WO2012117421A1 - Histone deacetylase inhibitors - Google Patents

Histone deacetylase inhibitors Download PDF

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Publication number
WO2012117421A1
WO2012117421A1 PCT/IN2012/000147 IN2012000147W WO2012117421A1 WO 2012117421 A1 WO2012117421 A1 WO 2012117421A1 IN 2012000147 W IN2012000147 W IN 2012000147W WO 2012117421 A1 WO2012117421 A1 WO 2012117421A1
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Prior art keywords
carboxamide
hydroxy
fluorophenyl
acryloyl
tetrahydroisoquinoline
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PCT/IN2012/000147
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French (fr)
Inventor
Sridharan Rajagopal
Narasimhan Kilambi
Virendra Kachhadia
Suresh Rathinasamy
Gopalan Balasubramanian
Umamaheswari Mani
Nirmala RAJAGOPALAN
Judy Auxcilia PUSHPARAJ
Anshu Mittal Roy
Lolaknath Santosh Vishwakarma
Shridhar Narayanan
Vadivel KALIYAMOORTHY
Ponpandian Thanasekaran
Rama THATAVARTHY KRISHNA
Kalaivani KANNAN
Jayanarayan Kulathingal
Jeyamurugan Mookkan
Srinivasan Chidambaram Venkateswaran
Fakrudeen AHAMED ALI
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Orchid Research Laboratories Ltd
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Publication of WO2012117421A1 publication Critical patent/WO2012117421A1/en

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    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
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    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/4365—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
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    • 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
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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    • C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
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    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
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Definitions

  • Described herein are compounds as isoform selective histone deacetylase inhibitors, their derivatives, analogs, tautomeric forms, stereoisomers, geometrical isomers, diastereomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, metabolites, intermediates and prodrugs thereof, the preparation of these compounds, the pharmaceutical compositions comprising these compounds and the use of these compounds for treating various diseases.
  • Transcriptional regulation is a major event in cell differentiation, proliferation and apoptosis.
  • Particularly the regulations of transcription factor are thought to involve by changes in the structure of chromatin. Changing the affinity of histone proteins for coiled DNA in the nucleosome alters the structure of chromatin. Hypoacetylated histones are believed to have greater affinity to the DNA and form a tightly bound DNA -histone complex and render the DNA inaccessible to transcriptional regulation.
  • the acetylating status of the histone is governed by the balancing activities of the histone acetyl transferase (HAT) and histone deacetylase (HDAC).
  • HAT histone acetyl transferase
  • HDAC histone deacetylase
  • HDACs Human HDACs are classified into two distinct classes, the HDACs and sirtuins.
  • the HDACs are further divided into two subclasses based on their similarity to yeast histone deacetylases, Rpd3 (class I includes HDAC 1, 2, 3, 8 and 1 1) and Hdal (class II includes HDAC 4, 5, 6, 7, 9 and 10).
  • Rpd3 class I includes HDAC 1, 2, 3, 8 and 1 1
  • Hdal class II includes HDAC 4, 5, 6, 7, 9 and 10
  • Biochemically all of these HDACs have a highly conserved zinc dependent catalytic domain, while Class- Ill (SIRTl -7) are dependent on nicotinamide adenine dinucleotide (NAD+) (Langley B., et al., Current Drug Targets-CNS & Neurological Disorders, 2005, 4, 41-50).
  • NAD+ nicotinamide adenine dinucleotide
  • SAHA Suberoylanilide hydroxamic acid
  • CCL cutaneous T-cell lymphoma
  • FDA Food and Drug Administration
  • HDAC inhibitors in clinical trials are Entinostat (MS-275), Belinostat (PXD101), Resminostat (4SC-201), Mocetinostat (MGCD0103), Panobinostat (LBH589), Sodium butyrate (NaB), Sodium valproate (VPA), Cyclic hydroxamic acid containing peptides (CHAPs), PCI-24781, J J-26481585 etc. (Tan J., et al., Journal of Hematology & Oncology, 2010, 3(5), 1-13).
  • HDAC inhibitors were shown to have both pro- and antiinflammatory effects in a wide range of inflammation relevant cell types. These inhibitors have shown promising effects in animal models in variety of inflammatory diseases such as arthritis, inflammatory bowel disease, septic shock, granuloma, airways inflammation and asthma. ITF2357 is found to reduce the production of proinflammatory cytokines in vitro and systemic inflammation in vivo (Halili M.A., et al., Current Topics in Medicinal Chemistry, 2009, 9, 309-319; Bonfils C, et al., Expert Opinion on Drug Discovery, 2008, 3, 1041-1065).
  • EDP-0334 is in the late preclinical stage for the treatment of Alzheimer's disease and other related CNS disorders (Hahnen E., et al., Expert Opinion on Investigational Drugs, 2008, 17(2), 169-184; Kazantsev A.G., et al., Nature Reviews Drug Discovery, 2008, 7, 854-868; Bonfils C, Expert Opinion on Drug Discovery, 2008, 3, 1041-1065).
  • pan-HDAC inhibitors Most of the above mentioned compounds are pan-HDAC inhibitors. At present, isoform selective HDAC inhibitors are gaining importance in treating various diseases such as inflammation, CNS disorders etc., since these might have better toxicological profile and more disease specific (Butler .V., et al., Current Pharmaceutical Design, 2008, 14, 505-528; Hahnen E., et al., Expert Opinion on Investigational Drugs, 2008, 17(2), 169-184).
  • HDACl mostly involves in cancer related problems/diseases.
  • the over-expression of HDACl mediates the reduction in the expression of p53 and pVHL (von Hippel Lindau protein), which results in the over-expression of HIF- ⁇ and its transcriptional target Vascular endothelial growth factor (VEGF).
  • VEGF Vascular endothelial growth factor
  • TSA HDACi Trichostatin-A
  • Some of the examples of HDACl selective inhibitors are trapoxin-A, SB-429201, MS275 and MGCD0103.
  • HDAC3 is another isoform which is involved in inflammatory diseases (Zhu H., et al., Journal of Biological Chemistry, 2010, 285, 9429-9436) and CNS disorders.
  • Triazol-4-ylphenyl bearing benzamide compounds are found to be HDAC3 selective inhibitors (He R., et al., Journal of Medicinal Chemistry, 2010, 53, 1347-1356).
  • Repligen Corporation disclosed the SAR and HDAC3 activity of the compounds including pimelic acid derivatives as HDAC inhibitors (WO2010028193A1). Recently in 2010, Repligen Corporation received orphan drug approval for their HDAC3 isoform selective compound (RG2833) to treat Friedreich's ataxia.
  • HDAC6 which is a cytoplasmic enzyme that mediates wide range of cellular functions including microtubule-dependent trafficking and signalling, ubiquitin level sensing, regulation of chaperone levels and responses to oxidative stress.
  • Over expression of HDAC6 has been identified in a variety of cancer cell lines and mouse tumor models. The up-regulation of HDAC6 in diverse tumors and cell lines are widely investigated (Aldana-Masangkay G.I., et al., Journal of Biomedicine and Biotechnology, 2011, ID875824, 1-10).
  • the miss folded protein clearance by formation of aggresomes and autophagy with the help of ubiquitin-binding HDAC6 looks promising for developing small isoform selective molecules for treating cancer.
  • Inhibition of HDAC6 can promote survival and regeneration of neurons.
  • HDAC6 a potential non-toxic therapeutic target for ameliorating CNS injury characterized by oxidative stress induced neurodegeneration and insufficient axonal regeneration (Rivieccio M.A., et al., Proceedings of the National Academy of Sciences, 2009, 106(46), 19599-19604).
  • a selective HDAC6 inhibitor, Tubastatin-A exhibited promising neuroprotective activity.
  • HDAC8 Another important isoform HDAC8, which belongs to Class-I family, have clinical relevance in neuroblastoma biology, a highly malignant embryonal childhood cancer (Oehme I., et al., Expert Opinion on Investigational Drugs, 2009, 18(1 1), 1605- 1617).
  • Linkerless hydroxamic acids are found to be HDAC8 isoform selective (Butler K.V., et al., Current Pharmaceutical Design, 2008, 14, 505-528).
  • WO2005108367A1 discloses the compounds for treatment of neurodegenerative diseases
  • WO2006010749A2 and WO2007082874A1 discloses following compounds, which have histone deacetylase inhibiting enzymatic activity,
  • One objective herein is to provide compound of the formula (I), their derivatives, analogs, tautomeric forms, stereoisomers, geometrical isomers, diastereomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, metabolites, intermediates and prodrugs thereof for the treatment of various cancers viz. liquid or solid tumours such as cancer of colon, pancreas, breast, etc.
  • Another objective herein is to provide a method of preventing or treating proliferative diseases or cancers.
  • Yet another objective herein is to provide a method of preventing or treating CNS disorders including but not limited to Huntington's disease, Parkinson's disease, Alzheimer's disease, Friedreich's ataxia and stroke by administering a therapeutic amount of compound of the formula (I).
  • Another objective is to provide a method of preventing or treating immune & inflammatory conditions.
  • Another objective herein is to provide a pharmaceutical composition containing compounds described herein.
  • Another objective herein is to provide a process for the preparation of compounds described herein.
  • Another object of the present invention is to provide a compound of potent isoform selective/ pan HDAC inhibitor; and/or an improved method for inhibiting HDACs in a cell; and/or an improved method for the treatment of a condition mediated by HDACs; and/or a method of treatment and/or prevention of proliferative condition or cancer; and/or a method of treatment and/or prevention of inflammatory disorders; and/or a method of treatment and/or prevention of neurodegenerative disorders; and/or a method of treatment and/or prevention of cancer induced bone pain; or at least to provide the public with a useful choice.
  • a X fp CONH R (I) its derivatives, analogs, tautomeric forms, stereoisomers, geometrical isomers, diastereomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, metabolites, intermediates and prodrugs thereof.
