WO2009155362A1 - Small molecule hematopoietic growth factor mimetic compounds and their uses - Google Patents

Small molecule hematopoietic growth factor mimetic compounds and their uses Download PDF

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Publication number
WO2009155362A1
WO2009155362A1 PCT/US2009/047687 US2009047687W WO2009155362A1 WO 2009155362 A1 WO2009155362 A1 WO 2009155362A1 US 2009047687 W US2009047687 W US 2009047687W WO 2009155362 A1 WO2009155362 A1 WO 2009155362A1
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optionally substituted
group
compound
substituted
unsubstituted
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PCT/US2009/047687
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French (fr)
Inventor
Jason C. Pickens
Andrew R. Hudson
Cornelis A. Van Oeveren
Steven L. Roach
Bijan Pedram
Yixing Shen
Lino J. Valdez
Jillian Basinger
Virginia Heather Sharron Grant
Lin Zhi
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Ligand Pharmaceuticals Inc.
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Publication of WO2009155362A1 publication Critical patent/WO2009155362A1/en

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    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
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    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
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    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07C2601/14—The ring being saturated

Definitions

  • Certain embodiments of the invention relate to compounds with physiological effects, such as the activation of hematopoietic growth factor receptors. Certain embodiments of the invention relate to use of such compounds to treat a variety of conditions, diseases and ailments such as hematopoietic conditions and disorders.
  • Hematopoietic growth factor represents a family of biological molecules such as glycoproteins with regulatory functions in the processes of cell proliferation, differentiation, and functional activation of hematopoietic progenitors and mature blood cells.
  • HGF compounds can regulate blood cell proliferation and development in the bone marrow.
  • HGF compounds can augment hematopoiesis when bone marrow dysfunction exists.
  • Recombinant DNA technology has made it possible to clone the genes responsible for certain HGFs.
  • TPO thrombopoietin
  • c-Mpl ligand also referred to as c-Mpl ligand, mpl ligand, megapoietin, and megakaryocyte growth and development factor
  • TPO thrombopoietin
  • c-Mpl ligand also referred to as c-Mpl ligand
  • mpl ligand mpl ligand
  • megapoietin and megakaryocyte growth and development factor
  • TPO has been cloned and both its amino acid sequence and the cDNA sequence encoding it have been described. See, e.g., U.S. 5,766,581; Kuter, DJ. et al, Proc. Natl. Acad. ScL, 91 :11104-11108 (1994); de Sauvage F.V., et al, Nature, 369: 533-538 (1994); Lok, S. et al, Nature 369:565-568 (1994); Wending, F. et al, Nature, 369: 571-574 (1994), all of which are incorporated herein by reference in their entireties.
  • TPO activity results from binding of TPO to the TPO receptor (also called MPL).
  • TPO receptor also called MPL.
  • the TPO receptor has been cloned and its amino acid sequence has been described. See, e.g., Vigon et al, Proc. Natl. Acad. Sci., 89:5640-5644 (1992), which is incorporated herein by reference in its entirety.
  • TPO modulators may be useful in treating a variety of hematopoietic conditions, including, but not limited to, thrombocytopenia. See e.g., Baser et al. Blood 89:3118-3128 (1997); Fanucchi et al. New Engl. J. Med.
  • patients undergoing certain chemotherapies including but not limited to chemotherapy and/or radiation therapy for the treatment of cancer, may have reduced platelet levels.
  • treating such patients with a selective TPO modulator increases platelet levels.
  • selective TPO modulators stimulate production of glial cells, which may result in repair of damaged nerve cells.
  • EPO glycoprotein hormone erythropoietin
  • EPO is an essential viability and growth factor for the erythrocytic progenitors.
  • EPO is a member of the family of class I cytokines which fold into a compact globular structure consisting of 4 ⁇ -helical bundles. Its molecular mass is 30.4 kDa, although it migrates with an apparent size of 34-38 kDa on SDS-polyacrylamide gels.
  • the peptide core of 165 amino acids suffices for receptor-binding and in vitro stimulation of erythropoiesis, while the carbohydrate portion (40% of the total molecule) is required for the in vivo survival of the hormone.
  • EPO The 4 carbohydrate chains of EPO have been analyzed in detail.
  • EPO is mainly produced by hepatocytes during the fetal stage. After birth, almost all circulating EPO originates from peritubular fibroblast-like cells located in the cortex of the kidneys. Transcription factors of the GATA-family may be important in the control of the time-specific and tissue-specific expression of the EPO gene. In adults, minor amounts of EPO mRNA are expressed in liver parenchyma, spleen, lung, testis and brain.
  • EPO exerts neurotrophic and neuroprotective effects, which are separate from the action of circulating EPO on erythropoietic tissues. See, e.g., Jelkmann, W., Internal Medicine Vol. 43, No.8 (March 2004).
  • A is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R 1 , R 2 , and R 3 , said aryl and heteroaryl in the definition of A are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle; or A is lower saturated alkyl or C 3 -C 7 cycloalkyl;
  • L 1 is selected from the group consisting of carbonyl, an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted heterocycle;
  • L 2 is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted heterocycle;
  • L 3 is selected from the group consisting of lower saturated alkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
  • G is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R , R 5 , and R , said aryl and heteroaryl in the definition of G are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle; or G is lower saturated alkylor C 3 -C 7 cycloalkyl; each R 1 is separately selected from the group consisting of halogen, an optionally substituted lower saturated alkyl, an optionally substituted Ci-C 6 alkoxy, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -C 6 alkynyl, an optionally substituted C 3 - C 7 cycloalkyl, an optionally substituted Cj-C 6 haloalkyl, an optionally substituted Ci-C 6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; each R 2 is separately selected from
  • each -NR R is separately selected, wherein R and R are each independently selected from the group consisting of hydrogen, an optionally substituted lower saturated alkyl, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -C 6 alkynyl, an optionally substituted C 3 -C 7 cycloalkyl, an optionally substituted Cj-C 6 haloalkyl, an optionally substituted Ci-C 6 heteroalkyl, -(CH 2 ) m R G , and -(CH 2 ) m OR G ; or NR E R F is an optionally substituted Cj-C 6 alkylideneaminyl; or -NR E R F is a three - to eight- membered optionally substituted aliphatic cyclic aminyl, which optionally has one to three additional hetero atoms incorporated in the ring; each R G is independently selected from an optionally substituted aryl and an optionally substituted heteroaryl
  • a 4 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R 11 , R 12 , and R 13 , said aryl and heteroaryl in the definition of A 4 are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle;
  • G 4 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R 14 , R 15 , and R 16 , said aryl and heteroaryl in the definition of G 4 are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle;
  • R 1 is selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted Ci-C 6 alkyl, a substituted or unsubstituted Ci-C 6 haloalkyl, a substituted or unsubstituted Ci-C 6 heteroalkyl, and null;
  • R 2 is selected from the group consisting of hydrogen, halogen, OR A , NR A R B , SR A , a substituted or unsubstituted Cj-C 6 alkyl, a substituted or unsubstituted Ci-C 6 haloalkyl, and a substituted or unsubstituted C 1 -C 6 heteroalkyl;
  • R 3 is selected from the group consisting of hydrogen, halogen, OR C , NR C R D , S(O) 0-2 R 0 , NO 2 , CN, (CH 2 ) m R E , a substituted or unsubstituted Cj-C 6 alkyl, a substituted or unsubstituted Ci-C 6 haloalkyl, a substituted or unsubstituted C 1 -C 6 heteroalkyl, and null;
  • R 4 is selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted Ci-C 6 alkyl, a substituted or unsubstituted Cj-C 6 haloalkyl, a substituted or unsubstituted Cj-C 6 heteroalkyl, and null;
  • R 5 is selected from the group consisting of hydrogen, halogen, OR ⁇ , NR A R B , SR A , a substituted or unsubstituted Ci-C 6 alkyl, a substituted or unsubstituted C 1 -C 6 haloalkyl, and a substituted or unsubstituted Cj-C 6 heteroalkyl;
  • R 6 is selected from the group consisting of hydrogen, halogen, OR C , NR C R D , S(O) 0-2 R 0 , NO 2 , CN, (CH 2 ) m R E , a substituted or unsubstituted Ci-C 6 alkyl, a substituted or unsubstituted Ci-C 6 haloalkyl, a substituted or unsubstituted Cj-C 6 heteroalkyl, and null;
  • R A is selected from the group consisting of hydrogen, Ci-C 6 alkyl, Cj-C 6 haloalkyl, Ci-C 6 heteroalkyl, and Ci-C 6 heterohaloalkyl;
  • R B is selected from hydrogen, SO 2 R F , C0R F , CONR C R D , Cj-C 6 alkyl, Cj-C 6 haloalkyl, C J -C 6 heteroalkyl, and Cj-C 6 heterohaloalkyl; or R A and R B are linked to form a substituted or unsubstituted C 3 -C 8 ring;
  • R c and R D are each independently selected from the group consisting of hydrogen, a substituted or unsubstituted Ci-C 6 alkyl, a substituted or unsubstituted Cj-C 6 haloalkyl, a substituted or unsubstituted Cj-C 6 heteroalkyl, and (CH 2 ) m R E ; or one of R c and R D is a substituted or unsubstituted C 2 -C 6 alkyl and the other of R c and R D is null; or R c and R D are linked to form a substituted or unsubstituted C 3 -C 8 ring;
  • R E is selected from a substituted or unsubstituted aryl and a substituted or unsubstituted heteroaryl;
  • R F is selected from the group consisting of hydrogen, Ci-C 3 alkyl, Ci-C 3 haloalkyl, and a substituted or unsubstituted aryl or heteroaryl;
  • A is selected from the group consisting of a Ci-C 6 alkyl, a C)-C 6 heteroalkyl, a monocyclic or bicyclic aromatic ring optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle;
  • G is selected from the group consisting of a Cj-C 6 alkyl, a C 1 -C 6 heteroalkyl, a monocyclic or bicyclic aromatic ring optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle;
  • D is a 1-6 atom spacer containing at least 2 heteroatoms separated by 3 or 4 bonds and comprising one or more groups selected from a substituted or unsubstituted Cj-C 6 heteroalkyl, a substituted or unsubstituted heterocycle, and a substituted or unsubstituted heteroalkylheterocycle;
  • E is a 1-6 atom spacer containing at least 2 heteroatoms separated by 3 or 4 bonds and comprising one or more groups selected from a substituted or unsubstituted C 1 -C 6 heteroalkyl, a substituted or unsubstituted heterocycle, and a substituted or unsubstituted heteroalkylheterocycle;
  • L is a 2-12 atom linker comprising one or more groups selected from O (oxygen), NR , S(O) 0-2 , NR B S(O) 1-2 NR A , NR B S(O)i -2 O, a substituted or unsubstituted C 1 -C] 0 alkyl, a substituted or unsubstituted C 1 -C 10 haloalkyl, a substituted or unsubstituted Ci-C 8 heteroalkyl, a substituted or unsubstituted aryl, and a substituted or unsubstituted heteroaryl; where the aryl and heteroaryl are optionally fused with a nonaromatic heterocycle or a nonaromatic carbocycle; m is O, 1, or 2; and each dashed line independently represents an optional double bond.
  • R 11 is selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted C 1 -C 6 alkyl, a substituted or unsubstituted Ci-C 6 haloalkyl, a substituted or unsubstituted Ci-C 6 heteroalkyl, and null;
  • R 12' is selected from the group consisting of hydrogen, halogen, -OR A , -NR A R B , -SR ⁇ , a substituted or unsubstituted Ci-C 6 alkyl, a substituted or unsubstituted Ci-C 6 haloalkyl, and a substituted or unsubstituted CpC 6 heteroalkyl;
  • R 13' is selected from the group consisting of hydrogen, halogen, -OR C , -NR C R D , -S(O) 0- 2 R C , -NO 2 , -CN, -(CH 2 ) m R E , a substituted or unsubstituted Ci-C 6 alkyl, a substituted or unsubstituted Ci-C 6 haloalkyl, a substituted or unsubstituted Ci-C 6 heteroalkyl, and null;
  • R 14 is selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted C]-C 6 alkyl, a substituted or unsubstituted Ci-C 6 haloalkyl, a substituted or unsubstituted Ci-C 6 heteroalkyl, and null;
  • R 15' is selected from the group consisting of hydrogen, halogen, -OR A , -NR A R B , -SR A , a substituted or unsubstituted Cj-C 6 alkyl, a substituted or unsubstituted Ci-C 6 haloalkyl, and a substituted or unsubstituted Ci-C 6 heteroalkyl;
  • R is selected from the group consisting of hydrogen, halogen, -OR , -NR R , -S(0)o- 2 R C , -NO 2 , -CN, - ⁇ CH 2 ) m R E , a substituted or unsubstituted Ci-C 6 alkyl, a substituted or unsubstituted Cj-C 6 haloalkyl, a substituted or unsubstituted Cj-C 6 heteroalkyl, and null;
  • R 17 , R 18 , R 19 , and R 20 are independently selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted Cj-C 4 alkyl, a substituted or unsubstituted.Cj- C 4 haloalkyl, and a substituted or unsubstituted Ci-C 4 heteroalkyl; or R 17 and R 18 are linked to form a substituted or unsubstituted ring; or R 19 and R 20 are linked to form a substituted or unsubstituted ring; or R 17 and R 2 can be independently split into two groups when the carbon atoms they are attached become saturated;
  • R A is selected from the group consisting of hydrogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, Cj-C 6 heteroalkyl, and Cj-C 6 heterohaloalkyl;
  • R c and R D are each independently selected from the group consisting of hydrogen, a substituted or unsubstituted Cj-C 6 alkyl, a substituted or unsubstituted Cj-C 6 haloalkyl, a substituted or unsubstituted Cj-C 6 heteroalkyl, and -(CH 2 ) m R ; or one of R and R is a substituted or unsubstituted C 2 -C 6 alkyl and the other of R and R is null; or R and R , are linked to form a substituted or unsubstituted C 3 -C 8 ring;
  • R E is selected from a substituted or unsubstituted aryl and a substituted or unsubstituted heteroaryl;
  • R F is selected from the group consisting of hydrogen, Cj-C 3 alkyl, Cj-C 3 haloalkyl, and a substituted or unsubstituted aryl or heteroaryl;
  • a 1' is selected from the group consisting of a Cj-C 6 alkyl, a Cj-C 6 heteroalkyl, and a monocyclic or bicyclic aromatic ring optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle;
  • G 1 is selected from the group consisting of a C 1 -C 6 alkyl, a Cj-C 6 heteroalkyl, and a monocyclic or bicyclic aromatic ring optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle;
  • L 1 is a 2-12 atom long linker comprising one or more groups selected from — O- (oxygen), -NR B -, -S(O) 0-2 -, -NR B S(O)i -2 NR A - -NR 8 S(O) I-2 O-, a substituted or unsubstituted Cj-Cio alkyl, a substituted or unsubstituted Ci-Ci 0 haloalkyl, a substituted or unsubstituted Cj-C 8 heteroalkyl, a substituted or unsubstituted aryl, and a substituted or unsubstituted heteroaryl; where the
  • X is selected from the group consisting of NR and C(R ) 2 ;
  • Y is selected from the group consisting of NR 19 and C(R 1 ) 2 ; m is O, 1, or 2; and each dashed line independently represents an optional double bond.
  • a compound of Formula I, II, IH or IV is a hematopoietic growth factor mimetic, hematopoietic growth factor receptor agonist, or hematopoietic growth factor receptor antagonist.
  • Some embodiments disclosed herein provide a selective HGF modulator. Some embodiments disclosed herein provide a selective HGF receptor agonist. Some embodiments disclosed herein provide a selective HGF receptor antagonist. Some embodiments disclosed herein provide a selective HGF partial agonist. Some embodiments disclosed herein provide a selective HGF receptor binding compound. Certain embodiments provide a HGF mimic.
  • Some embodiments disclosed herein provide a selective EPO modulator. Some embodiments disclosed herein provide a selective EPO receptor agonist. Some embodiments disclosed herein provide a selective EPO receptor antagonist. Some embodiments disclosed herein provide a selective EPO partial agonist. Some embodiments disclosed herein provide a selective EPO receptor binding compound. Some embodiments disclosed herein provide an EPO mimic.
  • Some embodiments disclosed herein provide methods for modulating activity of HGF receptors. Such methods comprise contacting a cell with one or more compounds of the present embodiments. Such methods include, but are not limited to, contacting HGF and/or HGF receptors with one or more compounds of the present embodiments. [0015] Some embodiments disclosed herein provide methods for identifying a compound that is capable of modulating HGF activity comprising: a) contacting a cell capable of a HGF activity with a compound of the present embodiments; and b) monitoring an effect on the cell. In certain such embodiments, the cell expresses a HGF receptor.
  • Some embodiments disclosed herein provide methods for modulating activity of EPO receptors. Such methods comprise contacting a cell with one or more compounds of the present embodiments. Such methods include, but are not limited to, contacting EPO and/or EPO receptors with one or more compounds of the present embodiments.
  • Some embodiments disclosed herein provide methods for identifying a compound that is capable of modulating EPO activity comprising: a) contacting a cell capable of a EPO activity with a compound of the present embodiments; and b) monitoring an effect on the cell.
  • the cell expresses an EPO receptor.
  • Some embodiments disclosed herein provide methods of treating a patient comprising administering to the patient a compound of the present embodiments.
  • a patient suffers from thrombocytopenia, anemia, neutropenia, a cardiovascular disorder, an immune/autoimmune disorder, an infectious disorder, and a neurologic disorder.
  • one or more compounds of the present embodiments are administered to a patient before, during or after chemotherapy, bone marrow transplantation, and/or radiation therapy.
  • patient treatment is prophylactic.
  • treatment includes harvesting cells from the patient.
  • one or more compounds of the embodiments are administered to a patient suffering from aplastic anemia, bone marrow failure, and/or idiopathic thrombocytopenia. In certain embodiments, one or more compounds of the present embodiments are administered to a patient suffering from a disease of the nervous system. In certain embodiments, one or more compounds of the present embodiments are administered to a patient suffering from amyotrophic lateral sclerosis, multiple sclerosis, or multiple dystrophy. In certain embodiments, one or more compounds of the present embodiments are administered to a patient with a nervous system injury, or a nerve injury, including, but not limited to, a spinal cord injury. [0019] Some embodiments disclosed herein provide pharmaceutical compositions comprising: (i) a physiologically acceptable carrier, diluent, or excipient, or a combination thereof; and (ii) one or more compounds of the present embodiments.
  • Some embodiments disclosed herein provide pharmaceutical compositions for use in treating a condition of an anemia, a neutropenia, a cardiovascular disorder, an immune/autoimmune disorder, an infectious disorder, and a neurologic disorder.
  • Standard techniques may be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients.
  • Standard techniques may be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection).
  • Reactions and purification techniques may be performed e.g., using kits according to manufacturer's specifications or as commonly accomplished in the art or as described herein.
  • the foregoing techniques and procedures may be generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See e.g., Sambrook et al. Molecular Cloning: A Laboratory Manual (2nd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N. Y. (1989)), which is incorporated herein by reference in its entirety for any purpose.
  • selective binding compound refers to a compound that selectively binds to any portion of one or more target.
  • selective HGF receptor binding compound refers to a compound that selectively binds to any portion of a HGF receptor.
  • selective EPO receptor binding compound refers to a compound that selectively binds to any portion of a EPO receptor.
  • selective binding refers to the ability of a selective binding compound to bind to a target receptor with greater affinity than it binds to a non-target receptor.
  • selective binding refers to binding to a target with an affinity that is at least 10, 50, 100, 250, 500, or 1000 times greater than the affinity for a non-target.
  • target receptor refers to a receptor or a portion of a receptor capable of being bound by a selective binding compound.
  • a target receptor is a HGF receptor.
  • modulator refers to a compound that alters an activity.
  • a modulator may cause an increase or decrease in the magnitude of a certain activity compared to the magnitude of the activity in the absence of the modulator.
  • a modulator is an inhibitor, which decreases the magnitude of one or more activities.
  • an inhibitor completely prevents one or more biological activities.
  • a modulator is an activator, which increases the magnitude of at least one activity.
  • the presence of a modulator results in an activity that does not occur in the absence of the modulator.
  • selective modulator refers to a compound that selectively modulates a target activity.
  • selective HGF modulator refers to a compound that selectively modulates at least one HGF activity.
  • selective HGF modulator includes, but is not limited to "HGF mimic” which refers to a compound, the presence of which results in at least one HGF activity. HGF mimics are described in WO 03/103686A1 and WO 01/21180, both of which are incorporated herein by reference in their entirety.
  • selective EPO modulator refers to a compound that selectively modulates at least one EPO activity.
  • selective EPO modulator includes, but is not limited to "EPO mimic” which refers to a compound, the presence of which results in at least one EPO activity.
  • selective modulates refers to the ability of a selective modulator to modulate a target activity to a greater extent than it modulates a non-target activity.
  • target activity refers to a biological activity capable of being modulated by a selective modulator.
  • Certain exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzymatic activity, the proliferation and/or differentiation of progenitor cells, generation of platelets, and alleviation of symptoms of a disease or condition.
  • HGF activity refers to a biological activity that results, either directly or indirectly from the presence of HGF.
  • exemplary HGF activities include, but are not limited to, proliferation and or differentiation of progenitor cells to produce platelets; hematopoiesis; growth and/or development of glial cells; repair of nerve cells; and alleviation of thrombocytopenia.
  • EPO activity refers to a biological activity that results, either directly or indirectly from the presence of EPO.
  • EPO activities include, but are not limited to, proliferation and or differentiation of progenitor cells to produce platelets; hematopoiesis; growth and/or development of glial cells; repair of nerve cells; and alleviation of thrombocytopenia.
  • thrombocytopenia refers to a condition wherein the concentration of platelets in the blood of a patient is below what is considered normal for a healthy patient.
  • thrombocytopenia is a platelet count less than 450,000, 400,000, 350,000, 300,000, 250,000, 200,000, 150,000, 140,000, 130,000, 120,000, 110,000, 100,000, 75,000, or 50,000 platelets per microliter of blood.
  • receptor mediated activity refers to any biological activity that results, either directly or indirectly, from binding of a ligand to a receptor.
  • agonist refers to a compound, the presence of which results in a biological activity of a receptor that is the same as the biological activity resulting from the presence of a naturally occurring ligand for the receptor.
  • partial agonist refers to a compound, the presence of which results in a biological activity of a receptor that is of the same type as that resulting from the presence of a naturally occurring ligand for the receptor, but of a lower magnitude.
  • antagonist refers to a compound, the presence of which results in a decrease in the magnitude of a biological activity of a receptor. In certain embodiments, the presence of an antagonist results in complete inhibition of a biological activity of a receptor.
  • alkyl refers to a branched or unbranched aliphatic hydrocarbon group.
  • An alkyl may be a "saturated alkyl,” which means that it does not contain any alkene or alkyne groups.
  • An alkyl group may be an "unsaturated alkyl,” which means that it comprises at least one alkene or alkyne group.
  • An alkyl, whether saturated or unsaturated, may be branched or straight chain.
  • Alkyls may be cyclic or non-cyclic. Cyclic alkyls may include multicyclic systems including fused alkyl rings or spirals. Alkyls may be substituted or unsubstituted.
  • Alkyls include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, each of which may be optionally substituted.
  • an alkyl comprises 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., "1 to 20 carbon atoms” means that an alkyl group may comprise only 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. , up to and including 20 carbon atoms, although the term "alkyl” also includes instances where no numerical range of carbon atoms is designated).
  • lower saturated alkyl refers to a branched or unbranched fully saturated acyclic aliphatic hydrocarbon group comprising 1 to 6 carbon atoms.
  • a lower saturated alkyl may be branched or straight chain.
  • Lower saturated alkyls may be optionally substituted.
  • Lower saturated alkyls include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.
  • alkenyl refers to a monovalent straight or branched chain aliphatic hydrocarbon radical of from two to twenty carbon atoms containing at least one carbon-carbon double bond including, but not limited to, 1- propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl, and the like.
  • an alkenyl comprises 2 to 20 carbon atoms (whenever it appears herein, a numerical range such as “2 to 20” refers to each integer in the given range; e.g., "2 to 20 carbon atoms” means that an alkenyl group may comprise only 2 carbon atoms, 3 carbon atoms, etc. , up to and including 20 carbon atoms, although the term “alkenyl” also includes instances where no numerical range of carbon atoms is designated).
  • An alkenyl may be designated as "C 2 -C 6 alkenyl" or similar designations.
  • C 2 -C 4 alkenyl indicates an alkenyl having two, three, or four carbon atoms, e.g., the alkenyl is selected from ethenyl, propenyl, and butenyl.
  • alkynyl refers to a monovalent straight or branched chain aliphatic hydrocarbon radical of from two to twenty carbon atoms containing at least one carbon-carbon triple bond including, but not limited to, 1 - propynyl, 1-butynyl, 2-butynyl, and the like.
  • an alkynyl comprises 2 to 20 carbon atoms (whenever it appears herein, a numerical range such as “2 to 20” refers to each integer in the given range; e.g., "2 to 20 carbon atoms” means that an alkynyl group may comprise only 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the term “alkynyl” also includes instances where no numerical range of carbon atoms is designated).
  • An alkynyl may be designated as "C 2 -C 6 alkynyl" or similar designations.
  • C 2 -C 4 alkynyl indicates an alkenyl having two, three, or four carbon atoms, e.g., the alkenyl is selected from ethynyl, propynyl, and butynyl.
  • cycloalkyl a subset within the definition of alkyl, refers to saturated aliphatic ring system radical having three to twenty carbon atoms.
  • a cycloalkyl refers to monocyclic and polycyclic saturated aliphatic ring system including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[4.4.0]decanyl, bicyclo[2.2.1]heptanyl, adamantyl, norbornyl, and the like.
  • a cycloalkyl comprises 3 to 20 carbon atoms (whenever it appears herein, a numerical range such as “3 to 20” refers to each integer in the given range; e.g., "3 to 20 carbon atoms” means that a cycloalkyl group may comprise only 3 carbon atoms, etc., up to and including 20 carbon atoms, although the term “cycloalkyl” also includes instances where no numerical range of carbon atoms is designated).
  • a cycloalkyl may be designated as "C 3 -C 7 cycloalkyl" or similar designations.
  • C 3 -C 6 cycloalkyl indicates an alkenyl having two, three, four, five or six carbon atoms, e.g., the cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • cycloalkenyl refers to aliphatic ring system radical having three to twenty carbon atoms having at least one carbon- carbon double bond in the ring.
  • a cycloalkenyl refers to monocyclic and polycyclic unsaturated aliphatic ring system including, but are not limited to, cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, bicyclo[3.1.0]hexyl, norbornylenyl, l,l'-bicyclopentenyl, and the like.
  • a cycloalkenyl comprises 3 to 20 carbon atoms (whenever it appears herein, a numerical range such as “3 to 20” refers to each integer in the given range; e.g., "3 to 20 carbon atoms” means that a cycloalkenyl group may comprise only 3 carbon atoms, etc. , up to and including 20 carbon atoms, although the term “cycloalkenyl” also includes instances where no numerical range of carbon atoms is designated).
  • a cycloalkenyl may be designated as "C 3 -C 7 cycloalkenyl" or similar designations.
  • C 3 -C 6 cycloalkenyl indicates an alkenyl having two, three, four, five or six carbon atoms, e.g., the cycloalkyl is selected from cyclopropenyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl.
  • haloalkyl refers to an alkyl in which at least one hydrogen atom is replaced with a halogen atom. In certain of the embodiments in which two or more hydrogen atom are replaced with halogen atoms, the halogen atoms are all the same as one another. In certain of such embodiments, the halogen atoms are not all the same as one another.
  • heteroalkyl refers to a branched or unbranched aliphatic hydrocarbon group comprising one or more oxygen, sulfur, nitrogen, or NH.
  • alkoxy refers to straight or branched chain alkyl radical covalently bonded to the parent molecule through an --O-- linkage.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, n-butoxy, sec-butoxy, t-butoxy and the like.
  • An alkoxy may be designated as "C 1 -C 6 alkoxy” or similar designations.
  • Cj-C 4 alkoxy indicates an alkyl having one, two, three, or four carbon atoms, e.g., the alkoxy is selected from methoxy, ethoxy, propoxy, /so-propoxy, butoxy, w ⁇ -butoxy, .sec-butoxy, and tert-butoxy.
  • Carbocycle refers to a group comprising a covalently closed ring, wherein each of the atoms forming the ring is a carbon atom.
  • Carbocylic rings may be formed by three, four, five, six, seven, eight, nine, or more than nine carbon atoms.
  • Carbocycles may be optionally substituted.
  • heterocycle refers to a group comprising a covalently closed ring wherein at least one atom forming the ring is a heteroatom.
  • Heterocyclic rings may be formed by three, four, five, six, seven, eight, nine, or more than nine atoms. Any number of those atoms may be heteroatoms (i.e., a heterocyclic ring may comprise one, two, three, four, five, six, seven, eight, nine, or more than nine heteroatoms). In heterocyclic rings comprising two or more heteroatoms, those two or more heteroatoms may be the same or different from one another. Heterocycles may be optionally substituted.
  • Binding to a heterocycle can be at a heteroatom or via a carbon atom.
  • binding for benzo-fused derivatives may be via a carbon of the benzenoid ring.
  • heterocycles include, but are not limited to the following:
  • D, E, F, and G independently represent a heteroatom.
  • Each of D, E, F, and G may be the same or different from one another.
  • heteroatom refers to an atom other than carbon or hydrogen. Heteroatoms are typically independently selected from oxygen, sulfur, nitrogen, and phosphorus, but are not limited to those atoms. In embodiments in which two or more heteroatoms are present, the two or more heteroatoms may all be the same as one another, or some or all of the two or more heteroatoms may each be different from the others.
  • aromatic refers to a group comprising a covalently closed ring having a delocalized ⁇ -electron system.
  • Aromatic rings may be formed by five, six, seven, eight, nine, or more than nine atoms.
  • Aromatics may be optionally substituted. Examples of aromatic groups include, but are not limited to phenyl, naphthalenyl, phenanthrenyl, anthracenyl, tetralinyl, fluorenyl, indenyl, and indanyl.
  • aromatic includes, for example, benzenoid groups, connected via one of the ring-forming carbon atoms, and optionally carrying one or more substituents selected from an aryl, a heteroaryl, a cycloalkyl, a non-aromatic heterocycle, a halo, a hydroxy, an amino, a cyano, a nitro, an alkylamido, an acyl, a Ci -6 alkoxy, a Ci -6 alkyl, a Ci -6 hydroxyalkyl, a Ci -6 aminoalkyl, a Ci -6 alkylamino, an alkylsulfenyl, an alkylsulf ⁇ nyl, an alkylsulfonyl, an sulfamoyl, or a trifluoromethyl.
  • an aromatic group is substituted at one or more of the para, meta, and/or ortho positions.
  • aromatic groups comprising substitutions include, but are not limited to, phenyl, 3-halophenyl, 4- halophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-aminophenyl, 4-aminophenyl, 3- methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, dimethylphenyl, naphthyl, hydroxynaphthyl, hydroxymethylphenyl, (trifluoromethyl)phenyl, alkoxyphenyl, 4-morpholin-4-ylphenyl, 4- pyrrolidin-1-ylphenyl, 4-pyrazolylphenyl, 4-triazolylphenyl, and 4-(2-oxopyrrolidin-l-yl)phenyl
  • aryl refers to an aromatic group wherein each of the atoms forming the ring is a carbon atom.
  • Aryl rings may be formed by five, six, seven, eight, nine, or more than nine carbon atoms.
  • Aryl groups may be optionally substituted.
  • heteroaryl refers to an aromatic group wherein at least one atom forming the aromatic ring is a heteroatom. Heteroaryl rings may be formed by three, four, five, six, seven, eight, nine, or more than nine atoms. Heteroaryl groups may be optionally substituted. Examples of heteroaryl groups include, but are not limited to, aromatic C 3-8 heterocyclic groups comprising one oxygen or sulfur atom or up to four nitrogen atoms, or a combination of one oxygen or sulfur atom and up to two nitrogen atoms, and their substituted as well as benzo- and pyrido-fused derivatives, for example, connected via one of the ring-forming carbon atoms.
  • heteroaryl groups are optionally substituted with one or more substituents, independently selected from halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, Ci -6 -alkoxy, Ci -6 -alkyl, C 1-6 -hydroxyalkyl, Ci -6 -aminoalkyl, Ci -6 -alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl.
  • substituents independently selected from halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, Ci -6 -alkoxy, Ci -6 -alkyl, C 1-6 -hydroxyalkyl, Ci -6 -aminoalkyl, Ci -6 -alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulf
  • heteroaryl groups include, but are not limited to, unsubstituted and mono- or di-substituted derivatives of furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole, quinoline, isoquinoline, pyridazine, pyrimidine, purine and pyrazine, furazan, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, triazole, benzotriazole, pteridine, phenoxazole, oxadiazole, benzopyrazole, quinolizine, cinnoline, phthalazin
  • the substituents are halo, hydroxy, cyano, O-Ci- 6 -alkyl, C 1-6 -alkyl, hydroxy-Ci -6 -alkyl, and amino-Ci -6 -alkyl.
  • non-aromatic ring refers to a group comprising a covalently closed ring that does not have a delocalized ⁇ -electron system.
  • cycloalkyl refers to a group comprising a non-aromatic ring wherein each of the atoms forming the ring is a carbon atom. Cycloalkyl rings may be formed by three, four, five, six, seven, eight, nine, or more than nine carbon atoms. Cycloalkyls may include multicyclic systems (e.g., fused ring systems). Cycloalkyls may be optionally substituted. In certain embodiments, a cycloalkyl comprises one or more unsaturated bonds.
  • cycloalkyls include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1 ,4-cyclohexadiene, cycloheptane, and cycloheptene.
  • non-aromatic heterocycle refers to a group comprising a non- aromatic ring wherein one or more atoms forming the ring is a heteroatom and optionally includes one or more carbonyl or thiocarbonyl groups as part of the ring.
  • Non-aromatic heterocyclic rings may be formed by three, four, five, six, seven, eight, nine, or more than nine atoms.
  • Non-aromatic heterocycles may be optionally substituted.
  • non-aromatic heterocycles include, but are not limited to, lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3- dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane, 1,4-oxathiin, 1 ,4-oxathiane, tetrahydro-l,4-thiazine, 2H-l,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-l,3,5-triazine, tetrahydrothioph
  • arylalkyl refers to a group comprising an aryl group bound to an alkyl group.
  • Carbocycloalkyl refers to a group comprising a carbocyclic cycloalkyl ring. Carbocycloalkyl rings may be formed by three, four, five, six, seven, eight, nine, or more than nine carbon atoms. Carbocycloalkyl groups may be optionally substituted.
  • Rings refers to any covalently closed structure. Rings include, for example, carbocycles (e.g., aryls and cycloalkyls), heterocycles (e.g., heteroaryls and non- aromatic heterocycles), aromatics (e.g., aryls and heteroaryls), and non-aromatics (e.g., cycloalkyls and non-aromatic heterocycles). Rings may be optionally substituted. Rings may form part of a ring system.
  • carbocycles e.g., aryls and cycloalkyls
  • heterocycles e.g., heteroaryls and non- aromatic heterocycles
  • aromatics e.g., aryls and heteroaryls
  • non-aromatics e.g., cycloalkyls and non-aromatic heterocycles. Rings may be optionally substituted. Rings may form part of a ring system.
  • ring system refers to a either a single ring or two or more rings, wherein, if two or more rings are present, the two or more of the rings are fused.
  • fused refers to structures in which two or more rings share one or more bonds.
  • spacer refers to an atom or group of atoms that separate two or more groups from one another by a desired number of atoms. For example, in certain embodiments, it may be desirable to separate two or more groups by one, two, three, four, five, six, or more than six atoms. In such embodiments, any atom or group of atoms may be used to separate those groups by the desired number of atoms. Spacers are optionally substituted. In certain embodiments, a spacer comprises saturated or unsaturated alkyls, heteroalkyls and/or haloalkyls. In certain embodiments, a spacer comprises atoms that are part of a ring.
  • spacers are provided.
  • 1 atom spacers include, but are not limited to, the following: where A and E represent groups which are separated by the desired number of atoms.
  • 2 atom spacers include, but are not limited to, the following:
  • a M E where A and E represent groups which are separated by the desired number of atoms.
  • Examples of 3 atom spacers include, but are not limited to, the following:
  • a and E represent groups which are separated by the desired number of atoms.
  • Examples of 4 atom spacers include, but are not limited to, the following:
  • a and E represent groups which are separated by the desired number of atoms.
  • the atoms that create the desired separation may themselves be part of a group. That group may be, for example, an alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic heterocycle, or substituted alkyl all of which are optionally substituted.
  • 1-5 atom spacer refers to a spacer that separates two groups by 1, 2, 3, 4, or 5 atoms and does not indicate the total size of the group that constitutes the spacer.
  • the term "linked to form a ring” refers to instances where two atoms that are bound either to a single atom or to atoms that are themselves ultimately bound, are each bound to a linking group, such that the resulting structure forms a ring. That resulting ring comprises the two atoms that are linked to form a ring, the atom (or atoms) that previously linked those atoms, and the linker. For example, if A and B below are "linked to form a ring"
  • resulting structures include, but are not limited to:
  • the two substituents that together form a ring are not immediately bound to the same atom. For example, if A and E, below, are linked to form a ring:
  • the resulting ring comprises A, E, the two atoms that already link A and E and a linking group.
  • Examples of resulting structures include, but are not limited to:
  • the atoms that together form a ring are separated by three or more atoms.
  • the resulting ring comprises A, E, the 3 atoms that already link A and E, and a linking group.
  • Examples of resulting structures include, but are not limited to: K E
  • nuclear refers to a group being absent from a structure.
  • the substituent "R” appearing by itself and without a number designation refers to a substituent selected from alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and non-aromatic heterocycle (bonded through a ring carbon). If “R” appears more than once in a formula then each "R” is individually is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and non-aromatic heterocycle (bonded through a ring carbon).
  • trihalomethanesulfonyl refers to the group consisting of formula X 3 CS ⁇ O) 2 - where X is a halogen.
  • cyano refers to the group consisting of formula -CN.
  • N-sulfonamido refers to the group consisting of formula RSC-O) 2 NH-.
  • C-amido refers to the group consisting of formula -C(O)-N(R) 2 .
  • amino refers to the group consisting of formula -N(R) 2 .
  • amide refers to a chemical moiety with formula -(R) n -C(O)NHR' or -(R) n -NHC(O)R', where R and R' are independently selected from alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), where n is 0 or 1.
  • R and R' are independently selected from alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), where n is 0 or 1.
  • an amide may be an amino acid or a peptide.
  • amine include such groups that have been esterified or amidifled. Procedures and specific groups used to achieve esterif ⁇ cation and amidification are known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley & Sons, New York, NY, 1999, which is incorporated herein in its entirety.
  • carrier refers to a compound that facilitates the incorporation of another compound into cells or tissues.
  • DMSO dimethyl sulfoxide
  • a pharmaceutical agent refers to a chemical compound or composition capable of inducing a desired therapeutic effect in a patient.
  • a pharmaceutical agent comprises an active agent, which is the agent that induces the desired therapeutic effect.
  • a pharmaceutical agent comprises a prodrug.
  • a pharmaceutical agent comprises inactive ingredients such as carriers, excipients, and the like.
  • terapéuticaally effective amount refers to an amount of a pharmaceutical agent sufficient to achieve a desired therapeutic effect.
  • prodrug refers to a pharmacologically inactive derivative of a parent drug molecule that requires biotransformation, either spontaneous or enzymatic, within the organism to release the active drug.
  • Prodrugs become the compounds of the invention which are pharmaceutically active in vivo when they undergo solvolysis under physiological conditions or undergo enzymatic degradation.
  • Prodrug compounds of this invention may be called single, double, triple, etc., depending on the number of biotransformation steps required to release the active drug within the organism, and indicating the number of functionalities present in a precursor-type form.
  • Prodrug forms often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (Bundgaard, Design of Prodrugs, pp.
  • Prodrugs commonly known in the art include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acids with a suitable alcohol, or amides prepared by reaction of the parent acid compound with an amine, or basic groups reacted to form an acylated base derivative.
  • the prodrug derivatives of this invention may be combined with other features herein taught to enhance bioavailability.
  • prodrugs include prodrug esters.
  • pro-drug ester groups include pivoyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, as well as other such groups known in the art, including a (5-R-2-oxo-l,3-dioxolen-4-yl)methyl group.
  • Other examples of pro-drug ester groups can be found in, for example, T. Higuchi and V. Stella, in "Pro-drugs as Novel Delivery Systems," Vol. 14, A.C.S. Symposium Series, American Chemical Society (1975); and "Bioreversible Carriers in Drug Design: Theory and Application," edited by E. B. Roche, Pergamon Press: New York, 14-21 (1987) (providing examples of esters useful as prodrugs for compounds containing carboxyl groups).
  • pharmaceutically acceptable refers to a formulation of a compound that does not significantly abrogate the biological activity, a pharmacological activity and/or other properties of the compound when the formulated compound is administered to a patient. In certain embodiments, a pharmaceutically acceptable formulation does not cause significant irritation to a patient.
  • co-administer refers to administering more than one pharmaceutical agent to a patient.
  • co-administered pharmaceutical agents are administered together in a single dosage unit.
  • coadministered pharmaceutical agents are administered separately.
  • coadministered pharmaceutical agents are administered at the same time.
  • co-administered pharmaceutical agents are administered at different times.
  • patient includes human and animal subjects.
  • substantially pure means an object species (e.g., compound) is the predominant species present (i.e., on a molar basis it is more abundant than any other individual species in the composition).
  • a substantially purified fraction is a composition wherein the object species comprises at least about 50 percent (on a molar basis) of all species present.
  • a substantially pure composition will comprise more than about 80%, 85%, 90%, 95%, or 99% of all species present in the composition.
  • the object species is purified to essential homogeneity (contaminant species cannot be detected in the composition by conventional detection methods) wherein the composition consists essentially of a single species.
  • tissue-selective refers to the ability of a compound to modulate a biological activity in one tissue to a greater or lesser degree than it modulates a biological activity in another tissue.
  • the biological activities in the different tissues may be the same or they may be different.
  • the biological activities in the different tissues may be mediated by the same type of target receptor.
  • a tissue-selective compound may modulate receptor mediated biological activity in one tissue and fail to modulate, or modulate to a lesser degree, receptor mediated biological activity in another tissue type.
  • the term "monitoring” refers to observing an effect or absence of any effect. In certain embodiments, one monitors cells after contacting those cells with a compound of the present embodiments. Examples of effects that may be monitored include, but are not limited to, changes in cell phenotype, cell proliferation, receptor activity, or the interaction between a receptor and a compound known to bind to the receptor.
  • cell phenotype refers to physical or biological characteristics. Examples of characteristics that constitute phenotype included, but are not limited to, cell size, cell proliferation, cell differentiation, cell survival, apoptosis (cell death), or the utilization of a metabolic nutrient (e.g., glucose uptake). Certain changes or the absence of changes in cell phenotype are readily monitored using techniques known in the art.
  • cell proliferation refers to the rate at which cells divide.
  • cells are in situ in an organism.
  • cells are grown in vitro in a vessel.
  • the number of cells growing in a vessel can be quantified by a person skilled in the art (e.g. , by counting cells in a defined area using a microscope or by using laboratory apparatus that measure the density of cells in an appropriate medium).
  • One skilled in that art can calculate cell proliferation by determining the number of cells at two or more times.
  • contacting refers to bringing two or more materials into close enough proximity that they may interact. In certain embodiments, contacting can be accomplished in a vessel such as a test tube, a Petri dish, or the like. In certain embodiments, contacting may be performed in the presence of additional materials. In certain embodiments, contacting may be performed in the presence of cells. In certain of such embodiments, one or more of the materials that are being contacted may be inside a cell. Cells may be alive or may dead. Cells may or may not be intact. Certain compounds
  • A is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R 1 , R 2 , and R 3 , said aryl and heteroaryl in the definition of A are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle; or A is lower saturated alkyl or C 3 -C 7 cycloalkyl;
  • L is L ⁇ O-L 3 or L'-O-l ⁇ -O- L 2 ;
  • L 1 is selected from the group consisting of carbonyl, an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted heterocycle;
  • L 2 is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted heterocycle;
  • L 3 is selected from the group consisting of lower saturated alkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
  • G is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R 4 , R 5 , and R 6 , said aryl and heteroaryl in the definition of G are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle; or G is lower saturated alkyl or C 3 -C 7 cycloalkyl; each R 1 is separately selected from the group consisting of halogen, an optionally substituted lower saturated alkyl, an optionally substituted Cj-C 6 alkoxy, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -C 6 alkynyl, an optionally substituted C 3 - C 7 cycloalkyl, an optionally substituted C 1 -C 6 haloalkyl, an optionally substituted C 1
  • each R 4 is separately selected from the group consisting of halogen, an optionally substituted lower saturated alkyl, an optionally substituted Cj-C 6 alkoxy, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -C 6 alkynyl, an optionally substituted C 3 - C 7 cycloalkyl, an optionally substituted Ci-C 6 haloalkyl, an optionally substituted Ci-C 6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; each R 4 is separately selected from the group consisting of halogen, an optionally substituted lower saturated alkyl, an optionally substituted Cj-C 6 alkoxy, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -C 6 alkynyl, an optionally substituted C 3 - C 7 cycloalkyl, an optionally substituted Cj-C 6 haloalkyl, an optionally substitute
  • Some embodiments include compounds of Formula I including the proviso that when L 1 is carbonyl then A and G are each individually selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R 1 , R 2 , and R 3 , said aryl and heteroaryl in the definition of A and G are each individually further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle; and including the proviso that when A is lower saturated alkyl or C 3 -C 7 cycloalkyl and G is lower saturated alkyl or C 3 -C 7 cycloalkyl then L comprises an aryl or heteroaryl.
  • Some embodiments include compounds of Formula I having the Formula Ia
  • each R 1 is separately selected from the group consisting of halogen, lower saturated alkyl, Cj-C 6 alkoxy, C 2 -C 6 alkenyl, C 3 -C 7 cycloalkyl, Cj-C 6 haloalkyl, Cj-C 6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; each R 2 is separately selected from the group consisting of halogen, -O(CH 2 ) m OR A , -(CH 2 ) m OR A , -NR B R C , -(CH 2 ) m SR A , -C(
  • each R 9 is separately selected from the group consisting of hydrogen and an optionally substituted lower saturated alkyl
  • Some embodiments include compounds of Formula I having the Formula Id:
  • Some embodiments include compounds of Formula I having the Formula Ie:
  • Some embodiments include compounds of Formula I having the Formula If:
  • Some embodiments include compounds of Formula I wherein:
  • A is selected from the group consisting of aryl and heteroaryl, each substituted with one or more substituents selected from the group consisting of R 1 , R 2 , and R 3 , said aryl and heteroaryl in the definition of A are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle; or A is lower saturated alkyl or C 3 - C 7 cycloalkyl;
  • R 1 is selected from the group consisting of fluorine, chlorine, and methyl
  • R 2 is selected from the group consisting of-(CH 2 ) m OR A , - NR B R C , and
  • R 3 is selected from the group consisting of-(CH2) m R G , -(CH 2 )PiOR 0 , and -(CH 2 ) m NR E R F ;
  • Some embodiments include compounds of Formula I including the proviso that when A and G are a phenyl then at least one of R 2 , R 3 , R 5 , and R 6 is selected from the group consisting of -CCH 2 ) m OR A , -(CH 2 ) m OR D , -NR B R C , -NR E R F , and an optionally substituted phenyl.
  • Some embodiments include compounds of Formula I wherein A and G are each independently selected from the group consisting of lower saturated alkyl and C 3 -C 7 cycloalkyl. In some embodiments A and G are each independently selected from the group consisting of iso-butyl and cyclohexyl. In some embodiments A and G are each independently selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R 1 , R 2 , and R 3 , said aryl and heteroaryl in the definition of A and G are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle. In some embodimenls L is selected from the group consisting of
  • L is selected from the group consisting of
  • a and G are each independently selected from the group consisting of phenyl, naphthyl, pyridinyl, pyrrolyl, pyrimidinyl, imidazolyl, isoxazolyl, thiazolyl, thienyl, furyl, indolyl, benzoxazolyl, benzthiazolyl, benzimidazolyl, 1 ,4-benzodioxan-6-yl, 1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl, benzothienyl, quinolinyl, and purinyl, said phenyl, naphthyl, pyridinyl, pyrrolyl, pyrimidinyl, imidazolyl, isoxazolyl,
  • L is selected from the group consisting of
  • L is selected from the group consisting of -(CH 2 )-O-L I -O-(CH 2 >-, -(CH 2 )-l ⁇ (CH 2 )-, -(CH ⁇ -L ⁇ CH ⁇ -, V-L 2 , h l -iCH 2 )-h 2 , and L'-O-L 2 ;
  • L 1 is selected from the group consisting of phenyl, pyridinyl, and piperidinyl, each optionally substituted with F, Cl, Br, Cj-C 3 lower saturated alkyl, Ci-C 3 alkoxy, and -(CH 2 )N(CH 3 ) 2 ;
  • L 2 is selected from the group consisting of phenyl and pyridinyl, each optionally substituted with F, Cl, Br, C 1 -C 3 lower saturated alkyl, C 1 -C 3 alkoxy, and -(CH 2 )N(CH 3 ),;
  • A is phenyl, optionally substituted with one or more substituents selected from the group consisting of R 1 , R 2 , and R 3 , said phenyl in the definition of A are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle;
  • G is phenyl, optionally substituted with one or more substituents selected from the group consisting of R 4 , R 5 , and R 6 , said phenyl in the definition of G are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle; each R 1 is separately selected from the group consisting of an optionally substituted aryl and an optionally substituted heteroaryl; each R 2 is separately selected from the group consisting of halogen, -(CH 2 ) m OR A , and -NR B R C , where R A in the definition of is R 2 selected from the group consisting of hydrogen, and lower saturated alkyl; each R 3 is fluoro; each NR B R C is separately selected, wherein R B and R are each independently selected from the group consisting of hydrogen and lower saturated alkyl; or NR R is a three - to six- membered optionally substituted aliphatic cyclic aminyl, which optionally has one additional hetero atom incorporated in the
  • A is substituted with one or more substituents selected from the group consisting of R 1 , R 2 , and R 3
  • G is substituted with one or more substituents selected from the group consisting of R 4 , R 5 , and R 6 .
  • A is phenyl, substituted with one or more substituents selected from the group consisting of R , R , and R , said phenyl in the definition of A are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle and G is phenyl, substituted with one or more substituents selected from the group consisting of R 4 , R 5 , and R 6 , said phenyl in the definition of G are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle.
