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WO2025010294A2 - Composés macrocycliques et leur utilisation en tant qu'inhibiteurs de tyk2 - Google Patents

Composés macrocycliques et leur utilisation en tant qu'inhibiteurs de tyk2 Download PDF

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WO2025010294A2
WO2025010294A2 PCT/US2024/036607 US2024036607W WO2025010294A2 WO 2025010294 A2 WO2025010294 A2 WO 2025010294A2 US 2024036607 W US2024036607 W US 2024036607W WO 2025010294 A2 WO2025010294 A2 WO 2025010294A2
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alkyl
deuterium
pharmaceutically acceptable
compound
acceptable salt
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WO2025010294A3 (fr
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Jingrong Jean Cui
Eugene Yuanjin Rui
Evan W. Rogers
Dayong Zhai
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Blossomhill Therapeutics Inc
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Blossomhill Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Definitions

  • the present disclosure relates to macrocyclic compounds, pharmaceutical compositions containing macrocyclic compounds, and methods of using macrocyclic compounds to treat disease, such as human autoimmune diseases or inflammatory diseases.
  • the molecular bases leading to various diseases include kinase gain- and loss-of-function mutations, gene amplifications and deletions, splicing changes, and translocations (Wilson LJ, et al New Perspectives, Opportunities, and Challenges in Exploring the Human Protein Kinome. Autoimmune disease Res. 2018, 78:15-29).
  • the critical role of kinases in autoimmune disease and other diseases makes them attractive targets for drug inventions with 52 small molecule kinase inhibitors have been approved and 46 of them for autoimmune disease targeted therapies (Roskoski R Jr, Properties of FDA-approved Small Molecule Protein Kinase Inhibitors: A 2020 Update. Pharmacol Res 2020, 152:104609).
  • JAK-associated pathways by JAK inhibitors has achieved clinical success for a wide array of diseases, including ruxolitinib and fedratinib for myeloproliferative neoplasms, and tofacitinib, upadacitinib, and baricitinib for rheumatoid arthritis and other immune-mediated inflammatory disease (McLoman DP, et al Lancet. 2021, 398:803-816).
  • isoform selective JAK inhibitors and almost all these approved kinase domain ATP competitive JAK inhibitors display significant undesirable adverse effects due to inhibition of multiple JAK family members.
  • the JAK kinases are large multidomain protein including the PER domain [JH6- JH7] and the SH2 domain [JH3-JH5], both mediating receptor interactions, the pseudokinase domain [JH2] with regulatory function, and the kinase catalytic domain [JH1] (Ganido-Trigo A and Salas, A., Journal of Crohn's and Colitis, 2020, S713-S724).
  • the pseudokinase domain regulates the kinase domain by steric inhibition of ATP binding and/or a reduction in flexibility of the kinase active site required for catalysis (Patrick J, et al PNAS 2014 111: 8025-8030).
  • JAK family members have high sequence homology within the catalytic domains, the distinguishing pseudokinase domain (JH2) in the JAK family could provide an ideal “allosteric” site for the development of highly selective JAK inhibitors.
  • TYK2 a member of JAK family, play important role in regulating the signaling of a wide range of proinflammatory cytokines including IL12, IL23, and type 1 interferons (IFNa).
  • IFNa type 1 interferons
  • a highly selective TYK2 inhibitor is needed for an optimal benefit-safety balance for the treatment of human autoimmune diseases including multiple sclerosis, Crohn’s disease, psoriasis, etc. (Leitner, N. R., et al Tyrosine kinase 2- surveillant of tumours and bona fide oncogene. Cytokine 2017, 89, 209-218).
  • the discoveiy and development of highly selective inhibitors of the JAK family such as TYK2 inhibitors targeting the TYK2 JH2 pseudokinase domain represents a new therapeutic invention for the treatment of human autoimmune diseases including multiple sclerosis, Crohn’s disease, psoriasis, and the like.
  • X is -O- or -NR 5 -;
  • R 1 and R 1a are each 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- to 8-membered heterocycloalkyl, C 6 -C 10 aiyl, 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) 2 NR a R b , -OS(O) 2 NR a R b , -OS(O)
  • R 2 is H, deuterium, C 1 -C 6 alkyl, or -OC 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl and -OC 1 -C 6 alkyl is independently optionally substituted by 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)NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e R f , -S(O)NR e R f , -NR e R f , -NR e
  • each of R 2a , R 5 , R 8 , R 9 , and R 11 is independently H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaiyl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C2- -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR e , -OC(O)
  • each of R 6 , R 6 ®, and R 7 is independently H, deuterium, halogen, or C 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted by 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 R f
  • R 10 is hydrogen or deuterium
  • each R a , R b , R c , R d , R e , and R f is independently selected from the group consisting of H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, C 1 -C 6 alkyl -C 6 -Cw aryl, and 5- to 10-membered heteroaryl; [015] provided that when X is -O-, then R 2 is:
  • each hydrogen atom in -OC 1 -C 6 alkyl is independently optionally substituted by 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 R f , -NR e R f , -NR e R f , -NR e R f , -NR e R
  • the disclosure provides a compound of the formula II, or a pharmaceutically acceptable salt thereof, II [020] wherein R 1 , R 1a , R 2 , R 23 , R 3 , R 4 , R 3a , R 4a , R 3b , R 4b , R 6 , R 6a , R 7 , R 8 , R 9 , R 10 , and R 11 are as described herein.
  • the disclosure provides a compound of the formula HI, or a pharmaceutically acceptable salt thereof, in [022] wherein R 1 , R 1a , R 2 , R 21 , R 3 , R 4 , R 3a , R 4a , R 3b , R 4b , R 5 , R 6 , R 6a , R 7 , R 8 , R 9 , R 10 , and R 11 are as described herein.
  • the disclosure provides a compound of the formula VI, or a pharmaceutically acceptable salt thereof, VI [028] wherein R 1 , R 2 , R 2a , R 3a , R 7 , R 8 , R 9 , and R 11 are as described herein.
  • the disclosure provides a compound of the formula VII, or a pharmaceutically acceptable salt thereof, VII [030] wherein R 1 , R 2 , R 2a , R 3a , R 5 , R 7 , R 8 , R 9 , and R 11 are as described herein.
  • the disclosure provides a compound of the formula VIII, or a pharmaceutically acceptable salt thereof,
  • R 1 , R 2 , R 2a , R 3a , R 7 , and R 9 are as described herein.
  • the disclosure provides a compound of the formula IX, or a pharmaceutically acceptable salt thereof,
  • R 1 , R 2 , R 2a , R 3a , R 5 , R 7 , and R 9 are as described herein.
  • the disclosure provides a compound of the formula X, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula XI, or a pharmaceutically acceptable salt thereof,
  • R 1 , R 2 , R 2a , R 3a , R 5 , R 7 , and R 9 are as described herein.
  • the compound of Formula (I)-(XI) is a compound selected from those species described or exemplified in the detailed description below.
  • compositions according to the disclosure relate to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of Formula (I)-(XI) or a pharmaceutically acceptable salt thereof.
  • Pharmaceutical compositions according to the disclosure may further comprise a pharmaceutically acceptable excipient.
  • the disclosure relates to a compound of Formula (I)-(XI), or a pharmaceutically acceptable salt thereof, for use as a medicament.
  • the disclosure relates to a method of treating disease, such as autoimmune disease comprising administering to a subject in need of such treatment an effective amount of at least one compound of Formula (I)-(XI), or a pharmaceutically acceptable salt thereof.
  • the disclosure relates to use of a compound of Formula (I)-(XI), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of disease, such as autoimmune disease, and the use of such compounds and salts for treatment of such diseases.
  • the disclosure relates to a method of inhibiting a tyrosine kinase, such as TYK2, comprising contacting a cell comprising one or more of kinase with an effective amount of at least one compound of Formula (I)-(XI), or a pharmaceutically acceptable salt thereof, and/or with at least one pharmaceutical composition of the disclosure, wherein the contacting is in vitro, ex vivo, or in vivo.
  • a tyrosine kinase such as TYK2
  • X is -O- or -NR 5 -;
  • R 1 and R 1a are each 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- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10- -P(O)NR a R b , -P(O)zNR a R b , -P(O)OR a , -P(O)2OR a , -CN, or -NO2, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium
  • R 2 is H, deuterium, C 1 -C 6 alkyl, or -OC 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl and -OC 1 -C 6 alkyl is independently optionally substituted by 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)iR e , -S(O)NR e R f , -S(O)NR e R f , -NR e R f , -NR
  • each of R 2a , R 5 , R 8 , R 9 , and R 11 is independently H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR e , -OC(O)R
  • each of R 6 , R 6a , and R 7 is independently H, deuterium, halogen, or C 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl independently optionally substituted by 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 R f
  • R 10 is hydrogen or deuterium
  • each R a , R b , R c , R d , R e , and R f is independently selected from the group consisting of H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, C 1 -C 6 alkyl-C 6 -C 10 aryl, and 5- to 10-membered heteroaryl;
  • R 2 is: deuterium; C 1 -C 6 alkyl, wherein at least one hydrogen atom is substituted by 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)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 C(0)R f , -NR e C(O)OR f ,
  • each hydrogen atom in -OC 1 -C 6 alkyl is independently optionally substituted by 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 C(0)R f , -NR e C(0)NR e R f ,
  • a pharmaceutical composition comprising at least one compound of any one of clauses 1 to 31, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.
  • a method of treating disease comprising administering to a subject in need of such treatment an effective amount of a compound of any one of clauses 1 to 31, or a pharmaceutically acceptable salt thereof.
  • alkyl refers to a straight- or branched-chain mono-valent hydrocarbon group.
  • alkylene refers to a straight- or branched-chain di-valent hydrocarbon group.
  • alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.
  • alkylene groups examples include methylene (-CH2-), ethylene ((-CH2-)2), n- propylene ((-CH2-)3), iso-propylene ((-C(H)(CH3)CH2-)), n-butylene ((-CH2-)4), and the like. It will be appreciated that an alkyl or alkylene group can be unsubstituted or substituted as described herein. An alkyl or alkylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.
  • alkenyl refers to a straight- or branched-chain mono-valent hydrocarbon group having one or more double bonds.
  • alkenylene refers to a straight- or branched-chain di-valent hydrocarbon group having one or more double bonds.
  • alkenyl groups include ethenyl (or vinyl), allyl, and but-3-en-l-yl.
