Macrocyclic compounds and use as tyk2 inhibitors

Abstract

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

Description

MACROCYCLIC COMPOUNDS AND USE AS TYK2 INHIBITORSRELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 524,781, filed July 3, 2023, the entire disclosure of which are incorporated herein by reference.TECHNICAL FIELD

[0002] The present disclosure relates to macrocyclic compounds, pharmaceutical compositions containing macrocyclic compounds, and methods of using macrocyclic compounds to treat disease, such as human autoimmune diseases or inflammatory diseases.BACKGROUND

[0003] Protein kinases are tightly regulated signaling proteins that orchestrate the activation of signaling cascades by phosphorylating target proteins in response to extracellular and intracellular stimuli. The human genome encodes approximately 518 protein kinases (Manning G, et al The protein kinase complement of the human genome. Science. 2002, 298:1912-34). Dysregulation of kinase activity is associated with many diseases, including autoimmune diseases, and cardiovascular, degenerative, immunological, infectious, inflammatory, and metabolic diseases (Levitzki, A. Protein kinase inhibitors as a therapeutic modality. Acc. Chem. Res. 2003, 36:462-469). The molecular bases leading to various diseases include kinase gain- and loss-of-function mutations, gene amplifications and deletions, splicing changes, and translocations (Wilson LJ, et al New Perspectives, Opportunities, and Challenges in Exploring the Human Protein Kinome. Autoimmune disease Res. 2018, 78:15-29). The critical role of kinases in autoimmune disease and other diseases makes them attractive targets for drug inventions with 52 small molecule kinase inhibitors have been approved and 46 of them for autoimmune disease targeted therapies (Roskoski R Jr, Properties of FDA-approved Small Molecule Protein Kinase Inhibitors: A 2020 Update. Pharmacol Res 2020, 152:104609). Cytokine signaling is essential for cell growth, hematopoiesis, and immune system function. Cytokine-mediated receptor dimerization induces intracellular activation of receptor-bound Janus kinases (JAKs), which then induce downstream transcriptional responses. The Janus Kinase Signal Transducer and Activator of Transcription (JAK-STAT) pathway plays a significant role in both normal and pathological states of immune-mediated inflammatory diseases (O’Shea JJ, et al The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu Rev Med. 2015, 66:311-28). Targeting JAK-associated pathways by JAK inhibitors has achieved clinical success for a wide array of diseases, including ruxolitinib andfedratinib for myeloproliferative neoplasms, and tofacitinib, upadacitinib, and baricitinib for rheumatoid arthritis and other immune-mediated inflammatory disease (McLoman DP, et al Lancet. 2021, 398:803-816). However, it is challenging to achieve isoform selective JAK inhibitors and almost all these approved kinase domain ATP competitive JAK inhibitors display significant undesirable adverse effects due to inhibition of multiple JAK family members. The JAK kinases are large multidomain protein including the PER domain [JH6- JH7] and the SH2 domain [JH3-JH5], both mediating receptor interactions, the pseudokinase domain [JH2] with regulatory function, and the kinase catalytic domain [JH1] (Ganido-Trigo A and Salas, A., Journal of Crohn's and Colitis, 2020, S713-S724). The pseudokinase domain regulates the kinase domain by steric inhibition of ATP binding and / or a reduction in flexibility of the kinase active site required for catalysis (Patrick J, et al PNAS 2014 111: 8025-8030). Although JAK family members have high sequence homology within the catalytic domains, the distinguishing pseudokinase domain (JH2) in the JAK family could provide an ideal “allosteric” site for the development of highly selective JAK inhibitors. TYK2, a member of JAK family, play important role in regulating the signaling of a wide range of proinflammatory cytokines including IL12, IL23, and type 1 interferons (IFNa). A highly selective TYK2 inhibitor is needed for an optimal benefit-safety balance for the treatment of human autoimmune diseases including multiple sclerosis, Crohn’s disease, psoriasis, etc. (Leitner, N. R., et al Tyrosine kinase 2- surveillant of tumours and bona fide oncogene. Cytokine 2017, 89, 209-218).

[0004] Therefore, the discoveiy and development of highly selective inhibitors of the JAK family, such as TYK2 inhibitors targeting the TYK2 JH2 pseudokinase domain represents a new therapeutic invention for the treatment of human autoimmune diseases including multiple sclerosis, Crohn’s disease, psoriasis, and the like.SUMMARY

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

[0006] wherein

[0007] X is -O- or -NR5-;

[0008] R1and R1aare each independently H, deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aiyl, 5- to 10- membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NR*C(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or-NCh, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaiyl, is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReR<’, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReR1, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(0)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, orNO2;

[0009] R2is H, deuterium, C1-C6alkyl, or -OC1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl and -OC1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O>2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;

[0010] each of R2a, R5, R8, R9, and R11is independently H, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaiyl, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2- -C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -0C(0)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O>2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P^R^, -P(O)2ReRf, -PfOJNReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;83573406614[Oil] each of R3, R4, R3a, R4a, R3b, and R4bis independently H, deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, -ORe, -OC(O)Re, -OC(O)NRcRd, -OC(=N)NRcRd, -OS(O)Re, -OS(O)2Re, -OS(O)NR°Rd, -OS(O)2NRcRd, -SRe, -S(O)Re, -S(O)2Re, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NReC(=N)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Re, -C(O)ORe, -C(O)NRcRd, -C(=N)NReRd, -PR°Rd, -P(O)RcRd, -P(O)2RcRd, -P(O)NR®Rd, -P(0)2NRcRd, -P(O)ORe, -P(0)20Rc, -CN, or -NO2; wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-Cw aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NRT^NR'R* -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NR*Rf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P^NRT^, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;

[0012] each of R6, R6®, and R7is independently H, deuterium, halogen, or C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O>2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf-P(O)2NReR1, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;

[0013] R10is hydrogen or deuterium; and

[0014] each Ra, Rb, Rc, Rd, Re, and Rfis independently selected from the group consisting of H, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, C1-C6alkyl -C6-Cw aryl, and 5- to 10-membered heteroaryl;

[0015] provided that when X is -O-, then R2is:

[0016] deuterium;

[0017] C1-C6alkyl, wherein at least one hydrogen atom is substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, --OC(O)NReR,f-OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NR*R.f, -S(O)NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; or4

[0018] -OC1-C6 alkyl, wherein each hydrogen atom in -OC1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re-S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf-P(O)ReRf, -P(0)2R^, -P(O)NReRf, -P(0)2NReRf, -P(O)ORe, -P(0)2ORe, -CN, or -NO2.

[0019] In some embodiments, the disclosure provides a compound of the formula II, or a pharmaceutically acceptable salt thereof,II

[0020] wherein R1, R1a, R2, R23, R3, R4, R3a, R4a, R3b, R4b, R6, R6a, R7, R8, R9, R10, and R11are as described herein.

[0021] In some embodiments, the disclosure provides a compound of the formula HI, or a pharmaceutically acceptable salt thereof,in

[0022] wherein R1, R1a, R2, R21, R3, R4, R3a, R4a, R3b, R4b, R5, R6, R6a, R7, R8, R9, R10, and R11are as described herein.

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

[0024] wherein R1, R2, R2a, R3a, R7, R8, R9, and R11are as described herein.

[0025] In some embodiments, the disclosure provides a compound of the formula V, or a pharmaceutically acceptable salt thereof,V

[0026] wherein R1, R2, R2a, R3a, R5, R7, R8, R9, and R11are as described herein.

[0027] In some embodiments, the disclosure provides a compound of the formula VI, or a pharmaceutically acceptable salt thereof,VI

[0028] wherein R1, R2, R2a, R3a, R7, R8, R9, and R11are as described herein.

[0029] In some embodiments, the disclosure provides a compound of the formula VII, or a pharmaceutically acceptable salt thereof,VII

[0030] wherein R1, R2, R2a, R3a, R5, R7, R8, R9, and R11are as described herein.

[0031] In some embodiments, the disclosure provides a compound of the formula VIII, or a pharmaceutically acceptable salt thereof,VIII

[0032] wherein R1, R2, R2a, R3a, R7, and R9are as described herein.

[0033] In some embodiments, the disclosure provides a compound of the formula IX, or a pharmaceutically acceptable salt thereof,IX

[0034] wherein R1, R2, R2a, R3a, R5, R7, and R9are as described herein.

[0035] In some embodiments, the disclosure provides a compound of the formula X, or a pharmaceutically acceptable salt thereof,X

[0036] wherein R1, R2, R2a, R3a, R7, and R9are as described herein.

[0037] In some embodiments, the disclosure provides a compound of the formula XI, or a pharmaceutically acceptable salt thereof,XI

[0038] wherein R1, R2, R2a, R3a, R5, R7, and R9are as described herein.

[0039] In certain embodiments of the above aspects, the compound of Formula (I)-(XI) is a compound selected from those species described or exemplified in the detailed description below.

[0040] In further aspects, the disclosure relates to a pharmaceutical composition comprising at least one compound of Formula (I)-(XI) or a pharmaceutically acceptable salt thereof. Pharmaceutical compositions according to the disclosure may further comprise a pharmaceutically acceptable excipient.

[0041] In further aspects, the disclosure relates to a compound of Formula (I)-(XI), or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0042] In further aspects, the disclosure relates to a method of treating disease, such as autoimmune disease comprising administering to a subject in need of such treatment an effective amount of at least one compound of Formula (I)-(XI), or a pharmaceutically acceptable salt thereof.

[0043] In further aspects, the disclosure relates to use of a compound of Formula (I)-(XI), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatmentof disease, such as autoimmune disease, and the use of such compounds and salts for treatment of such diseases.

[0044] In further aspects, the disclosure relates to a method of inhibiting a tyrosine kinase, such as TYK2, comprising contacting a cell comprising one or more of kinase with an effective amount of at least one compound of Formula (I)-(XI), or a pharmaceutically acceptable salt thereof, and / or with at least one pharmaceutical composition of the disclosure, wherein the contacting is in vitro, ex vivo, or in vivo.

[0045] Additional embodiments, features, and advantages of the disclosure will be apparent from the following detailed description and through practice of the disclosure. The compounds of the present disclosure can be described as embodiments in any of the following enumerated clauses. It will be understood that any of the embodiments described herein can be used in connection with any other embodiments described herein to the extent that the embodiments do not contradict one another.

[0046] 1. A compound of the formula I, or a pharmaceutically acceptable salt thereof,I

[0047] wherein

[0048] X is -O- or -NR5-;

[0049] R1and R1aare each independently H, deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, 5- to 10--P(O)NRaRb, -P(O)zNRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)NReRf, -SRe, -S(O)Re, -S(O)2Re,-S(OJNR*Rf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NR’QOJNRTlS -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -PCO^R1', -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;

[0050] R2is H, deuterium, C1-C6alkyl, or -OC1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl and -OC1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)iRe, -S(O)NReRf, -S(O)NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;

[0051] each of R2a, R5, R8, R9, and R11is independently H, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P^R^, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;

[0052] each of R3, R4, R3a, R4a, R3b, and R4bis independently H, deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, -ORe, -OC(O)Re, -OC(O)NRcRd, -OC(=N)NRcRd, -OS(O)Re, -OS(O)2Re, -OS^NR^*1, -OS(O)2NRcRd, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRd, -S(O)2NReRf, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=N)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Re, -C(O)ORe, -C(O)NRK*1, -C(=N)NRcRd, -PRcRd, -P(O)R°Rd, -P(O)2RcRd, -P(O)NRcRd-P(O)2NRcRd, -P(O)ORe, -P(0)2OR0, -CN, or -NO2; wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -0C(0)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf-S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NR^COJNR'Rf, -NReS(O)Rf, -NR^fO)^, -NReRfOJNReRf, -NReS(O)2NReRf, -C(O)Re,-C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReR.f, -P(O)2ReRf, -P(O)NReRf, -P^NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;

[0053] each of R6, R6a, and R7is independently H, deuterium, halogen, or C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O>2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;

[0054] R10is hydrogen or deuterium; and

[0055] each Ra, Rb, Rc, Rd, Re, and Rfis independently selected from the group consisting of H, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, C1-C6alkyl-C6-C10aryl, and 5- to 10-membered heteroaryl;

[0056] provided that when X is -O-, then R2is: deuterium; C1-C6alkyl, wherein at least one hydrogen atom is substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, - -OC(O)NReRf-OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf-S(O)2NReRf, -NReRf, -NReC(0)Rf, -NReC(O)ORf, -NReC(0)NReRf, -NReS(O)Rf, -NReS(O)2Rf, NReS(0)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(0)NReRf, -PReRf, -P(O)ReRf', -P(0)2Re'Rf-P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P^ORe, -CN, or -NO2; or-OC1-C6alkyl, wherein each hydrogen atom in -OC1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, - -OC(O)NReRf-OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2-NReRf, -NReC(0)Rf, -NReC(0)0Rf, -NReC(0)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(0)NReRf, -PReRf, -P(0)ReRf, -P(0)2ReRf, -P(O)NReRf-P(0)2NReRf, -P(O)ORe, -P^ORe, -CN, or -NO2.

[0057] 2. The compound of clause 1, or a pharmaceutically acceptable salt thereof, wherein X is -O-.

[0058] 3. The compound of clause 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R2is deuterium.

[0059] 4. The compound of clause 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R2is C1-C6alkyl, wherein at least one hydrogen atom is optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, --OC(O)NReR,f-OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -O8(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NR’R* -PR^, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(0)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2.

[0060] 5. The compound of clause 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R2is -OC1-C6alkyl, wherein each hydrogen atom in -OC1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -8(0)^®, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NR*Rf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(OJR*R.f, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P^ORe, -CN, or -NO2.

[0061] 6. The compound of clause 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X is -NR5-.

[0062] 7. The compound of any one of clauses 1, 2, or 6, or a pharmaceutically acceptable salt thereof, wherein R2is H.

[0063] 8. The compound of any one of clauses 1, 2, or 6, or a pharmaceutically acceptable salt thereof, wherein R2is deuterium.

[0064] 9. The compound of any one of clauses 1, 2, or 6, or a pharmaceutically acceptable salt thereof, wherein R2is C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -O8(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -8(0)^®, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(0)2ORe, -CN, or -NO2.

[0065] 10. The compound of any one of clauses 1, 2, or 6, or a pharmaceutically acceptable salt thereof, wherein R2is -OC1-C6alkyl, wherein each hydrogen atom in -OC1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, --OC(O)NReR,f-OS(O)Re, -O8(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re-S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NR^COJNR'Rf, -NReS(O)Rf, -NR^fO)^, -NReRfOJNReRf, -NReS(O)2NReRf, -C(O)Re,-C(O)ORe, -C(O)NReRf, -PReRf, -P(OJR*R.f, -P(O)2ReRf, -P(O)NReRf, -P^NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2.

[0066] 11. The compound of any one of clauses 1, 2, 3, 5, 6, or 10, or a pharmaceutically acceptable salt thereof, wherein R2is -OC1-C6alkyl.

[0067] 12. The compound of any one of clauses 1, 2, 3, 5, 6, 10, or 11, or a pharmaceutically acceptable salt thereof, wherein R2is -OCH3, -OCH2CH3, or -OCH2(CH3)2.

[0068] 13. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R1is H, halogen, or C1-C6alkyl.

[0069] 14. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R1is H, deuterium, fluoro, or methyl.

[0070] 15. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R1ais H or deuterium.

[0071] 16. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R2ais C1-C6alkyl.

[0072] 17. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R2ais methyl.

[0073] 18. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein one of R3, R4, R3a, R4*, R3b, or R46is C1-C6alkyl wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by deuterium, halogen, Ci-C6alkyl, Ci-C6haloalkyl, -ORe, -OC(O)Re, --OC(O)NReR,f-OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OSfO^NR^1, -SRe, -S(O)Re, -S(O>2Re, -S(O)NReRf, -S(O)NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NR*S(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2, and the remaining of R3, R4, R3a, R4a, R3b, and R4bare each H.

[0074] 19. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R3ais C1-C6alkyl.

[0075] 20. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R3ais methyl.

[0076] 21. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R5, when present, is H or C1-C6alkyl.

[0077] 22. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R5, when present, is H or methyl.

[0078] 23. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R6is H.

[0079] 24. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R6ais H.

[0080] 25. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R7is H or halogen.

[0081] 26. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R7is fluoro or chloro.

[0082] 27. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R8is H.

[0083] 28. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R9is C1-C6alkyl.

[0084] 29. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R9is methyl.

[0085] 30. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R11is H.

[0086] 31. The compound of clause 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: [3a(4)Z,10R]-20-chloro-6,9,10,15-tetramethyl-2,5,9,10,l l,12,13,15-octahydro-l,17- ethenopyrazolo[4,3 -m]dipyrrolo[3 ,2-f.3 ',4'- / ] [ 1 ,4]diazacyclopentadecine-3 , 8-dione;[3a(4)Z, 10R]-20-chloro-6,9, 10, 12, 15-pentamethyl-2,5,9, 10, 11 , 12, 13, 15 -octahydro- 1, 17- ethenopyrazolo[4,3 -m]dipyrrolo[3 3 ',4* -z] [ 1 ,4]diazacyclopentadecine-3 , 8-dione;[3 a(4)Z, 10R]-20-chloro- 16-methoxy-9, 10, 15-trimethyl- 10, 11 , 13 , 15 -tetrahydro-2H- 1,17- ethenopyrazolo[4,3-m]dipyrrolo[3,2-f3',4'-z][l,4]oxazacyclopentadecine-3, 8(5H , 9H) -dione; [3a(4)Z,10R]-20-chloro-16-methoxy-6,9,10,12,15-pentamethyl-2,5,9,10,l l,12,13,15- octahydro-l,17-ethenopyrazolo[4,3-m]dipyrrolo[3,2-f3',4'- / ][l,4]diazacyclopentadecine-3,8- dione;[3a(4)Z,10R]-20-chloro-16-methoxy-9,10,12,15-tetramethyl-2,5,9,10,l 1,12,13,15-octahydro-1.17-ethenopyrazolo[4,3 -m]dipyrrolo[3,2-f:3',4'-f] [ 1 ,4]diazacyclopentadecine-3, 8-dione;[3a(4)Z, 10R]-20-chloro-6-fluoro-l 6-methoxy-9, 10, 15-trimethyl- 10, 11,13,15-tetrahydro-2H-1.17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3 ,2-f 3',4'-z] [ 1 ,4]oxazacyclopentadecine- 3, 8(5H , 9H) -di one;[3a(4)Z, 10R]-20-chloro-6-fluoro- 16-methoxy-9, 10, 12, 15-tetramethyl-2,5,9, 10,11,12,13,15- octahydro-l,17-ethenopyrazolo[4,3-m]dipyrrolo[3,2-f3',4'-z][l,4]diazacyclopentadecine-3,8- dione; and[3a(4)Z,10R]-6-fluoro-16-methoxy-9,10,12,15,20-pentamethyl-2,5,9,10,ll,12,13,15- octahydro-l,17-ethenopyrazolo[4,3-m]dipyrrolo[3,2-f3',4'- / ][l,4]diazacyclopentadecine-3,8- dione.

[0087] 32. A pharmaceutical composition comprising at least one compound of any one of clauses 1 to 31, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.

[0088] 33. A method of treating disease, such as autoimmune disease, comprising administering to a subject in need of such treatment an effective amount of a compound of any one of clauses 1 to 31, or a pharmaceutically acceptable salt thereof.

[0089] 34. A compound of any one of clauses 1 to 31, or a pharmaceutically acceptable salt thereof, for use in a method of treating an autoimmune disease in a subject.

[0090] 35. A compound of any one of clauses 1 to 31, or a pharmaceutically acceptable salt thereof, for treating an autoimmune disease in a subject.

[0091] 36. Use of a compound of any one of clauses 1 to 31, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating an autoimmune disease in a subject.DETAILED DESCRIPTION

[0092] Before the present disclosure is further described, it is to be understood that this disclosure is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.

[0093] For the sake of brevity, the disclosures of the publications cited in this specification, including patents, are herein incorporated by reference. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications and other publications referred to herein are incorporated by reference in their entireties. If a definition set forth in this section is contrary to or otherwise inconsistent with a definition set forth in a patent, application, or other publication that is herein incorporated by reference, the definition set forth in this section prevails over the definition incorporated herein by reference.

[0094] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended toserve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation.

[0095] As used herein, the terms “including,” “containing,” and “comprising” are used in their open, non-limiting sense.

[0096] To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term “about.” It is understood that, whether the term “about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including equivalents and approximations due to the experimental and / or measurement conditions for such given value. Whenever a yield is given as a percentage, such yield refers to a mass of the entity for which the yield is given with respect to the maximum amount of the same entity that could be obtained under the particular stoichiometric conditions. Concentrations that are given as percentages refer to mass ratios, unless indicated differently.

[0097] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited.

[0098] Except as otherwise noted, the methods and techniques of the present embodiments are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See, e.g., Loudon, Organic Chemistry, Fourth Edition, New York: Oxford University Press, 2002, pp. 360-361, 1084-1085; Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, 2001.

[0099] Chemical nomenclature for compounds described herein has generally been derived using the commercially-available ACD / Name 2020 (ACD / Labs) or ChemBioDraw Ultra 20.0 (Perkin Elmer).

