Macrocyclic compounds and their use as kinase inhibitors

Abstract

The present disclosure relates to macrocyclic compounds, pharmaceutical compositions containing the macrocyclic compounds, and methods of using the macrocyclic compounds to treat diseases, such as autoimmune diseases.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 63 / 296,705, filed January 5, 2022, and U.S. Provisional Application No. 63 / 435,654, filed December 28, 2022, the entire disclosures of which are incorporated herein by reference. Technical Field The present disclosure relates to macrocyclic compounds, pharmaceutical compositions containing the macrocyclic compounds, and methods of using the macrocyclic compounds for treating diseases, such as autoimmune diseases in humans. [Background technology]

[0002] Protein kinases are tightly regulated signaling proteins that coordinate the activation of signaling cascades by phosphorylating target proteins in response to extracellular and intracellular stimuli. Approximately 518 protein kinases are encoded in the human genome (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 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 basis leading to various diseases includes kinase gain-of-function 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 important role of kinases in autoimmune and other diseases makes them attractive targets for drug discovery, with 52 small molecule kinase inhibitors approved, 46 of which are therapeutics targeting autoimmune diseases (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 induce downstream transcriptional responses.The Janus kinase signal transduction and activator of transcription (JAK-STAT) pathway plays a key role in both normal and pathological conditions 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-related pathways with JAK inhibitors has achieved clinical success for a variety of diseases, including ruxolitinib and fedratinib for myeloproliferative neoplasms, and tofacitinib, upadacitinib, and baricitinib for rheumatoid arthritis and other immune-mediated inflammatory diseases (McLornan DP., et al Lancet, 2021, 398:803-816). However, isoform-selective JAK inhibitors are difficult to achieve, and nearly all approved kinase domain ATP-competitive JAK inhibitors exhibit significant undesirable side effects because they inhibit multiple JAK family members. JAK kinases are large multi-domain proteins that contain FER domains [JH6-JH7] and SH2 domains [JH3-JH5] that mediate receptor interaction, a pseudokinase domain [JH2] with regulatory functions, and a kinase catalytic domain [JH1] (Garrido-Trigo A and SalasJournal A., Journal of Crohn's and Colitis, 2020, S713-S724). The pseudokinase domain controls the kinase domain by steric inhibition of ATP binding and / or by reducing the flexibility of the kinase active site required for catalysis (Patrick J., et al PNAS2014111:8025-8030). Although members of the JAK family share high sequence homology within the catalytic domain, the characteristic pseudokinase domain (JH2) of the JAK family may provide an ideal "allosteric" site for the development of highly selective JAK inhibitors. TYK2, a member of the JAK family, plays a key role in regulating the signaling of a wide range of proinflammatory cytokines, including IL12, IL23, and type 1 interferon (IFNα).Highly selective TYK2 inhibitors are needed to balance optimal benefit and safety in the treatment of human autoimmune diseases such as multiple sclerosis, Crohn's disease, and psoriasis (Leitner, NR, et al Tyrosine kinase 2- surveillant of tumours and bona fide oncogene. Cytokine 2017, 89, 209-218). Summary of the Invention [Problem to be solved by the invention]

[0003] Therefore, the discovery 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 such as multiple sclerosis, Crohn's disease and psoriasis. [Means for solving the problem]

[0004] overview In one aspect, the disclosure provides a compound of formula I: [ka] I [In the formula, A is, [ka] and; B is, [ka] and; Each L is independently -C(R 3 )(R 4 )-, -C(O)-, -O-, -N(R 5 )-, -S-, -S(O)- or -S(O) 2 -where: (L) n -OO-, -OS-, -SS-, or -ON(R 5)-bonds, and (L) n -N(R 9 )- is -ON(R 9 )-, -SN(R 9 ) - does not contain bonds; Y and Y 1 are each independently O or S; R 1 , R 1a , and R 2 are independently H, deuterium, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -OS(O)NR a R b , -OS(O) 2 NR a R b , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR a R b , -NR a S(O)R b , -NRa S(O) 2 R b , -NR a S(O)NR a R b , -NR a S(O) 2 NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -PR a R b , -P(O)R a R b , -P(O) 2 R a R b , -P(O)NR a R b , -P(O) 2 NR a R b , -P(O)OR a , -P(O) 2 OR a , -CN, or -NO 2 where C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 Each hydrogen atom in an aryl or 5-10 membered heteroaryl is independently selected from deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -OS(O) 2 NRe R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e R f , -S(O) 2 NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O) 2 R f , -NR e S(O)NR e R f , -NR e S(O) 2 NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O) 2 R e R f , -P(O)NR e R f , -P(O) 2 NR e R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 optionally replaced by; R 2a , R 5 , R 8 , and R 9 are independently H, deuterium, and C 1 -C6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 aryl, or 5-10 membered heteroaryl, where C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 Each hydrogen atom in an aryl or 5-10 membered heteroaryl is independently selected from deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e R f , -S(O) 2 NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e Rf , -NR e S(O)R f , -NR e S(O) 2 R f , -NR e S(O)NR e R f , -NR e S(O) 2 NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O) 2 R e R f , -P(O)NR e R f , -P(O) 2 NR e R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 optionally replaced by; R 2b is C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 3 -C 4 cycloalkyl, or 3-4 membered heterocycloalkyl, where C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 3 -C 4 Each hydrogen atom in a cycloalkyl and a 3- to 4-membered heterocycloalkyl is independently selected from deuterium, halogen, -O(H or C 1 -C 2 alkyl), -OC(O)C1 -C 2 Alkyl, -OC(O)N(H or C 1 -C 2 Alkyl) 2 , -OS(O)C 1 -C 2 Alkyl, -OS(O) 2 C 1 -C 2 Alkyl, -OS(O)N(H or C 1 -C 2 Alkyl) 2 , -OS(O) 2 N(H or C 1 -C 2 Alkyl) 2 , -S(H or C 1 -C 2 alkyl), -S(O)C 1 -C 2 Alkyl, -S(O) 2 C 1 -C 2 Alkyl, -S(O)N(H or C 1 -C 2 Alkyl) 2 , -S(O) 2 N(H or C 1 -C 2 Alkyl) 2 , -N(H or C 1 -C 2 Alkyl) 2 , -N(H or C 1 -C 2 Alkyl)C(O)C 1 -C 2 Alkyl, -N(H or C 1 -C 2 alkyl)C(O)O(H or C 1 -C 2 alkyl), -N(H or C 1 -C 2 Alkyl)C(O)N(H or C 1 -C 2 Alkyl) 2 , -N(H or C 1 -C 2 Alkyl)S(O)C 1 -C 2 Alkyl, -N(H or C 1-C 2 Alkyl)S(O) 2 C 1 -C 2 Alkyl, -N(H or C 1 -C 2 Alkyl)S(O)N(H or C 1 -C 2 Alkyl) 2 , -N(H or C 1 -C 2 Alkyl)S(O) 2 N(H or C 1 -C 2 Alkyl) 2 , -C(O)C 1 -C 2 Alkyl, -C(O)O(H or C 1 -C 2 alkyl), -C(O)N(H or C 1 -C 2 Alkyl) 2 , -P(H or C 1 -C 2 Alkyl) 2 , -P(O)(H or C 1 -C 2 Alkyl) 2 , -P(O) 2 (H or C 1 -C 2 Alkyl) 2 , -P(O)N(H or C 1 -C 2 Alkyl) 2 , -P(O) 2 N(H or C 1 -C 2 Alkyl) 2 , -P(O)O(H or C 1 -C 2 alkyl), -P(O) 2 O(H or C 1 -C 2 alkyl), -CN, or -NO 2 optionally replaced by; R 3 and R 4 are independently H, deuterium, halogen, C 1 -C 6 Alkyl, C 2 -C6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, -OR c , -OC(O)R c , -OC(O)NR c R d , -OC(=N)NR c R d , -OS(O)R c , -OS(O) 2 R c , -OS(O)NR c R d , -OS(O) 2 NR c R d , -SR c , -S(O)R c , -S(O) 2 R c , -S(O)NR c R d , -S(O) 2 NR c R d , -NR c R d , -NR c C(O)R d , -N(C(O)R c )(C(O)R d ), -NR c C(O)OR d , -NR c C(O)NR c R d , -NR c C(=N)NR c R d , -NR c S(O)R d , -NR c S(O) 2 R d , -NR c S(O)NR c R d , -NR c S(O) 2 NR c R d, -C(O)R c , -C(O)OR c , -C(O)NR c R d , -C(=N)NR c R d , -PR c R d , -P(O)R c R d , -P(O) 2 R c R d , -P(O)NR c R d , -P(O) 2 NR c R d , -P(O)OR c , -P(O) 2 OR c , -CN, -NO 2 or R 3 , R 4 , and R 5 Two of the atoms, together with the atoms to which they are attached, form C 3 -C 6 cycloalkyl or 4-8 membered heterocycloalkyl, where C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 Each hydrogen atom in an aryl or 5-10 membered heteroaryl is independently selected from deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -OS(O)2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e R f , -S(O) 2 NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O) 2 R f , -NR e S(O)NR e R f , -NR e S(O) 2 NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O) 2 R e R f , -P(O)NR e R f , -P(O) 2 NR e R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 optionally replaced by; R 6 and R 7 are independently H, deuterium, halogen, C 1 -C 6 Alkyl, C2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -OS(O)NR a R b , -OS(O) 2 NR a R b , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR a R b , -NR a S(O)R b , -NR a S(O) 2 R b , -NR a S(O)NR a R b , -NR a S(O) 2 NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -PR a R b , -P(O)Ra R b , -P(O) 2 R a R b , -P(O)NR a R b , -P(O) 2 NR a R b , -P(O)OR a , -P(O) 2 OR a , -CN, or -NO 2 is; R a , R b , R c , R d , R e , and R f are independently H, deuterium, and C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 Aryl, C 1 -C 6 Alkyl-C 6 -C 10 aryl, and 5-10 membered heteroaryl; and n is 2, 3, 4, 5, 6, 7, or 8] or a pharma- ceutically acceptable salt thereof.

[0005] In some embodiments, L is -N(R 5 In some embodiments, each L is independently -C(R 3 )(R 4 )-, -C(O)-, -O-, -S-, -S(O)- or -S(O) 2 -where: (L) n does not contain an -OO-, -SS-, or -OS- bond. 2 -OR aIn some embodiments, R 2 H, deuterium, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -OS(O)NR a R b , -OS(O) 2 NR a R b , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR a R b , -NR a S(O)R b , -NR a S(O) 2 R b , -NR a S(O)NR a R b , -NR a S(O) 2 NR a R b , -C(O)R a , -C(O)OR a , -C(O)NRa R b , -PR a R b , -P(O)R a R b , -P(O) 2 R a R b , -P(O)NR a R b , -P(O) 2 NR a R b , -P(O)OR a , -P(O) 2 OR a , -CN, or -NO 2 where C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 Each hydrogen atom in an aryl or 5-10 membered heteroaryl is independently selected from deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e R f , -S(O) 2 NR e R f , -NR e R f, -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O) 2 R f , -NR e S(O)NR e R f , -NR e S(O) 2 NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O) 2 R e R f , -P(O)NR e R f , -P(O) 2 NR e R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 is optionally replaced by

[0006] In some embodiments, the present disclosure provides a compound of formula II: [ka] II [In the formula, A, B, L, R 7 , R 8 , R 9 and n is as defined herein. or a pharma- ceutically acceptable salt thereof.

[0007] In some embodiments, the present disclosure provides a compound of formula III: [ka] III [In the formula, B, L, R 1 , R 1a , R 7 , R 8 , R 9 and n is as defined herein. or a pharma- ceutically acceptable salt thereof.

[0008] In some embodiments, the present disclosure provides a compound of formula IV: [ka] IV [In the formula, B, L, R 1 , R 7 , R 8 , R 9 and n is as defined herein. or a pharma- ceutically acceptable salt thereof.

[0009] In some embodiments, the present disclosure provides a compound of formula V: [ka] V [In the formula, L, R 2 , R 2b , R 7 , R 8 , R 9 and n is as defined herein. or a pharma- ceutically acceptable salt thereof.

[0010] In some embodiments, the present disclosure provides a compound of formula VI: [ka] VI [In the formula, L, R 2a , R 2b , R 7 , R 8 , R 9and n is as defined herein. or a pharma- ceutically acceptable salt thereof.

[0011] In some embodiments, the present disclosure provides a compound of formula VII: [ka] VII [In the formula, L, R 1 , R 1a , R 2 , R 2b , R 7 , R 8 , R 9 and n is as defined herein. or a pharma- ceutically acceptable salt thereof.

[0012] In some embodiments, the present disclosure provides a compound of formula VIII: [ka] VIII [In the formula, L, R 1 , R 2 , R 2b , R 7 , R 8 , R 9 and n is as defined herein. or a pharma- ceutically acceptable salt thereof.

[0013] In some embodiments, the present disclosure provides a compound of formula IX: [ka] IX [In the formula, L, R 1 , R 1a , R 2a , R 2b , R 7 , R 8 , R 9 and n is as defined herein. or a pharma- ceutically acceptable salt thereof.

[0014] In some embodiments, the present disclosure provides a compound of formula X: [ka] X [In the formula, L, R 1 , R 2a , R 2b , R 7 , R 8 , R 9 and n is as defined herein. or a pharma- ceutically acceptable salt thereof.

[0015] In some embodiments, the present disclosure provides a compound of formula XI: [ka] XI [In the formula, L, R 1 , R 1a , R 2 , R 2b , R 7 and n is as defined herein. or a pharma- ceutically acceptable salt thereof.

[0016] In some embodiments, the present disclosure provides a compound of formula XII: [ka] XII [In the formula, L, R 1 , R 1a , R 2a , R 2b , R 7 and n is as defined herein. or a pharma- ceutically acceptable salt thereof.

[0017] In some embodiments, ring A is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] isn't it.

[0018] In some embodiments, R 7 is H, deuterium, C 1 -C 6 In some embodiments, R is an alkyl, fluoro, chloro, or -CN. 7 is H. In some embodiments, R 7 is deuterium. In some embodiments, R 7 is C 1 -C 6 In some embodiments, R 7 is -F. In some embodiments, R 7 is -Cl. In some embodiments, R 7 is -CN.

[0019] In some embodiments, ring B is [ka] and R 7 is H. In some embodiments, ring A is [ka] and ring B is [ka] and R 7 is H. In some embodiments, ring B is [ka] and R 7 is not H. In some embodiments, ring A is [ka] and ring B is [ka] and R 7 is not H. In some embodiments, ring B is [ka] and R 7 is -F, -Cl or -CN. In some embodiments, Ring B is [ka] and R 7 is -Cl or -CN. In some embodiments, Ring A is [ka] and ring B is [ka] and R 7 is -F, -Cl or -CN. In some embodiments, Ring A is [ka] and ring B is [ka] and R 7 is -Cl or -CN. In some embodiments, Ring B is [ka] and R 7 In some embodiments, ring B is [ka] and R 7In some embodiments, Ring B is [ka] and R 7 In some embodiments, ring A is [ka] and ring B is [ka] and R 7 In some embodiments, ring A is [ka] and ring B is [ka] and R 7 In some embodiments, ring A is [ka] and ring B is [ka] and R 7 is -CN.

[0020] In certain embodiments of the above aspects, the compound of formula (I)-(XII) is a compound selected from the species described or exemplified in the detailed description below.

[0021] In a further aspect, the present disclosure relates to a pharmaceutical composition comprising at least one compound of formula (I)-(XII) or a pharma- ceutically acceptable salt thereof. The pharmaceutical composition according to the present disclosure may further comprise a pharma- ceutically acceptable excipient.

[0022] In a further aspect, the present invention relates to at least one compound of Formulae (I)-(XII), or a pharma- ceutically acceptable salt thereof, for use as a medicament.

[0023] In a further aspect, the present disclosure relates to a method of treating a disease, such as an autoimmune disease, comprising administering to a subject in need of treatment an effective amount of at least one compound of Formulae (I)-(XII), or a pharma- ceutically acceptable salt thereof.

[0024] In a further aspect, the present disclosure relates to the use of compounds of Formulas (I)-(XII), or pharma- ceutically acceptable salts thereof, in the manufacture of a medicament for the treatment of diseases, such as autoimmune diseases, and the use of such compounds and salts for the treatment of such diseases.

[0025] In a further aspect, the present invention relates to a method of inhibiting a tyrosine kinase, such as TYK2, comprising contacting a cell containing one or more kinases with an effective amount of at least one compound of Formula (I)-(XII), or a pharma- ceutically acceptable salt thereof, and / or at least one pharmaceutical composition of the present disclosure, wherein the contacting is effected in vitro, ex vivo, or in vivo.

[0026] Further embodiments, features, and advantages of the present disclosure will become apparent from the following detailed description and through the practice of the present disclosure. The compounds of the present disclosure can be described as any of the embodiments listed below. It will be understood that any of the embodiments described herein can be used in combination with other embodiments described herein, unless the embodiments are mutually inconsistent.