  • alkynyl refers to a straight- or branched-chain mono-valent hydrocarbon group having one or more triple bonds.
  • alkynylene refers to a straight- or branched- chain di-valent hydrocarbon group having one or more triple bonds.
  • cycloalkyl refers to a saturated or partially saturated, monocyclic or polycyclic mono-valent carbocycle.
  • cycloalkylene refers to a saturated or partially saturated, monocyclic or polycyclic di-valent carbocycle. In some embodiments, it can be advantageous to limit the number of atoms in a “cycloalkyl” or “cycloalkylene” to a specific range of atoms, such as having 3 to 12 ring atoms.
  • Polycyclic carbocycles include fused, bridged, and spiro polycyclic systems.
  • Illustrative examples of cycloalkyl groups include mono-valent radicals of the following entities, while cycloalkylene groups include di-valent radicals of the following entities, in the form of properly bonded moieties:
  • a cyclopropyl moiety can be depicted by the structural formula
  • a cyclopropylene moiety can be depicted by the structural formula .
  • a cycloalkyl or cycloalkylene group can be unsubstituted or substituted as described herein.
  • a cycloalkyl or cycloalkylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.
  • halogen represents chlorine, fluorine, bromine, or iodine.
  • haloalkyl refers to an alkyl group with one or more halo substituents.
  • haloalkyl groups include -CF3, -(CH2)F, -CHF2, -CH2Br, -CH2CF3, and -CH2CH2F.
  • haloalkylene refers to an alkyl group with one or more halo substituents. Examples of haloalkyl groups include -CF2-, -C(H)(F)-, -C(H)(Br)-, -CH2CF2-, and -CH 2 C(H)(F)-.
  • aryl refers to a mono-valent all -carbon monocyclic or fused-ring polycyclic group having a completely conjugated pi-electron system.
  • arylene refers to a monovalent all-carbon monocyclic or fused-ring polycyclic group having a completely conjugated pi-electron system.
  • aryl or arylene can be advantageous to limit the number of atoms in an “aryl” or “arylene” to a specific range of atoms, such as mono-valent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 14 carbon atoms (C 6 -Cu aryl), mono-valent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 10 carbon atoms (C 6 -Cw aryl), di-valent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 14 carbon atoms (C 6 - C14 arylene), di-valent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 10 carbon atoms (Cs-Cw arylene).
  • C 6 -Cu aryl mono-valent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 14 carbon atoms
  • C 6 -Cw aryl mono-valent all-carbon monocyclic or fused-ring polycyclic groups of 6
  • aryl groups examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl. E-xamples, without limitation, of aryl groups are phenylene, naphtha! enylene and anthracenylene. It will be appreciated that an aryl or arylene group can be unsubstituted or substituted as described herein. An aryl or arylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.
  • heterocycloalkyl refers to a mono-valent monocyclic or polycyclic ring structure that is saturated or partially saturated having one or more non-carbon ring atoms.
  • heterocycloalkylene refers to a mono-valent monocyclic or polycyclic ring structure that is saturated or partially saturated having one or more non-carbon ring atoms.
  • a “heterocycloalkyl” or “heterocycloalkylene” can be advantageous to limit the number of atoms in a “heterocycloalkyl” or “heterocycloalkylene” to a specific range of ring atoms, such as from 3 to 12 ring atoms (3- to 12-membered), or 3 to 7 ring atoms (3- to 7-membered), or 3 to 6 ring atoms (3- to 6- membered), or 4 to 8 ring atoms (4- to 8-membered), or 5 to 7 ring atoms (5- to 7-membered).
  • heterocycloalkyl or “heterocycloalkylene”
  • Polycyclic ring systems include fused, bridged, and spiro systems.
  • the ring structure may optionally contain an oxo group on a carbon ring member or up to two oxo groups on sulfur ring members.
  • heterocycloalkyl groups include mono-valent radicals of the following entities, while heterocycloalkylene groups include di-valent radicals of the following entities, in the form of properly bonded moieties:
  • a three-membered heterocycle may contain at least one heteroatom ring atom, where the heteroatom ring atom is a sulfur, oxygen, or nitrogen.
  • threemembered heterocycle groups include monovalent and divalent radicals of oxirane, azetidine, and thiirane.
  • a four-membered heterocycle may contain at least one heteroatom ring atom, where the heteroatom ring atom is a sulfur, oxygen, or nitrogen.
  • Non-limiting examples of four-membered heterocycle groups include monovalent and divalent radicals of azitidine, oxtenane, and thietane.
  • a five-membered heterocycle can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen.
  • Non-limiting examples of five-membered heterocyle groups include mono-valent and divalent radicals of pyrrolidine, tetrahydrofuran, 2, 5-dihydro-lH- pyrrole, pyrazolidine, thiazolidine, 4,5-dihydro-lH-imidazole, dihydrothiophen-2(3H)-one, tetrahydrothiophene 1,1- dioxide, imidazolidin-2-one, pyrrolidin-2-one, dihydrofuran-2(3H)-one, l,3-dioxolan-2-one, and oxazolidin-2-one.
  • a six-membered heterocycle can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen.
  • Non-limiting examples of six-membered heterocycle groups include mono-valent or divalent radicals of piperidine, morpholine, 4H-l,4-thi azine, 1,2,3,4-tetrahydropyridine, piperazine, l,3-oxazinan-2-one, piperazin-2-one, thiomorpholine, and thiomorpholine 1,1- dioxide.
  • a “heterobicycle” is a fused bicyclic system comprising one heterocycle ring fused to a cycloalkyl or another heterocycle ring.
  • heterocycloalkyl or heterocycloalkylene group can be unsubstituted or substituted as described herein.
  • a heterocycloalkyl or heterocycloalkylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.
  • heteroaryl refers to a mono-valent monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms or members selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) that is fully unsaturated and having from 3 to 12 ring atoms per heterocycle.
  • heteroarylene refers to a di-valent monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms or members selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms per heterocycle.
  • a 5- to 10- membered heteroaryl can be a monocyclic ring or fused bicyclic rings having 5- to 10-ring atoms wherein at least one ring atom is a heteroatom, such as N, O, or S.
  • a 5- to 10-membered heteroarylene can be a monocyclic ring or fused bicyclic rings having 5- to 10-ring atoms wherein at least one ring atom is a heteroatom, such as N, O, or S.
  • Illustrative examples of 5- to 10-membered heteroaryl groups include mono-valent radicals of the following entities, while examples of 5- to 10-membered heteroarylene groups include divalent radicals of the following entities, in the form of properly bonded moieties:
  • a “monocyclic” heteroaryl can be an aromatic five- or six-membered heterocycle.
  • a five-membered heteroaryl or heteroarylene can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen.
  • Non-limiting examples of five-membered heteroaryl groups include mono-valent radicals of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole.
  • Non-limiting examples of fivemembered heteroarylene groups include di-valent radicals of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole.
  • a six-membered heteroaryl or heteroarylene can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen.
  • Non-limiting examples of six-membered heteroaryl groups include monovalent radicals of pyridine, pyrazine, pyrimidine, pyridazine, or triazine.
  • Non-limiting examples of six-membered heteroarylene groups include divalent radicals of pyridine, pyrazine, pyrimidine, pyridazine, or triazine.
  • bicyclic heteroaryl or “bicyclic heteroarylene” is a fused bicyclic system comprising one heteroaryl ring fused to a phenyl or another heteroaryl ring.
  • bicyclic heteroaryl groups include monovalent radicals of quinoline, isoquinoline, quinazoline, quinoxaline, indole, 1,5-naphthyridine, 1,8- naphthyridine, isoquinolin-3(2H)-one, thieno[3,2-Z>]thiophene, lZ/-pyrrolo[2,3-Z>]pyridine, 1H -benzo[t/] imidazole, benzo[d]oxazole, and benzo[d]thiazole.
  • Non-limiting examples of bicyclic heteroarylene groups include divalent radicals of quinoline, isoquinoline, quinazoline, quinoxaline, indole, 1,5-naphthyridine, 1,8-naphthyridine, isoquinolin-3(2H)-one, thieno[3,2- 6]thiophene, 117-pyrrolo[2,3-Z>]pyridine, 1H -benzo[d]imidazole, benzo[ ⁇ 7]oxazole, and benzo[ ⁇ /] thiazole.
  • a pyrrolyl moiety can be depicted by the structural formula
  • a pyrrolylene moiety can be depicted by the structural formula
  • a pyrazolyl moiety can be depicted by the structural formula In
  • heteroaryl or heteroarylene group can be unsubstituted or substituted as described herein.
  • a heteroaryl or heteroarylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.
  • oxo represents a carbonyl oxygen.
  • a cyclopentyl substituted with oxo is cyclopentanone.
  • C 6 rtain chemical entities of Formula (I)-(XI) may be depicted in two or more tautomeric forms. Any and all alternative tautomers are included within the scope of these formulas, and no inference should be made as to whether the chemical entity exists as the tautomeric form in which it is drawn. It will be understood that the chemical entities described herein, and their constituent rings A, B, etc. can exist in different tautomeric forms. It will be readily appreciated by one of skill in the art that because of rapid interconversion, tautomers can generally be considered to be the same chemical compound. Examples of tautomers include but are not limited to enol-keto tautomers, amine-imine tautomers, and the like. Enol form Keto form Lactam form Lactim form
  • a ring option of indolin-2-oneylene can exist as the following tautomers
  • substituted means that the specified group or moiety bears one or more substituents.
  • unsubstituted means that the specified group bears no substituents.
  • substitution is meant to occur at any valency-allowed position on the system.
  • substituted means that the specified group or moiety bears one, two, or three substituents.
  • substituted means that the specified group or moiety bears one or two substituents.
  • substituted means the specified group or moiety bears one substituent.
  • Any formula depicted herein is intended to represent a compound of that structural formula as well as certain variations or forms.
  • a formula given herein is intended to include a racemic form, or one or more enantiomeric, diastereomeric, or geometric isomers, or a mixture thereof.
  • any formula given herein is intended to refer also to a hydrate, solvate, or polymorph of such a compound, or a mixture thereof.
  • any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
  • Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, n C, 13 C, 14 C, 15 N, 18 O, 17 0, 31 P, 32 P, 35 S, 1S F, 36 C1, and 125 I, respectively.