[0100] 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 suitablesubcombination. All combinations of the embodiments pertaining to the chemical groups represented by the variables are specifically embraced by the present disclosure and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). In addition, all subcombinations of the chemical groups listed in the embodiments describing such variables are also specifically embraced by the present disclosure and are disclosed herein just as if each and every such sub-combination of chemical groups was individually and explicitly disclosed herein.CHEMICAL DEFINITIONS

[0101] The term “alkyl” refers to a straight- or branched-chain mono-valent hydrocarbon group. The term “alkylene” refers to a straight- or branched-chain di-valent hydrocarbon group. In some embodiments, it can be advantageous to limit the number of atoms in an “alkyl” or “alkylene” to a specific range of atoms, such as C1-C20 alkyl or C1-C20 alkylene, C1-C12 alkyl or Ci-Cu alkylene, or C1-C6alkyl or C1-C6alkylene. Examples of alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples. Examples of alkylene groups include methylene (-CH2-), ethylene ((-CH2-)2), n- propylene ((-CH2-)3), iso-propylene ((-C(H)(CH3)CH2-)), n-butylene ((-CH2-)4), and the like. It will be appreciated that an alkyl or alkylene group can be unsubstituted or substituted as described herein. An alkyl or alkylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0102] The term “alkenyl” refers to a straight- or branched-chain mono-valent hydrocarbon group having one or more double bonds. The term “alkenylene” refers to a straight- or branched-chain di-valent hydrocarbon group having one or more double bonds. In some embodiments, it can be advantageous to limit the number of atoms in an “alkenyl” or “alkenylene” to a specific range of atoms, such as C2-C20 alkenyl or C2-C20 alkenylene, C2-C12 alkenyl or C2-C12 alkenylene, or C2-C6alkenyl or C2-C6alkenylene. 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(CH3)-), and the like. Included within this term are cis and trans isomers and mixtures thereof. It will be appreciated that an alkenyl or alkenyl ene group can be unsubstitutedor 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.

[0103] The term “alkynyl” refers to a straight- or branched-chain mono-valent hydrocarbon group having one or more triple bonds. The term “alkynylene” refers to a straight- or branched- chain di-valent hydrocarbon group having one or more triple bonds. In some embodiments, it can be advantageous to limit the number of atoms in an “alkynyl” or “alkynylene” to a specific range of atoms, such as C2-C20 alkynyl or C2-C20 alkynylene, C2-C12 alkynyl or C2-C12 alkynylene, or C2-C6alkynyl or C2-C6alkynylene. Examples of alkynyl groups include acetylenyl (-C=CH) and propargyl (-CH2CN2H), but-3-yn-l,4-diyl (-C=C-CH2CH2-), and the like. It will be appreciated that an alkynyl or alkynylene group can be unsubstituted or substituted as described herein. An alkynyl or alkynylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0104] 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 di-valent carbocycle. In some embodiments, it can be advantageous to limit the number of atoms in a “cycloalkyl” or “cycloalkylene” to a specific range of atoms, such as having 3 to 12 ring atoms. Polycyclic carbocycles include fused, bridged, and spiro polycyclic systems. Illustrative examples of cycloalkyl groups include mono-valent radicals of the following entities, while cycloalkylene groups include di-valent radicals of the 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. It will be appreciated that a cycloalkyl or cycloalkylene group can be unsubstituted or substituted as described herein. A cycloalkyl or cycloalkylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0105] The term “halogen” or “halo” represents chlorine, fluorine, bromine, or iodine.

[0106] The term “haloalkyl” refers to an alkyl group with one or more halo substituents. Examples of haloalkyl groups include -CF3, -(CH2)F, -CHF2, -CH2Br, -CH2CF3, and -CH2CH2F. The term “haloalkylene” refers to an alkyl group with one or more halo substituents. Examples of haloalkyl groups include -CF2-, -C(H)(F)-, -C(H)(Br)-, -CH2CF2-, and -CH2C(H)(F)-.

[0107] 'fhe term “aryl” refers to a mono-valent all -carbon monocyclic or fused-ring polycyclic group having a completely conjugated pi-electron system. The term “arylene” refers to a monovalent all-carbon monocyclic or fused-ring polycyclic group having a completely conjugated pi-electron system. In some embodiments, it can be advantageous to limit the number of atoms in an “aryl” or “arylene” to a specific range of atoms, such as mono-valent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 14 carbon atoms (C6-Cu aryl), mono-valent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 10 carbon atoms (C6-Cw aryl), di-valent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 14 carbon atoms (C6- C14 arylene), di-valent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 10 carbon atoms (Cs-Cw arylene). Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl. E-xamples, without limitation, of aryl groups are phenylene, naphtha! enylene and anthracenylene. It will be appreciated that an aryl or arylene group can be unsubstituted or substituted as described herein. An aryl or arylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0108] 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 mono-valent monocyclic or polycyclic ring structure that is saturated or partially saturated having one or more non-carbon ring atoms. In some embodiments, it can be advantageous to limit the number of atoms in a “heterocycloalkyl” or “heterocycloalkylene” to a specific range of ring atoms, such as from 3 to 12 ring atoms (3- to 12-membered), or 3 to 7 ring atoms (3- to 7-membered), or 3 to 6 ring atoms (3- to 6-membered), or 4 to 8 ring atoms (4- to 8-membered), or 5 to 7 ring atoms (5- to 7-membered). In some embodiments, it can be advantageous to limit the number and type of ring heteroatoms in “heterocycloalkyl” or “heterocycloalkylene” to a specific range or type of heteroatoms, such as 1 to 5 ring heteroatoms selected from nitrogen, oxygen, and sulfur. Polycyclic ring systems include fused, bridged, and spiro systems. The ring structure may optionally contain an oxo group on a carbon ring member or up to two oxo groups on sulfur ring members. Illustrative examples of heterocycloalkyl groups include mono-valent radicals of the following entities, while heterocycloalkylene groups include di-valent radicals of the following entities, in the form of properly bonded moieties:

[0109] A three-membered heterocycle may contain at least one heteroatom ring atom, where the heteroatom ring atom is a sulfur, oxygen, or nitrogen. Non-limiting examples of threemembered heterocycle groups include monovalent and divalent radicals of oxirane, azetidine, and thiirane. A four-membered heterocycle may contain at least one heteroatom ring atom, where the heteroatom ring atom is a sulfur, oxygen, or nitrogen. Non-limiting examples of four-membered heterocycle groups include monovalent and divalent radicals of azitidine, oxtenane, and thietane. A five-membered heterocycle can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of five-membered heterocyle groups include mono-valent and divalent radicals of pyrrolidine, tetrahydrofuran, 2, 5-dihydro-lH- pyrrole, pyrazolidine, thiazolidine, 4,5-dihydro-lH-imidazole, dihydrothiophen-2(3H)-one, tetrahydrothiophene 1,1- dioxide, imidazolidin-2-one, pyrrolidin-2-one, dihydrofuran-2(3H)-one, 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 zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of six-membered heterocycle groups include mono-valent or divalent radicals of piperidine, morpholine, 4H-l,4-thi azine, 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.

[0110] 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.

[0111] The term “heteroaryl” refers to a mono-valent monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms or members selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) that is fully unsaturated and having from 3 to 12 ring atoms per heterocycle. The term “heteroarylene” refers to a di-valent monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms or members selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms per heterocycle. In some embodiments, it can be advantageous to limit the number of ring atoms in a “heteroaryl” or “heteroarylene” to a specific range of atom members, such as 5- to 10-membered heteroaryl or 5- to 10-membered heteroarylene. In some instances, a 5- to 10- membered heteroaryl can be a monocyclic ring or fused bicyclic rings having 5- to 10-ring atoms wherein at least one ring atom is a heteroatom, such as N, O, or S. In some instances, a 5- to 10-membered heteroarylene can be a monocyclic ring or fused bicyclic rings having 5- to 10-ring atoms wherein at least one ring atom is a heteroatom, such as N, O, or S. Illustrative examples of 5- to 10-membered heteroaryl groups include mono-valent 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:In some embodiments, a “monocyclic” heteroaryl can be an aromatic five- or six-membered heterocycle. A five-membered heteroaryl or heteroarylene can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of five-membered heteroaryl groups include mono-valent radicals of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole. Non-limiting examples of 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 zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of six-membered heteroaryl groups include monovalent radicals of pyridine, pyrazine, pyrimidine, pyridazine, or triazine. Non-limiting examples of six-membered heteroarylene groups include divalent radicals of pyridine, pyrazine, pyrimidine, pyridazine, or triazine. A “bicyclic heteroaryl” or “bicyclic heteroarylene” is a fused bicyclic system comprising one heteroaryl ring fused to a phenyl or another heteroaryl ring. Non-limiting examples of bicyclic heteroaryl groups include monovalent radicals of quinoline, isoquinoline, quinazoline, quinoxaline, indole, 1,5-naphthyridine, 1,8- naphthyridine, isoquinolin-3(2H)-one, thieno[3,2-Z>]thiophene, lZ / -pyrrolo[2,3-Z>]pyridine, 1H -benzo[t / ] imidazole, benzo[d]oxazole, and benzo[d]thiazole. Non-limiting examples of bicyclic heteroarylene groups include divalent radicals of quinoline, isoquinoline, quinazoline, quinoxaline, indole, 1,5-naphthyridine, 1,8-naphthyridine, isoquinolin-3(2H)-one, thieno[3,2- 6]thiophene, 117-pyrrolo[2,3-Z>]pyridine, 1H -benzo[d]imidazole, benzo[<7]oxazole, and benzo[< / ] thiazole.In particular, a pyrrolyl moiety can be depicted by the structural formulaparticular, a pyrrolylene moiety can be depicted by the structural formulaIn particular, a pyrazolyl moiety can be depicted by the structural formula InH particular, a pyrazolylene moiety can be depicted by the structural formula

[0112] 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.

[0113] The term “oxo” represents a carbonyl oxygen. For example, a cyclopentyl substituted with oxo is cyclopentanone.

[0114] C6rtain chemical entities of Formula (I)-(XI) may be depicted in two or more tautomeric forms. Any and all alternative tautomers are included within the scope of these formulas, and no inference should be made as to whether the chemical entity exists as the tautomeric form in which it is drawn. It will be understood that the chemical entities described herein, and their constituent rings A, B, etc. 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 Keto form Lactam form Lactim formOH O O OHC NH N k H H HAmide form Imidic acid form Amine form Imine formO OH NH2NHN NHH

[0115] In particular, a ring option of indolin-2-oneylene can exist as the following tautomersHN N H

[0116] The term “substituted" means that the specified group or moiety bears one or more substituents. The term “unsubstituted” means that the specified group bears no substituents. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system. In some embodiments, “substituted" means that the specified group or moiety bears one, two, or three substituents. In other embodiments, “substituted” means that the specified group or moiety bears one or two substituents. In still other embodiments, “substituted” means the specified group or moiety bears one substituent.

[0117] Any formula depicted herein is intended to represent a compound of that structural formula as well as certain variations or forms. For example, a formula given herein is intended to include a racemic form, or one or more enantiomeric, diastereomeric, or geometric isomers, or a mixture thereof. Additionally, any formula given herein is intended to refer also to a hydrate, solvate, or polymorph of such a compound, or a mixture thereof.

[0118] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as2H,3H,nC,13C,14C,15N,18O,170,31P,32P,35S,1SF,36C1, and125I, respectively. Such isotopically labelled compounds are usefill in metabolic studies (preferably with14C), reaction kinetic studies (with, for example2H or3H),detection or imaging techniques [such as positron emission tomography (PET) or singlephoton emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients. Further, substitution with heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0119] The nomenclature “(ATOM);. / ’ with j > i, when applied herein to a class of substituents, is meant to refer to embodiments of this disclosure for which each and every one of the number of atom members, from i to j including i and j, is independently realized. By way of example, the term C1.3 refers independently to embodiments that have one carbon member (Ci), embodiments that have two carbon members (C2), and embodiments that have three carbon members (C3).

[0120] Any disubstituent referred to herein is meant to encompass the various attachment possibilities when more than one of such possibilities are allowed. For example, reference to disubstituent -A-B-, where A + B, refers herein to such disubstituent with A attached to a first substituted member and B attached to a second substituted member, and it also refers to such disubstituent with A attached to the second substituted member and B attached to the first substituted member.

[0121] The disclosure also includes pharmaceutically acceptable salts of the compounds represented by Formula (I)-(XI), preferably of those described above and of the specific compounds exemplified herein, and pharmaceutical compositions comprising such salts, and methods of using such salts.

[0122] A “pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of a compound represented herein that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S.M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977, 66, 1-19. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of subjects without undue toxicity, irritation, or allergic response. A compound described herein may possess a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one of each type, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.

[0123] Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne- 1,4-dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates, besylates, xylenesulfonates, naphthal ene-1 -sulfonates, naphthalene-2- sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, y- hydroxybutyrates, glycolates, tartrates, and mandelates. Lists of other suitable pharmaceutically acceptable salts are found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985.

[0124] For a compound of Formula (I)-(XI) that contains a basic nitrogen, a pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as mandelic acid, citric acid, or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid, 2 -acetoxybenzoic acid, naphthoic acid, or cinnamic acid, a sulfonic acid, such as laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, or ethanesulfonic acid, or any compatible mixture of acids such as those given as examples herein, and any other acid and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology.

[0125] The disclosure also relates to pharmaceutically acceptable prodrugs of the compounds of Formula (I)-(X[), and treatment methods employing such pharmaceutically acceptable prodrugs. The term “prodrug” means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to the compound of Formula (I)-(XI)). A "pharmaceutically acceptable prodrug” is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject. Illustrative proceduresfor the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

[0126] The present disclosure also relates to pharmaceutically active metabolites of compounds of Formula (I)-(XI), and uses of such metabolites in the methods of the disclosure. A “pharmaceutically active metabolite” means a pharmacologically active product of metabolism in the body of a compound of Formula (I)-(XI) or salt thereof. Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertolini et al., J. Med. Chem. 1997, 40, 2011-2016; Shan et al., J. Pharm. Sci. 1997, 86 (7), 765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res. 1984, 13, 255-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991).

[0127] As used herein, the term “protecting group” or “PG” refers to any group as commonly known to one of ordinary skill in the art that can be introduced into a molecule by chemical modification of a functional group, such as an amine or hydroxyl, to obtain chemoselectivity in a subsequent chemical reaction. It will be appreciated that such protecting groups can be subsequently removed from the functional group at a later point in a synthesis to provide further opportunity for reaction at such functional groups or, in the case of a final product, to unmask such functional group. Protecting groups have been described in, for example, Wuts, P. G. M., Greene, T. W., Greene, T. W., & John Wiley & Sons. (2006). Greene's protective groups in organic synthesis. Hoboken, N.J: Wiley-Interscience. One of skill in the art will readily appreciate the chemical process conditions under which such protecting groups can be installed on a functional group. Suitable amine protecting groups useful in connection with the present disclosure include, but are not limited to, 9-Fluorenylmethyl-carbonyl (FMOC), t- butylcarbonyl (Boc), benzyl oxycarbonyl (Cbz), acetyl (Ac), trifluoroacetyl, phthalimide, benzyl (Bn), triphenylmethyl (trityl, Tr), benzylidene, and p-toluenesulfonyl (tosylamide, Ts).REPRESENTATIVE EMBODIMENTS

[0128] In some embodiments, the disclosure provides a compound of the formula I, or a pharmaceutically acceptable salt thereof,I

[0129] wherein X, R1, R1a, R2, R2a, R3, R4, R3a, R4a, R3b, R4b, R6, R6a, R7, R8, R9, R10, and R11are as described herein.

[0130] In some embodiments, the disclosure provides a compound of the formula II, or a pharmaceutically acceptable salt thereof,n

[0131] wherein R1, R1a, R2, R28, R3, R4, R3a, R4*, R3b, R4b, R6, R6a, R7, R8, R9, R10, and R11are as described herein.

[0132] In some embodiments, the disclosure provides a compound of the formula m, or a pharmaceutically acceptable salt thereof,in

[0133] wherein R1, R1a, R2, R21, R3, R4, R3a, R4*, R3b, R4**, R5, R6, R6a, R7, R8, R9, R10, and R11are as described herein.

[0134] In some embodiments, the disclosure provides a compound of the formula IV, or a pharmaceutically acceptable salt thereof,IV

[0135] wherein R1, R2, R2a, R3a, R7, R8, R9, and R11are as described herein.

[0136] In some embodiments, the disclosure provides a compound of the formula V, or a pharmaceutically acceptable salt thereof,V

[0137] wherein R1, R2, R2a, R3a, R5, R7, R8, R9, and Ruare as described herein.

[0138] In some embodiments, the disclosure provides a compound of the formula VI, or a pharmaceutically acceptable salt thereof,VI

[0139] wherein R1, R2, R28, R3a, R7, R8, R9, and R11are as described herein.

[0140] In some embodiments, the disclosure provides a compound of the formula XU, or a pharmaceutically acceptable salt thereof,

[0141] wherein R1, R2, R2a, R3a, R5, R7, R8, R9, and R11are as described herein.

[0142] In some embodiments, the disclosure provides a compound of the formula VIII, or a pharmaceutically acceptable salt thereof,

[0143] wherein R1, R2, R2a, R3a, R7, and R9are as described herein.

[0144] In some embodiments, the disclosure provides a compound of the formula IX, or a pharmaceutically acceptable salt thereof,

[0145] wherein R1, R2, R2a, R3a, R5, R7, and R9are as described herein.

[0146] In some embodiments, the disclosure provides a compound of the formula X, or a pharmaceutically acceptable salt thereof,X

[0147] wherein R1, R2, R2a, R3a, R7, and R9are as described herein.

[0148] In some embodiments, the disclosure provides a compound of the formula XI, or a pharmaceutically acceptable salt thereof,XI

[0149] wherein R1, R2, R2a, R3a, R5, R7, and R9are as described herein.

[0150] In some embodiments, R1and R1aare each independently H, deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)zRaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl,-P(O)ORe, -P(O)2ORe, -CN, or -NO2.

[0151] In some embodiments, R1is H, deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O>2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)OR1, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2.

[0152] In some embodiments, R1ais H, deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)zNRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2. In some embodiments, R1ais H or deuterium.

[0153] In some embodiments, R1is H, deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NR*C(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb,-NRaS(0)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)iRaRb, -P(O)NRaRb, -P(0)2NRaRb, -P(O)ORa, -P(0)20Ra, -CN, or -NO2, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re,

[0154] In some embodiments, R1is H, deuterium, halogen, or C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8- membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re,-P(O)2ORe, -CN, or -NO2.

[0155] In some embodiments, R1is H, deuterium, halogen, or C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8- membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re,

[0156] In some embodiments, R1is H, deuterium, fluoro, or methyl. In some embodiments, R1is H, deuterium, fluoro, chloro, or methyl.

[0157] In some embodiments, R1is H, deuterium, fluoro, or methyl; and R1ais H. In some embodiments, R1is H, deuterium, fluoro, chloro, or methyl; and R1ais H.

[0158] In some embodiments, R2is H, deuterium, C1-C6alkyl, or -OC1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl and -O C1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re,

[0159] In some embodiments, R2is H, deuterium, C1-C6alkyl, or -OC1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl and -OC1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, --OC(O)NReR,f-OS(O)Re, -OS(O)2Re, -OSCOJNReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(0)2NReRf, -NReRf, -NReC(0)Rf, -NReC(0)0Rf, -NRT^NReRf, -NReS(0)Rf, -NReS(O)2Rf, -NReS(0)NReRf, -NReS(0)2NReRf, -C(0)Re, -C(0)0Re, -C(0)NReRf, -PR^, -P(0)ReRf, -P(0)2ReRf, -P(0)NReRf, -P(0)2NReRf, -P(0)0Re, -P(O)2ORe, -CN, or -NO2; and R2ais C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe,-P(O)ORe, -P(O)2ORe, -CN, or -NO2. In some embodiments, R2is deuterium. In some embodiments, R2is H, deuterium, or -OCH3.

[0160] In some embodiments, if R2is H, then X is -NR5-, or R2ais optionally substituted ethyl, or R7is optionally substituted C1-C6alkyl (e.g., methyl).

[0161] In some embodiments, R2is H, deuterium, C1-C6alkyl, or -OC1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl and -OC1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, --OC(O)NReR,f-OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(0)Rf, -NReC(O)ORf, -NRT^NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NR’R1’, -PR^, -P(O)ReRf, -P(O)2ReRf, -PCOJNRTC, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; and R2ais C1-C6alkyl, such as methyl, ethyl, or isopropyl. In some embodiments, R2is H, deuterium, or -OCH3; and R2ais C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, or -ORe.

[0162] In some embodiments, if X is -NH-, then R2ais deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, Cs-C10aryl, or 5- to 10- membered heteroaryl, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, or 5- to 10- membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -0C(0)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf,

[0163] In some embodiments, R2ais H, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl,-P(O)ORe, -P(O)2ORe, -CN, or -NO2. In some embodiments, R21is C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NR*Rf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O>2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NR*Rf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2. In some embodiments, R2ais C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, or -ORe. In some embodiments, R2ais C1-C6alkyl, such as methyl, ethyl, or isopropyl, optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, or -ORe.

[0164] In some embodiments, X is -O-, and

[0165] R2is deuterium; or

[0166] R2is C1-C6alkyl, wherein at least one hydrogen atom is optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, - -OC(O)NReR,f-OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf-NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf-PReRf, -P^R^, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; or

[0167] R2is -OC1-C6alkyl, wherein each hydrogen atom in -OC1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl,-P(O)ORe, -P(0)2ORe, -CN, or -NO2.

[0168] In some embodiments, X is -O-, and

[0169] R2is deuterium; or

[0170] R2is C1-C6alkyl, wherein at least one hydrogen atom is substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re-S(O)NReRf, -S(O)NReRf, -NReRf, -NReC(O)Rf, -NReC(0)0Rf, -NReC(0)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; or

[0171] R2is -OC1-C6alkyl, wherein each hydrogen atom in -OC1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl,-P(O)ORe, -P(0)2ORe, -CN, or -NO2.

[0172] In some embodiments, X is -O-, and

[0173] R2is deuterium; or

[0174] R2is C1-C6alkyl, wherein at least one hydrogen atom is optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, --OC(O)NReR,f-OS(O)Re, -O8(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf-NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf ,-NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(0)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; or

[0175] R2is -OC1-C6alkyl, wherein each hydrogen atom in -OC1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl,-C(O)ORe, -C(O)NReRf, -PReRf, -P(OJR*R.f, -P(O)2ReRf, -P(O)NReRf, -P^NReRf, -P(O)ORe, -P(0)20Re, -CN, or -NO2; and R2ais C1-C6alkyl, such as methyl, ethyl, or isopropyl.

[0176] In some embodiments, X is -O-, and R2is C1-C6alkyl, wherein at least one hydrogen atom is optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl,-P(O)ORe, -P(O)2ORe, -CN, or -NO2.

[0177] In some embodiments, X is -O-, and R2is C1-C6alkyl, wherein at least one hydrogen atom is substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl,-P(O)ORe, -P(O)2ORe, -CN, or -NO2.

