OA22148A

OA22148A - Indazole Macrocycles And Their Use.

Info

Publication number: OA22148A
Application number: OA1202400442
Authority: OA
Inventors: Jingrong Jean Cui; Eugene Yuanjin Rui; Dayong Zhai; Jane Ung; Wei Deng; Evan W Rogers; Ping Jiang
Original assignee: Blossomhill Therapeutics, Inc.
Priority date: 2022-06-08
Filing date: 2023-06-07
Publication date: 2025-12-24

Abstract

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

Description

INDAZOLE MACROCYCLES AND THEIR USE

RELATED APPLICATIONS

This application daims the benefît of U.S. Provisional Application No. 63/350,307, filed June 8, 2022, and U.S. Provisional Application No. 63/501,114, filed May 9, 2023, the entire disclosures of ail of which are incorporated herein by reference.

SEQUENCE LISTING

The application contains a Sequence Listing which has been submitted electronically in XML format and is hcreby incorporated by reference in its entirety. Said XML copy, created on May 23, 2023, is named 83573-39033 l_SL.xml, and is 21,203 bytes in size.

TECHNICAL FIELD

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

BACKGROUND

Protein kinases are tightly regulated signaling proteins that orchestrale 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 complément of the human genome. Science. 2002, 298:1912-34). Dysrégulation of kinase activity is associated with many diseases, including cancers, and cardiovascular, dégénérative, immunological, infectious, inflammalory, 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 délétions, splicing changes, and translocations (Wilson LJ, et al New Perspectives, Opportunités, and Challenges in Exploring the Human Protein Kinome. Cancer Res. 2018, 78:15-29). The critical rôle of kinases in cancer and other diseases makes them attractive targets for drug inventions with 62 small molécule kinase inhibitors hâve been approved and 55 of them for cancer targeted thérapies (Roskoski R Jr, Properties of FDA-approved Small Molécule Protein Kinase Inhibitors: A 2021 Update. Pharmacol Res 2021, 165:105463). Although kinase inhibitors hâve achieved dramatic success in cancer targeted thérapies, the development of treatment résistance has remained as a challenge for small molécule kinase inhibitors. Acquired secondary mutations within kinase domain during the treatment often lead to treatment résistance to kinase inhibitors (Pottier C, et al Tyrosine Kinase Inhibitors in Cancer: Breakthrough and Challenges ofTargeted Therapy. Cancers (Basel), 2020, 12:73 l). Résistance can also arise from subpopulations of tolerant/persister cells that survive in the présence of the treatment. Different processes contribute to the émergence of tolérant persister cells, including pathway rebound through the relcase of négative 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 Résistance 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 résistance mutations, but also tolérant persister cancer cells for overcoming résistance, achieving better efficacy and longer disease control.

Acute myeloid leukemia (AML) is a complex malignancy with many cytogenctic or chromosomal aberrations. The most frequentiy identified mutation in AML is FMS-like tyrosine kinase 3 (FLT3) with about 25% of adult patients having FLT3 internai tandem duplication (FLT3ITD) and 7-10% with point mutations or délétions (Daver N, et al Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia 2019, 33:299 312). Two FLT3 inhibitors hâve been approved by the Food and Drug Administration (FDA) for AML indications: midostaurin for newly diagnosed FLT3 mutated AML in combination with standard induction and consolidation chemotherapy and gilteritinib for relapsed or refractory FLT3 mutated AML as monotherapy. Although significant progress has been made in the treatment of AML with FLT3 inhibitors, leukemia relapse remains to be a major cause of treatment failure. Mechanisms of drug résistance include évolution of FLT3 résistance mutations, adaptive cellular mechanisms, and a protective leukemia microenvironment. Frequentiy récurrent locations for résistance mutations are in the activating loop residues (e.g., D835, 1836, D839, and Y842) or in the gatekeeper residue F691 of FLT3. Alterations of the leukemia microenvironment, including increased FGF2 and CXCLI2/CXCR4 signaling, may protect FZ,73-mutated progenitors. Increased signaling through parallel prosurvival pathways, including RAS-RAF-MEK-ERK, PI3K-AKT mTOR, and JAKSTAT5-PIM1 pathways may also contribute to FLT3 inhibitor résistance (Short NJ, et al Advances in the Treatment of Acute Myeloid Leukemia: New Drugs and New Challenges. Cancer Discov. 2020, 10:506-525).

The proviral intégration for the Moloney murine leukemia virus (PIM) kinases are oncogenic serine/threonine kinases that phosphorylate a wide range of substrates that regulate several of the hallmarks of cancer including tumor metabolism, survival, metastasis, immune évasion and inflammation (Toth RK, Warfel NA. Targeting PIM Kinases to Overcome Therapeutic Résistance in Cancer. Mol Cancer Ther. 2021, 20(1):3-10). PIM kinases interact with numerous major oncogenic players, including stabilization of p53, synergism with c-Myc, and notable parallel signalîng with PI3K/Akt. The aberrant PIM kinase activity plays an important rôle in résistance mechanisms of chemotherapy, radiotherapy, anti-angiogenic thérapies and targeted thérapies, providing a rationale for co-targeting treatment strategies for a more durable patient response (Malone T, ct al Cuiront perspectives on targeting PIM kinases to overcome mechanisms of drug résistance and immune évasion in cancer. Pharmacol Ther 2020 Mar; 207).

Cdc-like kinases (CLKs) are evolutionary conserved dual-spccificity kinases that are able to phosphorylate serine, threonine, and tyrosine residues. CLKs catalyze the phosphorylation of SR proteins, serine, and arginine-rich splicing factors 1-12 (SRSFl-12), which regulate the spliceosome molecular machinery (Martin Moyano P, et al Cdc-Like Kinases (CLKs): Biology, Chemical Probes, and Therapeutic Potential. Int J Mol Sci 2020, 21(20):7549). Dysrégulation of alternative splicing is a feature of cancer. High-frequency mutations of SF3B1 or SRSF2 hâve been described in patients with myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia, and acute myeloid leukemia (AML) (Papaemmanuil et al, Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016, 374:2209 - 2221). In addition, mutations in splicing-related genes hâve also been found in varions solid cancers, including lung, breast, and pancreatic cancers (Dvinge H, et al RNA splicing factors as oncoproteins and tumour suppressors. Nat Rev Cancer 2016, 16: 413 - 430). The modulation of pre-mRNA splicing via inhibition of CLK kinases is an attractive anti-neoplastic strategy, especially for the cancers that exhibît aberrant pre-mRNA splicing.

Therefore, it is necessary to develop a new génération multitargeted FLT3 inhibitors that are potent against oncogenic driver FLT3 mutations, other emerging and established FLT3 résistance mutations, as well as emerging résistance targets for tolerant/persistent cancer cells, e.g., PIM kinases and CLK kinases.

SUMMARY

In one aspect, the disclosure provides a compound of the formula I, or a pharmaceutically acceptable sait thereof,

wherein R¹, R², R³, R⁴, R⁵, A, B, L, m, n, p, and q are as described herein.

In some embodiments, the disclosure provides a compound of the formula II, or a 5 pharmaceutically acceptable sait thereof,

wherein R¹, R², R³, R⁴, R⁵, A, B, L, m, n, p, q, and “------” are as described herein.

In some embodiments, the disclosure provides a compound of the formula III, or a 10 pharmaceutically acceptable sait thereof,

wherein R^l, R², R³, R⁴, R⁵, A, B, L, X¹, X², X³, m, n, p, q, and “------’’ are as described herein.

In further aspects, the disclosure relates to a pharmaceutical composition comprising at least one compound of Formula (I)-(V1) or a pharmaceutically acceptable sait thereof. Pharmaceutical compositions according to the disclosure may further comprise a pharmaceutically acceptable excipient.

In further aspects, the disclosure relates to a compound of Formula (I)-(V1), or a pharmaceutically acceptable sait thereof, for use as a médicament.

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

In further aspects, the disclosure relates to use of a compound of Formula (I)-(VI), or a pharmaceutically acceptable sait thereof, in the préparation of a médicament for the treatment of disease, such as cancer, and the use of such compounds and salts for treatment of such diseases.

In further aspects, the disclosure relates to a method of inhibiting one or more of aberrant FLT3, including oncogenic driver mutations such as FL73-ITD and FLT3 résistance mutations, such as résistance mutations in the activating loop residues (e.g., D835, 1836, D839, and Y842), or in the gatekeeper residue F691 of FLT3, aberrant PIM kinases, and/or aberrant CLK kinases comprising contacting a cell comprising one or more of aberrant FLT3, including oncogenic driver mutations such as FLF3-ITD and FLT3 résistance mutations, such as résistance mutations in the activating loop residues (e.g., D835, 1836, D839, and Y842), or in the gatekeeper residue F691 of FLT3, aberrant PIM kinases, and/or aberrant CLK kinases, with an effective amount of at least one compound of Formula (I)-(VI), or a pharmaceutically acceptable sait thereof, and/or with at least one pharmaceutical composition of the disclosure, wherein the contacting is in vitro, ex vivo, or in vivo.

[00011 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 présent disclosure can be described as embodiments in any of the following enumerated clauses. It will be understood that any of the embodiments described herein can be used in connection with any other embodiments described herein to the extent that the embodiments do not contradict one another.

1. A compound of the formula I

wherein ring A is a 5- to 10-membered heteroarylene;

ring B is a 5- to 10-membered heteroarylene or Cô-Cio arylene;

each L is independently -O-, -S-, -S(O)-, -S(O)₂-, -N(R⁶)C(O)-, -C(O)N(R⁶)-, -N(R⁶)-, -N(R⁶)S(O)-, -S(O)N(R⁶)-, -N(R⁶)S(O)2-, -S(O)2N(R⁶)-, or-C(R⁷)(R⁸)-, provided that (L)p does not comprise an O-O, S-O, or N-N bond, and the point of covalent attachment of (L)_pto -NR³- does not form a -N-N- or a -O-N- bond;

each R¹ and R² when présent, is independently deuterium, halogen, Ci-Cô alkyl, C2-C& alkenyl, Ο2-Ο(,alkynyl, Cj-Côcycloalkyl, 3- to 7-membered heterocycloalkyl, Ct>-Cioaryl, 5- to 10-membered hcteroaryl, -OR^a, -OC(O)R^a, -OC(O)NR^aR^b, -OS(O)R^a, -OS(O)2R^a, -SR^a, -S(O)R^a, -S(O)2R^a, -S(O)NR^aR^b, -S(O)2NR^aR^b, -OS(O)NR^aR^b, -OS(O)2NR^aR^b, -NR^aR^b, -NR^aC(O)R^b, -NR^aC(O)OR^b, -NR^aC(O)NR^aR^b, -NR^aS(O)R^b, -NR^aS(O)2R^b, -NR^aS(O)NR^aR^b, -NR^aS(O)2NR^aR^b, -C(O)R^a, -C(O)OR^a, -C(O)NR^aR^b, -PR^aR^b, -P(O)R^aR^b, -P(O)2R^aR^b, -P(O)NR^aR^h, -P(O)2NR^aR^b, -P(O)OR^a, -P(O)2OR^a, -CN, or -NO₂, wherein each hydrogen atom in Cj-Cô alkyl, C₂-Cô alkenyl, C2-C6 alkynyl, Cj-Cô cycloalkyl, 3- to 7-membered heterocycloalkyl, Cè-Cioaryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Cô alkyl, Ci-Côhaloalkyl, -OR^C, -OC(O)R^C, -OC(O)NR^cR^d, -OC(=N)NR^cR^d, -OS(O)R^C, -OS(O)2R^C, -OS(O)NR^cR^d, -OS(O)2NR^cR^d, -SR^C, -S(O)R^C, -S(O)2R^C, -S(O)NR^cR^d, -S(O)?NR^cR^d, -NR^eR^d, -NR^cC(O)R^d, -N(C(O)R^c)(C(O)R^d), -NR^cC(O)OR^d, -NR^cC(O)NR^cR^d, -NR^cC(=N)NR^cR^d, -NR^cS(O)R^d, -NR^cS(O)2R^d, -NR^cS(O)NR^cR^d, -NR^cS(O)2NR^cR^d, -C(O)R^C, -C(O)OR^C, -C(O)NR^cR^d, -C(=N)NR^cR^d, -PR^cR^d, -P(O)R^cR^d, -P(O)2R^cR^d, -P(O)NR^cR^d, -P(O)2NR^cR^d, -P(O)OR^C, -P(O)2OR^C, -CN, or -NO₂;

R³ is H, deuterium, Ci-Cô alkyl, C2-C& alkenyl, C2-Cô alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cioaryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in Ci-Cô alkyl, C2-Cô alkenyl, C2-Cô alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cioaryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, -OR^C, -OC(O)R^C, -OC(O)NR^cR^d, -OC(=N)NR^cR^d, -OS(O)R^C, -OS(O)2R^c, -OS(O)NR^cR^d, -OS(O)2NR^cR^d, -SR^C, -S(O)R^C, -S(O)2R^C, -S(O)NR^cR^d, -S(O)2NR^cR^d, -NR^cR^d, -NR^cC(O)R^d, -N(C(O)R^c)(C(O)R^d), -NR^cC(O)OR^d, -NR^cC(O)NR^L'R^d, -NR^cC(=N)NR^cR^d, -NR^eS(O)R^d, -NR^cS(O)2R^d, -NR^cS(O)NR^cR^d, -NR^cS(O)2NR^eR^d, -C(O)R^C, -C(O)OR^C, -C(O)NR^cR^d, -C(=N)NR^cR^d, -PR^cR^d, -P(O)R^cR^d, -P(O)2R^cR^d, -P(O)NR^cR^d, -P(O)2NR^eR^d, -P(O)OR^e, -P(O)2OR^c, -CN, or -NO₂;

each R⁴ is independently deuterium, halogen, Ci-Cô alkyl, C2-Cô alkenyl, C2-Cô alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cioaryl, 5- to 10-membered heteroaryl, -OR^a, -OC(O)R^a, -OC(O)NR^aR^b, -OS(O)R^a, -OS(O)2R^a, -SR^a, -S(O)R^a, -S(O)2R^a, -S(O)NR^aR^b, -S(O)2NR^aR^b, -OS(O)NR^aR^b, -OS(O)2NR^aR^b, -NR^aR^b, -NR^aC(O)R^b, -NR^aC(O)OR^b, -NR^aC(O)NR^aR^b, -NR^aS(O)R^b, -NR^aS(O)2R^b, -NR^aS(O)NR^aR^b, -NR^aS(O)2NR^aR^b, -C(O)R^a, -C(O)OR^a, -C(O)NR^aR^b, -PR^aR^b, -P(O)R^aR^b, -P(O)2R^aR^b, -P(O)NR^aR^b, -P(O)2NR^aR^b, -P(O)OR^a, -P(O)2OR^a, -CN, or -NO2, wherein each hydrogen atom in Ci-Cô alkyl, C2-Cô alkenyl, C2-Cô alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cioaryl, and 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-C6 alkyl, Ci-C6haloalkyl, -OR^e, -OC(O)R^e, -OC(O)NR^eR^f, -OS(O)R^e, -OS(O)2R^e, -OS(O)NR^eR^r, -OS(O)?NR^eR^f, -SR^e, -S(O)R^e, -S(O)2R^e, -S(O)NR^eR^r, -S(O)2NR^eR^t, -NR^cR^f, -NR^eC(O)R^r, -NR^eC(O)OR^f, -NR^eC(O)NR^eR^r, -NR^eS(O)R^f, -NR^eS(O)2R^f, -NR^eS(O)NR^cR^r, -NR^eS(O)2NR^eR^r, -C(O)R^e, -C(O)OR^e, -C(O)NR^eR^f, -PR^cR^f, -P(O)R^eR^f, -P(O)2R^cR^f, -P(O)NR^eR^r, -P(O)2NR^cR^r, -P(O)OR^e, -P(O)2OR^e, -CN, or -NO₂;

R⁵ is H, deuterium, -C(O)R^C, -C(O)OR^C, -C(O)NR^cR^d, -P(O)2R^cR^d, -P(O)2NR^cR^d, -P(O)2OR^c, or-S(O)2OR^c;

each R⁶, when présent, is independently H, deuterium, Ci-Cô alkyl, C₂-C6 alkenyl, C2-C6 alkynyl, Ci-CT cycloalkyl, 3- to 7-membered heterocycloalkyl, C₍₁-Cioaryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in Ci-C* alkyl, C₂-C& alkenyl, C₂-Cô alkynyl, Ci-C, cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cioaryl, or 5- to 10-membered heteroaryl is independently optionally substituted by -OR^C, -OC(O)R^C, -OC(O)NR^cR^d, -OC(=N)NR^cR^d, -OS(O)R^C, -OS(O)2R^C, -OS(O)NR^cR^d, -OS(O)2NR^cR^d, -SR^C, -S(O)R^e, -S(O)₂R^C, -S(O)NR^cR^d, -S(O)2NR^cR^d, -NR^cR^d, -NR^cC(O)R^d, -N(C(O)R^e)(C(O)R^d), -NR^eC(O)OR^d, -NlCC(O)NR^cR^l1, -NR^cC(=N)NR^cR^d, -NR^cS(O)R^d, -NR^cS(O)2R^d, -NR^cS(O)NR^cR^d, -NR^cS(O)2NR^i;R^d, -C(O)R^C, -C(O)OR^C, -C(O)NR^cR^d, -C(=N)NR^cR^d, -PR^cR^d, -P(O)R^cR^d, -P(O)2R^cR^d, -P(O)NR^eR^d, -P(O)2NR^cR^d, -P(O)OR^C, -P(O)2OR^C, -CN, or-NO₂;

each R⁷ and R⁸, is independently H, deuterium, halogen, Ci-Cô alkyl, C2-Cô alkenyl, C2-Cô alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cioaryl, 5- to 10membered heteroaryl, -OR^a, -OC(O)R^a, -OC(O)NR^aR^b, -OS(O)R^a, -OS(O)2R^a, -SR^a, -S(O)R^a, -S(O)2R^a, -S(O)NR^aR^b, -S(O)2NR^aR^b, -OS(O)NR^aR^b, -OS(O)2NR^aR^b, -NR^aR^b, -NR^aC(O)R^b, -NR^aC(O)OR^b, -NR^aC(O)NR^aR^b, -NR^aS(O)R^b, -NR^aS(O)2R^b, -NR^aS(O)NR^aR^b, -NR^aS(O)2NR^aR^b, -C(O)R^a, -C(O)OR^a, -C(O)NR^aR^h, -PR^aR^b, -P(O)R^aR^b, -P(O)2R^aR^b, -P(O)NR^aR^b, -P(O)2NR^aR^b, -P(O)OR^a, -P(O)2OR\ -CN, or -NO2, wherein each hydrogen atom in Ci-Cô alkyl, C₂-Cè alkenyl, C₂-C& alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Cè-Cioaryl, and 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Cj-Cô alkyl, Ci-Cô haloalkyl, -OR^e, -OC(O)R^e, -OC(O)NR^eR^f, -OS(O)R^e, -OS(O)2R^e, -OS(O)NR^eR^r, -OS(O)2NR^cR^r, -SR^e, -S(O)R^e, -S(O)2R^e, -S(O)NR^eR^f, -S(O)2NR^cR^f, -NR^L'R^f, -NR^cC(O)R^r, -NR^eC(O)OR^f, -NR^eC(O)NR^eR^f, -NR^eS(O)R^f, -NR^eS(O)2R^f, -NR^eS(O)NR^cR^f, -NR^eS(O)2NR^cR^r, -C(O)R^e, -C(O)OR^e, -C(O)NR^eR^f, -PR^eR^f, -P(O)R^eR^r, -P(O)2R^eR^f, -P(O)NR^cR^f, -P(O)2NR^eR^r, -P(O)OR^e, -P(O)2OR^e, -CN, or -NO2; or two of R⁷ and R⁸, taken together with the carbon or carbons to which they are attached, optionally combine to form a C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in the C3-Cô cycloalkyl or 3- to 7-membered heterocycloalkyl formed when two of R⁷ and R⁸ are taken together is independently optionally substituted by -OR^e, -OC(O)R^e, -OC(O)NR^cR^f, -OS(O)R^e, -OS(O)2R^e, -OS(O)NR^eR^f, -OS(O)2NR^eR^r, -SR^e, -S(O)R^e, -S(O)2R^e, -S(O)NR^eR^f, -S(O)2NR^eR^f, -NR^eR^r, -NR^eC(O)R^f, -NR^eC(O)OR^f, -NR^eC(O)NR^eR^f, -NR^eS(O)R^f, -NR^eS(O)2R^f, -NR^eS(O)NR^eR^f, -NR^eS(O)2NR^eR^r, -C(O)R^e, -C(O)OR^e, -C(O)NR^eR^f, -PR^cR^f, -P(O)R^cR^f, -P(O)2R^cR^f, -P(O)NR^cR^f, -P(O)2NR^cR‘, -P(O)OR^e, -P(O)2OR^e, -CN, or -NO₂;

each R^a, R^b, R^c, R^d, R^e, and R^f is independently selected from the group consisting of H, deuterium, Ci-Cô alkyl, C₂-Cô alkenyl, C₂-Cô alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cioaryl, Cj-Côaikylene-Câ-Cioaryl, 5- to 10-membered heteroaryl, and

Ci-Cô alkylene-5- to 10-inembered heteroaryl, or R^a and R^h or R^c and R^d or R^c and R^r, taken together with the atom to which they are attached, form a 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in Ci-Cô alkyl, C₂-Cô alkenyl, C₂-Cô alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cioaryl, Ci-Cô alkylene-Cô-Cioaryl, 5- to 10-membered heteroaryl, or Cj-Cô alkylene-5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, Cj-Côalkyl, Cj-Côhaloalkyl, -OH, -OCi-Cô alkyl, -OC(O)-(H or Ci-Cô alkyl), -OC(O)N(H or Ci-C₆ alkyt)₂, -OC(O)N(C₂-Cô alkylene), -OS(O)-(H or C|-C₆alkyl), -OS(O)₂-(H or C,-Cô alkyl), -OS(O)N(H or Ci-C₆ alkyl)₂, -OS(O)N(C₂-Cô alkylene), -OS(O)₂N(H or Ci-C₆ alkyl)₂, -OS(O)₂N(C₂-C₆ alkylene), -S(H or Ci-C₆ alkyl), -S(O)(H or C|-C₆ alkyl), -S(O)₂(H or Ci-C₆ alkyl), -S(O)N(H or Cj-C₆ alkyl)₂, -S(O)N(C₂-C₆ alkylene), -S(O)₂N(H or Ci-C₆ alkyl)₂, -S(O)₂N(C₂-C₆ alkylene), -N(H or C1-C0 alkyl)₂, -N(C₂-C₆alkylene), -N(H or Ci-C₆ alkyl)C(O)-(H or Cj-C₆ alkyl), -N(H or Ci-Cô alkyl)C(O)O(H or C,-C₆alkyl), -N(H or Ci-C₆ alkyl)C(O)N(H or C|-C₆ alkyl)₂, -N(H or Ci-Cô alkyl )C(O)N(C₂-C₆alkylene), -N(H or Cj-C₆ alkyl)S(O)-(H or Ci-C₆ alkyl), -N(H or C1-C0 alkyl)S(O)₂(H or Ci-C₆alkyl), -N(H or Ci-C₆ alkyl)S(O)N(H or Cj-C₆ alkyl)₂, -N(H or Ci-C₆ alkyl)S(O)N(C₂-C₆alkylene), -N(H or Cj-Cô alkyl)S(O)₂N(H or Ci-Cô alkyl)₂, -N(H or Cj-Cô alkyl)S(O)₂N(C₂-Cô alkylene), -C(O)-(H or C1-C0 alkyl), -C(O)O(H or Ci-C₆ alkyl), -C(O)N(C₂-C₆ alkylene), -P(H or Cj-Cô alkyl)₂, -P(C₂-Cô alkylene), -P(O)(H or Ci-C₆ alkyl)₂, -P(O)(C₂-C₆ alkylene), -P(O)₂(H or Cj-Cô alkyl)₂, -P(O)₂(C₂-Cô alkylene), -P(O)N(H or Ci-C₆ alkyl)₂, -P(O)N(C₂-C₆alkylene), -P(O)₂N(H or Ci-C₆ alkyl)₂, -P(O)₂N(C₂-C₆ alkylene), -P(O)O(H or Ci-C₆alkyl), -P(O)₂O(H or Ci-Cô alkyl), -CN, or -NO₂;

m is 0, 1, 2, or 3;

n is 0, 1, 2, 3, or 4;

p is 3, 4, 5, 6, or 7; and q is 0, 1, or 2 or a pharmaceutically acceptable sait thereof.

2. A compound of the formula I

wherein ring A is a 5- to 10-membered heteroarylene;

ring B îs a 5- to 10-membered heteroarylene or Cô-Cio arylene;

each R¹ and R² when présent, is independently deuterium, halogen, Ci-Cô alkyl, C2-Cé alkenyl, C2-Cô alkynyl, Ca-Côcycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cioaryl, 5- to 10-membered heteroaryl, -OR^a, -OC(O)R^a, -OC(O)NR^aR^b, -OS(O)R^a, -OS(O)2R^a, -SR^a, -S(O)R^a, -S(O)2R^a, -S(O)NR^aR^b, -S(O)2NR^aR^b, -OS(O)NR^aR^b, -OS(O)2NR^aR^b, -NR^aR^b, -NR^aC(O)R^b, -NR^aC(O)OR^b, -NR^aC(O)NR^aR^b, -NR^aS(O)R^b, -NR^aS(O)2R^b, -NR^aS(0)NR^aR^b, -NR^aS(O)2NR^aR^b, -C(O)R^a, -C(O)OR^a, -C(0)NR^aR^b, -PR^aR^b, -P(O)R^aR^b, -P(O)₂R^aR^b, -P(O)NR^aR^b, -P(O)2NR^aR^b, -P(O)OR^a, -P(O)2OR^a, -CN, or -NO₂, wherein each hydrogen atom in Ci-Cô alkyl, C₂-Cô alkenyl, C₂-Ce alkynyl, Ci-Cô cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cioaryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Cô alkyl, C1-C0 haloalkyl, -OR^C, -OC(O)R^e, -OC(O)NR^cR^d, -OC(=N)NR^cR^d, -OS(O)R^C, -OS(O)2R^C, -OS(O)NR^cR^d, -OS(O)2NR^cR^d, -SR^C, -S(O)R^C, -S(O)2R^C, -S(O)NR^cR^d, -S(O)2NR^cR^d, -NR^cR^d, -NR^cC(O)R^d, -N(C(O)R^c)(C(O)R^d), -NR^cC(O)OR^d, -NR^cC(O)NR^cR^d, -NR^eC(=N)NR^cR^d, -NR^cS(O)R^d, -NR^cS(O)2R^d, -NR^cS(O)NR^cR^d, -NR^cS(O)2NR^ÎR^d, -C(O)R^C, -C(O)OR^C, -C(O)NR^cR^d, -C(=N)NR^cR^d, -PR^cR^d, -P(O)R^cR^d, -P(O)2R^cR^d, -P(O)NR^cR^d, -P(O)2NR^cR^d, -P(O)OR^C, -P(O)2OR^C, -CN, or -NO₂;

R³ is H, deuterium, C|-C₆ alkyl, Cz-Cô alkenyl, Cz-Cô alkynyl, C3-C0 cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cioaryl, or 5- to l O-membered hcteroaryl, wherein each hydrogen atom in Cj-Cô alkyl, C₂-Cô alkenyl, C2-C0 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cioaryl, or 5- to l O-membered heteroaryl is independently optionally substituted by -OR^C, -OC(O)R^C, -OC(O)NR^cR^d, -OC(=N)NR^cR^d, -OS(O)R^C, -OS(O)zR^c, -OS(O)NR^cR^d, -OS(O)zNR^cR^d, -SR^C, -S(O)R^C, -S(O)2R^C, -S(O)NR^cR^d, -S(O)2NR^cR^d, -NR^cR^d, -NR^cC(O)R^d, -N(C(O)R^c)(C(O)R^d), -NR^cC(O)OR^d, -NR^cC(O)NR^cR^d, -NR^cC(=N)NR^eR^d, -NR^cS(O)R^d, -NR^eS(O)zR^d, -NR^cS(O)NR^cR^d, -NR^cS(O)zNR^vR^d, -C(O)R^C, -C(O)OR^C, -C(O)NR^cR^d, -C(=N)NR^cR^d, -PR^cR^d, -P(O)R^cR^d, -P(O)zR^cR^d, -P(O)NR^cR^d, -P(O)₂NR^cR^d,

-P(O)OR^C, -P(O)₂OR^c, -CN, or -NOz;

each R⁴ is independently deuterium, halogen, Ci-Cô alkyl, Cz-Cô alkenyl, Cz-Cô alkynyl, Cz-Côcycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cioaryl, 5- to lO-membered heteroaryl, -OR^a, -OC(O)R^a, -OC(O)NR^aR^b, -OS(O)R^a, -OS(O)₂R^a, -SR^a, -S(O)R^a, -S(O)2R^a, -S(O)NR^aR^b, -S(O)2NR^aR^b, -OS(O)NR^aR^b, -OS(O)₂NR^aR^b, -NR^aR^b, -NR^aC(O)R^b,

-NR^aC(O)OR^b, -NR^aC(O)NR^aR^b, -NR^aS(O)R^b, -NR^aS(O)₂R^b, -NR^aS(O)NR^aR^b, -NR^aS(O)2NR^aR^b, -C(O)R^a, -C(O)OR^a, -C(O)NR^aR^b, -PR^aR^b, -P(O)R^aR^b, -P(O)2R^aR^b, -P(O)NR^dR^b, -P(O)₂NR^aR^b, -P(O)OR^a, -P(O)2OR^a, -CN, or -NOz, wherein each hydrogen atom in Ci-Cô alkyl, C2-Cô alkenyl, Cz-Cô alkynyl, Cz-Cô cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cioaryl, and 5- to lO-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Cô alkyl, Ci-Côhaloalkyl, -OR^e, -OC(O)R^e, -OC(O)NR^eR^f, -OS(O)R^e, -OS(O)?R^e, -OS(O)NR^eR^f, -OS(O)zNR^eR^r, -SR^e, -S(O)R^e, -S(O)zR^e, -S(O)NR^eR^l, -S(O)zNR^cR^f, -NR^eR^f, -NR^eC(O)R^r, -NR^eC(O)OR^r, -NR^cC(O)NR^eR^f, -NR^eS(O)R^r, -NR^cS(O)2R^r, -NR^eS(O)NR^cR^f, -NR^eS(O)2NR^cR^l, -C(O)R^e, -C(O)OR^e, -C(O)NR^eR^r, -PR^eR^f, -P(O)R^eR^f, -P(O)zR^eR^f, -P(O)NR^eR^f, -P(O)₂NR^eR^r, -P(O)OR^e, -P(O)2OR^e, -CN, or -NO2;

R⁵ is H, deuterium, -C(O)R^C, -C(O)OR^C, -C(O)NR^eR^d, -P(O)2RR^d, -P(O)2NR^cR^d,

-P(O)zOR^c, or S(O)₂OR^c;

each R⁶, when présent, is independently H, deuterium, Ct-Cô alkyl, C₂-Cô alkenyl, Cz-Côalkynyl, Cz-Côcycloalkyl, 3- to 7-membcrcd heterocycloalkyl, Cô-Cioaryl, or 5- to 10membered heteroaryl, wherein each hydrogen atom in Ci-Cô alkyl, C₂-Cô alkenyl, C₂-Cô alkynyl, 30 Cz-Côcycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cioaryl, or 5- to lO-membered heteroaryl is independently optionally substituted by -OR^C, -OC(O)R^C, -OC(O)NR^eR^d, -OC(=N)NR^cR^d, -OS(O)R^C, -OS(O)zR^c, -OS(O)NR^cR^d, -OS(O)2NR^cR^d, -SR^C, -S(O)R^C, -S(O)2R^C, -S(O)NR^eR^d, -S(O)zNR^cR^d, -NR^cR^d, -NR^cC(O)R^d, -N(C(O)R^c)(C(O)R^d), -NR^cC(O)OR^d, -NR^cC(O)NR^cR^d, -NR^cC(=N)NR^cR^d, -NR^cS(O)R^d, -NR^cS(O)₂R^d, -NR^cS(O)NR^eR^d,

H

-NR^eS(O)2NR^cR^d, -C(O)R^C, -C(O)OR^C. -C(O)NR^cR^d, -C(=N)NR^cR^d, -PR^cR^d, -P(O)R^cR^d, -P(O)₂R^cR^d, -P(O)NR^cR^d, -P(O)2NR^cR^d, -P(O)OR^C, -P(O)2OR^C, -CN, or -NO₂;

each R⁷ and R^s, is independently H, deuterium, halogen, Ci-Ce alkyl, C2-C& alkenyl, C2-Cô alkynyl, C3-C6 cycloalkyl, 3- to 7-membered hcterocycloalkyl, Cô-Cioaryl, 5- to IOmembered heteroaryl, -OR^a, -OC(O)R^a, -OC(O)NR^aR^b, -OS(O)R^a, -OS(O)2R^a, -SR^a, -S(O)R^a, -S(O)2R^a, -S(O)NR^aR^b, -S(O)2NR^aR^b, -OS(O)NR^aR^b, -OS(O)2NR^aR^b, -NR^aR^b, -NR^aC(O)R^b, -NR^aC(O)OR^b, -NR^aC(O)NR^aR^b, -NR^aS(O)R^b, -NR^aS(O)2R^b, -NR^aS(O)NR^aR^b, -NR^aS(O)2NR^aR^b, -C(O)R^a, -C(O)OR^a, -C(O)NR^aR^b, -PR^aR^b, -P(O)R^aR^b, -P(O)2R^aR^b, -P(O)NR^dR^b, -P(O)₂NR^aR^b, -P(O)OR^a, -P(O)2OR^a, -CN, or -NO2, wherein each hydrogen atom in Ci-Cô alkyl, C₂-Cô alkenyl, C₂-Cô alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cioaryl, and 5- to 10-membcred heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Cf,alkyl, Cj-C₆ haloalkyl, -OR^e, -OC(O)R^e, -OC(O)NR^cR^r, -OS(O)R^e, -OS(O)₂R^e, -OS(O)NR^eR^r, -OS(O)2NR^eR^r, -SR^e, -S(O)R^e, -S(O)2R^e, -S(O)NR^eR^r, -S(O)2NR^eR^r, -NR^eR^f, -NR^eC(O)R^r, -NR^eC(O)OR^f, -NR^eC(O)NR^vR^r, -NR^eS(O)R‘, -NR^eS(O)2R^r, -NR^eS(O)NR^eR^f, -NR^cS(O)2NR^eR^f, -C(O)R^e, -C(O)OR^C, -C(O)NR^eR^f, -PR^LR^f, -P(O)R^cR^r, -P(O)2R^cR^f, -P(O)NR^eR^f, -P(O)₂NR^eR^r, -P(O)OR^e, -P(O)2OR^e, -CN, or -NO2; or two of R⁷ and R^s, taken together with the carbon or carbons to which they are attached, optionally combine to form a C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in the C3-C6 cycloalkyl or 3- to 7-membered heterocycloalkyl formed when two of R⁷ and R⁸ are taken together is independently optionally substituted by -OR^e, -OC(O)R^e, -OC(O)NR^CR‘, -OS(O)R^e, -OS(O)₂R^e, -OS(O)NR^eR^f, -OS(O)2NR^eR^f, -SR^e, -S(O)R^e, -S(O)2R^e, -S(O)NR^eR^f, -S(O)2NR^eR^r, -NR^eR^f, -NR^eC(O)R^r, -NR^eC(O)OR^f, -NR^eC(O)NR^eR^t, -NR^eS(O)R^f, -NR^eS(O)2R^f, -NR^eS(O)NR^cR^r, -NR^eS(O)2NR^eR^r, -C(O)R^e, -C(O)OR^e, -C(O)NR^eR^f, -PR^eR^f, -P(O)R^eR^f, -P(O)2R^eR^r, -P(O)NR^eR^f, -P(O)2NR^eR^r, -P(O)OR^C, -P(O)2OR^e, -CN, or -NO₂;

each R^a, R^b, R^c, R^d, R^e, and R^f is independently selected from the group consîsting of H, deuterium, Ci-Ce alkyl, C2-Cô alkenyl, C2-Cô alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cjoaryl, Ci-Cèalkylene-Cô-Cioaryl, 5- to 10-membered heteroaryl, and Ci-Côalkylene-5- to 10-membered heteroaryl, or R^a and R^b or R^c and R^d or R^e and R^r, taken together with the atom to which they are attached, form a 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in Ci-Cô alkyl, C2-Cô alkenyl, C₂-C& alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Cé-Cioaryl, Ci-C& alkylene-Cô-Cio aryl, 5- to 10-membered heteroaryl, or Cî-Côalkylene-5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C|-C₆ alkyl, C]-C₆ haloalkyl, -OH, -OCi-C₆ alkyl, -OC(O)-(H or Ci-C₆ alkyl), -OC(O)N(H or Ci-C₆ alkyl)₂, -OC(O)N(C₂-C₆ alkylene), -OS(O)-(H or C,-C₆alkyl), -OS(O)₂-(H or C|-C₆ alkyl), -OS(O)N(H or Ci-C₆ alkyl)₂, -OS(O)N(C₂-C₆ alkylene),

-OS(O)₂N(H or C|-C₆ alkyl):, -OSfOjjN'iCj-Cf, alkylene), -S(H or Ci-C₆ alkyl), -S(O)(H or Ci-Cô alkyl), -S(O):(H or Cj-Cô alkyl), -S(O)N(H or Ci-C₆ alkyl):, -S(O)N(C₂-C₆ alkylene), -S(O)₂N(H or C|-C₆ alkyl)₂, -S(O)₂N(C₂-Cô alkylene), -N(H or Ci-Cô alkyl):, -N(C₂-Cô alkylene), -N(H or C,-C₆ alkyl)C(O)-(H or Ci-C₆ alkyl), -N(H or Ci-C₆ alkyl)C(O)O(H or Ci-C₆alkyl), -N(H or C|-C₆ alkyl)C(O)N(H or Ci-C₆ alkyl):, -N(H or Ci-C₆ alkyl)C(O)N(C₂-C₆alkylene), -N(H or Ci-C₆ alkyl)S(O)-(H or C_t-C₆ alkyl), -N(H or Ci-C₆ alkyl)S(O)₂(H or Ci-C₆alkyl), -N(H or Cj-Cô alkyl)S(O)N(H or Ci-Cô alkyl)₂, -N(H or Ci-Cô alkyl)S(O)N(C₂-Cô alkylene), -N(H or Ci-Cô alkyl)S{O):N(H or Ci-Cô alkyl):, -N(H or Cj-Cô alkyl)S(O):N(C₂-Cô alkylene), -C(O)-(H or Ci-Cô alkyl), -C(O)O(H or Ci-Cô alkyl), -C(O)N(C:-Cô alkylene), -P(H or Ci-Cô alkyl)₂, -P(C:-Cô alkylene), -P(O)(H or Ci-Cô alkyl):, -P(O)(C₂-Cô alkylene), -P(O):(H or Ci-Cô alkyl):, -P(O)₂(C₂-C₆ alkylene), -P(O)N(H or Ci-C₆ alkyl):, -P(O)N(C₂-C₆alkylene), -P(O):N(H or Ci-C₆ alkyl):, -P(O):N(C:-Cô alkylene), -P(O)O(H or C|-C₆alkyl), -P(O):O(H or Ci-C₆ alkyl), -CN, or -NO₂;

m is 0, l, 2, or 3;

n is 0, l, 2, 3, or 4;

p is 3, 4, 5, 6, or 7; and q is 0, l, or 2 or a pharmaccutically acceptable sait thereof.