  • Such isotopically labelled compounds are usefill in metabolic studies (preferably with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques [such as positron emission tomography (PET) or singlephoton emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • detection or imaging techniques such as positron emission tomography (PET) or singlephoton emission computed tomography (SPECT)
  • PET positron emission tomography
  • SPECT singlephoton emission computed tomography
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
  • Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • any disubstituent referred to herein is meant to encompass the various attachment possibilities when more than one of such possibilities are allowed.
  • reference to disubstituent -A-B-, where A + B, refers herein to such disubstituent with A attached to a first substituted member and B attached to a second substituted member, and it also refers to such disubstituent with A attached to the second substituted member and B attached to the first substituted member.
  • the disclosure also includes pharmaceutically acceptable salts of the compounds represented by Formula (I)-(XI), preferably of those described above and of the specific compounds exemplified herein, and pharmaceutical compositions comprising such salts, and methods of using such salts.
  • a “pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of a compound represented herein that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S.M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977, 66, 1-19.
  • Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of subjects without undue toxicity, irritation, or allergic response.
  • a compound described herein may possess a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one of each type, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne- 1,4-dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfon
  • a pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as mandelic acid,
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid,
  • the disclosure also relates to pharmaceutically acceptable prodrugs of the compounds of Formula (I)-(X[), and treatment methods employing such pharmaceutically acceptable prodrugs.
  • prodrug means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to the compound of Formula (I)-(XI)).
  • a "pharmaceutically acceptable prodrug” is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject. Illustrative procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.
  • the present disclosure also relates to pharmaceutically active metabolites of compounds of Formula (I)-(XI), and uses of such metabolites in the methods of the disclosure.
  • a “pharmaceutically active metabolite” means a pharmacologically active product of metabolism in the body of a compound of Formula (I)-(XI) or salt thereof.
  • Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertolini et al., J. Med. Chem. 1997, 40, 2011-2016; Shan et al., J. Pharm. Sci. 1997, 86 (7), 765-767; Bagshawe, Drug Dev. Res.
  • protecting group refers to any group as commonly known to one of ordinary skill in the art that can be introduced into a molecule by chemical modification of a functional group, such as an amine or hydroxyl, to obtain chemoselectivity in a subsequent chemical reaction. It will be appreciated that such protecting groups can be subsequently removed from the functional group at a later point in a synthesis to provide further opportunity for reaction at such functional groups or, in the case of a final product, to unmask such functional group.
  • protecting groups have been described in, for example, Wuts, P. G. M., Greene, T. W., Greene, T. W., & John Wiley & Sons. (2006).
  • Suitable amine protecting groups useful in connection with the present disclosure include, but are not limited to, 9-Fluorenylmethyl-carbonyl (FMOC), t- butylcarbonyl (Boc), benzyl oxycarbonyl (Cbz), acetyl (Ac), trifluoroacetyl, phthalimide, benzyl (Bn), triphenylmethyl (trityl, Tr), benzylidene, and p-toluenesulfonyl (tosylamide, Ts).
  • the disclosure provides a compound of the formula I, or a pharmaceutically acceptable salt thereof, I [0129] wherein X, R 1 , R 1a , R 2 , R 2a , R 3 , R 4 , R 3a , R 4a , R 3b , R 4b , R 6 , R 6a , R 7 , R 8 , R 9 , R 10 , and R 11 are as described herein.
  • the disclosure provides a compound of the formula II, or a pharmaceutically acceptable salt thereof, n
  • R 1 , R 1a , R 2 , R 28 , R 3 , R 4 , R 3a , R 4 *, R 3b , R 4b , R 6 , R 6a , R 7 , R 8 , R 9 , R 10 , and R 11 are as described herein.
  • the disclosure provides a compound of the formula m, or a pharmaceutically acceptable salt thereof, in
  • R 1 , R 1a , R 2 , R 21 , R 3 , R 4 , R 3a , R 4 *, R 3b , R 4 **, R 5 , R 6 , R 6a , R 7 , R 8 , R 9 , R 10 , and R 11 are as described herein.
  • the disclosure provides a compound of the formula IV, or a pharmaceutically acceptable salt thereof, IV [0135] wherein R 1 , R 2 , R 2a , R 3a , R 7 , R 8 , R 9 , and R 11 are as described herein.
  • the disclosure provides a compound of the formula V, or a pharmaceutically acceptable salt thereof, V [0137] wherein R 1 , R 2 , R 2a , R 3a , R 5 , R 7 , R 8 , R 9 , and R u are as described herein. [0138] In some embodiments, the disclosure provides a compound of the formula VI, or a pharmaceutically acceptable salt thereof, VI [0139] wherein R 1 , R 2 , R 28 , R 3a , R 7 , R 8 , R 9 , and R 11 are as described herein. [0140] In some embodiments, the disclosure provides a compound of the formula XU, or a pharmaceutically acceptable salt thereof,
  • R 1 , R 2 , R 2a , R 3a , R 5 , R 7 , R 8 , R 9 , and R 11 are as described herein.
  • the disclosure provides a compound of the formula VIII, or a pharmaceutically acceptable salt thereof,
  • R 1 , R 2 , R 2a , R 3a , R 7 , and R 9 are as described herein.
  • the disclosure provides a compound of the formula IX, or a pharmaceutically acceptable salt thereof,
  • R 1 , R 2 , R 2a , R 3a , R 5 , R 7 , and R 9 are as described herein.
  • the disclosure provides a compound of the formula X, or a pharmaceutically acceptable salt thereof,
  • R 1 , R 2 , R 2a , R 3a , R 7 , and R 9 are as described herein.
  • the disclosure provides a compound of the formula XI, or a pharmaceutically acceptable salt thereof, XI
  • R 1 , R 2 , R 2a , R 3a , R 5 , R 7 , and R 9 are as described herein.
  • R 1 and R 1a are each 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- to 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 , -OS(O) 2 NR
  • R 1 is H, deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 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 , -OS(O)NR a R b , -
  • R 1a is H, deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 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 , -OS(O)NR a R b ,
  • R 1 is H, deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 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 , -OS(O)NR a R b , -
  • R 1 is H, deuterium, halogen, or C 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 8- membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR e , -OC(O)R e , -P(O) 2 OR e , -CN, or -NO2.
  • R 1 is H, deuterium, halogen, or C 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 8- membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR e , -OC(O)R e ,
  • R 1 is H, deuterium, fluoro, or methyl. In some embodiments, R 1 is H, deuterium, fluoro, chloro, or methyl.
  • R 1 is H, deuterium, fluoro, or methyl; and R 1a is H. In some embodiments, R 1 is H, deuterium, fluoro, chloro, or methyl; and R 1a is H.
  • R 2 is H, deuterium, C 1 -C 6 alkyl, or -OC 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl and -O C 1 -C 6 alkyl is independently optionally substituted by 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 ,
  • R 2 is H, deuterium, C 1 -C 6 alkyl, or -OC 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl and -OC 1 -C 6 alkyl is independently optionally substituted by 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 , -OSCOJNR 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(0) 2 NR e R f , -NR e R f , -NR e R
  • R 2 is H
  • X is -NR 5 -
  • R 2a is optionally substituted ethyl
  • R 7 is optionally substituted C 1 -C 6 alkyl (e.g., methyl).
  • R 2 is H, deuterium, C 1 -C 6 alkyl, or -OC 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl and -OC 1 -C 6 alkyl is independently optionally substituted by 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)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
  • R 2 is H, deuterium, or -OCH3; and R 2a is C 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or -OR e .
  • R 2a is deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 8-membered heterocycloalkyl, Cs-C 10 aryl, or 5- to 10- membered heteroaryl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10- membered heteroaryl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR e , -OC(O)R e , -0C
  • R 2a is H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -P(O)OR e , -P(O) 2 OR e , -CN, or -
  • R 21 is C 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR*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 ,
  • R 2a is C 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or -OR e .
  • R 2a is C 1 -C 6 alkyl, such as methyl, ethyl, or isopropyl, optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or -OR e .
  • X is -O-
  • R 2 is deuterium
  • R 2 is C 1 -C 6 alkyl, wherein at least one hydrogen atom is optionally substituted by 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 , -S(O) 2 NR e R f , -NR e C(O)OR f , -NR e C(O)
  • X is -O-
  • R 2 is deuterium
  • R 2 is C 1 -C 6 alkyl, wherein at least one hydrogen atom is substituted by 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)NR e R f , -S(O)NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(0)0R f , -NR e C
  • R 2 is -OC 1 -C 6 alkyl, wherein each hydrogen atom in -OC 1 -C 6 alkyl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -P(O)OR e , -P(0) 2 OR e , -CN, or -NO 2 .
  • X is -O-
  • R 2 is deuterium
  • R 2 is C 1 -C 6 alkyl, wherein at least one hydrogen atom is optionally substituted by 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 , -O8(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 , -S(O) 2 NR e R f , -S(O) 2 NR e R f , -NR e C(O)R f , -NR e C
  • R 2a is C 1 -C 6 alkyl, such as methyl, ethyl, or isopropyl.
  • X is -O-
  • R 2 is C 1 -C 6 alkyl, wherein at least one hydrogen atom is optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 .
  • X is -O-
  • R 2 is C 1 -C 6 alkyl, wherein at least one hydrogen atom is substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 .
  • X is -O-
  • R 2 is C 1 -C 6 alkyl, wherein at least one hydrogen atom is optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -P(O)OR e , -P(O) 2 OR e , -CN, or -NO2
  • R 2a is C 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted by 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)2R e , -OS(O)NR e R f , -OS(O) 2 NR NR NR NR f
  • X is -O-
  • R 2 is C 1 -C 6 alkyl, wherein at least one hydrogen atom is substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(OJR*R.
  • R 2a is C 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted by 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 ,
  • X is -O-
  • R 2 is C 1 -C 6 alkyl, wherein at least one hydrogen atom is optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -P(O)OR e , -P(O) 2 OR e , -CN, or -NCh
  • R 2a is C 1 -C 6 alkyl, such as methyl, ethyl, or isopropyl.
  • X is -O-
  • R 2 is C 1 -C 6 alkyl, wherein at least one hydrogen atom is substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -P(O)OR e , -P(O) 2 OR e , -CN, or -NCh
  • R 28 is C 1 -C 6 alkyl, such as methyl, ethyl, or isopropyl.
