WO2014145023A1 - 1,2,4-triazol-5-ones and analogs exhibiting anti-cancer and anti-proliferative activities - Google Patents

1,2,4-triazol-5-ones and analogs exhibiting anti-cancer and anti-proliferative activities Download PDF

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Publication number
WO2014145023A1
WO2014145023A1 PCT/US2014/029659 US2014029659W WO2014145023A1 WO 2014145023 A1 WO2014145023 A1 WO 2014145023A1 US 2014029659 W US2014029659 W US 2014029659W WO 2014145023 A1 WO2014145023 A1 WO 2014145023A1
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Prior art keywords
pyridin
methyl
oxy
triazol
mmol
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PCT/US2014/029659
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French (fr)
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Gary E. L. BRANDT
Hanumaiah TELIKEPALLI
Timothy Malcolm CALDWELL
Thiwanka SAMARAKOON
Daniel L. Flynn
Michael D. Kaufman
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Deciphera Pharmaceuticals, Llc
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Publication of WO2014145023A1 publication Critical patent/WO2014145023A1/en

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    • 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
    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings

Definitions

  • CSF-IR c-FMS
  • c-KIT c-KIT
  • PDGFR PDGFR kinases
  • Kinases represent a protein family that play critical roles in mammalian cell function, including cell proliferation, survival, motility, response to growth factors, and secretion of cytokines and other proinflammatory, proangiogenic, and immunomodulatory substances.
  • cytokines and other proinflammatory, proangiogenic, and immunomodulatory substances.
  • Imatinib is a marketed kinase inhibitor for the treatment of the cancer chronic myelogenous leukemia (CML, Druker, B.J. et al, New England Journal of Medicine (2001) 344: 1031) and for the treatment of gastrointestinal stromal tumors (GIST, Demetri, G.D., et al, New England Journal of Medicine (2002) 347: 472).
  • Imatinib has also shown benefit in cancer patients co-presenting with autoimmune diseases such as rheumatoid arthritis (Ihara, M.K. et al, Clinical Rheumatology (2003) 22: 362; Eklund, K.K.
  • the kinases inhibited by imatinib which confer its efficacy in the treatment of CML and GIST are BCR-ABL kinase and c-KIT kinase, respectively. Beyond these two kinases, other kinases inhibited by imatinib include c-FMS, PDGFR- ⁇ / ⁇ , and FOGFR-beta (Dewer, A.L. et al, Blood (2005) 105: 3127; Fabian, M.A. et al, Nature Biotechnology (2005) 23: 329.
  • c-FMS kinase to be associated with activation of synovial macrophages
  • PDGFR kinase to be associated with activation of fibroblast-like synoviocytes
  • c-KIT kinase to be associated with activation of mast cells
  • c-FMS kinase has also been associated with the proliferation and differentiation of monocytes into macrophages and osteoclasts, which are recruited to mediate joint damage in rheumatoid arthritis (Paniagua, R.T.
  • TAMs tumor-associated macrophages
  • TAMs are known to express c-FMS receptor tyrosine kinase (also known as CSF-1R) on their surfaces and to rely on signaling through this kinase by binding to the activating ligands CSF- 1 (also known as macrophase colony stimulating factor, or MCSF) and interleukin-34 (IL-34).
  • CSF- 1 also known as macrophase colony stimulating factor, or MCSF
  • IL-34 interleukin-34
  • Activation of this c-FMS/MCSF (CSFl -R/CSF-1) signaling axis stimulates monocyte proliferation, differentiation into tumor associated macrophages, and promotion of macrophage cell survival.
  • c-FMS kinase activation is associated with tumor cell migration, invasion, and metastasis (J.
  • MCSF-mediated activation of both LYVE-1+ and LYVE1- macrophages also mediates pathological angiogenesis and lymphangiogenesis in murine models of cancer, and blockade of c-FMS signaling resulted in suppression of tumor angiogenesis/lymphangiogenesis (Y. Kubota et al., Journal of Experimental Medicine (2009) 206: 1089).
  • Administration of a CSF-1R inhibitor blocked the recruitment of bone marrow derived TAMs and also bone marrow derived monocytic myeloid-derived suppressor cells (MDSCs) to tumor sites; this blockade led to a significant decrease in tumor angiogenesis and when combined with anti-VEGFR-2 therapy synergistically suppressed tumor growth (S.J.
  • CSF- 1R blockade has also been shown to reverse immuno tolerance mechanisms in an immunocompetent murine breast cancer model and promote the appearance of anti-tumor immune programs by upregulating CD8+ T-cell-mediated tumor suppression.
  • Restoration of an anti-tumor immune program was mechanistically linked to c-FMS inhibitor blockade of TAM-mediated Programmed Death Ligand-1 (PDL- 1) immunotolerance (D. G. DeNardo, et al. Cancer Discovery (201 1) 1 : OF52).
  • PDL- 1 TAM-mediated Programmed Death Ligand-1
  • small molecule inhibitors of c-FMS kinase, c-KIT kinase, or PDGFR kinases provide a rational approach to new therapies for the treatment of autoimmune diseases, and to particularly block the chronic tissue destruction mediated by the innate immune system.
  • Inhibition of c-FMS kinase also provides a rational approach to new therapies for the treatment of cancers, especially for the treatment of cancer invasiveness, cancer angiogenesis or vasculogenesis, cancer metastasis, cancer immunotolerance, and for the treatment of cancers prone to bone metastases.
  • kinase inhibitors which selectively inhibit kinases causative of the chronic tissue destruction in autoimmune disease (c-FMS, c-KIT, PDGFR), without inhibiting other kinases targeted by marketed cancer therapeutics (ABL, BCR-ABL, KDR, SRC, LCK, LYN, FGFR and other kinases).
  • the present invention discloses novel inhibitors that inhibit c-FMS, c-KIT, and/or PDGFR kinases for the treatment of autoimmune diseases which also exhibit selectivity by not potently inhibiting other kinases including ABL, BCR-ABL, KDR, SRC, LCK, LYN, FGFR, MET and other kinases.
  • the inhibitors of the present invention also find utility in the treatment of other mammalian diseases, including human diseases, mediated by c-FMS, c-KIT, or PDGFR kinases.
  • Such diseases include, without limitation, cancers, autoimmune diseases, and bone resorptive diseases.
  • A is selected from the group consisting of C1-C6 alkyl, branched C3-C8 alkyl, fluoroCl- C6alkyl wherein the alkyl is fully or partially fluorinated, C3-C8carbocyclyl, phenyl, 4-8 membered heterocyclic ring and heteroaryl, wherein each A moiety may be further substituted with one, two, or three R3 moieties;
  • W is C5-C6heteroaryl, phenyl, -NHC(0)R6, -NHC(0)R7, -NHC(0)N(R8)R9 or - C(0)N(R8)R9, and wherein each C5-C6heteroaryl or phenyl is optionally substituted by one, two, or three R5 moieties;
  • Ql is CH or ;
  • XI and X2 are individually and independently hydrogen or C1-C6 alkyl
  • Y is NR4 or O
  • Z is N or CR11 ;
  • R4 is hydrogen, C1-C6 alkyl, deutero-Cl-C6 alkyl wherein the alkyl chain is partially or completely deuterated, or branched C3-C8 alkyl;
  • each R5 is individually and independently hydrogen, C1-C6 alkyl, deutero-Cl-C6 alkyl wherein the alkyl chain is partially or completely deuterated, branched C3-C8 alkyl, halogen, cyano, fluoro-Cl-C6 alkyl wherein the alkyl chain is partially or completely fluorinated, - (CH 2 ) m -C(0)NR8(R9), -(CH 2 ) m -C(0)R7, -(CH 2 ) m -OR8, -(CH 2 ) m -NR8(R9), or -(CH 2 ) m -R7, wherein each alkylene is optionally substituted with C 1 -C4 alkyl;
  • each R6 is individually and independently hydrogen, C1-C6 alkyl, branched C3-C8 alkyl, C3-C8 cycloalkyl, -(CH 2 ) m -CN, -(CH 2 ) m -OR8, -(CH 2 ) m -NR8(R9), or -(CH 2 ) m -R7, wherein each alkylene is optionally substituted with C 1 -C4 alkyl;
  • each R7 is independently and individually selected from the group consisting of
  • each alkylene is optionally substituted with C 1 -C4 alkyl
  • Rl 1 is hydrogen, C1-C6 alkyl, deutero-Cl-C6 alkyl wherein the alkyl chain is partially or completely deuterated, or branched C3-C8 alkyl; each m is individually and independently 0, 1 , 2, or 3;
  • each n is individually and independently 0, 1 , 2, or 3;
  • each p is 0, 1 , 2, or 3;
  • each q is 0, 1 , or 2.
  • Y is NR4 or O.
  • Y is NR4.
  • Y is O.
  • Z is N or CR1 1.
  • Z is N.
  • Z is CR1 1.
  • W is C5-C6heteroaryl optionally substituted by one, two, or three R5.
  • W is -NHC(0)R6, -NHC(0)R7, or - NHC(0)N(R8)R9.
  • W is -NHC(0)R6. [0022] In one embodiment of Formula I, W is -NHC(0)R7. [0023] In one embodiment of Formula I, W is -NHC(0)N(R8)R9. [0024] In one embodiment of Formula I, W is - C(0)N(R8)R9.
  • W is phenyl optionally substituted by one, two, or three R5.
  • XI and X2 are individually and independently hydrogen or C 1 -C6 alkyl.
  • XI and X2 are hydrogen.
  • one of XI and X2 is hydrogen and the other is Cl- C6alkyl.
  • A is taken from the group consisting of C1 -C6 alkyl, branched C3-C8alkyl, fluoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, C3-C8carbocyclyl, phenyl, a 4-8 membered heterocyclic ring and heteroaryl; and wherein each A moiety may be further substituted with one, two, or three R3 moieties.
  • each Rl and R2 is individually and independently hydrogen, C1 -C6 alkyl, deutero-Cl-C6 alkyl wherein the alkyl chain is partially or completely deuterated, fiuoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, hydroxyl, C1-C6 alkoxy, fiuoroC 1 -C6alkoxy wherein the alkyl group is fully or partially fluorinated, or halogen.
  • each Rl is hydrogen.
  • each Rl and R2 is hydrogen.
  • each R3 is individually and independently hydrogen, halogen, C1 -C6 alkyl, fluoro-Cl-C6 alkyl wherein the alkyl chain is partially or completely fluorinated, branched C3-C8 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, fluoro-Cl-C6 alkoxy wherein the alkyl chain is partially or completely fluorinated, branched C3-C6 alkoxy, hydroxyl, or cyano.
  • q is 0, 1 , or 2.
  • q is 1.
  • q is 2.
  • n is 0, 1 , or 2.
  • n 0.
  • n 1
  • n is 2.
  • the compound of Formula I is a compound of Formula la wherein: W is C5-C6heteroaryl, phenyl, -NHC(0)R6, -NHC(0)R7, -NHC(0)N(R8)R9 or - C(0)N(R8)R9, and wherein each C5-C6heteroaryl or phenyl is optionally substituted by one, two, or three R5 moieties; or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.
  • W is C5-C6heteroaryl optionally substituted by one, two, or three R5.
  • W is pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, triazolyl, or pyridinyl and wherein each W is optionally substituted by one, two, or three R5.
  • W is pyrazolyl optionally substituted by one, two, or three R5.
  • W is imidazolyl optionally substituted by one, two, or three R5.
  • W is isoxazolyl optionally substituted by one or two R5.
  • W is oxazolyl optionally substituted by one or two R5.
  • W is thiazolyl optionally substituted by one or two R5.
  • W is triazolyl optionally substituted by one or two R5.
  • W is pyridinyl optionally substituted by one, two, or three R5.
  • W is -NHC(0)R6, -NHC(0)R7, or - NHC(0)N(R8)R9.
  • W is -NHC(0)R6.
  • W is -NHC(0)R7.
  • W is -NHC(0)N(R8)R9.
  • W is -C(0)N(R8)R9.
  • W is phenyl optionally substituted by one, two, or three R5.
  • XI and X2 are individually and independently hydrogen or C 1 -C6 alkyl.
  • XI and X2 are hydrogen.
  • one of XI and X2 is hydrogen and the other is Cl- C6alkyl.
  • Y is NR4 and R4 is hydrogen, C1 -C6 alkyl, deutero-Cl-C6 alkyl wherein the alkyl chain is partially or completely deuterated, or branched C3-C8 alkyl.
  • Y is NR4 and R4 is hydrogen or C1 -C6 alkyl. [0064] In one embodiment of Formula la, Y is NR4 and R4 is hydrogen. [0065] In one embodiment of Formula la, Y is NR4 and R4 is C1-C6 alkyl. [0066] In one embodiment of Formula la, Y is O.
  • A is taken from the group consisting of C1 -C6 alkyl, branched C3-C8alkyl, fluoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, C3-C8carbocyclyl, phenyl, a 4-8 membered heterocyclic ring and heteroaryl; and wherein each A moiety may be further substituted with one, two, or three R3 moieties.
  • A is taken from the group consisting of C1 -C6 alkyl, branched C3-C8alkyl, C3-C8carbocyclyl, phenyl and a 4-8 membered heterocyclic ring; and wherein each A moiety may be further substituted with one, two, or three R3 moieties.
  • A is branched C3-C8alkyl, optionally further substituted with one, two, or three R3 moieties.
  • A is C3-C8carbocyclyl, optionally further substituted with one, two, or three R3 moieties.
  • A is phenyl, optionally further substituted with one, two, or three R3 moieties.
  • A is a 4-8 membered heterocyclic ring, optionally further substituted with one, two, or three R3 moieties.
  • each Rl and R2 is individually and independently hydrogen, C1 -C6 alkyl, deutero-Cl-C6 alkyl wherein the alkyl chain is partially or completely deuterated, fiuoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, hydroxyl, C1-C6 alkoxy, fiuoroC 1 -C6alkoxy wherein the alkyl group is fully or partially fluorinated, or halogen.
  • each Rl is hydrogen.
  • each Rl and R2 is hydrogen.
  • each R3 is individually and independently hydrogen, halogen, C1 -C6 alkyl, fluoro-Cl-C6 alkyl wherein the alkyl chain is partially or completely fluorinated, branched C3-C8 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, fluoro-Cl-C6 alkoxy wherein the alkyl chain is partially or completely fluorinated, branched C3-C6 alkoxy, hydroxyl, or cyano.
  • q is 0, 1 , or 2. [0078] In one embodiment of Formula la, q is 0. [0079] In one embodiment of Formula la, q is 1. [0080] In one embodiment of Formula la, q is 2. [0081] In one embodiment of Formula la, n is 0, 1 , or 2. [0082] In one embodiment of Formula la, n is 0. [0083] In one embodiment of Formula la, n is 1. [0084] In one embodiment of Formula la, n is 2. [0085] In one embodiment of Formula la, n is 3.
  • the compound of Formula I is a compound of Formula lb wherein: W is C5-C6heteroaryl, phenyl, -NHC(0)R6, -NHC(0)R7, -NHC(0)N(R8)R9 or - C(0)N(R8)R9, and wherein each C5-C6heteroaryl or phenyl is optionally substituted by one, two, or three R5 moieties; or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.
  • W is C5-C6heteroaryl optionally substituted by one, two, or three R5.
  • W is pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, triazolyl, or pyridinyl and wherein each W is optionally substituted by one, two, or three R5.
  • W is pyrazolyl optionally substituted by one, two, or three R5.
  • W is imidazolyl optionally substituted by one, two, or three R5.
  • W is isoxazolyl optionally substituted by one or two R5.
  • W is oxazolyl optionally substituted by one or two R5.
  • W is thiazolyl optionally substituted by one or two R5.
  • W is triazolyl optionally substituted by one or two R5.
  • W is pyridinyl optionally substituted by one, two, or three R5.
  • W is -NHC(0)R6, -NHC(0)R7, or - NHC(0)N(R8)R9.
  • W is -NHC(0)R6.
  • W is -NHC(0)R7.
  • W is -NHC(0)N(R8)R9.
  • W is - C(0)N(R8)R9. [0101] In one embodiment of Formula lb, W is phenyl optionally substituted by one, two, or three R5.
  • XI and X2 are individually and independently hydrogen or C 1 -C6 alkyl.
  • XI and X2 are hydrogen.
  • one of XI and X2 is hydrogen and the other is Cl -C6alkyl.
  • R4 is hydrogen, C1-C6 alkyl, deutero-Cl -C6 alkyl wherein the alkyl chain is partially or completely deuterated, or branched C3-C8 alkyl.
  • R4 is hydrogen or C1-C6 alkyl.
  • R4 is hydrogen
  • R4 is C1-C6 alkyl.
  • A is taken from the group consisting of C1-C6 alkyl, branched C3-C8alkyl, fluoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, C3-C8carbocyclyl, phenyl, a 4-8 membered heterocyclic ring and heteroaryl; and wherein each A moiety may be further substituted with one, two, or three R3 moieties.
  • A is taken from the group consisting of C1-C6 alkyl, branched C3-C8alkyl, C3-C8carbocyclyl, phenyl and a 4-8 membered heterocyclic ring; and wherein each A moiety may be further substituted with one, two, or three R3 moieties.
  • A is branched C3-C8alkyl, optionally further substituted with one, two, or three R3 moieties.
  • A is tert-butyl, optionally further substituted with one, two, or three R3 moieties.
  • A is tert-pentyl, optionally further substituted with one, two, or three R3 moieties.
  • A is neo-pentyl, optionally further substituted with one, two, or three R3 moieties.
  • A is isobutyl, optionally further substituted with one, two, or three R3 moieties.
  • A is isopropyl, optionally further substituted with one, two, or three R3 moieties.
  • A is C3-C8carbocyclyl, optionally further substituted with one, two, or three R3 moieties.
  • A is cyclopropyl, optionally further substituted with one, two, or three R3 moieties.
  • A is cyclobutyl, optionally further substituted with one, two, or three R3 moieties.
  • A is cyclopentyl, optionally further substituted with one, two, or three R3 moieties.
  • A is cyclohexyl, optionally further substituted with one, two, or three R3 moieties.
  • A is phenyl, optionally further substituted with one, two, or three R3 moieties.
  • A is a 4-8 membered heterocyclic ring, optionally further substituted with one, two, or three R3 moieties
  • A is tetrahydrofuranyl, optionally further substituted with one, two, or three R3 moieties.
  • A is tetrahydropyranyl, optionally further substituted with one, two, or three R3 moieties.
  • each R3 is individually and independently hydrogen, halogen, C1 -C6 alkyl, fluoro-Cl-C6 alkyl wherein the alkyl chain is partially or completely fluorinated, branched C3-C8 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, fluoro-Cl-C6 alkoxy wherein the alkyl chain is partially or completely fluorinated, branched C3-C6 alkoxy, hydroxyl, or cyano.
  • n is 0, 1 , or 2. [0128] In one embodiment of Formula lb, n is 0. [0129] In one embodiment of Formula lb, n is 1. [0130] In one embodiment of Formula lb, n is 2. [0131] In one embodiment of Formula lb, n is 3. [0132] In one embodiment, the compound of Formula I is a compound of Formula Ic wherein: XI and X2 are individually and independently hydrogen or C1-C6 alkyl; or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.
  • XI and X2 are hydrogen.
  • one of XI and X2 is hydrogen and the other is Cl- C6alkyl.
  • one of XI and X2 is hydrogen and the other is methyl.
  • R3 is hydrogen, halogen, C1-C6 alkyl, fluoro-Cl- C6 alkyl wherein the alkyl chain is partially or completely fluorinated, branched C3-C8 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, fluoro-Cl-C6 alkoxy wherein the alkyl chain is partially or completely fluorinated, branched C3-C6 alkoxy, hydroxyl, or cyano.
  • R3 is hydrogen, C1-C6 alkyl, fluoro-Cl-C6 alkyl wherein the alkyl chain is partially or completely fluorinated, or C1-C6 alkoxy.
  • R5 is hydrogen, C1-C6 alkyl, deutero-Cl-C6 alkyl wherein the alkyl chain is partially or completely deuterated, branched C3-C8 alkyl, -(CH 2 ) m - C(0)NR8(R9), -(CH 2 ) m -C(0)R7, -(CH 2 ) m -OR8, -(CH 2 ) m -NR8(R9), or -(CH 2 ) m -R7, wherein each alkylene is optionally substituted with C 1 -C4 alkyl.
  • R5 is hydrogen, C1 -C6 alkyl, or deutero-Cl -C6 alkyl wherein the alkyl chain is partially or completely deuterated.
  • R5 is C1-C6 alkyl, or deutero-Cl -C6 alkyl wherein the alkyl chain is partially or completely deuterated.
  • R5 is methyl
  • q is 0, 1 , or 2.
  • q is 0 or 1.
  • q is 2.
  • the compound of Formula I is a compound of Formula Id wherein: W is C5-C6heteroaryl, phenyl, -NHC(0)R6, -NHC(0)R7, -NHC(0)N(R8)R9 or - C(0)N(R8)R9, and wherein each C5-C6heteroaryl or phenyl is optionally substituted by one, two, or three R5 moieties; or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.
  • W is C5-C6heteroaryl optionally substituted by one, two, or three R5.
  • W is pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, triazolyl, or pyridinyl and wherein each W is optionally substituted by one, two, or three R5.
  • W is pyrazolyl optionally substituted by one, two, or three R5.
  • W is imidazolyl optionally substituted by one, two, or three R5.
  • W is isoxazolyl optionally substituted by one or two R5.
  • W is oxazolyl optionally substituted by one or two
  • W is thiazolyl optionally substituted by one or two
  • W is triazolyl optionally substituted by one or two R5.
  • W is pyridinyl optionally substituted by one, two, or three R5.
  • W is -NHC(0)R6, -NHC(0)R7, or - NHC(0)N(R8)R9.
  • W is -NHC(0)R6. [0159] In one embodiment of Formula Id, W is -NHC(0)R7. [0160] In one embodiment of Formula Id, W is -NHC(0)N(R8)R9. [0161] In one embodiment of Formula Id, W is - C(0)N(R8)R9.
  • W is phenyl optionally substituted by one, two, or three R5.
  • XI and X2 are individually and independently hydrogen or C 1 -C6 alkyl.
  • XI and X2 are hydrogen.
  • one of XI and X2 is hydrogen and the other is Cl-C6alkyl.
  • Y is NR4 and R4 is hydrogen, C1-C6 alkyl, deutero-Cl-C6 alkyl wherein the alkyl chain is partially or completely deuterated, or branched C3-C8 alkyl.
  • Y is NR4 and R4 is hydrogen or C1-C6 alkyl.
  • Y is NR4 and R4 is hydrogen.
  • Y is NR4 and R4 is CI -C6 alkyl.
  • Y is O.
  • A is taken from the group consisting of C1-C6 alkyl, branched C3-C8alkyl, fluoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, C3-C8carbocyclyl, phenyl, a 4-8 membered heterocyclic ring and heteroaryl; and wherein each A moiety may be further substituted with one, two, or three R3 moieties.
  • A is taken from the group consisting of C1-C6 alkyl, branched C3-C8alkyl, C3-C8carbocyclyl, phenyl and a 4-8 membered heterocyclic ring; and wherein each A moiety may be further substituted with one, two, or three R3 moieties.
  • A is branched C3-C8alkyl, optionally further substituted with one, two, or three R3 moieties.
  • A is C3-C8carbocyclyl, optionally further substituted with one, two, or three R3 moieties.
  • A is phenyl, optionally further substituted with one, two, or three R3 moieties.
  • A is a 4-8 membered heterocyclic ring, optionally further substituted with one, two, or three R3 moieties.
  • each Rl and R2 is individually and independently hydrogen, C1 -C6 alkyl, deutero-Cl-C6 alkyl wherein the alkyl chain is partially or completely deuterated, fiuoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, hydroxyl, C1-C6 alkoxy, fiuoroC 1 -C6alkoxy wherein the alkyl group is fully or partially fluorinated, or halogen.
  • each Rl is hydrogen.
  • each Rl and R2 is hydrogen.
  • each R3 is individually and independently hydrogen, halogen, C1 -C6 alkyl, fluoro-Cl-C6 alkyl wherein the alkyl chain is partially or completely fluorinated, branched C3-C8 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, fluoro-Cl-C6 alkoxy wherein the alkyl chain is partially or completely fluorinated, branched C3-C6 alkoxy, hydroxyl, or cyano.
  • Rl l is hydrogen, C1 -C6 alkyl, deutero-Cl-C6 alkyl wherein the alkyl chain is partially or completely deuterated, or branched C3-C8 alkyl.
  • Rl 1 is hydrogen
  • q is 0, 1 , or 2.
  • q is 1.
  • q is 2.
  • n is 0, 1 , or 2.
  • n is 0. [0189] In one embodiment of Formula Id, n is 1. [0190] In one embodiment of Formula Id, n is 2. [0191] In one embodiment of Formula Id, n is 3.
  • the compound of Formula I is a compound of Formula Ie wherein: W is C5-C6heteroaryl, phenyl, -NHC(0)R6, -NHC(0)R7, -NHC(0)N(R8)R9 or - C(0)N(R8)R9, and wherein each C5-C6heteroaryl or phenyl is optionally substituted by one, two, or three R5 moieties; or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.
  • W is C5-C6heteroaryl optionally substituted by one, two, or three R5.
  • W is pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, triazolyl, or pyridinyl and wherein each W is optionally substituted by one, two, or three R5.
  • W is pyrazolyl optionally substituted by one, two, or three R5.
  • W is imidazolyl optionally substituted by one, two, or three R5.
  • W is isoxazolyl optionally substituted by one or two R5.
  • W is oxazolyl optionally substituted by one or two R5.
  • W is thiazolyl optionally substituted by one or two R5.
  • W is triazolyl optionally substituted by one or two R5.
  • W is pyridinyl optionally substituted by one, two, or three R5.
  • W is -NHC(0)R6, -NHC(0)R7, or - NHC(0)N(R8)R9.
  • W is -NHC(0)R6.
  • W is -NHC(0)R7.
  • W is -NHC(0)N(R8)R9.
  • W is - C(0)N(R8)R9.
  • W is phenyl optionally substituted by one, two, or three R5.
  • XI and X2 are individually and independently hydrogen or C 1 -C6 alkyl.
  • XI and X2 are hydrogen.
  • one of XI and X2 is hydrogen and the other is Cl- C6alkyl.
  • R4 is hydrogen, C1 -C6 alkyl, deutero-Cl-C6 alkyl wherein the alkyl chain is partially or completely deuterated, or branched C3-C8 alkyl.
  • R4 is hydrogen or C1-C6 alkyl.
  • R4 is hydrogen
  • R4 is C1-C6 alkyl.
  • A is taken from the group consisting of C1 -C6 alkyl, branched C3-C8alkyl, fluoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, C3-C8carbocyclyl, phenyl, a 4-8 membered heterocyclic ring and heteroaryl; and wherein each A moiety may be further substituted with one, two, or three R3 moieties.
  • A is taken from the group consisting of C1 -C6 alkyl, branched C3-C8alkyl, C3-C8carbocyclyl, phenyl and a 4-8 membered heterocyclic ring; and wherein each A moiety may be further substituted with one, two, or three R3 moieties.
  • A is branched C3-C8alkyl, optionally further substituted with one, two, or three R3 moieties.
  • A is tert-butyl, optionally further substituted with one, two, or three R3 moieties.
  • A is tert-pentyl, optionally further substituted with one, two, or three R3 moieties.
  • A is neo-pentyl, optionally further substituted with one, two, or three R3 moieties.
  • A is isobutyl, optionally further substituted with one, two, or three R3 moieties.
  • A is isopropyl, optionally further substituted with one, two, or three R3 moieties.
  • A is C3-C8carbocyclyl, optionally further substituted with one, two, or three R3 moieties.
  • A is cyclopropyl, optionally further substituted with one, two, or three R3 moieties.
  • A is cyclobutyl, optionally further substituted with one, two, or three R3 moieties.
  • A is cyclopentyl, optionally further substituted with one, two, or three R3 moieties.
  • A is cyclohexyl, optionally further substituted with one, two, or three R3 moieties.
  • A is phenyl, optionally further substituted with one, two, or three R3 moieties.
  • A is a 4-8 membered heterocyclic ring, optionally further substituted with one, two, or three R3 moieties.
  • A is tetrahydrofuranyl, optionally further substituted with one, two, or three R3 moieties.
  • A is tetrahydropyranyl, optionally further substituted with one, two, or three R3 moieties.
  • each R3 is individually and independently hydrogen, halogen, C1 -C6 alkyl, fluoro-Cl-C6 alkyl wherein the alkyl chain is partially or completely fluorinated, branched C3-C8 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, fluoro-Cl-C6 alkoxy wherein the alkyl chain is partially or completely fluorinated, branched C3-C6 alkoxy, hydroxyl, or cyano.
  • Rl l is hydrogen, C1-C6 alkyl, deutero-Cl -C6 alkyl wherein the alkyl chain is partially or completely deuterated, or branched C3-C8 alkyl.
  • Rl 1 is hydrogen
  • n is 0, 1 , or 2.
  • n 0.
  • n 1
  • n is 2. [0239] In one embodiment of Formula Ie, n is 3.
  • the compound of Formula I is a compound of Formula If wherein: XI and X2 are individually and independently hydrogen or C1-C6 alkyl; or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.
  • XI and X2 are hydrogen.
  • one of XI and X2 is hydrogen and the other is Cl- C6alkyl.
  • one of XI and X2 is hydrogen and the other is methyl.
  • R3 is hydrogen, halogen, C1-C6 alkyl, fluoro-Cl- C6 alkyl wherein the alkyl chain is partially or completely fluorinated, branched C3-C8 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, fluoro-Cl-C6 alkoxy wherein the alkyl chain is partially or completely fluorinated, branched C3-C6 alkoxy, hydroxyl, or cyano.
  • R3 is hydrogen, C1-C6 alkyl, fluoro-Cl-C6 alkyl wherein the alkyl chain is partially or completely fluorinated, or C1-C6 alkoxy.
  • R5 is hydrogen, C1 -C6 alkyl, deutero-Cl -C6 alkyl wherein the alkyl chain is partially or completely deuterated, branched C3-C8 alkyl, -(CH 2 ) m - C(0)NR8(R9), -(CH 2 ) m -C(0)R7, -(CH 2 ) m -OR8, -(CH 2 ) m -NR8(R9), or -(CH 2 ) m -R7, wherein each alkylene is optionally substituted with C 1 -C4 alkyl.
  • R5 is hydrogen, C1-C6 alkyl, or deutero-C 1 -C6 alkyl wherein the alkyl chain is partially or completely deuterated.
  • R5 is C1 -C6 alkyl, or deutero-C 1 -C6 alkyl wherein the alkyl chain is partially or completely deuterated.
  • R5 is methyl
  • the compound of Formula I is a compound of Formula Ig wherein: W is C5-C6heteroaryl, phenyl, -NHC(0)R6, -NHC(0)R7, -NHC(0)N(R8)R9 or - C(0)N(R8)R9, and wherein each C5-C6heteroaryl or phenyl is optionally substituted by one, two, or three R5 moieties; or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.
  • W is C5-C6heteroaryl optionally substituted by one, two, or three R5.
  • W is pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, triazolyl, or pyridinyl and wherein each W is optionally substituted by one, two, or three R5.
  • W is pyrazolyl optionally substituted by one, two, or three R5.
  • W is imidazolyl optionally substituted by one, two, or three R5.
  • W is isoxazolyl optionally substituted by one or two R5.
  • W is oxazolyl optionally substituted by one or two
  • W is thiazolyl optionally substituted by one or two
  • W is triazolyl optionally substituted by one or two R5.
  • W is pyridinyl optionally substituted by one, two, or three R5.
  • W is -NHC(0)R6, -NHC(0)R7, or - NHC(0)N(R8)R9.
  • W is -NHC(0)R6. [0267] In one embodiment of Formula Ig, W is -NHC(0)R7. [0268] In one embodiment of Formula Ig, W is -NHC(0)N(R8)R9. [0269] In one embodiment of Formula Ig, W is - C(0)N(R8)R9.
  • W is phenyl optionally substituted by one, two, or three R5.
  • XI and X2 are individually and independently hydrogen or C 1 -C6 alkyl.
  • XI and X2 are hydrogen.
  • one of XI and X2 is hydrogen and the other is Cl- C6alkyl.
  • A is taken from the group consisting of C1-C6 alkyl, branched C3-C8alkyl, fluoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, C3-C8carbocyclyl, phenyl, a 4-8 membered heterocyclic ring and heteroaryl.
  • A is taken from the group consisting of C1-C6 alkyl, branched C3-C8alkyl, C3-C8carbocyclyl, phenyl and a 4-8 membered heterocyclic ring; and wherein each A moiety may be further substituted with one, two, or three R3 moieties.
  • A is branched C3-C8alkyl, optionally further substituted with one, two, or three R3 moieties.
  • A is tert-butyl, optionally further substituted with one, two, or three R3 moieties.
  • A is tert-pentyl, optionally further substituted with one, two, or three R3 moieties.
  • A is neo-pentyl, optionally further substituted with one, two, or three R3 moieties.
  • A is isobutyl, optionally further substituted with one, two, or three R3 moieties.
  • A is isopropyl, optionally further substituted with one, two, or three R3 moieties.
  • A is C3-C8carbocyclyl, optionally further substituted with one, two, or three R3 moieties.
  • A is cyclopropyl, optionally further substituted with one, two, or three R3 moieties.
  • A is cyclobutyl, optionally further substituted with one, two, or three R3 moieties.
  • A is cyclopentyl, optionally further substituted with one, two, or three R3 moieties.
  • A is cyclohexyl, optionally further substituted with one, two, or three R3 moieties.
  • A is phenyl, optionally further substituted with one, two, or three R3 moieties.
  • A is a 4-8 membered heterocyclic ring, optionally further substituted with one, two, or three R3 moieties.
  • A is tetrahydrofuranyl, optionally further substituted with one, two, or three R3 moieties.
  • A is tetrahydropyranyl, optionally further substituted with one, two, or three R3 moieties.
  • each R3 is individually and independently hydrogen, halogen, C1 -C6 alkyl, fluoro-Cl-C6 alkyl wherein the alkyl chain is partially or completely fluorinated, branched C3-C8 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, fluoro-Cl-C6 alkoxy wherein the alkyl chain is partially or completely fluorinated, branched C3-C6 alkoxy, hydroxyl, or cyano.
  • n is 0, 1 , or 2. [0293] In one embodiment of Formula Ig, n is 0. [0294] In one embodiment of Formula Ig, n is 1. [0295] In one embodiment of Formula Ig, n is 2. [0296] In one embodiment of Formula Ig, n is 3.
  • the compound of Formula I is a compound of Formula Ih wherein: XI and X2 are individually and independently hydrogen or C1-C6 alkyl; or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.
  • XI and X2 are hydrogen.
  • one of XI and X2 is hydrogen and the other is Cl- C6alkyl.
  • one of XI and X2 is hydrogen and the other is methyl.
  • R3 is hydrogen, halogen, C1-C6 alkyl, fluoro-Cl - C6 alkyl wherein the alkyl chain is partially or completely fluorinated, branched C3-C8 alkyl, C3-C8 cycloalkyl, C1 -C6 alkoxy, fluoro-Cl-C6 alkoxy wherein the alkyl chain is partially or completely fluorinated, branched C3-C6 alkoxy, hydroxyl, or cyano.
  • R3 is hydrogen, C1 -C6 alkyl, fluoro-Cl -C6 alkyl wherein the alkyl chain is partially or completely fluorinated, or C1-C6 alkoxy.
  • R5 is hydrogen, C1-C6 alkyl, deutero-Cl -C6 alkyl wherein the alkyl chain is partially or completely deuterated, branched C3-C8 alkyl, -(CH 2 ) m - C(0)NR8(R9), -(CH 2 ) m -C(0)R7, -(CH 2 ) m -OR8, -(CH 2 ) m -NR8(R9), or -(CH 2 ) m -R7, wherein each alkylene is optionally substituted with C 1 -C4 alkyl.
  • R5 is hydrogen, C1 -C6 alkyl, or deutero-Cl-C6 alkyl wherein the alkyl chain is partially or completely deuterated.
  • R5 is C1 -C6 alkyl, or deutero-Cl-C6 alkyl wherein the alkyl chain is partially or completely deuterated.
  • R5 is methyl
  • q is 0, 1 , or 2.
  • q is 0 or 1.
  • q is 1.
  • the invention comprises a compound selected from the group consisting of 3-(4-fluorobenzyl)- 1 -(6-methyl-5-((2-( 1 -methyl- 1 H-pyrazol-4-yl)pyridin-4- yl)oxy)pyridin-2-yl)- lH-l ,2,4-triazol-5(4H)-one, 3-benzyl-l-(6-methyl-5-((2-(l -methyl-lH- pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5(4H)-one, 3-(4-fiuorobenzyl)- 1 - (5-((2-( 1 -methyl- 1 H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5(4H)-one,
  • the invention comprises a method of treating mammalian disease at least partially mediated by the kinase activity of c-FMS, PDGFR- ⁇ , or c-KIT kinases, wherein the kinase is a wildtype form, a mutant oncogenic form, an aberrant fusion protein form or a polymorph therof, the method comprising administering to a mammal in need thereof an effective amount of a compound of Formula I.
  • the present invention comprises a pharmaceutical composition, comprising a compound of Formula I and a pharmaceutically acceptable carrier.
  • the composition comprises an additive selected from adjuvants, excipients, diluents, or stabilizers.
  • the invention includes a method of treating cancer, gastrointestinal stromal tumors, hyperproliferative diseases, metabolic diseases,
  • neurodegenerative diseases solid tumors, melanomas, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, renal cancers, hepatic cancers,
  • osteosarcomas multiple myelomas, cervical carcinomas, metastasis of primary tumor sites, cancers that are metastatic to bone, papillary thyroid carcinoma, non-small cell lung cancer, colonic cancers, rheumatoid arthritis, osteoarthritis, multiple sclerosis, autoimmune nephritis, lupus, Crohn's disease, asthma, chronic obstructive pulmonary disease, osteoporosis,
  • mastocytosis or mast cell leukemia
  • the method comprising administering to a patient in need thereof an effective amount of a compound of Formula I.
  • the invention includes a method of treating glioblastomas, breast cancers, pancreatic cancers, metastasis of primary tumor sites, or cancers that are metastatic to bone, the method comprising administering to a patient in need thereof an effective amount of a compound of Formula I.
  • the compound is administered orally, parenterally, by inhalation, or subcutaneously.
  • the invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the treatment of cancer, gastrointestinal stromal tumors, hyperproliferative diseases, metabolic diseases, neurodegenerative diseases, solid tumors, melanomas, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, renal cancers, hepatic cancers, osteosarcomas, multiple myelomas, cervical carcinomas, metastasis of primary tumor sites, cancers that are metastatic to bone, papillary thyroid carcinoma, non-small cell lung cancer, colonic cancers, rheumatoid arthritis, osteoarthritis, multiple sclerosis, autoimmune nephritis, lupus, Crohn's disease, asthma, chronic obstructive pulmonary disease, osteoporosis, mastocytosis, or mast cell leukemia, the method comprising administering to a patient in need thereof an effective amount of a compound of
  • the invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the treatment of glioblastomas, breast cancers, pancreatic cancers, metastasis of primary tumor sites, or cancers that are metastatic to bone, the method comprising administering to a patient in need thereof an effective amount of a compound of Formula I.
  • the invention provides for the use of a compound of Formula
  • a medicament for the treatment of cancer gastrointestinal stromal tumors, hyperproliferative diseases, metabolic diseases, neurodegenerative diseases, solid tumors, melanomas, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, renal cancers, hepatic cancers, osteosarcomas, multiple myelomas, cervical carcinomas, metastasis of primary tumor sites, cancers that are metastatic to bone, papillary thyroid carcinoma, non-small cell lung cancer, colonic cancers, rheumatoid arthritis, osteoarthritis, multiple sclerosis, autoimmune nephritis, lupus, Crohn's disease, asthma, chronic obstructive pulmonary disease, osteoporosis, mastocytosis, or mast cell leukemia.
  • the invention provides for the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of glioblastomas, breast cancers, pancreatic cancers, metastasis of primary tumor sites, or cancers that are metastatic to bone.
  • the compounds of this disclosure include any and all possible isomers, stereoisomers, enantiomers, diastereomers, tautomers, and pharmaceutically acceptable salts.
  • the terms "compound”, “compounds”, “test compound” or “test compounds” as used in this disclosure refer to the compounds of this disclosure and any and all possible isomers, stereoisomers, enantiomers, diastereomers, tautomers, and pharmaceutically acceptable salts thereof.
  • alkyl refers to a straight chain alkyl, wherein alkyl chain length is indicated by a range of numbers.
  • alkyl refers to an alkyl chain as defined above containing 1 , 2, 3, 4, 5, or 6 carbons (i.e., C1-C6 alkyl).
  • alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, and hexyl.
  • branched alkyl refers to an alkyl chain wherein a branching point in the chain exists, and the total number of carbons in the chain is indicated by a range of numbers.
  • branched alkyl refers to an alkyl chain as defined above containing from 3, 4, 5, 6, 7, or 8 carbons (i.e., branched C3-C8 alkyl).
  • Examples of a branched alkyl group include, but are not limited to, z ' so-propyl, z ' so-butyl, secondary-butyl, and tertiary- butyl, 2-pentyl, 3-pentyl, 2-hexyl, and 3-hexyl.
  • alkoxy refers to -O-(alkyl), wherein “alkyl” is as defined above.
  • branched alkoxy refers to -0-(branched alkyl), wherein “branched alkyl” is as defined above.
  • alkylene refers to an alkyl moiety interposed between two other atoms.
  • alkylene refers to an alkyl moiety as defined above containing 1 , 2, or 3 carbons.
  • Examples of an alkylene group include, but are not limited to -CH 2 - -CH 2 CH 2 -, and -CH 2 CH 2 CH 2 -.
  • alkylene groups are branched.
  • alkynyl refers to a carbon chain containing one carbon- carbon triple bond.
  • alkynyl refers to a carbon chain as described above containing 2 or 3 carbons (i.e., C2-C3 alkynyl). Examples of an alkynyl group include, but are not limited to, ethyne and propyne.
  • aryl refers to a cyclic hydrocarbon, where the ring is characterized by delocalized ⁇ electrons (aromaticity) shared among the ring members, and wherein the number of ring atoms is indicated by a range of numbers.
  • aryl refers to a cyclic hydrocarbon as described above containing 6, 7, 8, 9, or 10 ring atoms (i.e., C6-C10 aryl). Examples of an aryl group include, but are not limited to, benzene, naphthalene, tetralin, indene, and indane.
  • cycloalkyl or “carbocyclyl” as used herein refers to a monocyclic saturated carbon ring, wherein the number of ring atoms is indicated by a range of numbers.
  • cycloalkyl or “carbocyclyl” refers to a carbon ring as defined above containing 3, 4, 5, 6, 7, or 8 ring atoms (i.e., C3-C8 cycloalkyl).
  • Examples of a cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • halogen or "halo” as used herein refers to fluorine, chlorine, bromine, and iodine.
  • heterocycle or “heterocyclyl” as used herein refers to a cyclic
  • heterocyclyl refers to a monocyclic hydrocarbon containing 4, 5, 6, 7 or 8 ring atoms (i.e., C4-C8 heterocyclyl).
  • heterocycle group examples include, but are not limited to, aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, tetrahydroiuran, pyran, thiopyran, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S-dioxide, oxazoline, tetrahydrothiophene, piperidine, tetrahydropyran, thiane, imidazolidine, oxazolidine, thiazolidine, dioxolane, dithiolane, piperazine, oxazine, dithiane, and dioxane.
  • heteroaryl refers to a cyclic hydrocarbon, where at least one of the ring atoms is an O, N, or S, the ring is characterized by delocalized ⁇ electrons (aromaticity) shared among the ring members, and wherein the number of ring atoms is indicated by a range of numbers.
  • Heteroaryl moieties as defined herein have C or N bonding hands through which the heteroaryl ring is connected to an adjacent moiety.
  • a ring N atom from the heteroaryl is the bonding atom of the heteroaryl moiety.
  • heteroaryl refers to a cyclic hydrocarbon as described above containing 5 or 6 ring atoms (i.e., C5-C6 heteroaryl).
  • heteroaryl group include, but are not limited to, pyrrole, furan, thiene, oxazole, thiazole, isoxazole, isothiazole, imidazole, pyrazole, oxadiazole, thiadiazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyridazine, and triazine.
  • substituted in connection with a moiety as used herein refers to a further substituent which is attached to the moiety at any acceptable location on the moiety. Unless otherwise indicated, moieties can bond through a carbon, nitrogen, oxygen, sulfur, or any other acceptable atom.
  • salts as used herein embraces pharmaceutically acceptable salts commonly used to form alkali metal salts of free acids and to form addition salts of free bases.
  • the nature of the salt is not critical, provided that it is pharmaceutically acceptable.
  • Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid.
  • Exemplary pharmaceutical salts are disclosed in Stahl, P.H., Wermuth, C.G., Eds. Handbook of Pharmaceutical Salts : Properties, Selection and Use; Verlag Helvetica Chimica Acta/Wiley-VCH: Zurich, 2002, the contents of which are hereby incorporated by reference in their entirety.
  • inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
  • Appropriate organic acids include, without limitation, aliphatic, cycloaliphatic, aromatic, arylaliphatic, and heterocyclyl containing carboxylic acids and sulfonic acids, for example formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p- hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2 -hydroxy
  • Suitable pharmaceutically acceptable salts of free acid-containing compounds disclosed herein include, without limitation, metallic salts and organic salts.
  • Exemplary metallic salts include, but are not limited to, appropriate alkali metal (group la) salts, alkaline earth metal (group Ila) salts, and other physiological acceptable metals.
  • Such salts can be made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
  • Exemplary organic salts can be made from primary amines, secondary amines, tertiary amines and quaternary ammonium salts, for example, tromethamine, diethylamine, tetra-N-methylammonium, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
  • administer refers to either directly administering a compound or pharmaceutically acceptable salt of the compound or a composition to a subject.
  • carrier as used herein encompasses carriers, excipients, and diluents, meaning a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ or portion of the body.
  • disorder is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.
  • the terms "effective amount” and “therapeutically effective amount” are used interchangeably in this disclosure and refer to an amount of a compound that, when administered to a subject, is capable of reducing a symptom of a disorder in a subject.
  • the actual amount which comprises the "effective amount” or “therapeutically effective amount” will vary depending on a number of conditions including, but not limited to, the particular disorder being treated, the severity of the disorder, the size and health of the patient, and the route of administration. A skilled medical practitioner can readily determine the appropriate amount using methods known in the medical arts.
  • the terms "isolated” and “purified” as used herein refer to a component separated from other components of a reaction mixture or a natural source.
  • the isolate contains at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 98% of the compound or pharmaceutically acceptable salt of the compound by weight of the isolate.
  • phrases "pharmaceutically acceptable” as used herein refers to those compounds, materials, compositions, and/or 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, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the terms "patient” or “subject” include, without limitation, a human or an animal.
  • exemplary animals include, but are not limited to, mammals such as mouse, rat, guinea pig, dog, feline, horse, cow, pig, monkey, chimpanzee, baboon, or rhesus monkey.
  • treatment is meant to include the full spectrum of intervention for the cancer from which the patient is suffering, such as administration of the active compound to alleviate, slow or reverse one or more of the symptoms and to delay progression of the cancer even if the cancer is not actually eliminated. Treating can be curing, improving, or at least partially ameliorating the disorder.
  • Atropisomers are defined as a subclass of conformers which can be isolated as separate chemical species and which arise from restricted rotation about a single bond.
  • Diastereomers or diastereoisomers are defined as stereoisomers other than enantiomers. Diastereomers or diastereoisomers are stereoisomers not related as mirror images. Diastereoisomers are characterized by differences in physical properties, and by some differences in chemical behavior towards achiral as well as chiral reagents.
  • tautomer refers to compounds produced by the phenomenon wherein a proton of one atom of a molecule shifts to another atom. See March, Advanced Organic Chemistry: Reactions, Mechanisms and Structures, 4th Ed., John Wiley & Sons, pp. 69-74 (1992). Tautomerism is defined as isomerism of the general form
  • Tautomers are defined as isomers that arise from tautomerism, independent of whether the isomers are isolable.
  • the exemplified compounds of the present invention are preferably formulated as a pharmaceutical composition using a pharmaceutically acceptable carrier and administered by a variety of routes. Preferably, such compositions are for oral administration.
  • Such pharmaceutical compositions and processes for preparing them are well known in the art. See, e.g., REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (A. Gennaro, et al, eds., 19 th ed., Mack Publishing Co., 1995).
  • the compounds of Formula I, or pharmaceutically acceptable salts thereof may be prepared by a variety of procedures known in the art, as well as those described below. The specific synthetic steps may be combined in different ways to prepare the Formula I compounds, or a pharmaceutically acceptable salt thereof.
  • ChemDraw version 10 or 12 was used to name the structures of intermediates and exemplified compounds.
  • ADP is adenosine diphosphate "cone.” is concentrated, “DBU” is 1 ,8- diazabicyclo[5.4.0]undec-7-ene, “DCM” is dichloromethane, “DIEA” is N,N- diisopropylethylamine, “DMA” is N,N-dimethylacetamide, “DMAP” is 4-
  • the compounds of Formula I are prepared by the general synthetic methods illustrated in the schemes below and the accompanying examples. Suitable reaction conditions for the steps of these schemes are well known in the art and appropriate substitutions of solvents and co-reagents are within the skill of the art. Those skilled in the art will understand that synthetic intermediates may be isolated and/or purified by well known techniques as needed or desired, and that it will be possible to use various intermediates directly in subsequent synthetic steps with little or no purification. Furthermore, those skilled in the art will appreciate that in some instances, the order in which moieties are introduced is not critical.
  • the compounds of Formula I may contain -NH or -OH moieties in the W, Rl , R2 and R3 positions. It will be understood by those skilled in the art that in some instances it may be advantageous to use an amine protecting group during synthesis to temporarily mask one or more -NH moieties. Said protecting group can be removed from any subsequent intermediate leading to the synthesis of the compounds of Formula I, using standard conditions that effect removal of said protecting group, said conditions of which will be familiar to those skilled in the art.
  • W, Rl , R2 and R3 moieties represented in the schemes below may optionally contain standard amino or hydroxyl protecting groups that can be removed at any opportune time in the synthetic sequence.
  • Scheme 1 illustrates the preparation of Compounds J_, examples of Formula I wherein Y is NR4 and Z is N.
  • iodide 2 can react with triazolone 3 in the presence of copper(I) iodide and a suitable ligand, for example N,N-dimethylethane-l ,2-diamine to afford 4. Additional conditions for the transformation of 2 to 4 include heating to about 100 °C with a carbonate base, for example potassium carbonate. Further reaction of 4 with M-W (5) in the presence of a palladium catalyst and a base, for example potassium carbonate provides compounds of formula 1.
  • to conversion of 4 to 1 is effected by reaction of 4 with reagent M-W (5), wherein M is trialkylstanyl or a boronic acid or boronate ester (when W is heteroaryl or phenyl).
  • to conversion of 4 to I is effected by reaction of 4 with reagent M-W (5), wherein M is H (when W is -NHC(0)R6, -NHC(0)R7, - NHC(0)N(R8)R9.
  • Hydrazine 6 is efficiently prepared from iodide 2 by a two-step process commencing with the reaction with benzophenone hydrazone in the presence of Pd(OAc) 2 , 2,2'-bis(diphenylphosphino)-l ,l '-binaphthalene, and sodium te/ -butoxide to provide 7. Acidic hydrolysis of 7 affords hydrazine 6.
  • compounds of formula 1 can be prepared directly from iodide 9 by reaction with M-W 5 using conditions described above.
  • Iodide 9 is prepared from amine 10 by diazotization in the presence of an iodide source, for example potassium iodide or tetrabutylammonium iodide. Additional conditions for the conversion of 10 to 9 include treatment with tert-butyl nitrite in diiodomethane.
  • compounds of formula 1 can be prepared directly from hydrazine 12 by reaction with 8. Hydrazine 12 is prepared by the two-step sequence commencing with amine 10.
  • diazotization of amine 10 in the resence of HF -pyridine affords fluoride Treatment of JJ_ with hydrazine or hydrazine hydrate affords 12.
  • General amine 10 can be prepared as illustrated in Scheme 3 by alternate reaction sequences, the selection of which will influenced by the nature of the W-moiey.
  • intermediate 20 (Y is halogen) is reacted with 2J_ in the presence of a base, for example potassium carbonate to provide the nitro ether 22.
  • Reduction of the nitro moiey of 22 provides 23.
  • Conditions to effect the conversion of 22 to 23 are known by those skilled in the art and include the use of zinc powder in the presence of ammonium chloride in a protic solvent such as methanol.
  • Further reaction of 23 with M-W (5) as described above provides 10.
  • 22 can be reacted with M-W (5) as described above to provide 24. Reduction of the nitro moiety of 24 provides 10.
  • amines of formula 23 can be prepared directly by reaction of 25 with 19 in the presence of a base.
  • Scheme 4 illustrates the preparation of Compounds 28, examples of Formula I wherein Y is NR4 and Z is CRl 1.
  • iodide 2 can react with 26 in the presence of copper(I) iodide and a suitable ligand, for example N,N-dimethylethane-l,2-diamine to afford 27.
  • M-W (5) in the presence of a palladium catalyst and a base, as described in scheme 1 , provides compounds of formula 28.
  • compounds of formula 28 can be prepared directly from compounds of formula 9 by reaction with 26 in the presence of copper(I) iodide and a suitable ligand.
  • Scheme 5 illustrates the preparation of Compounds 3J_, examples of Formula I wherein Y is O and Z is N.
  • treatment of hydrazine 12 with acid chloride 29 provides compound 30.
  • acid chloride 29 provides acid halides, anhydrides or "activated esters.”
  • Compound 30 may be isolated or generated and used in situ. Further reaction of 30 with triphosgene (or other suitable carbonylation reagent, such as phosgene or carbonyl diimidazole) in the presence of a base provides compounds of formula 31.
  • Scheme 6 illustrates the preparation of compounds of Formula I or 28 wherein R4 is not hydrogen from compounds 32 or 34 resepectively by alkylation of the NH moiety of 32 or 34 with an alkylating agent 33.
  • Suitable conditions for the reaction include contacting alkylating agent 33 with 32 or 34 in an aprotic solvent, such as acetone, in the presence of a base, for example cesium carbonate or potassium carbonate.
  • 33 is an alkyl halide (X is halide).
  • Scheme 7 illustrates a general preparation of triazolones of formula 35, examples of general reagent 3 wherein R4 is hydrogen.
  • reaction of acid chlorides 29 with semicarbazide (36) provide triazolones 35 after cyclodehydration of the intermediate 2- acylhydrazine- 1 carboxamide 37.
  • the reaction is performed by treating an aqueous solution of semicarbazide with acid chloride 29 to afford 37 followed by the treatment of 37 with aqueous sodium hydroxide and the heating of the mixture to effect cyclodehydration.
  • Those skilled in the art will appreciate that numerous equivalents for 29 may be found, including acid halides, anhydrides or "activated esters.”
