Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • 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
  • C07D403/06—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 carbon chain containing only aliphatic carbon atoms

Definitions

• Protein kinases constitute the largest family of human enzymes, encompassing well over 500 proteins. It has been found that kinases play a key role in many basic biological processes in the cell including but not limited to cell proliferation, survival, motility, morphogenesis, angiogenesis, and so on. In addition, many kinases were found involved and implicated in a number of pathological settings such as cancers, autoimmune and inflammatory diseases, eye diseases, and cardiovascular diseases. In general, kinases transmit cell-to-cell or intracellular signals by phosphorylating downstream proteins in the signal transduction pathways such that the downstream proteins are activated and thus signals can be passed from one step to the next down the signaling cascade. These signal transduction pathways are well regulated in the cell under normal physiological conditions.
• receptor tyrosine kinases c-Met HGF/SF receptor
• VEGFR2 VEGFR2
• PDGFR ⁇ c-Kit
• HGF/SF receptor HGF/SF receptor
• VEGFR2 VEGFR2
• PDGFR ⁇ PDGFR ⁇
• c-Kit a receptor tyrosine kinases c-Met (HGF/SF receptor), VEGFR2 (KDR, Flkl), PDGFR ⁇ and c-Kit
• HGF/SF receptor HGF/SF receptor
• VEGFR2 VEGFR2
• PDGFR ⁇ c-Kit
• Angiogenesis the formation of new blood vessels from preexisting ones, plays a significant role in many pathological settings, including cancer, chronic inflammation, diabetic retinopathy, psoriasis, rheumatoid arthritis, and macular degeneration.
• Anti-angiogenesis therapy represents an important approach for the treatment of solid tumors and other diseases associated with dysregulated vascularization.
• angiogenesis inhibitor drugs such as bevacizumab, sorafenib, and sunitinib for the treatment of cancers, the clinical benefit from anti-angiogenesis therapy has become increasingly evident. See, .e.g., Atkins, M. et al., Discovery, 2006, 5: 279-280; Wilhelm, S. et al., Nature Reviews: Drug Discovery, 2006, 5: 835-844.
• angiogenesis mediators include VEGF, FGF, and angiopoietin 1 and 2 (Angl and Ang2) that bind to their cognate receptors (VEGFRs, FGFRs and Tiel and Tie2, respectively) expressed on endothelial cells, as well as platelet-derived growth factor (PDGF) that binds to its receptor (PDGFR ⁇ ) expressed on VEGF -producing stromal cells or its receptor (PDGFR ⁇ ) expressed on pericytes and smooth muscle cells.
• VEGF vascular endoietin 1 and 2
• PDGF platelet-derived growth factor
• Molecules including VEGF, FGF, PDGF, VEGFRs, FGFRs, PDGFRs, Tiel, and Tie2 are key components of multiple different signaling pathways that function in parallel to regulate angiogenesis in both physiological and clinical settings.
• the signal transduction pathway mediated by VEGFR2 plays the most critical role in tumor angiogenesis.
• a number of monoclonal antibodies (mAbs) against single angiogenesis pathway components such as VEGF and FGF have been developed to block angiogenesis and shown to slow down tumor growth in preclinical and clinical studies.
• mAbs monoclonal antibodies against single angiogenesis pathway components
• FGF FGF
• a linear pathway targeting a single component of the pathway is less effective than simultaneous blocking multiple components of the pathway.
• development of multiplex small molecular kinase inhibitors is desirable for achieving more efficient angiogenesis inhibition.
• VEGFR2 and PDGFR ⁇ are targeted by both sorafenib and sunitinib, the clinical benefits demonstrated in the use of both drugs unambiguously validate VEGFR2 and/or PDGFR ⁇ kinase as effective target in the treatment of diseases such as cancer. See, .e.g., Atkins, M. et al., supra; Wilhelm, S. et al., supra.
• the c-Kit proto-oncogene also known as KIT, CD-I 17, stem cell factor receptor, or mast cell growth factor receptor, is a receptor tyrosine kinase and a member of the split kinase domain subfamily.
• SCF stem cell factor
• C-Kit expression has been reported in a wide variety of human malignancies such as small cell lung cancer (SCLC), gastrointestinal stromal tumors (GIST), colorectal cancer and so on.
• SCLC small cell lung cancer
• GIST gastrointestinal stromal tumors
• colorectal cancer colorectal cancer
• c-Kit inhibitor such as Gleevec ® has been used to treat CML, GIST, and other cancers.
• C-Met tyrosine kinase is a cell surface receptor normally activated by its natural ligand, hepatocyte growth factor/scatter factor (HGF/SF).
• HGF/SF hepatocyte growth factor/scatter factor
• c- Met protein Upon HGF binding, c- Met protein is activated by autophosphorylation and recruits downstream effectors to its cytoplasmic domain.
• the resulting multi-protein signaling complex can in turn activate a number of downstream intracellular signaling events in epithelial cells and lead to a wide range of cellular responses including but not limited to proliferation, survival, angiogenesis, wound healing, tissue regeneration, scattering, motility and invasion. See, e.g., Comoglio, P. M. et al., supra; and Benvenuti, S. and Comoglio, P. M., J. Cellular Physiology, 2007, 213: 316-325.
• C-Met has been implicated as a proto-oncogene, which is found genomically amplified, over-expressed, mutated, or aberrantly activated in many types of cancers, suggesting its roles in the tumor growth, invasiveness and metastasis.
• c-Met activation has been found in solid tumors which develop resistance to anti-EGFR therapies during the course of treatment, implicating a compensatory role of c-Met activation to the EGFR signaling pathway (see, e.g., Smolen, G. A et al., Proc. Natl Acad. Sci. USA, 2006, 103: 2316-2321; Lutterbach, B. et al., Cancer Res., 2007, 67: 2081-2088).
• inhibition of c-Met signaling is considered as a potentially effective therapeutic strategy against solid tumors whose growth is wholly or partially c-Met driven (see, e.g., Smolen, G. A et al., supra). It is thus pharmacologically preferable to develop small molecule kinase inhibitors against c-Met for the treatment of cancer.
• anti-angiogenesis therapies can lead to increased local invasion and distal metastasis of tumor cells and thus elicit malignant progression of tumors (see, e.g., Ebos, J.M.L. et al, Cancer Cell, 2009, 15: 232-239; Paez-Ribes, M. et al, Cancer Cell, 2009, 15: 220-231).
• This unexpected yet important finding calls for a new generation of anti-angiogenesis therapies which can not only disrupt tumor angiogenesis and arrest tumor growth but also are able to prevent tumor invasion and metastasis at the same time.
• This invention provides a solution by combining two anti-tumor therapeutic mechanisms with small molecule drugs targeting one or more protein kinases (e.g., both VEGFR2 and c-Met), which offer unexpected clinical advantages over the currently available anti-angiogenesis therapeutics.
