Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/415—1,2-Diazoles
  • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders

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.
• Protein kinases are tightly regulated signaling proteins that orchestrate the activation of signaling cascades by phosphorylating target proteins in response to extracellular and intracellular stimuli.
• the human genome encodes approximately 518 protein kinases (Manning G, et al The protein kinase complement of the human genome. Science. 2002, 298:1912-34).
• Dysregulation of kinase activity is associated with many diseases, including autoimmune diseases, and cardiovascular, degenerative, immunological, infectious, inflammatory, and metabolic diseases (Levitzki, A. Protein kinase inhibitors as a therapeutic modality. Acc. Chem. Res. 2003, 36:462-469).
• the molecular bases leading to various diseases include kinase gain- and loss-of-function mutations, gene amplifications and deletions, splicing changes, and translocations (Wilson LJ, et al New Perspectives, Opportunities, and Challenges in Exploring the Human Protein Kinome. Autoimmune disease Res. 2018, 78:15-29).
• the critical role of kinases in autoimmune disease and other diseases makes them attractive targets for drug inventions with 52 small molecule kinase inhibitors have been approved and 46 of them for autoimmune disease targeted therapies (Roskoski R Jr, Properties of FDA-approved Small Molecule Protein Kinase Inhibitors: A 2020 Update. Pharmacol Res 2020, 152:104609).
• Cytokine signaling is essential for cell growth, hematopoiesis, and immune system function. Cytokine-mediated receptor dimerization induces intracellular activation of receptor-bound Janus kinases (JAKs), which then induce downstream transcriptional responses.
• the Janus Kinase Signal Transducer and Activator of Transcription (JAK-STAT) pathway plays a significant role in both normal and pathological states of immune-mediated inflammatory diseases (O’Shea JJ, et al The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu Rev Med. 2015, 66:311-28).
• 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 (McLornan DP, et al Lancet. 2021, 398:803-816).
• McLornan DP et al Lancet. 2021, 398:803-816
• the JAK kinases are large multidomain protein including the FER 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] (Garrido-Trigo A and SalasJoumal 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 (IFN ⁇ ).
• 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).
• 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.
• the disclosure relates to a compound of the formula I, or a pharmaceutically acceptable salt thereof,
• each L is independently -C(R 3 )(R 4 )-, -C(O)-, -O-, -N(R 5 )-, -S-, -S(O)- or -S(O) 2 -, provided that (L) n does not comprise a -O-O-, a -O-S-, a -S-S-, or a -O-N(R 5 )- bond, and (L)n-N(R 9 )- does not comprise a -O-N(R 9 )- a -S-N(R 9 )- bond;
• Y and Y 1 are each independently O or S;
• each of R , R , and R is independently H, deuterium, halogen, C1-C6 alkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, C3-C6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10 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
• each of R 2a , R 5 , R 8 , and R 9 is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C 6 haloalkyl, -OR e , -OC(O
• R 2b is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C4 cycloalkyl, or 3- to 4-membered heterocycloalkyl, wherein each hydrogen atom in C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C4 cycloalkyl, and 3- to 4-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, -O(H or C1-C2 alkyl), -OC(O)C1-C2 alkyl, -OC(O)N(H or C1-C2 alkyl) 2 , -OS(O)C1-C 2 alkyl, -OS(O) 2 C1-C 2 alkyl, -OS(O)N(H or C1-C2 alkyl) 2 , -OS(O) 2 N(H or C1-C2
• each of R 6 and R 7 is independently H, deuterium, halogen, C1-C6 alkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, C3-C6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10 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
• each R a , R b , R c , R d , R e , and R f is independently selected from the group consisting of H, deuterium, C1-C6 alkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, C3-C6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10 aryl, C1-C6alkyl-C6-C10 aryl, and 5- to 10-membered heteroaryl; and [017] n is 2, 3, 4, 5, 6, 7, or 8.
• L does not comprise a -N(R 5 )-.
• each L is independently -C(R 3 )(R 4 )-, -C(O)-, -O-, -S-, -S(O)- or -S(O) 2 -, provided that (L) n does not comprise a -O-O-, -S-S-, or -O-S- bond.
• R 2 is not -OR a .
• R 2 is H, deuterium, halogen, C1-C6 alkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, C3-C6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -OS(O)NR a R b , -OS(O) 2 NR a R b , -OS(O)NR a R b , -OS(O) 2 NR a R
• the disclosure provides a compound of the formula II, or a pharmaceutically acceptable salt thereof,
• the disclosure provides a compound of the formula III, or a pharmaceutically acceptable salt thereof,
• the disclosure provides a compound of the formula IV, or a pharmaceutically acceptable salt thereof,
• the disclosure provides a compound of the formula V, or a pharmaceutically acceptable salt thereof,
• the disclosure provides a compound of the formula VI, or a pharmaceutically acceptable salt thereof,
• the disclosure provides a compound of the formula VII, or a pharmaceutically acceptable salt thereof,
• the disclosure provides a compound of the formula VIII, or a pharmaceutically acceptable salt thereof,
• the disclosure provides a compound of the formula IX, or a pharmaceutically acceptable salt thereof,
• 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,
• the disclosure provides a compound of the formula XII, or a pharmaceutically acceptable salt thereof, wherein L, R 1 , R la , R 2a , R 2b , R 7 , and n are as described herein. ,
• R 7 is H, deuterium, C1-C6 alkyl, fluoro, chloro, or-CN. In some embodiments, R 7 is H. In some embodiments, R 7 is deuterium. In some embodiments, R 7 is C1-C6 alkyl. In some embodiments, R 7 is -F. In some embodiments, R 7 -Cl. In some embodiments, R 7 is -CN. and R 7 is H. In some embodiments, Ring Ring B
• Ring , Ring B is
• the compound of Formula (I)-(XII) is a compound selected from those species described or exemplified in the detailed description below.