  • Example Al A solution of 3-hydroxy-2-methylpyridine (20.0 g, 183 mmol) and Na 2 CC>3 (38.8 g, 367 mmol) in H 2 0 (320 mL) and MeOH (200 mL) was treated with I 2 (46.5 g, 183 mmol) and stirred at RT for 1 h. The mixture was acidified with HC1 (2 M), extracted with EtOAc (2x) and the combined organics were washed with brine, dried over Na 2 SC>4 and concentrated to dryness. The material was suspended in 1 : 1 EtO Ac/Hex, sonicated and the solid collected via filtration and dried.
  • Example A2 A mixture of Example Al (10.0 g, 28.9 mmol), benzophenone hydrazone (5.46 g, 27.8 mmol), 2,2'-bis(diphenylphosphino)-l,l '-binaphthalene (1.13 g, 1.82 mmol), and sodium te/ -butoxide (3.90 g, 40.6 mmol) in toluene (57.7 mL) was sonicated and sparged with Ar for 10 min. Palladium(II) acetate (0.14 g, 0.61 mmol) was added and the reaction mixture was stirred vigorously at 105 °C for 16 h.
  • Example A3 Method 1 : Concentrated HC1 (21.31 mL, 256 mmol) was added to a solution of Example A2 (4.2 g, 10.1 mmol) in toluene (80 mL) and the reaction mixture was stirred at 110 °C for 1.5 h. The organic solvent was removed in vacuo and the remaining aqueous solution was diluted with water (50 mL), washed with toluene (2 x 20 mL), cooled in an ice bath, and adjusted to pH - 12 with 50 % NaOH (aq). The suspension was saturated with solid NaCl and extracted with EtOAc (3 x 50 mL).
  • Method 2 A suspension of Example CI (7.00 g, 49.6 mmol), Example Al (13.00 g, 37.5 mmol), copper iodide (0.700 g, 3.68 mmol), K 2 C0 3 (10.00 g, 72.4 mmol) and N1 ,N2- dimethylethane-l ,2-diamine (0.700 g, 7.94 mmol) in DMF (70 mL) was heated at 100 °C under argon overnight.
  • Example A4 Example A2 (9.2 g, 22.9 mmol) and l-methyl-4-(4,4,5,5-tetramethyl- 1 ,3,2- dioxaborolan-2-yl)- 1 H-pyrazole (6.2 g, 29.8 mmol) were dissolved in dioxane (92 mL). A solution of K 2 CO 3 (9.0 g, 65.1 mmol) in water (22.9 mL) was added and the mixture was sonicated and sparged with Ar for 10 min. Tetrakis(triphenylphosphine)-palladium(0)
  • Example A5 A solution of 5-bromo-2-nitropyridine (15 g, 73.9 mmol) in DMF (300 mL) was sparged with Ar, treated with CS 2 CO 3 (48.2 g, 148 mmol) and 2-chloro-4-hydroxypyridine (10.53 g, 81 mmol), sparged again with Ar and heated at 85°C overnight. The mixture was cooled to RT, filtered through a bed of silica gel, washed thoroughly with EtOAc, and the filtrate treated with 5% LiCl and stirred overnight. The layers were separated, the aqueous layer extracted with additional EtOAc (4x) and the combined organics were dried over Na 2 S0 4 and concentrated to dryness.
  • Example A6 Example A5 (1.0 g, 3.8 mmol) was added to a solution of HF-pyridine (5.6 mL, 62.0 mmol) in pyridine (5.6 mL) at 0 °C. The mixture was stirred for 30 min, cooled to -10 °C, and treated with sodium nitrite (0.39 g, 5.6 mmol). The mixture was allowed to warm to RT, stirred for 12 h, cooled back to 0 °C, and poured into cold sat. NaHC0 3 (aq) (50 mL). The slurry was extracted with EtOAc (3 x 50 mL) and the combined organics were dried (Na 2 S0 4 ) and concentrated in vacuo.
  • Example A7 DMF (25 mL) was slowly treated with SOQ 2 (125 mL) to maintain a temperature of 40-50°C. The mixture was then treated portion-wise with pyridine-2-carboxylic acid (25 g, 0.2 mol) over 0.5 h, then heated at reflux for 16 h, cooled to RT, diluted with toluene (80 mL) and concentrated to dryness (this process was repeated three times). The resulting residue was washed with toluene and dried under reduced pressure to yield 4-chloro-pyridine-2-carbonyl chloride (27.6 g, 79% yield), which was used in the next step without purification.
  • Example A8 A suspension of Example C5 (0.75 g, 4.19 mmol), Example Al (1.400 g, 4.04 mmol), copper iodide (0.080 g, 0.420 mmol), trans l,2-dimethylcyclohexane-l,2- diamine (0.090 g, 0.633 mmol) and K 2 C0 3 (1.00 g, 7.24 mmol) in DMF (15 mL) was briefly degassed and heated at 100 °C under argon for 8 hours. The residue was partitioned between dichloromethane (50mL) and water (50mL). The aqueous layer was separated and extracted with DCM (2 x 30mL). The combined organics were dried and concentrated to a small volume and subjected to chromatography using (0-100%
  • Example A9 A 0°C solution of H 2 S0 4 (12 mL) was treated with H 2 0 2 (9.72 mL, 95 mmol), stirred for 10 min, treated with a solution of 2-amino-5-fluoro-4-methylpyridine (2 g, 15.86 mmol) in H 2 SO 4 (8 mL), stirred for 15 min, then warmed to RT and stirred for 3 h. The mixture was re-cooled to 0°C, neutralized slowly with solid NaHC0 3 and the resulting solid collected via filtration and dried to afford 5-fluoro-4-methyl-2-nitropyridine (2 g, 81%). !
  • Example AlO A suspension of Example A9 (0.62 g, 2.2 mmol), KI (3.7 g, 22.3 mmol), and diiodomethane (5 mL, 62 mmol) was treated with i-butylnitrite (1.4 mL, 11.7 mmol) and stirred at RT for 12 h. The mixture was treated with EtOAc, washed successively with satd. NaHC0 3 (3x), 10 % Na 2 S 2 0 3 (2x), and brine (2x) and the combined aqueous washes were back-extracted with EtOAc (2x).
  • Example All A suspension of Example C6 (0.800 g, 5.22 mmol), Example Al (1.00 g, 2.89 mmol), copper iodide (0.050 g, 0.263 mmol), Cs 2 CO 3 (2.000 g, 6.14 mmol) and
  • Nl,N2-dimethylethane-l,2-diamine (0.050 g, 0.567 mmol) in acetonitrile (20 mL) was heated at 100 °C under argon for 14 hours. The solvent from the reaction mixture was evaporated and the residue was partitioned between DCM (50 mL) and water (50mL).
  • Example A12 4-(tert-butyl)-lH-imidazol-2(3H)-one (3 g, 21.40 mmol), copper(I) iodide (0.815 g, 4.28 mmol), and K 2 CO 3 (16.33 g, 118 mmol) were suspended in DMF (100 mL) and placed under an atmosphere of argon.
  • Example Al (8.16 g, 23.54 mmol) and then N,N-dimethylethane- 1,2-diamine (0.377 g, 4.28 mmol) were added and the reaction mixture was stirred at 100 °C overnight. The reaction mixture was allowed to cool to RT and concentrated to dryness under high vacuum.
  • Example Bl 2-(4-Fluorophenyl)acetonitrile (1.0 g, 7.4 mmol) was dissolved in anhydrous ethanol (2 mL) under an atmosphere of Ar. The solution was cooled to 0 °C, saturated with HC1 gas, stirred for 6 h, allowed to warm to RT, and stirred for 6 h. Organic solvent was removed in vacuo to afford ethyl 2-(4-fluorophenyl)acetimidate hydrochloride (1.6 g, 100 %) as a white solid. !
  • Ethyl 2-(4-fluorophenyl)acetimidate hydrochloride (1.6 g, 7.4 mmol) was suspended in hexanes (18.5 mL) and DCM (18.5 mL) at 0 °C. 2,4,6-collidine (3.9 mL, 29.6 mmol) and ethyl chloroformate (1.6 g, 14.8 mmol) were added sequentially and the reaction mixture was allowed to warm to RT and stirred for 12 h. The solvent was removed in vacuo and the residue was suspended in EtOAc (100 mL) and sonicated for 10 minutes.
  • Ethyl 2-phenylacetimidate hydrochloride (1.7 g, 8.5 mmol) was dissolved in DCM (10.6 mL) and cooled to 0 °C.
  • TEA 7.1 mL, 51.1 mmol
  • Ethyl chloroformate (1.6 g, 14.8 mmol) was added and the reaction mixture was allowed to warm to RT and stirred for 12 h.
  • the mixture was diluted with EtOAc (100 mL) and the solids were removed by filtration through diatomaceous earth.
  • Example B4 Ethyl pivalimidate hydrochloride (Example B3) (0.75 g, 4.5 mmol) was suspended in hexanes (1 1.3 mL) and DCM (1 1.3 mL) and cooled to 0 °C. 2,4,6-Collidine (2.1 mL, 15.9 mmol) and ethyl chloroformate (0.98 g, 9.1 mmol) were sequentially added and the reaction mixture was allowed to warm to RT and stirred for 12 h. The solvent was removed in vacuo and the residue was slurried with EtOAc (50 mL). The solids were removed by filtration through a pad of diatomaceous earth. The filter cake was washed with EtOAc (3 x 10 mL) and the combined filtrates were concentrated in vacuo to afford ethyl N-ethoxycarbonylpivalimidate
  • Example B5 Isobutyronitrile (1 g, 14.5 mmol) was dissolved in anhydrous ethanol (30 mL) under an atmosphere of Ar. The solution was cooled to 0 °C, saturated with HCl gas, stirred for 6 h, allowed to warm to RT, and stirred for 6 h. The solvent was removed in vacuo to afford ethyl isobutyrimidate hydrochloride (1.8 g, 82 %) as a colorless solid. !
  • Example B6 Cyclohexanecarbonitrile (1.0 g, 9.2 mmol) was dissolved in anhydrous ethanol under an atmosphere of Ar. The solution was cooled to 0 °C, saturated with HCl gas, stirred for 6 h, allowed to warm to RT, and stirred for 6 h. The solvent was removed in vacuo to afford ethyl cyclohexanecarbimidate hydrochloride (1.8 g, 100 %) as a colorless solid. ! H NMR (400 MHz,
  • Ethyl cyclohexanecarbimidate hydrochloride (1.8 g, 9.2 mmol) was suspended in hexanes (22.9 mL) and cooled to 0 °C. 2,4,6-Collidine (4.1 mL, 30.9 mmol) and ethyl chloroformate (1.9 g, 17.8 mmol) were sequentially added and the mixture was allowed to warm to RT and stirred for 12 h. The solvent was removed in vacuo. The residue was suspended in EtOAc (50 mL) and the solids were removed by filtration through diatomaceous earth.
  • Example B7 3-Methoxypropanenitrile (5.0 g, 58.8 mmol) was dissolved in anhydrous ethanol (50 mL) under an atmosphere of Ar. The solution was cooled to 0 °C, saturated with HC1 gas, stirred for 6 h, allowed to warm to RT, and stirred for 6 h. The solvent was removed in vacuo. The residue was slurried with hexanes (50 mL) and sonicated for 10 min. The solids were allowed to settle and the solvent was removed by decantation. This was repeated (3 x).
  • Ethyl 3-methoxypropanimidate hydrochloride (1.0 g, 6.0 mmol) was suspended in DCM (12 mL) and cooled to 0 °C. Pyridine (2 mL, 24.7 mmol) was added dropwise and the mixture was stirred for 15 min.
  • Ethyl chloro formate (0.97 g, 9.0 mmol) was added dropwise and the mixture was diluted with DCM (20 mL), allowed to warm to RT, and stirred for 12 h. The mixture was diluted with a mixture of EtOAc and hexanes (1 : 1 , 200 mL) and the solids were removed by filtration through a pad of diatomaceous earth.
  • Example B8 2-Methoxyacetonitrile (1.0 g, 14.1 mmol) was dissolved in anhydrous ethanol (28.1 mL) under an atmosphere of Ar. The solution was cooled to 0 °C, saturated with HC1 gas, stirred for 6 h, allowed to warm to RT, and stirred for 6 h. The solvent was removed in vacuo to afford ethyl 2-methoxyacetimidate hydrochloride (1.0 g, 44.0 %) as a white solid. !
  • Ethyl 2-methoxyacetimidate hydrochloride (0.95 g, 6.18 mmol) was suspended in DCM (12.4 mL) and the mixture was cooled to 0 °C. Pyridine (2.5 mL, 30.9 mmol) and ethyl chloro formate (1.2 mL, 12.4 mmol) were added sequentially and the solution was allowed to warm to RT and stirred for 12 h. EtOAc (100 mL) was added and solids were removed by filtration through a pad of diatomaceous earth. The filtrate was concentrated in vacuo to afford ethyl N-ethoxycarbonyl-2-methoxyacetimidate (1.2 g, 100 %) as a white solid.
  • Example B9 Isovaleronitrile (2.0 g, 24.1 mmol) was dissolved in anhydrous ethanol (48 mL) under an atmosphere of Ar. The solution was cooled to 0 °C, saturated with HC1 gas, stirred for 6 h, allowed to warm to RT, and stirred for 6 h. The solvent was removed in vacuo to afford ethyl 3-methylbutanimidate hydrochloride (4.0 g, 100 %) as a white solid. !
  • Ethyl 3-methylbutanimidate hydrochloride (4.0 g, 24.2 mmol) was suspended in DCM (48 mL) and the mixture was cooled to 0 °C. Pyridine (10.0 mL, 124 mmol) was added and the mixture was stirred for 15 minutes. Ethyl chloroformate (5.3 mL, 48.3 mmol) was added and the solution was allowed to warm to RT and stirred for 12 h. The mixture was diluted with a mixture of EtOAc and hexanes (1 : 1 , 200 mL) and solids were removed by filtration through a diatomaceous earth.
  • Example BIO Tetrahydro-2H-pyran-4-carbonitrile (1 g, 9.00 mmol) was dissolved in dry ethanol (10 mL) and cooled to 0 °C. HC1 (gas) was bubbled through the solution for five minutes. The reaction mixture was allowed to warm to RT and stir for 2 days. The solvent was removed under reduced pressure and the resulting solid was dried under high vacuum to yield ethyl tetrahydro-2H-pyran-4-carbimidate hydrochloride (1.646 g, 94%). !
  • Ethyl tetrahydro-2H-pyran-4-carbimidate hydrochloride (1.646 g, 8.50 mmol) was suspended in DCM (21.25 mL) and cooled to 0 °C. Pyridine (3.09 mL, 38.2 mmol) was added and the solution was stirred for 15 min. Ethyl chloroformate (1.384 g, 12.75 mmol) was added dropwise. The reaction mixture was allowed to warm to RT and stir overnight. The reaction mixture was diluted with 50 % hexane/EtOAc and the resulting suspension was filtered through a plug of diatomaceous earth.
  • Example CI Semicarbazide hydrochloride (25.0 g, 224 mmol) was dissolved in water (200 mL). NaHC0 3 (40.0 g, 476 mmol) was slowly added to the solution over 30 min at RT followed by the addition of trimethylacetyl chloride (30.0 g, 249 mmol). The mixture was stirred at RT for 12 h. Solids were collected by filtration, washed with cold water, and dried in vacuo. A solution of NaOH (20.0 g, 500 mmol) in water (200 mL) was added. The mixture was stirred at 100 °C for 2 h, cooled with an ice-bath, and neutralized by the drop-wise addition of concentrated HCl.
  • Example C2 2-Methoxyisobutyric acid (0.50 g, 4.23 mmol) was dissolved in MeCN (8.5 mL). lH-Benzo[d][l ,2,3]triazol-l-ol (20 % hydrate) (0.65 g, 4.23 mmol) and N-(3- dimethylaminopropyl)-7V-ethylcarbodiimide hydrochloride (0.81 g, 4.23 mmol) were added and the mixture was stirred at RT for 2 h. Semicarbazide hydrochloride (0.47 g, 4.23 mmol) was added and the mixture was stirred for an additional 12 h.
  • Example C3 2,2-Dimethylbutyric acid (1 g, 8.6 mmol) was dissolved in DCM (10 mL) and cooled to 0 °C. The solution was treated with oxalyl chloride (1.2 mL, 13.8 mmol) and DMF (0.07 mL, 0.87 mmol), allowed to warm to RT, and stirred for 2 h for complete conversion to 2,2-dimethylbutyric acid chloride.
  • Example C4 2-Methylcyclopropanecarboxylic acid (0.86 g, 8.6 mmol) was dissolved in DCM (10 mL) and cooled to 0 °C. The solution was treated with oxalyl chloride (1.2 mL, 13.8 mmol) and DMF (0.07 mL, 0.87 mmol), allowed to warm to RT, and stirred for 2 h for complete conversion to 2-methylcyclopropanecarboxylic acid chloride.
  • Example C5 4-Fluorobenzoyl chloride (2.50 g, 15.77 mmol) was added to a solution of semicarbazide hydrochloride (2.00 g, 17.93 mmol) and sodium bicarbonate (2.50 g, 29.8 mmol) in water (25 mL) and the mixture was stirred at RT for 2 h. The solids were collected by filtation, and washed and dried under suction to obtain a white solid.
  • Example C6 To a suspension of semicarbazide hydrochloride (5.00 g, 44.8 mmol) in DCM (100 mL) was added triethylamine (10.00 g, 99 mmol) and the mixture was stirred at -10 °C for 30 min. Cyclopentane carbonylchloride (5.00 g, 37.7 mmol) was added at the same temp and the mixture was allowed to warm to RT over night. The solvent from the reaction mixture was completely removed and the residue stirred in MeCN (200 mL) for 1 h. The solids were collected by filtration, washed and dried. The solid was treated with sodium hydroxide (7.00 g, 175 mmol) and water (20 mL).
  • Example C7 To a 0 °C solution of 1-trifluoromethyl-l-cyclobutylcarboxylic acid (1.50 g, 8.92 mmol) in DCM (15 mL) was added oxalyl chloride (1.50 g, 11.82 mmol) followed by catalytic amount of DMF. The reaction mixture was stirred at RT for 1 h. The solvent from the reaction mixture was completely evaporated. In a different flask, a suspension of semicarbazide hydrochloride (1.50 g, 13.45 mmol) in water (15mL) was treated with NaHC0 3 (1.50 g, 17.86 mmol) and stirred at RT for 30 minutes till a clear solution forms.
  • Example C8 3-Hydroxy-2,2-dimethylpropanoic acid (15.00 g, 127.0 mmol) was dissolved in a solution of MeOH (200 mL) and cone. H 2 SO 4 (13.5 g, 254 mmol) and stirred at reflux for 16 h. The reaction mixture was concentrated in vacuo, diluted with EtOAc (100 mL), washed with water (2 x 50 mL), sat. NaHC0 3 (aq) (50 mL), water (50 mL), brine (1 x 50 mL), and dried ( a 2 S0 4 ).
  • the reaction mixture was filtered through a pad of diatomaceous earth and the filter cake was washed with THF (2 x 35 mL). The filtrates were combined and diluted with water (150 mL). Lithium hydroxide hydrate (8.13 g, 194 mmol) was added and the reaction mixture was stirred at RT for 16 h. The aqueous phase was collected and the organic phase was extracted with 0.5 N NaOH (aq) (3 x 50 mL). The combined aqueous phases were washed with Et 2 0 (20 mL) and hexanes (2 x 100 mL), saturated with solid NaCl, and the pH of the solution was adjusted to ⁇ 2 by the careful addition of cone. HC1 (aq).
  • Example Dl A -78°C solution of 2-methylthiazole (2 g, 20.17 mmol) in THF (50 mL) was treated drop-wise with n-butyllithium (2.5 M in Hex, 10.49 mL, 26.2 mmol), stirred for 1 h, treated drop- wise with a solution of tributyltin chloride (7.11 mL, 26.2 mmol) in THF (25 mL) and stirred for an additional 1 h at -78°C. The mixture was allowed to warm to RT, stirred for 1 h, treated slowly with ice-cold satd. NaHC0 3 (20 mL) and quickly extracted with Et 2 0 (3X).
  • Example D2 A solution of 4-iodopyrazole (20g, 0.10 mol) in anhydrous DMF (300 mL) was treated with Cs 2 C0 3 (32.5g, 0.10 mol) and 2-(2-bromoethoxy)tetrahydro-2H pyran. The resultant reaction mixture was stirred at 70 °C overnight. The cooled mixture was diluted with EtOAc (500 mL) and water (500 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with water, dried over Na 2 SC>4, and concentrated to afford yellow oil.
  • Example 1 Example A4 (0.05 g, 0.17 mmol) and Example Bl (0.43 g, 1.7 mmol) were suspended in toluene (0.35 mL). The mixture was stirred at 45 °C for 30 min and allowed to cool to RT. TEA (0.05 mL, 0.4 mmol) was added and the mixture was stirred at 100 °C for 12 h. The reaction was concentrated in vacuo and the residue was purified by silica gel chromatography (MeOH/DCM).
  • Example 2 Example A4 (0.05 g, 0.17 mmol) and Example B2 (0.40 g, 1.7 mmol) were suspended in toluene (0.35 mL). The mixture was stirred at 45 °C for 30 min and allowed to cool to RT. TEA (0.05 mL, 0.4 mmol) was added and the mixture was stirred at 100 °C for 12 h. The reaction was concentrated in vacuo and the residue was purified by silica gel chromatography (MeOH/DCM).
  • Example 3 Example A6 (0.2 g, 0.71 mmol) and Example Bl (1.8 g, 7.1 mmol) were suspended in toluene (1.4 mL). The mixture was stirred at 45 °C for 30 min and allowed to cool to RT. TEA (0.22 mL, 1.6 mmol) was added and the mixture was stirred at 100 °C for 12 h. The reaction was concentrated in vacuo and the residue was purified by silica gel chromatography (MeOH/DCM).
  • Example 4 Example A6 (0.2 g, 0.71 mmol) and Example B4 (1.4 g, 7.1 mmol) were suspended in toluene (1.4 mL). The mixture was stirred at 45 °C for 30 min and allowed to cool to RT. TEA (0.22 mL, 1.6 mmol) was added and the mixture was stirred at 100 °C for 12 h. The reaction was concentrated in vacuo and the residue was purified by silica gel chromatography
  • Example 5 Example A4 (0.08 g, 0.27 mmol) and Example B5 (0.51 g, 2.7 mmol) were suspended in toluene (0.54 mL). The mixture was stirred at 45 °C for 30 min and allowed to cool to RT. TEA (0.08 mL, 0.6 mmol) was added and the mixture was stirred at 100 °C for 12 h. The reaction was concentrated in vacuo and the residue was purified by silica gel chromatography (MeOH/DCM).
  • Example 6 Example A4 (0.08 g, 0.27 mmol) and Example B6 (0.61 g, 2.7 mmol) were suspended in toluene (0.54 mL). The mixture was stirred at 45 °C for 30 min and allowed to cool to RT. TEA (0.08 mL, 0.6 mmol) was added and the mixture was stirred at 100 °C for 12 h. The reaction was concentrated in vacuo and the residue was purified by silica gel chromatography (MeOH/DCM).
  • Example 7 Method 1 : Example A4 (0.2 g, 0.68 mmol) and Example B3 (0.22 g, 1.4 mmol) were suspended in DCE (1 mL) and stirred at RT for 30 min. The mixture was diluted with DCM
  • Method 2 A suspension of Example A3 (3.00 g, 8.34 mmol), l-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (3.00 g, 14.42 mmol), K 2 C0 3 (3.000 g, 21.71 mmol) in dioxane/water (10: 1) (60 mL) was degassed for 5 minutes with argon purge. The reaction mixture was treated with Pd(PPh 3 )4 (0.300 g, 0.260 mmol) heated at 100 °C under argon over night. The residue was partitioned between dichloromethane (150mL) and water (150mL).
  • Example 8 2-Amino-6-ethylpyridine (3.0 g, 24.6 mmol) was dissolved in chloroform (25 mL) and cooled to 0 °C. NBS (4.4 g, 24.6 mmol) was added portion-wise over 30 min and the mixture was stirred for 30 min at 0 °C. The solvent was removed in vacuo and the residue was slurried with EtOAc (8 mL). The resultant solids were removed by filtration through a pad of diatomaceous earth and filtrate was concentrated in vacuo.
  • NBS 4.4 g, 24.6 mmol
  • the filter cake was washed with EtOAc (2 x 15 mL) and the combined filtrates were concentrated in vacuo. The residue was slurried with EtOAc (6 mL) and warmed to 77 °C for 5 min. Solids were collected by filtration, slurried with EtOAc (10 mL), and warmed to 77 °C for 5 min. The slurry was immediately filtered to collect solid product. The filtrates were combined and purified by silica gel chromatography (MeOH/EtOAc).
  • Example 9 K 2 CO 3 (0.1 g, 0.72 mmol) was dissolved in water (0.2 mL) and the solution was diluted with dioxane (1.2 mL).
  • Example A3 (0.10 g, 0.28 mmol) and 2-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (0.08 g, 0.37 mmol) were added and the mixture was sonicated and sparged with Ar for 10 min.
  • Pd(PPh 3 )4 0.04 g, 0.04 mmol was added and the reaction mixture was stirred at 85 °C for 16 h.
  • the purified product was dissolved in MeCN and water, frozen to -78 °C, and lyophilized to afford 3-(/er/-butyl)-l-(6-methyl-5-((2'- methyl-[2,4'-bipyridin]-4-yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one (0.038 g, 29.8 %) as a yellow solid.
  • Example 10 K 2 CO 3 (0.1 g, 0.72 mmol) was dissolved in water (0.2 mL) and the solution was diluted with dioxane (1.2 mL).
  • Example A3 (0.10 g, 0.28 mmol) and 2-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (0.08 g, 0.37 mmol) were added and the mixture was sonicated and sparged with Ar for 10 min.
  • Pd(PPh 3 )4 (0.04 g, 0.04 mmol) was added and the reaction mixture was stirred at 85 °C for 16 h.
  • Example 11 Example A3 (0.09 g, 0.25 mmol), acetamide (0.065 g, 1.1 mmol), Cs 2 C0 3 (0.09 g, 0.28 mmol), and X-Phos (0.012 g, 0.025 mmol) were combined and suspended in dioxane (1.5 mL) and the mixture was sonicated and sparged with Ar for 10 min. Pd 2 (dba) 3 (0.023 g, 0.025 mmol) was added and the mixture was stirred at 80 °C for 16 h. EtOAc (10 mL) was added and solids were removed by filtration through a pad of diatomaceous earth.
  • Example 12 Example A3 (0.20 g, 0.56 mmol) and Example Dl (0.28 g, 0.72 mmol) were suspended in toluene (3 mL). The mixture was sonicated and sparged with Ar for 10 minutes. Pd(PPh 3 )4 (0.03 g, 0.03 mmol) was added and the reaction mixture was stirred at 105 °C for 12 h. Additional Pd(PPh 3 )4 (0.02 g, 0.02 mmol) was added and stirring was continued at 105 °C for 18 h.
  • Example 13 A suspension of Example 7 (0.050 g, 0.12 mmol) in acetone (2.5 mL) was treated with CS 2 CO 3 (0.080 g, 0.25 mmol) and iodomethane (0.02 mL, 0.32 mmol) and the mixture was stirred at RT for 12 h. The solvent was removed in vacuo and the residue was dissolved in DCM (3 mL) and washed with water (3 mL). The aqueous phase was extracted with DCM (4 x 5 mL) and the combined organics were dried (MgSC ⁇ ) and concentrated in in vacuo.
  • Example 14 In a sealed tube, PdCl 2 (dppf)-CH 2 Ci 2 (0.025 g, 0.030 mmol), potassium acetate (0.089 g, 0.908 mmol), bis(pinacolato)diboron (0.1 15 g, 0.454 mmol) and 4-(4-bromo-phenyl)-l- methyl-piperidine (0.1 g, 0.393 mmol) were suspended in dioxane (6 mL). The mixture was degassed with Ar and heated at 100 °C for 20 h.
  • Example A3 (0.109 g, 0.303 mmol), Pd(PPh 3 ) 4 (0.035 g, 0.030 mmol), K 2 C0 3 (0.125 g, 0.908 mmol) and water (1.500 mL) were added.
  • the reaction was degassed with Ar and heated at 100 °C for 3 h.
  • the mixture was partitioned between EtOAc and IN NaOH and extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried and evaporated.
  • the crude product was purified by reverse phase chromatography (C-18) eluting with water/acetonitrile (0.1% TFA). Fractions containing the desired product were combined and concentrated until mostly water remained.
  • Example 15 Example A4 (0.20 g, 0.68 mmol) and Example B7 (0.27 g, 1.35 mmol) were suspended in DCM (1.4 mL). The mixture was cooled to 0 °C and stirred for 30 min. TEA (0.60 mL, 4.30 mmol) was added dropwise and the reaction mixture was warmed to 40 °C and stirred for 12 h. Sat. NH 4 CI (aq) (3 mL) was added and the mixture was extracted with EtOAc (4 x 5 mL). The combined organics were dried (Na 2 SC>4) and concentrated in vacuo.
  • Example 16 Example C2 (0.075 g, 0.48 mmol), copper ⁇ iodide (0.01 g, 0.05 mmol), and K 2 CO3 (0.20 g, 1.45 mmol) were suspended in DMF (1 mL). The mixture was sonicated and sparged with Ar for 10 min.
  • Example Al (0.34 g, 0.98 mmol) and N,N-dimethylethane-l ,2- diamine (10 mg, 0.11 mmol) were sequentially added and the mixture was stirred under an atmosphere of Ar at 100 °C for 12 h. Water (10 mL) was added and the mixture was extracted with EtOAc (5 x 10 mL).
  • Example 17 Example A4 (0.20 g, 0.68 mmol) and Example B8 (0.26 g, 1.4 mmol) were suspended in DCM (1.4 mL). The mixture was cooled to 0 °C and stirred for 30 min. TEA (0.60 mL, 4.3 mmol) was added dropwise and the mixture was stirred at 40 °C for 12 h. Sat. NH 4 CI (aq) (15 mL) was added and the mixture was extracted with DCM (4 x 10 mL). The combined organics were dried (Na 2 S04) and concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM).
  • Example 18 Example A3 (0.20 g, 0.56 mmol) and Example D2 (0.14 g, 0.43 mmol) were dissolved in dioxane (1.8 mL). A solution of K 2 C0 3 (0.15 g, 1.11 mmol) in water (0.36 mL) was added and the mixture was sonicated and sparged with Ar for 10 min. Pd(PPh 3 ) 4 (0.05 g, 0.04 mmol) was added and the mixture was stirred at 85 °C for 12 h. Water (5 mL) was added and the mixture was extracted with EtOAc (4 x 15 mL).
  • Example 19 To a degassed solution of dioxane (12 mL) and toluene (3 mL) was added Pd 2 (dba) 3 (0.020 g, 0.022 mmol) and Me 4 tBuXPhos (0.020 g, 0.042 mmol) and the mixture was heated in a sealed vessel (vol. 40mL) at 110 °C for 5minutes. The reaction mixture was cooled to T and Example A3 (0.250 g, 0.695 mmol), 4-methylimidazole (0.100 g, 1.218 mmol) and potassium phosphate (0.300 g, 1.413 mmol) were added. The vessel was sealed and heated at 110 °C for 14 hours.
  • Pd 2 (dba) 3 0.020 g, 0.022 mmol
  • Me 4 tBuXPhos 0.020 g, 0.042 mmol
  • Example 20 Example A4 (0.2 g, 0.675 mmol) was suspended in DCM (3 mL) and cooled to 0
  • Example B10 0.309 g, 1.350 mmol
  • DCM 3.75 mL
  • TEA 0.659 mL, 4.72 mmol
  • the mixture was heated at 40 °C for 3 days.
  • the reaction was cooled to RT and partitioned between DCM and saturated NaHC0 3 (aq) and the aqueous was extracted with
  • Example 21 A round bottom flask was charged with Example A3 (0.189 g, 0.525 mmol) in dioxane (5 mL) and sparged with Ar under sonication for 20 minutes after which 1- methylpiperidine-4-carboxamide (0.149 g, 1.051 mmol), CS2CO3 (0.342 g, 1.051 mmol), and DPPF (0.029 g, 0.053 mmol) was added and the mixture sparged with Ar under sonication for 15 minutes.
  • Pd 2 (dba) 3 (0.024 g, 0.026 mmol) was added and the mixture was sparged with Ar under sonication for 15 minutes. The reaction was then heated to 100 °C under Ar and stirred overnight.
  • reaction mixture was cooled to RT, sparged with Ar under sonication and added Pd 2 (dba) 3 (0.024 g, 0.026 mmol), DPPF (0.029 g, 0.053 mmol), sparged with Ar under sonication and then heated to 100 °C and stirred overnight.
  • the reaction mixture was cooled to RT, sparged with Ar under sonication and added Pd 2 (dba) 3 (0.024 g, 0.026 mmol), DPPF (0.029 g, 0.053 mmol), sparged with Ar under sonication and then heated to 100 °C and stirred overnight.
  • the reaction mixture was cooled to RT, diluted with EtOAc and filtered through diatomaceous earth and washed with EtOAc. The filtrates were concentrated to dryness to afford a brown solid.
  • the crude product was subject to reverse-phase silica gel chromatography (10% - 45% MeCN/water, 0.1% TFA). The appropriate fractions were collected, concentrated and stirred with EtOAc and sat'd NaHC0 3 . The aqueous layer was back-extracted with EtOAc (3x), the organic phases combined, dried (Na 2 S0 4 ) and concentrated to dryness to afford a white solid.
  • Example 22 Example A4 (0.20 g, 0.68 mmol) was suspended in DCM (6 mL) and cooled to 0 °C.
  • Example B9 (0.27 g, 1.4 mmol) was added and the reaction mixture was allowed to warm to RT, stirred for 30 min, and cooled back to 0 °C.
  • TEA (0.56 mL, 4.1 mmol) was added dropwise and the mixture was stirred at RT for 12 h. Sat. NH 4 CI (aq) (15 mL) was added and the resultant suspension was extracted with DCM (4 x 10 mL). The combined organics were dried ( a 2 S0 4 ) and concentrated in vacuo.
  • the resultant residue was purified by a three step sequence involving silica gel chromatography (MeOH/DCM), reverse-phase chromatography (30 g CI 8 column) [MeCN(0.1 % TFA)/water(0.1 % TFA)], and additional silica gel chromatography (EtOAc/DCM and MeOH/EtOAc) to afford a colorless solid.
  • Example 23 To a degassed solution of Example A3 (0.200 g, 0.556 mmol) in toluene
  • Example 24 A mixture of Example A3 (0.060 g, 0.17 mmol), 4-(4,4,5,5-tetramethyl- 1 ,3,2- dioxaborolan-2-yl)-lH-pyrazole (0.042 g, 0.22 mmol) and K 2 CO 3 (0.060 g, 0.43 mmol) were suspended in dioxane (0.70 mL) and water (0.14 mL). The mixture was sonicated and sparged with Ar for 10 min. Pd(PPh 3 )4 (0.019 g, 0.017 mmol) was added and the reaction mixture was stirred at 85 °C for 12 h.
  • Example 25 Example C3 (0.21 g, 1.3 mmol), copper(I) iodide (0.050 g, 0.26 mmol), and K 2 CO 3 (1.0 g, 7.2 mmol) were suspended in DMF (6 mL) under an atmosphere of Ar.
  • Example Al (0.50 g, 1.4 mmol) and N,N-dimethylethane-l,2-diamine (0.023 g, 0.26 mmol) were added sequentially and the reaction mixture was stirred at 100 °C for 12 h. Sat. NH 4 CI (aq) (30 mL) was added and the resultant emulsion was extracted with EtOAc (5 x 25 mL).
  • Example 26 Example CI (0.055 g, 0.392 mmol), copper (I) iodide (0.01 1 g, 0.060 mmol), Example A7 (0.107 g, 0.301 mmol), N,N-dimethylethane-l,2-diamine (5.31 mg, 0.060 mmol) and K 2 CO 3 (0.230 g, 1.663 mmol) were suspended in DMF (3 mL) and degassed with Ar. The reaction mixture was stirred at 100 °C for 20 h. The reaction was cooled to RT and partitioned between DCM and saturated NH 4 CI (aq). The mixture was extracted with saturated NH 4 CI (aq) (2x). The combined aqueous extracts were back-extracted with DCM (3x). The organic extracts were combined, dried and evaporated. The crude product was purified by silica gel
  • Example 27 Example C4 (0.18 g, 1.3 mmol), copper(I) iodide (0.050 g, 0.26 mmol), and K 2 C0 3 (1.0 g, 7.2 mmol) were suspended in DMF (6 mL) under an atmosphere of Ar.
  • Example Al (0.50 g, 1.4 mmol) and N,N-dimethylethane-l,2-diamine (0.023 g, 0.26 mmol) were added sequentially and the reaction mixture was stirred at 100 °C for 12 h. Sat. NH 4 CI (aq) (30 mL) was added and the resultant emulsion was extracted with EtOAc (5 x 25 mL).
  • Example 28 A suspension of Example A8 (0.300 g, 0.754 mmol), l-methyl-4-
  • Example 29 A solution of Pd 2 (dba) 3 (0.012 g, 0.013 mmol) and Me 4 tBuXPhos (0.012 g, 0.025 mmol) in toluene (2 mL) and dioxane (4 mL) was heated in a screw capped tube (lOmL) at 120 °C for 3 min.
  • the reaction mixture was cooled to RT and the pre-formed catalyst was transferred to a re-sealable pressure tube (50mL) containing a degassed suspension of Example A8 (0.250 g, 0.628 mmol), 4-methyl imadazole (0.100 g, 1.218 mmol) and potassium phosphate (0.250 g, 1.178 mmol) in a mixture of toluene (4 mL) and dioxane (8 mL) followed by heating at 110 °C for 8 hours. The solids from the reaction mixture was filtered and washed with DCM and THF.
  • Example 30 A suspension of Example A3 (0.250 g, 0.695 mmol), ⁇ , ⁇ -dimethyl urea (0.100 g, 1.135 mmol), Cs 2 C0 3 (0.500 g, 1.535 mmol) and Xantphos (0.016 g, 0.028 mmol) in dioxane (20 mL) was purged with argon for 5 minutes. Pd 2 (dba) 3 (0.025 g, 0.028 mmol) was added and the reaction mixture was heated in a reclosable sealed tube (50 mL) at 100 °C. The solids from the reaction mixture was filtered and washed with DCM and THF.
  • Example 31 Example CI (0.10 g, 0.71 mmol), copper(I) iodide (0.022 g, 0.116 mmol), and K 2 CO 3 (0.44 g, 3.2 mmol) were combined in DMF (3 mL) under argon.
  • Example A10 (0.25 g, 0.64 mmol) and N,N-dimethylethane-l ,2-diamine (0. 010 g, 0.12 mmol) were added sequentially and the reaction mixture was stirred at 100 °C for 18 h. Sat. NH 4 CI (aq) (10 mL) was added and the resultant suspension was extracted with EtOAc ( 4 x 20 mL).
  • Example 32 A suspension of Example A8 (0.250 g, 0.628 mmol), cyclopropane carboxamide (O.lOOg, 1.175 mmol), Cs 2 C0 3 (0.400 g, 1.228 mmol) and X-Phos (0.012 g, 0.025 mmol) in dioxane (20 mL) was purged with argon for 5 minutes. To the reaction mixture was added Pd 2 (dba) 3 (0.012 g, 0.013 mmol) and the mixture wass heated in a reclosable sealed tube (lOOmL) at 110 °C for 8 h. The solids from the reaction mixture was filtered and washed with DCM and THF.
  • dba reclosable sealed tube
  • Example 33 A solution of concentrated H 2 SO 4 (9 mL) was cooled to 0 °C and the temperature was carefully maintained as 30 % H 2 0 2 (6.1 mL, 60 mmol) was added over 30 min and 5-bromo- 4,6-dimethylpyridin-2-amine (2.0 g, 9.95 mmol) in sulphuric acid (6 mL) was added over 2 h. The solution was allowed to warm to RT and stirred for 1 h. The mixture was poured onto ice (200 g), and the resultant suspension was stirred as it warmed to RT.
  • the mixture was diluted with MeCN (10 mL), additional ieri-butylnitrite (1.0 mL, 8.3 mmol) was added and stirring was continued at RT for 24 h.
  • the reaction mixture was partitioned between EtOAc (120 mL) and sat. NaHC0 3 (aq) (20 mL).
  • the aqueous phase was collected and the organic phase was washed with sat. NaHC0 3 (aq) (2 x 20 mL), 10 % Na 2 S 2 0 3 (aq) (2 x 20 mL), and brine (2 x 20 mL).
  • Example CI (0.10 g, 0.71 mmol), copper(I) iodide (0.020 g, 0.11 mmol), and K 2 C0 3 (0.41 g, 3.0 mmol) were suspended in DMF (3 mL) under an atmosphere of Ar. 6-Iodo-2,4- dimethyl-3-((2-(l -methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridine (0.24 g, 0.59 mmol) and N,N-dimethylethane- 1 ,2-diamine (0. 010 g, 0.11 mmol) were added sequentially and the reaction mixture was stirred at 100 °C for 18 h. Sat.
  • Example 34 A suspension of Example All (0.340 g, 0.91 mmol), l-methyl-4-(4,4,5,5- tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.250 g, 1.202 mmol), Cs 2 C0 3 (0.680 g, 2.087 mmol) and Pd(PPh 3 ) 4 (0.050 g, 0.043 mmol) in MeCN (20 mL) was heated at 100 °C under argon for 4 hours. The solvent from the reaction mixture was completely evaporated and the residue was partitioned between DCM (50 mL) and water (50 mL).
  • Example 35 To a suspension of semicarbazide hydrochloride (5.00 g, 44.8 mmol) in DCM (100 mL) was added triethylamine (10.00 g, 99 mmol) and the mixture was stirred at -10 °C for 30 min. Cyclopropane carbonylchloride (5.00 g, 47.8 mmol) was added at the same temp and the mixture was stirred to T over night. The solvent from the reaction mixture was completely removed and the residue stirred in MeCN (200 mL) for 1 h. The solids were collected by filtration, washed and dried. The solid was transferred to a RB flask and treated with sodium hydroxide (7.00 g, 175 mmol) and water (20 mL).
  • Example 36 Semicarbazide hydrochloride (1.50 g, 13.6 mmol) was dissolved in water (15 mL).
  • Example Al (0.50 g, 1.44 mmol), 3-neopentyl-lH-l ,2,4-triazol-5(4H)-one (0.20 g, 1.29 mmol), and K 2 CO 3 (1.00 g, 7.24 mmol) were suspended in DMF (4.5 mL). The mixture was sonicated and sparged with Ar for 10 min followed by sequential addition of copper(I) iodide (0.05 g, 0.26 mmol) and N,N-dimethylethane- 1 ,2-diamine (0.02 g, 0.26 mmol). The reaction mixture was stirred at 100 °C for 12 h, allowed to cool to RT, and subsequently diluted with sat.
  • Example 37 To a 0 °C solution of cyclobutane carboxylic acid (7.50 g, 74.9 mmol) in DCM (100 mL) was added oxalyl chloride (12.00 g, 95 mmol) followed by catalytic amount of DMF. The resultant mixture was stirred at T for 1 h. The solvent from the reaction mixture was completely evaporated to a light coloured viscous mass. In a different RB flask, a suspension of semicarbazide hydrochloride (9.00 g, 81 mmol) in DCM (100 mL) was treated with triethylamine (18.00 g, 178 mmol) and stirred at -10 °C for 30 minutes.
  • Example 38 Example A3 (80 mg, 0.22 mmol), l-ethyl-4-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)-lH-pyrazole (55 mg, 0.24 mmol), and K 2 CO 3 (90 g, 0.66 mmol) were combined in the mixture of dioxane/water (4: 1 , 5 mL). The mixture was sparged with Ar and then Pd(PPh 3 )4 (26 mg, 0.022 mmol) was added. The mixture was sparge with Ar again and then heated at 90 °C overnight. The reaction mixture was diluted with saturated aqueous NaHC0 3 and then the solution was extracted with EtOAc (3x).
  • Example 39 Example A3 (0.14 g, 0.39 mmol), 5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)oxazole (0.10 g, 0.51 mmol), and K 2 CO 3 (0.14 g, 1.04 mmol) were suspended in a solution of dioxane (2.5 mL) and water (0.50 mL). The suspension was sonicated and sparged with Ar for 10 min. Pd(PPh 3 )4 (0.05 g, 0.04 mmol) was added and the reaction mixture was stirred at 85 °C for 12 h, allowed to cool to RT, diluted with sat.
  • Example 40 In a sealed tube, Pd(PPh 3 ) 4 (0.016 g, 0.014 mmol), K 2 C0 3 (0.115 g, 0.834 mmol), Example A3 (0.100 g, 0.278 mmol), and 2-(4-methylpiperazino)pyridine-5-boronic acid pinacol ester (0.126 g, 0.417 mmol) were suspended in dioxane (6 mL) and water (1.5 mL). The mixture was degassed with Ar and heated at 90 °C overnight. The reaction mixture was partitioned between EtOAc and IN NaOH and extracted with EtOAc (2x). The EtOAc extracts were combined and washed with brine.
  • Example 41 In a sealed tube, Pd(PPh 3 ) 4 (0.016 g, 0.014 mmol), K 2 C0 3 (0.1 15 g, 0.834 mmol), Example A3 (0.100 g, 0.278 mmol), and 2-(4-methylpiperazino)pyridine-4-boronic acid pinacol ester (0.126 g, 0.417 mmol) were suspended in dioxane (6 mL) and water (1.5 mL). The mixture was degassed with Ar and heated at 90 °C for 20 h. The reaction mixture was partitioned between EtOAc and IN NaOH and extracted with EtOAc (2x). The EtOAc extracts were combined and washed with brine.
  • Example 42 3-(Benzyloxy)-2,2-dimethylpropanoic acid (1.00 g, 4.80 mmol) was dissolved in DCM (10 mL) at RT. Oxalyl chloride (0.70 mL, 8.00 mmol) and DMF (0.10 mL, 1.29 mmol) were added sequentially and the reaction mixture was stirred at RT for 2 h. In a separate flask, semicarbazide hydrochloride (0.8 g, 7.24 mmol) and aOH (0.80 g, 20.0 mmol) were dissolved in a solution of dioxane (2.0 mL) and water (10.0 mL).
  • Example Al (0.40 g, 1.15 mmol), 3-(l-(benzyloxy)-2-methylpropan-2-yl)-lH-l ,2,4- triazol-5(4H)-one (0.29, 1.15 mmol), and K 2 C0 3 (1.00 g, 7.24 mmol) were combined in DMF (4.0 mL) and the mixture was sonicated and sparged with Ar for 10 min. Copper(I) iodide (0.04 g, 0.23 mmol) and N,N-dimethylethane- 1 ,2-diamine (0.02 g, 0.23 mmol) were added.
  • reaction mixture was stirred at 100 °C for 12 h, allowed to cool to RT, and subsequently diluted with 3 ⁇ 4 sat. NH 4 CI (aq.) (50 mL) and EtOAc (50 mL). The biphasic solution was mixed vigorously and extracted with EtOAc (2 x 50 mL)).
  • Example 43 A suspension of Example C7 (1.00 g, 4.83 mmol), Example Al (0.500 g, 1.443 mmol), copper iodide (0.050 g, 0.263 mmol), Cs 2 C0 3 (1.000 g, 3.07 mmol) and l ,N2- dimethylethane-l ,2-diamine (0.050 g, 0.567 mmol) in MeCN (20 mL) was heated at 100 °C under argon for 14 hours. The solvent from the reaction mixture was completely evaporated and the residue partitioned between DCM (50 mL) and water (50 mL). The organic layer was separated and the aqueous layer saturated with solid sodium chloride and extracted with DCM (2 x 20 mL).
  • Example 44 Example A13 (0.74 g, 2.87 mmol), potassium iodide (4.80 g, 28.9 mmol), and diiodomethane (6.00 mL, 74.4 mmol) were comnbined at RT. ieri-Butylnitrite (2.00 mL, 16.7 mmol) was added dropwise and the reaction mixture was stirred for 12 h at RT. The reaction mixture was diluted with MeCN (15 mL), additional ieri-butylnitrite (1.00 mL, 8.34 mmol) was added and stirring was continued for an additional 24 h. The mixture was partitioned between sat. NaHC0 3 (aq) (80 mL) and EtOAc (200 mL).
  • the aqueous phase was removed and the organic phase was wshed with sat. NaHC0 3 (aq) (1 x 50 mL), 10 % Na 2 S 2 0 3 (aq) (2 x 35 mL), and brine (2 x 35 mL).
  • the combined aqueous washes were back-extracted with EtOAc (1 x 50 mL).
  • the combined organics were dried (MgSO ⁇ and concentrated in vacuo.
  • N-(4-((6-iodo-4-methylpyridin-3-yl)oxy)pyridin-2-yl)acetamide (0.15 g, 0.41 mmol)
  • Example C2 (0.11 g, 0.70 mmol)
  • K 2 C0 3 (0.55 g, 3.98 mmol) were suspended in DMF (5 mL). The suspension was sonicated and sparged with Ar for 10 min. Copper(I) iodide (0.03 g, 0.16 mmol) and N,N-dimethylethane-l,2-diamine (0.012 g, 0.14 mmol) were added and the reaction mixture was stirred at 100 °C for 12 h.
  • reaction mixture was diluted with EtOAc (5 mL) and filtered through a pad of diatomaceous earth.
  • the filter cake was washed with EtOAc (2 x 5 mL) and the combined filtrates were concentrated in vacuo.
  • the residue was purified by silica gel chromatography (MeOH/DCM) to provide impure product as a brown solid.
  • Example 45 A round bottom flask was charged with cyclopropane carboxamide (0.473 g, 5.56 mmol), Example A3 (0.400 g, 1.112 mmol), Cs 2 C0 3 (0.54 g, 1.668 mmol), XPhos (0.053 g, 0.11 1 mmol) and dioxane (6 mL). The mixture was sparged with Ar under sonication for 10 min. Pd 2 (dba) 3 (0.051 g, 0.056 mmol) was added and the mixture was sparged with Ar under sonication for 10 minutes. The reaction was then stirred at 100 °C overnight. The reaction was allowed to cool to RT, diluted with EtOAc.
  • Example 46 Example C8 (0.60 g, 3.50 mmol), Example Al (1.20 g, 3.50 mmol), and K 2 C0 3 (2.50 g, 18.1 mmol) were suspended in DMF (4.5 mL). The mixture was sonicated and sparged with Ar for 10 min followed by sequential addition of copper(I) iodide (0.13 g, 0.70 mmol) and N,N-dimethylethane- 1 ,2-diamine (0.06 g, 0.70 mmol). The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was partitioned between sat.
  • Example 47 2-Methylpyridin-3-ol (3.00 g, 27.5 mmol) was dissolved in a solution of Na 2 C0 3 (5.83 g, 55.0 mmol) in water (48 mL) and MeOH (30 mL). Iodine (6.98 g, 27.5 mmol) was added and the reaction mixture was stirred for 1 h at RT. The mixture was treated with 2 M HC1 solution (14 mL) and the resultant suspension was extracted with EtOAc (2 x 65 mL). The combined organics were washed with brine, dried (Na 2 S0 4 ) and concentrated.
  • Example CI (0.20 g, 1.42 mmol), 4-chloro-6-((6-iodo-2-methylpyridin-3- yl)oxy)pyrimidine (0.50 g, 1.44 mmol), and K 2 C0 3 (1.10 g, 7.94 mmol) were suspended in MeCN (14 mL). The suspension was sonicated and sparged with Ar for 10 min. Copper(I) iodide (0.055 g, 0.29 mmol) and N,N-dimethylethane-l ,2-diamine (0.020 g, 0.14 mmol) were added and the reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with sat.
  • Example 48 A round bottom flask was charged with Example A12 (2.4 g, 6.69 mmol), 1 - methyl-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole (1.531 g, 7.36 mmol), K 2 CO 3 (1.017 g, 7.36 mmol), dioxane (40 mL) and water (10 mL) and spargd with Ar under sonication for ⁇ 10 minutes. Pd(PPh 3 ) 4 (0.309 g, 0.268 mmol) was added and the reaction was sparged again with Ar under sonication for ⁇ 10 minutes and then heated to 100 °C overnight.
  • Example A12 2.4 g, 6.69 mmol
  • 1 - methyl-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole 1.531 g, 7.36 mmol
  • reaction mixture was allowed to cool to RT, and extracted with EtOAc and sat'd NaHC0 3 .
  • the Aqeous layer was back-extracted with EtOAc (3x), the organic phases combined, dried ( a 2 S04) and concentrated to dryness to afford a white solid.
  • Example 49 A mixture of Example A4 (0.20 g, 0.67 mmol) in DCM (4 mL) was cooled in an ice-water bath and treated with trimethylacetyl chloride (0.16 g, 1.35 mmol). The mixture was allowed to warm up to RT and stirred for 30 min. The reaction mixture was cooled to 0 °C and then diluted with DCM (4 mL). Triethylamine (0.5 mL, 3.61 mmol) was added and then a solution of triphosgene (80 mg, 0.26 mmol) in DCM (4 mL) was added drop-by-drop under the same conditions. The reaction mixture was allowed to warm to RT and stirred at RT overnight.
  • the following assays demonstrate that certain compounds of Formula I inhibit kinase activity of c-FMS kinase, c-KIT kinase, or PDGFRP kinase in enzymatic asssays and also inhibit the activity of c-FMS kinase in M-NFS-60 and THP- 1 cell lines.
  • In vivo evaluations of certain compounds of Formula I also demonstrate inhibition of c-FMS in a pharmcodynamic model or also exhibit efficacy in a peritibial implant model, a U-251 or GL-261 glioma model, or in a MDA-MB-231 breast cancer xenograft model.
  • uFMS kinase (Seq. ID No. 1) Assay
  • Activity of unphosphorylated c-FMS kinase was determined by following the production of ADP from the FMS kinase reaction with ATP and poly E4Y as substrates through coupling with the pyruvate kinase/lactate dehydrogenase system (e.g., Schindler et al. Science (2000) 289: 1938-1942). In this assay, the oxidation of NADH (thus the decrease at A340nm) was continuously monitored spectrophometrically.
  • the reaction mixture (100 contained FMS (purchased from Millipore) (10 nM), polyE4Y (1 mg/mL), MgCl 2 (10 mM), pyruvate kinase (4 units), lactate dehydrogenase (0.7 units), phosphoenol pyruvate (1 mM), NADH (0.28 mM) and ATP (500 ⁇ ) in 90 mM Tris buffer containing 0.2 % octyl- glucoside and 1 % DMSO, pH 7.5.
  • the inhibition reaction was started by mixing serial diluted test compound with the above reaction mixture. The absorption at 340 nm was monitored continuously for 4 hours at 30 °C on Synergy 2 plate reader.
  • reaction rate was calculated using the 3 to 4 h time frame. Percent inhibition was obtained by comparison of reaction rate with that of a control (i.e. in the absence of test compound).
  • IC 50 values were calculated from a series of percent inhibition values determined at a range of inhibitor concentrations using software routines as implemented in the GraphPad Prism software package.