[0178] In some embodiments, X is -O-, and R2is C1-C6alkyl, wherein at least one hydrogen atom is optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl,-P(O)ORe, -P(O)2ORe, -CN, or -NO2; and R2ais C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, --OC(O)NReR,f-OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NR=Rf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(0)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P^R^, -P(O)2ReRf, -P(O)NReRf, -P(0)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2.

[0179] In some embodiments, X is -O-, and R2is C1-C6alkyl, wherein at least one hydrogen atom is substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl,-C(O)ORe, -C(O)NReRf, -PReRf, -P(OJR*R.f, -P(O)2ReRf, -P(O)NReRf, -P^NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NCh; and R2ais C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, --OC(O)NReR,f-OS(O)Re, -OS(O)2Re, -OS(O)NReRf,

[0180] In some embodiments, X is -O-, and R2is C1-C6alkyl, wherein at least one hydrogen atom is optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl,-P(O)ORe, -P(O)2ORe, -CN, or -NCh; and R2ais C1-C6alkyl, such as methyl, ethyl, or isopropyl.

[0181] In some embodiments, X is -O-, and R2is C1-C6alkyl, wherein at least one hydrogen atom is substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl,-P(O)ORe, -P(O)2ORe, -CN, or -NCh; and R28is C1-C6alkyl, such as methyl, ethyl, or isopropyl.

[0182] In some embodiments, X is -O-, and R2is -OC1-C6alkyl, wherein each hydrogen atom in -OC1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, --OC(O)NReR,f-OS(O)Re, -OS(O)2Re, -0S(0)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -StO^Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(0)Rf, -NReC(0)0Rf, -NReC(0)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(0)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(0)NReRf, -P(0)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2.

[0183] In some embodiments, X is -O-, and R2is -OC1-C6alkyl, wherein each hydrogen atom in -OC1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)NReRf, -SRe, -S(O)Re, -S(O)2Re-S(O)NReRf, -S(O)NReRf, -NReRf, -NReC(0)Rf,wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -O8(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NRR fNReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf-PReRf, -P^R’Rf -P(O)ReRf-P(O)NRRf, -P(0)2NReRf-P(O)ORe, -P(0)2ORe, -CN, or -NO2.

[0184] In some embodiments, X is -O-, and R2is -OC1-C6alkyl, wherein each hydrogen atom in -OC1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -0C(0)NRRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf,-P(0)NRRf, -P(0)2NRRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; and R2ais C1-C6alkyl, such as methyl, ethyl, or isopropyl.

[0185] In some embodiments, X is -O-, and

[0186] R2is deuterium, or

[0187] R2ais ethyl, wherein each hydrogen atom in ethyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl,-P(O)ORe, -P(0)2ORe, -CN, or -NO2, or

[0188] R7is C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl,-P(O) ORe - P(O)2ORe-CN, or -NO2, or

[0189] R2is C1-C6alkyl, wherein at least one hydrogen atom is substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -0S(O)2Re

[0190] R2is -OC1-C6alkyl, wherein each hydrogen atom in -OC1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl,-P(O)ORe, -P^ORe, -CN, or -NO2.

[0191] In some embodiments, X is -O- and R2ais ethyl, wherein each hydrogen atom in ethyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl,-P(O)ORe, -P(O)2ORe, -CN, or -NO2.

[0192] In some embodiments, X is -O- and R7is C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)NReRf, -SRe, -S(O)Re, -S(0^, -S(O)NReRf, -S(O)NReRf, -NReRf, -NReC(0)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(0)2NReRf, -P(O)ORe, -P(0)2ORe, -CN, or -NO2. In certain embodiments, X is -O- and R7is C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl independently optionally substituted by -ORe. In certain embodiments, X is -O- and R7is methyl, wherein each hydrogen atom in methyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, --OC(O)NReR,f-OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -8(0^% -NReRf, -NReC(0)Rf, -NReC(0)0Rf, -NReC(0)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(0)NReRf, -P(0)2NReRf, -P(O)ORe, -P(0)2ORe, -CN, or -NO2, for example R7can be methyl that is substituted by -OC1-C6alkyl (e.g., methoxy).

[0193] In certain embodiments, R2ais C1-C6alkyl (e.g., methyl or ethyl), wherein each hydrogen atom is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe(e.g., OH), -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -0S(O)2Re-OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re-S(O)NReRf, -S(O)2NReR.f, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReR.f, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2, R2is H or OC1-C6alkyl (e.g., methoxy), wherein each hydrogen atom in -OC1-C6alkyl (e.g., methoxy) is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl,-P(O)ORe, -P(O)2ORe, -CN, or -NO2

[0194] In some embodiments, if X is -NR5-, then R2ais optionally substituted C1-C6alkyl (e.g., methyl).

[0195] In some embodiments, R3and R4are each independently H, deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, -ORe, -OC(O)Re, -OC(O)NRcRd,wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl,-P(O)ORe, -P(O)2ORe, -CN, or -NO2. In some embodiments, each of R3and R4is independently H or deuterium.

[0196] In some embodiments, R3aand R4aare each independently H, deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-memberedheterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, -ORe, -OC(O)Re, -OC(O)NRcRd,wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl,-P(O)ORe, -P^ORe, -CN, or -NO2.

[0197] In some embodiments, R3band R 44b6are each independently H, deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, -ORe, -OC(O)Re, -OC(O)NRcRd,wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, Ci-Cb haloalkyl, -ORe, -0C(0)Re, --OC(O)NReR,f-OS(O)Re, -OS(O)2Re, -OSfOJNReRf, -0S(0)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(0)NReRf, -S(O)NReRf, -NReRf, -NReC(0)Rf, -NReC(0)0Rf, -NR’C(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NR^^NReRf, -NReS(O)2NReRf, -C(O)Re, -C(0)0Re, -C(0)NReRf, -PR'Rf -P(0)ReRf, -P(0)2R^, -P(O)NReRf, -P(0)2NR'R1’, -P(O)ORe, -P(O)2ORe, -CN, or -NO2. In some embodiments, each of R3band R4*1is independently H or deuterium.

[0198] In some embodiments, R3and R4are each independently H, deuterium, or Ci-Cb alkyl; wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, --OC(O)NReR,f-OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf,

[0199] In some embodiments, R3aand R4aare each independently H, deuterium, or C i-C6alkyl; wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, --OC(O)NReR,f-OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)iReRf, -P(O)NR*Rf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2.

[0200] In some embodiments, R3band R* are each independently H, deuterium, or C1-C6alkyl; wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NR’R' -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2R1, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O>2ReRf, -P(O)NReRf, -P(O)zNReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2.

[0201] In some embodiments, R3aand R4* are each independently H, deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, -ORe, -OC(O)Re, -OC(O)NRcRd, -OC(=N)NRcRd, -OS(O)Re, -OS(O)2Re, -OS(O)NR°Rd, -OS(O)NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRd, -S(O)2NRcRd, -NR°Rd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRc^NReRd, -NRcC(=N)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NReS(O)2NRcRd, -C(O)Re, -C(O)ORc, -C(O)NRcRd, -C(=N)NRcRd, -PRcRd, -P(O)R°Rd, -P(O)2ReRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl,-P(O)ORe, -P(O)2ORe, -CN, or -NO2; and each of R3, R4, R3b, and R4bis independently H or deuterium.

[0202] In some embodiments, R3® is H, deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered-P(O)2NRcRd, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, --OC(O)NReR,f-OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NR*Rf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; and each of R3, R4, R4a, R3b, and R4bis independently H or deuterium.

[0203] In some embodiments, R3aand R4aare each independently H, deuterium, or C1-C6alkyl; wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReR, -fP(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; and each of R3, R4, R3b, and R4bis independently H or deuterium.

[0204] In some embodiments, R3ais H, deuterium, or C1-C6alkyl; wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl,-P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; and each of R3, R4, R4*, R3b, and R4bis independently H or deuterium . In some embodiments, R3® is H, deuterium, or methyl; and each of R3, R4, R4a, R3b, and R4bis independently H or deuterium.

[0205] In some embodiments, R5is H, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-memberedheteroaiyl, wherein each hydrogen atom in C1-C6alkyl, Cj-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl,-P(O)ORe, -P(0)20Re, -CN, or -NO2.

[0206] In some embodiments, R5is H, deuterium, or C1-C6alkyl, wherein each hydrogen atom in Cj-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -8(0)^®, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NR*S(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2. In some embodiments, R5is H, deuterium, or C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, or -ORe.

[0207] In some embodiments, R5is H, deuterium, or C1-C6alkyl, such as methyl, ethyl, or isopropyl. In some embodiments, R5is H or methyl. In some embodiments, R5is methyl. In some embodiments, if R5is H, methyl, or difluoroethyl, then R2ais optionally substituted C1-C6alkyl (e.g., methyl).

[0208] In some embodiments, each of R6, R6®, and R7is independently H, deuterium, halogen, or C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re,-P(O)2ORe, -CN, or -NO2. In some embodiments, each of R6and R6ais independently H or deuterium.

[0209] In some embodiments, R6is H, deuterium, halogen, or C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -8(0)^®, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf,

[0210] In some embodiments, R6ais H, deuterium, halogen, or C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, --OC(O)NReR,f-OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(0)NReRf, -P(0)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2.

[0211] In some embodiments, R7is H, deuterium, halogen, or C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re,

[0212] In some embodiments, R7is H, deuterium, halogen, or C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NR*Rf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(0)Rf, -NReC(0)0Rf, -NReC(0)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(0)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(0)ReRf, -P(0)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; and R6and R6aare H.

[0213] In some embodiments, R7is H, deuterium, halogen, or C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf-OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(0)2NReRf, -NReRf, -NReC(O)Rf, -NReC(0)0Rf, -NReC(0)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(0)NReRf, -NReS(0)2NReRf, -C(O)Re, -C(0)0Re, -C(0)NReRf, -PReRf, -P(0)ReRf, -P(0)2ReRf, -P(0)NReRf, -P(0)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;and R6and R6aare H.

[0214] In some embodiments, R8is H, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl,-P(O)ORe, -P^ORe, -CN, or -NO2.

[0215] In some embodiments, R8is H, deuterium, or C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P^NR'R*, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2.

[0216] In some embodiments, R8is H, deuterium, or C1-C6alkyl, such as methyl, ethyl, or isopropyl. In some embodiments, R8is H or methyl. In some embodiments, R8is hydrogen.

[0217] In some embodiments, R9is H, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl,-P(OK)Re, -P(0)2ORe, -CN, or -NO2.

[0218] In some embodiments, R9is H, deuterium, or C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, --OC(O)NReR,f-OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re-S(O)NReRf, -S(O>2NReRf, -NReRf, -NReC(0)Rf, -NReC(0)0Rf, -NR^COjNReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReRfO^NRTlS -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P^R^, -P(O)2ReRf, -P(0)NReRf, -P(0)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2.

[0219] In some embodiments, R9is H, deuterium, or C1-C6alkyl, such as methyl, ethyl, or isopropyl. In some embodiments, R9is H or methyl. In some embodiments, R9is methyl.

[0220] In some embodiments, R10is H or deuterium. In some embodiments, R10is H. In some embodiments, R10is deuterium.

[0221] In some embodiments, R11is H, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, Cg-C10aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, Cg-C10aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl,-P(O)ORe, -P(O)zORe, -CN, or -NOz.

[0222] In some embodiments, R11is H, deuterium, or C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)zRe, -OS(O)NReRf,

[0223] In some embodiments, R11is H, deuterium, or C1-C6alkyl, such as methyl, ethyl, or iso-propyl. In some embodiments, R11is H or methyl. In some embodiments, R11is methyl.

[0224] In some embodiments, the disclosure provides a compound selected from the group consisting of [3a(4)Z, 10R]-20-chloro-6,9, 10, 15-tetramethyl-2,5,9, 10, 11 , 12, 13, 15-octahydro-1.17-ethenopyrazolo[4,3-m]dipyrrolo[3,2-f3',4'-z][l,4]diazacyclopentadecine-3, 8-dione;

[0225] [3a(4)Z, 10R]-20-chloro-6,9, 10, 12, 15-pentamethyl-2,5,9, 10, 11 , 12, 13, 15-octahydro-1.17-ethenopyrazolo[4,3-m]dipyrrolo[3, 2-f3', 4'-z][l,4]diazacyclopentadecine-3, 8-dione;

[0226] [3 a(4)Z,10R] -20-chloro- 16-methoxy-9, 10,15 -trimethyl -10,11,13,15 -tetrahy dro-2H-1.17-ethenopyrazolo[4,3-m]dipyrrolo[3 ,2-f 3 ',4'- / ] [ 1 ,4]oxazacyclopentadecine-3 , 8(5H , 9H)- dione;

[0227] [3a(4)Z, 10R]-20-chloro-16-methoxy-6,9, 10, 12, 15-pentamethyl-2,5,9, 10, 11 , 12, 13, 15- octahydro- 1,17 -ethenopyrazolo[4,3 -m]dipyrrolo[3 ,2-f 3 ',4'-z] [ 1 ,4]diazacyclopentadecine-3, 8- dione;

[0228] [3a(4)Z,10^]-20-chloro-16-methoxy-9,10,12,15-tetramethyl-2,5,9,10,ll,12,13,15- octahydro-l,17-ethenopyrazolo[4,3-m]dipyrrolo[3,2-f3',4'-i][l,4]diazacyclopentadecine-3,8- dione;

[0229] [3 a(4)Z, 10R]-20-chl oro-6-fluoro- 16-methoxy-9, 10, 15-trimethyl - 10, 11 , 13 , 15- tetrahydro-2H- 1 , 17-(ethanediylidene)pyrazolo[4,3 -m]dipyrrolo[3 ,2-f.3 ' ,4* - z] [ 1 ,4]oxazacycl opentadecine-3 , 8(5H , 9 / 0-dione;

[0230] [3a(4)Z, 10R]-20-chloro-6-fluoro-16-methoxy-9, 10, 12, 15-tetramethyl- 2,5,9,10,11, 12, 13, 15-octahydro-l, 17-ethenopyrazolo[4,3-m]dipyrrolo[3,2-f3',4'- z] [ 1 ,4]diazacycl opentadecine-3 , 8-dione; and

[0231] [3a(4)Z,10R]-6-fluoro-16-methoxy-9, 10, 12,15, 20-pentamethyl-2, 5, 9, 10, 11, 12, 13, 15- octahydro-l, 17-ethenopyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-z][l,4]diazacyclopentadecine-3, 8- dione;

[0232] or a pharmaceutically acceptable salt thereof.

[0233] The following represent illustrative embodiments of compounds of Formula (I):

[0234] and pharmaceutically acceptable salts thereof.

[0235] In certain embodiments, the compound is not

[0236] In certain embodiments, the compound is not:[3a(4)Z]-6,9, 15,16-tetramethyl- 10, 11 , 13, 15-tetrahydro-2H - 1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f3',4'-i][l,4]oxazacyclopentadecine- 3, 8(5H , 977) -dione;[3a(4)Z, 10R]-20-chl oro-6, 10, 15-trimethyl- 10, 11 , 13, 15-tetrahydro-2H - 1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2;f:3',4'-i][l,4]oxazacyclopentadecine- 3,8(5H ,9H)-dione;[3a(4)Z, 10R]-20-chloro- 10, 15-dimethyl- 10, 11 , 13, 15-tetrahydro-2H - 1,17-(ethanediylidene)pyrazolo[4,3 -m]dipyrrolo[3 ,2-f.3 ',4'-z] [ 1 ,4]oxazacyclopentadecine- 3,8(5H ,9H )-dione;[3a(4)Z, 10R]-20-chloro-6,9, 10, 15-tetramethyl- 10, 11 , 13, 15-tetrahydro-2H - 1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f3',4'-z][l,4]oxazacyclopentadecine- 3, 8(5H , 9H) -dione;[3a(4)Z, 10S]-20-chloro-6,9, 10, 15-tetramethyl-l 0, 11,13,15-tetrahydro-2H -l , 17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2; / :3',4l-z][l,4]oxazacyclopentadecine- 3,8(5H ,9H )-dione;[3a(4)Z]-20-chloro-6,9, 15-trimethyl- 10, 11 , 13, 15 -tetrahydro- 2H - 1,17-(ethanediyli dene)pyrazolo[4,3 -m]dipyrrolo[3 3 ',4'- / ] [ 1 ,4]oxazacycl opentadecine- 3,8(5H ,9H)-dione;[3a(4)Z, 10R]-20-chloro-6,9, 10, 15-tetramethyl- 10, 11 , 13, 15-tetrahydro-2H - 1,17-(ethanediylidene)imidazo[4,5-f|pyrazolo[4,3-m]pyrrolo[3,4-z][l,4]oxazacyclopentadecine- 3, 8(5H , 9H) -dione;[3a(4)Z, 10R]-20-chloro-6,9, 10, 15-tetramethyl- 10, 11 , 13, 16-tetrahydro-2H- 1,17-(ethanediylidene)imidazo[4,5-m]dipyrrolo[3,2-f3',4'- / ][l,4]oxazacyclopentadecine-3, 8(5H , 9H)-dione;[3a(4)Z,101?]-6,9,10,15-tetramethyl-3,8-dioxo-3,5,8,9,10,ll,13,15-octahydro-217-l,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f3',4'-i][l,4]oxazacyclopentadecine-20- carbonitrile;[3a(4)Z, 101?]-20-fluoro-6,9, 10, 15, 16-pentamethyl- 10, 11 , 13, 15-tetrahydro-2H- 1,17- ethenopyrazolo[4,3-m]dipyrrolo[3, 2-f3', 4'-z][l,4]oxazacyclopentadecine-3, 8(5H , 9H) -dione;[3a(4)Z, 10R]-20-chloro-6,9, 10, 15, 16-pentamethyl- 10, 11 , 13, 15-tetrahydro-2H- 1,17- ethenopyrazolo[4,3 -m]di pyrrol o[3 ,2-f 3 ',4'- / ] [ 1 ,4]oxazacyclopentadecine-3 ,8(5H , 9H) -di one, or[3a(4)Z, 10R]-20-fluoro-6,9, 10, 15-tetramethyl- 10, 11,13,15-tetrahydro-2H-1 , 17- ethenopyrazolo[4,3 -m]dipyrrolo[3 ,2-f 3 ',4'- / ] [ 1 ,4]oxazacyclopentadecine-3 ,8(5H , 9H) -dione.

[0237] 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.ALTERNATIVE EMBODIMENTS

[0238] 1. A compound of the formula I, or a pharmaceutically acceptable salt thereof,I

[0239] wherein

[0240] X is -O- or -NR3-;

[0241] R1and R1aare each independently H, deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, 5- to 10- membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRa(O)ORb-NR*C(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb,-P(O)NRaRb, -P(0)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or-NCh, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaiyl, is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re,-P(O)2ORe, -CN, or -NO2;

[0242] R2is H, deuterium, C1-C6alkyl, or -OC1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl and -OC1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf,

[0243] each of R2a, R5, R8, R9, and R11is independently H, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O>2Re, -S(O)NReRf, -S(O)NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P^R^, -P(O)2ReRf, -PfOJNReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;

[0244] each of R3, R4, R3a, R4a, R3b, and R4bis independently H, deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, -ORe, -OC(O)Re, -OC(O)NRcRd,wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4-to 8-membered heterocycloalkyl, C6-C10aryl, and 5- to 10-membered heteroaiyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl,-P(0)0Re, -P(0)2ORe, -CN, or -N02;

[0245] each of R6, R6a, and R7is independently H, deuterium, halogen, or C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -0C(0)Re, --OC(O)NReR,f-OS(O)Re, -0S(O)2Re-0S(0)NReRf, -0S(0)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(0)NReRf, -S(O)2NReRf, -NReRf, -NReC(0)Rf, -NReC(0)0Rf, -NReC(0)NReRf, -NReS(0)Rf, -NReS(O)2Rf, -NReS(0)NReRf, -NReS(0)2NReRf, -C(0)Re, -C(0)0Re, -C(0)NR*Rf, -PReRf, -P(0)ReRf, -P(0)2ReRf, -P(0)NReRf, -P(0)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -N02;

[0246] R10is hydrogen or deuterium; and

[0247] each Ra, Rb, Rc, Rd, Re, and Rfis independently selected from the group consisting of H, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Cg-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, C1-C6alkyl -C6-Cw aryl, and 5- to 10-membered heteroaryl;

[0248] provided that when X is -O-, then

[0249] R2is deuterium, or

[0250] R2ais ethyl, wherein each hydrogen atom in ethyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl,-P(O)ORe, -P(O)ORe, -CN, or -NO2, or

[0251] R7is C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl,-P(O)ORe, -P^ORe, -CN, or -NO2, or

[0252] R2is C1-C6alkyl, wherein at least one hydrogen atom is substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, --OC(O)NReR,f-OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NRT^NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PR^, -P(O)ReRf, -P(O)2ReRf, -P^NR'Rf, -P(0)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2, or

[0253] R2is -OC1-C6 alkyl, wherein each hydrogen atom in -OC1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl,-P(O)ORe, -P(0)2ORe, -CN, or -NO2.

