[go: up one dir, main page]

WO2019224773A1 - Heterocyclic amides as rip1 kinase inhibitors - Google Patents

Heterocyclic amides as rip1 kinase inhibitors Download PDF

Info

Publication number
WO2019224773A1
WO2019224773A1 PCT/IB2019/054286 IB2019054286W WO2019224773A1 WO 2019224773 A1 WO2019224773 A1 WO 2019224773A1 IB 2019054286 W IB2019054286 W IB 2019054286W WO 2019224773 A1 WO2019224773 A1 WO 2019224773A1
Authority
WO
WIPO (PCT)
Prior art keywords
dihydro
alkyl
difluorophenyl
piperidin
pyrazol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2019/054286
Other languages
French (fr)
Inventor
Ryan Michael Fox
Philip Anthony Harris
Mark Andrew Seefeld
Ding Zhou
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
GlaxoSmithKline Intellectual Property Development Ltd
Original Assignee
GlaxoSmithKline Intellectual Property Development Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by GlaxoSmithKline Intellectual Property Development Ltd filed Critical GlaxoSmithKline Intellectual Property Development Ltd
Publication of WO2019224773A1 publication Critical patent/WO2019224773A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • 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

  • the present invention relates to heterocyclic amides that inhibit RIP1 kinase and methods of making and using the same.
  • Receptor-interacting protein-1 (RIP1) kinase is a TKL family serine/threonine protein kinase involved in innate immune signaling.
  • RIP1 kinase is a RHIM domain containing protein, with an N-terminal kinase domain and a C-terminal death domain (Trends Biochem. Sci., 30, 151-159 (2005)).
  • the death domain of RIP1 mediates interaction with other death domain containing proteins including Fas and TNFR-1 (Cell, 81 513–523 (1995)), TRAIL-R1 and TRAIL-R2 (Immunity, 7, 821–830 (1997)), and TRADD (Immunity, 4, 387–396 (1996)), while the RHIM domain is crucial for binding other RHIM domain containing proteins such as TRIF (Nat. Immunol., 5, 503–507 (2004)), DAI (EMBO Rep.10, 916–922 (2009)) and RIP3 (J. Biol. Chem., 274, 16871–16875 (1999)); Curr. Biol., 9, 539–542 (1999)) and exerts many of its effects through these interactions.
  • RIP1 is a central regulator of cell signaling and is involved in mediating both pro-survival and programmed cell death pathways which will be discussed below.
  • TLR3 Non Immunol., 5, 503–507 (2004)
  • TLR4 J. Biol. Chem., 280, 36560– 6566 (2005)
  • TRAIL Cell Signal., 27(2), 306–314 (2015)
  • FAS J. Biol. Chem., 279, 7925–7933 (2004)
  • Engagement of the TNFR by TNF leads to its oligomerization, and the recruitment of multiple proteins, including linear K63- linked polyubiquitinated RIP1 (Mol. Cell, 22, 245–257 (2006)), TRAF2/5 (J. Mol.
  • complex I This complex which is dependent on RIP1 as a scaffolding protein (i.e. kinase independent), termed complex I, provides a platform for pro-survival signaling through the activation of the NFkB and MAP kinases pathways (Sci. Signal., 115, re4 (2010)).
  • RIP3 can now enter this complex, become phosphorylated by RIP1 and initiate a caspase-independent programmed necrotic cell death through the activation of MLKL and PGAM5 (Cell, 148, 213–227 (2012)); (Cell, 148, 228– 243 (2012)); (Proc. Natl. Acad. Sci. USA., 109, 5322–5327 (2012)).
  • DAMPs danger associated molecular patterns
  • Dysregulation of RIP1 kinase-mediated programmed cell death has been linked to various inflammatory diseases, as demonstrated by use of the RIP3 knockout mouse (where RIP1-mediated programmed necrosis is completely blocked) and by Necrostatin-1 (a tool inhibitor of RIP1 kinase activity with poor oral bioavailability).
  • the RIP3 knockout mouse has been shown to be protective in inflammatory bowel disease (including ulcerative colitis and Crohn’s disease) (Nature, 477, 330–334 (2011)), psoriasis (Immunity, 35, 572–582 (2011)), retinal-detachment-induced photoreceptor necrosis (PNAS, 107, 21695–21700, (2010)), retinitis pigmentosa (Proc. Natl. Acad.
  • Necrostatin-1 has been shown to be effective in alleviating ischemic brain injury (Nat. Chem. Biol., 1, 112–119 (2005)), retinal ischemia/reperfusion injury (J. Neurosci.
  • RIP1-dependent apoptosis, necrosis or cytokine production include hematological and solid organ malignancies (Genes Dev., 27, 1640–1649 (2013)), bacterial infections and viral infections (Cell Host & Microbe, 15, 23–35 (2014)) (including, but not limited to, tuberculosis and influenza (Cell, 153, 1–14 (2013)) and Lysosomal storage diseases (particularly, Gaucher Disease, Nature Medicine Advance Online Publication, 19 January 2014, doi:10.1038/nm.3449).
  • a potent, selective, small molecule inhibitor of RIP1 kinase activity would block RIP1-dependent cellular necrosis and thereby provide a therapeutic benefit in diseases or events associated with DAMPs, cell death, and/or inflammation.
  • 5-6 membered heteroaryl or 9-10 membered heteroaryl is optionally substituted by 1 or 2 substituents independently selected from hydroxyl, cyano, halogen, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, hydroxy(C 1 -C 4 )alkyl, (C 2 -C 4 )alkynyl, (C 1 - C4)alkoxy, 5-6 membered heterocycloalkyl-CO-, fused 5-6 membered
  • heterocycloalkyl H 2 N-, (C 1 -C 4 )alkyl-NH-, ((C 1 -C 4 )alkyl)((C 1 -C 4 )alkyl)N-, -CONH 2 , H2NCO-(C1-C4)alkyl-, (C1-C4)alkylNHCO-, (hydroxy-(C1-C4)alkyl)NHCO-, (C3- C 6 )cycloalkyl-NHCO-, 5-6 membered heterocycloalkyl-NHCO-, ((C 1 -C 4 )alkyl)((C 1 - C4)alkyl)N-CO-, (C1-C4)alkyl-CONH-, ((C1-C4)alkyl)((C1-C4)alkyl)N-NHCO-, - CO 2 H, -CO 2 (C 1 -C 4 )alkyl, (C 1 -C 4 )alkylthi
  • (C 1 -C 4 )alkoxy is optionally substituted by hydroxyl, -CO 2 H, -CONH2, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; or said
  • 5-6 membered heterocycloalkyl-CO-, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl is optionally substituted by (C 1 -C 4 )alkyl or oxo; or said 5-6 membered heterocycloalkyl-NHCO- is optionally substituted by (C1- C 4 )alkyl-CO-;
  • R 2 is phenyl or 5-6 membered heteroaryl
  • phenyl or 5-6 membered heteroaryl is optionally substituted by one, two, or three substituents independently selected from halogen, (C1-C4)alkyl,
  • each R 3 is independently selected from hydrogen, halogen, (C1-C4)alkyl, and -(C2-C4)alkenyl, or R 1 and R 3 taken together with the atoms to which they are attached, form a 5-6 membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by
  • 5-6 membered heteroaryl or 9-10 membered heteroaryl is optionally substituted by 1 or 2 substituents independently selected from hydroxyl, cyano, halogen, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, hydroxy(C 1 -C 4 )alkyl, (C 2 -C 4 )alkynyl, (C 1 - C4)alkoxy, substituted 5-6 membered heterocycloalkyl-CO-, fused 5-6 membered heterocycloalkyl, H 2 N-, (C 1 -C 4 )alkyl-NH-, ((C 1 -C 4 )alkyl)((C 1 -C 4 )alkyl)N-, -CONH 2 , H2NCO-(C1-C4)alkyl-, (C1-C4)alkylNHCO-, (hydroxy-(C1-C4)alkyl)NHCO-, (C1-
  • (C1-C4)alkoxy is optionally substituted by hydroxyl, -CO2H, -CONH 2 , 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; or said
  • 5-6 membered heterocycloalkyl-CO-, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl is optionally substituted by (C1-C4)alkyl or oxo; or said 5-6 membered heterocycloalkyl-NHCO- is optionally substituted by (C1- C 4 )alkyl-CO-;
  • R 2 is phenyl or 5-6 membered heteroaryl
  • phenyl or 5-6 membered heteroaryl is optionally substituted by one, two, or three substituents independently selected from halogen, (C1-C4)alkyl,
  • each R 3 is independently selected from hydrogen, halogen, (C1-C4)alkyl, and -(C2-C4)alkenyl, or R 1 and R 3 taken together with the atoms to which they are attached, form a 5-6 membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by
  • 5-6 membered heteroaryl or 9-10 membered heteroaryl is optionally substituted by 1 or 2 substituents independently selected from hydroxyl, cyano, halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C2-C4)alkynyl, (C1- C 4 )alkoxy, 5-6 membered heterocycloalkyl-CO-, fused 5-6 membered
  • heterocycloalkyl H2N-, (C1-C4)alkyl-NH-, ((C1-C4)alkyl)((C1-C4)alkyl)N-, -CONH2, H 2 NCO-(C 1 -C 4 )alkyl-, (C 1 -C 4 )alkylNHCO-, H 2 N(C 1 -C 4 )alkylNHCO-, (C 1 -C 4 )alkyl HN(C1-C4)alkylNHCO-, ((C1-C4)alkyl)((C1-C4)alkyl)N(C1-C4)alkylNHCO- (hydroxy-(C 1 -C 4 )alkyl)NHCO-, (C 3 -C 6 )cycloalkyl-NHCO-, 5-6 membered heterocycloalkyl-NHCO-, ((C1-C4)alkyl)((C1-C4)alkyl)N-CO-, (C
  • (C1-C4)alkoxy is optionally substituted by hydroxyl, -CO2H, -CONH2, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; or said
  • 5-6 membered heterocycloalkyl-CO-, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl is optionally substituted by (C 1 -C 4 )alkyl or oxo; or said 5-6 membered heterocycloalkyl-NHCO- is optionally substituted by (C1- C 4 )alkyl-CO-;
  • R 2 is phenyl or 5-6 membered heteroaryl, wherein said phenyl or 5-6 membered heteroaryl is optionally substituted by one, two, or three substituents independently selected from halogen, (C 1 -C 4 )alkyl, -(C 1 - C4)alkyl-NH2, -(C1-C4)alkyl-NH(C1-C4)alkyl, -(C1-C4)alkyl-N-((C1-C4)alkyl)((C1- C 4 )alkyl), (C 1 -C 4 )alkoxy, and cyano; and
  • R 1 and R 3 taken together with the atoms to which they are attached, form a 5-6 membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by
  • the present invention relates to compounds according to Formula (I) or
  • 5-6 membered heteroaryl or 9-10 membered heteroaryl is optionally substituted by one or two substituents independently selected from hydroxyl, cyano, halogen, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, hydroxy(C 1 -C 4 )alkyl, (C 2 -C 4 )alkynyl, (C 1 - C4)alkoxy, 5-6 membered heterocycloalkyl-CO-, fused 5-6 membered
  • heterocycloalkyl H 2 N-, (C 1 -C 4 )alkylNH-, ((C 1 -C 4 )alkyl)((C 1 -C 4 )alkyl)N-, -CONH 2 , H2NCO-(C1-C4)alkyl-, (C1-C4)alkylNHCO-, (hydroxy-(C1-C4)alkyl)NHCO-, (C3- C 6 )cycloalkyl-NHCO-, 5-6 membered heterocycloalkyl-NHCO-, ((C 1 -C 4 )alkyl)((C 1 - C4)alkyl)N-CO-, (C1-C4)alkyl-CONH-, ((C1-C4)alkyl)((C1-C4)alkyl)N-NHCO-, - CO 2 H, -CO 2 (C 1 -C 4 )alkyl, (C 1 -C 4 )alkylthio
  • (C1-C4)alkoxy is optionally substituted by hydroxyl, -CO2H, -CONH 2 , 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; or said 5-6 membered heterocycloalkyl-CO-, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl is optionally substituted by (C 1 -C 4 )alkyl or oxo; or said 5-6 membered heterocycloalkyl-NHCO- is optionally substituted by (C1- C 4 )alkyl-CO-;
  • R 2 is phenyl or 5-6 membered heteroaryl
  • phenyl or 5-6 membered heteroaryl is optionally substituted by one, two, or three substituents independently selected from halogen, (C1-C4)alkyl,
  • each R 3 is independently selected from hydrogen, halogen, (C1-C4)alkyl, and (C2-C4)alkenyl, or R 1 and R 3 taken together with the atoms to which they are attached, form a 5-6 membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by
  • the present invention relates to compounds according to Formula (I) or
  • 5-6 membered heteroaryl or 9-10 membered heteroaryl is optionally substituted by one or two substituents independently selected from hydroxyl, cyano, halogen, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, hydroxy(C 1 -C 4 )alkyl, (C 2 -C 4 )alkynyl, (C 1 - C4)alkoxy, substituted 5-6 membered heterocycloalkyl-CO-, fused 5-6 membered heterocycloalkyl, H 2 N-, (C 1 -C 4 )alkylNH-, ((C 1 -C 4 )alkyl)((C 1 -C 4 )alkyl)N-, -CONH 2 , H2NCO-(C1-C4)alkyl-, (C1-C4)alkylNHCO-, (hydroxy-(C1-C4)alkyl)NHCO-, (C3
  • (C1-C4)alkoxy is optionally substituted by hydroxyl, -CO2H, -CONH 2 , 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; or said 5-6 membered heterocycloalkyl-CO-, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl is optionally substituted by (C 1 -C 4 )alkyl or oxo; or said 5-6 membered heterocycloalkyl-NHCO- is optionally substituted by (C1- C 4 )alkyl-CO-;
  • R 2 is phenyl or 5-6 membered heteroaryl
  • phenyl or 5-6 membered heteroaryl is optionally substituted by one, two, or three substituents independently selected from halogen, (C 1 -C 4 )alkyl,
  • each R 3 is independently selected from hydrogen, halogen, (C 1 -C 4 )alkyl, and (C 2 -C 4 )alkenyl, or R 1 and R 3 taken together with the atoms to which they are attached, form a 5-6 membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by
  • the present invention relates to compounds according to Formula (I) or
  • 5-6 membered heteroaryl or 9-10 membered heteroaryl is optionally substituted by 1 or 2 substituents independently selected from hydroxyl, cyano, halogen, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, hydroxy(C 1 -C 4 )alkyl, (C 2 -C 4 )alkynyl, (C 1 - C4)alkoxy, 5-6 membered heterocycloalkyl-CO-, fused 5-6 membered
  • heterocycloalkyl H 2 N-, (C 1 -C 4 )alkyl-NH-, ((C 1 -C 4 )alkyl)((C 1 -C 4 )alkyl)N-, -CONH 2 , H2NCO-(C1-C4)alkyl-, (C1-C4)alkylNHCO-, H2N(C1-C4)alkylNHCO-, (C1-C4)alkyl HN(C 1 -C 4 )alkylNHCO-, ((C 1 -C 4 )alkyl)((C 1 -C 4 )alkyl)N(C 1 -C 4 )alkylNHCO- (hydroxy-(C1-C4)alkyl)NHCO-, (C3-C6)cycloalkyl-NHCO-, 5-6 membered heterocycloalkyl-NHCO-, ((C1-C4)alkyl)((C1-C4)alkyl)N-
  • 5-6 membered heterocycloalkyl-CO-, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl is optionally substituted by (C1-C4)alkyl or oxo; or said 5-6 membered heterocycloalkyl-NHCO- is optionally substituted by (C 1 - C4)alkyl-CO-;
  • R 2 is phenyl or 5-6 membered heteroaryl
  • phenyl or 5-6 membered heteroaryl is optionally substituted by one, two, or three substituents independently selected from halogen, (C 1 -C 4 )alkyl, -(C 1 - C4)alkyl-NH2, -(C1-C4)alkyl-NH(C1-C4)alkyl, -(C1-C4)alkyl-N-((C1-C4)alkyl)((C1- C 4 )alkyl), (C 1 -C 4 )alkoxy, and cyano; and
  • R 1 and R 3 taken together with the atoms to which they are attached, form a 5-6 membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by
  • RIP1 kinase-mediated diseases or disorders are diseases or disorders that are mediated by activation of RIP1 kinase, and as such, are diseases or disorders where inhibition of RIP1 kinase would provide benefit.
  • Another aspect of this invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I) or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • Another aspect of this invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (II) or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • Another aspect of this invention relates to a method of treating a RIP1-mediated disease or disorder in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound of Formula (I) or pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising of a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • Another aspect of this invention relates to a method of treating a RIP1-mediated disease or disorder in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound of Formula (II) or pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising of a compound of Formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • Another aspect of this invention relates to a method of treating RIP1-mediated disease or disorder in a human in need thereof, wherein the RIP1-mediated disease is amyotrophic lateral sclerosis.
  • the invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.
  • the invention provides a compound of Formula (II) or a pharmaceutically acceptable salt thereof for use in therapy.
  • a compound of Formula (II) or a pharmaceutically acceptable salt thereof for use in the treatment of RIP1-mediated disease or disorders, wherein the RIP1-mediated disease or disorder is amyotrophic lateral sclerosis.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of diseases or disorders mediated by RIP1.
  • FIG.1A shows the temperature loss over time in mice after oral pre-dosing with Compounds A, B, C, D, or vehicle followed by simultaneous i.v. administration of mouse TNF and zVAD.
  • FIG.1B shows the temperature loss in mice 3 hours after oral pre-dosing with Compounds A, B, C, D, or vehicle followed by simultaneous i.v. administration of mouse TNF and zVAD.
  • FIG.2A shows the temperature loss over time in mice after oral pre-dosing with Compounds E, F, G, H or vehicle followed by simultaneous i.v. administration of mouse TNF and zVAD.
  • FIG.2B shows the temperature loss in mice 3 hours after oral pre-dosing with Compounds E, F, G, H or vehicle followed by simultaneous i.v. administration of mouse TNF and zVAD.
  • FIG.3A shows the temperature loss over time in mice after oral pre-dosing with Compound A or vehicle followed by simultaneous i.v. administration of mouse TNF and zVAD.
  • FIG.3B shows the temperature loss in mice 3 hours after oral pre-dosing with Compound A or vehicle followed by simultaneous i.v. administration of mouse TNF and zVAD.
  • Figure 4A shows the temperature loss over time in mice after oral pre-dosing with Compound H or vehicle followed by simultaneous i.v. administration of mouse TNF and zVAD.
  • FIG.4B shows the temperature loss in mice 2 hours after oral pre-dosing with Compound H or vehicle followed by simultaneous i.v. administration of mouse TNF and zVAD.
  • FIG.5A shows the temperature loss over time in mice after oral pre-dosing with Compound A or vehicle followed by simultaneous i.v. administration of mouse TNF.
  • FIG.5B shows the temperature loss in mice 7.5 hours after oral pre-dosing with Compound A or vehicle followed by simultaneous i.v. administration of mouse TNF.
  • FIG 6A shows the scotopic B-wave electroretinography recordings at P39 and P46 in Rd10 mice after startof daily in-diet dosing with Compound A or control diet at P28 followed by switch from dark rearing to 12-hour light/dark cycle at P30.
  • FIG.6B shows the photopic B-wave electroretinography recordings at P39 and P46 in Rd10 mice after startof daily in-diet dosing with Compound A or control diet at P28 followed by switch from dark rearing to 12-hour light/dark cycle at P30.
  • FIG.6C shows the measurement of the thickness of the Outer Nuclear Cell (ONL) layers at various distances from the Optic Nerve Head (ONH) in hematoxylin and eosin stained retinal tissue sections collected at P46 in Rd10 mice after start of daily in-diet dosing with Compound A or control diet at P28 followed by switch from dark rearing to 12-hour light/dark cycle at P30.
  • ONL Outer Nuclear Cell
  • FIG.7 shows the clinical scores over time in mice after daily in-diet dosing with Compound A or control diet followed by induction of experimental autoimmune
  • FIG.8A shows Compound A improves fed blood glucose over time without altering body weight in db/db mice. (* p ⁇ 0.05)
  • FIG.8B shows Compound A improves fed blood glucose over time without altering body weight in db/db mice.
  • FIG.9A shows Compound A improves fasted blood glucose without altering body weight in db/db mice at 8 weeks of dosing. (* p ⁇ 0.05)
  • FIG.9B shows Compound A improves fasted blood glucose without altering body weight in db/db mice at 8 weeks of dosing.
  • FIG 10A shows effect of Compound A on food intake and body weight in obese, high fat diet-fed mice. (* p ⁇ 0.05; ** p ⁇ 0.001)
  • FIG 10B shows effect of Compound A on food intake and body weight in obese, high fat diet-fed mice. (**p ⁇ 0.001)
  • FIG.11A shows subcutaneous pancreatic tumor model with Compound A alone or in combination with anti-PD1.
  • FIG.11B shows subcutaneous bladder tumor model with Compound A alone or in combination with anti-PD1.
  • FIG.12A shows the percentage of mice without severe dermatitis over time. After weaning mice received daily in-diet dosing with Compound A or control diet as indicated and were monitored for development of dermatitis.
  • FIG.12B shows the percentage of mice without severe dermatitis over time. Once mice developed clinical signs of dermatitis (about 6 weeks of age), mice received daily in- diet dosing with Compound A or control diet as indicated and were monitored for development of severe dermatitis.
  • FIG.13 shows an Oak Ridge Thermal Ellipsoid Plot (ORTEP), a representation of molecular structure as determined by X-ray diffraction, of 6-((3R,4S)-4-((S)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide.
  • ORTEP Oak Ridge Thermal Ellipsoid Plot
  • This invention relates to compounds of Formulas (I) and (II) as defined above or pharmaceutically acceptable salts thereof.
  • this invention relates to compounds of Formula (I) wherein: R 1 is furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl,
  • the invention relates to compounds of Formula (I) wherein R 1 is oxadiazolyl, thiadiazolyl, or pyrimidinyl, wherein said oxadiazolyl, thiadiazolyl, or pyrimidinyl is optionally substituted by one or two substituents independently selected from (C 1 -C 4 )alkyl, -CONH 2 , (C 1 -C 4 )alkylNH-CO-, ((C 1 -C 4 )alkyl)((C 1 -C 4 )alkyl)N-CO-, (C 1 - C4)alkyl-SO-, and (C1-C4)alkyl-SO2-.
  • the invention relates to compounds of Formula (I) wherein R 1 is oxadiazolyl, thiadiazolyl, or pyrimidinyl, wherein said oxadiazolyl, thiadiazolyl, or pyrimidinyl is optionally substituted by one substitutent selected from methyl, - another embodiment, the invention relates to compounds of Formula (I) wherein R 1 is pyrimidinyl, wherein said pyrimidinyl is optionally substituted by one substituent selected from -CONH2, CH3NHCO-, (CH3)2NCO-, CH3-SO-, and CH3-SO2-.
  • the invention relates to compound of Formula (I) wherein R 1 is oxadiazolyl, wherein oxadiazolyl is substituted once by methyl.
  • the invention relates to compounds of Formula (I) wherein R 1 is pyrimidinyl, wherein said pyrimidinyl is substituted once by (CH3)2NCO-.
  • the invention relates to compounds of Formula (I) wherein R 1 is pyrimidinyl, wherein said pyrimidinyl is substituted once by (CH3)NHCO-.
  • the invention relates to componds of Formula (I) wherein R 1 is pyrimidinyl, wherein said pyrimidinyl is substituted once by -CONH2.
  • this invention relates to compounds of Formula (I) wherein R 2 is phenyl, wherein said phenyl is optionally substituted by two or three halogens. In another embodiment, this invention relates to compounds of Formula (I) wherein R 2 is phenyl, wherein said phenyl is optionally substituted by two or three fluoros. In another embodiment, this invention relates to compounds of Formula (I) wherein R 2 is phenyl, wherein said phenyl is substituted by two or three fluoros. In a specific embodiment, this invention relates to compounds of Formula (I) wherein R 2 is phenyl, wherein said phenyl is substituted by two fluoros. In yet another specific embodiment, this invention relates to compounds of Formula (I) wherein R 2 is phenyl, wherein said phenyl is substituted by three fluoros.
  • this invention relates to compounds of Formula (I) wherein each R 3 is independently selected from hydrogen, halogen, (C 1 -C 4 )alkyl, wherein at least one R 3 is not hydrogen. In yet another embodiment, this invention relates to compounds of Formula (I) wherein each R 3 is independently selected from hydrogen, fluoro, or methyl, wherein at least one R 3 is not hydrogen. In a specific embodiment, this invention relates to compounds of Formula (I) wherein each R 3 is independently selected from hydrogen and fluoro, wherein at least one R 3 is not hydrogen. In a specific embodiment, this invention relates to compounds of Formula (I) wherein each R 3 is independently selected from hydrogen and methyl, wherein at least one R 3 is not hydrogen.
  • said 5-6 membered heteroaryl is optionally substituted by 1 or 2 substituents selected from (C 1 -C 4 )alkyl, -CONH 2 , (C 1 -C 4 )alkylNHCO-, ((C 1 -C 4 )alkyl)((C 1 - C4)alkyl)NCO-, (C1-C4)alkyl-SO-, and (C1-C4)alkyl-SO2-;
  • R 2 is phenyl, wherein said phenyl optionally substituted by one, two, or three halogens;
  • each R 3 is independently selected from hydrogen, halogen, (C 1 -C 4 )alkyl, and -(C 2 - C4)alkenyl,
  • R 1 and R 3 taken together with the atoms to which they are attached, form a 5-6 membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by
  • this invention relates compounds of Formula (I) wherein: R 1 is 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl is optionally substituted by 1 or 2 substituents selected from (C 1 -C 4 )alkyl, -CONH 2 , (C 1 -C 4 )alkyl-NHCO-, ((C1-C4)alkyl)((C1-C4)alkyl)NCO-, (C1-C4)alkyl-SO-, and (C1-C4)alkyl-SO2-;
  • R 2 is phenyl, wherein said phenyl optionally substituted by one, two, or three halogens;
  • each R 3 is independently selected from hydrogen, halogen, (C 1 -C 4 )alkyl, and
  • R 1 and R 3 taken together with the atoms to which they are attached, form a 5-6 membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by
  • R 3 groups taken together with the atoms to which they are attached, form a 4-, 5-, 6-, or 7-membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; and wherein at least one R 3 is not hydrogen.
  • this invention relates compounds of Formula (I) wherein: R 1 is 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl is optionally substituted by 1 or 2 substituents selected from (C 1 -C 4 )alkyl, -CONH 2 ,
  • R 2 is phenyl, wherein said phenyl optionally substituted by two or three halogens; each R 3 is independently selected from hydrogen, halogen, (C 1 -C 4 )alkyl, and
  • R 1 and R 3 taken together with the atoms to which they are attached, form a 5-6 membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by
  • this invention relates compounds of Formula (I) wherein: R 1 is oxadiazolyl, thiadiazolyl, or pyrimidinyl, wherein said oxadiazolyl, thiadiazolyl, or pyrimidinyl is optionally substituted by 1 or 2 substituents selected from (C 1 -C 4 )alkyl, - CONH2, (C1-C4)alkylNHCO-, ((C1-C4)alkyl)((C1-C4)alkyl)NCO-, (C1-C4)alkyl-SO-, and (C1- C 4 )alkyl-SO 2 -;
  • R 2 is phenyl, wherein said phenyl optionally substituted by two or three halogens; each R 3 is independently selected from hydrogen, halogen, (C 1 -C 4 )alkyl, and
  • R 1 and R 3 taken together with the atoms to which they are attached, form a 5-6 membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by
  • R 3 groups taken together with the atoms to which they are attached, form a 4-, 5-, 6-, or 7-membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; and wherein at least one R 3 is not hydrogen.
  • this invention relates to compounds of Formula (II) wherein: R 1 is furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl,
  • the invention relates to compounds of Formula (II) wherein R 1 is oxadiazolyl, thiadiazolyl, or pyrimidinyl, wherein said oxadiazolyl, thiadiazolyl, or pyrimidinyl is optionally substituted by one or two substituents independently selected from (C 1 -C 4 )alkyl, -CONH 2 , (C 1 -C 4 )alkylNH-CO-, ((C 1 -C 4 )alkyl)((C 1 -C 4 )alkyl)N-CO-, (C 1 - C4)alkyl-SO-, and (C1-C4)alkyl-SO2-.
  • the invention relates to compounds of Formula (II) wherein R 1 is oxadiazolyl, thiadiazolyl, or pyrimidinyl, wherein said oxadiazolyl, thiadiazolyl, or pyrimidinyl is optionally substituted by one substitutent selected from methyl, -CONH 2 , CH 3 NHCO-, (CH 3 ) 2 NCO-, CH 3 -SO-, and CH 3 -SO 2 -.
  • the invention relates to compounds of Formula (II) wherein R 1 is pyrimidinyl, wherein said pyrimidinyl is optionally substituted by one substituent selected from -CONH2, CH3NHCO-, (CH3)2NCO-, CH3-SO-, and CH3-SO2-.
  • the invention relates to compound of Formula (II) wherein R 1 is oxadiazolyl, wherein oxadiazolyl is substituted once by methyl.
  • the invention relates to compounds of Formula (II) wherein R 1 is pyrimidinyl, wherein said pyrimidinyl is substituted once by (CH3)2NCO-.
  • the invention relates to compounds of Formula (II) wherein R 1 is pyrimidinyl, wherein said pyrimidinyl is substituted once by (CH3)NHCO-.
  • the invention relates to componds of Formula (II) wherein R 1 is pyrimidinyl, wherein said pyrimidinyl is substituted once by -CONH2.
  • this invention relates to compounds of Formula (II) wherein R 2 is phenyl, wherein said phenyl is optionally substituted by two or three halogens. In another embodiment, this invention relates to compounds of Formula (II) wherein R 2 is phenyl, wherein said phenyl is optionally substituted by two or three fluoros. In another embodiment, this invention relates to compounds of Formula (II) wherein R 2 is phenyl, wherein said phenyl is substituted by two or three fluoros. In a specific embodiment, this invention relates to compounds of Formula (II) wherein R 2 is phenyl, wherein said phenyl is substituted by two fluoros. In yet another specific embodiment, this invention relates to compounds of Formula (II) wherein R 2 is phenyl, wherein said phenyl is substituted by three fluoros.
  • this invention relates to compounds of Formula (II) wherein each R 3 is independently selected from hydrogen, halogen, (C 1 -C 4 )alkyl, wherein at least one R 3 is not hydrogen. In yet another embodiment, this invention relates to compounds of Formula (II) wherein each R 3 is independently selected from hydrogen, fluoro, or methyl, wherein at least one R 3 is not hydrogen. In a specific embodiment, this invention relates to compounds of Formula (II) wherein each R 3 is independently selected from hydrogen and fluoro, wherein at least one R 3 is not hydrogen. In a specific embodiment, this invention relates to compounds of Formula (II) wherein each R 3 is independently selected from hydrogen and methyl, wherein at least one R 3 is not hydrogen. In one embodiment, this invention relates compounds of Formula (II) wherein:
  • R 2 is phenyl, wherein said phenyl optionally substituted by one, two, or three halogens;
  • each R 3 is independently selected from hydrogen, halogen, (C 1 -C 4 )alkyl, and -(C 2 - C4)alkenyl,
  • R 1 and R 3 taken together with the atoms to which they are attached, form a 5-6 membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by
  • this invention relates compounds of Formula (II) wherein: R 1 is 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl is optionally substituted by 1 or 2 substituents selected from (C 1 -C 4 )alkyl, -CONH 2 , (C 1 -C 4 )alkylNHCO-, ((C1-C4)alkyl)((C1-C4)alkyl)NCO-, (C1-C4)alkyl-SO-, and (C1-C4)alkyl-SO2-;
  • R 2 is phenyl, wherein said phenyl optionally substituted by one, two, or three halogens;
  • each R 3 is independently selected from hydrogen, halogen, (C 1 -C 4 )alkyl, and -(C2-C4)alkenyl,
  • R 1 and R 3 taken together with the atoms to which they are attached, form a 5-6 membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by
  • this invention relates compounds of Formula (II) wherein: R 1 is 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl is optionally substituted by 1 or 2 substituents selected from (C 1 -C 4 )alkyl, -CONH 2 ,
  • R 2 is phenyl, wherein said phenyl optionally substituted by two or three halogens; each R 3 is independently selected from hydrogen, halogen, (C 1 -C 4 )alkyl, and
  • R 1 and R 3 taken together with the atoms to which they are attached, form a 5-6 membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by
  • this invention relates compounds of Formula (II) wherein: R 1 is oxadiazolyl, thiadiazolyl, or pyrimidinyl, wherein said oxadiazolyl, thiadiazolyl, or pyrimidinyl is optionally substituted by 1 or 2 substituents selected from (C 1 -C 4 )alkyl, - CONH2, (C1-C4)alkylNHCO-, ((C1-C4)alkyl)((C1-C4)alkyl)NCO-, (C1-C4)alkyl-SO-, and (C1- C 4 )alkyl-SO 2 -;
  • R 2 is phenyl, wherein said phenyl optionally substituted by two or three halogens; each R 3 is independently selected from hydrogen, halogen, (C 1 -C 4 )alkyl, and
  • R 1 and R 3 taken together with the atoms to which they are attached, form a 5-6 membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by
  • R 3 is not hydrogen.
  • Specific compounds of this invention include:
  • this invention is directed to 6-((3R,4R)-4-((R)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide or a pharmaceutically acceptable salt thereof.
  • this invention is directed to 6-((3S,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide or a pharmaceutically acceptable salt thereof.
  • this invention is directed to 6-((3S,4S)-4-((R)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide or pharmaceutically acceptable salt thereof.
  • this invention is directed to 6-((3R,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide or a pharmaceutically acceptable salt thereof.
  • this invention is directed to 6-((3S,4R)-4-((S)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide or a pharmaceutically acceptable salt thereof.
  • this invention is directed to 6-((3S,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide or a pharmaceutically acceptable salt thereof.
  • this invention is directed to 6-((3R,4S)-4-((S)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide or a pharmaceutically acceptable salt thereof.
  • this invention is directed to 6-((3R,4S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide or a pharmaceutically acceptable salt thereof.
  • the present invention encompasses compounds of Formula (I) and Formula (II) as the free base or free acid and as pharmaceutically acceptable salts thereof.
  • the invention relates to compounds of Formula (I) and Formula (II) in the form of a free base.
  • the invention relates to compounds of Formula (I) and Formula (II) in the form of a free acid.
  • the invention relates to compounds of Formulas (I) and (II) in the form of a pharmaceutically acceptable salt.
  • the invention relates to compounds of the Examples in the form of a free base.
  • the invention relates to compounds of the Examples in the form of a a pharmaceutically acceptable salt.
  • references herein to a compound of Formula (I) or Formula (II), or a salt thereof includes a compound of Formula (I) or Formula (II) as a free base, acid, or as a salt thereof, for example as a pharmaceutically acceptable salt thereof.
  • the invention is directed to a compound of Formula (I) or Formula (II).
  • the invention is directed to a pharmaceutically acceptable salt of a compound of Formula (I) or Formula (II).
  • the invention is directed to a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof.
  • a salt of a compound of Formula (I) or Formula (II) is preferably pharmaceutically acceptable.
  • Suitable pharmaceutically acceptable salts can include acid or base addition salts.
  • salts include, amongst others, those described in Berge, J. Pharm. Sci., 66, 1-19, (1977) or those listed in P.H. Stahl and C.G. Wermuth, editors, Handbook of Pharmaceutical Salts; Properties, Selection and Use, Second Edition
  • Suitable pharmaceutically acceptable salts can include acid or base addition salts.
  • Such base addition salts can be formed by reaction of a compound of Formula (I) or Formula (II) (which, for example, contains a carboxylic acid or other acidic functional group) with the appropriate base, optionally in a suitable solvent such as an organic solvent, to give the salt which can be isolated by a variety of methods, including crystallisation and filtration.
  • Such acid addition salts can be formed by reaction of a compound of Formula (I) or Formula (II) (which, for example contains a basic amine or other basic functional group) with the appropriate acid, optionally in a suitable solvent such as an organic solvent, to give the salt which can be isolated by a variety of methods, including crystallisation and filtration.
  • Salts may be prepared in situ during the final isolation and purification of a compound of Formula (I) or Formula (II). If a basic compound of Formula (I) or Formula (II) is isolated as a salt, the corresponding free base form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic base, suitably an inorganic or organic base having a higher pK a than the free base form of the compound. Similarly, if a compound of Formula (I) or Formula (II) containing a carboxylic acid or other acidic functional group is isolated as a salt, the corresponding free acid form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic acid. This invention also provides for the conversion of one salt of a compound of this invention, e.g., a hydrochloride salt, into another salt of a compound of this invention, e.g., a sulfate salt.
  • salt formation may include 1, 2 or more equivalents of acid.
  • Such salts would contain 1, 2 or more acid counterions, for example, a dihydrochloride salt.
  • Stoichiometric and non-stoichiometric forms of a pharmaceutically acceptable salt of a compound of Formula (I) or Formula (II) are included within the scope of the invention, including sub-stoichiometric salts, for example where a counterion contains more than one acidic proton.
  • Representative pharmaceutically acceptable acid addition salts include, but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate,
  • benzenesulfonate (besylate), benzoate, bisulfate, bitartrate, butyrate, calcium edetate, camphorate, camphorsulfonate (camsylate), caprate (decanoate), caproate (hexanoate), caprylate (octanoate), cinnamate, citrate, cyclamate, digluconate, 2,5-dihydroxybenzoate, disuccinate, dodecylsulfate (estolate), edetate (ethylenediaminetetraacetate), estolate (lauryl sulfate), ethane-1,2-disulfonate (edisylate), ethanesulfonate (esylate), formate, fumarate, galactarate (mucate), gentisate (2,5-dihydroxybenzoate), glucoheptonate (gluceptate), gluconate, glucuronate, glutamate, glutarate
  • Representative pharmaceutically acceptable base addition salts include, but are not limited to, aluminium, 2-amino-2-(hydroxymethyl)-1,3-propanediol (TRIS), arginine, benethamine (N-benzylphenethylamine), benzathine (N,N’-dibenzylethylenediamine), bis-(2- hydroxyethyl)amine, bismuth, calcium, chloroprocaine, choline, clemizole (1-p chlorobenzyl- 2-pyrrolildine-1’-ylmethylbenzimidazole), cyclohexylamine, dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lepidine, lithium, lysine, magnesium, meglumine (N-methylglucamine), piperazine, piperidine, potassium, procaine, qui
  • salt formation may include 1, 2 or more equivalents of acid.
  • Such salts would contain 1, 2 or more acid counterions, for example, a diacetate or a dihydrochloride salt.
  • the compounds of Formulas (I) and (II), or a pharmaceutically acceptable salt thereof are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions.
  • the compounds of this invention may be particularly useful for the treatment of RIP1 kinase-mediated diseases or disorders.
  • RIP1 kinase-mediated diseases or disorders are diseases or disorders that are mediated by activation of RIP1 kinase, and as such, are diseases or disorders where inhibition of RIP1 kinase would provide benefit.
  • RIP1 kinase-mediated diseases or disorders are diseases or disorders that are mediated by activation of RIP1 kinase, and as such, are diseases or disorders where inhibition of RIP1 kinase would provide benefit.
  • Such RIP1 kinase-mediated diseases or disorders are diseases/disorders which are likely to be regulated at least in part by programmed necrosis, apoptosis or the production of inflammatory cytokines, particularly inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), psoriasis, retinal detachment, retinal degeneration, retinitis pigmentosa, macular degeneration, age- related macular degeneration, pancreatitis, atopic dermatitis, arthritis (including rheumatoid arthritis, spondyloarthritis, gout, juvenile idiopathic arthritis (systemic onset juvenile idiopathic arthritis (SoJIA)), psoriatic arthritis), l
  • cisplatin acute kidney injury (AKI)) Celiac disease, autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP), transplant rejection (rejection of transplant organs, tissues and cells), ischemia reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome (SIRS), cerebrovascular accident (CVA, stroke), myocardial infarction (MI), atherosclerosis, Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), neonatal brain injury, neonatal hypoxic brain injury, ischemic brain injury, traumatic brain injury allergic diseases (including asthma and atopic dermatitis), peripheral nerve injury, burns, multiple sclerosis, type I diabetes, type II diabetes, obesity, Wegener’s granulomatosis, pulmonary sarcoidosis, Behcet’s disease, interleukin-1 converting enzyme (ICE, also known as caspase-
  • mycobacterium (tuberculosis)), and Lysosomal storage diseases (particularly, Gaucher disease, and including GM2 gangliosidosis, alpha-mannosidosis, aspartylglucosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis, infantile free sialic acid storage disease, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidoses disorders, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinoses, Pompe disease, pycnodysostosis, Sandhoff disease,
  • NSCLC nerve cell induced necrosis
  • ischemic kidney damage ischemic kidney damage
  • ophthalmologic ischemia ischemic ischemia
  • intracerebral hemorrhage ischemic kidney damage
  • subarachnoid hemorrhage ischemic kidney damage
  • acute liver failure ischemic kidney damage
  • radiation protection/mitigation auditory disorders such as noise-induced hearing loss and drugs associated with ototoxicity such as cisplatin, or for the treatment of cells ex vivo to preserve vitality and function.
  • the compounds of the invention may be particularly useful for the treatment of the following RIP1 kinase-mediated diseases or disorders: inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), psoriasis, retinal detachment, retinal degeneration, retinitis pigmentosa, macular degeneration, age-related macular degeneration, pancreatitis, atopic dermatitis, arthritis (including rheumatoid arthritis, spondyloarthritis, gout, systemic onset juvenile idiopathic arthritis (SoJIA), psoriatic arthritis), lupus, systemic lupus erythematosus (SLE), Sjogren’s syndrome, systemic scleroderma, anti-phospholipid syndrome (APS), vasculitis, osteoarthritis, liver
  • inflammatory bowel disease including Crohn’s disease and ulcerative colitis
  • psoriasis retinal detachment
  • retinal degeneration retin
  • non-alcohol steatohepatitis NASH
  • alcohol steatohepatitis ASH
  • autoimmune hepatitis autoimmune hepatobiliary diseases
  • primary sclerosing cholangitis PSC
  • acetaminophen toxicity hepatotoxicity
  • non-alcholic steatohepatitis NASH
  • ASH alcoholic steatohepatitis
  • NAFLD non-alcoholic fatty liver disease
  • kidney damage/injury nephritis, renal transplant, surgery, administration of nephrotoxic drugs e.g.
  • cisplatin acute kidney injury (AKI)) Celiac disease, autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP), transplant rejection (rejection of transplant organs, tissues and cells), ischemia reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome (SIRS), cerebrovascular accident (CVA, stroke), myocardial infarction (MI), atherosclerosis, Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), neonatal brain injury, neonatal hypoxic brain injury, traumatic brain injury, allergic diseases (including asthma and atopic dermatitis), peripheral nerve injury, burns, multiple sclerosis, type I diabetes, type II diabetes, obesity, Wegener’s granulomatosis, pulmonary sarcoidosis, Behcet’s disease, interleukin-1 converting enzyme (ICE, also known as caspase- 1) associated fever syndrome,
  • NEMO-mutations mutantations of NF-kappa-B essential modulator gene (also known as IKK gamma or IKKG)), particularly, NEMO-deficiency syndrome, HOIL-1 deficiency ((also known as RBCK1) heme-oxidized IRP2 ubiquitin ligase-1 deficiency), linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome, hematological and solid organ malignancies, bacterial infections and viral infections (such as influenza, staphylococcus, and mycobacterium (tuberculosis)), and Lysosomal storage diseases (particularly, Gaucher disease, and including GM2 gangliosidosis, alpha-mannosidosis, aspartylglucosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A de
  • the compounds of the invention may be particularly useful for the treatment of the following RIP1 kinase-mediated diseases or disorders, that is,
  • diseases/disorders which are likely to be regulated at least in part by RIP1 kinase activity, particularly inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), asthma, cigarette smoke-induced damage, cystic fibrosis, psoriasis, retinal detachment, retinal degeneration, retinitis pigmentosa, macular degeneration, atopic dermatitis, burn injury, periodontitis, a bacterial or viral infection (an infection with a pathogen including but not limited to influenza, staphylococcus, and/or mycobacterium (tuberculosis), systemic scleroderma (particularly, topical treatment of hardened and/or tightened skin areas), and/or ischemia reperfusion injury of solid organs/transplant rejection (particularly, topical treatment of donor organ (particularly kidney, liver, and heart and/or lung transplants), infusion of organ recipient), and
  • the compounds of the invention may be useful for the treatment of glaucoma.
  • the compounds of the invention may be particularly useful for treatment of pancreatic ductal adenocarcinoma, hepatocellular carcinoma, mesothelioma, or melanoma.
  • the compounds of the invention, particularly the compounds of Formulas (I) and (II), or a pharmaceutically acceptable salt thereof may be particularly useful for the treatment of the following RIP1 kinase-mediated disease or disorder: rheumatoid arthritis, inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), and psoriasis.
  • the treatment of the above-noted diseases/disorders may concern, more specifically, the amelioration of organ injury or damage sustained as a result of the noted
  • the compounds of this invention may be particularly useful for amelioration of brain tissue injury or damage following ischemic brain injury or traumatic brain injury, or for amelioration of heart tissue injury or damage following myocardial infarction, or for amelioration of brain tissue injury or damage associated with Huntington’s disease, Alzheimer’s disease or Parkinson’s disease, or for amelioration of liver tissue injury or damage associated with non-alcohol steatohepatitis, alcohol steatohepatitis, autoimmune hepatitis autoimmune hepatobiliary diseases, or primary sclerosing cholangitis, or overdose of acetaminophen.
  • the compounds of this invention may be particularly useful for the amelioration of organ injury or damage sustained as a result of radiation therapy, or amelioration of spinal tissue injury or damage following spinal cord injury or amelioration of liver tissue injury or damage associated acute liver failure.
  • the compounds of this invention may be particularly useful for amelioration of auditory disorders, such as noise-induced hearing loss or auditory disorders following the administration of ototoxic drugs or substances e.g. cisplatin.
  • the compounds of this invention may be particularly useful for amelioration of solid organ tissue (particularly kidney, liver, and heart and/or lung) injury or damage following transplant or the administration of nephrotoxic drugs or substances e.g. cisplatin.
  • amelioration of such tissue damage may be achieved where possible, by pre- treatment with a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof; for example, by pre-treatment of a patient prior to administration of cisplatin or pre-treatment of an organ or the organ recipient prior to transplant surgery.
  • Amelioration of such tissue damage may be achieved by treatment with a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, during transplant surgery.
  • Amelioration of such tissue damage may also be achieved by short-term treatment of a patient with a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, after transplant surgery.
  • the compounds of the invention may be useful for the treatment of retinal detachment, macular degeneration, and retinitis pigmentosa.
  • the compounds of the invention may be useful for the treatment of multiple sclerosis.
  • the compounds of the invention may be useful for the treatment of traumatic brain injury.
  • the compounds of the invention may be useful for the treatment of Huntington's Disease, Alzheimer's Disease, amyotrophic lateral sclerosis, and Niemann-Pick disease.
  • the compounds of the invention may be useful for the treatment of amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), and Alzheimer’s disease.
  • ALS amyotrophic lateral sclerosis
  • PSP progressive supranuclear palsy
  • Alzheimer’s disease amyotrophic lateral sclerosis
  • the compounds of the invention may be useful for the treatment of age-related macular degeneration.
  • the treatment of retinal detachment, macular degeneration, retinitis pigmentosa, multiple sclerosis, traumatic brain injury, Huntington's Disease, Alzheimer's Disease, amyotrophic lateral sclerosis, and Niemann-Pick disease may concern, more specifically, the amelioration of organ injury or damage sustained as a result of these diseases/disorders.
  • the compounds of this invention may be particularly useful for amelioration of brain tissue injury or damage following traumatic brain injury, or for amelioration of brain tissue injury or damage associated of Huntington's Disease, Alzheimer's Disease, amyotrophic lateral sclerosis, and Niemann-Pick disease.
  • the compounds of the invention may be useful for the treatment of retinal detachment, macular degeneration, and retinitis pigmentosa, and the amelioration of brain tissue injury or damage as a result of multiple sclerosis, traumatic brain injury, Huntington's Disease, Alzheimer's Disease, amyotrophic lateral sclerosis, and Niemann-Pick disease.
  • the compounds of the invention, particularly the compounds of Formulas (I) and (II), or a pharmaceutically acceptable salt thereof may be useful for the treatment of Crohn’s disease, ulcerative colitis, psoriasis, rheumatoid arthritis,
  • SoJIA systemic onset juvenile idiopathic arthritis
  • the compounds of this invention may be useful for the treatment of psoriasis, rheumatoid arthritis, and ulcerative and colitis.
  • the compounds of this invention may be useful for the treatment of lupus, inflammatory bowel disease (IBD), Crohn’s disease, and ulcerative colitis.
  • the compounds of the invention may be useful for the treatment of cerebrovascular accident (CVA, stroke), Huntington’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), traumatic brain injury, multiple sclerosis, Gaucher disease, Niemann-Pick disease, and spinal cord injury.
  • CVA cerebrovascular accident
  • Huntington’s disease Alzheimer’s disease
  • amyotrophic lateral sclerosis (ALS) amyotrophic lateral sclerosis
  • traumatic brain injury multiple sclerosis
  • Gaucher disease Niemann-Pick disease
  • spinal cord injury spinal cord injury
  • the compounds of the invention may be useful for the treatment of amyotrophic lateral sclerosis (ALS).
  • ALS amyotrophic lateral sclerosis
  • the compounds of the invention may be useful for the treatment of multiple sclerosis.
  • the compounds of the invention may be useful for the treatment of pancreatic ductal adenocarcinoma (PDAC), metastasis, melanoma, breast cancer, non-small cell lung carcinoma (NSCLC), and radiation induced necrosis.
  • PDAC pancreatic ductal adenocarcinoma
  • NSCLC non-small cell lung carcinoma
  • the compounds of the invention may be useful for the treatment of pancreatic ductal adenocarcinoma (PDAC), metastasis, melanoma, breast cancer, and non-small cell lung carcinoma (NSCLC).
  • PDAC pancreatic ductal adenocarcinoma
  • NSCLC non-small cell lung carcinoma
  • the compounds of the invention may be useful for the treatment of pancreatic ductal adenocarcinoma (PDAC).
  • PDAC pancreatic ductal adenocarcinoma
  • the compounds of the invention, particularly the compounds of Formula (I) and Formula (II), or a pharmaceutically acceptable salt thereof may be useful for the treatment of intracerebral hemorrhage and subarachnoid hemorrhage.
  • the compounds of the invention may be useful for the treatment of type II diabetes and obesity.
  • the compounds of the invention may be useful for the treatment of atherosclerosis.
  • the compounds of the invention may be useful for the treatment of vasculitis.
  • the compounds of the invention may be useful for the treatment of burns.
  • the compounds of the invention may be useful for the treatment of ischemic kidney damage, ophthalmologic ischemia, intracerebral hemorrhage, and subarachnoid hemorrhage.
  • the compounds of the invention may be useful for the treatment of non-alcholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), autoimmune hepatitis, and non-alcoholic fatty liver disease (NAFLD).
  • NASH non-alcholic steatohepatitis
  • ASH alcoholic steatohepatitis
  • NAFLD non-alcoholic fatty liver disease
  • the compounds of the invention may be particularly useful for the treatment of the following RIP1 kinase-mediated diseases or disorders.
  • the human has a solid tumor.
  • the tumor is selected from head and neck cancer, gastric cancer, melanoma, renal cell carcinoma (RCC), esophageal cancer, non-small cell lung carcinoma (NSCLC), prostate cancer, colorectal cancer, ovarian cancer, pancreatic cancer, and pancreatic ductal adenocarcinoma.
  • the human has one or more of the following: colorectal cancer (CRC), esophageal cancer, cervical, bladder, breast cancer, head and neck cancer, ovarian cancer, melanoma, renal cell carcinoma (RCC), EC squamous cell carcinoma, non-small cell lung carcinoma, mesothelioma, prostate cancer, and pancreatic ductal adenocarcinoma.
  • CRC colorectal cancer
  • esophageal cancer cervical, bladder, breast cancer, head and neck cancer
  • ovarian cancer melanoma
  • RRCC renal cell carcinoma
  • EC squamous cell carcinoma non-small cell lung carcinoma
  • mesothelioma mesothelioma
  • prostate cancer pancreatic ductal adenocarcinoma
  • pancreatic ductal adenocarcinoma adenocarcinoma
  • the human has a liquid tumor such as diffuse large B cell lymphoma (DLBCL), multiple mye
  • the present disclosure also relates to a method for treating or lessening the severity of a cancer selected from: brain (gliomas), glioblastomas, astrocytomas, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, triple negative breast cancer, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, head and neck cancer (including squamous cell carcinoma of head and neck), kidney cancer, lung cancer (including lung squamous cell carcinoma, lung adenocarcinoma, lung small cell carcinoma, and non-small cell lung carcinoma), liver cancer (including hepatocellular carcinoma), melanoma, ovarian cancer, pancreatic cancer (including squamous pancreatic cancer), prostate cancer, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid cancer, lymphoblastic
  • leukemias such as chronic myelocytic leukemia, acute myelocytic leukemia, chronic lymphocytic leukemia and acute lymphocytic leukemia
  • plasma cell malignancies such as multiple myeloma, MGUS and Waldenstrom’s macroglobulinemia
  • lymphomas such as non- Hodgkin’s lymphoma, Hodgkin’s lymphoma; and the like.
  • the cancer may be any cancer in which an abnormal number of blast cells or unwanted cell proliferation is present or that is diagnosed as a hematological cancer, including both lymphoid and myeloid malignancies.
  • Myeloid malignancies include, but are not limited to, acute myeloid (or myelocytic or myelogenous or myeloblastic) leukemia (undifferentiated or differentiated), acute promyeloid (or promyelocytic or promyelogenous or promyeloblastic) leukemia, acute myelomonocytic (or myelomonoblastic) leukemia, acute monocytic (or monoblastic) leukemia, erythroleukemia and megakaryocytic (or
  • megakaryoblastic leukemia may be referred together as acute myeloid (or myelocytic or myelogenous) leukemia (AML).
  • Myeloid malignancies also include myeloproliferative disorders (MPD) which include, but are not limited to, chronic myelogenous (or myeloid) leukemia (CML), chronic myelomonocytic leukemia (CMML), essential thrombocythemia (or thrombocytosis), and polcythemia vera (PCV).
  • CML chronic myelogenous leukemia
  • CMML chronic myelomonocytic leukemia
  • PCV polcythemia vera
  • Myeloid malignancies also include myelodysplasia (or myelodysplastic syndrome or MDS), which may be referred to as refractory anemia (RA), refractory anemia with excess blasts (RAEB), and refractory anemia with excess blasts in transformation (RAEBT); as well as
  • MFS myelofibrosis
  • leukemias such as chronic myelocytic leukemia, acute myelocytic leukemia, chronic lymphocytic leukemia and acute lymphocytic leukemia
  • plasma cell malignancies such as multiple myeloma, MGUS and Waldenstrom’s macroglobulinemia
  • lymphomas such as non- Hodgkin’s lymphoma, Hodgkin’s lymphoma; and the like.
  • Hematopoietic cancers also include lymphoid malignancies, which may affect the lymph nodes, spleens, bone marrow, peripheral blood, and/or extranodal sites.
  • Lymphoid cancers include B-cell malignancies, which include, but are not limited to, B-cell non- Hodgkin’s lymphomas (B-NHLs).
  • B-NHLs may be indolent (or low-grade), intermediate- grade (or aggressive) or high-grade (very aggressive).
  • Indolent B cell lymphomas include follicular lymphoma (FL); small lymphocytic lymphoma (SLL); marginal zone lymphoma (MZL) including nodal MZL, extranodal MZL, splenic MZL and splenic MZL with villous lymphocytes; lymphoplasmacytic lymphoma (LPL); and mucosa-associated-lymphoid tissue (MALT or extranodal marginal zone) lymphoma.
  • FL follicular lymphoma
  • SLL small lymphocytic lymphoma
  • MZL marginal zone lymphoma
  • LPL lymphoplasmacytic lymphoma
  • MALT mucosa-associated-lymphoid tissue
  • Intermediate-grade B-NHLs include mantle cell lymphoma (MCL) with or without leukemic involvement, diffuse large cell lymphoma (DLBCL), follicular large cell (or grade 3 or grade 3B) lymphoma, and primary mediastinal lymphoma (PML).
  • High-grade B-NHLs include Burkitt’s lymphoma (BL), Burkitt-like lymphoma, small non-cleaved cell lymphoma (SNCCL) and lymphoblastic lymphoma.
  • B-NHLs include immunoblastic lymphoma (or immunocytoma), primary effusion lymphoma, HIV associated (or AIDS related) lymphomas, and post-transplant lymphoproliferative disorder (PTLD) or lymphoma.
  • B-cell malignancies also include, but are not limited to, chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), Waldenstrom’s macroglobulinemia (WM), hairy cell leukemia (HCL), large granular lymphocyte (LGL) leukemia, acute lymphoid (or lymphocytic or lymphoblastic) leukemia, and Castleman’s disease.
  • NHL may also include T-cell non-Hodgkin’s lymphoma s(T- NHLs), which include, but are not limited to T-cell non-Hodgkin’s lymphoma not otherwise specified (NOS), peripheral T-cell lymphoma (PTCL), anaplastic large cell lymphoma (ALCL), angioimmunoblastic lymphoid disorder (AILD), nasal natural killer (NK) cell / T- cell lymphoma, gamma/delta lymphoma, cutaneous T cell lymphoma, mycosis fungoides, and Sezary syndrome.
  • T- NHLs T-cell non-Hodgkin’s lymphoma s
  • T- NHLs T-cell non-Hodgkin’s lymphoma not otherwise specified
  • PTCL peripheral T-cell lymphoma
  • ALCL anaplastic large cell lymphoma
  • AILD angioimmunoblastic lymphoid disorder
  • NK nasal natural killer
  • Hematopoietic cancers also include Hodgkin’s lymphoma (or disease) including classical Hodgkin’s lymphoma, nodular sclerosing Hodgkin’s lymphoma, mixed cellularity Hodgkin’s lymphoma, lymphocyte predominant (LP) Hodgkin’s lymphoma, nodular LP Hodgkin’s lymphoma,and lymphocyte depleted Hodgkin’s lymphoma.
  • Hodgkin’s lymphoma or disease
  • classical Hodgkin’s lymphoma including classical Hodgkin’s lymphoma, nodular sclerosing Hodgkin’s lymphoma, mixed cellularity Hodgkin’s lymphoma, lymphocyte predominant (LP) Hodgkin’s lymphoma, nodular LP Hodgkin’s lymphoma,and lymphocyte depleted Hodgkin’s lymphoma.
  • LP lymphocyte predominant
  • Hematopoietic cancers also include plasma cell diseases or cancers such as multiple myeloma (MM) including smoldering MM, monoclonal gammopathy of undetermined (or unknown or unclear) significance (MGUS), plasmacytoma (bone, extramedullary), lymphoplasmacytic lymphoma (LPL), Waldenström’s Macroglobulinemia, plasma cell leukemia, and primary amyloidosis (AL).
  • MM multiple myeloma
  • MGUS monoclonal gammopathy of undetermined (or unknown or unclear) significance
  • MGUS monoclonal gammopathy of undetermined (or unknown or unclear) significance
  • plasmacytoma bone, extramedullary
  • LPL lymphoplasmacytic lymphoma
  • Waldenström’s Macroglobulinemia plasma cell leukemia
  • AL primary amyloidosis
  • Hematopoietic cancers may also include other cancers of additional hematopoietic cells
  • Tissues which include hematopoietic cells referred herein to as "hematopoietic cell tissues” include bone marrow; peripheral blood; thymus; and peripheral lymphoid tissues, such as spleen, lymph nodes, lymphoid tissues associated with mucosa (such as the gut-associated lymphoid tissues), tonsils, Peyer's patches and appendix, and lymphoid tissues associated with other mucosa, for example, the bronchial linings.
  • hematopoietic cell tissues include bone marrow; peripheral blood; thymus; and peripheral lymphoid tissues, such as spleen, lymph nodes, lymphoid tissues associated with mucosa (such as the gut-associated lymphoid tissues), tonsils, Peyer's patches and appendix, and lymphoid tissues associated with other mucosa, for example, the bronchial linings.
  • Treatment of RIP1-mediated disease conditions may be achieved using a compound of the invention, particularly a compound of Formula (I) or Formula (II), or a
  • compositions of the invention may be employed alone or in combination with one or more other therapeutic agents, e.g., pharmaceutically active compounds or biologic products (e.g., monoclonal antibodies).
  • Combination therapies according to the present invention thus comprise the administration of at least one compound of the invention, particularly a compound of Formula (I) or Formula (II), or a
  • Combination therapies according to the present invention comprise the administration of at least one compound of the invention, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, and at least one other therapeutic ally active agent, specifically one or two other therapeutically active agents, more specifically one other therapeutically active agent.
  • amelioration of tissue damage may be achieved by treatment with a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, and at least one other therapeutically active agent during transplant surgery.
  • Amelioration of tissue damage may also be achieved by short-term treatment of a patient with a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, and at least one other therapeutic ally active agent after transplant surgery.
  • Amelioration of tissue damage ex vivo that is ex vivo preservation of tissues, organs and cells may also be achieved by short-term treatment of tissues, organs and cells with a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, and at least one other therapeutic ally active agent, prior to or during transplant surgery.
  • the compound(s) of the invention particularly the compounds of Formula (I) and Formula (II), or pharmaceutically acceptable salts thereof, and the other therapeutic agent(s) may be administered together in a single pharmaceutical composition or separately and, when administered separately this may occur simultaneously or sequentially in any order.
  • the amounts of the compound(s) of the invention, particularly a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salts thereof, and the other therapeutic agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • a combination comprising a compound of the invention, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, together with one or more other therapeutic agents, specifically one or two other therapeutically active agents, more specifically one other therapeutically active agent.
  • a combination comprising 6-((S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3,3-dimethylpiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof, together with one or more other therapeutic agents, specifically one or two other therapeutically active agents, more specifically one other therapeutically active agent.
  • a combination comprising 6-((R)-4-((S)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3,3-dimethylpiperidin-1- yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof, together with one or more other therapeutic agents, specifically one or two other therapeutically active agents, more specifically one other therapeutically active agent.
  • a combination comprising 6-((S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H- pyrazole-1-carbonyl)-3,3-dimethylpiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof, together with one or more other therapeutic agents, specifically one or two other therapeutically active agents, more specifically one other therapeutically active agent.
  • a combination comprising 6- ((R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3,3- dimethylpiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof, together with one or more other therapeutic agents, specifically one or two other therapeutically active agents, more specifically one other therapeutically active agent.
  • a compound of the invention particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of the invention, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be used in combination with or include one or more other therapeutic agents, for example an anti-inflammatory agent and/or an anti-TNF agent.
  • compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. In other embodiments, the pharmaceutical compositions of the invention may comprise one or more additional therapeutic agents, specifically one or two other therapeutically active agents, more specifically one other therapeutically active agent.
  • a compound that inhibits RIP1 kinase may be administered in combination with other anti-inflammatory agents for any of the indications above, including oral or topical corticosteroids, anti-TNF agents, 5-aminosalicyclic acid and mesalamine preparations, hydroxycloroquine, thiopurines, methotrexate, cyclophosphamide, cyclosporine, calcineurin inhibitors, mycophenolic acid, mTOR inhibitors, JAK inhibitors, Syk inhibitors, anti-inflammatory biologic agents, including anti-IL6 biologics, anti-IL1 agents, anti-IL17 biologics, anti-CD22, anti-integrin agents, anti-IFNa, anti-CD20 or CD4 biologics and other cytokine inhibitors or biologics to T-cell or B-cell receptors or interleukins.
  • anti-inflammatory agents including anti-IL6 biologics, anti-IL1 agents, anti-IL17 biologics, anti-CD22, anti-integrin agents, anti-IFNa, anti
  • a compound that inhibits RIP1 kinase may be administered in combination with antiplatelets (e.g., aspirin, clopidogrel (Plavix®), dipyridamole (Persantine®), ticolpidine (Ticlid®); aspirin and omeprazole (Ysprala®)), anticoagulants (e.g., warfarin (Coumadin®), heparin®, dabigitran (Pradaxa®), apixaban (Eliquis®), rivaroxaban®), antihypertensives– diruetics (e.g., Hygroton®, Diuril®, Lasix®, Esidrix®, Hydrodiuril®, Microzide®, Lozol®, Mykrox®, Zaroxolyn®, Midarmar®, Aldactone®, Dy
  • antiplatelets e.g., aspirin, clopidogrel (Plavix®), dipyrid
  • a compound that inhibits RIP1 kinase may be administered in combination with a broad-spectrum antibiotic (such as vacomycin) or other anti-MRSA therapy (cefeprime (Maxipime®), piperacillin/tazobactam(Zosyn®), carbapenem (imipenem, meropenem, doripenem), quinolones (ciprofloxacin, levofloxacin, ofloxacin, moxifloxacin, etc.), or low dose steroids such as hydrocortisones.
  • a broad-spectrum antibiotic such as vacomycin
  • other anti-MRSA therapy cefeprime (Maxipime®)
  • piperacillin/tazobactam(Zosyn®) carbapenem (imipenem, meropenem, doripenem)
  • quinolones ciprofloxacin, levofloxacin, ofloxacin, moxifloxacin, etc.
  • a compound that inhibits RIP1 kinase may be administered in combination with vedolizumab (Entyvio®), alicaforsen, remestemcel-L (Prochymal®), etrolizumab, eldelumab, or bertilimumab.
  • a compound that inhibits RIP1 kinase may be administered in combination with ixekizumab, tildrakizumab (MK-3222), secukinumab (AIN457), Alefacept (Amevive®), calcipotriene and betamethasone dipropionate (Enstilar®), prednisone (Rayos®), tazorac topical gel, Methotrexate (Trexall®, Rheumatrex®, Folex PFS®, Otrexup®, Rasuvo®, Methotrexate LPF Sodium®), Cyclosporine®, fumaric acid, acitretin®, Tretinate®, UVA, UVB, Psoralen, coal tar, TNF inhibitors (Etanercept (Enbrel®), Infliximab (Remicade®
  • a compound that inhibits RIP1 kinase may be administered in combination with an antimicrobial agent, (such as chlorhexidine
  • an antibiotic such as doxycycline (Vibrox®, Periostat®, Monodox®, Oracea®, Doryx®, etc.), or minocycline (Dynacin®, Minocin®, Arestin®, Dynacin®, etc.).
  • a compound that inhibits RIP1 kinase may be administered in combination with an inhaled corticosteroid (ICS) such as fluticasone proprionate (Flovent®), fluticasone furoate (Veramyst®/Avamys®), beclomethasone dipropionate (QVAR®), budesonide (Pulmicort), trimcinolone acetonide (Azmacort®), flunisolide (Aerobid®), mometasone fuorate (Asmanex® Twisthaler®), or Ciclesonide (Alvesco®), a long acting beta agonist (LABA) such as formoterol fumarate (Foradil®), salmeterol xinafoate (Serevent®), indacaterol (Arcapta®Neohaler®); a combination of an inhaled corticosteroid (ICS) such as fluticasone proprionate (Flovent®), fluticasone fur
  • a short acting beta agonist such as salbutamol dry- powder inhalation, albuterol sulfate (ProAir®, Proventil HFA®, Ventolin HFA®, AccuNeb® Inhalation Solution), levalbuterol tartrate (Xopenex® HFA), an antimuscarinic agent such as ipratropium bromide (Atrovent® HFA); an antimuscarinic in combination with a beta-agonist such as ipratropium bromide/albuterol (Combivent® Respimat®); a long-acting muscarinic antagonist ((LAMA) such as umeclidinium bromide (Incruse®) or tiotropium bromide (Spiriva®HandiHaler; a combination of a LAMA and a LABA, such as umeclidinium bromide and vilanterol (Anoro®) a leukotriene
  • SABA short acting beta agonist
  • LAMA long-acting
  • masitinib protein tyrosine kinase inhibitor
  • AMG 853 CRTH2/D-prostanoid receptor antangonist
  • E004 epinephrine inhalation aerosol
  • reslizumab reslizumab
  • PDE combination phosphodiesterase
  • PDE PDE-3 and (PDE)-4 inhibitor
  • a compound that inhibits RIP1 kinase may be administered in combination with a LABA (such as salmeterol xinafoate (Serevent), aformoterol tartrate (Brovana®), formoterol fumarate inhalation powder (Foradil®), indacterol maleate (Arcapta® Neohaler®), a long-acting inhaled anticholinergic (or muscarinic antagonist, such as umeclidinium (Incruse Ellipta®), tiotropium bromide (Spiriva®), and aclidinium bromide (Tudorza® Pressair®), a phosphodiesterase (PDE-r) inhibitor (such as roflumilast, Daliresp®), a combination ICS/LABA (such as fluticasone furoate and vilante
  • a LABA such as salmeterol xinafoate (Serevent), aformote
  • SCH527123 a CXCR2 antagonist
  • NVA23-7 glycoprronium bromide
  • NVA149 glycoprronium bromide and indacaterol maleate
  • QVA149 Ultibro® Breezhaler®
  • a compound that inhibits RIP1 kinase may be administered in combination with an antimycobacterial agent (such as isoniazid (INH), ehambutol (Myambutol®), rifampin (Rifadin®), and pyrazinamide (PZA)) a bactericidal antibiotic (such as rifabutin (Mycobutin®) or rifapentine (Priftin®)), an aminoglycoside (Capreomycin®), a fluorquinolone (levofloxacin, moxifloxicin, ofloxacin), thioamide (ehionamide), cyclosporine (Sandimmune®), para-aminosalicyclic acid
  • an antimycobacterial agent such as isoniazid (INH), ehambutol (Myambutol®), rifampin (Rifadin®), and pyrazinamide (PZA)
  • a bactericidal antibiotic such as rifabut
  • a compound that inhibits RIP1 kinase may be administered in combination with an oral corticosteroid (such as prednisolone (Delatsone®, Orapred, Millipred, Omnipred, Econopred, Flo-Pred), an immunosuppressive agent (such as methotrexate (Rhuematrex®, Trexall®), cyclosporine (Sandimmune®), anti- thymocyte globulin (Atgam®), mycophenolate mofetil (CellCept®), cyclophosphamide (Cytoxan®), FK506 (tacrolimus), thalidomide (Thalomid®), chlorambucil (Leukeran®), azathioprine (Imuran®, Azasan®)), a calcium channel
  • an oral corticosteroid such as prednisolone (Delatsone®, Orapred, Millipred, Omnipre
  • nicardipine Cardene®
  • a topical emollient nitrogenglycerin ointment
  • an ACE inhibitor such as lisinopril (Zestril®, Prinivil®), diltaizem (Cardizem®, Cardizem SR®, Cardizem CD®, Cardia®, Dilacor®, Tiazac®)
  • a serotonin reuptake inhibitor such as fluoxetine (Prozac®)
  • an endothelin-1 receptor inhibitor such as bosentan (Tracleer®) or epoprostenol (Flolan®, Veletri®, Prostacyclin®)
  • an anti-fibrotic agent such as colchicines (Colcrys®), para-aminobenzoic acid (PABA), dimethyl sulfoxide (KMSO), and D-penicillamine (Cuprimine®, Depen®), interferon alpha and interferon gam
  • a compound that inhibits RIP1 kinase may be administered in combination with a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator (ivacftor (Kalydeco®)) a mucolytic agent (such as dornase alpha (Pulmozyme®)), pancreatic enzymes (such as Pancrelipase (Creon®, Pancreaze®, Ultresa®, Zenpep®)), a bronchodilator (such as albuterol (AccuNeb®, ProAir®, Proventil HFA®, VoSpire ER®, Ventolin HFA®)), an antibiotic (including inhaled, oral or parenteral, such as tobramycin solution for inhalation (TOBI®, Bethkis®, TOBI Podhaler®), aztreon
  • CFTR cystic fibrosis transmembrane conductance regulator
  • ivacftor ivacftor (K
  • a compound that inhibits RIP1 kinase may be administered in combination with a ciliary neurtotrophic growth factor (NT- 501-CNTF) or gene transfer agent, UshStat®.
  • NT- 501-CNTF ciliary neurtotrophic growth factor
  • UshStat® ciliary neurtotrophic growth factor
  • a compound that inhibits RIP1 kinase may be administered in combination with opthalmalic intravitreal injections (afibercept (Eylea®)) or with an anti-vascular endothelial growth factor (VEGF) inhibitor (such as ranibizumab (Lucentis®) or pegaptanib sodium (Macugen®)), a ciliary neurotrophic growth factor agent (NT501), iSONEP®, or bevacizumab (Avastin®).
  • VEGF anti-vascular endothelial growth factor
  • a compound that inhibits RIP1 kinase may be administered in combination with a trivalent (IIV3) inactivated influenza vaccine (such as Afluria®, Fluarix®, Flucelvax®, FluLaval®, Fluvirin®, Fluzone®), a quadrivalent (IIV4) inactivated influenza vaccine (such as Fluarix® Quadrivalent, Flulaval® Quadrivalent, Fluzone® Quadrivalent), a trivalent recombinant influenza vaccine (such as FluBlok®), a quadrivalent live attenuated influenza vaccine (such as FluMist® Quadrivalent), an antiviral agent (such as oseltamivir (Tamiflu®), zanamivir (Relenza®), rimantadine (Flumadine®), or amantadine (Symmetrel®)), or Fluad®, Fludase, Flua inactivated influenza vaccine (such as Afluria®, Fluarix®, Flucelvax®, FluLaval
  • a compound that inhibits RIP1 kinase may be administered in combination with an antibiotic (such as a b-Lactam cephalosporin (Duricef®, Kefzol®, Ancef®, Biocef®, etc.), nafcillin (Unipen®), a sulfonamide (sulfamethoxazolyl and trimethoprim (Bacrim®, Septra®,) sulfasalazine (Azulfidine®), acetyl sulfisoxazolyl (Gantrisin®, etc.), or vancomycin (Vancocin®)).
  • an antibiotic such as a b-Lactam cephalosporin (Duricef®, Kefzol®, Ancef®, Biocef®, etc.), nafcillin (Unipen®), a sulfonamide (sulfamethoxazolyl and trimethoprim (B
  • a compound that inhibits RIP1 kinase may be administered in combination with a high-dose corticosteroid (such as prednisone (Deltasone®), methylprednisolone (SoluMedrol®) etc.) a calcineurin inhibitor (such as cyclosporine (Sandimmune®, Neoral®, Gengraf®), tacrolimus (Prograf®, Astragraf XL®)), an mTor inhibitor (such as sirolimus (Rapamune®) or everolimus (Afinitor®)), an anti-proliferative agent (such as azathioprine (Imuran®, Azasan®), mycophenolate mofetil (CellCept®), or mycophenolate sodium (Myfortic®)), a monoclonal antibody (such as muromonab-CD3 (
