WO2008002676A9 - Compositions de biaryle et procédés de modulation d'une cascade de kinases - Google Patents

Compositions de biaryle et procédés de modulation d'une cascade de kinases

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Publication number
WO2008002676A9
WO2008002676A9 PCT/US2007/015273 US2007015273W WO2008002676A9 WO 2008002676 A9 WO2008002676 A9 WO 2008002676A9 US 2007015273 W US2007015273 W US 2007015273W WO 2008002676 A9 WO2008002676 A9 WO 2008002676A9
Authority
WO
WIPO (PCT)
Prior art keywords
compound
alkyl
compounds
aryl
kinase
Prior art date
Application number
PCT/US2007/015273
Other languages
English (en)
Other versions
WO2008002676A2 (fr
WO2008002676A3 (fr
Inventor
David G Hangauer Jr
Original Assignee
Kinex Pharmaceuticals Llc
David G Hangauer Jr
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US11/480,174 external-priority patent/US7968574B2/en
Priority to EP07810102.9A priority Critical patent/EP2041071B1/fr
Priority to CA2656564A priority patent/CA2656564C/fr
Priority to CN200780031980XA priority patent/CN101595084B/zh
Priority to JP2009518322A priority patent/JP5564251B2/ja
Priority to ES07810102.9T priority patent/ES2500165T3/es
Application filed by Kinex Pharmaceuticals Llc, David G Hangauer Jr filed Critical Kinex Pharmaceuticals Llc
Priority to DK07810102.9T priority patent/DK2041071T3/da
Priority to AU2007265373A priority patent/AU2007265373B2/en
Priority to SI200731516T priority patent/SI2041071T1/sl
Publication of WO2008002676A2 publication Critical patent/WO2008002676A2/fr
Publication of WO2008002676A3 publication Critical patent/WO2008002676A3/fr
Publication of WO2008002676A9 publication Critical patent/WO2008002676A9/fr
Priority to IL196168A priority patent/IL196168A/en
Priority to IL242374A priority patent/IL242374A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—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
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—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
    • C07D213/56—Amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
    • C07C233/13—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/22—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—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
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/52—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—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
    • 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
    • C07D213/89—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 with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—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

Definitions

  • Signal transduction is any process by which a cell converts one kind of signal or stimulus into another.
  • Processes referred to as signal transduction often involve a sequence of biochemical reactions inside the cell, which are carried out by enzymes and linked through second messengers.
  • an increasing number of enzymes and other molecules become engaged in the events that proceed from the initial stimulus.
  • the chain of steps is referred to as a “signaling cascade” or a "second messenger pathway” and often results in a small stimulus eliciting a large response.
  • One class of molecules involved in signal transduction is the kinase family of enzymes.
  • the largest group of kinases are protein kinases, which act on and modify the activity of specific proteins. These are used extensively to transmit signals and control complex processes in cells.
  • Protein kinases are a large class of enzymes which catalyze the transfer of the ⁇ -phosphate from ATP to the hydroxyl group on the side chain of Ser/Thr or Tyr in proteins and peptides and are intimately involved in the control of various important cell functions, perhaps most notably: signal transduction, differentiation, and proliferation.
  • signal transduction, differentiation, and proliferation There are estimated to be about 2,000 distinct protein kinases in the human body, and although each of these phosphorylate particular protein/peptide substrates, they all bind the same second substrate, ATP, in a highly conserved pocket. Protein phosphatases catalyze the transfer of phosphate in the opposite direction.
  • a tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a tyrosine residue in a protein. Phosphorylation of proteins by kinases is an important mechanism in signal transduction for regulation of enzyme activity.
  • the tyrosine kinases are divided into two groups; those that are cytoplasmic proteins and the transmembrane receptor- linked kinases. In humans, there are 32 cytoplasmic protein tyrosine kinases and 58 receptor- linked protein-tyrosine kinases.
  • the hormones and growth factors that act on cell surface tyrosine kinase-linked receptors are generally growth-promoting and function to stimulate cell division (e.g., insulin, insulin-like growth factor 1, epidermal growth factor).
  • Inhibitors of various known protein kinases or protein phosphatases have a variety of therapeutic applications.
  • One promising potential therapeutic use for protein kinase or protein phosphatase inhibitors is as anti-cancer agents.
  • About 50% of the known oncogene products are protein tyrosine kinases (PTKs) and their kinase activity has been shown to lead to cell transformation.
  • PTKs protein tyrosine kinases
  • the PTKs can be classified into two categories, the membrane receptor PTKs
  • Src growth factor receptor PTKs
  • Src growth factor receptor PTKs
  • pp60 c src
  • src proto- oncogene products
  • the hyperactivation of Src has been reported in a number of human cancers, including those of the colon, breast, lung, bladder, and skin, as well as in gastric cancer, hairy cell leukemia, and neuroblastoma.
  • Overstimulated cell proliferation signals from transmembrane receptors e.g.
  • Src is a universal target for cancer therapy, because hyperactivation (without mutation) is involved in tumor initiation, progression, and metastasis for many important human tumor types.
  • kinases are involved in the regulation of a wide variety of normal cellular signal transduction pathways (e.g., cell growth, differentiation, survival, adhesion, migration, etc.), kinases are thought to play a role in a variety of diseases and disorders. Thus, modulation of kinase signaling cascades may be an important way to treat or prevent such diseases and disorders.
  • Compounds of the invention are useful in modulation a component of the kinase signaling cascade. Some compounds may be useful in modulation of more than one component of a kinase signaling cascade.
  • the compounds of the present invention are useful as pharmaceutical agents.
  • the compounds of the invention may be useful for modulating regulation of a kinase which may be involved in a normal cellular signal transduction pathway (e.g., cell growth, differentiation, survival, adhesion, migration, etc.), or a kinase involved in a disease or disorder.
  • diseases and disorders include, without limitation, cancers, osteoporosis, cardiovascular disorders, immune system dysfunction, type II diabetes, obesity, and transplant rejection.
  • the compounds of the invention are useful in treating diseases and disorders that are modulated by tyrosine kinase inhibition.
  • the compounds of the invention are useful in treating diseases and disorders that are modulated by Src kinase.
  • the compounds of the invention may also be useful in treating diseases and disorders that are modulated by focal adhesion kinase (FAK).
  • FAK focal adhesion kinase
  • the compounds may be useful as anti-proliferative agents, for treating mammals, such as for treating humans and animals.
  • the compounds may be used without limitation, for example, as anti-cancer, anti-angiogenesis, anti-metastatic, antimicrobial, anti-bacterial, anti-fungal, anti-parasitic and/or anti-viral agents.
  • the compounds of the invention are useful, for example, in treating lung cancer.
  • the compounds of the invention are also useful, for example, in treating colon cancer.
  • the compounds of the invention are also useful, for example, in treating breast cancer.
  • Compounds of the invention include compounds of Formula I, and salts, solvates, hydrates, or prodrugs thereof:
  • T is absent (i.e., the rings are connected by a bond), CRi 2 Rn, C(O), O, S,
  • Xy is CZ, CY, N, or N-O;
  • X 2 is CZ, CY, N, or N-O;
  • At least one of X y and X z is CZ
  • Y is selected from hydrogen, hydroxyl, halogen, lower (Ci, C 2 , C 3 , C 4 , C 5 , or
  • X a is CR 3 , N, or N-O;
  • X b is CR b , N, or N-O;
  • X 0 is CR c , N, or N-O;
  • X 4 is CR d , N, or N-O;
  • X 6 is CR e , N, or N-O;
  • R 3 , R b , R 0 , R d , R 6 , R 4 , R 5 , and Re are, independently, hydrogen, hydroxyl, halogen, P, Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, O-lower (Ci, C 2 ,
  • C 3 , C 4 , C 5 , or C 6 alkyl-aryl O-benzyl, Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-OH, COOH, COO- lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl, SO 2 H, SO 2 -lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl, or C 3 , C 4 , C 5 , or C 6 alkyl, Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-aryl;
  • P is SO 3 H, OSO 3 H, OPO 3 H 2 , OPO 3 H 2 , NH 2 , NHRi 9 , NHR 20 R 2 I, > ⁇ Hx ° , tetrazole, O- lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-K, O-C(O)-lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-L, NH-lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-M, or O-aryl-Q, further wherein lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl is linear or branched alkyl; K is C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 ,
  • glycoside lower Ci, C 2 , C 3 , C 4 , Cs, C 6 alkoxy, aryl, heteroaryl, or
  • L is aryl, heteroaryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 ,
  • M is aryl, heteroaryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 ,
  • Q is aryl, heteroaryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H 5 PO 3 H 2 , OPO 3 H 2 , NH 2 ,
  • R 20 and R 2 i are independently Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl or Ri 9 and R 20 taken together with the attached nitrogen atom form a five membered ring;
  • V is a bond, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -0-CH 2 -, -OCH 2 CH 2 - or -
  • R 12 , Ri 3 , Ri 4 , R 1 5, Rie, Rn, and Ri 8 are, independently, H or Ci, C 2 , C 3 , C 4 ,
  • Z is (CHRi) n -C(O)-NR 2 (CHR 3 ) m -Ar, where Ar is a substituted or unsubstituted aryl or nitrogen-containing heteroaryl group, such as benzene, pyridine, or pyrimidine.
  • Ar is a substituted or unsubstituted aryl or nitrogen-containing heteroaryl group, such as benzene, pyridine, or pyrimidine.
  • Z is; (CHR 1 )-
  • Ri, R 2 , and R 3 are independently H or d, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl;
  • n and m are, independently 0, 1, or 2;
  • R 7 , Rg, R 9 , Rio, and Ri 1 are, independently, hydrogen, hydroxyl, halogen, P,
  • Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, O-lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-aryl, O-benzyl, Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-OH, COOH 5 COO-lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl, SO 2 H, SO 2 -lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl,
  • W is H 5 or Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-aryl;
  • P is SO 3 H 5 OSO 3 H, OPO 3 H 2 , OPO 3 H 2 , NH 2 , NHRi 9 , NHR 20 R 2 I, " ° , tetrazole, O-lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-K, O-C(O)-lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-L, NH-lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-M, or O-aryl-Q, further wherein lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl is linear or branched alkyl; [00030] K is C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3
  • L is aryl, heteroaryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 ,
  • M is aryl, heteroaryl, OH, C(O)NH 2 , COOH, SO 3 H 5 OSO 3 H, PO 3 H 2 ,
  • Q is aryl, heteroaryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 ,
  • Ri 9 , R 2 o and R 2 i are independently Ci, C 2 , C 3 , C 4 , C5, or C 6 alkyl or Ri 9 and
  • V is a bond, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -O-CH 2 -, -OCH 2 CH 2 -, or -
  • Z is R ⁇
  • the compound of the invention is Compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 93, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114,
  • Compounds of the invention include Compounds 33, 38, 40, 76, 133, 134, 136 and 137.
  • Certain compounds of the invention are selected from Compounds 138-246 and 247.
  • the compound of the invention is Compound 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217
  • Compounds of the invention include Compounds 146 and 147.
  • Certain compounds of the invention are selected from Compounds 248-273 and 274.
  • the compound of the invention is Compound 248, 249, 250, 251, 252,
  • At least one of X a , Xb, X 0 , X d and Xe is N.
  • X a is N and X b is CR t , X 0 is CR ⁇ ,
  • X d is CR d and X e is CR e .
  • X y is CY
  • X z is CZ
  • Y is hydrogen
  • Rb is Ci, C 2 , C3, C4, Cs, or Ce alkoxy.
  • R b is methoxy or ethoxy.
  • R b is hydrogen.
  • Rb is selected from F, Cl, Br, and I.
  • R b is
  • W is H, or Ci, C 2 , C 3 , C 4 , C 5 , or
  • V is a bond, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, - O-CH 2 -, -OCH 2 CH 2 - or -OCH Z CH Z CH 2 -.
  • W is hydrogen.
  • W is Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl.
  • R 0 is Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy.
  • R 0 is methoxy or ethoxy.
  • R,. is hydrogen, F, Cl, Br, or I.
  • R 0 is Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy.
  • R 0 is methoxy or ethoxy.
  • R,. is hydrogen, F, Cl, Br, or I.
  • V ( N — W , V — N ) , V N O , or V N N — W is ⁇ — / N — / N — / N — / where W is H, or Ci, C 2 , C 3 , C 4 ,
  • V is a bond, -CH 2 -, -CH 2 CH 2 -, - CH 2 CH 2 CH 2 -, -0-CH 2 -, -OCH 2 CH 2 - or -OCH 2 CH 2 CH 2 -.
  • V is a bond.
  • W is hydrogen.
  • W is Ci, C 2 , C 3 , C 4 , Cs, or C 6 alkyl.
  • Ra is Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy.
  • Rd is methoxy or ethoxy.
  • Rd is hydrogen, F, Cl, Br, or I.
  • V _J ( ⁇ ⁇ N-W , v — N / — ⁇ > , V — N /— ⁇ O , or V — N / — ⁇ N-W ,
  • W is H, or Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-aryl; and V is a bond, -CH 2 -, -CH 2 CH 2 -, - CH 2 CH 2 CH 2 -, -O-CH 2 -, -OCH 2 CH 2 - or -OCH 2 CH 2 CH 2 -.
  • V is a bond.
  • W is hydrogen.
  • W is Ci, C 2 , C 3 , C4, C5, or Ce alkyl.
  • the invention includes a solvate of a compound according to Formula I.
  • the invention also includes a hydrate of a compound according to Formula I.
  • the invention also includes an acid addition salt of a compound according to
  • Formula I Fo ⁇ example, a hydrochloride salt e.g., dihydrochloride.
  • the invention also includes a prodrug of a compound according to Formula I.
  • the invention also includes a pharmaceutically acceptable salt of a compound of Formula I.
  • the invention also includes a composition of a compound according to
  • Formula I and at least one pharmaceutically acceptable excipient.
  • the invention relates to a compound of Formula I, having a structure according to one of Formulae II, IH, IV, V, VI, VII, VDI, DC, X, XI, XII, and XDI:
  • R b , R 4 , R 5 , Rs, and Rio are, independently, hydrogen, hydroxyl, halogen, P, Ct, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, C], C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, O-lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-aryl, O-benzyl, Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-OH, COOH, COO-lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl, SO 2 H, SO 2 -lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl, where: R b , R 4 , R 5 , Rs, and Rio are, independently, hydrogen,
  • P is SO 3 H, OSO 3 H, OPO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NHR 20 R 2 I, H NX ° , tetrazole, O- lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-K, O-C(O)-lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-L, NH-lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-M, or O-aryl-Q, further wherein lower (Ci, C 2 , C 3 , Gj, C 5 , or C 6 ) alkyl is linear or branched alkyl; Kis C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2
  • glycoside lower Ci, C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, aryl, heteroaryl, or
  • L is aryl, heteroaryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 ,
  • M is aryl, heteroaryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 ,
  • Q is aryl, heteroaryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 ,
  • Ri9, R 20 and R 21 are independently Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl or Ri 9 and R 2 o taken together with the attached nitrogen atom form a five membered ring; and
  • V is a bond, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -0-CH 2 -, -OCH 2 CH 2 - or -
  • R 8 is hydrogen, F, Cl, Br, or I.
  • R 8 is F.
  • Rg is H.
  • R b is Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy.
  • Rb is methoxy or ethoxy.
  • R b is hydrogen, Cl, Br, or I.
  • Rb is
  • W is H, or Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-aryl, and V is a bond, -CH 2 -, -CH 2 CH 2 -, - CH 2 CH 2 CH 2 -, -O-CH 2 -, -OCH 2 CH 2 - or -OCH 2 CH 2 CH 2 -.
  • R 4 is hydrogen, Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, F, Cl, Br, or I.
  • R 4 is hydrogen, Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, F, Cl, Br, or I.
  • R 4 is hydrogen, Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, F, Cl, Br, or I.
  • R 4 is N — / N — / ⁇ — / ⁇ — / where W is H, or C 1 ,
  • V is a bond, -CH 2 -, - CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -0-CH 2 -, -OCH 2 CH 2 - or -OCH 2 CH 2 CH 2 -.
  • R 5 is Hydrogen, Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, F, Cl, Br, or I.
  • R 5 is Hydrogen, Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, F, Cl, Br, or I.
  • R 5 is Hydrogen, Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, F, Cl, Br, or I.
  • R 5 is N — / V-/ V ⁇ ⁇ — / where W is H, or Ci, C 2 , C 3 ,
  • R 1 O is hydrogen, Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, F, Cl, Br, or I.
  • Rio is methoxy, ethoxy or isobutoxy.
  • V is a bond, -CH 2 -, - CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -0-CH 2 -, -OCH 2 CH 2 - or -OCH 2 CH 2 CH 2 -.
  • XI, XII, and XlH, W is hydrogen, or Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl.
  • the invention relates to a solvate of a compound according to one of Formulae
  • the invention also relates to a hydrate of a compound according to one of Formulae II, III, IV, V, VI 5 VTl, VIII, IX, X, XI, XII, and
  • the invention also relates to an acid addition salt of a compound according to one of Formulae ⁇ , IH, IV, V, VI, VII, VIU, IX, X, XI, XII, and XIII.
  • a hydrochloride salt for example, a hydrochloride salt.
  • the invention relates to a prodrug of a compound according to one of
  • the invention also relates to a pharmaceutically acceptable salt of a compound of one of Formulae II, HI, IV, V, VI, VII, VIII, IX, X, XI, XII, and XHH.
  • compositions comprising a compound according to one of Formulae I, H, III, IV, V, VI, VII, VTII, IX, X, XI, XII, and XIII and at least one pharmaceutically acceptable excipient.
  • the invention relates to compounds and methods of using the compounds to modulate a component of the kinase signaling cascade. Some compounds may be useful in modulation of more than one component of a kinase signaling cascade. The compounds of the present invention are useful as pharmaceutical agents.
  • Certain compounds of the invention are non-ATP competitive kinase inhibitors.
  • the invention relates to compounds and methods of using the compounds to treat cell proliferation disorders.
  • the invention also includes a method of preventing or treating a cell proliferation disorder by administering a pharmaceutical composition that includes a compound according to one of Formulae I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, and XIII, or a salt, solvate, hydrate, or prodrug thereof, and at least one pharmaceutically acceptable excipient to a subject in need thereof.
  • a pharmaceutical composition that includes a compound according to one of Formulae I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, and XIII, or a salt, solvate, hydrate, or prodrug thereof, and at least one pharmaceutically acceptable excipient to a subject in need thereof.
  • the invention includes use of a compound of the present invention in the manufacture of a medicament to prevent or treat a cell proliferation disorder.
  • the cell proliferation disorder is pre-cancer or cancer.
  • the cell proliferation disorder treated or prevented by the compounds of the invention may be a cancer, such as, for example, colon cancer or lung cancer.
  • the cell proliferation disorder treated or prevented by the compounds of the invention may be a hyperproliferative disorder
  • the cell proliferation disorder treated or prevented by the compounds of the invention may be psoriases.
  • the treatment or prevention of the proliferative disorder may occur through the inhibition of a tyrosine kinase.
  • the tyrosine kinase can be a Src kinase or focal adhesion kinase (FAK).
  • the invention relates to a method of treating or preventing a disease or disorder that is modulated by tyrosine kinase inhibition, by administering a pharmaceutical composition that includes a compound according to Formula I or one of Formulae II, III, IV, V, VI, VII, VIII,
  • the disease or disorder that is modulated by tyrosine kinase inhibition is cancer, pre-cancer, a hyperproliferative disorder, or a microbial infection.
  • the compound is a compound according to Formula I or II.
  • the invention relates to use of a compound of the present invention in the manufacture of a medicament to treat or prevent a disease or disorder that is modulated by tyrosine kinase inhibition.
  • the pharmaceutical composition of the invention may modulate a kinase pathway.
  • the kinase pathway is a Src kinase pathway, or a focal adhesion kinase pathway.
  • composition of the invention may modulate a kinase directly.
  • the kinase is Src kinase, or focal adhesion kinase.
  • compositions of the invention are non-ATP competitive kinase inhibitors.
  • the compounds of the invention are also useful to treat or prevent a microbial infection, such as a bacterial, fungal, parasitic or viral infection.
  • compositions of the invention include a compound selected from Compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,
  • the pharmaceutical composition includes Compound 33, 38, 40, 76, 133, 134,
  • compositions of the invention include a compound selected from Compound 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220,
  • the compound of the invention is Compound 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, or 274.
  • a compound of the invention may be used as a pharmaceutical agent.
  • a compound of the invention is used as an anti-proliferative agent, for treating humans and/or animals, such as for treating humans and/or other mammals.
  • the compounds may be used without limitation, for example, as anti-cancer, anti-angiogenesis, antimicrobial, anti-bacterial, anti-fungal, anti-parasitic and/or anti-viral agents. Additionally, the compounds may be used for other cell proliferation-related disorders such as diabetic retinopathy, macular degeneration and psoriases.
  • Anti-cancer agents include anti-metastatic agents.
  • a compound of the present invention may be used in the manufacture of a medicament to be used as an anti-proliferative agent.
  • a compound may be used in the manufacture of a medicament as an anti-cancer, anti-angiogenesis, anti-microbial, antibacterial, anti-fungal, anti-parasitic and/or anti-viral agent.
  • a compound may be used in the manufacture of a medicament for the treatment or prevention of other cell- proliferation-related disorders such as diabetic retinopathy, macular degeneration and psoriases.
  • the compound of the invention used as a pharmaceutical agent includes a compound selected from Compounds 1-136 and 137.
  • the compound of the invention used as a pharmaceutical agent is Compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 93, 95, 96, 97, 98, 99, 100, 101, 102, 103
  • Certain pharmaceutical agents include a compound selected from the compounds listed in Table 2.