[0027] 1. Compound of Formula I: [ka] I [In the formula, A is, [ka] and; B is, [ka] and; Each L is independently -C(R 3 )(R 4 )-, -C(O)-, -O-, -N(R 5 )-, -S-, -S(O)- or -S(O) 2 -where: (L) n -OO-, -OS-, -SS-, or -ON(R 5 )-bonds, and (L) n -N(R 9 )- is -ON(R 9 )-, -SN(R 9 ) - does not contain bonds; Y and Y 1 are each independently O or S; R 1 , R 1a , and R 2 are independently H, deuterium, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -OS(O)NRa R b , -OS(O) 2 NR a R b , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR a R b , -NR a S(O)R b , -NR a S(O) 2 R b , -NR a S(O)NR a R b , -NR a S(O) 2 NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -PR a R b , -P(O)R a R b , -P(O) 2 R a R b , -P(O)NR a R b , -P(O) 2 NR a R b , -P(O)OR a , -P(O) 2 OR a , -CN, or -NO 2 where C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10Each hydrogen atom in an aryl or 5-10 membered heteroaryl is independently selected from deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e R f , -S(O) 2 NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O) 2 R f , -NR e S(O)NR e R f , -NR e S(O) 2 NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O) 2 R eR f , -P(O)NR e R f , -P(O) 2 NR e R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 optionally replaced by; R 2a , R 5 , R 8 , and R 9 are independently H, deuterium, and C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 aryl, or 5-10 membered heteroaryl, where C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 Each hydrogen atom in an aryl or 5-10 membered heteroaryl is independently selected from deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -OS(O) 2 NR e Rf , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e R f , -S(O) 2 NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O) 2 R f , -NR e S(O)NR e R f , -NR e S(O) 2 NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O) 2 R e R f , -P(O)NR e R f , -P(O) 2 NR e R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 optionally replaced by; R 2b is C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4Alkynyl, C 3 -C 4 cycloalkyl, or 3-4 membered heterocycloalkyl, where C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 3 -C 4 Each hydrogen atom in a cycloalkyl and a 3- to 4-membered heterocycloalkyl is independently selected from deuterium, halogen, -O(H or C 1 -C 2 alkyl), -OC(O)C 1 -C 2 Alkyl, -OC(O)N(H or C 1 -C 2 Alkyl) 2 , -OS(O)C 1 -C 2 Alkyl, -OS(O) 2 C 1 -C 2 Alkyl, -OS(O)N(H or C 1 -C 2 Alkyl) 2 , -OS(O) 2 N(H or C 1 -C 2 Alkyl) 2 , -S(H or C 1 -C 2 alkyl), -S(O)C 1 -C 2 Alkyl, -S(O) 2 C 1 -C 2 Alkyl, -S(O)N(H or C 1 -C 2 Alkyl) 2 , -S(O) 2 N(H or C 1 -C 2 Alkyl) 2 , -N(H or C 1 -C 2 Alkyl) 2 , -N(H or C 1 -C 2 Alkyl)C(O)C 1 -C2 Alkyl, -N(H or C 1 -C 2 alkyl)C(O)O(H or C 1 -C 2 alkyl), -N(H or C 1 -C 2 Alkyl)C(O)N(H or C 1 -C 2 Alkyl) 2 , -N(H or C 1 -C 2 Alkyl)S(O)C 1 -C 2 Alkyl, -N(H or C 1 -C 2 Alkyl)S(O) 2 C 1 -C 2 Alkyl, -N(H or C 1 -C 2 Alkyl)S(O)N(H or C 1 -C 2 Alkyl) 2 , -N(H or C 1 -C 2 Alkyl)S(O) 2 N(H or C 1 -C 2 Alkyl) 2 , -C(O)C 1 -C 2 Alkyl, -C(O)O(H or C 1 -C 2 alkyl), -C(O)N(H or C 1 -C 2 Alkyl) 2 , -P(H or C 1 -C 2 Alkyl) 2 , -P(O)(H or C 1 -C 2 Alkyl) 2 , -P(O) 2 (H or C 1 -C 2 Alkyl) 2 , -P(O)N(H or C 1 -C 2 Alkyl) 2 , -P(O) 2 N(H or C1 -C 2 Alkyl) 2 , -P(O)O(H or C 1 -C 2 alkyl), -P(O) 2 O(H or C 1 -C 2 alkyl), -CN, or -NO 2 optionally replaced by; R 3 and R 4 are independently H, deuterium, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, -OR c , -OC(O)R c , -OC(O)NR c R d , -OC(=N)NR c R d , -OS(O)R c , -OS(O) 2 R c , -OS(O)NR c R d , -OS(O) 2 NR c R d , -SR c , -S(O)R c , -S(O) 2 R c , -S(O)NR c R d , -S(O) 2 NR c R d , -NR c R d , -NR c C(O)R d , -N(C(O)R c )(C(O)R d ), -NR c C(O)OR d, -NR c C(O)NR c R d , -NR c C(=N)NR c R d , -NR c S(O)R d , -NR c S(O) 2 R d , -NR c S(O)NR c R d , -NR c S(O) 2 NR c R d , -C(O)R c , -C(O)OR c , -C(O)NR c R d , -C(=N)NR c R d , -PR c R d , -P(O)R c R d , -P(O) 2 R c R d , -P(O)NR c R d , -P(O) 2 NR c R d , -P(O)OR c , -P(O) 2 OR c , -CN, -NO 2 or R 3 , R 4 , and R 5 Two of the atoms, together with the atoms to which they are attached, form C 3 -C 6 cycloalkyl or 4-8 membered heterocycloalkyl, where C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C10 Each hydrogen atom in an aryl or 5-10 membered heteroaryl is independently selected from deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e R f , -S(O) 2 NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O) 2 R f , -NR e S(O)NR e R f , -NR e S(O) 2 NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O) 2 Re R f , -P(O)NR e R f , -P(O) 2 NR e R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 optionally replaced by; R 6 and R 7 are independently H, deuterium, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -OS(O)NR a R b , -OS(O) 2 NR a R b , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR a R b , -NR aS(O)R b , -NR a S(O) 2 R b , -NR a S(O)NR a R b , -NR a S(O) 2 NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -PR a R b , -P(O)R a R b , -P(O) 2 R a R b , -P(O)NR a R b , -P(O) 2 NR a R b , -P(O)OR a , -P(O) 2 OR a , -CN, or -NO 2 or R 6 and R 7 together with the carbon to which they are attached, C 4 -C 6 Cycloalkyl, 4-7 membered heterocycloalkyl, or C 6 -C 10 aryl, where C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, C 4 -C 6 Cycloalkyl, 4-7 membered heterocycloalkyl, C 6 -C 10 Each hydrogen atom in an aryl, 5- to 10-membered heteroaryl, or 4- to 8-membered heterocycloalkyl is independently selected from deuterium, halogen, C 1 -C 6アルキル、C 1 -C 6 ハロアルキル、-OR e 、-OC(O)R e 、-OC(O)NR e R f 、-OS(O)R e 、-OS(O) 2 R e 、-OS(O)NR e R f 、-OS(O) 2 NR e R f 、-SR e 、-S(O)R e 、-S(O) 2 R e 、-S(O)NR e R f 、-S(O) 2 NR e R f 、-NR e R f 、-NR e C(O)R f 、-NR e C(O)OR f 、-NR e C(O)NR e R f 、-NR e S(O)R f 、-NR e S(O) 2 R f 、-NR e S(O)NR e R f 、-NR e S(O) 2 NR e R f 、-C(O)R e 、-C(O)OR e 、-C(O)NR e R f 、-PR e R f 、-P(O)R e R f 、-P(O) 2 R e R f 、-P(O)NR e R f 、-P(O) 2 NRe R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 optionally replaced by; R a , R b , R c , R d , R e , and R f are independently H, deuterium, and C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 Aryl, C 1 -C 6 Alkyl-C 6 -C 10 aryl, and 5-10 membered heteroaryl; and [n is 2, 3, 4, 5, 6, 7, or 8]. or a pharma- ceutically acceptable salt thereof.

[0028] 2. The compound according to clause 1, having formula II: [ka] II or a pharma- ceutically acceptable salt thereof.

[0029] 3. The compound according to clause 1, represented by formula III: [ka] III or a pharma- ceutically acceptable salt thereof.

[0030] 4. The compound according to clause 1 or 2, represented by formula IV: [ka] IV or a pharma- ceutically acceptable salt thereof.

[0031] 5. The compound according to clause 1 or 2, having formula V: [ka] V or a pharma- ceutically acceptable salt thereof.

[0032] 6. The compound according to clause 1 or 2, having formula VI: [ka] VI or a pharma- ceutically acceptable salt thereof.

[0033] 7. The compound according to any one of clauses 1 to 3, having formula VII: [ka] VII or a pharma- ceutically acceptable salt thereof.

[0034] 8. The compound according to clause 1 or 2, represented by formula VIII: [ka] VIII or a pharma- ceutically acceptable salt thereof.

[0035] 9. The compound according to any one of clauses 1 to 3, having formula IX: [ka] IX or a pharma- ceutically acceptable salt thereof.

[0036] 10. The compound according to clause 1 or 2, having the formula X: [ka] X or a pharma- ceutically acceptable salt thereof.

[0037] 11. The compound according to any one of clauses 1 to 3, having formula XI: [ka] XI or a pharma- ceutically acceptable salt thereof.

[0038] 12. The compound according to any one of clauses 1 to 3, having formula XII: [ka] XII or a pharma- ceutically acceptable salt thereof.

[0039] 13.R 1 If present, H, -CN or C 1 -C 6 alkyl, where C 1 -C 6 Each hydrogen atom in an alkyl group can be independently deuterium, halogen, or C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e R f , -S(O) 2NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O) 2 R f , -NR e S(O)NR e R f , -NR e S(O) 2 NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O) 2 R e R f , -P(O)NR e R f , -P(O) 2 NR e R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 or R 1 is H, -CN or methyl, or a pharma- ceutically acceptable salt thereof.

[0040] 14.R 1a If present, H, -CN or C 1 -C 6 alkyl, where C 1 -C 6 Each hydrogen atom in an alkyl group can be independently deuterium, halogen, or C 1 -C 6アルキル、C 1 -C 6 ハロアルキル、-OR e 、-OC(O)R e 、-OC(O)NR e R f 、-OS(O)R e 、-OS(O) 2 R e 、-OS(O)NR e R f 、-OS(O) 2 NR e R f 、-SR e 、-S(O)R e 、-S(O) 2 R e 、-S(O)NR e R f 、-S(O) 2 NR e R f 、-NR e R f 、-NR e C(O)R f 、-NR e C(O)OR f 、-NR e C(O)NR e R f 、-NR e S(O)R f 、-NR e S(O) 2 R f 、-NR e S(O)NR e R f 、-NR e S(O) 2 NR e R f 、-C(O)R e 、-C(O)OR e 、-C(O)NR e R f 、-PR e R f 、-P(O)R e R f 、-P(O) 2 R e R f 、-P(O)NR e R f 、-P(O) 2 NRe R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 or R 1a 14. The compound according to any one of clauses 1-3, 5-7, 9, 11, 12, or 13, or a pharma- ceutically acceptable salt thereof, wherein: is H, -CN or methyl.

[0041] 15.R 2 If present, H, deuterium, halogens, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -OS(O)NR a R b , -OS(O) 2 NR a R b , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR a R b , -NR aS(O)R b , -NR a S(O) 2 R b , -NR a S(O)NR a R b , -NR a S(O) 2 NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -PR a R b , -P(O)R a R b , -P(O) 2 R a R b , -P(O)NR a R b , -P(O) 2 NR a R b , -P(O)OR a , -P(O) 2 OR a , -CN, or -NO 2 where C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 Each hydrogen atom in an aryl or 5-10 membered heteroaryl is independently selected from deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f, -OS(O) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e R f , -S(O) 2 NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O) 2 R f , -NR e S(O)NR e R f , -NR e S(O) 2 NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O) 2 R e R f , -P(O)NR e R f , -P(O) 2 NR e R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 or R 2 If present, H, -CN, or C 1 -C 6 alkyl, where C 1-C 6 Each hydrogen atom in an alkyl group can be independently deuterium, halogen, or C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e R f , -S(O) 2 NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O) 2 R f , -NR e S(O)NR e R f , -NR e S(O) 2 NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O) 2 R e Rf , -P(O)NR e R f , -P(O) 2 NR e R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 or R 2 15. The compound according to any one of clauses 1 to 5, 7, 8, 11, 13, or 14, or a pharma- ceutically acceptable salt thereof, wherein, if present, is H, -CN, or methyl.

[0042] 16.R 2a If present, H or C 1 -C 6 alkyl, where C 1 -C 6 Each hydrogen atom in an alkyl group can be independently deuterium, halogen, or C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e R f , -S(O) 2 NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR eC(O)NR e R f , -NR e S(O)R f , -NR e S(O) 2 R f , -NR e S(O)NR e R f , -NR e S(O) 2 NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O) 2 R e R f , -P(O)NR e R f , -P(O) 2 NR e R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 or R 2a 16. The compound according to any one of clauses 1-4, 6, 9, 10, or 12-15, or a pharma- ceutically acceptable salt thereof, wherein, if present, is H or methyl.

[0043] 17.R 2b If present, C 1 -C 4 Alkyl or C 3 -C 4 cycloalkyl, where C 1 -C 6 Alkyl and C 3 -C 4 Each hydrogen atom in a cycloalkyl is independently deuterium or halogen; or R 2bis a compound according to any one of the preceding clauses optionally substituted with methyl, ethyl, isopropyl, or cyclopropyl, or a pharma- ceutically acceptable salt thereof.

[0044] 18. A compound according to any one of the preceding clauses, wherein n is 3, or a pharma- ceutically acceptable salt thereof.

[0045] 19. A compound according to any one of clauses 1 to 17, or a pharma- ceutically acceptable salt thereof, wherein n is 4.

[0046] 20. A compound according to any one of clauses 1 to 17, or a pharma- ceutically acceptable salt thereof, wherein n is 5.

[0047] 21. A compound according to any one of clauses 1 to 17, or a pharma- ceutically acceptable salt thereof, wherein n is 6.

[0048] 22. Each L is independently -C(O)-, -O-, or -CH 2 -, -C(H)(CH 3 )-, -C(H)(OH)-, -C(H)(C(O)OR c )-, -C(H)(C(O)NR c R d )-, -NH-, and -NCH 3 -; or each L is independently selected from the group consisting of -C(O)-, -O-, -CH 2 -, -C(H)(CH 3 )-, -C(H)(OH)-, -C(H)(C(O)OR c )-, and -C(H)(C(O)NR c R d )-, or a pharma- ceutically acceptable salt thereof.

[0049] 23. A compound according to any one of clauses 1 or 13-22, or a pharma- ceutically acceptable salt thereof, wherein Y is O.

[0050] 24.Y 124. The compound according to any one of clauses 1 or 13-23, wherein is O, or a pharma- ceutically acceptable salt thereof.

[0051] 25.R 6 26. The compound according to any one of clauses 1 or 13-25, wherein, if present, is independently H, deuterium, fluoro, chloro, -CN, or methyl, or a pharma- ceutically acceptable salt thereof.

[0052] 26.R 7 is each independently H, deuterium, fluoro, chloro, -CN, or methyl, or a pharma- ceutically acceptable salt thereof.

[0053] 27.R 8 is H or methyl, or a pharma- ceutically acceptable salt thereof.

[0054] 28.R 9 is H or methyl, or a pharma- ceutically acceptable salt thereof.

[0055] 29.-(L) n -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, -(CH 2 ) 6 -, -C(O)NH-(CH 2 ) 2 O(CH 2 ) 2 -, -C(O)N(CH 3 )-(CH 2 ) 2 O(CH 2 ) 2 -, -NHC(O)CH 2 O(CH 2 ) 2 -, -N(CH3 )-C(O)CH 2 O(CH 2 ) 2 -、-CH 2 O(CH 2 ) 2 -、-CH 2 O(CH 2 ) 3 -、-CH 2 O(C(CH 3 )H) 2 -、-(CH 2 ) 2 O(CH 2 ) 2 -、-CH 2 OCH 2 (C(CH 3 )H)-、-(CH 2 ) 2 OCH 2 (C(CH 3 )H)-、-(CH 2 ) 2 S(CH 2 ) 2 -、-O(CH 2 ) 2 S(CH 2 ) 2 -、-(CH 2 ) 2 SO 2 (CH 2 ) 2 -、-O(CH 2 ) 2 SO 2 (CH 2 ) 2 -、-(CH 2 ) 2 SO(CH 2 ) 2 -、-O(CH 2 ) 2 SO(CH 2 ) 2 -、-(CH 2 ) 2 O(C(H)(C(O)N(H)(CH 3 ))-CH 2 -、-(CH 2 ) 2 O(C(H)(C(O)N(CH 3 ) 2 )-CH 2 -、-(CH2 ) 2 O(C(H)(C(O)OCH 3 )-CH 2 -、-(CH 2 ) 3 O(CH 2 ) 2 -、-(CH 2 ) 2 O(CH 2 ) 3 -、-CH 2 CH(CH 3 )-O(CH 2 ) 2 -、-CH(CH 3 )-CH 2 O(CH 2 ) 2 -、-O(CH 2 ) 2 -、-O-(CH 2 ) 3 -、-O-(CH 2 ) 4 -、-O-(CH 2 ) 2 CH(CH 3 )-、-OCH 2 O(CH 2 ) 2 -、-O-CH 2 CH(OH)CH 2 -、-O-(CH 2 ) 2 O(CH 2 ) 2 -、-O-CH 2 CH(CH 3 )-O(CH 2 ) 2 -、-O-CH(CH 3 )-CH 2 O(CH 2 ) 2 -、-O-(CH 2 ) 2 NH-(CH 2 ) 2 -、-O-CH 2 CH(CH 3 )-NH-(CH 2 ) 2 -、-O-CH(CH 3 )-CH 2 NH-(CH 2 )2 -、-CH 2 NH-(CH 2 ) 2 -、-(CH 2 ) 2 NH-(CH 2 ) 2 -、-CH 2 CH(CH 3 )-NH-(CH 2 ) 2 -、-CH(CH 3 )-CH 2 NH-(CH 2 ) 2 -、-O-(CH 2 ) 2 N(CH 3 )-(CH 2 ) 2 -、-O-CH 2 CH(CH 3 )-N(CH 3 )-(CH 2 ) 2 -、-O-CH(CH 3 )-CH 2 N(CH 3 )-(CH 2 ) 2 -、-CH 2 N(CH 3 )-(CH 2 ) 2 -、-CH 2 N(CH 2 CH 3 )-(CH 2 ) 2 -、-CH 2 N((CH 2 ) 2 CH 3 )-(CH 2 ) 2 -、-CH 2 N(CH(CH 3 ) 2 )-(CH 2 ) 2 -、-(CH 2 ) 2 N(CH 3 )-(CH 2 ) 2 -、-CH 2 CH(CH 3 )-N(CH 3)-(CH 2 ) 2 - or -O-CH(CH 3 )-CH 2 N(CH 3 )-(CH 2 ) 2 -; or -O(CH 2 ) 2 -, -O(CH 2 ) 3 -, -O(CH 2 ) 4 -, -CH 2 OCH 2 (C(CH 3 )H)-, -CH 2 O(CH 2 ) 2 -, or -CH 2 O(CH 2 ) 3 -; or -O(CH 2 ) 3 -, -CH 2 OCH 2 (C(CH 3 )H)- or -CH 2 O(CH 2 ) 2 -, or a pharma- ceutically acceptable salt thereof.

[0056] 30.[3a(4)Z]-6,9,15,16-tetramethyl-9,10,11,12-tetrahydro-15H-1,17-(ethanediylidene)pyrazolo[4,3-n]dipyrrolo[3,2-g:3',4'-j][1,5]oxazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-6,9,15,16-tetramethyl-10,11,13,15-tetrahydro-2H-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione; [3a(4)Z,10R]-20-chloro-6,10,15-trimethyl-10,11,13,15-tetrahydro-2H-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-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'-i][1,4]oxazacyclopentadecyne-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-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione; [3a(4)Z,10S]-20-chloro-6,9,10,15-tetramethyl-10,11,13,15-tetrahydro-2H-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione; [3a(4)Z]-20-chloro-6,9,15-trimethyl-10,11,13,15-tetrahydro-2H-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-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-i][1,4]oxazacyclopentadecyne-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-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione; [3a(4)Z,10R]-6,9,10,15-tetramethyl-3,8-dioxo-3,5,8,9,10,11,13,15-octahydro-2H-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-20-carbonitrile; [3a(4)Z,10R]-20-fluoro-6,9,10,15,16-pentamethyl-10,11,13,15-tetrahydro-2H-1,17-ethenopyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-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]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione; and [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'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione; 2. The compound according to clause 1, selected from the group consisting of:

[0057] 31. A pharmaceutical composition comprising at least one compound according to any one of clauses 1 to 30, or a pharma- ceutically acceptable salt thereof, and optionally one or more pharma- ceutically acceptable excipients.

[0058] 32. A method for treating a disease, such as an autoimmune disease, comprising administering to a subject in need of treatment an effective amount of at least one compound according to any one of clauses 1 to 30, or a pharma- ceutically acceptable salt thereof.

[0059] 33. A compound according to any one of clauses 1 to 30, or a pharma- ceutically acceptable salt thereof, for use in a method for treating an autoimmune disease in a subject.

[0060] 34. A compound according to any one of clauses 1 to 30, or a pharma- ceutically acceptable salt thereof, for treating an autoimmune disease in a subject.

[0061] 35. Use of a compound according to any one of clauses 1 to 30, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating an autoimmune disease in a subject.

[0062] Detailed Description Before the present disclosure is further described, it is to be understood that this disclosure is not limited to particular embodiments described, which 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.

[0063] For the sake of brevity, the disclosures of the publications cited herein, including patents, are incorporated herein by reference.Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs.All patents, applications, published applications and other publications referenced herein are incorporated herein by reference in their entirety.If the definitions set forth in this section conflict or are inconsistent with the definitions set forth in the patents, applications or other publications incorporated herein by reference, the definitions set forth in this section shall take precedence over the definitions incorporated herein by reference.

[0064] 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 element. Accordingly, this statement is intended as a precondition for using exclusive terminology, such as "solely," "only," and the like, or for using "negative" limitations in connection with the recitation of claim elements.

[0065] As used herein, the terms "comprise", "include", and "including" are used in an open, non-limiting sense.

[0066] In order to provide a more concise description, some of the quantitative expressions shown herein are not accompanied by the term "about". It is understood that all amounts shown herein, whether or not the term "about" is explicitly used, are intended to indicate the actual given value, and also to indicate the approximation of the given value that is reasonably estimated based on ordinary skill in the art, including the equivalent and approximation of the given value by experimental and / or measurement conditions. When a yield is shown as a percentage, such a yield indicates the mass of the material for which the yield is shown, relative to the maximum amount of the same material that can be obtained under specific stoichiometric conditions. Concentrations shown as percentages indicate mass ratios, unless otherwise indicated.

[0067] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by ordinary skilled artisans in the field to which this disclosure belongs.Methods and materials similar or equivalent to those described herein can also be used to carry out or test this disclosure, but preferred methods and materials are described herein.All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials for which they are cited.

[0068] Unless otherwise indicated, the methods and techniques of the present embodiments are generally carried out according to conventional methods well known in the art and described in various general and more specific references cited and described throughout this specification. See, for example, 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.

[0069] The chemical nomenclature of the compounds described herein is generally derived using the commercially available ACD / Name 2020 (ACD / Labs) or ChemBioDraw Ultra 20.0 (Perkin Elmer).

