Macrocyclic compounds and their use

Abstract

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

Description

83573-420992 MACROCYCLIC COMPOUNDS AND THEIR USE RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 574,044, filed April 3, 2024, the entire disclosure of which is incorporated herein by reference. TECHNICAL FIELD

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

[0003] Protein kinases are tightly regulated signaling proteins that orchestrate the activation of signaling cascades by phosphorylating target proteins in response to extracellular and intracellular stimuli. The human genome encodes approximately 518 protein kinases (Manning G, et al. The protein kinase complement of the human genome. Science.2002, 298:1912–34). Dysregulation of kinase activity is associated with many diseases, including cancers, and cardiovascular, degenerative, immunological, infectious, inflammatory, and metabolic diseases (Levitzki, A. Protein kinase inhibitors as a therapeutic modality. Acc. Chem. Res. 2003, 36:462–469). The molecular bases leading to various diseases include kinase gain- and loss-of-function mutations, gene amplifications and deletions, splicing changes, and translocations (Wilson LJ, et al. New Perspectives, Opportunities, and Challenges in Exploring the Human Protein Kinome. Cancer Res.2018, 78:15-29). The critical role of kinases in cancer and other diseases makes them attractive targets for drug inventions with 62 small molecule kinase inhibitors have been approved and 55 of them for cancer targeted therapies (Roskoski R Jr, Properties of FDA-approved Small Molecule Protein Kinase Inhibitors: A 2021 Update. Pharmacol Res 2021, 165:105463). Although kinase inhibitors have achieved dramatic success in cancer targeted therapies, the development of treatment resistance has remained as a challenge for small molecule kinase inhibitors. Acquired secondary mutations within kinase domain during the treatment often lead to treatment resistance to kinase inhibitors (Pottier C, et al. Tyrosine Kinase Inhibitors in Cancer: Breakthrough and Challenges of Targeted Therapy. Cancers (Basel), 2020, 12:731). Resistance can also arise from subpopulations of tolerant / persister cells that survive in the presence of the treatment. Different processes contribute to the emergence of tolerant persister cells, including pathway rebound through the83573-420992 release of negative feedback loops, transcriptional rewiring mediated by chromatin remodeling and autocrine / paracrine communication among tumor cells and within the tumor microenvironment (Swayden M, et al. Tolerant / Persister Cancer Cells and the Path to Resistance to Targeted Therapy. Cells 2020, 9, 2601). Therefore, it is necessary to invent kinase inhibitors that can target not only the kinase oncogenic drivers, overcome most frequent resistance mutations, but also tolerant persister cancer cells for overcoming resistance, achieving better efficacy and longer disease control.

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

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

[0006] wherein R1,X7, m, n, p, and“ ” are as described herein.

[0007] In some embodiments, the disclosure provides a compound of the formula II, or a pharmaceutically acceptable salt thereof,83573-420992

[0008] wherein R1, X6, X7, Y, Y1, m, n, q,and “ ” are as

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

[0010] wherein R1,n, p, and “ ” areas described herein.

[0011] In some embodiments, the disclosure provides a compound of the formula IV, or a pharmaceutically acceptable salt thereof,83573-420992or a pharmaceutically acceptable salt thereof,

[0014] wherein R1,n, p, and “ ” areas described herein.

[0015] In some embodiments, the disclosure provides a compound of the formula VI, or a pharmaceutically acceptable salt thereof,83573-420992

[0016] wherein R1, X7, Y, Y1, m, n, q, and“ ” are as

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

[0018] wherein R1,Z2, Z3, m, n, p, and“ ” are as described herein.

[0019] In some embodiments, the disclosure provides a compound of the formula VIII, or a pharmaceutically acceptable salt thereof,83573-420992

[0020] wherein R1, X7, Y, Y1, Z1, Z2, Z3, m,n, q, and “ ” are as

[0021] In further aspects, the disclosure relates to a pharmaceutical composition comprising at least one compound of Formula (I)-(VIII) or a pharmaceutically acceptable salt thereof. Pharmaceutical compositions according to the disclosure may further comprise a pharmaceutically acceptable excipient.

[0022] In further aspects, the disclosure relates to a compound of Formula (I)-(VIII), or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0023] 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)-(VIII), or a pharmaceutically acceptable salt thereof.

[0024] In further aspects, the disclosure relates to use of a compound of Formula (I)-(VIII), 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.

[0025] 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)-(VIII), 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.

[0026] 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 in83573-420992 connection with any other embodiments described herein to the extent that the embodiments do not contradict one another.

[0027] 1. A compound of the formula I

[0028] wherein

[0029] A is a 5- to 10-membered heteroarylene or C6-C10 arylene;

[0030] B is a 5- to 10-membered heteroarylene or C6-C10arylene;

[0031] C / D is a 9-membered bicyclic heteroarylene, wherein

[0032] X1is C(R5), N(R6), or N;

[0033] X2is C(R7), N(R8), or N;

[0034] X3is C or N;

[0035] X4is C or N;

[0036] X5is C(R9) or N;

[0037] X6is C(R10) or N; and

[0038] X7is C(R11) or N; provided that at least one of X1to X7is a nitrogen atom and one of X1or X2is a carbon atom;

[0039] 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;

[0040] 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-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,83573-420992 -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-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-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;

[0041] each of R3and R4is independently H, deuterium, halogen, C1-C6alkyl, 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-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;

[0042] 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-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,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,83573-420992 -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;

[0043] 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;

[0044] each R12and R13, when present, is independently H, deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRb)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaC(=NRb)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(=NRb)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; or two of R12and R13, taken together with the carbon or carbons to which they are attached, combine to form C3-C6 cycloalkyl or 3- to 7-membered heterocycloalkyl; wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;

[0045] 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-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently83573-420992 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;

[0046] 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-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-C6alkyl)2, -S(O)2N(C2-C6alkylene), -N(H or C1-C6alkyl)2, -N(C2-C6alkylene), -N(H or C1-C6 alkyl)C(O)-(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)C(O)O(H or C1- C6 alkyl), -N(H or C1-C6 alkyl)C(O)N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)C(O)N(C2-C6 alkylene), -N(H or C1-C6 alkyl)S(O)-(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)S(O)2(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)S(O)N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)S(O)N(C2-C6 alkylene), -N(H or C1-C6alkyl)S(O)2N(H or C1-C6alkyl)2, -N(H or C1-C6alkyl)S(O)2N(C2-C6alkylene), -C(O)-(H or C1-C6 alkyl), -C(O)O(H or C1-C6 alkyl), -C(O)N(C2-C6 alkylene), -P(H or C1-C6alkyl)2, -P(C2-C6alkylene), -P(O)(H or C1-C6alkyl)2, -P(O)(C2-C6alkylene), -P(O)2(H or C1-C6 alkyl)2, -P(O)2(C2-C6 alkylene), -P(O)N(H or C1-C6 alkyl)2, -P(O)N(C2-C6 alkylene), -P(O)2N(H or C1-C6alkyl)2, -P(O)2N(C2-C6alkylene), -P(O)O(H or C1-C6alkyl), -P(O)2O(H or C1-C6 alkyl), -CN, or -NO2;

[0047] m is 0, 1, 2, 3, or 4;

[0048] n is 0, 1, 2, 3, or 4; and

[0049] p is 3, 4, 5, 6, 7, or 8;83573-420992

[0050] or a pharmaceutically acceptable salt thereof.

[0051] 2. The compound of clause 1, or a pharmaceutically acceptable salt thereof, having the formula II

[0052] wherein

[0053] each of Y and Y1is 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-;

[0054] 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)-;

[0055] L2is a bond, -C(R12)(R13)-, -C(R12)(R13)-C(R12)(R13)-, or -C(R12)(R13)-C(R12)(R13)- C(R12)(R13)-; and

[0056] q is 0, 1, or 2.

[0057] 3. The compound of clause 1, having the formula III

[0058] or a

[0059] 4. The compound of any one of the preceding clauses, having the formula IV83573-420992

[0060] or a

[0061] 5. The

[0062] or a

[0063] 6. The compound of any one of clauses 1, 2, or 5, having the formula VI83573-420992

[0064] or a pharmaceutically acceptable salt thereof.

[0065] 7. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein ring C / D is of the formula or”represents a point of covalent attachment.one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein ring A in the portion

[0068] is a 5- or 6-membered” represents a point of covalentattachment.

[0069] 9. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein ring A in the portion

[0070] is a 5- or 6-memberedthe group consisting of ,83573-420992 ,of covalent attachment.or a pharmaceuticallyacceptable salt thereof, and m is 1 or 2.

[0073] 11. The compound of any one of the preceding clauses, 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, -O-CH2-CN, -O-CH2CH2- CN, 2-pyrrolidinyleth-1-yl, or 4-piperidinyl.

[0074] 12. The compound of any one of the preceding clauses, 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, -O-CH2-CN, 2-pyrrolidinyleth-1-yl, or 4-piperidinyl.

[0075] 13. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein ring A in the portion is a 5- or 6-memberedconsisting of ,,83573-420992 ,

[0077] 14. The compound of any one of clauses 1 to 7, or a pharmaceutically acceptable salt thereof, wherein ring A in the portion

[0078] is a C6-C10 arylene, m is” represents a point of covalentattachment.

[0079] 15. The compound of any one of clauses 1 to 7, or 14, or a pharmaceutically acceptable salt thereof, wherein ring A in the portion

[0080] is a phenylene, m is 0,” represents a point of covalent83573-420992 attachment.

[0081] 16. The compound of any one of clauses 1 to 7, 14, or 15, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2.

[0082] 17. The compound of any one of clauses 1 to 7, or 14 to 16, 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.

[0083] 18. The compound of any one of clauses 1 to 7, or 14 to 17, or a pharmaceutically acceptable salt thereof, wherein ring A in the portion

[0084] is selected from the, ,83573-420992 ,

[0085]

[0086] acceptable salt thereof, wherein ring B in the portion

[0087] is a 5- or 6-memberedor 2, and each “ ” represents apoint of covalent attachment.

[0088] 20. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein ring B in the portion

[0089] is a 5- or 6-memberedthe group consisting of ,83573-420992 ,

[0090] wherein n is 0, 1, or 2, and a point of covalent attachment.

[0091] 21. The compound of any one clauses, or a pharmaceuticallyacceptable salt thereof, wherein each present and bonded to carbon, is independently fluoro, chloro, methyl, ethyl, methoxy, ethoxy, 2-fluoroeth-1-yl, 2,2-difluoroeth-1-yl, or methoxymethyl.

[0092] 22. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein each R2, when present and bonded to nitrogen, is independently methyl or ethyl.

[0093] 23. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein ring B in the portion ,24. The compound of any one of clauses 1 to 18, or a pharmaceutically acceptable salt thereof, wherein ring B in the portion83573-420992

[0096] is a C6-C10 arylene, m is ” represents a point of covalentattachment.

[0097] 25. The compound of any one of clauses 1 to or or a pharmaceutically acceptable salt thereof, wherein ring B in the portion

[0098] is a phenylene, m is 0, 1, ” represents a point of covalentattachment.

[0099] 26. The compound of any one of clauses 2, 4, or 6 to 25, 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)-.

[0100] 27. The compound of any one of clauses 2, 4, or 6 to 26, 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.

[0101] 28. The compound of any one of clauses 2, 4, or 6 to 27, 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.

[0102] 29. The compound of any one of clauses 2, 4, or 6 to 28, or a pharmaceutically acceptable salt thereof, wherein q, when present, is 1.

[0103] 30. The compound of any one of clauses 2, 4, or 6 to 29, or a pharmaceutically acceptable salt thereof, wherein L1, when present, is -C(R12)(R13)-C(R12)(R13)-.

[0104] 31. The compound of any one of clauses 2, 4, or 6 to 28, or a pharmaceutically acceptable salt thereof, wherein q, when present, is 2.

[0105] 32. The compound of any one of clauses 2, 4, or 6 to 28, or 31, 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)-.83573-420992

[0106] 33. The compound of any one of clauses 2, 4, or 6 to 32, or a pharmaceutically acceptable salt thereof, wherein Y, when present, is -O-.

[0107] 34. The compound of any one of clauses 2, 4, or 6 to 32, or a pharmaceutically acceptable salt thereof, wherein Y, when present, is -N(R14)C(O)-.

[0108] 35. The compound of any one of clauses 2, 4, or 6 to 32, or a pharmaceutically acceptable salt thereof, wherein Y, when present, is a bond.

[0109] 36. The compound of any one of clauses 2, 4, or 6 to 35, or a pharmaceutically acceptable salt thereof, wherein each Y1, when present, is independently -O- or -N(R14)-.

[0110] 37. The compound of any one of clauses 2, 4, or 6 to 36, or a pharmaceutically acceptable salt thereof, wherein each L2, when present, is a bond.

[0111] 38. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein -(L)p- or -L2-(Y1-L1)q-Y is of the formula ,83573-420992

[0113] 39. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R3is H or deuterium.

[0114] 40. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R4is H or deuterium.

[0115] 41. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R5, when present, is H or deuterium.

[0116] 42. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R6, when present, is H, deuterium, or C1-C6 alkyl.

[0117] 43. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R7, when present, is H or deuterium.

[0118] 44. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R8, when present, is H, deuterium, or C1-C6 alkyl.

[0119] 45. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R9, when present, is H or deuterium.

[0120] 46. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R10, when present, is H or deuterium.

[0121] 47. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R11, when present, is H, deuterium, halogen, C1-C6alkyl, or -NRaRb.

[0122] 48. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R14, when present, is H or C1-C6 alkyl.

[0123] 49. The compound of clause 1, selected from the group consisting of

[0124] (2S)-1-[(10S,17E)-12-ethyl-6-(methoxymethyl)-8,10-dimethyl-16-[(propan-2- yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-(azenometheno)dipyrazolo[3,4-f:4',3'- n]pyrrolo[3,4-j][1,4]oxazacyclopentadecin-14-yl]propan-2-ol;

[0125] (2S)-1-[(11S,18E)-13-ethyl-9,11-dimethyl-17-[(propan-2-yl)oxy]-11,12,13,14- tetrahydro-9H,15H-3,6-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-2-ol;

[0126] (2S)-2-[(11S,18E)-17-ethoxy-7,9,11,13-tetramethyl-11,12,13,14-tetrahydro-9H,15H- 3,6-ethenoimidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11,12]oxatriazacyclopentadecin-15- yl]propan-1-ol;

[0127] (2S)-1-[(11S,18E)-13-ethyl-7-(methoxymethyl)-9,11-dimethyl-17-[(propan-2- yl)oxy]-11,12,13,14-tetrahydro-9H,15H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4- f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-2-ol;

[0128] (2S)-1-{(11S,18E)-13-ethyl-7-(methoxymethyl)-9,11-dimethyl-17-[(propan-2-83573-420992 yl)oxy]-11,12,13,14-tetrahydro-9H,15H-3,6-ethenoimidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl}propan-2-ol;

[0129] (18E)-17-ethyl-9,13,15-trimethyl-12,13-dihydro-9H,11H-3,6-ethenoimidazo[5,1- j]dipyrazolo[3,4-f:4',3'-n][1,4,11,12]oxatriazacyclopentadecin-14(15H)-one;

[0130] (18E)-17-ethyl-9,13,15-trimethyl-12,13-dihydro-9H,11H-6,3- (azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin- 14(15H)-one;

[0131] (2S)-1-[(11S,18E)-17-ethoxy-7,9,11,13,21-pentamethyl-11,12,13,14-tetrahydro- 9H,15H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-2-ol;

[0132] (2S)-1-{(11S,18E)-13-ethyl-9,11-dimethyl-17-[(propan-2-yl)oxy]-11,12,13,14- tetrahydro-9H,15H-3,6-ethenoimidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl}propan-2-ol;

[0133] (11S,18E)-13-ethyl-7-(methoxymethyl)-9,11,15-trimethyl-17-[(propan-2-yl)oxy]- 12,13,14,15-tetrahydro-9H,11H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-21-amine;

[0134] (11S,18E)-17-ethoxy-13-ethyl-7-(methoxymethyl)-9,11,15-trimethyl-12,13,14,15- tetrahydro-9H,11H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-21-amine;

[0135] 2-[(11S,18E)-17-ethoxy-13-ethyl-9,11-dimethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15- yl]ethan-1-ol;

[0136] (2S)-1-[(11S,18E)-13-ethyl-7-(methoxymethyl)-9,11-dimethyl-17-[(propan-2- yl)oxy]-11,12,13,14-tetrahydro-9H,15H-3,6-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4- f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-2-ol;

[0137] (2S)-2-[(11S,18E)-17-ethoxy-7,9,11,13-tetramethyl-11,12,13,14-tetrahydro-9H,15H- 6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin- 15-yl]propan-1-ol;

[0138] (2S)-2-[(11S,18E)-17-ethoxy-7,9,11,13,21-pentamethyl-11,12,13,14-tetrahydro- 9H,15H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0139] (2S)-1-[(4E,12S)-10-ethyl-16-(methoxymethyl)-12,14-dimethyl-6-[(propan-2- yl)oxy]-9,11,12,14-tetrahydro-1,17-ethenotripyrazolo[3,4-f:4',3'-j:4'',3''- n][1,4]oxazacyclopentadecin-8(10H)-yl]propan-2-ol;

[0140] (2S)-1-[(4E,12S)-10-ethyl-12,14-dimethyl-6-[(propan-2-yl)oxy]-9,11,12,14-83573-420992 tetrahydro-1,17-ethenotripyrazolo[3,4-f:4',3'-j:4'',3''-n][1,4]oxazacyclopentadecin-8(10H)- yl]propan-2-ol;

[0141] 2-[(11S,18E)-21-amino-17-ethoxy-13-ethyl-9,11-dimethyl-11,12,13,14-tetrahydro- 9H,15H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]ethan-1-ol;

[0142] 2-[(11S,18E)-21-amino-17-ethoxy-13-ethyl-9,11-dimethyl-11,12,13,14-tetrahydro- 9H,15H-3,6-ethenoimidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin- 15-yl]ethan-1-ol;

[0143] (11S,18E)-13-ethyl-9,11,15-trimethyl-17-[(propan-2-yl)oxy]-12,13,14,15-tetrahydro- 9H,11H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-21-amine;

[0144] (11S,18E)-13-ethyl-9,11,15-trimethyl-17-[(propan-2-yl)oxy]-12,13,14,15-tetrahydro- 9H,11H-3,6-ethenoimidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin- 21-amine;

[0145] (11S,18E)-17-ethoxy-13-ethyl-7,9,11,15-tetramethyl-12,13,14,15-tetrahydro-9H,11H- 6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin- 21-amine;

[0146] (11S,18E)-17-ethoxy-7,9,11,13,15-pentamethyl-12,13,14,15-tetrahydro-9H,11H-6,3- (azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-21- amine;

[0147] (11S,18E)-9,11,13,15-tetramethyl-17-[(propan-2-yl)oxy]-12,13,14,15-tetrahydro- 9H,11H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-21-amine;

[0148] (11S,18E)-7-(methoxymethyl)-9,11,13,15-tetramethyl-17-[(propan-2-yl)oxy]- 12,13,14,15-tetrahydro-9H,11H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-21-amine;

[0149] 2-[(11S,18E)-21-amino-7-(methoxymethyl)-9,11,13-trimethyl-17-[(propan-2-yl)oxy]- 11,12,13,14-tetrahydro-9H,15H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]ethan-1-ol;

[0150] 2-[(11S,18E)-21-amino-9,11,13-trimethyl-17-[(propan-2-yl)oxy]-11,12,13,14- tetrahydro-9H,15H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]ethan-1-ol;

[0151] (11S,18E)-13-ethyl-7-(methoxymethyl)-9,11,15,17-tetramethyl-12,13,14,15- tetrahydro-9H,11H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-21-amine;83573-420992

[0152] (11S,18E)-21-amino-13-ethyl-7-(methoxymethyl)-9,11,15-trimethyl-12,13,14,15- tetrahydro-9H,11H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecine-17-carbonitrile;

[0153] [(11S,18E)-21-amino-13-ethyl-7-(methoxymethyl)-9,11-dimethyl-17-[(propan-2- yl)oxy]-11,12,13,14-tetrahydro-9H,15H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4- f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15-yl]acetonitrile;

[0154] (2R)-1-[(11S,18E)-21-amino-13-ethyl-7-(methoxymethyl)-9,11-dimethyl-17- [(propan-2-yl)oxy]-11,12,13,14-tetrahydro-9H,15H-6,3-(azenometheno)imidazo[5,1- j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-2-ol;

[0155] (2S)-1-[(11S,18E)-21-amino-13-ethyl-7-(methoxymethyl)-9,11-dimethyl-17- [(propan-2-yl)oxy]-11,12,13,14-tetrahydro-9H,15H-6,3-(azenometheno)imidazo[5,1- j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-2-ol;

[0156] 2-[(11S,18E)-21-amino-17-ethoxy-7,9,11,13-tetramethyl-11,12,13,14-tetrahydro- 9H,15H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]ethan-1-ol; and

[0157] 2-[(11S,18E)-21-amino-17-ethoxy-7-(methoxymethyl)-9,11,13-trimethyl- 11,12,13,14-tetrahydro-9H,15H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]ethan-1-ol;

[0158] or a pharmaceutically acceptable salt thereof.

[0159] 50. The compound of clause 1, selected from the group consisting of

[0160] (2S)-2-[(11S,18E)-17-ethoxy-7,9,11,13-tetramethyl-11,12,13,14-tetrahydro-9H,15H- 6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin- 15-yl]propan-1-ol;

[0161] (2S)-1-[(11S,18E)-7-(methoxymethyl)-9,11-dimethyl-17-[(propan-2-yl)oxy]- 11,12,13,14-tetrahydro-9H,15H-3,6-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-2-ol;

[0162] (2S)-1-[(11S,18E)-13-ethyl-7-(methoxymethyl)-9,11-dimethyl-17-[(propan-2- yl)oxy]-11,12,13,14-tetrahydro-9H,15H-3,6-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4- f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-2-ol;

[0163] (2S)-1-{(11S,18E)-13-ethyl-7-(methoxymethyl)-9,11-dimethyl-17-[(propan-2- yl)oxy]-11,12,13,14-tetrahydro-9H,15H-3,6-ethenoimidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl}propan-2-ol;

[0164] (2S)-2-[(11S,18E)-17-ethoxy-7,9,11,13,21-pentamethyl-11,12,13,14-tetrahydro- 9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;83573-420992

[0165] (19E)-9-methyl-12,13-dihydro-9H,11H-6,3-(azenometheno)imidazo[1,2- j]pyrazolo[3,4-f][1,5,10]benzodioxazacyclopentadecine;

[0166] (19E)-9-methyl-12,13-dihydro-9H,11H-3,6-ethenoimidazo[1,2-j]pyrazolo[3,4- f][1,5,10]benzodioxazacyclopentadecine;

[0167] (17E)-16-ethyl-8,12,14-trimethyl-8,11,12,14-tetrahydro-3,5-ethenoimidazo[4,5- j]dipyrazolo[3,4-f:4',3'-n][1,4]oxazacyclopentadecin-13(10H)-one;

[0168] (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12-tetramethyl-10,11,12,13-tetrahydro-5,3- (azenometheno)imidazo[4,5-j]dipyrazolo[3,4-f:4',3'-n][1,4]oxazacyclopentadecin-14(8H)- yl]propan-1-ol;

[0169] (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-10,11,12,13-tetrahydro-5,3- (azenometheno)imidazo[4,5-j]dipyrazolo[3,4-f:4',3'-n][1,4]oxazacyclopentadecin-14(8H)- yl]propan-1-ol;

[0170] (18E)-8-methyl-11,12-dihydro-8H,10H-5,3- (azenometheno)imidazo[4',5':10,11][1,5]benzodioxacyclopentadecino[6,7-c]pyrazole;

[0171] (18E)-8-methyl-11,12-dihydro-8H,10H-3,5- ethenoimidazo[4',5':10,11][1,5]benzodioxacyclopentadecino[6,7-c]pyrazole;

[0172] (2S)-2-[(11S,18E)-17-ethoxy-9,11,13-trimethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15- yl]propan-1-ol;

[0173] (2S)-2-[(11S,18E)-17-ethoxy-9,11,13,21-tetramethyl-11,12,13,14-tetrahydro-9H,15H- 6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin- 15-yl]propan-1-ol;

[0174] (11S,18E)-9,11,13,15,17-pentamethyl-12,13,14,15-tetrahydro-9H,11H-6,3- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecine;

[0175] 2-[(11S,18E)-17-ethoxy-13-ethyl-9,11-dimethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15- yl]ethan-1-ol;

[0176] (2S)-2-[(11S,18E)-17-ethoxy-13-ethyl-9,11-dimethyl-11,12,13,14-tetrahydro- 9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol; and

[0177] (18E)-17-ethyl-9,13,15-trimethyl-12,13-dihydro-9H,11H-6,3- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin- 14(15H)-one

[0178] or a pharmaceutically acceptable salt thereof.

[0179] 51. The compound of clause 1, selected from the group consisting of83573-420992

[0180] 2-[(11S,18E)-21-amino-17-ethoxy-9,11,13-trimethyl-11,12,13,14-tetrahydro- 9H,15H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]ethan-1-ol;

[0181] (2S)-2-[(11S,18E)-17-ethoxy-13-ethyl-7,9,11-trimethyl-11,12,13,14-tetrahydro- 9H,15H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0182] (2S)-1-[(11S,18E)-17-ethoxy-7,9,11,13-tetramethyl-11,12,13,14-tetrahydro-9H,15H- 6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin- 15-yl]propan-2-ol;

[0183] (2S)-2-[(11S,18E)-17-ethoxy-7-(methoxymethyl)-9,11,13-trimethyl-11,12,13,14- tetrahydro-9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0184] 2-[(11S,18E)-17-ethoxy-9,11,13-trimethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15- yl]ethan-1-ol;

[0185] {[(11S,18E)-15-[(2S)-1-hydroxypropan-2-yl]-7,9,11,13-tetramethyl-12,13,14,15- tetrahydro-9H,11H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-17-yl]oxy}acetonitrile;

[0186] (2S)-2-[(11S,18E)-17-ethoxy-13-ethyl-7-(methoxymethyl)-9,11-dimethyl- 11,12,13,14-tetrahydro-9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0187] (2S)-1-[(11S,18E)-17-ethoxy-9,11,13-trimethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15- yl]propan-2-ol;

[0188] {[(11S,18E)-13-ethyl-15-[(2S)-1-hydroxypropan-2-yl]-7,9,11-trimethyl-12,13,14,15- tetrahydro-9H,11H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-17-yl]oxy}acetonitrile;

[0189] 2-[(11S,18E)-7,9,11,13,21-pentamethyl-11,12,13,14-tetrahydro-9H,16H-6,3- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-16- yl]ethan-1-ol;

[0190] (11S,18E)-7,9,11,13,16,21-hexamethyl-12,13,14,16-tetrahydro-9H,11H-6,3- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecine;

[0191] (2S)-1-[(11S,18E)-17-ethoxy-7-(methoxymethyl)-9,11,13-trimethyl-11,12,13,14- tetrahydro-9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-2-ol;83573-420992

[0192] (11S,18E)-7,9,11,13,21-pentamethyl-16-[2-(pyrrolidin-1-yl)ethyl]-12,13,14,16- tetrahydro-9H,11H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecine;

[0193] (2S)-2-[(11S,18E)-17-ethoxy-13-ethyl-7,9,11-trimethyl-11,12,13,14-tetrahydro- 9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0194] (2S)-2-[(11S,18E)-17-ethoxy-13-ethyl-7,9,11-trimethyl-11,12,13,14-tetrahydro- 9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0195] (2R)-1-[(11S,18E)-17-ethoxy-7-(methoxymethyl)-9,11,13-trimethyl-11,12,13,14- tetrahydro-9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-2-ol;

[0196] (11S,19E)-7,9,11,13-tetramethyl-11,12,13,14-tetrahydro-9H-6,3- (azenometheno)imidazo[1,2-j]pyrazolo[3,4-f][5,2,10]benzoxadiazacyclopentadecine;

[0197] 2-[(11S,18E)-7,9,11,13-tetramethyl-11,12,13,14-tetrahydro-9H,16H-6,3- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-16- yl]ethan-1-ol;

[0198] (11S,18E)-7,9,11,13,16-pentamethyl-12,13,14,16-tetrahydro-9H,11H-6,3- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecine;

[0199] (11S,18E)-7,9,11,13-tetramethyl-16-[2-(pyrrolidin-1-yl)ethyl]-12,13,14,16- tetrahydro-9H,11H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecine;

[0200] (11S,19E)-9,11,13-trimethyl-11,12,13,14-tetrahydro-9H-6,3- (azenometheno)imidazo[1,2-j]pyrazolo[3,4-f][5,2,10]benzoxadiazacyclopentadecine;

[0201] (2S)-2-[(12R,18E)-17-ethoxy-9,11,12,13-tetramethyl-11,12,13,14-tetrahydro- 9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0202] (2S)-2-[(11S,18E)-17-ethoxy-13-ethyl-7,9,11,21-tetramethyl-11,12,13,14-tetrahydro- 9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0203] (2S)-2-[(11S,18E)-17-ethoxy-13-ethyl-7-(methoxymethyl)-9,11,21-trimethyl- 11,12,13,14-tetrahydro-9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0204] {[(11S,18E)-13-ethyl-15-[(2S)-1-hydroxypropan-2-yl]-7,9,11,21-tetramethyl- 12,13,14,15-tetrahydro-9H,11H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-83573-420992 n][1,4,11]oxadiazacyclopentadecin-17-yl]oxy}acetonitrile;

[0205] (2S)-2-[(8aR,9S,20E)-1-ethoxy-9,11,13-trimethyl-7,8,8a,9-tetrahydro-6H,11H-14,17- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n]pyrrolo[2,1- c][1,4,11]oxadiazacyclopentadecin-3(4H)-yl]propan-1-ol;

[0206] (2S)-2-[(8aR,9R,20E)-1-ethoxy-9,11,13-trimethyl-7,8,8a,9-tetrahydro-6H,11H-14,17- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n]pyrrolo[2,1- c][1,4,11]oxadiazacyclopentadecin-3(4H)-yl]propan-1-ol;