[0254] 2. A compound of the formula I, or a pharmaceutically acceptable salt thereof,I

[0255] wherein

[0256] X is -O- or -NR5-;

[0257] R1and R1aare each independently H, deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, -ORe, -OC(O)Re, -OC(O)NRaRb, -OS(O)Re, -OS(O)2Ra, -SRe,-P(O)NReRb, -P(O)zNReRb, -P(O)ORe, -P(O)2ORe, -CN, or -NO2, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re,-P(O)2ORe, -CN, or -NO2;

[0258] R2is H, deuterium, C1-C6alkyl, or -OC1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl and -OC1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)iRe, -S(O)NReRf, -S(O)2NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;

[0259] each of R2a, R5, R8, R9, and R11is independently H, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, or 5- to 10- membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)2NReRf-S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P^R^, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;

[0260] each of R3, R4, R3a, R4a, R3b, and R4bis independently H, deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, -ORe, -OC(O)Re, -OC(O)NRcRd,wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl,-C(O)ORe, -C(O)NReRf, -PReRf, -P(OJR*R.f, -P(O)2ReRf, -P(O)NReRf, -P^NReRf, -P(O)ORe, -P(0)20Re, -CN, or -N02;

[0261] each of R6, R6a, and R7is independently H, deuterium, halogen, or C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, --OC(O)NReR,f-OS(O)Re, -OS(O>2Re,

[0262] R10is hydrogen or deuterium; and

[0263] each Ra, Rb, Rc, Rd, Re, and Rfis independently selected from the group consisting of H, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, C1-C6alkyl-C6-C10aryl, and 5- to 10-membered heteroaryl;

[0264] provided that when X is -O-, then

[0265] R2is deuterium;

[0266] R2is C1-C6alkyl, wherein at least one hydrogen atom is substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NR*Rf, -OS(O)Re, -OS(OhRe, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NRT^NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PR^, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P^NReRf, -P(O)ORe, -PfO^ORe, -CN, or -NO2, or

[0267] R2is -OC1-C6alkyl, wherein each hydrogen atom in -OC1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl,-P(O)ORe, -P(O)2ORe, -CN, or -NO2.

[0268] 3. The compound of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X is -O-.

[0269] 4. The compound of any one of embodiments 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R2is deuterium.

[0270] 5. The compound of any one of embodiments 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R2is C1-C6alkyl, wherein at least one hydrogen atom is optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl,-P(O)ORe, -P^ORe, -CN, or -NO2.

[0271] 6. The compound of any one of embodiments 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R2is -OC1-C6alkyl, wherein each hydrogen atom in -OC1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl,-P(O)ORe, -P(0)2ORe, -CN, or -NO2.

[0272] 7. The compound of any one of embodiments 1 to 3, or a pharmaceutically acceptable salt thereof, wherein X is -NR5-.

[0273] 8. The compound of any one of embodiments 1, 2, 3, or 7, or a pharmaceutically acceptable salt thereof, wherein R2is H.

[0274] 9. The compound of any one of embodiments 1, 2, 3, or 7, or a pharmaceutically acceptable salt thereof, wherein R2is deuterium.

[0275] 10. The compound of any one of embodiments 1, 2, or 6, or a pharmaceutically acceptable salt thereof, wherein R2is C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl,-P(O)ORe, -P(O)2ORe, -CN, or -NO2.

[0276] 11. The compound of any one of embodiments 1, 2, 3, or 7, or a pharmaceutically acceptable salt thereof, wherein R2is -OC1-C6alkyl, wherein each hydrogen atom in -OC1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, --OC(O)NReR,f-OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OSfO^NR^1, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NR'SfOJNReRf, -NR^CO^NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, ^(0^% -P(O)2ReRf, -PfOJNReRf, -P^NR'Rf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2.

[0277] 12. The compound of any one of embodiments 1, 2, 3, 4, 6, 7, or 11, or a pharmaceutically acceptable salt thereof, wherein R2is -OC1-C6alkyl.

[0278] 13. The compound of any one of embodiments 1, 2, 3, 4, 6, 7, 11, or 12, or a pharmaceutically acceptable salt thereof, wherein R2is -OCHs, -OCH2CH3, or -OCHJCCHQJ.

[0279] 14. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R1ais H or deuterium.

[0280] 15. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R1, when present, is H, halogen, or C1-C6alkyl.

[0281] 16. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R1, when present, is H, deuterium, fluoro, or methyl.

[0282] 17. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R2ais deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaiyl, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl,-P(O)ORe, -P(O)2ORe, -CN, or -NO2.

[0283] 18. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R2ais C1-C6alkyl.

[0284] 19. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R2ais methyl.

[0285] 20. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R2ais optionally substituted ethyl.

[0286] 21. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein one of R3, R4, R3a, R4a, R3b, or R4*5is C1-C6alkyl wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by deuterium, halogen,-P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2, and the remaining of R3, R4, R3a, R4a, R3b, and R4bare each H.

[0287] 22. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R3ais C1-C6alkyl.

[0288] 23. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R3ais methyl.

[0289] 24. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R5, when present, is H or C1-C6alkyl.

[0290] 25. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R5, when present, is H or methyl.

[0291] 26. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R6is H.

[0292] 27. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R6ais H.

[0293] 28. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R7is H or halogen.

[0294] 29. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R7is fluoro or chloro.

[0295] 30. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R8is H.

[0296] 31. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R9is C1-C6alkyl.

[0297] 32. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R9is methyl.

[0298] 33. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R11is H.

[0299] 34. The compound of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, selected from the group consisting of [3a(4)Z,10R]-20-chloro-6,9,10,15-tetramethyl- 2,5,9,10,11,12, 13, 15-octahydro-l,17-ethenopyrazolo[4,3- / w]dipyrrolo[3,2-f3', 4'- z] [ 1 ,4]di azacyclopen tadecine-3 , 8-dione;

[0300] [3a(4)Z,10R]-20-chloro-6,9,10,12,15-pentamethyl-2,5,9,10,ll,12,13,15-octahydro-1.17-ethenopyrazolo[4,3-m]dipyrrolo[3, 2-f3', 4'- / ][l,4]diazacyclopentadecine-3, 8-dione;

[0301] [3 a(4)Z, 10R]-20-chloro- 16-methoxy-9, 10, 15-trimethyl- 10, 11, 13, 15 -tetrahydro-2H-1.17-ethenopyrazolo[4,3 -m]dipyrrolo[3,2-f 3',4'-z] [ 1 ,4]oxazacyclopentadecine-3 ,8(52 / , 9H)- dione;

[0302] [3a(4)Z, 10R]-20-chloro-16-methoxy-6,9, 10, 12, 15-pentamethyl-2,5,9, 10,11,12,13,15- octahydro-l,17-ethenopyrazolo[4,3-m]dipyrrolo[3,2-f3',4'-z][l,4]diazacyclopentadecine-3,8- dione;

[0303] [3a(4)Z,10R]-20-chloro-16-methoxy-9,10,12,15-tetramethyl-2,5,9,10,l l,12,13,15- octahydro-l,17-ethenopyrazolo[4,3-m]dipyrrolo[3,2-f3',4'-z][l,4]diazacyclopentadecine-3,8- dione;

[0304] [3a(4)Z,10R]-20-chloro-6-fluoro-16-methoxy-9,10,15-ttimethyl-10,ll,13,15- tetrahydro-2H-l,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f3',4'- z] [ 1 ,4]oxazacyclopentadecine-3 , 8(5H , 9H)-dione;

[0305] [3a(4)Z, 10R]-20-chloro-6-fluoro-l 6-methoxy-9, 10, 12, 15-tetramethyl-2,5,9, 10, 11, 12, 13, 15-octahydro-l, 17-ethenopyrazolo[4,3-m]dipyrrolo[3,2-f3',4'- z] [ 1 ,4] di azacyclopentadecine-3 , 8-dione;

[0306] [3a(4)Z,10R]-6-fluoro-16-methoxy-9,10,12,15,20-pentamethyl-2,5,9,10,ll,12,13,15- octahydro-l,17-ethenopyrazolo[4,3-m]dipyrrolo[3,2-f3',4'-z][l,4]diazacyclopentadecine-3,8- dione;

[0307] [3a(4)Z,10 / i?]-20-chloro-15-ethyl-6,9,10-trimethyl-10,l l,13,15-tetrahydro-2H-l,17- ethenopyrazolo[4,3-m]dipyrrolo[3, 2-f3', 4'-z][l,4]oxazacyclopentadecine-3, 8(5H , 9H) -dione;

[0308] [3 a(4)Z, 10R]-20-(methoxymethyl)-6,9, 10, 15-tetramethyl- 10, 11 , 13 , 15-tetrahydro-2H- 1 , 17-ethenopyrazolo[4, 3 -m]di pyrrol o[3 ,2-f 3 ',4'- / ] [ 1 ,4]oxazacyclopentadecine-3 , 8(5H ,9 / / )- dione;

[0309] [3a(4)Z, 10 / <|-20-chloro- 15-(2-hydroxyethyl)-6,9, 10-trimethyl- 10,11,13,15- tetrahydro-2H-l,17-ethenopyrazolo[4,3-m]dipyrrolo[3,2-f3',4'-z][l,4]oxazacyclopentadecine- 3, 8(5H , 9H) -dione;

[0310] [3a(4)Z, 10R]-20-(methoxymethyl)-6,9, 10, 12, 15-pentamethyl-2,5,9, 10,11,12,13,15- octahydro-l,17-ethenopyrazolo[4,3-m]dipyrrolo[3,2-f3',4'-z][l,4]diazacyclopentadecine-3,8- dione;

[0311] [3a(4)Z, 10R]-20-chloro- 12-(2,2-difluoroethyl)-6,9, 10, 15-tetramethyl-2,5,9,10,11,12, 13,15-octahydro-l, 17-ethenopyrazolo[4,3-m]dipyrrolo[3, 2-f3', 4'- z] [ 1 ,4]diazacyclopentadecine-3 , 8-dione;

[0312] [3a(4)Z, 10jR]-6-chloro-20-(methoxymethyl)-9, 10, 15-trimethyl-l 0, 11,13,15- tetrahydro-2H- 1 , 17-ethenopyrazolo[4,3 -m]dipyrrolo[3 ,2-f3 ' ,4' -z] [ 1 ,4]oxazacyclopentadecine- 3,8(5H ,9 / / )-dione; and

[0313] [3a(4)Z, 10R]-6-fluoro-20-(methoxymethyl)-9, 10, 15-trimethyl- 10,11,13,15- tetrahydro-2 / 7- 1 , 17-ethenopyrazolo[4,3 -m]dipyrrol o[3 ,2-f 3 *,4'-z] [ 1 ,4]oxazacyclopentadecine- 3,8(5H ,9 / / )-dione.

[0314] 35. A pharmaceutical composition comprising at least one compound of any one of embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.

[0315] 36. A method of treating disease, such as autoimmune disease, comprising administering to a subject in need of such treatment an effective amount of a compound of any one of embodiments 1 to 34, or a pharmaceutically acceptable salt thereof.

[0316] 37. A compound of any one of embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, for use in a method of treating an autoimmune disease in a subject.

[0317] 38. A compound of any one of embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, for treating an autoimmune disease in a subject.

[0318] 39. Use of a compound of any one of embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating an autoimmune disease in a subject.PHARMACEUTICAL COMPOSITIONS

[0319] For treatment purposes, pharmaceutical compositions comprising the compounds described herein may further comprise one or more pharmaceutically-acceptable excipients. A pharmaceutically-acceptable excipient is a substance that is non-toxic and otherwise biologically suitable for administration to a subject. Such excipients facilitate administration of the compounds described herein and are compatible with the active ingredient. Examples of pharmaceutically-acceptable excipients include stabilizers, lubricants, surfactants, diluents, anti-oxidants, binders, coloring agents, bulking agents, emulsifiers, or taste-modifying agents. In preferred embodiments, pharmaceutical compositions according to the disclosure are sterile compositions. Pharmaceutical compositions may be prepared using compounding techniques known or that become available to those skilled in the art.

[0320] Sterile compositions are also contemplated by the disclosure, including compositions that are in accord with national and local regulations governing such compositions.

[0321] The pharmaceutical compositions and compounds described herein may be formulated as solutions, emulsions, suspensions, or dispersions in suitable pharmaceutical solvents or carriers, or as pills, tablets, lozenges, suppositories, sachets, dragees, granules, powders, powders for reconstitution, or capsules along with solid carriers according to conventional methods known in the art for preparation of various dosage forms. Pharmaceutical compositions of the disclosure may be administered by a suitable route of delivery, such asoral, parenteral, rectal, nasal, topical, or ocular routes, or by inhalation. Preferably, the compositions are formulated for intravenous or oral administration.

[0322] For oral administration, the compounds the disclosure may be provided in a solid form, such as a tablet or capsule, or as a solution, emulsion, or suspension. To prepare the oral compositions, the compounds of the disclosure may be formulated to yield a dosage of, e.g., from about 0.1 mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to 1 g daily. Oral tablets may include the active ingredients) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquid oral excipients include ethanol, glycerol, water, and the like. Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are exemplary disintegrating agents. Binding agents may include starch and gelatin. The lubricating agent, if present, may be magnesium stearate, stearic acid, or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.

[0323] Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, active ingredients) may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules may be prepared by mixing the active ingredient with water, an oil, such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.

[0324] Liquids for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.

[0325] For parenteral use, including intravenous, intramuscular, intraperitoneal, intranasal, or subcutaneous routes, the agents of the disclosure may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil.Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms may be presented in unit-dose form such as ampoules or disposable injection devices, in multidose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation. Illustrative infusion doses range from about 1 to 1000 pg / kg / minute of agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.

[0326] 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.

[0327] For topical applications, the compounds of the present disclosure are preferably formulated as creams or ointments or a similar vehicle suitable for topical administration. For topical administration, the inventive compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle. Another mode of administering the agents of the disclosure may utilize a patch formulation to effect transdermal delivery.

[0328] As used herein, the terms “treat” or “treatment” encompass both “preventative” and “curative” treatment. “Preventative” treatment is meant to indicate a postponement of development of a disease, a symptom of a disease, or medical condition, suppressing symptoms that may appear, or reducing the risk of developing or recurrence of a disease or symptom. “Curative” treatment includes reducing the severity of or suppressing the worsening of an existing disease, symptom, or condition. Thus, treatment includes ameliorating or preventing the worsening of existing disease symptoms, preventing additional symptoms from occurring, ameliorating or preventing the underlying systemic causes of symptoms, inhibiting the disorder or disease, e.g., arresting the development of the disorder or disease, relieving the disorder or disease, causing regression of the disorder or disease, relieving a condition caused by the disease or disorder, or stopping the symptoms of the disease or disorder.

[0329] The term “subject” refers to a mammalian patient in need of such treatment, such as a human.

[0330] Exemplary diseases include autoimmune diseases and inflammation. Autoimmune diseases include, for example, rheumatoid arthritis, psoriasis, inflammatory bowel disease and systemic lupus erythematosus, Sjogren syndrome, Type I diabetes, and lupus. Exemplary neurological diseases include Alzheimer’s Disease, Parkinson’s Disease, Amyotrophic lateral sclerosis, and Huntington’s disease. In some embodiments, exemplary neurological diseases include Alzheimer’s Disease, Parkinson’s Disease, multiple sclerosis (MS), Amyotrophiclateral sclerosis, and Huntington’s disease Exemplary inflammatory diseases include atherosclerosis, allergy, and inflammation from infection or injury.

[0331] In one aspect, the compounds and pharmaceutical compositions of the disclosure specifically target TYK2. Thus, these compounds and pharmaceutical compositions can be used to prevent, reverse, slow, or inhibit the activity of TYK2. In preferred embodiments, methods of treatment target autoimmune disease. In other embodiments, methods are for treating autoimmune disease, such as rheumatoid arthritis, psoriasis, inflammatory bowel disease and systemic lupus erythematosus, Sjogren syndrome, Type I diabetes, and lupus.

[0332] In the inhibitory methods of the disclosure, an “effective amount” means an amount sufficient to inhibit the target protein. Measuring such target modulation may be performed by routine analytical methods such as those described below. Such modulation is useful in a variety of settings, including in vitro assays. In such methods, the cell is preferably an autoimmune disease cell with abnormal signaling due to upregulation of TYK2.

[0333] In treatment methods according to the disclosure, an “effective amount” means an amount or dose sufficient to generally bring about the desired therapeutic benefit in subjects needing such treatment. Effective amounts or doses of the compounds of the disclosure may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the infection, the subject’s health status, condition, and weight, and the judgment of the treating physician. An exemplary dose is in the range of about from about 0.1 mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to 1 g daily. The total dosage may be given in single or divided dosage units (e.g., BID, TID, QID).

[0334] Once improvement of the patient’s disease has occurred, the dose may be adjusted for preventative or maintenance treatment. For example, the dosage or the frequency of administration, or both, may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained. Of course, if symptoms have been alleviated to an appropriate level, treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms. Patients may also require chronic treatment on a long-term basis.DRUG COMBINATIONS

[0335] The inventive compounds described herein may be used in pharmaceutical compositions or methods in combination with one or more additional active ingredients in the treatment of the diseases and disorders described herein. Further additional active ingredients include other therapeutics or agents that mitigate adverse effects of therapies for the intended disease targets. Such combinations may serve to increase efficacy, ameliorate other disease symptoms, decrease one or more side effects, or decrease the required dose of an inventive compound. The additional active ingredients may be administered in a separate pharmaceutical composition from a compound of the present disclosure or may be included with a compound of the present disclosure in a single pharmaceutical composition. The additional active ingredients may be administered simultaneously with, prior to, or after administration of a compound of the present disclosure.

[0336] Combination agents include additional active ingredients are those that are known or discovered to be effective in treating the diseases and disorders described herein, including those active against another target associated with the disease. For example, compositions and formulations of the disclosure, as well as methods of treatment, can further comprise other drugs or pharmaceuticals, e.g., other active agents useful for treating or palliative for the target diseases or related symptoms or conditions.CHEMICAL SYNTHESIS METHODS

[0337] The following examples are offered to illustrate but not to limit the disclosure. One of skill in the art will recognize that the following synthetic reactions and schemes may be modified by choice of suitable starting materials and reagents in order to access other compounds of Formula (I)-(XI).

[0338] 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 grams eq equivalents mmol millimoles mL millilitersEtO Ac or EA ethyl acetateMHz megahertzPPm parts per million5 chemical shift s singlet

[0339] Preparation of Starting Material Type A

[0340] Preparation of tert-butyl (R)-( 1 -(((benzyl oxy)carbonyl)((4-bromo-l -methyl- 1H - pyrazol-3-yl)methyl)amino)propan-2-yl)(methyl)carbamate (S)-2-(isopropylamino)propan-l- ol (Al):

[0341] Step 1. To a solution of commercially available l-methylpyazole-3 -carboxamide (5 g, 39.9 mmol, 1 eq) in dioxane (50 mL) was added LiAlH, (4.55 g, 119 mmol, 3 eq) at 0 °C. The mixture was stirred at 100 °C for 3 h. On completion, the mixture was quenched by H2O (5 mL) and 15% NaOH (5 mL), filtered, the filtrate was diluted with H2O (50 mL), and extracted with EtOAc (50 mL x 2). The combined organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuum to give (l-methyl-1H -pyrazol-3-yl) (5.02 g, 45.17 mmol, crude) as a colorless oil.

[0342] Step 2. To a solution of (l-methylpyrazol-3-yl)methanamine (5 g, 44.9 mmol, 1 eq) in sat. NaHCO3(20 mL) in THF (20 mL) was added CbzCI (11.5 g, 67.4 mmol, 9.59 mL, 1.5 eq). The mixture was stirred at 25 °C for 2 h. On completion, the reaction mixture was partitioned between ethyl acetate (50 mL x 3) and water (50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by flash silica gel chromatography (0-50% THF / PE) to give benzyl N-[(l- methylpyrazol-3-yl)methyl]carbamate (5.39 g, 21.3 mmol, 47% yield, 97% purity) as a white solid. LCMS: (M+l: 245.9).

[0343] Step 3. To a solution of benzyl ^-[(l-methylpyrazol-3-yl)methyl]carbamate (5.19 g, 21.1 mmol, 1 eq) in ACN (50 mL) was added NBS (3.77 g, 21.1 mmol, 1 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. On completion. The mixture was quenched with sat. Na2SO3 (50 mL) at 0 °C and extracted with ethyl acetate (30 mL x 3). The combined organicphase was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to give a residue. The residue was purified by flash silica gel chromatography (0-100% EA / PE) to give benzyl Ar-[(4-bromo-l-methyl-pyrazol-3-yl)methyl]carbamate (6.2 g, 19.1 mmol, 90% yield) as a light yellow solid. LCMS: (M+l: 325.6).

[0344] Step 4. To a solution of benzyl Ar-[(4-bromo-l-methyl-pyrazol-3-yl)methyl]carbamate (6 g, 18.5 mmol, 1 eq) in DMF (120 mL) was added NaH (1.48 g, 37.0 mmol, 60% purity, 2 eq), and the mixture was stirred at 25 °C for 0.5 h. Commercially available Tert-butyl (4R)-4- methyl-2,2-dioxo-oxathiazolidine-3-carboxylate (6.59 g, 27.7 mmol, 1.5 eq) was then added, and the mixture was stirred at 25 °C for 1 h. On completion, the mixture was quenched by H2O (180 mL) and extracted with EtOAc (180 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuum. The residue was purified by flash silica gel chromatography (EA in PE, 0-100%) to give benzyl N-[(4-bromo-1-methyl-pyrazol-3-yl)methyl]-N-[(2R)-2-(tert-butoxycarbonylamino)propyl]carbamate (8.59 g, 17.8 mmol, 96% yield) as a colorless oil.1H NMR (400 MHz, DMSO-d6) δ = 7.87 (s, 1H), 747 - 7.16 (m, 5H), 6.68 (d, J= 8.8 Hz, 1H), 5.18 - 5.00 (m, 2H), 4.43 (s, 2H), 3.82 (d, . / = 6.8 Hz, 1H), 3.78 (s, 3H), 3.24 - 3.12 (m, 2H), 1.36 (s, 9H), 0.98 (d, J= 6.8 Hz, 3H). LCMS: (M+l: 482.6).

[0345] Step 5. To a solution of benzyl N-[(4-bromo-l-methyl-pyrazol-3-yl)methyl]- N-[(2R)-2-(tert-butoxycarbonylamino)propyl]carbamate (2 g, 4.15 mmol, 1 eq) and iodomethane (884 mg, 6.23 mmol, 0.387 mL, 1.5 eq) in DMF (20 mL) was added NaH (332 mg, 8.31 mmol, 60% purity, 2 eq). The mixture was stirred at 0 °C for 0.5 h. On completion, the mixture was quenched by H2O (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuum. The residue was purified by flash silica gel chromatography (EA in PE, 0-100%) to give tertbutyl N-[(1R)-2-[benzyloxycarbonyl-[(4-bromo-l-methyl-pyrazol-3-yl)rnethyl]arnino]-l- methyl-ethyl]- N-methyl-carbamate (1.43 g, 2.88 mmol, 69% yield) as a light yellow oil (Al). LCMS: (M+l: 496.8).