  • a polyclonal anti-T-cell antibody such as anti-thymocyte gamma globulin-equine (Atgam®), or antithymocyte globulin-rabbit (Thymoglobulin®)
  • an anti-CD40 antagonist ASKP-1240
  • ASP015K JAK inhibitor
  • TOL101 anti-TCR murine mAb
  • a compound that inhibits RIP1 kinase may be administered in combination with a topical immunomodulator or calcineurin inhibitor (such as pimecrolimus (Elidel®) or tacrolimus ointment (Protopic®)), a topical corticosteroid (such as hydrocortizone (Synacort®, Westcort®), betamethasone (Diprolene®), flurandrenolide (Cordan®), fluticasone (Cutivate®), triamcinolone (Kenalog®), fluocinonide (Lidex®), and clobetasol (Temovate®)), an oral corticosteroid (such as hydrocortisone (Cortef®), methylprednisolone (Medrol®), or prednisolone (Pediapred®, Prelone®),
  • a topical immunomodulator or calcineurin inhibitor such as pimecrolimus (Elidel®) or tacrolimus o
  • a compound that inhibits RIP 1 kinase may be administered in combination with NSAIDs, DMARDs such as Sulfasalazine®,
  • Methotrexate® and corticosteroids; prednisolone delayed-release tablets (Rayos®), TNF inhibitors (Enbrel®, Remicade®, Humira® and Simponi®), or IL-17A (Cosentyx®).
  • sJIA systemic onset juvenile idiopathic arthritis
  • a compound that inhibits RIP 1 kinase particularly a compound of Formula (I) or Formula (II), or a
  • NSAIDs such as Celebrex®, diclofenac (Voltaran®), ibuprofen (Advil®, Motrin®), naproxen (Aleve, Naprosyn®), corticosteroids (prednisone, glucocorticoids), Methotrexate®, or biologics (ankinra (Kineret®), tocilizumab (Actemra®), canakinumab (ILARIS®)).
  • NSAIDs such as Celebrex®, diclofenac (Voltaran®), ibuprofen (Advil®, Motrin®), naproxen (Aleve, Naprosyn®), corticosteroids (prednisone, glucocorticoids), Methotrexate®, or biologics (ankinra (Kineret®), tocilizumab (Actemra®), canakinumab (ILARIS®)).
  • a compound that inhibits RIP 1 kinase may be administered in combination with analgesics and NSAIDs (acetaminophen, opioid narcotics (e.g., tramadol®, Vicodin®, Darvon®, Percocet®); ibuprofen and famotidine (Duexis®); Etadolac®; naproxen sodium (Naprelan®), diclofenac sodium topical solution (Pennsaid®); sodium hyaluronate (Supartz®); meloxicam (Vivlodex®, Mobic®);
  • opioid narcotics e.g., tramadol®, Vicodin®, Darvon®, Percocet®
  • ibuprofen and famotidine Duexis®
  • Etadolac® naproxen sodium (Naprelan®), diclofenac sodium topical solution (Pennsaid®); sodium hyaluronate (Su
  • a compound that inhibits RIP 1 kinase may be administered in combination with tetrabenazine (Xenazine®), antipsychotic drugs (haloperidol (Haldol®), chlorpromazine HCL (Thorazine®), risperidone (Risperdal®) and quetiapine (Seroquel®)), drugs to suppress chorea (amantadine, devetiracetam (Keppra®), clonazepam (Klonopin®)), antidepressants (citalopram (Celexa®, Lexapro®), fluoxetine (Prozac®, Sarafem®), sertraline (Zoloft®)), antipsychotics (quetiapine (Seroquel®), risperidone (Risperdal®),
  • a compound that inhibits RIP 1 kinase may be administered in combination with Donepzil hydrocholoride (Aricept®), Rivastigmine tartrate (Exelon®), caprylidene (Axona®), butoconazole nitrate 2% (Femstat 3®),
  • Galantamine hydrobromide (Razadyne®, Reminyl®), Memantine HCL (Namenda®), memantine hydrocholoride extended release + donepezil hydrochloride (Namzaric®), Solanezumab, beta-secretase with Merck (MK-8931), beta-secretase with Cerespir (CSP- 1103), or drugs that targets tau protein (AADvac1).
  • a compound that inhibits RIP 1 kinase may be administered in combination with a glutamate blocker (Riluzole (Rilutek®)).
  • a compound that inhibits RIP 1 kinase may be administered in combination with a edaravone (Radicava®, Radicut®).
  • a compound that inhibits RIP 1 kinase may be administered in combination with quinidine (Nuedexta®), anticholinergics (amitriptyline®, Artane®, scopolamine patch (Transderm Scop®)), sympathomimetics (pseudoephedrine), mucolytics (guaifenesin), or analgesics (tramadol (Ultram®); ketorolac (Toradol®); morphine; fentanyl patch (Duragesic®)).
  • quinidine Nuedexta®
  • anticholinergics amitriptyline®, Artane®, scopolamine patch (Transderm Scop®)
  • sympathomimetics pseudoephedrine
  • mucolytics guaifenesin
  • analgesics tramadol (Ultram®); ketorolac (Toradol®); morphine; fentanyl
  • a compound that inhibits RIP 1 kinase may be administered in combination with corticosteroids (prednisone,
  • Interferon Beta 1–A (Avonex®, Extavia®, Rebif®, Betaseron®), peginterferon beta-1A (Plegridy®), Glatiramer acetate (Copaxone®); glatiramer acetate (Glatopa® - generic equivalent of Copaxone); Dimethyl fumarate (Tecfidera®); Fingolimod (Gilenya®); teriflunomide (Aubagio®); dalfampridine (Ampyra®); daclizumab (Zinbryta); alemtuzumab (Lemtrada®); natalizumab (Tysabri®); or mitoxantrone hydrochloride (Novantrone®).
  • a compound that inhibits RIP 1 kinase may be administered in combination with enzyme replacement therapy (imiglucerase (Cerezyme®), velaglucerase alfa (VPRIV®), taliglucerase alfa (Elelyso®)) or substrate reduction therapy (miglustat (Zavesca®), eliglustat (Cerdelga®)).
  • enzyme replacement therapy imiglucerase (Cerezyme®), velaglucerase alfa (VPRIV®), taliglucerase alfa (Elelyso®)
  • substrate reduction therapy miglustat (Zavesca®), eliglustat (Cerdelga®)
  • a compound that inhibits RIP 1 kinase may be administered in combination with bone marrow transplant, enzyme replacement therapy, gene therapy, miglustat (Zavesca®), Arimoclomol (BRX-345), NCT02612129, Hydroxypropyl-beta-cyclodexin (HPbCD), NCT01747135, or
  • VTS-2702 Hydroxypropyl-b-cyclodextrin (VTS-2702) (NCT02534844).
  • a compound that inhibits RIP 1 kinase may be administered in combination with Tocilizumab (Actemra®), Arava, sulfasalazine delayed release tablets (Azulfidine EN-tabs®, Bextra, certolizumab pegol (Cimzia®), ibuprofen and famotidine (Duexis®), naproxen sodium (Etodolac®), adalimumab (Humira®), Kineret; etodolac (Lodine®), naproxen sodium (Naprelan), abatacept (Orencia), prednisone (Rayos®), inflimimab (Remicade®), golimuma (Simponi®), rofecoxib (Vioxx®), tofacitinib (
  • a compound that inhibits RIP 1 kinase may be administered in combination with alicafosen, Mesalamine (Asacol®), balsalazide disodium (Colazal®), vedolizumab (Entyvio®), golimumab (Simponi®), budesonide (Uceris®), adalimumab (Humira®), RG-7413 (alpha4beta7 integrin), CNTO- 1275 (ustekinumab), biosimiar infliximab (Remsima (Inflectra®)), BMS eldelumab (CXCL 10), or Immune Pharma bertilimumab (CCR3).
  • a compound that inhibits RIP 1 kinase may be administered in combination with Remestemcel-L (Prochymal®), vedolizumab (Entyvio®), ustekinumab (Stelara®), certolizumab pegol (Cimzia®), natalizumab (Tysabri®), budesonide (Entocort EC®), anti-inflammatories (mesalamine (Lialda®, Apriso®, Canasa®, Asacol®, Rowasa®), sulfasalazine (Azulfidine®)), steroids (hydrocortisone, prednisone), immunosuppressants (methotrexate (Trexall®, Rasuvo®, Rheumatrex®), infliximab (Remicade®), azathi
  • the at least one other therapeutically active agent is selected from a thrombolytic agent, a tissue plasminogen activator, an anticoagulant, and a platelet aggregation inhibitor.
  • the at least one other therapeutically active agent is selected from heparin, coumadin, clopidrogel, dipyridamole, ticlopidine HCL, eptifibatide, and aspirin.
  • the RIP1 kinase-mediated disease or disorder treated with these agents is a cerebrovascular accident.
  • the at least one other therapeutically active agent is selected from broad-spectrum antibiotic, anti-MRSA therapy and a low dose steroid.
  • the at least one other therapeutically active agent is selected from vacomycin, cefeprime, a combination of piperacillin and tazobactam, imipenem, meropenem, doripenem, ciprofloxacin, levofloxacin, ofloxacin, moxifloxacin, and hydrocortisone.
  • the RIP1 kinase-mediated disease or disorder treated with these agents is systemic inflammatory response syndrome.
  • the at least one other therapeutically active agent is alicaforse or remestemcel-L.
  • the RIP1 kinase-mediated disease or disorder treated with these agents is Crohn’s disease or ulcerative colitis.
  • the at least one other therapeutically active agent is ixekizumab, or tildrakizumab.
  • the RIP1 kinase-mediated disease or disorder treated with these agents is psoriasis.
  • the at least one other therapeutically active agent is an antimicrobial agent or an antibiotic. In another embodiment, the at least one other therapeutically active agent is selected from chlorhexidine, doxycycline and minocycline. In one embodiment, the RIP1 kinase-mediated disease or disorder treated with these agents is periodonitis.
  • the at least one other therapeutically active agent is selected from an inhaled corticosteroid, a long acting beta agonist, a combination of an inhaled corticosteroid and a long acting beta agonist, a short acting beta agonist, a leukotriene modifier, an anti-IgE, a methylxanthine bronchodilator, a mast cell inhibitor, and a long-acting muscarinic antagonist.
  • the at least one other therapeutically active agent is selected from fluticasone proprionate, beclomethasone dipropionate, budesonide, trimcinolone acetonide, flunisolide, mometasone fuorate, or ciclesonide, formoterol fumarate, salmeterol xinafoate, a combination of fluticasone furoate and vilanterol, a combination of formoterol and budesonide inhalation, a combination of beclomethasone dipropionate and formoterol, a combination of fluticasone propionate and salmeterol, albuterol sulfate, levalbuterol tartrate, a combination of ipratropium bromide and albuterol, ipratropium bromide, montelukast sodium, zafirlukast, zileuton, omalizumab theophylline, cromulyn sodium, nedocromil sodium
  • the at least one other therapeutically active agent is selected from protein tyrosine kinase inhibitor, a CRTH2/D-prostanoid receptor antangonist, an epinephrine inhalation aerosol, and a combination of a phosphodiesterase-3 inhibitor and a phosphodiesterase-4 inhibitor.
  • the at least one other therapeutically active agent is selected from masitinib, AMG 853, indacaterol, E004, a combination of fluticasone furoate and fluticasone proprionate, a combination of vinanterol fluticasone furoate, a combination of fluticasone propionate and eformoterol fumarate dehydrate, reslizumab, salbutamol, tiotropium bromide, a combination of formoterol and budesonide, fluticasone furoate, VR506, lebrikizumab, and RPL554.
  • the RIP1 kinase-mediated disease or disorder treated with these agents is asthma.
  • the at least one other therapeutically active agent is selected from a long acting beta agonist, a long-acting inhaled anticholinergic or muscarinic antagonist, a phosphodiesterase inhibitor, a combination an inhaled corticosteroid long acting beta agonist, a short acting beta agonist, and an inhaled corticosteroid.
  • a long acting beta agonist a long-acting inhaled anticholinergic or muscarinic antagonist
  • a phosphodiesterase inhibitor a combination an inhaled corticosteroid long acting beta agonist, a short acting beta agonist, and an inhaled corticosteroid.
  • the at least one other therapeutically active agent is selected from salmeterol xinafoate, a combination of umeclidinium and vilanterol, umeclidinium, aformoterol tartrate, formoterol fumarate, indacterol maleate, a combination of fluticasone propionate and eformoterol fumarate dehydrate, tiotropium bromide, aclidinium bromide, roflumilast, a combination of fluticasone furoate and vilanterol, a combination of fluticasone propionate and salmeterol, a combination of budesonide and formoterol, a combination of mometasone and formoterol, a combination of ipratropium bromide and albuterol sulfate, a combination of albuterol and ipratropium, ipratropium bromide, albuterol sulfate, budesonide, fluticasone propionat
  • the at least one other therapeutically active agent is selected from SCH527123, glycoprronium bromide, a combination of glycopyrronium bromide and indacaterol maleate, a combination of glycopyrrolate and formoterol fumarate, indacaterol maleate, olodaterol, tiotropium, olodaterol, and a combination of aclidinium and formoterol.
  • the RIP1 kinase-mediated disease or disorder treated with these agents is COPD.
  • the at least one other therapeutically active agent is an antimycobacterial agent or a bactericidal antibiotic.
  • the at least one other therapeutically active agent is selected from isoniazid, ehambutol, rifampin, pyrazinamide, rifabutin, rifapentine, capreomycin, levofloxacin, moxifloxicin, ofloxacin, ehionamide, cycloserine, kanamycin, streptomycin, viomycin, bedaquiline fumarate, PNU- 100480, and delamanid.
  • the RIP1 kinase-mediated disease or disorder treated with these agents is a mycobacterium infection.
  • the at least one other therapeutically active agent is selected from an oral corticosteroid, anti-thymocyte globulin, thalidomide, chlorambucil, a calcium channel blocker, a topical emollient, an ACE inhibitor, a serotonin reuptake inhibitor, an endothelin-1 receptor inhibitor, an anti-fibrotic agent, a proton-pump inhibitor or imatinib, ARG201, and tocilizumab.
  • the at least one other therapeutically active agent is selected from prednisolone, anti-thymocyte globulin, FK506 (tacrolimus), thalidomide, chlorambucil, nifedipine, nicardipine, nitroglycerin ointment, lisinopril, diltaizem, fluoxetine, bosentan, epoprostenol, colchicines, para-aminobenzoic acid, dimethyl sulfoxide, D-penicillamine, interferon alpha, interferon gamma (INF-g)), omeprazole, metoclopramide, lansoprazole, esomeprazole, pantoprazole, rabeprazole, imatinib, ARG201, and tocilizumab.
  • the RIP1 kinase-mediated disease or disorder treated with these agents is systemic scleroderma.
  • the at least one other therapeutically active agent is selected from a cystic fibrosis transmembrane conductance regulator potentiator, a mucolytic agent, pancreatic enzymes, a bronchodilator, an antibiotic, or ivacftor/lumacaftor, ataluren, and tiopropium bromide.
  • the at least one other therapeutically active agent is selected from a cystic fibrosis transmembrane conductance regulator potentiator, a mucolytic agent, pancreatic enzymes, a bronchodilator, an antibiotic, or ivacftor/lumacaftor, ataluren, and tiopropium bromide.
  • the at least one other therapeutically active agent is selected from a cystic fibrosis transmembrane conductance regulator potentiator, a mucolytic agent, pancreatic enzymes, a bronchodilator, an antibiotic, or ivacftor/lumacaftor
  • therapeutically active agent is selected from ivacftor, dornase alpha, pancrelipase, albuterol, tobramycin, aztreonam, colistimethate sodium, cefadroxil monohydrate, cefazolin, cephalexin, cefazolin, moxifloxacin, levofloxacin, gemifloxacin, azithromycin, gentamicin,
  • the RIP1 kinase-mediated disease or disorder treated with these agents is cystic fibrosis.
  • the at least one other therapeutically active agent is a ciliary neurtotrophic growth factor or a gene transfer agent.
  • the at least one other therapeutically active agent is NT-501-CNTF or a gene transfer agent encoding myosin VIIA (MY07A).
  • the RIP1 kinase-mediated disease or disorder treated with these agents is retinitis pigmentosa.
  • the at least one other therapeutically active agent is selected from opthalmalic intravitreal injections, an anti-vascular endothelial growth factor inhibitor, and a ciliary neurotrophic growth factor agent.
  • the at least one other therapeutically active agent is selected from afibercept, ranibizumab, pegaptanib sodium, NT501, humanized sphingomab, and bevacizumab.
  • the RIP1 kinase-mediated disease or disorder treated with these agents is macular degeneration.
  • the at least one other therapeutically active agent is selected from a trivalent (IIV3) inactivated influenza vaccine, a quadrivalent (IIV4) inactivated influenza vaccine, a trivalent recombinant influenza vaccine, a quadrivalent live attenuated influenza vaccine, an antiviral agent, or inactivated influenza vaccine.
  • the at least one other therapeutically active agent is selected from oseltamivir, zanamivir, rimantadine, or amantadine.
  • the RIP1 kinase-mediated disease or disorder treated with these agents is influenza.
  • the at least one other therapeutically active agent is selected from a b-Lactam, nafcillin, sulfamethoxazolylm, trimethoprim, sulfasalazine, acetyl sulfisoxazolyl, and vancomycin.
  • the RIP1 kinase-mediated disease or disorder treated with these agents is a staphylococcus infection.
  • the at least one other therapeutically active agent is selected from a monoclonal antibody, a polyclonal anti-T-cell antibody, an anti-thymocyte gamma globulin-equine antibody, an antithymocyte globulin-rabbit antibody, an anti-CD40 antagonist, a JAK inhibitor, and an anti-TCR murine mAb.
  • the at least one other therapeutically active agent is selected from muromonab-CD3, ASKP-1240, ASP015K, and TOL101.
  • the RIP1 kinase-mediated disease or disorder treated with these agents is transplant rejection.
  • the at least one other therapeutically active agent is selected from a topical immunomodulator or calcineurin inhibitor, a topical corticosteroid, an oral corticosteroid, an interferon gamma, an antihistamine, or an antibiotic.
  • the at least one other therapeutically active agent is selected from pimecrolimus, tacrolimus, hydrocortizone, betamethasone, flurandrenolide, fluticasone, triamcinolone, fluocinonide, clobetasol, hydrocortisone, methylprednisolone, prednisolone, an interferon alpha protein, a recombinant synthetic type I interferon, interferon alpha-2a, interferon alpha- 2b, hydroxyzine, diphenhydramine, flucloxacillin, dicloxacillin, and erythromycin.
  • the RIP1 kinase-mediated disease or disorder treated with these agents is atopic dermatitis.
  • a compound that inhibits RIP 1 kinase may be administered to a patient in need thereof, in combination with at least one other therapy and/or with at least one other active therapeutic agent that is considered standard of care (U.S. Department of Health and Human Services, Agency for Healthcare Research and Quality, National Guideline Clearinghouse, https://www.guideline.gov/ and World Health Organization, http://www.who.int/management/quality/standards/en/) for any of the diseases and/or disorders recited herein.
  • a compound that inhibits RIP 1 kinase may be administered to a patient in need thereof, in combination with at least one other active therapeutic agent, wherein the at least one other active therapeutic agent is: a corticosteroid [administered orally, topically, by injection, or as a suppository; prednisone, methylprednisolone, prednisolone, budesonide, betamethasone, dexamethasone, hydrocortisone, triamcinolone, fluticasone (fluticasone furoate, fluticasone propionate), fludroxycortide (flurandrenolide, flurandrenolone), fluocinonide, clobetasol (clobetasol propionate)], an anti-TNF biologic agent (etanecerpt, adalimumab, infliximab, cert
  • mercaptopurine a JAK inhibitor
  • tofacitinib Baracitinib
  • NSAID aspirin
  • an anti-IL6 biologic agent tocilizumab
  • an anti-IL1 biologic agent anakinra, canakinumab, rilonacept
  • an anti-IL12 or IL23 biologic agent ustekinumab, risankizumab, guselkumab, tildrakizumab
  • an anti-CD6 biologic agent itolizumab
  • an anti-integrin agent natalizumab (Tysabri®), etrolizumab
  • an anti-IL17 biologic agent secukinumab, ixekizumab, brodalumab
  • an anti-CD22 biologic agent epratuzumab
  • an anti-CD20 biologic agent rituximab, ofatumumab
  • tacrolimus acitretin, fumaric acid, dimethyl fumarate, cyclophosphamide, cyclosporine (or ciclosporin), methotrexate, mycophenolic acid (or mycophenolate mofetil), topical vitamin D (calcipotriol or calcipotriene), an mTOR inhibitor (temsirolimus, everolimus), a Syk inhibitor (fostamatinib), an anti-IFNa biologic agent (sifalimumab), a retinoid (tazarotene), coal tar preparations, aryl hydrocarbon receptor agonist or modulating agent (tapinarof), hydroxyurea, 6-tioguanineor light therapy with or without psoralen.
  • mTOR inhibitor temsirolimus, everolimus
  • Syk inhibitor fostamatinib
  • an anti-IFNa biologic agent sifalimumab
  • a retinoid tazarotene
  • Examples of other active therapeutic agents that may be used in combination with a compound of this invention for the treatment of ulcerative colitis and/or Crohn’s disease include vedolizumab, etrolizumab, eldelumab, or bertilimumab.
  • biologic agents examples include abatacept, belimumab, and alicafosen.
  • active therapeutic agent examples include baracitinib and Remestemcel-L.
  • a compound that inhibits RIP 1 kinase may be administered to a pediatric or an adult patient in need thereof, in combination with at least one other therapy, for example, in combination with UVA and/or UVB phototherapy as indicated for the treatment of psoriasis.
  • a compound that inhibits RIP 1 kinase may be administered to reduce the signs and symptoms including body surface area, pruritis, nail disease, and scalp involvement, and to improve quality of life, in pediatric and/or adult patients with moderate to severe psoriasis.
  • a compound that inhibits RIP 1 kinase may be administered as initial treatment or after treatment with another agent in pediatric and/or adult patients with moderate to severe psoriasis.
  • a compound that inhibits RIP 1 kinase may be administered to maintain reductions in signs and symptoms and improvements in quality of life after treatment with another agent in pediatric and/or adult patients with moderate to severe psoriasis.
  • a compound that inhibits RIP 1 kinase may be administered for the treatment of moderately to severely active rheumatoid arthritis.
  • a compound that inhibits RIP 1 kinase may be administered to reduce the signs and symptoms, to induce a major clinical response, to inhibit the progression of structural damage, or to improve physical function in a patient, particularly an adult patient with moderately to severely active rheumatoid arthritis.
  • a compound that inhibits RIP 1 kinase in the treatment of rheumatoid arthritis, may be administered alone or in combination with methotrexate or other non- biologic disease-modifying anti-rheumatic drugs (DMARDs).
  • DMARDs non- biologic disease-modifying anti-rheumatic drugs
  • a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof may be administered alone or in combination with methotrexate, or corticosteroids in the treatment of rheumatoid arthritis.
  • a compound that inhibits RIP 1 kinase particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered to reduce the signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older.
  • a compound that inhibits RIP 1 kinase particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered alone or in combination with methotrexate.
  • a compound that inhibits RIP 1 kinase may be administered to reduce the signs and symptoms, inhibiting the progression of structural damage, of active arthritis, and/or to improve physical function in adult patients with psoriatic arthritis.
  • a compound that inhibits RIP 1 kinase may be administered alone or in combination with methotrexate, corticosteroids, or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs).
  • DMARDs non-biologic disease-modifying anti-rheumatic drugs
  • a compound that inhibits RIP 1 kinase may be administered alone or in combination with methotrexate for the treatment of psoriatic arthritis.
  • a compound that inhibits RIP 1 kinase may be administered to a patient, particularly an adult patient with moderate to severe chronic plaque psoriasis, who is a candidate for systemic therapy or phototherapy.
  • a compound that inhibits RIP 1 kinase may be administered to reduce the signs and symptoms of active ankylosing spondylitis in a patient, either an adult or a pediatric patient, in need thereof.
  • a compound that inhibits RIP 1 kinase may be administered alone or in combination with methotrexate, corticosteroids, or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs).
  • DMARDs non-biologic disease-modifying anti-rheumatic drugs
  • a compound that inhibits RIP 1 kinase may be administered to reduce the signs and symptoms of Crohn’s disease.
  • a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof may be administered to induce or maintain a clinical response (clinical remission) in a patient, particularly an adult patient with moderately to severely active Crohn’s disease.
  • a compound that inhibits RIP 1 kinase may be administered to reduce the signs and symptoms of Crohn’s disease.
  • a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof may be administered to induce or maintain a clinical response (clinical remission) in a patient, particularly a pediatric patient 6 years of age and older with moderately to severely active Crohn’s disease.
  • a compound that inhibits RIP 1 kinase may be administered to reduce the signs and symptoms of Crohn’s disease, particularly, moderately to severely active Crohn’s disease, in a patient who has had an inadequate response to corticosteroids or immunomodulators such as azathioprine, 6-mercaptopurine, or methotrexate.
  • a compound that inhibits RIP 1 kinase may be administered to treat a patient, particularly an adult patient or a pediatric patient 6 years and older, with moderately to severely active ulcerative colitis.
  • a compound that inhibits RIP 1 kinase may be administered to induce and/or sustain clinical remission in a patient, particularly an adult patient or a pediatric patient 6 years and older, with moderately to severely active ulcerative colitis.
  • a compound that inhibits RIP 1 kinase may be administered to induce and/or sustain a clinical response (clinical remission) in a patient, particularly a patient with moderately to severely active ulcerative colitis, who has had an inadequate response to immunosuppressants such as aminosalicylates, corticosteroids, azathioprine or 6- mercaptopurine (6-MP).
  • immunosuppressants such as aminosalicylates, corticosteroids, azathioprine or 6- mercaptopurine (6-MP).
  • a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof may be administered for the treatment of moderate to severe hidradenitis suppurativa.
  • a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof may be administered for the treatment of uveitis, particularly non-infectious intermediate, posterior and panuveitis, in a patient, particularly an adult patient, in need thereof.
  • one embodiment of this invention is directed to a method of inhibiting RIP1 kinase comprising contacting a cell with a compound of the invention.
  • Another embodiment of this invention is a method of inhibiting RIP1 kinase comprising contacting a cell with a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof.
  • a particular embodiment of this invention is to a method of inhibiting RIP1 kinase comprising contacting a cell with a compound of Formula (II) or Formula (II) or a pharmaceutically acceptable salt thereof.
  • the invention is directed to a method of treating a RIP1 kinase-mediated disease or disorder (for example, a disease or disorder recited herein) in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof.
  • the invention is directed to a method of treating a RIP1 kinase-mediated disease or disorder (for example, a disease or disorder recited herein) in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof.
  • the invention is directed to a method of treating a RIP1 kinase-mediated disease or disorder disclosed herein in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof.
  • the invention is directed to a method of treating a RIP1 kinase-mediated disease or disorder disclosed herein in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof.
  • the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof.
  • the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof.
  • the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of 6-((3R,4R)-4-((R)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide, or a pharmaceutically acceptable salt thereof.
  • the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of 6- ((3S,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide or a pharmaceutically acceptable salt thereof.
  • the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of 6-((3S,4S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H- pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide or a pharmaceutically acceptable salt thereof.
  • the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of 6-((3R,4R)-4-((S)-5-(3,5-difluorophenyl)- 4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof.
  • the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of 6-((3S,4R)-4-((S)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide, or a pharmaceutically acceptable salt thereof.
  • the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of 6- ((3S,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof.
  • the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of 6-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5- dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof.
  • the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of 6-((3R,4S)-4-((R)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide, or a pharmaceutically acceptable salt thereof.
  • the invention is directed to a method of treating a RIP1- mediated disease or disorder (for example, a disease or disorder recited herein) in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salt thereof, which further comprises at least one other therapeutically active agent.
  • a RIP1- mediated disease or disorder for example, a disease or disorder recited herein
  • the invention is directed to a method of treating a RIP1-mediated disease or disorder (for example, a disease or disorder recited herein) in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound disclosed herein, or pharmaceutically acceptable salt thereof, which further comprises at least one other therapeutically active agent.
  • a RIP1-mediated disease or disorder for example, a disease or disorder recited herein
  • a pharmaceutical composition comprising a compound disclosed herein, or pharmaceutically acceptable salt thereof, which further comprises at least one other therapeutically active agent.
  • the invention is directed to a method of treating a RIP1-mediated disease or disorder disclosed herein in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salt thereof, which further comprises at least one other therapeutically active agent.
  • the invention is directed to a method of treating a RIP1- mediated disease or disorder disclosed herein in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound disclosed herein, or pharmaceutically acceptable salt thereof, which further comprises at least one other therapeutically active agent.
  • the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salt thereof, which further comprises at least one other therapeutically active agent.
  • the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound disclosed herein, or pharmaceutically acceptable salt thereof, which further comprises at least one other therapeutically active agent.
  • the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of a 6- ((3R,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising 6-((3R,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5- dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or pharmaceutically acceptable salt thereof, which further comprises at least one other therapeutically active agent.
  • the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of a 6-((3S,4S)-4-((S)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising 6-((3S,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or pharmaceutically acceptable salt thereof, which further comprises at least one other therapeutically active agent.
  • the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of a 6-((3S,4S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)- 3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising 6-((3S,4S)-4-((R)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide, or pharmaceutically acceptable salt thereof, which further comprises at least one other therapeutically active agent.
  • the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of a 6-((3R,4R)-4-((S)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising 6-((3R,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)- 3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or pharmaceutically acceptable salt thereof, which further comprises at least one other therapeutically active agent.
  • the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of a 6-((3S,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)- 3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising 6-((3S,4R)-4-((S)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide, or pharmaceutically acceptable salt thereof, which further comprises at least one other therapeutically active agent.
  • the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of a 6-((3S,4R)-4-((R)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising 6-((3S,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)- 3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or pharmaceutically acceptable salt thereof, which further comprises at least one other therapeutically active agent.
  • the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of a 6-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)- 3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising 6-((3R,4S)-4-((S)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide, or pharmaceutically acceptable salt thereof, which further comprises at least one other therapeutically active agent.
  • the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of 6-((3R,4S)-4- ((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1- yl)pyrimidine-4-carboxamide, or pharmaceutically acceptable salt thereof, or a
  • composition comprising 6-((3R,4S)-4-((R)-5-(3,5-difluorophenyl)-4,5- dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or pharmaceutically acceptable salt thereof, which further comprises at least one other therapeutically active agent.
  • the invention is directed to a method of treating a RIP1 kinase-mediated disease or disorder (specifically, a disease or disorder recited herein) comprising administering a therapeutically effective amount of 6-((3R,4R)-4-((R)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide, or a pharmaceutically acceptable salt thereof, to a human in need thereof.
  • the invention is directed to a method of treating a RIP1 kinase- mediated disease or disorder (specifically, a disease or disorder recited herein) comprising administering a therapeutically effective amount of 6-((3S,4S)-4-((S)-5-(3,5-difluorophenyl)- 4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof, to a human in need thereof.
  • the invention is directed to a method of treating a RIP1 kinase-mediated disease or disorder (specifically, a disease or disorder recited herein) comprising administering a therapeutically effective amount of 6-((3S,4S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H- pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a
  • the invention is directed to a method of treating a RIP1 kinase-mediated disease or disorder (specifically, a disease or disorder recited herein) comprising administering a therapeutically effective amount of 6-((3R,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro- 1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a
  • the invention is directed to a method of treating a RIP1 kinase-mediated disease or disorder (specifically, a disease or disorder recited herein) comprising administering a therapeutically effective amount of 6-((3S,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H- pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, to a human in need thereof.
  • the invention is directed to a method of treating a RIP1 kinase-mediated disease or disorder (specifically, a disease or disorder recited herein) comprising administering a therapeutically effective amount of 6-((3S,4R)-4-((R)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide, to a human in need thereof.
  • the invention is directed to a method of treating a RIP1 kinase-mediated disease or disorder (specifically, a disease or disorder recited herein) comprising administering a therapeutically effective amount of 6-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide to a human in need thereof.
  • the invention is directed to a method of treating a RIP1 kinase- mediated disease or disorder (specifically, a disease or disorder recited herein) comprising administering a therapeutically effective amount of 6-((3R,4S)-4-((R)-5-(3,5-difluorophenyl)- 4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, to a human in need thereof.
  • This invention also provides a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, for use in therapy.
  • This invention provides a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, for use in the treatment of a RIP1 kinase-mediated disease or disorder (for example, a disease or disorder recited herein).
  • this invention provides a compound described herein, or a pharmaceutically acceptable salt thereof, for use in therapy.
  • this invention provides 6-((3R,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof, for use in therapy. More specifically, this invention provides 6- ((3S,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof, for use in therapy.
  • this invention provides 6-((3S,4S)-4-((R)-5- (3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1- yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof, for use in therapy. More specifically, this invention provides 6-((3R,4R)-4-((S)-5-(3,5-difluorophenyl)- 4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof, for use in therapy.
  • this invention provides 6-((3S,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide for use in therapy. More specifically, this invention provides 6-((3S,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide for use in therapy.
  • this invention provides 6-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro- 1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide for use in therapy. More specifically, this invention provides 6-((3R,4S)-4-((R)-5-(3,5-difluorophenyl)- 4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide for use in therapy.
  • this invention provides a compound of the invention for use in the treatment of a RIP1 kinase-mediated disease or disorder, specifically, a disease or disorder recited herein.
  • This invention provides a compound described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a RIP1 kinase-mediated disease or disorder, specifically, a disease or disorder recited herein.
  • this invention provides 6-((3R,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro- 1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof, for use in the treatment of a RIP1 kinase-mediated disease or disorder, specifically a disease or disorder recited herein.
  • this invention provides 6-((3S,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro- 1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof, for use in the treatment of a RIP1 kinase-mediated disease or disorder, specifically a disease or disorder recited herein.
  • this invention provides 6-((3S,4S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro- 1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof, for use in the treatment of a RIP1 kinase-mediated disease or disorder, specifically a disease or disorder recited herein.
  • this invention provides 6-((3R,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro- 1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof, for use in the treatment of a RIP1 kinase-mediated disease or disorder, specifically a disease or disorder recited herein.
  • this invention provides 6-((3S,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro- 1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide for use in the treatment of a RIP1 kinase-mediated disease or disorder, specifically a disease or disorder recited herein.
  • this invention provides 6-((3S,4R)-4-((R)-5- (3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1- yl)pyrimidine-4-carboxamide for use in the treatment of a RIP1 kinase-mediated disease or disorder, specifically a disease or disorder recited herein.
  • this invention provides 6-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide for use in the treatment of a RIP1 kinase-mediated disease or disorder, specifically a disease or disorder recited herein.
  • this invention provides 6-((3R,4S)-4-((R)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide for use in the treatment of a RIP1 kinase-mediated disease or disorder, specifically a disease or disorder recited herein.
  • This invention specifically provides for the use of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, as an active therapeutic substance.
  • this invention provides for the use of the compounds described herein for the treatment of a RIP1 kinase-mediated disease or disorder, specifically, a disease or disorder recited herein. Accordingly, the invention provides for the use of a compound of Formula (I) or Formula (II) as an active therapeutic substance in the treatment of a human in need thereof with a RIP1 kinase-mediated disease or disorder, specifically, a disease or disorder recited herein.
  • this invention provides for the use of 6- ((3R,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof, as an active therapeutic substance for the treatment of a RIP1 kinase-mediated disease or disorder, specifically a disease or disorder recited herein.
  • this invention provides for the use of 6-((3S,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H- pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a
  • this invention provides for the use of 6-((3S,4S)-4-((R)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide, or a pharmaceutically acceptable salt thereof, as an active therapeutic substance for the treatment of a RIP1 kinase-mediated disease or disorder, specifically a disease or disorder recited herein.
  • this invention provides for the use of 6- ((3R,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof, as an active therapeutic substance for the treatment of a RIP1 kinase-mediated disease or disorder, specifically a disease or disorder recited herein.
  • this invention provides for the use of 6-((3S,4R)-4-((S)-5-(3,5-difluorophenyl)- 4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide as an active therapeutic substance for the treatment of a RIP1 kinase-mediated disease or disorder, specifically a disease or disorder recited herein.
  • this invention provides for the use of 6-((3S,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H- pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide as an active therapeutic substance for the treatment of a RIP1 kinase-mediated disease or disorder, specifically a disease or disorder recited herein.
  • this invention provides for the use of 6-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H- pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide as an active therapeutic substance for the treatment of a RIP1 kinase-mediated disease or disorder, specifically a disease or disorder recited herein.
  • this invention provides for the use of 6-((3R,4S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H- pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide as an active therapeutic substance for the treatment of a RIP1 kinase-mediated disease or disorder, specifically a disease or disorder recited herein.
  • the invention further provides for the use of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a RIP1 kinase-mediated disease or disorder, for example the diseases and disorders recited herein.
  • the invention also provides for the use of a compound described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a RIP1 kinase-mediated disease or disorder, for example the diseases and disorders recited herein.
  • the invention provides for the use of 6-((3R,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a RIP1 kinase-mediated disease or disorder, for example the diseases and disorders recited herein.
  • the invention provides for the use of 6-((3S,4S)-4-((S)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a RIP1 kinase-mediated disease or disorder, for example the diseases and disorders recited herein.
  • the invention provides for the use of 6-((3S,4S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a RIP1 kinase-mediated disease or disorder, for example the diseases and disorders recited herein.
  • the invention provides for the use of 6-((3R,4R)-4-((S)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a RIP1 kinase-mediated disease or disorder, for example the diseases and disorders recited herein.
  • the invention provides for the use of 6-((3S,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide in the manufacture of a medicament for use in the treatment of a RIP1 kinase-mediated disease or disorder, for example the diseases and disorders recited herein.
  • the invention provides for the use of 6-((3S,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide in the manufacture of a medicament for use in the treatment of a RIP1 kinase-mediated disease or disorder, for example the diseases and disorders recited herein.
  • the invention provides for the use of 6-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide in the manufacture of a medicament for use in the treatment of a RIP1 kinase-mediated disease or disorder, for example the diseases and disorders recited herein.
  • the invention provides for the use of 6-((3R,4S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide in the manufacture of a medicament for use in the treatment of a RIP1 kinase-mediated disease or disorder, for example the diseases and disorders recited herein.
  • the compounds of the invention may be administered by any suitable route of administration, including both systemic administration and topical administration.
  • Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation.
  • Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion.
  • Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion.
  • Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages.
  • Topical administration includes application to the skin.
  • the compounds of the invention may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan.
  • suitable dosing regimens including the duration such regimens are administered, for a compound of the invention depend on the disease or disorder being treated, the severity of the disease or disorder being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change. Total daily dosages range from 1 mg to 2000 mg.
  • the compounds of the invention will be normally, but not necessarily, formulated into a pharmaceutical composition prior to administration to a patient. Accordingly, the invention also is directed to pharmaceutical compositions comprising a compound of the invention and one or more pharmaceutically acceptable excipients.
  • the invention is directed to a pharmaceutical composition comprising a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • a pharmaceutical composition comprising 6-((3R,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5- dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • a pharmaceutical composition comprising 6-((3S,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • a pharmaceutical composition comprising 6-((3S,4S)-4-((R)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide, or a pharmaceutically acceptable salt thereof, and one or more
  • composition comprising 6-((3R,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5- dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • a pharmaceutical composition comprising 6-((3S,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)- 3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, and one or more pharmaceutically acceptable excipients.
  • composition comprising 6-((3S,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole- 1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, and one or more
  • composition comprising 6-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5- dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, and one or more pharmaceutically acceptable excipients.
  • a pharmaceutical composition comprising 6-((3R,4S)-4-((R)-5-(3,5-difluorophenyl)-4,5- dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, and one or more pharmaceutically acceptable excipients.
  • the invention is further directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients and at least one other therapeutically active agent, specifically one or two other therapeutically active agents, more specifically one other therapeutically active agent.
  • a pharmaceutical composition comprising 6-((3R,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole- 1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically salt thereof, one or more pharmaceutically acceptable excipients, and at least one other therapeutically active agent, specifically one or two other therapeutically active agents, more specifically one other therapeutically active agent.
  • a pharmaceutical composition comprising 6-((3S,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5- dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically salt thereof, one or more pharmaceutically acceptable excipients, and at least one other therapeutically active agent, specifically one or two other therapeutically active agents, more specifically one other therapeutically active agent.
  • a pharmaceutical composition comprising 6-((3S,4S)-4-((R)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide, or a pharmaceutically salt thereof, one or more pharmaceutically acceptable excipients, and at least one other therapeutically active agent, specifically one or two other therapeutically active agents, more specifically one other therapeutically active agent.
  • a pharmaceutical composition comprising 6-((3R,4R)-4-((S)- 5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1- yl)pyrimidine-4-carboxamide, or a pharmaceutically salt thereof, one or more
  • a pharmaceutical composition comprising 6-((3S,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole- 1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, one or more pharmaceutically acceptable excipients, and at least one other therapeutically active agent, specifically one or two other therapeutically active agents, more specifically one other therapeutically active agent.
  • a pharmaceutical composition comprising 6-((3S,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide, one or more pharmaceutically acceptable excipients, and at least one other therapeutically active agent, specifically one or two other therapeutically active agents, more specifically one other therapeutically active agent.
  • a pharmaceutical composition comprising 6-((3R,4S)- 4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1- yl)pyrimidine-4-carboxamide, one or more pharmaceutically acceptable excipients, and at least one other therapeutically active agent, specifically one or two other therapeutically active agents, more specifically one other therapeutically active agent.
  • a pharmaceutical composition comprising 6-((3R,4S)-4-((R)- 5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1- yl)pyrimidine-4-carboxamide, one or more pharmaceutically acceptable excipients, and at least one other therapeutically active agent, specifically one or two other therapeutically active agents, more specifically one other therapeutically active agent.
  • compositions of the invention may be prepared and packaged in bulk form wherein an effective amount of a compound of the invention can be extracted and then given to the patient such as with powders, syrups, and solutions for injection.
  • the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form.
  • a dose of the pharmaceutical composition contains at least a therapeutically effective amount of a compound of this invention (i.e., a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, thereof).
  • the pharmaceutical compositions may contain from 1 mg to 1000 mg of a compound of this invention.
  • unit dosage forms containing from 1 mg to 1000 mg of a compound of the invention may be administered one, two, three, or four times per day, preferably one, two, or three times per day, and more preferably, one or two times per day, to effect treatment of a RIP1 kinase-mediated disease or disorder.
  • the compounds of the invention and the pharmaceutically acceptable excipient or excipients will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration.
  • Conventional dosage forms suitable for use with the compounds of this invention include those adapted for (1) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as aerosols and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.
  • oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets
  • parenteral administration such as sterile solutions, suspensions, and powders for reconstitution
  • transdermal administration such as transdermal patches
  • Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form chosen.
  • suitable pharmaceutically acceptable excipients may be chosen for a particular function that they may serve in the composition.
  • certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms.
  • Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms.
  • Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the carrying or transporting the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body.
  • Certain pharmaceutically acceptable excipients may be chosen for their ability to enhance patient compliance.
  • Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents.
  • excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.
  • compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington’s Pharmaceutical Sciences (Mack Publishing Company).
  • Another embodiment of this invention is a method of preparing a
  • composition comprising the step of admixing a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, thereof, with one or more
  • the invention is directed to a topical dosage form such as a cream, ointment, lotion, paste, or gel comprising an effective amount of a compound of the invention and one or more pharmaceutically acceptable excipients.
  • Lipophilic formulations such as anhydrous creams and ointments, generally will have a base derived from fatty alcohols, and polyethylene glycols. Additional additives include alcohols, non-ionic surfactants, and antioxidants.
  • the base normally will be an oil or mixture of oil and wax, e.g., petrolatum. Also, an antioxidant normally will be included in minor amounts. Because the compositions are applied topically and the effective dosage can be controlled by the total composition applied, the percentage of active ingredient in the composition can vary widely. Convenient concentrations range from 0.5% to 20%.
  • Topically applied gels can also be a foamable suspension gel comprising a compound of the invention, as an active agent, one or more thickening agents, and optionally, a dispersing/wetting agent, a pH-adjusting agent, a surfactant, a propellent, an antioxidant, an additional foaming agent, a chelating/sequestering agent, a solvent, a fragrance, a coloring agent, a preservative, wherein the gel is aqueous and forms a homogenous foam.
  • a foamable suspension gel comprising a compound of the invention, as an active agent, one or more thickening agents, and optionally, a dispersing/wetting agent, a pH-adjusting agent, a surfactant, a propellent, an antioxidant, an additional foaming agent, a chelating/sequestering agent, a solvent, a fragrance, a coloring agent, a preservative, wherein the gel is aqueous and forms a homogenous foam.
  • the invention is directed to a topical dosage form that can be administered by inhalation, that is, by intranasal and oral inhalation administration.
  • Appropriate dosage forms for such administration may be prepared by conventional techniques.
  • Intranasal sprays may be formulated with aqueous or non-aqueous vehicles with the addition of agents such as thickening agents, buffer salts or acid or alkali to adjust the pH, isotonicity adjusting agents or anti-oxidants.
  • Solutions for inhalation by nebulization may be formulated with an aqueous vehicle with the addition of agents such as acid or alkali, buffer salts, isotonicity adjusting agents or antimicrobials.
  • Formulations for administration by inhalation or foamable gel often require the use of a suitable propellant.
  • Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated using a suitable powder base such as lactose or starch.
  • the invention is directed to a solid oral dosage form such as a tablet or capsule comprising an effective amount of a compound of the invention and a diluent or filler.
  • Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate.
  • the oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g.
  • the oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose.
  • the oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc.
  • alkyl represents a saturated, straight or branched hydrocarbon group having the specified number of carbon atoms.
  • (C 2 -C 6 )alkyl refers to an alkyl moiety containing from 2 to 6 carbon atoms.
  • Exemplary alkyls include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, and t-butyl.
  • the linking substituent term e.g., alkyl
  • the linking substituent is intended to encompass a multi-valent moiety, wherein the point of attachment is through that linking substituent.
  • the linking substituent is di-valent.
  • An example of a“(C3-C7)cycloalkyl-alkyl-” group includes, but is not limited to, cyclopentyl-methyl-.
  • halo(C 1 -C 4 )alkyl represents a group having one or more halogen atoms, which may be the same or different, at one or more carbon atoms of an alkyl moiety containing from 1 to 4 carbon atoms.
  • halo(C 1 -C 4 )alkyl groups include, but are not limited to, -CF3 (trifluoromethyl), -CCl3 (trichloromethyl), 1,1-difluoroethyl, 2,2,2- trifluoroethyl, and hexafluoroisopropyl.
  • Alkenyl refers to straight or branched hydrocarbon group having at least 1 and up to 3 carbon-carbon double bonds. Examples include ethenyl and propenyl.
  • Alkoxy refers to an "alkyl-oxy-" group, containing an alkyl moiety attached through an oxygen linking atom.
  • the term “(C 1 -C 4 )alkoxy” represents a saturated, straight or branched hydrocarbon moiety having at least 1 and up to 4 carbon atoms attached through an oxygen linking atom.
  • Exemplary "(C 1 -C 4 )alkoxy” groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, and t-butoxy.
  • halo(C 1 -C 4 )alkoxy refers to a "haloalkyl-oxy-" group, containing a “halo(C1-C4)alkyl” moiety attached through an oxygen linking atom, which
  • halo(C 1 -C 4 )alkyl refers to a moiety having one or more halogen atoms, which may be the same or different, at one or more carbon atoms of an alkyl moiety containing from 1 to 4 carbon atoms.
  • Exemplary“halo(C 1 -C 4 )alkoxy” groups include, but are not limited to, - OCHF2 (difluoromethoxy), -OCF3 (trifluoromethoxy), -OCH2CF3 (trifluoroethoxy), and -OCH(CF3)2 (hexafluoroisopropoxy).
  • Cycloalkyl refers to a non-aromatic, saturated, cyclic hydrocarbon group containing the specified number of carbon atoms.
  • the term“(C3-C6)cycloalkyl” refers to a non-aromatic cyclic hydrocarbon ring having from three to six ring carbon atoms.
  • Exemplary“(C3-C6)cycloalkyl” groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • Aryl refers to a group or moiety comprising an aromatic, monocyclic or bicyclic hydrocarbon radical containing from 6 to 10 carbon ring atoms and having at least one aromatic ring.
  • aryl groups are phenyl, naphthyl, indenyl, and dihydroindenyl (indanyl). Generally, aryl is phenyl.
  • a heterocyclic group is a cyclic group having, as ring members, atoms of at least two different elements, which cyclic group may be saturated, partially unsaturated (non-aromatic) or fully unsaturated (aromatic).
  • Heterocycloalkyl refers to a non-aromatic, monocyclic or bicyclic group containing 3-10 ring atoms, being saturated and containing one or more (generally one or two) ring heteroatoms independently selected from oxygen, sulfur, and nitrogen.
  • heterocycloalkyl groups include, but are not limited to, aziridinyl, thiiranyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,4-dioxanyl, 1,4-oxathiolanyl, 1,4- oxathianyl, 1,4-dithianyl, morpholinyl, and thiomorpholinyl, and dihydroimidazole.
  • 5-6-membered heterocycloalkyl represents a nonaromatic, monocyclic group, which is fully saturated, containing 5 or 6 ring atoms, which includes one or two heteroatoms selected independently from oxygen, sulfur, and nitrogen.
  • Illustrative examples of 5 to 6-membered heterocycloalkyl groups include, but are not limited to pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, and dihydroimidazole.
  • Heteroaryl represents a group or moiety comprising an aromatic monocyclic or bicyclic radical, containing 5 to 10 ring atoms, including 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. This term also encompasses bicyclic heterocyclic- aryl groups containing either an aryl ring moiety fused to a heterocycloalkyl ring moiety or a heteroaryl ring moiety fused to a cycloalkyl ring moiety.
  • heteroaryls include, but are not limited to, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl (pyridyl), oxo-pyridyl (pyridyl-N-oxide), pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, benzofuranyl, isobenzofuryl, 2,3- dihydrobenzofuryl, 1,3-benzodioxolyl, dihydrobenzodioxinyl, benzothienyl, indolizinyl, indolyl, isoindolyl, dihydroindolyl, benzimid
  • 5-6-membered heteroaryl represents an aromatic monocyclic group containing 5 or 6 ring atoms, including at least one carbon atom and 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • Selected 5-membered heteroaryl groups contain one nitrogen, oxygen, or sulfur ring heteroatom, and optionally contain 1, 2, or 3 additional nitrogen ring atoms.
  • Selected 6-membered heteroaryl groups contain 1, 2, or 3 nitrogen ring heteroatoms.
  • Examples of 5- membered heteroaryl groups include furyl (furanyl), thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl and oxo-oxadiazolyl.
  • Selected 6-membered heteroaryl groups include pyridinyl, oxo-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazinyl.
  • 9-10-membered heteroaryl represents an aromatic cyclic group containing 9 or 10 ring atoms, including at least one carbon atom and 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • Selected 9-membered heteroaryl groups contain one nitrogen, oxygen, or sulfur ring heteroatom, and optionally contain 1, 2, or 3 additional nitrogen ring atoms.
  • Selected 10-membered heteroaryl groups contain 1, 2, or 3 nitrogen ring heteroatoms.
  • 9-membered heteroaryl groups include 7H-purinyl, 9H-purinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, 1H-pyrazolo[3,4- d]pyrimidinyl, and imidazo[1,2-b]pyridazinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, indolizinyl, indolyl, isoindolyl, and indazolyl.
  • Selected 10-membered heteroaryl groups include quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, and pteridinyl.
  • Bicyclic heteroaryl groups include 6,5-fused heteroaryl (9-membered heteroaryl) and 6,6-fused heteroaryl (10-membered heteroaryl) groups.
  • 6,5-fused heteroaryl (9-membered heteroaryl) groups include benzothienyl, benzofuranyl, indolyl, indolinyl, isoindolyl, isoindolinyl, indazolyl, indolizinyl, isobenzofuryl, 2,3-dihydrobenzofuryl, benzo- 1,3-dioxyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzoxadiazolyl,
  • bicyclic ring systems may be attached at any suitable position on either ring.
  • halogen and “halo” represent chloro, fluoro, bromo, or iodo substituents.
  • Hydroxo or“hydroxyl” is intended to mean the radical -OH.
  • cyano refers to the group -CN.
  • the term "optionally” means that the subsequently described event(s) may or may not occur, and includes both event(s) that occur and event(s) that do not occur.
  • the selected groups may be the same or different.
  • substituents independently means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.
  • pharmaceutically acceptable refers to those compounds (including salts), materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • treatment refers to alleviating the specified condition, eliminating or reducing one or more symptoms of the condition, slowing or eliminating the progression of the condition, and delaying the reoccurrence of the condition in a previously afflicted or diagnosed patient or subject.
  • cancer refers to cells that have undergone a malignant transformation that makes them pathological to the host organism.
  • Primary cancer cells can be readily distinguished from non-cancerous cells by well-established techniques, particularly histological examination.
  • the definition of a cancer cell includes not only a primary cancer cell, but any cell derived from a cancer cell ancestor. This includes metastasized cancer cells, and in vitro cultures and cell lines derived from cancer cells.
  • tumor is one that is detectable on the basis of tumor mass; e.g., by procedures such as computed tomography (CT) scan, magnetic resonance imaging (MRI), X- ray, ultrasound or palpation on physical examination, and/or which is detectable because of the expression of one or more cancer-specific antigens in a sample obtainable from a patient.
  • Tumors may be a hematopoietic (or hematologic or hematological or blood-related) cancer, for example, cancers derived from blood cells or immune cells, which may be referred to as “liquid tumors.”
  • a therapeutically "effective amount” is intended to mean that amount of a compound that, when administered to a patient in need of such treatment, is sufficient to effect treatment, as defined herein.
  • a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof is a quantity of an inventive agent that, when administered to a human in need thereof, is sufficient to modulate and/or inhibit the activity of RIP1 kinase such that a disease condition which is mediated by that activity is reduced, alleviated or prevented.
  • the amount of a given compound that will correspond to such an amount will vary depending upon factors such as the particular compound (e.g., the potency (pIC50), efficacy (EC50), and the biological half-life of the particular compound), disease condition and its severity, the identity (e.g., age, size and weight) of the patient in need of treatment, but can nevertheless be routinely determined by one skilled in the art. Likewise, the duration of treatment and the time period of
  • time period between dosages and the timing of the dosages, e.g., before/with/after meals of the compound will vary according to the identity of the mammal in need of treatment (e.g., weight), the particular compound and its properties (e.g., pharmacokinetic properties), disease or disorder and its severity and the specific composition and method being used, but can nevertheless be determined by one of skill in the art.
  • pharmaceutically acceptable excipient means a material, composition or vehicle involved in giving form or consistency to the composition.
  • Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided.
  • each excipient must of course be of sufficiently high purity to render it pharmaceutically acceptable.
  • the compounds of this invention may be made by a variety of methods, including well-known standard synthetic methods. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the working examples. The skilled artisan will appreciate that if a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions. The protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound. In all of the schemes described below, protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of synthetic chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Green and P.G.M.
  • references to preparations carried out in a similar manner to, or by the general method of, other preparations may encompass variations in routine parameters such as time, temperature, workup conditions, minor changes in reagent amounts, etc.
  • condensation of a an aldehyde of Formula A with acetaldehyde affords an unsaturated aldehyde of Formula B.
  • Reaction of an aldehyde of Formula B with hydrazine provides a dihydropyrazole of Formula C.
  • An amide bond formation between a piperidine-4-carboxylic acid of Formula D with a 4,5-dihydropyrazole of Formula C affords a compound of Formula E.
  • the removal of the amine protecting group e.g. tert-butoxycarbonyl
  • An SNAr reaction between an amine of Formula F and a heteroaryl halide of Formula G furnishes compounds of Formula (I).
  • compounds of Formula (I) can be prepared according to Scheme 2.
  • An amide bond coupling of a piperidine-4-carboxylic acid of Formula H with a 4,5- dihydropyrazole of Formula C provides compounds of Formula (I).
  • compounds of Formula (II) can be prepared according to Scheme 4.
  • Scheme 4 chiral compounds of Formula J, prepared according to methods described herein, can be reacted with a compound of Formula H under amide bond forming conditions to afford a compound of Formula (II).
  • Scheme 1 Synthesis of Compounds of Formula (I).
  • Scheme 2 Alternate Synthesis of Compounds of Formula (I).
  • Scheme 3 Synthesis of Compounds of Formula (II).
  • NIS (4.21 g, 18.7 mmol) was added to a mixture of methyl pyrazolo[1,5-a] pyridine-5- carboxylate (3 g, 17 mmol) in MeCN (70 mL). The resulting mixture was stirred at rt for 4 hours, filtered, and the filtrate was concentrated under vacuum to afford a residue. The resulting residue was diluted with H2O (60 mL) and extracted with EA (3 x 80 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under vacuum.
  • DIEA (2.13 g, 16.5 mmol) was added to a mixture of cis-1-(tert-butoxycarbonyl)-3- fluoropiperidine-4-carboxylic acid (4.07 g, 16.5 mmol) and py-Brop (7.69 g, 16.5 mmol) in DMF (30 mL), followed by addition of 5-(2,3,5-trifluorophenyl)-4,5-dihydro-1H-pyrazole (3.3 g, 16.5 mmol). The resulting mixture was stirred at rt for 18 hours, diluted with H 2 O (20 mL), and extracted with DCM (3 x 100 mL).
  • DIEA (1.55 g, 12 mmol) was added to a stirred mixture of HATU (2.28 g, 6 mmol) and 3- methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carboxylic acid (720 mg, 4 mmol) in DMF (40 mL). The resulting mixture was stirred for 10 minutes at room temperature, followed by addition of 5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole (728 mg, 4 mmol). The resulting mixture was stirred at rt for 16 hours, diluted with H 2 O (30 mL), and extracted with DCM (3 x 50 mL).
  • the crude product was re-purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column 19 x 150 mm 5 um; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 5% B to 35% B in 4 min; UV 254 & 220 nm; Rt1: 10.20 min; Rt2: 11.42 min to afford two diastereomers of 5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl-(3- methyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-5-yl)methanone.
  • Enantiomers of racemate 160 mg, 0.46 mmol were separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IG-03, 2.0 cm I.D x 25cm L (5 um); Mobile Phase A: Hexane, Mobile Phase B: EtOH; Flow rate: 18 mL/min; Gradient: 50% B to 50% B in 20 min; UV 220 & 254 nm; Rt1: 12.8 min; Rt2: 15.1 min to afford two titled compounds.
  • the following compounds were synthesized in an analogous manner.
  • the compounds were synthesized via amide coupling using HATU, DIEA and DMF at rt for 18 hours.
  • the isomers were separated by chiral separation.
  • Examples 9– 12 correspond to the following: (m 1H) 310- 04 (m 1H)
  • Diastereomer 1 LCMS (m/z) 427 (M+H) + , retention time: 1.135 min, LCMS Method 5.
  • Diastereomer 2 LCMS (m/z) 427 (M+H) + , retention time: 1.222 min, LCMS Method 5.
  • Enantiomers of a racemate were separated by Prep-Chiral-SFC with the following conditions: Column: Lux Su Cellulose 4, AXIA Packed 2.12 x 25 cm, 5 um; Mobile Phase A: CO2, 50%; Mobile Phase B: EtOH, 50%; Flow rate: 40 mL/min; Gradient: 100% B to 100% B in 11 min; UV 254 & 220 nm; Rt1: 6.41 min; Rt2: 8.60 min to afford two title compounds: Example 13
  • Example 14 An enantiomer was afforded as a white solid (62.1 mg, 27 % yield).
  • LCMS (m/z) 427 (M+H) + retention time: 1.135 min, LCMS Method 5.
  • Chiral SFC Anal. Method 1, retention time: 3.607 min, % ee 100.0 %.
  • Enantiomers of a racemate were separated by Prep-Chiral-SFC with the following conditions: Column: (R,R)WHELK-015/100 Kromasil, 2.11 x 25 cm, 5 um; Mobile Phase A: CO 2 , 50%; Mobile Phase B: MeOH, 50%; Flow rate: 50 mL/min; UV 254 & 220 nm; Rt1: 5.78 min; Rt2: 9.7 min to afford last two title compounds: Example 15 An enantiomer was afforded as a white solid (58.5 mg, 25.5 % yield). LCMS (m/z) 427 (M+H) + , retention time: 1.222 min, LCMS Method 5. Chiral SFC Anal.
  • DIEA (1.79 g, 13.74 mmol) was added to a mixture of cis-1-(tert-butoxycarbonyl)-3- fluoropiperidine-4-carboxylic acid (3.40 g, 13.74 mmol) and py-Brop (6.4 g, 13.74 mmol) in DMF (10 mL). Then 5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole (2.5 g, 13.74 mmol) was added to the mixture. The resulting mixture was stirred at room temperature overnight. The mixture was diluted with H 2 O (10 mL) and extracted with DCM (3 x 100 mL).
  • DIEA (180 mg, 1.38 mmol) was added to a mixture of a diastereomer of (5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-fluoropiperidin-4-yl)methanone hydrochloride (160.0 mg, 0.46mmol) and 6-chloro-N-methylpyrimidine-4-carboxamide (79 mg, 0.46 mmol) in DMF (5.0 mL). The mixture was stirred at rt for 2 hours, diluted with water (50 mL), and extracted with DCM (3 x 100 mL).
  • DIEA (168 mg, 1.29 mmol) was added to a mixture of a diastereomer of (5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-fluoropiperidin-4-yl)methanone hydrochloride (150.0 mg, 0.43 mmol) and 6-chloro-N-methylpyrimidine-4-carboxamide (74 mg, 0.43 mmol) in DMF (5.0 mL). The mixture was stirred at rt for 2 hours, diluted with water (50 mL) and extracted with DCM (3 x 100 mL).
  • Examples 25– 28 corresponds to the following: Chiral HPLC/ LC: retention Chiral HPLC (m 3H) 543-536 (m
  • Examples 29– 32 correspond to the following: Chi l HPLC/
  • Examples 33– 40 correspond to the following: Anal Method 6 666 (m 3H) 542-532
  • Examples 41– 44 correspond to the following: Chi l HPLC/
  • Examples 57– 60 correspond to the following:
  • Examples 61– 64 correspond to the following: 235-229 (m 1H) 189-
  • Examples 69– 76 correspond to the following: Analtic Method
  • Examples 77– 80 correspond to the following:
  • Examples 81– 84 correspond to the following:
  • Examples 85– 88 correspond to the following:
  • t-BuOK (4.44 g, 39.50 mmol) was added in portions to a stirred solution of PPh3CH2OCH3Cl (13.58 g, 36.61 mmol) in anhydrous THF (100 mL) under nitrogen at ice cold temperature. The mixture was stirred for 1 hour, and tert-butyl 3,3-dimethyl-4-oxopiperidine-1- carboxylate (6 g, 26.39 mmol) in THF (100 mL) was added slowly. The resulting reaction mixture was warmed to room temperature and stirred overnight. Water was added, and organic material was extracted with EA (3 x 200 mL), dried over Na 2 SO 4 , filtered and concentrated to afford a resulting residue.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Disclosed are compounds having the formula: (I) wherein R1, R2, and R3 are as defined herein, and methods of making and using the same.