[0207] (2S)-2-[(11S,12R,18E)-17-ethoxy-7-(methoxymethyl)-9,11,12,13-tetramethyl- 11,12,13,14-tetrahydro-9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0208] (18E)-17-ethyl-9,13,15-trimethyl-12,13-dihydro-9H,11H-3,6-ethenoimidazo[2,1- j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-14(15H)-one;

[0209] (2S)-2-[(8aR,9S,20E)-1-ethoxy-9,11-dimethyl-7,8,8a,9-tetrahydro-6H,11H-14,17- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n]pyrrolo[2,1- c][1,4,11]oxadiazacyclopentadecin-3(4H)-yl]propan-1-ol;

[0210] (2S)-2-[(8aR,9R,20E)-1-ethoxy-9,11-dimethyl-7,8,8a,9-tetrahydro-6H,11H-14,17- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n]pyrrolo[2,1- c][1,4,11]oxadiazacyclopentadecin-3(4H)-yl]propan-1-ol;

[0211] (2S)-2-[(12S,19E)-18-ethoxy-12,14-dimethyl-12,13,14,15-tetrahydro-16H-6,3- (azenometheno)imidazo[2,1-j]pyrazolo[3,4-f]pyrido[3,4-n][1,4,11]oxadiazacyclopentadecin- 16-yl]propan-1-ol;

[0212] (2S)-2-[(11S,12R,18E)-17-ethoxy-7-(methoxymethyl)-9,11,12,13,21-pentamethyl- 11,12,13,14-tetrahydro-9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0213] (2S)-2-[(11S,12R,18E)-17-ethoxy-7,9,11,12,13,21-hexamethyl-11,12,13,14- tetrahydro-9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0214] (2S)-2-[(11R,12R,18E)-17-ethoxy-7,9,11,12,13,21-hexamethyl-11,12,13,14- tetrahydro-9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0215] (2S)-2-[(11S,12R,18E)-17-ethoxy-7,9,11,12,13-pentamethyl-11,12,13,14-tetrahydro- 9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0216] (2S)-2-[(8aR,9S,20E)-1-ethoxy-9,11,13,22-tetramethyl-7,8,8a,9-tetrahydro-6H,11H- 14,17-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n]pyrrolo[2,1-83573-420992 c][1,4,11]oxadiazacyclopentadecin-3(4H)-yl]propan-1-ol;

[0217] (18E)-9,13,15-trimethyl-12,13,14,15-tetrahydro-9H,11H-6,3- (azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-21- amine;

[0218] (18E)-8,13,15-trimethyl-12,13,14,15-tetrahydro-8H,11H-6,3- (azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-21- amine;

[0219] (18E)-17-ethoxy-8,13,15-trimethyl-12,13,14,15-tetrahydro-8H,11H-6,3- (azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-21- amine;

[0220] (2S)-2-[(11S,18E)-13-(2,2-difluoroethyl)-17-ethoxy-7,9,11-trimethyl-11,12,13,14- tetrahydro-9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0221] {[(11S,18E)-13-(2,2-difluoroethyl)-15-[(2S)-1-hydroxypropan-2-yl]-7,9,11-trimethyl- 12,13,14,15-tetrahydro-9H,11H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-17-yl]oxy}acetonitrile;

[0222] (2S)-2-[(11S,18E)-13-cyclopropyl-17-ethoxy-7,9,11-trimethyl-11,12,13,14- tetrahydro-9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0223] {[(11S,18E)-13-cyclopropyl-15-[(2S)-1-hydroxypropan-2-yl]-7,9,11-trimethyl- 12,13,14,15-tetrahydro-9H,11H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-17-yl]oxy}acetonitrile;

[0224] (2S)-2-[(11S,18E)-17-ethoxy-13-ethyl-7,11-dimethyl-11,12,13,14-tetrahydro-15H- 6,3-(azenometheno)imidazo[2,1-j]pyrazolo[3,4-f][1,2]thiazolo[4,5- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0225] (2S)-2-[(11S,18E)-17-ethoxy-13-ethyl-7,11-dimethyl-11,12,13,14-tetrahydro-15H- 6,3-(azenometheno)imidazo[2,1-j][1,2]oxazolo[4,5-n]pyrazolo[3,4- f][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0226] (2S)-2-[(11S,18E)-17-ethoxy-13-ethyl-7,9,11-trimethyl-11,12,13,14-tetrahydro- 9H,15H-6,3-(azenometheno)imidazo[2,1-j]pyrazolo[3,4-f]pyrrolo[3,2- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0227] (2S)-2-[(11S,18E)-17-ethoxy-9,13-diethyl-7,11-dimethyl-11,12,13,14-tetrahydro- 9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0228] (2S)-2-[(11S,18E)-17-ethoxy-7,13-diethyl-9,11-dimethyl-11,12,13,14-tetrahydro-83573-420992 9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0229] (11S,18E)-7-(methoxymethyl)-9,11,13,16-tetramethyl-12,13,14,16-tetrahydro- 9H,11H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecine;

[0230] (11S,18E)-7-(methoxymethyl)-9,11,13,16,17-pentamethyl-12,13,14,16-tetrahydro- 9H,11H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecine;

[0231] (11S,18E)-7-(methoxymethyl)-9,11,13,15,17-pentamethyl-12,13,14,15-tetrahydro- 9H,11H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecine; and

[0232] (2S)-2-[(11S,18E)-7-(2,2-difluoroethyl)-17-ethoxy-13-ethyl-9,11-dimethyl- 11,12,13,14-tetrahydro-9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0233] or a pharmaceutically acceptable salt thereof.

[0234] 52. A pharmaceutical composition comprising a compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, and optionally one or more excipients.

[0235] 53. A method of treating disease in a subject comprising, administering a therapeutically effective amount of a compound of any one of clauses 1 to 51, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of clauses 52.

[0236] 54. A compound according to any one of clauses 1 to 51, or a pharmaceutically acceptable salt thereof, for use in a method of treating disease in a subject.

[0237] 55. Use of a compound according to any one of clauses 1 to 51, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of disease in a subject. DETAILED DESCRIPTION

[0238] 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.

[0239] 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 of83573-420992 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.

[0240] 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.

[0241] As used herein, the terms “including,” “containing,” and “comprising” are used in their open, non-limiting sense.

[0242] 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.

[0243] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited.

[0244] 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 Advanced83573-420992 Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, 2001.

[0245] 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.).

[0246] 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

[0247] As described herein, a “macrocycle” is a compound comprising a continuous chain of at least 12 atoms connected to form a ring, in which the continuous chain of atoms includes but is not limited to C, N, O, and S. The continuous chain of at least 12 atoms that forms a macrocycle, as described herein, can be counted along the shortest path in the chain of atoms within the ring. For example, in compounds of the Formula I, as described herein, the continuous chain of at least 12 atoms in the macrocycle ring can be counted starting from the 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 atom that served as the starting point.

[0248] 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” or83573-420992 “alkylene” to a specific range of atoms, such as C1-C20 alkyl or C1-C20 alkylene, C1-C12 alkyl or C1-C12 alkylene, or C1-C6 alkyl or C1-C6 alkylene. Examples of alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples. Examples of alkylene groups include methylene (-CH2-), ethylene ((-CH2-)2), n- propylene ((-CH2-)3), iso-propylene ((-C(H)(CH3)CH2-)), n-butylene ((-CH2-)4), and the like. It will be appreciated that an alkyl or alkylene group can be unsubstituted or substituted as described herein. An alkyl or alkylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0249] The term “alkenyl” refers to a straight- or branched-chain mono-valent hydrocarbon group having one or more double bonds. The term “alkenylene” refers to a straight- or branched-chain di-valent hydrocarbon group having one or more double bonds. In some embodiments, it can be advantageous to limit the number of atoms in an “alkenyl” or “alkenylene” to a specific range of atoms, such as C2-C20 alkenyl or C2-C20 alkenylene, C2-C12 alkenyl or C2-C12alkenylene, or C2-C6alkenyl or C2-C6alkenylene. 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.

[0250] The term “alkynyl” refers to a straight- or branched-chain monovalent hydrocarbon group having one or more triple bonds. The term “alkynylene” refers to a straight- or branched- chain divalent hydrocarbon group having one or more triple bonds. In some embodiments, it can be advantageous to limit the number of atoms in an “alkynyl” or “alkynylene” to a specific range of atoms, such as C2-C20 alkynyl or C2-C20 alkynylene, C2-C12 alkynyl or C2-C12 alkynylene, or C2-C6alkynyl or C2-C6alkynylene. Examples of alkynyl groups include acetylenyl (-C≡CH) and propargyl (-CH2C≡CH), but-3-yn-1,4-diyl (-C≡C-CH2CH2-), and the like. It will be appreciated that an alkynyl or alkynylene group can be unsubstituted or substituted as described herein. An alkynyl or alkynylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.83573-420992

[0251] The term “cycloalkyl” refers to a saturated or partially saturated, monocyclic or polycyclic mono-valent carbocycle. The term “cycloalkylene” refers to a saturated or partially saturated, monocyclic or polycyclic divalent carbocycle. In some embodiments, it can be advantageous to limit the number of atoms in a “cycloalkyl” or “cycloalkylene” to a specific range of atoms, such as having 3 to 12 ring atoms. Polycyclic carbocycles include fused, bridged, and spiro polycyclic systems. Illustrative examples of cycloalkyl groups include monovalent radicals of the following entities, while cycloalkylene groups include divalent radicals of the following entities, in the form of properly bonded moieties: ,In particular, a cyclopropyl moiety can be depicted by the structural Inparticular, a cyclopropylene moiety can be depicted by the structural It will be appreciated that a cycloalkyl or cycloalkylene group can beas described herein. A cycloalkyl or cycloalkylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0252] The term “halogen” or “halo” represents chlorine, fluorine, bromine, or iodine.

[0253] 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)-.

[0254] 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 conjugated83573-420992 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.

[0255] The term “heterocycloalkyl” refers to a mono-valent monocyclic or polycyclic ring structure that is saturated or partially saturated having one or more non-carbon ring atoms. The term “heterocycloalkylene” refers to a divalent monocyclic or polycyclic ring structure that is saturated or partially saturated having one or more non-carbon ring atoms. In some embodiments, it can be advantageous to limit the number of atoms in a “heterocycloalkyl” or “heterocycloalkylene” to a specific range of ring atoms, such as from 3 to 12 ring atoms (3- to 12-membered), or 3 to 7 ring atoms (3- to 7-membered), or 3 to 6 ring atoms (3- to 6- membered), or 4 to 6 ring atoms (4- to 6-membered), 5 to 7 ring atoms (5- to 7-membered), or 4 to 10 ring atoms (4- to 10-membered). In some embodiments, it can be advantageous to limit the number and type of ring heteroatoms in “heterocycloalkyl” or “heterocycloalkylene” to a specific range or type of heteroatoms, such as 1 to 5 ring heteroatoms selected from nitrogen, oxygen, and sulfur. Polycyclic ring systems include fused, bridged, and spiro systems. The ring structure may optionally contain an oxo group or an imino group on a carbon ring member or up to two oxo groups on sulfur ring members. Illustrative examples of heterocycloalkyl groups include monovalent radicals of the following entities, while heterocycloalkylene groups include divalent radicals of the following entities, in the form of properly bonded moieties:83573-420992

[0256] 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.

[0257] 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.

[0258] 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 is83573-420992 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: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-liniting 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-liniting examples of five-membered heteroarylene groups include di-valent radicals of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole,83573-420992 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 .

[0260] 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.

[0261] The term “oxo” represents a carbonyl oxygen. For example, a cyclopentyl substituted with oxo is cyclopentanone.

[0262] 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.83573-420992

[0263] 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.

[0264] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as2H,3H,11C,13C,14C,15N,18O,17O,31P,32P,35S,18F,36Cl, and125I, respectively. Such isotopically labelled compounds are useful in metabolic studies (preferably with14C), reaction kinetic studies (with, for example2H or3H), detection or imaging techniques [such as positron emission tomography (PET) or single- photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients. Further, substitution with heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0265] Certain chemical entities of Formula (I)-(VIII) 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.83573-420992

[0266] to a class ofand 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-C3refers independently to embodiments that have one carbon member (C1), embodiments that have two carbon members (C2), and embodiments that have three carbon members (C3).

[0267] 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.

[0268] 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 below83573-420992 where Ra> Rb> Rc

[0269] As used 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 anadjacent chemical group or 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 , ,or , where each of “-*”, “-**”, and “ ” represents aandembodiments, the portionof A-B defined by the group or chemical structure B can be represented by ,,or , where each of “-*”, “-**”, and “ ” represents a and

[0270] 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 ” symbol is located can be either“̶ ̶ ̶̶ ̶̶̶ ̶ ̶ “ or “ ” bonds, and the ” represents the delocalized electrons of π-bondswithin the ring structure. Inmembered heteroarylene described by the structure83573-420992

[0271] where X1is a carbon, are all carbons, can be depicted as either

[0272]

[0273] The disclosure also includes pharmaceutically acceptable salts of the compounds represented by Formula (I)-(VIII), preferably of those described above and of the specific compounds exemplified herein, and pharmaceutical compositions comprising such salts, and methods of using such salts.

[0274] A “pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of a compound represented herein that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S.M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977, 66, 1-19. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of subjects without undue toxicity, irritation, or allergic response. A compound described herein may possess a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one of each type, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.

[0275] 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-2-83573-420992 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.

[0276] For a compound of Formula (I)-(VIII) 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.

[0277] The disclosure also relates to pharmaceutically acceptable prodrugs of the compounds of Formula (I)-(VIII), and treatment methods employing such pharmaceutically acceptable prodrugs. The term “prodrug” means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to the compound of Formula (I)-(VIII)). 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.

[0278] The present disclosure also relates to pharmaceutically active metabolites of compounds of Formula (I)-(VIII), 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)-(VIII) 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.,83573-420992 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

[0279] The present disclosure provides macrocyclic compounds that bind and / or modulate the activity of specific kinases. In some embodiments, the disclosure provides a compound of the formula I, or a pharmaceutically acceptable salt thereof,

[0280] wherein R1, R2, R3, R4, A, B, C, D, L, X1, X2, X3, X4, X5, X6, X7, m, n, p, and“ ” are as described herein.

[0281] In some embodiments, the disclosure provides a compound of the formula II, or a pharmaceutically acceptable salt thereof,

[0282] wherein R1,X6, X7, Y, Y1, m, n, q,and “ ” are as described herein.83573-420992

[0283] In some embodiments, the disclosure provides a compound of the formula III, or a pharmaceutically acceptable salt thereof,

[0284] wherein R1, n, p, and “ ” areas described herein.

[0285] In some embodiments, the disclosure provides a compound of the formula IV, or a pharmaceutically acceptable salt thereof,

[0286] wherein R1, R2, R3, R4, R5, A, B, C, D, L1, L2, X3, X4, X5, X6, X7, Y, Y1, m, n, q, and“ ” are as described herein.

[0287] In some embodiments, the disclosure provides a compound of the formula V, or a pharmaceutically acceptable salt thereof,83573-420992

[0288] wherein R1, n, p, and “ ” areas described

[0289] In some a or a pharmaceutically acceptable salt thereof,

[0290] wherein R1,X7, Y, Y1, m, n, q, and“ ” are as described herein.

[0291] In some embodiments, the disclosure provides a compound of the formula VII, or a pharmaceutically acceptable salt thereof,83573-420992

[0292] wherein R1, Z1, Z2, Z3, m, n, p, and“ ” are as

[0293] In some embodiments, the disclosure provides a compound of the formula VIII, or a pharmaceutically acceptable salt thereof,

[0294] wherein R1,X7, Y, Y1, Z1, Z2, Z3, m,n, q, and “ ” are as described herein.

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

[0296] wherein ring A is asis optionally a carbon-carbon singlebond or a carbon-carbon double bond, each “ ” represents a point of covalentattachment, and R1and m are as described herein.83573-420992

[0297] In some embodiments, ring A is a 5- to 10-membered heteroarylene. In some embodiments, ring A is a 5- or 5-membered heteroarylene. In some embodiments, ring A is a 5-membered heteroarylene. In some embodiments, ring A is a 6-membered heteroarylene.

[0298] 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-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.

[0299] 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-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -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-C6 alkyl, C1-C6 haloalkyl,83573-420992 -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.

[0300] In some embodiments, ring A in the portion is a 5- or 6-membered consisting of,each“ ” represents a point of covalent attachment.

[0302] 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-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, -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,83573-420992 -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.

[0303] In some embodiments, ring A in the portion is a 6-membered heteroarylene of“ ” represents a point of covalent attachment.In some embodiments, ring A is of the formula m

[0306] wherein “ ” isbond 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.

[0307] 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-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, -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 present83573-420992 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-C6 alkyl, 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-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.

[0308] In some embodiments, ring A is of the formula

[0309] wherein “ ” issingle bond or a carbon-carbon doublebond, each “ ” represents a point of covalent attachment, and Y2, Y3, and Y4 are eachindependently -O-, -S-, =C(H)-, =C(R1)-, -N(H)-, -N(R1)- or =N- and ring A is a 5-membered heteroarylene, provided that at least one of Y2, Y3, and Y4is not =C(H)-, or =C(R1)-.

[0310] In some embodiments, ring A is of the formula

[0311] wherein “ ” issingle bond or a carbon-carbon doublebond, each “a point of covalent attachment, Y3, is –O-, -S-, -N(H)-, -N(R1)-or =N-, Y2and Y4are each independently –O-, -S-, =C(H)-, =C(R1)-, -N(H)-, N(R1)- or =N-, and ring A is a 5-membered heteroarylene, provided that at least one of X1, X2, and X3is not =C(H)-, or =C(R1)-, ring A is a 5-membered heteroarylene, and R1and m are as described herein.

[0312] In some embodiments, ring A in the portion83573-420992 is a 5-membered heteroarylene of,

[0313] wherein 0, 1, or 2, and each“ ”

[0314] 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-C10aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, or 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-C6 alkyl, 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, -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.

[0315] 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. In83573-420992 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.

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

[0317] R1 isindependently as described herein.

[0318] In some embodiments, ring A is a 5-membered heteroarylene selected from the group consisting of ,

[0319] isindependently as described herein.83573-420992

[0320] In some embodiments, ring A is a 5-membered heteroarylene selected from the group consisting of ,

[0321] wherein each “ attachment, and each R1 isindependently as described

[0322] In some embodiments, each R1, when present and bonded to a carbon atom, is independently deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRb)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaC(=NRb)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(=NRb)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, and / 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-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.

[0323] 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-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,83573-420992 -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd,-PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2.

[0324] 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-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.

[0325] 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-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.

[0326] 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,83573-420992 -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.

[0327] 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.

[0328] 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, 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, or 4-piperidinyl. 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, 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, or 4-piperidinyl.

[0329] 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, -O-CH2-CN, -O-CH2CH2- CN, 2-pyrrolidinyleth-1-yl, or 4-piperidinyl.83573-420992

[0330] 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, -O-CH2- CN, 2-pyrrolidinyleth-1-yl, or 4-piperidinyl

[0331] In some embodiments, ring A is a 5-membered heteroarylene selected from the group consisting of ,,83573-420992 O N ,

[0332]

[0333] In some embodiments, ring A is a 5-membered heteroarylene selected from the group consisting of ,,,a point of covalent attachment.ring A in the portion83573-420992 is a 5- or 6-membered consisting of,,,83573-420992

[0336] wherein

[0337] In someis a 5- or 6-membered consisting of,,83573-420992

[0338] wherein each “ ” represents a point of covalent attachment.

[0339] In some embodiments, ring A is C6-C10 arylene. In some embodiments, ring A in the portion

[0340] is a C6-C10arylene, each herein, m is 0, 1, 2, or 3, andeach “ ” represents aIn some embodiments, ring A is a phenylene. In some embodiments, ring A in the portion

[0342] is a phenylene, m is 0,” represents a point of covalentattachment.

[0343] 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.

[0344] In some embodiments, each R1, when present, is independently deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRb)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb,to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORc, -OC(O)Rc,83573-420992 -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.

[0345] In some embodiments, ring A in the portion , ,83573-420992 ,

[0346]

[0347] In

[0348] 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-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 each R2, 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 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.

[0349] 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-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,83573-420992 -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.

[0350] In some embodiments, ring B in the portion

[0351] is a 5- or 6-memberedor 2, and each “ ” represents apoint of covalent attachment.

[0352] In some embodiments, ring B is of the formula

[0353] wherein “ ” isbond or a carbon-carbon doublebond, each “ ” represents a point of covalent attachment, and R2 and n are as describedherein.

[0354] In some embodiments, ring B is of the formula83573-420992

[0355] wherein “ ” is bond or a carbon-carbon doublebond, each “ ”ring A is a 5-memberedheteroarylene, and R2and n are as described herein.

[0356] In some embodiments, ring B is of the formula

[0357] wherein each “ ” covale 1 2 3nt attachment, Z , Z , and Z areeach independently -O-, -S-, =C(H)-, =C(R2)-, -N(H)-, -N(R2)- or =N- and ring B is a 5- membered heteroarylene, provided that at least one of Z1, Z2, and Z3is not =C(H)-, or =C(R2)-.

[0358] In some embodiments, ring B is of the formula

[0359] wherein each “ ” 2 1 3covalent attachment, Z is =N-, Z and Zare each independently -O-, -S-, =C(H)-, =C(R2)-, -N(H)-, or -N(R2)-, and ring B is a 5- membered heteroarylene.

[0360] 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-C6 alkyl, 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 each R2,83573-420992 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-C6 alkyl, 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-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.

[0361] In some embodiments, ring B in the portion is a 5- or 6-memberedconsisting of ,

[0363] In some embodiments, ring Bis a 5- or 6-memberedconsisting of83573-420992 ,someembodiments, 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.

[0366] In some embodiments, ring B is a 5-membered heteroarylene selected from the group consisting of ,isindependently as described herein.

[0368] In some embodiments, ring B is a 5-membered heteroarylene selected from the group consisting of83573-420992 ,,

[0370] In some embodiments, each 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, 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, 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. In some embodiments, each R2, when present and bonded to carbon, is independently fluoro, chloro,83573-420992 methyl, ethyl, methoxy, ethoxy, 2-fluoroeth-1-yl, 2,2-difluoroeth-1-yl, or methoxymethyl.

[0371] In some embodiments, each R2, 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. In some embodiments, each R2, when present and bonded to nitrogen, is independently methyl or ethyl.

[0372] In some embodiments, ring B in the portion ,

[0374] In some embodiments, ring B in the portion83573-420992 is selected from the group,somea group consisting of ,

[0378] In some embodiments, ring B is a 5-membered heteroarylene selected from the group consisting of ,83573-420992 In some embodiments, ring B in the portion

[0380] is a C6-C10 arylene, m is ” represents a point ofcovalent attachment.

[0381] In some embodiments, ring B in the portion

[0382] is a phenylene, m is 0, 1, ” represents a point of covalentattachment.

[0383] In some embodiments, each of R3and R4is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-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.

[0384] In some embodiments, each of R3and R4is independently H, deuterium, or C1-C6alkyl. In some embodiments, R3is H or deuterium. In some embodiments, R4is H or deuterium. In some embodiments, R3and R4are H.

[0385] In some embodiments, ring C / D is a 9-membered bicyclic heteroarylene wherein 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(R10) or N; or N; provided that at least one of X1to X7is a nitrogen atom (e.g., N or one of X1or X2is a carbon atom (e.g., CR5or CR7). In some embodiments, some embodiments, X2is C(R7). In some embodiments, X1is N(R6) or N. InX1is N. In some embodiments, X2is N(R8) or N. In some embodiments, X2is N. In some embodiments, one of X1or X2is N. In some embodiments, X183573-420992 is C(R5), and X2is N(R8) or N. In some embodiments, X1is C(R5) and X2is N. In some embodiments, X1is N(R6) or N, and X2is C(R7). In some embodiments, X1is N and X2is C(R7).

[0386] In some embodiments, X3is C or N. In some embodiments, X3is C. In some embodiments, X3is N. In some embodiments, X4is C or N. In some embodiments, X4is C. In some embodiments, X4is N. In some embodiments, X5is C(R9) or N. In some embodiments, X5is C(R9). In some embodiments, X5is N. In some embodiments, X6is C(R10) or N. In some embodiments, X6is C(R10). In some embodiments, X6is N. In some embodiments, X7is C(R11) or N. In some embodiments, X7is C(R11). In some embodiments, X7is N.

[0387] In some embodiments, X3is N, X4is C, X5is C(R9), X6is C(R10), and X7is C(R11). In some embodiments, X3is N, X4is C, X5is N, X6is C(R10), and X7is C(R11). In some embodiments, X3is N, X4is C, X5is C(R9), X6is C(R10), and X7is N. In some embodiments, X3is N, X4is C, X5is C(R9), X6is N, and X7is C(R11). In some embodiments, X3is C, X4is N, X5is C(R9), X6is C(R10), and X7is C(R11). In some embodiments, X3is C, X4is N, X5is C(R9), X6is N, and X7is C(R11). In some embodiments, X3is C, X4is C, X5is C(R9), X6is C(R10), and X7is C(R11). In some embodiments, X3is C, X4is C, X5is C(R9), X6is C(R10), and X7is N. In some embodiments, X3is C, X4is C, X5is C(R9), X6is N, and X7is C(R11).

[0388] In some embodiments, ring C / D is of the formula ,or

[0390] In some embodiments, each of R5, R7, R9, R10, or R11, when present, is independently H, deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to83573-420992 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRb)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaC(=NRb)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(=NRb)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORc, -OC(O)Rc, -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 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.

[0392] 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.

[0393] In some embodiments, R5, 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,83573-420992 -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-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, R5, when present, is H, deuterium, halogen, or C1-C6alkyl. 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.

[0394] 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-C6 alkyl and C3- C6cycloalkyl 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-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,83573-420992 -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, 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-C6alkyl, wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2. In some embodiments, R6, when present, is H, deuterium, C1-C6 alkyl, or C3-C6cycloalkyl. In some embodiments, R6, when present, is H or C1-C6alkyl. 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.

[0396] In some embodiments, R7, when present, is H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRb)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaC(=NRb)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(=NRb)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6 alkyl, C2-C683573-420992 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2. In some embodiments, R7, when present, is H, deuterium, halogen, or C1-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, R7, when present, is H, deuterium, halogen, or C1-C6 alkyl. In some embodiments, R7, when present, is H or deuterium. In some embodiments, R7, when present, is H. In some embodiments, R7, when present, is deuterium.

[0397] In some embodiments, R8, 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-C6 alkyl and C3-C6cycloalkyl 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-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 -NO2.83573-420992

[0398] In some embodiments, R8, 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, R8, when present, is H, deuterium, 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, R8, when present, is H, deuterium, C1-C6alkyl, or C3-C6 cycloalkyl. In some embodiments, R8, when present, is H or C1-C6 alkyl. 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.

[0399] In some embodiments, R9, when present, is H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRb)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaC(=NRb)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(=NRb)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-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,83573-420992 -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.

[0400] In some embodiments, R10, when present, is H, deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRb)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaC(=NRb)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(=NRb)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-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-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,83573-420992 -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-C6 alkyl. 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.

[0401] In some embodiments, R11, 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-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, R11, when present, is H, deuterium, halogen, C1-C6alkyl, or -NRaRb, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2. In some embodiments, R11, when present, is H, deuterium, halogen, C1-C6 alkyl, -NRaRb. In some embodiments, R11, when present, is H or deuterium. In some embodiments, R11, when present, is H. In some embodiments, R11, when present, is deuterium. In some embodiments, R11, when present, is halogen. In some embodiments, R11, when present, is C1-C6alkyl. In some embodiments, R11, when present, is -NRaRb.

[0402] In some embodiments, ring C / D is of the formula83573-420992 ,some p a - -, -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)pis 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.

[0405] 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.

[0406] In some embodiments, (L)p comprises the moieties Y, Y1, L1, and L2. In some embodiments, each of Y and Y1is 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)-83573-420992 C(R12)(R13)-C(R12)(R13)-, wherein one or two of R12is a C1-C6 alkyl, and the remaining R12and R13are H or deuterium. 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)-.

[0407] 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. In some embodiments, each of Y and Y1is independently a bond, -O-, -N(R14)C(O)-, -C(O)N(R14)-, -N(R14)-. In some embodiments, Y is a bond, -O-, -N(R14)C(O)-, -C(O)N(R14)- , -N(R14)-. In some embodiments, Y is a bond, -O-, -N(R14)C(O)-, or -C(O)N(R14)-. In some embodiments, Y is -O- or -N(R14)C(O)-. In some embodiments, Y is -O-. In some embodiments, Y is -N(R14)C(O)-. In some embodiments, Y is -C(O)N(R14)-. In some embodiments, Y is -N(R14)-. In some embodiments, each Y1is independently a bond, -O-, -N(R14)C(O)-, -C(O)N(R14)-, -N(R14)-. In some embodiments, each Y1is independently -O- or -N(R14)-. In some embodiments, each Y1is -O-. In some embodiments, each Y1is -N(R14)-.

[0408] In some embodiments, (L)pis of the formula -L2-(Y1-L1)q-Y-, -(L2-Y1)q-L1-Y-, -L2-(Y1- L1)q-. -(L2-Y1)q-L1-, or -(Y1-L1)q-Y-. In some formula -L2-(Y1-L1)q-Y-. In some embodiments, q is 0, 1, or 2. 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.

[0409] 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-C6 cycloalkyl or 3- to 7-membered heterocycloalkyl; wherein each hydrogen atom in C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf,83573-420992 -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.

[0410] 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.

[0411] 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-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.

[0412] 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,83573-420992 C1-C6 alkyl, 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,.

[0413] In some embodiments, each R14, when present, is independently H, deuterium, -C(O)Rc, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd,-PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2; or 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.

[0414] 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-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl is independently optionally substituted by -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2.

[0415] In some embodiments, each R14, when present, is independently C1-C6alkyl or C3-C6cycloalkyl, wherein each hydrogen atom in C1-C6 alkyl and C3-C6 cycloalkyl is independently optionally substituted by -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc,83573-420992 -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.

[0416] In some embodiments, each R14is independently H, deuterium, C1-C6 alkyl, or C3-C6 cycloalkyl. In some embodiments, each R14, when present, is independently H, C1-C6alkyl, or C3-C6 cycloalkyl. 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.