[0346] Preparation of tert-butyl (R)-(l-((4-bromo-5-methoxy-l-methyl-1H -pyrazol-3- yl)methoxy)propan-2-yl)(methyl)carbamate (A2):

[0347] Step 1. To a solution of commercially available methyl 5-hydroxy-l-methyl-pyrazole- 3-carboxylate (20.0 g, 128 mmol, 1 eq) in DMF (50 mL) was added Mel (21.8 g, 153 mmol, 1.2 eq) and K2CO3 (26.5 g, 192 mmol, 1.5 eq). The mixture was stirred at 25 °C for 12 hours. On completion, the mixture was quenched with H2O (1000 mL) and extracted with EA (200 mL x 3). The combined organic phase was dried over Na2SC>4, filtered and the filtrate was concentrated to give methyl 5-methoxy-l-methyl-pyrazole-3-carboxylate (13.0 g, 76.0 mmol, 59 % yield) as a yellow oil. LCMS: (M+l: 171.1).

[0348] Step 2. To a solution of methyl 5-methoxy-l-methyl-pyrazole-3-carboxylate (13.0 g, 76.4 mmol, 1 eq) in THF (20 mL) was added LAH (2.5 M, 30.6 mL, 1 eq) at 0 °C, and the mixture was stirred at 25 °C for 2 hours. On completion, the mixture was quenched by H2O (3 mL) and 15% NaOH (3 mL), diluted with H2O (9 mL), extracted with EtOAc (75 mL x 3). The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to give (5 -methoxy- l-methyl-pyrazol-3-yl)methanol (10.0 g, 70.3 mmol, 92% yield) as white oil.1H NMR (400 MHz, CDCh) δ = 5.46 (s, 1H), 4.47 (s, 2H), 3.79 (s, 3H), 3.51 (s, 3H).

[0349] Step 3. To a solution of (5-methoxy-l-methyl-pyrazol-3-yl)methanol (10.0 g, 70.3 mmol, 1.2 eq) in ACN (50 mL) was added NBS (11.4 g, 64.4 mmol, 1.1 eq), and the mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=l:l) to give (4-bromo-5-methoxy-l-methyl-pyrazol-3- yl)methanol (8.00 g, 36.1 mmol, 61% yield) as a yellow solid. LCMS: (M+l: 202.9).

[0350] Step 4. To a solution of (4-bromo-5-methoxy-l-methyl-pyrazol-3-yl)methanol (7.00 g, 31.6 mmol, 1 eq) in DCM (20 mL) was added PPh3(12.4 g, 47.5 mmol, 1.5 eq) and CBr4(15.7g, 47.5 mmol, 1.5 eq). The mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiOz, Petroleum ether / Ethyl acetate=5: 1) to give 4-bromo-3-(bromomethyl)- 5-methoxy-l -methyl -pyrazole (6.30 g, 22.1 mmol, 70% yield) as a white solid. LCMS: (M+l: 284.8).

[0351] Step 5. To a solution of 4-bromo-3-(bromomethyl)-5-methoxy-l-methyl-pyrazole (4.00 g, 14.0 mmol, 1 eq) and commercially available tert-butyl N-[(1R)-2-hydroxy-l -methyl - ethylcarbamate (2.96 g, 16.9 mmol, 1.2 eq) in THF (25 mL) was added TBAC (391 mg, 1.41 mmol, 0.1 eq) and KOH (2.37 g, 42.2 mmol, 3 eq), and the mixture was stirred at 25 °C for 12 hours. On completion, the residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=3:l) to give tert-butyl N- [( 1R)-2-[(4-brom o-5 -methoxy- 1 -methyl -pyrazol- 3-yl)methoxy]-l-methyl-ethyl] carbamate (4.20 g, 11.1 mmol, 78% yield) as yellow oil. LCMS: (M+l: 379.9).

[0352] Step 6. To a solution of tert-butyl N- [(1R)-2-[(4-bromo- 5 -methoxy- 1 -methyl -pyrazol- 3-yl) methoxy]-1 -methyl -ethyl] carbamate (4.20 g, 11.1 mmol, 1 eq) in DMF (20 mL) was added NaH (888 mg, 22.2 mmol, 60% purity, 2 eq). The mixture was stirred at 0 °C for 0.5 hours, then CH3I (1.89 g, 13.3 mmol, 1.2 eq) was added into the mixture, and the mixture was stirred at 0 °C for 1 hour. On completion, the reaction mixture was quenched by addition H2O (100 mL), and then extracted with EA (100 mL * 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Petroleum ether / THF=l:l) to give tert-butyl N-[(1R)-2-[(4-bromo-5- methoxy-l-methyl-pyrazol-3-yl)methoxy]-l-methyl-ethyl]-N-methyl-carbamate (3.50 g, 8.92 mmol, 80% yield) as a white oil (A2). LCMS: (M+l: 393.8).

[0353] Preparation of tert-butyl (R)-(l-(((4-bromo-5-methoxy-l-methyl-1H -pyrazol-3- yl)methylXmethyl)amino)propan-2-yl)(methyl)carbamate (A3):H I N TEA hk,BocN'n BOCLAH (BOC)N2O NBSN NTHF ACN~N 1 DCM -75 ~N'70eCBr°\ °\ °\A3-3 A3-4 A3

[0354] Step 1. To a solution of A2-5 (5.90 g, 20.7 mmol, 1 eq) in THF (30 mL) was added MeNH2 (2 M, 103 mL, 10 eq). The mixture was stirred at 25 °C for 4 hours. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH=T:0 to 4:1) to give 1 -(4-bromo-5-m ethoxy- 1 -methyl - pyrazol-3-yl)-N-methyl-methanamine (4.50 g, 19.2 mmol, 92% yield) as a red oil. LCMS: (M+l: 235.8).

[0355] Step 2. To a solution of l-(4-bromo-5-methoxy-l-methyl-pyrazol-3-yl)-N-methyl- methanamine (4.50 g, 19.2 mmol, 1 eq) in DMF (100 mL) was added NaH (1.54 g, 38.4 mmol, 60% purity, 2 eq) at 0 °C, and then commercially available tert-butyl(4R)-4-methyl-2,2-dioxo- oxathiazolidine-3-caiboxylate (6.84 g, 28.8 mmol, 1.5 eq) was added. The mixture was stirred at 25 °C for 1 hour. On completion, the mixture was quenched with water (100 mL) and extracted with DCM / MeOH=10:l (100 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiC>2, Petroleum ether / THF=l :0 to 0: 1) to give tert-butyl-jV-[(1R)-2-[(4-bromo-5-methoxy-l-methyl-pyrazol-3-yl)methyl-methyl-amino]-l-methyl- ethyl]carbamate (3.30 g, 8.43 mmol, 43% yield) as a yellow oil. LCMS: (M+l: 393.0).

[0356] Step 3. To a solution of tert-butyl A^-[( 1R)-2 -[(4-bromo- 5 -methoxy- 1 -methyl -pyrazol-3-yl)methyl-methyl-amino]-l-methyl-ethyl]carbamate (3.30 g, 8.43 mmol, 1 eq) in THF (50 mL) was added LiA1H4(2.5 M, 16.8 mL, 5 eq) at 0 °C. The mixture was stirred at 70 °C for 4 hours. On completion, the mixture was quenched with water (1.6 mL) / 15%NaOH (1.6 mL) / water (4.8 mL), filtered, and concentrated to give (2R)-Nl-[(5-methoxy-l-methyl- pyrazol-3-yl)methyl]-N ,N2-dimethyl-propane-l,2-diamine (1.45 g, 6.41 mmol, 75% yield) as a yellow oil.1HNMR (400 MHz, DMSO-d6) δ = 5.55 (s, 1H), 3.83 (s, 3H), 3.48 (s, 3H), 3.38 - 3.20 (m, 3H), 2.58 - 2.53 (m, 1H), 2.51 - 2.50(m, 2H), 2.27 (s, 3H), 2.14 - 2.10 (m, 3H), 0.88 (d, J= 6.4 Hz, 3H).

[0357] Step 4. To a solution of (2R)-N1-[(5-methoxy-l-methyl-pyrazol-3-yl)methyl]-N1N 2- dimethyl-propane-l,2-diamine (1.45 g, 6.41 mmol, 1 eq) in DCM (50 mL) was added TEA (1.94 g, 19.2 mmol, 3 eq) and tert-butoxycarbonyl tert-butyl carbonate (2.80 g, 12.8 mmol, 2eq). The mixture was stirred at 25 °C for 2 hours. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiOz, DCM / MeOH=l:0 to 4:1) to give tert-butyl A-[(1R)-2-[(5-methoxy-l-methyl-pyrazol-3- yl)methyl -methyl -amino]- 1 -methyl -ethyl ]- N-m ethyl -carbamate (1.60 g, 4.90 mmol, 76% yield) as a yellow oil. LCMS: (M+l: 327.1).

[0358] Step 5. A mixture of tert-butyl N-[(1R)-2-[(5-methoxy-l-methyl-pyrazol-3-yl)methyl- methyl-amino]-l-methyl-ethyl]-A-methyl-carbamate (1.60 g, 4.90 mmol, 1 eq) and NBS (872 mg, 4.90 mmol, 1 eq) in ACN (30 mL) was degassed and purged with N23 times, and then the mixture was stirred at 0 °C for 2 hours under N2atmosphere. On completion, the mixture was quenched with a saturated solution of Na2SO3(20 mL), extracted with THF (20 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF=l :0 to 0: 1) to give tert-butyl N-[(1R)-2-[(4-brom o-5 -meth oxy-1 -methyl - pyrazol-3-yl)methyl-methyl-amino]-l-methyl-ethyl]-?vr-methyl-carbamate (1.40 g, 3.45 mmol, 70% yield) as yellow oil (A3). LCMS: (M+2: 407.0).

[0359] Preparation of tert-butyl (R)-(l-((4-bromo-l-ethyl-lH-pyrazol-3-yl)methoxy)propan- 2-yl)(methyl)carbamate (A4):

[0360] Step 1. To a solution of commercially available l-ethyl-lH-pyrazole-3-carbaldehyde (5.00 g, 40.3 mmol, 1 eq) in THF (50 mL) was added LiAlH4(2.5 M, 17.7 mL, 1.1 eq) at 0 °C. The mixture was stirred at 25 °C for 30 min. On completion, the reaction mixture was quenched by addition of H2O (1.68 mL) dropwise, 15% NaOH (1.68 mL), H2O (5.04 mL) in turn at 0 °C, dried over anhydrous sodium sulfate, filtered and concentrated to give (l-ethyl-lH-pyrazol-3- yl)methanol (5.00 g, 39.6 mmol, 98% yield) as a colorless oil without further purification.1HNMR (400 MHz, CDCh) δ = 8.32 (d, J = 1.6 Hz, 1H), 7.23 (d, J = 1.6 Hz, 1H), 5.64 (s, 2H), 5.17 (s, 1H), 5.10 (d, J= 7.2 Hz, 2H), 2.42 (t, J= 7.6 Hz, 3H).

[0361] Step 2. To a solution of tert-butyl (R)-4-methyl-l,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (9.40 g, 39.6 mmol, 1 eq) in DMF (52 mL) was added NaH (3.17 g, 79.3 mmol, 60% purity, 2 eq) at 0 °C and stirred at 25 °C for 30 min. Then commercially available (1- ethyl-lH-pyrazol-3-yl)m ethanol (5.00 g, 39.6 mmol, 1 eq) was added to the mixture and stirred at 25 °C for 30 min. On completion, the mixture was quenched with 10% H2SO4 (10.4 mL) at 0 °C for 4 h, then adjusted with saturated solution of NaHCCh to pH=7, then extracted with EA (200 mL x 3) and water (200 mL). The combined organic phase was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiOi, Petroleum ether / Ethyl acetate=l :0 to 0:1) to give tert-butyl (R)-(l-((l-ethyl-lH-pyrazol-3-yl)methoxy)propan-2-yl)carbamate (6.50 g, 22.9 mmol, 58% yield) as a colorless oil. ’H NMR (400 MHz, DMSO-fife) δ = 7.64 (d, J= 2.0 Hz, 1H), 6.17 (d, J= 2.0 Hz, 1H), 4.37 (s, 2H), 4.08 (d, J= 7.2 Hz, 2H), 3.60 (s, 1H), 3.40 - 3.12 (m, 4H), 1.37 (s, 9H), 0.99 (d, J= 6.4 Hz, 3H). LCMS: (M+l-100: 184.2).

[0362] Step 3. To a solution of tert-butyl (R)-(l-((l-ethyl-lH-pyrazol-3-yl)methoxy)propan- 2-yl)carbamate (6.50 g, 22.9 mmol, 1 eq) in DMF (65 mL) was added NaH (2.02 g, 50.5 mmol, 60% purity, 2.2 eq) at 0 °C and stirred at 25 °C for 30 min. Then Mel (3.91 g, 27.5 mmol, 1.71 mL, 1.2 eq) was added to the mixture and stirred at 25 °C for 30 min. On completion, the mixture was poured into the saturated solution of NH4CI (200 mL), then partitioned between ethyl acetate (100 mL x 3). The combined organic phase was washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (Si O2, Petroleum ether / THF=l :0 to 0:1) to give tert-butyl (R)-(l-((l-ethyl-lH-pyrazol-3-yl)methoxy)propan-2- yl)(methyl)carbamate (5.30 g, 17.8 mmol, 78% yield) as a colorless oil. LCMS: (M+l: 298.2).

[0363] Step 4. To a solution of tert-butyl (R)-(l-((l-ethyl-lH-pyrazol-3-yl)methoxy)propan- 2-yl)(methyl)carbamate (5.20 g, 17.5 mmol, 1 eq) in ACN (52 mL) was added NBS (3.73 g, 21.0 mmol, 1.2 e<?)at 0 °C. The mixture was stirred at 20 °C for 2 hr. On completion, the mixture was quenched with solution of Na2SO3 (50 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (100 mL), then dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF=l:O to 71:29) to give tert-butyl (R)- (l-((4-bromo-l-ethyl-lH-pyrazol-3-yl)methoxy)propan-2-yl)(methyl)carbamate (5.30 g, 14.1 mmol, 82% yield) as an orange oil. LCMS: (M+l : 375.9).

[0364] Preparation of tteerrtt--bbuuttyyll (R)-(l-((4-bromo-l-methyl-lH-pyrazol-3-yl)methoxy)propan-2-yl)(methyl)carbamate (A5):

[0365] Step 1. To a solution of commercially available (4-bromo-l-methyl-lH-pyrazol-3- yl)methanol (10.5 g, 54.9 mmol, 1 eq) in DCM (100 mL) was added PBr3(14.9 g, 54.9 mmol, 1 eq) at 0 °C. The mixture was stirred at 25 °C for 0.5 h. The pH was adjusted to pH = 7~ 8 with Sat. NaHCO3and extracted with EA (3 * lOOmL) and water (100 ml). The combined organic layers were washed with brine (2 * 50 mL), dried over Na2SC>4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EA = 10: 1 - 3:1) to give 4-bromo-3 -(bromomethyl)- 1 -methyl- lH-pyrazole (10 g, 31.5 mmol, 57.3% yield, 80% purity) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ = 7.94 (s, 1H), 4.53 (s, 2H), 3.82 (s, 3H). LCMS: (M+l: 255.1).

[0366] Step 2. To a solution of 4-bromo-3-(bromomethyl)-l-methyl-lH-pyrazole (9.76 g, 38.4 mmol, 1 eq) in THF (100 mL) was added commercially available tert-butyl (R)-(l- hydroxypropan-2-yl)carbamate (8.08 g, 46.1mmol, 1.2 eq), TBAI (1.42 g, 3.84 mmol, 0.1 eq) and KOH (6.47 g, 115 mmol, 3 eq). The mixture was stirred at 25 °C for 16 hours under N2. The reaction mixture was quenched by water (50 mL) and extracted with EA (3 * 50 mL). The combined organic layers were washed with brine (2 * 50mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate=10 / l to 3 / 1) to give tert-butyl (R)-(l-((4-bromo-l-methyl-lH-pyrazol-3- yl)methoxy)propan-2-yl)carbamate (11 g, 28.4 mmol, 73.9% yield, 90% purity) was obtained as yellow oil.1H NMR (400 MHz, DMSO-d6δ = 7.90 (s, 1H), 6.68 - 6.44 (m, 2H), 4.33 (d, J = 3.6 Hz, 3H), 3.80 (s, 3H), 3.64 - 3.40 (m, 2H), 1.38 - 1.36 (m, 9H), 1.00 - 0.97 (m, 6H). LCMS. (M+l: 348.1).

[0367] Step 3. To a solution of tert-butyl (R)-(l-((4-bromo-l-methyl-lH-pyrazol-3- yl)methoxy)propan-2-yl)carbamate (2.50 g, 7.18 mmol, 1.0 eq) in THF (20 mL) was added NaH (861 mg, 21.5 mmol, 60% purity, 3.0 eq). The mixture was stirred at 0 °C for 0.5 h and then CH3I (1.53 g, 10.8 mmol, 670 uL, 1.5 eq) was added at 0 °C. The mixture was stirred at 0 - 25 °C for 2 h. The mixture was quenched with NH4CI (200 mL) and extracted with ethyl acetate (100 mL * 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give tert-butyl (R)-(l-((4-bromo-l-methyl-lH-pyrazol-3- yl)methoxy)propan-2-yl)(methyl)carbamate (2.55 g, crude) as a colorless oil. LCMS: (M+l: 362.0).

[0368] Preparation of tert-butyl (R)-(l-((4-bromo-l-(2-((tert-butyldiphenylsilyl)oxy)ethyl)- lH-pyrazol-3-yl)methoxy)propan-2-ylXmethyl)caibamate (A6):

[0369] Step 1. To a mixture of commercially available 2-bromoethanol (5.00 g, 40.0 mmol, 2.84 mL, 1 eq), imidazole (8.17 g, 120 mmol, 3 eq) in DCM (50 mL) at 0 °C was added TBDPS-C1 (13.2 g, 48.0 mmol, 12.3 mL, 1.2 eq). On completion, the mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated in vacuum. The residue was purified bycombine flash (40 g silica gel column, THE in PE from 0% to 5%) to give (2- bromoethoxy)(tert-butyl)diphenylsilane (13.0 g, 35.7 mmol, 89.4% yield) as a yellow oil.]H NMR (400 MHz, CDCh) δ = 7.69 - 7.45 (dd, J= 1.2, 7.6 Hz, 4H), 7.52 - 7.32 (m, 6H), 3.94 (t, J = 6.4 Hz, 2H), 3.44 (t, J = 6.4 Hz, 2H), 1.09 (s, 9H).

[0370] Step 2. To a mixture of commercially available methyl lH-pyrazole-3-carboxylate (2.50 g, 19.8 mmol, 1 eq), K2CO3 (8.22 g, 59.4 mmol, 3 eq) in DMF (30 mL) at 25 °C was added (2-bromoethoxy)(tert-butyl)diphenylsilane (10.8 g, 29.7 mmol, 1.5 eq). The mixture was stirred at 80 °C for 16 h. To the reaction mixture was added water (100 ml) and extracted with ethyl acetate (30 ml * 3), washed with brine (20 ml * 3) and concentrated in vacuum. The residue was purified by combine flash (40 g silica gel column, THF in PE from 0% to 10%) to give methyl l-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-lH-pyrazole-3-carboxylate (4.40 g, 9.80 mmol, 49.4% yield, 91% purity) as a yellow oil. LCMS: (M+l: 409.0).

[0371] Step 3. To a solution of methyl l-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-lH-pyrazole- 3-carboxylate (4.20 g, 10.3 mmol, 1 eq) in THF (45 mL) at 0 °C was added slowly LiAlHt (2.5 M, 4.11 mL, 1 eq) at 0 °C and stirred at 0 °C for 0.5 h. On completion, the reaction was quenched by addition of 0.4 mL of water at 0 °C, followed by the addition of 0.4 ml of 15% sodium hydroxide. Then, the reaction was quenched further by added 1.2 mL of water, dried over Na2SO4, filtered and concentrated under reduced pressure to produce a residue to give (1- (2-((tert-butyldiphenylsilyl)oxy)ethyl)-lH-pyrazol-3-yl)methanol (3.90 g, 10.2 mmol, 99.7% yield) as a white solid. LCMS: (M+l: 381.2).

[0372] Step 4. To a solution of (l-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-lH-pyrazol-3- yl)methanol (3.60 g, 9.46 mmol, 1 eq) in ACN (40 mL) at 0 °C, was added NBS (1.68 g, 9.46 mmol, 1 eq) at 0 °C. The mixture was stirred at 25 °C for 0.5 hour. On completion, the reaction mixture was quenched by addition Na2SOs (50 mL) at 25 °C, and extracted with EA (30 mL * 3). The combined organic layers were washed with brine (20 mL * 3), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether / Ethyl acetate=l / l, 0 / 1) to give (4-bromo-l-(2-((tert- butyldiphenylsilyl)oxy)ethyl)-lH-pyrazol-3-yl)methanol (4.00 g, 8.71 mmol, 92.0% yield, 100% purity) as a white solid.]H NMR (400 MHz, DMS(W<5) δ = 7.89 (s, 1H), 7.56 - 7.32 (m, 10H), 5.04 (t, J= 5.6 Hz, 1H), 4.37 (d, J= 5.6 Hz, 2H), 4.23 (t, J= 5.2 Hz, 2H), 3.89 (t, J = 5.2 Hz, 2H), 0.93 (s, 9H). LCMS: (M+l: 459.9).