[0070] For clarity, it will be understood that certain features of the present disclosure that are described in the context of separate embodiments can also be provided in combination in a single embodiment. Conversely, for brevity, various features of the present disclosure that are described in the context of a single embodiment can also be provided separately or in any suitable subcombination. All combinations of the embodiments with respect to chemical groups represented by variables, to the extent that such combinations include compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity), are specifically embraced by the present disclosure and are disclosed herein as if each and every combination were individually and expressly disclosed. Furthermore, all subcombinations of chemical groups listed in the embodiments describing such variables are also specifically embraced by the present disclosure and are disclosed herein as if each such subcombination of chemical groups were individually and expressly disclosed herein.

[0071] chemical definition The term "alkyl" refers to a straight or branched chain monovalent hydrocarbon group. The term "alkylene" refers to a straight or branched chain divalent hydrocarbon group. In some embodiments, the number of atoms in an "alkyl" or "alkylene" is defined as C. 1 -C 20 Alkyl or C 1 -C 20 Alkylene, C 1 -C 12 Alkyl or C 1 -C 12 Alkylene, or C 1 -C 6 Alkyl or C 1 -C 6 It may be advantageous to restrict the range of atoms to a particular range, such as alkylene. Examples of alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that would be considered equivalent to any of the foregoing examples in light of the common knowledge of one of ordinary skill in the art and the teachings provided herein. Examples of alkylene groups include methylene (-CH 2 -), ethylene ((-CH 2 -) 2 ), n-propylene ((-CH 2 -) 3 ), iso-propylene ((-C(H)(CH 3 )CH 2 -)), n-butylene ((-CH 2 -) 4 ) and the like. It will be understood that the alkyl or alkylene group can be unsubstituted or substituted as described herein. The alkyl or alkylene group can be substituted with any of the substituents in the various embodiments described herein, for example, with one or more of such substituents.

[0072] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon group having one or more double bonds. The term "alkenylene" refers to a linear or branched divalent hydrocarbon group having one or more double bonds. In some embodiments, the number of atoms in the "alkenyl" or "alkenylene" is C. 2 -C 20 Alkenyl or C 2 -C 20 Alkenylene, C 2 -C 12 Alkenyl or C 2 -C 12 Alkenylene, or C 2 -C 6 Alkenyl or C 2 -C 6 It may be advantageous to restrict the group to a particular range of atoms, such as alkenylene. Examples of alkenyl groups include ethenyl (or vinyl), allyl, and but-3-en-1-yl. Examples of alkenylene groups include ethenylene (or vinylene) (-CH=CH-), n-propenylene (-CH=CHCH 2 -), isopropenylene (-CH=CH(CH 3 )-). It will be understood that the alkenyl or alkenylene group can be unsubstituted or substituted as described herein. The alkenyl or alkenylene group can be substituted with any of the substituents in the various embodiments described herein, for example, with one or more of such substituents.

[0073] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon group having one or more triple bonds. The term "alkynylene" refers to a linear or branched divalent hydrocarbon group having one or more triple bonds. In some embodiments, the number of atoms in the "alkynyl" or "alkynylene" can be any combination of C, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C32, C43, C54, C65, C76, C87, C98, C12, C14, C25, C36, C48, C54, C66, C77, C88, C99, C12, C13, C22, C36, C48, C54, C67, C78, ​​C79, C89, C99, C14, C15, C22, C36, C48, C54, C67, C79, C89, C99, C15, C16, C21 ...17, C18, C21, C36, C48, C54, C67, C79, C19, C22, C36, C48, C54, C67, C79, C89, C99, C15, C16, C21, C36, C48, C54, C67, C79, C18, C21, C36, C48, C54, C67, C79, C19, C2 2 -C 20 Alkynyl or C 2 -C 20 Alkynylene, C 2 -C 12 Alkynyl or C 2 -C 12 Alkynylene, or C2 -C 6 Alkynyl or C 2 -C 6 It may be advantageous to restrict the group to a particular range of atoms, such as alkynylene. Examples of alkynyl groups include: TIFF2025503592000053.tif14159 and the like. It will be understood that the alkynyl or alkynylene group can be unsubstituted or substituted as described herein. The alkynyl or alkynylene group can be substituted with any of the substituents in the various embodiments described herein, for example, with one or more of such substituents.

[0074] The term "cycloalkyl" refers to a saturated or partially saturated, monocyclic or polycyclic monovalent carbocyclic ring. The term "cycloalkylene" refers to a saturated or partially saturated, monocyclic or polycyclic divalent carbocyclic ring. In some embodiments, it may be advantageous to limit the number of atoms in a "cycloalkyl" or "cycloalkylene" to a particular range of atoms, such as 3 to 12 ring atoms. Polycyclic carbocyclic rings include fused polycyclic, bridged polycyclic, and spiropolycyclic systems. Specific examples of cycloalkyl groups include, when appropriately bonded moieties, monovalent radicals of the following substances, while cycloalkylene groups include, when appropriately bonded moieties, divalent radicals of the following substances: [ka]

[0075] In particular, the cyclopropyl moiety has the structural formula: [ka] In particular, the cyclopropylene moiety can be represented by the structural formula: [ka] It will be understood that the cycloalkyl or cycloalkylene group can be unsubstituted or substituted as described herein. The cycloalkyl or cycloalkylene group can be substituted with any of the substituents in the various embodiments described herein, for example, with one or more of such substituents.

[0076] The term "halogen" or "halo" refers to chlorine, fluorine, bromine, or iodine.

[0077] The term "haloalkyl" refers to an alkyl group having one or more halo substituents. Exemplary haloalkyl groups include -CF 3 , -(CH 2 )F, -CHF 2 , -CH 2 Br, -CH 2 CF 3 , and -CH 2 CH 2 The term "haloalkylene" refers to an alkylene group having one or more halo substituents. Exemplary haloalkylene groups include -CF 2 -, -C(H)(F)-, -C(H)(Br)-, -CH 2 CF 2 - and -CH 2 C(H)(F)-.

[0078] The term "aryl" refers to a monovalent all-carbon monocyclic or fused-ring polycyclic group having a fully conjugated pi-electron system. The term "arylene" refers to a divalent all-carbon monocyclic or fused-ring polycyclic group having a fully conjugated pi-electron system. In some embodiments, the number of atoms in an "aryl" or "arylene" is from 6 to 14 carbon atoms in a monovalent all-carbon monocyclic or fused-ring polycyclic group (C 6 -C 14 aryl), monovalent all-carbon monocyclic or fused-ring polycyclic radicals of 6 to 10 carbon atoms (C 6 -C 10 aryl), a divalent all-carbon monocyclic or fused-ring polycyclic group of 6 to 14 carbon atoms (C 6 -C 14arylene), a divalent all-carbon monocyclic or fused-ring polycyclic group of 6 to 10 carbon atoms (C 6 -C 10 It may be advantageous to restrict the aryl group to a particular range of atoms, such as aryl, aryl, arylene, aryl ...

[0079] The term "heterocycloalkyl" refers to a monovalent, saturated or partially saturated monocyclic or polycyclic ring structure having one or more non-carbon ring atoms. The term "heterocycloalkylene" refers to a divalent, saturated or partially saturated monocyclic or polycyclic ring structure having one or more non-carbon ring atoms. In some embodiments, it may be advantageous to restrict the number of atoms in a "heterocycloalkyl" or "heterocycloalkylene" to a particular range of ring atoms, such as 3-12 ring atoms (3-12 membered ring), 3-7 ring atoms (3-7 membered ring), 3-6 ring atoms (3-6 membered ring), 4-8 ring atoms (4-8 membered ring), or 5-7 ring atoms (5-7 membered ring). In some embodiments, it may be advantageous to restrict the number and type of ring heteroatoms in a "heterocycloalkyl" or "heterocycloalkylene" to a particular range or type of heteroatoms, such as 1-5 ring heteroatoms selected from nitrogen, oxygen, and sulfur. Polycyclic ring systems include fused, bridged, and spiro ring systems. The ring structure can optionally contain one oxo group on a carbon ring member or up to two oxo groups on a sulfur ring member. Specific examples of heterocycloalkyl groups include, when appropriately bonded, monovalent radicals of the following substances, while heterocycloalkylene groups include, when appropriately bonded, divalent radicals of the following substances: [ka]

[0080] A 3-membered heterocycle can contain at least one heteroatom ring atom, where the heteroatom ring atom is sulfur, oxygen, or nitrogen. Non-limiting examples of 3-membered heterocycle groups include the monovalent and divalent radicals of oxirane, azetidine, and thiirane. A 4-membered heterocycle can contain at least one heteroatom ring atom, where the heteroatom ring atom is sulfur, oxygen, or nitrogen. Non-limiting examples of 4-membered heterocycle groups include the monovalent and divalent radicals of azitidine, octenane, and thietane. A 5-membered heterocycle can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and 0, 1, 2, or 3 ring atoms are nitrogen, or (b) 0 ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of 5-membered heterocyclic groups include monovalent and divalent radicals of pyrrolidine, tetrahydrofuran, 2,5-dihydro-1H-pyrrole, pyrazolidine, thiazolidine, 4,5-dihydro-1H-imidazole, dihydrothiophen-2(3H)-one, tetrahydrothiophene 1,1-dioxide, imidazolidin-2-one, pyrrolidin-2-one, dihydrofuran-2(3H)-one, 1,3-dioxolan-2-one, and oxazolidin-2-one. A 6-membered heterocycle can contain up to 4 heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and 0, 1, 2, or 3 ring atoms are nitrogen, or (b) 0 ring atoms are oxygen or sulfur and up to 4 ring atoms are nitrogen. Non-limiting examples of 6-membered heterocyclic groups include monovalent or divalent radicals of piperidine, morpholine, 4H-1,4-thiazine, 1,2,3,4-tetrahydropyridine, piperazine, 1,3-oxazinan-2-one, piperazin-2-one, thiomorpholine, and thiomorpholine 1,1-dioxide. "Heterobicyclic" is a fused bicyclic ring system containing one heterocycle fused to a cycloalkyl or another heterocycle.

[0081] It will be understood that the heterocycloalkyl or heterocycloalkylene group can be unsubstituted or substituted as described herein. The heterocycloalkyl or heterocycloalkylene group can be substituted with any of the substituents in the various embodiments described herein, for example, with one or more of such substituents.

[0082] The term "heteroaryl" refers to a monovalent monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (a ring structure having carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) that is fully unsaturated and has 3-12 ring atoms per heterocycle. The term "heteroarylene" refers to a divalent monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (a ring structure having carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) that has 3-12 ring atoms per heterocycle. In some embodiments, it may be advantageous to limit the number of atoms in a "heteroaryl" or "heteroarylene" to a particular range of atoms, such as a 5-10 membered heteroaryl or a 5-10 membered heteroarylene. In some cases, the 5-10 membered heteroaryl is a monocyclic or fused bicyclic ring having 5-10 ring atoms, where at least one ring atom is a heteroatom, such as N, O, or S. In some cases, the 5-10 membered heteroarylene is a monocyclic or fused bicyclic ring having 5-10 ring atoms, where at least one ring atom is a heteroatom, such as N, O, or S. Specific examples of 5-10 membered heteroaryl groups include, when appropriately bonded moieties, monovalent radicals of the following substances, while 5-10 membered heteroarylene groups include, when appropriately bonded moieties, divalent radicals of the following substances: [ka]

[0083] In some embodiments, a "monocyclic" heteroaryl is an aromatic 5- or 6-membered heterocycle. A 5-membered heteroaryl or heteroarylene can contain up to 4 heteroatom ring atoms, where (a) at least 1 ring atom is oxygen and sulfur and 0, 1, 2, or 3 ring atoms are nitrogen, or (b) 0 ring atoms are oxygen or sulfur and up to 4 ring atoms are nitrogen. Non-limiting examples of 5-membered heteroaryl groups include monovalent radicals of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole. Non-limiting examples of 5-membered heteroarylene groups include divalent radicals of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole. A 6-membered heteroaryl or heteroarylene can contain up to 4 heteroatom ring atoms, where (a) at least 1 ring atom is oxygen and sulfur and 0, 1, 2, or 3 ring atoms are nitrogen, or (b) 0 ring atoms are oxygen or sulfur and up to 4 ring atoms are nitrogen. Non-limiting examples of 6-membered heteroaryl groups include monovalent radicals of pyridine, pyrazine, pyrimidine, pyridazine, or triazine. Non-limiting examples of 6-membered heteroarylene groups include divalent radicals of pyridine, pyrazine, pyrimidine, pyridazine, or triazine. A "bicyclic heteroaryl" or "bicyclic heteroarylene" is a fused bicyclic ring system containing 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-b]thiophene, 1H-pyrrolo[2,3-b]pyridine, 1H-benzo[d]imidazole, benzo[d]oxazole, and benzo[d]thiazole.Non-limiting examples of bicyclic heteroarylene groups include divalent radicals of quinoline, isoquinoline, quinazoline, quinoxaline, indole, 1,5-naphthyridine, 1,8-naphthyridine, isoquinolin-3(2H)-one, thieno[3,2-b]thiophene, 1H-pyrrolo[2,3-b]pyridine, 1H-benzo[d]imidazole, benzo[d]oxazole, and benzo[d]thiazole.

[0084] In particular, the pyrrolyl moiety has the structural formula: [ka] In particular, the pyrrolylene moiety can be represented by the structural formula: [ka] In particular, the pyrazolyl moiety can be represented by the structural formula: [ka] In particular, the pyrazolylene moiety can be represented by the structural formula: [ka] It can be expressed as:

[0085] It will be understood that the heteroaryl or heteroarylene group can be unsubstituted or substituted as described herein. The heteroaryl or heteroarylene group can be substituted with any of the substituents in the various embodiments described herein, for example, with one or more of such substituents.

[0086] The term "oxo" refers to a carbonyl oxygen. For example, cyclopentyl substituted with oxo is cyclopentanone.

[0087] Certain chemicals of formulas (I)-(XII) may be represented as two or more tautomers. All alternative tautomers are included within the scope of these formulas, and no inference should be made as to whether a chemical exists as the tautomer in which it is represented. It will be understood that chemicals described herein, and their constituent rings A, B, etc., can exist in different tautomeric forms. One of ordinary skill in the art will readily appreciate that tautomers can generally be considered the same compound due to rapid interconversion. Examples of tautomers include, but are not limited to, enol-keto tautomers, amine-imine tautomers, and the like. [ka]

[0088] In particular, the ring options of indolin-2-ones include the following tautomers: [ka] It can exist as.

[0089] The term "substituted" means that a particular group or moiety has one or more substituents. The term "unsubstituted" means that a particular group has no substituents. When the term "substituted" is used to describe a structural system, it means that the substitution occurs at any valence-allowed position on the system. In some embodiments, "substituted" means that a particular group or moiety has one, two, or three substituents. In other embodiments, it means that a particular group or moiety has one or two substituents. In yet other embodiments, it means that a particular group or moiety has one substituent.

[0090] Any formula shown herein is intended to represent a compound of that structural formula, as well as specific variations or forms. For example, any formula shown herein is intended to include a racemate, or one or more enantiomers, diastereomers, or geometric isomers, or mixtures thereof. Additionally, any formula shown herein is intended to represent a hydrate, solvate, or polymorph of such a compound, or mixtures thereof.

[0091] Any formula described herein is intended to represent unlabeled and isotopically labeled forms of the compound.Isotopically labeled compounds have the structure shown in the formula described herein, except that one or more atoms are replaced with an atom having a selected atomic mass or mass number.Examples of isotopes that can be incorporated into the compounds of the present disclosure include, respectively: 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, and 125 I, I, and other isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine. Such isotopically labeled compounds are useful in metabolic studies ( 14 C is preferably used), reaction kinetic studies (e.g., 2 H or 3 H), detection or imaging techniques including drug or substrate tissue distribution assays [positron emission tomography (PET) or single photon emission computed tomography (SPECT)], or radiation treatment of patients. 2Substitution with heavier isotopes such as H) may confer certain therapeutic advantages, such as increased metabolic stability, increased half-life in the body, and reduced dosage requirements. Isotopically labeled compounds of the present disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or examples and preparation methods set forth below, using readily available isotopically labeled reagents in place of non-isotopically labeled reagents.

[0092] The term "(ATOM) i-j " (j>i), as applied to a class of substituents herein, is intended to indicate an embodiment of the disclosure in which each of the atomic members i through j, inclusive, is independently realized. As an example, the term C 1-3 independently denotes an embodiment having one carbon member (C1), an embodiment having two carbon members (C2), and an embodiment having three carbon members (C3).

[0093] Any disubstituent referred to herein is intended to encompass the various attachment possibilities where multiple attachment possibilities are recognized. For example, reference to a disubstituent -AB-, where A≠B, is used herein to refer to such a disubstituent where A is attached to a first substitution member and B is attached to a second substitution member, and also to such a disubstituent where A is attached to the second substitution member and B is attached to the first substitution member. For example, in certain embodiments, the formula -CH, linking two groups A and B, where applicable, is used. 2 OCH 2 (C(CH 3 )H)-having compound portion-(L) n -, -CH 2 OCH 2 (C(CH 3 )H)- is embodiment A-CH 2 OCH 2 (C(CH 3 )H)-B and B-CH 2 OCH 2 (C(CH 3)H)-A. More specifically, in this case, 2 OCH 2 (C(CH 3 )H)-compound portion-(L) n - and the linking groups -B- and -NR 9 The compounds of formulae (I) to (XII) having the formula 2 OCH 2 (C(CH 3 )H)-NR 9 and -NR 9 -CH 2 OCH 2 (C(CH 3 )H)-B.

[0094] The present disclosure also includes pharma- ceutically acceptable salts of the compounds represented by formulas (I)-(XII), preferably the compounds described above and the specific compounds exemplified herein, and pharmaceutical compositions containing such salts, as well as methods of using such salts.

[0095] "Pharmaceutically acceptable salt" is intended to mean a free acid or base salt of a compound described herein that is non-toxic, biologically acceptable, or biologically suitable for administration to a subject. See generally SM 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 a subject without undue toxicity, irritation, or allergic reaction. The compounds described herein have sufficiently acidic groups, sufficiently basic groups, both types of functional groups, or one or more of each type of functional group, and thus react with a number of inorganic or organic bases, and inorganic and organic acids to form pharmaceutically acceptable salts.

[0096] Examples of pharma- ceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1, Examples of suitable pharma- ceutically acceptable salts include 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, besylate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, and mandelate. A list of other suitable pharma-ceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985.

[0097] For compounds of formula (I)-(XII) containing a basic nitrogen, pharma- ceutically acceptable salts can be prepared by any suitable method available in the art, for example by reacting the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, or with a pyranosidyl 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, glucuronic acid, or galacturonic acid. The polysaccharides may be prepared by treatment with an organic acid such as 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 a mixture of compatible acids, as exemplified herein, and other acids and mixtures thereof which are deemed equivalent or acceptable substitutes in light of the skill or ordinary level of this art.

[0098] The present disclosure also relates to pharma- ceutically acceptable prodrugs of compounds of formulae (I)-(XII) and methods of treatment using such pharma- ceutically acceptable prodrugs. The term "prodrug" refers to a precursor of a specified compound that, after administration to a subject, generates the compound in the body via a chemical or physiological process, such as solvation or enzymatic degradation, or under physiological conditions (e.g., a prodrug adjusted to physiological pH is converted to a compound of formula (I)-(XII)). A "pharma- ceutically acceptable prodrug" is a prodrug that is non-toxic, biologically acceptable, and biologically suitable for administration to a subject. Illustrative procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

[0099] The present disclosure also relates to pharmacologically active metabolites of the compounds of formula (I)-(XII) and the use of such metabolites in the methods of the present disclosure. "Pharmacologically active metabolite" means a pharmacologically active product resulting from metabolism in the body of a compound of formula (I)-(XII) or a salt thereof. Prodrugs and active metabolites of a compound can be determined using routine techniques known or available in the art. For example, 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).