• small molecule drugs targeting one or more protein kinases (e.g., both VEGFR2 and c-Met), which offer unexpected clinical advantages over the currently available anti-angiogenesis therapeutics.
• the present invention in general provides compounds of Formula I or II, and methods of using these compounds for the treatment of conditions mediated by one or more protein kinases (e.g., VEGFR2 or c-Met or PDGFR ⁇ or c-Kit or CSFlR, or EphA2, or any of their combinations) such as tumor, rheumatoid arthritis, autoimmune disease, acute inflammation, nephritis, diabetic retinitis, psoriasis, or macular degeneration.
• protein kinases e.g., VEGFR2 or c-Met or PDGFR ⁇ or c-Kit or CSFlR, or EphA2, or any of their combinations
• the present invention provides compounds of Formula I or II, crystal forms, chelates, non-covalent complexes, prodrugs, stereoisomers, solvates, N- oxides, pharmaceutically acceptable salts, and mixtures thereof.
• U, V, X, Y, and Z are each independently N or C-R 1 ;
• L is O, S(O) n , N-R , or alkylene which is optionally substituted with one or more independent R 3 group;
• B, D, E, G, and J are each independently N or C-R ;
• the 5-membered ring of A is connected to L and the 6-membered ring of A is connected to the urea group in Formula I or II; in other words, the fixed nitrogen in A as shown in Al, A2, and A3 is connected to the linker L;
• Ar is aryl or heteroaryl, and is optionally substituted with one or more
• R 1 , R 3 , R 4 , R 5 , and R 6 are each independently H, halo, -CN, -CF 3 , -NO 2 , -NH 2 , -OH, -OCF 3 , -OCH 3 , -CO 2 H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted with one or more independent Q 2 groups;
• Q 1 and Q 2 are each independently H, halo, -CN, -CF 3 , -OCF 3 , -NO 2 , oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heterocycloaryl, -OR , -S(O) n R 8 , -NR 9 R 10 , -SO 2 NR 9
• -NR S(O)NR R each of which is optionally substituted with one or more independent H, halo, -CN, -OH, -NH 2 , -NO 2 , oxo, -CF 3 , -OCF 3 , -CO 2 H, -S(O) n H, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, heterocycloaryl, or -O-alkyl, each of which may be partially or fully halogenated;
• R 7 , R 8 , R 11 , R 12 , R 13 , R 14 , or R 15 are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heterocycloaryl;
• R and R are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heterocycloaryl; or when in -NR 9 R 10 , R 9 and R 10 , together with the nitrogen atom to which they are attached, form a 3- to 12-membered saturated or unsaturated ring, wherein said ring optionally includes one or more heteroatoms each independently being O, N, or S(O) n ; and
• n O, 1, or 2.
• X, Y, Z, V, and U are each independently C-R 1 , thus giving the compound of Formula Ia or Ha, in which the R 1 groups can be the same or different.
• each R is H, and L' is a covalent bond.
• Y is N
• X, Z, V, and U are each independently C-R 1 , thus giving the compound of Formula Ib or Hb, in which the R 1 groups can be the same or different.
• each R is H and L' is a covalent bond.
• Z is N; and X, Y, V, and U are each independently C-R 1 , thus giving the compound of Formula Ic or Hc, in which the R 1 groups can be the same or different.
• each R 1 is H and L' is a covalent bond.
• the compound is of Formula I; X is N; and Y, Z, and V are each independently C-R , thus giving the compound of Formula Id, in which the R groups can be the same or different.
• each R is H and L' is a covalent bond.
• the compound is of Formula I; X and Z are each N; and Y and V are each independently C-R , thus giving the compound of Formula Ie in which the R groups can be the same or different.
• each R is H and L' is a covalent bond.
• L is alkylene optionally substituted with one or more independent R 3 groups.
• L is alkylene (e.g., methylene, ethylene, propylene, or i-propylene).
• L' is a covalent bond
• Ar is phenyl or indolinyl, and is optionally substituted with one or more groups each independent being halo, alkoxy, alkyl, haloalkoxy, cyano, oxo, or optionally substituted heterocycloalkyl.
• A is Al-a, Al-b, Al-c, Al-d, Al-e, Al-f, Al-g, Al-h,
• Al-i, A2-a, A2-b, A3-a, A3-b, A3-c, A3-d, or A3-e (as shown below), and is optionally substituted with one or more independent R 5 groups.
• A is Al-a, Al-b, Al-d, Al-e, Al-g, A2-a, A2-b, A3-a, or A3-c, and is optionally substituted with one or more independent R 5 groups.
• A is Al-a, Al-b, Al-d, Al-g, A2-a, or A2-b, and is optionally substituted with one or more independent R groups.
• A is Al-a or A2-a, and is optionally substituted with one or more independent R 5 groups.
• A is Al-a or A2-a without optional substituent.
• the compound is of the structure:
• Ar is phenyl, naphthyl, pyridinyl, pyridonyl, pyrimidinyl, pyridazinyl, triazinyl, imidazolyl, thiophenyl, furyl, thiazolyl, oxazolyl, triazolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuryl, benzothiophenyl, benzotriazolyl, 2-oxindolyl, or indolinyl, each of which is optionally substituted with one or more groups each independent being halo, alkoxy, alkyl, haloalkoxy, cyano, oxo, or optionally substituted heterocycloalkyl.
• the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoe)-2-[0033]
• the compound is:
• the compound is: l-(2-Chlorophenyl)-3-[l-(lH-pyrrolo[2,3- ⁇ ]pyridin-4-ylmethyl)-lH-indol-4- yljurea;
• the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
• the compound is:
• the compound is:
• the compound is:
• the compound is:
• the compound is:
• the compound is:
• the compound is:
• the compound is:
• the compound is:
• the compound is: l-(3-Cyanophenyl)-3-[l-(lH-pyrrolo[2,3-6]pyridin-4-ylmethyl)-lH-indol-4- yljurea;
• compositions each including a therapeutically effective amount of any of the compounds described above and a pharmaceutically acceptable carrier.
• the pharmaceutical compositions can be any form that is suitable for an intended administration method, e.g., injectable, aerosol, cream, gel, capsule, pill, tablet, syrup, eye drop, or ointment.
• the compounds described above exhibit inhibitory effect on one or more protein kinases, e.g., c-Met, VEGFR2, PDGFR ⁇ , c-Kit, CSFlR, and EphA2.
• protein kinases e.g., c-Met, VEGFR2, PDGFR ⁇ , c-Kit, CSFlR, and EphA2.
• another aspect of the present invention provides a method for treating a patient having a condition mediated by an abnormal protein kinase activity (e.g., overexpressed protein kinase).
• the method includes administering to the patient in need thereof a therapeutically effective amount of any of the compounds or
• the compound or pharmaceutical composition can be administered in a suitable manner, e.g., intravenously,
• Examples of such a protein kinase include VEGFR2, c-Met, RON, PDGFR ⁇ , PDGFR ⁇ , c-Kit, CSFlR, EphA2, AIk, Tie-1, Tie-2, Flt3, FGFRl, FGFR2, FGFR3, FGFR4, EGFR, ⁇ er2, AbI, Aurora A, Aurora B, Aurora C, Src, Lck, IGF- 1 R, and IR.
• Examples of such a condition include cancer, tumor, rheumatoid arthritis, autoimmune disease, acute inflammation, nephritis, diabetic retinitis, psoriasis, and macular degeneration.