  • Ar represents substituted or unsubstituted groups selected from (C 6 -Ci4)aryl, 5- 15 membered heterocyclyl and 5-15 membered heteroaryl;
  • Ar 1 represents optionally substituted groups selected from (C 6 -Ci4)aryl, 5-15 membered heterocyclyl and 5-15 membered heteroaryl;
  • Ar 2 represents substituted or unsubstituted groups selected from (Ci- C 6 )alkylene, (Ce-C ⁇ arylene and 5-15 membered heteroarylene;
  • B represents hydrogen, -COOR 1 , -CONR'R 2 , -CH S NR'R 2 , -CH S OR 1 , -CH 2 OCONR'R 2 , -CH 2 NR'C0R 2 , substituted or unsubstituted groups selected from (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -Ci 4 )aryl and (C 3 -Ci 2 )cycloalkyl;
  • B 1 represents hydrogen, -COOR 1 , -CONR , -CH Z NR'R, -CH 2 0R', -CH 2 0C0NR'R 2 , -CH ⁇ R ⁇ OR 2 , substituted or unsubstituted groups selected from (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -Ci 4 )aryl and (C 3 -Ci 2 )cycloalkyl;
  • D represents hydrogen, -COOR 1 , -CONR ! R 2 , -CHbNR ⁇ , -CH 2 0R 1 , -CH 2 0C0NR 1 R 2 , -CH ⁇ R ⁇ OR 2 , substituted or unsubstituted groups selected from (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -Ci 4 )aryl and (C 3 -Ci 2 )cycloalkyl;
  • R 1 represents hydrogen, substituted or unsubstituted groups selected from (Cj- C 6 )alkyl, (C 3 -C 12 )cycloalkyl, 5-15 membered heterocyclyl, (C 6 -Ci4)aryl, (C 6 - (C 6 -Ci 4 )aryl(C 2 -C 6 )alkenyl, (C 6 -Ci 4 )aryl(C 2 -C 6 )alkynyl, 5-15 membered heteroaryl, 5-15 membered heteroaryl(Ci-C 6 )alkyl, 5-15 membered heteroaryl(C 2 -C 6 )alkenyl and 5-15 membered heteroaryl(C 2 -C6)alkynyl;
  • R 2 represents hydrogen, substituted or unsubstituted groups selected from (Q- C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -Ci 2 )cycloalkyl, 5-15 membered heterocyclyl, (C 6 -C I4 )aryl, (C 6 -Ci 4 )aryl(Ci-C 6 )alkyl, (C 6 -Ci 4 )aryl(C 2 -C 6 )alkenyl, (C 6 - Ci4)aryl(C 2 -Ce)alkynyl, 5-15 membered heteroaryl, 5-15 membered heteroaryl(Ci- C 6 )alkyl, 5-15 membered heteroaryl(C 2 -C 6 )alkenyl and 5-15 membered heteroaryl(C 2 - C 6 )alkynyl; or R 1 and R 2 combine together to form substitute
  • B 1 or D when one of B 1 or D is hydrogen or unsubstituted alkyl, the other is neither of hydrogen nor of unsubstituted alkyl;
  • X represents a bond, -CO-, -S0 2 -, -CS-, -CH 2 -, -CONR 3 -, -CONR 3 CH 2 -, -CH 2 OCO-, -CONR 3 CO-, -CH 2 NR 3 CO-, -CH 2 NR 3 - or -CH 2 NR 3 CH 2 -; wherein R 3 represents hydrogen or substituted or unsubstituted groups selected from (Ci-C 6 )alkyl and (C3-Ci 2 )cycloalkyl; re resents substituted or unsubstituted groups selected from
  • W, W 1 , W 2 , W 3 and W 4 independently represent C or N;
  • ring Q 1 is a substituted or unsubstituted 4 to 8 membered heterocyclyl ring;
  • R 4 represents hydrogen, halogen, hydroxy, nitro, amino, cyano or substituted or unsubstituted (Ci-C6)alkyl, amino(Ci-C 6 )alkyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxy and halo(C i -C 6 )alkoxy;
  • R represents -OH, ortho substituted aniline or substituted or unsubstituted group selected from aminoaryl and hydroxyaryl;
  • provided herein is the method of inhibiting the histone deacetylase enzyme comprising administering therapeutically effective amount of compound of formula (I).
  • composition comprising compound of formula (I).
  • the compound of formula (I) for use in the treatment of proliferative conditions or cancer in combination with other clinically relevant cytotoxic agents or non-cytotoxic agents or radiation or monoclonal antibodies.
  • the compound of formula (I) for use in the treatment of proliferative conditions or cancer selected from lung cancer, non- small-cell lung cancer (NSCLC), small cell lung cancer (SCLC), colon cancer, fibrosarcoma, kidney cancer, lymphoma, leukemia, skin cancer, pancreatic cancer, breast cancer, prostate cancer, bone cancer, oral cancer, multiple myeloma, brain cancer, head and neck cancer, ovarian cancer, gastric cancer, liver cancer, cervical cancer, solid tumors, cutaneous T-cell lymphoma (CTCL), acute myeloid leukemia, chronic lymphocytic leukemia and acute lymphoblastic leukemia.
  • NSCLC non- small-cell lung cancer
  • SCLC small cell lung cancer
  • colon cancer fibrosarcoma
  • kidney cancer lymphoma
  • leukemia skin cancer
  • pancreatic cancer breast cancer
  • prostate cancer prostate cancer
  • oral cancer multiple myeloma
  • brain cancer head and neck cancer
  • ovarian cancer gastric cancer
  • liver cancer cervical
  • the compound of formula (I) for use in the treatment of the inflammatory diseases, comprising rheumatoid arthritis, inflammatory bowel disease, psoriasis, dermatitis, granuloma, uveitis, chronic obstructive pulmonary disease (COPD), ulcerative colitis, Crohn's disease, multiple sclerosis and sepsis.
  • inflammatory diseases comprising rheumatoid arthritis, inflammatory bowel disease, psoriasis, dermatitis, granuloma, uveitis, chronic obstructive pulmonary disease (COPD), ulcerative colitis, Crohn's disease, multiple sclerosis and sepsis.
  • the compound of formula (I) for use in the treatment of neurodegenerative disorders selected from Huntington's disease, Alzheimer's disease, Parkinson's disease, Friedreich's ataxia and stroke.
  • the compound of formula (I) described herein is efficiently transported across the blood brain barrier (BBB).
  • BBB blood brain barrier
  • A represents
  • Ar represents substituted or unsubstituted groups selected from (C 6 - Ci4)aryl or 5-15 membered heteroaryl;
  • Ar represents substituted or unsubstituted (C6-C )4 )aryl
  • Ar represents substituted or unsubstituted 5-15 membered heterocyclyl or 5-15 membered heteroaryl
  • X represents -CO-, -CH 2 - -CONR 3 -, -CONR 3 CH 2 - -S0 2 - or -NR 3 CO-;
  • X represents -CO- -CH 2 - -CONR 3 - or -CONR 3 CH 2 -; In one embodiment, X represents -CO- or -CH 2 -;
  • X represents -CO-, -CONR -, -NR CO- -CONR 3 CH 2 -;
  • ring Q 1 represents piperidinyl, piperazinyl, pyrrolidinyl azepan
  • the group is selected from,
  • R represents OH or
  • Ar represents phenyl, naphthyl, benzo[d][l,3]dioxolyl, indolyl, pyridyl, quinolinyl or thienyl;
  • Ar 1 represents phenyl, naphthyl, benzo[d][l,3]dioxolyl, indolyl, pyridyl, quinolinyl or thienyl;
  • X represents -CO-, -CH 2 - -CONH- or -CONHCH 2 -;
  • A represents ;
  • Ar a represents substituted or unsubstituted groups selected from (C6-Cio)aryl, 5- 10 membered heterocyclyl and 5-10 membered heteroaryl;
  • Ar la represents optionally substituted groups selected from (C 6 -Qo)aryl, 5-10 membered heterocyclyl and 5-10 membered heteroaryl;
  • Ar 2a represents substituted or unsubstituted groups selected from (C 6 -
  • B represents hydrogen, substituted or unsubstituted groups selected from (Ci- C 6 )alkyl and (C 3 -C 6 )cycloalkyl;
  • B l represents hydrogen, -CONR la R 2a , substituted or unsubstituted groups selected from (Ci-C 6 )alkyl and (C 3 -C 6 )cycloalkyl;
  • D a represents hydrogen, -COOR la , -CONR ,a R 2a , substituted or unsubstituted groups selected from (Ci-Ce)alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -Ci 0 )aryl and (C 3 -C 6 )cycloalkyl;
  • B la or D a when one of B la or D a is hydrogen or unsubstituted alkyl, the other is neither of hydrogen nor of unsubstituted alkyl;
  • R la represents hydrogen, substituted or unsubstituted groups selected from (Ci-C 6 )alkyl and (C 3 -C 6 )cycloalkyl;
  • R 2 represents hydrogen, substituted or unsubstituted groups selected from (Ci-C 6 )alkyl and (C 3 -C 6 )cycloalkyl; or R Ia and R 2a combine together to form substituted or unsubstituted 3-7 membered ring having 0-3 heteroatoms selected from O, S and N;
  • X a represents a bond, -CO-, -CH 2 -, -CONR 3a -, -CONR 3a CH 2 - or -CH 2 NR 3a -;
  • 3 a represents hydrogen, (Ci-C 6 )alkyl or (C3-C6)cycloalkyl;
  • T represents C, S, O or N
  • W lb represents C, S, O or N
  • W 2b represents C or N
  • W 3b represents C or N
  • a is an integer selected from 1 and 2;
  • b at each occurence is independently selected from an interger 0 and 1 ;
  • R 4 represents hydrogen, halogen, hydroxy, nitro, amino, cyano or substituted or unsubstituted groups selected from (Ci-C6)alkyl, amino(C]-C6)alkyl, halo(C]-C 6 )alkyl, (Ci-C6)alkoxy and halo(Ci-Ce)alkoxy;
  • R x represents OH or
  • substituents are one or more groups, selected from halogens, hydroxy, nitro, cyano, amino, formyl, (Ci-Ce)alkyl, halo(Ci-C 6 )alkyl, (Ci-C 6 )alkoxy, halo(Ci-C 6 )alkoxy, (C 6 -Ci4)arylalkoxy, (C3-Ci )cycloalkyloxy, (C6-Ci 4 )aryl, (C 6 -Ci 4 )aryloxy, (Ci-C 6 )alkylamino, -COOR a , -C(0)R b , -C(0)NR a R b , -NR a C(0)NR b R c , -NR a C(S) R b R°, -N(R a )SOR b , -N(R a )S0 2 R b , -NR a C(0)
  • a a represents In another embodiment, A represents ;
  • Ar 2a represents (C6-Ci 0 )arylene
  • T represents C, O, S or N;
  • W la represents C, O, S or N;
  • W 2a represents C or N
  • a is an integer selected from 1 and 2;
  • b at each occurence is independently selected from integer 0 and 1;
  • W 3a represents C or N
  • described herein is the compound of formula (Ila), (lib), (lie), (lid), (He), (Ilf) or (Ilg), derived from compound of formula (I).
  • the hydrogen atom in -CH-, -CH 2 -, -NH- optionally be replaced with the groups, not limited to, halogen, hydroxy, nitro, cyano, amino, formyl, substituted or unsubstituted groups selected from (C[-C6)alkyl, halo(Q- C 6 )alkyl, (Ci-C6)alkoxy, halo(C 1 -C6)alkoxy, (C6-Ci4)arylalkoxy, (C 3 -Ci 2 )cycloalkyl, (C6-Ci 4 )aryl, (C6-Ci4)aryloxy and the like.
  • the -CH 2 - groups can be alkylene chain such as -CH 2 - -CH 2 -CH 2 - -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH(CH 3 )-, -CH 2 -CH(CH 3 )-CH 2 - and the like.
  • the ⁇ - ⁇ or ⁇ - ⁇ can have zero, one or more substituents.
  • (Ci-C6)alkyl refers to straight or branched aliphatic hydrocarbon groups having the specified number of carbon atoms, which are attached to the rest of the molecule by a single atom, which may be optionally substituted by one or more substituents. Examples include, without limitation, methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, t-butyl, pentyl and hexyl.
  • (Ci-C 6 )alkylene refers to a diradical of a branched or unbranched saturated hydrocarbon chain, which may be optionally substituted by one or more substituents. Examples include, without limitation, methylene, ethylene, isopropylene, n-propylene, n-butylene, isobutylene, t-butylene, pentylene and hexylene.
  • (C6-Ci4)aryl refers to aromatic radicals having 6 to 14 carbon atoms, which may be optionally substituted by one or more substituents.
  • “(C6-Ci4)aryl” moiety is (C6-Cio)aryl. Examples include, without limitation, phenyl, naphthyl, indanyl and biphenyl.
  • heterocyclyl refers to a stable 5 to 15 membered ring radical, which consists of carbon atoms and one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclic ring radical may be monocyclic, bicyclic, tricyclic or polycyclic ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
  • the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated.