  • the compound of the invention used as a pharmaceutical agent is Compound 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216,
  • Certain pharmaceutical agents include a compound selected from the compounds listed in Table 3.
  • the compound of the invention used as a pharmaceutical agent is Compound 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, or 274.
  • a compound of the invention for example, a compound of Formula I or one of Formulae II, III, IV, V, VI, VII, VIII, DC, X, XI, XII, and XIII, is used to modulate a kinase cascade.
  • the compound is used to modulate a component of a kinase cascade which is responsible for the manifestation of a disease or disorder.
  • a compound of the invention may be used to treat or prevent a cell proliferation disorder in an subject.
  • the cell proliferation disorder is pre-cancer or cancer.
  • the cell proliferation disorder is a hyperproliferative disorder.
  • prevention or treatment of the cell proliferation disorder, cancer or hyperproliferative disorder occurs through the inhibition of a kinase.
  • prevention or treatment of the cell proliferation disorder, cancer or hyperproliferative disorder occurs through the inhibition of a tyrosine kinase.
  • prevention or treatment of the cell proliferation disorder, cancer or hyperproliferative disorder occurs through the inhibition of Src kinase or focal adhesion kinase (FAK).
  • FAK focal adhesion kinase
  • the subject is a mammal. In one embodiment, the subject is human.
  • the invention is also drawn to a method of treating or preventing cancer or a proliferation disorder in a subject, comprising administering an effective amount of a compound of the invention, for example, a compound of Formula I or one of Formulae II, III, rv, V, Vl, Vn, Vm, IX, X, XT, XII, and XIII.
  • a compound of the invention for example, a compound of Formula I or one of Formulae II, III, rv, V, Vl, Vn, Vm, IX, X, XT, XII, and XIII.
  • the compound of the invention may be a kinase inhibitor.
  • the compound of the invention may be a non-ATP competitive kinase inhibitor.
  • the compound of the invention may inhibit a kinase directly, or it may affect the kinase pathway.
  • Another aspect of the invention includes compounds of Formula IA, and salts, solvates, hydrates, or prodrugs thereof:
  • T is absent (i.e., the rings are connected by a bond), CR 12 R 13 , C(O), O, S, S(O), S(O) 2 , NR 14 ,
  • Xy is CZ, CY, N, or N-O;
  • X z is CZ, CY, N, or N-O;
  • At least one of X y and X 2 is CZ;
  • Y is selected from hydrogen, hydroxyl, halogen, lower (C 1 , C2, C3, C4, Cs, or C 6 ) alkyl, Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, O-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl- aryl, and O-benzyl;
  • Xa is CR 3 or N, or N-O;
  • X b is CRb, N, or N-O;
  • X c is CR 0 or N, or N-O;
  • X d is CR d or N, or N-O;
  • Xe is CR 8 , N, or N-O;
  • R a , R b , R 0 , R d , R 8 , R 4 , R 5 , and Re are, independently, hydrogen, hydroxyl, halogen, P, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, O-lower (Ci,
  • P is SO 3 H, OSO 3 H, OPO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NHR 20 R 2 I, H ° , tetrazole, O-lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-K, O-C(O)-lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-L, NH-lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-M, or O-aryl-Q, further wherein lower (Ci, C 2 , C 3 , C 4 , Cs, or C 6 ) alkyl is linear or branched alkyl; [000117] K is C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 ,
  • L is aryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 ,
  • M is aryl, heteroaryl, OH, C(O)NH 2 , COOH.
  • Q is aryl, heteroaryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 ,
  • Ri 9 , R 20 and R 2 i are independently Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl or R i9 and
  • V is a bond, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -O-CH 2 -, -OCH 2 CH 2 - or -
  • Ri 2 , Ri 3 , R H , R !5 , Ri 6 , R n , and Ri 8 are, independently, H or Ci, C 2 , C 3 , C 4 ,
  • Z is (CHRi) n -C(O)-NR 2 (CHR 3 ) m -Ar, where Ar is a substituted or unsubstituted aryl or nitrogen-containing heteroaryl group, R], R 2 , and R 3 are independently H or Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl; and n and m are, independently 0, 1, or
  • At least one of X a , Xb, Xc, Xa, Xe, Xy and X z is N. In another embodiment, at least two OfX 3 , Xb, Xc, Xd, Xe, Xy and X z are N.
  • At least one of X a and X y is N.
  • both X a and X y are N.
  • X a , Xb, Xc, Xd, and Xe are not each N or N-O.
  • X 0 , X 0 , and X 6 are not each N or N-O.
  • T is absent.
  • Xb is CRb-
  • R b is P.
  • P is O-lower (Ci, C2, C3, Q, C 5 , or Ce) alkyl-K.
  • lower (Ci, C 2 , C3, C 4 , Cs, or C 6 ) alkyl is CH 2 CH 2 CH 2 .
  • lower (Ci, C 2 , C 3 , C4, C 5 , or Ce) alkyl is branched
  • alkyl For example, branched alkyl is .
  • K, L, M, or Q, if present, is lower Ci, C 2 , C 3 , C 4 , C 5 or Ce alkoxy.
  • K is methoxy.
  • branched alkyl is * and K is methoxy.
  • K is methoxy.
  • L, M, or Q if present, is COOH.
  • K is COOH.
  • heteroaryl is tetrazole.
  • Rb is ⁇ ' .
  • Rb is W .
  • V is -OCH2CH2.
  • V is a bond.
  • W is Ci, C 2 , C3, C4, C5, or Ce alkyl.
  • W is methyl or ethyl.
  • X z is CZ, further wherein Z is R 7 , Rs, R9, Rio, and Rn are selected from hydrogen, hydroxyl, halogen, Ci, C2, C3, C4, Cs, or Ce alkyl, Ci, C 2 , C 3 , C 4 , Cs, or C 6 alkoxy, O-lower (Ci, C 2 , C3, C 4 , CS, or C ⁇ ) alkyl-aryl, O-benzyl, Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-OH, Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-O-Ci, C 2 , C 3 ,
  • W is H, or Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-aryl.
  • at least one of R 7 , Rg, R9, Rio, and Rn is halogen, Ci, C 2 , C3, C 4 , C 5 , or C 6 alkoxy, or O-benzyl.
  • at least one of Rg or Rio is halogen.
  • halogen is fluorine.
  • at least one OfR 7 or Rn is Ci, C 2 , C3, C 4 , C 5 , or C 6 alkoxy or O-benzyl.
  • At least one OfR 7 or Rn is ethoxy or at least one OfR 7 or Rn is O-benzyl.
  • Ri is H.
  • n is 1.
  • R 2 is H.
  • R 3 is H.
  • m is 1.
  • m and n are each 1 and R2 and R3 are each H. [000129]
  • R4 and Re are each H.
  • R 5 is selected from halogen and Ci, C 2 , C 3 , C 4 , C 5 , or Ce alkyl.
  • R 5 is halogen.
  • R 5 is Cl or F.
  • Rs is Ci, C2, C3, C 4 , Cs, or Ce alkyl.
  • R 5 is methyl or ethyl.
  • the invention includes a solvate of a compound according to Formula IA.
  • the invention includes a hydrate of compound according to Formula IA.
  • the invention includes an acid addition salt of a compound according to Formula IA.
  • a hydrochloride salt for example, a hydrochloride salt.
  • the invention includes a pharmaceutically acceptable salt.
  • the invention includes a composition comprising a compound of Formula IA and at least one pharmaceutically acceptable excipient.
  • Certain compounds of the invention include compounds selected from Compound 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, and 274.
  • Another aspect of the invention includes a method of protecting against or treating hearing loss in a subject comprising administering a compound having the Formulae I, IA, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, and XIII.
  • the compound inhibits one or more components of a kinase signaling cascade.
  • the compound is an allosteric inhibitor.
  • the compound is a peptide substrate inhibitor.
  • the compound does not inhibit ATP binding to the protein kinase.
  • the compound inhibits a Src family protein kinase.
  • the Src family protein kinase is pp ⁇ O 0"8 " 1 tyrosine kinase.
  • the administration of the compound is carried out orally, parentally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, topically e.g., by administering drops into the ear, intraarterially, intralesionally, by metering pump, or by application to mucous membranes.
  • the compound is administered with a pharmaceutically acceptable carrier.
  • the compound is administered before initiation of hearing loss. In another embodiment, the compound is administered after initiation of hearing loss. [000135] In one embodiment, the compound is administered in combination with a drug that causes hearing loss e.g., cis platinum or an aminoglycoside antibiotic. In another embodiment, the compound is administered in combination with a drug that targets hairy cells.
  • a drug that causes hearing loss e.g., cis platinum or an aminoglycoside antibiotic.
  • the compound is administered in combination with a drug that targets hairy cells.
  • At least one of Xa, Xb, X 0 , Xd, Xe, Xy and X 2 is N.
  • T is absent e.g., a bond.
  • X 2 is CZ and Z is
  • m and n are each 1 and R 2 and R 3 are each H.
  • at least one of R7, R 8 , R 9 , R 1 O and Rn is halogen, Ci, Cz, C3, C 4 , C5,
  • the compound is
  • Another aspect of the invention includes a method of protecting against or treating osteoporosis in a subject comprising administering a compound having a Formulae I, IA, II, JH, IV, V, VI, VII, VIII, IX, X, XI, XH, and XIII.
  • the compound inhibits one or more components of a kinase signaling cascade.
  • the compound is an allosteric inhibitor.
  • the compound is a peptide substrate inhibitor.
  • the compound inhibits a Src family protein kinase.
  • the Src family protein kinase is pp ⁇ 0" " 0 tyrosine kinase.
  • At least one of X a , X b , X ⁇ , Xd, X 6 , X y and X 2 is N.
  • T is absent e.g., a bond.
  • X z is CZ and Z is
  • m and n are each 1 and R 2 and R 3 are each H.
  • at least one OfR 7 , Rg, R9, Rio and Ri 1 is halogen, Ci, C 2 , C 3 , C4, Cs, or C ⁇ alkyl, or O-benzyl.
  • the compound is Compound 25 (KXl -329), Compound 38 (KX2-377), Compound 76 (KX2-361), Compound 133 (KX2-392), Compound 134 (KX2-391), or Compound 137 (KX2-394).
  • the administration of the compound is carried out orally, parentally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, topically, intraarterially, intralesionally, by metering pump, or by application to mucous membranes.
  • the compound is administered with a pharmaceutically acceptable carrier.
  • the compound is administered before initiation of osteoporosis.
  • the compound is administered after initiation of osteoporosis.
  • Another aspect of the invention includes a method of protecting against or treating ophthalmic diseases e.g., macular degeneration, retinopathy, macular edema, etc. in a subject comprising administering a compound having a Formulae I, IA, ⁇ , III, IV, V, VI, VII, Vi ⁇ , IX, X, XI, X ⁇ , and XIII.
  • Another aspect of the invention includes use of a compound of the invention in the manufacture of a medicament to protect against or treat ophthalmic diseases.
  • the compound inhibits one or more components of a kinase signaling cascade.
  • the compound is an allosteric inhibitor.
  • the compound is a peptide substrate inhibitor.
  • the compound inhibits a Src family protein kinase.
  • the Src family protein kinase is pp ⁇ 0 *" 1 tyrosine kinase.
  • the compound inhibits one or more components in the VEGF pathway.
  • the administration of the compound is carried out orally, parentally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, topically (e.g., by administering drops to the eye), intraarterially, intralesionally, by metering pump, or by application to mucous membranes.
  • the compound is administered with a pharmaceutically acceptable carrier.
  • the compound is administered before initiation of the ophthalmic disease.
  • the compound is administered after initiation of ophthalmic disease.
  • Another aspect of the invention includes a method of protecting against or treating diabetes in a subject comprising administering a compound having a Formulae I, IA, H, m, IV, V, VI, VII, VIII, IX, X, XI, XII, and Xm.
  • Another aspect of the invention includes use of a compound of the invention in the manufacture of a medicament to protect against or treat diabetes.
  • the compound inhibits one or more components of a kinase signaling cascade.
  • the compound is an allosteric inhibitor.
  • the compound is a peptide substrate inhibitor.
  • the compound inhibits a Src family protein kinase.
  • the Src family protein kinase is pp ⁇ O 0"510 tyrosine kinase.
  • the administration of the compound is carried out orally, parentally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, topically, intraarterially, intralesionally, by metering pump, or by application to mucous membranes.
  • the compound is administered with a pharmaceutically acceptable carrier.
  • the compound is administered before the onset of diabetes. In another embodiment, the compound is administered after the onset of diabetes.
  • Another aspect of the invention includes a method of protecting against or treating obesity in a subject comprising administering a compound having a Formulae I, IA, H, IE, IV, V, VI, VII, VIII, IX, X, XI, XII, and Xm.
  • Another aspect of the invention includes use of a compound of the invention in the manufacture of a medicament to protect against or treat obesity.
  • the compound inhibits one or more components of a kinase signaling cascade.
  • the compound is an allosteric inhibitor.
  • the compound is a peptide substrate inhibitor.
  • the compound inhibits a Src family protein kinase.
  • the Src family protein kinase is pp ⁇ O 0"5 " 5 tyrosine kinase.
  • the administration of the compound is carried out orally, parentally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, topically, intraarterially, intralesionally, by metering pump, or by application to mucous membranes.
  • the compound is administered with a pharmaceutically acceptable carrier.
  • the compound is administered before the subject is obese. In another embodiment, the compound is administered after the subject is obese.
  • Another aspect of the invention includes a method of protecting against or treating stroke in a subject comprising administering a compound having a Formulae I, IA, II, III, IV, V, VT, VII, Vi ⁇ , IX, X, XI, XII, and Xm.
  • Another aspect of the invention includes use of a compound of the invention in the manufacture of a medicament to protect against or treat stroke.
  • the compound is an allosteric inhibitor.
  • the compound is a peptide substrate inhibitor.
  • the compound inhibits a Src family protein kinase.
  • the Src family protein kinase is pp60 c"src tyrosine kinase.
  • the administration of the compound is carried out orally, parentally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, topically, intraarterially, intralesionally, by metering pump, or by application to mucous membranes.
  • the compound is administered with a pharmaceutically acceptable carrier.
  • the compound is administered before a stroke has occurred. In another embodiment, the compound is administered after a stroke has occurred.
  • Another aspect of the invention includes a method of protecting against or treating athrosclerosis in a subject comprising administering a compound having a Formulae I, IA, II, III, TV, V, VI, VII, VHI, IX, X, XI, XU, and XIII.
  • Another aspect of the invention includes use of a compound of the invention in the manufacture of a medicament to protect against or treat athrosclerosis.
  • the compound inhibits one or more components of a kinase signaling cascade.
  • the compound is an allosteric inhibitor.
  • the compound is a peptide substrate inhibitor.
  • the compound inhibits a Src family protein kinase.
  • the Src family protein kinase is pp ⁇ O 0"3 * 0 tyrosine kinase.
  • the administration of the compound is carried out orally, parentally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, topically, intraarterially, intralesionally, by metering pump, or by application to mucous membranes.
  • the compound is administered with a pharmaceutically acceptable carrier.
  • Another aspect of the invention includes a method of regulating immune system activity in a subject comprising administering a compound having a Formulae I, IA, II, in, IV, V, VI, V ⁇ , Vm, IX, X, XI, XII, and X ⁇ i.
  • Another aspect of the invention includes use of a compound of the invention in the manufacture of a medicament to regulate immune system activity.
  • the compound inhibits one or more components of a kinase signaling cascade.
  • the compound is an allosteric inhibitor.
  • the compound is a peptide substrate inhibitor.
  • the compound inhibits a Src family protein kinase.
  • the Src family protein kinase is p ⁇ p60 c's ⁇ tyrosine kinase.
  • the administration of the compound is carried out orally, parentally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, topically, intraarterially, intralesionally, by metering pump, or by application to mucous membranes.
  • the compound is administered with a pharmaceutically acceptable carrier.
  • Another aspect of the invention includes a method of protecting against or treating chronic neuropathic pain in a subject comprising administering a compound having a Formulae I, IA, II, HI, IV, V, VI, VII, VIII, DC, X, XI, XII, and XIII.
  • Another aspect of the invention includes use of a compound of the invention in the manufacture of a medicament to protect against or treat chronic neuropathic pain.
  • the compound inhibits one or more components of a kinase signaling cascade.
  • the compound is an allosteric inhibitor.
  • the compound is a peptide substrate inhibitor.
  • the compound inhibits a Src family protein kinase.
  • the Src family protein kinase is pp ⁇ O 0"3 TM tyrosine kinase.
  • the administration of the compound is carried out orally, parentally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, topically, intraarterially, intralesionally, by metering pump, or by application to mucous membranes.
  • the compound is administered with a pharmaceutically acceptable carrier.
  • the compound is administered before the onset of chronic neuropathic pain.
  • the compound is administered after the onset of chronic neuropathic pain.
  • Another aspect of the invention includes a method of protecting against or treating hepatitis B in a subject comprising administering a compound having a Formulae I, IA, H, in, IV, V, VI, VII, Vi ⁇ , IX, X, XI, X ⁇ , and XIII.
  • Another aspect of the invention includes use of a compound of. the invention in the manufacture of a medicament to protect against or treat hepatitis B.
  • the compound inhibits one or more components of a kinase signaling cascade.
  • the compound is an allosteric inhibitor.
  • the compound is a peptide substrate inhibitor.
  • the compound inhibits a Src family protein kinase.
  • the Src family protein kinase is pp ⁇ O 0 " 3 TM tyrosine kinase.
  • the administration of the compound is carried out orally, parentally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, topically, intraarterially, intralesionally, by metering pump, or by application to mucous membranes.
  • the compound is administered with a pharmaceutically acceptable carrier.
  • the compound is administered before the onset of hepatitis B.
  • the compound is administered after the onset of hepatitis B.
  • Another aspect of the invention is a method of preventing or treating a cell proliferation disorder comprising administering to a subject in need thereof a compound having the Formula IA.
  • Another aspect of the invention includes use of a compound of the invention in the manufacture of a medicament to protect against or treat a cell proliferation disorder.
  • the compound inhibits one or more components of a protein kinase signaling cascade.
  • the compound is an allosteric inhibitor.
  • the compound is a peptide substrate inhibitor.
  • the compound does not inhibit ATP binding to a protein kinase.
  • the compound inhibits a Src family protein kinase.
  • the Src family protein kinase is pp60 c'src tyrosine kinase.
  • At least one of X a , Xb, X 0 , Xd. Xe, Xy and X z is N.
  • X 2 is CZ, further wherein Z is R ⁇ and R 7 , Re, R9, Rio, and Rn are selected from hydrogen, hydroxyl, halogen, Ci, C 2 , C3, C4, C5, or Ce alkyl, Ci, C2, C 3 , C 4 , C 5 , or C 6 alkoxy, O-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-aryl, O-benzyl, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-OH, Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-O-Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, where W is H, or Ci, C 2 , C 3 ,
  • R 7 , Re, R 9 , Rio, and Ri 1 is halogen, Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, or O-benzyl.
  • m and n are each 1 and R 2 and R 3 are each H.
  • R 4 and R 6 are each H.
  • a compound is selected from 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, ' 273, or 274.
  • another aspect of the invention is a method for treating leukemia in a host comprising administering to a patient a compound having a Formulae I, IA, II, III, IV, V, VI, VII, V ⁇ i, IX, X, XI, XII, and XIII.
  • Another aspect of the invention includes use of a compound of the invention in the manufacture of a medicament to treat leukemia.
  • a method for treating leukemia in a host comprising administering to a patient a therapeutically effective amount of a compound according to Formulae I, IA, II, III, IV, V, VI, VH, VIII, IX, X, XI, XII, and XEI, as defined above, and at least one further therapeutic agent selected from the group consisting of antiproliferative agents, cytotoxic agents, cytostatic agents, and chemotherapeutic agents and salts and derivatives thereof.
  • the compound of the present invention may be used in the treatment of a leukemia in combination therapy with one or more of the drugs selected from a group consisting of an alkaloid, an alkylating agent, an antitumor antibiotic, an antimetabolite, an Bcr-Abl tyrosine kinase inhibitor, a nucleoside analog, a multidrug resistance reversing agent, a DNA binding agent, microtubule binding drug, a toxin and a DNA antagonist.
  • the drugs selected from a group consisting of an alkaloid, an alkylating agent, an antitumor antibiotic, an antimetabolite, an Bcr-Abl tyrosine kinase inhibitor, a nucleoside analog, a multidrug resistance reversing agent, a DNA binding agent, microtubule binding drug, a toxin and a DNA antagonist.
  • a method for treating leukemia in a host comprising administering to a patient that has been previously treated with a Bcr-Abl tyrosine kinase inhibitor and has become resistant to the Bcr-Abl tyrosine kinase inhibitor treatment, a therapeutically effective amount of a compound according to Formulae I, IA, II, III, IV, V, VI, Vn, VIH, IX, X, XI, XII, and XIII.
  • Figure 1 A is a graph indicating the effect of AZ28 and KX2-391 on Src autophosphorylation in c-Src/NIH-3T3 cells;
  • Figure IB is a graph indicating the effect of
  • Figure 2 A is a graph indicating the effect of AZ28 and KX2-391 on FAK phosphorylation in c-Src/NIH-3T3 cells
  • Figure 2B is a graph indicating the effect of AZ28 and KX2-391 on FAK phosphorylation in HT-29 cells.
  • Figure 3 A is a graph indicating the effect of AZ28 and KX2-391 on She phosphorylation in c-Src/NIH-3T3 cells
  • Figure 3B is a graph indicating the effect of AZ28 and KX2-391 on She phosphorylation in HT-29 cells.
