WO2023084449A1 - Dérivés diaminocyclopentylpyridines pour le traitement d'une maladie ou d'un trouble - Google Patents

Dérivés diaminocyclopentylpyridines pour le traitement d'une maladie ou d'un trouble Download PDF

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WO2023084449A1
WO2023084449A1 PCT/IB2022/060845 IB2022060845W WO2023084449A1 WO 2023084449 A1 WO2023084449 A1 WO 2023084449A1 IB 2022060845 W IB2022060845 W IB 2022060845W WO 2023084449 A1 WO2023084449 A1 WO 2023084449A1
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amino
pyridin
cyclopentyl
oxadiazol
pharmaceutically acceptable
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PCT/IB2022/060845
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English (en)
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Fupeng Ma
Folkert Reck
Kayo Yasoshima
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Novartis Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • DIAMINOCYCLOPENTYLPYRIDINE DERIVATIVES FOR THE TREATMENT OF A DISEASE OR DISORDER RELATED APPLICATIONS [001] This application claims the benefit of and priority to U.S. Provisional Application Nos. 63/278,754, filed November 12, 2021, 63/325,988 filed March 31, 2022, and 63/379,562 filed October 14, 2022, the entire contents of each of which are hereby incorporated by reference in their entireties.
  • TECHNICAL FIELD [002] The present disclosure is directed to modulators of proprotein convertase subtilisin/ kexin type 9 (PCSK9) useful in the treatment of diseases or disorders.
  • PCSK9 Proprotein convertase subtilisin/kexin type 9
  • the PCSK9 protein contains a signal sequence, a prodomain, a catalytic domain containing a conserved triad of residues (D186, H226 and S386), and a C-terminal domain and is synthesized as a soluble 74-kDa precursor that undergoes autocatalytic cleavage in the endoplasmic reticulum.
  • PCSK9 has pronounced effects on plasma low density lipoprotein cholesterol (LDL-C) levels via its modulation of hepatic low density lipoprotein receptors (LDLR), the main route by which cholesterol is removed from the circulation.
  • LDL-C plasma low density lipoprotein cholesterol
  • LDLR hepatic low density lipoprotein receptors
  • PCSK9 binds the LDLR and directs it to lysosomal degradation, thereby increasing plasma LDL-C levels and, in turn, coronary heart disease (CHD) risk.
  • CHD coronary heart disease
  • PCSK9 knockout mice show an approximate 50% reduction in plasma cholesterol levels and enhanced sensitivity to statins in reducing plasma cholesterol (Rashid, S., et al., Proc. Natl. Acad. Sci., 2005, 102:5374-5379). Human genetic data strongly support the role of PCSK9 in LDL homeostasis.
  • PCSK9 protein-semiconductor
  • plasma LDL-C levels were first established by the discovery of PCSK9 missense mutations in patients with an autosomal dominant form of familial hypercholesterolemia (Abifadel, M., et al., Nature, 2003, 34:154-6).
  • Patients carrying PCSK9 gain-of-function alleles have increased plasma LDL-C levels and premature CHD, whereas those with PCSK9 loss-of-function alleles have markedly reduced plasma LDL-C and are protected from CHD.
  • PCSK9 also plays a role in Lipoprotein (a) (Lp(a)) metabolism.
  • Lp(a) is a proatherogenic lipoprotein comprised of an LDL particle covalently linked to apoLp(a).
  • PCSK9 therapeutic antibodies have been shown to significantly reduce Lp(a) levels in patients with hypercholesterolemia. (Desai, N.R., et. al., Circulation. 2013, 128(9):962-969; Lambert, G., et. al., Clin. Sci., 2017, 131, 261-268).
  • PCSK9 plays an important role in sepsis, a lifethreatening condition caused by a body’s response to infection.
  • Overexpression of PSCK9 in septic mice has been shown to aggravate sepsis by increasing inflammation, while inhibition of PCSK9 has been shown to reduce mortality. (Dwivedi, D. J., et al., Shock, 2016, 46(6), 672-680).
  • PCSK9 negatively regulates gram-negative lipopolysaccharide (LPS) uptake by hepatocytes through the regulation of the LDLR-mediated bacterial lipid uptake of lipoteichoic acid (LTA) and LPS through an LDL-dependent mechanism.
  • LPS gram-negative lipopolysaccharide
  • LTA lipoteichoic acid
  • PCSK9 inhibition of PCSK9 has the potential to treat sepsis by reducing the body’s immune response to an infection.
  • the disclosure relates to a compound of Formula (I):
  • A is a 5 or 6 membered heterocycle or heteroaryl containing at least one N and at least one oxo at a ring carbon and is optionally substituted with (C 1 -C 6 )alkyl;
  • X is N, 0, or S
  • Y is CR 1 or N
  • Z is CR 2 , NR 3 , 0, or S
  • R 1 and R 2 are each, independently selected from H, halogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 6 - C 10 )aryl, a 4 to 6 membered heterocyclyl comprising 1, 2 or 3 heteroatoms selected from 0 and N, or a 5 or 6 membered heteroaryl comprising 1, 2 or 3 heteroatoms selected from 0 and N, wherein the (C 1 - C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 6 -C 10 )aryl, heterocyclyl, or heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, -OH, -CN, (C 1 -C 6 )alkyl, (C 1 - C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, -SO 2 (
  • R 3 is absent, H or (C 1 -C 6 )alkyl
  • R 4 is H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy or (C 3 -C 6 )cycloalkyl, wherein the (C 1 -C 6 )alkoxy is optionally substituted with halogen.
  • the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.
  • the present disclosure relates to a combination comprising a compound of Formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutical agents.
  • the present disclosure relates to a method for treating a disease or disorder comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • the disease or disorder is selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, xanthoma, peripheral arterial disease, elevated Lp(a), elevated LDL, elevated TRL, and elevated triglycerides.
  • the disease or disorder is selected from sepsis, psoriasis and cancer.
  • the present disclosure relates to a method of modulating PCSK9 comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • the present disclosure relates to a method of inhibiting PCSK9 comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • the present disclosure relates to a compound of Formula I or a pharmaceutically acceptable salt thereof for use as a medicament.
  • the present disclosure relates to a compound of Formula I or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder.
  • the present disclosure relates to a compound of Formula I for use in the manufacture of a medicament for treating a disease or disorder.
  • the present disclosure relates to use of a compound of Formula I or a pharmaceutically acceptable salt thereof in the treatment of a disease or disorder.
  • the disclosure provides substituted diaminocyclopentylpyridine compounds, and pharmaceutical compositions thereof.
  • substituted compounds are useful as PCSK9 inhibitors, and thus can be used to treat or prevent a disease or condition.
  • the disclosure therefore provides a compound of formula (I)
  • A is a 5 or 6 membered heterocycle or heteroaryl containing at least one N and at least one oxo at a ring carbon and is optionally substituted with (C 1 -C 6 )alkyl;
  • X is N, 0, or S
  • Y is CR 1 or N
  • Z is CR 2 , NR 3 , 0, or S
  • R 1 and R 2 are each, independently selected from H, halogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 5 - C 10 )aryl, a 4 to 6 membered heterocyclyl comprising 1, 2 or 3 heteroatoms selected from 0 and N, or a 5 or 6 membered heteroaryl comprising 1, 2 or 3 heteroatoms selected from 0 and N, wherein the (C 1 - C 6 )alkyl, (C 3 -C 6 )cycloalkyl, ( C 6 - C 10 )aryl, heterocyclyl, or heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, -OH, -CN, (C 1 -C 6 )alkyl, (C 1 - C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, -SO 2 (
  • R 3 is absent, H or (C 1 -C 6 )alkyl
  • R 4 is H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy or (C 3 -C 6 )cycloalkyl, wherein the (C 1 -C 6 )alkoxy is optionally substituted with halogen.
  • the term “compounds of the present disclosure” or “compound of the present disclosure” refers to compounds of formula (I) thereof, and exemplified compounds, and salts thereof, as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers and isotopically labeled compounds (including deuterium substitutions), as well as inherently formed moieties.
  • the compound is a compound of formula II or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula III or a pharmaceutically acceptable salt thereof.
  • At least one of X, Y and Z is N.
  • Z is CR 2 or N.
  • Z is O or S, X is N.
  • X is N. In some embodiments, X is N, Y is CR 1 , and Z is O or S
  • B is In some embodiments, B is , particularly B is or , more particularly B is
  • B is . In some embodiments, B is
  • A is , or . In some embodiments, A is . In some embodiments, A is . In some embodiments, A is . In some embodiments, A is , particularly A is
  • R 1 is H, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, ( C 6 - C 10 )aryl, a 4 to 6 membered heterocyclyl comprising 1, 2 or 3 heteroatoms selected from 0 and N, or a 5 or 6 membered heteroaryl comprising 1, 2 or 3 heteroatoms selected from 0 and N, wherein the (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 6 -C 10 )aryl, heterocyclyl, or heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, -OH, -CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 3 - C 6 )cycloalkyl, -SO 2 (C 1 -C 6 )alkyl,
  • R 1 is H, (C 1 - C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 6 -C 10 )aryl, a 4 to 6 membered heterocyclyl comprising 1 heteroatom selected from 0 and N, or a 5 or 6 membered heteroaryl comprising 1 or 3 heteroatoms selected from N, wherein the (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 6 -C 10 )aryl, heterocyclyl, or heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, -OH, -CN, (C 1 C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, -SO 2 (C 1 -C 6 )alkyl, -COOH, and
  • R 1 is H, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, or (C 6 -C 10 )aryl, wherein the (C 1 - C 6 )alkyl, (C 3 -C 6 )cycloalkyl, or (C 6 -C 10 )aryl are each independently optionally substituted with one or more substituents selected from halogen, -OH, -CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, and (C 1 -C 6 )alkoxy.
  • R 1 is H, (C 1 -C 6 )alkyl optionally substituted with one or more halogen, -CN, (C 3 - C 6 )cycloalkyl optionally substituted with one or more substituents selected from halogen, -OH, (C 1 - C 6 )alkyl and (C 1 -C 6 )haloalkyl, or (C 6 -C 10 )aryl optionally substituted one or more with halogen or CN.
  • R 1 is (C 1 -C 6 )alkyl optionally substituted with one or more halogen or -CN, (C 3 - C 6 )cycloalkyl optionally substituted with one or more substituents selected from halogen, -OH, (C 1 - C 6 )alkyl and (C 1 -C 6 )haloalkyl, or (C 6 -C 10 )aryl optionally substituted with one or more halogen or -CN.
  • R 1 is H, (C 1 -C 6 )alkyl optionally substituted with one or more halogen, (C 3 - C 6 )cycloalkyl optionally substituted with one or more substituents selected from halogen, -OH, (C 1 - C 6 )alkyl and (C 1 -C 6 )haloalkyl, or (C 6 -C 10 )aryl optionally substituted one or more with halogen.
  • R 1 is (C 1 -C 6 )alkyl optionally substituted with one or more halogen, (C 3 -C 6 )cyclo alkyl optionally substituted with one or more substituents selected from halogen, -OH, (C 1 -C 6 )alkyl and (C 1 - C 6 )haloalkyl, or (C 6 -C 10 )aryl optionally substituted with one or more halogen.
  • R 1 is H, (C 1 -C 6 )alkyl optionally substituted with one or more fluoro, (C 3 -C 6 )cyclo alkyl optionally substituted with one or more substituents selected from fluoro, -OH, (C 1 -C 6 )alkyl and (C 1 -C 6 )fluoroalkyl, or ( C 6 - C 10 )aryl optionally substituted one or more with fluorine.
  • R 1 is (C 1 -C 6 )alkyl optionally substituted with fluoro, (C 3 -C 6 )cycloalkyl optionally substituted with one or more substituents selected from fluoro, -OH, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl, or (C 6 -C 10 )aryl optionally substituted with one or more fluoro.
  • R 1 is (C 1 -C 6 )alkyl optionally substituted with one or more fluoro or -CN.
  • R 1 is (C 1 -C 6 )alkyl optionally substituted with one or more fluoro.
  • R 1 is unsubstituted (C 1 -C 6 )alkyl.
  • R 1 is (C 3 -C 6 )cycloalkyl optionally substituted with one or more substituents selected from fluoro, -OH, (C 1 -C 6 )alkyl and (C 1 - C 6 )fluoroalkyl.
  • R 1 is (C 3 -C 6 )cycloalkyl.
  • R 1 is phenyl optionally substituted with one or more fluoro.
  • R 1 is -CH 3 , -CH 2 CH 3 , -CHF 2 , -CF 3 , -CF 2 CH 3 , -CH 2 CF 3 , -CH 2 CN, or In certain embodiments, R 1 is -CH 3 , -CH 2 CH 3 , -CHF 2 , -CF 3 , -CF 2 CH 3 , or . In certain embodiments, R 1 is -CH 3 , -CH 2 CH 3 , -CHF 2 , -CF 3 , or -CF 2 CH 3 . In certain preferred embodiments,
  • R 1 is -CH 3 , -CHF 2 , or -CF 3 .
  • R 1 is In some embodiments, R 1 is
  • R 1 is In some embodiments, R is
  • R 1 is . In some embodiments, R 1 is
  • R 2 is H, halogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, or (C 6 -C 10 )aryl.
  • R 2 is H, fluoro, chloro, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, or (C 6 -C 10 )aryl.
  • R 2 is halogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, or phenyl.
  • R 2 is fluoro, chloro, (C 1 -C 6 )alkyl, (C 3 -C 6 lcycloalkyl, or phenyl. In some embodiments, R 2 is -Cl, -CH?. or [039] In some preferred embodiments, R 3 is H.
  • R 4 is (C 1 -C 6 )alkyl or (C 3 -C 6 ) cycloalkyl. In some embodiments, R 4 is (C 1 -C 6 )alkyl.
  • R 4 is methyl, ethyl, or cyclopropyl. In some embodiments, R 4 is methyl or ethyl. In some embodiments, R 4 is (C 1 -C 6 )alkoxy optionally substituted with halogen. In some embodiments, R 4 is -OCF 3 .
  • B is
  • B is . In some embodiments, B is , or
  • B is
  • Embodiment 1 A compound of formula (I), or a pharmaceutically acceptable salt thereof, as described above.
  • Embodiment 2 A compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein at least one of X, Y and Z is N.
  • Embodiment 3 A compound according to embodiment 1 or embodiment 2 or a pharmaceutically acceptable salt thereof, wherein when X is 0 or S, Z is CR 2 or N.
  • Embodiment 4 A compound according to any one of embodiments 1 to 3 or a pharmaceutically acceptable salt thereof, wherein when Z is 0 or S, X is N.
  • Embodiment 5 A compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is methyl, ethyl, or cyclopropyl. [046] Embodiment 6. A compound according to any one of embodiments 1 to 5 or a pharmaceutically acceptable salt thereof, wherein A is
  • Embodiment 7 A compound according to any one of embodiments 1 to 6 or a pharmaceutically acceptable salt thereof, wherein A is
  • Embodiment 8 A compound according to any one of embodiments 1 to 7 or a pharmaceutically acceptable salt thereof, wherein X is N.
  • Embodiment 9 A compound according to any one of embodiments 1 to 8 or a pharmaceutically acceptable salt thereof, wherein X is N, Y is CR 1 , and Z is 0 or S.
  • Embodiment 10 A compound according to any one of embodiments 1 to 9 or a pharmaceutically acceptable salt thereof, wherein X is N, Y is CR 1 , and Z is O.