Description

HETEROCYCLIC AMIDES AS KINASE INHIBITORS FIELD OF THE INVENTION
The present invention relates to heterocyclic amides that inhibit RIP1 kinase and methods of making and using the same. BACKGROUND OF THE INVENTION
Receptor-interacting protein-1 (RIP1) kinase, originally referred to as RIP, is a TKL family serine/threonine protein kinase involved in innate immune signaling. RIP1 kinase is a RHIM domain containing protein, with an N-terminal kinase domain and a C-terminal death domain (Trends Biochem. Sci., 30, 151-159 (2005)). The death domain of RIP1 mediates interaction with other death domain containing proteins including Fas and TNFR-1 (Cell, 81 513–523 (1995)), TRAIL-R1 and TRAIL-R2 (Immunity, 7, 821–830 (1997)), and TRADD (Immunity, 4, 387–396 (1996)), while the RHIM domain is crucial for binding other RHIM domain containing proteins such as TRIF (Nat. Immunol., 5, 503–507 (2004)), DAI (EMBO Rep.10, 916–922 (2009)) and RIP3 (J. Biol. Chem., 274, 16871–16875 (1999)); Curr. Biol., 9, 539–542 (1999)) and exerts many of its effects through these interactions. RIP1 is a central regulator of cell signaling and is involved in mediating both pro-survival and programmed cell death pathways which will be discussed below.
The role for RIP1 in cell signaling has been assessed under various conditions
[including TLR3 (Nat Immunol., 5, 503–507 (2004)), TLR4 (J. Biol. Chem., 280, 36560– 6566 (2005)), TRAIL (Cell Signal., 27(2), 306–314 (2015)), FAS (J. Biol. Chem., 279, 7925–7933 (2004))], but is best understood in the context of mediating signals downstream of the death receptor TNFR1 (Cell, 114, 181–190 (2003)). Engagement of the TNFR by TNF leads to its oligomerization, and the recruitment of multiple proteins, including linear K63- linked polyubiquitinated RIP1 (Mol. Cell, 22, 245–257 (2006)), TRAF2/5 (J. Mol. Biol., 396, 528–539 (2010)), TRADD (Nat. Immunol., 9, 1037–1046 (2008)), and cIAPs (Proc. Natl. Acad. Sci. USA., 105, 11778–11783 (2008)), to the cytoplasmic tail of the receptor. This complex which is dependent on RIP1 as a scaffolding protein (i.e. kinase independent), termed complex I, provides a platform for pro-survival signaling through the activation of the NFkB and MAP kinases pathways (Sci. Signal., 115, re4 (2010)). Alternatively, binding of TNF to its receptor under conditions promoting the deubiquitination of RIP1 (by proteins such as A20 and CYLD or inhibition of the cIAPs) results in receptor internalization and the formation of complex II or DISC (death-inducing signaling complex) (Cell Death Dis., 2, e230 (2011)). Formation of the DISC, which contains RIP1, TRADD, FADD and caspase 8, results in the activation of caspase 8 and the onset of programmed apoptotic cell death also in a RIP1 kinase independent fashion (FEBS J, 278, 877–887 (2012)). Apoptosis is largely a quiescent form of cell death and is involved in routine processes such as development and cellular homeostasis.
Under conditions where the DISC forms and RIP3 is expressed, but apoptosis is inhibited (such as FADD/caspase 8 deletion, caspase inhibition, or viral infection), a third RIP1 kinase-dependent possibility exists. RIP3 can now enter this complex, become phosphorylated by RIP1 and initiate a caspase-independent programmed necrotic cell death through the activation of MLKL and PGAM5 (Cell, 148, 213–227 (2012)); (Cell, 148, 228– 243 (2012)); (Proc. Natl. Acad. Sci. USA., 109, 5322–5327 (2012)). As opposed to apoptosis, programmed necrosis (not to be confused with passive necrosis which is not programmed) results in the release of danger associated molecular patterns (DAMPs) from the cell. These DAMPs are capable of providing a“danger signal” to surrounding cells and tissues, eliciting proinflammatory responses including inflammasome activation, cytokine production and cellular recruitment (Nat. Rev. Immunol., 8, 279–289 (2008)).
Dysregulation of RIP1 kinase-mediated programmed cell death has been linked to various inflammatory diseases, as demonstrated by use of the RIP3 knockout mouse (where RIP1-mediated programmed necrosis is completely blocked) and by Necrostatin-1 (a tool inhibitor of RIP1 kinase activity with poor oral bioavailability). The RIP3 knockout mouse has been shown to be protective in inflammatory bowel disease (including ulcerative colitis and Crohn’s disease) (Nature, 477, 330–334 (2011)), psoriasis (Immunity, 35, 572–582 (2011)), retinal-detachment-induced photoreceptor necrosis (PNAS, 107, 21695–21700, (2010)), retinitis pigmentosa (Proc. Natl. Acad. Sci., 109:36, 14598–14603 (2012)), cerulein- induced acute pancreatits (Cell, 137, 1100–1111 (2009)), and sepsis/systemic inflammatory response syndrome (SIRS) (Immunity, 35, 908–918 (2011)). Necrostatin-1 has been shown to be effective in alleviating ischemic brain injury (Nat. Chem. Biol., 1, 112–119 (2005)), retinal ischemia/reperfusion injury (J. Neurosci. Res., 88, 1569–1576 (2010)), Huntington’s disease (Cell Death Dis., 2 e115 (2011)), renal ischemia reperfusion injury (Kidney Int., 81, 751–761 (2012)), cisplatin induced kidney injury (Ren. Fail., 34, 373–377 (2012)), and traumatic brain injury (Neurochem. Res., 37, 1849–1858 (2012)). Other diseases or disorders regulated at least in part by RIP1-dependent apoptosis, necrosis or cytokine production include hematological and solid organ malignancies (Genes Dev., 27, 1640–1649 (2013)), bacterial infections and viral infections (Cell Host & Microbe, 15, 23–35 (2014)) (including, but not limited to, tuberculosis and influenza (Cell, 153, 1–14 (2013)) and Lysosomal storage diseases (particularly, Gaucher Disease, Nature Medicine Advance Online Publication, 19 January 2014, doi:10.1038/nm.3449).
A potent, selective, small molecule inhibitor of RIP1 kinase activity would block RIP1-dependent cellular necrosis and thereby provide a therapeutic benefit in diseases or events associated with DAMPs, cell death, and/or inflammation.
SUMMARY OF THE INVENTION The present invention relates to compounds according to Formula (I)
pharmaceutically acceptable salts thereof:
Figure imgf000004_0001
wherein:
R1 is hydrogen, (C2-C4)alkenyl, (C2-C4)alkenyl-NH2, -(C1-C4)alkyl=NH, -NH2, 5-6 membered heteroaryl or 9-10 membered heteroaryl,
wherein said 5-6 membered heteroaryl or 9-10 membered heteroaryl is optionally substituted by 1 or 2 substituents independently selected from hydroxyl, cyano, halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C2-C4)alkynyl, (C1- C4)alkoxy, 5-6 membered heterocycloalkyl-CO-, fused 5-6 membered
heterocycloalkyl, H2N-, (C1-C4)alkyl-NH-, ((C1-C4)alkyl)((C1-C4)alkyl)N-, -CONH2, H2NCO-(C1-C4)alkyl-, (C1-C4)alkylNHCO-, (hydroxy-(C1-C4)alkyl)NHCO-, (C3- C6)cycloalkyl-NHCO-, 5-6 membered heterocycloalkyl-NHCO-, ((C1-C4)alkyl)((C1- C4)alkyl)N-CO-, (C1-C4)alkyl-CONH-, ((C1-C4)alkyl)((C1-C4)alkyl)N-NHCO-, - CO2H, -CO2(C1-C4)alkyl, (C1-C4)alkylthio-, phenyl-(C1-C4)alkylthio-, (C1-C4)alkyl- SO-, (C1-C4)alkyl-SO2-, phenyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl,
wherein said (C1-C4)alkoxy is optionally substituted by hydroxyl, -CO2H, -CONH2, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; or said
5-6 membered heterocycloalkyl-CO-, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl is optionally substituted by (C1-C4)alkyl or oxo; or said 5-6 membered heterocycloalkyl-NHCO- is optionally substituted by (C1- C4)alkyl-CO-;
R2 is phenyl or 5-6 membered heteroaryl,
wherein said phenyl or 5-6 membered heteroaryl is optionally substituted by one, two, or three substituents independently selected from halogen, (C1-C4)alkyl,
(C1-C4)alkoxy, and cyano; and
each R3 is independently selected from hydrogen, halogen, (C1-C4)alkyl, and -(C2-C4)alkenyl, or R1 and R3 taken together with the atoms to which they are attached, form a 5-6 membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by
(C1-C4)alkyl;
or any two R3 groups taken together with the atoms to which they are attached, form a 4-, 5-, 6-, or 7-membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; and
wherein at least one R3 is not hydrogen. The present invention relates to compounds according to Formula (I)
pharmaceutically acceptable salts thereof:
wherein:
Figure imgf000005_0001
R1 is hydrogen, (C2-C4)alkenyl, (C2-C4)alkenyl-NH2, -(C1-C4)alkyl=NH, -NH2, 5-6 membered heteroaryl or 9-10 membered heteroaryl,
wherein said 5-6 membered heteroaryl or 9-10 membered heteroaryl is optionally substituted by 1 or 2 substituents independently selected from hydroxyl, cyano, halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C2-C4)alkynyl, (C1- C4)alkoxy, substituted 5-6 membered heterocycloalkyl-CO-, fused 5-6 membered heterocycloalkyl, H2N-, (C1-C4)alkyl-NH-, ((C1-C4)alkyl)((C1-C4)alkyl)N-, -CONH2, H2NCO-(C1-C4)alkyl-, (C1-C4)alkylNHCO-, (hydroxy-(C1-C4)alkyl)NHCO-, (C3- C6)cycloalkyl-NHCO-, substituted 5-6 membered heterocycloalkyl-NHCO-, ((C1- C4)alkyl)((C1-C4)alkyl)N-CO-, (C1-C4)alkyl-CONH-, ((C1-C4)alkyl)((C1-C4)alkyl)N- NHCO-, -CO2H, -CO2(C1-C4)alkyl, (C1-C4)alkylthio-, phenyl-(C1-C4)alkylthio-, (C1- C4)alkyl-SO-, (C1-C4)alkyl-SO2-, phenyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl,
wherein said (C1-C4)alkoxy is optionally substituted by hydroxyl, -CO2H, -CONH2, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; or said
5-6 membered heterocycloalkyl-CO-, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl is optionally substituted by (C1-C4)alkyl or oxo; or said 5-6 membered heterocycloalkyl-NHCO- is optionally substituted by (C1- C4)alkyl-CO-;
R2 is phenyl or 5-6 membered heteroaryl,
wherein said phenyl or 5-6 membered heteroaryl is optionally substituted by one, two, or three substituents independently selected from halogen, (C1-C4)alkyl,
(C1-C4)alkoxy, and cyano; and
each R3 is independently selected from hydrogen, halogen, (C1-C4)alkyl, and -(C2-C4)alkenyl, or R1 and R3 taken together with the atoms to which they are attached, form a 5-6 membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by
(C1-C4)alkyl;
or any two R3 groups taken together with the atoms to which they are attached, form a 4-, 5-, 6-, or 7-membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; and
wherein at least one R3 is not hydrogen. The present invention relates to compounds according to Formula (I)
pharmaceutically acceptable salts thereof:
Figure imgf000007_0001
wherein:
R1 is hydrogen, (C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkenyl-NH2, -(C1- C4)alkyl=NH, -NH2, 5-6 membered heteroaryl or 9-10 membered heteroaryl,
wherein said 5-6 membered heteroaryl or 9-10 membered heteroaryl is optionally substituted by 1 or 2 substituents independently selected from hydroxyl, cyano, halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C2-C4)alkynyl, (C1- C4)alkoxy, 5-6 membered heterocycloalkyl-CO-, fused 5-6 membered
heterocycloalkyl, H2N-, (C1-C4)alkyl-NH-, ((C1-C4)alkyl)((C1-C4)alkyl)N-, -CONH2, H2NCO-(C1-C4)alkyl-, (C1-C4)alkylNHCO-, H2N(C1-C4)alkylNHCO-, (C1-C4)alkyl HN(C1-C4)alkylNHCO-, ((C1-C4)alkyl)((C1-C4)alkyl)N(C1-C4)alkylNHCO- (hydroxy-(C1-C4)alkyl)NHCO-, (C3-C6)cycloalkyl-NHCO-, 5-6 membered heterocycloalkyl-NHCO-, ((C1-C4)alkyl)((C1-C4)alkyl)N-CO-, (C1-C4)alkyl-CONH-, ((C1-C4)alkyl)((C1-C4)alkyl)N-NHCO-, -CO2H, -CO2(C1-C4)alkyl, (C1-C4)alkylthio-, phenyl-(C1-C4)alkylthio-, (C1-C4)alkyl-SO-, (C1-C4)alkyl-SO2-, phenyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl,
wherein said (C1-C4)alkoxy is optionally substituted by hydroxyl, -CO2H, -CONH2, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; or said
5-6 membered heterocycloalkyl-CO-, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl is optionally substituted by (C1-C4)alkyl or oxo; or said 5-6 membered heterocycloalkyl-NHCO- is optionally substituted by (C1- C4)alkyl-CO-;
R2 is phenyl or 5-6 membered heteroaryl, wherein said phenyl or 5-6 membered heteroaryl is optionally substituted by one, two, or three substituents independently selected from halogen, (C1-C4)alkyl, -(C1- C4)alkyl-NH2, -(C1-C4)alkyl-NH(C1-C4)alkyl, -(C1-C4)alkyl-N-((C1-C4)alkyl)((C1- C4)alkyl), (C1-C4)alkoxy, and cyano; and
each R3 is independently selected from hydrogen, halogen, (C1-C4)alkyl, -(C2-C4)alkenyl, and =O,
or R1 and R3 taken together with the atoms to which they are attached, form a 5-6 membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by
(C1-C4)alkyl;
or any two R3 groups taken together with the atoms to which they are attached, form a 4-, 5-, 6-, or 7-membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; and
wherein at least one R3 is not hydrogen.
The present invention relates to compounds according to Formula (I) or
pharmaceutically acceptable salts thereof:
Figure imgf000008_0001
wherein:
R1 is hydrogen, (C2-C4)alkenyl, -(C2-C4)alkenyl-NH2, -(C1-C4)alkyl=NH, -NH2, 5-6 membered heteroaryl or 9-10 membered heteroaryl,
wherein said 5-6 membered heteroaryl or 9-10 membered heteroaryl is optionally substituted by one or two substituents independently selected from hydroxyl, cyano, halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C2-C4)alkynyl, (C1- C4)alkoxy, 5-6 membered heterocycloalkyl-CO-, fused 5-6 membered
heterocycloalkyl, H2N-, (C1-C4)alkylNH-, ((C1-C4)alkyl)((C1-C4)alkyl)N-, -CONH2, H2NCO-(C1-C4)alkyl-, (C1-C4)alkylNHCO-, (hydroxy-(C1-C4)alkyl)NHCO-, (C3- C6)cycloalkyl-NHCO-, 5-6 membered heterocycloalkyl-NHCO-, ((C1-C4)alkyl)((C1- C4)alkyl)N-CO-, (C1-C4)alkyl-CONH-, ((C1-C4)alkyl)((C1-C4)alkyl)N-NHCO-, - CO2H, -CO2(C1-C4)alkyl, (C1-C4)alkylthio-, phenyl-(C1-C4)alkylthio-, (C1-C4)alkyl- SO-, (C1-C4)alkyl-SO2-, phenyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl,
wherein said (C1-C4)alkoxy is optionally substituted by hydroxyl, -CO2H, -CONH2, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; or said 5-6 membered heterocycloalkyl-CO-, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl is optionally substituted by (C1-C4)alkyl or oxo; or said 5-6 membered heterocycloalkyl-NHCO- is optionally substituted by (C1- C4)alkyl-CO-;
R2 is phenyl or 5-6 membered heteroaryl,
wherein said phenyl or 5-6 membered heteroaryl is optionally substituted by one, two, or three substituents independently selected from halogen, (C1-C4)alkyl,
(C1-C4)alkoxy, and cyano; and
each R3 is independently selected from hydrogen, halogen, (C1-C4)alkyl, and (C2-C4)alkenyl, or R1 and R3 taken together with the atoms to which they are attached, form a 5-6 membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by
(C1-C4)alkyl;
or any two R3 groups taken together with the atoms to which they are attached, form a 4-, 5-, 6-, or 7-membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; and
wherein at least one R3 is not hydrogen.
The present invention relates to compounds according to Formula (I) or
pharmaceutically acceptable salts thereof:
Figure imgf000010_0001
wherein:
R1 is hydrogen, (C2-C4)alkenyl, -(C2-C4)alkenyl-NH2, -(C1-C4)alkyl=NH, -NH2, 5-6 membered heteroaryl or 9-10 membered heteroaryl,
wherein said 5-6 membered heteroaryl or 9-10 membered heteroaryl is optionally substituted by one or two substituents independently selected from hydroxyl, cyano, halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C2-C4)alkynyl, (C1- C4)alkoxy, substituted 5-6 membered heterocycloalkyl-CO-, fused 5-6 membered heterocycloalkyl, H2N-, (C1-C4)alkylNH-, ((C1-C4)alkyl)((C1-C4)alkyl)N-, -CONH2, H2NCO-(C1-C4)alkyl-, (C1-C4)alkylNHCO-, (hydroxy-(C1-C4)alkyl)NHCO-, (C3- C6)cycloalkyl-NHCO-, substituted 5-6 membered heterocycloalkyl-NHCO-, ((C1- C4)alkyl)((C1-C4)alkyl)N-CO-, (C1-C4)alkyl-CONH-, ((C1-C4)alkyl)((C1-C4)alkyl)N- NHCO-, -CO2H, -CO2(C1-C4)alkyl, (C1-C4)alkylthio-, phenyl-(C1-C4)alkylthio-, (C1- C4)alkyl-SO-, (C1-C4)alkyl-SO2-, phenyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl,
wherein said (C1-C4)alkoxy is optionally substituted by hydroxyl, -CO2H, -CONH2, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; or said 5-6 membered heterocycloalkyl-CO-, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl is optionally substituted by (C1-C4)alkyl or oxo; or said 5-6 membered heterocycloalkyl-NHCO- is optionally substituted by (C1- C4)alkyl-CO-;
R2 is phenyl or 5-6 membered heteroaryl,
wherein said phenyl or 5-6 membered heteroaryl is optionally substituted by one, two, or three substituents independently selected from halogen, (C1-C4)alkyl,
(C1-C4)alkoxy, and cyano; and
each R3 is independently selected from hydrogen, halogen, (C1-C4)alkyl, and (C2-C4)alkenyl, or R1 and R3 taken together with the atoms to which they are attached, form a 5-6 membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by
(C1-C4)alkyl;
or any two R3 groups taken together with the atoms to which they are attached, form a 4-, 5-, 6-, or 7-membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; and
wherein at least one R3 is not hydrogen.
The present invention relates to compounds according to Formula (I) or
pharmaceutically acceptable salts thereof:
Figure imgf000011_0001
wherein:
R1 is hydrogen, (C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkenyl-NH2, -(C1- C4)alkyl=NH, -NH2, 5-6 membered heteroaryl or 9-10 membered heteroaryl,
wherein said 5-6 membered heteroaryl or 9-10 membered heteroaryl is optionally substituted by 1 or 2 substituents independently selected from hydroxyl, cyano, halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C2-C4)alkynyl, (C1- C4)alkoxy, 5-6 membered heterocycloalkyl-CO-, fused 5-6 membered
heterocycloalkyl, H2N-, (C1-C4)alkyl-NH-, ((C1-C4)alkyl)((C1-C4)alkyl)N-, -CONH2, H2NCO-(C1-C4)alkyl-, (C1-C4)alkylNHCO-, H2N(C1-C4)alkylNHCO-, (C1-C4)alkyl HN(C1-C4)alkylNHCO-, ((C1-C4)alkyl)((C1-C4)alkyl)N(C1-C4)alkylNHCO- (hydroxy-(C1-C4)alkyl)NHCO-, (C3-C6)cycloalkyl-NHCO-, 5-6 membered heterocycloalkyl-NHCO-, ((C1-C4)alkyl)((C1-C4)alkyl)N-CO-, (C1-C4)alkyl-CONH-, ((C1-C4)alkyl)((C1-C4)alkyl)N-NHCO-, -CO2H, -CO2(C1-C4)alkyl, (C1-C4)alkylthio-, phenyl-(C1-C4)alkylthio-, (C1-C4)alkyl-SO-, (C1-C4)alkyl-SO2-, phenyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein said (C1-C4)alkoxy is optionally substituted by hydroxyl, -CO2H, -CONH2, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; or said
5-6 membered heterocycloalkyl-CO-, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl is optionally substituted by (C1-C4)alkyl or oxo; or said 5-6 membered heterocycloalkyl-NHCO- is optionally substituted by (C1- C4)alkyl-CO-;
R2 is phenyl or 5-6 membered heteroaryl,
wherein said phenyl or 5-6 membered heteroaryl is optionally substituted by one, two, or three substituents independently selected from halogen, (C1-C4)alkyl, -(C1- C4)alkyl-NH2, -(C1-C4)alkyl-NH(C1-C4)alkyl, -(C1-C4)alkyl-N-((C1-C4)alkyl)((C1- C4)alkyl), (C1-C4)alkoxy, and cyano; and
each R3 is independently selected from hydrogen, halogen, (C1-C4)alkyl, -(C2-C4)alkenyl, and =O,
or R1 and R3 taken together with the atoms to which they are attached, form a 5-6 membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by
(C1-C4)alkyl;
or any two R3 groups taken together with the atoms to which they are attached, form a 4-, 5-, 6-, or 7-membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; and
wherein at least one R3 is not hydrogen. The compounds according to Formulas (I) and (II), or pharmaceutically acceptable salts thereof, inhibit the activity and/or function of RIP1 kinase. Accordingly, these compounds may be particularly useful for the treatment of RIP1 kinase-mediated diseases or disorders. Such RIP1 kinase-mediated diseases or disorders are diseases or disorders that are mediated by activation of RIP1 kinase, and as such, are diseases or disorders where inhibition of RIP1 kinase would provide benefit.
Another aspect of this invention relates to a pharmaceutical composition comprising a compound of Formula (I) or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
Another aspect of this invention relates to a pharmaceutical composition comprising a compound of Formula (II) or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
Another aspect of this invention relates to a method of treating a RIP1-mediated disease or disorder in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound of Formula (I) or pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising of a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
Another aspect of this invention relates to a method of treating a RIP1-mediated disease or disorder in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound of Formula (II) or pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising of a compound of Formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
Another aspect of this invention relates to a method of treating RIP1-mediated disease or disorder in a human in need thereof, wherein the the RIP1-mediated disease is amyotrophic lateral sclerosis.
In another aspect, the invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.
In another aspect, the invention provides a compound of Formula (II) or a pharmaceutically acceptable salt thereof for use in therapy.
In another aspect, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of RIP1-mediated diseases or disorders.
In another aspect, there is provided a compound of Formula (II) or a pharmaceutically acceptable salt thereof for use in the treatment of RIP1-mediated diseases or disorders.
In another aspect, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of RIP1-mediated diseases or disorders, wherein the RIP-1 mediated disease or disorder is amyotrophic lateral sclerosis.
In another aspect, there is provided a compound of Formula (II) or a pharmaceutically acceptable salt thereof for use in the treatment of RIP1-mediated disease or disorders, wherein the RIP1-mediated disease or disorder is amyotrophic lateral sclerosis. In another aspect, there is provided the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of diseases or disorders mediated by RIP1.
In another aspect, there is provided the use of a compound of Formula (II) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of diseases or disorders mediated by RIP1.
In another aspect, there is provided the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of amyotrophic lateral sclerosis.
In another aspect, there is provided the use of a compound of Formula (II) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of amyotrophic lateral sclerosis.
In another aspect, there is provided methods of co-administering the presently invented compounds of Formula (I) or a pharmaceutically acceptable salt thererof with other active ingredients.
In another aspect, there is provided methods of co-administering the presently invented compounds of Formula (II) or a pharmaceutically acceptable salt thererof with other active ingredients. BRIEF DESCRIPTION OF THE DRAWINGS FIG.1A shows the temperature loss over time in mice after oral pre-dosing with Compounds A, B, C, D, or vehicle followed by simultaneous i.v. administration of mouse TNF and zVAD.
FIG.1B shows the temperature loss in mice 3 hours after oral pre-dosing with Compounds A, B, C, D, or vehicle followed by simultaneous i.v. administration of mouse TNF and zVAD.
FIG.2A shows the temperature loss over time in mice after oral pre-dosing with Compounds E, F, G, H or vehicle followed by simultaneous i.v. administration of mouse TNF and zVAD.
FIG.2B shows the temperature loss in mice 3 hours after oral pre-dosing with Compounds E, F, G, H or vehicle followed by simultaneous i.v. administration of mouse TNF and zVAD. FIG.3A shows the temperature loss over time in mice after oral pre-dosing with Compound A or vehicle followed by simultaneous i.v. administration of mouse TNF and zVAD.
FIG.3B shows the temperature loss in mice 3 hours after oral pre-dosing with Compound A or vehicle followed by simultaneous i.v. administration of mouse TNF and zVAD.
Figure 4A shows the temperature loss over time in mice after oral pre-dosing with Compound H or vehicle followed by simultaneous i.v. administration of mouse TNF and zVAD.
FIG.4B shows the temperature loss in mice 2 hours after oral pre-dosing with Compound H or vehicle followed by simultaneous i.v. administration of mouse TNF and zVAD.
FIG.5A shows the temperature loss over time in mice after oral pre-dosing with Compound A or vehicle followed by simultaneous i.v. administration of mouse TNF.
FIG.5B shows the temperature loss in mice 7.5 hours after oral pre-dosing with Compound A or vehicle followed by simultaneous i.v. administration of mouse TNF.
FIG 6A shows the scotopic B-wave electroretinography recordings at P39 and P46 in Rd10 mice after startof daily in-diet dosing with Compound A or control diet at P28 followed by switch from dark rearing to 12-hour light/dark cycle at P30.
FIG.6B shows the photopic B-wave electroretinography recordings at P39 and P46 in Rd10 mice after startof daily in-diet dosing with Compound A or control diet at P28 followed by switch from dark rearing to 12-hour light/dark cycle at P30.
FIG.6C shows the measurement of the thickness of the Outer Nuclear Cell (ONL) layers at various distances from the Optic Nerve Head (ONH) in hematoxylin and eosin stained retinal tissue sections collected at P46 in Rd10 mice after start of daily in-diet dosing with Compound A or control diet at P28 followed by switch from dark rearing to 12-hour light/dark cycle at P30.
FIG.7 shows the clinical scores over time in mice after daily in-diet dosing with Compound A or control diet followed by induction of experimental autoimmune
encephalomyelitis with MOG35-55, heat inactivated Mycobacterium tuberculosis, and pertussis toxin.
FIG.8A shows Compound A improves fed blood glucose over time without altering body weight in db/db mice. (* p<0.05)
FIG.8B shows Compound A improves fed blood glucose over time without altering body weight in db/db mice.
FIG.9A shows Compound A improves fasted blood glucose without altering body weight in db/db mice at 8 weeks of dosing. (* p<0.05)
FIG.9B shows Compound A improves fasted blood glucose without altering body weight in db/db mice at 8 weeks of dosing.
FIG 10A shows effect of Compound A on food intake and body weight in obese, high fat diet-fed mice. (* p<0.05; ** p<0.001)
FIG 10B shows effect of Compound A on food intake and body weight in obese, high fat diet-fed mice. (**p<0.001)
FIG.11A shows subcutaneous pancreatic tumor model with Compound A alone or in combination with anti-PD1. 
FIG.11B shows subcutaneous bladder tumor model with Compound A alone or in combination with anti-PD1.
FIG.12A shows the percentage of mice without severe dermatitis over time. After weaning mice received daily in-diet dosing with Compound A or control diet as indicated and were monitored for development of dermatitis.
FIG.12B shows the percentage of mice without severe dermatitis over time. Once mice developed clinical signs of dermatitis (about 6 weeks of age), mice received daily in- diet dosing with Compound A or control diet as indicated and were monitored for development of severe dermatitis.
FIG.13 shows an Oak Ridge Thermal Ellipsoid Plot (ORTEP), a representation of molecular structure as determined by X-ray diffraction, of 6-((3R,4S)-4-((S)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide.
DETAILED DESCRIPTION OF THE INVENTION This invention relates to compounds of Formulas (I) and (II) as defined above or pharmaceutically acceptable salts thereof.
In one embodiment, this invention relates to compounds of Formula (I) wherein: R1 is furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl,
wherein said furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl is optionally substituted by 1 or 2 substituents independently selected from hydroxyl, cyano, halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C2-C4)alkynyl, (C1-C4)alkoxy, 5-6 membered heterocycloalkyl-CO-, fused 5-6 membered heterocycloalkyl; H2N-, (C1-C4)alkyl-NH-, ((C1-C4)alkyl)((C1- C4)alkyl)N-, -CONH2, H2NCO-(C1-C4)alkyl-, (C1-C4)alkylNHCO-, (hydroxy-(C1- C4)alkyl)NHCO-, (C3-C6)cycloalkyl-NHCO-, 5-6 membered heterocycloalkyl-NHCO-, ((C1- C4)alkyl)((C1-C4)alkyl)NCO-, (C1-C4)alkyl-CONH-, ((C1-C4)alkyl)((C1-C4)alkyl)N-NHCO-, -CO2H, -CO2(C1-C4)alkyl, (C1-C4)alkylthio-, phenyl-(C1-C4)alkylthio-, (C1-C4)alkyl-SO-, (C1-C4)alkyl-SO2-, phenyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein said (C1-C4)alkoxy is optionally substituted by hydroxyl, -CO2H, -CONH2, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; or said 5-6 membered heterocycloalkyl-CO-, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl is optionally substituted by (C1-C4)alkyl or oxo; or said 5-6 membered heterocycloalkyl- NHCO- is optionally substituted by (C1-C4)alkyl-CO-. In another embodiment, the invention relates to compounds of Formula (I) wherein R1 is oxadiazolyl, thiadiazolyl, or pyrimidinyl, wherein said oxadiazolyl, thiadiazolyl, or pyrimidinyl is optionally substituted by one or two substituents independently selected from (C1-C4)alkyl, -CONH2, (C1-C4)alkylNH-CO-, ((C1-C4)alkyl)((C1-C4)alkyl)N-CO-, (C1- C4)alkyl-SO-, and (C1-C4)alkyl-SO2-. In another embodiment, the invention relates to compounds of Formula (I) wherein R1 is oxadiazolyl, thiadiazolyl, or pyrimidinyl, wherein said oxadiazolyl, thiadiazolyl, or pyrimidinyl is optionally substituted by one substitutent selected from methyl, -
Figure imgf000017_0001
another embodiment, the invention relates to compounds of Formula (I) wherein R1 is pyrimidinyl, wherein said pyrimidinyl is optionally substituted by one substituent selected from -CONH2, CH3NHCO-, (CH3)2NCO-, CH3-SO-, and CH3-SO2-. In a specific embodiment, the invention relates to compound of Formula (I) wherein R1 is oxadiazolyl, wherein oxadiazolyl is substituted once by methyl. In another specific embodiment, the invention relates to compounds of Formula (I) wherein R1 is pyrimidinyl, wherein said pyrimidinyl is substituted once by (CH3)2NCO-. In another specific embodiement, the invention relates to compounds of Formula (I) wherein R1 is pyrimidinyl, wherein said pyrimidinyl is substituted once by (CH3)NHCO-. In yet another specific embodiment, the invention relates to componds of Formula (I) wherein R1 is pyrimidinyl, wherein said pyrimidinyl is substituted once by -CONH2.
In one embodiment, this invention relates to compounds of Formula (I) wherein R2 is phenyl, wherein said phenyl is optionally substituted by two or three halogens. In another embodiment, this invention relates to compounds of Formula (I) wherein R2 is phenyl, wherein said phenyl is optionally substituted by two or three fluoros. In another embodiment, this invention relates to compounds of Formula (I) wherein R2 is phenyl, wherein said phenyl is substituted by two or three fluoros. In a specific embodiment, this invention relates to compounds of Formula (I) wherein R2 is phenyl, wherein said phenyl is substituted by two fluoros. In yet another specific embodiment, this invention relates to compounds of Formula (I) wherein R2 is phenyl, wherein said phenyl is substituted by three fluoros.
In one embodiment, this invention relates to compounds of Formula (I) wherein each R3 is independently selected from hydrogen, halogen, (C1-C4)alkyl, wherein at least one R3 is not hydrogen. In yet another embodiment, this invention relates to compounds of Formula (I) wherein each R3 is independently selected from hydrogen, fluoro, or methyl, wherein at least one R3 is not hydrogen. In a specific embodiment, this invention relates to compounds of Formula (I) wherein each R3 is independently selected from hydrogen and fluoro, wherein at least one R3 is not hydrogen. In a specific embodiment, this invention relates to compounds of Formula (I) wherein each R3 is independently selected from hydrogen and methyl, wherein at least one R3 is not hydrogen. In one embodiment, this invention relates compounds of Formula (I) wherein: R1 is hydrogen, -(C2-C4)alkenyl, -(C2-C4)alkenyl-NH2, -(C1-C4)alkyl=NH, -NH2, or 5- 6 membered heteroaryl,
wherein said 5-6 membered heteroaryl is optionally substituted by 1 or 2 substituents selected from (C1-C4)alkyl, -CONH2, (C1-C4)alkylNHCO-, ((C1-C4)alkyl)((C1- C4)alkyl)NCO-, (C1-C4)alkyl-SO-, and (C1-C4)alkyl-SO2-;
R2 is phenyl, wherein said phenyl optionally substituted by one, two, or three halogens;
each R3 is independently selected from hydrogen, halogen, (C1-C4)alkyl, and -(C2- C4)alkenyl,
or R1 and R3 taken together with the atoms to which they are attached, form a 5-6 membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by
(C1-C4)alkyl;
or any two R3 groups taken together with the atoms to which they are attached, form a 4-, 5-, 6-, or 7-membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; and
wherein at least one R3 is not hydrogen. In another embodiment, this invention relates compounds of Formula (I) wherein: R1 is 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl is optionally substituted by 1 or 2 substituents selected from (C1-C4)alkyl, -CONH2, (C1-C4)alkyl-NHCO-, ((C1-C4)alkyl)((C1-C4)alkyl)NCO-, (C1-C4)alkyl-SO-, and (C1-C4)alkyl-SO2-;
R2 is phenyl, wherein said phenyl optionally substituted by one, two, or three halogens;
each R3 is independently selected from hydrogen, halogen, (C1-C4)alkyl, and
-(C2-C4)alkenyl,
or R1 and R3 taken together with the atoms to which they are attached, form a 5-6 membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by
(C1-C4)alkyl;
or any two R3 groups taken together with the atoms to which they are attached, form a 4-, 5-, 6-, or 7-membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; and wherein at least one R3 is not hydrogen.
In another embodiment, this invention relates compounds of Formula (I) wherein: R1 is 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl is optionally substituted by 1 or 2 substituents selected from (C1-C4)alkyl, -CONH2,
(C1-C4)alkylNHCO-, ((C1-C4)alkyl)((C1-C4)alkyl)NCO-, (C1-C4)alkyl-SO-, and (C1-C4)alkyl- SO2-;
R2 is phenyl, wherein said phenyl optionally substituted by two or three halogens; each R3 is independently selected from hydrogen, halogen, (C1-C4)alkyl, and
-(C2-C4)alkenyl,
or R1 and R3 taken together with the atoms to which they are attached, form a 5-6 membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by
(C1-C4)alkyl;
or any two R3 groups taken together with the atoms to which they are attached, form a 4-, 5-, 6-, or 7-membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; and
wherein at least one R3 is not hydrogen. In another embodiment, this invention relates compounds of Formula (I) wherein: R1 is oxadiazolyl, thiadiazolyl, or pyrimidinyl, wherein said oxadiazolyl, thiadiazolyl, or pyrimidinyl is optionally substituted by 1 or 2 substituents selected from (C1-C4)alkyl, - CONH2, (C1-C4)alkylNHCO-, ((C1-C4)alkyl)((C1-C4)alkyl)NCO-, (C1-C4)alkyl-SO-, and (C1- C4)alkyl-SO2-;
R2 is phenyl, wherein said phenyl optionally substituted by two or three halogens; each R3 is independently selected from hydrogen, halogen, (C1-C4)alkyl, and
-(C2-C4)alkenyl,
or R1 and R3 taken together with the atoms to which they are attached, form a 5-6 membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by
(C1-C4)alkyl;
or any two R3 groups taken together with the atoms to which they are attached, form a 4-, 5-, 6-, or 7-membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; and wherein at least one R3 is not hydrogen. In one embodiment, this invention relates to compounds of Formula (II) wherein: R1 is furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl,
wherein said furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl is optionally substituted by 1 or 2 substituents independently selected from hydroxyl, cyano, halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C2-C4)alkynyl, (C1-C4)alkoxy, 5-6 membered heterocycloalkyl-CO-, fused 5-6 membered heterocycloalkyl; H2N-, (C1-C4)alkyl-NH-, ((C1-C4)alkyl)((C1- C4)alkyl)N-, -CONH2, H2NCO-(C1-C4)alkyl-, ((C1-C4)alkyl)NHCO-, (hydroxy-(C1- C4)alkyl)NHCO-, (C3-C6)cycloalkyl-NHCO-, 5-6 membered heterocycloalkyl-NHCO-, ((C1- C4)alkyl)((C1-C4)alkyl)NCO-, (C1-C4)alkyl-CONH-, ((C1-C4)alkyl)((C1-C4)alkyl)N-NHCO-, -CO2H, -CO2(C1-C4)alkyl, (C1-C4)alkylthio-, phenyl-(C1-C4)alkylthio-, (C1-C4)alkyl-SO-, (C1-C4)alkyl-SO2-, phenyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein said (C1-C4)alkoxy is optionally substituted by hydroxyl, -CO2H, -CONH2, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; or said 5-6 membered heterocycloalkyl-CO-, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl is optionally substituted by (C1-C4)alkyl or oxo; or said 5-6 membered heterocycloalkyl- NHCO- is optionally substituted by (C1-C4)alkyl-CO-. In another embodiment, the invention relates to compounds of Formula (II) wherein R1 is oxadiazolyl, thiadiazolyl, or pyrimidinyl, wherein said oxadiazolyl, thiadiazolyl, or pyrimidinyl is optionally substituted by one or two substituents independently selected from (C1-C4)alkyl, -CONH2, (C1-C4)alkylNH-CO-, ((C1-C4)alkyl)((C1-C4)alkyl)N-CO-, (C1- C4)alkyl-SO-, and (C1-C4)alkyl-SO2-. In another embodiment, the invention relates to compounds of Formula (II) wherein R1 is oxadiazolyl, thiadiazolyl, or pyrimidinyl, wherein said oxadiazolyl, thiadiazolyl, or pyrimidinyl is optionally substituted by one substitutent selected from methyl, -CONH2, CH3NHCO-, (CH3)2NCO-, CH3-SO-, and CH3-SO2-. In another embodiment, the invention relates to compounds of Formula (II) wherein R1 is pyrimidinyl, wherein said pyrimidinyl is optionally substituted by one substituent selected from -CONH2, CH3NHCO-, (CH3)2NCO-, CH3-SO-, and CH3-SO2-. In a specific embodiment, the invention relates to compound of Formula (II) wherein R1 is oxadiazolyl, wherein oxadiazolyl is substituted once by methyl. In another specific embodiment, the invention relates to compounds of Formula (II) wherein R1 is pyrimidinyl, wherein said pyrimidinyl is substituted once by (CH3)2NCO-. In another specific embodiement, the invention relates to compounds of Formula (II) wherein R1 is pyrimidinyl, wherein said pyrimidinyl is substituted once by (CH3)NHCO-. In yet another specific embodiment, the invention relates to componds of Formula (II) wherein R1 is pyrimidinyl, wherein said pyrimidinyl is substituted once by -CONH2.
In one embodiment, this invention relates to compounds of Formula (II) wherein R2 is phenyl, wherein said phenyl is optionally substituted by two or three halogens. In another embodiment, this invention relates to compounds of Formula (II) wherein R2 is phenyl, wherein said phenyl is optionally substituted by two or three fluoros. In another embodiment, this invention relates to compounds of Formula (II) wherein R2 is phenyl, wherein said phenyl is substituted by two or three fluoros. In a specific embodiment, this invention relates to compounds of Formula (II) wherein R2 is phenyl, wherein said phenyl is substituted by two fluoros. In yet another specific embodiment, this invention relates to compounds of Formula (II) wherein R2 is phenyl, wherein said phenyl is substituted by three fluoros.
In one embodiment, this invention relates to compounds of Formula (II) wherein each R3 is independently selected from hydrogen, halogen, (C1-C4)alkyl, wherein at least one R3 is not hydrogen. In yet another embodiment, this invention relates to compounds of Formula (II) wherein each R3 is independently selected from hydrogen, fluoro, or methyl, wherein at least one R3 is not hydrogen. In a specific embodiment, this invention relates to compounds of Formula (II) wherein each R3 is independently selected from hydrogen and fluoro, wherein at least one R3 is not hydrogen. In a specific embodiment, this invention relates to compounds of Formula (II) wherein each R3 is independently selected from hydrogen and methyl, wherein at least one R3 is not hydrogen. In one embodiment, this invention relates compounds of Formula (II) wherein:
R1 is hydrogen, -(C2-C4)alkenyl, -(C2-C4)alkenyl-NH2, -(C1-C4)alkyl=NH, -NH2, or 5- 6 membered heteroaryl, wherein said 5-6 membered heteroaryl is optionally substituted by 1 or 2 substituents selected from (C1-C4)alkyl, -CONH2, (C1-C4)alkylNHCO-, ((C1-C4)alkyl)((C1- C4)alkyl)NCO-, (C1-C4)alkyl-SO-, and (C1-C4)alkyl-SO2-;
R2 is phenyl, wherein said phenyl optionally substituted by one, two, or three halogens;
each R3 is independently selected from hydrogen, halogen, (C1-C4)alkyl, and -(C2- C4)alkenyl,
or R1 and R3 taken together with the atoms to which they are attached, form a 5-6 membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by
(C1-C4)alkyl;
or any two R3 groups taken together with the atoms to which they are attached, form a 4-, 5-, 6-, or 7-membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; and
wherein at least one R3 is not hydrogen. In another embodiment, this invention relates compounds of Formula (II) wherein: R1 is 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl is optionally substituted by 1 or 2 substituents selected from (C1-C4)alkyl, -CONH2, (C1-C4)alkylNHCO-, ((C1-C4)alkyl)((C1-C4)alkyl)NCO-, (C1-C4)alkyl-SO-, and (C1-C4)alkyl-SO2-;
R2 is phenyl, wherein said phenyl optionally substituted by one, two, or three halogens;
each R3 is independently selected from hydrogen, halogen, (C1-C4)alkyl, and -(C2-C4)alkenyl,
or R1 and R3 taken together with the atoms to which they are attached, form a 5-6 membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by
(C1-C4)alkyl;
or any two R3 groups taken together with the atoms to which they are attached, form a 4-, 5-, 6-, or 7-membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; and
wherein at least one R3 is not hydrogen.
In another embodiment, this invention relates compounds of Formula (II) wherein: R1 is 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl is optionally substituted by 1 or 2 substituents selected from (C1-C4)alkyl, -CONH2,
(C1-C4)alkylNHCO-, ((C1-C4)alkyl)((C1-C4)alkyl)NCO-, (C1-C4)alkyl-SO-, and (C1-C4)alkyl- SO2-;
R2 is phenyl, wherein said phenyl optionally substituted by two or three halogens; each R3 is independently selected from hydrogen, halogen, (C1-C4)alkyl, and
-(C2-C4)alkenyl,
or R1 and R3 taken together with the atoms to which they are attached, form a 5-6 membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by
(C1-C4)alkyl;
or any two R3 groups taken together with the atoms to which they are attached, form a 4-, 5-, 6-, or 7-membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; and
wherein at least one R3 is not hydrogen. In another embodiment, this invention relates compounds of Formula (II) wherein: R1 is oxadiazolyl, thiadiazolyl, or pyrimidinyl, wherein said oxadiazolyl, thiadiazolyl, or pyrimidinyl is optionally substituted by 1 or 2 substituents selected from (C1-C4)alkyl, - CONH2, (C1-C4)alkylNHCO-, ((C1-C4)alkyl)((C1-C4)alkyl)NCO-, (C1-C4)alkyl-SO-, and (C1- C4)alkyl-SO2-;
R2 is phenyl, wherein said phenyl optionally substituted by two or three halogens; each R3 is independently selected from hydrogen, halogen, (C1-C4)alkyl, and
-(C2-C4)alkenyl,
or R1 and R3 taken together with the atoms to which they are attached, form a 5-6 membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by
(C1-C4)alkyl;
or any two R3 groups taken together with the atoms to which they are attached, form a 4-, 5-, 6-, or 7-membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; and
wherein at least one R3 is not hydrogen. Specific compounds of this invention include:
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((R)-3-methyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyridin-5-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((S)-3-methyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyridin-5-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((S)-3-methyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyridin-5-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((R)-3-methyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyridin-5-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((R)-2-methyl-4,5,6,7- tetrahydro-pyrazolo[1,5-a]pyridin-5-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((S)-2-methyl-4,5,6,7- tetrahydro-pyrazolo[1,5-a]pyridin-5-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((S)-2-methyl-4,5,6,7- tetrahydro-pyrazolo[1,5-a]pyridin-5-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((R)-2-methyl-4,5,6,7- tetrahydro-pyrazolo[1,5-a]pyridin-5-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((R)-1-methyl-5,6,7,8- tetrahydro-imidazo[1,5-a]pyridin-7-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((S)-1-methyl-5,6,7,8- tetrahydro-imidazo[1,5-a]pyridin-7-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((S)-1-methyl-5,6,7,8- tetrahydro-imidazo[1,5-a]pyridin-7-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((R)-1-methyl-5,6,7,8- tetrahydro-imidazo[1,5-a]pyridin-7-yl)methanone;
6-((1S,5R)-6-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-aza- bicyclo[3.1.1]heptan-3-yl)pyrimidine-4-carboxamide;
6-((1R,5S)-6-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-aza- bicyclo[3.1.1]heptan-3-yl)pyrimidine-4-carboxamide;
6-((1R,5S)-6-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-aza- bicyclo[3.1.1]heptan-3-yl)pyrimidine-4-carboxamide;
6-((1S,5R)-6-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- aza-bicyclo[3.1.1]heptan-3-yl)pyrimidine-4-carboxamide; ((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((1R,5S,6s)-3-(5-methyl- 1,3,4-oxadiazol-2-yl)-3-azabicyclo[3.1.1]heptan-6-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((1R,5S,6r)-3-(5-methyl- 1,3,4-oxadiazol-2-yl)-3-azabicyclo[3.1.1]heptan-6-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((1R,5S,6r)-3-(5-methyl- 1,3,4-oxadiazol-2-yl)-3-azabicyclo[3.1.1]heptan-6-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((1R,5S,6s)-3-(5-methyl- 1,3,4-oxadiazol-2-yl)-3-azabicyclo[3.1.1]heptan-6-yl)methanone;
6-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)-N-methylpyrimidine-4-carboxamide;
6-((3S,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)-N-methylpyrimidine-4-carboxamide;
6-((3S,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)-N-methylpyrimidine-4-carboxamide;
6-((3R,4S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)-N-methylpyrimidine-4-carboxamide;
6-((3S,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)-N,N-dimethylpyrimidine-4-carboxamide;
6-((3R,4S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)-N,N-dimethylpyrimidine-4-carboxamide;
6-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)-N,N-dimethylpyrimidine-4-carboxamide;
6-((3S,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)-N,N-dimethylpyrimidine-4-carboxamide;
(S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)-3-fluoro-1-(6- (methylsulfonyl)pyrimidin-4-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4R)-3-fluoro-1-(6- (methylsulfonyl)pyrimidin-4-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4R)-3-fluoro-1-(6- (methylsulfonyl)pyrimidin-4-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)-3-fluoro-1-(6- (methylsulfonyl)pyrimidin-4-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)-3-fluoro-1-(6-((S)- methylsulfinyl)pyrimidin-4-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4R)-3-fluoro-1-(6-((S)- methylsulfinyl)pyrimidin-4-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)-3-fluoro-1-(6-((R)- methylsulfinyl)pyrimidin-4-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4R)-3-fluoro-1-(6- ((R)-methylsulfinyl)pyrimidin-4-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4R)-3-fluoro-1-(6-((S)- methylsulfinyl)pyrimidin-4-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)-3-fluoro-1-(6-((S)- methylsulfinyl)pyrimidin-4-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4R)-3-fluoro-1-(6-((R)- methylsulfinyl)pyrimidin-4-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)-3-fluoro-1-(6- ((R)-methylsulfinyl)pyrimidin-4-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4R)-3-fluoro-1-(1,3,4- oxadiazol-2-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)-3-fluoro-1-(1,3,4- oxadiazol-2-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)-3-fluoro-1-(1,3,4- oxadiazol-2-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4R)-3-fluoro-1-(1,3,4- oxadiazol-2-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4R)-3-fluoro-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4R)-3-fluoro-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)-3-fluoro-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)-3-fluoro-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
6-((3R,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide; 6-((3S,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide;
6-((3S,4S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide;
6-((3R,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((2R,4R)-2-methyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((2R,4R)-2-methyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((2S,4S)-2-methyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((2S,4S)-2-methyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)-3-fluoro-1-(5- methyl-1,3,4-thiadiazol-2-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4R)-3-fluoro-1-(5- methyl-1,3,4-thiadiazol-2-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4R)-3-fluoro-1-(5- methyl-1,3,4-thiadiazol-2-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)-3-fluoro-1-(5- methyl-1,3,4-thiadiazol-2-yl)piperidin-4-yl)methanone;
6-((3R,4S)-3-fluoro-4-((S)-5-(2,3,5-trifluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)piperidin-1-yl)-N-methylpyrimidine-4-carboxamide;
6-((3S,4R)-3-fluoro-4-((R)-5-(2,3,5-trifluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)piperidin-1-yl)-N-methylpyrimidine-4-carboxamide;
6-((3S,4R)-3-fluoro-4-((S)-5-(2,3,5-trifluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)piperidin-1-yl)-N-methylpyrimidine-4-carboxamide;
6-((3R,4S)-3-fluoro-4-((R)-5-(2,3,5-trifluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)piperidin-1-yl)-N-methylpyrimidine-4-carboxamide;
6-((3R,4S)-3-fluoro-4-((S)-5-(2,3,5-trifluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)piperidin-1-yl)-N,N-dimethylpyrimidine-4-carboxamide;
6-((3S,4R)-3-fluoro-4-((R)-5-(2,3,5-trifluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)piperidin-1-yl)-N,N-dimethylpyrimidine-4-carboxamide;
6-((3S,4R)-3-fluoro-4-((S)-5-(2,3,5-trifluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)piperidin-1-yl)-N,N-dimethylpyrimidine-4-carboxamide;
6-((3R,4S)-3-fluoro-4-((R)-5-(2,3,5-trifluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)piperidin-1-yl)-N,N-dimethylpyrimidine-4-carboxamide;
((3S,4R)-3-fluoro-1-(6-((S)-methylsulfinyl)pyrimidin-4-yl)piperidin-4-yl)((S)-5- (2,3,5-trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((3R,4S)-3-fluoro-1-(6-((S)-methylsulfinyl)pyrimidin-4-yl)piperidin-4-yl)((R)-5- (2,3,5-trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((3S,4R)-3-fluoro-1-(6-((R)-methylsulfinyl)pyrimidin-4-yl)piperidin-4-yl)((S)-5- (2,3,5-trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((3R,4S)-3-fluoro-1-(6-((R)-methylsulfinyl)pyrimidin-4-yl)piperidin-4-yl)((R)-5- (2,3,5-trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((3R,4S)-3-fluoro-1-(6-((S)-methylsulfinyl)pyrimidin-4-yl)piperidin-4-yl)((S)-5- (2,3,5-trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((3S,4R)-3-fluoro-1-(6-((S)-methylsulfinyl)pyrimidin-4-yl)piperidin-4-yl)((R)-5- (2,3,5-trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((3R,4S)-3-fluoro-1-(6-((R)-methylsulfinyl)pyrimidin-4-yl)piperidin-4-yl)((S)-5- (2,3,5-trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((3S,4R)-3-fluoro-1-(6-((R)-methylsulfinyl)pyrimidin-4-yl)piperidin-4-yl)((R)-5- (2,3,5-trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((3R,4S)-3-fluoro-1-(6-(methylsulfonyl)pyrimidin-4-yl)piperidin-4-yl)((S)-5-(2,3,5- trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((3S,4R)-3-fluoro-1-(6-(methylsulfonyl)pyrimidin-4-yl)piperidin-4-yl)((R)-5-(2,3,5- trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((3S,4R)-3-fluoro-1-(6-(methylsulfonyl)pyrimidin-4-yl)piperidin-4-yl)((S)-5-(2,3,5- trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((3R,4S)-3-fluoro-1-(6-(methylsulfonyl)pyrimidin-4-yl)piperidin-4-yl)((R)-5-(2,3,5- trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((3R,4S)-3-fluoro-1-(1,3,4-oxadiazol-2-yl)piperidin-4-yl)((S)-5-(2,3,5- trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((3S,4R)-3-fluoro-1-(1,3,4-oxadiazol-2-yl)piperidin-4-yl)((R)-5-(2,3,5- trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone; ((3S,4R)-3-fluoro-1-(1,3,4-oxadiazol-2-yl)piperidin-4-yl)((S)-5-(2,3,5- trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((3R,4S)-3-fluoro-1-(1,3,4-oxadiazol-2-yl)piperidin-4-yl)((R)-5-(2,3,5- trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((3R,4S)-3-fluoro-1-(5-methyl-1,3,4-thiadiazol-2-yl)piperidin-4-yl)((S)-5-(2,3,5- trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((3S,4R)-3-fluoro-1-(5-methyl-1,3,4-thiadiazol-2-yl)piperidin-4-yl)((R)-5-(2,3,5- trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((3S,4R)-3-fluoro-1-(5-methyl-1,3,4-thiadiazol-2-yl)piperidin-4-yl)((S)-5-(2,3,5- trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((3R,4S)-3-fluoro-1-(5-methyl-1,3,4-thiadiazol-2-yl)piperidin-4-yl)((R)-5-(2,3,5- trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((R)-3,3-dimethyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((S)-3,3-dimethyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((R)-3,3-dimethyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((S)-3,3-dimethyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((R)-3,3-difluoro-1-(5-methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)((R)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((S)-3,3-difluoro-1-(5-methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)((S)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((R)-3,3-difluoro-1-(5-methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)((S)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((S)-3,3-difluoro-1-(5-methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)((R)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((R)-3,3-dimethyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((R)-3,3-dimethyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((S)-3,3-dimethyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((S)-3,3-dimethyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4R)-3-fluoro-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4R)-3-fluoro-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4R)-3-methyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4S)-3-methyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4S)-3-methyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4R)-3-methyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4R)-3-methyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)-3-methyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4R)-3-methyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)-3-methyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
6-((3R,4S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- methylpiperidin-1-yl)pyrimidine-4-carboxamide;
6-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- methylpiperidin-1-yl)pyrimidine-4-carboxamide;
6-((3S,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- methylpiperidin-1-yl)pyrimidine-4-carboxamide;
6-((3S,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- methylpiperidin-1-yl)pyrimidine-4-carboxamide;
6-((3S,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- methylpiperidin-1-yl)pyrimidine-4-carboxamide; 6-((3R,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- methylpiperidin-1-yl)pyrimidine-4-carboxamide;
6-((3R,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- methylpiperidin-1-yl)pyrimidine-4-carboxamide;
6-((3S,4S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- methylpiperidin-1-yl)pyrimidine-4-carboxamide;
6-((2R,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-2- methylpiperidin-1-yl)pyrimidine-4-carboxamide;
6-((2R,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-2- methylpiperidin-1-yl)pyrimidine-4-carboxamide;
6-((2S,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-2- methylpiperidin-1-yl)pyrimidine-4-carboxamide;
6-((2S,4S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-2- methylpiperidin-1-yl)pyrimidine-4-carboxamide;
6-((3S,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide;
6-((3S,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide;
6-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide;
6-((3R,4S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide;
6-((S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3,3- dimethylpiperidin-1-yl)pyrimidine-4-carboxamide;
6-((R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3,3- dimethylpiperidin-1-yl)pyrimidine-4-carboxamide;
6-((S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3,3- dimethylpiperidin-1-yl)pyrimidine-4-carboxamide;
6-((R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3,3- dimethylpiperidin-1-yl)pyrimidine-4-carboxamide;
6-((R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3,3- difluoropiperidin-1-yl)pyrimidine-4-carboxamide;
6-((R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3,3- difluoropiperidin-1-yl)pyrimidine-4-carboxamide;
6-((S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3,3- difluoropiperidin-1-yl)pyrimidine-4-carboxamide;
6-((S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3,3- difluoropiperidin-1-yl)pyrimidine-4-carboxamide;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((R)-2,2-dimethyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((S)-2,2-dimethyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((R)-2,2-dimethyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((S)-2,2-dimethyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
6-((R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-2,2- dimethylpiperidin-1-yl)pyrimidine-4-carboxamide;
6-((S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-2,2- dimethylpiperidin-1-yl)pyrimidine-4-carboxamide;
6-((R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-2,2- dimethylpiperidin-1-yl)pyrimidine-4-carboxamide; and
6-((S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-2,2- dimethylpiperidin-1-yl)pyrimidine-4-carboxamide;
or pharmaceutically acceptable salts thereof. Specific compounds of this invention include:
2-((3S,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)thiazole-5-carbonitrile;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4R)-3-fluoro-1-(3- methyl-1,2,4-thiadiazol-5-yl)piperidin-4-yl)methanone;
((3S,4R)-1-(6-chloro-5-fluoropyrimidin-4-yl)-3-fluoropiperidin-4-yl)((S)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone’
6-((3S,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)picolinamide;
2-((3S,4R)-3-fluoro-4-((S)-5-(5-fluoropyridin-3-yl)-4,5-dihydro-1H-pyrazole-1- carbonyl)piperidin-1-yl)thiazole-5-carbonitrile;
6-((3S,4R)-3-fluoro-4-((S)-5-(5-fluoropyridin-3-yl)-4,5-dihydro-1H-pyrazole-1- carbonyl)piperidin-1-yl)pyrimidine-4-carboxamide;
6-((3S,4R)-3-fluoro-4-((S)-5-(2-fluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)piperidin-1-yl)pyrimidine-4-carboxamide;
6-((3S,4R)-3-fluoro-4-((R)-5-(2-fluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)piperidin-1-yl)pyrimidine-4-carboxamide;
6-((3S,4R)-3-fluoro-4-((R)-5-(3-fluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)piperidin-1-yl)pyrimidine-4-carboxamide;
6-((3S,4R)-3-fluoro-4-((S)-5-(3-fluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)piperidin-1-yl)pyrimidine-4-carboxamide;
6-((3S,4R)-4-((R)-5-(2,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide;
6-((3S,4R)-4-((S)-5-(2,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide;
2-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)thiazole-5-carbonitrile;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)-3-fluoro-1-(3- methyl-1,2,4-thiadiazol-5-yl)piperidin-4-yl)methanone;
6-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)picolinamide;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)-3-fluoro-1-(1,3,4- thiadiazol-2-yl)piperidin-4-yl)methanone;
2-((3R,4S)-3-fluoro-4-((S)-5-(5-fluoropyridin-3-yl)-4,5-dihydro-1H-pyrazole-1- carbonyl)piperidin-1-yl)thiazole-5-carbonitrile;
6-((3R,4S)-3-fluoro-4-((S)-5-(5-fluoropyridin-3-yl)-4,5-dihydro-1H-pyrazole-1- carbonyl)piperidin-1-yl)pyrimidine-4-carboxamide;
6-((3R,4S)-3-fluoro-4-((S)-5-(2-fluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)piperidin-1-yl)pyrimidine-4-carboxamide;
6-((3R,4S)-3-fluoro-4-((R)-5-(2-fluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)piperidin-1-yl)pyrimidine-4-carboxamide;
6-((3R,4S)-3-fluoro-4-((S)-5-(3-fluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)piperidin-1-yl)pyrimidine-4-carboxamide; 6-((3R,4S)-3-fluoro-4-((R)-5-(3-fluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)piperidin-1-yl)pyrimidine-4-carboxamide;
6-((3R,4S)-4-((S)-5-(2,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide;
6-((3R,4S)-4-((R)-5-(2,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide;
6-((3R,4S)-4-((S)-5-(3-cyano-5-fluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide;
6-((3R,4S)-4-((R)-5-(3-cyano-5-fluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide;
6-((3R,4S)-4-((S)-5-(3-(aminomethyl)-5-fluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide;
6-((3R,4S)-4-((R)-5-(3-(aminomethyl)-5-fluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide;
N-(2-aminoethyl)-6-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H- pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide;
N-(2-aminoethyl)-6-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H- pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide;
(R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-1- methylpiperidin-2-one;
(S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-1- methylpiperidin-2-one;
(S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-1- methylpiperidin-2-one;
(R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-1- methylpiperidin-2-one;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)-3-fluoro-1-(1,2,4- oxadiazol-3-yl)piperidin-4-yl)methanone;
or pharmaceutically acceptable salts thereof. In one embodiment, this invention is directed to 6-((3R,4R)-4-((R)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide or a pharmaceutically acceptable salt thereof. In another embodiment, this invention is directed to 6-((3S,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide or a pharmaceutically acceptable salt thereof. In another embodiment, this invention is directed to 6-((3S,4S)-4-((R)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide or pharmaceutically acceptable salt thereof. In still another embodiment, this invention is directed to 6-((3R,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide or a pharmaceutically acceptable salt thereof. In another embodiment, this invention is directed to 6-((3S,4R)-4-((S)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide or a pharmaceutically acceptable salt thereof. In another embodiment, this invention is directed to 6-((3S,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide or a pharmaceutically acceptable salt thereof. In another embodiment, this invention is directed to 6-((3R,4S)-4-((S)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide or a pharmaceutically acceptable salt thereof. In another embodiment, this invention is directed to 6-((3R,4S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide or a pharmaceutically acceptable salt thereof. It will be appreciated that the present invention encompasses compounds of Formula (I) and Formula (II) as the free base or free acid and as pharmaceutically acceptable salts thereof. In one embodiment, the invention relates to compounds of Formula (I) and Formula (II) in the form of a free base. In one embodiment, the invention relates to compounds of Formula (I) and Formula (II) in the form of a free acid. In another embodiment, the invention relates to compounds of Formulas (I) and (II) in the form of a pharmaceutically acceptable salt. It will be further appreciated that, in one embodiment, the invention relates to compounds of the Examples in the form of a free base. In another embodiment, the invention relates to compounds of the Examples in the form of a a pharmaceutically acceptable salt.
It is to be understood that the references herein to a compound of Formula (I) or Formula (II), or a salt thereof, includes a compound of Formula (I) or Formula (II) as a free base, acid, or as a salt thereof, for example as a pharmaceutically acceptable salt thereof. Thus, in one embodiment, the invention is directed to a compound of Formula (I) or Formula (II). In a further embodiment, the invention is directed to a pharmaceutically acceptable salt of a compound of Formula (I) or Formula (II). In a further embodiment, the invention is directed to a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof.
Because of their potential use in medicine, it will be appreciated that a salt of a compound of Formula (I) or Formula (II) is preferably pharmaceutically acceptable. Suitable pharmaceutically acceptable salts can include acid or base addition salts.
Pharmaceutically acceptable salts include, amongst others, those described in Berge, J. Pharm. Sci., 66, 1-19, (1977) or those listed in P.H. Stahl and C.G. Wermuth, editors, Handbook of Pharmaceutical Salts; Properties, Selection and Use, Second Edition
Stahl/Wermuth: Wiley- VCH/VHCA (2011) (see
http://www.wiley.com/WileyCDA/WileyTitle/productCd-3906390519.html).
Suitable pharmaceutically acceptable salts can include acid or base addition salts. Such base addition salts can be formed by reaction of a compound of Formula (I) or Formula (II) (which, for example, contains a carboxylic acid or other acidic functional group) with the appropriate base, optionally in a suitable solvent such as an organic solvent, to give the salt which can be isolated by a variety of methods, including crystallisation and filtration.
Such acid addition salts can be formed by reaction of a compound of Formula (I) or Formula (II) (which, for example contains a basic amine or other basic functional group) with the appropriate acid, optionally in a suitable solvent such as an organic solvent, to give the salt which can be isolated by a variety of methods, including crystallisation and filtration.
Salts may be prepared in situ during the final isolation and purification of a compound of Formula (I) or Formula (II). If a basic compound of Formula (I) or Formula (II) is isolated as a salt, the corresponding free base form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic base, suitably an inorganic or organic base having a higher pKa than the free base form of the compound. Similarly, if a compound of Formula (I) or Formula (II) containing a carboxylic acid or other acidic functional group is isolated as a salt, the corresponding free acid form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic acid. This invention also provides for the conversion of one salt of a compound of this invention, e.g., a hydrochloride salt, into another salt of a compound of this invention, e.g., a sulfate salt.
It will be understood that if a compound of Formula (I) or Formula (II) contains two or more basic moieties, the stoichiometry of salt formation may include 1, 2 or more equivalents of acid. Such salts would contain 1, 2 or more acid counterions, for example, a dihydrochloride salt.
Stoichiometric and non-stoichiometric forms of a pharmaceutically acceptable salt of a compound of Formula (I) or Formula (II) are included within the scope of the invention, including sub-stoichiometric salts, for example where a counterion contains more than one acidic proton.
Representative pharmaceutically acceptable acid addition salts include, but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate,
benzenesulfonate (besylate), benzoate, bisulfate, bitartrate, butyrate, calcium edetate, camphorate, camphorsulfonate (camsylate), caprate (decanoate), caproate (hexanoate), caprylate (octanoate), cinnamate, citrate, cyclamate, digluconate, 2,5-dihydroxybenzoate, disuccinate, dodecylsulfate (estolate), edetate (ethylenediaminetetraacetate), estolate (lauryl sulfate), ethane-1,2-disulfonate (edisylate), ethanesulfonate (esylate), formate, fumarate, galactarate (mucate), gentisate (2,5-dihydroxybenzoate), glucoheptonate (gluceptate), gluconate, glucuronate, glutamate, glutarate, glycerophosphorate, glycolate, hexylresorcinate, hippurate, hydrabamine (N,N'-di(dehydroabietyl)-ethylenediamine), hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, isobutyrate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, methanesulfonate (mesylate), methylsulfate, mucate, naphthalene-1,5-disulfonate (napadisylate), naphthalene-2-sulfonate (napsylate), nicotinate, nitrate, oleate, palmitate, p-aminobenzenesulfonate, p-aminosalicyclate, pamoate (embonate), pantothenate, pectinate, persulfate, phenylacetate, phenylethylbarbiturate, phosphate, polygalacturonate, propionate, p-toluenesulfonate (tosylate), pyroglutamate, pyruvate, salicylate, sebacate, stearate, subacetate, succinate, sulfamate, sulfate, tannate, tartrate, teoclate (8-chlorotheophyllinate), thiocyanate, triethiodide, undecanoate, undecylenate, and valerate.
Representative pharmaceutically acceptable base addition salts include, but are not limited to, aluminium, 2-amino-2-(hydroxymethyl)-1,3-propanediol (TRIS), arginine, benethamine (N-benzylphenethylamine), benzathine (N,N’-dibenzylethylenediamine), bis-(2- hydroxyethyl)amine, bismuth, calcium, chloroprocaine, choline, clemizole (1-p chlorobenzyl- 2-pyrrolildine-1’-ylmethylbenzimidazole), cyclohexylamine, dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lepidine, lithium, lysine, magnesium, meglumine (N-methylglucamine), piperazine, piperidine, potassium, procaine, quinine, quinoline, sodium, strontium, t-butylamine, tromethamine
(tris(hydroxymethyl)aminomethane), and zinc.
It will be understood that if a compound of Formula (I) or Formula (II) contained two or more basic moieties, the stoichiometry of salt formation may include 1, 2 or more equivalents of acid. Such salts would contain 1, 2 or more acid counterions, for example, a diacetate or a dihydrochloride salt.
Because the compounds of Formulas (I) and (II), or a pharmaceutically acceptable salt thereof, are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions.
The compounds of this invention may be particularly useful for the treatment of RIP1 kinase-mediated diseases or disorders. Such RIP1 kinase-mediated diseases or disorders are diseases or disorders that are mediated by activation of RIP1 kinase, and as such, are diseases or disorders where inhibition of RIP1 kinase would provide benefit.
In this invention, RIP1 kinase-mediated diseases or disorders are diseases or disorders that are mediated by activation of RIP1 kinase, and as such, are diseases or disorders where inhibition of RIP1 kinase would provide benefit. Such RIP1 kinase-mediated diseases or disorders are diseases/disorders which are likely to be regulated at least in part by programmed necrosis, apoptosis or the production of inflammatory cytokines, particularly inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), psoriasis, retinal detachment, retinal degeneration, retinitis pigmentosa, macular degeneration, age- related macular degeneration, pancreatitis, atopic dermatitis, arthritis (including rheumatoid arthritis, spondyloarthritis, gout, juvenile idiopathic arthritis (systemic onset juvenile idiopathic arthritis (SoJIA)), psoriatic arthritis), lupus, systemic lupus erythematosus (SLE), Sjogren’s syndrome, systemic scleroderma, anti-phospholipid syndrome (APS), vasculitis, osteoarthritis, liver damage/diseases (non-alcohol steatohepatitis (NASH), alcohol steatohepatitis (ASH), autoimmune hepatitis, autoimmune hepatobiliary diseases, primary sclerosing cholangitis (PSC), acetaminophen toxicity, hepatotoxicity), non-alcohol steatohepatitis (NASH), alcohol steatohepatitis (ASH), autoimmune hepatitis, non-alcoholic fatty liver disease (NAFLD), kidney damage/injury (nephritis, renal transplant, surgery, administration of nephrotoxic drugs e.g. cisplatin, acute kidney injury (AKI)) Celiac disease, autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP), transplant rejection (rejection of transplant organs, tissues and cells), ischemia reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome (SIRS), cerebrovascular accident (CVA, stroke), myocardial infarction (MI), atherosclerosis, Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), neonatal brain injury, neonatal hypoxic brain injury, ischemic brain injury, traumatic brain injury allergic diseases (including asthma and atopic dermatitis), peripheral nerve injury, burns, multiple sclerosis, type I diabetes, type II diabetes, obesity, Wegener’s granulomatosis, pulmonary sarcoidosis, Behcet’s disease, interleukin-1 converting enzyme (ICE, also known as caspase-1) associated fever syndrome, chronic obstructive pulmonary disease (COPD), cigarette smoke-induced damage, cystic fibrosis, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), a neoplastic tumor, peridontitis, NEMO- mutations (mutations of NF-kappa-B essential modulator gene (also known as IKK gamma or IKKG)), particularly, NEMO-deficiency syndrome, HOIL-1 deficiency (also known as RBCK1) heme-oxidized IRP2 ubiquitin ligase-1 deficiency), linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome, hematological and solid organ malignancies, bacterial infections and viral infections (such as influenza, staphylococcus, and
mycobacterium (tuberculosis)), and Lysosomal storage diseases (particularly, Gaucher disease, and including GM2 gangliosidosis, alpha-mannosidosis, aspartylglucosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis, infantile free sialic acid storage disease, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidoses disorders, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinoses, Pompe disease, pycnodysostosis, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay-Sachs, and Wolman disease), Stevens-Johnson syndrome, toxic epidermal necrolysis, glaucoma, spinal cord injury, fibrosis, complement- mediated cytotoxicity, pancreatic ductal adenocarcinoma, hepatocellular carcinoma, mesothelioma, melanoma, metastasis, breast cancer, non-small cell lung carcinoma
(NSCLC), radiation induced necrosis, ischemic kidney damage, ophthalmologic ischemia, intracerebral hemorrhage, subarachnoid hemorrhage, acute liver failure and radiation protection/mitigation, auditory disorders such as noise-induced hearing loss and drugs associated with ototoxicity such as cisplatin, or for the treatment of cells ex vivo to preserve vitality and function.
The compounds of the invention, particularly the compounds of Formula (I) and Formula (II), or a pharmaceutically acceptable salt thereof, may be particularly useful for the treatment of the following RIP1 kinase-mediated diseases or disorders: inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), psoriasis, retinal detachment, retinal degeneration, retinitis pigmentosa, macular degeneration, age-related macular degeneration, pancreatitis, atopic dermatitis, arthritis (including rheumatoid arthritis, spondyloarthritis, gout, systemic onset juvenile idiopathic arthritis (SoJIA), psoriatic arthritis), lupus, systemic lupus erythematosus (SLE), Sjogren’s syndrome, systemic scleroderma, anti-phospholipid syndrome (APS), vasculitis, osteoarthritis, liver
damage/diseases (non-alcohol steatohepatitis (NASH), alcohol steatohepatitis (ASH), autoimmune hepatitis, autoimmune hepatobiliary diseases, primary sclerosing cholangitis (PSC), acetaminophen toxicity, hepatotoxicity), non-alcholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), autoimmune hepatitis, non-alcoholic fatty liver disease (NAFLD), kidney damage/injury (nephritis, renal transplant, surgery, administration of nephrotoxic drugs e.g. cisplatin, acute kidney injury (AKI)) Celiac disease, autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP), transplant rejection (rejection of transplant organs, tissues and cells), ischemia reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome (SIRS), cerebrovascular accident (CVA, stroke), myocardial infarction (MI), atherosclerosis, Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), neonatal brain injury, neonatal hypoxic brain injury, traumatic brain injury, allergic diseases (including asthma and atopic dermatitis), peripheral nerve injury, burns, multiple sclerosis, type I diabetes, type II diabetes, obesity, Wegener’s granulomatosis, pulmonary sarcoidosis, Behcet’s disease, interleukin-1 converting enzyme (ICE, also known as caspase- 1) associated fever syndrome, chronic obstructive pulmonary disease (COPD), cigarette smoke-induced damage, cystic fibrosis, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), a neoplastic tumor, melanoma, metastasis, breast cancer, non-small cell lung carcinoma (NSCLC), radiation induced necrosis, ischemic kidney damage,
ophthalmologic ischemia, intracerebral hemorrhage, subarachnoid hemorrhage, peridontitis, NEMO-mutations (mutations of NF-kappa-B essential modulator gene (also known as IKK gamma or IKKG)), particularly, NEMO-deficiency syndrome, HOIL-1 deficiency ((also known as RBCK1) heme-oxidized IRP2 ubiquitin ligase-1 deficiency), linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome, hematological and solid organ malignancies, bacterial infections and viral infections (such as influenza, staphylococcus, and mycobacterium (tuberculosis)), and Lysosomal storage diseases (particularly, Gaucher disease, and including GM2 gangliosidosis, alpha-mannosidosis, aspartylglucosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis, infantile free sialic acid storage disease, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidoses disorders, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinoses, Pompe disease, pycnodysostosis, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay-Sachs, and Wolman disease), spinal cord injury, Stevens-Johnson syndrome, fibrosis, complement-mediated cytotoxicity, toxic epidermal necrolysis, and/or for the treatment of cells ex vivo to preserve vitality and function.
The compounds of the invention, particularly the compounds of Formula (I) and Formula (II), or a pharmaceutically acceptable salt thereof, may be particularly useful for the treatment of the following RIP1 kinase-mediated diseases or disorders, that is,
diseases/disorders which are likely to be regulated at least in part by RIP1 kinase activity, particularly inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), asthma, cigarette smoke-induced damage, cystic fibrosis, psoriasis, retinal detachment, retinal degeneration, retinitis pigmentosa, macular degeneration, atopic dermatitis, burn injury, periodontitis, a bacterial or viral infection (an infection with a pathogen including but not limited to influenza, staphylococcus, and/or mycobacterium (tuberculosis), systemic scleroderma (particularly, topical treatment of hardened and/or tightened skin areas), and/or ischemia reperfusion injury of solid organs/transplant rejection (particularly, topical treatment of donor organ (particularly kidney, liver, and heart and/or lung transplants), infusion of organ recipient), and topical treatment of bowels.
The compounds of the invention, particularly the compounds of Formula (I) and Formula (II), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of glaucoma.
The compounds of the invention, particularly the compounds of Formulas (I) and (II), or a pharmaceutically acceptable salt thereof, may be particularly useful for treatment of pancreatic ductal adenocarcinoma, hepatocellular carcinoma, mesothelioma, or melanoma. The compounds of the invention, particularly the compounds of Formulas (I) and (II), or a pharmaceutically acceptable salt thereof, may be particularly useful for the treatment of the following RIP1 kinase-mediated disease or disorder: rheumatoid arthritis, inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), and psoriasis.
The treatment of the above-noted diseases/disorders may concern, more specifically, the amelioration of organ injury or damage sustained as a result of the noted
diseases/disorders. For example, the compounds of this invention may be particularly useful for amelioration of brain tissue injury or damage following ischemic brain injury or traumatic brain injury, or for amelioration of heart tissue injury or damage following myocardial infarction, or for amelioration of brain tissue injury or damage associated with Huntington’s disease, Alzheimer’s disease or Parkinson’s disease, or for amelioration of liver tissue injury or damage associated with non-alcohol steatohepatitis, alcohol steatohepatitis, autoimmune hepatitis autoimmune hepatobiliary diseases, or primary sclerosing cholangitis, or overdose of acetaminophen.
The compounds of this invention may be particularly useful for the amelioration of organ injury or damage sustained as a result of radiation therapy, or amelioration of spinal tissue injury or damage following spinal cord injury or amelioration of liver tissue injury or damage associated acute liver failure. The compounds of this invention may be particularly useful for amelioration of auditory disorders, such as noise-induced hearing loss or auditory disorders following the administration of ototoxic drugs or substances e.g. cisplatin.
The compounds of this invention may be particularly useful for amelioration of solid organ tissue (particularly kidney, liver, and heart and/or lung) injury or damage following transplant or the administration of nephrotoxic drugs or substances e.g. cisplatin. It will be understood that amelioration of such tissue damage may be achieved where possible, by pre- treatment with a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof; for example, by pre-treatment of a patient prior to administration of cisplatin or pre-treatment of an organ or the organ recipient prior to transplant surgery. Amelioration of such tissue damage may be achieved by treatment with a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, during transplant surgery.
Amelioration of such tissue damage may also be achieved by short-term treatment of a patient with a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, after transplant surgery.
In one embodiment, the compounds of the invention, particularly the compounds of Formulas (I) and (II), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of retinal detachment, macular degeneration, and retinitis pigmentosa.
In another embodiment, the compounds of the invention, particularly the compounds of Formulas (I) and (II), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of multiple sclerosis.
In one embodiment, the compounds of the invention, particularly the compounds of Formulas (I) and (II), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of traumatic brain injury.
In another embodiment, the compounds of the invention, particularly the compounds of Formulas (I) and (II), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of Huntington's Disease, Alzheimer's Disease, amyotrophic lateral sclerosis, and Niemann-Pick disease.
In another embodiment, the compounds of the invention, particularly the compounds of Formula (I) and Formula (II), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), and Alzheimer’s disease.
In another embodiment, the compounds of the invention, particularly the compounds of Formulas (I) and (II), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of age-related macular degeneration.
The treatment of retinal detachment, macular degeneration, retinitis pigmentosa, multiple sclerosis, traumatic brain injury, Huntington's Disease, Alzheimer's Disease, amyotrophic lateral sclerosis, and Niemann-Pick disease may concern, more specifically, the amelioration of organ injury or damage sustained as a result of these diseases/disorders. For example, the compounds of this invention may be particularly useful for amelioration of brain tissue injury or damage following traumatic brain injury, or for amelioration of brain tissue injury or damage associated of Huntington's Disease, Alzheimer's Disease, amyotrophic lateral sclerosis, and Niemann-Pick disease.