3. The compound of clause l or 2, or a pharmaceutically acceptable sait thereof, having the formula 11

wherein “------” is optionally a carbon-carbon single bond or a carbon-carbon double bond, and ring A is a 5-membered heteroarylene.

4. The compound of clause l, 2, or 3, or a pharmaceutically acceptable sait thereof, having the formula III

wherein

X¹, X², and X³ are each independently -O-, -S-, =C(H)-, -CiR¹)-, -N(H)-, -N(R^!)- or =N- and ring A is a 5-membered heteroarylene, provided that at least one of X¹, X², and X³ is not =C(H)-, or=C(R‘)-;and “------” is optionally a carbon-carbon single bond or a carbon-carbon double bond.

5. The compound of any one of the preceding clauses, or a pharmaceutically acceptable sait thereof, wherein ring A is a 5-membered heteroarylene selected from the group consisting of

wherein each “Λαλτ represents a point of covalent attachment.

6. The compound of any one of the preceding clauses, or a pharmaceutically acceptable sait thereof, wherein ring A is a 5-membered heteroarylene selected from the group consisting of

R¹ , and R¹ , wherein each “jwv”’ represents a point of covalent attachment.

7. The compound of any one of the preceding clauses, or a pharmaceutically acceptable sait thereof, wherein ring A is a 5-membered heteroarylene selected from the group consisting of

wherein each “owv’ represents a point of covalent attachment.

8. The compound of any one of the preceding clauses, or a pharmaceutically acceptable sait thereof, wherein ring B is a C&-Cio arylene, and n is 0, l, or 2.

9. The compound of any one of the preceding clauses, or a pharmaceutically acceptable sait thereof, wherein ring B is a phenylene, and n is 0, l, or 2.

10. The compound of any one of the preceding clauses, or a pharmaceutically acceptable sait thereof, wherein ring B is a phenylene, and n is 0 or l.

11. The compound of any one of the preceding clauses, or a pharmaceutically acceptable sait thereof, wherein ring B is a phenylene, n is l, and R² is methyl, ethyl, F, Cl, or Br.

12. The compound of any one of the preceding clauses, or a pharmaceutically acceptable sait thereof, wherein ring B is wherein each λλλ?” represents a point of covalent attachment.

13. The compound of any one of clauses l to 7, or a pharmaceutically acceptable sait thereof, wherein ring B is a 5- to 10-membered heteroarylene.

14. The compound of any one of clauses l to 7 or 13, or a pharmaceutically acceptable sait thereof, wherein ring B is a 5-membered heteroarylene selected from the group consisting of

wherein each represents a point of covalent attachment.

15. The compound of any one of clauses l to 7, 13, or 14, or a pharmaceutically acceptable sait thereof, wherein ring B is a 5-membered heteroarylene selected from the group consisting of

wherein each “uwv'” represents a point of covalent attachment.

16. The compound of any one of the preceding clauses, or a pharmaceutically acceptable sait thereof, wherein R³ is H or methyl.

17. The compound of any one of the preceding clauses, or a pharmaceutically acceptable sait thereof, wherein R⁴ is H or methyl.

18. The compound of any one of the preceding clauses, or a pharmaceutically acceptable sait thereof, wherein R⁵ is H.

19. The compound of any one of the preceding clauses, or a pharmaceutically acceptable sait thereof, wherein each L is independently each L is independently -C(R⁷)(R⁸)-, C(O)-, -O-, or -N(R⁶)-, provided that (L)p does not comprise a -O-O- or a -O-N(R⁶)- bond, and the point of covalent attachment of (L)p to -NR³- does not form a -N-N- or a O-N- bond.

20. The compound of any one of the preceding clauses, or a pharmaceutically acceptable sait thereof, wherein -(L)_p- is -(CR⁷R⁸)C(O)N(R⁶)-(CR⁷R^S)2-, -(CR⁷R⁸)N(R⁶)C(O)-( CR⁷R⁸)2-, -N(R⁶)-C(O)(CR⁷R⁸)2O(CR⁷R⁸)2-,-CR⁷R⁸O(CR⁷R⁸)2O-(CR⁷R⁸)2, -O(CR⁷R⁸)2O(CR⁷R⁸)2-, -CR⁷R⁸O-CR⁷R⁸-C(O)N(R⁶)-(CR⁷R⁸)2-, -(CR⁷R⁸)îO(CR⁷R⁸)2-, -(CR⁷R⁸)2O(CR⁷R⁸)3-,

-CR⁷R⁸-N(R⁶)-(CR⁷R⁸)2-, -CR⁷R⁸-N(R⁶)-(CR⁷R^s)3-, -O(CR'R⁸)2O(CR⁷R^s)3-, -(CR⁷R⁸)2-N(R⁶)-(CR⁷R⁸)3-, -(CR⁷R⁸)2-N(R⁶)-(CR⁷R⁸)2-, -O-(CR⁷R⁸)2-, -O-(CR⁷R⁸)3-, or -O-(CR⁷R⁸)4-.

21. The compound of any one of the preceding clauses, or a pharmaceutically acceptable sait thereof, wherein R⁶ is H or methyl.

22. The compound of any one of the preceding clauses, or a pharmaceutically acceptable sait thereof, wherein each R' and R⁸ is H.

23. The compound of any one of the preceding clauses, or a pharmaceutically acceptable sait thereof, wherein -(L)_p- is -CH2N(H)-(CH₂)2-, -CH₂N(CH₃)-(CH₂)₂-, -O(CH₂)₂-, 10 -OCH(CH₃)CH₂-, -O(CH₂)3-, -O(CH₂)₄-, and -O(CH₂)₂O(CH₂)₂-.

24. The compound of clause l, selected from the group consistîng of

HN-N HN-N HN-N

ΗΝ-Ν , HN-N , HN-N

pharmaceutically acceptable sait thereof.

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

26. A method of treating disease in a subject comprising, administering a therapeutically effective amount of a compound of any one of clauses l to 24, or a pharmaceutical composition of clause 25.

27. A compound according to any one of clauses l to 24, for use in a method of treating disease in a subject.

28. Use of a compound according to any one of clauses l to 24 in the manufacture of a médicament for the treatment of disease in a subject.

DETAILED DESCRIPTION

Before the présent 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 présent disclosure will be limited only by the appended claims.

For the sake of brevity, the disclosures of the publications cited in this spécification, including patents, are herein incorporated by reference. Unless defined otherwise, ail technical and scientific tenus used herein hâve the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs. Ail patents, applications, published applications and other publications refen’ed to herein are incorporated by reference in their entireties. If a définition set forth in this section is contrary to or otherwise inconsistent with a définition set forth in a patent, application, or other publication that is herein incorporated by reference, the définition set forth in this section prevails over the définition incorporated herein by reference.

As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictâtes 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 antécédent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the récitation of claim éléments, or use of a “négative” limitation.

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

To provide a more concise description, some of the quantitative expressions given herein are not qualified with the tenu “about.” It is understood that, whether the tenu “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 équivalents 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.

Unless defined otherwise, ail technîcal and scientific terms used herein hâve the same mcaning as commonly understood by one of ordinary ski 11 in the art to which this disclosure 5 belongs. Although any methods and materials similar or équivalent 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. Ail publications mentioncd herein are incorporated hercin by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

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 spécifie référencés that are cited and discussed throughout the present spécification. See, e.g., Loudon, Organic Chemistry, Fourth Edition, New York: Oxford University Press, 2002, pp. 360-361, 1084-1085; Smith and March, March's Advanced Organic 15 Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-lnterscience, 2001.

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

As used herein and in connection with Chemical structures depicting the various 20 embodiments described herein, and “άλα”, each represent a point of covalent attachment of the Chemical group or Chemical structure în which the identifier is shown to an adjacent Chemical group or Chemical structure. For example, in a hypothetical Chemical structure A-B, where A and B are joined by a covalent bond, in some embodiments, the portion of A-B

Il A ___ *1’ Il Λ ___ sJisjsK defined by the group or Chemical structure A can be represented by ,, or

A—l·'— £ ’ , where each of and “ ” represents a bond to A and the point of covalent bond attachment to B. Alternatively, in some embodiments, the portion of A-B defined by the '1$___β!Ι ”**___DU ?β group or Chemical structure B can be represented by , , or ? , where each of and “ represents a bond to B and the point of covalent bond attachment to A.

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. Ail combinations of the embodiments pertaining to the Chemical groups represented by the variables are specifically embraced by the présent 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 activîty). In addition, ail subcombinations of the Chemical groups listed in the embodiments describing such variables are also specifically embraced by the présent disclosure and are disclosed herein just as if each and every such subcombination of Chemical groups was individually and explicitly disclosed herein.

CHEMICAL DEFINITIONS

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 iimit the number of atoms in an “alkyl” or “alkylene” to a spécifie range of atoms, such as C1-C20 alkyl or C1-C20 alkylene, Ci-Cj2 alkyl orC]-Ci2 alkylene, or Ci-Cô alkyl or Ci-C& alkylene. Examples of alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered équivalent to any one of the foregoing examples. Examples of alkylene groups include methylene (-CH2-), ethylene ((-CH?-)?), n-propylene ((-CHa-jj), îso-propylene ((-C(H)(CH3)CH2-)), n-butylene ((-CH2-)-i), 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.

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 spécifie range of atoms, such as C2-C20 alkenyl or C2-C20 alkenylene, C2-C12 alkenyl or C2-C12 alkenylene, or C2-C6 alkenyl or C2-C6 alkenylene. Examples of alkenyl groups include ethenyl (or vinyl), allyl, and but-3-en-l-yl. Examples of alkenylene groups include ethenylene (or vinylene) (-CH=CH-), n-propenylene (-CH=CHCH2-), iso-propenylene (-CH=CH(CHî)-), 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.

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 spécifie range of atoms, such as C2-C20 alkynyl or C2-C20 alkynylene, C2-C12 alkynyl or C2-C12 alkynylene, or C2-C6 alkynyl or C2-C6 alkynylene. Examples of alkynyl groups include acetylenyl (-C=CH) and propargyl (-CH2C=CH), but-3-yn-l,4-diyl (-C^C-CEbCH?-), 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.

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 spécifie 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 ofthe following entities, in the form of properly bonded moieties:

In particular, a cyclopropyl moiety can be depicted by the structural formula

In particular, a cyclopropylene moiety can be depicted by the structural formula

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

The terni “halogen” or “halo” represents chlorine, fluorine, brominc, or iodine.

The tenu “haloalkyl” refers to an alkyl group with one or more halo substituents. Examples ot haloalkyl groups include -CF3, -(CHi)F, -CHFj, -CHiBr, -CH2CF3, and -CH2CH2F. The tcrm “haloalkylcne” 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)-.

The tenu “aryl refers to a monovalent all-carbon monocyclic or fused-ring polycyclic group having a completely conjugated pi-electron System. The terni “arylene” refers to a divalent all-carbon monocyclic or fused-ring polycyclic group having a completely conjugated pi-electron System. In some embodiments, it can be advantageous to limit the number of atoms in an “aryl” or “arylene” to a spécifie range of atoms, such as mono-valent all-carbon monocyclic or fusedring polycyclic groups of 6 to 14 carbon atoms (C6-C14 aryl), monovalent all-carboii monocyclic or fused-ring polycyclic groups of 6 to IO carbon atoms (Cô-Cio aryl), divalent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 14 carbon atoms (Cô-Ch arylene), divalent allcarbon monocyclic or fused-ring polycyclic groups of 6 to IO carbon atoms (Câ-Cio 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 ofthe substituents in the various embodiments described herein, including one or more of such substituents.

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 spécifie range of ring atoms, such as from 3 to 12 ring atoms (3- to 12membered), 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 IO ring atoms (4- to lO-membered). In some embodiments, it can be advantageous to limit the number and type of ring heteroatoms in “heterocycloalkyl” or “heterocycloalkylene” to a spécifie range or type of heteroatoms, such as l 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:

A three-membered heterocycle may contain at least one heteroatom ring atom, where the heteroatom ring atom is a sulfur, oxygen, or nitrogen. Non-limiting examples of three-membered heterocycle groups include monovalent and divalent radicals of oxirane, azetidine, and thiirane. A four-membered heterocycle may contain at least one heteroatom ring atom, where the heteroatom ring atom is a sulfur, oxygen, or nitrogen. Non-limiting examples of four-membered heterocycle groups include monovalent and divalent radicals of azitidine, oxtenane, and thietane. A fîve-membered heterocycle can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zéro, one, two, or three ring atoms are nitrogen, or (b) zéro ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of fivemembered heterocyle groups include mono-valent and divalent radicals of pyrrolidine, tetrahydrofuran, 2, 5-dihydro-lH- pyrrole, pyrazolidine, thiazolidine, 4,5-dihydro-lH-imidazole, dihydrothiophen-2(3H)-one, tetrahydrothiophene l,l-dioxide, imidazolidin-2-one, pyrrolidin-2one, dihydrofuran-2(3H)-one, l,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 zéro, one, two, or three ring atoms are nitrogen, or (b) zéro 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-l,4thiazine, 1,2,3,4-tetrahydropyridine, piperazine, l,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.

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.

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 hcteroatoms selected from nitrogen, oxygen, and sulfur) that is fully unsaturated and having from 3 to 12 ring atoms per heterocycle. The term “heteroarylene” refers to a divalent monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms or members selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms per heterocycle. In some embodiments, it can be advantageous to limit the number of ring atoms in a “heteroaryl” or “heteroarylene” to a spécifie range of atom members, such as 5- to 10-membered heteroaryl or 5to 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 lO-mcmbered 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:

H H u H

O N S NI ,0 q S_x c A

O.O.aQuQÛQÛV.

In some embodiments, a “monocyclic” heteroaryl can be an aromatic five- or sixmembered heterocycle. A five-membered heteroaryl or heteroarylene can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zéro, one, two, or three ring atoms are nitrogen, or (b) zéro ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of five-membered heteroaryl groups include mono valent radicals of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazolc, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole. Non-limiting examples of fivemembered heteroarylene groups include di-valent radicals of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole. A six-membered heteroaryl or heteroarylene can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zéro, one, two, or three ring atoms are nitrogen, or (b) zéro 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, pyridazîne, or triazine. Non-limiting examples of six-membered heteroarylene groups include divalent radicals of pyridine, pyrazine, pyrimidine, pyridazîne, 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, l,5naphthyridine, l,8-naphthyridine, isoquinolin-3(2H)-one, thieno[3,2-6]thiophene, l/Zpyrrolo[2,3-ô]pyridine, !/7-benzo[r/]imidazole, benzo[i/]oxazole, and benzo[i/]thiazole. Nonlimiting examples of bicyclic heteroarylene groups include divalent radicals of quinoline, isoquinoline, quinazoline, quinoxaline, l,5-naphthyridine, l,8-naphthyridîne, isoquinolin-3(2H)one, thieno[3,2-ô]thiophene, lH-pyrrolo[2,3-6]pyridine, l//-benzo[W]imidazole, benzo[i/]oxazole, and benzo[(7]thiazole.

In particular, a pyrazolyl moiety can be depicted by the structural formula n-nh

. In particular, an example of a pyrazolylene moiety can be depicted by the structural formula

N-NH

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

The terni “oxo” représente a carbonyl oxygen. For example, a cyclopentyl substituted with oxo is cyclopentanone.

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 specitîed 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.

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, diastcreomeric, or géométrie isomers, or a mixture thereof. Additionally, any formula given herein is intended to refer also to a hydrate, solvaté, or polymorph of such a compound, or a mixture thereof.

Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds hâve 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 diselosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as ²H, ³H, C, ^l3C, ^l4C, ^l5N, ^l8O, ^l7O, ³¹ P, ³²P, ³⁵S, ¹⁸F, ³⁶C1, and ^l25I, respectively. Such isotopically labelled compounds are useful in metabolic studies (preferably with ¹⁴C), reaction kinetic studies (with, for example ²H or ³H), détection or imaging techniques [such as positron émission tomography (PET) or single-photon émission computed tomography (SPECT)] including drug or substrate tissuc 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 diselosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and préparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

Certain Chemical entities of Formula (I)-(V1) may be depicted in two or more tautomeric forms. Any and ail 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 îs 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.

Enol form

OH

K cto form

Amide form linidic acid form

Amine form Irnine form

Nil, Nil

The nomenclature “(ATOM)|.(ATOM)j” with j > i, w^rhen applied herein to a class of substitueras, is meant to refer to embodiments of this disclosure for which each and every one of the number of atom members, from i to j including i and j, is independently realized. By way of example, the term C1-C3 refers independently to embodiments that hâve one carbon member (Ci), embodiments that hâve two carbon members (C₂), and embodiments that hâve three carbon members (C3).

Any disubstituent referrcd to herein is meant to encompass the various attachaient possibilities when more than one of such possibilitîes 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.

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-lngold Prelog Rules known to one of skill in the art will be understood herein as describing no particular stereochemical définition as in the structure on the left below, and also as describing both possible stereoisomers (S) and (R) as shown below

R^a

(S)

(R) where R^a > R^h > R^e > R^d according to the Cahn-lngold Prelog Rules.

The disclosure also includes pharmaceutically acceptable salts of the compounds represcntcd by Formula (l)-(VI), preferably of those described above and of the spécifie compounds exemplified herein, and pharmaceutical compositions comprising such salts, and methods of using such salts.

A “pharmaceutically acceptable sait” is intended to mean a sait of a free acid or base of a compound represented herein that is non-toxic, biologically tolerable, or otherwise biologically suitabie for administration to the subject. See, generally, S.M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977, 66, 1-19. Preferrcd pharmaceutically acceptable salts are those that are pharmacologically effective and suitabie for contact with the tissues of subjects without undue toxicity, irritation, or allergie 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 fonn a pharmaceutically acceptable sait.

|0002| Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acétates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-l,4-dioates, hexyne-l,6dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates, besylates, xylenesulfonates, naphthalene-l-sulfonates, naphthalene-2-sulfonates, phenyl acétates, phenylpropionates, phenylbutyrates, citrates, lactatcs, γ-hydroxybutyrates, glycolates, tartrates, and mandelates. Lists of other suitabie pharmaceutically acceptable salts are found in Remington's Pharmaceutical Sciences, I7th Edition, Mack Publishing Company, Easton, Pa., 1985.

For a compound of Formula (I)-(VI) that contains a basic nitrogen, a pharmaceutically acceptable sait may be prepared by any suitabie 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 équivalents or acceptable substitutes in light of the ordinary level of skill in this technology.

The disclosure also relates to pharmaceutically acceptable prodrugs of the compounds of Formula (I)-(VI), and treatment methods employing such pharmaceutically acceptable prodrugs. The terni “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 (l)-(VI)). A “pharmaceutically acceptable prodrug” is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject. Illustrative procedures for the sélection and préparation of suitable prodrug dérivatives are described, for example, in “Design of Prodrugs,” ed. H. Bundgaard, Elsevier, 1985.

The présent disclosure also relates to pharmaceutically active métabolites of compounds of Formula (I)-(VI), and uses of such métabolites in the methods of the disclosure. A “pharmaceutically active métabolite” means a pharmacologically active product of metabolism in the body of a compound of Formula (I)-(VI) or sait thereof. Prodrugs and active métabolites of a compound may be determined using routine techniques known or availabié in the art. See, e.g., Bertolini et al., J. Med. Chem. 1997, 40, 2011-2016; Shan et al., J. Pharm, Sci. 1997, 86 (7), 765767; 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 Academie Publishers, 1991).

REPRESENTATIVE EMBODIMENTS

In some embodiments, the disclosure provides a compound of the formula I, or a pharmaceutically acceptable sait thereof,

In some embodiments, the disclosure provides a compound of the formula II, or a pharmaceutically acceptable sait thereof,

ΙΟ wherein R¹, R², R³, R⁴, R⁵, A, B, L, m, n, p, q, and “------” are as described herein.

In some embodiments, the disclosure provides a compound of the formula III, or a pharmaceutically acceptable sait thereof,

wherein R¹, R², R³, R⁴, R⁵, A, B, L, X¹, X², X³, m, n, p, q, and “------” are as described herein.

In some embodiments, the disclosure provides a compound of the formula IV, or a pharmaceutically acceptable sait thereof,

wherein R¹, R², R³, R⁴, R⁵, A, B, L, m, n, and p are as described herein.

In some embodiments, the disclosure provides a compound of the formula V, or a pharmaceutically acceptable sait thereof,

wherein R¹, R², R³, R⁴, R⁵, A, B, L, m, n, p, and “------” are as described herein.

In some embodiments, the disclosure provides a compound of the formula VI, or a pharmaceutically acceptable sait thereof,

wherein R¹, R², R³, R⁴, R⁵, A, B, L, X¹, X², X³, m, n, p, and “------” are as described herein.

In some embodiments, ring A is a 5- to 10-membered heteroarylene. In some embodiments, ring A is a 5- or 6-membered heteroarylene. In some embodiments, ring A is a 5-membered heteroarylene. In some embodiments, ring A is a 6-membered heteroarylene. In some embodiments, ring A is a fused bicyclic 8- to 10-membered heteroarylene.

In some embodiments, ring A is a 5- to 10-membered heteroarylene, such as a mono-cyclic

5- or 6-membered heteroarylene or a bicyclic 8- to 10-membered heteroarylene, wherein each hydrogen atom in the 5- to I0-membered heteroarylene, as described herein, is independently optionally substituted by an R¹ that is deuterium, halogen, Ci-Ce alkyl, C2-Cô alkenyl, C2-C& alkynyl, Ca-Cô cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cio aryl, 5- to 10-membered heteroaryl, -OR^a, -OC(O)R^a, -OC(O)NR^aR^b, -OS(O)R^a, -OS(O)2R^a, -SR^a, -S(O)R^a, -S(O)2R^a, -S(O)NR^aR^b, -S(O)2NR^aR^b, -OS(O)NR^aR^b, -OS(O)2NR^aR^b, -NR^aR^b, -NR^aC(O)R^b, -NR^aC(O)OR^b, -NR^aC(O)NR^aR^b, -NR^aS(O)R^b, -NR^aS(O)2R^b, -NR^aS(O)NR^aR^b, -NR^aS(O)2NR^aR^b, -C(O)R^a, -C(O)OR^a, -C(O)NR^aR^b, -PR^aR^b, -P(O)R^aR^b, -P(O)2R^aR^b, -P(O)NR^aR^b, -P(O)2NR^aR^b, -P(O)OR^a, -P(O)2OR^a, -CN, or -NO₂, wherein each hydrogen atom in Ci-Cô alkyl, C₂-C& alkenyl, C₂-Cô alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cjoaryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Cô alkyl, Ci-Cô haloalkyl, -OR^C, -OC(O)R^C, -OC(O)NR^cR^d, -OC(=N)NR^cR^d, -OS(O)R^C, -OS(O)2R^C, -OS(O)NR^cR^d, -OS(O)2NR^cR^d, -SR^C, -S(O)R^C, -S(O)2R^C, -S(O)NR^cR^d, -S(O)2NR^eR^d, -NR^cR^d, -NR^cC(O)R^d, -N(C(O)R^c)(C(O)R^d), -NR^cC(O)OR^d, -NR^eC(O)NR^eR^d, -NR^cC(=N)NR^cR^d, -NR^cS(O)R^d, -NR^cS(O)₂R^d, -NR^cS(O)NR^cR^d, -NR^eS(O)2NR^cR^d, -C(O)R^C, -C(O)OR^C, -C(O)NR^cR^d, -C(=N)NR^cR^d, -PR^cR^d, -P(O)R^cR^d, -P(O)2R^cR^d, -P(O)NR^cR^d, -P(O)2NR^cR^d, -P(O)OR^C, -P(O)2OR^C, -CN, or -NO₂.

In some embodiments, ring A is pyrrolylene, isoxazolylene, isothiazolylene, pyrazolylene, or imidazolylene, wherein each hydrogen atom in pyrrolylene, isoxazolylene, isothiazolylene, pyrazolylene, and imidazolylene, is independently optionally substituted by an R¹ that is deuterium, halogen, Ci-Côalkyl, C2-Cô alkenyl, C2-C6 alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-Cioaryl, 5- to 10-membered heteroaryl, -OR^a, -OC(O)R^a, -OC(O)NR^aR^b, OS(O)R^a, -OS(O)2R^a, -SR^a, -S(O)R^a, -S(O)2R^a, -S(O)NR^aR^b, -S(O)2NR^aR^b, -OS(O)NR^aR^b, -OS(O)2NR³R^b, -NR^aR^b, -NR^aC(O)R^b, -NR^aC(O)OR^b, -NR^aC(O)NR^aR^b, -NR^aS(O)R^b, -NR^aS(O)2R^b, -NR^aS(O)NR^aR^b, -NR^aS(O)2NR^aR^b, -C(O)R^a, -C(O)OR^a, -C(O)NR^aR^b, -PR^aR^b, -P(O)R^aR^b, -P(O)2R^aR^b, -P(O)NR^aR^b, -P(O)2NR^aR^b, -P(O)OR³, -P(O)2OR^a, -CN, or -NO2, wherein each hydrogen atom in Ci-Cô alkyl, C2-C6 alkenyl, C₂-Cô alkynyl, Cs-Ct, cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cioaryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Cô alkyl, Ci-Cè haloalkyl, -OR^C, -OC(O)R^C, -OC(O)NR^cR^d, -OC(=N)NR^cR^d, -OS(O)R^C, -OS(O)2R^C, -OS(O)NR^cR^d, -OS(O)2NR^vR^d, -SR^C, -S(O)R^C, -S(O)2R^C, -S(O)NR^cR^d, -S(O)2NR^cR^d, -NR^cR^d, -NR^cC(O)R^d, -N(C(O)R^c)(C(O)R^d), -NR^cC(O)OR^d, -NR^cC(O)NR^cR^d, -NR^cC(=N)NR^cR^d, -NR^cS(O)R^d, -NR^cS(O)2R^d, -NR^cS(O)NR^cR^d, -NR^cS(O)2NR^cR^d, -C(O)R^C, -C(O)OR^e, -C(O)NR^cR^d, -C(=N)NR^cR^d, -PR^cR^d, -P(O)R^eR^d, -P(O)₂R^cR^d, -P(O)NR^cR^d, -P(O)2NR^cR^d, -P(O)OR^C, -P(O)2OR^c, -CN, or-NO₂.

In some embodiments, ring A is pyridinylene, pyrazinylene, pyrimidinylene, pyridazineylene, or triazinylene, wherein each hydrogen atom in pyridinylene, pyrazinylene, pyrimidinylene, pyridazineylene, and triazinylene, is independently optionally substituted by an R.¹ that is deuterium, halogen, Ci-Côalkyl, C2-Cô alkenyl, C2-Cô alkynyl, C3-C6 cycloalkyl, 3- to 7membered heterocycloalkyl, Cô-Cio aryl, 5- to 10-membered heteroaryl, -OR^a, -OC(O)R^a, -OC(O)NR^aR^b, -OS(O)R^a, -OS(O)2R^a, -SR^a, -S(O)R^a, -S(O)2R^a, -S(O)NR^aR^b, -S(O)2NR^aR^b, -OS(O)NR^aR^b, -OS(O)2NR^aR^b, -NR^aR^b, -NR^aC(O)R^b, -NR^aC(O)OR^b, -NR^aC(O)NR^aR^b, -NR^aS(O)R^b, -NR^aS(O)₂R^b, -NR^aS(O)NR^aR^b, -NR^aS(O)2NR^aR^b, -C(O)R^a, -C(O)OR^a, -C(O)NR^aR^b, -PR^aR^b, -P(O)R^aR^b, -P(O)2R^aR^b, -P(O)NR^aR^b, -P(O)2NR^aR^b, -P(O)OR^a, -P(O)2OR^a, -CN, or -NO2, wherein each hydrogen atom in Cj-Cô alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cioaryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Cô alkyl, Ci-C& haloalkyl, -OR^C, -OC(O)R^C, -OC(O)NR^cR^d, -OC(=N)NR^cR^d, -OS(O)R^C, -OS(O)2R^C, -OS(O)NR^cR^d, -OS(O)2NR^cR^d, -SR^C, -S(O)R^e, -S(O)₂R^C, -S(O)NR^cR^d, -S(O)2NR^cR^d, -NR^cR^d, -NR^cC(O)R^d, -N(C(O)R^c)(C(O)R^d), -NR^cC(O)OR^d, -NR^cC(O)NR^eR^d, -NR^cC(=N)NR^cR^d, -NR^cS(O)R^d, -NR^cS(O)2R^d, -NR^cS(O)NR^cR^d, -NR^cS(O)2NR^cR^d, -C(O)R^C, -C(O)OR^C, -C(O)NR^cR^d, -C(=N)NR^cR^d, -PR^cR^d, -P(O)R^cR^d, -P(O)2R^cR^d, -P(O)NR^cR^d, -P(O)2NR^cR^d, -P(O)OR^C, -P(O)2OR^c, -CN, or -NO₂.

In some embodiments, ring A is a 5- to 10-membered heteroarylene, such as a mono-cyclic 5- or 6-membered heteroarylene or a bicyclic 8- to 10-membered heteroarylene, wherein the 5- to 10-membered heteroarylene, as described herein, is optionally substituted with 1, 2, 3, 4, or 5 of R¹ (m of R¹), each of which is independently selected from the group consisting of deuterium, halogen, Ci-C& alkyl, C2-Cô alkenyl, C2-Cô alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cioaryl, 5- to 10-membered heteroaryl, -OR^a, -OC(O)R^a, -OC(O)NR^aR^b, OS(O)R^a, -OS(O)2R^a, -SR^a, -S(O)R“, -S(O)2R^a, -S(O)NR^aR^b, -S(O)2NR^aR^b, -OS(O)NR^aR^b, -OS(O)2NR^aR^b, -NR^aR^b, -NR^aC(O)R^b, -NR^aC(O)OR^b, -NR^aC(O)NR^aR^b, -NR^aS(O)R^b, -NR^aS(O)2R^b, -NR^aS(O)NR^aR^b, -NR^aS(O)2NR^aR^b, -C(O)R^a, -C(O)OR^a, -C(O)NR^aR^b, -PR^aR^b, P(O)R^aR^b, -P(O)2R^aR^b, -P(O)NR^aR^b, -P(O)2NR^aR^b, -P(O)OR^a, -P(O)2OR^a, -CN, and -NO₂, wherein each hydrogen atom in Ci-Cô alkyl, C₂-Cô alkenyl, C₂-Cè alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cioaryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Cô haloalkyl, -OR^C, -OC(O)R^C, -OC(O)NR^cR^d, -OC(=N)NR^cR^d, -OS(O)R^C, -OS(O)2R^C, -OS(O)NR^cR^d, -OS(O)2NR^cR^d, -SR^C, -S(O)R^C, -S(O)₂R^c, -S(O)NR^eR^d, -S(O)2NR^cR^d, -NR^cR^d, -NR^cC(O)R^d, -N(C(O)R^c)(C(O)R^d), -NR^cC(O)OR^d, -NR^cC(O)NR^<R^d, -NR^cC(=N)NR^€R^d, -NR^cS(O)R^d, -NR^cS(O)2R^d,

-NR^cS(O)NR^cR^d, -NR^cS(O)2NR^cR^d, -C(O)R^C, -C(O)OR^C, -C(O)NR^cR^d, -C(=N)NR^cR^d, -PR^cR^d, -P(O)R^cR^d, -P(O)2R^cR^d, -P(O)NR^cR^d, -P(O)2NR^cR^d, -P(O)OR^C, -P(O)2OR^C, -CN, or -NO₂.

In some embodiments, ring A is pynolylene, isoxazolylene, isothiazolylene, pyrazolylene, or imidazolylene, wherein each is optionally substituted with l, 2, 3, 4, or 5 of R¹ (m of R¹), each of which is independently selected from the group consisting of deuterium, halogen, Ci-Cô alkyl, C2-Cô alkenyl, C2-Cô alkynyl, Cj-Cô cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cioaryl, 5- to 10-membered heteroaryl, -OR^a, -OC(O)R^a, -OC(O)NR^aR^b, -OS(O)R^a, -OS(O)2R^a, -SR^a, S(O)R^a, -S(O)2R^a, -S(O)NR^aR^b, -S(O)2NR^aR^b, -OS(O)NR^aR^b, -OS(O)2NR^aR^b, -NR^aR^b, -NR^aC(O)R^b, -NR^aC(O)OR^b, -NR^aC(O)NR^aR^b, -NR^aS(O)R^b, -NR^aS(O)2R^b, -NR^aS(O)NR^aR^b, -NR^aS(O)2NR^üR^b, -C(O)R^a, -C(O)OR^a, -C(O)NR^aR^b, -PR^aR^b, -P(O)R^aR^b, -P(O)2R^aR^b, -P(O)NR^aR^b, -P(O)2NR^aR^b, -P(O)OR^a, -P(O)2OR^a, -CN, or -NO2, wherein each hydrogen atom in Ci-Cô alkyl, C2-Cô alkenyl, C2-Cô alkynyl, Cî-Cô cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cio aryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, C|-C6 alkyl, Ci-C6 haloalkyl, -OR^C, -OC(O)R^C, -OC(O)NR^cR^d, -OC(=N)NR^cR^d, -OS(O)R^C, -OS(O)2R^c, -OS(O)NR^cR^d, -OS(O)2NR^cR^d, -SR^C, -S(O)R^C, -S(O)2R^C, -S(O)NR^cR^d, -S(O)2NR^cR^d, -NR^cR^d, -NR^eC(O)R^d, -N(C(O)R^c)(C(O)R^d), -NR^cC(O)OR^d, -NR^cC(O)NR^vR^d, -NR^eC(=N)NR^cR^d, -NR^cS(O)R^d, -NR^cS(O)2R^d, -NR^cS(O)NR^cR^d, -NR^cS(O)2NR^cR^d, -C(O)R^C, -C(O)OR^C, -C(O)NR^cR^d, -C(=N)NR^cR^d, -PR^cR^d, -P(O)R^cR^d, -P(O)2R^cR^d, -P(O)NR^cR^d, -P(O)2NR^cR^d, -P(O)OR^C, -P(O)2OR^C, -CN, and -NO₂.

In some embodiments, ring A is of the formula

wherein “------” is optionally a carbon-carbon single bond or a carbon-carbon double bond, each “vwv’ represents a point of covalent attachment, and R¹ and m are as described herein. In some embodiments, ring A is of the formula

wherein “------” is optionally a carbon-carbon single bond or a carbon-carbon double bond, each represents a point of covalent attachment, ring A is a 5-membered heteroarylene, and R¹ and m are as described herein.

In some embodiments, ring A is of the formula

wherein “------” is optionally a carbon-carbon single bond or a carbon-carbon double bond, each “tvw'” represents a point of covalent attachaient, X¹, X², and X³ are each independently-O-, -S-, =C(H)-, -CiR¹)-, -N(H)-, -N(R')- or=N-, provided that at least one of X¹, X², and X³ is not =C(H)-, or ^C(R')-, ring A is a 5-membered heteroarylene, and R¹ and m are as described herein.