• the disclosure relates to a pharmaceutical composition comprising at least one compound of Formula (I)-(XII) 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)-(XII), 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)-(XII), or a pharmaceutically acceptable salt thereof.
• the disclosure relates to use of a compound of Formula (I)-(XII), or a 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)-(XII), or a 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
• each L is independently -C(R 3 )(R 4 )-, -C(O)-, -O-, -N(R 5 )-, -S-, -S(O)- or -S(O) 2 -, provided that (L) n does not comprise a -O-O-, a -O-S-, a -S-S-, or a -O-N(R 5 )- bond, and (L)n-N(R 9 )- does not comprise a -O-N(R 9 )- a -S-N(R 9 )- bond;
• Y and Y 1 are each independently O or S;
• each of R 1 , R la , and R 2 is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10 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
• each of R 2a , R 5 , R 8 , and R 9 is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C 6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS
• R 2b is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C4 cycloalkyl, or 3- to 4-membered heterocycloalkyl, wherein each hydrogen atom in C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C4 cycloalkyl, and 3- to 4-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, -O(H or C1-C2 alkyl), -OC(O)C1-C2 alkyl, -OC(O)N(H or C1-C2 alkyl) 2 , -OS(O)C1-C 2 alkyl, -OS(O) 2 C1-C 2 alkyl, -OS(O)N(H or C1-C2 alkyl) 2 , -OS(O) 2 N(H or C1-C2
• each of R 6 and R 7 is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10 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 , -OS
• each R a , R b , R c , R d , R e , and R f is independently selected from the group consisting of H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10 aryl, C1-C6alkyl-C6-C10 aryl, and 5- to 10-membered heteroaryl; and [061] n is 2, 3, 4, 5, 6, 7, or 8.
• R 1 when present, is H, -CN or C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium, halogen, C1-C 6 alkyl, C1-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
• R la when present, is H, -CN or C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 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 , -S(O) 2 NR e R f , -S(O
• R 2b when present, is C1-C4 alkyl or C3-C4 cycloalkyl, wherein each hydrogen atom in C1-C6 alkyl and C3-C4 cycloalkyl is independently optionally substituted by deuterium or halogen; or R 2b is methyl, ethyl, isopropyl, or cyclopropyl.
• each L is independently selected from the group consisting of -C(O)-, -O-, -CH 2 -, -C(H)(CH 3 )-, -C(H)(OH)-, -C(H)(C(O)OR C )-, -C(H)(C(O)NR c R d )-, -NH-, and -NCH3-; or each L is independently selected from the group consisting of -C(O)-, -O-, -CH2-, -C(H)(CH 3 )-, -C(H)(OH)-, -C(H)(C(O)OR C )-, and -C(H)(C(O)NR c R d )-.
• a pharmaceutical composition comprising at least one compound of any one of clauses 1 to 30, 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 30, 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 depiected by the structural formula .
• a cyclopropylene moiety can be depiected 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, -CTH2Br, -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 mono- valent 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 (C6-C14 aryl), mono- valent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 10 carbon atoms (C6-C10 aryl), di- valent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 14 carbon atoms (C6- C14 arylene), di-valent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 10 carbon atoms (C6-C 10 arylene).
• C6-C14 aryl mono- valent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 14 carbon atoms
• C6-C10 aryl mono- valent all-carbon monocyclic or fused-ring polycyclic groups
• aryl groups are phenyl, naphthalenyl and anthracenyl.
• aryl groups are phenylene, naphthalenylene and anthracenylene. It will be appreciated that an aryl or arylene group can be unsubstituted or substituted as described herein. An aryl or arylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.
• 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-membereed), 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.
• Non-limiting examples of three- membered heterocycle groups include monovalent and divalent radicals of oxirane, azetidine, and thiirane.
• a four-membered heterocycle may contain at least one heteroatom ring atom, where the heteroatom ring atom is a sulfur, oxygen, or nitrogen.
• Non-limiting examples of four-membered heterocycle groups include monovalent and divalent radicals of aziridine, 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-thiazine, 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 di- valent 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-liniting examples of five-membered heteroaryl groups include mono- valent radicals of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole.
• Non-liniting examples of five- membered heteroarylene groups include di-valent radicals of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, 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-b]thiophene, 1H-pyrrolo[2,3-b]pyridine, 1H-benzo[d]imidazole, benzo[d]oxazole, and benzo[d]thiazole.
• 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-
• a pyrrolyl moiety can be depiected by the structural formula particular
• a pyrrolylene moiety can be depiected by the structural formula particular
• a pyrazolyl moiety can be depiected by the structural formula particular
• a pyrazolylene moiety can be depiected by the structural formula
• 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.
• Certain chemical entities of Formula (I)-(XII) 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 tutomers, and the like.
• 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 O, 31 P, 32 P, 35 S, 18 F, 36 C1, and 125 I, respectively.
• Such isotopically labelled compounds are useful 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 single- photon 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 single- photon emission computed tomography (SPECT)
• PET positron emission tomography
• SPECT single- photon 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.