  • Activity of unphosphorylated c-KIT kinase was determined by following the production of ADP from the KIT kinase reaction with ATP and poly E4Y as substrates through coupling with the pyruvate kinase/lactate dehydrogenase system (e.g., Schindler et al. Science (2000) 289: 1938-1942). In this assay, the oxidation of NADH (thus the decrease at A340nm) was continuously monitored spectrophometrically.
  • the reaction mixture (100 ⁇ ) contained unphosphorylated KIT (12 nM), polyE4Y (1 mg/mL), MgCl 2 (10 mM), pyruvate kinase (4 units), lactate dehydrogenase (0.7 units), phosphoenol pyruvate (1 mM), and NADH (0.28 mM) and ATP (2000 ⁇ ) in 90 mM Tris buffer containing 0.2 % octyl-glucoside and 1% DMSO, pH 7.5.
  • the inhibition reaction was started by mixing serial diluted test compound with the above reaction mixture. The absorption at 340 nm was monitored continuously for 4 hours at 30 °C on Synergy 2 plate reader (BioTech). Reaction rates around 3 to 4 h time frame were used to calculate % inhibitions, from which IC 50 values were generated.
  • Unphosphorylated PDGFRB (uPDGFRB) kinase (Sea. ID No. 3 assay
  • the reaction mixture (100 ⁇ ) contained PDGFRp (DeCode, 15.7 nM), polyE4Y (2.5 mg/mL), MgCl 2 (10 mM), pyruvate kinase (4 units), lactate dehydrogenase (0.7 units), phosphoenol pyruvate (1 mM) and NADH (0.28 mM) and ATP (500 ⁇ ) in a 90 mM Tris buffer containing 0.2% octyl-glucoside and 1% DMSO, at pH 7.5.
  • the inhibition reaction was started by mixing serial diluted test compound with the above reaction mixture.
  • M-NFS-60 cells (catalog #CRL-1838) were obtained from the American Type Culture Collection (ATCC, Manassas, VA). Briefly, cells were grown in suspension in RPMI 1640 medium supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, CA), 0.05 mM 2-mercaptoethanol, and 20 ng/mL mouse recombinant macrophage colony stimulating factor (M-CSF) at 37 °C, 5%C0 2 , and 95% humidity. Cells were allowed to expand until reaching saturation at which point they were subcultured or harvested for assay use.
  • ATCC American Type Culture Collection
  • M-CSF mouse recombinant macrophage colony stimulating factor
  • test compound was dispensed into a 384-well black clear bottom plate (Corning, Corning, NY). Two thousand five hundred cells were added per well in 50 ⁇ L complete growth medium. Plates were incubated for 67 h at 37 °C, 5%C0 2 , and 95% humidity. At the end of the incubation period 10 ⁇ . of a 440 ⁇ solution of resazurin (Sigma, St. Louis, MO) in PBS was added to each well and incubated for an additional 5 h at 37 °C, 5% C0 2 , and 95% humidity.
  • IC 50 values were calculated from a series of percent inhibition values determined at a range of inhibitor concentrations using software routines as implemented in the GraphPad Prism software package.
  • THP-1 cells (catalog #TIB-202) were obtained from the ATCC. Briefly, cells were grown in RPMI 1640 supplemented with 10% characterized fetal bovine serum, 1% sodium pyruvate, 1% Penicillin-Streptomycin-Glutamine (PSG) and 55uM 2-mercaptoethanol (Invitrogen, Carlsbad, CA) at 37 degrees Celsius, 5% C0 2 , 95% humidity. Cells were allowed to expand until reaching 70-95% confluency at which point they were subcultured or harvested for assay use.
  • PSG Penicillin-Streptomycin-Glutamine
  • test compound was diluted 1 : 100 in assay medium (RPMI 1640 supplemented with 10% characterized fetal bovine serum) in a 96 well black clear bottom plate (Corning, Corning, NY).
  • assay medium RPMI 1640 supplemented with 10% characterized fetal bovine serum
  • a separate 96 well black clear bottom plate one hundred and fifty thousand THP-1 cells were added per well in 100 ⁇ L ⁇ in assay medium. Fifty microliters of diluted compound was then added to the cells. Plates were incubated for 4 hours at 37 degrees Celsius, 5% C0 2 , 95% humidity. At the end of the incubation period, cells were stimulated with 50 ⁇ .
  • test compound was dispensed into a 384-well black clear bottom plate ( alge Nunc International, Rochester, NY). Compound was diluted by the addition of DMEM media supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, CA). Diluted compound was transferred to a 384-well black clear bottom plate. Two-thousand five hundred osteoclast precursors (Lonza, Walkersville, MD) were added per well in growth media containing Receptor Activator of Nuclear Factor Kappa-beta ligand (RANKL) and M- CSF (R&D Systems, Minneapolis, MN).
  • R&D Systems Minneapolis, MN
  • NT Not Tested; +: IC 50 > 1 uM; ++: 0.1 uM ⁇ IC 50 ⁇ 1 uM; +++: 0.01 uM ⁇ IC 50 ⁇ 0.1 uM; ++++: IC 50 ⁇ 0.01 uM

Abstract

Described are compounds of Formula I which find utility in the treatment of cancer, autoimmune diseases and metabolic bone disorders through inhibition of c-FMS (CSF-lR), c-KIT, and/or PDGFR kinases. These compounds also find utility in the treatment of other mammalian diseases mediated by c-FMS, c-KIT, or PDGFR kinases.

Description

l,2,4-TRIAZOL-5-ONES AND ANALOGS EXHIBITING ANTI-CANCER AND ANTIPROLIFERATIVE ACTIVITIES
Priority:
[0001] This application claims the benefit of U.S. Provisional Application No. 61/792,662, filed March 15, 2013. The entire disclosure of this application is relied on and incorporated into this application by reference.
Description of the Text File Submitted Electronically:
[0002] The contents of the text file submitted electronically herewith are incorporated herein by reference in their entirety: A computer readable format copy of the Sequence Listing (filename: DECP_061_01US_SeqList_ST25.txt, date recorded: March 15, 2014, file size 18 kilobytes).
Field of the Invention
[0003] Disclosed are compounds which find utility in the treatment of cancer, autoimmune diseases and metabolic bone disorders through inhibition of c-FMS (CSF-IR), c-KIT, and/or PDGFR kinases. These compounds also find utility in the treatment of other mammalian diseases mediated by c-FMS, c-KIT, or PDGFR kinases.
Background of the Invention
[0004] Autoimmune diseases, including autoimmune arthritis, represent significant human diseases of high morbidity and prevalence. Rheumatoid arthritis affects ~ 0.6% of the world population (Firestein, G.S., Nature (2003) 423: 356). While the adaptive immune response, involving generation of auto-antibodies which react with tissue antigen, is involved in the etiology and initial propagation of these diseases (Edwards, J.C. et al, New England Journal of Medicine (2004) 350: 2572; Genovese, M.C. et al, New England Journal of Medicine (2005) 353: 1 1 14), the chronic manifestations of tissue and joint damage are mediated in large part by cellular events mediated by the innate immune response (Firestein, G.S., Nature (2003) 423: 356; Paniagua, R.T. et al, Arthritis Research & Therapy (2010) 12: R32). Contributing cell types from the innate immune response which mediate chronic tissue damage include fibroblast- like synoviocytes, macrophages, mast cells, and osteoclasts.
[0005] Kinases represent a protein family that play critical roles in mammalian cell function, including cell proliferation, survival, motility, response to growth factors, and secretion of cytokines and other proinflammatory, proangiogenic, and immunomodulatory substances. Thus, elucidation of kinases which mediate these events in fibroblast-like synoviocytes, macrophages, mast cells, and osteoclasts represents a rational approach to new therapies for the treatment of autoimmune diseases.
[0006] Imatinib is a marketed kinase inhibitor for the treatment of the cancer chronic myelogenous leukemia (CML, Druker, B.J. et al, New England Journal of Medicine (2001) 344: 1031) and for the treatment of gastrointestinal stromal tumors (GIST, Demetri, G.D., et al, New England Journal of Medicine (2002) 347: 472). Imatinib has also shown benefit in cancer patients co-presenting with autoimmune diseases such as rheumatoid arthritis (Ihara, M.K. et al, Clinical Rheumatology (2003) 22: 362; Eklund, K.K. and Joensuu, H., Ann Medicine (2003) 35: 362; Ames, P.R. et al, Journal of Rheumatology (2008) 35: 1682). The kinases inhibited by imatinib which confer its efficacy in the treatment of CML and GIST are BCR-ABL kinase and c-KIT kinase, respectively. Beyond these two kinases, other kinases inhibited by imatinib include c-FMS, PDGFR-α/ρΑα, and FOGFR-beta (Dewer, A.L. et al, Blood (2005) 105: 3127; Fabian, M.A. et al, Nature Biotechnology (2005) 23: 329.
[0007] Recent research disclosures have identified c-FMS kinase to be associated with activation of synovial macrophages, PDGFR kinase to be associated with activation of fibroblast-like synoviocytes, and c-KIT kinase to be associated with activation of mast cells (Paniagua, R.T., et al Journal of Clinical Investigation (2006) 1 16: 2633). c-FMS kinase has also been associated with the proliferation and differentiation of monocytes into macrophages and osteoclasts, which are recruited to mediate joint damage in rheumatoid arthritis (Paniagua, R.T. et al, Arthritis Research & Therapy (2010) 12: R32; Yao, Z. et al, Journal of Biological Chemistry (2006) 281 : 1 1846; Patel, S. and Player, M.R. Current Topics in Medicinal Chemistry (2009) 9: 599; Pixley, F.J. et al, Trends in Cell Biology (2004) 14: 628).
[0008] In recent years, the importance of the tumor microenvironment in cancer motility, invasion, and metastasis has become more clearly defined. Specifically, the role of tumor- associated macrophages (TAMs) in tumor progression has been studied. These host (stromal) macrophages are recruited to tumor sites or to pre-metastatic niches to modify the tumor environment and render that environment more conducive to tumor motility, invasion and metastasis. These TAMs are known to express c-FMS receptor tyrosine kinase (also known as CSF-1R) on their surfaces and to rely on signaling through this kinase by binding to the activating ligands CSF- 1 (also known as macrophase colony stimulating factor, or MCSF) and interleukin-34 (IL-34). Activation of this c-FMS/MCSF (CSFl -R/CSF-1) signaling axis stimulates monocyte proliferation, differentiation into tumor associated macrophages, and promotion of macrophage cell survival. By stimulating the TAM component of the tumor microenvironment, c-FMS kinase activation is associated with tumor cell migration, invasion, and metastasis (J. Condeelis and J.W. Pollard, Cell (2006) 124: 263; S. Patel and M.R. Player, Current Topics in Medicinal Chemistry (2009) 9: 599). Ablation of CSF-1, the ligand for c- FMS kinase, in mice reduced tumor progression and significantly reduced metastasis in a murine model of breast cancer; whereas overexpression of CSF-1 accelerated metastasis in this model (E.Y. Lin et al, Journal of Experimental Medicine (2001) 193: 727). Furthermore, an interaction between tumor cells and macrophages has been described, wherein macrophage secretion of the tumor growth factor EGF and tumor cell secretion of CSF-1 establish a paracrine loop that promotes tumor migration and invasiveness. This paracrine loop was blocked by administration of an antibody to the c-FMS kinase (J. Wyckoff et al, Cancer Research (2004) 64: 7022). Correlative clinical data have also shown that overexpression of CSF- 1 in tumors is a predictor of poor prognosis (R.D. Leek and A.L. Harris, Journal of Mammary Gland Biology Neoplasia (2002) 7: 177; E.Y. Lin et al, Journal of Mammary Gland Biology Neoplasia (2002) 7: 147). c- FMS kinase activation is also required for osteoclast differentiation and activation. Its involvement in mediating bone metastases of various cancers, including breast and prostate cancers, has been reported (S. Patel and M.R. Player, Current Topics in Medicinal Chemistry (2009) 9: 599). High plasma concentrations of CSF-1 have been reported in bone metastatic prostate cancer, implicating activation of osteoclast c-FMS kinase in prostate cancer bone metastases (H. Ide, et al, Human Cell (2008) 21 : 1). c-FMS inhibitors have been reported to reduce radiographic bone lesions when evaluated in models of metastatic bone disease (C.L. Manthey, et al, Molecular Cancer Therapy (2009) 8: 3151 ; H. Ohno et al, Mol. Cancer Therapy (2006) 5: 2634). MCSF-mediated activation of both LYVE-1+ and LYVE1- macrophages also mediates pathological angiogenesis and lymphangiogenesis in murine models of cancer, and blockade of c-FMS signaling resulted in suppression of tumor angiogenesis/lymphangiogenesis (Y. Kubota et al., Journal of Experimental Medicine (2009) 206: 1089). Administration of a CSF-1R inhibitor blocked the recruitment of bone marrow derived TAMs and also bone marrow derived monocytic myeloid-derived suppressor cells (MDSCs) to tumor sites; this blockade led to a significant decrease in tumor angiogenesis and when combined with anti-VEGFR-2 therapy synergistically suppressed tumor growth (S.J. Priceman, et al. Blood (2010) 1 15: 1461). Irradiation of glioblastoma tumors in mice was shown to cause a temporary decrease in tumor size only to be followed by a rebound tumor vasculogenesis mediated by the recruitment of bone marrow derived monocytes expressing CD1 lb and F4/80 surface antigens (M. Kioi et al, Journal of Clinical Investigation (2010) 120: 694). CDl lb+ and F4/80+ monocytes are also known to express functional c-FMS receptors. Hence, blockade of tumor infiltrating C-FMS+ bone marrow derived monocytes by the use of c-FMS kinase inhibitors offers the potential to prevent tumor rebound vasculogenesis and glioblastoma tumor progression. CSF- 1R blockade has also been shown to reverse immuno tolerance mechanisms in an immunocompetent murine breast cancer model and promote the appearance of anti-tumor immune programs by upregulating CD8+ T-cell-mediated tumor suppression. Restoration of an anti-tumor immune program was mechanistically linked to c-FMS inhibitor blockade of TAM-mediated Programmed Death Ligand-1 (PDL- 1) immunotolerance (D. G. DeNardo, et al. Cancer Discovery (201 1) 1 : OF52).
[0009] Hence, small molecule inhibitors of c-FMS kinase, c-KIT kinase, or PDGFR kinases provide a rational approach to new therapies for the treatment of autoimmune diseases, and to particularly block the chronic tissue destruction mediated by the innate immune system. Inhibition of c-FMS kinase also provides a rational approach to new therapies for the treatment of cancers, especially for the treatment of cancer invasiveness, cancer angiogenesis or vasculogenesis, cancer metastasis, cancer immunotolerance, and for the treatment of cancers prone to bone metastases.
[0010] There is a need to provide kinase inhibitors which selectively inhibit kinases causative of the chronic tissue destruction in autoimmune disease (c-FMS, c-KIT, PDGFR), without inhibiting other kinases targeted by marketed cancer therapeutics (ABL, BCR-ABL, KDR, SRC, LCK, LYN, FGFR and other kinases). The present invention discloses novel inhibitors that inhibit c-FMS, c-KIT, and/or PDGFR kinases for the treatment of autoimmune diseases which also exhibit selectivity by not potently inhibiting other kinases including ABL, BCR-ABL, KDR, SRC, LCK, LYN, FGFR, MET and other kinases. The inhibitors of the present invention also find utility in the treatment of other mammalian diseases, including human diseases, mediated by c-FMS, c-KIT, or PDGFR kinases.
[0011] Such diseases include, without limitation, cancers, autoimmune diseases, and bone resorptive diseases.
Summary of the Invention
[0012] In one aspect, compounds of the Formula I are described:
Figure imgf000008_0001
Formula I
and pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof, wherein
A is selected from the group consisting of C1-C6 alkyl, branched C3-C8 alkyl, fluoroCl- C6alkyl wherein the alkyl is fully or partially fluorinated, C3-C8carbocyclyl, phenyl, 4-8 membered heterocyclic ring and heteroaryl, wherein each A moiety may be further substituted with one, two, or three R3 moieties;
W is C5-C6heteroaryl, phenyl, -NHC(0)R6, -NHC(0)R7, -NHC(0)N(R8)R9 or - C(0)N(R8)R9, and wherein each C5-C6heteroaryl or phenyl is optionally substituted by one, two, or three R5 moieties;
Ql is CH or ;
XI and X2 are individually and independently hydrogen or C1-C6 alkyl;
Y is NR4 or O;
Z is N or CR11 ;
each Rl and R2 is individually and independently hydrogen, C1-C6 alkyl, deutero-Cl-C6 alkyl wherein the alkyl chain is partially or completely deuterated, fluoroC 1 -C6alkyl wherein the alkyl is fully or partially fluorinated, hydro xyl, C1-C6 alkoxy, fluoroCl-C6alkoxy wherein the alkyl group is fully or partially fluorinated, or halogen; each R3 is individually and independently hydrogen, halogen, C1-C6 alkyl, fluoro-Cl-C6 alkyl wherein the alkyl chain is partially or completely fluorinated, branched C3-C8 alkyl, C3- C8 cycloalkyl, C1-C6 alkoxy, fluoro-Cl-C6 alkoxy wherein the alkyl chain is partially or completely fluorinated, branched C3-C6 alkoxy, hydroxyl, or cyano;
R4 is hydrogen, C1-C6 alkyl, deutero-Cl-C6 alkyl wherein the alkyl chain is partially or completely deuterated, or branched C3-C8 alkyl;
each R5 is individually and independently hydrogen, C1-C6 alkyl, deutero-Cl-C6 alkyl wherein the alkyl chain is partially or completely deuterated, branched C3-C8 alkyl, halogen, cyano, fluoro-Cl-C6 alkyl wherein the alkyl chain is partially or completely fluorinated, - (CH2)m-C(0)NR8(R9), -(CH2)m-C(0)R7, -(CH2)m-OR8, -(CH2)m-NR8(R9), or -(CH2)m-R7, wherein each alkylene is optionally substituted with C 1 -C4 alkyl;
each R6 is individually and independently hydrogen, C1-C6 alkyl, branched C3-C8 alkyl, C3-C8 cycloalkyl, -(CH2)m-CN, -(CH2)m-OR8, -(CH2)m-NR8(R9), or -(CH2)m-R7, wherein each alkylene is optionally substituted with C 1 -C4 alkyl;
each R7 is independently and individually selected from the group consisting of
Figure imgf000009_0001
and wherein the symbol (##) is the point of attachment to respective W, R5 or R6 moieties containing a R7 moiety; each R7 is optionally substituted with -(R10)p; each R8 and R9 is individually and independently hydrogen, C1 -C6 alkyl, fluoro-Cl-C6 alkyl wherein the alkyl chain is partially or completely fluorinated, or branched C3-C8 alkyl; each RIO is individually and independently C1-C6 alkyl, -(CH2)m-CN, -(CH2)m-OR3, - (CH2)m-NR8(R9), or -(CH2)m-C(0)-R6, wherein each alkyl or alkylene is optionally substituted with one or two C1-C6 alkyl;
wherein each alkylene is optionally substituted with C 1 -C4 alkyl;
Rl 1 is hydrogen, C1-C6 alkyl, deutero-Cl-C6 alkyl wherein the alkyl chain is partially or completely deuterated, or branched C3-C8 alkyl; each m is individually and independently 0, 1 , 2, or 3;
each n is individually and independently 0, 1 , 2, or 3;
each p is 0, 1 , 2, or 3;
each q is 0, 1 , or 2.
[0013] In one embodiment of Formula I, Y is NR4 or O.
[0014] In one embodiment of Formula I, Y is NR4.
[0015] In one embodiment of Formula I, Y is O.
[0016] In one embodiment of Formula I, Z is N or CR1 1.
[0017] In one embodiment of Formula I, Z is N.
[0018] In one embodiment of Formula I, Z is CR1 1. [0019] In one embodiment of Formula I, W is C5-C6heteroaryl optionally substituted by one, two, or three R5.
[0020] In one embodiment of Formula I, W is -NHC(0)R6, -NHC(0)R7, or - NHC(0)N(R8)R9.
[0021] In one embodiment of Formula I, W is -NHC(0)R6. [0022] In one embodiment of Formula I, W is -NHC(0)R7. [0023] In one embodiment of Formula I, W is -NHC(0)N(R8)R9. [0024] In one embodiment of Formula I, W is - C(0)N(R8)R9.
[0025] In one embodiment of Formula I, W is phenyl optionally substituted by one, two, or three R5.
[0026] In one embodiment of Formula I, XI and X2 are individually and independently hydrogen or C 1 -C6 alkyl.
[0027] In one embodiment of Formula I, XI and X2 are hydrogen.
[0028] In one embodiment of Formula I, one of XI and X2 is hydrogen and the other is Cl- C6alkyl.
[0029] In one embodiment of Formula I, A is taken from the group consisting of C1 -C6 alkyl, branched C3-C8alkyl, fluoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, C3-C8carbocyclyl, phenyl, a 4-8 membered heterocyclic ring and heteroaryl; and wherein each A moiety may be further substituted with one, two, or three R3 moieties. [0030] In one embodiment of Formula I, each Rl and R2 is individually and independently hydrogen, C1 -C6 alkyl, deutero-Cl-C6 alkyl wherein the alkyl chain is partially or completely deuterated, fiuoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, hydroxyl, C1-C6 alkoxy, fiuoroC 1 -C6alkoxy wherein the alkyl group is fully or partially fluorinated, or halogen.
[0031] In one embodiment of Formula I, each Rl is hydrogen.
[0032] In one embodiment of Formula I, each Rl and R2 is hydrogen.
[0033] In one embodiment of Formula I, each R3 is individually and independently hydrogen, halogen, C1 -C6 alkyl, fluoro-Cl-C6 alkyl wherein the alkyl chain is partially or completely fluorinated, branched C3-C8 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, fluoro-Cl-C6 alkoxy wherein the alkyl chain is partially or completely fluorinated, branched C3-C6 alkoxy, hydroxyl, or cyano.
[0034] In one embodiment of Formula I, q is 0, 1 , or 2.
[0035] In one embodiment of Formula I, q is 0.
[0036] In one embodiment of Formula I, q is 1.
[0037] In one embodiment of Formula I, q is 2.
[0038] In one embodiment of Formula I, n is 0, 1 , or 2.
[0039] In one embodiment of Formula I, n is 0.
[0040] In one embodiment of Formula I, n is 1.
[0041] In one embodiment of Formula I, n is 2.
[0042] In one embodiment of Formula I, n is 3. [0043] In one embodiment, the compound of Formula I is a compound of Formula la wherein: W is C5-C6heteroaryl, phenyl, -NHC(0)R6, -NHC(0)R7, -NHC(0)N(R8)R9 or - C(0)N(R8)R9, and wherein each C5-C6heteroaryl or phenyl is optionally substituted by one, two, or three R5 moieties; or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.
Figure imgf000013_0001
Formula la.
[0044] In one embodiment of Formula la, W is C5-C6heteroaryl optionally substituted by one, two, or three R5.
[0045] In one embodiment of Formula la, W is pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, triazolyl, or pyridinyl and wherein each W is optionally substituted by one, two, or three R5.
[0046] In one embodiment of Formula la, W is pyrazolyl optionally substituted by one, two, or three R5.
[0047] In one embodiment of Formula la, W is imidazolyl optionally substituted by one, two, or three R5.
[0048] In one embodiment of Formula la, W is isoxazolyl optionally substituted by one or two R5. [0049] In one embodiment of Formula la, W is oxazolyl optionally substituted by one or two R5.
[0050] In one embodiment of Formula la, W is thiazolyl optionally substituted by one or two R5.
[0051] In one embodiment of Formula la, W is triazolyl optionally substituted by one or two R5.
[0052] In one embodiment of Formula la, W is pyridinyl optionally substituted by one, two, or three R5.
[0053] In one embodiment of Formula la, W is -NHC(0)R6, -NHC(0)R7, or - NHC(0)N(R8)R9.
[0054] In one embodiment of Formula la, W is -NHC(0)R6.
[0055] In one embodiment of Formula la, W is -NHC(0)R7.
[0056] In one embodiment of Formula la, W is -NHC(0)N(R8)R9.
[0057] In one embodiment of Formula la, W is -C(0)N(R8)R9.
[0058] In one embodiment of Formula la, W is phenyl optionally substituted by one, two, or three R5.
[0059] In one embodiment of Formula la, XI and X2 are individually and independently hydrogen or C 1 -C6 alkyl.
[0060] In one embodiment of Formula la, XI and X2 are hydrogen. [0061] In one embodiment of Formula la, one of XI and X2 is hydrogen and the other is Cl- C6alkyl.
[0062] In one embodiment of Formula la, Y is NR4 and R4 is hydrogen, C1 -C6 alkyl, deutero-Cl-C6 alkyl wherein the alkyl chain is partially or completely deuterated, or branched C3-C8 alkyl.
[0063] In one embodiment of Formula la, Y is NR4 and R4 is hydrogen or C1 -C6 alkyl. [0064] In one embodiment of Formula la, Y is NR4 and R4 is hydrogen. [0065] In one embodiment of Formula la, Y is NR4 and R4 is C1-C6 alkyl. [0066] In one embodiment of Formula la, Y is O.
[0067] In one embodiment of Formula la, A is taken from the group consisting of C1 -C6 alkyl, branched C3-C8alkyl, fluoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, C3-C8carbocyclyl, phenyl, a 4-8 membered heterocyclic ring and heteroaryl; and wherein each A moiety may be further substituted with one, two, or three R3 moieties.
[0068] In one embodiment of Formula la, A is taken from the group consisting of C1 -C6 alkyl, branched C3-C8alkyl, C3-C8carbocyclyl, phenyl and a 4-8 membered heterocyclic ring; and wherein each A moiety may be further substituted with one, two, or three R3 moieties.
[0069] In one embodiment of Formula la, A is branched C3-C8alkyl, optionally further substituted with one, two, or three R3 moieties.
[0070] In one embodiment of Formula la, A is C3-C8carbocyclyl, optionally further substituted with one, two, or three R3 moieties. [0071] In one embodiment of Formula la, A is phenyl, optionally further substituted with one, two, or three R3 moieties.
[0072] In one embodiment of Formula la, A is a 4-8 membered heterocyclic ring, optionally further substituted with one, two, or three R3 moieties.
[0073] In one embodiment of Formula la, each Rl and R2 is individually and independently hydrogen, C1 -C6 alkyl, deutero-Cl-C6 alkyl wherein the alkyl chain is partially or completely deuterated, fiuoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, hydroxyl, C1-C6 alkoxy, fiuoroC 1 -C6alkoxy wherein the alkyl group is fully or partially fluorinated, or halogen.
[0074] In one embodiment of Formula la, each Rl is hydrogen.
[0075] In one embodiment of Formula la, each Rl and R2 is hydrogen.
[0076] In one embodiment of Formula la, each R3 is individually and independently hydrogen, halogen, C1 -C6 alkyl, fluoro-Cl-C6 alkyl wherein the alkyl chain is partially or completely fluorinated, branched C3-C8 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, fluoro-Cl-C6 alkoxy wherein the alkyl chain is partially or completely fluorinated, branched C3-C6 alkoxy, hydroxyl, or cyano.
[0077] In one embodiment of Formula la, q is 0, 1 , or 2. [0078] In one embodiment of Formula la, q is 0. [0079] In one embodiment of Formula la, q is 1. [0080] In one embodiment of Formula la, q is 2. [0081] In one embodiment of Formula la, n is 0, 1 , or 2. [0082] In one embodiment of Formula la, n is 0. [0083] In one embodiment of Formula la, n is 1. [0084] In one embodiment of Formula la, n is 2. [0085] In one embodiment of Formula la, n is 3.
[0086] In one embodiment, the compound of Formula I is a compound of Formula lb wherein: W is C5-C6heteroaryl, phenyl, -NHC(0)R6, -NHC(0)R7, -NHC(0)N(R8)R9 or - C(0)N(R8)R9, and wherein each C5-C6heteroaryl or phenyl is optionally substituted by one, two, or three R5 moieties; or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.
Figure imgf000017_0001
Formula lb.
[0087] In one embodiment of Formula lb, W is C5-C6heteroaryl optionally substituted by one, two, or three R5.
[0088] In one embodiment of Formula lb, W is pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, triazolyl, or pyridinyl and wherein each W is optionally substituted by one, two, or three R5. [0089] In one embodiment of Formula lb, W is pyrazolyl optionally substituted by one, two, or three R5.
[0090] In one embodiment of Formula lb, W is imidazolyl optionally substituted by one, two, or three R5.
[0091] In one embodiment of Formula lb, W is isoxazolyl optionally substituted by one or two R5.
[0092] In one embodiment of Formula lb, W is oxazolyl optionally substituted by one or two R5.
[0093] In one embodiment of Formula lb, W is thiazolyl optionally substituted by one or two R5.
[0094] In one embodiment of Formula lb, W is triazolyl optionally substituted by one or two R5.
[0095] In one embodiment of Formula lb, W is pyridinyl optionally substituted by one, two, or three R5.
[0096] In one embodiment of Formula lb, W is -NHC(0)R6, -NHC(0)R7, or - NHC(0)N(R8)R9.
[0097] In one embodiment of Formula lb, W is -NHC(0)R6.
[0098] In one embodiment of Formula lb, W is -NHC(0)R7.
[0099] In one embodiment of Formula lb, W is -NHC(0)N(R8)R9.
[0100] In one embodiment of Formula lb, W is - C(0)N(R8)R9. [0101] In one embodiment of Formula lb, W is phenyl optionally substituted by one, two, or three R5.
[0102] In one embodiment of Formula lb, XI and X2 are individually and independently hydrogen or C 1 -C6 alkyl.
[0103] In one embodiment of Formula lb, XI and X2 are hydrogen.
[0104] In one embodiment of Formula lb, one of XI and X2 is hydrogen and the other is Cl -C6alkyl.
[0105] In one embodiment of Formula lb, R4 is hydrogen, C1-C6 alkyl, deutero-Cl -C6 alkyl wherein the alkyl chain is partially or completely deuterated, or branched C3-C8 alkyl.
[0106] In one embodiment of Formula lb, R4 is hydrogen or C1-C6 alkyl.
[0107] In one embodiment of Formula lb, R4 is hydrogen.
[0108] In one embodiment of Formula lb, R4 is C1-C6 alkyl.
[0109] In one embodiment of Formula lb, A is taken from the group consisting of C1-C6 alkyl, branched C3-C8alkyl, fluoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, C3-C8carbocyclyl, phenyl, a 4-8 membered heterocyclic ring and heteroaryl; and wherein each A moiety may be further substituted with one, two, or three R3 moieties.
[0110] In one embodiment of Formula lb, A is taken from the group consisting of C1-C6 alkyl, branched C3-C8alkyl, C3-C8carbocyclyl, phenyl and a 4-8 membered heterocyclic ring; and wherein each A moiety may be further substituted with one, two, or three R3 moieties. [0111] In one embodiment of Formula lb, A is branched C3-C8alkyl, optionally further substituted with one, two, or three R3 moieties.
[0112] In one embodiment of Formula lb, A is tert-butyl, optionally further substituted with one, two, or three R3 moieties.
[0113] In one embodiment of Formula lb, A is tert-pentyl, optionally further substituted with one, two, or three R3 moieties.
[0114] In one embodiment of Formula lb, A is neo-pentyl, optionally further substituted with one, two, or three R3 moieties.
[0115] In one embodiment of Formula lb, A is isobutyl, optionally further substituted with one, two, or three R3 moieties.
[0116] In one embodiment of Formula lb, A is isopropyl, optionally further substituted with one, two, or three R3 moieties.
[0117] In one embodiment of Formula lb, A is C3-C8carbocyclyl, optionally further substituted with one, two, or three R3 moieties.
[0118] In one embodiment of Formula lb, A is cyclopropyl, optionally further substituted with one, two, or three R3 moieties.
[0119] In one embodiment of Formula lb, A is cyclobutyl, optionally further substituted with one, two, or three R3 moieties.
[0120] In one embodiment of Formula lb, A is cyclopentyl, optionally further substituted with one, two, or three R3 moieties. [0121] In one embodiment of Formula lb, A is cyclohexyl, optionally further substituted with one, two, or three R3 moieties.
[0122] In one embodiment of Formula lb, A is phenyl, optionally further substituted with one, two, or three R3 moieties.
[0123] In one embodiment of Formula lb, A is a 4-8 membered heterocyclic ring, optionally further substituted with one, two, or three R3 moieties
[0124] In one embodiment of Formula lb, A is tetrahydrofuranyl, optionally further substituted with one, two, or three R3 moieties.
[0125] In one embodiment of Formula lb, A is tetrahydropyranyl, optionally further substituted with one, two, or three R3 moieties.
[0126] In one embodiment of Formula lb, each R3 is individually and independently hydrogen, halogen, C1 -C6 alkyl, fluoro-Cl-C6 alkyl wherein the alkyl chain is partially or completely fluorinated, branched C3-C8 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, fluoro-Cl-C6 alkoxy wherein the alkyl chain is partially or completely fluorinated, branched C3-C6 alkoxy, hydroxyl, or cyano.
[0127] In one embodiment of Formula lb, n is 0, 1 , or 2. [0128] In one embodiment of Formula lb, n is 0. [0129] In one embodiment of Formula lb, n is 1. [0130] In one embodiment of Formula lb, n is 2. [0131] In one embodiment of Formula lb, n is 3. [0132] In one embodiment, the compound of Formula I is a compound of Formula Ic wherein: XI and X2 are individually and independently hydrogen or C1-C6 alkyl; or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.
Figure imgf000022_0001
Formula Ic.
[0133] In one embodiment of Formula Ic, XI and X2 are hydrogen.
[0134] In one embodiment of Formula Ic, one of XI and X2 is hydrogen and the other is Cl- C6alkyl.
[0135] In one embodiment of Formula Ic, one of XI and X2 is hydrogen and the other is methyl.
[0136] In one embodiment of Formula Ic, R3 is hydrogen, halogen, C1-C6 alkyl, fluoro-Cl- C6 alkyl wherein the alkyl chain is partially or completely fluorinated, branched C3-C8 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, fluoro-Cl-C6 alkoxy wherein the alkyl chain is partially or completely fluorinated, branched C3-C6 alkoxy, hydroxyl, or cyano.
[0137] In one embodiment of Formula Ic, R3 is hydrogen, C1-C6 alkyl, fluoro-Cl-C6 alkyl wherein the alkyl chain is partially or completely fluorinated, or C1-C6 alkoxy. [0138] In one embodiment of Formula Ic, R5 is hydrogen, C1-C6 alkyl, deutero-Cl-C6 alkyl wherein the alkyl chain is partially or completely deuterated, branched C3-C8 alkyl, -(CH2)m- C(0)NR8(R9), -(CH2)m-C(0)R7, -(CH2)m-OR8, -(CH2)m-NR8(R9), or -(CH2)m-R7, wherein each alkylene is optionally substituted with C 1 -C4 alkyl.
[0139] In one embodiment of Formula Ic, R5 is hydrogen, C1 -C6 alkyl, or deutero-Cl -C6 alkyl wherein the alkyl chain is partially or completely deuterated.
[0140] In one embodiment of Formula Ic, R5 is C1-C6 alkyl, or deutero-Cl -C6 alkyl wherein the alkyl chain is partially or completely deuterated.
[0141] In one embodiment of Formula Ic, R5 is methyl.
[0142] In one embodiment of Formula Ic, q is 0, 1 , or 2.
[0143] In one embodiment of Formula Ic, q is 0 or 1.
[0144] In one embodiment of Formula Ic, q is 0.
[0145] In one embodiment of Formula Ic, q is 1.
[0146] In one embodiment of Formula Ic, q is 2.
[0147] In one embodiment, the compound of Formula I is a compound of Formula Id wherein: W is C5-C6heteroaryl, phenyl, -NHC(0)R6, -NHC(0)R7, -NHC(0)N(R8)R9 or - C(0)N(R8)R9, and wherein each C5-C6heteroaryl or phenyl is optionally substituted by one, two, or three R5 moieties; or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.
Figure imgf000024_0001
Formula Id.
[0148] In one embodiment of Formula Id, W is C5-C6heteroaryl optionally substituted by one, two, or three R5.
[0149] In one embodiment of Formula Id, W is pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, triazolyl, or pyridinyl and wherein each W is optionally substituted by one, two, or three R5.
[0150] In one embodiment of Formula Id, W is pyrazolyl optionally substituted by one, two, or three R5.
[0151] In one embodiment of Formula Id, W is imidazolyl optionally substituted by one, two, or three R5.
[0152] In one embodiment of Formula Id, W is isoxazolyl optionally substituted by one or two R5.
[0153] In one embodiment of Formula Id, W is oxazolyl optionally substituted by one or two
R5.
[0154] In one embodiment of Formula Id, W is thiazolyl optionally substituted by one or two
R5. [0155] In one embodiment of Formula Id, W is triazolyl optionally substituted by one or two R5.
[0156] In one embodiment of Formula Id, W is pyridinyl optionally substituted by one, two, or three R5.
[0157] In one embodiment of Formula Id, W is -NHC(0)R6, -NHC(0)R7, or - NHC(0)N(R8)R9.
[0158] In one embodiment of Formula Id, W is -NHC(0)R6. [0159] In one embodiment of Formula Id, W is -NHC(0)R7. [0160] In one embodiment of Formula Id, W is -NHC(0)N(R8)R9. [0161] In one embodiment of Formula Id, W is - C(0)N(R8)R9.
[0162] In one embodiment of Formula Id, W is phenyl optionally substituted by one, two, or three R5.
[0163] In one embodiment of Formula Id, XI and X2 are individually and independently hydrogen or C 1 -C6 alkyl.
[0164] In one embodiment of Formula Id, XI and X2 are hydrogen.
[0165] In one embodiment of Formula Id, one of XI and X2 is hydrogen and the other is Cl-C6alkyl.
[0166] In one embodiment of Formula Id, Y is NR4 and R4 is hydrogen, C1-C6 alkyl, deutero-Cl-C6 alkyl wherein the alkyl chain is partially or completely deuterated, or branched C3-C8 alkyl. [0167] In one embodiment of Formula Id, Y is NR4 and R4 is hydrogen or C1-C6 alkyl. [0168] In one embodiment of Formula Id, Y is NR4 and R4 is hydrogen. [0169] In one embodiment of Formula Id, Y is NR4 and R4 is CI -C6 alkyl. [0170] In one embodiment of Formula Id, Y is O.
[0171] In one embodiment of Formula Id, A is taken from the group consisting of C1-C6 alkyl, branched C3-C8alkyl, fluoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, C3-C8carbocyclyl, phenyl, a 4-8 membered heterocyclic ring and heteroaryl; and wherein each A moiety may be further substituted with one, two, or three R3 moieties.
[0172] In one embodiment of Formula Id, A is taken from the group consisting of C1-C6 alkyl, branched C3-C8alkyl, C3-C8carbocyclyl, phenyl and a 4-8 membered heterocyclic ring; and wherein each A moiety may be further substituted with one, two, or three R3 moieties.
[0173] In one embodiment of Formula Id, A is branched C3-C8alkyl, optionally further substituted with one, two, or three R3 moieties.
[0174] In one embodiment of Formula Id, A is C3-C8carbocyclyl, optionally further substituted with one, two, or three R3 moieties.
[0175] In one embodiment of Formula Id, A is phenyl, optionally further substituted with one, two, or three R3 moieties.
[0176] In one embodiment of Formula Id, A is a 4-8 membered heterocyclic ring, optionally further substituted with one, two, or three R3 moieties. [0177] In one embodiment of Formula Id, each Rl and R2 is individually and independently hydrogen, C1 -C6 alkyl, deutero-Cl-C6 alkyl wherein the alkyl chain is partially or completely deuterated, fiuoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, hydroxyl, C1-C6 alkoxy, fiuoroC 1 -C6alkoxy wherein the alkyl group is fully or partially fluorinated, or halogen.
[0178] In one embodiment of Formula Id, each Rl is hydrogen.
[0179] In one embodiment of Formula Id, each Rl and R2 is hydrogen.
[0180] In one embodiment of Formula Id, each R3 is individually and independently hydrogen, halogen, C1 -C6 alkyl, fluoro-Cl-C6 alkyl wherein the alkyl chain is partially or completely fluorinated, branched C3-C8 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, fluoro-Cl-C6 alkoxy wherein the alkyl chain is partially or completely fluorinated, branched C3-C6 alkoxy, hydroxyl, or cyano.
[0181] In one embodiment of Formula Id, Rl l is hydrogen, C1 -C6 alkyl, deutero-Cl-C6 alkyl wherein the alkyl chain is partially or completely deuterated, or branched C3-C8 alkyl.
[0182] In one embodiment of Formula Id, Rl 1 is hydrogen.
[0183] In one embodiment of Formula Id, q is 0, 1 , or 2.
[0184] In one embodiment of Formula Id, q is 0.
[0185] In one embodiment of Formula Id, q is 1.
[0186] In one embodiment of Formula Id, q is 2.
[0187] In one embodiment of Formula Id, n is 0, 1 , or 2.
[0188] In one embodiment of Formula Id, n is 0. [0189] In one embodiment of Formula Id, n is 1. [0190] In one embodiment of Formula Id, n is 2. [0191] In one embodiment of Formula Id, n is 3.
[0192] In one embodiment, the compound of Formula I is a compound of Formula Ie wherein: W is C5-C6heteroaryl, phenyl, -NHC(0)R6, -NHC(0)R7, -NHC(0)N(R8)R9 or - C(0)N(R8)R9, and wherein each C5-C6heteroaryl or phenyl is optionally substituted by one, two, or three R5 moieties; or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.
Figure imgf000028_0001
Formula Ie.
[0193] In one embodiment of Formula Ie, W is C5-C6heteroaryl optionally substituted by one, two, or three R5.
[0194] In one embodiment of Formula Ie, W is pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, triazolyl, or pyridinyl and wherein each W is optionally substituted by one, two, or three R5.
[0195] In one embodiment of Formula Ie, W is pyrazolyl optionally substituted by one, two, or three R5. [0196] In one embodiment of Formula le, W is imidazolyl optionally substituted by one, two, or three R5.
[0197] In one embodiment of Formula le, W is isoxazolyl optionally substituted by one or two R5.
[0198] In one embodiment of Formula le, W is oxazolyl optionally substituted by one or two R5.
[0199] In one embodiment of Formula le, W is thiazolyl optionally substituted by one or two R5.
[0200] In one embodiment of Formula le, W is triazolyl optionally substituted by one or two R5.
[0201] In one embodiment of Formula le, W is pyridinyl optionally substituted by one, two, or three R5.
[0202] In one embodiment of Formula le, W is -NHC(0)R6, -NHC(0)R7, or - NHC(0)N(R8)R9.
[0203] In one embodiment of Formula le, W is -NHC(0)R6.
[0204] In one embodiment of Formula le, W is -NHC(0)R7.
[0205] In one embodiment of Formula le, W is -NHC(0)N(R8)R9.
[0206] In one embodiment of Formula le, W is - C(0)N(R8)R9.
[0207] In one embodiment of Formula le, W is phenyl optionally substituted by one, two, or three R5. [0208] In one embodiment of Formula le, XI and X2 are individually and independently hydrogen or C 1 -C6 alkyl.
[0209] In one embodiment of Formula le, XI and X2 are hydrogen.
[0210] In one embodiment of Formula le, one of XI and X2 is hydrogen and the other is Cl- C6alkyl.
[0211] In one embodiment of Formula le, R4 is hydrogen, C1 -C6 alkyl, deutero-Cl-C6 alkyl wherein the alkyl chain is partially or completely deuterated, or branched C3-C8 alkyl.
[0212] In one embodiment of Formula le, R4 is hydrogen or C1-C6 alkyl.
[0213] In one embodiment of Formula le, R4 is hydrogen.
[0214] In one embodiment of Formula le, R4 is C1-C6 alkyl.
[0215] In one embodiment of Formula le, A is taken from the group consisting of C1 -C6 alkyl, branched C3-C8alkyl, fluoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, C3-C8carbocyclyl, phenyl, a 4-8 membered heterocyclic ring and heteroaryl; and wherein each A moiety may be further substituted with one, two, or three R3 moieties.
[0216] In one embodiment of Formula le, A is taken from the group consisting of C1 -C6 alkyl, branched C3-C8alkyl, C3-C8carbocyclyl, phenyl and a 4-8 membered heterocyclic ring; and wherein each A moiety may be further substituted with one, two, or three R3 moieties.
[0217] In one embodiment of Formula le, A is branched C3-C8alkyl, optionally further substituted with one, two, or three R3 moieties. [0218] In one embodiment of Formula le, A is tert-butyl, optionally further substituted with one, two, or three R3 moieties.
[0219] In one embodiment of Formula le, A is tert-pentyl, optionally further substituted with one, two, or three R3 moieties.
[0220] In one embodiment of Formula le, A is neo-pentyl, optionally further substituted with one, two, or three R3 moieties.
[0221] In one embodiment of Formula le, A is isobutyl, optionally further substituted with one, two, or three R3 moieties.
[0222] In one embodiment of Formula le, A is isopropyl, optionally further substituted with one, two, or three R3 moieties.
[0223] In one embodiment of Formula le, A is C3-C8carbocyclyl, optionally further substituted with one, two, or three R3 moieties.
[0224] In one embodiment of Formula le, A is cyclopropyl, optionally further substituted with one, two, or three R3 moieties.
[0225] In one embodiment of Formula le, A is cyclobutyl, optionally further substituted with one, two, or three R3 moieties.
[0226] In one embodiment of Formula le, A is cyclopentyl, optionally further substituted with one, two, or three R3 moieties.
[0227] In one embodiment of Formula le, A is cyclohexyl, optionally further substituted with one, two, or three R3 moieties. [0228] In one embodiment of Formula Ie, A is phenyl, optionally further substituted with one, two, or three R3 moieties.
[0229] In one embodiment of Formula Ie, A is a 4-8 membered heterocyclic ring, optionally further substituted with one, two, or three R3 moieties.
[0230] In one embodiment of Formula Ie, A is tetrahydrofuranyl, optionally further substituted with one, two, or three R3 moieties.
[0231] In one embodiment of Formula Ie, A is tetrahydropyranyl, optionally further substituted with one, two, or three R3 moieties.
[0232] In one embodiment of Formula Ie, each R3 is individually and independently hydrogen, halogen, C1 -C6 alkyl, fluoro-Cl-C6 alkyl wherein the alkyl chain is partially or completely fluorinated, branched C3-C8 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, fluoro-Cl-C6 alkoxy wherein the alkyl chain is partially or completely fluorinated, branched C3-C6 alkoxy, hydroxyl, or cyano.
[0233] In one embodiment of Formula Ie, Rl l is hydrogen, C1-C6 alkyl, deutero-Cl -C6 alkyl wherein the alkyl chain is partially or completely deuterated, or branched C3-C8 alkyl.
[0234] In one embodiment of Formula Ie, Rl 1 is hydrogen.
[0235] In one embodiment of Formula Ie, n is 0, 1 , or 2.
[0236] In one embodiment of Formula Ie, n is 0.
[0237] In one embodiment of Formula Ie, n is 1.
[0238] In one embodiment of Formula Ie, n is 2. [0239] In one embodiment of Formula Ie, n is 3.
[0240] In one embodiment, the compound of Formula I is a compound of Formula If wherein: XI and X2 are individually and independently hydrogen or C1-C6 alkyl; or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.
Figure imgf000033_0001
Formula If.
[0241] In one embodiment of Formula If, XI and X2 are hydrogen.
[0242] In one embodiment of Formula If, one of XI and X2 is hydrogen and the other is Cl- C6alkyl.
[0243] In one embodiment of Formula If, one of XI and X2 is hydrogen and the other is methyl.
[0244] In one embodiment of Formula If, R3 is hydrogen, halogen, C1-C6 alkyl, fluoro-Cl- C6 alkyl wherein the alkyl chain is partially or completely fluorinated, branched C3-C8 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, fluoro-Cl-C6 alkoxy wherein the alkyl chain is partially or completely fluorinated, branched C3-C6 alkoxy, hydroxyl, or cyano.
[0245] In one embodiment of Formula If, R3 is hydrogen, C1-C6 alkyl, fluoro-Cl-C6 alkyl wherein the alkyl chain is partially or completely fluorinated, or C1-C6 alkoxy. [0246] In one embodiment of Formula If, R5 is hydrogen, C1 -C6 alkyl, deutero-Cl -C6 alkyl wherein the alkyl chain is partially or completely deuterated, branched C3-C8 alkyl, -(CH2)m- C(0)NR8(R9), -(CH2)m-C(0)R7, -(CH2)m-OR8, -(CH2)m-NR8(R9), or -(CH2)m-R7, wherein each alkylene is optionally substituted with C 1 -C4 alkyl.
[0247] In one embodiment of Formula If, R5 is hydrogen, C1-C6 alkyl, or deutero-C 1 -C6 alkyl wherein the alkyl chain is partially or completely deuterated.
[0248] In one embodiment of Formula If, R5 is C1 -C6 alkyl, or deutero-C 1 -C6 alkyl wherein the alkyl chain is partially or completely deuterated.
[0249] In one embodiment of Formula If, R5 is methyl.
[0250] In one embodiment of Formula If, q is 0, 1 , or 2.
[0251] In one embodiment of Formula If, q is 0 or 1.
[0252] In one embodiment of Formula If, q is 0.
[0253] In one embodiment of Formula If, q is 1.
[0254] In one embodiment of Formula If, q is 2.
[0255] In one embodiment, the compound of Formula I is a compound of Formula Ig wherein: W is C5-C6heteroaryl, phenyl, -NHC(0)R6, -NHC(0)R7, -NHC(0)N(R8)R9 or - C(0)N(R8)R9, and wherein each C5-C6heteroaryl or phenyl is optionally substituted by one, two, or three R5 moieties; or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.
Formula Ig.
[0256] In one embodiment of Formula Ig, W is C5-C6heteroaryl optionally substituted by one, two, or three R5.
[0257] In one embodiment of Formula Ig, W is pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, triazolyl, or pyridinyl and wherein each W is optionally substituted by one, two, or three R5.
[0258] In one embodiment of Formula Ig, W is pyrazolyl optionally substituted by one, two, or three R5.
[0259] In one embodiment of Formula Ig, W is imidazolyl optionally substituted by one, two, or three R5.
[0260] In one embodiment of Formula Ig, W is isoxazolyl optionally substituted by one or two R5.
[0261] In one embodiment of Formula Ig, W is oxazolyl optionally substituted by one or two
R5f.
[0262] In one embodiment of Formula Ig, W is thiazolyl optionally substituted by one or two
R5. [0263] In one embodiment of Formula Ig, W is triazolyl optionally substituted by one or two R5.
[0264] In one embodiment of Formula Ig, W is pyridinyl optionally substituted by one, two, or three R5.
[0265] In one embodiment of Formula Ig, W is -NHC(0)R6, -NHC(0)R7, or - NHC(0)N(R8)R9.
[0266] In one embodiment of Formula Ig, W is -NHC(0)R6. [0267] In one embodiment of Formula Ig, W is -NHC(0)R7. [0268] In one embodiment of Formula Ig, W is -NHC(0)N(R8)R9. [0269] In one embodiment of Formula Ig, W is - C(0)N(R8)R9.
[0270] In one embodiment of Formula Ig, W is phenyl optionally substituted by one, two, or three R5.
[0271] In one embodiment of Formula Ig, XI and X2 are individually and independently hydrogen or C 1 -C6 alkyl.
[0272] In one embodiment of Formula Ig, XI and X2 are hydrogen.
[0273] In one embodiment of Formula Ig, one of XI and X2 is hydrogen and the other is Cl- C6alkyl.
[0274] In one embodiment of Formula Ig, A is taken from the group consisting of C1-C6 alkyl, branched C3-C8alkyl, fluoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, C3-C8carbocyclyl, phenyl, a 4-8 membered heterocyclic ring and heteroaryl. [0275] In one embodiment of Formula Ig, A is taken from the group consisting of C1-C6 alkyl, branched C3-C8alkyl, C3-C8carbocyclyl, phenyl and a 4-8 membered heterocyclic ring; and wherein each A moiety may be further substituted with one, two, or three R3 moieties.
[0276] In one embodiment of Formula Ig, A is branched C3-C8alkyl, optionally further substituted with one, two, or three R3 moieties.
[0277] In one embodiment of Formula Ig, A is tert-butyl, optionally further substituted with one, two, or three R3 moieties.
[0278] In one embodiment of Formula Ig, A is tert-pentyl, optionally further substituted with one, two, or three R3 moieties.
[0279] In one embodiment of Formula Ig, A is neo-pentyl, optionally further substituted with one, two, or three R3 moieties.
[0280] In one embodiment of Formula Ig, A is isobutyl, optionally further substituted with one, two, or three R3 moieties.
[0281] In one embodiment of Formula Ig, A is isopropyl, optionally further substituted with one, two, or three R3 moieties.
[0282] In one embodiment of Formula Ig, A is C3-C8carbocyclyl, optionally further substituted with one, two, or three R3 moieties.
[0283] In one embodiment of Formula Ig, A is cyclopropyl, optionally further substituted with one, two, or three R3 moieties.
[0284] In one embodiment of Formula Ig, A is cyclobutyl, optionally further substituted with one, two, or three R3 moieties. [0285] In one embodiment of Formula Ig, A is cyclopentyl, optionally further substituted with one, two, or three R3 moieties.
[0286] In one embodiment of Formula Ig, A is cyclohexyl, optionally further substituted with one, two, or three R3 moieties.
[0287] In one embodiment of Formula Ig, A is phenyl, optionally further substituted with one, two, or three R3 moieties.
[0288] In one embodiment of Formula Ig, A is a 4-8 membered heterocyclic ring, optionally further substituted with one, two, or three R3 moieties.
[0289] In one embodiment of Formula Ig, A is tetrahydrofuranyl, optionally further substituted with one, two, or three R3 moieties.
[0290] In one embodiment of Formula Ig, A is tetrahydropyranyl, optionally further substituted with one, two, or three R3 moieties.
[0291] In one embodiment of Formula Ig, each R3 is individually and independently hydrogen, halogen, C1 -C6 alkyl, fluoro-Cl-C6 alkyl wherein the alkyl chain is partially or completely fluorinated, branched C3-C8 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, fluoro-Cl-C6 alkoxy wherein the alkyl chain is partially or completely fluorinated, branched C3-C6 alkoxy, hydroxyl, or cyano.
[0292] In one embodiment of Formula Ig, n is 0, 1 , or 2. [0293] In one embodiment of Formula Ig, n is 0. [0294] In one embodiment of Formula Ig, n is 1. [0295] In one embodiment of Formula Ig, n is 2. [0296] In one embodiment of Formula Ig, n is 3.
[0297] In one embodiment, the compound of Formula I is a compound of Formula Ih wherein: XI and X2 are individually and independently hydrogen or C1-C6 alkyl; or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.
Figure imgf000039_0001
Formula Ih.
[0298] In one embodiment of Formula Ih, XI and X2 are hydrogen.
[0299] In one embodiment of Formula Ih, one of XI and X2 is hydrogen and the other is Cl- C6alkyl.
[0300] In one embodiment of Formula Ih, one of XI and X2 is hydrogen and the other is methyl.