  • Embodiment 11 A compound according to any one of embodiments 1 to 10 or a pharmaceutically acceptable salt thereof, wherein R 1 is H, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 6 -C 10 )aryl, a 4 to 6 membered heterocyclyl comprising 1, 2 or 3 heteroatoms selected from O and N, or a 5 or 6 membered heteroaryl comprising 1, 2 or 3 heteroatoms selected from O and N, wherein the (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 6 -C 10 )aryl, heterocyclyl, or heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, -OH, -CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 - C 6 )alkoxy, (C 3
  • Embodiment 12 A compound according to any one of embodiments 1 to 11 or a pharmaceutically acceptable salt thereof, wherein R 1 is H, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 6 -C 10 )aryl, a 4 to 6 membered heterocyclyl comprising 1 heteroatom selected from O and N, or a 5 or 6 membered heteroaryl comprising 1 or 3 heteroatoms selected from N, wherein the (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 6 -C 10 )aryl, heterocyclyl, or heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, -OH, -CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 3 - C 6 )cycl
  • Embodiment 13 A compound according to any one of embodiments 1 to 12 or a pharmaceutically acceptable salt thereof, wherein R 1 is H, (C 1 -C 6 )alkyl optionally substituted with one or more halogen, -CN, (C 3 -C 6 )cycloalkyl optionally substituted with one or more substituents selected from halogen, -OH, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl, or (C 6 -C 10 )aryl optionally substituted one or more with halogen or -CN.
  • R 1 is H, (C 1 -C 6 )alkyl optionally substituted with one or more halogen, -CN, (C 3 -C 6 )cycloalkyl optionally substituted with one or more substituents selected from halogen, -OH, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl, or (C 6
  • Embodiment 14 A compound according to any one of embodiments 1 to 13 or a pharmaceutically acceptable salt thereof, wherein R 1 is (C 1 -C 6 )alkyl optionally substituted with one or more halogen or -CN, (C 3 -C 6 )cyclo alkyl optionally substituted with one or more substituents selected from halogen, -OH, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl, or (C 6 -C 10 )aryl optionally substituted with one or more halogen or -CN.
  • R 1 is (C 1 -C 6 )alkyl optionally substituted with one or more halogen or -CN, (C 3 -C 6 )cyclo alkyl optionally substituted with one or more substituents selected from halogen, -OH, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl, or (C 6 -C 10
  • Embodiment 15 A compound according to embodiment 13 or a pharmaceutically acceptable salt thereof, wherein each halogen is fluoro.
  • Embodiment 16 A compound according to any one of embodiments 1 to 15 or a pharmaceutically acceptable salt thereof, wherein R 1 is (C 1 -C 6 )alkyl optionally substituted with one or more fluoro or -CN.
  • Embodiment 17 A compound according to any one of embodiments 1 to 16, wherein R 1 is -CH3,
  • Embodiment 18 A compound according to any one of embodiments 1 to 17, wherein R 1 is -CH 3 , -CHF 2 , or -CF 3 .
  • Embodiment 19 A compound according to any one of embodiments 1 to 14 or a pharmaceutically acceptable salt thereof, wherein R 1 is (C 3 -C 6 )cycloalkyl optionally substituted with one or more substituents selected from fluoro, -OH, (C 1 -C 6 )alkyl and (C 1 -C 6 )fluoroalkyl.
  • Embodiment 20 A compound according to any one of embodiments 1 to 13 or a pharmaceutically acceptable salt thereof, wherein R 1 is
  • Embodiment 21 A compound according to any one of embodiments 1 to 13 or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl optionally substituted with one or more fluoro.
  • Embodiment 22 A compound according to embodiments 21 or a pharmaceutically acceptable salt thereof, wherein R 1 is
  • Embodiment 23 A compound according to any one of embodiments 1 to 13 or a pharmaceutically acceptable salt thereof, wherein R 1 is
  • Embodiment 24 A compound according to any one of embodiments 1 to 13 or a pharmaceutically acceptable salt thereof, wherein R 1 is ,
  • Embodiment 25 A compound according to any one of embodiments 1 to 3, 5 to 8, and 11 to 24 or a pharmaceutically acceptable salt thereof, wherein R 2 is H, halogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, or (C 6 -C 10 )aryl.
  • Embodiment 26 A compound according to any one of embodiments Ito 3, 5 to 8, and 11 to 22 or a pharmaceutically acceptable salt thereof, wherein R 2 is halogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl. or phenyl
  • Embodiment 27 A compound according to any one of embodiments 1 to 3, 5 to 8, and 11 to 26 or a pharmaceutically acceptable salt thereof, wherein R 2 is -Cl, -CH 3 .
  • Embodiment 28 A compound according to any one of embodiments 1 to 3, 5 to 8, and 11 to 27 or a pharmaceutically acceptable salt thereof, wherein R 3 is H.
  • Embodiment 29 A compound according to any one of embodiments 1 to 4 or a pharmaceutically acceptable salt thereof, wherein B is
  • Embodiment 30 A compound according to any one of embodiments 1 to 4 or a pharmaceutically acceptable salt thereof,, wherein B is or
  • Embodiment 31 A compound according to any one of embodiments 1 to 4 or a pharmaceutically acceptable salt thereof, wherein B is
  • Embodiments 32 and 33 A compound according to embodiment 1 or a pharmaceutically acceptable salt thereof selected from: [072] Additionally, Applicants have surprisingly and unexpectedly found that compounds of Formula (I) exhibit low or no inhibition of the human Ether-a-go-go-Related Gene (hERG). As discussed herein, some aspects of cardiovascular toxicity of a compound can be measured using a hERG assay.
  • the hERG gene encodes the inward rectifying voltage gated potassium channel in the heart known as K V 11.1, which is involved in cardiac repolarization. Inhibition of the hERG current causes QT interval prolongation resulting in potentially fatal ventricular tachyarrhythmia. hERG inhibition an important antitarget that must be avoided.
  • compounds of Formula I exhibited no measurable hERG inhibition.
  • This lack of cardiovascular toxicity by the compounds of Formula I is surprising and unexpected, especially considering the inhibition of hERG by 2-(6-(((lS,3S)-3-((5- cyclopropylpyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyridazin-3(2H)-one and 3-(6- ((( IS, 3 S)-3 -((5 -(difluoromethoxy )pyrimidin-2-yl)am ino)cyclopentyl)am ino)pyridin-3-y 1)-1- methylimidazolidine-2, 4-dione.
  • salt refers to an acid addition or base addition salt of a compound of the present disclosure.
  • Salts include in particular “pharmaceutical acceptable salts”.
  • pharmaceutically acceptable salts refers to salts that retain the biological effectiveness and properties of the compounds of this disclosure and, which typically are not biologically or otherwise undesirable.
  • the compounds of the present disclosure are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • the compounds of the present disclosure may also form internal salts, e.g., zwitterionic molecules.
  • compositions can be formed with inorganic acids and organic acids.
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.
  • compositions can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table.
  • the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like.
  • C 6 rtain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
  • the present disclosure provides compounds of the present disclosure in acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, caprate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate,
  • 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 formulae 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, for example, isotopes of hydrogen.
  • the disclosure provides a compound of formula (la) or a pharmaceutically acceptable salt thereof, wherein each R 10a , R 10b , R 10c , R lla , R llb , R 12a , R 12b , R 12c , R 12d , R 12e and R 12 is independently selected from H or deuterium; and A and B are as defined herein.
  • isotopes particularly deuterium (i.e., 2 H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index or tolerability.
  • deuterium in this context is regarded as a substituent of a compound of the present disclosure.
  • concentration of deuterium may be defined by the isotopic enrichment factor.
  • isotopic enrichment factor as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a substituent in a compound of this disclosure is denoted as being deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • isotopic enrichment factor can be applied to any isotope in the same manner as described for deuterium.
  • isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 3 H, n C, 13 C, 14 C, 15 N, 18 F 31 P, 32 P, 35 S, 36 C1, 123 I, 124 1, 125 I respectively. Accordingly it should be understood that the disclosure includes compounds that incorporate one or more of any of the aforementioned isotopes, including for example, radioactive isotopes, such as 3 H and 14 C, or those into which non-radio active isotopes, such as 2 H and 13 C are present.
  • Such isotopically labelled compounds are useful in metabolic studies (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.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F or labeled compound may be particularly desirable for PET or SPECT studies.
  • Isotopically-labeled compounds of the present disclosure can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.
  • any asymmetric atom (e.g., carbon or the like) of the compound(s) of the present disclosure can be present in racemic or enantiomerically enriched, for example the (R ⁇ )-, (5)- or (R, 5)- configuration.
  • each asymmetric atom has at least 50 % enantiomeric excess, at least 60 % enantiomeric excess, at least 70 % enantiomeric excess, at least 80 % enantiomeric excess, at least 90 % enantiomeric excess, at least 95 % enantiomeric excess, or at least 99 % enantiomeric excess in the (R ⁇ )- or (5)- configuration.
  • Substituents at atoms with unsaturated double bonds may, if possible, be present in cis- (Z)- or trans- (E)- form.
  • a compound of the present disclosure can be in the form of one of the possible stereoisomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) stereoisomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.
  • Any resulting mixtures of stereoisomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
  • any resulting racemates of compounds of the present disclosure or of intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound.
  • a basic moiety may thus be employed to resolve the compounds of the present disclosure into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-G.G'-/)-toluoyl tartaric acid, mandelic acid, malic acid or camphor- 10-sulfonic acid.
  • Racemic compounds of the present disclosure or racemic intermediates can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high pressure liquid chromatography
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
  • the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein.
  • pharmaceutical composition further comprises at least one additional pharmaceutically active agent.
  • the additional pharmaceutically active agent is selected from hypolipidemic agents, niacin and analogs thereof, bile acid sequestrants, a thyroid hormone mimetic, thyroid hormone receptor (THR) 0-selective agonist, a microsomal triglyceride transfer protein (MTP) inhibitor, an acyl CoA: diacylglycerol acyltransferase 1 (DGAT1) inhibitor, a Niemann Pick Cl- like 1 (NPC1-L 1) inhibitor, an agonist of ATP Binding Cassette (ABC) proteins G5 or G8, an inhibitory nucleic acid targeting PCSK9, an inhibitory nucleic acid targeting Lp(a), an inhibitory nucleic acid targeting apoB 100, apoA-I up-regulator/inducer, ABCA 1 stabilizer or inducer, phospholipid transfer protein (PL TP) inhibitor, fish oil, anti-dia
  • TTR thyroid hormone receptor
  • MTP
  • the additional pharmaceutically active agent is selected from bempedoic acid, statins, ezetimibe, inclisiran, pelacarsen, evolocumab, PD-1, PD-L1, PD-L2 and combinations thereof [091]
  • the pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration (e.g. by injection, infusion, transdermal or topical administration), and rectal administration. Topical administration may also pertain to inhalation or intranasal application.
  • compositions of the present disclosure can be made up in a solid form (including, without limitation, capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including, without limitation, solutions, suspensions or emulsions). Tablets may be either film coated or enteric coated according to methods known in the art.
  • the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with one or more of: a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and e) absorbents, colorants, flavors and sweeteners.
  • diluents e.g., lactose, dextrose
  • Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc.
  • the disclosed compound is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable isotonic solution or suspension.
  • a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like.
  • Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds.
  • the disclosed compounds can be also formulated as a suppository that can be prepared from fatty emulsions or suspensions; using polyalkylene glycols such as propylene glycol, as the carrier.
  • Parental injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions.
  • Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection.
  • compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% of the disclosed compound by weight or volume.
  • the dosage regimen utilizing the disclosed compound is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the patient; and the particular disclosed compound employed.
  • a physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
  • the pharmaceutical composition or combination of the present disclosure may, for example, be in unit dosage of about 1-1000 mg of active ingredient(s) for a subject of about 50-70 kg.
  • the compositions are in the form of a tablet that can be scored.
  • the therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof, is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated.
  • Embodiment 34 A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 33 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.
  • Embodiment 35 The pharmaceutical composition of embodiment 34, further comprising at least one additional pharmaceutically active agent.
  • Embodiment 36 The pharmaceutical composition of embodiment 35, wherein the additional pharmaceutically active agent is selected from hypolipidemic agents, niacin and analogs thereof, bile acid sequestrants, a thyroid hormone mimetic, thyroid hormone receptor (THR) P-selective agonist, a microsomal triglyceride transfer protein (MTP) inhibitor, an acyl CoA:diacylglycerol acyltransferase 1 (DGAT1) inhibitor, a Niemann Pick Cl-like 1 (NPC1-L 1) inhibitor, an agonist of ATP Binding Cassette (ABC) proteins G5 or G8, an inhibitory nucleic acid targeting PCSK9 protein expression, an inhibitory nucleic acid targeting Lp(a) protein expression, an inhibitory nucleic acid targeting apoB 100, apoA-I up- regulator/inducer, ABCA 1 stabilizer or inducer, phospholipid transfer protein (PL TP) inhibitor, fish oil, anti-diabetic agent, anti-di
  • TR-FRET time resolved fluorescence resonance energy transfer
  • Solutions of varying concentrations are prepared by diluting a compound of the disclosure in dimethylsulfoxide (DMSO) and the resulting solutions are pipetted into a plate.
  • DMSO dimethylsulfoxide
  • An intermediate plate is prepared in by transferring a known amount of each compound solution and of the control from the compound plate into a corresponding well containing assay buffer and mixing thoroughly.
  • a third plate is then prepared to be used for the assay by adding Terbium labeled human PCSK9, followed by a known amount of each solution from the intermediate plate. Unlabeled human PCSK9 in assay buffer containing DMSO is used as a control for the assay.
  • Alexa Fluor 647 labeled probe is added to each well of the assay plate and the resulting mixture is incubated for an additional period of time.
  • the TR-FRET signal is measured and the FRET ratio (FRET/Terbium) is used to calculate the IC50 and Amax of the compounds.
  • the compounds of Formula (I) may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of their execution, shall be consistent with the preparation of compounds of Formula (I).
  • the present disclosure includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but the individual enantiomers and/or diastereomers as well.
  • a compound When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).
  • the compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and/or enzymatic processes.
  • the present disclosure is directed to a method of treating or preventing a disease or disorder comprising administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.
  • the disclosure is directed to a method of modulating PCSK9 comprising administering to a patient in need thereof a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the disclosure is directed to a method of inhibiting PCSK9.
  • the method involves administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Another aspect of the disclosure relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder in which PCSK9 plays a role.
  • the method comprises administering to a patient in need of a treatment for diseases or disorders in which PCSK9 plays a role an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Another aspect of the present disclosure relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder in a patient associated with the inhibition of PCSK9, the method comprising administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present disclosure relates to a method of treating, preventing, inhibiting, or eliminating a PCSK9-mediated disease or disorder.
  • the method comprises administering to a patient in need of a treatment for a PCSK9-mediated disease or disorder an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.
  • the present disclosure relates to a method of reducing Lp(a), reducing Lp(a) plasma levels, reducing Lp(a) serum levels, reducing serum TRL or LDL levels, reducing serum triglyceride levels, reducing LDL-C, reducing total plasma apoB concentrations, reducing LDL apoB, reducing TRL apoB, or reducing non HDL-C.
  • the method comprises administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present disclosure relates to a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use a medicament.
  • Another aspect of the present disclosure relates to a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier for use in the treatment, prevention, inhibition, or elimination of a PCSK9-mediated disease or disorder.
  • the present disclosure relates to a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, thereof, and a pharmaceutically acceptable carrier for use in the treatment, prevention, inhibition, or elimination of a disease or disorder in which PCSK9 plays a role.
  • the present disclosure relates to a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, thereof, and a pharmaceutically acceptable carrier for use in the treatment, prevention, inhibition, or elimination of a disease or disorder , wherein the disease or disorder is selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, xanthoma, peripheral arterial disease, , elevated Lp(a), elevated LDL, elevated TRL, and elevated triglycerides.
  • the disease or disorder is selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, xanthoma, peripheral arterial disease, , elevated Lp(a), elevated LDL, elevated TRL, and elevated t
  • the present disclosure relates to a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, thereof, and a pharmaceutically acceptable carrier for use in the treatment, prevention, inhibition, or elimination of a disease or disorder , the disease or disorder is selected from sepsis, psoriasis, psoriasis and cancer.
  • Another aspect of the present disclosure relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier in the manufacture of a medicament for treating of a PCSK9-mediated disease or disorder.
  • Another aspect of the present disclosure relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable thereof, and a pharmaceutically acceptable carrier for use in the treatment, prevention, inhibition, or elimination of hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, xanthoma, peripheral arterial disease, elevated Lp(a), elevated LDL, elevated TRL, and elevated triglycerides.