In some embodiments, ring A is a pyridinylene, pyrazinylene, pyrimidinylene, pyridazineylene, or triazinylene, wherein each is optionally substituted with I, 2, 3, 4, or 5 of R¹(m of R¹), each of which is independently selected from the group consisting of deutérium, halogen, Ci-Cô alkyl, C2-Cô alkenyl, C2-C6 alkynyl, Cî-Cô cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cioaryl, 5- to 10-membered heteroaryl, -OR^a, -OC(O)R^a, -OC(O)NR^aR^b, OS(O)R^a, -OS(O)2R^a, -SR^a, -S(O)R^a, -S(O)2R^a, -S(O)NR^aR^b, -S(O)2NR^aR^b, -OS(O)NR^aR^b, -OS(O)2NR^aR^b, -NR^aR^b, -NR^aC(O)R^b, -NR^aC(O)OR^b, -NR^aC(O)NR^aR^b, -NR^aS(O)R^b, -NR^aS(O)2R^b, -NR^aS(O)NR^aR^b, -NR^aS(O)2NR^aR^b, -C(O)R^a, -C(O)OR^a, -C(O)NR^aR^b, -PR^aR^b, P(O)R^aR^b, -P(O)2R^aR^b, -P(O)NR^aR^b, -P(O)2NR^aR^b, -P(O)OR^a, -P(O)2OR^a, -CN, or-NG₂, wherein each hydrogen atom in Ci-Cô alkyl, C₂-Cô alkenyl, C₂-Cô alkynyl, C3-C6 cycloalkyl, 3- to 7membered heterocycloalkyl, Cô-Cio aryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Cô alkyl, Ci-Cô haloalkyl, -OR^C, -OC(O)R^C, -OC(O)NR^cR^d, -OC(=N)NR^cR^d, -OS(O)R^C, -OS(O)2R^C, -OS(O)NR^cR^d, -OS(O)2NR^cR^d, -SR^C, -S(O)R^C, -S(O)₂R^c, -S(O)NR^cR^d, -S(O)2NR^cR^d, -NR^cR^d, -NR^cC(O)R^d, -N(C(O)R^c)(C(O)R^d), -NR^cC(O)OR^d, -NR^cC(O)NR^cR^d, -NR^cC(=N)NR^cR^d, -NR^cS(O)R^d, -NR^cS(O)2R^d, -NR^cS(O)NR^cR^d, -NR^eS(O)2NR^cR^d, -C(O)R^C, -C(O)OR^C, -C(O)NR^cR^d, -C(=N)NR^cR^d, -PR^eR^d, -P(O)R^cR^d, -P(O)2R^cR^d, -P(O)NR^cR^d, -P(O)2NR^cR^d, -P(O)OR^C, -P(O)2OR^C, -CN, or -NO₂.

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

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

wherein each “λλλρ represents a point of covalent attachment, and each R¹ is independently as described herein.

In some embodiments, ring A is a 5-membered heteroarylene selected from the group consistîng of

wherein each “άλλρ” represents a point of covalent attachment, and each R¹ is independently as described herein.

wherein each “<λλλρ” represents a point of covalent attachment, and each R¹ is independently as described herein.

wherein each “owv' represents a point of covalent attachment, and each R¹ is independently as described herein.

wherein each “<νν\Λ” represents a point of covalent attachment, and R¹ is as described herein.

wherein each “«Λ/υν’ represents a point of covalent attachment, and each R¹ is independently as described herein.

ΙΟ

wherein each “'Swxr· represents a point of covalent attachment.

In some embodiments, each R¹ is independently deuterium, halogen. or Ci-Cô alkyl, wherein each hydrogen atom in Ci-C& alkyl is independently optionally substituted deuterium, halogen, Ci-C₆ alkyl, Ci-C₆ haloalkyl, -OR^C, -OC(O)R^C, -OC(O)NR^cR^d, -OC(=N)NR^cR^d, -OS(O)R^C, -OS(O)2R^C, -OS(O)NR^cR^d, -OS(O)2NR^eR^d, -SR^C, -S(O)R^C, -S(O)₂R^C, -S(O)NR^cR^d, -S(O)2NR^cR^d, -NR^cR^d, -NR^eC(O)R^d, -N(C(O)R^c)(C(O)R^d), -NR^cC(O)OR^d, -NR^cC(O)NR^cR^d, -NR^cC(=N)NR^cR^d, -NR^cS(O)R^d, -NR^cS(O)2R^d, -NR^cS(O)NR^cR^d, -NR^cS(O)2NR^cR^d, -C(O)R^C, -C(O)OR^C, -C(O)NR^cR^d, -C(=N)NR^cR^d, -PR^cR^d, -P(O)R^eR^d, -P(O)2R^cR^d, -P(O)NR^cR^d, -P(O)2NR^eR^d, -P(O)OR^e, -P(O)2OR^C, -CN, or -NO₂. In some embodiments, R¹ is each R¹ is independently methyl, ethyl, F, Cl, Br, , _Or \, wherein “ΛΑ/ν’ represents a point of covalent attachment

wherein each “άλλ/”’ represents a point of covalent attachment.

In some embodiments, ring B is a 5- to 10-membered heteroarylene or a Cô-C io arylene. In some embodiments, Ring B is mono- or bi-cyclic Cô-Ciq arylene or mono- or bi-cyclic 5- to 10membered heteroarylene.

In some embodiments, ring B is a 5- to 10-membered heteroarylene. In some embodiments, ring B is a 5- or 6-membered heteroarylene. In some embodiments, ring B is a 5-membered heteroarylene. In some embodiments, ring B is a 6-membered heteroarylene. In some embodiments, ring B is a fused bicyclîc 8- to 10-membered heteroarylene.

In some embodiments, ring B is a 5- to 10-membered heteroarylene, such as a mono-cyclic 5- or 6-membered heteroarylene or a bicyclic 8- to 10-membered heteroarylene, wherein each hydrogen atom in the 5- to 10-membered heteroarylene, as described herein, is independently optionally substituted by an R² that is deuterium, halogen, Ci-Cô alkyl, C2-C6 alkenyl, C₂-Cô alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cio aryl, 5- to 10-membered heteroaryl, -OR^a, -OC(O)R^a, -OC(O)NR^aR^b, -OS(O)R^a, -OS(O)2R^a, -SR^a, -S(O)R^a, -S(O)2R^a, -S(O)NR^aR^b, -S(O)2NR^aR^b, -OS(O)NR^aR^b, -OS(O)₂NR^aR^h, -NR^aR^b, -NR^aC(O)R^b, -NR^aC(O)OR^b, -NR^aC(O)NR^aR^b, -NR^aS(O)R^b, -NR^aS(O)2R^b, -NR^aS(O)NR^aR^b, -NR^aS(O)2NR^aR^h, -C(O)R^a, -C(O)OR^a, -C(O)NR^aR^b, -PR^aR^b, -P(O)R^aR^b, -P(O)₂R^aR^b, -P(O)NR^aR^b, -P(O)2NR^aR^b, -P(O)OR^a, -P(O)2OR^a, -CN, or -NO₂, wherein each hydrogen atom in Ci-C& alkyl, C₂-Cô alkenyl, C₂-Cô alkynyl, Cj-Cô cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cio aryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Cô alkyl, Ci-Cô haloalkyl, -OR^C, -OC(O)R^C, -OC{O)NR^cR^d, -OC(=N)NR^cR^d, -OS(O)R^C, -OS(O)2R^C, -OS(O)NR^cR^d, -OS(O)2NR^cR^d, -SR^C, -S(O)R^C, -S(O)2R^C, -S(O)NR^cR^d, -S(O)2NR^cR^d, -NR^cR^d, -NR^cC(O)R^d, -N(C(O)R^c)(C(O)R^d), -NR^cC(O)OR^d, -NR^cC(O)NR^cR^d, -NR^eC(=N)NR^cR^d, -NR^cS(O)R^d, -NR^L’S(O)2R^d, -NR^cS(O)NR^cR^d, -NR^cS(O)2NR^cR^d, -C(O)R^C, -C(O)OR^C, -C(O)NR^cR^d, -C(=N)NR^cR^d, -PR^cR^d, -P(O)R^LR^d, -P(O)2R^cR^d, -P(O)NR^cR^d, -P(O)2NR^eR^d, -P(O)OR^C, -P(O)2OR^c, -CN, or -NO₂.

In some embodiments, ring B is isoxazolylene, isothiazolylene, or pyrazolylene, wherein each hydrogen atom in isoxazolylene, isothiazolylene, or pyrazolylene, and imidazolylene, is independently optionally substituted by an R² that is deuterium, halogen, Ci-Cô alkyl, C2-Cô alkenyl, C2-Cô alkynyl, C3-C0 cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-C loaryl, 5- to 10membered heteroaryl, -OR^a, -OC(O)R^a, -OC(O)NR^aR^b, -OS(O)R^a, -OS(O)2R^a, -SR^a, -S(O)R^a, -S(O)2R^a, -S(O)NR^aR^b, -S(O)2NR^aR^b, -OS(O)NR^aR^b, -OS(O)2NR^aR^b, -NR^aR^b, -NR^aC(O)R^b, -NR^aC(O)OR^b, -NR^aC(O)NR^aR^b, -NR^aS(O)R^b, -NR^aS(O)2R^b, -NR^aS(O)NR^aR^b, -NR^aS(O)2NR^aR^b, -C(O)R^a, -C(O)OR^a, -C(O)NR^aR^b, -PR^aR^b, -P(O)R^aR^b, -P(O)2R^aR^b, -P(O)NR^aR^b, -P(O)2NR^aR^b, -P(O)OR^a, -P(O)2OR^a, -CN, or -NO₂, wherein each hydrogen atom in Ci-Cô alkyl, C₂-Cô alkenyl, C₂-Cô alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cio aryl, or 5- to 10membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Cô alkyl, Ci-C₆ haloalkyl, -OR^C, -OC(O)R^C, -OC(O)NR^cR^d, -OC(=N)NR^cR^d, -OS(O)R^C, -OS(O)2R^C, -OS(O)NR^cR^d, -OS(O)2NR^cR^d, -SR^C, -S(O)R^C, -S(O)2R^C, -S(O)NR^cR^d, -S(O)2NR^cR^d, -NR^cR^d, -NR^cC(O)R^d, -N(C(O)R^c)(C(O)R^d), -NR^cC(O)OR^d, -NR^cC(O)NR^cR^d, -NR^cC(=N)NR^cR^d, -NR^cS(O)R^d, -NR^cS(O)2R^d, -NR^cS(O)NR^cR^d, -NR^cS(O)2NR^cR^d, -C(O)R^C, -C(O)OR^C, -C(O)NR^cR^d, -C(=N)NR^cR^d, -PR^R*¹, -P(O)R^cR^d, -P(O)₂R^cR^d, -P(O)NR^cR^d, -P(O)2NR^cR^d, -P(O)OR^C, -P(O)2OR^c, -CN, or -NO₂.

In some embodiments, ring B is isoxazolylene, isothiazolylene, or pyrazolylene, wherein each hydrogen atom in isoxazolylene, isothiazolylene, or pyrazolylene, is independently optionally substituted by an R² that is deuterium, halogen, Ci-C6 alkyl, C2-Cô alkenyl, C2-C& alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cioaryl, 5- to 10-membered heteroaryl, -OR^a, -OC(O)R^a, -OC(O)NR^aR^b, -OS(O)R^a, -OS(O)2R^a, -SR^a, -S(O)R^a, -S(O)2R^a, -S(O)NR^aR^b, -S(O)2NR^aR^b, -OS(O)NR^aR^b, -OS(O)2NR^aR^b, -NR^aR^b, -NR^aC(O)R^b, -NR^aC(O)OR^b, -NR^aC(O)NR^aR^b, -NR^aS(O)R^b, -NR^aS(O)2R^b, -NR^aS(O)NR^aR^b, -NR^aS(O)?NR^aR^b, -C(O)R^a, -C(O)OR^a, -C(O)NR^aR^b, -PR^aR^b, -P(O)R^aR^b, -P(O)₂R^aR^b, -P(O)NR^aR^b, -P(O)2NR^aR^b, -P(O)OR^a, -P(O)2OR^a, -CN, or -NO₂, wherein each hydrogen atom in Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-Cô alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cio aryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Cô alkyl, Ci-Cô haloalkyl, -OR^C, -OC(O)R^C, -OC(O)NR^eR^d, -OC(=N)NR^cR^d, -OS(O)R^C, -OS(O)2R^C, -OS(O)NR^cR^d, -OS(O)2NR^cR^d, -SR^C, -S(O)R^C, -S(O)2R^C, -S(O)NR^cR^d, -S(O)2NR^cR^d, -NR^cR^d, -NR^cC(O)R^d, -N(C(O)R^c)(C(O)R^d), -NR^cC(O)OR^d, -NR^cC(O)NR^cR^d, -NR^cC(=N)NR^cR^d, -NR^cS(O)R^d, -NR^cS(O)2R^d, -NR^cS(O)NR^eR^d, -NR^cS(O)2NR^cR^d, -C(O)R^C, -C(O)OR^C, -C(O)NR^cR^d, -C(=N)NR^cR^d, -PR^cR^d, -P(O)R^cR^d, -P(O)2R^cR^d, -P(O)NR^cR^d, -P(O)2NR^eR^d, -P(O)OR^C, -P(O)2OR^c, -CN, or -NO2.

In some embodiments, ring B is a 5- to 10-membered heteroarylene, such as a mono-cyclic 5- or 6-membered heteroarylene or a bicyclic 8- to 10-membered heteroarylene, wherein the 5- to 10-membered heteroarylene, as described herein, is optionally substituted with l, 2, 3, 4, or 5 of R² (m of R²), each of which is independently selected from the group consisting of deuterium, halogen, Ci-Cô alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cio aryl, 5- to 10-membered heteroaryl, -OR^a, -OC(O)R^a, -OC(O)NR^aR^h, OS(O)R^a, -OS(O)₂R^a, -SR^a, -S(O)R^a, -S(O)2R^a, -S(O)NR^aR^b, -S(O)2NR^aR^b, -OS(O)NR^aR^b, -OS(O)2NR^aR^b, -NR^aR^b, -NR^aC(O)R^b, -NR^aC(O)OR^b, -NR^aC(O)NR^aR^b, -NR^aS(O)R^b, -NR^aS(O)2R^b, -NR^aS(O)NR^aR^b, -NR^aS(O)2NR^aR^b, -C(O)R^a, -C(O)OR^a, -C(O)NR^aR^b, -PR^aR^b, P(O)R^aR^b, -P(O)2R^aR^b, -P(O)NR^aR^b, -P(O)2NR^aR^b, -P(O)OR^a, -P(O)2OR^a, -CN, or -NO2, wherein each hydrogen atom in Ci-Cô alkyl, C₂-Cô alkenyl, C₂-Cô alkynyl, C3-C6 cycloalkyl, 3- to 7membered heterocycloalkyl, Cô-Cio aryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Cô alkyl, Ci-Cô haloalkyl, -OR^C, -OC(O)R^C, -OC(O)NR^cR^d, -OC(=N)NR^cR^d, -OS(O)R^C, -OS(O)2R^C, -OS(O)NR^cR^d, -OS(O)2NR^eR^d, -SR^C, -S(O)R^C, -S(O)2R^C, -S(O)NR^cR^d, -S(O)2NR^cR^d, -NR^cR^d, -NR^cC(O)R^d, -N(C(O)R^c)(C(O)R^d), -NR^cC(O)OR^d, -NR^cC(O)NR^cR^d, -NR^cC(=N)NR^vR^d, -NR^cS(O)R^d, -NR^cS(O)₂R^d, -NR^cS(O)NR^cR^d, -NR^cS(O)2NR^cR^d, -C(O)R^C, -C(O)OR^C, -C(O)NR^cR^d, -C(=N)NR^cR^d, -PR^cR^d, -P(O)R^cR^d, -P(O)2R^cR^d, -P(O)NR^cR^d, -P(O)2NR^cR^d, -P(O)OR^C, -P(O)2OR^C, -CN, or-NO₂.

In some embodiments, ring B is isoxazolylene, isothiazolylene, or pyrazolylene, wherein each is optionally substituted with l, 2, 3, 4, or 5 of R² (m of R²), each of which is independently selected from the group consisting of deuterium, halogen, Ci-Cô alkyl, C2-Cô alkenyl, C2-Cô alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cio aryl, 5- to 10-membered heteroaryl, -OR^a, -OC(O)R^a, -OC(O)NR^aR^b, -OS(O)R^a, -OS(O)2R^a, -SR^a, -S(O)R^a, -S(O)2R^a, -S(O)NR^aR^b, -S(O)2NR^aR^b, -OS(O)NR^aR^b, -OS(O)2NR^aR^b, -NR^aR^b, -NR^aC(O)R^b, -NR^aC(O)OR^b, -NR^aC(O)NR^aR^b, -NR^aS(O)R^b, -NR^aS(O)2R^b, -NR^aS(O)NR^aR^b, -NR^aS(O)2NR^aR^b, -C(O)R^a, -C(O)OR^a, -C(O)NR^aR^b, -PR^aR^b, -P(O)R^aR^b, -P(O)2R^aR^b, -P(O)NR^aR^b, -P(O)2NR^aR^b, -P(O)OR^a, -P(O)2OR^a, -CN, or -NO₂, wherein each hydrogen atom in Ci-Cô alkyl, C₂-Cô alkenyl, C₂-Cô alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cio aryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-C₆ alkyl, Ci-C₆haloalkyl, -OR^C, -OC(O)R^C, -OC(O)NR^cR^d, -OC(=N)NR^cR^d, -OS(O)R^C, -OS(O)₂R^C, -OS(O)NR^cR^d, -OS(O)2NR^cR^d, -SR^C, -S(O)R^C, -S(O)2R^C, -S(O)NR^cR^d, -S(O)2NR^eR^d, -NR^cR^d, -NR^cC(O)R^d, -N(C(O)R^c)(C(O)R^d), -NR^cC(O)OR^d, -NR^cC(O)NR^cR^d, -NR^cC(=N)NR^cR^d, -NR^cS(O)R^d, -NR^cS(O)₂R^d, -NR^cS(O)NR^cR^d, -NR^cS(O)2NR^cR^d, -C(O)R^C, -C(O)OR^C, -C(O)NR^cR^d, -C(=N)NR^cR^d, -PR^cR^d, -P(O)R^cR^d, -P(O)2R^cR^d, -P(O)NR^eR^d, -P(O)2NR^cR^d, -P(O)OR^C, -P(O)2OR^c, -CN, or -NO₂.

In some embodiments, n is 0, l, 2, 3, or 4. In some embodiments, n is 0, l, 2, or 3. In some embodiments, n is 0, l, or 2. In some embodiments, n is 0 or l. In some embodiments, n is 0. In some embodiments, n is l. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

In some embodiments, ring B is a 5-membered heteroarylene selected from the group consistîng of wherein each “WW” represents a point of covalent attachment, and each R² is independently as described herein.

In some embodiments, R² is deuterium, halogen, Ci-C6 alkyl, C2-C6alkenyl, C2-C6 alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, Cé-Cioaryl, 5- to 10-membered heteroaryl, -OR^a, -OC(O)R^a, -OC(O)NR^aR^b, -OS(O)R^a, -OS(O)2R^a, -SR^a, -S(O)R^a, -S(O)2R^a, -S(O)NR^aR^b, -S(O)2NR^aR^b, -OS(O)NR^aR^b, -OS(O)2NR^aR^b, -NR^aR^b, -NR^aC(O)R^b, -NR^aC(O)OR^b, -NR^aC(O)NR^aR^b, -NR^aS(O)R^h, -NR^aS(O)2R^b, -NR^aS(O)NR^aR^b, -NR^aS(O)2NR^aR^b, -C(O)R^a, -C(O)OR^a, -C(O)NR^aR^b, -PR^aR^h, -P(O)R^aR^b, -P(O)2R^aR^b, -P(O)NR^aR^b, -P(O)2NR^aR^b, -P(O)OR^a, -P(O)2OR^a, -CN, or -NO2, wherein each hydrogen atom in Cj-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C&-Cioaryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-C6 alkyl, Ci-C6 haloalkyl, -OR^C, -OC(O)R^C, -OC(O)NR^cR^d, -OC(=N)NR^cR^d, -OS(O)R^C, -OS(O)2R^C,

-OS(O)NR^cR^d, -OS(O)2NR^cR^d, -SR^C, -S(O)R^C, -S(O)2R^C, -S(O)NR^LR^d, -S(O)2NR^eR^d, -NR^cR^d, -NR^cC(O)R^d, -N(C(O)R^c)(C(O)R^d), -NR^cC(O)OR^d, -NR^cC(O)NR^cR^d, -NR^cC(=N)NR^cR^d, -NR^cS(O)R^d, -NR^cS(O)2R^d, -NR^cS(O)NR^cR^d, -NR^eS(O)2NR^cR^d, -C(O)R^C, -C(O)OR^C, -C(O)NR^cR^d, -C(=N)NR^cR^d, -PR^cR^d, -P(O)R^cR^d, -P(O)2R^cR^d, -P(O)NR^cR^d, -P(O)2NR^cR^d, -P(O)OR^C, -P(O)2OR^c, -CN, or -NO₂. In some embodîments, R² is methyl, or ethyl.

In some embodîments, ring B is a 5-membered heteroarylene selected from the group consisting of

wherein each “άλλτ” represents a point of covalent attachment.

In some embodîments, Ring B is mono- or bi-cyclic Cô-C to arylene. In some embodîments, Ring B is monocyclic Cô-Cio arylene. In some embodîments, Ring B is bicyclic Cô-Cio arylene.

In some embodîments, Ring B is a Cô-Cio mono-or bi-cyclic arylene, wherein each hydrogen atom in Cô-Cio mono- or bi-cyclic arylene is independently optionally substituted by an R² that is deuterium, halogen, Cj-C6 alkyl, C2-C6 alkenyl, C2-C6alkynyl, C3-C6 cycloalkyl, 3- to Ίmembered heterocycloalkyl, Cô-Cio aryl, 5- to 10-membered heteroaryl, -OR^a, -OC(O)R^a, -OC(O)NR^aR^b, -OS(O)R^a, -OS(O)2R^a, -SR^a, -S(O)R^a, -S(O)2R^a, -S(O)NR^aR^b, -S(O)2NR^aR^b, -OS(O)NR^aR^b, -OS(O)2NR^aR^b, -NR^aR^b, -NR^aC(O)R^b, -NR^aC(O)OR^b, -NR^aC(O)NR^aR^b, -NR^aS(O)R^b, -NR^aS(O)2R^b, -NR^aS(O)NR^aR^b, -NR^aS(O)2NR^aR^b, -C(O)R^a, -C(O)OR^a, -C(O)NR^aR^b, -PR^aR^b, -P(O)R^aR^b, -P(O)2R^aR^b, -P(O)NR^aR^b, -P(O)2NR^aR^b, -P(O)OR^a, -P(O)2OR^a, -CN, or -NO₂, wherein each hydrogen atom in C|-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-Cô cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cioaryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Cô alkyl, Ci-C₆haloalkyl, -OR^C, -OC(O)R^C, -OC(O)NR^cR^d, -OC(=N)NR^cR^d, -OS(O)R^C, -OS(O)2R^C, -OS(O)NR^cR^d, -OS(O)2NR^cR^d, -SR^C, -S(O)R^C, -S(O)2R^C, -S(O)NR^cR^d, -S(O)2NR^cR^d, -NR^cR^d, -NR^cC(O)R^d, -N(C(O)R^e)(C(O)R^d), -NR^cC(O)OR^d, -NR^cC(O)NR^cR^d, -NR^cC(=N)NR^cR^d, -NR^cS(O)R^d, -NR^cS(O)₂R^d, -NR^cS(O)NR^cR^d, -NR^cS(O)2NR^cR^d, -C(O)R^C, -C(O)OR^C, -C(O)NR^cR^d, -C(=N)NR^LR^d, -PR^cR^d, -P(O)R^cR^d, -P(O)2R^eR^d, -P(O)NR^cR^d, -P(O)2NR^cR^d, -P(O)OR^C, -P(O)2OR^c, -CN, or -NO₂.

In some embodîments, Ring B is phenylene or naphthylene, wherein each hydrogen atom in phenylene or naphthylene is independently optionally substituted by an R² that is deuterium, halogen, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-Cô cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cio aryl, 5- to 10-membered heteroaryl, -OR^a, -OC(O)R^a, -OC(O)NR^aR^b, OS(O)R^a, -OS(O)2R^a, -SR^a, -S(O)R^a, -S(O)₂R^a, -S(O)NR^aR^b,

-S(O)₂NR^aR^b, -OS(O)NR^aR^b, -OS(O)2NR^aR^b, -NR^aR^b, -NR^aC(O)R^b, -NR^aC(O)OR^b, -NR^aC(O)NR^aR^b, -NR^aS(O)R^b, -NR^aS(O)2R^b, -NR^aS(O)NR^aR^b, -NR^aS(O)2NR^aR^b, -C(O)R^a, -C(O)OR^a, -C(O)NR^aR^b, -PR^aR^b, -P(O)R^aR^b, -P(O)2R^aR^b, -P(O)NR^aR^b, -P(O)2NR^aR^b, -P(O)OR^a, -P(O)2OR^a, -CN, or -NO2, wherein each hydrogen atom in Ci-Cô alkyl, C2-Cô alkenyl, C2-Câ alkynyl, C2-C& cycloalkyl, 3- to 7-mcmbercd heterocycloalkyl, Cô-Cioaryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Cô alkyl, Ci-Cô haloalkyl, -OR^C, -OC(O)R^C, -OC(O)NR^cR^d, -OC(=N)NR^eR^d, -OS(O)R^C, -OS(O)2R^C, -OS(O)NR^cR^d, -OS(O)2NR^cR^d, -SR^C, -S(O)R^C, -S(O)2R^C, -S(O)NR^eR^d, -S(O)2NR^cR^d, -NR^eR^d, -NR^cC(O)R^d, -N(C(O)R^c)(C(O)R^d), -NR^cC(O)OR^d, -NR^cC(O)NR^cR^d, -NR^cC(=N)NR^cR^d, -NR^L'S(O)R^d, -NR^cS(O)2R^d, -NR^cS(O)NR^cR^d, -NR^eS(O)2NR^cR^d, -C(O)R^C, -C(O)OR^C, -C(O)NR^cR^d, -C(=N)NR^cR^d, -PR^cR^d, -P(O)R^cR^d, -P(O)2R^cR^d, -P(O)NR^cR^d, -P(O)2NR^cR^d, -P(O)OR^C, -P(O)2OR^c, -CN, or -NO₂.

In some embodiments, ring B is a Cô-Ciq mono-or bi-cyclic arylene, wherein each is optionally substituted with 1, 2, 3, 4, or 5 of R² (n of R²), each of which is independently selected from the group consisting of deuterium, halogen, Ci-C& alkyl, C2-C6 alkenyl, C2-Cè alkynyl, Ca-Cè cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cioaryl, 5- to 10-membered heteroaryl, -OR^a, -OC(O)R^a, -OC(O)NR^aR^b, -OS(O)R^a, -OS(O)2R^a, -SR^a, -S(O)R^a, -S(O)2R^a, -S(O)NR^aR^b, -S(O)2NR^aR^b, -OS(O)NR^aR^b, -OS(O)2NR^aR^b, -NR^aR^b, -NR^aC(O)R^b, -NR^aC(O)OR^b, -NR^aC(O)NR^aR^b, -NR^aS(O)R^b, -NR^aS(O)2R^b, -NR^aS(O)NR^aR^b, -NR^aS(O)2NR^aR^b, -C(O)R^a, -C(O)OR^a, -C(O)NR^aR^b, -PR^aR^b, -P(O)R^aR^b, -P(O)2R^aR^b, -P(O)NR^aR^b, -P(O)2NR^aR^b, -P(O)OR^a, -P(O)2OR^a, -CN, or -NO2, wherein each hydrogen atom in Ci-Cô alkyl, C2-C& alkenyl, C2-Cô alkynyl, Cj-Cô cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cioaryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Cô alkyl, Cj-Cô haloalkyl, -OR^C, -OC(O)R^C, -OC(O)NR^eR^d, -OC(=N)NR^cR^d, -OS(O)R^C, -OS(O)2R^c, -OS(O)NR^cR^d, -OS(O)2NR^cR^d, -SR^C, -S(O)R^C, -S(O)2R^C, -S(O)NR^cR^d, -S(O)2NR^cR^d, -NR^eR^d, -NR^cC(O)R^d, -N(C(O)R^c)(C(O)R^d), -NR^cC(O)OR^d, -NR^eC(O)NR^cR^d, -NR^cC(=N)NR^cR^d, -NR^eS(O)R^d, -NR^cS(O)2R^d, -NR^cS(O)NR^cR^d, -NR^cS(O)2NR^cR^d, -C(O)R^C, -C(O)OR^C, -C(O)NR^cR^d, -C(=N)NR^cR^d, -PR^cR^d, -P(O)R^cR^d, -P(O)2R^cR^d, -P(O)NR^cR^d, -P(O)2NR^cR^d, -P(O)OR^C, -P(O)2OR^c, -CN, and -NO₂.

In some embodiments, ring B is phenylene or naphthylene, wherein each is optionally substituted with 1,2, 3, 4, or 5 of R² (n of R²), each of which is independently selected from the group consisting of deuterium, halogen, Ci-Cô alkyl, C2-Cô alkenyl, C2-C& alkynyl, Cî-Cô cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cjoaryl, 5- to 10-membered heteroaryl, -OR^a, -OC(O)R^a, -OC(O)NR^aR^b, -OS(O)R^a, -OS(O)2R^a, -SR^a, -S(O)R^a, -S(O)2R^a, -S(O)NR^aR^b, -S(O)2NR^aR^b, -OS(O)NR^aR^b, -OS(0)₂NR^aR^h, -NR^aR^b, -NR^aC(O)R^b, -NR^aC(O)OR^b,

-NR^aC(O)NR^aR^b, -NR^aS(O)R^b, -NR^aS(O)₂R^b, -NR^aS(O)NR^aR^b, -NR^aS(O)2NR^aR^b, -C(O)R^a, -C(O)OR^a, -C(O)NR^aR^b, -PR^aR^b, -P(O)R^aR^b, -P(O)2R^aR^b, -P(O)NR^aR^h, -P(O)2NR^aR^b, -P(O)OR^a, -P(O)2OR^a, -CN, or -NO₂, wherein each hytlrogen atom in Ci-Cô alkyl, C₂-Cô alkenyl, C₂-Cô alkynyl, Cj-Côcycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cioaryl, or 5- to lO-membercd heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Cf, alkyl, Ci-Cô haloalkyl, -OR^C, -OC(O)R^C, -OC(O)NR^eR^d, -OC(=N)NR^cR^d, -OS(O)R^e, -OS(O)2R^C, -OS(O)NR^cR^d, -OS(O)2NR^cR^d, -SR^C, -S(O)R^C, -S(O)2R^C, -S(O)NR^cR^d, -S(O)2NR^cR^d, -NR^cR^d, -NR^cC(O)R^d, -N(C(O)R^c)(C(O)R^d), -NR^eC(O)OR^d, -NR^cC(O)NR^cR^d, -NR^cC(=N)NR^cR^d, -NR^cS(O)R^d, -NR^cS(O)2R^d, -NR^cS(O)NR^cR^d, -NR^cS(O)2NR^cR^d, -C(O)R^C, -C(O)OR^C, -C(O)NR^cR^d, -C(=N)NR^cR^d, -PR^cR^d, -P{O)R^cR^d, -P(O)2R^eR^d, -P(O)NR^cR^d, -P(O)2NR^cR^d, -P(O)OR^e, -P(O)2OR^C, -CN, or -NO2.

In sonie embodiments, ring B is a Cô-Cio arylene, and n is as deftned herein. In some embodiments, ring B is a phenylene, and n is as defined herein.

In some embodiments, R² is methyl, ethyl, F, Cl, or Br. In some embodiments, ring B is a phenylene, n is l, and R² is methyl, ethyl, F, Cl, or Br.

In some embodiments, ring B is of the formula

wherein each “vvw” represents a point of covalent attachment.

In some embodiments, R³ is H, deuterium, Ci-Cô alkyl, C₂-Cô alkenyl, C₂-Cô alkynyl, C3Cô cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cjoaryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in Ci-Cô alkyl, C₂-Cô alkenyl, C₂-Cô alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cio aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by -OR^C, -OC(O)R^C, -OC(O)NR^cR^d, -OC(=N)NR^cR^d, -OS(O)R^C, -OS(O)2R^C, -OS(O)NR^cR^d, -OS(O)2NR^cR^d, -SR^C, -S(O)R^C, -S(O)₂R^C, -S(O)NR^£R^d, -S(O)2NR^cR^d, -NR^cR^d, -NR^cC(O)R^d, -N(C(O)R^c)(C(O)R^d), -NR^cC(O)OR^d, -NR^cC(O)NR^£R^d, -NR^£C(=N)NR^cR^d, -NR^cS(O)R^d, -NR^£S(O)2R^d, -NR^cS(O)NR^cR^d, -NR^cS(O)2NR^£R^d, -C(O)R^C, -C(O)OR^C, -C(O)NR^cR^d, -C(=N)NR^cR^d, -PR^£R^d, -P(O)R^cR^d, -P(O)2R^cR^d, -P(O)NR^cR^d, -P(O)2NR^£R^d, -P(O)OR^C, -P(O)2OR^c, -CN, or -NO2, In some embodiments, R³ is H or Ci-Cô alkyl, wherein each hydrogen atom in Ci-Cô alkyl, C2-Cô alkenyl, C₂-Cô alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cio aryl, or 5- to 10-nicmbered heteroaryl is independently optionally substituted by -OR^C, -OC(O)R^C, -OC(O)NR'-'R^d, -OC(=N)NR^cR^d, -OS(O)R^C, -OS(O)₂R^C, -OS(O)NR^cR^d, -OS(O)2NR^cR^d, -SR^C, -S(O)R^C, -S(O)2R^C, -S(O)NR^CR¹‘, -S(O)₂NR^cR^d, -NR^cR^d, -NR^cC(O)R^d, -N(C(O)R^c)(C(O)R^d), -NR^cC(O)OR^d, -NR^eC(O)NR^cR^d, -NR^cC(=N)NR^cR^d, -NR^cS(O)R^d, -NR^cS(O)2R^d, -NR^cS(O)NR^cR^d, -NR^cS(O)2NR^cR^d, -C(O)R^C, -C(O)OR^C. -C(O)NR^cR^d, -C(=N)NR^LR^d, -PR^cR^d. -P(O)R^cR^d, -P(O)_;R^cR^d, -P(O)NR^cR^d, -P(O)2NR^cR^d, -P(O)OR^C, -P(O)2OR^c, -CN, or-NO₂. In some embodiments, R³ is H, deuterium, Ci-C&alkyl, C2Cô alkenyl, C2-C& alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cio aryl, or 5to lO-membered heteroaryl, wherein each hydrogen atom in Ct-CValkyl, C2-Cô alkenyl, C2-Cô alkynyl, C3-C6 cycloalkyl, 3- to 7-inembered heterocycloalkyl, Cô-C 10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, -OR^C, -OC(O)R^C, -OC(O)NR^cR^d, -OC(=N)NR^cR^d, -OS(O)R^C, -OS(O)2R^c, -OS(O)NR^cR^d, -OS(O)2NR^cR^d, -SR^C, -S(O)R^C, -S(O)2R^C, -S(O)NR^cR^d, -S(O)2NR^cR^d, -NR^t'R^d, -NR^cC(O)R^d, -N(C(O)R^c)(C(O)R^d), -NR^cC(O)OR^d, -NR^cC(O)NR^cR^d, -NR^cC(=N)NR^cR^d, -NR^cS(O)R^d, -NR^cS(O)2R^d, -NR^cS(O)NR^cR^d, -NR^cS(O)2NR^cR^d, -C(O)R^C, -C(O)OR^C, -C(O)NR^cR^d, -C(=N)NR^cR^d, -PR^eR^d, -P(O)R^cR^d, -P(O)2R^cR^d, -P(O)NR^cR^d, -P(O)2NR^cR^d, -P(O)OR^C, -P(O)2OR^C, -CN, or -NO₂. In some embodiments, R³ is H or Ci-Côalkyl. In some embodiments, R³ is H or methyl.

In some embodiments, q is 0, l, or 2. In some embodiments, q is 0 or l. In some embodiments, q is 0. In some embodiments, q is l. In some embodiments, q is 2.

In some embodiments, each R⁴ is independently deuterium, halogen, Ci-Côalkyl, C2-Cô alkenyl, C2-C&alkynyl, C3-C6cycloalkyl, 3- to 7-memberedheterocycloalkyl, Cô-Cæaryl, 5- to 10membered heteroaryl, -OR^a, -OC(O)R^a, -OC(O)NR^aR^b, -OS(O)R^a, -OS(O)2R^a, -SR^a, -S(O)R^a, -S(O)2R^a, -S(O)NR^aR^b, -S(O)2NR^aR^b, -OS(O)NR^aR^b, -OS(O)2NR^aR^b, -NR^aR^b, -NR^aC(O)R^b, -NR^aC(O)OR^b, -NR^aC(O)NR^aR^b, -NR^aS(O)R^b, -NR^aS(O)2R^b, -NR^aS(O)NR^aR^b, -NR^aS(O)2NR^aR^b, -C(O)R^a, -C(O)OR^a, -C(O)NR^aR^b, -PR^aR^b, -P(O)R^aR^b, -P(O)2R^aR^b, -P(O)NR^aR^b, -P(O)2NR^aR^b, P(O)OR^a, -P(O)2OR^a, -CN, or -NO2, wherein each hydrogen atom in Ci-C&alkyl, C2-C6 alkenyl, C2-Cô alkynyl, C3-C6 cycloalkyl, 3- to 7-membercd heterocycloalkyl, Cô-Cioaryl, and 5- to 10membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Côalkyl, Ci-Cô haloalkyl, -OR^e, -OC(O)R^e, -OC(O)NR^cR^r, -OS(O)R^e, -OS(O)2R^e, -OS(O)NR^eR^r, OS(O)2NR^cR^f, -SR^e, -S(O)R^e, -S(O)2R^e, -S(O)NR^cR^f, -S(O)2NR^cR^f, -NR^eR^f, -NR^eC(O)R^f, NR^eC(O)OR^f, -NR^eC(O)NR^eR^f, -NR^eS(O)R^r, -NR^eS(O)2R^r, -NR^eS(O)NR^cR^f, -NR^eS(O)2NR^cR‘, C(O)R^e, -C(O)OR^C, -C(O)NR^eR^r, -PR^eR^r, -P(O)R^eR‘, -P(O)2R^L'R', -P(O)NR^cR^f, -P(O)2NR^LR^f, -P(O)OR^e, -P(O)2OR^e, -CN, or -NO₂. In some embodiments, each R⁴ is independently deuterium, halogen, or Ci-Côalkyl. In some embodiments, each R⁴ is H, fluoro, chloro, or methyl.