[0373] Step 5. To a solution of [4-(4-bromo-l-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-lH- pyrazol-3-yl)methanol (3.40 g, 7.40 mmol, 1 eq) in DMF (34 mL) at 0 °C, then was added NaH (592 mg, 14.8 mmol, 60% purity, 2 eq) at 0 °C for 30 min, then was added commerciallyavailable tert-butyl rac-(4R)-4-methyl-2,2-dioxo-oxathiazolidine-3 -carboxylate (2.63 g, 11.1 mmol, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 16 hours. On completion, the mixture was slowly added to 4M (HC1) (1 mL) to quench and NaHCOs was added to adjust the pH to 7. Then was added water (100 ml), extracted with ethyl acetate (30 * 3 ml), washed with brine (20 ml * 2) and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether / Ethyl acetate=l / O, 1 / 1) to give tert-butyl (R)-(l-((4-bromo-l-(2-((tert- butyldiphenylsilyl)oxy)ethyl)-lH-pyrazol-3-yl)methoxy)propan-2-yl)carbamate (1.20 g, 1.95 mmol, 26.3% yield) as a yellow oil.!H NMR (400 MHz, CDCh) δ = 7.57 - 7.48 (m, 5H), 7.46 - 7.34 (m, 6H), 4.99 (s, 1H), 4.51 (s, 2H), 4.20 (t, J= 5.2 Hz, 2H), 3.94 (t, J= 5.2 Hz, 2H), 3.52 - 3.35 (m, 2H), 1.43 (s, 9H), 1.17 (d, J= 6.8 Hz, 3H), 1.02 (s, 9H). LCMS: (M+l: 618.2).

[0374] Step 6. To aa solution of tert-butyl (R)-(l-((4-bromo-l-(2-((tert- butyldiphenylsilyl)oxy)ethyl)-lH-pyrazol-3-yl)methoxy)propan-2-yl)carbamate (1.10 g, 1.78 mmol, 1 eq) in DMF (11 mL) at 0 °C, was added NaH (164 mg, 4.10 mmol, 60% purity, 2.3 eq) at 0 °C for 30 min, then was added Mel (379 mg, 2.68 mmol, 166 pL, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hour. On completion, the mixture was poured into sat. NH*C1 (20.0 mL) aqueous solution slowly under N2. Then the mixture was extracted with EtOAc (20.0 mL * 3). The combined organic layers were washed with brine (20 * 2 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The residue was purified by combine flash (12 g silica gel column, THE in PE from 0% to 30%) to give tert-butyl (R)-(l- ((4-bromo-l-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-lH-pyrazol-3-yl)methoxy)propan-2- yl)(methyl)carbamate (350 mg, 554 pmol, 31.1% yield) as a yellow oil. LCMS: (M+l: 632.1).

[0375] Preparation of tert-butyl (R)-(l-(((4-bromo-l -methyl- lH-pyrazol-3-yl)methyl)(2, 2- difluoroethyl)amino)propan-2-ylXmethyl)carbamate (A7) :

[0376] Step 1. To a solution of tert-butyl (R)-(l-(((benzyloxy)carbonyl)((4-bromo-l-methyl- lH-pyrazol-3-yl)methyl)amino)propan-2-yl)(methyl)carbamate (8.20 g, 16.5 mmol, 1 eq) in THF (82 mL) was added Pd / C (820 mg, 771μmol, 10% purity, 4.66 e"2eq) under H2 (15 psi). The mixture was stirred at 25 °C for 16 h. On completion, the reaction mixture was filtered and the filtrate was concentrated to give tert-butyl (R)-methyl(l-(((l-methyl-lH-pyrazol-3- yl)methyl)amino)propan-2-yl)carbamate (6.20 g, 22.0 mmol, 1 eq) as a yellow oil. ‘H NMR (400 MHz, DMSO-d6) δ = 8.89 - 8.71 (m, 2H), 7.81 - 7.68 (m, 1H), 6.44 - 6.30 (m, 1H), 3.85 (s, 3H), 3.17 (d, J= 5.2 Hz, 2H), 3.14 - 3.07 (m, 1H), 2.95 - 2.87 (m, 1H), 2.64 (s, 3H), 1.53 - 1.32 (m, 9H), 1.08 ( s, 3H).

[0377] Step 2. To a solution of tert-butyl (R)-methyl(l-(((l-methyl-lH-pyrazol-3- yl)methyl)amino)propan-2-yl)carbamate (6.20 g, 22.0 mmol, 1 eq) and 2,2-difluoroethyl trifluoromethanesulfonate (5.64 g, 26.3 mmol, 1.2 eq) in ACN (62 mL) was added TEA (5.55 g, 54.9 mmol, 7.64 mL, 2.5 eq). The mixture was stirred at 25 °C for 16 h. On completion, the reaction was concentrated under vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / THF=l / O to 7 / 3) to give tert-butyl (R)-(l-((2,2-difluoroethyl)(l- methyl-lH-pyrazol-3-yl)methyl)amino)propan-2-yl)(methyl)carbamate (3.80 g, 8.34 mmol, 38% yield, 76% purity) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ = 7.66 - 7.55 (m, 1H), 6.10 (d, J= 2.0 Hz, 1H), 6.01 - 5.77 (m, 1H), 6.34 - 5.74 (m, 1H), 4.07 (d, J= 12.4 Hz, 1H), 3.82 - 3.75 (m, 3H), 3.72 - 3.61 (m, 2H), 2.91 - 2.71 (m, 2H), 2.55 ( d, J= 4.4 Hz, 3H), 2.49 - 2.30 (m, 2H), 1.39 ( s, 9H), 1.02 - 0.93 (m, 3H).

[0378] Step 3. To a solution tert-butyl (R)-(l-((2,2-difluoroethylX(l-methyl-lH-pyrazol-3- yl)methyl)amino)propan-2-yl)(methyl)carbamate (3.30 g, 9.53 mmol, 1 eq) in DCM (33 mL) was added NBS (1.78 g, 10.0 mmol, 1.05 eq) at 0 °C. On completion, the mixture was stirredat 25 °C for 2 h. The mixture was poured into NazSOs (100 mL) aqueous solution, and the aqueous phase was extracted with DCM (50 mL x 2). The combined organic phase was washed with brine (100 mL x 2), dried over anhydrous NazSO4, filtered and concentrated under vacuum. The residue was purified by column chromatography (SiOz, Petroleum ether / THF=l / 0 to 3 / 1) to give tert-butyl (R)-(l-(((4-bromo-l-methyl-lH-pyrazol-3- yl)methylX2,2-difluoroethyl)amino)propan-2-ylXmethyl)carbamate (1.50 g, 3.39 mmol, 35.54% yield, 96% purity) as a yellow oil. LCMS: (M+l: 425.2).

[0379] Preparation of Starting Material Type B

[0380] Preparation of 2-formyl-5-methyl-l / 7-pyrrole-3-carboxylic acid (Bl)O. _ OMe ,OHOH O OPOCI3H KOH HMDCE.DMF O N MeOH,H2O OH H HB1-1 B1-2 B1

[0381] Step 1. To a solution of commercially available 5-methyl-1H -pyrrole-3-carboxylic acid (5.00 g, 39.9 mmol, 1 eq) in mixed solvents DCE (100 mL) and DMF (30 mL) was added POCh (61.2 g, 399 mmol, 37.1 mL, 10 eq) at 0 °C. The reaction mixture was stirred at 60 °C for 16 h. On completion, the mixture was slowly added to methanol to quench. The residue was concentrated in vacuo. To the mixture was then added sat. NaHCOs. (aq.) to adjust the pH to 7~ 8, and extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over NazSO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (EtOAc in PE, 0-100%) to give methyl 2- formyl-5-methyl-1H -pyrrole-3-carboxylate (2.30 g, 13.7 mmol, 34% yield) as a light-yellow solid. LCMS: (M+l: 168.0).

[0382] Step 2. A mixture of methyl 2-formyl-5-methyl-1H -pyrrole-3-carboxylate (1.38 g, 8.23 mmol, 1 eq), KOH (1.85 g, 32.9 mmol, 4 eq) in MeOH (4.2 mL) and HzO (12.6 mL) was stirred at 60 °C for 1 h. On completion, HzO (20 mL) was added, the mixture was concentrated in vacuum to remove MeOH. The pH of the mixture was then adjusted to 4~6, extracted with ethyl acetate (30 mL), and washed with water (50 mL). The organic layer was dried over NazSO4, filtered and filtrate was concentrated to give 2-formyl-5-methyl-1H -pyrrole-3- carboxylic acid (1.10 g, crude) as a blackish-brown solid (Bl). LCMS:(M+1: 154.0).

[0383] Preparation of 2-formyl-1H -pyrrole-3-carboxylic acid (B2)

[0384] Step 1. To a solution of commercially available methyl l / 7-pyrrole-3 -carboxylate (10.0 g, 79.9 mmol, 1 eq) in THF (15 mL) was added Pyridine (632 mg, 7.99 mmol, 0.1 eq) and NBS (14.2 g, 79.9 mmol, 1 eq), and the mixture was stirred at -78 °C for 2 hours. On completion, the combined organic layers were filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=5:l) to give methyl 5-bromo-1H -pyrrole-3-carboxylate (8.50 g, 41.6 mmol, 52% yield) as a white solid. LCMS: (M+L205.9).

[0385] Step 2. To a solution of methyl 5-bromo-1H -pyrrole-3 -carboxyl ate (7.00 g, 34.3 mmol, 1 eq) in DCE (30 mL) and DMF (6 mL) was added POCI3 (26.3 g, 171 mmol, 5 eq), and the mixture was stirred at 80 °C for 4 hours. On completion, the reaction was quenched by slowly adding the mixture to water, the pH was adjusted to 7~ 8 with sat. NaHCO3and extracted with EA (100 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered, and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10: 1) to give methyl 5-bromo-2-formyl-1H -pyrrole-3-carboxylate (3.60 g, 15.5 mmol, 45% yield) as a white solid.

[0386] Step 3. To a mixture of methyl 5-bromo-2-formyl-1H -pyrrole-3-carboxylate (3.60 g, 15.5 mmol, 1 eq) and Pd / C (900 mg, 0.845 mmol, 60% purity) in toluene (20 mL) and THF (4 mL) was added DIEA (4.01 g, 31.0 mmol, 2 eq). The mixture was degassed and purged thrice with H2, and then the mixture was stirred at 25 °C for 2 hours under H2 atmosphere. On completion, the reaction mixture was filtered and concentrated to give methyl 2 -formyl- 1H - pyrrole-3 -carboxylate (2.20 g, 14.3 mmol, 92% yield) as a white solid.1H NMR (400 MHz, CDCI3) δ = 12.98 - 12.49 (m, 1H), 10.16 (s, 1H), 7.26 (t, J= 2.4 Hz, 1H), 6.70 (t, J= 2.4 Hz, 1H), 3.87(s, 3H).

[0387] Step 4. A mixture of methyl 2 -formyl- l / 7-pyrrole-3-carb oxy late (800 mg, 5.22 mmol, 1 eq) and LiOH (375 mg, 15.6 mmol, 3 eq) in MeOH (8 mL), H2O (2 mL) and THF (8 mL)was stirred at 25 °C for 5 hours. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give 2-formyl-ll / -pyrrole-3-carboxylic acid (700 mg, 5.03 mmol, 96% yield) as a yellow solid (B2).1H NMR (400 MHz, DMSO-d6) δ = 12.81 - 12.63 (m, 1H), 12.57 - 12.38 (m, 1H), 10.05 (s, 1H), 7.10 (d, . / = 2.4 Hz, 1H), 6.54(t, . / = 2.4 Hz, 1H).

[0388] Preparation of 5-fluoro-2-formyl-lH-pyrrole-3-carboxylic acid (B3):O

[0389] Step 1 : To a solution of commercially available methyl 1H -pyrrole-3 -carboxylate (10.0 g, 79.9 mmol, 1 eq) in THF (150 mL) was added Selectfluor (33.9 g, 95.9 mmol, 1.2 eq), Na2CC>3 (7.96 g, 95.9 mmol, 1.2 eq) and 13-hydroxy-10,16-bis(2,4,6-triisopropylphenyl)- 12, 14-dioxa- 13 phosphapentacyclo [13.8.0.02,11.03,8.018,23]tricosa-l(15),2,4,6,8,10,16,18(23), 19,21 -decaene 13 -oxide (6.02 g, 7.99 mmol, 0.1 eq), and the mixture was stirred at 25 °C for 16 hours. On completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=5: 1) to give methyl 5 -fluoro- 1H -pyrrole-3 -carboxyl ate (2.00 g, 13.9 mmol, 17% yield) as a white solid.]H NMR (400 MHz, CDCh) 8 8.52 - 8.27 (m, 1H), 6.91 (td, J= 1.6, 3.2 Hz, 1H), 5.87 - 5.82 (m, 1H), 3.76 - 3.73 (m, 3H).

[0390] Step 2: To a solution of methyl 5-fluoro-1H -pyrrole-3-carboxylate (2.00 g, 13.9 mmol, 1 eq) in DCE (15 mL) and DMF (3 mL) was added POCI3 (10.7 g, 69.8 mmol, 5 eq) at 0 °C, and the mixture was stirred at 0 °C for 2 hours. On completion, the pH of the mixture was adjusted to 7 with NaHCO3(300 mL) and extracted with EA (100 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiOz, Petroleum ether / Ethyl acetate=5:l) to give methyl 5-fluoro-2-formyl-1H -pyrrole-3- carboxylate (130 mg, 0.759 mmol, 5% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 8 13.59 (d, J = 2.0 Hz, 1H), 10.03 (d, J= 3.2 Hz, 1H), 6.21 (d, J= 4.0 Hz, 1H), 3.82 (s, 3H).

[0391] Step 3. Methyl 5-fluoro-2-formyl-1H -pyrrole-3-carboxylate (130 mg, 0.759 mmol, 1 eq) was taken in MeOH (3 mL), THF (3 mL) and H2O (1 mL). LiOH (54.5 mg, 2.28 mmol, 3 eq) was added to the mixture, and the mixture was stirred at 50 °C for 12 hours. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give 5-fluoro-2- formyl-1H -pyrrole-3-carboxylic acid (70.0 mg, 0.445 mmol, 58% yield) as a white solid (B3). 1HNMR (400 MHz, DMSO-d6) δ 13.56 - 13.32 (m, 1H), 13.17 - 12.93 (m, 1H), 10.04 (s, 1H), 6.15 (d, J = 4.0 Hz, 1H).

[0392] Preparation of 5-fhioro-2-formyl-lH-pyrrole-3-carboxylic acid (B4):

[0393] Step 1. To a solution of methyl lH-pyrrole-3 -carboxylate (10.0 g, 79.9 mmol, 1 eq) in THF (100 mL) was added Py (632 mg, 7.99 mmol, 645 μL, 0.1 eq) and NCS (10.7 g, 79.9 mmol, 1 eq) at -78 °C. The mixture was stirred at 40 °C for 16 h. The mixture was poured into Na2SO3(200 mL) aqueous solution, and the aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with brine (100 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=l / O to 3 / 1) to give methyl 5- chloro-lH-pyrrole-3-carboxylate (8.00 g, 50.1 mmol, 63% yield) as a white solid. LCMS: (M+l: 160.1).

[0394] Step 2. To a solution of methyl 5-chloro-lH-pyrrole-3-carboxylate (3.20 g, 20.1 mmol, 1 eq) in DCE (90 mL) and DMF (27 mL) was added POCI3 (30.7 g, 200 mmol, 18.7 mL, 10 eq) at 0 °C. The mixture was stirred at 60 °C for 4 h. On completion, the residue was concentrated in vacuo. The pH was adjusted to pH = 7~ 8 and the mixture was extracted with EA (2 * 100 mL) and water (200 mL). The combined organic layers were washed with brine (200 mL * 3), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purifiedby column chromatography (SiC>2, Petroleum ether / Ethyl acetate=l / O to 3 / 1) to give methyl 5- chloro-2-formyl-lH-pyrrole-3-carboxylate (6.00 g, 32.0 mmol, 80% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 13.65 - 13.43 (m, 1H), 10.06 - 9.92 (m, 1H), 6.74 - 6.56 (m, 1H), 3.83 - 3.80 (m, 3H).

[0395] Step 3. To a solution of methyl 5-chloro-2-formyl-lH-pyrrole-3-carboxylate (5.00 g, 26.7 mmol, 1 eq) in H2O (36 mL) and MeOH (12 mL) was added KOH (5.98 g, 107 mmol, 4 eq). The mixture was stirred at 60 °C for 1 h. The mixture was concentrated under vacuum. The reaction mixture was adjusted to pH~3 with hydrochloric acid (6 M in water). The mixture was filtered and the filter cake was concentrated under vacuum to give 5-chloro-2-formyl-lH- pyrrole-3-carboxylic acid (5.20 g, crude) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 8 = 13.77 - 13.73 (m, 1H), 13.73 - 12.90 (m, 1H), 0.14 - 9.94 (m, 1H), 6.68 - 6.50 (m, 1H).

[0396] Preparation of Starting Material Type C

[0397] Preparation of 7-chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indolin-2-one (Cl)

[0398] Step 1. A mixture of commercially available 7-chloroindolin-2-one (12.6 g, 75.2 mmol, 1 eq) and MBS (13.4 g, 75.2 mmol, 1 eq) in TFA (200 mL) was degassed and purged with Nz3 times, and the mixture was stirred at 0 °C for 6 hours under N2 atmosphere. On completion, the reaction mixture was concentrated in vacuo with DCM (25 mL) and then with EtOAc to give a residue. The residue was triturated with ethanol to give 5-bromo-7-chloro-indolin-2-one (15.0 g, 60.9 mmol, 81% yield) as a brown solid. LCMS: (M+l: 245.8).

[0399] Step 2. To a solution of 5-bromo-7-chloro-indolin-2-one (3 g, 12.1 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (9.27 g, 36.5 mmol, 3 eq) in dioxane (45 mL) was added potassium acetate (4.78 g, 48.6 mmol,4 eq), and the mixture was degassed and purged thrice with N2. Pd(dppf)Ch (993 mg, 1.22 mmol, 0.1 eq) was added, and the mixture was stirred at 100 °C for 16 h under N2. On completion, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (0-100% THF / PE) to give 7-chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indolin-2-one (3.05 g, 10.3 mmol, 85% yield) as a yellow solid (Cl). LCMS: (M+l : 294.0).

[0400] Preparation of 7-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indolin-2-one(C2)

[0401] Steps 1 and 2 were performed in a similar manner to the synthesis of Cl starting with commercially available C2-1 to give C2.]H NMR (400 MHz, DMSO-d6) δ = 10.56 (s, 1H), 7.32 (d, J= 5.6 Hz, 2H), 3.47 (s, 2H), 2.19 (s, 3H), 1.27 (s, 12H).

[0402] Preparation of 7-(methoxymethyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)indolin-2-one (C3)

[0403] Steps 1. To a solution of commercially available methyl 5-bromo-2-oxoindoline-7- carboxylate (5.00 g, 18.5 mmol, 1 eq) in THF (50 mL) was added LiBH4(2 M, 37.0 mL, 4 eq) at 0 °C. The mixture was stirred at 25 °C for 2 h. On completion, the mixture was poured into NH4CI (50 mL) aqueous solution, and the aqueous phase was extracted with DCM (50 mL x 2). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was triturated with MeOH: CAN=1 :1 (20 mL) at 25 °C for 15 min to give 5-bromo-7-(hydroxymethyl)indolin-2- one (2.40 g, 9.91 mmol, 54% yield) as an off-mhite solid. LCMS: (M+l: 242.4).

[0404] Step 2. To a solution of 5-bromo-7-(hydroxymethyl)indolin-2-one (2.10 g, 8.68 mmol, 1 eq) in DCM (21 mL) was added PBr3(2.82 g, 10.4 mmol, 1.2 eq) under N2 at 0 °C. On completion, the mixture was stirred at 25 °C for 2 h. The mixture was poured into NaHCO3(80 mL) aqueous solution, and the aqueous phase was extracted with DCM (50 mL x 2). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give 5-bromo-7-(bromomethyl)indolin-2-one (3.70 g, 7.04 mmol, 81% yield, 58% purity) as a white solid. LCMS: (M+l : 305.9).

[0405] Step 3. A solution of 5-bromo-7-(bromomethyl)indolin-2-one (2.70 g, 8.85 mmol, 1 eq) in MeOH (30 mL) was stirred at 25 °C for 4 h. On completion, the mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give 5-bromo- 7-(methoxymethyl)indolin-2-one (3.10 g, crude) as a white solid. LCMS: (M+l : 257.9).

[0406] Step 4. A mixture of 5-bromo-7-(methoxymethyl)indolin-2-one (2.90 g, 11.3 mmol, 1 eq), BPD (4.31 g, 17.0 mmol, 1.5 eq), KO Ac (3.33 g, 34.0 mmol, 3 eq) and Pd(dppf)Cl2CH2Cl2(925 mg, 1.13 mmol, 0.1 eq) in dioxane (30 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 1 h under N2 atmosphere. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0-30% Ethyl acetate / Petroleum ethergradient @100 mL / min) to give 7-(methoxymethyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indolin-2-one (1.88 & 5.72 mmol, 51% yield, 92% purity) as a white solid. . LCMS: (M+l : 304.1).

[0407] General Method I-A:

[0408] Preparation of (R)-7-chloro-5-(l-ethyl-3-((2-(methylamino)propoxy)methyl)-lH- pyrazol-4-yl)indolin-2-one (DI):r~o iNBoc trBN„O BocNO'D1

[0409] Step 1. AA mmiixxttuurree of tert-butyl (R)-( 1 -((4-bromo- 1 -ethyl- lH-pyrazol-3- yl)methoxy)propan-2-yl)(methyl)carbamate (2.00 g, 5.32 mmol, 1 eq), 7-chloro-5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)indolin-2-one (2.34 g, 7.97 mmol, 1.5 eq), CS2CO3 (5.20 g, 15.9 mmol, 3 eq), Pd(dtbpf)Ch (346 mg, 532 pmol, 0.1 eq) in dioxane (20 mL) and H2O (4 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 1 hr under N2 atmosphere. On completion, the reaction mixture was separated, and the water phase was partitioned between ethyl acetate (10 mL x 3) and water (20 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=l:O to 0:1) to give tert-butyl (R)-(l-((4-(7-chloro-2-oxoindolin-5-yl)-l- ethyl-lH-pyrazol-3-yl)methoxy)propan-2-ylXmethyl)carbamate (1.50 g, 3.24 mmol, 61% yield) as a colorless oil. LCMS: (M+L463.1).