  • a 4 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R 11 , R 12 , and R 13 , said aryl and heteroaryl in the definition of A 4 are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle;
  • G 4 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R , R , and R , said aryl and heteroaryl in the definition of G 4 are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle;
  • Some embodiments include compounds of Formula II including the proviso that when L is phenyl then at least one of A and G 4 is selected from the group consisting of aryl and heteroaryl, said A substituted with one or more substituents selected from the group consisting of R 11 , R 12 , and R 13 and said G 4 substituted with one or more substituents selected from the group consisting of R 14 , R 15 , and R 1 .
  • A is substituted with one or more substituents selected from the group consisting of R 11 , R 12 , and R 13 .
  • G is substituted with one or more substituents selected from the group consisting ofR 14 , R 15 , and R 16 .
  • Some embodiments include compounds of Formula II where A 4 is selected from the group consisting of phenyl, naphthyl, and indolyl, each optionally substituted with one or more substituents selected from the group consisting of R 11 , R 12 , and R 13 , said phenyl, naphthyl, and indolyl in the definition of A 4 are each further optionally fused with a nonaromatic heterocycle or carbocycle.
  • Some embodiments include compounds of Formula II having the Formula Ha:
  • a 4 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R 11 , R 12 , and R 13 , said aryl and heteroaryl in the definition of A 4 are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle;
  • G 4 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R 14 , R 15 , and R 16 , said aryl and heteroaryl in the definition of G are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle;
  • the compound of Formula II is selected from:
  • R 1 is selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted Ci-C 6 alkyl, a substituted or unsubstituted Ci-C 6 haloalkyl, a substituted or unsubstituted C 1 -C 6 heteroalkyl, and null;
  • R 2 is selected from the group consisting of hydrogen, halogen, OR A , NR ⁇ R B , SR A , a substituted or unsubstituted Ci-C 6 alkyl, a substituted or unsubstituted Ci-C 6 haloalkyl, and a substituted or unsubstituted Cj-C 6 heteroalkyl;
  • R 3 is selected from the group consisting of hydrogen, halogen, OR C , NR C R D , S(O) 0-2 R 0 , NO 2 , CN, (CH 2 ) m R E , a substituted or unsubstituted Cj-C 6 alkyl, a substituted or unsubstituted Q- C 6 haloalkyl, a substituted or unsubstituted Ci-C 6 heteroalkyl, and null;
  • R 4 is selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted Ci-C 6 alkyl, a substituted or unsubstituted Ci-C 6 haloalkyl, a substituted or unsubstituted Ci-C 6 heteroalkyl, and null;
  • R 5 is selected from the group consisting of hydrogen, halogen, 0R ⁇ , NR A R B , SR A , a substituted or unsubstituted Ci-C 6 alkyl, a substituted or unsubstituted Cj-C 6 haloalkyl, and a substituted or unsubstituted Cj-C 6 heteroalkyl;
  • R 6 is selected from the group consisting of hydrogen, halogen, OR C , NR C R D , S(O) 0-2 R 0 , NO 2 , CN, (CH 2 ) m R E , a substituted or unsubstituted Ci-C 6 alkyl, a substituted or unsubstituted Cj- C 6 haloalkyl, a substituted or unsubstituted Ci-C 6 heteroalkyl, and null;
  • R A is selected from the group consisting of hydrogen, Cj-C 6 alkyl, Ci-C 6 haloalkyl, Cj-C 6 heteroalkyl, and Cj-C 6 heterohaloalkyl;
  • R B is selected from hydrogen, SO 2 R F , COR F , CONR 0 R 0 , Ci-C 6 alkyl, Cj-C 6 haloalkyl, C]-C 6 heteroalkyl, and Cj-C 6 heterohaloalkyl; or R A and R B are linked to form a substituted or unsubstituted C 3 -C 8 ring;
  • R c and R D are each independently selected from the group consisting of hydrogen, a substituted or unsubstituted Ci-C 6 alkyl, a substituted or unsubstituted C]-C 6 haloalkyl, a substituted or unsubstituted Cj-C 6 heteroalkyl, and (CH 2 ) m R ; or one of R and R is a substituted or unsubstituted C 2 -C 6 alkyl and the other of R° and R D is null; or R° and R D are linked to form a substituted or unsubstituted C 3 -Cg ring;
  • R E is selected from a substituted or unsubstituted aryl and a substituted or unsubstituted heteroaryl;
  • R F is selected from the group consisting of hydrogen, C]-C 3 alkyl, Cj-C 3 haloalkyl, and a substituted or unsubstituted aryl or heteroaryl;
  • A is selected from the group consisting of a Cj-C 6 alkyl, a Cj-C 6 heteroalkyl, a monocyclic or bicyclic aromatic ring optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle;
  • G is selected from the group consisting of a Cj-C 6 alkyl, a Ci-C 6 heteroalkyl, a monocyclic or bicyclic aromatic ring optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle;
  • D is a 1 -6 atom spacer containing at least 2 heteroatoms separated by 3 or 4 bonds and comprising one or more groups selected from a substituted or unsubstituted C 1 -C 6 heteroalkyl, a substituted or unsubstituted heterocycle, and a substituted or unsubstituted heteroalkylheterocycle;
  • E is a 1-6 atom spacer containing at least 2 heteroatoms separated by 3 or 4 bonds and comprising one or more groups selected from a substituted or unsubstituted Ci-C 6 heteroalkyl, a substituted or unsubstituted heterocycle, and a substituted or unsubstituted heteroalkylheterocycle;
  • L is a 2-12 atom linker comprising one or more groups selected from O (oxygen), NR B , S(O) 0-2 , NR B S(O)i -2 NR A , NR B S(O)i -2 O, a substituted or unsubstituted Ci-Ci 0 alkyl, a substituted or unsubstituted Ci-Ci 0 haloalkyl, a substituted or unsubstituted Ci-C 8 heteroalkyl, a substituted or unsubstituted aryl, and a substituted or unsubstituted heteroaryl; where the aryl and heteroaryl are optionally fused with a nonaromatic heterocycle or a nonaromatic carbocycle; m is O, 1, or 2, and each dashed line independently represents an optional double bond.
  • Some embodiments include compounds of Formula III having the Formula IHa:
  • A is selected from the group consisting of aryl and heteroaryl, said aryl and heteroaryl in the definition of A are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle; or A is Ci-C 6 alkyl;
  • L 1 is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted heterocycle;
  • L 2 is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted heterocycle;
  • L 3 is selected from the group consisting of Ci-C 6 alkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
  • R 1 is selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted Cj-C 6 alkyl, a substituted or unsubstituted Ci-C 6 haloalkyl, and null;
  • R 2 is selected from the group consisting of hydrogen, halogen, -0R A , -NR A R B , -SR A , a substituted or unsubstituted Ci-C 6 alkyl, and a substituted or unsubstituted C]-C 6 haloalkyl;
  • R is selected from the group consisting of hydrogen, halogen, -OR , -NR R , -S(0)o -2 R C , -NO 2 , -CN, -(CH 2 ) m R E , a substituted or unsubstituted Ci-C 6 alkyl, a substituted or unsubstituted Ci-C 6 haloalkyl, and null;
  • R 4 is selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted Ci-C 6 alkyl, a substituted or unsubstituted C 1 -C 6 haloalkyl, and null;
  • R 5 is selected from the group consisting of hydrogen, halogen, -0R A , -NR ⁇ R B , -SR A , a substituted or unsubstituted Cj-C 6 alkyl, and a substituted or unsubstituted C 1 -C 6 haloalkyl;
  • R is selected from the group consisting of hydrogen, halogen, -OR , -NR R , -S(O) 0-2 R 0 , -NO 2 , -CN, -(CH 2 ) m R E , a substituted or unsubstituted Cj-C 6 alkyl, a substituted or unsubstituted Ci-C 6 haloalkyl, and null; each R 9 is separately selected from the group consisting of hydrogen, an optionally substituted C 3 -C 6 cycloalkyl, and an optionally substituted C 1 -C 3 lower saturated alkyl;
  • R A is selected from the group consisting of hydrogen, Ci-C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, and Ci-C 6 heterohaloalkyl;
  • R c and R D are each independently selected from the group consisting of hydrogen, a substituted or unsubstituted Ci-C 6 alkyl, a substituted or unsubstituted Ci-C 6 haloalkyl, a substituted or unsubstituted Ci-C 6 heteroalkyl, and -(CH 2 ) m R ;
  • R E is selected from a substituted or unsubstituted aryl and a substituted or unsubstituted heteroaryl;
  • R F is selected from the group consisting of hydrogen, Ci-C 3 alkyl, C 1 -C 3 haloalkyl, and a substituted or unsubstituted aryl or heteroaryl;
  • X is NH
  • Some embodiments include compounds of Formula Ha where L is selected
  • a and G are each independently selected from the group consisting of phenyl and wo-propyl.
  • the compound of Formula III is selected from:
  • R 11 is selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted C]-C 6 alkyl, a substituted or unsubstituted Ci-C 6 haloalkyl, a substituted or unsubstituted Cj-C 6 heteroalkyl, and null;
  • R 12' is selected from the group consisting of hydrogen, halogen, -0R A , -NR A R B , -SR A , a substituted or unsubstituted Cj-C 6 alkyl, a substituted or unsubstituted Cj-C 6 haloalkyl, and a substituted or unsubstituted Cj-C 6 heteroalkyl;
  • R 13' is selected from the group consisting of hydrogen, halogen, -OR C , -NR C R D , -S(O) 0- 2 R , -NO 2 , -CN, -(CH 2 ) m R , a substituted or unsubstituted Cj-C 6 alkyl, a substituted or unsubstituted C]-C 6 haloalkyl, a substituted or unsubstituted Ci-C 6 heteroalkyl, and null;
  • R 14 is selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted Cj-C 6 alkyl, a substituted or unsubstituted Ci-C 6 haloalkyl, a substituted or unsubstituted C]-C 6 heteroalkyl, and null;
  • R 15 is selected from the group consisting of hydrogen, halogen, -0R A , -NR A R B , -SR A , a substituted or unsubstituted C]-C 6 alkyl, a substituted or unsubstituted C]-C 6 haloalkyl, and a substituted or unsubstituted C]-C 6 heteroalkyl;
  • R 16' is selected from the group consisting of hydrogen, halogen, -OR C , -NR C R D , -S(0)o- 2 R C , -NO 2 , -CN, -(CH 2 ) m R E , a substituted or unsubstituted Ci -C 6 alkyl, a substituted or unsubstituted C)-C 6 haloalkyl, a substituted or unsubstituted Ci-C 6 heteroalkyl, and null;
  • R 17' , R 18' , R 19' , and R 20' are independently selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted C 1 -C 4 alkyl, a substituted or unsubstituted Ci- C 4 haloalkyl, and a substituted or unsubstituted C]-C 4 heteroalkyl; or R 17' and R 18 ' are linked to form a substituted or unsubstituted ring; or R 19 and R 2 are linked to form a substituted or unsubstituted ring; or R 17 and R 20 can be independently split into two groups when the carbon atoms they are attached become saturated;
  • R A is selected from the group consisting of hydrogen, CpC 6 alkyl, Ci-C 6 haloalkyl, Cj-C 6 heteroalkyl, and Ci-C 6 heterohaloalkyl;
  • R c and R D are each independently selected from the group consisting of hydrogen, a substituted or unsubstituted Ci-C 6 alkyl, a substituted or unsubstituted Ci-C 6 haloalkyl, a substituted or unsubstituted Ci-C 6 heteroalkyl, and -(CH 2 ) m R E ; or one of R c and R D is a substituted or unsubstituted C 2 -C 6 alkyl and the other of R and R is null; or R and R are linked to form a substituted or unsubstituted C 3 -Cg ring;
  • R E is selected from a substituted or unsubstituted aryl and a substituted or unsubstituted heteroaryl;
  • R F is selected from the group consisting of hydrogen, Cj-C 3 alkyl, Ci-C 3 haloalkyl, and a substituted or unsubstituted aryl or heteroaryl;
  • a 1 is selected from the group consisting of a Ci-C 6 alkyl, a Cj-C 6 heteroalkyl, and a monocyclic or bicyclic aromatic ring optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle;
  • G 1' is selected from the group consisting of a C 1 -C 6 alkyl, a C 1 -C 6 heteroalkyl, and a monocyclic or bicyclic aromatic ring optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle;
  • L 1' is a 2-12 atom long linker comprising one or more groups selected from -O- (oxygen), -NR B -, -S(O) 0-2 -, -NR 8 S(O) i -2 NR A - -NR B S(O) ]-2 O-, a substituted or unsubstituted C 1 -Ci O alkyl, a substituted or unsubstituted Ci-Ci 0 haloalkyl, a substituted or unsubstituted Ci-Ci 0 haloalkyl, a substituted or unsubstituted Ci-C 8 heteroalkyl, a substituted
  • X is selected from the group consisting of NR and C(R ) 2 ;
  • Y is selected from the group consisting of NR 19 and C(R 19 ) 2 ; m is O, 1, or 2; and each dashed line independently represents an optional double bond.
  • Some embodiments include compounds of Formula IV having the Formula IVa:
  • a 1' is selected from the group consisting of lower saturated alkyl, aryl and heteroaryl, said aryl and heteroaryl in the definition of A 1 are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle;
  • G 1' is selected from the group consisting of lower saturated alkyl, aryl and heteroaryl, said aryl and heteroaryl in the definition of G 1' are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle;
  • L 1 is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted heterocycle;
  • L 2 is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted heterocycle;
  • L 3 is selected from the group consisting of lower saturated alkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; each R 9 is separately selected from the group consisting of hydrogen, an optionally substituted C 3 -C 6 cycloalkyl, and an optionally substituted Ci-C 3 lower saturated alkyl;
  • R 11 is selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted lower saturated alkyl, a substituted or unsubstituted C 1 -C 6 haloalkyl, and null;
  • R 12 ' is selected from the group consisting of hydrogen, halogen, -OR A , -NR A R B , -SR A , a substituted or unsubstituted lower saturated alkyl, and a substituted or unsubstituted Ci-C 6 haloalkyl;
  • R is selected from the group consisting of hydrogen, halogen, -OR , -NR R , -S(O) 0-2 R c , -NO 2 , -CN, -(CH 2 ) m R E , a substituted or unsubstituted lower saturated alkyl, a substituted or unsubstituted Cj-C 6 haloalkyl, and null;
  • R 14' is selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted lower saturated alkyl, a substituted or unsubstituted Ci-C 6 haloalkyl, and null;
  • R 15 is selected from the group consisting of hydrogen, halogen, -OR A , -NR A R , -SR A , a substituted or unsubstituted lower saturated alkyl, and a substituted or unsubstituted C]-C 6 haloalkyl;
  • R 16 is selected from the group consisting of hydrogen, halogen, -OR C , -NR C R D , -S(0)o -2 R c , -NO 2 , -CN, -(CH 2 ) m R E , a substituted or unsubstituted lower saturated alkyl, a substituted or unsubstituted C 1 -C 6 haloalkyl, and null;
  • R A is selected from the group consisting of hydrogen, lower saturated alkyl, Ci-C 6 haloalkyl, Ci-C 6 heteroalkyl, and Cj-C 6 heterohaloalkyl
  • R c and R D are each independently selected from the group consisting of hydrogen, a substituted or unsubstituted lower saturated alkyl, a substituted or unsubstituted Ci-C 6 haloalkyl, a substituted or unsubstituted Ci-C 6 heteroalkyl, and - (CH 2 ) m R ;
  • R E is selected from a substituted or unsubstituted aryl and a substituted or unsubstituted heteroaryl;
  • R F is selected from the group consisting of hydrogen, Ci-C 3 alkyl, Ci-C 3 haloalkyl, and a substituted or unsubstituted aryl or heteroaryl; each p is independently 0, 1, 2, 3, 4, 5, or 6; and each q is independently 1, 2, 3, 4, 5, or 6. [0138] Some embodiments include compounds of Formula IVa where L 1 is selected
  • A' and G ' are each independently selected from the group consisting of phenyl and iso-propyl.
  • Certain compounds that modulate one or more HGF activity and/or bind to HGF receptors play a role in health.
  • compounds are useful for treating any of a variety of diseases or conditions.
  • a surprising discovery has been made that compounds with activity at the TPO receptor or other specific receptors also have broader HGF activity which can modulate HGF receptors affecting a wide range of diseases and disorders.
  • Some embodiments include compounds of Formulae I, II, III, or IV that can be an HGF mimetic, an HGF receptor agonist or an HGF receptor antagonist.
  • Some embodiments include compounds of Formulae I, II, HI, or IV that can be a hematopoietic growth factor mimetic, a hematopoietic growth factor receptor agonist or a a hematopoietic growth factor receptor antagonist. Some embodiments include compounds of Formulae I, II, III, or IV that can be an EPO mimic. Some embodiments include compounds of Formulae I, H, III, or IV that can be a selective EPO receptor agonist. Some embodiments include compounds of Formulae I, H, III, or IV that can be a selective EPO receptor partial agonist. Some embodiments include compounds of Formulae I, II, HI, or IV that can be a selective EPO receptor antagonist. Some embodiments include compounds of Formulae I, H, III, or IV that can be a selective EPO receptor binding compound.
  • Certain embodiments provide selective HGF modulators. Certain embodiments provide selective HGF receptor binding agents. Certain embodiments provide methods of making and methods of using selective HGF modulators and/or selective HGF receptor binding agents. In certain embodiments, selective HGF modulators are agonists, partial agonists, and/or antagonists for the HGF receptor.
  • Certain compounds that modulate one or more EPO activity and/or bind to EPO receptors play a role in health.
  • compounds are useful for treating any of a variety of diseases or conditions.
  • a surprising discovery has been made that compounds with activity at the TPO receptor or other specific receptors also have broader EPO activity which can modulate EPO receptors affecting a wide range of diseases and disorders.
  • Certain embodiments provide selective EPO modulators. Certain embodiments provide selective EPO receptor binding agents. Certain embodiments provide methods of making and methods of using selective EPO modulators and/or selective EPO receptor binding agents. In certain embodiments, selective EPO modulators are agonists, partial agonists, and/or antagonists for the EPO receptor.
  • the compounds disclosed herein can be used alone or in combination with other agents, for example, to modulate hematopoiesis, erythropoiesis, granulopoiesis, thrombopoiesis, and myelopoiesis.
  • the instant compounds can also be used alone or in combination with other agents in treatment or prevention of a disease or condition caused by abnormal function of hematopoiesis, erythropoiesis, granulopoiesis, thrombopoiesis, and myelopoiesis.
  • diseases include anemia, neutropenia, thrombocytopenia, cardiovascular disorders, immune/autoimmune disorders, cancers, infectious disorders or diseases, and neurologic disorders.
  • Certain compounds of the present embodiments may exist as stereoisomers including optical isomers.
  • the present disclosure is intended to include all stereoisomers and both the racemic mixtures of such stereoisomers as well as the individual enantiomers that may be separated according to methods that are known in the art or that may be excluded by synthesis schemes known in the art designed to yield predominantly one enantiomer relative to another.
  • a salt corresponding to a selective HGF modulator is provided.
  • a salt corresponding to a selective HGF receptor binding agent is provided.
  • a salt is obtained by reacting a compound with an acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • a salt is obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as choline, dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, 4-(2- hydroxyethyl)-morpholine, l-(2-hydroxyethyl)-pyrrolidine, ethanolamine and salts with amino acids such as arginine, lysine, and the like.
  • a salt is obtained by reacting a free acid form of a selective HGF modulator or selective HGF binding agent with multiple molar equivalents of a base, such as bis-sodium, bis-ethanolamine, and the like.
  • a salt corresponding to a selective EPO modulator is provided.
  • a salt corresponding to a selective EPO receptor binding agent is provided.
  • a salt is obtained by reacting a compound with an acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • a salt is obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as choline, dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, 4-(2- hydroxyethyl)-morpholine, l-(2-hydroxyethyl)-pyrrolidine, ethanolamine and salts with amino acids such as arginine, lysine, and the like.
  • a salt is obtained by reacting a free acid form of a selective EPO modulator or selective EPO binding agent with multiple molar equivalents of a base, such as bis-sodium, bis-ethanolamine, and the like.
  • a salt corresponding to a compound of the present embodiments is selected from acetate, ammonium, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, cholinate, clavulanate, citrate, dihydrochloride, diphosphate, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabanine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mucate, napsylate, nitrate, N-methylglucamine, oxalate
  • Some embodiments provide a pharmaceutical composition
  • a pharmaceutical composition comprising a physiologically acceptable carrier, diluent, or excipient; and a compqund of Formulae I, II, III, or IV.
  • one or more carbon atoms of a compound of the present embodiments are replaced with silicon. See e.g., WO 03/037905 Al; Tacke and Zilch, Endeavour, New Series, 10, 191-197 (1986); Bains and Tacke, Curr. Opin. Drug Discov Devel. Jul:6(4):526-43(2003), all of which are incorporated herein by reference in their entirety.
  • compounds comprising one or more silicon atoms possess certain desired properties, including, but not limited to, greater stability and/or longer half-life in a patient, when compared to the same compound in which none of the carbon atoms have been replaced with a silicon atom.
  • assays may be used to determine the level of HGF modulating activity of the compounds of the present embodiments.
  • assays may be used to determine the level of EPO modulating activity of the compounds of the present embodiments.
  • Proliferation Assays may be used to determine the level of EPO modulating activity of the compounds of the present embodiments.
  • compounds are tested in an in vitro proliferation assay using the cell lines that express EPO, TPO, GCSF or other cytokine receptors that may be dependant upon these cytokines for their growth.
  • Luciferase Assay uses the cell lines that express EPO, TPO, GCSF or other cytokine receptors that may be dependant upon these cytokines for their growth.
  • compounds are tested in a reporter assay using the cell lines that express EPO, TPO, GCSF or other cytokine receptors. These cells are transfected with the STAT responsive reporter (such as luciferase) and the activity of the compounds is determined by a reporter assay.
  • STAT responsive reporter such as luciferase
  • compounds are tested in purified human CD34+ progenitor cells. After addition of the compounds to the cells, the number of cells expressing markers of hematopoiesis, erythropoiesis, granulopoiesis, thrombopoiesis, or myelopoiesis is measured by flow cytometry or by analyzing expression of genes associated with these pathways.
  • Techniques for formulation and administration of compounds of the present embodiments may be found for example, in "Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, PA, 18th edition, 1990, which is incorporated herein by reference in its entirety.
  • Techniques for formulation and administration of compounds of the present embodiments may be found for example, in "Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, PA, 18th edition, 1990, which is incorporated herein by reference in its entirety.
  • a pharmaceutical agent comprising one or more compounds of the present embodiments is prepared using known techniques, including, but not limited to mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tabletting processes.
  • a pharmaceutical agent comprising one or more compounds of the present embodiments is a liquid (e.g., a suspension, elixir and/or solution).
  • a liquid pharmaceutical agent comprising one or more compounds of the present embodiments is prepared using ingredients known in the art, including, but not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.
  • a pharmaceutical agent comprising one or more compounds of the present embodiments is a solid (e.g. , a powder, tablet, and/or capsule).
  • a solid pharmaceutical agent comprising one or more compounds of the present embodiments is prepared using ingredients known in the art, including, but not limited to, starches, sugars, diluents, granulating agents, lubricants, binders, and disintegrating agents.
  • a pharmaceutical agent comprising one or more compounds of the present embodiments is formulated as a depot preparation.
  • Certain such depot preparations are typically longer acting than non-depot preparations.
  • such preparations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • depot preparations are prepared using suitable polymeric or hydrophobic materials (for example an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • a pharmaceutical agent comprising one or more compounds of the present embodiments comprises a delivery system.
  • delivery systems include, but are not limited to, liposomes and emulsions. Certain delivery systems are useful for preparing certain pharmaceutical agents including those comprising hydrophobic compounds. In certain embodiments, certain organic solvents such as dimethylsulfoxide are used.
  • a pharmaceutical agent comprising one or more compounds of the present embodiments comprises one or more tissue-specific delivery molecules designed to deliver the pharmaceutical agent to specific tissues or cell types.
  • pharmaceutical agents include liposomes coated with a tissue-specific antibody.
  • a pharmaceutical agent comprising one or more compounds of the present embodiments comprises a co-solvent system.
  • co-solvent systems comprise, for example, benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • co-solvent systems are used for hydrophobic compounds.
  • VPD co-solvent system is a solution of absolute ethanol comprising 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant POL YSORBATE 80TM , and 65% w/v polyethylene glycol 300.
  • co-solvent systems may be varied considerably without significantly altering their solubility and toxicity characteristics.
  • identity of co-solvent components may be varied: for example, other surfactants may be used instead of POLYSORBATE 80TM; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.
  • a pharmaceutical agent comprising one or more compounds of the present embodiments comprises a sustained-release system.
  • a sustained-release system is a semi-permeable matrix of solid hydrophobic polymers.
  • sustained-release systems may, depending on their chemical nature, release compounds over a period of hours, days, weeks or months.
  • compositions used in pharmaceutical agent of the present embodiments may be provided as pharmaceutically acceptable salts with pharmaceutically compatible counterions.
  • Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc.
  • a pharmaceutical agent comprising one or more compounds of the present embodiments comprises an active ingredient in a therapeutically effective amount.
  • the therapeutically effective amount is sufficient to prevent, alleviate or ameliorate symptoms of a disease or to prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art.
  • a pharmaceutical agent comprising one or more compounds of the present embodiments is formulated as a prodrug.
  • prodrugs are useful because they are easier to administer than the corresponding active form.
  • a prodrug may be more bioavailable (e.g., through oral administration) than is the corresponding active form.
  • a prodrug may have improved solubility compared to the corresponding active form.
  • a prodrug is an ester.
  • such prodrugs are less water soluble than the corresponding active form.
  • such prodrugs possess superior transmittal across cell membranes, where water solubility is detrimental to mobility.
  • the ester in such prodrugs is metabolically hydrolyzed to carboxylic acid.
  • the carboxylic acid containing compound is the corresponding active form.
  • a prodrug comprises a short peptide (polyaminoacid) bound to an acid group.
  • the peptide is metabolized to form the corresponding active form.
  • a pharmaceutical agent comprising one or more compounds of the present embodiments is useful for treating a conditions or disorder in a mammalian, and particularly in a human patient.
  • Suitable administration routes include, but are not limited to, oral, rectal, transmucosal, intestinal, enteral, topical, suppository, through inhalation, intrathecal, intraventricular, intraperitoneal, intranasal, intraocular and parenteral (e.g., intravenous, intramuscular, intramedullary, and subcutaneous).
  • pharmaceutical intrathecals are administered to achieve local rather than systemic exposures.
  • pharmaceutical agents may be injected directly in the area of desired effect (e.g., in the renal or cardiac area).
  • a pharmaceutical agent comprising one or more compounds of the present embodiments is administered in the form of a dosage unit (e.g., tablet, capsule, bolus, etc.).
  • dosage units comprise a selective EPO modulator in a dose from about 1 ⁇ g/kg of body weight to about 50 mg/kg of body weight.
  • dosage units comprise a selective EPO modulator in a dose from about 2 ⁇ g/kg of body weight to about 25 mg/kg of body weight.
  • such dosage units comprise a selective EPO modulator in a dose from about 10 ⁇ g/kg of body weight to about 5 mg/kg of body weight.
  • pharmaceutical agents are administered as needed, once per day, twice per day, three times per day, or four or more times per day. It is recognized by those skilled in the art that the particular dose, frequency, and duration of administration depends on a number of factors, including, without limitation, the biological activity desired, the condition of the patient, and tolerance for the pharmaceutical agent.
  • a pharmaceutical agent comprising a compound of the present embodiments is prepared for oral administration.
  • a pharmaceutical agent is formulated by combining one or more compounds of the present embodiments with one or more pharmaceutically acceptable carriers.
  • compositions of the present embodiments enable compounds of the present embodiments to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient.
  • pharmaceutical agents for oral use are obtained by mixing one or more compounds of the present embodiments and one or more solid excipient.
  • Suitable excipients include, but are not limited to, fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • such a mixture is optionally ground and auxiliaries are optionally added.
  • pharmaceutical agents are formed to obtain tablets or dragee cores.
  • disintegrating agents e.g., cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate are added.
  • dragee cores are provided with coatings.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to tablets or dragee coatings.
  • pharmaceutical agents for oral administration are push-fit capsules made of gelatin. Certain of such push-fit capsules comprise one or more compounds of the present embodiments in admixture with one or more filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • pharmaceutical agents for oral administration are soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • one or more compounds of the present embodiments are be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • pharmaceutical agents are prepared for buccal administration. Certain of such pharmaceutical agents are tablets or lozenges formulated in conventional manner.
  • a pharmaceutical agent is prepared for administration by injection (e.g., intravenous, subcutaneous, intramuscular, etc.).
  • a pharmaceutical agent comprises a carrier and is formulated in aqueous solution, such as water or physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
  • other ingredients are included (e.g., ingredients that aid in solubility or serve as preservatives).
  • injectable suspensions are prepared using appropriate liquid carriers, suspending agents and the like. Certain pharmaceutical agents for injection are presented in unit dosage form, e.g., in ampoules or in multi-dose containers.
  • Certain pharmaceutical agents for injection are suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • Certain solvents suitable for use in pharmaceutical agents for injection include, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes.
  • Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • such suspensions may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • a pharmaceutical agent is prepared for transmucosal administration.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • a pharmaceutical agent is prepared for administration by inhalation.
  • Certain of such pharmaceutical agents for inhalation are prepared in the form of an aerosol spray in a pressurized pack or a nebulizer.
  • Certain of such pharmaceutical agents comprise a propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined with a valve that delivers a metered amount.
  • capsules and cartridges for use in an inhaler or insufflator may be formulated.
  • Certain of such formulations comprise a powder mixture of a compound of the present embodiments and a suitable powder base such as lactose or starch.
  • a pharmaceutical agent is prepared for rectal administration, such as a suppositories or retention enema.
  • Certain of such pharmaceutical agents comprise known ingredients, such as cocoa butter and/or other glycerides.
  • a pharmaceutical agent is prepared for topical administration.
  • Certain of such pharmaceutical agents comprise bland moisturizing bases, such as ointments or creams.
  • ointment bases include, but are not limited to, petrolatum, petrolatum plus volatile silicones, lanolin and water in oil emulsions such as EUCERINTM, available from Beiersdorf (Cincinnati, Ohio).
  • Exemplary suitable cream bases include, but are not limited to, NIVEATM Cream, available from Beiersdorf (Cincinnati, Ohio), cold cream (USP), PURPOSE CREAMTM, available from Johnson & Johnson (New Brunswick, New Jersey), hydrophilic ointment (USP) and LUBRIDERMTM, available from Pfizer (Morris Plains, New Jersey).
  • the formulation, route of administration and dosage for a pharmaceutical agent of the present embodiments can be chosen in view of a particular patient's condition. (See e.g., Fingl et al. 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p. 1, which is incorporated herein by reference in its entirety).
  • a pharmaceutical agent is administered as a single dose.
  • a pharmaceutical agent is administered as a series of two or more doses administered over one or more days.
  • a pharmaceutical agent of the present embodiments is administered to a patient between about 0.1% and 500%, 5% and 200%, 10% and 100%, 15% and 85%, 25% and 75%, or 40% and 60% of an established human dosage.
  • a suitable human dosage may be inferred from ED 50 or ID 50 values, or other appropriate values derived from in vitro or in vivo studies.
  • a daily dosage regimen for a patient comprises an oral dose of between 0.1 mg and 2000 mg, 5 mg and 1500 mg, 10 mg and 1000 mg, 20 mg and 500 mg, 30 mg and 200 mg, or 40 mg and 100 mg of a compound of the present embodiments.
  • a daily dosage regimen is administered as a single daily dose.
  • a daily dosage regimen is administered as two, three, four, or more than four doses.
  • a pharmaceutical agent of the present embodiments is administered by continuous intravenous infusion. In certain of such embodiments, from 0.1 mg to 500 mg of a composition of the present embodiments is administered per day.
  • a pharmaceutical agent of the present embodiments is administered for a period of continuous therapy.
  • a pharmaceutical agent of the present embodiments may be administered over a period of days, weeks, months, or years.
  • Dosage amount, interval between doses, and duration of treatment may be adjusted to achieve a desired effect.
  • dosage amount and interval between doses are adjusted to maintain a desired concentration on compound in a patient.
  • dosage amount and interval between doses are adjusted to provide plasma concentration of a compound of the present embodiments at an amount sufficient to achieve a desired effect.
  • the plasma concentration is maintained above the minimal effective concentration (MEC).
  • pharmaceutical agents of the present embodiments are administered with a dosage regimen designed to maintain a concentration above the MEC for 10-90% of the time, between 30-90% of the time, or between 50-90% of the time.
  • the dosage regimen is adjusted to achieve a desired local concentration of a compound of the present embodiments.
  • a pharmaceutical agent may be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
  • Compositions comprising a compound of the present embodiments formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • a pharmaceutical agent is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • one or more pharmaceutical agents of the present embodiments are co-administered with one or more other pharmaceutical agents.
  • such one or more other pharmaceutical agents are designed to treat the same disease or condition as the one or more pharmaceutical agents of the present embodiments.
  • such one or more other pharmaceutical agents are designed to treat a different disease or condition as the one or more pharmaceutical agents of the present embodiments.
  • such one or more other pharmaceutical agents are designed to treat an undesired effect of one or more pharmaceutical agents of the present embodiments.
  • one or more pharmaceutical agents of the present embodiments are co-administered with another pharmaceutical agent to treat an undesired effect of that other pharmaceutical agent.
  • one or more pharmaceutical agents of the present embodiments and one or more other pharmaceutical agents are administered at the same time. In certain embodiments, one or more pharmaceutical agents of the present embodiments and one or more other pharmaceutical agents are administered at the different times. In certain embodiments, one or more pharmaceutical agents of the present embodiments and one or more other pharmaceutical agents are prepared together in a single formulation. In certain embodiments, one or more pharmaceutical agents of the present embodiments and one or more other pharmaceutical agents are prepared separately.
  • Examples of pharmaceutical agents that may be co-administered with a pharmaceutical agent of the present embodiments include, but are not limited to, anti-cancer treatments, including, but not limited to, chemotherapy and radiation treatment; corticosteroids, including but not limited to prednisone; immunoglobulins, including, but not limited to intravenous immunoglobulin (IVIg); erythropoiesis-stimulating agents, including, but not limited to, biologically engineered erythropoietin regiments; analgesics (e.g., acetaminophen); anti- inflammatory agents, including, but not limited to non-steroidal anti-inflammatory drugs (e.g., ibuprofen, COX-I inhibitors, and COX-2, inhibitors); salicylates; antibiotics; antivirals; antifungal agents; antidiabetic agents (e.g., biguanides, glucosidase inhibitors, insulins, sulfonylurea
  • thrombocytopenia results from chemotherapy and/or radiation treatment.
  • thrombocytopenia results bone marrow failure resulting from bone marrow transplantation and/or aplastic anemia.
  • thrombocytopenia is idiopathic.
  • one or more compounds of the present embodiments are administered to a patient to in conjunction with harvesting peripheral blood progenitor cells and/or in conjunction with platelet apheresis. Such administration may be done before, during, and/or after such harvesting.
  • Some embodiments provide a method for modulating an EPO activity in a cell comprising contacting a cell with a compound of Formulae I, II, III, or IV. Some embodiments provide a method for modulating an EPO activity in a cell comprising contacting a cell with a compound of Formulae I, II, III, or IV. Some embodiments provide a method for identifying a compound that modulates an EPO activity, comprising contacting a cell that expresses an EPO receptor with a compound of Formulae I, II, HI, or IV; and monitoring an effect of the compound on the cell.
  • Some embodiments provide a method of treating a patient, comprising administering to the patient a compound of Formulae I, II, HI, or IV.
  • the patient suffers from an anemia, a neutropenia, a cardiovascular disorder, an immune/autoimmune disorder, an infectious disorder, and a neurologic disorder.
  • the patient suffers from an anemia, a neutropenia, a cardiovascular disorder, an immune/autoimmune disorder, an infectious disorder, and a neurologic disorder.
  • the disease or condition results from radiation or chemotherapy.
  • the disease or condition results from radiation and chemotherapy.
  • the method further comprises harvesting cells from the patient.
  • the treatment is prophylactic.
  • the patient suffers from a condition affecting the nervous system. In some embodiments the patient suffers from a disease selected from amyotrophic lateral sclerosis, multiple sclerosis, and multiple dystrophy. In some embodiments the patient suffers from injury to the nervous system. In some embodiments the patient suffers from injury to the spinal cord.
  • Some embodiments provide a pharmaceutical composition comprising a compound of Formulae I, II, III, or IV for use in treating a condition selected from an anemia, a neutropenia, a cardiovascular disorder, an immune/autoimmune disorder, a cancer, an infectious disorder, and a neurologic disorder.
  • one or more compounds of the present embodiments are administered to a patient who suffers from a condition affecting the nervous system, including, but are not limited to, diseases affecting the nervous system and injuries to the nervous system. Such diseases, include, but not limited to, amyotrophic lateral sclerosis, multiple sclerosis, and multiple dystrophy.
  • Damage to the nervous system include, but are not limited to spinal cord injury or peripheral nerve damage, including, but not limited to, injury resulting from trauma or from stroke.
  • one or more compounds of the present embodiments are used to promote growth and/or development of glial cells. Such glial cells may repair nerve cells.
  • compounds of the present embodiments are used to treat psychological disorders, including, but not limited to, cognitive disorders.
  • EXAMPLE 170 1 ,4-Phenylene-bis(3E-acryl-2-(3-cyanobenzylidene)hydrazide) (Compound 270)

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Abstract

Compounds with physiological effects, such as the activation of hematopoietic growth factor receptors, are disclosed. These compounds can be used to treat a variety of conditions, diseases and ailments, including hematopoietic conditions and disorders.

Description

SMALL MOLECULE HEMATOPOIETIC GROWTH FACTOR MIMETIC COMPOUNDS AND THEIR USES
FIELD OF THE INVENTION
[0001] Certain embodiments of the invention relate to compounds with physiological effects, such as the activation of hematopoietic growth factor receptors. Certain embodiments of the invention relate to use of such compounds to treat a variety of conditions, diseases and ailments such as hematopoietic conditions and disorders.
BACKGROUND
[0002] Hematopoietic growth factor (HGF) represents a family of biological molecules such as glycoproteins with regulatory functions in the processes of cell proliferation, differentiation, and functional activation of hematopoietic progenitors and mature blood cells. HGF compounds can regulate blood cell proliferation and development in the bone marrow. HGF compounds can augment hematopoiesis when bone marrow dysfunction exists. Recombinant DNA technology has made it possible to clone the genes responsible for certain HGFs.
[0003] One example of an HGF is thrombopoietin (TPO), also referred to as c-Mpl ligand, mpl ligand, megapoietin, and megakaryocyte growth and development factor, is a glycoprotein that has been shown to be involved in production of platelets. See, e.g., Wendling, F., et al., Biotherapy 10(4):269-77 (1998); Kuter D.J. et al, The Oncologist, 1 :98-106(1996); Metcalf, Nature 369: 519-520 (1994), all of which are incorporated herein by reference in their entirety. TPO has been cloned and both its amino acid sequence and the cDNA sequence encoding it have been described. See, e.g., U.S. 5,766,581; Kuter, DJ. et al, Proc. Natl. Acad. ScL, 91 :11104-11108 (1994); de Sauvage F.V., et al, Nature, 369: 533-538 (1994); Lok, S. et al, Nature 369:565-568 (1994); Wending, F. et al, Nature, 369: 571-574 (1994), all of which are incorporated herein by reference in their entireties.
[0004] In certain instances, TPO activity results from binding of TPO to the TPO receptor (also called MPL). The TPO receptor has been cloned and its amino acid sequence has been described. See, e.g., Vigon et al, Proc. Natl. Acad. Sci., 89:5640-5644 (1992), which is incorporated herein by reference in its entirety. [0005] In certain instances, TPO modulators may be useful in treating a variety of hematopoietic conditions, including, but not limited to, thrombocytopenia. See e.g., Baser et al. Blood 89:3118-3128 (1997); Fanucchi et al. New Engl. J. Med. 336:404-409 (1997), both of which are incorporated herein by reference in their entirety. For example, patients undergoing certain chemotherapies, including but not limited to chemotherapy and/or radiation therapy for the treatment of cancer, may have reduced platelet levels. In certain instances, treating such patients with a selective TPO modulator increases platelet levels. In certain instances, selective TPO modulators stimulate production of glial cells, which may result in repair of damaged nerve cells.
[0006] Another example of an HGF is the glycoprotein hormone erythropoietin (EPO). EPO is an essential viability and growth factor for the erythrocytic progenitors. EPO is a member of the family of class I cytokines which fold into a compact globular structure consisting of 4 α-helical bundles. Its molecular mass is 30.4 kDa, although it migrates with an apparent size of 34-38 kDa on SDS-polyacrylamide gels. The peptide core of 165 amino acids suffices for receptor-binding and in vitro stimulation of erythropoiesis, while the carbohydrate portion (40% of the total molecule) is required for the in vivo survival of the hormone. The 4 carbohydrate chains of EPO have been analyzed in detail. The 3 complex-type N-linked oligosaccharides at asparagines 24, 38 and 83 appear involved in stabilizing EPO in circulation. EPO is mainly produced by hepatocytes during the fetal stage. After birth, almost all circulating EPO originates from peritubular fibroblast-like cells located in the cortex of the kidneys. Transcription factors of the GATA-family may be important in the control of the time-specific and tissue-specific expression of the EPO gene. In adults, minor amounts of EPO mRNA are expressed in liver parenchyma, spleen, lung, testis and brain. In brain, EPO exerts neurotrophic and neuroprotective effects, which are separate from the action of circulating EPO on erythropoietic tissues. See, e.g., Jelkmann, W., Internal Medicine Vol. 43, No.8 (August 2004).
SUMMARY OF THE INVENTION [0007] Some embodiments disclosed herein provide a compound of Formula I:
Figure imgf000004_0001
and pharmaceutically acceptable salts, esters, or prodrugs thereof; wherein:
A is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R1, R2, and R3, said aryl and heteroaryl in the definition of A are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle; or A is lower saturated alkyl or C3-C7 cycloalkyl;
J is -(CH2)mNR9C(=O)(CH2)ra-;
L is selected from the group consisting of lower saturated alkyl -L1, lower saturated alkyl-L'-lower saturated alkyl, lower saturated alkylNR9(CH2)in-L1, lower saturated alkylNR9C(=O)-lΛ -(CH2)mC(=O)NR9(CH2)q-L1, -(CH2)mO-L1-O(CH2)q-, -(CH2)m-lΛ(CH2)q-, -(CH=CH)1n-L1^CH=CH)4-, L1 L2, L'-O-L2, L'-(CH=CH)q-L2, L^(CH2VL2, L^O(CH2)PO-L2, and L1-C(=O)NR9-L2; or L is L'-O-L3 or L!-O-L3-O- L2;
L1 is selected from the group consisting of carbonyl, an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted heterocycle;
L2 is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted heterocycle;
L3 is selected from the group consisting of lower saturated alkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
Q is -(CH2)mNR9C(=O)(CH2)m-;
G is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R , R5, and R , said aryl and heteroaryl in the definition of G are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle; or G is lower saturated alkylor C3-C7 cycloalkyl; each R1 is separately selected from the group consisting of halogen, an optionally substituted lower saturated alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3- C7 cycloalkyl, an optionally substituted Cj-C6 haloalkyl, an optionally substituted Ci-C6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; each R2 is separately selected from the group consisting of halogen, -O(CH2)mORA, -(CH2)mORA, -NRBRC, -(CH2)mSRA, -C(=0)RH, -(CH2)mRH, an optionally substituted lower saturated alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted Ci-C6 haloalkyl, an optionally substituted Ci-C6 heteroalkyl, and an optionally substituted C3-7 cycloalkyl where said C3-7 cycloalkyl is further optionally fused with aryl or heteroaryl; each R3 is separately selected from the group consisting of halogen, -(CH2)mORD, -NRHC(=0)RD, -NRERF, -(CH2)mS(O)0-2RD, -(CH2)mNO2, -(CH2)mCN, -(CH2)mRG, an optionally substituted lower saturated alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3- C7 cycloalkyl, an optionally substituted Ci-C6 haloalkyl, an optionally substituted Ci-C6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; each R4 is separately selected from the group consisting of halogen, an optionally substituted lower saturated alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3- C7 cycloalkyl, an optionally substituted Ci-C6 haloalkyl, an optionally substituted Cj-C6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; each R5 is separately selected from the group consisting of halogen, -O(CH2)mORA, -(CH2)raORA, -NRBRC, -(CH2)mSRA, -C(=O)RH, -(CH2)mRH, an optionally substituted lower saturated alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, an optionally substituted Ci-C6 haloalkyl, and an optionally substituted Cj-C6 heteroalkyl; each R6 is separately selected from the group consisting of halogen, -(CH2)mORD, -NRHC(=0)RD, -NRERF, -(CH2)raS(O)0-2RD, -(CH2)mNO2, -(CH2)raCN, -(CH2)mRG, an optionally substituted lower saturated alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, an optionally substituted Ci-C6 haloalkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; each R7 is separately selected from the group consisting of hydrogen, C3-C7 cycloalkyl, and lower saturated alkyl; each R9 is separately selected from the group consisting of hydrogen, an optionally substituted C3-C7 cycloalkyl, and an optionally substituted lower saturated alkyl;
R is selected from the group consisting of hydrogen, -SO2R , -C(=O)R , -C(=O)NRERF, lower saturated alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, C]-C6 haloalkyl, Ci-C6 heteroalkyl, and C1-C6 heterohaloalkyl;
H I"1 ft tf~* each -NR R is separately selected, wherein R and R are each independently selected from the group consisting of hydrogen, -(CH2)mRH, -(CH2)raORH, -SO2RH, -C(=O)RH, -C(=0)NRERF, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, lower saturated alkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, and C]-C6 heterohaloalkyl, where the lower saturated alkyl and the Ci-C6 heteroalkyl in the definition of R and R are optionally substituted with an optionally substituted aryl or an optionally substituted heteroaryl, and where the optionally substituted C3-C7 cycloalkyl in the definition of R and R is further optionally fused with an optionally substituted aryl or an optionally substituted heteroaryl; or -NRBRC is a three - to eight- membered optionally substituted aliphatic cyclic aminyl, which optionally has one to three additional hetero atoms incorporated in the ring; or -NR R is an optionally substituted Cj-C6 alkylideneaminyl; each RD is independently selected from the group consisting of hydrogen, an optionally substituted lower saturated alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, an optionally substituted Ci-C6 haloalkyl, an optionally substituted C1-C6 heteroalkyl, and -(CH2)mRG;
V V V V each -NR R is separately selected, wherein R and R are each independently selected from the group consisting of hydrogen, an optionally substituted lower saturated alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, an optionally substituted Cj-C6 haloalkyl, an optionally substituted Ci-C6 heteroalkyl, -(CH2)mRG, and -(CH2)mORG; or NRERF is an optionally substituted Cj-C6 alkylideneaminyl; or -NRERF is a three - to eight- membered optionally substituted aliphatic cyclic aminyl, which optionally has one to three additional hetero atoms incorporated in the ring; each RG is independently selected from an optionally substituted aryl and an optionally substituted heteroaryl; each RH is independently selected from the group consisting of hydrogen, -OH, Cj-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, an optionally substituted C3-C7 cycloalkyl, Ci-C3 haloalkyl, an optionally substituted aryl and an optionally substituted heteroaryl; each m is independently 0, 1, 2, or 3; each n is independently 0, 1, 2, or 3; each p is independently 0, 1, 2, 3, 4, 5, or 6; each q is independently 1, 2, 3, 4, 5, or 6; and each dashed line independently represents an optional double bond.