In some embodiments, R⁵ is H, deuterium, -C(O)R^C, -C(O)OR^C, -C(O)NR^cR^d, -P(O)2R^cR^d, -P(O)2NR^(;R^d, -P(O)2OR^C, or -S(O)2OR^C. In some embodiments, R⁵ is H deuterium. In some embodiments, R⁵ is -C(O)R^C, -C(O)OR^C, -C(O)NR^cR^d, -P(O)2R^cR^d, -P(O)2NR^cR^d, -P(O)2OR^C, or -S(O)2OR^C. In some embodiments, R⁵ is Ci-C(, alkyl. In some embodiments, R⁵ is methyl or ethyl.

In some embodiments, each L is independently O-, -S-, -S(O)-, -S(O)₂-, -N(R⁶)C(O)-, C(O)N(R⁶)-, -N(R⁶)-, -N(R⁶)S(O)-, -S(O)N(R⁶)-, -N(R⁶)S(O)2-, -S(O)2N(R⁶)-, or -C(R⁷)(R⁸)-, provided that (L)p does not comprise an O-O, S-O, or N-N bond. In some embodiments, each L is independently each L is independently -C(R⁷)(R⁸)-, -C(O)-, -O-, or -N(R⁶)-, provided that (L)p does not comprise a -O-O- or a -O-N(R⁶)- bond, and the point of covalent attachaient of (L)p to NR³- does not form a -N-N- or a -O-N- bond.

In some embodiments, p is 3, 4, 5, 6, 7, 8, or 9. In some embodiments, p is 5, 6, 7, 8, or 9. In some embodiments, p is 4, 5, 6, 7, or 8. In some embodiments, p is 5, 6, 7, or 8. In some embodiments, p is 6, 7, 8, or 9. In some embodiments, p is 5, 6, or 7. 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. 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. In some embodiments, p is 9.

In some embodiments, -(L)_p- comprises -(CR⁷R⁸)C(O)N(R⁶)-(CR⁷R⁸)2-, -(CR⁷R⁸)N(R⁶)C(O)-(CR⁷R⁸)2-, -N(R⁶)-C(O)(CR⁷R⁸)2O(CR⁷R⁸)2-,

-CR⁷R⁸O(CR⁷R⁸)2O-(CR⁷R⁸)2, -O(CR⁷R⁸)2O(CR⁷R⁸)2-, -CR⁷R⁸O-CR⁷R⁸-C(O)N(R⁶)-(CR⁷R⁸)2-, -(CR⁷R⁸)3O(CR⁷R⁸)2-, -(CR⁷R⁸)2O(CR⁷R⁸)î-, -CR⁷R⁸-N(R⁶)-(CR⁷R⁸)2-, -CR⁷R⁸-N(R⁶)-(CR⁷R⁸)a, -O(CR⁷R⁸)2O(CR⁷R⁸)3-, -(CR⁷R⁸)2-N(R⁶)-(CR⁷R⁸)3-, -(CR⁷R⁸)2-N(R⁶)-(CR⁷R⁸)2-, -O-(CR⁷R⁸)2, -O-(CR⁷R⁸)3-, or -O-(CR⁷R⁸)4-.

In some embodiments, -(L)_p- is -(CR⁷R⁸)C(O)N(R⁶)-(CR⁷R⁸)2-, -(CR⁷R⁸)N(R⁶)C(O)-(CR⁷R⁸)2-, -N(R⁶)-C(O)(CR⁷R⁸hO(CR⁷R⁸)₂-,

-CR⁷R⁸O(CR⁷R⁸)2O-(CR⁷R⁸)2, -O(CR⁷R⁸)2O(CR⁷R⁸)2-, -CR⁷R⁸O-CR⁷R⁸-C(O)N(R⁶)-(CR⁷R⁸)2-, -(CR⁷R⁸)3O(CR⁷R⁸)2-, -(CR⁷R⁸)2O(CR^?R⁸)3-, -CR⁷R⁸-N(R⁶)-(CR⁷R⁸)2-, -CR⁷R⁸-N(R⁶)-(CR⁷R⁸)3, -O(CR⁷R⁸)2O(CR⁷R⁸)3-, -(CR⁷R⁸)2-N(R⁶)-(CR⁷R⁸)3-, -(CR⁷R⁸)2-N(R⁶)-(CR⁷R⁸)2-, -O-(CR⁷R⁸)2, -O-(CR⁷R⁸)3-, or -O-(CR⁷R⁸)4-.

In some embodiments, R⁶, when présent, is H or Ci-Cô alkyl. In some embodiments, R⁶, when présent, is H or methyl. In some embodiments, R⁷, when présent, is H, Ci-C& alkyl, -OH, or -OCH₃. In some embodiments, R⁷, when présent, is H, methyl, -OH, or -OCH3. In some embodiments, R⁸, when présent, is H, Ci-Cô alkyl, -OH, or -OCH3. In some embodiments, R⁸, when présent, is H, methyl, -OH, or OCH3. In some embodiments, each R⁷ and R⁸, when présent, is H.

ln some embodiments, -(L)_p- is -CH₂C(O)N(H)-(CH₂)2O-, -CH₂C(O)N(CH3)-(CH₂)₂O-, -CH2C(O)N(CH₂CH₃)-(CH2)2O-, -CH₂N(H)C(O)-(CH₂)₂O-, -CH₂C(O)N(CH3)C(O)-(CH₂)₂O-, -CH2C(O)N(CH₂CH3)C(O)-(CH2)₂O-, -C(O)N(H)-(CH₂)₂O(CH₂)₂-,

-N(H)-C(O)(CH₂)₂O(CH₂)₂-, -CH₂O(CH₂)3O-, -CH2O(CH2)₂OCH₂-, -(CH2)2O(CH₂)₂O-,

-CH₂O-CH2-C(O)N(H)-(CH₂)₂-, -CH₂O(CH₂)₂C(O)N(H)-CH₂-, -CH₂O(CH₂)₂N(H)C(O)-,

-CH₂O(CH₂)₃N(H)C(O)-, -(CH₂)₂O(CH2)₂N(H)C(O)-, -CH(CH3)-CH₂O(CH₂)₂N(CH3)C(O)-, -CH(CH₃)-CH₂O(CH₂)₂N(H)C(O)-, -CH(OCH3)’CH₂O(CH₂)₂N(CH3)C(O)-,

-CH(OCH3)-CH₂O(CH₂)₂N(H)C(O)-, -O(CH₂)₂O(CH₂)₂N(H)C(O)-,

-CH₂O(CH₂)₂N(H)C(O)-CH₂-, or -O-(CH₂)3C(O)N(H)-.

In some embodiments, -(L)_p- is -CH2C(O)N(H)-(CH₂)2OCH2-, -C(O)N(H)-(CH₂)₂O(CH₂)₂-, -N(H)-C(O)(CH₂)₂O(CH₂)₂-, -CH₂O(CH₂)₂O-(CH₂)₂,

-O(CH₂)2O{CH₂)₂O-, -CH₂O-CH₂-C(O)N(H)-(CH₂)₂-, -CH₂O(CH₂)₂C(O)N(H)-CH2-,

-CH₂O(CH₂)₂N(H)C(O)-, -CH₂O(CH₂)3N(H)C(O)-, -(CH₂)₂O(CH₂)₂N(H)C(O)-,

-CH(CH3)-CH₂O(CH₂)₂N(CH3)C(O)-, -CH(CH3)-CH₂O(CH₂)₂N(H)C(O)-,

-CH(OCH3)-CH₂O(CH₂)₂N(CH3)C(O)-, -CH(OCH₃)-CH₂O(CH₂)₂N(H)C(O)-,

-O(CH₂)₂O(CH₂)₂N(H)C(O)-, -CH₂O(CH₂)₂N(H)C(O)-CH₂-, or -O-(CH₂)₃C(O)N(H)-.

In some embodiments, -(L)_p- comprises -CH₂N(H)-(CH₂)₂-, -CH₂N(CH3)-(CH₂)₂-, -O(CH₂)₂-, -O(CH₂)3-, -O(CH₂)4-, and -O(CH₂)₂O(CH₂)₂-.

In some embodiments, -(L)_p- is -CH₂N(H)-(CH₂)₂-, -CH₂N(CH3)-(CH₂)₂-, -O(CH₂)₂-, -O(CH₂)₃-, -O(CH₂)4-, and -O(CH₂)₂O(CH₂)2-.

In some embodiments, -(L)_p- is -CH₂N(H)-(CH₂)₂-, -CH₂N(CH3)-(CH₂)₂-, -O(CH₂)₂-, -OCH(CH3)CH₂-, -O(CH₂)₃-, -O(CH₂)₄-, and -O(CH₂)2O(CH₂)₂-.

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

BN-N , or a pharmaceutically acceptable sait thereof.

In some embodiments, the disclosure provides a compound selected from the group consisting of ( 17E)-8,12,l 5-trimethyl-2,l l ,l 2,l 5-tetrahydro-8£-3,5-ethenotripyrazolo[3,4-f:3',4'y:4,3-/î][ l ,4]oxazacyclopentadecin-13( 10£/)-one;

( 17£)-16-ethyl-8,12,14-trimethyl-2,11,12,14-tetrahydro-8//-3,5-ethenotripyrazolo[3,4/:3',4'-7:4,3 -«] [ l ,4]oxazacyclopentadecin-13( 1077)-one;

( l ΊΕ}-16-ethyl-8,12,15-trimethyl-2,11,12,15-tetrahydro-8/7-3,5-ethenotripyrazolo[3,4/:3',4'-7:4,3-rt][ l ,4]oxazacyclopentadecin-l 3( 10//)-one;

( 17£)-8,12,14,16-tetramethyl-2,11,12,14-tetrahydro-8//-3,5-ethenotrîpyrazolo[3,4-/:3',4'y:4,3-w][l,4]oxazacyclopentadecin-l3(IO//)-one;

( 17E)-8,12,15,16-tetramethyl-2,11,12,l 5-tetrahydro-8/7-3,5-ethenotripyrazolo[3,4_:/:3',4’j :4,3’’-π] [ l ,4]oxazacyclopentadecin-13( 1077)-one;

( 17£)-8,15, l6-trimethyl-2,l 1,12,15-tetrahydro-8H-3,5-ethenotripyrazolo[3,4-/:3’,4'y:4,3-n][ l ,4]oxazacyclopentadecin-l 3(l0/7)-one;

( 17£)-14-ethyl-8,12,16-trimethyl-2,11,12,14-tetrahydro-8//-3,5-ethenotripyrazolo[3,4/:3',4'-y :4,3-«] [ 1,4]oxazacyclopentadecin-13( 10£/)-one;

(19£)-8,14,16,18-tetramethyl-2,11,12,13,14,16-hexahydro-8/7-3,5-ethenotripyrazolo[3,4h :3',4'-/:4,3 -/?] [ l ,6]oxazacycloheptadecin-15( 10£/)-one;

( 18£)-8,13,15,17-tetramcthyl-2,10,11,12,13,15-hexahydro-3,5-ethenotripyrazolo[3,4g:3',4'-A’:4,3-o][ l,5]oxazacydohexadecin-l4(8/7)-one;

( 15 £)-3,10,12,14-tetramethyl-5,6,9,10,12,18-hexahydro-3/f-19,21 -ethenotripyrazolo[3,4/:3',4'-ffl:4,3-ç][l,4,7]dioxazacyclooctadecin-l l(8£/)-one;

( 18E)-8,10,13,15,17-pentamethyl-2,8,9,10,11,12,13,15-octahydro-14Æ-3.5ethenotripyrazolo[3,4-/:3',4'-y:4,3-/7][l,4]diazacyclohexadecin-l4-one;

( 17£)-14-(2-hydroxyethyl)-8,12,16-trimethyl-2,11,12,14-tetrahydro-8/f-3,5ethenotripyrazolo[3,4-/:3',4^,-y:4,3-/7][ l ,4]oxazacyclopentadecin-l3( I07¥)-one;

( 17£)-15-(2-hydroxyethyl)-8,12,16-trimethyl-2,11,12,15-tetrahydro-8H-3,5ethenotripyrazolo[3,4_:/:3',4'-/:4,3-n][ l ,4]oxazacyclopentadecin-13( 10£/)-one;

(17£)-8,12,16-trimethyl-14-[2-(pyrrolidin-1-yl)ethyl]-2,11,12,14-tetrahydro-8H-3,5ethenotripyrazolo[3,4-/:3',4'-7:4,3-/î][1,4]oxazacyclopentadecin-13(10A/)-one; and ( 17£)-8,12,16-trimethyl-15-(2-(pynolidin-1-yl)cthyI]-2,11,12,15-tetrahydro-8/7-3,5ethenotripyrazolo[3,4_:/:3',4'-_/:4.3^,,-/i][ l ,4]oxazacyclopentadecin-13( 10//)-one or a pharmaceutically acceptable sait thereof.

In some embodiments, the disclosure provides a compound selected from the group consisting of ( 18£)-17-ethyl-7-fluoro-13,16-dimethyl-2,12,13,16-tetrahydro-3,5ethenodipyrazolo[3,4-/:3',4'-y][ l ,4]benzoxazacyclopentadecin-14( 11/7)-one;

( 18/:)-17-ethyl-7-fluoro-13,15-dimethyl-2,12,13,15-tetrahydro-3,5-ethenodipyrazolo[3,4/:3',4'-y][l ,4]benzoxazacyclopentadecin-14( 117/)-one ( 18£)-13,16-dimethyl-2,12,13,16-tetrahydro-3,5-ethenodipyrazolo[3,4-/:3',4'y][l,4]benzoxazacyclopentadecin-l4(l l//)-one; and ( 18 £)-21 -chloro-17-ethyl-7-fluoro-13,16-dimethyl-2,12,13,16-tetrahydro-3,5ethenodipyrazolo[3,4-/:3',4'-y][ l ,4]benzoxazacyclopentadecin-l4(l l/7)-one;

or a pharmaceutically acceptable sait thereof.

In some embodiments, the disclosure provides a compound selected from the group consisting of ( 17£)-8,12,15-trimethyl-2,11,12,15-tetrahydro-8/7-3,5-ethenotripyrazolo[3,4-/;3',4'7':4,3-λϊ][ l ,4]oxazacyclopentadecin-13( 1077)-one;

( 177?)-16-ethyI-8,12,14-trimethyl-2,11,12,14-tetrahydro-8F/-3,5-ethenotripyrazolo[3,4f'SA'-j :4,3 -«] [ 1,4]oxazacyclopentadecin-13(10/7)-one;

( 17E)-16-ethyl-8,12,15-trimethyl-2,11,12,15-tetrahydro-8/7-3,5-ethenotripyrazolo[3,4/:3',4'-y:4,3-n]( l,4]oxazacyclopentadecin-13( 10//)-one;

( 17£)-8,12,14,16-tetramethyl-2,11,12,14-tetrahydro-8/7-3,5-ethenotripyrazolo[3,4_:/: 3',4^rj :4,3-π] [ 1,4]oxazacyclopentadecin-13(10/7)-one;

( 17£)-8,12,15,16-tetramethyl-2,11,12,15-tetrahydro-8/7-3,5-ethenotripyrazolo[3,4_:/:3 ',4'j :4,3-/ί] [ 1,4]oxazacyclopentadecin-13(1077)-one;

( 17£)-8,15,16-trimethyl-2,11,12,15-tetrahydro-8/7-3,5-ethenotripyrazolo[3,4-^3',4'j :4,3-π][ 1,4]oxazacyclopentadecin-13(10/7)-one;

( 17£)-14-ethyl-8,12,16-trimethyl-2,11,12,14-tetrahydro-877-3,5-ethenotripyrazolo[3,4/:3',4'-y:4,3-H][l,4]oxazacyclopentadecin-13( 1077)-one;

( 19£)-8,14,16,18-tetramethyl-2,11,12,13,14,16-hexahydro-8/7-3,5-ethenotripyrazolo[3,4A:3',4'-/:4,3 -/?][ 1,6]oxazacycloheptadecin-15( 10/7)-one;

( 18£)-8,13,15,17-tetramethyl-2,10,11,12,13,15-hexahydro-3,5-ethenotripyrazolo[3,4g:3',4'-A:4,3-o][ 1,5]oxazacyclohexadecin-14(877)-one;

( 15£)-3,10,12,14-tetramethyl-5,6,9,10,12,18-hexahydro-3/7-19,21 -ethenotripyrazolo[3,4i':3',4'-m:4,3'^,-^][ 1,4,7]dioxazacyclooctadecin-11 (8/7)-one;

( 18 £)-8,10,13,15,17-pentamethyl-2,8,9,10,11,12,13,15-octahydro-142/-3,5ethenotripyrazolo[3,4-/:3',4'-/:4,3-n][l,4]diazacyclohexadecin-l 4-one;

( 1727)-14-(2-hydroxyethyl)-8,12,16-trimethyl-2,11,12,14-tetrahydro-827-3,5ethenotripyrazolo[3,4-f:3',4'-y:4,3-H][ l ,4]oxazacyclopentadecin-13( 1022)-one;

( 17£)-15-(2-hydroxyethyl )-8,12,16-trimethyl-2,11,12,15-tetrahydro-877-3,5ethenotripyrazolo[3,4-/:3',4’;/':4,3-/?][ 1,4]oxazacyclopentadecin-l 3( 10/7)-one;

( 17£)-8,12,16-trimethyl-14-[2-(pyrroltdîn-1 -yl )et hyl ]-2,11,12,14-tetrahydro-827-3,5ethenotripyrazolo[3,4-/:3',4’-y':4,3-n][ l,4]oxazacyclopentadecin-l 3( 1027)-one;

( 17£)-8,12,16-trimethyl-15-[2-(pyrrolidin-1 -yl )ethyl]-2,11,12,15-tetrahydro-82/-3,5ethenotripyrazolo[3,4-/:3',4'-j:4,3-fl][ l,4]oxazacyclopentadecin-l 3( 10/7)-one;

( 17£)-8,12,16-trimethyl-14-(propan-2-yl)-2,11,12,14-tetrahydro-8/7-3,5ethenotripyrazolo[3,47f:3',4^,-7:4,3-/7][l,4]oxazacyclopentadecin-13(1077)-one;

( 1727)-16-ethyl-8-methyl-12,14-bis[(²H₃)methyl]-2,11,12,14-tetrahydro-827-3,5ethenotripyrazolo[3,4_:/:3',4';/:4,3-n][l,4]oxazacyclopentadecin-13(1027)-one;

( 1727)-16-ethoxy-8,12,14-trimethyl-2,11,12,14-tetrahydro-8//-3,5-ethenotripyrazolo[3,4./:3 ',4'-_/:4,3-η] [ 1,4]oxazacyclopentadecin-13 ( 1077)-one;

( 1 OS, 17£)-16-ethyl-8,10,12,14-tetramethyl-2,11,12,14-tetrahydro-8/7-3,5ethenotripyrazolo[3,4-/13¹,4'-7:4,3-n][l,4]oxazacyclopentadecin-13(10/7)-one;

( 1727)-8,12,14-trimethyl-13-oxo-2,10,11,12,13,14-hexahydro-82/-3,5ethenotripyrazolo[3,4-/3',4'-y:4,3-n][ l,4]oxazacyclopentadecine-16-carbonitrile;

( 1727)-16-ethyl-8,12-dimethyl-2,8,11,12-tetrahydro-3,5-etheno[ 1,2]oxazolo[5,4/]dipyrazolo[3,4-7;4',3'-n][l,4]oxazacyclopentadecin-13( 102/)-one;

( 18£)-15-(2-hydroxyethyl)-8,10,13,17-tetramethyl-2,8,9,10,11,12,13,15-octahydro-14223,5-ethenotripyrazolo[3,4-/:3',4'-j:4,3-/i][ 1,4]diazacyclohexadecin-14-one; and ( 1727)-16-ethoxy-14-(2-hydroxyethyl )-8,12-dimethyl-2,11,12,14-tetrahydro-827-3,5 ethenotripyrazolo[3,4-/3',4'-y:4,3-»][l,4]oxazacyclopentadecin-13(1027)-one;

or a pharmaceutically acceptable sait thereof.

The following represent illustrative embodiments of compounds of Formula (I):

Ex.#	Structure	Name
1	A?- / Z \__/ \ O O π \\—£ i z	(1827)-17-ethyl-7-fluoro-13,I6dimethyl-2,12,13,16-tetrahydro-3,5- ethenodîpyrazolo[3,4_:/:3',4'- ./] [ 1,4]benzoxazacyclopentadecin- 14(1 l/7)-one

Ex. #	Structure	Name
2	τι i z k // I y— I Z^/ o O V^^Z <~ν· / ^z	( 18£j-l 7-ethyl-7-fluoro-l 3,15dimethyl-2,1 2,13,15-tetrahydro-3,5- ethenodipyrazolo[3,4-/:3',4'- y][ 1,4]benzoxazacyclopentadecin- 14( 11 //)-one
3	। >— / zy O \=- °\^? \ y/ ^X z	( 18£)-13,16-dimethyl-2,12,13,16tetrahydro-3,5 -ethenodi pyrazol o [ 3,4/:3',4'-y] [ 1,4]benzoxazacyclopentadecin14(1 l/f)-one
4	Γ^Ν\ <z^0 A \| 0 >=N (àj Il HN-N	( 17£)-8,12,15-trimethyl-2,11,12,15- tetrahydro-8//-3,5- ethenotripyrazolo[3,4-/:3',4'-j:4,3- n] [ 1,4]oxazacyclopentadecin-13(10//)one
5	ο 7¹ ^yîr^ Z^ O A- o A. \Λζ_χΓ z Ύ	( 182:)-21 -chloro-17-ethyl-7-fluoro13,16-dimethyl-2,12,13,16-tetrahydro3,5-ethenodipyrazolo[3,4-/:3',4'- y][ 1,4]benzoxazacyclopentadecin- 14(1177)-one
6	//Λ A^ A / L ⁰ /T~^N' u^L '^N HN-N	( 17£’)-16-ethyl-8,12,14-trimethyl- 2,11,12,14-tetrahydro-8//-3,5ethenotripyrazolo[3,4-/:3',4'-y:4,3- n] [ 1,4]oxazacyclopentadecin-13(10/7)one

Ex. #	Structure	Namc
7	/ \ ° o / .--/ I / V? । /—\ / ^T	( l ΊΕ)-16-ethyl-8,12,15-trimethyl- 2, l l, 12,15-tetrahydro-8//-3,5ethenotripyrazolo[3,4-/:3’,4^,-7':4^,,,3- /ï][ l ,4]oxazacyclopentadecin-13( 10/7)- one
8	Γ^Ν\ \Λθ Λ / z/n Qfj \ /7 HN-N	( 17£)-8,12,14,16-tetramethyl- 2,l 1,12,14-tetrahydro-8H-3,5- ethenotripyrazolo[3,4-/:3',4'-y:4,3- «] [ 1,4]oxazacyclopentadecin-13(10/7)one
9	। >— / ζ-γ o o Alf	( 17£)-8,12,15,16-tetramethyl2,11,12,15-tetrahydro-8//-3,5ethenotripyrazolo[3,4-f:3',4’-7:4,3n][l ,4]oxazacyclopentadecin-13( 10/7)one
ΙΟ	/7 ^N\ ^NH NZ ⁰ A \| οΛ^ν \z/ HN-N	( 17£)-8,15,16-triinethyl-2,11,12,15- tetrahydro-8/7-3,5- ethenotripyrazolo[3,4_:/:3',4'-y:4,3«][ 1,4]oxazacyclopentadecin-13(10/7)- one
H	ΓΧ Λ'<.Z~0 À ;— T ° Vn il //f'^N HN-N	( 1ΊΕ)-14-ethyl-8,12,16-trimethyl2,11,12,14-tetrahydro-8/7-3,5ethenotripyrazolo[3,47/:3',4'-y:4,3n][ 1,4]oxazacyclopentadecîn-13( 10//)one

Ex. #	Structure	Name
12	N-N^Z L ίΊ °A_ / \ // HN-N Y	( 19£j-8,14,16,18-tetramethyl- 2,11,12,13,14,16-hexahydro-8/7-3,5ethenotripyrazolo[3,4-/7:3’,4'-/:4,3- p] [ l ,6]oxazacycloheptadecin-15( 10Λ/)one
13	N~N ^jYcYY___χ X N A °=V / //^N' \ // HN-N Y	(18F)-8,13,15,17-tetramethyl- 2,10,11,12,13,15-hexahydro-3,5ethenotripyrazolo[3,4-g:3',4'-A':4,3- o] [ 1,5]oxazacyclohexadecin-14(8/7)-one
14	N-N P y L ^N~~ o ^o=V / il Y. //“N HN-N Y	( 15£)-3,10,12,14-tetramethyl5,6,9,10,12,18-hexahydro-3H-19,21 ethenotripyrazolo[3,4-z:3',4'-/?2:4,3<?][ 1,4,7]dioxazacyclooctadecin-11 (8/7)one
15	N-/ / L ^N~ ίίΊ ⁰⁼V / V Y. /Y N HN-N Y	( 18£)-8,10,13,15,17-pentamethyl2,8,9,10,11,12,13,15-octahydro-14/73,5-ethenotripyrazolo[3,4-/:3^,,4'-;:4,3«][ 1,4]diazacyclohexadecin-14-one
16	/T^N\ /^N p^h %P° À \| 0 N Π /Γύ'^ν ^k \ ^X// HN-N	( 17£)-14-(2-hydroxyethyl)-8,12,16trimethyl-2,11,12,14-tetrahydro-8//-3,5ethenotripyrazolo[3,4_:/:3',4'-y:4,3n] [ 1,4]oxazacyclopentadecin-13(10//)one

Ex. #	Structure	Name
17	//Λ AA ΧχΧ'~^^0Η // HN-N	( 17£)-15-(2-hydroxyethyl )-8,12,16trimethyl-2,l l,l2,15-tctrahydro-8/f-3,5cthcnotripyrazolo[3,4-/:3',4’-/:4,3«][l ,4]oxazacyclopentadecin-l3( 10/7)- one
18	N~^N. Λ n-^ X / ⁷ Ί 0 \— N fi ir^\^N \// HN-N	( 17£)-8,12,16-trimethyl-14-[2(pyrrolidin-1 -yl)ethyl]-2,11,12,14tetrahydro-8//-3,5- ethenotripyrazolo[3,4_:/:3',4'-y:4,3’’«][ l ,4]oxazacyclopentadecin-13( 107/)one
19	//Λ TA X^o A I O^X^N /\ A, A>A j Π/] \// HN-N	( 17£)-8,12,16-trimethyl-15-[2(pyrrolidin-1 -yl )ethyl]-2,11,12,15- tetrahydro-8//-3,5- ethenotripyrazolo[3,4-/;3',4’-y;4,3- n] [ 1,4]oxazacyclopentadecin-13(10/7)one
20	XXo A A y ⁰ /ΤΛ /X JL/n CXj\ HN-N	( 17E)-8,12,16-trimethyl-14-(propan-2yl)-2,11,12,14-tetrahydro-8/7-3,5ethenotripyrazolo[3,47/:3',4'-_/:4,3»] [ 1,4]oxazacyclopentadecin-13(10/7)- one
21	, A N'^N _X / N DD ^;ΖΧ~ο <4 J<^DΎ ⁰ /J^N, ^D /¼ aL/ⁿ // HN-N	( 17E)-16-ethyl-8-methyl-12,14bis[(²H3)methyl]-2,11,12,14-tetrahydro8//-3,5-ethenotripyrazolo[3,47/:3',4'j :4,3 -n] [ 1,4]oxazacyclopentadecin- 13(10/7)-one

Ex. #	Structure	Naine
22	N'N A ⁷l ⁰ /Γ'Ή zL· JL z N // HN-N	( 11E\-16-ethoxy-8,12,14-trimethyl2,11,12,14-tetrahydro-8//-3,5ethenotripyrazolo[3,4_:/:3',4'-7:4,3/?][ 1,4]oxazacyclopentadecin-13( 10/f)one
23	/ K N^_N /^'N' AÀo A / V ° /fN A- // _ZN Ο<Γν^ // HN-N	( 105,17E)-16-ethyl-8,10,12,14tetramethyl-2,11,12,14-tetrahydro-8/7S^-ethenotripyrazoloD/E/ïS’/V-/^''^/1] [ 1,4]oxazacyclopentadecin-13(10//)one
24	να ' I l ⁰ jQ XY N HN-N	( 17E)-8,12,14-trimethyl-13-oxo2,10,11,12,13,14-hexahydro-8//-3,5ethenotripyrazolo[3,4_:/:3',4'-7:4,3''/!][ 1,4]oxazacyclopentadecine-16carbonitrile
25	/ .... AÂo A Ύ ⁰ F° A- JL Z^N (1Γγ il II HN-N	( 17£)-16-ethyl-8,12-dimethyl-2,8,11,12tetrahydro-3,5-etheno[ 1,2]oxazolo[5,4/]dipyrazolo[3,4-7:4',3’«][ l,4]oxazacyclopentadecin-l 3( 10/7)- one
26	T O L ,z z À—^-' \ A/ C - \ -JyAj'¹-Z.=J -^==^	( 18E)-15-(2-hydroxyethyl )-8,10,13,17tetramethyl-2,8,9,10,11,12,13,15octahydro-14//-3,5ethenotripyrazolo[3,4_:/:3',4^,-7:4,3/?] [ 1,4]diazacyclohexadecin-14-one

Ex. #	Structure	Name
27	T CL L· h v-° \ λ-4 \ ° ''-o Àz Zi X—'	(17/0-16-ethoxy-14-(2-hydroxyethyI)8,12-dimethyl-2,11,12,14-tetrahydro8/7-3,5-ethenotripyrazolo[3,4_:/:3',4'j :4,3 -//][ l,4]oxazacyclopentadecin- 13( 10//)-one

and pharmaceutically acceptable salts thereof.

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

PHARMACEUTICAL COMPOSITIONS

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 ingrédient. Examples of pharmaceuticallyacceptable 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 stérile compositions. Pharmaceutical compositions may be prepared using compounding techniques known or that become available to those skilled in the art.

Stérile compositions are also contemplated by the disclosure, including compositions that are in accord with national and local régulations goveming such compositions.

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

For oral administration, the compounds the disclosure may be provided in a solid form, such as a tablet or capsule, or as a solution, émulsion, or suspension. To préparé the oral compositions, the compounds of the disclosure may be formulated to yield a dosage of, e.g., from about 0.1 mg to l g daily, or about l mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to l 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, magnésium stéarate, mannitol, sorbitol, and the like. Exemplary liquid oral excipients include éthanol, 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 présent, may be magnésium stéarate, 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 coatcd with an entcric coating.

Capsules for oral administration include hard and soft gelatin capsules. To préparé 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 ingrédient with water, an oil, such as peanut oil or olive oil, liquid paraffm, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.

Liquids for oral administration may be in the form of suspensions, solutions, émulsions, 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: pharmaceuticallyacceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stéarate 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 phydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.

For parentéral use, including intravenous, intramuscular, intraperitoneal, intranasal, or subeutaneous routes, the agents of the disclosure may be provided in stérile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonie sodium chloride. Such fomis may be presented in unit-dose form such as ampoules or disposable injection devices, in multidose fomis such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to préparé an injectable formulation. Illustrative infusion doses range from about l to I000 pg/kg/minute of agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.

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.

For topical applications, the compounds of the présent 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. l% to about 10% of drug to vehicle. Another mode of administering the agents of the disclosure may utilize a patch formulation to effect transdermai delivery.

As used herein, the tenus “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 récurrence 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 régression of the disorder or disease, relieving a condition causcd by the disease or disorder, or stopping the symptoms of the disease or disorder.

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

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 rénal cell carcinoma, pédiatrie rénal cell carcinoma, breast cancer, ER⁺ breast cancer, colonie adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, gastric adenocarcinoma, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioendothelîoma, intrahepatic cholangiocarcinoma, thyroid papillary cancer, spitzoid neoplasms, sarcoma, astrocytoma, brain lower grade glioma, sccretory breast carcinoma, mammary analogue carcinoma, myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CML), acute myeloid leukemîa (AML), congénital mesoblastic nephroma, congénital fibrosarcomas, Ph-like acute lymphoblastic leukemia, thyroid carcinoma, skin cutaneous melanoma, head and neck squamous cell carcinoma, pédiatrie glioma prostate cancer, lung squamous carcinoma, ovarian serons cystadenocarcinoma, skin cutaneous melanoma, castratcresistant prostate cancer, Hodgkin lymphoma, and serons and clear cell endométrial cancer. In some embodiments, cancer includes, lung cancer, colon cancer, breast cancer, prostate cancer, hepatocellular carcinoma, rénal cell carcinoma, gastric and esophago-gastric cancers, glioblastoma, head and neck cancers, inflammatory myofibroblastic tumors, and anaplastic large cell lymphoma.

In one aspect, the compounds and pharmaceutical compositions of the disclosure specifîcally target FLT3, Thus, these compounds and pharmaceutical compositions can be used to prevent, reverse, slow, or inhibit diseases, such as cancers driven by the activity of FLT3. In some embodiments, the compounds described herein can target FLT3 in a oncogenic driver mutation, such as FZ.F3-ITD. In some embodiments, the compounds described herein can target FLT3 (e.g. in such as FZ.F3-ITD) having one or more résistance mutations, such as such as résistance mutations in the activating loop residues (e.g., D835, I836, D839, and Y842), or in the gatekeeper residue F691 of FLT3. In some embodiments, methods of treating a target cancer, such as AML, are described.

In one aspect, the compounds and pharmaceutical compositions of the disclosure specifîcally target PIM kinases. In some embodiments, the compounds described herein can target PIM kinase activity to overcome résistance mechanisms of chemotherapy, radiotherapy, antiangiogenic thérapies and targeted thérapies. In some embodiments, methods of treating a target cancer, such as AML, are described.

In one aspect, the compounds and pharmaceutical compositions of the disclosure specifîcally target CLK kinases. In some embodiments, the compounds described herein can target CLK kinase activity to treat diseases, such as cancers, through modulation of pre-mRNA splicing via inhibition of CLK kinase activity. In some embodiments, methods of treating a target cancer, such as myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia, AML, lung cancer, breast cancer, and pancreatic cancer are described.

In some embodiments, compounds as described herein can be useful in connection with the treatment of diseases, such as cancer, such as AML, by inhibiting one or more of aberrant FLT3, including oncogenic driver mutations such as FL73-ITD and FLT3 résistance mutations, such as résistance mutations in the activating loop residues (e.g., D835, I836, D839, and Y842), or in the gatekeeper residue F69l of FLT3, aberrant PIM kinases, and/or aberrant CLK kinases.

In the inhibitory methods of the disclosure, an “effective amount” means an amount sufticient to inhibit the target protein. Measuring such target modulation may be performed by routine analytical methods such as those described below. Such modulation is useful in a variety of settings, including in vitro assays. In such methods, the cell is preferably a cancer cell with abnormal signaling due to a mutation of FLT3, PIM, and/or CLK as described herein.

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, such as AML, including those associated with aberrant FLT3, including oncogenic driver mutations such as ÆZ.T3-1TD and FLT3 résistance mutations, such as résistance mutations in the activating loop residues (e.g., D835, 1836, D839, and Y842), or in the gatekeeper residue F691 of FLT3, aberrant PIM kinases, and/or aberrant CLK kinases. 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 l g daily, or about l mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to l g daily. The total dosage may be given in single or divided dosage units (e.g., BID, TID, QID).

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 hâve been alleviated to an appropriate level, treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any récurrence of symptoms. Patients may also require chronic treatment on a long-term basis.

DRUG COMBINATIONS

The inventive compounds described herein may be used in pharmaceutical compositions or methods in combination with one or more additional active ingrédients in the treatment of the diseases and disorders described herein. Further additional active ingrédients include other therapeutics or agents that mitigate adverse effects of thérapies 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 ingrédients may be administered in a separate pharmaceutical composition from a compound of the présent disclosure or may be included with a compound of the présent disclosure in a single pharmaceutical composition. The additional active ingrédients may be administered simultaneously with, prior to, or after administration of a compound of the présent disclosure.

Combination agents include additional active ingrédients 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 5 or pharmaccuticals, 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 10 drugs, mitotic inhibitors, antibodies, hormone thérapies, or corticosteroids.

CHEMICAL SYNTHESIS METHODS

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 schcmes may be modifted by 15 choice of suitable starting materials and reagents in order to access other compounds of Formula (l)-(VI).