  • heterocyclyl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure, which may be optionally substituted by one or more substituents.
  • “5-15 membered heterocyclyl” moiety includes 5-10 membered heterocyclyl.
  • Examples include, without limitation, azetidinyl, acridinyl, benzodioxolyl, benzo[d][l,3]dioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazolyl, imidazolyl, tetrahydroisoquinolinyl, piperidinyl, piperazinyl, homopiperazinyl, 2-oxoazepinyl, azepinyl, pyrrolyl
  • 5-15 membered heterocyclyl are selected from benzo[d][l,3]dioxolyl, benzothiazolyl, benzoxazolyl, thienyl, furyl, pyrrolyl, thiazolyl, indolyl, isoindolyl, mo holinyl, quinolyl, isoquinolyl, oxazolyl, pyridinyl and pyrimidinyl.
  • 5-15 membered heteroaryl refers to an aromatic heterocyclyl ring radical as defined above.
  • the heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of stable structure.
  • “5-15 membered heteroaryl” moiety is 5-10 membered heteroaryl.
  • (C 6 -Ci4)arylene or “5-15 membered heteroarylene” refers to bivalent aryl or heteroaryl respectively.
  • arylene include, without limitation, phenylene, naphthylene and indanylene.
  • heteroarylene include, without limitation, benzo[d][l,3]dioxolylene, benzothiazolylene, benzoxazolylene, thienylene, furylene, pyrrolylene, thiazolylene, indolylene, isoindolylene, morpholinylene, quinolylene, isoquinolylene, oxazolylene, pyridinylene and pyrimidinylene.
  • (C3-Ci2)cycloalkyl refers to non-aromatic mono or polycyclic ring system of about 3 to 12 carbon atoms, which may be optionally substituted by one or more substituents.
  • the polycyclic ring denotes hydrocarbon systems containing two or more ring systems with one or more ring carbon atoms in common i.e. a spiro, fused or bridged structures.
  • “(C 3 -Ci 2 )cycloalkyl” moiety is "(C 3 -C6)cycloalkyl”.
  • Examples include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, perhydronaphthyl, adamantyl, homoadamantyl, noradamantyl and norbornyl groups, bridged cyclic groups and spirobicyclic groups e.g spiro [4.4] non-2-yl.
  • (Ci-C 6 )alkoxy refers to an alkyl group attached via an oxygen linkage to the rest of the molecule, which may be optionally substituted by one or more substituents. Examples include, without limitation, -OCH 3j -OC 2 Hs and -OC3H7.
  • (C 1 -C 6 )alkylamino refers to an alkyl group as defined above attached via amino linkage to the rest of the molecule, which may be optionally substituted by one or more substituents.
  • Preferred alkylamino groups include, without limitation -NHCH 3 , -N(CH 3 ) 2 and -NHCH 2 CH 3 .
  • (C 2 -C 6 )alkenyl refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched chain having about 2 to 6 carbon atoms, which may be optionally substituted by one or more substituents. Examples include, without limitation, ethenyl, 1-propenyl, 2-propenyl, iso-propenyl, 2-methyl- 1-propenyl, 1-butenyl, 2-butenyl and pentenyl.
  • (C2-C6)alkynyl refers to a straight or branched hydrocarbyl radicals having at least one carbon-carbon triple bond and having in the range of 2-6 carbon atoms, which may be optionally substituted by one or more substituents. Examples include, without limitation, ethynyl, propynyl, butynyl and pentynyl.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • halo(C] -C6)alkyl refers to halogen group attached via an alkyl linkage to the rest of the molecule, which may be optionally substituted by one or more substituents. Examples include, without limitation, -CH 2 C1, -C 2 H 4 C1, trifluoromethyl, tribromomethyl and trichloromethyl.
  • halo(Ci-C6)alkoxy refers to a group resulting from the replacement of one or more hydrogen atoms from an alkoxy group with one or more halogen atoms, which can be the same or different, which may be optionally substituted by one or more substituents. Examples include, without limitation, chloromethoxy, chloroethoxy, trifluoromethoxy, trifluoroethoxy and trichloromethoxy.
  • (C 6 -C 1 4)aryl(Ci-C6)alkoxy refers to an alkoxy group attached to aryl substituent, which may be substituted by one or more substituents.
  • Preferred arylalkoxy groups include, without limitation, benzyloxy and phenylethoxy.
  • (C3-Ci 2 )cycloalkyloxy refers to a cycloalkyl group attached via an oxygen linkage to the rest of the molecule, which may be substituted. Examples include, without limitation -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl and -O- cyclohexyl.
  • amino(Ci-C 6 )alkyl refers to an amino group attached via alkyl linkage to the rest of the molecule, which may be optionally substituted by one or more substituents. Examples include, without limitation -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 NHCH 3 and -CH 2 N(CH 3 ) 2 .
  • (C6-Ci 4 )aryl(Ci-C 6 )alkyl refers to an aryl group directly bonded to an alkyl group, which may be optionally substituted by one or more substituents. Examples, include, without limitation, -CH 2 C 6 H 5 and -C 2 H 4 C 6 H 5 .
  • (C6-C 14 )aryl(C 2 -C6)alkenyl refers to an aryl group directly bonded to an alkenyl group, which may be optionally substituted by one or more substituents. Examples, include, without limitation, -C 2 H 2 C 6 H5 and -C3H5C6H5.
  • (C6-Ci 4 )aryl(C 2 -C6)alkynyl refers to an aryl group directly bonded to an alkynyl group, which may be optionally substituted by one or more substituents. Examples, include, without limitation, -C 2 C 6 H5 and -C 3 H 2 C 6 H5.
  • heteroaryl(Ci-C6)alkyl refers to a heteroaryl group directly bonded to an alkyl group, which may be optionally substituted by one or more substituents. Examples include, without limitation, -CH 2 -pyridinyl and -C 2 H4-furyl.
  • heteroaryl(C 2 -C6)alkenyl refers to a heteroaryl group directly bonded to an alkenyl group, which may be optionally substituted by one or more substituents. Examples include, without limitation, -C 2 H 2 -pyridinyl and - C 3 H 5 -furyl.
  • heteroaryl(C 2 -C6)alkynyl refers to a heteroaryl group directly bonded to an alkynyl group, which may be optionally substituted by one or more substituents. Examples include, without limitation, -C 2 -pyridinyl and -C 3 H 2 - furyl.
  • aminoaryl refers to aryl group substituted with amino group.
  • hydroxyaryl refers to aryl group substituted with hydroxy group.
  • R a , R b or R c can also combine to form a substituted or unsubstituted 3-10 membered heterocyclic rings including spiro-fused heterocyclic ring having 0-3 heteroatoms; the substituents are optionally further substituted by one or more substituents as defined above.
  • substitutents refers to one or more groups selected from halogens, hydroxy, nitro, cyano, amino, formyl, (C]-C6)alkyl, halo(Ci- C 6 )alkyl, (C,-C 6 )alkoxy, (C 6 -Ci 4 )aryl, (C 6 -Ci 4 )aryloxy, (d-C 6 )alkylamino, -COOR 3 , -C(0)NR a R b , -SR a , -SOR a and -S0 2 R , wherein R a , R b or R c in each of the above groups represent hydrogen, optionally substituted groups selected from (Ci-C 6 )alkyl, (C3-C 12 )cycloalkyl, (C6-C 14 )aryl; the substituents are optionally further substituted by one or more substituents as defined above.
  • the compounds described herein can be either E or Z geometrical isomers and in some cases mixtures can also be present. In cases where two or more double bonds are present in formula (I), then it can give rise to more than two geometrical isomers and in these cases the invention is said to cover all the isomers.
  • stereoisomers are isomers that differ in the arrangement of their atoms in space.
  • Compounds disclosed herein may exist as single stereoisomers, racemates and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the subject matter described.
  • solvates includes combinations of solvent molecules with molecules or ions of the solute compound.
  • derivatives refers to a chemical compound or molecule made from a parent compound by one or more chemical reactions such as, by oxidation, hydrogenation, alkylation, esterification, halogenation and the like.
  • tautomer refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.
  • metabolic refers to compounds that result from a metabolic process either by breakdown or modifications of parent compound through phase I or phase II metabolism. Examples of metabolism on the compounds of the present invention include addition of -OH, hydrolysis and cleavage.
  • analog refers to a chemical compound that is structurally similar to another compound but differs slightly 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.
  • the pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, cream, suspensions, aerosols, and the like, may contain flavorants, sweeteners, excipients etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions.
  • suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions.
  • the active compound will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage.
  • Suitable routes of administration includes, not limited to, oral, transdermal, rectal, nasal, topical, sublingual, intrathecal, intra-articular, intracisternal, intravaginal, ophthalmic, epidural, intracerebral, intracerebroventricular, intravesical, intravitreal, intracavernous intrauterine transmucosal or parenteral administration such as subcutaneous, intramuscular, intravenous, intraperitoneal and intradermal routes.
  • parenteral administration the compounds can be combined with a sterile aqueous or organic media to form injectable solutions or suspensions.
  • solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically acceptable acid addition salts or alkali or alkaline earth metal salts of the compounds.
  • the injectable solutions prepared in this manner can then be, administered intravenously, intraperitoneally, subcutaneously or intramuscularly.
  • phrases “pharmaceutically acceptable” refers to compounds or compositions that are physiologically tolerable and do not typically produce allergic or similar untoward reaction, including but not limited to gastric upset or dizziness when administered to mammal.
  • Pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Al, Zn and Mn salts; salts of organic bases such as N, N'-diacetylethylenediamine, glucamine, triethylamine, choline, dicyclohexylamine, benzylamine, trialkylamine, thiamine, guanidine, diethanolamine, a-phenylethylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, hydroxyethylpiperidine, ammonium, substituted ammonium salts and the like.
  • inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Al, Zn and Mn salts
  • salts of organic bases such as N, N'-diacetylethylenediamine, glucamine, triethylamine, choline, dicycl
  • Salts also include amino acid salts such as glycine, alanine, cystine, cysteine, lysine, arginine, phenylalanine, guanidine, etc.
  • Salts may include acid addition salts where appropriate which are sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, tosylates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like.
  • prodrugs refers to any pharmacologically inactive or less active compound which, when metabolized or chemically transformed by a mammalian system is converted into a pharmacologically active compound of formula (I) of the present invention.
  • some of the prodrugs are esters of the compound of formula (I), during metabolism the ester group is cleaved to form the active compound of formula (I).
  • a general overview of prodrug is provided in H Surya Prakash Rao, Resonance, 2003, 8, 19-27.
  • the compounds described herein can also be prepared in any solid or liquid physical form, for example the compound can be in a crystalline form, in amorphous form and have any particle size.
  • the compound particles may be micronized or nanoized, or may be agglomerated, or in the form of particulate granules, powders, oils, oily suspensions or any other form of solid or liquid physical forms.
  • the compounds described herein may also exhibit polymorphism.
  • This invention further includes different polymorphs of the compounds of the present invention.
  • polymorph refers to a particular crystalline state of a substance, having particular physical properties such as X-ray diffraction, IR spectra, melting point and the like.
  • histone deacetylase inhibitor or "inhibitor of histone deacetylase” is used to identify a compound, which is capable of interacting with a histone deacetylase and inhibiting its activity, more particularly its enzymatic activity. Inhibiting histone deacetylase enzymatic activity means reducing the ability of a histone deacetylase to remove an acetyl group from a histone. Preferably, such inhibition is specific, i.e. the histone deacetylase inhibitor reduces the ability of histone deacetylase to remove an acetyl group from a histone at a concentration that is lower than the concentration of the inhibitor that is required to produce some other, unrelated biological effect.