[0301] In one embodiment of Formula Ih, R3 is hydrogen, halogen, C1-C6 alkyl, fluoro-Cl - C6 alkyl wherein the alkyl chain is partially or completely fluorinated, branched C3-C8 alkyl, C3-C8 cycloalkyl, C1 -C6 alkoxy, fluoro-Cl-C6 alkoxy wherein the alkyl chain is partially or completely fluorinated, branched C3-C6 alkoxy, hydroxyl, or cyano. [0302] In one embodiment of Formula Ih, R3 is hydrogen, C1 -C6 alkyl, fluoro-Cl -C6 alkyl wherein the alkyl chain is partially or completely fluorinated, or C1-C6 alkoxy.
[0303] In one embodiment of Formula Ih, R5 is hydrogen, C1-C6 alkyl, deutero-Cl -C6 alkyl wherein the alkyl chain is partially or completely deuterated, branched C3-C8 alkyl, -(CH2)m- C(0)NR8(R9), -(CH2)m-C(0)R7, -(CH2)m-OR8, -(CH2)m-NR8(R9), or -(CH2)m-R7, wherein each alkylene is optionally substituted with C 1 -C4 alkyl.
[0304] In one embodiment of Formula Ih, R5 is hydrogen, C1 -C6 alkyl, or deutero-Cl-C6 alkyl wherein the alkyl chain is partially or completely deuterated.
[0305] In one embodiment of Formula Ih, R5 is C1 -C6 alkyl, or deutero-Cl-C6 alkyl wherein the alkyl chain is partially or completely deuterated.
[0306] In one embodiment of Formula Ih, R5 is methyl.
[0307] In one embodiment of Formula Ih, q is 0, 1 , or 2.
[0308] In one embodiment of Formula Ih, q is 0 or 1.
[0309] In one embodiment of Formula Ih, q is 0.
[0310] In one embodiment of Formula Ih, q is 1.
[0311] In one embodiment of Formula Ih, q is 2.
[0312] In some embodiments, the invention comprises a compound selected from the group consisting of 3-(4-fluorobenzyl)- 1 -(6-methyl-5-((2-( 1 -methyl- 1 H-pyrazol-4-yl)pyridin-4- yl)oxy)pyridin-2-yl)- lH-l ,2,4-triazol-5(4H)-one, 3-benzyl-l-(6-methyl-5-((2-(l -methyl-lH- pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5(4H)-one, 3-(4-fiuorobenzyl)- 1 - (5-((2-( 1 -methyl- 1 H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5(4H)-one, 3-(tert-butyl) - 1 -(5-((2-( 1 -methyl- 1 H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)- 1 H- 1 ,2,4- triazol-5(4H)-one, 3-isopropyl-l-(6-methyl-5-((2-(l -methyl- lH-pyrazol-4-yl)pyridin-4- yl)oxy)pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5(4H)-one, 3-cyclohexyl- 1 -(6-methyl-5-((2-( 1 -methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5(4H)-one, 3-(tert-butyl)- 1 - (6-methyl-5-((2-( 1 -methyl- 1 H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)- 1 H- 1 ,2,4-triazol- 5(4H)-one, 3-(tert-butyl)- 1 -(6-ethyl-5-((2-( 1 -methyl- 1 H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-
2- yl)-lH-l,2,4-triazol-5(4H)-one, 3-(tert-butyl)-l-(6-methyl-5-((2'-methyl-[2,4'-bipyridin]-4- yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one, 3-(tert-butyl)-l-(6-methyl-5-((6'-methyl- [2,3'-bipyridin]-4-yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one, N-(4-((6-(3-(tert-butyl)-5- oxo-4,5-dihydro- 1 H- 1 ,2,4-triazol- 1 -yl)-2-methylpyridin-3-yl)oxy)pyridin-2-yl)acetamide, 3- (tert-butyl)- 1 -(6-methyl-5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)- 1 H- 1 ,2,4- triazol-5(4H)-one, 3-(tert-butyl)-4-methyl-l-(6-methyl-5-((2-(l-methyl-lH-pyrazol-4- yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-l,2,4-triazol-5(4H)-one, 3-(tert-butyl)-l-(6-methyl-5-((2- (4-(l-methylpiperidin-4-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one,
3- (2-methoxyethyl)-l-(6-methyl-5-((2-(l -methyl- lH-pyrazo l-4-yl)pyridin-4-yl)oxy)pyridin-2- yl)- 1 H- 1 ,2,4-triazol-5(4H)-one, 3-(2-methoxypropan-2-yl)- 1 -(6-methyl-5-((2-( 1 -methyl- 1 H- pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5(4H)-one, 3-(methoxymethyl)- 1 - (6-methyl-5-((2-( 1 -methyl- 1 H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)- 1 H- 1 ,2,4-triazol- 5(4H)-one, 3-(tert-butyl)-l-(5-((2-(l-(2-hydroxy ethyl)- lH-pyrazo l-4-yl)pyridin-4-yl)oxy)-6- methylpyridin-2-yl)- 1 H- 1 ,2,4-triazol-5(4H)-one, 3-(tert-butyl)- 1 -(6-methyl-5-((2-(4-methyl- 1 H-imidazol- 1 -yl)pyridin-4-yl)oxy)pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5(4H)-one, 1 -(6-methyl-5- ((2-(l -methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)-lH- l,2,4-triazol-5(4H)-one, N-(4-((6-(3-(tert-butyl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-l-yl)-2- methylpyridin-3-yl)oxy)pyridin-2-yl)- 1 -methylpiperidine-4-carboxamide, 3-isobutyl- 1 -(6- methyl-5-((2-( 1 -methyl- 1 H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5(4H)- one, 3-(tert-butyl)- 1 -(6-methyl-5-((2-( 1 -methyl- 1 H-imidazol-4-yl)pyridin-4-yl)oxy)pyridin-2- yl)-lH-l,2,4-triazol-5(4H)-one, l-(5-((2-(lH-pyrazol-4-yl)pyridin-4-yl)oxy)-6-methylpyridin- 2-yl)-3-(tert-butyl)-lH-l ,2,4-triazol-5(4H)-one, l-(6-methyl-5-((2-(l -methyl- lH-pyrazol-4- yl)pyridin-4-yl)oxy)pyridin-2-yl)-3-(tert-pentyl)-lH-l,2,4-triazol-5(4H)-one, 4-((6-(3-(tert- butyl)-5-oxo-4,5-dihydro- 1H- 1 ,2,4-triazol- 1 -yl)pyridin-3-yl)oxy)-N-methylpicolinamide, 1 -(6- methyl-5-((2-(l -methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-3-(l - methylcyclopropyl)- 1 H- 1 ,2,4-triazol-5(4H)-one, 3-(4-fluorophenyl)- 1 -(6-methyl-5-((2-( 1 - methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one, 3-(4- fluorophenyl)- 1 -(6-methyl-5-((2-(4-methyl- 1 H-imidazol- 1 -yl)pyridin-4-yl)oxy)pyridin-2-yl)- 1 H- l,2,4-triazol-5(4H)-one, 3-(4-((6-(3-(tert-butyl)-5-oxo-4,5-dihydro-lH-l ,2,4-triazol-l-yl)-2- methylpyridin-3-yl)oxy)pyridin-2-yl)- 1 , 1 -dimethylurea, 3-(tert-butyl)- 1 -(4-methyl-5-((2-( 1 - methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one, N-(4-((6- (3-(4-fluorophenyl)-5-oxo-4,5-dihydro-lH-l ,2,4-triazol-l-yl)-2-methylpyridin-3-yl)oxy)pyridin- 2-yl)cyclopropanecarboxamide, 3-(tert-butyl)-l-(4,6-dimethyl-5-((2-(l -methyl- lH-pyrazo 1-4- yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-l,2,4-triazol-5(4H)-one, 3-cyclopentyl-l-(6-methyl-5- ((2-(l -methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-l,2,4-triazol-5(4H)-one, 3- cyclopropyl- 1 -(6-methyl-5-((2-( 1 -methyl- 1 H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)- 1 H- l,2,4-triazol-5(4H)-one, l-(6-methyl-5-((2-(l-methyl-lH-pyrazol-4-yl)pyridin-4- yl)oxy)pyridin-2-yl)-3-neopentyl- lH-l ,2,4-triazol-5(4H)-one, 3-cyclobutyl-l -(6-methyl-5-((2- (1 -methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one , 3-(tert- butyl)- 1 -(5-((2-( 1 -ethyl- 1 H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-methylpyridin-2-yl)- 1 H- 1 ,2,4- triazol-5(4H)-one, 3-(tert-butyl)-l -(6-methyl-5-((2-(oxazol-5-yl)pyridin-4-yl)oxy)pyridin-2- yl)- 1 H- 1 ,2,4-triazol-5(4H)-one, 3-(tert-butyl)- 1 -(6-methyl-5-((6'-(4-methylpiperazin- 1 -yl)-
[2,3'-bipyridin]-4-yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one, 3-(tert-butyl)-l-(6-methyl- 5-((2'-(4-methylpiperazin-l-yl)-[2,4'-bipyridin]-4-yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)- one, 3-(l -hydroxy-2-methylpropan-2-yl)-l -(6-methyl-5-((2-(l -methyl- lH-pyrazol-4-yl)pyridin- 4-yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one, 1 -(6-methy 1-5 -((2-(l -methyl- lH-pyrazol-4- yl)pyridin-4-yl)oxy)pyridin-2-yl)-3-(l -(trifiuoromethyl)cyclobutyl)- 1 H- 1 ,2,4-triazol-5(4H)-one, N-(4-((6-(3-(2-methoxypropan-2-yl)-5-oxo-4,5-dihydro-lH-l ,2,4-triazol-l -yl)-4-methylpyridin- 3-yl)oxy)pyridin-2-yl)acetamide, N-(4-((6-(3-(tert-butyl)-5-oxo-4,5-dihydro-lH-l ,2,4-triazol- l-yl)-2-methylpyridin-3-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide, 3-(l-methoxy-2- methylpropan-2-yl)-l-(6-methyl-5-((2-(l -methyl- lH-pyrazo l-4-yl)pyridin-4-yl)oxy)pyridin-2- yl)- 1 H- 1 ,2,4-triazol-5(4H)-one, 3-(tert-butyl)- 1 -(6-methyl-5-((6-( 1 -methyl- 1 H-pyrazol-4- yl)pyrimidin-4-yl)oxy)pyridin-2-yl)- 1H- 1 ,2,4-triazol-5(4H)-one, 4-(tert-butyl)- 1 -(6-methyl-5- ((2-(l -methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-imidazol-2(3H)-one, and 5- (tert-butyl)-3-(6-methyl-5-((2-(l -methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)- 1 ,3,4- oxadiazol-2(3H)-one.
[0313] In certain embodiments, the invention comprises a method of treating mammalian disease at least partially mediated by the kinase activity of c-FMS, PDGFR-β, or c-KIT kinases, wherein the kinase is a wildtype form, a mutant oncogenic form, an aberrant fusion protein form or a polymorph therof, the method comprising administering to a mammal in need thereof an effective amount of a compound of Formula I.
[0314] In other embodiments, the present invention comprises a pharmaceutical composition, comprising a compound of Formula I and a pharmaceutically acceptable carrier.
[0315] In certain embodiments, the composition comprises an additive selected from adjuvants, excipients, diluents, or stabilizers.
[0316] In some embodiments, the invention includes a method of treating cancer, gastrointestinal stromal tumors, hyperproliferative diseases, metabolic diseases,
neurodegenerative diseases, solid tumors, melanomas, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, renal cancers, hepatic cancers,
osteosarcomas, multiple myelomas, cervical carcinomas, metastasis of primary tumor sites, cancers that are metastatic to bone, papillary thyroid carcinoma, non-small cell lung cancer, colonic cancers, rheumatoid arthritis, osteoarthritis, multiple sclerosis, autoimmune nephritis, lupus, Crohn's disease, asthma, chronic obstructive pulmonary disease, osteoporosis,
mastocytosis, or mast cell leukemia, the method comprising administering to a patient in need thereof an effective amount of a compound of Formula I.
[0317] In some embodiments, the invention includes a method of treating glioblastomas, breast cancers, pancreatic cancers, metastasis of primary tumor sites, or cancers that are metastatic to bone, the method comprising administering to a patient in need thereof an effective amount of a compound of Formula I. [0318] In certain embodiments of the present methods, the compound is administered orally, parenterally, by inhalation, or subcutaneously.
[0319] In some embodiments, the invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the treatment of cancer, gastrointestinal stromal tumors, hyperproliferative diseases, metabolic diseases, neurodegenerative diseases, solid tumors, melanomas, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, renal cancers, hepatic cancers, osteosarcomas, multiple myelomas, cervical carcinomas, metastasis of primary tumor sites, cancers that are metastatic to bone, papillary thyroid carcinoma, non-small cell lung cancer, colonic cancers, rheumatoid arthritis, osteoarthritis, multiple sclerosis, autoimmune nephritis, lupus, Crohn's disease, asthma, chronic obstructive pulmonary disease, osteoporosis, mastocytosis, or mast cell leukemia, the method comprising administering to a patient in need thereof an effective amount of a compound of Formula I.
[0320] In some embodiments, the invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the treatment of glioblastomas, breast cancers, pancreatic cancers, metastasis of primary tumor sites, or cancers that are metastatic to bone, the method comprising administering to a patient in need thereof an effective amount of a compound of Formula I.
[0321] In some embodiments, the invention provides for the use of a compound of Formula
I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer, gastrointestinal stromal tumors, hyperproliferative diseases, metabolic diseases, neurodegenerative diseases, solid tumors, melanomas, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, renal cancers, hepatic cancers, osteosarcomas, multiple myelomas, cervical carcinomas, metastasis of primary tumor sites, cancers that are metastatic to bone, papillary thyroid carcinoma, non-small cell lung cancer, colonic cancers, rheumatoid arthritis, osteoarthritis, multiple sclerosis, autoimmune nephritis, lupus, Crohn's disease, asthma, chronic obstructive pulmonary disease, osteoporosis, mastocytosis, or mast cell leukemia.
[0322] In certain embodiments, the invention provides for the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of glioblastomas, breast cancers, pancreatic cancers, metastasis of primary tumor sites, or cancers that are metastatic to bone.
[0323] The details of the invention are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, illustrative methods and materials are now described. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
[0324] Throughout this disclosure, various patents, patent applications and publications are referenced. The disclosures of these patents, patent applications and publications in their entireties are incorporated into this disclosure by reference in order to more fully describe the state of the art as known to those skilled therein as of the date of this disclosure. This disclosure will govern in the instance that there is any inconsistency between the patents, patent applications and publications and this disclosure.
[0325] For convenience, certain terms employed in the specification, examples and claims are collected here. Unless defined otherwise, all technical and scientific terms used in this disclosure have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The initial definition provided for a group or term provided in this disclosure applies to that group or term throughout the present disclosure individually or as part of another group, unless otherwise indicated.
[0326] The compounds of this disclosure include any and all possible isomers, stereoisomers, enantiomers, diastereomers, tautomers, and pharmaceutically acceptable salts. Thus, the terms "compound", "compounds", "test compound" or "test compounds" as used in this disclosure refer to the compounds of this disclosure and any and all possible isomers, stereoisomers, enantiomers, diastereomers, tautomers, and pharmaceutically acceptable salts thereof.
Definitions
[0327] The term "alkyl" as used herein refers to a straight chain alkyl, wherein alkyl chain length is indicated by a range of numbers. In exemplary embodiments, "alkyl" refers to an alkyl chain as defined above containing 1 , 2, 3, 4, 5, or 6 carbons (i.e., C1-C6 alkyl). Examples of an alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, and hexyl.
[0328] The term "branched alkyl" as used herein refers to an alkyl chain wherein a branching point in the chain exists, and the total number of carbons in the chain is indicated by a range of numbers. In exemplary embodiments, "branched alkyl" refers to an alkyl chain as defined above containing from 3, 4, 5, 6, 7, or 8 carbons (i.e., branched C3-C8 alkyl). Examples of a branched alkyl group include, but are not limited to, z'so-propyl, z'so-butyl, secondary-butyl, and tertiary- butyl, 2-pentyl, 3-pentyl, 2-hexyl, and 3-hexyl.
[0329] The term "alkoxy" as used herein refers to -O-(alkyl), wherein "alkyl" is as defined above.
[0330] The term "branched alkoxy" as used herein refers to -0-(branched alkyl), wherein "branched alkyl" is as defined above.
[0331] The term "alkylene" as used herein refers to an alkyl moiety interposed between two other atoms. In exemplary embodiments, "alkylene" refers to an alkyl moiety as defined above containing 1 , 2, or 3 carbons. Examples of an alkylene group include, but are not limited to -CH2- -CH2CH2-, and -CH2CH2CH2-. In exemplary embodiments, alkylene groups are branched.
[0332] The term "alkynyl" as used herein refers to a carbon chain containing one carbon- carbon triple bond. In exemplary embodiments, "alkynyl" refers to a carbon chain as described above containing 2 or 3 carbons (i.e., C2-C3 alkynyl). Examples of an alkynyl group include, but are not limited to, ethyne and propyne.
[0333] The term "aryl" as used herein refers to a cyclic hydrocarbon, where the ring is characterized by delocalized π electrons (aromaticity) shared among the ring members, and wherein the number of ring atoms is indicated by a range of numbers. In exemplary embodiments, "aryl" refers to a cyclic hydrocarbon as described above containing 6, 7, 8, 9, or 10 ring atoms (i.e., C6-C10 aryl). Examples of an aryl group include, but are not limited to, benzene, naphthalene, tetralin, indene, and indane.
[0334] The term "cycloalkyl" or "carbocyclyl" as used herein refers to a monocyclic saturated carbon ring, wherein the number of ring atoms is indicated by a range of numbers. In exemplary embodiments, "cycloalkyl" or "carbocyclyl" refers to a carbon ring as defined above containing 3, 4, 5, 6, 7, or 8 ring atoms (i.e., C3-C8 cycloalkyl). Examples of a cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
[0335] The term "halogen" or "halo" as used herein refers to fluorine, chlorine, bromine, and iodine.
[0336] The term "heterocycle" or "heterocyclyl" as used herein refers to a cyclic
hydrocarbon, wherein at least one of the ring atoms is an O, N, or S, wherein the number of ring atoms is indicated by a range of numbers. Heterocyclyl moieties as defined herein have C or N bonding hands through which the heterocyclyl ring is connected to an adjacent moiety. For example, in some embodiments, a ring N atom from the heterocyclyl is the bonding atom of the heterocylic moiety. In exemplary embodiments, "heterocyclyl" refers to a monocyclic hydrocarbon containing 4, 5, 6, 7 or 8 ring atoms (i.e., C4-C8 heterocyclyl). Examples of a heterocycle group include, but are not limited to, aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, tetrahydroiuran, pyran, thiopyran, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S-dioxide, oxazoline, tetrahydrothiophene, piperidine, tetrahydropyran, thiane, imidazolidine, oxazolidine, thiazolidine, dioxolane, dithiolane, piperazine, oxazine, dithiane, and dioxane. [0337] The term "heteroaryl" as used herein refers to a cyclic hydrocarbon, where at least one of the ring atoms is an O, N, or S, the ring is characterized by delocalized π electrons (aromaticity) shared among the ring members, and wherein the number of ring atoms is indicated by a range of numbers. Heteroaryl moieties as defined herein have C or N bonding hands through which the heteroaryl ring is connected to an adjacent moiety. For example, in some embodiments, a ring N atom from the heteroaryl is the bonding atom of the heteroaryl moiety. In exemplary embodiments, "heteroaryl" refers to a cyclic hydrocarbon as described above containing 5 or 6 ring atoms (i.e., C5-C6 heteroaryl). Examples of a heteroaryl group include, but are not limited to, pyrrole, furan, thiene, oxazole, thiazole, isoxazole, isothiazole, imidazole, pyrazole, oxadiazole, thiadiazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyridazine, and triazine.
[0338] The term "substituted" in connection with a moiety as used herein refers to a further substituent which is attached to the moiety at any acceptable location on the moiety. Unless otherwise indicated, moieties can bond through a carbon, nitrogen, oxygen, sulfur, or any other acceptable atom.
[0339] The term "salts" as used herein embraces pharmaceutically acceptable salts commonly used to form alkali metal salts of free acids and to form addition salts of free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Exemplary pharmaceutical salts are disclosed in Stahl, P.H., Wermuth, C.G., Eds. Handbook of Pharmaceutical Salts : Properties, Selection and Use; Verlag Helvetica Chimica Acta/Wiley-VCH: Zurich, 2002, the contents of which are hereby incorporated by reference in their entirety. Specific non-limiting examples of inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids include, without limitation, aliphatic, cycloaliphatic, aromatic, arylaliphatic, and heterocyclyl containing carboxylic acids and sulfonic acids, for example formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p- hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2 -hydroxy ethanesulfonic, sulfanilic,
cyclohexylaminosulfonic, algenic, 3-hydroxybutyric, galactaric or galacturonic acid. Suitable pharmaceutically acceptable salts of free acid-containing compounds disclosed herein include, without limitation, metallic salts and organic salts. Exemplary metallic salts include, but are not limited to, appropriate alkali metal (group la) salts, alkaline earth metal (group Ila) salts, and other physiological acceptable metals. Such salts can be made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Exemplary organic salts can be made from primary amines, secondary amines, tertiary amines and quaternary ammonium salts, for example, tromethamine, diethylamine, tetra-N-methylammonium, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
[0340] The terms "administer," "administering, or "administration" as used herein refer to either directly administering a compound or pharmaceutically acceptable salt of the compound or a composition to a subject. [0341] The term "carrier" as used herein encompasses carriers, excipients, and diluents, meaning a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ or portion of the body.
[0342] The term "disorder" is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.
[0343] The terms "effective amount" and "therapeutically effective amount" are used interchangeably in this disclosure and refer to an amount of a compound that, when administered to a subject, is capable of reducing a symptom of a disorder in a subject. The actual amount which comprises the "effective amount" or "therapeutically effective amount" will vary depending on a number of conditions including, but not limited to, the particular disorder being treated, the severity of the disorder, the size and health of the patient, and the route of administration. A skilled medical practitioner can readily determine the appropriate amount using methods known in the medical arts.
[0344] The terms "isolated" and "purified" as used herein refer to a component separated from other components of a reaction mixture or a natural source. In certain embodiments, the isolate contains at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 98% of the compound or pharmaceutically acceptable salt of the compound by weight of the isolate.
[0345] The phrase "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and/or 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, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
[0346] As used in this disclosure, the terms "patient" or "subject" include, without limitation, a human or an animal. Exemplary animals include, but are not limited to, mammals such as mouse, rat, guinea pig, dog, feline, horse, cow, pig, monkey, chimpanzee, baboon, or rhesus monkey.
[0347] The terms "treatment," "treat," and "treating," are meant to include the full spectrum of intervention for the cancer from which the patient is suffering, such as administration of the active compound to alleviate, slow or reverse one or more of the symptoms and to delay progression of the cancer even if the cancer is not actually eliminated. Treating can be curing, improving, or at least partially ameliorating the disorder.
[0348] Structural, chemical and stereochemical definitions are broadly taken from IUPAC recommendations, and more specifically from Glossary of Terms used in Physical Organic Chemistry (IUPAC Recommendations 1994) as summarized by Muller, P. Pure Appl. Chem. 1994, 66, pp. 1077-1 184 and Basic Terminology of Stereochemistry (IUPAC Recommendations 1996) as summarized by Moss, G.P. Pure Appl. Chem. 1996, 68, pp. 2193-2222.
[0349] Atropisomers are defined as a subclass of conformers which can be isolated as separate chemical species and which arise from restricted rotation about a single bond.
[0350] Regioisomers or structural isomers are defined as isomers involving the same atoms in different arrangements. [0351] Enantiomers are defined as one of a pair of molecular entities which are mirror images of each other and non-superimposable.
[0352] Diastereomers or diastereoisomers are defined as stereoisomers other than enantiomers. Diastereomers or diastereoisomers are stereoisomers not related as mirror images. Diastereoisomers are characterized by differences in physical properties, and by some differences in chemical behavior towards achiral as well as chiral reagents.
[0353] The term "tautomer" as used herein refers to compounds produced by the phenomenon wherein a proton of one atom of a molecule shifts to another atom. See March, Advanced Organic Chemistry: Reactions, Mechanisms and Structures, 4th Ed., John Wiley & Sons, pp. 69-74 (1992). Tautomerism is defined as isomerism of the general form
G-X-Y=Z ^=^X=Y-Z-G
where the isomers (called tautomers) are readily interconvertible; the atoms connecting the groups X, Y and Z are typically any of C, H, O, or S, and G is a group which becomes an electrofuge or nucleofuge during isomerization. The most common case, when the electro fuge is
H+, is also known as "prototropy." Tautomers are defined as isomers that arise from tautomerism, independent of whether the isomers are isolable.
[0354] The exemplified compounds of the present invention are preferably formulated as a pharmaceutical composition using a pharmaceutically acceptable carrier and administered by a variety of routes. Preferably, such compositions are for oral administration. Such pharmaceutical compositions and processes for preparing them are well known in the art. See, e.g., REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (A. Gennaro, et al, eds., 19th ed., Mack Publishing Co., 1995). [0355] The compounds of Formula I, or pharmaceutically acceptable salts thereof, may be prepared by a variety of procedures known in the art, as well as those described below. The specific synthetic steps may be combined in different ways to prepare the Formula I compounds, or a pharmaceutically acceptable salt thereof.
[0356] The compounds employed as initial starting materials in the synthesis of the compounds of Formula la are well known and, to the extent not commercially available, are readily synthesized using specific references provided, by standard procedures commonly employed by those of ordinary skill in the art, or are found in general reference texts.
[0357] Examples of known procedures and methods include those described in general reference texts such as Comprehensive Organic Transformations, VCH Publishers Inc, 1989; Compendium of Organic Synthetic Methods, Volumes 1 -10, 1974-2002, Wiley Interscience; Advanced Organic Chemistry, Reactions Mechanisms, and Structure, 5th Edition, Michael B. Smith and Jerry March, Wiley Interscience, 2001 ; Advanced Organic Chemistry, 4th Edition, Part B, Reactions and Synthesis, Francis A. Carey and Richard J. Sundberg, Kluwer Academic / Plenum Publishers, 2000, etc., and references cited therein.
[0358] ChemDraw version 10 or 12 (CambridgeSoft Corporation, Cambridge, MA) was used to name the structures of intermediates and exemplified compounds.
[0359] The following abbreviations are used in this disclosure and have the following definitions: "ADP" is adenosine diphosphate "cone." is concentrated, "DBU" is 1 ,8- diazabicyclo[5.4.0]undec-7-ene, "DCM" is dichloromethane, "DIEA" is N,N- diisopropylethylamine, "DMA" is N,N-dimethylacetamide, "DMAP" is 4-
(dimethylamino)pyridine, "DMF" is N,N-dimethylformamide, "dppf is 1 ,1 '- bis(diphenylphosphino)ferrocene,"DMEM" is Dulbecco's Modified Eagle Media, "DMSO" is dimethylsulfoxide, "DPP A" is diphenylphosphryl azide, "ESI" is electrospray ionization, "Et20" is diethylether, "EtOAc" is ethyl acetate, "EtOH" is ethanol, "GST" is glutathione S-transferase, "h" is hour or hours, "Hex" is hexane, "IC50" is half maximal inhibitory concentration, "LiMHDS" is lithium bis(trimethylsilyl)amide, "MeCN" is acetonitrile, "MeOH" is methanol, "Me4tBuXPhos" is di-tert-butyl(2',4',6'-triisopropyl-3,4,5,6-tetramethyl-[l,l'-biphenyl]-2- yl)phosphine, "MHz" is megahertz, "min" is minute or minutes, "MS" is mass spectrometry, "MTBE" is methyl tert-butyl ether, "NADH" is nicotinamide adenine dinucleotide, "NBS" is N- bromosuccinimide, "NMR" is nuclear magnetic resonance, "PBS" is phosphate buffered saline, "Pd/C" is palladium on carbon, "Pd2(dba)3" is tris(dibenzylideneacetone)dipalladium(0), "Pd(PPli3)4" is tetrakis(triphenylphosphine)palladium (0), "prep-HPLC" is preparative high performance liquid chromatography, "RT" is room temperature which is also known as "ambient temp," which will be understood to consist of a range of normal laboratory temperatures ranging from 15-25 °C, "satd." is saturated, "TEA" is triethylamine, "TFA" is trifiuoroacetic acid, "THF" is tetrahydrofuran, "Tris" is tris(hydroxymethyl)aminomethane, "Xantphos" is 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene, and "X-Phos" is 2-dicyclohexylphosphino- 2',4',6'-triisopropylbiphenyl.
General Chemistry
[0360] The compounds of Formula I are prepared by the general synthetic methods illustrated in the schemes below and the accompanying examples. Suitable reaction conditions for the steps of these schemes are well known in the art and appropriate substitutions of solvents and co-reagents are within the skill of the art. Those skilled in the art will understand that synthetic intermediates may be isolated and/or purified by well known techniques as needed or desired, and that it will be possible to use various intermediates directly in subsequent synthetic steps with little or no purification. Furthermore, those skilled in the art will appreciate that in some instances, the order in which moieties are introduced is not critical. The particular order of steps required to produce the compounds of Formula1 is dependent upon the particular compound being synthesized, the starting compound, and the relative lability of the substituted moieties, as is well appreciated by the ordinary skilled chemist. All substituents, unless otherwise indicated, are as defined above.
[0361] The compounds of Formula I may contain -NH or -OH moieties in the W, Rl , R2 and R3 positions. It will be understood by those skilled in the art that in some instances it may be advantageous to use an amine protecting group during synthesis to temporarily mask one or more -NH moieties. Said protecting group can be removed from any subsequent intermediate leading to the synthesis of the compounds of Formula I, using standard conditions that effect removal of said protecting group, said conditions of which will be familiar to those skilled in the art. When not specified in a scheme, it will be understood by those skilled in the art that the W, Rl , R2 and R3 moieties represented in the schemes below may optionally contain standard amino or hydroxyl protecting groups that can be removed at any opportune time in the synthetic sequence.
[0362] Scheme 1 illustrates the preparation of Compounds J_, examples of Formula I wherein Y is NR4 and Z is N. In one embodiment, iodide 2 can react with triazolone 3 in the presence of copper(I) iodide and a suitable ligand, for example N,N-dimethylethane-l ,2-diamine to afford 4. Additional conditions for the transformation of 2 to 4 include heating to about 100 °C with a carbonate base, for example potassium carbonate. Further reaction of 4 with M-W (5) in the presence of a palladium catalyst and a base, for example potassium carbonate provides compounds of formula 1. In one embodiment, to conversion of 4 to 1 is effected by reaction of 4 with reagent M-W (5), wherein M is trialkylstanyl or a boronic acid or boronate ester (when W is heteroaryl or phenyl). In another embodiment, to conversion of 4 to I is effected by reaction of 4 with reagent M-W (5), wherein M is H (when W is -NHC(0)R6, -NHC(0)R7, - NHC(0)N(R8)R9. Additional onditions for the transformation of 4 to 1 are dependent on the nature of the W-moiety, but generally include the use of palladium catalysts, for example Pd(PPh3)4 or Pd2(dba)3, optionally in the presence of additional ligands, for example Xantphos. General conditions to accomplish these transformation are well known to those skilled in the art and are further illustrated in the accompanying examples.
[0363] In another embodiment of Scheme 1 , intermediate 4 (R4=H) can be prepared by the reaction of hydrazine 6 with reagent 8. Hydrazine 6 is efficiently prepared from iodide 2 by a two-step process commencing with the reaction with benzophenone hydrazone in the presence of Pd(OAc)2, 2,2'-bis(diphenylphosphino)-l ,l '-binaphthalene, and sodium te/ -butoxide to provide 7. Acidic hydrolysis of 7 affords hydrazine 6.
[0364] In another embodiment of Scheme 1 , compounds of formula 1 can be prepared directly from iodide 9 by reaction with M-W 5 using conditions described above. Iodide 9 is prepared from amine 10 by diazotization in the presence of an iodide source, for example potassium iodide or tetrabutylammonium iodide. Additional conditions for the conversion of 10 to 9 include treatment with tert-butyl nitrite in diiodomethane. [0365] In another embodiment of Scheme 1 , compounds of formula 1 can be prepared directly from hydrazine 12 by reaction with 8. Hydrazine 12 is prepared by the two-step sequence commencing with amine 10. Thus, diazotization of amine 10 in the resence of HF -pyridine affords fluoride Treatment of JJ_ with hydrazine or hydrazine hydrate affords 12.
Figure imgf000060_0001
10 Scheme 1
[0366] General intermediate 2 is prepared as illustrated in Scheme 2. Treatment of 3- hydroxypyridine J 7 with iodine in the presence of a carbonate base affords iodide J_8. Further treatment of j_8 with 2,4-dichloropyridine (19, Ql is CH) or 4,6-dichloropyrimdine (19, Ql is N) in the presence of a base, for example potassium carbonate, provides 2.
Figure imgf000061_0001
17 18 2
Scheme 2
[0367] General amine 10 can be prepared as illustrated in Scheme 3 by alternate reaction sequences, the selection of which will influenced by the nature of the W-moiey. In one embodiment, intermediate 20 (Y is halogen) is reacted with 2J_ in the presence of a base, for example potassium carbonate to provide the nitro ether 22. Reduction of the nitro moiey of 22 provides 23. Conditions to effect the conversion of 22 to 23 are known by those skilled in the art and include the use of zinc powder in the presence of ammonium chloride in a protic solvent such as methanol. Further reaction of 23 with M-W (5) as described above provides 10. In an alternative embodiment, 22 can be reacted with M-W (5) as described above to provide 24. Reduction of the nitro moiety of 24 provides 10. In another embodiment, amines of formula 23 can be prepared directly by reaction of 25 with 19 in the presence of a base.
Figure imgf000062_0001
Figure imgf000062_0002
Scheme 3
Scheme 4 illustrates the preparation of Compounds 28, examples of Formula I wherein Y is NR4 and Z is CRl 1. In one embodiment, following the general procedures of Scheme 1 , iodide 2 can react with 26 in the presence of copper(I) iodide and a suitable ligand, for example N,N-dimethylethane-l,2-diamine to afford 27. Further reaction of 27 with M-W (5) in the presence of a palladium catalyst and a base, as described in scheme 1 , provides compounds of formula 28. In an alternate embodiment, compounds of formula 28 can be prepared directly from compounds of formula 9 by reaction with 26 in the presence of copper(I) iodide and a suitable ligand.
Scheme 4
Scheme 5 illustrates the preparation of Compounds 3J_, examples of Formula I wherein Y is O and Z is N. Thus treatment of hydrazine 12 with acid chloride 29 provides compound 30. Those skilled in the art will appreciate that numerous equivalents for 29 may be found, including acid halides, anhydrides or "activated esters." Compound 30 may be isolated or generated and used in situ. Further reaction of 30 with triphosgene (or other suitable carbonylation reagent, such as phosgene or carbonyl diimidazole) in the presence of a base provides compounds of formula 31.
Figure imgf000064_0001
In another embodiment, Scheme 6 illustrates the preparation of compounds of Formula I or 28 wherein R4 is not hydrogen from compounds 32 or 34 resepectively by alkylation of the NH moiety of 32 or 34 with an alkylating agent 33. Suitable conditions for the reaction include contacting alkylating agent 33 with 32 or 34 in an aprotic solvent, such as acetone, in the presence of a base, for example cesium carbonate or potassium carbonate. In one embodiment, 33 is an alkyl halide (X is halide). In another embodiment, 33 is a sulfonate ester, for example a trifiate (Y= OS(0)2CF3).
Figure imgf000065_0001
32 (Z = N) 1 (Z = N) 34 (Z = CR11) 28 (Z=CR11)
Scheme 6
Scheme 7 illustrates a general preparation of triazolones of formula 35, examples of general reagent 3 wherein R4 is hydrogen. As indicated in scheme 7, reaction of acid chlorides 29 with semicarbazide (36) provide triazolones 35 after cyclodehydration of the intermediate 2- acylhydrazine- 1 carboxamide 37. In one embodiment, the reaction is performed by treating an aqueous solution of semicarbazide with acid chloride 29 to afford 37 followed by the treatment of 37 with aqueous sodium hydroxide and the heating of the mixture to effect cyclodehydration. Those skilled in the art will appreciate that numerous equivalents for 29 may be found, including acid halides, anhydrides or "activated esters."
Figure imgf000065_0002
Scheme 7 [0368] Using the synthetic procedures and methods described herein and methods known to those skilled in the art, the following compounds were made: 3-(4-fluorobenzyl)-l-(6-methyl-5- ((2-(l -methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH- l ,2,4-triazol-5(4H)-one, 3- benzyl- 1 -(6-methyl-5-((2-(l -methyl- 1 H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)- 1 H- 1 ,2,4- triazol-5(4H)-one, 3-(4-fluorobenzyl)-l -(5-((2-(l -methyl- 1 H-pyrazol-4-yl)pyridin-4- yl)oxy)pyridin-2-yl)- lH-l ,2,4-triazol-5(4H)-one, 3-(tert-butyl)-l-(5-((2-(l -methyl- lH-pyrazol- 4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one, 3-isopropyl-l-(6-methyl-5- ((2-(l -methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH- l ,2,4-triazol-5(4H)-one, 3- cyclohexyl- 1 -(6-methyl-5-((2-( 1 -methyl- 1 H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)- 1 H- l ,2,4-triazol-5(4H)-one, 3-(tert-butyl)-l-(6-methyl-5-((2-(l-methyl-lH-pyrazol-4-yl)pyridin-4- yl)oxy)pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5(4H)-one, 3-(tert-butyl)- 1 -(6-ethyl-5-((2-( 1 -methyl- 1 H- pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5(4H)-one, 3-(tert-butyl)- 1 -(6- methyl-5-((2'-methyl-[2,4'-bipyridin]-4-yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one, 3- (tert-butyl)-l -(6-methyl-5-((6'-methyl-[2,3'-bipyridin]-4-yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol- 5(4H)-one, N-(4-((6-(3-(tert-butyl)-5-oxo-4,5-dihydro- 1 H- 1 ,2,4-triazol- 1 -yl)-2-methylpyridin- 3-yl)oxy)pyridin-2-yl)acetamide, 3-(tert-butyl)- 1 -(6-methyl-5-((2-(2-methylthiazol-5- yl)pyridin-4-yl)oxy)pyridin-2-yl)- 1H- 1 ,2,4-triazol-5(4H)-one, 3-(tert-butyl)-4-methyl- 1 -(6- methyl-5-((2-( 1 -methyl- 1 H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5(4H)- one, 3-(tert-butyl)-l-(6-methyl-5-((2-(4-(l -methylpiperidin-4-yl)phenyl)pyridin-4- yl)oxy)pyridin-2-yl)- lH-l ,2,4-triazol-5(4H)-one, 3-(2-methoxyethyl)-l-(6-methyl-5-((2-(l- methyl-lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one, 3-(2- methoxypropan-2-yl)- 1 -(6-methyl-5-((2-( 1 -methyl- 1 H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2- yl)- 1 H- 1 ,2,4-triazol-5(4H)-one, 3-(methoxymethyl)- 1 -(6-methyl-5-((2-( 1 -methyl- 1 H-pyrazol- 4-yl)pyridin-4-yl)oxy)pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5(4H)-one, 3-(tert-butyl)- 1 -(5-((2-( 1 -(2- hydroxyethyl)- 1 H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-methylpyridin-2-yl)- 1 H- 1 ,2,4-triazol-5(4H)- one, 3-(tert-butyl)- 1 -(6-methyl-5-((2-(4-methyl- 1 H-imidazol- 1 -yl)pyridin-4-yl)oxy)pyridin-2- yl)- 1 H- 1 ,2,4-triazol-5(4H)-one, 1 -(6-methyl-5-((2-( 1 -methyl- 1 H-pyrazol-4-yl)pyridin-4- yl)oxy)pyridin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)-lH-l ,2,4-triazol-5(4H)-one, N-(4-((6-(3- (tert-butyl)-5-oxo-4,5-dihydro- 1 H- 1 ,2,4-triazol- 1 -yl)-2-methylpyridin-3-yl)oxy)pyridin-2-yl)- 1 - methylpiperidine-4-carboxamide, 3-isobutyl- 1 -(6-methyl-5-((2-(l -methyl- 1 H-pyrazol-4- yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-l,2,4-triazol-5(4H)-one, 3-(tert-butyl)-l-(6-methyl-5-((2- (1 -methyl- lH-imidazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-l,2,4-triazol-5(4H)-one, l-(5- ((2-(lH-pyrazol-4-yl)pyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-(tert-butyl)-lH-l ,2,4-triazol- 5(4H)-one, 1 -(6-methyl-5-((2-(l -methyl- 1 H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-3-
(tert-pentyl)-lH-l,2,4-triazol-5(4H)-one, 4-((6-(3-(tert-butyl)-5-oxo-4,5-dihydro-lH- 1 ,2,4- triazol- 1 -yl)pyridin-3-yl)oxy)-N-methylpicolinamide, 1 -(6-methyl-5-((2-(l -methyl- 1 H- pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-3-(l -methylcyclopropyl)- 1 H- 1 ,2,4-triazol-5(4H)- one, 3-(4-fluorophenyl)- 1 -(6-methyl-5-((2-( 1 -methyl- 1 H-pyrazol-4-yl)pyridin-4- yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one, 3-(4-fluorophenyl)-l-(6-methyl-5-((2-(4- methyl-lH-imidazol-l-yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one, 3-(4-((6- (3-(tert-butyl)-5-oxo-4,5-dihydro- 1 H- 1 ,2,4-triazol- 1 -yl)-2-methylpyridin-3-yl)oxy)pyridin-2-yl)- 1 , 1 -dimethylurea, 3-(tert-butyl)- 1 -(4-methyl-5-((2-( 1 -methyl- 1 H-pyrazol-4-yl)pyridin-4- yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one, N-(4-((6-(3-(4-fluorophenyl)-5-oxo-4,5- dihydro- 1 H- 1 ,2,4-triazol- 1 -yl)-2-methylpyridin-3-yl)oxy)pyridin-2- yl)cyclopropanecarboxamide, 3-(tert-butyl)-l-(4,6-dimethyl-5-((2-(l -methyl- 1 H-pyrazol-4- yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-l,2,4-triazol-5(4H)-one, 3-cyclopentyl-l-(6-methyl-5- ((2-(l -methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-l,2,4-triazol-5(4H)-one, 3- cyclopropyl- 1 -(6-methyl-5-((2-( 1 -methyl- 1 H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)- 1 H- l,2,4-triazol-5(4H)-one, l-(6-methyl-5-((2-(l-methyl-lH-pyrazol-4-yl)pyridin-4- yl)oxy)pyridin-2-yl)-3-neopentyl-lH-l ,2,4-triazol-5(4H)-one, 3-cyclobutyl-l-(6-methyl-5-((2- (1 -methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one , 3-(tert- butyl)- 1 -(5-((2-( 1 -ethyl- 1 H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-methylpyridin-2-yl)- 1 H- 1 ,2,4- triazol-5(4H)-one, 3-(tert-butyl)-l-(6-methyl-5-((2-(oxazol-5-yl)pyridin-4-yl)oxy)pyridin-2- yl)- 1 H- 1 ,2,4-triazol-5(4H)-one, 3-(tert-butyl)- 1 -(6-methyl-5-((6'-(4-methylpiperazin- 1 -yl)-
[2,3'-bipyridin]-4-yl)oxy)pyridin-2-yl)-lH-l,2,4-triazol-5(4H)-one, 3-(tert-butyl)-l-(6-methyl- 5-((2'-(4-methylpiperazin-l-yl)-[2,4'-bipyridin]-4-yl)oxy)pyridin-2-yl)-lH-l,2,4-triazol-5(4H)- one, 3-(l-hydroxy-2-methylpropan-2-yl)-l-(6-methyl-5-((2-(l -methyl- lH-pyrazol-4-yl)pyridin- 4-yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one, 1 -(6-methy 1-5 -((2-(l -methyl- lH-pyrazol-4- yl)pyridin-4-yl)oxy)pyridin-2-yl)-3-(l -(trifluoromethyl)cyclobutyl)- 1 H- 1 ,2,4-triazol-5(4H)-one, N-(4-((6-(3-(2-methoxypropan-2-yl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-l-yl)-4-methylpyridin- 3-yl)oxy)pyridin-2-yl)acetamide, N-(4-((6-(3-(tert-butyl)-5-oxo-4,5-dihydro-lH-l ,2,4-triazol- l-yl)-2-methylpyridin-3-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide, 3-(l-methoxy-2- methylpropan-2-yl)-l-(6-methyl-5-((2-(l -methyl- lH-pyrazo l-4-yl)pyridin-4-yl)oxy)pyridin-2- yl)- 1 H- 1 ,2,4-triazol-5(4H)-one, 3-(tert-butyl)- 1 -(6-methyl-5-((6-( 1 -methyl- 1 H-pyrazol-4- yl)pyrimidin-4-yl)oxy)pyridin-2-yl)- 1H- 1 ,2,4-triazol-5(4H)-one, 4-(tert-butyl)- 1 -(6-methyl-5- ((2-(l -methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-imidazol-2(3H)-one, and 5- (tert-butyl)-3-(6-methyl-5-((2-(l -methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)- 1 ,3,4- oxadiazol-2(3H)-one.
Examples
[0369] The disclosure is further illustrated by the following examples, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and/or scope of the appended claims.
Figure imgf000069_0001
Example Al: A solution of 3-hydroxy-2-methylpyridine (20.0 g, 183 mmol) and Na2CC>3 (38.8 g, 367 mmol) in H20 (320 mL) and MeOH (200 mL) was treated with I2 (46.5 g, 183 mmol) and stirred at RT for 1 h. The mixture was acidified with HC1 (2 M), extracted with EtOAc (2x) and the combined organics were washed with brine, dried over Na2SC>4 and concentrated to dryness. The material was suspended in 1 : 1 EtO Ac/Hex, sonicated and the solid collected via filtration and dried. The filtrate was concentrated to dryness, treated with DCM, the solid collected via filtration and combined with the first solid to afford 6-iodo-2-methylpyridin-3-ol (20.5 g, 48%). MS (ESI) m/z: 236.0 (M+H+). [0370] A mixture of 6-iodo-2-methylpyridin-3-ol (6.8 g, 28.9 mmol), 2,4-dichloropyridine (8.56 g, 57.9 mmol) and K2C03 (4.00 g, 28.9 mmol) in DMA (50 mL) was heated at 110°C for 16 h under argon. The mixture was cooled to RT, treated with H20, extracted with EtOAc (2x) and the combined organics were washed with H20, then brine, dried over Na2SC>4, concentrated to dryness and purified via silica gel chromatography (EtO Ac/Hex) to afford 3-((2- chloropyridin-4-yl)oxy)-6-iodo-2-methylpyridine (7.35 g, 73 %) as a white solid. MS (ESI) m/z: 346.9 (M+H+).
Figure imgf000070_0001
Example A2: A mixture of Example Al (10.0 g, 28.9 mmol), benzophenone hydrazone (5.46 g, 27.8 mmol), 2,2'-bis(diphenylphosphino)-l,l '-binaphthalene (1.13 g, 1.82 mmol), and sodium te/ -butoxide (3.90 g, 40.6 mmol) in toluene (57.7 mL) was sonicated and sparged with Ar for 10 min. Palladium(II) acetate (0.14 g, 0.61 mmol) was added and the reaction mixture was stirred vigorously at 105 °C for 16 h. The mixture was diluted with EtOAc (50 mL) and filtered through a pad of diatomaceous earth. The filter cake was washed with EtOAc (3 x 10 mL) and the combined filtrates were concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc/hexanes) to afford 3-((2-chloropyridin-4-yl)oxy)-6-(2- (diphenylmethylene)hydrazinyl)-2-methylpyridine (4.3 g, 100 % yield) as a white solid. !H NMR (400 MHz, DMSO-i¼): δ 8.37 (s, 1 H), 8.26 (d, J = 5.8 Hz, 1 H), 7.64-7.63 (m, 1 H), 7.57-7.56 (m, 2 H), 7.37-7.33 (m, 8 H), 6.96 (d, J = 2.3 Hz, 1 H), 6.90 (dd, J= 5.8, 2.3 Hz, 1 H), 2.09 (s, 3 H); MS (ESI) m/z: 415.1 (M+H+).
Figure imgf000071_0001
Example A3: Method 1 : Concentrated HC1 (21.31 mL, 256 mmol) was added to a solution of Example A2 (4.2 g, 10.1 mmol) in toluene (80 mL) and the reaction mixture was stirred at 110 °C for 1.5 h. The organic solvent was removed in vacuo and the remaining aqueous solution was diluted with water (50 mL), washed with toluene (2 x 20 mL), cooled in an ice bath, and adjusted to pH - 12 with 50 % NaOH (aq). The suspension was saturated with solid NaCl and extracted with EtOAc (3 x 50 mL). The combined organics were dried (Na2SC>4) and concentrated in vacuo to afford 3-((2-chloropyridin-4-yl)oxy)-6-hydrazinyl-2-methylpyridine (2.1 g, 83 %) as a white solid. !H NMR (400 MHz, DMSO-i¾: δ 8.24 (d, J= 5.7 Hz, 1 H), 7.50 (s, 1 H), 7.30 (d, J= 8.8 Hz, 1 H), 6.88 (d, J= 2.2 Hz, 1 H), 6.85-6.84 (m, 1 H), 6.63 (d, J= 9.0 Hz, 1 H), 4.13 (br s, 2 H), 2.09 (s, 3 H); MS (ESI) m/z: 251.1 (M+H+).
[0371] 3-((2-Chloropyridin-4-yl)oxy)-6-hydrazinyl-2-methylpyridine (2.0 g, 8.0 mmol) was suspended in DCM (14 mL) at 0 °C. Example B3 (2.7 g, 16.3 mmol) was added and the mixture was allowed to warm to RT and stirred for 25 min. The mixture was cooled back to 0 °C and diluted with DCM (70 mL). TEA (5.6 mL, 40.2 mmol) and a solution of bis(trichloromethyl) carbonate (1.2 g, 4.0 mmol) in DCM (10 mL) were sequentially added and the mixture was allowed to warm to RT and stirred for 30 min. Sat. NaHC03 (aq) (100 mL) was added the mixture was extracted with DCM (4 x 50 mL). The combined organics were dried (MgSC^) and concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM) to afford 3-(/er/-butyl)- 1 -(5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)- 1 H- 1 ,2,4-triazol- 5(4H)-one (1.25 g, 43.5 %) as an off white solid. 1H NMR (400 MHz, DMSO-i¾: δ 1 1.97 (s, 1 H), 8.29 (d, J= 5.8 Hz, 1 H), 7.86 (d, J= 8.8 Hz, 1 H), 7.73 (d, J= 8.8 Hz, 1 H), 7.06 (d, J= 2.3 Hz, 1 H), 6.96 (dd, J= 5.8, 2.3 Hz, 1 H), 2.30 (s, 3 H), 1.27 (s, 9 H); MS (ESI) m/z: 360.1 (M+H+).
[0372] Method 2: A suspension of Example CI (7.00 g, 49.6 mmol), Example Al (13.00 g, 37.5 mmol), copper iodide (0.700 g, 3.68 mmol), K2C03 (10.00 g, 72.4 mmol) and N1 ,N2- dimethylethane-l ,2-diamine (0.700 g, 7.94 mmol) in DMF (70 mL) was heated at 100 °C under argon overnight.
[0373] The solvent from the reaction mixture was evaporated under vacuum. The residue was partitioned between DCM (300 mL) and water (300 mL). The organic layer was separated and the aqueous layer extracted with DCM (2 x 200 mL). The combined organics were washed with brine, dried and evaporated. The residue was subjected to chromatography using (0-20% MeOH/DCM) to provide 3-(tert-butyl)-l-(5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)- lH-l ,2,4-triazol-5(4H)-one, (6.7 g, 49.6%) as a white solid. MS(ESI) m/z: 360.2 (M+H+).
Figure imgf000072_0001
Example A4: Example A2 (9.2 g, 22.9 mmol) and l-methyl-4-(4,4,5,5-tetramethyl- 1 ,3,2- dioxaborolan-2-yl)- 1 H-pyrazole (6.2 g, 29.8 mmol) were dissolved in dioxane (92 mL). A solution of K2CO3 (9.0 g, 65.1 mmol) in water (22.9 mL) was added and the mixture was sonicated and sparged with Ar for 10 min. Tetrakis(triphenylphosphine)-palladium(0)
[Pd(PPh3)4] (1.4 g, 1.2 mmol) was added and the reaction mixture was stirred at 85 °C for 16 h. The mixture was partitioned between water (250 mL) and DCM (200 mL). The organic phase was collected and the aqueous phase was extracted with DCM (4 x 100 mL). The combined organics were dried (Na2S04) and concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM) to afford 6-(2-(diphenylmethylene)hydrazinyl)-2-methyl-3-((2- (1 -methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyri dine (9.3 g, 88 %) as a light yellow solid. !H NMR (400 MHz, DMSO-i¾: δ 8.33 (d, J= 5.1 Hz, 2 H), 8.24 (s, 1 H), 7.94 (s, 1 H), 7.58-7.57 (m, 6 H), 7.38-7.36 (m, 6 H), 7.12 (d, J= 2.5 Hz, 1 H), 6.58 (dd, J = 5.7, 2.4 Hz, 1 H), 3.84 (s, 3 H), 2.12 (s, 3 H); MS (ESI) m/z: 461.2 (M+H+).
[0374] 6-(2-(Diphenylmethylene)hydrazinyl)-2-methyl-3-((2-(l -methyl- lH-pyrazol-4- yl)pyridin-4-yl)oxy)pyridine (9.3 g, 20.19 mmol) was dissolved in toluene (497 mL).
Concentrated HCl (134 mL, 1608 mmol) was added and the reaction mixture was stirred for 1.5 h at 1 10 °C, allowed to cool to RT, and stirred for 10 h. The organic phase was removed and the aqueous phase was extracted with toluene (1 x 100 mL). The combined organics were back extracted with 1 N HCl (1 x 100 mL). The combined aqueous phases were adjusted to pH - 1 1 with 50 % NaOH (aq), saturated with solid NaCl, and extracted with EtOAc (3 x 200 mL). The combined organics were dried ( a2S04) and concentrated in vacuo to afford 6-hydrazinyl-2- methyl-3-((2-(l -methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyri dine (4.7 g, 79 %) as a tan solid. 1H NMR (400 MHz, DMSO-i¾: δ 8.31 (d, J = 5.7 Hz, 1 H), 8.22 (s, 1 H), 7.92 (s, 1 H), 7.44 (s, 1 H), 7.28 (d, J = 8.8 Hz, 1 H), 7.1 1 (d, J= 2.4 Hz, 1 H), 6.64 (d, J = 8.8 Hz, 1 H), 6.49 (dd, J = 5.7, 2.4 Hz, 1 H), 4.14 (s, 2 H), 3.84 (s, 3 H), 2.1 1 (s, 3 H); MS (ESI) m/z: 297 '.1 (M+H+).