• (ATOM)i.j” with j > i when applied herein to a class of substituents, is meant to refer to embodiments of this disclosure for which each and every one of the number of atom members, from i to j including i and j, is independently realized.
• C1-3 refers independently to embodiments that have one carbon member (Ci), embodiments that have two carbon members (C2), and embodiments that have three carbon members (C3).
• any disubstituent referred to herein is meant to encompass the various attachment possibilities when more than one of such possibilities are allowed.
• a compound portion -(L) n - having the formula -CH2OCH2(C(CH3)H)-, connecting two groups, A and B, will be understood that -CH2OCH2(C(CH3)H)-, can include both of the embodiments A- CH2OCH2(C(CH3)H)-B and B-CH2OCH2(C(CH3)H)-A.
• compounds of the formula (I)-(XII) having a compound portion -(L) n - of the formula -CH2OCH2(C(CH3)H)- connecting groups -B- and -NR 9 - will be understood to include both embodiments B-CH 2 OCH 2 (C(CH 3 )H)-NR 9 and -NR 9 -CH 2 OCH 2 (C(CH 3 )H)-B.
• the disclosure also includes pharmaceutically acceptable salts of the compounds represented by Formula (I)-(XII), 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)-(XII), 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)-(XII)).
• 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)-(XII), 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)-(XII) 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), benzyloxycarbonyl (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,
• the disclosure provides a compound of the formula II, or a pharmaceutically acceptable salt thereof,
• the disclosure provides a compound of the formula III, or a pharmaceutically acceptable salt thereof,
• the disclosure provides a compound of the formula IV, or a pharmaceutically acceptable salt thereof,
• the disclosure provides a compound of the formula V, or a pharmaceutically acceptable salt thereof,
• the disclosure provides a compound of the formula VI, or a pharmaceutically acceptable salt thereof,
• the disclosure provides a compound of the formula VII, or a pharmaceutically acceptable salt thereof,
• the disclosure provides a compound of the formula VIII, or a pharmaceutically acceptable salt thereof,
• the disclosure provides a compound of the formula IX, or a pharmaceutically acceptable salt thereof,
• 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,
• the disclosure provides a compound of the formula XII, or a pharmaceutically acceptable salt thereof,
• Ring [0179] In some embodiments, Ring
• Ring and R 7 is H. In some embodiments, Ring Ring B
• R 1 is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10 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 , -OS(O) 2
• R 1 is H, -CN or C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 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 e C(O)R f , -NR e C(O)R f
• R 1 is H, -CN, or methyl.
• R la is H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10 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) 2 NR a R b , -OS(O)
• R la is H, -CN or C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 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 e C(O)R f , -NR e C(O)R f
• R 2 is H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -OS(O)NR a R b , -OS(O) 2 NR a R b , -OS(O)NR a R b , -OS(O) 2 NR a R b ,
• R 2 is independently H, deuterium, C1-C6 alkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, C3-C6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, C3-C6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C 6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)
• R 2 is H, -CN, or C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 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 e C(O)R f , -NR e C(O)R
• R 2a is H, deuterium, C1-C6 alkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, C3-C6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, C3-C6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)
• R 2a is H or C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 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 e C(O)OR e , -OC(O)R e , -OC(
• R 2b is C1-C4 alkyl, C 2 -C4 alkenyl, C 2 -C4 alkynyl, C3-C4 cycloalkyl, or 3- to 4-membered heterocycloalkyl, wherein each hydrogen atom in C1-C4 alkyl, C 2 -C 4 alkenyl, C 2 -C4 alkynyl, C3-C4 cycloalkyl, and 3- to 4-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, -O(H or C1-C2 alkyl), -OC(O)C1-C 2 alkyl, -OC(O)N(H or C1-C2 alkyl) 2 , -OS(O)C1-C 2 alkyl, -OS(O) 2 C1C- 2 alkyl, -OS(O)N(H or C1-C 2 alkyl) 2 ,
• R 2b is C1-C4 alkyl or C3-C4 cycloalkyl, wherein each hydrogen atom in C1-C6 alkyl and C3-C4 cycloalkyl is independently optionally substituted by deuterium or halogen. In some embodiments, R 2b is methyl, ethyl, isopropyl, or cyclopropyl.
• each L is independently -C(R 3 )(R 4 )-, -C(O)-, -O-, -N(R 5 )-, -S-, -S(O)- or -S(O) 2 -, provided that (L) n does not comprise a -O-O-, a -O-S-, a a -S-S-, or a -O- N(R 5 )- bond.
• each L is independently -C(R 3 )(R 4 )-, -C(O)-, -O-, -S-, - S(O)- or -S(O) 2 -, provided that (L) n does not comprise a -O-O-, -S-S-, or -O-S- bond. In some embodiments, L does not comprise a -N(R 5 )-.
• each L is independently selected from the group consisting of -C(O)-, -O-, -CH2-, -C(H)(CH3)-, -C(H)(OH)-, -NH-, and -NCH3-.
• -(L) n - is -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, -(CH 2 ) 6 -, -C(O)NH-(CH 2 )2O(CH 2 )2-, -C(O)N(CH 3 )-(CH2)2O(CH 2 )2-, -NHC(O)CH 2 O(CH 2 )2-, -N(CH 3 )-C(O)CH 2 O(CH2)2-,
• -Z -(L) n -Z 1 - does not comrpise an -O-O-, a -O-S-, or an -O- N(R X )- bond.