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	grains
eq	équivalents
mmol	millimoles
mL	milliliters
EtOAc	ethyl acetate
MHz	mégahertz
ppm	parts per million
δ	chcmical shift
s	singlet
d	doublet
t	triplet
q	quart et
quin	quintet
br	broad

m	multiplet
Hz	hertz
THF	tetrahydrofuran
°C	degrecs Celsius
PE	petroleum ether
EA	ethyl acetate
Rr	retardation factor
N	normal
J	coupling constant
DMSO-î/ô	deuterated dimethyl sulfoxide
n-BuOH	n-butanol
DIEA	n,n-diisopropylethylamine
TMSCl	trimethylsilyl chloride
min	minutes
hr	hours
Me	methyl
Et	ethyl
i-Pr	isopropyl
TLC	thin layer chromatography
M	molar
Compd#	compound number
MS	mass spectrum
m/z	mass-to-charge ratio
Ms	methanesulfonyl
FDPP	pentafluorophenyl diphenylphosphinate
Boc	tert-butyloxycarbonyl
TFA	trifluoroacetic acid
Tos	toluenesulfonyl
DMAP	4-(dimethylamino)pyridine
mM	micromolar
ATP	adenosine triphosphate

IC50	half maximal inhibitory concentration
U/mL	units of activity per milliliter
KHMDS	potassium bis(trimethylsilyl)amide
DlAD	diisopropyl azodicarboxylate
MeTHF	2-methyltctrahydrofuran
MOM	methoxymethyl
DCM	dicbloromethane
DMF	,V. N- dimethyl form am i d e
DPPA	diphenyl phosphoryl azide
DBU	l ,8-diazabicyclo[5,4.0]undec-7-ene
DIPEA	A,jV-diisopropylethylamine
SEM	[2-(Trimethylsilyl)ethoxy]methyl acetal
Hex	hexânes
Pd(dppf)Cl₂	[ l, l '-Bis(diphenylphosphino)ferrocene]dichloropalladium(n)
MeCN (ACN)	Acetonitrile
Pd₂(dba)₃	Tris(dibenzylideneacetone)dipalladium(0)
Hunig's Base	ïVJV-diisopropylcthylamine
TBAF	Tert butyl ammonium fluoride
PPh₃	Triphenyl phosphine
RT	Room Température
p-TSA	Para-Tolylsulfonic acid
t-BuOH	7er/-Butanol
Pd(amphos)Cl₂	Dichlorobis[di-tert-butyl(4dimethylaminophenyl)phosphine]palladium(II)
mCPBA	AFe/tz-Chloroperoxy benzoic acid
AcOH	Acetic Acid
DMAc	N, N- D î methyIformamide
BPD	4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl)-l,3,2-dioxaborolane
MTBE	Methy fe/7-Butyl Ether
NBS	N-bromosuccinimide

NIS	N-iodosuccinimide
T₃P	Propylphosphonic anhydride
HATLJ	1 -[Bis(dimethylamino)methylene]-1 H-l ,2,3-triazolo[4,5b]pyridinium 3-oxid hexafluorophosphate
Bipini	Bis(pinacolato)diboron

The proposed targets can be prepared via the conventional chemistry or following the general schemes as shown below which use a selected example for illustration:

General Scheme I

NBoc

I-7 Ex. ¹

General Scheme I is using Example 1 as an illustration. Compounds 1-1 and 1-2 are prepared via convcntional chemistry from commercially available materials. Under palladium catalyzed coupling condition A, compounds I-l and I-2 are convertcd to a product, I-3, which then reacted with iodine under condition B to generate I-4, de-Boc under condition C to generate I-5, and amide coupling with a variety of carboxylic acid I-6 under condition D to generate l-7. Under palladium-catalyzed Heck coupling condition E l-7 is macrocyclized to the final product, e.g., Ex. I.

General Scheme II

Ex. 13

General scheme II is using Example 13 as an illustration. Compound 11-1 and 11-2 are prepared via conventional chemistry from commercîally available materials. Under palladium catalyzed coupling condition F, compounds II-1 and II-2 are converted to a product, II-3, which 5 then de-Boc under condition G to generate II-4 and followed by amide coupling with a variety of carboxylic acid, e.g. Π-5 under condition H to generate II-6. Π-6 is dcprotected under condition I to provide II-7, which is converted to a boronic ester 11-8 under condition J. Under palladiumcatalyzed Suzuki coupling condition II-8 is macrocyclized to generate 11-9. After deprotection under condition L, 11-9 is converted to the final product, e.g., Ex. 13.

General Scheme III

The general scheme III is using Example 13 as an illustration. The boronic ester lll-l and 5 bromo-starting material III-3 are exchanged in comparison with Compound II-1 and II-2. Under palladium catalyzed coupling condition M, compounds III-1 and III-2 are converted to the same product as that in General Scheme II, II-3, which then de-Boc under condition G to generate II-4 and followed by amide coupling with a varîety of carboxylic acid, e.g. H-5 under condition H to generate II-6. 11-6 is deprotected under condition I to provide II-7, which is converted to a boronic 10 ester II-8 under condition J. Under palladium-catalyzcd Suzuki coupling condition II-8 is macrocyclized to generate II-9. After deprotection under condition L, Π-9 is converted to the final product, e.g., Ex. 13.

Préparation of tert-butyl N-[2-(2-bromo-4-fluoro-phenoxy) ethyl]-N-methyl-carbamate (I-2-l)

Mel/NaH rf - n ------” Jt A ¹DM F F^^Br 1-2-1

Step 1. To a solution of 2-bromo-4-fluoro-phenol (5.00 g, 26.2 tnmol, 1 eq) in DMF (120 mL) was added K2CO3 (10.8 g, 78.5 mmol, 3 eq) and tert-butyl N-(2-bromoethyl) carbamate (7.04 g, 31.4 mmol, 1.2 eq). The mixture was stirred at 80 °C for 2 hours. LCMS showed starting material was consumed completely and desired MS in main peak. The mixture was diluted with water (300 mL) and extracted with EtOAc (50 mL*4). The combined organic layer was dried over anhydrous Na?SO₄, filtered and the filtrate was concentrated in vacuum to give tert-butyl N-[2-(2-bromo-4-fluoro-phenoxy) ethyl] carbamate (9.45 g, crude) was obtained as light yellow oil. Ή NMR (400 MHz, CDCI3) δ = 7.30 (dd, J = 8.0, 3.2 Hz, 1 H), 6.94 - 7.02 (m, 1 H), 6.82 - 6.89 (m, 1 H), 5.07 (s, 1 H), 4.05 (t, J = 4.8 Hz, 2 H), 3.57 (q, J=10.4, 5.2 Hz, 2 H), 1.46 (s, 11 H).

Step 2. To a solution of tert-butyl N-[2-(2-bromo-4-fluoro-phenoxy)ethyl]carbamate (7.50 g, 22.4 mmol, 1 eq) in DMF (80 mL) was added NaH (1.35 g, 33.7 mmol, 60% purity, 1.5 eq) at 0 °C and stirred for 30 minutes. Then Mel (3.82 g, 26.9 mmol, 1.2 eq) was added to the mixture and stirred at 15 °C for 3 hours. The mixture was quenched by water ( 150 mL) and extracted with EtOAc (50 mL*4). The combined organic layer was dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated in vacuum to give 1-2-1 (7.80 g, 22.4 mmol, 99.8% yield) was obtained as yellow solid.

Préparation of tert-butyl N-[2-(2-bromo-4-fluoro-phenoxy) ethyl]-N-methyl-carbamate (L2-2) a O. „ Boc

I

Br

1-2-2

I-2-2 was préparée] following similar procedures as I-2-l using 2-bromo-phenol as starting material.

Préparation of tert-butyl N-[2-(4-bromo-2-methyl- pyrazol-3-yl)oxycthyl]-N-methylcarbamate (I-2-3)

I-2-3

I-2-3 was prepared first following similar procedures as I-2-1 using 2-methylpyrazol-3-ol as starting material. Then the bromo-group was introduced. To a solution of tert-butyl N-methylN-[2-(2-methylpyrazol-3-yl)oxyethyl]carbamate (2 g, 7.83 mmol, l eq) in ACN (20 mL) was added NBS (1.44 g, 8.07 mmol, l .03 eq). The mixture was stirred at 25 °C for 2 hr. On completion, the mixture was concentrated and the residue was purified by silica gel column chromatography to provide 1-2-3 (1.73 g, 5.18 mmol, 66.08% yield) as red oil. 'H NMR. (400 MHz, DMSO-ώΟ δ = 7.32 (s, IH), 4.24 (t, J= 5.6 Hz, 2H), 3.54 (s, 3H), 3.48 (t, J= 5.6 Hz, 2H), 2.81 (s, 3H), l .31 (d, J = 4.0 Hz, 9H).

Préparation of 5-ethyl-l-methyl-4-vinyl-pyrazole-3-carboxylic acid (I-6-l ) and 5-ethyl-215 methyl-4-vinyl-pyrazole-3-carboxylic acid ( I-6-2)

Step l. To a solution of ethyl 2, 4-dioxohexanoate (10.0 g, 58.1 mmol, l eq) in AcOH (65.7 g, l.09 mol, 18.8 eq) was added methyihydrazine (7.45 g, 64.7 mmol, 40% purity, l.l l eq) at 0 °C. The mixture was stirred at 15 °C for 5 hours and concentrated in vacuum. The residue was puritied by combi flash chromatography (120 g silica gel column, EtOAc in PE from 0% to 50%) to provide ethyl 5-ethyl-l-methyl-pyrazole-3-carboxylate (10.1 g, 55.5 mmol, 95.5% yield) as yellowoil. Ή NMR (400MHz, CDCb) 0 = 6.59 (s, l H), 4.39 (q, J= 14.4, 7.2 Hz, 2 H), 3.85 (s, 3 H), 2.62 (q, J= 14.4, 7.2 Hz, 2 H), 1.39 (t,7= 7.2 Hz, 3 H), 1.28 (t, J = 7.6 Hz, 3 H).

Ethyl 5-ethyl-2-methyl-pyrazole-3-carboxylate (1.33 g. 7.30 mmol, 12.6% yield) was obtained as colorless oil. ‘H NMR (400 MHz, CDCb) δ = 6.65 (s, 1 H), 4.34 (q, 7=7.2 Hz, 2 H), 4.18-4.11 (m, 4 H), 2.65 (q, J= 15.2, 7.6 Hz, 2 H), 1.38 (t,7=7.2 Hz, 3 H), 1.25 (t,7=7.6 Hz, 3 H).

Step 2. To a solution of ethyl 5-ethyl-1 -methyl-pyrazole-3-carboxylate ( 10.0 g, 54.9 mmol, 1 eq) in MeCN (200 mL) was added NBS (10.7 g, 60.4 mmol, 1.1 eq). The mixture was stirred at 1 5 °C for 3 hours. The mixture was dilutcd with water (200 mL) and extracted with EtOAc (50 mL*3). The combined organic layer was dried over anhydrous NaiSO-i, filtered and the filtrate was concentrated in vacuum to give crudc ethyl 4-bromo-5-ethyl-l-methyl-pyrazole-3carboxylate (13.4 g, 5 1.4 mmol, 93.8% yield) as yellow oil. 'il NMR (400 MHz, CDCb) δ = 4.41 (q,7=7.2 Hz, 2 H), 3.91 (s, 3 H), 2.78 - 2.64 (m, 2 H), 1.40 (t,7=7.2 Hz, 3 H), 1.18 (t, 7= 7.6 Hz, 3 H).

Step 3. To a solution of ethyl 4-bromo-5-ethyl-l-methyl-pyrazole-3-carboxylate (13.4 g, 51.5 mmol, 1 eq), potassium hydride; trifluoro (vinyl) boron (13.8 g, 103 mmol, 2 eq), CS2CO3 (50.3 g, 154 mmol, 3 eq), Pd(dppf)C12 (3.77 g, 5.15 mmol, 0.1 eq) in dioxane (200 mL) and H₂O (40 mL) was stirred at 80 °C under N₂ for 3 hours. The mixture was stirred at 80 °C for 16 hour and cooled to ambient température. The mixture was separated, and the organic layer was concentrated in vacuum. The residue was puritied by combi flash chromatography (120 g silica gel column, EtOAc in PE from 0% to 60%) to provide ethyl 5-ethyl- l-methyl-4-vinyl-pyrazole-3carboxylate (7.62 g, 36.6 mmol, 71.1% yield) as brown oil. 'H NMR (400 MHz, CDCb) δ = 7.05 (dd, 7= 14.0, 11.6 Hz, 1 H), 5.47 - 5.26 (m, 2 H), 4.42 (7 = 7.2 Hz, 2 H), 3.90 (s, 3 H), 2.83 - 2.69 (m, 2 H), 1.46 - 1.37 (m, 3 H), 1.27 - 1.17 (m, 3 H)

Step 4. To a solution of ethyl 5-ethyl-l-methyl-4-vinyl-pyrazole-3-carboxylate (1.00 g, 4.80 mmol, 1 eq) in THF (5 mL), MeOH (5 mL), H₂O (3 mL) was added LiOH.H₂O (604 mg, 14.4 mmol, 3 eq). The mixture was stirred at 15 °C for 5 hours. LCMS showed desired MS in main peak. The mixture was added 2 N HCl to just pH-5. The resuit solution was extracted with EtOAc (10 mL*4). The combined organic layer was dried over anhydrous Na₂SÛ4, filtered and the filtrate was concentrated in vacuum to give crude. The residue was puritied by Prep-HPLC (column: Phenomenex luna Cl8 l50*25mm* lOum; mobile phase: [water (0.225%FA)-ACN]; B%: 40%-79%, llmin). 5-ethyl-l-methyl-4-vinyl-pyrazole-3-carboxylic acid (746 mg, 4.14 mmol, 86.2% yield) was obtained as brown solid. 'H NMR (400 MHz, MeOD-i/4) δ = 7.03 (dd, J = 18.0, I I.6 Hz, l H), 5.44 (dd, 18.0, I.6 Hz, l H), 5.27 (dd, J= I I.8, 1.6 Hz, l H), 3.87 (s, 3

H), 2.84 (q, J= 7.6 Hz, 2 H) 1.23 (t, J=7.6 Hz, 3 H).

I-6-2 was prepared as white solid using ethyl 5-ethyl-2-methyl-pyrazole-3-carboxylate in step 2. 'H NMR (400 MHz, MeOD-r/₄) Ô = 7.07 (dd, J = 18.0, 11.6 Hz, l H), 5.44 (dd, J = 18.0, 1.6 Hz, l H), 5.30 (dd,J = H.6, 1.6 Hz, l H), 4.04 (s, 3 H), 2.74 (q, J=12 Hz, 2 H), 1.25 (t, J = 7.6 Hz, 3 H).

Préparation of l-methyl-4-vinyl-pyrazole-3-carboxylic acid (I-6-3)

I-6-3 was prepared as yellow solid following similar methods as Step 3 and Step 4 in I-6l préparation using methyl 4-bromo-l-methyl-pyrazole-3-carboxylate as starting material. 'H NMR (400 MHz, DMSO-dô) Ô = 12.79 - 12.48 (m, IH), 8.09 (s, IH), 7.02 (dd, J= H.2, 18.0 Hz, 15 lH), 5.54 (dd, J = 1.6, 18.0 Hz, IH), 5.13 (dd, J= 1.6, ll.2Hz, IH), 3.87 (s, 3H).

General Method A: Préparation of (l8£’)-l7-ethyl-7-fluoro-l3,l6-dimethyl-2,l2,l3,l6tetrahydro-3,5-ethenodipyrazolo[3,4_:/:3',4’“y][l,4]benzoxazacyclopentadecin-l4(l l//)-onc (Ex. I)

NBoc

HN-N

1-7-1

Step 1. To a mixture of 1-2-1 (4.00 g, 11.5 mmol, 1 eq) and 5-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-lH-indazole (3.37 g, 13.8 mmol, 1.2 eq) m dioxane (60 mL) and H₂O (12 mL) was added K3PO4 (7.32 g, 34.5 mmol, 3 eq), tritert-butylphosphonium;tetrafluoroborate (333 mg, 1.15 mmol, 0.1 eq), and Pd₂(dba)j (526 mg, 0.575 mmol, 0.05 eq). The resulting mixture was stirred at 120 °C under N₂ for 16 hours. The mixture was separated and the organic layer was dried over anhydrous Na₂SO4 and filtered. The filtrate was concentrated in vacuum and the residue was purified by Combi flash chromatography to provide 1-3-1 (2.44 g, 6.33 mmol, 55.1% yield) as brownoil. 'H NMR (400 MHz, CDCI3) δ = 8.12 (s, 1 H), 7.87 (s, 1 H), 7.60 - 7.47 (m, 2 H), 7.10 (d, J=8.8Hz, 1 H), 7.04- 6.97 (m, 1 H), 6.96 - 6.89 (m, 1 H), 5.03 (d, J = 21.2 Hz, 2 H), 3.49 (s, 2 H), 2.70 (d, J = 18 Hz, 2H), 1.41 (s, 9 H).

Step 2. To a solution of 1-3-1 (2.44 g, 6.33 mmol, 1 eq) in THF (40 mL) was added t-BuOK. (2.13 g, 18.9 mmol, 3 eq). The resulting mixture was stirred at 0 °C for 5 minutes followed by addition of I₂ (2.09 g, 8.23 mmol, 1.3 eq) in THF (5 mL) in dropwise method. The resulting mixture was stirred at 25 °C for another 2 hours and the mixture was filtered. The filtrate was concentrated in vacuum and the residue was purified by Combi flash to provide 1-4-1 ( 1.87 g, 3.66 mmol, 57.77% yield) as brown oil. 'H NMR (400 MHz, CDCI3) δ = 7.63 (s, 2 H), 7.52 (d, J= 8.8 Hz, 1 H), 7.12 (d, J = 7.2 Hz, 1 H), 7.07 - 6.99 (m, 1 H), 6.97 - 6.90 (m, 1 H), 4.07 (d, J = 22.8 Hz, 2 H), 3.51 (s, 2 H), 2.72 (d, J= 15.2 Hz, 3 H), 1.42 (s, 9 H).

Step 3. To a solution of 1-4-1 (1.00 g, 1.96 mmol, 1 eq) in dioxane (8 mL) was added HCl/dioxane (4 M, 8.77 mL, 17.9 eq). The mixture was stirred at 15 °C for 3 hours. The mixture was filtered and the solid was dried in vacuum to give I-5-I (890 mg, crude) as white solid. 41 NMR (400 MHz, MeOD-tA) Ô = 7.68 - 7.57 (m, 3 H), 7.25 - 7.06 (m, 3 H), 4.24-4.16 (m, 2 H), 3.35 - 3.33 (m, 2 H), 2.61 (s, 3 H).

Step 4. To a solution of I-5-l (417 mg, 0.932 mmol, l .05 eq, HCl sait) and I-6-l (160 mg, 0.888 mmol, l eq), DlEA (574 mg, 4.44 mmol, 5 eq) in DCM (8 mL) was added T3P (847 mg, I.33 mmol, 50% purity, l .5 eq) at 0 °C. The mixture was stirred at 15 °C for 2.5 hours, diluted with water (30 mL), and extracted with EtOAc (15 mL*3). The combined organic layers were dried over anhydrous Na?SO4, filtered and the filtrate was concentrated in vacuum. The residue was purified by combi flash (40 g silica gel column, EtOAc in PE from 0% to 100%) to provide I7-1 (147 mg, 0.256 mmol, 28.9% yield) as white solid. LCMS: m/z 574.4 (M+l ).

Step 5. To a solution of 1-7-1 (147 mg, 0.256 mmol, 1 eq) in DMF (28 mL) was added triso-tolylphosphane (7.80 mg, 0.0256 mmol, 0.1 eq), N-ethyl-N-isopropyl-propan-2-amine (66.3 mg, 0.513 mmol, 2 eq) and Pd(OAc)i (2.88 mg, 0.128 mmol, 0.05 eq). The resulting mixture was stirred at 120 °C for 12 hours. The mixture was concentrated in vacuum and the residue was purified by prep-HPLC (column: Phenomenex Luna C18 100*30mm*5um; mobile phase: [water (0.225%FA)-ACN]; B%: 38%-68%, 10min) to provide Ex. 1 (5.09 mg, 4.42% yield) as a white solid.

Ex. 2-5 were prepared following General Method A.

Préparation of 2-(5-bromo-1 -tetrahydropyran-2-yl-indazol-3-yl)ethynyl-triisopropylsilane (II-1-1)

Step 1. A solution of 5-bromo-1 H-indazole (21.0 g, 107 mmol, 1 eq ) in THF (250 mL) was cooled down on an ice bath and KOtBu (35.9 g, 320 mmol, 3 eq) was added portion wise. The resulting slurry was stirred at 0 °C and a solution of I2 (54.1 g, 213 mmol, 42.9 mL, 2 eq) in THF (250 mL) was added dropwise. The mixture was stirred at 25 °C for 12 hours. On completion, the reaction mixture was filtered and the filtrate was diluted with H₂O (20 mL) and extracted with EtOAc (20 mL * 3). The combined organic layers were washed with brine (20 mL*3), dried over Na₂SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to afford 5-bromo-3-iodo-l H-indazole (120 g, 350 mmol, 82% yield, 94% purity) as a white solid. LCMS: 324.7 (M+l).

Step 2. To a mixture of 5-bromo-3-iodo-l H-indazole (25.0 g, 77.4 mmol, l eq) and 3,4dihydro-2H-pyran (13.0 g, 155 mmol, 2 eq) in toluene (250 mL) was added 4methylbenzenesulfonic acid (2.67 g, 15.5 mmol, 0.2 eq). The mixture was stirred at 90 °C for 12 hours. On completion, the reaction was diluted with H₂O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to afford 5-bromo-3-iodol-tetrahydropyran-2-yl-indazole (24.0 g, 58.9 mmol, 76% yield) as a white solid. 'H NMR (400 MHz, CDCb) Ô = 7.64 (d, J = 1.6 Hz, IH), 7.54 - 7.44 (m, 2H), 5.68 (dd, 7= 3.2, 9.1 Hz, IH), 4.04 - 3.95 (m, IH), 3.79 - 3.66 (m, IH), 2.58 - 2.46 (m, IH), 2.20 - 2.03 (m, 2H), 1.87 - 1.54 (m, 3H).

Step 3. To a mixture of 5-bromo-3-iodo-l-tetrahydropyran-2-yl-indazole (23.0 g, 56.5 mmol, l eq) and ethynyl(triisopropyl)silane (l 1.3 g, 62.2 mmol, l.l eq) in DMF (250 mL) was added Cs₂CO₂ (55.2 g, 170 mmol, 3 eq), Pd(dppf)Cl₂ (2.48 g, 3.39 mmol, 0.06 eq) and Cul (646 mg, 3.39 mmol, 0.06 eq) under N₂. The mixture was stirred at 25 °C for 3 hours. On completion, the reaction was diluted with H₂O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to afford compound 2-(5-bromo-ltetrahydropyran-2-yl-indazol-3-yl)ethynyI-triisopropyl-silane (Il-l-l, 38.0 g, 79.9 mmol, 70% yield) as a white solid. ^lH NMR (400 MHz, CDCI3) δ = 7.87 (s, IH), 7.57 - 7.43 (m, 2H), 5.70 (dd,7=2.4,9.2 Hz, IH), 4.02 (bd, J= 11.2 Hz, IH), 3.80 - 3.65 (m, IH), 2.59-2.41 (m, 1H),2.14 (d, J= 3.2 Hz, IH), 2.08 (s, IH), 1.79 - 1.70 (m, 2H), 1.67 (s, IH), 1.22 - I.l8 (m, 18H), 1.18 I.l4 (m, 3H).

Préparation of tert-butyl N-methyl-N-[3-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2dîoxaborolan -2-yl)pyrazol-3-yl]oxyethyl]carbamate (11-2-1 )

Br

I-6-3

To a solution of tert-butyl N-[2-(4-bromo-2-methyl-pyrazol-3-yl)oxyethyl]-N-methylcarbamate (20. 0 g, 59. 8 mmol, 1 eq) in THF (200 mL) was added n-BuLi (2. 5 M, 23. 9 mL, 1 eq) at -78 °C, the mixture was stirred at this température for 30 mins followed by addition of 25 isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (22. 2 g, 119 mmol, 2 eq) dropwise at -78 °C. The mixture was stirred at -78 °C for 2 hr. On completion, the mixture was quenched with water (200 mL) and extracted with ethyl acetate (250 mL x 3). The combincd organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a rcsidue. The residue was purifîed by column chromatography to give II-2-1 (21.2 g, 55.6 mmol, 92% yield) as a yellow oil. LCMS: m/z 381.9 (M+l).

Préparation of tert-butyl N-[3-[2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan -2yl)pyrazol-3-yl]oxyethyl]carbamate (11-2-2)

11-2-2

11-2-2 was prepared following similar methods as II-2-1.

Préparation of tert-butyl N-methyl-N- [4-[2-methyl-4- (4,4,5,5- tetramethyl-1,3,2dioxaborolan-2-yl)pyrazol-3-yl]oxybutyl]carbamate (11-2-3)

11-2-3

Π-2-3 was préparée! following similar methods as II-2-l.

Préparation of tert-butyl N-methyl-N- [4-[2-methyl-4- (4,4,5,5- tetramethyl-1,3,2dioxaborolan-2-yl)pyrazol-3-yl]oxypropyl]carbamate (11-2-4)

II-2-4 was prepared following similar methods as II-2-1.

Préparation of Tert-butyl N-methyl-N-[2-[2-[2-methyl-4-(4,4,5,5-tetramethyl-l ,3,2dioxaborolan-2-yl)pyrazol-3-yl]oxyethoxy]ethyl]carbamate (II-2-5)

11-2-5 was prepared following similar methods as 11-2-1.

Préparation of 5-ethyl-4-iodo-2-methyl-pyrazole-3-carboxylic acid (11-5-1)

OH

To a solution of 5-ethyl-2-methyl-pyrazole-3-carboxylic acid ( 1 g, 6.49 mmol, 1 cq) in AcOH ( 10 mL) was added NIS ( 1.75 g, 7.78 mmol, 1.2 eq). The mixture was stirred at 90 °C for 2 hours. Additional NIS (291.87 mg, 1.30 mmol, 0.2 eq) was added to the mixture and the resuit mixture was stirred at 90 °C for 12 hours. The réaction mixture was quenched by addition sat.aq. Na₂SO3 (20 mL) at 0 °C, and then diluted with H₂O (10 mL), K₂CO3 (20 mg) was added to the mixture, then adjust pH=5 with HCI (2 N) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtcred and concentrated under rcduced pressure to give a residue, which was trîturated with Petroleum ether : Ethyl acetate= 10:1 to provide II-5-l (705 mg, 2.41 mmol, 37% yieid) as a light yellow solid. LCMS: m/z 280.9 (M+l ).

Préparation of 5-ethyl-4-iodo-l-methyl-pyrazole-3-carboxylic acid (II-5-2), 5-methyl-4iodo-2-methyl-pyrazole-3-carboxylic acid ( II-5-3 ), 5-methyl-4-iodo-l -methyl-pyrazole-3carboxylic acid (H-5-4), and 2-ethyl-4-iodo-5-methyl-pyrazole-3-carboxylic acid (Π-5-5)

II-5-3

Π-5-2, II-5-3, II-5-4 and H-5-5 were prepared following similar methods as II-5-l using the corresponding pyrazole-3-carboxylic acid as starting materials.

Préparation of l-(2-ethoxy-2-oxo-ethyl)-4-iodo-5-methyl-pyrazole-3-carboxylic acid (II5-5) and 2-(2-ethoxy-2-oxo-cthyl)-4-iodo-5-methyl-pyrazole-3-carboxylic acid (II-5-5)

II-5-6

Step l. To a solution of 3-methyl-l H-pyrazole-5-carboxylic acid (10.0 g, 79.3 mmol, l.O eq) in DMSO (200 mL) was added NaHCO₃ (7.99 g, 95.2 mmol, 3.70 mL, 1.2 eq). The mixture was stirred at 20 °C for 0.5 hr followed by addition of bromomethylbenzene (13.6 g, 79.3 mmol, l .0 eq) was added. The mixture was stirred at 20 °C for 4 hr, quenched with water ( 100 mL), and extracted with ethyl acetate (250 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography to give benzyl 3-methyl-l H-pyrazole-5-carboxylate (3.20 g, 14.1 mmol, 17.7% yield, 95% purity) as a white solid. LCMS: m/z (M+l ).

Step 2. To a solution of benzyl 3-methyl-lH-pyrazole-5-carboxylate (3.00 g, 13.9 mmol, l.O eq) in DMF (30 mL) were added K2CO3 (5.75 g, 41.6 mmol, 3.0 eq) and ethyl 2-bromoacetate (3.48 g, 20.8 mmol, l .5 eq). The mixture was stirred at 25 °C for 16 hr, quenched with water (200 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography to give benzyl 2-(2-ethoxy-2-oxo-ethyl)-5-methyl-pyrazole-3-carboxylate (850 mg, 2.8l mmol, 20.3% yield) as a colorless oil from the first fraction. 'H NMR (400 MHz, CDCI3) Ô = 7.38 - 7.35 (m, 4H), 7.34 - 7.33 (m, IH), 6.70 (s, IH), 5.26 (s, 2H), 5.22 (s, 2H), 4.22 - 4.21 (m, 2H), 2.26 (s, 3H), 1.23- l.l9(m,3H).

The second fraction provided benzyl l-(2-ethoxy-2-oxoethyl)-5-methyl-lH-pyrazole-3carboxylate (2.52 g, 8.34 mmol, 60.1% yield) as a white solid. ‘H NMR (400 MHz, CDCI3) δ = 7.44 (d, 7=6.4 Hz, 2H), 7.39 - 7.30 (m, 3H), 6.63 (s, IH), 5.37 (s, 2H), 4.93 (s, 2H), 4.23 (q, J = 7.2 Hz, 2H), 2.27 (s, 3H), 1.27 (t, J = 12 Hz, 3H).

Step 3. To a solution of benzyl l-(2-ethoxy-2-oxoethyl)-5-methyl-1 H-pyrazole-3carboxylate (2.50 g, 8.27 mmol, 1.0 eq) in MeOH (40 mL) was added Pd/C (300 mg, 0.331 mmol, 10% purity, 1.0 eq) under N₂. The suspension was degassed under vacuum and purged with H₂several times. The mixture was stirred under H₂ (15 psi) at 20 °C for 16 hr. The reaction mixture was filtered and the filtrate was concentrated to give l-(2-ethoxy-2-oxoethyl)-5-methyl-lHpyrazole-3-carboxylic acid (1.9 g, crude) as a colorless oil. 'H NMR (400 MHz, DMSO-d<,) δ = 6.49 (s, IH), 5.10 (s, 2H), 4.17 (q, J= 7.2 Hz, 2H), 2.22 (s, 3H), 1.21 (t, 7=7.2 Hz, 3H).

Step 4. To a solution of I -(2-ethoxy-2-oxo-cthyl)-5-methyl-pyrazole-3-carboxylic acid (1.42 g, 6.69 mmol, l.O eq) in ACN (20 mL) was added NIS ( l .66 g, 7.36 mmol, l.l eq). The mixture was stirred at 60 °C for 16 hr. The mixture was dried over anhydrous sodium sulfate, flltered, and concentrated. The residue was purified by column chromatography to give l-(25 ethoxy-2-oxo-ethyl)-4-iodo-5-methyl-pyrazole-3-carboxylic acid (II-5-5, l .6 g, 4.26 mmol, 63.7% yield) as a yellow solid. 'H NMR (400 MHz, DMSO-dQ δ = 12.79 - 9.38 (m, IH), 5.23 (s, 2H), 4.17 (q, 7=7.2 Hz, 2H), 4.03 (q, J= 7.2 Hz, 2H), 2.26 (s, 3H), l.l7 (t,7=7.2 Hz, 3H)

II-5-6 was prepared from benzyl 2-(2-ethoxy-2-oxo-ethyl)-5-methyl-pyrazole-3carboxylate from Step 2 following Step 3 and 4 as H-5-5.

General Method B: Préparation of (l7£)-l6-ethyl-8,l2,l4-trimethyl-2,ll,l2,l4tetrahydro-8//-3,5-ethenotripyrazolo[3,47/:3',4^,-7:4,3-n][l,4]oxazacyclopentadeciii-l3( 10//)one (Ex. 6)

/ Br N'\ 11 c i A B \ // ₊ O I N~ N THP^{Z Z}\ ^X H-1-1 ||-2 n-n Kf-O H ZnBr₂/CH₂CI₂ J. ^_s>^TIPS \ Il N—N THP^Z 11-4-1

N-N O Boc > Pd(dppf)CI₂ I \ Cs₂CO₃ /% N— dioxane \ .1 ^^-TIPS r-, / ----------------------*- Boc A // _zN-N THP' -1 11-3-1 n-7 Y . ,^0H , O-o-⁷ KJ A / DIPEA T O II Cr\-~N L * F N ^T3P'CH₂CI₂ /¼. I L A <i=^^TIPS / Y il N—N THP^Z 11-5-1 11-6-1

11-7-1

Cu₂O/ PPh₃

B₂pin₂, dioxane

11-8-1

Step l. A mixture of 2-(5-bromo-l-tetrahydropyran-2-yl-indazol-3-yl)ethynyltriisopropyl-silane (11-1-1, 5.00 g, 10.83 mmol, I eq), Ze/7-butyl N-methyl-N-[2-[2-methyl-4(4,4,5,5-tetramcthyl-l,3,2-dioxaborolan-2-yl)pyrazol-3-yl]oxyethyl]carbamate (II-2-1, 4.96 g, 13.00 mmol, 1.2 eq), Pd(dppf)Cl₂ (1.59 g, 2.17 mmol, 0.2 eq), CS2CO3 (2 M, 16.25 mL, 3 eq) in dioxane (50 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 80 °C for 5 hours under N₂ atmosphère. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H2O (50mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography to provide II-3-1 (5.00 g, 7.86 mmol, 72.6% yield) as a yellow oil. 'H NMR (400 MHz, CDCI3) δ = 7.82 (s, 1 H), 7.65 - 7.55 (m, 3H), 5.72 (dd, J = 2.8, 9.2 Hz, IH), 4.00 (s, 2H), 3.76 (s, 3H), 3.56 - 3.47 (m, 2H), 2.99 - 2.93 (m, 3H), 2.62 - 2.48 (m, IH), 2.16 (dd, J= 3.6, 8.4 Hz, IH), 1.83 - 1.59 (m,5H), 1.47 (s,3H), 1.41 - 1.31 (m, 6H), 1.21 -1.18 (m, 21H).

Step 2. To a solution of 11-3-1 (I g, 1.57 mmol, 1 eq) in CH₂C1₂ (10 mL) was added ZnBr? ( 1.77 g, 7.86 mmol, 5 eq). The mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography to give II-4-1 (800 mg, 1.49 mmol, 95.0% yield) as a yellow solid. LCMS: m/z 536.1 (M+l).

Step 3. To a solution of Il-4-l (1.5 g, 2.80 mmol, l eq) and 5-ethyl-4-iodo-2-inethylpyrazole-3-carboxylic acid (Π-5-1, 705 mg, 2.52 mmol, 0.9 eq) in CH₂Cl₂ (30 mL) were added DIPEA (2.89 g, 22.4 mmol, 8 eq) and T3P (3.56 g, 5.60 mmol, 50% purity, 2 eq). The mixture was stirred at 40 °C for I2 hours. The reaction mixture was partitioncd between H?O (50 mL) and CH2CI2 (30 mL). The organic phase was separated, washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography to give Π-6-1 (Ll5 g, 1.37 mmol, 49.0% yield, 95. l% purity) as a yellow gum.

LCMS: EC5257-79-PIE (M+l : 798.4).

Step 4. To a solution of Il-6-l (I.l5 g, 1.44 mmol, l eq) in DMSO (12 mL) was added CsF (438 mg, 2.88 mmol, 2 eq). The mixture was stirred at 40 °C for 12 hours. The reaction mixture was partitioned between H₂O (10 mL) and EtOAc (I0 mL). The organic phase was separated, washed with brine ( 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography to give Π-7-1 (650 mg, LOI mmol, 70.3% yield) as a yellow oil. ^JH NMR (400 MHz, DMSO-<7₆) δ = 7.87 - 7.43 (m, 4H), 5.93 - 5.85 (m, IH), 4.55 (d, J= 7.6 Hz, IH), 4.22 - 4.09 (m, IH), 3.94 - 3.61 (m, 8H), 3.58 - 3.46 (m, 2H), 3.16 - 3.00 (m, 3H), 2.56 - 2.52 (m, 3H), 2,40 - 2.28 (m, l H), 2.09 - 1.95 (m, 2H), L81 - 1.68 (m, IH), L65 - 1.55 (m, 2H), 1.20- Ll3(m, 3H).

Step 5. A mixture of II-7-I (650 mg, LOI mmol, l eq), Pin₂B₂ (257 mg, LOI mmol, l eq), PPI13 (266 mg, l .01 mmol, l eq) and Cu₂O (72.5 mg, 0.507 mmol, 0.5 eq) in dioxane ( 12 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 100 °C for 12 hours under N₂ atmosphère. The reaction mixture was partitioned between H₂O (30 mL) and EtOAc (30 mL). The organic phase was separated, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography to give II-8-l (750 mg, 0.974 mmol, 96.2% yield) as a yellow solid. LCMS: m/z 770.4 (M+l).

Step 6. A mixture of Π-8-1 (700 mg, 0.91 mmol, l eq), CS2CO3 (889 mg, 2.73 mmol, 3 eq) and Pd(dppf)CI₂ (66.6 mg, 0.91 mmol, O.l eq) in dioxane (12 mL) and H₂O (I.2 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 90 °C for 12 hours under N₂atmosphère. The reaction mixture was partitioned between H₂O ( 10 mL) and EtOAc ( 10 mL). The organic phase was separated, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography to give II-9-l (140 mg, 0.271 mmol, 29.7% yield) as a yellow oil. LCMS: m/z 516.3 (M+l).