Figure imgf000074_0001
Example A5: A solution of 5-bromo-2-nitropyridine (15 g, 73.9 mmol) in DMF (300 mL) was sparged with Ar, treated with CS2CO3 (48.2 g, 148 mmol) and 2-chloro-4-hydroxypyridine (10.53 g, 81 mmol), sparged again with Ar and heated at 85°C overnight. The mixture was cooled to RT, filtered through a bed of silica gel, washed thoroughly with EtOAc, and the filtrate treated with 5% LiCl and stirred overnight. The layers were separated, the aqueous layer extracted with additional EtOAc (4x) and the combined organics were dried over Na2S04 and concentrated to dryness. The residue was dissolved in EtOAc, treated with 5% LiCl, stirred for 1 h, the layers separated and the aqueous layer extracted with EtOAc (3x). The combined organics were dried over Na2S04, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex). The material was suspended in MTBE, sonicated and the resulting solid collected via filtration to afford 2-chloro-4-((6-nitropyridin-3-yl)oxy)pyridine (6.06 g, 33%). !H NMR (400 MHz, DMSO-ί/ί): δ 8.62 (d, J = 2.4, 1 H), 8.43-8.39 (m, 2 H), 8.06 (dd, J = 8.8, 2.8 Hz, 1 H), 7.36 (d, J = 2.0 Hz, 1 H), 7.23 (dd, J = 5.6, 2.0 Hz, 1 H); MS (ESI) m/z: 252.0 (M+H+).
A suspension of 2-chloro-4-((6-nitropyridin-3-yl)oxy)pyridine (14.38 g, 57.1 mmol), 1- methyl-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole (13.08 g, 62.9 mmol) and Cs2C03 (55.9 g, 171 mmol) in DMF (150 mL) was sparged with Ar , treated with Pd(PPh3)4 (6.60 g, 5.71 mmol), sparged again with Ar and heated at 90°C overnight. The mixture was cooled to RT, the solids removed via filtration through diatomaceous earth, washed with EtOAc and the filtrate concentrated to near-dryness. The residue was treated with EtOAc, washed with 5% LiCl (lx) and the aqueous layer back-extracted with EtOAc (4x). The combined organics were dried over Na2S04, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 2-(l -methyl- lH-pyrazol-4-yl)-4-((6-nitropyridin-3-yl)oxy)pyri dine (12.28 g, 72%). !H NMR (400 MHz, DMSO-i¾: δ 8.59 (d, J = 2.8 Hz, 1 H), 8.49 (d, J = 5.6 Hz, 1 H), 8.41 (d, J = 8.9 Hz, 1 H), 8.29 (s, 1 H), 8.00 (d, J = 0.7 Hz, 1 H), 7.97 (dd, J = 8.9, 2.8 Hz, 1 H), 7.44 (d, J = 2.4 Hz, 1 H), 6.97 (dd, J = 5.6, 2.4 Hz, 1 H), 3.85 (s, 3 H); MS (ESI) m/z: 298.1 (M+H+).
[0375] A mixture of 2-(l -methyl-lH-pyrazol-4-yl)-4-((6-nitropyridin-3-yl)oxy)pyridine (1 1.88 g, 40.0 mmol) and NH4C1 (22.4g, 419 mmol) in EtOH (200 mL) and water (200 mL) was treated portion-wise with iron powder (22.4 g, 401 mmol), stirred for 0.5 h, treated with additional NH4CI (22.4g, 419 mmol) and iron powder (22.4 g, 401 mmol) and stirred at RT for 3 h. The solids were removed via filtration through diatomaceous earth and washed with EtOAc and DCM. The filtrate was washed with water, the aqueous layer back-extracted with DCM (4x) and the combined organics were dried over a2S04, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 5-((2-(l -methyl- lH-pyrazol-4-yl)pyridin-4- yl)oxy)pyridin-2-amine (6.4 g, 60%). MS (ESI) m/z: 268.1 (M+H+).
Figure imgf000076_0001
Example A6: Example A5 (1.0 g, 3.8 mmol) was added to a solution of HF-pyridine (5.6 mL, 62.0 mmol) in pyridine (5.6 mL) at 0 °C. The mixture was stirred for 30 min, cooled to -10 °C, and treated with sodium nitrite (0.39 g, 5.6 mmol). The mixture was allowed to warm to RT, stirred for 12 h, cooled back to 0 °C, and poured into cold sat. NaHC03 (aq) (50 mL). The slurry was extracted with EtOAc (3 x 50 mL) and the combined organics were dried (Na2S04) and concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM) to afford 4-((6-fiuoropyridin-3-yl)oxy)-2-(l -methyl- lH-pyrazol-4-yl)pyri dine (0.99 g, 98 %) as a white solid. MS (ESI) m/z: 271.1 (M+H+).
[0376] 4-((6-Fluoropyridin-3-yl)oxy)-2-(l-methyl-lH-pyrazol-4-yl)pyridine (0.99 g, 3.66 mmol) was dissolved in 2-propanol (7.3 mL) in a screw-cap reaction vessel. Hydrazine hydrate (64 %) (0.9 mL, 18.3 mmol) was added, the vessel was sealed, and the reaction mixture was stirred at 80 °C for 12 h. The mixture was partitioned between sat. aqueous NaHC03 (aq) (30 mL) and EtOAc (30 mL). The organic phase was collected and the aqueous phase was extracted with EtOAc (4 x 30 mL). The combined organics were dried ( a2S04) and concentrated in vacuo to afford 4-((6-hydrazinylpyridin-3-yl)oxy)-2-(l -methyl- lH-pyrazol-4-yl)pyridine (0.9 g, 87 %) as an off-white solid. !H NMR (400 MHz, DMSO-i¾: δ 9.29 (s, 1 H), 8.33 (d, J= 5.7 Hz, 1 H), 8.23 (s, 1 H), 8.00 (d, J= 2.9 Hz, 1 H), 7.93 (s, 1 H), 7.48 (dd, J= 9.0, 2.9 Hz, 1 H), 7.16 (d, J = 2.4 Hz, 1 H), 7.12 (d, J= 9.0 Hz, 1 H), 6.62 (dd, J= 5.7, 2.4 Hz, 1 H), 4.10 (d, J= 4.5 Hz, 2 H), 3.84 (s, 3 H); MS (ESI) m/z: 283.1 (M+H+).
Figure imgf000077_0001
Example A7: DMF (25 mL) was slowly treated with SOQ2 (125 mL) to maintain a temperature of 40-50°C. The mixture was then treated portion-wise with pyridine-2-carboxylic acid (25 g, 0.2 mol) over 0.5 h, then heated at reflux for 16 h, cooled to RT, diluted with toluene (80 mL) and concentrated to dryness (this process was repeated three times). The resulting residue was washed with toluene and dried under reduced pressure to yield 4-chloro-pyridine-2-carbonyl chloride (27.6 g, 79% yield), which was used in the next step without purification.
[0377] A 0°C solution of 4-chloro-pyridine-2-carbonyl chloride (27.6 g, 0.16 mol) in THF (100 mL) at was treated drop- wise with a solution of MeNH2 in EtOH, stirred at 3°C for 4 h, then concentrated to dryness. The material was suspended in EtOAc, the solids removed via filtration and the filtrate was washed with brine (2x), dried and concentrated to yield 4-chloro-N- methylpicolinamide (16.4 g, 60%) as a yellow solid. 'H NMR (400 MHz, DMSO-i¾ δ 8.78 (br s, 1H), 8.55 (d, J= 5.2 Hz, 1H), 7.97 (d, J = 2.0 Hz, 1H), 7. 66 (m, 1H), 2.82 (d, J= 4.8 Hz, 3H); MS (ESI) m/z: 171.0 (M+H+).
[0378] A solution of 2-amino-5-hydroxypyridine (0.968 g, 8.79 mmol) in DMA (15 mL) was treated with potassium tert-butoxide (0.987 g, 8.79 mmol), stirred at RT for 3 h, treated with 4- chloro-N-methylpicolinamide (1.5 g, 8.79 mmol) and stirred at RT for 2 days. The mixture was concentrated to dryness, treated with water, extracted with EtOAc (3x) and the combined organics were washed with brine, dried over Na2S04, concentrated to dryness and purified via silica gel chromatography (EtOAc, MeOH/DCM) to afford 4-((6-aminopyridin-3-yl)oxy)-N- methylpicolinamide (1.3 g, 61 %). !H NMR (400 MHz, DMSO-i¾: δ 8.75 (m, 1 H), 8.46 (d, J = 5.6 Hz, 1 H), 7.82 (d, J = 2.9 Hz, 1 H), 7.34 (d, J = 2.6 Hz, 1 H), 7.30 (dd, J = 8.9, 3.0 Hz, 1 H), 7.10 (dd, J = 5.6, 2.7 Hz, 1 H), 6.53 (d, J = 8.9 Hz, 1 H), 6.07 (s, 2 H), 2.77 (d, J = 4.8 Hz, 3 H); MS (ESI) m/z: 245.1 (M+H+).
[0379] A mixture of 4-((6-aminopyridin-3-yl)oxy)-N-methylpicolinamide (0.4 g, 1.64 mmol) and potassium iodide (1.36 g, 8.19 mmol) in methylene iodide (5.46 mL) was treated dropwise with t4outylnitrite (1.95 mL, 16.4 mmol). The mixture was stirred overnight at RT, diluted with EtOAc (75 mL), and washed with 10% sodium carbonate (50 mL), 10% thiosulfate (50 mL), and brine (50 mL). The organics were dried over sodium sulfate, evaporated to dryness and purified by silica gel chromatography ((EtO Ac/Hex) to afford 4-((6-iodopyridin-3-yl)oxy)- N-methylpicolinamide (0.214 g, 36.8%). 1H NMR (400 MHz, DMSO-i¾: δ 8.78 (br d, J = 5.6 Hz, 1 H), 8.54 (d, J = 5.6 Hz, 1 H), 8.40 (d, J = 3.0 Hz, 1 H), 7.95 (d, J = 8.6 Hz, 1 H), 7.50 (dd, J = 8.6, 3.1 Hz, 1 H), 7.45 (d, J = 2.6 Hz, 1 H), 7.23 (dd, J = 5.6, 2.7 Hz, 1 H), 2.78 (d, J = 4.9 Hz, 3 H); MS (ESI) m/z: 356.0 (M+H+).
Figure imgf000078_0001
Example A8: A suspension of Example C5 (0.75 g, 4.19 mmol), Example Al (1.400 g, 4.04 mmol), copper iodide (0.080 g, 0.420 mmol), trans l,2-dimethylcyclohexane-l,2- diamine (0.090 g, 0.633 mmol) and K2C03 (1.00 g, 7.24 mmol) in DMF (15 mL) was briefly degassed and heated at 100 °C under argon for 8 hours. The residue was partitioned between dichloromethane (50mL) and water (50mL). The aqueous layer was separated and extracted with DCM (2 x 30mL). The combined organics were dried and concentrated to a small volume and subjected to chromatography using (0-100%
EtOAc/DCM) to provide l-(5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-(4- fluorophenyl)-lH-l ,2,4-triazol-5(4H)-one (1.01 g, 63 %) as a white solid. 1H NMR (400 MHz, DMSO-i¾): δ 12.70 (s, 1 H), 8.30 (d, J = 5.8 Hz, 1 H), 7.97-7.93 (m, 3 H), 7.78 (d, J = 8.8 Hz, 1 H), 7.39 (m, 2 H), 7.08 (d, J = 2.2 Hz, 1 H), 6.98 (dd, J = 5.8, 2.3 Hz, 1 H), 2.34 (s, 3 H); MS(ESI) m/z :398.1 (M+H+).
Figure imgf000079_0001
Example A9: A 0°C solution of H2S04 (12 mL) was treated with H202 (9.72 mL, 95 mmol), stirred for 10 min, treated with a solution of 2-amino-5-fluoro-4-methylpyridine (2 g, 15.86 mmol) in H2SO4 (8 mL), stirred for 15 min, then warmed to RT and stirred for 3 h. The mixture was re-cooled to 0°C, neutralized slowly with solid NaHC03 and the resulting solid collected via filtration and dried to afford 5-fluoro-4-methyl-2-nitropyridine (2 g, 81%). !H NMR (400 MHz, DMSO-i¼): δ 8.57 (s, 1 H), 8.42 (d, J = 5.3 Hz, 1 H), 2.42 (d, J = 1.9 Hz, 3 H); MS (ESI) m/z: 157.1 (M+H+).
[0380] A mixture of 5-fluoro-4-methyl-2-nitropyridine (2 g, 12.81 mmol) and 2-chloro-4- hydroxypyridine (1.66 g, 12.81 mmol) in DMF (26 mL) was sparged with Ar, treated with K2CO3 (2.66 g, 19.22 mmol), heated at 88°C for 24 h, then at 50°C for 2 days. The mixture was treated with water and the resulting solid collected via filtration and dried to afford 5-((2- chloropyridin-4-yl)oxy)-4-methyl-2-nitropyridine (2.72 g, 80%). 1H NMR (400 MHz, DMSO- d6): δ 8.49 (s, 1 H), 8.47 (s, 1 H), 8.35 (d, J = 5.7 Hz, 1 H), 7.24 (d, J = 2.3 Hz, 1 H), 7.12 (dd, J = 5.7, 2.3 Hz, 1 H), 2.32 (s, 3 H); MS (ESI) m/z: 266.0 (M+H+).
[0381] A solution of 5-((2-chloropyridin-4-yl)oxy)-4-methyl-2-nitropyridine (1.5 g, 5.65 mmol) and l-methyl-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole (1.527 g, 7.34 mmol) in dioxane (20 mL) was sparged with Ar, treated with a solution of K2CO3 (1.171 g, 8.47 mmol) in water (5 mL) and Pd(PPh3)4 (0.326 g, 0.282 mmol) and heated at 80°C overnight. The mixture was cooled to RT, treated with water, extracted with DCM (4x) and the combined organics were dried over Na2S04, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 4-methyl-5-((2-(l-methyl-lH-pyrazol-4-yl)pyridin-4- yl)oxy)-2-nitropyridine (2.3 g, 75%). 1H NMR (400 MHz, DMSO-i¾: δ 8.48 (s, 1 H), 8.43-8.42 (m, 2 H), 8.27 (s, 1 H), 7.98 (s, 1 H), 7.30 (d, J = 2.4 Hz, 1 H), 6.83 (dd, J = 5.7, 2.4 Hz, 1 H), 3.84 (s, 3 H), 2.34 (s, 3 H); MS (ESI) m/z: 312.1 (M+H+).
[0382] A solution of 4-methyl-5-((2-(l -methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)-2- nitropyridine (2.3 g, 7.39 mmol) in MeOH (37 mL) and THF (37 mL) was treated with NH4C1 (1 1.86 g, 222 mmol) followed by the portion-wise addition of zinc dust (4.83 g, 73.9 mmol) and the mixture stirred at RT overnight. The mixture was diluted with EtOAc, the solids removed via filtration through diatomaceous earth and the filtrate concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 4-methyl-5-((2-(l -methyl- lH-pyrazo 1-4- yl)pyridin-4-yl)oxy)pyridin-2-amine (1.4 g, 67%). MS (ESI) m/z: 282.1 (M+H+).
Figure imgf000081_0001
Example AlO A suspension of Example A9 (0.62 g, 2.2 mmol), KI (3.7 g, 22.3 mmol), and diiodomethane (5 mL, 62 mmol) was treated with i-butylnitrite (1.4 mL, 11.7 mmol) and stirred at RT for 12 h. The mixture was treated with EtOAc, washed successively with satd. NaHC03 (3x), 10 % Na2S203 (2x), and brine (2x) and the combined aqueous washes were back-extracted with EtOAc (2x). The combined organics were dried over MgSC>4, concentrated to dryness and purified by silica gel chromatography (EtOAc/DCM) to afford 2-iodo-4-methyl-5-((2-(l-methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridine (0.51 g, 59%). MS (ESI) m/z: 393.0 (M+H+).
Figure imgf000081_0002
Example All: A suspension of Example C6 (0.800 g, 5.22 mmol), Example Al (1.00 g, 2.89 mmol), copper iodide (0.050 g, 0.263 mmol), Cs2CO3 (2.000 g, 6.14 mmol) and
Nl,N2-dimethylethane-l,2-diamine (0.050 g, 0.567 mmol) in acetonitrile (20 mL) was heated at 100 °C under argon for 14 hours. The solvent from the reaction mixture was evaporated and the residue was partitioned between DCM (50 mL) and water (50mL).
The organic layer was separated and the aqueous layer saturated with solid sodium chloride and extracted with DCM (2 x 20 mL). The combined organics were dried, concentrated and purified by silica gel chromatography using (0-100% EtOAc/DCM) to provide 1 -(5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-cyclopentyl- 1 H- 1 ,2,4- triazol-5(4H)-one (0.342 g, 32 % yield) as white solid. !H NMR (400 MHz, DMSO-i¾: δ 11.92 (s, 1 H), 8.29 (d, J = 5.8 Hz, 1 H), 7.88 (d, J = 8.8 Hz, 1 H), 7.73 (d, J = 8.8 Hz, 1 H), 7.06 (d, J = 2.3 Hz, 1 H), 6.95 (dd, J = 5.8, 2.3 Hz, 1 H), 2.95 (m, 1 H), 2.29 (s, 3 H), 1.94 (m, 2 H), 1.62 (m, 6 H); MS (ESI) m/z: 372.1 (M+H+).
Figure imgf000082_0001
Example A12: 4-(tert-butyl)-lH-imidazol-2(3H)-one (3 g, 21.40 mmol), copper(I) iodide (0.815 g, 4.28 mmol), and K2CO3 (16.33 g, 118 mmol) were suspended in DMF (100 mL) and placed under an atmosphere of argon. Example Al (8.16 g, 23.54 mmol) and then N,N-dimethylethane- 1,2-diamine (0.377 g, 4.28 mmol) were added and the reaction mixture was stirred at 100 °C overnight. The reaction mixture was allowed to cool to RT and concentrated to dryness under high vacuum. The residue was stirred with sat'd NH4CI and EtOAc for ~ 60 minutes and the aqueous layer separated and back-extracted with EtOAc (3x). The organic phases were combined, dried (Na2S04), concentrated to dryness and dried further under high vaccum for ~ 15 minutes to afford a yellow solid. The solid was suspended in MeCN, sonicated, filtered and the solid washed with MeCN to afford 4-(tert-butyl)-l-(5-((2-chloropyridin-4-yl)oxy)-6- methylpyridin-2-yl)-lH-imidazol-2(3H)-one as a white solid (2.44 g, 31.8%). MS (ESI) m/z: 359.2 (M+H+).
Figure imgf000083_0001
Example A13: A solution of 5-((2-chloropyridin-4-yl)oxy)-4-methyl-2-nitropyridine
(0.52 g, 1.957 mmol; See: Example A9) in dioxane (15 mL) was sparged with Ar, treated with acetamide (0.347 g, 5.87 mmol), Cs2C03 (0.638 g, 1.957 mmol), X-Phos (0.093 g, 0.196 mmol) and Pd2(dba)3 (0.179 g, 0.196 mmol) and heated at 90°C overnight. The mixture was cooled to RT, diluted with EtOAc, the solids removed via filtration through diatomaceous earth, washed with EtOAc and the filtrate was washed with water, then brine, dried over Na2SC>4, concentrated to dryness and purified via silica gel chromatography (EtOAc/DCM) to afford N-(4-((4-methyl- 6-nitropyridin-3-yl)oxy)pyridin-2-yl)acetamide (360 mg, 64%). !H NMR (400 MHz, DMSO- d6): δ 10.66 (s, 1 H), 8.47 (s, 1 H), 8.43 (s, 1 H), 8.24 (d, J = 5.7 Hz, 1 H), 7.72 (d, J = 2.4 Hz, 1 H), 6.74 (dd, J = 5.7, 2.4 Hz, 1 H), 2.33 (s, 3 H), 2.05 (s, 3 H); MS (ESI) m/z: 289.1 (M+H+).
A solution of N-(4-((4-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)acetamide (0.36 g, 1.249 mmol) in EtOAc (15 mL) was treated with 10% Pd/C (50% w/w water, 0.133 g, 0.125 mmol) and hydrogenated (1 atm) overnight. The solids were removed via filtration through diatomaceous earth, washed with EtOAc and the filtrate was concentrated to dryness to afford N- (4-((6-amino-4-methylpyridin-3-yl)oxy)pyridin-2-yl)acetamide (320 mg, 99%). !H NMR (400 MHz, DMSO-ί ί): δ 10.47 (s, 1 H), 8.1 1 (d, J = 5.7 Hz, 1 H), 7.66 (s, 1 H), 7.55 (d, J = 2.4 Hz, 1 H), 6.55 (dd, J = 5.7, 2.4 Hz, 1 H), 6.37 (s, 1 H), 5.88 (s, 2 H), 2.02 (s, 3 H), 1.93 (s, 3 H); MS (ESI) m/z: 259.1 (M+H+).
Figure imgf000084_0001
Example Bl: 2-(4-Fluorophenyl)acetonitrile (1.0 g, 7.4 mmol) was dissolved in anhydrous ethanol (2 mL) under an atmosphere of Ar. The solution was cooled to 0 °C, saturated with HC1 gas, stirred for 6 h, allowed to warm to RT, and stirred for 6 h. Organic solvent was removed in vacuo to afford ethyl 2-(4-fluorophenyl)acetimidate hydrochloride (1.6 g, 100 %) as a white solid. !H NMR (400 MHz, DMSO-i¾: δ 12.27 (m, 1 H), 11.20 (m, 1 H), 7.40 (dd, J= 8.3, 5.5 Hz, 2 H), 7.19 (t, J = 8.8 Hz, 2 H), 4.38 (q, J= 7.0 Hz, 2 H), 3.99 (s, 2 H), 1.25 (t, J= 7.0 Hz, 3 H).
[0383] Ethyl 2-(4-fluorophenyl)acetimidate hydrochloride (1.6 g, 7.4 mmol) was suspended in hexanes (18.5 mL) and DCM (18.5 mL) at 0 °C. 2,4,6-collidine (3.9 mL, 29.6 mmol) and ethyl chloroformate (1.6 g, 14.8 mmol) were added sequentially and the reaction mixture was allowed to warm to RT and stirred for 12 h. The solvent was removed in vacuo and the residue was suspended in EtOAc (100 mL) and sonicated for 10 minutes. The solids were removed by filtration through a pad of diatomaceous earth and the filter cake was washed with EtOAc (3 x 10 mL). The combined filtrates were concentrated in vacuo to afford ethyl N-ethoxycarbonyl-2-(4- fluorophenyl)acetimidate (0.99 g, 52.7 %) as an amorphous yellow solid. !H NMR (400 MHz, DMSO-ί ί): δ 7.25 (dd, J = 8.5, 5.6 Hz, 2 H), 7.13 (t, J = 8.8 Hz, 2 H), 4.06 (q, J = 7.1 Hz, 2 H), 4.04 (q, J= 7.1 Hz, 2 H), 3.66 (s, 2 H), 1.15 (t, J= 7.1 Hz, 3 H), 1.14 (t, J= 7.1 Hz, 3 H).
Figure imgf000085_0001
Example B2: 2-Phenylacetonitrile was dissolved in anhydrous ethanol (2 mL) under an atmosphere of Ar. The solution was cooled to 0 °C, saturated with HC1 gas, stirred for 6 h, allowed to warm to RT, and stirred for 6 h. The solvent was removed in vacuo to afford ethyl 2- phenylacetimidate hydrochloride (1.7 g, 99 %) as a white solid. !H NMR (400 MHz, DMSO-i¾: δ 7.36-7.35 (m, 5 H), 4.39 (q, J = 7.0 Hz, 2 H), 3.99 (s, 2 H), 1.26 (t, J = 7.0 Hz, 3 H).
[0384] Ethyl 2-phenylacetimidate hydrochloride (1.7 g, 8.5 mmol) was dissolved in DCM (10.6 mL) and cooled to 0 °C. TEA (7.1 mL, 51.1 mmol) was added dropwise the mixture was stirred for 1 h. Ethyl chloroformate (1.6 g, 14.8 mmol) was added and the reaction mixture was allowed to warm to RT and stirred for 12 h. The mixture was diluted with EtOAc (100 mL) and the solids were removed by filtration through diatomaceous earth. The filter cake was washed with EtOAc (3 x 10 mL) and the combined filtrates were concentrated in vacuo to afford ethyl N- ethoxycarbonyl-2-phenylacetimidate (1.9 g, 93 %) as a yellow oil. !H NMR (400 MHz, DMSO- d6): δ 7.27-7.26 (m, 5 H), 4.01 -4.00 (m, 4 H), 3.70 (s, 2 H), 1.18-1.08 (m, 6 H).
Figure imgf000085_0002
Example B3: Pivalonitrile (1.3 mL, 12.0 mmol) was dissolved in anhydrous ethanol (28 mL) under an atmosphere of Ar. The solution was cooled to 0 °C, saturated with HC1 gas, stirred for 6 h, allowed to warm to RT, and stirred for 54 h. The solvent was removed in vacuo to afford ethyl pivalimidate hydrochloride (2.0 g, 100 %) as an off white solid. !H NMR (400 MHz, DMSO-i¾: δ 1 1.19 (br s, 1 H), 4.42 (q, J = 6.9 Hz, 2 H), 1.33 (t, J= 6.8 Hz, 3 H), 1.24 (s, 9 H).
Figure imgf000086_0001
Example B4: Ethyl pivalimidate hydrochloride (Example B3) (0.75 g, 4.5 mmol) was suspended in hexanes (1 1.3 mL) and DCM (1 1.3 mL) and cooled to 0 °C. 2,4,6-Collidine (2.1 mL, 15.9 mmol) and ethyl chloroformate (0.98 g, 9.1 mmol) were sequentially added and the reaction mixture was allowed to warm to RT and stirred for 12 h. The solvent was removed in vacuo and the residue was slurried with EtOAc (50 mL). The solids were removed by filtration through a pad of diatomaceous earth. The filter cake was washed with EtOAc (3 x 10 mL) and the combined filtrates were concentrated in vacuo to afford ethyl N-ethoxycarbonylpivalimidate
(0.81 g, 89 %) as a yellow solid. 1H NMR (400 MHz, DMSO-i¾: δ 4.05 (q, J = 7.1 Hz, 2 H), 3.95 (q, J = 7.0 Hz, 2 H), 1.18 (t, J= 7.1 Hz, 3 H), 1.18 (t, 7.1 Hz, 3 H), 1.15 (s, 9 H).
Figure imgf000086_0002
Example B5: Isobutyronitrile (1 g, 14.5 mmol) was dissolved in anhydrous ethanol (30 mL) under an atmosphere of Ar. The solution was cooled to 0 °C, saturated with HCl gas, stirred for 6 h, allowed to warm to RT, and stirred for 6 h. The solvent was removed in vacuo to afford ethyl isobutyrimidate hydrochloride (1.8 g, 82 %) as a colorless solid. !H NMR (400 MHz, DMSO- δ 1 1.78 (br s, 1 H), 1 1.05 (br s, 1 H), 4.40 (q, J = 7.0 Hz, 2 H), 2.93-2.92 (m, 1 H), 1.33 (t, J = 7.0 Hz, 3 H), 1.16 (d, J= 6.9 Hz, 6 H). [0385] Ethyl isobutyrimidate hydrochloride (1.8 g, 1 1.9 mmol) was suspended in hexanes (29.7 mL) and cooled to 0 °C. 2,4,6-Collidine (4.1 mL, 30.9 mmol) and ethyl chloroformate (1.9 g, 17.8 mmol) were sequentially added and the mixture was allowed to warm to RT and stirred for 12 h. Organic solvent was removed in vacuo. The residue was suspended in EtOAc (50 mL) and solids were removed by filtration through a pad of diatomaceous earth. The filter cake was washed with EtOAc (3 x 10 mL) and the combined filtrates were concentrated in vacuo to afford ethyl N-ethoxycarbonylisobutyrimidate (2.2 g, 99 %) as a yellow amorphous solid. !H NMR
(400 MHz, DMSO-i¼): δ 4.09 (q, J = 7.1 Hz, 2 H),4.03 (q, J = 7.1 Hz, 2 H), 2.65-2.64 (m, 1 H), 1.20 (t, J = 7.1 Hz, 3 H), 1.19 (t, J = 7.1 Hz, 3 H), 1.07 (d, J = 6.8 Hz, 6 H).
Figure imgf000087_0001
Example B6: Cyclohexanecarbonitrile (1.0 g, 9.2 mmol) was dissolved in anhydrous ethanol under an atmosphere of Ar. The solution was cooled to 0 °C, saturated with HCl gas, stirred for 6 h, allowed to warm to RT, and stirred for 6 h. The solvent was removed in vacuo to afford ethyl cyclohexanecarbimidate hydrochloride (1.8 g, 100 %) as a colorless solid. !H NMR (400 MHz,
DMSO-ί/ί): δ 1 1.66 (m, 1 H), 1 1.03 (m, 1 H), 4.39 (q, J = 7.0 Hz, 2 H), 2.62 (m, 1 H), 1.84 (d, J = 12.6 Hz, 2 H), 1.70-1.65 (m, 3 H), 1.40-1.38 (m, 2 H), 1.33 (t, J = 7.0 Hz, 3 H), 1.23-1.19 (m,
3 H).
[0386] Ethyl cyclohexanecarbimidate hydrochloride (1.8 g, 9.2 mmol) was suspended in hexanes (22.9 mL) and cooled to 0 °C. 2,4,6-Collidine (4.1 mL, 30.9 mmol) and ethyl chloroformate (1.9 g, 17.8 mmol) were sequentially added and the mixture was allowed to warm to RT and stirred for 12 h. The solvent was removed in vacuo. The residue was suspended in EtOAc (50 mL) and the solids were removed by filtration through diatomaceous earth. The filter cake was washed with EtOAc (3 x 10 mL) and the combined filtrates were concentrated in vacuo to afford ethyl N-ethoxycarbonylcyclohexanecarbimidate (2.0 g, 96 %) as a yellow amorphous solid. 1H NMR (400 MHz, DMSO-i¾: δ 4.09 (q, J = 7.1 Hz, 2 H), 4.02 (q, J = 7.1 Hz, 2 H), 2.41-2.31 (m, 1 H), 1.70-1.65 (m, 4 H), 1.40-1.36 (m, 2 H), 1.26-1.09 (m, 4 H), 1.19 (t, J = 7.1
Hz, 6 H).
Figure imgf000088_0001
Example B7: 3-Methoxypropanenitrile (5.0 g, 58.8 mmol) was dissolved in anhydrous ethanol (50 mL) under an atmosphere of Ar. The solution was cooled to 0 °C, saturated with HC1 gas, stirred for 6 h, allowed to warm to RT, and stirred for 6 h. The solvent was removed in vacuo. The residue was slurried with hexanes (50 mL) and sonicated for 10 min. The solids were allowed to settle and the solvent was removed by decantation. This was repeated (3 x). The solid was collected and dried under high vacuum for 5 h to afford ethyl 3-methoxypropanimidate hydrochloride (6.2 g, 63 %) as a white solid. !H NMR (400 MHz, DMSO-i/5): δ 12.03 (br s, 1 H), 1 1.22 (br s, 1 H), 4.42 (q, J= 7.0 Hz, 2 H), 3.60 (t, J = 5.9 Hz, 2 H), 3.23 (s, 3 H), 2.87 (t, J = 5.9 Hz, 2 H), 1.33 (t, J = 7.0 Hz, 3 H).
[0387] Ethyl 3-methoxypropanimidate hydrochloride (1.0 g, 6.0 mmol) was suspended in DCM (12 mL) and cooled to 0 °C. Pyridine (2 mL, 24.7 mmol) was added dropwise and the mixture was stirred for 15 min. Ethyl chloro formate (0.97 g, 9.0 mmol) was added dropwise and the mixture was diluted with DCM (20 mL), allowed to warm to RT, and stirred for 12 h. The mixture was diluted with a mixture of EtOAc and hexanes (1 : 1 , 200 mL) and the solids were removed by filtration through a pad of diatomaceous earth. The filtrate was concentrated in vacuo to afford ethyl N-ethoxycarbonyl-3-methoxy-propanimidate (1.0 g, 83 %) as a light green solid. !H NMR (400 MHz, DMSO-i¾: δ 4.08 (q, J = 7.0 Hz, 2 H), 4.05 (q, J = 7.0 Hz, 2 H), 3.50 (t, J = 6.4 Hz, 2 H), 3.19 (s, 3 H), 2.57 (t, J = 6.4 Hz, 2 H), 1.20 (t, J = 7.0 Hz, 3 H), 1.19 (t, J = 7.0 Hz, 3 H).
Figure imgf000089_0001
Example B8: 2-Methoxyacetonitrile (1.0 g, 14.1 mmol) was dissolved in anhydrous ethanol (28.1 mL) under an atmosphere of Ar. The solution was cooled to 0 °C, saturated with HC1 gas, stirred for 6 h, allowed to warm to RT, and stirred for 6 h. The solvent was removed in vacuo to afford ethyl 2-methoxyacetimidate hydrochloride (1.0 g, 44.0 %) as a white solid. !H NMR (400 MHz, DMSO-ί ί): δ 4.42 (q, J = 7.0 Hz, 2 H), 4.31 (s, 2 H), 3.36 (s, 3 H), 1.32 (t, J = 7.0 Hz, 3
H).
[0388] Ethyl 2-methoxyacetimidate hydrochloride (0.95 g, 6.18 mmol) was suspended in DCM (12.4 mL) and the mixture was cooled to 0 °C. Pyridine (2.5 mL, 30.9 mmol) and ethyl chloro formate (1.2 mL, 12.4 mmol) were added sequentially and the solution was allowed to warm to RT and stirred for 12 h. EtOAc (100 mL) was added and solids were removed by filtration through a pad of diatomaceous earth. The filtrate was concentrated in vacuo to afford ethyl N-ethoxycarbonyl-2-methoxyacetimidate (1.2 g, 100 %) as a white solid. !H NMR (400 MHz, DMSO-ί ί): δ 4.08-4.03 (m, 2 H), 3.90 (q, J = 7.0 Hz, 4 H), 3.20 (s, 3 H), 1.1 1 (t, J = 6.9 Hz, 6 H).
Figure imgf000090_0001
Example B9: Isovaleronitrile (2.0 g, 24.1 mmol) was dissolved in anhydrous ethanol (48 mL) under an atmosphere of Ar. The solution was cooled to 0 °C, saturated with HC1 gas, stirred for 6 h, allowed to warm to RT, and stirred for 6 h. The solvent was removed in vacuo to afford ethyl 3-methylbutanimidate hydrochloride (4.0 g, 100 %) as a white solid. !H NMR (400 MHz, DMSO-i¾: δ 12.00 (br s, 1 H), 1 1.09 (br s, 1 H), 4.42 (q, J = 7.0 Hz, 2 H), 2.48-2.47 (m, 2 H), 2.02-2.01 (m, 1 H), 1.33 (t, J = 7.0 Hz, 3 H), 0.91 (d, J= 6.7 Hz, 6 H).
[0389] Ethyl 3-methylbutanimidate hydrochloride (4.0 g, 24.2 mmol) was suspended in DCM (48 mL) and the mixture was cooled to 0 °C. Pyridine (10.0 mL, 124 mmol) was added and the mixture was stirred for 15 minutes. Ethyl chloroformate (5.3 mL, 48.3 mmol) was added and the solution was allowed to warm to RT and stirred for 12 h. The mixture was diluted with a mixture of EtOAc and hexanes (1 : 1 , 200 mL) and solids were removed by filtration through a diatomaceous earth. The filtrate was concentrated in vacuo to afford ethyl N-ethoxycarbonyl-3- methyl-butanimidate (4.3 g, 88 %) as a colorless viscous oil. 1H NMR (400 MHz, DMSO-i¾: δ
4.09 (q, J = 7.1 Hz, 2 H), 4.05 (q, J = 7.1 Hz, 2 H), 2.18 (d, J = 7.4 Hz, 2 H), 1.95-1.94 (m, 1 H), 1.20 (t, J = 7.1 Hz, 3 H), 1.19 (t, J = 7.1 Hz, 3 H), 0.86 (d, J= 6.7 Hz, 6 H).
Figure imgf000091_0001
Example BIO: Tetrahydro-2H-pyran-4-carbonitrile (1 g, 9.00 mmol) was dissolved in dry ethanol (10 mL) and cooled to 0 °C. HC1 (gas) was bubbled through the solution for five minutes. The reaction mixture was allowed to warm to RT and stir for 2 days. The solvent was removed under reduced pressure and the resulting solid was dried under high vacuum to yield ethyl tetrahydro-2H-pyran-4-carbimidate hydrochloride (1.646 g, 94%). !H NMR (400 MHz, DMSO-de): δ 11.54 (br s, 1 H), 7.35 (s, 1 H), 4.41 (q, J = 7.0 Hz, 2 H), 3.88-3.86 (m, 2 H), 3.33- 3.27 (m, 2 H), 2.98 (tt, J = 11.7, 3.9 Hz, 1 H), 1.77 (dd, J = 13.1 , 3.4 Hz, 2 H), 1.65-1.63 (m, 2 H), 1.34 (t, J = 7.0 Hz, 3 H).
[0390] Ethyl tetrahydro-2H-pyran-4-carbimidate hydrochloride (1.646 g, 8.50 mmol) was suspended in DCM (21.25 mL) and cooled to 0 °C. Pyridine (3.09 mL, 38.2 mmol) was added and the solution was stirred for 15 min. Ethyl chloroformate (1.384 g, 12.75 mmol) was added dropwise. The reaction mixture was allowed to warm to RT and stir overnight. The reaction mixture was diluted with 50 % hexane/EtOAc and the resulting suspension was filtered through a plug of diatomaceous earth. The filtrate was concentrated under reduced pressure and the residue dried under high vacuum for several hours to yield ethyl N-ethoxycarbonyltetrahydro-2H-pyran- 4-carbimidate (1.80 g, 92 %). !H NMR (400 MHz, DMSO-d6): δ 4.12 (m, 2 H), 4.07 (m, 2 H), 3.85-3.83 (m, 2 H), 3.31-3.24 (m, 2 H), 2.69-2.68 (m, 1 H), 1.69-1.68 (m, 4 H), 1.23 (m, 6 H).
Figure imgf000092_0001
Example CI: Semicarbazide hydrochloride (25.0 g, 224 mmol) was dissolved in water (200 mL). NaHC03 (40.0 g, 476 mmol) was slowly added to the solution over 30 min at RT followed by the addition of trimethylacetyl chloride (30.0 g, 249 mmol). The mixture was stirred at RT for 12 h. Solids were collected by filtration, washed with cold water, and dried in vacuo. A solution of NaOH (20.0 g, 500 mmol) in water (200 mL) was added. The mixture was stirred at 100 °C for 2 h, cooled with an ice-bath, and neutralized by the drop-wise addition of concentrated HCl. The solids were collected by filtration, washed with water, and dried in vacuo to afford 3-(tert- butyl)-lH-l,2,4-triazol-5(4H)-one (19.6 g, 61.9 %) as a white solid. 1H NMR (400 MHz, DMSO-ί ί): δ 11.26 (s, 1 H), 11.04 (s, 1 H), 1.16 (s, 9 H); MS (ESI) m/z: 142.1 (M+H+).
Figure imgf000092_0002
Example C2: 2-Methoxyisobutyric acid (0.50 g, 4.23 mmol) was dissolved in MeCN (8.5 mL). lH-Benzo[d][l ,2,3]triazol-l-ol (20 % hydrate) (0.65 g, 4.23 mmol) and N-(3- dimethylaminopropyl)-7V-ethylcarbodiimide hydrochloride (0.81 g, 4.23 mmol) were added and the mixture was stirred at RT for 2 h. Semicarbazide hydrochloride (0.47 g, 4.23 mmol) was added and the mixture was stirred for an additional 12 h. Organic solvent was removed in vacuo and the residue was suspended in water (85 mL). Potassium hydroxide (0.48 g, 8.5 mmol) was added and the mixture was stirred at RT until complete dissolution of solids. The mixture was then stirred at 100 °C for 12 h and then allowed to cool to RT. The solution was saturated with solid NH4CI and extracted with EtOAc (8 x 50 mL). The combined organics were dried
( a2S04) and concentrated in vacuo to afford 3-(2-methoxypropan-2-yl)-lH-l,2,4-triazol-5(4H)- one (0.35 g, 52.6 %) as an amorphous solid. 1H NMR (400 MHz, DMSO-i¾: δ 11.44 (s, 1 H), 11.28 (s, 1 H), 2.96 (s, 3 H), 1.36 (s, 6 H).
Figure imgf000093_0001
Example C3: 2,2-Dimethylbutyric acid (1 g, 8.6 mmol) was dissolved in DCM (10 mL) and cooled to 0 °C. The solution was treated with oxalyl chloride (1.2 mL, 13.8 mmol) and DMF (0.07 mL, 0.87 mmol), allowed to warm to RT, and stirred for 2 h for complete conversion to 2,2-dimethylbutyric acid chloride. The solution was cooled to 0 °C and added to a stirred solution of semicarbazide hydrochloride (1.4 g, 12.9 mmol) and NaOH (1.4 g, 34.4 mmol) in a mixture of dioxane (10 mL) and water (2.0 mL) at 0 °C. The reaction mixture was allowed to warm to RT and stirred for 12 h. Organic solvent was evaporated in vacuo, and the resultant slurry was diluted with 2 M NaOH (aq) (50 mL, 100 mmol). The suspension was stirred at 100 °C for 24 h. The aqueous solution was saturated with solid NH4CI and extracted with EtOAc (5 x 50 mL). The combined organics were dried (Na2S04) and concentrated in vacuo to afford 3-
(teri-pentyl)-lH-l ,2,4-triazol-5(4H)-one (0.71 g, 53.1 %) as a white solid. 1H NMR (400 MHz, DMSO-i¾: δ 11.17 (s, 1 H), 11.02 (s, 1 H), 1.49 (q, J= 7.5 Hz, 2 H), 1.11 (s, 6 H), 0.68 (t, J = 7.4 Hz, 3 H); MS (ESI) m/z: 156.1 (M+H+).
Figure imgf000094_0001
Example C4: 2-Methylcyclopropanecarboxylic acid (0.86 g, 8.6 mmol) was dissolved in DCM (10 mL) and cooled to 0 °C. The solution was treated with oxalyl chloride (1.2 mL, 13.8 mmol) and DMF (0.07 mL, 0.87 mmol), allowed to warm to RT, and stirred for 2 h for complete conversion to 2-methylcyclopropanecarboxylic acid chloride. The solution was cooled to 0 °C and added via syringe to a stirred solution of semicarbazide hydrochloride (1.4 g, 12.9 mmol) and NaOH (1.4 g, 34.4 mmol) in a mixture of dioxane (10 mL) and water (2.0 mL) at 0 °C. The reaction mixture was allowed to warm to RT and stirred for 12 h. The organic solvent was evaporated in vacuo, and the resultant slurry was diluted with 2 M NaOH (aq) (50 mL, 100 mmol). The suspension was stirred at 100 °C for 24 h. The aqueous solution was saturated with solid NH4CI and extracted with EtOAc (5 x 50 mL). The combined organics were dried
( a2S04) and concentrated in vacuo to afford 3-(l-methylcyclopropyl)-lH-l ,2,4-triazol-5(4H)- one (0.65 g, 54.3 %) as a white solid. 1H NMR (400 MHz, DMSO-i¾: δ 11.02 (m, 2 H), 1.26 (s, 3 H), 0.90-0.89 (m, 2 H), 0.66-0.65 (m, 2 H); MS (ESI) m/z: 140.1 (M+H+).
Figure imgf000094_0002
Example C5: 4-Fluorobenzoyl chloride (2.50 g, 15.77 mmol) was added to a solution of semicarbazide hydrochloride (2.00 g, 17.93 mmol) and sodium bicarbonate (2.50 g, 29.8 mmol) in water (25 mL) and the mixture was stirred at RT for 2 h. The solids were collected by filtation, and washed and dried under suction to obtain a white solid.
MS(ESI) m/z : 198.1 (M+H+). The solid was suspended in water (25 mL), treated with sodium hydroxide (1.50 g, 37.5 mmol) and heated at 100 °C for 5 hours. The reaction mixture was cooled in ice bath, acidified with cone. HC1 and stirred for 20 min. The solids were collected by filtration. The white solid was stirred in acetonitrile filtered, washed and dried to provide 3-(4-fluorophenyl)-lH-l,2,4-triazol-5(4H)-one (1.1 g, 38.9
% yield) as white solid. 1H NMR (400 MHz, DMSO-</5): δ 12.03 (s, 1 H), 11.65 (s, 1 H), 7.81 (m, 2 H), 7.31 ( m, 2 H); MS(ESI) m/z: 180.1 (M+H+).
Figure imgf000095_0001
Example C6: To a suspension of semicarbazide hydrochloride (5.00 g, 44.8 mmol) in DCM (100 mL) was added triethylamine (10.00 g, 99 mmol) and the mixture was stirred at -10 °C for 30 min. Cyclopentane carbonylchloride (5.00 g, 37.7 mmol) was added at the same temp and the mixture was allowed to warm to RT over night. The solvent from the reaction mixture was completely removed and the residue stirred in MeCN (200 mL) for 1 h. The solids were collected by filtration, washed and dried. The solid was treated with sodium hydroxide (7.00 g, 175 mmol) and water (20 mL). The resulting reaction mixture was heated at 100 °C for 3 h. The reaction mixture was cooled and acidified with cone. HC1. The solids were collected, washed and dried to provide 3-cyclopentyl- lH-l,2,4-triazol-5(4H)-one (2.24 g, 38.8 % yield) as white solid. 1H NMR (400 MHz, DMSO-i¾: δ 11.17 (s, 1 H), 11.03 (s, 1 H), 2.80 (m, 1 H), 1.86(m, 2 H), 1.58 (m, 6 H);
MS(ESI) m/z: 154.1 (M+H+).
Figure imgf000096_0001
Example C7: To a 0 °C solution of 1-trifluoromethyl-l-cyclobutylcarboxylic acid (1.50 g, 8.92 mmol) in DCM (15 mL) was added oxalyl chloride (1.50 g, 11.82 mmol) followed by catalytic amount of DMF. The reaction mixture was stirred at RT for 1 h. The solvent from the reaction mixture was completely evaporated. In a different flask, a suspension of semicarbazide hydrochloride (1.50 g, 13.45 mmol) in water (15mL) was treated with NaHC03 (1.50 g, 17.86 mmol) and stirred at RT for 30 minutes till a clear solution forms. To this solution was added the above acid chloride dissolved in EtOAc (20 mL) and the resultant mixture was stirred at RT over night. The organic layer was separated and the aqueous layer was extracted with DCM (2 x 10 mL). The combined organics were concentrated and the residue was treated with sodium hydroxide (1.50 g, 37.5 mmol) in water (15 mL), heated at 100 °C for 3 h, and stirred for 20 h at RT. The reaction mixture was acidified with cone. HCl to pH 1 and stirrred at RT for 1 h. The reaction mixture was concentrated to a small volume under high vacuum and diluted with MeOH. The separted solids were filtered and washed with methanol. The filtrate was evaporated and further dried by azeotropic distillation from toluene to provide 5-(l- (trifluoromethyl)cyclobutyl)-2,4-dihydro-3H-l ,2,4-triazol-3-one (1.05 g, 57%) as a light brownish residue, sutiable for use without further purification. MS(ESI) m/z: 208.1 (M+H+).
Figure imgf000097_0001
Example C8: 3-Hydroxy-2,2-dimethylpropanoic acid (15.00 g, 127.0 mmol) was dissolved in a solution of MeOH (200 mL) and cone. H2SO4 (13.5 g, 254 mmol) and stirred at reflux for 16 h. The reaction mixture was concentrated in vacuo, diluted with EtOAc (100 mL), washed with water (2 x 50 mL), sat. NaHC03 (aq) (50 mL), water (50 mL), brine (1 x 50 mL), and dried ( a2S04). Organic solvent was removed in vacuo to afford methyl 3-hydroxy-2,2- dimethylpropanoate (6.4 g, 57.2 %) as a colorless liquid. !H NMR (400 MHz, DMSO-i¾: δ 3.71 (s, 3 H), 3.56 (s, 2 H), 2.05-2.04 (m, 1 H), 1.19 (s, 6 H).
[0391] Sodium hydride (1.16 g, 48.4 mmol) was dissolved in THF (48 mL) and cooled to 0 °C. 3-Hydroxy-2,2-dimethylpropanoate (6.4 g, 48.4 mmol) was added dropwise and the mixture was stirred at 0 °C for 30 min, allowed to warm to RT, and stirred an additional 1 h. The mixture was cooled back to 0 °C and iodomethane (3.0 mL), 48.4 mmol) was added. The reaction mixture was allowed to warm to RT and stirred for 16 h. The reaction mixture was filtered through a pad of diatomaceous earth and the filter cake was washed with THF (2 x 35 mL). The filtrates were combined and diluted with water (150 mL). Lithium hydroxide hydrate (8.13 g, 194 mmol) was added and the reaction mixture was stirred at RT for 16 h. The aqueous phase was collected and the organic phase was extracted with 0.5 N NaOH (aq) (3 x 50 mL). The combined aqueous phases were washed with Et20 (20 mL) and hexanes (2 x 100 mL), saturated with solid NaCl, and the pH of the solution was adjusted to ~ 2 by the careful addition of cone. HC1 (aq). The acidic solution was extracted with EtOAc (4 x 100 mL) and the combined organics were dried (Na2S04) and concentrated in vacuo to afford 3-methoxy-2,2- dimethylpropanoic acid (5.8 g, 91 %) as a red oil. 1H NMR (400 MHz, DMSO-i¾: δ 12.02 (s, 1 H), 3.29 (s, 2 H), 3.23 (s, 3 H), 1.06 (s, 6 H).
[0392] 3-Methoxy-2,2-dimethylpropanoic acid (3.00 g, 22.7 mmol) was dissolved in DCM (21 mL) at RT. Oxalyl chloride (2.4 mL, 27.2 mmol) and DMF (0.2 mL, 2.6 mmol) were added and the reaction mixture was stirred at RT for 2 h. In a separate flask, semicarbozide hydrochloride (3.0 g, 27.2 mmol) and NaOH (3.0 g, 75.0 mmol) were dissolved in a solution of dioxane (4.2 mL) and water (21.0 mL). The solution of acid chloride was added in one portion to the latter solution and the reaction mixture was stirred at RT for 12 h. 2 M NaOH (aq) (45.4 mL, 91 mmol) was added and the reaction mixture was stirred at 100 °C for 4 h and allowed to cool to RT. The pH of the solution was adjusted to ~ 3 by the careful addition of cone. HC1 (aq) and subsequently extracted with EtOAc (2 x 50 mL). The combined organics were dried (Na2S04) and concentrated in vacuo to afford 3-(l -methoxy-2-methylpropan-2-yl)-lH-l ,2,4-triazol-5(4H)- one (0.8 g, 20.6 %) as a white solid. !H NMR (400 MHz, DMSO-i¾: δ 1 1.19 (s, 1 H), 1 1.08 (s, 1 H), 3.29 (s, 2 H), 3.20 (s, 3 H), 1.12 (s, 6 H).
Figure imgf000098_0001
Example Dl: A -78°C solution of 2-methylthiazole (2 g, 20.17 mmol) in THF (50 mL) was treated drop-wise with n-butyllithium (2.5 M in Hex, 10.49 mL, 26.2 mmol), stirred for 1 h, treated drop- wise with a solution of tributyltin chloride (7.11 mL, 26.2 mmol) in THF (25 mL) and stirred for an additional 1 h at -78°C. The mixture was allowed to warm to RT, stirred for 1 h, treated slowly with ice-cold satd. NaHC03 (20 mL) and quickly extracted with Et20 (3X). The combined organics were washed with brine, dried over Na2SC>4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 2-methyl-5- (tributylstannyl)thiazole (6.67 g, 85%). 'H NMR (400 MHz, DMSO-i¾: δ 7.55 (s, 1 H), 2.67 (s, 3 H), 1.54-1.45 (m, 6 H), 1.30-1.23 (m, 6 H), 1.09-1.04 (m, 6 H), 0.83 (t, J = 7.3 Hz, 9 H).
Figure imgf000099_0001
Example D2: A solution of 4-iodopyrazole (20g, 0.10 mol) in anhydrous DMF (300 mL) was treated with Cs2C03 (32.5g, 0.10 mol) and 2-(2-bromoethoxy)tetrahydro-2H pyran. The resultant reaction mixture was stirred at 70 °C overnight. The cooled mixture was diluted with EtOAc (500 mL) and water (500 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with water, dried over Na2SC>4, and concentrated to afford yellow oil. Purification on a silica gel provided 4- iodo-l-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-lH-pyrazole (22g, 66.2 % yield). 1H-NMR (300 MHz, CDC13): δ 7.55 (s, 1H), 7.50 (s, 1H), 4.53 (s, 1 H), 4.33 (m, 2 H), 4.03 (m, 1 H), 3.74 (m, 1 H), 3.61 (m, 1 H), 3.46 (m, 1 H), 1.60-1.48 (m, 6 H).
[0393] A solution of iPrMgCl (2M in THF, 68.3mL, 136.6 mmol) was added drop wise to a solution of 4-iodo-l-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-lH-pyrazole(22 g, 68.3 mmol) in anhydrous THF (200 mL) 0 °C. The reaction was stirred for 1 hour at 0 °C under nitrogen. 2- Methoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (16.1 g, 0.101 mol) was added and the resulting yellow solution was allowed to stir for 1 hour at ambient temperature under nitrogen. The reaction was quenched with sat. aqueous solution of NH4CI and was diluted with EtOAc. The organic layer was washed with brine, and dried over Na2SC>4, concentrated under reduced pressure, and purified by silica gel chromatography to give l-(2-((tetrahydro-2H-pyran-2- yl)oxy)ethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole as a oil. !H-NMR
(400 MHz, CDCI3): δ 7.75 (m, 2 H), 4.48 (s, 1 H), 4.30 (m, 2 H), 4.10 (m, 1 H), 3.78-3.71 (m, 1 H), 3.63-3.59 (m, 1 H), 3.42-3.38 (m, 1 H), 1.60-1.46 (m, 6 H), 1.29 (s, 12 H).
Figure imgf000100_0001
Example 1: Example A4 (0.05 g, 0.17 mmol) and Example Bl (0.43 g, 1.7 mmol) were suspended in toluene (0.35 mL). The mixture was stirred at 45 °C for 30 min and allowed to cool to RT. TEA (0.05 mL, 0.4 mmol) was added and the mixture was stirred at 100 °C for 12 h. The reaction was concentrated in vacuo and the residue was purified by silica gel chromatography (MeOH/DCM). The product was dissolved in MeCN and water, frozen to -78 °C, and lyophilized to afford 3-(4-fluorobenzyl)-l-(6-methyl-5-((2-(l -methyl- 1 H-pyrazol-4-yl)pyri din-4- yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one (0.02 g, 26 %) as a light yellow solid. 1H NMR (400 MHz, DMSO-ί/ί): δ 12.02 (s, 1 H), 8.39 (d, J= 5.9 Hz, 1 H), 8.31-8.28 (m, 1 H), 8.01-7.98 (m, 1 H), 7.89 (d, J= 8.8 Hz, 1 H), 7.70 (d, J= 8.8 Hz, 1 H), 7.36-7.35 (m, 2 H), 7.23-7.22 (m, 4 H), 3.89 (s, 2 H), 3.84 (s, 3 H), 2.32 (s, 3 H); MS (ESI) m/z: 458.1 (M+H+).