[0100] The term "protecting group" or "PG" as used herein refers to any group commonly known to those skilled 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 understood that such protecting groups can be removed from the functional group at a later point in the synthesis to provide further opportunities for reaction at such functional group or to expose such functional group in the case of the final product. Protecting groups are described, for example, in Wuts, PGM, Greene, TW, Greene, TW, & John Wiley & Sons. (2006). Greene's protective groups in organic synthesis. Hoboken, NJ: Wiley-Interscience. Those skilled in the art will readily understand the chemical process conditions under which such protecting groups can be introduced into functional groups. Suitable amine protecting groups useful in the context of the present disclosure include, but are not limited to, 9-fluorenylmethylcarbonyl (FMOC), t-butylcarbonyl (Boc), benzyloxycarbonyl (Cbz), acetyl (Ac), trifluoroacetyl, phthalimide, benzyl (Bn), triphenylmethyl (trityl, Tr), benzylidene, and p-toluenesulfonyl (tosylamide, Ts). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0101] Representative Embodiments In some embodiments, the disclosure provides a compound of formula I, or a pharma- ceutically acceptable salt thereof. [ka] I [In the formula, A, B, L, R 6 , R 7 , R 8 , R 9 , Y, Y 1 and n is as defined herein.

[0102] In some embodiments, the disclosure provides a compound of formula II, or a pharma- ceutically acceptable salt thereof. [ka] II [In the formula, A, B, L, R 7 , R 8 , R 9 and n is as defined herein.

[0103] In some embodiments, the disclosure provides a compound of formula III, or a pharma- ceutically acceptable salt thereof. [ka] III [In the formula, B, L, R 1 , R 1a , R 7 , R 8 , R 9 and n is as defined herein.

[0104] In some embodiments, the disclosure provides a compound of formula IV, or a pharma- ceutically acceptable salt thereof. [ka] IV [In the formula, B, L, R 1a , R 7 , R 8 , R 9 and n is as defined herein.

[0105] In some embodiments, the disclosure provides a compound of formula V, or a pharma- ceutically acceptable salt thereof. [ka] V [In the formula, A, L, R 2 , R 2b , R 7 , R 8 , R 9and n is as defined herein.

[0106] In some embodiments, the disclosure provides a compound of formula VI, or a pharma- ceutically acceptable salt thereof. [ka] VI [In the formula, A, L, R 2a , R 2b , R 7 , R 8 , R 9 and n is as defined herein.

[0107] In some embodiments, the disclosure provides a compound of formula VII, or a pharma- ceutically acceptable salt thereof. [ka] VII [In the formula, L, R 1 , R 1a , R 2 , R 2b , R 7 , R 8 , R 9 and n is as defined herein.

[0108] In some embodiments, the disclosure provides a compound of formula VIII, or a pharma- ceutically acceptable salt thereof. [ka] VIII [In the formula, L, R 1 , R 2 , R 2b , R 7 , R 8 , R 9 and n is as defined herein.

[0109] In some embodiments, the disclosure provides a compound of formula IX, or a pharma- ceutically acceptable salt thereof. [ka] IX [In the formula, L, R 1 , R 1a , R 2a , R 2b , R 7 , R 8 , R 9 and n is as defined herein.

[0110] In some embodiments, the disclosure provides a compound of formula X, or a pharma- ceutically acceptable salt thereof. [ka] X [In the formula, L, R 1 , R 2a , R 2b , R 7 , R 8 , R 9 and n is as defined herein.

[0111] In some embodiments, the disclosure provides a compound of formula XI, or a pharma- ceutically acceptable salt thereof. [ka] XI [In the formula, L, R 1 , R 1a , R 2 , R 2b , R 7 and n is as defined herein.

[0112] In some embodiments, the disclosure provides a compound of formula XII, or a pharma- ceutically acceptable salt thereof. [ka] XII [In the formula, L, R 1 , R 1a , R 2a , R 2b , R 7and n is as defined herein.

[0113] In some embodiments, ring A is [ka] It is.

[0114] In some embodiments, ring B is [ka] It is.

[0115] In some embodiments, ring B is [ka] and R 7 is H. In some embodiments, ring A is [ka] and ring B is [ka] and R 7 is H. In some embodiments, ring B is [ka] and R 7 is not H. In some embodiments, ring A is [ka] and ring B is [ka] and R 7 is not H. In some embodiments, ring B is [ka] and R7 is -Cl or -CN. In some embodiments, Ring A is [ka] and ring B is [ka] and R 7 is -Cl or -CN. In some embodiments, Ring B is [ka] and R 7 In some embodiments, ring A is [ka] and ring B is [ka] and R 7 In some embodiments, Ring B is [ka] and R 7 In some embodiments, ring A is [ka] and ring B is [ka] and R 7 is -CN.

[0116] In some embodiments, R 1 are independently H, deuterium, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -OS(O)NR a R b , -OS(O) 2 NR a R b , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR a R b , -NR a S(O)R b , -NR a S(O) 2 R b , -NR a S(O)NR a R b , -NR a S(O) 2 NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -PR a R b , -P(O)R a R b , -P(O) 2 R a Rb , -P(O)NR a R b , -P(O) 2 NR a R b , -P(O)OR a , -P(O) 2 OR a , -CN, or -NO 2 where C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 Each hydrogen atom in an aryl or 5-10 membered heteroaryl is independently selected from deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e R f , -S(O) 2 NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f, -NR e S(O)R f , -NR e S(O) 2 R f , -NR e S(O)NR e R f , -NR e S(O) 2 NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O) 2 R e R f , -P(O)NR e R f , -P(O) 2 NR e R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 is optionally replaced by

[0117] In some embodiments, R 1 is H, -CN or C 1 -C 6 alkyl, where C 1 -C 6 Each hydrogen atom in an alkyl group can be independently deuterium, halogen, or C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -OS(O) 2 NR e Rf , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e R f , -S(O) 2 NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O) 2 R f , -NR e S(O)NR e R f , -NR e S(O) 2 NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O) 2 R e R f , -P(O)NR e R f , -P(O) 2 NR e R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 In some embodiments, R 1 is H, -CN, or methyl.

[0118] In some embodiments, R 1a H, deuterium, halogen, C1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -OS(O)NR a R b , -OS(O) 2 NR a R b , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR a R b , -NR a S(O)R b , -NR a S(O) 2 R b , -NR a S(O)NR a R b , -NR a S(O) 2 NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -PRa R b , -P(O)R a R b , -P(O) 2 R a R b , -P(O)NR a R b , -P(O) 2 NR a R b , -P(O)OR a , -P(O) 2 OR a , -CN, or -NO 2 where C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 Each hydrogen atom in an aryl or 5-10 membered heteroaryl is independently selected from deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e R f , -S(O) 2 NR e R f , -NR e R f , -NR e C(O)Rf , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O) 2 R f , -NR e S(O)NR e R f , -NR e S(O) 2 NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O) 2 R e R f , -P(O)NR e R f , -P(O) 2 NR e R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 is optionally replaced by

[0119] In some embodiments, R 1a is H, -CN or C 1 -C 6 alkyl, where C 1 -C 6 Each hydrogen atom in an alkyl group can be independently deuterium, halogen, or C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O)2 R e , -OS(O)NR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e R f , -S(O) 2 NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O) 2 R f , -NR e S(O)NR e R f , -NR e S(O) 2 NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O) 2 R e R f , -P(O)NR e R f , -P(O) 2 NR e R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 In some embodiments, R 1aWhen present, it is H, —CN, or methyl.

[0120] In some embodiments, R 2 H, deuterium, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -OS(O)NR a R b , -OS(O) 2 NR a R b , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR a R b , -NR a S(O)R b , -NR a S(O) 2 R b , -NR a S(O)NR a R b , -NR a S(O) 2 NR a Rb , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -PR a R b , -P(O)R a R b , -P(O) 2 R a R b , -P(O)NR a R b , -P(O) 2 NR a R b , -P(O)OR a , -P(O) 2 OR a , -CN, or -NO 2 where C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 Each hydrogen atom in an aryl or 5-10 membered heteroaryl is independently selected from deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e R f , -S(O)2 NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O) 2 R f , -NR e S(O)NR e R f , -NR e S(O) 2 NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O) 2 R e R f , -P(O)NR e R f , -P(O) 2 NR e R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 is optionally replaced by

[0121] In some embodiments, R 2 are independently H, deuterium, and C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6-C 10 aryl, or 5-10 membered heteroaryl, where C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 Each hydrogen atom in an aryl or 5-10 membered heteroaryl is independently selected from deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e R f , -S(O) 2 NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O) 2 R f , -NR e S(O)NR e R f , -NRe S(O) 2 NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O) 2 R e R f , -P(O)NR e R f , -P(O) 2 NR e R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 is optionally replaced by

[0122] In some embodiments, R 2 is H, -CN, or C 1 -C 6 alkyl, where C 1 -C 6 Each hydrogen atom in an alkyl group can be independently deuterium, halogen, or C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e R f , -S(O) 2 NRe R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O) 2 R f , -NR e S(O)NR e R f , -NR e S(O) 2 NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O) 2 R e R f , -P(O)NR e R f , -P(O) 2 NR e R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 In some embodiments, R 2 is H, -CN, or methyl.

[0123] In some embodiments, R 2a is H, deuterium, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 aryl, or 5-10 membered heteroaryl, where C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 Each hydrogen atom in an aryl or 5-10 membered heteroaryl is independently selected from deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e R f , -S(O) 2 NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O) 2 R f , -NR eS(O)NR e R f , -NR e S(O) 2 NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O) 2 R e R f , -P(O)NR e R f , -P(O) 2 NR e R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 is optionally replaced by

[0124] In some embodiments, R 2a is H or C 1 -C 6 alkyl, where C 1 -C 6 Each hydrogen atom in an alkyl group can be independently deuterium, halogen, or C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e Rf , -S(O) 2 NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O) 2 R f , -NR e S(O)NR e R f , -NR e S(O) 2 NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O) 2 R e R f , -P(O)NR e R f , -P(O) 2 NR e R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 In some embodiments, R 2a is H or methyl.

[0125] In some embodiments, R 2b is C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 3 -C4 cycloalkyl, or 3-4 membered heterocycloalkyl, where C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 3 -C 4 Each hydrogen atom in a cycloalkyl and a 3- to 4-membered heterocycloalkyl is independently selected from deuterium, halogen, -O(H or C 1 -C 2 alkyl), -OC(O)C 1 -C 2 Alkyl, -OC(O)N(H or C 1 -C 2 Alkyl) 2 , -OS(O)C 1 -C 2 Alkyl, -OS(O) 2 C 1 -C 2 Alkyl, -OS(O)N(H or C 1 -C 2 Alkyl) 2 , -OS(O) 2 N(H or C 1 -C 2 Alkyl) 2 , -S(H or C 1 -C 2 alkyl), -S(O)C 1 -C 2 Alkyl, -S(O) 2 C 1 -C 2 Alkyl, -S(O)N(H or C 1 -C 2 Alkyl) 2 , -S(O) 2 N(H or C 1 -C 2 Alkyl) 2 , -N(H or C 1 -C 2 Alkyl) 2 , -N(H or C 1 -C 2 Alkyl)C(O)C 1 -C 2 Alkyl, -N(H or C1 -C 2 alkyl)C(O)O(H or C 1 -C 2 alkyl), -N(H or C 1 -C 2 Alkyl)C(O)N(H or C 1 -C 2 Alkyl) 2 , -N(H or C 1 -C 2 Alkyl)S(O)C 1 -C 2 Alkyl, -N(H or C 1 -C 2 Alkyl)S(O) 2 C 1 -C 2 Alkyl, -N(H or C 1 -C 2 Alkyl)S(O)N(H or C 1 -C 2 Alkyl) 2 , -N(H or C 1 -C 2 Alkyl)S(O) 2 N(H or C 1 -C 2 Alkyl) 2 , -C(O)C 1 -C 2 Alkyl, -C(O)O(H or C 1 -C 2 alkyl), -C(O)N(H or C 1 -C 2 Alkyl) 2 , -P(H or C 1 -C 2 Alkyl) 2 , -P(O)(H or C 1 -C 2 Alkyl) 2 , -P(O) 2 (H or C 1 -C 2 Alkyl) 2 , -P(O)N(H or C 1 -C 2 Alkyl) 2 , -P(O) 2 N(H or C 1 -C 2Alkyl) 2 , -P(O)O(H or C 1 -C 2 alkyl), -P(O) 2 O(H or C 1 -C 2 alkyl), -CN, or -NO 2 is optionally replaced by

[0126] In some embodiments, R 2b is C 1 -C 4 Alkyl or C 3 -C 4 cycloalkyl, where C 1 -C 6 Alkyl and C 3 -C 4 Each hydrogen atom in the cycloalkyl is independently optionally replaced with deuterium or halogen. 2b is methyl, ethyl, isopropyl, or cyclopropyl.

[0127] In some embodiments, each L is independently -C(R 3 )(R 4 )-, -C(O)-, -O-, -N(R 5 )-, -S-, -S(O)- or -S(O) 2 -where: (L) n -OO-, -OS-, a -SS-, or -ON(R 5 In some embodiments, each L is independently -C(R 3 )(R 4 )-, -C(O)-, -O-, -S-, -S(O)- or -S(O) 2 -where: (L) n does not contain an -OO-, -SS-, or -OS- bond. In some embodiments, L is -N(R 5 )- not included.

[0128] In some embodiments, R 3 , and R 4 are independently H, deuterium, halogen, C1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, -OR c , -OC(O)R c , -OC(O)NR c R d , -OC(=N)NR c R d , -OS(O)R c , -OS(O) 2 R c , -OS(O)NR c R d , -OS(O) 2 NR c R d , -SR c , -S(O)R c , -S(O) 2 R c , -S(O)NR c R d , -S(O) 2 NR c R d , -NR c R d , -NR c C(O)R d , -N(C(O)R c )(C(O)R d ), -NR c C(O)OR d , -NR c C(O)NR c R d , -NR c C(=N)NR c R d , -NR c S(O)R d , -NR c S(O) 2 R d , -NR c S(O)NR c R d , -NR cS(O) 2 NR c R d , -C(O)R c , -C(O)OR c , -C(O)NR c R d , -C(=N)NR c R d , -PR c R d , -P(O)R c R d , -P(O) 2 R c R d , -P(O)NR c R d , -P(O) 2 NR c R d , -P(O)OR c , -P(O) 2 OR c , -CN, -NO 2 or R 3 , R 4 , and R 5 Two of the atoms, together with the atoms to which they are attached, form C 3 -C 6 cycloalkyl or 4-8 membered heterocycloalkyl, where C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 Each hydrogen atom in an aryl or 5-10 membered heteroaryl is independently selected from deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e, -OS(O)NR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e R f , -S(O) 2 NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O) 2 R f , -NR e S(O)NR e R f , -NR e S(O) 2 NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O) 2 R e R f , -P(O)NR e R f , -P(O) 2 NR e R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 is optionally replaced by

[0129] In some embodiments, each L is independently -C(O)-, -O-, -CH 2 -, -C(H)(CH 3 )-, -C(H)(OH)-, -NH-, and -NCH 3 In some embodiments, -(L) n - is -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, -(CH 2 ) 6 -, -C(O)NH-(CH 2 ) 2 O(CH 2 ) 2 -, -C(O)N(CH 3 )-(CH 2 ) 2 O(CH 2 ) 2 -, -NHC(O)CH 2 O(CH 2 ) 2 -, -N(CH 3 )-C(O)CH 2 O(CH 2 ) 2 -, -CH 2 O(CH 2 ) 2 -, -CH 2 O(CH 2 ) 3 -, -CH 2 O(C(CH 3 )H) 2 -, -(CH 2 ) 2 O(CH 2 ) 2 -, -CH 2 OCH 2 (C(CH 3 )H)-, -(CH 2 ) 2 OCH 2 (C(CH 3 )H)-, -(CH 2 ) 2 S(CH 2 )2 -、-O(CH 2 ) 2 S(CH 2 ) 2 -、-(CH 2 ) 2 SO 2 (CH 2 ) 2 -、-O(CH 2 ) 2 SO 2 (CH 2 ) 2 -、-(CH 2 ) 2 SO(CH 2 ) 2 -、-O(CH 2 ) 2 SO(CH 2 ) 2 -、-(CH 2 ) 2 O(C(H)(C(O)N(H)(CH 3 ))-CH 2 -、-(CH 2 ) 2 O(C(H)(C(O)N(CH 3 ) 2 )-CH 2 -、-(CH 2 ) 2 O(C(H)(C(O)OCH 3 )-CH 2 -、-(CH 2 ) 3 O(CH 2 ) 2 -、-(CH 2 ) 2 O(CH 2 ) 3 -、-CH 2 CH(CH 3 )-O(CH 2 ) 2 -、-CH(CH 3 )-CH 2 O(CH 2 ) 2 -、-O(CH 2 ) 2 -、-O-(CH 2 ) 3 -、-O-(CH 2 ) 4 -、-O-(CH2 ) 2 CH(CH 3 )-、-OCH 2 O(CH 2 ) 2 -、-O-CH 2 CH(OH)CH 2 -、-O-(CH 2 ) 2 O(CH 2 ) 2 -、-O-CH 2 CH(CH 3 )-O(CH 2 ) 2 -、-O-CH(CH 3 )-CH 2 O(CH 2 ) 2 -、-O-(CH 2 ) 2 NH-(CH 2 ) 2 -、-O-CH 2 CH(CH 3 )-NH-(CH 2 ) 2 -、-O-CH(CH 3 )-CH 2 NH-(CH 2 ) 2 -、-CH 2 NH-(CH 2 ) 2 -、-(CH 2 ) 2 NH-(CH 2 ) 2 -、-CH 2 CH(CH 3 )-NH-(CH 2 ) 2 -、-CH(CH 3 )-CH 2 NH-(CH 2 ) 2 -、-O-(CH 2 ) 2 N(CH 3 )-(CH 2 ) 2 -、-O-CH 2 CH(CH 3 )-N(CH 3 )-(CH 2 ) 2 -、-O-CH(CH3 )-CH 2 N(CH 3 )-(CH 2 ) 2 -, -CH 2 N(CH 3 )-(CH 2 ) 2 -, -CH 2 N(CH 2 CH 3 )-(CH 2 ) 2 -, -CH 2 N((CH 2 ) 2 CH 3 )-(CH 2 ) 2 -, -CH 2 N(CH(CH 3 ) 2 )-(CH 2 ) 2 -, -(CH 2 ) 2 N(CH 3 )-(CH 2 ) 2 -, -CH 2 CH(CH 3 )-N(CH 3 )-(CH 2 ) 2 - or -O-CH(CH 3 )-CH 2 N(CH 3 )-(CH 2 ) 2 In some embodiments, -Z-(L) n -Z 1 - is -OO-, -OS-, or -ON(R x In some embodiments, the -(L) n - is -O(CH 2 ) 2 -, -O-(CH 2 ) 3 -, -O-(CH 2 ) 4 -, -CH 2 OCH 2 (C(CH 3 )(H))-, -CH 2 O(CH 2 )2 -, or -CH 2 O(CH 2 ) 3 In some embodiments, -(L) n - is -O(CH 2 ) 3 -, -CH 2 OCH 2 (C(CH 3 )(H))- or -CH 2 O(CH 2 ) 2 -It is.

[0130] In some embodiments, R 1a , R 2a , R 5 , R 8 , and R 9 are each independently H or C 1 -C 6 alkyl, where C 1 -C 6 Each hydrogen atom in an alkyl group can be independently deuterium, halogen, or C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e R f , -S(O) 2 NR e R f , -NR e R f , -NR e C(O)R f , -NR eC(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O) 2 R f , -NR e S(O)NR e R f , -NR e S(O) 2 NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O) 2 R e R f , -P(O)NR e R f , -P(O) 2 NR e R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 In some embodiments, R 1a is H or methyl. In some embodiments, R 2a is H or methyl. In some embodiments, R 5 is H or methyl. In some embodiments, R 8 is H or methyl. In some embodiments, R 9 is H or methyl.