• -(L) n - is -O(CH2)2-, -O-(CH2)3-, -O-(CH2)4-, -CH2OCH2(C(CH3)(H))-, -CH 2 O(CH 2 ) 2 -, or -CH2O(CH2)3-.
• -(L) n - is - O(CH 2 )3-, -CH 2 OCH 2 (C(CH 3 )(H))-, or -CH 2 O(CH 2 )2-.
• R la , R 2a , R 5 , R 8 , and R 9 are each independently H or C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 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
• R la is H or methyl. In some embodiments, R 2a is H or methyl. In some embodiments, R 5 is H or methyl. In some embodiments, R 8 is H or methyl. In some embodiments, R 9 is H or methyl.
• each of R 6 and R 7 is independently H, deuterium, halogen, C1-C6 alkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, C3-C6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10 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 a R
• R 6 is H, deuterium, fluoro, chloro, -CN, or C1-C6 alkyl, such as methyl or ethyl.
• R 7 is H, deuterium, fluoro, chloro, -CN, or C1-C6 alkyl, such as methyl or ethyl.
• R 6 is H or deuterium
• R 7 is deuterium, fluoro, chloro, -CN, or C1-C6 alkyl, such as methyl or ethyl.
• R 7 is H.
• R 7 is deuterium.
• R 7 is C1-C6 alkyl, such as methyl or ethyl. In some embodiments, R 7 is -F. In some embodiments, R 7 -Cl. In some embodiments, R 7 is -CN.
• n is 2, 3, 4, 5, 6, 7, or 8. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8.
• the disclosure provides a compound selected from the group consisting of [3a(4)Z]-6,9,15,16-tetramethyl-9,10,ll,12-tetrahydro-15H-l,17- (ethanediylidene)pyrazolo[4,3-n]dipyrrolo[3,2-g:3',4'-j][l,5]oxazacyclopentadecine- 3,8(2H,5H)-dione; [0201] [3a(4)Z]-6,9,15,16-tetramethyl-10,ll,13,15-tetrahydro-2H-l,17-
• 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 ingredient(s) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents.
• Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like.
• Exemplary liquid oral excipients include ethanol, glycerol, water, and the like.
• Starch, poly vinyl-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 ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent.
• Soft gelatin capsules may be prepared by mixing the active ingredient with water, an oil, such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.
• 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, hydroxy ethylcellulose, 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, hydroxy ethylcellulose, carb
• the agents of the disclosure may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil.
• Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride.
• Such forms may be presented in unit-dose form such as ampoules or disposable injection devices, in multi- dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation.
• Illustrative infusion doses range from about 1 to 1000 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 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 a 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.
• Example 1 Preparation of tert-butyl N-[3-(4-bromo-l,5-dimethyl-pyrazol-3- yl)oxypropyl]-N-methyl-carbamate (Al)
• Step 1 To a solution of but-2-ynoic acid (5 g, 59.5 mmol, 1 eq), DMAP (726 mg, 5.95 mmol, 0.1 eq) in DCM (200 mL) was added tert-butyl A-amino-A-methyl-carbamate (9.22 g, 63.0 mmol, 1.06 eq) and EDCI (12.5 g, 65.4 mmol, 1.1 eq) at 0 °C. The reaction mixture was stirred at 25 °C for 16 hr.
• Step 2 To a solution of tert-butyl A-(but-2-ynoylamino)-A-methyl -carbamate (5.5 g, 25.9 mmol, 1.00 eq) in 2-propanol (60 mL), hydrogen chloride (4.84 g, 133 mmol, 4.75 mL, 5.13 eq) was added at 25 °C, the mixture was stirred for 16 hours at 63 °C under N2. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The resulting residue was then charged with CH3CN (50 mL, 10 mL/g) and concentrated in vacuo. This process was repeated for three times.
• CH3CN 50 mL, 10 mL/g
• Step 3 A mixture of l,5-dimethylpyrazol-3-ol (800 mg, 7.13 mmol, 1 eq), tert-butyl N-(3-chloropropyl)-N-methyl-carbamate (1.63 g, 7.85 mmol, 1.1 eq), K2CO3 (1.48 g, 10.7 mmol, 1.5 eq) in DMF (35 mL). The mixture was stirred at 80 °C for 16 h. After cooled to 25 °C, the mixture was diluted with water (10 mL), extracted with EA (3 X 10 mL).
• Step 4 To a solution of tert-butyl N-[3-(l,5-dimethylpyrazol-3-yl)oxypropyl]-N- methyl-carbamate (600 mg, 2.12 mmol, 1 eq) in ACN (10 mL) was added NBS (376 mg, 2.12 mmol, 1 eq) at 25 °C for 16 h under N2. The reaction mixture was concentrated in vacuo.
• Step 2 To a solution of methyl 4-bromo- 1,5 -dimethyl -pyrazole-3 -carboxylate (8.0 g, 34.33 mmol, 1 eq) in THF (100 mL) was added LiAlH4 (1.56 g, 41.19 mmol, 1.2 eq) at 0 °C. The mixture was stirred at 15 °C for 3 h.
• Step 3 To a solution of (4-bromo-l,5-dimethyl-pyrazol-3-yl)methanol (4.30 g, 21.0 mmol, 1 eq) in DCM (40 mL), PB13 (5.68 g, 21.0 mmol, 1 eq) was added dropwise at 0 °C. The mixture was stirred at 0-25 °C for 4 hours. On completion, the mixture was concentrated in vacuum. It was added NaHCO3 solution to adjust pH to the value of 7 and extracted with DCM (30 mL x 4).