[0008] Some embodiments disclosed herein provide a compound of Formula II:
Figure imgf000007_0001
and pharmaceutically acceptable salts, esters, or prodrugs thereof; wherein:
A4 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R11, R12, and R13, said aryl and heteroaryl in the definition of A4 are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle;
G4 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R14, R15, and R16, said aryl and heteroaryl in the definition of G4 are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle;
L4 is selected from the group consisting of an optionally substituted C2-Ci0 alkenyl, an optionally substituted C2-C)0 alkynyl, an optionally substituted aryl, and an optionally substituted heteroaryl; each R11 is separately selected from the group consisting of an optionally substituted Q- C6 alkoxy, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, an optionally substituted Ci-C6 haloalkyl, an optionally substituted Cj-C6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; each R12 is separately selected from the group consisting of -O(CH2)mORA, -(CH2)mORA, -NRBRC, -(CH2)mSRA, -C(=O)RH, -CCH2)mRH, and an optionally substituted C3-7 cycloalkyl where said C3-7 cycloalkyl is further optionally fused with aryl or heteroaryl; each R13 is separately selected from the group consisting of -(CH2)mORD, -NRHC(=0)RD, -NRERF, -(CH2)mS(O)0-2RD, -(CH2)mNO2, -(CH2)mCN, and -(CH2)mRG; each R14 is separately selected from the group consisting of an optionally substituted Ci- C6 alkoxy, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted Cj-C6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; each R15 is separately selected from the group consisting of -O(CH2)mORA, -(CH2)mORA, -NRBRC, -(CH2)mSRA, -C(=O)RH, -(CH2)mRH, and an optionally substituted C3-7 cycloalkyl where said C3-7 cycloalkyl is further optionally fused with aryl or heteroaryl; each R16 is separately selected from the group consisting of -(CH2)mORD, -NRHC(=O)RD, -NRERF, -(CH2)mS(O)0-2RD, -(CH2)mNO2, -(CH2)mCN, and -(CH2)mRG; each R17 is separately selected from the group consisting of hydrogen, C3-C7 cycloalkyl,. and lower saturated alkyl; each R19 is separately selected from the group consisting of hydrogen, an optionally substituted C3-C7 cycloalkyl, and an optionally substituted lower saturated alkyl;
RA is selected from the group consisting of hydrogen, -SO2RH, -C(=O)RH, -C(=0)NRERF, lower saturated alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, and Cj-C6 heterohaloalkyl; each -NRBRC is separately selected, wherein RB and Rc are each independently selected from the group consisting of hydrogen, -(CH2)mRH, -(CH2)mORH, -SO2RH, -C(=O)RH, - C(=O)NRERF, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, lower saturated alkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, and Ci-C6 heterohaloalkyl, where the lower saturated alkyl and the Cj-C6 heteroalkyl in the definition of RB and Rc are optionally substituted with an optionally substituted aryl or an optionally substituted heteroaryl, and where the optionally substituted C3- C7 cycloalkyl in the definition of RB and Rc is further optionally fused with an optionally substituted aryl or an optionally substituted heteroaryl; or -NRBRC is a three - to eight- membered optionally substituted aliphatic cyclic aminyl, which optionally has one to three additional hetero atoms incorporated in the ring; each RD is independently selected from the group consisting of hydrogen, an optionally substituted lower saturated alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, an optionally substituted Ci-C6 haloalkyl, an optionally substituted Ci-C6 heteroalkyl, and -(CH2)mR ; each -NRERF is separately selected, wherein RE and RF are each independently selected from the group consisting of hydrogen, an optionally substituted lower saturated alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, an optionally substituted Ci-C6 haloalkyl, an optionally substituted Ci-C6 heteroalkyl, -(CH2)mRG, and -(CH2)mORG; or -NRERF is a three - to eight- membered optionally substituted aliphatic cyclic aminyl, which optionally has one to three additional hetero atoms incorporated in the ring; each R is independently selected from an optionally substituted aryl and an optionally substituted heteroaryl; each RH is independently selected from the group consisting of-OH, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl and an optionally substituted heteroaryl; each m is independently 0, 1, or 2; each n is independently 0, 1, 2, or 3; and each dashed line independently represents an optional double bond, including the proviso that the compound of Formula II is not selected from the group
consisting of
Figure imgf000010_0001
Figure imgf000010_0002
[0009] Some embodiments disclosed herein provide a compound of Formula III:
Figure imgf000010_0003
wherein:
R1 is selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted Ci-C6 alkyl, a substituted or unsubstituted Ci-C6 haloalkyl, a substituted or unsubstituted Ci-C6 heteroalkyl, and null;
R2 is selected from the group consisting of hydrogen, halogen, ORA, NRARB, SRA, a substituted or unsubstituted Cj-C6 alkyl, a substituted or unsubstituted Ci-C6 haloalkyl, and a substituted or unsubstituted C1-C6 heteroalkyl;
R3 is selected from the group consisting of hydrogen, halogen, ORC, NRCRD, S(O)0-2R0, NO2, CN, (CH2)mRE, a substituted or unsubstituted Cj-C6 alkyl, a substituted or unsubstituted Ci-C6 haloalkyl, a substituted or unsubstituted C1-C6 heteroalkyl, and null;
R4 is selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted Ci-C6 alkyl, a substituted or unsubstituted Cj-C6 haloalkyl, a substituted or unsubstituted Cj-C6 heteroalkyl, and null;
R5 is selected from the group consisting of hydrogen, halogen, ORΛ, NRARB, SRA, a substituted or unsubstituted Ci-C6 alkyl, a substituted or unsubstituted C1-C6 haloalkyl, and a substituted or unsubstituted Cj-C6 heteroalkyl; R6 is selected from the group consisting of hydrogen, halogen, ORC, NRCRD, S(O)0-2R0, NO2, CN, (CH2)mRE, a substituted or unsubstituted Ci-C6 alkyl, a substituted or unsubstituted Ci-C6 haloalkyl, a substituted or unsubstituted Cj-C6 heteroalkyl, and null;
RA is selected from the group consisting of hydrogen, Ci-C6 alkyl, Cj-C6 haloalkyl, Ci-C6 heteroalkyl, and Ci-C6 heterohaloalkyl;
RB is selected from hydrogen, SO2RF, C0RF, CONRCRD, Cj-C6 alkyl, Cj-C6 haloalkyl, CJ-C6 heteroalkyl, and Cj-C6 heterohaloalkyl; or RA and RB are linked to form a substituted or unsubstituted C3-C8 ring;
Rc and RD are each independently selected from the group consisting of hydrogen, a substituted or unsubstituted Ci-C6 alkyl, a substituted or unsubstituted Cj-C6 haloalkyl, a substituted or unsubstituted Cj-C6 heteroalkyl, and (CH2)mRE; or one of Rc and RD is a substituted or unsubstituted C2-C6 alkyl and the other of Rc and RD is null; or Rc and RD are linked to form a substituted or unsubstituted C3-C8 ring;
RE is selected from a substituted or unsubstituted aryl and a substituted or unsubstituted heteroaryl;
RF is selected from the group consisting of hydrogen, Ci-C3 alkyl, Ci-C3 haloalkyl, and a substituted or unsubstituted aryl or heteroaryl;
A is selected from the group consisting of a Ci-C6 alkyl, a C)-C6 heteroalkyl, a monocyclic or bicyclic aromatic ring optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle;
G is selected from the group consisting of a Cj-C6 alkyl, a C1-C6 heteroalkyl, a monocyclic or bicyclic aromatic ring optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle;
D is a 1-6 atom spacer containing at least 2 heteroatoms separated by 3 or 4 bonds and comprising one or more groups selected from a substituted or unsubstituted Cj-C6 heteroalkyl, a substituted or unsubstituted heterocycle, and a substituted or unsubstituted heteroalkylheterocycle;
E is a 1-6 atom spacer containing at least 2 heteroatoms separated by 3 or 4 bonds and comprising one or more groups selected from a substituted or unsubstituted C1-C6 heteroalkyl, a substituted or unsubstituted heterocycle, and a substituted or unsubstituted heteroalkylheterocycle;
L is a 2-12 atom linker comprising one or more groups selected from O (oxygen), NR , S(O)0-2, NRBS(O)1-2NRA, NRBS(O)i-2O, a substituted or unsubstituted C1-C]0 alkyl, a substituted or unsubstituted C1-C10 haloalkyl, a substituted or unsubstituted Ci-C8 heteroalkyl, a substituted or unsubstituted aryl, and a substituted or unsubstituted heteroaryl; where the aryl and heteroaryl are optionally fused with a nonaromatic heterocycle or a nonaromatic carbocycle; m is O, 1, or 2; and each dashed line independently represents an optional double bond.
[0010] Some embodiments disclosed herein provide a compound of Formula IV:
Figure imgf000012_0001
and pharmaceutically acceptable salts, esters, or prodrugs thereof; wherein:
R11 is selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted Ci-C6 haloalkyl, a substituted or unsubstituted Ci-C6 heteroalkyl, and null;
R12' is selected from the group consisting of hydrogen, halogen, -ORA, -NRARB, -SRΛ, a substituted or unsubstituted Ci-C6 alkyl, a substituted or unsubstituted Ci-C6 haloalkyl, and a substituted or unsubstituted CpC6 heteroalkyl;
R13' is selected from the group consisting of hydrogen, halogen, -ORC, -NRCRD, -S(O)0- 2RC, -NO2, -CN, -(CH2)mRE, a substituted or unsubstituted Ci-C6 alkyl, a substituted or unsubstituted Ci-C6 haloalkyl, a substituted or unsubstituted Ci-C6 heteroalkyl, and null;
R14 is selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted C]-C6 alkyl, a substituted or unsubstituted Ci-C6 haloalkyl, a substituted or unsubstituted Ci-C6 heteroalkyl, and null;
R15' is selected from the group consisting of hydrogen, halogen, -ORA, -NRARB, -SRA, a substituted or unsubstituted Cj-C6 alkyl, a substituted or unsubstituted Ci-C6 haloalkyl, and a substituted or unsubstituted Ci-C6 heteroalkyl; R is selected from the group consisting of hydrogen, halogen, -OR , -NR R , -S(0)o- 2RC, -NO2, -CN, -<CH2)mRE, a substituted or unsubstituted Ci-C6 alkyl, a substituted or unsubstituted Cj-C6 haloalkyl, a substituted or unsubstituted Cj-C6 heteroalkyl, and null;
R17 , R18 , R19 , and R20 are independently selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted Cj-C4 alkyl, a substituted or unsubstituted.Cj- C4 haloalkyl, and a substituted or unsubstituted Ci-C4 heteroalkyl; or R17 and R18 are linked to form a substituted or unsubstituted ring; or R19 and R20 are linked to form a substituted or unsubstituted ring; or R17 and R2 can be independently split into two groups when the carbon atoms they are attached become saturated;
RA is selected from the group consisting of hydrogen, Ci-C6 alkyl, Ci-C6 haloalkyl, Cj-C6 heteroalkyl, and Cj-C6 heterohaloalkyl;
RB is selected from hydrogen, -SO2RF, -C(=O)RF, -C(=O)NRCRD, Cj-C6 alkyl, Cj-C6 haloalkyl, Cj-C6 heteroalkyl, and Cj-C6 heterohaloalkyl; or RA and RB are linked to form a substituted or unsubstituted C3-C8 ring;
Rc and RD are each independently selected from the group consisting of hydrogen, a substituted or unsubstituted Cj-C6 alkyl, a substituted or unsubstituted Cj-C6 haloalkyl, a substituted or unsubstituted Cj-C6 heteroalkyl, and -(CH2)mR ; or one of R and R is a substituted or unsubstituted C2-C6 alkyl and the other of R and R is null; or R and R , are linked to form a substituted or unsubstituted C3-C8 ring;
RE is selected from a substituted or unsubstituted aryl and a substituted or unsubstituted heteroaryl;
RF is selected from the group consisting of hydrogen, Cj-C3 alkyl, Cj-C3 haloalkyl, and a substituted or unsubstituted aryl or heteroaryl;
A1' is selected from the group consisting of a Cj-C6 alkyl, a Cj-C6 heteroalkyl, and a monocyclic or bicyclic aromatic ring optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle;
G1 is selected from the group consisting of a C1-C6 alkyl, a Cj-C6 heteroalkyl, and a monocyclic or bicyclic aromatic ring optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; L1 is a 2-12 atom long linker comprising one or more groups selected from — O- (oxygen), -NRB-, -S(O)0-2-, -NRBS(O)i-2NRA- -NR8S(O) I-2O-, a substituted or unsubstituted Cj-Cio alkyl, a substituted or unsubstituted Ci-Ci0 haloalkyl, a substituted or unsubstituted Cj-C8 heteroalkyl, a substituted or unsubstituted aryl, and a substituted or unsubstituted heteroaryl; where the aryl and heteroaryl are optionally fused with a nonaromatic heterocycle or a nonaromatic carbocycle;
X is selected from the group consisting of NR and C(R )2;
Y is selected from the group consisting of NR19 and C(R1 )2; m is O, 1, or 2; and each dashed line independently represents an optional double bond.
[0011] In certain embodiments, a compound of Formula I, II, IH or IV is a hematopoietic growth factor mimetic, hematopoietic growth factor receptor agonist, or hematopoietic growth factor receptor antagonist.
[0012] Some embodiments disclosed herein provide a selective HGF modulator. Some embodiments disclosed herein provide a selective HGF receptor agonist. Some embodiments disclosed herein provide a selective HGF receptor antagonist. Some embodiments disclosed herein provide a selective HGF partial agonist. Some embodiments disclosed herein provide a selective HGF receptor binding compound. Certain embodiments provide a HGF mimic.
[0013] Some embodiments disclosed herein provide a selective EPO modulator. Some embodiments disclosed herein provide a selective EPO receptor agonist. Some embodiments disclosed herein provide a selective EPO receptor antagonist. Some embodiments disclosed herein provide a selective EPO partial agonist. Some embodiments disclosed herein provide a selective EPO receptor binding compound. Some embodiments disclosed herein provide an EPO mimic.
[0014] Some embodiments disclosed herein provide methods for modulating activity of HGF receptors. Such methods comprise contacting a cell with one or more compounds of the present embodiments. Such methods include, but are not limited to, contacting HGF and/or HGF receptors with one or more compounds of the present embodiments. [0015] Some embodiments disclosed herein provide methods for identifying a compound that is capable of modulating HGF activity comprising: a) contacting a cell capable of a HGF activity with a compound of the present embodiments; and b) monitoring an effect on the cell. In certain such embodiments, the cell expresses a HGF receptor.
[0016] Some embodiments disclosed herein provide methods for modulating activity of EPO receptors. Such methods comprise contacting a cell with one or more compounds of the present embodiments. Such methods include, but are not limited to, contacting EPO and/or EPO receptors with one or more compounds of the present embodiments.
[0017] Some embodiments disclosed herein provide methods for identifying a compound that is capable of modulating EPO activity comprising: a) contacting a cell capable of a EPO activity with a compound of the present embodiments; and b) monitoring an effect on the cell. In certain such embodiments, the cell expresses an EPO receptor.
[0018] Some embodiments disclosed herein provide methods of treating a patient comprising administering to the patient a compound of the present embodiments. In certain embodiments, such a patient suffers from thrombocytopenia, anemia, neutropenia, a cardiovascular disorder, an immune/autoimmune disorder, an infectious disorder, and a neurologic disorder. In certain embodiments, one or more compounds of the present embodiments are administered to a patient before, during or after chemotherapy, bone marrow transplantation, and/or radiation therapy. In certain embodiments patient treatment is prophylactic. In certain embodiments treatment includes harvesting cells from the patient. In certain embodiments, one or more compounds of the embodiments are administered to a patient suffering from aplastic anemia, bone marrow failure, and/or idiopathic thrombocytopenia. In certain embodiments, one or more compounds of the present embodiments are administered to a patient suffering from a disease of the nervous system. In certain embodiments, one or more compounds of the present embodiments are administered to a patient suffering from amyotrophic lateral sclerosis, multiple sclerosis, or multiple dystrophy. In certain embodiments, one or more compounds of the present embodiments are administered to a patient with a nervous system injury, or a nerve injury, including, but not limited to, a spinal cord injury. [0019] Some embodiments disclosed herein provide pharmaceutical compositions comprising: (i) a physiologically acceptable carrier, diluent, or excipient, or a combination thereof; and (ii) one or more compounds of the present embodiments.
[0020] Some embodiments disclosed herein provide pharmaceutical compositions for use in treating a condition of an anemia, a neutropenia, a cardiovascular disorder, an immune/autoimmune disorder, an infectious disorder, and a neurologic disorder.
DETAILED DESCRIPTION OF THE EMBODIMENTS
[0021] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the embodiments claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. In this application, the use of "or" means "and/or" unless stated otherwise. Furthermore, use of the term "including" as well as other forms, such as "includes," and "included," is not limiting.
[0022] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in the application including, but not limited to, patents, patent applications, articles, books, manuals, and treatises are hereby expressly incorporated by reference in their entirety for any purpose.
Definitions
[0023] Unless specific definitions are provided, the nomenclatures utilized in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those known in the art. Standard chemical symbols are used interchangeably with the full names represented by such symbols. Thus, for example, the terms "hydrogen" and "H" are understood to have identical meaning. When a radical is structurally required to have more than one connection point it is understood that the chemical nomenclature does not limit the connectivity. For example, if the term "aryl" necessarily must have two or more connection points due to the position of the radical in a structure, then the "aryl" is understood to be a radical that completes the structure, such as a diradical, triradical, etc. Standard techniques may be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. Standard techniques may be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Reactions and purification techniques may be performed e.g., using kits according to manufacturer's specifications or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures may be generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See e.g., Sambrook et al. Molecular Cloning: A Laboratory Manual (2nd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N. Y. (1989)), which is incorporated herein by reference in its entirety for any purpose.
[0024] As used herein, the following terms are defined with the following meanings, unless expressly stated otherwise.
[0025] The term "selective binding compound" refers to a compound that selectively binds to any portion of one or more target.
[0026] The term "selective HGF receptor binding compound" refers to a compound that selectively binds to any portion of a HGF receptor.
[0027] The term "selective EPO receptor binding compound" refers to a compound that selectively binds to any portion of a EPO receptor.
[0028] The term "selectively binds" refers to the ability of a selective binding compound to bind to a target receptor with greater affinity than it binds to a non-target receptor. In certain embodiments, selective binding refers to binding to a target with an affinity that is at least 10, 50, 100, 250, 500, or 1000 times greater than the affinity for a non-target.
[0029] The term "target receptor" refers to a receptor or a portion of a receptor capable of being bound by a selective binding compound. In certain embodiments, a target receptor is a HGF receptor.
[0030] The term "modulator" refers to a compound that alters an activity. For example, a modulator may cause an increase or decrease in the magnitude of a certain activity compared to the magnitude of the activity in the absence of the modulator. In certain embodiments, a modulator is an inhibitor, which decreases the magnitude of one or more activities. In certain embodiments, an inhibitor completely prevents one or more biological activities. In certain embodiments, a modulator is an activator, which increases the magnitude of at least one activity. In certain embodiments the presence of a modulator results in an activity that does not occur in the absence of the modulator.
[0031] The term "selective modulator" refers to a compound that selectively modulates a target activity.
[0032] The term "selective HGF modulator" refers to a compound that selectively modulates at least one HGF activity. The term selective HGF modulator includes, but is not limited to "HGF mimic" which refers to a compound, the presence of which results in at least one HGF activity. HGF mimics are described in WO 03/103686A1 and WO 01/21180, both of which are incorporated herein by reference in their entirety.
[0033] The term "selective EPO modulator" refers to a compound that selectively modulates at least one EPO activity. The term selective EPO modulator includes, but is not limited to "EPO mimic" which refers to a compound, the presence of which results in at least one EPO activity.
[0034] The term "selectively modulates" refers to the ability of a selective modulator to modulate a target activity to a greater extent than it modulates a non-target activity.
[0035] The term "target activity" refers to a biological activity capable of being modulated by a selective modulator. Certain exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzymatic activity, the proliferation and/or differentiation of progenitor cells, generation of platelets, and alleviation of symptoms of a disease or condition.
[0036] The term "HGF activity" refers to a biological activity that results, either directly or indirectly from the presence of HGF. Exemplary HGF activities include, but are not limited to, proliferation and or differentiation of progenitor cells to produce platelets; hematopoiesis; growth and/or development of glial cells; repair of nerve cells; and alleviation of thrombocytopenia.
[0037] The term "EPO activity" refers to a biological activity that results, either directly or indirectly from the presence of EPO. Exemplary EPO activities include, but are not limited to, proliferation and or differentiation of progenitor cells to produce platelets; hematopoiesis; growth and/or development of glial cells; repair of nerve cells; and alleviation of thrombocytopenia.
[0038] The term "thrombocytopenia" refers to a condition wherein the concentration of platelets in the blood of a patient is below what is considered normal for a healthy patient. In certain embodiments, thrombocytopenia is a platelet count less than 450,000, 400,000, 350,000, 300,000, 250,000, 200,000, 150,000, 140,000, 130,000, 120,000, 110,000, 100,000, 75,000, or 50,000 platelets per microliter of blood.
[0039] The term "receptor mediated activity" refers to any biological activity that results, either directly or indirectly, from binding of a ligand to a receptor.
[0040] The term "agonist" refers to a compound, the presence of which results in a biological activity of a receptor that is the same as the biological activity resulting from the presence of a naturally occurring ligand for the receptor.
[0041] The term "partial agonist" refers to a compound, the presence of which results in a biological activity of a receptor that is of the same type as that resulting from the presence of a naturally occurring ligand for the receptor, but of a lower magnitude.
[0042] The term "antagonist" refers to a compound, the presence of which results in a decrease in the magnitude of a biological activity of a receptor. In certain embodiments, the presence of an antagonist results in complete inhibition of a biological activity of a receptor. ■
[0043] The term "alkyl" refers to a branched or unbranched aliphatic hydrocarbon group. An alkyl may be a "saturated alkyl," which means that it does not contain any alkene or alkyne groups. An alkyl group may be an "unsaturated alkyl," which means that it comprises at least one alkene or alkyne group. An alkyl, whether saturated or unsaturated, may be branched or straight chain. Alkyls may be cyclic or non-cyclic. Cyclic alkyls may include multicyclic systems including fused alkyl rings or spirals. Alkyls may be substituted or unsubstituted. Alkyls include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, each of which may be optionally substituted.
[0044] In certain embodiments, an alkyl comprises 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as "1 to 20" refers to each integer in the given range; e.g., "1 to 20 carbon atoms" means that an alkyl group may comprise only 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. , up to and including 20 carbon atoms, although the term "alkyl" also includes instances where no numerical range of carbon atoms is designated).
[0045] The term "lower saturated alkyl," a subset within the definition of alkyl, refers to a branched or unbranched fully saturated acyclic aliphatic hydrocarbon group comprising 1 to 6 carbon atoms. A lower saturated alkyl may be branched or straight chain. Lower saturated alkyls may be optionally substituted. Lower saturated alkyls include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.
[0046] The term "alkenyl," a subset within the definition of alkyl, refers to a monovalent straight or branched chain aliphatic hydrocarbon radical of from two to twenty carbon atoms containing at least one carbon-carbon double bond including, but not limited to, 1- propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl, and the like. In certain embodiments, an alkenyl comprises 2 to 20 carbon atoms (whenever it appears herein, a numerical range such as "2 to 20" refers to each integer in the given range; e.g., "2 to 20 carbon atoms" means that an alkenyl group may comprise only 2 carbon atoms, 3 carbon atoms, etc. , up to and including 20 carbon atoms, although the term "alkenyl" also includes instances where no numerical range of carbon atoms is designated). An alkenyl may be designated as "C2-C6 alkenyl" or similar designations. By way of example only, "C2-C4 alkenyl" indicates an alkenyl having two, three, or four carbon atoms, e.g., the alkenyl is selected from ethenyl, propenyl, and butenyl.
[0047] The term "alkynyl," a subset within the definition of alkyl, refers to a monovalent straight or branched chain aliphatic hydrocarbon radical of from two to twenty carbon atoms containing at least one carbon-carbon triple bond including, but not limited to, 1 - propynyl, 1-butynyl, 2-butynyl, and the like. In certain embodiments, an alkynyl comprises 2 to 20 carbon atoms (whenever it appears herein, a numerical range such as "2 to 20" refers to each integer in the given range; e.g., "2 to 20 carbon atoms" means that an alkynyl group may comprise only 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the term "alkynyl" also includes instances where no numerical range of carbon atoms is designated). An alkynyl may be designated as "C2-C6 alkynyl" or similar designations. By way of example only, "C2-C4 alkynyl" indicates an alkenyl having two, three, or four carbon atoms, e.g., the alkenyl is selected from ethynyl, propynyl, and butynyl. [0048] The term "cycloalkyl," a subset within the definition of alkyl, refers to saturated aliphatic ring system radical having three to twenty carbon atoms. A cycloalkyl refers to monocyclic and polycyclic saturated aliphatic ring system including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[4.4.0]decanyl, bicyclo[2.2.1]heptanyl, adamantyl, norbornyl, and the like. In certain embodiments, a cycloalkyl comprises 3 to 20 carbon atoms (whenever it appears herein, a numerical range such as "3 to 20" refers to each integer in the given range; e.g., "3 to 20 carbon atoms" means that a cycloalkyl group may comprise only 3 carbon atoms, etc., up to and including 20 carbon atoms, although the term "cycloalkyl" also includes instances where no numerical range of carbon atoms is designated). A cycloalkyl may be designated as "C3-C7 cycloalkyl" or similar designations. By way of example only, "C3-C6 cycloalkyl" indicates an alkenyl having two, three, four, five or six carbon atoms, e.g., the cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
[0049] The term "cycloalkenyl," a subset within the definition of alkyl, refers to aliphatic ring system radical having three to twenty carbon atoms having at least one carbon- carbon double bond in the ring. A cycloalkenyl refers to monocyclic and polycyclic unsaturated aliphatic ring system including, but are not limited to, cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, bicyclo[3.1.0]hexyl, norbornylenyl, l,l'-bicyclopentenyl, and the like. In certain embodiments, a cycloalkenyl comprises 3 to 20 carbon atoms (whenever it appears herein, a numerical range such as "3 to 20" refers to each integer in the given range; e.g., "3 to 20 carbon atoms" means that a cycloalkenyl group may comprise only 3 carbon atoms, etc. , up to and including 20 carbon atoms, although the term "cycloalkenyl" also includes instances where no numerical range of carbon atoms is designated). A cycloalkenyl may be designated as "C3-C7 cycloalkenyl" or similar designations. By way of example only, "C3-C6 cycloalkenyl" indicates an alkenyl having two, three, four, five or six carbon atoms, e.g., the cycloalkyl is selected from cyclopropenyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl.
[0050] The term "haloalkyl" refers to an alkyl in which at least one hydrogen atom is replaced with a halogen atom. In certain of the embodiments in which two or more hydrogen atom are replaced with halogen atoms, the halogen atoms are all the same as one another. In certain of such embodiments, the halogen atoms are not all the same as one another. [0051] The term "heteroalkyl" refers to a branched or unbranched aliphatic hydrocarbon group comprising one or more oxygen, sulfur, nitrogen, or NH. Examples of heteroalkyls include, but are not limited to, CH3C(=O)CH2-, CH3CC=O)CH2CH2-, CH3CH2CC=O)CH2CH2-, CH3CC=O)CH2CH2CH2-, CH3NHCC=O)CH2-, CH3CC=O)NHCH2-, CH3OCH2CH2-, CH3NHCH2-, and the like.
[0052] The term "alkoxy" used herein refers to straight or branched chain alkyl radical covalently bonded to the parent molecule through an --O-- linkage. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, n-butoxy, sec-butoxy, t-butoxy and the like. An alkoxy may be designated as "C1-C6 alkoxy" or similar designations. By way of example only, "Cj-C4 alkoxy" indicates an alkyl having one, two, three, or four carbon atoms, e.g., the alkoxy is selected from methoxy, ethoxy, propoxy, /so-propoxy, butoxy, wø-butoxy, .sec-butoxy, and tert-butoxy.
[0053] The term "olefin" refers to a C=C bond.
[0054] The term "carbocycle" refers to a group comprising a covalently closed ring, wherein each of the atoms forming the ring is a carbon atom. Carbocylic rings may be formed by three, four, five, six, seven, eight, nine, or more than nine carbon atoms. Carbocycles may be optionally substituted.
[0055] The term "heterocycle" refers to a group comprising a covalently closed ring wherein at least one atom forming the ring is a heteroatom. Heterocyclic rings may be formed by three, four, five, six, seven, eight, nine, or more than nine atoms. Any number of those atoms may be heteroatoms (i.e., a heterocyclic ring may comprise one, two, three, four, five, six, seven, eight, nine, or more than nine heteroatoms). In heterocyclic rings comprising two or more heteroatoms, those two or more heteroatoms may be the same or different from one another. Heterocycles may be optionally substituted. Binding to a heterocycle can be at a heteroatom or via a carbon atom. For example, binding for benzo-fused derivatives, may be via a carbon of the benzenoid ring. Examples of heterocycles include, but are not limited to the following:
Figure imgf000023_0001
Figure imgf000023_0002
wherein D, E, F, and G independently represent a heteroatom. Each of D, E, F, and G may be the same or different from one another.
[0056] The term "heteroatom" refers to an atom other than carbon or hydrogen. Heteroatoms are typically independently selected from oxygen, sulfur, nitrogen, and phosphorus, but are not limited to those atoms. In embodiments in which two or more heteroatoms are present, the two or more heteroatoms may all be the same as one another, or some or all of the two or more heteroatoms may each be different from the others.
[0057] The term "aromatic" refers to a group comprising a covalently closed ring having a delocalized π-electron system. Aromatic rings may be formed by five, six, seven, eight, nine, or more than nine atoms. Aromatics may be optionally substituted. Examples of aromatic groups include, but are not limited to phenyl, naphthalenyl, phenanthrenyl, anthracenyl, tetralinyl, fluorenyl, indenyl, and indanyl. The term aromatic includes, for example, benzenoid groups, connected via one of the ring-forming carbon atoms, and optionally carrying one or more substituents selected from an aryl, a heteroaryl, a cycloalkyl, a non-aromatic heterocycle, a halo, a hydroxy, an amino, a cyano, a nitro, an alkylamido, an acyl, a Ci-6 alkoxy, a Ci-6 alkyl, a Ci-6 hydroxyalkyl, a Ci-6 aminoalkyl, a Ci-6 alkylamino, an alkylsulfenyl, an alkylsulfϊnyl, an alkylsulfonyl, an sulfamoyl, or a trifluoromethyl. In certain embodiments, an aromatic group is substituted at one or more of the para, meta, and/or ortho positions. Examples of aromatic groups comprising substitutions include, but are not limited to, phenyl, 3-halophenyl, 4- halophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-aminophenyl, 4-aminophenyl, 3- methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, dimethylphenyl, naphthyl, hydroxynaphthyl, hydroxymethylphenyl, (trifluoromethyl)phenyl, alkoxyphenyl, 4-morpholin-4-ylphenyl, 4- pyrrolidin-1-ylphenyl, 4-pyrazolylphenyl, 4-triazolylphenyl, and 4-(2-oxopyrrolidin-l-yl)phenyl.
[0058] The term "aryl" refers to an aromatic group wherein each of the atoms forming the ring is a carbon atom. Aryl rings may be formed by five, six, seven, eight, nine, or more than nine carbon atoms. Aryl groups may be optionally substituted.
[0059] The term "heteroaryl" refers to an aromatic group wherein at least one atom forming the aromatic ring is a heteroatom. Heteroaryl rings may be formed by three, four, five, six, seven, eight, nine, or more than nine atoms. Heteroaryl groups may be optionally substituted. Examples of heteroaryl groups include, but are not limited to, aromatic C3-8 heterocyclic groups comprising one oxygen or sulfur atom or up to four nitrogen atoms, or a combination of one oxygen or sulfur atom and up to two nitrogen atoms, and their substituted as well as benzo- and pyrido-fused derivatives, for example, connected via one of the ring-forming carbon atoms. In certain embodiments, heteroaryl groups are optionally substituted with one or more substituents, independently selected from halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, Ci-6-alkoxy, Ci-6-alkyl, C1-6-hydroxyalkyl, Ci-6-aminoalkyl, Ci-6-alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl. Examples of heteroaryl groups include, but are not limited to, unsubstituted and mono- or di-substituted derivatives of furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole, quinoline, isoquinoline, pyridazine, pyrimidine, purine and pyrazine, furazan, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, triazole, benzotriazole, pteridine, phenoxazole, oxadiazole, benzopyrazole, quinolizine, cinnoline, phthalazine, quinazoline, and quinoxaline. In some embodiments, the substituents are halo, hydroxy, cyano, O-Ci-6-alkyl, C1-6-alkyl, hydroxy-Ci-6-alkyl, and amino-Ci-6-alkyl.
[0060] The term "non-aromatic ring" refers to a group comprising a covalently closed ring that does not have a delocalized π-electron system.
[0061] The term "cycloalkyl" refers to a group comprising a non-aromatic ring wherein each of the atoms forming the ring is a carbon atom. Cycloalkyl rings may be formed by three, four, five, six, seven, eight, nine, or more than nine carbon atoms. Cycloalkyls may include multicyclic systems (e.g., fused ring systems). Cycloalkyls may be optionally substituted. In certain embodiments, a cycloalkyl comprises one or more unsaturated bonds. Examples of cycloalkyls include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1 ,4-cyclohexadiene, cycloheptane, and cycloheptene.
[0062] The term "non-aromatic heterocycle" refers to a group comprising a non- aromatic ring wherein one or more atoms forming the ring is a heteroatom and optionally includes one or more carbonyl or thiocarbonyl groups as part of the ring. Non-aromatic heterocyclic rings may be formed by three, four, five, six, seven, eight, nine, or more than nine atoms. Non-aromatic heterocycles may be optionally substituted. Examples of non-aromatic heterocycles include, but are not limited to, lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3- dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane, 1,4-oxathiin, 1 ,4-oxathiane, tetrahydro-l,4-thiazine, 2H-l,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-l,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, pyrrolidone, pyrrolidione, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, and 1,3-oxathiolane.
[0063] The term "arylalkyl" refers to a group comprising an aryl group bound to an alkyl group.
[0064] The term "carbocycloalkyl" refers to a group comprising a carbocyclic cycloalkyl ring. Carbocycloalkyl rings may be formed by three, four, five, six, seven, eight, nine, or more than nine carbon atoms. Carbocycloalkyl groups may be optionally substituted.
[0065] The term "ring" refers to any covalently closed structure. Rings include, for example, carbocycles (e.g., aryls and cycloalkyls), heterocycles (e.g., heteroaryls and non- aromatic heterocycles), aromatics (e.g., aryls and heteroaryls), and non-aromatics (e.g., cycloalkyls and non-aromatic heterocycles). Rings may be optionally substituted. Rings may form part of a ring system.
[0066] The term "ring system" refers to a either a single ring or two or more rings, wherein, if two or more rings are present, the two or more of the rings are fused. The term "fused" refers to structures in which two or more rings share one or more bonds.
[0067] The term "spacer" refers to an atom or group of atoms that separate two or more groups from one another by a desired number of atoms. For example, in certain embodiments, it may be desirable to separate two or more groups by one, two, three, four, five, six, or more than six atoms. In such embodiments, any atom or group of atoms may be used to separate those groups by the desired number of atoms. Spacers are optionally substituted. In certain embodiments, a spacer comprises saturated or unsaturated alkyls, heteroalkyls and/or haloalkyls. In certain embodiments, a spacer comprises atoms that are part of a ring. [0068] Solely for the purposes of illustration, and without limiting the above definition, some examples of spacers are provided. Examples of 1 atom spacers include, but are not limited to, the following:
Figure imgf000027_0001
where A and E represent groups which are separated by the desired number of atoms. Examples of 2 atom spacers include, but are not limited to, the following:
Figure imgf000027_0002
A M E where A and E represent groups which are separated by the desired number of atoms.
[0069] Examples of 3 atom spacers include, but are not limited to, the following:
Figure imgf000027_0003
where A and E represent groups which are separated by the desired number of atoms. [0070] Examples of 4 atom spacers include, but are not limited to, the following:
Figure imgf000028_0001
where A and E represent groups which are separated by the desired number of atoms. As is evident from the above examples, the atoms that create the desired separation may themselves be part of a group. That group may be, for example, an alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic heterocycle, or substituted alkyl all of which are optionally substituted. Thus the term "1-5 atom spacer" refers to a spacer that separates two groups by 1, 2, 3, 4, or 5 atoms and does not indicate the total size of the group that constitutes the spacer.
[0071] As used herein, the term "linked to form a ring" refers to instances where two atoms that are bound either to a single atom or to atoms that are themselves ultimately bound, are each bound to a linking group, such that the resulting structure forms a ring. That resulting ring comprises the two atoms that are linked to form a ring, the atom (or atoms) that previously linked those atoms, and the linker. For example, if A and B below are "linked to form a ring"
A^ ^E A^ ^E
Cv N
/ \ and A ■jvv /v the resulting ring includes A, E, the C (carbon) or N (nitrogen) to which they are attached, and a linking group. Unless otherwise indicated, that linking group may be of any length and may be optionally substituted. Referring to the above example, resulting structures include, but are not limited to:
Figure imgf000029_0001
Figure imgf000029_0002
, and the like.
[0072] In certain embodiments, the two substituents that together form a ring are not immediately bound to the same atom. For example, if A and E, below, are linked to form a ring:
A E
, the resulting ring comprises A, E, the two atoms that already link A and E and a linking group. Examples of resulting structures include, but are not limited to:
Figure imgf000029_0003
; and the like.
[0073] In certain embodiments, the atoms that together form a ring are separated by three or more atoms. For example, if A and E, below, are linked to form a ring:
Figure imgf000029_0004
, the resulting ring comprises A, E, the 3 atoms that already link A and E, and a linking group. Examples of resulting structures include, but are not limited to: K E
^VW ^w ? and the like.
[0074] As used herein, the term "together form a bond" refers to the instance in which two substituents to neighboring atoms are null the bond between the neighboring atoms becomes a double bond. For example, if A and E below "together form a bond"
the resulting structure is:
Figure imgf000030_0001
[0075] The term "null" refers to a group being absent from a structure. For example,
R;x'R" in the structure ^ ^ , where in certain instances X is N (nitrogen), if X is N (nitrogen), one of R' or R" is null, meaning that only three groups are bound to the N (nitrogen).
[0076] The substituent "R" appearing by itself and without a number designation refers to a substituent selected from alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and non-aromatic heterocycle (bonded through a ring carbon). If "R" appears more than once in a formula then each "R" is individually is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and non-aromatic heterocycle (bonded through a ring carbon).
[0077] The term "O-carboxy" refers to the group consisting of formula RC(=O)O-.
[0078] The term "C-carboxy" refers to the group consisting of formula -C(=O)OR.
[0079] The term "acetyl" refers to the group consisting of formula -C(=O)CH3.
[0080] The term "trihalomethanesulfonyl" refers to the group consisting of formula X3CS^O)2- where X is a halogen.
[0081] The term "cyano" refers to the group consisting of formula -CN.
[0082] The term "isocyanato" refers to the group consisting of formula — NC(=O).
[0083] The term "thiocyanato" refers to the group consisting of formula -CNS.
[0084] The term "isothiocyanato" refers to the group consisting of formula -NC(=S).
[0085] The term "sulfonyl" refers to the group consisting of formula -S(=O)-R. [0086] The term "S-sulfonamido" refers to the group consisting of formula -SC=O)2NR.
[0087] The term "N-sulfonamido" refers to the group consisting of formula RSC-O)2NH-.
[0088] The term "trihalomethanesulfonamido" refers to the group consisting of formula X3CSC=O)2NR-.
[0089] The term "O-carbamyl" refers to the group consisting of formula -OCC=O)-NR.
[0090] The term "N-carbamyl" refers to the group consisting of formula ROCC=O)NH-.
[0091] The term "O-thiocarbamyl" refers to the group consisting of formula -OCC=S)-NR.
[0092] The term "N-thiocarbamyl" refers to the group consisting of formula ROCC=S)NH-.
[0093] The term "C-amido" refers to the group consisting of formula -C(O)-N(R)2.
[0094] The term "N-amido" refers to the group consisting of formula RC(=0)NH-.
[0095] The term "amino" refers to the group consisting of formula -N(R)2.
[0096] The term "oxo" refers to the group consisting of formula =0.
[0097] The term "keto" and "carbonyl" used herein refers to the group consisting of formula C=O .
[0098] The term "thiocarbonyl" used herein refers to the group consisting of formula C=S.
[0099] The term "ester" refers to a chemical moiety with formula -(R)n-CC=O)OR', where R and R' are independently selected from alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and non-aromatic heterocycle (bonded through a ring carbon), where n is O or 1.
[0100] The term "amide" refers to a chemical moiety with formula -(R)n-C(O)NHR' or -(R)n-NHC(O)R', where R and R' are independently selected from alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), where n is 0 or 1. In certain embodiments, an amide may be an amino acid or a peptide.
[0101] The terms "amine," "hydroxy," and "carboxyl" include such groups that have been esterified or amidifled. Procedures and specific groups used to achieve esterifϊcation and amidification are known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, which is incorporated herein in its entirety.
[0102] Unless otherwise indicated, the term "optionally substituted," refers to a group in which none, one, or more than one of the hydrogen atoms has been replaced with one or more group(s) individually and independently selected from: alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cycloalkyl, aryl, arylalkyl, arylalkylO-, arylalkylNH-, alkenylO-, arylC(=O)-, arylC(=O)NH- arylNHC(=O)-, aryl(CH2)0-30(CH2)o-3-, HO(CH2)0-3NH-, HO(CH2V3O-, heteroaryl, non-aromatic heterocycle, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, oxo, amino(CH2)1-3- and amino, including mono- and di-substituted amino groups, and the protected derivatives of amino groups. Such protective derivatives (and protecting groups that may form such protective derivatives) are known to those of skill in the art and may be found in references such as Greene and Wuts, above. In embodiments in which two or more hydrogen atoms have been substituted, the substituent groups may together form a ring.
[0103] Unless otherwise indicated, the term "substituted," refers to a group in which one, or more than one of the hydrogen atoms has been replaced with one or more group(s) individually and independently selected from: alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cycloalkyl, aryl, arylalkyl, arylalkylO-, arylalkylNH-, alkenylO-, arylC(=O)-, arylC(=O)NH-, arylNHC(=OK aryl(CH2)0-3θ(CH2)0-3- HO(CH2V3NH-, HO(CH2V3O-, heteroaryl, non- aromatic heterocycle, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, oxo, amino(CH2)i-3- and amino, including mono- and di-substituted amino groups, and the protected derivatives of amino groups. Such protective derivatives (and protecting groups that may form such protective derivatives) are known to those of skill in the art and may be found in references such as Greene and Wuts, above. In embodiments in which two or more hydrogen atoms have been substituted, the substituent groups may together form a ring.
[0104] Throughout the specification, groups and substituents thereof can be chosen by one skilled in the field to provide stable moieties and compounds.
[0105] The term "carrier" refers to a compound that facilitates the incorporation of another compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is a commonly used carrier for improving incorporation of certain organic compounds into cells or tissues.
[0106] The term "pharmaceutical agent" refers to a chemical compound or composition capable of inducing a desired therapeutic effect in a patient. In certain embodiments, a pharmaceutical agent comprises an active agent, which is the agent that induces the desired therapeutic effect. In certain embodiments, a pharmaceutical agent comprises a prodrug. In certain embodiments, a pharmaceutical agent comprises inactive ingredients such as carriers, excipients, and the like.
[0107] The term "therapeutically effective amount" refers to an amount of a pharmaceutical agent sufficient to achieve a desired therapeutic effect.
[0108] The term "prodrug" refers to a pharmacologically inactive derivative of a parent drug molecule that requires biotransformation, either spontaneous or enzymatic, within the organism to release the active drug. Prodrugs become the compounds of the invention which are pharmaceutically active in vivo when they undergo solvolysis under physiological conditions or undergo enzymatic degradation. Prodrug compounds of this invention may be called single, double, triple, etc., depending on the number of biotransformation steps required to release the active drug within the organism, and indicating the number of functionalities present in a precursor-type form. Prodrug forms often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (Bundgaard, Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam (1985); Silverman, The Organic Chemistry of Drug Design and Drug Action, pp. 352-401, Academic Press, San Diego, Calif. (1992)). Prodrugs commonly known in the art include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acids with a suitable alcohol, or amides prepared by reaction of the parent acid compound with an amine, or basic groups reacted to form an acylated base derivative. Moreover, the prodrug derivatives of this invention may be combined with other features herein taught to enhance bioavailability.
[0140] Some examples of prodrugs include prodrug esters. Examples of pro-drug ester groups include pivoyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, as well as other such groups known in the art, including a (5-R-2-oxo-l,3-dioxolen-4-yl)methyl group. Other examples of pro-drug ester groups can be found in, for example, T. Higuchi and V. Stella, in "Pro-drugs as Novel Delivery Systems," Vol. 14, A.C.S. Symposium Series, American Chemical Society (1975); and "Bioreversible Carriers in Drug Design: Theory and Application," edited by E. B. Roche, Pergamon Press: New York, 14-21 (1987) (providing examples of esters useful as prodrugs for compounds containing carboxyl groups).
[0109] The term "pharmaceutically acceptable" refers to a formulation of a compound that does not significantly abrogate the biological activity, a pharmacological activity and/or other properties of the compound when the formulated compound is administered to a patient. In certain embodiments, a pharmaceutically acceptable formulation does not cause significant irritation to a patient.
[0110] The term "co-administer" refers to administering more than one pharmaceutical agent to a patient. In certain embodiments, co-administered pharmaceutical agents are administered together in a single dosage unit. In certain embodiments, coadministered pharmaceutical agents are administered separately. In certain embodiments, coadministered pharmaceutical agents are administered at the same time. In certain embodiments, co-administered pharmaceutical agents are administered at different times.
[0111] The term "patient" includes human and animal subjects.
[0112] The term "substantially pure" means an object species (e.g., compound) is the predominant species present (i.e., on a molar basis it is more abundant than any other individual species in the composition). In certain embodiments, a substantially purified fraction is a composition wherein the object species comprises at least about 50 percent (on a molar basis) of all species present. In certain embodiments, a substantially pure composition will comprise more than about 80%, 85%, 90%, 95%, or 99% of all species present in the composition. In certain embodiments, the object species is purified to essential homogeneity (contaminant species cannot be detected in the composition by conventional detection methods) wherein the composition consists essentially of a single species.
[0113] The term "tissue-selective" refers to the ability of a compound to modulate a biological activity in one tissue to a greater or lesser degree than it modulates a biological activity in another tissue. The biological activities in the different tissues may be the same or they may be different. The biological activities in the different tissues may be mediated by the same type of target receptor. For example, in certain embodiments, a tissue-selective compound may modulate receptor mediated biological activity in one tissue and fail to modulate, or modulate to a lesser degree, receptor mediated biological activity in another tissue type.
[0114] The term "monitoring" refers to observing an effect or absence of any effect. In certain embodiments, one monitors cells after contacting those cells with a compound of the present embodiments. Examples of effects that may be monitored include, but are not limited to, changes in cell phenotype, cell proliferation, receptor activity, or the interaction between a receptor and a compound known to bind to the receptor.
[0115] The term "cell phenotype" refers to physical or biological characteristics. Examples of characteristics that constitute phenotype included, but are not limited to, cell size, cell proliferation, cell differentiation, cell survival, apoptosis (cell death), or the utilization of a metabolic nutrient (e.g., glucose uptake). Certain changes or the absence of changes in cell phenotype are readily monitored using techniques known in the art.
[0116] The term "cell proliferation" refers to the rate at which cells divide. In certain embodiments, cells are in situ in an organism. In certain embodiments, cells are grown in vitro in a vessel. The number of cells growing in a vessel can be quantified by a person skilled in the art (e.g. , by counting cells in a defined area using a microscope or by using laboratory apparatus that measure the density of cells in an appropriate medium). One skilled in that art can calculate cell proliferation by determining the number of cells at two or more times.
[0117] The term "contacting" refers to bringing two or more materials into close enough proximity that they may interact. In certain embodiments, contacting can be accomplished in a vessel such as a test tube, a Petri dish, or the like. In certain embodiments, contacting may be performed in the presence of additional materials. In certain embodiments, contacting may be performed in the presence of cells. In certain of such embodiments, one or more of the materials that are being contacted may be inside a cell. Cells may be alive or may dead. Cells may or may not be intact. Certain compounds
[0118] The embodiments provide a compound of Formula I:
Figure imgf000036_0001
and pharmaceutically acceptable salts, esters, or prodrugs thereof; wherein:
A is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R1, R2, and R3, said aryl and heteroaryl in the definition of A are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle; or A is lower saturated alkyl or C3-C7 cycloalkyl;
J is -(CH2)mNR9C(=O)(CH2)m-;
L is selected from the group consisting of lower saturated alkyl-L1, lower saturated alkyl-L'-lower saturated alkyl, lower saturated alkylNR9(CH2)m-L1, lower saturated alkylNR9C(=O)-L\ -(CH2)mC(=O)NR9(CH2)q-L1, -(CH2)mO-lΛθ(CH2)q- -(CH2)m-lΛ(CH2)q-, -(CH=CH)m-L1-(CH=CH)q-, L1 L2, L!-O-L2, L!-(CH=CH)q-L2, L'-(CH2)q-L2, lΛθ(CH2)pO-L2, and L1-C(=O)NR9-L2; or L is L^O-L3 or L'-O-lΛ-O- L2;
L1 is selected from the group consisting of carbonyl, an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted heterocycle;
L2 is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted heterocycle;
L3 is selected from the group consisting of lower saturated alkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
Q is -(CH2)mNR9C(=O)(CH2)m-; G is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R4, R5, and R6, said aryl and heteroaryl in the definition of G are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle; or G is lower saturated alkyl or C3-C7 cycloalkyl; each R1 is separately selected from the group consisting of halogen, an optionally substituted lower saturated alkyl, an optionally substituted Cj-C6 alkoxy, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3- C7 cycloalkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; each R2 is separately selected from the group consisting of halogen, -0(CH2)m0RA, -(CH2)mORA, -NRBRC, -CCH2)mSRA, -C(=O)RH, -(CH2)mRH, an optionally substituted lower saturated alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted Ci-C6 haloalkyl, an optionally substituted Ci-C6 heteroalkyl, and an optionally substituted C3-7 cycloalkyl where said C3-7 cycloalkyl is further optionally fused with aryl or heteroaryl; each R3 is separately selected from the group consisting of halogen, -(CH2)mORD, -NRHC(=0)RD, -NRERF, -(CH2)mS(O)0-2RD, -(CH2)mNO2, -(CH2)mCN, -(CH2)mRG, . an optionally substituted lower saturated alkyl, an optionally substituted Cj-C6 alkoxy, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3- C7 cycloalkyl, an optionally substituted Ci-C6 haloalkyl, an optionally substituted Ci-C6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; each R4 is separately selected from the group consisting of halogen, an optionally substituted lower saturated alkyl, an optionally substituted Cj-C6 alkoxy, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3- C7 cycloalkyl, an optionally substituted Cj-C6 haloalkyl, an optionally substituted Ci-C6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; each R5 is separately selected from the group consisting of halogen, -O(CH2)mORA, -(CH2)mORA, -NRBRC, -<CH2)mSRA, -C(=O)RH, -(CH2)mRH, an optionally substituted lower saturated alkyl, an optionally substituted C1-C6 alkoxy, an optionally substituted C2-C6 alkenyl, an optionally substituted Ci-C^ alkynyl, an optionally substituted C3-C7 cycloalkyl, an optionally substituted Ci-C6 haloalkyl, and an optionally substituted Ci-C6 heteroalkyl; each R6 is separately selected from the group consisting of halogen, -(CH2)mORD, -NRHC(=0)RD, -NRERF, -(CHz)nS(O)0-2R0, -<CH2)mNO2, -<CH2)mCN, -(CH2)mRG, an optionally substituted lower saturated alkyl, an optionally substituted C1-C6 alkoxy, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3- C7 cycloalkyl, an optionally substituted Ci-C6 haloalkyl, an optionally substituted Cj-C6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; each R7 is separately selected from the group consisting of hydrogen, C3-C7 cycloalkyl, and lower saturated alkyl; each R9 is separately selected from the group consisting of hydrogen, an optionally substituted C3-C7 cycloalkyl, and an optionally substituted lower saturated alkyl;
RA is selected from the group consisting of hydrogen, -S02RH, -C(=0)RH, -C(=0)NRERF, lower saturated alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, C]-C6 haloalkyl, Cj-C6 heteroalkyl, and Cj-C6 heterohaloalkyl; each -NRBRC is separately selected, wherein RB and Rc are each independently selected from the group consisting of hydrogen, -(CH2)mRH, -(CH2)mORH, -SO2RH, -C(=0)RH, - C(=0)NRERF, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, lower saturated alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, and Cj-C6 heterohaloalkyl, where the lower saturated alkyl and the Cj-C6 heteroalkyl in the definition of R and R are optionally substituted with an optionally substituted aryl or an optionally substituted heteroaryl, and where the optionally substituted C3- C7 cycloalkyl in the definition of RB and Rc is further optionally fused with an optionally substituted aryl or an optionally substituted heteroaryl; or -NR R is a three - to eight- membered optionally substituted aliphatic cyclic aminyl, which optionally has one to three additional hetero atoms incorporated in the ring; or -NR R is an optionally substituted C1-C6 alkylideneaminyl; each RD is independently selected from the group consisting of hydrogen, an optionally substituted lower saturated alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, an optionally substituted Ci-C6 haloalkyl, an optionally substituted Ci-C6 heteroalkyl, and -(CH2)mR ; each -NRERF is separately selected, wherein RE and RF are each independently selected from the group consisting of hydrogen, an optionally substituted lower saturated alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, an optionally substituted Ci-C6 haloalkyl, an optionally substituted Ci-C6 heteroalkyl, -(CH2)mRG, and -(CH2)mORG; or NRERF is an optionally substituted Ci-C6 alkylideneaminyl; or -NRERF is a three - to eight- membered optionally substituted aliphatic cyclic aminyl, which optionally has one to three additional hetero atoms incorporated in the ring; each RG is independently selected from an optionally substituted aryl and an optionally substituted heteroaryl; each RH is independently selected from the group consisting of hydrogen, -OH, Ci-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, an optionally substituted C3-C7 cycloalkyl, C1-C3 haloalkyl, an optionally substituted aryl and an optionally substituted heteroaryl; each m is independently 0, 1, 2, or 3; each n is independently 0, 1, 2, or 3; each p is independently 0, 1, 2, 3, 4, 5, or 6; each q is independently 1, 2, 3, 4, 5, or 6; and each dashed line independently represents an optional double bond.