[0417] In some embodiments, -(L)p- or -L2-(Y1-L1)q-Y is of the formula ,83573-420992

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

[0419] In some embodiments, -(L)p- or -L2-(Y1-L1)q-Y is of the formula ,,is independently optionally substituted with deuterium..

[0421] In some embodiments, the portion -L1-Y- is of the formula ,83573-420992 ,,

[0423] In some embodiments, each Ra, Rb, Rc, Rd, Re, and Rfis independently selected from the group consisting of H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, C1-C6 alkylene-C6-C10 aryl, 5- to 10-membered heteroaryl, C1-C6alkylene-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-C6alkyl, C1-C6haloalkyl, -OH, -OC1-C6alkyl, -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-C6alkyl), -OS(O)2-(H or C1-C6alkyl), -OS(O)N(H or C1-C6alkyl)2, -OS(O)N(C2-C6alkylene), -OS(O)2N(H or C1-C6 alkyl)2, -OS(O)2N(C2-C6 alkylene), -S(H or C1-C6 alkyl), -S(O)(H or C1-C6 alkyl), -S(O)2(H or C1-C6 alkyl), -S(O)N(H or C1-C6 alkyl)2, -S(O)N(C2-C6 alkylene), -S(O)2N(H or C1-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-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-C6 alkylene), -C(O)-(H or C1-C6 alkyl), -C(O)O(H or C1-C6 alkyl), -C(O)N(C2-C6 alkylene), -P(H or C1-C6 alkyl)2, -P(C2-C6 alkylene), -P(O)(H or C1-C6 alkyl)2, -P(O)(C2-C6 alkylene), -P(O)2(H or C1-C6 alkyl)2, -P(O)2(C2-C6 alkylene), -P(O)N(H or C1-C6 alkyl)2, -P(O)N(C2-C6 alkylene), -P(O)2N(H or C1-C6 alkyl)2, -P(O)2N(C2-C6 alkylene),83573-420992 -P(O)O(H or C1-C6 alkyl), -P(O)2O(H or C1-C6 alkyl), -CN, or -NO2.

[0424] 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.

[0425] In some embodiments, the disclosure provides a compound selected from the group consisting of

[0426] (2S)-1-[(10S,17E)-12-ethyl-6-(methoxymethyl)-8,10-dimethyl-16-[(propan-2- yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-(azenometheno)dipyrazolo[3,4-f:4',3'- n]pyrrolo[3,4-j][1,4]oxazacyclopentadecin-14-yl]propan-2-ol;

[0427] (2S)-1-[(11S,18E)-13-ethyl-9,11-dimethyl-17-[(propan-2-yl)oxy]-11,12,13,14- tetrahydro-9H,15H-3,6-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-2-ol;

[0428] (2S)-2-[(11S,18E)-17-ethoxy-7,9,11,13-tetramethyl-11,12,13,14-tetrahydro-9H,15H- 3,6-ethenoimidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11,12]oxatriazacyclopentadecin-15- yl]propan-1-ol;

[0429] (2S)-1-[(11S,18E)-13-ethyl-7-(methoxymethyl)-9,11-dimethyl-17-[(propan-2- yl)oxy]-11,12,13,14-tetrahydro-9H,15H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4- f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-2-ol;

[0430] (2S)-1-{(11S,18E)-13-ethyl-7-(methoxymethyl)-9,11-dimethyl-17-[(propan-2- yl)oxy]-11,12,13,14-tetrahydro-9H,15H-3,6-ethenoimidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl}propan-2-ol;

[0431] (18E)-17-ethyl-9,13,15-trimethyl-12,13-dihydro-9H,11H-3,6-ethenoimidazo[5,1- j]dipyrazolo[3,4-f:4',3'-n][1,4,11,12]oxatriazacyclopentadecin-14(15H)-one;

[0432] (18E)-17-ethyl-9,13,15-trimethyl-12,13-dihydro-9H,11H-6,3- (azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin- 14(15H)-one;

[0433] (2S)-1-[(11S,18E)-17-ethoxy-7,9,11,13,21-pentamethyl-11,12,13,14-tetrahydro- 9H,15H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-2-ol;

[0434] (2S)-1-{(11S,18E)-13-ethyl-9,11-dimethyl-17-[(propan-2-yl)oxy]-11,12,13,14- tetrahydro-9H,15H-3,6-ethenoimidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl}propan-2-ol;

[0435] (11S,18E)-13-ethyl-7-(methoxymethyl)-9,11,15-trimethyl-17-[(propan-2-yl)oxy]- 12,13,14,15-tetrahydro-9H,11H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'-83573-420992 n][1,4,11]oxadiazacyclopentadecin-21-amine;

[0436] (11S,18E)-17-ethoxy-13-ethyl-7-(methoxymethyl)-9,11,15-trimethyl-12,13,14,15- tetrahydro-9H,11H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-21-amine;

[0437] 2-[(11S,18E)-17-ethoxy-13-ethyl-9,11-dimethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15- yl]ethan-1-ol;

[0438] (2S)-1-[(11S,18E)-13-ethyl-7-(methoxymethyl)-9,11-dimethyl-17-[(propan-2- yl)oxy]-11,12,13,14-tetrahydro-9H,15H-3,6-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4- f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-2-ol;

[0439] (2S)-2-[(11S,18E)-17-ethoxy-7,9,11,13-tetramethyl-11,12,13,14-tetrahydro-9H,15H- 6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin- 15-yl]propan-1-ol;

[0440] (2S)-2-[(11S,18E)-17-ethoxy-7,9,11,13,21-pentamethyl-11,12,13,14-tetrahydro- 9H,15H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0441] (2S)-1-[(4E,12S)-10-ethyl-16-(methoxymethyl)-12,14-dimethyl-6-[(propan-2- yl)oxy]-9,11,12,14-tetrahydro-1,17-ethenotripyrazolo[3,4-f:4',3'-j:4'',3''- n][1,4]oxazacyclopentadecin-8(10H)-yl]propan-2-ol;

[0442] (2S)-1-[(4E,12S)-10-ethyl-12,14-dimethyl-6-[(propan-2-yl)oxy]-9,11,12,14- tetrahydro-1,17-ethenotripyrazolo[3,4-f:4',3'-j:4'',3''-n][1,4]oxazacyclopentadecin-8(10H)- yl]propan-2-ol;

[0443] 2-[(11S,18E)-21-amino-17-ethoxy-13-ethyl-9,11-dimethyl-11,12,13,14-tetrahydro- 9H,15H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]ethan-1-ol;

[0444] 2-[(11S,18E)-21-amino-17-ethoxy-13-ethyl-9,11-dimethyl-11,12,13,14-tetrahydro- 9H,15H-3,6-ethenoimidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin- 15-yl]ethan-1-ol;

[0445] (11S,18E)-13-ethyl-9,11,15-trimethyl-17-[(propan-2-yl)oxy]-12,13,14,15-tetrahydro- 9H,11H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-21-amine;

[0446] (11S,18E)-13-ethyl-9,11,15-trimethyl-17-[(propan-2-yl)oxy]-12,13,14,15-tetrahydro- 9H,11H-3,6-ethenoimidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin- 21-amine;

[0447] (11S,18E)-17-ethoxy-13-ethyl-7,9,11,15-tetramethyl-12,13,14,15-tetrahydro-9H,11H-83573-420992 6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin- 21-amine;

[0448] (11S,18E)-17-ethoxy-7,9,11,13,15-pentamethyl-12,13,14,15-tetrahydro-9H,11H-6,3- (azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-21- amine;

[0449] (11S,18E)-9,11,13,15-tetramethyl-17-[(propan-2-yl)oxy]-12,13,14,15-tetrahydro- 9H,11H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-21-amine;

[0450] (11S,18E)-7-(methoxymethyl)-9,11,13,15-tetramethyl-17-[(propan-2-yl)oxy]- 12,13,14,15-tetrahydro-9H,11H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-21-amine;

[0451] 2-[(11S,18E)-21-amino-7-(methoxymethyl)-9,11,13-trimethyl-17-[(propan-2-yl)oxy]- 11,12,13,14-tetrahydro-9H,15H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]ethan-1-ol;

[0452] 2-[(11S,18E)-21-amino-9,11,13-trimethyl-17-[(propan-2-yl)oxy]-11,12,13,14- tetrahydro-9H,15H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]ethan-1-ol;

[0453] (11S,18E)-13-ethyl-7-(methoxymethyl)-9,11,15,17-tetramethyl-12,13,14,15- tetrahydro-9H,11H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-21-amine;

[0454] (11S,18E)-21-amino-13-ethyl-7-(methoxymethyl)-9,11,15-trimethyl-12,13,14,15- tetrahydro-9H,11H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecine-17-carbonitrile;

[0455] [(11S,18E)-21-amino-13-ethyl-7-(methoxymethyl)-9,11-dimethyl-17-[(propan-2- yl)oxy]-11,12,13,14-tetrahydro-9H,15H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4- f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15-yl]acetonitrile;

[0456] (2R)-1-[(11S,18E)-21-amino-13-ethyl-7-(methoxymethyl)-9,11-dimethyl-17- [(propan-2-yl)oxy]-11,12,13,14-tetrahydro-9H,15H-6,3-(azenometheno)imidazo[5,1- j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-2-ol;

[0457] (2S)-1-[(11S,18E)-21-amino-13-ethyl-7-(methoxymethyl)-9,11-dimethyl-17- [(propan-2-yl)oxy]-11,12,13,14-tetrahydro-9H,15H-6,3-(azenometheno)imidazo[5,1- j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-2-ol;

[0458] 2-[(11S,18E)-21-amino-17-ethoxy-7,9,11,13-tetramethyl-11,12,13,14-tetrahydro- 9H,15H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]ethan-1-ol; and83573-420992

[0459] 2-[(11S,18E)-21-amino-17-ethoxy-7-(methoxymethyl)-9,11,13-trimethyl- 11,12,13,14-tetrahydro-9H,15H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]ethan-1-ol;

[0460] or a pharmaceutically acceptable salt thereof.

[0461] In some embodiments, the disclosure provides a compound selected from the group consisting of

[0462] (2S)-2-[(11S,18E)-17-ethoxy-7,9,11,13-tetramethyl-11,12,13,14-tetrahydro-9H,15H- 6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin- 15-yl]propan-1-ol;

[0463] (2S)-1-[(11S,18E)-7-(methoxymethyl)-9,11-dimethyl-17-[(propan-2-yl)oxy]- 11,12,13,14-tetrahydro-9H,15H-3,6-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-2-ol;

[0464] (2S)-1-[(11S,18E)-13-ethyl-7-(methoxymethyl)-9,11-dimethyl-17-[(propan-2- yl)oxy]-11,12,13,14-tetrahydro-9H,15H-3,6-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4- f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-2-ol;

[0465] (2S)-1-{(11S,18E)-13-ethyl-7-(methoxymethyl)-9,11-dimethyl-17-[(propan-2- yl)oxy]-11,12,13,14-tetrahydro-9H,15H-3,6-ethenoimidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl}propan-2-ol;

[0466] (2S)-2-[(11S,18E)-17-ethoxy-7,9,11,13,21-pentamethyl-11,12,13,14-tetrahydro- 9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0467] (19E)-9-methyl-12,13-dihydro-9H,11H-6,3-(azenometheno)imidazo[1,2- j]pyrazolo[3,4-f][1,5,10]benzodioxazacyclopentadecine;

[0468] (19E)-9-methyl-12,13-dihydro-9H,11H-3,6-ethenoimidazo[1,2-j]pyrazolo[3,4- f][1,5,10]benzodioxazacyclopentadecine;

[0469] (17E)-16-ethyl-8,12,14-trimethyl-8,11,12,14-tetrahydro-3,5-ethenoimidazo[4,5- j]dipyrazolo[3,4-f:4',3'-n][1,4]oxazacyclopentadecin-13(10H)-one;

[0470] (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12-tetramethyl-10,11,12,13-tetrahydro-5,3- (azenometheno)imidazo[4,5-j]dipyrazolo[3,4-f:4',3'-n][1,4]oxazacyclopentadecin-14(8H)- yl]propan-1-ol;

[0471] (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-10,11,12,13-tetrahydro-5,3- (azenometheno)imidazo[4,5-j]dipyrazolo[3,4-f:4',3'-n][1,4]oxazacyclopentadecin-14(8H)- yl]propan-1-ol;

[0472] (18E)-8-methyl-11,12-dihydro-8H,10H-5,3- (azenometheno)imidazo[4',5':10,11][1,5]benzodioxacyclopentadecino[6,7-c]pyrazole;83573-420992

[0473] (18E)-8-methyl-11,12-dihydro-8H,10H-3,5- ethenoimidazo[4',5':10,11][1,5]benzodioxacyclopentadecino[6,7-c]pyrazole;

[0474] (2S)-2-[(11S,18E)-17-ethoxy-9,11,13-trimethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15- yl]propan-1-ol;

[0475] (2S)-2-[(11S,18E)-17-ethoxy-9,11,13,21-tetramethyl-11,12,13,14-tetrahydro-9H,15H- 6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin- 15-yl]propan-1-ol;

[0476] (11S,18E)-9,11,13,15,17-pentamethyl-12,13,14,15-tetrahydro-9H,11H-6,3- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecine;

[0477] 2-[(11S,18E)-17-ethoxy-13-ethyl-9,11-dimethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15- yl]ethan-1-ol;

[0478] (2S)-2-[(11S,18E)-17-ethoxy-13-ethyl-9,11-dimethyl-11,12,13,14-tetrahydro- 9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol; and

[0479] (18E)-17-ethyl-9,13,15-trimethyl-12,13-dihydro-9H,11H-6,3- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin- 14(15H)-one;

[0480] or a pharmaceutically acceptable salt thereof.

[0481] In some embodiments, the disclosure provides a compound selected from the group consisting of

[0482] 2-[(11S,18E)-21-amino-17-ethoxy-9,11,13-trimethyl-11,12,13,14-tetrahydro- 9H,15H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]ethan-1-ol;

[0483] (2S)-2-[(11S,18E)-17-ethoxy-13-ethyl-7,9,11-trimethyl-11,12,13,14-tetrahydro- 9H,15H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0484] (2S)-1-[(11S,18E)-17-ethoxy-7,9,11,13-tetramethyl-11,12,13,14-tetrahydro-9H,15H- 6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin- 15-yl]propan-2-ol;

[0485] (2S)-2-[(11S,18E)-17-ethoxy-7-(methoxymethyl)-9,11,13-trimethyl-11,12,13,14- tetrahydro-9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0486] 2-[(11S,18E)-17-ethoxy-9,11,13-trimethyl-11,12,13,14-tetrahydro-9H,15H-6,3-83573-420992 (azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15- yl]ethan-1-ol;

[0487] {[(11S,18E)-15-[(2S)-1-hydroxypropan-2-yl]-7,9,11,13-tetramethyl-12,13,14,15- tetrahydro-9H,11H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-17-yl]oxy}acetonitrile;

[0488] (2S)-2-[(11S,18E)-17-ethoxy-13-ethyl-7-(methoxymethyl)-9,11-dimethyl- 11,12,13,14-tetrahydro-9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0489] (2S)-1-[(11S,18E)-17-ethoxy-9,11,13-trimethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15- yl]propan-2-ol;

[0490] {[(11S,18E)-13-ethyl-15-[(2S)-1-hydroxypropan-2-yl]-7,9,11-trimethyl-12,13,14,15- tetrahydro-9H,11H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-17-yl]oxy}acetonitrile;

[0491] 2-[(11S,18E)-7,9,11,13,21-pentamethyl-11,12,13,14-tetrahydro-9H,16H-6,3- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-16- yl]ethan-1-ol;

[0492] (11S,18E)-7,9,11,13,16,21-hexamethyl-12,13,14,16-tetrahydro-9H,11H-6,3- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecine;

[0493] (2S)-1-[(11S,18E)-17-ethoxy-7-(methoxymethyl)-9,11,13-trimethyl-11,12,13,14- tetrahydro-9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-2-ol;

[0494] (11S,18E)-7,9,11,13,21-pentamethyl-16-[2-(pyrrolidin-1-yl)ethyl]-12,13,14,16- tetrahydro-9H,11H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecine;

[0495] (2S)-2-[(11S,18E)-17-ethoxy-13-ethyl-7,9,11-trimethyl-11,12,13,14-tetrahydro- 9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0496] (2S)-2-[(11S,18E)-17-ethoxy-13-ethyl-7,9,11-trimethyl-11,12,13,14-tetrahydro- 9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0497] (2R)-1-[(11S,18E)-17-ethoxy-7-(methoxymethyl)-9,11,13-trimethyl-11,12,13,14- tetrahydro-9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-2-ol;

[0498] (11S,19E)-7,9,11,13-tetramethyl-11,12,13,14-tetrahydro-9H-6,3-83573-420992 (azenometheno)imidazo[1,2-j]pyrazolo[3,4-f][5,2,10]benzoxadiazacyclopentadecine;

[0499] 2-[(11S,18E)-7,9,11,13-tetramethyl-11,12,13,14-tetrahydro-9H,16H-6,3- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-16- yl]ethan-1-ol;

[0500] (11S,18E)-7,9,11,13,16-pentamethyl-12,13,14,16-tetrahydro-9H,11H-6,3- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecine;

[0501] (11S,18E)-7,9,11,13-tetramethyl-16-[2-(pyrrolidin-1-yl)ethyl]-12,13,14,16- tetrahydro-9H,11H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecine;

[0502] (11S,19E)-9,11,13-trimethyl-11,12,13,14-tetrahydro-9H-6,3- (azenometheno)imidazo[1,2-j]pyrazolo[3,4-f][5,2,10]benzoxadiazacyclopentadecine;

[0503] (2S)-2-[(12R,18E)-17-ethoxy-9,11,12,13-tetramethyl-11,12,13,14-tetrahydro- 9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0504] (2S)-2-[(11S,18E)-17-ethoxy-13-ethyl-7,9,11,21-tetramethyl-11,12,13,14-tetrahydro- 9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0505] (2S)-2-[(11S,18E)-17-ethoxy-13-ethyl-7-(methoxymethyl)-9,11,21-trimethyl- 11,12,13,14-tetrahydro-9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0506] {[(11S,18E)-13-ethyl-15-[(2S)-1-hydroxypropan-2-yl]-7,9,11,21-tetramethyl- 12,13,14,15-tetrahydro-9H,11H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-17-yl]oxy}acetonitrile;

[0507] (2S)-2-[(8aR,9S,20E)-1-ethoxy-9,11,13-trimethyl-7,8,8a,9-tetrahydro-6H,11H-14,17- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n]pyrrolo[2,1- c][1,4,11]oxadiazacyclopentadecin-3(4H)-yl]propan-1-ol;

[0508] (2S)-2-[(8aR,9R,20E)-1-ethoxy-9,11,13-trimethyl-7,8,8a,9-tetrahydro-6H,11H-14,17- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n]pyrrolo[2,1- c][1,4,11]oxadiazacyclopentadecin-3(4H)-yl]propan-1-ol;

[0509] (2S)-2-[(11S,12R,18E)-17-ethoxy-7-(methoxymethyl)-9,11,12,13-tetramethyl- 11,12,13,14-tetrahydro-9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0510] (18E)-17-ethyl-9,13,15-trimethyl-12,13-dihydro-9H,11H-3,6-ethenoimidazo[2,1- j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-14(15H)-one;

[0511] (2S)-2-[(8aR,9S,20E)-1-ethoxy-9,11-dimethyl-7,8,8a,9-tetrahydro-6H,11H-14,17-83573-420992 (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n]pyrrolo[2,1- c][1,4,11]oxadiazacyclopentadecin-3(4H)-yl]propan-1-ol;

[0512] (2S)-2-[(8aR,9R,20E)-1-ethoxy-9,11-dimethyl-7,8,8a,9-tetrahydro-6H,11H-14,17- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n]pyrrolo[2,1- c][1,4,11]oxadiazacyclopentadecin-3(4H)-yl]propan-1-ol;

[0513] (2S)-2-[(12S,19E)-18-ethoxy-12,14-dimethyl-12,13,14,15-tetrahydro-16H-6,3- (azenometheno)imidazo[2,1-j]pyrazolo[3,4-f]pyrido[3,4-n][1,4,11]oxadiazacyclopentadecin- 16-yl]propan-1-ol;

[0514] (2S)-2-[(11S,12R,18E)-17-ethoxy-7-(methoxymethyl)-9,11,12,13,21-pentamethyl- 11,12,13,14-tetrahydro-9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0515] (2S)-2-[(11S,12R,18E)-17-ethoxy-7,9,11,12,13,21-hexamethyl-11,12,13,14- tetrahydro-9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0516] (2S)-2-[(11R,12R,18E)-17-ethoxy-7,9,11,12,13,21-hexamethyl-11,12,13,14- tetrahydro-9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0517] (2S)-2-[(11S,12R,18E)-17-ethoxy-7,9,11,12,13-pentamethyl-11,12,13,14-tetrahydro- 9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0518] (2S)-2-[(8aR,9S,20E)-1-ethoxy-9,11,13,22-tetramethyl-7,8,8a,9-tetrahydro-6H,11H- 14,17-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n]pyrrolo[2,1- c][1,4,11]oxadiazacyclopentadecin-3(4H)-yl]propan-1-ol;

[0519] (18E)-9,13,15-trimethyl-12,13,14,15-tetrahydro-9H,11H-6,3- (azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-21- amine;

[0520] (18E)-8,13,15-trimethyl-12,13,14,15-tetrahydro-8H,11H-6,3- (azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-21- amine;

[0521] (18E)-17-ethoxy-8,13,15-trimethyl-12,13,14,15-tetrahydro-8H,11H-6,3- (azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-21- amine;

[0522] (2S)-2-[(11S,18E)-13-(2,2-difluoroethyl)-17-ethoxy-7,9,11-trimethyl-11,12,13,14- tetrahydro-9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;83573-420992

[0523] {[(11S,18E)-13-(2,2-difluoroethyl)-15-[(2S)-1-hydroxypropan-2-yl]-7,9,11-trimethyl- 12,13,14,15-tetrahydro-9H,11H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-17-yl]oxy}acetonitrile;

[0524] (2S)-2-[(11S,18E)-13-cyclopropyl-17-ethoxy-7,9,11-trimethyl-11,12,13,14- tetrahydro-9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0525] {[(11S,18E)-13-cyclopropyl-15-[(2S)-1-hydroxypropan-2-yl]-7,9,11-trimethyl- 12,13,14,15-tetrahydro-9H,11H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-17-yl]oxy}acetonitrile;

[0526] (2S)-2-[(11S,18E)-17-ethoxy-13-ethyl-7,11-dimethyl-11,12,13,14-tetrahydro-15H- 6,3-(azenometheno)imidazo[2,1-j]pyrazolo[3,4-f][1,2]thiazolo[4,5- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0527] (2S)-2-[(11S,18E)-17-ethoxy-13-ethyl-7,11-dimethyl-11,12,13,14-tetrahydro-15H- 6,3-(azenometheno)imidazo[2,1-j][1,2]oxazolo[4,5-n]pyrazolo[3,4- f][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0528] (2S)-2-[(11S,18E)-17-ethoxy-13-ethyl-7,9,11-trimethyl-11,12,13,14-tetrahydro- 9H,15H-6,3-(azenometheno)imidazo[2,1-j]pyrazolo[3,4-f]pyrrolo[3,2- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0529] (2S)-2-[(11S,18E)-17-ethoxy-9,13-diethyl-7,11-dimethyl-11,12,13,14-tetrahydro- 9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0530] (2S)-2-[(11S,18E)-17-ethoxy-7,13-diethyl-9,11-dimethyl-11,12,13,14-tetrahydro- 9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0531] (11S,18E)-7-(methoxymethyl)-9,11,13,16-tetramethyl-12,13,14,16-tetrahydro- 9H,11H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecine;

[0532] (11S,18E)-7-(methoxymethyl)-9,11,13,16,17-pentamethyl-12,13,14,16-tetrahydro- 9H,11H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecine;

[0533] (11S,18E)-7-(methoxymethyl)-9,11,13,15,17-pentamethyl-12,13,14,15-tetrahydro- 9H,11H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecine; and

[0534] (2S)-2-[(11S,18E)-7-(2,2-difluoroethyl)-17-ethoxy-13-ethyl-9,11-dimethyl- 11,12,13,14-tetrahydro-9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-83573-420992 n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0535] or a pharmaceutically acceptable salt thereof.

[0536] The following represent illustrative embodiments of compounds of Formula (I-VIII): Ex.# Structure (ChemDraw) Name (ACD) - - - -83573-420992 Ex.# Structure (ChemDraw) Name (ACD) - 1- - - - - - - - -83573-420992 Ex.# Structure (ChemDraw) Name (ACD) - - - - - ]- - -83573-420992 Ex.# Structure (ChemDraw) Name (ACD) - - - - e - e83573-420992 Ex.# Structure (ChemDraw) Name (ACD) - - - - ] - o - 1- -83573-420992 Ex.# Structure (ChemDraw) Name (ACD) - - 1- - - -83573-420992 Ex.# Structure (ChemDraw) Name (ACD) - - 7- - 7- -83573-420992 Ex.# Structure (ChemDraw) Name (ACD) 5- 1- - 1- - - - - - -83573-420992 Ex.# Structure (ChemDraw) Name (ACD) - - - - -83573-420992 Ex.# Structure (ChemDraw) Name (ACD) - - - - - - 1- -83573-420992 Ex.# Structure (ChemDraw) Name (ACD) 1- 1- - - 1- - - 1- - -83573-420992 Ex.# Structure (ChemDraw) Name (ACD) - - - 1- - - 1- - -83573-420992 Ex.# Structure (ChemDraw) Name (ACD) 1- - - - - 7- - 1- -83573-420992 Ex.# Structure (ChemDraw) Name (ACD) - - l- - - - -83573-420992 Ex.# Structure (ChemDraw) Name (ACD) - - 1- - - - 1- - - e -83573-420992 Ex.# Structure (ChemDraw) Name (ACD) - e 3- 1- - - -83573-420992 Ex.# Structure (ChemDraw) Name (ACD) 7- - 1- - - -83573-420992 Ex.# Structure (ChemDraw) Name (ACD) 1- - - - -83573-420992 Ex.# Structure (ChemDraw) Name (ACD) 1- - 4- - 4- - - -83573-420992 Ex.# Structure (ChemDraw) Name (ACD) - - -83573-420992 Ex.# Structure (ChemDraw) Name (ACD) 1- - - 1- - - - - -83573-420992 Ex.# Structure (ChemDraw) Name (ACD) - - - - - - 1- - - -83573-420992 Ex.# Structure (ChemDraw) Name (ACD) - - - -.

[0537] 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.83573-420992 PHARMACEUTICAL COMPOSITIONS

[0538] 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.

[0539] Sterile compositions are also contemplated by the disclosure, including compositions that are in accord with national and local regulations governing such compositions.

[0540] 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.

[0541] 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 magnesium83573-420992 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.

[0542] 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.

[0543] 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.

[0544] 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.

[0545] 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.

[0546] 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.83573-420992

[0547] 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.

[0548] The term “subject” refers to a mammalian patient in need of such treatment, such as a human.

[0549] 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.

[0550] 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 a83573-420992 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.

[0551] 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).

[0552] 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

[0553] 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.83573-420992

[0554] 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

[0555] 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)-(VIII).

[0556] Abbreviations: The examples described herein use materials, including but not limited to, those described by the following abbreviations known to those skilled in the art: g grams83573-420992 min minutes hr hours83573-420992 LAH or LiAlH4 lithium aluminum hydride LiBH4 lithium borohydride83573-420992 XPhos-Pd-G2 Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′- biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) ′ ′ ′ ′ [055mediates and products of the disclosure. The materials, intermediates and products are either commercially available or prepared via conventional chemistry from commercially available materials. Examples of commercially available materials that can be used in the syntheses of the disclosure include 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine; (5-bromopyridin-2- yl)methanamine; 5-bromopyrimidin-2-amine; 2-bromo-1,1-diethoxyethane; 6- bromoimidazo[1,2-b]pyridazine; 6-bromo-3-iodoimidazo[1,2-a]pyrazine; 6,8- dibromoimidazo[1,2-a]pyrazine; 5-bromo-3-methylpyrazin-2-amine; 5-bromo-6- methylpyrazin-2-amine; 7-bromoimidazo[1,5-a]pyridine; 3-bromopyridin-4-amine; 6-bromo- 3-iodoimidazo[1,2-a]pyridin-8-amine; (5-chloropyrazin-2-yl)methanamine; 2- methoxypyridine; (5-bromopyrimidin-2-yl)methanamine; methyl 4-methoxy-3-oxo- butanoate; 1-methyl-1H-pyrazol-3-ol; 1-methyl-1H-pyrazol-5-ol; 2-methylpyrazol-3-ol; 1,3- dimethyl-1H-pyrazol-5-ol; 2,5-dimethylpyrazol-3-ol; tert-butyl ((2R)-3-hydroxybutan-2- yl)carbamate; tert-butyl (R)-(1-oxopropan-2-yl)carbamate; methyl 5-hydroxy-1-methyl-1H- pyrazole-3-carboxylate; methyl 3-hydroxy-1-methyl-1H-pyrazole-5-carboxylate; tert-butyl (R)-5-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide; 2-isopropoxy-4,4,5,5- tetramethyl-1,3,2-dioxaborolane; 4,4,5,5-tetramethyl-1,3,2-dioxaborolane; tert-butyl (R)-2- acetylpyrrolidine-1-carboxylate; (2R)-2-methyloxirane; ethanamine; ethyl 3-hydroxy-1H- pyrazole-5-carboxylate; ethyl (2S)-2-hydroxypropanoate; ethyl 3-oxobutanoate; ethyl 3- oxopentanoate; dimethyl but-2-ynedioate; and (R)-propane-1,2-diol. 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.