  • Figure 4 is a graph indicating the effect of AZ28 and KX2-391 on paxillin phosphorylation in c-Src/NIH-3T3 cells.
  • Figure 5 A is a graph indicating the effect of AZ28 and KX2-391 on caspase-3 cleavage in c-Src/NIH-3T3 cells;
  • Figure 5B is a graph indicating the effect of AZ28 and
  • Figure 6A is a graph indicating the effect of AZ28 and KX2-391 on total phosphotyrosine levels in c-Src/NIH-3T3 cells;
  • Figure 6B is a graph indicating the effect of
  • Figure 7 is a graph indicating the effect of AZ28 and KX2-391 on autophosphorylation of PDGFR in c-Src/NIH-3T3 cells.
  • Figure 8A is a graph indicating the effect of AZ28 and KX2-391 on autophosphorylation of FAK in c-Src/NIH-3T3 cells;
  • Figure 8B is a graph indicating the effect of AZ28 and KX2-391 on autophosphorylation of FAK in HT-29 cells.
  • Figure 9A is a graph indicating the effect of AZ28 and KX2-391 on autophosphorylation of EGFR in c-Src/NIH-3T3 cells
  • Figure 9B is a graph indicating the effect of AZ28 and KX2-391 on autophosphorylation of EGFR in HT-29 cells.
  • Figure 10 is a bar chart showing the average threshold shifts (dB) in chinchilla cochleas after exposure to 0.5 kHz, 1 kHz, 2 kHz, 4 kHz, and 8 kHz band noise on day 1 after experimental manipulation.
  • Figure 11 is a graph showing the average threshold shifts (dB) in chinchilla cochleas after exposure to 0.5 kHz, 1 kHz, 2 kHz, 4 kHz, and 8 kHz band noise on day 7 after experimental manipulation.
  • Figure 12 is a graph showing the average threshold shifts (dB) in chinchilla cochleas after exposure to 0.5 kHz, 1 kHz, 2 kHz, 4 kHz; and 8 kHz band noise on day 21 after experimental manipulation.
  • Figure 13 is a line graph showing the threshold shifts (dB) in guinea pig cochleas after exposure to 2 kHz, 4 kHz, 8 kHz, 12 kHz, 16 kHz and 20 kHz band noise after treatment with cisplatin.
  • Figure 14 is a line graph showing the threshold shifts (dB) in KXl-004-treated guinea pig cochleas after exposure to 2 kHz, 4 kHz, 8 kHz, 12 kHz, 16 kHz and 20 kHz band noise after treatment with cisplatin.
  • Figure 15 is a line graph showing the average threshold shifts (dB) in KXl- 004-treated guinea pig cochleas and untreated control guinea pig cochleas after exposure to 2 kHz, 4 kHz, 8 kHz, 12 kHz, 16 kHz and 20 kHz band noise after treatment with cisplatin.
  • Figure 16A shows a comparison of taxol and doxorubicin (they were more effective than etoposide and cisplatin in this tumor cell culture) with the three Src inhibitors (45, 43-meta, and 49-meta from Table V) utilizing ovarian tumor cells from tumor NO 15.
  • Figure 16B shows the results from tests of the Src inhibitors for inhibition of normal human fibroblast cell growth. No inhibition of normal cell growth (both subconfluent and confluent; some enhanced growth was observed instead) was found, indicating that these inhibitors are not toxic to normal cells even at a 10-fold higher concentration.
  • Figure 16C shows the results from tests of two of the Src inhibitors for inhibition of ts v-Src stimulated LA25 cell growth.
  • Figure 16D shows the results from tests of two of the Src inhibitors for inhibition of normal rat kidney cell growth.
  • Figure 16E provides the structures of the Src inhibitors 45, 43-meta, and 49-meta. [000178]
  • Figure 16 is a series of illustrations depicting the effect of compounds on osteoclast formation.
  • Figure 17 is a bar chart demonstrating the effect of compounds on osteoclast formation.
  • Figure 18 is a series of illustrations showing the effect of compounds on osteoclast survival.
  • Figure 19 is a bar chart depicting the effect of compounds on osteoclast survival.
  • Figure 2OA is a bar chart demonstrating the effect of compounds on bone resorption in vitro.
  • Figure 2OB is a bar chart showing. the effect of compounds on resorption pit formation.
  • Figure 21 A is a series of illustrations depicting the effect of compounds on osteoclast formation on bone slices.
  • Figure 21B is a series of illustrations demonstrating the effect of compounds on the formation of resorption pits on bone slices.
  • Figure 22 is a bar chart showing the effect of compounds on alkaline phosphatase expression by osteoblasts.
  • Figure 23 is a bar chart depicting the effect of compounds on protein expression by osteoblasts.
  • Figure 24 shows growth inhibition curves and EC 50 / IC 50 for Compound 134
  • Figure 25 shows growth inhibition curves and EC50/ IC50 for Compound 134
  • Figure 26 shows growth inhibition curves and EC 5 0/ IC50 for Compound 134
  • Figure 27 shows growth inhibition curves and EC 50 / IC 5 0 for Compound 134
  • Figure 28 shows growth inhibition curves and EC 50 / IC 5 0 for Compound 134
  • FIG. 29 shows growth inhibition curves and EC 5 o/ ICs 0 for Compound 134
  • Figure 30 shows growth inhibition curves and EC50/ IC50 for Compound 134
  • Figure 31 shows growth inhibition curves and EC 5 0/ IC 50 for Compound 134
  • Figure 32 is a graph indicating the effect of Dasatinib on Dasatinib and
  • Imatinib resistant leukemia cells Imatinib resistant leukemia cells.
  • Figure 33 is a graph indicating the effect of compound 134 (KX2-391/KXO1) on Dasatinib and Imatinib resistant leukemia cells.
  • Figure 34 shows the growth inhibition curves and GI50 of the combination of
  • Figure 35 shows the growth inhibition curves and GI 50 of Gemzar and
  • Figure 36 shows the growth inhibition curves and GI50 of Compound 134
  • Figure 37 shows the growth inhibition curves and GI 50 of Compound 134
  • Figure 38 shows the growth inhibition curves and GI 5 0 of Compound 134
  • Figure 39 shows the growth inhibition curves and GI 50 of Compound 134
  • Figure 40 shows the growth inhibition curves and GI 50 of Compound 134
  • Figure 41 shows the tumor weight from the orthotopic prostate model for measuring in vivo metastases at various concentration of Compound 134 (KXO1/KX2-391).
  • Figure 42 is a bar graph of the screening results for Anti-HBV efficacy and cellular cytotoxicity.
  • Figures 44A, 44B, 44C, and 44D are a series of graphs depicting the inhibition of Src kinase activity in whole cells.
  • Figure 44 A is a graph depicting the effect of KXOl on
  • Figure 44B is a graph indicating the effect of KXOl on Src autophosphorylation in HT-29 cells
  • Figure 44C is a graph depicting the effect of KXOl on Src transphosphorylation in c-Src/NIH-3T3 cells
  • Figure 44D is a graph indicating the effect of KXOl on Src autophosphorylation in HT-29 cells.
  • Figure 45 is an illustration depicting the selectivity of KXOl for protein tyrosine kinases (PTKs) in whole cells as compared to Dasatinib, an ATP-competitive Src inhibitor currently in clinical trials.
  • PTKs protein tyrosine kinases
  • Figure 46 is a graph depicting the oral potency of KXOl in mouse xenografts.
  • KXOl demonstrated higher oral potency in staged HT29 (a human colon cancer cell line) mouse than Dasatinib.
  • Figure 47 shows a second week IVIS follow up study after the treatment of
  • kinases are involved in the regulation of a wide variety of normal cellular signal transduction pathways (e.g., cell growth, differentiation, survival, adhesion, migration, etc.), kinases are thought to play a role in a variety of diseases and disorders.
  • modulation of kinase signaling cascades may be an important way to treat or prevent such diseases and disorders.
  • diseases and disorders include, for example, cancers, osteoporosis, cardiovascular disorders, immune system dysfunction, type II diabetes, obesity, and transplant rejection.
  • Compounds of the invention are useful in modulation a component of the kinase signaling cascade. Some compounds may be useful in modulation of more than one component of a kinase signaling cascade.
  • modulates one or more components of a protein kinase signaling cascade means that one or more components of the kinase signaling cascade are affected such that the functioning of a cell changes.
  • Components of a protein kinase signaling cascade include any proteins involved directly or indirectly in the kinase signaling pathway including second messengers and upstream and downstream targets.
  • RTKs insulin receptor kinase
  • EGFR epidermal growth factor receptor
  • FGFR basic fibroblast growth factor receptor
  • PDGFR platelet- derived growth factor receptor
  • VEGFR-2 or Flkl/KDR vascular endothelial growth factor receptor
  • NGFR nerve growth factor receptor
  • Src family Src, Fyn, Yes, BIk, Yrk, Fgr, Hck, Lck, and Lyn
  • Fak Jak, AbI and Zap70
  • Src inhibitors are sought as therapeutics for a variety of cancers, including, for example, colon cancer, precancerous colon lesions, ovarian cancer, breast cancer, epithelial cancers, esophageal cancer, non-small cell lung cancer, pancreatic cancer, and others. See, e.g., Frame, Biochim. Biophys. Acta, 2002, 1602:114-130 and Parang and Sun, Expert Opin. Ther. Patents, 2005, 15:1183-1207.
  • Inhibition of other kinases may be useful in the treatment and modulation of other types of diseases and disorders.
  • various eye diseases may be inhibited or prevented by administration of VEGF receptor tyrosine kinase inhibitors.
  • Inhibitors of the tyrosine phosphatase PTP-IB and/or glycogen phosphorylase may provide treatments for Type II diabetes or obesity.
  • Inhibitors of p561ck may be useful in treating immune system disorders.
  • Other targets include HIV reverse transcriptase, thromboxane synthase, EGFRTK, p55 fyn, etc.
  • Compounds of the invention may be Src signaling inhibitors that bind in the Src peptide substrate site.
  • the activity of various compounds of the invention has been studied in c-Src (527F, constitutively active and transforming) transformed NIH3T3 cells and in human colon cancer cells (HT29).
  • c-Src 527F, constitutively active and transforming transformed NIH3T3 cells and in human colon cancer cells (HT29).
  • KX2-391 was shown to reduce the phosphorylation level of known Src protein substrates in a dose-dependent fashion and in good correlation with growth inhibitory effects.
  • compounds of the invention may directly inhibit Src, and may do so by binding in the peptide binding site (as opposed to binding at an allosteric site).
  • Src has been proposed to be a "universal" target for cancer therapy since it has been found to be overactivated in a growing number of human tumors (Levitzki, Current Opinion in Cell Biology, 8, 239-244 (1996); Levitzki, Anti-Cancer Drug Design, 11, 175- 182 (1996)).
  • the potential benefits of Src inhibition for cancer therapy appear to be four-fold inhibition of uncontrolled cell growth caused by autocrine growth factor loop effects, inhibition of metastasis due to triggering apoptosis upon breaking free from the cell matrix, inhibition of tumor angiogenesis via reduced VEGF levels, low toxicity.
  • Prostate cancer cells have been reported to have both an over expression of paxillin and pl30cas and are hyperphosphorylated (Tremblay et al., Int. J. Cancer, 68, 164- 171, 1996) and may thus be a prime target for Src inhibitors.
  • the invention relates to compounds and methods of using compounds to treat cell proliferation disorders.
  • the compounds of the present invention are useful as pharmaceutical agents, for example, as therapeutic agents for treating humans and animals.
  • the compounds may be used without limitation, for example, as anti-cancer, anti-angiogenesis, anti-metastatic, antimicrobial, anti-bacterial, anti-fungal, anti-parasitic and/or anti-viral agents.
  • the compounds may be used for other cell proliferation-related disorders such as psoriases.
  • a compound of the invention may be used to protect against or prevent hearing loss in a subject.
  • Another aspect of the invention includes use of a compound of the invention in the manufacture of a medicament to protect against or treat hearing loss.
  • the compound may be administered prior to noise exposure or exposure to a drug which induces hearing loss.
  • drugs may include chemotherapeutic drugs (e.g., platinum-based drugs which target hair cells) and aminoglycoside antibiotics.
  • a compound of the invention may provide a synergistic effect with certain cancer drugs. For example, promising inhibitors can be screened in primary human tumor tissue assays, particularly to look for synergy with other known anti-cancer drugs.
  • the protein kinase inhibitors may reduce toxicity of certain cancer drugs (e.g., platinum-based drugs which are toxic to the cochlea and kidney), thereby allowing increased dosage.
  • a compound of the invention may be used to treat hearing loss in a subject.
  • the compound is administered to the subject subsequent to the initiation of hearing loss to reduce the level of hearing loss.
  • a compound of the invention may be involved in modulating a kinase cascade, e.g. a kinase inhibitor, a non-ATP competitive inhibitor, a tyrosine kinase inhibitor, a Src inhibitor or a focal adhesion kinase (FAK) modulator.
  • a kinase cascade e.g. a kinase inhibitor, a non-ATP competitive inhibitor, a tyrosine kinase inhibitor, a Src inhibitor or a focal adhesion kinase (FAK) modulator.
  • FAK focal adhesion kinase
  • administration of a compound of the invention is administered to a subject suffering from hearing loss in order to prevent further hearing loss.
  • administration of a compound of the invention is administered to a subject suffering from hearing loss in order to restore lost hearing.
  • the tight cell junctures between the cochlear hair cells, as well as the cell-extracellular matrix interaction are torn and stressed. The stressing of these tight cell junctures initiates apoptosis in the cells through a complex signaling pathway in which tyrosine kinases act as molecular switches, interacting with focal adhesion kinase to transduce signals of cell-matrix disruptions to the nucleus.
  • NIHL noise-induced hearing loss
  • the ear can be protected from NIHL by administration of antioxidant drugs to the round window of the ear (Hight, et al. ⁇ 2003, Hear. Res., 179, 21-32; Hu, et al. ⁇ Hear. Res. 113, 198-206).
  • NEHL has been reduced by the administration of FDA-approved antioxidant compounds (N-L-acetylcysteine (L-NAC) and salicylate) in the chinchilla (Kopke, et aL; 2000, Hear. Res., 149, 138-146).
  • L-NAC N-L-acetylcysteine
  • salicylate N-L-acetylcysteine
  • Harris et al. have recently described prevention of NIHL with Src-PTK inhibitors (Harris, et aL; 2005, Hear. Res., 208, 14-25).
  • the Src PTK signaling cascade is thought to be involved in both metabolic- and mechanically-induced initiation of apoptosis in sensory cells of the cochlea.
  • Src inhibitors provided protection from a 4 hour, 4 kHz octave band noise at 106 dB, indicating that Src-PTKs might be activated in outer hair cells following noise exposure (Harris, et aL; 2005, Hear. Res., 208, 14-25).
  • compounds of the instant invention that modulate the activity of Src are useful in treating hearing loss.
  • the present invention relates to a method for protecting against or treating osteoporosis in a subject.
  • Another aspect of the invention includes use of a compound of the invention in the manufacture of a medicament to protect against or treat osteoporosis.
  • This method involves administering an effective amount of a compound of the invention to the subject to protect against or to treat osteoporosis.
  • the compound may be administered prior to the development of osteoporosis.
  • the compound may be used to treat osteoporosis in a subject.
  • the compound is administered to the subject subsequent to the initiation of osteoporosis to reduce the level of osteoporosis.
  • a compound of the invention can be, e.g. a non-ATP competitive inhibitor.
  • the compound of the invention can modulate a kinase signaling cascade, depending upon the particular side chains and scaffold modifications selected.
  • the compound of the invention can be a kinase inhibitor.
  • the compound can be a protein tyrosine kinase (PTK) inhibitor.
  • the proline-rich tyrosine kinase (PYK2; also known as cell adhesion kinase ⁇ , related adhesion focal tyrosine kinase, or calcium-dependent tyrosine kinase) and focal adhesion kinase (FAK) are members of a distinct family of non receptor protein-tyrosine kinases that are regulated by a variety of extracellular stimuli (Avraham, et al.; 2000, Cell Signal, 12, 123-133; Schlaepfer, et al.; 1999, Prog. Biophys. MoI. Biol., 71, 435-478).
  • the compound of the invention can be a Src inhibitor.
  • the compound of the invention can modulate the expression of interleukin-1 receptor associated kinase M (IRAK-M).
  • IRAK-M interleukin-1 receptor associated kinase M
  • Mice that lack IRAK-M develop severe osteoporosis, which is associated with the accelerated differentiation of osteoclasts, an increase in the half-life of osteoclasts, and their activation (Hongmei, et al.; 2005,7. Exp. Med., 201, 1169-1177).
  • Multinucleated osteoclasts originate from the fusion of mononuclear phagocytes and play a major role in bone development and remodeling via the resorption of bone. Osteoclasts are multinucleated, terminally differentiated cells that degrade mineralized matrix. In normal bone tissue, there is a balance between bone formation by osteoblasts and bone resorption by osteoclasts. When the balance of this dynamic and highly regulated process is disrupted, bone resorption can exceed bone formation resulting in quantitative bone loss.
  • osteoclasts are essential for the development and remodeling of bone, increases in their number and /or activity lead to diseases that are associated with generalized bone loss (e.g., osteoporosis) and others with localized bone loss (e.g., rheumatoid arthritis, periodontal disease).
  • generalized bone loss e.g., osteoporosis
  • localized bone loss e.g., rheumatoid arthritis, periodontal disease
  • Osteoclasts and osteoblasts both command a multitude of cellular signaling pathways involving protein kinases. Osteoclast activation is initiated by adhesion to bone, cytoskeletal rearrangement, formation of the sealing zone, and formation of the polarized ruffled membrane. It is believed that protein-tyrosine kinase 2 (PYK2) participates in the transfer of signals from the cell surface to the cytoskeleton, as it is tyrosine phosphorylated and activated by adhesion-initiated signaling in osteoclasts (Duong, et al.; 1998, J. Clin. Invest., 102, 881-892).
  • PYK2 protein-tyrosine kinase 2
  • Src tyrosine kinase stands out as a promising therapeutic target for bone disease as validated by Src knockout mouse studies and in vitro cellular experiments, suggesting a regulatory role for Src in both osteoclasts (positive) and osteoblasts (negative).
  • Src plays key roles in motility, polarization, survival, activation (ruffled border formation) and adhesion, by mediating various signal transduction pathways, especially in cytokine and integrin signaling (Parang and Sun; 2005, Expert Opin. Ther. Patents, 15, 1183- 1207).
  • osteopetrosis a disorder characterized by decreased bone resorption, without showing any obvious morphological or functional abnormalities in other tissues or cells (Soriano, et al. ⁇ 1991, Cell, 64, 693-702).
  • the osteopetrotic phenotype of src 1" mice is cell-autonomous and results from defects in mature osteoclasts, which normally express high levels of Src protein (Home, et al. ⁇ 1991, Cell, 119, 1003-1013).
  • Src tyrosine kinase which triggers osteoclast activity and inhibits osteoblasts, Src inhibitors are thought to lessen bone break down and encourage bone formation.
  • a compound of the invention may be used to protect against or prevent obesity in a subject.
  • Another aspect of the invention includes use of a compound of the invention in the manufacture of a medicament to protect against or treat obesity.
  • the compound may be administered prior to the development of obesity in a subject.
  • the compound may be used to treat . obesity in a subject.
  • a compound of the instant invention may be involved in modulating a kinase signaling cascade, e.g., a kinase inhibitor, a non-ATP competitive inhibitor, a tyrosine kinase inhibitor, a protein tyrosine phosphatase inhibitor, or a protein-tyrosine phosphatase IB inhibitor.
  • a kinase signaling cascade e.g., a kinase inhibitor, a non-ATP competitive inhibitor, a tyrosine kinase inhibitor, a protein tyrosine phosphatase inhibitor, or a protein-tyrosine phosphatase IB inhibitor.
  • Obesity is associated with diabetes and increased insulin resistance in insulin responsive tissues, such as skeletal muscle, liver, and white adipose tissue (Klaman, et al. ⁇ 2000, MoI. Cell. Biol, 20, 5479-5489).
  • Insulin plays a critical role in the regulation of glucose homeostasis, lipid metabolism, and energy balance. Insulin signaling is initiated by binding of insulin to the insulin receptor (IR), a receptor tyrosine kinase. Insulin binding evokes a cascade of phosphorylation events, beginning with the autophosphorylation of the IR on multiple tyrosyl residues. Autophosphorylation enhances IR kinase activity and triggers downstream signaling events.
  • IR insulin receptor
  • the stimulatory effects of protein tyrosine kinases and the inhibitory effects of protein tyrosine phosphatases largely define the action of insulin.
  • Appropriate insulin signaling minimizes large fluctuations in blood glucose concentrations and ensures adequate delivery of glucose to cells.
  • insulin stimulation leads to multiple tyrosyl phosphorylation events, enhanced activity of one or more protein-tyrosine phosphatases (PTPs) could lead to insulin resistance, which may lead to obesity.
  • PTPs protein-tyrosine phosphatases
  • increased PTP activity has been reported in several insulin-resistant states, including obesity (Ahmad, et al; 1997, Metabolism, 46, 1140-1145).
  • the administration of a compound of the instant invention modulates kinase (e.g., PTP) activity, thereby treating obesity in a subject.
  • kinase e.g., PTP
  • Insulin signaling begins with the activation of the IR via tyrosine phosphorylation and culminates in the uptake of glucose into cells by the glucose transporter, GLUT4 (Saltiel and Kahn; 2001, Nature, 414, 799-806).