• the tumor or cancer can be, e.g., bone cancer (e.g., Ewing's sarcoma, osteosarcoma, chondrosarcoma, or orthopaedics links), brain and CNS tumor (e.g., acoustic neuroma, spinal cord tumor, brain tumor ring of hope), breast cancer, breast cancer, colorectal cancer (e.g., anal cancer), endocrine cancer (e.g., adrenocortical carcinoma, pancreatic cancer(e.g.
• bone cancer e.g., Ewing's sarcoma, osteosarcoma, chondrosarcoma, or orthopaedics links
• brain and CNS tumor e.g., acoustic neuroma, spinal cord tumor, brain tumor ring of hope
• breast cancer breast cancer
• colorectal cancer e.g., anal cancer
• endocrine cancer e.g., adrenocortical carcinoma
• pancreatic carcinoma such as exocrine pancreatic carcinoma
• pituitary cancer thyroid cancer, parathyroid cancer, thymus cancer, multiple endocrine neoplasia, or other endocrine cancer
• gastrointestinal cancer e.g., stomach cancer, esophageal cancer, small intestine cancer, gall bladder cancer, liver cancer, extra-hepatic bile duct cancer, or gastrointestinal carcinoid tumor
• genitourinary cancer e.g., testicular cancer, penile cancer, or prostate cancer
• gynecological cancer e.g., cervical cancer, ovarian cancer, vaginal cancer
• uterus/endometrium cancer vulva cancer, gestational trophoblastic cancer, fallopian tube cancer, or uterine sarcoma
• head and neck cancer e.g., oral cavity, lip, salivary gland cancer, larynx, hypopharynx, oropharynx cancer, nasal, paranasal, or nasopharynx cancer
• leukemia e.g., acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, acute lymphocytic leukemia, acute myeloid leukemia
• lung cancer e.g., adenocarcinoma, small cell lung cancer, or non-small cell lung cancer
• lymphoma e.g., Hodgkin's Disease, Non-Hodgkin's Lymphoma, AIDS-related Lymphoma
• eye cancer e.g., retinoblastoma or intraocular melanoma
• skin cancer e.g., melanoma, non-melanoma skin cancer or Merkel cell cancer
• soft tissue sarcoma e.g., Kaposi's Sarcoma
• urinary system cancer e.g., kidney cancer, Wilm's tumor, bladder cancer, urethral cancer, or transitional cell cancer
• other types or related disorders e.g., histiocytosis, mesothelioma, metastatic cancer, carcinoid tumors, neurofibromatosis, germ cell tumors, desmoplasic small round cell
• Chemical entities of the present invention include, but are not limited to compounds of Formula I or II and all pharmaceutically acceptable forms thereof.
• Pharmaceutically acceptable forms of the compounds recited herein include
• pharmaceutically acceptable salts pharmaceutically acceptable salts, solvates, crystal forms (including polymorphs and clathrates), chelates, non-covalent complexes, prodrugs, and mixtures thereof.
• the compounds described herein are in the form of pharmaceutically acceptable salts.
• the terms "chemical entity” and “chemical entities” also encompass pharmaceutically acceptable salts, solvates, crystal forms, chelates, non- covalent complexes, prodrugs, and mixtures.
• prodrugs also fall within the scope of chemical entities, for example ester or amide derivatives of the compounds of Formula I or II.
• the term "prodrugs” includes any compounds that become compounds of Formula I or II when administered to a patient, e.g., upon metabolic processing of the prodrug.
• Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate and like derivatives of functional groups (such as alcohol or amine groups) in the compounds of Formula I or II.
• solvate refers to the chemical entity formed by the interaction of a solvent and a compound. Suitable solvates are pharmaceutically acceptable solvates, such as hydrates, including monohydrates and hemi-hydrates.
• chelate refers to the chemical entity formed by the coordination of a compound to a metal ion at two (or more) points.
• non-covalent complex refers to the chemical entity formed by the interaction of a compound and another molecule wherein a covalent bond is not formed between the compound and the molecule.
• complexation can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also called ionic bonding).
• an active agent is used to indicate a chemical entity which has biological activity.
• an “active agent” is a compound having pharmaceutical utility.
• an active agent may be an anti-cancer therapeutic.
• alkyl used alone or as part of a larger moiety (e.g., as in “cycloalkenyl ⁇ /fcy/” or “halo ⁇ /ty/oxy”), refers to a saturated aliphatic hydrocarbon group. It can contain 1 to 8 (e.g., 1 to 6 or 1 to 4) carbon atoms. As a moiety, it can be denoted as -C n H 2n+I .
• An alkyl group can be straight or branched.
• alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, and 2-ethylhexyl.
• An alkyl group can be substituted (i.e., optionally substituted) with one or more substituents.
• alkylene used alone or as part of a larger moiety (e.g., as in “a ⁇ ylalkyleneoxy” or “arylhalo ⁇ /£y/er ⁇ oxy”), refers to a saturated aliphatic hydrocarbon group with two radical points for forming two covalent bonds with two other moieties. It can contain 1 to 8 (e.g., 1 to 6 or 1 to 4) carbon atoms. As a moiety, it can be denoted as -C n H 2n -. Examples of an alkylene group include, but are not limited to, methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), and propylene (-CH 2 CH 2 CH 2 -).
• alkynyl used alone or as part of a larger moiety (e.g., as in “ ⁇ /Ajwy/alkyl” or “halo ⁇ /£y ⁇ ry/alkoxy”), refers to an aliphatic hydrocarbon group with at least one triple bond. It can contain 2 to 8 (e.g., 2 to 6 or 2 to 4) carbon atoms.
• An alkynyl group can be straight or branched. Examples of an alkynyl group include, but are not limited to, propargyl and butynyl.
• alkenyl used alone or as part of a larger moiety (e.g., as in “ ⁇ /fewy/alkyl” or “ ⁇ /fewy/alkoxy”), refers to an aliphatic hydrocarbon group with at least one double bond. It can contain 2 to 8 (e.g., 2 to 6 or 2 to 4) carbon atoms.
• An alkenyl group with one double bond can be denoted as -C n H 2n-I , or -C n H 2n-3 with two double bonds.
• an alkenyl group can be straight or branched.
• alkenyl group examples include, but are not limited to, allyl, isoprenyl, 2-butenyl, and 2-hexenyl.
• cycloalkyl used alone or as part of a larger moiety (e.g., as in “cycloalkylalkyl” or “halocyc/o ⁇ /fcy/alkoxy”), refers to a saturated carbocyclic mono-, bi-, or tri-cyclic (fused or bridged or spiral) ring system. It can contain 3 to 12 (e.g., 3 to 10, or 5 to 10) carbon atoms.
• cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cubyl, octahydro-indenyl, decahydro-naphthyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2.]decyl, bicyclo[2.2.2]octyl, adamantyl, azacycloalkyl, or ((aminocarbonyl)cycloalkyl)cycloalkyl.
• cycloalkenyl used alone or as part of a larger moiety (e.g., as in “cycloalkenylalkyl” or u cyanocycloalkenyla ⁇ koxy”), refers to a non- aromatic carbocyclic ring system having one or more double bonds. It can contain 3 to 12 (e.g., 3 to 10, or 5 to 10) carbon atoms.