[0558] Preparation of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-3-vinyl-1H- pyrrolo[2,3-b]pyridine (I-1-1).83573-420992

[0559] Step 1. To 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine (3 g, 9.29 mmol) in DMF (31 mL) was added NaH (60% dispersion in oil (743 mg, 18.6 mmol) at 0 °C under argon. The mixture was stirred for 1 h at ambient temperature, then Tosyl chloride (2.66 g, 13.93 mmol) was added. The mixture was stirred at ambient temperature overnight. On completion, the mixture was quenched with saturated ammonium chloride (20 mL), and diluted with water and DCM (100 mL each). The layers were partitioned, and the aqueous layer was extracted again with DCM (2 × 50mL). The combined organic layer was washed with brine and dried over sodium sulfate. Salts were filtered and washed thoroughly with DCM (40 mL) and filtrate concentrated. The residue was triturated with Hexanes (50mL) and DCM / EA (5 mL) to give 5- bromo-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (3.87 g, 8.10 mmol, 87 % yield) as a light yellow solid. LCMS: m / z 476.9 (M+1).

[0560] Step 2. To 5-bromo-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (840 mg, 1.76 mmol) in solvent, Dioxane (8.6 mL), was added Potassium vinyltrifluoroborate (1.18 g, 8.80 mmol) and sodium carbonate (560 mg, 5.28 mmol). The reaction mixture was stirred as argon was bubbling through and catalyst, Pd(dppf)Cl2.CH2Cl2(72 mg, 0.088 mmol), was added. The vessel was sealed at 40 °C for 4 days. On completion, the reaction was diluted with equal parts DCM and water (20 mL each) and the layers were separated. The aqueous layer was extracted again with DCM (2 x 10 mL). The combined organic layer was washed with brine and dried over sodium sulfate. Flash column chromatography (automated system, 40 g silica, 0-25% EA in Hexanes) provided 5-bromo-1-tosyl-3-vinyl-1H-pyrrolo[2,3-b]pyridine (506 mg, 1.34 mmol, 76 % yield) as a white solid. LCMS: m / z 377.0 (M+1).

[0561] Step 3. To 5-bromo-1-tosyl-3-vinyl-1H-pyrrolo[2,3-b]pyridine (300 mg, 0.795 mmol) in Dioxane (3.8 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,3,2-dioxaborolane (404 mg, 1.59 mmol) and KOAc (234 mg, 2.39 mmol). Argon was bubbled through the reaction mixture when Pd(dppf)Cl2.CH2Cl2 (65 mg,83573-420992 0.080 mmol) was added, and then argon bubbled through for an additional 5 minutes. The vessel was sealed and the mixture was stirred at 80 °C for 18 hr. The reaction was cooled and filtered through a celite plug, washed with DCM (5 mL), and the filtrate concentrated. Flash column chromatography (automated system, 12g silica, 0-100% EA in Hexanes) provided 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-3-vinyl-1H- pyrrolo[2,3-b]pyridine (240 mg, 0.566 mmol, 71 % yield) as a white solid. LCMS: m / z 425.2 (M+1).

[0562] Preparation of 6-bromo-3-vinylimidazo[1,2-a]pyrimidine (I-1-2).EtOH (100 mL) was added HBr (14.9 g, 92.1 mmol, 1.34 eq) and 2-bromo-1,1-diethoxyethane (27.2 g, 137 mmol, 2 eq). The mixture was stirred at 80 °C for 2 h. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with EA (50 ml) to give 6-bromoimidazo[1,2-a]pyrimidine (13.0 g, 65.6 mmol, 95% yield) as a white solid. LCMS: m / z 200.0 (M+1).

[0564] Step 2. To a solution of 6-bromoimidazo[1,2-a]pyrimidine (8.70 g, 43.9 mmol, 1 eq) in ACN (80 mL) was added NIS (14.8 g, 65.9 mmol, 1.5 eq). The mixture was stirred at 40 °C for 2 h. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with ACN (50 ml) to give 6-bromo- 3-iodoimidazo[1,2-a]pyrimidine (11.0 g, 33.9 mmol, 77% yield) as a yellow solid. LCMS: m / z 323.6 (M+1).

[0565] Step 3. A mixture of 6-bromo-3-iodoimidazo[1,2-a]pyrimidine (11.0 g, 33.9 mmol, 1 eq), potassium vinyltrifluoroborate (5.00 g, 37.3 mmol, 1.1 eq), Cs2CO3 (33.2 g, 101 mmol, 3 eq), Pd(dppf)Cl2(2.48 g, 3.40 mmol, 0.1 eq) in dioxane (50 mL) and H2O (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60 °C for 2 h under N2atmosphere. On completion, the reaction mixture was diluted with H2O (100 mL)83573-420992 and extracted with EA (150 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 1 / 0 to 5 / 1) to give 6-bromo-3-vinylimidazo[1,2-a]pyrimidine (5.00 g, 21.6 mmol, 64% yield, 97% purity) as a yellow solid.

[0566] Preparation of 6-bromo-3-vinylimidazo[1,2-b]pyridazine (I-1-3).

[0567] 1 eq) in DMF (160 mL) was added NIS (36.3 g, 161 mmol, 2 eq) at 0 °C. The mixture was stirred at 60 °C for 16 h. On completion, the reaction mixture was quenched by addition of sat. Na2SO3(1000 mL) at 25 °C, and then diluted with H2O (1000 mL) and extracted with EA (5 × 1000 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 6-bromo-3-iodoimidazo[1,2-b]pyridazine (25.0 g, 70.2 mmol, 86% yield, 91% purity) as a yellow solid. LCMS: m / z 325.8 (M+1).

[0568] Step 2. A mixture of 6-bromo-3-iodoimidazo[1,2-b]pyridazine (14.0 g, 43.2 mmol, 1 eq), potassium vinyltrifluoroborate (5.79 g, 43.2 mmol, 1 eq) and Cs2CO3 (28.1 g, 86.4 mmol, 2 eq), Pd(dppf)Cl2 (3.16 g, 4.32 mmol, 0.1 eq) in dioxane (140 mL) and H2O (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 16 h under N2atmosphere. On completion, the reaction mixture was diluted with H2O (500 mL) and extracted with EA (3 × 300 mL). The combined organic layers were washed with brine (2 × 300 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue. And then the residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 1 / 0 to 1 / 1) to give 6-bromo-3-vinylimidazo[1,2-b]pyridazine (6.45 g, 27.6 mmol, 63% yield, 96% purity) as a yellow solid.

[0569] Preparation of 6-bromo-3-vinylimidazo[1,2-a]pyrazine (I-1-4).

[0570] Step 1. To(24.0 g, 74.1 mmol, 1 eq) and potassium vinyltrifluoroborate (10.9 g, 81.5 mmol, 1.1 eq) in dioxane (250 mL) and83573-420992 H2O (50 mL) was added Cs2CO3 (48.3 g, 148 mmol, 2 eq) and Pd(dppf)Cl2 (3.25 g, 4.45 mmol, 0.06 eq). The mixture was stirred at 80 °C for 2 h under N2. On completion, the mixture was quenched with water (200 mL) and extracted with ethyl acetate (250 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:THF= 1:0 to 1:1) to give 6-bromo-3-vinylimidazo[1,2-a]pyrazine (11.7 g, 52.2 mmol, 70% yield) as a white solid.

[0571] Preparation of 6-chloro-3-vinylimidazo[1,5-a]pyrazine (I-1-5).

[0572] mmol, 1 eq, HCl) and acryloyl chloride (3.05 mmol, 248 μL, 1.1 eq) in THF (5 mL) was added DIEA (8.33 mmol, 1.45 mL, 3 eq). The mixture was stirred at 25 °C for 0.5 h. On completion, the reaction mixture was diluted with H2O (10mL) and extracted with EA (10 mL × 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 100 / 1 to 0 / 1) to give N-((5-chloropyrazin-2- yl)methyl)acrylamide (440 mg, 2.16 mmol, 78% yield, 97% purity) as a yellow solid.1H NMR (400 MHz, CDCl3) δ = 8.54 (d, J = 1.2 Hz, 1H), 8.43 (s, 1H), 6.49 (s, 1H), 6.38 - 6.32 (m, 1H), 6.22 - 6.15 (m, 1H), 5.75 - 5.70 (m, 1H), 4.68 (d, J = 5.6 Hz, 2H). LCMS: m / z 197.9 (M+1).

[0573] Step 2. To a solution of N-((5-chloropyrazin-2-yl)methyl)acrylamide (340 mg, 1.72 mmol, 1 eq) in DCM (1.5 mL) was added Tf2O (2.06 mmol, 341 μL, 1.2 eq) and 2- methoxypyridine (1.89 mmol, 197 μL, 1.1 eq). The mixture was stirred at 50 °C for 1.5 h. On completion, the reaction mixture was quenched by addition of sat. Na2CO3 (5 mL) at 25 °C, and then diluted with H2O (5 mL) and extracted with DCM (5 mL ×2). The combined organic layers were washed with brine (2 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 100 / 1 to 0 / 1) to give 6-chloro-3-vinylimidazo[1,5-a]pyrazine (150 mg, 835 μmol, 48% yield) as a yellow solid.83573-420992

[0574] Preparation of 3-bromo-6-vinylimidazo[1,5-a]pyrimidine (I-1-6).g, 7.98 mmol) in DCM (62 mL) was cooled to 0 °C. To the solution was added Acryloyl chloride (1.08 g, 11.97 mmol, 0.972 mL), followed by Triethylamine (1.21 g, 11.97 mmol, 1.67 mL). The solution was allowed to warm to room temperature and stirred for 0.5 h. The reaction was then washed twice with brine, dried with anhydrous sodium sulfate, and the crude mixture purified by flash column chromatography (0-100% Ethyl Acetate in Hexanes) to give N-((5-bromopyrimidin-2-yl)methyl)acrylamide (1.44 g, 5.95 mmol, 74.57% yield). LCMS: m / z 244.0 (M+1).

[0576] Step 2. A solution of N-((5-bromopyrimidin-2-yl)methyl)acrylamide (1.44 g, 5.96 mmol) in POCl3(16.44 g, 107.22 mmol, 10.0 mL) was heated at 80 °C for 0.5 h. The mixture was then evaporated to dryness, and to the residue was added saturated sodium bicarbonate solution (80 mL) and stirred at 0 °C for 5 minutes. The suspension was then extracted with DCM (3 × 150 mL), and the combined organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by flash column chromatography (5-15% Methanol in DCM) to give 3-bromo-6-vinyl-imidazo[1,5- a]pyrimidine (1.23 g, 5.49 mmol, 92.2% yield).

[0577] Intermediate I-1-7 was prepared in a manner similar to those described in the preparation of I-1-2, steps 2-3 starting from 6-bromoimidazo[1,2-a]pyridine.

[0578] Preparation of 6-bromo-8-methyl-3-vinylimidazo[1,2-a]pyrazine (I-1-8)

[0579] Step mmol, 1 eq)83573-420992 in H2O (50 mL) was added 2-bromoacetaldehyde (43.8 g, 223 mmol, 40% purity, 6 eq). The mixture was stirred at 100 °C for 3 hours. On completion, the reaction mixture was concentrated under reduced pressure to remove solvent and give 6-bromo-8- methylimidazo[1,2-a]pyrazine (8.30 g, 35.2 mmol, 94% yield, 90% purity) as a yellow solid.1H NMR (400 MHz, D2O) δ = 8.83 (s, 1H), 8.21 (s, 1H), 8.10 (s, 1H), 2.87 (s, 3H). LCMS: m / z 213.9 (M+1).

[0580] Step 2. To a solution of 6-bromo-8-methylimidazo[1,2-a]pyrazine (8.80 g, 41.5 mmol, 1 eq) in DMF (90 mL) was added NIS (14.0 g, 62.2 mmol, 1.5 eq). The mixture was stirred at 60 °C for 3 hours. Upon completion, the reaction mixture was quenched by addition Na2SO3(200 mL) at 0 °C. Then the mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF= 1:0 to 3:1) to give 6-bromo-3-iodo-8-methylimidazo[1,2-a]pyrazine (5.00 g, 14.8 mmol, 36% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 8.41 (s, 1H), 7.90 (s, 1H), 2.73 (s, 3H). LCMS: m / z 339.7 (M+1)

[0581] Step 3 was performed according to the preparation of I-1-4, step 1.

[0582] Preparation of 6-bromo-N-(4-methoxybenzyl)-3-vinylimidazo[1,2-a]pyrazin-8-amine (I-1-9)mmol, 1 eq) in DMF (50 mL) was added NIS (4.87 g, 21.6 mmol, 1.2 eq). The mixture was stirred at 60 °C for 1 h. On completion, the reaction mixture was partitioned between EA (150 mL × 3) and water (150 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 6,8-dibromo-3-iodoimidazo[1,2-a]pyrazine (3.00 g, 7.45 mmol, 41% yield) as a white solid. LCMS: m / z 403.8(M+1)

[0584] Step 2. To a solution of 6,8-dibromo-3-iodoimidazo[1,2-a]pyrazine (4.00 g, 9.93 mmol, 1 eq) in isopropanol (28 mL) was added DIEA (2.57 g, 19.8 mmol, 2 eq) and PMBNH2 (1.4883573-420992 g, 10.8 mmol, 1.09 eq). The mixture was stirred at 110 °C for 1 h. On completion, the mixture was concentrated to give a residue. The crude product was triturated with iPrOH:H2O= 4:1 (450 mL) at 25 °C for 10 mins to give 6-bromo-3-iodo-N-(4-methoxybenzyl)imidazo[1,2- a]pyrazin-8-amine (6.90 g, 15.0 mmol, 75% yield) as a white solid. LCMS: m / z 460.6 (M+1)

[0585] Step 3. To a solution of 6-bromo-3-iodo-N-(4-methoxybenzyl)imidazo[1,2-a]pyrazin- 8-amine (6.40 g, 13.9 mmol, 1 eq) in dioxane (65 mL) and H2O (13 mL) was added potassium vinyltrifluoroborate (2.05 g, 15.3 mmol, 1.1 eq), Na2CO3(4.43 g, 41.8 mmol, 3 eq) and Pd(dppf)Cl2 (612 mg, 0.836 mmol, 0.06 eq). The mixture was stirred at 80 °C for 1 h. Upon completion, the reaction mixture was partitioned between EA (70 mL × 3) and water (70 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:THF= 6:1) to give 6-bromo-N-(4-methoxybenzyl)-3-vinylimidazo[1,2-a]pyrazin-8-amine (3.40 g, 9.46 mmol, 68% yield) as a white solid. LCMS: m / z 359.1 (M+1)

[0586] Preparation of 6-bromo-3-vinylimidazo[1,5-a]pyridine (I-1-10)eq) in ACN (464 mL) and H2O (46.4 mL) was added DIEA (16.0 g, 124mmol, 21.6 mL, 2 eq) and acryloyl chloride (5.61 g, 62.0 mmol, 5.04 mL, 1 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 hour. Upon completion, the mixture was quenched with ice water (200 mL) and extracted with ethyl acetate (200 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give N-((5-bromopyridin-2- yl)methyl)acrylamide (13.5 g, 56.0 mmol, 90% yield) as a yellow solid. LCMS: m / z 243.0 (M+1)

[0588] Step 2. To a solution of N-((5-bromopyridin-2-yl)methyl)acrylamide (3.00 g, 12.4 mmol, 1 eq) in DCM (50 mL) was added 2-methoxypyridine (1.49 g, 13.7 mmol, 1.42 mL, 1.1 eq) at 25 °C, and then was added Tf2O (4.21 g, 14.9 mmol, 2.46 mL, 1.2 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was quenched by addition sodium carbonate solution (30 mL) at 0 °C, and then diluted with H2O (40 mL) and extracted with DCM (50 mL ×2). The combined organic layers were washed with brine solution (30 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to83573-420992 give a residue. The residue was purified by column chromatography (20.0 g silica gel column, THF in PE from 0-100%) to give 6-bromo-3-vinylimidazo[1,5-a]pyridine (1.80 g, 8.07 mmol, 65% yield) as a brown oil.

[0589] Preparation of 6-chloro-8-methyl-3-vinylimidazo[1,5-a]pyrazine (I-1-11)1 eq), CuCl (789 mg, 7.98 mmol, 1.5 eq) and CuCl2(1.07 g, 7.98 mmol, 1.5 eq) in ACN (10 mL) was added t-butyl nitrite (13.3 mmol, 1.58 mL, 2.5 eq) dropwise at -10 °C under nitrogen atmosphere. The mixture was heated to 65 °C for 16 hours with stirring. Upon completion, the reaction mixture was quenched by addition H2O (20 mL) at 25 °C, and then extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 0 to 95 / 5) to give 2- bromo-5-chloro-3-methylpyrazine (566 mg, 2.51 mmol, 47% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ = 8.22 (s, 1H), 2.68 (s, 3H). LCMS: m / z 208.7 (M+3)

[0591] Step 2. A mixture of 2-bromo-5-chloro-3-methylpyrazine (550 mg, 2.65 mmol, 1 eq), potassium (((tert-butoxycarbonyl)amino)methyl)trifluoroborate (628 mg, 2.65 mmol, 1 eq), Cy3P Pd G3(172 mg, 0.265 mmol, 0.1 eq) and a solution of Cs2CO3(3 M in H2O, 2.65 mL, 3 eq) in dioxane (14.8 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 16 hours under N2atmosphere. On completion, the reaction mixture was quenched by addition H2O (20 mL) at 25 °C, and then extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 1 to 90 / 10), and the crude product was purified by reversed-phase HPLC (0.1% FA condition) to give tert-butyl ((5-83573-420992 chloro-3-methylpyrazin-2-yl)methyl)carbamate (271 mg, 0.988 mmol, 37% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ = 8.36 (s, 1H), 5.71 (s, 1H), 4.46 (d, J = 4.4 Hz, 2H), 2.56 (s, 3H), 1.48 (s, 9H). LCMS: m / z 158.1 (M-100)

[0592] Step 3. A solution of tert-butyl ((5-chloro-3-methylpyrazin-2-yl)methyl)carbamate (270 mg, 1.05 mmol, 1 eq) in 2 M HCl / dioxane (2 mL, 3.82 eq) was stirred at 30 °C for 16 hours. On completion, the reaction mixture was concentrated in vacuo to give (5-chloro-3- methylpyrazin-2-yl)methanamine (200 mg, 1.03 mmol, 98% yield, HCl salt) as a white solid. LCMS: m / z 158.1 (M+1)

[0593] Steps 4 and 5 were conducted in a similar manner to those described in the preparation of I-1-5 steps 1 and 2.

[0594] Intermediate I-1-12 was prepared in a manner similar to those described in the preparation of I-1-3 starting from 7-bromoimidazo[1,5-a]pyridine and using DCM / MeOH in step 1 and Na2CO3as the base in step 2.

[0595] Intermediate I-1-13 was prepared in a manner similar to those described in the preparation of I-1-3 starting from 6-bromo-3-iodoimidazo[1,2-a]pyridin-8-amine and using THF as solvent in step 1.

[0596] Intermediate Table 1. Int. # Structurem / z 1H NMR 683573-420992 I-1-5 1802 .2 6 5 , , ), =

[0597] Preparation of 3-(methoxymethyl)-1-methyl-1H-pyrazol-5-ol (I-2-1).83573-420992

[0598] Step 1. To a solution of methyl 4-methoxy-3-oxo-butanoate (5.00 g, 34.2 mmol, 1 eq) in toluene (150 mL) was added dropwise methylhydrazine (3.94 g, 34.2 mmol, 4.5 mL, 40% purity, 1 eq) at 0 °C over 0.5 h. The resulting mixture was stirred at 100 °C for 1.5 h. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:THF= 1:0 to 1:1) to give 3-(methoxymethyl)-1-methyl-1H- pyrazol-5-ol (3.90 g, 27.4 mmol, 80% yield) as a yellow solid.

[0599] Preparation of (S)-N-(2-((4-bromo-3-(methoxymethyl)-1-methyl-1H-pyrazol-5- yl)oxy)propyl)-N-ethyl-2,2,2-trifluoroacetamide (I-2-2)., (R)- N-ethyl-2,2,2-trifluoro-N-(2-hydroxypropyl)acetamide (325 mg, 1.63 mmol) , and DBAD (648 mg, 2.81 mmol) in dry DCM (2.8 mL) at 0 °C was added PPh3 (1.11 g, 4.22 mmol). The reaction mixture was stirred for 2 hr at 22 °C. On completion, the reaction was diluted with equal parts DCM and water (10 mL each) and the layers were separated. The aqueous layer was extracted again with DCM (2 × 5 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Flash column chromatography (automated system, 24 g silica, 20-100% EA in Hexanes) provided (S)-N-ethyl-2,2,2-trifluoro-N-(2-((3- (methoxymethyl)-1-methyl-1H-pyrazol-5-yl)oxy)propyl)acetamide (904 mg) , heavily contaminated. The reaction product was taken forward without further purification. LCMS: m / z 324.2 (M+1).

[0601] Step 2. To (S)-N-ethyl-2,2,2-trifluoro-N-(2-((3-(methoxymethyl)-1-methyl-1H- pyrazol-5-yl)oxy)propyl)acetamide (455 mg, 1.41 mmol) in acetonitrile (7 mL) was83573-420992 added NBS (300 mg, 1.69 mmol). The reaction mixture was stirred at 22 °C for 18 hr. On completion, the mixture was quenched with water and diluted with DCM (20 mL) and water (20 mL). The layers were separated and the aqueous layer was extracted again with DCM (2 × 20 mL). The combined organic layers were washed with brine and dried over sodium sulfate. The salts were filtered and washed with DCM (20 mL), and the filtrate was concentrated under reduced pressure. Flash column chromatography (automated system with ELSD, 12 g silica, 20-80% EA in Hexanes) provided (S)-N-(2-((4-bromo-3-(methoxymethyl)-1-methyl- 1H-pyrazol-5-yl)oxy)propyl)-N-ethyl-2,2,2-trifluoroacetamide (172 mg, 427 mmol, 30 % yield over 2 steps). LCMS: m / z 402.09 (M+1).

[0602] Preparation of tert-butyl (S)-(2-((4-bromo-1-methyl-1H-pyrazol-5- yl)oxy)propyl)carbamate (I-2-3).2-yl (29.0 g, 114 mmol, 1 eq) and 2-methylpyrazol-3-ol (13.4 g, 137 mmol, 1.2 eq) in DMF (200 mL) was added K2CO3 (47.4 g, 343 mmol, 3 eq). The reaction mixture was stirred at 80 °C for 12 hours. On completion, the residue was diluted with water (300 mL) and extracted with EA (2 × 300 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo afford to tert-butyl (S)-(2-((1-methyl-1H-pyrazol-5- yl)oxy)propyl)carbamate (29.0 g, 113 mmol, 99% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 2H), 7.22 (d, J = 2.0 Hz, 1H), 4.32 - 4.23 (m, 1H), 3.56 (s, 3H), 3.27 - 3.14 (m, 2H), 1.41 (s, 12H). LCMS: m / z 256.3 (M+1).

[0604] Step 2. To a mixture of tert-butyl (S)-(2-((1-methyl-1H-pyrazol-5- yl)oxy)propyl)carbamate (29.0 g, 113 mmol, 1 eq) in ACN (300 mL) was added NBS (22.2 g, 124 mmol, 1.1 eq) at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours. On completion, the residue was diluted with water (200 mL) and extracted with EA (2 × 150 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography to afford tert-butyl (S)- (2-((4-bromo-1-methyl-1H-pyrazol-5-yl)oxy)propyl)carbamate (15.4 g, 46.0 mmol, 40% yield) as a yellow oil.

[0605] Preparation of tert-butyl (S)-ethyl(2-((1-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazol-5-yl)oxy)propyl)carbamate (I-2-4).83573-420992 5-yl)oxy)propyl)carbamate (20.0 g, 59.8 mmol, 1 eq) in DMF (200 mL) was added NaH (7.18 g, 179 mmol, 60% purity, 3 eq) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 hour, and then iodoethane (18.6 g, 119 mmol, 2 eq) was added to the reaction mixture at 0 °C. The reaction mixture was stirred at 25 °C for 8 hours. On completion, the reaction mixture was quenched with water (50 mL) at 0 °C, and then the residue was diluted with water (250 mL) and extracted with EA (2 × 250 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, PE:EA= 50:1 to 5:1) to afford tert-butyl (S)-(2-((4-bromo-1-methyl- 1H-pyrazol-5-yl)oxy)propyl)(ethyl)carbamate (15.7 g, 43.5 mmol, 72% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 7.40 (s, 1H), 4.72 - 4.63 (m, 1H), 3.61 (s, 3H), 3.39 (d, J = 5.6 Hz, 2H), 3.30 - 3.23 (m, 2H), 1.38 (s, 9H), 1.21 (d, J = 6.4 Hz, 3H), 1.05 (t, J = 6.8 Hz, 3H).

[0607] Step 2. To a solution of tert-butyl (S)-(2-((4-bromo-1-methyl-1H-pyrazol-5- yl)oxy)propyl)(ethyl)carbamate (10.0 g, 27.6 mmol, 1 eq) in THF (100 mL) was added n-BuLi (2.5 M in hexanes, 22.1 mL, 2 eq) dropwise at -78 °C. After addition, the mixture was stirred at this temperature for 30 mins, and then 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (15.4 g, 82.8 mmol, 3 eq) was added dropwise at -78 °C. The resulting mixture was stirred at -78 °C for 0.5 hr. On completion, the mixture was quenched with saturated ammonium chloride (30 mL) and water (50 mL), and extracted with ethyl acetate (125 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= 5:1 to 2:1) to give tert-butyl (S)-ethyl(2-((1-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-5-yl)oxy)propyl)carbamate (9.50 g, 23.2 mmol, 84% yield) as a yellow oil.

[0608] Intermediate I-2-5 was synthesized according to methods used for synthesis of I-2-3 using commercially available 1,3-dimethyl-1H-pyrazol-5-ol.

[0609] Preparation of tert-butyl (S)-(2-((1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazol-5-yl)oxy)propyl)(methyl)carbamate (I-2-6).83573-420992

[0610] I- 2-4 using iodomethane instead of iodoethane.

[0611] Step 2. To a solution of tert-butyl (S)-(2-((4-bromo-1,3-dimethyl-1H-pyrazol-5- yl)oxy)propyl)(methyl)carbamate (1.00 g, 2.76 mmol, 1 eq) in dioxane (3 mL) was added dropwise dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (131 mg, 0.276 mmol, 0.1 eq) at 110 °C. After addition, the mixture was stirred at this temperature for 0.5 hours, and then 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.06 g, 8.28 mmol, 3 eq), Bis(acetonitrile)dichloropalladium (II) (71.6 mg, 0.276 mmol, 0.1 eq), and TEA (2.76 mmol, 1 eq) were added into the mixture. The resulting mixture was stirred at 110 °C for 2 hours. On completion, the reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 9:1 to 5:1) to give tert-butyl (S)-(2-((1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1H-pyrazol-5-yl)oxy)propyl)(methyl)carbamate (1.10 g, 2.69 mmol, 97% yield) as a yellow solid.

[0612] Preparation of tert-butyl (S)-(2-((3-(methoxymethyl)-1-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazol-5-yl)oxy)propyl)carbamate (I-2-7).83573-420992- 3.52 mmol), K2CO3 (1.33g, 9.59mmol), and tert-butyl (R)-5-methyl-1,2,3-oxathiazolidine-3- carboxylate 2,2-dioxide (0.759 g, 3.2 mmol) in DMF (12 mL) was heated to 80 °C overnight. The suspension was filtered over Celite, diluted with DCM (50 mL). To the mixture was added 1 M Citric acid (25 mL), and stirred for 1 h until only product peak was observed by Mass Spectrometry. The layers were separated, and the aqueous layer was extracted with DCM (50 mL × 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude residue was purified by column chromatography over silica gel (0-100% EtOAc in Hexanes) to give tert- butyl (S)-(2-((3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl)oxy)propyl)carbamate (902 mg, 3.01 mmol, 94.2% yield). LCMS: m / z 300.3 (M+1).

[0614] Step 2 was performed in a similar manner to step 2 of the synthesis of I-2-3.

[0615] Step 3 was performed in a similar manner to step 2 of the synthesis of I-2-4.

[0616] Preparation of tert-butyl methyl(2-((1-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazol-5-yl)oxy)ethyl)carbamate (I-2-8)83573-420992

[0617] Step 1. To a mixture of 1-methyl-1H-pyrazol-5-ol (5 g, 50.9 mmol, 1 eq) and tert-butyl (2-bromoethyl)carbamate (13.7 g, 61.1 mmol, 1.2 eq) in DMF (50 mL) was added K2CO3 (21.1 g, 152 mmol, 3 eq). The mixture was stirred at 80 °C for 2 hours. On completion, the mixture was quenched with water (100 mL) and extracted with ethyl acetate (40 mL × 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give tert-butyl (2-((1-methyl-1H-pyrazol-5-yl)oxy)ethyl)carbamate (11 g, 45.5 mmol, 89.45% yield) as a black oil. LCMS: m / z 242.2 (M+1)

[0618] Step 2. To a solution of tert-butyl (2-((1-methyl-1H-pyrazol-5-yl)oxy)ethyl)carbamate (2 g, 8.29 mmol, 1 eq) in THF (20 mL) was added NaH (497 mg, 12.4 mmol, 60% in mineral oil, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 0.5 hours, and then methyl iodide (1.41 g, 9.95 mmol, 0.619 mL, 1.2 eq) was added at 25 °C. The mixture was stirred at 25°C for 3 hours. On completion, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give tert-butyl methyl(2-((1-methyl-1H-pyrazol-5- yl)oxy)ethyl)carbamate (2 g, 7.83 mmol, 94.51% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 7.20 (d, J = 2.0 Hz, 1H), 5.65 (d, J = 2.0 Hz, 1H), 4.17 - 4.10 (m, 2H), 3.58 - 3.48 (m, 5H), 2.85 (d, J = 6.4 Hz, 3H), 1.37 (d, J = 19.2 Hz, 9H).

[0619] Step 3 was performed in a similar manner to step 2 of I-2-2.

[0620] Step 4 was performed in a similar manner to step 2 of I-2-4.