  • histone deacetylase and "HDAC” are intended to refer to any one of a family of enzymes that remove acetyl groups from the ⁇ -amino groups of lysine residues at the N-terminus of a histone. Unless otherwise indicated by context, the term “histone” is meant to refer to any histone protein, including HI, H2A, H2B, H3, H4 and H5, from any species.
  • Human HDAC proteins or gene products include but are not limited to, HDAC-1, HDAC-2, HDAC-3, HDAC-4, HDAC-5, HDAC-6, HDAC-7, HDAC-8, HDAC-9, HDAC- 10 and HDAC-11.
  • the histone deacetylase can also be derived from a protozoal or fungal source.
  • isoform selective/specific HDAC inhibitors are one which affects a single HDAC isoform and the term “class selective/specific HDAC inhibitors” are one which affects several isoforms within a single class.
  • the compounds described herein are used in the treatment or prevention of cancer.
  • the cancer includes solid tumors or hematologic malignancies. Examples include, without limitation, multiple myeloma, lung cancer, breast cancer, prostate cancer, colon cancer and fibrosarcoma.
  • the present invention provides a method of treatment of a disorder caused by, associated with or accompanied by disruptions of cell proliferation and/or angiogenesis including administration of a therapeutically effective amount of a compound of formula (I).
  • described herein is the use of the compound of formula (I) for treating cancer, without limitation, tumors, sarcomas, lymphomas, carcinomas, leukemias, myelomas and melanomas.
  • the present invention provides a method of treatment of a disorder, disease or condition that can be treated by the inhibition of HDAC enzymes including administration of therapeutically effective amount of compound of formula (I).
  • proliferative diseases include, for example, a tumor disease and/or metastasis.
  • the proliferative disease may furthermore be a hyperproliferative condition such as leukemia, fibrosis, angiogenesis, psoriasis, atherosclerosis and smooth muscle proliferation in the blood vessels, such as stenosis or restenosis following angioplasty.
  • the compounds described herein are selectively toxic or toxic to rapidly proliferating cells than to normal cells, including, for example, human cancer cells, e.g. cancerous tumors, the compounds have significant antiproliferative effects and promotes differentiation, e.g., cell cycle arrest and apoptosis.
  • the compounds induce p21, cyclin-CDK interacting protein, which includes either apoptosis or Gl arrest in variety of cell lines.
  • a method of treatment and/or prevention of inflammatory diseases which are mediated by HDAC's comprising rheumatoid arthritis (RA), inflammatory bowel disease (IBD), pelvic inflammatory disease (PID), human airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), cancer-induced bone pain (CIBP), atherosclerosis, endometriosis, granuloma, sepsis, multiple sclerosis, organ transplant rejection and other systemic inflammatory diseases, comprising administering to a subject suffering from the inflammatory diseases, a therapeutically effective amount of a compound of formula (I) (Bonfils C, et al., Expert Opinion on Drug Discovery, 2008, 3, 1041-1065).
  • a method of treatment and/or prevention of neurodegenerative disorders/CNS disorders including but not limited to Huntingtons's disease, Alzheimer's disease, Parkinson's disease, Friedreich's ataxia, stroke, spinal muscle atrophy, anxiety, traumatic brain injury, cerebral palsy, schizophrenia, spinocerebellar ataxia, Rett syndrome, fragile X disease, seizure disorders, depression, unipolar depression, bipolar disorder, amyotrophic lateral sclerosis, ischemia, Rubinstein-taybi syndrome, AIDS dementia, dementia, Korsakoff s syndrome, brain cancers, Wilson disease, Tay-Sach's disease, Tourette's disease, epilepsy and the like comprising administering to a subject suffering from the CNS disorder, a therapeutically effective amount of a compound of formula (I).
  • a method of treatment and/or prevention of CIBP comprising administering to a subject suffering from such a disorder, a therapeutically effective dose of compound of formula (I).
  • the present invention provides a method of treatment of various fungal diseases by the inhibition of fungal HDAC enzymes, comprising administration of therapeutically effective amount of compound of formula (I).
  • the present invention also provides a method of treatment and/or prevention of human immunovirus (HIV) latent disease, comprising, administering a therapeutically effective amount of a compound of formula (I).
  • HAV human immunovirus
  • the compounds described herein are also used for the treatment and/or prevention of protozoal infections such as malaria by inhibiting protozoal HDAC, comprising administering therapeutically effective amount of compound of formula (I).
  • Compounds disclosed herein are also used to treat Gaucher disease by inhibiting HDAC enzyme.
  • terapéuticaally effective amount or “effective amount” is an amount sufficient to effect beneficial or desired results.
  • An effective amount can be administered in one or more administrations.
  • An effective amount is typically sufficient to palliate, ameliorate, stabilize, reverse, slow or delay the progression of the disease state.
  • the compound may be administered in combination therapy by combining the compound of formula (I) with one or more separate agents, not limited to targets such as HDAC, DNA methyltransferase, heat shock proteins (e.g. HSP90), kinase, matrix metalloproteinases, proteasome inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors or other known HDAC inhibitors.
  • targets such as HDAC, DNA methyltransferase, heat shock proteins (e.g. HSP90), kinase, matrix metalloproteinases, proteasome inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors or other known HDAC inhibitors.
  • Combination therapy includes the administration of the subject compounds in further combination with other biologically active ingredients (such as, but are not limited to, different antineoplastic agent) and non-drug therapies (such as, but are not limited to, surgery or radiation treatment).
  • biologically active ingredients such as, but are not limited to, different antineoplastic agent
  • non-drug therapies such as, but are not limited to, surgery or radiation treatment.
  • the compounds described herein can be used in combination with other pharmaceutically active compounds, preferably, which will enhance the effect of the compounds of the invention.
  • the compounds can be administered simultaneously or sequentially to the other drug therapy.
  • cytotoxic agents are those which possesses a specific destructive action on certain cells or that may be genotoxic, oncogenic, mutagenic, teratogenic, or hazardous to cells in any way and includes most anti-cancer drugs substances. It acts by killing the cell or inhibiting the growth or proliferation of cells.
  • non-cytotoxic agents are substances that can be employed in treatment of cancers, which are more often cytostatic than cytotoxic (no tumor regression but inhibition of tumor progression). Examples include but not limited to tyrosine kinase inhibitors, angiogenesis inhibitors etc.,
  • the compound of formula (I) described herein may be coadministered with the other cytotoxic agents/non-cytotoxic agents, selected from but not limited to, bortezomib, disulfiram, salinosporamide A and carfilzomib, afatinib, axitinib, bevacizumab, cetuximab, crizotinib, dasatinib, erlotinib, fostamatinib, gefitinib, imatinib, lapatinib, lenvatinib, mubritinib, nilotinib, panitumumab, pazopanib, pegaptanib, ranibizumab, ruxolitinib, sorafenib, sunitinib, trastuzumab, vandetanib and vemurafenib, raloxifene, tamoxifen and related analogs
  • the subject compounds may be combined with the antineoplastic agents (e.g. small molecules, monoclonal antibodies, antisense R A and fusion proteins) that inhibit one or more biological targets.
  • antineoplastic agents e.g. small molecules, monoclonal antibodies, antisense R A and fusion proteins
  • Such combination may enhance therapeutic efficacy over the efficacy achieved by any of the agents alone and may prevent or delay the appearance of resistant variants.
  • HDAC6 in another aspect, described herein is inhibiting HDAC6, in a biological sample includes in vitro, in vivo, ex vivo, cell cultures, blood and other body fluids.
  • subject refers to animals including, not limited to mammals, and in particular humans, in need of treatment.
  • the therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the particular compound of formula (I) chosen, the dosing regimen to be followed, timing of administration, the manner of administration and the like, all of which can readily be determined by one of ordinary skill in the art.
  • the term "transported across the blood-brain barrier” refers to targeting moiety that is able to cross the BBB.
  • the permeability will be determined by the BBB uptake parameters like K p , Kpu etc.
  • prophylaxis or "prevention” means preventing the disease, i.e, causing the clinical symptoms of the disease not to develop.
  • treatment'V'treating mean any treatment of a disease in a mammal, including: (a) Inhibiting the disease, i.e, slowing or arresting the development of clinical symptoms; and/or (b) Relieving the disease, i.e, causing the regression of clinical symptoms.
  • a beneficial outcome of the treatment may include, but not limited to either a decrease in the severity of systems or delay in the onset of symptoms or a substantial reversal of the symptom or condition.
  • compound(s) for use embrace any one or more of the following: (1) use of compound(s), (2) method of use of compound(s), (3) use in the treatment of, (4) the use for the manufacture of pharmaceutical composition / medicament for treatment/treating or (5) method of treatment / treating/ preventing / reducing / inhibiting comprising administering an effective amount of the active compound to a subject in need thereof.
  • Y -COOH or -S0 2 CI or -CHO or CH 2 OH;
  • R Y Methyl or ethyl
  • the pharmaceutically acceptable salts of the compounds of formula (I) are also prepared.
  • Acid addition salts are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p- toluenesulfonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid, fumaric acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, tetrahydrofuran (THF), dioxane, etc. Mixture of solvents may also be used.
  • Step A 4-Cyanomethyl-benzoic acid methyl ester
  • TMSCN trimethylsilylcyanide
  • TBAF tetra-M- butylammonium fluoride
  • 4-Bromethyl benzoic acid methyl ester (20 g, 87.3 mmol) dissolved in acetonitrile (100 mL) was added drop wise over a period of 30 minutes, the reaction temperature was increased to 80 °C and stirring continued for another 30 minutes.
  • solvent was distilled out under reduced pressure, the crude material obtained was purified by column chromatography to give the pure title compound (10 g, Yield 68.7 %).
  • Step D Methyl 2-(2,2,2-trifluoroacetyl)-l,2,3,4-tetrahydroisoquinoline-7-carboxylate
  • Step E Methyl l,2,3,4-tetrahydroisoquinoline-7-carboxylate
  • Step A tert-Butyl 4-chloro-3-formyl-5,6-dihydropyridine-l(2H)-carboxylate
  • Step B 5-tert-Butyl 2-ethyl 6,7-dihydrofuro[3,2-c]pyridine-2,5(4H)-dicarboxylate
  • Step C Ethyl 4,5,6,7-tetrahydrofuro[3,2-c]pyridine-2-carboxylate
  • Step A 5-tert-butyl 2-ethyl oxylate
  • a solution of tert-Butyl 4-chloro-5-formyl-3,6-dihydropyridine-l(2H)- carboxylate (10 g, 40.9 mmol) in DCM was added triethylamine (11.8 mL, 81.8 mmol) and ethyl mercaptoacetate (7.8 g, 65.4 mmol) at room temperature.
  • the reaction mixture was refluxed for 2 hours, quenched with water and extracted with ethyl acetate (2 x 100 mL).
  • the organic layer was separated, dried over anhydrous Na 2 S0 4 and concentrated under reduced pressure to afford the crude product.
  • the crude product obtained on purification by column chromatography affords the title compound. (4.0 g, Yield 35%).