• cycloalkenyl groups include, but are not limited to, cyclopentenyl, 1 ,4-cyclohexa-di-enyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, cyclopentenyl,
• heterocycloalkyl used alone or as part of a larger moiety (e.g., as in “heterocychalkyMkyl” or “heterocychalkoxy”), refers to a 3- to 16- membered mono-, bi-, or tri-cyclic (fused or bridged or spiral)) saturated ring structure, in which one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof).
• the heterocycloalkyl can contain 3 to 15 carbon atoms (e.g., 3 to 12 or 5 to 10).
• heterocycloalkyl group examples include, but are not limited to, piperidyl, piperazyl, tetrahydropyranyl, tetrahydrofuryl, 1 ,4- dioxolanyl, 1 ,4-dithianyl, 1,3-dioxolanyl, oxazolidyl, isoxazolidyl, morpholinyl, thiomorpholyl, octahydrobenzofuryl, octahydrochromenyl, octahydrothiochromenyl, octahydroindolyl, octahydropyrindinyl, decahydroquinolinyl,
• a monocyclic heterocycloalkyl group can be fused with a phenyl moiety such as tetrahydroisoquinoline.
• aryl used alone or as part of a larger moiety (e.g., as in “ ⁇ ralkyl”, “ ⁇ ralkoxy,” or “halo ⁇ ry/oxyalkyl”), refers to a monocyclic (e.g., phenyl); bicyclic (e.g., indenyl, naphthalenyl, or tetrahydronaphthyl); and tricyclic (e.g., fluorenyl, tetrahydrofluorenyl, tetrahydroanthracenyl, or anthracenyl) ring system in which the monocyclic ring system is aromatic (e.g., phenyl) or at least one of the rings in a bicyclic or tricyclic ring system is aromatic (e.g., phenyl).
• the bicyclic and tricyclic groups include, but are not limited to, benzo-fused 2- or 3-membered carbocyclic rings.
• a benzo-fused group includes phenyl fused with two or more C 4-8 carbocyclic moieties.
• heteroaryl refers to a monocyclic, bicyclic, or tricyclic ring system having 5 to 15 ring atoms wherein at least one of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof) and in which the monocyclic ring system is aromatic or at least one of the rings in the bicyclic or tricyclic ring systems is aromatic. It can contain e.g., 5 to 12 or 8 to 10 ring atoms.
• a heteroaryl group includes, but is not limited to, a benzo-fused ring system having 2 to 3 rings.
• a benzo-fused group includes benzo fused with one or two 4- to 8-membered
• heterocycloalkyl moieties e.g., indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [bjfuryl, benzo[b]thiophenyl, quinolinyl, or isoquinolinyl.
• heteroaryl are pyridyl, 1 H-indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzithiazolyl, xanthenyl,
• thioxanthenyl phenothiazinyl, dihydroindolyl, benzo[l,3]dioxolyl, benzo [bjfuryl, benzo[b]thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, puryl, quinolinyl, quinazolinyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolinyl, 4H-quinolizyl, benzo- 1 ,2,5-thiadiazolyl, and 1,8-naphthyridyl.
• bridged bicyclic ring system refers to a bicyclic heterocycloalkyl ring system or bicyclic cycloalkyl ring system in which the rings have at least two common atoms.
• bridged bicyclic ring systems include, but are not limited to, adamantanyl, norbornanyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.2.3]nonyl, 2-oxabicyclo[2.2.2]octyl, 1- azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.1]octyl, and 2,6-dioxatricyclo[3.3.1.03,7]nonyl.
• halo refers to fluoro, chloro, bromo, or iodo.
• independent e.g., as in “optionally substituted with one or more independent R groups” means that when the number of substituent is more than one (e.g., two or three), these multiple substituents can be the same or different.
• a "cyano” group refers to -CN.
• a "urea” group refers to the structure -NR ⁇ -CO-NR ⁇ Rz when terminally included in a compound or -NRx-CO-NRy- when internally included in a compound.
• an optionally substituted group can have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position.
• a ring substituent such as a heterocycloalkyl, can be bound to another ring, such as a cycloalkyl, to form a spiro-bicyclic ring system, e.g., both rings share one common atom.
• substituents envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds.
• the phrase "each of which is optionally substituted with one or more independent Q 1 groups” gramatically applies to H, but since H (hydrogen atom) chemicall cannot be substitued, the phase therefore does not actually apply to H.
• stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein.
• a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40 0 C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
• the term "or” as in, e.g., "one or more independent halo, alkoxy, alkyl ... cyano, oxo, or optionally substituted heterocycloalkyl” (emphasis added) can mean “or” or "and.”
• the substituents when more than one can be two halo groups or one halo and one alkyl.
• VEGFR2 or c-Met can mean “VEGFR2,” “c-Met,” or “VEGFR2 and c-Met.”
• pharmaceutically acceptable salt(s) means those salts of the compounds of the invention that are safe and effective for internal use (or topical use, if needed) in a subject (e.g., a mammal such as a human patient, a dog, or a cat) and that possess the desired biological activity.
• Pharmaceutically acceptable salts include salts of acidic or basic groups present in compounds of the invention.
• Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate,
• benzensulfonate, p-toluenesulfonate and pamoate i.e., l,l'-methylene-bis-(2-hydroxy-3- naphthoate)
• Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and
• a "subject" for treatment generally refers to and thus may be interchangeable with a "patient,” such as an animal (e.g., a mammal such as a human, a cat, or a dog).
• a patient such as an animal (e.g., a mammal such as a human, a cat, or a dog).
• an "effective amount” is defined as the amount required to confer a therapeutic effect on the treated patient, and is typically determined based on age, surface area, weight, and condition of the patient. The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described by Freireich et al., Cancer Chemother. Rep., 50: 219 (1966). Body surface area may be approximately determined from height and weight of the patient. See, e.g.,
• the structures depicted herein are meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and
• a therapeutically effective amount of a compound of this invention refers to an amount effective, when administered to a human or non-human patient, for the treatment of a disease, e.g., a therapeutically effective amount may be an amount sufficient to treat a disease or disorder responsive to kinase inhibition.
• the therapeutically effective amount may be ascertained experimentally, for example by assaying blood concentration of the chemical entity, or theoretically, by calculating bioavailability.
• the term "significant” refers to any detectable change that is statistically significant in a standard parametric or nonparametric test of hypothesis such as Student's T-test, where p ⁇ 0.05.
• the term "patient” or “subject” refers to an animal, such as a mammal, for example a human, a dog, or a cat, that has been or will be the object of treatment, observation or experiment.