  • hypercholesterolemia hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, xanthoma, peripheral arterial disease, elevated Lp(a), elevated LDL, elevated TRL, and elevated triglycerides.
  • Another aspect of the present disclosure relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable thereof, and a pharmaceutically acceptable carrier for use in the treatment, prevention, inhibition, or elimination of sepsis, psoriasis, and cancer.
  • Another aspect of the present disclosure relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier for use in the manufacture of a medicament for treating a disease in which PCSK9 plays a role.
  • the present disclosure relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier in the manufacture of a medicament treating a PCSK9-mediated disease or disorder.
  • the present disclosure relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, xanthoma, peripheral arterial disease, elevated Lp(a), elevated LDL, elevated TRL, and elevated triglycerides.
  • the present disclosure relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating sepsis, psoriasis, and cancer.
  • the disease or disorder is a PCSK9-mediated disease or disorder.
  • the PCSK9-mediated disease or disorder is selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, xanthoma, peripheral arterial disease, elevated Lp(a), elevated LDL, elevated TRL, and elevated triglycerides.
  • the PCSK9-mediated disease or disorder is selected from sepsis, psoriasis, and cancer.
  • the disease or disorder is selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, xanthoma, peripheral arterial disease, elevated Lp(a), elevated LDL, elevated TRL, and elevated triglycerides.
  • the disease or disorder is selected from sepsis, psoriasis, and cancer.
  • the disclosed compounds of the disclosure can be administered in effective amounts to treat or prevent a disorder and/or prevent the development thereof in subjects.
  • Embodiment 37 The pharmaceutical composition of any one of embodiments 34 to 36 for use in the treatment of a PCSK9-mediated disease or disorder.
  • Embodiment 38 The pharmaceutical composition of any one of embodiments 34 to 36 for use in the treatment of a disease or disorder, wherein the disease or disorder is selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, xanthoma, peripheral arterial disease, elevated Lp(a), elevated LDL, elevated TRL, and elevated triglycerides.
  • the disease or disorder is selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, xanthoma, peripheral arterial disease, elevated Lp(a), elevated LDL, elevated TRL, and elevated triglycerides.
  • Embodiment 41 A method for treating or preventing a disease or disorder comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of the embodiments 1 to 33, or a pharmaceutically acceptable salt thereof.
  • Embodiment 42 The method of embodiment 41, wherein the disease or disorder is a PCSK9- mediated disease or disorder.
  • Embodiment 43 The method of embodiments 42, wherein the PCSK9-mediated disease or disorder is selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, xanthoma, peripheral arterial disease, elevated Lp(a), elevated LDL, elevated TRL, and elevated triglycerides.
  • Embodiment 44 A method for treating a disease or disorder comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of the embodiments 1-33, or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is selected from selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, xanthoma, peripheral arterial disease, elevated Lp(a), elevated LDL, elevated TRL, and elevated triglycerides.
  • Embodiment 45 A method of modulating PCSK9 comprising administering to a patient in need thereof a compound of any one of embodiments 1 to 33 or a pharmaceutically acceptable salt thereof.
  • Embodiment 46 A method of inhibiting PCSK9 comprising administering to a patient in need thereof a compound of any one of embodiments 1 to 33 or a pharmaceutically acceptable salt thereof.
  • Embodiment 47 The method of any one of embodiments 41 to 46, wherein administering the compound is oral, parental, subcutaneous, by injection, or by infusion.
  • Embodiment 48 A compound according to any one of embodiments 1 to 33 or a pharmaceutically acceptable salt thereof, for use as a medicament.
  • Embodiment 49 A compound according to any one of embodiments 1 to 33 or a pharmaceutically acceptable salt thereof, for use in the treatment of a PCSK9-mediated disease or disorder.
  • Embodiment 50 The compound of embodiment 49, wherein the PCSK9-mediated disease or disorder selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, xanthoma, peripheral arterial disease, elevated Lp(a), elevated LDL, elevated TRL, and elevated triglycerides.
  • the PCSK9-mediated disease or disorder selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, xanthoma, peripheral arterial disease, elevated Lp(a), elevated LDL, elevated TRL, and elevated triglycerides.
  • Embodiment 51 A compound according to any one of embodiments 1 to 33 or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder, wherein the disease or disorder is selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, xanthoma, peripheral arterial disease, elevated Lp(a), elevated LDL, elevated TRL, and elevated triglycerides.
  • the disease or disorder is selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, xanthoma, peripheral arterial disease, elevated Lp(a), elevated LDL, elevated TRL, and elevated triglycerides.
  • Embodiment 52 A compound according to any one of the embodiments 1 to 33, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for treating of a PCSK9-mediated disease or disorder.
  • Embodiment 53 The compound for use in the manufacture of a medicament of embodiment 52, wherein the disease or disorder is selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, xanthoma, peripheral arterial disease, elevated Lp(a), elevated LDL, elevated TRL, and elevated triglycerides.
  • the disease or disorder is selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, xanthoma, peripheral arterial disease, elevated Lp(a), elevated LDL, elevated TRL, and elevated triglycerides.
  • Embodiment 54 Use of a compound according to any one of embodiments 1 to 33, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a PCSK9- mediated disease or disorder.
  • Embodiment 55 The use of embodiment 54, wherein said PCSK9-mediated disease or disorder selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, xanthoma, peripheral arterial disease, elevated Lp(a), elevated LDL, elevated TRL, and elevated triglycerides.
  • said PCSK9-mediated disease or disorder selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, xanthoma, peripheral arterial disease, elevated Lp(a), elevated LDL, elevated TRL, and elevated triglycerides.
  • a compound according to any one of embodiments 1 to 33, or a pharmaceutically acceptable salt thereof, in the treatment of a disease or disorder wherein the disease or disorder is selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, xanthoma, peripheral arterial disease, elevated Lp(a), elevated LDL, elevated TRL, and elevated triglycerides.
  • the compounds of the disclosure can be administered in therapeutically effective amounts in a combinational therapy with one or more therapeutic agents (pharmaceutical combinations) or modalities, e.g., non-drug therapies.
  • therapeutic agents pharmaceutical combinations
  • modalities e.g., non-drug therapies.
  • synergistic effects can occur with other cardiovascular agents, antihypertensive agents, coronary vasodilators, and diuretic substances.
  • dosages of the co-administered compounds will of course vary depending on the type of co-drug employed, on the specific drug employed, on the condition being treated and so forth.
  • the compounds of the present disclosure may be administered either simultaneously with, or before or after, one or more other therapeutic agent.
  • the compound of the present disclosure may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agents.
  • a therapeutic agent is, for example, a chemical compound, peptide, antibody, antibody fragment or nucleic acid, which is therapeutically active or enhances the therapeutic activity when administered to a patient in combination with a compound of the present disclosure.
  • the disclosure provides a product comprising a compound of the present disclosure and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy.
  • the therapy is the treatment of a disease or condition mediated by PCSK9.
  • Products provided as a combined preparation include a composition comprising the compound of the present disclosure and the other therapeutic agent(s) together in the same pharmaceutical composition, or the compound of the present disclosure and the other therapeutic agent(s) in separate form, e.g. in the form of a kit.
  • the disclosure includes a compound of Formula (I) or a pharmaceutically acceptable salt thereof, for use in a combination therapy.
  • a compound, composition, medicament and compounds for use of Formula according to any one of embodiments 1 to 33 or embodiments 41 to 44, or any embodiment of Formula (I) or a pharmaceutically acceptable salt thereof, may also be used to advantage in combination with one or more other therapeutic agents.
  • Another aspect of the disclosure is directed to pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and one or more therapeutic agents.
  • the pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.
  • Combination therapy includes the administration of the subject compounds in further combination with other biologically active ingredients (such as, but not limited to, a second agent such as, but not limited to, a cardiovascular agent, an adrenergic blocker, an antihypertensive agent, an angiotensin system inhibitor, an angiotensin-converting enzyme (ACE) inhibitor, a coronary vasodilator, a diuretic, or an adrenergic stimulant or a second agent that targets PCSK9) and non-drug therapies (such as, but not limited to, surgery or radiation treatment).
  • the compounds of the application can be used in combination with other pharmaceutically active compounds, preferably compounds that are able to enhance the effect of the compounds of the application.
  • the compounds of the application can be administered simultaneously (as a single preparation or separate preparation) or sequentially to the other drug therapy or treatment modality.
  • a combination therapy envisions administration of two or more drugs during a single cycle or course of therapy.
  • compounds of the application can be used in combination with agents known to be beneficial for reducing cholesterol, including LDL-C, non-HDL-C, triglyceride-lowering agents, and total cholesterol and/or raising HDL-C.
  • Exemplary therapeutic agents that may be used in combination with the compounds of the disclosure, include, but are not limited to, hypolipidemic agents, niacin and analogs thereof, bile acid sequestrants, a thyroid hormone mimetic, thyroid hormone receptor (THR) P-selective agonist, a microsomal triglyceride transfer protein (MTP) inhibitor, an acyl CoA:diacylglycerol acyltransferase 1 (DGAT1) inhibitor, a Niemann Pick Cl-like 1 (NPC1-L 1) inhibitor, an agonist of ATP Binding Cassette (ABC) proteins G5 or G8, an inhibitory nucleic acid targeting PCSK9 protein expression (e.g., inclisiran), an inhibitory nucleic acid targeting Lp(a) protein expression (e.g., pelacarsen, an inhibitory nucleic acid targeting apoB 100, apoA-I up-regulator/inducer, ABCA 1 stabilizer or inducer
  • hypolipidemic agents examples include, but are not limited to, an HMG-CoA reductase inhibitor, squalene synthase inhibitors, LXR agonist, FXR agonist, fibrates, cholesterol absorption inhibitors, nicotinic acid bile acid binding resins, bempedoic acid, nicotinic acid and other GPR109 agonists, and aspirin.
  • HMG-CoA reductase inhibitors i.e., statins
  • statins are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver.
  • statins include, but are not limited to, atorvastatin, cerivastatin, compactin, dalvastatin, dihydrocompactin, fluindostatin, fluvastatin, lovastatin, pitavastatin, mevastatin, pravastatin, rivastatin, simvastatin, and velostatin, or pharmaceutically acceptable salts thereof.
  • Fibrates or fibric acid derivatives lower triglycerides and raise HDL cholesterol. They may have little effect on LDL cholesterol.
  • Gemfibrozil or fenofibrate is prescribed for people who have very high triglycerides or who have low HDL and high triglycerides. Gemfibrozil may be used to reduce the risk of heart attack in people with coronary artery disease (CAD) who have low HDL and high triglycerides.
  • fibrates include, but are not limited to, clofibrate, gemfibrozil, fenofibrate, ciprofibrate, and bezafibrate.
  • Cholesterol absorption inhibitors are a class of compounds that prevents the uptake of cholesterol from the small intestine into the circulatory system, and, in turn, reduce plasma LDL-C concentrations. Increased cholesterol levels are associated with increased CVD risk; thus, cholesterol absorption inhibitors are used with the goal of reducing CVD risk.
  • a non-limiting example of a cholesterol absorption inhibitor is Ezetimibe.
  • bile acid sequestrants examples include, but are not limited to, cholestyramine, colestipol, and colesvelam.
  • a non-limiting example of a thyroid hormone mimetic that may be used in combination with the compounds of the disclosure is compound KB2115.
  • TRR thyroid hormone receptor
  • MGL-3196 A non-limiting example of a thyroid hormone receptor (THR) P-selective agonist that may be used in combination with the compounds of the disclosure is MGL-3196.
  • DGAT is an enzyme that catalyzes the last step in triacylglycerol biosynthesis. DGAT catalyzes the coupling of a 1,2-diacylglycerol with a fatty acyl-CoA resulting in Coenzyme A and triacylglycerol.
  • DGAT1 acyl coA-diacylglycerol acyl transferase 1
  • DGAT2 acyl coA- diacylglycerol acyl transferase 2 see Cases et al, J. Biol. Chem.
  • DGAT1 and DGAT2 do not share significant protein sequence homology. Importantly, DGAT1 knockout mice are protected from high fat diet-induced weight gain and insulin resistance (Smith et al, Nature Genetics 25:87-90, 2000). The phenotype of the DGAT1 knockout mice suggests that a DGAT1 inhibitor has utility for the treatment of obesity and obesity-associated complications.
  • DGAT1 inhibitors useful in said combination are compounds and analogs generically and specifically disclosed e.g. in WO2007/126957 and W02009/040410, in particular in the compound claims and the final products of the working examples, the subject-matter of the final products, the pharmaceutical preparations and the claims.
  • Examples of DGAT1 inhibitors suitable for use in combination with compounds of the present disclosure include but are not limited to, ⁇ 4-[4-(3-Methoxy-5-phenylamino-pyridin-2-yl)-phenyl]- cyclohexyl ⁇ -acetic acid, (4- ⁇ 4-[5-(l-Methyl-lH-pyrazol-3-ylamino)-pyridin-2-yl]-phenyl ⁇ -cyclohexyl)- acetic acid, (4- ⁇ 4-[5-(5-Fluoro-6-methoxy-pyridin-3-ylamino)-pyridin-2-yl]-phenyl ⁇ -cyclohexyl)-acetic acid, (4- ⁇ 5-[5-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridin-2-yl]-spirocyclohexylidenyl-l,l ’-indanyl
  • a non-limiting example of a Niemann Pick Cl-like 1 (NPC1-L1) inhibitor that may be used in combination with the compounds of the disclosure is ezetimibe.
  • Apolipoprotein A-I is a protein that in humans is encoded by the APOA1 gene. It has a specific role in lipid metabolism. Apolipoprotein A-I is the major protein component of high density lipoprotein (HDL) in plasma. Chylomicrons secreted from enterocytes also contain ApoA-I but it is quickly transferred to HDL in the bloodstream. The protein promotes cholesterol efflux from tissues to the liver for excretion. It is a cofactor for lecithin cholesterolacyltransferase (LCAT) which is responsible for the formation of most plasma cholesteryl esters.
  • HDL high density lipoprotein
  • LCAT lecithin cholesterolacyltransferase
  • apoA-I Infusion of a variant of apoA-I in humans has been shown to regress atherosclerotic plaque, as assessed by intravascular ultrasound; thus, apoA-I reduces CVD risk and has the ability to both slow progression and induce regression of atherosclerosis.
  • a non-limiting example of an apoA-I up-regulator/inducer is RVX208.
  • ABCA1 member 1 of human transporter sub-family ABCA
  • CHRP cholesterol efflux regulatory protein
  • This transporter is a major regulator of cellular cholesterol and phospholipid homeostasis.
  • a non-limiting example of an ABCA1 regulator is Probucol.
  • Probucol lowers the level of cholesterol in the bloodstream by increasing the rate of LDL catabolism. Additionally, probucol may inhibit cholesterol synthesis and delay cholesterol absorption.
  • Probucol is a powerful antioxidant, which inhibits the oxidation of cholesterol in LDLs; this slows the formation of foam cells, which contribute to atherosclerotic plaques.
  • LXR liver X receptor
  • LXRs Liver X receptors
  • LXR agonists are effective for treatment of murine models of atherosclerosis, diabetes, anti-inflammation and Alzheimer’s disease.
  • Treatment with LXR agonists include but are not limited to, hypocholamide, T0901317, GW3965, or N,N- dimethyl-3-beta-hydroxy-cholenamide (DMHCA)) lowers the cholesterol level in serum and liver and inhibits the development of atherosclerosis in murine disease models.
  • LXR agonists include, but are not limited to, GW3965 (a synthetic nonsteroidal liver X receptor (LXR) agonist/activator) and T0901317 (a dual LXR, FXR agonist).
  • the famesoid X receptor also known as NR1H4 (nuclear receptor subfamily 1, group H, member 4) is a nuclear hormone receptor with activity similar to that seen in other steroid receptors such as estrogen or progesterone but more similar in form to PPAR, LXR and RXR. Activation of the nuclear receptor FXR is known to improve hyperglycemia and hyperlipidemia.