  • X is -O-
  • R 2 is -OC 1 -C 6 alkyl, wherein each hydrogen atom in -OC 1 -C 6 alkyl is independently optionally substituted by 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 , -0S(0)NR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R e , -StO ⁇ R e , -S(O)NR e R f , -S(O) 2 NR e R f , -NR e C(0)R f , -NR
  • X is -O-
  • R 2 is -OC 1 -C 6 alkyl, wherein each hydrogen atom in -OC 1 -C 6 alkyl is independently optionally substituted by 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)NR e R f , -SR e , -S(O)R e , -S(O) 2 R e -S(O)NR e R f , -S(O)NR e R f , -NR e C(0)R f , wherein each hydrogen atom in -OC 1 -C 6 alkyl is independently optionally substitute
  • X is -O-
  • R 2 is -OC 1 -C 6 alkyl, wherein each hydrogen atom in -OC 1 -C 6 alkyl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR e , -OC(O)R e , -0C(0)NRR f , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -P(0)NRR f , -P(0) 2 NRR f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 ; and R 2a is C 1 -C 6 alkyl, such as methyl, ethyl, or isopropyl.
  • X is -O-
  • R 2 is deuterium
  • R 2a is ethyl, wherein each hydrogen atom in ethyl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -P(O)OR e , -P(0) 2 OR e , -CN, or -NO 2 , or
  • R 7 is C 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -P(O) ORe - P(O) 2 OR e -CN, or -NO 2 , or
  • R 2 is C 1 -C 6 alkyl, wherein at least one hydrogen atom is substituted by 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 , -0S(O) 2 R e
  • R 2 is -OC 1 -C 6 alkyl, wherein each hydrogen atom in -OC 1 -C 6 alkyl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -P(O)OR e , -P ⁇ OR e , -CN, or -NO 2 .
  • X is -O- and R 2a is ethyl, wherein each hydrogen atom in ethyl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 .
  • X is -O- and R 7 is C 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl independently optionally substituted by 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)NR e R f , -SR e , -S(O)R e , -S(0 ⁇ , -S(O)NR e R f , -S(O)NR e R f , -NR e R f , -NR e C(0)R f , -NR e C(O)OR f ,
  • X is -O- and R 7 is C 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl independently optionally substituted by -OR e .
  • X is -O- and R 7 is methyl, wherein each hydrogen atom in methyl is independently optionally substituted by 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)2R 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 , -8(0 ⁇ %
  • R 2a is C 1 -C 6 alkyl (e.g., methyl or ethyl), wherein each hydrogen atom is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR e (e.g., OH), -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -0S(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.
  • -OR e e.g., OH
  • -OC(O)R e e.g., -OC(
  • R 2a is optionally substituted C 1 -C 6 alkyl (e.g., methyl).
  • R 3 and R 4 are each 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- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -OR e , -OC(O)R e , -OC(O)NR c R d , wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -
  • R 3a and R 4a are each 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- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -OR e , -OC(O)R e , -OC(O)NR c R d , wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1
  • R 3b and R 4 4 b 6 are each 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- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -OR e , -OC(O)R e , -OC(O)NR c R d , wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl
  • R 3 and R 4 are each independently H, deuterium, or Ci-Cb alkyl; wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted by 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 ,
  • R 3a and R 4a are each independently H, deuterium, or C i-C 6 alkyl; wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted by 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 C(O)R f
  • R 3b and R* are each independently H, deuterium, or C 1 -C 6 alkyl; wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR’R' -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 C(O)R f ,
  • R 3 ® is H, deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered -P(O) 2 NR c R d , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO2; wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C 1 -
  • R 3a and R 4a are each independently H, deuterium, or C 1 -C 6 alkyl; wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted by 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 C(O)R
  • R 3a is H, deuterium, or C 1 -C 6 alkyl; wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, -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 ; and each of R 3 , R 4 , R 4 *, R 3b , and R 4b is independently H or deuterium .
  • R 3 ® is H, deuterium, or methyl; and each of R 3 , R 4 , R 4a , R 3b , and R 4b is independently H or deuterium.
  • R 5 is H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaiyl, wherein each hydrogen atom in C 1 -C 6 alkyl, Cj-C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -P(O)OR e , -P(0)20R e , -CN, or -NO 2
  • R 5 is H, deuterium, or C 1 -C 6 alkyl, wherein each hydrogen atom in Cj-C 6 alkyl is independently optionally substituted by 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 , -8(0) ⁇ ®, -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
  • R 5 is H, deuterium, or C 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or -OR e .
  • R 5 is H, deuterium, or C 1 -C 6 alkyl, such as methyl, ethyl, or isopropyl. In some embodiments, R 5 is H or methyl. In some embodiments, R 5 is methyl. In some embodiments, if R 5 is H, methyl, or difluoroethyl, then R 2a is optionally substituted C 1 -C 6 alkyl (e.g., methyl).
  • each of R 6 , R 6 ®, and R 7 is independently H, deuterium, halogen, or C 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR e , -OC(O)R e , -P(O) 2 OR e , -CN, or -NO 2 .
  • each of R 6 and R 6a is independently H or deuterium.
  • R 6 is H, deuterium, halogen, or C 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl independently optionally substituted by 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 , -8(0) ⁇ ®, -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
  • R 7 is H, deuterium, halogen, or C 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl independently optionally substituted by 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 ,
  • R 7 is H, deuterium, halogen, or C 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR*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 C(0)R f , -NR
  • R 7 is H, deuterium, halogen, or C 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl independently optionally substituted by 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)2R 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(0) 2 NR e R f , -NR e R f , -NR e R f , -NR e C(O)R f , -
  • R 8 is H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -P(O)OR e , -P ⁇ OR e , -CN, or -NO 2 .
  • R 8 is H, deuterium, or C 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted by 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 C(O)R f , -NR
  • R 8 is H, deuterium, or C 1 -C 6 alkyl, such as methyl, ethyl, or isopropyl. In some embodiments, R 8 is H or methyl. In some embodiments, R 8 is hydrogen.
  • R 9 is H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -P(OK)R e , -P(0) 2 OR e , -CN, or -NO 2
  • R 9 is H, deuterium, or C 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted by 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 R f , -NR e C(0)R f , -NR e C(0)
  • R 9 is H, deuterium, or C 1 -C 6 alkyl, such as methyl, ethyl, or isopropyl. In some embodiments, R 9 is H or methyl. In some embodiments, R 9 is methyl.
  • R 10 is H or deuterium. In some embodiments, R 10 is H. In some embodiments, R 10 is deuterium. [0221] In some embodiments, R 11 is H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 8-membered heterocycloalkyl, Cg-C 10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 8-membered heterocycloalkyl, Cg-C 10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6
  • R 11 is H, deuterium, or C 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted by 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)zR e , -OS(O)NR e R f ,
  • R 11 is H, deuterium, or C 1 -C 6 alkyl, such as methyl, ethyl, or iso-propyl. In some embodiments, R 11 is H or methyl. In some embodiments, R 11 is methyl.
  • the disclosure provides a compound selected from the group consisting of [3a(4)Z, 10R]-20-chloro-6,9, 10, 15-tetramethyl-2,5,9, 10, 11 , 12, 13, 15-octahydro-
  • the compound is not
  • the compound is not:
  • X is -O- or -NR 3 -;
  • R 1 and R 1a are each 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- to 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) 2 NR a R b , -OS(O)NR a R b , -OS(O) 2 NR
  • R 2 is H, deuterium, C 1 -C 6 alkyl, or -OC 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl and -OC 1 -C 6 alkyl is independently optionally substituted by 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 ,
  • each of R 2a , R 5 , R 8 , R 9 , and R 11 is independently H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR e , -OC(O)R
  • each of R 3 , R 4 , R 3a , R 4a , R 3b , and R 4b is 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- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -OR e , -OC(O)R e , -OC(O)NR c R d , wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, and 5- to 10-membered heteroaiyl is independently optionally substituted by deuterium,
  • each of R 6 , R 6a , and R 7 is independently H, deuterium, halogen, or C 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR e , -0C(0)R e , --OC(O)NR e R, f -OS(O)R e , -0S(O) 2 R e -0S(0)NR e R f , -0S(0) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(0)NR e R f , -S(O) 2 NR e R f , -NR e C(0)R f , -OR e , -0C(0)R e
  • R 10 is hydrogen or deuterium
  • each R a , R b , R c , R d , R e , and R f is independently selected from the group consisting of H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Cg-C 6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, C 1 -C 6 alkyl -C 6 -Cw aryl, and 5- to 10-membered heteroaryl;
  • R 2 is deuterium
  • R 2a is ethyl, wherein each hydrogen atom in ethyl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -P(O)OR e , -P(O)OR e , -CN, or -NO 2 , or
  • R 7 is C 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -P(O)OR e , -P ⁇ OR e , -CN, or -NO 2 , or [0252] R 2 is C 1 -C 6 alkyl, wherein at least one hydrogen atom is substituted by 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)NR e R f , -OS(O)NR e R f ,
  • X is -O- or -NR 5 -;
  • R 1 and R 1a are each 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- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -OR e , -OC(O)R e , -OC(O)NR a R b , -OS(O)R e , -OS(O) 2 R a , -SR e , -P(O)NR e R b , -P(O)zNR e R b , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 , wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2
  • R 2 is H, deuterium, C 1 -C 6 alkyl, or -OC 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl and -OC 1 -C 6 alkyl is independently optionally substituted by 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)iR e , -S(O)NR e R f , -S(O) 2 NR e R f , -NR e C(O
  • each of R 2a , R 5 , R 8 , R 9 , and R 11 is independently H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10- membered heteroaryl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR e , -OC(O)R
  • each of R 3 , R 4 , R 3a , R 4a , R 3b , and R 4b is 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- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -OR e , -OC(O)R e , -OC(O)NR c R d , wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium,
  • each of R 6 , R 6a , and R 7 is independently H, deuterium, halogen, or C 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl independently optionally substituted by 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 ,
  • R 10 is hydrogen or deuterium
  • each R a , R b , R c , R d , R e , and R f is independently selected from the group consisting of H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, C 1 -C 6 alkyl-C 6 -C 10 aryl, and 5- to 10-membered heteroaryl;
  • R 2 is deuterium
  • R 2 is C 1 -C 6 alkyl, wherein at least one hydrogen atom is substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR*R f , -OS(O)R e , -OS(OhR 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 , -S(O) 2 NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -
  • [0299] 34 The compound of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, selected from the group consisting of [3a(4)Z,10R]-20-chloro-6,9,10,15-tetramethyl- 2,5,9,10,11,12, 13, 15-octahydro-l,17-ethenopyrazolo[4,3-/w]dipyrrolo[3,2-f3', 4'- z] [ 1 ,4]di azacyclopen tadecine-3 , 8-dione;
  • a pharmaceutical composition comprising at least one compound of any one of embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.