  • the activated IR must then be deactivated and returned to a basal state, a process that is believed to involve protein-tyrosine phosphatase-lB (PTP-IB) (Ahmad, et al; 1997, J. Biol. Chem., 270, 20503-20508).
  • a compound of the invention may be used to protect against or prevent diabetes in a subject.
  • Another aspect of the invention includes use of a compound of the invention in the manufacture of a medicament to protect against or prevent diabetes.
  • the compound may be administered prior to the development of diabetes in a subject.
  • the compound may be used to treat diabetes in a subject.
  • the compound of the instant invention may be involved in modulating a kinase signaling cascade, e.g. a kinase inhibitor, a non-ATP competitive inhibitor, a tyrosine kinase inhibitor, a phosphatase and tension homologue on chromosome 10 (PTEN) inhibitor, or a sequence homology 2-containing inositol 5 '-phosphatase 2 (SHIP2) inhibitor.
  • T2DM Type 2 diabetes mellitus
  • T2DM is a disorder of dysregulated energy metabolism. Energy metabolism is largely controlled by the hormone insulin, a potent anabolic agent that promotes the synthesis and storage of proteins, carbohydrates and lipids, and inhibits their breakdown and release back into the circulation.
  • Insulin action is initiated by binding to its tyrosine kinase receptor, which results in autophosphorylation and increased catalytic activity of the kinase (Patti, et al; 1998, J. Basic CHn. Physiol. Pharmacol. 9, 89- 109).
  • Tyrosine phosphorylation causes insulin receptor substrate (IRS) proteins to interact with the p85 regulatory subunit of phosphatidylinositol 3-kinase (PBK), leading to the activation of the enzyme and its targeting to a specific subcellular location, depending on the cell type.
  • IRS insulin receptor substrate
  • the enzyme generates the lipid product phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P 3 ), which regulates the localization and activity of numerous proteins (Kido, et al; 2001, J. Clin. Endocrinol. Metab., 86, 972-979).
  • PI3K has an essential role in insulin- stimulated glucose uptake and storage, inhibition of lipolysis and regulation of hepatic gene expression (Saltiel, et al; 2001, Nature, 414, 799-806).
  • PTEN is a major regulator of PI3K signaling in may cell types, and functions as a tumor suppressor due to antagonism of the anti-apoptotic, proliferative and hypertrophic activities of the PI3K pathway (Goberdhan, et ah; 2003, Hum.
  • PtdIns(3,4,5)P 3 levels are also controlled by the family of SRC homology 2 (SH2)- containing inositol 5 '-phosphatase (SHIP) proteins, SHIPl and SHIP2 (Lazar and Saltiel; 2006, Nature Reviews, 5, 333-342).
  • SHIP2 expressed in skeletal muscle, among other insulin-sensitive tissues, catalyzes the conversion of PtdIns(3,4,5)P3 into PtdIns(3,4)P 2 (Pesesse, et al; 1997; Biochem Biophys. Res. Commun., 239, 697-700; Backers, et al; 2003, Adv.
  • a compound of the invention may be used to protect against or prevent eye disease in a subject.
  • Another aspect of the invention includes use of a compound of the invention in the manufacture of a medicament to protect against or prevent eye disease.
  • the compound may be administered prior to the development of eye disease in a subject.
  • the compound may be used to treat eye disease in a subject, e.g. macular degeneration, retinopathy, and macular edema.
  • the compound of the instant invention may be involved in modulating a kinase cascade, e.g. a kinase inhibitor, a non-ATP competitive inhibitor, a tyrosine kinase inhibitor, e.g. a vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor.
  • a kinase cascade e.g. a kinase inhibitor, a non-ATP competitive inhibitor, a tyrosine kinase inhibitor, e.g. a vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor.
  • VEGF vascular endothelial growth factor
  • VEGF vascular endothelial growth factor
  • a compound of the instant invention which modulates kinase activity, e.g. tyrosine kinase activity, and results in the inhibition of angiogenesis and/or neovascularization, is useful for treating an eye disease, e.g. macular degeneration, retinopathy and/or macular edema.
  • an eye disease e.g. macular degeneration, retinopathy and/or macular edema.
  • Macular degeneration is characterized by VEGF-mediated retinal leakage (an increase in vascular permeability) and by the abnormal growth of small blood vessels in the back of the eye (angiogenesis).
  • VEGF has been identified in neovascular membranes in both diabetic retinopathy and age-related macular degeneration, and intraocular levels of the factor correlate with the severity of neovascularization in diabetic retinopathy (Kvanta, et al. ⁇ 1996, Invest. Ophthal. Vis. ScL, 37, 1929-1934.; Aiello, et al; 1994, N. Engl. J. Med., 331, 1480- 1487).
  • Therapeutic antagonism of VEGF in these models results in significant inhibition of both retinal and choroidal neovascularization, as well as a reduction in vascular permeability (Aiello, et al.; 1995, Proc. Natl. Acad. ScL USA., 92, 10457-10461; Krzystolik, et al.; 2002, Arch. Ophthal, 120, 338-346; Qaum, et al; 200 ⁇ , Invest. Ophthal. Vis. ScL, 42, 2408-2413).
  • a compound of the instant invention which modulates VEGF activity, and results in the inhibition of angiogenesis and/or neovascularization, is useful for treating an eye disease, e.g. macular degeneration, retinopathy and/or macular edema.
  • the compounds of the invention are used in methods of treating, preventing, or ameliorating a stroke in a subject who is at risk of suffering a stroke, is suffering from a stroke or has suffered a stroke.
  • the compounds of the invention are useful in methods of treating patients who are undergoing post-stroke rehabilitation.
  • Another aspect of the invention includes use of a compound of the invention in the manufacture of a medicament to treat, prevent, or ameliorating stroke.
  • a stroke also known as a cerebrovascular accident (CVA)
  • CVA cerebrovascular accident
  • the part of the brain in which blood supply is interrupted no longer receives oxygen and/or nutrients carried by the blood.
  • the brain cells become damaged or necrotic, thereby impairing function in or from that part of the brain.
  • Brain tissue ceases to function if deprived of oxygen for more than 60 to 90 seconds and after a few minutes will suffer irreversible injury possibly leading to a death of the tissue, i.e., infarction.
  • Strokes are classified into two major types: ischemic, i.e., blockage of a blood vessel supplying the brain, and hemorrhagic, Le., bleeding into or around the brain.
  • Ischemic stroke is commonly divided into thrombotic stroke, embolic stroke, systemic hypoperfusion (Watershed stroke), or venous thrombosis.
  • thrombotic stroke a thrombus-forming process develops in the affected artery, the thrombus, Le., blood clot, gradually narrows the lumen of the artery, thereby impeding blood flow to distal tissue. These clots usually form around atherosclerotic plaques.
  • thrombotic strokes There are two types of thrombotic strokes, which are categorized based on the type of vessel on which the thrombus is formed. Large vessel thrombotic stroke involves the common and internal carotids, vertebral, and the Circle of Willis. Small vessel thrombotic stroke involves the intracerebral arteries, branches of the Circle of Willis, middle cerebral artery stem, and arteries arising from the distal vertebral and basilar artery. [000252] A thrombus, even if non-occluding, can lead to an embolic stroke if the thrombus breaks off, at which point it becomes an embolus. An embolus refers to a traveling particle or debris in the arterial bloodstream originating from elsewhere.
  • Embolic stroke refers to the blockage of arterial access to a part of the brain by an embolus.
  • An embolus is frequently a blood clot, but it can also be a plaque that has broken off from an atherosclerotic blood vessel or a number of other substances including fat, air, and even cancerous cells. Because an embolus arises from elsewhere, local therapy only solves the problem temporarily. Thus, the source of the embolus must be identified.
  • embolic stroke There are four categories of embolic stroke: those with a known cardiac source; those with a potential cardiac or aortic source (from trans-thoracic or trans-esophageal echocardiogram); those with an arterial source; and those with unknown source.
  • Systemic hypoperfusion is the reduction of blood flow to all parts of the body- It is most commonly due to cardiac pump failure from cardiac arrest or arrhythmias, or from reduced cardiac output as a result of myocardial infarction, pulmonary embolism, pericardial effusion, or bleeding. Hypoxemia (i.e., low blood oxygen content) may precipitate the hypoperfusion. Because the reduction in blood flow is global, all parts of the brain may be affected, especially the "watershed" areas which are border zone regions supplied by the major cerebral arteries. Blood flow to these area has not necessary stopped, but instead may have lessened to the point where brain damage occurs.
  • Stroke is diagnosed in a subject or patient using one or more of a variety of techniques known in the art, such as, for example, neurological examination, blood tests, CT scans (without contrast enhancements), MRI scans, Doppler ultrasound, and arteriography (i.e., roentgenography of arteries after injection of radiopacque material into the blood stream).
  • various other studies are performed to determine whether there is a peripheral source of emboli. These studies include, e.g., an ultrasound/doppler study of the carotid arteries (to detect carotid stenosis); an electrocardiogram (ECG) and echocardiogram (to identify arrhythmias and resultant clots in the heart which may spread to the brain vessels through the bloodstream); a Holter monitor study to identify intermittent arrhythmias and an angiogram of the cerebral vasculature (if a bleed is thought to have originated from an aneurysm or arteriovenous malformation).
  • ECG electrocardiogram
  • ECG electrocardiogram
  • echocardiogram to identify arrhythmias and resultant clots in the heart which may spread to the brain vessels through the bloodstream
  • Holter monitor study to identify intermittent arrhythmias and an angiogram of the cerebral vasculature (if a bleed is thought to have originated from an aneurysm or arteriovenous malformation).
  • Compounds useful in these methods of treating, preventing or ameliorating stroke or a symptom associated with stroke are compounds that modulate kinase signaling cascade preceding, during or after a stroke.
  • the compound is a kinase inhibitor.
  • the compound is a tyrosine kinase inhibitor.
  • the tyrosine kinase inhibitor is an Src inhibitor.
  • the compound used in the methods of treating, preventing or ameliorating stroke or a symptom associated with stroke described herein is an allosteric inhibitor of kinase signaling cascade preceding, during or after a stroke.
  • the compound used in the methods of treating, preventing or ameliorating stroke or a symptom associated with stroke described herein is a non-ATP competitive inhibitor of kinase signaling cascade preceding, during or after a stroke.
  • VEGF Vascular endothelia growth factor
  • Src inhibition may be useful in the prevention, treatment or amelioration of secondary damage following a stroke.
  • the compounds of the invention prevent, treat or ameliorate stroke or a symptom associated with stroke.
  • Another aspect of the invention includes use of a compound of the invention in the manufacture of a medicament to prevent, treat, or ameliorate stroke or a symptom associated with stroke.
  • Symptoms of a stroke include sudden numbness or weakness, especially on one side of the body; sudden confusion or trouble speaking or understanding speech; sudden trouble seeing in one or both eyes; sudden trouble with walking, dizziness, or loss of balance or coordination; or sudden severe headache with no known cause.
  • Acute stroke therapies try to stop a stroke while it is happening by quickly dissolving the blood clot causing an ischemic stroke or by stopping the bleeding of a hemorrhagic stroke.
  • Post-stroke rehabilitation helps individuals overcome disabilities that result from stroke damage. Medication or drug therapy is the most common treatment for stroke.
  • anti-thrombotics e.g., anti-platelet agents and anticoagulants
  • thrombolytics e.g., thrombolytics.
  • the compounds are administered to a patient who is at risk of suffering a stroke, is suffering from a stroke or has suffered a stroke at a time before, during, after, or any combination thereof, the occurrence of a stroke.
  • the compounds of the invention are administered alone, in pharmaceutical compositions, or in combination with any of a variety of known treatments, such as, for example, an anti-platelet medication (e.g., aspirin, clopidogrel, dipyridamole), an anti-coagulant (e.g., warfarin), or a thrombolytic medication ⁇ e.g., tissue plasminogen activator (t-PA), reteplase, Urokinase, streptokinase, tenectaplase, lanoteplase, or anistreplase.
  • an anti-platelet medication e.g., aspirin, clopidogrel, dipyridamole
  • an anti-coagulant e.g., warfarin
  • a thrombolytic medication ⁇ e.g., tissue plasminogen activator (t-PA), reteplase, Urokinase, streptokinase, tenectaplase, lanoteplas
  • the compounds of the invention are used in methods of treating, preventing, ameliorating atherosclerosis or a symptom thereof in a subject who is at risk for or suffering from atherosclerosis.
  • Another aspect of the invention includes use of a compound of the invention in the manufacture of a medicament to treat, prevent, or ameliorate atherosclerosis.
  • Atherosclerosis is a disease affecting the arterial blood vessel and is commonly referred to as a "hardening" of the arteries. It is caused by the formation of multiple plaques within the arteries.
  • Atherosclerotic plaques though compensated for by artery enlargement, eventually lead to plaque ruptures and stenosis (i.e., narrowing) of the artery, which, in turn, leads to an insufficient blood supply to the organ it feeds.
  • stenosis i.e., narrowing
  • a net aneurysm results.
  • These complications are chronic, slowly progressing and cumulative.
  • soft plaque suddenly ruptures, causing the formation of a blood clot (Le., thrombus) that rapidly slows or stops blood flow, which, in turn, leads to death of the tissues fed by the artery. This catastrophic event is called an infarction.
  • coronary thrombosis of a coronary artery causes a myocardial infarction, commonly known as a heart attack.
  • a myocardial infarction occurs when an atherosclerotic plaque slowly builds up in the inner lining of a coronary artery and then suddenly ruptures, totally occluding the artery and preventing blood flow downstream.
  • Atherosclerosis and acute myocardial infarction are diagnosed in a patient using any of a variety of clinical and/or laboratory tests such as, physical examination, radiologic or ultrasound examination and blood analysis.
  • a doctor or clinical can listen to a subject's arteries to detect an abnormal whooshing sound, called a Son.
  • a Son can be heard with a stethoscope when placed over the affected artery.
  • the clinician or physician can check pulses, e.g. , in the leg or foot, for abnormalities such as weakness or absence.
  • the physician or clinical may perform blood work to check for cholesterol levels or to check the levels of cardiac enzymes, such as creatine kinase, troponin and lactate dehydrogenase, to detect abnormalities.
  • cardiac enzymes such as creatine kinase, troponin and lactate dehydrogenase
  • troponin sub-units I or T which are very specific for the myocardium, rise before permanent injury develops.
  • a positive troponin in the setting of chest pain may accurately predict a high likelihood of a myocardial infarction in the near future.
  • EKG electrocardiogram
  • chest X-ray measuring ankle/brachial index, which compares the blood pressure in the ankle with the blood pressure in the arm
  • ultrasound analysis of arteries CT scan of areas of interest
  • angiography an exercise stress test
  • nuclear heart scanning nuclear heart scanning
  • PET positron emission tomography
  • Compounds useful in these methods of treating, preventing or ameliorating atherosclerosis or a symptom thereof are compounds that modulate kinase signaling cascade in a patient at risk for or suffering from atherosclerosis.
  • the compound is a kinase inhibitor.
  • the compound is a tyrosine kinase inhibitor.
  • the tyrosine kinase inhibitor is an Src inhibitor.
  • the compound used in the methods of treating, preventing or ameliorating atherosclerosis or a symptom thereof described herein is an allosteric inhibitor of kinase signaling cascade involved in atherosclerosis.
  • the compound used in the methods of treating, preventing or ameliorating atherosclerosis or a symptom associated with atherosclerosis described herein is a non-ATP competitive inhibitor of kinase signaling cascade involved in atherosclerosis.
  • VP vascular permeability
  • VEGF Vascular endothelia growth factor
  • the compounds of the invention prevent, treat or ameliorate stroke or a symptom associated with atherosclerosis.
  • Another aspect of the invention includes use of a compound of the invention in the manufacture of a medicament to prevent, treat, or ameliorate stroke or a symptom associated with atherosclerosis.
  • Atherosclerosis generally does not produce symptoms until it severely narrows the artery and restricts blood flow, or until it causes a sudden obstruction. Symptoms depend on where the plaques and narrowing develop, e.g., in the heart, brain, other vital organs and legs or almost anywhere in the body.
  • the initial symptoms of atherosclerosis may be pain or cramps when the body requires more oxygen, for example during exercise, when a person may feel chest pain (angina) because of lack of oxygen to the heart or leg cramps because of lack of oxygen to the legs. Narrowing of the arteries supplying blood to the brain may cause dizziness or transient ischemic attacks (TIA's) where the symptoms and signs of a stroke last less than 24 hours. Typically, these symptoms develop gradually.
  • TAA's transient ischemic attacks
  • Chest pain is the most common symptom of acute myocardial infarction and is often described as a tightness, pressure, or squeezing sensation. Pain may radiate to the jaw, neck, arms, back, and epigastrium, most often to the left arm or neck. Chest pain is more likely caused by myocardial infarction when it lasts for more than 30 minutes.
  • Patients suffering from a myocardial infarction may exhibit shortness of breath (dyspnea) especially if the decrease in myocardial contractility due to the infarct is sufficient to cause left ventricular failure with pulmonary congestion or even pulmonary edema.
  • the compounds of the invention are administered alone, in pharmaceutical compositions, or in combination with any of a variety of known treatments for atherosclerosis, such as, for example, cholesterol-lowering drugs (e.g., statins), anti-platelet medications, or anti-coagulants.
  • the compounds of the invention are used in methods of treating, preventing, ameliorating neuropathic pain, such as chronic neuropathic pain, or a symptom thereof in a subject who is at risk of suffering from, is suffering from, or has suffered neuropathic pain.
  • Another aspect of the invention includes use of a compound of the invention in the manufacture of a medicament to treat, prevent or ameliorate neuropathic pain.
  • Neuropathic pain also known as neuralgia, is qualitatively different from ordinary nociceptive pain. Neuropathic pain usually presents as a steady burning and/or "pins and needles" and/or "electric shock” sensations.
  • nociceptive pain is due to the fact that "ordinary", nociceptive pain stimulates only pain nerves, while a neuropathy often results in the stimulation of both pain and non-pain sensory nerves ⁇ e.g., nerves that respond to touch, warmth, cool) in the same area, thereby producing signals that the spinal cord and brain do not normally expect to receive.
  • Neuropathic pain is a complex, chronic pain state that usually is accompanied by tissue injury. With neuropathic pain, the nerve fibers themselves may be damaged, dysfunctional or injured. These damaged nerve fibers send incorrect signals to other pain centers.
  • the impact of nerve fiber injury includes a change in nerve function both at the site of injury and areas around the injury.
  • Neuropathic pain is diagnosed in a subject or patient using one or more of a variety of laboratory and/or clinical techniques known in the art, such as, for example, physical examination.
  • Compounds useful in these methods of treating, preventing or ameliorating neuropathic pain, such as chronic neuropathic pain, or a symptom associated with neuropathic pain are compounds that modulate kinase signaling cascade involved in neuropathic pain.
  • the compound is a kinase inhibitor.
  • the compound is a tyrosine kinase inhibitor.
  • the tyrosine kinase inhibitor is an Src inhibitor.
  • the compound used in the methods of treating, preventing or ameliorating neuropathic pain or a symptom thereof is an allosteric inhibitor of kinase signaling cascade involved in neuropathic pain.
  • the compound used in the methods of treating, preventing or ameliorating neuropathic pain or a symptom thereof is a non-ATP competitive inhibitor of kinase signaling cascade involved in neuropathic pain.
  • NMDA N-methyl-D-aspartate
  • PP2 a low molecular weight Src kinase inhibitor, decreases phosphorylation of the NMDA receptor NM2 subunit.
  • Src inhibition which in turn, inhibits the activity NMDA receptors, may be useful in the prevention, treatment or amelioration of neuropathic pain, such as chronic neuropathic pain.
  • the compounds of the invention prevent, treat or ameliorate neuropathic pain, such as chronic neuropathic pain, or a symptom associated with neuropathic pain. Symptoms of neuropathic pain include shooting and burning pain, tingling and numbness.
  • neuropathic pain such as chronic neuropathic pain, or a symptom associated with neuropathic pain. Symptoms of neuropathic pain include shooting and burning pain, tingling and numbness.
  • the compounds of the invention are administered alone, in pharmaceutical compositions, or in combination with any of a variety of known treatments, such as, for example, analgesics, opioids, tricyclic antidepressants, anticonvulsants and serotonin norepinephrine reuptake inhibitors
  • the compounds of the invention are used in methods of treating, preventing, ameliorating hepatitis B or a symptom thereof in a subject who is at risk for or suffering from hepatitis B.
  • Another aspect of the invention includes use of a compound of the invention in the manufacture of a medicament to treat, prevent, or ameliorate hepatitis B.
  • the hepatitis B virus a member of the Hepadnavirus family, consists of a proteinaceous core particle containing the viral genome in the form of double stranded DNA with single-stranded regions and an outer lipid-based envelope with embedded proteins. The envelope proteins .are involved in viral binding and release into susceptible cells.
  • the inner capsid relocates the DNA genome to the cell's nucleus where viral mKNAs are transcribed. Three subgenomic transcripts encoding the envelope proteins are made, along with a transcript encoding the X protein. A fourth pre-genomic RNA is transcribed, which ' is exported to the cytosol and translates the viral polymerase and core proteins. Polymerase and pre-genomic RNA are encapsidated in assembling core particles, where reverse transcription of the pre-genomic RNA to genomic DNA occurs by the polymerase protein. The mature core particle then exits the cell via normal secretory pathways, acquiring an envelope along the way.
  • Hepatitis B is one of a few known non-retroviral viruses that employ reverse transcription as part of the replication process.