Figure imgf000101_0001
Example 2: Example A4 (0.05 g, 0.17 mmol) and Example B2 (0.40 g, 1.7 mmol) were suspended in toluene (0.35 mL). The mixture was stirred at 45 °C for 30 min and allowed to cool to RT. TEA (0.05 mL, 0.4 mmol) was added and the mixture was stirred at 100 °C for 12 h. The reaction was concentrated in vacuo and the residue was purified by silica gel chromatography (MeOH/DCM). The product was dissolved in MeCN and water, frozen to -78 °C, and lyophilized to afford 3-benzyl-l-(6-methyl-5-((2-(l-methyl-lH-pyrazol-4-yl)pyridin-4- yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one (0.025 g, 33.7 %) as a light orange solid. H NMR (400 MHz, DMSO-i¾: δ 12.02 (s, 1 H), 8.35 (d, J= 5.7 Hz, 1 H), 8.25 (s, 1 H), 7.95 (s, 1 H), 7.88 (d, J= 8.8 Hz, 1 H), 7.68 (d, J= 8.8 Hz, 1 H), 7.33-7.32 (m, 5 H), 7.18 (d, J= 2.4 Hz, 1 H), 6.64 (dd, J= 5.7, 2.4 Hz, 1 H), 3.89 (s, 2 H), 3.83 (s, 3 H), 2.32 (s, 3 H); MS (ESI) m/z: 440.2 (M+H+).
Figure imgf000101_0002
Example 3: Example A6 (0.2 g, 0.71 mmol) and Example Bl (1.8 g, 7.1 mmol) were suspended in toluene (1.4 mL). The mixture was stirred at 45 °C for 30 min and allowed to cool to RT. TEA (0.22 mL, 1.6 mmol) was added and the mixture was stirred at 100 °C for 12 h. The reaction was concentrated in vacuo and the residue was purified by silica gel chromatography (MeOH/DCM). The product was dissolved in MeCN and water, frozen to -78 °C, and lyophilized to afford 3-(4-fluorobenzyl)-l-(5-((2-(l-methyl-lH-pyrazol-4-yl)pyridin-4- yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one (0.212 g, 66 %) as an off white solid. !H NMR (400 MHz, DMSO-ί/ί): δ 12.03 (s, 1 H), 8.37-8.36 (m, 2 H), 8.25 (s, 1 H), 8.01 (d, J= 9.0 Hz, 1 H), 7.95 (s, 1 H), 7.79 (dd, J= 9.0, 2.9 Hz, 1 H), 7.36 (dd, J= 8.5, 5.6 Hz, 2 H), 7.25 (d, J= 2.4 Hz, 1 H), 7.17 (t, J= 8.9 Hz, 2 H), 6.74 (dd, J= 5.7, 2.4 Hz, 1 H), 3.83 (s, 3 H); MS (ESI) m/z: 444.2 (M+H+).
Figure imgf000102_0001
Example 4: Example A6 (0.2 g, 0.71 mmol) and Example B4 (1.4 g, 7.1 mmol) were suspended in toluene (1.4 mL). The mixture was stirred at 45 °C for 30 min and allowed to cool to RT. TEA (0.22 mL, 1.6 mmol) was added and the mixture was stirred at 100 °C for 12 h. The reaction was concentrated in vacuo and the residue was purified by silica gel chromatography
(MeOH/DCM). The product was dissolved in MeCN and water, frozen to -78 °C, and lyophilized to afford 3-(/er/-butyl)- 1 -(5-((2-( 1 -methyl- 1 H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin- 2-yl)-lH-l ,2,4-triazol-5(4H)-one (0.026 g, 8.7 %) as an off white solid. 'H NMR (400 MHz, DMSO-ί/ί): δ 11.99 (s, 1 H), 8.39-8.38 (m, 2 H), 8.25 (s, 1 H), 8.04 (d, J= 9.0 Hz, 1 H), 7.96 (s, 1 H), 7.79 (dd, J= 9.0, 2.9 Hz, 1 H), 7.24 (d, J= 2.4 Hz, 1 H), 6.74 (dd, J= 5.7, 2.4 Hz, 1 H), 3.83 (s, 3 H), 1.26 (s, 9 H); MS (ESI) m/z: 392.2 (M+H+).
Figure imgf000103_0001
Example 5: Example A4 (0.08 g, 0.27 mmol) and Example B5 (0.51 g, 2.7 mmol) were suspended in toluene (0.54 mL). The mixture was stirred at 45 °C for 30 min and allowed to cool to RT. TEA (0.08 mL, 0.6 mmol) was added and the mixture was stirred at 100 °C for 12 h. The reaction was concentrated in vacuo and the residue was purified by silica gel chromatography (MeOH/DCM). The product was dissolved in MeCN and water, frozen to -78 °C, and lyophilized to afford 3-isopropyl-l-(6-methyl-5-((2-(l-methyl-lH-pyrazol-4-yl)pyridin-4- yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one (0.012 g, 10.3 %) as a light orange solid. !H NMR (400 MHz, DMSO-i¾: δ 1 1.92 (s, 1 H), 8.37 (d, J = 5.7 Hz, 1 H), 8.26 (s, 1 H), 7.96 (s, 1 H), 7.87 (d, J= 8.8 Hz, 1 H), 7.69 (d, J= 8.8 Hz, 1 H), 7.19 (d, J= 2.4 Hz, 1 H), 6.64 (dd, J = 5.7, 2.4 Hz, 1 H), 3.84 (s, 3 H), 2.84 (t, J= 6.9 Hz, 1 H), 2.33 (s, 3 H), 1.23 (d, J = 7.0 Hz, 6 H); MS (ESI) m/z: 392.2 (M+H+).
Figure imgf000104_0001
Example 6: Example A4 (0.08 g, 0.27 mmol) and Example B6 (0.61 g, 2.7 mmol) were suspended in toluene (0.54 mL). The mixture was stirred at 45 °C for 30 min and allowed to cool to RT. TEA (0.08 mL, 0.6 mmol) was added and the mixture was stirred at 100 °C for 12 h. The reaction was concentrated in vacuo and the residue was purified by silica gel chromatography (MeOH/DCM). The product was dissolved in MeCN and water, frozen to -78 °C, and lyophilized to afford 3-cyclohexyl-l-(6-methyl-5-((2-(l-methyl-lH-pyrazol-4-yl)pyridin-4- yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one (0.016 g, 12.4 %) as a light orange solid. !H NMR (400 MHz, DMSO-i¾: δ 1 1.88 (s, 1 H), 8.36 (d, J= 5.7 Hz, 1 H), 8.26 (s, 1 H), 7.96 (s, 1 H), 7.87 (d, J= 8.7 Hz, 1 H), 7.68 (d, J= 8.8 Hz, 1 H), 7.19 (d, J= 2.4 Hz, 1 H), 6.64 (dd, J = 5.7, 2.5 Hz, 1 H), 3.84 (s, 3 H), 2.65 (m, 1 H), 2.32 (s, 3 H), 1.93-1.19 (m, 10 H); MS (ESI) m/z: 432.2 (M+H+).
Figure imgf000104_0002
Example 7: Method 1 : Example A4 (0.2 g, 0.68 mmol) and Example B3 (0.22 g, 1.4 mmol) were suspended in DCE (1 mL) and stirred at RT for 30 min. The mixture was diluted with DCM
(4 mL) and cooled to 0 °C. TEA (0.3 mL, 2.2 mmol) was added dropwise and the mixture was treated with a solution of bis(trichloromethyl) carbonate (0.1 g, 0.34 mmol) in DCM (1 mL), allowed to warm to RT, and stirred for 1 h. Sat. NaHC03 (aq) (5 mL) was added and the resultant suspension was extracted with DCM (4 x 5 mL). The combined organics were dried ( a2S04), concentrated in vacuo, and the residue was purified by silica gel chromatography (MeOH/DCM). The isolated product was dissolved in MeCN and water, frozen to -78 °C, and lyophilized to afford 3-(ieri-butyl)-l-(6-methyl-5-((2-(l-methyl-lH-pyrazol-4-yl)pyridin-4- yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one (0.063 g, 22.3 %). !H NMR (400 MHz, acetone- δ 8.40 (d, J= 5.7 Hz, 1 H), 8.13 (s, 1 H), 7.98-7.97 (m, 1 H), 7.94 (s, 1 H), 7.63 (d, J= 8.7 Hz, 1 H), 7.16 (d, J= 2.4 Hz, 1 H), 6.68 (dd, J= 5.7, 2.4 Hz, 1 H), 3.90 (s, 3 H), 2.39 (s, 3 H), 1.40 (s, 9 H); MS (ESI) m/z: 406.2 (M+H+).
[0394] Method 2: A suspension of Example A3 (3.00 g, 8.34 mmol), l-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (3.00 g, 14.42 mmol), K2C03 (3.000 g, 21.71 mmol) in dioxane/water (10: 1) (60 mL) was degassed for 5 minutes with argon purge. The reaction mixture was treated with Pd(PPh3)4 (0.300 g, 0.260 mmol) heated at 100 °C under argon over night. The residue was partitioned between dichloromethane (150mL) and water (150mL). Organic layer separated and the aqueous layer extracted with dichloromethane (2 x 70 mL). The combined organics were dried, concentrated in vacuo and purified by silica gel chromatography (0-100% THF/DCM). Pure fractions were combined and the solvent was evaporated. The residue was dissolved in THF, stirred with thiol-modified silica gel (1.4 mmol thiol g, 3 g, 4.2 mmol) over night (to scavenge Pd). The reaction mixture was filtered and the filtrate completely evaporated. The residue was crystallized from acetonitrile to provide 3-(tert- butyl)-l-(6-methyl-5-((2-(l -methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH- 1 ,2,4- triazol-5(4H)-one (2.40 g, 70%) as white solid. !H NMR (400 MHz, DMSO-i¾ : δ 11.96 (s, 1 H), 8.37 (d, J = 5.7 Hz, 1 H), 8.26 (s, 1 H), 7.96 (s, 1 H), 7.85 (d, J = 8.8 Hz, 1 H), 7.68 (d, J = Hz, 1 H), 7.18 (d, J = 2.4 Hz, 1 H), 6.64 (dd, J = 5.7, 2.4 Hz, 1 H), 3.84 (s, 3 H), 2.33 (s, 3 1.27 (s, 9 H); MS(ESI) m/z: 406.2 (M+H+).
Figure imgf000106_0001
Example 8: 2-Amino-6-ethylpyridine (3.0 g, 24.6 mmol) was dissolved in chloroform (25 mL) and cooled to 0 °C. NBS (4.4 g, 24.6 mmol) was added portion-wise over 30 min and the mixture was stirred for 30 min at 0 °C. The solvent was removed in vacuo and the residue was slurried with EtOAc (8 mL). The resultant solids were removed by filtration through a pad of diatomaceous earth and filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc/hexanes) to afford 5-bromo-6-ethylpyridin-2-amine (3.83 g, 78%) as a white solid. !H NMR (400 MHz, DMSO-i¾: δ 7.42 (d, J= 8.6 Hz, 1 H), 6.20 (d, J= 8.7 Hz, 1 H), 6.03 (s, 2 H), 2.60 (q, J= 7.5 Hz, 2 H), 1.10 (t, J= 7.5 Hz, 3 H); MS (ESI) m/z: 201.0/203.0 (M+H+).
[0395] A solution of concentrated H2SO4 (25 mL) was cooled to 0 °C. Temperature was carefully maintained as 30 % H202 (5.5 mL) was added over 30 min and 5-bromo-6- ethylpyridin-2-amine (3.77 g, 18.8 mmol) dissolved in concentrated H2SO4 (25 mL) was added dropwise. The mixture was allowed to slowly warm to RT, and stirred for an additional 4 h. at RT. The mixture was poured onto ice (-110 g), and the resultant emulsion was stirred as it was allowed to warm to RT. The emulsion was extracted with EtOAc (4 x 150 mL) and the combined organics were dried (Na2S04) and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc/hexanes) to afford 3-bromo-2-ethyl-6-nitropyridine (2.6 g, 60 %) as a yellow oil. !H NMR (400 MHz, DMSO-i¾: δ 8.44 (d, J = 8.5 Hz, 1 H), 8.05 (d, J = 8.5 Hz, 1 H), 2.97 (q, J= 7.5 Hz, 2 H), 1.24 (t, J = 7.5 Hz, 3 H); MS (ESI) m/z: 231.0/233.0 (M+H+).
[0396] 3-Bromo-2-ethyl-6-nitropyridine (2.6 g, 1 1.3 mmol) and 2-chloro-4-hydroxypyridine (2.9 g, 22.5 mmol) were dissolved in DMA (20 mL). The solution was sonicated and sparged with Ar for 10 min. K2C03 (4.7 g, 33.8 mmol) was added and the reaction mixture was stirred at 1 10 °C for 12 h. EtOAc (80 mL) was added and the suspension was washed with 10 % K2C03 (aq) (2 x 50 mL), 5 % LiCl (aq) (2 x 50 mL), and brine (2 x 50 mL). The solution was dried (Na2SC>4), concentrated in vacuo, and the resultant residue was purified by silica gel chromatography (EtOAc/hexanes) to afford 3-((2-chloropyridin-4-yl)oxy)-2-ethyl-6- nitropyridine (1.3 g, 37.2 %) as a yellow oil. !H NMR (400 MHz, DMSO-i¾: δ 8.38 (d, J = 5.7 Hz, 1 H), 8.25 (d, J = 8.7 Hz, 1 H), 7.96 (d, J = 8.7 Hz, 1 H), 7.82 (d, J = 8.6 Hz, 1 H), 7.16 (dd, J = 5.7, 2.3 Hz, 1 H), 2.79 (q, J = 7.5 Hz, 2 H), 1.21 (t, J = 7.5 Hz, 3 H); MS (ESI) m/z: 280.0 (M+H+).
[0397] 3-((2-chloropyridin-4-yl)oxy)-2-ethyl-6-nitropyridine (1.0 g, 3.6 mmol) and 1 - methyl-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole (1.0 g, 4.6 mmol) were dissolved in dioxane (10 mL). A solution of K2C03 (1.5 g, 10.6 mmol) in water (2 mL) was added and the mixture was sonicated and sparged with Ar for 10 min. Pd(PPh3)4 (0.21 g, 0.18 mmol) was added and the reaction mixture was stirred at 80 °C for 24 h. EtOAc (60 mL) was added and the mixture was washed with sat. NaHC03 (aq) (60 mL) and brine (60 mL), dried ( a2S04), and concentrated in vacuo to afford 2-ethyl-3-((2-(l -methyl- lH-pyrazol-4-yl)pyridin- 4-yl)oxy)-6-nitropyridine (1.2 g, 100 %) as a brown viscous oil that was carried forward without further purification. MS (ESI) m/z: 326.1 (M+H+).
[0398] 2-Ethyl-3-((2-(l -methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)-6-nitropyridine (1.1 g, 3.2 mmol) and NH4C1 (6.8 g, 128 mmol) were suspended in MeOH (12 mL) and THF (12 mL) at 0 °C. The temperature was carefully maintained while Zn (2.1 g, 31.9 mmol) was added portion- wise over 20 min. The mixture was stirred vigorously for 12 h. EtOAc (75 mL) was added and solids were removed by filtration through a pad of diatomaceous earth. The filter cake was washed with EtOAc (2 x 15 mL) and the combined filtrates were concentrated in vacuo. The residue was slurried with EtOAc (6 mL) and warmed to 77 °C for 5 min. Solids were collected by filtration, slurried with EtOAc (10 mL), and warmed to 77 °C for 5 min. The slurry was immediately filtered to collect solid product. The filtrates were combined and purified by silica gel chromatography (MeOH/EtOAc). Product material was combined and residual solvent was removed in vacuo to afford 6-ethyl-5-((2-(l -methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2- amine (0.48 g, 51 %) as an off white solid. 1H NMR (400 MHz, DMSO-i¾: δ 8.30 (d, J = 5.7 Hz, 1 H), 8.22 (s, 1 H), 7.93 (s, 1 H), 7.17 (d, J = 8.7 Hz, 1 H), 7.1 1 (d, J = 2.4 Hz, 1 H), 6.50 (dd, J = 5.7, 2.4 Hz, 1 H), 6.35 (d, J = 8.7 Hz, 1 H), 5.94 (s, 2 H), 3.84 (s, 3 H), 2.39 (q, J = 7.5 Hz, 2 H), 1.04 (t, J = 7.5 Hz, 3 H); MS (ESI) m/z: 296.2 (M+H+).
[0399] 6-Ethyl-5-((2-(l -methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine (0.15 g, 0.51 mmol) was added to a solution of HF -pyridine (0.76 mL, 8.4 mmol) and pyridine (0.76 mL) at 0 °C and the mixture was stirred for 10 min. Sodium nitrite (0.063 g, 0.91 mmol) was added and the reaction mixture was allowed to warm to RT and stirred for 12 h. The mixture was cooled to 0 °C and poured into cold sat. NaHC03 (aq) (5 mL), stirred for 30 min, and extracted with EtOAc (4 x 10 mL). The combined organics were dried (Na2SC>4) and concentrated in vacuo to afford 2-ethyl-6-fluoro-3-((2-(l -methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridine (0.15 g, 99 %) as a yellow solid that was used in the next step without further purification. MS (ESI) m/z: 299.1 (M+H+).
[0400] 2-Ethyl-6-fluoro-3-((2-(l -methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridine (0.15 g, 0.51 mmol) was suspended in 2-propanol (1.0 mL) in a screw-cap reaction vessel. Hydrazine hydrate (0.12 mL, 2.5 mmol) was added, the reaction vessel was sealed and the mixture was stirred at 90 °C for 18 h. Sat. NaHC03 (aq) (20 mL) was added and the mixture was extracted wth EtOAc (4 x 35 mL). The combined organics were dried (Na2SC>4) and concentrated in vacuo to afford 2-ethyl-6-hydrazinyl-3-((2-(l -methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyri dine (0.15 g, 96 %) as a light yellow solid that was used in the next step without further purification. MS (ESI) m/z: 31 1.2 (M+H+).
[0401] 2-Ethyl-6-hydrazinyl-3-((2-( 1 -methyl- 1 H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridine (0.15 g, 0.483 mmol) Example B4 (0.81 g, 4.0 mmol) were suspended in toluene (1 mL), stirred at 45 °C for 30 min, and allowed to cooled to RT. TEA (0.08 mL, 0.57 mmol) was added and the reaction mixture was stirred at 105 °C overnight, cooled to 0 °C, and diluted with DCM (4 mL). A solution of bis(trichloromethyl) carbonate (0.2 g, 0.7 mmol) in DCM (2 mL) was added and the mixture was stirred for 1.5 h. Sat. NaHC03 (aq) (5 mL) was added the mixture was extracted with DCM (4 x 5 mL). The combined organics were dried (Na2SC>4) and concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM) and again by reverse- phase silica gel chromatography (MeCN/water (0.1 % TFA) to afford 3-(tert-butyl)-l-(6-ethyl-5- ((2-(l-me l-lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-l,2,4-triazol-5(4H)-one (0.022 g, 9.2 %) as a white solid. 1H NMR (400 MHz, Acetone-i¾: δ 8.40 (d, J= 5.7 Hz, 1 H), 8.13 (s, 1 H), 7.94 (t, J = 4.4 Hz, 2 H), 7.63 (d, J = 8.7 Hz, 1 H), 7.18 (d, J = 2.4 Hz, 1 H), 6.69 (dd, J = 5.7, 2.4 Hz, 1 H), 3.90 (s, 3 H), 2.74 (d, J = 7.5 Hz, 2 H), 1.40 (s, 9 H), 1.24 (t, J = 7.5 Hz, 3 H); MS (ESI) m/z: 420.2 (M+H+).
Figure imgf000110_0001
Example 9: K2CO3 (0.1 g, 0.72 mmol) was dissolved in water (0.2 mL) and the solution was diluted with dioxane (1.2 mL). Example A3 (0.10 g, 0.28 mmol) and 2-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (0.08 g, 0.37 mmol) were added and the mixture was sonicated and sparged with Ar for 10 min. Pd(PPh3)4 (0.04 g, 0.04 mmol) was added and the reaction mixture was stirred at 85 °C for 16 h. EtOAc (5 mL) was added and solids were removed by filtration through a pad of diatomaceous earth. The filter cake was washed with EtOAc (3 x 5 mL) and the combined filtrates were concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM). The purified product was dissolved in MeCN and water, frozen to -78 °C, and lyophilized to afford 3-(/er/-butyl)-l-(6-methyl-5-((2'- methyl-[2,4'-bipyridin]-4-yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one (0.038 g, 29.8 %) as a yellow solid. 1H NMR (400 MHz, DMSO-i¾: δ 11.99 (s, 1 H), 8.61 (s, 1 H), 8.53 (s, 1 H), 7.91 (s, 1 H), 7.89 (s, 1 H), 7.81 (d, J= 2.7 Hz, 1 H), 7.75 (s, 1 H), 7.69 (s, 1 H), 6.93 (d, J= 2.9 Hz, 1 H), 2.53 (s, 3 H), 2.35 (s, 3 H), 1.28 (s, 9 H); MS (ESI) m/z: All 2 (M+H+).
Figure imgf000111_0001
Example 10: K2CO3 (0.1 g, 0.72 mmol) was dissolved in water (0.2 mL) and the solution was diluted with dioxane (1.2 mL). Example A3 (0.10 g, 0.28 mmol) and 2-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (0.08 g, 0.37 mmol) were added and the mixture was sonicated and sparged with Ar for 10 min. Pd(PPh3)4 (0.04 g, 0.04 mmol) was added and the reaction mixture was stirred at 85 °C for 16 h. EtOAc (5 mL) was added and solids were removed by filtration through a pad of diatomaceous earth. The filter cake was washed with EtOAc (3 x 5 mL) and the combined filtrates were concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM). The isolated product was dissolved in MeCN and water, frozen to -78 °C, and lyophilized to afford 3-(/er/-butyl)-l-(6-methyl-5-((6'- methyl-[2,3'-bipyridin]-4-yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one (0.064 g, 55.0 %) as a yellow solid. !H NMR (400 MHz, DMSO-i¾: δ 11.99 (s, 1 H), 9.1 1 (s, 1 H), 8.57 (s, 1 H), 8.29 (d, J= 4.2 Hz, 1 H), 7.88 (s, 1 H), 7.75 (s, 1 H), 7.61 (s, 1 H), 7.36 (s, 1 H), 6.84 (d, J= 2.9 Hz, 1 H), 2.51 (s, 3 H), 2.36 (s, 3 H), 1.28 (s, 9 H); MS (ESI) m/z: All 2 (M+H+).
Figure imgf000111_0002
Example 11: Example A3 (0.09 g, 0.25 mmol), acetamide (0.065 g, 1.1 mmol), Cs2C03 (0.09 g, 0.28 mmol), and X-Phos (0.012 g, 0.025 mmol) were combined and suspended in dioxane (1.5 mL) and the mixture was sonicated and sparged with Ar for 10 min. Pd2(dba)3 (0.023 g, 0.025 mmol) was added and the mixture was stirred at 80 °C for 16 h. EtOAc (10 mL) was added and solids were removed by filtration through a pad of diatomaceous earth. The filter cake was washed with EtOAc (3 x 10 mL) and the combined filtrates were concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM). The product was dissolved in MeCN and water, frozen to -78 °C, and lyophilized to afford N-(4-((6-(3-(/er/-butyl)-5-oxo-4,5- dihydro-lH-l,2,4-triazol-l-yl)-2-methylpyridin-3-yl)oxy)pyridin-2-yl)acetamide (0.056 g, 58.5 %) as a white solid. 1H NMR (400 MHz, DMSO-i¾: δ 11.98 (s, 1 H), 10.57 (s, 1 H), 8.19 (br s, 1 H), 7.86 (s, 1 H), 7.70 (s, 1 H), 7.59 (s, 1 H), 6.66-6.66 (m, 1 H), 2.30 (s, 3 H), 2.03 (s, 3 H), 1.27 (s, 9 H); MS (ESI) m/z: 383.2 (M+H+).
Figure imgf000112_0001
Example 12: Example A3 (0.20 g, 0.56 mmol) and Example Dl (0.28 g, 0.72 mmol) were suspended in toluene (3 mL). The mixture was sonicated and sparged with Ar for 10 minutes. Pd(PPh3)4 (0.03 g, 0.03 mmol) was added and the reaction mixture was stirred at 105 °C for 12 h. Additional Pd(PPh3)4 (0.02 g, 0.02 mmol) was added and stirring was continued at 105 °C for 18 h. The mixture was partitioned between 10 % KF (aq) (10 mL) and EtOAc (10 mL) and the biphasic mixture was stirred vigorously at RT for 2 h. The solids were removed by filtration through a plug of diatomaceous earth. The filter cake was washed with EtOAc (3 x 10 mL) and the combined filtrates were extracted with EtOAc (4 x 20 mL). The combined organics were dried (MgSC^) and concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM) to afford 3-(ieri-butyl)-l -(6-methyl-5-((2-(2-methylthiazol-5-yl)pyridin-4- yl)oxy)pyridin-2-yl)- lH-l ,2,4-triazol-5(4H)-one (0.16 g, 67.8 %) as a white solid. ' l NMR (400 MHz, DMSO-ί ί): δ 1 1.97 (s, 1 H), 8.40 (d, J = 5.8 Hz, 1 H), 8.33 (s, 1 H), 7.86 (d, J = 8.8 Hz, 1 H), 7.71 (d, J= 8.8 Hz, 1 H), 7.58 (d, J = 2.4 Hz, 1 H), 6.76 (dd, J = 5.8, 2.4 Hz, 1 H), 2.65 (s, 3 H), 2.34 (s, 3 H), 1.27 (s, 9 H); MS (ESI) m/z: 423.2 (M+H+).
Figure imgf000113_0001
Example 13: A suspension of Example 7 (0.050 g, 0.12 mmol) in acetone (2.5 mL) was treated with CS2CO3 (0.080 g, 0.25 mmol) and iodomethane (0.02 mL, 0.32 mmol) and the mixture was stirred at RT for 12 h. The solvent was removed in vacuo and the residue was dissolved in DCM (3 mL) and washed with water (3 mL). The aqueous phase was extracted with DCM (4 x 5 mL) and the combined organics were dried (MgSC^) and concentrated in in vacuo. The residue was triturated with Et20 (2 mL) and sonicated for 5 min, which lead to the precipitation of an off white solid. Solid was isolated by filtration and washed with Et20 (3 x 1 mL). The solid was dried under high vacuum for 3 h, and was then dissolved in MeCN and water, frozen to -78 °C, and lyophilized to afford 3-(ieri-butyl)-4-methyl- l-(6-methyl-5-((2-(l -methyl-lH-pyrazol-4- yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH- l ,2,4-triazol-5(4H)-one (0.024 g, 46.4 %) as an off white solid. 1H NMR (400 MHz, DMSO-i¾: δ 8.37 (d, J = 5.7 Hz, 1 H), 8.26 (s, 1 H), 7.96 (s, 1 H), 7.85 (d, J = 8.7 Hz, 1 H), 7.72 (d, J = 8.7 Hz, 1 H), 7.20 (d, J= 2.4 Hz, 1 H), 6.65 (dd, J= 5.7, 2.4 Hz, 1 H), 3.84 (s, 3 H), 3.39 (s, 3 H), 2.34 (s, 3 H), 1.37 (s, 9 H); MS (ESI) m/z: 420.2
Figure imgf000114_0001
Example 14: In a sealed tube, PdCl2(dppf)-CH2Ci2 (0.025 g, 0.030 mmol), potassium acetate (0.089 g, 0.908 mmol), bis(pinacolato)diboron (0.1 15 g, 0.454 mmol) and 4-(4-bromo-phenyl)-l- methyl-piperidine (0.1 g, 0.393 mmol) were suspended in dioxane (6 mL). The mixture was degassed with Ar and heated at 100 °C for 20 h. The reaction was cooled to RT and Example A3 (0.109 g, 0.303 mmol), Pd(PPh3)4 (0.035 g, 0.030 mmol), K2C03 (0.125 g, 0.908 mmol) and water (1.500 mL) were added. The reaction was degassed with Ar and heated at 100 °C for 3 h. The mixture was partitioned between EtOAc and IN NaOH and extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried and evaporated. The crude product was purified by reverse phase chromatography (C-18) eluting with water/acetonitrile (0.1% TFA). Fractions containing the desired product were combined and concentrated until mostly water remained. The mixture was made basic with IN NaOH and extracted with DCM (3x). The combined organic extracts were dried and evaporated to yield the product, which was suspended in acetonitrile (~5 mL) and sonicated for 30 min. The resulting solid was collected by filtration and dried under high vacuum to yield 3-(tert-butyl)-l-(6-methyl-5-((2-(4-(l-methylpiperidin-4- yl)phenyl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-l,2,4-triazol-5(4H)-one (30 mg, 19.9%). Ή NMR (400 MHz, DMSO-de): δ 1 1.95 (br s, 1 H), 8.52 (d, J = 5.6 Hz, 1 H), 7.94 (d, J = 8.2 Hz, 2 H), 7.86 (d, J = 8.8 Hz, 1 H), 7.72 (d, J = 8.8 Hz, 1 H), 7.42 (d, J = 2.4 Hz, 1 H), 7.32 (d, J = 8.2 Hz, 2 H), 6.80 (dd, J = 5.6, 2.4 Hz, 1 H), 2.85 (d, J = 10.9 Hz, 2 H), 2.53-2.43 (m, 1 H), 2.34 (s, 3 H), 2.18 (s, 3 H), 1.95 (t, J = 1 1.3 Hz, 2 H), 1.76-1.60 (m, 4 H), 1.27 (s, 9 H); MS (ESI) m/z: 499.3 (M+H+).
Figure imgf000115_0001
Example 15: Example A4 (0.20 g, 0.68 mmol) and Example B7 (0.27 g, 1.35 mmol) were suspended in DCM (1.4 mL). The mixture was cooled to 0 °C and stirred for 30 min. TEA (0.60 mL, 4.30 mmol) was added dropwise and the reaction mixture was warmed to 40 °C and stirred for 12 h. Sat. NH4CI (aq) (3 mL) was added and the mixture was extracted with EtOAc (4 x 5 mL). The combined organics were dried (Na2SC>4) and concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM) to afford 3-(2-metho xy ethyl)- 1 -(6-methyl- 5-((2-(l -methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one (0.18 g, 63.8 %) as white solid. !H NMR (400 MHz, DMSO-i¾: δ 11.90 (s, 1 H), 8.37 (d, J= 5.7 Hz, 1 H), 8.26 (s, 1 H), 7.96 (d, J= 0.7 Hz, 1 H), 7.88 (d, J= 8.8 Hz, 1 H), 7.69 (d, J= 8.8 Hz, 1 H), 7.19 (d, J= 2.4 Hz, 1 H), 6.65 (dd, J= 5.7, 2.4 Hz, 1 H), 3.84 (s, 3 H), 3.63 (t, J= 6.4 Hz, 2 H), 3.26 (s, 3 H), 2.76 (t, J= 6.4 Hz, 2 H), 2.33 (s, 3 H). MS (ESI) m/z: 408.2 (M+H+).
Figure imgf000116_0001
Example 16: Example C2 (0.075 g, 0.48 mmol), copper© iodide (0.01 g, 0.05 mmol), and K2CO3 (0.20 g, 1.45 mmol) were suspended in DMF (1 mL). The mixture was sonicated and sparged with Ar for 10 min. Example Al (0.34 g, 0.98 mmol) and N,N-dimethylethane-l ,2- diamine (10 mg, 0.11 mmol) were sequentially added and the mixture was stirred under an atmosphere of Ar at 100 °C for 12 h. Water (10 mL) was added and the mixture was extracted with EtOAc (5 x 10 mL). The combined organics were dried (Na2S04) and concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM) to afford 3-(2- methoxypropan-2-yl)- 1 -(6-methyl-5-((2-( 1 -methyl- 1 H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2- yl)-lH-l,2,4-triazol-5(4H)-one (0.1 g, 55.8 %) as a brown oil. 1H NMR (400 MHz, DMSO-i¾: δ 9.63 (s, 1 H), 8.30 (d, J= 5.7 Hz, 1 H), 8.03 (d, J= 8.8 Hz, 1 H), 7.71 (d, J= 8.8 Hz, 1 H), 7.00 (d, J= 2.2 Hz, 1 H), 6.96 (dd, J= 5.7, 2.3 Hz, 1 H), 3.18 (s, 3 H), 2.38 (s, 3 H), 1.56 (s, 6 H); MS (ESI) m/z: 376.2 (M+H+).
[0402] 3-(2-Methoxypropan-2-yl)-l-(6-methyl-5-((2-(l-methyl-lH-pyrazol-4-yl)pyridin-4- yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one (0.10 g, 0.27 mmol) and l-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole were dissolved in dioxane (2.2 mL). A solution of K2CO3 (0.10 g, 0.7 mmol) in water (0.44 mL) was added and the mixture was sonicated and sparged with Ar for 10 min. Pd(PPh3)4 (0.03 g, 0.03 mmol) was added and the reaction mixture was stirred at 85 °C for 12 h. Sat. NaHC03 (aq) (10 mL) was added and the mixture was extracted with EtOAc (5 x 10 mL). The combined organics were dried ( a2S04), concentrated in vacuo, and the residue was purified by silica gel chromatography (MeOH/DCM). The product was suspended in MeCN (1 mL) and sonicated for 5 min. The slvent solvent was removed by decantation. The residual solid was dissolved in MeCN and water, frozen to -78 °C, and lyophilized to afford 3-(2-methoxypropan-2-yl)-l-(6-methyl-5-((2-(l -methyl- 1 H-pyrazol-4- yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-l,2,4-triazol-5(4H)-one (0.026 g, 22.8 %) as a white solid. !H NMR (400 MHz, DMSO-i¾: δ 12.15 (s, 1 H), 8.37 (d, J = 5.7 Hz, 1 H), 8.26 (s, 1 H), 7.96 (d, J= 0.7 Hz, 1 H), 7.89 (d, J= 8.8 Hz, 1 H), 7.70 (d, J= 8.8 Hz, 1 H), 7.19 (d, J= 2.4 Hz, 1 H), 6.66 (dd, J= 5.7, 2.4 Hz, 1 H), 3.84 (s, 3 H), 3.07 (s, 3 H), 2.34 (s, 3 H), 1.48 (s, 6 H); MS (ESI) m/z: Ml 2 (M+H+).
Figure imgf000117_0001
Example 17: Example A4 (0.20 g, 0.68 mmol) and Example B8 (0.26 g, 1.4 mmol) were suspended in DCM (1.4 mL). The mixture was cooled to 0 °C and stirred for 30 min. TEA (0.60 mL, 4.3 mmol) was added dropwise and the mixture was stirred at 40 °C for 12 h. Sat. NH4CI (aq) (15 mL) was added and the mixture was extracted with DCM (4 x 10 mL). The combined organics were dried (Na2S04) and concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM). The product was further purified by trituration with MeCN (2 mL), and was then dissolved in MeCN and water, frozen to -78 °C, and lyophilized to afford 3- (methoxymethyl)- 1 -(6-methyl-5-((2-( 1 -methyl- 1 H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)- lH-l ,2,4-triazol-5(4H)-one (0.035 g, 12 %) as a light yellow solid. !H NMR (400 MHz, DMSO- d6): δ 12.24-12.22 (m, 1 H), 8.37 (d, J= 5.7 Hz, 1 H), 8.26 (s, 1 H), 7.96 (d, J= 0.7 Hz, 1 H), 7.91 (d, J= 8.8 Hz, 1 H), 7.71 (d, J= 8.8 Hz, 1 H), 7.21 (d, J= 2.4 Hz, 1 H), 6.65 (dd, J= 5.7, 2.4 Hz, 1 H), 4.33 (s, 2 H), 3.84 (s, 3 H), 3.31 (s, 3 H), 2.33 (s, 3 H); MS (ESI) m/z: 394.2 (M+H+).
Figure imgf000118_0001
Example 18: Example A3 (0.20 g, 0.56 mmol) and Example D2 (0.14 g, 0.43 mmol) were dissolved in dioxane (1.8 mL). A solution of K2C03 (0.15 g, 1.11 mmol) in water (0.36 mL) was added and the mixture was sonicated and sparged with Ar for 10 min. Pd(PPh3)4 (0.05 g, 0.04 mmol) was added and the mixture was stirred at 85 °C for 12 h. Water (5 mL) was added and the mixture was extracted with EtOAc (4 x 15 mL). The combined organics were dried (Na2SC>4) and concentrated in vacuo to afford 3-(ieri-butyl)-l-(6-methyl-5-((2-(l-(2-((tetrahydro-2H- pyran-2-yl)oxy)ethyl)-lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)- one (0.18 g, 80 %) as a yellow oil that was used in the next step without further purification. MS (ESI) m/z: 520.3 (M+H+).
[0403] 3-(teri-Butyl)- 1 -(6-methyl-5-((2-( 1 -(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)- 1 H- pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-l,2,4-triazol-5(4H)-one (0.18 g, 0.34 mmol) was dissolved in MeCN and treated with a HC1 (4 M in dioxane) (0.25 mL, 1.0 mmol). The mixture was stirred at RT for 20 min. Sat. NaHC03 (aq) (15 mL) was added and the suspension was extracted with EtOAc (5 x 15 mL). The combined organics were dried (Na2SC>4) and concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM). The product was triturated with MeCN (5 mL) and sonicated for 5 min. The solid was isolated by filtration, redissolved in MeCN and water, frozen to -78 °C, and lyophilized to afford 3-(iert- butyl)- 1 -(5-((2-( 1 -(2-hydroxy ethyl)- 1 H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-methylpyridin-2-yl)- lH-l ,2,4-triazol-5(4H)-one (0.13 g, 82 %) as an off white solid. 'rl NMR (400 MHz, DMSO-i¾: δ 1 1.97 (s, 1 H), 8.37 (d, J = 5.7 Hz, 1 H), 8.27 (s, 1 H), 7.99 (s, 1 H), 7.85 (d, J = 8.8 Hz, 1 H), 7.68 (d, J = 8.8 Hz, 1 H), 7.21 (d, J = 2.4 Hz, 1 H), 6.64 (dd, J = 5.7, 2.4 Hz, 1 H), 4.89 (t, J = 5.3 Hz, 1 H), 4.13 (t, J = 5.6 Hz, 2 H), 3.73 (q, J = 5.5 Hz, 2 H), 2.33 (s, 3 H), 1.27 (s, 9 H); MS (ESI) m/z: 436.2 (M+H+).
Figure imgf000119_0001
Example 19: To a degassed solution of dioxane (12 mL) and toluene (3 mL) was added Pd2(dba)3 (0.020 g, 0.022 mmol) and Me4tBuXPhos (0.020 g, 0.042 mmol) and the mixture was heated in a sealed vessel (vol. 40mL) at 110 °C for 5minutes. The reaction mixture was cooled to T and Example A3 (0.250 g, 0.695 mmol), 4-methylimidazole (0.100 g, 1.218 mmol) and potassium phosphate (0.300 g, 1.413 mmol) were added. The vessel was sealed and heated at 110 °C for 14 hours. The reaction mixture was filtered and washed well with DCM and THF. The filtrate was completely evaporated and the residue was subjected to reverse phase chromatography using [10-90% MeCN- water (containing 1% TFA)] to provide colorless oily mass, which on lyophilization after dissolving in a mixture of MeCN (2 mL) and water (2 mL) provided 3-(tert-butyl)-l-(6- methyl-5-((2-(4-methyl- lH-imidazol- 1 -yl)pyridin-4-yl)oxy)pyridin-2-yl)- 1 H- 1 ,2,4- triazol-5(4H)-one (0.070 g, 25% yield) as white solid. !H NMR (400 MHz, DMSO- d6): δ 12.00 (s, 1 H), 9.58 (s, 1 H), 8.47 (d, J = 5.8 Hz, 1 H), 8.11 (s, 1 H), 7.90 (d, J = 8.8 Hz, 1 H), 7.74 (d, J = 8.8 Hz, 1 H), 7.52 (d, J = 2.2 Hz, 1 H), 7.07 (dd, J = 5.8, 2.2 Hz, 1 H), 2.34 (s, 3 H), 2.29 (s, 3 H), 1.27 (s, 9 H); MS(ESI) m/z :406.2 (M+H+).
Figure imgf000120_0001
Example 20: Example A4 (0.2 g, 0.675 mmol) was suspended in DCM (3 mL) and cooled to 0
°C. A solution of Example B10 (0.309 g, 1.350 mmol) in DCM (3.75 mL) was added and the mixture stirred for 30 min. The reaction was allowed to warm to RT and TEA (0.659 mL, 4.72 mmol) was added. The mixture was heated at 40 °C for 3 days. The reaction was cooled to RT and partitioned between DCM and saturated NaHC03 (aq) and the aqueous was extracted with
DCM (2x). The organic extracts were combined, washed with brine, dried and evaporated. The crude product was purified silica gel chromatography eluting with DCM/MeOH to give the product which was purified further by preparatory silica gel TLC eluting with DCM/MeOH. The desired product was dissolved in acetonitrile/water, frozen and lyophilized to yield l-(6-methyl-
5-((2-(l -methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)- lH-l ,2,4-triazol-5(4H)-one (9 mg, 3%). 'H NMR (400 MHz, DMSO-i¾: δ 11.98 (s, 1 H), 8.37 (d, J = 5.7 Hz, 1 H), 8.26 (s, 1 H), 7.96 (d, J = 0.7 Hz, 1 H), 7.87 (d, J = 8.8 Hz, 1 H), 7.69 (d, J = 8.8 Hz, 1 H), 7.19 (d, J = 2.4 Hz, 1 H), 6.64 (dd, J = 5.7, 2.4 Hz, 1 H), 3.90-3.89 (m, 2 H), 3.84 (s, 3 H), 3.41 (td, J = 11.5, 2.2 Hz, 2 H), 2.85-2.84 (m, 1 H), 2.33 (s, 3 H); 1.84-1.82 (m, 2 H), 1.71-1.69 (m, 2 H); MS (ESI) m/z: 434.2 (M+H+).
Figure imgf000121_0001
Example 21: A round bottom flask was charged with Example A3 (0.189 g, 0.525 mmol) in dioxane (5 mL) and sparged with Ar under sonication for 20 minutes after which 1- methylpiperidine-4-carboxamide (0.149 g, 1.051 mmol), CS2CO3 (0.342 g, 1.051 mmol), and DPPF (0.029 g, 0.053 mmol) was added and the mixture sparged with Ar under sonication for 15 minutes. Pd2(dba)3 (0.024 g, 0.026 mmol) was added and the mixture was sparged with Ar under sonication for 15 minutes. The reaction was then heated to 100 °C under Ar and stirred overnight. The reaction mixture was cooled to RT, sparged with Ar under sonication and added Pd2(dba)3 (0.024 g, 0.026 mmol), DPPF (0.029 g, 0.053 mmol), sparged with Ar under sonication and then heated to 100 °C and stirred overnight. The reaction mixture was cooled to RT, sparged with Ar under sonication and added Pd2(dba)3 (0.024 g, 0.026 mmol), DPPF (0.029 g, 0.053 mmol), sparged with Ar under sonication and then heated to 100 °C and stirred overnight. The reaction mixture was cooled to RT, diluted with EtOAc and filtered through diatomaceous earth and washed with EtOAc. The filtrates were concentrated to dryness to afford a brown solid. The crude product was subject to reverse-phase silica gel chromatography (10% - 45% MeCN/water, 0.1% TFA). The appropriate fractions were collected, concentrated and stirred with EtOAc and sat'd NaHC03. The aqueous layer was back-extracted with EtOAc (3x), the organic phases combined, dried (Na2S04) and concentrated to dryness to afford a white solid. The product was suspended in MeCN/H20, frozen and lyopholized overnight to furnish N-(4- ((6-(3-(tert-butyl)-5-oxo-4,5-dihydro- 1H- 1 ,2,4-triazol- 1 -yl)-2-methylpyridin-3-yl)oxy)pyridin-2- yl)-l-methylpiperidine-4-carboxamide an off white solid. (0.0428 g, 16.5%). ' l NMR (400
MHz, OMSO-d6: δ 1 1.98 (br s, 1 H), 10.52 (s, 1 H), 8.19 (d, J = 5.7 Hz, 1 H), 7.86 (d, J = 8.8 Hz,
1 H), 7.69 (d, J = 8.8 Hz, 1 H), 7.58 (d, J = 2.4 Hz, 1 H), 6.69 (dd, J = 5.7, 2.4 Hz, 1 H), 2.81 - 2.71 (m, 2 H), 2.41 -2.33 (m, 1 H), 2.29 (s, 3 H), 2.13 (s, 3 H), 1.87-1.76 (m, 2 H), 1.71 -1.62 (m,
2 H), 1.56-1.47 (m, 2 H), 1.27 (s, 9 H); MS (ESI) m/z: 466.3 (M+H+).
Figure imgf000122_0001
Example 22: Example A4 (0.20 g, 0.68 mmol) was suspended in DCM (6 mL) and cooled to 0 °C. Example B9 (0.27 g, 1.4 mmol) was added and the reaction mixture was allowed to warm to RT, stirred for 30 min, and cooled back to 0 °C. TEA (0.56 mL, 4.1 mmol) was added dropwise and the mixture was stirred at RT for 12 h. Sat. NH4CI (aq) (15 mL) was added and the resultant suspension was extracted with DCM (4 x 10 mL). The combined organics were dried ( a2S04) and concentrated in vacuo. The resultant residue was purified by a three step sequence involving silica gel chromatography (MeOH/DCM), reverse-phase chromatography (30 g CI 8 column) [MeCN(0.1 % TFA)/water(0.1 % TFA)], and additional silica gel chromatography (EtOAc/DCM and MeOH/EtOAc) to afford a colorless solid. The isolated product was dissolved in MeCN/water, frozen to -78 °C, and lyophilized to afford 3-(methoxymethyl)-l-(6-methyl-5- ((2-(l-me l-lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one (0.030 g, 10.8 %) as a white solid. !H NMR (400 MHz, DMSO-i¾: δ 8.34 (d, J= 5.7 Hz, 1 H), 8.24 (s, 1 H), 8.18-8.17 (m, 1 H), 7.95 (d, J= 0.7 Hz, 1 H), 7.53-7.52 (m, 1 H), 7.15 (d, J= 2.4 Hz, 1 H), 6.60 (dd, J= 5.7, 2.4 Hz, 1 H), 3.83 (s, 3 H), 2.27 (s, 3 H), 1.97-1.96 (m, 1 H), 1.63-1.61 (m, 2 H), 0.90 (d, J= 6.6 Hz, 6 H); MS (ESI) m/z: 406.2 (M+H+).
Figure imgf000123_0001
Example 23: To a degassed solution of Example A3 (0.200 g, 0.556 mmol) in toluene
(10 mL) was added N-methyl-4-(tributylstannyl)imidazole (0.400 g, 1.078 mmol) followed by Pd(PPh3)4 (0.040 g, 0.035 mmol) and the resultant mixture was heated in a sealed tube (vol. 20mL) at 105 °C over night. The reaction mixture was diluted with
EtOAc (8 mL) and stirred with aq KF solution for 1 h. The organic layer was separated and the aqueous layer extracted with DCM (2 x 10 mL) and combined with the previous organic layer. The organic layer was directly subjected to chromatography using (0-20%
MeOH/DCM) to provide 3-(tert-butyl)-l-(6-methyl-5-((2-(l-methyl-lH-imidazol-4- yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-l,2,4-triazol-5(4H)-one (0.060 g, 25 % yield) as a white solid. 1H NMR (400 MHz, dmso): δ 1 1.98 (s, 1 H), 8.37 (d, J = 5.7 Hz, 1 H), 7.86 (d, J = 8.7 Hz, 1 H), 7.73 (d, J = 8.8 Hz, 1 H), 7.68 (d, J = 1.3 Hz, 1 H), 7.59 (s, 1 H), 7.17 (d, J = 2.6 Hz, 1 H), 6.79 (dd, J = 5.7, 2.6 Hz, 1 H), 3.67 (s, 3 H), 2.31 (s, 3 H), 1.27 (s, 9 H); MS(ESI) m/z :406.2 (M+H+).
Figure imgf000124_0001
Example 24: A mixture of Example A3 (0.060 g, 0.17 mmol), 4-(4,4,5,5-tetramethyl- 1 ,3,2- dioxaborolan-2-yl)-lH-pyrazole (0.042 g, 0.22 mmol) and K2CO3 (0.060 g, 0.43 mmol) were suspended in dioxane (0.70 mL) and water (0.14 mL). The mixture was sonicated and sparged with Ar for 10 min. Pd(PPh3)4 (0.019 g, 0.017 mmol) was added and the reaction mixture was stirred at 85 °C for 12 h. EtOAc (10 mL) was added and solids were removed by filtration through a pad of diatomaceous earth. The filter cake was washed with EtOAc ( 3 x 5 mL) and the combined filtrates were concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM) to afford l -(5-((2-(lH-pyrazol-4-yl)pyridin-4-yl)oxy)-6- methylpyridin-2-yl)-3-(ieri-butyl)-lH-l ,2,4-triazol-5(4H)-one (0.042 g, 64 %) as a white solid. 1H NMR (400 MHz, acetone-i¾: δ 10.70 (m, 1 H), 8.42 (d, J = 5.7 Hz, 1 H), 8.18-8.16 (m, 1 H), 7.97 (d, J = 8.7 Hz, 1 H), 7.63 (d, J = 8.7 Hz, 1 H), 7.26 (d, J= 2.4 Hz, 1 H), 6.68 (dd, J= 5.7, 2.4 Hz, 1 H), 2.39 (s, 3 H), 1.40 (s, 9 H); MS (ESI) m/z: 392.2 (M+H+).
Figure imgf000125_0001
Example 25: Example C3 (0.21 g, 1.3 mmol), copper(I) iodide (0.050 g, 0.26 mmol), and K2CO3 (1.0 g, 7.2 mmol) were suspended in DMF (6 mL) under an atmosphere of Ar. Example Al (0.50 g, 1.4 mmol) and N,N-dimethylethane-l,2-diamine (0.023 g, 0.26 mmol) were added sequentially and the reaction mixture was stirred at 100 °C for 12 h. Sat. NH4CI (aq) (30 mL) was added and the resultant emulsion was extracted with EtOAc (5 x 25 mL). The combined organics were dried and concentrated in vacuo to afford a yellow oil that was triturated with MeCN (5 mL) and sonicated for 30 min. The resultant suspension was collected by filtration and washed with cold MeCN (2 x 2.5 mL) to afford l-(5-((2-chloropyridin-4-yl)oxy)-6- methylpyridin-2-yl)-3-(ieri-pentyl)-lH-l,2,4-triazol-5(4H)-one (0.44 g, 89 %) as a light yellow solid that was carried forward without further purification. MS (ESI) m/z: 374.1 (M+H+).
[0404] l-(5-((2-Chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-(ieri-pentyl)-lH-l ,2,4- triazol-5(4H)-one (0.15 g, 0.40 mmol), l-methyl-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)-lH-pyrazole (0.1 1 g, 0.52 mmol), and K2CO3 (0.14 g, 1.04 mmol) were suspended in dioxane (1.7 mL) and water (0.33 mL). The suspension was sonicated and sparged with Ar for 10 min. Pd(PPli3)4 (0.046 g, 0.040 mmol) was added and the reaction mixture was stirred at 85 °C for 12 h. EtOAc (15 mL) was added and the suspension was filtered through a pad of diatomaceous earth. The filter cake was washed with EtOAc (3 x 5 mL) and the combined filtrates were concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM). Product was isolated as a colorless oil that was dissolved in MeCN/water, frozen to -78 °C, and lyophilized to afford l-(6-methyl-5-((2-(l-methyl-lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2- yl)-3-(teri-pentyl)-lH-l ,2,4-triazol-5(4H)-one (0.143 g, 79 %) as a white solid. 1H NMR (400 MHz, DMSO-ί/ί): δ 11.91 (s, 1 H), 8.37 (d, J= 5.7 Hz, 1 H), 8.25 (s, 1 H), 7.96 (s, 1 H), 7.86 (d, J = 8.7 Hz, 1 H), 7.68 (d, J = 8.7 Hz, 1 H), 7.18 (s, 1 H), 6.66 (d, J= 5.6 Hz, 1 H), 3.84 (s, 3 H), 2.33 (s, 3 H), 1.61 (q, J = 7.6 Hz, 2 H), 1.23 (s, 6 H), 0.76 (t, J = 7.3 Hz, 3 H); MS (ESI) m/z: (M+H+).
Figure imgf000126_0001
Example 26: Example CI (0.055 g, 0.392 mmol), copper (I) iodide (0.01 1 g, 0.060 mmol), Example A7 (0.107 g, 0.301 mmol), N,N-dimethylethane-l,2-diamine (5.31 mg, 0.060 mmol) and K2CO3 (0.230 g, 1.663 mmol) were suspended in DMF (3 mL) and degassed with Ar. The reaction mixture was stirred at 100 °C for 20 h. The reaction was cooled to RT and partitioned between DCM and saturated NH4CI (aq). The mixture was extracted with saturated NH4CI (aq) (2x). The combined aqueous extracts were back-extracted with DCM (3x). The organic extracts were combined, dried and evaporated. The crude product was purified by silica gel
chromatography eluting with EtOAc/MeOH to give the product, which was purified further by silica gel preparatory TLC eluting with DCM/MeOH to give the desired product. The product was dissolved in MeCN/water, frozen and lyophilized to yield 4-((6-(3-(tert-butyl)-5-oxo-4,5- dihydro-lH-l,2,4-triazol-l-yl)pyridin-3-yl)oxy)-N-methylpicolinamide (27 mg, 24.3%). !H
NMR (400 MHz, DMSO-de): δ 12.02-11.98 (m, 1 H), 8.79-8.76 (m, 1 H), 8.54 (d, J = 5.6 Hz, 1 H), 8.44 (d, J = 2.7 Hz, 1 H), 8.07 (d, J = 8.9 Hz, 1 H), 7.87-7.85 (m, 1 H), 7.44 (d, J = 2.4 Hz, 1 H), 7.21 (dd, J = 5.4, 2.4 Hz, 1 H), 2.78 (d, J = 4.8 Hz, 3 H), 1.27 (s, 9 H); MS (ESI) m/z: 369.2 (M+H+).
Figure imgf000127_0001
Example 27: Example C4 (0.18 g, 1.3 mmol), copper(I) iodide (0.050 g, 0.26 mmol), and K2C03 (1.0 g, 7.2 mmol) were suspended in DMF (6 mL) under an atmosphere of Ar. Example Al (0.50 g, 1.4 mmol) and N,N-dimethylethane-l,2-diamine (0.023 g, 0.26 mmol) were added sequentially and the reaction mixture was stirred at 100 °C for 12 h. Sat. NH4CI (aq) (30 mL) was added and the resultant emulsion was extracted with EtOAc (5 x 25 mL). The combined organics were dried and concentrated in vacuo to afford a yellow oil that was triturated with EtOAc (5 mL) and sonicated for 30 min. The resultant suspension was filtered and washed with cold EtOAc (2 x 2.5 mL) to afford l-(5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-(l- methylcyclopropyl)-lH-l ,2,4-triazol-5(4H)-one (0.32 g, 68.2 %) as a white amorphous solid that was carried forward without further purification. MS (ESI) m/z: 358.1 (M+H+).