[0131] In some embodiments, R 6 and R 7 are independently H, deuterium, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2-C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -OS(O)NR a R b , -OS(O) 2 NR a R b , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR a R b , -NR a S(O)R b , -NR a S(O) 2 R b , -NR a S(O)NR a R b , -NR a S(O) 2 NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -PR a R b , -P(O)R a R b , -P(O) 2 Ra R b , -P(O)NR a R b , -P(O) 2 NR a R b , -P(O)OR a , -P(O) 2 OR a , -CN, or -NO 2 or R 6 and R 7 together with the carbon to which they are attached, C 4 -C 6 Cycloalkyl, 4-7 membered heterocycloalkyl, or C 6 -C 10 aryl, where C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, C 4 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 Each hydrogen atom in an aryl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocycloalkyl is independently selected from deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e Rf , -S(O) 2 NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O) 2 R f , -NR e S(O)NR e R f , -NR e S(O) 2 NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O) 2 R e R f , -P(O)NR e R f , -P(O) 2 NR e R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 is optionally replaced by

[0132] In some embodiments, R 6 is H, deuterium, fluoro, chloro, -CN, or C such as methyl or ethyl. 1 -C 6 In some embodiments, R 7 is H, deuterium, fluoro, chloro, -CN, or C such as methyl or ethyl. 1 -C 6In some embodiments, R 6 is H or deuterium, and R 7 is deuterium, fluoro, chloro, -CN, or C such as methyl or ethyl. 1 -C 6 In some embodiments, R 7 is H. In some embodiments, R 7 is deuterium. In some embodiments, R 7 is C, such as methyl or ethyl. 1 -C 6 In some embodiments, R 7 is -F. In some embodiments, R 7 is -Cl. In some embodiments, R 7 is -CN.

[0133] In some embodiments, n is 2, 3, 4, 5, 6, 7, or 8. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8.

[0134] In some embodiments, the present disclosure provides: [3a(4)Z]-6,9,15,16-tetramethyl-9,10,11,12-tetrahydro-15H-1,17-(ethanediylidene)pyrazolo[4,3-n]dipyrrolo[3,2-g:3',4'-j][1,5]oxazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-6,9,15,16-tetramethyl-10,11,13,15-tetrahydro-2H-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione; [3a(4)Z,10R]-20-chloro-6,10,15-trimethyl-10,11,13,15-tetrahydro-2H-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-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'-i][1,4]oxazacyclopentadecyne-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-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione; [3a(4)Z,10S]-20-chloro-6,9,10,15-tetramethyl-10,11,13,15-tetrahydro-2H-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione; [3a(4)Z]-20-chloro-6,9,15-trimethyl-10,11,13,15-tetrahydro-2H-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-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-i][1,4]oxazacyclopentadecyne-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-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione; [3a(4)Z,10R]-6,9,10,15-tetramethyl-3,8-dioxo-3,5,8,9,10,11,13,15-octahydro-2H-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-20-carbonitrile; [3a(4)Z,10R]-20-fluoro-6,9,10,15,16-pentamethyl-10,11,13,15-tetrahydro-2H-1,17-ethenopyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-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]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione; and [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'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione; or a pharma- ceutically acceptable salt thereof.

[0135] The following is a compound of formula (I): [Table 1] [Table 2] and pharma- ceutically acceptable salts thereof.

[0136] Those of skill in the art will recognize that the species listed or illustrated herein are not exhaustive and that additional species may be selected within the scope of these defined terms.

[0137] Pharmaceutical Compositions For therapeutic purposes, pharmaceutical compositions comprising the compounds described herein may further comprise one or more pharma- ceutically acceptable excipients. Pharmaceutically acceptable excipients are non-toxic and biologically suitable substances for administration to a subject. Such excipients facilitate administration of the compounds described herein and are compatible with the active ingredient. Examples of pharma- ceutically acceptable excipients include stabilizers, lubricants, surfactants, diluents, antioxidants, binders, colorants, bulking agents, emulsifiers, or taste modifiers. In a preferred embodiment, the pharmaceutical composition according to the present disclosure is a sterile composition. The pharmaceutical composition can be prepared using compounding techniques known or available to those skilled in the art.

[0138] Sterile compositions are also contemplated by the present disclosure, including compositions that comply with national and local regulations governing such compositions.

[0139] The pharmaceutical compositions and compounds described herein can be formulated as solutions, emulsions, suspensions, or dispersions in suitable pharmaceutical solvents or carriers, or as pills, tablets, troches, suppositories, sachets, dragees, granules, powders, powders for reconstitution, or capsules with solid carriers, according to conventional methods known in the art for preparing various dosage forms.The pharmaceutical compositions of the present disclosure can be administered by suitable delivery routes, such as oral, parenteral, rectal, nasal, topical, or ocular routes, or inhalation.Preferably, the compositions are formulated for intravenous or oral administration.

[0140] For oral administration, the compounds of the disclosure can be provided in solid form, such as tablets or capsules, or as a solution, emulsion, or suspension. To prepare oral compositions, the compounds of the disclosure can be formulated to provide a dosage of, for example, about 0.1 mg to 1 g per day, or about 1 mg to 50 mg per day, or about 50 to 250 mg per day, or about 250 mg to 1 g per day. Oral tablets may include the active ingredient mixed with compatible pharma- ceutically acceptable excipients, such as diluents, disintegrants, binders, lubricants, sweeteners, flavorings, colorings, and preservatives. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquid oral excipients include ethanol, glycerol, water, and the like. Examples of disintegrants include starch, polyvinylpyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid. Binders may include starch and gelatin. Lubricants, if present, are magnesium stearate, stearic acid, or talc. If necessary, the tablets can be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the digestive tract or to provide an enteric coating.

[0141] Capsules for oral administration include hard gelatin capsules and soft gelatin capsules.Hard gelatin capsules can be prepared by mixing the active ingredient with a solid, semi-solid, or liquid diluent.Soft gelatin capsules are prepared by mixing the active ingredient with water, oil such as peanut oil or olive oil, liquid paraffin, a mixture of monoglycerides and diglycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.

[0142] Liquids for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be provided as lyophilized or dry products for reconstitution with water or other suitable medium before use. Such liquid compositions may optionally contain: Pharmacologically acceptable excipients, such as suspending agents (e.g., sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, etc.); non-aqueous vehicles, such as oils (e.g., almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acids); wetting agents, such as lecithin; and, if desired, flavorings or colorings.

[0143] For parenteral use, including intravenous, intramuscular, intraperitoneal, intranasal, or subcutaneous routes, the agents of the present disclosure may be provided in a sterile aqueous solution or suspension buffered to an appropriate pH and isotonicity, or in a parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms may be provided in unit dose forms, such as ampoules or disposable syringes, in multiple dose forms, such as vials from which the appropriate dose can be withdrawn, or in solid forms or preconcentrates that can be used to prepare injectable formulations. Exemplary infusion doses range from about 1 to 1000 μg / kg / min of agent mixed with a pharmaceutical carrier over a period ranging from a few minutes to several days.

[0144] For nasal, inhaled, or oral administration, the pharmaceutical compositions of the present invention can be administered, for example, using a spray formulation also containing a suitable carrier. The compositions of the present invention can be formulated for rectal administration as suppositories.

[0145] For topical application, the compound of the present invention is preferably formulated as cream or ointment, or similar vehicle suitable for topical administration.For topical administration, the compound of the present invention can be mixed with a pharmaceutical carrier with a drug concentration of about 0.1% to about 10% relative to the vehicle.As another method of administering the drug of the present invention, a patch formulation that provides transdermal delivery can be used.

[0146] The term "treat" or "treatment" as used herein includes both "preventive" and "curative" treatment. "Preventive" treatment means delaying the onset of a disease, disease symptom, or condition, suppressing symptoms that may appear, or reducing the risk of onset or recurrence of a disease or condition. "Curative" treatment includes reducing the severity or suppressing the worsening of an existing disease, condition, or condition. Thus, treatment includes improving or preventing the worsening of symptoms of an existing illness, preventing the development of additional symptoms, improving or preventing the underlying systemic cause of a symptom, inhibiting a disorder or disease, e.g., arresting the progression of a disorder or disease, alleviating a disorder or disease, regressing a disorder or disease, alleviating a condition caused by a disease or disorder, or halting a symptom of a disease or disorder.

[0147] The term "subject" refers to a mammalian patient, e.g., a human, in need of such treatment.

[0148] Representative diseases include autoimmune diseases and inflammation. Autoimmune diseases include, for example, rheumatoid arthritis, psoriasis, inflammatory bowel disease, systemic lupus erythematosus, Sjogren's syndrome, type I diabetes, lupus, etc. Representative neurological diseases include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, etc. Representative inflammatory diseases include atherosclerosis, allergies, inflammation due to infection or injury, etc.

[0149] In one aspect, the compounds and pharmaceutical compositions of the present disclosure specifically target TYK2.Thus, these compounds and pharmaceutical compositions can be used to prevent, reverse, delay, or inhibit the activity of TYK2.In a preferred embodiment, the treatment method targets autoimmune disease.In other embodiments, these methods are used to treat autoimmune diseases such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, systemic lupus erythematosus, Sjogren's syndrome, type I diabetes, lupus, etc.

[0150] In the inhibitory method of the present disclosure, "effective amount" means an amount sufficient to inhibit target protein. Such target modulation can be measured by conventional analytical methods as described below. Such modulation is useful in various settings, including in vitro assays. In such methods, the cell is preferably an autoimmune disease cell with abnormal signaling due to upregulation of TYK2.

[0151] In the therapeutic methods according to the present disclosure, an "effective amount" means an amount or dosage sufficient to generally produce a desired therapeutic effect in a subject in need of such treatment. Effective amounts or dosages of the compounds of the present disclosure can be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors such as the mode or route of administration or drug delivery, the pharmacokinetics of the drug, the severity and course of the infection, the subject's health, condition, and weight, and the judgment of the treating physician. Exemplary dosages range from about 0.1 mg to 1 g per day, or about 1 mg to 50 mg per day, or about 50 to 250 mg per day, or about 250 mg to 1 g per day. The total dosage can be administered in single or divided dosage units (e.g., BID, TID, QID).

[0152] Once the patient's condition improves, the dosage can be adjusted for preventive or maintenance treatment. For example, the dosage or frequency of administration, or both, can be reduced to a level at which the desired therapeutic or preventive effect is maintained, depending on the symptoms. Of course, when the symptoms are alleviated to an appropriate level, treatment can be discontinued. However, if symptoms recur, the patient may require intermittent treatment over the long term. The patient may also require chronic treatment over the long term.

[0153] Concomitant medications The compounds of the invention described herein can be used in pharmaceutical compositions or methods in combination with one or more additional active ingredients in the treatment of diseases and disorders described herein. Further additional active ingredients include other therapeutic agents or drugs that reduce the side effects of treatment against the intended disease target. Such combinations may help to increase efficacy, improve other disease symptoms, reduce one or more side effects, or reduce the required dose of the compounds of the invention. The additional active ingredients may be administered in a pharmaceutical composition separate from the compounds of the present disclosure, or may be included in a single pharmaceutical composition with the compounds of the present disclosure. The additional active ingredients may be administered simultaneously with, before, or after administration of the compounds of the present disclosure.

[0154] The combination includes additional active ingredients known or discovered to be effective in treating the diseases and disorders described herein, including combination drugs that are effective against another target associated with the disease. For example, the compositions and formulations, and treatment methods of the present disclosure can further include other drugs or pharmaceuticals, e.g., other active ingredients useful in treating or alleviating the target disease or associated symptoms or conditions.

[0155] chemical synthesis method The following examples are provided for illustrative purposes and are not intended to limit the disclosure. Those skilled in the art will appreciate that the following synthetic reactions and schemes can be modified by the selection of appropriate starting materials and reagents to provide other compounds of formulas (I)-(XII).

[0156] Abbreviations: The examples described herein make use of materials that are referred to by the following abbreviations, including but not limited to those skilled in the art: [Table 3] [Table 4] EXAMPLES

[0157] Preparation of Intermediates A, B, and C Example 1: Preparation of tert-butyl N-[3-(4-bromo-1,5-dimethylpyrazol-3-yl)oxypropyl]-N-methylcarbamate (A1) [ka]

[0158] Step 1: To a solution of but-2-ynoic acid (5 g, 59.5 mmol, 1 equiv), DMAP (726 mg, 5.95 mmol, 0.1 equiv) in DCM (200 mL) was added tert-butyl N-amino-N-methylcarbamate (9.22 g, 63.0 mmol, 1.06 equiv) and EDCI (12.5 g, 65.4 mmol, 1.1 equiv) at 0° C. The reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was concentrated in vacuo to give tert-butyl N-(but-2-ynoylamino)-N-methylcarbamate (5.5 g, 25.9 mmol, 43.5% yield) as a white oil. 1 H NMR (400 MHz, CDCl 3 ) δ = 7.75 (s, 1H), 3.11 (s, 3H), 1.95 (s, 3H), 1.44 (s, 9H).

[0159] Step 2: To a solution of tert-butyl N-(but-2-ynoylamino)-N-methyl-carbamate (5.5 g, 25.9 mmol, 1.00 equiv.) in 2-propanol (60 mL) was added hydrogen chloride (4.84 g, 133 mmol, 4.75 mL, 5.13 equiv.) at 25 °C and the mixture was cooled to 10 °C. 2 The mixture was stirred at 63° C. for 16 hours. The reaction mixture was cooled to room temperature and concentrated in vacuum. The resulting residue was dissolved in CH 3 CN (50 mL, 10 mL / g) was added and concentrated in vacuo. This process was repeated three times. The final residue was diluted with CH 3 CN (20 mL, 4 mL / g) was added and warmed to 75 °C for 16 h. The resulting slurry was then cooled to room temperature over 1 h and continued to desaturate overnight. The solids were filtered and resuspended in CH 3 Washing with CN (2×20 mL) followed by drying in vacuum at room temperature gave the salt 1,5-dimethylpyrazol-3-ol (5.5 g, 24.5 mmol, 94.6% yield) as a white crystalline solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 10.98 (s, 1H), 5.64 (s, 3H), 3.64 (s, 3H), 2.22 (s, 3H).

[0160] Step 3: 1,5-Dimethylpyrazol-3-ol (800 mg, 7.13 mmol, 1 equiv.), tert-butyl N-(3-chloropropyl)-N-methylcarbamate (1.63 g, 7.85 mmol, 1.1 equiv.), K 2 CO 3 (1.48 g, 10.7 mmol, 1.5 equiv) was mixed in DMF (35 mL). The mixture was stirred at 80° C. for 16 h. After cooling to 25° C., the mixture was diluted with water (10 mL) and extracted with EA (3×10 mL). The combined organic layers were washed with brine (10 mL) and diluted with Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated in vacuo, and the residue was purified by silica gel column chromatography (PE:EA = 30:1-0:1) to give tert-butyl N-[3-(1,5-methyldipyrazol-3-yl)oxypropyl]-N-methyl-carbamate (600 mg, 2.12 mmol, yield 29.6%) as a yellow oil. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 5.41 (s, 1H), 3.97 - 3.93 (m, 2H), 3.52 (s, 3H), 3.32 - 3.23 (m, 2H), 2.76 (s, 3H), 2.14 (s, 3H), 1.84 - 1.80 (m, 2H), 1.36 (s, 9H).

[0161] Step 4: To a solution of tert-butyl N-[3-(1,5-dimethylpyrazol-3-yl)oxypropyl]-N-methylcarbamate (600 mg, 2.12 mmol, 1 equiv.) in ACN (10 mL), 2 NBS (376 mg, 2.12 mmol, 1 equiv.) was added at 25° C. for 16 h under reduced pressure. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EA = 25:1-0:1) to give tert-butyl N-[3-(4-bromo-1,5-dimethylpyrazol-3-yl)oxypropyl]-N-methylcarbamate (550 mg, 1.49 mmol, 70.3% yield, 98% purity) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 4.07 (t, J = 6.4 Hz, 2H), 3.61 (s, 3H), 3.28 (t, J = 6.8 Hz, 2H), 2.77 (s, 3H), 2.16 (s, 3H), 1.87 (t, J = 6.4 Hz, 2H), 1.36 (s, 9H).

[0162] Example 2: Preparation of tert-butyl N-[2-(4-bromo-1,5-dimethylpyrazol-3-yl)methoxy]ethyl]-N-methylcarbamate (A2) [ka]

[0163] Step 1: To a solution of ethyl 1,5-dimethylpyrazole-3-carboxylate (10.0 g, 59.5 mmol, 1 equiv.) in DCE (150 mL) was added NBS (15.9 g, 89.2 mmol, 1.5 equiv.). The mixture was stirred at 80° C. for 16 h. After completion, the mixture was concentrated in vacuo to give the crude product. The residue was purified by column chromatography (SiO 2 , and purified with petroleum ether / ethyl acetate = 0% to 30%) to give ethyl 4-bromo-1,5-dimethylpyrazole-3-carboxylate (7.00 g, 28.3 mmol, 47.7% yield) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ = 4.43 (t, J = 7.2 Hz, 2H), 3.90 (s, 3H), 2.31 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H).

[0164] Step 2: A solution of methyl 4-bromo-1,5-dimethyl-pyrazole-3-carboxylate (8.0 g, 34.33 mmol, 1 equiv.) in THF (100 mL) was added to LiAlH 4 (1.56 g, 41.19 mmol, 1.2 equiv.) was added. The mixture was stirred at 15° C. for 3 h. Upon completion, the mixture was diluted with H 2 The mixture was quenched with O (30 mL), extracted with ethyl acetate (20 mL × 3), and the obtained organic layer was washed with anhydrous Na 2 SO 4 It was dried over 400 ml, filtered, and the filtrate was concentrated in vacuo to give (4-bromo-1,5-dimethyl-pyrazol-3-yl)methanol (4.3 g, 20.97 mmol, 61.09% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 4.93 (t, J = 5.6 Hz, 2H), 4.30 - 4.27 (m, 2H), 3.72 (s, 3H), 3.32 (s, 3H).

[0165] Step 3: A solution of (4-bromo-1,5-dimethyl-pyrazol-3-yl)methanol (4.30 g, 21.0 mmol, 1 equiv.) in DCM (40 mL) was added to PBr at 0 °C. 3 (5.68 g, 21.0 mmol, 1 equiv.) was added dropwise. The mixture was stirred at 0-25 °C for 4 h. After completion, the mixture was concentrated in vacuo. NaHCO 3 The pH was adjusted to 7 by adding hexanes, and the mixture was extracted with DCM (30 mL×4). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by Combi-Flash (40 g silica gel column, DCM / MeOH=0-20%) to give (3.70 g, 13.8 mmol, 65.9% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ = 4.51 (s, 3H), 3.80 (s, 3H), 2.50 (s, 3H).

[0166] Step 4: To a solution of 4-bromo-3-(bromomethyl)-1,5-dimethylpyrazole (4.80 g, 17.9 mmol, 1 equiv.) in THF (100 mL) was added tert-butyl N-(2-hydroxyethyl)-N-methylcarbamate (3.45 g, 19.7 mmol, 63.6 μL, 1.1 equiv.), TBAI (661 mg, 1.79 mmol, 0.1 equiv.), and KOH (3.02 g, 53.7 mmol, 3 equiv.). The mixture was diluted with N 2 The mixture was stirred at 25° C. for 16 h under reduced pressure. After completion, the mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO 2 The crude product was purified with petroleum ether / ethyl acetate = 50%~70%. tert-Butyl N-[2-[(4-bromo-1,5-dimethyl-pyrazol-3-yl)methoxy]ethyl]-N-methyl-carbamate (5.6 g, 15.5 mmol, 86.3% yield) was obtained as a white solid. 1 H NMR (400 MHz, CDCl 3) δ = 4.43 (s, 2H), 3.78 (s, 3H), 3.60 - 3.55 (m, 2H), 3.38 - 3.35 (m, 2H), 2.23 (s, 3H), 1.44 (s, 3H), 1.42 (s, 9H).