  • Step B Ethyl 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate
  • Step C te -Butyl 4-(pyrrolidin-l-yl)-5,6-dihydropyridine-l(2H)-carboxylate
  • Step D 5-tert-Butyl 3-ethyl 7a-(pyrrolidin-l-yl)-3a,4,7,7a-tetrahydroisoxazolo[4,5- c]pyridine-3,5(6H)-dicarboxylate
  • Step E Ethyl 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-3-carboxylate
  • Step A (E)-3-(4-(methoxycarbonyl)phenyl)acrylic acid
  • Methyl 4-formyl benzoate (5.0 g, 30.5 mmol), malonic acid (9.5 g, 91.5 mmol) and piperidine (0.5 mL, mmol) were added to a solution of pyridine (30 mL) and refluxed at 100 °C for 4 hours. The reaction mixture was cooled, neutralised with concentrated HC1 and filtered to obtain the crude product (4.5 g, Yield 59 %).
  • Step B (E)-Methyl 4-(3-amino-3-oxoprop-l-enyl)benzoate
  • Step C (E)-Methyl 4-(2-cyanovinyl)benzoate (£ ⁇ -Methyl 4-(3-amino-3-oxoprop-l-enyl)benzoate (1.0 g, 4.8 mmol) was dissolved in THF (50 mL). To this triethylamine (2.56 mL, 18.4 mmol) was added and cooled to 0 °C. Trifluoro acetic anhydride (1.2 mL, 8.8 mmol) was added slowly to the reaction mixture and stirred at room temperature for 1 hour.
  • reaction mixture was poured into ice mixture and the resultant precipitate was filtered which was further purified by silica column chromatography eluting with acetone/hexane solvent mixture to get the title compound (0.35 g, Yield 38.5 %).
  • Step E Methyl 4-(3-(2,2,2-trifluoroacetamido)propyl)benzoate
  • Methyl 4-(3-aminopropyl)benzoate (10 g, 43.66 mmol) was added portion wise to the well stirred trifluoroacetic anhydride (30 mL). This was further stirred for 3 hours at room temperature. The reaction mixture was poured into 100 mL of ice cold water and stirred for another 30 minutes. The resulting solid was filtered, washed with hexane and dried under vacuum to get the title compound (9 g, Yield 71.3 %).
  • Step F Methyl 2-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-lH-benzo[c]azepine-8- carboxylate
  • Methyl 4-(3-(2,2,2-trifluoroacetamido)propyl)benzoate (5.0 g, 18.18 mmol) was stirred at room temperature with paraformaldehyde (2.1 g, 72.7 mmol), acetic acid (25mL) and cone. H 2 S0 4 (38 mL) for 18 hours. The clear solution was added to cold water (100 mL) and extracted with ethyl acetate (2x 100 mL). The organic layer was washed with 50 mL of saturated sodium bicarbonate solution, water (200 mL) and dried over anhydrous sodium sulphate, concentrated under vacuum to get the title compound (3.0 g, Yield 52.5 %).
  • Methyl 2-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-lH-benzo[c]azepine-8- carboxylate (3 g, 9.9 mmol) was dissolved in methanol (20 mL) and added to potassium carbonate (4.18 g, 29.9 mmol) and water (2 mL) and then stirred at room temperature for 3 hours. Methanol was removed from the reaction mixture and water (100 mL) was added, extracted with ethyl acetate (100 mL), followed by washing with water (100 mL). The organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to get colourless solid (1.23 g, Yield 60.6 %).
  • Step B Ethyl 2-(methylsulfonyl)pyrimidine-5-carboxylate
  • Step C Ethyl 2-(4-(tert-butoxycarbonyl)piperazin-l-yl)pyrimidine-5-carboxylate
  • Step D Ethyl 2-(piperazin-l-yl)pyrimidine-5-carboxylate
  • Step-I Methyl 2-(2,3-Diphenylacryloyl)- 1 ,2,3,4-tetrahydroisoquinoline-7-carboxylate
  • Step-II 2-(2,3-Diphenylacryloyl)-N-hydroxy- 1 ,2,3,4-tetrahydroisoquinoline-7- carboxamide
  • Example 154 2-(2-(4-Fluorophenyl)-3-phenylallyl)-N-hydroxy-l,2,3,4-tetrahydro isoquinoline-7-carboxamide
  • Step A 2-(4-fluorophenyl)-3-phenylprop-2-en-l-ol
  • Step B 2-(4-fluorophenyl)-3-phenylallyl methanesulfonate
  • Step C Methyl 2-(2-(4-fluorophenyl)-3-phenylallyl)-l,2,3,4-tetrahydroisoquinoline-7- carboxylate
  • Step D 2-(2-(4-Fluorophenyl)-3-phenylallyl)-N-hydroxy-l,2,3,4-tetrahydro isoquinoline-7-carboxamide
  • step II Methyl 2-(2-(4- fluorophenyl)-3-phenylallyl)- 1 ,2,3,4-tetrahydroisoquinoline-7-carboxylate was converted to title compound (0.2 g, 57 %).
  • Step-I 2-(2,3-Diphenylacryloyl)-l,2,3,4-tetrahydroisoquinoline-7-carboxylic acid
  • 2-(2,3-Diphenylacryloyl)-l,2,3,4-tetrahydroisoquinoline-7- carboxylic acid methyl ester (0.300 g, 0.7 mmol) in methanol (15 mL) was added aqueous LiOH (0.090 g, 3.7 mmol in 2 mL of water) solution.
  • the reaction mixture was stirred at room temperature for 4 hours and diluted with 100 mL of cold water.
  • Step-II N-(2-Aminophenyl)-2-(2,3-diphenylacryloyl)-l,2,3,4-tetrahydroisoquinoline-
  • HDAC Histone Deacetylase
  • rhHDACl or rhHDAC6 The Histone Deacetylase (HDAC) inhibitory activity of molecules to specific isoforms (rhHDACl or rhHDAC6) were assayed with Boc-Lys (q-Ac)-AMC substrate, (Bachem 1-1875) which has been previously described as a small -molecule screening method for HDAC enzymes in vitro.
  • the total HDAC assay volume was 100 /L and the assay components were diluted in HDAC buffer (50 mM Tris-HCl, 137 mM NaCl, 2.7 mM KCl and 2 mM MgCl 2 , pH 8.0). The reaction was carried out in black 96-well plates (Nunc).
  • the HDAC assay mixture contained HDAC substrate (37.5 ⁇ , 40 ⁇ ,), rhHDACl or rhHDAC6 enzymes (final concentration 30 ⁇ , diluted to 10 //L final volumes) and inhibitor (2X, the required assay concentration, diluted to 50 ⁇ , final volume).
  • HDAC1 inhibitory activity the assay components were incubated at 37 °C for 3 Hours, whereas for HDAC6 the components were incubated for 1 hour.
  • Positive control termed as total activity (TA) contained all the above components except the inhibitor.
  • the negative control or blank contained neither enzyme nor inhibitor. In each case inhibitor volumes were replaced with an equivalent volume of buffer.
  • ICso values of the test compounds were computed by analyzing dose-response inhibition curves (Graph Pad prism, 4) (Bonfils C, et al., Clinical Cancer Research, 2008, 14, 3441 - 3449).
  • test compounds were screened for HDAC6 enzyme inhibitory activity.
  • the compounds whose IC50 values in the range of less than 1 nM to 50 nM are 1, 4, 5, 6, 7, 8, 9, 10, 12, 11, 14, 17, 19, 20, 21, 22, 23, 24, 25, 29, 32, 43, 44, 45, 46, 48, 49, 52, 53, 54, 55, 59, 62, 64, 69, 70, 71, 72, 76, 77, 78, 80, 85, 87, 88, 28, 86, 152 and 153.
  • a few of the compounds showed greater than 2000 fold selectivity for HDAC6 over HDAC1. In another embodiment some of the compounds showed greater than 1000 fold selectivity for HDAC6 over HDAC1. Several compounds have greater than 100 fold selectivity for HDAC6 over HDAC 1.
  • test compounds were screened in ten cancer cell lines for cell viability using Sulforhodamine B (SRB) cell viability assay (Vichai V. et al., Nature Protocols, 2006, 1(3), 1112-1116) and CCK8 assay.
  • SRB Sulforhodamine B
  • the cell lines - MCF7 and MDA MB231 human breast cancer cell lines
  • NCIH460 human lung cancer cell line
  • HCT116 human colon cancer cell line
  • PC3 human prostate cancer cell line
  • HT1080 human fibrosarcoma cell line
  • DMEM Dulbecco's modified eagle's medium
  • test compounds were added to the plates in triplicates with appropriate dilutions along with the cytotoxic standard and control (untreated) wells.
  • Test compounds were dissolved in dimethyl sulfoxide (DMSO) to prepare 100 mM stock solutions on the day of drug addition and serial dilutions were carried out in complete growth medium at 5x strength such that 50 iL added to wells gave final concentrations of 0.0064, 0.032, 0.16, 0.8, 4, 20 and 100 uM in the well.
  • DMSO dimethyl sulfoxide
  • the plates were then incubated for 72 hours at 37 °C, 5 % C0 2 , 95 % air and 100 % relative humidity.
  • TCA ice-cold trichloroacetic acid
  • Percent growth was calculated relative to the control and zero measurement wells (T 0 ) as followsj.
  • PG (OD530test - OD530T 0 ) / (OD530T 0 ) x 100 (If OD530test ⁇ OD530T 0 ).
  • GI50 the concentration required to decrease PG by 50 % vs control
  • PC- 12 pheochromocytoma
  • a semi suspension cells were seeded in Poly -D Lysine coated plate and incubated overnight at 37 °C and 5% C0 2 . After 24 hours, the cells were treated with test compounds along with 3-Nitropropionic acid and kept for 48 hours incubation at 37 °C, 5% C0 2 . Lactate dehydrogenase (LDH) in the cell supernatant was estimated using an LDH kit for cytotoxicity (Roche, Cat. No.11644793001). To determine the LDH activity of supematants, 100 reaction mixture was added to each well and incubated for 30 minutes at 25 °C and the absorbance of the samples measured at 490 nm. The results obtained were tabulated below.
  • LDH Lactate dehydrogenase
  • RAW 264.7 cells were seeded in a 24 well plate and incubated for 48 hours. After 48 hours, the cells were treated with various concentrations of the test compounds for 24 hours followed by lipopolysaccharide (LPS) stimulation (10 ng/mL) for 3 hours. TNF-a in the cell supernatant was estimated using an ELISA kit (R&D Systems) as per manufacturer's instructions.
  • LPS lipopolysaccharide
  • RAW 264.7 cells were seeded in a 24 well plate and incubated for 48 hours. After 48 hours the cells were treated with various concentrations of the test compounds for 24 hours followed by LPS stimulation (100 ng/mL) for 3 hours. IL-6 in the cell supernatant was estimated using an ELISA kit (R&D Systems) as per manufacturer's instructions.
  • THP1 cells were seeded in a 24 well plate along with phorbol myristate acetate (PMA) (32 nM) and incubated for 24 hours. After 24 hours, the media were changed and cells were incubated for another 24 hours. Then cells were treated with various concentrations of the test compounds for 24 hours followed by LPS stimulation (10 ng/mL) for 4 hours. TNF-a in the cell supernatant was estimated using an ELISA kit (R&D Systems) as per manufacturer's instructions.
  • PMA phorbol myristate acetate
  • THP1 cells were seeded in 24 well plates along with PMA (32 nM) and incubated for 24 hours. After 24 hours media were changed and cells were incubated for another 24 hours. Then cells were treated with various concentrations of the test compounds for 24 hours followed by LPS stimulation (100 ng/mL) for 8 hours. IL-6 in the cell supernatant was estimated using an ELISA kit (R&D Systems) as per manufacturer's instructions.