  • Other viruses which use reverse transcription include, eg., HTLV or HTV.
  • CTLs virus-specific cytotoxic T lymphocytes
  • Hepatitis B is diagnosed in a patient using any of a variety of clinical and/or laboratory tests such as, physical examination, and blood or serum analysis. For example, blood or serum is assayed for the presence of viral antigens and/or antibodies produced by the host.
  • detection of hepatitis B surface antigen is used to screen for the presence of infection. It is the first detectable viral antigen to appear during infection with this virus; however, early in an infection, this antigen may not be present and it may be undetectable later in the infection as it is being cleared by the host.
  • IgM antibodies to the hepatitis B core antigen may be the only serologic evidence of disease.
  • HBeAg another antigen named as the hepatitis B e antigen (HBeAg) will appear.
  • HBeAg the hepatitis B e antigen
  • the HBeAg may be cleared, and antibodies to the "e” antigen (anti-HBe) will arise immediately afterward.
  • Compounds useful in these methods of treating, preventing or ameliorating hepatitis B or a symptom thereof are compounds that modulate kinase signaling cascade in a patient at risk for or suffering from hepatitis B.
  • the compound is a kinase inhibitor.
  • the compound is a tyrosine kinase inhibitor.
  • the tyrosine kinase inhibitor is an Src inhibitor.
  • the compound used in the methods of treating, preventing or ameliorating hepatitis B or a symptom thereof described herein is an allosteric inhibitor of kinase signaling cascade involved in hepatitis B.
  • the compound used in the methods of treating, preventing or ameliorating hepatitis B or a symptom associated with hepatitis B described herein is a non-ATP competitive inhibitor of kinase signaling cascade involved in hepatitis B.
  • Src plays a role in the replication of the hepatitis B virus.
  • the virally encoded transcription factor HBx activates Src in a step that is required from propagation of the HBV virus. ⁇ See, e.g., Klein et al., EMBO J., vol. 18:5019-5027 (1999); Klein et al., MoI. Cell. Biol., vol.
  • Src inhibition which in turn, inhibits Src-mediated propagation of the HBV virus, may be useful in the prevention, treatment or amelioration of hepatitis B or a symptom thereof.
  • the compounds of the invention prevent, treat or ameliorate hepatitis B or a symptom associated with hepatitis B.
  • Symptoms of hepatitis B typically develop within 30- 180 days of exposure to the virus. However, up to half of all people infected with the hepatitis B virus have no symptoms.
  • the symptoms of hepatitis B are often compared to flu, and include, e.g., appetite loss; fatigue; nausea and vomiting, itching all over the body; pain over the liver (e.g. , on the right side of the abdomen, under the lower rib cage), jaundice, and changes in excretory functions.
  • the compounds of the invention are administered alone, in pharmaceutical compositions, or in combination with any of a variety of known treatments for hepatitis B, such as, for example, interferon alpha, lamivudine (Epivir-HBV) and baraclude (entecavir).
  • the compounds of the invention may be used to regulate immune system activity in a subject, thereby protecting against or preventing autoimmune disease, e.g., rheumatoid arthritis, multiple sclerosis, sepsis and lupus as well as transplant rejection and allergic diseases.
  • Another aspect of the invention includes use of a compound of the invention in the manufacture of a medicament to regulate the immune system.
  • the compound may be used to treat autoimmune disease in a subject.
  • the compound may result in reduction in the severity of symptoms or halt impending progression of the autoimmune disease in a subject.
  • the compound of the invention may be involved in modulating a kinase signaling cascade, e.g., a kinase inhibitor, a non-ATP competitive inhibitor, a tyrosine kinase inhibitor, e.g., a Src inhibitor, a p59fyn (Fyn) inhibitor or a p561ck (Lck) inhibitor.
  • a kinase signaling cascade e.g., a kinase inhibitor, a non-ATP competitive inhibitor, a tyrosine kinase inhibitor, e.g., a Src inhibitor, a p59fyn (Fyn) inhibitor or a p561ck (Lck) inhibitor.
  • Autoimmune diseases are diseases caused by a breakdown of self-tolerance such that the adaptive immune system responds to self antigens and mediates cell and tissue damage.
  • Autoimmune diseases can be organ specific (e.g., thyroiditis or diabetes) or systemic (e.g., systemic lupus erythematosus).
  • T cells modulate the cell-mediated immune response in the adaptive immune system. Under normal conditions, T cells express antigen receptors (T cell receptors) that recognize peptide fragments of foreign proteins bound to self major histocompatibility complex molecules.
  • TCR T cell receptor
  • tyrosine kinases lck and fyn are both activated in the TCR pathway; thus, inhibitors of lck and/or fyn have potential utility as autoimmune agents (Palacios and Weiss; 2004, Oncogene, 23, 7990-8000).
  • Lck and Fyn are predominantly expressed by T cells through most of their lifespan.
  • the roles of Lck and Fyn in T cell development, homeostasis and activation have been demonstrated by animal and cell line studies (Parang and Sun; 2005, Expert Opin. The. Patents, 15, 1183-1207). Lck activation is involved in autoimmune diseases and transplant rejection (Kamens, et al; 2001, Curr. Opin. Investig.
  • an agent inhibiting lck would effectively block T cell function, act as an immunosuppressive agent, and have potential utility in autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, and lupus, as well as in the area of transplant rejection and allergic diseases (Hanke and Pollok; 1995, Inflammation Res., 44, 357-371).
  • autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, and lupus
  • a compound of the instant invention which modulates one or more members of the Src family of protein tyrosine kinases (e.g., lck and/or fyn) is useful in the treatment of autoimmune disease.
  • Compounds of the invention include compounds with water solubilizing groups appended on the compound (Wermuth, C.G., The Practice of Medicinal Chemistry
  • Compounds of the invention include compounds of Formula I, and salts thereof:
  • T is absent (/. e. , the rings are connected by a bond),CR 12 Ri 3 , C(O), O, S, S(O), S(O) 2 , NR 14 , C(R 15 Ri 6 )C(R 17 Ri 8 ), CH 2 O, or OCH 2 ;
  • X y is CZ, CY, N, or N-O;
  • X 2 is CZ, CY, N, or N-O;
  • at least one of X y and X 2 is CZ;
  • Y is selected from hydrogen, hydroxyl, halogen, lower (Cu C 2 , C 3 , C4, Cs, or C 6 ) alkyl, Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, 0-lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-aryl, and O-benzyl;
  • X a is CR 3 or N, or N-O;
  • X b is CR b , N, or N-O;
  • X c is CR c or N, or N-O;
  • X d is CR d or N, or N-O;
  • X 6 is CRe, N, or N-O
  • R 3 , R b , R « R d , Re, R4, R5, and Re are, independently, hydrogen, hydroxyl, halogen, P, Ci, C 2 ,
  • C 3 , C 4 , C 5 , or C 6 alkyl Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, O-lower (C u C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-aryl, O-benzyl, Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-OH, COOH, COO-lower (C,, C 2 , C 3 , C 4 ,
  • P is SO 3 H, OSO 3 H, OPO 3 H 2 , OPO 3 H 2 , NH 2 , NHRi 9 , NHR 20 R 2 I, " °, tetrazole, O-lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-K, O-C(O)-lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-L, NH-lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-M, or O-aryl-Q, further wherein lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl is linear or branched alkyl; [000302] K is C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3
  • NRigR ⁇ o * SO2R 2 U glycoside lower Cu C2, C3, C 4 , Cs, CO alkoxy, aryl, heteroaryl, or
  • L is aryl, heteroaryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHRi 9 , NR 19 R 20 , SO 2 R 2 ], glycoside, lower Ci, C 2 , C 3 , C 4 , C 5 , C 6 alkoxy,
  • M is aryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR, 9 R 20 ,
  • Q is aryl, heteroaryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 ,
  • Ri 9 , R 20 and R 2 i are independently Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl or Ri 9 and
  • V is a bond, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -0-CH 2 -, -OCH 2 CH 2 - or -
  • R 12 , Ri 3 , Ri 4 , R15, R-16, Rn, and R] 8 are, independently, H or Ci , C 2 , C 3 , C 4 ,
  • Z is (CHRi) n -C(O)-NR 2 (CHR 3 ) m -Ar, where Ar is a substituted or unsubstituted aryl or nitrogen-containing heteroaryl group, such as benzene, pyridine, or pyrimidine.
  • Ar is a substituted or unsubstituted aryl or nitrogen-containing heteroaryl group, such as benzene, pyridine, or pyrimidine.
  • Z is:
  • Ri, R 2 , and R 3 are independently H or Ci, C 2 , C 3 , C 4 , C 5 , or C ⁇ alkyl;
  • n and m are, independently 0, 1 , or 2;
  • R 7 , R 8 , R 9 , Ri 0 , and Ri i are, independently, hydrogen, hydroxyl, halogen, P, Ci, C 2 , C 3 , C 4 , Cs, or Ce alkyl, Ci, C2, C 3 , C4, C 5 , or C 6 alkoxy, O-lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-aryl, O-benzyl, Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-OH, COOH, COO-lower (Ci, C 2 , C 3 , C 4 , C s , or C 6 ) alkyl, SO 2 H, SO 2 H-lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl,
  • W is H, or Ci, C 2 , C 3 ,
  • P is SO 3 H, OSO 3 H, OPO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NHR 20 R 2 I, " ° , tetrazole, O-lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-K, O-C(O)-lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-L, NH-lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-M, or O-aryl-Q, further wherein lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl is linear or branched alkyl; [000311] K is C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3
  • L is aryl, heteroaryl, OH, C(O)NH 2 , COOH 5 SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NRi 9 R 2 O, SO 2 R 2 I, glycoside, lower Ci, C 2 , C 3 , C 4 , C 5 , C 6 alkoxy,
  • M is aryl, heteroaryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 ,
  • Q is aryl, heteroaryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 ,
  • Ri 9 , R 20 and R 2 i are independently Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl or R 1 9 and
  • R 20 taken together with the attached nitrogen atom form a five membered ring
  • V is a bond, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -O-CH 2 -, -OCH 2 CH 2 -, or -
  • the compound of the invention is Compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 93, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107,
  • Compounds of the invention include Compounds 33, 38, 40, 76, 133, 134, 136 and 137.
  • Certain compounds of the invention are selected from Compounds 138-246 and 247.
  • the compound of the invention is Compound 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214,
  • Compounds of the invention include Compounds 146 and 147.
  • Certain compounds of the invention are selected from Compounds 248-273 and 274.
  • the compound of the invention is Compound 248, 249, 250, 251 , 252,
  • At least one OfX 3 , X b , X 0 , Xa and Xe is N.
  • X a is N and each of X b is CR b , X 0 is CRc, Xd is CRd and Xe is CRe.
  • X y is CY
  • X z is CZ
  • Y is hydrogen
  • the compounds of the invention can tolerate a wide variety of functional groups, so various substituted starting materials can be used to synthesize them.
  • the syntheses described herein generally provide the desired final bi-aryl compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt, ester, or prodrug thereof.
  • Rb is Ci, C 2 , C 3 , C 4 , C 5 , or Ce alkoxy.
  • Rb is methoxy or ethoxy.
  • Rb is hydrogen.
  • R b is selected from F, Cl, Br, and I.
  • R b is F.
  • R b is — W , where W is H, or Ci, C 2 , C 3 ,
  • V is a bond.
  • V is -CH 2 -, -CH 2 CH 2 -Or -CH 2 CH 2 CH 2 -.
  • V is -O-CH 2 -, -OCH 2 CH 2 - or -OCH 2 CH 2 CH 2 -.
  • W is hydrogen. In other compounds, W is
  • Ci Ci, C 2 , C 3 , C 4 , C 5 , or C ⁇ alkyl.
  • W is methyl.
  • R 0 is halogen, for example, R 0 is F, Cl, Br, or I. In some compounds, Rc is F. In other compounds, R 0 is Cl.
  • R 0 is Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy. In some compounds, R 0 is methoxy or ethoxy. In some embodiments, Rc is ethoxy.
  • R 0 is hydrogen.
  • R 0 is , where W is H, Or Ci 3 C 2 ,
  • V is a bond, -CH 2 -, -CH 2 CH 2 -, -
  • V is a bond.
  • V is -CH 2 -, -CH 2 CH 2 -Or -CHaCH 2 CH 2 -. In other compounds, V is -O-
  • W is hydrogen. In other compounds, W is
  • Ci Ci, C 2 , C 3 , C 4 , C 5 , or Ce alkyl.
  • ' W is methyl.
  • R b is Ci, C 2 , C 3 , C4, C5, or Ce alkoxy.
  • R b is methoxy or ethoxy.
  • R b is hydrogen.
  • R b is selected from F, Cl, Br, and I.
  • Rb is F.
  • Rb is , where W is H, or Ci, C 2 , C 3 ,
  • V is a bond, -CH 2 -, -CH 2 CH 2 -, - CH 2 CH 2 CH 2 -, -O-CH 2 -, -OCH 2 CH 2 - or -OCH 2 CH 2 CH 2 -.
  • V is a bond.
  • V is -CH 2 -, -CH 2 CH 2 -Or -CH 2 CH 2 CH 2 -.
  • V is -O-CH 2 -, -OCH 2 CH 2 - or -OCH 2 CH 2 CH 2 -.
  • W is hydrogen. In other compounds, W is Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl. In some compounds, W is methyl.
  • Rd is halogen, for example, Rd is F, Cl, Br, or I. In some compounds, Ra is F. In other compounds, Ra is Cl. [000340] In some compounds, Rd is Ci, C 2 , C 3 , C 4 , C5, or C 6 alkoxy. In some compounds, R d is methoxy or ethoxy. In some embodiments, R d is ethoxy. [000341] In other compounds of Formula I, R d is hydrogen. [000342] In other compounds of Formula I, R d is
  • V is a bond, -CH 2 -, -CH 2 CH 2 -, - CH 2 CH 2 CH 2 -, -O-CH 2 -, -OCH 2 CH 2 - or -OCH 2 CH 2 CH 2 -.
  • V is a bond.
  • V is -CH 2 -, -CH 2 CH 2 -Or -CH 2 CH 2 CH 2 -.
  • V is -O- CH 2 -, -OCH 2 CH 2 - or -OCH 2 CH 2 CH 2 -.
  • W is hydrogen. In other compounds, W is Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl. In certain compounds, W is methyl. [000344]
  • the invention relates to a compound of Formula I, having a structure according to one of Formulae H, III, IV, V, VI, VII, VIII, IX, X, XI, XII, and XIII:
  • Formula XUI or a salt, solvate, hydrate, or prodrug thereof, where:
  • Rb, R 4 , Rs, Rs, and Rio are, independently, hydrogen, hydroxyl, halogen, Ci,
  • C 2 , C 3 , C 4 , C 5 , or C 6 alkyl Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, O-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-aryl, O-benzyl, Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-OH, Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-O- lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl, COOH, COO-lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl, SO 2 H, SO 2 -lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl,
  • W is H, or Ci, C 2 , C 3 ,
  • V is a bond, -CH 2 -, -CH 2 CH 2 -, - CH 2 CH 2 CH 2 -, -O-CH 2 -, -OCH 2 CH 2 - or -OCH 2 CH 2 CH 2 -.
  • Rg is hydrogen, F, Cl, Br, or I.
  • Rg is F.
  • Re is H.
  • R b is C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy.
  • Rb is methoxy or ethoxy.
  • R b is ethoxy.
  • R b is hydrogen.
  • R b is Cl, Br, or I.
  • Rb is F or Cl.
  • R b is where W is H, or Ci, C 2 , C 3 ,
  • V is a bond, -CH 2 -, -CH 2 CH 2 -, - CH 2 CH 2 CH 2 -, -O-CH 2 -, -OCH 2 CH 2 - or -OCH 2 CH 2 CH 2 -.
  • V is -0-CH 2 -, -OCH 2 CH 2 - or -OCH 2 CH 2 CH 2 -.
  • W is H.
  • W is Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl.
  • W is methyl.
  • R 4 is hydrogen, Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, F, Cl, Br, o ⁇ I.
  • R 4 is Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy.
  • R 4 is methoxy or ethoxy.
  • R 4 is ethoxy.
  • R 4 is where W is H, or
  • Ci Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl
  • Ci Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-aryl
  • V is a bond, -CH 2 -, - CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -0-CH 2 -, -OCH 2 CH 2 - or -OCH 2 CH 2 CH 2 -.
  • V is a bond.
  • V is -CH 2 -, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -.
  • V is -O-CH 2 -, -OCH 2 CH 2 - or -OCH 2 CH 2 CH 2 -.
  • R 5 is hydrogen, Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, F, Cl, Br, or I.
  • R 5 is hydrogen.
  • R 5 is ethoxy.
  • Rs is F.
  • XIII 5 R 5 is where W is H, or Ci,
  • V is a bond, -CH 2 -, - CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -O-CH 2 -, -OCH 2 CH 2 - or -OCH 2 CH 2 CH 2 -.
  • V is a bond. In other compounds, V is -CH 2 -, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -. In other compounds, V is -O-CH 2 -, -OCH 2 CH 2 - or -OCH 2 CH 2 CH 2 -.
  • Rio is hydrogen, Ci, C 2 , C3, C4, C 5 , or Ce alkoxy, F, Cl, Br, or I.
  • Rio Ci, C 2 , C 3 , C4, C 5 , or C 6 alkoxy.
  • Rio is methoxy or ethoxy.
  • Rio is isobutoxy.
  • Rio is hydrogen.
  • Rio is halogen.
  • Rio is F or Cl.
  • Ci Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl
  • Ci Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-aryl
  • V is a bond, -CH 2 -, - CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -O-CH 2 -, -OCH 2 CH 2 - or -OCH 2 CH 2 CH 2 -.
  • V is a bond. In other compounds, V is -CH 2 -, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -. In other compounds, V is -O-CH 2 -, -OCH 2 CH 2 - or -OCH 2 CH 2 CH 2 -.
  • W is hydrogen, or Ci, C 2 , C3, C 4 , C 5 , or C 6 alkyl. In some compounds, W is methyl.
  • Certain compounds of the invention include compounds according to Formula
  • Compounds of the invention include compounds of Formula IA, and salts, solvates, hydrates, or prodrugs thereof:
  • T is absent (i.e., the rings are connected by a bond), CR 1 2R13, C(O), O, S, S(O), S(O) 2 , NRi 4 ,
  • X y is CZ, CY, N, or N-O;
  • X 2 is CZ, CY, N, or N-O;
  • At least one of X y and X 2 is CZ;
  • Y is selected from hydrogen, hydroxyl, halogen, lower (Ci, C2, C3, G», Cs, or C 6 ) alkyl, C u C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, O-lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl- aryl, and O-benzyl;
  • X a is CR a or N, or N-O
  • Xb is CRb, N, or N-O
  • X d is CR d or N, or N-O;
  • X is CR 6 , N, or N-O;
  • R a , R b , R 0 , R d , R e , R 4 , Rs, and Re are, independently, hydrogen, hydroxyl, halogen, P, Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, O-lower (Ci,
  • P is SO 3 H, OSO 3 H, OPO 3 H 2 , OPO 3 H 2 , NH 2 , NHR !9 , NHR 20 R 2 I, " ' ° , tetrazole, O-lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-K, O-C(O)-lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-L, NH-lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-M, or O-aryl-Q, further wherein lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl is linear or branched alkyl; [000371] K is C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2
  • L is aryl, heteroaryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHRi 9 , NRi 9 R 20 , SO 2 R 2 I, glycoside, lower Ci, C 2 , C 3 , C 4 , C 5 , C 6 alkoxy,
  • M is aryl, heteroaryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 ,
  • Q is aryl, heteroaryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 ,
  • Ri 9 , R 20 and R 2 i are independently Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl or Ri 9 and
  • V is a bond, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -O-CH 2 -, -OCH 2 CH 2 - or -
  • Ri 2 , Rn, Ri 4 , Ris, Ri ⁇ , Rn, and R i8 are, independently, H or Ci, C 2 , C 3 , C 4 , C5, or Ce alkyl; and
  • Z is (CHRi) n -C(O)-NR 2 (CHR 3 )m-Ar, where Ar is a substituted or unsubstituted aryl or nitrogen-containing heteroaryl group, Ri, R 2 , and R 3 are independently H or Ci, C 2 , C 3 , C 4 , C5, or Ce alkyl; and n and m are, independently 0, 1, or 2,
  • At least one OfR 3 , Rb, Rc, Rd, R 8 , R 4 , Rs, and R 6 is P.
  • at least one OfX 3 , Xb, X 0 , Xd, Xe, Xy and X z is N.
  • at least two of X a , Xb 5 Xc, Xa, X « Xy and X 2 are N.
  • at least one OfX 3 and X y is N. For example, both X 3 and X y are N.
  • X 3 , Xb, X 0 , Xd, and X 6 are not each N or N-O. In another embodiment, X 0 , X d , and X e are not each N or N-O.
  • T is absent e.g., a bond.
  • Xb is CR b -
  • R b is P.
  • P is O-lower (Ci, C2, C 3 , C 4 , C 5 , or Ce) alkyl-K.
  • lower (Ci, C2, C 3 , C 4 , Cs, or Ce) alkyl is CH2CH2CH2.
  • lower (Ci, C2, C 3 , C 4 , Cs, or Ce) alkyl is branched
  • alkyl For example, branched alkyl is In another embodiment, K, L, M, or Q, if present, is lower Ci, C 2 , C 3 , C4, Cs or Ce alkoxy. For example, K is methoxy. In one
  • branched alkyl is and K is methoxy.
  • K, L, M, or Q, if present is COOH.
  • K is COOH.
