5,9,11,12,16,17-octaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3-cd]inden-11(5H)- yl]propan-1-ol; 2-[(7S,14E)-13-ethoxy-5,7,9-trimethyl-7,8,9,10-tetrahydro-1,18-(metheno)-6-oxa- 1,4,5,9,11,12,16,17-octaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3-cd]inden-11(5H)- yl]ethan-1-ol; and (2S)-1-[(7S,14E)-5,7,9-trimethyl-13-[(propan-2-yl)oxy]-5,7,8,9,10,17-hexahydro-18,1- (azeno)-2,6-dioxa-4,5,9,11,12,16,17-heptaazadicyclopenta[5,6:9,10]cyclopentadeca[1,2,3- cd]inden-11(3H)-yl]propan-2-ol; an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof.

60. A pharmaceutical composition comprising a compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, and optionally one or more excipients.

61. A method of treating disease in a subject comprising, administering a therapeutically effective amount of a compound of any one of claims 1 to 59, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 60.

62. A compound according to any one of claims 1 to 59, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, for use in a method of treating disease in a subject.

63. Use of a compound according to any one of claims 1 to 59, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of disease in a subject.

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