In another embodiment, the compounds of the invention, particularly the compounds of Formulas (I) and (II), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of retinal detachment, macular degeneration, and retinitis pigmentosa, and the amelioration of brain tissue injury or damage as a result of multiple sclerosis, traumatic brain injury, Huntington's Disease, Alzheimer's Disease, amyotrophic lateral sclerosis, and Niemann-Pick disease. In another embodiment, the compounds of the invention, particularly the compounds of Formulas (I) and (II), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of Crohn’s disease, ulcerative colitis, psoriasis, rheumatoid arthritis,
spondyloarthritis, systemic onset juvenile idiopathic arthritis (SoJIA), and osteoarthritis.
In yet another embodiment, the compounds of this invention, particularly the compounds of Formula (I) and Formula (II), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of psoriasis, rheumatoid arthritis, and ulcerative and colitis.
In another embodiment, the compounds of this invention, particularly the compounds of Formula (I) and Formula (II), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of lupus, inflammatory bowel disease (IBD), Crohn’s disease, and ulcerative colitis.
In another embodiment, the compounds of the invention, particularly the compounds of Formulas (I) and (II), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of cerebrovascular accident (CVA, stroke), Huntington’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), traumatic brain injury, multiple sclerosis, Gaucher disease, Niemann-Pick disease, and spinal cord injury.
In another embodiment, the compounds of the invention, particularly the compounds of Formulas (I) and (II), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of amyotrophic lateral sclerosis (ALS).
In another embodiment, the compounds of the invention, particularly the compounds of Formulas (I) and (II), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of multiple sclerosis.
In another embodiment, the compounds of the invention, particularly the compounds of Formula (I) and Formula (II), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of pancreatic ductal adenocarcinoma (PDAC), metastasis, melanoma, breast cancer, non-small cell lung carcinoma (NSCLC), and radiation induced necrosis.
In another embodiment, the compounds of the invention, particularly the compounds of Formula (I) and Formula (II), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of pancreatic ductal adenocarcinoma (PDAC), metastasis, melanoma, breast cancer, and non-small cell lung carcinoma (NSCLC).
In another embodiment, the compounds of the invention, particularly the compounds of Formula (I) and Formula (II), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of pancreatic ductal adenocarcinoma (PDAC). In another emobodiment, the compounds of the invention, particularly the compounds of Formula (I) and Formula (II), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of intracerebral hemorrhage and subarachnoid hemorrhage.
In another emobodiment, the compounds of the invention, particularly the compounds of Formula (I) and Formula (II), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of type II diabetes and obesity.
In another emobodiment, the compounds of the invention, particularly the compounds of Formula (I) and Formula (II), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of atherosclerosis.
In another emobodiment, the compounds of the invention, particularly the compounds of Formula (I) and Formula (II), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of vasculitis.
In another emobodiment, the compounds of the invention, particularly the compounds of Formula (I) and Formula (II), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of burns.
In another emobodiment, the compounds of the invention, particularly the compounds of Formula (I) and Formula (II), or pharmaceutically acceptable salt thereof, may be useful for the treatment of ischemic kidney damage, ophthalmologic ischemia, intracerebral hemorrhage, and subarachnoid hemorrhage.
In another emobodiment, the compounds of the invention, particularly the compounds of Formula (I) and Formula (II), or pharmaceutically acceptable salt thereof, may be useful for the treatment of non-alcholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), autoimmune hepatitis, and non-alcoholic fatty liver disease (NAFLD).
The compounds of the invention, particularly the compounds of Formulas (I) and (II), or a pharmaceutically acceptable salt thereof, may be particularly useful for the treatment of the following RIP1 kinase-mediated diseases or disorders. In one aspect the human has a solid tumor. In one aspect the tumor is selected from head and neck cancer, gastric cancer, melanoma, renal cell carcinoma (RCC), esophageal cancer, non-small cell lung carcinoma (NSCLC), prostate cancer, colorectal cancer, ovarian cancer, pancreatic cancer, and pancreatic ductal adenocarcinoma. In one aspect the human has one or more of the following: colorectal cancer (CRC), esophageal cancer, cervical, bladder, breast cancer, head and neck cancer, ovarian cancer, melanoma, renal cell carcinoma (RCC), EC squamous cell carcinoma, non-small cell lung carcinoma, mesothelioma, prostate cancer, and pancreatic ductal adenocarcinoma. In another aspect, the human has a liquid tumor such as diffuse large B cell lymphoma (DLBCL), multiple myeloma, chronic lyphomblastic leukemia (CLL), follicular lymphoma, acute myeloid leukemia and chronic myelogenous leukemia.
The present disclosure also relates to a method for treating or lessening the severity of a cancer selected from: brain (gliomas), glioblastomas, astrocytomas, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, triple negative breast cancer, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, head and neck cancer (including squamous cell carcinoma of head and neck), kidney cancer, lung cancer (including lung squamous cell carcinoma, lung adenocarcinoma, lung small cell carcinoma, and non-small cell lung carcinoma), liver cancer (including hepatocellular carcinoma), melanoma, ovarian cancer, pancreatic cancer (including squamous pancreatic cancer), prostate cancer, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid cancer, lymphoblastic T-cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, Hodgkin’s lymphoma, Non-Hodgkin’s lymphoma, lymphoblastic T cell lymphoma, Burkitt’s lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, lung cancer, vulval cancer, cervical cancer, endometrial cancer, cancer of the uterus, renal cancer (including kidney clear cell cancer, kidney papillary cancer, renal cell carcinoma), mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer.
Specific examples of clinical conditions based on hematologic tumors include leukemias such as chronic myelocytic leukemia, acute myelocytic leukemia, chronic lymphocytic leukemia and acute lymphocytic leukemia; plasma cell malignancies such as multiple myeloma, MGUS and Waldenstrom’s macroglobulinemia; lymphomas such as non- Hodgkin’s lymphoma, Hodgkin’s lymphoma; and the like.
The cancer may be any cancer in which an abnormal number of blast cells or unwanted cell proliferation is present or that is diagnosed as a hematological cancer, including both lymphoid and myeloid malignancies. Myeloid malignancies include, but are not limited to, acute myeloid (or myelocytic or myelogenous or myeloblastic) leukemia (undifferentiated or differentiated), acute promyeloid (or promyelocytic or promyelogenous or promyeloblastic) leukemia, acute myelomonocytic (or myelomonoblastic) leukemia, acute monocytic (or monoblastic) leukemia, erythroleukemia and megakaryocytic (or
megakaryoblastic) leukemia. These leukemias may be referred together as acute myeloid (or myelocytic or myelogenous) leukemia (AML). Myeloid malignancies also include myeloproliferative disorders (MPD) which include, but are not limited to, chronic myelogenous (or myeloid) leukemia (CML), chronic myelomonocytic leukemia (CMML), essential thrombocythemia (or thrombocytosis), and polcythemia vera (PCV). Myeloid malignancies also include myelodysplasia (or myelodysplastic syndrome or MDS), which may be referred to as refractory anemia (RA), refractory anemia with excess blasts (RAEB), and refractory anemia with excess blasts in transformation (RAEBT); as well as
myelofibrosis (MFS) with or without agnogenic myeloid metaplasia.
Specific examples of clinical conditions based on hematologic tumors include leukemias such as chronic myelocytic leukemia, acute myelocytic leukemia, chronic lymphocytic leukemia and acute lymphocytic leukemia; plasma cell malignancies such as multiple myeloma, MGUS and Waldenstrom’s macroglobulinemia; lymphomas such as non- Hodgkin’s lymphoma, Hodgkin’s lymphoma; and the like.
Hematopoietic cancers also include lymphoid malignancies, which may affect the lymph nodes, spleens, bone marrow, peripheral blood, and/or extranodal sites. Lymphoid cancers include B-cell malignancies, which include, but are not limited to, B-cell non- Hodgkin’s lymphomas (B-NHLs). B-NHLs may be indolent (or low-grade), intermediate- grade (or aggressive) or high-grade (very aggressive). Indolent B cell lymphomas include follicular lymphoma (FL); small lymphocytic lymphoma (SLL); marginal zone lymphoma (MZL) including nodal MZL, extranodal MZL, splenic MZL and splenic MZL with villous lymphocytes; lymphoplasmacytic lymphoma (LPL); and mucosa-associated-lymphoid tissue (MALT or extranodal marginal zone) lymphoma. Intermediate-grade B-NHLs include mantle cell lymphoma (MCL) with or without leukemic involvement, diffuse large cell lymphoma (DLBCL), follicular large cell (or grade 3 or grade 3B) lymphoma, and primary mediastinal lymphoma (PML). High-grade B-NHLs include Burkitt’s lymphoma (BL), Burkitt-like lymphoma, small non-cleaved cell lymphoma (SNCCL) and lymphoblastic lymphoma. Other B-NHLs include immunoblastic lymphoma (or immunocytoma), primary effusion lymphoma, HIV associated (or AIDS related) lymphomas, and post-transplant lymphoproliferative disorder (PTLD) or lymphoma. B-cell malignancies also include, but are not limited to, chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), Waldenstrom’s macroglobulinemia (WM), hairy cell leukemia (HCL), large granular lymphocyte (LGL) leukemia, acute lymphoid (or lymphocytic or lymphoblastic) leukemia, and Castleman’s disease. NHL may also include T-cell non-Hodgkin’s lymphoma s(T- NHLs), which include, but are not limited to T-cell non-Hodgkin’s lymphoma not otherwise specified (NOS), peripheral T-cell lymphoma (PTCL), anaplastic large cell lymphoma (ALCL), angioimmunoblastic lymphoid disorder (AILD), nasal natural killer (NK) cell / T- cell lymphoma, gamma/delta lymphoma, cutaneous T cell lymphoma, mycosis fungoides, and Sezary syndrome.
Hematopoietic cancers also include Hodgkin’s lymphoma (or disease) including classical Hodgkin’s lymphoma, nodular sclerosing Hodgkin’s lymphoma, mixed cellularity Hodgkin’s lymphoma, lymphocyte predominant (LP) Hodgkin’s lymphoma, nodular LP Hodgkin’s lymphoma,and lymphocyte depleted Hodgkin’s lymphoma. Hematopoietic cancers also include plasma cell diseases or cancers such as multiple myeloma (MM) including smoldering MM, monoclonal gammopathy of undetermined (or unknown or unclear) significance (MGUS), plasmacytoma (bone, extramedullary), lymphoplasmacytic lymphoma (LPL), Waldenström’s Macroglobulinemia, plasma cell leukemia, and primary amyloidosis (AL). Hematopoietic cancers may also include other cancers of additional hematopoietic cells, including polymorphonuclear leukocytes (or neutrophils), basophils, eosinophils, dendritic cells, platelets, erythrocytes and natural killer cells. Tissues which include hematopoietic cells referred herein to as "hematopoietic cell tissues" include bone marrow; peripheral blood; thymus; and peripheral lymphoid tissues, such as spleen, lymph nodes, lymphoid tissues associated with mucosa (such as the gut-associated lymphoid tissues), tonsils, Peyer's patches and appendix, and lymphoid tissues associated with other mucosa, for example, the bronchial linings.
Treatment of RIP1-mediated disease conditions may be achieved using a compound of the invention, particularly a compound of Formula (I) or Formula (II), or a
pharmaceutically acceptable salt thereof, of as a monotherapy, or in dual or multiple combination therapy, particularly for the treatment of refractory cases, such as in combination with other anti-inflammatory and/or anti-TNF agents, which may be administered in therapeutically effective amounts as is known in the art. The compounds of the invention, particularly the compounds of Formula (I) and Formula (II), or a pharmaceutically acceptable salt thereof, may be employed alone or in combination with one or more other therapeutic agents, e.g., pharmaceutically active compounds or biologic products (e.g., monoclonal antibodies). Combination therapies according to the present invention thus comprise the administration of at least one compound of the invention, particularly a compound of Formula (I) or Formula (II), or a
pharmaceutically acceptable salt thereof, and at least one other theraputically active agent. Combination therapies according to the present invention comprise the administration of at least one compound of the invention, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, and at least one other therapeutic ally active agent, specifically one or two other therapeutically active agents, more specifically one other therapeutically active agent.
For example, amelioration of tissue damage may be achieved by treatment with a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, and at least one other therapeutically active agent during transplant surgery. Amelioration of tissue damage may also be achieved by short-term treatment of a patient with a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, and at least one other therapeutic ally active agent after transplant surgery. Amelioration of tissue damage ex vivo, that is ex vivo preservation of tissues, organs and cells may also be achieved by short-term treatment of tissues, organs and cells with a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, and at least one other therapeutic ally active agent, prior to or during transplant surgery.
The compound(s) of the invention, particularly the compounds of Formula (I) and Formula (II), or pharmaceutically acceptable salts thereof, and the other therapeutic agent(s) may be administered together in a single pharmaceutical composition or separately and, when administered separately this may occur simultaneously or sequentially in any order. The amounts of the compound(s) of the invention, particularly a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salts thereof, and the other therapeutic agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect. Thus, in a further aspect, there is provided a combination comprising a compound of the invention, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, together with one or more other therapeutic agents, specifically one or two other therapeutically active agents, more specifically one other therapeutically active agent. In one aspect, there is provided a combination comprising 6-((S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3,3-dimethylpiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof, together with one or more other therapeutic agents, specifically one or two other therapeutically active agents, more specifically one other therapeutically active agent. In one aspect, there is provided a combination comprising 6-((R)-4-((S)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3,3-dimethylpiperidin-1- yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof, together with one or more other therapeutic agents, specifically one or two other therapeutically active agents, more specifically one other therapeutically active agent. In another aspect, there is provided a combination comprising 6-((S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H- pyrazole-1-carbonyl)-3,3-dimethylpiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof, together with one or more other therapeutic agents, specifically one or two other therapeutically active agents, more specifically one other therapeutically active agent. In one aspect, there is provided a combination comprising 6- ((R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3,3- dimethylpiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof, together with one or more other therapeutic agents, specifically one or two other therapeutically active agents, more specifically one other therapeutically active agent.
Thus, in one aspect of this invention, a compound of the invention, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of the invention, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be used in combination with or include one or more other therapeutic agents, for example an anti-inflammatory agent and/or an anti-TNF agent.
The pharmaceutical compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. In other embodiments, the pharmaceutical compositions of the invention may comprise one or more additional therapeutic agents, specifically one or two other therapeutically active agents, more specifically one other therapeutically active agent.
A compound that inhibits RIP1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with other anti-inflammatory agents for any of the indications above, including oral or topical corticosteroids, anti-TNF agents, 5-aminosalicyclic acid and mesalamine preparations, hydroxycloroquine, thiopurines, methotrexate, cyclophosphamide, cyclosporine, calcineurin inhibitors, mycophenolic acid, mTOR inhibitors, JAK inhibitors, Syk inhibitors, anti-inflammatory biologic agents, including anti-IL6 biologics, anti-IL1 agents, anti-IL17 biologics, anti-CD22, anti-integrin agents, anti-IFNa, anti-CD20 or CD4 biologics and other cytokine inhibitors or biologics to T-cell or B-cell receptors or interleukins.
In the treatment of CVA, a compound that inhibits RIP1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with antiplatelets (e.g., aspirin, clopidogrel (Plavix®), dipyridamole (Persantine®), ticolpidine (Ticlid®); aspirin and omeprazole (Ysprala®)), anticoagulants (e.g., warfarin (Coumadin®), heparin®, dabigitran (Pradaxa®), apixaban (Eliquis®), rivaroxaban®), antihypertensives– diruetics (e.g., Hygroton®, Diuril®, Lasix®, Esidrix®, Hydrodiuril®, Microzide®, Lozol®, Mykrox®, Zaroxolyn®, Midarmar®, Aldactone®, Dyrenium®, Bumex®, Moduretic®, Aldatazide®, Dyazide®, Maxzide®), other antihypertensives– beta blockers, ace inhibitors, angiotensin II receptor blockers, calcium channel blockers, alpha blockers, alpha2 receptor agonist, combined alpha and beta-blockers, central agonists, peripheral adrenergic inhibitors, blood vessel dilators, or tissue plasminogen activator (Alteplase®).
In the treatment of SIRS, a compound that inhibits RIP1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with a broad-spectrum antibiotic (such as vacomycin) or other anti-MRSA therapy (cefeprime (Maxipime®), piperacillin/tazobactam(Zosyn®), carbapenem (imipenem, meropenem, doripenem), quinolones (ciprofloxacin, levofloxacin, ofloxacin, moxifloxacin, etc.), or low dose steroids such as hydrocortisones.
In the treatment of inflammatory bowel disease (particularly, Crohn’s disease and/or ulcerative colitis), a compound that inhibits RIP1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with vedolizumab (Entyvio®), alicaforsen, remestemcel-L (Prochymal®), etrolizumab, eldelumab, or bertilimumab.
In the treatment of psoriasis, a compound that inhibits RIP1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with ixekizumab, tildrakizumab (MK-3222), secukinumab (AIN457), Alefacept (Amevive®), calcipotriene and betamethasone dipropionate (Enstilar®), prednisone (Rayos®), tazorac topical gel, Methotrexate (Trexall®, Rheumatrex®, Folex PFS®, Otrexup®, Rasuvo®, Methotrexate LPF Sodium®), Cyclosporine®, fumaric acid, acitretin®, Tretinate®, UVA, UVB, Psoralen, coal tar, TNF inhibitors (Etanercept (Enbrel®), Infliximab (Remicade®), adalimumab (Humira®); certolizumab pegol (Cimzia®)), PDE-4 inhibitors (apremilast (Otezla®)), JAK inhibitors (Tofacitinib (Xeljanz® CP-690550), IL 12/23 (ustekinumab (Stelara®)), IL17 (secukinumab (Coxentyx®), ixekizumab (Taltz®), brodalumab with AMG-827), IL23 (tildrakizumab with MK-3222, guselkumab CNTO-1959, BI 655066, itolizumab (Alzumab®), biosimilars infliximab (Remsima (Inflectra®), Sandoz GP 11111), biosimilars rituximab (CT-P10 (Mabthera®), PF-05280586 (MabThera®)), biosimilars etanercept (CHS-2014), biosimilars adalimumab (GP-2017), M-518101 topical vitamin D; Maruho GK-664, or CT-327 (topical Tropomyosin-receptor kinase A), CF-101, or dimethyl fumarate LAS-41008.
In the treatment of periodonitis, a compound that inhibits RIP1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with an antimicrobial agent, (such as chlorhexidine
(Peridex®, PerioChip®, PerioGard®, etc.)) or an antibiotic (such as doxycycline (Vibrox®, Periostat®, Monodox®, Oracea®, Doryx®, etc.), or minocycline (Dynacin®, Minocin®, Arestin®, Dynacin®, etc.).
In the treatment of asthma, a compound that inhibits RIP1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with an inhaled corticosteroid (ICS) such as fluticasone proprionate (Flovent®), fluticasone furoate (Veramyst®/Avamys®), beclomethasone dipropionate (QVAR®), budesonide (Pulmicort), trimcinolone acetonide (Azmacort®), flunisolide (Aerobid®), mometasone fuorate (Asmanex® Twisthaler®), or Ciclesonide (Alvesco®), a long acting beta agonist (LABA) such as formoterol fumarate (Foradil®), salmeterol xinafoate (Serevent®), indacaterol (Arcapta®Neohaler®); a combination of an ICS and LABA (such as fluticasone furoate and vilanterol (Breo Ellipta®/Relvar Ellipta®), formoterol/budesonide inhalation (Symbicort®), mometasone furoate/ formoterol fumarate dihydrate (Dulera®), beclomethasone dipropionate/formoterol (Inuvair®), fluticasone propionate/eformoterol fumarate dehydrate (Flutiform®), and fluticasone
propionate/salmeterol (Advair®), a short acting beta agonist ((SABA) such as salbutamol dry- powder inhalation, albuterol sulfate (ProAir®, Proventil HFA®, Ventolin HFA®, AccuNeb® Inhalation Solution), levalbuterol tartrate (Xopenex® HFA), an antimuscarinic agent such as ipratropium bromide (Atrovent® HFA); an antimuscarinic in combination with a beta-agonist such as ipratropium bromide/albuterol (Combivent® Respimat®); a long-acting muscarinic antagonist ((LAMA) such as umeclidinium bromide (Incruse®) or tiotropium bromide (Spiriva®HandiHaler; a combination of a LAMA and a LABA, such as umeclidinium bromide and vilanterol (Anoro®) a leukotriene modifier (such as montelukast sodium (Singulair®), zafirlukast (Accolate®),or zileuton (Zyflo®), and anti-IgE (such as omalizumab (Xolair®)), a methylxanthine bronchodilator (such as theophylline (Accurbron®, Aerolate®, Aquaphyllin®, Asbron®, Bronkodyl®, Duraphyl®, Elixicon®, Elixomin®, Elixophyllin®, Labid®, Lanophyllin®, Quibron-T®, Slo-Bid®, Slo-Phyllin®, Somophyllin®, Sustaire®, Synophylate®, T-Phyll®, Theo-24®, Theo-Dur®, Theobid®, Theochron®, Theoclear®, Theolair®, Theolixir®, Theophyl®, Theovent®, Uni-dur®, Uniphyl®), a mast cell inhibitor (such as cromulyn sodium (Nasalcrom®) and nedocromil sodium (Tilade®)).
Other agents that may be suitable for use in combination therapy in the treatment of asthma include a protein tyrosine kinase inhibitor (masitinib), CRTH2/D-prostanoid receptor antangonist (AMG 853), an epinephrine inhalation aerosol (E004), reslizumab, Vectura’s VR506, lebrikizumab (RG3637), a combination phosphodiesterase (PDE)-3 and (PDE)-4 inhibitor (RPL554).
In the treatment of COPD, a compound that inhibits RIP1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with a LABA (such as salmeterol xinafoate (Serevent), aformoterol tartrate (Brovana®), formoterol fumarate inhalation powder (Foradil®), indacterol maleate (Arcapta® Neohaler®), a long-acting inhaled anticholinergic (or muscarinic antagonist, such as umeclidinium (Incruse Ellipta®), tiotropium bromide (Spiriva®), and aclidinium bromide (Tudorza® Pressair®), a phosphodiesterase (PDE-r) inhibitor (such as roflumilast, Daliresp®), a combination ICS/LABA (such as fluticasone furoate and vilanterol (Breo Ellipta®/Relvar Ellipta®), fluticasone propionate/salmeterol (Advair®), budesonide/formoterol (Symbicort®), mometasone/formoterol (Dulera®), or fluticasone propionate/eformoterol fumarate dehydrate (Flutiform®); an antimuscarinic such as such as ipratropium bromide (Atrovent®); an antimuscarinic in combination with a beta- agonist such as ipratropium bromide/albuterol (Combivent® Respimat®); a long-acting antimuscarinic such as umeclidinium bromide (Incruse®) or tiotropium bromide (Spiriva®); umeclidinium/vilanterol (Anoro Ellipta®); a combination of a LAMA and a LABA, such as umeclidinium bromide and vilanterol (Anoro®) .
Other agents that may be suitable for use in combination therapy in the treatment of COPD include SCH527123 (a CXCR2 antagonist), glycoprronium bromide ((NVA237) Seebri® Breezhaler®), glycopyrronium bromide and indacaterol maleate ((QVA149) Ultibro® Breezhaler®), glycopyrrolate and formoterol fumarate (PT003), indacaterol maleate (QVA149), olodaterol (Striverdi® Respimat®), tiotropium (Spiriva®)/olodaterol (Striverdi® Respimat®), and aclidinium/formoterol inhalation.
In the treatment of a mycobacterium infection (tuberculosis), a compound that inhibits RIP1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with an antimycobacterial agent (such as isoniazid (INH), ehambutol (Myambutol®), rifampin (Rifadin®), and pyrazinamide (PZA)) a bactericidal antibiotic (such as rifabutin (Mycobutin®) or rifapentine (Priftin®)), an aminoglycoside (Capreomycin®), a fluorquinolone (levofloxacin, moxifloxicin, ofloxacin), thioamide (ehionamide), cyclosporine (Sandimmune®), para-aminosalicyclic acid
(Paser®),cycloserine (Seromycin®), kanamycin (Kantrex®), streptomycin, viomycin, capreomycin (Capastat®)), bedaquiline fumarate (Sirturo®), oxazolidinone (Sutezolid®), or delamanid (OPC-67683).
In the treatment of systemic scleroderma, a compound that inhibits RIP1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with an oral corticosteroid (such as prednisolone (Delatsone®, Orapred, Millipred, Omnipred, Econopred, Flo-Pred), an immunosuppressive agent (such as methotrexate (Rhuematrex®, Trexall®), cyclosporine (Sandimmune®), anti- thymocyte globulin (Atgam®), mycophenolate mofetil (CellCept®), cyclophosphamide (Cytoxan®), FK506 (tacrolimus), thalidomide (Thalomid®), chlorambucil (Leukeran®), azathioprine (Imuran®, Azasan®)), a calcium channel blocker (such as nifedipine
(Procardia®, Adalat®) or nicardipine (Cardene®), a topical emollient (nitroglycerin ointment), an ACE inhibitor (such as lisinopril (Zestril®, Prinivil®), diltaizem (Cardizem®, Cardizem SR®, Cardizem CD®, Cardia®, Dilacor®, Tiazac®)), a serotonin reuptake inhibitor (such as fluoxetine (Prozac®)), an endothelin-1 receptor inhibitor (such as bosentan (Tracleer®) or epoprostenol (Flolan®, Veletri®, Prostacyclin®)) an anti-fibrotic agent (such as colchicines (Colcrys®), para-aminobenzoic acid (PABA), dimethyl sulfoxide (KMSO), and D-penicillamine (Cuprimine®, Depen®), interferon alpha and interferon gamma (INF-g)), a proton-pump Inhibitor (such as omeprazole (Prilosec®), metoclopramide (Reglan®), lansoprazole (Prevacid®), esomeprazole (Nexium®), pantoprazole (Protonix®), rabeprazole (Aciphex®)) or imatinib (Gleevec®) ARG201 (arGentis Pharmaceutical), belimumab (Benlysta®), tocilizumab (Actema®).
In the treatment of cystic fibrosis, a compound that inhibits RIP1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator (ivacftor (Kalydeco®)) a mucolytic agent (such as dornase alpha (Pulmozyme®)), pancreatic enzymes (such as Pancrelipase (Creon®, Pancreaze®, Ultresa®, Zenpep®)), a bronchodilator (such as albuterol (AccuNeb®, ProAir®, Proventil HFA®, VoSpire ER®, Ventolin HFA®)), an antibiotic (including inhaled, oral or parenteral, such as tobramycin solution for inhalation (TOBI®, Bethkis®, TOBI Podhaler®), aztreonam inhalation (Azactam®, Cayston®), colistimethate sodium (Coly-Mycin®), cephalosporins (cefadroxil monohydrate (Duricef®), cefazolin (Kefzol®), cephalexin (Keflex®), cefazolin (Ancef®, etc.), fluoroquinolones (moxifloxacin, levofloxacin, gemifloxacin, etc.), azithromycin (Zithromax®), gentamicin (Garamycin®), piperacillin/tazobacam (Zosyn®), cephalexin (Keflex), ceftazidime (Fortaz, Tazicef), ciprofloxin (Cipro XR, Proquin XR), trimethoprim/sulfamethoxazolyl (Bactrim DS, Septra DS), chloramphenicol)), or ivacftor (Kalydeco®)/lumacaftor (VX-809), ataluren (Translarna®), or with tiopropium bromide (Spiriva® Handihaler®) as add on to standard therapy.
In the treatment of retinitis pigmentosa, a compound that inhibits RIP1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with a ciliary neurtotrophic growth factor (NT- 501-CNTF) or gene transfer agent, UshStat®.
In the treatment of macular degeneration, a compound that inhibits RIP1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with opthalmalic intravitreal injections (afibercept (Eylea®)) or with an anti-vascular endothelial growth factor (VEGF) inhibitor (such as ranibizumab (Lucentis®) or pegaptanib sodium (Macugen®)), a ciliary neurotrophic growth factor agent (NT501), iSONEP®, or bevacizumab (Avastin®).
In the treatment of influenza, a compound that inhibits RIP1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with a trivalent (IIV3) inactivated influenza vaccine (such as Afluria®, Fluarix®, Flucelvax®, FluLaval®, Fluvirin®, Fluzone®), a quadrivalent (IIV4) inactivated influenza vaccine (such as Fluarix® Quadrivalent, Flulaval® Quadrivalent, Fluzone® Quadrivalent), a trivalent recombinant influenza vaccine (such as FluBlok®), a quadrivalent live attenuated influenza vaccine (such as FluMist® Quadrivalent), an antiviral agent (such as oseltamivir (Tamiflu®), zanamivir (Relenza®), rimantadine (Flumadine®), or amantadine (Symmetrel®)), or Fluad®, Fludase, FluNhance®, Preflucel, or VaxiGrip®.
In the treatment of a staphylococcus infection, a compound that inhibits RIP1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with an antibiotic (such as a b-Lactam cephalosporin (Duricef®, Kefzol®, Ancef®, Biocef®, etc.), nafcillin (Unipen®), a sulfonamide (sulfamethoxazolyl and trimethoprim (Bacrim®, Septra®,) sulfasalazine (Azulfidine®), acetyl sulfisoxazolyl (Gantrisin®, etc.), or vancomycin (Vancocin®)).
In the treatment of transplant rejection, a compound that inhibits RIP1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with a high-dose corticosteroid (such as prednisone (Deltasone®), methylprednisolone (SoluMedrol®) etc.) a calcineurin inhibitor (such as cyclosporine (Sandimmune®, Neoral®, Gengraf®), tacrolimus (Prograf®, Astragraf XL®)), an mTor inhibitor (such as sirolimus (Rapamune®) or everolimus (Afinitor®)), an anti-proliferative agent (such as azathioprine (Imuran®, Azasan®), mycophenolate mofetil (CellCept®), or mycophenolate sodium (Myfortic®)), a monoclonal antibody (such as muromonab-CD3 (Orthoclone OKT3®)),an interleukine-2 receptor antagonist
((Basiliximab®, Simulect®), daclizumab (Zenapax®), or rituximab (Rituxan®)), a polyclonal anti-T-cell antibody (such as anti-thymocyte gamma globulin-equine (Atgam®), or antithymocyte globulin-rabbit (Thymoglobulin®)) an anti-CD40 antagonist (ASKP-1240), a JAK inhibitor (ASP015K), or an anti-TCR murine mAb (TOL101).
In the treatment of atopic dermatitis, a compound that inhibits RIP1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with a topical immunomodulator or calcineurin inhibitor (such as pimecrolimus (Elidel®) or tacrolimus ointment (Protopic®)), a topical corticosteroid (such as hydrocortizone (Synacort®, Westcort®), betamethasone (Diprolene®), flurandrenolide (Cordan®), fluticasone (Cutivate®), triamcinolone (Kenalog®), fluocinonide (Lidex®), and clobetasol (Temovate®)), an oral corticosteroid (such as hydrocortisone (Cortef®), methylprednisolone (Medrol®), or prednisolone (Pediapred®, Prelone®), an immunosuppressant (such as cyclosporine (Neoral®) or interferon gamma (Alferon N®, Infergen®, Intron A, Roferon-A®)), an antihistamine (for itching such as Atarax®, Vistaril®, Benadryl®), an antibiotic (such as penicillin derivatives flucloxacillin (Floxapen®) or dicloxacillin (Dynapen®), erythromycin (Eryc®, T-Stat®, Erythra-Derm®, etc.)), anon- steroidal immunosuppressive agent (such as azathioprine (Imuran®, Azasan®), methotrexate (Rhuematrex®, Trexall®), cyclosporin (Sandimmune®), or mycophenolate mofetil
(CellCept®)).
In the treatment of spondyloarthritis, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with NSAIDs, DMARDs such as Sulfasalazine®,
Methotrexate®, and corticosteroids; prednisolone delayed-release tablets (Rayos®), TNF inhibitors (Enbrel®, Remicade®, Humira® and Simponi®), or IL-17A (Cosentyx®).
In the treatment of systemic onset juvenile idiopathic arthritis (sJIA), a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a
pharmaceutically acceptable salt thereof, may be administered in combination with NSAIDs such as Celebrex®, diclofenac (Voltaran®), ibuprofen (Advil®, Motrin®), naproxen (Aleve, Naprosyn®), corticosteroids (prednisone, glucocorticoids), Methotrexate®, or biologics (ankinra (Kineret®), tocilizumab (Actemra®), canakinumab (ILARIS®)).
In the treatment of osteoarthritis, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with analgesics and NSAIDs (acetaminophen, opioid narcotics (e.g., tramadol®, Vicodin®, Darvon®, Percocet®); ibuprofen and famotidine (Duexis®); Etadolac®; naproxen sodium (Naprelan®), diclofenac sodium topical solution (Pennsaid®); sodium hyaluronate (Supartz®); meloxicam (Vivlodex®, Mobic®);
acetaminophen, ibuprofen, aspirin, Celecoxib®, COX-2 (Celebrex®), valdecoxib (Bextra®)), corticosteroid injections, hyaluronic acid injection (Gelsyn-3®); hylan GF 20 (Synvisc, ® Synvisc-One®), or duloxetine hydrochloride (Cymbalta®).
In the treatment of or medication management of Huntington’s disease, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with tetrabenazine (Xenazine®), antipsychotic drugs (haloperidol (Haldol®), chlorpromazine HCL (Thorazine®), risperidone (Risperdal®) and quetiapine (Seroquel®)), drugs to suppress chorea (amantadine, devetiracetam (Keppra®), clonazepam (Klonopin®)), antidepressants (citalopram (Celexa®, Lexapro®), fluoxetine (Prozac®, Sarafem®), sertraline (Zoloft®)), antipsychotics (quetiapine (Seroquel®), risperidone (Risperdal®), olanzapine (Zyprexa®)), or mood-stabilizing drugs (vaproate (Depacon®), carbamazepine (Carbatrol®, Epitol®, Equetro®), lamotrigine (Lamictal®)).
In the treatment of Alzheimer’s, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with Donepzil hydrocholoride (Aricept®), Rivastigmine tartrate (Exelon®), caprylidene (Axona®), butoconazole nitrate 2% (Femstat 3®),
Galantamine hydrobromide (Razadyne®, Reminyl®), Memantine HCL (Namenda®), memantine hydrocholoride extended release + donepezil hydrochloride (Namzaric®), Solanezumab, beta-secretase with Merck (MK-8931), beta-secretase with Cerespir (CSP- 1103), or drugs that targets tau protein (AADvac1).
In the treatment of amyotrophic lateral sclerosis (ALS), a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with a glutamate blocker (Riluzole (Rilutek®)).
In the treatment of amyotrophic lateral sclerosis (ALS), a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with a edaravone (Radicava®, Radicut®).
In the treatment of symptoms with ALS, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with quinidine (Nuedexta®), anticholinergics (amitriptyline®, Artane®, scopolamine patch (Transderm Scop®)), sympathomimetics (pseudoephedrine), mucolytics (guaifenesin), or analgesics (tramadol (Ultram®); ketorolac (Toradol®); morphine; fentanyl patch (Duragesic®)).
In the treatment of multiple sclerosis, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with corticosteroids (prednisone,
methylprednisolone), Interferon Beta 1–A (Avonex®, Extavia®, Rebif®, Betaseron®), peginterferon beta-1A (Plegridy®), Glatiramer acetate (Copaxone®); glatiramer acetate (Glatopa® - generic equivalent of Copaxone); Dimethyl fumarate (Tecfidera®); Fingolimod (Gilenya®); teriflunomide (Aubagio®); dalfampridine (Ampyra®); daclizumab (Zinbryta); alemtuzumab (Lemtrada®); natalizumab (Tysabri®); or mitoxantrone hydrochloride (Novantrone®). In the treatment of gaucher disease, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with enzyme replacement therapy (imiglucerase (Cerezyme®), velaglucerase alfa (VPRIV®), taliglucerase alfa (Elelyso®)) or substrate reduction therapy (miglustat (Zavesca®), eliglustat (Cerdelga®)).
In the treatment of Niemann-Pick Disease, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with bone marrow transplant, enzyme replacement therapy, gene therapy, miglustat (Zavesca®), Arimoclomol (BRX-345), NCT02612129, Hydroxypropyl-beta-cyclodexin (HPbCD), NCT01747135, or
Hydroxypropyl-b-cyclodextrin (VTS-2702) (NCT02534844).
In the treatment of rheumatoid arthritis, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with Tocilizumab (Actemra®), Arava, sulfasalazine delayed release tablets (Azulfidine EN-tabs®, Bextra, certolizumab pegol (Cimzia®), ibuprofen and famotidine (Duexis®), naproxen sodium (Etodolac®), adalimumab (Humira®), Kineret; etodolac (Lodine®), naproxen sodium (Naprelan), abatacept (Orencia), prednisone (Rayos®), inflimimab (Remicade®), golimuma (Simponi®), rofecoxib (Vioxx®), tofacitinib (Xeljanz®), methotrexate (Trexall®, Rheumatrex®, Folex PFS®, Otrexup®, Rasuvo®, Methotrexate LPF Sodium®, selective JAK1 & JAK2 inhbitor (baracitinib), antisense oligonucleotide (alicafosen), biosimilars for infliximab (Remsima (Inflectra®)), GS-071 infliximab (Aprogen), SB2 infliximab, PF-06438179 infliximab, GP 11111, biosimilars for rituximab (CT-P10 rituximab Celltrion), BI-695500, GP-2013, PF-05280586, biosimilars for etanercept (etanercept SB4 (Brenzys™), Benepali®; CHS-0214 etanercept, GP-2015, biosimilars for adalimumab (ABP-501 adalimumab, BI-695501, Samsung SB5, GP-2017. PF-06410293, Momenta M923, or biosimilar for abatacept (M834).
In the treatment of ulcerative colitis, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with alicafosen, Mesalamine (Asacol®), balsalazide disodium (Colazal®), vedolizumab (Entyvio®), golimumab (Simponi®), budesonide (Uceris®), adalimumab (Humira®), RG-7413 (alpha4beta7 integrin), CNTO- 1275 (ustekinumab), biosimiar infliximab (Remsima (Inflectra®)), BMS eldelumab (CXCL 10), or Immune Pharma bertilimumab (CCR3). In the treatment of Crohn’s disease, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with Remestemcel-L (Prochymal®), vedolizumab (Entyvio®), ustekinumab (Stelara®), certolizumab pegol (Cimzia®), natalizumab (Tysabri®), budesonide (Entocort EC®), anti-inflammatories (mesalamine (Lialda®, Apriso®, Canasa®, Asacol®, Rowasa®), sulfasalazine (Azulfidine®)), steroids (hydrocortisone, prednisone), immunosuppressants (methotrexate (Trexall®, Rasuvo®, Rheumatrex®), infliximab (Remicade®), azathioprine (Azasan®, Imuran®), adalimumab (Humira®), mercaptopurine (Purinethol®, Purixan®); cyclosporine (Gengraf®, Neoral®, Sandimuune®); tacrolimus (Astagraf XL®, Hecoria®)), or antibiotics (metronidazole (Flagyl®, Metrogel®, Noritate®, MetroCream®, Rosadan®, MetroLotion®); ciprofloxacin (Cipro®)).
In one embodiment of this invention, the at least one other therapeutically active agent is selected from a thrombolytic agent, a tissue plasminogen activator, an anticoagulant, and a platelet aggregation inhibitor. In another embodiment, the at least one other therapeutically active agent is selected from heparin, coumadin, clopidrogel, dipyridamole, ticlopidine HCL, eptifibatide, and aspirin. In one embodiment, the RIP1 kinase-mediated disease or disorder treated with these agents is a cerebrovascular accident.
In one embodiment of this invention, the at least one other therapeutically active agent is selected from broad-spectrum antibiotic, anti-MRSA therapy and a low dose steroid. In another embodiment, the at least one other therapeutically active agent is selected from vacomycin, cefeprime, a combination of piperacillin and tazobactam, imipenem, meropenem, doripenem, ciprofloxacin, levofloxacin, ofloxacin, moxifloxacin, and hydrocortisone. In one embodiment, the RIP1 kinase-mediated disease or disorder treated with these agents is systemic inflammatory response syndrome.
In one embodiment of this invention, the at least one other therapeutically active agent is alicaforse or remestemcel-L. In one embodiment, the RIP1 kinase-mediated disease or disorder treated with these agents is Crohn’s disease or ulcerative colitis.
In one embodiment of this invention, the at least one other therapeutically active agent is ixekizumab, or tildrakizumab. In one embodiment, the RIP1 kinase-mediated disease or disorder treated with these agents is psoriasis.
In one embodiment of this invention, the at least one other therapeutically active agent is an antimicrobial agent or an antibiotic. In another embodiment, the at least one other therapeutically active agent is selected from chlorhexidine, doxycycline and minocycline. In one embodiment, the RIP1 kinase-mediated disease or disorder treated with these agents is periodonitis.
In one embodiment of this invention, the at least one other therapeutically active agent is selected from an inhaled corticosteroid, a long acting beta agonist, a combination of an inhaled corticosteroid and a long acting beta agonist, a short acting beta agonist, a leukotriene modifier, an anti-IgE, a methylxanthine bronchodilator, a mast cell inhibitor, and a long-acting muscarinic antagonist. In another embodiment, the at least one other therapeutically active agent is selected from fluticasone proprionate, beclomethasone dipropionate, budesonide, trimcinolone acetonide, flunisolide, mometasone fuorate, or ciclesonide, formoterol fumarate, salmeterol xinafoate, a combination of fluticasone furoate and vilanterol, a combination of formoterol and budesonide inhalation, a combination of beclomethasone dipropionate and formoterol, a combination of fluticasone propionate and salmeterol, albuterol sulfate, levalbuterol tartrate, a combination of ipratropium bromide and albuterol, ipratropium bromide, montelukast sodium, zafirlukast, zileuton, omalizumab theophylline, cromulyn sodium, nedocromil sodium, and a combination of mometasone furoate and formoterol fumarate dihydrate. In another embodiment, the at least one other therapeutically active agent is selected from protein tyrosine kinase inhibitor, a CRTH2/D-prostanoid receptor antangonist, an epinephrine inhalation aerosol, and a combination of a phosphodiesterase-3 inhibitor and a phosphodiesterase-4 inhibitor. In another embodiment, the at least one other therapeutically active agent is selected from masitinib, AMG 853, indacaterol, E004, a combination of fluticasone furoate and fluticasone proprionate, a combination of vinanterol fluticasone furoate, a combination of fluticasone propionate and eformoterol fumarate dehydrate, reslizumab, salbutamol, tiotropium bromide, a combination of formoterol and budesonide, fluticasone furoate, VR506, lebrikizumab, and RPL554. In one embodiment, the RIP1 kinase-mediated disease or disorder treated with these agents is asthma.
In one embodiment of this invention, the at least one other therapeutically active agent is selected from a long acting beta agonist, a long-acting inhaled anticholinergic or muscarinic antagonist, a phosphodiesterase inhibitor, a combination an inhaled corticosteroid long acting beta agonist, a short acting beta agonist, and an inhaled corticosteroid. In another
embodiment, the at least one other therapeutically active agent is selected from salmeterol xinafoate, a combination of umeclidinium and vilanterol, umeclidinium, aformoterol tartrate, formoterol fumarate, indacterol maleate, a combination of fluticasone propionate and eformoterol fumarate dehydrate, tiotropium bromide, aclidinium bromide, roflumilast, a combination of fluticasone furoate and vilanterol, a combination of fluticasone propionate and salmeterol, a combination of budesonide and formoterol, a combination of mometasone and formoterol, a combination of ipratropium bromide and albuterol sulfate, a combination of albuterol and ipratropium, ipratropium bromide, albuterol sulfate, budesonide, fluticasone propionate, and beclometasone dipropionate. In another embodiment, the at least one other therapeutically active agent is selected from SCH527123, glycoprronium bromide, a combination of glycopyrronium bromide and indacaterol maleate, a combination of glycopyrrolate and formoterol fumarate, indacaterol maleate, olodaterol, tiotropium, olodaterol, and a combination of aclidinium and formoterol. In one embodiment, the RIP1 kinase-mediated disease or disorder treated with these agents is COPD.
In one embodiment of this invention, the at least one other therapeutically active agent is an antimycobacterial agent or a bactericidal antibiotic. In another embodiment, the at least one other therapeutically active agent is selected from isoniazid, ehambutol, rifampin, pyrazinamide, rifabutin, rifapentine, capreomycin, levofloxacin, moxifloxicin, ofloxacin, ehionamide, cycloserine, kanamycin, streptomycin, viomycin, bedaquiline fumarate, PNU- 100480, and delamanid. In one embodiment, the RIP1 kinase-mediated disease or disorder treated with these agents is a mycobacterium infection.
In one embodiment of this invention, the at least one other therapeutically active agent is selected from an oral corticosteroid, anti-thymocyte globulin, thalidomide, chlorambucil, a calcium channel blocker, a topical emollient, an ACE inhibitor, a serotonin reuptake inhibitor, an endothelin-1 receptor inhibitor, an anti-fibrotic agent, a proton-pump inhibitor or imatinib, ARG201, and tocilizumab. In another embodiment, the at least one other therapeutically active agent is selected from prednisolone, anti-thymocyte globulin, FK506 (tacrolimus), thalidomide, chlorambucil, nifedipine, nicardipine, nitroglycerin ointment, lisinopril, diltaizem, fluoxetine, bosentan, epoprostenol, colchicines, para-aminobenzoic acid, dimethyl sulfoxide, D-penicillamine, interferon alpha, interferon gamma (INF-g)), omeprazole, metoclopramide, lansoprazole, esomeprazole, pantoprazole, rabeprazole, imatinib, ARG201, and tocilizumab. In one embodiment, the RIP1 kinase-mediated disease or disorder treated with these agents is systemic scleroderma.
In one embodiment of this invention, the at least one other therapeutically active agent is selected from a cystic fibrosis transmembrane conductance regulator potentiator, a mucolytic agent, pancreatic enzymes, a bronchodilator, an antibiotic, or ivacftor/lumacaftor, ataluren, and tiopropium bromide. In another embodiment, the at least one other
therapeutically active agent is selected from ivacftor, dornase alpha, pancrelipase, albuterol, tobramycin, aztreonam, colistimethate sodium, cefadroxil monohydrate, cefazolin, cephalexin, cefazolin, moxifloxacin, levofloxacin, gemifloxacin, azithromycin, gentamicin,
piperacillin/tazobacam, ceftazidime, ciprofloxin, trimethoprim/sulfamethoxazolyl, chloramphenicol, or ivacftor/lumacaftor, ataluren, and tiopropium bromide. In one embodiment, the RIP1 kinase-mediated disease or disorder treated with these agents is cystic fibrosis.
In one embodiment of this invention, the at least one other therapeutically active agent is a ciliary neurtotrophic growth factor or a gene transfer agent. In another embodiment, the at least one other therapeutically active agent is NT-501-CNTF or a gene transfer agent encoding myosin VIIA (MY07A). In one embodiment, the RIP1 kinase-mediated disease or disorder treated with these agents is retinitis pigmentosa.
In one embodiment of this invention, the at least one other therapeutically active agent is selected from opthalmalic intravitreal injections, an anti-vascular endothelial growth factor inhibitor, and a ciliary neurotrophic growth factor agent. In another embodiment, the at least one other therapeutically active agent is selected from afibercept, ranibizumab, pegaptanib sodium, NT501, humanized sphingomab, and bevacizumab. In one embodiment, the RIP1 kinase-mediated disease or disorder treated with these agents is macular degeneration.
In one embodiment of this invention, the at least one other therapeutically active agent is selected from a trivalent (IIV3) inactivated influenza vaccine, a quadrivalent (IIV4) inactivated influenza vaccine, a trivalent recombinant influenza vaccine, a quadrivalent live attenuated influenza vaccine, an antiviral agent, or inactivated influenza vaccine. In another embodiment, the at least one other therapeutically active agent is selected from oseltamivir, zanamivir, rimantadine, or amantadine. In one embodiment, the RIP1 kinase-mediated disease or disorder treated with these agents is influenza.
In one embodiment of this invention, the at least one other therapeutically active agent is selected from a b-Lactam, nafcillin, sulfamethoxazolylm, trimethoprim, sulfasalazine, acetyl sulfisoxazolyl, and vancomycin. In one embodiment, the RIP1 kinase-mediated disease or disorder treated with these agents is a staphylococcus infection.
In one embodiment of this invention, the at least one other therapeutically active agent is selected from a monoclonal antibody, a polyclonal anti-T-cell antibody, an anti-thymocyte gamma globulin-equine antibody, an antithymocyte globulin-rabbit antibody, an anti-CD40 antagonist, a JAK inhibitor, and an anti-TCR murine mAb. In another embodiment, the at least one other therapeutically active agent is selected from muromonab-CD3, ASKP-1240, ASP015K, and TOL101. In one embodiment, the RIP1 kinase-mediated disease or disorder treated with these agents is transplant rejection.
In one embodiment of this invention, the at least one other therapeutically active agent is selected from a topical immunomodulator or calcineurin inhibitor, a topical corticosteroid, an oral corticosteroid, an interferon gamma, an antihistamine, or an antibiotic. In another embodiment, the at least one other therapeutically active agent is selected from pimecrolimus, tacrolimus, hydrocortizone, betamethasone, flurandrenolide, fluticasone, triamcinolone, fluocinonide, clobetasol, hydrocortisone, methylprednisolone, prednisolone, an interferon alpha protein, a recombinant synthetic type I interferon, interferon alpha-2a, interferon alpha- 2b, hydroxyzine, diphenhydramine, flucloxacillin, dicloxacillin, and erythromycin. In one embodiment, the RIP1 kinase-mediated disease or disorder treated with these agents is atopic dermatitis.
In another embodiment, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered to a patient in need thereof, in combination with at least one other therapy and/or with at least one other active therapeutic agent that is considered standard of care (U.S. Department of Health and Human Services, Agency for Healthcare Research and Quality, National Guideline Clearinghouse, https://www.guideline.gov/ and World Health Organization, http://www.who.int/management/quality/standards/en/) for any of the diseases and/or disorders recited herein.
A compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered to a patient in need thereof, in combination with at least one other active therapeutic agent, wherein the at least one other active therapeutic agent is: a corticosteroid [administered orally, topically, by injection, or as a suppository; prednisone, methylprednisolone, prednisolone, budesonide, betamethasone, dexamethasone, hydrocortisone, triamcinolone, fluticasone (fluticasone furoate, fluticasone propionate), fludroxycortide (flurandrenolide, flurandrenolone), fluocinonide, clobetasol (clobetasol propionate)], an anti-TNF biologic agent (etanecerpt, adalimumab, infliximab, certolizumab, golimumab), an other biologic agent (vedolizumab, etrolizumab, eldelumab, or bertilimumab), biosimilars to any of the above biologic agents, a PDE-4 inhibitor (apremilast), 5-aminosalicyclic acid (mesalazine/mesalamine; sulfasalazine, balsalazide), a DMARD (a disease-modifying anti-rheumatic drug: methotrexate, hydroxychloroquine, sulfasalazine, leflunomide), a thiopurine (azathioprine,
mercaptopurine), a JAK inhibitor (tofacitinib, Baracitinib), an NSAID (aspirin,
acetaminophen, ibuprofen, naproxen (naproxen sodium), etodolac, celecoxib, diclofenac, meloxicam), an anti-IL6 biologic agent (tocilizumab), an anti-IL1 biologic agent (anakinra, canakinumab, rilonacept), an anti-IL12 or IL23 biologic agent (ustekinumab, risankizumab, guselkumab, tildrakizumab), an anti-CD6 biologic agent (itolizumab), an anti-integrin agent (natalizumab (Tysabri®), etrolizumab), an anti-IL17 biologic agent (secukinumab, ixekizumab, brodalumab), an anti-CD22 biologic agent (epratuzumab), an anti-CD20 biologic agent (rituximab, ofatumumab), an anti-CD20 or CD4 biologic agent and other cytokine inhibitor or biologic to T-cell or B-cell receptors or interleukins, T cell inhibitors (abatacept) a calcineurin inhibitor (cyclosporine, pimecrolimus,
tacrolimus), acitretin, fumaric acid, dimethyl fumarate, cyclophosphamide, cyclosporine (or ciclosporin), methotrexate, mycophenolic acid (or mycophenolate mofetil), topical vitamin D (calcipotriol or calcipotriene), an mTOR inhibitor (temsirolimus, everolimus), a Syk inhibitor (fostamatinib), an anti-IFNa biologic agent (sifalimumab), a retinoid (tazarotene), coal tar preparations, aryl hydrocarbon receptor agonist or modulating agent (tapinarof), hydroxyurea, 6-tioguanineor light therapy with or without psoralen.
Examples of other active therapeutic agents that may be used in combination with a compound of this invention for the treatment of ulcerative colitis and/or Crohn’s disease include vedolizumab, etrolizumab, eldelumab, or bertilimumab.
Examples of other suitable biologic agents include abatacept, belimumab, and alicafosen. Examples of other active therapeutic agent that may be used in combination with a compound of this invention include baracitinib and Remestemcel-L.
A compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered to a pediatric or an adult patient in need thereof, in combination with at least one other therapy, for example, in combination with UVA and/or UVB phototherapy as indicated for the treatment of psoriasis.
In the treatment of pediatric and/or adult psoriasis, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered to reduce the signs and symptoms including body surface area, pruritis, nail disease, and scalp involvement, and to improve quality of life, in pediatric and/or adult patients with moderate to severe psoriasis.
In the treatment of pediatric and/or adult psoriasis, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered as initial treatment or after treatment with another agent in pediatric and/or adult patients with moderate to severe psoriasis.
In the treatment of pediatric and/or adult psoriasis, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered to maintain reductions in signs and symptoms and improvements in quality of life after treatment with another agent in pediatric and/or adult patients with moderate to severe psoriasis.
A compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered for the treatment of moderately to severely active rheumatoid arthritis.
In the treatment of rheumatoid arthritis, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered to reduce the signs and symptoms, to induce a major clinical response, to inhibit the progression of structural damage, or to improve physical function in a patient, particularly an adult patient with moderately to severely active rheumatoid arthritis.
In the treatment of rheumatoid arthritis, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered alone or in combination with methotrexate or other non- biologic disease-modifying anti-rheumatic drugs (DMARDs). In a specific embodiment, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered alone or in combination with methotrexate, or corticosteroids in the treatment of rheumatoid arthritis.
In the treatment of juvenile idiopathic arthritis (JIA), a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered to reduce the signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older.
In the treatment of juvenile idiopathic arthritis, particularly polyarticular juvenile idiopathic arthritis, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered alone or in combination with methotrexate.
In the treatment of psoriatic arthritis, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered to reduce the signs and symptoms, inhibiting the progression of structural damage, of active arthritis, and/or to improve physical function in adult patients with psoriatic arthritis.
In the treatment of psoriatic arthritis, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered alone or in combination with methotrexate, corticosteroids, or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs).
In a specific embodiment, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered alone or in combination with methotrexate for the treatment of psoriatic arthritis.
In the treatment of psoriatic arthritis, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered to a patient, particularly an adult patient with moderate to severe chronic plaque psoriasis, who is a candidate for systemic therapy or phototherapy.
In the treatment of axial Spondyloarthritis and ankylosing spondylitis, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered to reduce the signs and symptoms of active ankylosing spondylitis in a patient, either an adult or a pediatric patient, in need thereof.
In the treatment of axial Spondyloarthritis and ankylosing spondylitis, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered alone or in combination with methotrexate, corticosteroids, or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs).
In the treatment of Crohn’s Disease, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered to reduce the signs and symptoms of Crohn’s disease. A compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered to induce or maintain a clinical response (clinical remission) in a patient, particularly an adult patient with moderately to severely active Crohn’s disease.
In the treatment of Crohn’s Disease, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered to reduce the signs and symptoms of Crohn’s disease. A compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered to induce or maintain a clinical response (clinical remission) in a patient, particularly a pediatric patient 6 years of age and older with moderately to severely active Crohn’s disease.
A compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered to reduce the signs and symptoms of Crohn’s disease, particularly, moderately to severely active Crohn’s disease, in a patient who has had an inadequate response to corticosteroids or immunomodulators such as azathioprine, 6-mercaptopurine, or methotrexate.
A compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered to treat a patient, particularly an adult patient or a pediatric patient 6 years and older, with moderately to severely active ulcerative colitis.
In the treatment of ulcerative colitis, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered to induce and/or sustain clinical remission in a patient, particularly an adult patient or a pediatric patient 6 years and older, with moderately to severely active ulcerative colitis.
A compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered to induce and/or sustain a clinical response (clinical remission) in a patient, particularly a patient with moderately to severely active ulcerative colitis, who has had an inadequate response to immunosuppressants such as aminosalicylates, corticosteroids, azathioprine or 6- mercaptopurine (6-MP).
A compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered for the treatment of moderate to severe hidradenitis suppurativa. A compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered for the treatment of uveitis, particularly non-infectious intermediate, posterior and panuveitis, in a patient, particularly an adult patient, in need thereof.
Accordingly, one embodiment of this invention is directed to a method of inhibiting RIP1 kinase comprising contacting a cell with a compound of the invention. Another embodiment of this invention is a method of inhibiting RIP1 kinase comprising contacting a cell with a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof. A particular embodiment of this invention is to a method of inhibiting RIP1 kinase comprising contacting a cell with a compound of Formula (II) or Formula (II) or a pharmaceutically acceptable salt thereof.
In another embodiment, the invention is directed to a method of treating a RIP1 kinase-mediated disease or disorder (for example, a disease or disorder recited herein) in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof. In a particular embodiment, the invention is directed to a method of treating a RIP1 kinase-mediated disease or disorder (for example, a disease or disorder recited herein) in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof. In another embodiment, the invention is directed to a method of treating a RIP1 kinase-mediated disease or disorder disclosed herein in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof. In a particular embodiment, the invention is directed to a method of treating a RIP1 kinase-mediated disease or disorder disclosed herein in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof. In another embodiment, the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof. In a particular embodiment, the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof. In a specific embodiment, the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of 6-((3R,4R)-4-((R)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide, or a pharmaceutically acceptable salt thereof. In a specific embodiment, the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of 6- ((3S,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide or a pharmaceutically acceptable salt thereof. In a specific embodiment, the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of 6-((3S,4S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H- pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide or a pharmaceutically acceptable salt thereof. In a specific embodiment, the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of 6-((3R,4R)-4-((S)-5-(3,5-difluorophenyl)- 4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof. In a specific embodiment, the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of 6-((3S,4R)-4-((S)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide, or a pharmaceutically acceptable salt thereof. In a specific embodiment, the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of 6- ((3S,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof. In a specific embodiment, the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of 6-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5- dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof. In a specific embodiment, the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of 6-((3R,4S)-4-((R)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide, or a pharmaceutically acceptable salt thereof.
In another embodiment, the invention is directed to a method of treating a RIP1- mediated disease or disorder (for example, a disease or disorder recited herein) in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salt thereof, which further comprises at least one other therapeutically active agent. In another embodiment, the invention is directed to a method of treating a RIP1-mediated disease or disorder (for example, a disease or disorder recited herein) in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound disclosed herein, or pharmaceutically acceptable salt thereof, which further comprises at least one other therapeutically active agent. In another embodiment, the invention is directed to a method of treating a RIP1-mediated disease or disorder disclosed herein in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salt thereof, which further comprises at least one other therapeutically active agent. In another embodiment, the invention is directed to a method of treating a RIP1- mediated disease or disorder disclosed herein in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound disclosed herein, or pharmaceutically acceptable salt thereof, which further comprises at least one other therapeutically active agent. In another embodiment, the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salt thereof, which further comprises at least one other therapeutically active agent. In another embodiment, the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound disclosed herein, or pharmaceutically acceptable salt thereof, which further comprises at least one other therapeutically active agent. In a specific embodiment, the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of a 6- ((3R,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising 6-((3R,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5- dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or pharmaceutically acceptable salt thereof, which further comprises at least one other therapeutically active agent. In a specific embodiment, the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of a 6-((3S,4S)-4-((S)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising 6-((3S,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or pharmaceutically acceptable salt thereof, which further comprises at least one other therapeutically active agent. In a specific embodiment, the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of a 6-((3S,4S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)- 3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising 6-((3S,4S)-4-((R)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide, or pharmaceutically acceptable salt thereof, which further comprises at least one other therapeutically active agent. In a specific embodiment, the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of a 6-((3R,4R)-4-((S)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising 6-((3R,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)- 3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or pharmaceutically acceptable salt thereof, which further comprises at least one other therapeutically active agent. In a specific embodiment, the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of a 6-((3S,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)- 3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising 6-((3S,4R)-4-((S)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide, or pharmaceutically acceptable salt thereof, which further comprises at least one other therapeutically active agent. In a specific embodiment, the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of a 6-((3S,4R)-4-((R)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising 6-((3S,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)- 3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or pharmaceutically acceptable salt thereof, which further comprises at least one other therapeutically active agent. In a specific embodiment, the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of a 6-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)- 3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising 6-((3R,4S)-4-((S)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide, or pharmaceutically acceptable salt thereof, which further comprises at least one other therapeutically active agent. In another specific embodiment, the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of 6-((3R,4S)-4- ((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1- yl)pyrimidine-4-carboxamide, or pharmaceutically acceptable salt thereof, or a
pharmaceutical composition comprising 6-((3R,4S)-4-((R)-5-(3,5-difluorophenyl)-4,5- dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or pharmaceutically acceptable salt thereof, which further comprises at least one other therapeutically active agent. In one specific embodiment, the invention is directed to a method of treating a RIP1 kinase-mediated disease or disorder (specifically, a disease or disorder recited herein) comprising administering a therapeutically effective amount of 6-((3R,4R)-4-((R)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide, or a pharmaceutically acceptable salt thereof, to a human in need thereof. In another specific embodiment, the invention is directed to a method of treating a RIP1 kinase- mediated disease or disorder (specifically, a disease or disorder recited herein) comprising administering a therapeutically effective amount of 6-((3S,4S)-4-((S)-5-(3,5-difluorophenyl)- 4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof, to a human in need thereof. In another specific embodiment, the invention is directed to a method of treating a RIP1 kinase-mediated disease or disorder (specifically, a disease or disorder recited herein) comprising administering a therapeutically effective amount of 6-((3S,4S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H- pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a
pharmaceutically acceptable salt thereof, to a human in need thereof. In another specific embodiment, the invention is directed to a method of treating a RIP1 kinase-mediated disease or disorder (specifically, a disease or disorder recited herein) comprising administering a therapeutically effective amount of 6-((3R,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro- 1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a
pharmaceutically acceptable salt thereof, to a human in need thereof. In another specific embodiment, the invention is directed to a method of treating a RIP1 kinase-mediated disease or disorder (specifically, a disease or disorder recited herein) comprising administering a therapeutically effective amount of 6-((3S,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H- pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, to a human in need thereof. In another specific embodiment, the invention is directed to a method of treating a RIP1 kinase-mediated disease or disorder (specifically, a disease or disorder recited herein) comprising administering a therapeutically effective amount of 6-((3S,4R)-4-((R)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide, to a human in need thereof. In another specific embodiment, the invention is directed to a method of treating a RIP1 kinase-mediated disease or disorder (specifically, a disease or disorder recited herein) comprising administering a therapeutically effective amount of 6-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide to a human in need thereof. In another specific embodiment, the invention is directed to a method of treating a RIP1 kinase- mediated disease or disorder (specifically, a disease or disorder recited herein) comprising administering a therapeutically effective amount of 6-((3R,4S)-4-((R)-5-(3,5-difluorophenyl)- 4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, to a human in need thereof.
This invention also provides a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, for use in therapy. This invention provides a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, for use in the treatment of a RIP1 kinase-mediated disease or disorder (for example, a disease or disorder recited herein). Specifically, this invention provides a compound described herein, or a pharmaceutically acceptable salt thereof, for use in therapy. More specifically, this invention provides 6-((3R,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof, for use in therapy. More specifically, this invention provides 6- ((3S,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof, for use in therapy. More specifically, this invention provides 6-((3S,4S)-4-((R)-5- (3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1- yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof, for use in therapy. More specifically, this invention provides 6-((3R,4R)-4-((S)-5-(3,5-difluorophenyl)- 4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof, for use in therapy. More specifically, this invention provides 6-((3S,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide for use in therapy. More specifically, this invention provides 6-((3S,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide for use in therapy. More specifically, this invention provides 6-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro- 1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide for use in therapy. More specifically, this invention provides 6-((3R,4S)-4-((R)-5-(3,5-difluorophenyl)- 4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide for use in therapy.
In another embodiment, this invention provides a compound of the invention for use in the treatment of a RIP1 kinase-mediated disease or disorder, specifically, a disease or disorder recited herein. This invention provides a compound described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a RIP1 kinase-mediated disease or disorder, specifically, a disease or disorder recited herein. In another specific embodiment, this invention provides 6-((3R,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro- 1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof, for use in the treatment of a RIP1 kinase-mediated disease or disorder, specifically a disease or disorder recited herein. In another specific embodiment, this invention provides 6-((3S,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro- 1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof, for use in the treatment of a RIP1 kinase-mediated disease or disorder, specifically a disease or disorder recited herein. In another specific embodiment, this invention provides 6-((3S,4S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro- 1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof, for use in the treatment of a RIP1 kinase-mediated disease or disorder, specifically a disease or disorder recited herein. In another specific embodiment, this invention provides 6-((3R,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro- 1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof, for use in the treatment of a RIP1 kinase-mediated disease or disorder, specifically a disease or disorder recited herein. In another specific embodiment, this invention provides 6-((3S,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro- 1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide for use in the treatment of a RIP1 kinase-mediated disease or disorder, specifically a disease or disorder recited herein. In another specific embodiment, this invention provides 6-((3S,4R)-4-((R)-5- (3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1- yl)pyrimidine-4-carboxamide for use in the treatment of a RIP1 kinase-mediated disease or disorder, specifically a disease or disorder recited herein. In another specific embodiment, this invention provides 6-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide for use in the treatment of a RIP1 kinase-mediated disease or disorder, specifically a disease or disorder recited herein. In another specific embodiment, this invention provides 6-((3R,4S)-4-((R)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide for use in the treatment of a RIP1 kinase-mediated disease or disorder, specifically a disease or disorder recited herein. This invention specifically provides for the use of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, as an active therapeutic substance. More specifically, this invention provides for the use of the compounds described herein for the treatment of a RIP1 kinase-mediated disease or disorder, specifically, a disease or disorder recited herein. Accordingly, the invention provides for the use of a compound of Formula (I) or Formula (II) as an active therapeutic substance in the treatment of a human in need thereof with a RIP1 kinase-mediated disease or disorder, specifically, a disease or disorder recited herein. In one embodiment, this invention provides for the use of 6- ((3R,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof, as an active therapeutic substance for the treatment of a RIP1 kinase-mediated disease or disorder, specifically a disease or disorder recited herein. In one embodiment, this invention provides for the use of 6-((3S,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H- pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a
pharmaceutically acceptable salt thereof, as an active therapeutic substance for the treatment of a RIP1 kinase-mediated disease or disorder, specifically a disease or disorder recited herein. In one embodiment, this invention provides for the use of 6-((3S,4S)-4-((R)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide, or a pharmaceutically acceptable salt thereof, as an active therapeutic substance for the treatment of a RIP1 kinase-mediated disease or disorder, specifically a disease or disorder recited herein. In one embodiment, this invention provides for the use of 6- ((3R,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof, as an active therapeutic substance for the treatment of a RIP1 kinase-mediated disease or disorder, specifically a disease or disorder recited herein. In a more specific embodiment, this invention provides for the use of 6-((3S,4R)-4-((S)-5-(3,5-difluorophenyl)- 4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide as an active therapeutic substance for the treatment of a RIP1 kinase-mediated disease or disorder, specifically a disease or disorder recited herein. In a more specific embodiment, this invention provides for the use of 6-((3S,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H- pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide as an active therapeutic substance for the treatment of a RIP1 kinase-mediated disease or disorder, specifically a disease or disorder recited herein. In a more specific embodiment, this invention provides for the use of 6-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H- pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide as an active therapeutic substance for the treatment of a RIP1 kinase-mediated disease or disorder, specifically a disease or disorder recited herein. In a more specific embodiment, this invention provides for the use of 6-((3R,4S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H- pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide as an active therapeutic substance for the treatment of a RIP1 kinase-mediated disease or disorder, specifically a disease or disorder recited herein.
The invention further provides for the use of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a RIP1 kinase-mediated disease or disorder, for example the diseases and disorders recited herein. Specifically, the invention also provides for the use of a compound described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a RIP1 kinase-mediated disease or disorder, for example the diseases and disorders recited herein. In one embodiment, the invention provides for the use of 6-((3R,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a RIP1 kinase-mediated disease or disorder, for example the diseases and disorders recited herein. In one embodiment, the invention provides for the use of 6-((3S,4S)-4-((S)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a RIP1 kinase-mediated disease or disorder, for example the diseases and disorders recited herein. In one embodiment, the invention provides for the use of 6-((3S,4S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a RIP1 kinase-mediated disease or disorder, for example the diseases and disorders recited herein. In one embodiment, the invention provides for the use of 6-((3R,4R)-4-((S)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a RIP1 kinase-mediated disease or disorder, for example the diseases and disorders recited herein. In another embodiment, the invention provides for the use of 6-((3S,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide in the manufacture of a medicament for use in the treatment of a RIP1 kinase-mediated disease or disorder, for example the diseases and disorders recited herein. In another embodiment, the invention provides for the use of 6-((3S,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide in the manufacture of a medicament for use in the treatment of a RIP1 kinase-mediated disease or disorder, for example the diseases and disorders recited herein. In another embodiment, the invention provides for the use of 6-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide in the manufacture of a medicament for use in the treatment of a RIP1 kinase-mediated disease or disorder, for example the diseases and disorders recited herein. In another embodiment, the invention provides for the use of 6-((3R,4S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide in the manufacture of a medicament for use in the treatment of a RIP1 kinase-mediated disease or disorder, for example the diseases and disorders recited herein.
The compounds of the invention may be administered by any suitable route of administration, including both systemic administration and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation. Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion. Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion. Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages. Topical administration includes application to the skin.
The compounds of the invention may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan. In addition, suitable dosing regimens, including the duration such regimens are administered, for a compound of the invention depend on the disease or disorder being treated, the severity of the disease or disorder being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change. Total daily dosages range from 1 mg to 2000 mg.
For use in therapy, the compounds of the invention will be normally, but not necessarily, formulated into a pharmaceutical composition prior to administration to a patient. Accordingly, the invention also is directed to pharmaceutical compositions comprising a compound of the invention and one or more pharmaceutically acceptable excipients. The invention is directed to a pharmaceutical composition comprising a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. In one embodiment, there is provided a pharmaceutical composition comprising 6-((3R,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5- dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. In one embodiment, there is provided a pharmaceutical composition comprising 6-((3S,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. In one embodiment, there is provided a pharmaceutical composition comprising 6-((3S,4S)-4-((R)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide, or a pharmaceutically acceptable salt thereof, and one or more
pharmaceutically acceptable excipients. In one embodiment, there is provided a
pharmaceutical composition comprising 6-((3R,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5- dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. In another embodiment, there is provided a pharmaceutical composition comprising 6-((3S,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)- 3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, and one or more pharmaceutically acceptable excipients. In another embodiment, there is provided a pharmaceutical composition comprising 6-((3S,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole- 1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, and one or more
pharmaceutically acceptable excipients. In another embodiment, there is provided a pharmaceutical composition comprising 6-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5- dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, and one or more pharmaceutically acceptable excipients. In another embodiment, there is provided a pharmaceutical composition comprising 6-((3R,4S)-4-((R)-5-(3,5-difluorophenyl)-4,5- dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, and one or more pharmaceutically acceptable excipients.