[0167] Example 2a: Preparation of tert-butyl N-[(1R)-2-[(4-bromo-1,5-dimethyl-pyrazol-3-yl)methoxy]-1-methyl-ethyl]-N-methyl-carbamate (A2a) [ka]

[0168] Step 1: To a solution of (4-bromo-1,5-dimethyl-pyrazol-3-yl)methanol (8.64 g, 42.1 mmol, 1 equiv) in DMF (180 mL) was added NaH (3.37 g, 84.2 mmol, 60% purity, 2 equiv) at 0° C. The mixture was stirred at 25° C. for 0.5 h, followed by the addition of tert-butyl (4R)-4-methyl-2,2-dioxo-oxathiazolidine-3-carboxylate (15.0 g, 63.2 mmol, 1.5 equiv) and stirring at 25° C. for an additional 1 h. After completion, the mixture was diluted with H 2 Quench with 200 mL of ethyl acetate (400 mL × 3), extract with ethyl acetate (100 mL × 3), and add anhydrous Na 2 SO 4 The filtrate was concentrated in vacuo and subjected to flash silica gel chromatography (80 g silica gel column, MeOH (0-10%) in DCM) to give tert-butyl N-[(1R)-2-[(4-bromo-1,5-dimethyl-pyrazol-3-yl)methoxy]-1-methyl-ethyl]carbamate (10.2 g, 28.1 mmol, 66% yield) as a pink solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 6.71 (d, J = 8.4 Hz, 1H), 4.36 - 4.25 (m, 2H), 3.74 (s, 3H), 3.64 -3.50 (m, 1H), 3.31 - 3.27 (m, 1H), 3.19 - 3.11 (m, 1H), 2.23 - 2.21 (m, 3H), 1.36 (s, 9H), 0.99 (d, J = 6.8 Hz, 3H).

[0169] Step 2: To a solution of tert-butyl N-[(1R)-2-[(4-bromo-1,5-dimethyl-pyrazol-3-yl)methoxy]-1-methyl-ethyl]carbamate (5.00 g, 13.8 mmol, 1 equiv.) in DMF (100 mL) was added NaH (1.10 g, 27.6 mmol, 60% purity, 2 equiv.) at 0° C. The mixture was stirred at 0° C. for 0.5 h and then diluted with CH 3 I (2.94 g, 20.7 mmol, 1.29 mL, 1.5 equiv) was added. The mixture was stirred at 25° C. for 1 h. Upon completion, the mixture was diluted with H 2 The mixture was quenched with O (50 mL) and extracted with ethyl acetate (40 mL×3). The combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, and the filtrate was concentrated in vacuo to give the crude product. The residue was purified by flash silica gel chromatography (40 g silica gel column, 0-50% THF in PE) to give tert-butyl N-[(1R)-2-[(4-bromo-1,5-dimethylpyrazol-3-yl)methoxy]-1-methylethyl]-N-methylcarbamate (3.35 g, 8.90 mmol, 64% yield). LCMS: m / z 377.7 (M+1).

[0170] Example 3: Preparation of tert-butyl N-[(1R)-2-[(4-bromo-1-methyl-pyrazol-3-yl)methoxy]-1-methyl-ethyl]carbamate (A3) [ka]

[0171] A3 was prepared by a similar procedure to A2, starting from methyl 1-methylpyrazole-3-carboxylate and tert-butyl N-[(1R)-2-hydroxy-1-methylethyl]carbamate in step 4 of the alkylation reaction. 1 H NMR (400 MHz, DMSO-d 6) δ = 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).

[0172] Example 4: tert-Butyl N-[(1R)-2-[(4-bromo-1-methyl-pyrazol-3-yl)methoxy]-1-methyl-ethyl]-N-methyl-carbamate (A4) [ka]

[0173] To a solution of tert-butyl N-[(1R)-2-[(4-bromo-1-methyl-pyrazol-3-yl)methoxy]-1-methyl-ethyl]carbamate (A3, 3.50 g, 10.05 mmol, 1.0 equiv.) in THF (40 mL) was added NaH (1.21 g, 30.2 mmol, 60% purity, 3.0 equiv.) at 0° C. The mixture was stirred at 0° C. for 0.5 h. Then, the mixture was cooled to 5° C. and cooled to 5° C. for 1 h. 3 I (2.14 g, 15.1 mmol, 939 μL, 1.5 equiv.) was added. The mixture was stirred at 25 °C for 1.5 h. The mixture was diluted with saturated NH 4 Quenched with Cl (150 mL), extracted with ethyl acetate (50 mL×3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl N-[(1R)-2-[(4-bromo-1-methyl-pyrazol-3-yl)methoxy]-1-methyl-ethyl]-N-methyl-carbamate (3.20 g, crude) as a colorless oil. LCMS m / z 385.9 (M+23).

[0174] Example 5: Preparation of tert-butyl N-[(1S)-2-[(4-bromo-1-methyl-pyrazol-3-yl)methoxy]-1-methyl-ethyl]-N-methyl-carbamate (A5) [ka] A5 was prepared by a similar procedure to A4. LCMS m / z 385.9 (M+23).

[0175] Example 6: Preparation of tert-butyl N-[2-[(4-bromo-1-methyl-pyrazol-3-yl)methoxy]ethyl]-N-methyl-carbamate (A6) [ka] A6 was prepared by a similar procedure to A2. LCMS m / z 371.9 (M+23).

[0176] Example 7: Preparation of tert-butyl N-[(1R)-2-[[5-bromo-2-methyl-1-(2-trimethylsilylethoxymethyl)imidazo1-4-yl]methoxy]-1-methyl-ethyl]-N-methyl-carbamate (A7) [ka]

[0177] Step 1: To a mixture of 2-methyl-1H-imidazole-4-carbaldehyde (5.00 g, 45.4 mmol, 1 equiv) in DCM (50.0 mL) at 0 °C was added SEM-Cl (9.84 g, 59.0 mmol, 10.5 mL, 1.3 equiv), followed by DIEA (7.63 g, 59.0 mmol, 10.2 mL, 1.3 equiv) and DMAP (277 mg, 2.27 mmol, 0.05 equiv), and the mixture was cooled to 5° C. with H NMR (Hz), and then cooled to 50° C. 2 The mixture was stirred under reduced pressure for 0.5 h at 25° C. The reaction mixture was quenched by the addition of MeOH (50 mL) to give 2-methyl-1-(2-trimethylsilylethoxymethyl)imidazole-4-carbaldehyde (5.00 g, 20.8 mmol, 45.8% yield) as a yellow oil.

[0178] Step 2: To a mixture of 2-methyl-1-(2-trimethylsilylethoxymethyl)imidazole-4-carbaldehyde (5.00 g, 20.8 mmol, 1 equiv.) in MeOH (50.0 mL) was added NaBH 4 (825 mg, 21.8 mmol, 1.05 equiv.) was added at 0° C. The mixture was diluted with N 2 The mixture was stirred at 25° C. for 0.5 h under reduced pressure, then the reaction mixture was quenched by the addition of water (20.0 mL), followed by extraction with EtOAc (20.0 mL×3). The combined organic layers were extracted with Na 2 SO 4The mixture was dried at 40° C., filtered, and concentrated in vacuo to give a crude residue. The residue was purified by flash silica gel chromatography (ISCO®; 40.0 g SepaFlash® silica flash column, eluent 0-6% ethyl acetate / petroleum ether gradient, 50 mL / min) to give [2-methyl-1-(2-trimethylsilylethoxymethyl)imidazo-l-4-yl]methanol (5.00 g, 18.46 mmol, 88.76% yield, 89.5% purity) as a yellow oil. LCMS m / z 243.3 (M+1).

[0179] Step 3: To a mixture of [2-methyl-1-(2-trimethylsilylethoxymethyl)imidazo1-4-yl]methanol (5.00 g, 20.6 mmol, 1 equiv.) in ACN (50.0 mL) was added NBS (4.41 g, 24.7 mmol, 1.2 equiv.) at 0° C. The mixture was cooled to 5° C. with 5% CO. 2 The mixture was stirred at 25° C. for 1 h under reduced pressure, then partitioned between EtOAc (20.0 mL) and water (20.0 mL). The organic phase was separated, washed with brine (10.0 mL×3), and sodium 2 SO 4 The mixture was dried at 40° C. and concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20.0 g SepaFlash® silica flash column, eluent 0-20% ethyl acetate / petroleum ether gradient, 60 mL / min) to give [5-bromo-2-methyl-1-(2-trimethylsilylethoxymethyl)imidazo1-4-yl]methanol (5.00 g, 14.78 mmol, 71.67% yield, 95.0% purity) as a yellow oil. LCMS m / z 323.1 (M+1).

[0180] Step 4: To a mixture of [5-bromo-2-methyl-1-(2-trimethylsilylethoxymethyl)-imidazo1-4-yl]methanol (500 mg, 1.56 mmol, 1 equiv.) in THF (10.0 mL) was added NaH (93.3 mg, 2.33 mmol, 60% purity, 1.5 equiv.) at 0° C. The mixture was stirred at 0° C. for 0.5 h. Then, (4R)-tert-butyl 4-methyl-2,2-dioxo-oxathiazolidine-3-carboxylate (443 mg, 1.87 mmol, 1.2 equiv.) was added and the mixture was stirred at 25° C. for 1.5 h. 2 The reaction mixture was quenched by the addition of O (5.00 mL). The filtrate was diluted with H 2 The mixture was diluted with 2×O (5.00 mL) and extracted with EtOAc (5.00 mL×3). The combined organic layers were washed with brine (5 mL×3) and then with Na 2 SO 4 The residue was analyzed by preparative TLC (SiO 2 , petroleum ether:ethyl acetate=0:1) to give tert-butyl N-[(1R)-2-[[5-bromo-2-methyl-1-(2-trimethylsilylethoxymethyl)imidazo1-4-yl]methoxy]-1-methyl-ethyl]carbamate (600 mg, 1.17 mmol, 75.1% yield) as a yellow oil. LCMS 479.5 (M+1).

[0181] Step 5: To a mixture of tert-butyl N-[(1R)-2-[[5-bromo-2-methyl-1-(2-trimethylsilylethoxymethyl)imidazo1-4-yl]methoxy]-1-methyl-ethyl]carbamate (600 mg, 1.25 mmol, 1 equiv.) in THF (7.00 mL) was added NaH (75.2 mg, 1.88 mmol, 60% purity, 1.5 equiv.) at 0° C. and the mixture was stirred at 0° C. for 0.5 h. Then, CH 3 I (267 mg, 1.88 mmol, 117 μL, 1.5 equiv) was added and the mixture was stirred at 25° C. for 1.5 h. 2 The reaction mixture was quenched at 25 °C by the addition of O (5.00 mL). The filtrate was purified by H 2The mixture was diluted with 2×O (5.00 mL) and extracted with EtOAc (5.00 mL×3). The combined organic layers were washed with brine (5.00 mL×3) and diluted with Na 2 SO 4 It was dried over 500 ml, filtered and concentrated in vacuo to give tert-butyl N-[(1R)-2-[[5-bromo-2-methyl-1-(2-trimethylsilylethoxymethyl)imidazo1-4-yl]methoxy]-1-methyl-ethyl]-N-methyl-carbamate (550 mg) as a yellow oil. LCMS 494.1 (M+1:494.1).

[0182] Example 8: Preparation of [3-[[(2R)-2-[tert-butoxycarbonyl(methyl)amino]propoxy]methyl]-1-methyl-pyrazol-4-yl]boronic acid (B1) [ka]

[0183] To a solution of tert-butyl N-[(1R)-2-[(4-bromo-1-methyl-pyrazol-3-yl)methoxy]-1-methyl-ethyl]-N-methyl-carbamate (2.00 g, 5.52 mmol, 1.0 equiv.) in THF (20 mL) was added n-BuLi (2.5 M, 5.52 mL, 2.5 equiv.). The mixture was stirred at -70°C for 1 h, then 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.08 g, 16.6 mmol, 3.38 mL, 3.0 equiv.) was added at -70°C. The mixture was stirred at -70°C for 3 h. The mixture was quenched with water (50 mL), extracted with ethyl acetate (25 mL×3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give [3-[[(2R)-2-[tert-butoxycarbonyl(methyl)amino]propoxy]methyl]-1-methyl-pyrazol-4-yl]boronic acid (1.75 g, crude) as a white solid. LCMS m / z 327.7 (M+1).

[0184] Example 8b: Preparation of 7-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (D1) [ka]

[0185] Step 1: To a solution of 7-fluoroindolin-2-one (10.0 g, 66.1 mmol, 1 equiv) in TFA (100 mL) was added NBS (12.9 g, 72.7 mmol, 1.1 equiv) at 0° C. and stirred for 0.5 h. The mixture was stirred at 25° C. for 6 h. After completion, the reaction mixture was concentrated under reduced pressure to remove the solvent. The crude product was triturated with DCM:PE (1:1, 400 mL) at 20° C. for 5 min to give 5-bromo-7-fluoro-indolin-2-one (15.4 g, 59.7 mmol, 90% yield) as a brown solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 11.05(s, 1H), 7.41(dd, J = 9.6 Hz, 1H), 7.27(s, 1H), 3.58(s, 2H).

[0186] Step 2: To a solution of 5-bromo-7-fluoro-indolin-2-one (16.8 g, 73.2 mmol, 1 equiv.) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (55.8 g, 219 mmol, 3 equiv.) in dioxane (250 mL) was added potassium acetate (28.7 g, 292 mmol, 4 equiv.) and cyclopentyl(diphenyl)phosphane; dichloromethane; dichloropalladium; iron (5.98 g, 7.32 mmol, 0.1 equiv.). The mixture was cooled to 100° C. for 2 h and cooled to 30° C. for 1 h. 2 The mixture was stirred at 100 °C under reduced pressure for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® silica flash column, eluent 0-20% MeOH / DCM, 40 mL / min) to give 7-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (14.3 g, 42.9 mmol, 58% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6) δ = 11.01(s, 1H), 7.32(s, 1H), 7.24(d, J = 10.4 Hz, 1H), 3.56(s, 2H), 1.27(s, 12H).

[0187] Example 9: Preparation of 5-formyl-2-methyl-3-(2-trimethylsilylethoxymethyl)-imidazole-4-carboxylic acid (C1) [ka]

[0188] Step 1: To a mixture of [5-bromo-2-methyl-1-(2-trimethylsilylethoxymethyl)-imidazo-l-4-yl]methanol (1.50 g, 4.67 mmol, 1 equiv.) in DCM (15.0 mL) was added Dess-Martin reagent (2.97 g, 7.00 mmol, 2.17 mL, 1.5 equiv.) at 0 °C. The mixture was stirred at 25 °C for 2 h, diluted with DCM (10.0 mL), and filtered to remove insoluble material. The filtrate was purified by H 2 The mixture was diluted with 2×O (10.0 mL) and extracted with DCM (10.0 mL×3). The combined organic layers were washed with brine (10.0 mL×3) and 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® silica flash column, eluent 0-10% ethyl acetate / petroleum ether gradient, 55 mL / min) to give 5-bromo-2-methyl-1-(2-trimethylsilylethoxymethyl)-imidazole-4-carbaldehyde (710 mg, 2.22 mmol, 47.63% yield) as a colorless oil. 1 H NMR (400 MHz, Chloroform-d) δ = 9.60(s, 1H), 5.75 - 5.68(m, 2H), 3.62 - 3.53(m, 2H), 2.55 - 2.46(m, 3H), 0.94 - 0.84(m, 2H), -0.02(s, 9H).

[0189] Step 2: A solution of 5-bromo-2-methyl-1-(2-trimethylsilylethoxymethyl)imidazole-4-carbaldehyde (700 mg, 2.19 mmol, 1 eq) in DMF (10.0 mL) and MeOH (5.00 mL) was added to the 2 Under Pd(dppf)Cl 2 (80.2 mg, 109 μmol, 0.05 equiv) and TEA (665 mg, 6.58 mmol, 915 μL, 3 equiv) were added. The mixture was degassed under vacuum and purged with CO several times. The mixture was stirred under CO at 80° C. for 16 h. The mixture was concentrated in vacuo. The crude product was purified by silica gel chromatography eluting with petroleum ether / ethyl acetate=5:1 to give methyl 5-formyl-2-methyl-3-(2-trimethylsilylethoxymethyl)imidazole-4-carboxylate (550 mg, 1.84 mmol, 84.06% yield)) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ = 10.4(s, 1H), 5.78(s, 2H), 3.98(s, 3H), 3.64 - 3.47(m, 2H), 2.56(s, 3H), 0.92 - 0.86(m, 2H), -0.03(s, 9H).

[0190] Step 3: MeOH (2.00 mL) and H 2 To a mixture of methyl 5-formyl-2-methyl-3-(2-trimethylsilylethoxymethyl)-imidazole-4-carboxylate (300 mg, 1.01 mmol, 1 equiv) in 2H2O (0.6 mL), 2 Under LiOH H 2 HO (210 mg, 5.03 mmol, 5 equiv.) was added. The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to remove MeOH. HCl (1 N) was added to the mixture until pH = 5-6. The residue was purified by H 2 The mixture was diluted with 2×O (5.00 mL) and extracted with EtOAc (5.00 mL×3). The combined organic layers were washed with brine (5.00 mL×3) and diluted with Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated in vacuo to give 5-formyl-2-methyl-3-(2-trimethylsilylethoxymethyl)imidazole-4-carboxylic acid (200 mg, 694 μmol, 69.12% yield, 98.8% purity) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 10.31(s, 1H), 5.70(s, 2H), 3.53 - 3.49(m, 2H), 2.45(s, 3H), 0.89 - 0.78(m, 3H), -0.05 - -0.07(m, 9H).

[0191] General method A Example 9: Preparation of [3a(4)Z]-6,9,15,16-tetramethyl-9,10,11,12-tetrahydro-15H-1,17-(ethanediylidene)pyrazolo[4,3-n]dipyrrolo[3,2-g:3',4'-j][1,5]oxazacyclopentadecyne-3,8(2H,5H)-dione (Compound 1) [ka]

[0192] Step 1: tert-Butyl N-[3-(4-bromo-1,5-dimethyl-pyrazol-3-yl)oxypropyl]-N-methyl-carbamate (500 mg, 1.38 mmol, 1 equiv.), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (643.73 mg, 2.48 mmol, 1.8 equiv.), Na 2 CO 3 (438 mg, 4.14 mmol, 3 equiv.) in dioxane (20 mL) and H 2 In a solution of Pd(dppf)Cl in 200 mL of HO (4 mL), 2 (100 mg, 138 μmol, 0.1 equiv.) was added. The reaction mixture was stirred at 100° C. for 2 h, cooled and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM:MeOH = 25:1 to 10:1) to give tert-butyl N-[3-[1,5-dimethyl-4-(2-oxoindolin-5-yl)pyrazol-3-yl]oxypropyl]-N-methyl-carbamate (450 mg, 662 μmol, 47.9% yield, 61% purity) as a yellow oil. LCMS m / z 415.2 ((M+1).

[0193] Step 2: A solution of 5-[1,5-dimethyl-3-[3-(methylamino)propoxy]pyrazol-4-yl]indolin-2-one (160 mg, 508 μmol, 1 equiv.), 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (116.90 mg, 763.40 μmol, 1.5 equiv.), 1-methylimidazole (417 mg, 5.09 mmol, 0.040 mL, 10 equiv.) and [chloro(dimethylamino)methylene]-dimethyl-ammonium;hexafluorophosphate (185 mg, 662 μmol, 1.3 equiv.) in MeCN (30 mL) was stirred at 25° C. for 1 h. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM:MeOH = 30:1 to 10:1) to give N-[3-[1,5-dimethyl-4-(2-oxoindolin-5-yl)pyrazol-3-yl]oxypropyl]-2-formyl-N,5-dimethyl-1H-pyrrole-3-carboxamide (50 mg, 0.0745 mmol, 14.6% yield, 67% purity) as a yellow solid. LCMS m / z 450.2 (M+1).

[0194] Step 3: To a mixture of N-[3-[1,5-dimethyl-4-(2-oxoindolin-5-yl)pyrazol-3-yl]oxypropyl]-2-formyl-N,5-dimethyl-1H-pyrrole-3-carboxamide (50 mg, 0.111 mmol, 1 equiv.) in EtOH (10 mL) was added piperidine (14.2 mg, 0.167 mmol, 1.5 equiv.) at 25 °C. The mixture was stirred at 80 °C for 1 h and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM:MeOH = 30:1 to 10:1) to give compound 1 (2.9 mg, 5.86% yield, 97% purity) as an orange solid.

[0195] Example 10:Using general method A, compounds 2 to 8 were prepared from the corresponding bromopyrazole analogs A1, A2, A3, A4, A5, or A6, the commercially available oxindole boronic acid esters 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one or 7-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one, and the pyrrole or imidazole aldehyde acids 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid, 2-formyl-1H-pyrrole-3-carboxylic acid, or 5-formyl-2-methyl-3-(2-trimethylsilylethoxymethyl)imidazole-4-carboxylic acid.