Step 7. To a solution of Il-9-l (140 mg, 0.271 mmol, l eq) in CH₂CI₂ (2 mL) was added TFA ( l mL). The mixture was stirred at 15 °C for I hour. The reaction mixture was concentrated under reduced pressure. The residue was diluted with NaHCCh ( 10 mL) and extracted with CH2CI2 (5 mL x 2). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography to provide Ex. 6 (56.9 mg, 0.130 mmol, 48.0% yield) as an off-white solid.

Ex. 6-14 were prepared following General Method B.

Préparation of triisopropyl-[2-[ l-tetrahydropyran-2-yl-5-(4,4,5,5-tetramcthyl-1,3,2dioxaborolan-2-yl)indazol-3-yl]ethynyl]silane (III-1-1)

111-1-1

To 2-(5-bromo-l-tetrahydropyran-2-yl-indazol-3-yl)ethynyl-triisopropyl-silane (2 g, 4.33 mmol) in solvent, 1,4-Dioxane (20.86 mL), was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyll,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane(1.43 g, 5.63 mmol) and Potassium Acetate(L28 g, 13.00 mmol). The mixture was stirred as argon was bubbled through for 5 minutes, followed by addition of catalyst, Pd(dppf)CI₂ (158.55 mg, 216.68 pmol). The vessel sealed and heat to 85 °C for 18 hr. The reaction was diluted with DCM and water (80 mL) and the layers were separated. The aqueous layer was extracted again with DCM (2 x 40 mL). The combined organic layer was washed with brine and dried over sodium sulfate. Flash column chromatography provided triisopropyl-[2-[ 1 -tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)indazol-3-yl]ethynyl]silane (1.87 g, 3.68 mmol, 84.85% yield). LCMS: [M+H]⁺ m/z = 509.28

Préparation of tert-butyl N-[2-[(4-bromo-2-mcthyl-pyrazol-3-yl)methyl-methylamino]ethyl]-N-methyl-carbamate (111-2-1 )

NBS

DMF

AcOH/ NaBH₃CN EtOH

Br (CH₂O)n/ NaBH₃CN

AcOH/MeOH

Br

111-2-1

Step 1. To a solution of 2-methylpyrazole-3-carbaldehyde (1 g, 9.08 mmol, 1 eq) in DMF (15 mL) was added NBS (1.78 g, 9.99 mmol, 1.1 eq). The reaction was stirred at 25 °C for 12 hours. The residue was diluted with H₂O (50 mL) and extracted with EtOAc (50 mL * 3). The combined organic layers were washed with brine (30 mL * 2), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to give 4-bromo-2-methyl-pyrazole-3-carbaldehyde (1.3 g, 6.88 mmol, 75.7% yield) as white solid. 'H NMR (400 MHz, DMSO-d₆) δ = 9.84 (s, III), 7.77 (s, III), 4.08 (s, 311).

Step 2. To a solution of 4-bromo-2-methyl-pyrazole-3-carbaldehyde (5 g, 26.45 mmol, 1 eq) in EtOH (100 mL) was added AcOH (159 mg, 2.65 mmol, 0.1 eq) and tert-butyl N-(2aminoethy!)-N-methyl-carbamate (5.53 g, 31.7 mmol, 1.2 eq). The reaction was stirred at 80 °C for 12 hours. And then NaBHaCN (4.99 g, 79.4 mmol, 3 eq) was added into the mixture and stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by reversed-phase HPLC to give tert-butyl N-[2-[(4-bromo-2-methyl-pyrazol-3yl)methylamino]ethyl]-N-methyl-carbamate (5 g, 14.4 mmol, 54.4% yield) as yellow gum. 'H NMR (400 MHz, DMSO-îZ₆) δ = 7.43 (s, 1 H), 3.84 (s, 3H), 3.75 (s, 2H), 3.19 (s, 2H), 2.75 (s, 3H), 2.57 (t, .7= 6.4 Hz, 2H), 1.43 - 1.30 (m, 9H).

Step 3. To a solution of tert-butyl N-[2-[(4-bromo-2-methyl-pyrazol-3yl)methylamino]ethyl]-N-methyl-carbamate (5 g, 14.4 mmol, 1 eq) in MeOH (50 mL) was added HCHO (2.34 g, 28.8 mmol, 37%purity, 2 eq), AcOH (86.5 mg, 1.44 mmol, 0.1 eq) and NaBHîCN (2.71 g, 43.2 mmol, 3 eq). The reaction was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure. The crude product was purified by reversed-phase HPLC to give tert-butyl N-[2-[(4-bromo-2-methyl-pyrazol-3-yl)methyl-methyl-amino]ethyl]-N-methylcarbamate (3.2 g, 8.86 mmol, 61.5% yield) as a yellow gum. ‘H NMR (400 MHz, DMSO-r/ô) δ = 7.46 (s, IH), 3.80 (s, 3H), 3.52 (s, 2H), 3.29 - 3.13 (m, 2H), 2.76 - 2.55 (m, 3H), 2.40 (d, J = 5.6 Hz, 2H), 2.29 - 2.07 (m, 3H), 1.42 - 1.26 (m, 9H).

General Method C: Préparation of ( 18E)-8,10,13,15,17-pentamethyl-2,8,9,10,11,12,13,1588 octahydro-14//-3,5-ethenotripyrazolo[3,4-/:3',4'-y:4,3-/z][l ,4]diazacyclohexadecin-14-one (Ex.

15)

Pd(dppf)CI₂/ Cs₂CO₃ dioxane/H₂O

Ex. 15

Step 1. A mixture of III-l-l (700 mg, 1.38 mmol, 1.1 eq), 111-2-1 (452 mg, 1.25 mmol, 1 eq), ditert-butyl(cyclopentyl)phosphane;dichloropalladium;iron (81.6 mg, 0.125 mmol, 0.1 eq), CS2CO3 (1.22 g, 3.75 mmol, 3 eq) in dioxane (10 mL) and H₂O (2 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 80 °C for 2 hours under N₂ atmosphère.

The réaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel chromatography to give tert-butyl N-methyl-N-[2-[rnethyl-[[2-methyl4-[ l -tctrahydropyran-2-yl-3-(2-triisopropylsilylcthynyl)indazol-5-yl]pyrazol-3yl]methyl]amino]ethyi]carbamate (182 mg. 0.239 mmol, I9.l% yield) as a yellow solid. LCMS: m/z 663.6 (MH) tcrt-Butyl N-mcthyl-N-[2-[methyl-[[2-methyl-4-[ l-tetrahydropyran-2-yl-3-(2triisopropylsilylcthynyl)indazol-5-yl]pyrazol-3-yl]mcthyl]amino]cthyl]carbamate was converted to Ex. 15 using similar methods as Step 2-Step 6 in General Method B.

General Method D: Préparation of (!7£j-l4-(2-hydroxycthyl)-8,l2,16-trimethyl2,l l,l2,l4-tetrahydro-8//-3,5-cthenotripyrazolo[3,4;/:3',4'-y:4,3-n][l,4]oxazacyclopentadecinl3(l0//)-one(Ex. 16)

Step l. D-l was prepared following General Method B. To a solution of D-l (30.8 mg, 0.536 mmol, l eq) in MeOH (2 mL) was added NaBH₄ (40.5 mg, l .07 mmol, 20 eq) at 0 °C. The mixture was stirred at 0 °C for 3 hr. On completion, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give D-2 (400 mg, crude) as a white solid. LCMS: m/z 532.2 (M+l).

Step 2. To a solution of D-2 (28.0 mg, 0.526 mmol, l eq) in DCM (l mL) was added TFA (1.54 g, 13.5 mmol, 256 eq). The mixture was stirred at 25 °C for l hr. On completion, the mixture was concentrated. The crude product was purified by prep HPLC to give Ex. 16 (4.49 mg, 0.100 mmol, 19% yield) as a white solid.

Ex. 17 was prepared following General Method D.

General Method E: Préparation of (l7E)-8,l2,l6-trimethyl-l4-[2-(pyrrolidin-l-yl)ethyl]2,11,12,14-tetrahydro-8//-3,5-ethenotripyrazolo[3,4;/:3',4'-y:4,3-n][ l ,4]oxazacyclopentadecin!3(l0H)-one(Ex. 18)

E-2

Ex. 18

Step 1. To a solution of D-2 (50.0 mg, 0.094 mmol, 1 eq) in DCM (2 mL) was added EtaN (47.5 mg, 0.470 mmol, 5 eq) and then MsCl (64.6 mg, 0.564 mmol, 6 eq) was added dropwise at 5 0 °C. The mixture was stirred at 0 °C for 2 hr. On completion, the mixture was quenched with water (20 mL) and extracted with DCM (25 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give E-l (57.0 mg, 0.0934 mmol, 99% yield) as a yellow oil.

Step 2. To a solution of E-l (57.0 mg, 0.0934 mmol, 1 eq) and pyrrolidine (9.97 mg, 0.140 10 mmol, 1.5 eq) in DMF (2 mL) was added K2CO3 (38.7 mg, 0.280 mmol, 3 eq). The mixture was stirred at 80 °C for 12 hr. On completion, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give E-2 (54.0 mg, 0.0923 mmol, 98% yield) as yellow oil. LCMS: m/z 585.3 (M+l).

Step 3. To a solution of E-2 (50.0 mg, 0.0855 mmol, 1 eq) in DCM ( 1 mL) was added TFA ( 1.54 g, 13.5 mmol, 157 eq). The mixture was stirred at 25 °C for 2 hr. On completion, the mixture was filtered and concentrated. The crude product was purified by prep HP LC to give Ex. 18 (4.54 mg, 0.009 mmol, 10% yield) as a yellow solid.

|0003] Ex. I9 was prepared following General Method E.

[0004] Préparation of 5-ethoxy-4-iodo-2-methyl-pyrazole-3-carboxylic acid (l-22):

NIS

AON ----►

Step l. To a solution of methyl 5-hydroxy-2-methyl-pyrazole-3-carboxylate (800 mg, 5.12 mmol, l eq) in DMF (10 mL) was added K.2CO3 (2.12 g. 15.4 mmol, 3 eq) and Et! (799 mg, 5.12 mmol, l eq), then the mixture was stirred at 80 °C for 2 h. On completion, the reaction mixture was diluted with H₂O (30 mL) and extracted with EA (10 mL x 3). The combined organic layers were washed with Brine ( 10 mL x 2), dried over Na₂SO₄, filtered and concentrated under reduced pressure to givc a residue. The residue was purificd by flash silica gel chromatography ( [SCO®; 12 g SepaFlash® Silica Flash Coiumn, Eluent of 0 -30% THF/Petroleum ether gradient @ 30 mL/min) to give methyl 5-ethoxy-2-methyl-pyrazole-3-carboxylate (780 mg, 4.23 mmol, 82.65% yield) as a yellow oil.

Step 2. To a solution of methyl 5-ethoxy-2-methyl-pyrazole-3-carboxylate (750 mg, 4.07 mmol, l eq) in ACN (10 mL) was added NIS ( 1.83 g, 8.14 mmol, 2 eq) at 0 °C, then the mixture was stirred at 60 °C for 12 h. On completion, the reaction mixture was quenched by addition saturated Na₂SO3 (20 mL) at 25 °C, and then diluted with FbO (10 mL) and extracted with EA (10 mL x 3). The combined organic layers were washed with Brine (10 mL x 2), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give methyl 5-ethoxy-4-iodo-2-methylpyrazole-3-carboxylate ( l .53 g, crude) as a yellow solid.

Step 3. To a solution of methyl 5-ethoxy-4-iodo-2-methyl-pyrazole-3-carboxylate (1.5 g, 4.84 mmol, l eq) in MeOH (3 mL), THF (6 mL) and H₂O (3 mL) was added LiOH H₂O (609 mg, 14.5 mmol, 3 eq), then the mixture was stirred at 25 °C for 2 h. On completion, the pH was adjusted to 4 with l M HCl. The precipitate was collected by filtration. The precipitate was triturated in H₂O and collected by filtration to give 5-ethoxy-4-iodo-2-methyLpyrazole-3-carboxylic acid ( l .00 g, 3.38 mmol, 70% yield) as a yellow solid.

Ex. 22 was prepared following General Method B using the I-22 in step 3.

Préparation of ZerZ-butyl ^-((25)-2-(4-(3-ethynyl-l-tetrahydropyran-2-yl-indazol-5-yl)-2methyl-pyrazol-3-yl]oxypropyl]-N-methyl-carbamate (I-23):

NaH, Mel DMF

Step I. To 2-methyl-4-[l-tetrahydropyran-2-yl-3-(2-triisopropylsilylethynyl)indazol-5yl]pyrazol-3-ol (3 g, 6.27 mmol) in DMF (31.33 mL) was added potassium carbonate (2.60 g, 18.80 mmol) followed by ie/7-butyl (57?)-5-methyl-2,2-dioxo-oxathiazolidîne-3-carboxylate (1.78 g, 7.52 mmol). The mixture was stirred at 80 °C for 18 h, diluted with DCM (50 mL) and coolcd. The mixture was then fîltered through a celite pad and the filtrate was concentrated. The remaining residue was worked up with DCM and water (50 mL) and the layers were séparaied. The aqueous laycr was extracted again with DCM (2 x 25 mL). The combined organic layer was washed with brine and dried over sodium sulfate. Flash column chromatography (automated System, 40g silica, 0-70% EA in Hexanes) provided iert-butyl A^r-[(2y)-2-[2-methyl-4-[l-tetrahydropyran2-yl-3-(2-triisopropylsilylethynyl)indazol-5-yl]pyrazol-3-yl]oxypropyl]carbamate (2.72 g, 4.28 mmol, 68.25% yield).

Step 2. To terAbutyl jV-[(25)-2-[2-methyl-4-[l-tetrahydropyran-2-yl-3-(2triisopropylsilylethynyl)indazol-5-yl]pyrazol-3-yl]oxypropyl]carbamate (2.2 g, 3.46 mmol) in anhydrous DMF ( 17 mL) was added Sodium hydride ( 145.29 mg, 3.63 mmol, 60% purity) at 0 “C. The mixture was stirred for l h and Methyl lodide (540.2 mg, 3.81 mmol, 237 pL) was added. The reaction was stirred as température increased to ambient, and the mixture was allowed to stir ovemight. The reaction was then quenched with saturated ammonium chloride (aq) carefully (~lmL) at 0 °C. The mixture was worked up with DCM and water (10 mL). The aqueous layer was extracted with DCM (2x 5 mL) and the combined organic layer was washed with brine and dried over sodium sulfate. Flash column chromatography (automated System, 12g silica, ΟΙ 00% E A in Hexanes) provided ier/-butyl 7V-[(2S)-2-[4-(3-ethynyl-l-tetrahydropyran-2-yl indazol-5-yl)-2-methyl-pyrazol-3-yl]oxypropyl]-N-methyl-carbamate (456 mg, 0.924 mmol, 26.70% yield).

Ex. 23 was prepared following General Method B using I-23 in Step 2.

Préparation of 5-biOmo-4-iodo-2-methyl-pyrazole-3-carboxylic acid (I-24):

Step l. To methyl 5-bromo-2-methyl-pyrazole-3-carboxylate (200 mg, 0.913 mmol) in acetonitrile (4 mL) was added NIS (616 mg, 2.7 mmol), and the mixture was stirred at 85 °C for 18 h. The reaction was then quenched with water (4 mL), diluted with DCM and water (10 mL) and the layers were separated. The aqueous layer was extracted again with DCM (2x5 mL). The combined organic layer was washed with brine and dried over sodium sulfate. Flash column chromatography (automated System, 12g silica, 0-40% EA in Hexanes) provided methyl 5bromo-4-iodo-2-methyl-pyrazole-3-carboxylate (23 l mg, 0.670 mmol, 73.34% yield).

Step 2. To methyl 5-bromo-4-iodo-2-methyl-pyrazole-3-carboxylate (231 mg, 0.670 mmol) in THF (2 mL) was added LiOH (2 M, 0.4 mL, aq), and the mixture was stirred at 22 °C for 4 h. The reaction was then cooled in -20 °C freezer, diluted with DCM (5 mL), and 2M HCl (aq., 0.5 mL) was added with vigorous stirring. The reaction was then diluted with DCM and water (20 mL) 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. The solids were filtered and washed with DCM to afford 5-bromo-4-iodo-2-methyl-pyrazole-3-carboxylic acid (223 mg, 0.674 mmol, 100% yield).

General Method F: Préparation of (17£')-8,12,14-trimethyl-13-oxo-2,10,ll,12,13,14hexahydro-8//-3,5-ethenotripyrazolo[3,4-f:3',4'-7:4,3-/i][l,4]oxazacyclopentadecine-16carbonitrile (Ex. 24)

/ N-N Γ'ν''’ \zJo -ïk ¹

TFA _r γ ⁰ ?r^N

DCM JC N ί Λ ^CN

HN-N

ΙΟ

Step 1. 5-bromo-l-tetrahydropyran-2-yl-3-viny[-indazole (10.08 g, 32.81 mmol), 2methylpyrazol-3-ol (4.18 g, 42.66 mmol) and Potassium Carbonate, anhydrous powder 325 mesh ( 11.34 g, 82.04 mmol) were added into a vial with dioxane (82.04 mL), Argon stream was bubbled for 15 minutes. ί-BuBrettPhos Pd G3 (1.12 g, 1.31 mmol) was added under Argon. The vial was sealed and stirred at 100 °C. Water (800 mL) was added to the reaction mixture, followed by 20% K.2CO3 aq. solution (150 mL) to adjust the pH to 9—10, followed by extraction with ether (100 mL x 2). The combined ether layers were washed with 20 mL 20% K.2CO3 aq. solution. The aqueous layer was cooled in an ice bath and acidified with NaHSCL to pH-6 and was extracted with 10% MeOH/DCM (200 mL x 6). The combined organic layers were washed with water and brine, dried over Na₂SO4. The solvents were retnoved in vacuo and the residue was dissolved in DCM (50 mL), added 15 w/w% activated charcoal (0.825 g), 20w/w% trisamine resin ( LI g), and stirred for 3 hours. The suspension was then filtered through a celite cake, and the cake was washed with DCM (20 mL). The filtratc was cvaporated to fumish 2-methyl-4-( l-tetrahydropyran-2-yl-3-vinylindazol-5-yl)pyrazol-3-ol, which was carried over to the next step without further purification.

Step 2. To 2-methyl-4-(l-tetrahydropyran-2-yl-3-vinyl-indazol-5-yl)pyrazol-3-ol (250 mg, 0.771 mmol) in NMP (3.85 mL) was added base, potassium carbonate (320 mg, 2.3 mmol) followed by ier/-butyl A-(2-chloroethyl)-/V-methyl-carbamate (224 mg, 1.2 mmol) . Stirred at 90 °C for 2 hr. Reaction was coolcd and dilutcd with DCM (20 mL). Filtered through a microfilter and filtrate was worked up with DCM and water (25 mL) 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 twice (automated System, 12g silica, 0-50% EA in Hexanes) provided to7-butyl jV-methyl-/V-[2-[2methyl-4-( l -tetrahydropyran-2-yl-3-vinyl-indazol-5-yl)pyrazol-3-yl]oxyethyl]carbamate ( 198 mg, 0.411 mmol, 53.35% yield).

Step 3. To /evr-butyl A-methyl-A^f-[2-[2-methyl-4-( l-tetrahydropyran-2-yl-3-vinyl-indazol5-yl)pyrazol-3-yl]oxyethyl]carbamate (198 mg, 0.4H mmol) in DCM (2 mL) was added zinc bromide (370 mg, l .6 mmol), and the reaction was stirred at 22 °C for 2 days. The reaction was diluted with DCM and water (20 mL) 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, 12g silica, 020% Methanol in DCM) provided A^r-methyl-2-[2-methyl-4-(l-tetrahydropyran-2-yl-3-vinylindazol-5-yl)pyrazol-3-yl]oxy-ethanamine (63 mg, 0.165 mmol, 40.17% yield).

Step 4. To 5-bromo-4-iodo-2-methyl-pyrazole-3-carboxylic acid (66 mg, 198.2 pmol)inDCM (1 mL) was added jV-methyl-2-[2-methyl-4-(l-tetrahydropyran-2-yl-3-vinylindazol-5-yl)pyrazol-3-yl]oxy-ethanamine (63 mg, 0.165 mmol) and DIPEA (1.65 mmol, 288 pL), followed by T3P (0.330 mmol, 193 pL, 50% in EA). The mixture was stirred at 40 °C for 18 h. The reaction was then diluted with DCM and water (5 mL) and the layers were separated. The aqueous layer was extracted again with DCM (2x3 mL). The combined organic layer was washed with brine and dried over sodium sulfate. Flash column chromatography (automated System, 12g silica, 40-100%EA in Hexanes) provided5-bromo-4-iodo-A,2-dimethyl-7V-[2-[2methyl-4-( l-tetrahydropyran-2-yl-3-vinyl-indazol-5-yl)pyrazol-3-yl]oxyethyl]pyrazole-3carboxamide (75 mg, 0.108 mmol, 65.40% yield).

Step 5. To 5-bromo-4-iodo-/V,2-dimethyl-V-[2-[2-methyl-4-(l-tetrahydropyran-2-yl-3vinyl-indazol-5-yl)pyrazol-3-yl]oxyethyl]pyrazole-3-carboxamide (75 mg, 0.108 mmol) in anhydrous DMF (2 mL) was added sodium bicarbonate (28 mg, 0,324 mmol), and TBAC (33 mg, O.l 19 mmol). The mixture was stirred while Argon was bubbled through and catalyst, palladium acetate (3 mg, 0.011 mmol) was added. Argon was bubbled through for an additional 5 minutes. The vessel was then sealed, and the reaction was hcatcd to 140 °C for 1.5 h. The reaction was diluted with DCM and water (20 mL) 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 (automatcd System, 12g silica, 0!0%Methanol in DCM) providcd(l7£)-l6-bromo-8,l2,l4-trimethyl-2-(oxan-2-yl)-2,ll,l2,l4tetrahydro-8/7-3,5-ethenotripyrazolo[3,4_;/:3',4'-y:4,3-/?] [l,4]oxazacyclopentadecin-13(10/7)one (58 mg, 0.102 mmol, 94.80% yield).

Step 6. To (13£j-22-bromo-29,30,32-trimethyl-31-tetrahydropyran-2-yl-34-oxa26,27,28,29,30,31,32-heptazapentacyclohexacosa3,5(15),6(26),13,16,18(23),19(21),20(27),22(28)-nonaen-25-one (58 mg, 0.102 mmol) in DMA (1 mL) was added Zinc (13.5 mg, 0.205 mmol) and zinc cyanide (132 mg, 1.13 mmol), argon was bubbled through as dppf (34 mg, 0.061 mmol) was added followed by Pd(dba)? (18 mg, 0.030 mmol). The mixture was stirred under argon for about 5 minutes. The vessel was closed and heated to 120 °C and stirred for 18 h. The reaction was diluted with DCM and water (10 mL) and the layers were separated. The aqueous layer was extracted again with DCM (2x5 mL). The combined organic layer was washed with brine and dried over sodium sulfate. Flash column chromatography (automated System, 12g silica, 0-10% Methanol in DCM) provided (17£)8,12,14-trimethyl-2-(oxan-2-yl)-13-oxo-2,10,11,12,13,14-hexahydro-8/7-3,5ethenotripyrazolo[3,4-/:3',4'-y:4,3-n][l,4]oxazacyclopentadecine-16-carbonitrile (30 mg, 0.585 mmol, 57.16% yield).

Step 7. To (13£)-31,32,34-trimethyl-26-oxo-33-tetrahydropyran-2-yl-36-oxa28,29,30,31,32,33,34-heptazapentacyclohexacosa3,5(16),6(28),13,17,19(24),20(23),21(29),22(30)-nonaene-22-carbonitrile (30 mg, 0.585 mmol) in DCM (1 mL) was added TFA (6.53 mmol, 0.5 mL). The mixture was stirred at 22 °C for 2 h. The volatiles were removed under reduccd pressure, and 0.5 mL of Triethylamine added. Flash column chromatography (automated System, 12g silica, 0-10% MeOH in DCM) followed by trituration in DCM/Ethanol (0.2/2mL) provided (17£)-8,12,14-trimethyl-13-oxo2,10,11,12,13,14-hexahydro-8//-3,5-ethenotripyrazolo[3,4-f:3',4'-y:4,3«][l,4]oxazacyclopentadecine-16-carbonitrile (15 mg, 0.035 mmol, 59.33% yield, 99.18% purity) after filtration (Ex. 24).

Préparation of 3-ethyl-4-iodo-isoxazole-5-carboxylic acid:

NIS

MeCN

To 3-ethylisoxazole-5-carboxylic acid (296 mg, 2.10 mmol) in TFA (5 mL) was added NIS (566 mg, 2.5 mmol). The mixture was stirred at 70 °C for 30 min. The reaction was diluted with DCM and water (25 mL) and the layers were separated. The aqueous layer was extracted again with DCM (2 x I5 mL). The combined organic layer was washed with brine and dried over sodium sulfate. Flash column chromatography (automated System, 12g silica, 2060% EA in Hexanes) provided 3-ethyl-4-iodo-isoxazole-5-carboxylic acid ( 109 mg, 0.408 mmol, 19.46% yield).

Ex. 25 was prepared by General Method F using the above 3-ethyl-4-iodo-isoxazole-5carboxylic acid in Step 1, following Steps 1-5 and Step 7.

Préparation of 2-[2-[/erCbutyl(dimethyl)silyl]oxyethyl]-4-iodo-5-methyI-pyrazole-3carboxylic acid;

tbso^-\_qh

PPh₃, DIAD, THF

NIS AC N ---►

LiOH

MeOH, THF, H₂O

Step 1: To a solution of methyl 3-methyl-1 H-pyrazole-5-carboxylate (1.00 g, 7.14 mmol, 1 eq) and 2-[ier/-butyl(dimethyl)silyl]oxyethanol (2.52 g, 14.3 mmol, 2 eq) in THF (10 mL) was added PPI13 (4.12 g, 15.7 mmol, 2.2 eq), the mixture was degassed and purged with Nz for 3 times and stirred at 25 °C for 30 mins, and then DIAD (3.17 g, 15.7 mmol, 2.2 eq) was added dropwise at 0 °C. The mixture was stirred at 25 °C for 12 h under Nz atmosphère. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiOz, PE/THF=l:0 to 8:1) to give methyl 2-[2-[tert-butyl(dimethyl)siIyl]oxyethyl]-5-methyl-pyrazole3-carboxyiate (1.84 g, 6.16 mmol, 86 % yield) as a colorless oil.

Step 2: To a solution of methyl 2-[2-[to7-butyl(dimethyl)silylJoxyethyl]-5-methylpyrazole-3-carboxylate (1.63 g, 5.46 mmol, 1 eq) in Acetonitrile (17 mL) was added NIS (3.69 g, 16.38 mmol, 3 eq) at 0 °C. The mixture was stirred at 80 °C for 12 h. On completion, the mixture was quenched with sat. NajSOj (25 mL) and extracted with ethyl acetate (25 mL*3), the eombined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiCb, PE/THF=l :0 to 15: l ) to give methyl 2-[2-[iÉ77-butyl(dimethyl)silyl]oxyethyl]-4-iodo-5-methyl-pyrazole-3-carboxylate (2.13 g, 5.02 mmol, 92% yield) as a yellow oil.

Step 3: To a solution of methyl 2-[2-[ie/7-butyl(dimethyl)silyl]oxyethyl]-4-iodo-5-inethylpyrazole-3-carboxylate ( l.OO g, 2.36 mmol, l eq) in MeOH (2 mL), THF (4 mL) and H2O (2 mL) was added LiOH.H₂O (98.9 mg, 2.36 mmol, l eq). The mixture was stirred at 0 °C for 4 h. On completion, the mixture was quenched with IM HCl (5 mL) and extracted with 2-MeTHF (15 mL*3), the eombined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 2-[2-[Zc^,ri-butyl(dimethyl)silyl]oxyethyl]-4-iodo-5-methyl-pyrazole-3carboxylic acid (783 mg, l .91 mmol, 81 % yield) as a white solid.

To a solution of zeri-butyl N-methyl-A^r-[2-[methyl-[[2-methyl-4-( 1 -tetrahydropyran-2-yl3-vinyl-îndazol-5-yl)pyrazol-3-yl]methyl]amino]ethyl]carbamate (700 mg, 1.38 mmol, 1 eq) in Acetonitrile (7 mL) was added TMSI (358 mg, 1.79 mmol, 1.3 eq) at 0 °C. The mixture was stirred at 0 °C for 2 h. On completion, the mixture was quenched with sat. NaHCOj (20 mL) and extracted with ethyl acetate (25 mL* 3), the eombined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (S1O2, DCM/MeOH=l:0 to 5:1) to give jV, jV-dimethyl-jV-[[2-mcthyl-4-(ltetrahydropyran-2-yl-3-vinyl-indazol-5-yl) pyrazol-3-yl] methyl]ethane-l ,2-diamine (100 mg, 0.245 mmol, 18% yield) as a yellow oil.

Préparation of (2-[2-[ierz-butyl(dimethyl)silyl]oxyethyl]-4-iodo-A,5-dimethyl-jV-[2[methyl-[[2-methyL4-(l-tetrahydropyran-2-yl-3-vinyl-indazol-5-yi)pyrazol-3-yl]methyl]amino] ethyl]pyrazole-3-carboxamide

Pd(dtbpf)CI₂/Cs₂CO₃dioxane/H₂O

TBSO

OTBS

HATU, DIEA.DMF

Step l: A mixture of Lv7-butyl jV-[2-[(4-bromo-2-methyl-pyrazol-3-yl)methyl-methylamino]ethyl]“A-methyl-carbamate (Intermediate IIl-2-l, 1.22 g, 3.39 mmol, 2 eq), ltetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3-vinyl-indazole (600 mg, 1.69 mmol, l eq, prepared using General Method F, Step l), K2CO3 (702 mg, 5.08 mmol, 3 eq), Pd(dppf)Cl2.CH2Cl2 (138 mg, 0.169 mmol, 0.1 eq) in dioxane (12 mL) and H₂O (1.5 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 100 °C for 12 h under N₂ atmosphère. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO₂, PE/THF=l :0 to 2: l ) to give tert-butyl Nmethyl-A-[2-[methyL[[2-methyl-4-( l-tetrahydropyran-2-yl-3-vinyl-indazol-5-yl) pyrazol-3-yl] methyl]amino]ethyl]carbamate (699 mg, l .37 mmol, 81% yield) as a yellow oil.

Step 2: To a solution of icri-butyl 7/-methyl-A-[2-[methyl-[[2-methyl-4-( ltetrahydropyran-2-yl-3-vinyl-indazol-5-yl)pyrazol-3-yl]methyl]amino]ethyl]carbamate (700 mg, L38 mmol, l eq) in Acetonitrile (7 mL) was added TMSI (358 mg, 1.79 mmol, 1.3 eq) at 0 °C. The mixture was stirred at 0 °C for 2 h. On completion, the mixture was quenched with sat. NaHCO3(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, DCM/MeOH=l:0 to 5:l) to give N, TV-dimethyl-jV[[2-methyl-4-(l-tetrahydropyran-2-yl-3-vinyl-indazol-5-yl) pyrazol-3-yl] methyl]ethane-l ,2diamine ( 100 mg, 0.245 mmol, 18% yield) as a yellow oil.

Step 3: To a solution of 2-[2-[/er/-butyl(dimethyl)silyl]oxyethyl]-4-iodo-5-methylpyrazole-3-carboxylic acid (80.4 mg, 0.196 mmol, l eq) in DMF (l mL) was added HATU (89.4 mg, 0.235 mmol, l .2 eq), DIEA (75.9 mg, 0.587 mmol, 3 eq) and stirred at 25 °C for 30 min, then A^r,A^r-dimethyl-A^/'-[[2-methyL4-(l-tetrahydropyran-2-yl-3-vinyl-indazol-5-yl)pyrazol-3yl]methyl]ethane-l,2-diamine (80.0 mg, 196 mmol, l eq) was added into the mixture and stirred at 25 °C for l h. On completion, the mixture was quenched with water (5 mL) and extracted with ethyl acetate (5 mL*3), the combined organic phase was dried over anhydrous sodium sulfate,

100 filtered and concentrated to give a residue. The residue was purified by column chromatography (SiOz, PE/THF=l :0 to 2: l ) to give 2-[2-[n?r/-butyl(dimethyl)silyl]oxyethyl]-4-iodo-N,5-dimethyljV-[2-[methyl-[[2-methyl-4-( I -tetrahydropyran-2-yl-3-vinyl-indazoI-5-yl)pyrazol-3yl]methyl]amino] ethyl]pyrazole-3-carboxamide (69.0 mg, 0.086 mmol, 44% yield) as a yellow oil.

Ex. 26 was prepared following General method F from the above intermediate following Stcps 5 and 7.

Préparation of 2-[2-[ier/-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodo-pyrazole-3carboxylic acid:

-, H lodoethane $__ύ ^Ν'ΝΗ K_?CO_{3 r} <1A DM F \ O

OTBS K₂CO₃

TBAI_XDMF

NIS _rMeCN

Step l. To ethyl 3-hydroxy-l77-pyrazole-5-carboxylate (250 mg, 1.60 mmol) in DMF (8 mL) was added potassium carbonate (664 mg, 4.8 mmol) followed by ethyl iodide (1.60 mmol, 130 pL). The mixture was stirred at 80 °C for 2 h. The reaction was cooled and diluted with DCM (20 mL), then filtered. The filtrate was worked up with DCM and water (l00 mL). After séparation of layers, the aqueous layer was extracted with DCM again (2x 50 mL). The combined organic layers were washed with brine and then dried over sodium sulfate. Flash column chromatography (automated System, 12g silica, 0-30% EA in Hexanes) provided ethyl 3-ethoxy-l//-pyrazole-5carboxylate (184 mg, 0.999 mmol, 62.39% yield).

Step 2. To ethyl 3-ethoxy-l//-pyrazole-5-carboxylate (I84 mg, 998.96 pmol) in DMF (5 mL) was added potassium carbonate (414 mg, 3 mmol), followed by 2-bromoethoxy-/er/-butyldimethyl-silane ( l .50 mmol, 322 pL) and TBAI (369 mg, 999 pmol). The mixture was stirred at 60 °C for 6 hr. The reaction was diluted with DCM and cooled in an ice bath and the mixture was then filtered and washed with more DCM. The filtrate was concentrated to dryness and the residue was purified by Flash column chromatography (automated System with ELSD, I2g silica, 020% EA in Hexanes) provided ethyl 2-[2-[ier/-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-pyrazole3-carboxylate (220 mg, 0.642 mmol, 64.30% yield).

ΙΟΙ

Step 3. To ethyl 2-[2-[to/7-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-pyrazole-3carboxylate (150 mg, 0.438 mmol) in Methanol (0.2 mL) and THF (l mL) was added LiOH (2 M, l mL) in water. The mixture was stirred at 22 °C for 18 h. The reaction was coolcd in -20 °C freezer and diluted with DCM and 2M HCl (aq) (ImL) was added with vigorous stirring. The reaction was then diluted with DCM and water (5 mL), and the layers were separated. The aqueous layer was extracted again with DCM (2x5 mL). The combined organic layer was washed with brine and dried over sodium sulfate. Flash column chromatography (automated System, 12g silica, 0-12.5 % MeOH in DCM) provided 2-[2-[n??7-butyl(dimethyl)silyl]oxyethyl]5-ethoxy-pyrazole-3-carboxylic acid (36 mg, 114.48 pmol, 26.14% yield) and 5-ethoxy-2-(2hydroxyethyl)pyrazole-3-carboxylic acid (4.2 mg, 0.021 mmol, 4.79% yield).

Step 4. To 2-[2-[ier/-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-pyrazole-3-carboxylic acid (36 mg, 0.114 mmol) in acetonitrile ( 1 mL) was added NIS (28 mg, 125.9 pmol). The reaction was stirred at 70 °C for 1.5 h. The mixture was then coolcd and quenched with water, worked up with DCM and water (10 mL) and the layers were separated. The aqueous layer was extracted again with DCM (2 x 5mL). The combined organic layer was washed with brine and dried over sodium sulfate. Flash column chromatography (automated System, 12g silica, 0-25% Methanol in DCM) provided 2-[2-[/erZ-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodo-pyrazole-3-carboxylic acid (34 mg, 0.077 mmol, 67.44% yield).

Ex. 27 was prepared using General method F using the above intermediate in Step 4, and following Steps 1-5 and Step 7.