The invention is further directed to a pharmaceutical composition comprising a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients and at least one other therapeutically active agent, specifically one or two other therapeutically active agents, more specifically one other therapeutically active agent. In one embodiment, there is provided a pharmaceutical composition comprising 6-((3R,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole- 1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically salt thereof, one or more pharmaceutically acceptable excipients, and at least one other therapeutically active agent, specifically one or two other therapeutically active agents, more specifically one other therapeutically active agent. In one embodiment, there is provided a pharmaceutical composition comprising 6-((3S,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5- dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically salt thereof, one or more pharmaceutically acceptable excipients, and at least one other therapeutically active agent, specifically one or two other therapeutically active agents, more specifically one other therapeutically active agent. In one embodiment, there is provided a pharmaceutical composition comprising 6-((3S,4S)-4-((R)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide, or a pharmaceutically salt thereof, one or more pharmaceutically acceptable excipients, and at least one other therapeutically active agent, specifically one or two other therapeutically active agents, more specifically one other therapeutically active agent. In one embodiment, there is provided a pharmaceutical composition comprising 6-((3R,4R)-4-((S)- 5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1- yl)pyrimidine-4-carboxamide, or a pharmaceutically salt thereof, one or more
pharmaceutically acceptable excipients, and at least one other therapeutically active agent, specifically one or two other therapeutically active agents, more specifically one other therapeutically active agent. In another embodiment, there is provided a pharmaceutical composition comprising 6-((3S,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole- 1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide, one or more pharmaceutically acceptable excipients, and at least one other therapeutically active agent, specifically one or two other therapeutically active agents, more specifically one other therapeutically active agent. In another embodiment, there is provided a pharmaceutical composition comprising 6-((3S,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide, one or more pharmaceutically acceptable excipients, and at least one other therapeutically active agent, specifically one or two other therapeutically active agents, more specifically one other therapeutically active agent. In another embodiment, there is provided a pharmaceutical composition comprising 6-((3R,4S)- 4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1- yl)pyrimidine-4-carboxamide, one or more pharmaceutically acceptable excipients, and at least one other therapeutically active agent, specifically one or two other therapeutically active agents, more specifically one other therapeutically active agent. In another embodiment, there is provided a pharmaceutical composition comprising 6-((3R,4S)-4-((R)- 5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1- yl)pyrimidine-4-carboxamide, one or more pharmaceutically acceptable excipients, and at least one other therapeutically active agent, specifically one or two other therapeutically active agents, more specifically one other therapeutically active agent.
The pharmaceutical compositions of the invention may be prepared and packaged in bulk form wherein an effective amount of a compound of the invention can be extracted and then given to the patient such as with powders, syrups, and solutions for injection.
Alternatively, the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form. A dose of the pharmaceutical composition contains at least a therapeutically effective amount of a compound of this invention (i.e., a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, thereof). When prepared in unit dosage form, the pharmaceutical compositions may contain from 1 mg to 1000 mg of a compound of this invention.
As provided herein, unit dosage forms (pharmaceutical compositions) containing from 1 mg to 1000 mg of a compound of the invention may be administered one, two, three, or four times per day, preferably one, two, or three times per day, and more preferably, one or two times per day, to effect treatment of a RIP1 kinase-mediated disease or disorder. The compounds of the invention and the pharmaceutically acceptable excipient or excipients will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration. Conventional dosage forms suitable for use with the compounds of this invention include those adapted for (1) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as aerosols and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.
Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the carrying or transporting the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body. Certain pharmaceutically acceptable excipients may be chosen for their ability to enhance patient compliance.
Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents. The skilled artisan will appreciate that certain pharmaceutically acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.
Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically acceptable excipients in appropriate amounts for use in the invention. In addition, there are a number of resources that are available to the skilled artisan which describe pharmaceutically acceptable excipients and may be useful in selecting suitable pharmaceutically acceptable excipients. Examples include Remington's
Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).
The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington’s Pharmaceutical Sciences (Mack Publishing Company).
Accordingly, another embodiment of this invention is a method of preparing a
pharmaceutical composition comprising the step of admixing a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, thereof, with one or more
pharmaceutically acceptable excipients.
In one aspect, the invention is directed to a topical dosage form such as a cream, ointment, lotion, paste, or gel comprising an effective amount of a compound of the invention and one or more pharmaceutically acceptable excipients. Lipophilic formulations, such as anhydrous creams and ointments, generally will have a base derived from fatty alcohols, and polyethylene glycols. Additional additives include alcohols, non-ionic surfactants, and antioxidants. For ointments, the base normally will be an oil or mixture of oil and wax, e.g., petrolatum. Also, an antioxidant normally will be included in minor amounts. Because the compositions are applied topically and the effective dosage can be controlled by the total composition applied, the percentage of active ingredient in the composition can vary widely. Convenient concentrations range from 0.5% to 20%.
Topically applied gels can also be a foamable suspension gel comprising a compound of the invention, as an active agent, one or more thickening agents, and optionally, a dispersing/wetting agent, a pH-adjusting agent, a surfactant, a propellent, an antioxidant, an additional foaming agent, a chelating/sequestering agent, a solvent, a fragrance, a coloring agent, a preservative, wherein the gel is aqueous and forms a homogenous foam.
In one aspect, the invention is directed to a topical dosage form that can be administered by inhalation, that is, by intranasal and oral inhalation administration.
Appropriate dosage forms for such administration, such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques. Intranasal sprays may be formulated with aqueous or non-aqueous vehicles with the addition of agents such as thickening agents, buffer salts or acid or alkali to adjust the pH, isotonicity adjusting agents or anti-oxidants. Solutions for inhalation by nebulization may be formulated with an aqueous vehicle with the addition of agents such as acid or alkali, buffer salts, isotonicity adjusting agents or antimicrobials.
Formulations for administration by inhalation or foamable gel often require the use of a suitable propellant. Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated using a suitable powder base such as lactose or starch.
In another aspect, the invention is directed to a solid oral dosage form such as a tablet or capsule comprising an effective amount of a compound of the invention and a diluent or filler. Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate. The oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g. corn starch, potato starch, and pre-gelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g. microcrystalline cellulose). The oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose. The oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc. DEFINITIONS
As used herein, the term "alkyl" represents a saturated, straight or branched hydrocarbon group having the specified number of carbon atoms. The term "(C2-C6)alkyl" refers to an alkyl moiety containing from 2 to 6 carbon atoms. Exemplary alkyls include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, and t-butyl.
When a substituent term such as "alkyl" is used in combination with another substituent term, for example as in“(C4-C6)cycloalkyl-alkyl-”, the linking substituent term (e.g., alkyl) is intended to encompass a multi-valent moiety, wherein the point of attachment is through that linking substituent. Generally, the linking substituent is di-valent. An example of a“(C3-C7)cycloalkyl-alkyl-” group includes, but is not limited to, cyclopentyl-methyl-.
The term“halo(C1-C4)alkyl” represents a group having one or more halogen atoms, which may be the same or different, at one or more carbon atoms of an alkyl moiety containing from 1 to 4 carbon atoms. Examples of "halo(C1-C4)alkyl" groups include, but are not limited to, -CF3 (trifluoromethyl), -CCl3 (trichloromethyl), 1,1-difluoroethyl, 2,2,2- trifluoroethyl, and hexafluoroisopropyl.
"Alkenyl" refers to straight or branched hydrocarbon group having at least 1 and up to 3 carbon-carbon double bonds. Examples include ethenyl and propenyl.
"Alkoxy" refers to an "alkyl-oxy-" group, containing an alkyl moiety attached through an oxygen linking atom. For example, the term "(C1-C4)alkoxy" represents a saturated, straight or branched hydrocarbon moiety having at least 1 and up to 4 carbon atoms attached through an oxygen linking atom. Exemplary "(C1-C4)alkoxy" groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, and t-butoxy.
The term“halo(C1-C4)alkoxy” refers to a "haloalkyl-oxy-" group, containing a “halo(C1-C4)alkyl” moiety attached through an oxygen linking atom, which
halo(C1-C4)alkyl” refers to a moiety having one or more halogen atoms, which may be the same or different, at one or more carbon atoms of an alkyl moiety containing from 1 to 4 carbon atoms. Exemplary“halo(C1-C4)alkoxy” groups include, but are not limited to, - OCHF2 (difluoromethoxy), -OCF3 (trifluoromethoxy), -OCH2CF3 (trifluoroethoxy), and -OCH(CF3)2 (hexafluoroisopropoxy).
“Cycloalkyl” refers to a non-aromatic, saturated, cyclic hydrocarbon group containing the specified number of carbon atoms. For example, the term“(C3-C6)cycloalkyl” refers to a non-aromatic cyclic hydrocarbon ring having from three to six ring carbon atoms. Exemplary“(C3-C6)cycloalkyl” groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
"Aryl" refers to a group or moiety comprising an aromatic, monocyclic or bicyclic hydrocarbon radical containing from 6 to 10 carbon ring atoms and having at least one aromatic ring. Examples of "aryl" groups are phenyl, naphthyl, indenyl, and dihydroindenyl (indanyl). Generally, aryl is phenyl.
A heterocyclic group is a cyclic group having, as ring members, atoms of at least two different elements, which cyclic group may be saturated, partially unsaturated (non-aromatic) or fully unsaturated (aromatic).
"Heterocycloalkyl" refers to a non-aromatic, monocyclic or bicyclic group containing 3-10 ring atoms, being saturated and containing one or more (generally one or two) ring heteroatoms independently selected from oxygen, sulfur, and nitrogen. Examples of “heterocycloalkyl” groups include, but are not limited to, aziridinyl, thiiranyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,4-dioxanyl, 1,4-oxathiolanyl, 1,4- oxathianyl, 1,4-dithianyl, morpholinyl, and thiomorpholinyl, and dihydroimidazole.
The term "5-6-membered heterocycloalkyl" represents a nonaromatic, monocyclic group, which is fully saturated, containing 5 or 6 ring atoms, which includes one or two heteroatoms selected independently from oxygen, sulfur, and nitrogen. Illustrative examples of 5 to 6-membered heterocycloalkyl groups include, but are not limited to pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, and dihydroimidazole.
"Heteroaryl" represents a group or moiety comprising an aromatic monocyclic or bicyclic radical, containing 5 to 10 ring atoms, including 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. This term also encompasses bicyclic heterocyclic- aryl groups containing either an aryl ring moiety fused to a heterocycloalkyl ring moiety or a heteroaryl ring moiety fused to a cycloalkyl ring moiety.
Illustrative examples of heteroaryls include, but are not limited to, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl (pyridyl), oxo-pyridyl (pyridyl-N-oxide), pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, benzofuranyl, isobenzofuryl, 2,3- dihydrobenzofuryl, 1,3-benzodioxolyl, dihydrobenzodioxinyl, benzothienyl, indolizinyl, indolyl, isoindolyl, dihydroindolyl, benzimidazolyl, dihydrobenzimidazolyl, benzoxazolyl, dihydrobenzoxazolyl, benzothiazolyl, benzoisothiazolyl, dihydrobenzoisothiazolyl, indazolyl, imidazopyridinyl, pyrazolopyridinyl, benzotriazolyl, triazolopyridinyl, purinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7- naphthyridinyl, 1,8-naphthyridinyl, and pteridinyl.
As used herein, "5-6-membered heteroaryl" represents an aromatic monocyclic group containing 5 or 6 ring atoms, including at least one carbon atom and 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Selected 5-membered heteroaryl groups contain one nitrogen, oxygen, or sulfur ring heteroatom, and optionally contain 1, 2, or 3 additional nitrogen ring atoms. Selected 6-membered heteroaryl groups contain 1, 2, or 3 nitrogen ring heteroatoms. Examples of 5- membered heteroaryl groups include furyl (furanyl), thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl and oxo-oxadiazolyl. Selected 6-membered heteroaryl groups include pyridinyl, oxo-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazinyl.
As used herein, "9-10-membered heteroaryl" represents an aromatic cyclic group containing 9 or 10 ring atoms, including at least one carbon atom and 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Selected 9-membered heteroaryl groups contain one nitrogen, oxygen, or sulfur ring heteroatom, and optionally contain 1, 2, or 3 additional nitrogen ring atoms. Selected 10-membered heteroaryl groups contain 1, 2, or 3 nitrogen ring heteroatoms. Examples of 9-membered heteroaryl groups include 7H-purinyl, 9H-purinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, 1H-pyrazolo[3,4- d]pyrimidinyl, and imidazo[1,2-b]pyridazinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, indolizinyl, indolyl, isoindolyl, and indazolyl. Selected 10-membered heteroaryl groups include quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, and pteridinyl.
Bicyclic heteroaryl groups include 6,5-fused heteroaryl (9-membered heteroaryl) and 6,6-fused heteroaryl (10-membered heteroaryl) groups. Examples of 6,5-fused heteroaryl (9-membered heteroaryl) groups include benzothienyl, benzofuranyl, indolyl, indolinyl, isoindolyl, isoindolinyl, indazolyl, indolizinyl, isobenzofuryl, 2,3-dihydrobenzofuryl, benzo- 1,3-dioxyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzoxadiazolyl,
benzothiadiazolyl, benzotriazolyl, purinyl and imidazopyridinyl.
Unless otherwise specified, all bicyclic ring systems may be attached at any suitable position on either ring.
The terms "halogen" and "halo" represent chloro, fluoro, bromo, or iodo substituents. “Oxo” represents a double-bonded oxygen moiety; for example, if attached directly to a carbon atom forms a carbonyl moiety (C = O). "Hydroxy" or“hydroxyl” is intended to mean the radical -OH. As used herein, the term“cyano” refers to the group -CN.
As used herein, the term "optionally" means that the subsequently described event(s) may or may not occur, and includes both event(s) that occur and event(s) that do not occur. In the case where groups may be selected from a number of alternative groups, the selected groups may be the same or different.
The term "independently" means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different. The term "pharmaceutically acceptable" refers to those compounds (including salts), materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, the term "treatment" or“treating” refers to alleviating the specified condition, eliminating or reducing one or more symptoms of the condition, slowing or eliminating the progression of the condition, and delaying the reoccurrence of the condition in a previously afflicted or diagnosed patient or subject.
As used herein, the term "cancer," refers to cells that have undergone a malignant transformation that makes them pathological to the host organism. Primary cancer cells can be readily distinguished from non-cancerous cells by well-established techniques, particularly histological examination. The definition of a cancer cell, as used herein, includes not only a primary cancer cell, but any cell derived from a cancer cell ancestor. This includes metastasized cancer cells, and in vitro cultures and cell lines derived from cancer cells. When referring to a type of cancer that normally manifests as a solid tumor, a
"clinically detectable" tumor is one that is detectable on the basis of tumor mass; e.g., by procedures such as computed tomography (CT) scan, magnetic resonance imaging (MRI), X- ray, ultrasound or palpation on physical examination, and/or which is detectable because of the expression of one or more cancer-specific antigens in a sample obtainable from a patient. Tumors may be a hematopoietic (or hematologic or hematological or blood-related) cancer, for example, cancers derived from blood cells or immune cells, which may be referred to as “liquid tumors.”
A therapeutically "effective amount" is intended to mean that amount of a compound that, when administered to a patient in need of such treatment, is sufficient to effect treatment, as defined herein. Thus, e.g., a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, is a quantity of an inventive agent that, when administered to a human in need thereof, is sufficient to modulate and/or inhibit the activity of RIP1 kinase such that a disease condition which is mediated by that activity is reduced, alleviated or prevented. The amount of a given compound that will correspond to such an amount will vary depending upon factors such as the particular compound (e.g., the potency (pIC50), efficacy (EC50), and the biological half-life of the particular compound), disease condition and its severity, the identity (e.g., age, size and weight) of the patient in need of treatment, but can nevertheless be routinely determined by one skilled in the art. Likewise, the duration of treatment and the time period of
administration (time period between dosages and the timing of the dosages, e.g., before/with/after meals) of the compound will vary according to the identity of the mammal in need of treatment (e.g., weight), the particular compound and its properties (e.g., pharmacokinetic properties), disease or disorder and its severity and the specific composition and method being used, but can nevertheless be determined by one of skill in the art.
As used herein, "pharmaceutically acceptable excipient" means a material, composition or vehicle involved in giving form or consistency to the composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided. In addition, each excipient must of course be of sufficiently high purity to render it pharmaceutically acceptable.
Compound Preparation Generic synthesis schemes
The compounds of this invention may be made by a variety of methods, including well-known standard synthetic methods. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the working examples. The skilled artisan will appreciate that if a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions. The protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound. In all of the schemes described below, protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of synthetic chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Green and P.G.M. Wuts, (1991) Protecting Groups in Organic Synthesis, John Wiley & Sons, incorporated by reference with regard to protecting groups). 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 of processes as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of the present invention. Starting materials are commercially available or are made from commercially available starting materials using methods known to those skilled in the art.
As will be understood by the skilled chemist, references to preparations carried out in a similar manner to, or by the general method of, other preparations, may encompass variations in routine parameters such as time, temperature, workup conditions, minor changes in reagent amounts, etc.
The syntheses of intermediates herein are applicable for producing intermediates of the invention having a variety of R groups employing appropriate precursors, which are protected if needed, to achieve compatibility with the reactions described.
Compounds of Formula (I) can be prepared according to Scheme 1, Scheme 2, Scheme 3, Scheme 4, or analogous methods. For Scheme 1, a Wittig reaction of an aldehyde of Formula A with (triphenylphosphoranylidene)-acetaldehyde or base mediated
condensation of a an aldehyde of Formula A with acetaldehyde affords an unsaturated aldehyde of Formula B. Reaction of an aldehyde of Formula B with hydrazine provides a dihydropyrazole of Formula C. An amide bond formation between a piperidine-4-carboxylic acid of Formula D with a 4,5-dihydropyrazole of Formula C affords a compound of Formula E. The removal of the amine protecting group (e.g. tert-butoxycarbonyl) provides an amine of Formula F. An SNAr reaction between an amine of Formula F and a heteroaryl halide of Formula G furnishes compounds of Formula (I).
Alternatively, compounds of Formula (I) can be prepared according to Scheme 2. An amide bond coupling of a piperidine-4-carboxylic acid of Formula H with a 4,5- dihydropyrazole of Formula C provides compounds of Formula (I).
Compounds of Formula (II) can be prepared according to Scheme 3. Compounds of Formula (I) can be subjected to chiral separation methods to afford compounds of Formula (II).
Alternatively, compounds of Formula (II) can be prepared according to Scheme 4. In Scheme 4, chiral compounds of Formula J, prepared according to methods described herein, can be reacted with a compound of Formula H under amide bond forming conditions to afford a compound of Formula (II). Scheme 1: Synthesis of Compounds of Formula (I).
Figure imgf000093_0002
Scheme 2: Alternate Synthesis of Compounds of Formula (I).
Figure imgf000093_0001
Scheme 3: Synthesis of Compounds of Formula (II).
Figure imgf000094_0001
Scheme 4: Alternate Synthesis of Compounds of Formula (II).
Figure imgf000094_0002
EXPERIMENTALS The following examples illustrate the invention. These examples are not intended to limit the scope of the present invention, but rather to provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the present invention. While particular embodiments of the present invention are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the invention.
The reactions described herein are applicable for producing compounds of Formulas (I) and (II) having a variety of different substituent groups (e.g., R1, R2, etc.), as defined herein. The skilled artisan will appreciate that if a particular substituent is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions. The protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound. Suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY, 1999.
Names for the intermediate and final compounds described herein were generated using the naming program in ChemDraw, Struct=Name Pro 12.0, as part of ChemBioDraw Ultra, available from CambridgeSoft.100 CambridgePark Drive, Cambridge, MA 02140 USA (www.cambridgesoft.com).
It will be appreciated by those skilled in the art that in certain instances these programs may name a structurally depicted compound as a tautomer of that compound. It is to be understood that any reference to a named compound or a structurally depicted compound is intended to encompass all tautomers of such compounds and any mixtures of tautomers thereof.
1H NMR spectra were recorded in either CDCl3 or DMSO-d6 on either a Bruker Mercury Plus 300 NMR or 400 NMR Spectrometer equipped with a Bruker 400 BBO probe. The internal standard used was either tetramethylsilane (0.03% to 0.05% v/v) or the residual protonated solvent at 7.26 ppm for CDCl3, 3.31 ppm for CD3OD-d4 or 2.50 ppm for DMSO- d6. Chemical shifts are reported in parts per million (ppm). Abbreviations for NMR data are as follows: s = singlet, d = doublet, t = triplet, m = multiplet, br s = broad singlet, dd = doublet of doublets, dt = doublet of triplets, tt = triplet of triplets, ddd = doublet of doublet of doublets, sextuplet of d = sextuplet of doublets. J indicates the 1H NMR coupling constant measured in Hertz.
Table 1. LCMS Analytical Method
Figure imgf000095_0001
ih l i f 2 i Th l
Figure imgf000096_0001
L M Th l d i PL H 1 1
Figure imgf000097_0001
L M Th l d A i E 1 2
Figure imgf000098_0001
M hd 21 FA i d di 1 B B 1 FA i A
Figure imgf000099_0001
4 id l i ih 2 H A i
Figure imgf000100_0001
M hd 2 A li di lid i A A 1
Figure imgf000101_0001
Table 2. Chiral HPLC Analytical Method
Figure imgf000101_0002
A l i l H D M= 1 1 DEA E H= 24 fl
Figure imgf000102_0001
hi l HPL HIRALPAK IF i 4 l
Figure imgf000103_0001
M hd 2 1 l/ i 2 °
Figure imgf000104_0001
Table 3. Chiral SFC Analytical Method
Figure imgf000104_0002
Table 4. Chiral HPLC Separation Method
Figure imgf000104_0003
S i h h i MOH EOH iPOH ih
Figure imgf000105_0002
In the following experimental descriptions, the following abbreviations may be used:
Figure imgf000105_0001
DM di hl lf id
Figure imgf000106_0001
di lf
Figure imgf000107_0001
Intermediates Intermediate 1
5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole
Figure imgf000108_0001
Step 1
A mixture of 3,5-difluorobenzaldehyde (50 g, 352 mmol) and acetaldehyde (139 mL, 2463 mmol) was cooled to -10 oC. A solution of potassium hydroxide (3.95 g, 70.4 mmol) in methanol (25 mL) was prepared and added dropwise maintaining a temperature below 10 oC. The resultant mixture was stirred for 1 hr at 10 oC. acetic anhydride (33.2 mL, 352 mmol) was added dropwise and the resultant mixture was heated to 80 oC for 2 hr and then cooled back to RT.1N HCl (281 mL, 563 mmol) was added and the reaction mixture was heated to reflux for 3 hr, then coold back to room temperature and was stirred for 72 hr. The reaction mixture was diluted with diethyl ether and the layers were separated. The organic extract was washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude residue was triturated with heptane to afford (E)-3-(3,5-difluorophenyl)acrylaldehyde (37g, 62.5 % yield). LCMS (m/z) 169 (M+H)+, retention time: 0.79 min, LCMS Method 9. 1H NMR (400 MHz, DMSO-d6) ppm 9.70 (m, 1H), 7.72 (m, 1H), 7.64-7.52 (m, 2H), 7.40 (m, 1H), 7.01 (m, 1H). Step 2
To a solution of hydrazine hydrate (220 mL, 3628 mmol) dissolved in 1,4-Dioxane (700 mL) at rt was added a solution of (E)-3-(3,5-difluorophenyl)acrylaldehyde (61 g, 363 mmol) in 1,4-Dioxane (700 mL) dropwise over 2 hr. The reaction mixture was stirred for 4 hr. The reaction mixture was diluted with brine (500 mL), water (500 mL) and diethyl ether (1 L) and the layers were separated. The aqueous layer was extracted with dichloromethane (4 x 500 mL). The diethyl ether and dichloromethane extracts were combined and dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified via silica gel chromatography (100% ethyl acetate) to afford 5-(3,5-difluorophenyl)-4,5-dihydro- 1H-pyrazole (64.5 g, 93 % yield). LCMS (m/z) 183 (M+H)+, retention time: 0.51min, LCMS Method 9. 1H NMR (DMSO-d6) ppm 7.36-7.28 (m, 1H), 7.10-6.98 (m, 3H), 6.73 (s, 1H), 4.66 (m, 1H), 3.09 (m, 1H), 2.55-2.42 (m, 1H). The following compounds were synthesized in an analogous manner. 1
Figure imgf000109_0002
Intermediate 4
3-(4,5-dihydro-1H-pyrazol-5-yl)-5-fluoropyridine
Figure imgf000109_0001
Step 1
To a stirred solution of 5-fluoronicotinaldehyde (4.3g, 34 mmol) in DCM (50 mL) was added 2-(triphenyl-l5- phosphaneylidene)acetaldehyde (11.5 g, 37.8 mmol) in one portion. The resultant mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. The resulting residue was triturated in 200 mL of Et2O and the solid precipitate was removed by filtration and the filtrate was concentrated. The residue was purified by normal phase column chromatography (EA in heptane from 5 to 60% EA) to afford (E)-3-(5-fluoropyridin-3-yl)acrylaldehyde (4.0 g, 77% yield) as a cream solid. LCMS (m/z) 159.1 (M+H)+, retention time: 0.45 min, LCMS Method 9. 1H NMR (400 MHz, DMSO-d6) d: 9.73 (d, J = 7.9 Hz, 1H), 8.56-8.88 (m, 2H), 8.12-8.41 (m, 1H), 7.82 (dd, J = 16.1, 1.4 Hz, 1H), 7.09 (dd, J = 16.1, 7.7 Hz, 1H).
Step 2
To a stirred solution of 85% hydrazine hydrate (8.40 mL, 146 mmol) in diethyl ether (150 mL) at rt was added a solution of (E)-3-(5-fluoropyridin-3-yl)acrylaldehyde (2.20 g, 14.6 mmol) in Diethyl ether (150 mL) dropwise over 1 hour. The resulting mixture was stirred at rt for 3 hours and diluted with 20 mL water and 500 mL of DCM. The aqueous layer was separated and extracted DCM (4 times). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by normal phase column chromatography (EA in Heptane from 10% to 100%) to afford 3-(4,5-dihydro-1H- pyrazol-5-yl)-5-fluoropyridine (1.1 g, 46% yield) as a yellow oil. LCMS (m/z) 183.0 (M+H)+, retention time: 0.24 min, LCMS Method 9. 1H NMR (400 MHz, DMSO-d6) d: 8.29-8.59 (m, 2H), 7.56-7.79 (m, 1H), 7.36 (br d, J = 3.8 Hz, 1H), 6.66-6.85 (m, 1H), 4.70 (td, J = 10.6, 4.1 Hz, 1H), 3.11 (ddd, J = 16.9, 10.7, 1.8 Hz, 1H), 2.57 (ddt, J = 17.0, 10.7, 1.2 Hz, 1H).
The following compounds were synthesized in an analogous manner with the exception of step 1 in toluene at 100 oC overnight. I di N S LC i i MS
Figure imgf000111_0002
Intermediate 7
3-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carboxylic acid
Figure imgf000111_0001
Step 1
To a mixture of pyrazolo[1,5-a]pyridine-5-carboxylic acid (3.24 g, 20 mmol) in MeOH (40 mL) was added concentrated HCl (1 mL) at rt. The resulting mixture was heated to 70 °C and stirred for 12 hours. After cooled to 0 °C, the resulting mixture was quenched by addition of saturated aqueous NaHCO3 (40 mL), and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to afford methyl pyrazolo[1,5-a] pyridine-5-carboxylate (3.18 g crude) as an off-white solid. LCMS (m/z) 177 (M+H)+, retention time: 0.843 min, LCMS Method 6. Step 2
NIS (4.21 g, 18.7 mmol) was added to a mixture of methyl pyrazolo[1,5-a] pyridine-5- carboxylate (3 g, 17 mmol) in MeCN (70 mL). The resulting mixture was stirred at rt for 4 hours, filtered, and the filtrate was concentrated under vacuum to afford a residue. The resulting residue was diluted with H2O (60 mL) and extracted with EA (3 x 80 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by normal phase column chromatograph (EA in PE from 0% to 8%) to afford methyl 3-iodopyrazolo [1,5-a]pyridine- 5-carboxylate (4.51 g, 75% yield for two steps) as a light yellow solid. LCMS (m/z) 303 (M+H)+, retention time: 1.561 min, LCMS Method 10. 1H NMR (CDCl3) d 8.48 (m, 1H), 8.22 (s, 1H), 8.04 (s, 1H), 7.35 (m, 1H), 3.98 (s, 3H). Step 3
Pd(dppf)Cl2.CH2Cl2 (572 mg, 0.7 mmol) was added to a mixture of methyl 3- iodopyrazolo[1,5-a]pyridine-5-carboxylate (2.0 g, 6.6 mmol), 2,4,6-trimethyl -1,3,5,2,4,6- trioxatriborinane (5 g, 19.8 mmol) and K2CO3 (2.7 g, 19.8 mmol) in DMF (20 mL) under nitrogen atmosphere. The resulting mixture was heated to 80 °C and stirred for 4 hours. After cooled to rt, the resulting mixture was diluted with H2O (100 mL) and extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to afford a residue. The resulting residue was purified by normal phase column chromatograph (EA in PE from 0% to 5%) to afford methyl 3-methylpyrazolo [1,5-a]pyridine-5-carboxylate (690 mg, 55% yield) as a light yellow solid. LCMS (m/z) 191 (M+H)+, retention time: 1.505 min, LCMS Method 10. 1H NMR (CDCl3) d 8.54 (m, 1H), 8.42 (s, 1H), 7.87 (s, 1H), 3.99 (s, 3H), 2.40 (s, 3H). Step 4
A mixture of methyl 3-methylpyrazolo [1,5-a]pyridine-5-carboxylate (570 mg, 3 mmol) in MeOH (100 mL) was hydrogenated in presence of palladium carbon (10%, 300 mg) under hydrogen atmosphere (20 atm). After stirred for 18 hours at 80 °C under hydrogen atmosphere (20 atm), the reaction mixture was filtered through Celite. The filtrate was concentrated under vacuum to afford a residue. The resulting residue was diluted with EA (30 mL), washed with saturated aqueous NaHCO3 (30 mL), washed with and brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to afford methyl 3- methyl-4,5,6,7-tetrahydropyrazolo[1,5-a] pyridine-5-carboxylate (380 mg crude) as a yellow oil. LCMS (m/z) 195 (M+H)+, retention time: 0.666 min, LCMS Method 6. Step 5
A mixture of methyl 3-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carboxylate (933 mg, 4.8 mmol) in H2O (60 mL) and concentrated HCl (20 mL) was heated to 80 °C and stirred for 1 hour. After cooled to rt, the resulting mixture was concentrated under high vacuum to afford 3-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carboxylic acid (1 g crude) as a yellow oil. LCMS (m/z) 181 (M+H)+, retention time: 0.526 min, LCMS Method 6.
Intermediate 8
2-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carboxylic acid
Figure imgf000114_0001
Step 1
Ethyl isonicotinate (15.1 g, 0.1 mol) was added into a mixture of O-(2,4-dinitrophenyl) hydroxylamine (21.9 g, 0.11 mol) in THF (50 mL) and H2O (50 mL). The resulting mixture was stirred at 40 °C for 18 hours and concentrated under high vacuum to afford a residue. The resulting residue was diluted with H2O (400 mL) and washed with EA (3 x 200 mL). The aqueous phase was concentrated under high vacuum to afford ethyl N-aminoisonicotinate 2,4-dinitrophenol salt (32 g) as a yellow solid. LCMS (m/z) 167 (M+H)+, retention time: 0.207 min, LCMS Method 18.
Step 2
K2CO3 (12.4 g, 90 mmol) was added into a mixture of ethyl N-aminoisonicotinate 2,4- dinitrophenol salt (32 g, 90 mmol) in EtOH (150 mL). The mixture was stirred for 30 minutes at rt, followed by addition of ethyl acetoacetate (11.4 mL, 90 mmol). The resulting mixture was heated to 60 °C and stirred for 5 hours. After cooled to rt, the mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by normal phase column chromatography (EA in PE from 0% to 20%) to afford diethyl 2-methylpyrazolo[1,5- a]pyridine-3,5-dicarboxylate (8.48 g, 29% yield for two steps) as a light yellow solid. LCMS (m/z) 277 (M+H)+, retention time: 1.068 min, LCMS Method 7. Step 3
A solution of NaOH (4.9 g, 121.5 mmol) in H2O (24 mL) was added to a mixture of diethyl 2-methylpyrazolo[1,5-a]pyridine-3,5-dicarboxylate (6 g, 21.7 mmol) in EtOH (48 mL). The resulting mixture was heated to 100 °C and stirred for 30 minutes. After cooled to rt, the mixture was adjusted to pH 4 with aqueous HCl (1 M, 150 mL) at 0 °C. The precipitate was collected by filtration and washed with H2O to afford 2-methylpyrazolo[1,5-a]pyridine-3,5- dicarboxylic acid (3.1 g crude) as a yellow solid. LCMS (m/z) 221 (M+H)+, retention time: 0.823 min, LCMS Method 4.
Step 4
2-Methylpyrazolo[1,5-a]pyridine-3,5-dicarboxylic acid (2.88 g, 13.09 mmol) was added to the stirred hot PPA (28.8 g). The resulting mixture was heated to 150 °C, stirred for 4 hours, and poured into ice-water (100 mL) slowly to quench the reaction. The resulting suspension was adjusted to pH 4 with aqueous NaOH (1 M) at 0 °C. The precipitate was collected by filtration and washed with ether to afford 2-methylpyrazolo[1,5-a]pyridine-5-carboxylic acid (1.9 g crude) as a pale-brown solid. LCMS (m/z) 177 (M+H)+, retention time: 0.727 min, LCMS Method 6. Step 5
The mixture of 2-methylpyrazolo[1,5-a]pyridine-5-carboxylic acid (1.8 g, 10 mmol) in MeOH (40 mL) was hydrogenated in presence of palladium carbon (10%, 900 mg) under hydrogen atmosphere (20 atm). After stirred for 18 hours at 80 °C under hydrogen atmosphere (20 atm), the reaction mixture was filtered through Celite. The filtrate was concentrated under vacuum to afford 2-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5- carboxylic acid (1.74 g crude) as a light gray solid. LCMS (m/z) 181 (M+H)+, retention time: 0.484 min, LCMS Method 6. Intermediate 9
1-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-7-carboxylic acid
Figure imgf000116_0001
Step 1
K2CO3 (579 mg, 1 mmol) was added into a mixture of 4-methyl-1H-imidazole-5- carbaldehyde (1.1 g, 10 mmol) and ethyl 4-bromobutanoate (2.14 g , 11 mmol) in DMF (20 mL). The resulting mixture was stirred at rt for 18 hours and concentrated under high vacuum to afford a residue. The resulting residue was purified by normal phase column
chromatography (MeOH in DCM from 0% to 5%) to afford ethyl 4-(5-formyl-4-methyl-1H- imidazol-1-yl)butanoate (1.06 g, 47.3%) as a yellow oil. LCMS (m/z) 225 (M+H)+, retention time: 0.744 min, LCMS Method 4.
Step 2
NaH (60%, 188 mg, 4.72 mmol) was added into a mixture of 4-(5-formyl-4-methyl-1H- imidazol-1-yl)butanoate (0.96 g, 4.28 mmol) and molecular sieves 4 Å (1.3 g) in toluene (20 mL) under nitrogen atmosphere. The reaction mixture was heated to 110 °C and stirred for 18 hours. After cooled to rt, the reaction mixture was quenched by the addition of H2O (50 mL) and extracted with EA (3 x 80 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to afford ethyl 1-methyl-5,6-dihydroimidazo[1,5-a]pyridine-7-carboxylate (800 mg, 94% yield) as a yellow oil. LCMS (m/z) 207 (M+H)+, retention time: 0.734 min, LCMS Method 4. Step 3
A mixture of ethyl 1-methyl-5,6-dihydroimidazo[1,5-a]pyridine-7-carboxylate (800 mg, 3.88 mmol) in methanol (50 mL) was hydrogenated in presence of palladium carbon (10%, 200 mg) under hydrogen atmosphere (2-3 atm). After stirred for 2 hours at rt under hydrogen atmosphere, the reaction mixture was filtered through Celite. The filtrate was concentrated under vacuum to afford ethyl 1-methyl-5,6,7,8-tetrahydroimidazo[1,5- a]pyridine-7-carboxylate (700 mg, 87% yield) as a yellow oil. LCMS (m/z) 209 (M+H)+, retention time: 0.725 min, LCMS Method 4. Step 4
A mixture of ethyl 1-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-7-carboxylate (700 mg, 3.36 mmol) in HCl (105 mL) and H2O (245 mL) was heated to 80 °C and stirred for 1 hour. After cooled to rt, the reaction mixture was concentrated under high vacuum to afford 1-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-7-carboxylic acid (500 mg crude) as a red solid. LCMS (m/z) 181 (M+H)+, retention time: 0.595 min, LCMS Method 4.
Intermediate 10
6-chloro-N-methylpyrimidine-4-carboxamide
Figure imgf000117_0001
Step 1
To a solution of 6-hydroxypyrimidine-4-carboxylic acid (4.5 g, 32.1 mmol) in POCl3 (80 mL) was added PCl5 (6.6g, 32.1 mmol). The resulting mixture was heated to 100 °C and stirred for 18 hours. After cooled to rt, the reaction mixture was concentrated under vacuum to afford 6-chloropyrimidine-4-carbonyl chloride (15.0 g crude) as a black oil. LCMS (m/z) 169 (M+H+), retention time: 0.532 min. LCMS Method 14. Step 2
A solution of methanamine in THF (2 M in THF, 6.7 mL, 13.4 mmol) was added to a solution of 6-chloropyrimidine-4-carbonyl chloride (2.3g, 13.1 mmol) in DCM (40 mL) at 0 °C under N2 atmosphere, followed by addition of DIEA (6.3 g, 49.1 mmol). The resulting mixture was stirred at 0 °C for an hour then stirred at rt for another hour. The resulting mixture was concentrated under vacuum to afford a residue. The resulting residue was purified by normal phase column chromatography (EA in PE from 0 % to 30 %) to give 6- chloro-N-methylpyrimidine-4-carboxamide (2.0 g, 89% yield) as a yellow solid. LCMS (m/z) 172 (M+H)+, retention time: 0.487 min. LCMS Method 14. 1H NMR (CDCl3) d 8.99 (s, 1H), 8.16 (s, 1H), 7.90 (br. s, 1H), 3.07 (s, 3H).
Intermediate 11
6-chloro-N,N-dimethylpyrimidine-4-carboxamide
Figure imgf000118_0001
A solution of dimethylamine in THF (2 M in THF, 6.4 mL, 12.8 mmol) was added to a solution of 6-chloropyrimidine-4-carbonyl chloride (2.2 g, 12.5 mmol) in DCM (40 mL), followed by addition of DIEA (6.0 g, 46.8 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 0 °C for an hour and rt for another hour. The mixture was concentrated under vacuum to afford a residue. The resulting residue was purified by normal phase column chromatography (EA in PE from 0% to 30%) to give 6-chloro-N,N- dimethylpyrimidine-4-carboxamide (2.0 g, 86% yield) as a yellow solid. LCMS (m/z) 186 (M+H)+, retention time: 0.457 min, LCMS Method 14. 1H NMR (CDCl3) d 9.01 (s, 1H), 7.67 (s, 1H), 3.15 (s, 3H), 3.10 (s, 3H). Intermediate 12
4-chloro-6-(methylsulfinyl)pyrimidine
Figure imgf000119_0001
Step 1
NaSCH3 (4.6 g, 66 mmol) was added to a mixture of 4-chloro-6-(methylthio)pyrimidine (9.8 g, 66 mmol) in THF (60 mL). The resulting mixture was stirred for 4 hours at 60 °C, quenched by the addition of H2O (50 mL), and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to afford 4-chloro-6-(methylthio)pyrimidine (8.2 g crude) as a yellow oil. LCMS (m/z) 161 (M+H)+, retention time: 0.857 min, LCMS Method 21.
Step 2
mCPBA (5.6 g, 32.6 mmol) was added to a stirred mixture of 4-chloro-6- (methylthio)pyrimidine (3.5 g, 21.7 mmol) in DCM (100 mL). The resulting mixture was stirred for 1 hour at rt, quenched by the addition of aqueous NaHCO3 (10%, 100 mL), and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by normal phase column chromatograph (EA in PE from 0% to 20%) to afford 4-chloro-6-(methylsulfinyl)pyrimidine (2.8 g, 73% yield) as a yellow solid. LCMS (m/z) 177 (M+H)+, retention time: 0.345 min, LCMS Method 21.
Intermediate 13
4-chloro-6-(methylsulfonyl)pyrimidine
Figure imgf000120_0001
mCPBA (16.0 g, 93 mmol) was added to a stirred mixture of 4-chloro-6- (methylthio)pyrimidine (5.0 g, 31 mmol) in DCM (120 mL). The resulting mixture was stirred for 30 minutes at rt, quenched by the addition of aqueous NaHCO3 (10%, 100 mL), and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to afford a residue. The resulting residue was purified by normal phase column chromatograph (EA in PE from 0% to 20%) to afford 4-chloro-6-(methylsulfonyl)pyrimidine (3.2 g, 54% yield) as a yellow solid. LCMS (m/z) 193 (M+H)+, retention time: 0.510 min, LCMS Method 21.
Intermediates 14 and 15
cis-(3-fluoropiperidin-4-yl)(5-(2,3,5-trifluorophenyl)-4,5-dihydro-1H-pyrazol-1- yl)methanone hydrochloride
and
trans-(3-fluoropiperidin-4-yl)(5-(2,3,5-trifluorophenyl)-4,5-dihydro-1H-pyrazol-1- yl)methanone hydrochloride
Figure imgf000121_0001
Step 1
2-(Triphenyl-l5-phosphaneylidene) acetaldehyde (20.9 g, 68.8 mmol) was added to a mixture of 2,3,5-trifluorobenzaldehyde (10.0 g, 62.5 mmol) in DCM (80 mL). The resulting mixture was stirred at rt for 18 hours and concentrated under vacuum to afford a residue. The resulting residue was purified by column chromatography (EA in PE from 0% to 15%) to afford (E)-3-(2,3,5-trifluorophenyl)acrylaldehyde (5.7 g, 49% yield) as a white solid. LCMS (m/z) no mass signal, retention time: 1.001 min, LCMS Method 15. 1H NMR (400 MHz, DMSO-d6) d 9.77 (d, J = 7.6 Hz, 1H), 7.86 (d, J = 16 Hz, 1H), 7.77 (m, 2H), 7.02 (m, 1H). Step 2
A solution of (E)-3-(2,3,5-trifluorophenyl)acrylaldehyde (5.7 g, 31 mmol) in Et2O (250 mL) was added to a mixture of hydrazine hydrate (15.33 g, 307 mmol) in Et2O (250 mL). The resulting mixture was stirred at rt for 30 minutes and diluted with H2O (100 mL). Et2O was evaporated off, and the resulting mixture was extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The solids were filtered off and rinsed by PE to afford 5-(2,3,5-trifluorophenyl)-4,5- dihydro-1H-pyrazole (3.3 g, 54% yield) as a white solid. LCMS (m/z) 201 (M+H)+, retention time: 0.837 min, LCMS Method 15. 1H NMR (DMSO- d6) d 7.09-7.03 (m, 1H), 6.90-6.81 (m, 2H), 5.85 (br. s., 1H), 5.03 (t, 1H), 3.31-3.21 (m, 1H), 2.67-2.57 (m, 1H). Step 3
DIEA (2.13 g, 16.5 mmol) was added to a mixture of cis-1-(tert-butoxycarbonyl)-3- fluoropiperidine-4-carboxylic acid (4.07 g, 16.5 mmol) and py-Brop (7.69 g, 16.5 mmol) in DMF (30 mL), followed by addition of 5-(2,3,5-trifluorophenyl)-4,5-dihydro-1H-pyrazole (3.3 g, 16.5 mmol). The resulting mixture was stirred at rt for 18 hours, diluted with H2O (20 mL), and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to afford a residue. The resulting residue was purified by normal phase column chromatography (EA in PE from 0% to 70%) to afford two diastereomers of tert-butyl 3-fluoro-4-(5-(2,3,5- trifluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperidine-1-carboxylate. Diastereomer 1 was afforded as a light yellow solid (1.0 g, 30% yield). LCMS (m/z) 374 (M+H-56)+, retention time: 1.113 min, LCMS Method 29. Diastereomer 2 was afforded as a light yellow solid (1.0 g, 30% yield). LCMS (m/z) 374 (M+H-56)+, retention time: 1.109 min, LCMS Method 15.
Step 4
A diastereomer of tert-butyl 3-fluoro-4-(5-(2,3,5-trifluorophenyl)-4,5-dihydro-1H-pyrazole- 1-carbonyl)piperidine-1-carboxylate (1.0 g, 2.4 mmol) was added to a solution of HCl in dioxane (4 N, 10 mL). The resulting mixture was stirred at rt for 1 hour, and concentrated under high vacuum to afford a diastereomer of (3-fluoropiperidin-4-yl)(5-(2,3,5- trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone hydrochloride (0.8 g crude) as a light yellow solid. LCMS (m/z) 330 (M+H-36)+, retention time: 0.880 min, LCMS Method 12. Step 5
A diastereomer of tert-butyl 3-fluoro-4-(5-(2,3,5-trifluorophenyl)-4,5-dihydro-1H-pyrazole- 1-carbonyl) piperidine-1-carboxylate (1.0 g, 2.4 mmol) was added to a solution of HCl in dioxane (4 N, 10 mL). The resulting mixture was stirred at rt for 1 hour, and concentrated under high vacuum to afford a diastereomer of (3-fluoropiperidin-4-yl)(5-(2,3,5- trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone hydrochloride (0.85 g, 96% yield) as a light yellow solid. LCMS (m/z) 330 (M+H-36)+, retention time: 0.716 min, LCMS Method 13.
Examples Examples 1– 4 ((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((R)-3-methyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyridin-5-yl)methanone
and
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((S)-3-methyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyridin-5-yl)methanone
and
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((S)-3-methyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyridin-5-yl)methanone
and
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((R)-3-methyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyridin-5-yl)methanone
Figure imgf000124_0001
Step 1
DIEA (1.55 g, 12 mmol) was added to a stirred mixture of HATU (2.28 g, 6 mmol) and 3- methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carboxylic acid (720 mg, 4 mmol) in DMF (40 mL). The resulting mixture was stirred for 10 minutes at room temperature, followed by addition of 5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole (728 mg, 4 mmol). The resulting mixture was stirred at rt for 16 hours, diluted with H2O (30 mL), and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to afford a residue. The resulting residue was purified by normal phase column chromatography (EA in PE from 50% to 90%) to afford the crude product. The crude product was re-purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column 19 x 150 mm 5 um; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 5% B to 35% B in 4 min; UV 254 & 220 nm; Rt1: 10.20 min; Rt2: 11.42 min to afford two diastereomers of 5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl-(3- methyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-5-yl)methanone. A diastereomer was afforded as a white solid (160 mg): LCMS (m/z) 345 (M+H)+, retention time: 1.052 min, LCMS Method 2. A disastereomer was afforded as a white solid (120 mg). LCMS (m/z) 345 (M+H)+, retention time: 1.059 min, LCMS Method 2. Step 2
Enantiomers of racemate (160 mg, 0.46 mmol) were separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IG-03, 2.0 cm I.D x 25cm L (5 um); Mobile Phase A: Hexane, Mobile Phase B: EtOH; Flow rate: 18 mL/min; Gradient: 50% B to 50% B in 20 min; UV 220 & 254 nm; Rt1: 12.8 min; Rt2: 15.1 min to afford two titled compounds. Example 1
An enantiomer was afforded as a light yellow solid (52.4 mg, 65% yield).
1H NMR (400 MHz, CD3OD-d4) ppm 7.21 (s, 1H), 7.20 (t, J=1.6 Hz, 1H), 6.88-6.82 (m, 3H), 5.38 (dd, J=11.6, 4.8 Hz, 1H), 4.15-4.05 (m, 2H), 3.70-3.68 (m, 1H), 3.59-3.50 (m, 1H), 2.93- 2.91 (m, 1H), 2.87-2.75 (m, 2H), 2.35-2.33 (m, 1H), 2.16-2.10 (m, 1H), 1.95 (s, 3H). LCMS (m/z) 345 (M+H) +, retention time: 1.394 min, LCMS Method 1. Chiral HPLC Anal. Method 23: 2.564 min, % ee = 100.0 %. Example 2
An enantiomer was afforded as a yellow solid (54.4 mg, 68% yield).1H NMR (400 MHz, CD3OD-d4)d 7.21 (s, 1H), 7.20 (t, J=1.6 Hz, 1H), 6.88-6.82 (m, 3H), 5.38 (dd, J=11.6, 4.8 Hz, 1H), 4.15-4.05 (m, 2H), 3.70-3.68 (m, 1H), 3.59-3.50 (m, 1H), 2.93-2.75 (m, 3H), 2.35-2.33 (m, 1H), 2.16-2.10(m, 1H), 1.95 (s, 3H). LCMS (m/z) 345 (M+H)+, retention time: 1.396 min , LCMS Method 1. Chiral HPLC Anal. Method 23: 3.059 min, % ee = 99.5%. Enantiomers of a racemate were separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IC, 2 x 25 cm, 5 um; Mobile Phase B: MeOH; Flow rate: 20 mL/min; Gradient: 100% B to 100% B in 11 min; UV 220 & 254 nm; Rt1: 4.5 min; Rt2: 6.9 min to afford two title compounds: Example 3
An enantiomer was afforded as a white solid (42.2 mg, 70% yield). 1H NMR (400 MHz, CD3OD-d4) ppm 7.22 (s, 1H), 7.19 (t, J=1.6 Hz, 1H), 6.88-6.81 (m, 3H), 5.39 (dd, J=12.0, 4.8 Hz, 1H), 4.22-4.18 (m, 1H), 4.06-4.03 (m, 1H), 3.71-3.68 (m, 1H), 3.59-3.50 (m, 1H), 3.07- 3.01 (m, 1H), 2.87-2.72 (m, 2H), 2.27-2.25 (m, 1H), 2.14-2.10 (m, 1H), 1.96 (s, 3H). LCMS (m/z) 345 (M+H)+, retention time: 2.385 min, LCMS Method 3. Chiral HPLC Anal. Method 1: 1.741 min,
% ee = 100.0 %. Example 4
An enantiomer was afforded as a white solid (41.6 mg, 69% yield).1H NMR (400 MHz, CD3OD-d4) ppm 7.22 (s, 1H), 7.19 (t, J=1.6 Hz, 1H), 6.88-6.81 (m, 3H), 5.39 (dd, J=12.0, 5.2 Hz, 1H), 4.23-4.18 (m, 1H), 4.05-4.02 (m, 1H), 3.71-3.68 (m, 1H), 3.59-3.50 (m, 1H), 3.07- 3.00 (m, 1H), 2.87-2.72 (m, 2H), 2.27-2.25 (m, 1H), 2.14-2.09 (m, 1H), 1.96 (s, 3H). LCMS (m/z) 345 (M+H)+, retention time: 1.422 min, LCMS Method 1. Chiral HPLC Anal. Method 1: 2.780 min, % ee = 99.7%.
The following compounds were synthesized in an analogous manner. The compounds were synthesized via amide coupling using HATU, DIEA and DMF at rt for 18 hours. The isomers were separated by chiral separation.
Examples 5– 8
Figure imgf000126_0001
Figure imgf000127_0002
Examples 5– 8 correspond to the following:
Figure imgf000127_0001
1H) 540 (dd
Figure imgf000128_0001
Examples 9– 12
Figure imgf000128_0002
Figure imgf000129_0002
Examples 9– 12 correspond to the following:
Figure imgf000129_0001
(m 1H) 310- 04 (m 1H)
Figure imgf000130_0001
Examples 13– 16 6-((1R,5S,6r)-6-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- azabicyclo[3.1.1]heptan-3-yl)pyrimidine-4-carboxamide and
6-((1R,5S,6r)-6-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- azabicyclo[3.1.1]heptan-3-yl)pyrimidine-4-carboxamide
and
6-((1R,5S,6s)-6-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- azabicyclo[3.1.1]heptan-3-yl)pyrimidine-4-carboxamide
and
6-((1R,5S,6s)-6-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- azabicyclo[3.1.1]heptan-3-yl)pyrimidine-4-carboxamide
Figure imgf000131_0001
Step 1
A solution of LiOH (329 mg, 13.7 mmol) in H2O (4 mL) was added to a solution of 3-(tert- butyl) 6-methyl 3-azabicyclo[3.1.1]heptane-3,6-dicarboxylate (1.75 g, 6.85 mmol) in THF (16 mL). The reaction mixture was stirred at rt for 5 hours. After removal of THF under reduced pressure, the resulting solution was adjusted to pH 5-6 with aqueous HCl (1 N, 15 mL). The resulting mixture was extracted with EA (3 x 60 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to afford 3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.1]heptane-6-carboxylic acid (1.47 g crude) as a colorless oil. LCMS (m/z) no mass signal, retention time: 1.030 min, LCMS Method 4. 1H NMR (300 MHz, DMSO-d6) d 12.22 (s, 1H), 3.77-3.66 (m, 1H), 3.55- 3.47 (m, 1H), 3.33-3.23 m, 1H), 2.60-2.51 (m, 3H), 2.41-2.29 (m, 1H), 1.41 (d, J = 9.3 Hz, 9H). Step 2
DIEA (2.38 g, 18.3 mmol) was added to a mixture of 3-(tert-butoxycarbonyl)-3-azabicyclo [3.1.1] heptane-6-carboxylic acid (1.47 g, 6.1 mmol) and HATU (2.78 g, 7.32 mmol ) in DCM (30.0 mL). The reaction mixture was stirred at rt for 10 min, followed by addition of 5- (3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole (1.11 g, 6.1 mmol). The resulting mixture was stirred at rt for 18 hours and concentrated under vacuum. The residue was purified by normal phase column chromatography (EA in PE from 0% to 30%) to afford tert-butyl 6-(5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-azabicyclo[3.1.1]heptane-3- carboxylate (2.4 g crude) as a colorless oil. LCMS (m/z) 350 (M+H-56)+, retention time: 1.317 min, LCMS Method 4. Step 3
Tert-butyl 6-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- azabicyclo[3.1.1] heptane-3-carboxylate (2.4 g, 5.93 mmol) was added to a solution of HCl in dioxane (4 N, 20 mL). The resulting mixture was stirred at rt for 5 hours and concentrated under vacuum to afford (3-azabicyclo [3.1.1] heptan-6-yl) (5-(3, 5-difluorophenyl)-4, 5- dihydro-1H-pyrazol-1-yl)methanone hydrochloride (2.0 g crude) as a yellow solid. LCMS (m/z) 306 (M+H-36)+, retention time: 1.031, 1.191 min, LCMS Method 2.
Step 4
DIEA (425 mg, 3.27 mmol) was added to a mixture of (3-azabicyclo[3.1.1]heptan-6-yl)(5- (3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone hydrochloride (370 mg, 1.09 mmol) and 6-chloropyrimidine-4-carboxamide (171 mg, 1.09 mmol) in DMF (15.0 mL). The resulting mixture was stirred at rt for 3 hours, diluted with H2O (50 mL), and extracted with DCM (3 x 60 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to afford a residue. The resulting residue was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP 18 OBD Column, 19 x 150 mm, 5 um; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 5% B to 25% B in 3 min; UV 254 & 220 nm; Rt1: 7.97 min; Rt2: 9.80 min to afford two diastereomers of 6-(6-(5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-azabicyclo [3.1.1]heptan-3- yl)pyrimidine-4-carboxamide as white solids. Diastereomer 1: LCMS (m/z) 427 (M+H)+, retention time: 1.135 min, LCMS Method 5. Diastereomer 2: LCMS (m/z) 427 (M+H)+, retention time: 1.222 min, LCMS Method 5. Step 5
Enantiomers of a racemate were separated by Prep-Chiral-SFC with the following conditions: Column: Lux Su Cellulose 4, AXIA Packed 2.12 x 25 cm, 5 um; Mobile Phase A: CO2, 50%; Mobile Phase B: EtOH, 50%; Flow rate: 40 mL/min; Gradient: 100% B to 100% B in 11 min; UV 254 & 220 nm; Rt1: 6.41 min; Rt2: 8.60 min to afford two title compounds: Example 13
An enantiomer was afforded as a white solid (62.8 mg, 27.5 % yield). LCMS (m/z) 427 (M+H)+, retention time: 1.135 min, LCMS Method 5. Chiral SFC Anal. Method 1, retention time: 2.813 min, % ee = 100.0 %.1H NMR (300 MHz, CD3OD-d4) ppm 8.55-8.49 (m, 1H), 7.21-7.13 (m, 2H), 6.69-6.57 (m, 3H), 5.26 (dd, J=12.0, 5.4 Hz, 1H), 4.20-3.87 (m, 2H), 3.66- 3.42 (m, 4H), 3.13 (s, 1H), 2.95-2.75 (m, 2H), 2.32-2.24 (m, 1H), 1.47-1.43 (m, 1H).
Example 14 An enantiomer was afforded as a white solid (62.1 mg, 27 % yield). LCMS (m/z) 427 (M+H)+, retention time: 1.135 min, LCMS Method 5. Chiral SFC Anal. Method 1, retention time: 3.607 min, % ee = 100.0 %.1H NMR (300 MHz, CD3OD-d4) ppm 8.56-8.49 (m, 1H), 7.20-7.13 (m, 2H), 6.69-6.57 (m, 3H), 5.26 (dd, J=12.0, 5.4 Hz, 1H), 4.20-3.86 (m, 2H), 3.66- 3.42 (m, 4H), 3.13 (s, 1H), 2.95-2.74 (m, 2H), 2.32-2.24 (m, 1H), 1.47-1.43 (m, 1H). Enantiomers of a racemate were separated by Prep-Chiral-SFC with the following conditions: Column: (R,R)WHELK-015/100 Kromasil, 2.11 x 25 cm, 5 um; Mobile Phase A: CO2, 50%; Mobile Phase B: MeOH, 50%; Flow rate: 50 mL/min; UV 254 & 220 nm; Rt1: 5.78 min; Rt2: 9.7 min to afford last two title compounds: Example 15 An enantiomer was afforded as a white solid (58.5 mg, 25.5 % yield). LCMS (m/z) 427 (M+H)+, retention time: 1.222 min, LCMS Method 5. Chiral SFC Anal. Method 2, retention time: 3.534 min, % ee = 100.0 %.1H NMR (300 MHz, DMSO-d6) ppm 8.63 (s, 1H), 8.10 (s, 1H), 7.77 (s, 1H), 7.22-7.10 (m, 3H), 6.92-6.88 (m, 2H), 5.41 (dd, J=12.0, 5.1 Hz, 1H), 3.89- 3.86 (m, 2H), 3.76-3.73 (m, 2H), 3.55-3.37 (m, 1H), 3.14-3.11 (m, 1H), 2.86-2.71 (m, 3H), 2.34-2.24 (m, 1H), 1.40-1.34 (m, 1H).
Example 16
An enantiomer was afforded as a white solid as a white solid (58.5 mg, 25.5 % yield).
LCMS (m/z) 427 (M+H)+, retention time: 1.224 min, LCMS Method 5. Chiral SFC Anal. Method 2, retention time: 4.077 min, % ee = 100.0 %.1H NMR (300 MHz, DMSO-d6) ppm 8.64 (s, 1H), 8.10 (s, 1H), 7.77 (s, 1H), 7.22-7.11 (m, 3H), 6.92-6.88 (m, 2H), 5.41 (dd, J=12.0, 5.1 Hz, 1H), 3.89-3.85 (m, 2H), 3.76-3.73 (m, 2H), 3.55-3.37 (m, 1H), 3.14- 3.11 (m, 1H), 2.86-2.71 (m, 3H), 2.34-2.24 (m, 1H), 1.40-1.34 (m, 1H).
Examples 17– 20 ((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((1R,5S,6s)-3-(5-methyl-1,3,4- oxadiazol-2-yl)-3-azabicyclo[3.1.1]heptan-6-yl)methanone
and
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((1R,5S,6r)-3-(5-methyl-1,3,4- oxadiazol-2-yl)-3-azabicyclo[3.1.1]heptan-6-yl)methanone
and
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((1R,5S,6r)-3-(5-methyl-1,3,4- oxadiazol-2-yl)-3-azabicyclo[3.1.1]heptan-6-yl)methanone
and
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((1R,5S,6s)-3-(5-methyl-1,3,4- oxadiazol-2-yl)-3-azabicyclo[3.1.1]heptan-6-yl)methanone
Figure imgf000135_0001
Step 1
A solution of LiOH (329 mg, 13.7 mmol) in H2O (4 mL) was added to a solution of 3-(tert- butyl) 6-methyl 3-azabicyclo[3.1.1]heptane-3,6-dicarboxylate (1.75 g, 6.85 mmol) in THF (16 mL). The reaction mixture was stirred at rt for 5 hours. After removal of THF under reduced pressure, the resulting solution was adjusted to pH 5-6 with aqueous HCl (1 N, 15 mL). The resulting mixture was extracted with EA (3 x 60 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to afford 3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.1]heptane-6-carboxylic acid (1.47 g crude) as a colorless oil. LCMS (m/z) no mass signal, retention time: 1.030 min, LCMS Method 4. 1H NMR (300 MHz, DMSO-d6) d 12.22 (s, 1H), 3.77-3.66 (m, 1H), 3.55- 3.47 (m, 1H), 3.33-3.23 m, 1H), 2.60-2.51 (m, 3H), 2.41-2.29 (m, 1H), 1.41 (d, J = 9.3 Hz, 9H). Step 2
DIEA (2.38 g, 18.3 mmol) was added to a mixture of 3-(tert-butoxycarbonyl)-3-azabicyclo [3.1.1] heptane-6-carboxylic acid (1.47 g, 6.1 mmol) and HATU (2.78 g, 7.32 mmol ) in DCM (30.0 mL). The reaction mixture was stirred at rt for 10 min, followed by addition of 5- (3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole (1.11 g, 6.1 mmol). The resulting mixture was stirred at rt for 18 hours and concentrated under vacuum. The residue was purified by normal phase column chromatography (EA in PE from 0% to 30%) to afford tert-butyl 6-(5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-azabicyclo[3.1.1]heptane-3- carboxylate (2.4 g crude) as a colorless oil. LCMS (m/z) 350 (M+H-56)+, retention time: 1.317 min, LCMS Method 4. Step 3
Tert-butyl 6-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- azabicyclo[3.1.1] heptane-3-carboxylate (2.4 g, 5.93 mmol) was added to a solution of HCl in dioxane (4 N, 20 mL). The resulting mixture was stirred at rt for 5 hours and concentrated under vacuum to afford (3-azabicyclo [3.1.1] heptan-6-yl) (5-(3, 5-difluorophenyl)-4, 5- dihydro-1H-pyrazol-1-yl)methanone hydrochloride (2.0 g crude) as a yellow solid. LCMS (m/z) 306 (M+H-36)+, retention time: 1.031, 1.191 min, LCMS Method 2.
Step 4
NaHCO3 (133 mg, 1.58 mmol) was added into a mixture of (3-azabicyclo[3.1.1]heptan-6- yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone hydrochloride (270 mg, 0.79 mmol) and 2-bromo-5-methyl-1,3,4- oxadiazole (129 mg, 0.79 mmol) in DMF (10 mL). The resulting mixture was heated to 80 °C, and stirred for 3 hours. After cooled to rt, the reaction mixture was quenched by addition of H2O (50 mL), and extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by normal phase column chromatography (MeOH in DCM from 0% to 5%) to afford (5-(3,5-difluorophenyl)- 4,5-dihydropyrazol-1-yl)(3-(5-methyl-1,3,4-oxadiazol-2-yl)-3-aza-bicyclo[3.1.1]heptan-6- yl)methanone (170 mg, 56% yield) as a yellow oil. LCMS (m/z) 388 (M+H)+, retention time: 0.888 min, LCMS Method 6. Step 5
The isomers of (5-(3,5-difluorophenyl)-4,5-dihydropyrazol-1-yl)(3-(5-methyl-1,3,4oxadiazol- 2-yl)-3-aza-bicyclo[3.1.1]heptan-6-yl)methanone (170 mg, 0.44 mmol) were separated by sequential Prep-Chiral-HPLC with the to afford ((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H- pyrazol-1-yl)((1R,5S,6r)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-3-azabicyclo[3.1.1]heptan-6- yl)methanone, ((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((1R,5S,6s)-3- (5methyl- 1,3,4-oxadiazol-2-yl)-3-azabicyclo[3.1.1]heptan-6-yl)methanone, ((S)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((1R,5S,6s)-3-(5-methyl-1,3,4-oxadiazol-2-yl)- 3-azabicyclo[3.1.1]heptan-6-yl)methanone, and ((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H- pyrazol-1-yl)((1R,5S,6r)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-3-azabicyclo[3.1.1]heptan-6-yl) methanone using the following conditions: Column: Chiralpak ID-2, 2 x 25 cm, 5 um; Mobile Phase A: Hexane, Mobile Phase B: IPA; Flow rate: 18 mL/min; Gradient: 40 B to 40 B in 50 min; UV 254/220 nm. Example 17
An isomer was afforded as a yellow oil (16.6 mg, 39% yield). LCMS (m/z) 388 (M+H)+, retention time: 1.217 min, LCMS Method 8. Chiral HPLC Anal. Method 2, retention time: 4.284 min, % ee = 100.0 %.1H NMR (400 MHz, CD3OD-d4) ppm 7.13 (t, J=1.6 Hz, 1H), 6.80-6.68 (m, 3H), 5.28 (dd, J=12.0, 5.6 Hz, 1H), 3.94-3.86 (m, 2H), 3.56-3.42 (m, 4H), 3.04- 2.98 (m, 1H), 2.88-2.74 (m, 2H), 2.36 (s, 3H), 2.30-2.20 (m, 1H).1.42 (d, J=9.2 Hz, 1H). Example 18
An isomer was afforded as a yellow oil (28.9 mg, 68% yield). LCMS (m/z) 388 (M+H)+, retention time: 1.297 min, LCMS Method 8. Chiral HPLC Anal. Method 2, retention time: 5.491 min, % ee = 100.0 %.1H NMR (400 MHz, CD3OD-d4) ppm 7.12 (t, J=1.6 Hz, 1H), 6.90-6.80 (m, 3H), 5.41 (dd, J=12.0, 4.8 Hz, 1H), 3.88-3.78 (m, 4H), 3.56-3.48 (m, 1H), 3.28- 3.22 (m, 1H), 2.88-2.74 (m, 3H), 2.48-2.30 (m, 4H), 1.46 (dd, J=9.6, 5.6 Hz, 1H). The mixture of two isomers were separated by Prep-Chiral HPLC with the following conditions: Column: CHIRALPAK IC, 2 x 25 cm, 5 um; Mobile Phase A: Hexane (8 mmol/L NH3 .MeOH), Mobile Phase B: EtOH; Flow rate: 16 mL/min; Gradient: 50 B to 50 B in 20 min; UV 254/20 nm; Rt1: 10.8 min; Rt2: 16.613 min to afford two title compounds: Example 19
An isomer was afforded as a yellow oil (11.9 mg, 28% yield) . LCMS (m/z) 388 (M+H)+, retention time: 1.217 min, LCMS Method 8. Chiral HPLC Anal. Method 3, retention time: 2.077 min, % ee = 100.0 %.1H NMR (400 MHz, CD3OD-d4) ppm 7.13 (t, J=1.6 Hz, 1H), 6.80-6.68 (m, 3H), 5.28 (dd, J=12.0, 5.6 Hz, 1H), 3.92-3.84 (m, 2H), 3.62-3.42 (m, 4H), 3.04- 2.96 (m, 1 H), 2.86-2.76 (m, 2 H), 2.36 (s, 3H), 2.30-2.20 (m, 1H).1.42 (d, J=9.2 Hz, 1H).
Example 20
An isomer was afforded as a yellow oil (28.4 mg, 67% yield). LCMS (m/z) 388 (M+H)+, retention time: 1.297 min, LCMS Method 8. Chiral HPLC Anal. Method 3, retention time: 3.148 min, % ee = 100.0 %.1H NMR (400 MHz, CD3OD-d4) ppm 7.12 (t, J=1.6 Hz, 1H), 6.90-6.78 (m, 3H), 5.41 (dd, J=12.0, 4.8 Hz, 1H), 3.88-3.76 (m, 4H), 3.56-3.48 (m, 1H), 3.28- 3.22 (m, 1H), 2.88-2.76 (m, 3H), 2.48-2.36 (m, 4H), 1.46 (dd, J=9.6, 5.6 Hz, 1H).
Examples 21– 24
6-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)-N-methylpyrimidine-4-carboxamide
and
6-((3S,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)-N-methylpyrimidine-4-carboxamide
and
6-((3S,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)-N-methylpyrimidine-4-carboxamide
and
6-((3R,4S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)-N-methylpyrimidine-4-carboxamide
Figure imgf000139_0001
Step 1
DIEA (1.79 g, 13.74 mmol) was added to a mixture of cis-1-(tert-butoxycarbonyl)-3- fluoropiperidine-4-carboxylic acid (3.40 g, 13.74 mmol) and py-Brop (6.4 g, 13.74 mmol) in DMF (10 mL). Then 5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole (2.5 g, 13.74 mmol) was added to the mixture. The resulting mixture was stirred at room temperature overnight. The mixture was diluted with H2O (10 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by normal phase column chromatography (EA in PE from 0% to 40%) to afford two diastereomers of tert-butyl 4-(5- (3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidine-1-carboxylate. Diastereomer 1 was afforded as a light yellow oil (1.0 g, 36% yield). LCMS (m/z) 356 (M+H-56)+, retention time: 1.111 min, LCMS Method 15. Diastereomer 2 was afforded as a light yellow oil (0.9 g, 33% yield). LCMS (m/z) 356 (M+H-56)+, retention time: 1.093 min, LCMS Method 15. Step 2
A diastereomer of tert-butyl 4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)- 3-fluoropiperidine-1-carboxylate (1.0 g, 2.5 mmol) was added to a solution of HCl in dioxane (4 N, 10 mL). The resulting mixture was stirred at rt for 1 hour and concentrated under high vacuum to afford a diastereomer of (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3- fluoropiperidin-4-yl)methanone hydrochloride as (800 mg, 95%) as a light yellow solid. LCMS (m/z) 312 (M+H-36)+, retention time: 0.563 min, LCMS Method 21. Step 3
A diastereomer of tert-butyl 4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)- 3-fluoropiperidine-1-carboxylate (830 mg, 2.0 mmol) was added to a solution of HCl in dioxane (4 N, 10 mL). The resulting mixture was stirred at rt for 1 hour and concentrated under high vacuum to afford a diastereomer of (5-(3,5-difluorophenyl)-4,5-dihydro-1H- pyrazol-1-yl)(3-fluoropiperidin-4-yl)methanone hydrochloride (690 mg, 98%) as a light yellow solid. LCMS (m/z) 312 (M+H-36)+, retention time: 0.553 min, LCMS Method 21. Step 4
DIEA (180 mg, 1.38 mmol) was added to a mixture of a diastereomer of (5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-fluoropiperidin-4-yl)methanone hydrochloride (160.0 mg, 0.46mmol) and 6-chloro-N-methylpyrimidine-4-carboxamide (79 mg, 0.46 mmol) in DMF (5.0 mL). The mixture was stirred at rt for 2 hours, diluted with water (50 mL), and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to afford a residue. The resulting residue was purified by Prep-TLC (EA: PE=3:1) to afford a diasteromer of 6-(-4-(-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)- 3-fluoropiperidin-1-yl)-N-methylpyrimidine-4-carboxamide (120 mg, 59% yield) as a white solid. LCMS (m/z) 447 (M+H)+, retention time: 0.745 min, LCMS Method 22. Step 5
Enantiomers of a racemate (100 mg, 0.23 mmol) were separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRAL ART Cellulose-SB, 2 x 25cm, 5 um; Mobile Phase A: HEX: DCM=3:1, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 17 min; UV 254 & 220 nm; Rt1: 6.763; Rt2: 14.186 to afford two title compounds: Example 21
An enantiomer was afforded as a white solid (20.0 mg, 40% yield). LCMS (m/z) 447 (M+H)+, retention time: 1.006 min, LCMS Method 23. Chiral-HPLC Method 8, retention time: 3.189 min, % ee = 100.0 %.1H NMR (300 MHz, CD3OD-d4) ppm 8.53-8.52 (m, 1H), 7.41-7.40 (m, 1H), 7.24-7.22 (m, 1H), 6.91-6.80 (m, 3H), 5.44-5.18 (m, 2H), 4.99 (brs, 1H), 4.68 (brs, 1H), 3.86-3.66 (m, 1H), 3.64-3.52 (m, 1H), 3.44-3.34 (m, 1H), 3.20-3.10 (m, 1H), 2.95 (s, 3H), 2.89-2.80 (m, 1H), 2.24-2.08 (m, 1H), 1.82-1.74 (m, 1H). Example 22
An enantiomer was afforded as a white solid (28.8 mg, 58% yield). LCMS (m/z) 447 (M+H)+, retention time: 1.002 min, LCMS Method 23. Chiral-HPLC Method 8, retention time: 6.109 min, % ee = 100.0 %.1H NMR (300 MHz, CD3OD-d4) ppm 8.53 (s, 1H), 7.41 (s, 1H), 7.23 (s, 1H), 6.90-6.80 (m, 3H), 5.44-5.18 (m, 2H), 5.00 (br s, 1H), 4.68 (br s, 1H), 3.85-3.68 (m, 1H), 3.63-3.38 (m, 2H), 3.20-3.10 (m, 1H), 2.95 (s, 3H), 2.89-2.80 (m, 1H), 2.24-2.09 (m, 1H), 1.81-1.75 (m, 1H). Step 6
DIEA (168 mg, 1.29 mmol) was added to a mixture of a diastereomer of (5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-fluoropiperidin-4-yl)methanone hydrochloride (150.0 mg, 0.43 mmol) and 6-chloro-N-methylpyrimidine-4-carboxamide (74 mg, 0.43 mmol) in DMF (5.0 mL). The mixture was stirred at rt for 2 hours, diluted with water (50 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under high vacuum. The residue was purified by Prep-TLC (EA: PE=1:3) to afford a diastereomer of 6-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1- yl)-N-methylpyrimidine-4-carboxamide (120 mg, 63% yield) as a white solid. LCMS (m/z) 447 (M+H)+, retention time: 0.732 min, LCMS Method 22. Step 7
Enantiomers of a racemate of 6-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3-fluoro-piperidin-1-yl)-N-methylpyrimidine-4-carboxamide (120 mg, 0.27 mmol) was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRAL ART Cellulose-SB, 2 x 25cm, 5um; Mobile Phase A: HEX: DCM=3:1, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 10 min; UV 254 & 220 nm; Rt1: 7.212; Rt2: 8.296 to afford two title compounds: Example 23
An enantiomer was afforded as a white solid (42.2 mg, 71% yield). LCMS (m/z) 447 (M+H)+, retention time: 0.978 min, LCMS Method 23. Chiral-HPLC Method 8, retention time: 3.336 min, % ee = 100.0 %.1H NMR (300 MHz, CD3OD-d4) ppm 8.54-8.53 (m, 1H), 7.42-7.41 (m, 1H), 7.22-7.19 (m, 1H), 6.87-6.77 (m, 3H), 5.60-5.40 (m, 2H), 4.98 (br s, 1H), 4.69 (br s, 1H), 3.76-3.41 (m, 3H), 3.19-3.08 (m, 1H), 2.95 (s, 3H), 2.87-2.77 (m, 1H), 2.23- 2.08 (m, 1H), 1.84-1.74 (m, 1H). Example 24
An enantiomer was afforded as a white solid (30.6 mg, 51% yield). LCMS (m/z) 447 (M+H)+, retention time: 0.981 min, LCMS Method 23. Chiral-HPLC Method 8, retention time: 3.756 min, % ee = 99.6 %.1H NMR (300 MHz, CD3OD-d4) ppm 8.54-8.53 (m, 1H), 7.43-7.42 (m, 1H), 7.22-7.19 (m, 1H), 6.87-6.79 (m, 3H), 5.60-5.41 (m, 2H), 5.01 (br s, 1H), 4.68 (br s, 1H), 3.75-3.41 (m, 3H), 3.19-3.08 (m, 1H), 2.95 (s, 3H), 2.87-2.78 (m, 1H), 2.19- 2.13 (m, 1H), 1.83-1.74 (m, 1H). Examples 25– 88 were synthesized in an analogous manner. For Examples 25– 32, the displacement took place using DIEA as base and NMP as solvent, heating at 120 °C for 36 hours. Examples 25– 28
Figure imgf000143_0001
Examples 25– 28 corresponds to the following: Chiral HPLC/ LC: retention
Figure imgf000144_0001
Chiral HPLC (m 3H) 543-536 (m
Figure imgf000145_0001
Examples 29– 32
Figure imgf000145_0002
Examples 29– 32 correspond to the following: Chi l HPLC/
Figure imgf000146_0001
240-220 (m 1H) 192-
Figure imgf000147_0001
Examples 33– 40
Figure imgf000147_0002
Figure imgf000148_0001
Examples 33– 40 correspond to the following:
Figure imgf000148_0002
Anal Method 6 666 (m 3H) 542-532
Figure imgf000149_0001
1H NMR (300 MHz
Figure imgf000150_0001
Examples 41– 44
Figure imgf000150_0002
Examples 41– 44 correspond to the following: Chi l HPLC/
Figure imgf000151_0001
1H) 352-331 (m 3H)
Figure imgf000152_0001
Examples 45– 48
Figure imgf000152_0002
Examples 45– 48 correspond to the following:
Figure imgf000152_0003
45 9160 min; Chiral 4296 min; 3940 678-663 (m 3H) 538
Figure imgf000153_0001
Examples 49– 52
Figure imgf000154_0001
Examples 49– 52 correspond to the following:
Figure imgf000154_0002
3470% () Hz 112 Hz 1H) 499-494
Figure imgf000155_0001
Examples 53– 56
Examples 53– 56 correspond to the following:
Figure imgf000156_0002
3H) 211-206 (m 1H)
Figure imgf000157_0001
Examples 57– 60
Figure imgf000158_0001
Examples 57– 60 correspond to the following:
Figure imgf000158_0002
255-240 (m 1H) 188-
Figure imgf000159_0001
Examples 61– 64
Figure imgf000159_0002
Figure imgf000160_0001
Examples 61– 64 correspond to the following:
Figure imgf000160_0002
235-229 (m 1H) 189-
Figure imgf000161_0001
Examples 65– 68
Figure imgf000161_0002
Figure imgf000162_0001
Examples 65– 68 correspond to the following:
Figure imgf000162_0002
(m 1H)
Figure imgf000163_0001
Examples 69– 76
Figure imgf000163_0002
Figure imgf000164_0001
Examples 69– 76 correspond to the following:
Figure imgf000164_0002
Analtic Method
Figure imgf000165_0001
73 7556 min 2409 min 470 1H) 723 (s 2H)
Figure imgf000166_0001
Examples 77– 80
Figure imgf000167_0001
Examples 77– 80 correspond to the following:
Figure imgf000167_0002
285 (m 1H) 237-230
Figure imgf000168_0001
Examples 81– 84
Figure imgf000169_0001
Examples 81– 84 correspond to the following:
Figure imgf000169_0002
(m 1H) 526-510 (d
Figure imgf000170_0001
Examples 85– 88
Figure imgf000171_0001
Examples 85– 88 correspond to the following:
Figure imgf000171_0002
261 (s 3H) 248-243 (m
Figure imgf000172_0001
Examples 89– 92
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((R)-3,3-dimethyl-1-(5-methyl- 1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone
and
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((S)-3,3-dimethyl-1-(5-methyl- 1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone
and
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((R)-3,3-dimethyl-1-(5-methyl- 1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone and
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((S)-3,3-dimethyl-1-(5-methyl- 1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone
Figure imgf000173_0001
Step 1
t-BuOK (4.44 g, 39.50 mmol) was added in portions to a stirred solution of PPh3CH2OCH3Cl (13.58 g, 36.61 mmol) in anhydrous THF (100 mL) under nitrogen at ice cold temperature. The mixture was stirred for 1 hour, and tert-butyl 3,3-dimethyl-4-oxopiperidine-1- carboxylate (6 g, 26.39 mmol) in THF (100 mL) was added slowly. The resulting reaction mixture was warmed to room temperature and stirred overnight. Water was added, and organic material was extracted with EA (3 x 200 mL), dried over Na2SO4, filtered and concentrated to afford a resulting residue. The resulting residue was purified by normal phase column chromatography (10% EA in PE) to afford tert-butyl 4-(methoxymethylene)- 3,3-dimethylpiperidine-1-carboxylate as colorless oil (6.2 g, 24.31 mmol, yield: 92.5 %).1H NMR (300 MHz, CDCl3) d 5.82 (s, 0.6 H), 5.72 (s, 0.4 H) 3.56 (s, 1.8 H), 3.51 (1.2 H), 3.38- 3.35 (m, 2H), 3.16-3.09 (m, 2H), 2.34-2.31 (m, 1H), 2.09 (t, J = 6.1 Hz, 1H), 1.46 (d, J = 1.5 Hz, 9H), 1.15 (s, 3H), 1.03 (s, 3H); MS (m/z) no mass (M+H)+, retention time : 0.876 min, LCMS Method 26 using 40%-95% ACN. Step 2
To a solution of tert-butyl 4-(methoxymethylene)-3,3-dimethylpiperidine-1-carboxylate (4.2 g, 16.47 mmol) in CH3CN (300 mL) at 0 oC was added slowly 1M HCl (20 mL). The resulting reaction mixture was stirred at 0 oC for 3 hours. To the reaction mixture was added aqueous NaHCO3 until the mixture reached pH 8. The organic material was extracted with EA (100 mL x 3), washed with brine solution, dried over Na2SO4, filtered, and concentrated to afford tert-butyl 4-formyl-3,3-dimethylpiperidine-1-carboxylate as colorless oil (4 g, 16.59 mmol, crude, contains little solvent, 100% yield).1H NMR (300 MHz, CDCl3) d 9.81 (s, 1H), 4.29-4.02 (m, 1H), 3.80-3.52 (m, 1H), 2.80-2.50 (m, 2H), 2.19-2.12 (m, 1H), 1.83-1.59 (m, 2H), 1.45 (s, 9H), 1.16 (s, 3H), 0.97 (s, 3H); MS (m/z) 186.1 (M+H)+, retention time: 1.399 min, LCMS Method 26 using 40%-95% ACN. Step 3
To a solution of tert-butyl 4-formyl-3,3-dimethylpiperidine-1-carboxylate (4 g, 16.59 mmol, crude) in t-BuOH (30 mL) and 2-methyl-2-butene (60 mL) at 0 oC was added NaH2PO4 (13.75 g, 114.60 mmol) in water (90 mL) and NaClO2 (15 g, 165.85 mmol) dropwise. After addition, the resulting mixture was stirred at rt for 4 hours. Water (50 mL) was added, and the mixture was extracted with EA (70 mL x 3). The combined organic layer was washed with brine solution (100 mL), dried over Na2SO4, filtered, and concentrated to afford 1-(tert- butoxycarbonyl)-3,3-dimethylpiperidine-4-carboxylic acid as pale yellow oil (5.5 g crude). 1H NMR (300 MHz, CDCl3) d 4.20-3.99 (m, 1H), 3.81-3.58 (m, 1H), 2.88-2.52 (m, 2H), 2.40 – 2.25 (m, 1H), 1.95-1.62 (m, 2H), 1.48 (s, 9H), 1.07 (s, 3H), 0.99 (s, 3H); MS (m/z) 200.1(M+H)+, retention time : 2.347 min, LCMS Method 26 using 20%-95% ACN. Step 4
To a solution of 1-(tert-butoxycarbonyl)-3,3-dimethylpiperidine-4-carboxylic acid (4 g, crude, 15.56 mmol ) and K2CO3 ( 3.22 g, 23.34 mmol) in acetone (40 mL) was added BnBr (3.19 g, 18.67 mmol). The resulting reaction mixture was refluxed for 4 hours. The resulting mixture was filtered and concentrated to afford a residue. The residue was purified by normal phase column chromatography (EA:PE: 1:30 to 1:10) to afford 4-benzyl 1-tert-butyl 3,3-dimethylpiperidine-1,4-dicarboxylate (4.9 g, 14.12 mmol, yield: 90 %) as colorless oil. 1H NMR (300 MHz, CDCl3) d 5.12 (s, 2H), 4.18-4.02 (m, 1H), 3.78-3.53 (m, 1H), 2.88-2.52 (m, 2H), 2.33 (dd, J=11.3, 4.0 Hz, 1H), 1.99-1.82 (m, 1H), 1.69 (s, 1H), 1.46 (s, 9H), 1.00 (s, 3H), 0.94 (s, 3H); MS (m/z) 292.2 (M+H)+, retention time : 2.341 min, LCMS Method 26 using 40%-95% ACN. Step 5
A solution of 4-benzyl 1-tert-butyl 3,3-dimethylpiperidine-1,4-dicarboxylate (4.9 g, 14.12 mmol) in HCl/dioxane (3 M, 30 mL) was stirred at rt for 16 hours. The reaction mixture was concentrated and co-evaporated with toluene (3 times) to afford benzyl 3,3- dimethylpiperidine-4-carboxylate hydrochloride salt (3.5 g, crude, yield: 100%) as white solid. MS (m/z) 248.2 (M+H)+, retention time : 1.401 min, LCMS Method 26 using 20%- 95% ACN. Step 6
A solution of benzyl 3,3-dimethylpiperidine-4-carboxylate hydrochloride (1 g, 3.53 mmol), 2-bromo-5-methyl-1,3,4-oxadiazole (915 mg, 5.65 mmol) and NaHCO3 (1.18 g, 14.13mmol) in DMF (8 mL) was stirred at 80 oC for 16 h. The resulting mixture was filtered and concentrated to afford a residue. The residue was purified by reverse phase column chromatography (C18, 20%-95% CH3CN in water) to afford benzyl 3,3-dimethyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidine-4-carboxylate as yellow sticky oil (1 g, 3.03 mmol, yield: 86 %). MS (m/z) 330.2 (M+H)+, retention time : 2.080 min, LCMS Method 26 using 20%-95% ACN. Step 7
To a solution of benzyl 3,3-dimethyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)piperidine-4- carboxylate (1 g, 3.03 mmol) in methanol (20 mL) was added 10% Pd/C (500 mg) and water (2 mL). The resulting mixture was stirred at room temperature under H2 (1 atm) for 16 hours. The resuting mixture was filtered, concentrated, and co-evaporate with toluene to afford 3,3- dimethyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)piperidine-4-carboxylic acid (710 mg, 2.97 mmol, yield: 98 %) as white solid.1H NMR (400 MHz, CDCl3) d 3.98 (dt, J = 12.8, 4.0 Hz, 1H), 3.59 (dd, J = 12.9, 0.7 Hz, 1H), 3.11-3.07 (m, 1H), 2.87 (d, J = 12.9 Hz, 1H), 2.39 (s, 3H), 2.36 (d, J = 4.0 Hz, 1H), 2.13– 1.95 (m, 1H), 1.94– 1.78 (m, 1H), 1.13 (s, 3H), 1.07 (s, 3H); MS (m/z) 240.1 (M+H)+, retention time : 0.279 min, LCMS Method 26 using 20%-95% ACN. Step 8
To a solution of 3,3-dimethyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)piperidine-4-carboxylic acid (1.1 g, 4.60 mmol) in DMF (5 mL) was added HATU (2.62 g, 6.90 mmol) and DIPEA (1.19 g, 9.20 mmol) at rt. The resulting mixture was stirred for 5 minutes. To the mixture was added 5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole (1.67 g, 9.20 mmol). The resulting reaction mixture was stirred for 3 days at 50 oC. Water was added. The organic material was extracted with EA and concentrated in vacuo to afford a residue. The resulting residue was partially purified by normal phase column chromatography (40:1 to 20:1: MeOH:DCM) and again purified by preparative HPLC to afford (5-(3,5-difluorophenyl)-4,5-dihydro-1H- pyrazol-1-yl)(3,3-dimethyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone (210 mg) as yellow solid.1H NMR (300 MHz, CDCl3) d 6.97 (s, 1H), 6.75-6.67 (m, 3H), 5.41- 5.33 (m, 1H), 3.99-3.91 (m, 1H), 3.65-3.37 (m, 3H), 3.22-3.18 (m, 1H), 2.96-2.68 (m, 2H), 2.38 (s, 3H), 2.03-1.98 (m, 1H), 1.80-1.75 (m, 1H), 1.67 (s, 3H), 1.10-0.98 (m, 6H); MS (m/z) 404.0 (M+H)+, retention time : 2.01 min, LCMS Method 26 using 20%-95% ACN. The racemate was separated via Chiral HPLC Separation Method 1 (using 80% heptane in EtOH + 0.05% DEA at 20 mL/min) to afford
Figure imgf000176_0001
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((R)-3,3-dimethyl-1-(5-methyl- 1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone, ((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H- pyrazol-1-yl)((S)-3,3-dimethyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone, ((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((R)-3,3-dimethyl-1-(5-methyl- 1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone, and ((R)-5-(3,5-difluorophenyl)-4,5-dihydro- 1H-pyrazol-1-yl)((S)-3,3-dimethyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)piperidin-4- yl)methanone. Example 89
An isomer was afforded as a solid (70 mg, 3.8% yield). LCMS (m/z) 404 (M+H)+, retention time: 3.104 min, LCMS Method 27. Chiral HPLC Anal. Method 22, retention time: 15.59 min, % ee = 100.0 %, % de = 100 %.1H NMR (400 MHz, CDCl3) ppm 6.95 (t, J = 1.6 Hz, 1H), 6.77-6.59 (m, 3H), 5.36 (dd, J = 12.0Hz, 4.8 Hz, 1H), 3.91-3.89 (m, 1H), 3.58 (d, J=12.8 Hz, 1H), 3.51-3.39 (m, 2H), 3.21-3.19 (m, 1H), 2.93 (d, J = 12.8 Hz, 1H), 2.81-2.78 (m, 1H), 2.37 (s, 3H), 2.10-1.91 (m, 1H), 1.84-1.76 (m, 1H), 1.09 (s, 3H), 1.01 (s, 3H). Example 90
An isomer was afforded as a solid (35 mg, 1.9% yield). LCMS (m/z) 404 (M+H)+, retention time: 3.286 min, LCMS Method 28. Chiral HPLC Anal. Method 22, retention time: 17.39 min, % ee = 100.0 %, % de = 100 %.1H NMR (400 MHz, CDCl3) ppm 6.95 (t, J = 1.6 Hz, 1H), 6.77-6.59 (m, 3H), 5.36 (dd, J = 12.0Hz, 4.8 Hz, 1H), 3.91-3.89 (m, 1H), 3.58 (d, J=12.8 Hz, 1H), 3.51-3.39 (m, 2H), 3.21-3.19 (m, 1H), 2.93 (d, J = 12.8 Hz, 1H), 2.81-2.78 (m, 1H), 2.37 (s, 3H), 2.10-1.91 (m, 1H), 1.84-1.76 (m, 1H), 1.09 (s, 3H), 1.01 (s, 3H). Example 91
An isomer was afforded as a solid (50 mg, 2.7% yield). LCMS (m/z) 404 (M+H)+, retention time: 3.195 min, LCMS Method 28. Chiral HPLC Anal. Method 22, retention time: 19.75 min, % ee = 96.4 %, % de = 100 %.1H NMR (400 MHz, CDCl3) ppm 6.95 (t, J = 1.6 Hz, 1H), 6.77-6.59 (m, 3H), 5.36 (dd, J = 12.0Hz, 4.8 Hz, 1H), 3.91-3.89 (m, 1H), 3.58 (d, J = 12.8 Hz, 1H), 3.51-3.39 (m, 2H), 3.21-3.19 (m, 1H), 2.93 (d, J = 12.8 Hz, 1H), 2.81-2.78 (m, 1H), 2.37 (s, 3H), 2.10-1.91 (m, 1H), 1.84-1.76 (m, 1H), 1.09 (s, 3H), 1.01 (s, 3H). Example 92
An isomer was afforded as a solid (70 mg, 3.8% yield) . LCMS (m/z) 404 (M+H)+, retention time: 2.142 min, LCMS Method 28. Chiral HPLC Anal. Method 22, retention time: 23.03 min, % ee = 100.0 %, % de = 97.9 %.1H NMR (400 MHz, CDCl3) ppm 6.96 (s, 1H), 6.81- 6.64 (m, 3H), 5.32-5.28 (dd, J=12.0Hz, 5.2 Hz, 1H), 3.93-3.90 (m, 1H), 3.56 (d, J = 12.8 Hz, 1H), 3.50-3.35 (m, 2H), 3.25-3.14 (m, 1H), 2.94 (d, J = 12.8 Hz, 1H), 2.83-2.77 (m, 1H), 2.37 (s, 3H), 2.08-1.91 (m, 1H), 1.77-1.72 (m, 1H), 1.04 (s, 3H), 0.99 (s, 3H). Examples 93– 96
Figure imgf000178_0001
Examples 93– 96 correspond to the following:
Figure imgf000179_0001
Examples 97– 100 ((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4S)-3-methyl-1-(5-methyl- 1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone
and
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4R)-3-methyl-1-(5-methyl- 1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone
and
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4S)-3-methyl-1-(5-methyl- 1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone
and
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4R)-3-methyl-1-(5-methyl- 1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone
 