  • FXR agonist is GW4064 (3-(2,6-Dichlorophenyl)-4-(3'-carboxy-2-chlorostilben-4-yl)oxymethyl-5- isopropylisoxazole).
  • Phospholipid transfer protein is a protein that in humans is encoded by the PLTP gene.
  • the protein encoded by this gene is one of at least two lipid transfer proteins found in human plasma, with CETP being the other.
  • the encoded protein transfers phospholipids from triglyceride-rich lipoproteins to HDL. In addition to regulating the size of HDL particles, this protein may be involved in cholesterol metabolism. At least two transcript variants encoding different isoforms have been found for this gene. Because PLTP influences the metabolism of both triglyceride-rich lipoproteins and HDL, modulation of this transfer protein has the potential to alter cardiovascular disease risk.
  • Fish oil is derived from the tissues of oily fish.
  • Fish oils contain the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), precursors of eicosanoids that are known to have many health benefits.
  • Fish oil and other omega-3 sources are most highly recommended for the following conditions: hypertriglyceridemia, secondary cardiovascular disease and prevention of high blood pressure.
  • Lovaza ® is used along with a low-fat and low-cholesterol diet to lower very high triglycerides (fats) in your blood.
  • omega-3 fatty acids that may be used in combination with the compounds of the disclosure include, but are not limited to Lovaza ® and Vascepa ® (icosapent ethyl).
  • anti-diabetic agents examples include, but are not limited to, insulin, insulin derivatives and mimetics; insulin secretagogues such as the sulfonylureas; insulinotropic sulfonylurea receptor ligands such as meglitinides, e.g., nateglinide and repaglinide; protein tyrosine phosphatase- IB (PTP-1B) inhibitors including, but not limited to, PTP-112; GSK3 (glycogen synthase kinase-3) inhibitors including, but not limited to, SB- 517955, SB-4195052, SB-216763, NN-57-05441 and NN-57-05445; RXR ligands including, but not limited to, GW-0791 and AGN- 194204; sodium -dependent glucose cotransporter inhibitors including, but not limited to, T-1095; glycogen phosphory
  • sulfonylureas include, but are not limited to, tolbutamide, chlorpropamide, tolazamide, acetohexamide, 4-chloro-V-[(l-pyrolidinylamino)carbonyl]-benzenesulfonamide (glycopyramide), glibenclamide (glyburide), gliclazide, l-butyl-3-metanilylurea, carbutamide, glibonuride, glipizide, gliquidone, glisoxepid, glybuthiazole, glibuzole, glyhexamide, glymidine, glypinamide, phenbutamide, amaryl, and tolylcyclamide, or pharmaceutically acceptable salts thereof.
  • DPP-IV dipeptidyl peptidase IV
  • GLP-1 is a major stimulator of pancreatic insulin secretion and has direct beneficial effects on glucose disposal.
  • the DPP-IV inhibitor can be peptidic or, preferably, non-peptidic.
  • DPP-IV inhibitors also include, but are not limited to, generically and specifically DPP-IV inhibitors disclosed in WO 98/19998, DE 196 16 486 Al, WO 00/34241 and WO 95/15309, in each case in particular in the compound claims and the final products of the working examples, the subject-matter of the final products, the pharmaceutical preparations and the claims are hereby incorporated into the present application by reference to these publications.
  • GLP-1 is an insulinotropic protein which is described, e.g., by W.E. Schmidt et al. in Diabetologia, 28, 1985, 704-707 and in US 5,705,483.
  • GLP-1 agonists includes variants and analogs of GLP-1 (7-36)NHz which are disclosed in particular in U.S. 5,120,712, U.S. 5,118666, U.S. 5,512,549, WO 91/11457 and by C. Orskov, et al, in J. Biol. Chem., 264 (1989) 12826.
  • GLP-l(7-37) in which compound the carboxy-terminal amide functionality of Arg 36 is displaced with Gly at the 37 th position of the GLP-1 (7-36)NHz molecule and variants and analogs thereof including GLN 9 -GLP-l(7-37), D-GLN 9 -GLP-l(7-37), acetyl LYS 9 -GLP-1(7- 37), LYS 18 -GLP-l(7-37) and, in particular, GLP-1 (7-37)OH, VAL 8 -GLP-l(7-37), GLY 8 -GLP-l(7-37), THR 8 -GLP-l(7-37), MET 8 -GLP-l(7-37) and 4-imidazopropionyl-GLP-l.
  • GLP agonist analog exendin-4 described by Greig, et al., in Diabetologia, 1999, 42, 45-50.
  • insulin sensitivity enhancers which restore impaired insulin receptor function to reduce insulin resistance and consequently enhance the insulin sensitivity.
  • examples include hypoglycemic thiazolidinedione derivatives (e.g., glitazone, (5)- ((3 ,4-dihydro-2-(phenyl-methyl)-2W- 1 -benzopyran-6-yl)methyl-thiazolidine-2, 4-dione (englitazone), 5- ⁇ [4-(3-(5-methyl-2-phenyl-4-oxazolyl)-l-oxopropyl)-phenyl]-methyl ⁇ -thiazolidine-2, 4-dione (darglitazone), 5- ⁇ [4-(l -methyl-cyclohexyl)methoxy)-phenyl]methyl ⁇ -thiazolidine-2, 4-dione (ciglitazone), 5 - ⁇ [4 - (2 - ( 1 )
  • anti-obesity agents examples include, but are not limited to, semaglutide, GDF15, orlistat, sibutramine, phentermine and Cannabinoid Receptor 1 (CB1) antagonists e.g., rimonabant.
  • CB1 Cannabinoid Receptor 1
  • Examples of agonists of peroxisome proliferator-activator receptors that may be used in combination with the compounds of the disclosure include, but are not limited to, fenofibrate, pioglitazone, rosiglitazone, tesaglitazar, BMS-298585, L-796449, the compounds specifically described in the patent application WO 2004/103995 i.e. compounds of examples 1 to 35 or compounds specifically listed in claim 21, or the compounds specifically described in the patent application WO 03/043985 i.e.
  • anti-hypertensive agents examples include, but are not limited to, loop diuretics; angiotensin converting enzyme (ACE); inhibitors of the Na-K-ATPase membrane pump; neutralendopeptidase (NEP) inhibitors; ACE/NEP inhibitors; angiotensin II antagonists; renin inhibitors; 0-adrenergic receptor blockers; inotropic agents; calcium channel; aldosterone receptor antagonists; and aldosterone synthase inhibitors.
  • ACE angiotensin converting enzyme
  • NEP neutralendopeptidase
  • ACE/NEP inhibitors angiotensin II antagonists
  • renin inhibitors renin inhibitors
  • 0-adrenergic receptor blockers inotropic agents
  • calcium channel aldosterone receptor antagonists
  • aldosterone synthase inhibitors aldosterone synthase inhibitors.
  • loop diuretics examples include, but are not limited to, ethacrynic acid, furosemide and torsemide.
  • ACE-inhibitor also called angiotensin converting enzyme inhibitors
  • ACE-inhibitor includes molecules that interrupt the enzymatic degradation of angiotensin I to angiotensin II. Such compounds may be used for the regulation of blood pressure and for the treatment of congestive heart failure.
  • Examples include, but are not limited to, alacepril, benazepril, benazeprilat, captopril, ceronapril, cilazapril, delapril, enalapril, enaprilat, fosinopril, imidapril, lisinopril, moexipril, moveltopril, perindopril, quinapril, ramipril, spirapril, temocapril, and trandolapril, or a pharmaceutically acceptable salt thereof.
  • a non-limiting example of an inhibitor of the Na-K-ATPase membrane pump is digoxin.
  • NEP inhibitor refers to a compound that inhibits neutral endopeptidase (NEP).
  • Examples include, but are not limited to, Candoxatril, Candoxatrilat, Dexecadotril, Ecadotril, Racecadotril, Sampatrilat, Fasidotril, Omapatrilat, Gemopatrilat, Daglutril, SCH-42495, SCH-32615, UK- 447841, AVE-0848, PL-37, and (2R,4s)-5-Biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl- pentanoic acid ethyl ester, or a pharmaceutically acceptable salt thereof.
  • NEP inhibitors also include Phosphono/biaryl substituted dipeptide derivatives, as disclosed in U.S. Patent 5,155,100. NEP inhibitors also include N-mercaptoacyl phenylalanine derivative as disclosed in PCT application WO 2003/104200. NEP inhibitors also include dual-acting antihypertensive agents as disclosed in PCT applications WO 2008/133896, WO 2009/035543, or WO 2009/134741. Other examples include compounds disclosed in U.S. applicationsl2/788,794; 12/788,766, and 12/947,029.
  • NEP inhibitors also include compounds disclosed in WO 2010/136474, WO 2010/136493, WO 2011/061271, WO 2012/065953, WO 2012/065956, WO 2014/126979, and WO 2014/015965.
  • Other examples of NEP inhibitors are compounds disclosed in WO2015116786, W02015116760, WO2014138053, WO2014025891, WO2013184934, WO2013067163, WO2012166389, WO2012166387, WO2012112742, and WO2012082853.
  • ACE/NEP inhibitors refers to a compound that inhibits both angiotensin converting enzyme(ACE) and neutral endopeptidase (NEP).
  • ACE/NEP inhibitors that may be used in combination with the compounds of the disclosure include, but are not limited to, omapatrilat, sampatrilat, and fasidotril.
  • the class of angiotensin II antagonists or ATi receptor antagonists comprises compounds having differing structural features, essentially preferred are the non-peptidic ones.
  • angiotensin II antagonists that may be used in combination with the compounds of the disclosure include, but are not limited to, valsartan, losartan, candesartan, eprosartan, irbesartan, saprisartan, tasosartan, telmisartan, the compounds with the designation E-1477 and ZD-8731 of the following formulae
  • renin inhibitor includes ditekiren (chemical name: [1S-[1R,2R,4R(1R,2R)]]- l-[(l,l-dimethylethoxy)carbonyl]-L-proly l-L-phenylalanyl-N-[2-hydroxy-5-methyl-l-(2-methylpropyl)- 4-[[[2-methyl-l-[[(2 pyridinylmrthyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-N-alfa-methyl-L- histidinamide); terlakiren (chemical name: [R-(R,S)]-N-(4-morpholinylcarbonyl)-L-phenylalanyl-N-[l- (cyclohexylmethyl)-2-hydroxy-3-(l-methylethoxy)-3-oxopropyl]-S-methyl-cysteineamide
  • 3-adrenergic receptor blockers examples include, but are not limited to, acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, nadolol, propranolol, sotalol, and timolol.
  • inotropic agents examples include, but are not limited to, digoxin, dobutamine, and milrinone; Inotropes as used herein include, for example, dobutamine, isoproterenol, milrinone, amirinone, levosimendan, epinephrine, norepinephrine, isoproterenol, and digoxin.
  • Examples of calcium channel blockers that may be used in combination with the compounds of the disclosure include, but are not limited to, amlodipine, bepridil, diltiazem, felodipine, nicardipine, nimodipine, nifedipine, nisoldipine and verapamil.
  • the class of aldosterone synthase inhibitors comprises both steroidal and non-steroidal aldosterone synthase inhibitors, the latter being most preferred.
  • the class of aldosterone synthase inhibitors comprises compounds having differing structural features. Examples of aldosterone synthase inhibitor that can be used in combination with the compounds of the present disclosure include, but are not limited to, the (+)-enantiomer of the hydrochloride of fadrozole (U.S. patents 4,617,307 and 4,889,861) of formula or, if appropriable, a pharmaceutically acceptable salt thereof; and compounds and analogs generically and specifically disclosed e.g.
  • aldosterone synthase inhibitors that can be used in combination with the compounds of the present disclosure include, but are not limited to, without limitation 4-(6,7-dihydro-5H- pyrrolo[l,2-c]imidazol-5-yl)-3-m ethylbenzonitrile; 5-(2-chloro-4-cyanophenyl)-6,7-dihydro-5H- pyrrolo[l,2-c]imidazole-5-carboxylic acid (4-methoxybenzyl)methylamide; 4 ’-fluoro -6 -(6, 7,8,9- tetrahydro-5H-imidazo[l,5-a]azepin-5-yl)biphenyl-3-carbonitrile; 5-(4-Cyan
  • aldosterone synthase inhibitors also include, but are not limited to, compounds and analogs disclosed in W02008/076860, W02008/076336, W02008/076862, W02008/027284, W02004/046145, W02004/014914, and WO2001/076574.
  • Aldosterone synthase inhibitors also include, but are not limited to, compounds and analogs disclosed in U.S. patent applications US2007/0225232, US2007/0208035, US2008/0318978, US2008/0076794, US2009/0012068, US20090048241 and in PCT applications W02006/005726, WO2006/128853, WO2006128851, WO2006/128852, W02007065942, W02007/116099, W02007/116908, W02008/119744 and in European patent application EP 1886695.
  • Preferred aldosterone synthase inhibitors suitable for use in the present disclosure include, without limitation 8-(4-Fluorophenyl)-5,6-dihydro-8H-imidazo[5,l-cl[l ,41oxazine; 4-(5,6-Dihydro-8H- imidazo[5,l-c][l ,4]oxazin-8-yl)-2-fluorobenzonitrile; 4-(5,6-Dihydro-8H-imidazo[5,l-c][l ,4]oxazin-8- yl)-2,6-difluorobenzonitrile; 4-(5,6-Dihydro-8H-imidazo[5,l-c][l ,4]oxazin-8-yl)-2-methoxybenzonitrile; 3-(5,6-Dihydro-8H-imidazo[5,l-c][l ,4]oxazin-8-yl)benzonitrile; 4-
  • Aldosterone synthase inhibitors useful in said combination include, but are not limited to, compounds and analogs generically and specifically disclosed e.g. in WO 2009/156462 and WO 2010/130796, in particular in the compound claims and the final products of the working examples, the subject-matter of the final products, the pharmaceutical preparations and the claims.
  • Preferred Aldosterone Synthase inhibitors suitable for combination in the present disclosure include, 3-(6-Fluoro-3- methyl-2-pyridin-3-yl-lH-indol-l-ylmethyl)-benzonitrile hydrochloride, l-(4-Methanesulfonyl-benzyl)-3- methyl -2 -pyridin-3 -yl- 1 H-indole, 2-(5 -Benzyloxy -pyridin-3 -yl)-6-chloro- 1 -methyl- 1 H-indole, 5-(3- Cyano-1 -methyl- lH-indol-2-yl)-nicotinic acid ethyl ester, N-[5-(6-chloro-3-cyano-l-methyl-lH-indol-2- yl)-pyridin-3-y Im ethyl] -ethanesulfonamide, Pyr
  • Lipid-lowering agents are known in the art, and described, e.g., in Goodman and Gilman ’s The Pharmacological Basis of Therapeutics, 11th Ed., Brunton, Lazo and Parker, Eds., McGraw-Hill (2006); 2009 Physicians ’ Desk Reference (PDR), for example, in the 63rd (2008) Eds., Thomson PDR.
  • Combination therapy is intended to embrace administration of these therapeutic agents in a sequential manner, wherein each therapeutic agent is administered at a different time and in any order, or in alternation and in any order, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner.
  • Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents.
  • Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues.
  • the therapeutic agents can be administered by the same route or by different routes.
  • a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally.
  • all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection.
  • the sequence in which the therapeutic agents are administered is not narrowly critical.
  • Embodiment 39 A combination comprising of a compound according to any one of embodiments 1 to 33 or a pharmaceutically acceptable salt thereof and one or more additional pharmaceutical agents.