• the methods of the invention can be useful in both human therapy and veterinary applications.
• angiogenesis kinase refers to a kinase involved in angiogenesis. Its examples include VEGFR2, PDGFR ⁇ , and c-Met.
• the term “inhibition” refers to a decrease in kinase activity as a direct or indirect response to the presence of compounds of Formula I or II, relative to the activity of the kinase in the absence of the compound. The decrease may be due to the direct interaction of the compound with the kinase, or due to the interaction of the compound with one or more other factors that in turn affect kinase activity.
• the presence of the compound may, for example, decrease kinase activity by directly binding to the kinase, by causing (directly or indirectly) another factor to decrease the kinase activity, or by (directly or indirectly) decreasing the amount of kinase present in the cell or organism.
• treatment refers to any treatment of a disease in a patient, including: (a) preventing the disease, that is, causing the clinical symptoms of the disease not to develop; (b) inhibiting the disease; (c) slowing or arresting the development of clinical symptoms; or (d) relieving the disease, that is, causing the regression of clinical symptoms.
• the term "diseases or disorders responsive to kinase inhibition” refer to pathologic conditions that depend, at least in part, on the activity of one or more protein kinases, for example, angiogenesis kinases.
• Kinases either directly or indirectly participate in the signal transduction pathways of a variety of cellular activities including cell proliferation, differentiation, and invasion.
• Diseases responsive to kinase inhibition include but are not limited to tumor growth, angiogenesis supporting solid tumor growth, and diseases characterized by excessive growth of local vasculature such as diabetic retinopathy, macular degeneration, and inflammation.
• change in angiogenesis refers to a change in the vascular network or quality of vasculature.
• Change in angiogenesis may be measured by many parameters and, for instance, may be assessed by delayed appearance of neovascular structures, slowed development of neovascular structures, decreased occurrence of neovascular structures, changes in vascular permeability, changes in blood flow, slowed or decreased severity of angiogenesis-dependent disease effects, arrested vasculature growth, or regression of previous vasculature.
• the present invention provides compounds of Formula I or II, or a pharmaceutically acceptable salt thereof.
• U, V, X, Y, and Z are each independently N or C-R ;
• L is O, S(O) n , N-R , or alkylene which is optionally substituted with one or more independent R 3 group;
• Ar is aryl or heteroaryl, each of which is optionally substituted with one or more independent R 6 groups;
• R 1 , R 3 , R 4 , R 5 , and R 6 are each independently H, halo, -CN, -CF 3 , -NO 2 , -NH 2 , -OH, -OCF 3 , -OCH 3 , -CO 2 H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted with one or more independent Q 2 groups;
• Q 1 and Q 2 are each independently H, halo, -CN, -CF 3 , -OCF 3 , -NO 2 , oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heterocycloaryl, -OR 7 , -S(O) n R 8 , -NR 9 R 10 , -SO 2 NR 9 R 10 , -C(O)R 11 , -C(O)NR 9 R 10 , -C(O)OR 12 , -OC(O)R 13 , -NR 9 C(O)R 11 , -NR 9 S(O) 2 R 14 , -NR 15 C(O)NR 9 R 10 , -NR 15 S(O) 2 NR 9 R 10 or
• -NR S(O)NR R each of which is optionally substituted with one or more independent H, halo, -CN, -OH, -NH 2 , -NO 2 , oxo, -CF 3 , -OCF 3 , -CO 2 H, -S(O) n H, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or heterocycloaryl, each of which may be partially or fully halogenated, or -O-alkyl which may be partially or fully halogenated;
• R 7 , R 8 , R 11 , R 12 , R 13 , R 14 , or R 15 are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heterocycloaryl;
• R 9 and R 10 are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heterocycloaryl; or when in -NR 9 R 10 , R 9 and R 10 , together with the nitrogen atom to which they are attached to, form a 3- to 12-membered saturated or unsaturated ring, wherein said ring optionally includes one or more heteroatoms each independently being O, N, or S(O) n ; and
• n O, 1, or 2.
• Intermediate 4 can be prepared in several steps from commercially available 7-azaindole (1) according to Scheme 1 illustrated above. Specifically, 4-chloro-7- azaindole (2) was obtained by oxidation of starting material 1 with an oxidant, such as m- chloroperoxybenzoic acid (mCPBA) or hydrogen peroxide or other peroxyacid, followed by treatment with POCl 3 or SOCl 2 . Compound 2 was then converted into alcohol 3 by Pd-catalyzed cyanation, base- or acid-mediated hydrolysis, esterification, and reduction.
• an oxidant such as m- chloroperoxybenzoic acid (mCPBA) or hydrogen peroxide or other peroxyacid
• the hydroxyl group in compound 3 was replaced with a leaving group (LG), such as Cl, Br, I, MeSO 3 -, TfO-, and TsO-, by reacting with SOCl 2 , CBr 4 +PPh 3 , PBr 3 , MeSO 2 Cl, Tf 2 O, TsCl, etc.
• LG leaving group
• the amino group (NH) on the azaindolyl ring was protected by a commonly used nitrogen protecting group (PG), e.g., Boc or Cbz or other carbamate, PhSO 2 - or other organosulfonyl, p-methoxybenzyl (PMB), methoxymethyl (MOM), [ ⁇ - (trimethylsilyl)ethoxy]methyl (SEM), etc.
• PG nitrogen protecting group
• Intermediate 7 can be easily prepared in three steps from commercially available 7-azaindole (1).
• compound 1 On treatment with Me 2 NH and formaldehyde, compound 1 was converted to amine 5, which was protected with a nitrogen protecting group (PG), e.g., Boc or Cbz or other carbamate, PhSO 2 - or other organosulfonyl, p-methoxybenzyl (PMB), methoxymethyl (MOM), [ ⁇ -(trimethylsilyl)ethoxy]methyl (SEM), etc, to give compound 6.
• PG nitrogen protecting group
• PMB e.g., Boc or Cbz or other carbamate
• PhSO 2 - or other organosulfonyl p-methoxybenzyl
• MOM methoxymethyl
• SEM [ ⁇ -(trimethylsilyl)ethoxy]methyl
• Compound 6 was converted to chloride 7 by reacting with a chloroformate, such as methyl, ethyl, ⁇ -propyl, /-propyl, n-huy ⁇ , or /-butyl chloroformate.
• a chloroformate such as methyl, ethyl, ⁇ -propyl, /-propyl, n-huy ⁇ , or /-butyl chloroformate.
• Scheme 4 shows the synthesis of exemplary compounds of Formula I or II.
• Intermediate A-I or A-2 prepared by Schemes 1-3, reacted with commercially available mono-cyclic or bicyclic aryl or heteroaryl nitro compounds under basic conditions to generate compound C-I or C-2.
• Scheme 5 shows another way to synthesize compounds of Formula I or II.
• Commercially available 4-nitroindole F was reduced to 4-aminoindole G, which reacted with isocyanate E-I or amine E-2 mediated by phosgene or triphosgene or carbonyl diimidazole to afford the urea product H.
• H Upon treatment with NaBH 3 CN+ AcOH, H was converted into compound I.
• Alkylation of I with intermediate A-I or A-2, prepared in Schemes 1-3 gave compounds J-I or J-2, which can be converted to product I or II after removal of protecting group (PG) under acidic or basic conditions.