[0119] Some embodiments include compounds of Formula I including the proviso that when L1 is carbonyl then A and G are each individually selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R1, R2, and R3, said aryl and heteroaryl in the definition of A and G are each individually further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle; and including the proviso that when A is lower saturated alkyl or C3-C7 cycloalkyl and G is lower saturated alkyl or C3-C7 cycloalkyl then L comprises an aryl or heteroaryl. [0120] Some embodiments include compounds of Formula I having the Formula Ia
Figure imgf000040_0001
and pharmaceutically acceptable salts, esters, or prodrugs thereof; wherein:
L is selected from the group consisting of Cj-C5 lower saturated alkyl-L1, Ci-C5 lower saturated alkyl-lΛCi-C5 alkyl, Cj-C5 lower saturated alkylNR9(CH2)m-L1, Cj-C5 lower saturated alkylNR9C(=O)-L\ -(CH2)mC(=O)NR9(CH2)q-lΛ -(CH2)mC-lΛθ(CH2)q- -(CH2)H1-L1^CH2).,-, -(CH=CH)m-L1-(CH=CHK L!-L2, L1- O-L2, L1^CH=CH)-L2, L'-{CH2)q-L2, L^O(CH2)PO-L2, and L1-C(=O)NR9-L2; or L is L*-O-L3; each R1 is separately selected from the group consisting of halogen, lower saturated alkyl, Cj-C6 alkoxy, C2-C6 alkenyl, C3-C7 cycloalkyl, Cj-C6 haloalkyl, Cj-C6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; each R2 is separately selected from the group consisting of halogen, -O(CH2)mORA, -(CH2)mORA, -NRBRC, -(CH2)mSRA, -C(=O)RH, -(CH2)mRH, and an optionally substituted C3-7 cycloalkyl where said C3-7 cycloalkyl is further optionally fused with aryl or heteroaryl; each R3 is separately selected from the group consisting of halogen, -(CH2)mORD, -(CH2)mNRERF, -0(CH2)mNRERF, -(CH2)mS(O)0-2RD, -(CH2)mNO2, -{CH2)mCN, and -(CH2)raRG; each R4 is separately selected from the group consisting of halogen, lower saturated alkyl, Ci-C6 alkoxy, C2-C6 alkenyl, C3-C7 cycloalkyl, Cj-C6 haloalkyl, Cj-C6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; each R5 is separately selected from the group consisting of halogen, -O(CH2)mORA, -(CH2)mORA, -NRBRC, -(CH2)mSRA, -C(=O)RH, and -<CH2)mRH; each R6 is separately selected from the group consisting of halogen, -(CH2)mORD, -(CH2)mNRERF, -0(CH2)mNRERF, -(CH2)mS(0)o.2RD, -(CH2)mNO2, -(CH2)mCN, and -(CH2)mR ; each R9 is separately selected from the group consisting of hydrogen and an optionally substituted lower saturated alkyl;
RA is selected from the group consisting of hydrogen, -SO2RH, -C(=O)RH, -C(=O)NRERF, lower saturated alkyl, C2-C6 alkenyl, Ci-C6 haloalkyl, and C1-C6 heteroalkyl; each -NR R is separately selected, wherein R and R are each independently selected from the group consisting of hydrogen, -<CH2)mRH, -(CH2)mORH, -SO2RH, -C(=O)RH, -C(=0)NRERF, lower saturated alkyl, and Cj-C6 haloalkyl, ; or -NRBRC is a three - to eight- membered optionally substituted aliphatic cyclic aminyl, which optionally has one to three additional hetero atoms incorporated in the ring; each RD is independently selected from the group consisting of hydrogen, lower saturated alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, and -(CH2)mRG; each -NRERF is separately selected, wherein RE and RF are each independently selected from the group consisting of hydrogen, lower saturated alkyl, -(CH2)mRG, and -(CH2)mORG; or -NRERF is a three - to eight- membered optionally substituted aliphatic cyclic aminyl, which optionally has one to three additional hetero atoms incorporated in the ring; each R is independently selected from aryl and heteroaryl; each RH is independently selected from the group consisting of hydrogen, -OH, Ci-C3 alkyl, C2-C4 alkenyl, C3-C7 cycloalkyl, Cj-C3 haloalkyl, an optionally substituted aryl and an optionally substituted heteroaryl; each m is independently 0, 1, 2, or 3; each n is independently 0, 1, 2, or 3; each p is independently 0, 1, 2, 3, 4, 5, or 6; and each dashed line independently represents an optional double bond. [0121] Some embodiments include compounds of Formula I having the Formula Ib:
Figure imgf000042_0001
and pharmaceutically acceptable salts, esters, or prodrugs thereof. Some embodiments include compounds of Formula I having the Formula Ic:
Figure imgf000042_0002
and pharmaceutically acceptable salts, esters, or prodrugs thereof. Some embodiments include compounds of Formula I having the Formula Id:
Figure imgf000042_0003
and pharmaceutically acceptable salts, esters, or prodrugs thereof. Some embodiments include compounds of Formula I having the Formula Ie:
Figure imgf000042_0004
and pharmaceutically acceptable salts, esters, or prodrugs thereof. Some embodiments include compounds of Formula I having the Formula If:
Figure imgf000042_0005
and pharmaceutically acceptable salts, esters, or prodrugs thereof. [0122] Some embodiments include compounds of Formula I wherein:
A is selected from the group consisting of aryl and heteroaryl, each substituted with one or more substituents selected from the group consisting of R1, R2, and R3, said aryl and heteroaryl in the definition of A are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle; or A is lower saturated alkyl or C3- C7 cycloalkyl;
R1 is selected from the group consisting of fluorine, chlorine, and methyl;
R2 is selected from the group consisting of-(CH2)mORA, - NRBRC, and
-(CH2)mSRA;
R3 is selected from the group consisting of-(CH2)mRG, -(CH2)PiOR0, and -(CH2)mNRERF;
RA is selected from the group consisting of hydrogen, -SO2RH, -C(=O)RH, -C(=O)NRERF, lower saturated alkyl, Q-C6 haloalkyl, and CrC6 heteroalkyl; each -NRBRC is separately selected, wherein RB and Rc are each independently selected from the group consisting of hydrogen, -SO2RH, -C(=0)RH, -C(=0)NRERF, lower saturated alkyl, and Ci-C6 haloalkyl; or -NRBRC is a three - to eight- membered optionally substituted aliphatic cyclic aminyl, which optionally has one to two additional hetero atoms incorporated in the ring; each RD is independently selected from the group consisting of hydrogen, lower saturated alkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, and -<CH2)mRG; each m is independently O, 1, or 2; each n is independently 0, 1, or 2; and each q is independently 1, 2, or 3.
[0123] Some embodiments include compounds of Formula I including the proviso that when A and G are a phenyl then at least one of R2, R3, R5, and R6 is selected from the group consisting of -CCH2)mORA, -(CH2)mORD, -NRBRC, -NRERF, and an optionally substituted phenyl.
[0124] Some embodiments include compounds of Formula I wherein A and G are each independently selected from the group consisting of lower saturated alkyl and C3-C7 cycloalkyl. In some embodiments A and G are each independently selected from the group consisting of iso-butyl and cyclohexyl. In some embodiments A and G are each independently selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R1, R2, and R3, said aryl and heteroaryl in the definition of A and G are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle. In some embodimenls L is selected from the group consisting of
Figure imgf000044_0001
[0125] wherein each phenyl, naphthyl, and pyridinyl in the definition of L is optionally substituted. In some embodiments L is selected from the group consisting of
Figure imgf000044_0002
Figure imgf000045_0001
wherein each phenyl, naphthyl, pyridinyl, indolyl, and piperidinyl in the definition of L is optionally substituted. In some embodiments A and G are each independently selected from the group consisting of phenyl, naphthyl, pyridinyl, pyrrolyl, pyrimidinyl, imidazolyl, isoxazolyl, thiazolyl, thienyl, furyl, indolyl, benzoxazolyl, benzthiazolyl, benzimidazolyl, 1 ,4-benzodioxan-6-yl, 1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl, benzothienyl, quinolinyl, and purinyl, said phenyl, naphthyl, pyridinyl, pyrrolyl, pyrimidinyl, imidazolyl, isoxazolyl, thiazolyl, thienyl, furyl, indolyl, benzoxazolyl, benzthiazolyl, benzimidazolyl, 1 ,4-benzodioxan-6-yl, 1,3-benzodioxolyl, 2,3- dihydrobenzofuranyl, benzothienyl, quinolinyl, and purinyl, each optionally substituted with one or more substituents selected from the group consisting of R1, R2, and R3, and said said phenyl, naphthyl, pyridinyl, pyrrolyl, pyrimidinyl, imidazolyl, isoxazolyl, thiazolyl, thienyl, furyl, indolyl, benzoxazolyl, benzthiazolyl, benzimidazolyl, 1,4- benzodioxan-6-yl, 1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl, benzothienyl, quinolinyl, and purinyl are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle. In some embodiments L is selected from the group consisting
Figure imgf000045_0002
Figure imgf000046_0001
wherein each phenyl, naphthyl, and pyridinyl in the definition of L is optionally substituted. In some embodiments L is selected from the group consisting of
Figure imgf000046_0002
Figure imgf000047_0001
wherein each phenyl, naphthyl, pyridinyl, indolyl, and piperidinyl in the definition of L is optionally substituted. In some embodiments L is selected from the group consisting of -(CH2)-O-LI-O-(CH2>-, -(CH2)-lΛ(CH2)-, -(CH^-L^CH^-, V-L2, hl-iCH2)-h2, and L'-O-L2;
L1 is selected from the group consisting of phenyl, pyridinyl, and piperidinyl, each optionally substituted with F, Cl, Br, Cj-C3 lower saturated alkyl, Ci-C3 alkoxy, and -(CH2)N(CH3)2;
L2 is selected from the group consisting of phenyl and pyridinyl, each optionally substituted with F, Cl, Br, C1-C3 lower saturated alkyl, C1-C3 alkoxy, and -(CH2)N(CH3),;
A is phenyl, optionally substituted with one or more substituents selected from the group consisting of R1, R2, and R3, said phenyl in the definition of A are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle;
G is phenyl, optionally substituted with one or more substituents selected from the group consisting of R4, R5, and R6, said phenyl in the definition of G are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle; each R1 is separately selected from the group consisting of an optionally substituted aryl and an optionally substituted heteroaryl; each R2 is separately selected from the group consisting of halogen, -(CH2)mORA, and -NRBRC, where RA in the definition of is R2 selected from the group consisting of hydrogen, and lower saturated alkyl; each R3 is fluoro; each NRBRC is separately selected, wherein RB and R are each independently selected from the group consisting of hydrogen and lower saturated alkyl; or NR R is a three - to six- membered optionally substituted aliphatic cyclic aminyl, which optionally has one additional hetero atom incorporated in the ring; each R4 is separately selected selected from the group consisting of chloro, fluoro, and an optionally substituted lower saturated alkyl; each R5 is separately selected from the group consisting of -OCH2CH2ORA, -(CH2)mORA, and -NRBRC, where RA in the definition of is R5 selected from the group consisting of hydrogen, and lower saturated alkyl; and each R6 is separately selected from the group consisting an optionally substituted aryl and an optionally substituted heteroaryl. In some embodiments A is substituted with one or more substituents selected from the group consisting of R1, R2, and R3 In some embodiments G is substituted with one or more substituents selected from the group consisting of R4, R5, and R6. In some embodiments A is phenyl, substituted with one or more substituents selected from the group consisting of R , R , and R , said phenyl in the definition of A are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle and G is phenyl, substituted with one or more substituents selected from the group consisting of R4, R5, and R6, said phenyl in the definition of G are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle.
[0126] The embodiments provide a compound of Formula II:
Figure imgf000048_0001
and pharmaceutically acceptable salts, esters, or prodrugs thereof; wherein:
A4 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R11, R12, and R13, said aryl and heteroaryl in the definition of A4 are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle;
G4 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R , R , and R , said aryl and heteroaryl in the definition of G4 are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle;
L4 is selected from the group consisting of an optionally substituted C2-CiO alkenyl, an optionally substituted C2-C10 alkynyl, an optionally substituted aryl, and an optionally substituted heteroaryl; each R11 is separately selected from the group consisting of an optionally substituted Cj- C6 alkoxy, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, an optionally substituted Ci-C6 haloalkyl, an optionally substituted Ci-C6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; each R12 is separately selected from the group consisting of -O(CH2)mORA, -(CH2)mORA, -NRBRC, -(CH2)mSRA, -C(=O)RH, -(CH2)mRH, and an optionally substituted C3-7 cycloalkyl where said C3-7 cycloalkyl is further optionally fused with aryl or heteroaryl; each R13 is separately selected from the group consisting of -(CH2)mORD, -NRHC(=O)RD, -NRERF, -(CH2)mS(O)0-2RD, -(CH2)mNO2, -(CH2)mCN, and -(CH2)mRG; each R14 is separately selected from the group consisting of an optionally substituted Cj- C6 alkoxy, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, an optionally substituted Cj-C6 haloalkyl, an optionally substituted Ci-C6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; each R15 is separately selected from the group consisting of -O(CH2)mORA, -(CH2)mORA, -NRBRC, -(CH2)mSRA, -C(=0)RH, -(CH2)mRH, and an optionally substituted C3-7 cycloalkyl where said C3-7 cycloalkyl is further optionally fused with aryl or heteroaryl; each R16 is separately selected from the group consisting of -(CH2)mORD, -NRHC(=0)RD, -NRERF, -(CH2)mS(O)0-2RD, -(CH2)mNO2, -<CH2)mCN, and -(CH2)mRG; each R17 is separately selected from the group consisting of hydrogen, C3-C7 cycloalkyl, and lower saturated alkyl; each R19 is separately selected from the group consisting of hydrogen, an optionally substituted C3-C7 cycloalkyl, and an optionally substituted lower saturated alkyl;
RA is selected from the group consisting of hydrogen, -SO2RH, -C(=O)RH, -C(=0)NR RF, lower saturated alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, Cj-C6 haloalkyl, C1-C6 heteroalkyl, and Ci-C6 heterohaloalkyl; each -NR R is separately selected, wherein R and R are each independently selected from the group consisting of hydrogen, -(CH2)mRH, -(CH2)mORH, -SO2RH, -C(=O)RH, - C(=O)NRERF, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, lower saturated alkyl, Ci-C6 haloalkyl, Cj-C6 heteroalkyl, and Ci-C6 heterohaloalkyl, where the lower saturated alkyl and the Ci-C6 heteroalkyl in the definition of R and R are optionally substituted with an optionally substituted aryl or an optionally substituted heteroaryl, and where the optionally substituted C3- C7 cycloalkyl in the definition of RB and Rc is further optionally fused with an optionally substituted aryl or an optionally substituted heteroaryl; or -NRBRC is a three - to eight- membered optionally substituted aliphatic cyclic aminyl, which optionally has one to three additional hetero atoms incorporated in the ring; each RD is independently selected from the group consisting of hydrogen, an optionally substituted lower saturated alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, an optionally substituted C]-C6 haloalkyl, an optionally substituted C1-C6 heteroalkyl, and -(CH2)raR ; each -NRERF is separately selected, wherein RE and RF are each independently selected from the group consisting of hydrogen, an optionally substituted lower saturated alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, an optionally substituted Ci-C6 haloalkyl, an optionally substituted Cj-C6 heteroalkyl, -(CH2)mRG, and -(CH2)mORG; or -NRERF is a three - to eight- membered optionally substituted aliphatic cyclic aminyl, which optionally has one to three additional hetero atoms incorporated in the ring; each RG is independently selected from an optionally substituted aryl and an optionally substituted heteroaryl; each RH is independently selected from the group consisting of-OH, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl and an optionally substituted heteroaryl; each m is independently 0, 1, or 2; each n is independently 0, 1, 2, or 3; and each dashed line independently represents an optional double bond, including the proviso that the compound of Formula II is not selected from the group
consisting of
Figure imgf000051_0002
Figure imgf000051_0001
[0127] Some embodiments include compounds of Formula II including the proviso that when L is phenyl then at least one of A and G4 is selected from the group consisting of aryl and heteroaryl, said A substituted with one or more substituents selected from the group consisting of R11, R12, and R13 and said G4 substituted with one or more substituents selected from the group consisting of R14, R15, and R1 . In some embodiments A is substituted with one or more substituents selected from the group consisting of R11, R12, and R13. In some embodiments G is substituted with one or more substituents selected from the group consisting ofR14, R15, and R16.
[0128] Some embodiments include compounds of Formula II where A4 is selected from the group consisting of phenyl, naphthyl, and indolyl, each optionally substituted with one or more substituents selected from the group consisting of R11, R12, and R13, said phenyl, naphthyl, and indolyl in the definition of A4 are each further optionally fused with a nonaromatic heterocycle or carbocycle. In some embodiments each R11 is separately selected from the group consisting of C1-C3 alkoxy, C2-C4 alkenyl; each R12 is separately selected from the group consisting of -O(CH2)mORA, -(CH2)mORA, and -NRBRC; each R13 is separately selected from the group consisting of -(CH2)mORD, and -NRERF; each R14 is separately selected from the group consisting of Ci-C3 alkoxy, C2-C4 alkenyl; each R15 is separately selected from the group consisting of -O(CH2)mORA, -(CH2)mORA, and -NRBRC; each R16 is separately selected from the group consisting of -(CH2)mORD, and -NRERF; each R17 is separately selected from the group consisting of hydrogen, C3-C6 cycloalkyl, and C]-C3 alkyl; each R19 is separately selected from the group consisting of hydrogen, an optionally substituted C3-C6 cycloalkyl, and an optionally substituted Ci-C3 lower saturated alkyl.
[0129] Some embodiments include compounds of Formula II having the Formula Ha:
Figure imgf000052_0001
and pharmaceutically acceptable salts, esters, or prodrugs thereof; wherein:
A4 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R11, R12, and R13, said aryl and heteroaryl in the definition of A4 are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle;
G4 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R14, R15, and R16, said aryl and heteroaryl in the definition of G are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle;
L4 is selected from the group consisting of an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted aryl, and an optionally substituted heteroaryl; each R11 is separately selected from the group consisting of an optionally substituted Ci-C3 alkoxy, an optionally substituted C2-C4 alkenyl, an optionally substituted aryl, and an optionally substituted heteroaryl; each R12 is separately selected from the group consisting of -0(CH2)m0RA, -(CH2)mORA, -NRBRC, -C(=O)RH, and an optionally substituted C3-7 cycloalkyl where said C3-7 cycloalkyl is further optionally fused with aryl or heteroaryl; each R13 is separately selected from the group consisting of -(CH2)mORD, -NRHC(=0)RD, and -NRERF; each R14 is separately selected from the group consisting of an optionally substituted CpC3 alkoxy, an optionally substituted C2-C4 alkenyl, an optionally substituted aryl, and an optionally substituted heteroaryl; each R15 is separately selected from the group consisting of -0(CH2)m0RA, -(CH2)mORA, -NRBRC, -C(=O)RH, and an optionally substituted C3-7 cycloalkyl where said C3-7 cycloalkyl is further optionally fused with aryl or heteroaryl; each R16 is separately selected from the group consisting of -(CH2)mORD, -NRHC(=0)RD, and -NRERF;
R is selected from the group consisting of hydrogen, Cj-C3 lower saturated alkyl, C2-C4 alkenyl, and C3-C6 cycloalkyl; each -NRBRC is separately selected, wherein RB and Rc are each independently selected from the group consisting of hydrogen, -(CH2)mRH, -(CH2)mORH, -SO2RH, -C(=O)RH, -C(=0)NRERF, C3-C7 c ycloalkyl, lower saturated alkyl, Ci-C6 haloalkyl, where the lower saturated alkyl in the definition of RB and Rc are optionally substituted with an optionally substituted aryl or an optionally substituted heteroaryl, and where the optionally substituted C3-C7 cycloalkyl in the definition of RB and Rc is further optionally fused with an optionally substituted aryl or an optionally substituted heteroaryl; or -NR R is a four - to seven- membered optionally substituted aliphatic cyclic aminyl, which optionally has one to two additional hetero atoms incorporated in the ring; each RD is independently selected from the group consisting of hydrogen, an lower saturated alkyl, C3-C7 cycloalkyl, Ci-C6 haloalkyl, and -(CH2)mR ; each -NRERF is separately selected, wherein RE and RF are each independently selected from the group consisting of hydrogen, lower saturated alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, -(CH2)mRG, and -(CH2)mORG; or -NRERF is a four - to seven- membered optionally substituted aliphatic cyclic aminyl, which optionally has one to two additional hetero atoms incorporated in the ring; each RG is independently selected from an optionally substituted aryl and an optionally substituted heteroaryl; each RH is independently selected from the group consisting of-OH, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl and an optionally substituted heteroaryl; each m is independently 0, 1, or 2; and each dashed line independently represents an optional double bond. [0130] Some embodiments include compounds of Formula Ha where A4 is selected from the group consisting of aryl and heteroaryl, each substituted with one or more substituents selected from the group consisting of R , R , and R , said aryl and heteroaryl in the definition of A4 are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle; each R11 is independently selected from the group consisting of -OCH3, and -CH=CH2; each R12 is independently selected from the group consisting of -CH2CH2ORA, and -NRBRC; each R13 is independently selected from the group consisting of -CH2CH2CH2OR0 and -(CH2)mR ; each R is separately selected from the group consisting of hydrogen, C1-C3 lower saturated alkyl, and Ci-C3 haloalkyl; each -NR R is separately selected, wherein R and R are each separately selected from the group consisting of hydrogen, -(CH2)mNRERir, Cj-C3 alkyl, C3- C6 cycloalkyl, and Ci-C6 haloalkyl; or -NR R is a three - to six- membered optionally substituted aliphatic cyclic aminyl, which optionally has one to two additional hetero atoms incorporated in the ring; each RD is separately selected from the group consisting of hydrogen, Ci-C3 lower saturated alkyl, CpC3 haloalkyl, and -<CH2)mRG; and each -NRERF is separately selected, wherein RE and RF are each independently selected from the group consisting of hydrogen, Cj-C3 lower saturated alkyl, Ci-C3 haloalkyl, and -(CH2)mRG; or -NRERF is a three - to six- membered optionally substituted aliphatic cyclic aminyl, which optionally has one to two additional hetero atoms incorporated in the ring. In some embodiments L4 is selected from, the group consisting of phenyl and butadienyl.
[0131] In certain embodiments, the compound of Formula II is selected from:
Figure imgf000055_0001
[0132] The embodiments provide a compound of Formula III:
Figure imgf000055_0002
wherein:
R1 is selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted Ci-C6 alkyl, a substituted or unsubstituted Ci-C6 haloalkyl, a substituted or unsubstituted C1-C6 heteroalkyl, and null;
R2 is selected from the group consisting of hydrogen, halogen, ORA, NRΛRB, SRA, a substituted or unsubstituted Ci-C6 alkyl, a substituted or unsubstituted Ci-C6 haloalkyl, and a substituted or unsubstituted Cj-C6 heteroalkyl; R3 is selected from the group consisting of hydrogen, halogen, ORC, NRCRD, S(O)0-2R0, NO2, CN, (CH2)mRE, a substituted or unsubstituted Cj-C6 alkyl, a substituted or unsubstituted Q- C6 haloalkyl, a substituted or unsubstituted Ci-C6 heteroalkyl, and null;
R4 is selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted Ci-C6 alkyl, a substituted or unsubstituted Ci-C6 haloalkyl, a substituted or unsubstituted Ci-C6 heteroalkyl, and null;
R5 is selected from the group consisting of hydrogen, halogen, 0RΛ, NRARB, SRA, a substituted or unsubstituted Ci-C6 alkyl, a substituted or unsubstituted Cj-C6 haloalkyl, and a substituted or unsubstituted Cj-C6 heteroalkyl;
R6 is selected from the group consisting of hydrogen, halogen, ORC, NRCRD, S(O)0-2R0, NO2, CN, (CH2)mRE, a substituted or unsubstituted Ci-C6 alkyl, a substituted or unsubstituted Cj- C6 haloalkyl, a substituted or unsubstituted Ci-C6 heteroalkyl, and null;
RA is selected from the group consisting of hydrogen, Cj-C6 alkyl, Ci-C6 haloalkyl, Cj-C6 heteroalkyl, and Cj-C6 heterohaloalkyl;
RB is selected from hydrogen, SO2RF, CORF, CONR0R0, Ci-C6 alkyl, Cj-C6 haloalkyl, C]-C6 heteroalkyl, and Cj-C6 heterohaloalkyl; or RA and RB are linked to form a substituted or unsubstituted C3-C8 ring;
Rc and RD are each independently selected from the group consisting of hydrogen, a substituted or unsubstituted Ci-C6 alkyl, a substituted or unsubstituted C]-C6 haloalkyl, a substituted or unsubstituted Cj-C6 heteroalkyl, and (CH2)mR ; or one of R and R is a substituted or unsubstituted C2-C6 alkyl and the other of R° and RD is null; or R° and RD are linked to form a substituted or unsubstituted C3-Cg ring;
RE is selected from a substituted or unsubstituted aryl and a substituted or unsubstituted heteroaryl;
RF is selected from the group consisting of hydrogen, C]-C3 alkyl, Cj-C3 haloalkyl, and a substituted or unsubstituted aryl or heteroaryl;
A is selected from the group consisting of a Cj-C6 alkyl, a Cj-C6 heteroalkyl, a monocyclic or bicyclic aromatic ring optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; G is selected from the group consisting of a Cj-C6 alkyl, a Ci-C6 heteroalkyl, a monocyclic or bicyclic aromatic ring optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle;
D is a 1 -6 atom spacer containing at least 2 heteroatoms separated by 3 or 4 bonds and comprising one or more groups selected from a substituted or unsubstituted C1-C6 heteroalkyl, a substituted or unsubstituted heterocycle, and a substituted or unsubstituted heteroalkylheterocycle;
E is a 1-6 atom spacer containing at least 2 heteroatoms separated by 3 or 4 bonds and comprising one or more groups selected from a substituted or unsubstituted Ci-C6 heteroalkyl, a substituted or unsubstituted heterocycle, and a substituted or unsubstituted heteroalkylheterocycle;
L is a 2-12 atom linker comprising one or more groups selected from O (oxygen), NRB, S(O)0-2, NRBS(O)i-2NRA, NRBS(O)i-2O, a substituted or unsubstituted Ci-Ci0 alkyl, a substituted or unsubstituted Ci-Ci0 haloalkyl, a substituted or unsubstituted Ci-C8 heteroalkyl, a substituted or unsubstituted aryl, and a substituted or unsubstituted heteroaryl; where the aryl and heteroaryl are optionally fused with a nonaromatic heterocycle or a nonaromatic carbocycle; m is O, 1, or 2, and each dashed line independently represents an optional double bond.
[0133] Some embodiments include compounds of Formula III having the Formula IHa:
Figure imgf000057_0001
wherein:
A is selected from the group consisting of aryl and heteroaryl, said aryl and heteroaryl in the definition of A are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle; or A is Ci-C6 alkyl;
G is selected from the group consisting of aryl and heteroaryl, said aryl and heteroaryl in the definition of G are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle; or G is Ci-C6 alkyl; L is selected from the group consisting of Ci-C5 alkyl-L1, Cj-C5 alkyl-L'-Ci-Cs alkyl, C-C5 alkylNR9(CH2)m-lΛ CrC5 ^yINR9Q=O)-L1, -(CH2)mC(=O)NR9(CH2)q-L1,
-(CH2)mO-L1-O(CH2)q-
Figure imgf000058_0001
Lr-L2, LJ-O-L2, L!-(CH=CH)-L2, L*-{CH2)q-L2, L^O(CH2)PO-L2, L1-C(=O)NR9-L2; or L is L^O-L3;
L1 is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted heterocycle;
L2 is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted heterocycle;
L3 is selected from the group consisting of Ci-C6 alkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
R1 is selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted Cj-C6 alkyl, a substituted or unsubstituted Ci-C6 haloalkyl, and null;
R2 is selected from the group consisting of hydrogen, halogen, -0RA, -NRARB, -SRA, a substituted or unsubstituted Ci-C6 alkyl, and a substituted or unsubstituted C]-C6 haloalkyl;
R is selected from the group consisting of hydrogen, halogen, -OR , -NR R , -S(0)o-2RC, -NO2, -CN, -(CH2)mRE, a substituted or unsubstituted Ci-C6 alkyl, a substituted or unsubstituted Ci-C6 haloalkyl, and null;
R4 is selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted Ci-C6 alkyl, a substituted or unsubstituted C1-C6 haloalkyl, and null;
R5 is selected from the group consisting of hydrogen, halogen, -0RA, -NRΛRB, -SRA, a substituted or unsubstituted Cj-C6 alkyl, and a substituted or unsubstituted C1-C6 haloalkyl;
R is selected from the group consisting of hydrogen, halogen, -OR , -NR R , -S(O)0-2R0, -NO2, -CN, -(CH2)mRE, a substituted or unsubstituted Cj-C6 alkyl, a substituted or unsubstituted Ci-C6 haloalkyl, and null; each R9 is separately selected from the group consisting of hydrogen, an optionally substituted C3-C6 cycloalkyl, and an optionally substituted C1-C3 lower saturated alkyl;
RA is selected from the group consisting of hydrogen, Ci-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, and Ci-C6 heterohaloalkyl;
RB is selected from hydrogen, -SO2RF, -C(=O)RF, -C(=O)NRCRD, Cj-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, and Cj-C6 heterohaloalkyl; Rc and RD are each independently selected from the group consisting of hydrogen, a substituted or unsubstituted Ci-C6 alkyl, a substituted or unsubstituted Ci-C6 haloalkyl, a substituted or unsubstituted Ci-C6 heteroalkyl, and -(CH2)mR ;
RE is selected from a substituted or unsubstituted aryl and a substituted or unsubstituted heteroaryl;
RF is selected from the group consisting of hydrogen, Ci-C3 alkyl, C1-C3 haloalkyl, and a substituted or unsubstituted aryl or heteroaryl;
X is NH;
Y is NH; each m is independently 0, 1, or 2; each p is independently 0, 1, 2, 3, 4, 5, or 6; each q is independently 1, 2, 3, 4, 5, or 6; and each dashed line independently represents an optional double bond.
[0134] Some embodiments include compounds of Formula Ha where L is selected
from the group consisting of
Figure imgf000059_0001
Figure imgf000059_0002
, and , wherein each phenyl in the definition of L is optionally substituted. In some embodiments A and G are each independently selected from the group consisting of phenyl and wo-propyl.
[0135] In certain embodiments, the compound of Formula III is selected from:
Figure imgf000059_0003
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
[0136] The embodiments provide a compound of Formula IV:
Figure imgf000063_0002
and pharmaceutically acceptable salts, esters, or prodrugs thereof; wherein:
R11 is selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted C]-C6 alkyl, a substituted or unsubstituted Ci-C6 haloalkyl, a substituted or unsubstituted Cj-C6 heteroalkyl, and null;
R12' is selected from the group consisting of hydrogen, halogen, -0RA, -NRARB, -SRA, a substituted or unsubstituted Cj-C6 alkyl, a substituted or unsubstituted Cj-C6 haloalkyl, and a substituted or unsubstituted Cj-C6 heteroalkyl;
R13' is selected from the group consisting of hydrogen, halogen, -ORC, -NRCRD, -S(O)0- 2R , -NO2, -CN, -(CH2)mR , a substituted or unsubstituted Cj-C6 alkyl, a substituted or unsubstituted C]-C6 haloalkyl, a substituted or unsubstituted Ci-C6 heteroalkyl, and null;
R14 is selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted Cj-C6 alkyl, a substituted or unsubstituted Ci-C6 haloalkyl, a substituted or unsubstituted C]-C6 heteroalkyl, and null;
R15 is selected from the group consisting of hydrogen, halogen, -0RA, -NRARB, -SRA, a substituted or unsubstituted C]-C6 alkyl, a substituted or unsubstituted C]-C6 haloalkyl, and a substituted or unsubstituted C]-C6 heteroalkyl; R16' is selected from the group consisting of hydrogen, halogen, -ORC, -NRCRD, -S(0)o- 2RC, -NO2, -CN, -(CH2)mRE, a substituted or unsubstituted Ci -C6 alkyl, a substituted or unsubstituted C)-C6 haloalkyl, a substituted or unsubstituted Ci-C6 heteroalkyl, and null;
R17', R18', R19', and R20' are independently selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted C1-C4 alkyl, a substituted or unsubstituted Ci- C4 haloalkyl, and a substituted or unsubstituted C]-C4 heteroalkyl; or R17' and R18' are linked to form a substituted or unsubstituted ring; or R19 and R2 are linked to form a substituted or unsubstituted ring; or R17 and R20 can be independently split into two groups when the carbon atoms they are attached become saturated;
RA is selected from the group consisting of hydrogen, CpC6 alkyl, Ci-C6 haloalkyl, Cj-C6 heteroalkyl, and Ci-C6 heterohaloalkyl;
RB is selected from hydrogen, -SO2RF, -C(=0)RF, -C(=O)NRCRD, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, and Ci-C6 heterohaloalkyl; or RA and RB are linked to form a substituted or unsubstituted C3-C8 ring;
Rc and RD are each independently selected from the group consisting of hydrogen, a substituted or unsubstituted Ci-C6 alkyl, a substituted or unsubstituted Ci-C6 haloalkyl, a substituted or unsubstituted Ci-C6 heteroalkyl, and -(CH2)mRE; or one of Rc and RD is a substituted or unsubstituted C2-C6 alkyl and the other of R and R is null; or R and R are linked to form a substituted or unsubstituted C3-Cg ring;
RE is selected from a substituted or unsubstituted aryl and a substituted or unsubstituted heteroaryl;
RF is selected from the group consisting of hydrogen, Cj-C3 alkyl, Ci-C3 haloalkyl, and a substituted or unsubstituted aryl or heteroaryl;
A1 is selected from the group consisting of a Ci-C6 alkyl, a Cj-C6 heteroalkyl, and a monocyclic or bicyclic aromatic ring optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle;
G1' is selected from the group consisting of a C1-C6 alkyl, a C1-C6 heteroalkyl, and a monocyclic or bicyclic aromatic ring optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; L1' is a 2-12 atom long linker comprising one or more groups selected from -O- (oxygen), -NRB-, -S(O)0-2-, -NR8S(O) i-2NRA- -NRBS(O)]-2O-, a substituted or unsubstituted C1-CiO alkyl, a substituted or unsubstituted Ci-Ci0 haloalkyl, a substituted or unsubstituted Ci-C8 heteroalkyl, a substituted or unsubstituted aryl, and a substituted or unsubstituted heteroaryl; where the aryl and heteroaryl are optionally fused with a nonaromatic heterocycle or a nonaromatic carbocycle;
X is selected from the group consisting of NR and C(R )2;
Y is selected from the group consisting of NR19 and C(R19 )2; m is O, 1, or 2; and each dashed line independently represents an optional double bond.
[0137] Some embodiments include compounds of Formula IV having the Formula IVa:
Figure imgf000065_0001
wherein:
A1' is selected from the group consisting of lower saturated alkyl, aryl and heteroaryl, said aryl and heteroaryl in the definition of A1 are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle;
G1' is selected from the group consisting of lower saturated alkyl, aryl and heteroaryl, said aryl and heteroaryl in the definition of G1' are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle;
L1' is selected from the group consisting of C]-C5 lower saturated alkyl-L1, Ci-C5 lower saturated alkyl-L'-Ci-Cs lower saturated alkyl, Cj-C5 lower saturated alkylNR9(CH2)m-L\ C , -C5 lower saturated alkylNR9C(=O)-L1,
-(CH2)mC(=O)NR9(CH2)q-lΛ -(CH2)mO-L1-O(CH2)q- -(CH2)ιn-L1-(CH2)<r,
-(CH=CH)1n-L1^CH=CH)-, L1 L2, L'-O-L2, L'-(CH=CH)-L2, L^(CH2VL2, L^O(CH2)PO-L2, and L1-C(=O)NR9-L2; or L is L!-O-L3; L1 is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted heterocycle;
L2 is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted heterocycle;
L3 is selected from the group consisting of lower saturated alkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; each R9 is separately selected from the group consisting of hydrogen, an optionally substituted C3-C6 cycloalkyl, and an optionally substituted Ci-C3 lower saturated alkyl;
R11 is selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted lower saturated alkyl, a substituted or unsubstituted C1-C6 haloalkyl, and null;
R12' is selected from the group consisting of hydrogen, halogen, -ORA, -NRARB, -SRA, a substituted or unsubstituted lower saturated alkyl, and a substituted or unsubstituted Ci-C6 haloalkyl;
R is selected from the group consisting of hydrogen, halogen, -OR , -NR R , -S(O)0-2Rc, -NO2, -CN, -(CH2)mRE, a substituted or unsubstituted lower saturated alkyl, a substituted or unsubstituted Cj-C6 haloalkyl, and null;
R14' is selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted lower saturated alkyl, a substituted or unsubstituted Ci-C6 haloalkyl, and null;
R15 is selected from the group consisting of hydrogen, halogen, -ORA, -NRAR , -SRA, a substituted or unsubstituted lower saturated alkyl, and a substituted or unsubstituted C]-C6 haloalkyl;
R16 is selected from the group consisting of hydrogen, halogen, -ORC, -NRCRD, -S(0)o-2Rc, -NO2, -CN, -(CH2)mRE, a substituted or unsubstituted lower saturated alkyl, a substituted or unsubstituted C1-C6 haloalkyl, and null;
RA is selected from the group consisting of hydrogen, lower saturated alkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, and Cj-C6 heterohaloalkyl; RB is selected from hydrogen, -SO2RF, -C(=O)RF, -C(=O)NRCRD, lower saturated alkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, and Ci-C6 heterohaloalkyl;
Rc and RD are each independently selected from the group consisting of hydrogen, a substituted or unsubstituted lower saturated alkyl, a substituted or unsubstituted Ci-C6 haloalkyl, a substituted or unsubstituted Ci-C6 heteroalkyl, and - (CH2)mR ;
RE is selected from a substituted or unsubstituted aryl and a substituted or unsubstituted heteroaryl;
RF is selected from the group consisting of hydrogen, Ci-C3 alkyl, Ci-C3 haloalkyl, and a substituted or unsubstituted aryl or heteroaryl; each p is independently 0, 1, 2, 3, 4, 5, or 6; and each q is independently 1, 2, 3, 4, 5, or 6. [0138] Some embodiments include compounds of Formula IVa where L1 is selected
from the group consisting of
Figure imgf000067_0001
Figure imgf000067_0002
definition of L1' is optionally substituted. In some embodiments A' and G' are each independently selected from the group consisting of phenyl and iso-propyl.
[0139] Certain compounds that modulate one or more HGF activity and/or bind to HGF receptors play a role in health. In certain embodiments, compounds are useful for treating any of a variety of diseases or conditions. A surprising discovery has been made that compounds with activity at the TPO receptor or other specific receptors also have broader HGF activity which can modulate HGF receptors affecting a wide range of diseases and disorders. [0140] Some embodiments include compounds of Formulae I, II, III, or IV that can be an HGF mimetic, an HGF receptor agonist or an HGF receptor antagonist. Some embodiments include compounds of Formulae I, II, HI, or IV that can be a hematopoietic growth factor mimetic, a hematopoietic growth factor receptor agonist or a a hematopoietic growth factor receptor antagonist. Some embodiments include compounds of Formulae I, II, III, or IV that can be an EPO mimic. Some embodiments include compounds of Formulae I, H, III, or IV that can be a selective EPO receptor agonist. Some embodiments include compounds of Formulae I, H, III, or IV that can be a selective EPO receptor partial agonist. Some embodiments include compounds of Formulae I, II, HI, or IV that can be a selective EPO receptor antagonist. Some embodiments include compounds of Formulae I, H, III, or IV that can be a selective EPO receptor binding compound.
[0141] Certain embodiments provide selective HGF modulators. Certain embodiments provide selective HGF receptor binding agents. Certain embodiments provide methods of making and methods of using selective HGF modulators and/or selective HGF receptor binding agents. In certain embodiments, selective HGF modulators are agonists, partial agonists, and/or antagonists for the HGF receptor.
[0142] Certain compounds that modulate one or more EPO activity and/or bind to EPO receptors play a role in health. In certain embodiments, compounds are useful for treating any of a variety of diseases or conditions. A surprising discovery has been made that compounds with activity at the TPO receptor or other specific receptors also have broader EPO activity which can modulate EPO receptors affecting a wide range of diseases and disorders.
[0143] Certain embodiments provide selective EPO modulators. Certain embodiments provide selective EPO receptor binding agents. Certain embodiments provide methods of making and methods of using selective EPO modulators and/or selective EPO receptor binding agents. In certain embodiments, selective EPO modulators are agonists, partial agonists, and/or antagonists for the EPO receptor.
[0144] The compounds disclosed herein can be used alone or in combination with other agents, for example, to modulate hematopoiesis, erythropoiesis, granulopoiesis, thrombopoiesis, and myelopoiesis. The instant compounds can also be used alone or in combination with other agents in treatment or prevention of a disease or condition caused by abnormal function of hematopoiesis, erythropoiesis, granulopoiesis, thrombopoiesis, and myelopoiesis. Some non-limiting examples of diseases include anemia, neutropenia, thrombocytopenia, cardiovascular disorders, immune/autoimmune disorders, cancers, infectious disorders or diseases, and neurologic disorders.
[0145] Certain compounds of the present embodiments may exist as stereoisomers including optical isomers. The present disclosure is intended to include all stereoisomers and both the racemic mixtures of such stereoisomers as well as the individual enantiomers that may be separated according to methods that are known in the art or that may be excluded by synthesis schemes known in the art designed to yield predominantly one enantiomer relative to another.
[0146] In certain embodiments, a salt corresponding to a selective HGF modulator is provided. In certain embodiments, a salt corresponding to a selective HGF receptor binding agent is provided. In certain embodiments, a salt is obtained by reacting a compound with an acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. In certain embodiments, a salt is obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as choline, dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, 4-(2- hydroxyethyl)-morpholine, l-(2-hydroxyethyl)-pyrrolidine, ethanolamine and salts with amino acids such as arginine, lysine, and the like. In certain embodiments, a salt is obtained by reacting a free acid form of a selective HGF modulator or selective HGF binding agent with multiple molar equivalents of a base, such as bis-sodium, bis-ethanolamine, and the like.
[0147] In certain embodiments, a salt corresponding to a selective EPO modulator is provided. In certain embodiments, a salt corresponding to a selective EPO receptor binding agent is provided. In certain embodiments, a salt is obtained by reacting a compound with an acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. In certain embodiments, a salt is obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as choline, dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, 4-(2- hydroxyethyl)-morpholine, l-(2-hydroxyethyl)-pyrrolidine, ethanolamine and salts with amino acids such as arginine, lysine, and the like. In certain embodiments, a salt is obtained by reacting a free acid form of a selective EPO modulator or selective EPO binding agent with multiple molar equivalents of a base, such as bis-sodium, bis-ethanolamine, and the like.
[0148] In certain embodiments, a salt corresponding to a compound of the present embodiments is selected from acetate, ammonium, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, cholinate, clavulanate, citrate, dihydrochloride, diphosphate, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabanine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mucate, napsylate, nitrate, N-methylglucamine, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate, polygalacturonate, potassium, salicylate, sodium, stearate, subaceatate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, triethiodide, tromethamine, trimethylammonium, and valerate salts.
[0149] Some embodiments provide a pharmaceutical composition comprising a physiologically acceptable carrier, diluent, or excipient; and a compqund of Formulae I, II, III, or IV.
[0150] In certain embodiments, one or more carbon atoms of a compound of the present embodiments are replaced with silicon. See e.g., WO 03/037905 Al; Tacke and Zilch, Endeavour, New Series, 10, 191-197 (1986); Bains and Tacke, Curr. Opin. Drug Discov Devel. Jul:6(4):526-43(2003), all of which are incorporated herein by reference in their entirety. In certain embodiments, compounds comprising one or more silicon atoms possess certain desired properties, including, but not limited to, greater stability and/or longer half-life in a patient, when compared to the same compound in which none of the carbon atoms have been replaced with a silicon atom. Certain Synthesis Methods
[0151] Scheme I
Figure imgf000071_0001
[0152] The process of Scheme I describes synthesis of certain compounds of Formula II.
Compounds of general structure 3 were prepared by treatment of diester of general structure 1 and substituted hydrazines under standard amide formation conditions. Intermediates of general structure 2 were also prepared using similar conditions. Condensition reactions of intermediates of general structure 2 and a ketone or aldehyde provided the final compounds of general structure 4. Alternatively, compounds of general structure 3 can also be obtained by reduction of compounds of general structure 4.
Certain Assays
[0153] In certain embodiments, assays may be used to determine the level of HGF modulating activity of the compounds of the present embodiments.
[0154] In certain embodiments, assays may be used to determine the level of EPO modulating activity of the compounds of the present embodiments. Proliferation Assay
[0155] In some embodiments, compounds are tested in an in vitro proliferation assay using the cell lines that express EPO, TPO, GCSF or other cytokine receptors that may be dependant upon these cytokines for their growth. Luciferase Assay
[0156] In some embodiments, compounds are tested in a reporter assay using the cell lines that express EPO, TPO, GCSF or other cytokine receptors. These cells are transfected with the STAT responsive reporter (such as luciferase) and the activity of the compounds is determined by a reporter assay. Differentiation Assay
[0157] In some embodiments, compounds are tested in purified human CD34+ progenitor cells. After addition of the compounds to the cells, the number of cells expressing markers of hematopoiesis, erythropoiesis, granulopoiesis, thrombopoiesis, or myelopoiesis is measured by flow cytometry or by analyzing expression of genes associated with these pathways. Certain Pharmaceutical Agents
[0158] In certain embodiments, at least one selective HGF modulator, or pharmaceutically acceptable salt, ester, amide, and/or prodrug thereof, either alone or combined with one or more pharmaceutically acceptable carriers, forms a pharmaceutical agent. Techniques for formulation and administration of compounds of the present embodiments may be found for example, in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, 18th edition, 1990, which is incorporated herein by reference in its entirety.
[0159] In certain embodiments, at least one selective EPO modulator, or pharmaceutically acceptable salt, ester, amide, and/or prodrug thereof, either alone or combined with one or more pharmaceutically acceptable carriers, forms a pharmaceutical agent. Techniques for formulation and administration of compounds of the present embodiments may be found for example, in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, 18th edition, 1990, which is incorporated herein by reference in its entirety.
[0160] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present embodiments is prepared using known techniques, including, but not limited to mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tabletting processes.
[0161] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present embodiments is a liquid (e.g., a suspension, elixir and/or solution). In certain of such embodiments, a liquid pharmaceutical agent comprising one or more compounds of the present embodiments is prepared using ingredients known in the art, including, but not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. [0162] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present embodiments is a solid (e.g. , a powder, tablet, and/or capsule). In certain of such embodiments, a solid pharmaceutical agent comprising one or more compounds of the present embodiments is prepared using ingredients known in the art, including, but not limited to, starches, sugars, diluents, granulating agents, lubricants, binders, and disintegrating agents.
[0163] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present embodiments is formulated as a depot preparation. Certain such depot preparations are typically longer acting than non-depot preparations. In certain embodiments, such preparations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. In certain embodiments, depot preparations are prepared using suitable polymeric or hydrophobic materials (for example an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
[0164] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present embodiments comprises a delivery system. Examples of delivery systems include, but are not limited to, liposomes and emulsions. Certain delivery systems are useful for preparing certain pharmaceutical agents including those comprising hydrophobic compounds. In certain embodiments, certain organic solvents such as dimethylsulfoxide are used.
[0165] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present embodiments comprises one or more tissue-specific delivery molecules designed to deliver the pharmaceutical agent to specific tissues or cell types. For example, in certain embodiments, pharmaceutical agents include liposomes coated with a tissue- specific antibody.
[0166] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present embodiments comprises a co-solvent system. Certain of such co- solvent systems comprise, for example, benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. In certain embodiments, such co-solvent systems are used for hydrophobic compounds. A non-limiting example of such a co-solvent system is the VPD co-solvent system, which is a solution of absolute ethanol comprising 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant POL YSORBATE 80™ , and 65% w/v polyethylene glycol 300. The proportions of such co-solvent systems may be varied considerably without significantly altering their solubility and toxicity characteristics. Furthermore, the identity of co-solvent components may be varied: for example, other surfactants may be used instead of POLYSORBATE 80™; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.
[0167] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present embodiments comprises a sustained-release system. A non-limiting example of such a sustained-release system is a semi-permeable matrix of solid hydrophobic polymers. In certain embodiments, sustained-release systems may, depending on their chemical nature, release compounds over a period of hours, days, weeks or months.
[0168] Certain compounds used in pharmaceutical agent of the present embodiments may be provided as pharmaceutically acceptable salts with pharmaceutically compatible counterions. Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc.
[0169] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present embodiments comprises an active ingredient in a therapeutically effective amount. In certain embodiments, the therapeutically effective amount is sufficient to prevent, alleviate or ameliorate symptoms of a disease or to prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art.
[0170] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present embodiments is formulated as a prodrug. In certain embodiments, prodrugs are useful because they are easier to administer than the corresponding active form. For example, in certain instances, a prodrug may be more bioavailable (e.g., through oral administration) than is the corresponding active form. In certain instances, a prodrug may have improved solubility compared to the corresponding active form. In certain embodiments, a prodrug is an ester. In certain embodiments, such prodrugs are less water soluble than the corresponding active form. In certain instances, such prodrugs possess superior transmittal across cell membranes, where water solubility is detrimental to mobility. In certain embodiments, the ester in such prodrugs is metabolically hydrolyzed to carboxylic acid. In certain instances the carboxylic acid containing compound is the corresponding active form. In certain embodiments, a prodrug comprises a short peptide (polyaminoacid) bound to an acid group. In certain of such embodiments, the peptide is metabolized to form the corresponding active form.
[0171] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present embodiments is useful for treating a conditions or disorder in a mammalian, and particularly in a human patient. Suitable administration routes include, but are not limited to, oral, rectal, transmucosal, intestinal, enteral, topical, suppository, through inhalation, intrathecal, intraventricular, intraperitoneal, intranasal, intraocular and parenteral (e.g., intravenous, intramuscular, intramedullary, and subcutaneous). In certain embodiments, pharmaceutical intrathecals are administered to achieve local rather than systemic exposures. For example, pharmaceutical agents may be injected directly in the area of desired effect (e.g., in the renal or cardiac area).