• Step 4 To a solution of 4-bromo-3-(bromomethyl)-l,5-dimethyl-pyrazole (4.80 g, 17.9 mmol, 1 eq) in THF (100 mL), tert-butyl N-(2-hydroxyethyl)-N-methyl-carbamate (3.45 g, 19.7 mmol, 63.6 ⁇ L, 1.1 eq), TBAI (661 mg, 1.79 mmol, 0.1 eq) and KOH (3.02 g, 53.7 mmol, 3 eq) was added. The mixture was stirred at 25 °C for 16 hours under N2. On completion, the mixture was concentrated in vacuum.
• Example 2a Preparation of tert-butyl N-[(lR)-2-[(4-bromo-l,5-dimethyl-pyrazol-3- yl)methoxy]- l-methyl-ethyl]-N-methyl-carbamate (A2a)
• Step 1 To a solution of (4-bromo-l,5-dimethyl-pyrazol-3-yl)methanol (8.64 g, 42.1 mmol, 1 eq) in DMF (180 mL) was added NaH (3.37 g, 84.2 mmol, 60% purity, 2 eq) at 0 °C. The mixture was stirred at 25 °C for 0.5 h followed by addition of tertbutyl(4R)-4-methyl-2,2- dioxo-oxathiazolidine-3-carboxylate (15.0 g, 63.2 mmol, 1.5 eq) and stirred at 25 °C for another 1 h.
• Step 2 To a solution of tert-butyl N-[(lR)-2-[(4-bromo-l,5-dimethyl-pyrazol-3- yl)methoxy]-l-methyl-ethyl]carbamate (5.00 g, 13.8 mmol, 1 eq) in DMF (100 mL) was added NaH (1.10 g, 27.6 mmol, 60% purity, 2 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 h and then CH3I (2.94 g, 20.7 mmol, 1.29 mL, 1.5 eq) was added. The mixture was stirred at 25 °C for 1 h.
• Example 3 Preparation of tert-butyl A-[(lR)-2-[(4-bromo-l-methyl-pyrazoL3- yl)methoxy]- l-methyl-ethyl]carbamate (A3)
• A3 was prepared using similar procedures as A2 starting with methyl 1- methylpyrazole-3-carboxylate and tert-butyl A-[( 1 R)-2-hydroxy- l-methyl-ethyl]carbamate in Step 4 for alkylation reaction.
• Example 5 Preparation of tert-butyl A-[(lS)-2-[(4-bromo-l-methyl-pyrazol-3-yl) methoxy]- 1 -methyl-ethyl] -A-methyLcarbamate (A5) Boc
• A5 was prepared using similar procedures as A4. LCMS m/z 385.9 (M+23).
• A6 was prepared using similar procedures as A2. LCMS m/z 371.9 (M+23).
• Example 7 Preparation of tert-butyl N-[(lR)-2-[[5-bromo-2-methyl-l-(2- trimethylsilylethoxymethyl)imidazol-4-yl]methoxy]-l-methyl-ethyl]-N-methyl-carbamate
• Step 1 To a mixture of 2-methyl-lH-imidazole-4-carbaldehyde (5.00 g, 45.4 mmol, 1 eq) in DCM (50.0 mL) was added SEM-C1 (9.84 g, 59.0 mmol, 10.5 mL, 1.3 eq) at 0 °C, followed by DIEA (7.63 g, 59.0 mmol, 10.2 mL, 1.3 eq) and DMAP (277 mg, 2.27 mmol, 0.05 eq), the mixture was stirred at 25 °C for 0.5 hour under N2.
• Step 2 To a mixture of 2-methyl-l-(2-trimethylsilylethoxymethyl)imidazole-4- carbaldehyde (5.00 g, 20.8 mmol, 1 eq) in MeOH (50.0 mL) was added NaBH4 (825 mg, 21.8 mmol, 1.05 eq) at 0 °C. The mixture was stirred at 25 °C for 0.5 hour under N2 and then quenched by addition of water (20.0 mL) followed by extraction with EtOAc (20.0 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude residue.
• Step 3 To a mixture of [2-methyl-l-(2-trimethylsilylethoxymethyl)imidazol-4- yl]methanol (5.00 g, 20.6 mmol, 1 eq) in ACN (50.0 mL) was added NBS (4.41 g, 24.7 mmol, 1.2 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hour under N2 and then partitioned between EtOAc (20.0 mL) and H2O (20.0 mL). The organic phase was separated, washed with brine (10.0 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
• Step 4 To a mixture of [5-bromo-2-methyl-l-(2-trimethylsilylethoxymethyl)- imidazol-4-yl]methanol (500 mg, 1.56 mmol, 1 eq) in THF (10.0 mL) was added NaH (93.3 mg, 2.33 mmol, 60% purity, 1.5 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 hour. Then tert-butyl (4R)-4-methyl-2,2-dioxo-oxathiazolidine-3-carboxylate (443 mg, 1.87 mmol, 1.2 eq) was added, the mixture was stirred at 25 °C for 1.5 hours.
• reaction mixture was quenched by addition of H2O (5.00 mL).
• the filter liquor was diluted with H2O (5.00 mL) and extracted with EtOAc (5.00 mL * 3).
• the combined organic layers were washed with brine (5 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure.