  • Embodiment 40 The combination of embodiment 39, where the one or more agents additional pharmaceutically active agent is selected from hypolipidemic agents, niacin and analogs thereof, bile acid sequestrants, a thyroid hormone mimetic, thyroid hormone receptor (THR) P-selective agonist, a microsomal triglyceride transfer protein (MTP) inhibitor, an acyl CoA: diacylglycerol acyltransferase 1 (DGAT1) inhibitor, a Niemann Pick Cl-like 1 (NPC1-L 1) inhibitor, an agonist of ATP Binding Cassette (ABC) proteins G5 or G8, an inhibitory nucleic acid targeting PCSK9 protein expression, an inhibitory nucleic acid targeting Lp(a) protein expression, an inhibitory nucleic acid targeting apoB 100, apoA-I up-regulator/inducer, ABCA 1 stabilizer or inducer, phospholipid transfer protein (PL TP) inhibitor, fish oil, anti-diabe, a thyroid
  • the present disclosure also provides a therapeutic combination, e.g., a kit, kit of parts, e.g., for use in any method as defined herein, comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to be used concomitantly or in sequence with at least one pharmaceutical composition comprising at least another therapeutic agent, selected from hypolipidemic agents, niacin and analogs thereof, bile acid sequestrants, a thyroid hormone mimetic, thyroid hormone receptor (THR) P-selective agonist, a microsomal triglyceride transfer protein (MTP) inhibitor, an acyl CoA:diacylglycerol acyltransferase 1 (DGAT1) inhibitor, a Niemann Pick Cl-like 1 (NPC1-L 1) inhibitor, an agonist of ATP Binding Cassette (ABC) proteins G5 or G8, an inhibitory nucleic acid targeting PCSK9 protein expression (e.g., a kit, kit of parts, e
  • kits of parts comprising: (i) a pharmaceutical composition of the disclosure; and (ii) a pharmaceutical composition comprising a compound selected from a hypolipidemic agents, niacin and analogs thereof, bile acid sequestrants, a thyroid hormone mimetic, thyroid hormone receptor (THR) P-selective agonist, a microsomal triglyceride transfer protein (MTP) inhibitor, an acyl CoA: diacylglycerol acyltransferase 1 (DGAT1) inhibitor, a Niemann Pick Cl- like 1 (NPC1-L 1) inhibitor, an agonist of ATP Binding Cassette (ABC) proteins G5 or G8, an inhibitory nucleic acid targeting PCSK9 protein expression (e.g., inclisiran), an inhibitory nucleic acid targeting Lp(a) protein expression (e.g., pelacarsen, an inhibitory nucleic acid targeting apoB 100, apoA-
  • the present disclosure provides a method as defined above comprising coadministration, e.g., concomitantly or in sequence, of a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a second drug substance, said second drug substance being hypolipidemic agents, niacin and analogs thereof, bile acid sequestrants, a thyroid hormone mimetic, thyroid hormone receptor (THR) P-selective agonist, a microsomal triglyceride transfer protein (MTP) inhibitor, an acyl CoA:diacylglycerol acyltransferase 1 (DGAT1) inhibitor, a Niemann Pick Cl-like 1 (NPC1-L 1) inhibitor, an agonist of ATP Binding Cassette (ABC) proteins G5 or G8, an inhibitory nucleic acid targeting PCSK9 protein expression (e.g., inclisiran), an inhibitory nucleic acid targeting Lp(a) protein expression (e
  • the include plural referents unless the context clearly dictates otherwise.
  • reference to “the pharmaceutical formulation” includes reference to one or more pharmaceutical formulations; and so forth.
  • acyl refers to a group represented by the general formula hydrocarbylC(O) — , preferably alkylC(O) — .
  • acyloxy refers to a group represented by the general formula hydrocarbylC(O)O — , preferably alkylC(O)O — .
  • alkenyl refers to an aliphatic group containing at least one double bond and is intended to include both “unsubstituted alkenyls” and “substituted alkenyls”, the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents may occur on one or more carbons that are included or not included in one or more double bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed below, except where stability is prohibitive.
  • alkenyl groups substitution of alkenyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.
  • alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl.
  • alkoxy refers to an alkyl group, preferably a lower alkyl group, having an oxygen attached thereto, e.g., -O(alkyl).
  • Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, tert-butoxy and the like.
  • Representative substituted alkoxy groups include, but are not limited to, — OCF3 and the like.
  • alkyl group or “alkane” is a straight chained or branched non-aromatic hydrocarbon which is completely saturated. Typically, a straight chained or branched, alkyl group has from 1 to about 20 carbon atoms, preferably from 1 to about 10 unless otherwise defined. Examples of straight chained and branched alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl and octyl.
  • a C 1 -C 6 straight chained or branched alkyl group is also referred to as a 'lower alkyl’’ group.
  • the term '“alkyl” (or ‘‘lower alkyl”) as used throughout the specification, examples, and claims is intended to include both “unsubstituted alkyls’’ and “substituted alkyls”, the latter of which refers to alkyl moselles having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • Such substituents can include, for example, a halogen., a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or .heteroaro
  • the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.
  • the substituents of a substituted alkyl may include substituted and unsubstituted forms of ammo, azido, imino, amido, phosphoryl (including phosphonate and. phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), CF,, CN and the like.
  • Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys. alkylthios, aminoalkyls, carbonyl-substituted alkyls, CF 3 , CN, and the like.
  • alkynyl refers to an aliphatic group containing at least one triple bond and is intended to include both, “unsubstituted alkynyls” and “substituted alkynyls”, the latter of which refers to alkynyl moieties having substituents replacing a hy drogen on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed above, except where stability is prohibitive.
  • alkynyl groups substitution of alkynyl groups by one or more alkyl, carbocycly 1, aryl, heterocyclyl, or heteroaryl groups is contemplated.
  • alkenyl groups include ethynyl, propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl.
  • aryl include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon.
  • the ring is a 5- to 7-membered ring, more preferably a 6-membered ring.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cyclo alkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like.
  • C x . y when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain.
  • C x . y alkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl, etc.
  • Co alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal.
  • C2- y alkenyl and C2- y alkynyl refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • carbocycle refers to a saturated or unsaturated ring in which each atom of the ring is carbon.
  • carbocycle includes both aromatic carbocycles and non-aromatic carbocycles.
  • Non-aromatic carbocycles include both cycloalkane rings, in which all carbon atoms are saturated, and cycloalkene rings, which contain at least one double bond.
  • Carbocycle includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings.
  • Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings.
  • the term “fused carbocycle” refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring.
  • Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings.
  • an aromatic ring e.g., phenyl
  • an aromatic ring e.g., phenyl
  • a saturated or unsaturated ring e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic.
  • Exemplary “carbocycles” include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5 -cyclooctadiene, 1, 2,3,4- tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene and adamantane.
  • Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4, 5,6,7- tetrahydro-lH-indene and bicyclo[4.1.0]hept-3-ene.
  • “Carbocycles” may be susbstituted at any one or more positions capable of bearing a hydrogen atom.
  • a “cycloalkyl” group is a cyclic hydrocarbon which is completely saturated.
  • “Cycloalkyl” includes monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl group has from 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms unless otherwise defined.
  • the second ring of a bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings. Cycloalkyl includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings.
  • the term “fused cycloalkyl” refers to a bicyclic cycloalkyl in which each of the rings shares two adjacent atoms with the other ring.
  • the second ring of a fused bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings.
  • halo and “halogen”, as used herein, means halogen and includes chloro, fluoro, bromo, and iodo.
  • haloalkyl refers to an alkyl group substituted by one or more halo.
  • Examples of (C 1 - 6 )haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, l,3-dibromopropan-2-yl, 3-bromo-2-fluoropropyl and 1,4,4- trifluorobutan-2-yl.
  • heteroalkyl and “hetero aralkyl”, as used herein, refers to an alkyl group substituted with a hetaryl group.
  • hetero alkyl refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, wherein no two heteroatoms are adjacent.
  • heteroaryl and “hetaryl” include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7 -membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • heteroaryl and “hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heteroaryl groups include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyridyl N-oxide, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[l,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[l,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyri
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.
  • heterocyclyl refers to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • heterocyclyl and “heterocyclic” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like. Heterocyclyl groups can also be substituted by oxo groups.
  • “heterocyclyl” encompasses both pyrrolidine and pyrrolidinone.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group.
  • Haloalkyl refers to an alkyl group substituted with one or more halogens.
  • haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.
  • ox_ o"XxOo refers to a carbonyl group.
  • an oxo substituent occurs on an otherwise saturated group, such as with an oxo-substituted cycloalkyl group (e.g., 3-oxo-cyclobutyl)
  • the substituted group is still intended to be a saturated group.
  • an alkyl group that is optionally substituted can be a fully saturated alkyl chain (e.g., a pure hydrocarbon).
  • the same optionally substituted alkyl group can have substituents different from hydrogen. For instance, it can, at any point along the chain be bounded to a halogen atom, a hydroxyl group, or any other substituent described herein.
  • the term “optionally substituted” means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any further functional groups.
  • Suitable substituents used in the optional substitution of the described groups include, without limitation, halogen, oxo, -OH, -CN, -COOH, -CH2CN, -O-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, (C 1 - C 6 )alkoxy, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, -O-(C 2 -C 6 )alkenyl, -O-(C 2 -C 6 )alkynyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, -OH, -OP(O)(OH) 2 , -OC(O)(C 1 -C 6 )alkyl, -C(O)(C 1 -C 6 )alkyl, -OC(O)O(C 1 -C 6
  • substituted means that the specified group or moiety bears one or more suitable substituents wherein the substituents may connect to the specified group or moiety at one or more positions.
  • an aryl substituted with a cycloalkyl may indicate that the cycloalkyl connects to one atom of the aryl with a bond or by fusing with the aryl and sharing two or more common atoms.
  • “Pharmaceutically-acceptable acid addition salt” means those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, and the like, and organic acids such as acetic acid, trichloroacetic acid, trifluoroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 2-acetoxybenzoic acid, butyric acid, camphoric acid, camphorsulfonic acid, cinnamic acid, citric acid, digluconic acid, ethanesulfonic acid, glutamic acid, glycolic acid, glycerophosphoric acid, hemisulfic acid, heptanoic acid, hexanoic acid, formic
  • “Pharmaceutically-acceptable base addition salt” means those salts which retain the biological effectiveness and properties of the free acids and which are not biologically or otherwise undesirable, formed with inorganic bases such as ammonia or hydroxide, carbonate, or bicarbonate of ammonium or a metal cation such as sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Particularly preferred are the ammonium, potassium, sodium, calcium, and magnesium salts.
  • Salts derived from pharmaceutically-acceptable organic nontoxic bases include salts of primary, secondary, and tertiary amines, quaternary amine compounds, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion-exchange resins, such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine, tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2- diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, A'-cthylpipcridinc.
  • tetramethylammonium compounds tetraethylammonium compounds, pyridine, N,N- dimethylaniline, A'-mcthylpipcridinc.
  • A'-mcthylmorpholinc dicyclohexylamine, dibenzylamine, N,N- dibenzylphenethylamine, 1 -ephenamine, N,N ’-dibenzylethylenediamine, polyamine resins, and the like.
  • Particularly preferred organic nontoxic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
  • a “patient” or “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or nonhuman primate, such as a monkey, chimpanzee, baboon or, rhesus.
  • the subject is a primate.
  • the subject is a human.
  • pharmaceutically effective amount or “therapeutically effective amount” or “effective amount” means an amount of a compound according to the disclosure which, when administered to a patient in need thereof, is sufficient to effect treatment for disease-states, conditions, or disorders for which the compounds have utility. Such an amount would be sufficient to elicit the biological or medical response of a tissue, system, or patient that is sought by a researcher or clinician.
  • the amount of a compound according to the disclosure which constitutes a therapeutically effective amount will vary depending on such factors as the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of treatment, the type of disease-state or disorder being treated and its severity, drugs used in combination with or coincidentally with the compounds of the disclosure, and the age, body weight, general health, sex, and diet of the patient.
  • a therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their own knowledge, the prior art, and this disclosure.
  • composition refers to a compound of the disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, together with at least one pharmaceutically acceptable carrier, in a form suitable for oral or parenteral administration.
  • Carrier encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject.
  • “Combination” refers to either a fixed combination in one dosage unit form, or a combined administration where a compound of the present disclosure and at least one combination partner (e.g.
  • therapeutic agent another drug as explained below, also referred to as “therapeutic agent” or “co-agent”) may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a beneficial effect from the co-action of these therapeutic agents.
  • the beneficial effect of the combination includes, but is not limited to, a cooperative, e.g., synergistic, effect and/or a pharmacokinetic or pharmacodynamic co-action, or any combination thereof, resulting from the combination of therapeutic agents.
  • administration of these therapeutic agents in combination is carried out over a defined time period (e.g., minutes, hours, days or weeks depending upon the combination selected). “
  • the single components may be packaged in a kit or separately.
  • One or both of the components e.g., powders or liquids
  • co -administration or “combined administration” or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof (e.g. a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • the term “pharmaceutical combination” as used herein means a product that results from the mixing or combining of more than one therapeutic agent and includes both fixed and non-fixed combinations of the therapeutic agents.
  • the term “fixed combination” means that the therapeutic agents, e.g., a compound of the present disclosure and a combination partner, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • the term “non-fixed combination” means that the therapeutic agents, e.g., a compound of the present disclosure and a combination partner, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient.
  • cocktail therapy e.g. the administration of three or more therapeutic agents.
  • a subject is “in need of’ a treatment if such subject would benefit biologically, medically, or in quality of life from such treatment (preferably, a human).
  • PCSK9 or “proprotein convertase subtilisin/kexin type 9” interchangeably refer to a naturally-occurring human proprotein convertase belonging to the proteinase K subfamily of the secretory subtilase family.
  • PCSK9 is synthesized as a soluble zymogen that undergoes autocatalytic intramolecular processing in the endoplasmic reticulum, and is thought to function as a proprotein convertase.
  • PCSK9 plays a role in cholesterol homeostasis and may have a role in the differentiation of cortical neurons. Mutations in the PCSK9 gene are a cause of autosomal dominant familial hypercholesterolemia. (Burnett and Hooper, Clin. Biochem. Rev. (2008) 29(1): 11 -26)
  • the term “inhibit”, “inhibition”, or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
  • treat refers to alleviating or ameliorating the disease or disorder (i.e., slowing or arresting the development of the disease or at least one of the clinical symptoms thereof); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those which may not be discernible to the patient.
  • the term “prevent”, “preventing”, or “prevention” of any disease or disorder refers to the prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder.
  • “Pharmaceutically acceptable” means that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
  • disorder means, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.
  • administering means to either directly administering a disclosed compound or pharmaceutically acceptable salt of the disclosed compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject’s body.
  • “Compounds of the present disclosure”, “Compounds of Formula (I)”, “compounds of the disclosure”, and equivalent expressions refer to compounds of Formulae (I) and (la) as herein described including the salts particularly the pharmaceutically acceptable salts thereof, where the context so permits thereof, as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, and isotopically labelled compounds (including deuterium (“D”) substitutions).
  • the term “about” or “approximately” means within 20%, preferably within 10%, and more preferably within 5% of a given value or range.
  • a “modulator of PCSK9” refers to a compound or molecule that is able to modulate PCSK9 biological activity or function, and/or downstream pathway(s) mediated by PCSK9 activity.
  • an “inhibitor of PCSK9” refers to a compound or molecule that is able to inhibit PCSK9 biological activity or function, and/or downstream pathway(s) mediated by PCSK9 signaling.
  • An inhibitor of PCSK9 activity encompasses compounds that block, antagonize, suppress or reduce (to any degree including significantly) PCSK9 biological activity, including downstream pathways mediated by PCSK9 activity.
  • disorders or diseases responsive to the inhibition of PCSK9 include, but are not limited to, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, xanthoma, peripheral arterial disease, sepsis, cancer, psoriasis, elevated Lp(a), elevated LDL, elevated TRL, and elevated triglycerides.
  • Inhibition of PCSK9 activity refers to a decrease in the PCSK9 activity, e.g., by administration of the compound of the disclosure.
  • hypercholesterolemia or “dyslipidemia” includes, e.g., familial and non-familial hypercholesterolemia.
  • Familial hypercholesterolemia FH is an autosomal dominant disorder characterized by elevation of serum cholesterol bound to low density lipoprotein (LDL).