  • K, L, M, or Q, if present is aryl or heteroaryl.
  • heteroaryl is tetrazole.
  • R b is In another embodiment, R b is v — N N — w
  • V is -OCH 2 CH 2 . In another embodiment, V is a bond.
  • W is Ci, C 2 , C3, C 4 , C 5 , or Ce alkyl. For example, W is methyl or ethyl. [000383] In one embodiment, X z is CZ, further wherein Z is and
  • R 7 , R 8 , Rg, Rio, and Rn are selected from hydrogen, hydroxyl, halogen, Ci, C2, C3, C 4 , C 5 , or C 6 alkyl, Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, O-lower (Cj, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-aryl, O-benzyl, Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-OH, Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-O-Ci, C 2 , C 3 ,
  • W is H, or Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-aryl.
  • at least one OfR 7 , R 8 , R 9 , Rio, and Ri 1 is halogen, Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, or O-benzyl.
  • at least one of R 8 or Rio is halogen.
  • halogen is fluorine.
  • At least one OfR 7 or Rn is Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy or O-benzyl.
  • at least one OfR 7 or Rn is ethoxy or at least one of R 7 or Rn is O-benzyl.
  • Ri is H.
  • n is 1.
  • R 2 is H.
  • R 3 is H.
  • m is 1.
  • m and n are each 1 and R 2 and R 3 are each H.
  • R 4 and R 6 are each H.
  • R 5 is selected from halogen and Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl.
  • R 5 is halogen.
  • R 5 is Cl or F.
  • R 5 is Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl.
  • R 5 is methyl or ethyl.
  • the invention includes a solvate of a compound according to Formula IA.
  • the invention includes a hydrate of compound according to Formula IA.
  • the invention includes an acid addition salt of a compound according to Formula IA.
  • a hydrochloride salt for example, a hydrochloride salt.
  • the invention includes a pharmaceutically acceptable salt.
  • the invention includes a composition comprising a compound of Formula IA and at least one pharmaceutically acceptable excipient.
  • Certain compounds of the invention include compounds selected from Table 3.
  • the invention relates to a solvate of a compound according to one of Formulae I, IA, ⁇ , in, IV, V, VT, VII, V ⁇ i, IX, X, XI, XII, or Xi ⁇ .
  • the invention also relates to a hydrate of a compound according to one of Formulae I, IA, II, III, IV, V, VI, VII, VHI, IX, X, XI, XII, or XIII.
  • the invention also relates to an acid addition salt of a compound according to one of Formulae I, IA, H, EI, IV, V, VI, VII, VIII, IX, X, XI, XII, or XIII.
  • a hydrochloride salt e.g., a dihydrochloride salt.
  • the invention relates to a prodrug of a compound according to one of
  • the invention also relates to a pharmaceutically acceptable salt of a compound of one of Formulae I, IA, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, or XIIII.
  • compositions comprising a compound according to one of Formulae I, IA, II, HI, IV, V, VI, VII, VIII, DC, X, XI, XII, or XIII and at least one pharmaceutically acceptable excipient.
  • Certain compounds of the invention are non-ATP competitive kinase inhibitors.
  • the invention also includes a method of preventing or treating a cell proliferation disorder by administering a pharmaceutical composition that includes a compound according to one of Formulae I, IA, H, III, IV, V, VI, VII, VIII, IX, X, XI, XH, or XHI, or a salt, solvate, hydrate, or prodrug thereof, and at least one pharmaceutically acceptable excipient to a subject in need thereof.
  • a pharmaceutical composition that includes a compound according to one of Formulae I, IA, H, III, IV, V, VI, VII, VIII, IX, X, XI, XH, or XHI, or a salt, solvate, hydrate, or prodrug thereof, or a salt, solvate, hydrate, or prodrug thereof, or a salt, solvate, hydrate, or prodrug thereof, and at least one pharmaceutically acceptable excipient to a subject in need thereof.
  • the invention also includes use of a compound of the invention in the manufacture of
  • the cell proliferation disorder is pre-cancer or cancer.
  • the cell proliferation disorder treated or prevented by the compounds of the invention may be a cancer, such as, for example, colon cancer or lung cancer.
  • the cell proliferation disorder treated or prevented by the compounds of the invention may be a hyperproliferative disorder
  • the cell proliferation disorder treated or prevented by the compounds of the invention may be psoriases.
  • the treatment or prevention of the proliferative disorder may occur through the inhibition of a tyrosine kinase.
  • the tyrosine kinase can be a Src kinase or focal adhesion kinase (FAK).
  • the invention relates to a method of treating or preventing a disease or disorder that is modulated by kinase inhibition, by administering a pharmaceutical composition that includes a compound according to Formula I or IA or one of Formulae ⁇ , HI, IV, V, VI, VII,
  • the disease or disorder that is modulated by tyrosine kinase inhibition is cancer, pre-cancer, a hyperproliferative disorder, or a microbial infection.
  • the compound is a compound according to Formula I, IA or II.
  • the pharmaceutical composition of the invention may modulate a kinase pathway.
  • the kinase pathway is a Src kinase pathway, or focal adhesion kinase pathway.
  • composition of the invention may modulate a kinase directly.
  • the kinase is Src kinase, or focal adhesion kinase.
  • compositions of the invention are non-ATP competitive kinase inhibitors.
  • the compounds of the invention are useful to treat or prevent a microbial infection, such as a bacterial, fungal, parasitic or viral infection.
  • a microbial infection such as a bacterial, fungal, parasitic or viral infection.
  • the invention also includes use of a compound of the invention in the manufacture of a medicament to prevent or treat a microbial infection.
  • compositions of the invention include a compound selected from Compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,
  • the pharmaceutical composition includes Compound 33, 38, 40, 76, 133, 134,
  • compositions of the invention include a compound selected from Compound 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150,
  • the pharmaceutical composition includes
  • compositions of the invention include a compound selected from Compounds 248-274.
  • the compound of the invention is
  • a compound of the invention may be used as a pharmaceutical agent.
  • a compound of the invention is used as an antiproliferative agent, for treating humans and/or animals, such as for treating humans and/or other mammals.
  • the compounds may be used without limitation, for example, as anti-cancer, anti-angiogenesis, antimicrobial, anti-bacterial, anti-fungal, anti-parasitic and/or anti-viral agents. Additionally, the compounds may be used for other cell proliferation-related disorders such as diabetic retinopathy, macular degeneration and psoriases.
  • Anti-cancer agents include anti-metastatic agents.
  • the compound of the invention used as a pharmaceutical agent may be selected from Compounds 1-136 and 137.
  • the compound of the invention used as a pharmaceutical agent is Compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 93, 95, 96, 97, 98, 99, 100, 101, 102, 103,
  • the compound of the invention used as a pharmaceutical agent is selected from Compounds 33, 38, 40, 76, 133, 134, 136 and 137.
  • Certain pharmaceutical agents include a compound selected from the Compound 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208,
  • Certain pharmaceutical agents include a compound selected from Compounds 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, or 274.
  • a compound of the invention for example, a compound of Formula I or IA, or one of Formulae H, HI, IV, V, VI, VII 5 VIII, IX, X, XI, XII, or Xi ⁇ , is used to treat or prevent a cell proliferation disorder in an subject.
  • the cell proliferation disorder is pre-cancer or cancer.
  • the cell proliferation disorder is a hyperproliferative disorder.
  • prevention or treatment of the cell proliferation disorder, cancer or hyperproliferative disorder occurs through the inhibition of a kinase.
  • prevention or treatment of the cell proliferation disorder, cancer or hyperproliferative disorder occurs through the inhibition of a tyrosine kinase. In another embodiment, prevention or treatment of the cell proliferation disorder, cancer or hyperproliferative disorder occurs through the inhibition of Src kinase or focal adhesion kinase (FAK).
  • the subject is a mammal. In one embodiment, the subject is human.
  • Another aspect of the invention includes a method of protecting against or treating hearing loss in a subject comprising administering a compound having the Formulae I, IA, II, III, IV, V, VI, VII, V ⁇ i, IX, X, XI, XII, and X ⁇ i.
  • the invention also includes use of a compound of the invention in the manufacture of a medicament to protect against or treat hearing loss.
  • the compound inhibits one or more components of a kinase signaling cascade.
  • the compound is an allosteric inhibitor.
  • the compound is a peptide substrate inhibitor.
  • the compound does not inhibit ATP binding to the protein kinase.
  • the compound inhibits a Src family protein kinase.
  • the Src family protein kinase is pp60 c ⁇ ⁇ c tyrosine kinase.
  • the administration of the compound is carried out orally, parentally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, topically e.g., by administering drops into the ear, intraarterially, intralesionally, by metering pump, or by application to mucous membranes.
  • the compound is administered with a pharmaceutically acceptable carrier.
  • the compound is administered before initiation of hearing loss. In another embodiment, the compound is administered after initiation of hearing loss.
  • the compound is administered in combination with a drug that causes hearing loss e.£., cis platinum or an aminoglycoside antibiotic.
  • the compound is administered in combination with a drug that targets hairy cells.
  • At least one OfX 3 , X b , X 0 , Xa, X e , Xy and X z is N.
  • T is absent e.g., a bond.
  • X z is CZ and Z is
  • Another aspect of the invention includes a method of protecting against or treating osteoporosis in a subject comprising administering a compound having a Formulae I, IA, II, III, IV, V, VI, VII, V ⁇ i, IX, X, XI, XII, and XIII.
  • the invention also includes use of a compound of the invention in the manufacture of a medicament to prevent or treat osteoporosis.
  • the compound inhibits one or more components of a kinase signaling cascade.
  • the compound is an allosteric inhibitor.
  • the compound is a peptide substrate inhibitor.
  • the compound inhibits a Src family protein kinase.
  • the Src family protein kinase is pp ⁇ 0"5 "* tyrosine kinase.
  • at least one of Xa, Xb, Xc, Xd, Xe 5 Xy and X z is N.
  • T is absent e.g., a bond.
  • X z is CZ and Z is
  • m and n are each 1 and R 2 and R 3 are each H.
  • at least one of R 7 , R 8 , R 9 , Rio arid R n is halogen, Ci, Cz, C 3 , C 4 , C 5 , or Ce alkyl, or O-benzyl.
  • the compound is Compound 25 (KXl -329), Compound 38 (KX2-377), Compound 76 (KX2-361), Compound 133 (KX2-392), Compound 134 (KX2-391), or Compound 137 (KX2-394).
  • the administration of the compound is carried out orally, parentally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, topically, intraarterially, intralesionally, by metering pump, or by application to mucous membranes.
  • the compound is administered with a pharmaceutically acceptable carrier.
  • the compound is administered before initiation of osteoporosis.
  • the compound is administered after initiation of osteoporosis.
  • Another aspect of the invention includes a method of protecting against or treating ophthalmic diseases e.g., macular degeneration, retinopathy, macular edema, etc. in a subject comprising administering a compound having a Formulae I 5 IA, ⁇ , IE, IV, V, VI, VII, VIII, IX, X, XI, XII, and XIIL
  • the invention also includes use of a compound of the invention in the manufacture of a medicament to prevent or treat ophthalmic diseases.
  • the compound inhibits one or more components of a kinase signaling cascade.
  • the compound is an allosteric inhibitor.
  • the compound is a peptide substrate inhibitor.
  • the compound inhibits a Src family protein kinase.
  • the Src family protein kinase is ppoO ⁇ 0 tyrosine kinase.
  • the compound inhibits one or more components in the VEGF pathway.
  • the administration of the compound is carried out orally, parentally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, topically (e.g., by administering drops to the eye), intraarterially, intralesionally, by metering pump, or by application to mucous membranes.
  • the compound is administered with a pharmaceutically acceptable carrier.
  • the compound is administered before initiation of the ophthalmic disease.
  • the compound is administered after initiation of ophthalmic disease.
  • Another aspect of the invention includes a method of protecting against or treating diabetes in a subject comprising administering a compound having a Formulae I, IA, II, III, IV,
  • the invention also includes use of a compound of the invention in the manufacture of a medicament to protect against or treat diabetes.
  • the compound inhibits one or more components of a kinase signaling cascade.
  • the compound is an allosteric inhibitor.
  • the compound is a peptide substrate inhibitor.
  • the compound inhibits a Src family protein kinase.
  • the Src family protein kinase is pp ⁇ O 0"5 " 5 tyrosine kinase.
  • the administration of the compound is carried out orally, parentally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, topically, intraarterially, intralesionally, by metering pump, or by application to mucous membranes.
  • the compound is administered with a pharmaceutically acceptable carrier.
  • the compound is administered before initiation of the diabetes.
  • the compound is administered after initiation of disease.
  • Another aspect of the invention includes a method of protecting against or treating obesity in a subject comprising administering a compound having a Formulae I, IA, II, HI, IV, V,
  • the invention also includes use of a compound of the invention in the manufacture of a medicament to protect against or treat obesity.
  • the compound inhibits one or more components of a kinase signaling cascade.
  • the compound is an allosteric inhibitoT.
  • the compound is a peptide substrate inhibitor.
  • the compound inhibits a Src family protein kinase.
  • the Src family protein kinase is pp ⁇ O 0"5 TM tyrosine kinase.
  • the administration of the compound is carried out orally, parentally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, topically, intraarterially, intralesionally, by metering pump, or by application to mucous membranes.
  • the compound is administered with a pharmaceutically acceptable carrier.
  • the compound is administered before the subject is obese. In another embodiment, the compound is administered after the subject is obese.
  • Another aspect of the invention includes a method of protecting against or treating stroke in a subject comprising administering a compound having a Formulae I, IA, II, III, IV, V, VI, V ⁇ , VIII, IX, X, XI, XII, and XIII.
  • the invention also includes use of a compound of the invention in the manufacture of a medicament to protect against or treat stroke.
  • the compound inhibits one or more components of a kinase signaling cascade.
  • the compound is an allosteric inhibitor.
  • the compound is a peptide substrate inhibitor. In one embodiment, the compound inhibits a Src family protein kinase.
  • the Src family protein kinase is pp ⁇ O 0"8 " 1 tyrosine kinase.
  • the administration of the compound is carried out orally, parentally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, topically, intraarterially, intralesionally, by metering pump, or by application to mucous membranes.
  • the compound is administered with a pharmaceutically acceptable carrier.
  • the compound is administered before a stroke has occurred. In another embodiment, the compound is administered after a stroke has occurred.
  • Another aspect of the invention includes a method of protecting against or treating athrosclerosis in a subject comprising administering a compound having a Formulae I, IA, II, III,
  • the invention also includes use of a compound of the invention in the manufacture of a medicament to protect against or treat athrosclerosis.
  • the compound inhibits one or more components of a kinase signaling cascade.
  • the compound is an allosteric inhibitor.
  • the compound is a peptide substrate inhibitor. In one embodiment, the compound inhibits a Src family protein kinase.
  • the Src family protein kinase is pp ⁇ O 0"510 tyrosine kinase.
  • the administration of the compound is carried out orally, parentally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, topically, intraarterially, intralesionally, by metering pump, or by application to mucous membranes.
  • the compound is administered with a pharmaceutically acceptable carrier.
  • Another aspect of the invention includes a method of regulating immune system activity in a subject comprising administering a compound having a Formulae I, IA, II, III, IV, V, VI, VII, VIII, DC, X, XI, XII, and XIII.
  • the invention also includes use of a compound of the invention in the manufacture of a medicament to regulate immune system activity.
  • the compound inhibits one or more components of a kinase signaling cascade.
  • the compound is an allosteric inhibitor.
  • the compound is a peptide substrate inhibitor.
  • the compound inhibits a Src family protein kinase.
  • the Src family protein kinase is pp ⁇ O 0"870 tyrosine kinase.
  • the administration of the compound is carried out orally, parentally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, topically, intraarterially, intralesionally, by metering pump, or by application to mucous membranes.
  • the compound is administered with a pharmaceutically acceptable carrier.
  • Another aspect of the invention includes a method of protecting against or treating hepatitis B in a subject comprising administering a compound having a Formulae I, IA, II, III, IV, V, VI, V ⁇ , "Yin, DC, X, XI, XII, and XIII.
  • the invention also includes use of a compound of the invention in the manufacture of a medicament to protect against or treat hepatitis B.
  • the compound inhibits one or more components of a kinase signaling cascade.
  • the compound is an allosteric inhibitor.
  • the compound is a peptide substrate inhibitor.
  • the compound inhibits a Src family protein kinase.
  • the Src family protein kinase is pp ⁇ O 0"8 TM tyrosine kinase.
  • the administration of the compound is carried out orally, parentally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, topically, intraarterially, intralesionally, by metering pump, or by application to mucous membranes.
  • the compound is administered with a pharmaceutically acceptable carrier.
  • the compound is administered before the subject has contracted hepatitis B.
  • the compound is administered after the subject has contracted hepatitis B.
  • Another aspect of the invention is a method of preventing or treating a cell proliferation disorder comprising administering to a subject in need thereof a compound having the Formula IA.
  • the compound inhibits one or more components of a protein kinase signaling cascade.
  • the compound is an allosteric inhibitor.
  • the compound is a peptide substrate inhibitor.
  • the compound does not inhibit ATP binding to a protein kinase.
  • the compound inhibits a Src family protein kinase.
  • the Src family protein kinase is ppoO 0" " 0 tyrosine kinase.
  • at least one of X a , Xb, Xc, Xd, Xe, X y and X 2 is N.
  • X 2 is CZ, further wherein Z is * ⁇ and R 7 , R 8 , R9, Rio, and Rn are selected from hydrogen, hydroxyl, halogen, Ci, C2, C 3 , C 4 , C5, or C 6 alkyl, Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, O-lower (Ci, C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-aryl, O-benzyl, Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-OH, Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-O-Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl,
  • W is H, or Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-aryl.
  • at least one of R 7 , Rg, R9, Rio, and Rn is halogen, Ci, C2, C 3 , C 4 , Cs, or C 6 alkoxy, or O-benzyl.
  • m and n are each 1 and R 2 and R 3 are each H.
  • R 4 and R 6 are each H.
  • a compound is selected from 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, or 274.
  • the invention is also drawn to a method of treating or preventing cancer or a proliferation disorder in a subject, comprising administering an effective amount of a compound of the invention, for example, a compound of Formula I or one of Formulae II, III, IV, V, VI, Vn, Vi ⁇ , IX, X, XI, XII, or Xi ⁇ .
  • a compound of the invention may be a kinase inhibitor.
  • the compound of the invention may be a non-ATP competitive kinase inhibitor.
  • the compound of the invention may inhibit a kinase directly, or it may affect the kinase pathway.
  • the cell proliferation disorder includes any type of cancer including solid tumors and non-solid tumors.
  • the solid tumors are selected from tumors in the CNS (central nervous system), liver cancer, colorectal carcinoma, breast cancer, gastric cancer, pancreatic cancer, bladder carcinoma, cervical carcinoma, head and neck tumors, vulvar cancer and dermatological neoplasms including melanoma, squamous cell carcinoma and basal cell carcinomas.
  • non- solid tumors include lymphoproliferative disorders including leukemias and lymphomas.
  • a disorder is metastatic disease.
  • the compounds of the present invention display broad solid tumor activity, as is reported in Table 4 below.
  • the compound of the present invention also may be used in the treatment of a cancer or cell proliferation disorder in combination therapy with one or more of anti-cancer treatments such as radiation therapy, and/or one or more anti-cancer agents selected from the group consisting of anti-proliferative agents, cytotoxic agents, cytostatic agents, and chemotherapeutic agents and salts and derivatives thereof.
  • anti-cancer treatments such as radiation therapy
  • anti-cancer agents selected from the group consisting of anti-proliferative agents, cytotoxic agents, cytostatic agents, and chemotherapeutic agents and salts and derivatives thereof.
  • the compound of the present invention may be used in the treatment of a cancer or cell proliferation disorder in combination therapy with any one of the drugs selected from a group consisting of an alkaloid, an alkylating agent, an antitumor antibiotic, an antimetabolite, an Bcr-Abl tyrosine kinase inhibitor, a nucleoside analogue, a multidrug resistance reversing agent, a DNA binding agent, microtubule binding drug, a toxin and a DNA antagonist.
  • drugs selected from a group consisting of an alkaloid, an alkylating agent, an antitumor antibiotic, an antimetabolite, an Bcr-Abl tyrosine kinase inhibitor, a nucleoside analogue, a multidrug resistance reversing agent, a DNA binding agent, microtubule binding drug, a toxin and a DNA antagonist.
  • the compound of the present invention may be used in the treatment of a cancer or cell proliferation disorder in combination therapy with one or more agents selected from the group consisting of antimetabolites (e.g., gemcitabine), inhibitors of topoisomerase I and II, alkylating agents and microtubule inhibitors (e.g., taxol), as well as tyrosine kinase inhibitors (e.g., surafenib), EGF kinase inhibitors ⁇ e.g., tarceva or erlotinib), platinum complexes (e.g., oxaliplatin); and ABL kinase inhibitors (e.g., Gleevec or Imatinib).
  • antimetabolites e.g., gemcitabine
  • inhibitors of topoisomerase I and II e.g., alkylating agents and microtubule inhibitors
  • tyrosine kinase inhibitors e.g., surafenib
  • Alkaloids include, but are not limited to, docetaxel, etoposide, irinotecan, paclitaxel (Taxol), teniposide, topotecan, vinblastine, vincristine, vindesine.
  • Alkylating agents include, but are not limited to, busulfan, improsulfan, piposulfan, benzodepa, carboquone, meturedepa, uredepa, altretamine, triethylenemelamine, triethylenephosphoramide, triethylenetiiiophosphoramide, chlorambucil, chloranaphazine, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide HCl, melphalan novemebichin, perfosfamide phenesterine, prednimustine, trofosfamide, uracil mustard, carmustine, chlorozotocin, fotemustine, lomustine, nimustine, semustine ranimustine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, temozolomide.