[0621] Preparation of tert-butyl (S)-ethyl(2-((3-(methoxymethyl)-1-methyl-4-(4,4,5,5-tetra methyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-5-yl)oxy)propyl)carbamate (I-2-9)83573-420992

[0622] Step 1. A mixture of 3-(methoxymethyl)-1-methyl-1H-pyrazol-5-ol (10.0 g, 70.3 mmol, 1 eq), tert-butyl (R)-(2-hydroxypropyl)carbamate (18.4 g, 105 mmol, 1.5 eq), PPh3 (40.5 g, 154 mmol, 2.2 eq), DBAD (35.6 g, 154 mmol, 2.2 eq) in THF (200 mL) was degassed and purged with N2 for 3 times, then DBAD (35.6 g, 154 mmol, 2.2 eq) was added at 0 °C, and then the mixture was stirred at 25 °C for 2 hours under N2. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1:0 to 1:1) to give tert-butyl (S)-(2- ((3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl)oxy)propyl)carbamate (12.8 g, 28.2 mmol, 40% yield, 66% purity) as a colorless oil.1H NMR (400 MHz, CDCl3) δ = 7.14 - 6.99 (m, 1H), 5.29 (s, 3H), 4.36 - 4.28 (m, 4H), 4.15 - 4.08 (m, 1H), 3.60 - 3.52 (m, 5H), 3.38 (s, 3H), 1.43 (s, 9H). LCMS: m / z 300.2 (M+1)

[0623] Steps 2-3 were performed according to those described in the preparation of I-2-8 steps 2-3 using ethyl iodide and DMF instead of methyl iodide and THF in step 2.

[0624] Step 4. To a solution of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9.26 g, 72.3 mmol, 10.5 mL, 6 eq), tert-butyl (S)-(2-((4-bromo-3-(methoxymethyl)-1-methyl-1H-pyrazol-5- yl)oxy)propyl) (ethyl)carbamate (4.90 g, 12.0 mmol, 1 eq), TEA (1.22 g, 12.0 mmol, 1.68 mL, 1 eq), XPhos (575 mg, 1.21 mmol, 0.1 eq) in dioxane (50 mL) was added Pd(CH3CN)2Cl2(312 mg, 1.21 mmol, 0.1 eq) at 25 °C. The mixture was stirred at 110 °C for 1 hour. On completion, the mixture was slowly added to water (100 mL) to quench and extracted with EA (3 × 60 mL). The combined organic layer was washed with brine (2 × 100 mL), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column83573-420992 height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether / Ethyl acetate= 1 / 0, 1 / 1) to give tert-butyl (S)-ethyl(2-((3-(methoxymethyl)-1-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazol-5-yl)oxy)propyl)carbamate (7.50 g, 15.1 mmol, 63% yield, 92% purity) as a yellow oil.

[0625] Preparation of tert-butyl (S)-(2-((1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazol-5-yl)oxy)propyl)(ethyl)carbamate (I-2-10)

[0626] I-2-was prepared according to preparation of I-2-3 starting from 1,3-dimethyl-1H-pyrazol-5-ol and (R)- 1-((tert-butoxycarbonyl)amino)propan-2-yl methanesulfonate.

[0627] Step 1. To a solution of tert-butyl (S)-(2-((1,3-dimethyl-1H-pyrazol-5- yl)oxy)propyl)carbamate (3.00 g, 11.1 mmol, 1 eq) in THF (30 mL) was added t-BuOK (2.50 g, 22.3 mmol, 2 eq) and EtI (3.47 g, 22.3 mmol, 1.78 mL, 2 eq). The mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was quenched by addition of H2O (40 mL) at 0 °C and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl (S)-(2-((1,3-dimethyl-1H-pyrazol-5-yl)oxy)propyl)(ethyl)carbamate (3.20 g, 10.8 mmol, 96% yield) as a colorless oil. LCMS: m / z 298.2 (M+1)

[0628] Steps 2 and 3 were performed according to the preparation of I-2-7 steps 2-3.

[0629] I-2-11 was prepared according to those described in the synthesis of I-2-4 starting from I-2-3 and Methyl Iodide in step 1.

[0630] I-2-12 was prepared following steps 2 through 4 in the preparation of I-2-8 starting from I-2-9a.

[0631] I-2-14 was prepared according to the preparation of I-2-8 starting from I-2-13 and tert- butyl ((2R)-3-hydroxybutan-2-yl)carbamate (I-4-6) and reversing steps 2 and 3.83573-420992

[0632] Preparation of tert-butyl (2R)-2-(1-((1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazol-5-yl)oxy)ethyl)pyrrolidine-1-carboxylate (I-2-15)g, 18.7 mmol, 1 eq) in THF (40 mL) was added LAH (2.5 M in THF, 4.50 mL, 0.6 eq) dropwise at 0 °C under N2 atmosphere. After addition, the resulting mixture was stirred at 0 °C for 1 h. On completion, the mixture was sequentially quenched with water (0.1 mL), 15% NaOH (0.1 mL) and water (0.3 mL), dried over Na2SO4, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 1:0 to 4:1) to give tert-butyl (2R)-2-(1-hydroxyethyl)pyrrolidine-1-carboxylate (5.50 g, crude) as a colorless oil.1H NMR (400 MHz, CDCl3) δ = 3.96 (d, J = 6.0 Hz, 1H), 3.78 - 3.64 (m, 1H), 3.59 - 3.47 (m, 1H), 3.32 - 3.21 (m, 1H), 2.04 - 1.92 (m, 1H), 1.89 - 1.59 (m, 3H), 1.48 (s, 9H), 1.18 - 1.07 (m, 3H).

[0634] Step 2. A mixture of tert-butyl (2R)-2-(1-hydroxyethyl)pyrrolidine-1-carboxylate (1.80 g, 8.36 mmol, 1.3 eq), 2,5-dimethylpyrazol-3-ol (721 mg, 6.43 mmol, 1 eq), PPh3 (3.37 g, 12.8 mmol, 2 eq) and DBAD (2.96 g, 12.9 mmol, 2 eq) was degassed and purged with N2 for 3 times, and then THF (18 mL) was added. The mixture was stirred at 25 °C for 1 h. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:THF= 1:0 to 7:3) to give tert-butyl (2R)-2-(1-((1,3- dimethyl-1H-pyrazol-5-yl)oxy)ethyl)pyrrolidine-1-carboxylate (905 mg, 2.92 mmol, 45% yield) as a colorless oil. LCMS: m / z 310.2 (M+1).

[0635] Step 3. To a solution of tert-butyl (2R)-2-(1-((1,3-dimethyl-1H-pyrazol-5- yl)oxy)ethyl)pyrrolidine-1-carboxylate (855 mg, 2.76 mmol, 1 eq) in ACN (8.5 mL) was added NBS (516 mg, 2.90 mmol, 1.05 eq). The mixture was stirred at 0 °C for 0.5 h. On completion, the mixture was quenched with sat. Na2SO3 (20 mL) and extracted with EA (15 mL × 3). The combined organic layers were washed with brine (15 mL × 2), dried over Na2SO4,filtered and83573-420992 concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:THF=1:0 to 3:1) to give tert-butyl (2R)-2-(1-((4-bromo-1,3-dimethyl-1H-pyrazol-5- yl)oxy)ethyl)pyrrolidine-1-carboxylate (600 mg, 1.55 mmol, 56% yield) as an orange oil. LCMS: m / z 388.0 (M+1).

[0636] Step 4. To a solution of tert-butyl (2R)-2-(1-((4-bromo-1,3-dimethyl-1H-pyrazol-5- yl)oxy)ethyl)pyrrolidine-1-carboxylate (500 mg, 1.29 mmol, 1 eq) in THF (10 mL) was added n-BuLi (2.5 M in hexane, 1.03 mL, 2 eq) dropwise at -78 °C under N2. The mixture was stirred at this temperature for 0.5 h, and then 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (718 mg, 3.86 mmol, 3 eq) was added dropwise at -78 °C. The resulting mixture was stirred at -78 °C for 0.5 h. On completion, the mixture was quenched with sat. NH4Cl (20 mL) and extracted with EA (15 mL × 3). The combined organic layers were washed with brine (15 mL× 2), dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:THF= 1:0 to 3:1) to give tert-butyl (2R)-2-(1-((1,3- dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-5- yl)oxy)ethyl)pyrrolidine-1-carboxylate (450 mg, 1.03 mmol, 80% yield) as a yellow oil.

[0637] Preparation of tert-butyl ((2R)-3-((3-(methoxymethyl)-1-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-5-yl)oxy)butan-2-yl)(methyl)carbamate (I- 2-16)1 eq) in THF (500 mL) was degassed and purged with N2for 3 times, and then was added MeMgBr (3 M in THF, 115 mL, 1.2 eq) at -78 °C. The mixture was stirred at -78 °C for 1 hour under N2atmosphere. On completion, the mixture was quenched with saturated solution of83573-420992 NH4Cl (300 mL) and extracted with ethyl acetate (300 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 ((2R)-3-hydroxybutan-2-yl)carbamate (48.0 g, 253 mmol, 87% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ = 9.49 (s, 1H), 4.75 - 4.62 (m, 1H), 4.10 - 4.00 (m, 1H), 3.82 - 3.74 (m, 1H), 3.68 - 3.57 (m, 1H), 2.55 - 2.26 (m, 1H), 1.98 (s, 1H), 1.39 - 1.36 (m, 14H), 1.11 (d, J = 6.4 Hz, 3H), 1.10 - 1.07 (m, 3H), 1.04 - 1.01 (m, 1H).

[0639] Step 2. A mixture of 3-(methoxymethyl)-1-methyl-1H-pyrazol-5-ol (5.00 g, 35.1 mmol, 1 eq), tert-butyl ((2R)-3-hydroxybutan-2-yl)carbamate (9.98 g, 52.7 mmol, 1.5 eq), DBAD (12.1 g, 52.7 mmol, 1.5 eq), PPh3 (13.8 g, 52.7 mmol, 1.5 eq) in dioxane (100 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred a 0 °C for 1 hour under N2 atmosphere. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF= 1:0 to 0:1) to give tert-butyl ((2R)-3-((3-(methoxymethyl)-1-methyl-1H-pyrazol-5- yl)oxy)butan-2-yl)carbamate (7.80 g, 24.8 mmol, 70% yield) as a yellow oil. LCMS: m / z 314.3 (M+1).

[0640] Step 3. To a solution of tert-butyl ((2R)-3-((3-(methoxymethyl)-1-methyl-1H-pyrazol- 5-yl)oxy)butan-2-yl)carbamate (7.60 g, 24.2 mmol, 1 eq) in ACN (70 mL) was added NBS (4.32 g, 24.2 mmol, 1 eq). The mixture was stirred at 0 °C for 1 hour. On completion, the mixture was quenched with saturated solution of Na2SO3(50 mL) and extracted with ethyl acetate (80 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 ((2R)-3-((4-bromo- 3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl)oxy)butan-2-yl)carbamate (4.30 g, 10.9 mmol, 45% yield) as a yellow oil.

[0641] Step 4. To a solution of tert-butyl ((2R)-3-((4-bromo-3-(methoxymethyl)-1-methyl- 1H-pyrazol-5-yl)oxy)butan-2-yl)carbamate (4.10 g, 10.4 mmol, 1 eq) in DMF (40 mL) was added MeI (2.23 g, 15.6 mmol, 1.5 eq) and NaH (627 mg, 15.6 mmol, 60% purity, 1.5 eq). The mixture was stirred at 0 °C for 1 hour. On completion, the mixture was quenched with saturated solution of NH4Cl (3 mL) and extracted with ethyl acetate (40 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 ((2R)-3-((4-bromo-3-(methoxymethyl)-1-methyl-1H-pyrazol-5- yl)oxy)butan-2-yl)(methyl)carbamate (3.60 g, 8.86 mmol, 84% yield) as a yellow oil. LCMS: m / z 428.0 (M+23).83573-420992

[0642] Step 5. A mixture of tert-butyl ((2R)-3-((4-bromo-3-(methoxymethyl)-1-methyl-1H- pyrazol-5-yl)oxy)butan-2-yl)(methyl)carbamate (3.50 g, 8.61 mmol, 1 eq) in THF (40 mL) was degassed and purged with N2 for 3 times, and was added n-BuLi (2.5 M in THF, 5.17 mL, 1.5 eq), 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.40 g, 12.9 mmol, 1.5 eq) at -78 °C, and then the mixture was stirred at -78 °C for 1 hour under N2atmosphere. On completion, the mixture was quenched with saturated solution of NH4Cl (50 mL) and extracted with ethyl acetate (40 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 ((2R)-3-((3- (methoxymethyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-5- yl)oxy)butan-2-yl)(methyl)carbamate (3.10 g, 6.84 mmol, 79% yield) as a yellow oil.

[0643] I-2-17 was prepared according to the preparation of I-2-15 using I-2-13 in step 2.

[0644] Preparation of (S)-(4-((1-((tert-butoxycarbonyl)(methyl)amino)propan-2- yl)oxy)pyridin-3-yl)boronic acid (I-2-18) I-4-23-bromopyridin-4-amine (5.00 g, 28.9 mmol, 1 eq) at 0 °C, then NaNO2(2.79 g, 40.5 mmol, 1.4 eq) was added. The mixture was stirred at 95 °C for 1 h. On completion, the reaction mixture was quenched by addition of aq. NaOH (6 mL) at 0 °C to adjust the pH to 7, and processed the pH to 8 by addition of aq. NaHCO3 (6 mL). Then, the reaction mixture was extracted with EA (20 mL × 10). To the aqueous phase was added citric acid to adjust the pH to 6, then was concentrated under reduced pressure to give a residue. The residue was triturated with MeOH at 25 °C for 30 min, then was filtered, and the filter cake was discarded while the filtrate was concentrated under reduced pressure to give a crude product. The crude product83573-420992 was purified by column chromatography (SiO2, DCM / MeOH= 1 / 0 to 8 / 1) to give 3- bromopyridin-4-ol (2.50 g, 14.4 mmol, 50% yield) as a white solid. LCMS: m / z 175.1 (M+1).

[0646] Step 2. A mixture of 3-bromopyridin-4-ol (2.30 g, 13.2 mmol, 1 eq), tert-butyl (R)-(2- hydroxypropyl)carbamate (3.47 g, 19.8 mmol, 1.5 eq) in THF (23 mL) was added PPh3 (6.93 g, 26.4 mmol, 2 eq), DBAD (4.57 g, 19.8 mmol, 1.5 eq) 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. Then the residue was triturated with MTBE at 0 °C for 30 mins. The crude product was purified by column chromatography (SiO2, PE / THF= 1 / 0 to 3 / 1) to give tert-butyl (S)-(2-((3-bromopyridin-4-yl)oxy)propyl)carbamate (3.80 g, 11.47 mmol, 87% yield) as a colorless oil.

[0647] Step 3. A mixture of tert-butyl (S)-(2-((3-bromopyridin-4-yl)oxy)propyl)carbamate (3.80 g, 11.5 mmol, 1 eq) in DMF (38 mL) was added NaH (918 mg, 22.9 mmol, 60% purity, 2 eq) at 0 °C and stirred for 10 mins. Then was added CH3I (1.79 g, 12.6 mmol, 1.1 eq) dropwise, and the mixture was stirred at 25 °C for 1 h under N2atmosphere. On completion, the reaction mixture was quenched by addition of aq. NH4Cl (10 mL) at 0 °C and then diluted with H2O (20 mL) and extracted with EA (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / THF= 1 / 0 to 3 / 1) to give tert-butyl (S)-(2-((3-bromopyridin-4- yl)oxy)propyl)(methyl)carbamate (3.70 g, 10.7 mmol, 93% yield) as a colorless oil.

[0648] Step 4. To a solution of tert-butyl (S)-(2-((3-bromopyridin-4- yl)oxy)propyl)(methyl)carbamate (2.00 g, 5.79 mmol, 1 eq) and 2-isopropoxy-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (3.23 g, 17.4 mmol, 3 eq) in THF (40 mL) was degassed and purged with N2 for 3 times and cooled to -78°C, then n-BuLi (2.5 M in n-hexane, 5.79 mL, 2.5 eq) was added dropwise at -78 °C over 10 min under N2 atmosphere. After addition, the resulting mixture was stirred at -78 °C for 1 h under N2 atmosphere. On completion, the reaction mixture was quenched by addition of aq. NH4Cl (1 mL) at 0 °C, and then concentrated under reduced pressure to give a residue, the residue was triturated with MeOH at 25 °C for 10 min, filtered and concentrated under reduce pressure to give the crude product. Then the crude product was purified by reversed-phase HPLC (0.1% NH4HCO3 condition) to give (S)- (4-((1-((tert-butoxycarbonyl)(methyl)amino)propan-2-yl)oxy)pyridin-3-yl)boronic acid (600 mg, 1.93 mmol, 33% yield) as a white solid.

[0649] I-2-19 was prepared according to the preparation of I-2-16 using 1,3-dimethyl-1H- pyrazol-5-ol in step 2.83573-420992

[0650] Preparation of tert-butyl methyl(2-((1-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazol-3-yl)oxy)ethyl)carbamate (I-2-20)was g, 0 °C. Then was added 1-methyl-1H-pyrazol-3-ol (500 mg, 5.10 mmol, 1 eq) and tert-butyl (2- hydroxyethyl)(methyl)carbamate (1.07 g, 6.12 mmol, 1.2 eq), and the mixture was stirred at 25 °C for 1 hour under N2 atmosphere. On completion, the reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography (SiO2, Petroleum ether / THF= 1:0 to 3:1) to tert-butyl methyl(2-((1-methyl- 1H-pyrazol-3-yl)oxy)ethyl)carbamate (680 mg, 2.66 mmol, 52% yield) as an off-white oil. LCMS: m / z 156.2 (M-100).1H NMR (400 MHz, CDCl3) δ = 7.55 (s, 1H), 7.41 (d, J = 2.4 Hz, 1H), 5.89 (s, 1H), 4.51 (t, J = 5.2 Hz, 2H), 4.02 (s, 3H), 3.86 (s, 2H), 3.25 (s, 3H), 1.74 (s, 8H).

[0652] Step 2. To a solution of tert-butyl methyl(2-((1-methyl-1H-pyrazol-3- yl)oxy)ethyl)carbamate (0.650 g, 2.55 mmol, 1 eq) in DMF (6 mL) was added NBS (498 mg, 2.80 mmol, 1.1 eq). The mixture was stirred at 25 °C for 1 hour. On completion, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF= 1:0 to 0:1) to give tert-butyl (2-((4-bromo-1-methyl-1H-pyrazol-3- yl)oxy)ethyl)(methyl)carbamate (330 mg, 987 μmol, 39% yield) as an off-white oil. LCMS: m / z 234.1 (M-100).

[0653] Step 3. A mixture of tert-butyl (2-((4-bromo-1-methyl-1H-pyrazol-3- yl)oxy)ethyl)(methyl)carbamate (1.70 g, 5.09 mmol, 1 eq) in 2-MeTHF (15 mL) was degassed and purged with N2for 3 times at -78 °C, and then was added n-BuLi (2.5 M in THF, 6.10 mL, 3 eq) at -78 °C, and then the mixture was stirred at -78 °C for 0.5 hour under N2 atmosphere.83573-420992 And then was added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.14 g, 6.10 mmol, 1.2 eq) at -78 °C, and the mixture was stirred at -78 °C for 0.5 hour under N2 atmosphere. On completion, the mixture was quenched with aqueous NH4Cl (50 mL) and was extracted with EA (30 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give tert-butyl methyl(2-((1-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-3-yl)oxy)ethyl)carbamate (2.10 g, 4.96 mmol, 97% yield, 90% purity) as a yellow oil.

[0654] Preparation of tert-butyl (S)-(2,2-difluoroethyl)(2-((1,3-dimethyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-5-yl)oxy)propyl)carbamate (I-2-21)(100 mL) was added 2,2-difluoroethan-1-amine (20.9 g, 258 mmol, 3 eq). The mixture was stirred at 25 °C for 14 hours. On completion, the mixture was concentrated to give (R)-1-((2,2- difluoroethyl)amino)propan-2-ol (7.70 g, 55.3 mmol, 64% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ = 5.85 (tt, J = 4.0, 56.4 Hz, 1H), 3.86 - 3.72 (m, 1H), 3.00 (dt, J = 4.0, 15.2 Hz, 2H), 2.81 (dd, J = 2.8, 12.0 Hz, 1H), 2.49 (dd, J = 9.2, 12.0 Hz, 1H), 1.20 - 1.14 (m, 3H).

[0656] Step 2. To a solution of (R)-1-((2,2-difluoroethyl)amino)propan-2-ol (6.80 g, 48.8 mmol, 1 eq) in DCM (100 mL) was added TEA (14.8 g, 146 mmol, 3 eq), tert-butoxycarbonyl tert-butyl carbonate (26.7 g, 122 mmol, 2.5 eq) and DMAP (597 mg, 4.89 mmol, 0.1 eq). The mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was partitioned between dichloromethane (100 mL × 3) and water (100 mL), and the combined organic phase83573-420992 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 5:1) to give tert-butyl (R)-(2,2-difluoroethyl)(2-hydroxypropyl)carbamate (8.00 g, 33.4 mmol, 68% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ = 6.22 - 5.70 (m, 1H), 4.01 (d, J = 4.4 Hz, 1H), 3.72 - 3.49 (m, 2H), 3.45 - 3.14 (m, 2H), 1.48 (s, 9H), 1.17 (d, J = 6.4 Hz, 3H).

[0657] Step 3. To a solution of tert-butyl (R)-(2,2-difluoroethyl)(2-hydroxypropyl)carbamate (7.00 g, 29.2 mmol, 1 eq) in DCM (100 mL) was added TEA (87.7 mmol, 12.0 mL, 3 eq) and methylsulfonyl methanesulfonate (12.7 g, 73.1 mmol, 2.5 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hour. On completion, the mixture was quenched with saturated solution of NH4Cl (100 mL) and extracted with dichloromethane (100 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give (R)-1-((tert- butoxycarbonyl)(2,2-difluoroethyl)amino)propan-2-yl methanesulfonate (9.00 g, 28.3 mmol, 96% yield) as a yellow oil.

[0658] Step 4. To a solution of (R)-1-((tert-butoxycarbonyl)(2,2-difluoroethyl)amino)propan- 2-yl methanesulfonate (9.00 g, 28.3 mmol, 1 eq) in DMF (100 mL) was added Cs2CO3 (27.7 g, 85.0 mmol, 3 eq) and 1,3-dimethyl-1H-pyrazol-5-ol (3.18 g, 28.3 mmol, 1 eq). The mixture was stirred at 80 °C for 16 hours. On completion, the reaction mixture was partitioned between ethyl acetate (100 mL × 3) and water (100 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF = 1:0 to 5:1) to give tert-butyl (S)-(2,2-difluoroethyl)(2-((1,3-dimethyl-1H-pyrazol-5-yl)oxy)propyl)carbamate (6.80 g, 20.4 mmol, 71% yield) as a colorless oil. LCMS: m / z 334.0 (M+1).

[0659] Step 5. To a solution of tert-butyl (S)-(2,2-difluoroethyl)(2-((1,3-dimethyl-1H-pyrazol- 5-yl)oxy)propyl)carbamate (2.94 g, 8.82 mmol, 1 eq) in ACN (30 mL) was added NBS (1.57 g, 8.82 mmol, 1 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hour. On completion, the reaction 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 5:1) to give tert-butyl (S)-(2-((4-bromo- 1,3-dimethyl-1H-pyrazol-5-yl)oxy)propyl)(2,2-difluoroethyl)carbamate (2.40 g, 5.82 mmol, 66% yield) as yellow oil.

[0660] Step 6. A mixture of tert-butyl (S)-(2-((4-bromo-1,3-dimethyl-1H-pyrazol-5- yl)oxy)propyl)(2,2-difluoroethyl)carbamate (2.00 g, 4.85 mmol, 1 eq), 4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (1.86 g, 14.5 mmol, 3 eq), XPhos (231 mg, 485 μmol, 0.1 eq), acetonitrile dichloropalladium (125 mg, 485 μmol, 0.1 eq) and TEA (736 mg, 7.28 mmol, 1.5 eq) in83573-420992 dioxane (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110 °C for 1 hour under N2 atmosphere. On completion, the reaction mixture was partitioned between ethyl acetate (20 mL × 3) and water (20 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 5:1) to give tert- butyl (S)-(2,2-difluoroethyl)(2-((1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-pyrazol-5-yl)oxy)propyl)carbamate (1.80 g, 3.92 mmol, 80% yield) as a yellow oil.

[0661] Preparation of 5-methoxy-1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-pyrazole (I-2-22)

[0662] eq) in DMF (200 mL) was added methyl 4-methylbenzenesulfonate (43.2 g, 232 mmol, 1.3 eq) and Cs2CO3(116 g, 357 mmol, 2 eq). The mixture was stirred at 60 °C for 5 hours. On completion, the reaction mixture was quenched by addition H2O (400 mL) at 0 °C and extracted with EA (100 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 / Ethyl acetate = 1:0 to 1:1) to give 5-methoxy-1,3- dimethyl-1H-pyrazole (16.0 g, 127 mmol, 71% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ = 5.30 (s, 1H), 3.82 (s, 3H), 3.55 (s, 3H), 2.17 (s, 3H).

[0663] Step 2. To a solution of 5-methoxy-1,3-dimethyl-1H-pyrazole (16.0 g, 127 mmol, 1 eq) in CH3CN (160 mL) was added NBS (27.1 g, 152 mmol, 1.2 eq). The mixture was stirred at 25 °C for 0.5 hours. On completion, the mixture was quenched with saturated solution of Na2SO3(100 mL) and extracted with EA (50 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 / Ethyl acetate = 1:0 to 1:1) to give 4-bromo-5-methoxy-1,3-dimethyl-1H-pyrazole (5.00 g, 24.4 mmol, 19% yield) as a yellow oil.83573-420992

[0664] Step 3. To a solution of 4-bromo-5-methoxy-1,3-dimethyl-1H-pyrazole (4.60 g, 22.4 mmol, 1 eq) in THF (50 mL) was added n-BuLi (2.5 M in THF, 10.7 mL, 1.2 eq) and 2- isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.01 g, 26.9 mmol, 1.2 eq). The mixture was stirred at -78 °C for 1 hour. On completion, the reaction mixture was quenched by addition of H2O (20 mL) at 0 °C 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 / Ethyl acetate = 1:0 to 1:1) to give 5-methoxy-1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole (4.60 g, 18.2 mmol, 81% yield) as yellow oil.

[0665] Preparation of tert-butyl (S)-ethyl(2-((1-ethyl-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazol-5-yl)oxy)propyl)carbamate (I-2-23) NHin EtOH (50 mL) was added KOAc (2.86 g, 29.1 mmol, 1.5 eq). The mixture was stirred at 25 °C for 0.1 hour. Then ethyl 3-oxobutanoate (2.52 g, 19.4 mmol, 2.46 mL, 1 eq) was added. The mixture was stirred at 80 °C for 0.9 hour. On completion, the solution was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, DCM / MeOH= 1:0 to 0:1) to give compound 1-ethyl-3-methyl-1H-pyrazol-5-ol (2.80 g, 15.5 mmol, 80% yield, 70% purity) as a yellow oil.1H NMR (400 MHz, CDCl3) δ = 5.97 (s, 1H), 4.21 (q, J = 7.2 Hz, 2H), 2.36 (s, 3H), 1.49 - 1.45 (m, 3H).83573-420992

[0667] Step 2. To a solution of 1-ethyl-3-methyl-1H-pyrazol-5-ol (2.60 g, 20.6 mmol, 1 eq) in DMF (30 mL) was added K2CO3 (8.54 g, 61.8 mmol, 3 eq) and (R)-1-((tert- butoxycarbonyl)amino)propan-2-yl methanesulfonate (5.22 g, 20.6 mmol, 1 eq). The mixture was stirred at 60 °C for 1 hour. On completion, the mixture was quenched with water (100 mL) and extracted with ethyl acetate (40 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 3:1), to give compound tert- butyl (S)-(2-((1-ethyl-3-methyl-1H-pyrazol-5-yl)oxy)propyl)carbamate (3.80 g, 13.4 mmol, 65% yield) as a yellow oil. LCMS: m / z 284.1 (M+1).1H NMR (400 MHz, CDCl3) δ = 5.36 - 5.28 (m, 1H), 4.90 - 4.82 (m, 1H), 3.93 (q, J = 7.2 Hz, 1H), 3.51 - 3.13 (m, 3H), 3.03 (s, 3H), 2.20 (s, 1H), 1.48 - 1.39 (m, 17H).

[0668] Step 3. To a solution of tert-butyl (S)-(2-((1-ethyl-3-methyl-1H-pyrazol-5- yl)oxy)propyl)carbamate (3.60 g, 12.7 mmol, 1 eq) in DMF (40 mL) was added NaH (1.02 g, 25.4 mmol, 60% purity, 2 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 hour, and then EtI (2.18 g, 13.9 mmol, 1.12 mL, 1.1 eq) was added at 0°C, the mixture was stirred at 25°C for 0.5 hour. On completion, the reaction mixture was quenched by addition NH4Cl (30 mL) at 0 °C, and then diluted with water (10 mL) and extracted with ethyl acetate (5 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF= 1:0 to 3:1) to give compound tert-butyl (S)-ethyl(2-((1-ethyl-3-methyl-1H-pyrazol-5-yl)oxy)propyl)carbamate (0.660 g, 2.12 mmol, 17% yield) as a yellow oil. LCMS: m / z 312.2 (M+1).1H NMR (400 MHz, CDCl3) δ = 5.30 (s, 1H), 4.55 - 4.31 (m, 1H), 3.91 (q, J = 7.2 Hz, 2H), 3.41 - 3.18 (m, 4H), 2.19 (s, 3H), 1.47 (s, 9H), 1.35 - 1.28 (m, 6H), 1.14 - 1.06 (m, 3H).