Figure imgf000180_0001
Step 1
To a solution of 5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole (3.39 g, 18.6mmol) and cis- 1-(tert-butoxycarbonyl)-3-methylpiperidine-4-carboxylic acid (3.16 g, 13.0 mmol) in DMF (43.0 mL) were added HATU (5.93 g, 15.6 mmol) and TEA (2.63 g, 26.0 mmol). The resulting mixture was stirred at 40 oC for 48 hours. After removal of TEA, the crude was purified by reverse phase chromatography (from 45% to 70% acetonitrile in water) to give the title product (3.2 g, 7.86 mmol, yield: 60%). MS (m/z) 352.2 (M-56+H)+, retention time: 2.082 min, LC/MS Method 27 using 30% MeCN. Step 2
To a cooled (0 oC) solution of tert-butyl cis-4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H- pyrazole-1-carbonyl)-3-methylpiperidine-1-carboxylate (3.0 g, 7.37 mmol) in DCM (20 mL) was added TFA (20 mL) slowly. Then the mixture was stirred at rt for 1 hour. The reaction mixture was neutralized by aq. solution of NH3H2O under ice water bath. the mixture was extracted with dichloromethane. The DCM layer was combined and dried over Na2SO4 and concentrated to give (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(cis-3- methylpiperidin-4-yl)methanone (2.3 g, crude) as a yellow solid. MS (m/z) 308.1 (M+H)+, retention time: 1.407 min, LC/MS Method 27 using 10% MeCN. Step 3
To a solution of (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(cis-3-methylpiperidin- 4-yl)methanone (1.30 g, 4.2 mmol) in DMF (20 mL) were added sodium bicarbonate (705 mg, 8.4 mmol), and then 2-bromo-5-methyl-1,3,4-oxadiazole (1.2 g, 6.34 mmol), then the mixture was stirred at 80 oC overnight. The reaction mixture was purified by reverse phase chromatography (from 25% to 65% acetonitrile in water ) to give (5-(3,5-difluorophenyl)- 4,5-dihydro-1H-pyrazol-1-yl)(cis-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)piperidin-4- yl)methanone (890 mg, 2.28 mmol, yield: 54%) as a pale yellow solid. MS (m/z) 390.0 (M+H)+, retention time: 1.889 min, LC/MS Method 27 using 10% MeCN. The racemate was separated via Chiral HPLC Separation Method 2. (Column: AD-H, 20mm × 250mm, Mobile phase: HEP/EtOH (0.01%DEA) = 80/20 (v/v), Flow: 20 mL/min, WL: UV 254 nm, T= 25 oC) to afford 4 isomers: Example 97
An isomer was afforded as a pale yellow solid (89.7 mg, 5.4% yield). LCMS (m/z) 390 (M+H)+, retention time: 3.273 min, LCMS Method 27. Chiral HPLC Anal. Method 19, retention time: 3.204 min.1H NMR (400 MHz, CD3OD) ppm 7.15 (s, 1H), 6.93-6.71 (m, 3H), 5.37 (dd, J = 12.0 Hz, 4.8 Hz, 1H), 3.81-3.59 (m, 3H), 3.58-3.45 (m, 1H), 3.43-3.34 (m, 1H), 3.29-3.19 (m, 1H), 2.85-2.74 (m, 1H), 2.36 (s, 3H), 2.44-2.27 (m, 1H), 2.11-1.96 (m, 1H), 1.75-1.61 (m, 1H), 0.96 (d, J = 6.8 Hz, 3H). Example 98
An isomer was afforded as a pale yellow solid (77.6 mg, 4.7% yield). LCMS (m/z) 390 (M+H)+, retention time: 3.275 min, LCMS Method 27. Chiral HPLC Anal. Method 19, retention time: 3.204 min, % ee = 100.0 %, % de = 99.9 %.1H NMR (400 MHz, CD3OD) ppm 7.15 (s, 1H), 6.93-6.71 (m, 3H), 5.37 (dd, J = 12.0 Hz, 4.8 Hz, 1H), 3.81-3.59 (m, 3H), 3.58-3.45 (m, 1H), 3.43-3.34 (m, 1H), 3.29-3.19 (m, 1H), 2.85-2.74 (m, 1H), 2.36 (s, 3H), 2.44-2.27 (m, 1H), 2.11-1.96 (m, 1H), 1.75-1.61 (m, 1H), 0.96 (d, J = 6.8 Hz, 3H). Example 99
An isomer was afforded as a pale yellow solid (205.5 mg, 12.5% yield). LCMS (m/z) 390 (M+H)+, retention time: 3.264 min, LCMS Method 27. Chiral HPLC Anal. Method 19, retention time: 3.308 min.1H NMR (400 MHz, CD3OD) ppm 7.15 (s, 1H), 6.91-6.74 (m, 3H), 5.35 (dd, J = 11.6 Hz, 5.2 Hz, 1H), 3.91-3.79 (m, 1H), 3.70 (dd, J = 12.8 Hz, 4.0 Hz, 1H), 3.60-3.44 (m, 2H), 3.36 (dd, J = 12.8 Hz, 3.6 Hz, 1H), 3.25-3.13 (m, 1H), 2.88-2.74 (m, 1H), 2.55-2.43 (m, 1H), 2.36 (s, 3H), 2.09-1.92 (m, 1H), 1.70-1.58 (m, 1H), 0.83 (d, J = 6.8 Hz, 3H). Example 100
An isomer was afforded as a pale yellow solid (197.4 mg, 12.0% yield). LCMS (m/z) 390 (M+H)+, retention time: 3.931 min, LCMS Method 27. Chiral HPLC Anal. Method 19, retention time: 3.848 min.1H NMR (400 MHz, CD3OD) ppm 7.15 (s, 1H), 6.93-6.71 (m, 3H), 5.37 (dd, J = 12.0 Hz, 4.8 Hz, 1H), 3.81-3.59 (m, 3H), 3.58-3.45 (m, 1H), 3.43-3.34 (m, 1H), 3.29-3.19 (m, 1H), 2.85-2.74 (m, 1H), 2.36 (s, 3H), 2.44-2.27 (m, 1H), 2.11-1.96 (m, 1H), 1.75-1.61 (m, 1H), 0.96 (d, J = 6.8 Hz, 3H). Examples 101– 104 ((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4R)-3-methyl-1-(5-methyl- 1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone
and
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)-3-methyl-1-(5-methyl- 1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone
and
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4R)-3-methyl-1-(5-methyl- 1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone
and
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)-3-methyl-1-(5-methyl- 1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone
Figure imgf000184_0001
   