  • Antibiotics and analogs thereof include, but are not limited to, aclacinomycins, actinomycins, anthramycin, azaserine, bleomycins, cactinomycin, carubicin, carzinophilin, cromomycins, dactinomycins, daunorubicin, 6-diazo-5-oxo-l-norleucine, doxorubicin, epirubicin, idarubicin, menogaril, mitomycins, mycophenolic acid, nogalamycine, olivomycins, peplomycin, pirarubicin, plicamycin, porfiromycin, puromycine, streptonigrin, streptozocin, tubercidin, zinostatin, zorubicin.
  • Antimetabolites include, but are not limited to, denopterin, edatrexate, mercaptopurine (6-MP), methotrexate, piritrexim, pteropterin, pentostatin (2'-DCF), tomudex, trimetrexate, cladridine, fludarabine, thiamiprine, ancitabine, azacitidine, 6-azauridine, carmoftir, cytarabine, doxifluridine, emitefur, floxuridine, fluorouracil, gemcitabine, tegafur, hydroxyurea and urethan.
  • Platinum complexes include, but are not limited to, caroplatin, cisplat ⁇ n, miboplatin, oxaliplatin.
  • Anti-mitotic agents or microtubule binding agents include, but are not limited to, vincristine, and vinblastine, and taxol.
  • the compounds of the present invention may enhance (e.g., synergize) the activity of these agents. Further, such synergism would permit the compounds of the present invention, additional anti-proliferation agents, or both to be administered at lower dosages, and/or may significantly enhance the anti-proliferation properties of the compounds at any given dose.
  • Table 5 provides the results of combination treatments using the compounds of the present invention and additional anti-proliferation agents. Table 5.
  • a method for treating leukemia in a host comprising administering to a patient a compound having a Formulae I, IA, ⁇ , III, IV, V, VI, V ⁇ , VIII, IX, X, XI, x ⁇ , and XHI.
  • a method for treating leukemia in a host comprising administering to a patient a therapeutically effective amount of a compound according to Formulae I, IA, II, HI, IV, V, VI, Vn, VHI, IX, X, XI, XII, and XIII, as defined above, and at least one further therapeutic agent selected from the group consisting of antiproliferative agents, cytotoxic agents, cytostatic agents, and chemotherapeutic agents and salts and derivatives thereof.
  • the compound of the present invention may be used in the treatment of a leukemia in combination therapy with one or more of the drugs selected from a group consisting of an alkaloid, an alkylating agent, an antitumor antibiotic, an antimetabolite, an Bcr-Abl tyrosine kinase inhibitor, a nucleoside analogue, a multidrug resistance reversing agent, a DNA binding agent, microtubule binding drug, a toxin and a DNA antagonist.
  • the drugs selected from a group consisting of an alkaloid, an alkylating agent, an antitumor antibiotic, an antimetabolite, an Bcr-Abl tyrosine kinase inhibitor, a nucleoside analogue, a multidrug resistance reversing agent, a DNA binding agent, microtubule binding drug, a toxin and a DNA antagonist.
  • Leukemia is a malignant cancer of the bone marrow and blood and is characterized by the uncontrolled growth of blood cells.
  • the common types of leukemia are divided into four categories: acute or chronic myelogenous, involving the myeloid elements of the bone marrow (white cells, red cells, megakaryocytes) and acute or chronic lymphocytic, involving the cells of the lymphoid lineage.
  • Treatment of leukemia generally depends upon the type of leukemia. Standard treatment for leukemia usually involves chemotherapy and/or bone marrow transplantation and/or radiation therapy. See e.g., U.S. Patent No. 6,645,972, hereby incorporated herein by reference in its entirety.
  • Chemotherapy in leukemia may involve a combination of two or more anticancer drugs. Approximately 40 different drugs are now being used in the treatment of leukemia, either alone or in combination. Other treatments for leukemia also include the reversal of multidrug resistance, involving the use of agents which decrease the mechanisms allowing the malignant cells to escape the damaging effects of the chemotherapeutic agent (and leads to refractoriness or relapses); and biological therapy, involving the use of monoclonal antibodies, in which toxins are attached to antibodies that react with the complementary antigen carried by the malignant cells; and cytokines (e.g.
  • t interferons interleukdns, colony-stimulating factors CSFs
  • these drugs include multidrug resistance reversing agent PSC 833, the monoclonal antibody Rituxan and the following cytokines: Erythropoetin and Epoetin, which stimulate the production of red cells; G-CSF, GM-CSF 5 filgrastim, and Sargramostim which stimulate the production of white cells; and thrombopoietin, which stimulate the production of platelets.
  • nucleoside analogues have been found to possess anticancer activity. Cytarabine, Fludarabine, Gemcitabine and Cladribine are some examples of nucleoside analogues which are currently important drugs in the treatment of leukemia.
  • ⁇ -L-OddC ((-)- ⁇ - L-Dioxolane-Cytidine, Troxatyl®, from Shire BioChem Inc.) is also a nucleoside analogue which was first described as an antiviral agent by Belleau et al. (EP 337713, herein incorporated by reference in its entirety) and was shown to have potent antitumor activity (K. L.
  • STI-571 (Gleevec®, lmatinib mesylate, from Novartis Pharmaceuticals Corp.), have shown significant antileukemic activity and specifically in chronic myeologenous leukemia.
  • STI-571 for example, has become a promising therapy in the group of patients targeting Bcr-Abl tyrosine kinase inhibition.
  • resistance to Bcr-Abl tyrosine kinase inhibitors occurs, particularly in the advanced phases of chronic myelogenous leukemia.
  • a method for treating leukemia in a host comprising administering to a patient that has been previously treated with a Bcr- Abl tyrosine kinase inhibitor and has become resistant to the Bcr-Abl tyrosine kinase inhibitor treatment, a therapeutically effective amount of a compound according to Formulae I, IA, ⁇ , in, IV, V, VI, VII, VIII, IX, X, XI, XII, and Xi ⁇ .
  • a method for combination therapy of leukemia in a host comprising administering to a patient a Bcr- Abl tyrosine kinase inhibitor in combination with a therapeutically effective amount of a compound according to Formulae I, IA, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, and XIII.
  • the combination is administered to a patient that has become resistant to the Bcr-Abl tyrosine kinase inhibitor treatment.
  • the compounds of the present invention display anti-leukemia activity as compared to existing therapeutic agents, as is show in Table 6 below.
  • the administration of the compound is carried out orally, parentally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, topically, intraarterially, intralesionally, by metering pump, or by application to mucous membranes.
  • the compound is administered with a pharmaceutically acceptable carrier.
  • Protein kinases are a large class of enzymes which catalyze the transfer of the ⁇ -phosphate from ATP to the hydroxyl group on the side chain of Ser/Thr or Tyr in proteins and peptides and are intimately involved in the control of various important cell functions, perhaps most notably: signal transduction, differentiation, and proliferation.
  • signal transduction, differentiation, and proliferation There are estimated to be about 2,000 distinct protein kinases in the human body, and although each of these phosphorylate particular prote ⁇ n/peptide substrates, they all bind the same second substrate ATP in a highly conserved pocket.
  • About 50% of the known oncogene products are protein tyrosine kinases (PTKs), and their kinase activity has been shown to lead to cell transformation.
  • PTKs protein tyrosine kinases
  • the PTKs can be classified into two categories, the membrane receptor PTKs
  • Src growth factor receptor PTKs
  • non-receptor PTKs e.g. the Src family of proto- oncogene products and focal adhesion kinase (FAK)
  • FK focal adhesion kinase
  • the phrase "inhibits one or more components of a protein kinase signaling cascade” means that one or more components of the kinase signaling cascade are effected such that the functioning of the cell changes.
  • Components of a protein kinase signaling cascade include any proteins involved directly or indirectly in the kinase signaling pathway including second messengers and upstream and downstream targets.
  • Treating includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder, etc.
  • Treating" or “treatment” of a disease state includes: (1) preventing the disease state, i.e. causing the clinical symptoms of the disease state not to develop in a subject that may be exposed to or predisposed to the disease state, but does not yet experience or display symptoms of the disease state; (2) inhibiting the disease state, i.e., arresting the development of the disease state or its clinical symptoms; or (3) relieving the disease state, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms.
  • Disease state means any disease, disorder, condition, symptom, or indication.
  • cell proliferative disorder refers to conditions in which the unregulated and/or abnormal growth of cells can lead to the development of an unwanted condition or disease, which can be cancerous or non-cancerous, for example a psoriatic condition.
  • psoriatic condition or “psoriasis” refers to disorders involving keratinocyte hyperproliferation, inflammatory cell infiltration, and cytokine alteration.
  • the cell proliferation disorder is cancer.
  • cancer includes solid tumors, such as lung, breast, colon, ovarian, brain, liver, pancreas, prostate, malignant melanoma, non-melanoma skin cancers, as well as hematologic tumors and/or malignancies, such as childhood leukemia and lymphomas, multiple myeloma, Hodgkin's disease, lymphomas of lymphocytic and cutaneous origin, acute and chronic leukemia such as acute lymphoblastic, acute myelocytic or chronic myelocytic leukemia, plasma cell neoplasm, lymphoid neoplasm and cancers associated with AIDS.
  • the types of proliferative diseases which may be treated using the compositions of the present invention are epidermic and dermoid cysts, lipomas, adenomas, capillary and cutaneous hemangiomas, lymphangiomas, nevi lesions, teratomas, nephromas, myofibromatosis, osteoplastic tumors, and other dysplastic masses and the like.
  • the proliferative diseases can include dysplasias and disorders of the like.
  • an "effective amount" of a compound of the disclosed invention is the quantity which, when administered to a subject having a disease or disorder, results in regression of the disease or disorder in the subject.
  • an effective amount of a compound of the disclosed invention is the quantity which, when administered to a subject having a cell proliferation disorder, results in regression of cell growth in the subject.
  • the amount of the disclosed compound to be administered to a subject will depend on the particular disorder, the mode of administration, co-administered compounds, if any. and the characteristics of the subject, such as general health, other diseases, age, sex, genotype, body weight and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors.
  • an effective amount refers to an amount of a compound, or a combination of compounds, of the present invention effective when administered alone or in combination as an anti-proliferative agent.
  • an effective amount refers to an amount of the compound present in a formulation or on a medical device given to a recipient patient or subject sufficient to elicit biological activity, for example, anti-proliferative activity, such as e.g., anti-cancer activity or anti-neoplastic activity.
  • the combination of compounds optionally is a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Adv. Enzyme Regul. vol. 22, pp.
  • a therapeutically effective amount means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
  • a therapeutically effective amount of one or more of the compounds can be formulated with a pharmaceutically acceptable carrier for administration to a human of an animal. Accordingly, the compounds or the formulations can be administered, for example, via oral, parenteral, or topical routes, to provide an effective amount of the compound.
  • the compounds prepared in accordance with the present invention can be used to coat or impregnate a medical device, e.g. , a stent.
  • prophylactically effective amount means an effective amount of a compound or compounds, of the present invention that is administered to prevent or reduce the risk of unwanted cellular proliferation.
  • pharmacological effect encompasses effects produced in the subject that achieve the intended purpose of a therapy.
  • a pharmacological effect means that primary indications of the subject being treated are prevented, alleviated, or reduced-
  • a pharmacological effect would be one that results in the prevention, alleviation or reduction of primary indications in a treated subject.
  • a pharmacological effect means that disorders or symptoms of the primary indications of the subject being treated are prevented, alleviated, or reduced.
  • a pharmacological effect would be one that results in the prevention or reduction of primary indications in a treated subject.
  • substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • 2 hydrogens on the atom are replaced.
  • Keto substituents are not present on aromatic moieties.
  • the present invention is intended to include all isotopes of atoms occurring in the present compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium
  • isotopes of carbon include C-13 and C-14.
  • the compounds described herein may have asymmetric centers.
  • Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials.
  • any variable e.g., Ri
  • its definition at each occurrence is independent of its definition at every other occurrence.
  • R 1 at each occurrence is selected independently from the definition of Ri.
  • substituents and/or variables are permissible, but only if such combinations result in stable compounds.
  • N-oxides by treatment with an oxidizing agent (e.g., 3-chloroperoxybenzoic acid (m-CPBA) and/or hydrogen peroxides) to afford other compounds of the present invention.
  • an oxidizing agent e.g., 3-chloroperoxybenzoic acid (m-CPBA) and/or hydrogen peroxides
  • m-CPBA 3-chloroperoxybenzoic acid
  • hydrogen peroxides hydrogen peroxides
  • all shown and claimed nitrogen-containing compounds are considered, when allowed by valency and structure, to include both the compound as shown and its N-oxide derivative (which can be designated as N— >O or N + -O " ).
  • the nitrogens in the compounds of the present invention can be converted to N-hydroxy or N-alkoxy compounds.
  • N-hydroxy compounds can be prepared by oxidation of the parent amine by an oxidizing agent such as m-CPBA.
  • nitrogen-containing compounds are also considered, when allowed by valency and structure, to cover both the compound as shown and its N-hydroxy (i.e., N-OH) and N-alkoxy (i.e., N-OR, wherein R is substituted or unsubstituted C 1-O alkyl, Ci- ⁇ alkenyl, Cj- ⁇ alkynyl, C3-14 ca ⁇ bocycle, or 3-14-membered heterocycle) derivatives.
  • alkyl is meant to include alkyl groups with 1, 2, 3, 4, 5, 6, 1-6, 1-5, 1-4, 1-3, 1-2, 2-6, 2-5, 2-4, 2-3, 3-6, 3-5, 3-4, 4-6, 4-5, and 5-6 carbons.
  • alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • Ci- 6 alkyl is intended to include C], C2, C 3 , C4, C 5 , and Cg alkyl groups.
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, and n-hexyl.
  • Alkyl further includes alkyl groups that have oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more hydrocarbon backbone carbon atoms.
  • a straight chain or branched chain alkyl has six or fewer carbon atoms in its backbone (e.g., Ci-Ce for straight chain, C3-C6 for branched chain), and in another embodiment, a straight chain or branched chain alkyl has four or fewer carbon atoms.
  • cycloalkyls have from three to eight carbon atoms in their ring structure, and in another embodiment, cycloalkyls have five or six carbons in the ring structure.
  • “lower alkyl” includes an alkyl group, as defined above, but having from one to ten, or in another embodiment from one to six, carbon atoms in its backbone structure.
  • “Lower alkenyl” and “lower alkynyl” have chain lengths of, for example, 2-5 carbon atoms.
  • substituted alkyls refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino).
  • acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylihio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Cycloalkyls can be further substituted, e.g., with the substituents described above. An "alkylaryl" or an "aralkyl".
  • alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)).
  • aryl e.g., phenylmethyl (benzyl)
  • alkenyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond.
  • alkenyl includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), branched-chain alkenyl groups, cycloalkenyl (e.g., alicyclic) groups (e.g., cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl or alkenyl substituted cycloalkenyl groups, and cycloalkyl or cycloalkenyl substituted alkenyl groups.
  • alkenyl includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octen
  • alkenyl further includes alkenyl groups, which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more hydrocarbon backbone carbons.
  • a straight chain or branched chain alkenyl group has six or fewer carbon atoms in its backbone (e.g., C2-C 6 for straight chain, C 3 -C 6 for branched chain).
  • cycloalkenyl groups may have from three to eight carbon atoms in their ring structure, and in one embodiment, cycloalkenyl groups have five or six carbons in the ring structure.
  • C2-C6 includes alkenyl groups containing two to six carbon atoms.
  • C 3 -C 6 includes alkenyl groups containing three to six carbon atoms.
  • substituted alkenyls refers to alkenyl moieties having substituents replacing a hydrogen on one or more hydrocarbon backbone carbon atoms.
  • substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino), acylamino (including al
  • Alkynyl includes unsaturated aliphatic, groups analogous in length and possible substitution to the alkyls ' described above, but which contain at least one triple bond.
  • alkynyl includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), branched-chain alkynyl groups, and cycloalkyl or cycloalkenyl substituted alkynyl groups.
  • alkynyl further includes alkynyl groups having oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more hydrocarbon backbone carbons.
  • a straight chain or branched chain alkynyl group has six or fewer carbon atoms in its backbone (e.g., C 2 -C 6 for straight chain, C3-C6 for branched chain).
  • C2-C6 includes alkynyl groups containing two to six carbon atoms.
  • C3-C6 includes alkynyl groups containing three to six carbon atoms.
  • substituted alkynyls refers to alkynyl moieties having substituents replacing a hydrogen on one or more hydrocarbon backbone carbon atoms.
  • substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcaibonylamino, aryl
  • Aryl includes groups with aromaticity, including 5- and 6-membered “unconjugated”, or single-ring, aromatic groups that may include from zero to four heteroatoms, as well as “conjugated”, or multicyclic, systems with at least one aromatic ring.
  • aryl groups include benzene, phenyl, pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isooxazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
  • aryl includes multicyclic aryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, napthridine, indole, benzofuran, purine, benzofuran, deazapurine, or indolizine.
  • aryl groups having heteroatoms in the ring structure may also be referred to as “aryl heterocycles", “heterocycles,” “heteroaryls” or “heteroaromatics”.
  • the aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, atylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and
  • halo or halogen refers to fluoro, chloro, bromo, and iodo.
  • perhalogenated generally refers to a moiety, wherein all hydrogens are replaced by halogen atoms.
  • Counterion is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate.
  • non-hydrogen substituent refers to substituents other than hydrogen.
  • Non-limiting examples include alkyl groups, alkoxy groups, halogen groups, hydroxyl groups, aryl groups, etc.
  • Carbocycle or “carbocyclic ring” is intended to mean any stable monocyclic, bicyclic, or tricyclic ring having the specified number of carbons, any of which may be saturated, unsaturated, or aromatic.
  • a C3-14 carbocycle is intended to mean a mono-, bi-, or tricyclic ring having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms.
  • carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.
  • Bridged rings are also included in the definition of carbocycle, including, for example, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, and [2.2.2]bicyclooctane.
  • a bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms.
  • bridge rings are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on. the bridge. Fused (e.g., naphthyl and tetrahydronaphthyl) and spiro rings are also included.
  • glycoside means any molecule in which a sugar group is bonded through its anomeric carbon to another group. Examples of glycosides
  • glycoside is bonded through its anomeric carbon to another group, it is also known as a non-reducing sugar (i.e., it is not subject to attack by reagents that attack carbonyl groups).
  • heterocycle or “heterocyclic” is intended to mean any stable monocyclic, bicyclic, or tricyclic ring which is saturated, unsaturated, or aromatic and comprises carbon atoms and one or more ring heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen, and sulfur.
  • a bicyclic or tricyclic heterocycle may have one or more heteroatoms located in one ring, or the heteroatoms may be located in more than one ring.
  • a nitrogen atom When a nitrogen atom is included in the ring it is either N or NH, depending on whether or not it is attached to a double bond in the ring (Le. , a hydrogen is present if needed to maintain the tri-valency of the nitrogen atom).
  • the nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, as defined).
  • the heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.
  • the heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable.
  • a nitrogen in the heterocycle may optionally be quaternized.
  • Bridged rings are also included in the definition of heterocycle.
  • a bridged ring occurs when one or more atoms (i.e., C, O, N, or S) link two non-adjacent carbon or nitrogen atoms.
  • Bridges include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge.
  • aromatic heterocycle or “heteroaryl” is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic aromatic heterocyclic ring or 7, 8, 9, 10, 11, or 12-membered bicyclic aromatic heterocyclic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the second ring can also be fused or bridged as defined above for heterocycles.
  • the nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, as defined).
  • heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, dihydrofuro[2 > 3-Z>]tetrahydroturan, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazo
  • Acyl includes compounds and moieties that contain the acyl radical (C ⁇ 3 CO-) or. a carbonyl group.
  • substituted acyl includes acyl groups where one or more of the hydrogen atoms are replaced by for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbon
  • Acylamino includes moieties wherein an acyl moiety is bonded to an amino group.
  • the term includes alkylca ⁇ bonylamino, arylcarbonylamino, carbamoyl and ureido groups.
  • Aroyl includes compounds and moieties with an aryl or heteroaromatic moiety bound to a carbonyl group. Examples of aroyl groups include phenylcarboxy, naphthyl carboxy, etc.
  • alkoxyalkyl include alkyl groups, as described above, which further include oxygen, nitrogen or sulfur atoms replacing one or more hydrocarbon backbone carbon atoms, e.g., oxygen, nitrogen or sulfur atoms.
  • alkoxy or "alkoxyl” includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom.
  • alkoxy groups or alkoxyl radicals
  • substituted alkoxy groups include halogenated alkoxy groups.
  • the alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxy
  • thiocarbonyl or "thiocarboxy” includes compounds and moieties which contain a carbon connected with a double bond to a sulfur atom.
  • ether or "alkoxy” includes compounds or moieties which contain an oxygen bonded to two different carbon atoms or heteroatoms.
  • alkoxyalkyl which refers to an alkyl, alkenyl, or alkynyl group covalently bonded to an oxygen atom which is covalently bonded to another alkyl group.
  • esters includes compounds and moieties which contain a carbon or a heteroatom bound to an oxygen atom which is bonded to the carbon of a carbonyl group.
  • ester includes alkoxycarboxy groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc.
  • alkyl, alkenyl, or alkynyl groups are as defined above.