Ex #	Structure	MS m/z [Μ+ΗΓ	IH NMR (400 MHz, DMSO-t/₆) δ ppm
1	o' J \| O V:N il HN-N	446.2	8.76 (s, 1 H), 7.52 (s, 2 H), 7.50 (d, J= 17.2 Hz, 1 H), 7.29 (dd, J = 9.6,3.2 Hz, 1 H), 7.22 (dd,J= 7.2,4.8 Hz, 1 H), 7.13 (d, J = 17.2 Hz, 1 H), 7.08 - 7.01 (m, 1 H), 4.65 -4.43 (m, 3 H), 3.91 (s, 3 H), 3.45 - 3.34 (m, 1 H), 3.11 (s, 3 H), 3.06 (q,J= 15.2, 7.2 Hz, 2 H), 1.37 (t,7=8.0 Hz, 3 H)

102

Ex#	Structure	MS m/z [M+Hf	1 H NMR (400 MHz, DMSO-i/_b) δ ppm
2	V Π । )— / o ¹ Λ A/ ^z f—X ^z / ^H	446.2	8.77 (s, 1 H), 7.61 (s, 2 H), 7.52 (d, J = 17.2 Hz, 1 H), 7.31 (dd, J = 9.6, 3.2 Hz, 1 H), 7.23 (dd, J = 9.2,4.4 Hz, 1 H), 7.17 (d,J = 17.2 Hz, 1 H), 7.08- 7.03 (m, 1 H), 4.61 -4.48 (m, 3 H), 3.85 (s, 3 H), 3.50 - 3.39 (m, 1 H), 3.16 (s, 3 H), 2.95 (q, J=7.6 Hz, 2 H), 1.39 (t, J = 7.6 Hz, 3 H)
3	ο X 1 0 \^N A- JZ n— // HN-N	400.1	13.07 - 12.98 (m, IH), 8.66 (s, 1 H), 8.30 (s, IH), 7.58 (s,2H), 7.54 (d, J=6.8 Hz, IH), 7.347.30 (m, 2H), 7.28-7.19 (m, 2H), 7.11 -7.05 (m, IH), 4.624.34 (m, 4H), 3.90 (s, 3H), 3.00 (s, 3H)
4	//Λ <xo a 1 O'Y^N rX XxA¹·— If HN-N	404.2	13.01 (s, IH), 8.46 (s, IH), 8.31 (s, IH), 7.94 (s, IH), 7.72 (d, J = 8.8 Hz, 1 H), 7.51 (d, J=8.8 Hz, IH), 7.22 (d,J = 1.2 Hz, 2H), 4.37-4.23 (m,2H), 3.94-3.89 (m, 3H), 3.77 (s, 3H), 3.29 (s, 2H), 3.11 (s, 3H)
5	O T xX Z<7 O A- °^X \ /''Z Xtt ^xr\ z / z	480.1	7.49 (s, IH), 7.38 (s, IH), 7.177.14 (m, IH), 7.02 -6.97 (m, IH), 6.77 (dd, J =2.0, 8.0 Hz, IH), 6.58 (d,J = 8.0 Hz, IH), 6.36 (s, IH), 5.27 (br s, IH), 4.22 (brd, J=9.2 Hz, IH), 3.94 (s, 3H), 3.91 -3.83 (m, 2H), 3.39 - 3.35 (m, IH), 2.96- 2.85 (m, 2H), 2.72 (s, 3H), 1.11 (br t, J = 7.2 Hz, 3H)
6	Άζ ° <Λ 1 θ \^ζΝ rX XxA'Q/I Il \ HN-N	432.0	13.06 (br s, IH), 8.45 (s, IH), 7.94 (s, IH), 7.72 (dd, J = 1.2, 8.8 Hz, IH), 7.52 (d, J = 8.8 Hz, IH), 7.30 (d, J= 17.3 Hz, IH), 7.08 (d, J= 17.3 Hz, IH), 5.75 (s, 1 H), 4.95 (brdd, J =4.1, 14.9 Hz, 1 H), 4.36 -4.24 (m, 2H), 3.78 (d, J = 3.4 Hz, 6H), 3.39 3.36 (m, 1 H), 3.16 (s, 3H), 2.87 (q, J = 7.5 Hz, 2H), 2.07 (s, IH), 1.31 (t, J = 7.5 Hz, 3H)

103

Ex #	Structure	MS m/z [M+H]-	IH NMR (400 MHz, DMSO-Λ) δ ppm
7	JA AA° J / I ° A-—n \// A HN—N____________	432.1	13.05 (brs, IH), 8.42 (s, 1 H), 7.94 (s, IH), 7.72 (brd, J = 8.5 Hz, IH), 7.52 (brd, J = 8.6 Hz, IH), 7.29 - 7.17 (m, IH), 7.03 (brd, J = 17.4 Hz, IH), 4.80 (br d, J = 12.6 Hz, IH),4.37-4.19 (ni, 2H), 3.85 (s, 3H), 3.77 (s, 3H), 3.27 -3.18 (m, IH), 3.09 (s, 3H), 3.03 -2.93 (m, 2H), 1.28 (br t, J = 7.4 Hz, 3H)
8	//“^N\ /A X7 ⁰ A / I ⁰ /)—N il Λ^ν \/Z HN-N	418.0	8.46 (s, IH), 7.94 (s, IH), 7.72 (dd, .7=2.0, 8.8 Hz, IH), 7.52 (d, J= 8.8 Hz, IH), 7.32 (d, J = 16.0 Hz, IH), 7.11 (d, J = 16.0 Hz, 1 H), 4.95 (br dd, J = 4.0, 12.0 Hz, 1 H), 4.36 -4.24 (m, 2H), 3.78 (s, 3H), 3.76 (s, 3H), 3.35 (br dd, .7= 8.0, 12.0 Hz, IH), 3.16 (s, 3H), 2.45 (s, 3H)
9	° A? AÏ \ I	418.0	13.03 (s, IH), 8.43 (s, IH), 7.93 (s, IH), 7.72 (brd, J= 8.4 Hz, IH), 7.52 (d, J = 8.8 Hz, IH), 7.28 - 7.22 (m, IH), 7.10-7.05 (m, IH), 4.82 (br d, J= 12.0 Hz, IH), 4.33 -4.24 (m, 2H), 3.83 (s, 3H), 3.77 (s, 3H), 3.36 (brd, .7 = 8.4 Hz, IH), 3.09 (s, 3H), 2.55 (s,3H)
ΙΟ	// ^N\ /X H AA ο χ \| O'y^N HN-N	404.1	13.12-12.88 (m, IH), 8.63 (t, J = 5.6 Hz, IH), 8.58 (s, IH), 7.93 (s, IH), 7.71 (d, J = 9.6 Hz, IH), 7.67 (d,J=8.0 Hz, IH), 7.51 (d, J= 8.4 Hz, IH), 7.03 (d, J = 17.2 Hz, IH), 4.18 -4.13 (m, 2H), 3.83 (s, 3H), 3.77 (s, IH), 3.75 (s, 3H), 3.70 (s, 1 H), 2.54 (s, 3H)
H	A A^ CpoA /— I ⁰ /A Îj< \/z HN-N	43 1.9	13.06 (s, IH), 8.45 (s, IH), 7.94 (s, IH), 7.72 (d,J=8.8 Hz, IH), 7.52 (d, J= 8.4 Hz, IH), 7.31 (d, J = 17.2 Hz, IH), 7.10 (d, J = 17.2 Ηζ,ΙΗ), 4.97- 4.89 (m, IH), 4.36 - 4.25 (m, 2H), 4.153.97 (m, 3H), 3.78 (s, 3H), 3.16 (s, 3H), 2.46 (s, 3H), 1.33 (t,J = 7.2 Hz, 3 H)

104

Ex #	Structure	MS m/z [M+H]‘	l H NMR (400 MHz, DMSO-î/₆) δ ppm
12	N-N \ L n— ίΐΊ °A_ / /H λ /Γ HN-N Y	446.0	7.96 (s, IH), 7.66 (s, IH), 7.527.48 (m, IH), 7.47 - 7.42 (m, IH), 7.33 (d,J = 16.4 Hz, IH), 6.81 (d, J= 16.4 Hz. 1 H), 4.444.26 (ni, 1 H), 4.07 -3.98 (m, IH), 3.75 (s, 3H), 3.70 (s, 3H), 3.27 (s, IH), 2.93 (s, 3H), 2.85 2.77 (m, IH), 2.48-2.36 (m, IH), 2.30 (s, 3H), 1.99- 1.83 (m, IH), 1.71 - 1.57 (m, 2H)
13	N'N L ^n— ίίΊ °A / V /A /H HN-N Y	432.2	8.17 (s, IH), 7.71 (s, IH), 7.63 7.59 (m, IH), 7.57-7.52 (m, 1 H), 7.34- 7.28 (m, 1H>, 7.287.22 (m, 1 H), 4,72 (ddd, J= 4.0, 9.6, 13.6 Hz, IH), 4.42 (td, J = 7.2, 10.0 Hz, IH), 4.26 (td, J = 6.4, 10.0 Hz, IH), 3.81 (d, J = 2.0 Hz, 6H), 3.24-3.12 (m, IH), 3.06 (s, 3H), 2.54 (s, 3H), 2.43 2.32 (m, IH), 2.32 - 2.17 (m, IH)
14	N-N ,0-7 A^-c/^⁷ ( L ^N~ /¼ ^0==I\ i! /)~ⁿ HN-N Y i	462.1	13.36- 12.61 (m, 1 H), 8.268.04 (m, IH), 7.80 -7.68 (m, IH), 7.61 -7.48 (m.2H), 7.277.11 (m, 1 H), 6.99 -6.88 (m, 1 H), 4.14 - 4.04 (m, 2H), 3.883.80 (m, 2H), 3.72 (d, J= 2.8 Hz, 3H), 3.68 (d, J=6.4 Hz, 3H), 3.62 - 3.57 (m, 2H), 3.503.38 (m, 2H), 3.18 (d, J= 9.6 Hz, 3H), 2.37 -2.22 (m, 3H)
15	n^n' I T ^N~ A / Il Y H \/ΥΥ-Χ.Υ HN-N Y	444.9	13.12 (s, IH), 8.37 (s, IH), 7.66 (s, IH), 7.55 (d, .7 = 8.4 Hz, IH), 7.43 (dd, J= 1.2, 8.4 Hz, IH), 7.11 (s, 2H), 4.86 -4.66 (m, IH), 3.92 (s, 3H), 3.71 (s, 3H), 3.50 (s, 2H), 3.06 - 2.93 (m, 5H), 2.63 -2.54 (m, IH), 2.40 (s, 3H), 2.25 (s, 3H)

105

Ex#	Structure	MS m/z [M+H]’	IH NMR (400 MHz, DMSO-î/₆) δ ppm
16	r^N\ /^oh JJo A Ί o y- n xC C. / 'n (Iji // HN-N	448.0	13.35 - 12.83 (m, IH), 8.47 (s, IH), 7.94 (s, IH), 7.72 (dd,7 = 1.2, 8.8 Hz, IH), 7.52 (d,7= 8.8 Hz, IH), 7.34 (d,7 = 16.0 Hz, IH), 7.1I (d, 7 = 16.0 Hz, IH), 4.96 (br dd, 7 = 4.4, 16.0 Hz, IH), 4.35 -4.24 (m, 2H), 4.18 4.l0(m, IH), 4.10-4.02 (m, lH), 3.78 (s, 3H), 3.72-3.61 (m, 3H), 3.28 (brs, IH), 3.17 (s, 3H), 2.47 (s, 3H)
17	Λν- \| 0^\=N Qjt 1/ HN-N	448.0	13.09- 12.95 (m, IH), 8.43 (s, IH), 7.94 (s, lH), 7.74 - 7.70 (m, IH), 7.52 (d,7 = 9.2 Hz, IH), 7.27 - 7.22 (m, IH), 7.09 - 7.04 (m, IH), 4.96 (t, J =5.6 Hz, IH), 4.80 (d,7= 11.6 Hz, IH), 4.374.25 (m, 2H), 4.18 (t, 7= 5.6 Hz, 2H), 3.77 (s, 3H), 3.75 (d,7 = 5.6 Hz, 2H), 3.47 - 3.38 (m, IH), 3.10 (s, 3H), 2.57 (s, 3H)
18	Y An J ψό l· ⁰ F ^N' A Jk z N LaT] II HN-N	501.3	13.40 - 12.94(m, IH), 9.66 (br d, 7 = 1.2 Hz, IH), 8.47 (s, IH), 7.95 (s, IH), 7.73 (dd, 7 = 1.0, 8.8 Hz, IH), 7.54 (d, 7=8.8 Hz, IH), 7.40-7.30 (m, IH), 7.237.13 (m, 1 H), 5.00 (brdd,7 = 5.6, 14.5 Hz, IH), 4.50-4.40 (m, 2H), 4.39 - 4.32 (m, IH), 4.31 -4.23 (m, IH), 3.79 (s, 3H), 3.72 -3.54 (m, 5H),3.31 (br d, 7 = 7.2 Hz, 3H), 3.18 (s, 3H),3.12 - 3.00 (m,2H), 2.02 (br s, 2H), 1.91 - 1.80 (m, 2H)
19	/7Λ γγοχ \| 0 >=N zk Js./n-Z'n a Qff Il HN-N	50l.l	10.09 (s, IH), 8.43 (s, IH), 7.94 (s, IH), 7.73 (dd, 7 = 1.2, 9.2 Hz, IH), 7.53 (d, 7=8.4 Hz, IH), 7.27-7.21 (m, IH), 7.15 - 7.10 (m, IH), 4.80 (br d, 7= 12.4 Hz, IH), 4.54 (brt, 7=6.4 Hz, 3H), 4.33 -4.25 (m, 2H),3,77(s, 3H), 3.69 (d, 7= 4.0 Hz, 2H), 3.59 (br d, 7=3.6 Hz, 2H), 3.37(brdd,7 = 8.4, 13.6 Hz, 1 H), 3.11 (s, 3H), 3.07 (br s, 2H), 2.62 (s, 3H), 2.08 - 1.98 (m, 2H), 1.921.81 (m, 2H)

106

Ex#	Structure	MS m/: [Μ+ΗΓ	IH NMR (400 MHz, DMSO-î/ô) δ ppm

20	/ N-N < \ LÀ'O À F \ ° T^N. A- il z ^N // HN-N	446.1	13.05 (s, 1 H), 8.45 (s, IH), 7.94 (s, IH), 7.72 (dd. J = 1.2, 8.8 Hz, IH), 7.52 (d, J = 8.8 Hz, IH), 7.32 - 7.27 (m, IH), 7.13 - 7.07 (m, 1 H), 4.44 (quin, J = 6.4 Hz, IH), 4.30 (d, J = 4.4 Hz. 2H), 3.78 (s, IH), 3.79 - 3.76 (m, IH), 3.44 - 3.37 (m,2H), 3.35-3.34 (m,3H), 3.16 (s, 3H), 2.47 (s, 3H), 1.43 (d, J = 6.4 Hz, 3H), 1.38 (d, J = 6.4 Hz, 3H)
21	i >— I Z </ o-.._ A- o \ αΓΥ Υ^σΓ Z' \ ^{σ σ}‘ A O O	438.2	13.06 (s, IH), 8.45 (s, IH), 7.94 (s, IH), 7.72 (d, J = 8.9 Hz, IH), 7.52 (d. J = 8.8 Hz, IH), 7.32 (s, IH), 7.06 (s, 1 H), 4.99-4.90 (m, 1 H), 4.36 -4.22 (m, 2H), 3.78 (s, 3H), 3.39- 3.35 (m, IH), 2.86 (q, J = 7.4 Hz, 2H), 1.31 (t, J = 7.5 Hz, 3H)
22	/ Yfo A / t ⁰ zA JL A / Il HN-N	448.2	8.46 (s, IH), 7.94 (s, IH), 7.71 (d, J = 8.8 Hz, IH), 7.51 (d, J = 8.8 Hz, 1 H), 7.36- 7.27 (m, IH), 7.25-7.15 (m, 1 H), 5.00 - 4.84 (m, IH), 4.39 -4.25 (m, 4H), 3.78 (s, 3H), 3.69 (s, 3H), 3.423.31 (m, 1 H), 3.20 (s, 3H), 1.44 (t, J = 7.2Hz, 3H)
23	/ K N'N yA' Cjo A / i ⁰ zA II z N If HN-N	446.5	8.73 (br s, 1 H), 7.97 (br s, 1 H), 7.68 - 7.76 (m, 1 H), 7.46 - 7.54 (m, 1 H), 7.42 (d, J=17.15 Hz, 1 H), 7.09 (brd, J=17.15 Hz, 1 H), 4.61 -4.84 (m, 2 H), 3.70-3.80 (m, 6 H), 3.63 (brd, J=15.78 Hz, 1 H), 3.35 - 3.36 (m, 3 H), 2.87 (q, J=7.32 Hz, 2 H), 1.29- 1.34 (m, 3H), 1.23 (br s, 3 H)

107

Ex#	Structure	MS m/~ [M+H]·	IH NMR (400 MHz, DMSO-rf₆) ô ppm
24	/ X“N' ζΧ ° jQ mn N HN'ⁿ	429.2	13.30 (s, 1 H), 8.46 (s, 1 H), 7.96 (s, 1 H), 7.76 (dd, >8.76, 1.10 Hz, 1 H), 7.61 (d, J= 17.25 Hz, 1 H), 7.56 (d, >8.76 Hz, 1 H), 7.28 (d, >16.97 Hz. 1 H), 4.91 4.98 (m, 1 H), 4.31 -4.38 (m, 2 H), 3.97 (s, 3 H), 3.79 (s, 3 H), 3.36 - 3.43 (m, 1 H), 3.19 (s, 3 H)
25	z'CHa 1 >— / ° / r~\ ' /—,o !	419.4	1H NMR (400 MHz, METHANOL-d4) δ ppm 8.56 (s, 1 H), 7.90 (s, 1 H), 7.76 (dd, >8.90, 1.51 Hz, 1 H), 7.57 (d, >8.76 Hz, 1 H), 7.42 - 7.47 (m, 1 H), 7.33 - 7.38 (m, 1 H), 5.02 5.09 (m, 1 H), 4.40-4.47 (m, 1 H), 4.32-4.39 (m, 1 H), 3.84 (s, 3 H), 3.33 - 3.35 (m, 4 H), 3.07 3.12 (m, 2 H), 1.47 (t, >7.39 Hz, 3 H)
26	¹ N'N 7 N- OH x \ ⁰ X'^N /L· 1/ _zn CXT\ II HN-N	475.1	IH NMR (400 MHz, METHANOL-d4 ) δ = 8.46 (s, IH), 7.64 (s, IH), 7.58 - 7.52 (m, IH), 7.49-7.44 (m, IH), 7.26 (s, 2H), 5.01 -4.92 (m, IH), 4.364.25 (m, IH), 4.17 -4.08 (m, IH), 3.98 (s, 3H), 3.85 - 3.77 (m, 2H), 3.55 (s, 2H), 3.20 -3.10 (m, IH), 3.08 (s, 3H), 3.00-2.91 (m, 1 H), 2.64- 2.56 (m. IH), 2.52 (s, 3H), 2.37 (s, 3H)
27	/ N-N /'' 'N' P^H L>0 Λ X \ ⁰ /X^N- X^ J>N Il HN-N	478.3	12.98 (s, 1 H), 8.47 (s, 1 H), 7.94 (s, 1 H), 7.71 (dd, J=8.90, 1.23 Hz, 1 H), 7.50 (d. J=8.76 Hz, 1 H), 7.28 -7.34 (m, 1 H), 7.19 7.24 (m, 1 H), 4.93 (br dd, >14.78,4.38 Hz, 2 H), 4.264.38 (m, 4 H), 4.04-4.12 (m, 1 H), 3.97 (dt, >14.03,3.66 Hz, 1 H), 3.78 (s, 3 H), 3.64 (br d, >4.38 Hz, 2 H), 3.21 (s, 3 H), 1.44 (t, >6.98 Hz, 4 H)

Screen assays

Biochemical Assay

FLT3 and PIM kinase activity évaluation at Reaction Biology Coiporation

108

The inhibition activitics against enzymatic kinases was evaluated using HotSpot assay platform (www.reactionbiology,.coin), a radiometric assay based on conventional filter-binding assays, that directly measures kinase catalytic activity toward a spécifie substrate (Anastassiadis T. et al. Comprehensive Assay of Kinase Catalytic Activity Reveals Features of Kinase Inhibitor Selcctivity. Nat Biotechnol. 2011,29:1039-45). Briefly, spécifie kinase / substrate pairs along with required cofactors were prepared in reaction buffer; 20 mM Hepes pH 7.5, 10 mM MgCb, 1 mM EGTA, 0.02% Brij35, 0.02 mg/ml BSA, 0.1 mM Na₃VO₄, 2 mM DTT, 1% DMSO. Compounds were delivered into the reaction, followed ~ 20 minutes later by addition of a mixture of ATP (Sigma, St. Louis MO) and ³³P ATP (Perkin Elmer, Waltham MA) to a final concentration of 10 μΜ. Reactions were carried out at room température for 120 min, followed by spotting of the reactions onto P81 ion exchange filter paper (Whatman Inc., Piscataway, NJ). Unbound phosphate was removed by extensive washing of filters in 0.75% phosphoric acid. After subtraction of background derived from control reactions containing inactive enzyme, kinase activity data was expressed as the percent remaining kinase activity in test samples compared to vehicle (dimethyl sulfoxide) reactions. IC50 values and curve fits were obtained using Prîsm (GraphPad Software).

Table L Inhibition of kinase activities of FLT3 and FLT3-1TD

Ex#	FLT3 IC50 (nM)	FLT3-ITD IC50 (nM)	PIM1 IC50 (nM)	PIM2 IC50 (nM)	PIM3 IC50 (nM)
6	0.088	0.348	2.65	5.68	0.115
7	0.247	0.537	6.72	14	0.221
8	0.217	0.487	1.64	8.17	0.0732
9	0.347	0.592	12.7	145	3.65
11	0.084	0.566
19	0.564	1.052
20	0.187	0.775
22	0.093	0.527
23	0.416	0.967
24	0.23	0.475

Evaluation of Binding affinity with wild type and mutant FLT3 kinases using KINOMExcîïw assay at Eurofins DiscoveRx

For most kinases, kinase-tagged T7 phage strains were prepared in an E. coli host derived from the BL21 strain. E. coli were grown to log-phase and infected with T7 phage and incubated with shaking at 32°C until lysis. The lysâtes were centrifuged and fîltered to remove cell débris. The remaining kinases were produced in HEK-293 cells and subséquent!y tagged with DNA for qPCR détection. Streptavidin-coated magnetic beads were treated with biotinylated small molécule ligands for 30 minutes at room température to generate affinity resins for kinase assays.

109

The liganded beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), l% BSA, 0.05% Tween 20, l mM DTT) to remove unbound ligand and to reduce nonspecifïc binding. Binding reactions were assembled by combining kinases, liganded affmity beads, and test compounds in Ix binding buffer (20% SeaBlock, 0.l7x PBS, 0.05% Tween 20, 6 mM DTT). Test compounds were prepared as H IX stocks in 100% DMSO. Kds were determined using an 11 -point 3-fold compound dilution sériés with three DMSO control points. Ail compounds for Kd measurcments are distributed by acoustic transfer (non-contact dispensing) in 100% DMSO. The compounds were then diluted directly into the assays such that the final concentration of DMSO was 0.9%. Ail reactions performed in polypropylene 384-well plate. Each was a final volume of 0.02 ml. The assay plates were incubated at room température with shaking for 1 hour and the affmity beads were washed with wash buffer (Ix PBS, 0.05% Tween 20). The beads were then re-suspended in elution buffer ( Ix PBS, 0.05% Tween 20, 0.5 μΜ nonbiotinylated affmity ligand) and incubated at room température with shaking for 30 minutes. The kinase concentration in the eluates was measured by qPCR. Binding constants (Kds) were calculated with a standard dose-response curve using a non-linear least square fit with the Levenberg-Marquardt algorithm.

Table 2. Binding affmity of Ex. 6 with wild type and mutant FLT3 kinases

Ex #	FLT3 K_d (nM)	FLT3 (D835H) Kd (nM)	FLT3 (D835V) K₍\| (nM)	FLT3 (D835Y) K_d (nM)	FLT3 (ITD) K_d (nM)	FLT3 (ITD, D835V) K_d (nM)	FLT3 (ITD, F691L) K_d (nM)
6	0.18	67	0.062	4.1	6.3	0.058	0.23
Ex.#	FLT3 (K663Q) K_d (nM)	FLT3 (N8411) K_d (nM)	FLT3 (R834Q) K_d (nM)	FLT3autoinhib ited Kd (nM)
6	16	2.2	0.89	9.1

Inhibition of CLK1, CLK2, CLK3 and CLK4 kinase acvtivity

Kinase protein and substrate were pre-diluted in the HEPES assay buffer (100 mM HEPES, pH 7.5, 0.01% Triton X-100, 0.1% BSA, 5 mM MgCl₂, 1 mM DTT, 10 μΜ Sodium Orthovanadate, 10 μΜ Beta-Glycerophosphate) dispensed into 384 well plate (5 pL per well). Control samples (0%-inhibition in the absence of inhibitor, DMSO only) and 100%-inhibition (in the absence of enzyme) were assembled in replicates of six and were used to calculate %-inhibition in the presence of compounds. Test compounds were added to the protein samples by acoustic dispensing (Labcyte Echo550). Concentration of DMSO was equalized to 1% in ail samples. Reactions were initiated by addition of ATP by acoustic dispensing (Labcyte Echo550) and incubated according to assay spécifie incubation time. After incubation, 5uL of Promega ADPGlo reagent was added and incubated for 40 minutes. After 40 minutes, lOuL of Promega kinase

110 détection reagent was added. After 10min of incubation with Kinase détection reagent, the luminescence was read on microplate reader (Biotek Synergy).

Table 3. Inhibition of CLKl, CLK2, CLK3 and CLK4 kinase activity

Ex#	CLKI IC50 (nM)	CLK2 IC50 (nM)	CLK3 IC50 (nM)	CLK4 IC50 (nM)
6	0.I34	0.165	5.87	0.446
15	0.157	0.161	2.77	0.53
16	0.299	0.16	10.4	0.758
22	0.355	0.253	9.47	0.668
23	0.843	0.225	5.53	1.39
24	0.415	0.67	92.9	0.593
26	0.233	0.386	31.1	0.605
27	1.55	1.11	108	3.03

Cell Prolifération Assay

MV-4-l l cell line was purchascd from ATCC and maintained in RPMI medium supplemented with 10% fêtai bovine sérum and 100 U/mL of penicillin/streptomycin. One thousand MV-4-11 cells/50 μΐ per well were seeded in white 384-well plate, followed by treatment with indicated compounds in a I l-dose dilution sériés. Cell prolifération was measured using 10 CelITiter-Glo 2.0 luciferase-based ATP détection assay (Promega, Madison, Wl) following the manufacturer’s protocol. Plates were then read on a TECAN Sparks multimode microplate reader. Data was analyzed using GraphPad Prism 9 (GraphPad Software, San Diego, CA) to obtain IC50 values.

Table 4. Inhibition of MV-4-I l cell prolifération.

Ex#	IC50 (nM)	Ex. #	IC50 (nM)
1	1162	15	4.6
2	352.7	16	<1
4	21.2	17
5	>10000	18	17.8
6	0.3	19	15.2
7	73.1	20	1.1
8	<0.2	21	<0.2
9	-1	22	<0.2
10	864.9	23	4.1
11	<0.2	24	141.4
12	148.4	25	0.52
13	15.5	26	15
14	384.5	27	7.6

Inhibition of cell prolifération in a broad panel of cell prolifération assays lll

Ba/F3 cells were purchased from DSMZ. The FLT3-ITD gene was synthesizcd at GenScript and cloned into pCDH-CMV-MCS-EFl-Puro piasmid (System Biosciences, Inc). FLT3-ITD/D835V and FLT3-ITD/F691 L cDNA clones were made at GenScript by PCR and confirmed by sequence. Ba/F3 FLT3-ITD, FLT3-1TD/D835V and FLT3-ITD/F691 L cell lines 5 were generated by infecting Ba/F3 cells with lentivirus containing FLT3-1TD, FLT3-1TD/D835V or FLT3-ITD/F691 L genes. Stable cell lines were selected by puromycin treatment, followed by IL-3 withdrawal.

Cell prolifération assay was carried out in a panel of 108 cell lines. 1000 (attached cells) or 3000 (suspension cells) cells/l00 μΐ per well were seeded in 96 well black plate with a clear 10 bottom (Corning #3904). Compounds were added using Tecan D300e Digital Dispenser in l:3 titration for 9 doses. Plates were incubated for 5 days at 37°C and 5% CO2. Cell prolifération was measured using CellTiter-Glo 2.0 luciferase-based ATP détection assay (Promega, Madison, WI) ai 50 μΐ per well following the manufacturées protocol. Plates were then read on a TECAN Sparks multimode microplate reader. Data was analyzed using GraphPad Prism 9 (GraphPad Software, 15 San Diego, CA) to obtain IC50 values. [C50 values were determined using Prism software (GraphPad Software, San Diego, CA).

Table 5. Anti-cell prolifération activity of Ex. 6 in a panel of 108 cell lines.

	Cell Line Nanie	IC50 (nM)	Tumor Type, Disease	Source, Catalog #	Culture Medium
l	BaF3	513	murine IL-3 dépendent pro-B cell line	DSMZ, ACC 300	90% RPMI 1640 + 10% h.i. FBS+ l ng/mL mouse IL-3
2	BaF3 FLT3ITD	0.55	murine pro-B cell line expressing FLT3-1TD	Engineered Cell line	90% RPMI 1640 + 10% h.i. FBS
3	BaF3 FLT3ITD/D835V	1.3	murine pro-B cell line expressing FLT3ITD/D835V	Engineered Cell line	90% RPMI 1640 + 10% h.i. FBS
4	BaF3 FLT3ITD/F691L	22.9	murine pro-B cell line expressing FLT3ITD/F691L	Engineered Cell line	90% RPMI 1640 + 10% h.i. FBS
5	MV-4-H	0.68	Biphenotypic BMyelomonocytic Leukemia	ATCC, CRL591	90% lMDM+10% FBS
6	MOLM14	2.26	Acute myeloid leukemia	DSMZ, ACC 777	90% RPMI 1640 + 10% h.i. FBS
7	MOLM13	2.39	Acute myeloid leukemia	DSMZ, ACC 554	90% RPMI 1640 + 10% h.i. FBS

112

	Cell Line Naine	ICso (iiM)	Tunior Type, Disease	Source, Catalog #	Culture Medium
8	KASUMI-4	11.16	Chronic Myeloblastic Leukemia	ATCC, CRL2726	80% RPMI 1640 + 20% h.i. FBS+10 ng/ml GM-CSF
9	IMR-32	11.16	Neuroblastoma	ATCC, CCL127	90% DM EM + 10% h.i. FBS
ΙΟ	KASUM1-1	13.98	Acute myeloblastic leukemia	ATCC, CRL- 2724	90% R PMI 1640 + 10% h.i. FBS
11	KP-N-RTBM-1	15.07	Neuroblastoma	JCRB, IFO50432	90% RPMI 1640 + 10% h.i. FBS
12	UCSDAMLl	15.47	Acute myeloid leukemia	DSMZ, ACC 691	80% RPMI 1640 + 20% h.i. FBS+10 ng/ml GM-CSF
13	SW403	18.04	Colorectal adenocarcinoma	ATCC, CCL230	90% Leibovitz's L-15 Medium + 10% h.i. FBS
14	EOL-1	18.92	Chronic éosinophilie leukemia	Sigma Aldrich, 94042252	90% RPMI 1640 + 10% h.i. FBS
15	JeKo-1	20.63	Mantle cell lymphoma	ATCC, CRL3006	80% RPMI 1640 + 20% h.i. FBS
16	N87	20.83	Gastric carcinoma	ATCC, CRL5822	90% RPMI 1640 + 10% h.i. FBS
17	SK-N-SH	21.72	Neuroblastoma	ATCC, HTB-11	90% DMEM + 10% h.i. FBS
18	HNT-34	22.31	Acute myeloid leukemia	DSMZ, ACC 600	90% RPMI 1640 + 10% h.i. FBS
19	SKNO-1	23.34	Acute myeloid leukemia	DSMZ, ACC 690	90% RPMI 1640 + 10% h.i. FBS+10 ng/ml GM-CSF
20	AU565	25.46	Breast adenocarcinoma	ATCC, CRL2351	90% RPMI 1640 + 10% h.i. FBS
21	CHP-212	27.44	Neuroblastoma	ATCC, CRL2273	90% DMEM + 10% h.i. FBS
22	SU-DHL-6	28.37	Diffuse Large B Cell Lymphoma	ATCC, CRL- 2959	90% RPMI 1640 + 10% h.i. FBS
23	LS513	30.11	Colorectal carcinoma	ATCC, CRL2134	90% RPMI 1640 + 10% h.i. FBS
24	Toledo	34.58	Diffuse Large B Cell Lymphoma	ATCC, CRL- 2631	90% RPMI 1640 + 10% h.i. FBS
25	MFM-223	36.75	Breast carcinoma	Sigma, 98050130-1VL	90% DMEM + 10% h.i. FBS
26	SK-BR-3	38.77	Breast adenocarcinoma	ATCC, HTB-30	90% McCoy's 5a Medium Modified+ 10% hi.i. FBS
27	HCC78	42.71	Non-small cell lung carcinoma	DSMZ, ACC 563	90% RPMI 1640 + 10% h.i. FBS

H3

	Cell Line Name	ICso (nM)	Tumor Type, Disease	Source, Catalog #	Culture Medium
28	KASUMI-3	43.32	Acute myeloblastic leukemia	ATCC, CRL2725	80% RPM1 1640 + 20% h.i. FBS
29	NB-I	45.04	Neuroblastoma	JCRB, JCRB0621	90% RPMI 1640 + 10% h.i. FBS
30	PA-I	47.97	Ovary Teratocarcinoma	ATCC, CRL- 1572	90% DMEM + 10% h.i. FBS
31	DLD1	48.70	Colorectal adenocarcinoma	ATCC, CCL- 221	90% RPMI 1640 + 10% h.i. FBS
32	Kelly	51.47	Neuroblastoma	DSMZ, ACC 355	90% RPMI 1640 + 10% h.i. FBS
33	MIAPaCa-2	53.25	Pancreatic carcinoma	ATCC, CRL1420	90% DMEM + 10% h.i. FBS
34	TF-1	57.62	Erythroleukemia	ATCC, CRL- 2003	90% RPMI 1640 + 10% h.i. FBS
35	HCT116	60.20	Colorectal adenocarcinoma	Sigma, 91091005	90% McCoy's 5a Medium Modified+ 10% hi.i. FBS
36	KCL22S	61.19	Chronic myeloid leukemia at blast crisis	ATCC, CRL- 3349	90% RPMI 1640 + 10% h.i. FBS
37	DU4475	61.44	Breast carcinoma	ATCC, HTB123	90% RPMI 1640 + 10% h.i. FBS
38	TOV-112D	62.54	Endometrioid ovarian cancer	ATCC, CRL- 11731	90% RPMI 1640 + 10% h.i. FBS
39	KCL22R	64.75	Chronic Myelogenous Leukemia	ATCC, CRL3350	90% RPMI 1640 + 10% h.i. FBS
40	A549	67.73	Lung carcinoma, NSCLC	ATCC, CCL185	90% RPMI 1640 + 10% h.i. FBS
41	Ovcar3	70.68	Ovarian adenocarcinoma	ATCC. HTB- 161	80% RPMI 1640 + 20% h.i. FBS
42	HCC827	70.90	Lung adenocarcinoma NSCLC	ATCC, CRL- 2868	90% RPMI 1640 + 10% h.i. FBS
43	22RV1	73.23	Prostate carcinoma	ATCC, CRL- 2505	90% RPMI 1640 + 10% h.i. FBS
44	H2122	73.72	Lung adenocarcinoma NSCLC	ATCC, CRL5985	90% RPMI 1640 + 10% h.i. FBS
45	H526	75.49	Small cell lung cancer	ATCC, CRL- 5811	90% RPMI 1640 + 10% h.i. FBS
46	MCF7	75.89	Breast adenocarcinoma	ATCC, HTB-22	90% DMEM + 10% h.i. FBS
47	SW620	76.50	Colorectal adenocarcinoma	ATCC, CCL227	90% Leibovitz's L-15 Medium + 10% h.i. FBS
48	SK-N-AS	77.23	Neuroblastoma	ATCC, CRL- 2137	90% DMEM + 10% h.i. FBS