[0410] Step 2. To a solution of tert-butyl (R)-(l-((4-(7-chloro-2-oxoindolin-5-yl)-l-ethyl-lH- pyrazol-3-yl)methoxy)propan-2-ylXmethyl)carbamate (500 mg, 1.08 mmol, 1 eq) in DCM (5 mL) was added HCI / EtOAc (2 M, 1.00 mL, 1.85 eq). The mixture was stirred at 20 °C for 2 hr. On completion, the mixture was concentrated in vacuo to give (R)-7-chloro-5-(l-ethyl-3- ((2-(methylamino)propoxy)methyl)-lH-pyrazol-4-yl)indolin-2-one (390 mg, crude) as a yellow solid. LCMS: (M+l:363.2).

[0411] Preparation ooff (R)-5-(l-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-3-((2-(methylamino)propoxy)methyl)-lH-pyrazol-4-yl)-7-chloroindolin-2-one (D3):

[0412] Step 1 was performed in a similar manner to step 1 of General Method I-A.

[0413] Step 2. To a mixture tert-butyl (R)-(l-((l-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-(7- chloro-2-oxoindolin-5-yl)-lH-pyrazol-3-yl)methoxy)propan-2-ylXniethyl)carbamate (210 mg, 292 pmol, 1 eq) in DCM (2 mL) at 0 °C was added HCI / EtOAc (2 M, 2 mL, 13.6 eq). The mixture was stirred at 0 °C for 1 h. On completion, the reaction mixture was concentrated in vacuum to give (R)-5-(l-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-3-((2- (methylamino)propoxy)methyl)-lH-pyrazol-4-yl)-7-chloroindolin-2-one (180 mg, 291 pmol, 99.6% yield) as a yellow solid. LCMS: (M+L617.2).

[0414] Intermediate Table 1 lists the intermediates prepared according to the procedures described in General Method I-A using the appropriate starting materials (SMs).

[0415] Intermediate Table 1

[0416] General Method A:

[0417] Preparation of [3a(4)Z,10R]-20-chloro-6,9,10,15-tetramethyl-2,5,9,10,ll,12,13,15- octahydro-l,17-ethenopyrazolo[4,3-m]dipyrrolo[3,2-f3',4'-z][l,4]diazacyclopentadecine-3,8- dione (Ex. 1) and [3a(4)Z,10R]-20-chloro-6,9,10,12,15-pentamethyl-2,5,9,10,l 1,12,13,15- octahydro- 1,17 -ethenopyrazol o[4,3 -m]dipyrrolo[3 ,2-f; 3 ',4' -z] [ 1 ,4]di azacyclopen tadecine-3, 8- dione (Ex. 2):

[0418] Step 1. A mixture of tert-butyl N-[(1R)-2-[benzyloxycarbonyl-[(4-bromo-l-methyl- pyrazol-3-yl)methyl]amino]-l-methyl-ethyl]-N-methyl-carbamate (Al, 1.37 g, 2.77 mmol, 1 eq) and 7-chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indolin-2-one (Cl, 811 mg, 2.77 mmol, 1 eq), Na2CO3(879 mg, 8.30 mmol, 3 eq), Pd(dppf)Cl2.CH2Cl2(225 mg, 0.276 mmol, 0.1 eq) in dioxane (14 mL) and H2O (3 mL) was degassed and purged with N23 times, and then the mixture was stirred at 80 °C for 2 h under N2 atmosphere. On completion, the combined organic phase was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue was purified by flash silica gel chromatography (0- 50% THF / PE) to give tert-butyl N-[(1R )-2-[benzyloxycarbonyl-[[4-(7-chloro-2-oxo-indolin- 5-yl)-l-methyl-pyrazol-3-yl]methyl]amino]-l-methyl-ethyl]-N-methyl-carbamate (1.08 g,1.85 mmol, 67% yield) as a yellow solid (1-1).1H NMR (400 MHz, DMSO-d6) δ = 10.80 (s, 1H), 7.87 (d, J = 16 Hz, 1H), 7.40 - 7.17 (m, 5H), 7.12 (d, J = 18.4 Hz,2H), 5.13 - 4.89 (m, 2H), 4.66 - 4.50 (m, 2H), 4.47 - 4.25 (m, 1H), 3.81 (s, 3H), 3.56 - 3.49 (m, 2H), 3.48 - 3.39 (m, 1H), 2.99 -2.79 (m, 1H), 2.58 (s, 2H), 1.39 - 1.31 (m, 12H), 0.99 - 0.84 (m, 3H); LCMS: (M+l:582.1).

[0419] Step 2. To a mixture of tert-butyl N-[(1R)-2-[benzyloxycarbonyl-[[4-(7-chloro-2-oxo- indolin-5-yl)- 1 -methyl -pyrazol-3-yl]methyl]amino]- 1 -methyl -ethyl]-N-methyl -carbamate (200 mg, 0.343 mmol, 1 eq) in DCM (2 mL) was added HCl / dioxane (4 M, 2 mL, 23.2 eq) and the mixture was stirred at 20 °C for 0.5 h. On completion, the mixture was concentrated under reduced pressure to give benzyl N-[[4-(7-chloro-2-oxo-indolin-5-yl)-l-methyl-pyrazol-3- yl]methyl]- N-[(2R)-2-(methylamino)propyl]carbamate (150 mg, 0.311 mmol, 90% yield) as a yellow solid (1-2). LCMS: (M+l: 482.0).

[0420] Step 3. To a solution of benzyl ;V-[[4-(7-chloro-2-oxo-indolin-5-yl)-l -methyl -pyrazol- 3-yl]methyl]- N-[(2R)-2-(methylamino)propyl]carbamate (150 mg, 0.311 mmol, 1 eq) and 2- formyl-5-methyl-1H -pyrrole-3-carboxylic acid (Bl, 57.1 mg, 0.373 mmol, 1.2 eq) in MeCN (7 mL) was added 1 -methylimidazole (255 mg, 3.11 mmol, 0.248 mL, 10 eq) and TCFH (130 mg, 0.466 mmol, 1.5 eq). The mixture was stirred at 20 °C for 1.5 h. On completion, the mixture filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0-20% DCM / MeOH).to give benzyl N-[[4-(7-chloro-2-oxo- indolin-5-yl)-l-methyl-pyrazol-3-yl]methyl]-N-[(2Z?)-2-[(2-formyl-5-methyl-1H -pyrrole-3- carbonyl)-methyl-amino]propyl]carbamate (143 mg, 0.231 mmol, 74% yield) as a yellow oil (1-3). LCMS: (M+l: 617.0).

[0421] Step 4-1. To a solution of benzyl N-[[4-(7-chloro-2-oxo-indolin-5-yl)-l-methyl- pyrazol-3-yl]methyl]- N-[(2R)-2-[(2-formyl-5-methyl-1H -pyrrole-3-carbonyl)-methyl- aminojpropyljcarbamate (143 mg, 0.231 mmol, 1 eq) in EtOH (14 mL) was added Piperidine (197 mg, 2.32 mmol, 0.228 mL, 10 eq). The mixture was stirred at 80 °C for 1.5 h. On completion, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (0-50% DCMZMeOH) to give benzyl (10R, 18Z)-23-chloro-4, 10,1 l,15-tetramethyl-12,20-dioxo-4,5,8,l l,16,21- hexazapentacyclo[17.5.2.02, 6.013, 17.022, 26]hexacosa-l(24), 2, 5, 13(17), 14, 18, 22,25- octaene-8-carboxylate (57 mg, 0.095 mmol, 41% yield) as an orange solid. LCMS: (M+l:599.1).

[0422] Step 4-2. A mixture of benzyl (10R,18Z)-23-chloro-4,10,ll,15-tetramethyl-12,20- dioxo-4,5,8, 11, 16,21-hexazapentacyclo[ 17.5.2.02,6.013,17.022,26]hexacosa- l(24),2,5,13(17),14,18,22,25-octaene-8-carboxylate (47 mg, 0.078 mmol, 1 eq) in TFA (1 mL)was stirred at 60 °C for 2 h. On completion, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give [3a(4)Z,10R]-20- chloro-6,9,10,15-tetramethyl-2,5,9,10,l l,12,13,15-octahydro-l,17-ethenopyrazolo[4,3- m]dipyrrolo[3, 2-f3', 4'-i][l,4]diazacyclopentadecine-3, 8-dione (11.09 mg, 0.022 mmol, 23% yield, 91% purity) as an orange solid (Ex. 1).1H NMR (400 MHz, DMSO-d6) δ = 11.91 - 11.81 (m, 1H), 10.88 - 10.78 (m, 1H), 8.19 - 8.12 (m, 1H), 7.70 - 7.64 (m, 1H), 7.34- 7.23 (m, 2H), 6.44 - 6.35 (m, 1H), 5.50 - 5.37 (m, 1H), 4.79 - 4.63 (m, 1H), 3.83 (s, 3H), 3.27 - 3.22 (m, 1H), 3.19 - 3.10 (m,lH), 2.77 - 2.65 (m, 1H), 2.44 - 2.35 (m, 4H), 2.29 (s, 3H), 1.05 (d, J= 6.4 Hz, 3H); LCMS: (M+l: 465.1).

[0423] Step 5. To aa ssoolluutitioonn of [3a(4)Z,10R]-20-chloro-6,9,10,15-tetramethyl- 2,5,9,10,ll,12,13,15-octahydro-l,17-ethenopyrazolo[4,3-m]dipyrrolo[3,2-f3',4'- / ][l,4]diazacyclopentadecine-3, 8-dione (Ex. 1, 51.0 mg, 0.109 mmol, 1 eq) in MeOH (5 mL) was added (CH2O)n (98 mg, 0.219 mmol, 30 eq) and NaBH3CN (13.7 mg, 0.219 mmol, 2 eq). The mixture was stirred at 25 °C for 2 h. On completion, the mixture was filtered, and the filtrate was concentrated to give a residue. The residue was purified by prep-HPLC to give [3a(4)Z,10R]-20-chloro-6,9,10,12,15-pentamethyl-2,5,9,10,l l,12,13,15-octahydro-l,17- ethenopyrazolo[4,3 -m]dipyrrolo[3 ,2-f 3 ',4'- / ] [ 1 ,4]di azacyclopentadecine-3 , 8-dione ( 14.76 mg, 28.66 umol, 26.13% yield, 93% purity) as orange solid (Ex. 2).1H NMR (400 MHz, DMSO- d6) δ = 11.77 - 11.65 (m, 1H), 11.27 - 11.14 (m, 1H), 8.87 - 8.76 (m, 1H), 8.12 - 8.03 (m, 1H), 7.57- 7.50 (m, 1H), 7.33 - 7.24 (m, 1H), 6.34 - 6.24 (m, 1H), 4.86 - 4.63 (m, 1H), 3.87 - 3.81 (m, 3H), 3.29 (br s, 1H), 3.23 - 3.12 (m.lH), 2.74 - 2.69 (m, 3H), 2.59 - 2.55 (m, 2H), 2.44 - 2.39 (m, 3H), 2.09 - 2.04 (m, 3H), 1.20 - 1.08 (m, 3H); LCMS: (M+l: 479.0).

[0424] General Method B:

[0425] Preparation of [3a(4)Z,10R]-20-chloro-16-methoxy-9,10,15-trimethyl-10,l l,13,15- tetrahydro-2H- 1 , 17-ethenopyrazolo[4,3-m]dipyrrol o[3 ,2-f 3 ',4'- / ] [ 1 ,4]oxazacyclopentadecine- 3,8(57 / ,9H)-dione (Ex. 3):

[0426] Step 1. A mixture of tert-butyl N-[( l / ?)-2-[(4-brom o-5-m ethoxy- 1 -methyl -pyrazol-3- yl) methoxy]-l-methyl-ethyl]-N-methyl-carbamate (A2, 1.50 g, 3.82 mmol, 1 eq), 7-chloro-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indolin-2-one (Cl, 1.68 g, 5.74 mmol, 1.5 eq), Na2CO3(1.22 g, 11.4 mmol, 3 eq), Pd(dppf)Cl2.CH2Cl2(312 mg, 0.382 mmol, 0.1 eq) in dioxane (20 mL) and H2O (4 mL) was degassed and purged with N2 3 times, and the mixture was stirred at 80 °C for 12 hours under N2 atmosphere. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF=2:l) to give tert-butyl N- [( 1R)-2-[[4-(7-chloro-2-oxo-indolin-5-yl)-5-methoxy- 1 -methyl -pyrazol -3-yl] methoxy]- 1 - methyl-ethyl]-N-methyl-carbamate (400 mg, 0.835 mmol, 21% yield) as a yellow solid (3-1). LCMS: (M+l: 479.0).

[0427] Step 2. A mixture of tert-butyl N-[(1R)-2-[[4-(7-chloro-2-oxo-indolin-5-yl)-5- methoxy- 1 -methyl -pyrazol-3-yl]methoxy]- 1 -methyl-ethyl]-N-methyl-carbamate (500 mg, 1.04 mmol, 1 eq), HCl / dioxane (4 M, 5.00 mL, 19 eq) in DCM (3 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 25 °C for 0.3 hours under N2 atmosphere. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give 7-chloro-5-[5-methoxy-l-methyl-3-[[(2R)-2-(methylamino)propoxy] methyl]pyrazol-4-yl]indolin-2-one (380 mg, 1.00 mmol, 96% yield) as a yellow solid (3-2). LCMS: (M+L379.1).

[0428] Step 3-1. To a mixture of the above 7-chloro-5-[5-methoxy-l -methyl -3-[[(2R)-2- (methylamino) propoxy]methyl]pyrazol-4-yl]indolin-2-one (380 mg, 1.00 mmol, 1 eq) and 2- formyl-1H -pyrrole-3-carboxylic acid (B2, 209 mg, 1.50 mmol, 1.5 eq) in MeCN (10 mL) was added NMI (494 mg, 6.02 mmol, 6 eq) and TCFH (562 mg, 2.01 mmol, 2 eq). Then the mixture was stirred at 25 °C for 0.5 hours. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give N-[(1R)-2-[[4-(7-chloro-2-oxo-indolin-5-yl)-5- m ethoxy- 1 -methyl -pyrazol-3-yl]methoxy]- 1 -methyl -ethyl]-2-formyl-Ar-m ethyl- 1H -pyrrole-3- carboxamide (400 mg, 0.800 mmol, 79% yield) as a yellow oil. LCMS: (M+l : 500.1).

[0429] Step 3-2. To a mixture of N-[(1R)-2-[[4-(7-chloro-2-oxo-indolin-5-yl)-5-methoxy-l- methyl-pyrazol-3-yl]methoxy]-l-methyl-ethyl]-2-formyl-N --methyl-l / 7-pyrrole-3- carboxamide (380 mg, 0.760 mmol, 1 eq) in EtOH (4 mL) was added Piperidine (194 mg, 2.28 mmol, 3 eq), and then the mixture was stirred at 25 °C for 0.5 hours. On completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether / THF=2:l), followed by purification by reversed-phase HPLC (with 0.1 % Formic acid) to give [3a(4)Z, 10R]-20-chloro- 16-methoxy-9, 10, 15-trim ethyl- 10, 11,13, 15 -tetrahydro-2H- 1 , 17-ethenopyrazolo[4,3- m]dipyrrolo[3, 2-f3', 4'-i][l,4]oxazacyclopentadecine-3, 8(5H , 9H)-dione (56.5 mg, 0.116 mmol, 15% yield) as an orange solid (Ex. 3).1H NMR (400 MHz, DMSO-d6) 6 11.67 (br s, 1H), 11.33 - 11.22 (m, 1H), 8.09 (d, J= 1.2 Hz, 1H), 7.50 (s, 1H), 7.40 (t, J= 2.4Hz, 1H), 7.27 (d, . / = 1.2 Hz, 1H), 6.49 (t, J= 2.4 Hz, 1H), 4.74 - 4.66 (m, 1H), 4.42 (d, . / = 11.2 Hz, 1H), 4.31 (d, J= 11.2 Hz,lH), 3.82 (s, 3H), 3.81 - 3.74 (m, 2H), 3.70 (s, 3H), 2.77 (s, 3H), 1.19 (d, . / = 7.2 Hz, 3H); LCMS: (M+l: 482.1).

[0430] Preparation ooff [3a(4)Z,10 / i!]-20-chloro-16-methoxy-6,9,10,12,15-pentamethyl- 2,5,9,10,l l,12,13,15-octahydro-l,17-ethenopyrazolo[4,3-m]dipyrrolo[3,2-f3',4'- z][l,4]diazacyclopentadecine-3, 8-dione (Ex. 4):

[0431] Step 1. A mixture of tert-butyl N-[(1R)-2-[(4-bromo-5-methoxy-l-methyl-pyrazol-3- yl)methyl-methyl-amino]-l-methylethyl]-Af-methyl-carbamate (A3, 1.00 g, 2.47 mmol, 1 eq), 7-chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indolin-2-one (Cl, 1.09 g, 3.70 mmol, 1.5 eq), CS2CO3 (1.61 g, 4.93 mmol, 2 eq), Pd(dppf)Cl2(160 mg, 0.246 mmol, 0.1 eq) in dioxane (15 mL) and H2O (3 mL) was degassed and purged with N23 times, and the mixture was stirred at 80 °C for 12 hours under N2 atmosphere. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by reversed-phase HPLC (with 0.1% HC1) to give ter / -butyl N- [(1R)-2-[ [4-(7-chl oro-2-oxo-indolin-5 -yl)-5 -methoxy- 1- methyl-pyrazol-3-yl]methyl-methylamino]-l-methyl-ethyl]-N-methyl-carbamate (180 mg, 0.365 mmol, 14% yield) as a brown solid (4-1). LCMS: (M+L492.2).

[0432] Step 2. To a solution of tert-butyl N-[(1R)-2-[[4-(7-chloro-2-oxo-indolin-5-yl)-5- methoxy-l-methyl-pyrazol-3-yl]methylmethyl-amino]-l-methyl-ethyl]-N-methyl-carbamate (130 mg, 0.264 mmol, 1 eq) in DCM (2 mL) was added HCI / dioxane (4 M, 0.5 mL). The mixture was stirred at 25 °C for 0.5 hours. On completion, the mixture was concentrated to give 7-chloro-5-[5-methoxy-l-methyl-3-[[methyl-[(2 / ?)-2-(methylamino)propyl] amino]methyl]pyrazol-4-yl]indolin-2-one (110 mg, 0.256 mmol, 97% yield, HC1 salt) as a brown solid (4-2). LCMS: (M+l: 392.1).

[0433] Step 3-1. To a solution of 7-chloro-5-[5-methoxy-l-methyl-3-[[methyl-[(2R)-2- (methylamino)propyl]amino]methyl]pyrazol-4-yl]indolin-2-one (110 mg, 0.256 mmol, 1 eq, HC1 salt), 2-formyl-5-methyl-lH-pyrrole-3-carboxylic acid (Bl, 39.3 mg, 0.256 mmol, 1 eq) in ACN (3 mL) was added TCFH (144 mg, 0.513 mmol, 2 eq) and NMI (105 mg, 1.28 mmol, 5 eq). The mixture was stirred at 25 °C for 0.5 hours. On completion, the mixture was concentrated to give the residue. The residue was purified by column chromatography (SiO2, DCM / MeOH=l / 0 to 10 / 1) to give N-[(1R)-2-[[4-(7-chloro-2-oxo-indolin-5-yl)-5-methoxy-l- methyl-pyrazol-3-yl]methyl-methyl-amino]-l-methyl-ethyl]-2-formyl-N,5-dimethyl-1H - pyrrole-3 -carboxamide (90.0 mg, 0.170 mmol, 66% yield) as a brown oil. LCMS: (M+L527.3).

[0434] Step 3-2. To a solution of N-[(1R)-2-[[4-(7-chloro-2-oxo-indolin-5-yl)-5-methoxy-l- methyl-pyrazol-3-yl]methyl-methylamino]-l-methyl-ethyl]-2-formyl-N,5-dimethyl-1H - pyrrole-3 -carboxamide (80.0 mg, 0.151 mmol, 1 eq) in EtOH (5 mL) was added Piperidine (38.7 mg, 0.455 mmol, 3 eq). The mixture was stirred at 70 °C for 10 minutes. On completion, the mixture was concentrated to give the residue. The crude product was purified by reversed- phase HPLC (with 0.1% FA) to give [3a(4)Z,10R]-20-chloro-16-methoxy-6,9,10,12,15- pentamethyl-2,5,9, 10, 11 , 12, 13, 15 -octahydro-1 , 17-ethenopyrazolo[4,3-m]dipyrrolo[3, 2- / 3',4'-z][l,4]diazacyclopentadecine-3, 8-dione (8.87 mg, 0.015 mmol, 9.9% yield, 94% purity, FA salt) as an orange solid (Ex. 4).1H NMR (400 MHz, DMSO-d6) δ = 11.74 (d, J = 0.8 Hz, 1H), 11.28 - 11.14 (m, 1H), 8.71 (s, 1H), 7.51 (s, 1H), 7.29 (d, J=1.2 Hz, 1H), 6.27 (d, J= 1.6 Hz, 1H), 4.81 - 4.70 (m, 1H), 3.83 - 3.81 (m, 3H), 3.77 (s, 1H), 3.68 (s, 3H), 3.16 (d, J = 12.4 Hz, 2H), 2.67 (s, 3H), 2.41 (s, 3H), 2.07 (s, 3H), 2.01 (d, . / = 14.0 Hz, 1H), 1.13 (d, J= 6.8 Hz, 3H); LCMS: (M+l : 509.2).