  • thioether includes compounds and moieties which contain a sulfur atom bonded to two different carbon or heteroatoms.
  • examples of thioethers include, but are not limited to alkthioalkyls, alkthioalkenyls, and alkthioalkynyls.
  • alkthioalkyls include compounds with an alkyl, alkenyl, or alkynyl group bonded to a sulfur atom which is bonded to an alkyl group.
  • alkthioalkenyls and alkthioalkynyls refer to compounds or moieties wherein an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkynyl group.
  • hydroxy or “hydroxyl” includes groups with an -OH or -O " .
  • Polycyclyl or. “polycyclic radical” refers to two or more cyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings. Rings that are joined through non-adjacent atoms are termed "bridged" rings.
  • Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and urei
  • anionic group refers to a group that is negatively charged at physiological pH.
  • Anionic groups include carboxylate, sulfate, sulfonate, sulfinate, sulfamate, tetrazolyl, phosphate, phosphonate, phosphinate, or phosphorothioate or functional equivalents thereof.
  • "Functional equivalents" of anionic groups are intended to include bioisosteres, e.g., bioisosteres of a carboxylate group. Bioisosteres encompass both classical bioisosteric equivalents and non-classical bioisosteric equivalents.
  • an anionic group is a carboxylate.
  • the structural formula of the compound represents a certain isomer for convenience in some cases, but the present invention includes all isomers such as geometrical isomer, optical isomer based on an asymmetrical carbon, stereoisomer, tautomer and the like which occur structurally and an isomer mixture and is not limited to the description of the formula for convenience, and may be any one of isomer or a mixture.
  • an asymmetrical carbon atom may be present in the molecule and an optically active compound and a racemic compound may be present in the present compound, but the present invention is not limited to them and includes any one.
  • a crystal polymorphism may be present but is not limiting, but any crystal form may be single or a crystal form mixture, or an anhydride or hydrate.
  • so-called metabolite which is produced by degradation of the present compound in vivo is included in the scope of the present invention.
  • “Isomerism” means compounds that have identical molecular formulae but that differ in the nature or the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereoisomers”, and stereoisomers that are non-superimposable mirror images are termed "enantiomers”, or sometimes optical isomers. A carbon atom bonded to four nonidentical substituents is termed a "chiral center”.
  • Chiral isomer means a compound with at least one chiral center. It has two enantiomeric forms of opposite chirality and may exist either as an individual enantiomer or as a mixture of enantiomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a "racemic mixture”. A compound that has more than one chiral center has 2" "1 enantiomeric pairs, where n is the number of chiral centers. Compounds with more than one chiral center may exist as either an individual diastereomer or as a mixture of diastereomers, termed a "diastereomeric mixture”.
  • a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center.
  • Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center.
  • the substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al, ⁇ ngew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J., Chem. Educ. 1964, 41, 116).
  • Gaometric Isomers means the diastereomers that owe their existence to hindered rotation about double bonds. These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.
  • the structures and other compounds discussed in this application include all atropic isomers thereof.
  • “Atropic isomers” are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atrdpic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases.
  • crystal polymorphs or “polymorphs” or “crystal forms” means crystal structures in which a compound (or salt or solvate thereof) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectral, melting points, density hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Crystal polymorphs of the compounds can be prepared by crystallization under different conditions.
  • the compounds of the present invention can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules.
  • hydrates include monohydrates, dihydrates, etc.
  • solvates include ethanol solvates, acetone solvates, etc.
  • Solvates means solvent addition forms that contain either stoichiometric or non stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ⁇ atio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as EfeO, such combination being able to form one or more hydrate.
  • Tautomers refers to compounds whose structures differ markedly in arrangement of atoms, but which exist in easy and rapid equilibrium. It is to be understood that the compounds of the invention may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be within the scope of the invention, and the naming of the compounds does not exclude any tautomer form. [000525] Some compounds of the present invention can exist in a tautomeric form which are also intended to be encompassed within the scope of the present invention.
  • the compounds, salts and prodrugs of the present invention can exist in several tautomeric forms, including the enol and imine form, and the keto and enamine form and geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of the present invention. Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, the present invention includes all tautomers of the present compounds [000527] A tautomer is one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.
  • keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs.
  • Ring-chain tautomerism is exhibited by glucose. It arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form.
  • Tautomerizations are catalyzed by: Base: 1. deprotonation; 2. formation of a delocalized anion (e.g. an enolate); 3. protonation at a different position of the anion; Acid: 1. protonation; 2. formation of a delocalized cation; 3. deprotonation at a different position adjacent to the cation.
  • Base 1. deprotonation; 2. formation of a delocalized anion (e.g. an enolate); 3. protonation at a different position of the anion
  • Acid 1. protonation; 2. formation of a delocalized cation; 3. deprotonation at a different position adjacent to the cation.
  • Common tautomeric pairs are: ketone - enol, amide - nitrile, lactam - lactim, amide - imidic acid tautomerism in heterocyclic rings ⁇ e.g. in the nucleobases guanine, thymine, and cytosine), amine - enamine and enamine - enamine. Examples include:
  • the structure of some of the compounds of the invention include asymmetric carbon atoms. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of the invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis. Furthermore, the structures and other compounds and moieties discussed in this application also include all tautomers thereof. Alkenes can include either the E- or Z-geometry, where appropriate. The compounds of this invention may exist in stereoisomeric form, therefore can be produced as individual stereoisomers or as mixtures.
  • analog refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group).
  • an analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound.
  • derivative refers to compounds that have a common core structure, and are substituted with various groups as described herein.
  • all of the compounds represented by formula I are indole derivatives, and have formula I as a common core.
  • bioisostere refers to a compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or group of atoms.
  • the objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound.
  • the bioisosteric replacement may be physicochemically or topologically based.
  • Examples of carboxylic acid bioisosteres include acyl sulfonimides, tetrazoles, sulfonates, and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147- 3176 (1996).
  • a "pharmaceutical composition” is a formulation containing the disclosed compounds in a form suitable for administration to a subject.
  • the pharmaceutical composition is in bulk or in unit dosage form.
  • the unit dosage form is any of a variety of forms, including, for example, a capsule, an TV bag, a tablet, a single pump on an aerosol inhaler, or a vial.
  • the quantity of active ingredient (e.g., a formulation of the disclosed compound or salt, hydrate, solvate, or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved.
  • active ingredient e.g., a formulation of the disclosed compound or salt, hydrate, solvate, or isomer thereof
  • the dosage will also depend on the route of administration.
  • routes of administration A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like.
  • Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.
  • flash dose refers to compound formulations that are rapidly dispersing dosage forms.
  • immediate release is defined as a release of compound from a dosage form in a relatively brief period of time, generally up to about 60 minutes.
  • modified release is defined to include, delayed release, extended release, and pulsed release.
  • pulse release is defined as a series of releases of drug from a dosage form.
  • sustained release or extended release is defined as continuous release of a compound from a dosage form over a prolonged period.
  • a "subject” includes mammals, e.g., humans, companion animals ⁇ e.g., dogs, cats, birds, and the like), farm animals (e.g., cows, sheep, pigs, horses, fowl, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, birds, and the like).
  • the subject is human.
  • the phrase "pharmaceutically, acceptable” refers to those compounds, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • a “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.
  • “Pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric,
  • Other examples include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4- chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfomc acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-l -carboxylic acid, 3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like.
  • the invention also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
  • a metal ion e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion
  • coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile can be used.
  • non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile can be used.
  • Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed. (Mack Publishing Company, 1990).
  • salts can include, but are not limited to, the hydrochloride and acetate salts of the aliphatic amine-containing, hydroxyl amine-containing, and imine-containing compounds of the
  • the compounds of the present invention can also be prepared as esters, for example pharmaceutically acceptable esters.
  • a carboxylic acid function group in a compound can be converted to its corresponding ester, e.g., a methyl, ethyl, or other ester.
  • an alcohol group in a compound can be converted to its corresponding ester, e.g., an acetate, propionate, or other ester.
  • the compounds of the present invention can also be prepared as prodrugs, for example pharmaceutically acceptable prodrugs.
  • pro-drug and “prodrug” are used interchangeably herein and refer to any compound which releases an active parent drug in vivo. Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.) the compounds of the present invention can be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same. "Prodrugs" are intended to include any covalently bonded carriers that release an active parent drug of the present invention in vivo when such prodrug is administered to a subject.
  • Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.
  • Prodrugs include compounds of the present invention wherein a hydroxy, amino, sulfhydryl, carboxy, or carbonyl group is bonded to any group that, may be cleaved in vivo to form a free hydroxyl, free amino, free sulfhydryl, free carboxy or free carbonyl group, respectively.
  • prodrugs include, but are not limited to, esters (e.g., acetate, dialkylaminoacetates, formates, phosphates, sulfates, and benzoate derivatives) and carbamates (e.g., N,N-dimethylammocarbonyl) of hydroxy functional groups, esters groups (e.g. ethyl esters, morpholinoethanol esters) of carboxyl functional groups, N-acyl derivatives (e.g.
  • Protecting group refers to a grouping of atoms that when attached to a reactive group in a molecule masks, reduces or prevents that reactivity. Examples of protecting groups can be found in Green and Wuts, Protective Groups in Organic Chemistry,
  • amine protecting group is intended to mean a functional group that converts an amine, amide, or other nitrogen-containing moiety into a different chemical group that is substantially inert to the conditions of a particular chemical reaction.
  • Amine protecting groups aTe preferably removed easily and selectively in good yield under conditions that do not affect other functional groups of the molecule.
  • amine protecting groups include, but are not limited to, formyl, acetyl, benzyl, *-butyldimethylsilyl, f-butdyldiphenylsilyl, f-butyloxycarbonyl (Boc),/?-methoxybenzyl, methoxymethyl, tosyl, trifluoroacetyl, trimethylsilyl (TMS), fluorenyl-rnethyloxycarbonyl, 2-trimethylsilyl- ethyoxycarbonyl, l-methyl-l-(4-biphenylyl) ethoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl (CBZ), 2-trimethylsilyl-ethanesulfonyl (SES), trityl and substituted trityl groups, 9-fluorenylmethyloxycarbonyl (FMOC), nitro-veratryloxycarbonyl (NVOC), and the like
  • Representative hydroxy protecting groups include those where the hydroxy group is either acylated or alkylated such as benzyl, and trityl ethers as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers.
  • “Stable compound”, and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • Combination therapy includes the administration of a compound of the invention and at least a second agent as part of a specific treatment regimen intended to provide the beneficial effect from the co-action of these therapeutic agents.
  • the beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents.
  • Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected).
  • “Combination therapy” may, but generally is not, intended to encompass the administration of two or more of these therapeutic agents as part of separate monotherapy regimens that incidentally and arbitrarily result in the combinations of the present invention.
  • Combination therapy is intended to embrace administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner.
  • Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents.
  • Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues.
  • the therapeutic agents can be administered by the same route or by different routes.
  • a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally.
  • all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection.
  • the sequence in which the therapeutic agents are administered is not narrowly critical.
  • Combination therapy also embraces the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non-drug therapies (e.g., surgery or radiation treatment) .
  • the combination therapy further comprises a non-drug treatment
  • the non-drug treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.
  • compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components.
  • processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps.
  • order of steps or order for performing certain actions are immaterial so long as the invention remains operable.
  • two or more steps or actions may be conducted simultaneously.
  • the compounds, or pharmaceutically acceptable salts thereof is administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperintoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally.
  • the compound is administered orally.
  • the dosage regimen utilizing the compounds is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
  • the compounds described herein, and the pharmaceutically acceptable salts thereof are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent.
  • suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein.
  • the compound is prepared for oral administration, wherein the disclosed compounds or salts thereof are combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, pills, powders, syrups, solutions, suspensions and the like.
  • the tablets, pills, capsules, and the like contain from about 1 to about 99 weight percent of the active ingredient and a binder such as gum tragacanth, acacias, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch or alginic acid; a lubricant such as magnesium stearate; and/or a sweetening agent such as sucrose, lactose, saccharin, xylitol, and the like.
  • a dosage unit form is a capsule, it often contains, in addition to materials of the above type, a liquid carrier such as a fatty oil.
  • various other materials are present as coatings or to modify the physical form of the dosage unit.
  • tablets are coated with shellac, sugar or both.
  • a syrup or elixir contains, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor, and the like.
  • sucrose as a sweetening agent
  • methyl and propylparabens as preservatives
  • a dye and a flavoring such as cherry or orange flavor, and the like.
  • the disclosed compounds, or salts, solvates, tautomers or polymorphs thereof can be combined with sterile aqueous or organic media to form injectable solutions or suspensions.
  • injectable compositions are aqueous isotonic solutions or suspensions.
  • the compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
  • the compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 to 75%, in another embodiment, the compositions contain about 1 to 50%, of the active ingredient.
  • injectable solutions are produced using solvents such as sesame or peanut oil or aqueous propylene glycol, as well as aqueous solutions of water-soluble pharmaceutically-acceptable salts of the compounds.
  • solvents such as sesame or peanut oil or aqueous propylene glycol
  • aqueous solutions of water-soluble pharmaceutically-acceptable salts of the compounds are prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.
  • suitable pharmaceutical compositions are, for example, topical preparations, suppositories or enemas. Suppositories are advantageously prepared from fatty emulsions or suspensions.
  • the compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
  • the compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 to 75%, in another embodiment, compositions contain about 1 to 50%, of the active ingredient.
  • the compounds are formulated to deliver the active agent by pulmonary administration, e.g. t administration of an aerosol formulation containing the active agent from, for example, a manual pump spray, nebulizer or pressurized metered-dose inhaler.
  • suitable formulations of this type also include other agents, such as antistatic agents, to maintain the disclosed compounds as effective aerosols.
  • a drug delivery device for delivering aerosols comprises a suitable aerosol canister with a metering valve containing a pharmaceutical aerosol formulation as described and an actuator housing adapted to hold the canister and allow for drug delivery.
  • the canister in the drug delivery device has a headspace representing greater than about 15% of the total volume of the canister.
  • the polymer intended for pulmonary administration is dissolved, suspended or emulsified in a mixture of a solvent, surfactant and propellant. The mixture is maintained under pressure in a canister that has been sealed with a metering valve.
  • a solid or a liquid carrier can be used for nasal administration.
  • the solid carrier includes a coarse powder having particle size in the range of, for example, from about 20 to about 500 microns and such formulation is administered by rapid inhalation through the nasal passages.
  • the formulation is administered as a nasal spray or drops and includes oil or aqueous solutions of the active ingredients.
  • formulations that are rapidly dispersing dosage forms also known as “flash dose” forms.
  • some embodiments of the present invention are formulated as compositions that release their active ingredients within a short period of time, e.g., typically less than about five minutes, in another embodiment, less than about ninety seconds, in another embodiment, less than about thirty seconds and in another embodiment, in less than about ten or fifteen seconds.
  • Such formulations are suitable for administration to a subject via a variety of routes, for example by insertion into a body cavity or application to a moist body surface or open wound.
  • a “flash dosage” is a solid dosage form that is administered orally, which rapidly disperses in the mouth, and hence does not require great effort in swallowing and allows the compound to be rapidly ingested or absorbed through the oral mucosal membranes.
  • suitable rapidly dispersing dosage forms are also used in other applications, including the treatment of wounds and other bodily insults and diseased states in which release of the medicament by externally supplied moisture is not possible.
  • flash dose forms are known in the art; see for example, effervescent dosage forms and quick release coatings of insoluble microparticles in U.S. Pat. Nos.
  • the compounds of the invention are also formulated as "pulsed release” formulations, in which the compound is released from the pharmaceutical compositions in a series of releases ⁇ i.e., pulses).
  • the compounds are also formulated as "sustained release” formulations in which the compound is continuously released from the pharmaceutical composition over a prolonged period.
  • formulations e.g., liquid formulations, including cyclic or acyclic encapsulating or solvating agents, e.g., cyclodextrins, polyethers, or polysaccharides (e.g., methylcellulose), or in another embodiment, polyanionic ⁇ - cyclodextrin derivatives with a sodium sulfonate salt group separate from the lipophilic cavity by an alkyl ether spacer group or polysaccharides.
  • the agent is methylcellulose.
  • the agent is a polyanionic ⁇ -cyclodextrin derivative with a sodium sulfonate salt separated from the lipophilic cavity by a butyl ether spacer group, e.g., CAPTISOL® (CyDex, Overland, KS).
  • a butyl ether spacer group e.g., CAPTISOL® (CyDex, Overland, KS).
  • reaction mixture was then poured on to ice cooled water acidified with (10 ml) 1 N HCl and extracted with ethyl acetate (100 ml) and the organic layer washed with saturated solution of NaHCO 3 , water and brine, dried over Na ⁇ SCM and the solvent removed under vacuum to give a yellowish-white powder of the desired compound (2.65 g) 62% yield.
  • Reagents i) SOCI 2 , DCM. ii) 3,5dibenzyloxybenzylamine (1.0eq), TEA (2.0eq) 20% yield (two steps, with chromatography), iii) 10% Pd/C (10 mol %), H 2 , 55psi, EtOAc 24hr (53%, after chromatography. BORMS.
  • Reagents i) SOCI 2, DCM. ii) 3-Fluorobenzylamine(1.1 eq), DIEA (2.2eq) (20%after chromatography), iii) Phenylboronic acid(1.2eq), 2M sodium carbonate, Pd(PPh 3 ) 4 (3 mol %), Toluene (inseparable miture).
  • the reaction was allowed to stir at room temperature till the TLC indicated consumption of the starting material (3 hrs), after completion of the reaction, the reaction mixture was washed with water, saturated NaHCO 3 solution, and saturated NaCl solution, dried using Na 2 SO 4 and evaporated to produce yellow oil, the oil produced was dissolved in 25 ml of 90% ethanol, KCN (1.05 gm, 16.2 mmole) was then added and it was heated under reflux overnight. Ethanol was evaporated; solid was washed with 50 ml water and filtered. The solid was dissolved in 30 ml of cone. HCl, refluxed for 48 hr; charcoal was added refluxed for 1 hr, filtered.
  • (2-Fluoro-biphenyl-4-yl)-acetic acid (2-Fluoro-biphenyl-4-yl)- methanol (0.75 gm, 3.7 mmole) was dissolved in 20 ml DCM, cooled using ice/methanol, triethylamine (0.55 ml, 4.0 mmole) was added followed by methanesulfonylchloride (0.3 ml, 4.0 mmole) added drop wise over 5 minutes.
  • the reaction was allowed to stir at room temperature till the TLC indicated consumption of the starting material (2 hrs), after completion of the reaction, the reaction mixture was washed with water, saturated NaHCO 3 solution, and saturated NaCl solution, dried using Na 2 SO 4 and evaporated to produce yellow oil, the oil produced was dissolved in 25 ml of 70% ethanol, KCN (0.4 gm, 6 mmole) was then added and it was heated under reflux overnight. Ethanol was evaporated; solid was washed with 50 ml water and filtered. The solid was dissolved in 20 ml of ethanol, then 20 ml of cone.
  • the reaction was allowed to cool to room temperature, filtered, solid washed with ethyl acetate, NaOH 10%, the aqueous layer was washed several times with ethyl acetate, neutralized by drop wise addition of HCl 1% having ethyl acetate in the medium with shaking after each addition of the HCl, ethyl acetate was evaporated and the solid formed was crystallized from methanol-water to produce a white solid (0.07 gm, 40%).

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Abstract

L'invention concerne des composés et des procédés permettant de moduler un ou plusieurs composants d'une cascade de kinases.
PCT/US2007/015273 2006-06-29 2007-06-29 Compositions de biaryle et procédés de modulation d'une cascade de kinases WO2008002676A2 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
SI200731516T SI2041071T1 (sl) 2006-06-29 2007-06-29 Biarilni sestavki in postopki za moduliranje kinazne kaskade
AU2007265373A AU2007265373B2 (en) 2006-06-29 2007-06-29 Biaryl compositions and methods for modulating a kinase cascade
CN200780031980XA CN101595084B (zh) 2006-06-29 2007-06-29 用于调整激酶级联的二芳基组合物和方法
JP2009518322A JP5564251B2 (ja) 2006-06-29 2007-06-29 キナーゼカスケードを調節するためのビアリール組成物および方法
ES07810102.9T ES2500165T3 (es) 2006-06-29 2007-06-29 Composiciones de biarilo y métodos para modular una cascada de quinasas
EP07810102.9A EP2041071B1 (fr) 2006-06-29 2007-06-29 Compositions de biaryle et procédés de modulation d'une cascade de kinases
DK07810102.9T DK2041071T3 (da) 2006-06-29 2007-06-29 Biarylsammensætninger og fremgangsmåder til modulering af en kinasekaskade
CA2656564A CA2656564C (fr) 2006-06-29 2007-06-29 Compositions de biaryle et procedes de modulation d'une cascade de kinases
IL196168A IL196168A (en) 2006-06-29 2008-12-25 Use of baryryl compounds to prepare drugs for the treatment of kinase-mediated disorders
IL242374A IL242374A (en) 2006-06-29 2015-10-29 Baryl compounds and their pharmaceutical preparations

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US11/480,174 2006-06-29
US11/480,174 US7968574B2 (en) 2004-12-28 2006-06-29 Biaryl compositions and methods for modulating a kinase cascade
US92349607P 2007-04-13 2007-04-13
US60/923,496 2007-04-13

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IL242374A (en) 2017-08-31
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WO2008002676A2 (fr) 2008-01-03
WO2008002676A3 (fr) 2008-05-02
ES2500165T3 (es) 2014-09-30

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