114

	Cell Line Name	ICîo (nM)	Tumor Type, Disease	Source, Catalog #	Culture Medium
49	HPAC	79.08	Pancreatic carcinoma	ATCC, CRL- 2119	DMEM:Fl2K + insulin + EGF + 5% FBS
50	MOLM-l	80.45	Chronic myeloid leukemia	DSMZ, ACC 720	80% RPMI 1640 + 20% h.i. FBS
51	H1573	80.64	Lung adenocarcinoma NSCLC	ATCC, CRL- 5877	90% RPMI 1640 + 10% h.i. FBS
52	PANC0504	82.22	Pancreatic carcinoma	ATCC, CRL2557	90% RPMI 1640 + 10% h.i. FBS
53	LSI 80	82.71	Colorectal adenocarcinoma	ATCC, CL-187	90% DMEM + 10% h.i. FBS
54	HCC1419	83.80	Breast carcinoma, TNBC	ATCC, CRL2326	90% RPMI 1640 + 10% h.i. FBS
55	COLO320	85.17	Colorectal adenocarcinoma	ATCC, CCL220	90% RPMI 1640 + 10% h.i. FBS
56	HCC 1806	85.87	Breast carcinoma, TNBC	ATCC, CRL- 2335	90% RPMI 1640 + 10% h.i. FBS
57	H1975	87.1 7	Lung adenocarcinoma NSCLC	ATCC, CRL5908	90% RPMI 1640 + 10% h.i. FBS
58	AGS	87.94	Gastric adenocarcinoma	ATCC, CRLI739	90% F-12K+ 10% h.i. FBS
59	H23	88.82	Lung adenocarcinoma NSCLC	ATCC, CRL5800	90% RPMI 1640 + 10% h.i. FBS
60	U87 MG	89.20	Glioblastoma	ATCC, HTB-14	90% DMEM + 10% h.i. FBS
61	SW480	90.46	Colorectal adenocarcinoma	ATCC, CCL228	90% Leibovitz's L-15 Medium + 10% h.i. FBS
62	SNU-16	90.47	Gastric carcinoma	ATCC, CRL5974	90% RPMI 1640 + 10% h.i. FBS
63	H44l	91.12	Lung adenocarcinoma NSCLC	ATCC, HTB174	90% RPMI 1640 + 10% h.i. FBS
64	769-P	91.60	Rénal cell adenocarcinoma	ATCC, CRL1933	90% RPMI 1640 + 10% h.i. FBS
65	COR-L23	98.44	Large cell lung carcinoma	DSMZ, ACC 882	90% RPMI 1640 + 10% h.i. FBS
66	HGC-27	ioo.io	Gastric carcinoma	Millipore Sigma, CB 94042256	90% EMEM + 2mM Glutamine + 1% Non Essential Amino Acids + 10% h.i. FBS
68	H69	100.30	Lung small cell carcinoma	ATCC, HTBH9	90% RPMI 1640 + 10% h.i. FBS

ns

	Cell Line Name	ICso (iiM)	Junior Type, Disease	Source, Catalog #	Culture Medium
69	H727	100.50	Bronchial lung carcinoid	ATCC, CRL5815	90% RPMI 1640 + 10% h.i. FBS
70	SW 1990	104.10	Pancreatic adenocarcinoma	ATCC, CRL2172	90% Leibovitz's L-15 Medium + 10% h.i. FBS
71	H2l l	104,80	Small cell lung carcinoma	ATCC, CRL- 5824	90% RPMI 1640 + 10% h.i. FBS
72	THP-l	106.90	Acute monocytic leukemia	ATCC, TIB202	90% RPMI 1640 + 10% h.i. FBS + 0.05mM BME
73	H446	112.20	Small cell lung carcinoma	ATCC, HTB- 171	90% RPMI 1640 + 10% h.i. FBS
74	T47D	114.26	Mammary gland ductal carcinoma	ATCC, HTB- 133	90% RPMI 1640 + 0.2 units/mL bovine insulin + 10% h.i. FBS
75	HI688	115.50	Small cell lung carcinoma	ATCC, CCL257	90% RPMI 1640 + 10% h.i. FBS
76	SKOV3	116.90	Ovarian adenocarcinoma	ATCC, HTB-77	90% McCoy's 5a Medium Modified + 10% h.i. FBS
77	H2444	117.10	Lung adenocarcinoma NSCLC	ATCC, CRL5945	90% RPMI 1640 + 10% h.i. FBS
78	H2228	117.93	Lung adenocarcinoma. NSCLC	ATCC, CRL5935	90% RPMI 1640 + 10% h.i. FBS
79	H1792	120.53	Lung adenocarcinoma NSCLC	ATCC, CRL5895	90% RPMI 1640 + 10% h.i. FBS
80	GP2D	121.30	Colon adenocarcinoma	Millipore Sigma, CB 950914	DMEM + 2mM Glutamine + 10% h.i. FBS
81	PANCO2O3	126.10	Pancreatic adenocarcinoma	ATCC, CRL2553	85% RPMI 1640 + lOU/mL human recombinatant insulin + 15% h.i. FBS
82	LNCaP	135.90	Prostate carcinoma	ATCC, CRL1740	90% RPMI 1640 + 10% h.i. FBS
83	786-0	138.40	Rénal cell adenocarcinoma	ATCC, CRL1932	90% RPMI 1640 + 10% h.i. FBS
84	H2087	141.20	Lung adenocarcinoma NSCLC	ATCC, CRL- 5922	95% RPMI 1640 + 5% h.i. FBS
85	Caki-2	141.70	Kidney clear cell carcinoma	ATCC, HTB-47	90% McCoy’s 5 a Medium Modified + 10% h.i. FBS
86	ZR-75-l	144.00	Mammary gland ductal carcinoma	ATCC, CRL1500	90% RPMI 1640 + 10% h.i. FBS

116

	Cell Line Name	ICso (nM)	Tunior Type, Disease	Source, Catalog #	Culture Medium
87	H358	147.60	Bronchioalveolar carcinoma NSCLC	ATCC, CRL- 5807	90% RP Ml 1640 + 10% h.i. FBS
88	HCC1569	151.3Ο	Mammary gland metaplastic carcinoma	ATCC, CRL- 2330	90% RPMI 1640 + 10% h.i. FBS
89	KG-l	152.80	Acute myelogenous leukemia	ATCC, CCL246	80% Iscove's Modified Dulbecco's Medium + 20% h.i. FBS
90	KATO! II	158.50	Gastric carcinoma	ATCC, HTB103	80% Iscove’s Modified Dulbecco's Medium + 20% h.i. FBS
91	HCC38	160.80	Mammary gland ductal carcinoma	ATCC, CRL- 2314	90% RPMI 1640 + 10% h.i. FBS
92	PC-9	163.79	Lung adenocarcinoma NSCLC	Millipore Sigma, CB 90071810	90% RPMI 1640 + 2iiiM Glutamine + !0%h.i. FBS
93	SK-LU-l	165.90	Lung adenocarcinoma NSCLC	ATCC, HTB-57	90% Eagle's Minimum Essential Medium + 10% h.i. FBS
94	A-498	169.20	Kidney carcinoma	ATCC, HTB-44	90% Eagle's Minimum Essential Medium + 10% h.i, FBS
95	U138-MG	169.50	Brain glioblastaoma	ATCC, HTB-16	90% Eagle's Minimum Essential Medium + 10% h.i. FBS
96	JPC3	170.80	Lung carcinoma	JCRB, JCRB0077	90% RPMI 1640 + 10% h.i. FBS
97	H1930	180.70	Lung carcinoma small cell lung cancer	ATCC, CRL5906	90% RPMI 1640 + 10% h.i. FBS
98	Hs746T	183.40	Gastric carcinoma	ATCC, HTB135	90% DMEM + 10% h.i. FBS
99	PANCl	212.60	Pancreatic ductal epithelioid carcinoma	ATCC, CRL- 1469	90% DMEM + 10% h.i. FBS
ΙΟΟ	CT26	214.59	Murine colon carcinoma fibroblasts	ATCC, CRL2638	90% RPMI 1640 + 10% h.i. FBS
ΙΟΙ	MC38	216.94	Murine colon adenocarcinoma	Creative Bioarray, CSC6983J	90% DMEM + 10% h.i. FBS
102	PANC0403	220.00	Pancreatic adenocarcinoma	ATCC, CRL2555	85% RPMI 1640 + 20U/mL human

117

	Cell Line Name	IC50 (nM)	Tunior Type, Disease	Source, Catalog #	Culture Medium
					recombinant insulin + I5%h.i. FBS
103	ASPCl	240.85	Pancreatic adenocarcinoma	ATCC, CRL- 1682	90% RPMI 1640 + IO%h.i. FBS
104	BT-474	277.60	Mammary gland ductal carcinoma	ATCC, HTB-20	Hybri-Care Medium reconstituted in l L water and L 5g/L of Sodium bicarbonate. 10% h.i. FBS
105	Ul I8-MG	310.00	Brain glioblastoma	ATCC, HTB-15	90% DMEM + 10% h.i. FBS
106	H2291	361.90	Lung adenocarcinoma NSCLC	ATCC, CRL- 5939	90% RPMI 1640 + 10% h.i. FBS
107	CAPAN2	365.20	Pancreatic adenocarcinoma	ATCC, HTB-80	McCoy's 5a Medium Modified + 10% h.i. FBS
108	SUIT-2	393.00	Pancreatic tubular adenocarcinoma	JCRB, JCRB1094	90% RPMI 1640 + 10% h.i. FBS
I09	BJ	516.I6	Skin fibroblast	ATCC, CRL- 2522	90% EMEM + 10% h.i. FBS

Inhibition of kinase phosphorylation in MV-4-l l and M0LM13 cell lines

Inhibition of kinase phosphorylation assay was performed by Western Blot using MV-411 and MOLM13 cell lines. Cells were plated in 24 well plates at l million cells per well and then 5 treated with compounds at different concentrations, starting at 100 nM, l:4 titration with DMSO as control. After 4 hour-incubation, cells were w^rashed once with ice-cold PBS, and lysed in RIPA lysis buffer with protease and phosphatase inhibitors. The cell lysâtes were then sonicated and spun down, and 40 ug of proteins were separated by sodium dodecyl sulfate electrophoresis on a 4 to 12% Bis-Tris polyacrylamide gel and transferred onto nitrocellulose membranes using Bio10 Rad Trans-Blot Turbo Transfer System (Bio-Rad). Blocking was performed using 3% BSA or 5% Non-fat dry milk (Fisher Scientific) in TBST (Tris-buffered saline contaîning 0.05% of Tween 20) (Bio-Rad Laboratories, Inc.). The membranes were incubated ovemight with anti-phospho-FLT3 (Υ589/Ύ591) (CST#604l3), anti-phospho-STAT5 (Y694) (CST#4322), anti-Phospho-p44/42 MAPK (Erkl/2) (T202/Y204) (CST#9l0l), anti-Phospho-S6 Ribosomal Protein (S235/236) (CST# 4858) and anti-P-Actin (CST#8457) each diluted 1000 times in 3% BSA in TBST. Membranes were washed with TBST and then incubated at room température for I hour with HRPlabeled anti-rabbit IgG polyclonal antibody (CST#7074) diluted 1000 times in 3% BSA. After TBST washing, blots were developed with a chemiluminescence System (SuperSignal West Femto Maximum Sensitivity Substrate, Pierce #34095). Luminescence was detected by Ll-COR Odyssey

H8

M imaging System and luminescence intensity were quantified using Empiria Studio 2.2 software. Data was analyzed using GraphPad Prism 9 (GraphPad Software, San Diego, CA) to obtain IC50 values.

Table 7. Inhibition of kinase phosphorylation with Ex. 6 and Gilteritinib in MV-4-I l and 5 MOLM-13 cells.

	MV-4-11 ICso(nM)	MOLM-13 IC₅₀(nM)
	Gilteritinib	Ex. 6	Gilteritinib	Ex. 6
pFLT3	0.84	0.16	1.03	0.32
pSTAT5	1.75	0.60	2.23	0.72
pERK	1.63	2.85	1.31	4.11
pS6	0.92	0.41	7.91	2.47

Modulation of alternative splicing in MV-4-l l and MOLM-13 cells with Ex. 6.

Alternative splicing ratio of RNA transcripts was measured by qPCR in MV-4-l l and MOLM-13 cell lines. Cells were plated in 24 well plates at 1 million cells per well and then treated 10 with compounds at different concentrations, with DMSO only as control. After 8-hour-incubation, cells were harvested and washed once with ice-cold PBS, and lysed in RNA lysis buffer (Invitrogen). Total RNA was extracted using the RNA Purification Kit (Invitrogen). 2 ug of RNA was used for cDNA synthesis using cDNA synthesis kit (ThermoFisher) and 20 ng of cDNA was used for qPCR using PROFLEX 96-Well PCR System (ThermoFisher).

Primers with the following sequences were used for the measurcment:

BCLAF1 exonl0-12/exon 10-11 (TaqMan, IDT)

BCLAF1 (ex 10-11) F: CAGGAGTTAGCCGACCACG (SEQ ID NO; 1) BCLAF1 (ex 10-11 ) R: GTTTGGACCAGTATTTGTCCCAG (SEQ ID NO: 2) BCLAF1 (ex 10-11 ) probe: AACCTTTTTTCGAATTAGAGGCA (SEQ ID NO: 3) 20 BCLAF1 (ex 10-12) F: TGCAGGAGTTAGCCGACCAC (SEQ ID NO: 4)

BCLAF1 (ex 10-12) R: TTGGCCCAATAATCCACACC (SEQ ID NO: 5) BCLAF1 (ex 10-12) probe: AACCTTTCATGACGACAGAG (SEQ ID NO: 6)

PRS6KB1 exon6-8/exon 6-7 (TaqMan. IDT)

S6K (ex6-7) F: TTATGCAGTTAGAAAGAGAGGGAATATTT (SEQ ID NO: 7) S6K (ex6-7) R: CCCCAAAGCCATGGAGATTT (SEQ ID NO: 8)

S6K (ex6-7) probe: TGGAAGACACTGCCTGCTTTTACTTGG (SEQ ID NO: 9) S6K (ex6-8) F: TTATGCAGTTAGAAAGAGAGGGAATATTT (SEQ ID NO: 10) S6K (ex6-8) R: GATTCTTTGCATAGTCCAAAGTCTGT (SEQ ID NO: 11)

S6K (ex6-8) probe: TGGAAGACACTGCCTGGTCATGTGAAA (SEQ ID NO: 12)

BCLxS/xL (SYBR Green, IDT)

BCLxS F: GAGCTTTGAACAGGATACTTTTGTG (SEQ ID NO: 13)

BCLxS R: GAAGAGTGAGCCCAGCAGAA (SEQ ID NO: 14)

119

BCLxL F: GATGGCCACTTACCTGAATGA (SEQ ID NO: 15)

BCLxL R: TGCTGCATTGTTCCCATAGA (SEQ ID NO: 16)

Table 8. Modulation of alternative splicing of BCLAFl, SK6K and BCL-x in MOLM-L3 cell 5 line with Ex. 6 by qPCR method.

Alternative Splicing Ratio in MOLM-13	BCLAFl Ex. 10-12/Ex. 10-11	S6K Ex. 6-8/Ex. 6-7	BCL-xS/xL
DMSO	1.00	1.02	1.00
30 nM (Ex. 6)	1.80	1.60	1.51
100 nM (Ex. 6)	5.76	2.71	3.54
300 nM ((Ex. 6)	6.89	8.08	4.20

Table 9. Modulation of alternative splicing of BCL-x in MV-4-l l cell line with Ex. 6 by qPCR method.

Alternative Splicing Ratio in MV-4-11	BCL-xS/xL 6-hour	BCL-xS/xL 24-hour
DMSO	1	1
2 nM (Ex. 6)	0.7	0.6
10 nM (Ex. 6)	1.1	0.9
50 nM (Ex. 6)	1.4	1.3
250 nM (Ex. 6)	3.7	7.3

Alternative splicing events by RNAseq in MOLM-13

Alternative splicing events were measured by RNAseq in MOLM-13 cell line. Cells were plated in 24 well plates at l million cells per well and then treated with compounds at different concentrations, with DMSO as control. After 8 hour-incubation, cells were harvested and washed once with ice-cold PBS, and lysed in RNA lysis buffer (Invitrogen). Total RNA was extracted 15 using the RNA Purification Kit (Invitrogen). RNAseq was performed by Biomiga (San Diego).

Table 10. Alternative splicing events by RNAseq in MOLM-13

AS Events	A3'SS	A5'SS	MXE	RI	SE
30 nM (Ex. 6)	371	289	187	536	2054
100 nM (Ex. 6)	559	443	325	841	4568
300 nM (Ex. 6)	722	590	355	1184	5093

A3’SS: alternative 3’ splice site; A5’SS: alternative 5’ splicesite; MXE: mutua ly exclusive exons; RI: retained intron; SE: skipped exon.

Inhibition of tumor growth by Ex. 6 in cell-derived xenograft (CDX) tumor models in mice.

120

Tumor cells were cultured using standard techniques described above and were harvested and pelleted by centrifugation at I000 rpm for 5 minutes. The pelleted cells were washed once with serum-free medium followed by subséquent re-suspension in the serum-free medium supplemented with 50% matrigel (Corning, Inc). Five million tumor cells were implanted 5 subcutaneously to the right flank of each mouse, followed by tumor volume and body weight measurement once or twice per week with an clectronic caliper (Fowler) and a balance, respectively. When the average tumor size reached a pre-determined volume, the mice were grouped and treated with Ex. 6. One group of mice were treated with vehicle as control. During treatment, mice were monitored daily by cage side observation. The tumor volume (TV) and body 10 weight was measured twice or three times per week during the treatment. Study ended either after 4-5 weeks of treatment or tumor volume of any mice reached 1000 or 2000 mm³. Tumor growth inhibition (TGI) was be calculated as follows: l 00%* j l [(TVTreated Last Day ofTreatment-TVTreated First Day of Treatment )/(TVControl on Last Day of Treatment-TVconlrol on First Day of Treatment )] j when TVTreated Last Day of Treatment + TVTreated First Day of Treatment. In the CBSC of TVTreated Last Day of Treatment < TVTreated First Day of Treatment, TGI l 5 was calculated as l 00%*(2- TVTreated Last Day ofTreatment/TVTreated First Day of Treatment)·

Table 11. Inhibition of tumor growth by Ex. 6 in CDX tumor models with orall, once a day (QD) or other dosing schedule.

Tumor Model	Ex. 6 Dose and Schedule	Treatment Duration (day)	N	TGI %
MV-4-1I	6.25 mg/kg QD	20	6	98.8
MV-4-H	12.5 mg/kg QD	20	6	189
MV-4-H	25 mg/kg QD	20	6	200
MV-4-H	25 mg/kg QD, 5dOn-2dOff	20	6	200
MOLM-13	12.5 mg/kg QD	I3	8	74
MOLM-13	25 mg/kg QD	13	8	94
IMR-32	25 mg/kg QD	8	3	82
SW403	25 mg/kg QD	20	5	84
SW480	25 mg/kg QD	28	4	93

Claims

l. A compound of the formula I

wherein ring A is a 5- to 10-membered heteroarylene;

ring B is a 5- to 10-membered heteroarylene or Co-Cio arylene;

each L is independently O-, -S-, -S(O)-, -S(O)₂-, -N(R⁶)C(O)-, -C(O)N(R⁶)-, -N(R⁶)-, -N(R⁶)S(O)-, -S(O)N(R⁶)-, -N(R⁶)S(O)2-, -S(O)2N(R⁶)-, or -C(R⁷)(R^S)-, provided that (L)p does not comprise an 0-0, S-0, or N-N bond, and the point of covalent attachment of (L)_p to -NR³- does not form a -N-N- or a -O-N- bond;

each R¹ and R² when présent, is independently deuterium, halogen, Ci-Cô alkyl, C2-Cô alkenyl, C2-Cô alkynyl, C2-Cô cycloalkyl, 3- to 7-membered heterocycloalkyl, Q-Cioaryl, 5- to 10-membered heteroaryl, -OR^a, -OC(O)R^a, -OC(O)NR^aR^b, -OS(O)R^a, -OS(O)2R^a, -SR^a, -S(O)R^a, -S(O)2R^a, -S(O)NR^aR^b, -S(O)2NR^aR^b. -OS(O)NR^aR^b, -OS(O)2NR^aR^b, -NR^aR^b, -NR^aC(O)R^b, -NR^aC(O)OR^b, -NR^aC(O)NR^aR^b, -NR^aS(O)R^b, -NR^aS(O)2R^b, -NR^aS(O)NR^aR^b, -NR^aS(O)2NR^aR^h, -C(O)R^a, -C(O)OR^a, -C(O)NR^aR^b, -PR^aR^b, -P(O)R^aR^b, -P(O)2R^aR^b, -P(O)NR^aR^b, -P(O)2NR^aR^b, -P(O)OR^a, P(O)2OR^a, -CN, or -NO2, wherein each hydrogen atom in Ci-Cô alkyl, C2-Cô alkenyl, C2-Cô alkynyl, Cj-Cô cycloalkyl, 3- to 7-membercd heterocycloalkyl, Cô-Cioaryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Cô alkyl, Ci-Cô haloalkyl, OR^C, -OC(O)R^C, -OC(O)NRR^d, - -OS(O)R^C, -OS(O)2R^e, -OS(O)NR^cR^d, -OS(O)₂NR^cR^d, -SR^C,

122

-S(O)R^C, -S(O)2R^C, -S(O)NR^cR^d, -S(O)2NR^cR^d, -NR^cR^d, -NR^cC(O)R^d, -N(C(O)R^e)(C(O)R^d), -NR^cC(O)OR^d, -NR^cC(O)NR^cR^d, -NR^cS(O)R^d, -NR^cS(O)2R^d, -NR^,:S(O)NR^à:R^d, -NR^cS(O)2NR^cR^d, -C(O)R^C, -C(O)OR^C, -C(O)NR^cR^d, -PR^cR^d, -P(O)R^eR^d, -P(O)2R^cR^d, -P(O)NR^cR^d, -P(O)2NR^eR^d, -P(O)OR^C, -P(O)2OR^e, -CN, or -NO2;

R³ is H, deuterium, Ci-Cô alkyl, C2-Cô alkenyl, C2-Cô alkynyl, C3-C6 cycloalkyl, 3- to 7membered heterocycloalkyl, Cft-Cjo aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C|-Co alkyl, C2-C0 alkenyl, C2-C& alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cioaryl, or 5- to 10-membered heteroaryl is independently optionally substituted by -OR^C, -OC(O)R^C, -OC(O)NR^çR^d, -OS(O)R^C, -OS(O)2R^c, -OS(O)NR^cR^d, -OS(O)₂NR^cR^d, -SR^C, -S(O)R^C, -S(O)2R^C, -S(O)NR^cR^d, -S(O)2NR^cR^d, -NR^cR^d, -NR^cC(O)R^d, -N(C(O)R^c)(C(O)R^d), -NR^cC(O)OR^d. -NR^cC(O)NR^cR^d, -NR^cS(O)R^d, -NR^cS(O)₂R^d, -NR^cS(O)NR^cR^d, -NR^cS(O)2NR^cR^d, -C(O)R^C, -C(O)OR^C, -C(O)NR^cR^d, -PR^eR^d, -P(O)R^cR^d, -P(O)2R^cR^d, -P(O)NR^cR^d, -P(O)2NR^cR^d, -P(O)OR^C, -P(O)2OR^c, -CN, or -NO₂;

each R⁴ is independently deuterium, halogen, Ci-Côalkyl, C2-Cô alkenyl, C2-Cô alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cioaryl, 5- to 10-membered heteroaryl, -OR^a, -OC(O)R^a, -OC(O)NR^aR^b, -OS(O)R^a, -OS(O)2R^a, -SR^a, -S(O)R^a, -S(O)2R^a, -S(O)NR^aR^b, -S(O)2NR^aR^b, -OS(O)NR^aR”, -OS(O)2NR^aR^b, -NR^aR^b, -NR^aC(O)R^b, -NR^aC(O)OR^b, -NR^aC(O)NR^aR^b, -NR^aS(O)R^b, -NR^aS(O)2R^b, -NR^aS(O)NR^aR^b, -NR^aS(O)2NR^aR^b, -C(O)R^a, -C(O)OR^a, -C(O)NR^aR^b, -PR^aR^b, -P(O)R^aR^b, -P(O)2R^aR^b, -P(O)NR^aR^h, -P(O)2NR^aR^b, -P(O)OR^a, P(O)2OR^a, -CN, or -NO2, wherein each hydrogen atom in Ci-Cô alkyl, C2-Cô alkenyl, C2-Cô alkynyl, Cî-Cô cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-C w aryl, and 5- to lü-membered heteroaryl, îs independently optionally substituted by deuterium, halogen, Ci-Cô alkyl, Ci-Cô haloalkyl, -OR^e, -OC(O)R^e, -OC(O)NR^eR^f, -OS(O)R^e, -OS(O)2R^e, -OS(O)NR^eR^r, -OS(O)2NR^eR^f, -SR^e, -S(O)R^e, S(O)2R^e, -S(O)NR^eR^f, -S(O)2NR^eR^r, -NR^eR^r, -NR^cC(O)R^r, -NR^eC(O)OR^r, -NR^eC(O)NR^eR^f, -NR^eS(O)R^f, -NR^eS(O)2R^r, -NR^cS(O)NR^eR^f, -NR^eS(O)2NR^eR^r, -C(O)R^e, -C(O)OR^e, -C(O)NR^eR', PR^eR^f, -P(O)R^eR^r, -P(O)2R^eR^r, -P(O)NR^eR^f, -Ρ(Ο)2ΝΚ^', -P(O)OR^C, -P(O)2OR^e, -CN, or -NO₂;

R⁵ is H, deuterium, -C(O)R^C, -C(O)OR^C, -C(O)NR^çR^d, -P(O)2R^cR^d, -P(O)2NR^cR^d, -P(O)2OR^C, or -S(O)2OR^c;

each R⁶, when present, is independently H, deuterium, Ci-Cô alkyl, C₂-Cô alkenyl, C₂-C& alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Ciq aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in Cj-Cô alkyl, C₂-Cô alkenyl, C₂-Cô alkynyl, Cj-Cô cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-C 10 aryl, or 5- to 10-membered heteroaryl is 123 independently optionally substituted by -OR^C, -OC(O)R^Ç, -OC(O)NR^eR^d, -OS(O)R^C, -OS(O)2R^C, -OS(O)NR^cR^d, -OS(O)2NRR^d, -SR^C, -S(O)R^C, -S(O)2R^C, -S(O)NR^cR^d, -S(O)2NR^cR^d, -NR^eR^d, -NR^cC(O)R^d, -N(C(O)R^e)(C(O)R^d), -NR^cC(O)OR^d, -NR^eC(O)NR^cR^d, -NR^cS(O)R^d, -NR^cS(O)2R^d, -NR^cS(O)NR^cR^d, -NR^cS(O)2NR^cR^d, -C(O)R^C. -C(O)OR^C, -C(O)NR^cR^d, -PR^cR^d, -P(O)R^cR^d, -P(O)₂R^cR^d, -P(O)NR^cR^d, -P(O)2NR^cR^d, -P(O)OR^C, -P(O)2OR^c, -CN, or -NO₂;

each R⁷ and R⁸, is independently H, deuterium, halogen, Ci-G, alkyl, C2-C& alkenyl, C2-C& alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C&-Cio aryl, 5- to 10-membered heteroaryl, -OR^a, -OC(O)R^a, -OC(O)NR^aR^b, -OS(O)R^a, -OS(O)2R^a, -SR^a, -S(O)R^a, -S(O)2R^a, -S(O)NR^aR^b, -S(O)2NR^aR^b, -OS(O)NR^aR^b, -OS(O)2NR^aR^b, -NR^aR^b, -NR^aC(O)R^b, -NR^aC(O)OR^b, -NR^aC(O)NR^aR^b, -NR^aS(O)R^b, -NR^aS(O)2R^b, -NR^aS(O)NR^aR^b, -NR^aS(O)2NR^aR^h, -C(O)R^a, -C(O)OR^a, -C(O)NR^aR^b, -PR^aR^h, -P(O)R^aR^b, -P(O)2R^aR^b, -P(O)NR^aR^b, -P(O)2NR^aR^b, -P(O)OR^a, P(O)2OR^a, -CN, or -NO2, wherein each hydrogen atom in Ci-Cè alkyl, C2-C« alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cioaryl, and 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, C|-Cô alkyl, C|-Cô haloalkyl, -OR^e, -OC(O)R^e, -OC(O)NR^eR^f, -05(0^, -OS(O)2R^e, -OS(O)NR^eR^f, -OS(O)2NR^eR^f, -SR^e, -S(O)R^e, S(O)2R^e, -S(O)NR^eR^f, -S(O)2NR^cR^r, -NR^eR^r, -NR^eC(O)R^r, -NR^eC(O)OR^f, -NR^eC(O)NR^cR‘·, -NR^eS(O)R^r, -NR^eS(O)2R^r, -NR^eS(O)NR^eR', -NR^eS(O)2NR^eR^f, -C(O)R^e, -C(O)OR^e, -C(O)NR^cR^r, PR^eR^r, -P(O)R^eR^r, -P(O)2R^eR^r, -P(O)NR^eR^f, -P(O)2NR^eR^r, -P(O)OR^e, -P(O)2OR^e. -CN, or -NO2; or two of R' and R⁸, taken together with the carbon or carbons to which they are attached, optionally combine to form a Cj-Cscycloalkyl, 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in the C3-Cf> cycloalkyl or 3- to 7-membered heterocycloalkyl formed when two of R⁷ and R⁸ are taken together is independently optionally substituted by -OR^e, -OC(O)R^e, -OC(O)NR^L'R^r, -OS(O)R^e, -OS(O)2R^e, -OS(O)NR^eR^r, -OS(O)2NR^eR^f, -SR^e, -S(O)R^e, -S(O)2R^e, -S(O)NR^eR^f, -S(O)2NR^eR^r, -NR^eR^f, -NR^eC(O)R^f, -NR^eC(O)OR^r, -NR^eC(O)NR^eR^r, -NR^eS(O)R^f, -NR^eS(O)2R^f, -NR^cS(O)NR^eR^r, -NR^eS(OhNR^eR^r, -C(O)R^e, -C(O)OR^e, -C(O)NR^eR^r, -PR^eR^r, -P(O)R^eR^r, -P(O)2R^cR^r, -P(O)NR^eR^f, P(O)2NR^cR‘, -P(O)OR^e, -P(O)2OR^e, -CN, or -NO₂;

each R^a, R^b, R^c, R^d, R^e, and R¹ is independently selected from the group consisting of H, deuterium, Ci-Ce alkyl, C2-Cô alkenyl, C2-Cô alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Cô-Cioaryl, Ci-Cô alkylene-Cô-Cio aryl, 5- to 10-membered heteroaryl, and Ci-C& alkylene-5- to 10-membered heteroaryl, or R^a and R^b or R^c and R^d or R^e and R¹, taken together with the atom to which they arc attached, form a 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in Ci-Cô alkyl, C2-Cft alkenyl, C₂-Cô alkynyl, C₃-Cô cycloalkyl, 3- to 7-membered 124 heterocycloalkyl, Cô-Cio aryl, Ci-Cô alkylene-Cô-Cw aryl, 5- to lO-membcrcd heteroaryl, or Ci-Cô alkylene-5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C|-C₆ alkyl, Ci-C₆ haloalkyl, -OH, -OC)-C₆ alkyl, -OC(O)-(H or Ci-C₆ alkyl), -OC(O)N(H or Ci-C₆alkyl)₂, -OC(O)N(C₂-C₆ alkylene), -OS(O)-(H or Ci-C_b alkyl), -OS(O)₂-(H or Ci-C₆ alkyl), -OS(O)N(H or Ci-C₆ alkyl)₂, -OS(O)N(C₂-C₆ alkylene), -OS(O)₂N(H or Ci-C₆ alkyl)₂, -OS(O)₂N(C₂Cô alkylene), -S(H or Ci-Cô alkyl), -S(O)(H or Ci-Cô alkyl), -S(O)₂(H or Ci-Cô alkyl), -S(O)N(H or Ci-Q alkyl)₂, -S(O)N(C₂-Cô alkylene), -S(O)₂N(H or Ci-Cô alkyl)₂, -S(O)₂N(C₂-Cô alkylene), -N(H or Ci-Cô alkyl)₂, -N(C₂-C₆ alkylene), -N(H or Ci-C₆ alkyl)C(O)-(H or Ci-C_b alkyl), -N(H or Ci-C₆alkyl)C(O)O(H or Ci-Cô alkyl), -N(H or Ci-Cô alkyl)C(O)N(H or C|-C₆ alkyl)₂, -N(H or C|-C& alkyl)C(O)N(C₂-C₆ alkylene), -N(H or Ci-C₆ alkyl)S(O)-(H or C)-Cô alkyl), -N(H or Ci-C₆alkyl)S(O)₂(H or Ci-C₆ alkyl), -N(H or Ci-C₆ alkyl)S(O)N(H or Ci-C₆ alkyl)₂, -N(H or Ci-C₆alkyl)S(O)N(C₂-Cô alkylene), -N(H or Ci-C₆ alkyl)S(O)₂N(H or Ci-C_b alkyl)₂, -N(H or Ci-C₆alkyl)S(O)₂N(C₂-C₆ alkylene), -C(O)-(H or Ci-C₆ alkyl), -C(O)O(H or Cj-Cô alkyl), -C(O)N(C₂-C₆alkylene), -P(H or Ci-Côalkyl)₂, -P(C₂-Cô alkylene), -P(O)(H or Ci-Cô alkyl)₂, -P(O)(C₂-C_b alkylene), -P(O)₂(H or Ci-Cô alkyl)?, -P(O)₂(C₂-Cô alkylene), -P(O)N(H or Ci-C₆ alkyl)₂, -P(O)N(C₂-C₆alkylene), -P(O)₂N(H or Ci-Cô alkyl)?, -P(O)₂N(C₂-Cô alkylene), -P(O)O(H or Ci-Cô alkyl), P(O)₂O(H or Ci-Cô alkyl), -CN, or -NO₂;

m îs 0, l, 2, or 3;

n is 0, l, 2, 3, or 4;

p is 3, 4, 5, 6, or 7; and q is 0, l, or 2 or a pharmaceutically acceptable sait thereof.
2. The compound of claim l, or a pharmaceutically acceptable sait thereof, having the formula II

125

wherein “------” is optionally a carbon-carbon single bond or a carbon-carbon double bond, and ring

A is a 5-membered heteroarylene.
3. The compound of claim l or 2, or a pharmaceutically acceptable sait thereof, having the formula

III

10 wherein

X¹, X², and X³ are each independently-O-, -S-, =C(H)-, =C(R’)-, -N(H)-, -N(R¹)- or=Nand ring A is a 5-membered heteroarylene, provided that at least one of X¹, X², and X³ is not =C(H)-

126 , or =C(R and “------” is optionally a carbon-carbon single bond or a carbon-carbon double bond.
4. The compound of any one of the preceding daims, or a pharmaceutically acceptable sait thereof,

5 wherein ring A is a 5-membercd heteroarylene selected from the group consisting of

10 wherein each “ΆΛΛΓ” represents a point of covalent attachment.
5. The compound of any one of the preceding daims, or a pharmaceutically acceptable sait thereof, wherein ring A is a 5-membered heteroarylene seleded from the group consisting of

127

wherein each “ ww’ represents a point of covalent attachment.

5
6. The compound of any one of the preceding ciaims, or a pharmaceutically acceptable sait thereof, wherein ring A is a 5-membered heteroarylene selected from the group consisting of

wherein each “^ΛΓυν” represents a point of covalent attachment.
7. The compound of any one of the preceding ciaims, or a pharmaceutically acceptable sait thereof,

15 wherein ring B is a phenylene, and n is 0, l, or 2.

128
8. The compound of any one of the preceding daims, or a pharmaceutically acceptable sait thereof, wherein ring B is a phenylene, and n is 0, or n is l and R² is methyl, ethyl, F, Cl, or Br.
9. The compound of any one of daims l to 6, or a pharmaceutically acceptable sait thereof, wherein ring B is a 5- to 10-membered heteroarylene.
10. The compound of any one of daims l to 6 or 9, or a pharmaceutically acceptable sait thereof, wherein ring B is a 5-membered heteroarylene selected from the group consisting of

wherein each “άλα/'” represents a point of covalent attachment.
11. The compound of any one of daims l to 6, 9, or 10, or a pharmaceutically acceptable sait thereof, wherein ring B is a 5-membered heteroarylene selected from the group consisting of

wherein each “ΆΛ/ν”' represents a point of covalent attachment.
12. The compound of any one of the preceding daims, or a pharmaceutically acceptable sait thereof, wherein R³ is H or methyl.
13. The compound of any one of the preceding daims, or a pharmaceutically acceptable sait thereof.

129 wherein R⁴ is H or methyl.
14. The compound of any one of the preceding claims, or a pharmaceutically acceptable sait thereof, wherein R⁵ is H.
15. The compound of any one of the preceding claims, or a pharmaceutically acceptable sait thereof, wherein each L is independently -C(R⁷)(R⁸)-, -C(O)-, -O-, or -N(R⁶)-, provided that (L)p does not comprise a -O-O- or a -O-N(R⁶)- bond, and the point of covalent attachaient of (L)p to -NR³- does not form a -N-N- or a -O-N- bond.
16. The compound ofany one of the preceding claims, or a pharmaceutically acceptable sait thereof, wherein -(L)_P- is -(CR⁷R⁸)C(O)N(R⁶)-(CR⁷R⁸)2-, -(CR⁷R⁸)N(R⁶)C(O)-( CR⁷R⁸)2-,

-N(R⁶)-C(O)(CR⁷R⁸)2O(CR⁷R⁸)2-, -CR⁷R⁸O(CR⁷R⁸)2O-(CR⁷R⁸)2, -O(CR⁷R⁸)2O(CR⁷R⁸)2-,

-CR⁷R⁸O-CR⁷R⁸-C(O)N(R⁶)-(CR⁷R⁸)2-, -(CR⁷R⁸)3O(CR⁷R⁸)2-, -(CR⁷R⁸)2O(CR⁷R⁸)₃-,

-CR⁷R⁸-N(R⁶)-(CR⁷R⁸)2-, -CR⁷R⁸-N(R⁶)-(CR⁷R⁸)3-, -O(CR⁷R⁸)2O(CR⁷R⁸)3-, -(CR⁷R⁸)2N(R⁶)-(CR⁷R⁸)3-, -(CR⁷R⁸)2-N(R⁶)-(CR⁷R⁸)2-, -O-(CR⁷R⁸)2-, -O-(CR⁷R⁸)₃-, oi -O-(CR⁷R⁸)4-.
17. The compound ofany one of the preceding claims, or a pharmaceutically acceptable sait thereof, wherein R⁶ is H or methyl.
18. The compound of any one of the preceding claims, or a pharmaceutically acceptable sait thereof, wherein each R⁷ and R⁸ is H.
19. The compound ofany one of the preceding claims, or a pharmaceutically acceptable sait thereof, wherein -(L)_P- is -CH₂N(H)-(CH₂)₂-, -CH₂N(CH₃)-(CH₂)₂-, -O(CH₂)₂-, -OCH(CH₃)CH₂-, -O(CH₂)₃-, -O(CH₂)4-, and -O(CH2)₂O(CH₂)₂-·
20. A compound selected from the group consisting of

130

I3l

Γ

thereof.
21. A compound selected from the group consisting of

acceptable sait thereof.
22. A pharmaceutical composition comprising a compound of any one of the preceding daims, and optionally one or more excipients.
23. A compound according to any one of daims l to 21, for use in a method of treating disease in a subject.
24. Use of a compound according to any one of daims l to 21 in the manufacture of a médicament 15 for the treatment of disease in a subject.