  • a method of treating disease comprising administering to a subject in need of such treatment an effective amount of a compound of any one of embodiments 1 to 34, or a pharmaceutically acceptable salt thereof.
  • compositions comprising the compounds described herein may further comprise one or more pharmaceutically-acceptable excipients.
  • a pharmaceutically-acceptable excipient is a substance that is non-toxic and otherwise biologically suitable for administration to a subject. Such excipients facilitate administration of the compounds described herein and are compatible with the active ingredient. Examples of pharmaceutically-acceptable excipients include stabilizers, lubricants, surfactants, diluents, anti-oxidants, binders, coloring agents, bulking agents, emulsifiers, or taste-modifying agents.
  • pharmaceutical compositions according to the disclosure are sterile compositions. Pharmaceutical compositions may be prepared using compounding techniques known or that become available to those skilled in the art.
  • compositions are also contemplated by the disclosure, including compositions that are in accord with national and local regulations governing such compositions.
  • compositions and compounds described herein may be formulated as solutions, emulsions, suspensions, or dispersions in suitable pharmaceutical solvents or carriers, or as pills, tablets, lozenges, suppositories, sachets, dragees, granules, powders, powders for reconstitution, or capsules along with solid carriers according to conventional methods known in the art for preparation of various dosage forms.
  • Pharmaceutical compositions of the disclosure may be administered by a suitable route of delivery, such as oral, parenteral, rectal, nasal, topical, or ocular routes, or by inhalation.
  • the compositions are formulated for intravenous or oral administration.
  • the compounds the disclosure may be provided in a solid form, such as a tablet or capsule, or as a solution, emulsion, or suspension.
  • the compounds of the disclosure may be formulated to yield a dosage of, e.g., from about 0.1 mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to 1 g daily.
  • Oral tablets may include the active ingredients) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents.
  • Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like.
  • Exemplary liquid oral excipients include ethanol, glycerol, water, and the like.
  • Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are exemplary disintegrating agents.
  • Binding agents may include starch and gelatin.
  • the lubricating agent if present, may be magnesium stearate, stearic acid, or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.
  • Capsules for oral administration include hard and soft gelatin capsules.
  • active ingredients may be mixed with a solid, semi-solid, or liquid diluent.
  • Soft gelatin capsules may be prepared by mixing the active ingredient with water, an oil, such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.
  • Liquids for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.
  • suspending agents for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethyl
  • the agents of the disclosure may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil.
  • Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride.
  • Such forms may be presented in unit-dose form such as ampoules or disposable injection devices, in multidose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation.
  • Illustrative infusion doses range from about 1 to 1000 pg/kg/minute of agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.
  • inventive pharmaceutical compositions may be administered using, for example, a spray formulation also containing a suitable carrier.
  • inventive compositions may be formulated for rectal administration as a suppository.
  • the compounds of the present disclosure are preferably formulated as creams or ointments or a similar vehicle suitable for topical administration.
  • the inventive compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle.
  • Another mode of administering the agents of the disclosure may utilize a patch formulation to effect transdermal delivery.
  • the terms “treat” or “treatment” encompass both “preventative” and “curative” treatment.
  • “Preventative” treatment is meant to indicate a postponement of development of a disease, a symptom of a disease, or medical condition, suppressing symptoms that may appear, or reducing the risk of developing or recurrence of a disease or symptom.
  • “Curative” treatment includes reducing the severity of or suppressing the worsening of an existing disease, symptom, or condition.
  • treatment includes ameliorating or preventing the worsening of existing disease symptoms, preventing additional symptoms from occurring, ameliorating or preventing the underlying systemic causes of symptoms, inhibiting the disorder or disease, e.g., arresting the development of the disorder or disease, relieving the disorder or disease, causing regression of the disorder or disease, relieving a condition caused by the disease or disorder, or stopping the symptoms of the disease or disorder.
  • subject refers to a mammalian patient in need of such treatment, such as a human.
  • Exemplary diseases include autoimmune diseases and inflammation.
  • Autoimmune diseases include, for example, rheumatoid arthritis, psoriasis, inflammatory bowel disease and systemic lupus erythematosus, Sjogren syndrome, Type I diabetes, and lupus.
  • Exemplary neurological diseases include Alzheimer’s Disease, Parkinson’s Disease, Amyotrophic lateral sclerosis, and Huntington’s disease.
  • exemplary neurological diseases include Alzheimer’s Disease, Parkinson’s Disease, multiple sclerosis (MS), Amyotrophic lateral sclerosis, and Huntington’s disease
  • Exemplary inflammatory diseases include atherosclerosis, allergy, and inflammation from infection or injury.
  • the compounds and pharmaceutical compositions of the disclosure specifically target TYK2.
  • these compounds and pharmaceutical compositions can be used to prevent, reverse, slow, or inhibit the activity of TYK2.
  • methods of treatment target autoimmune disease.
  • methods are for treating autoimmune disease, such as rheumatoid arthritis, psoriasis, inflammatory bowel disease and systemic lupus erythematosus, Sjogren syndrome, Type I diabetes, and lupus.
  • an “effective amount” means an amount sufficient to inhibit the target protein. Measuring such target modulation may be performed by routine analytical methods such as those described below. Such modulation is useful in a variety of settings, including in vitro assays.
  • the cell is preferably an autoimmune disease cell with abnormal signaling due to upregulation of TYK2.
  • an “effective amount” means an amount or dose sufficient to generally bring about the desired therapeutic benefit in subjects needing such treatment.
  • Effective amounts or doses of the compounds of the disclosure may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the infection, the subject’s health status, condition, and weight, and the judgment of the treating physician.
  • An exemplary dose is in the range of about from about 0.1 mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to 1 g daily.
  • the total dosage may be given in single or divided dosage units (e.g., BID, TID, QID).
  • the dose may be adjusted for preventative or maintenance treatment.
  • the dosage or the frequency of administration, or both may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained.
  • treatment may cease.
  • Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms. Patients may also require chronic treatment on a long-term basis.
  • inventive compounds described herein may be used in pharmaceutical compositions or methods in combination with one or more additional active ingredients in the treatment of the diseases and disorders described herein.
  • Further additional active ingredients include other therapeutics or agents that mitigate adverse effects of therapies for the intended disease targets. Such combinations may serve to increase efficacy, ameliorate other disease symptoms, decrease one or more side effects, or decrease the required dose of an inventive compound.
  • the additional active ingredients may be administered in a separate pharmaceutical composition from a compound of the present disclosure or may be included with a compound of the present disclosure in a single pharmaceutical composition.
  • the additional active ingredients may be administered simultaneously with, prior to, or after administration of a compound of the present disclosure.
  • Combination agents include additional active ingredients are those that are known or discovered to be effective in treating the diseases and disorders described herein, including those active against another target associated with the disease.
  • compositions and formulations of the disclosure, as well as methods of treatment can further comprise other drugs or pharmaceuticals, e.g., other active agents useful for treating or palliative for the target diseases or related symptoms or conditions.
  • Step 1 To a solution of commercially available l-methylpyazole-3 -carboxamide (5 g, 39.9 mmol, 1 eq) in dioxane (50 mL) was added LiAlH, (4.55 g, 119 mmol, 3 eq) at 0 °C. The mixture was stirred at 100 °C for 3 h. On completion, the mixture was quenched by H2O (5 mL) and 15% NaOH (5 mL), filtered, the filtrate was diluted with H2O (50 mL), and extracted with EtOAc (50 mL x 2).
  • Step 2 To a solution of (l-methylpyrazol-3-yl)methanamine (5 g, 44.9 mmol, 1 eq) in sat. NaHCO 3 (20 mL) in THF (20 mL) was added CbzCI (11.5 g, 67.4 mmol, 9.59 mL, 1.5 eq). The mixture was stirred at 25 °C for 2 h. On completion, the reaction mixture was partitioned between ethyl acetate (50 mL x 3) and water (50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue.
  • Step 3 To a solution of benzyl ⁇ -[(l-methylpyrazol-3-yl)methyl]carbamate (5.19 g, 21.1 mmol, 1 eq) in ACN (50 mL) was added NBS (3.77 g, 21.1 mmol, 1 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. On completion. The mixture was quenched with sat. Na2SO3 (50 mL) at 0 °C and extracted with ethyl acetate (30 mL x 3). The combined organic phase was dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated to give a residue.
  • Step 4 To a solution of benzyl A r -[(4-bromo-l-methyl-pyrazol-3-yl)methyl]carbamate (6 g, 18.5 mmol, 1 eq) in DMF (120 mL) was added NaH (1.48 g, 37.0 mmol, 60% purity, 2 eq), and the mixture was stirred at 25 °C for 0.5 h.
  • Commercially available Tert-butyl (4R)-4- methyl-2,2-dioxo-oxathiazolidine-3-carboxylate (6.59 g, 27.7 mmol, 1.5 eq) was then added, and the mixture was stirred at 25 °C for 1 h.
  • Step 5 To a solution of benzyl N-[(4-bromo-l-methyl-pyrazol-3-yl)methyl]- N-[(2R)-
  • Step 1 To a solution of commercially available methyl 5-hydroxy-l-methyl-pyrazole- 3-carboxylate (20.0 g, 128 mmol, 1 eq) in DMF (50 mL) was added Mel (21.8 g, 153 mmol, 1.2 eq) and K2CO3 (26.5 g, 192 mmol, 1.5 eq). The mixture was stirred at 25 °C for 12 hours. On completion, the mixture was quenched with H2O (1000 mL) and extracted with EA (200 mL x 3).
  • Step 2 To a solution of methyl 5-methoxy-l-methyl-pyrazole-3-carboxylate (13.0 g, 76.4 mmol, 1 eq) in THF (20 mL) was added LAH (2.5 M, 30.6 mL, 1 eq) at 0 °C, and the mixture was stirred at 25 °C for 2 hours. On completion, the mixture was quenched by H 2 O (3 mL) and 15% NaOH (3 mL), diluted with H2O (9 mL), extracted with EtOAc (75 mL x 3).
  • Step 4 To a solution of (4-bromo-5-methoxy-l-methyl-pyrazol-3-yl)methanol (7.00 g, 31.6 mmol, 1 eq) in DCM (20 mL) was added PPh 3 (12.4 g, 47.5 mmol, 1.5 eq) and CBr 4 (15.7 g, 47.5 mmol, 1.5 eq). The mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was concentrated under reduced pressure.