[0669] Step 4. To a solution of tert-butyl (S)-ethyl(2-((1-ethyl-3-methyl-1H-pyrazol-5- yl)oxy)propyl)carbamate (600 mg, 1.93 mmol, 1 eq) in ACN (6 mL) was added NBS (377 mg, 2.12 mmol, 1.1 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hour. On completion, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF=1:0 to 1:0), to give compound tert-butyl (S)-(2-((4-bromo-1-ethyl-3-methyl-1H- pyrazol-5-yl)oxy)propyl)(ethyl)carbamate (580 mg, 1.49 mmol, 77% yield) as a yellow oil. LCMS: m / z 411.9 (M+23).1H NMR (400 MHz, CDCl3) δ = 4.85 (d, J = 3.2 Hz, 1H), 3.94 (q, J = 7.2 Hz, 2H), 3.53 - 3.16 (m, 4H), 2.18 (s, 3H), 1.47 (s, 9H), 1.35 (t, J = 7.2 Hz, 3H), 1.26 (d, J = 6.0 Hz, 3H).83573-420992

[0670] Step 5. A mixture of tert-butyl (S)-(2-((4-bromo-1-ethyl-3-methyl-1H-pyrazol-5- yl)oxy)propyl)(ethyl)carbamate (0.530 g, 1.36 mmol, 1 eq) in 2-Me THF (8 mL) was degassed and purged with N2 for 3 times at -78 °C, and then was added n-BuLi (2.50 M, 1.63 mL, in THF, 3 eq) at -78 °C. Then the mixture was stirred at -78 °C for 0.5 hour under N2 atmosphere, and then was added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (303 mg, 1.63 mmol, 1.2 eq) at -78 °C, and the mixture was stirred at -78 °C for 0.5 hour under N2 atmosphere. On completion, the mixture was quenched with aqueous NH4Cl (10 mL) and was extracted with EA (10 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 compound tert-butyl (S)- ethyl(2-((1-ethyl-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-5- yl)oxy)propyl)carbamate (270 mg, 617 μmol, 45% yield) as a yellow oil.

[0671] Preparation of tert-butyl (S)-ethyl(2-((3-ethyl-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazol-5-yl)oxy)propyl)carbamate (I-2-24)(65 mL) was added TEA (6.84 g, 67.6 mmol, 9.41 mL, 1.5 eq) and the mixture was stirred at 25 °C for 15 mins. Then was added ethyl 3-oxopentanoate (6.50 g, 45.1 mmol, 1 eq). The mixture was stirred at 40 °C for 2 hours. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EA = 2:1 to 0:1), and the eluent was concentrated to remove EA and PE to get 3-83573-420992 ethyl-1-methyl-1H-pyrazol-5-ol (4.80 g, 38.1 mmol, 84% yield) as a white solid. LCMS: m / z 127.0 (M+1).

[0673] Step 2 was performed in a similar manner to step 2 of the synthesis for I-2-23 except substituting Cs2CO3 for K2CO3.

[0674] Steps 3 and 4 were performed in a similar manner to steps 3 and 4 of the synthesis for I-2-23.

[0675] Step 5 was performed in a similar manner to step 5 of the synthesis for I-2-23 except substituting THF for Me-THF.

[0676] Preparation of tert-butyl (S)-(2-((3-(2,2-difluoroethyl)-1-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-5-yl)oxy)propyl)(ethyl)carbamate (I-2-25) NHBoc NNOMsI-4-3 NNEtI, NaH NNg, 128 mmol, 1 eq) in DMF (300 mL) was added Cs2CO3 (125 g, 384 mmol, 3 eq) and (R)-1- ((tert-butoxycarbonyl)amino)propan-2-yl methanesulfonate (64.9 g, 256 mmol, 2 eq). The mixture was stirred at 80 °C for 2 h. On completion, the mixture was quenched with water (600 mL) and extracted with EA (500 mL × 3). The combined organic layers were washed with brine (500 mL× 2), dried over Na2SO4, filtered and concentrated to give methyl (S)-5-((1-((tert-83573-420992 butoxycarbonyl)amino)propan-2-yl)oxy)-1-methyl-1H-pyrazole-3-carboxylate (33.0 g, 105 mmol, 82% yield) as a brown oil. LCMS: m / z 314.1 (M+1).

[0678] Step 2. To a solution of methyl (S)-5-((1-((tert-butoxycarbonyl)amino)propan-2- yl)oxy)-1-methyl-1H-pyrazole-3-carboxylate (32.0 g, 102 mmol, 1 eq) and EtI (31.8 g, 204 mmol, 2 eq) in DMF (320 mL) was added NaH (12.2 g, 306 mmol, 60% purity, 3 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h, then warmed to 25 °C and stirred for 12 h. On completion, the mixture was quenched with sat. NH4Cl (500 mL) and pH was adjusted to 5 with dilute citric acid (200 mL), then extracted with ethyl acetate (300 mL × 5). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give (S)- 5-((1-((tert-butoxycarbonyl)(ethyl)amino)propan-2-yl)oxy)-1-methyl-1H-pyrazole-3- carboxylic acid (35.0 g, crude) as a yellow oil. LCMS: m / z 350.1 (M+23).

[0679] Step 3. To a solution of (S)-5-((1-((tert-butoxycarbonyl)(ethyl)amino)propan-2- yl)oxy)-1-methyl-1H-pyrazole-3-carboxylic acid (34.0 g, 104 mmol, 1 eq) in DMF (340 mL) was added DIEA (53.7 g, 415 mmol, 4 eq), N-methoxymethanamine hydrochloride (10.1 g, 104 mmol, 1 eq) and HATU (43.4 g, 114 mmol, 1.1 eq). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was quenched with water (500 mL) and extracted with EA (300 mL × 3). The combined organic layers were washed with brine (300 mL× 3), dried over Na2SO4,filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:THF= 1:0 to 3:1) to give tert-butyl (S)-ethyl(2-((3- (methoxy(methyl)carbamoyl)-1-methyl-1H-pyrazol-5-yl)oxy)propyl)carbamate (15.0 g, 40.5 mmol, 39% yield) as a yellow oil. LCMS: m / z 371.2 (M+1).1H NMR (400 MHz, DMSO-d6) δ = 6.12 - 6.02 (m, 1H), 4.61 - 4.48 (m, 1H), 3.70 - 3.65 (m, 3H), 3.60 - 3.56 (m, 3H), 3.31 - .07 (m, 4H), 1.40 - 1.35 (m, 9H), 1.31 - 1.24 (m, 3H), 1.05 - 1.00 (m, 3H).

[0680] Step 4. A solution of tert-butyl (S)-ethyl(2-((3-(methoxy(methyl)carbamoyl)-1-methyl- 1H-pyrazol-5-yl)oxy)propyl)carbamate (14.0 g, 37.8 mmol, 1 eq) in THF (140 mL) was degassed and purged with N2 for 3 times, and then DIBAL-H (1 M in Toluene, 56.7 mL, 1.5 eq) was added dropwise at 0 °C. The mixture was stirred at 25 °C for 1 h under N2atmosphere. On completion, the mixture was sequentially quenched with water (2.4 mL), 15% NaOH (2.4 mL), and water (6 mL), and then the mixture 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 3:1) to give tert-butyl (S)-ethyl(2-((3-formyl-1-methyl- 1H-pyrazol-5-yl)oxy)propyl)carbamate (5.80 g, 18.6 mmol, 49% yield) as a colorless oil. LCMS: m / z 256.1 (M+1).

[0681] Step 5. A solution of tert-butyl (S)-ethyl(2-((3-formyl-1-methyl-1H-pyrazol-5- yl)oxy)propyl)carbamate (5.32 g, 17.10 mmol, 1 eq) and 2,2-difluoro-2-83573-420992 triphenylphosphaniumyl-acetate (10.3 g, 29.1 mmol, 1.7 eq) in DMF (54 mL) was stirred at 80 °C for 2 h under N2. On completion, the mixture was quenched with water (200 mL) and extracted with EA (150 mL × 3). The combined organic layers were washed with brine (150 mL× 2), dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:THF= 1:0 to 6:1) to give tert-butyl (S)-(2-((3- (2,2-difluorovinyl)-1-methyl-1H-pyrazol-5-yl)oxy)propyl)(ethyl)carbamate (2.20 g, 6.37 mmol, 37% yield) as a colorless oil. LCMS: m / z 346.1 (M+1).1H NMR (400 MHz, CDCl3) δ = 5.59 (d, J = 2.4 Hz, 1H), 5.35 - 5.22 (m, 1H), 4.59 - 4.38 (m, 1H), 4.14 - 3.95 (m, 1H), 3.59 (s, 3H), 3.43 - 3.17 (m, 3H), 1.46 (s, 9H), 1.35 - 1.26 (m, 3H), 1.16 - 1.06 (m, 3H).

[0682] Step 6. A mixture of tert-butyl (S)-(2-((3-(2,2-difluorovinyl)-1-methyl-1H-pyrazol-5- yl)oxy)propyl)(ethyl)carbamate (2.20 g, 6.37 mmol, 1 eq) and Pd / C (880 mg, 827 μmol, 10% purity, 0.13 eq) in MeOH (100 mL) and EtOAc (100 mL) was degassed and purged with H2 for 3 times, and then the mixture was stirred at 25 °C for 4 h under H2atmosphere. On completion, the mixture was filtered by diatomaceous earth and concentrated to give tert-butyl (S)-(2-((3-(2,2-difluoroethyl)-1-methyl-1H-pyrazol-5-yl)oxy)propyl)(ethyl)carbamate (2.11 g, 5.95 mmol, 93% yield, 98% purity) as a colorless oil. LCMS: m / z 348.1 (M+1).

[0683] Step 7. To a solution of tert-butyl (S)-(2-((3-(2,2-difluoroethyl)-1-methyl-1H-pyrazol- 5-yl)oxy)propyl)(ethyl)carbamate (2.10 g, 6.04 mmol, 1 eq) in ACN (20 mL) was added NBS (1.13 g, 6.35 mmol, 1.05 eq). The mixture was stirred at 0 °C for 1 h. On completion, the mixture was quenched with sat. Na2SO3(50 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 to give a residue. The residue was purified by column chromatography (SiO2, PE:THF= 1:0 to 5:1) to give tert-butyl (S)-(2-((4-bromo-3-(2,2-difluoroethyl)-1-methyl-1H- pyrazol-5-yl)oxy)propyl)(ethyl)carbamate (2.50 g, 5.86 mmol, 97% yield) as a colorless oil. LCMS: m / z 428.0 (M+1).

[0684] Step 8. To a solution of tert-butyl (S)-(2-((4-bromo-3-(2,2-difluoroethyl)-1-methyl-1H- pyrazol-5-yl)oxy)propyl)(ethyl)carbamate (2.30 g, 5.40 mmol, 1 eq) in THF (23 mL) was added n-BuLi (2.5 M in n-hexane, 4.32 mL, 2 eq) dropwise at -78 °C under N2. The mixture was stirred at this temperature for 0.5 h, and then 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (3.01 g, 16.2 mmol, 3.30 mL, 3 eq) was added dropwise at -78 °C. The resulting mixture was stirred at -78 °C for 0.5 h. On completion, the mixture was quenched with sat. NH4Cl (50 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 to give a residue. The residue was purified by column chromatography (SiO2, PE:THF= 1:0 to 5:1) to give tert-butyl83573-420992 (S)-(2-((3-(2,2-difluoroethyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazol-5-yl)oxy)propyl)(ethyl)carbamate (800 mg, 845 μmol, 16% yield, 50% purity).

[0685] Intermediate Table 2. Int. # Structure m / z1H NMR (400 MHz CDCl3) δ = 4.18 (s 2H), ), 9 083573-420992 ), 2 , 8 , - 083573-420992 - - 783573-420992

[0686] Preparation of 3-(methoxymethyl)-1-methyl-4-(3-vinylimidazo[1,2-a]pyrazin-6-yl)- 1H-pyrazol-5-ol (I-3-1).

[0687] Stepg, 11.1 mmol, 1 eq) in dioxane (25 mL) was added 3-(methoxymethyl)-1-methyl-1H-pyrazol-5-ol (2.06 g, 14.51 mmol, 1.3 eq), tBuBrettPhosPdG3 (572 mg, 0.669 mmol, 0.06 eq) and K2CO3 (4.71 g, 34.1 mmol, 3 eq). The mixture was stirred at 130 °C for 1 h. On completion, the reaction mixture was partitioned between (DCM:MeOH= 15:1) (20 mL × 3) and water (20 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, DCM:MeOH =15:183573-420992 to 15:1) to give 3-(methoxymethyl)-1-methyl-4-(3-vinylimidazo[1,2-a]pyrazin-6-yl)-1H- pyrazol-5-ol (3.60 g, 8.58 mmol, 77% yield, 68% purity) as a brown solid.

[0688] I-3-2 was prepared in a manner similar to those described in the synthesis of I-3-1 starting from I-2-1 and I-1-7.

[0689] I-3-3 was prepared in a manner similar to those described in the synthesis of I-3-1 starting from I-1-9 and I-2-13 and heating for 3 h at 140 °C.

[0690] I-3-4 was prepared according to the preparation of I-3-1 starting from I-1-9 and I-2-1.

[0691] Preparation of 1,3-dimethyl-4-(3-vinylimidazo[1,5-a]pyrazin-6-yl)-1H-pyrazol-5-ol (I-3-5).

[0692] 1,3,2- dioxaborolan-2-yl)-1H-pyrazole (4.60 g, 18.2 mmol, 1 eq), 6-chloro-3-vinylimidazo[1,5- a]pyrazine (3.28 g, 18.2 mmol, 1 eq), [2-(2-aminophenyl)phenyl]-chloro-palladium dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (1.44 g, 1.82 mmol, 0.1 eq) and K3PO4 (11.6 g, 54.7 mmol, 3 eq) in dioxane (50 mL) and H2O (10 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 quenched by addition of H2O (20 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 / Ethyl acetate = 1:0 to 0:1) to give 6-(5-methoxy-1,3-dimethyl-1H-pyrazol-4-yl)-3-vinylimidazo[1,5-a]pyrazine (3.50 g, 12.1 mmol, 66% yield) as a yellow solid. LCMS: m / z 270.1 (M+1).1H NMR (400 MHz, CDCl3) δ = 8.99 (d, J = 1.2 Hz, 1H), 7.89 (s, 1H), 7.84 (s, 1H), 6.91 (dd, J = 11.2, 17.2 Hz, 1H), 6.38 (d, J = 16.8 Hz, 1H), 5.64 (d, J = 11.2 Hz, 1H), 3.86 (s, 3H), 3.71 (s, 3H), 2.36 (s, 3H).

[0693] Step 2. To a solution of 6-(5-methoxy-1,3-dimethyl-1H-pyrazol-4-yl)-3- vinylimidazo[1,5-a]pyrazine (500 mg, 1.86 mmol, 1 eq) in DCM (5 mL) was added BBr3 (2 M, 1.11 mL, 1.2 eq). The mixture was stirred at 25 °C for 5 hours. On completion, the mixture83573-420992 was quenched with water (5 mL) and sodium hydroxide solution (5 mL), then extracted with DCM (5 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 / Ethyl acetate = 1:0 to 0:1) to give 1,3- dimethyl-4-(3-vinylimidazo[1,5-a]pyrazin-6-yl)-1H-pyrazol-5-ol (900 mg, crude) as a yellow solid.

[0694] Intermediate Table 3. Int. # SMs Structurem / z 1H NMR s, J , z, ,

[0695] Preparation of (R)-N-ethyl-2,2,2-trifluoro-N-(2-hydroxypropyl)acetamide (I-4-1)83573-420992 (100mL) was . was for 12 h. On completion, the mixture was concentrated to give (R)-1-(ethylamino)propan-2-ol (8.13 g, 78.8 mmol, 46% yield) as a brown solid.1H NMR (400 MHz, CDCl3) δ = 3.84 - 3.70 (m, 1H), 2.74 - 2.55 (m, 3H), 2.45 - 2.34 (m, 2H), 1.16 - 1.05 (m, 6H).

[0697] Step 2. To a solution of (R)-1-(ethylamino)propan-2-ol (8.13 g, 78.8 mmol, 1 eq) in DCM (80 mL) was added trifluoroacetic anhydride (24.8 g, 118 mmol, 16.4 mL, 1.5 eq) and TEA (39.9 g, 394 mmol, 5 eq) at 0 °C, then the mixture was stirred at 0 °C for 1 h. On completion, the reaction mixture was partitioned between DCM (100 mL × 3) and water (100 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:THF= 1:1 to 1:1) to give (R)-N-ethyl-2,2,2-trifluoro-N-(2-hydroxypropyl)acetamide (7.92 g, 39.8 mmol, 50% yield) as a white solid. LCMS: m / z 200.1 (M+1).

[0698] Preparation of (R)-1-((tert-butoxycarbonyl)amino)propan-2-yl methanesulfonate (I-4- 3)

[0699] Step 1. To a(5.00 g, 26.7 mmol, 1 eq) in DCM (50 mL) was added TEA (8.11 g, 80.1 mmol, 3 eq) and Ms2O (6.98 g, 40.0 mmol, 1.5 eq). The mixture was stirred at 0 °C for 2 h. On completion, the mixture was quenched with water (40 mL) and extracted with DCM (40 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give (R)-1-((tert- butoxycarbonyl)amino)propan-2-yl methanesulfonate (6.30 g, 23.7 mmol, 89% yield) as a yellow oil.

[0700] I-4-4 was prepared in a similar manner to those described in the preparation of I-4-1 using methylamine instead in step 1.

[0701] Preparation of (S)-1-(cyclopropylamino)propan-2-ol (I-4-5)83573-420992

[0702] Step 1. To a solution 17.2 mmol, 1 eq) in MeOH (20mL) was added . The mixture was stirred at 25 °C for 5 hours. On completion, the reaction mixture was concentrated under reduced pressure to give (S)-1-(cyclopropylamino)propan-2-ol (1.60 g, 13.9 mmol, 80% yield) as a colorless oil.

[0703] Intermediate Table 4. Intermediate. # Structurem / z 1H NMR

[0704] Preparation of ethyl 3-isopropoxy-1H-pyrazole-5-carboxylate (I-5-1a).

[0705] Step 1.(30.0 g, 192 mmol, 1 eq) in DMF (300 mL) was added K2CO3(39.8 g, 288 mmol, 1.5 eq) and 2-iodopropane (34.2 g, 202 mmol, 20.1 mL, 1.05 eq). The mixture was stirred at 80 °C for 1 hr. On completion, the83573-420992 reaction mixture was diluted with H2O (500 mL) and extracted with EA mL (200 mL × 5). The combined organic layers were washed with H2O mL (200 mL × 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 1 / 0 to 0 / 1) to give ethyl 3-isopropoxy- 1H-pyrazole-5-carboxylate (23.0 g, 116 mmol, 60% yield) as a yellow oil. LCMS: m / z 199.0 (M+1).

[0706] Preparation of (S)-1-(2-((tert-butyldimethylsilyl)oxy) propyl)-4-iodo-5-(iodomethyl)- 3-isopropoxy-1H-pyrazole (I-5-1)in DCM (30 mL) was added imidazole (5.19 g, 76.2 mmol, 3 eq), then TBSCl (5.74 g, 38.1 mmol, 1.5 eq) was added at 0 °C. The mixture was stirred at 25 °C for 1 h. On completion, the mixture was quenched with dilute citric acid (100 mL) and extracted with DCM (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, PE: EA=10:1) to give ethyl (S)-2-((tert-butyldimethylsilyl)oxy)propanoate (5.80 g, crude) as a white oil.1H NMR (400 MHz, DMSO-d6) δ = 4.32 (d, J = 6.8 Hz, 1H), 4.15 - 4.03 (m, 2H), 1.30 - 1.26 (m, 3H), 1.21 - 1.16 (m, 3H), 0.86 (s, 9H), 0.04 (d, J = 3.2 Hz, 6H)

[0708] Step 2. A mixture of ethyl (S)-2-((tert-butyldimethylsilyl)oxy)propanoate (20.0 g, 86.1 mmol, 1 eq) in THF (200 mL) was degassed and purged with N2for 3 times, and LiBH4(2 M83573-420992 in THF, 215 mL, 5 eq) was added at 0 °C. The mixture was stirred at 25 °C for 4 h under N2 atmosphere. The reaction mixture was quenched by addition of MeOH (100 mL) at 0 °C, then the mixture was quenched by addition of NH4Cl (100 mL) at 0 °C. The reaction mixture was diluted with H2O (100 mL) and extracted with EA (50 mL × 4). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 0 / 1) to give (S)-2-((tert-butyldimethylsilyl)oxy)propan-1-ol (16.4 g, 81.9 mmol, 95% yield, 95% purity) as a colorless oil.1H NMR (400 MHz, CDCl3) δ = 3.87 - 3.76 (m, 1H), 3.64 - 3.56 (m, 1H), 3.38 - 3.34 (m, 1H), 2.48 (br s, 1H), 1.14 - 1.10 (m, 3H), 0.94 - 0.89 (m, 9H), 0.12 - 0.06 (m, 6H).

[0709] Step 3. A mixture of ethyl 3-isopropoxy-1H-pyrazole-5-carboxylate (9.30 g, 46.9 mmol, 1 eq), (S)-2-((tert-butyldimethylsilyl)oxy)propan-1-ol (13.4 g, 70.4 mmol, 1.5 eq), PPh3 (27.1 g, 103 mmol, 2.2 eq) in THF (100 mL) was degassed and purged with N2for 3 times, and the mixture was stirred at 25 °C for 0.5 h under N2atmosphere. DIAD (20.9 g, 103 mmol, 20.0 mL, 2.2 eq) was added at 0 °C. The mixture was stirred at 25 °C for 2 hr under N2 atmosphere. On completion, the reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 1 / 0 to 0 / 1) to give ethyl (S)-1-(2-((tert-butyldimethylsilyl)oxy)propyl)-3- isopropoxy-1H-pyrazole-5-carboxylate (12.5 g, 33.7 mmol, 72% yield, 100% purity) as colorless oil. LCMS: m / z 371.2 (M+1)

[0710] Step 4. To a solution of ethyl (S)-1-(2-((tert-butyldimethylsilyl)oxy)propyl)-3- isopropoxy-1H-pyrazole-5-carboxylate (13.9 g, 37.5 mmol, 1 eq) in THF (140 mL) was added LiAlH4 (2.5 M in THF, 22.5 mL, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 2 hr. On completion, the mixture was sequentially quenched with water (0.3 mL): NaOH (15%) (0.3 mL): water (0.9 mL). Then the mixture 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). (S)-(1-(2-((tert-butyldimethylsilyl)oxy)propyl)-3- isopropoxy-1H-pyrazol-5-yl)methanol (9.90 g, 30.1 mmol, 80% yield) was obtained as a yellow oil. LCMS: m / z 329.1 (M+1).

[0711] Step 5. To a solution of (S)-(1-(2-((tert-butyldimethylsilyl)oxy)propyl)-3-isopropoxy- 1H-pyrazol-5-yl)methanol (8.90 g, 27.1 mmol, 1 eq) in ACN (90 mL) was added NIS (6.70 g, 29.8 mmol, 1.1 eq) at 0 °C. The mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was quenched by addition Na2SO3(50 mL) at 0 °C, and then diluted with H2O (50 mL) and extracted with EA (50 mL x 4). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue83573-420992 was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 1 / 0 to 0 / 1). (S)- (1-(2-((tert-butyldimethylsilyl)oxy)propyl)-4-iodo-3-isopropoxy-1H-pyrazol-5-yl)methanol (12.8 g, 25.4 mmol, 94% yield, 90% purity) was obtained as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ = 5.30 - 5.23 (m, 1H), 4.81 - 4.69 (m, 1H), 4.54 - 4.45 (m, 2H), 4.40 - 4.29 (m, 1H), 3.67 (s, 1H), 3.66 - 3.64 (m, 1H), 1.30 - 1.25 (m, 9H), 0.75 (s, 9H), -0.06 - -0.09 (m, 3H), -0.16 (s, 3H).

[0712] Step 6. To (S)-(1-(2-((tert-butyldimethylsilyl)oxy)propyl)-4-iodo-3-isopropoxy-1H- pyrazol-5-yl)methanol (0.294 g, 0.647 mmol) in DCM (3.23 mL) was added NIS (291 mg, 1.29 mmol) at 0 °C, followed by PPh3(255 mg, 0.970 mmol). The reaction mixture was stirred for 2.5 hr at ambient temperature. The mixture was quenched with 1M sodium sulfite (aq) (5 mL) and worked up with DCM and water (10 mL each). The organic layer was extracted again with DCM (2× 5mL) and then dried over sodium sulfate. The salts were filtered and washed with DCM. The filtrate was concentrated and purified by flash column chromatography (automated system, 12g silica, 0-10% EA in Hexanes) to provide (S)-1-(2-((tert- butyldimethylsilyl)oxy)propyl)-4-iodo-5-(iodomethyl)-3-isopropoxy-1H-pyrazole (261 mg, 0.463 mmol, 71 % yield) as an off white solid. LCMS: m / z 565.13 (M+1).

[0713] Preparation of (S)-1-(2-((tert-butyldimethylsilyl)oxy) propyl)-4-iodo-5-(iodomethyl)- 3-isopropoxy-1H-pyrazole (I-5-2)

[0714] Step 1.propyl)-4-iodo-3- isopropoxy-1H-pyrazol-5-yl)methanol (8.90 g, 19.6 mmol, 1 eq), PPh3 (6.16 g, 23.5 mmol, 1.2 eq) in DCM (120 mL) was degassed and purged with N2 for 3 times, and CBr4 (7.79 g, 23.5 mmol, 1.2 eq) was added at 0 °C. The mixture was stirred at 25 °C for 2 hr under N2atmosphere. On completion, the reaction mixture was diluted with H2O (100 mL) and extracted with DCM (50 mL × 4). The combined organic layers were washed dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 0 / 1) to give [(1S)-2-[5- (bromomethyl)-4-iodo-3-isopropoxy-pyrazol-1-yl]-1-methyl-ethoxy]-tert-butyl-dimethyl- silane (1.98 g, 3.64 mmol, 19% yield, 95% purity) as yellow oil and (S)-5-(bromomethyl)-1-83573-420992 (2-((tert-butyldimethylsilyl)oxy)propyl)-4-iodo-3-isopropoxy-1H-pyrazole (7.80 g, 5.38 mmol, 27% yield, 27% purity) as a yellow oil.

[0715] Preparation of (S)-1-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo-5- (iodomethyl)-1H-pyrazole (I-5-3)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).

[0717] 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 × 4). The combined organic phase was washed with H2O (300 mL × 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),83573-420992 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).

[0718] 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).

[0719] Steps 4-7 followed the procedures of steps 3-6 of the synthesis of intermediate I-5-1 using I-5-3a instead of I-5-1a.

[0720] Preparation of 3-ethyl-4-iodo-1-methyl-1H-pyrazole-5-carboxylic acid (I-5-4)(150 mL) was added TEA (13.2 g, 131 mmol, 18.2 mL, 1.5 eq) followed by ethyl 2,4- dioxohexanoate (15.0 g, 87.1 mmol, 1 eq). The mixture was stirred at 25 °C for 1 hour. On completion, the mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by combi flash (80.0 g silica gel column, THF in PE from 0-100%) to give ethyl 3-ethyl-1-methyl-1H-pyrazole-5-carboxylate (9.50 g, 52.1 mmol, 60% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ = 6.64 (s, 1H), 4.33 (q, J = 7.2 Hz, 2H), 4.12 (s, 3H), 2.64 (q, J = 7.6 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H), 1.25 (t, J = 7.6 Hz, 3H). LCMS: m / z 183.1 (M+1)

[0722] Step 2. To a solution of ethyl 3-ethyl-1-methyl-1H-pyrazole-5-carboxylate (16.1 g, 88.4 mmol, 1 eq) in AcOH (160 mL) was added NIS (21.9 g, 97.2 mmol, 1.1 eq). The mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was quenched by addition of Sodium sulfite solution (100 mL) at 0 °C, and then neutralized with sodium bicarbonate solution and extracted with EA (80 mL × 3). The combined organic layers were washed with sodium chloride solution (100 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (120 g silica gel column, THF in PE from 0-100%) to give ethyl 3-ethyl-4-iodo-1-methyl-1H- pyrazole-5-carboxylate (24.0 g, 77.9 mmol, 88% yield) as a white oil. LCMS: m / z 308.9 (M+1)83573-420992

[0723] Step 3. To a solution of ethyl 3-ethyl-4-iodo-1-methyl-1H-pyrazole-5-carboxylate (5.00 g, 16.2 mmol, 1 eq) in THF (50 mL) and H2O (10 mL) was added LiOH.H2O (2.04 g, 48.7 mmol, 3 eq). The mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was extracted with THF (30 mL × 2). The combined organic layers were washed with salt solution (20 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (20.0 g silica gel column, MeOH in DCM from 0-20%) to give 3-ethyl-4-iodo-1-methyl-1H-pyrazole-5- carboxylic acid (4.20 g, 15.0 mmol, 92 % yield) as a white solid. LCMS: m / z 280.9 (M+1)

[0724] Preparation of (S)-1-(2-((tert-butyldimethylsilyl)oxy)propyl)-3-ethoxy-4-iodo-5- (iodomethyl)-1H-pyrazole (I-5-5)

[0725] I-5-5a was prepared in a manner similar to those described in the synthesis of I-5-1a starting from ethyl 3-hydroxy-1H-pyrazole-5-carboxylate and ethyl iodide.eq) in DCM (30 mL) was added imidazole (5.19 g, 76.2 mmol, 3 eq), then TBSCl (5.74 g, 38.1 mmol, 1.5 eq) was added at 0 °C. The mixture was stirred at 25 °C for 1 h. On completion, the mixture was quenched with diluted citric acid (100 mL) and extracted with DCM (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, PE: EA= 10:1) to give ethyl (S)-2-((tert-butyldimethylsilyl)oxy)propanoate (5.80 g, crude) as a white oil.1H NMR (400 MHz, DMSO-d6) δ = 4.32 (d, J = 6.8 Hz, 1H), 4.15 - 4.03 (m, 2H), 1.30 - 1.26 (m, 3H), 1.21 - 1.16 (m, 3H), 0.86 (s, 9H), 0.04 (d, J = 3.2 Hz, 6H)

[0727] Step 2. To a solution of ethyl (S)-2-((tert-butyldimethylsilyl)oxy)propanoate (3.00 g, 12.9 mmol, 1 eq) in THF (30 mL), N2 was replaced, BH3-Me2S (10 M, 2.58 mL, 2 eq) was added at 0 °C, and the mixture was stirred at 25 °C for 0.5 h. And then, the mixture was stirred83573-420992 at 70 °C for 2 h. On completion, the mixture was quenched with MeOH (10 mL) and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE: EA= 10:1) to give (S)-2-((tert-butyldimethylsilyl)oxy)propan-1-ol (1.96 g, crude) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ = 4.54 (t, J = 5.6 Hz, 1H), 3.77 - 3.68 (m, 1H), 3.31 - 3.10 (m, 2H), 1.04 (d, J = 6.0 Hz, 3H), 0.85 (s, 9H), 0.03 (s, 6H)

[0728] Steps 3-6 were conducted in a manner similar to those described in steps 3-6 of I-5-1 preparation with solvent in step 3 changed to Me-THF.