  • Familial hypercholesterolemia includes both heterozygous FH and homozygous FH.
  • Hypercholesterolemia (or dyslipidemia) is the presence of high levels of cholesterol in the blood. It is a form of hyperlipidemia (elevated levels of lipids in the blood) and hyperlipoproteinemia (elevated levels of lipoproteins in the blood).
  • Hyperlipidemia is an elevation of lipids in the bloodstream. These lipids include cholesterol, cholesterol esters, phospholipids and triglycerides. Hyperlipidemia includes for example, type I, Ila, lib, III, IV and V.
  • Hypertriglyceridemia denotes high blood levels of triglycerides. Elevated levels of triglycerides are associated with atherosclerosis, even in the absence of hypercholesterolemia, and predispose to cardiovascular disease.
  • “Sitosterolemia” or “phytosterolemia” is a rare autosomal recessively inherited lipid metabolic disorder characterized by hyperab sorption of sitosterol from the gastrointestinal tract and decreased biliary excretion of dietary sterols (i.e., leading to hypercholesterolemia, tendon and tuberous xanthomas, premature development of atherosclerosis) and altered cholesterol synthesis.
  • “Atherosclerosis” includes hardening of arteries associated with deposition of fatty substances, cholesterol, cellular waste products, calcium and fibrin in the inner lining of an artery. The buildup that results is called plaque.
  • Atherosclerosis or “arteriosclerotic vascular disease (ASVD)” is a specific form of arteriosclerosis involving thickening, hardening and loss of elasticity of the walls of arteries as a result of invasion and accumulation of white blood cells, containing both living, active white blood cells (producing inflammation) and remnants of dead cells, including cholesterol and triglycerides. Atherosclerosis is therefore a syndrome affecting arterial blood vessels due to a chronic inflammatory response of white blood cells in the walls of arteries.
  • ASVD arteriosclerotic vascular disease
  • Atherosclerotic artery disease also known as atherosclerotic artery disease, atherosclerotic cardiovascular disease, coronary heart disease or ischemic heart disease is the most common type of heart disease and cause of heart attacks. The disease is caused by plaque building up along the inner walls of the arteries of the heart, which narrows the lumen of arteries and reduces blood flow to the heart.
  • Xanthoma is a cutaneous manifestation of lipidosis in which lipids accumulate in large foam cells within the skin. Xanthomas are associated with hyperlipidemias.
  • elevated Lp(a) concentration refers to a serum Lp(a) concentration above 30 mg/dl (75 nmol/L).
  • elevated serum Lp(a) means a serum Lp(a) level greater than about 14 mg/dL.
  • a patient is considered to exhibit elevated serum Lp(a) if the level of serum Lp ⁇ a) measured in the patient is greater than about 15 mg/dL, about 20 mg/dL, about 25 mg/dL, about 30 mg/dL, about 35 mg/dL, about 40 mg/dL, about 45 mg/dL, about 50 mg/dL, about 60 mg/dL, about 70 mg/dL, about 80 mg/dL, about 90 mg/dL, about 100 mg/dL, about 20 mg/dL, about 140 mg/dL, about 150 mg dL, about 180 mg/dL, or about 200 mg/dL
  • the serum Lp(a) level can be measured in a patient post-prandial.
  • the Lp(a) level is measured after a period of time of fasting (e.g., after fasting for 8 hrs, 8 hrs, 10 hrs, 12 hrs or more).
  • exemplary methods for measuring serum Lp(a) in a patient include, but are not limited to, rate immunonephelometry, ELISA, nephelometry, immunoturbidimetry, and dissociation-enhanced lanthanide fluorescent immunoassay, although any clinically acceptable diagnostic method can be used in the context of the present disclosure.
  • ETL elevated triglyceride levels
  • Sepsis is a systemic reaction characterized by arterial hypotension, metabolic acidosis, decreased systemic vascular resistance, tachypnea, and organ dysfunction. Sepsis can result from septicemia (i.e., organisms, their metabolic end-products or toxins in the blood stream), including bacteremia (i.e., bacteria in the blood), as well as toxemia (i.e., toxins in the blood), including endotoxemia (i.e., endotoxin in the blood).
  • septicemia i.e., organisms, their metabolic end-products or toxins in the blood stream
  • bacteremia i.e., bacteria in the blood
  • toxemia i.e., toxins in the blood
  • endotoxemia i.e., endotoxin in the blood
  • septicemia also encompasses systemic reactions resulting from fungemia (i.e., fungi in the blood), viremia (i.e., viruses or virus particles in the blood), and parasitemia (i.e., helminthic or protozoan parasites in the blood).
  • fungemia i.e., fungi in the blood
  • viremia i.e., viruses or virus particles in the blood
  • parasitemia i.e., helminthic or protozoan parasites in the blood.
  • septicemia and septic shock acute circulatory failure resulting from septicemia often associated with multiple organ failure and a high mortality rate
  • septicemia and septic shock acute circulatory failure resulting from septicemia often associated with multiple organ failure and a high mortality rate
  • Compounds of the present disclosure may be prepared by methods known in the art of organic synthesis. In all of the methods it is understood that protecting groups for sensitive or reactive groups may be employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Green and P. G. M. Wuts (1999) Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art.
  • Mass spectra were collected using a Waters System (Acquity UPLC and a Micromass ZQ mass spectrometer) or Agilent-1260 Infinity (6120 Quadrupole); all masses reported are the m/z of the protonated parent ions unless recorded otherwise.
  • the chemical names were generated using ChemBioDraw Ultra vl4 from CambridgeSoft.
  • Scheme 1 represents the general synthesis of a compound of formula (I). wherein R 1 , A are as defined in herein.
  • Step A tert-butyl (3-aminocyclopentyl)carbamate is reacted with la in the presence of a suitable base such as diisopropylethylamine at a suitable temperature such as 120 °C to form lb.
  • a suitable base such as diisopropylethylamine at a suitable temperature such as 120 °C to form lb.
  • Step B Deprotection of the protecting group to form 1c in the presence of a strong acid such as hydrochloric acid or trifluoroacetic acid.
  • Step C Cyanamide Id can be formed through a nucleophilic substitution reaction of 1c with cyanogen bromide and a suitable base such as sodium acetate.
  • Step D Cyanamide Id is reacted with hydroxyamine to form A'-hydroxyguanidinc le.
  • Step E A'-hydroxyguanidinc le can be converted to the target compound 1,2,4-oxadiazole 1g by the following two conditions.
  • Condition E-2 Cyclization at a suitable temperature such as 100 °C to form 1g.
  • Scheme 2 represents the alternative synthesis of a compound of formula (I) in Scheme 1. wherein R 1 , A are as defined in herein.
  • Step A A'-hydroxyguanidinc le can be converted to the target compound 1,2,4-oxadiazole 1g by reacting with an orthoester 2a.
  • Scheme 3 represents the alternative synthesis of a compound of formula (I) in Scheme 1. wherein R 1 , A are as defined in herein.
  • Step A Amine 1c is reacted with 3-chloro-l,2,4-thiadiazole 3a to form the target compound 1g in the presence of a suitable base such as A'.
  • A' diisopropylcthylaminc at a suitable temperature such as 100 °C.
  • Scheme 4 represents the general synthesis of a compound of formula (I). wherein R 2 , A are as defined in herein.
  • Step A Amine 1c is reacted with 5-chloro-l,2,4-thiadiazole 4a to form the target compound 4b in the presence of a suitable base such as A'.
  • Scheme 5 represents the general synthesis of a compound of Formula (I). wherein R 1 , A are as defined in herein.
  • Step A Amine 1c is reacted with l,3,4-oxadiazol-2)(3H )-one 5a to form the target compound 5b with a coupling reagent such as PyBroP in the presence of a suitable base such as A'.
  • A' diisopropylcthylaminc.
  • Scheme 6 represents the general synthesis of a compound of Formula (I). wherein R 4 , A are as defined in herein.
  • Step A Amine 1c is reacted with 3 -(methylsulfinyl)- 1,2, 4-triazine 6a or 3 -(methylsulfonyl)- 1, 2, 4-triazine 6a’ to form the target compound 6b in the presence of a suitable base such as sodium carbonate.
  • a suitable base such as sodium carbonate.
  • Scheme 7 represents the general synthesis of a compound of formula (I). wherein A is as defined herein.
  • Step A Cyanamide Id reacted with sodium azide to form the target compound 7a.
  • Scheme 8 represents the general synthesis of a compound of formula (I). wherein X, Y, Z, and A are as defined in herein.
  • Step A Intermediate 8a can be formed by either of the following conditions
  • Step B Deprotection of the protecting group to form amine 8b in the presence of a strong acid such as hydrochloric acid or trifluoro acetic acid.
  • Step C Amine 8b is reacted with la to form the target compound 8c following Scheme 1 Step A.
  • Scheme 9 represents the general synthesis of a compound of formula (I). wherein R 4 , and A are as defined in in herein.
  • Step A Intermediate 9a is formed following Scheme 6 Step A.
  • Step B Deprotection of the protecting group to form 9 b in the presence of a strong acid such as hydrochloric acid or trifluoroacetic acid.
  • Step C Amine 9b is reacted with la to form the target compound 9c following Scheme 1 Step A.
  • Example 1 Synthesis of 2-(6-(((1S,3S) -3-((5-methvl-l,2,4-oxadiazol-3-vl) amino)cyclopentyl)amino) pyridin-3-vl)pvridazin-3(2H)-one
  • Step-2 Synthesis of tert-butyl ((LS',3.S')-3-((5-(6-oxopyridazin-l(6H )-yl)pyridin-2- yl)amino)cyclopentyl)carbamate (Int-2)
  • Step-3 Synthesis of 2-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)pyridazin-3(2H)-one hydrochloride (Int-3)
  • Step-4 Synthesis of /V-((LS',3.S')-3-((5-(6-oxopyridazin-l(6H )-yl)pyridin-2- yl)amino)cyclopentyl)cyanamide (Int-4)
  • Step-5 Synthesis of 2-hydroxy-l-((1S,3S)-3-((5-(6-oxopyridazin-l(6H )-yl)pyridin-2-yl)amino) cyclopentyl)guanidine (Int-5)
  • Step-6 Synthesis of 2-(6-(((1S,3S')-3-((5-methyl-l,2,4-oxadiazol-3-yl)amino)cyclopentyl)amino) pyridin-3-yl)pyridazin-3(2H)-one (Example 1)
  • Step-2 Synthesis of 3-(6-fhioropyridin-3-yl)-l-methylimidazolidine-2, 4-dione (Int-7)
  • Step-3 Synthesis of tert-butyl ((1S,3S)-3-((5-(3-methyl-2,5-dioxoimidazolidin-l-yl)pyridin-2- yl)amino)cyclopentyl)carbamate (Int-8)
  • Step-4 Synthesis of 3-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)-l-methylimidazolidine- 2, 4-dione hydrochloride (Int-9)
  • Step-5 Synthesis of N-((1S,3S)-3-((5-(3-methyl-2,5-dioxoimidazolidin-l-yl)pyridin-2- yl)amino)cyclopentyl)cyanamide (Int-10)
  • Step-6 Synthesis of 2-hydroxy-l-((1S,3S)-3-((5-(3-methyl-2,5-dioxoimidazolidin-l-yl)pyridin-2- yl)amino)cyclopentyl)guanidine (Int-11)
  • Step-7 Synthesis of l-methyl-3-(6-(((1S,3S)-3-((5-methyl-l,2,4-oxadiazol-3- yl)amino)cyclopentyl)amino)pyridin-3-yl)imidazolidine-2, 4-dione (Example 10)
  • Example 13 Synthesis of 2-(6-(((1S,3S) -3-((5-(3-hvdroxvcvclobutvl)-l,2,4-oxadiazol-3- yl)amino)cyclopentyl)amino)pyridin-3-vl)pyridazin-3(2H)-one
  • Example 14 Synthesis of 2-(6-(((1S,3S) -3-((5-ethvl-l,2,4-oxadiazol-3-vl)amino) cvclopentvl)amino)pyridin-3-vl)pyridazin-3(2H)-one
  • Example 15 Synthesis of 2-(6-(((1S,3S)-3-((5-(l-(trifluoromethvl)cvclopropvl)-l,2,4-oxadiazol-3- vl)amino)cvclopentvl)amino)pyridin-3-yl)pyridazin-3(2H)-one
  • Step-1 Synthesis of 2,5-dioxopyrrolidin-l-yl l-(trifluoromethyl)cyclopropane-l-carboxylate (Int- 12)
  • Step-2 Synthesis of 2-(6-(((15,3S')-3-((5-(l-(trifhioromethyl)cyclopropyl)-l,2,4-oxadiazol-3- yl)amino)cyclopentyl)amino)pyridin-3-yl)pyridazin-3(2H)-one (Example 15)
  • Example 17 Synthesis of 2-(6-(((1S,3S)-3-((3-cvclopropyl-l,2,4-thiadiazol-5- vl)amino)cvclopentvl)amino)pvridin-3-yl)pvridazin-3(2H)-one
  • the crude product was purified by preparative HPLC (20-40% acetonitrile/0.02% NH4OH in water; WATERS XB RIDGE (150 mm x 19 mm), 5.0 ⁇ m column, flow rate 15 mL/min) to provide the title compound as a yellow solid (40 mg, 31%), ESI-MS m/z: 396.25 [M+H] + .
  • Step-1- Synthesis of tert-butyl ((1S,3S)-3-((5-iodopyridm-2-yl)ammo)cyclopentyl)carbamate (Int-13)
  • Step-2- Synthesis of tert-butyl ((1S,3S)-3-((5-(2-oxopyrrolidin-l-yl)pyridin-2- yl)amino)cyclopentyl)carbamate (Int-14)
  • Step-4 Synthesis of V-((l.S’.3.S’)-3-((5-(2-o ⁇ opyrroli(lin-l-yl)pyriilin-2- yl)amino)cyclopentyl)cyanamide (Int-16)
  • Step-5 Synthesis of 2-hydroxy-l-((15,35)-3-((5-(2-oxopyrrolidin-l-yl)pyridin-2- yl)amino)cyclopentyl) guanidine (Int-17)
  • Step-6 Synthesis of l-(6-(((1S,3S)-3-((5-methyl-l,2,4-oxadiazol-3-yl)amino) cyclopentyl)amino)pyridin-3-yl)pyrrolidin-2-one (Example 20)
  • Step-1 Synthesis of tert-butyl ((1S,3S)-3-((5-(3-methyl-2,4-dioxoimidazolidin-l-yl)pyridin-2- yl)amino)cyclopentyl)carbamate (Int-18)
  • Step-3 Synthesis of A-((1S,3S)-3-((5-(3-methyl-2,4-dioxoimidazolidin-l-yl)pyridin-2- yl)amino)cyclopentyl)cyan amide
  • Step-4 Synthesis of 2-hydroxy-l-((15,35)-3-((5-(3-methyl-2,4-dioxoimidazolidine-l-yl)pyridin-2- yl)amino)cyclopentyl)guanidine (Int-21) [312] To a solution of Int-20 (395 mg, 1.26 mmol) in EtOH (10 mL), was added hydroxylamine hydrochloride (96 mg, 1.38 mmol) and TEA (0.35 mL, 2.51 mmol). The mixture was heated under stirring at 50 °C for 1 h, then concentrated under reduced pressure.