  • Step 5 To a solution of 4-bromo-3-(bromomethyl)-5-methoxy-l-methyl-pyrazole (4.00 g, 14.0 mmol, 1 eq) and commercially available tert-butyl N-[(1R)-2-hydroxy-l -methyl - ethylcarbamate (2.96 g, 16.9 mmol, 1.2 eq) in THF (25 mL) was added TBAC (391 mg, 1.41 mmol, 0.1 eq) and KOH (2.37 g, 42.2 mmol, 3 eq), and the mixture was stirred at 25 °C for 12 hours.
  • Step 6 To a solution of tert-butyl N- [(1R)-2-[(4-bromo- 5 -methoxy- 1 -methyl -pyrazol- 3-yl) methoxy]-1 -methyl -ethyl] carbamate (4.20 g, 11.1 mmol, 1 eq) in DMF (20 mL) was added NaH (888 mg, 22.2 mmol, 60% purity, 2 eq). The mixture was stirred at 0 °C for 0.5 hours, then CH3I (1.89 g, 13.3 mmol, 1.2 eq) was added into the mixture, and the mixture was stirred at 0 °C for 1 hour.
  • Step 2 To a solution of l-(4-bromo-5-methoxy-l-methyl-pyrazol-3-yl)-N-methyl- methanamine (4.50 g, 19.2 mmol, 1 eq) in DMF (100 mL) was added NaH (1.54 g, 38.4 mmol, 60% purity, 2 eq) at 0 °C, and then commercially available tert-butyl(4R)-4-methyl-2,2-dioxo- oxathiazolidine-3-caiboxylate (6.84 g, 28.8 mmol, 1.5 eq) was added. The mixture was stirred at 25 °C for 1 hour.
  • Step 3 To a solution of tert-butyl A ⁇ -[( 1R)-2 -[(4-bromo- 5 -methoxy- 1 -methyl -pyrazol-
  • Step 4 To a solution of (2R)-N1-[(5-methoxy-l-methyl-pyrazol-3-yl)methyl]-N1N 2- dimethyl-propane-l,2-diamine (1.45 g, 6.41 mmol, 1 eq) in DCM (50 mL) was added TEA (1.94 g, 19.2 mmol, 3 eq) and tert-butoxycarbonyl tert-butyl carbonate (2.80 g, 12.8 mmol, 2 eq). The mixture was stirred at 25 °C for 2 hours. On completion, the mixture was filtered and concentrated to give a residue.
  • Step 5 A mixture of tert-butyl N-[(1R)-2-[(5-methoxy-l-methyl-pyrazol-3-yl)methyl- methyl-amino]-l-methyl-ethyl]-A-methyl-carbamate (1.60 g, 4.90 mmol, 1 eq) and NBS (872 mg, 4.90 mmol, 1 eq) in ACN (30 mL) was degassed and purged with N 2 3 times, and then the mixture was stirred at 0 °C for 2 hours under N 2 atmosphere.
  • Step 1 To a solution of commercially available l-ethyl-lH-pyrazole-3-carbaldehyde (5.00 g, 40.3 mmol, 1 eq) in THF (50 mL) was added LiAlH 4 (2.5 M, 17.7 mL, 1.1 eq) at 0 °C. The mixture was stirred at 25 °C for 30 min.
  • Step 2 To a solution of tert-butyl (R)-4-methyl-l,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (9.40 g, 39.6 mmol, 1 eq) in DMF (52 mL) was added NaH (3.17 g, 79.3 mmol, 60% purity, 2 eq) at 0 °C and stirred at 25 °C for 30 min. Then commercially available (1- ethyl-lH-pyrazol-3-yl)m ethanol (5.00 g, 39.6 mmol, 1 eq) was added to the mixture and stirred at 25 °C for 30 min.
  • Step 3 To a solution of tert-butyl (R)-(l-((l-ethyl-lH-pyrazol-3-yl)methoxy)propan- 2-yl)carbamate (6.50 g, 22.9 mmol, 1 eq) in DMF (65 mL) was added NaH (2.02 g, 50.5 mmol, 60% purity, 2.2 eq) at 0 °C and stirred at 25 °C for 30 min. Then Mel (3.91 g, 27.5 mmol, 1.71 mL, 1.2 eq) was added to the mixture and stirred at 25 °C for 30 min.
  • Step 2 To a solution of 4-bromo-3-(bromomethyl)-l-methyl-lH-pyrazole (9.76 g, 38.4 mmol, 1 eq) in THF (100 mL) was added commercially available tert-butyl (R)-(l- hydroxypropan-2-yl)carbamate (8.08 g, 46.1mmol, 1.2 eq), TBAI (1.42 g, 3.84 mmol, 0.1 eq) and KOH (6.47 g, 115 mmol, 3 eq). The mixture was stirred at 25 °C for 16 hours under N2.
  • Step 1 To a mixture of commercially available 2-bromoethanol (5.00 g, 40.0 mmol, 2.84 mL, 1 eq), imidazole (8.17 g, 120 mmol, 3 eq) in DCM (50 mL) at 0 °C was added TBDPS-C1 (13.2 g, 48.0 mmol, 12.3 mL, 1.2 eq). On completion, the mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated in vacuum.
  • Step 2 To a mixture of commercially available methyl lH-pyrazole-3-carboxylate (2.50 g, 19.8 mmol, 1 eq), K2CO3 (8.22 g, 59.4 mmol, 3 eq) in DMF (30 mL) at 25 °C was added (2-bromoethoxy)(tert-butyl)diphenylsilane (10.8 g, 29.7 mmol, 1.5 eq). The mixture was stirred at 80 °C for 16 h. To the reaction mixture was added water (100 ml) and extracted with ethyl acetate (30 ml * 3), washed with brine (20 ml * 3) and concentrated in vacuum.
  • Step 3 To a solution of methyl l-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-lH-pyrazole- 3-carboxylate (4.20 g, 10.3 mmol, 1 eq) in THF (45 mL) at 0 °C was added slowly LiAlHt (2.5 M, 4.11 mL, 1 eq) at 0 °C and stirred at 0 °C for 0.5 h. On completion, the reaction was quenched by addition of 0.4 mL of water at 0 °C, followed by the addition of 0.4 ml of 15% sodium hydroxide.
  • Step 4 To a solution of (l-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-lH-pyrazol-3- yl)methanol (3.60 g, 9.46 mmol, 1 eq) in ACN (40 mL) at 0 °C, was added NBS (1.68 g, 9.46 mmol, 1 eq) at 0 °C. The mixture was stirred at 25 °C for 0.5 hour. On completion, the reaction mixture was quenched by addition Na2SOs (50 mL) at 25 °C, and extracted with EA (30 mL * 3).
  • Step 5 To a solution of [4-(4-bromo-l-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-lH- pyrazol-3-yl)methanol (3.40 g, 7.40 mmol, 1 eq) in DMF (34 mL) at 0 °C, then was added NaH (592 mg, 14.8 mmol, 60% purity, 2 eq) at 0 °C for 30 min, then was added commercially available tert-butyl rac-(4R)-4-methyl-2,2-dioxo-oxathiazolidine-3 -carboxylate (2.63 g, 11.1 mmol, 1.5 eq) at 0 °C.
  • Step 1 To a solution of tert-butyl (R)-(l-(((benzyloxy)carbonyl)((4-bromo-l-methyl- lH-pyrazol-3-yl)methyl)amino)propan-2-yl)(methyl)carbamate (8.20 g, 16.5 mmol, 1 eq) in THF (82 mL) was added Pd/C (820 mg, 771 ⁇ mol, 10% purity, 4.66 e" 2 eq) under H2 (15 psi). The mixture was stirred at 25 °C for 16 h.
  • Step 2 To a solution of tert-butyl (R)-methyl(l-(((l-methyl-lH-pyrazol-3- yl)methyl)amino)propan-2-yl)carbamate (6.20 g, 22.0 mmol, 1 eq) and 2,2-difluoroethyl trifluoromethanesulfonate (5.64 g, 26.3 mmol, 1.2 eq) in ACN (62 mL) was added TEA (5.55 g, 54.9 mmol, 7.64 mL, 2.5 eq). The mixture was stirred at 25 °C for 16 h. On completion, the reaction was concentrated under vacuum.
  • Step 3 To a solution tert-butyl (R)-(l-((2,2-difluoroethylX(l-methyl-lH-pyrazol-3- yl)methyl)amino)propan-2-yl)(methyl)carbamate (3.30 g, 9.53 mmol, 1 eq) in DCM (33 mL) was added NBS (1.78 g, 10.0 mmol, 1.05 eq) at 0 °C. On completion, the mixture was stirred at 25 °C for 2 h. The mixture was poured into NazSOs (100 mL) aqueous solution, and the aqueous phase was extracted with DCM (50 mL x 2).
  • Step 1 To a solution of commercially available 5-methyl-1H -pyrrole-3-carboxylic acid (5.00 g, 39.9 mmol, 1 eq) in mixed solvents DCE (100 mL) and DMF (30 mL) was added POCh (61.2 g, 399 mmol, 37.1 mL, 10 eq) at 0 °C. The reaction mixture was stirred at 60 °C for 16 h. On completion, the mixture was slowly added to methanol to quench. The residue was concentrated in vacuo. To the mixture was then added sat. NaHCOs. (aq.) to adjust the pH to 7 ⁇ 8, and extracted with EA (3 x 20 mL).
  • Step 2 A mixture of methyl 2-formyl-5-methyl-1H -pyrrole-3-carboxylate (1.38 g, 8.23 mmol, 1 eq), KOH (1.85 g, 32.9 mmol, 4 eq) in MeOH (4.2 mL) and HzO (12.6 mL) was stirred at 60 °C for 1 h. On completion, HzO (20 mL) was added, the mixture was concentrated in vacuum to remove MeOH. The pH of the mixture was then adjusted to 4 ⁇ 6, extracted with ethyl acetate (30 mL), and washed with water (50 mL).
  • Step 1 To a solution of commercially available methyl l/7-pyrrole-3 -carboxylate (10.0 g, 79.9 mmol, 1 eq) in THF (15 mL) was added Pyridine (632 mg, 7.99 mmol, 0.1 eq) and NBS (14.2 g, 79.9 mmol, 1 eq), and the mixture was stirred at -78 °C for 2 hours. On completion, the combined organic layers were filtered and concentrated in vacuo.