• Example 8b Preparation of 7-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)indolin-2-one (DI)
• Step 2 To a solution of 5-bromo-7-fluoro-indolin-2-one (16.8 g, 73.2 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 (55.8 g, 219 mmol, 3 eq) in dioxane (250 mL) was added potassium acetate (28.7 g, 292 mmol, 4 eq) and cyclopentyl(diphenyl)phosphane; dichloromethane; dichloropalladium;iron (5.98 g, 7.32 mmol, 0.1 eq).
• Step 1 To a mixture of [5-bromo-2-methyl-l-(2-trimethylsilylethoxymethyl)- imidazol-4-yl]methanol (1.50 g, 4.67 mmol, 1 eq) in DCM (15.0 mL) at 0 °C was added Dess- Martin reagent (2.97 g, 7.00 mmol, 2.17 mL, 1.5 eq). The mixture was stirred at 25 °C for 2 hours, diluted with DCM (10.0 mL), and filtered to remove the insoluble. The filter liquor was diluted with H2O (10.0 mL) and extracted with DCM (10.0 mL * 3).
• Step 2 To a solution of 5-bromo-2-methyl-l-(2-trimethylsilylethoxymethyl)imidazole- 4-carbaldehyde (700 mg, 2.19 mmol, leq) in DMF (10.0 mL) and MeOH (5.00 mL) were added Pd(dppf)Ch (80.2 mg, 109 pmol, 0.05 eq) and TEA (665 mg, 6.58mmol, 915 ⁇ L, 3 eq) under N2. The mixture was degassed under vacuum and purged with CO several times. The mixture was stirred under CO (2.19 mmol, 1 eq) (50 psi) at 80 °C for 16 hours. The mixture was concentrated in vacuum.
• Example 9 Preparation of [3a(4)Z]-6,9,15,16-tetramethyl-9,10,ll,12-tetrahydro-15H- l,17-(ethanediylidene)pyrazolo[4,3-n]dipyrrolo[3,2-g:3',4'-j][l,5]oxazacyclopentadecine- 3,8(2H,5H)-dione (Cpd. 1)
• Step 1 To a solution of tert-butyl N-[3-(4-bromo-l,5-dimethyl-pyrazoL3- yl)oxypropyl]-N-methyl-carbamate (500 mg, 1.38 mmol, 1 eq), 5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)indolin-2-one (643.73 mg, 2.48 mmol, 1.8 eq), Na2CO3 (438 mg, 4.14 mmol, 3 eq) in dioxane (20 mL) and H2O (4 mL) was added Pd(dppf)C12 (100 mg, 138 pmol, 0.1 eq).
• Step 2 To a solution of 5-[l,5-dimethyl-3-[3-(methylamino)propoxy]pyrazol-4- yl]indolin-2-one (160 mg, 508 pmol, 1 eq), 2-formyl-5-methyl-lH-pyrrole-3-carboxylic acid (116.90 mg, 763.40 pmol, 1.5 eq), 1-methylimidazole (417 mg, 5.09 mmol, 0.040 mL, 10 eq) and [chloro(dimethylamino)methylene]-dimethyl-ammonium;hexafluorophosphate (185 mg, 662 pmol, 1.3 eq) in MeCN (30 mL) was stirred at 25 °C for 1 h.
• Example 10 Cpd. 2 - Cpd. 8 were prepared using General Method A with corresponding bromo pyrazole analog Al, A2, A3, A4, A5 or A6, commercially available oxindole boronic ester 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indolin-2-one or 7- chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indolin-2-one, and pyrrole or imidazole aldehyde acid 2-formyl-5-methyl-lH-pyrrole-3-carboxylic acid, 2-formyl-lH- pyrrole-3-carboxylic acid, or 5-formyl-2-methyl-3-(2-trimethylsilylethoxymethyl)imidazole- 4-carboxylic acid.
• Cpd. 8 was obtained with an addition deprotection step: To a mixture of SEM- protected Cpd. 8 on imidazole ring (40.0 mg, 0.067.0 mmol, 1 eq) in DCM (3 mL) was added TFA (1.54 g, 13.5 mmol, 1 mL, 201 eq). The mixture was stirred at 25 °C for 1 hour and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex C18 150*25mm*10pm;mobile phase: [water( NH4HCC>3)-ACN];B%: 9%-
• Example 11 Preparation of [3a(4)Z,10R]-20-chloro-6,9,10,15-tetramethyl- 10,ll,13,16-tetrahydro-2H-l,17-(ethanediylidene)imidazo[4,5-m]dipyrrolo[3,2-f:3',4'- z][l,4]oxazacyclopentadecine-3,8(5H,9H)-dione (Cpd. 9)
• Step 1 To a mixture of 5-bromo-l-chloro-3-fluoro-2-nitro-benzene (2.75 g, 10.8 mmol, 1 eq) and dimethyl propanedioate (1.86 g, 14.0 mmol, 1.61 mL, 1.3 eq) in DMF (30 mL) was added K2CO3 (2.99 g, 21.6 mmol, 2 eq) under N2. The mixture was stirred at 80 °C for 12 h. The residue was diluted with H2O (15.0 mL) and extracted with EtOAc (15.0 mL * 3).
• Step 2 To a mixture of dimethyl 2-(5-bromo-3-chloro-2-nitro-phenyl)propanedioate (3.1 g, 8.46 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 (2.36 g, 9.30 mmol, 1.1 eq) in dioxane (35.0 mL) was added Pd(dppf)Ch (619 mg, 845 pmol, 0.1 eq) and KO Ac (2.49 g, 25.3 mmol, 3 eq) under N2.