  • Metabolic stability is defined as the percentage of parent compound lost over time in the presence of liver microsomes, liver S9, or hepatocytes, depending on the goal of the assay.
  • the stock solutions of test compound were prepared using DMSO or water.
  • Incubation of reaction mixture including cryopreserved mouse or human liver microsomes (1 mg/mL), test compound (50 ⁇ ), and nicotinamide adenine dinucleotide phosphate (NADPH) for different time points, e.g. 10, 15, 30, and 60 minutes or single time points, e.g. 60 minutes.
  • Reaction is started by the addition of NADPH and stopped either immediately or after 60 minutes for screening assay or at 5, 15, 30 and 60 minutes for a more precise estimate of clearance by addition of ice- cold acetonitrile, followed by sample preparation. Determination of loss of parent compound (compared to zero time point control and/or no NADPH-control) was done using HPLC or LC-MS methods. Metabolism was expressed as percentage of test compound metabolized after a certain time. A marker reaction and marker substrate (e.g. testosterone) was employed as quality criteria of the metabolic capability of the microsomes. (Rodrigues, A.D., et al. Biochemical Pharmacology, 1994, 48(12): 2147- 2156).
  • Metabolic stability was expressed as % metabolism of the compound after 30 minutes of incubation in the presence of active microsomes.
  • Compound that had a % metabolism less than 30 % were defined as highly stable.
  • Compound that had a metabolism between 30 % and 60 % were defined as moderately stable and compounds that showed a % metabolism higher than 60 % were defined as less stable. Some of the test compounds were found to be moderately stable.
  • Dialysis membranes Cellulose acetate membranes with 12,000-14,000 molecular weight cut-off were charged by serially wetting in distilled water and distilled water containing 20 % ethanol for 60 and 20 minutes, respectively. Charged dialysis membranes were rinsed with distilled water three times and stored in isotonic sodium phosphate buffer until use.
  • the 96-well dialysis apparatus was assembled by following the manufacturers instructions using the charged membranes 0.15 mL of sodium phosphate buffer (pH 7.4) was placed on the dialysate side of each well and 0.15 mL of plasma spiked with the test compound (predetermined concentrations) on the other side, and the plate was completely sealed with adhesive membrane and incubated in a shaking dry incubator preset at 100 rpm at 37 °C to equilibrate for 8 hours (as determined previously). All samples were incubated in triplicates at predetermined concentrations. At the end of equilibration time, the volume of plasma and the buffer was measured for each well. 80 of plasma and the buffer was diluted with an equal volume of acetonitrile and centrifuged for 10 minutes to precipitate the proteins. The supernatant was analyzed using HPLC. The test compound shows moderate plasma protein binding.
  • test compounds were administered to separate sets of two animals for each time point at 15 mg/kg dose intravenously to check for its blood-brain barrier permeability.
  • Cerebrospinal fluid (CSF) was collected by direct cisterna-magna (CM) puncture at the specified time points from anesthetized rats.
  • mice were housed in individually ventilated cages (IVC), maintained in 12 hours light dark cycle with standard laboratory chow diet and water ad libitum in controlled room temperature (22 + 3 ° C) and humidity (50 ⁇ 20 %).
  • IVC individually ventilated cages
  • the animals were grouped based on body weight and treated with test compound at 50 mg/kg i.p for seven days. After the treatment period, the animals were observed for 14 days, during which body weight and clinical symptoms were recorded. Mean changes in body weight was calculated as compared to the control. On the day of termination, the animals were sacrificed using C0 2 asphyxiation and gross pathological examination carried out. Organs of interest were collected and subjected to histopathological analysis.
  • mice were housed in IVC, maintained in 12 hours light dark cycle with standard laboratory chow diet and water ad libitum in controlled room temperature (22 + 3 ° C) and humidity (50 ⁇ 20 %).
  • Tumors rose from cells obtained from ATCC, USA and maintained in vivo by subcutaneous (s.c.) passage of tumor fragments (-30 mg) in healthy mice according to standard reporting procedures.
  • Each experimental group included 6-8 mice bearing s.c tumors. Tumors were implanted into the auxiliary region using precision trochar and tumor growth was monitored by measuring diameters with a vernier caliper.
  • Tumor volume (TV) was calculated according to the formula:
  • L and W are the longest diameter and shortest diameter of the tumor respectively.
  • Test compound treatment started when tumors were palpable (-100 mm 3 ). Test compound was administered by per oral or by intra peritoneal once daily for a period of 21 days. Control mice were administered with vehicle at equivalent volume. Tumor size was measured twice a week and body weight taken daily prior to dosing. Parameters such as survival, change in the tumor volume, body weight and clinical symptoms were observed and recorded. Test compound efficacy was assessed by calculating tumor volume with respect to vehicle control
  • T/C % (1-TVtreatment / TV control) X 100
  • Oxazolone induced dermatitis in mice was performed using the protocol described in Tamura T., et al., European Journal of Pharmacology, 2005, 524, 149- 154.
  • Balb/C mice were acclimatized to laboratory conditions five to seven days prior to the start of the experiment. They were randomly distributed to various groups based on body weight. The abdomen of animals was shaved using a small animal clipper. All the animals were sensitized with 15 % oxazolone by application to the clipped abdomen (20 ⁇ ,) 7 days before challenge. On 7 th day, the animals were challenged with 2 % oxazolone at the ears (20 uL per ear). Test compounds were applied over the ears of sensitized mice 30 minutes before and 4 hours after challenge.
  • ear thickness was measured using a thickness gauge. Animals were sacrificed after 24 hours and ears collected by punch biopsy for ear weight and histopathology. Percent reduction in the ear thickness and ear weight was calculated using the following equation.
  • Ear thickness ⁇ ar thick* 1658 in Oxazolone group - Ear thickness in Treatment group

Abstract

Provided herein are isoform selective histone deacetylase inhibitors of the formula (I), their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, metabolites, prodrugs, solvates, pharmaceutically acceptable salts and compositions thereof. These compounds are isoform selective inhibitors of HDACs and are useful as a therapeutic or ameliorating agent for diseases that are involved in cellular growth such as cancer, malignant tumors, autoimmune diseases, skin diseases, fungal infections, protozoal infections, HIV, inflammation and CNS disorders.

Description

HISTONE DEACETYLASE INHIBITORS
FIELD
Described herein are compounds as isoform selective histone deacetylase inhibitors, their derivatives, analogs, tautomeric forms, stereoisomers, geometrical isomers, diastereomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, metabolites, intermediates and prodrugs thereof, the preparation of these compounds, the pharmaceutical compositions comprising these compounds and the use of these compounds for treating various diseases.
BACKGROUND
Transcriptional regulation is a major event in cell differentiation, proliferation and apoptosis. Particularly the regulations of transcription factor are thought to involve by changes in the structure of chromatin. Changing the affinity of histone proteins for coiled DNA in the nucleosome alters the structure of chromatin. Hypoacetylated histones are believed to have greater affinity to the DNA and form a tightly bound DNA -histone complex and render the DNA inaccessible to transcriptional regulation. The acetylating status of the histone is governed by the balancing activities of the histone acetyl transferase (HAT) and histone deacetylase (HDAC). The post translational modifications of protein play a critical role in regulating cellular function. Human HDACs are classified into two distinct classes, the HDACs and sirtuins. The HDACs are further divided into two subclasses based on their similarity to yeast histone deacetylases, Rpd3 (class I includes HDAC 1, 2, 3, 8 and 1 1) and Hdal (class II includes HDAC 4, 5, 6, 7, 9 and 10). Biochemically all of these HDACs have a highly conserved zinc dependent catalytic domain, while Class- Ill (SIRTl -7) are dependent on nicotinamide adenine dinucleotide (NAD+) (Langley B., et al., Current Drug Targets-CNS & Neurological Disorders, 2005, 4, 41-50). Given that the apoptosis is a crucial function for cancer progression, HDAC inhibitors are promising reagents for cancer therapy as effective inducers of apoptosis.
Suberoylanilide hydroxamic acid (SAHA) was launched as an antitumor agent for treating cutaneous T-cell lymphoma (CTCL) and another HDAC inhibitor, Istodax was also approved by Food and Drug Administration (FDA) for the treatment of CTCL. Some of the other HDAC inhibitors in clinical trials are Entinostat (MS-275), Belinostat (PXD101), Resminostat (4SC-201), Mocetinostat (MGCD0103), Panobinostat (LBH589), Sodium butyrate (NaB), Sodium valproate (VPA), Cyclic hydroxamic acid containing peptides (CHAPs), PCI-24781, J J-26481585 etc. (Tan J., et al., Journal of Hematology & Oncology, 2010, 3(5), 1-13).
In new role, HDAC inhibitors were shown to have both pro- and antiinflammatory effects in a wide range of inflammation relevant cell types. These inhibitors have shown promising effects in animal models in variety of inflammatory diseases such as arthritis, inflammatory bowel disease, septic shock, granuloma, airways inflammation and asthma. ITF2357 is found to reduce the production of proinflammatory cytokines in vitro and systemic inflammation in vivo (Halili M.A., et al., Current Topics in Medicinal Chemistry, 2009, 9, 309-319; Bonfils C, et al., Expert Opinion on Drug Discovery, 2008, 3, 1041-1065).
In the field of Central Nervous System (CNS) related disorders, the identification of two neuroprotective mechanisms of HDAC inhibitors viz. the transcriptional activation of disease modifying genes and the correction of perturbations in histone acetylation homeostasis are shown to be intimately involved in the neurodegenerative patho mechanisms of Huntington's disease, Parkinson's disease, Alzheimer's disease, anxiety, Friedreich's ataxia, etc. Envivo pharmaceuticals has revealed that its compound (EVP-0334) is in the late preclinical stage for the treatment of Alzheimer's disease and other related CNS disorders (Hahnen E., et al., Expert Opinion on Investigational Drugs, 2008, 17(2), 169-184; Kazantsev A.G., et al., Nature Reviews Drug Discovery, 2008, 7, 854-868; Bonfils C, Expert Opinion on Drug Discovery, 2008, 3, 1041-1065).
Most of the above mentioned compounds are pan-HDAC inhibitors. At present, isoform selective HDAC inhibitors are gaining importance in treating various diseases such as inflammation, CNS disorders etc., since these might have better toxicological profile and more disease specific (Butler .V., et al., Current Pharmaceutical Design, 2008, 14, 505-528; Hahnen E., et al., Expert Opinion on Investigational Drugs, 2008, 17(2), 169-184).
Although the molecular mechanistics of the HDAC isoforms are not so clear, HDACl mostly involves in cancer related problems/diseases. The over-expression of HDACl mediates the reduction in the expression of p53 and pVHL (von Hippel Lindau protein), which results in the over-expression of HIF-Ια and its transcriptional target Vascular endothelial growth factor (VEGF). The same was reversed by the use of the HDACi Trichostatin-A (TSA) both in vitro and in vivo (Ellis L., et al., Pharmaceuticals, 2010, 3, 2441-2469). Some of the examples of HDACl selective inhibitors are trapoxin-A, SB-429201, MS275 and MGCD0103.
HDAC3 is another isoform which is involved in inflammatory diseases (Zhu H., et al., Journal of Biological Chemistry, 2010, 285, 9429-9436) and CNS disorders. Triazol-4-ylphenyl bearing benzamide compounds are found to be HDAC3 selective inhibitors (He R., et al., Journal of Medicinal Chemistry, 2010, 53, 1347-1356). Repligen Corporation disclosed the SAR and HDAC3 activity of the compounds including pimelic acid derivatives as HDAC inhibitors (WO2010028193A1). Recently in 2010, Repligen Corporation received orphan drug approval for their HDAC3 isoform selective compound (RG2833) to treat Friedreich's ataxia.