[0729] Preparation of 4-iodo-5-(iodomethyl)-3-isopropoxy-1-methyl-1H-pyrazole (I-5-6)g, 76.8 mmol, 1 eq) in DMF (120 mL) was added K2CO3 (15.9 g, 115 mmol, 1.5 eq) and 2- iodopropane (13.7 g, 80.7 mmol, 1.05 eq) at 0 °C. The mixture was stirred at 25 °C for 2 h. On completion, the reaction mixture was partitioned between EA (360 mL × 3) and water (360 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:THF= 10:1 to 10:1) to give methyl 3-isopropoxy-1-methyl-1H-pyrazole-5-carboxylate (11.0 g, 55.5 mmol, 72% yield) as a colorless oil. LCMS: m / z 198.8 (M+1)

[0731] Steps 2-4 were performed according to steps 4-6 in the preparation of I-5-1.

[0732] I-5-7 was prepared according to those described in the synthesis of I-5-6 starting from methyl 3-hydroxy-1-methyl-1H-pyrazole-5-carboxylate and ethyl iodide in step 1.

[0733] Preparation of 5-(bromomethyl)-3-ethoxy-4-iodo-1-methyl-1H-pyrazole (I-5-8)

[0734] Stepssteps 1 to 3 using ethyl iodide instead of 2-iodopropane in step 1.

[0735] Step 4 was conducted in a manner similar to those described in the preparation of I-5- 2.83573-420992

[0736] Preparation of 5-(bromomethyl)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-ethoxy-4- iodo-1H-pyrazole (I-5-9)

[0737] g, 58.7mmol, 1 eq), (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 sat. NaCl (80 mL x 2) and dried over Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 1:0 to 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)

[0738] Steps 2 and 3 were conducted in a manner similar to steps 4-5 in the preparation of I- 5-1.

[0739] Step 4 was conducted in a similar manner to those described in the preparation of I-5- 2.

[0740] I-5-10 was prepared in a similar manner to those described in the preparation of I-5-9 starting from methyl 3-hydroxy-1H-pyrazole-5-carboxylate and 2-bromopropane.

[0741] Preparation of 5-(bromomethyl)-4-iodo-1,3-dimethyl-1H-pyrazole (I-5-11)83573-420992

[0742] Step 1. To a solution of ethyl 1,3-dimethyl-1H-pyrazole-5-carboxylate (10 g, 59.5 mmol, 1.0 eq) in ACN (100 mL) was added NIS (14.7 g, 65.4 mmol, 1.1 eq). The mixture was stirred at 60 °C for 16 hr. The mixture was quenched with Na2SO3 (200 mL) and water (500 mL), and extracted with EA (250 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give ethyl 4-iodo-1,3-dimethyl-1H- pyrazole-5-carboxylate (17 g, crude) as a colorless oil. LCMS: m / z 295.2 (M+1)

[0743] Step 2. To a solution of ethyl 4-iodo-1,3-dimethyl-1H-pyrazole-5-carboxylate (8 g, 27.2 mmol, 1.0 eq) in MeOH (150 mL) was added LiBH4 (14.8 g, 680 mmol, 25 eq) at 0 °C. The mixture was stirred at 0-25 °C for 16 hr. The mixture was quenched with water (10 mL) and concentrated in vacuum to give a residue. Then to the residue was added water (200 mL) and the mixture was extracted with ethyl acetate (200 mL × 8). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The crude product was triturated with PE / EA= 10:1 at 25 °C for 10 min to give (4-iodo-1,3-dimethyl-1H- pyrazol-5-yl)methanol (6.3 g, 22.5 mmol, 82.7% yield, 90% purity) as a white solid. LCMS: m / z 252.9 (M+1)

[0744] Step 3. To a solution of (4-iodo-1,3-dimethyl-1H-pyrazol-5-yl)methanol (4 g, 15.9 mmol, 1.0 eq) in DCM (40 mL) was added PBr3 (4.73 g, 17.5 mmol, 1.1 eq) at 0 °C. The mixture was stirred at 0-25 °C for 2 hr. The mixture was adjusted to pH= 7~8, water (200 mL) was added, and then the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed with brine dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 5 / 1 to 1 / 1) to give 5-(bromomethyl)-4-iodo-1,3- dimethyl-1H-pyrazole (2.7 g, 8.57 mmol, 54.0% yield, 100% purity) as a white solid.

[0745] Preparation of 3-bromo-5-(bromomethyl)-4-iodo-1-methyl-1H-pyrazole (I-5-12)

[0746] (5.00 g, 22.8 mmol, 1 eq) in MeOH (50 mL) was added NaBH4 (2.70 g, 71.4 mmol, 3.13 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hour. On completion, the mixture was poured into water (200 mL), and the aqueous phase was extracted with ethyl acetate (50 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 column chromatography (SiO2,83573-420992 Petroleum ether / THF= 1 / 0 to 3 / 1) to give (3-bromo-1-methyl-1H-pyrazol-5-yl)methanol (1.90 g, 8.95 mmol, 39.2% yield, 90% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 6.18 - 6.06 (m, 1H), 4.27 - 4.17 (m, 2H), 3.76 - 3.70 (m, 3H)

[0747] Step 2 was performed according to step 5 of I-5-1.

[0748] Step 3 was performed according to preparation of I-5-2.

[0749] I-5-13 was prepared according to preparation of I-5-1 starting from ethyl (R)-2- hydroxypropanoate and using methyl 3-isopropoxy-1H-pyrazole-5-carboxylate in step 3.

[0750] Preparation of (R)-1-((tert-butyldiphenylsilyl)oxy)propan-2-ol (I-5-14a)

[0751] Step 1. mL, 1 eq) in DCM(1500 mL) was g, (701 g, 2.55 mol, 653 mL, 1.05 eq). The mixture was stirred at 0 °C for 2 hours and stirred at 25 °C for 14 hours. On completion, the reaction mixture was concentrated in vacuo to give (R)-1-((tert- butyldiphenylsilyl)oxy)propan-2-ol (880 g, 1.70 mol, 70% yield, 61% purity) as a brown oil. LCMS: m / z 337.1 (M+23)

[0752] Preparation of (S)-2-((1-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-4-iodo-5- (iodomethyl)-1H-pyrazol-3-yl)oxy)acetonitrie (I-5-14)

[0753] g, 960 mmol, 1 eq) in DCM (1500 mL) was added imidazole (78.5 g, 1.15 mol, 1.2 eq) and TBSCl (159 g,83573-420992 1.06 mol, 130 mL, 1.1 eq). The mixture was stirred at 0 °C for 2 hours. The mixture was stirred at 25 °C for 14 hours. On completion, the reaction mixture was concentrated in vacuo to give ethyl 3-((tert-butyldimethylsilyl)oxy)-1H-pyrazole-5-carboxylate (340 g, 943 mmol, 98% yield, 75% purity) as a colorless oil. LCMS: m / z 271.2 (M+1)

[0754] Steps 2-3 followed steps 3-4 in the preparation of I-5-1 using I-5-14a in step 2.

[0755] Step 4. To a solution of (S)-(3-((tert-butyldimethylsilyl)oxy)-1-(1-((tert- butyldiphenylsilyl)oxy)propan-2-yl)-1H-pyrazol-5-yl)methanol (370 g, 705 mmol, 1 eq) in DCM (2000 mL) was added HCOOH (33.9 g, 705 mmol, 200 mL, 1 eq). The mixture was stirred at 25 °C for 4 hours. On completion, the mixture was slowly added to a saturated solution of sodium bicarbonate (3000 mL) at 0 °C. Then the mixture was extracted with DCM (1000 mL × 3). The combined organic phase was washed with brine (1000mL×2) and dried over Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography on silica gel (3000 g silica gel, MeOH in DCM 0% to 10%) to give (S)-1-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-5-(hydroxymethyl)-1H- pyrazol-3-ol (195 g, 432 mmol, 61% yield, 91% purity) as a white solid.

[0756] Step 5. To a solution of (S)-1-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-5- (hydroxymethyl)-1H-pyrazol-3-ol (170 g, 414 mmol, 1 eq) in ACN (1500 mL) was added K2CO3(172 g, 1.24 mol, 3 eq) and 2-iodoacetonitrile (104 g, 621 mmol, 1.5 eq). The mixture was stirred at 60 °C for 1 hour. On completion, the reaction mixture was concentrated in vacuo The residue was purified by column chromatography on silica gel (1500 g silica gel, EA in Petroleum ether from 0% to 100%) to give (S)-2-((1-(1-((tert-butyldiphenylsilyl)oxy)propan- 2-yl)-5-(hydroxymethyl)-1H-pyrazol-3-yl)oxy)acetonitrile (167 g, 360 mmol, 87% yield, 97% purity) as a yellow oil. LCMS: m / z 450.2 (M+1)

[0757] Step 6-7 follows the preparation of I-5-1, steps 5-6.

[0758] Preparation of 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-iodo-3-(iodomethyl)-1H- pyrazole (I-5-15)83573-420992

[0759] Step 1. To a solution of ethyl 1H-pyrazole-3-carboxylate (12.5 g, 89.2 mmol, 1 eq) in ACN (135 mL) was added K2CO3 (37.0 g, 267 mmol, 3 eq) and 2-bromoethoxy-tert-butyl- dimethyl-silane (42.7 g, 178 mmol, 2 eq). The mixture was stirred at 80 °C for 16 hours. On completion, the mixture was poured into water (500 mL), and the aqueous phase was extracted with ethyl acetate (100 mL × 2). The combined organic phase was washed with brine (200 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 1 / 0 to 94 / 6) to give ethyl 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazole-3-carboxylate (20.4 g, 68.3 mmol, 77% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ = 7.51 - 7.44 (m, 1H), 6.81 - 6.72 (m, 1H), 4.40 (q, J = 7.2 Hz, 2H), 4.29 (t, J = 4.8 Hz, 2H), 3.94 (t, J = 4.8 Hz, 2H), 1.43 - 1.35 (m, 3H), 0.83 (s, 9H), -0.07 (s, 6H)

[0760] Steps 2-4 were performed according to steps 4-6 in the preparation of I-5-1.

[0761] I-5-16 was prepared in a similar manner to those described in steps 5-6 in the preparation of I-5-1 starting from (1-methyl-1H-pyrazol-3-yl)methanol.

[0762] Preparation of ethyl 3-ethoxy-1H-pyrazole-5-carboxylate (I-5-17a)

[0763] I-5-17a was preparedof I-5-1a with iodoethane.

[0764] I-5-17 was prepared according to the preparation of I-5-1 starting from ethyl (R)-2- hydroxypropanoate and using I-5-17a in step 3.

[0765] Preparation of 5-(bromomethyl)-4-iodo-1-methyl-1H-pyrazole (I-5-19)g, 71.4 mmol, 1 eq) in THF (100 mL) was added LAH (2.5 M in THF, 42.8 mL, 1.5 eq) at 0 °C .The mixture was stirred at 0 °C for 6 hr. On completion, the reaction mixture was quenched with H2O (4 mL) dropwise at 0 °C, pH adjusted with 15% NaOH (4 mL), then added H2O (4 mL) and Na2SO4, stirred at 25 °C for 20 min, and filtered. The filtrate was concentrated under reduced pressure to give (1-methyl-1H-pyrazol-5-yl)methanol (7.88 g, crude) as a colorless oil.1H NMR (400 MHz, DMSO-d6) δ = 7.31 (s, 1H), 6.17 (s, 1H), 5.31 (t, J = 5.2 Hz, 1H), 4.52 (d, J = 5.2 Hz, 2H), 3.79 (s, 3H).83573-420992

[0767] Step 2. To a solution of (1-methyl-1H-pyrazol-5-yl)methanol (7.30 g, 65.1 mmol, 1 eq) in ACN (50 mL) was added NIS (17.6 g, 78.1 mmol, 1.2 eq) at 0 °C. The mixture was stirred at 25 °C for 16 hr. On completion, the mixture was quenched with saturated solution of Na2SO3 (30 mL), partitioned between water (300 mL) and ethyl acetate(100 mL × 7), and the combined organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give (4-iodo-1-methyl-1H-pyrazol-5-yl)methanol (13.0 g, 54.6 mmol, 84% yield) as a white solid. LCMS: m / z 238.9 (M+1).1H NMR (400 MHz, DMSO-d6) δ = 7.43 (s, 1H), 5.32 (s, 1H), 4.48 (s, 2H), 3.87 (s, 3H).

[0768] Step 3. To a solution of (4-iodo-1-methyl-1H-pyrazol-5-yl)methanol (5.00 g, 21.0 mmol, 1 eq) in DCM (50 mL) was added tribromophosphane (6.82 g, 25.2 mmol, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 6 h. On completion, the mixture was quenched with sat. NaHCO3 (100 mL), and extracted with DCM (100 mL). The organic layer was washed with water (100 mL), and brine (2×200 mL). The organic layer was dried over sodium sulfate, concentrated in vacuum to afford 5-(bromomethyl)-4-iodo-1-methyl-1H-pyrazole (4.50 g, 15.0 mmol, 71% yield) as a white solid.

[0769] Preparation of 4-iodo-3-(iodomethyl)-1,5-dimethyl-1H-pyrazole (I-5-20)of I-5-19.

[0771] Step 3. A mixture of (4-iodo-1,5-dimethyl-1H-pyrazol-3-yl)methanol (500 mg, 1.98 mmol, 1 eq), NIS (892 mg, 3.97 mmol, 2 eq) in DCM (3 mL) was degassed and purged with N2 for 3 times. Then, PPh3 (780 mg, 2.98 mmol, 1.5 eq) in DCM (1 mL) was added at 0 °C, and the mixture was stirred at 25 °C for 2 hours under N2atmosphere. On completion, the reaction mixture was quenched by addition saturated solution of Na2SO3 (5 mL) at 0 °C and then diluted with H2O (10 mL) and extracted with EA (10 mL × 3). The combined organic layers 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= 100 / 1 to 10 / 1) to give 4-iodo-3-(iodomethyl)-1,5-dimethyl-1H-pyrazole (600 mg, 1.59 mmol, 80% yield) as a white solid.

[0772] Preparation of 5-(bromomethyl)-4-iodo-1,3-dimethyl-1H-pyrazole (I-5-21)83573-420992 g, 59.4was g, . was stirred at 60 °C for 2 h. On completion, the mixture was diluted with water (100 mL) and extracted with EtOAc (30 mL×3). The combined organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuum to give crude ethyl 4-iodo-1,3- dimethyl-1H-pyrazole-5-carboxylate (15.0 g, 51.0 mmol, 85.8% yield) as a white solid.1H NMR (400 MHz, CDCl3) δ = 4.46 - 4.36 (m, 2H), 4.14 (s, 3H), 2.28 (s, 3H), 1.51 - 1.40 (m, 3H).

[0774] Step 2. To a solution of ethyl 4-iodo-1,3-dimethyl-1H-pyrazole-5-carboxylate (5.00 g, 17.0 mmol, 1 eq) in THF (50 mL) was added LiBH4 (555 mg, 25.5 mmol, 1.5 eq) at 0 °C. The mixture was stirred at 40 °C for 16 h. The mixture was quenched with MeOH (100 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH= 10:1) to give (4-iodo-1,3-dimethyl-1H-pyrazol-5-yl)methanol (1.00 g, 3.97 mmol, 23% yield) as a white solid. LCMS: m / z 252.7 (M+1).

[0775] Step 3. To a solution of (4-iodo-1,3-dimethyl-1H-pyrazol-5-yl)methanol (1.00 g, 3.97 mmol, 1 eq) in DCM (10 mL) was added PBr3 (1.61 g, 5.95 mmol, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 2 h. The mixture was quenched with a solution of NaHCO3(100 mL) and extracted with dichloromethane (25 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 1:0 to 87:13) to give 5- (bromomethyl)-4-iodo-1,3-dimethyl-1H-pyrazole (1.22 g, 3.87 mmol, 98% yield) as a white solid.

[0776] Intermediate Table 5.83573-420992 083573-420992 ) m, ),83573-420992 I-5-20 (400 MHz, DMSO-d6) δ = 4.31 (s,

[0778] General Method A.

[0779] Preparation of (S)-N-((1-((S)-2-((tert-butyldimethylsilyl)oxy)propyl)-4-iodo-3- isopropoxy-1H-pyrazol-5-yl)methyl)-N-ethyl-2-((3-(methoxymethyl)-1-methyl-4-(1-tosyl-3- vinyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-5-yl)oxy)propan-1-amine (Ex. 1-1)1H- pyrrolo[2,3-b]pyridine (120 mg, 0.283 mmol) in solvent, dioxane (1 mL), was added (S)-N-(2- ((4-bromo-3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl)oxy)propyl)-N-ethyl-2,2,2- trifluoroacetamide (57 mg, 0.141 mmol) and Cs2CO3 (138 mg, 0.424 mmol). The reaction mixture was stirred as argon was bubbled through and catalyst, Pd(dtbpf)Cl2(9 mg, 0.01483573-420992 mmol) was added. The vessel was sealed and heated to 80 °C for 5 hr. The reaction was cooled and diluted with equal parts DCM and water (4 mL each) and the layers were separated. The aqueous layer was extracted again with DCM (2 × 4 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Flash column chromatography (automated system, 12 g silica, 30-100% EA in Hexanes with 5% DCM as modifier) provided (S)-N-ethyl- 2,2,2-trifluoro-N-(2-((3-(methoxymethyl)-1-methyl-4-(1-tosyl-3-vinyl-1H-pyrrolo[2,3- b]pyridin-5-yl)-1H-pyrazol-5-yl)oxy)propyl)acetamide (39 mg, 0.063 mmol, 45% yield). LCMS: m / z 620.4 (M+1).

[0781] Step 2. To (S)-N-ethyl-2,2,2-trifluoro-N-(2-((3-(methoxymethyl)-1-methyl-4-(1-tosyl- 3-vinyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-5-yl)oxy)propyl)acetamide (39 mg, 0.063 mmol) in THF (1 mL) was added LiOH (2 M aq, 1 mL). The reaction mixture was stirred at 22 °C for 18 hr. The reaction was diluted with equal parts DCM and water (5 mL each) and the layers were separated. The aqueous layer was extracted again with DCM (2 × 5 mL). The combined organic layers were washed with brine and dried over sodium sulfate. The filtrate was concentrated and used directly in the next step assuming quantitative yield. (S)-N-ethyl- 2-((3-(methoxymethyl)-1-methyl-4-(1-tosyl-3-vinyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H- pyrazol-5-yl)oxy)propan-1-amine. LCMS: m / z 524.3 (M+1).

[0782] Step 3. (S)-N-ethyl-2-((3-(methoxymethyl)-1-methyl-4-(1-tosyl-3-vinyl-1H- pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-5-yl)oxy)propan-1-amine (33 mg, 0.063 mmol) in DMF (0.5 mL) was added base, K2CO3(26 mg, 0.189 mmol), followed by (S)-1-(2- ((tert-butyldimethylsilyl)oxy)propyl)-4-iodo-5-(iodomethyl)-3-isopropoxy-1H-pyrazole (71 mg, 0.126 mmol). The reaction mixture was stirred at 60 °C for 1 hr, then cooled to ambient temperature and diluted with DCM (5 mL). The reaction was filtered through a microfilter and washed with DCM (5 mL). The filtrate was concentrated to dryness under reduced pressure. Residue was purified by flash column chromatography (automated system, 12 g silica, 0- 80% EA in Hexanes with 5% DCM as modifier to aid with solubility) to provide (S)-N-((1- ((S)-2-((tert-butyldimethylsilyl)oxy)propyl)-4-iodo-3-isopropoxy-1H-pyrazol-5-yl)methyl)- N-ethyl-2-((3-(methoxymethyl)-1-methyl-4-(1-tosyl-3-vinyl-1H-pyrrolo[2,3-b]pyridin-5-yl)- 1H-pyrazol-5-yl)oxy)propan-1-amine (37.2 mg, 0.039 mmol, 61 % yield) as a light yellow residue. LCMS: m / z 960.5 (M+1).

[0783] General Method B.

[0784] Preparation of (S)-1-(5-((ethyl((S)-2-((1-methyl-4-(3-vinylimidazo[1,2-a]pyrimidin- 6-yl)-1H-pyrazol-5-yl)oxy)propyl)amino)methyl)-4-iodo-3-isopropoxy-1H-pyrazol-1- yl)propan-2-ol (Ex.2-1)83573-4209921,3,2- dioxaborolan-2-yl)-1H-pyrazol-5-yl)oxy)propyl)carbamate (1.83 g, 4.46 mmol, 1 eq), 6- bromo-3-vinylimidazo[1,2-a]pyrimidine (1.00 g, 4.46 mmol, 1 eq), Na2CO3 (1.42 g, 13.3 mmol, 3 eq), Pd(dppf)Cl2 (326 mg, 0.446 mmol, 0.1 eq) in dioxane (15 mL) and H2O (3 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 80 °C for 2 h under N2 atmosphere. On completion, the reaction mixture was diluted with H2O (20 mL) and extracted with EA (30 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 10 / 1 to 0 / 1) to give tert-butyl (S)-ethyl(2-((1-methyl-4-(3-vinylimidazo[1,2-a]pyrimidin-6-yl)-1H- pyrazol-5-yl)oxy)propyl)carbamate (500 mg, 1.09 mmol, 24% yield, 93% purity) as a yellow solid. LCMS: m / z 427.1 (M+1).

[0786] Step 2. To a solution of tert-butyl (S)-ethyl(2-((1-methyl-4-(3-vinylimidazo[1,2- a]pyrimidin-6-yl)-1H-pyrazol-5-yl)oxy)propyl)carbamate (500 mg, 1.17 mmol, 1 eq) in DCM (1 mL) was added HCl / dioxane (2 M, 2 mL, 3.41 eq). The mixture was stirred at 25 °C for 0.5 h. On completion, The reaction mixture was filtered and concentrated under reduced pressure to give (S)-N-ethyl-2-((1-methyl-4-(3-vinylimidazo[1,2-a]pyrimidin-6-yl)-1H-pyrazol-5- yl)oxy)propan-1-amine (350 mg, 1.07 mmol, 91% yield) as a yellow solid. LCMS: m / z 327.083573-420992 (M+1).

[0787] Step 3. To a solution of (S)-N-ethyl-2-((1-methyl-4-(3-vinylimidazo[1,2-a]pyrimidin- 6-yl)-1H-pyrazol-5-yl)oxy)propan-1-amine (350 mg, 1.07 mmol, 1 eq) in DMF (4 mL) was added K2CO3 (741 mg, 5.36 mmol, 5 eq) and (S)-5-(bromomethyl)-1-(2-((tert- butyldimethylsilyl)oxy)propyl)-4-iodo-3-isopropoxy-1H-pyrazole (665 mg, 1.29 mmol, 1.2 eq). The mixture was stirred at 60 °C for 1 h. On completion, the reaction mixture was diluted with H2O (10 mL) and extracted with EA (30 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EA= 1 / 0 to 0 / 1) to give (S)-1-(5-((ethyl((S)-2-((1-methyl-4-(3-vinylimidazo[1,2-a]pyrimidin-6-yl)-1H- pyrazol-5-yl)oxy)propyl)amino)methyl)-4-iodo-3-isopropoxy-1H-pyrazol-1-yl)propan-2-ol (150 mg, 0.231 mmol, 22% yield) as a yellow solid. LCMS: m / z 649.1 (M+1).

[0788] General Method C.

[0789] Preparation of (S)-N-((1-((S)-2-((tert-butyldimethylsilyl)oxy)propyl)-4-iodo-3- isopropoxy-1H-pyrazol-5-yl)methyl)-N-ethyl-2-((3-(methoxymethyl)-1-methyl-4-(3- vinylimidazo[1,2-a]pyrazin-6-yl)-1H-pyrazol-5-yl)oxy)propan-1-amine (Ex.4-1)a]pyrazin-6-yl)-1H-pyrazol-5-ol (3.30 g, 7.87 mmol, 1 eq) in 2-MeTHF (33 mL) was added (R)-N-ethyl-2,2,2-trifluoro-N-(2-hydroxypropyl)acetamide (2.04 g, 10.2 mmol, 1.3 eq) and PPh3(3.09 g, 11.8 mmol, 1.5 eq), then DBAD (3.62 g, 15.7 mmol, 2 eq) in 2-MeTHF (33 mL) was added at 0 °C. The mixture was stirred at 25 °C for 2 h. On completion, the mixture was83573-420992 concentrated to give a residue. The crude product was triturated with MTBE (10 mL) at 0 °C for 15 mins to give (S)-N-ethyl-2,2,2-trifluoro-N-(2-((3-(methoxymethyl)-1-methyl-4-(3- vinylimidazo[1,2-a]pyrazin-6-yl)-1H-pyrazol-5-yl)oxy)propyl)acetamide (4.20 g, 5.58 mmol, 71% yield, 62% purity) as a brown oil. LCMS: m / z 467.2 (M+1).

[0791] Step 2. To a solution of (S)-N-ethyl-2,2,2-trifluoro-N-(2-((3-(methoxymethyl)-1- methyl-4-(3-vinylimidazo[1,2-a]pyrazin-6-yl)-1H-pyrazol-5-yl)oxy)propyl)acetamide (3.90 g, 8.36 mmol, 1 eq) in THF (35 mL) was added LiOH.H2O (1.05 g, 25.1 mmol, 3 eq) and H2O (7 mL). The mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was partitioned between 2-MeTHF (40 mL × 3) and water (40 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, DCM:MeOH= 15:1 to 15:1) to give (S)-N-ethyl-2-((3-(methoxymethyl)-1-methyl-4-(3-vinylimidazo[1,2-a]pyrazin-6-yl)-1H- pyrazol-5-yl)oxy)propan-1-amine (1.05 g, 2.83 mmol, 34% yield) as a brown oil. LCMS: m / z 371.1 (M+1).

[0792] Step 3. To a solution of (S)-N-ethyl-2-((3-(methoxymethyl)-1-methyl-4-(3- vinylimidazo[1,2-a]pyrazin-6-yl)-1H-pyrazol-5-yl)oxy)propan-1-amine (905 mg, 2.44 mmol, 1 eq) in DMF (9 mL) was added (S)-1-(2-((tert-butyldimethylsilyl)oxy)propyl)-4-iodo-5- (iodomethyl)-3-isopropoxy-1H-pyrazole (1.65 g, 2.93 mmol, 1.2 eq) and K3PO4(1.04 g, 4.89 mmol, 2 eq). The mixture was stirred at 60 °C for 0.5 h. On completion, the reaction mixture was partitioned between EA (30 mL × 3) and water (30 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, (PE:THF):MeOH= (2:1):0.01 to (2:1):0.01) to give (S)-N-((1-((S)-2-((tert-butyldimethylsilyl)oxy)propyl)-4-iodo-3-isopropoxy-1H-pyrazol- 5-yl)methyl)-N-ethyl-2-((3-(methoxymethyl)-1-methyl-4-(3-vinylimidazo[1,2-a]pyrazin-6- yl)-1H-pyrazol-5-yl)oxy)propan-1-amine (1.40 g, 1.74 mmol, 71% yield) as a colorless solid.

[0793] General Method D.

[0794] Preparation of tert-butyl ((1-((S)-2-((tert-butyldimethylsilyl)oxy)propyl)-4-iodo-3- isopropoxy-1H-pyrazol-5-yl)methyl)((S)-2-((3-(methoxymethyl)-1-methyl-4-(6- vinylimidazo[1,5-a]pyrimidin-3-yl)-1H-pyrazol-5-yl)oxy)propyl)carbamate (Ex.6-1)83573-420992

[0795] Step 1. To a mixture of tert-butyl (S)-(2-((3-(methoxymethyl)-1-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-5-yl)oxy)propyl)carbamate (668 mg, 1.57 mmol) and 3-bromo-6-vinylimidazo[1,5-a]pyrimidine (0.335 g, 1.50 mmol) in Dioxane (7.8 mL) and Water (1.6 mL) was added Cs2CO3 (1.46 g, 4.49 mmol), and argon was bubbled through the mixture for 15 minutes. Pd(dtbpf)Cl2 (97.45 mg, 0.15 mmol) was then added, and the vessel was sealed and heated to 85 °C for 1.5 h. The reaction was diluted with DCM (50 mL) and water (15 mL), and the layers were separated. The aqueous layer was extracted again with DCM (2×40 mL). The combined organic layers were washed with brine and dried over sodium sulfate. The solvent was evaporated and the residue was purified by flash column chromatography (0-100% Ethyl Acetate in Hexanes) to obtain tert-butyl (S)-(2-((3- (methoxymethyl)-1-methyl-4-(6-vinylimidazo[1,5-a]pyrimidin-3-yl)-1H-pyrazol-5- yl)oxy)propyl)carbamate (78 mg, 0.176 mmol, 11.79% yield). LCMS: m / z 444.3 (M+1).

[0796] Step 2. Sodium hydride (14.1 mg, 353 mmol, 60% dispersion in mineral oil) was added to a stirring solution of tert-butyl (S)-(2-((3-(methoxymethyl)-1-methyl-4-(6- vinylimidazo[1,5-a]pyrimidin-3-yl)-1H-pyrazol-5-yl)oxy)propyl)carbamate (78 mg, 0.176 mmol) in DMF (0.9 mL) at 0 °C and stirred for 10 minutes. A solution of (S)-5-83573-420992 (bromomethyl)-1-(2-((tert-butyldimethylsilyl)oxy)propyl)-4-iodo-3-isopropoxy-1H-pyrazole (182 mg, 0.353 mmol) in DMF (0.9 mL) was then added at 0 °C, and the resulting mixture was stirred at 23 °C for 0.5 h. The reaction mixture was then quenched with water (2 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (0-100% EA in Hexanes) to afford tert-butyl ((1- ((S)-2-((tert-butyldimethylsilyl)oxy)propyl)-4-iodo-3-isopropoxy-1H-pyrazol-5- yl)methyl)((S)-2-((3-(methoxymethyl)-1-methyl-4-(6-vinylimidazo[1,5-a]pyrimidin-3-yl)- 1H-pyrazol-5-yl)oxy)propyl)carbamate (126 mg, 0.143 mmol, 81.3% yield).