  • Step-5 1 Synthesis of 3-methyl-l-(6-(((1S,3S)-3-((5-methyl-l,2,4-oxadiazol-3- yl)amino)cyclopentyl)amino)pyridin-3-yl)imidazolidine-2, 4-dione (Example 21)
  • Step-1 1 Synthesis of 2,5-dioxopyrrolidin-l-yl 1-hydroxycyclopentane-l-carboxylate
  • Step-1 1 Synthesis of 6'-fhioro-27/-[l,3'-bipyridin]-2-one (Int-23)
  • Step-2 Synthesis of tert-butyl ((l 1 $',3 1 S')-3-((2-oxo-27/-[l,3 , -bipyridin]-6 , -yl)amino) cyclopentyl)carbamate
  • Step-3 Synthesis of 6'-(((1S,3S)-3-aminocyclopentyl)amino)-27/-[l,3'-bipyridin]-2-one hydrochloride (Int-25)
  • Step-4 Synthesis of A-((1S,3S)-3-((2-oxo-277-[l,3'-bipyridin]-6'-yl)amino)cyclopentyl)cyanamide (Int-26)
  • Step-5 Synthesis of 2-hydroxy-l-((1S,3S)-3-((2-oxo-27/-[l,3'-bipyridin]-6'- yl)amino)cyclopentyl)guanidine (Int-27)
  • Step-6 Synthesis of bMflLS'vLS'l-d-flS-methyl-LZH-oxadiazol-d-yllamino) cyclo pentyl )am in o)-2//- [l,3'-bipyridin]-2-one (Example 23)
  • Example 25 Synthesis of 2-(6-(((l 1 S , ,3 1 S)-3-((5-(4-fluorophenvl)-l,2,4-thiadiazol-3- vl)amino)cvclopentvl)amino)pvridin-3-vl)pyridazin-3(2H)-one
  • Example 28 Synthesis of 3-(6-((2-(6'-(((1S,3S)-3-((5-cvcloDroDvlDvrimidin-2- vl)amino)cvcloDentvl)amino)-2-oxo-27/-[l,3'-biDvridine]-5-carboxamido)ethvl)amino)-6-oxohexvl)-
  • Step-1 Synthesis of 2-chloro-5-cyclopropylpyrimidine (Int-28)
  • Step-2 Synthesis of tert-butyl ((15,35)-3-((5-cyclopropylpyrimidin-2- yl)amino)cyclopentyl)carbamate (Int-29)
  • Step-3 Synthesis of (15,3S')-/V 1 -(5-cyclopropylpyrimidin-2-yl)cyclopentane-l,3-diamine hydrochloride (Int-30)
  • Step-4 Synthesis of tert-butyl (2-(6-oxo-l,6-dihydropyridine-3-carboxamido)ethyl)carbamate (Int- 31)
  • Step-5 Synthesis ooff tert-butyl (2-(6'-fluoro-2-o ⁇ o-2//-
  • Step-6 Synthesis of tert-butyl (2-(6'-(((1S,3S)-3-((5-cyclopropylpyrimidin-2- yl)amino)cyclopentyl)amino)-2-oxo-27/-[l,3'-bipyridine]-5-carboxamido)ethyl)carbamate (Int-33)
  • Step-7 Synthesis of 2V-(2-aminoethyl)-6'-(((lS',3S')-3-((5-cyclopropylpyrimidin-2- yl)amino)cyclopentyl)amino)-2-oxo-27/-[l,3'-bipyridine]-5-carboxamide (Int-34)
  • Step-8 Synthesis of 3-(6-((2-(6'-(((1S,3S)-3-((5-cyclopropylpyrimidin-2- yl)amino)cyclopentyl)amino)-2-oxo-27/-[l,3'-bipyridine]-5-carboxamido)ethyl)amino)-6-oxohexyl)- 2-((12j,32j)-5-((2j)-3,3-dimethyl-5-sulfo-l-(3-sulfopropyl)indolin-2-ylidene)penta-l,3-dien-l-yl)-3- methyl-5-sulfo-l-(4-sulfobutyl)-37/-indol-l-ium
  • Step-3 Synthesis of 2-(6-(((1S,3S)-3-((6-methyl-l,2,4-triazin-3-yl)amino) cyclopentyl)amino)pyridin- 3-yl)pyridazin-3(2H)-one (Example 29)
  • Step-2 Synthesis of tert-butyl ((ES',3,S')-3-((5-(5-methyl-6-oxopyridazin- l(6//)-yl) pyridine-2-yl) amino) cyclopentyl) carbamate (lnt-38)
  • StepS Synthesis of 2-(6-(((15',35')-3-aminocyclopentyl)amino)pyridin-3-yl)-4-methylpyridazin- 3(2//)-one (Int-39) [339] To a mixture of Int-38 (1.5 g, 3.89 mmol) in MeOH (10 ml) was added 4 M HC1 in 1,4-dioxane (6 mL). After stirring for 2 h at room temperature, the mixture was concentrated under reduced pressure. The crude product was treated with Amberlyst® A21 ion exchange resin (3 g) in MeOH (20 mL) and stirred for 15 min.
  • Amberlyst® A21 ion exchange resin 3 g
  • Step-4 Synthesis of 4-methyl-2-(6-(((1S,3S)-3-((6-methyl-l,2,4-triazin-3- yl)amino)cyclopentyl)amino)pyridin-3-yl)pyridazin-3(2H)-one (Example 30)
  • Step-2 Synthesis of tert-butyl ((l 1 S',3 1 S')-3-((l,2,4-triazin-3-yl)amino)cyclopentyl) carbamate (Int-41)
  • Step-3 Synthesis of tert-butyl ((f 1 S',3 1 S')-3-((6-bromo-l,2,4-triazin-3-yl)amino)cyclopentyl)carbamate (Int-42)
  • Step-4 Synthesis of tert-butyl ((LS',3.S')-3-((6-cyclopropyl-l,2,4-triazin-3-yl)amino) cyclopentyl)carbamate (Int-43)
  • Step-5 Synthesis of (15',35')-A7-(6-cyclopropyl-l,2,4-triazin-3-yl)cyclopentane-l,3-diamine (Int-44)
  • Step-6 Synthesis of 2-(6-(((1S,3S)-3-((6-cyclopropyl-l,2,4-triazin-3- yl)amino)cyclopentyl)amino)pyridin-3-yl)pyridazin-3(2H)-one (Example 31)
  • Example 33 Synthesis of 2-(6-(((l 1 S , ,3 1 S)-3-((6-ethvl-l,2,4-triazin-3-yl)amino)cvclopentvl) amino)pvridin-3-vl)-4-methvlpyridazin-3(277)-one
  • Step-2 Synthesis of /V,2,2-trimethoxy-/V-methylacetamide (Int-46)
  • Step-4 Synthesis of 6-ethyl-3-(methylthio)-l,2,4-triazine (lnt-48) [351]
  • a mixture of methyl hydrazinecarbimidothioate hydroiodide (5 g, 21.4 mmol) and Int-47 (2.5 g, 21.4 mmol) in EtOH (100 mL) was heated at 70 °C for 4 h.
  • the reaction mixture was concentrated under reduced pressure.
  • Step-5 Synthesis of 6-ethyl-3-(methylsulfonyl)-l, 2, 4-triazine and 6-ethyl-3-(methylsulfinyl)-l,2,4- triazine (Int-49 / Int-49a)
  • Step-6 Synthesis of 2-(6-(((lS,3S)-3-((6-ethyl-l,2,4-triazin-3-yl)amino)cyclopentyl) amino)pyridin-3- yl)-4-methylpyridazin-3(2H)-one (Example 33)
  • Batch-1 To a solution of Int-39 (330 mg, 1.16 mmol) in NMP (5 mL), was added NazCOs (243 mg, 2.32 mmol) followed by Int-49a (200 mg, 1.16 mmol). The reaction mixture was stirred at rt for 16 h.
  • Batch-2 To the stirred solution of Int-39 (732 mg, 2.56 mmol) in NMP (5 mL), was added NazCOs (537 mg, 5.12 mmol) followed by Int-49 (480 mg, 2.56 mmol). The reaction mixture was stirred at rt for 16 h. The combined reaction mixtures were quenched with water and the product was extracted with EtOAc.
  • Example 35 Synthesis Of 2-(6-(((15',35')-3-((5-(l-hvdroxvcvcloDentvl)-l,2,4-oxadiazol-3- vl)amino)cvcloDentvl)amino)Dvridin-3-yl)Dvridazin-3(2H)-one
  • Step-1 Synthesis of 2,5-dioxopyrrolidin-l-yl 1-hydroxycyclopentane-l-carboxylate (Int-35) lnt-60 was synthesized following the Int-12 starting from commercially available 1 -hydroxycyclopentane- 1 -carboxylic acid.
  • 'H NMR 300 MHz, CDC1 3 ) 5 2.86 (s, 4H), 2.61 (s, IH), 2.38 - 2.33 (m, 2H), 2.04 - 1.84 (m, 6H).
  • Step-2 Synthesis of 2-(6-(((1S,3S)-3-((5-(l-hydroxycyclopentyl)-l,2,4-oxadiazol-3- yl)amino)cyclopentyl)amino)pyridin-3-yl)pyridazin-3(2H)-one (Example 35)
  • Example 35 was synthesized following the Example 15 starting from Int-5. ESI-MS m/z: 424.1 [M+H] + .
  • Example 36 Synthesis of l,5,5-trimethyl-3-(6-(((l 1 S',3 1 S)-3-((5-methyl-l,2,4-oxadiazol-3- vl)amino)cvdopentvl)amino)pyridin-3-vl)imidazolidine-2, 4-dione
  • Step-1 Synthesis of tert-butyl ((15',35')-3-((5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-l-yl)pyridin-2- yl)amino)cyclopentyl)carbamate (Int-61)
  • Int-61 was synthesized following the Int-14 starting from commercially available 1,5,5- trimethylimidazolidine-2, 4-dione, ESI-MS m/z: 418.25 [M+H] + .
  • Step-2 Synthesis ooff 3-(6-(((LS',3.S')-3-aminocyclopentyl) amino) pyridin-3-yl)-l ,5,5- trimethylimidazolidine-2, 4-dione hydrochloride (Int-62)
  • Int-62 was synthesized following the Int-3 starting from Int-61, ESI-MS m/z: 318.15 [M+H] + .
  • Step-3 Synthesis ooff N-((1S,3S)-3-((5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-l-yl)pyridin-2- yl)amino)cyclopentyl)cyanamide (Int-63)
  • Int-63 was synthesized following the Int-4 starting from Int-62, ESI-MS m/z: 343.15 [M+H] + .
  • Step-4 Synthesis of 2-hydroxy-l-((15,3 ⁇ )-3-((5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-l-yl)pyridin- 2-yl)amino)cyclopentyl)guanidine (Int-64)
  • Int-64 was synthesized following the Int-5 starting from Int-63, ESI-MS m/z: 375.95 [M+H] + .
  • Step-5 Synthesis of l,5,5-trimethyl-3-(6-(((15,35)-3-((5-methyl-l,2,4-oxadiazol-3- yl)amino)cyclopentyl)amino)pyridin-3-yl)imidazolidine-2, 4-dione (Example 36)
  • Example 36 was synthesized following the Example 1 starting from Int-64. ESI-MS m/z: 400.1 [M+H] + .
  • Example 37 Synthesis of 4-methyl-2-(6-(((1S,3S)-3-((5-methyl-l,2,4-oxadiazol-3- vl)amino)cvcloDentvl)amino)Dvridin-3-vl)Dvridazin-3(27Q-one
  • Int-65 was synthesized following the Int-1 starting from commercially available 4-methylpyridazin- 3(2H)-one, ESI-MS m/z: 205.70 [M+H] + .
  • Step-2 Synthesis ooff tert-butyl ((1S,3S)-3-((5-(5-methyl-6-oxopyridazin-l(67/)-yl)pyridin-2- yl)amino)cyclopentyl)carbamate (Int-66)
  • Int-66 was synthesized following the Int-2 starting from Int-65, ESI-MS m/z: 385.75 [M+H] + .
  • Step-3 Synthesis of 2-(6-(((1S,3S)-3-aminocyclopentyl) amino) pyridin-3-yl)-4-methylpyridazin- 3(2H)-one hydrochloride (lnt-67) lnt-67 was synthesized following the Int-3 starting from Int-66, ESI-MS m/z: 286.10 [M+H] + .
  • Step-4 Synthesis ooff A L ((1S,3S)-3-((5-(5-methyl-6-oxopyridazin-l(67/)-yl) pyridin-2- yl)amino)cyclopentyl)cyanamide (Int-68)
  • Int-68 was synthesized following the Int-4 starting from lnt-67, ESI-MS m/z: 310.95 [M+H] + .
  • Step-5 Synthesis of 2-hydroxy-l-((1S,3S)-3-((5-(5-methyl-6-oxopyridazin-l(67/)-yl)pyridin-2- yl)amino)cyclopentyl)guanidine (Int-69)
  • Int-69 was synthesized following the Int-5 starting from Int-68, ESI-MS m/z: 344.20 [M+H] + .
  • Step-6 Synthesis ooff 4-methyl-2-(6-(((15,35)-3-((5-methyl-l,2,4-oxadiazol-3- yl)amino)cyclopentyl)amino)pyridin-3-yl)pyridazin-3(2H)-one (Example 37)
  • Example 38 Synthesis of 2-(6-(((15',35')-3-((5-(3-methvloxetan-3-vl)-l,2,4-oxadiazol-3- vl)amino)cvcloDentvl)amino)Dvridin-3-yl)Dvridazin-3(27D-one
  • Example 39 Synthesis Of 2-(6-(((15',35')-3-((5-(cvcloDroDvlmethvl)-l,2,4-oxadiazol-3- vl)amino)cvclopentvl)amino)pvridin-3-vl)pyridazin-3(27D-one
  • Step-1 Synthesis of Synthesis of 2-acetoxy-2-methylpropanoic acid (Int-70)
  • Int-71 was synthesized following the Int-12 starting from Int-71.
  • Step-3 Synthesis of 2-(3-(((1S,3S)-3-((5-(6-oxopyridazin-l(67/)-yl)pyridin-2- yl)amino)cyclopentyl)amino)-l,2,4-oxadiazol-5-yl)propan-2-yl acetate (Int-72)
  • Int-72 was synthesized following the Example 15 starting from Int-5 and Int-71.
  • Step-4 Synthesis ooff 2-(6-(((15,35)-3-((5-(2-hydroxypropan-2-yl)-l,2,4-oxadiazol-3- yl)amino)cyclopentyl)amino)pyridin-3-yl)pyridazin-3(2H)-one (Example 40)
  • Int-73 was synthesized following the Int-70 starting from commercially available 1-hydroxycyclobutane- 1 -carboxylic acid.
  • Int-74 was synthesized following the Int-12 starting from Int-73.
  • Step-3 Synthesis of l-(3-(((l 1 S',3 1 S')-3-((5-(6-oxopyridazin-l(6H)-yl)pyridin-2- yl)amino)cyclopentyl)amino)-l,2,4-oxadiazol-5-yl)cyclobutyl acetate (Int-75)
  • Int-75 was synthesized following the Example 15 starting from Int-5 and Int-74.
  • Step-4 1 Synthesis oOff 2-(6-(((1S,3S)-3-((5-(l-hydroxycyclobutyl)-l,2,4-oxadiazol-3- yl)amino)cyclopentyl)amino)pyridin-3-yl)pyridazin-3(2H)-one (Example 41)
  • Example 42 was synthesized following the Example 2 starting from Int-5 with commercially available cyclohexanecarboxylic acid. ESI-MS m/z: 422.40 [M+H] + .
  • Example 43 2-(6-(((1S,3S)-3-((5-phenvl-l,2,4-oxadiazol-3-vl)amino) cvclopentvl)amino)pyridin-3- vl)pyridazin-3(277)-one
  • Example 44 2-(6-(((1S,3S)-3-((5-(pvridin-3-vl)-l,2,4-oxadiazol-3- vl)amino)cvclonentvl)amino)pvridin-3-vl)pyridazin-3(277)-one
  • Example 44 was synthesized following the Example 2 starting from Int-5 with commercially available nicotinic acid. ESI-MS m/z: 416.95 [M+H] + .
  • 1 H NMR 400 MHz, CD 3 OD
  • Example 46 Synthesis of 2-(6-(((1S,3S)-3-((5-((methvlsulfonvl)methvl)-l,2,4-oxadiazol-3- vl)amino)cvcloDentvl)amino)Dvridin-3-vl)Dvridazin-3(2H)-one
  • Step-1 Synthesis of 3-acetoxy-2,2-dimethylpropanoic acid (Int-76)
  • Int-76 was synthesized following the Int-70 starting from commercially available 3-hydroxy-2,2- dimethylpropanoic acid. 'H NMR (300 MHz, CDC1 3 ) 5 4.18 (s, 2H), 2.08 (s, 3 H), 1.35 (s, 6 H).