• protecting group PG
• NMR spectra were recorded on a Bruker or Varian 300 or 400 MHz instrument at ambient temperature with TMS or the residual solvent peak as the internal standard. The line positions or multiples are given in ppm ( ⁇ ) and the coupling constants (J) are given as absolute values in Hertz (Hz).
• the multiplicities in 1 H NMR spectra are abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), m c (centered multiplet), br or broad (broadened).
• Mass spectra were measured by ESI methods. Reactions were monitored by thin layer chromatography (TLC) on silica gel 60 F-254 (0.2 mm) and visualized using UV light. Flash chromatography was performed with silica gel (400- 230 mesh).
• Example 1 l-(2-Methoxyl-5-chlorophenyl)-3-[l-(lH-pyrrolo[2,3-Z>]pyridin-4- ylmethyl)-2,3-dihydro-lH-indol-4-yl] urea hydrochloride
• Example 2a l-(2-Methoxyl-5-chlorophenyl)-3-[l-(lH-pyrrolo[2,3-Z>]pyridin-4- ylmethyl)-lH-indol-4-yl] urea hydrochloride
• Example 2b l-(2-Methoxyl-5-chlorophenyl)-3-[l-(lH-pyrrolo[2,3-Z>]pyridin-4- ylmethyl)-lH-indol-4-yl] urea hydrochloride
• the title compound was also prepared according to the following method. Specifically, sodium hydride (144 mg, 6 mmol) was added to a solution of 4-nitro indole (973 mg, 6 mmol) in THF and the resulting mixture was stirred for 4 h. 1 - ⁇ t- butyloxycarbonyl)-4-chloromethyl-7-azaindole (Int-11, 1.5 g, 5.5 mmol) was then added. After the reaction was complete (by TLC), the mixture was quenched with saturated aqueous ammonium chloride. The organic layer was separated and the aqueous layer was extracted with ethyl acetate.
• Example 4A l-Phenyl-3- ⁇ l-[l-(M>utyloxycarbonyl)-lH-pyrrolo[2,3-Z>]pyridin-3- ylmethyl] -lH-indol-4-yl ⁇ urea
• Example 8A l-(2-Chlorophenyl)-3- ⁇ l-[l-(*-butyloxycarbonyl)-lH-pyrrolo[2,3- b] pyridin-3-ylmethyl] -lH-indol-4-yl ⁇ urea
• Example 12A l-(3-Bromophenyl)-3- ⁇ l-[l-(*-butyloxycarbonyl)-lH-pyrrolo[2,3- 6] pyridin-3-ylmethyl] -lH-indol-4-yl ⁇ urea
• Example 18A l-(3-Methoxyphenyl)-3- ⁇ l-[l-(*-butyloxycarbonyl)-lH-pyrrolo[2,3- b] pyridin-3-ylmethyl] -lH-indol-4-yl ⁇ urea
• Example 22 l-(4-Trifluoromethoxyphenyl)-3-[l-(lH-pyrrolo[2,3-6]pyridin-3- ylmethyl)-lH-indol-4-yl] urea hydrochloride
• Example 22A l-(4-Trifluoromethoxyphenyl)-3- ⁇ l-[l-(*-butyloxycarbonyl)-lH- pyrrolo [2,3-6] pyridin-3-ylm ethyl] -lH-indol-4-yl ⁇ urea
• Example 28 l-(2-Fluoro-4-chlorophenyl)-3-[l-(lH-pyrrolo[2,3-Z>]pyridin-3- ylmethyl)-lH-indol-4-yl] urea hydrochloride
• Example 31A l-(2-Fluoro-5-methoxyphenyl)-3-[l-(lH-pyrrolo[2,3-Z>]pyridin-3- ylmethyl)-lH-indol-4-yl] urea
• Example 35A l-(3-Fluorophenyl)-3- ⁇ l-[l-(M>utyloxycarbonyl)-lH-pyrrolo[2,3- b] pyridin-4-ylmethyl] -2,3-dihydro-lH-indol-4-yl ⁇ urea
• Example 36 l-(4-Fluorophenyl)-3-[l-(lH-pyrrolo[2,3-Z>]pyridin-4-ylmethyl)-lH- indol-4-yl]urea hydrochloride
• Example 38 l-(3-Chlorophenyl)-3-[l-(lH-pyrrolo[2,3-6]pyridin-4-ylmethyl)-lH- indol-4-yl]urea hydrochloride
• Example 40 l-(2-Bromophenyl)-3-[l-(lH-pyrrolo [2,3-b] pyridin-4-ylmethyl)-lH- indol-4-yl]urea hydrochloride
• Example 42 l-(4-Bromophenyl)-3-[l-(lH-pyrrolo [2,3-6] pyridin-4-ylmethyl)-lH- indol-4-yl]urea hydrochloride
• Example 42A l-(4-Bromophenyl)-3- ⁇ l-[l-(*-butyloxycarbonyl)-lH-pyrrolo[2,3- b] pyridin-4-ylmethyl] -lH-indol-4-yl ⁇ urea
• Example 48 l-(2-Trifluoromethoxyphenyl)-3-[l-(lH-pyrrolo[2,3-Z>]pyridin-4- ylmethyl)-lH-indol-4-yl] urea hydrochloride
• Example 49A l-(4-Trifluoromethoxyphenyl)-3- ⁇ l-[l-(*-butyloxycarbonyl)-lH- pyrrolo[2,3-Z>]pyridin-4-ylmethyl]-2,3-dihydro-lH-indol-4-yl ⁇ urea
• Example 52A l-(4-Trifluoromethylphenyl)-3- ⁇ l-[l-(*-butyloxycarbonyl)-lH- pyrrolo [2,3-6] pyridin-4-ylm ethyl] -lH-indol-4-yl ⁇ urea
• Example 53A l-(3-Cyanophenyl)-3- ⁇ l-[l-(*-butyloxycarbonyl)-lH-pyrrolo[2,3- b] pyridin-4-ylmethyl] -2,3-dihydro-lH-indol-4-yl ⁇ urea
• Example 54 l-(4-Cyanophenyl)-3-[l-(lH-pyrrolo[2,3-Z>]pyridin-4-ylmethyl)-lH- indol-4-yl]urea hydrochloride
• Example 56 l-(2-Fluoro-5-chlorophenyl)-3-[l-(lH-pyrrolo[2,3-Z>]pyridin-4- ylmethyl)-lH-indol-4-yl] urea hydrochloride
• Example 57A l-(2-Fluoro-5-bromophenyl)-3- ⁇ l-[l-(*-butyloxycarbonyl)-lH- pyrrolo[2,3-Z>]pyridin-4-ylmethyl]-2,3-dihydro-lH-indol-4-yl ⁇ urea
• Example 58A l-(2-Bromo-5-methylphenyl)-3- ⁇ l-[l-(*-butyloxycarbonyl)-lH- pyrrolo[2,3-Z>]pyridin-4-ylmethyl]-2,3-dihydro-lH-indol-4-yl ⁇ urea
• a standard competition binding assay can be used to test the ability of a compound of this invention on competing with both intended and unintended kinases in vitro.
• a standard cell-based assay for PDGFR ⁇ kinase activity can be used to test a compound of this invention and to identify PDGFR ⁇ antagonists.
• a compound to be tested was first dissolved in DMSO to a concentration of 10 mM and stored at -2O 0 C.
• the activity of PDGFR ⁇ in cells depends on the phosphorylation level of its intracellular domain induced by the ligand.
• full length PDGFR ⁇ sequence was cloned into PC-DNA3.1 vector.
• the plasmid was then transfected into CHO cells. After 48 hours following the transfection, the expression of PDGFR ⁇ in transfected CHO cells was confirmed by regular western blotting.
• CHO cells transfected with full length PDGFR ⁇ plasmid were grown in DMEM medium without the presence of serum.
• various concentrations of compounds from 0.5 nM to 500 nM were added into DMEM medium.
• 20% of FBS Fetal Bovine Serum was added into the medium to stimulate the expression of phosphor-PDGFR ⁇ .
• Cell lysate from approximately 5x10 transfected CHO cells were reacted with anti- phosphor-PDGFR ⁇ or anti-total PDGFR ⁇ antibody in 96 well plates, in the presence of detection antibody, the phosphor-PDGFR ⁇ or total PDGFR ⁇ were detected with Streptavidin-HRP (R&D Systems), followed by chemiluminescent detection.
• the compounds thus tested generally showed potent inhibitory effect on growth-factor induced or constitutively activated PDGFR ⁇ phosphorylation. Some of these compounds were found to exhibit an IC 50 of 100 nM or less, and some other compounds exhibited an even lower IC 50 , such as 10 nM or less. As such, the compounds of this invention may be used in the treatment of diseases implicated by angiogenesis.
• the percentage of PDGFR ⁇ kinase activity that remained in the presence of a compound at the concentration of 100 nM is listed in the following table for each tested compound, wherein A indicates that the percentage of kinase activity remains is below 70% and B indicates that the percentage is greater or equal to 70%.
• a standard cell-based assay for VEGFR2 kinase activity can be used to test compounds of this invention and to identify VEGFR2 antagonists.
• VEGFR2 a compound to be tested was first dissolved in DMSO to a concentration of 10 mM and stored at -20 0 C.
• the activity of VEGFR2 in cells depends on the phosphorylation level at its intracellular domain induced by the ligand.