[0172] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present embodiments is administered in the form of a dosage unit (e.g., tablet, capsule, bolus, etc.). In certain embodiments, such dosage units comprise a selective EPO modulator in a dose from about 1 μg/kg of body weight to about 50 mg/kg of body weight. In certain embodiments, such dosage units comprise a selective EPO modulator in a dose from about 2 μg/kg of body weight to about 25 mg/kg of body weight. In certain embodiments, such dosage units comprise a selective EPO modulator in a dose from about 10 μg/kg of body weight to about 5 mg/kg of body weight. In certain embodiments, pharmaceutical agents are administered as needed, once per day, twice per day, three times per day, or four or more times per day. It is recognized by those skilled in the art that the particular dose, frequency, and duration of administration depends on a number of factors, including, without limitation, the biological activity desired, the condition of the patient, and tolerance for the pharmaceutical agent. [0173] In certain embodiments, a pharmaceutical agent comprising a compound of the present embodiments is prepared for oral administration. In certain of such embodiments, a pharmaceutical agent is formulated by combining one or more compounds of the present embodiments with one or more pharmaceutically acceptable carriers. Certain of such carriers enable compounds of the present embodiments to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient. In certain embodiments, pharmaceutical agents for oral use are obtained by mixing one or more compounds of the present embodiments and one or more solid excipient. Suitable excipients include, but are not limited to, fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). In certain embodiments, such a mixture is optionally ground and auxiliaries are optionally added. In certain embodiments, pharmaceutical agents are formed to obtain tablets or dragee cores. In certain embodiments, disintegrating agents (e.g., cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate) are added.
[0174] In certain embodiments, dragee cores are provided with coatings. In certain of such embodiments, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to tablets or dragee coatings.
[0175] In certain embodiments, pharmaceutical agents for oral administration are push-fit capsules made of gelatin. Certain of such push-fit capsules comprise one or more compounds of the present embodiments in admixture with one or more filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In certain embodiments, pharmaceutical agents for oral administration are soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In certain soft capsules, one or more compounds of the present embodiments are be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. [0176] In certain embodiments, pharmaceutical agents are prepared for buccal administration. Certain of such pharmaceutical agents are tablets or lozenges formulated in conventional manner.
[0177] In certain embodiments, a pharmaceutical agent is prepared for administration by injection (e.g., intravenous, subcutaneous, intramuscular, etc.). In certain of such embodiments, a pharmaceutical agent comprises a carrier and is formulated in aqueous solution, such as water or physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer. In certain embodiments, other ingredients are included (e.g., ingredients that aid in solubility or serve as preservatives). In certain embodiments, injectable suspensions are prepared using appropriate liquid carriers, suspending agents and the like. Certain pharmaceutical agents for injection are presented in unit dosage form, e.g., in ampoules or in multi-dose containers. Certain pharmaceutical agents for injection are suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Certain solvents suitable for use in pharmaceutical agents for injection include, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, such suspensions may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
[0178] In certain embodiments, a pharmaceutical agent is prepared for transmucosal administration. In certain of such embodiments penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
[0179] In certain embodiments, a pharmaceutical agent is prepared for administration by inhalation. Certain of such pharmaceutical agents for inhalation are prepared in the form of an aerosol spray in a pressurized pack or a nebulizer. Certain of such pharmaceutical agents comprise a propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In certain embodiments using a pressurized aerosol, the dosage unit may be determined with a valve that delivers a metered amount. In certain embodiments, capsules and cartridges for use in an inhaler or insufflator may be formulated. Certain of such formulations comprise a powder mixture of a compound of the present embodiments and a suitable powder base such as lactose or starch.
[0180] In certain embodiments, a pharmaceutical agent is prepared for rectal administration, such as a suppositories or retention enema. Certain of such pharmaceutical agents comprise known ingredients, such as cocoa butter and/or other glycerides.
[0181] In certain embodiments, a pharmaceutical agent is prepared for topical administration. Certain of such pharmaceutical agents comprise bland moisturizing bases, such as ointments or creams. Exemplary suitable ointment bases include, but are not limited to, petrolatum, petrolatum plus volatile silicones, lanolin and water in oil emulsions such as EUCERIN™, available from Beiersdorf (Cincinnati, Ohio). Exemplary suitable cream bases include, but are not limited to, NIVEA™ Cream, available from Beiersdorf (Cincinnati, Ohio), cold cream (USP), PURPOSE CREAM™, available from Johnson & Johnson (New Brunswick, New Jersey), hydrophilic ointment (USP) and LUBRIDERM™, available from Pfizer (Morris Plains, New Jersey).
[0182] In certain embodiments, the formulation, route of administration and dosage for a pharmaceutical agent of the present embodiments can be chosen in view of a particular patient's condition. (See e.g., Fingl et al. 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p. 1, which is incorporated herein by reference in its entirety). In certain embodiments, a pharmaceutical agent is administered as a single dose. In certain embodiments, a pharmaceutical agent is administered as a series of two or more doses administered over one or more days.
[0183] In certain embodiments, a pharmaceutical agent of the present embodiments is administered to a patient between about 0.1% and 500%, 5% and 200%, 10% and 100%, 15% and 85%, 25% and 75%, or 40% and 60% of an established human dosage. Where no human dosage is established, a suitable human dosage may be inferred from ED50 or ID50 values, or other appropriate values derived from in vitro or in vivo studies.
[0184] In certain embodiments, a daily dosage regimen for a patient comprises an oral dose of between 0.1 mg and 2000 mg, 5 mg and 1500 mg, 10 mg and 1000 mg, 20 mg and 500 mg, 30 mg and 200 mg, or 40 mg and 100 mg of a compound of the present embodiments. In certain embodiments, a daily dosage regimen is administered as a single daily dose. In certain embodiments, a daily dosage regimen is administered as two, three, four, or more than four doses.
[0185] In certain embodiments, a pharmaceutical agent of the present embodiments is administered by continuous intravenous infusion. In certain of such embodiments, from 0.1 mg to 500 mg of a composition of the present embodiments is administered per day.
[0186] In certain embodiments, a pharmaceutical agent of the present embodiments is administered for a period of continuous therapy. For example, a pharmaceutical agent of the present embodiments may be administered over a period of days, weeks, months, or years.
[0187] Dosage amount, interval between doses, and duration of treatment may be adjusted to achieve a desired effect. In certain embodiments, dosage amount and interval between doses are adjusted to maintain a desired concentration on compound in a patient. For example, in certain embodiments, dosage amount and interval between doses are adjusted to provide plasma concentration of a compound of the present embodiments at an amount sufficient to achieve a desired effect. In certain of such embodiments the plasma concentration is maintained above the minimal effective concentration (MEC). In certain embodiments, pharmaceutical agents of the present embodiments are administered with a dosage regimen designed to maintain a concentration above the MEC for 10-90% of the time, between 30-90% of the time, or between 50-90% of the time.
[0188] In certain embodiments in which a pharmaceutical agent is administered locally, the dosage regimen is adjusted to achieve a desired local concentration of a compound of the present embodiments.
[0189] In certain embodiments, a pharmaceutical agent may be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions comprising a compound of the present embodiments formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
[0190] In certain embodiments, a pharmaceutical agent is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. Certain Combination Therapies
[0191] In certain embodiments, one or more pharmaceutical agents of the present embodiments are co-administered with one or more other pharmaceutical agents. In certain embodiments, such one or more other pharmaceutical agents are designed to treat the same disease or condition as the one or more pharmaceutical agents of the present embodiments. In certain embodiments, such one or more other pharmaceutical agents are designed to treat a different disease or condition as the one or more pharmaceutical agents of the present embodiments. In certain embodiments, such one or more other pharmaceutical agents are designed to treat an undesired effect of one or more pharmaceutical agents of the present embodiments. In certain embodiments, one or more pharmaceutical agents of the present embodiments are co-administered with another pharmaceutical agent to treat an undesired effect of that other pharmaceutical agent. In certain embodiments, one or more pharmaceutical agents of the present embodiments and one or more other pharmaceutical agents are administered at the same time. In certain embodiments, one or more pharmaceutical agents of the present embodiments and one or more other pharmaceutical agents are administered at the different times. In certain embodiments, one or more pharmaceutical agents of the present embodiments and one or more other pharmaceutical agents are prepared together in a single formulation. In certain embodiments, one or more pharmaceutical agents of the present embodiments and one or more other pharmaceutical agents are prepared separately.
[0192] Examples of pharmaceutical agents that may be co-administered with a pharmaceutical agent of the present embodiments include, but are not limited to, anti-cancer treatments, including, but not limited to, chemotherapy and radiation treatment; corticosteroids, including but not limited to prednisone; immunoglobulins, including, but not limited to intravenous immunoglobulin (IVIg); erythropoiesis-stimulating agents, including, but not limited to, biologically engineered erythropoietin regiments; analgesics (e.g., acetaminophen); anti- inflammatory agents, including, but not limited to non-steroidal anti-inflammatory drugs (e.g., ibuprofen, COX-I inhibitors, and COX-2, inhibitors); salicylates; antibiotics; antivirals; antifungal agents; antidiabetic agents (e.g., biguanides, glucosidase inhibitors, insulins, sulfonylureas, and thiazolidenediones); adrenergic modifiers; diuretics; hormones (e.g., anabolic steroids, androgen, estrogen, calcitonin, progestin, somatostan, and thyroid hormones); immunomodulators; muscle relaxants; antihistamines; osteoporosis agents (e.g., biphosphonates, calcitonin, and estrogens); prostaglandins, antineoplastic agents; psychotherapeutic agents; sedatives; poison oak or poison sumac products; antibodies; and vaccines.
Certain Indications
[0193] In certain embodiments, provided are methods of treating a patient comprising administering one or more compounds of the present embodiments. In certain embodiments, such patient suffers from thrombocytopenia. In certain such embodiments, thrombocytopenia results from chemotherapy and/or radiation treatment. In certain embodiments, thrombocytopenia results bone marrow failure resulting from bone marrow transplantation and/or aplastic anemia. In certain embodiments thrombocytopenia is idiopathic. In certain embodiments, one or more compounds of the present embodiments are administered to a patient to in conjunction with harvesting peripheral blood progenitor cells and/or in conjunction with platelet apheresis. Such administration may be done before, during, and/or after such harvesting.
[0194] Some embodiments provide a method for modulating an EPO activity in a cell comprising contacting a cell with a compound of Formulae I, II, III, or IV. Some embodiments provide a method for modulating an EPO activity in a cell comprising contacting a cell with a compound of Formulae I, II, III, or IV. Some embodiments provide a method for identifying a compound that modulates an EPO activity, comprising contacting a cell that expresses an EPO receptor with a compound of Formulae I, II, HI, or IV; and monitoring an effect of the compound on the cell.
[0195] Some embodiments provide a method of treating a patient, comprising administering to the patient a compound of Formulae I, II, HI, or IV. In some embodiments the patient suffers from an anemia, a neutropenia, a cardiovascular disorder, an immune/autoimmune disorder, an infectious disorder, and a neurologic disorder. . In some embodiments the patient suffers from an anemia, a neutropenia, a cardiovascular disorder, an immune/autoimmune disorder, an infectious disorder, and a neurologic disorder. . In some embodiments the disease or condition results from radiation or chemotherapy. . In some embodiments the disease or condition results from radiation and chemotherapy. In some embodiments the method further comprises harvesting cells from the patient. In some embodiments the treatment is prophylactic. In some embodiments the patient suffers from a condition affecting the nervous system. In some embodiments the patient suffers from a disease selected from amyotrophic lateral sclerosis, multiple sclerosis, and multiple dystrophy. In some embodiments the patient suffers from injury to the nervous system. In some embodiments the patient suffers from injury to the spinal cord.
[0196] Some embodiments provide a pharmaceutical composition comprising a compound of Formulae I, II, III, or IV for use in treating a condition selected from an anemia, a neutropenia, a cardiovascular disorder, an immune/autoimmune disorder, a cancer, an infectious disorder, and a neurologic disorder.
[0197] In certain embodiments, one or more compounds of the present embodiments are administered to a patient who suffers from a condition affecting the nervous system, including, but are not limited to, diseases affecting the nervous system and injuries to the nervous system. Such diseases, include, but not limited to, amyotrophic lateral sclerosis, multiple sclerosis, and multiple dystrophy. Injury to the nervous system include, but are not limited to spinal cord injury or peripheral nerve damage, including, but not limited to, injury resulting from trauma or from stroke. In certain embodiments, one or more compounds of the present embodiments are used to promote growth and/or development of glial cells. Such glial cells may repair nerve cells. In certain embodiments, compounds of the present embodiments are used to treat psychological disorders, including, but not limited to, cognitive disorders.
EXAMPLES
[0198] The following examples are set forth merely to assist in understanding the embodiments and should not be construed as limiting the embodiments described and claimed herein in any way. Variations of the invention, including the substitution of all equivalents now known or later developed, which would be within the purview of those skilled in the art, and changes in formulation or minor changes in experimental design, are to be considered to fall within the scope of the invention incorporated herein. EXAMPLE 1 4,4'-Oxybis(benz-2-benzylidenehydrazide) (Compound 101)
Figure imgf000083_0001
[0199] Compound 101 was prepared according to the procedure described in Scheme I from dimethyl 4,4'-oxybisbenzoate and benzaldehyde. 1H NMR (300MHz, DMSO-</6) δ 11.85 (s 2H), 8.46 (s, 2H), 8.00 (d, 4H), 7.73 (d, 4H) 7.46 (m, 6H), 7.22 (d, 4H).
EXAMPLE 2 4,4'-Oxybis(benz-2-(3-methoxybenzylidene)hydrazide) (Compound 102)
Figure imgf000083_0002
[0200] Compound 102 was prepared according to the procedure described in Scheme I from dimethyl 4,4'-oxybisbenzoate and 3 -methoxy benzaldehyde. [M+H]+, calcd for C30H26N4O5: 523.19; found: 523.10.
EXAMPLE 3 4,4'-Bis(benz-2-benzylidenehydrazide) (Compound 103)
Figure imgf000083_0003
[0201] Compound 103 was prepared according to the procedure described in Scheme I from dimethyl biphenyl-4,4'-dicarboxylate and benzaldehyde. 1H NMR (300MHz, DMSO- d6) δ 11.95 (s, 2H), 8.50 (s, 2H), 8.07 (d, J = 8.0 Hz, 4H), 7.94 (d, J = 8.0 Hz, 4H), 7.74 (d, J = 6.6 Hz, 4H), 7.46 (d, J= 6.6 Hz, 2H), 6.4 (t, J= 6.6 Hz, 4H).
EXAMPLE 4
4,4'-Bis(benz-2-(3-methoxybenzylidene)hydrazide) (Compound 104)
Figure imgf000084_0001
[0202] Compound 104 was prepared according to the procedure described in Scheme I from dimethyl biphenyl-4,4'-dicarboxylate and 3-methoxybenzaldehyde. 1H NMR (300MHz, OMSO-d6) δ 11.94 (s, 2H), 8.46 (s, 2H), 7.93 (d, J = 8.3 Hz, 4H), 7.37 (d, J = 8.3 Hz, 4H), 7.37 (t, J = 8.0 Hz, 2H5), 7.30 (d, J = 7.8 Hz, 2H), 7.29 (s, 2H), 7.01 (d, J = 7.8 Hz, 2H), 3.81 (s, 6H).
EXAMPLE 5
4,4'-Bis(benz-2-(3-methylbenzylidene)hydrazide) (Compound 105)
Figure imgf000084_0002
[0203] Compound 105 was prepared according to the procedure described in Scheme I from dimethyl biphenyl-4,4'-dicarboxylate and 3-methylbenzaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.92 (s, 2H), 8.46 (s, 2H), 8.06 (d, J = 8.2 Hz, 4H), 7.94 (d, J = 8.2 Hz, 4H), 7.59 (s, 2H), 7.54 (d, J = 8.3 Hz, 2H ), 7.35 (t, J = 7.3 Hz, 2H ), 7.27 (d, J = 7.3 Hz, 2H), 2.38 (s. 6H).
EXAMPLE 6
4,4'-Bis(benz-2-(2-hydroxy-5-methoxybenzylidene)hydrazide) (Compound 106)
Figure imgf000084_0003
[0204] Compound 106 was prepared according to the procedure described in Scheme I from dimethyl biphenyl-4,4'-dicarboxylate and 2-hydroxy-5-methoxybenzaldehyde. 1H NMR (300MHz, DMSO-^6) δ 12.17 (s, 2H), 10.73 (br. s, 2H), 8.66 (s, 2H), 8.07 (d, J = 8.3 Hz, 4H), 7.94 (d, J = 8.3 Hz, 4H), 7.13 (d, J = 2.5 Hz, 2H), 6.90 (dd, J = 9.0, 2.5 Hz, 2H), 6.86 (d, J= 9.0 Hz, 2H), 3.73 (s, 6H). EXAMPLE 7
4,4'-Bis(benz-2-(3-vinylbenzylidene)hydrazide) (Compound 107)
Figure imgf000085_0001
[0205] Compound 107 was prepared according to the procedure described in Scheme I from dimethyl biphenyl-4,4'-dicarboxylate and 3-vinylbenzaldehyde. 1H NMR (300MHz, DMSO-J6) δ 12.01 (s, 2H), 8.51 (s, 2H), 8.06 (d, J = 8.0 Hz, 4H), 7.93 (d, J = 8.0 Hz, 4H), 7.80 (s, 2H), 7.65 (d, J = 7.6 Hz, 2H), 7.56 (d, J = 7.6 Hz, 2H), 7.46 (t, J = 7.6 Hz, 2H), 6.90 (dd, J- 17.6, 11.0 Hz, 2H), 6.91 (d, J= 17.6 Hz, 2H), 5.34 (d, J= 11.0 Hz, 2H).
EXAMPLE 8 4,4'-Bis(benz-2-(3,5-dimethylbenzylidene)hydrazide) (Compound 108)
Figure imgf000085_0002
[0206] Compound 108 was prepared according to the procedure described in Scheme I from dimethyl biphenyl-4,4'-dicarboxylate and 3,5-dimethylbenzaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.91 (s, 2H), 8.39 (s, 2H), 8.04 (d, J = 8.3 Hz, 4H), 7.92 (d, J = 8.3 Hz, 4H), 7.35 (s, 4H), 7.08 (s, 4H), 2.31 (s, 12H).
EXAMPLE 9 4,4'-Bis(benz-2-(3,4-dimethylbenzylidene)hydrazide) (Compound 109)
Figure imgf000085_0003
[0207] Compound 109 was prepared according to the procedure described in Scheme I from dimethyl biphenyl-4,4'-dicarboxylate and 3,4-dimethylbenzaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.86 (s, 2H), 8.40 (s, 2H), 8.04 (d, J = 8.3 Hz, 4H), 7.92 (d, J = 8.3 Hz, 4H), 7.52 (s, 2H), 7.43 (d, J = 8.2 Hz, 4H), 7.22 (d, J = 8.2 Hz, 4H), 2.27 (s, 6H), 2.25 (s, 6H). EXAMPLE 10 4,4'-Bis(benz-2-(3,5-dimethoxybenzylidene)hydrazide) (Compound 110)
Figure imgf000086_0001
[0208] Compound 110 was prepared according to the procedure described in Scheme I from dimethyl biphenyl-4,4'-dicarboxylate and 3,5-dimethoxybenzaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.95 (s, 2H), 8.41 (s, 2H), 8.04 (d, J = 8.3 Hz, 4H), 7.92 (d, J = 8.3 Hz, 4H), 6.88 (d, J = 2.0 Hz, 4H), 6.58 (t, J = 2.0 Hz, 2H), 3.79 (s, 12H).
EXAMPLE 11 4,4'-Bis(benz-2-(3-hydroxybenzylidene)hydrazide) (Compound 111)
Figure imgf000086_0002
[0209] Compound 1 10 was prepared according to the procedure described in Scheme I from dimethyl biphenyl-4,4'-dicarboxylate and 3-hydroxybenzaldehyde. 1H NMR (300MHz, DMSO-^6) δ 11.91 (s, 2H), 9.65 (br. s, 2H), 8.41 (s, 2H), 8.05 (d, J = 8.3 Hz, 4H), 7.92 (d, J = 8.3 Hz, 4H), 7.25 (t, J = 7.8 Hz, 2H,), 7.21 (s, 2H), 7.11 (d, J = 7.6 Hz, 2H), 6.83 (dd, J = 8.0, 1.7 Hz, 2H).
EXAMPLE 12
4,4'-Bis(benz-2-(2-methylpropylidene)hydrazide) (Compound 112)
Figure imgf000086_0003
[0210] Compound 112 was prepared according to the procedure described in Scheme I from dimethyl biphenyl-4,4'-dicarboxylate and 2-methylpropionaldehyde. 1H NMR (300MHz, DMSCW6) δ 11.45 (s, 2H), 7.96 (d, J = 8.3 Hz, 4H), 7.86 (d, J = 8.3 Hz, 4H), 7.70 (d, J = 5.4 Hz, 2H), 2.52 (ds, J = 6.8 Hz, 2H), (d, J= 5.4, 6.8 Hz, 12H).
EXAMPLE 13 4,4'-Bis(benz-2-(2-methylpropyl)hydrazide) (Compound 113)
HN-NH "^=/ ^- ^ HN-NH /
[0211] Compound 113 was prepared according to the procedure described in Scheme I from dimethyl biphenyl-4,4'-dicarboxylate and 2-methylpropylhydrazine. 1H NMR (300MHz, DMSO-^6) δ 7.83 (d, J = 7.6 Hz, 4H), 7.66 (d, J = 7.6 Hz, 4H), 7.58 (s, 2H), 2.80 (d, J = 6.7 Hz, 4H), 2.10 (s, 2H), 1.87-1.83 (m, 2H), 1.00 (d, J = 6.7 Hz, 12H).
EXAMPLE 14
4-(4-(2-Benzylidene-l-hydrazinocarbonyl)phenyl)aminobutyr-(2-benzylidene)hydrazide
(Compound 114)
Figure imgf000087_0001
[0212] Compound 114 was prepared according to the procedure described in Scheme I from 4-(4-hydrazinocarbonylphenyl)aminobutyric hydrazide and benzaldehyde. 1H NMR (300MHz, DMSO-^6) δ 11.47 (s), 1 1.40 (s), 11.28 (s), 3.22-3.10 (m), 2.75 (t), 2.33 (t), 1.92-1.85 (m). [M+H]+ calcd for C25H25N5O2 428.20; found: 428.13.
EXAMPLE 15
4-(4-(2-(3-Methoxybenzylidene)-l-hydrazinocarbonyl)phenyl)aminobutyr-2-(3- methoxybenzylidene)hydrazide (Compound 115)
Figure imgf000087_0002
[0213] Compound 115 was prepared according to the procedure described in Scheme I from 4-(4-hydrazinocarbonylphenyl)aminobutyric hydrazide and 3-methoxybenzaldehyde. H NMR (300MHz, DMSO-J6) δ 11.48 (s), 11.42 (s), 11.30 (s), 3.81 (s), 3.80 (s), 3.78 (s), 3.19 - 3.12 (m), 2.75 (t), 2.33 (t), 1.89-1.84 (m). [M+H]+ calcd for C27H29N5O4 488.23; found: 488.18.
EXAMPLE 16
4-(4-(2-(2-Hydroxy-5-methoxybenzylidene)-l-hydrazinocarbonyl)phenyl)aminobutyr-2-(2- hydroxy-5-methoxybenzylidene)hydrazide (Compound 116)
Figure imgf000088_0001
[0214] Compound 116 was prepared according to the procedure described in Scheme I from 4-(4-hydrazinocarbonylphenyl)aminobutyric hydrazide and 2-hydroxy-5- methoxybenzaldehyde. 1H NMR (300MHz, DMSO-J6) δ 8.54 (s), 8.33 (s), 8.24 (s), 3.73 (s), 3.72 (s), 3.69 (s), 3.17-3.13 (m), 2.72 (t), 2.35 (t), 1.91-1.86 (m). [M+H]+ calcd for C27H29N5O6: 520.21; found: 520.16.
EXAMPLE 17
4-(4-(2-(3 -Methoxy-4-fluorobenzylidene)- 1 -hydrazinocarbonyl)phenyl)aminobutyr-2-(3 - methoxy-4-fluorobenzylidene)hydrazide (Compound 117)
Figure imgf000088_0002
[0215] Compound 117 was prepared according to the procedure described in Scheme I from 4-(4-hydrazinocarbonylphenyl)aminobutyric hydrazide and 3-methoxy-4- fluorobenzaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.47 (s), 11.40 (s), 11.31 (s), 3.91(s), 3.89 (s), 3.87(s), 3.17-3.12 (m), 2.75 (t), 2.33 (t), 1.89-1.86 (m). [M+H]+ calcd for C27H26F2N5O4: 524.20; found: 524.13.
EXAMPLE 18 4-(4-(2-(3-Methoxy-2-fluorobenzylidene)-l-hydrazinocarbonyl)phenyl)aminobutyr-2-(3- methoxy-2-fluorobenzylidene)hydrazide (Compound 118)
Figure imgf000089_0001
[0216] Compound 118 was prepared according to the procedure described in Scheme I from 4-(4-hydrazinocarbonylphenyl)aminobutyric hydrazide and 3-methoxy-2- fluorobenzaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.60 (s), 11.54 (s), 11.38 (s), 3.85 (s), 3.84 (s), 3.83 (s), 3.16-3.10 (m), 2.72 (t), 2.31 (t), 1.85 (m). [M+H]+ calcd for C27H26F2N5O4: 524.20; found: 524.16.
EXAMPLE 19
4-(4-(2-(3-Methoxy-5-fluorobenzylidene)-l-hydrazinocarbonyl)phenyl)aminobutyr-2-(3- methoxy-5-fluorobenzylidene)hydrazide (Compound 119)
Figure imgf000089_0002
[0217] Compound 1 19 was prepared according to the procedure described in Scheme I from 4-(4-hydrazinocarbonylphenyl)aminobutyric hydrazide and 3-methoxy-5- fluorobenzaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.60 (s), 11.56 (s), 11.41 (s), 3.78 (s), 3.77 (s), 3.75 (s), 3.16-3.11 (m), 2.75 (t), 2.35-2.31 (m), 1.85 (m). [M+H]+ calcd for C27H26F2N5O4: 524.20; found: 524.17.
EXAMPLE 20
4-(4-(2-(3,5-Dimethoxybenzylidene)-l-hydrazinocarbonyl)phenyl)aminobutyr-2-(3,5- dimethoxybenzylidene)hydrazide (Compound 120)
Figure imgf000090_0001
[0218] Compound 120 was prepared according to the procedure described in Scheme
I from 4-(4-hydrazinocarbonylphenyl)aminobutyric hydrazide and 3,5-dimethoxybenzaldehyde.
1H NMR (300MHz, DMSO-^6) δ 11.46 (s), 11.41 (s), 11.30 (s), 3.77 (s), 3.76 (s), 3.75 (s), 3.15 -
3.11 (m), 2.73 (t), 2.31 (t), 1.86-1.84 (m). [M+H]+ calcd for C29H33N5O6: 548.24; found:
548.21.
EXAMPLE 21
4-(4-(2-(3,5-Dimethylbenzylidene)-l-hydrazinocarbonyl)phenyl)aminobutyr-2-(3,5- dimethylbenzylidene)hydrazide (Compound 121)
Figure imgf000090_0002
[0219] Compound 121 was prepared according to the procedure described in Scheme I from 4-(4-hydrazinocarbonylphenyl)aminobutyric hydrazide and 3,5-dimethylbenzaldehyde.
EXAMPLE 22
4-(4-(2-(3 ,4-Dimethylbenzylidene)- 1 -hydrazinocarbonyl)phenyl)aminobutyr-2-(3 ,4- dimethylbenzylidene)hydrazide (Compound 122)
Figure imgf000090_0003
[0220] Compound 122 was prepared according to the procedure described in Scheme I from 4-(4-hydrazinocarbonylphenyl)aminobutyric hydrazide and 3,4-dimethylbenzaldehyde.
EXAMPLE 23 4-(4-(2-(3 -Methoxy-4-methylbenzylidene)- 1 -hydrazinocarbony l)phenyl)aminobutyr-2-(3 - methoxy-4-methylbenzylidene)hydrazide (Compound 123)
Figure imgf000091_0001
[0221] Compound 123 was prepared according to the procedure described in Scheme I from 4-(4-hydrazinocarbonylphenyl)aminobutyric hydrazide and 3-methoxy-4- methylbenzaldehyde. 1H NMR (300MHz, DMSO-Cf6) δ 11.39 (s), 11.32 (s), 11.23 (s), 3.83 (s), 3.82 (s), 3.79 (s), 3.16-3.11 (m), 2.73 (t), 2.31 (t), 2.16 (s), 2.15 (s), 2.14 (s), 1.87-1.85 (m). [M+H]+ calcd for C29H33N5O4: 516.25; found: 516.21.
EXAMPLE 24
3 -(4-(2 -(3 -Methoxybenzy lidene)- 1 -hydrazinocarbony l)pheny l)aminopropion-2-(3 - methoxybenzylidene)hydrazide (Compound 124)
Figure imgf000091_0002
[0222] Compound 124 was prepared according to the procedure described in Scheme I from 3-(4-hydrazinocarbonylphenyl)aminopropionic hydrazide and 3-methoxybenzaldehyde. 1U NMR (300MHz, DMSO-cfe) δ 11.48 (s), 11.40 (s), 3.81 (s), 3.79 (s), 3.77 (s), 3.43 (q), 2.94 (t). [M+H]+ calcd for C26H27N5O4: 574.21; found: 574.11.
EXAMPLE 25
5-(4-(2-(3-Methoxybenzylidene)-l-hydrazinocarbonyl)phenyl)aminopentano-2-(3- methoxybenzylidene)hydrazide (Compound 125)
Figure imgf000091_0003
[0223] Compound 125 was prepared according to the procedure described in Scheme I from 5-(4-hydrazinocarbonylphenyl)aminopentanoic hydrazide and 3-methoxybenzaldehyde. 1H NMR (300MHz, DMSO-^6) δ 11.45 (s), 11.36 (s), 11.26 (s), 3.81 (s), 3.79 (s), 3.78 (s), 3.12- 3.10 (m), 2.68 (t), 2.26 (t), 1.72-1.58 (m). [M+H]+ calcd for C28H3iN5O4: 502.24; found: 502.17.
EXAMPLE 26 4,4'-Stilbenedicarboxyl-2-(3-methoxybenzylidene)hydrazide (Compound 126)
Figure imgf000092_0001
[0224] Compound 126 was prepared according to the procedure described in Scheme I from dimethyl 4,4'-stilbenedicarboxylate and 3-methoxybenzaldehyde. 1H NMR (300MHz, OMSO-dβ) δ 12.80 (s, 2H), 8.38 (s, 2H), 7.91 (m, 2H), 7.89 (d, J = 8.6 Hz, 4H), 7.78 (d, J = 7.8, 2H), 7.88 (d, J = 8.6 Hz, 4H), 7.41 (s, 2H), 7.33 (m, 2H), 7.32 (d, J = 7.8 Hz, IH), 7.28 (d, J = 7.8 Hz, IH), 3.56 (s, 6H).
EXAMPLE 27 2,2' -(1 ,4-Phenylenebisoxyacet-2-(3-methoxybenzylidene)hydrazide) (Compound 127)
Figure imgf000092_0002
[0225] Compound 127 was prepared according to the procedure described in Scheme I from 2,2'-(l,4-phenylenebisoxy)acetate and 3-methoxybenzaldehyde. 1H NMR (300MHz, DMSO-^6) δ 12.82 (s, 2H), 7.94 (s, 2H), 7.36-7.30 (m, 2H), 7.26-7.18 (m, 4H), 7.00-6.84 (m, 6H), 5.02 (s, 4H), 3.57 (s, 6H).
EXAMPLE 28 4,4'-Oxybis(benz-2-(2-hydroxy-5-methoxybenzylidene)hydrazide) (Compound 128)
Figure imgf000092_0003
[0226] Compound 128 was prepared according to the procedure described in Scheme I from dimethyl 4,4'-oxybisbenzoate and 2-hydroxy-5-methoxybenzaldehyde. [M+H]+ calcd for C30H26N4O7: 555.18; found: 555.16.
EXAMPLE 29 4,4'-Oxybis(benz-2-methyl(3-methoxybenzylidene)hydrazide) (Compound 129)
Figure imgf000093_0001
[0227] Compound 129 was prepared according to the procedure described in Scheme I from dimethyl 4,4'-oxybisbenzoate and 3-methoxyphenylmethylketone. [M+H]+ calcd for C32H30N4O5: 551.22; found, 551.72.
EXAMPLE 30
4,4'-Oxybis(benz-2-methyl(2-hydroxy-5-methoxybenzylidene)hydrazide) (Compound 130)
Figure imgf000093_0002
[0228] Compound 130 was prepared according to the procedure described in Scheme I from dimethyl 4,4'-oxybisbenzoate and 2-hydroxy-5-methoxyphenylmethylketone. 1H NMR (300MHz, DMSO-J6) δ 12.79 (s 2H), 1 1.29 (s, 2H), 8.04 (d, 4H), 7.23 (d, 4H) 7.13 (s, 2H), 6.95 (d, 2H), 6.85 (d, 2H), 3.74 (s, 6H), 2.5 (s, 6H, obscured due to overlap of NMR solvent).
EXAMPLE 31 4,4'-Oxybis(benz-2-(3,5-dimethoxybenzylidene)-2'-(6-indolylmethylidene)hydrazide)
(Compound 131)
Figure imgf000093_0003
[0229] Compound 131 was prepared according to the procedure described in Scheme I from dimethyl 4,4'-oxybisbenzoate, 6-fbrmylindole, and 3,5-dimethoxybenzaldehyde. [M+H]+ calcd for C32H27N5O5: 562.20; found: 562.17.
EXAMPLE 32 4,4'-Oxybis(benz-2-(4-N,N-dimethylaminobenzylidene)hydrazide) (Compound 132)
Figure imgf000094_0001
[0230] Compound 132 was prepared according to the procedure described in Scheme I from dimethyl 4,4'-oxybisbenzoate and 4-N,N-dimethylaminobenzaldehyde. [M+H]+ calcd for C32H32N6O3: 549.25; found: 549.22.
EXAMPLE 33 4,4'-Oxybis(benz-2-(5-indolylmethylidene)hydrazide) (Compound 133)
Figure imgf000094_0002
[0231] Compound 133 was prepared according to the procedure described in Scheme I from dimethyl 4,4'-oxybisbenzoate and 5-formylindole. [M+H]+ calcd for C32H24N6O3: 541.19; found: 541.12.
EXAMPLE 34 4,4'-Oxybis(benz-2-(3-chlorobenzylidene)hydrazide) (Compound 134)
Figure imgf000095_0001
Compound 134 was prepared according to the procedure described in Scheme I from dimethyl 4,4'-oxybisbenzoate and 3-chlorobenzaldehyde. [M+H]+ calcd for C28H20Cl2N4O3: 531.09; found: 531.05.
EXAMPLE 35 4,4'-Oxybis(benz-2-(3-methylsulfanylbenzylidene)hydrazide) (Compound 135)
Figure imgf000095_0002
[0232] Compound 135 was prepared according to the procedure described in Scheme I from dimethyl 4,4'-oxybisbenzoate and 3-methylsulfanylbenzaldehyde. [M+H]+ calcd for C30H26N4O3S2: 555.14; found: 555.09.
EXAMPLE 36 4,4'-Oxybis(benz-2-(3-allyl-4-hydroxy-5-methoxybenzylidene)hydrazide) (Compound 136)
Figure imgf000095_0003
[0233] Compound 136 was prepared according to the procedure described in Scheme I from dimethyl 4,4'-oxybisbenzoate and 3-allyl-4-hydroxy-5-methoxybenzaldehyde. [M+H]+ calcd for C36H34N4O7: 635.24; found: 635.24.
EXAMPLE 37 4,4'-Oxybis(benz-2-(3-allyloxybenzylidene)hydrazide) (Compound 137)
Figure imgf000096_0001
[0234] Compound 137 was prepared according to the procedure described in Scheme I from dimethyl 4,4'-oxybisbenzoate and 3-allyloxybenzaldehyde. [M+H]+ calcd for C34H30N4O5: 575.22; found: 575.19.
EXAMPLE 38 4,4'-Oxybis(benz-2-(3-methyl-4-pyrrolidinylbenzylidene)hydrazide) (Compound 138)
Figure imgf000096_0002
[0235] Compound 138 was prepared according to the procedure described in Scheme I from dimethyl 4,4'-oxybisbenzoate and 3-methyl-4-pyrrolidinylbenzaldehyde. [M+H]+ calcd for C38H40N6O3: 629.32; found: 629.30.
EXAMPLE 39 4,4'-Oxybis(benz-2-(3,4-dimethylbenzylidene)hydrazide) (Compound 139)
Figure imgf000096_0003
[0236] Compound 139 was prepared according to the procedure described in Scheme I from dimethyl 4,4'-oxybisbenzoate and 3,4-dimethylbenzaldehyde. [M+H]+ calcd for C32H30N4O3: 519.23; found: 519.17.
EXAMPLE 40
4,4' -Oxybis(benz-2-(3 ,4-dimethylbenzylidene)hydrazide) (Compound 140)
Figure imgf000097_0001
[0237] Compound 140 was prepared according to the procedure described in Scheme I from dimethyl 4,4'-oxybisbenzoate and 3,5-dimethyl-4-hydroxybenzaldehyde. [M+H]+ calcd for C32H30N4O5: 551.22, found: 551.18.
EXAMPLE 41
4-(4-(2-(3-Pyrazolylbenzylidene)-l-hydrazinocarbonyl)phenyl)aminobutyr-2-(3- pyrazolylbenzylidene)hydrazide (Compound 141)
Figure imgf000097_0002
[0238] Compound 141 was prepared according to the procedure described in Scheme I from 4-(4-hydrazinocarbonylphenyl)aminobutyric hydrazide and 3-pyrazolylbenzaldehyde. [M+H]+ calcd for C3]H29N9O2: 560.24; found: 560.02.
EXAMPLE 42
(2-(2-(3-Methoxybenzylidene)-l-hydrazinocarbonyl)indolyloxy-5-)acet-2-(3- methoxybenzylidene)hydrazide (Compound 142)
Figure imgf000097_0003
[0239] Compound 142 was prepared according to the procedure described in Scheme I from (2-hydrazinocarbonyl)indolyloxy-5-)acethydrazide and 3-methoxybenzaldehyde. [M+H]+ calcd for C27H25N5O5: 500.19; found: 500.09.
EXAMPLE 43 1 ,3-Phenylenedioxy-bis(acet-2-(3-methoxybenzylidene)hydrazide) (Compound 143)
Figure imgf000098_0001
[0240] Compound 143 was prepared according to the procedure described in Scheme I from dimethyl 1,3-phenylenedioxy-bis-acetate and 3-methoxybenzaldehyde. [M+H]+ calcd for C26H26N4O6: 491.19; found: 491.00.
EXAMPLE 44 1 ,4-Phenylenedioxy-bis(acet-2-(3 -methylsulfanylbenzylidene)hydrazide) (Compound 144)
Figure imgf000098_0002
[0241] Compound 144 was prepared according to the procedure described in Scheme I from dimethyl 1 ,4-phenylenedioxy-bis-acetate and 3-methylsulfanylbenzaldehyde. [M+H]+ calcd for C26H26N4O4S2: 523.14; found: 523.09.
EXAMPLE 45 1 ,4-Phenylenedioxy-bis(acet-2-(3-acetylbenzylidene)hydrazide) (Compound 145)
Figure imgf000098_0003
[0242] Compound 145 was prepared according to the procedure described in Scheme I from dimethyl 1 ,4-phenylenedioxy-bis-acetate and 3-acetylbenzaldehyde. [M+H]+ calcd for C28H26N4O6: 515.19; found: 515.13.
EXAMPLE 46
1 ,4-Phenylenedioxy-bis(acet-2-(4-hydroxy-3-methylbenzylidene)hydrazide) (Compound 146)
Figure imgf000099_0001
[0243] Compound 146 was prepared according to the procedure described in Scheme I from dimethyl 1 ,4-phenylenedioxy-bis-acetate and 3-methyl-4-hydroxybenzaldehyde. [M+H]+ calcd for C26H26N4O6: 491.19; found: 491.10.
EXAMPLE 47 l,4-Phenylenedioxy-bis(acet-2-(3-allyl-4-hydroxy-5-methoxybenzylidene)hydrazide)
(Compound 147)
Figure imgf000099_0002
[0244] Compound 147 was prepared according to the procedure described in Scheme I from dimethyl 1 ,4-phenylenedioxy-bis-acetate and (3-allyl-4-hydroxy-5- methoxy)benzaldehyde. [M+H]+ calcd for C32H34N4O8: 603.24; found: 603.23.
EXAMPLE 48 1 ,4-Phenylenedioxy-bis(acet-2-(3,5-dimethoxybenzylidene)hydrazide) (Compound 148)
Figure imgf000099_0003
[0245] Compound 148 was prepared according to the procedure described in Scheme I from dimethyl 1 ,4-phenylenedioxy-bis-acetate and (3,5-dimethoxy)benzaldehyde. [M+H]+ calcd for C28H30N4O8: 551.21; found: 551.18.
EXAMPLE 49
1 ,4-Phenylenedioxy-bis(acet(6-indolylmethylidene)hydrazide) (Compound 149)
Figure imgf000100_0001
[0246] Compound 149 was prepared according to the procedure described in Scheme I from dimethyl 1 ,4-phenylenedioxy-bis-acetate and 6-indolecarboxaldehyde. [M+H]+ calcd for C28H24N6O4: 509.19; found: 509.12.
EXAMPLE 50 1 ,4-Phenylenedioxy-bis(acet-2-(3,4-dimethylbenzylidene)hydrazide) (Compound 150)
Figure imgf000100_0002
[0247] Compound 150 was prepared according to the procedure described in Scheme I from dimethyl 1 ,4-phenylenedioxy-bis-acetate and (3,4-dimethyl)benzaldehyde. [M+H]+ calcd for C28H30N4O4: 487.23; found: 487.17.
EXAMPLE 51 1 ,4-Phenylenedioxy-bis(acet-2-(3-methylbenzylidene)hydrazide) (Compound 151)
Figure imgf000100_0003
[0248] Compound 151 was prepared according to the procedure described in Scheme I from dimethyl 1 ,4-phenylenedioxy-bis-acetate and (3-methyl)benzaldehyde. [M+H]+ calcd for C26H26N4O4: 459.20; found: 459.11.
EXAMPLE 52 l,4-Phenylenedioxy-bis(acet-2-(4-hydroxy-3,5-dimethylbenzylidene)hydrazide) (Compound
152)
Figure imgf000101_0001
[0249] Compound 152 was prepared according to the procedure described in Scheme I from dimethyl 1 ,4-phenylenedioxy-bis-acetate and (4-hydroxy-3,5-dimethyl)benzaldehyde. [M+H]+ calcd for C28H30N4O6: 519.22; found: 519.17.
EXAMPLE 53 1 ,4-Phenylenedioxy-bis(acet-2-(4-fluoro-3-methoxybenzylidene)hydrazide) (Compound 153)
Figure imgf000101_0002
[0250] Compound 153 was prepared according to the procedure described in Scheme I from dimethyl 1,4-phenylenedioxy-bis-acetate and (4-fluoro-3-methoxy)benzaldehyde. [M+H]+ calcd for C26H24F2N4O6: 527.17; found: 527.11.
EXAMPLE 54 3,3-bis-(l ,4-Phenylenepropion-2-(3-methoxybenzylidene)hydrazide) (Compound 154)
[0251] Compound 154 was prepared according to the procedure described in Scheme I from dimethyl 1 ,4-phenylenedipropionate and (3-methoxy)benzaldehyde. [M+H]+ calcd for C28H30N4O4: 487.23; found: 487.12.
EXAMPLE 55
2,2 ' -( 1 ,4-Phenylenedioxy)-bis(propion-2-(2-hydroxy-5 -methoxybenzylidene)hydrazide)
(Compound 155)
Figure imgf000102_0001
[0252] Compound 155 was prepared according to the procedure described in Scheme I from dimethyl l,4-phenylenedioxy-bis-2,2'-propionate and 4-hydroxy-3,5- dimethylbenzaldehyde. [M+H]+ calcd for C28H30N4O8: 551.21 ; found: 551.18.
EXAMPLE 56
(2-(2-(3-Methoxybenzylidene)-l-hydrazinocarbonyl)-5-methoxyindolyl-6-)aminoacet-2-(3- methoxybenzylidene)hydrazide (Compound 156)
Figure imgf000102_0002
[0253] Compound 156 was prepared according to the procedure described in Scheme I from (2-methoxycarbonyl)-5-methoxyindolyl-6-amino)acetate and 3-methoxybenzaldehyde. [M+H]+ calcd for C28H28N6O5: 529.21; found: 529.17.
EXAMPLE 57
(2-(2-(2-Hydroxy-5-methoxybenzylidene)-l-hydrazinocarbonyl)indolyloxy-5-)acet-2-(2- hydroxy-5-methoxybenzylidene)hydrazide (Compound 157)
Figure imgf000102_0003
[0254] Compound 157 was prepared according to the procedure described in Scheme I from (2-methoxycarbonyl)indolyloxy-5-)acetate and 2-hydroxy-5-methoxybenzaldehyde. [M+H]+ calcd for C27H25N5O7: 532.18; found: 532.12.
EXAMPLE 58 (2-(2-(4-Fluoro-3-methoxybenzylidene)-l-hydrazinocarbonyl)indolyloxy-5-)acet-2-(4-fluoro-3- methoxybenzylidene)hydrazide (Compound 158)
Figure imgf000103_0001
[0255] Compound 158 was prepared according to the procedure described in Scheme I from (2-methoxycarbonylindolyloxy-5-)acetate and 3-methoxybenzaldehyde. [M+H]+ calcd for C27H23F2N5O5: 536.17; found: 536.12.
EXAMPLE 59
(2-(2-(l,4-Benzodioxane-6-methylidene)-l-hydrazinocarbonyl)indolyloxy-5-)acet-2-(l,4- benzodioxane-6-methylidene)hydrazide (Compound 159)
Figure imgf000103_0002
[0256] Compound 159 was prepared according to the procedure described in Scheme I from (2-methoxycarbonyl)-6-fluoroindolyloxy-5-)acetate and 1 ,4-benzodioxane-6- carboxaldehyde. [M+H]+ calcd for C29H25N5O7: 556.18; found: 556.13.
EXAMPLE 60
(2-(2-(Indolyl-5-methylidene)-l-hydrazinocarbonyl)indolyloxy-5-)acet-2-(indolyl-5- methylidene)hydrazide (Compound 160)
Figure imgf000103_0003
[0257] Compound 160 was prepared according to the procedure described in Scheme I from (2-methoxycarbonyl)indolyloxy-5-)acetate and indole-5-carboxaldehyde. [M+H]+ calcd for C29H23N7O3: 518.19; found: 518.11.
EXAMPLE 61 2,6-Naphthylenedioxy-bis-acet-2-(2-hydroxy-5-methoxybenzylidene)hydrazide (Compound 161)
Figure imgf000104_0001
[0258] Compound 161 was prepared according to the procedure described in Scheme I from 2,6-naphthylenedioxy-bis-acetate and 2-hydroxy-5-methoxybenzaldehyde. [M+H]+ calcd for C30H28N4O8: 573.19; found: 573.18.
EXAMPLE 62
4-(4-(2-(3-Methoxy)benzylidene-l-hydrazinocarbonyl)phenyloxy)butyr-2-(3- methoxybenzylidene)hydrazide (Compound 162)
Figure imgf000104_0002
[0259] Compound 162 was prepared according to the procedure described in Scheme I from 4-(4-hydrazinocarbonylphenyloxy)butyric hydrazide and 3-methoxybenzaldehyde. [M+H]+ calcd for C27H28N4O5: 489.21; found, 489.14.
EXAMPLE 63
(2-(2-(2-Hydroxy-5-methoxy)benzylidene-l-hydrazinocarbonyl)naphthyloxy-6-)acet-2-(2- hydroxy-5-methoxybenzylidene)hydrazide (Compound 163)
Figure imgf000105_0001
[0260] Compound 163 was prepared according to the procedure described in Scheme I from (2-methoxycarbonylnaphthyloxy-6-)acetate and 2-hydroxy-5-methoxybenzaldehyde. [M+H]+ calcd for C29H26N4O7: 543.18; found: 543.14.
EXAMPLE 64
(2-(2-(2-Hydroxy-5-methoxybenzylidene)-l-hydrazinocarbonyl)indolyl-5-)aminoacet-2-(3- methoxybenzylidene)hydrazide (Compound 164)
Figure imgf000105_0002
[0261] Compound 164 was prepared according to the procedure described in Scheme I from (2-methoxycarbonyl)indolyl-5-amino)acetate and 3-methoxybenzaldehyde. [M+H]+ calcd for C27H26N6O6: 531.19; found: 531.12.
EXAMPLE 65
(2-(2-(2-Hydroxy-5-methoxybenzylidene)- 1 -hydrazinocarbonyl)indolyloxy-6-)acet-2-(3 - methoxybenzylidene)hydrazide (Compound 165)
Figure imgf000105_0003
[0262] Compound 165 was prepared according to the procedure described in Scheme I from (2-methoxycarbonylindolyloxy-6-)acetate and 3-methoxybenzaldehyde. [M+H]+ calcd for C27H25N5O7: 532.18; found: 532.01. EXAMPLE 66
(2-(2-(Benzimidazolyl-5-)methylidene)-l-hydrazinocarbonyl)indolyloxy-5-)acet-2- (benzimidazolyl-5-methylidene)hydrazide (Compound 166)
Figure imgf000106_0001
[0263] Compound 166 was prepared according to the procedure described in Scheme I from (2-methoxycarbonyl)indolyloxy-5-)acetate and 3-methoxybenzaldehyde. [M+H]+ calcd for C27H2[N9O3: 520.18; found: 520.00.
EXAMPLE 67
4-(4-(2-(4-Hydroxy-3 -methoxy)benzylidene- 1 -hydrazinocarbonyl)phenyl)aminobutyr-2-(4- hydroxy-3-methoxybenzylidene)hydrazide (Compound 167)
Figure imgf000106_0002
[0264] Compound 167 was prepared according to the procedure described in Scheme I from 4-(4-hydrazinocarbonylphenyl)aminobutyric hydrazide and 3-methoxy-4- hydroxybenzaldehyde. 1H NMR (300MHz, DMSCM6) δ 11.26 (s), 11.18 (s), 11.09 (s), 3.81 (s), 3.80 (s), 3.77 (s), 3.16-3.14 (m), 2.71 (t), 2.28 (t), 1.85 (p). [M+H]+ calcd for C27H29N5O6: 520.21; found: 520.12.
EXAMPLE 68 1 ,4-Phenylene-bis(acet-2-(3-methoxybenzylidene)hydrazide) (Compound 168)
Figure imgf000106_0003
[0265] Compound 168 was prepared according to the procedure described in Scheme I from dimethyl 1 ,4-phenylenediacetate and (3-methoxy)benzaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.37 (s, 2H), 7.93 (s, 2H), 7.36-7.30 (m, 2H), 7.26-7.20 (m, 4H), 7.23 (s, 4H), 6.80-6.40 (m, 2H), 3.93 (s, 4H), 3.77 (s, 6H).