 
Step 1
To a mixture of trans-1-(tert-butoxycarbonyl)-3-methylpiperidine-4-carboxylic acid (1.76 g, 7.23mmol) and K2CO3 (1.50 g, 10.8 mmol) in DMF (16 mL) was added benzyl bromide (1.85 g, 10.8 mmol) at 0 oC. Then the mixture was stirred at RT for 15 hours. The reaction mixture was diluted with EA and washed with H2O, the organic layer was concentrated to give the residue, which was purified by silica gel column chromatagraphy using 2% - 10% EtOAc in PE to afford trans-4-benzyl 1-tert-butyl 3-methylpiperidine-1,4-dicarboxylate (2.30 g, 7.00 mmol, 95% yield).1H NMR (300 MHz, CDCl3) d 7.36 (s, 5H), 5.15 (s, 2H), 4.34– 3.79 (m, 2H), 2.70 (t, J = 12.0 Hz, 1H), 2.49– 2.25 (m, 1H), 2.24– 2.05 (m, 1H), 1.97– 1.77 (m, 2H), 1.76– 1.65 (m, 1H), 1.47 (s, 9H), 0.89 (d, J = 6.6 Hz, 3H). Step 2
To a solution of trans-4-benzyl 1-tert-butyl 3-methylpiperidine-1,4-dicarboxylate (2.33 g, 7.00 mmol) in DCM (8 mL) was added TFA (4 mL) slowly at 0 oC and the resulting mixture was stirred at rt overnight. After completion, the mixture was quenched with saturated aqueous ammonia (6 mL) and extracted with DCM, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated afford the crude title product (1.40 g, purity: 86%) without further purification.1H NMR (300 MHz, CDCl3) d 7.36 (s, 5H), 5.14 (s, 2H), 3.20– 2.94 (m, 2H), 2.58 (td, J = 12.0, 3.0 Hz, 1H), 2.34– 2.20 (t, J = 12.0, 1H), 2.20-2.09 (m, 1H), 1.92– 1.74 (m, 3H), 1.73– 1.55 (m, 1H), 0.85 (d, J = 6.5 Hz, 3H). LCMS (m/z) 234.2 (M+H)+, retention time: 1.330 min, LC/MS Method 27 using 5% MeCN. Step 3
Isopropyl nitrite (76.7 g, 655 mmol) was added slowly to a mixture of 5-methyl-1,3,4- oxadiazol-2-amine (54 g, 545 mmol) and cupric bromide (183 g, 817.5 mmol) in MeCN (1.8 L) at room temperature. After then, the resulting mixture was stirred at 65 oC overnight. The mixture was cooled to rt, 2N HCl (20 mL) was added followed by water (2 L) and the mixture was extracted with EtOAc (2 L x 3), washed with H2O (1 L), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to afford the crude title product (44.88 g, crude) without further purification.1H NMR (400 MHz, CDCl3) d 2.58 (s, 3H); LCMS (m/z) 163.0 (M+H)+, retention time: 0.754 min, LC/MS Method 27 using 5% MeCN. Step 4
A mixture 2-Bromo-5-methyl-1,3,4-oxadiazole (1.94 g, 12.0 mmol), trans-benzyl 3- methylpiperidine-4-carboxylate (1.40 g, 6.01 mmol) and NaHCO3 (1.01 g, 12.0 mmol) in DMF (14 mL) at 50 oC overnight. The concentrated in vacuo and the residue was purified by medium pressure chromatography using 30%-65% acetonitrile in H2O to afford trans-benzyl 3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)piperidine-4-carboxylate (850 mg, 2.70 mmol, 45% yield) as pale yellow solid.1H NMR (400 MHz, CDCl3) d 7.45– 7.29 (m, 5H), 5.15 (s, 2H), 4.06– 3.84 (m, 2H), 2.96 (td, J = 12.8, 3.2 Hz, 1H), 2.63 (dd, J = 13.2, 11.2 Hz, 1H), 2.38 (s, 3H), 2.27– 2.16 (m, 1H), 2.10– 1.91 (m, 2H), 1.90– 1.75 (m, 1H), 0.93 (d, J = 6.4 Hz, 3H). LCMS (m/z) 316.2 (M+H)+, retention time: 1.594 min, LC/MS Method 27 using 20% MeCN. Step 5
A mixture of 10% palladium on charcoal (420 mg) and trans-benzyl 3-methyl-1-(5-methyl- 1,3,4-oxadiazol-2-yl)piperidine-4-carboxylate (795 mg, 2.58 mmol) in MeOH (32 mL) was stirred at r.t. under hydrogen atmosphere for 20 hours. After removal of the catalyst, the filtrate was concentrated in vacuo to give the crude of trans-1-(5-methyl-1,3,4-oxadiazol-2- yl)piperidine-4-carboxylic acid (592 mg, 2.57 mmol, 97% yield) as white solid.1H NMR (300 MHz, CDCl3) d 4.13– 3.83 (m, 2H), 3.12– 2.92 (m, 1H), 2.68 (dd, J = 12.9, 11.4 Hz, 1H), 2.41 (s, 3H), 2.27– 2.11 (m, 1H), 2.11– 1.95 (m, 2H), 1.93– 1.74 (m, 1H), 1.02 (d, J = 6.6 Hz, 3H); LCMS (m/z) 226.1 (M+H)+, retention time: 0.269 min, LC/MS Method 27 using 20% MeCN. Step 6
A mixture of 5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole(700 mg, 3.85 mmol), trans-1- (5-methyl-1,3,4-oxadiazol-2-yl)piperidine-4-carboxylic acid (580 mg, 2.57 mmol), HATU (1.46 g, 3.85 mmol) and TEA (519 mg, 5.14 mmol) in DMF (10 mL) was stirred at rt for 48 hours. After removal of TEA, the crude was purified by medium pressure chromatography using 20%-70% acetonitrile in H2O to afford (5-(3,5-difluorophenyl)-4,5-dihydro-1H- pyrazol-1-yl)(3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone (410 mg, 1.05 mmol, yield: 41%) as a yellow solid. LCMS (m/z) 389.9 (M+H)+, retention time: 1.821 min, LC/MS Method 27 using 10% MeCN. The racemate was separated via chiral HPLC separation method: (Column: IC-H, 20 mm × 250 mm, Mobile phase: Hep/EtOH/DEA = 60/40/0.05 (v/v/v), Flow: 3.0 mL/min, WL: UV 254 nm, T = 25 oC) to afford 4 isomers: Example 101
An isomer was afforded as a solid (76.1 mg, 7.6% yield). LCMS (m/z) 390 (M+H)+, retention time: 3.216 min, LCMS Method 27. Chiral HPLC Anal. Method 22, retention time: 14.966 min.1H NMR (400 MHz, CDCl3) ppm 6.98 (s, 1H), 6.76-6.64 (m, 3H), 5.33 (dd, J = 12.0 Hz, 5.2 Hz, 1H), 4.09-3.99 (m, 1H), 3.97-3.88 (m, 1H), 3.51-3.40 (m, 1H), 3.14 (td, J = 11.2 Hz, 4.0 Hz, 1H), 3.01 (td, J = 12.8 Hz, 3.2 Hz, 1H), 2.86-2.76 (m, 1H), 2.74-2.64 (m, 1H), 2.38 (s, 3H), 2.15-2.02 (m, 1H), 1.91-1.73 (m, 2H), 0.86 (d, J = 6.8 Hz, 3H). Example 102
An isomer was afforded as a solid (84.9 mg, 8.5% yield). LCMS (m/z) 390 (M+H)+, retention time: 3.419 min, LCMS Method 27. Chiral HPLC Anal. Method 22, retention time: 18.014 min.1H NMR (400 MHz, CDCl3) ppm 6.98 (s, 1H), 6.77-6.62 (m, 3H), 5.36 (dd, J = 12.0 Hz, 5.2 Hz, 1H), 4.07-3.99 (m, 1H), 3.99-3.91 (m, 1H), 3.51-3.40 (m, 1H), 3.16-2.99 (m, 2H), 2.84-2.74 (m, 1H), 2.73-2.63 (m, 1H), 2.37 (s, 3H), 2.18-2.05 (m, 1H), 2.00-1.91 (m, 1H), 1.83-1.70 (m, 1H), 0.91 (d, J = 6.4 Hz, 3H). Example 103
An isomer was afforded as a solid (90.1 mg, 9.0% yield). LCMS (m/z) 390 (M+H)+, retention time: 2.574 min, LCMS Method 27. Chiral HPLC Anal. Method 22, retention time: 11.960 min.1H NMR (400 MHz, CDCl3) ppm 6.98 (s, 1H), 6.77-6.62 (m, 3H), 5.36 (dd, J = 12.0 Hz, 5.2 Hz, 1H), 4.07-3.99 (m, 1H), 3.99-3.91 (m, 1H), 3.51-3.40 (m, 1H), 3.16-2.99 (m, 2H), 2.84-2.74 (m, 1H), 2.73-2.63 (m, 1H), 2.37 (s, 3H), 2.18-2.05 (m, 1H), 2.00-1.91 (m, 1H), 1.83-1.70 (m, 1H), 0.92 (d, J = 6.4 Hz, 3H). Example 104
An isomer was afforded as a solid (77.4 mg, 7.7% yield). LCMS (m/z) 390 (M+H)+, retention time: 2.574 min, LCMS Method 27. Chiral HPLC Anal. Method 22, retention time: 11.960 min.1H NMR (400 MHz, CDCl3) ppm 6.98 (s, 1H), 6.76-6.64 (m, 3H), 5.33 (dd, J=12.0 Hz, 5.2 Hz, 1H), 4.09-3.99 (m, 1H), 3.97-3.88 (m, 1H), 3.51-3.40 (m, 1H), 3.14 (td, J=11.2 Hz, 4.0 Hz, 1H), 3.01 (td, J=12.8 Hz, 3.2 Hz, 1H), 2.86-2.76 (m, 1H), 2.74-2.64 (m, 1H), 2.38 (s, 3H), 2.15-2.02 (m, 1H), 1.91-1.73 (m, 2H), 0.86 (d, J=6.8 Hz, 3H).
Examples 105– 109 6-((3R,4S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- methylpiperidin-1-yl)pyrimidine-4-carboxamide and
6-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- methylpiperidin-1-yl)pyrimidine-4-carboxamide
and
6-((3S,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- methylpiperidin-1-yl)pyrimidine-4-carboxamide
and
6-((3S,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- methylpiperidin-1-yl)pyrimidine-4-carboxamide
 
 
Figure imgf000188_0001
Figure imgf000189_0001
    Step 1
A mixture of 1-(tert-butoxycarbonyl)-trans-3-methylpiperidine-4-carboxylic acid (2.0 g, 8.2 mmol), 5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole (2.4 g, 12 mmol), HATU (4.7 g, 12 mmol) and TEA (1.7g, 16 mmol) in DMF (27 mL) was stirred at 40 oC for 2 days. The reaction mixture was concentrated and the residue was purified by reverse phase chromatography (30-90% MeCN in water) to afford tert-butyl-trans-4-(5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-methylpiperidine-1-carboxylate (2 g, 60% yield) as a yellow gel. MS (m/z) 352 (M-56+H)+. 1H NMR (400 MHz, CDCl3) ppm 6.96 (s, 1H), 6.71-6.64 (m, 3H), 5.38-5.30 (m, 1H), 4.18-4.06 (m, 2H), 3.48-3.39 (m, 1H), 3.09-3.03 (m, 1H), 2.82-2.71 (m, 2H), 2.40-2.37 (br.s, 1H), 1.95-1,65 (m, 3H), 1.46 (s, 9H), 0.85 (m, 3H). Step 2
A solution of tert-butyl-trans-4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3-methylpiperidine-1-carboxylate (2 g, 4.9 mmol) in TFA (40 mL) and methanol (40 mL) was stirred at room temperature for 2 days and concentrated. The resulting residue was diluted with DCM (100 mL) and saturated aqueous NaHCO3 solution (50 mL). The organic layer was separated, dried over sodium sulfate, and concentrated to give (5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-trans-(3-methylpiperidin-4-yl)methanone (1.4 g, 93% yield) as a yellow oil. MS (m/z) 308 (M+H)+. 1H NMR (300 MHz, CDCl3) ppm 6.96 (s, 1H), 6.72-6.65 (m, 3H), 5.36-5.34 (m, 1H), 3.49-3.39 (m, 1H), 3.15-3.01 (m, 3H), 2.81- 2.66 (m, 1H), 2.38-2.30 (t, J = 12 Hz, 1H), 1.90-1.83 (m, 3H), 0.8 (m, 3H). Step 3
A mixture of give (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-trans-(3- methylpiperidin-4-yl)methanone (1.4 g, 4.6 mmol), 6-chloropyrimidine-4-carbonitrile (1.0 g, 7.3 mmol) and K2CO3 (1.3 g, 9.1 mmol) in DMF (20 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was diluted with DCM (150 mL) and filtered. The filtrate was concentrated and the resulting residue was purified by silica gel column chromatography (2.5-10% MeOH in DCM) to give the 6-(trans-4-(5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-methylpiperidin-1-yl)pyrimidine-4- carbonitrile (1.34 g, 72% yield) as a yellow gel. MS (m/z) 411 (M+H)+. The racemate was separated via chiral HPLC separation using IC-H Column to provide 6- ((3R,4S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- methylpiperidin-1-yl)pyrimidine-4-carbonitril and 6-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)- 4,5-dihydro-1H-pyrazole-1-carbonyl)-3-methylpiperidin-1-yl)pyrimidine-4-carbonitrile and 6-((3S,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- methylpiperidin-1-yl)pyrimidine-4-carbonitrile and 6-((3S,4R)-4-((S)-5-(3,5-difluorophenyl)- 4,5-dihydro-1H-pyrazole-1-carbonyl)-3-methylpiperidin-1-yl)pyrimidine-4-carbonitrile. The first isomer was afforded as a solid (270 mg, 20% yield). Chiral HPLC Anal. Method 22, retention time: 9.536 min, % ee = 100%. The second isomer was afforded as a solid (240 mg, 18% yield). Chiral HPLC Anal. Method 22, retention time: 11.061 min, % ee = 99.7%. The third isomer was afforded as a solid (260 mg, 19% yield). Chiral HPLC Anal. Method 22, retention time: 14.190 min, % ee = 99.7%. The fourth isomer was afforded as a solid (230 mg, 17% yield). Chiral HPLC Anal. Method 22, retention time: 17.474 min, % ee = 98.9%. Step 4
Example 105
To a solution of isomer 1 (270 mg, 0.66 mmol) in DMSO (3.5 mL) at 0 oC was added 30% H2O2 aqueous solution (223 mg, 1.97 mmol) followed by a solution of potassium carbonate (272 mg, 1.97 mmol) in water (1 mL) and the mixture was stirred at 0 oC for 30 minutes. The resulting precipitate was collected by filtration and washed with water to give example 105 (144 mg, 51%) as a white solid. LCMS (m/z) 429 (M+H)+, retention time: 3.339 min, LCMS Method 28.1H NMR (400 MHz, DMSO-d6) ppm 8.53 (d, J=1.2 Hz, 1H), 8.03 (s, 1H), 7.32 (s, 1H), 7.25 (s, 1H), 7.13-7.07 (m, 1H), 6.84-6.80 (m, 2H), 5.38 (dd, J = 12.0 Hz, 4.8 Hz, 1H), 4.98-4.18 (m, 2H), 3.50 (ddd, J = 18.8 Hz, 12.0 Hz, 1.6 Hz, 1H), 3.25-3.17 (m, 1H), 3.01 (t, J = 12.4 Hz, 1H), 2.81-2.65 (m, 2H), 1.95 (dd, J = 12.8 Hz, 3.6 Hz, 1H), 1.85-1.71 (m, 1H), 1.45-1.32 (m, 1H), 0.86 (d, J = 6.8 Hz, 3H). Step 4
Example 106
To a solution of isomer 4 (230 mg, 0.56 mmol) in DMSO (3.5 mL) at 0 oC was added 30% H2O2 aqueous solution (190 mg, 1.68 mmol) followed by a solution of potassium carbonate (232 mg, 1.68 mmol) in water (1 mL) and the mixture was stirred at 0 oC for 30 minutes. The resulting precipitate was collected by filtration and washed with water to give example 106 (208 mg, 87%) as a white solid. LCMS (m/z) 429 (M+H)+, retention time: 3.249 min, LCMS Method 28.1H NMR (400 MHz, DMSO-d6) ppm 8.54 (s, 1H), 8.04 (s, 1H), 7.33 (s, 1H), 7.25 (s, 1H), 7.17-7.08 (m, 1H), 6.89-6.82 (m, 2H), 5.35 (dd, J = 12.0 Hz, 5.2 Hz, 1H), 4.87-4.10 (m, 2H), 3.50 (ddd, J = 19.2 Hz, 12.0 Hz, 1.2 Hz, 1H), 3.30-3.22 (m, 1H), 2.98 (t, J = 12.0 Hz, 1H), 2.81-2.67 (m, 2H), 1.87-1.68 (m, 2H), 1.49-1.36 (m, 1H), 0.80 (d, J = 6.8 Hz, 3H). Step 4
Example 107
To a solution of isomer 2 (240 mg, 0.58 mmol) in DMSO (3.5 mL) at 0 oC was added 30% H2O2 aqueous solution (200 mg, 1.76 mmol) followed by a solution of potassium carbonate (243 mg, 1.76 mmol) in water (1 mL) and the mixture was stirred at 0 oC for 30 minutes. The resulting precipitate was collected by filtration and washed with water to give example 107 (225 mg, 90%) as a white solid. LCMS (m/z) 429 (M+H)+, retention time: 3.234 min, LCMS Method 28.1H NMR (400 MHz, DMSO-d6) ppm 8.54 (s, 1H), 8.04 (s, 1H), 7.33 (s, 1H), 7.25 (s, 1H), 7.17-7.08 (m, 1H), 6.89-6.82 (m, 2H), 5.35 (dd, J = 12.0 Hz, 5.2 Hz, 1H), 4.87-4.10 (m, 2H), 3.50 (ddd, J = 19.2 Hz, 12.0 Hz, 1.2 Hz, 1H), 3.30-3.22 (m, 1H), 2.98 (t, J = 12.0 Hz, 1H), 2.81-2.67 (m, 2H), 1.87-1.68 (m, 2H), 1.49-1.36 (m, 1H), 0.80 (d, J = 6.8 Hz, 3H). Step 4
Example 108
To a solution of isomer 3 (260 mg, 0.63 mmol) in DMSO (3.5 mL) at 0 oC was added 30% H2O2 aqueous solution (216 mg, 1.90 mmol) followed by a solution of potassium carbonate (263 mg, 1.90 mmol) in water (1 mL) and the mixture was stirred at 0 oC for 30 minutes. The resulting precipitate was collected by filtration and washed with water to give example 108 (146 mg, 54%) as a white solid. LCMS (m/z) 429 (M+H)+, retention time: 3.027 min, LCMS Method 28.1H NMR (400 MHz, DMSO-d6) ppm 8.53 (d, J = 1.2 Hz, 1H), 8.03 (s, 1H), 7.32 (s, 1H), 7.25 (s, 1H), 7.13-7.07 (m, 1H), 6.84-6.80 (m, 2H), 5.38 (dd, J = 12.0 Hz, 4.8 Hz, 1H), 4.98-4.18 (m, 2H), 3.50 (ddd, J = 18.8 Hz, 12.0 Hz, 1.6 Hz, 1H), 3.25-3.17 (m, 1H), 3.01 (t, J = 12.4 Hz, 1H), 2.81-2.65 (m, 2H), 1.95 (dd, J = 12.8 Hz, 3.6 Hz, 1H), 1.85-1.71 (m, 1H), 1.45-1.32 (m, 1H), 0.86 (d, J = 6.8 Hz, 3H). Examples 109– 112 were synthesized analogously to Examples 105– 108. Examples 109– 112
Figure imgf000193_0001
Examples 109– 112 correspond to the following:
Figure imgf000193_0002
249-237 (m 1H) 207-194 (m
Figure imgf000194_0001
Examples 109– 112 were obtained by hydrolysis of the corresponding cyano intermediate. The cyano intermediates were isolated and correspond to the following:
Figure imgf000194_0002
DEA
Figure imgf000195_0001
The following compounds were synthesized in an analogous manner.
Examples 113– 116
Figure imgf000195_0002
Examples 113– 116 correspond to the following:
Figure imgf000196_0001
1H NMR (400 MHz CDCl ) d
Figure imgf000197_0001
Examples 113– 116 were obtained by hydrolysis of the corresponding cyano intermediate. The cyano intermediates were isolated and correspond to the following:
Figure imgf000197_0002
Examples 117– 120
Figure imgf000198_0001
Examples 117– 120 correspond to the following:
Figure imgf000198_0002
158 (m 1H)
Figure imgf000199_0001
Examples 117– 120 were obtained by hydrolysis of the corresponding cyano intermediate. The cyano intermediate were isolated and correspond to the following:
Figure imgf000199_0002
120 (c ano intermediate) 5544 min; Chiral HPLC
Figure imgf000200_0003
Examples 121– 124
Figure imgf000200_0001
Examples 121– 124 correspond to the following:
Figure imgf000200_0002
40%-60% ACN 1H) 550-390 (m 2H) 351-349 (m
Figure imgf000201_0001
Examples 121– 124 were obtained by hydrolysis of the corresponding cyano intermediate. The cyano intermediates were isolated and correspond to the following:
Figure imgf000201_0002
Examples 125– 128
l
Figure imgf000202_0001
Examples 125– 128 correspond to the following:
Figure imgf000202_0002
1H NMR (400 MHz DMSO-d6) d860
Figure imgf000203_0001
Examples 125– 128 were obtained by hydrolysis of the corresponding cyano intermediate. The cyano intermediates were isolated and correspond to the following:
Figure imgf000203_0002
Examples 129– 132
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((R)-2,2-dimethyl-1-(5-methyl- 1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone
and
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((S)-2,2-dimethyl-1-(5-methyl- 1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone
and
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((R)-2,2-dimethyl-1-(5-methyl- 1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone
and
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((S)-2,2-dimethyl-1-(5-methyl- 1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone
Figure imgf000204_0001
 
Figure imgf000205_0001
To a stirred solution of PPh3CH2OCH3 Cl (13.6 g, 39.7 mmol) in THF (100 mL) at 0 oC was added portionwise potassium tert-butoxide (4.44 g, 39.6 mmol) and the reaction was stirred at 0 oC for 1 hour. A a solution of neopentyl 2,2-dimethyl-4-oxopiperidine-1-carboxylate (6 g, 26.4 mmol) in THF (100 mL) was slowly added and the reaction mixture was allowed to warm to room temperature overnight. The reaction was diluted with water and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column
chromatography (5%-10% ethyl acetate in petroleum ether) to afford tert-butyl 4- (methoxymethylene)-2,2-dimethylpiperidine-1-carboxylate (1.5 g, 89% yield) as a colorless oil. Step 2
To a solution of afford tert-butyl 4-(methoxymethylene)-2,2-dimethylpiperidine-1- carboxylate (5.5 g, 20.4 mmol) in acetonitrile (500 mL) at 0 oC was added 1 M HCl aqueous solution (25 mL, 25 mmol) and the reaction was stirred at 0 oC for 5 hours. The mixture was treated with saturated aqueous NaHCO3 solution (100 mL) and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate, and concentrated to afford tert-butyl 4-formyl-2,2-dimethylpiperidine-1-carboxylate (5 g, 98% yield) as a white solid. Step 3
To a mixture of tert-butyl 4-formyl-2,2-dimethylpiperidine-1-carboxylate (5 g, 20 mmol) in tert-butanol (30 mL) and 2-Me-2-butane (60 mL) at 0 oC was added a solution of NaClO2 (16 g, 200 mmol) and NaH2PO4 (15 g, 140 mmol) in water (90 mL) and the resulting mixture was stirred at room temperature for 4 hours. The mixture was diluted with water (50 mL) ad extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated to afford 1-(tert-butoxycarbonyl)-2,2- dimethylpiperidine-4-carboxylic acid (5 g, 94% yield) as a white solid. Step 4
To a solution of 1-(tert-butoxycarbonyl)-2,2-dimethylpiperidine-4-carboxylic acid (3.3 g, 12.8 mmol) in DCM (100 mL) was added DIPEA (2.15 g, 16.6 mmol) and PyBROP (7.16 g, 15.4 mmol). The mixture was stirred for 5 minutes before a solution of 5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole (3.02 g, 16.6 mmol) was added and the resulting mixture was stirred at room temperature overnight. The mixture was diluted with water (15 mL) and extracted with DCM (3 x 20 mL). The combined organic extracts were washed with brine and concentrated and purified by reverse phase column chromatography (40%-95% MeCN in water) to afford 4 diastereomers of tert-butyl 4-(5-(3,5-difluorophenyl)-4,5- dihydro-1H-pyrazole-1-carbonyl)-2,2-dimethylpiperidine-1-carboxylate (3.3 g, 61% yield) as a yellow solid. The racemate was separated via chiral chromatography to provide (S)-tert-butyl 4-((S)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-2,2-dimethylpiperidine-1-carboxylate and (S)-tert-butyl 4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-2,2- dimethylpiperidine-1-carboxylate and (R)-tert-butyl 4-((S)-5-(3,5-difluorophenyl)-4,5- dihydro-1H-pyrazole-1-carbonyl)-2,2-dimethylpiperidine-1-carboxylate and (R)-tert-butyl 4- ((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-2,2-dimethylpiperidine-1- carboxylate. The first isomer (isomer 1) was afforded as a solid (860 mg, 16% yield). The second isomer (isomer 2) was afforded as a solid (650 mg, 12% yield). The third isomer (isomer 3) was afforded as a solid (750 mg, 14% yield). The fourth isomer (isomer 4) was afforded as a solid (890 mg, 17% yield). Step 5 and 6
Example 129
To a solution of isomer 3 (750 mg, 1.8 mmol) in DCM (1.5 mL) was added TFA (1.5 mL) and the reaction mixture was stirred at room temperature for 1 hour and concentrated. The residue was diluted with DCM and the organic layer was washed with saturated NaHCO3 solution, washed with water and concentrated to give a single diastereomer of (5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(2,2-dimethylpiperidin-4-yl)methanone (470 mg, 84% yield). MS (m/z) 322 (M+H)+. 1H NMR (300 MHz, CDCl3) ppm 6.92 (s, 1H), 6.73-6.67 (m, 3H), 5.31-5.26 (dd, J = 12.0 Hz, 5.1 Hz, 1H), 3.48-3.37 (m, 2H), 2.97-2.92 (m, 2H), 2.81-2.73 (m, 1H), 1.76-1.72 (m, 3H), 1.53-1.39 (m, 2H), 1.22 (s, 3H), 1.15 (s, 3H). To a solution of (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(2,2-dimethylpiperidin- 4-yl)methanone (200 mg, 0.62 mmol) and 2-bromo-5-methyl-1,3,4-oxadiazole (200 mg, 1.3 mmol) in DMF (4 mL) was added NaHCO3 (100 mg, 1.2 mmol) and the reaction mixture was stirred at 100 oC overnight. The mixture was diluted with ethyl acetate (20 mL) and the organic layer was washed with brine, concentrated and purified by reverse phase HPLC to afford a isomer of (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(2,2-dimethyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone (112 mg, 47%) as a white solid.
LCMS (m/z) 404 (M+H)+, retention time: 3.262 min, LCMS Method 28.1H NMR (400 MHz, CD3OD) ppm 7.17 (s, 1H), 6.86-6.77 (m, 3H), 5.34 (dd, J = 12.0 Hz, 5.2 Hz, 1H), 3.77-3.71 (m, 3H), 3.65-3.48 (m, 2H), 3.24 (d, J = 12.0 Hz, 1H), 2.80 (ddd, J = 1.6 Hz, 4.8 Hz, 18.8 Hz, 1H), 2.05-1.99 (m, 1H), 1.78-1.67 (m, 3H), 1.53 (s, 3H), 1.34 (s, 3H). Step 5 and 6
Example 130
To a solution of isomer 4 (890 mg, 2.1 mmol) in DCM (3 mL) was added TFA (3 mL) and the reaction mixture was stirred at room temperature for 1 hour and concentrated. The residue was diluted with DCM and the organic layer was washed with saturated NaHCO3 solution, washed with water and concentrated to give a single diastereomer of (5-(3,5-difluorophenyl)- 4,5-dihydro-1H-pyrazol-1-yl)(2,2-dimethylpiperidin-4-yl)methanone (643 mg, 95% yield). MS (m/z) 322 (M+H)+. 1H NMR (300 MHz, CDCl3) ppm 6.96 (s, 1H), 6.71-6.66 (m, 3H), 5.32-5.28 (m, 1H), 3.46-3.38 (m, 2H), 3.08-2.96 (m, 3H), 2.81-2.73 (m, 1H), 1.78-1.74 (m, 2H), 1.63-1.55 (m, 2H), 1.28 (s, 3H), 1.22 (s, 3H). To a solution of (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(2,2-dimethylpiperidin- 4-yl)methanone (250 mg, 0.78 mmol) and 2-bromo-5-methyl-1,3,4-oxadiazole (190 mg, 1.2 mmol) in DMF (5 mL) was added NaHCO3 (130 mg, 1.6 mmol) and the reaction mixture was stirred at 100 oC overnight. The mixture was diluted with ethyl acetate (20 mL) and the organic layer was washed with brine, concentrated and purified by reverse phase HPLC to afford a isomer of (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(2,2-dimethyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone (182 mg, 58%) as a white solid.
LCMS (m/z) 404 (M+H)+, retention time: 3.026 min, LCMS Method 28.1H NMR (400 MHz, CD3OD) ppm 7.17 (s, 1H), 6.89-6.77 (m, 3H), 5.35 (dd, J = 12.0 Hz, 5.6 Hz, 1H), 3.75-3.70 (m, 1H), 3.63-3.48 (m, 2H), 3.25 (dd, J = 12.8Hz, 2.8 Hz, 1H), 2.80 (ddd, J = 1.6 Hz, 5.2 Hz, 24.0 Hz, 1H), 2.39 (s, 3H), 1.94-1.84 (m, 2H), 1.80-1.68 (m, 2H), 1.56 (s, 3H) , 1.37 (s, 3H). Step 5 and 6
Example 131
To a solution of isomer 2 (650 mg, 1.5 mmol) in DCM (1.5 mL) was added TFA (1.5 mL) and the reaction mixture was stirred at 0 oC for 1 hour and concentrated. The residue was diluted with DCM and the organic layer was washed with saturated NaHCO3 solution, washed with water and concentrated to give a single diastereomer of (5-(3,5-difluorophenyl)-4,5-dihydro- 1H-pyrazol-1-yl)(2,2-dimethylpiperidin-4-yl)methanone (469 mg, 95% yield). MS (m/z) 322 (M+H)+.1H NMR (300 MHz, CDCl3) ppm 6.98 (s, 1H), 6.73-6.67 (m, 3H), 5.31-5.28 (dd, J = 12.0 Hz, 5.1 Hz, 1H), 3.48-3.37 (m, 2H), 2.97-2.92 (m, 2H), 2.81-2.73 (m, 1H), 1.75-1.72 (m, 3H), 1.53-1.40 (m, 2H), 1.22 (s, 3H), 1.15 (s, 3H). To a solution of (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(2,2-dimethylpiperidin- 4-yl)methanone (200 mg, 0.62 mmol) and 2-bromo-5-methyl-1,3,4-oxadiazole (200 mg, 1.2 mmol) in DMF (4 mL) was added NaHCO3 (105 mg, 1.2 mmol) and the reaction mixture was stirred at 100 oC overnight. The mixture was diluted with ethyl acetate (20 mL) and the organic layer was washed with brine, concentrated and purified by reverse phase HPLC to afford a isomer of (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(2,2-dimethyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone (103 mg, 41%) as a white solid.
LCMS (m/z) 404 (M+H)+, retention time: 3.404 min, LCMS Method 27.1H NMR (400 MHz, CD3OD) ppm 7.17 (s, 1H), 6.89-6.77 (m, 3H), 5.35 (dd, J = 12.0 Hz, 5.6 Hz, 1H), 3.75-3.70 (m, 1H), 3.63-3.48 (m, 2H), 3.25 (dd, J = 12.8Hz, 2.8 Hz, 1H), 2.80 (ddd, J = 1.6 Hz, 5.2 Hz, 24.0 Hz, 1H), 2.39 (s, 3H), 1.94-1.84 (m, 2H), 1.80-1.68 (m, 2H), 1.56 (s, 3H) , 1.37 (s, 3H). Step 5 and 6
Example 132
To a solution of isomer 1 (600 mg, 1.4 mmol) in DCM (1.5 mL) was added TFA (1.5 mL) and the reaction mixture was stirred at room temperature for 1 hour and concentrated. The residue was diluted with DCM and the organic layer was washed with saturated NaHCO3 solution, washed with water and concentrated to give a single diastereomer of (5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(2,2-dimethylpiperidin-4-yl)methanone (440 mg, 98% yield). MS (m/z) 322 (M+H)+. To a solution of (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(2,2-dimethylpiperidin- 4-yl)methanone (250 mg, 0.78 mmol) and 2-bromo-5-methyl-1,3,4-oxadiazole (190 mg, 1.2 mmol) in DMF (5 mL) was added NaHCO3 (130 mg, 1.6 mmol) and the reaction mixture was stirred at 85 oC overnight. The mixture was diluted with ethyl acetate and the organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by reverse phase HPLC to afford a isomer of (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(2,2- dimethyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone (142 mg, 45%) as a white solid. LCMS (m/z) 404 (M+H)+, retention time: 3.337 min, LCMS Method 28.1H NMR (400 MHz, CD3OD) ppm 7.17 (s, 1H), 6.86-6.77 (m, 3H), 5.34 (dd, J = 12.0 Hz, 5.2 Hz, 1H), 3.77-3.71 (m, 3H), 3.65-3.48 (m, 2H), 3.24 (d, J = 12.0 Hz, 1H), 2.80 (ddd, J = 1.6 Hz, 4.8 Hz, 18.8 Hz, 1H), 2.05-1.99 (m, 1H), 1.78-1.67 (m, 3H), 1.53 (s, 3H), 1.34 (s, 3H). Examples 133-136 were synthesized analogously to Examples 129– 132. Examples 133– 136
Figure imgf000210_0001
Examples 133– 136 correspond to the following:
Figure imgf000210_0002
J=120 Hz 52 Hz 1H) 375-
Figure imgf000211_0001
Examples 133– 136 were obtained by a deprotection of the corresponding Boc-protected intermediate, followed by an SNAr (with an appropriate halo pyrimidine). The Boc-protected intermediates were isolated and correspond to the following:
Figure imgf000211_0002
he tane in EtOH + 001% ( ) DEA
Figure imgf000212_0002
Alternatively, Examples 117 and 119 were synthesized and isolated in the following manner: Example 117
6-((3S,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide
Figure imgf000212_0001
Step 1
To a stirred solution of 5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole (31 g, 170 mmol) in dichloromethane (1 L) at 0 oC was added (3S,4R)-1-(tert-butoxycarbonyl)-3-fluoropiperidine- 4-carboxylic acid (42.1 g, 170 mmol), PyBROP (111 g, 238 mmol) and DIPEA (59.4 mL, 340 mmol). The reaction mixture was stirred at room temperature for 24 hr. The reaction mixture was diluted with water and additional DCM and the layers separated. The aqueous layers was extracted with additional DCM (2 x 500 mL). The combined organics extracts were washed with water, brine, dried over sodium sulfate and concentrated. The residue was suspended in DCM (500 mL) and filtered. The filtrate was concentrated under reduced pressure and was purified by silica gel chromatography (25-100% ethyl acetate/heptane). The first diastereomer to elute was collected and concentrated under reduced pressure. The residue was crystallized from 30% ethyl acetate/heptane to afford tert-butyl (3S,4R)-4-((R)-5- (3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidine-1-carboxylate (17.4 g, 24.8 % yield) as a light yellow solid. LCMS (m/z) 356 (M-56+H)+, retention time: 1.05 min, LCMS Method 9.1H NMR (DMSO-d6) ppm 7.26 (s, 1H), 7.03-7.19 (m, 1H), 6.88 (dd, J = 8.3, 2.0 Hz, 2H), 5.38 (dd, J = 12.0, 4.6 Hz, 1H), 4.86-5.16 (m, 1H), 4.10-4.40 (m, 1H), 3.99 (br d, J = 4.4 Hz, 1H), 3.34-3.62 (m, 2H), 2.65-3.27 (m, 3H), 1.84 (qd, J = 13.0, 4.4 Hz, 1H), 1.54 (br dd, J = 13.4, 3.7 Hz, 1H), 1.39 (s, 9H). The second diastereomer to elute was collected and concentrated under reduced pressure. The residue was crystalized from 30% ethyl acetate/heptane to afford tert-butyl (3S,4R)-4- ((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidine-1- carboxylate (23.6 g, 33.7 % yield). LCMS (m/z) 356 (M-56+H)+, retention time: 1.05 min, LCMS Method 9. 1H NMR (DMSO-d6) ppm 7.26 (m, 1H), 7.18-7.09 (m, 1H), 6.86 (m, 2H), 5.44-5.16 (m, 2H), 4.36-4.15 (m, 1H), 4.11-3.93 (m, 1H), 3.57-3.38 (m, 1H), 3.34 (s, 2H), 2.82-2.66 (m, 2H), 1.92-1.74 (m, 1H), 1.58-1.46 (m, 1H), 1.40 (s, 9H). Step 2
To a suspension of tert-butyl (3S,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole- 1-carbonyl)-3-fluoropiperidine-1-carboxylate (23.4 g, 56.9 mmol) in diethyl ether (50 mL) was added 3M HCl in CPMe (190 mL, 569 mmol). The reaction mixture was stirred at room temperature for 16 hr. The reaction mixture was filtered and the solid washed with diethyl ether to afford ((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4R)-3- fluoropiperidin-4-yl)methanone hydrochloride (19.2 g, 97 % yield LCMS (m/z) 312 (M+H)+, retention time: 0.45 min, LCMS Method 9. 1H NMR (DMSO-d6) ppm 9.71 (m, 1H), 8.85- 8.69 (m, 1H), 7.31 (m, 1H), 7.15 (m, 1H), 6.87 (m, 2H), 5.63-5.46 (m, 1H), 5.41 (m, 1H), 4.05-3.68 (m, 1H), 3.65-3.19 (m, 4H), 3.04 (m, 1H), 2.78 (m, 1H), 2.10 (m, 1H), 1.73 (m, 1H). Step 3
To a mixture of ((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4R)-3- fluoropiperidin-4-yl)methanone, hydrochloride (4g, 11.5 mmol) and 6-chloropyrimidine-4- carboxamide (1.81 g, 11.5 mmol) in acetonitrile (40 mL) at 0 oC was added triethylamine (4.81 mL, 34.5 mmol). The reaction mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with ethyl acetate and water and the layers separated. The aqueous layer was extracted twice more with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (50%-100% EA/Hex, 100% 3:1 ethyl acetate/ethanol). The residue was crystalized from DMF and water to afford 6-((3S,4R)-4- ((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1- yl)pyrimidine-4-carboxamide (650 mg, 1.50 mmol, 13.1 % yield) as a cream solid.. LCMS (m/z) 433 (M+H)+, retention time: 0.60 min, LCMS Method 9. 1H NMR (DMSO-d6) ppm 8.56 (m, 1H), 8.07 (m, 1H), 7.77 s, 1H), 7.25-7.40 (m, 2H), 7.06-7.17 (m, 1H), 6.85 (m, 2H), 5.33-5.57 (m, 2H), 4.38-5.07 (m, 2H), 3.52 (m, 3H), 3.03-3.20 (m, 1H), 2.77 (m, 1H), 1.91 (m, 1H), 1.67 (m, 1H). The following compounds were synthesized in an analogous manner using the appropriate heteroaryl halide in step 3. When 6-chloropyrimidine-4-carboxamide was used, the reactions were run at room temperature in MeCN while all other heteroaryl halides required heating between 100-130 oC in dioxane, DMF, or NMP. For Example143 and Exmaple 144 , the diastereomers were carried through to step 3 as a mixture and then separated using Prep-SFC with the following conditions: Column: CHIRALPAK IC, 2x25 cm, 5 µm; Mobile Phase A: CO2: 55% Mobile Phase B: MeOH:DCM=1:1: 45%; Flow rate: 40 mL/min; 254 nm; RT1: 7.75 min; RT2: 11.02 min to afford the two desired products. Eamle Name Strctre 1H NMR LC: retention MS
Figure imgf000215_0001
J = 1312 925 Hz 1
Figure imgf000216_0001
305-321 (m 1H) 286
Figure imgf000217_0001
146 6-((3S4R)- DMSO-d) m 856 (s 1181 min 415
Figure imgf000218_0001
Example 119
6-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide
F F F F F
Figure imgf000219_0001
Step 1
To a mixture of 5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole (1.50 g, 8.25 mmol), (3R,4S)-1-(tert-butoxycarbonyl)-3-fluoropiperidine-4-carboxylic acid (1.7 g, 6.88 mmol) and DIPEA (2.40 mL, 13.8 mmol) in dichloromethane (30 mL) was added PyBROP (4.65 g, 8.94 mmol). The resultant mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with water and the layers separated. The organic layer was washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was suspended in ethyl acetate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (0-100% ethyl acetate/heptane) to afford tert-butyl (3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidine-1-carboxylate (first eluting diastereomer) (740 mg, 26.2 % yield). LCMS (m/z) 356 (M-56+H)+, retention time: 1.06 min, LCMS Method 9. 1H NMR (DMSO-d6) ppm 7.27 (s, 1H), 7.17-7.10 (m, 1H), 6.92-6.85 (m, 2H), 5.41-5.35 (m, 1H), 5.15-4.93 (m, 1H), 4.32-3.94 (m, 2H), 3.57-3.40 (m, 2H), 3.34 (s, 1H), 2.80-2.66 (m, 2H), 1.91-1.77 (m, 1H), 1.58-1.50 (m, 1H), 1.40 (s, 9H) and
tert-butyl (3R,4S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidine-1-carboxylate (second eluting diastereomer) (920 mg, 32.5 % yield) as a cream solid. LCMS (m/z) 356 (M-56+H)+, retention time: 1.05 min, LCMS Method 9.1H NMR (DMSO-d6) ppm 7.26 (t, J = 1.6 Hz, 1H), 7.04-7.19 (m, 1H), 6.86 (dd, J = 8.6, 2.0 Hz, 2H), 5.39 (dd, J = 11.9, 5.3 Hz, 1H), 5.17-5.35 (m, 1H), 4.17-4.37 (m, 1H), 3.93-4.05 (m, 1H), 3.34-3.62 (m, 2H), 2.66-3.21 (m, 3H), 1.83 (qd, J = 13.1, 4.4 Hz, 1H), 1.51 (m, 1H), 1.40 (s, 8H). Step 2
tert-butyl (3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidine-1-carboxylate (920 mg, 2.236 mmol) was suspended in 3M HCl in CPMe (7.40 mL, 22.4 mmol) and stirred at room temperature for 18 hr. The reaction mixture was diluted with diethyl ether and filtered to afford to afford ((S)-5-(3,5-difluorophenyl)-4,5- dihydro-1H-pyrazol-1-yl)((3R,4S)-3-fluoropiperidin-4-yl)methanone (570 mg, 82 % yield). LCMS (m/z) 312 (M+H)+, retention time: 0.47 min, LCMS Method 9. 1H NMR (DMSO-d6) ppm 9.61-9.43 (m, 1H), 8.82-8.62 (m, 1H), 7.32 (m, 1H), 7.20-7.09 (m, 1H), 6.90 (m, 2H), 5.46-5.16 (m, 2H), 4.38-3.92 (m, 2H), 3.53 (m, 3H), 3.12-2.94 (m, 1H), 2.88-2.71 (m, 1H), 2.20-2.01 (m, 1H), 1.85-1.71 (m, 1H). Step 3
To a stirred suspension of ((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)- 3-fluoropiperidin-4-yl)methanone, hydrochloride (450 mg, 1.30 mmol) and 6- chloropyrimidine-4-carboxamide (245 mg, 1.55 mmol) in acetonitrile (10 mL) was added triethylamine (0.721 mL, 5.18 mmol). The resultant mixture was stirred at room temperature for 18 hrs. The reaction mixture was diluted with ethyl acetate and water and the layers separated. The organic extract was washed with saturated ammonium chloride, washed with brine, dried over sodium sulfate and concentrated to afford a yellow solid. The solid was crystalized from ethyl acetate/heptane to afford 6-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5- dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide (270 mg, 48.3 % yield). LCMS (m/z) 433 (M+H)+, retention time: 0.60 min, LCMS Method 9. 1H NMR (DMSO-d6) ppm 8.56 (m, 1H), 8.07 (m, 1H), 7.77 (m, 1H), 7.35 (m, 1H), 7.32-7.27 (m, 1H), 7.14 (s, 1H), 6.90 (m, 2H), 5.44-5.35 (m, 1H), 5.30-5.07 (m, 1H), 5.01-4.19 (m, 2H), 3.78-3.59 (m, 1H), 3.59-3.47 (m, 1H), 3.36-3.29 (m, 1H), 3.18-3.02 (m, 1H), 2.83-2.71 (m, 1H), 2.00-1.86 (m, 1H), 1.75-1.64 (m, 1H). The following compounds were synthesized in an analogous manner using the appropriate heteroaryl halide in Step 3. When 6-chloropyrimidine-4-carboxamide was used, the reactions were run at room temperature in MeCN and all other heteroaryl halides required heating between 100-130 oC in dioxane, DMF, or NMP. For Example 155 and Example 156, the diastereomers were separated after Step 1 using by Chiral HPLC on CHIRALPAK IE 2x25 cm, 5 µm column; Mobile Phase A: Hexane (8 M NH3 in MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL/min; %40 B with a total run time of 13 min; 220/254 nm. The first peak to elute (retention time 7.04 min) was used to synthesize Example 156 and the second peak to elute (retention time 8.674 min) was used to synthesize Example 155.
Figure imgf000221_0001
45-dihdro-1H- Hz 1H) 677-697 Method 9
Figure imgf000222_0001
30 Hz 1H)
Figure imgf000223_0001
241-217 (m 1H)
Figure imgf000224_0001
1H NMR (400 MHz
Figure imgf000225_0001
379-360 (m 1H)
Figure imgf000226_0002
Example 163
6-((3R,4S)-4-((S)-5-(3-(aminomethyl)-5-fluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide
Figure imgf000226_0001
A mixture of of 6-((3R,4S)-4-((S)-5-(3-cyano-5-fluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide (200 mg, 0.46 mmol) and nickel (27 mg, 0.46 mmol) in 7 M ammonia (5 mL, 35 mmol) in MeOH (7 M) was stirred at room temperature under hydrogen atmosphere for 3 hours. The resulting mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (from 10-30% acetonitrile in water; with 10 mM NH4HCO3 modifier) to afford 6-((3R,4S)-4-((S)-5-(3-(aminomethyl)-5-fluorophenyl)-4,5- dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide (34 mg, 16% yield) as a white solid. LCMS (m/z) 444 (M+H)+, retention time: 0.688 min, LCMS Method 16.
1H NMR (400 MHz, DMSO-d6) ppm 8.55 (s, 1H), 8.08 (brs, 1H), 7.77 (brs, 1H), 7.34-7.26 (m, 2H), 7.10-7.03 (m, 1H), 6.94 (s, 1H), 6.78-6.72 (m, 1H), 5.34 (dd, J = 12.0, 4.8 Hz, 1H), 5.28-5.09 (m, 1H), 4.94-4.10 (m, 2H), 3.72-3.44 (m, 3H), 3.45-3.37 (m, 1H), 3.33-3.23 (m, 2H), 3.18-3.02 (m, 1H), 2.76-2.65 (m, 1H), 2.26-2.03 (m, 1H), 1.98-1.83 (m, 1H), 1.69-1.59 (m, 1H).
Example 164 was synthesized in an analogous manner.
Figure imgf000227_0001
Example 165
N-(2-aminoethyl)-6-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide
Figure imgf000228_0001
Step 1
A mixture of 6-hydroxypyrimidine-4-carboxylic acid (2.8 g, 20 mmol) in phosphorus oxychloride (28 ml, 300 mmol) at 0 degree was treated with phosphorus pentachloride (8.3 g, 40 mmol) and the resulting mixture was heated to 110 °C and for 3 hours. The reaction mixture was concentrated under high vacuum to afford the crude desired product 6- chloropyrimidine-4-carbonyl chloride (3.4 g, 93% yield) as a black solid.
Step 2
A mixture of tert-butyl (2-aminoethyl)carbamate (1.6 g, 10 mmol) and triethylamine (7.0 mL, 50 mmol) in DCM (20 mL) at 0 oC was slowly treated with 6-chloropyrimidine-4-carbonyl chloride (1.7 g, 9.6 mmol) and the resulting mixture was stirred at rt for 3 hours. The mixture was diluted with water (30 mL), extracted with DCM (3x50 mL) and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by normal phase column chromatography (EA in PE from 0% to 40%) to afford tert-butyl (2-(6-chloropyrimidine-4-carboxamido)ethyl)carbamate (1.8 g, 62% yield) as a white solid. LCMS (m/z) 301 (M+H)+, retention time: 1.280 min, LCMS Method 18. 1H NMR (300 MHz, DMSO-d6) ppm 9.20 (s, 1H), 9.10 (m, 1H), 6.95 (t, J = 6 Hz, 1H), 2.39-3.33 (m, 2H), 3.13 (q, J = 6 Hz, 2H), 1.36 (s, 9H).
Step 3
A mixture of ((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)-3- fluoropiperidin-4-yl)methanone, Hydrochloride (150 mg, 0.43 mmol) and DIEA (0.23 mL, 1.3 mmol) in DMF (5 mL) was treated with tert-butyl (2-(6-chloropyrimidine-4- carboxamido)ethyl)carbamate (140 mg, 0.47 mmol) and the resulting mixture was stirred for 3 hours at rt. The mixture was diluted with water (20 mL) and , extracted with DCM (3x25 mL) and the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford tert-butyl (2-(6-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5- dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamido)ethyl)carbamate (200 mg, 65 % yield) as a light yellow solid. LCMS (m/z) 576 (M+H)+, retention time: 1.123 min, LCMS Method 19.
Step 4
tert-butyl (2-(6-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)- 3-fluoropiperidin-1-yl)pyrimidine-4-carboxamido)ethyl)carbamate (200 mg, 0.35 mmol) was treated with 4M HCl in dioxane (5 mL, 20 mmol) and the resulting mixture was stirred at rt for 2 hours and concentrated under reduced pressure. The resulting residue was purified by reverse reverse phase chromatography (from 21-38% acetonitrile in water; with 10 mM NH4HCO3 m+ 0.1%NH4OH modifier) to afford N-(2-aminoethyl)-6-((3R,4S)-4-((S)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4- carboxamide (68 mg, 40 % yield) as a white solid. LCMS (m/z) 476 (M+H)+, retention time: 0.934 min, LCMS Method 23. 1H NMR (300 MHz, DMSO-d6) ppm 8.84-8.70 (m, 1H), 8.55 (s, 1H), 7.32 (s, 1H), 7.29 (t, J = 1.5 Hz, 1H), 7.20-7.08 (m, 1H), 6.94-6.84 (m, 2H), 5.39 (dd, J = 12.0, 4.8 Hz, 1H), 5.31-5.08 (m, 1H), 5.02-4.34 (m, 2H), 3.80-3.46 (m, 4H), 3.30-3.21 (m, 3H), 3.20-2.99 (m, 2H), 2.83-2.63 (m, 2H), 2.05-1.84 (m, 1H), 1.76-1.62 (m, 1H). Example 166 was synthesized in an analogous manner.
E l 1H MR L M
Figure imgf000230_0001
Examples 167– 170
(R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)- 1-methylpiperidin-2-one
and
(S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)- 1-methylpiperidin-2-one
and
(S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)- 1-methylpiperidin-2-one
and
(R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)- 1-methylpiperidin-2-one
Figure imgf000231_0001
Step 1
A mixture of 1-methyl-2-oxopiperidine-4-carboxylic acid (600 mg, 3.8 mmol) and HATU (1.4 g, 3.8 mmol) in DMF (10 mL) was treated with DIEA (2.0 mL, 11 mmol) followed by 5- (3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole (760 mg, 4.2 mmol) and the resulting mixture was stirred at 25 °C overnight. The reaction mixture was diluted with water (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was first purified by normal phase column chromatography (MeOH in DCM from 0% to 3%) to afford two diastereomers. tert-butyl (2-(6-chloropyrimidine-4- carboxamido)ethyl)carbamate (1.8 g, 62% yield) as a white solid. The first diasteromer was separated into the enantiomers by Prep-Chiral HPLC with the following conditions: Column: CHIRALPAK IF, 2x25cm, 5µm; Mobile Phase
A:Hex:DCM=3:1(10mM NH3 in MeOH), Mobile Phase B:EtOH; Flow rate:18 mL/min; Gradient:30 %B to 30 B in 35 min; 220/254 nm; RT1:1.41 min; RT2:1.65 min to afford two title compounds. Example 167
An enantiomer was afforded as a light yellow solid (31 mg, 2% yield). LCMS (m/z) 322 (M+H)+, retention time: 0.934 min, LCMS Method 34. Chiral HPLC Anal. Method 10, retention time 1.426 min, %ee = 100%. 1H NMR (400 MHz, CDCl3) ppm 6.98 (t, J = 1.6 Hz, 1H), 6.74-6.68 (m, 1H), 6.67-6.64 (m, 2H), 5.29 (dd, J = 12.0, 5.2 Hz, 1H), 3.62-3.53 (m, 1H), 3.48-3.39 (m, 1H), 3.34-3.28 (m, 2H), 2.95 (s, 3H), 2.83-2.72 (m, 2H), 2.53-2.45 (m, 1H), 2.07-1.92 (m, 2H). Example 168
An enantiomer was afforded as a light yellow solid (32 mg, 2% yield). LCMS (m/z) 322 (M+H)+, retention time: 0.994 min, LCMS Method 34. Chiral HPLC Anal. Method 10, retention time 4.291 min, %ee = 100%. 1H NMR (400 MHz, CDCl3) ppm 6.97 (t, J = 1.6 Hz, 1H), 6.74-6.68 (m, 1H), 6.67-6.63 (m, 2H), 5.29 (dd, J = 12.0, 4.8 Hz, 1H), 3.61-3.53 (m, 1H), 3.47-3.39 (m, 1H), 3.38-3.30 (m, 2H), 2.95 (s, 3H), 2.84-2.73 (m, 2H), 2.53-2.44 (m, 1H), 2.09-1.92 (m,2H).
The second diasteromer was separated into the enantiomers by Prep-Chiral HPLC with the following conditions: Column: CHIRALPAK IG, 2x25cm, 5µm; Mobile Phase
A:Hex:DCM=3:1(10mM NH3 in MeOH), Mobile Phase B:EtOH; Flow rate:18 mL/min; Gradient:30 %B to 30 B in 35 min; 220/254 nm; RT1:10.916 min; RT2:16.037 min to afford two title compounds. Example 169
An enantiomer was afforded as a light yellow solid (31 mg, 2% yield). LCMS (m/z) 322 (M+H)+, retention time: 1.044 min, LCMS Method 34. Chiral HPLC Anal. Method 12, retention time 1.937 min, %ee = 100%. 1H NMR (400 MHz, CDCl3) ppm 6.99 (s, 1H), 6.74- 6.64 (m, 3H), 5.31 (dd, J = 12.0, 4.8 Hz, 1H), 3.65-3.57 (m, 1H), 3.51-3.28 (m, 3H), 2.95 (s, 3H), 2.82-2.76 (m, 1H), 2.62-2.52 (m, 2H), 2.16-2.08 (m, 1H), 2.02-1.92 (m, 1H). Example 170
An enantiomer was afforded as a light yellow solid (32 mg, 2% yield). LCMS (m/z) 322 (M+H)+, retention time: 1.044 min, LCMS Method 34. Chiral HPLC Anal. Method 12, retention time 2.517 min, %ee = 100%. 1H NMR (400 MHz, CDCl3) ppm 6.99 (s, 1H), 6.73- 6.63 (m, 3H), 5.32 (dd, J = 11.6, 4.8 Hz, 1H), 3.65-3.56 (m, 1H), 3.51-3.28 (m, 3H), 2.94 (s, 3H), 2.83-2.76 (m, 1H), 2.62-2.53 (m, 2H), 2.15-2.07 (m, 1H), 2.05-1.93 (m, 1H).
Example 171
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)-3-fluoro-1-(1,2,4- oxadiazol-3-yl)piperidin-4-yl)methanone
Figure imgf000233_0001
Step 1
To a solution of ((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)-3- fluoropiperidin-4-yl)methanone, Hydrochloride (400 mg, 1.2 mmol), and potassium carbonate (480 mg, 3.4 mmol) in Acetonitrile (35 mL) at 0 °C under nitrogen was added cyanic bromide (180 mg, 1.7 mmol) in Acetonitrile (3 mL). The mixture was
stirred at 0 °C for 1.5 hours and the reaction mixture was quenched with the addition of 1N NaOH aqueous solution (20 ml) and extracted with ethyl acetate (2 x 50 ml). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to afford (3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidine-1-carbonitrile (370 mg, 96% yield) as a yellow solid. LCMS (m/z) 337 (M+H)+, retention time: 0.76 min, LCMS Method 9. 1H NMR (300 MHz, DMSO-d6) ppm 7.21-7.34 (m, 1H), 7.13 (tt, J = 9.4, 2.4 Hz, 1H), 6.88 (dd, J = 8.3, 2.0 Hz, 2H), 5.39 (dd, J = 11.7, 4.9 Hz, 1H), 4.94-5.22 (m, 1H), 3.35-3.71 (m, 5H), 3.21 (td, J = 12.7, 2.4 Hz, 1H), 2.77 (ddd, J = 19.1, 4.6, 1.7 Hz, 1H), 2.00-2.17 (m, 1H), 1.60 (br dd, J = 13.9, 3.2 Hz, 1H).
Step 2
A mixture of (3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidine-1-carbonitrile (370 mg, 1.1 mmol) in Ethanol (10 mL) and
Water (3 mL) was treated with hydroxylamine hydrochloride (150 mg, 2.2 mmol) followed by sodium carbonate (230 mg, 2.2 mmol) and the reaction mixture was stirred at
room temperature for 3 hours. The reaction mixture was diluted with water (30 mL) and extracted with DCM (3 x 50 mL) and the combined organic layers were washed with brine (2 x 100 mL), dried over sodium sulfate, and concentrated. The resulting residue was purified by normal phase silica gel column chromatography (MeOH in DCM 0% to 40%) to afford (3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-fluoro-N- hydroxypiperidine-1-carboximidamide (160 mg, 40% yield) as a white solid. LCMS (m/z) 370 (M+H)+, retention time: 0.52 min, LCMS Method 9. 1H NMR (400 MHz, DMSO-d6) ppm 8.28 (s, 1H), 7.25 (t, J = 1.5 Hz, 1H), 7.13 (tt, J = 9.3, 2.2 Hz, 1H), 6.88 (dd, J = 8.3, 2.0 Hz, 2H), 5.38 (dd, J = 11.7, 4.9 Hz, 1H), 5.16 (s, 2H), 4.94-5.12 (m, 1H), 3.70- 3.85 (m, 1H), 3.63 (br d, J = 12.2 Hz, 1H), 3.37-3.57 (m, 2H), 2.53-2.87 (m, 2H), 1.92-2.07 (m, 1H), 1.54 (br dd, J = 13.7, 3.4 Hz, 1H). Note: 1H hidden under solvent.
Step 3
A mixture of (3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoro-N-hydroxypiperidine-1-carboximidamide (160 mg, 0.43 mmol) in triethyl orthoformate (3.0 mL, 18 mmol) was treated with concentrated hydrochloric acid (10 ml, 0.12 mmol) and the resulting reaction mixture was heated at 110 °C for 12 hours under nitrogen in a sealed vial. The reaction mixture was diluted with DCM and sat. aqs. NaHCO3 solution. The organic layer was separated and the aqueous layer extracted with DCM (1x20 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by normal phase silica gel column chromatography (MeOH in DCM 0%-30%) to afford ((S)-5-(3,5-difluorophenyl)- 4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)-3-fluoro-1-(1,2,4-oxadiazol-3-yl)piperidin-4- yl)methanone (24 mg, 15% yield) as a white solid. LCMS (m/z) 380 (M+H)+, retention time: 0.84 min, LCMS Method 9. 1H NMR (400 MHz, DMSO-d6) ppm 9.12 (s, 1H), 7.28 (t, J = 1.5 Hz, 1H), 7.13 (tt, J = 9.4, 2.1 Hz, 1H), 6.84-6.93 (m, 2H), 5.39 (dd, J = 11.7, 4.9 Hz, 1H), 5.06- 5.22 (m, 1H), 4.17 (br t, J = 12.0 Hz, 1H), 3.92 (br d, J = 13.2 Hz, 1H), 3.44-3.69 (m, 2H), 3.23-3.38 (m, 1H), 3.12 (td, J = 13.0, 2.4 Hz, 1H), 2.77 (ddd, J = 19.1, 4.6, 1.7 Hz, 1H), 2.02 (qd, J = 13.1, 4.6 Hz, 1H), 1.59-1.69 (m, 1H).
Biological Assays
Biological in vitro cell assay
The efficacy of RIP1 inhibitors can be tested in mice in vitro using a human monocytic leukemia U937 cells in a necroptosis assay. As determined using the method described in S. He et al., Cell, 137(6):1100-1111 (2009) and International Patent Appln.No. PCT/IB2014/059004, now, International Patent Appln. Pub. No. WO2014/125444, the compounds of Examples 1-143, 145, 146-148, 155, 156-161, and 163-166 exhibited a pIC50 between approximately 5.0 and 9.0.
For instance, the compounds of Examples 8, 21-23, 25, 27, 28, 30, 31, 35, 36, 39-45, 47, 49, 50, 52-54, 58-60, 62, 64, 66-69, 71-79, 82-85, 87, 90-92, 94, 95, 98, 99, 102, 102, 104, 106, 108-110, 113-122, 125, 127, 129, 134, 143, 145, 146-148, 155, 156-161, and 163- 166 inhibited necrosis in U937 cells in the above method with a pIC50 between
approximately 5.5 and 9.0.
For instance, the compounds of Examples 21-23, 25, 28, 36, 40, 41, 44, 45, 47, 50, 52, 54, 58, 62, 64, 66, 67, 72, 76, 78, 82, 83, 85, 87, 90, 94, 98, 101, 102, 106, 108-110, 113, 114, 117, 119-121, 125, 127, 146-148, 155, 157-159, 161, 163, and 165 inhibited necrosis in U937 cells in the above method with a pIC50 between approximately 6.5 and 9.0.
For instance, the compounds of Examples 22, 23, 36, 52, 54, 62, 64, 66, 76, 82, 83, 90, 98, 102, 106, 108, 110, 117, 119, 121, 125, 146, 148, 155, 157, and 159 inhibited necrosis in U937 cells in the above method with a pIC50 between approximately 7.5 and 9.0 For instance, the compounds of Examples 22, 23, 25, 45, 52, 54, 64, 66, 90, 98, 102, 110, 117, 119, 121, 146, 148, 155, 157, 159, and 165 inhibited necrosis in U937 cells in the above method with a mean pIC50 of approximately 7.7, 7.6, 7.3, 7.0, 7.8, 7.5, 7.8, 7.5, 8.2, 7.6, 7.6, 8.5, 8.0, 8.3, 8.2, 7.8, 8.0, 7.8, 8.3, 8.2, and 7.2 respectively.
Viability was measured by quantitating cellular levels of ATP using the Cell Titer- Glo kit. All data are means ± standard deviation of the mean. Biological ADP-Glo Kinase Assay
The potency of RIP1 inhibitors can be tested in ADP-Glo kinase assay. As determined using the method described in J. Med. Chem.60, 1247-1261 (2017), the compounds of Examples 137-171 exhibited a pIC50 between approximately 6.0 and 9.0.
For instance, the compounds of Examples 137-143, 146, 148, 149, 150-155, 157, 159, and 161 exhibited a pIC50 between approximately 7.0 and 9.0.
For instance, the compounds of Examples 137-140, 143, 146, 148, 149, 151, 155, 157, and 159 exhibited a pIC50 between approximately 8.0 and 9.0. Biological in vivo assay
For biological in vivo assays and models, Compounds A, B, C, D, E, F, G, and H were used. Compounds A, B, C, D, E, F, G, and H, or pharmaceutically acceptable salts thereof, and the methods of making are disclosed in PCT/IB2017/057225.
Figure imgf000236_0001
Compound A Compound B Compound C
Figure imgf000237_0001
Compound D Compound E Compound F
Figure imgf000237_0002
Compound G Compound H
The efficacy of RIP1 inhibitors can be tested in mice in vivo using a TNF-driven systemic inflammatory response syndrome model (L. Duprez et al. Immunity 35(6):908-918, (2011)) using TNF plus the caspase inhibitor zVAD or TNF alone. The TNF/zVAD model is terminated at ~3hrs and the TNF alone model is terminated at ~8hrs (under IACUC guidelines for temperature loss). TNF (or TNF/zVAD) induced manifestations include temperature loss, the production of numerous cytokines (including IL-6, IL-1b, MIP1 ^ and MIP2) in the periphery, liver and intestinal inflammation and an increase of markers of cellular (LDH and CK) and liver damage (AST and ALT) in the serum. Inhibition of these TNF alone or TNF/zVAD induced manifestations can be shown by PO pre-dosing with selected compounds. For example, mice (8 mice per group) were pre-dosed PO with vehicle or compound 15 minutes before i.v. administration of mouse TNF (30 ^g/mouse) alone or in combination with zVAD (0.4 mg/mouse) simultaneously. Temperature loss in the mice was measured by rectal probe. The study was terminated when the control group lost 7 degrees, per our IACUC protocol. All data are shown as means ± standard error of the mean.
Representative data for Compounds A, B, C, D, E, F, G, and H were expressed over time and at the 2.0, 3.0, and 7.5 hour time points, respectively, are provided in FIGS.1A-5B. Data for Compounds A, B, C, D, E, F, G, and H were tested in this model are provided in Table A.
Figure imgf000238_0001
Rd10 mouse model of human retinitis pigmentosa
Inhibition of RIP1 has been implicated in protection against the Rd10 mouse model of human retinitis pigmentosa (RP) (Y. Murakami et al., PNAS 109(36):14598-14603 (2012)). Rd10 mice have a mutation, the rod-specific gene that encodes rod cGMP phosphodiesterase ^-subunit. Mice were dark reared to P30, at which point they were moved to a 12-hour light/dark cycle to induce retinal degeneration. Mice were pre-dosed with RIP1 inhibitors in food-based dosing on day P28, two days prior to the switch to normal cyclic light, such that mice (15 mice per group) received on average 100 mg/kg/day RIP1 inhibitor in diet or control diet. Electroretinography (ERG) recordings were made at P39 and P46 as a measure of retinal cell function. Retinal cell loss was assessed by measurement of the thickness of the Outer Nuclear Cell (ONL) layers at various distances from the Optic Nerve Head (ONH) in hematoxylin and eosin stained retinal tissue sections collected at P46.
Representative data for Compound A are provided in FIGS.6A and 6B. EAE mouse model of human MS
Inhibition of RIP1 has been implicated in protection against the experimental autoimmune encephalomyelitis (EAE) mouse model of human Multiple Sclerosis (MS) (D. Ofengeim et al. Cell Reports 10(11):1836-1849, (2015)). Mice were pre-dosed with RIP1 inhibitors in food-based dosing one day prior to EAE induction, such that mice (15 mice per group) received on average 96 mg/kg/day or 9.6 mg/kg/day of RIP1 inhibitor in diet or control diet. Mice were inoculated with 100 ul of inoculum containing 100 ug of myelin oligodendrocyte protein amino acid 35-55 (MOG35-55) and 200ug heat inactivated
Mycobacterium tuberculosis in mineral oil. Inoculation was done by giving each mouse two 100 ul injections subcutaneously to the lower and higher aspect of the back, respectively. Intraperitoneal injections of pertussis toxin (4 ug/ml) 100 ul each were given at 2 hours and 24 hours after inoculation. Mice were monitored daily until day 35 post-induction and clinical signs were scored as follows: 0.5 for partial tail weakness, 1.0 for complete tail paralysis (all of tail dragging along), 1.5 for flaccid tail and abnormal gait, 2.0 for flaccid tail and clear weakness of hind legs, 2.5 for partial paralysis in one hindlimb (no movement preserved in affected limb), 3.0 for complete paralysis in both hindlimbs, 4.0 for complete paralysis in hindlimbs and partial weakness in forelimbs, and 5.0 for complete paralysis in both forelimbs and hindlimbs (tetraplegia) or moribund. Representative data for Compound A are provided in FIG.7. Glucose homeostasis
Blocking the actions of TNF at the TNF receptor has been shown to improve glucose homeostasis in animals and humans (Stagakis et al., Arthritis Research & Therapy (2012)). We therefore investigated the ability of our small molecule RIPK1 inhibitor to improve glucose homeostasis in a diabetic animal model. Mice genetically deficient for the leptin receptor (db/db mice; Jackson Labs, BKS.Cg-Dock7m +/+ Leprdb/J) are a widely used animal model of insulin resistance and diabetes. In our study, 4-week old male db/db mice were acclimated for a period of one week. At this point, when the mice were 5 weeks of age, the study was started. Mice were then divided into two group (n = 10/group) and baseline measurements of non-fasted blood glucoses (using a glucometer) and body weight were taken. After baseline measurements, one group of mice was fed chow containing RIPK1 inhibitor (100 mg/kg/day, n = 10) and the other remained on normal chow (n = 10). Animals remained on these diets for 6 weeks. Additional measurements of non-fasted blood glucose and body weight were taken 2 and 4 weeks after study start. At week 8, mice were fasted overnight (16 hours) and fasted blood glucose and body weight were measured on the following day. Reduced non-fasted blood glucose at weeks 2 and 4 was observed (FIGS.8A and 8B). Additionally, fasted blood glucose at week 8 was also significantly lower in db/db mice receiving the RIPK1 inhibitor versus normal chow controls (FIGS.9A and 9B). These data demonstrate a significant improvement in glucose homeostasis, in db/db mice receiving RIPK1 inhibitor in their diet versus the control diet cohort. Measurements of both non-fasted and fasted body weight showed no difference between groups, suggesting that the improved glycemic control observed in mice receiving RIPK1 inhibitor were not secondary to a loss in body weight. These data therefore demonstrate a direct, beneficial effect of blocking RIPK1 kinase activity to improve glucose homeostasis. Representative data for Compound A are provided in FIGS.8A, 8B, 9A, and 9B.
Obesity
Inflammation is known to be a contributing factor in the pathogenesis of diabetes and obesity (Chen. et. al., International Journal of Endocrinology (2015)). We therefore explored the effect of blocking RIPK1 kinase activity on body weight in mice made obese by chronic feeding of a high fat diet (HFD). Diet-induced obese, male mice C57Bl/6J (Jackson Labs Stock#380050) arrived at 22 weeks of age, with average body weight of 40 g and acclimated for one week and maintained on HFD. Mice were then acclimated to oral gavage with water for 7 days before study start. Thereafter mice received RIPK 1 inhibitor (50 mg/kg, bid, n = 9) or vehicle (bid, n = 9) for 19 days. Food intake was measured twice weekly and body weight was measured daily throughout the study. Although high fat diet-fed mice dosed with the RIPK1 inhibitor initially reduced their food intake (day 2 and day 5 (FIG.10A)), after the first week food intake in the two groups was equivalent. However while control animals continued to gain weight on the HFD, the HFD-fed mice PO dosed with the RIPK1 inhibitor did not gain weight and in fact showed a modest decrease in body weight from pre- compound exposure levels (FIG.10B). By the end of the first week, control animals were significantly heavier than mice given treated with RIPK1 inhibitor and this was maintained for at least 21 days. We demonstrated, therefore, that RIPK1 inhibition has therapeutic potential as a treatment for obesity. Representative data for Compound A are provided in FIGS.10A and 10B. Subcutaneous tumor efficacy
The efficacy of RIP1 inhibition was tested in 12 different murine (6-8 week old) syngeneic subcutaenous tumor models. RIP1 inhibition was tested as a single agent in all models, with anti-PD1 combination arms added to the five of the final models.
Table B. Study Design
Figure imgf000241_0001
Note:
^ N: animal number
^ Dosing volume: adjust dosing volume based on body weight (10 ^l/g).
^ Treatment regimen may be changed per BW (body weight) loss.
^ The interval of BID dosing is 8 hours. Study endpoints: The major endpoints of the study include the following:
1) Tumor growth inhibition (TGI): TGI% is an indication of antitumor effectiveness, and expressed as: TGI (%)=100 x (1-T/C). T and C are the mean tumor volume of the treated and control groups, respectively, on a given day. 2) Tumor and plasma collection at study end for further investigation.
Experimental Methods Cell Culture
The 12 syngenic cell lines were maintained in vitro with different medium (indiciated in Table C) at 37 ºC in an atmosphere of 5% CO2 in air. The tumor cells were routinely subcultured twice weekly. The cells in an exponential growth phase were harvested and counted for tumor inoculation.
Table C. Medium information
Figure imgf000242_0001
B1 F1 l DMEM+1 FB
Figure imgf000243_0001
Tumor Inoculation Each mouse was inoculated subcutaneously with tumor cells in 0.1 mL of PBS for tumor development. The treatments were started when the mean tumor size reached approximately 80-120mm3(around 100mm3). The test article (Compound A or anti-PD1 (anti-mouse PD-1 antibody (clone RPM1-14), BioXcell) administration and the animal numbers in each study group are shown in the experimental design Table B. The date of tumor cell inoculation is denoted as day 0.
Study Results Table D. Mean tumor growth inhibition (TGI) at model termination
Figure imgf000243_0002
R 1
Figure imgf000244_0001
Sharpin-deficient mouse model of TNF-dependent dermatitis
Sharpin-deficient mice (cpdm) develop a spontaneous and severe TNF- and RIPK1- dependent dermatitis and multi-organ immunopathology around 6-8 weeks of age (S.B. Berger et al., Journal of Immunology, 192(12):5476-5480, (2014)). Mice were dosed with RIP1 inhibitors at the time of weaning (3-4 weeks of age) prior to the development of dermatitis lesions or therapeutically after the development of dermatitis lesions (about 6 weeks of age) using a food-based dosing regimen, such that mice (4-7 mice per group) received on average 100 mg/kg/day or 10 mg/kg/day of RIP1 inhibitor in diet or control diet. Mice were observed for signs of proliferative dermatitis by using a dermatitis scoring system based on lesion character and regions affected. The character of the lesion was categorized according the following, in order of increasing severity, 0 = none, 1 = excoriation only or one small punctuated crust (£ 2 mm), 2 = multiple, small punctuate crusts or coalescing crust (> 2 mm), 3 = erosion or ulceration. The regions were identified as: Region 1: the head cranial to the medial pinna attachment and/or lesions affecting the mandible cranial to the sternum, Region 2: inner and outer pinna, dorsal cervical region caudal to the medial pinna attachment, dorsal and ventral thorax, and thoracic limbs, Region 3: any region caudal to the ribcage. A score for the regions affected was categorized per the following: 0 = none; 1 = Region 2 or 3; 2 = Region 2 and 3; 3 = Region 1+/- other affected regions. To calculate the dermatitis severity score, the lesion score and regions affected score were summed, divided by 6, and then multiplied by 100. A severity score of 66 was considered severe dermatitis. Pre-dosing with RIP1 inhibitors in food-based dosing resulted in a complete protection from the development of severe dermatitis. Additionally, therapeutic dosing with RIP1 inhibitors in food-based dosing rescued established dermatitis. Representative data for Compound A are provided in FIGS.12A and 12B.