[0405] l-(5-((2-Chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-(l-methylcyclopropyl)-lH- l,2,4-triazol-5(4H)-one (0.10 g, 0.28 mmol), l-methyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (0.08 g, 0.36 mmol), and K2CO3 (0.10 g, 0.73 mmol) were suspended in dioxane (1.7 mL) and water (0.33 mL). The suspension was sonicated and sparged with Ar for 10 min. Pd(PPh3)4 (0.032 g, 0.028 mmol) was added and the reaction mixture was stirred at 85 °C for 12 h. Sat. NH4CI (aq) (10 mL) was added and the resultant emulsion was extracted with EtOAc (4 x 10 mL). The combined organics were dried (Na2SC>4) and concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM) to afford l-(6-methyl-5-((2-(l -methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-3-(l- methylcyclopropyl)-lH-l,2,4-triazol-5(4H)-one (0.052 g, 46.1 %) as an white solid. !H NMR (400 MHz, DMSO-i¼): δ 11.76 (s, 1 H), 8.37 (d, J = 5.7 Hz, 1 H), 8.25 (s, 1 H), 7.96 (s, 1 H), 7.83 (d, J = 8.8 Hz, 1 H), 7.68 (d, J = 8.8 Hz, 1 H), 7.19 (d, J = 2.4 Hz, 1 H), 6.64 (dd, J = 5.7, 2.4 Hz, 1 H), 3.84 (s, 3 H), 2.33 (s, 3 H), 1.38 (s, 3 H), 1.06 (d, J = 2.3 Hz, 2 H), 0.81 (t, J = 2.3 Hz, 2 H).; MS (ESI) m/z: 404.2 (M+H+).
Figure imgf000128_0001
Example 28: A suspension of Example A8 (0.300 g, 0.754 mmol), l-methyl-4-
(4,4,5, 5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.250 g, 1.202 mmol),
K2C03 (0.200 g, 1.447 mmol) in a mixture of dioxane/ water (10: 1) (11 mL) was degassed for 5 minutes with argon purge. The reaction mixture was treated with
Pd(PPh3)4 (0.020 g, 0.017 mmol) and heated at 100 °C under argon over night. The solvent from the reaction mixture was completely evaporated and the residue was partitioned between DCM (30 mL) and water (30 mL). The organic layer separated and the aqueous layer extracted with dichloromethane (2 x 15mL). The combined organics were dried and concentrated to a small volume and purified by silica gel chromatography (0-100% THF/DCM) to provide 3 -(4- fluorophenyl)- 1 -(6-methyl-5-((2-( 1 -methyl- 1 H- pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-l,2,4-triazol-5(4H)-one (0.152 g , 45 %) as white solid. 1H NMR (400 MHz, DMSO-c¼): δ 12.71 (s, 1 H), 8.38 (d, J = 5.7 Hz, 1 H), 8.27 (s, 1 H), 7.98-7.94 (m, 4 H), 7.74 (d, J = 8.8 Hz, 1 H), 7.40 (t, J = 8.8 Hz, 2 H), 7.23 (d, J = 2.4 Hz, 1 H), 6.67 (dd, J = 5.7, 2.4 Hz, 1 H), 3.84 (s, 3 H), 2.37 (s, 3 H); MS(ESI) m z :444.2 (M+H+).
Figure imgf000129_0001
Example 29: A solution of Pd2(dba)3 (0.012 g, 0.013 mmol) and Me4tBuXPhos (0.012 g, 0.025 mmol) in toluene (2 mL) and dioxane (4 mL) was heated in a screw capped tube (lOmL) at 120 °C for 3 min. The reaction mixture was cooled to RT and the pre-formed catalyst was transferred to a re-sealable pressure tube (50mL) containing a degassed suspension of Example A8 (0.250 g, 0.628 mmol), 4-methyl imadazole (0.100 g, 1.218 mmol) and potassium phosphate (0.250 g, 1.178 mmol) in a mixture of toluene (4 mL) and dioxane (8 mL) followed by heating at 110 °C for 8 hours. The solids from the reaction mixture was filtered and washed with DCM and THF. The filtrate was completely evaporated and the residue was subjected to chromatography using (0-15% MeOH/DCM) to provide 3-(4-fluorophenyl)-l-(6-methyl-5-((2-(4-methyl-lH-imidazol- l-yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-l,2,4-triazol-5(4H)-one (0.050 g, 18 % yield) as white solid. 1H NMR (400 MHz, DMSO- ): δ 12.71 (s, 1 H), 8.41 (d, J = 1.4 Hz, 1 H), 8.34 (d, J = 5.8 Hz, 1 H), 7.98-7.93 (m, 3 H), 7.78 (d, J = 8.8 Hz, 1 H), 7.65 (t, J = 1.3 Hz, 1 H), 7.48 (br s, 1 H), 7.40 (m, 2 H), 6.82 (dd, J = 5.8, 2.2 Hz, 1 H), 2.38 (s, 3 H), 2.13 (s, 3 H); MS(ESI) m/z :444.2 (M+H).
Figure imgf000130_0001
Example 30: A suspension of Example A3 (0.250 g, 0.695 mmol), Ν,Ν-dimethyl urea (0.100 g, 1.135 mmol), Cs2C03 (0.500 g, 1.535 mmol) and Xantphos (0.016 g, 0.028 mmol) in dioxane (20 mL) was purged with argon for 5 minutes. Pd2(dba)3 (0.025 g, 0.028 mmol) was added and the reaction mixture was heated in a reclosable sealed tube (50 mL) at 100 °C. The solids from the reaction mixture was filtered and washed with DCM and THF. The filtrate was concentrated and the residue purified by silica gel chromatography (0-100% THF/DCM) to provide 3-(4-((6-(3-(tert-butyl)-5-oxo-4,5- dihydro- 1 H- 1 ,2,4-triazol- 1 -yl)-2-methylpyridin-3-yl)oxy)pyridin-2-yl)- 1 , 1 -dimethylurea (0.090 g, 31 % yield) as white solid. 1H NMR (400 MHz, DMSO-c¼): δ 11.98 (s, 1 H), 8.92 (s, 1 H), 8.11 (d, J = 5.7 Hz, 1 H), 7.84 (d, J = 8.7 Hz, 1 H), 7.67 (d, J = 8.8 Hz, 1 H), 7.30 (d, J = 2.4 Hz, 1 H), 6.58 (dd, J = 5.7, 2.4 Hz, 1 H), 2.87 (s, 6 H), 2.30 (s, 3 H), 1.27 (s, 9 H); MS(ESI) m/z: 412.2 (M+H+).
Figure imgf000131_0001
Example 31: Example CI (0.10 g, 0.71 mmol), copper(I) iodide (0.022 g, 0.116 mmol), and K2CO3 (0.44 g, 3.2 mmol) were combined in DMF (3 mL) under argon. Example A10 (0.25 g, 0.64 mmol) and N,N-dimethylethane-l ,2-diamine (0. 010 g, 0.12 mmol) were added sequentially and the reaction mixture was stirred at 100 °C for 18 h. Sat. NH4CI (aq) (10 mL) was added and the resultant suspension was extracted with EtOAc ( 4 x 20 mL). The combined organics were dried (MgSC^) and concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM) to afford 3-(/er/-butyl)-l-(4-methyl-5-((2-(l -methyl- lH-pyrazo l-4-yl)pyridin-4- yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one (0.122 g, 46.3 %) as a white solid. 1H NMR (400 MHz, DMSO-i¾: δ 12.02 (s, 1 H), 8.36 (d, J= 5.7 Hz, 1 H), 8.27 (s, 1 H), 8.26 (s, 1 H), 7.98 (s, 1 H), 7.96 (d, J= 0.7 Hz, 1 H), 7.18 (d, J= 2.4 Hz, 1 H), 6.64 (dd, J= 5.7, 2.5 Hz, 1 H), 3.84 (s, 3 H), 2.19 (s, 3 H), 1.26 (s, 9 H); MS (ESI) m/z: 406.2 (M+H+).
Figure imgf000131_0002
Example 32: A suspension of Example A8 (0.250 g, 0.628 mmol), cyclopropane carboxamide (O.lOOg, 1.175 mmol), Cs2C03 (0.400 g, 1.228 mmol) and X-Phos (0.012 g, 0.025 mmol) in dioxane (20 mL) was purged with argon for 5 minutes. To the reaction mixture was added Pd2(dba)3 (0.012 g, 0.013 mmol) and the mixture wass heated in a reclosable sealed tube (lOOmL) at 110 °C for 8 h. The solids from the reaction mixture was filtered and washed with DCM and THF. The filtrate was evaporated and the residue subjected to chromatography using (0-100% EtOAc/DCM) to provide N-(4-((6-(3-(4- fluorophenyl)-5-oxo-4,5-dihydro- 1 H- 1 ,2,4-triazol- 1 -yl)-2-methylpyridin-3- yl)oxy)pyridin-2-yl)cyclopropanecarboxamide (0.072 g, 24 %) as a white solid. 1H NMR (400 MHz, DMSO-i¾: δ 12.73 (s, 1 H), 10.89 (s, 1 H), 8.21 (d, J = 5.7 Hz, 1 H), 7.98- 7.93 (m, 3 H), 7.75 (d, J = 8.8 Hz, 1 H), 7.59 (d, J = 2.4 Hz, 1 H), 7.40 (t, J = 8.8 Hz, 2 H), 6.71 (dd, J = 5.7, 2.4 Hz, 1 H), 2.33 (s, 3 H), 1.95 (t, J = 6.1 Hz, 1 H), 0.75 (d, J = 6.2 Hz, 4 H), MS(ESI) m/z:447.2 (M+H+).
Figure imgf000132_0001
Example 33: A solution of concentrated H2SO4 (9 mL) was cooled to 0 °C and the temperature was carefully maintained as 30 % H202 (6.1 mL, 60 mmol) was added over 30 min and 5-bromo- 4,6-dimethylpyridin-2-amine (2.0 g, 9.95 mmol) in sulphuric acid (6 mL) was added over 2 h. The solution was allowed to warm to RT and stirred for 1 h. The mixture was poured onto ice (200 g), and the resultant suspension was stirred as it warmed to RT. The solids were collected by filtration, washed with water (3 x 50 mL), and subjected to high vacuum for 5 h to afford 3- bromo-2,4-dimethyl-6-nitropyridine (2.2 g, 96 %) as a yellow solid. !H NMR (400 MHz, DMSO-i¾: δ 8.20 (s, 1 H), 2.67 (s, 3 H), 2.52 (s, 3 H); MS (ESI) m/z: 231.0 (M+H+).
[0406] 3-Bromo-2,4-dimethyl-6-nitropyridine (2.2 g, 9.5 mmol) and 2-chloro-4- hydroxypyridine (2.5 g, 19 mmol) were combined in DMA (10 mL) and the solution was sonicated and sparged with Ar for 10 min. K2CO3 (4.0 g, 29 mmol) was added and the reaction mixture was stirred at 100 °C for 12 h. The reaction mixture was poured into water (200 mL) and the precipitated solids were isolated by filtration. The solids were washed with ½ sat. K2CO3 (aq) (3 x 50 mL) and water (3 x 50 mL) and dried under high vacuum for 5 h. The crude product was purified by silica gel chromatography (EtOAc/hexanes) to afford 3-((2-chloropyridin-4-yl)oxy)- 2,4-dimethyl-6-nitropyridine (0.50 g, 19 %) as a brown solid. !H NMR (400 MHz, DMSO-i¾: δ 8.33-8.30 (m, 2 H), 7.15 (d, J = 2.3 Hz, 1 H), 7.01 (dd, J = 5.8, 2.3 Hz, 1 H), 2.33 (s, 3 H), 2.23 (s, 3 H); MS (ESI) m/z: 280.0 (M+H+).
[0407] 3-((2-Chloropyridin-4-yl)oxy)-2,4-dimethyl-6-nitropyridine (0.50 g, 1.8 mmol), 1- methyl-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.48 g, 2.3 mmol), and K2CO3 (0.37 g, 2.7 mmol) were suspended in dioxane (6 mL) and water (1.2 mL) and sonicated and sparged with Ar for 10 min. Pd(PPh3)4 (0.10 g, 0.089 mmol) was added and the reaction mixture was stirred at 80 °C for 12 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (4 x 25 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM) to afford 2,4-dimethyl-3-((2- (1 -methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)-6-nitropyri dine (0.56 g, 96 %) as a brown oil. MS (ESI) m/z: 326.1 (M+H+).
[0408] 2,4-Dimethyl-3-((2-(l -methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)-6-nitropyridine (0.56 g, 1.8 mmol) and NELCl (2.76 g, 51.6 mmol) were combined in a solution of MeOH (8.6 mL) and THF (8.6 mL) and cooled to 0 °C. Zinc powder (1.13 g, 17.2 mmol) was added portion- wise over 30 min and the reaction mixture was allowed to warm to RT and stirred vigorously for 12 h. EtOAc (100 mL) was added and the resultant suspension was filtered through a pad of diatomaceous earth. The filter cake was washed with EtOAc (3 x 10 mL) and the combined filtrates were concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM) to afford 4,6-dimethyl-5-((2-(l-methyl-lH-pyrazol-4-yl)pyridin-4- yl)oxy)pyridin-2-amine (0.41 g, 81 %) as a light red solid. MS (ESI) m/z: 296.1 (M+H+).
[0409] 4,6-Dimethyl-5-((2-(l -methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine (0.41 g, 1.4 mmol), KI (2.30 g, 13.9 mmol), and diiodomethane (4 mL, 49.6 mmol) were combined and stirred at RT. The suspension was treated with ieri-butylnitrite (1.0 mL, 8.3 mmol) and the reaction mixture was stirred at RT for 12 h. The mixture was diluted with MeCN (10 mL), additional ieri-butylnitrite (1.0 mL, 8.3 mmol) was added and stirring was continued at RT for 24 h. The reaction mixture was partitioned between EtOAc (120 mL) and sat. NaHC03 (aq) (20 mL). The aqueous phase was collected and the organic phase was washed with sat. NaHC03 (aq) (2 x 20 mL), 10 % Na2S203 (aq) (2 x 20 mL), and brine (2 x 20 mL). The combined aqueous washes were back-extracted with EtOAc (2 x 20 mL) and the combined organics were dried (MgS04) and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc/DCM) to afford 6-iodo-2,4-dimethyl-3-((2-(l -methyl- lH-pyrazol-4-yl)pyridin-4- yl)oxy)pyridine (0.24 g, 43 %) as an off white solid that was used in the next step without further purification. MS (ESI) m/z: 407.0 (M+H+).
[0410] Example CI (0.10 g, 0.71 mmol), copper(I) iodide (0.020 g, 0.11 mmol), and K2C03 (0.41 g, 3.0 mmol) were suspended in DMF (3 mL) under an atmosphere of Ar. 6-Iodo-2,4- dimethyl-3-((2-(l -methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridine (0.24 g, 0.59 mmol) and N,N-dimethylethane- 1 ,2-diamine (0. 010 g, 0.11 mmol) were added sequentially and the reaction mixture was stirred at 100 °C for 18 h. Sat. NH4CI (aq) (10 mL) was added and the resultant suspension was extracted with EtOAc ( 4 x 20 mL). The combined organics were dried (MgSC^) and concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM) to afford 3-(tert-butyl)-l-(4,6-dimethyl-5-((2-(l -methyl- 1 H-pyrazol-4-yl)pyridin- 4-yl)oxy)pyridin-2-yl)-lH-l,2,4-triazol-5(4H)-one (0.114 g, 48.0 %) as a white solid. 1H NMR (400 MHz, DMSO-i¼): δ 11.99 (s, 1 H), 8.34 (d, J = 5.7 Hz, 1 H), 8.26 (s, 1 H), 7.96 (s, 1 H), 7.79 (s, 1 H), 7.13 (d, J = 2.4 Hz, 1 H), 6.55 (dd, J = 5.7, 2.4 Hz, 1 H), 3.84 (s, 3 H), 2.25 (s, 3 H), 2.13 (s, 3 H), 1.27 (s, 9 H); MS (ESI) m/z: 420.2 (M+H+).
Figure imgf000135_0001
Example 34: A suspension of Example All (0.340 g, 0.91 mmol), l-methyl-4-(4,4,5,5- tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.250 g, 1.202 mmol), Cs2C03 (0.680 g, 2.087 mmol) and Pd(PPh3)4 (0.050 g, 0.043 mmol) in MeCN (20 mL) was heated at 100 °C under argon for 4 hours. The solvent from the reaction mixture was completely evaporated and the residue was partitioned between DCM (50 mL) and water (50 mL). The organic layer was separated and the aqueous layer saturated with solid sodium chloride and extracted with DCM (2 x 20 mL). The combined organic layer was dried and concentrated to a small volume and subjected to chromatography using (0-20% MeOH/DCM) to provide 3-cyclopentyl-l-(6-methyl-5-((2-(l -methyl- 1 H-pyrazol-4- yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-l,2,4-triazol-5(4H)-one (0.191 g, 49.5 %) as a white solid. 1H NMR (400 MHz, DMSO-i¾: δ 11.90 (s, 1 H), 8.36 (d, J = 5.7 Hz, 1 H), 8.26 (s, 1 H), 7.96 (s, 1 H), 7.86 (d, J = 8.8 Hz, 1 H), 7.68 (d, J = 8.8 Hz, 1 H), 7.19 (d, J = 2.4 Hz, 1 H), 6.64 (dd, J = 5.7, 2.4 Hz, 1 H), 3.84 (s, 3 H), 2.96 (m, 1 H), 2.32 (s, 3 H), 1.94 (t, J = 7.8 Hz, 2 H), 1.74 (m, 4 H), 1.61 (m, 2 H); MS(ESI) m/z:418.2 (M+H+).
Figure imgf000136_0001
Example 35: To a suspension of semicarbazide hydrochloride (5.00 g, 44.8 mmol) in DCM (100 mL) was added triethylamine (10.00 g, 99 mmol) and the mixture was stirred at -10 °C for 30 min. Cyclopropane carbonylchloride (5.00 g, 47.8 mmol) was added at the same temp and the mixture was stirred to T over night. The solvent from the reaction mixture was completely removed and the residue stirred in MeCN (200 mL) for 1 h. The solids were collected by filtration, washed and dried. The solid was transferred to a RB flask and treated with sodium hydroxide (7.00 g, 175 mmol) and water (20 mL). The resulting reaction mixture was heated at 100 °C for 2 hours. The reaction mixture was cooled and acidified with cone. HCl. The solids were collected by filtration, washed and dried to provide 3-cyclopropyl-lH-l,2,4-triazol-5(4H)-one (1.82 g, 30.4 % yield) as white solid. 'H NMR ^OO MHZ, DMSO-i¾: 511.03 (br s, 2 H), 1.67 (m, 1 H), 0.82 (m, 2 H), 0.73 (m, 2 H); MS(ESI) m/r. 126.1 (M+H+).
[0411] A suspension of 3-cyclopropyl-lH-l,2,4-triazol-5(4H)-one (0.600 g, 4.80 mmol), Example Al (1.00 g, 2.89 mmol), copper iodide (0.050 g, 0.263 mmol), Cs2C03 (2.00 g, 6.14 mmol) and Nl,N2-dimethylethane-l,2-diamine (0.050 g, 0.567 mmol) in MeCN (20 mL) was heated at 100 °C under argon for 14 hours. The solvent from the reaction mixture was completely evaporated and the residue was partitioned between DCM (50 mL) and water (50 mL). The organic layer was separated and the aqueous layer saturated with solid sodium chloride and extracted with DCM (2 x 20mL). The combined organic layer was dried, concentrated to a small volume and purified by silica gel chromatography (0-100% EtOAc/DCM) to provide l-(5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-cyclopropyl- lH-l ,2,4-triazol-5(4H)-one (0.288 g, 29%) as a white solid. !H NMR (400 MHz, DMSO-i¾: δ 11.81 (s, 1 H), 8.29 (d, J = 5.8 Hz, 1 H), 7.87 (d, J = 8.8 Hz, 1 H), 7.72 (d, J = 8.8 Hz, 1 H), 7.06 (d, J = 2.3 Hz, 1 H), 6.95 (dd, J = 5.8, 2.3 Hz, 1 H), 2.29 (s, 3 H), 1.87 (m, 1 H), 0.95 (m, 4 H); MS(ESI) m/z: 344.1 (M+H+).
[0412] A suspension of l-(5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3- cyclopropyl-lH-l ,2,4-triazol-5(4H)-one (0.285 g, 0.829 mmol), l-methyl-4-(4,4,5,5- tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.250 g, 1.202 mmol), Cs2C03 (0.600 g, 1.842 mmol) and Pd(PPh3)4 (0.050 g, 0.043 mmol) in MeCN (20 mL) was heated at 100 °C under argon for 4 hours. The solvent from the reaction mixture was completely evaporated and the residue was partitioned between DCM (50 mL) and water (50 mL). The organic layer was separated and the aqueous layer saturated with solid sodium chloride and extracted with DCM (2 x 20 mL). The combined organics were dried, concentrated, and purified by silica gel chromatography (0-20% MeOH/DCM) to provide 3-cyclopropyl-l-(6-methyl-5-((2-(l-methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-l,2,4-triazol-5(4H)-one (0.228 g, 66 %) as a white solid. 1H NMR (400 MHz, dmso): δ 1 1.80 (s, 1 H), 8.36 (d, J = 5.7 Hz, 1 H), 8.26 (s, 1 H), 7.96 (s, 1 H), 7.86 (d, J = 8.8 Hz, 1 H), 7.68 (d, J = 8.8 Hz, 1 H), 7.20 (d, J = 2.4 Hz, 1 H), 6.63 (dd, J = 5.7, 2.4 Hz, 1 H), 3.84 (s, 3 H), 2.32 (s, 3 H), 1.87 (tt, J = 8.4, 5.1 Hz, 1 H), 0.95 (m, 4 H); MS(ESI) m/z: 390.2 (M+H+).
Figure imgf000138_0001
Example 36: Semicarbazide hydrochloride (1.50 g, 13.6 mmol) was dissolved in water (15 mL).
NaHC03 (2.40g, 28.6 mmol) was slowly added to the solution over 30 min at RT followed by the addition of 3,3-dimethylbutyryl chloride (2 g, 14.86 mmol). The mixture was stirred at RT for 12 h followed by the addition of solid NaOH (1.08 g, 27 mmol). The reaction mixture was stirred at 100 °C for 3 h, allowed to cool to RT and stirred for an additional 12 h. The reaction mixture was neutralized by the drop-wise addition of concentrated HC1. The solids were collected by filtration, washed with water, and dried in vacuo to afford 3-neopentyl-lH- 1,2,4- triazol-5(4H)-one (0.65 g, 31 %) as a white solid. 1H NMR (400 MHz, DMSO-i¾: δ 11.12 (s, 1 H), 1 1.10 (s, 1 H), 2.20 (s, 2 H), 0.90 (s, 9 H).
[0413] Example Al (0.50 g, 1.44 mmol), 3-neopentyl-lH-l ,2,4-triazol-5(4H)-one (0.20 g, 1.29 mmol), and K2CO3 (1.00 g, 7.24 mmol) were suspended in DMF (4.5 mL). The mixture was sonicated and sparged with Ar for 10 min followed by sequential addition of copper(I) iodide (0.05 g, 0.26 mmol) and N,N-dimethylethane- 1 ,2-diamine (0.02 g, 0.26 mmol). The reaction mixture was stirred at 100 °C for 12 h, allowed to cool to RT, and subsequently diluted with sat. NH4CI (aq.) (15 mL), and extracted with EtOAc (5 x 20 mL). The combined organics were dried (MgS04) and concentrated in vacuo. The resultant yellow oil was triturated with MeCN (3 mL) and sonicated to afford a pale yellow solid that was isolated by filtration and dried in vacuo to afford 1 -(5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-neopentyl- 1 H- 1 ,2,4-triazol- 5(4H)-one (0.37 g, 77 %) as a pale yellow solid. !H NMR (400 MHz, DMSO-i¾: δ 11.85 (s, 1 H), 8.29 (d, J = 5.8 Hz, 1 H), 7.90 (d, J = 8.8 Hz, 1 H), 7.74 (d, J = 8.8 Hz, 1 H), 7.08 (d, J = 2.3 Hz, 1 H), 6.97 (dd, J = 5.8, 2.3 Hz, 1 H), 2.37 (s, 2 H), 2.30 (s, 3 H), 0.97 (s, 9 H); MS (ESI) m/z: 374.1 (M+H+).
[0414] l-(5-((2-Chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-neopentyl-lH- 1,2,4- triazol-5(4H)-one (0.15 g, 0.40 mmol), l-methyl-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)-lH-pyrazole (0.1 1 g, 0.52 mmol), and K2CO3 (0.14 g, 1.04 mmol) were suspended in a solution of dioxane (2.0 mL) and water (0.40 mL). The suspension was sonicated and sparged with Ar for 10 min. Pd(PPh3)4 (0.05 g, 0.04 mmol) was added and the reaction mixture was stirred at 85 °C for 12 h, allowed to cool to RT, diluted with water (5 mL), and extracted with EtOAc (5 x 10 mL). The combined organics were dried (MgSC^) and concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM) to afford l-(6-methyl-5-((2-(l- methyl- 1 H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-3-neopentyl- 1 H- 1 ,2,4-triazol-5(4H)-one (0.124 g, 69%) as a white solid. !H NMR (400 MHz, DMSO-c¼): δ 11.83 (s, 1 H), 8.36 (d, J = 5.7 Hz, 1 H), 8.26 (s, 1 H), 7.97 (s, 1 H), 7.89 (d, J = 8.8 Hz, 1 H), 7.69 (d, J = 8.8 Hz, 1 H), 7.21 (d, J = 2.4 Hz, 1 H), 6.65 (dd, J = 5.7, 2.4 Hz, 1 H), 3.84 (s, 3 H), 2.38 (s, 2 H), 2.33 (s, 3 H), 0.98 (s, 9 H); MS (ESI) m/z: 420.2 (M+H+).
Figure imgf000140_0001
Example 37: To a 0 °C solution of cyclobutane carboxylic acid (7.50 g, 74.9 mmol) in DCM (100 mL) was added oxalyl chloride (12.00 g, 95 mmol) followed by catalytic amount of DMF. The resultant mixture was stirred at T for 1 h. The solvent from the reaction mixture was completely evaporated to a light coloured viscous mass. In a different RB flask, a suspension of semicarbazide hydrochloride (9.00 g, 81 mmol) in DCM (100 mL) was treated with triethylamine (18.00 g, 178 mmol) and stirred at -10 °C for 30 minutes. To the reaction mixture was added the acid chloride dissolved in DCM (20 mL) at the same temp and the resultant mixture was stirred at RT over night. The solvent from the reaction mixture was completely removed and the residue was stirred in MeCN (100 mL) for 1 h. The solids were collected by filtration, washed and dried. The solid was transferred to a RB flask and was treated with sodium hydroxide (7.50 g, 188 mmol) and water (20 mL). The resulting reaction mixture was heated at 100 °C for 3 h, cooled to RT, and acidified with cone, sulfuric acid. The solids were collected, washed sparingly with cold water, and dried to provide 3-cy clobutyl-lH- 1,2,4- triazol-5(4H)-one, (6.40 g, 61.4 % yield) as white solid. 1H NMR (400 MHz, DMSO- d6) δ 11.27 (s,l H), 11.10 (s, 1 H), 2.15 (m, 7 H); MS(ESI) m/z : 140.1 (M+H+).
[0415] A suspension of 3-cyclobutyl-lH-l ,2,4-triazol-5(4H)-one (0.800 g, 5.75 mmol), Example Al (1.000 g, 2.89 mmol), copper iodide (0.050 g, 0.263 mmol), Cs2C03 (2.000 g, 6.14 mmol) and Nl ,N2-dimethylethane-l,2-diamine (0.050 g, 0.567 mmol) in acetonitrile (20 mL) was heated at 100 °C under argon for 4 h. The solvent was completely evaporated and the residue was stirred in water. The solids were collected, washed and dried to provide l-(5-((2- chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-cyclobutyl-lH-l ,2,4-triazol-5(4H)-one (0.820 g, 79 %) as a yellow solid. !H NMR (400 MHz, DMSO-i¾: δ 8.48 (d, J = 9.0 Hz, 1 H), 8.26 (d, J = 5.7 Hz, 1 H), 7.77 (d, J = 9.0 Hz, 1 H), 6.95-6.89 (m, 2 H), 3.10 (m, 1 H), 2.20 (m, 4 H), 2.03 (s, 3 H), 1.70 (m, 2 H); MS(ESI) m/z :358.1 (M+H+).
[0416] A suspension of l-(5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3- cyclobutyl-lH-l ,2,4-triazol-5(4H)-one (0.300 g, 0.838 mmol), l-methyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.250 g, 1.202 mmol), Cs2C03 (0.600 g, 1.842 mmol) and Pd(PPh3)4 (0.050 g, 0.043 mmol) in acetonitrile (20 mL) was heated at 100 °C under argon for 2 h. The solvent from the reaction mixture was completely evaporated and the residue partitioned between DCM (50 mL) and water (50 mL). The organic layer was separated and the aqueous layer saturated with solid sodium chloride and extracted with DCM (2 x 20 mL). The combined organics were dried, concentrated, subjected to silica gel chromatography (0-100% THF/EtOAc) to provide 3-cyclobutyl-l-(6-methyl-5-((2-(l-methyl-lH-pyrazol-4-yl)pyridin-4- yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one (0.055 g, 15%) as a white solid. 1H NMR (400 MHz, DMSO-i¼): δ 11.97 (s, 1 H), 8.37 (d, J = 5.7 Hz, 1 H), 8.26 (s, 1 H), 7.96 (s, 1 H), 7.87 (d, J = 8.8 Hz, 1 H), 7.69 (d, J = 8.8 Hz, 1 H), 7.20 (d, J = 2.4 Hz, 1 H), 6.64 (dd, J = 5.7, 2.4 Hz, 1 H), 3.84 (s, 3 H), 3.44 (m, 1 H), 2.33 (s, 3 H), 2.26 (m, 4 H), 2.04 (m, 1 H), 1.90 (m, 1 H); MS(ESI) m/z: 404.2 (M+H+).
Figure imgf000142_0001
Example 38: Example A3 (80 mg, 0.22 mmol), l-ethyl-4-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)-lH-pyrazole (55 mg, 0.24 mmol), and K2CO3 (90 g, 0.66 mmol) were combined in the mixture of dioxane/water (4: 1 , 5 mL). The mixture was sparged with Ar and then Pd(PPh3)4 (26 mg, 0.022 mmol) was added. The mixture was sparge with Ar again and then heated at 90 °C overnight. The reaction mixture was diluted with saturated aqueous NaHC03 and then the solution was extracted with EtOAc (3x). The combined organics were dried ( a2S04), filtered and concentrated to dryness. The material was purified via silica gel chromatography (MeOH/DCM) to obtain 3-(tert-butyl)-l-(5-((2-(l-ethyl-lH-pyrazol-4- yl)pyridin-4-yl)oxy)-6-methylpyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one (35 mg, 36.6%). 1H NMR (400 MHz, DMSO-i¾: δ 1 1.99 (s, 1 H), 8.37 (d, J = 5.7 Hz, 1 H), 8.32 (s, 1 H), 7.98 (s, 1 H), 7.86 (d, J = 8.8 Hz, 1 H), 7.69 (d, J = 8.8 Hz, 1 H), 7.20 (d, J = 2.4 Hz, 1 H), 6.65 (dd, J = 5.7, 2.4 Hz, 1 H), 4.13 (q, J = 7.3 Hz, 2 H), 2.34 (s, 3 H), 1.37 (t, J = 7.3 Hz, 3 H), 1.28 (s, 9 H); MS (ESI) m/z: 420.2 (M+H+).
Figure imgf000143_0001
Example 39: Example A3 (0.14 g, 0.39 mmol), 5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)oxazole (0.10 g, 0.51 mmol), and K2CO3 (0.14 g, 1.04 mmol) were suspended in a solution of dioxane (2.5 mL) and water (0.50 mL). The suspension was sonicated and sparged with Ar for 10 min. Pd(PPh3)4 (0.05 g, 0.04 mmol) was added and the reaction mixture was stirred at 85 °C for 12 h, allowed to cool to RT, diluted with sat. NH4CI (aq.) (5 mL), and extracted with EtOAc (4 x 5 mL). The combined organics were dried (Na2SC>4) and concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM) to afford 3-(tert-butyl)-l-(6-methyl-5- ((2-(oxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one (0.025 g, 15.6 %) as an off white solid. !H NMR (400 MHz, DMSO-i¾: δ 11.99 (s, 1 H), 8.51 (d, J = 5.7 Hz, 1 H), 8.49 (s, 1 H), 7.87 (d, J = 8.8 Hz, 1 H), 7.80 (s, 1 H), 7.76 (d, J = 8.8 Hz, 1 H), 7.21 (d, J = 2.5 Hz, 1 H), 6.91 (dd, J = 5.7, 2.4 Hz, 1 H), 2.33 (s, 3 H), 1.27 (s, 9 H); MS (ESI) m/z: 393.2
(M+H ).
Figure imgf000144_0001
Example 40: In a sealed tube, Pd(PPh3)4 (0.016 g, 0.014 mmol), K2C03 (0.115 g, 0.834 mmol), Example A3 (0.100 g, 0.278 mmol), and 2-(4-methylpiperazino)pyridine-5-boronic acid pinacol ester (0.126 g, 0.417 mmol) were suspended in dioxane (6 mL) and water (1.5 mL). The mixture was degassed with Ar and heated at 90 °C overnight. The reaction mixture was partitioned between EtOAc and IN NaOH and extracted with EtOAc (2x). The EtOAc extracts were combined and washed with brine. The aqueous extracts were combined and back-extracted with DCM (3x). The DCM extracts were combined with the EtOAc extracts, dried, and evaporated. The crude product was purified by silica gel preparatory TLC (DCM/MeOH(10% NEt3)) to give the desired product, which was dissolved in acetonitrile/water, frozen and lyophilized to yield 3- (tert-butyl)- 1 -(6-methyl-5-((6'-(4-methylpiperazin- 1 -yl)-[2,3'-bipyridin]-4-yl)oxy)pyridin-2-yl)- lH-l ,2,4-triazol-5(4H)-one (49 mg, 35.2%). 1H NMR (400 MHz, DMSO-de): δ 1 1.99 (s, 1 H), 8.85 (d, J = 2.5 Hz, 1 H), 8.49 (d, J = 5.7 Hz, 1 H), 8.27 (dd, J = 9.0, 2.5 Hz, 1 H), 7.86 (d, J = 8.8 Hz, 1 H), 7.71 (d, J = 8.8 Hz, 1 H), 7.56-7.54 (m, 1 H), 7.03 (d, J = 9.0 Hz, 1 H), 6.77-6.75 (m, 1 H), 4.51-4.49 (m, 2 H), 3.56-3.46 (m, 2 H), 3.22-3.20 (m, 2 H), 3.08-3.05 (m, 2 H), 2.81 (d, J = 4.5 Hz, 3 H), 2.35 (s, 3 H), 1.27 (s, 9 H); MS (ESI) m/z: 501.3 (M+H+).
Figure imgf000145_0001
Example 41: In a sealed tube, Pd(PPh3)4 (0.016 g, 0.014 mmol), K2C03 (0.1 15 g, 0.834 mmol), Example A3 (0.100 g, 0.278 mmol), and 2-(4-methylpiperazino)pyridine-4-boronic acid pinacol ester (0.126 g, 0.417 mmol) were suspended in dioxane (6 mL) and water (1.5 mL). The mixture was degassed with Ar and heated at 90 °C for 20 h. The reaction mixture was partitioned between EtOAc and IN NaOH and extracted with EtOAc (2x). The EtOAc extracts were combined and washed with brine. The aqueous extracts were combined and back-extracted with DCM (3x). The DCM extracts were combined with the EtOAc extracts, dried and evaporated. The crude product was purified by silica gel preparatory TLC [DCM/MeOH(10% NEt3)] to give the desired product which was dissolved in acetonitrile/water, frozen and lyophilized to yield 3- (tert-butyl)- 1 -(6-methyl-5-((2'-(4-methylpiperazin- 1 -yl)-[2,4'-bipyridin]-4-yl)oxy)pyridin-2-yl)- lH-l ,2,4-triazol-5(4H)-one (45 mg, 32.3%). 1H NMR (400 MHz, DMSO-i¾: δ 1 1.99 (s, 1 H), 8.57 (d, J = 5.7 Hz, 1 H), 8.25 (d, J = 5.3 Hz, 1 H), 7.87 (d, J = 8.8 Hz, 1 H), 7.81 (d, J = 2.3 Hz, 1 H), 7.72 (d, J = 8.8 Hz, 1 H), 7.58 (s, 1 H), 7.40-7.39 (m, 1 H), 6.85-6.84 (m, 1 H), 4.52-4.49 (m, 2 H), 3.42 (m, 2 H), 3.18-3.17 (m, 2 H), 3.13-3.04 (m, 2 H), 2.83 (d, J = 4.6 Hz, 3 H), 2.35 (s, 3 H), 1.27 (s, 9 H); MS (ESI) m/z: 501.3 (M+H+).
Figure imgf000146_0001
Example 42: 3-(Benzyloxy)-2,2-dimethylpropanoic acid (1.00 g, 4.80 mmol) was dissolved in DCM (10 mL) at RT. Oxalyl chloride (0.70 mL, 8.00 mmol) and DMF (0.10 mL, 1.29 mmol) were added sequentially and the reaction mixture was stirred at RT for 2 h. In a separate flask, semicarbazide hydrochloride (0.8 g, 7.24 mmol) and aOH (0.80 g, 20.0 mmol) were dissolved in a solution of dioxane (2.0 mL) and water (10.0 mL). The solution of the acid chloride was added in one portion to the solution of the semicarbazide and the reaction mixture was stirred at RT for 12 h. 2 M NaOH (aq.) (28.0 mL, 56.0 mmol) was then added and the reaction mixture was stirred at 100 °C for 2 h, allowed to cool to RT, and neutralized by the addition of ¾ sat. NH4CI (aq.) (75 mL). The resultant homogenous solution was sonicated for 12 h and the resultant precipitated solids were collected by filtration and dried in vacuo to afford 3-(l- (benzyloxy)-2-methylpropan-2-yl)-lH-l ,2,4-triazol-5(4H)-one (0.57 g, 48.0 %) as a white solid. !H NMR (400 MHz, DMSO-i¾: δ 1 1.22 (s, 1 H), 1 1.09 (s, 1 H), 7.34-7.23 (m, 5 H), 4.44 (s, 2 H), 3.39 (s, 2 H), 1.16 (s, 5 H).
[0417] Example Al (0.40 g, 1.15 mmol), 3-(l-(benzyloxy)-2-methylpropan-2-yl)-lH-l ,2,4- triazol-5(4H)-one (0.29, 1.15 mmol), and K2C03 (1.00 g, 7.24 mmol) were combined in DMF (4.0 mL) and the mixture was sonicated and sparged with Ar for 10 min. Copper(I) iodide (0.04 g, 0.23 mmol) and N,N-dimethylethane- 1 ,2-diamine (0.02 g, 0.23 mmol) were added. The reaction mixture was stirred at 100 °C for 12 h, allowed to cool to RT, and subsequently diluted with ¾ sat. NH4CI (aq.) (50 mL) and EtOAc (50 mL). The biphasic solution was mixed vigorously and extracted with EtOAc (2 x 50 mL)). The combined organics were dried (Na2S04) and concentrated in vacuo to afford 3-(l-(benzyloxy)-2-methylpropan-2-yl)-l-(5-((2- chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one (0.41 g, 76 %) as a pale yellow oil. !H NMR (400 MHz, DMSO-i¾: δ 1 1.96 (s, 1 H), 8.29 (d, J = 5.8 Hz, 1 H), 7.87 (d, J = 8.8 Hz, 1 H), 7.74 (d, J = 8.8 Hz, 1 H), 7.29-7.27 (m, 5 H), 7.07 (d, J = 2.3 Hz, 1 H), 6.96 (dd, J = 5.8, 2.3 Hz, 1 H), 4.49 (s, 2 H), 3.49 (s, 2 H), 2.31 (s, 3 H), 1.26 (s, 6 H); MS (ESI) m/z: A662 (M+H+).
[0418] 3-(l -(Benzyloxy)-2-methylpropan-2-yl)-l -(5-((2-chloropyridin-4-yl)oxy)-6- methylpyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one (0.41 g, 0.88 mmol), l-methyl-4-(4,4,5,5- tetramethyl-l ,3,2-dioxaborolan-2-yl)- lH-pyrazole (0.24 g, 1.14 mmol), and K2C03 (0.32 g, 2.29 mmol) were suspended in a solution of dioxane (5.0 mL) and water (1.0 mL). The suspension was sonicated and sparged with Ar for 10 min followed by the addition of Pd(PPh3)4 (0.10 g, 0.09 mmol). The reaction mixture was stirred at 85 °C for 12 h, allowed to cool to RT, and suspended between sat. NH4CI (aq.) (15 mL) and EtOAc (20 mL). The organic phase was collected and the aqueous phase was extracted with EtOAc (3 x 15 mL). The combined organics were dried (Na2SC>4) and concentrated in vacuo to afford an orange oil. The residue was purified by silica gel chromatography (MeOH/DCM) to afford 3-(l-(benzyloxy)-2-methylpropan-2-yl)-l- (6-methyl-5-((2-( 1 -methyl- 1 H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)- 1 H- 1 ,2,4-triazol- 5(4H)-one (0.41 g, 91 %) as a viscous, pale yellow oil. 1H NMR (400 MHz, DMSO-i¾: δ 1 1.95 (s, 1 H), 8.36 (d, J = 5.6 Hz, 1 H), 8.26 (s, 1 H), 7.96 (s, 1 H), 7.86 (d, J = 8.8 Hz, 1 H), 7.69 (d, J = 8.8 Hz, 1 H), 7.31 -7.29 (m, 5 H), 7.18 (d, J = 2.4 Hz, 1 H), 6.66 (dd, J = 5.7, 2.4 Hz, 1 H), 4.49 (s, 2 H), 3.83 (s, 3 H), 3.50 (s, 2 H), 2.33 (s, 3 H), 1.27 (s, 6 H); MS (ESI) m/z: 512.3 (M+H+). [0419] 3-(l-(Benzyloxy)-2-methylpropan-2-yl)-l-(6-methyl-5-((2-(l-methyl-lH-pyrazol-4- yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-l,2,4-triazol-5(4H)-one (0.41 g, 0.80 mmol), and palladium(O) on carbon (10% w/w, 0.20 g, 0.19 mmol) were combined in EtOAc (4.0 mL) under an atmosphere of Ar. The reaction flask was depressurized and back-filled with H2 (g). This process was repeated (2 x) and the reaction mixture was stirred under a balloon of H2 (g) for 12 h. Formic acid (0.5 mL) was added and stirring was continued an additional 12 h at RT. The reaction mixture was transferred to a Parr hydrogenation shaker and reaction was continued under 40 psi H2 (g) atmosphere. After 5 h, the Pd was removed by filtration through a pad of diatomaceous earth and the filter cake was washed with EtOAc (4 x 25 mL). The combined filtrates were concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM) to afford 3-(l-hydroxy-2-methylpropan-2-yl)-l-(6-methyl-5-((2-(l -methyl- 1H- pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-l,2,4-triazol-5(4H)-one (0.053 g, 15%) as a white solid. 1H NMR (400 MHz, DMSO-i¾: δ 11.85-1 1.83 (m, 1 H), 8.36 (d, J = 5.7 Hz, 1 H), 8.26 (s, 1 H), 7.96 (s, 1 H), 7.86 (d, J = 8.8 Hz, 1 H), 7.69 (d, J = 8.8 Hz, 1 H), 7.18 (d, J = 2.4 Hz, 1 H), 6.65 (dd, J = 5.7, 2.4 Hz, 1 H), 4.92-4.91 (m, 1 H), 3.84 (s, 3 H), 3.45-3.43 (m, 2 H), 2.33 (s, 3 H), 1.20 (s, 6 H); MS (ESI) m/z: 422.2 (M+H+).
Figure imgf000148_0001
Example 43: A suspension of Example C7 (1.00 g, 4.83 mmol), Example Al (0.500 g, 1.443 mmol), copper iodide (0.050 g, 0.263 mmol), Cs2C03 (1.000 g, 3.07 mmol) and l ,N2- dimethylethane-l ,2-diamine (0.050 g, 0.567 mmol) in MeCN (20 mL) was heated at 100 °C under argon for 14 hours. The solvent from the reaction mixture was completely evaporated and the residue partitioned between DCM (50 mL) and water (50 mL). The organic layer was separated and the aqueous layer saturated with solid sodium chloride and extracted with DCM (2 x 20 mL). The organics were dried, concentrated, and purified by silica gel chromatography (0- 100% EtOAc/DCM) to provide l -(5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-(l - (trifluoromethyl)cyclobutyl)-lH-l ,2,4-triazol-5(4H)-one (0.240 g, 39 % yield) as light greenish solid, suitable for use in the next reaction. MS(ESI) m/z: 426.1 (M+H+).
[0420] To a suspension of l -(5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-(l- (trifluoromethyl)cyclobutyl)-lH-l ,2,4-triazol-5(4H)-one (0.240 g, 0.564 mmol), l-methyl-4- (4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.250 g, 1.202 mmol), Cs2C03 (0.500 g, 1.535 mmol) and Pd(PPh3)4 (0.030 g, 0.026 mmol) in EtOH (20 mL) was heated at 100 °C. The solvent from the reaction mixture was completely evaporated and the residue was partitioned between DCM (30 mL) and water (30 mL). The organic layer was separated and the aqueous layer saturated with solid sodium chloride and extracted with DCM (2 x 20 mL). The combined organics were dried, concentrated in vacuo, and purifed by silica gel chromatography (0-40% THF/EtOAc) to provide l-(6-methyl-5-((2-(l -methyl- lH-pyrazo l-4-yl)pyridin-4- yl)oxy)pyridin-2-yl)-3-(l-(trifluoromethyl)cyclobutyl)-lH-l ,2,4-triazol-5(4H)-one (0.013 g, 4.6%) as a white solid. !H NMR (400 MHz, DMSO-i¾: δ 12.48 (s, 1 H), 8.37 (d, J = 5.7 Hz, 1 H), 8.26 (s, 1 H), 7.97 (s, 1 H), 7.91 (d, J = 8.8 Hz, 1 H), 7.73 (d, J = 8.8 Hz, 1 H), 7.20 (d, J = 2.4 Hz, 1 H), 6.67 (dd, J = 5.7, 2.4 Hz, 1 H), 3.84 (s, 3 H), 2.61 (m, 4 H), 2.35 (s, 3 H), 2.03 (t, J = 8.2 Hz, 2 H); MS(ESI) m/z: 472.2 (M+H+).
Figure imgf000150_0001
Example 44: Example A13 (0.74 g, 2.87 mmol), potassium iodide (4.80 g, 28.9 mmol), and diiodomethane (6.00 mL, 74.4 mmol) were comnbined at RT. ieri-Butylnitrite (2.00 mL, 16.7 mmol) was added dropwise and the reaction mixture was stirred for 12 h at RT. The reaction mixture was diluted with MeCN (15 mL), additional ieri-butylnitrite (1.00 mL, 8.34 mmol) was added and stirring was continued for an additional 24 h. The mixture was partitioned between sat. NaHC03 (aq) (80 mL) and EtOAc (200 mL). The aqueous phase was removed and the organic phase was wshed with sat. NaHC03 (aq) (1 x 50 mL), 10 % Na2S203 (aq) (2 x 35 mL), and brine (2 x 35 mL). The combined aqueous washes were back-extracted with EtOAc (1 x 50 mL). The combined organics were dried (MgSO^ and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc/DCM) to afford N-(4-((6-iodo-4-methylpyridin-3- yl)oxy)pyridin-2-yl)acetamide (0.52 g, 49.2 %) as a light yellow solid. !H NMR (400 MHz, DMSO-ί/ί): δ 10.59 (s, 1 H), 8.19 (s, 1 H), 8.18 (d, J = 5.7 Hz, 1 H), 7.92 (s, 1 H), 7.59 (s, 1 H), 6.64 (dd, J = 5.7, 2.5 Hz, 1 H), 2.08 (s, 3 H), 2.03 (s, 3 H); MS (ESI) m/z: 370.0 (M+H+).
[0421] N-(4-((6-iodo-4-methylpyridin-3-yl)oxy)pyridin-2-yl)acetamide (0.15 g, 0.41 mmol), Example C2 (0.11 g, 0.70 mmol), and K2C03 (0.55 g, 3.98 mmol) were suspended in DMF (5 mL). The suspension was sonicated and sparged with Ar for 10 min. Copper(I) iodide (0.03 g, 0.16 mmol) and N,N-dimethylethane-l,2-diamine (0.012 g, 0.14 mmol) were added and the reaction mixture was stirred at 100 °C for 12 h. The reaction mixture was diluted with EtOAc (5 mL) and filtered through a pad of diatomaceous earth. The filter cake was washed with EtOAc (2 x 5 mL) and the combined filtrates were concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM) to provide impure product as a brown solid. The solid was repurified by silica gel chromatography (MeOH/EtOAc) to afford N-(4-((6-(3-(2- methoxypropan-2-yl)-5-oxo-4,5-dihydro- 1 H- 1 ,2,4-triazol- 1 -yl)-4-methylpyridin-3- yl)oxy)pyridin-2-yl)acetamide (0.035 g, 19%) as a white solid. !H NMR (400 MHz, DMSO-i¾: δ 12.20-12.18 (m, 1 H), 10.57 (s, 1 H), 8.27 (s, 1 H), 8.18 (d, J = 5.7 Hz, 1 H), 7.98 (s, 1 H), 7.59 (d, J = 2.4 Hz, 1 H), 6.67 (dd, J = 5.7, 2.4 Hz, 1 H), 3.06 (s, 3 H), 2.18 (s, 3 H), 2.02 (s, 3 H), 1.46 (s, 6 H); MS (ESI) m/z: 399.2 (M+H+).
Figure imgf000151_0001
Example 45: A round bottom flask was charged with cyclopropane carboxamide (0.473 g, 5.56 mmol), Example A3 (0.400 g, 1.112 mmol), Cs2C03 (0.54 g, 1.668 mmol), XPhos (0.053 g, 0.11 1 mmol) and dioxane (6 mL). The mixture was sparged with Ar under sonication for 10 min. Pd2(dba)3 (0.051 g, 0.056 mmol) was added and the mixture was sparged with Ar under sonication for 10 minutes. The reaction was then stirred at 100 °C overnight. The reaction was allowed to cool to RT, diluted with EtOAc. The mixture was washed with water, dried over anhydrous Na2SC>4 and concentrated to dryness to afford a redish orange solid. The solid was chromatographed (0-5% MeOH/EtOAc) to afford a white solid. The product was suspended in CH3CN / H20, frozen and lyopholized to provide N-(4-((6-(3-(tert-butyl)-5-oxo-4,5-dihydro-lH- l,2,4-triazol-l-yl)-2-methylpyridin-3-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide as a fluffy white solid. (0.120g, 26.4%) 1H MR (400 MHz, OMSO-d6) 11.98 (s, 1 H), 10.88 (s, 1 H), 8.20 (d, J = 5.7 Hz, 1 H), 7.85 (d, J = 8.8 Hz, 1 H), 7.69 (d, J = 8.8 Hz, 1 H), 7.54 (d, J = 2.4 Hz, 1 H), 6.70 (dd, J = 5.7, 2.4 Hz, 1 H), 2.28 (s, 3 H), 1.98-1.90 (m, 1 H), 1.27 (s, 9 H), 0.77-0.72 (m, 4 H); MS (ESI) m/z: 409.2 (M+H+).
Figure imgf000152_0001
Example 46: Example C8 (0.60 g, 3.50 mmol), Example Al (1.20 g, 3.50 mmol), and K2C03 (2.50 g, 18.1 mmol) were suspended in DMF (4.5 mL). The mixture was sonicated and sparged with Ar for 10 min followed by sequential addition of copper(I) iodide (0.13 g, 0.70 mmol) and N,N-dimethylethane- 1 ,2-diamine (0.06 g, 0.70 mmol). The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was partitioned between sat. NH4C1 (aq) (100 mL) and EtOAc (150 mL) and the resultant biphasic solution was mixed vigously for 10 min. The organic phase was collected and the aqueous phase was extracted with EtOAc (5 x 50 mL) and the combined organics were dried (Na2SC>4) and concentrated in vacuo. The residue was triturated with MeCN (5 mL), sonicated, and the resultant white solid was collected by filtration to afford l-(5-((2- chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-( 1 -methoxy-2-methylpropan-2-yl)- 1 H- 1 ,2,4- triazol-5(4H)-one (1.12 g, 82 %) as a white solid. 1H NMR (400 MHz, DMSO-i¾: δ 11.93 (s, 1 H), 8.29 (d, J = 5.8 Hz, 1 H), 7.86 (d, J = 8.8 Hz, 1 H), 7.74 (d, J = 8.8 Hz, 1 H), 7.06 (d, J = 2.3 Hz, 1 H), 6.96 (dd, J = 5.8, 2.3 Hz, 1 H), 3.39 (s, 2 H), 3.24 (s, 3 H), 2.31 (s, 3 H), 1.24 (s, 6 H); MS (ESI) m/z: 390.2 (M+H+). [0422] l-(5-((2-Chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-(l-methoxy-2- methylpropan-2-yl)-lH-l,2,4-triazol-5(4H)-one (0.10 g, 0.26 mmol), l-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.07 g, 0.33 mmol), and K2C03 (0.09 g, 0.66 mmol) were suspended in a solution of dioxane (2.0 mL) and water (0.4 mL). The suspension was sonicated and sparged with Ar for 10 min followed by the addition of Pd(PPh3)4 (0.03 g, 0.026 mmol). The reaction mixture was stirred at 85 °C for 12 h, allowed to cool to RT, diluted with water (2.0 mL), and extracted with EtOAc (5 x 3 mL). The combined organics were dried (Na2SC>4) and concentrated in vacuo to afford an orange oil. The residue was purified by silica gel chromatography (MeOH/DCM) to afford 3-(l-methoxy-2-methylpropan-2-yl)-l-(6-methyl- 5-((2-(l -methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one (0.085 g, 76 %) as a white solid. 1H NMR (400 MHz, DMSO-c¼): δ 11.93 (s, 1 H), 8.37 (d, J = 5.7 Hz, 1 H), 8.26 (s, 1 H), 7.96 (s, 1 H),7.85 (d, J = 8.8 Hz, 1 H), 7.69 (d, J = 8.8 Hz, 1 H), 7.18 (d, J = 2.4 Hz, 1 H), 6.65 (dd, J = 5.7, 2.5 Hz, 1 H), 3.84 (s, 3 H), 3.39 (s, 2 H), 3.25 (s, 3 H), 2.33 (s, 3 H), 1.24 (s, 6 H); MS (ESI) m/z: 436.2 (M+H+).