[0797] General Method E.

[0798] Preparation of 3-ethyl-4-iodo-N,1-dimethyl-N-(2-((1-methyl-4-(3-vinylimidazo[1,2- b]pyridazin-6-yl)-1H-pyrazol-5-yl)oxy)ethyl)-1H-pyrazole-5-carboxamide (Ex.9-1)

[0799] Step 1. A mixture of tert-butyl methyl(2-((1-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazol-5-yl)oxy)ethyl)carbamate (500 mg, 1.31 mmol, 2 eq,), 6- bromo-3-vinylimidazo[1,2-b]pyridazine (146 mg, 0.655 mmol, 1 eq), Pd(dtbpf)Cl2 (47.9 mg, 0.0655 mmol, 0.1 eq), K2CO3(181 mg, 1.31 mmol, 2 eq) in dioxane (2 mL) and H2O (0.2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 2 hours under N2atmosphere. On completion, the mixture was poured into H2O (15 mL) and was extracted with EA (8 mL × 3). The combined organic phase was concentrated in vacuo to give a residue. The residue was purified by prep-TLC (SiO2, PE: EA = 0:1) to give tert-butyl83573-420992 methyl(2-((1-methyl-4-(3-vinylimidazo[1,2-b]pyridazin-6-yl)-1H-pyrazol-5- yl)oxy)ethyl)carbamate (200 mg, 62% yield) as a yellow oil. LCMS: m / z 399.1 (M+1)

[0800] Step 2. To a solution of tert-butyl methyl(2-((1-methyl-4-(3-vinylimidazo[1,2- b]pyridazin-6-yl)-1H-pyrazol-5-yl)oxy)ethyl)carbamate (130 mg, 0.326 mmol, 1 eq) in DCM (1 mL) was added HCl / dioxane (2 M, 2 mL). The mixture was stirred at 25 °C for 1 hour. On completion, the mixture was concentrated in vacuo to give N-methyl-2-((1-methyl-4-(3- vinylimidazo[1,2-b]pyridazin-6-yl)-1H-pyrazol-5-yl)oxy)ethan-1-amine (97.0 mg, 99% yield) as a white solid. LCMS: m / z 298.9 (M+1)

[0801] Step 3. To a solution of N-methyl-2-((1-methyl-4-(3-vinylimidazo[1,...

Claims

83573-420992 WHAT IS CLAIMED IS:

1. A compound of the formula I whereinA is a 5- to 10-membered heteroarylene or C6-C10arylene; B is a 5- to 10-membered heteroarylene or C6-C10 arylene; C / D is a 9-membered bicyclic heteroarylene, wherein wherein 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(R10) or N; and X7is C(R11) or N; provided that at least one of X1to X7is a nitrogen atom and one of X1or X2is a carbon atom; 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-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,83573-420992 -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-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-C6alkyl, C2-C6alkenyl, 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, 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-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,83573-420992 -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; 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-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; 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-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 7-83573-420992 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-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-C6alkyl, C1-C6haloalkyl, -OH, -OC1-C6alkyl, -OC(O)-(H or C1-C6alkyl), -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-C6 alkyl)C(O)-(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)C(O)O(H or C1- C6 alkyl), -N(H or C1-C6 alkyl)C(O)N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)C(O)N(C2-C6 alkylene), -N(H or C1-C6 alkyl)S(O)-(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)S(O)2(H or C1-C6 alkyl), -N(H or C1-C6alkyl)S(O)N(H or C1-C6alkyl)2, -N(H or C1-C6alkyl)S(O)N(C2-C6alkylene), -N(H or C1-C6 alkyl)S(O)2N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)S(O)2N(C2-C6 alkylene), -C(O)-(H or C1-C6alkyl), -C(O)O(H or C1-C6alkyl), -C(O)N(C2-C6alkylene), -P(H or C1-C6 alkyl)2, -P(C2-C6 alkylene), -P(O)(H or C1-C6 alkyl)2, -P(O)(C2-C6 alkylene), -P(O)2(H or C1-C6alkyl)2, -P(O)2(C2-C6alkylene), -P(O)N(H or C1-C6alkyl)2, -P(O)N(C2-C6alkylene), -P(O)2N(H or C1-C6 alkyl)2, -P(O)2N(C2-C6 alkylene), -P(O)O(H or C1-C6 alkyl), -P(O)2O(H or C1-C6alkyl), -CN, or -NO2; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; and83573-420992 p is 3, 4, 5, 6, 7, or 8; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the formula II whereineach of Y and Y1is 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 q is 0, 1, or 2.

3. The compound of claim 1, having the formula III83573-420992 III or a pharmaceutically acceptable salt thereof.

4. The compound of any one of the preceding claims, having the formula IV or a5. The compound of claim 1, having the formula V or a6. The compound of any one of claims 1, 2, or 5, having the formula VI83573-420992 or a7. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein ring C / D is of the formula ,or8. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein ring A in the portion83573-420992is a 5- or 6-membered ” represents a point of covalentattachment.

9. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein ring A in the portion is a 5- or 6-membered consisting of,10. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and m is 1 or 2.

11. The compound of any one of the preceding claims, 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, -O-CH2-CN, -O-CH2CH2-CN, 2- pyrrolidinyleth-1-yl, or 4-piperidinyl.

12. The compound of any one of the preceding claims, 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, -O-CH2-CN, 2-83573-420992 pyrrolidinyleth-1-yl, or 4-piperidinyl.

13. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein ring A in the portion is a 5- or 6-membered consisting of,,,83573-420992 ,14. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein ring A in the portionis a C6-C10 arylene, m is 0, 1,” represents a point of covalentattachment.

15. The compound of any one of claims 1 to 7, or 14, or a pharmaceutically acceptable salt thereof, wherein ring A in the portionis a phenylene, m is 0, 1, 2, or 3,a point of covalent attachment.

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

17. The compound of any one of claims 1 to 7, or 14 to 16, 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.83573-420992 18. The compound of any one of claims 1 to 7, or 14 to 17, or a pharmaceutically acceptable salt thereof, wherein ring A in the portion , ,83573-420992wherein each “19. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein ring B in the portionis a 5- or 6-membered each “ ” represents a point ofcovalent attachment.

20. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein ring B in the portion ,83573-420992 21. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each R2, when present and bonded to carbon, is independently fluoro, chloro, methyl, ethyl, methoxy, ethoxy, 2-fluoroeth-1-yl, 2,2-difluoroeth-1-yl, or methoxymethyl.

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

23. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein ring B in the portion ,24. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein ring B in the portionis a C6-C10 arylene, m is 0, 1,” represents a point of covalent83573-420992 attachment.

25. The compound of any one of claims 1 to 18, or 24, or a pharmaceutically acceptable salt thereof, wherein ring B in the portionis a phenylene, m is 0, 1, 2, or 3, a point of covalent attachment.

26. The compound of any one of claims 2, 4, or 6 to 25, 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)-.

27. The compound of any one of claims 2, 4, or 6 to 26, 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.

28. The compound of any one of claims 2, 4, or 6 to 27, 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.

29. The compound of any one of claims 2, 4, or 6 to 28, or a pharmaceutically acceptable salt thereof, wherein q, when present, is 1.

30. The compound of any one of claims 2, 4, or 6 to 29, or a pharmaceutically acceptable salt thereof, wherein L1, when present, is -C(R12)(R13)-C(R12)(R13)-.

31. The compound of any one of claims 2, 4, or 6 to 28, or a pharmaceutically acceptable salt thereof, wherein q, when present, is 2.

32. The compound of any one of claims 2, 4, or 6 to 28, or 31, or a pharmaceutically acceptable salt thereof, wherein one of L1, when present, is -C(R12)(R13)- and one of L1, when present, is83573-420992 -C(R12)(R13)-C(R12)(R13)-.

33. The compound of any one of claims 2, 4, or 6 to 32, or a pharmaceutically acceptable salt thereof, wherein Y, when present, is -O-.

34. The compound of any one of claims 2, 4, or 6 to 32, or a pharmaceutically acceptable salt thereof, wherein Y, when present, is -N(R14)C(O)-.

35. The compound of any one of claims 2, 4, or 6 to 32, or a pharmaceutically acceptable salt thereof, wherein Y, when present, is a bond.

36. The compound of any one of claims 2, 4, or 6 to 35, or a pharmaceutically acceptable salt thereof, wherein each Y1, when present, is independently -O- or -N(R14)-.

37. The compound of any one of claims 2, 4, or 6 to 36, or a pharmaceutically acceptable salt thereof, wherein each L2, when present, is a bond.

38. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein -(L)p- or -L2-(Y1-L1)q-Y is of the formula ,83573-420992 ,39. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R3is H or deuterium.

40. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R4is H or deuterium.

41. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R5, when present, is H or deuterium.

42. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R6, when present, is H, deuterium, or C1-C6alkyl.

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

44. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R8, when present, is H, deuterium, or C1-C6alkyl.

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

46. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R10, when present, is H or deuterium.

47. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R11, when present, is H, deuterium, halogen, C1-C6alkyl, or -NRaRb.83573-420992 48. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R14, when present, is H or C1-C6 alkyl.

49. The compound of claim 1, selected from the group consisting of (2S)-1-[(10S,17E)-12-ethyl-6-(methoxymethyl)-8,10-dimethyl-16-[(propan-2-yl)oxy]- 2,8,10,11,12,13-hexahydro-14H-3,5-(azenometheno)dipyrazolo[3,4-f:4',3'-n]pyrrolo[3,4- j][1,4]oxazacyclopentadecin-14-yl]propan-2-ol; (2S)-1-[(11S,18E)-13-ethyl-9,11-dimethyl-17-[(propan-2-yl)oxy]-11,12,13,14-tetrahydro- 9H,15H-3,6-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-2-ol; (2S)-2-[(11S,18E)-17-ethoxy-7,9,11,13-tetramethyl-11,12,13,14-tetrahydro-9H,15H-3,6- ethenoimidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11,12]oxatriazacyclopentadecin-15- yl]propan-1-ol; (2S)-1-[(11S,18E)-13-ethyl-7-(methoxymethyl)-9,11-dimethyl-17-[(propan-2-yl)oxy]- 11,12,13,14-tetrahydro-9H,15H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-2-ol; (2S)-1-{(11S,18E)-13-ethyl-7-(methoxymethyl)-9,11-dimethyl-17-[(propan-2-yl)oxy]- 11,12,13,14-tetrahydro-9H,15H-3,6-ethenoimidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl}propan-2-ol; (18E)-17-ethyl-9,13,15-trimethyl-12,13-dihydro-9H,11H-3,6-ethenoimidazo[5,1- j]dipyrazolo[3,4-f:4',3'-n][1,4,11,12]oxatriazacyclopentadecin-14(15H)-one; (18E)-17-ethyl-9,13,15-trimethyl-12,13-dihydro-9H,11H-6,3-(azenometheno)imidazo[5,1- j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-14(15H)-one; (2S)-1-[(11S,18E)-17-ethoxy-7,9,11,13,21-pentamethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15- yl]propan-2-ol; (2S)-1-{(11S,18E)-13-ethyl-9,11-dimethyl-17-[(propan-2-yl)oxy]-11,12,13,14-tetrahydro- 9H,15H-3,6-ethenoimidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin- 15-yl}propan-2-ol; (11S,18E)-13-ethyl-7-(methoxymethyl)-9,11,15-trimethyl-17-[(propan-2-yl)oxy]- 12,13,14,15-tetrahydro-9H,11H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-21-amine; (11S,18E)-17-ethoxy-13-ethyl-7-(methoxymethyl)-9,11,15-trimethyl-12,13,14,15-tetrahydro- 9H,11H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'-83573-420992 n][1,4,11]oxadiazacyclopentadecin-21-amine; 2-[(11S,18E)-17-ethoxy-13-ethyl-9,11-dimethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15- yl]ethan-1-ol; (2S)-1-[(11S,18E)-13-ethyl-7-(methoxymethyl)-9,11-dimethyl-17-[(propan-2-yl)oxy]- 11,12,13,14-tetrahydro-9H,15H-3,6-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-2-ol; (2S)-2-[(11S,18E)-17-ethoxy-7,9,11,13-tetramethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15- yl]propan-1-ol; (2S)-2-[(11S,18E)-17-ethoxy-7,9,11,13,21-pentamethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15- yl]propan-1-ol; (2S)-1-[(4E,12S)-10-ethyl-16-(methoxymethyl)-12,14-dimethyl-6-[(propan-2-yl)oxy]- 9,11,12,14-tetrahydro-1,17-ethenotripyrazolo[3,4-f:4',3'-j:4'',3''-n][1,4]oxazacyclopentadecin- 8(10H)-yl]propan-2-ol; (2S)-1-[(4E,12S)-10-ethyl-12,14-dimethyl-6-[(propan-2-yl)oxy]-9,11,12,14-tetrahydro-1,17- ethenotripyrazolo[3,4-f:4',3'-j:4'',3''-n][1,4]oxazacyclopentadecin-8(10H)-yl]propan-2-ol; 2-[(11S,18E)-21-amino-17-ethoxy-13-ethyl-9,11-dimethyl-11,12,13,14-tetrahydro-9H,15H- 6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin- 15-yl]ethan-1-ol; 2-[(11S,18E)-21-amino-17-ethoxy-13-ethyl-9,11-dimethyl-11,12,13,14-tetrahydro-9H,15H- 3,6-ethenoimidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15- yl]ethan-1-ol; (11S,18E)-13-ethyl-9,11,15-trimethyl-17-[(propan-2-yl)oxy]-12,13,14,15-tetrahydro- 9H,11H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-21-amine; (11S,18E)-13-ethyl-9,11,15-trimethyl-17-[(propan-2-yl)oxy]-12,13,14,15-tetrahydro- 9H,11H-3,6-ethenoimidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin- 21-amine; (11S,18E)-17-ethoxy-13-ethyl-7,9,11,15-tetramethyl-12,13,14,15-tetrahydro-9H,11H-6,3- (azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-21- amine; (11S,18E)-17-ethoxy-7,9,11,13,15-pentamethyl-12,13,14,15-tetrahydro-9H,11H-6,3- (azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-21-83573-420992 amine; (11S,18E)-9,11,13,15-tetramethyl-17-[(propan-2-yl)oxy]-12,13,14,15-tetrahydro-9H,11H- 6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin- 21-amine; (11S,18E)-7-(methoxymethyl)-9,11,13,15-tetramethyl-17-[(propan-2-yl)oxy]-12,13,14,15- tetrahydro-9H,11H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-21-amine; 2-[(11S,18E)-21-amino-7-(methoxymethyl)-9,11,13-trimethyl-17-[(propan-2-yl)oxy]- 11,12,13,14-tetrahydro-9H,15H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]ethan-1-ol; 2-[(11S,18E)-21-amino-9,11,13-trimethyl-17-[(propan-2-yl)oxy]-11,12,13,14-tetrahydro- 9H,15H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]ethan-1-ol; (11S,18E)-13-ethyl-7-(methoxymethyl)-9,11,15,17-tetramethyl-12,13,14,15-tetrahydro- 9H,11H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-21-amine; (11S,18E)-21-amino-13-ethyl-7-(methoxymethyl)-9,11,15-trimethyl-12,13,14,15-tetrahydro- 9H,11H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecine-17-carbonitrile; [(11S,18E)-21-amino-13-ethyl-7-(methoxymethyl)-9,11-dimethyl-17-[(propan-2-yl)oxy]- 11,12,13,14-tetrahydro-9H,15H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]acetonitrile; (2R)-1-[(11S,18E)-21-amino-13-ethyl-7-(methoxymethyl)-9,11-dimethyl-17-[(propan-2- yl)oxy]-11,12,13,14-tetrahydro-9H,15H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4- f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-2-ol; (2S)-1-[(11S,18E)-21-amino-13-ethyl-7-(methoxymethyl)-9,11-dimethyl-17-[(propan-2- yl)oxy]-11,12,13,14-tetrahydro-9H,15H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4- f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-2-ol; 2-[(11S,18E)-21-amino-17-ethoxy-7,9,11,13-tetramethyl-11,12,13,14-tetrahydro-9H,15H- 6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin- 15-yl]ethan-1-ol; and 2-[(11S,18E)-21-amino-17-ethoxy-7-(methoxymethyl)-9,11,13-trimethyl-11,12,13,14- tetrahydro-9H,15H-6,3-(azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]ethan-1-ol; or a pharmaceutically acceptable salt thereof.83573-420992 50. The compound of claim 1, selected from the group consisting of (2S)-2-[(11S,18E)-17-ethoxy-7,9,11,13-tetramethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15- yl]propan-1-ol; (2S)-1-[(11S,18E)-7-(methoxymethyl)-9,11-dimethyl-17-[(propan-2-yl)oxy]-11,12,13,14- tetrahydro-9H,15H-3,6-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-2-ol; (2S)-1-[(11S,18E)-13-ethyl-7-(methoxymethyl)-9,11-dimethyl-17-[(propan-2-yl)oxy]- 11,12,13,14-tetrahydro-9H,15H-3,6-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-2-ol; (2S)-1-{(11S,18E)-13-ethyl-7-(methoxymethyl)-9,11-dimethyl-17-[(propan-2-yl)oxy]- 11,12,13,14-tetrahydro-9H,15H-3,6-ethenoimidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl}propan-2-ol; (2S)-2-[(11S,18E)-17-ethoxy-7,9,11,13,21-pentamethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15- yl]propan-1-ol; (19E)-9-methyl-12,13-dihydro-9H,11H-6,3-(azenometheno)imidazo[1,2-j]pyrazolo[3,4- f][1,5,10]benzodioxazacyclopentadecine; (19E)-9-methyl-12,13-dihydro-9H,11H-3,6-ethenoimidazo[1,2-j]pyrazolo[3,4- f][1,5,10]benzodioxazacyclopentadecine; (17E)-16-ethyl-8,12,14-trimethyl-8,11,12,14-tetrahydro-3,5-ethenoimidazo[4,5- j]dipyrazolo[3,4-f:4',3'-n][1,4]oxazacyclopentadecin-13(10H)-one; (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12-tetramethyl-10,11,12,13-tetrahydro-5,3- (azenometheno)imidazo[4,5-j]dipyrazolo[3,4-f:4',3'-n][1,4]oxazacyclopentadecin-14(8H)- yl]propan-1-ol; (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-10,11,12,13-tetrahydro-5,3- (azenometheno)imidazo[4,5-j]dipyrazolo[3,4-f:4',3'-n][1,4]oxazacyclopentadecin-14(8H)- yl]propan-1-ol; (18E)-8-methyl-11,12-dihydro-8H,10H-5,3- (azenometheno)imidazo[4',5':10,11][1,5]benzodioxacyclopentadecino[6,7-c]pyrazole; (18E)-8-methyl-11,12-dihydro-8H,10H-3,5- ethenoimidazo[4',5':10,11][1,5]benzodioxacyclopentadecino[6,7-c]pyrazole; (2S)-2-[(11S,18E)-17-ethoxy-9,11,13-trimethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15-83573-420992 yl]propan-1-ol; (2S)-2-[(11S,18E)-17-ethoxy-9,11,13,21-tetramethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15- yl]propan-1-ol; (11S,18E)-9,11,13,15,17-pentamethyl-12,13,14,15-tetrahydro-9H,11H-6,3- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecine; 2-[(11S,18E)-17-ethoxy-13-ethyl-9,11-dimethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15- yl]ethan-1-ol; (2S)-2-[(11S,18E)-17-ethoxy-13-ethyl-9,11-dimethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15- yl]propan-1-ol; and (18E)-17-ethyl-9,13,15-trimethyl-12,13-dihydro-9H,11H-6,3-(azenometheno)imidazo[2,1- j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-14(15H)-one or a pharmaceutically acceptable salt thereof.

51. The compound of claim 1, selected from the group consisting of 2-[(11S,18E)-21-amino-17-ethoxy-9,11,13-trimethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15- yl]ethan-1-ol; (2S)-2-[(11S,18E)-17-ethoxy-13-ethyl-7,9,11-trimethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15- yl]propan-1-ol; (2S)-1-[(11S,18E)-17-ethoxy-7,9,11,13-tetramethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15- yl]propan-2-ol; (2S)-2-[(11S,18E)-17-ethoxy-7-(methoxymethyl)-9,11,13-trimethyl-11,12,13,14-tetrahydro- 9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol; 2-[(11S,18E)-17-ethoxy-9,11,13-trimethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15- yl]ethan-1-ol; {[(11S,18E)-15-[(2S)-1-hydroxypropan-2-yl]-7,9,11,13-tetramethyl-12,13,14,15-tetrahydro- 9H,11H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-17-yl]oxy}acetonitrile;83573-420992 (2S)-2-[(11S,18E)-17-ethoxy-13-ethyl-7-(methoxymethyl)-9,11-dimethyl-11,12,13,14- tetrahydro-9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol; (2S)-1-[(11S,18E)-17-ethoxy-9,11,13-trimethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15- yl]propan-2-ol; {[(11S,18E)-13-ethyl-15-[(2S)-1-hydroxypropan-2-yl]-7,9,11-trimethyl-12,13,14,15- tetrahydro-9H,11H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-17-yl]oxy}acetonitrile; 2-[(11S,18E)-7,9,11,13,21-pentamethyl-11,12,13,14-tetrahydro-9H,16H-6,3- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-16- yl]ethan-1-ol; (11S,18E)-7,9,11,13,16,21-hexamethyl-12,13,14,16-tetrahydro-9H,11H-6,3- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecine; (2S)-1-[(11S,18E)-17-ethoxy-7-(methoxymethyl)-9,11,13-trimethyl-11,12,13,14-tetrahydro- 9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-2-ol; (11S,18E)-7,9,11,13,21-pentamethyl-16-[2-(pyrrolidin-1-yl)ethyl]-12,13,14,16-tetrahydro- 9H,11H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecine; (2S)-2-[(11S,18E)-17-ethoxy-13-ethyl-7,9,11-trimethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15- yl]propan-1-ol; (2S)-2-[(11S,18E)-17-ethoxy-13-ethyl-7,9,11-trimethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15- yl]propan-1-ol; (2R)-1-[(11S,18E)-17-ethoxy-7-(methoxymethyl)-9,11,13-trimethyl-11,12,13,14-tetrahydro- 9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-2-ol; (11S,19E)-7,9,11,13-tetramethyl-11,12,13,14-tetrahydro-9H-6,3- (azenometheno)imidazo[1,2-j]pyrazolo[3,4-f][5,2,10]benzoxadiazacyclopentadecine; 2-[(11S,18E)-7,9,11,13-tetramethyl-11,12,13,14-tetrahydro-9H,16H-6,3- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-16- yl]ethan-1-ol; (11S,18E)-7,9,11,13,16-pentamethyl-12,13,14,16-tetrahydro-9H,11H-6,3-83573-420992 (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecine; (11S,18E)-7,9,11,13-tetramethyl-16-[2-(pyrrolidin-1-yl)ethyl]-12,13,14,16-tetrahydro- 9H,11H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecine; (11S,19E)-9,11,13-trimethyl-11,12,13,14-tetrahydro-9H-6,3-(azenometheno)imidazo[1,2- j]pyrazolo[3,4-f][5,2,10]benzoxadiazacyclopentadecine; (2S)-2-[(12R,18E)-17-ethoxy-9,11,12,13-tetramethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15- yl]propan-1-ol; (2S)-2-[(11S,18E)-17-ethoxy-13-ethyl-7,9,11,21-tetramethyl-11,12,13,14-tetrahydro- 9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol; (2S)-2-[(11S,18E)-17-ethoxy-13-ethyl-7-(methoxymethyl)-9,11,21-trimethyl-11,12,13,14- tetrahydro-9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol; {[(11S,18E)-13-ethyl-15-[(2S)-1-hydroxypropan-2-yl]-7,9,11,21-tetramethyl-12,13,14,15- tetrahydro-9H,11H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-17-yl]oxy}acetonitrile; (2S)-2-[(8aR,9S,20E)-1-ethoxy-9,11,13-trimethyl-7,8,8a,9-tetrahydro-6H,11H-14,17- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n]pyrrolo[2,1- c][1,4,11]oxadiazacyclopentadecin-3(4H)-yl]propan-1-ol; (2S)-2-[(8aR,9R,20E)-1-ethoxy-9,11,13-trimethyl-7,8,8a,9-tetrahydro-6H,11H-14,17- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n]pyrrolo[2,1- c][1,4,11]oxadiazacyclopentadecin-3(4H)-yl]propan-1-ol; (2S)-2-[(11S,12R,18E)-17-ethoxy-7-(methoxymethyl)-9,11,12,13-tetramethyl-11,12,13,14- tetrahydro-9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol; (18E)-17-ethyl-9,13,15-trimethyl-12,13-dihydro-9H,11H-3,6-ethenoimidazo[2,1- j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-14(15H)-one; (2S)-2-[(8aR,9S,20E)-1-ethoxy-9,11-dimethyl-7,8,8a,9-tetrahydro-6H,11H-14,17- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n]pyrrolo[2,1- c][1,4,11]oxadiazacyclopentadecin-3(4H)-yl]propan-1-ol; (2S)-2-[(8aR,9R,20E)-1-ethoxy-9,11-dimethyl-7,8,8a,9-tetrahydro-6H,11H-14,17- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n]pyrrolo[2,1- c][1,4,11]oxadiazacyclopentadecin-3(4H)-yl]propan-1-ol;83573-420992 (2S)-2-[(12S,19E)-18-ethoxy-12,14-dimethyl-12,13,14,15-tetrahydro-16H-6,3- (azenometheno)imidazo[2,1-j]pyrazolo[3,4-f]pyrido[3,4-n][1,4,11]oxadiazacyclopentadecin- 16-yl]propan-1-ol; (2S)-2-[(11S,12R,18E)-17-ethoxy-7-(methoxymethyl)-9,11,12,13,21-pentamethyl- 11,12,13,14-tetrahydro-9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol; (2S)-2-[(11S,12R,18E)-17-ethoxy-7,9,11,12,13,21-hexamethyl-11,12,13,14-tetrahydro- 9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol; (2S)-2-[(11R,12R,18E)-17-ethoxy-7,9,11,12,13,21-hexamethyl-11,12,13,14-tetrahydro- 9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol; (2S)-2-[(11S,12R,18E)-17-ethoxy-7,9,11,12,13-pentamethyl-11,12,13,14-tetrahydro- 9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol; (2S)-2-[(8aR,9S,20E)-1-ethoxy-9,11,13,22-tetramethyl-7,8,8a,9-tetrahydro-6H,11H-14,17- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n]pyrrolo[2,1- c][1,4,11]oxadiazacyclopentadecin-3(4H)-yl]propan-1-ol; (18E)-9,13,15-trimethyl-12,13,14,15-tetrahydro-9H,11H-6,3-(azenometheno)imidazo[5,1- j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-21-amine; (18E)-8,13,15-trimethyl-12,13,14,15-tetrahydro-8H,11H-6,3-(azenometheno)imidazo[5,1- j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-21-amine; (18E)-17-ethoxy-8,13,15-trimethyl-12,13,14,15-tetrahydro-8H,11H-6,3- (azenometheno)imidazo[5,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-21- amine; (2S)-2-[(11S,18E)-13-(2,2-difluoroethyl)-17-ethoxy-7,9,11-trimethyl-11,12,13,14- tetrahydro-9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol; {[(11S,18E)-13-(2,2-difluoroethyl)-15-[(2S)-1-hydroxypropan-2-yl]-7,9,11-trimethyl- 12,13,14,15-tetrahydro-9H,11H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-17-yl]oxy}acetonitrile; (2S)-2-[(11S,18E)-13-cyclopropyl-17-ethoxy-7,9,11-trimethyl-11,12,13,14-tetrahydro- 9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol; {[(11S,18E)-13-cyclopropyl-15-[(2S)-1-hydroxypropan-2-yl]-7,9,11-trimethyl-12,13,14,15-83573-420992 tetrahydro-9H,11H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-17-yl]oxy}acetonitrile; (2S)-2-[(11S,18E)-17-ethoxy-13-ethyl-7,11-dimethyl-11,12,13,14-tetrahydro-15H-6,3- (azenometheno)imidazo[2,1-j]pyrazolo[3,4-f][1,2]thiazolo[4,5- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol; (2S)-2-[(11S,18E)-17-ethoxy-13-ethyl-7,11-dimethyl-11,12,13,14-tetrahydro-15H-6,3- (azenometheno)imidazo[2,1-j][1,2]oxazolo[4,5-n]pyrazolo[3,4- f][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol; (2S)-2-[(11S,18E)-17-ethoxy-13-ethyl-7,9,11-trimethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)imidazo[2,1-j]pyrazolo[3,4-f]pyrrolo[3,2- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol; (2S)-2-[(11S,18E)-17-ethoxy-9,13-diethyl-7,11-dimethyl-11,12,13,14-tetrahydro-9H,15H- 6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin- 15-yl]propan-1-ol; (2S)-2-[(11S,18E)-17-ethoxy-7,13-diethyl-9,11-dimethyl-11,12,13,14-tetrahydro-9H,15H- 6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin- 15-yl]propan-1-ol; (11S,18E)-7-(methoxymethyl)-9,11,13,16-tetramethyl-12,13,14,16-tetrahydro-9H,11H-6,3- (azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecine; (11S,18E)-7-(methoxymethyl)-9,11,13,16,17-pentamethyl-12,13,14,16-tetrahydro-9H,11H- 6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecine; (11S,18E)-7-(methoxymethyl)-9,11,13,15,17-pentamethyl-12,13,14,15-tetrahydro-9H,11H- 6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecine; and (2S)-2-[(11S,18E)-7-(2,2-difluoroethyl)-17-ethoxy-13-ethyl-9,11-dimethyl-11,12,13,14- tetrahydro-9H,15H-6,3-(azenometheno)imidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol; or a pharmaceutically acceptable salt thereof.

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

53. A method of treating disease in a subject comprising, administering a therapeutically effective amount of a compound of any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 52.83573-420992 54. A compound according to any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof, for use in a method of treating disease in a subject.

55. Use of a compound according to any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of disease in a subject.

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