• Step 3 To a mixture of dimethyl 2-[3-chloro-2-nitro-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]propanedioate (295 mg, 0.714 mmol, 1.1 eq) and tert-butyl N-[(1R)- 2-[[5-bromo-2-methyl-l-(2-trimethylsilylethoxymethyl)imidazol-4-yl]methoxy]-l-methyl- ethyl]-N-methyl-carbamate (320 mg, 0.649 mmol, 1 eq) in dioxane (5.00 mL) and H2O (0.8 mL) was added ditert-butyl(cyclopentyl)phosphane;dichloropalladium;iron (42.3 mg, 64.9 pmol, 0.1 eq) and CS2CO3 (635 mg, 1.95 mmol, 3 e
• Step 4 To a mixture of dimethyl 2-[5-[5-[[(2R)-2-[tert- butoxycarbonyl(methyl)amino]propoxy]methyl]-2-methyl-3-(2-trimethylsilylethoxy methyl)imidazol-4-yl]-3-chloro-2-nitro-phenyl]propanedioate (100 mg, 0.143 mmol, 1 eq) in DCM (2.00 mL) was added HCl/dioxane (4 M, 2.50 mL, 69.9 eq). The mixture was stirred at 20 °C for 1 hour.
• Step 5 To a mixture of dimethyl 2-[3-chloro-5-[2-methyl-4-[[(2R)-2- (methylamino)propoxy]methyl]-lH-imidazol-5-yl]-2-nitro-phenyl]propanedioate (80.0 mg, 0.158 mmol, 1 eq, HC1) and 2-formyl-5-methyl-lH-pyrrole-3-carboxylic acid (36.3 mg, 0.237 mmol, 1.5 eq) in MeCN (1.50 mL) was added [chloro(dimethylamino)methylene]-dimethyl- ammonium;hexafluorophosphate (66.6 mg, 0.237 mmol, 1.5 eq) and 1 -methylimidazole (38.9 mg, 0.475 mmol, 3 eq), the mixture was stirred at 25 °C for 0.5 hour.
• Step 6 To a mixture of dimethyl 2-[3-chloro-5-[4-[[(2R)-2-[(2-formyl-5-methyl-lH- pyrrole-3-carbonyl)-methyl-amino]propoxy]methyl]-2-methyl-lH-imidazol-5-yl]-2-nitro- phenyl]propanedioate (80.0 mg, 0.132 pmol, 1 eq) in DMSO (1.50 mL) and H2O (0.3 mL) was added LiCl (22.4 mg, 0.529 mmol, 4 eq). The mixture was stirred at 100 °C for 12 hours.
• the filter liquor was diluted with H2O (5.00 mL) and extracted with EtOAc (5.00 mL * 3). The combined organic layers were washed with brine (5.00 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
• Step 7 To a solution of methyl 2-[3-chloro-5-[4-[[(2R)-2-[(2-formyl-5-methyl-lH- pyrrole-3-carbonyl)-methyl-amino]propoxy]methyl]-2-methyl-lH-imidazol-5-yl]-2-nitro- phenyl] acetate (40.0 mg, 0.0732 mmol, 1 eq) in MeOH (6.00 mL) and AcOH (0.100 mL) was added Pt/V/C (1.91 mg, 7.33 pmol, 0.1 eq) under N2. The suspension was degassed under vacuum and purged with H2 several times.
• Step 8 To a mixture of methyl 2-[2-amino-3-chloro-5-[4-[[(2R)-2-[(2-formyl-5- methyl-lH-pyrrole-3-carbonyl)-methyl-amino]propoxy]methyl]-2-methyl-lH-imidazol-5- yl]phenyl] acetate (35.0 mg, 67.8 pmol, 1 eq) in MeOH (2.00 mL) was added AcOH (0.4 mg, 0.0068 mmol, 0.1 eq), the mixture was stirred at 70 °C for 12 hours.
• Step 9 To a mixture of N-[(lR)-2-[[5-(7-chloro-2-oxo-indolin-5-yl)-2-methyl-lH- imidazol-4-yl]methoxy]-l-methyl-ethyl]-2-formyl-N,5-dimethyl-lH-pyrrole-3-carboxamide (25.0 mg, 0.052 mmol, 1 eq) in EtOH (2.00 mL) was added Piperidine (0.44 mg, 0.0052 mmol,
• Example 12 Preparation of [3a(4)Z,10R]-6,9,10,15-tetramethyl-3,8-dioxo- 3,5,8,9,10,ll,13,15-octahydro-2H-l,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2--f:3',4'-i][l,4]oxazacyclopentadecine-20-carbonitrile (Cpd. 10) [0291] Step 1.
• Step 3 The mixture of dimethyl 2-(5-bromo-3-cyano-2-nitro-phenyl)propanedioate (2.00 g, 5.60 mmol, 1.0 eq), [3-[[(2R)-2-[tert-butoxycarbonyl(methyl)amino] propoxy] methyl]- l-methyl-pyrazol-4-yl] boronic acid (9.16 g, 28.0 mmol, 5.0 eq), ditert-butyl (cyclopentyl) phosphane;dichloropalladium;iron (365 mg, 0.56 mmol, 0.1 eq), K2CO3 (2.32 g, 16.8 mmol, 3.0 eq) in dioxane (40 mL) and H2O (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 70 °C for 3 h under N2 atmosphere.