Figure imgf000153_0001
Example 47: 2-Methylpyridin-3-ol (3.00 g, 27.5 mmol) was dissolved in a solution of Na2C03 (5.83 g, 55.0 mmol) in water (48 mL) and MeOH (30 mL). Iodine (6.98 g, 27.5 mmol) was added and the reaction mixture was stirred for 1 h at RT. The mixture was treated with 2 M HC1 solution (14 mL) and the resultant suspension was extracted with EtOAc (2 x 65 mL). The combined organics were washed with brine, dried (Na2S04) and concentrated. The residue was slurried with DCM (20 mL) and the resultant solid was collected to afford 6-iodo-2- methylpyridin-3-ol (3.6 g, 55.7% yield) as a white solid. !H NMR (400 MHz, CDC13): δ 7.41 (d, J = 8.26 Hz, 1 H), 6.78 (d, J = 8.26 Hz, 1 H), 5.03 (br s, 1 H), 2.47 (s, 3 H); MS (ESI) m/z: 236.0 (M+H+).
[0423] 6-Iodo-2-methylpyridin-3-ol (2.00 g, 8.51 mmol) and 4,6-dichloropyrimidine (5.00 g, 33.6 mmol) were dissolved in DMA (40 mL) and sonicated and sparged with Ar for 10 min. K2C03 (2.00 g, 14.5 mmol) was added and the reaction mixture was stirred at 1 10 °C for 16 h. The mixture was partitioned between water (260 mL) and EtOAc (100 mL). The solids were removed by filtration through a pad of diatomaceous earth. The filter cake was washed with EtOAc (3 x 25 mL). The organic phase was collected and the aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organics were dried ( a2S04) and concentrated in vacuo to afford 4-chloro-6-((6-iodo-2-methylpyridin-3-yl)oxy)pyrimidine (2.8 g, 95 %) as a yellow solid. !H NMR (400 MHz, DMSO-i¾: δ 8.63 (s, 1 H), 7.77 (d, J = 8.3 Hz, 1 H), 7.57 (s, 1 H), 7.41 (d, J = 8.3 Hz, 1 H), 2.25 (s, 3 H). MS (ESI) m/z: 348.0 (M+H+).
[0424] Example CI (0.20 g, 1.42 mmol), 4-chloro-6-((6-iodo-2-methylpyridin-3- yl)oxy)pyrimidine (0.50 g, 1.44 mmol), and K2C03 (1.10 g, 7.94 mmol) were suspended in MeCN (14 mL). The suspension was sonicated and sparged with Ar for 10 min. Copper(I) iodide (0.055 g, 0.29 mmol) and N,N-dimethylethane-l ,2-diamine (0.020 g, 0.14 mmol) were added and the reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with sat. NH4CI (aq) (20 mL), filtered, and concentrated in vacuo. The aqueous suspension was extracted with EtOAc (5 x 15 mL) and the combined organics were dried (Na2SC>4) and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc/DCM followed by MeOH/EtOAc) to afford 3-(tert-butyl)-l -(5-((6-chloropyrimidin-4-yl)oxy)-6-methylpyridin-2- yl)-lH- l ,2,4-triazol-5(4H)-one (0.10 g, 19.3 %) as a white solid. 1H NMR (400 MHz, DMSO- δ 1 1.96 (s, 1 H), 8.64 (d, J = 0.9 Hz, 1 H), 7.81 (d, J = 8.8 Hz, 1 H), 7.75 (d, J = 8.8 Hz, 1 H), 7.55 (s, 1 H), 2.28 (s, 3 H), 1.26 (s, 9 H); MS (ESI) m/z: 361.1 (M+H+).
[0425] 3-(ieri-Butyl)- l-(5-((6-chloropyrimidin-4-yl)oxy)-6-methylpyridin-2-yl)-lH-l ,2,4- triazol-5(4H)-one (0.10 g, 0.28 mmol), l -methyl-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)-lH-pyrazole (0.08 g, 0.36 mmol), and K2C03 (0.10 g, 0.72 mmol) were suspended in a solution of dioxane (2.5 mL) and water (0.50 mL). The suspension was sonicated and sparged with Ar for 10 min. Pd(PPh3)4 (0.032 g, 0.028 mmol) was added and the reaction mixture was stirred at 85 °C for 16 h. The mixture was diluted with sat. NH4CI (aq) 5 mL) and the resultant emulsion was extracted with EtOAc (4 x 10 mL). The combined organics were dried (Na2SC>4) and concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM) to afford a brown amorphous solid that was triturated with MeCN (1.5 mL). A white precipitate formed following sonication and was isolated by filtration and dried to afford 3- (tert-butyl)- 1 -(6-methyl-5-((6-( 1 -methyl- 1 H-pyrazol-4-yl)pyrimidin-4-yl)oxy)pyridin-2-yl)- 1 H-
I , 2,4-triazol-5(4H)-one (0.055 g, 48.3 %) as a white solid. !H NMR (400 MHz, DMSO-i¾: δ
I I .95 (s, 1 H), 8.61 (d, J = 1.1 Hz, 1 H), 8.48 (s, 1 H), 8.17 (s, 1 H), 7.80 (d, J = 8.7 Hz, 1 H), 7.73 (d, J = 8.7 Hz, 1 H), 7.46 (d, J = 1.1 Hz, 1 H), 3.89 (s, 3 H), 2.29 (s, 3 H), 1.27 (s, 9 H); MS (ESI) m/z: 420.3 (M+H+).
Figure imgf000156_0001
Example 48: A round bottom flask was charged with Example A12 (2.4 g, 6.69 mmol), 1 - methyl-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole (1.531 g, 7.36 mmol), K2CO3 (1.017 g, 7.36 mmol), dioxane (40 mL) and water (10 mL) and spargd with Ar under sonication for ~ 10 minutes. Pd(PPh3)4 (0.309 g, 0.268 mmol) was added and the reaction was sparged again with Ar under sonication for ~ 10 minutes and then heated to 100 °C overnight. The reaction mixture was allowed to cool to RT, and extracted with EtOAc and sat'd NaHC03. The Aqeous layer was back-extracted with EtOAc (3x), the organic phases combined, dried ( a2S04) and concentrated to dryness to afford a white solid. The solid was suspended in MeCN, sonicated and the solids were collected by filtration, washed with MeCN, and dried in the vaccum oven to afford 4-(tert-butyl)-l -(6-methyl-5-((2-(l-methyl-lH-pyrazol-4-yl)pyridin-4- yl)oxy)pyridin-2-yl)- lH-imidazol-2(3H)-one as a white solid (1.89 g, 69.9%). !H NMR (400 MHz, DMSO-i¼): 10.59 (d, J = 2.5 Hz, 1 H), 8.36 (d, J = 5.7 Hz, 1 H), 8.26-8.25 (m, 2 H), 7.96 (s, 1 H), 7.67 (d, J = 8.9 Hz, 1 H), 7.16 (d, J = 2.4 Hz, 1 H), 6.87 (d, J = 2.5 Hz, 1 H), 6.62 (dd, J = 5.7, 2.4 Hz, 1 H), 3.84 (s, 3 H), 2.31 (s, 3 H), 1.19 (s, 9 H); MS (ESI) m/z: 405.2 (M+H+).
Figure imgf000157_0001
Example 49: A mixture of Example A4 (0.20 g, 0.67 mmol) in DCM (4 mL) was cooled in an ice-water bath and treated with trimethylacetyl chloride (0.16 g, 1.35 mmol). The mixture was allowed to warm up to RT and stirred for 30 min. The reaction mixture was cooled to 0 °C and then diluted with DCM (4 mL). Triethylamine (0.5 mL, 3.61 mmol) was added and then a solution of triphosgene (80 mg, 0.26 mmol) in DCM (4 mL) was added drop-by-drop under the same conditions. The reaction mixture was allowed to warm to RT and stirred at RT overnight. The mixture was quenched with NaHC03 solution and extracted with DCM (2x). The organic was dried over Na2SC>4, filtered and concentrated in vacuo. The crude product was purified via silica gel chromatography (EtOAc) to obtain 5-(tert-butyl)-3-(6-methyl-5-((2-(l -methyl-lH- pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-l ,3,4-oxadiazol-2(3H)-one (1 14 mg, 37.8%). !H NMR (400 MHz, DMSO-i¾ : δ 8.39 (d, J = 5.7 Hz, 1 H), 8.27 (s, 1 H), 7.97 (s, 1 H), 7.78 (d, J = 8.7 Hz, 1 H), 7.70 (d, J = 8.8 Hz, 1 H), 7.23 (d, J = 2.4 Hz, 1 H), 6.67 (dd, J = 5.7, 2.4 Hz, 1 H), 3.85 (s, 3 H), 2.37 (s, 3 H), 1.33 (s, 9 H); MS (ESI) m/z: 407.2 (M+H+).
[0426] The following assays demonstrate that certain compounds of Formula I inhibit kinase activity of c-FMS kinase, c-KIT kinase, or PDGFRP kinase in enzymatic asssays and also inhibit the activity of c-FMS kinase in M-NFS-60 and THP- 1 cell lines. In vivo evaluations of certain compounds of Formula I also demonstrate inhibition of c-FMS in a pharmcodynamic model or also exhibit efficacy in a peritibial implant model, a U-251 or GL-261 glioma model, or in a MDA-MB-231 breast cancer xenograft model. uFMS kinase (Seq. ID No. 1) Assay
[0427] Activity of unphosphorylated c-FMS kinase (uFMS, Seq. ID no. 1) was determined by following the production of ADP from the FMS kinase reaction with ATP and poly E4Y as substrates through coupling with the pyruvate kinase/lactate dehydrogenase system (e.g., Schindler et al. Science (2000) 289: 1938-1942). In this assay, the oxidation of NADH (thus the decrease at A340nm) was continuously monitored spectrophometrically. The reaction mixture (100 contained FMS (purchased from Millipore) (10 nM), polyE4Y (1 mg/mL), MgCl2 (10 mM), pyruvate kinase (4 units), lactate dehydrogenase (0.7 units), phosphoenol pyruvate (1 mM), NADH (0.28 mM) and ATP (500 μΜ) in 90 mM Tris buffer containing 0.2 % octyl- glucoside and 1 % DMSO, pH 7.5. The inhibition reaction was started by mixing serial diluted test compound with the above reaction mixture. The absorption at 340 nm was monitored continuously for 4 hours at 30 °C on Synergy 2 plate reader. The reaction rate was calculated using the 3 to 4 h time frame. Percent inhibition was obtained by comparison of reaction rate with that of a control (i.e. in the absence of test compound). IC50 values were calculated from a series of percent inhibition values determined at a range of inhibitor concentrations using software routines as implemented in the GraphPad Prism software package.
uFMS Kinase sequence (Y538-end) used for screening (Seq. ID No. 1)
YKYKQKPKYQ VRWKIIESYE GNSYTFIDPT QLPYNEKWEF PRNNLQFGKT
LGAGAFGKW EATAFGLGKE DAVLKVAVKM LKSTAHADEK EALMSELKIM
SHLGQHENIV NLLGACTHGG PVLVITEYCC YGDLLNFLRR KAEAMLGPSL
SPGQDPEGGV DYKNIHLEKK YVRRDSGFSS QGVDTYVEMR PVSTSSNDSF
SEQDLDKEDG RPLELRDLLH FSSQVAQGMA FLASKNCIHR DVAARNVLLT NGHVAKIGDF GLARDIMNDS NYIVKGNARL PVKWMAPESI FDCVYTVQSD VWSYGILLWE IFSLGLNPYP GILV SKFYK LVKDGYQMAQ PAFAPK IYS IMQACWALEP THRPTFQQIC SFLQEQAQED RRERDYTNLP SSSRSGGSGS SSSELEEESS SEHLTCCEQG DIAQPLLQPN NYQFC
uKit kinase (Seq. ID No. 2) assay
[0428] Activity of unphosphorylated c-KIT kinase (uKIT, Seq. ID no. 2) was determined by following the production of ADP from the KIT kinase reaction with ATP and poly E4Y as substrates through coupling with the pyruvate kinase/lactate dehydrogenase system (e.g., Schindler et al. Science (2000) 289: 1938-1942). In this assay, the oxidation of NADH (thus the decrease at A340nm) was continuously monitored spectrophometrically. The reaction mixture (100 μΐ) contained unphosphorylated KIT (12 nM), polyE4Y (1 mg/mL), MgCl2 (10 mM), pyruvate kinase (4 units), lactate dehydrogenase (0.7 units), phosphoenol pyruvate (1 mM), and NADH (0.28 mM) and ATP (2000 μΜ) in 90 mM Tris buffer containing 0.2 % octyl-glucoside and 1% DMSO, pH 7.5. The inhibition reaction was started by mixing serial diluted test compound with the above reaction mixture. The absorption at 340 nm was monitored continuously for 4 hours at 30 °C on Synergy 2 plate reader (BioTech). Reaction rates around 3 to 4 h time frame were used to calculate % inhibitions, from which IC50 values were generated.
uKit with N-terminal GST fusion used for screening (Seq ID No. 2)
LGYWKIKGLV QPTRLLLEYL EEKYEEHLYE RDEGDKWRNK KFELGLEFPN
LPYYIDGDVK LTQSMAIIRY IADKHNMLGG CPKERAEISM LEGAVDIRYG
VSRIAYSKDF ETLKVDFLSK LPEMLKMFED RLCHKTYLNG DHVTHPDFML
YDALDWLYM DPMCLDAFPK LVCFKKRIEA IPQIDKYLKS SKYIWPLQGW
QATFGGGDHP PKSDLVPRHN QTSLYKKAGS AAAVLEENLY FQGTYKYLQK
PMYEVQWKW EEINGNNYVY IDPTQLPYDH KWEFPRNRLS FGKTLGAGAF
GKWEATAYG LIKSDAAMTV AVKMLKPSAH LTEREALMSE LKVLSYLGNH MNIVNLLGAC TIGGPTLVIT EYCCYGDLLN FLRRKRDSFI CSKQEDHAEA
ALYK LLHSK ESSCSDSTNE YMDMKPGVSY VVPT AD RR SVRIGSYIER
DVTPAIMEDD ELALDLEDLL SFSYQVAKGM AFLASK CIH RDLAARNILL
THGRITKICD FGLARDIK D SNYVV GNAR LPVKWMAPES IFNCVYTFESD
VWSYGIFLWE LFSLGSSPYP GMPVDSKFYK MIKEGFRMLS PEHAPAEMYD
IMKTCWDADP LKRPTFKQIV QLIEKQISES TNHIYSNLAN CSPNPvQKPW
DHSVRINSVG STASSSQPLL VHDDV
Unphosphorylated PDGFRB (uPDGFRB) kinase (Sea. ID No. 3 assay
[0429] Activity of unphosphorylated PDGFRp kinase (uPDGFRp, Seq. ID No. 3) was determined by following the production of ADP from the kinase reaction with ATP and poly E4Y as substrates through coupling with the pyruvate kinase/lactate dehydrogenase system (e.g., Schindler et al. Science (2000) 289: 1938-1942).. In this assay, the oxidation of NADH (thus the decrease at A340nm) was continuously monitored spectrophometrically. The reaction mixture (100 μί) contained PDGFRp (DeCode, 15.7 nM), polyE4Y (2.5 mg/mL), MgCl2 (10 mM), pyruvate kinase (4 units), lactate dehydrogenase (0.7 units), phosphoenol pyruvate (1 mM) and NADH (0.28 mM) and ATP (500 μΜ) in a 90 mM Tris buffer containing 0.2% octyl-glucoside and 1% DMSO, at pH 7.5. The inhibition reaction was started by mixing serial diluted test compound with the above reaction mixture. The absorption at 340 nm was monitored continuously for 4 h at 30 °C on a Polarstar Optima or Synergy 2 plate reader. The reaction rate was calculated using the 1.5 to 2.5 h time frame. Percent inhibition was obtained by comparison of reaction rate with that of a control (i.e. with no test compound). IC50 values were calculated from a series of percent inhibition values determined at a range of inhibitor concentrations using software routines as implemented in the GraphPad Prism software package. uPDGFR Kinase Sequence (residues 557-1106) used for screening (Seq ID No. 3)
QKKP RYEIRW KVIE SVSSDG HEYI YVDPMQ LPYDSTWELP RDQLVLGRTL
GSGAFGQWE ATAHGLSHSQ ATMKVAVKML KSTARSSEKQ ALMSELKIMS
HLGPHLNWN LLGACTKGGP IYIITEYCRY GDLVDYLHRN KHTFLQHHSD
KRRPPSAELY SNALPVGLPL PSHVSLTGE SDGGYMDMSK DESVDYVPML
DMKGDVKYAD IESSNYMAPY DNYVPSAPER TCRAT LINES PVLSYMDLVG
FSYQVANGME FLASKNCVHR DLAARNVLIC EGKLVKICDF GLARDIMRDS
NYISKGSTFL PLKWMAPESI FNSLYTTLSD VWSFGILLWE IFTLGGTPYP
ELPMNEQFYN AIKRGYRMAQ PAHASDEIYE IMQKCWEEKF EIRPPFSQLV
LLLERLLGEG YKKKYQQVDE EFLRSDHPAI LRSQARLPGF HGLRSPLDTS
SVLYTAVQPN EGDNDYIIPL PDPKPEVADE GPLEGSPSLA SSTLNEVNTS
STISCDSPLE PQDEPEPEPQ LELQVEPEPE LEQLPDSGCP APRAEAEDSF
L
[0430] Using the enzymatic protocols described above, compounds of Formula I were shown to be inhibitors in assays measuring the kinase activity of uFMS kinase, uKIT kinase, or uPDGFRP kinase, as indicated below in Table 1.
Table 1. Activity of Compounds of Formula I in Enyzmatic Assays of uFMS kinase, uKIT kinase, or uPDGFRp kinase.
Figure imgf000161_0001
10 +++ + +
11 +++ + +
12 +++ ++ +
13 +++ ++ +
14 ++++ +++ +
15 +++ + +
16 +++ + +
17 ++ + NT
18 +++ ++ +
19 +++ + +
20 ++++ ++ +
21 ++ + +
22 ++++ +++ +
23 +++ + +
24 ++ + +
25 ++++ +++ +
26 +++ + +
27 ++++ ++ +
28 ++++ +++ +
29 +++ ++ +
30 +++ + +
31 ++++ +++ ++
32 +++ +++ ++
33 +++ ++ ++
34 ++++ ++++ +++
35 ++ ++ +
36 ++++ +++ ++
37 ++++ ++ ++
38 ++++ + +
39 +++ + +
40 +++ ++ +
41 ++ + +
42 +++ + +
43 ++++ +++ ++
44 ++ ++ ++
45 ++ + +
46 +++ ++ +
47 +++ + +
48 +++ + +
49 +++ ++ + NT: Not Tested; +: IC50 > 1 uM; ++: 0.1 uM < IC50 < 1 uM; +++: 0.01 uM < IC50 < 0.1 uM; ++++: IC50 < 0.01 uM
M-NFS-60 Cell Culture
[0431] M-NFS-60 cells (catalog #CRL-1838) were obtained from the American Type Culture Collection (ATCC, Manassas, VA). Briefly, cells were grown in suspension in RPMI 1640 medium supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, CA), 0.05 mM 2-mercaptoethanol, and 20 ng/mL mouse recombinant macrophage colony stimulating factor (M-CSF) at 37 °C, 5%C02, and 95% humidity. Cells were allowed to expand until reaching saturation at which point they were subcultured or harvested for assay use.
M-NFS-60 Cell Proliferation Assay
[0432] A serial dilution of test compound was dispensed into a 384-well black clear bottom plate (Corning, Corning, NY). Two thousand five hundred cells were added per well in 50 μL complete growth medium. Plates were incubated for 67 h at 37 °C, 5%C02, and 95% humidity. At the end of the incubation period 10 μΐ. of a 440 μΜ solution of resazurin (Sigma, St. Louis, MO) in PBS was added to each well and incubated for an additional 5 h at 37 °C, 5% C02, and 95% humidity. Plates were read on a Synergy2 reader (Biotek, Winooski, VT) using an excitation of 540 nM and an emission of 600 nM. IC50 values were calculated from a series of percent inhibition values determined at a range of inhibitor concentrations using software routines as implemented in the GraphPad Prism software package.
THP-1 Cell Culture
[0433] THP-1 cells (catalog #TIB-202) were obtained from the ATCC. Briefly, cells were grown in RPMI 1640 supplemented with 10% characterized fetal bovine serum, 1% sodium pyruvate, 1% Penicillin-Streptomycin-Glutamine (PSG) and 55uM 2-mercaptoethanol (Invitrogen, Carlsbad, CA) at 37 degrees Celsius, 5% C02, 95% humidity. Cells were allowed to expand until reaching 70-95% confluency at which point they were subcultured or harvested for assay use.
Phospho-FMS ELISA Assay
[0434] A serial dilution of test compound was diluted 1 : 100 in assay medium (RPMI 1640 supplemented with 10% characterized fetal bovine serum) in a 96 well black clear bottom plate (Corning, Corning, NY). In a separate 96 well black clear bottom plate, one hundred and fifty thousand THP-1 cells were added per well in 100 μL· in assay medium. Fifty microliters of diluted compound was then added to the cells. Plates were incubated for 4 hours at 37 degrees Celsius, 5% C02, 95% humidity. At the end of the incubation period, cells were stimulated with 50 μΐ. of a 100 nM solution of recombinant human M-CSF (catalog #216-MC, R & D Systems, Minneapolis, MN) in assay medium and the plate was incubated for 5 minutes at 37 degrees Celsius, 5% C02, 95% humidity. Lysates were prepared and used to perform the phospho-FMS ELISA as described by the manufacturer (catalog #DYC3268, R & D Systems, Minneapolis, MN). GraphPad Prism was used to calculate IC50 values obtained from data generated from the ELISA assay. Osteoclast Tartrate-Resistant Acid Phosphatase Assay
[0435] A serial dilution of test compound was dispensed into a 384-well black clear bottom plate ( alge Nunc International, Rochester, NY). Compound was diluted by the addition of DMEM media supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, CA). Diluted compound was transferred to a 384-well black clear bottom plate. Two-thousand five hundred osteoclast precursors (Lonza, Walkersville, MD) were added per well in growth media containing Receptor Activator of Nuclear Factor Kappa-beta ligand (RANKL) and M- CSF (R&D Systems, Minneapolis, MN). Plates were incubated for 7-14 days at 37 degrees Celsius, 5% C02, and 95% humidity to allow differentiation of osteoclast precursors. At the end of the incubation period, 10 of supernatant from each well was transferred to a clear 384-well plate. Tartrate-resistant acid phosphatase activity in the supernatant samples was determined using an acid phosphatase assay kit (Sigma, St. Louis, MO). Absorbance was measured at 550 nm using a plate reader. Data was analyzed using Prism software (Graphpad, San Diego, CA) to calculate IC5o values.
[0436] The compounds of Formula I were demonstrated to be functional inhibitors in one or more of the cellular assays described above, as indicated in Table 2.
Table 2. Inhibitory effects of compounds of Formula I versus M-NFS-60, THP-1 and
Osteoclast Cells
Example M-NFS-60 cell Osteoclast pFMS inhibition in
proliferation assay THP-1 cells
1 +++ +++ +++
2 +++ +++ ++++
3 +++ +++ +++
4 +++ +++ +++ 5 +++ +++ +++
6 ++++ +++ ++++
7 +++ +++ +++
8 ++ ++ NT
9 +++ +++ +++
10 +++ +++ +++
1 1 ++ ++ NT
12 +++ +++ NT
13 ++ ++ ++
14 +++ ++++ +++
15 + ++ NT
16 ++ +++ ++
17 + + NT
18 ++ ++ NT
19 ++ ++ NT
20 ++ ++ ++
21 + ++ NT
22 ++++ +++ ++++
23 ++ +++ NT
24 ++ ++ NT
25 +++ +++ +++
26 + ++ NT
27 +++ +++ +++
28 +++ +++ NT
29 ++ ++ NT
30 + +++ ++
31 +++ +++ +++
32 ++ ++ NT
33 ++ ++ +++
34 ++++ +++ NT
35 + ++ NT
36 +++ +++ +++
37 +++ ++++ ++++
38 +++ +++ ++
39 +++ +++ ++
40 +++ +++ NT
41 + ++ NT
42 + ++ NT
43 ++ +++ ++
44 ++ ++ NT 45 ++ +++ NT
46 ++ +++ ++
47 ++ +++ +++
48 +++ +++ +++
49 +++ +++ +++
NT: Not Tested; +: IC50 > 1 uM; ++: 0.1 uM < IC50 < 1 uM; +++: 0.01 uM < IC50 < 0.1 uM; ++++: IC50 < 0.01 uM
Measurements of in vivo Activity
Analysis of cFOS mRNA production in a c-FMS mouse spleen pharmacodynamic model
[0437] To examine the in vivo modulation of FMS activity by compounds of Formula I, spleen samples from female DBA/1 mice were collected and analyzed for M-CSF stimulated production of cFOS mRNA. Briefly, six to seven week old female Taconic DBA/1 BO J Bom
Tac mice were treated with a single oral dose (by gavage) of either vehicle or compound. Plasma and spleen samples were collected from four mice at each timepoint 2, 4, 6, 8, 12, 18, and 24 hours after dosing. Fifteen minutes prior to euthanasia, all mice were injected IV with ^g (100 uL fixed volume) of M-CSF. M-CSF, Recombinant Mouse Macrophage Colony Stimulating
Factor (36.4 kDa homodimer, >98% purity) was obtained from Gibco. All procedures carried out in this experiment were conducted in compliance with all the laws, regulations and guidelines of the National Institutes of Health (NIH). cFOS mRNA levels in spleen extracts were determined using a quantitative reverse transcriptase PCR kit from Life Technologies.
Plasma levels of FMS inhibitors were determined by mass spectrometer analysis. The degree of FMS inhibition was correlative to the amount of decrease observed in cFOS mRNA levels in the spleen samples of treated animals compared to vehicle.
[0438] In this model, Examples 7, 9, 25 and 48 afforded >70% inhibition of cFOS mRNA levels out to 8 h post 30 mg/kg dose.
PC-3 peritibial implant model of cancer bone metastasis
[0439] To evaluate in vivo anti-cancer activity of compounds of Formula I, the PC-3 M-luc peritibial injection model of bone invasiveness model is employed. Briefly, PC-3 M-luc cells are obtained from Xenogen Corporation (Caliper Life Sciences) and expanded using MEM media modified with L-Glutamine (Cell Gro® #10-045-CV) supplemented with 10% fetal bovine serum, 1% penicillin-streptomycin-glutamine, 1% non-essential amino acids, and 1% MEM vitamins in 5%C02 atmosphere at 37°C. Six to 7 week old male nude mice (Crl:NU-Foxnlnu ) are obtained from Charles River Laboratories. Test mice are implanted peritibially on Day 0 with lxlO6 cells/mouse (O.lmL) using an insulin syringe with a fixed 28-gauge needle. The needle is inserted at the ankle between the tibia and fibula until the bevel of the needle reaches approximately half way between the knee and ankle. Treatments begin on Day 0. Animals are dosed by oral gavage twice daily for the study duration. All procedures carried out in this experiment are conducted in compliance with all the laws, regulations and guidelines of the National Institutes of Health (NIH). When the primary tumor reaches approximately 800 mg in size, ex-vivo micro-CT is performed on the tumor bearing fixed hind limb samples using a GE RSI 50 small animal micro-CT scanner using with the following settings:
X-ray tube voltage = 70k Vp
X-ray tube current = 25 niA Exposure time = 20ms
Number of frames = 500
Angle increment between frames = 0.4o
Number of averages per frame = 2
Acquisition method = Parker
[0440] Images are then reconstructed at high resolution (100 microns; isotropic). Isosurface volume renderings are used to delineate lesions in the hind limbs. A constant threshold is used to produce consistent representation of the isosurface between different anatomical sites and samples. Lesions in the right hind limb are scored with values of 0, 1, 2, 3, or 4 based on a qualitative assessment of lesion size as defined by:
0: Normal Bone
1 : Minimal lesions. Some roughening of the isosurface. Small areas of apparent bone resorption.
2: Mild. More numerous lesions. Significant roughening of the isosurface. Full thickness lesions apparent.
3: Moderate. Full thickness lesions larger and more numerous.
4: Marked. Many, large, full thickness lesions. Significant distortion of remaining structure. Marked bone loss.
U251 Intra-cerebro- ventricular implant in mice
[0441] To evaluate in vivo anti-cancer activity compounds of Formula I in combination with fractionated, localized head radiation, an orthotopic U251-luc (Luc) human glioma carcinoma model in female outbred nu/nu mice is employed. Briefly, U251 cells are obtained from the ATCC and altered to be luciferase expressing. They are grown in RPMI 1640 Media supplemented with 10% FBS and 1% PSG. The growth environment is maintained in an incubator with a 5% C02 atmosphere at 37°C. Female Harlan Nude mice (Hsd:AthymicNude- Foxlnu) 8-9 weeks old are used in this study. Test animals are implanted intracranially with U251-luc (LucmCherry) cells. Briefly, animals are injected subcutaneously with 5mg/kg carprofen and anesthetized using 2% isoflurane in air. The animals are then secured in a stereotaxic frame (ASIinstruments, Inc.) and a hole drilled 2mm right lateral, 1mm anterior to the coronal suture. The cell suspension (stored on wet ice) is mixed thoroughly and drawn up into a 50μ1 syringe. The syringe needle is centered over the burr hole and lowered 3mm into the brain and retracted 1mm to form a "reservoir" for the deposition of the cell suspension. ΙΟμΙ of the cell suspension (lxlO6 cells/mouse) is then injected slowly into the brain tissue. Tumor progression is tracked with in vivo bioluminescence imaging performed using an IVIS 50 optical imaging system (Xenogen, Alameda, CA). Bioluminescence images are acquired at periodic intervals for tumor burden estimation. All procedures carried out in this experiment are conducted in compliance with all the laws, regulations and guidelines of the National Institutes of Health (NIH). Treatment begins when the mean brain bioluminescence signal for all groups in the experiment is -1.3x109 photons/sec (typically 9 days post- implant). All mice receive 2Gy of radiation each day for five consecutive days from a RadSource RS-2000 irradiator. Additionally, mice receive test compound dosed by oral gavage or optionally with co-administered bevacizumab by tail vein injection. Bioluminescence images are acquired generally on days 8, 10, 14, 17, 21 , 22, 24, 28 and 35 post-implant for tumor burden estimation. For each measurement, each mouse is injected subcutaneously with 150mg/kg D-Luciferin (Promega) and imaged 10 minutes after the injection. Images are analyzed using Living Image (Xenogen, Alameda, CA) software. The BLI signal in the brain is calculated with a fixed area ROI to estimate the tumor burden. Average BLI signal for each group is compared to vehicle control to determine therapeutic benefit. Twenty-eight days after the first radiation treatment mice are euthanized, via over-exposure to carbon dioxide, for blood and brain collection. Whole blood is collected via terminal cardiac puncture and placed into EDTA Microtainer® tubes. Brains are excised and placed into 10% neutral buffered formalin.
GL261 intracranial implant model
[0442] To evaluate the in vivo anti-cancer activity of compounds of Formula I, an intracranial implant of GL261-luc2 murine glioma is employed. Briefly GL261-luc2 cells are obtained from Caliper Life Sciences, Inc and expaned in Dulbecco's Modified Eagle Media
(DMEM) which is supplemented with 10% FBS and 1% PSG. The growth environment is maintained in an incubator with a 5% C02 atmosphere at 37°C. Following expansion, cells are re-suspended using serum- free media to generate a concentration of 1x10 cells/mL. Six to seven week old female C57BL/6J- Tyrc-2J/J from Jackson Labs are implanted intracranially on
Day 0 with GL261 -luc2 cells. For aseptic surgical implantation, animals are injected subcutaneously with 5mg/kg carprofen, anesthetized using 2% isoflurane in air. The animals are then secured in a stereotaxic frame (ASIinstruments, Inc.) and a hole is drilled 2mm right lateral, lmm anterior to the coronal suture. The cell suspension (stored on wet ice) is mixed thoroughly and drawn up into a 50μL· syringe. The syringe needle is centered over the burr hole and lowered
3mm into the brain and retracted lmm to form a "reservoir" for the deposition of the cell suspension. Ι ΟμΙ^ of the cell suspension (lxl 06 cells/mouse) is then injected slowly into the brain tissue. Tumor progression is tracked with in vivo bioluminescence imaging performed using an IVIS 50 optical imaging system (Xenogen, Alameda, CA). Bioluminescence images are acquired at periodic intervals for tumor burden estimation. The quantity of emitted light from the tumor after systemic injection of D-Luciferin is expected to correlate with tumor size. Each mouse is injected intraperitoneally (IP) with 150mg/kg D-Luciferin and imaged in the prone position 10 minutes after the injection. Medium and small binning of the CCD chip is used, and the exposure time is adjusted (10 seconds to 1 minute) to obtain at least several hundred counts from the tumors and to avoid saturation of the CCD chip. Images are analyzed using Living Image (Xenogen, Alameda, CA) software. Each unique signal is circled manually and labeled by group and mouse number. Treatment begins by oral gavage of test compound when the mean brain bioluminescence signal for all groups in the experiment is 280xl06 photons/sec. All procedures carried out in this experiment are conducted in compliance with all the laws, regulations and guidelines of the National Institutes of Health (NIH).
[0443] At the end of study all mice are euthanized via over-exposure to carbon dioxide for blood and brain collection. Whole blood is collected via terminal cardiac puncture and placed into EDTA Microtainer® tubes. Brains are excised and placed into 10% neutral buffered formalin.
MDA-MB-231 xenograft study
[0444] To evaluate the in vivo anti-cancer activity compounds of Formula I, a MDA-MB-
231-luc-D3H2LN human breast carcinoma xenograft was employed. Briefly, MDA-MB-231- luc-D3H2LN cells were obtained from Xenogen and expanded in Minimal Essential Media
(MEM) with EBSS which was modified with 1% L-glutamine and supplemented with 10% FBS, 1% PSG, 1% non-essential amino acids, and 1% sodium pyruvate. The growth environment was maintained in an incubator with a 5% C02 atmosphere at 37°C. Cells were harvested and re- suspended using 50% serum-free media and 50% Matrigel® to generate a stock concentration of 5xl06cells/mL.
[0445] Six to 7 week old female C.B- 17/IcrHsd-PrkdcscidLystbg mice were injected with 200μL· of cell suspension subcutaneously, just below the right axilla. All procedures carried out in this experiment were conducted in compliance with all the laws, regulations and guidelines of the National Institutes of Health (NIH). Treatment began when the mean tumor burden is approximately 150 mg. All mice were dosed with test compound by oral gavage. Body weights and tumor measurements were recorded three times weekly. Tumor burden (mg) was estimated from caliper measurements by the formula for the volume of a prolate ellipsoid assuming unit density as: Tumor burden (mg) = (L x W2)/2, where L and W are the respective orthogonal tumor length and width measurements (mm). The primary endpoints to evaluate efficacy were %T/C. %T/C is defined as the median tumor mass of a Treated Group divided by the median tumor mass of the Control Group x 100. Ex vivo bioluminescence imaging was performed as animals exit the study, using an IVIS 50 optical imaging system (Xenogen, Alameda, CA). Animals were injected IP with 150mg/kg D-Luciferin (Promega) and euthanized 10 minutes following the injection. The primary tumor was removed and snap frozen for future analysis and the mouse opened and imaged in the supine position. Large binning of the CCD chip was used, and the exposure time is adjusted (1 to 2 minutes) to obtain at least several hundred counts from the tumors and to avoid saturation of the CCD chip. Images were analyzed using Living Image (Xenogen, Alameda, CA) software. Each unique signal was circled manually and labeled by group and mouse number. Total BLI signal was correlative to tumor size and compared to vehicle control to determine treatment benefit.
[0446] Example 7 exhibited 39% tumor growth inhibion in this model when orally dosed at 15 mpk twice daily.
Equivalents
[0447] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically in this disclosure. Such equivalents are intended to be encompassed in the scope of the following claims.

Claims

What is claimed is:
1. A compound of Formula I,
Figure imgf000175_0001
Formula I
or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein
A is selected from the group consisting of C1-C6 alkyl, branched C3-C8 alkyl, fluoroCl- C6alkyl wherein the alkyl is fully or partially fluorinated, C3-C8carbocyclyl, phenyl, 4-8 membered heterocyclic ring and heteroaryl, wherein each A moiety may be further substituted with one, two, or three R3 moieties;
W is C5-C6heteroaryl, phenyl, -NHC(0)R6, -NHC(0)R7, -NHC(0)N(R8)R9 or - C(0)N(R8)R9, and wherein each C5-C6heteroaryl or phenyl is optionally substituted by one, two, or three R5 moieties;
Ql is CH or ;
XI and X2 are individually and independently hydrogen, or C1-C6 alkyl;
Y is NR4 or O;
Z is N or CR11 ;
each Rl and R2 is individually and independently hydrogen, C1-C6 alkyl, deutero-Cl-C6 alkyl wherein the alkyl chain is partially or completely deuterated, fluoroC 1 -C6alkyl wherein the alkyl is fully or partially fluorinated, hydro xyl, C1-C6 alkoxy, fluoroCl-C6alkoxy wherein the alkyl group is fully or partially fluorinated, or halogen;
each R3 is individually and independently hydrogen, halogen, C1-C6 alkyl, fluoro-Cl-C6 alkyl wherein the alkyl chain is partially or completely fluorinated, branched C3-C8 alkyl, C3- C8 cycloalkyl, C1-C6 alkoxy, fluoro-Cl-C6 alkoxy wherein the alkyl chain is partially or completely fluorinated, branched C3-C6 alkoxy, hydroxyl, or cyano;
R4 is hydrogen, C1-C6 alkyl, deutero-Cl-C6 alkyl wherein the alkyl chain is partially or completely deuterated, or branched C3-C8 alkyl;
each R5 is individually and independently hydrogen, C1-C6 alkyl, deutero-Cl-C6 alkyl wherein the alkyl chain is partially or completely deuterated, branched C3-C8 alkyl, halogen, cyano, fluoro-Cl-C6 alkyl wherein the alkyl chain is partially or completely fluorinated, - (CH2)m-C(0)NR8(R9), -(CH2)m-C(0)R7, -(CH2)m-OR8, -(CH2)m-NR8(R9), or -(CH2)m-R7, wherein each alkylene is optionally substituted with C 1 -C4 alkyl;
Each R6 is individually and independently hydrogen, C1-C6 alkyl, branched C3-C8 alkyl, C3-C8 cycloalkyl, -(CH2)m-CN ,-(CH2)m-OR8, -(CH2)m-NR8(R9), or -(CH2)m-R7, wherein each alkylene is optionally substituted with C 1 -C4 alkyl; each R7 is inde endently and individually selected from the group consisting of
Figure imgf000176_0001
and wherein the symbol (##) is the point of attachment to respective W, R5 or R6 moieties containing a R7 moiety; each R7 is optionally substituted with -(R10)p; each R8 and R9 is individually and independently hydrogen, C1-C6 alkyl, fluoro-Cl-C6 alkyl wherein the alkyl chain is partially or completely fluorinated, or branched C3-C8 alkyl; each RIO is individually and independently C1-C6 alkyl, -(CH2)m-CN, -(CH2)m-OR3, - (CH2)m-NR8(R9), or -(CH2)m-C(0)-R6, wherein each alkyl or alkylene is optionally substituted with one or two C1-C6 alkyl;
wherein each alkylene is optionally substituted with C 1 -C4 alkyl; Rl 1 is hydrogen, C1-C6 alkyl, deutero-Cl-C6 alkyl wherein the alkyl chain is partially or completely deuterated, or branched C3-C8 alkyl; each m is individually and independently 0, 1, 2, or 3;
each n is individually and independently 0, 1, 2, or 3;
each p is 0, 1, 2, or 3; and
each q is 0, 1, or 2.
2. The compound of claim 1 , wherein W is selected from the group consisting of pyrazolyl, phenyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, triazolyl, pyridinyl, -NHC(0)R6, - NHC(0)R7, -NHC(0)N(R8)R9, or -C(0)N(R8)R9.
3. The compound of claim 2, wherein the compound is a compound of Formula la,
Figure imgf000177_0001
Formula la
or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof,
4. The compound of claim 3, wherein A is C1-C6 alkyl, branched C3-C8alkyl, C3- C8carbocyclyl, phenyl or a 4-8 membered heterocyclic ring and q is 0 or 1.
5. The compound of claim 4, wherein W is pyrazolyl or pyridinyl, optionally substituted with -(R5)p.
6. The compound of claim 5 wherein Y is NR4 and R4 is hydrogen.
7. The compound of claim 2, wherein the compound is a compound of Formula lb,
Figure imgf000178_0001
Formula lb
or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein the A moiety is selected from C1-C6 alkyl, branched C3-C8alkyl, C3- C8carbocyclyl, phenyl or a 4-8 membered heterocyclic ring.
8. The compound of claim 7, wherein W is pyrazolyl or pyridinyl, optionally substituted with -(R5)p.
9. The compound of claim 8, wherein R4 is hydrogen.
10. The compound of claim 1 , wherein the compound is a compound of Formula Ic,
Figure imgf000178_0002
Formula Ic
or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein q is 0 or 1.
11. The compound of claim 2, wherein the compound is a compound of Formula Id,
Figure imgf000179_0001
Formula Id
or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, The compound of claim 2, wherein the compound is a compound of Formula Ie,
Figure imgf000179_0002
Formula Ie
or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein the A moiety is selected from C1-C6 alkyl, branched C3-C8alkyl, C3- C8carbocyclyl, phenyl or a 4-8 membered heterocyclic ring.
13. The compound of claim 12, wherein W is pyrazolyl, optionally substituted with -(R5)p.
14. The compound of claim 13, wherein R4 is hydrogen.
The compound of claim 1 , wherein the compound is a compound of Formula If,
Figure imgf000180_0001
Formula If
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof,
wherein q is 0 or 1.
The compound of claim 2, wherein the compound is a compound of Formula Ig,
Figure imgf000180_0002
Formula Ig
or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein the A moiety is selected from C1-C6 alkyl, branched C3-C8alkyl, C3- C8carbocyclyl, phenyl or a 4-8 membered heterocyclic ring.
The compound of claim 16, wherein W is pyrazolyl or pyridinyl, optionally substituted with -(R5)p.
The compound of claim 1 , wherein the compound is a compound of Formula Ih,
Figure imgf000181_0001
Formula Ih
or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.
The compound of claim 1 is selected from the group consisting of 3-(4-fluorobenzyl)-l- (6-methyl-5-((2-(l -methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH- 1 ,2,4- triazol-5(4H)-one, 3-benzyl-l-(6-methyl-5-((2-(l -methyl- lH-pyrazol-4-yl)pyridin-4- yl)oxy)pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5(4H)-one, 3-(4-fluorobenzyl)- 1 - (5-((2-( 1 - methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one, 3- (tert-butyl)- 1 -(5-((2-( 1 -methyl- 1 H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)- 1 H- 1 ,2,4- triazol-5(4H)-one, 3-isopropyl-l-(6-methyl-5-((2-(l -methyl- lH-pyrazo l-4-yl)pyridin-4- yl)oxy)pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5(4H)-one, 3-cyclohexyl- 1 -(6-methyl-5-((2-( 1 - methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one, 3- (tert-butyl)- 1 -(6-methyl-5-((2-( 1 -methyl- 1 H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)- lH-l ,2,4-triazol-5(4H)-one, 3-(tert-butyl)-l-(6-ethyl-5-((2-(l-methyl-lH-pyrazol-4- yl)pyridin-4-yl)oxy)pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5(4H)-one, 3-(tert-butyl)- 1 -(6- methyl-5-((2'-methyl-[2,4'-bipyridin]-4-yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one, 3-(tert-butyl)-l-(6-methyl-5-((6'-methyl-[2,3'-bipyridin]-4-yl)oxy)pyridin-2-yl)-lH-l ,2,4- triazol-5(4H)-one, N-(4-((6-(3-(tert-butyl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-l-yl)-2- methylpyridin-3-yl)oxy)pyridin-2-yl)acetamide, 3-(tert-butyl)- 1 -(6-methyl-5-((2-(2- methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5(4H)-one, 3-(tert- butyl)-4-methyl- 1 -(6-methyl-5-((2-( 1 -methyl- 1 H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-
2- yl)- 1 H- 1 ,2,4-triazol-5(4H)-one, 3-(tert-butyl)- 1 -(6-methyl-5-((2-(4-( 1 - methylpiperidin-4-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5(4H)-one,
3- (2-methoxyethyl)- 1 -(6-methyl-5-((2-( 1 -methyl- 1 H-pyrazol-4-yl)pyridin-4- yl)oxy)pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5(4H)-one, 3-(2-methoxypropan-2-yl)- 1 -(6- methyl-5-((2-(l -methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol- 5(4H)-one, 3-(methoxymethyl)-l-(6-methyl-5-((2-(l -methyl- lH-pyrazol-4-yl)pyridin-
4- yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one, 3-(tert-butyl)-l-(5-((2-(l-(2- hydroxyethyl)- 1 H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-methylpyridin-2-yl)- 1 H- 1 ,2,4- triazol-5(4H)-one, 3-(tert-butyl)- 1 -(6-methyl-5-((2-(4-methyl- 1 H-imidazol- 1 - yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-l,2,4-triazol-5(4H)-one, l-(6-methyl-5-((2-(l- methyl-lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)- 1 H- 1 ,2,4-triazol-5(4H)-one, N-(4-((6-(3-(tert-butyl)-5-oxo-4,5-dihydro- 1 H- 1 ,2,4- triazol- 1 -yl)-2-methylpyridin-3-yl)oxy)pyridin-2-yl)- 1 -methylpiperidine-4-carboxamide, 3-isobutyl-l-(6-methyl-5-((2-(l -methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)- lH-l ,2,4-triazol-5(4H)-one, 3-(tert-butyl)-l-(6-methyl-5-((2-(l -methyl- lH-imidazo 1-4- yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-l,2,4-triazol-5(4H)-one, l-(5-((2-(lH-pyrazol-4- yl)pyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-(tert-butyl)-lH-l,2,4-triazol-5(4H)-one, l-(6-methyl-5-((2-(l -methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-3-(tert- pentyl)-lH-l ,2,4-triazol-5(4H)-one, 4-((6-(3-(tert-butyl)-5-oxo-4,5-dihydro-lH- 1,2,4- triazol-l-yl)pyridin-3-yl)oxy)-N-methylpicolinamide, 1 -(6-methyl-5-((2-(l -methyl- 1 H- pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-3-(l-methylcyclopropyl)-lH-l ,2,4-triazol- 5(4H)-one, 3-(4-fluorophenyl)-l-(6-methyl-5-((2-(l -methyl- lH-pyrazo l-4-yl)pyridin-4- yl)oxy)pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5(4H)-one, 3-(4-fluorophenyl)- 1 -(6-methyl-5-((2- (4-methyl- 1 H-imidazol- 1 -yl)pyridin-4-yl)oxy)pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5(4H)-one, 3-(4-((6-(3-(tert-butyl)-5-oxo-4,5-dihydro-lH-l ,2,4-triazol-l-yl)-2-methylpyridin-3- yl)oxy)pyridin-2-yl)- 1 , 1 -dimethylurea, 3-(tert-butyl)- 1 -(4-methyl-5-((2-( 1 -methyl- 1 H- pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one, N-(4-((6-(3- (4-fluorophenyl)-5-oxo-4,5-dihydro- 1H- 1 ,2,4-triazol- 1 -yl)-2-methylpyridin-3- yl)oxy)pyridin-2-yl)cyclopropanecarboxamide, 3-(tert-butyl)-l-(4,6-dimethyl-5-((2-(l- methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one, 3- cyclopentyl-l-(6-methyl-5-((2-(l -methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2- yl)- 1 H- 1 ,2,4-triazol-5(4H)-one, 3-cyclopropyl- 1 -(6-methyl-5-((2-( 1 -methyl- 1 H- pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one, l-(6-methyl-5- ((2-( 1 -methyl- 1 H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-3-neopentyl- 1 H- 1 ,2,4- triazol-5(4H)-one, 3-cyclobutyl- 1 -(6-methyl-5-((2-(l -methyl- 1 H-pyrazol-4-yl)pyridin- 4-yl)oxy)pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5(4H)-one , 3-(tert-butyl)- 1 -(5-((2-( 1 -ethyl- 1 H- pyrazol-4-yl)pyridin-4-yl)oxy)-6-methylpyridin-2-yl)- 1 H- 1 ,2,4-triazol-5(4H)-one, 3- (tert-butyl)- 1 -(6-methyl-5-((2-(oxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)- 1 H- 1 ,2,4- triazol-5(4H)-one, 3-(tert-butyl)-l-(6-methyl-5-((6'-(4-methylpiperazin-l-yl)-[2,3'- bipyridin]-4-yl)oxy)pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5(4H)-one, 3-(tert-butyl)- 1 -(6- methyl-5-((2'-(4-methylpiperazin- 1 -yl)-[2,4'-bipyridin]-4-yl)oxy)pyridin-2-yl)- 1 H- 1 ,2,4- triazol-5(4H)-one, 3-(l-hydroxy-2-methylpropan-2-yl)-l-(6-methyl-5-((2-(l -methyl- 1H- pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one, l-(6-methyl-5- ((2-(l -methyl- lH-pyrazo l-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-3-(l- (trifluoromethyl)cyclobutyl)-lH-l,2,4-triazol-5(4H)-one, N-(4-((6-(3-(2- methoxypropan-2-yl)-5-oxo-4,5-dihydro-lH-l ,2,4-triazol-l-yl)-4-methylpyridin-3- yl)oxy)pyridin-2-yl)acetamide, N-(4-((6-(3-(tert-butyl)-5-oxo-4,5-dihydro-lH-l,2,4- triazol-l-yl)-2-methylpyridin-3-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide, 3-(l- methoxy-2-methylpropan-2-yl)-l-(6-methyl-5-((2-(l -methyl- lH-pyrazo l-4-yl)pyri din-4- yl)oxy)pyridin-2-yl)-lH-l ,2,4-triazol-5(4H)-one, 3-(tert-butyl)-l-(6-methyl-5-((6-(l- methyl- 1 H-pyrazol-4-yl)pyrimidin-4-yl)oxy)pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5(4H)-one, 4-(tert-butyl)- 1 -(6-methyl-5-((2-( 1 -methyl- 1 H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2- yl)-lH-imidazol-2(3H)-one, and 5-(tert-butyl)-3-(6-methyl-5-((2-(l -methyl- 1 H-pyrazol- 4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-l,3,4-oxadiazol-2(3H)-one.
20. A pharmaceutical composition, comprising a compound of claim 19 and a
pharmaceutically acceptable carrier.
21. The compound 3-(tert-butyl)-l-(6-methyl-5-((2-(l-methyl-lH-pyrazol-4-yl)pyridin-4- yl)oxy)pyridin-2-yl)- 1 H- 1 ,2 ,4-triazol-5(4H)-one .
22. A pharmaceutical composition, comprising a compound of claim 21 and a
pharmaceutically acceptable carrier.
23. The compound 3-isopropyl-l-(6-methyl-5-((2-(l -methyl- lH-pyrazo l-4-yl)pyri din-4- yl)oxy)pyridin-2-yl)- 1 H- 1 ,2 ,4-triazol-5(4H)-one .
24. A pharmaceutical composition, comprising a compound of claim 23 and a
pharmaceutically acceptable carrier.
25. The compound l-(6-methyl-5-((2-(l-methyl-lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin- 2-y l)-3 -(tert-pentyl)- 1 H- 1 ,2 ,4-triazol-5(4H)-one .
26. A pharmaceutical composition, comprising a compound of claim 25 and a
pharmaceutically acceptable carrier.
27. The compound 3-(tert-butyl)-l-(6-methyl-5-((2'-methyl-[2,4'-bipyridin]-4-yl)oxy)pyridin- 2-yl)- 1 H- 1 ,2 ,4-triazol-5(4H)-one .
28. A pharmaceutical composition, comprising a compound of claim 27 and a
pharmaceutically acceptable carrier.
29. The compound 4-(tert-butyl)-l-(6-methyl-5-((2-(l -methyl- 1 H-pyrazol-4-yl)pyridin-4- yl)oxy)pyridin-2-yl)-lH-imidazol-2(3H)-one.
30. A pharmaceutical composition, comprising a compound of claim 29 and a
pharmaceutically acceptable carrier.
31. A pharmaceutical composition, comprising a compound of claim 1 and a
pharmaceutically acceptable carrier.
32. The composition of claim 31 further comprising an additive selected from adjuvants, excipients, diluents, or stabilizers. A method of treating cancer, gastrointestinal stromal tumors, hyperproliferative diseases, metabolic diseases, neurodegenerative diseases, solid tumors, melanomas, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, renal cancers, hepatic cancers, osteosarcomas, multiple myelomas, cervical carcinomas, metastasis of primary tumor sites, cancers that are metastatic to bone, papillary thyroid carcinoma, non-small cell lung cancer, colonic cancers, rheumatoid arthritis,
osteoarthritis, multiple sclerosis, autoimmune nephritis, lupus, Crohn's disease, asthma, chronic obstructive pulmonary disease, osteoporosis, mastocytosis, or mast cell leukemia, the method comprising administering to a patient in need thereof an effective amount of a compound of claim 1.
A method of treating glioblastomas, breast cancers, pancreatic cancers, metastasis of primary tumor sites, or cancers that are metastatic to bone, the method comprising administering to a patient in need thereof an effective amount of a compound of claim 1.
The method of claim 33, wherein the compound is administered orally, parenterally, by inhalation, or subcutaneously.
The method of claim 34, wherein the compound is administered orally, parenterally, by inhalation, or subcutaneously.
Use of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, in the treatment of cancer, gastrointestinal stromal tumors, hyperproliferative diseases, metabolic diseases, neurodegenerative diseases, solid tumors, melanomas, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, renal cancers, hepatic cancers, osteosarcomas, multiple myelomas, cervical carcinomas, metastasis of primary tumor sites, cancers that are metastatic to bone, papillary thyroid carcinoma, non-small cell lung cancer, colonic cancers, rheumatoid arthritis,
osteoarthritis, multiple sclerosis, autoimmune nephritis, lupus, Crohn's disease, asthma, chronic obstructive pulmonary disease, osteoporosis, mastocytosis, or mast cell leukemia.
38. Use of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, in the treatment of glioblastomas, breast cancers, pancreatic cancers, metastasis of primary tumor sites, or cancers that are metastatic to bone.
39. Use of a compound of Claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer, gastrointestinal stromal tumors, hyperproliferative diseases, metabolic diseases, neurodegenerative diseases, solid tumors, melanomas, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, renal cancers, hepatic cancers, osteosarcomas, multiple myelomas, cervical carcinomas, metastasis of primary tumor sites, cancers that are metastatic to bone, papillary thyroid carcinoma, non-small cell lung cancer, colonic cancers, rheumatoid arthritis, osteoarthritis, multiple sclerosis, autoimmune nephritis, lupus, Crohn's disease, asthma, chronic obstructive pulmonary disease, osteoporosis, mastocytosis, or mast cell leukemia.
40. Use of a compound of Claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of glioblastomas, breast cancers, pancreatic cancers, metastasis of primary tumor sites, or cancers that are metastatic to bone.
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