  • Int-77 was synthesized following the Int-12 starting from Int-76. ’H NMR: (400MHz, DMSO-de) 5 4.15 (s, 2H), 3.32 (s, 4 H), 2.03 (s, 3 H), 1.33 (s, 6H)
  • Step-3 Synthesis of 2-methyl-2-(3-(((1S,3S)-3-((5-(6-oxopyridazin-l(6H)-yl)pyridin-2- yl)amino)cyclopentyl)amino)-l,2,4-oxadiazol-5-yl)propyl acetate (Int-78)
  • Int-78 was synthesized following the Example 15 starting from Int-5 and Int-77.
  • Step-4 Synthesis of Synthesis of 2-(6-(((15,35)-3-((5-(l-hydroxy-2-methylpropan-2-yl)-l,2,4- oxadiazol-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyridazin-3(2H)-one (Example 47)
  • Example 48 Synthesis ooff 2-(6-(((1S,3S)-3-((5-(2,2,2-trifluoroethvl)-l,2,4-oxadiazol-3- vl)amino)cvclopentvl)amino)pvridin-3-vl)pyridazin-3(27O-one
  • Example _ 49 _ methyl _ l-(3-(((l 1 $',3 1 S')-3-((5-(6-oxopvridazin-l(6H)-vl)pvridin-2- vl)amino)cvclopentvl)amino)-l,2,4-oxadiazol-5-vl)cvclopropane-l-carboxylate
  • Example 49 was synthesized following the Example 2 starting from Int-5 with commercially available 1- (methoxycarbonyl)cyclopropane-l -carboxylic acid. ESI-MS m/z: 438.15 [M+H] + .
  • Example 50 Synthesis of l-methyl-6'-(((15,35)-3-((5-methyl-l,2,4-oxadiazol-3- vl)amino)cvclopentvl)amino)-[3,3'-bipyridin]-2(lZ7)-one Step-1; Synthesis of Synthesis of tert-butyl ((15,35)-3-((5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl) pyridin-2-yl) amino) cyclopentyl) carbamate (Int-79)
  • Step-2- Synthesis of tert-butyl ((lS,35)-3-((r-methyl-2'-oxo-r,2'-dihydro-[3,3'-bipyridin]-6-yl) amino) cyclopentyl) carbamate (Int-80)
  • Step-3 Synthesis of 6'-(((LS',3 > S')-3-aminocyclopcntyl) amino)-l-methyl-[3,3'-bipyridin]-2(17/)-one hydrochloride (Int-81)
  • Int-81 was synthesized following the Int-3 starting from Int-80, ESI-MS m/z: 285.10 [M+H] + .
  • Step-4- Synthesis of N-((15,35)-3-((l'-methyl-2'-oxo-l',2'-dihydro-[3,3'-bipyridin]-6-yl) amino) cyclopentyl) cyanamide (Int-82)
  • Int-82 was synthesized following the Int-4 starting from Int-81, ESI-MS m/z: 310.05 [M+H] + .
  • Step-5 Synthesis of 2-hydroxy-l-((15,35)-3-((l'-methyl-2'-oxo-l',2'-dihydro-[3,3'-bipyridin]-6- yl)amino)cyclopentyl)guanidine (Int-83)
  • Int-83 was synthesized following the Int-5 starting from Int-82, ESI-MS m/z: 343.15 [M+H] + .
  • Step-6 Synthesis of l-methyl-6'-(((1S,3S)-3-((5-methyl-l,2,4-oxadiazol-3- yl)amino)cyclopentyl)amino)-[3,3'-bipyridin]-2(17/)-one (Example 50)
  • Example 51 Synthesis of 2-methyl-2-(3-(((1S,3S)-3-((5-(6-oxopyridazin-l(67f)-yl) pyridin-2- vl)amino)cvclopentvl)amino)-l,2,4-oxadiazol-5-yl)propanenitrile
  • Example 53 Synthesis of l-(3-(((15',35')-3-((5-(6-oxopyridazin-l(6Zf)-yl)pyridin-2- vl)amino)cvclopentvl)amino)-l,2,4-oxadiazol-5-vl)cvclopropane-l-carboxylic acid
  • Example 49 To a solution of Example 49 (200 mg, 0.45 mmol) in MeOH (3.0 mL) and THF(7.0 mL) was added LiOH.H2O (56 mg, 1.37 mmol) in H2O (1.0 mL). After stirred for 2 h, the reaction was quenched with water and the product was extracted with EtOAc. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. .
  • Example 54 Synthesis of 2-(6-(((1S,3S)-3-((5-(l-methvl-lH-l,2,4-triazol-3-vl)-l,2,4-oxadiazol-3- vl)amino)cvclopentvl)amino)pvridin-3-vl)pyridazin-3(2H)-one
  • Step-1 Synthesis of l-methyl-lH-l,2,4-triazole-3-carboxylic acid (Int-84)
  • Step-2 Synthesis ooff 2-(6-(((1S,3S)-3-((5-(l-methyl-lH-l,2,4-triazol-3-yl)-l,2,4-oxadiazol-3- yl)amino)cyclopentyl)amino)pyridin-3-yl)pyridazin-3(2Z/)-one (Example 54)
  • Example 54 was synthesized following the Example 2 starting from Int-5 and Int-84. ESI-MS m/z: 421.10 [M+H] + .
  • Example 55 Synthesis of 2-(3-(((LS',3.S')-3-((5-(6-oxopvridazin-l(6//)-vl)i)vridin-2- vl)amino)cvclopentvl)amino)-l,2,4-oxadiazol-5-vl)acetonitrile
  • Int-85 was synthesized following the Int-12 starting from commercially available 2-cyanoacetic acid. ’H NMR (300 MHz, CD 3 OD) 5 3.68 (s, 2H), 2.67 (s, 4H).
  • Step-2 Synthesis of 2-(3-(((1S,3S)-3-((5-(6-oxopyridazin-l(67/)-yl)pyridin-2- yl)amino)cyclopentyl)amino)-l ,2,4-oxadiazol-5-yl)acetonitrile (Example 55)
  • Example 55 was synthesized following the Example 15 starting from Int-5 and Int-85. ESI-MS m/z: 378.90 [M+H] + .
  • Example 56 Synthesis of 2 - (6 -((( l 1 S',3 1 S')-3-((5-eth yl-1 ,2,4-oxadiazol-3- vl)amino)cvcloDentvl)amino)Dvridin-3-vl)-4-methvlpvridazin-3(2ZD-one
  • Example 57 Synthesis of l-(3-(((1S,3S)-3-((5-(6-oxoDvridazin-l(6Zn-vl)Dvridin-2- vl)amino)cvcloDentvl)amino)-l,2,4-oxadiazol-5-vl)cvcloDropane-l-carbonitrile
  • Example 57 was synthesized following the Example 2 starting from Int-5 with commercially available 1- cy anocyclopropane- 1 -carboxylic acid. ESI-MS m/z: 405.02 [M+H] + .
  • 'HNMR 400 MHz, CD3OD
  • Example 58 Synthesis of ethyl l-(3-(((f 1 S',3 1 S')-3-((5-(6-oxopvridazin-l(677)-vl)pvridin-2- vl)amino)cvclopentvl)amino)-l,2,4-oxadiazol-5-vl)cvclobutane-l-carboxylate
  • Example 58 was synthesized following the Example 2 starting from Int-5 with commercially available 1- (ethoxycarbonyl)cyclobutane-l -carboxylic acid. ESI-MS m/z: 466.0 [M+H] + .
  • Example 59 Synthesis of l-(3-(((1S,3S)-3-((5-(6-oxopvridazin-l(6Z7)-vl)pvridin-2- vl)amino)cvclopentvl)amino)-l,2,4-oxadiazol-5-vl)cvclobutane-l-carboxylic acid
  • Example 60 Synthesis of l-methyl-3-(6-(((l 1 $',3 1 S')-3-((5-(l-methvlcvclonropvl)-l,2,4-oxadiazol-3- vl)amino)cvclonentvl)amino)pyridin-3-vl)imidazolidine-2,4-dione
  • Example 61 Synthesis of 3-(6-(((l 1 $',3 1 S')-3-((5-cvclobutvl-l,2,4-oxadiazol-3-vl)amino) cvclopentvl)amino)pyridin-3-vl)-l-methvlimidazolidine-2, 4-dione
  • Example 62 Synthesis of l
  • Example 62 was synthesized following the Example 2 starting from Int-64 with commercially available 1 -methylcyclopropane- 1 -carboxylic acid. ESI-MS m/z: 440.0 [M+H] + .
  • Example 63 Synthesis of l-(3-(((15 , ,35 , )-3-((5-(6-oxopvridazin-l(6H)-vl)pyridin-2- vl)amino)cvclopentvl)amino)-l,2,4-oxadiazol-5-yl)cvclobutane-l-carbonitrile
  • Step-1 Synthesis ooff Synthesis ooff l-(3-(((LS',3.S')-3-((5-(6-oxopyridazin-l(6//)-yl)pyridin-2- yl)amino)cyclopentyl)amino)-l,2,4-oxadiazol-5-yl)cyclobutane-l-carboxamide (Int-86)
  • Example 59 To a solution of Example 59 (35 mg, 0.08 mmol) in DMF (1.0 mL) were added ammonium chloride (21 mg, 0.40 mmol), HATH (45 mg, 0.12 mmol) and DIPEA ( 0.06 mL, 0.40 mmol). After stirring for 48 h, the reaction was quenched with water and the product was extracted with EtOAc. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide crude product as a pale brown sticky solid (50 mg, Crude) . ESI-MS m/z: 436.95 [M+H] + .
  • Step-2 Synthesis oOff l-(3-(((1S,3S)-3-((5-(6-oxopyridazin-l(6H)-yl)pyridin-2- yl)amino)cyclopentyl)amino)-l,2,4-oxadiazol-5-yl)cyclobutane-l-carbonitrile (Example 63)
  • Example 64 Synthesis of 3-(6-(((lS'.3S r )-3-((5-cvclopropvl-1.2.4-oxadiazol-3- vl)amino)cvclopentvl)amino)pvridin-3-vl)-l,5,5-trimethylimidazolidine-2,4-dione
  • Example 65 Synthesis of 3-(6-(((lS , ,3S)-3-((5-cyclopropyl-l,2,4-oxadiazol-3- vl)amino)cvclopentvl)amino)pyridin-3-vl)-l-methvlimidazolidine-2,4-dione
  • Example 66 Synthesis of 2-(6-(((1S,3S)-3-((5-cvclopropvl-l,2,4-thiadiazol-3- vl)amino)cvclopentvl)amino)pvridin-3-vl)-4-methvlpyridazin-3(2ZD-one
  • Int-76 was synthesized following the Int-70 starting from commercially available 1 -hydroxy cyclopropane- 1 -carboxylic acid. *H NMR (400 MHz, DMSO-d s ) 5 12.86 (s, 1H), 2.01 (s, 3H), 1.36 - 1.33 (m, 2H), 1.17
  • Step-2 Synthesis ooff l-(3-(((1S,3S)-3-((5-(3-methyl-2,5-dioxoimidazolidin-l-yl)pyridin-2- yl)amino)cyclopentyl)amino)-l,2,4-oxadiazol-5-yl)cyclopropyl acetate (Int-77)
  • Int-77 was synthesized following the Example 2 starting from Int-76 and Int-11.
  • Step-3 Synthesis ooff 3-(6-(((LS',3.S')-3-((5-(l-hydroxycyclopropyl)-l,2,4-oxadiazol-3- yl)amino)cyclopentyl)amino)pyridin-3-yl)-l-methylimidazolidine-2, 4-dione (Example 67)
  • TR-FRET time resolved fluorescence resonance energy transfer
  • a master compound plate was prepared in a Greiner V bottom plate by diluting compounds of the disclosure in dimethylsulfoxide to the correct concentration for the desired top concentration based on the desired final concentration: for a 30 pM final concentration the master plate concentration is 1.5 mM (68 pL DMSO + 12 pL 10 mM of a compound of the disclosure), for a 10 pM final concentration the master plate concentration is 0.5 mM (76 pL DMSO + 4 pL 10 mM of a compound of the disclosure), for a 3 pM final concentration the master plate concentration is 150 pM (69 pL DMSO + 1 pL 10 mM of a compound of the disclosure).
  • An intermediate plate was generated in a Greiner V bottom plate by transferring 8 pL from each well of the master plate into a corresponding well containing 92 pL of assay buffer and mixing thoroughly.
  • a Proxi plate-low volume assay plate was used for the assay. To all wells of the plate was added 10 pL of 7 nM Human PCSK9 Terbium, followed by 5 pL from the intermediate plate. For the competition displacement control wells in columns 23 and 24 of the plate, 5 pL of unlabeled human PCSK9 was added at 4 pM in assay buffer containing 8% DMSO. Following a 30 minute incubation, 5 pL of 120 pM Alexa Fluor 647 labeled probe was added and the mixture was incubated for an additional 2 hours.
  • TR-FRET TR-FRET signal was measured on an EnVision instrument with a 60 ms delay, 330 nm excitation and 665 nm emission (FRET), and 330 nM excitation and 615 nm (Terbium).
  • FRET 330 nm excitation and 665 nm emission
  • Terbium 330 nM excitation and 615 nm
  • hERG expressing cell lines were produced using CH0-K1 T-Rex inducible plasmid system (Invitrogen) as described previously (Cao et al, Assay Drug Dev. Technol. 2010, 8, 766-780).
  • C 6 ll lines were maintained in Ham’s F12 nutrient mixture containing 10% FBS, blasticidin (10 mg/mL; InvivoGen), hygromycin B (200 mg/mL;InvivoGen), Zeocin (200 mg/mL, Invitrogen), and neomycin (200 mg/mL, Invitrogen) using SelecT automated cell culture system (TAP Biosystems, Cambridge, U.K.).
  • hERG and hCavl.2 channels expression was induced with tetracycline (0.25-1 ⁇ g/mL, Invitrogen) at least 24 h prior to the experiment.
  • hERG currents were recorded using the Qpatch automated patch clamp systems (Sophion Bioscience Inc., North Brunswick, NJ) in the whole (single) cell configuration.
  • hERG expressing CHO-K1 cells were harvested with Detachin (Genlantis) and stored in the modified serum-free SFM-2 media (Life Technologies) at room temperature.
  • the extracellular solution contained (in mM) NaCl (145), KC1 (4), MgC12 (1), CaC12 (2), and HEPES (10), pH 7.4, with NaOH.
  • the intracellular solution contained KC1 (135), MgC12 (1.75), CaC12 (5.4), EGTA (10), K2-ATP (4), and HEPES (10), pH 7.2, with KOH.
  • Reference Compound 1 is 2-(6-(((lS,3S)-3-((5-cyclopropylpyrimidin-2- yl)amino)cyclopentyl)amino)pyridin-3-yl)pyridazin-3(2H)-one. The compound was prepared following the procedure reported in W02020150473.
  • Reference Compound 2 is 3-(6-(((lS,3S)-3-((5- (difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-l-methylimidazolidine-2,4- dione The compound was prepared following the procedure reported in W02020150473.
  • Examples 1, 2, 5, 6, 10, 24, 29 and 31 showed unexpectedly reduced inhibition of the hERG channel, compared to the reference compounds (Reference compounds 1 and 2). Reduced inhibition of the hERG channel may translate into an improved safety profile for the compounds as compared to reference compounds.

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Abstract

La divulgation concerne un composé de formule (I) : (I) ou un sel pharmaceutiquement acceptable de celui-ci, A et B étant tels que présentés dans la description, ainsi que des compositions et des méthodes d'utilisation de tels composés.
PCT/IB2022/060845 2021-11-12 2022-11-10 Dérivés diaminocyclopentylpyridines pour le traitement d'une maladie ou d'un trouble WO2023084449A1 (fr)

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