[0435] General Method C:

[0436] Preparation of [3a(4)Z, 10R]-20-chloro- 16-methoxy-9, 10, 12, 15-tetramethyl-2,5,9,10,l l,12,13,15-octahydro-l,17-ethenopyrazolo[4,3-m]dipyrrolo[3,2-f3',4'- z][l,4]diazacyclopentadecine-3, 8-dione (Ex. 5):

[0437] Step 1-1. To a solution of 7-chloro-5-[5-methoxy-l-methyl-3-[[methyl-[(2R)-2- (methylamino)propyl]amino]methyl]pyrazol-4-yl]indolin-2-one (4-2, 60.0 mg, 0.140 mmol, 1 eq, HC1 salt), 2-formyl-1H -pyrrole-3-carboxylic acid (B2, 19.4 mg, 0.140 mmol, 1 eq) in ACN (5 mL) was added NMI (57.5 mg, 0.700 mmol, 5 eq) and TCFH (78.6 mg, 0.280 mmol, 2 eq). The mixture was stirred at 25 °C for 0.5 hours. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiOi, DCM / MeOH=l / 0 to 10 / 1) to give N-[(1R)-2-[[4-(7-chloro-2-oxo-indolin-5-yl)-5-methoxy-l- methyl-pyrazol-3-yl]methyl-methyl-amino]-l-methyl-ethyl]-2-formyl-N-methyl-1H -pyrrole- 3-caiboxamide (55.0 mg, 0.107 mmol, 76% yield) as a brown oil. LCMS: (M+l: 513.2).

[0438] Step 1-2. To a solution of N- [(l / ?)-2-[ [4-(7-chl oro-2-ox o-indolin-5-yl )-5 -meth oxy-1 - methyl-pyrazol-3-yl]methyl-methylamino]-l-methyl-ethyl]-2-formyl-N-methyl-1H -pyrrole- 3-caiboxamide (50.0 mg, 0.097 mmol, 1 eq) in EtOH (5 mL) was added Piperidine (24.9 mg, 0.292 mmol, 3 eq). The mixture was stirred at 70 °C for 0.5 hours. On completion, the mixture was concentrated to give the residue. The residue was purified by reverse phase HPLC (with 0.1% Formic acid) to give [3a(4)Z,10R]-20-chloro-16-methoxy-9,10,12,15-tetramethyl-2.5.9.10.11.12.13.15-octahydro- 1 ,17-ethenopyrazolo[4,3-m]dipyrrolo[3,2-f3,,4'- z][l,4]di azacyclopen tadecine-3, 8-dione (7.09 mg, 0.014 mmol, 14.2% yield, 95.2% purity, Formic acid salt) as an orange solid (Ex. 5).1HNMR (400 MHz, DMSO-d6) δ = 11.93 (s, 1H), 11.27 (s, lH), 8.74 (s, 1H), 7.58 (s, 1H), 7.40 (t, J = 2.4 Hz, 1H), 7.32 (d, J=1.2 Hz, 1H), 6.48 (t, J= 2.4 Hz, 1H), 4.82 - 4.73 (m, 1H), 3.83 (s, 3H), 3.79 (s, 1H), 3.69 (s, 3H), 3.21 - 3.10 (m, 2H), 2.68 (s,3H), 2.08 (s, 3H), 2.07 - 1.99 (m, 1H), 1.14 (d, J = 6.4 Hz, 3H); LCMS. (M+l: 495.1).

[0439] General Method D:

[0440] Preparation ooff [3a(4)Z,10R]-20-chloro-6-fluoro-16-methoxy-9,10,15-trimethyl-10.11.13.15-tetrahydro-22 / -l, 17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2^:3',4'- z][l,4]oxazacyclopentadecine-3,8(5H , 9H)-dione (Ex. 6):

[0441] Step 1-1. To a mixture of 7-chloro-5-[5-methoxy-l-methyl-3-[[(2R)-2-(methylamino) propoxy]methyl]pyrazol-4-yl]indolin-2-one (3-2, 102 mg, 0.269 mmol, 1 eq) and 5-fluoro-2- formyl-1H -pyrrole-3-carboxylic acid (B3, 63.4 mg, 0.403 mmol, 1.5 eq) in ACN (3 mL) was added NMI (132 mg, 1.62 mmol, 6 eq) and TCFH (151 mg, 0.538 mmol, 2 eq). The mixture was stirred at 25 °C for 0.5 hours. On completion, the mixture was filtered, and the filtrate was concentrated to give N-[(1R)-2-[[4-(7-chloro-2-oxo-indolin-5-yl)-5-methoxy-l-methyl- pyrazol-3-yl]methoxy]-l-methyl-ethyl]-5-fhioro-2-formyl-N-methyl-l / 7-pyrrole-3- carboxamide (30.0 mg, 0.0578 mmol, 21% yield) as a yellow solid. LCMS: (M+l: 518.2).

[0442] Step 1-2. To a solution of N- [(1R)-2-[ [4-(7-chl oro-2-oxo-indolin-5 -yl)-5 -methoxy- 1- methyl-pyrazol-3-yl]methoxy]-l-methyl-ethyl]-5-fluoro-2-formyl-N-methyl-1H -pyrrole-3- carboxamide (10.0 mg, 0.019 mmol, 1 eq) in EtOH (3 mL) was added Piperdine (24.3 mg, 0.058 mmol, 3 eq). The mixture was stirred at 25 °C for 0.5 hours. On completion, the mixture was filtered and concentrated under reduced pressure to give a residue, and the crude product was purified by reversed-phase HPLC (with 0.1% Formic acid) to give [3a(4)Z,10R]-20- chloro-6-fluoro- 16-methoxy-9, 10,15 -trimethyl- 10,11,13,15 -tetrahy dro-2H- 1,17- (ethanediyli dene)pyrazolo[4,3 -m]dipyrrolo[3 ,1-f; 3 ',4'- / ] [ 1 ,4]oxazacycl opentadecine- 3,8(5H ,9H)-dione (1.42 mg, 0.0024 mmol, 12% yield, 93% purity, Formic acid salt) as a yellow solid (Ex. 6).!H NMR (400 MHz, DMSO-d6) δ = 10.32 (s, 1H), 7.61 (d, J= 7.2 Hz, 2H), 6.98 (s, 1H), 5.63 (d, J= 7.2 Hz, 1H), 5.03 - 4.89(m, 1H), 4.22 (d, J= 12.8 Hz, 1H), 3.93 (d, J= 12.8 Hz, 1H), 3.79 (s, 1H), 3.72 (s, 3H), 3.70 (s, 3H), 2.79 (s, 1H), 2.25 (s, 3H), 1.24 (s, 1H), 1.14 (d, J= 7.2 Hz, 3H); LCMS: (M+l : 500.0).

[0443] General Method E:

[0444] Preparation ooff [3a(4)Z,10R]-6-fluoro-16-methoxy-9,10,12,15,20-pentamethyl- 2,5,9,10,ll,12,13,15-octahydro-l,17-ethenopyrazolo[4,3-m]dipyrrolo[3,2; / :3',4'- i][l,4]diazacyclopentadecine-3, 8-dione (Ex. 8):8-2 Ex. 8

[0445] Steps 1 and 2 were performed in a similar manner to steps 1 and 2 of General Method B using C2 in step 1.

[0446] Step 3-1. To aa ssoolluuttiioonn ooff (R)-5-(5-methoxy-l-methyl-3-((methyl(2- (methylamino)propyl)amino)methyl)-lH-pyrazol-4-yl)-7-methylindolin-2-one (240 mg, 588 pmol, 1 eq, HC1), 5-fluoro-2-formyl-lH-pyrrole-3-carboxylic acid (92.4 mg, 588 pmol, 1 eq), NMI (241 mg, 2.94 mmol, 5 eq) in ACN (2 mL) was added TCFH (330 mg, 1.18 mmol, 2 eq). The mixture was stirred at 25 °C for 10 minutes. On completion, the mixture was concentrated to give the residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* Sum; mobile phase: [water (NH3H2O)-ACN]; gradient:0%-29% B over 10 minutes) to give (R)-5-fluoro-2-formyl-N-(l-(((5-methoxy-l-methyl-4-(7-methyl-2- oxoindolin-5-yl)-lH-pyrazol-3-yl)methyl)(methyl)amino)propan-2-yl)-N-methyl-lH-pyrrole- 3-carboxamide (35.0 mg, 68.5 pmol, 11% yield) as an orange solid. LCMS: (M+l:511.3).

[0447] Step 3-2. To a solution of (R)-5-fluoro-2-formyl-N-(l-(((5-methoxy-l-methyl-4-(7- methyl-2-oxoindolin-5-yl)-lH-pyrazol-3-yl)methyl)(methyl)amino)propan-2-yl)-N-methyl- lH-pyrrole-3-carboxamide (25.0 mg, 48.9 pmol, 1 eq) in EtOH (1 mL) was added NMI (12.0 mg, 146 pmol, 3 eq). The mixture was stirred at 70 °C for 10 minutes. On completion, the mixture was concentrated to give the residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* lOum; mobile phase: [water (FA)-ACN]; gradient: 23%-53% B over 10 min) to give (Ex. 8).Preparation of [3a(4)Z,10R]-20-chloro-15-(2- hydroxyethyl)-6,9, 10-trimethyl-10, 11,13,15-tetrahydro-2H-l,17-ethenopyrazolo[4,3- m]dipyrrolo[3, 2-f3', 4'-i'][l,4]oxazacyclopentadecine-3, 8(5H , 9H)-dione (Ex. 11):11-1

[0448] Steps 1-1 and 1-2 followed the procedures of General Method C.

[0449] Step 2. To a solution of (R,Z)-ll-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-27-chloro- 45,6,7-trimethyl-l lH,41H-9-oxa-6-aza-2(5,3)-indolina-l(4,3)-pyrazola-4(2,3)- pyrrolacyclodecaphane-22, 5-dione (36.0 mg, 0.049 mmol, 1 eq) in DMSO (1 mL), was added CsF (37.2 mg, 0.245 mmol, 5 eq) at 25 °C. The reaction was stirred at 25 °C for 0.5 h. On completion, the aqueous phase was extracted with ethyl acetate / 2-MeTHF=5: 1 (20 mL*3). The combined organic phase was washed with brine (10 mL * 2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography on silica gel (DCM: MeOH = 30:1-10:1) to give [3a(4)Z,10R]-20-chloro-15-(2-hydroxyethyl)- 6,9, 10-trimethyl-10, 11,13,15 -tetrahydro-2H- 1, 17-ethenopyrazolo[4,3-m]dipyrrolo[3,2-f3',4'- z][l,4]oxazacyclopentadecine-3, 8(5H , 9H)-dione (21.49 mg, 0.041 mmol, 83% yield, 93.9% purity) as an orange solid.

[0450] General Method F:

[0451] Preparation ooff [3a(4)Z,10R]-20-(methoxymethyl)-6,9,10,12,15-pentamethyl- 2,5,9,10,11,12, 13,15-octahydro-l,17-ethenopyrazolo[4,3-m]dipyrrolo[3, 2-f3', 4'-z][l, 4] diazacyclopentadecine-3, 8-dione (Ex. 12):

[0452] Steps 1-1 and 1-2 followed the procedures of General Method C using 80 °C instead of 70 °C in step 1-2.

[0453] Step 2. To a solution of benzyl [3a(4)Z,10R]-20-(methoxymethyl)-6,9,10,15- tetramethyl-3,8-dioxo-3,5,8,9, 10, 11 , 13 , 15 -octahydro- 1 , 17-ethenopyrazolo[4,3 - m]dipyrrolo[3,2-f:3',4'-i][l,4]diazacyclopentadecine-12(2H)-carboxylate (225 mg, 369.65 pmol, 1 eq) was added in TFA (3.07 g, 26.9 mmol, 2 mL, 72.84 eq). The mixture was stirred at 60 °C for 2 hr. The reaction mixture was concentrated under reduced pressure to remove solvent. The reaction mixture was quenched by addition of NaHCO3(10 mL) at 0 °C. The residue was purified by prep-HPLC (TFA condition) to give [3a(4)Z,10R]-20- (methoxymethyl)-6,9, 10, 15-tetramethyl-2,5,9, 10, 11, 12, 13,15-octahydro-l , 17- ethenopyrazolo[4,3-m]dipyrrolo[3,2-f3',4'-z][l,4]diazacyclopentadecine-3, 8-dione (29.0 mg, 22.6 pmol, 6% yield, 37% purity) as a yellow oil. LCMS: (M+L475.3).

[0454] Step 3. To a solution of [3a(4)Z,10R]-20-(methoxymethyl)-6,9,10,15-tetramethyl- 2,5,9, 10, 11, 12, 13, 15-octahydro-l, 17-ethenopyrazolo[4,3-m]dipyrrolo[3,2; / :3',4'- z][l,4]diazacyclopentadecine-3, 8-dione (29.0 mg, 61.1 pmol, 1 eq) in MeOH (0.5 mL) was added NaBH3CN (8.45 mg, 134 μmol, 2.2 eq) and (CH2O)n (12.1 mg, 400 pmol, 6.54 eq). The mixture was stirred at 50 °C for 12 hr. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography (SiOz, DCM / MeOH=l / 0 to 0 / 1) to give [3a(4)Z,10R]-20-(methoxymethyl)-6,9,10,12,15- pentamethyl-2,5,9, 10, 11 , 12, 13, 15 -octahydro-1 , 17-ethenopyrazolo[4,3-m]dipyrrolo[3, 2- f3',4'-z][l,4]diazacyclopentadecine-3, 8-dione (3.59 mg, 7.35 pmol, 12.02% yield) as a red solid.

[0455] The table below lists the starting material and general methods used to synthesize various examples.Ex Starting Material GeneralStarting Material 1 Product# 2 MethodNH1Step 1-2 used 80 °C instead of 70 °C.2Step 1-1 used 1 h instead of 0.5 h and step 1 -2 used 80 °C instead of 70 °C.3Following the procedure of General Method E steps 3-1 and 3-2.

[0456] Biochemical Assay

[0457] Kinase binding assays were performed at Eurofins / DiscoveRx using the general KINOMEscnn Protocol (Fabian, M. A. et al., “A small molecule-kinase interaction map for clinical kinase inhibitors,” Nat. Biotechnol. 2005, 23(3):329-36). For most assays, kinase- tagged T7 phage strains were prepared in an E. coli host derived from the BL21 strain. E. coll were grown to log-phase and infected with T7 phage and incubated with shaking at 32°C until lysis. The lysates were centrifuged and filtered to remove cell debris. The remaining kinases were produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays. The liganded beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and to reduce nonspecific binding. Binding reactions were assembled by combining kinases, liganded affinity beads, and test compounds in lx binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT). All reactions were performed in polystyrene 96-mell plates in a final volume of 0.135 mL. The assay plates were incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (lx PBS, 0.05% Tween 20). The beads were then re-suspended in elution buffer (lx PBS, 0.05% Tween 20, 0.5 pM non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. Dissociation constants (Kds) for test compound-kinase interactions were calculated by measuring the amount of kinase captured on the solid support as a function of the test compound concentration.

[0458] Table 2. Dissociation constants (Kds) against JAK Family

Claims

WHAT IS CLAIMED IS:

1. A compound of the formula I, or a pharmaceutically acceptable salt thereof,whereinX is -O- or -NR5-;R1and R1aare each independently H, deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, 5- to 10--P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(0)20Ra, -CN, or -NO2, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re,-P(0)20Re, -CN, orNO2;R2is H, deuterium, C1-C6alkyl, or -OC1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl and -OC1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S^NRRf, -S(O>2NReRf, -NRRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(0)2Rf, -NR'SfOJNRRf, -NR^CO^NRRf, -C(O)Re, C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(0)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;each of R2a, R5, R8, R9, and R11is independently H, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2- Cs alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaiyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OSfOJNReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; each of R3, R4, R3a, R4a, R3b, and R4bis independently H, deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, -ORe, -OC(O)Re, -OC(O)NRcRd, -OC(=N)NRcRd, -OS(O)Re, -OS(O)2Re, -OS(O)NR°Rd, -OS(O)2NRcRd, -SRe, -S(O)Re, -S(O)2Re, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd-NRcC(O)NR°Rd, -NRcC(=N)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Re, C(O)ORe, -C(O)NRcRd, -C(=N)NRcRd, -PRcRd, -P(O)R°Rd, -P(O)2RcRd, -P(O)NR=Rd, -P(O)2NRcRd, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; wherein each hydrogen atom in Cj-Cs alkyl, Cz-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, - OC(O)NReR,f-OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(0)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PR’R1, -P^R^, -P(O)2ReRf, P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; each of R6, R6a, and R7is independently H, deuterium, halogen, or C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NRe,f-NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReR1, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf-P(O>2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;R10is hydrogen or deuterium; andeach Ra, Rb, Rc, Rd, Re, and Rfis independently selected from the group consisting of H, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10aryl, C1-C6alkyl-C6-C10aiyl, and 5- to 10-membered heteroaryl; provided that when X is -O-, then R2is: deuterium; C1-C6alkyl, wherein at least one hydrogen atom is substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf-OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe,-C(O)NReRf, -PReRf, -P(O)ReRf, -P(0)2R^, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; or-OC1-C6alkyl, wherein each hydrogen atom in -OC1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl,or -NO2.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is O.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R2is deuterium.

4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R2is C1-C6alkyl, wherein at least one hydrogen atom is optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, --OC(O)NReR,f-OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(0)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2.

5. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R2is OC1-C6alkyl, wherein each hydrogen atom in -OC1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl,-P(O)ORe, -P^ORe, -CN, or -NO2.

6. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X is -NR3-.

7. The compound of any one of claims 1, 2, or 6, or a pharmaceutically acceptable salt thereof, wherein R2is H.

8. The compound any one of claims 1, 2, or 6, or a pharmaceutically acceptable salt thereof, wherein R2is deuterium.

9. The compound any one of claims 1, 2, or 6, or a pharmaceutically acceptable salt thereof, wherein R2is C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl,-P(O)ORe, -P(0)2ORe, -CN, or -NO2.

10. The compound any one of claims 1, 2, or 6, or a pharmaceutically acceptable salt thereof, wherein R2is -OC1-C6alkyl, wherein each hydrogen atom in -OC1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl,-P(O)ORe, -P(0)2ORe, -CN, or -NO2.

11. The compound of any one of claims 1, 2, 5, 6, or 10, or a pharmaceutically acceptable salt thereof, wherein R2is unsubstituted -OC1-C6alkyl.

12. The compound of any one of claims 1, 2, 5, 6, 10, or 11, or a pharmaceutically acceptable salt thereof, wherein R2is -OCH3, -OCH2CH3, or -OCH2(CH3)2.

13. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R1is H, halogen, or C1-C6alkyl.

14. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R1is H, deuterium, fluoro, or methyl.

15. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R,ais H or deuterium.

16. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R2ais C1-C6alkyl.

17. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R2ais methyl.

18. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein one of R3, R4, R3a, R4a, R3b, or R* is C1-C6alkyl wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, --OC(O)NReR,f-OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(0)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P^RT^, -P(O)2ReRf, -P(O)NReRf, -P(0)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2, and the remaining of R3, R4, R3a, R48, R3b, and R4bare each H.

19. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R3ais C1-C6alkyl.

20. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R3ais methyl.

21. The compound of any one claims 1 or 3 to 20, or a pharmaceutically acceptable salt thereof, wherein R5, when present, is H or C1-C6alkyl.

22. The compound of any one of claims 1 or 3 to 20, or a pharmaceutically acceptable salt thereof, wherein R5, when present, is H or methyl.

23. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R6is H.

24. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R6ais H.

25. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R7is H or halogen.

26. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R7is fluoro or chloro.

27. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R8is H.

28. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R9is C1-C6alkyl.

29. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R9is methyl.

30. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R11is H.

31. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of [3a(4)Z,10R]-20-chloro-6,9,10,15-tetramethyl-2,5,9,10,l 1,12,13,15-octahydro-1, 17-ethenopyrazolo[4,3-m]dipyrrolo[3,2-f3', 4'-i][l,4]diazacyclopentadecine-3, 8- dione;[3a(4)Z,10R]-20-chloro-6,9,10,12,15-pentamethyl-2,5,9,10,l l,12,13,15-octahydro-l,17- ethenopyrazolo[4,3-m]dipyrrolo[3 ,2-f 3 ',4'- / ] [ 1 ,4]diazacyclopentadecine-3 , 8-dione;[3 a(4)Z, 10R]-20-chloro- 16-methoxy-9, 10, 15-trimethyl- 10, 11 , 13 , 15-tetrahydro-2H- 1,17- ethenopyrazolo[4,3 -m]dipyrrolo[3 ,2-f 3 *,4* -z] [ 1 ,4]oxazacyclopentadecine-3 ,8(5H , 9H) -di one;[3a(4)Z,10R]-20-chloro-16-methoxy-6,9,10,12,15-pentamethyl-2,5,9,10,ll,12,13,15- octahydro- 1,17 -ethenopyrazol o[4,3-m]dipyrrolo[3 ,2-f 3 ',4'-z] [ 1 ,4] di azacyclopen tadecine-3, 8- dione;[3a(4)Z,10R]-20-chloro-16-m ethoxy-9, 10, 12, 15-tetramethyl-2,5,9, 10, 11 , 12, 13, 15-octahydro-1.17-ethenopyrazolo[4,3-m]dipyrrolo[3, 2-f3', 4'-z][l,4]diazacyclopentadecine-3, 8-dione;[3a(4)Z,10R]-20-chloro-6-fluoro-l 6-methoxy-9, 10, 15-ttimethyl- 10, 11 , 13, 15-tetrahydro-2H-1.17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2 / 3',4'-z][l,4]oxazacyclopentadecine- 3, 8(5H , 9H) -dione;[3a(4)Z, 10R]-20-chloro-6-fluoro-l 6-methoxy-9, 10, 12, 15-tetramethyl-2,5,9, 10, 11,12, 13,15- octahydro-l,17-ethenopyrazolo[4,3-m]dipyrrolo[3, 2-f3', 4'-z][l,4]diazacyclopen tadecine-3, 8- dione; and[3a(4)Z,10R]-6-fluoro-16-methoxy-9,10,12,15,20-pentamethyl-2,5,9,10,ll,12,13,15- octahydro-l,17-ethenopyrazolo[4,3-m]dipyrrolo[3,2-f3',4'-z][l,4]diazacyclopentadecine-3,8- dione.

32. A pharmaceutical composition comprising at least one compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.

33. A method of treating disease, such as an autoimmune disease or an inflammatory disease, comprising administering to a subject in need of such treatment an effective amount of a compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof.

34. A compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, for use in a method of treating an autoimmune disease or an inflammatory disease in a subject.

35. A compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, for treating an autoimmune disease or an inflammatory disease in a subject.

36. Use of a compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating an autoimmune disease or an inflammatory disease in a subject.

Images