EXAMPLE 69 Trans,trans-mucon-bis(2-(3-methoxybenzylidene)hydrazide) (Compound 169)
Figure imgf000107_0001
[0266] Compound 169 was prepared according to the procedure described in Scheme I from dimethyl trans,trans-muconate and (3-methoxy)benzaldehyde. 1H NMR (300MHz, DMSO-J6) δ 1 1.76 (s, 2H), 8.20 (s, 2H), 7.56-7.40 (m, 2H), 7.38-7.24 (m, 7H), 7.03-6.96 (m, 2H), 6.46 (s, IH), 3.80 (s, 6H).
EXAMPLE 70 4,4'-(l,6-Hexyldioxyphenyl)-biscarboxyl-2-(3-methoxybenzylidene)hydrazide (Compound 170)
Figure imgf000107_0002
[0267] Compound 170 was prepared according to the procedure described in Scheme I from the corresponding bis-benzoate and (3-methoxy)benzaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.70 (s, 2H), 8.40 (s, 2H), 7.88 (d, J = 8.6 Hz, 4H), 7.37 (t, J = 8.0 Hz, 2H), 7.26 (m, 4H), 7.04 (d, J = 8.6 Hz, 4H), 6.99 (d, J = 7.6, Hz, 2H), 4.06 (t, J = 6.2 Hz, 4H), 3.79 (s, 6H), 1.77 (m, 4H), 1.50 (m, 4H).
EXAMPLE 71 1 ,4-Phenylenedioxy-bis(acet-2-benzylidenehydrazide) (Compound 171)
Figure imgf000108_0001
[0268] Compound 171 was prepared according to the procedure described in Scheme I from dimethyl 1 ,4-phenylenedioxy-bis-acetate and benzaldehyde. 1H NMR (300MHz, DMSO- d6) δ 11.60 (s, 2H), 7.99 (s, 2H), 1.12-1.64 (m, 4H), 7.46-7.40 (m, 2H), 7.42 (s, 4H), 6.96-6.88 (m, 4H), 5.05 (s, 4H).
EXAMPLE 72 1 ,4-Phenylenedioxy-bis(acet-2-(2-hydroxy-5-methoxybenzylidene)hydrazide) (Compound 172)
Figure imgf000108_0002
[0269] Compound 172 was prepared according to the procedure described in Scheme I from dimethyl 1 ,4-phenylenedioxy-bis-acetate and (2-hydroxy-5-methoxy)benzaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.50 (s, 2H), 10.50 (br. s, 2H), 8.52 (s, 2H), 7.07 (s, 2H), 6.96 (s, 4H), 6.90-6.80 (m, 4H), 4.60 (s, 4H), 3.70 (s, 6H).
EXAMPLE 73 4,4'-Methylene-bis(benz-2-(2-hydroxy-5-methoxybenzylidene)hydrazide) (Compound 173)
Figure imgf000108_0003
[0270] Compound 173 was prepared according to the procedure described in Scheme I from dimethyl 4,4'-methylenebisbenzoate and 2-hydroxy-5-methoxybenzaldehyde. 1H NMR (300MHz, DMSO-J6) δ 12.09 (s, 2H), 10.72 (br. s, 2H), 8.63 (s, 2H), 7.88 (d, J = 8.0 Hz, 4H), 7.42 (d, J = 8.0 Hz, 4H), 7.09 (d, J= 2.5 Hz, 2H), 6.90 (dd, J= 8.8, 2.5 Hz, 2H), 6.87 (d, J= 8.8 Hz, 2H), 4.11 (s, 2H), 3.71 (s, 6H).
EXAMPLE 74 1 ,4-Phenylenedioxy-bis(acet-2-(3-vinylbenzylidene)hydrazide) (Compound 174)
Figure imgf000109_0001
[0271] Compound 174 was prepared according to the procedure described in Scheme I from dimethyl 1 ,4-phenylenedioxy-bis-acetate and (3-vinyl)benzaldehyde. 1H NMR (300MHz, DMSCwZ6) δ 11.59(s, 2H), 8.34 (s, 2H), 8.00 (s, 2H), 7.76-7.36 (m, 8H), 6.70-6.98 (m, 2H), 6.96-6.82 (m, 2H), 6.80-6.72 (m, 2H), 5.94-5.84 (m, 2H), 5.08 (s, 4H).
EXAMPLE 75
4,4'-Bis(benz-2-(2-fluoro-5-methoxybenzylidene)hydrazide) (Compound 175)
Figure imgf000109_0002
[0272] Compound 175 was prepared according to the procedure described in Scheme I from dimethyl biphenyl-4,4'-dicarboxylate and 2-fluoro-5-methoxybenzaldehyde. ' H NMR (300MHz, DMSO-J6) δ 12.07 (s, 2H), 8.70 (s, 2H), 8.06 (d, J = 8.0 Hz, 4H), 7.94 (d, J = 8.0 Hz, 4H), 7.40 (s, 2H), 7.24 (t, J = 4.9 Hz, 2H), 7.01-7.09 (m, 2H), 3.80 (s, 6H).
EXAMPLE 76 4,4'-Bis(benz-2-(3-methyl-2-thienylmethylidene)hydrazide) (Compound 176)
Figure imgf000109_0003
[0273] Compound 176 was prepared according to the procedure described in Scheme I from dimethyl biphenyl-4,4'-dicarboxylate and 3-methylthiophenecarboxaldehyde. 1H NMR (300MHz, DMSO-^6) δ 11.84 (s, 2H), 8.78 (s, 2H), 8.04 (d, J = 8.3 Hz, 4H), 7.92 (d, J = 8.3 Hz, 4H), 7.57 (d, J = 5.1 Hz, 2H), 6.98 (d, 5.1 Hz, 2H), 2.32 (s, 6H).
EXAMPLE 77 4,4'-Bis(benz-2-(4-fluoro-5-methoxybenzylidene)hydrazide) (Compound 177)
Figure imgf000110_0001
[0274] Compound 177 was prepared according to the procedure described in Scheme I from dimethyl biphenyl-4,4'-dicarboxylate and 4-fluoro-5-methoxybenzaldehyde. ' H NMR (300MHz, DMSCW6) δ 11.96 (s, 2H), 8.46 (s, 2H), 8.04 (d, J = 8.3 Hz, 4H), 7.93 (d, J = 8.3 Hz, 4H), 7.52 (d, J = 7.6 Hz, 2H), 7.33-7.26 (m, 2H), 7.30 (s, 2H), 3.91 (s, 6H).
EXAMPLE 78 4,4'-Bis(benz-2-(4-hydroxy-5-methoxybenzylidene)hydrazide) (Compound 178)
Figure imgf000110_0002
[0275] Compound 178 was prepared according to the procedure described in Scheme I from dimethyl biphenyl-4,4'-dicarboxylate and 4-hydroxy-5-methoxybenzaldehyde. 1H NMR (300MHz, DMSCW6) δ 11.80 (s, 2H), 9.35 (br. s, 2H), 8.51 (s, 2H), 8.05 (d, J = 8.3 Hz, 4H), 7.93 (d, J = 8.3 Hz, 4H), 7.35 (s, 2H), 7.10-6.95 (m, 4H), 3.83 (s, 6H).
EXAMPLE 79 4,4'-Bis(benz-2-(4-phenylbenzylidene)hydrazide) (Compound 179)
Figure imgf000110_0003
[0276] Compound 179 was prepared according to the procedure described in Scheme I from dimethyl biphenyl-4,4'-dicarboxylate and 4-phenylbenzaldehyde. 1H NMR (300MHz, DMSO-J6) δ 12.00 (s, 2H), 8.54 (s, 2H), 8.20-7.70 (m, 22H), 7.56-7.48 (m, 4H).
EXAMPLE 80 4,4'-Bis(benz-2-(3-bromo-5-pyridylmethylidene)hydrazide) (Compound 180)
Figure imgf000111_0001
[0277] Compound 180 was prepared according to the procedure described in Scheme I from dimethyl bipheny 1-4,4 '-dicarboxy late and 3-bromo-5-carboxaldehyde. 1H NMR (300MHz, DMSO-J6) δ 12.28 (s, 2H), 9.03 (s, 2H), 8.86 (s, 2H), 8.77 (s, 4H), 8.49 (s, 2H), 8.08 (d, J = 8.3 Hz, 4H), 7.95 (d, J = 8.3 Hz, 4H).
EXAMPLE 81 4,4'-Bis(benz-2-(4-indolylmethylidene)hydrazide) (Compound 181)
Figure imgf000111_0002
[0278] Compound 181 was prepared according to the procedure described in Scheme I from dimethyl biphenyl-4,4' -dicarboxy late and 4-indolecarboxaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.90 (s, 2H), 11.38 (s, 2H), 8.74 (s, 2H), 8.12 (d, J= 8.2 Hz, 4H), 7.97 (d, J = 8.2 Hz, 4H), 7.54 (d, J = 6.7Hz, 2H ), 7.51 (s, 2H), 7.30 (d, J = 6.7Hz, 2H ), 7.24-7.12 (m, 4H).
EXAMPLE 82 4,4'-Bis(benz-2-(7-indolylmethylidene)hydrazide) (Compound 182)
Figure imgf000111_0003
[0279] Compound 182 was prepared according to the procedure described in Scheme I from dimethyl biphenyl -4,4 '-dicarboxy late and 7-indolecarboxaldehyde. 1H NMR (300MHz, DMSO-έfc) δ 12.24 (s, 2H), 10.84 (s, 2H), 8.73 (s, 2H), 8.16 (d, J= 8.2 Hz, 4H), 8.00 (d, J = 8.2 Hz, 4H), 7.74 (d, J = 7.9 Hz, 2H ), 7.61 (s, 2H), 7.40 (d, J = 7.9 Hz, 2H ), 7.16 (t, J = 7.6 Hz, 2H), 6.61 (s, 2H).
EXAMPLE 83 4,4'-Bis(benz-2-(2-naphthylmethylidene)hydrazide) (Compound 183)
Figure imgf000112_0001
[0280] Compound 183 was prepared according to the procedure described in Scheme I from dimethyl biphenyl-4,4'-dicarboxylate and 2-naphthaldehyde. 1H NMR (300MHz, DMSO- ck) δ 12.05 (s, 2H), 8.64 (s, 2H), 8.20-7.90 (m, 18H), 7.62-7.52 (m, 4H).
EXAMPLE 84
4,4'-Bis(benz-2-(3-methylbutylidene)hydrazide) (Compound 184)
Figure imgf000112_0002
[0281] Compound 184 was prepared according to the procedure described in Scheme I from dimethyl biphenyl-4,4' -dicarboxy late and 3-methylbutaldehyde. 1H NMR (300MHz, DMSO-cfe) δ 11.52 (s, 2H), 7.98 (d, J= 7.9 Hz, 4H), 7.88 (d, J= 7.9 Hz, 4H), 7.78 (t, J = 5.0 Hz, 2H), 2.18 (t, J = 6.4 Hz, 4H ), 1.80-1.78 (m, 2H), 2.17 (d, J = 6.7 Hz, 12H).
EXAMPLE 85 4,4'-Bis(benz-2-(4-hydroxy-3-methylbenzylidene)hydrazide) (Compound 185)
Figure imgf000112_0003
[0282] Compound 185 was prepared according to the procedure described in Scheme I from dimethyl biphenyl-4,4'-dicarboxylate and 4-hydroxy-3-methylbenzaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.73 (s, 2H), 9.90 (br. s, 2H), 8.34 (s, 2H), 8.04 (d, J = 8.2 Hz, 4H), 7.92 (d, J= 8.2 Hz, 4H), 7.49 (s, 2H), 7.39 (d, J = 7.9 Hz, 2H), 6.86 (d, J = 7.9 Hz, 2H ), 2.17 (s, 6H).
EXAMPLE 86 4,4'-Bis(benz-2-(3-cyanobenzylidene)hydrazide) (Compound 186)
Figure imgf000113_0001
[0283] Compound 186 was prepared according to the procedure described in Scheme I from dimethyl biphenyl -4,4 '-dicarboxy late and 3-cyanobenzaldehyde. 1H NMR (300MHz, DMSO-^6) δ 12.19 (s, 2H), 8.53 (s, 2H), 8.17 (s, 2H), 8.08 (d, J = 8.2 Hz, 4H), 7.96 (d, J = 8.2 Hz, 4H), 8.12 (d, J = 8.5 Hz, 2H ), 7.92 (d, J = 8.5 Hz, 2H ), 7.70 (t, J = 7.6 Hz, 2H).
EXAMPLE 87 4,4'-Bis(benz-2-(5-indolylmethylidene)hydrazide) (Compound 187)
Figure imgf000113_0002
[0284] Compound 187 was prepared according to the procedure described in Scheme I from dimethyl biphenyl -4,4' -dicarboxylate and 5-indolecarboxaldehyde. 1H NMR (300MHz, DMSO-fife) δ 11.78 (s, 2H), 11.36 (s, 2H), 8.55 (s, 2H), 8.08 (d, J= 8.2 Hz, 4H), 7.94 (d, J = 8.2 Hz, 4H), 7.86 (s, 2H), 7.64 (d, J = 8.5 Hz, 2H ), 7.46 (d, J = 8.5 Hz, 2H ), 7.40 (s, 2H), 6.53 (s, 2H).
EXAMPLE 88 4,4'-Bis(benz-2-(3-indolylmethylidene)hydrazide) (Compound 188)
Figure imgf000114_0001
[0285] Compound 188 was prepared according to the procedure described in Scheme I from dimethyl biphenyl -4,4 '-dicarboxy late and 3-indolecarboxaldehyde. 1H NMR (300MHz, DMSO-J6) δ 1 1.68 (s, 2H), 11.63 (s, 2H), 8.90 (s, 2H), 8.34 (d, J = 7.3 Hz, 4H), 7.86 (s, 2H), 7.46 (d, J = 7.3 Hz, 4H), 7.28-7.14 (m, 8H).
EXAMPLE 89 4,4 '-Bis(benz-2-(2-indolylmethylidene)hydrazide) (Compound 189)
Figure imgf000114_0002
[0286] Compound 189 was prepared according to the procedure described in Scheme I from dimethyl biphenyl-4,4'-dicarboxylate and 2-indolecarboxaldehyde. Spectral data for compound 143: A mixture of almost 1.2:1 rotamers at room temperature:
Major Rotamer 1H NMR (300 MHz, DMSO-Uf6) δ 11.94 (s, 2H), 11.62 (s, 2H), 8.54 (s, 2H), 8.10 (d, J = 8.2 Hz, 4H), 7.97(d, J = 8.2 Hz, 4H), 7.58(d, J = 7.6 Hz, 2H), 7.18(d, J = 7.9 Hz, 2H), 7.09-6.98 (m, 4H), 6.86 (s, 2H). Minor Rotamer 1H NMR (300 MHz, DMSO-J6) δ 11.94 (s, 2H), 11.70 (s, 2H), 8.70 (s, 2H), 7.63 (d, J = 7.9 Hz, 2H), 7.46 (d, J = 8.2 Hz, 4H), 7.45 (s, 2H), 7.26-7.14 (m, 4H), 7.08 (d, J = 8.2 Hz, 4H ), 7.00 (d, J = 7.9 Hz, 2H).
EXAMPLE 90 4,4'-Bis(benz-2-(3-furylmethylidene)hydrazide) (Compound 190)
Figure imgf000114_0003
[0287] Compound 190 was prepared according to the procedure described in Scheme I from dimethyl biphenyl-4,4' -dicarboxy late and 3-furancarboxaldehyde. 1H NMR (300MHz, OMSO-dβ) δ 11.81 (s, 2H), 8.42 (s, 2H), 8.16 (s, 2H), 8.00 (d, J = 8.2 Hz, 4H), 7.90 (d, J = 8.2 Hz, 4H), 7.76 (s, 2H), 6.82 (s, 2H).
EXAMPLE 91 4,4'-Bis(benz-2-(4-N,N-di-(2-hydroxyethyl)aminobenzylidene)hydrazide) (Compound 191)
Figure imgf000115_0001
[0288] Compound 191 was prepared according to the procedure described in Scheme I from dimethyl biphenyl-4,4'-dicarboxylate and 4-di(2-hydroxyethyl)aminobenzaldehyde. 1H NMR (300MHz, DMSO-</6) δ 11.62 (s, 2H), 8.32 (s, 2H), 8.04 (d, J = 8.3 Hz, 4H), 7.92 (d, J = 8.3 Hz, 4H), 7.52 (d, J = 8.8 Hz, 4H), 6.76 (d, J = 8.8 Hz, 4H), 4.81 (s, 4H), 3.56 (d, J = 4.7 Hz, 8H), 3.49 (d, J = 4.7 Hz, 8H).
EXAMPLE 92 4,4'-Bis(benz-2-(3-acetylbenzylidene)hydrazide) (Compound 192)
Figure imgf000115_0002
[0289] Compound 192 was prepared according to the procedure described in Scheme I from dimethyl biphenyl-4,4'-dicarboxylate and 3-acetylbenzaldehyde. 1H NMR (300MHz, DMSO-βfe) δ 12.01 (s, 2H), 8.58 (s, 2H), 8.29 (s, 2H), 8.14-7.90 (m, 12H), 7.65 (t, J = 7.3 Hz, 2H,), 2.65 (s, 6H).
EXAMPLE 93 4,4'-Bis(benz-2-(5-methoxy-3-indolylmethylidene)hydrazide) (Compound 193)
Figure imgf000115_0003
[0290] Compound 193 was prepared according to the procedure described in Scheme I from dimethyl biphenyl-4,4'-dicarboxylate and 5-methoxy-3-indolecarboxaldehyde. 1H NMR (300MHz, OMSO-dβ) δ 11.60 (s, 2H), 10.80 (s, 2H), 8.87 (s, 2H), 8.07-7.88 (m, 12H), 7.34 (d, J = 9.1 Hz, 2H), 7.46 (d, J = 9.1 Hz, 2H), 3.81 (s, 6H).
EXAMPLE 94 4,4'-Bis(benz-2-(6-indolylmethylidene)hydrazide) (Compound 194)
Figure imgf000116_0001
[0291] Compound 194 was prepared according to the procedure described in Scheme I from dimethyl biphenyl-4,4'-dicarboxylate and 6-indolecarboxaldehyde. 1H NMR (300MHz, OMSO-d6) δ 11.82 (s, 2H), 11.34 (s, 2H), 8.56 (s, 2H), 8.08 (d, J = 8.2 Hz, 4H), 7.95 (d, J = 8.2 Hz, 4H), 7.77 (s, 2H), 7.63 (d, J = 8.5 Hz, 2H ), 7.49 (s, 2H), 7.45 (d, J = 8.5 Hz, 2H ), 6.49 (s, 2H).
EXAMPLE 95 4,4'-Bis(benz-2-(3-methylsulfanylbenzylidene)hydrazide) (Compound 195)
Figure imgf000116_0002
[0292] Compound 195 was prepared according to the procedure described in Scheme I from dimethyl biphenyl-4,4'-dicarboxylate and 3- methylsulfanylbenzaldehyde. 1H NMR (300MHz, DMSO-</6) δ 12.02 (s, 2H), 8.47 (s, 2H), 8.06 (d, J = 7.9 Hz, 4H), 7.37 (d, J = 7.9 Hz, 4H), 7.62 (s, 2H), 7.52 (d, J = 7.3 Hz, 2H), 7.43 (t, J = 7.5 Hz, 2H,), 7.34 (d, J = 7.9 Hz, 2H), 2.53 (s, 6H).
EXAMPLE 96 4,4'-Bis(benz-2-(4-hydroxy-3-methoxy-5-vinylbenzylidene)hydrazide) (Compound 196)
Figure imgf000117_0001
[0293] Compound 196 was prepared according to the procedure described in Scheme I from dimethyl biphenyl-4,4'-dicarboxylate and 4-hydroxy-3-methoxy-5-vinylbenzaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.78 (s, 2H), 9.16 (s, br, 2H), 8.36 (s, 2H), 8.05 (d, J = 7.9 Hz, 4H), 7.93 (d, J = 7.9 Hz, 4H), 7.22 (s, 2H), 7.05 (s, 2H), 5.96 (m, 2H), 5.07 (d, J= 15.8 Hz, 2H), 5.03 (d, 9.0 Hz, 2H), 3.88 (s, 6H).
EXAMPLE 97 4,4'-Bis(benz-2-(3-allyloxybenzylidene)hydrazide) (Compound 197)
Figure imgf000117_0002
[0294] Compound 197 was prepared according to the procedure described in Scheme I from dimethyl biphenyl-4,4'-dicarboxylate and 3-allyloxybenzaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.98 (s, 2H), 8.47 (s, 2H), 8.06 (d, J = 7.9 Hz, 4H), 7.95 (d, J - 8.2 Hz, 4H), 7.40 (t, J = 7.6 Hz, 2H), 7.36 (d, J = 7.6 Hz, 2H), 7.32 (s, 2H), 7.05 (d, J = 7.6 Hz, 2H), 6.10 (ddd, J = 17.6, 10.8, 3.5Hz, 2H), 5.44 (d, 17.6 Hz, 2H), 5.28 (d, 10.8 Hz, 2H), 5.28 (d, 3.5 Hz, 4H).
EXAMPLE 98 2,2'-Bis(pyridine-5-carboxyl-2-(3-methoxybenzylidene)hydrazide) (Compound 198)
Figure imgf000117_0003
[0295] Compound 198 was prepared according to the procedure described in Scheme I from dimethyl 2,2'-bipyridine-4,4'-dicarboxylate and 3-methoxybenzaldehyde. 1H NMR (300MHz, DMSO-J6) δ 12.16 (s, 2H), 9.22 (s, 2H), 8.62 (d, J = 7.9 Hz, 2H), 8.48 (d, J = 7.9 Hz, 2H), 8.46 (s, 2H), 7.42 (t, J = 7.0 Hz, 2H), 7.38 (d, J = 7.3 Hz, 2H), 7.33 (s, 2H), 7.04 (d, J = 7.3
Hz, 2H), 3.83 (s, 6H). EXAMPLE 99 2,2'-Bis(pyridine-5-carboxyl-2-(3,5-dimethoxybenzylidene)hydrazide) (Compound 199)
Figure imgf000118_0001
[0296] Compound 199 was prepared according to the procedure described in Scheme I from dimethyl 2,2'-bipyridine-4,4'-dicarboxylate and 3,5-dimethoxybenzaldehyde. 1H NMR (300MHz, DMSO-<4) δ 12.16 (s, 2H), 9.22 (s, 2H), 8.63 (d, J = 8.2 Hz, 2H), 8.48 (d, J = 8.2 Hz, 2H), 8.41 (s, 2H), 6.92 (s, 4H), 6.61 (s, 2H), 3.81 (s, 12H).
EXAMPLE 100 2,2'-(Bipyridine-5-carboxylic-2-(3-vinylbenzylidene)hydrazide) (Compound 200)
Figure imgf000118_0002
[0297] Compound 200 was prepared according to the procedure described in Scheme I from dimethyl 2,2'-bipyridine-4,4'-dicarboxylate and 3-vinylbenzaldehyde. 1H NMR (300MHz, DMSO-^6) δ 12.19 (s, 2H), 9.24 (s, 2H), 8.63 (d, J = 8.2 Hz, 2H), 8.50 (s, 2H), 8.48 (d, J = 8.2 Hz, 2H), 7.84 (s, 2H), 7.70 (d, J = 7.3 Hz, 2H), 7.61 (d, J = 7.6 Hz, 2H), 7.48 (t, J = 7.8 Hz, 2H), 6.84 (dd, J = 17.6, 10.8 Hz, 2H), 5.44 (d, 17.6 Hz, 2H), 5.36 (d, 10.8 Hz, 2H).
EXAMPLE 101
4-(4-(2-(3-Cyanobenzylidene)-l-hydrazinocarbonyl)phenyl)aminobutyric-2-(3- cyanobenzylidene)hydrazide (Compound 201)
Figure imgf000118_0003
[0298] Compound 201 was prepared according to the procedure described in Scheme I from 4-(4-hydrazinocarbonylphenyl)aminobutyric hydrazide and 3-cyanobenzaldehyde/ 1H NMR (300MHz, DMSO-J6) δ 11.66 (s), 11.59 (s), 11.46 (s), 3.18-3.12 (m), 2.77 (t), 2.34 (t), 1.89-1.84 (m). [M+H]+ calcd for C27H23N7O2: 478.19; found: 478.13.
EXAMPLE 102
4-(4-(2-(3 -Hydroxycarbonylbenzylidene)- 1 -hydrazinocarbonyl)phenyl)aminobutyr-2-(3 - hydroxycarbonylbenzylidene)hydrazide (Compound 202)
Figure imgf000119_0001
[0299] Compound 202 was prepared according to the procedure described in Scheme I from 4-(4-hydrazinocarbonylphenyl)aminobutyric hydrazide and 3-formylbenzoic acid. 1H NMR (300MHz, DMSO-J6) δ 11.57 (s), 11.50 (s), 11.35 (s), 3.20-3.12 (m), 2.78 (t), 2.35-2.32 (m), 1.89-1.86 (m). [M+H]+ calcd for C27H25N5O6: 516.18; found: 516.13.
EXAMPLE 103
4-(4-(2-(6-Memoxy-2-naphthylidene)-l-hydrazinocarbonyl)phenyl)aminobutyr-2-(6-methoxy-2- naphthylidene)hydrazide (Compound 203)
Figure imgf000119_0002
[0300] Compound 203 was prepared according to the procedure described in Scheme I from 4-(4-hydrazinocarbonylphenyl)aminobutyric hydrazide and 6-methoxy-2- naphthylcarboxaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.49 (s), 11.41 (s), 11.28 (s), 3.88 (s), 3.87 (s), 3.83 (s), 3.23-3.12 (m), 2.78 (t), 2.35-2.32 (m), 1.90-1.86 (m). [M+H]+ calcd for C35H33N5O4: 588.25; found: 588.24.
EXAMPLE 104
4-(4-(2-(3 -Indolemethy lidene)- 1 -hydrazinocarbonyl)phenyl)aminobutyr-2-(3 - indolemethylidene)hydrazide (Compound 204)
Figure imgf000120_0001
[0301] Compound 204 was prepared according to the procedure described in Scheme I from 4-(4-hydrazinocarbonylphenyl)aminobutyric hydrazide and 3-indolecarboxaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.12 (s), 11.02 (s), 10.94 (s), 3.20-3.15 (m), 2.78 (t), 2.30 (t), 1.93-1.89 (m). [M+H]+ calcd for C29H27N7O2: 506.22; found: 506.15.
EXAMPLE 105
4-(4-(2-(3-Hydroxybenzylidene)-l-hydrazinocarbonyl)phenyl)aminobutyr-2-(3- hydroxybenzylidene)hydrazide (Compound 205)
Figure imgf000120_0002
[0302] Compound 205 was prepared according to the procedure described in Scheme I from 4-(4-hydrazinocarbonylphenyl)aminobutyric hydrazide and 3 -hydroxy benzaldehyde. 1H NMR (300MHz, DMSO-J6) δ 1 1.41 (s), 1 1.34 (s), 11.22 (s), 3.15 (m), 2.73 (t), 2.32-2.27 (m), 1.90-1.87 (m). [M+H]+ calcd for C25H25N5O4: 460.19; found: 460.12.
EXAMPLE 106
4-(4-(2-(2-Naphthylidene)-l-hydrazinocarbonyl)phenyl)aminobutyr-2-(2- naphthylidene)hydrazide (Compound 206)
Figure imgf000120_0003
[0303] Compound 206 was prepared according to the procedure described in Scheme I from 4-(4-hydrazinocarbonylphenyl)aminobutyric hydrazide and 2-naphthylcarboxaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.54 (s), 11.47 (s), 11.34 (s), 3.21-3.13 (m), 2.80 (t), 2.37- 2.33 (m), 1.92-1.87 (m). [M+H]+ calcd for C33H29N5O2: 528.23; found: 528.18.
EXAMPLE 107 4-(4-(2-(6-Indolemethylidene)-l-hydrazinocarbonyl)phenyl)aminobutyr-2-(6- indolemethylidene)hydrazide (Compound 207)
Figure imgf000121_0001
[0304] Compound 207 was prepared according to the procedure described in Scheme I from 4-(4-hydrazinocarbonylphenyl)aminobutyric hydrazide and 6-indolecarboxaldehyde. 1H NMR (300MHz, DMSO-^6) δ 11.27 (s), 11.24 (s), 11.23 (s), 11.10 (s), 3.20-3.12 (m), 2.77 (t), 2.33 (t), 1.91-1.87 (m). [M+HJ+ calcd for C29H27N7O2: 506.22; found: 506.15.
EXAMPLE 108
4-(4-(2-(2-Indolemethylidene)-l-hydrazinocarbonyl)phenyl)aminobutyr-2-(2- indolemethylidene)hydrazide (Compound 208)
Figure imgf000121_0002
[0305] Compound 208 was prepared according to the procedure described in Scheme I from 4-(4-hydrazinocarbonylphenyl)aminobutyric hydrazide and 2-indolecarboxaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.48 (s), 11.42 (s), 11.35 (s), 11.27 (s), 1 1.26 (s), 8.42 (s), 3.21 - 3.12 (m), 2.84 (t), 2.34 (t), 1.92-1.86 (m).
EXAMPLE 109
4-(4-(2-Cyclohexylmethylidene)- 1 -hydrazinocarbonylphenyl)aminobutyr-2- cyclohexylmethylidenehydrazide (Compound 209)
Figure imgf000121_0003
[0306] Compound 209 was prepared according to the procedure described in Scheme I from 4-(4-hydrazinocarbonylphenyl)aminobutyric hydrazide and cyclohexylcarboxaldehyde. 1H NMR (300MHz, DMSO-J6) δ 10.59 (s), 10.58 (s), 10.57 (s), 7.56 (d), 6.54 (d), 3.04 - 3.01 (m), 2.54 (t), 2.23 - 2.08 (m), 1.81 - 1.55 (m), 1.32-1.10 (m).
EXAMPLE 110
4-(4-(3E-(4-Nitrophenyl)propenylidene)-l-hydrazinocarbonylphenyl)aminobutyr-2-(3E-(4- nitrophenyl)propenylidene)hydrazide (Compound 210)
Figure imgf000122_0001
[0307] Compound 210 was prepared according to the procedure described in Scheme I from 4-(4-hydrazinocarbonylphenyl)aminobutyric hydrazide and 3E-(4- nitrophenyl)acrylaldehyde. 1H NMR (SOOMHZ, DMSO-J6) δ 11.50 (s), 11.41 (s), 11.31 (s), 3.15 - 3.09 (m), 2.66 (t), 2.31 (t), 1.81 - 1.55 (m), 1.83 (m).
EXAMPLE 111
4-(4-(2-Isopropylmethylidene)-l-hydrazinocarbonylphenyl)aminobutyr-2- isopropylmethylidenehydrazide (Compound 211)
Figure imgf000122_0002
[0308] Compound 211 was prepared according to the procedure described in Scheme I from 4-(4-hydrazinocarbonylphenyl)aminobutyric hydrazide and 2-methylpropanaldehyde. [M+H]+ calcd for C19H29N5O2: 360.23; found: 360.21.
EXAMPLE 112
4-(4-(2-(3-Methylsulfonylaminobenzylidene)-l-hydrazinocarbonyl)phenyl)aminobutyr-2-(3- methylsulfonylaminobenzylidene)hydrazide (Compound 212)
Figure imgf000122_0003
[0309] Compound 212 was prepared according to the procedure described in Scheme I from 4-(4-hydrazinocarbonylphenyl)aminobutyric hydrazide and 3-hydroxybenzaldehyde. [M+H]+ calcd for C27H3 IN7O6S2: 614.18; found: 614.17.
EXAMPLE 113
4-(4-(2-(5-Indolemethylidene)-l-hydrazinocarbonyl)phenyl)aminobutyr-2-(5- indolemethylidene)hydrazide (Compound 213)
Figure imgf000123_0001
[0310] Compound 213 was prepared according to the procedure described in Scheme I from 4-(4-hydrazinocarbonylphenyl)aminobutyric hydrazide and 5-indolecarboxaldehyde. 1H NMR (300MHz, DMSO-^6) δ 1 1.37 (s), 1 1.35 (s), 11.26 (s), 11.14 (s), 8.53 (s), 3.28-3.19 (m), 2.84 (t), 2.39 (t), 2.00 1.92 (m).
EXAMPLE 114
4-(4-(2-(4-Indolemethylidene)-l-hydrazinocarbonyl)phenyl)aminobutyr-2-(4- indolemethylidene)hydrazide (Compound 214)
Figure imgf000123_0002
[0311] Compound 214 was prepared according to the procedure described in Scheme I from 4-(4-hydrazinocarbonylphenyi)aminobutyric hydrazide and 4-indolecarboxaldehyde. 1H NMR (300MHz, DMSO-</6) δ 11.39 (s), 11.34 (s), 11.31 (s), 11.30 (s), 11.18 (s), 8.61 (s), 3.21 (q), 3.15 (q), 2.82 (t), 2.35 (t), 1.96-1.88 (m).
EXAMPLE 115
4-(4-(2-(4-Pyrrolidinylbenzylidene)-l-hydrazinocarbonyl)phenyl)aminobutyr-2-(4- pyrrolidinylbenzylidene)hydrazide (Compound 215)
[0312] Compound 215 was prepared according to the procedure described in Scheme I from 4-(4-hydrazinocarbonylphenyl)aminobutyric hydrazide and 4-pyrrolidinebenzaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.22 (s), 11.03 (s), 10.89 (s), 7.25 (d), 6.49 (d), 3.3 - 3.21 (m), 3.16 (q), 3.09 (q), 2.66 (t), 2.26 (t), 1.99-1.81 (m).
EXAMPLE 116
4-(4-(2-(5-Methoxy-3-indolemethylidene)-l-hydrazinocarbonyl)phenyl)aminobutyr-2-(5- methoxy-3-indolemethylidene)hydrazide (Compound 216)
Figure imgf000124_0002
[0313] Compound 216 was prepared according to the procedure described in Scheme I from 4-(4-hydrazinocarbonylphenyl)aminobutyric hydrazide and 5-methoxy-3- indolecarboxaldehyde. 1H NMR (300MHz, DMSO-^6) δ 1 1.39 (s), 1 1.12 (s), 11.01 (s), 10.95 (s), 3.79 (s), 3.77 (s), 3.68 (s), 3.16-3.15 (m), 2.84 (t), 1.95-1.89 (m).
EXAMPLE 117 1 ,4-Phenylenedioxy-bis(acet-2-(4-quinolinemethylidene)hydrazide) (Compound 217)
Figure imgf000124_0003
[0314] Compound 217 was prepared according to the procedure described in Scheme I from dimethyl 1 ,4-phenylenedioxy-bis-acetate and quinoline-4-carboxaldehyde. [M+H]+ calcd for C30H34N6O4: 533.19; found: 532.94.
EXAMPLE 118 4,4'-Stilbene-bis(carboxyl-2-(5-indolemethylidene)hydrazide) (Compound 218)
Figure imgf000125_0001
[0315] Compound 218 was prepared according to the procedure described in Scheme I from 4,4'-stilbenedicarboxylic acid and 5-indolecarboxaldehyde. 1H NMR (300MHz, DMSO- ck) δ 11.71 (s, 2H), 11.40 (s, 2H), 8.04-7.78 (m, 8H), 7.76 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 8.5 Hz, 2H), 7.52-7.44 (m, 4H ), 7.86 (s, 2H), 7.42 (s, 2H), 6.54 (s, 2H).
EXAMPLE 119 l,4-Phenylenedioxy-bis(acet-2-(3E-(2-methoxyphenyl)propenylidene)hydrazide) (Compound
219)
Figure imgf000125_0002
[0316] Compound 219 was prepared according to the procedure described in Scheme I from dimethyl 1 ,4-phenylenedioxy-bis-acetate and 2-methoxy-3E-propenaldehyde. [M+H]+ calcd for C30H30N4O6: 543.22; found: 542.97.
EXAMPLE 120 1 ,4-Phenylenedioxy-bis(acet-2-(l ,3-dioxolinobenzylidene)hydrazide) (Compound 220)
Figure imgf000125_0003
[0317] Compound 220 was prepared according to the procedure described in Scheme I from dimethyl 1 ,4-phenylenedioxy-bis-acetate and piperonaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.44 (s, 2H), 7.88 (s, 2H), 7.32 (s, 2H), 7.12 (d, J = 7.6 Hz, 2H), 6.96 (d, J = 7.6 Hz, 2H), 6.84 (s, 4H), 6.06 (s, 4H), 5.02 (s, 4H). EXAMPLE 121
4-(2-(3-Methoxybenzylidene)hydrozinocarboxymethoxy)benz-2-(3- methoxybenzylidene)hydrazide (Compound 221)
Figure imgf000126_0001
[0318] Compound 221 was prepared according to the procedure described in Scheme I from 4-carboxyphenylacetic acid and 3-methoxybenzaldehyde. 1H NMR (300MHz, DMSO- dβ) δ 11.97 (s, IH), 11.68 (s, IH), 8.42 (s, IH), 8.00 (s, IH), 7.96-7.86 (m, 2H), 7.42-7.34 (m, 2H), 7.32-7.24 (s, 4H), 7.16-7.98 (m, 2H), 5.27 (s, 4H), 3.80 (s, 6H).
EXAMPLE 122
4-(2-(3,5-Dimethoxybenzylidene)hydrozinocarboxymethoxy)benz-2-(3,5- dimethoxybenzylidene)hydrazide (Compound 222)
Figure imgf000126_0002
[0319] Compound 222 was prepared according to the procedure described in Scheme I from 4-carboxyphenylacetic acid and 3,5-dimethoxybenzaldehyde. Spectral data for compound 153: A mixture of 1.2: 1 rotamers at room temperature:
Major Rotamer 1H NMR (300 MHz, DMSO-^6) δ 12.02 (s, IH), 11.93 (s, IH), 8.39 (s, 2H), 7.93 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 6.88 (s, 4H), 6.57 (s, 2H), 5.27 (s, 2H), 3.80 (s, 6H), 3.78 (s, 6H). Minor Rotamer 1H NMR (300 MHz, DMSO-έfc) δ 12.02 (s, IH), 11.93 (s, IH), 8.25 (s, 2H), 7.89 (d, J = 7.3 Hz, 2H), 7.12 (d, J = 7.3 Hz, 2H), 6.84 (s, 4H), 6.56 (s, 2H), 4.78 (s, 2H), 3.80 (s, 12H).
EXAMPLE 123 4-(2-(4-Fluoro-3-methoxybenzylidene)hydrozinocarboxymethoxy)benz-2-(4-fluoro-3- methoxybenzylidene)hydrazide (Compound 223)
Figure imgf000127_0001
[0320] Compound 223 was prepared according to the procedure described in Scheme I from 4-carboxyphenylacetic acid and 4-fluoro-3-methoxybenzaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.77 (s, IH), 11.71 (s, IH), 8.72 (s, IH), 8.00 (s, IH), 7.96-7.02 (m, 8H), 5.28 (s, 4H), 3.91 (s, 6H).
EXAMPLE 124
4-(2-(2-Hydroxy-5-methoxybenzylidene)hydrozinocarboxymethoxy)benz-2-(2-hydroxy-5- methoxybenzylidene)hydrazide (Compound 224)
Figure imgf000127_0002
[0321] Compound 224 was prepared according to the procedure described in Scheme I from 4-carboxyphenylacetic acid and 2-hydroxy-5-methoxybenzaldehyde. [M+H]+ calcd for C25H24N4O7: 493.16; found: 492.91.
EXAMPLE 125
4-(2-(4-Indolemethylidene)hydrozinocarboxymethoxy)benz-2-(4-indolemethylidene)hydrazide
(Compound 225)
Figure imgf000127_0003
[0322] Compound 225 was prepared according to the procedure described in Scheme I from 4-carboxyphenylacetic acid and 4-indolecarboxaldehyde. 1H NMR (300MHz, DMSO- J6) δ 11.70 (s, IH), 11.59 (s, IH), 11.41 (s, IH), 11.36 (s, IH), 8.68 (s, IH), 8.29 (s, IH), 8.0- 7.86 (m, 2H), 7.49 (s, 4H), 7.307.00 (m, 8H), 5.34 (m, 2H).
EXAMPLE 126 1 ,3-Phenylenedioxy-bis(acet-2-(3,5-dimethoxybenzylidene)hydrazide) (Compound 226)
Figure imgf000128_0001
[0323] Compound 226 was prepared according to the procedure described in Scheme I from dimethyl 1,3-phenylenedioxy-bis-acetate and 3,5-dimethoxybenzaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.62 (s, 2H), 8.25 (s, IH), 7.92 (s, IH), 7.30-7.20 (m, 2H), 6.84 (s, 4H), 6.68-6.42 (m, 4H), 5.27 (s, 4H), 3.77 (s, 12H).
EXAMPLE 127
3 -(4-(2-(3 -Methoxybenzylidene)- 1 -hydrazinocarbonylphenyl)aminocarbonyl)propion-2-(3 - methoxybenzylidene)hydrazide (Compound 227)
Figure imgf000128_0002
[0324] Compound 227 was prepared according to the procedure described in Scheme I from 3-(4-hydrazinocarbonylphenyl)aminocarbonylpropionic hydrazide and 3- methoxybenzaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.31 (s, IH), 10.39 (s, IH), 8.68 (s, 2H), 7.92 (s, IH), 7.90 (d, 2H), 7.75 (d, 2H), 7.44 (m, 4H), 7.22 (m, 2H), 7.09 (dt, 2H), 3.78 (d, 6H), 2.95 (t, 2H), 2.69 (m, 2H).
EXAMPLE 128 l-(4-(2-(3-Methoxybenzylidene)-l-hydrazinocarbonyl)phenyl)piperidine-4-carboxyl-2-(3- methoxybenzylidene)hydrazide (Compound 228)
Figure imgf000129_0001
[0325] Compound 228 was prepared according to the procedure described in Scheme I from l-(4-hydrazinocarbonylphenyl)piperidine-4-carboxylic hydrazide and 3- methoxybenzaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.58 (s, IH), 11.49 (s, 0.5H), 11.25 (s, 0.5H), 8.41 (s, IH), 8.16 (s, 0.5H), 7.95 (s, 0.5H), 7.82-7.80 (m, 2H), 7.37-6.99 (m, 10H), 4.01- 3.90 (m, 2H), 3.81-3.78 (m, 6H), 3.04-2.93 (m, IH), 2.87-2.81 (m, IH), 1.88-1.80 (m, 2H), 1.78- 1.66 (m, 2H).
EXAMPLE 129
4,4'-Bis(benz-2-(l ,4-benzodioxan-6-methylidene)hydrazide) (Compound 229)
Figure imgf000129_0002
[0326] Compound 229 was prepared according to the procedure described in Scheme I from dimethyl biphenyl-4,4'-dicarboxylate and l,4-benzodioxan-6-carboxaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.82 (s, 2H), 8.58 (s, IH), 8.39 (s, IH), 8.06 (d, 4H), 7.95 (d, 4H), 7.38 (m, 2H), 7.25 (m, 2H), 6.98 (dd, 2H), 4.37 (s, 8H).
EXAMPLE 130
4,4'-Bis(benz-2-(2,3-dihydrobenzo[b]furan-5-methylidene)hydrazide) (Compound 230)
Figure imgf000129_0003
[0327] Compound 230 was prepared according to the procedure described in Scheme I from dimethyl biphenyl-4,4'-dicarboxylate and 2,3-dihydrobenzo[b]furan-5-carboxaldehyde. 1H NMR (300MHz, OMSO-d6) δ 8.60 (s, IH), 8.42 (s, IH), 8.07 (d, 4H), 7.95 (d, 4H), 7.79 (s, IH), 7.70 (s, IH), 7.61 (d, IH), 7.48 (d, IH), 6.88 (dd, 2H), 4.63 (t, 4H), 3.38 (t, 4H).
EXAMPLE 131 4,4'-Bis(benz-2-(3-benzo[b]thiophenemethylidene)hydrazide) (Compound 231)
Figure imgf000130_0001
[0328] Compound 231 was prepared according to the procedure described in Scheme I from dimethyl biphenyl-4,4'-dicarboxylate and 3-benzo[b]thiophenecarboxaldehyde. 1H NMR (300MHz, DMS(W6) δ 9.16 (s, IH), 8.92 (d, 4H), 8.79 (s, IH), 8.52 (s, IH), 8.30 (s, IH), 8.13 (d, 4H), 8.10 (d, 2H), 8.01 (d, 2H), 7.57 (t, 2H), 7.53 (t, 2H).
EXAMPLE 132 4,4'-Bis(benz-2-(4-pyridylmethylidene)hydrazide) (Compound 232)
Figure imgf000130_0002
[0329] Compound 232 was prepared according to the procedure described in Scheme I from dimethyl bipheny 1-4,4 '-dicarboxy late and 4-pyridylcarboxaldehyde. 1H NMR (300MHz, DMSO-c/6) δ 8.82 (d, 4H), 8.52 (s, IH), 8.34 (s, IH), 8.14 (d, 4H), 8.00 (d, 2H), 7.95 (d, 4H), 7.83 (d, 2H).
EXAMPLE 133 4,4'-Bis(benz-2-(2-imidazolemethylidene)hydrazide) (Compound 233)
Figure imgf000130_0003
[0330] Compound 233 was prepared according to the procedure described in Scheme I from dimethyl biphenyl-4,4'-dicarboxylate and 2-imidazolecarboxaldehyde. [M+H]+ calcd for C22Hi8N8O2: 427.16; found: 427.09.
EXAMPLE 134
4-(3-(2-(3-Methoxybenzylidene)-l-hydrazinocarbonyl)pyridyl-6-)aminobutyr-2-(3- methoxybenzylidene)hydrazide (Compound 234)
Figure imgf000131_0001
[0331] Compound 234 was prepared according to the procedure described in Scheme I from 4-(3-hydrazinocarbonyl-6-pyridyl)aminobutyric hydrazide and 3-methoxybenzaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.55 (s, IH), 11.25 (s, IH), 7.92 (s, IH), 7.44 (m, 2H), 7.32 (m, 2H), 7.23 (m, 2H), 7.08 (dt, IH), 6.98 (m, 2H), 6.51 (d, IH), 3.79 (m, 6H), 2.70 (t, 2H), 2.25 (t, 2H), 1.84 (m, 2H).
EXAMPLE 135
4-(4-(2-(6-Methoxy-3-pyridylmethylidene)-l-hydrazinocarbonyl)phenyl)aminobutyr-2-(6- methoxy-3-pyridylmethylidene)hydrazide (Compound 235)
Figure imgf000131_0002
[0332] Compound 235 was prepared according to the procedure described in Scheme I from 4-(3-hydrazinocarbonyl-6-pyridyl)aminobutyric hydrazide and 6-methoxy-3- pyridylcarboxaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.45 (s, IH), 11.25 (s, IH), 8.70 (s, IH), 8.59 (d, IH), 8.35 (dd, IH), 8.19 (dd, 2H), 8.00 (m, 2H), 7.70 (d, IH), 6.92 (dd, 2H), 6.63 (m, IH), 6.44 (m,lH), 3.91 (m, 6H), 2.71 (t, 2H), 2.42 (t, 2H), 1.84 (m, 2H).
EXAMPLE 136
4-(4-(2-( 1 -Methyl-5 -indolemethylidene)- 1 -hydrazinocarbonyl)phenyl)aminobutyr-2-( 1 -methyl-
5-indolemethylidene)hydrazide (Compound 236)
Figure imgf000132_0001
[0333] Compound 236 was prepared according to the procedure described in Scheme I from 4-(3-hydrazinocarbonyl-6-pyridyl)aminobutyric hydrazide and l-methyl-5- indolecarboxaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.62 (s, 2H), 8.78 (s, IH), 8.51 (s, IH), 8.01 (d, IH), 7.94 (d, 2H), 7.79 (m, 3H), 7.64 (d, IH), 7.52 (m, 3H), 7.39 (dd, 2H), 6.52 (dd, 2H), 3.88 (t, 2H), 3.81 (d, 6H), 2.54 (t, 2H), 2.07 (m, 2H).
EXAMPLE 137
4-(4-(2-( 1 -Methyl-6-indolemethylidene)- 1 -hydrazinocarbonyl)phenyl)aminobutyr-2-( 1 -methyl -
6-indolemethylidene)hydrazide (Compound 237)
Figure imgf000132_0002
[0334] Compound 237 was prepared according to the procedure described in Scheme I from 4-(3-hydrazinocarbonyl-6-pyridyl)aminobutyric hydrazide and l-methyl-6- indolecarboxaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.72 (s, 2H), 8.81 (s, IH), 8.54 (s, IH), 7.94 (m, 3H), 7.82 (d, 2H), 7.74 (s, IH), 7.63 (m, 3H), 7.49 (m, 2H), 7.43 (m, IH), 6.48 (dd, 2H), 3.88 (t, 2H), 3.84 (d, 6H), 2.54 (t, 2H), 2.08 (m, 2H).
EXAMPLE 138
4-(4-(2-(2-Benzo[b]thiophenemethylidene)-l-hydrazinocarbonyl)phenyl)aminobutyr-2-(2- benzo[b]thiophenemethylidene)hydrazide (Compound 238)
Figure imgf000132_0003
[0335] Compound 238 was prepared according to the procedure described in Scheme I from 4-(3-hydrazinocarbonyl-6-pyridyl)aminobutyric hydrazide and 2-benzo[b]thiophene- carboxaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.62 (s,lH), 11.44 (s, IH), 8.77 (s, IH), 8.29 (s, IH), 7.97 (m, 2H), 7.85 (m, 2H), 7.76 (m, 4H), 7.41 (m, 4H), 6.66 (m, 2H), 3.19 (m, 2H), 2.73 (t, IH), 2.56 (t, IH), 1.90 (m, 2H).
EXAMPLE 139
4-(4-(2-(2,3-Dihydrofuran-4-methylidene)-l-hydrazinocarbonyl)phenyl)aminobutyr-2-(2,3- dihydrofuran-4-methylidene)hydrazide (Compound 239)
Figure imgf000133_0001
[0336] Compound 239 was prepared according to the procedure described in Scheme I from 4-(3-hydrazinocarbonyl-6-pyridyl)aminobutyric hydrazide and 2,3-dihydrofuran-4- carboxaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.25 (s,lH), 11.05 (s, IH), 8.29 (s, IH), 7.88 (s, IH), 7.72 (m, 2H), 7.57 (m, 2H), 7.35 (m, 2H), 6.80 (m, 2H), 6.60 (m, 2H), 4.56 (m, 4H), 3.19 (m, 6H), 2.72 (t, 2H), 1.84 (m, 2H).