  • Step 2 To a solution of methyl 5-bromo-1H -pyrrole-3 -carboxyl ate (7.00 g, 34.3 mmol, 1 eq) in DCE (30 mL) and DMF (6 mL) was added POCI3 (26.3 g, 171 mmol, 5 eq), and the mixture was stirred at 80 °C for 4 hours. On completion, the reaction was quenched by slowly adding the mixture to water, the pH was adjusted to 7 ⁇ 8 with sat. NaHCO 3 and extracted with EA (100 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered, and the filtrate was concentrated to give a residue.
  • Step 3 To a mixture of methyl 5-bromo-2-formyl-1H -pyrrole-3-carboxylate (3.60 g, 15.5 mmol, 1 eq) and Pd/C (900 mg, 0.845 mmol, 60% purity) in toluene (20 mL) and THF (4 mL) was added DIEA (4.01 g, 31.0 mmol, 2 eq).
  • Step 4 A mixture of methyl 2 -formyl- l/7-pyrrole-3-carb oxy late (800 mg, 5.22 mmol, 1 eq) and LiOH (375 mg, 15.6 mmol, 3 eq) in MeOH (8 mL), H2O (2 mL) and THF (8 mL) was stirred at 25 °C for 5 hours. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give 2-formyl-ll/-pyrrole-3-carboxylic acid (700 mg, 5.03 mmol, 96% yield) as a yellow solid (B2).
  • Step 1 To a solution of commercially available methyl 1H -pyrrole-3 -carboxylate (10.0 g, 79.9 mmol, 1 eq) in THF (150 mL) was added Selectfluor (33.9 g, 95.9 mmol, 1.2 eq), Na2CC>3 (7.96 g, 95.9 mmol, 1.2 eq) and 13-hydroxy-10,16-bis(2,4,6-triisopropylphenyl)- 12, 14-dioxa- 13 phosphapentacyclo [13.8.0.02,11.03,8.018,23]tricosa-l(15),2,4,6,8,10,16,
  • Step 2 To a solution of methyl 5-fluoro-1H -pyrrole-3-carboxylate (2.00 g, 13.9 mmol, 1 eq) in DCE (15 mL) and DMF (3 mL) was added POCI3 (10.7 g, 69.8 mmol, 5 eq) at 0 °C, and the mixture was stirred at 0 °C for 2 hours. On completion, the pH of the mixture was adjusted to 7 with NaHCO 3 (300 mL) and extracted with EA (100 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over Na 2 SO 4 , filtered, and concentrated to give a residue.
  • Methyl 5-fluoro-2-formyl-1H -pyrrole-3-carboxylate 130 mg, 0.759 mmol, 1 eq was taken in MeOH (3 mL), THF (3 mL) and H2O (1 mL). LiOH (54.5 mg, 2.28 mmol, 3 eq) was added to the mixture, and the mixture was stirred at 50 °C for 12 hours. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give 5-fluoro-2- formyl-1H -pyrrole-3-carboxylic acid (70.0 mg, 0.445 mmol, 58% yield) as a white solid (B3).
  • Step 1 To a solution of methyl lH-pyrrole-3 -carboxylate (10.0 g, 79.9 mmol, 1 eq) in THF (100 mL) was added Py (632 mg, 7.99 mmol, 645 ⁇ L, 0.1 eq) and NCS (10.7 g, 79.9 mmol, 1 eq) at -78 °C. The mixture was stirred at 40 °C for 16 h. The mixture was poured into Na 2 SO 3 (200 mL) aqueous solution, and the aqueous phase was extracted with ethyl acetate (50 mL x 2).
  • Step 3 To a solution of methyl 5-chloro-2-formyl-lH-pyrrole-3-carboxylate (5.00 g, 26.7 mmol, 1 eq) in H2O (36 mL) and MeOH (12 mL) was added KOH (5.98 g, 107 mmol, 4 eq). The mixture was stirred at 60 °C for 1 h. The mixture was concentrated under vacuum. The reaction mixture was adjusted to pH ⁇ 3 with hydrochloric acid (6 M in water). The mixture was filtered and the filter cake was concentrated under vacuum to give 5-chloro-2-formyl-lH- pyrrole-3-carboxylic acid (5.20 g, crude) as a yellow solid.
  • Step 1 A mixture of commercially available 7-chloroindolin-2-one (12.6 g, 75.2 mmol, 1 eq) and MBS (13.4 g, 75.2 mmol, 1 eq) in TFA (200 mL) was degassed and purged with Nz
  • Step 2 To a solution of 5-bromo-7-chloro-indolin-2-one (3 g, 12.1 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (9.27 g, 36.5 mmol, 3 eq) in dioxane (45 mL) was added potassium acetate (4.78 g, 48.6 mmol,
  • Steps 1 To a solution of commercially available methyl 5-bromo-2-oxoindoline-7- carboxylate (5.00 g, 18.5 mmol, 1 eq) in THF (50 mL) was added LiBH 4 (2 M, 37.0 mL, 4 eq) at 0 °C. The mixture was stirred at 25 °C for 2 h. On completion, the mixture was poured into NH4CI (50 mL) aqueous solution, and the aqueous phase was extracted with DCM (50 mL x 2). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous Na2SO 4 , filtered and concentrated under vacuum.
  • LiBH 4 2 M, 37.0 mL, 4 eq
  • Step 2 To a solution of 5-bromo-7-(hydroxymethyl)indolin-2-one (2.10 g, 8.68 mmol, 1 eq) in DCM (21 mL) was added PBr 3 (2.82 g, 10.4 mmol, 1.2 eq) under N2 at 0 °C. On completion, the mixture was stirred at 25 °C for 2 h. The mixture was poured into NaHCO 3 (80 mL) aqueous solution, and the aqueous phase was extracted with DCM (50 mL x 2).
  • Step 3 A solution of 5-bromo-7-(bromomethyl)indolin-2-one (2.70 g, 8.85 mmol, 1 eq) in MeOH (30 mL) was stirred at 25 °C for 4 h. On completion, the mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give 5-bromo- 7-(methoxymethyl)indolin-2-one (3.10 g, crude) as a white solid.
  • Step 4 A mixture of 5-bromo-7-(methoxymethyl)indolin-2-one (2.90 g, 11.3 mmol, 1 eq), BPD (4.31 g, 17.0 mmol, 1.5 eq), KO Ac (3.33 g, 34.0 mmol, 3 eq) and Pd(dppf)Cl 2 CH2Cl 2 (925 mg, 1.13 mmol, 0.1 eq) in dioxane (30 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 1 h under N2 atmosphere. On completion, the reaction mixture was concentrated under reduced pressure to give a residue.
  • Step 1 AA mmiixxttuurree of tert-butyl (R)-( 1 -((4-bromo- 1 -ethyl- lH-pyrazol-3- yl)methoxy)propan-2-yl)(methyl)carbamate (2.00 g, 5.32 mmol, 1 eq), 7-chloro-5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)indolin-2-one (2.34 g, 7.97 mmol, 1.5 eq), CS2CO3 (5.20 g, 15.9 mmol, 3 eq), Pd(dtbpf)Ch (346 mg, 532 pmol, 0.1 eq) in dioxane (20 mL) and H2O (4 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 1 h
  • Step 2 To a solution of tert-butyl (R)-(l-((4-(7-chloro-2-oxoindolin-5-yl)-l-ethyl-lH- pyrazol-3-yl)methoxy)propan-2-ylXmethyl)carbamate (500 mg, 1.08 mmol, 1 eq) in DCM (5 mL) was added HCI/EtOAc (2 M, 1.00 mL, 1.85 eq). The mixture was stirred at 20 °C for 2 hr.
  • Step 1 was performed in a similar manner to step 1 of General Method I-A.
  • Step 2 To a mixture tert-butyl (R)-(l-((l-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-(7- chloro-2-oxoindolin-5-yl)-lH-pyrazol-3-yl)methoxy)propan-2-ylXniethyl)carbamate (210 mg, 292 pmol, 1 eq) in DCM (2 mL) at 0 °C was added HCI/EtOAc (2 M, 2 mL, 13.6 eq). The mixture was stirred at 0 °C for 1 h.
  • Step 1 A mixture of tert-butyl N-[(1R)-2-[benzyloxycarbonyl-[(4-bromo-l-methyl- pyrazol-3-yl)methyl]amino]-l-methyl-ethyl]-N-methyl-carbamate (Al, 1.37 g, 2.77 mmol, 1 eq) and 7-chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indolin-2-one (Cl, 811 mg, 2.77 mmol, 1 eq), Na 2 CO 3 (879 mg, 8.30 mmol, 3 eq), Pd(dppf)Cl 2 .CH2Cl 2 (225 mg, 0.276 mmol, 0.1 eq) in dioxane (14 mL) and H2O (3 mL) was degassed and purged with N23 times, and then the mixture was stirred at 80
  • Step 2 To a mixture of tert-butyl N-[(1R)-2-[benzyloxycarbonyl-[[4-(7-chloro-2-oxo- indolin-5-yl)- 1 -methyl -pyrazol-3-yl]methyl]amino]- 1 -methyl -ethyl]-N-methyl -carbamate (200 mg, 0.343 mmol, 1 eq) in DCM (2 mL) was added HCl/dioxane (4 M, 2 mL, 23.2 eq) and the mixture was stirred at 20 °C for 0.5 h.
  • Step 3 To a solution of benzyl ;V-[[4-(7-chloro-2-oxo-indolin-5-yl)-l -methyl -pyrazol- 3-yl]methyl]- N-[(2R)-2-(methylamino)propyl]carbamate (150 mg, 0.311 mmol, 1 eq) and 2- formyl-5-methyl-1H -pyrrole-3-carboxylic acid (Bl, 57.1 mg, 0.373 mmol, 1.2 eq) in MeCN (7 mL) was added 1 -methylimidazole (255 mg, 3.11 mmol, 0.248 mL, 10 eq) and TCFH (130 mg, 0.466 mmol, 1.5 eq).
  • Step 4-1 To a solution of benzyl N-[[4-(7-chloro-2-oxo-indolin-5-yl)-l-methyl- pyrazol-3-yl]methyl]- N-[(2R)-2-[(2-formyl-5-methyl-1H -pyrrole-3-carbonyl)-methyl- aminojpropyljcarbamate (143 mg, 0.231 mmol, 1 eq) in EtOH (14 mL) was added Piperidine (197 mg, 2.32 mmol, 0.228 mL, 10 eq). The mixture was stirred at 80 °C for 1.5 h. On completion, the mixture was concentrated under reduced pressure to give a residue.