• full length VEGFR2 sequence was cloned into PC-DNA3.1 vector, the plasmid was then transfected into CHO cells. After 48 hours, the expression of VEGFR2 in transfected CHO cells was confirmed by regular western blotting.
• the ELISA kit (R&D Systems) was used. One day before the screening, CHO cells transfected with full length VEGFR2 plasmid were grown in DMEM medium without the presence of serum. On the day of screening, various concentrations of compounds (From 0.5 nM to 500 nM) were added into DMEM medium. Two hours later, 20% of FBS (Fetal Bovine Serum) was added into the medium to stimulate the production of phosphor- VEGFR2. Cell lysate from approximately 5x10 5 transfected CHO cells were reacted with anti-phosphor- VEGFR2 or anti -total VEGFR2 antibody in 96 well plates. In the presence of detection antibody, the phosphor- VEGFR2 or total VEGFR2 were detected with Streptavidin-HRP (R&D Systems) followed by chemiluminescence detection.
• Streptavidin-HRP R&D Systems
• the compounds thus tested generally showed potent inhibitory effect on growth factor-induced or constitutively activated VEGFR2 phosphorylation. Some of these compounds were found to exhibit an IC 50 of 100 nM or less, and some other compounds exhibited an even lower IC50, such as 10 nM or less. As such, the compounds of this invention may be used in the treatment of diseases implicated by angiogenesis.
• VEGFR2 kinase activity The percentage of VEGFR2 kinase activity that remained in the presence of a compound at the concentration of 100 nM is listed in the following table for each tested compound, wherein A indicates that the percentage of kinase activity remains is below 70% and B indicates that the percentage is greater or equal to 70%.
• a procedure for standard cell-based assay for c-Met kinase activity can be used to test compounds of this invention for their inhibitory effect on this kinase and to identify c-Met antagonists.
• a compound to be tested was first dissolved in DMSO to a concentration of 10 mM and stored at -20 0 C.
• the activity of c-Met in cells depends on the phosphorylation level at its intracellular domain induced by its ligand, Hepatocyte growth factor (HGF).
• HGF Hepatocyte growth factor
• paracrine HGF-dependent NSCLC Ni Small Cell Lung Cancer
• the compounds thus tested generally exhibited potent inhibitory effect on growth factor- induced or constitutive Iy activated c-Met phosphorylation. Some of these compounds exhibited an IC50 of 100 nM or less, and some others were even more effective with an IC 50 of 10 nM or less.
• Such a kinase inhibitory activity is valuable in the treatment of diseases associated with angiogenesis, invasive growth, epithelial-to- mesenchymal transition (EMT), and cell migration such as cancers.
• the percentage of c-Met kinase activity remains in the presence of a compound at the concentration of 100 nM is listed in the following table for each tested compounds, wherein A indicates that the percentage of kinase activity remains is below 70% and B indicates that the percentage is greater or equal to 70%.
• Some other compounds of the present invention possess good inhibitory activity against both VEGFR2 and c-Met, or VEGFR2, PDGFR ⁇ and c-Met, or VEGFR2, c-Met, and c-Kit, or some other combinations of kinases from among VEGFR2, c-Met, RON, PDGFR ⁇ , PDGFR ⁇ , c-Kit,CSFlR, EphA2, AIk, Tie-1, Tie-2, Flt3, FGFRl, FGFR2, FGFR3, FGFR4, EGFR, Her2, AbI, Aurora A, Aurora B, Aurora C, Src, Lck, IGF-IR, or IR receptor tyrosine kinases.
• Such multiplex inhibitory activities against several receptor tyrosine kinases which are among targets of some drugs that have shown effectiveness in the treatment of certain clinical indications, are of extreme interests in the treatment of diseases associated with angiogenesis, invasive growth, epithelial-to-mesenchymal transition (EMT), and cell migration, including cancer, rheumatoid arthritis, arterial restenosis, autoimmune diseases, acute inflammation, acute and chronic nephropathies, diabetic retinopathy, psoriasis, and macular degeneration.
• diseases associated with angiogenesis invasive growth
• EMT epithelial-to-mesenchymal transition
• cell migration including cancer, rheumatoid arthritis, arterial restenosis, autoimmune diseases, acute inflammation, acute and chronic nephropathies, diabetic retinopathy, psoriasis, and macular degeneration.
• mice Female ⁇ nulnu) Balb/c athymic mice at 4-6 weeks of age were injected subcutaneously (s.c.) with MDA-MB-231 human breast cancer cells, A549 human non- small cell lung cancer cells, U87-MG human glioblastoma cells, PC-3 human prostate cancer cells, HT-29 human colon cancer, BEL-7404 human hepatocellular carcinoma, or MKN-45 human gastric cancer cells (ATCC, 5x 10 6 cells suspended in 100 ⁇ l DMEM medium). Treatment was initiated after the tumor mass grown from s.c. implanted tumor cells reached a median volume of 200-400 mm 3 .
• mice were randomized into groups with three in each group for small-sample efficacy tests such that the median tumor volume is nearly equal among all groups.
• mice were randomized into groups with thirteen or fourteen in each group.
• Each group was treated either with compounds (dissolved in 2: 1 mixture of PEG400 and 0.0 IN HCl (v/v)) or without compounds (vehicle only, 2: 1 mixture of PEG400 and 0.01N HCl (v/v)) once per day at dose 12.5, 25, 50 or 100 mg/kg by oral gavage.
• Tumor volumes were assessed at least twice weekly by caliper measurement from the start of treatment.
• Tumor volume was calculated using the formula /4xLxW 2 (L: length of tumor's long axis, W: length of tumor's short axis). Treatment was applied for at least two weeks or until the tumor volume reaches a size of -2500 mm 3 or greater. Mice were humanly sacrificed after the experiment.
• TGI Tumor Growth Inhibition
• TGI 100 x (Vvehicle_group— V ⁇ reatment_group) ⁇ Vvehicle_group wherein Vvehicie group represents the mean tumor volume for the group treated with vehicle and Vxreatmenf group represents the mean tumor volume of the group treated with a compound.
• TGI for the compounds of this invention in in vivo anti -tumor efficacy test is listed in the following table for each tested compound, wherein B indicates that the
• TGI for the compound of this invention is between 0% and 50% and A indicates that the
• TGI is greater or equal to 50%.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Engineering & Computer Science (AREA)
• Immunology (AREA)
• Diabetes (AREA)
• Rheumatology (AREA)
• Urology & Nephrology (AREA)
• Dermatology (AREA)
• Pain & Pain Management (AREA)
• Endocrinology (AREA)
• Hematology (AREA)
• Vascular Medicine (AREA)
• Cardiology (AREA)
• Heart & Thoracic Surgery (AREA)
• Emergency Medicine (AREA)
• Transplantation (AREA)
• Ophthalmology & Optometry (AREA)
• Obesity (AREA)
• Orthopedic Medicine & Surgery (AREA)
• Physical Education & Sports Medicine (AREA)
• Epidemiology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Plural Heterocyclic Compounds (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Priority Applications (16)