EXAMPLE 140
4-(N-4-(2-(3-Methoxybenzylidene)-l-hydrazinocarbonyl)phenyl-N-methyl)aminobutyr-2-(3- methoxybenzylidene)hydrazide (Compound 240)
Figure imgf000133_0002
[0337] Compound 240 was prepared according to the procedure described in Scheme I from 4-(N-4-hydrazinocarbonylphenyl-N-methyl)aminobutyric hydrazide and 3- methoxybenzaldehyde. 1H NMR (300MHz, CD3OD) δ 8.27 (d, IH), 7.98 (s, IH), 7.85 (t, 2H), 7.60 (s, 2H), 7.34 (m, 3H), 7.23 (m, IH), 7.01 (t, 2H), 6.87 (dd, 2H), 3.88 (m, 6H), 3.60 (m, 2H), 3.11 (d, 3H), 2.84 (t, IH), 2.42 (t, IH), 2.08 (m, 2H).
EXAMPLE 141
4-(4-(2-(4-Pyridylmethylidene)-l-hydrazinocarbonyl)phenyl)aminobutyr-2-(4- pyridylmethylidene)hydrazide (Compound 241)
Figure imgf000134_0001
[0338] Compound 241 was prepared according to the procedure described in Scheme I from 4-(4-hydrazinocarbonylphenyl)aminobutyric hydrazide and 4-pyridylcarboxaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.82 (s, IH), 11.63 (s, IH), 8.72 (s, 2H), 8.68 (s, IH), 8.48 (s, IH), 8.40 (s, IH), 7.84 (d, 2H), 7.72 (s, 2H), 7.65 (s, IH), 6.74 (m, 2H), 6.60 (m, 2H), 4.19 (m, 2H), 3.30 (t, IH), 2.88 (t, IH), 1.97 (m, 2H).
EXAMPLE 142
4-(4-(2-(3-Acetylbenzylidene)-l-hydrazinocarbonyl)phenyl)aminobutyr-2-(3- acetylbenzylidene)hydrazide (Compound 242)
Figure imgf000134_0002
[0339] Compound 242 was prepared according to the procedure described in Scheme I from 4-(N-4-hydrazinocarbonylphenyl)aminobutyric hydrazide and 3-acetylbenzaldehyde. 1H NMR (300MHz, DMSO-J6) δ 12.01(s, IH), 11.65 (s, IH), 8.94 (s, 2H), 8.54 (s, 2H), 8.22 (dd, 4H), 8.02 (d, 2H), 7.92 (d, 2H), 7.77 (t, 2H), 3.98 (t, 2H), 2.73 (m, 6H), 2.64 (t, 2H), 2.18 (m, 2H).
EXAMPLE 143
4-(3 -(2-(5 -Indolemethy lidene)- 1 -hydrazinocarbonyl)pyridyl-6-)aminobutyr-2-(5- indolemethylidene)hydrazide (Compound 243)
Figure imgf000134_0003
[0340] Compound 243 was prepared according to the procedure described in Scheme I from 4-(3-hydrazinocarbonyl-6-pyridyl)aminobutyric hydrazide and 5-indolecarboxaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.82 (s, IH), 11.47 (s, 2H), 11.42 (s, IH), 8.84 (s, IH), 8.58 (s, IH), 8.51 (d, IH), 8.38 (d, IH), 8.09 (s, IH), 7.93 (s, IH), 7.81 (d, 2H), 7.56 (d, IH), 7.51 (m, 4H), 6.62 (m, 3H), 4.13 (t, 2H), 2.71 (t, 2H), 2.16 (m, 2H).
EXAMPLE 144
4-(3 -(2-(6-Indolemethylidene)- 1 -hydrazinocarbonyl)pyridyl-6-)aminobutyr-2-(6- indolemethylidene)hydrazide (Compound 244)
Figure imgf000135_0001
[0341] Compound 244 was prepared according to the procedure described in Scheme I from 4-(3-hydrazinocarbonyl-6-pyridyl)aminobutyric hydrazide and 6-indolecarboxaldehyde. 1H NMR (300MHz, DMSO-^6) δ 11.41 (s, IH), 11.27 (s, 2H), 11.21 (s, IH), 8.59 (s, IH), 8.43 (s, IH), 8.19 (s, IH), 7.88 (s, IH), 7.71 (s, IH), 7.56 (dd, 2H), 7.43 (dt, 2H), 7.34 (d, IH), 7.26 (m, IH), 6.53 (dd, IH), 6.43 (d, 2H), 2.73 (t, 2H), 2.28 (t, 2H), 1.87 (m, 2H).
EXAMPLE 145
4-(3-(2-(2-Naphthylmethylidene)-l-hydrazinocarbonyl)pyridyl-6-)aminobutyric-2-(2- naphthylmethylidene)hydrazide (Compound 245)
Figure imgf000135_0002
[0342] Compound 245 was prepared according to the procedure described in Scheme I from 4-(3-hydrazinocarbonyl-6-pyridyl)aminobutyric hydrazide and 2- naphthylcarboxaldehyde. 1H NMR (300MHz, DMSO-^6) δ 11.63 (s, IH), 11.33 (s, IH), 8.62 (s, IH), 8.59 (s, IH), 8.18-8.01 (m, 5H), 8.00-7.87 (m, 6H), 7.69 (dt, 2H), 7.54 (m, 2H), 7.33 (m, IH), 6.55 (m, IH), 3.44 (m, 2H), 2.77 (t, 2H), 1.90 (m, 2H).
EXAMPLE 146
4-(3 -(2-(6-Indolemethylidene)- 1 -hydrazinocarbonyl)pyridyl-6-)aminocarbonylbenz-2-(6- indolemethylidene)hydrazide (Compound 246)
Figure imgf000136_0001
[0343] Compound 246 was prepared according to the procedure described in Scheme I from 4-(3-hydrazinocarbonyl-6-pyridyl)aminocarbonylbenzoic hydrazide and 6- indolecarboxaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.88 (s, IH), 11.84 (s, 2H), 11.83 (s, IH), 11.33 (s, 2H), 8.96 (s, IH), 8.53 (s, 2H), 8.37 (d, IH), 8.19 (d, IH), 8.06 (s, 3H), 7.77 (s, 2H), 7.60 (d, 2H), 7.48 (t, 2H), 7.42 (d, 2H), 6.48 (s, 2H).
EXAMPLE 147 1 ,6-Hex-2,4-diene-bis(carboxy-2-(3-vinylbenzylidene)hydrazide) (Compound 247)
Figure imgf000136_0002
[0344] Compound 247 was prepared according to the procedure described in Scheme I from 1 ,6-hex-2,4-dienedicarboxylic acid and 3-vinylbenzaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.82 (s, 2H), 8.23 (s, 2H), 7.78-7.40 (m, 12H), 6.80 (dd, J = 17.6, 11.0 Hz, 2H), 5.92 (d, J= 17.6, Hz, 2H), 5.32 (d, J= 11.0 Hz, 2H).
EXAMPLE 148 1 ,4-Phenylene-bis(carboxy-2-(3-vinylbenzylidene)hydrazide) (Compound 248)
Figure imgf000136_0003
[0345] Compound 248 was prepared according to the procedure described in Scheme I from 1 ,4-phenylenedicarboxylic acid and 3-vinylbenzaldehyde. 1H NMR (300MHz, DMSO- d6) δ 12.05 (s, 2H), 8.50 (s, 2H), 8.07 (s, 4H), 7.94 (s, 2H), 7.67 (d, J = 7. 9 Hz, 2H5), 7.59 (d, J = 7.9 Hz, 2H), 7.47 (t, J = 7.6 Hz, 2H), 6.84 (dd, J = 17.6, 11.0 Hz, 2H), 5.93 (d, J = 17.6 Hz, 2H), 5.35 (d, J= 11.0 Hz, 2H). EXAMPLE 149 1 ,4-Phenylene-bis(carboxy-2-(3-methoxybenzylidene)hydrazide) (Compound 249)
Figure imgf000137_0001
[0346] Compound 249 was prepared according to the procedure described in Scheme I from 1 ,4-phenylenedicarboxylic acid and 3-methoxybenzaldehyde. 1H NMR (300MHz, DMSO-J6) δ 12.01 (s, 2H), 8.46 (s, 2H), 8.07 (s, 4H), 7.40 (t, J = 7.6 Hz, 2H), 7.63 (d, J = 7.6 Hz, 2H), 7.30 (s, 2H), 7.03 (d, J = 7.6 Hz, 2H), 3.82 (s, 6H).
EXAMPLE 150 1 ,4-Phenylene-bis(carboxy-2-(5-indolemethylidene)hydrazide) (Compound 250)
Figure imgf000137_0002
[0347] Compound 250 was prepared according to the procedure described in Scheme I from 1 ,4-phenylenedicarboxylic acid and 5-indolecarboxaldehyde. 1H NMR (300MHz, DMSO- d6) δ 11.82 (s, 2H), 11.39 (s, 2H), 8.54 (s, 2H), 8.06 (s, 4H), 7.86 (s, 2H), 7.62 (d, J = 8.5 Hz, 2H), 7.48 (d, J = 8.5 Hz, 2H), 7.41 (s, 2H), 6.53 (s, 2H).
EXAMPLE 151 1 ,4-Phenylene-bis(carboxy-2-(2-naphthylmethylidene)hydrazide) (Compound 251)
Figure imgf000137_0003
[0348] Compound 251 was prepared according to the procedure described in Scheme I from 1 ,4-phenylenedicarboxylic acid and 2-naphthylcarboxaldehyde. 1H NMR (300MHz, DMSO-J6) δ 12.12 (s, 2H), 8.93 (s, 2H), 8.39 (s, 2H), 8.1 1 (s, 4H), 8.36-7.84 (m, 8H), 7.66-7.54 (m, 4H).
EXAMPLE 152 1 ,4-Phenylene-bis(carboxy-2-(3,5-dimethoxybenzylidene)hydrazide) (Compound 252)
Figure imgf000138_0001
[0349] Compound 252 was prepared according to the procedure described in Scheme I from 1 ,4-phenylenedicarboxylic acid and 3,5-dimethoxybenzaldehyde. 1H NMR (300MHz, DMSO-J6) δ 12.03 (s, 2H), 8.40 (s, 2H), 8.05 (s, 4H), 6.91 (s, 4H), 6.60 (s, 2H), 3.81 (s, 12H).
EXAMPLE 153 2,2'-(Bipyridine-5-carboxylic-2-(5-indolemethylidene)hydrazide) (Compound 253)
Figure imgf000138_0002
[0350] Compound 253 was prepared according to the procedure described in Scheme I from dimethyl 2,2'-bipyridine-4,4'-dicarboxylate and 5-indolecarboxaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.40 (s, 2H), 9.23 (s, 2H), 8.77 (s, 2H), 8.52-8.48 (m, 4H), 8.34 (d, J = 7.0 Hz, 2H), 8.01 (s, 2H), 7.73 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 9.7 Hz, 2H ), 7.44 (s, 2H), 6.55 (s, 2H).
EXAMPLE 154 1 ,3-Acetone-bis(carboxy-2-(3,5-dimethoxybenzylidene)hydrazide) (Compound 254)
Figure imgf000138_0003
[0351] Compound 254 was prepared according to the procedure described in Scheme I from 1,3-acetonedicarboxylic acid and 3,5-dimethoxybenzaldehyde. 1H NMR (300MHz, DMSO-^6) δ 8.64 (s, 2H), 8.13 (s, 2H), 7.05 (s, 4H), 6.66 (s, 2H), 3.80 (s, 12H), 1.91 (s, 4H).
EXAMPLE 155 4,4'-Bis(benz-2-(2-hydroxy-5-methoxybenzyl)hydrazide) (Compound 255)
Figure imgf000139_0001
[0352] Compound 255 was prepared according to the procedure described in Scheme I from dimethyl biphenyl-4,4'-dicarboxylate and 4-hydroxy-5-methoxybenzaldehyde. 1H NMR (300MHz, DMSO-^6) δ 10.23 (s, 2H), 9.18 (s, 2H), 7.92 (d, J = 7.6 Hz, 4H), 7.82 (d, J = 7.6 Hz, 4H), 6.86 (s, 2H), 6.73-6.65 (m, 4H), 5.60 (br. s, 2H), 3.95 (s, 4H), 3.66 (s, 6H).
EXAMPLE 156 2,2'-(Bipyridine-5-carboxy-2-(3-methoxybenzyl)hydrazide) (Compound 256)
Figure imgf000139_0002
[0353] Compound 256 was prepared according to the procedure described in Scheme I from dimethyl 2,2'-bipyridine-4,4'-dicarboxylate and 3-methoxybenzaldehyde. 1H NMR (300MHz, Acetone) δ 9.12 (s, 2H), 8.58 (d, J = 7.6 Hz, 2H), 8.47 (d, J = 7.6 Hz, 2H), 7.30-7.20 (m, 4H), 7.15-7.05 (m, 2H), 7.04 (s, 2H), 6.86 (m, 2H), 5.40 (s, 2H), 4.07 (s, 4H), 3.80 (s, 6H).
EXAMPLE 157 4,4'-Bis(benz-2-(3,5-dimethylbenzyl)hydrazide) (Compound 257)
Figure imgf000140_0001
[0354] Compound 257 was prepared according to the procedure described in Scheme I from dimethyl biphenyl-4,4'-dicarboxylate and 3,5-dimethylbenzaldehyde. 1H NMR (300MHz, Acetone) δ 9.46 (s, 2H), 8.00(d, J = 7.6 Hz, 4H), 7.86 (d, J = 7.6 Hz, 4H), 7.05 (s, 4H), 6.93 (s, 2H), 5.20 (br. s, 2H), 4.00 (s, 4H), 2.30 (s, 12H).
EXAMPLE 158 4,4'-Bis(benz-2-(3-methoxymethylbenzylidene)hydrazide) (Compound 258)
Figure imgf000140_0002
[0355] Compound 258 was prepared according to the procedure described in Scheme I from dimethyl biphenyl-4,4'-dicarboxylate and 3-methoxymethylbenzaldehyde. 1H NMR (300MHz, DMSO-^6) δ 11.95 (s, 2H), 8.47 (s, 2H), 8.04 (d, 4H), 7.93 (d, 4H), 7.72 (s), 7.64 (d), 7.42 (t), 7.39 (s), 7.38 (d), 4.47 (s, 4H), 3.32 (s, 6H).
EXAMPLE 159
1 ,4-Phenylene-bis(3E-acryl-2-(3-methoxybenzylidene)hydrazide) (Compound 259)
Figure imgf000140_0003
[0356] Compound 259 was prepared according to the procedure described in Scheme I from dimethyl l,4-phenylene-bis-3E-acrylate and 3-methoxybenzaldehyde. 1H NMR (300MHz, DMS(W6) δ 11.72 (s, 2H), 8.20 (s, 2H), 7.82-7.58 (m, 6H), 7.40-7.32 (m, 2H), 7.27 (s, 4H), 7.00 (d, J = 6.7 Hz, 2H), 6.76 (d, J = 14.8 Hz, 2H), 3.79 (s, 6H). EXAMPLE 160 1 ,4-Phenylene-bis(3E-acryl-2-(3-vinylbenzylidene)hydrazide) (Compound 260)
Figure imgf000141_0001
[0357] Compound 260 was prepared according to the procedure described in Scheme I from dimethyl l,4-phenylene-bis-3E-acrylate and 3-vinylbenzaldehyde. 1H NMR (300MHz, OMSO-dβ) δ 11.75 (s, 2H), 8.24 (s, 2H), 7.90-7.60 (m, 6H), 7.78 (s, 2H), 7.69 (s, 4H), 7.54 (d, J = 6.7 Hz, 2H), 7.43 (t, J = 7.3 Hz, 2H), 6.88-6.70 (m, 2H), 5.98-5.84 (m, 2H), 5.32 (d, J = 11.1 Hz, 2H).
EXAMPLE 161 l,4-Phenylene-bis(3E-acryl-2-(3-acetylbenzylidene)hydrazide) (Compound 261)
Figure imgf000141_0002
[0358] Compound 261 was prepared according to the procedure described in Scheme I from dimethyl 1 ,4-phenylene-bis-3E-acrylate and 3-acetylbenzaldehyde. 1H NMR (300MHz, DMSO-c/6) δ 11.85 (s, 2H), 8.34 (s, 2H), 8.17 (s, 2H), 8.06-7.82 (m, 4H), 7.76-7.60 (m, 4H), 7.72 (s, 4H), 6.80 (d, J = 14.9 Hz, 2H), 2.65 (s, 6H).
EXAMPLE 162
1 ,4-Phenylene-bis(3E-acryl-2-(3,5-dimethoxybenzylidene)hydrazide) (Compound 262)
Figure imgf000141_0003
[0359] Compound 262 was prepared according to the procedure described in Scheme I from dimethyl l,4-phenylene-bis-3E-acrylate and 3,5-dimethoxybenzaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.71 (s, 2H), 8.16 (s, 2H), 7.84-7.58 (m, 6H), 6.90 (s, 4H), 6.88 (d, J = 6.7 Hz, 2H), 6.55 (s, 2H) 3.79 (s, 12H).
EXAMPLE 163
1 ,4-Phenylene-bis(3E-acryl-2-(6-indolemethylidene)hydrazide) (Compound 263)
Figure imgf000142_0001
[0360] Compound 263 was prepared according to the procedure described in Scheme I from dimethyl l,4-phenylene-bis-3E-acrylate and 6-indolecarboxaldehyde. 1H NMR (300MHz, DMSO-<4) δ 11.57 (s, 2H), 11.31 (s, 2H), 8.29 (s, 2H), 7.84-7.38 (m, 10H), 7.74 (s, 4H), 7.75 (d, J = 16.1 Hz, 2H), 6.46 (s, 2H).
EXAMPLE 164 4,4'-Oxybis(benz-2-benzylhydrazide) (Compound 264)
Figure imgf000142_0002
[0361] Compound 264 was prepared according to the procedure described in Scheme I from dimethyl 4,4'-oxybisbenzoate and benzaldehyde. [M+H]+ calcd. 467.20; found, 467.00.
EXAMPLE 165 4,4'-Bis(benz-2-(3-methoxybenzyl)hydrazide) (Compound 265)
Figure imgf000142_0003
[0362] Compound 265 was prepared according to the procedure described in Scheme I from dimethyl biphenyl-4,4'-dicarboxylate and 3-methoxybenzaldehyde. 1H NMR (300MHz, DMSO-J6) δ 10.14 (s, 2H), 7.86 (d, J = 6.2 Hz, 4H), 7.78 (d, J = 6.2 Hz, 4H), 7.22 (t, J = 7.8 Hz, 2H), 7.10 (s, 2H), 6.96 (d, J = 6.7 Hz, 2H), 6.82 (d, J = 6.7 Hz, 2H), 5.50 (s, 2H), 3.98 (s, 4H), 3.75 (s, 6H).
EXAMPLE 166
4,4'-Bis(benz-2-benzylhydrazide) (Compound 266)
Figure imgf000143_0001
[0363] Compound 266 was prepared according to the procedure described in Scheme I from dimethyl biphenyl-4,4'-dicarboxylate and benzaldehyde. 1H NMR (300MHz, DMSO- J6) δ 10.14 (s, 2H), 7.90 (d, J = 8.2 Hz, 4H), 7.80 (d, J = 8.2 Hz, 4H), 7.44-7.24 (m, 10H), 5.48 (m, 2H), 4.03 (s, 4H).
EXAMPLE 167
3 -(2-(3 -Methoxybenzylidene)hydrazinocarbonylmethyl)aminomethyl-4-hydroxybenz-2-(3 - methoxybenzylidene)hydrazide (Compound 267)
Figure imgf000143_0002
[0364] Compound 267 was prepared according to the procedure described in Scheme I from3-(2-hydrazinocarbonylmethyl)aminomethyl-4-hydroxybenz-2-hydrazide and 3- methoxybenzaldehyde. [M+H]+ calcd for C26H27N5O5: 490.20; found: 490.02.
EXAMPLE 168 1 ,4-Phenylene-bis(3E-acryl-2-(4-indolemethylidene)hydrazide) (Compound 268)
Figure imgf000144_0001
[0365] Compound 268 was prepared according to the procedure described in Scheme I from dimethyl l,4-phenylene-bis-3E-acrylate and 4-indolecarboxaldehyde. 1H NMR (300MHz, DMSO-J6) δ 1 1.56 (s, 2H), 11.35 (s, 2H), 8.31 (s, 2H), 7.71 (s, 4H), 7.78-7.58 (m, 6H), 7.50- 7.42 (m, 2H), 7.41 (s, 2H), 6.80 (d, J = 18.8 Hz, 2H), 6.56 (s, 2H).
EXAMPLE 169
1 ,4-Phenylene-bis(3E-acryl-2-(5-indolemethylidene)hydrazide) (Compound 269)
Figure imgf000144_0002
[0366] Compound 269 was prepared according to the procedure described in Scheme I from dimethyl l,4-phenylene-bis-3E-acrylate and 5-indolecarboxaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.68 (s, 2H), 11.36 (s, 2H), 8.49 (s, 2H), 7.86-7.62 (m, 4H), 7.74 (s, 4H), 7.50 (s, 2H), 7.30 (d, J = 7.9 Hz, 2H), 7.24-7.14 (m, 4H), 6.86-6.78 (m, 2H).
EXAMPLE 170 1 ,4-Phenylene-bis(3E-acryl-2-(3-cyanobenzylidene)hydrazide) (Compound 270)
Figure imgf000144_0003
[0367] Compound 270 was prepared according to the procedure described in Scheme I from dimethyl l,4-phenylene-bis-3E-acrylate and 3-cyanobenzaldehyde as a mixture of E/Z isomers. 1H NMR (300MHz, DMSO-J6) δ 1 1.94 (s, 2H), 8.29 (s, 2H), 8.20-8.06 (m, 4H), 7.90 (s, 2H), 7.88 (d, J = 6.7 Hz, 2H), 7.72 (s, 4H), 7.76-7.60 (m, 3H), 6.8 (d, J = 16.7 Hz, IH). [M+H]+ calcd for C28H20N6O2: 473.16; found: 472.94.
EXAMPLE 171
3E-(4-(2-(3-Methoxybenzylidene)hydrazinocarbonyl)phenyl)acryl-2-(3- methoxybenzylidene)hydrazide (Compound 271)
Figure imgf000145_0001
[0368] Compound 271 was prepared according to the procedure described in Scheme I from 3E-(4-(2-hydrazinocarbonyl)phenyl)acrylic-2-hydrazide and 3-methoxybenzaldehyde. 1H NMR (300MHz, DMSO-J6) δ 12.28 (s, IH), 11.95 (s, IH), 8.45 (s, IH), 8.24 (s, IH), 8.02-7.90 (m, 3H), 7.82-7.64 (m, 2H), 7.44-7.24 (m, 2H), 7.06-6.88 (m, 2H), 6.84 (d, J = 7.6 Hz, 2H), 6.84 (d, J = 16.1 Hz, IH), 3.82 (s, 6H).
EXAMPLE 172
3E-(4-(2-(3,5-Dimethoxybenzylidene)hydrazinocarbonyl)phenyl)acryl-2-(3,5- dimethoxybenzylidene)hydrazide (Compound 272)
Figure imgf000145_0002
[0369] Compound 272 was prepared according to the procedure described in Scheme I from 3E-(4-(2-hydrazinocarbonyl)phenyl)acrylic-2-hydrazide and 3,5-dimethoxybenzaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.95 (s, IH), 11.78 (s, IH), 8.39 (s, IH), 8.18 (s, IH), 7.88 (d, J = 8.2 Hz, 2H), 8.02-7.88 (m, IH), 7.82-7.64 (m, 3H), 6.90 (s, 4H), 6.58 (s, 2H), 3.80 (s, 12H).
EXAMPLE 173
3E-(4-(2-(3-Vinylbenzylidene)hydrazinocarbonyl)phenyl)acryl-2-(3-vinylbenzylidene)hydrazide
(Compound 273)
Figure imgf000146_0001
[0370] Compound 273 was prepared according to the procedure described in Scheme I from 3E-(4-(2-hydrazinocarbonyl)phenyl)acrylic-2-hydrazide and 3-vinylbenzaldehyde. 1H NMR (300MHz, DMSCM6) δ 11.98 (s, IH), 11.80 (s, IH), 8.48 (s, IH), 8.26 (s, IH), 8.02-7.94 (m, 3H), 7.86-7.72 (m, 5H), 7.67 (d, J = 7.6 Hz, 2H), 7.62-7.54 (m, 2H), 7.50-7.42 (m, 2H), 6.84 (d, J = 16.1 Hz, 2H), 5.94 (d, J = 17.6 Hz, 2H), 5.35 (d, J = 11.1 Hz, 2H).
EXAMPLE 174
3E-(4-(2-(2-Hydroxy-5-methoxybenzylidene)hydrazinocarbonyl)phenyl)acryl-2-(2-hydroxy-5- methoxybenzylidene)hydrazide (Compound 274)
Figure imgf000146_0002
[0371] Compound 274 was prepared according to the procedure described in Scheme I from 3E-(4-(2-hydrazinocarbonyl)phenyl)acrylic-2-hydrazide and 2-hydroxy-5- methoxybenzaldehyde. 1H NMR (300MHz, DMSO-c4) δ 12.15 (s, IH), 11.98 (s, IH), 10.67 (s, IH), 10.58 (s, IH), 8.65 (s, IH), 8.46 (s, IH), 8.02 (d, J = 7.6 Hz, 2H), 7.90 (d, J = 18.1 Hz, IH), 7.82 (d, J = 7.9 Hz, 2H), 7.76-7.66 (m, IH), 7.16 (s, 2H), 6.88-6.80 (m, 4H), 3.74 (s, 6H).
EXAMPLE 175 3E-(4-(2-(5-Indolemethylidene)hydrazinocarbonyl)phenyl)acryl-2-(5- indolemethylidene)hydrazide (Compound 275)
Figure imgf000146_0003
[0372] Compound 275 was prepared according to the procedure described in Scheme I from 3E-(4-(2-hydrazinocarbonyl)phenyl)acrylic-2-hydrazide and 5-indolecarboxaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.74 (s, IH), 11.54 (s, IH), 11.32 (s, 2H), 11.36 (s, IH), 8.50 (s, IH), 8.30 (s, IH), 8.0-7.80 (m, 4H), 7.78-7.50 (m, 4H), 7.48-7.34 (m, 4H), 6.80 (d, J = 15.8 Hz, IH), 6.48 (s, 2H).
EXAMPLE 176
3E-(4-(2-(4-Dimethylaminobenzylidene)hydrazinocarbonyl)phenyl)acryl-2-(4- dimethylaminobenzylidene)hydrazide (Compound 276)
Figure imgf000147_0001
[0373] Compound 276 was prepared according to the procedure described in Scheme
I from 3E-(4-(2-hydrazinocarbonyl)phenyl)acrylic-2-hydrazide and 4- dimethylaminobenzaldehyde. 1H NMR (300MHz, DMSO-^6) δ 11.60 (s, IH), 11.42 (s, IH), 8.30 (s, IH), 8.08 (s, IH), 7.92 (d, J = 6.4 Hz, 2H), 7.84 (d, J = 7.3 Hz, 2H), 7.72 (d, J = 9.0 Hz, 2H), 7.63 (d, J = 9.4 Hz, 2H), 7.60-7.48 (m, 2H), 6.80-6.64 (m, 4H), 2.95 (s, 12 H).
EXAMPLE 177
1 ,4-Phenylene-bis(3E-acryl-2-(2-hydroxy-5-methoxybenzylidene)hydrazide) (Compound 277)
Figure imgf000147_0002
[0374] Compound 277 was prepared according to the procedure described in Scheme I from dimethyl l,4-phenylene-bis-3E-acrylate and 2-hydroxy-5-methoxybenzaldehyde. 1H NMR (300MHz, DMSO-^6) δ 11.91 (s, 2H), 10.55 (s, 2H), 8.41(s, 2H), 7.82-7.58 (m, 8H), 7.12 (s, 2H), 6.92-6.66 (m, 4H), 3.70 (s, 6H). EXAMPLE 178
3 E-(4-(2-(3 -(2-Hydroxyethoxy)benzylidene)hydrazinocarbonyl)phenyl)acryl-2-(3 -(2- hydroxyethoxy)benzylidene)hydrazide (Compound 278)
Figure imgf000148_0001
[0375] Compound 278 was prepared according to the procedure described in Scheme I from 3E-(4-(2-hydrazinocarbonyl)phenyl)acrylic-2-hydrazide and 3-(2- hydroxyethoxy)benzaldehyde. 1H NMR (300MHz, OMSO-d6) δ 11.90 (s, IH), 11.74 (s, IH), 8.40 (s, IH), 8.18 (s, IH), 8.04-7.84 (m, 2H), 7.80-7.62 (m, 2H), 7.40-7.32 (m, 4H), 7.28 (s, 2H), 6.98 (m, 2H), 4.86 (t, J= 5.1 Hz, 2H), 4.06-3.96 (m, 4H), 3.76-3.66 (m, 4H).
EXAMPLE 179
4,4'-Bis(benz-2-(3-(2-hydroxyethoxy)benzylidene)hydrazide) (Compound 279)
Figure imgf000148_0002
[0376] Compound 279 was prepared according to the procedure described in Scheme I from dimethyl biphenyl-4,4'-dicarboxylate and 3-(2-hydroxyethoxy)benzaldehyde. 1H NMR (300MHz, DMSO-^6) δ 11.98 (s, 2H), 8.43 (s, 2H), 8.04 (d, J = 8.2 Hz, 4H), 7.92 (d, J = 8.2 Hz, 4H), 7.42-7.22 (m, 6H), 7.36 (d, J = 8.0 Hz, 2H),4.88 (t, 5.1 Hz, 2H), 4.06-3.96 (m, 4H), 3.76-3.66 (m, 4H).
EXAMPLE 180 4,4'-Bis(benz-2-(4-(2-hydroxyethoxy)benzylidene)hydrazide) (Compound 280)
Figure imgf000148_0003
[0377] Compound 280 was prepared according to the procedure described in Scheme
I from dimethyl biphenyl-4,4'-dicarboxylate and 4-(2-hydroxyethoxy)benzaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.79 (s, 2H), 8.40 (s, 2H), 8.02 (d, J = 8.2 Hz, 4H), 7.90 (d, J = 7.9 Hz, 4H), 7.65 (d, J = 8.2 Hz, 4H), 7.00 (d, J = 7.9 Hz, 4H), 4.88 (t, 5.1 Hz, 2H), 4.06-3.96 (m, 4H), 3.76-3.66 (m, 4H).
EXAMPLE 181 1 ,4-Phenylene-bis(3E-acryl-2-(3-(2-hydroxyethoxy)benzylidene)hydrazide) (Compound 281 )
Figure imgf000149_0001
[0378] Compound 281 was prepared according to the procedure described in Scheme I from dimethyl l,4-phenylene-bis-3E-acrylate and 3-(2-hydroxyethoxy)benzaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.71 (s, 2H), 8.19 (s, 2H), 7.80 (s, 2H), 7.72-7.56 (m, 4H), 7.34 (m, 2H), 7.26 (s, 4H), 6.98 (d, J = 6.7 Hz, 2H), 6.62 (d, J = 14.7 Hz, 2H), 4.88 (br. s, 2H), 4.06-3.96 (m, 4H), 3.74-3.64 (m, 4H).
EXAMPLE 182
1 ,4-Phenylene-bis(3E-acryl-2-(3-(2-hydroxyethoxy)benzylidene)hydrazide) (Compound 282)
Figure imgf000149_0002
[0379] Compound 282 was prepared according to the procedure described in Scheme I from dimethyl 1 ,4-phenylene-bis-3E-acrylate and 3-(2-hydroxyethoxy)benzaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.40 (s, 2H), 8.16 (s, 2H), 7.80 (s, 2H), 1.14-1.66 (m, 2H), 7.66 (s, 4H), 7.60 (d, J = 8.5 Hz, 4H), 6.99 (d, J = 8.5 Hz, 4H), 6.62 (d, J = 15.5 Hz, 2H), 4.88 (br. s, 2H), 4.06-3.96 (m, 4H), 3.74-3.64 (m, 4H).
EXAMPLE 183 4,4'-Bis(phenylcarbonylmethylidene-2-(3-methoxybenzylidene)hydrazine) (Compound 283)
Figure imgf000150_0001
[0380] Compound 283 was prepared according to the procedure described in Scheme I from biphenyl-4,4'-dioxoethaldehyde and 3-methoxybenzhydrazine. 1H NMR (300MHz, DMSO-J6) δ 10.40 (s, 2H), 7.89 (s, 2H), 7.78-7.74 (m, 4H), 7.13 (t, J = 8.1 Hz, 2H), 6.68-6.65 (m, 4H), 6.35 (dd, J = 8.3, 2.4 Hz, 2H), 3.75 (s, 6H).
EXAMPLE 184
4-(4-(2-(3 -Chlorobenzylidene)- 1 -hydrazinocarbonyl)phenyl)aminobutyr-2-(3 - chlorobenzylidene)hydrazide (Compound 284)
Figure imgf000150_0002
[0381] Compound 284 was prepared according to the procedure described in Scheme I from 4-(4-hydrazinocarbonylphenyl)aminobutyric hydrazide and 3-chlorobenzaldehyde. 1H NMR (300MHz, DMSCwZ6) δ 11.60 (s), 11.53 (s), 11.38 (s), 8.38 (s), 6.61 (d), 3.20 - 3.03 (m), 2.73 (t), 2.33 (t), 1.91-1.80 (m).
EXAMPLE 185
4-(4-(2-(3-Dimethylaminobenzylidene)-l-hydrazinocarbonyl)phenyl)aminobutyr-2-(3- dimethylaminobenzylidene)hydrazide (Compound 285)
Figure imgf000150_0003
[0382] Compound 285 was prepared according to the procedure described in Scheme
I from 4-(4-hydrazinocarbonylphenyl)aminobutyric hydrazide and 3- dimethylaminobenzaldehyde. 1H NMR (300MHz, DMSO-^6) δ 11.38 (s), 11.30 (s), 11.21 (s),
8.33 (s), 6.61 (d), 3.17 - 3.09 (m), 2.73 (t), 2.31 (t), 1.89-1.82 (m). EXAMPLE 186
4-(4-(2-(4-Fluorobenzylidene)-l-hydrazinocarbonyl)phenyl)aminobutyr-2-(4- fluorobenzylidene)hydrazide (Compound 286)
Figure imgf000151_0001
[0383] Compound 286 was prepared according to the procedure described in Scheme I from 4-(4-hydrazinocarbonylphenyl)aminobutyric hydrazide and 3-fluorobenzaldehyde. H NMR (300MHz, DMSO-J6) δ 11.47 (s), 11.39 (s), 11.26 (s), 3.20-3.11 (m), 2.74 (t), 2.33 (t), 1.87 (p).
EXAMPLE 187
6-(4-(2-(3-Methoxybenzylidene)-l-hydrazinocarbonyl)phenyl)aminohexano-2-(3- methoxybenzylidene)hydrazide (Compound 287)
Figure imgf000151_0002
[0384] Compound 287 was prepared according to the procedure described in Scheme I from 6-(4-hydrazinocarbonylphenyl)aminohexanoic hydrazide and 3-methoxybenzaldehyde. H NMR (300MHz, DMSO-Ci6) δ 11.45 (s), 11.34 (s), 1 1.23 (s), 3.81 (s), 3.79 (s), 3.78 (s), 3.47-3.40 (m), 3.08 (q), 2.22 (t), 1.66-1.57 (m), 1.46-1.40 (m). [M+H]+ calcd for C29H33N5O4: 516.25; found: 516.19.
EXAMPLE 188
4-(4-(2-(3 -Methoxybenzylidene)- 1 -hydrazinocarbonyl)phenyl)acetaminobutyric-2-(3 - methoxybenzylidene)hydrazide (Compound 288)
Figure imgf000151_0003
[0385] Compound 288 was prepared according to the procedure described in Scheme I from 4-(4-hydrazinocarbonylphenyl)acetaminobutyric hydrazide and 3-methoxybenzaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.94 (s), 11.39 (s), 11.28 (s), 3.82 (s), 3.79 (s), 3.76 (s), 2.72 (t), 2.29 (t), 1.89-1.85 (m).
EXAMPLE 189
3 -(4-(2-(3 -Methoxybenzylidene)- 1 -hydrazinocarbonyl)phenyl)acetaminopropion-2-(3 - methoxybenzylidene)hydrazide (Compound 289)
Figure imgf000152_0001
[0386] Compound 289 was prepared according to the procedure described in Scheme I from 3-(4-hydrazinocarbonylphenyl)acetaminopropionic hydrazide and 3- methoxybenzaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.94 (s), 11.47 (s), 11.36 (s), 3.82 (s), 3.79 (S), 2.96 (t), 2.54 (t).
EXAMPLE 190
3-(4-(2-(3-Methoxybenzylidene)-l-hydrazinocarbonyl)phenyl)methylamino-3-oxopropion-2-(3- methoxybenzylidene)hydrazide (Compound 290)
Figure imgf000152_0002
[0387] Compound 290 was prepared according to the procedure described in Scheme I from 3-(4-hydrazinocarbonylphenyl)methylamino-3-oxopropionic hydrazide and 3- methoxybenzaldehyde. 1H NMR (300MHz, DMSO-J6) δ 11.78 (s), 1 1.57 (s), 11.44 (s), 3.81 (s), 3.80 (s), 3.76 (s). [M+H]+ calcd for C27H27N5O5: 502.20; found: 502.11.
EXAMPLE 191
3-(4-(2-(3-Methoxybenzylidene)-l-hydrazinocarbonyl)phenyl)methylaminopropion-2-(3- methoxybenzylidene)hydrazide (Compound 291)
Figure imgf000153_0001
[0388] Compound 291 was prepared according to the procedure described in Scheme I from 3-(4-hydrazinocarbonylphenyl)methylaminopropionic hydrazide and 3- methoxybenzaldehyde. 1H NMR (300MHz, DMSO-^6) δ 4.21 (s), 4.09 (s), 3.86 (s), 3.83 (s), 3.81 (s), 3.15 (t), 2.66 (t). [M+H]+ calcd for C27H29N5O4: 488.22; found: 488.06.
EXAMPLE 192
4-(4-(2-(3-(2-Hydroxyethoxy)benzylidene)-l-hydrazinocarbonyl)phenyl)aminobutyr-2-(3-(2- hydroxyethoxy)benzylidene)hydrazide (Compound 292)
Figure imgf000153_0002
[0389] Compound 292 was prepared according to the procedure described in Scheme I from 4-(4-hydrazinocarbonylphenyl)aminobutyric hydrazide and 3-(2- hydroxyethoxy)benzaldehyde. 1H NMR (300MHz, DMSO-Cf6) [M+H]+ calcd for C29H33N5O6: 548.24; found: 548.
EXAMPLE 193
4-(5 -(2-(3 -Methoxybenzylidene)- 1 -hydrazinocarbonyl)indoly 1- 1 -)butyr-2-(3 - methoxybenzylidene)hydrazide (Compound 293)
Figure imgf000153_0003
[0390] Compound 293 was prepared according to the procedure described in Scheme I from 4-(5-hydrazinocarbonylindolyl-l-)butyric hydrazide and 3-methoxybenzaldehyde. 1H NMR (300MHz, DMSO-έfc) δ 1 1.79 (s), 11.38 (s), 11.32 (s), 3.83 (s), 3.79 (s), 3.77 (s). [M+H]+ calcd for C29H29N5O4: 512.22; found: 512.6. EXAMPLE 194
1 -(5-(2-(3-Methoxybenzylidene)- 1 -hydrazinocarbonyl)pyridyl-2-)piperidine-4-carboxyl-2-(3- methoxybenzylidene)hydrazide (Compound 294)
Figure imgf000154_0001
[039 IJ Compound 294 was prepared according to the procedure described in Scheme I from l-(5-hydrazinocarbonylpyridyl-2-)piperidine-4-carboxylic hydrazide and 3- methoxybenzaldehyde. 1H NMR (SOOMHZ, DMSO-<*6) δ 11.61 (s, IH), 11.43 (s, 0.5H), 11.26 (s, 0.5H), 8.67 (s, IH), 8.38 (s, IH), 8.15 (s, 0.5H), 8.01-7.95 (s, IH), 7.90 (s, 0.5H), 7.35-6.96 (m, 8H), 4.49-4.40 (m, 2H), 3.79-3.75 (m, 6H), 3.36-2.96 (m, 2H), 1.89-1.81 (m, 2H), 1.62-1.54 (m, 2H).
EXAMPLE 195
4-(5-(2-(3-Dimethylaminobenzylidene)- 1 -hydrazinocarbonyl)indolyl- 1 -)butyr-2-(3- dimethylaminobenzylidene)hydrazide (Compound 295)
Figure imgf000154_0002
[0392] Compound 295 was prepared according to the procedure described in Scheme I from 4-(5-hydrazinocarbonylindolyl-l-)butyric hydrazide and 3-dimethylaminobenzaldehyde. [M+H]+ calcd for C3]H35N7O2: 538.29; found: 539.
EXAMPLE 196
4-(5-(2-(3,5-Dimethoxybenzylidene)-l-hydrazinocarbonyl)indolyl-l-)butyr-2-(3,5- dimethoxybenzylidene)hydrazide (Compound 296)
Figure imgf000155_0001
[0393] Compound 296 was prepared according to the procedure described in Scheme I from 4-(5-hydrazinocarbonylindolyl-l-)butyric hydrazide and 3,5-dimethoxybenzaldehyde. [M+H]+ calcd for C31H33N5O6: 572.24; found: 573.
EXAMPLE 197
4-(5-(2-(2-Hydroxy-5-methoxybenzylidene)- 1 -hydrazinocarbonyl)indolyl- 1 -)butyr-2-(2- hydroxy-5-methoxybenzylidene)hydrazide (Compound 297)
Figure imgf000155_0002
[0394] Compound 297 was prepared according to the procedure described in Scheme I from 4-(5-hydrazinocarbonylindolyl-l-)butyric hydrazide and 2-hydroxy-5- methoxybenzaldehyde. [M+H]+ calcd for C29H29N5O6: 544.21; found: 544.
EXAMPLE 198
4-(5-(2-(4-Hydroxy-5-methoxybenzylidene)- 1 -hydrazinocarbonyl)indolyl- 1 -)butyr-2-(4- hydroxy-5-methoxybenzylidene)hydrazide (Compound 298)
Figure imgf000155_0003
[0395] Compound 298 was prepared according to the procedure described in Scheme I from 4-(5-hydrazinocarbonylindolyl-l-)butyric hydrazide and 4-hydroxy-5- methoxybenzaldehyde. [M+H]+ calcd for C29H29N5O6: 544.21; found: 544.
EXAMPLE 199
4-(5-(2-(3-Methoxybenzylidene)-l-hydrazinocarbonyl)pyridyl-2-)aminocarbonylbenz-2-(3- methoxybenzylidene)hydrazide (Compound 299)
Figure imgf000156_0001
[0396] Compound 299 was prepared according to the procedure described in Scheme I from 4-(5-hydrazinocarbonylpyridyl-2-)aminocarbonylbenzoic hydrazide and 3- methoxybenzaldehyde. [M+H]+ calcd for C30H26N6O5: 551.20; found: 551.50.
EXAMPLE 200
4-(5 -(2-(6-Indolemethylidene)- 1 -hydrazinocarbonyl)indoly 1- 1 -)butyr-2-(6- indolemethylidene)hydrazide (Compound 300)
Figure imgf000156_0002
[0397] Compound 300 was prepared according to the procedure described in Scheme I from 4-(5-hydrazinocarbonylindolyl-l-)butyric hydrazide and 6-indolecarboxaldehyde. [M+H]+ calcd for C3]H27N7O2: 530.22; found: 530.
EXAMPLE 201
4-(5-(2-(3-Dimethylaminobenzylidene)-l-hydrazinocarbonyl)pyridyl-2-)aminocarbonylbenz-2- (3-dimethylaminobenzylidene)hydrazide (Compound 301)
Figure imgf000157_0001
[0398] Compound 301 was prepared according to the procedure described in Scheme I from 4-(5-hydrazinocarbonylpyridyl-2-)aminocarbonylbenzoic hydrazide and 3- dimethylaminobenzaldehyde. [M+H]+ calcd for C32H32N8O3: 577.26; found: 577.69.
EXAMPLE 202
4-(5-(2-(3-( 1 -Pyrrolyl)benzylidene)- 1 -hydrazinocarbonyl)indolyl- 1 -)butyr-2-(3-( 1 - pyrrolyl)benzylidene)hydrazide (Compound 302)
Figure imgf000157_0002
[0399] Compound 302 was prepared according to the procedure described in Scheme I from 4-(5-hydrazinocarbonylindolyl-l-)butyric hydrazide and 3-(l-pyrrolyl)benzaldehyde. [M+Hf calcd for C35H3,N7O2: 582.25; found: 582.
EXAMPLE 203
4-(5-(2-(3-Moφholinobenzylidene)-l-hydrazinocarbonyl)indolyl-l-)butyr-2-(3- morpholinobenzylidene)hydrazide (Compound 303)
Figure imgf000157_0003
[0400] Compound 303 was prepared according to the procedure described in Scheme I from 4-(5-hydrazinocarbonylindolyl-l-)butyric hydrazide and 3-morpholinobenzaldehyde. [M+H]+ calcd for C35H39N7O4: 622.31; found: 622. EXAMPLE 204
4-(5-(2-(3-Piperidinobenzylidene)-l-hydrazinocarbonyl)indolyl-l-)butyr-2-(3- piperidinobenzylidene)hydrazide (Compound 304)
Figure imgf000158_0001
[0401] Compound 304 was prepared according to the procedure described in Scheme I from 4-(5-hydrazinocarbonylindolyl-l-)butyric hydrazide and 3-piperidinobenzaldehyde. [M+H]+ calcd for C37H43N7O2: 618.35; found: 618.
EXAMPLE 205
4-(5-(2-(3-Pyrrolidinobenzylidene)-l-hydrazinocarbonyl)indolyl-l-)butyr-2-(3- pyrrolidinobenzylidene)hydrazide (Compound 305)
Figure imgf000158_0002
[0402] Compound 305 was prepared according to the procedure described in Scheme I from 4-(5-hydrazinocarbonylindolyl-l-)butyric hydrazide and 3-pyrrolidinobenzaldehyde. [M+H]+ calcd for C35H39N7O2: 590.32; found: 590.
EXAMPLE 206
4-(5-(2-(3-Pyrazolylbenzylidene)-l-hydrazinocarbonyl)indolyl-l-)butyr-2-(3- pyrazolylbenzylidene)hydrazide (Compound 306)
[0403] Compound 306 was prepared according to the procedure described in Scheme I from 4-(5-hydrazinocarbonylindolyl-l-)butyric hydrazide and 3-pyrazolylbenzaldehyde. [M+H]+ calcd for C33H29N9O2: 584.24; found: 584.
EXAMPLE 207
4-(5-(2-(3-(2-Morpholinoethoxy)benzylidene)-l-hydrazinocarbonyl)indolyl-l-)butyr-2-(3-(2- morpholinoethoxy)benzylidene)hydrazide (Compound 307)
Figure imgf000159_0001
[0404] Compound 307 was prepared according to the procedure described in Scheme I from 4-(5-hydrazinocarbonylindolyl-l-)butyric hydrazide and 3-(2- morpholinoethoxy)benzaldehyde. [M+H]+ calcd for C39H47N7O6: 710.36; found: 710.
EXAMPLE 208
4-(5-(2-(3-Methylsulfonamidobenzylidene)-l-hydrazinocarbonyl)pyridyl-2-)aminocarbonylbenz- 2-(3-methylsulfonamidobenzylidene)hydrazide (Compound 308)
Figure imgf000159_0002
[0405] Compound 308 was prepared according to the procedure described in Scheme I from 4-(5-hydrazinocarbonylpyridyl-2-)aminocarbonylbenzoic hydrazide and 3- methylsulfonamidobenzaldehyde. [M+H]+ calcd for C30H28N8O7S2: 638.18; found: 638.
EXAMPLE 209
4-(3-Chloro-5-(2-(3-methoxybenzylidene)-l-hydrazinocarbonyl)indolyl-l-)butyr-2-(3- methoxybenzylidene)hydrazide (Compo\md 309)
Figure imgf000160_0001
[0406] Compound 309 was prepared according to the procedure described in Scheme I from 4-(3-chloro-5-hydrazinocarbonylindolyl-l-)butyric hydrazide and 3- methoxybenzaldehyde. 1H NMR (300MHz, DMSCW6) δ 11.87 (s), 8.42 (s), 4.34-4.26 (m), 3.81 (s), 2.60 (t), 2.18 (t), 2.11-2.03 (m).
EXAMPLE 210
4-(3-Dimethylaminomethyl-5-(2-(3-pyrazolylbenzylidene)-l-hydrazinocarbonyl)indolyl-l- )butyr-2-(3-pyrazolylbenzylidene)hydrazide (Compound 310)
Figure imgf000160_0002
[0407J Compound 310 was prepared according to the procedure described in Scheme I from 4-(3-dimethylaminomethyl-5-hydrazinocarbonylindolyl-l-)butyric hydrazide and 3- pyrazolylbenzaldehyde. 1H NMR (300MHz, CD3OD) δ 6.57 (s) 4.40 (t), 4.30 (s), 4.24 (s), 2.77 (t), 2.74 (s), 2.68 (s), 2.40-2.26 (m).
EXAMPLE 211
[0408] Cell proliferation assay
The primary testing for the examplfied compounds was performed in UT7/EPO Cell line. UT7/EPO is human leukemia cell line, obtained from Dr. Norio Komatsu {Blood, VoI 82 (2), pp 456-464, 1993). These cells express endogenous EPO receptor and are dependant upon EPO for growth and proliferation. Briefely, the cells were starved of EPO overnight and plated in 96 or 384 well plates. The compounds were added to the cells at 10 μM concentration. The plates were then incubated at 37 0C for 72 hours. The proliferative effect of the compounds was measured by a commercially available kit from Lonza (ViaLight Plus). The activities of the selected compounds are listed in the following table.
Figure imgf000161_0001
Notes: 1) Activity represents efficacy of a compound tested at 10 μM concentration relative to EPO ( 100%) in the UT7/EPO proliferation assay.