  • Step 4-2 A mixture of benzyl (10R,18Z)-23-chloro-4,10,ll,15-tetramethyl-12,20- dioxo-4,5,8, 11, 16,21-hexazapentacyclo[ 17.5.2.02,6.013,17.022,26]hexacosa- l(24),2,5,13(17),14,18,22,25-octaene-8-carboxylate (47 mg, 0.078 mmol, 1 eq) in TFA (1 mL) was stirred at 60 °C for 2 h. On completion, the mixture was concentrated under reduced pressure to give a residue.
  • Step 5 To aa ssoolluutitioonn of [3a(4)Z,10R]-20-chloro-6,9,10,15-tetramethyl- 2,5,9,10,ll,12,13,15-octahydro-l,17-ethenopyrazolo[4,3-m]dipyrrolo[3,2-f3',4'-
  • Step 1 A mixture of tert-butyl N-[( l/?)-2-[(4-brom o-5-m ethoxy- 1 -methyl -pyrazol-3- yl) methoxy]-l-methyl-ethyl]-N-methyl-carbamate (A2, 1.50 g, 3.82 mmol, 1 eq), 7-chloro-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indolin-2-one (Cl, 1.68 g, 5.74 mmol, 1.5 eq), Na 2 CO 3 (1.22 g, 11.4 mmol, 3 eq), Pd(dppf)Cl 2 .CH 2 Cl 2 (312 mg, 0.382 mmol, 0.1 eq) in dioxane (20 mL) and H2O (4 mL) was degassed and purged with N2 3 times, and the mixture was stirred at 80
  • Step 2 A mixture of tert-butyl N-[(1R)-2-[[4-(7-chloro-2-oxo-indolin-5-yl)-5- methoxy- 1 -methyl -pyrazol-3-yl]methoxy]- 1 -methyl-ethyl]-N-methyl-carbamate (500 mg, 1.04 mmol, 1 eq), HCl/dioxane (4 M, 5.00 mL, 19 eq) in DCM (3 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 25 °C for 0.3 hours under N2 atmosphere.
  • Step 3-1 To a mixture of the above 7-chloro-5-[5-methoxy-l -methyl -3-[[(2R)-2- (methylamino) propoxy]methyl]pyrazol-4-yl]indolin-2-one (380 mg, 1.00 mmol, 1 eq) and 2- formyl-1H -pyrrole-3-carboxylic acid (B2, 209 mg, 1.50 mmol, 1.5 eq) in MeCN (10 mL) was added NMI (494 mg, 6.02 mmol, 6 eq) and TCFH (562 mg, 2.01 mmol, 2 eq). Then the mixture was stirred at 25 °C for 0.5 hours.
  • Step 3-2 To a mixture of N-[(1R)-2-[[4-(7-chloro-2-oxo-indolin-5-yl)-5-methoxy-l- methyl-pyrazol-3-yl]methoxy]-l-methyl-ethyl]-2-formyl-N --methyl-l/7-pyrrole-3- carboxamide (380 mg, 0.760 mmol, 1 eq) in EtOH (4 mL) was added Piperidine (194 mg, 2.28 mmol, 3 eq), and then the mixture was stirred at 25 °C for 0.5 hours. On completion, the reaction mixture was filtered and concentrated under reduced pressure.
  • Step 1 A mixture of tert-butyl N-[(1R)-2-[(4-bromo-5-methoxy-l-methyl-pyrazol-3- yl)methyl-methyl-amino]-l-methylethyl]-A f -methyl-carbamate (A3, 1.00 g, 2.47 mmol, 1 eq), 7-chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indolin-2-one (Cl, 1.09 g, 3.70 mmol, 1.5 eq), CS2CO3 (1.61 g, 4.93 mmol, 2 eq), Pd(dppf)Cl 2 (160 mg, 0.246 mmol, 0.1 eq) in dioxane (15 mL) and H2O (3 mL) was degassed and purged with N23 times, and the mixture was stirred at 80 °C for 12 hours under
  • Step 2 To a solution of tert-butyl N-[(1R)-2-[[4-(7-chloro-2-oxo-indolin-5-yl)-5- methoxy-l-methyl-pyrazol-3-yl]methylmethyl-amino]-l-methyl-ethyl]-N-methyl-carbamate (130 mg, 0.264 mmol, 1 eq) in DCM (2 mL) was added HCI/dioxane (4 M, 0.5 mL). The mixture was stirred at 25 °C for 0.5 hours.
  • Step 3-2 To a solution of N-[(1R)-2-[[4-(7-chloro-2-oxo-indolin-5-yl)-5-methoxy-l- methyl-pyrazol-3-yl]methyl-methylamino]-l-methyl-ethyl]-2-formyl-N,5-dimethyl-1H - pyrrole-3 -carboxamide (80.0 mg, 0.151 mmol, 1 eq) in EtOH (5 mL) was added Piperidine (38.7 mg, 0.455 mmol, 3 eq). The mixture was stirred at 70 °C for 10 minutes. On completion, the mixture was concentrated to give the residue.
  • Step 1-2 To a solution of N- [(l/?)-2-[ [4-(7-chl oro-2-ox o-indolin-5-yl )-5 -meth oxy-1 - methyl-pyrazol-3-yl]methyl-methylamino]-l-methyl-ethyl]-2-formyl-N-methyl-1H -pyrrole- 3-caiboxamide (50.0 mg, 0.097 mmol, 1 eq) in EtOH (5 mL) was added Piperidine (24.9 mg, 0.292 mmol, 3 eq). The mixture was stirred at 70 °C for 0.5 hours. On completion, the mixture was concentrated to give the residue. The residue was purified by reverse phase HPLC (with 0.1% Formic acid) to give [3a(4)Z,10R]-20-chloro-16-methoxy-9,10,12,15-tetramethyl-
  • Steps 1 and 2 were performed in a similar manner to steps 1 and 2 of General Method B using C2 in step 1.
  • Step 3-1 To aa ssoolluuttiioonn ooff (R)-5-(5-methoxy-l-methyl-3-((methyl(2- (methylamino)propyl)amino)methyl)-lH-pyrazol-4-yl)-7-methylindolin-2-one (240 mg, 588 pmol, 1 eq, HC1), 5-fluoro-2-formyl-lH-pyrrole-3-carboxylic acid (92.4 mg, 588 pmol, 1 eq), NMI (241 mg, 2.94 mmol, 5 eq) in ACN (2 mL) was added TCFH (330 mg, 1.18 mmol, 2 eq).
  • Step 3-2 To a solution of (R)-5-fluoro-2-formyl-N-(l-(((5-methoxy-l-methyl-4-(7- methyl-2-oxoindolin-5-yl)-lH-pyrazol-3-yl)methyl)(methyl)amino)propan-2-yl)-N-methyl- lH-pyrrole-3-carboxamide (25.0 mg, 48.9 pmol, 1 eq) in EtOH (1 mL) was added NMI (12.0 mg, 146 pmol, 3 eq). The mixture was stirred at 70 °C for 10 minutes. On completion, the mixture was concentrated to give the residue.
  • Step 2 To a solution of (R,Z)-ll-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-27-chloro- 45,6,7-trimethyl-l lH,41H-9-oxa-6-aza-2(5,3)-indolina-l(4,3)-pyrazola-4(2,3)- pyrrolacyclodecaphane-22, 5-dione (36.0 mg, 0.049 mmol, 1 eq) in DMSO (1 mL), was added CsF (37.2 mg, 0.245 mmol, 5 eq) at 25 °C. The reaction was stirred at 25 °C for 0.5 h.
  • the combined organic phase was washed with brine (10 mL * 2), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum.
  • Steps 1-1 and 1-2 followed the procedures of General Method C using 80 °C instead of 70 °C in step 1-2.
  • Step 2 To a solution of benzyl [3a(4)Z,10R]-20-(methoxymethyl)-6,9,10,15- tetramethyl-3,8-dioxo-3,5,8,9, 10, 11 , 13 , 15 -octahydro- 1 , 17-ethenopyrazolo[4,3 - m]dipyrrolo[3,2-f:3',4'-i][l,4]diazacyclopentadecine-12(2H)-carboxylate (225 mg, 369.65 pmol, 1 eq) was added in TFA (3.07 g, 26.9 mmol, 2 mL, 72.84 eq).
  • Step 1-2 used 80 °C instead of 70 °C.
  • Step 1-1 used 1 h instead of 0.5 h and step 1 -2 used 80 °C instead of 70 °C.
  • kinase binding assays were performed at Eurofins/DiscoveRx using the general KINOMEscnn Protocol (Fabian, M. A. et al., “A small molecule-kinase interaction map for clinical kinase inhibitors,” Nat. Biotechnol. 2005, 23(3):329-36).
  • kinase- tagged T7 phage strains were prepared in an E. coli host derived from the BL21 strain. E. coll were grown to log-phase and infected with T7 phage and incubated with shaking at 32°C until lysis. The lysates were centrifuged and filtered to remove cell debris.
  • the remaining kinases were produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection.
  • Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays.
  • the liganded beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and to reduce nonspecific binding.
  • Binding reactions were assembled by combining kinases, liganded affinity beads, and test compounds in lx binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT). All reactions were performed in polystyrene 96-mell plates in a final volume of 0.135 mL. The assay plates were incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (lx PBS, 0.05% Tween 20). The beads were then re-suspended in elution buffer (lx PBS, 0.05% Tween 20, 0.5 pM non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes.
  • lx binding buffer 20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT. All reactions were performed in polystyrene 96-mell plates in a final volume of 0.135 mL. The as
  • Dissociation constants (Kds) for test compound-kinase interactions were calculated by measuring the amount of kinase captured on the solid support as a function of the test compound concentration. [0458] Table 2. Dissociation constants (Kds) against JAK Family

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Abstract

La présente divulgation concerne des composés macrocycliques, des compositions pharmaceutiques contenant des composés macrocycliques, et des méthodes d'utilisation de composés macrocycliques pour traiter une maladie, telle qu'une maladie auto-immune ou une maladie inflammatoire.
PCT/US2024/036607 2023-07-03 2024-07-02 Composés macrocycliques et leur utilisation en tant qu'inhibiteurs de tyk2 Pending WO2025010294A2 (fr)

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