HDAC6, which is a cytoplasmic enzyme that mediates wide range of cellular functions including microtubule-dependent trafficking and signalling, ubiquitin level sensing, regulation of chaperone levels and responses to oxidative stress. Over expression of HDAC6 has been identified in a variety of cancer cell lines and mouse tumor models. The up-regulation of HDAC6 in diverse tumors and cell lines are widely investigated (Aldana-Masangkay G.I., et al., Journal of Biomedicine and Biotechnology, 2011, ID875824, 1-10). The miss folded protein clearance by formation of aggresomes and autophagy with the help of ubiquitin-binding HDAC6 looks promising for developing small isoform selective molecules for treating cancer. Due to the multiple role of HDAC6, it can have potential utility when used alone or in combination with other chemotherapeutic drugs. The proteasome inhibitor, Velcade® (bortezomib) from Millennium Pharmaceuticals is a known drug for treating many types of cancers and it was found that the combination of Velcade® with HDAC6 selective inhibitor tubacin shows synergic effect in multiple myeloma cells (Hideshima T., et al., Proceedings of the National Academy of Sciences, 2005, 102(24), 8567- 8572). Acetylon Pharmaceuticals disclosed US20110300134A1 with HDAC6 selective inhibitors, interesting to note that one of its isoform selective molecules ACY-1215 shows interesting results in multiple myeloma when treated in combination with bortezomib (Santo L., et al., Blood, 201 1, In press).
Inhibition of HDAC6 can promote survival and regeneration of neurons.
Consistent with a cytoplasmic localization, the biological effects of HDAC6 inhibition appear transcription independent. Specifically, the selective inhibition of HDAC6 avoids cell death associated with pan-HDAC inhibition due to their toxicity toward a host of CNS cell types. These findings define HDAC6 as a potential non-toxic therapeutic target for ameliorating CNS injury characterized by oxidative stress induced neurodegeneration and insufficient axonal regeneration (Rivieccio M.A., et al., Proceedings of the National Academy of Sciences, 2009, 106(46), 19599-19604). Interestingly, a selective HDAC6 inhibitor, Tubastatin-A exhibited promising neuroprotective activity. (Butler K.V., et al., Journal of the American Chemical Society, 2010, 132 (31), 10842-10846). Inhibition of HDAC6 may also have a role in cardiovascular disease (Tannous P., et al., Circulation, 2008, 1 17(24), 3070-3078).
Another important isoform HDAC8, which belongs to Class-I family, have clinical relevance in neuroblastoma biology, a highly malignant embryonal childhood cancer (Oehme I., et al., Expert Opinion on Investigational Drugs, 2009, 18(1 1), 1605- 1617). Linkerless hydroxamic acids are found to be HDAC8 isoform selective (Butler K.V., et al., Current Pharmaceutical Design, 2008, 14, 505-528).
WO2005108367A1 discloses the compounds for treatment of neurodegenerative diseases,
Figure imgf000006_0001
Millennium Pharmaceuticals, discloses the substituted hydroxamic acids with two general formulae in WO2010151317A1 & WO2010151318 Al .
Figure imgf000006_0002
WO2006010749A2 and WO2007082874A1 discloses following compounds, which have histone deacetylase inhibiting enzymatic activity,
Figure imgf000006_0003
There is a widespread need for the isoform or class specific HDAC inhibitors which possess higher potency and fewer side effects compared to the pan HDAC inhibitors. OBJECTIVE
There are still huge unmet medical needs for treating various cancers viz. liquid or solid tumours such as cancer of colon, pancreas, breast etc. One objective herein is to provide compound of the formula (I), their derivatives, analogs, tautomeric forms, stereoisomers, geometrical isomers, diastereomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, metabolites, intermediates and prodrugs thereof for the treatment of various cancers viz. liquid or solid tumours such as cancer of colon, pancreas, breast, etc.
Another objective herein is to provide a method of preventing or treating proliferative diseases or cancers.
Yet another objective herein is to provide a method of preventing or treating CNS disorders including but not limited to Huntington's disease, Parkinson's disease, Alzheimer's disease, Friedreich's ataxia and stroke by administering a therapeutic amount of compound of the formula (I).
Herein another objective is to provide a method of preventing or treating immune & inflammatory conditions.
Another objective herein is to provide a pharmaceutical composition containing compounds described herein.
Another objective herein is to provide a process for the preparation of compounds described herein.
Another object of the present invention is to provide a compound of potent isoform selective/ pan HDAC inhibitor; and/or an improved method for inhibiting HDACs in a cell; and/or an improved method for the treatment of a condition mediated by HDACs; and/or a method of treatment and/or prevention of proliferative condition or cancer; and/or a method of treatment and/or prevention of inflammatory disorders; and/or a method of treatment and/or prevention of neurodegenerative disorders; and/or a method of treatment and/or prevention of cancer induced bone pain; or at least to provide the public with a useful choice.
SUMMARY
Described herein is the compound of formula (I),
A X fp CONH R (I) its derivatives, analogs, tautomeric forms, stereoisomers, geometrical isomers, diastereomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, metabolites, intermediates and prodrugs thereof. wherein A represents
Figure imgf000008_0001
Ar represents substituted or unsubstituted groups selected from (C6-Ci4)aryl, 5- 15 membered heterocyclyl and 5-15 membered heteroaryl;
Ar1 represents optionally substituted groups selected from (C6-Ci4)aryl, 5-15 membered heterocyclyl and 5-15 membered heteroaryl;
Ar2 represents substituted or unsubstituted groups selected from (Ci- C6)alkylene, (Ce-C^arylene and 5-15 membered heteroarylene;
B represents hydrogen, -COOR1, -CONR'R2, -CHSNR'R2, -CHSOR1, -CH2OCONR'R2, -CH2NR'C0R2, substituted or unsubstituted groups selected from (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci4)aryl and (C3-Ci2)cycloalkyl;
B1 represents hydrogen, -COOR1, -CONR , -CHZNR'R, -CH20R', -CH20C0NR'R2, -CH^R^OR2, substituted or unsubstituted groups selected from (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci4)aryl and (C3-Ci2)cycloalkyl;
D represents hydrogen, -COOR1, -CONR!R2, -CHbNR^ , -CH20R1, -CH20C0NR1R2, -CH^R^OR2, substituted or unsubstituted groups selected from (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci4)aryl and (C3-Ci2)cycloalkyl;
R1 represents hydrogen, substituted or unsubstituted groups selected from (Cj- C6)alkyl, (C3-C12)cycloalkyl, 5-15 membered heterocyclyl, (C6-Ci4)aryl, (C6-
Figure imgf000008_0002
(C6-Ci4)aryl(C2-C6)alkenyl, (C6-Ci4)aryl(C2-C6)alkynyl, 5-15 membered heteroaryl, 5-15 membered heteroaryl(Ci-C6)alkyl, 5-15 membered heteroaryl(C2-C6)alkenyl and 5-15 membered heteroaryl(C2-C6)alkynyl;
R2 represents hydrogen, substituted or unsubstituted groups selected from (Q- C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-Ci2)cycloalkyl, 5-15 membered heterocyclyl, (C6-CI4)aryl, (C6-Ci4)aryl(Ci-C6)alkyl, (C6-Ci4)aryl(C2-C6)alkenyl, (C6- Ci4)aryl(C2-Ce)alkynyl, 5-15 membered heteroaryl, 5-15 membered heteroaryl(Ci- C6)alkyl, 5-15 membered heteroaryl(C2-C6)alkenyl and 5-15 membered heteroaryl(C2- C6)alkynyl; or R1 and R2 combine together to form substituted or unsubstituted 3-7 membered ring having 0-3 heteroatoms selected from O, S and N;
when one of B1 or D is hydrogen or unsubstituted alkyl, the other is neither of hydrogen nor of unsubstituted alkyl;
X represents a bond, -CO-, -S02-, -CS-, -CH2-, -CONR3-, -CONR3CH2-, -CH2OCO-, -CONR3CO-, -CH2NR3CO-, -CH2NR3- or -CH2NR3CH2-; wherein R3 represents hydrogen or substituted or unsubstituted groups selected from (Ci-C6)alkyl and (C3-Ci2)cycloalkyl; re resents substituted or unsubstituted groups selected from
Figure imgf000009_0001
W, W1, W2, W3 and W4 independently represent C or N;
W5 represents O, S or N; W6 represents C or N;
ring Q1 is a substituted or unsubstituted 4 to 8 membered heterocyclyl ring; R4 represents hydrogen, halogen, hydroxy, nitro, amino, cyano or substituted or unsubstituted (Ci-C6)alkyl, amino(Ci-C6)alkyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxy and halo(C i -C6)alkoxy;
R represents -OH, ortho substituted aniline or substituted or unsubstituted group selected from aminoaryl and hydroxyaryl;
when the groups are substituted, the substituents are one or more, selected from halogens, hydroxy, nitro, cyano, azido, nitroso, oxo (=0), thioxo (=S), amino, hydrazino, formyl, (Ci-C6)alkyl, halo(Ci-C6)alkyl, (Ci-Ce)alkoxy, halo(Ci-C6)alkoxy, (C6-Ci4)arylalkoxy, (C3-Ci2)cycloalkyl, (C3-C12)cycloalkyloxy, (C6-Ci4)aryl, (C6-C[4)aryloxy, 5-15 membered heterocyclyl, 5-15 membered heteroaryi, (Ci-Q)alkylamino, -SONRaRb, -S02NRaRb, -SRa, -SORa, -S02Ra, -COORa, -C(0)Rb, -C(S)Ra, -C(0)NRaR , -C(S)NRaRb, -NRaC(0)NRbRc, -NRaC(S)NRbRc, -N(Ra)SORb, -N(Ra)S02Rb, -NRaC(0)ORb, -NRaRb, -NRaC(0)Rb, -NRaC(S)Rb, -ORa, -ORaC(0)ORb, -OC(0)NRaRb, -OC(0)Ra, -RaNRbRc and -RaORb, wherein Ra, Rb and Rc in each of the above groups represent hydrogen, optionally substituted groups selected from (Ci-C6)alkyl, (Ci-Ce)alkylene, (C3-Q2)cycloalkyl, (C6-Ci )aryl, (C6-Ci )aryl(C1-C6)alkyl, 5-15 membered heterocyclyl, 5-15 membered heteroaryi and 5-15 membered heteroaryl(C]-C6)alkyl; Ra, Rb or R° can also combine to form a substituted or unsubstituted 3-10 membered heterocyclic ring including spiro-fused heterocyclic ring having 0-3 heteroatoms; the substituents are optionally further substituted by one or more substituents.
In another aspect, provided herein is the compound of formula (I) for use in the inhibition of histone deacetylase enzyme.
In yet another aspect, provided herein is the method of inhibiting the histone deacetylase enzyme comprising administering therapeutically effective amount of compound of formula (I).
In yet another aspect, described herein is the pharmaceutical composition comprising compound of formula (I).
In yet another aspect, described herein is the process for the preparation of the compound of formula (I).
In yet another aspect, described herein is the compound of formula (I) for use in the treatment of proliferative conditions or cancer.