Claims

WHAT IS CLAIMED IS:
1. A compound of Formula I:
Figure imgf000163_0001
and pharmaceutically acceptable salts, esters, or prodrugs thereof; wherein:
A is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R1, R2, and R3, said aryl and heteroaryl in the definition of A are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle; or A is lower saturated alkyl or C3-C7 cycloalkyl;
J is -(CH2)mNR9C(=O)(CH2)m-;
L is selected from the group consisting of lower saturated alkyl-L1, lower saturated alkyl-L'-lower saturated alkyl, lower saturated alkylNR9(CH2)m-L1, lower saturated alkylNR9C(=O)-lΛ -(CH2)mC(=O)NR9(CH2)q-lΛ -(CH2)mO-L1-O(CH2)q-,
Figure imgf000163_0002
L1-(CH2)q-L2,
Figure imgf000163_0003
and L1-C(=O)NR9-L2; or L is L'-O-L3 or lΛθ-L3-O-L2;
L1 is selected from the group consisting of carbonyl, an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted heterocycle;
L2 is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted heterocycle;
L3 is selected from the group consisting of lower saturated alkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
Q is -(CH2)mNR9C(=O)(CH2)m-; G is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R , R5, and R6, said aryl and heteroaryl in the definition of G are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle; or G is lower saturated alkyl or C3-C7 cycloalkyl; each R1 is separately selected from the group consisting of halogen, an optionally substituted lower saturated alkyl, an optionally substituted C1-C6 alkoxy, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, an optionally substituted Ci-C6 haloalkyl, an optionally substituted Ci-C6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; each R2 is separately selected from the group consisting of halogen, -0(CH2)m0RA, -(CH2)mORA, -NRBRC, -(CH2)mSRA, -C(=0)RH, -CCH2)mRH, an optionally substituted lower saturated alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted Ci-C6 haloalkyl, an optionally substituted Cj-C6 heteroalkyl, and an optionally substituted C3-7 cycloalkyl where said C3-7 cycloalkyl is further optionally fused with aryl or heteroaryl; each R3 is separately selected from the group consisting of halogen, -(CH2)mORD, -NRHC(=0)RD, -NRERF, -(CH2)mS(O)0-2RD, -<CH2)raNO2, -{CH2)mCN, -(CH2)mRG, an optionally substituted lower saturated alkyl, an optionally substituted Cj-C6 alkoxy, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, an optionally substituted Ci-C6 haloalkyl, an optionally substituted Ci-C6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; each R4 is separately selected from the group consisting of halogen, an optionally substituted lower saturated alkyl, an optionally substituted Cj-C6 alkoxy, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted Cj-C6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; each R5 is separately selected from the group consisting of halogen, -O(CH2)mORA, -(CH2)mORA, -NRBRC, -(CH2)mSRA, -C(=O)RH, -(CH2)mRH, an optionally substituted lower saturated alkyl, an optionally substituted C1-C6 alkoxy, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, an optionally substituted Cj-C6 haloalkyl, and an optionally substituted Cj-C6 heteroalkyl; each R6 is separately selected from the group consisting of halogen, -(CH2)mORD, -NRHC(=0)RD, -NRERF, -(CH2)mS(O)0-2RD, -(CH2)mNO2, -<CH2)mCN, -(CH2)mRG, an optionally substituted lower saturated alkyl, an optionally substituted C1-C6 alkoxy, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, an optionally substituted Cj-C6 haloalkyl, an optionally substituted Cj-C6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; each R is separately selected from the group consisting of hydrogen, C3-C7 cycloalkyl, and lower saturated alkyl; each R is separately selected from the group consisting of hydrogen, an optionally substituted C3-C7 cycloalkyl, and an optionally substituted lower saturated alkyl;
RA is selected from the group consisting of hydrogen, -SO2RH, -C(=O)RH, -C(=O)NR R , lower saturated alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, Cj-C6 haloalkyl, Cj-C6 heteroalkyl, and Cj-C6 heterohaloalkyl; each -NR R is separately selected, wherein R and R are each independently selected from the group consisting of hydrogen, -CCH2)mRH, -(CH2)mORH, -SO2RH, -C(=O)RH, -C(=O)NRERF, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, lower saturated alkyl, Cj-C6 haloalkyl, Cj-C6 heteroalkyl, and Cj-C6 heterohaloalkyl, where the lower saturated alkyl and the Cj-C6 heteroalkyl in the definition of RB and Rc are optionally substituted with an optionally substituted aryl or an optionally substituted heteroaryl, and where the optionally substituted C3-C7 cycloalkyl in the definition of R and R is further optionally fused with an optionally substituted aryl or an optionally substituted heteroaryl; or -NRBRC is a three - to eight- membered optionally substituted aliphatic cyclic aminyl, which optionally has one to three additional hetero atoms incorporated in the ring; or -NRBRC is an optionally substituted C1-C6 alkylideneaminyl; each RD is independently selected from the group consisting of hydrogen, an optionally substituted lower saturated alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, an optionally substituted Ci-C6 haloalkyl, an optionally substituted Cj-C6 heteroalkyl, and -(CH2)mRG; each -NRERF is separately selected, wherein RE and RF are each independently selected from the group consisting of hydrogen, an optionally substituted lower saturated alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, an optionally substituted Cj-C6 haloalkyl, an optionally substituted CrC6 heteroalkyl, -(CH2)mRG, and -(CH2)mORG; or -NRERF is an optionally substituted Cj-C6 alkylideneaminyl; or -NRERF is a three - to eight- membered optionally substituted aliphatic cyclic aminyl, which optionally has one to three additional hetero atoms incorporated in the ring; each RG is independently selected from an optionally substituted aryl and an optionally substituted heteroaryl; each RH is independently selected from the group consisting of hydrogen, -OH, Cj-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, an optionally substituted C3-C7 cycloalkyl, Ci-C3 haloalkyl, an optionally substituted aryl and an optionally substituted heteroaryl; each m is independently 0, 1, 2, or 3; each n is independently 0, 1, 2, or 3; each p is independently 0, 1, 2, 3, 4, 5, or 6; each q is independently 1, 2, 3, 4, 5, or 6; and each dashed line independently represents an optional double bond.
2. The compound of Claim 1, including the proviso that when L1 is carbonyl then A and G are each individually selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R1, R2, and R3, said aryl and heteroaryl in the definition of A and G are each individually further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle; and including the proviso that when A is lower saturated alkyl or C3-C7 cycloalkyl and G is lower saturated alkyl or C3-C7 cycloalkyl then L comprises an aryl or heteroaryl.
3. The compound of any of Claims 1 to 2, having the Formula Ia
Figure imgf000167_0001
and pharmaceutically acceptable salts, esters, or prodrugs thereof; wherein:
L is selected from the group consisting of Cj-C5 lower saturated alkyl-L1, Ci-C5 lower saturated alkyl-lΛCi-C5 alkyl, C1-C5 lower saturated alkylNR9(CH2)m-lΛ C1-C5 lower saturated alkylNR9C(=O)-lΛ -(CH2)mC(=O)NR9(CH2)q-L1, -(CH2)mC-lΛθ(CH2)q- -(CH2)m-L1-(CH2)q-, -(CH=CH)1n-L1^CH=CHH LJ-L2, iΛO-L2, L'-(CH=CH)-L2, L1^CH2)C-L2, L!-O(CH2)PO-L2, and L!-C(=O)NR9-L2; or L is L!-O-L3; each R1 is separately selected from the group consisting of halogen, lower saturated alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, Ci-C6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; each R2 is separately selected from the group consisting of halogen, -O(CH2)mORA, -(CH2)mORA, -NRBRC, -(CH2)mSRA, -C(=O)RH, -(CH2)mRH, and an optionally substituted C3-7 cycloalkyl where said C3-7 cycloalkyl is further optionally fused with aryl or heteroaryl; each R3 is separately selected from the group consisting of halogen, -(CH2)mORD, -(CH2)mNRERF, -O(CH2)mNRERF, -(CH2)mS(O)0-2RD, -(CHz)1nNO2, -(CH2)mCN, and -(CH2)mRG; each R4 is separately selected from the group consisting of halogen, lower saturated alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, Cj-C6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; each R5 is separately selected from the group consisting of halogen, -O(CH2)mORA, -(CH2)mORA, -NRBRC, -(CH2)mSRA, -C(=O)RH, and -(CH2)mRH; each R6 is separately selected from the group consisting of halogen, -(CH2)mORD, -(CH2)mNRERF, -O(CH2)mNRERF, -(CH2)mS(0)o-2RD, -(CH2)mNO2, -(CH2)mCN, and -(CH2)mR ; each R9 is separately selected from the group consisting of hydrogen and an optionally substituted lower saturated alkyl;
RA is selected from the group consisting of hydrogen, -SO2RH, -C(=O)RH, -C(=0)NRERF, lower saturated alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, and Ci-C6 heteroalkyl; each -NR R is separately selected, wherein R and R are each independently selected from the group consisting of hydrogen, -(CH2)mRH, -(CH2)mORH, -SO2RH, -C(=0)RH, -C(=0)NRERF, lower saturated alkyl, and C1-C6 haloalkyl; or -NRBRC is a three - to eight- membered optionally substituted aliphatic cyclic aminyl, which optionally has one to three additional hetero atoms incorporated in the ring; each RD is independently selected from the group consisting of hydrogen, lower saturated alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C]-C6 haloalkyl, Cj-C6 heteroalkyl, and
-(CH2)mRc each -NR R is separately selected, wherein R and R are each independently selected from the group consisting of hydrogen, lower saturated alkyl, -(CH2)mRG, and -(CH2)mORG; or -NRERF is a three - to eight- membered optionally substituted aliphatic cyclic aminyl, which optionally has one to three additional hetero atoms incorporated in the ring; each R is independently selected from aryl and heteroaryl; each RH is independently selected from the group consisting of hydrogen, -OH, Ci-C3 alkyl, C2-C4 alkenyl, C3-C7 cycloalkyl, Ci-C3 haloalkyl, an optionally substituted aryl and an optionally substituted heteroaryl; each m is independently 0, 1, 2, or 3; each n is independently 0, 1, 2, or 3; each p is independently 0, 1, 2, 3, 4, 5, or 6; and each dashed line independently represents an optional double bond.
4. The compound of any of Claims 1 to 3, having the Formula Ib:
Figure imgf000169_0001
and pharmaceutically acceptable salts, esters, or prodrugs thereof.
5. The compound of any of Claims 1 to 4, having the Formula Ic:
Figure imgf000169_0002
and pharmaceutically acceptable salts, esters, or prodrugs thereof.
6. The compound of any of Claims 1 to 4, having the Formula Id:
Figure imgf000169_0003
and pharmaceutically acceptable salts, esters, or prodrugs thereof.
7. The compound of any of Claims 1 to 4, having the Formula Ie: R7 R9 R9 R7
O O (Ie) and pharmaceutically acceptable salts, esters, or prodrugs thereof.
8. The compound of any of Claims 1 to 7, having the Formula If:
Figure imgf000170_0001
and pharmaceutically acceptable salts, esters, or prodrugs thereof.
9. The compound of any of Claims 1 to 6, wherein:
A is selected from the group consisting of aryl and heteroaryl, each substituted with one or more substituents selected from the group consisting of R1, R2, and R3, said aryl and heteroaryl in the definition of A are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle; or A is lower saturated alkyl or C3-C7 cycloalkyl;
R1 is selected from the group consisting of fluorine, chlorine, and methyl;
R2 is selected from the group consisting of-(CH2)mORA, - NRBRC, and -(CH2)mSRA;
R3 is selected from the group consisting of-(CH2)mRG, -(CH2)mORD, and -(CH2)mNRERF;
RA is selected from the group consisting of hydrogen, -SO2RH, -C(=0)RH, -C(=0)NRERF, lower saturated alkyl, Ci-C6 haloalkyl, and Cj-C6 heteroalkyl; each -NRBRC is separately selected, wherein RB and Rc are each independently selected from the group consisting of hydrogen, -SO2RH, -C(=O)RH, -C(=O)NRERF, lower saturated alkyl, and Ci-C6 haloalkyl; or -NR R is a three - to eight- membered optionally substituted aliphatic cyclic aminyl, which optionally has one to two additional hetero atoms incorporated in the ring; each RD is independently selected from the group consisting of hydrogen, lower saturated alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, and -(CH2)mRG; each m is independently 0, 1, or 2; each n is independently 0, 1, or 2; and each q is independently 1, 2, or 3.
10. The compound of Claim 9, including the proviso that when A and G are a phenyl then at least one of R2, R3, R5, and R6 is selected from the group consisting of -(CH2)mORA, -(CH2)mORD, -NRBRC, -NRERF, and an optionally substituted phenyl.
11. The compound of Claim 1 , wherein A and G are each independently selected from the group consisting of lower saturated alkyl and C3-C7 cycloalkyl.
12. The compound of Claim 11, wherein A and G are each independently selected from the group consisting of iso-butyl and cyclohexyl.
13. The compound of Claim 1, wherein A and G are each independently selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R1, R2, and R3, said aryl and heteroaryl in the definition of A and G are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle.
14. The compound of any of Claims 1 to 13, wherein L is selected from the group
Figure imgf000171_0001
Figure imgf000172_0001
wherein each phenyl, naphthyl, and pyridinyl in the definition of L is optionally substituted.
15. The compound of any of Claims 1 to 13, wherein L is selected from the group
Figure imgf000172_0002
Figure imgf000173_0001
Figure imgf000173_0002
Figure imgf000173_0003
wherein each phenyl, naphthyl, pyridinyl, indolyl, and piperidinyl in the definition of L is optionally substituted.
16. The compound of any of Claims 1 to 9, wherein A and G are each independently selected from the group consisting of phenyl, naphthyl, pyridinyl, pyrrolyl, pyrimidinyl, imidazolyl, isoxazolyl, thiazolyl, thienyl, furyl, indolyl, benzoxazolyl, benzthiazolyl, benzimidazolyl, 1 ,4-benzodioxan-6-yl, 1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl, benzothienyl, quinolinyl, and purinyl, said phenyl, naphthyl, pyridinyl, pyrrolyl, pyrimidinyl, imidazolyl, isoxazolyl, thiazolyl, thienyl, furyl, indolyl, benzoxazolyl, benzthiazolyl, benzimidazolyl, l,4-benzodioxan-6-yl, 1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl, benzothienyl, quinolinyl, and purinyl, each optionally substituted with one or more substituents selected from the group consisting of R1, R2, and R3, and said said phenyl, naphthyl, pyridinyl, pyrrolyl, pyrimidinyl, imidazolyl, isoxazolyl, thiazolyl, thienyl, furyl, indolyl, benzoxazolyl, benzthiazolyl, benzimidazolyl, 1 ,4-benzodioxan-6-yl, 1,3-benzodioxolyl, 2,3- dihydrobenzofuranyl, benzothienyl, quinolinyl, and purinyl are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle.
17. The compound of Claim 16, wherein L is selected from the group consisting of
Figure imgf000173_0004
Figure imgf000174_0001
wherein each phenyl, naphthyl, and pyridinyl in the definition of L is optionally substituted.
18. The compound of Claim 16, wherein L is selected from the group consisting of
Figure imgf000174_0002
Figure imgf000175_0001
wherein each phenyl, naphthyl, pyridinyl, indolyl, and piperidinyl in the definition of L is optionally substituted.
19. The compound of any of Claims 1 to 8, wherein:
L is selected from the group consisting of -(CH2)-O-L1-O-(CH2)-, -(CH2)-L1-(CH2)-, -(CH2)2-lΛ(CH2)2- I,'-!,2, ^-(CH^-L2, and iΛO-L2;
L1 is selected from the group consisting of phenyl, pyridinyl, and piperidinyl, each optionally substituted with F, Cl, Br, Ci-C3 lower saturated alkyl, Cj-C3 alkoxy, and -(CH2)N(CH3)2;
L is selected from the group consisting of phenyl and pyridinyl, each optionally substituted with F, Cl, Br, Cj-C3 lower saturated alkyl, C]-C3 alkoxy, and -(CH2)N(CH3),;
A is phenyl, optionally substituted with one or more substituents selected from the group consisting of R1, R2, and R3, said phenyl in the definition of A are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle;
G is phenyl, optionally substituted with one or more substituents selected from the group consisting of R4, R5, and R6, said phenyl in the definition of G are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle; each R1 is separately selected from the group consisting of an optionally substituted aryl and an optionally substituted heteroaryl; each R2 is separately selected from the group consisting of halogen, -(CH2)mOR , and -NRBRC, where RA in the definition of is R2 selected from the group consisting of hydrogen, and lower saturated alkyl; each R3 is fluoro; each NRBRC is separately selected, wherein RB and R are each independently selected from the group consisting of hydrogen and lower saturated alkyl; or NR R is a three - to six- membered optionally substituted aliphatic cyclic aminyl, which optionally has one additional hetero atom incorporated in the ring; each R4 is separately selected selected from the group consisting of chloro, fluoro, and an optionally substituted lower saturated alkyl; each R5 is separately selected from the group consisting of -OCH2CH2ORA, -(CH2)mORA, and -NRBRC, where RA in the definition of is R5 selected from the group consisting of hydrogen, and lower saturated alkyl; and each R6 is separately selected from the group consisting an optionally substituted aryl and an optionally substituted heteroaryl.
20. The compound of Claim 1 selected from the group consisting of:
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
21. A compound of Formula II :
Figure imgf000194_0002
and pharmaceutically acceptable salts, esters, or prodrugs thereof; wherein:
A4 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R11, R12, and R13, said aryl and heteroaryl in the definition of A4 are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle;
G4 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R , R , and R16, said aryl and heteroaryl in the definition of G4 are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle;
L4 is selected from the group consisting of an optionally substituted C2-Ci0 alkenyl, an optionally substituted C2-C10 alkynyl, an optionally substituted aryl, and an optionally substituted heteroaryl; each R11 is separately selected from the group consisting of an optionally substituted Cj-C6 alkoxy, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, an optionally substituted Cj-C6 haloalkyl, an optionally substituted Cj-C6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; each R12 is separately selected from the group consisting of -O(CH2)mORA, -(CH2)mORA, -NRBRC, -(CH2)mSRA, -C(=0)RH, -(CH2)mRH, and an optionally substituted C3-7 cycloalkyl where said C3-7 cycloalkyl is further optionally fused with aryl or heteroaryl; each R 3 is separately selected from the group consisting of -(CH2)mORD, -NRHC(=0)RD, -NRERF, -(CH2)mS(O)0-2RD, -(CH2)mNO2, -(CH2)mCN, and -CCH2)mRG; each R 4 is separately selected from the group consisting of an optionally substituted Cj-C6 alkoxy, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, an optionally substituted Cj-C6 haloalkyl, an optionally substituted Cj-C6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; each R15 is separately selected from the group consisting of -O(CH2)mORΛ, -(CH2)mORA, -NRBRC, -(CH2)mSRA, -C(=O)RH, -(CH2)mRH, and an optionally substituted C3-7 cycloalkyl where said C3-7 cycloalkyl is further optionally fused with aryl or heteroaryl; each R16 is separately selected from the group consisting of -(CH2)mORD, -NRHC(=0)RD, -NRERF, -(CH2)mS(O)0-2RD, -<CH2)mNO2, -(CH2)mCN, and -(CH2)mRG; each R 7 is separately selected from the group consisting of hydrogen, C3-C7 cycloalkyl, and lower saturated alkyl; each R is separately selected from the group consisting of hydrogen, an optionally substituted C3-C7 cycloalkyl, and an optionally substituted lower saturated alkyl;
RA is selected from the group consisting of hydrogen, -SO2RH, -C(=O)RH, -C(=O)NR R , lower saturated alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, Ci-C6 haloalkyl, CpC6 heteroalkyl, and Cj-C6 heterohaloalkyl; each -NRBRC is separately selected, wherein RB and Rc are each independently selected from the group consisting of hydrogen, -(CH2)mRH, -(CH2)mORH, -SO2R", -C(=0)RH, -C(=0)NRERF, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, lower saturated alkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, and C]-C6 heterohaloalkyl, where the lower saturated alkyl and the Ci-C6 heteroalkyl in the definition of R and R are optionally substituted with an optionally substituted aryl or an optionally substituted heteroaryl, and where the optionally substituted C3-C7 cycloalkyl in the definition of RB and Rc is further optionally fused with an optionally substituted aryl or an optionally substituted heteroaryl; or -NRBRC is a three - to eight- membered optionally substituted aliphatic cyclic aminyl, which optionally has one to three additional hetero atoms incorporated in the ring; each RD is independently selected from the group consisting of hydrogen, an optionally substituted lower saturated alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, an optionally substituted Cj-C6 haloalkyl, an optionally substituted CpC6 heteroalkyl, and -(CH2)mRG; each -NRERF is separately selected, wherein RE and RF are each independently selected from the group consisting of hydrogen, an optionally substituted lower saturated alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, an optionally substituted Ci-C6 haloalkyl, an optionally substituted Ci -C6 heteroalkyl, -(CH2)mRG, and -(CH2)mORG; or -NRERF is a three - to eight- membered optionally substituted aliphatic cyclic aminyl, which optionally has one to three additional hetero atoms incorporated in the ring; each R is independently selected from an optionally substituted aryl and an optionally substituted heteroaryl; each R is independently selected from the group consisting of-OH, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl and an optionally substituted heteroaryl; each m is independently 0, 1, or 2; each n is independently 0, 1, 2, or 3; and each dashed line independently represents an optional double bond, including the proviso that the compound of Formula II is not selected from the
group consisting of
Figure imgf000197_0001
Figure imgf000197_0002
22. The compound of Claim 21 including the proviso that when L4 is phenyl then at least one of A4 and G4 is selected from the group consisting of aryl and heteroaryl, said A4 substituted with one or more substituents selected from the group consisting of R11, R12, and R13 and said G4 substituted with one or more substituents selected from the group consisting of R14, R15, and R16.
23. The compound of Claim 21 , wherein:
A4 is selected from the group consisting of phenyl, naphthyl, and indolyl, each optionally substituted with one or more substituents selected from the group consisting of R11, R12, and R13, said phenyl, naphthyl, and indolyl in the definition of A4 are each further optionally fused with a nonaromatic heterocycle or carbocycle.
24. The compound of Claim 23, wherein: each R11 is separately selected from the group consisting of CpC3 alkoxy, and C2-C4 alkenyl; each R12 is separately selected from the group consisting of -0(CH2)m0RA, -(CH2)mORA, and -NRBRc; each R13 is separately selected from the group consisting of -(CH2)mORD, and -NRERF; each R14 is separately selected from the group consisting of Cj-C3 alkoxy, and C2-C4 alkenyl; each R15 is separately selected from the group consisting of -O(CH2)mORA, -(CH2)mORA, and -NRBRC; each R16 is separately selected from the group consisting of -(CH2)mORD, and -NRERF; each R17 is separately selected from the group consisting of hydrogen, C3-C6 cycloalkyl, and Ci-C3 alkyl; each R1 is separately selected from the group consisting of hydrogen, an optionally substituted C3-C6 cycloalkyl, and an optionally substituted C]-C3 lower saturated alkyl.
25. The compound of any of Claims 21 to 22 having the Formula Ha:
Figure imgf000198_0001
and pharmaceutically acceptable salts, esters, or prodrugs thereof; wherein: A4 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R , R12, and R13, said aryl and heteroaryl in the definition of A4 are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle;
G4 is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R14, R15, and R16, said aryl and heteroaryl in the definition of G4 are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle;
L4 is selected from the group consisting of an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted aryl, and an optionally substituted heteroaryl; each R11 is separately selected from the group consisting of an optionally substituted Cj-C3 alkoxy, an optionally substituted C2-C4 alkenyl, an optionally substituted aryl, and an optionally substituted heteroaryl; each R12 is separately selected from the group consisting of -0(CH2)m0RA, -(CH2)mORA, -NRBRC, -C(=O)RH, and an optionally substituted C3-7 cycloalkyl where said C3-7 cycloalkyl is further optionally fused with aryl or heteroaryl; each R13 is separately selected from the group consisting of -(CH2)mORD, -NRHC(=0)RD, and -NRERF; each R14 is separately selected from the group consisting of an optionally substituted C1-C3 alkoxy, an optionally substituted C2-C4 alkenyl, an optionally substituted aryl, and an optionally substituted heteroaryl; each R15 is separately selected from the group consisting of -O(CH2)mORA, -(CH2)mORA, -NRBRC, -C(=O)RH, and an optionally substituted C3-7 cycloalkyl where said C3-7 cycloalkyl is further optionally fused with aryl or heteroaryl; each R16 is separately selected from the group consisting of -(CH2)mORD, -NRHC(=0)RD, and -NRERF;
RA is selected from the group consisting of hydrogen, C1-C3 lower saturated alkyl, C2-C4 alkenyl, and C3-C6 cycloalkyl; each -NRBRC is separately selected, wherein RB and Rc are each independently selected from the group consisting of hydrogen, -(CH2)mRH, -(CH2)mORH, -SO2RH, -C(=O)RH, -C(=O)NRERF, C3-C7 c ycloalkyl, lower saturated alkyl, Cj-C6 haloalkyl, where the lower saturated alkyl in the definition of R and R are optionally substituted with an optionally substituted aryl or an optionally substituted heteroaryl, and where the optionally substituted C3-C7 cycloalkyl in the definition of R and R is further optionally fused with an optionally substituted aryl or an optionally substituted heteroaryl; or -NRBRC is a four - to seven- membered optionally substituted aliphatic cyclic aminyl, which optionally has one to two additional hetero atoms incorporated in the ring; each RD is independently selected from the group consisting of hydrogen, an lower saturated alkyl, C3-C7 cycloalkyl, Ci-C6 haloalkyl, and -(CH2)mR ; each -NRERF is separately selected, wherein RE and RF are each independently selected from the group consisting of hydrogen, lower saturated alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, -(CH2)mRG, and -(CH2)mORG; or -NRERF is a four - to seven- membered optionally substituted aliphatic cyclic aminyl, which optionally has one to two additional hetero atoms incorporated in the ring; each RG is independently selected from an optionally substituted aryl and an optionally substituted heteroaryl; each R is independently selected from the group consisting of-OH, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl and an optionally substituted heteroaryl; each m is independently 0, 1, or 2; and each dashed line independently represents an optional double bond.
26. The compound of Claim 25, wherein:
A4 is selected from the group consisting of aryl and heteroaryl, each substituted with one or more substituents selected from the group consisting of Rπ, R12, and R13, said aryl and heteroaryl in the definition of A4 are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle; each R11 is independently selected from the group consisting of -OCH3, and -CH=CH2; each R12 is independently selected from the group consisting of -CH2CH2OR , and -NRBRC; each R13 is independently selected from the group consisting of -CH2CH2CH2OR0 and -(CH2)mRG; each RA is separately selected from the group consisting of hydrogen, C] -C3 lower saturated alkyl, and Ci-C3 haloalkyl; each -NRBRC is separately selected, wherein RB and Rc are each separately selected from the group consisting of hydrogen, -(CH2)mNRERF, Ci-C3 alkyl, C3-C6 cycloalkyl, and Ci-C6 haloalkyl; or -NRBRC is a three - to six- membered optionally substituted aliphatic cyclic aminyl, which optionally has one to two additional hetero atoms incorporated in the ring; each RD is separately selected from the group consisting of hydrogen, Cj-C3 lower saturated alkyl, Ci-C3 haloalkyl, and -(CH2)mR ; and each -NRERF is separately selected, wherein RE and RF are each independently selected from the group consisting of hydrogen, Cj-C3 lower saturated alkyl, Cj-C3 haloalkyl, and -(CH2)raRG; or -NRERF is a three - to six- membered optionally substituted aliphatic cyclic aminyl, which optionally has one to two additional hetero atoms incorporated in the ring.
27. The compound of any of Claims 21 to 26, wherein L4 is selected from the group consisting of phenyl and butadienyl.
28. The compound of Claim 21 , selected from the group consisting of:
Figure imgf000202_0001
29. A compound of Formula III:
Figure imgf000202_0002
and pharmaceutically acceptable salts, esters, or prodrugs thereof; wherein:
R1 is selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted Ci-C6 alkyl, a substituted or unsubstituted Ci-C6 haloalkyl, a substituted or unsubstituted Cj-C6 heteroalkyl, and null;
R2 is selected from the group consisting of hydrogen, halogen, -0RA, -NRΛRB, -SRA, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 haloalkyl, and a substituted or unsubstituted Ci-C6 heteroalkyl;
R3 is selected from the group consisting of hydrogen, halogen, -ORC, -NRCRD, -S(O)0-2R0, -NO2, -CN, -<CH2)mRE, a substituted or unsubstituted Ci-C6 alkyl, a substituted or unsubstituted CpC6 haloalkyl, a substituted or unsubstituted Ci-C6 heteroalkyl, and null; R4 is selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted Ci-C6 alkyl, a substituted or unsubstituted Ci-C6 haloalkyl, a substituted or unsubstituted Ci-C6 heteroalkyl, and null;
R5 is selected from the group consisting of hydrogen, halogen, -ORA, -NRARB, -SRA, a substituted or unsubstituted C]-C6 alkyl, a substituted or unsubstituted Cj-C6 haloalkyl, and a substituted or unsubstituted Ci-C6 heteroalkyl;
R is selected from the group consisting of hydrogen, halogen, -OR , -NR R , -S(O)0-2Rc, -NO2, -CN, -(CH2)mRE, a substituted or unsubstituted C-C6 alkyl, a substituted or unsubstituted C1-C6 haloalkyl, a substituted or unsubstituted Ci-C6 heteroalkyl, and null;
RA is selected from the group consisting of hydrogen, Ci-C6 alkyl, Cj-C6 haloalkyl, Ci-C6 heteroalkyl, and Ci-C6 heterohaloalkyl;
RB is selected from hydrogen, -SO2RF, -C(=0)RF, -C(=O)NRCRD, Ci-C6 alkyl, Cj-C6 haloalkyl, Ci-C6 heteroalkyl, and C]-C6 heterohaloalkyl; or RA and RB are linked to form a substituted or unsubstituted C3-C8 ring;
Rc and RD are each independently selected from the group consisting of hydrogen, a substituted or unsubstituted Cj-C6 alkyl, a substituted or unsubstituted Ci-C6 haloalkyl, a substituted or unsubstituted C]-C6 heteroalkyl, and -(CH2)mR ; or one of R and RD is a substituted or unsubstituted C2-C6 alkyl and the other of R and R is null; or Rc and RD are linked to form a substituted or unsubstituted C3-C8 ring;
RE is selected from a substituted or unsubstituted aryl and a substituted or unsubstituted heteroaryl;
RF is selected from the group consisting of hydrogen, Ci-C3 alkyl, C]-C3 haloalkyl, and a substituted or unsubstituted aryl or heteroaryl;
A is selected from the group consisting of a Ci-C6 alkyl, a Ci-C6 heteroalkyl, a monocyclic or bicyclic aromatic ring optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle;
G is selected from the group consisting of a Ci-C6 alkyl, a Ci-C6 heteroalkyl, a monocyclic or bicyclic aromatic ring optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; D is a 1-6 atom spacer containing at least 2 heteroatoms separated by 3 or 4 bonds and comprising one or more groups selected from a substituted or unsubstituted Ci-C6 heteroalkyl, a substituted or unsubstituted heterocycle, and a substituted or unsubstituted heteroalkylheterocycle;
E is a 1-6 atom spacer containing at least 2 heteroatoms separated by 3 or 4 bonds and comprising one or more groups selected from a substituted or unsubstituted Ci-C6 heteroalkyl, a substituted or unsubstituted heterocycle, and a substituted or unsubstituted heteroalkylheterocycle;
L is a 2-12 atom long linker comprising one or more groups selected from -O- (oxygen), -NRB, -S(O)0-2, -NR8S(O) ,.2NRA, -NRBS(O)i-2O- a substituted or unsubstituted Ci-Ci0 alkyl, a substituted or unsubstituted Ci-Ci0 haloalkyl, a substituted or unsubstituted Ci-C8 heteroalkyl, a substituted or unsubstituted aryl, and a substituted or unsubstituted heteroaryl; where the aryl and heteroaryl are optionally fused with a nonaromatic heterocycle or a nonaromatic carbocycle; and m is O, 1, or 2.
30. The compound of Claim 29, having the Formula IHa:
Figure imgf000204_0001
wherein:
A is selected from the group consisting of aryl and heteroaryl, said aryl and heteroaryl in the definition of A are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle; or A is Ci-C6 alkyl;
G is selected from the group consisting of aryl and heteroaryl, said aryl and heteroaryl in the definition of G are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle; or G is Ci-C6 alkyl;
L is selected from the group consisting of Ci-C5 alkyl-L1, Ci-C5 alkyl-lΛd-Cs alkyl, Cj-C5 alkylNR9(CH2)in-L1, Ci-C5 alkylNR9C(=O)-L1, -(CH2)mC(=O)NR9(CH2)q-lΛ -(CH2)mO-L1-O(CH2)q-, -(CH2)m-L1-(CH2)q- -(CH=CH)m-L1-(CH=CH)-, V-L2, I^-O-L2, L1^CH=CH)-L2, L1-CCH2)q-L2, L^O(CH2)PO-L2, L1-C(=O)NR9-L2; or L is L*-O-L3;
L1 is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted heterocycle;
L2 is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted heterocycle;
L3 is selected from the group consisting of Ci-C6 alkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
R1 is selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted Cj-C6 haloalkyl, and null;
R2 is selected from the group consisting of hydrogen, halogen, -0RA, -NRARB, -SRA, a substituted or unsubstituted Ci-C6 alkyl, and a substituted or unsubstituted Ci-C6 haloalkyl;
R3 is selected from the group consisting of hydrogen, halogen, -ORC, -NRCRD, -S(0)o-2Rc, -NO2, -CN, -(CH2)mRE, a substituted or unsubstituted C,-C6 alkyl, a substituted or unsubstituted Ci-C6 haloalkyl, and null;
R4 is selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted Cj-C6 alkyl, a substituted or unsubstituted Ci-C6 haloalkyl, and null;
R5 is selected from the group consisting of hydrogen, halogen, -0RA, -NRARB, -SRA, a substituted or unsubstituted Cj-C6 alkyl, and a substituted or unsubstituted Ci-C6 haloalkyl;
R6 is selected from the group consisting of hydrogen, halogen, -ORC, -NRCRD, -S(O)0-2R0, -NO2, -CN, -(CH2)mRE, a substituted or unsubstituted CrC6 alkyl, a substituted or unsubstituted Cj-C6 haloalkyl, and null; each R9 is separately selected from the group consisting of hydrogen, an optionally substituted C3-C6 cycloalkyl, and an optionally substituted Cj-C3 lower saturated alkyl;
RA is selected from the group consisting of hydrogen, Cj-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, and Ci-C6 heterohaloalkyl; RB is selected from hydrogen, -SO2RF, -C(=O)RF, -C(=O)NRCRD, Ci-C6 alkyl, Ci-C6 haloalkyl, Cj-C6 heteroalkyl, and Ci-C6 heterohaloalkyl;
Rc and RD are each independently selected from the group consisting of hydrogen, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted Ci-C6 haloalkyl, a substituted or unsubstituted C1-C6 heteroalkyl, and -(CH2)mRE;
RE is selected from a substituted or unsubstituted aryl and a substituted or unsubstituted heteroaryl;
RF is selected from the group consisting of hydrogen, Cj-C3 alkyl, Cj-C3 haloalkyl, and a substituted or unsubstituted aryl or heteroaryl;
X is NH;
Y is NH; each m is independently 0, 1, or 2; each p is independently 0, 1, 2, 3, 4, 5, or 6; each q is independently 1, 2, 3, 4, 5, or 6; and each dashed line independently represents an optional double bond.
31. The compound of any of Claims 29 to 30, wherein L is selected from the group
consisting of
Figure imgf000206_0001
Figure imgf000206_0002
, and , wherein each phenyl in the definition of L is optionally substituted.
32. The compound of any of Claims 29 to 31, wherein A and G are each independently selected from the group consisting of phenyl and wo-propyl.
33. The compound of claim 29, wherein the compound is
Figure imgf000207_0001
, a pharmaceutically acceptable salt thereof, ester thereof, or prodrug thereof.
34. The compound of claim 29, wherein the compound is
Figure imgf000207_0002
, a pharmaceutically acceptable salt thereof, ester thereof, or prodrug thereof.
35. The compound of claim 29, wherein the compound is
Figure imgf000207_0003
, a pharmaceutically acceptable salt thereof, ester thereof, or prodrug thereof.
36. The compound of claim 29, wherein the compound is
Figure imgf000207_0004
, a pharmaceutically acceptable salt thereof, ester thereof, or prodrug thereof.
37. The compound of claim 29, wherein the compound is
Figure imgf000207_0005
, a pharmaceutically acceptable salt thereof, ester thereof, or prodrug thereof.
38. The compound of claim 29, wherein the compound is
Figure imgf000208_0001
5 a pharmaceutically acceptable salt thereof, ester thereof, or prodrug thereof.
39. The compound of claim 29, wherein the compound is
Figure imgf000208_0002
, a pharmaceutically acceptable salt thereof, ester thereof, or prodrug thereof.
40. The compound of claim 29, wherein the compound is
Figure imgf000208_0003
; a pharmaceutically acceptable salt thereof, ester thereof, or prodrug thereof.
41. The compound of claim 29, wherein the compound is
Figure imgf000208_0004
, a pharmaceutically acceptable salt thereof, ester thereof, or prodrug thereof.
42. The compound of claim 29, wherein the compound is
Figure imgf000208_0005
5 a pharmaceutically acceptable salt thereof, ester thereof, or prodrug thereof.
43. The compound of claim 29, wherein the compound is
Figure imgf000209_0001
, a pharmaceutically acceptable salt thereof, ester thereof, or prodrug thereof.
44. The compound of claim 29, wherein the compound is
Figure imgf000209_0002
, a pharmaceutically acceptable salt thereof, ester thereof, or prodrug thereof.
45. The compound of claim 29, wherein the compound is
Figure imgf000209_0003
, a pharmaceutically acceptable salt thereof, ester thereof, or prodrug thereof.
46. The compound of claim 29, wherein the compound is
Figure imgf000209_0004
, a pharmaceutically acceptable salt thereof, ester thereof, or prodrug thereof.
47. The compound of claim 29, wherein the compound is
Figure imgf000209_0005
, a pharmaceutically acceptable salt thereof, ester thereof, or prodrug thereof.
48. The compound of claim 29, wherein the compound is
Figure imgf000210_0001
, a pharmaceutically acceptable salt thereof, ester thereof, or prodrug thereof.
49. The compound of claim 29, wherein the compound is
Figure imgf000210_0002
, a pharmaceutically acceptable salt thereof, ester thereof, or prodrug thereof.
50. The compound of claim 29, wherein the compound is
Figure imgf000210_0003
, a pharmaceutically acceptable salt thereof, ester thereof, or prodrug thereof.
51. The compound of claim 29, wherein the compound is
Figure imgf000210_0004
a pharmaceutically acceptable salt thereof, ester thereof, or prodrug thereof.
52. The compound of claim 29, wherein the compound is
Figure imgf000210_0005
, a pharmaceutically acceptable salt thereof, ester thereof, or prodrug thereof.
53. The compound of claim 29, wherein the compound is
Figure imgf000211_0001
, a pharmaceutically acceptable salt thereof, ester thereof, or prodrug thereof.
54. The compound of claim 29, wherein the compound is
Figure imgf000211_0002
, a pharmaceutically acceptable salt thereof, ester thereof, or prodrug thereof.
55. The compound of claim 29, wherein the compound is
Figure imgf000211_0003
, a pharmaceutically acceptable salt thereof, ester thereof, or prodrug thereof.
56. The compound of claim 29, wherein the compound is
Figure imgf000211_0004
, a pharmaceutically acceptable salt thereof, ester thereof, or prodrug thereof.
57. The compound of claim 29, wherein the compound is
Figure imgf000211_0005
, a pharmaceutically acceptable salt thereof, ester thereof, or prodrug thereof.
Figure imgf000212_0001
salt thereof, ester thereof, or prodrug thereof.
59. The compound of claim 29, wherein the compound is
Figure imgf000212_0002
a pharmaceutically acceptable salt thereof, ester thereof, or prodrug thereof.
60. A compound with the following structure:
Figure imgf000212_0003
and pharmaceutically acceptable salts, esters, or prodrugs thereof; wherein: R11' is selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted Ci-C6 alkyl, a substituted or unsubstituted Ci-C6 haloalkyl, a substituted or unsubstituted Ci-C6 heteroalkyl, and null;
R » 12 is selected from the group consisting of hydrogen, halogen, -OR , -NR An RB , -SRΛ, a substituted or unsubstituted Cj-C6 alkyl, a substituted or unsubstituted Ci-C6 haloalkyl, and a substituted or unsubstituted Cj-C6 heteroalkyl;
R13 is selected from the group consisting of hydrogen, halogen, -ORC, -NRCRD, -S(O)0-2R0, -NO2, -CN, -<CH2)mRE, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted Ci-C6 haloalkyl, a substituted or unsubstituted Cj-C6 heteroalkyl, and null; R14' is selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted Ci-C6 alkyl, a substituted or unsubstituted Ci-C6 haloalkyl, a substituted or unsubstituted Ci-C6 heteroalkyl, and null;
R15' is selected from the group consisting of hydrogen, halogen, -ORA, -NRARB, -SRΛ, a substituted or unsubstituted Cj-C6 alkyl, a substituted or unsubstituted Ci-C6 haloalkyl, and a substituted or unsubstituted Cj-C6 heteroalkyl;
R16' is selected from the group consisting of hydrogen, halogen, -ORC, -NRCRD, -S(O)0-2Rc, -NO2, -CN, -(CH2)mRE, a substituted or unsubstituted Ci-C6 alkyl, a substituted or unsubstituted Ci-C6 haloalkyl, a substituted or unsubstituted Cj-C6 heteroalkyl, and null;
R17', R18', R19 , and R20 are independently selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted Cj-C4 alkyl, a substituted or unsubstituted Ci-C4 haloalkyl, and a substituted or unsubstituted Ci-C4 heteroalkyl; or R17 and R18 are linked to form a substituted or unsubstituted ring; or R19 and R are linked to form a substituted or unsubstituted ring; or R17' and R20' can be independently split into two groups when the carbon atoms they are attached become saturated;
RA is selected from the group consisting of hydrogen, Ci-C6 alkyl, C)-C6 haloalkyl, Ci-C6 heteroalkyl, and Ci-C6 heterohaloalkyl;
RB is selected from hydrogen, -SO2RF, -C(=O)RF, -C(=O)NRCRD, C,-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, and Cj-C6 heterohaloalkyl; or RA and RB are linked to form a substituted or unsubstituted C3-C8 ring;
R and R are each independently selected from the group consisting of hydrogen, a substituted or unsubstituted CpC6 alkyl, a substituted or unsubstituted Ci-C6 haloalkyl, a substituted or unsubstituted Cj-C6 heteroalkyl, and -(CH2)mRE; or one of Rc and RD is a substituted or unsubstituted C2-C6 alkyl and the other of Rc and RD is null; or R and R are linked to form a substituted or unsubstituted C3-C8 ring;
RE is selected from a substituted or unsubstituted aryl and a substituted or unsubstituted heteroaryl;
RF is selected from the group consisting of hydrogen, Ci-C3 alkyl, Ci-C3 haloalkyl, and a substituted or unsubstituted aryl or heteroaryl; A1' is selected from the group consisting of a Ci-C6 alkyl, a Ci-C6 heteroalkyl, and a monocyclic or bicyclic aromatic ring optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle;
G1 is selected from the group consisting of a Cj-C6 alkyl, a Ci-C6 heteroalkyl, and a monocyclic or bicyclic aromatic ring optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle;
L1 is a 2-12 atom long linker comprising one or more groups selected from -O- (oxygen), -NRB- -S(O)0-2-, -NR8S(O) i-2NRA- -NR8S(O) I-2O-, a substituted or unsubstituted Cj-Ci0 alkyl, a substituted or unsubstituted Ci-Ci0 haloalkyl, a substituted or unsubstituted Ci-C8 heteroalkyl, a substituted or unsubstituted aryl, and a substituted or unsubstituted heteroaryl; where the aryl and heteroaryl are optionally fused with a nonaromatic heterocycle or a nonaromatic carbocycle;
X is selected from the group consisting of NR18 and C(R18')2;
Y is selected from the group consisting of NR19 and C(R19>)2; m is O, 1, or 2; and each dashed line independently represents an optional double bond.
61. The compound of Claim 60, having the Formula IVa:
Figure imgf000214_0001
wherein:
A1 is selected from the group consisting of lower saturated alkyl, aryl and heteroaryl, said aryl and heteroaryl in the definition of A1 are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle;
G1 is selected from the group consisting of lower saturated alkyl, aryl and heteroaryl, said aryl and heteroaryl in the definition of G1 are each further optionally fused with a nonaromatic heterocycle or nonaromatic carbocycle;
L1 is selected from the group consisting of C]-C5 lower saturated alkyl-L1, Cj-C5 lower saturated alkyl-lΛd-Cs lower saturated alkyl, Ci-C5 lower saturated alkylNR9(CH2)m-L\ Ci-C5 lower saturated alkylNR9C(=O)-L\
-(CH2)mC(=O)NR9(CH2)q-LI, -(CH2)mO-L1-O(CH2)q- -(CH2)m-L1-(CH2)q-
-(CH=CH)1n-L1^CH=CH)-, V-L2, L'-O-L2, L1^CH=CH)-L2, L1^CH2VL2, L1O(CH2)PO-L2, and L1-C(=O)NR9-L2; or L is L^O-L3;
L1 is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted heterocycle;
L2 is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted heterocycle;
L3 is selected from the group consisting of lower saturated alkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; each R9 is separately selected from the group consisting of hydrogen, an optionally substituted C3-C6 cycloalkyl, and an optionally substituted Ci-C3 lower saturated alkyl;
R11' is selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted lower saturated alkyl, a substituted or unsubstituted Cj-C6 haloalkyl, and null;
R12 is selected from the group consisting of hydrogen, halogen, -0RA, -NRARB, -SRA, a substituted or unsubstituted lower saturated alkyl, and a substituted or unsubstituted Cj-C6 haloalkyl;
R13' is selected from the group consisting of hydrogen, halogen, -ORC, -NR0R0, -S(O)0-2R0, -NO2, -CN, -(CH2)mRE, a substituted or unsubstituted lower saturated alkyl, a substituted or unsubstituted Ci-C6 haloalkyl, and null;
R14 is selected from the group consisting of hydrogen, halogen, a substituted or unsubstituted lower saturated alkyl, a substituted or unsubstituted Ci-C6 haloalkyl, and null;
R15 is selected from the group consisting of hydrogen, halogen, -0RA, -NRARB, -SRA, a substituted or unsubstituted lower saturated alkyl, and a substituted or unsubstituted Cj-C6 haloalkyl; R ,16 is selected from the group consisting of hydrogen, halogen, -OR , -NR CRnD , -S(O)0-2Rc, -NO2, -CN, -(CH2)mRE, a substituted or unsubstituted lower saturated alkyl, a substituted or unsubstituted Cj-C6 haloalkyl, and null;
RA is selected from the group consisting of hydrogen, lower saturated alkyl, C]-C6 haloalkyl, C]-C6 heteroalkyl, and C]-C6 heterohaloalkyl;
RB is selected from hydrogen, -SO2RF, -C(=0)RF, -C(=O)NRCRD, lower saturated alkyl, C1-C6 haloalkyl, Ci-C6 heteroalkyl, and Ci-C6 heterohaloalkyl;
R and RD are each independently selected from the group consisting of hydrogen, a substituted or unsubstituted lower saturated alkyl, a substituted or unsubstituted Ci-C6 haloalkyl, a substituted or unsubstituted CpC6 heteroalkyl, and -(CH2)mRE;
RE is selected from a substituted or unsubstituted aryl and a substituted or unsubstituted heteroaryl;
RF is selected from the group consisting of hydrogen, Ci-C3 alkyl, C]-C3 haloalkyl, and a substituted or unsubstituted aryl or heteroaryl; each p is independently 0, 1, 2, 3, 4, 5, or 6; and each q is independently 1 , 2, 3, 4, 5, or 6.
62. The compound of any of Claims 60 to 61, wherein L1' is selected from the group
consisting of
Figure imgf000216_0001
Figure imgf000216_0002
Figure imgf000216_0003
wherein each phenyl in the definition of L1 is optionally substituted.
63. The compound of any of Claims 60 to 62, wherein A and G are each independently selected from the group consisting of phenyl and iso-propyl.
64. A compound of any of Claims 1 to 63 that is an HGF mimetic, an HGF receptor agonist or an HGF receptor antagonist.
65. A compound of any of Claims 1 to 63 that is a hematopoietic growth factor mimetic, a hematopoietic growth factor receptor agonist or a a hematopoietic growth factor receptor antagonist.
66. A compound of any of Claims 1 to 63 that is an EPO mimic.
67. A compound of any of Claims 1 to 63 that is a selective EPO receptor agonist.
68. A compound of any of Claims 1 to 63 to that is a selective EPO receptor partial agonist.
69. A compound of any of Claims 1 to 63 that is a selective EPO receptor antagonist.
70. A compound of any of Claims 1 to 63 that is a selective EPO receptor binding compound.
71. A method for modulating an EPO activity in a cell comprising contacting a cell with a compound of any of Claims 1 to 63.
72. A method for modulating an EPO activity in a cell comprising contacting a cell with a compound of Claim 29.
73. A method for identifying a compound that modulates an EPO activity, comprising contacting a cell that expresses an EPO receptor with a compound of any of Claims 1 to 63; and monitoring an effect of the compound on the cell.
74. A method of treating a patient, comprising administering to the patient a compound of any of Claims 1 to 63.
75. A method of treating a patient, comprising administering to the patient a compound of Claim 29.
76. The method of claim 74, wherein the patient suffers from an anemia, a neutropenia, a cardiovascular disorder, an immune/autoimmune disorder, an infectious disorder, and a neurologic disorder.
77. The method of claim 75, wherein the patient suffers from an anemia, a neutropenia, a cardiovascular disorder, an immune/autoimmune disorder, an infectious disorder, and a neurologic disorder.
78. The method of claim 74, wherein the disease or condition results from radiation or chemotherapy.
79. The method of claim 75, wherein the disease or condition results from radiation or chemotherapy.
80. The method of claim 78, further comprising harvesting cells from the patient.
81. The method of claim 79, further comprising harvesting cells from the patient.
82. The method of claim 78, wherein the treatment is prophylactic.
83. The method of claim 79, wherein the treatment is prophylactic.
84. The method of claim 78, wherein the patient suffers from a condition affecting the nervous system.
85. The method of claim 79, wherein the patient suffers from a condition affecting the nervous system.
86. The method of claim 84, wherein the patient suffers from a disease selected from amyotrophic lateral sclerosis, multiple sclerosis, and multiple dystrophy.
87. The method of claim 85, wherein the patient suffers from a disease selected from amyotrophic lateral sclerosis, multiple sclerosis, and multiple dystrophy.
88. The method of claim 84, wherein the patient suffers from injury to the nervous system.
89. The method of claim 85, wherein the patient suffers from injury to the nervous system.
90. The method of claim 84, wherein the patient suffers from injury to the spinal cord.
91. The method of claim 85, wherein the patient suffers from injury to the spinal cord.
92. A pharmaceutical composition comprising a physiologically acceptable carrier, diluent, or excipient; and a compound of any of Claims 1 to 70.
93. A pharmaceutical composition comprising a physiologically acceptable carrier, diluent, or excipient; and a compound of Claim 60.
94. The pharmaceutical composition of claim 92 for use in treating a condition selected from an anemia, a neutropenia, a cardiovascular disorder, an immune/autoimmune disorder, a cancer, an infectious disorder, and a neurologic disorder.
95. The pharmaceutical composition of claim 93 for use in treating a condition selected from an anemia, a neutropenia, a cardiovascular disorder, an immune/autoimmune disorder, a cancer, an infectious disorder, and a neurologic disorder.
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