Applications Claiming Priority (2)

Publications (1)

Family

ID=43627250

Family Applications (1)

Country Status (19)

Cited By (9)

Families Citing this family (8)

Citations (4)

Family Cites Families (38)

• 2010
  • 2010-08-20 JP JP2012525875A patent/JP2013502444A/ja active Pending
  • 2010-08-20 EP EP10811241A patent/EP2470533A4/en not_active Withdrawn
  • 2010-08-20 US US12/922,527 patent/US8648086B2/en not_active Expired - Fee Related
  • 2010-08-20 SG SG2012004917A patent/SG178092A1/en unknown
  • 2010-08-20 CA CA2769151A patent/CA2769151A1/en not_active Abandoned
  • 2010-08-20 AU AU2010289143A patent/AU2010289143A1/en not_active Abandoned
  • 2010-08-20 CN CN201080001560.9A patent/CN102066372B/zh not_active Expired - Fee Related
  • 2010-08-20 MX MX2012002317A patent/MX2012002317A/es not_active Application Discontinuation
  • 2010-08-20 IN IN1983DEN2012 patent/IN2012DN01983A/en unknown
  • 2010-08-20 WO PCT/CN2010/076199 patent/WO2011023081A1/en active Application Filing
  • 2010-08-20 EA EA201290073A patent/EA201290073A1/ru unknown
  • 2010-08-20 BR BR112012003462A patent/BR112012003462A2/pt not_active Application Discontinuation
  • 2010-08-20 KR KR1020127006772A patent/KR20120089459A/ko not_active Application Discontinuation
• 2012
  • 2012-01-26 TN TNP2012000042A patent/TN2012000042A1/en unknown
  • 2012-01-26 CO CO12012075A patent/CO6491087A2/es not_active Application Discontinuation
  • 2012-02-06 ZA ZA2012/00890A patent/ZA201200890B/en unknown
  • 2012-02-14 IL IL218114A patent/IL218114A0/en unknown
  • 2012-02-22 MA MA34647A patent/MA33559B1/fr unknown
  • 2012-02-23 EC ECSP12011691 patent/ECSP12011691A/es unknown

Patent Citations (4)

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events