[0196] Further deprotection steps gave compound 8: To a mixture of compound 8 (40.0 mg, 0.067.0 mmol, 1 equiv.) SEM-protected on the imidazole ring in DCM (3 mL) was added TFA (1.54 g, 13.5 mmol, 1 mL, 201 equiv.). The mixture was stirred at 25° C. for 1 h and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex C18 150×25 mm×10 μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 9% to 39%, 8 min) to give compound 8 (5.48 mg, 0.012 mmol) as a yellow solid.

[0197] [Table 5] [Table 6]

[0198] Example 11: Preparation of [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-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione (compound 9) [ka] [ka] [ka]

[0199] Step 1: To a mixture of 5-bromo-1-chloro-3-fluoro-2-nitro-benzene (2.75 g, 10.8 mmol, 1 equiv.) and dimethyl propanedioate (1.86 g, 14.0 mmol, 1.61 mL, 1.3 equiv.) in DMF (30 mL), 2 K below 2 CO 3 (2.99 g, 21.6 mmol, 2 equiv.) was added. The mixture was stirred at 80° C. for 12 h. The residue was 2 The mixture was diluted with 2×O (15.0 mL) and extracted with EtOAc (15.0 mL×3). The combined organic layers were washed with brine (15 mL×3) and then with Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent 0-16% ethyl acetate / petroleum ether gradient, 80 mL / min) to give dimethyl 2-(5-bromo-3-chloro-2-nitro-phenyl)propanedioate (3.20 g, crude) as a yellow solid. LCMS: m / z 367.7 (M+1).

[0200] Step 2: A mixture of dimethyl 2-(5-bromo-3-chloro-2-nitro-phenyl)propanedioate (3.1 g, 8.46 mmol, 1 equiv.) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.36 g, 9.30 mmol, 1.1 equiv.) in dioxane (35.0 mL) was added to the reaction mixture. 2 Under Pd(dppf)Cl 2 (619 mg, 845 μmol, 0.1 equiv.) and KOAc (2.49 g, 25.3 mmol, 3 equiv.) were added. The mixture was stirred at 80° C. for 5 h. The reaction mixture was concentrated under reduced pressure to remove dioxane. The residue was purified by column chromatography (SiO2 , petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to obtain the compound 2-[3-chloro-2-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]dimethylpropanedioate (2.00 g, 4.84 mmol, 57.17% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 7.90(d, J = 0.8 Hz, 1H), 7.81(d, J = 0.8 Hz, 1H), 5.10(s, 1H), 3.71(s, 6H), 1.32(s, 12H).

[0201] Step 3: Dioxane (5.00 mL) and H 2 To a mixture of dimethyl 2-[3-chloro-2-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanedioate (295 mg, 0.714 mmol, 1.1 equiv.) and tert-butyl N-[(1R)-2-[[5-bromo-2-methyl-1-(2-trimethylsilylethoxymethyl)imidazo1-4-yl]methoxy]-1-methyl-ethyl]-N-methyl-carbamate (320 mg, 0.649 mmol, 1 equiv.) in 2H2O (0.8 mL), 2 Di-tert-butyl(cyclopentyl)phosphane; dichloropalladium; iron (42.3 mg, 64.9 μmol, 0.1 equiv.) and Cs 2 CO 3 (635 mg, 1.95 mmol, 3 equiv.) was added. The mixture was stirred at 70° C. for 2 h. The reaction mixture was concentrated under reduced pressure to remove dioxane. The residue was analyzed by preparative TLC (SiO 2, petroleum ether:ethyl acetate=1:1) to give dimethyl 2-[5-[5-[[(2R)-2-[tert-butoxycarbonyl(methyl)amino]propoxy]methyl]-2-methyl-3-(2-trimethylsilylethoxymethyl)imidazo1-4-yl]-3-chloro-2-nitro-phenyl]propanedioate (250 mg, 0.312 mmol, 48.09% yield) as a colorless oil. LCMS: m / z 699.3 (M+1).

[0202] Step 4: To a mixture of dimethyl 2-[5-[5-[[(2R)-2-[tert-butoxycarbonyl(methyl)amino]propoxy]methyl]-2-methyl-3-(2-trimethylsilylethoxy methyl)imidazo l-4-yl]-3-chloro-2-nitro-phenyl]propanedioate (100 mg, 0.143 mmol, 1 equiv.) in DCM (2.00 mL) was added HCl / dioxane (4 M, 2.50 mL, 69.9 equiv.). The mixture was stirred at 20° C. for 1 h. The reaction mixture was concentrated under reduced pressure and the DCM was removed to give dimethyl 2-[3-chloro-5-[2-methyl-4-[[(2R)-2-(methylamino)propoxy]methyl]-1H-imidazo l-5-yl]-2-nitro-phenyl]propanedioate (80.0 mg) as a yellow solid. LCMS m / z 469.0(M+1)

[0203] Step 5: To a mixture of dimethyl 2-[3-chloro-5-[2-methyl-4-[[(2R)-2-(methylamino)propoxy]methyl]-1H-imidazo l-5-yl]-2-nitro-phenyl]propanedioate (80.0 mg, 0.158 mmol, 1 eq, HCl) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (36.3 mg, 0.237 mmol, 1.5 eq) in MeCN (1.50 mL) was added [chloro(dimethylamino)methylene]-dimethyl-ammonium;hexafluorophosphate (66.6 mg, 0.237 mmol, 1.5 eq) and 1-methylimidazole (38.9 mg, 0.475 mmol, 3 eq) and the mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to remove DCM. The residue was analyzed by preparative TLC (SiO 2 , dichloromethane:methanol=10:1) to give dimethyl 2-[3-chloro-5-[4-[[(2R)-2-[(2-formyl-5-methyl-1H-pyrrole-3-carbonyl)-methyl-amino]propoxy]methyl]-2-methyl-1H-imidazo1-5-yl]-2-nitro-phenyl]propanedioate (80.0 mg, 0.114 mmol, 72.45% yield) as a yellow oil. LCMS m / z 604.3 (M+1).

[0204] Step 6: DMSO (1.50 mL) and H 2 To a mixture of dimethyl 2-[3-chloro-5-[4-[[(2R)-2-[(2-formyl-5-methyl-1H-pyrrole-3-carbonyl)-methyl-amino]propoxy]methyl]-2-methyl-1H-imidazo1-5-yl]-2-nitro-phenyl]propanedioate (80.0 mg, 0.132 μmol, 1 equiv.) in 2H2O (0.3 mL) was added LiCl (22.4 mg, 0.529 mmol, 4 equiv.). The mixture was stirred at 100 °C for 12 h. The filtrate was purified by HCl distillation. 2 The mixture was diluted with 2×O (5.00 mL) and extracted with EtOAc (5.00 mL×3). The combined organic layers were washed with brine (5.00 mL×3) and diluted with Na 2 SO 4The residue was analyzed by preparative TLC (SiO 2 , dichloromethane:methanol=10:1) to give dimethyl 2-[3-chloro-5-[4-[[(2R)-2-[(2-formyl-5-methyl-1H-pyrrole-3-carbonyl)-methyl-amino]propoxy]methyl]-2-methyl-1H-imidazo1-5-yl]-2-nitro-phenyl]acetate (70.0 mg, crude) as a yellow oil. LCMS m / z 546.0 (M+1).

[0205] Step 7: To a solution of methyl 2-[3-chloro-5-[4-[[(2R)-2-[(2-formyl-5-methyl-1H-pyrrole-3-carbonyl)-methyl-amino]propoxy]methyl]-2-methyl-1H-imidazo1-5-yl]-2-nitro-phenyl]acetate (40.0 mg, 0.0732 mmol, 1 equiv) in MeOH (6.00 mL) and AcOH (0.100 mL), was added N 2 Pt / V / C (1.91 mg, 7.33 μmol, 0.1 equiv.) was added under vacuum. The suspension was degassed under H 2 The mixture was purged with H several times. 2 The mixture was stirred under reduced pressure at 25° C. for 2 h. The reaction mixture was filtered and the filtrate was concentrated to give methyl 2-[2-amino-3-chloro-5-[4-[[(2R)-2-[(2-formyl-5-methyl-1H-pyrrole-3-carbonyl)-methyl-amino]propoxy]methyl]-2-methyl-1H-imidazo1-5-yl]phenyl]acetate (35.0 mg, crude) as a yellow oil. LCMS m / z 516.2 (M+1).

[0206] Step 8: To a mixture of methyl 2-[2-amino-3-chloro-5-[4-[[(2R)-2-[(2-formyl-5-methyl-1H-pyrrole-3-carbonyl)-methyl-amino]propoxy]methyl]-2-methyl-1H-imidazo1-5-yl]phenyl]acetate (35.0 mg, 67.8 μmol, 1 equiv) in MeOH (2.00 mL) was added AcOH (0.4 mg, 0.0068 mmol, 0.1 equiv) and the mixture was stirred at 70 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove MeOH to give N-[(1R)-2-[[5-(7-chloro-2-oxo-indolin-5-yl)-2-methyl-1H-imidazo1-4-yl]methoxy]-1-methyl-ethyl]-2-formyl-N,5-dimethyl-1H-pyrrole-3-carboxamide (25.0 mg, crude) as a yellow oil. LCMS m / z 484.2 (M+1).

[0207] Step 9: To a mixture of N-[(1R)-2-[[5-(7-chloro-2-oxo-indolin-5-yl)-2-methyl-1H-imidazo1-4-yl]methoxy]-1-methyl-ethyl]-2-formyl-N,5-dimethyl-1H-pyrrole-3-carboxamide (25.0 mg, 0.052 mmol, 1 equiv.) in EtOH (2.00 mL) was added piperidine (0.44 mg, 0.0052 mmol, 0.1 equiv.). The mixture was stirred at 80° C. for 1 h. The reaction mixture was concentrated under reduced pressure to remove EtOH. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [water (FA)-ACN]; B%: 10%-40%, 10 min) to give dimethyl 2-[3-chloro-5-[4-[[(2R)-2-[(2-formyl-5-methyl-1H-pyrrole-3-carbonyl)-methyl-amino]propoxy]methyl]-2-methyl-1H-imidazo l-5-yl]-2-nitro-phenyl]acetate (70.0 mg, crude product) as an orange solid. 1 H NMR (400 MHz, DMSO-d 6) δ = 12.45 - 11.88(m, 1H), 11.51 - 11.09(m, 2H), 8.37(s, 1H), 8.14 - 7.98(m, 1H), 7.79 - 7.51(m, 1H), 7.49 - 7.23(m, 2H), 6.39 - 6.22(m, 1H), 4.83 - 4.70(m, 1H), 4.47 - 4.33(m, 2H), 3.76(d, J = 1.2 Hz, 2H), 2.84 - 2.78(m, 3H), 2.43 - 2.39(m, 3H), 2.29(d, J = 5.2 Hz, 3H), 1.29 - 1.16(m, 3H). LCMS m / z 466.1(M+1).

[0208] Example 12: Preparation of [3a(4)Z,10R]-6,9,10,15-tetramethyl-3,8-dioxo-3,5,8,9,10,11,13,15-octahydro-2H-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-20-carbonitrile (compound 10) [ka] [ka]

[0209] Step 1: 3-Bromo-5-fluoro-benzonitrile (3.00 g, 15.0 mmol, 1 equiv.) 2 SO 4 (20 mL) solution at 0°C with KNO 3 (3.03 g, 30.0 mmol, 2.0 equiv.) was added. The mixture was quenched with water (20 mL) at 0° C., extracted with ethyl acetate (25 mL×3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=10 / 1 to 2 / 1) to give 5-bromo-3-fluoro-2-nitro-benzonitrile (130 mg, 0.53 mmol, 3.54% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 8.44(dd, J = 2.0, 10.4 Hz, 1H), 8.39(t, J = 1.8 Hz, 1H).

[0210] Step 2: To a solution of 5-bromo-3-fluoro-2-nitro-benzonitrile (1.30 g, 5.31 mmol, 1.0 equiv.), dimethyl diacetate (841 mg, 6.37 mmol, 1.2 equiv.) in DMF (15 mL) was added K 2 CO 3 (1.47 g, 10.6 mmol, 2 equiv.) was added. The mixture was stirred at 80° C. for 17 h. The mixture was quenched with water (20 mL), extracted with ethyl acetate (25 mL×3), the combined organic phase was dried over anhydrous sodium sulfate, and the combined organic phase was dried over anhydrous sodium sulfate and concentrated to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=20 / 1 to 2 / 1) to give dimethyl 2-(5-bromo-3-cyano-2-nitro-phenyl)propanedioate (1.05 g, 2.94 mmol, 55.4% yield) as a colorless oil. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 8.57(d, J = 2.0 Hz, 1H), 8.21(d, J = 2.0 Hz, 1H), 5.53(s, 1H), 3.69(s, 6H).

[0211] Step 3: Dioxane (40 mL) and H 2 Dimethyl 2-(5-bromo-3-cyano-2-nitro-phenyl)dioate (2.00 g, 5.60 mmol, 1.0 equiv), [3-[[(2R)-2-[tert-butoxycarbonyl(methyl)amino]propoxy] methyl]-1-methyl-pyrazol-4-yl]boronic acid (9.16 g, 28.0 mmol, 5.0 equiv), di-tert-butyl(cyclopentyl)phosphane; dichloropalladium; iron (365 mg, 0.56 mmol, 0.1 equiv), K 2 CO 3 A mixture of (2.32 g, 16.8 mmol, 3.0 equiv.) was degassed and diluted with N 2 Purge the mixture three times with N 2The mixture was stirred under atmospheric conditions at 70° C. for 3 hours. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to give dimethyl 2-[5-[3-[[(2R)-2-[tert-butoxycarbonyl(methyl)amino]propoxy]methyl]-1-methyl-pyrazol-4-yl]-3-cyano-2-nitro-phenyl]dioate (1.72 g, 3.07 mmol, 54.9% yield) as an orange oil. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 8.43(d, J = 2.0 Hz, 1H), 8.13(s, 1H), 7.61(d, J = 1.6 Hz, 1H), 5.60(s, 1H), 4.46 - 4.41(m, 2H), 4.38 - 4.32(m, 2H), 3.92(s, 3H), 3.79(s, 3H), 3.72(s, 6H), 2.63(d, J = 12.8 Hz, 3H), 1.37(s, 9H).

[0212] Step 4: To a solution of dimethyl 2-[5-[3-[[(2R)-2-[tert-butoxycarbonyl(methyl)amino]propoxy]methyl]-1-methyl-pyrazol-4-yl]-3-cyano-2-nitro-phenyl]dioate (80.0 mg, 0.143 mmol, 1.0 equiv.) in DCM (4 mL) was added HCl / dioxane (4 M, 0.036 mL, 1.0 equiv.). The mixture was stirred at 25° C. for 1 h. The mixture was concentrated to give dimethyl 2-[3-cyano-5-[1-methyl-3-[[(2R)-2-(methylamino)propoxy]methyl]pyrazol-4-yl]-2-nitro-phenyl]dioate (80 mg, crude) as a brown oil. LCMS m / z 460.3 (M+1).

[0213] Step 5: To a solution of 2-[3-cyano-5-[1-methyl-3-[[(2R)-2-(methylamino)propoxy]methyl]pyrazol-4-yl]-2-nitro-phenyl]dimethyl diacid (100 mg, 0.217 mmol, 1.0 equiv.) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (40.0 mg, 0.261 mmol, 1.2 equiv.) in ACN (10 mL) was added 1-methylimidazole (179 mg, 2.18 mmol, 10.0 equiv.) and [chloro(dimethylamino)methylene]-dimethyl-ammonium; hexafluorophosphate (91.6 mg, 0.326 mmol, 1.5 equiv.). The mixture was stirred at 20° C. for 1 h. The mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO 2 , DCM / MeOH=1 / 0~10 / 1) to give dimethyl 2-[3-cyano-5-[3-[[(2R)-2-[(2-formyl-5-methyl-1H-pyrrole-3-carbonyl)-methyl-amino]propoxy]methyl]-1-methyl-pyrazol-4-yl]-2-nitro-phenyl]dioate (60.0 mg, 0.087 mmol, 40.0% yield) as a red solid. LCMS m / z 595.1 (M+1).

[0214] Step 6: DMSO (2 mL) and H 2To a solution of dimethyl 2-[3-cyano-5-[3-[[(2R)-2-[(2-formyl-5-methyl-1H-pyrrole-3-carbonyl)-methyl-amino]propoxy]methyl]-1-methyl-pyrazol-4-yl]-2-nitro-phenyl]dioate (50.0 mg, 0.084 mmol, 1.0 equiv) in 0 (0.4 mL) was added LiCl (17.8 mg, 0.42 mmol, 5.0 equiv). The mixture was stirred at 90 °C for 20 h. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (5 mL×3), and the combined organic phase was dried over anhydrous sodium sulfate and concentrated to give methyl 2-[3-cyano-5-[3-[[(2R)-2-[(2-formyl-5-methyl-1H-pyrrole-3-carbonyl)-methyl-amino]propoxy]methyl]-1-methyl-pyrazol-4-yl]-2-nitro-phenyl]acetate (80 mg, crude) as a colorless oil. LCMS m / z 537.1 (M+1).

[0215] Step 7: To a solution of methyl 2-[3-cyano-5-[3-[[(2R)-2-[(2-formyl-5-methyl-1H-pyrrole-3-carbonyl)-methyl-amino]propoxy]methyl]-1-methyl-pyrazol-4-yl]-2-nitro-phenyl]acetate (80.0 mg, 0.149 mmol, 1.0 equiv) in AcOH (2 mL) was added Fe (41.6 mg, 0.746 mmol, 5.0 equiv). The mixture was stirred at 90° C. for 1 h. The mixture was filtered and concentrated to give a residue. The residue was purified by preparative HPLC (TFA condition; column: Welch Xtimate C18 150×25 mm×5 μm; mobile phase: [water (TFA)-ACN]; B%: 21% to 51%, 10 min) to give compound 10 (2.25 mg, 2.55% yield) as an orange solid. 1 H NMR (400 MHz, CDCl 3) δ = 11.28(d, J = 4.0 Hz, 1H), 8.49(s, 1H), 7.66(s, 1H), 7.56(s, 1H), 7.35(d, J = 2.0 Hz, 1H), 6.36(d, J = 2.4 Hz, 1H), 5.38 - 5.33 (m, 1H), 5.09 - 4.96 (m, 1H), 4.55 - 4.51 (m, 2H), 3.96 (s, 3H), 3.95 - 3.93 (m, 1H), 3.84 - 3.77(m, 1H), 2.90(s, 3H), 2.46(s, 3H), 1.26(s, 3H). LCMS m / z 457.2(M+1).

[0216] Example 13: Using general method A, compounds 11–13 were prepared with the corresponding bromopyrazole analogs A2a or A4, boronic ester D1 or the commercially available oxindole boronic ester 7-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one, and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid. [Table 7]

[0217] Biochemical assays Example 14: Kinase binding assays were performed at Eurofins / DiscoveRx using the general KINOMEscan protocol (Fabian, MA 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 stocks were prepared in E. coli host from the BL21 strain. E. coli was in logarithmic growth phase, infected with T7 phage, and incubated at 32°C with shaking until lysis. Lysates were centrifuged and filtered to remove cell debris. Remaining kinases were produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection. Affinity resins for kinase assays were prepared by treating streptavidin-coated magnetic beads with biotinylated small molecule ligands for 30 min at room temperature. Ligandized 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 reduce nonspecific binding. Binding reactions were assembled by combining kinase, liganded affinity beads and test compounds in 1× binding buffer (20% SeaBlock, 0.17× PBS, 0.05% Tween 20, 6 mM DTT). All reactions were performed in polystyrene 96-well plates in a final volume of 0.135 mL. The assay plate was incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (1× PBS, 0.05% Tween 20). The beads were then resuspended in elution buffer (1× PBS, 0.05% Tween 20, 0.5 μM non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. Kinase concentrations in the eluates were measured by qPCR. Results for compounds tested at a concentration in this assay are reported as "% Ctrl," where a lower number indicates stronger binding in the matrix. %Ctrl was calculated as: (Test compound signal, positive control signal) / (Negative control signal, positive control signal)×100 The dissociation constant (Kd) of the test compound-kinase interaction was calculated by measuring the amount of kinase captured on the solid support as a function of test compound concentration.