Claims

1. A compound according to Formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000246_0001
wherein:
R1 is hydrogen, (C1-C4)alkenyl, (C2-C4)alkenyl-NH2, -(C1-C4)alkyl=NH, -NH2, 5-6 membered heteroaryl or 9-10 membered heteroaryl,
wherein said 5-6 membered heteroaryl or 9-10 membered heteroaryl is optionally substituted by 1 or 2 substituents independently selected from hydroxyl, cyano, halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C2-C4)alkynyl, (C1- C4)alkoxy, 5-6 membered heterocycloalkyl-CO-, fused 5-6 membered
heterocycloalkyl, H2N-, (C1-C4)alkylNH-, ((C1-C4)alkyl)((C1-C4)alkyl)N-,
-CONH2, H2NCO-(C1-C4)alkyl-, (C1-C4)alkylNHCO-, (hydroxy-(C1-C4)alkyl)NHCO- , (C3-C6)cycloalkyl-NHCO-, 5-6 membered heterocycloalkyl-NHCO-, ((C1- C4)alkyl)((C1-C4)alkyl)N-CO-, (C1-C4)alkyl-CONH-, ((C1-C4)alkyl)((C1-C4)alkyl)N- NHCO-, -CO2H, -CO2(C1-C4)alkyl, (C1-C4)alkylthio-, phenyl-(C1-C4)alkylthio-, (C1- C4)alkyl-SO-, (C1-C4)alkyl-SO2-, phenyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl,
wherein said (C1-C4)alkoxy is optionally substituted by hydroxyl, -CO2H, -CONH2, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; or said 5-6 membered heterocycloalkyl-CO-, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl is optionally substituted by (C1-C4)alkyl or oxo; or said 5-6 membered heterocycloalkyl-NHCO- is optionally substituted by (C1- C4)alkyl-CO-; R2 is phenyl or 5-6 membered heteroaryl,
wherein said phenyl or 5-6 membered heteroaryl is optionally substituted by one, two, or three substituents independently selected from halogen, (C1-C4)alkyl,
(C1-C4)alkoxy, and cyano; and
each R3 is independently selected from hydrogen, halogen, (C1-C4)alkyl, and -(C2-C4)alkenyl, or R1 and R3 taken together with the atoms to which they are attached, form a 5-6 membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by
(C1-C4)alkyl;
or any two R3 groups taken together with the atoms to which they are attached, form a 4-, 5-, 6-, or 7-membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; and
wherein at least one R3 is not hydrogen.
2. The compound according to claim 1, wherein:
R1 is hydrogen, (C1-C4)alkenyl, (C2-C4)alkenyl-NH2, -(C1-C4)alkyl=NH, -NH2, 5-6 membered heteroaryl or 9-10 membered heteroaryl,
wherein said 5-6 membered heteroaryl or 9-10 membered heteroaryl is optionally substituted by 1 or 2 substituents independently selected from hydroxyl, cyano, halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C2-C4)alkynyl, (C1- C4)alkoxy, substituted 5-6 membered heterocycloalkyl-CO-, fused 5-6 membered heterocycloalkyl, H2N-, (C1-C4)alkylNH-, ((C1-C4)alkyl)((C1-C4)alkyl)N-,
-CONH2, H2NCO-(C1-C4)alkyl-, (C1-C4)alkylNHCO-, (hydroxy-(C1-C4)alkyl)NHCO- , (C3-C6)cycloalkyl-NHCO-, substituted 5-6 membered heterocycloalkyl-NHCO-, ((C1-C4)alkyl)((C1-C4)alkyl)N-CO-, (C1-C4)alkyl-CONH-, ((C1-C4)alkyl)((C1- C4)alkyl)N-NHCO-, -CO2H, -CO2(C1-C4)alkyl, (C1-C4)alkylthio-, phenyl-(C1- C4)alkylthio-, (C1-C4)alkyl-SO-, (C1-C4)alkyl-SO2-, phenyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl,
wherein said (C1-C4)alkoxy is optionally substituted by hydroxyl, -CO2H, -CONH2, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; or said 5-6 membered heterocycloalkyl-CO-, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl is optionally substituted by (C1-C4)alkyl or oxo; or said 5-6 membered heterocycloalkyl-NHCO- is optionally substituted by (C1- C4)alkyl-CO-;
R2 is phenyl or 5-6 membered heteroaryl,
wherein said phenyl or 5-6 membered heteroaryl is optionally substituted by one, two, or three substituents independently selected from halogen, (C1-C4)alkyl,
(C1-C4)alkoxy, and cyano; and
each R3 is independently selected from hydrogen, halogen, (C1-C4)alkyl, and -(C2-C4)alkenyl, or R1 and R3 taken together with the atoms to which they are attached, form a 5-6 membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by
(C1-C4)alkyl;
or any two R3 groups taken together with the atoms to which they are attached, form a 4-, 5-, 6-, or 7-membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; and
wherein at least one R3 is not hydrogen.
3. A compound according to Formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000248_0001
wherein:
R1 is hydrogen, (C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkenyl-NH2, -(C1- C4)alkyl=NH, -NH2, 5-6 membered heteroaryl or 9-10 membered heteroaryl,
wherein said 5-6 membered heteroaryl or 9-10 membered heteroaryl is optionally substituted by 1 or 2 substituents independently selected from hydroxyl, cyano, halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C2-C4)alkynyl, (C1- C4)alkoxy, 5-6 membered heterocycloalkyl-CO-, fused 5-6 membered
heterocycloalkyl, H2N-, (C1-C4)alkyl-NH-, ((C1-C4)alkyl)((C1-C4)alkyl)N-, -CONH2, H2NCO-(C1-C4)alkyl-, (C1-C4)alkylNHCO-, H2N(C1-C4)alkylNHCO-, (C1-C4)alkyl HN(C1-C4)alkylNHCO-, ((C1-C4)alkyl)((C1-C4)alkyl)N(C1-C4)alkylNHCO- (hydroxy-(C1-C4)alkyl)NHCO-, (C3-C6)cycloalkyl-NHCO-, 5-6 membered heterocycloalkyl-NHCO-, ((C1-C4)alkyl)((C1-C4)alkyl)N-CO-, (C1-C4)alkyl-CONH-, ((C1-C4)alkyl)((C1-C4)alkyl)N-NHCO-, -CO2H, -CO2(C1-C4)alkyl, (C1-C4)alkylthio-, phenyl-(C1-C4)alkylthio-, (C1-C4)alkyl-SO-, (C1-C4)alkyl-SO2-, phenyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl,
wherein said (C1-C4)alkoxy is optionally substituted by hydroxyl, -CO2H, -CONH2, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; or said 5-6 membered heterocycloalkyl-CO-, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl is optionally substituted by (C1-C4)alkyl or oxo; or said 5-6 membered heterocycloalkyl-NHCO- is optionally substituted by (C1- C4)alkyl-CO-;
R2 is phenyl or 5-6 membered heteroaryl,
wherein said phenyl or 5-6 membered heteroaryl is optionally substituted by one, two, or three substituents independently selected from halogen, (C1-C4)alkyl, -(C1- C4)alkyl-NH2, -(C1-C4)alkyl-NH(C1-C4)alkyl, -(C1-C4)alkyl-N-((C1-C4)alkyl)((C1- C4)alkyl), (C1-C4)alkoxy, and cyano; and
each R3 is independently selected from hydrogen, halogen, (C1-C4)alkyl, -(C2-C4)alkenyl, and =O,
or R1 and R3 taken together with the atoms to which they are attached, form a 5-6 membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by
(C1-C4)alkyl;
or any two R3 groups taken together with the atoms to which they are attached, form a 4-, 5-, 6-, or 7-membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; and
wherein at least one R3 is not hydrogen.
4. A compound according to Formula (II) or a pharmaceutically acceptable salt thereof:
Figure imgf000250_0001
wherein:
R1 is hydrogen, (C1-C4)alkenyl, (C2-C4)alkenyl-NH2, -(C1-C4)alkyl=NH, -NH2, 5-6 membered heteroaryl or 9-10 membered heteroaryl,
wherein said 5-6 membered heteroaryl or 9-10 membered heteroaryl is optionally substituted by 1 or 2 substituents independently selected from hydroxyl, cyano, halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C2-C4)alkynyl, (C1- C4)alkoxy, 5-6 membered heterocycloalkyl-CO-, fused 5-6 membered
heterocycloalkyl, H2N-, (C1-C4)alkylNH-, ((C1-C4)alkyl)((C1-C4)alkyl)N-,
-CONH2, H2NCO-(C1-C4)alkyl-, (C1-C4)alkylNHCO-, (hydroxy-(C1-C4)alkyl)NHCO- , (C3-C6)cycloalkyl-NHCO-, 5-6 membered heterocycloalkyl-NHCO-, ((C1- C4)alkyl)((C1-C4)alkyl)N-CO-, (C1-C4)alkyl-CONH-, ((C1-C4)alkyl)((C1-C4)alkyl)N- NHCO-, -CO2H, -CO2(C1-C4)alkyl, (C1-C4)alkylthio-, phenyl-(C1-C4)alkylthio-, (C1- C4)alkyl-SO-, (C1-C4)alkyl-SO2-, phenyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl,
wherein said (C1-C4)alkoxy is optionally substituted by hydroxyl, -CO2H, -CONH2, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; or said 5-6 membered heterocycloalkyl-CO-, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl is optionally substituted by (C1-C4)alkyl or oxo; or said 5-6 membered heterocycloalkyl-NHCO- is optionally substituted by (C1- C4)alkyl-CO-;
R2 is phenyl or 5-6 membered heteroaryl,
wherein said phenyl or 5-6 membered heteroaryl is optionally substituted by one, two, or three substituents independently selected from halogen, (C1-C4)alkyl,
(C1-C4)alkoxy, and cyano; and each R3 is independently selected from hydrogen, halogen, (C1-C4)alkyl, and -(C2-C4)alkenyl, or R1 and R3 taken together with the atoms to which they are attached, form a 5-6 membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by
(C1-C4)alkyl;
or any two R3 groups taken together with the atoms to which they are attached, form a 4-, 5-, 6-, or 7-membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; and
wherein at least one R3 is not hydrogen.
5. The compound according to claim 4, wherein:
R1 is hydrogen, (C1-C4)alkenyl, (C2-C4)alkenyl-NH2, -(C1-C4)alkyl=NH, -NH2, 5-6 membered heteroaryl or 9-10 membered heteroaryl,
wherein said 5-6 membered heteroaryl or 9-10 membered heteroaryl is optionally substituted by 1 or 2 substituents independently selected from hydroxyl, cyano, halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C2-C4)alkynyl, (C1- C4)alkoxy, substituted 5-6 membered heterocycloalkyl-CO-, fused 5-6 membered heterocycloalkyl, H2N-, (C1-C4)alkylNH-, ((C1-C4)alkyl)((C1-C4)alkyl)N-,
-CONH2, H2NCO-(C1-C4)alkyl-, (C1-C4)alkylNHCO-, (hydroxy-(C1-C4)alkyl)NHCO- , (C3-C6)cycloalkyl-NHCO-, substituted 5-6 membered heterocycloalkyl-NHCO-, ((C1-C4)alkyl)((C1-C4)alkyl)N-CO-, (C1-C4)alkyl-CONH-, ((C1-C4)alkyl)((C1- C4)alkyl)N-NHCO-, -CO2H, -CO2(C1-C4)alkyl, (C1-C4)alkylthio-, phenyl-(C1- C4)alkylthio-, (C1-C4)alkyl-SO-, (C1-C4)alkyl-SO2-, phenyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl,
wherein said (C1-C4)alkoxy is optionally substituted by hydroxyl, -CO2H, -CONH2, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; or said 5-6 membered heterocycloalkyl-CO-, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl is optionally substituted by (C1-C4)alkyl or oxo; or said 5-6 membered heterocycloalkyl-NHCO- is optionally substituted by (C1- C4)alkyl-CO-;
R2 is phenyl or 5-6 membered heteroaryl, wherein said phenyl or 5-6 membered heteroaryl is optionally substituted by one, two, or three substituents independently selected from halogen, (C1-C4)alkyl,
(C1-C4)alkoxy, and cyano; and
each R3 is independently selected from hydrogen, halogen, (C1-C4)alkyl, and -(C2-C4)alkenyl, or R1 and R3 taken together with the atoms to which they are attached, form a 5-6 membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by
(C1-C4)alkyl;
or any two R3 groups taken together with the atoms to which they are attached, form a 4-, 5-, 6-, or 7-membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; and
wherein at least one R3 is not hydrogen. 6. A compound according to Formula (II) or a pharmaceutically acceptable salt thereof:
Figure imgf000252_0001
wherein:
R1 is hydrogen, (C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkenyl-NH2, -(C1- C4)alkyl=NH, -NH2, 5-6 membered heteroaryl or 9-10 membered heteroaryl,
wherein said 5-6 membered heteroaryl or 9-10 membered heteroaryl is optionally substituted by 1 or 2 substituents independently selected from hydroxyl, cyano, halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C2-C4)alkynyl, (C1- C4)alkoxy, 5-6 membered heterocycloalkyl-CO-, fused 5-6 membered
heterocycloalkyl, H2N-, (C1-C4)alkyl-NH-, ((C1-C4)alkyl)((C1-C4)alkyl)N-, -CONH2, H2NCO-(C1-C4)alkyl-, (C1-C4)alkylNHCO-, H2N(C1-C4)alkylNHCO-, (C1-C4)alkyl HN(C1-C4)alkylNHCO-, ((C1-C4)alkyl)((C1-C4)alkyl)N(C1-C4)alkylNHCO- (hydroxy-(C1-C4)alkyl)NHCO-, (C3-C6)cycloalkyl-NHCO-, 5-6 membered heterocycloalkyl-NHCO-, ((C1-C4)alkyl)((C1-C4)alkyl)N-CO-, (C1-C4)alkyl-CONH-, ((C1-C4)alkyl)((C1-C4)alkyl)N-NHCO-, -CO2H, -CO2(C1-C4)alkyl, (C1-C4)alkylthio-, phenyl-(C1-C4)alkylthio-, (C1-C4)alkyl-SO-, (C1-C4)alkyl-SO2-, phenyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl,
wherein said (C1-C4)alkoxy is optionally substituted by hydroxyl, -CO2H, -CONH2, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; or said 5-6 membered heterocycloalkyl-CO-, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl is optionally substituted by (C1-C4)alkyl or oxo; or said 5-6 membered heterocycloalkyl-NHCO- is optionally substituted by (C1- C4)alkyl-CO-;
R2 is phenyl or 5-6 membered heteroaryl,
wherein said phenyl or 5-6 membered heteroaryl is optionally substituted by one, two, or three substituents independently selected from halogen, (C1-C4)alkyl, -(C1- C4)alkyl-NH2, -(C1-C4)alkyl-NH(C1-C4)alkyl, -(C1-C4)alkyl-N-((C1-C4)alkyl)((C1- C4)alkyl), (C1-C4)alkoxy, and cyano; and
each R3 is independently selected from hydrogen, halogen, (C1-C4)alkyl, -(C2-C4)alkenyl, and or R1 and R3 taken together with the atoms to which they are attached, form a 5-6 membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by
(C1-C4)alkyl;
or any two R3 groups taken together with the atoms to which they are attached, form a 4-, 5-,
6-, or 7-membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; and
wherein at least one R3 is not hydrogen.
7. The compound, or a pharmaceutically acceptable salt thereof, according to claims 1-6, wherein:
R1 is furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl,
wherein said furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl is optionally substituted by 1 or 2 substituents independently selected from hydroxyl, cyano, halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C2-C4)alkynyl, (C1-C4)alkoxy, 5-6 membered heterocycloalkyl-CO-, fused 5-6 membered heterocycloalkyl; H2N-, (C1-C4)alkylNH-, ((C1-C4)alkyl)((C1- C4)alkyl)N-, -CONH2, H2NCO-(C1-C4)alkyl-, (C1-C4)alkylNHCO-, (hydroxy-(C1- C4)alkyl)NHCO-, (C3-C6)cycloalkyl-NHCO-, 5-6 membered heterocycloalkyl-NHCO-, ((C1- C4)alkyl)((C1-C4)alkyl)NCO-, (C1-C4)alkyl-CONH-, ((C1-C4)alkyl)((C1-C4)alkyl)N-NHCO-, -CO2H, -CO2(C1-C4)alkyl, (C1-C4)alkylthio-, phenyl-(C1-C4)alkylthio-, (C1-C4)alkyl-SO-, (C1-C4)alkyl-SO2-, phenyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein said (C1-C4)alkoxy is optionally substituted by hydroxyl, -CO2H, -CONH2, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; or said 5-6 membered heterocycloalkyl-CO-, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl is optionally substituted by (C1-C4)alkyl or oxo; or said 5-6 membered
heterocycloalkyl-NHCO- is optionally substituted by (C1-C4)alkyl-CO-.
8. The compound or a pharmaceutically acceptable salt thereof according to claims 1- 7, wherein:
R1 is oxadiazolyl, thiadiazolyl, or pyrimidinyl,
wherein said oxadiazolyl, thiadiazolyl, or pyrimidinyl is optionally substituted by one or two substituents independently selected from (C1-C4)alkyl, -CONH2, (C1-C4)alkylNHCO-, ((C1-C4)alkyl)((C1-C4)alkyl)NCO-, (C1-C4)alkyl-SO-, and (C1-C4)alkyl-SO2-.
9. The compound, or a pharmaceutically acceptable salt thereof, according to claims 1-7, wherein
R1 is oxadiazolyl, thiadiazolyl, or pyrimidinyl,
wherein said oxadiazolyl, thiadiazolyl, or pyrimidinyl is optionally substituted by one substituent independently selected from methyl, -CONH2, CH3NHCO-, (CH3)2NCO-, CH3- SO-, and CH3-SO2-.
10. The compound or pharmaceutically acceptable salt thereof according to claims 1- 7, wherein R1 is pyrimidinyl, wherein said pyrimidinyl is substituted once by -CONH2.
11. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-6 , wherein R2 is phenyl, wherein said phenyl is optionally substituted by two or three halogens.
12. The compound or pharmaceutically acceptable salt thereof according to claim 11, wherein R2 is phenyl, wherein said phenyl is substituted by two or three fluoros.
13. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-12, wherein each R3 is independently selected from hydrogen, halogen,
(C1-C4)alkyl, wherein at least one R3 is not hydrogen.
14. The compound or pharmaceutically acceptable salt thereof according to claim 13, wherein each R3 is independently selected from hydrogen, fluoro, or methyl, wherein at least one R3 is not hydrogen.
15. The compound or pharmaceutically acceptable salt thereof according to claims 1 and 4, wherein:
R1 is hydrogen, -(C2-C4)alkenyl, -(C2-C4)alkenyl-NH2, -(C1-C4)alkyl=NH, -NH2, or 5- 6 membered heteroaryl,
wherein said 5-6 membered heteroaryl is optionally substituted by 1 or 2 substituents selected from (C1-C4)alkyl, -CONH2, (C1-C4)alkylNHCO-, ((C1-C4)alkyl)((C1- C4)alkyl)NCO-, (C1-C4)alkyl-SO-, and (C1-C4)alkyl-SO2-;
R2 is phenyl, wherein said phenyl optionally substituted by one, two, or three halogens;
each R3 is independently selected from hydrogen, halogen, (C1-C4)alkyl, and -(C2- C4)alkenyl,
or R1 and R3 taken together with the atoms to which they are attached, form a 5-6 membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by
(C1-C4)alkyl;
or any two R3 groups taken together with the atoms to which they are attached, form a 4-, 5-, 6-, or 7-membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; and wherein at least one R3 is not hydrogen.
16. The compound according to claim 1 which is:
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((R)-3-methyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyridin-5-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((S)-3-methyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyridin-5-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((S)-3-methyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyridin-5-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((R)-3-methyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyridin-5-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((R)-2-methyl-4,5,6,7- tetrahydro-pyrazolo[1,5-a]pyridin-5-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((S)-2-methyl-4,5,6,7- tetrahydro-pyrazolo[1,5-a]pyridin-5-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((S)-2-methyl-4,5,6,7- tetrahydro-pyrazolo[1,5-a]pyridin-5-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((R)-2-methyl-4,5,6,7- tetrahydro-pyrazolo[1,5-a]pyridin-5-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((R)-1-methyl-5,6,7,8- tetrahydro-imidazo[1,5-a]pyridin-7-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((S)-1-methyl-5,6,7,8- tetrahydro-imidazo[1,5-a]pyridin-7-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((S)-1-methyl-5,6,7,8- tetrahydro-imidazo[1,5-a]pyridin-7-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((R)-1-methyl-5,6,7,8- tetrahydro-imidazo[1,5-a]pyridin-7-yl)methanone;
6-((1R,5S,6r)-6-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- azabicyclo[3.1.1]heptan-3-yl)pyrimidine-4-carboxamide;
6-((1R,5S,6r)-6-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)- 3-azabicyclo[3.1.1]heptan-3-yl)pyrimidine-4-carboxamide;
6-((1R,5S,6s)-6-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)- 3-azabicyclo[3.1.1]heptan-3-yl)pyrimidine-4-carboxamide; 6-((1R,5S,6s)-6-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- azabicyclo[3.1.1]heptan-3-yl)pyrimidine-4-carboxamide;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((1R,5S,6s)-3-(5-methyl- 1,3,4-oxadiazol-2-yl)-3-azabicyclo[3.1.1]heptan-6-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((1R,5S,6r)-3-(5-methyl- 1,3,4-oxadiazol-2-yl)-3-azabicyclo[3.1.1]heptan-6-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((1R,5S,6r)-3-(5-methyl- 1,3,4-oxadiazol-2-yl)-3-azabicyclo[3.1.1]heptan-6-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((1R,5S,6s)-3-(5-methyl- 1,3,4-oxadiazol-2-yl)-3-azabicyclo[3.1.1]heptan-6-yl)methanone;
6-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)-N-methylpyrimidine-4-carboxamide;
6-((3S,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)-N-methylpyrimidine-4-carboxamide;
6-((3S,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)-N-methylpyrimidine-4-carboxamide;
6-((3R,4S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)-N-methylpyrimidine-4-carboxamide;
6-((3S,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)-N,N-dimethylpyrimidine-4-carboxamide;
6-((3R,4S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)-N,N-dimethylpyrimidine-4-carboxamide;
6-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)-N,N-dimethylpyrimidine-4-carboxamide;
6-((3S,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)-N,N-dimethylpyrimidine-4-carboxamide;
(S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)-3-fluoro-1-(6- (methylsulfonyl)pyrimidin-4-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4R)-3-fluoro-1-(6- (methylsulfonyl)pyrimidin-4-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4R)-3-fluoro-1-(6- (methylsulfonyl)pyrimidin-4-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)-3-fluoro-1-(6- (methylsulfonyl)pyrimidin-4-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)-3-fluoro-1-(6-((S)- methylsulfinyl)pyrimidin-4-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4R)-3-fluoro-1-(6-((S)- methylsulfinyl)pyrimidin-4-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)-3-fluoro-1-(6-((R)- methylsulfinyl)pyrimidin-4-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4R)-3-fluoro-1-(6- ((R)-methylsulfinyl)pyrimidin-4-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4R)-3-fluoro-1-(6-((S)- methylsulfinyl)pyrimidin-4-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)-3-fluoro-1-(6-((S)- methylsulfinyl)pyrimidin-4-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4R)-3-fluoro-1-(6-((R)- methylsulfinyl)pyrimidin-4-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)-3-fluoro-1-(6- ((R)-methylsulfinyl)pyrimidin-4-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4R)-3-fluoro-1-(1,3,4- oxadiazol-2-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)-3-fluoro-1-(1,3,4- oxadiazol-2-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)-3-fluoro-1-(1,3,4- oxadiazol-2-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4R)-3-fluoro-1-(1,3,4- oxadiazol-2-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4R)-3-fluoro-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4R)-3-fluoro-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)-3-fluoro-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)-3-fluoro-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone; 6-((3R,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide;
6-((3S,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide;
6-((3S,4S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide;
6-((3R,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((2R,4R)-2-methyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((2R,4R)-2-methyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((2S,4S)-2-methyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((2S,4S)-2-methyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)-3-fluoro-1-(5- methyl-1,3,4-thiadiazol-2-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4R)-3-fluoro-1-(5- methyl-1,3,4-thiadiazol-2-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4R)-3-fluoro-1-(5- methyl-1,3,4-thiadiazol-2-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)-3-fluoro-1-(5- methyl-1,3,4-thiadiazol-2-yl)piperidin-4-yl)methanone;
6-((3R,4S)-3-fluoro-4-((S)-5-(2,3,5-trifluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)piperidin-1-yl)-N-methylpyrimidine-4-carboxamide;
6-((3S,4R)-3-fluoro-4-((R)-5-(2,3,5-trifluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)piperidin-1-yl)-N-methylpyrimidine-4-carboxamide;
6-((3S,4R)-3-fluoro-4-((S)-5-(2,3,5-trifluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)piperidin-1-yl)-N-methylpyrimidine-4-carboxamide;
6-((3R,4S)-3-fluoro-4-((R)-5-(2,3,5-trifluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)piperidin-1-yl)-N-methylpyrimidine-4-carboxamide;
6-((3R,4S)-3-fluoro-4-((S)-5-(2,3,5-trifluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)piperidin-1-yl)-N,N-dimethylpyrimidine-4-carboxamide;
6-((3S,4R)-3-fluoro-4-((R)-5-(2,3,5-trifluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)piperidin-1-yl)-N,N-dimethylpyrimidine-4-carboxamide;
6-((3S,4R)-3-fluoro-4-((S)-5-(2,3,5-trifluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)piperidin-1-yl)-N,N-dimethylpyrimidine-4-carboxamide;
6-((3R,4S)-3-fluoro-4-((R)-5-(2,3,5-trifluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)piperidin-1-yl)-N,N-dimethylpyrimidine-4-carboxamide;
((3S,4R)-3-fluoro-1-(6-((S)-methylsulfinyl)pyrimidin-4-yl)piperidin-4-yl)((S)-5- (2,3,5-trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((3R,4S)-3-fluoro-1-(6-((S)-methylsulfinyl)pyrimidin-4-yl)piperidin-4-yl)((R)-5- (2,3,5-trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((3S,4R)-3-fluoro-1-(6-((R)-methylsulfinyl)pyrimidin-4-yl)piperidin-4-yl)((S)-5- (2,3,5-trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((3R,4S)-3-fluoro-1-(6-((R)-methylsulfinyl)pyrimidin-4-yl)piperidin-4-yl)((R)-5- (2,3,5-trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((3R,4S)-3-fluoro-1-(6-((S)-methylsulfinyl)pyrimidin-4-yl)piperidin-4-yl)((S)-5- (2,3,5-trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((3S,4R)-3-fluoro-1-(6-((S)-methylsulfinyl)pyrimidin-4-yl)piperidin-4-yl)((R)-5- (2,3,5-trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((3R,4S)-3-fluoro-1-(6-((R)-methylsulfinyl)pyrimidin-4-yl)piperidin-4-yl)((S)-5- (2,3,5-trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((3S,4R)-3-fluoro-1-(6-((R)-methylsulfinyl)pyrimidin-4-yl)piperidin-4-yl)((R)-5- (2,3,5-trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((3R,4S)-3-fluoro-1-(6-(methylsulfonyl)pyrimidin-4-yl)piperidin-4-yl)((S)-5-(2,3,5- trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((3S,4R)-3-fluoro-1-(6-(methylsulfonyl)pyrimidin-4-yl)piperidin-4-yl)((R)-5-(2,3,5- trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((3S,4R)-3-fluoro-1-(6-(methylsulfonyl)pyrimidin-4-yl)piperidin-4-yl)((S)-5-(2,3,5- trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((3R,4S)-3-fluoro-1-(6-(methylsulfonyl)pyrimidin-4-yl)piperidin-4-yl)((R)-5-(2,3,5- trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((3R,4S)-3-fluoro-1-(1,3,4-oxadiazol-2-yl)piperidin-4-yl)((S)-5-(2,3,5- trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone; ((3S,4R)-3-fluoro-1-(1,3,4-oxadiazol-2-yl)piperidin-4-yl)((R)-5-(2,3,5- trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((3S,4R)-3-fluoro-1-(1,3,4-oxadiazol-2-yl)piperidin-4-yl)((S)-5-(2,3,5- trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((3R,4S)-3-fluoro-1-(1,3,4-oxadiazol-2-yl)piperidin-4-yl)((R)-5-(2,3,5- trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((3R,4S)-3-fluoro-1-(5-methyl-1,3,4-thiadiazol-2-yl)piperidin-4-yl)((S)-5-(2,3,5- trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((3S,4R)-3-fluoro-1-(5-methyl-1,3,4-thiadiazol-2-yl)piperidin-4-yl)((R)-5-(2,3,5- trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((3S,4R)-3-fluoro-1-(5-methyl-1,3,4-thiadiazol-2-yl)piperidin-4-yl)((S)-5-(2,3,5- trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((3R,4S)-3-fluoro-1-(5-methyl-1,3,4-thiadiazol-2-yl)piperidin-4-yl)((R)-5-(2,3,5- trifluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((R)-3,3-dimethyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((S)-3,3-dimethyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((R)-3,3-dimethyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((S)-3,3-dimethyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((R)-3,3-difluoro-1-(5-methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)((R)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((S)-3,3-difluoro-1-(5-methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)((S)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((R)-3,3-difluoro-1-(5-methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)((S)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((S)-3,3-difluoro-1-(5-methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)((R)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((R)-3,3-dimethyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((R)-3,3-dimethyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((S)-3,3-dimethyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((S)-3,3-dimethyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4R)-3-fluoro-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4R)-3-fluoro-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4R)-3-methyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4S)-3-methyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4S)-3-methyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4R)-3-methyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4R)-3-methyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)-3-methyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4R)-3-methyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)-3-methyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
6-((3R,4S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- methylpiperidin-1-yl)pyrimidine-4-carboxamide;
6-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- methylpiperidin-1-yl)pyrimidine-4-carboxamide;
6-((3S,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- methylpiperidin-1-yl)pyrimidine-4-carboxamide;
6-((3S,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- methylpiperidin-1-yl)pyrimidine-4-carboxamide; 6-((3S,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- methylpiperidin-1-yl)pyrimidine-4-carboxamide;
6-((3R,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- methylpiperidin-1-yl)pyrimidine-4-carboxamide;
6-((3R,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- methylpiperidin-1-yl)pyrimidine-4-carboxamide;
6-((3S,4S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- methylpiperidin-1-yl)pyrimidine-4-carboxamide;
6-((2R,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-2- methylpiperidin-1-yl)pyrimidine-4-carboxamide;
6-((2R,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-2- methylpiperidin-1-yl)pyrimidine-4-carboxamide;
6-((2S,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-2- methylpiperidin-1-yl)pyrimidine-4-carboxamide;
6-((2S,4S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-2- methylpiperidin-1-yl)pyrimidine-4-carboxamide;
6-((3S,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide;
6-((3S,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide;
6-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide;
6-((3R,4S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide;
6-((S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3,3- dimethylpiperidin-1-yl)pyrimidine-4-carboxamide;
6-((R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3,3- dimethylpiperidin-1-yl)pyrimidine-4-carboxamide;
6-((S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3,3- dimethylpiperidin-1-yl)pyrimidine-4-carboxamide;
6-((R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3,3- dimethylpiperidin-1-yl)pyrimidine-4-carboxamide;
6-((R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3,3- difluoropiperidin-1-yl)pyrimidine-4-carboxamide;
6-((R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3,3- difluoropiperidin-1-yl)pyrimidine-4-carboxamide;
6-((S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3,3- difluoropiperidin-1-yl)pyrimidine-4-carboxamide;
6-((S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3,3- difluoropiperidin-1-yl)pyrimidine-4-carboxamide;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((R)-2,2-dimethyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((S)-2,2-dimethyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((R)-2,2-dimethyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((S)-2,2-dimethyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone;
6-((R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-2,2- dimethylpiperidin-1-yl)pyrimidine-4-carboxamide;
6-((S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-2,2- dimethylpiperidin-1-yl)pyrimidine-4-carboxamide;
6-((R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-2,2- dimethylpiperidin-1-yl)pyrimidine-4-carboxamide; and
6-((S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-2,2- dimethylpiperidin-1-yl)pyrimidine-4-carboxamide;
or a pharmaceutically acceptable salt thereof.
17. The compound according to claim 4 which is:
2-((3S,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)thiazole-5-carbonitrile;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3S,4R)-3-fluoro-1-(3- methyl-1,2,4-thiadiazol-5-yl)piperidin-4-yl)methanone;
((3S,4R)-1-(6-chloro-5-fluoropyrimidin-4-yl)-3-fluoropiperidin-4-yl)((S)-5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone’ 6-((3S,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)picolinamide;
2-((3S,4R)-3-fluoro-4-((S)-5-(5-fluoropyridin-3-yl)-4,5-dihydro-1H-pyrazole-1- carbonyl)piperidin-1-yl)thiazole-5-carbonitrile;
6-((3S,4R)-3-fluoro-4-((S)-5-(5-fluoropyridin-3-yl)-4,5-dihydro-1H-pyrazole-1- carbonyl)piperidin-1-yl)pyrimidine-4-carboxamide;
6-((3S,4R)-3-fluoro-4-((S)-5-(2-fluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)piperidin-1-yl)pyrimidine-4-carboxamide;
6-((3S,4R)-3-fluoro-4-((R)-5-(2-fluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)piperidin-1-yl)pyrimidine-4-carboxamide;
6-((3S,4R)-3-fluoro-4-((R)-5-(3-fluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)piperidin-1-yl)pyrimidine-4-carboxamide;
6-((3S,4R)-3-fluoro-4-((S)-5-(3-fluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)piperidin-1-yl)pyrimidine-4-carboxamide;
6-((3S,4R)-4-((R)-5-(2,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide;
6-((3S,4R)-4-((S)-5-(2,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide;
2-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)thiazole-5-carbonitrile;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)-3-fluoro-1-(3- methyl-1,2,4-thiadiazol-5-yl)piperidin-4-yl)methanone;
6-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)picolinamide;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)-3-fluoro-1-(1,3,4- thiadiazol-2-yl)piperidin-4-yl)methanone;
2-((3R,4S)-3-fluoro-4-((S)-5-(5-fluoropyridin-3-yl)-4,5-dihydro-1H-pyrazole-1- carbonyl)piperidin-1-yl)thiazole-5-carbonitrile;
6-((3R,4S)-3-fluoro-4-((S)-5-(5-fluoropyridin-3-yl)-4,5-dihydro-1H-pyrazole-1- carbonyl)piperidin-1-yl)pyrimidine-4-carboxamide;
6-((3R,4S)-3-fluoro-4-((S)-5-(2-fluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)piperidin-1-yl)pyrimidine-4-carboxamide;
6-((3R,4S)-3-fluoro-4-((R)-5-(2-fluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)piperidin-1-yl)pyrimidine-4-carboxamide;
6-((3R,4S)-3-fluoro-4-((S)-5-(3-fluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)piperidin-1-yl)pyrimidine-4-carboxamide;
6-((3R,4S)-3-fluoro-4-((R)-5-(3-fluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)piperidin-1-yl)pyrimidine-4-carboxamide;
6-((3R,4S)-4-((S)-5-(2,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide;
6-((3R,4S)-4-((R)-5-(2,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide;
6-((3R,4S)-4-((S)-5-(3-cyano-5-fluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide;
6-((3R,4S)-4-((R)-5-(3-cyano-5-fluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide;
6-((3R,4S)-4-((S)-5-(3-(aminomethyl)-5-fluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide;
6-((3R,4S)-4-((R)-5-(3-(aminomethyl)-5-fluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide;
N-(2-aminoethyl)-6-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H- pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide;
N-(2-aminoethyl)-6-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H- pyrazole-1-carbonyl)-3-fluoropiperidin-1-yl)pyrimidine-4-carboxamide;
(R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-1- methylpiperidin-2-one;
(S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-1- methylpiperidin-2-one;
(S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-1- methylpiperidin-2-one;
(R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-1- methylpiperidin-2-one;
((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((3R,4S)-3-fluoro-1-(1,2,4- oxadiazol-3-yl)piperidin-4-yl)methanone;
or pharmaceutically acceptable salts thereof.
18. A compound of the formula:
Figure imgf000267_0001
, which is 6-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof.
19. A compound of the formula:
Figure imgf000267_0002
, which is 6-((3S,4R)-4-((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- fluoropiperidin-1-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof.
20. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof according to any one of claims 1-19 and a pharmaceutically acceptable excipient.
21. The pharmaceutical composition according to claim 20, which further comprises at least one other therapeutically active agent.
22. A method of treating a RIP1-mediated disease or disorder in a human in need thereof comprising administering to the human a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1-19 or the pharmaceutical composition according to claim 20 or 21.
23. The method according claim 22, wherein the disease or disorder is amyotrophic lateral sclerosis.
24. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-19 for use in therapy.
25. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-19 for the use in the treatment of amyotrophic lateral sclerosis.
26. Use of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1-19.
27. Use of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1-19 in the manufacture of a medicament for use in the treatment of a RIP1 kinase-mediated disease or disorder.
28. The use according to claim 27 wherein the disease or disorder is amyotrophic lateral sclerosis.
PCT/IB2019/054286 2018-05-23 2019-05-23 Heterocyclic amides as rip1 kinase inhibitors Ceased WO2019224773A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2018088083 2018-05-23
CNPCT/CN2018/088083 2018-05-23

Publications (1)

Publication Number Publication Date
WO2019224773A1 true WO2019224773A1 (en) 2019-11-28

Family

ID=67226306

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2019/054286 Ceased WO2019224773A1 (en) 2018-05-23 2019-05-23 Heterocyclic amides as rip1 kinase inhibitors

Country Status (1)

Country Link
WO (1) WO2019224773A1 (en)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110922354A (en) * 2019-12-12 2020-03-27 丽水绿氟科技有限公司 Chemical resolution preparation method of 1-R-3-fluoropiperidine-4-carboxylic acid and product thereof
WO2020224656A1 (en) * 2019-05-09 2020-11-12 劲方医药科技(上海)有限公司 Bisheterocyclic carbonyl substituted dihydropyrazole compound, preparation method therefor and pharmaceutical use thereof
WO2021233394A1 (en) * 2020-05-20 2021-11-25 Sironax Ltd. Receptor-interacting protein 1 inhibitors including piperazine heterocyclic amide ureas
WO2021233397A1 (en) 2020-05-20 2021-11-25 Sironax Ltd. Piperazine cyclic ureas
WO2021233396A1 (en) * 2020-05-20 2021-11-25 Sironax Ltd. Azetidine cyclic ureas
WO2022242581A1 (en) * 2021-05-20 2022-11-24 Sironax Ltd. Rip1 modulators including azetidine cyclic ureas, preparations, and uses thereof
JP2022550099A (en) * 2019-09-27 2022-11-30 ボード オブ レジェンツ，ザ ユニバーシティ オブ テキサス システム Inhibitors of receptor-interacting protein kinase I for the treatment of diseases - Patents.com
WO2023131116A1 (en) * 2022-01-04 2023-07-13 北京赛特明强医药科技有限公司 Carbonyl bridged heterocyclic compound, and composition and application thereof
JP2023550609A (en) * 2020-11-11 2023-12-04 ジェネンテック， インコーポレイテッド 1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)acetyl)-4-hydroxypyrrolidine-2-carboxamide derivatives as VHL inhibitors for the treatment of anemia
WO2024102754A3 (en) * 2022-11-07 2024-06-27 Humanwell Pharmacuetical Us, Inc. Somatostatin receptor subtype 4 (sstr4) agonists and their applications
EP4200281A4 (en) * 2020-08-18 2024-09-25 Hutchison Medipharma Limited PYRIMIDINONE COMPOUNDS AND USES THEREOF
WO2025185732A1 (en) * 2024-03-08 2025-09-12 山东全重生物医药科技有限公司 Ripk1 inhibitor and preparation method therefor and pharmaceutical use thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014125444A1 (en) 2013-02-15 2014-08-21 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides as kinase inhibitors
WO2016185423A1 (en) * 2015-05-19 2016-11-24 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides as kinase inhibitors
WO2018092089A1 (en) * 2016-11-18 2018-05-24 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides as kinase inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014125444A1 (en) 2013-02-15 2014-08-21 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides as kinase inhibitors
WO2016185423A1 (en) * 2015-05-19 2016-11-24 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides as kinase inhibitors
WO2018092089A1 (en) * 2016-11-18 2018-05-24 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides as kinase inhibitors

Non-Patent Citations (48)

* Cited by examiner, † Cited by third party
Title
"Handbook of Pharmaceutical Salts; Properties, Selection and Use", 2011, WILEY- VCH/VHCA
BERGE, J. PHARM. SCI., vol. 66, 1977, pages 1 - 19
BERGER ET AL., JOURNAL OF IMMUNOLOGY, vol. 192, no. 12, 2014, pages 5476 - 5480
CELL DEATH DIS., vol. 2, 2011, pages 15
CELL HOST & MICROBE, vol. 15, 2014, pages 23 - 35
CELL SIGNAL., vol. 27, no. 2, 2015, pages 306 - 314
CELL, vol. 114, 2003, pages 181 - 190
CELL, vol. 148, 2012, pages 228 - 243
CELL, vol. 153, 2013, pages 1 - 14
CELL, vol. 81, 1995, pages 513 - 523
CHEN., INTERNATIONAL JOURNAL OF ENDOCRINOLOGY, 2015
CURR. BIOL., vol. 9, 1999, pages 539 - 542
EMBO REP., vol. 10, 2009, pages 916 - 922
FEBS J, vol. 278, 2012, pages 877 - 887
GAUCHER DISEASE, NATURE MEDICINE ADVANCE ONLINE PUBLICATION, 19 January 2014 (2014-01-19)
GENES DEV., vol. 27, 2013, pages 1640 - 1649
IMMUNITY, vol. 4, 1996, pages 387 - 396
IMMUNITY, vol. 7, 1997, pages 821 - 830
J. BIOL. CHEM., vol. 274, 1999, pages 16871 - 16875
J. BIOL. CHEM., vol. 279, 2004, pages 7925 - 7933
J. BIOL. CHEM., vol. 280, 2005, pages 36560 - 6566
J. MED. CHEM., vol. 60, 2017, pages 1247 - 1261
J. MOL. BIOL., vol. 396, 2010, pages 528 - 539
J. NEUROSCI. RES., vol. 88, 2010, pages 1569 - 1576
KIDNEY INT., vol. 81, 2012, pages 751 - 761
L. DUPREZ ET AL., IMMUNITY, vol. 35, no. 6, 2011, pages 908 - 918
MOL. CELL, vol. 22, 2006, pages 245 - 257
NAT IMMUNOL., vol. 5, 2004, pages 503 - 507
NAT. CHEM. BIOL., vol. 1, 2005, pages 112 - 119
NAT. IMMUNOL., vol. 5, 2004, pages 503 - 507
NAT. IMMUNOL., vol. 9, 2008, pages 1037 - 1046
NAT. REV. IMMUNOL., vol. 8, 2008, pages 279 - 289
NATURE, vol. 477, 2011, pages 330 - 334
NEUROCHEM. RES., vol. 37, 2012, pages 1849 - 1858
OFENGEIM ET AL., CELL REPORTS, vol. 10, no. 11, 2015, pages 1836 - 1849
PHILIP A. HARRIS ET AL: "Discovery and Lead-Optimization of 4,5-Dihydropyrazoles as Mono-Kinase Selective, Orally Bioavailable and Efficacious Inhibitors of Receptor Interacting Protein 1 (RIP1) Kinase", JOURNAL OF MEDICINAL CHEMISTRY, vol. 62, no. 10, 23 April 2019 (2019-04-23), pages 5096 - 5110, XP055616358, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.9b00318 *
PNAS, vol. 107, 2010, pages 21695 - 21700
PROC. NATL. ACAD. SCI. USA., vol. 105, 2008, pages 11778 - 11783
PROC. NATL. ACAD. SCI. USA., vol. 109, 2012, pages 5322 - 5327
PROC. NATL. ACAD. SCI., vol. 109, no. 36, 2012, pages 14598 - 14603
REN. FAIL., vol. 34, 2012, pages 373 - 377
S. HE ET AL., CELL, vol. 137, no. 6, 2009, pages 1100 - 1111
SCI. SIGNAL., vol. 115, 2010, pages re4
STAGAKIS ET AL., ARTHRITIS RESEARCH & THERAPY, 2012
T. GREENEP. WUTS: "Protecting Groups in Chemical Synthesis", 1999, JOHN WILEY & SONS
T.W. GREENP.G.M. WUTS: "The Handbook of Pharmaceutical Excipients", 1991, THE AMERICAN PHARMACEUTICAL ASSOCIATION AND THE PHARMACEUTICAL PRESS
TRENDS BIOCHEM. SCI., vol. 30, 2005, pages 151 - 159
Y. MURAKAMI ET AL., PNAS, vol. 109, no. 36, 2012, pages 14598 - 14603

Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3967682A4 (en) * 2019-05-09 2023-01-11 Genfleet Therapeutics (Shanghai) Inc. Bisheterocyclic carbonyl substituted dihydropyrazole compound, preparation method therefor and pharmaceutical use thereof
WO2020224656A1 (en) * 2019-05-09 2020-11-12 劲方医药科技(上海)有限公司 Bisheterocyclic carbonyl substituted dihydropyrazole compound, preparation method therefor and pharmaceutical use thereof
CN113767092B (en) * 2019-05-09 2024-07-16 劲方医药科技(上海)有限公司 Di-heterocyclic carbonyl substituted dihydropyrazoles, their preparation and their use in medicine
JP7367062B2 (en) 2019-05-09 2023-10-23 ▲勁▼方医▲薬▼科技（上海）有限公司 Bisheterocyclic carbonyl-substituted dihydropyrazole compounds, methods of preparation thereof, and pharmaceutical uses thereof
CN113767092A (en) * 2019-05-09 2021-12-07 劲方医药科技(上海)有限公司 Bi-heterocyclic carbonyl-substituted dihydropyrazole compounds, preparation method and medical use thereof
JP2022533572A (en) * 2019-05-09 2022-07-25 ジェンフリート セラピューティクス（シャンハイ）インコーポレイテッド Bis-heterocyclic carbonyl-substituted dihydropyrazole compounds, processes for their preparation, and pharmaceutical uses thereof
US20220235032A1 (en) * 2019-05-09 2022-07-28 Genfleet Therapeutics (Shanghai) Inc. Bisheterocyclic carbonyl substituted dihydropyrazole compound, preparation method therefor and pharmaceutical use thereof
AU2020268933B2 (en) * 2019-05-09 2022-12-22 Genfleet Therapeutics (Shanghai) Inc. Bisheterocyclic carbonyl substituted dihydropyrazole compound, preparation method therefor and pharmaceutical use thereof
EP4034530A4 (en) * 2019-09-27 2023-09-06 Board of Regents, The University of Texas System INHIBITORS OF RECEPTOR INTERACTING PROTEIN KINASE I FOR THE TREATMENT OF DISEASES
JP2022550099A (en) * 2019-09-27 2022-11-30 ボード オブ レジェンツ，ザ ユニバーシティ オブ テキサス システム Inhibitors of receptor-interacting protein kinase I for the treatment of diseases - Patents.com
CN110922354A (en) * 2019-12-12 2020-03-27 丽水绿氟科技有限公司 Chemical resolution preparation method of 1-R-3-fluoropiperidine-4-carboxylic acid and product thereof
JP2023526841A (en) * 2020-05-20 2023-06-23 シロナックス リミテッド． piperazine cyclic ureas
JP7764398B2 (en) 2020-05-20 2025-11-05 シロナックス リミテッド． Azetidine cyclic ureas
CN115697972A (en) * 2020-05-20 2023-02-03 维泰瑞隆有限公司 Receptor-interacting protein 1 inhibitors including piperazine heterocyclic amide ureas
JP2023526839A (en) * 2020-05-20 2023-06-23 シロナックス リミテッド． Azetidine cyclic ureas
JP2023526840A (en) * 2020-05-20 2023-06-23 シロナックス リミテッド． Receptor-Coupling Protein 1 Inhibitors Containing Piperazine Heterocyclic Amidoureas
CN115697991B (en) * 2020-05-20 2024-11-22 维泰瑞隆有限公司 Piperazine Cyclic Urea
JP7774579B2 (en) 2020-05-20 2025-11-21 シロナックス リミテッド． Receptor-Coupled Protein 1 Inhibitors Containing Piperazine Heterocyclic Amidoureas
JP7760530B2 (en) 2020-05-20 2025-10-27 シロナックス リミテッド． Piperazine Cyclic Ureas
WO2021233396A1 (en) * 2020-05-20 2021-11-25 Sironax Ltd. Azetidine cyclic ureas
WO2021233397A1 (en) 2020-05-20 2021-11-25 Sironax Ltd. Piperazine cyclic ureas
WO2021233394A1 (en) * 2020-05-20 2021-11-25 Sironax Ltd. Receptor-interacting protein 1 inhibitors including piperazine heterocyclic amide ureas
CN115697991A (en) * 2020-05-20 2023-02-03 维泰瑞隆有限公司 Piperazine cyclic ureas
US12454529B2 (en) 2020-05-20 2025-10-28 Sironax Ltd. Piperazine cyclic ureas
EP4200281A4 (en) * 2020-08-18 2024-09-25 Hutchison Medipharma Limited PYRIMIDINONE COMPOUNDS AND USES THEREOF
JP2023550609A (en) * 2020-11-11 2023-12-04 ジェネンテック， インコーポレイテッド 1-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)acetyl)-4-hydroxypyrrolidine-2-carboxamide derivatives as VHL inhibitors for the treatment of anemia
WO2022242581A1 (en) * 2021-05-20 2022-11-24 Sironax Ltd. Rip1 modulators including azetidine cyclic ureas, preparations, and uses thereof
TWI827429B (en) * 2022-01-04 2023-12-21 大陸商北京賽特明強醫藥科技有限公司 Carbonyl bridged heterocyclic compounds, compositions and applications thereof
JP2025501347A (en) * 2022-01-04 2025-01-17 北京賽特明強医薬科技有限公司 Carbonyl-bridged heterocyclic compounds, and compositions and uses thereof
CN116496256A (en) * 2022-01-04 2023-07-28 北京赛特明强医药科技有限公司 Carbonyl bridged heterocyclic compound, and composition and application thereof
WO2023131116A1 (en) * 2022-01-04 2023-07-13 北京赛特明强医药科技有限公司 Carbonyl bridged heterocyclic compound, and composition and application thereof
WO2024102754A3 (en) * 2022-11-07 2024-06-27 Humanwell Pharmacuetical Us, Inc. Somatostatin receptor subtype 4 (sstr4) agonists and their applications
WO2025185732A1 (en) * 2024-03-08 2025-09-12 山东全重生物医药科技有限公司 Ripk1 inhibitor and preparation method therefor and pharmaceutical use thereof

Similar Documents

Publication Publication Date Title
WO2019224773A1 (en) Heterocyclic amides as rip1 kinase inhibitors
US20190345138A1 (en) Heterocyclic amides as kinase inhibitors
JP7187729B2 (en) RIP1 inhibitor compounds and methods for making and using same
JP7760493B2 (en) RIP1 inhibitor compounds and methods for making and using same
US20230120185A1 (en) Heterocyclic amides as kinase inhibitors
KR102849047B1 (en) Pyrrolopyrimidine ITK inhibitors
JP7644023B2 (en) Phosphatidylinositol 3-kinase inhibitors
JP6385954B2 (en) Compounds and methods for kinase regulation and indications thereof
CA2948589C (en) 5-chloro-2-difluoromethoxyphenyl pyrazolopyrimidine compounds which are jak inhibitors
US20230192676A1 (en) Heterocyclic Amides as Kinase Inhibitors
TWI603977B (en) Compounds and compositions as kinase inhibitors
KR20200108301A (en) Benzamide compound
CN107108637A (en) Triazolopyrimidine compound and application thereof
PH12015502055B1 (en) Compounds and pharmaceutical compositions thereof for the treatment of inflammatory disorders
JP2023501399A (en) Heterocyclic RIP1 inhibitor compounds
US20160272635A1 (en) Substituted dihydropyrido[3,4-b]pyrazinones as dual inhibitors of bet proteins and polo-like kinases
AU2017227900A1 (en) Novel compounds and pharmaceutical compositions thereof for the treatment of fibrosis
JP2017503834A (en) Benzimidazole derivatives and pharmaceutical compositions thereof for the treatment of inflammatory diseases
CA3145864A1 (en) Tyrosine kinase non-receptor 1 (tnk1) inhibitors and uses thereof
WO2019224774A1 (en) Heterocyclic amides as rip1 kinase inhibitors
AU2017324281A1 (en) 8-(azetidin-1-yl)-[1,2,4]triazolo[1,5-A]pyridinyl compounds, compositions and methods of use thereof
EP3452464A1 (en) Pyrazole derivatives, compositions and therapeutic use thereof
JP2018507236A (en) Triazolopyridine compounds and methods of use thereof
JP2025539086A (en) Pyridone and pyrimidinone inhibitors of hematopoietic progenitor cell kinase 1

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19737885

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19737885

Country of ref document: EP

Kind code of ref document: A1