• Step 4 To a solution of dimethyl 2-[5-[3-[[(2R)-2-[tert- butoxycarbonyl(methyl)amino]propoxy]methyl]-l-methyl-pyrazol-4-yl]-3-cyano-2-nitro- phenyl]propanedioate (80.0 mg, 0.143 mmol, 1.0 eq) in DCM (4 mL) was added HCl/dioxane (4 M, 0.036 mL, 1.0 eq). The mixture was stirred at 25 °C for 1 h.
• Step 5 To a solution of dimethyl 2-[3-cyano-5-[l-methyl-3-[[(2R)-2- (methylamino)propoxy] methyl]pyrazol-4-yl]-2-nitro-phenyl] propanedioate (100 mg, 0.217 mmol, 1.0 eq) and 2-formyl-5-methyl-lH-pyrrole-3-carboxylic acid (40.0 mg, 0.261 mmol, 1.2 eq) in ACN (10 mL) was added 1 -methylimidazole (179 mg, 2.18 mmol, 10.0 eq) and [chloro(dimethylamino)methylene]-dimethyl-ammonium;hexafluorophosphate (91.6 mg, 0.326 mmol, 1.5 eq).
• Step 6 To a solution of dimethyl 2-[3-cyano-5-[3-[[(2R)-2-[(2-formyl-5-methyl-lH- pyrrole-3-carbonyl)-methyl-amino]propoxy]methyl]-l-methyl-pyrazol-4-yl]-2-nitro- phenyl]propanedioate (50.0 mg, 0.084 mmol, 1.0 eq) in DMSO (2 mL) and H2O (0.4 mL) was added LiCl (17.8 mg, 0.42 mmol, 5.0 eq). The mixture was stirred at 90 °C for 20 h.
• Step 7 To a solution of methyl 2-[3-cyano-5-[3-[[(2R)-2-[(2-formyl-5-methyl-lH- pyrrole-3-carbonyl)-methyl-amino]propoxy]methyl]-l-methyl-pyrazol-4-yl]-2-nitro- phenyl] acetate (80.0 mg, 0.149 mmol, 1.0 eq) in AcOH (2 mL) was added Fe (41.6 mg, 0.746 mmol, 5.0 eq). The mixture was stirred at 90 °C for 1 hr. The mixture was filtered and concentrated to give a residue.
• Example 13 Compounds 11-13 were prepared following General Method A with corresponding bromo pyrazole analog A2a or A4, boronic ester DI or commercially available oxindole boronic ester 7-chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indolin-2-one, and 2-formyl-5-methyl-lH-pyrrole-3-carboxylic acid.
• Example 14 Kinase binding assays were performed at Eurofins/DiscoveRx using the general KINOMEscan 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. coli 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-well 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-well plates in a final volume of 0.135 mL. The assay plates
• kinase concentration in the eluates was measured by qPCR. Results for compounds tested in this assay at a given concentration are reported as “%Ctrl”, where lower numbers indicate stronger binding in the matrix. %Ctrl was calculated as (test compound signal-positive control signal)/(negative control signal-positive control signal) X100. 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.
• Example 15 Phosphorylation of STAT5 in IFNa-stimulated CD3+ T cells
• PBMC isolation Human whole blood was obtained from San Diego Blood Bank in a tube containing heparin. Peripheral blood mononuclear cells (PBMCs) were isolated by density gradient centrifugation with lymphoprep. Briefly, 15mL Lymphoprep buffer was added to the bottom of the SepMate tube. The tube was spined down shortly. 8ml blood was diluted using Robosep buffer. Blood/Robosep buffer mixture was added into the tube and was centrifuged at 1200 x g for 10 min at room temperature. The pellet was washed with Robosep buffer by centrifuge 300 x g for 8 min at room temperature.
• PBMCs Peripheral blood mononuclear cells
• the pellet was re- suspended in 10mL lx RBC lysis buffer and incubated for 10 min at room temperature. 20mL Robosep buffer was added to stop the reaction. The pellet was spined down and resuspended in 2mL Robosep buffer.
• PBMC plating and IFNa treatment PBMC cells were resuspended at a concentration of 1.25e6 cells/mL. CD3 antibodies were added at a ratio of luL antibody per 90 ⁇ L cell suspension. 80 ⁇ L/well (le5 cells) was plated in the 96 well plate. The cells were treated with indicated compounds and were incubated at 37 °C for 30 minutes. 20 ⁇ L of IFNa (PBL, Cat#11101) was added to the cells and the cells were incubated at 37 °C for 30 minutes.
• IFNa PBL, Cat#11101
• the cells were further washed with centrifuge at 500 x g for 5 minutes with 500 ⁇ L IX Permeabilization buffer and were resuspended in 100 ⁇ L IX Permeabilization buffer containing 2.5 ⁇ L pSTAT5 antibody (BD Biosciences, Cat#562077). The cells were stained at room temperature for 1 hour, followed by centrifuge at 500 x g for 5 minutes to remove the supernatant. The cells were washed with 300 ⁇ L FACS staining buffer with centrifuge and were resuspended cells in 300 ⁇ L of FACS buffer. pSTAT5 expression was analyzed via flow cytometry. Results are shown in Table 3.

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• 2023
  • 2023-01-03 AU AU2023204770A patent/AU2023204770A1/en active Pending
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