[0218] Table 1: Tyrosine kinase selectivity profile of compounds 1 to 5 (%Ctrl at 1 μM) [Table 8] [Table 9] [Table 10] [Table 11]

[0219] Table 2: Dissociation constants (Kd) for the JAK family [Table 12]

[0220] Example 15: Phosphorylation of STAT5 in IFNa-stimulated CD3+ T cells Inhibition of STAT5 phosphorylation in IFNa-stimulated CD3+ T cells was assessed at HD Bioscience, Inc. (6122 Nancy Ridge Drive, San Diego, CA 92121).

[0221] PBMC isolation: Human whole blood was obtained from the San Diego Blood Bank in tubes containing heparin. Peripheral blood mononuclear cells (PBMCs) were isolated by density gradient centrifugation using Lymphoprep. Briefly, 15 mL of Lymphoprep buffer was added to the bottom of a SepMate tube. The tube was immediately centrifuged. 8 mL of blood was diluted with Robosep buffer. The blood / Robosep buffer mixture was added to the tube and centrifuged at 1200 x g for 10 min at room temperature. The pellet was washed with Robosep buffer and centrifuged at 300 x g for 8 min at room temperature. The pellet was resuspended in 10 mL of 1 x RBC lysis buffer and incubated at room temperature for 10 min. The reaction was stopped by adding 20 mL of Robosep buffer. The pellet was spun down and resuspended in 2 mL of Robosep buffer.

[0222] PBMC plating and IFNa treatment: PBMC cells were resuspended at a concentration of 1.25e6 cells / mL. CD3 antibody was added at 1 μL antibody per 90 μL cell suspension. 80 μL / well (1e5 cells) were plated in a 96-well plate. Cells were treated with the indicated compounds and incubated for 30 minutes at 37°C. 20 μL of IFNa (PBL, Cat#11101) was added to the cells and the cells were incubated for 30 minutes at 37°C.

[0223] Fixation, permeabilization, and intracellular staining: After stimulation, PBMC cells were immediately fixed with 500 μL (per well) pre-warmed 1X Lyse / Fix buffer for 10 min at 37°C. Cells were washed with 300 μL FACS staining buffer and centrifuged at 500 xg for 5 min. Cells were thoroughly resuspended in 500 μL BD Phosflow Perm Buffer III. Cells were permeabilized for 30 min at 4°C in the dark. Cells were further washed with 500 μL 1X permeabilization buffer by centrifugation at 500 xg for 5 min and resuspended in 100 μL 1X permeabilization buffer containing 2.5 μL pSTAT5 antibody (BD Biosciences, Cat#562077). Cells were stained for 1 h at room temperature, followed by centrifugation at 500 xg for 5 min and the supernatant was removed. Cells were washed with 300 μL FACS staining buffer in a centrifuge and resuspended in 300 μL FACS buffer. pSTAT5 expression was analyzed by flow cytometry, and the results are shown in Table 3.

[0224] Table 3 [Table 13]

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt thereof; 【Chemistry 1】 I [In the formula, A is, 【Chemistry 2】 and B is 【Transformation 3】 and Each L is independently -C(R 3 )(R 4 )-, -C(O)-, -O-, -N(R 5 )-, -S-, -S(O)- or -S(O) 2 -where: (L) n -OO-, -OS-, -SS-, or -ON(R 5 )-bonds, and (L) n -N(R 9 )- is -ON(R 9 )-, or -SN(R 9 )-bonds; Y and Y 1 are each independently O or S; R 1 , R 1a , and R 2 are independently H, deuterium, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 Aryl, 5- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -OS(O)NR a R b , -OS(O) 2 NR a R b , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR a R b , -NR a S(O)R b , -NR a S(O) 2 R b , -NR a S(O)NR a R b , -NR a S(O) 2 NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -PR a R b , -P(O)R a R b , -P(O) 2 R a R b , -P(O)NR a R b , -P(O) 2 NR a R b , -P(O)OR a , -P(O) 2 OR a , -CN, or -NO 2 where C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 Each hydrogen atom in an aryl or 5- to 10-membered heteroaryl is independently selected from deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e R f , -S(O) 2 NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O) 2 R f , -NR e S(O)NR e R f , -NR e S(O) 2 NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O) 2 R e R f , -P(O)NR e R f , -P(O) 2 NR e R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 optionally substituted with; R 2a , R 5 , R 8 , and R 9 are independently H, deuterium, and C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 aryl, or 5-10 membered heteroaryl, where C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 Each hydrogen atom in an aryl or 5- to 10-membered heteroaryl is independently selected from deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e R f , -S(O) 2 NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O) 2 R f , -NR e S(O)NR e R f , -NR e S(O) 2 NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O) 2 R e R f , -P(O)NR e R f , -P(O) 2 NR e R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 optionally substituted with; R 2b is C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 3 -C 4 cycloalkyl, or 3-4 membered heterocycloalkyl, where C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 3 -C 4 Each hydrogen atom in a cycloalkyl and a 3- to 4-membered heterocycloalkyl is independently selected from deuterium, halogen, —O(H or C 1 -C 2 alkyl), -OC(O)C 1 -C 2 Alkyl, -OC(O)N(H or C 1 -C 2 alkyl) 2 , -OS(O)C 1 -C 2 Alkyl, -OS(O) 2 C 1 -C 2 Alkyl, -OS(O)N(H or C 1 -C 2 alkyl) 2 , -OS(O) 2 N(H or C 1 -C 2 alkyl) 2 , -S(H or C 1 -C 2 alkyl), -S(O)C 1 -C 2 Alkyl, -S(O) 2 C 1 -C 2 Alkyl, -S(O)N(H or C 1 -C 2 alkyl) 2 , -S(O) 2 N(H or C 1 -C 2 alkyl) 2 , -N(H or C 1 -C 2 alkyl) 2 , -N(H or C 1 -C 2 alkyl)C(O)C 1 -C 2 Alkyl, -N(H or C 1 -C 2 alkyl)C(O)O(H or C 1 -C 2 alkyl), -N(H or C 1 -C 2 alkyl)C(O)N(H or C 1 -C 2 alkyl) 2 , -N(H or C 1 -C 2 alkyl)S(O)C 1 -C 2 Alkyl, -N(H or C 1 -C 2 alkyl)S(O) 2 C 1 -C 2 Alkyl, -N(H or C 1 -C 2 alkyl)S(O)N(H or C 1 -C 2 alkyl) 2 , -N(H or C 1 -C 2 alkyl)S(O) 2 N(H or C 1 -C 2 alkyl) 2 , -C(O)C 1 -C 2 Alkyl, -C(O)O(H or C 1 -C 2 alkyl), -C(O)N(H or C 1 -C 2 alkyl) 2 , -P(H or C 1 -C 2 alkyl) 2 , -P(O)(H or C 1 -C 2 alkyl) 2 , -P(O) 2 (H or C 1 -C 2 alkyl) 2 , -P(O)N(H or C 1 -C 2 alkyl) 2 , -P(O) 2 N(H or C 1 -C 2 alkyl) 2 , -P(O)O(H or C 1 -C 2 alkyl), -P(O) 2 O(H or C 1 -C 2 alkyl), -CN, or -NO 2 optionally substituted with; R 3 and R 4 are independently H, deuterium, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 Aryl, 5- to 10-membered heteroaryl, -OR c , -OC(O)R c , -OC(O)NR c R d , -OS(O)R c , -OS(O) 2 R c , -OS(O)NR c R d , -OS(O) 2 NR c R d , -SR c , -S(O)R c , -S(O) 2 R c , -S(O)NR c R d , -S(O) 2 NR c R d , -NR c R d , -NR c C(O)R d , -N(C(O)R c )(C(O)R d ), -NR c C(O)OR d , -NR c C(O)NR c R d , -NR c S(O)R d , -NR c S(O) 2 R d , -NR c S(O)NR c R d , -NR c S(O) 2 NR c R d , -C(O)R c , -C(O)OR c , -C(O)NR c R d , -PR c R d , -P(O)R c R d , -P(O) 2 R c R d , -P(O)NR c R d , -P(O) 2 NR c R d , -P(O)OR c , -P(O) 2 OR c , -CN, -NO 2 or R 3 , R 4 , and R 5 Two of the atoms, together with the atoms to which they are attached, form C 3 -C 6 forms a cycloalkyl or a 4- to 8-membered heterocycloalkyl, where C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 Each hydrogen atom in an aryl or 5- to 10-membered heteroaryl is independently selected from deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e R f , -S(O) 2 NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O) 2 R f , -NR e S(O)NR e R f , -NR e S(O) 2 NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O) 2 R e R f , -P(O)NR e R f , -P(O) 2 NR e R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 optionally substituted with; R 6 and R 7 are independently H, deuterium, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 Aryl, 5- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -OS(O)NR a R b , -OS(O) 2 NR a R b , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR a R b , -NR a S(O)R b , -NR a S(O) 2 R b , -NR a S(O)NR a R b , -NR a S(O) 2 NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -PR a R b , -P(O)R a R b , -P(O) 2 R a R b , -P(O)NR a R b , -P(O) 2 NR a R b , -P(O)OR a , -P(O) 2 OR a , -CN, or -NO 2 or R 6 and R 7 together with the carbon to which they are attached, C 4 -C 6 cycloalkyl, 4- to 7-membered heterocycloalkyl, or C 6 -C 10 aryl, where C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, C 4 -C 6 Cycloalkyl, 4- to 7-membered heterocycloalkyl, C 6 -C 10 Each hydrogen atom in an aryl, 5- to 10-membered heteroaryl, or 4- to 8-membered heterocycloalkyl is independently selected from deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e R f , -S(O) 2 NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O) 2 R f , -NR e S(O)NR e R f , -NR e S(O) 2 NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O) 2 R e R f , -P(O)NR e R f , -P(O) 2 NR e R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 optionally substituted with; R a , R b , R c , R d , R e , and R f are independently H, deuterium, and C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 Aryl, C 1 -C 6 Alkyl-C 6 -C 10 selected from the group consisting of aryl, and 5- to 10-membered heteroaryl; and n is 2, 3, 4, 5, 6, 7, or 8].

2. The compound of claim 1, represented by formula II: 【Chemistry 4】 II or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, represented by formula III: 【Transformation 5】 III or a pharmaceutically acceptable salt thereof.

4. Compounds of formula IV: 【Transformation 6】 IV or A compound of formula V: 【Transformation 7】 V or A compound of formula VI: 【Transformation 8】 VI or Compounds of Formula VIII: 【Chemistry 9】 VIII or A compound of formula X: 【Chemistry 10】 X 2. The compound of claim 1, wherein:

5. Compounds of Formula VII: 【Chemistry 11】 VII or Compounds of Formula IX: 【Chemistry 12】 IX or A compound of formula XI: 【Chemistry 13】 XI or Compounds of Formula XII: 【Chemistry 14】 XII 2. The compound of claim 1, wherein:

6. R 1 If present, H, -CN or C 1 -C 6 alkyl, where C 1 -C 6 Each hydrogen atom in an alkyl can be independently replaced by a deuterium, halogen, or C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e R f , -S(O) 2 NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O) 2 R f , -NR e S(O)NR e R f , -NR e S(O) 2 NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O) 2 R e R f , -P(O)NR e R f , -P(O) 2 NR e R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 or R 1 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is H, —CN, or methyl.

7. R 1a If present, H, -CN or C 1 -C 6 alkyl, where C 1 -C 6 Each hydrogen atom in an alkyl can be independently replaced by a deuterium, halogen, or C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e R f , -S(O) 2 NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O) 2 R f , -NR e S(O)NR e R f , -NR e S(O) 2 NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O) 2 R e R f , -P(O)NR e R f , -P(O) 2 NR e R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 or R 1a 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is H, —CN, or methyl.

8. R 2 If present, H, deuterium, halogens, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 Aryl, 5- to 10-membered heteroaryl, -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -OS(O)NR a R b , -OS(O) 2 NR a R b , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR a R b , -NR a S(O)R b , -NR a S(O) 2 R b , -NR a S(O)NR a R b , -NR a S(O) 2 NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -PR a R b , -P(O)R a R b , -P(O) 2 R a R b , -P(O)NR a R b , -P(O) 2 NR a R b , -P(O)OR a , -P(O) 2 OR a , -CN, or -NO 2 where C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10 Each hydrogen atom in an aryl or 5- to 10-membered heteroaryl is independently selected from deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e R f , -S(O) 2 NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O) 2 R f , -NR e S(O)NR e R f , -NR e S(O) 2 NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O) 2 R e R f , -P(O)NR e R f , -P(O) 2 NR e R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 optionally substituted with; or R 2 If present, H, -CN, or C 1 -C 6 alkyl, where C 1 -C 6 Each hydrogen atom in an alkyl can be independently replaced by a deuterium, halogen, or C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e R f , -S(O) 2 NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O) 2 R f , -NR e S(O)NR e R f , -NR e S(O) 2 NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O) 2 R e R f , -P(O)NR e R f , -P(O) 2 NR e R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 optionally substituted with; or R 2 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, if present, is H, —CN, or methyl.

9. R 2a If present, H or C 1 -C 6 alkyl, where C 1 -C 6 Each hydrogen atom in an alkyl can be independently replaced by a deuterium, halogen, or C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e R f , -S(O) 2 NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O) 2 R f , -NR e S(O)NR e R f , -NR e S(O) 2 NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O) 2 R e R f , -P(O)NR e R f , -P(O) 2 NR e R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 optionally substituted with; or R 2a 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, if present, is H or methyl.

10. R 2b If there is a C 1 -C 4 Alkyl or C 3 -C 4 cycloalkyl, where C 1 -C 6 Alkyl and C 3 -C 4 Each hydrogen atom in a cycloalkyl is independently deuterium or halogen; or R 2b 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, optionally substituted with methyl, ethyl, isopropyl, or cyclopropyl.

11. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 3, or n is 4, or n is 5, or n is 6.

12. Each L is independently -C(O)-, -O-, or -CH 2 -, -C(H)(CH 3 )-, -C(H)(OH)-, -C(H)(C(O)OR c )-, -C(H)(C(O)NR c R d )-, -NH-, and -NCH 3 -; or each L is independently selected from the group consisting of -C(O)-, -O-, -CH 2 -, -C(H)(CH 3 )-, -C(H)(OH)-, -C(H)(C(O)OR c )-, and -C(H)(C(O)NR c R d 2. The compound of claim 1, selected from the group consisting of:

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

14. Y 1 is O, or a pharmaceutically acceptable salt thereof.

15. R 6 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, if present, is independently H, deuterium, fluoro, chloro, -CN, or methyl.

16. R 7 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each is independently H, deuterium, fluoro, chloro, -CN, or methyl.

17. R 8 is H or methyl, or a pharmaceutically acceptable salt thereof.

18. R 9 is H or methyl, or a pharmaceutically acceptable salt thereof.

19. -(L) n -が、-(CH 2 ) 2 -、-(CH 2 ) 3 -、-(CH 2 ) 4 -、-(CH 2 ) 5 -、-(CH 2 ) 6 -C(O)NH-(CH 2 ) 2 O(CH 2 ) 2 -C(O)N(CH 3 )-(CH 2 ) 2 O(CH 2 ) 2 -NHC(O)CH 2 O(CH 2 ) 2 -、-N(CH 3 )-C(O)CH 2 O(CH 2 ) 2 -、-CH 2 O(CH 2 ) 2 -、-CH 2 O(CH 2 ) 3 -、-CH 2 O(C(CH 3 )H) 2 -、-(CH 2 ) 2 O(CH 2 ) 2 -、-CH 2 OCH 2 (C(CH 3 )H)-、-(CH 2 ) 2 OCH 2 (C(CH 3 )H)-、-(CH 2 ) 2 S(CH 2 ) 2 -、-O(CH 2 ) 2 S(CH 2 ) 2 -、-(CH 2 ) 2 SO 2 (CH 2 ) 2 -、-O(CH 2 ) 2 SO 2 (CH 2 ) 2 -、-(CH 2 ) 2 SO(CH 2 ) 2 -、-O(CH 2 ) 2 SO(CH 2 ) 2 -、-(CH 2 ) 2 O(C(H)(C(O)N(H)(CH 3 ))-CH 2 -、-(CH 2 ) 2 O(C(H)(C(O)N(CH 3 ) 2 )-CH 2 -、-(CH 2 ) 2 O(C(H)(C(O)OCH 3 )-CH 2 -、-(CH 2 ) 3 O(CH 2 ) 2 -、-(CH 2 ) 2 O(CH 2 ) 3 -、-CH 2 CH(CH 3 )-O(CH 2 ) 2 -、-CH(CH 3 )-CH 2 O(CH 2 ) 2 -、-O(CH 2 ) 2 -、-O-(CH 2 ) 3 -、-O-(CH 2 ) 4 -、-O-(CH 2 ) 2 CH(CH 3 )-、-OCH 2 O(CH 2 ) 2 -、-O-CH 2 CH(OH)CH 2 -、-O-(CH 2 ) 2 O(CH 2 ) 2 -、-O-CH 2 CH(CH 3 )-O(CH 2 ) 2 -O-CH(CH 3 )-CH 2 O(CH 2 ) 2 -、-O-(CH 2 ) 2 NH-(CH 2 ) 2 -、-O-CH 2 CH(CH 3 )-NH-(CH 2 ) 2 -O-CH(CH 3 )-CH 2 NH-(CH 2 ) 2 -、-CH 2 NH-(CH 2 ) 2 -、-(CH 2 ) 2 NH-(CH 2 ) 2 -、-CH 2 CH(CH 3 )-NH-(CH 2 ) 2 -、-CH(CH 3 )-CH 2 NH-(CH 2 ) 2 -、-O-(CH 2 ) 2 N(CH 3 )-(CH 2 ) 2 -、-O-CH 2 CH(CH 3 )-N(CH 3 )-(CH 2 ) 2 -O-CH(CH 3 )-CH 2 N(CH 3 )-(CH 2 ) 2 -、-CH 2 N(CH 3 )-(CH 2 ) 2 -, -CH 2 N(CH 2 CH 3 )-(CH 2 ) 2 -, -CH 2 N((CH 2 ) 2 CH 3 )-(CH 2 ) 2 -, -CH 2 N(CH(CH 3 ) 2 )-(CH 2 ) 2 -, -(CH 2 ) 2 N(CH 3 )-(CH 2 ) 2 -, -CH 2 CH(CH 3 )-N(CH 3 )-(CH 2 ) 2 - or -O-CH(CH 3 )-CH 2 N(CH 3 )-(CH 2 ) 2 - or -O(CH 2 ) 2 -, -O(CH 2 ) 3 -, -O(CH 2 ) 4 -, -CH 2 OCH 2 (C(CH 3 )H)-, -CH 2 O(CH 2 ) 2 -, or -CH 2 O(CH 2 ) 3 - or -O(CH 2 ) 3 -, -CH 2 OCH 2 (C(CH 3 )H)- or -CH 2 O(CH 2 ) 2 2. The compound of claim 1, wherein:

20. [3a(4)Z]-6,9,15,16-tetramethyl-9,10,11,12-tetrahydro-15H-1,17-(ethanediylidene)pyrazolo[4,3-n]dipyrrolo[3,2-g:3',4'-j][1,5]oxazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-6,9,15,16-tetramethyl-10,11,13,15-tetrahydro-2H-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione; [3a(4)Z,10R]-20-chloro-6,10,15-trimethyl-10,11,13,15-tetrahydro-2H-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-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'-i][1,4]oxazacyclopentadecyne-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-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione; [3a(4)Z,10S]-20-chloro-6,9,10,15-tetramethyl-10,11,13,15-tetrahydro-2H-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione; [3a(4)Z]-20-chloro-6,9,15-trimethyl-10,11,13,15-tetrahydro-2H-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-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-i][1,4]oxazacyclopentadecyne-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-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione; [3a(4)Z,10R]-6,9,10,15-tetramethyl-3,8-dioxo-3,5,8,9,10,11,13,15-octahydro-2H-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecine-20-carbonitrile; [3a(4)Z,10R]-20-fluoro-6,9,10,15,16-pentamethyl-10,11,13,15-tetrahydro-2H-1,17-ethenopyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-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]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione; and [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'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione; 2. The compound of claim 1, selected from the group consisting of:

21. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.

22. 21. Use of a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating an autoimmune disease in a subject.

23. A pharmaceutical composition for treating an autoimmune disease, comprising a compound according to any one of claims 1 to 20.

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