In yet another aspect, described herein is the compound of formula (I), for use in the treatment of proliferative conditions or cancer in combination with other clinically relevant cytotoxic agents or non-cytotoxic agents or radiation or monoclonal antibodies.
In yet another aspect, described herein is the compound of formula (I) for use in the treatment of proliferative conditions or cancer selected from lung cancer, non- small-cell lung cancer (NSCLC), small cell lung cancer (SCLC), colon cancer, fibrosarcoma, kidney cancer, lymphoma, leukemia, skin cancer, pancreatic cancer, breast cancer, prostate cancer, bone cancer, oral cancer, multiple myeloma, brain cancer, head and neck cancer, ovarian cancer, gastric cancer, liver cancer, cervical cancer, solid tumors, cutaneous T-cell lymphoma (CTCL), acute myeloid leukemia, chronic lymphocytic leukemia and acute lymphoblastic leukemia.
In yet another aspect, described herein is the compound of formula (I) for use in the treatment of inflammatory diseases and autoimmune diseases.
In yet another aspect, described herein is the compound of formula (I) for use in the treatment of the inflammatory diseases, comprising rheumatoid arthritis, inflammatory bowel disease, psoriasis, dermatitis, granuloma, uveitis, chronic obstructive pulmonary disease (COPD), ulcerative colitis, Crohn's disease, multiple sclerosis and sepsis.
In yet another aspect, described herein is the compound of formula (I) for use in the treatment of neurodegenerative disorders selected from Huntington's disease, Alzheimer's disease, Parkinson's disease, Friedreich's ataxia and stroke.
In other aspect, the compound of formula (I) described herein is efficiently transported across the blood brain barrier (BBB).
In yet another aspect, described herein is the compound of formula (I) for use in the treatment of central nervous system (CNS) disorders.
In another aspect, described herein is the compound of formula (I) for use in treatment of condition mediated by HDAC.
In another aspect, described herein is the compound of formula (I) for use in inhibiting HDAC6.
DETAILED DESCRIPTION
Described herein is the compound of formula (I), its derivatives, analogs, tautomeric forms, stereoisomers, geometrical isomers, diastereomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, metabolites, intermediates and prodru
Figure imgf000011_0001
In another embodiment, A represents
Figure imgf000011_0002
Preferably, Ar represents substituted or unsubstituted groups selected from (C6- Ci4)aryl or 5-15 membered heteroaryl;
In one embodiment, Ar represents substituted or unsubstituted (C6-C)4)aryl;
In another embodiment, Ar represents substituted or unsubstituted 5-15 membered heterocyclyl or 5-15 membered heteroaryl;
Preferably, X represents -CO-, -CH2- -CONR3-, -CONR3CH2- -S02- or -NR3CO-;
More preferably, X represents -CO- -CH2- -CONR3- or -CONR3CH2-; In one embodiment, X represents -CO- or -CH2-;
3 3
In another embodiment, X represents -CO-, -CONR -, -NR CO- -CONR3CH2-;
More preferably, ring Q1 represents piperidinyl, piperazinyl, pyrrolidinyl azepan
Figure imgf000012_0001
In another embodiment, the group is selected from,
Figure imgf000012_0002
More Preferably, R represents OH or
Figure imgf000013_0001
More preferably, Ar represents phenyl, naphthyl, benzo[d][l,3]dioxolyl, indolyl, pyridyl, quinolinyl or thienyl;
More preferably, Ar1 represents phenyl, naphthyl, benzo[d][l,3]dioxolyl, indolyl, pyridyl, quinolinyl or thienyl;
Most preferred X represents -CO-, -CH2- -CONH- or -CONHCH2-;
In one embodiment, described herein is the compound of formula (IA),
Figure imgf000013_0002
wherein: A represents
Figure imgf000013_0003
;
Ara represents substituted or unsubstituted groups selected from (C6-Cio)aryl, 5- 10 membered heterocyclyl and 5-10 membered heteroaryl;
Arla represents optionally substituted groups selected from (C6-Qo)aryl, 5-10 membered heterocyclyl and 5-10 membered heteroaryl;
Ar2a represents substituted or unsubstituted groups selected from (C6-
Cio)arylene and 5-10 membered heteroarylene;
B represents hydrogen, substituted or unsubstituted groups selected from (Ci- C6)alkyl and (C3-C6)cycloalkyl;
Bl represents hydrogen, -CONRlaR2a, substituted or unsubstituted groups selected from (Ci-C6)alkyl and (C3-C6)cycloalkyl;
Da represents hydrogen, -COORla, -CONR,aR2a, substituted or unsubstituted groups selected from (Ci-Ce)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci0)aryl and (C3-C6)cycloalkyl;
when one of Bla or Da is hydrogen or unsubstituted alkyl, the other is neither of hydrogen nor of unsubstituted alkyl;
Rla represents hydrogen, substituted or unsubstituted groups selected from (Ci-C6)alkyl and (C3-C6)cycloalkyl;
R2 represents hydrogen, substituted or unsubstituted groups selected from (Ci-C6)alkyl and (C3-C6)cycloalkyl; or RIa and R2a combine together to form substituted or unsubstituted 3-7 membered ring having 0-3 heteroatoms selected from O, S and N;
Xa represents a bond, -CO-, -CH2-, -CONR3a-, -CONR3aCH2- or -CH2NR3a-;
3a represents hydrogen, (Ci-C6)alkyl or (C3-C6)cycloalkyl;
Figure imgf000014_0001
wherein:
T represents C, S, O or N; Wlb represents C, S, O or N; W2b represents C or N;
W3b represents C or N;
a is an integer selected from 1 and 2;
b at each occurence is independently selected from an interger 0 and 1 ;
" " represents single or double bond;
R4 represents hydrogen, halogen, hydroxy, nitro, amino, cyano or substituted or unsubstituted groups selected from (Ci-C6)alkyl, amino(C]-C6)alkyl, halo(C]-C6)alkyl, (Ci-C6)alkoxy and halo(Ci-Ce)alkoxy;
Rx represents OH or
Figure imgf000014_0002
wherein the substituents are one or more groups, selected from halogens, hydroxy, nitro, cyano, amino, formyl, (Ci-Ce)alkyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, (C6-Ci4)arylalkoxy, (C3-Ci )cycloalkyloxy, (C6-Ci4)aryl, (C6-Ci4)aryloxy, (Ci-C6)alkylamino, -COORa, -C(0)Rb, -C(0)NRaRb, -NRaC(0)NRbRc, -NRaC(S) RbR°, -N(Ra)SORb, -N(Ra)S02Rb, -NRaC(0)ORb, -NRaRb, -NRaC(0)Rb, -NRaC(S)Rb, -SONRaRb, -S02NRaRb, -ORa, -SRa, -SORa and -S02Ra, wherein Ra, Rb and Rc in each of the above groups represent hydrogen, optionally substituted groups selected from (Ci-C6)alkyl, (C3-C]2)cycloalkyl, (C6- Ci4)aryl, the substituents are optionally further substituted by one or more substituents as defined above.
In one embodiment, Aa represents
Figure imgf000014_0003
In another embodiment, A represents ;
Preferably, Ar2a represents (C6-Ci0)arylene;
In one embodiment, described herein is the compound of formula (IA), derived from compound of formula (I).
Figure imgf000015_0001
Preferably,
In some embodiments described herein are the compounds of formula (II),
Figure imgf000015_0002
wherein:
T represents C, O, S or N;
Wla represents C, O, S or N;
W2a represents C or N;
a is an integer selected from 1 and 2;
b at each occurence is independently selected from integer 0 and 1;
" " represents single or double bond; Rx represents OH or
Figure imgf000015_0003
wherein the terms A, X, R4 are as defined earlier.
In some embodiments described herein are the compounds of formula (II), derived from compound of formula (I).
In certain other embodiments, provided herein are the compound of formula (III);
Figure imgf000015_0004
W3a represents C or N;
wherein the groups, A, X, R4 and Rx are as defined earlier.
In certain other embodiments, provided herein are the compound of formula (III), derived from compound of formula (I). In some other embodiments, described herein is the compound of formula (Ila), (lib), (lie), (li
Figure imgf000016_0001
In some other embodiments, described herein is the compound of formula (Ila), (lib), (lie), (lid), (He), (Ilf) or (Ilg), derived from compound of formula (I).
In some embodiments, the hydrogen atom in -CH-, -CH2-, -NH-, optionally be replaced with the groups, not limited to, halogen, hydroxy, nitro, cyano, amino, formyl, substituted or unsubstituted groups selected from (C[-C6)alkyl, halo(Q- C6)alkyl, (Ci-C6)alkoxy, halo(C1-C6)alkoxy, (C6-Ci4)arylalkoxy, (C3-Ci2)cycloalkyl, (C6-Ci4)aryl, (C6-Ci4)aryloxy and the like. The -CH2- groups can be alkylene chain such as -CH2- -CH2-CH2- -CH2-CH2-CH2- -CH2-CH(CH3)-, -CH2-CH(CH3)-CH2- and the like.
G) (?)
In yet another embodiment, the ^-^ or ^-^ can have zero, one or more substituents.
The term "(Ci-C6)alkyl" refers to straight or branched aliphatic hydrocarbon groups having the specified number of carbon atoms, which are attached to the rest of the molecule by a single atom, which may be optionally substituted by one or more substituents. Examples include, without limitation, methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, t-butyl, pentyl and hexyl.
The term "(Ci-C6)alkylene" refers to a diradical of a branched or unbranched saturated hydrocarbon chain, which may be optionally substituted by one or more substituents. Examples include, without limitation, methylene, ethylene, isopropylene, n-propylene, n-butylene, isobutylene, t-butylene, pentylene and hexylene.
The term "(C6-Ci4)aryl" refers to aromatic radicals having 6 to 14 carbon atoms, which may be optionally substituted by one or more substituents. Typically, "(C6-Ci4)aryl" moiety is (C6-Cio)aryl. Examples include, without limitation, phenyl, naphthyl, indanyl and biphenyl.
The term "5-15 membered heterocyclyl", refers to a stable 5 to 15 membered ring radical, which consists of carbon atoms and one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. For purposes of this invention the heterocyclic ring radical may be monocyclic, bicyclic, tricyclic or polycyclic ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated. The heterocyclyl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure, which may be optionally substituted by one or more substituents. Typically, "5-15 membered heterocyclyl" moiety includes 5-10 membered heterocyclyl. Preferably "5-15 membered heterocyclyl" moiety includes 4-8 membered heterocyclyl.
Examples include, without limitation, azetidinyl, acridinyl, benzodioxolyl, benzo[d][l,3]dioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazolyl, imidazolyl, tetrahydroisoquinolinyl, piperidinyl, piperazinyl, homopiperazinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyridinyl, pyrimidinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, thienyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, furyl, tetrahydrofuryl, tetrahydropyranyl, chromanyl and isochromanyl.
Preferably, 5-15 membered heterocyclyl are selected from benzo[d][l,3]dioxolyl, benzothiazolyl, benzoxazolyl, thienyl, furyl, pyrrolyl, thiazolyl, indolyl, isoindolyl, mo holinyl, quinolyl, isoquinolyl, oxazolyl, pyridinyl and pyrimidinyl.
The term "5-15 membered heteroaryl" refers to an aromatic heterocyclyl ring radical as defined above. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of stable structure. Typically, "5-15 membered heteroaryl" moiety is 5-10 membered heteroaryl.
The term "(C6-Ci4)arylene" or "5-15 membered heteroarylene" refers to bivalent aryl or heteroaryl respectively. Examples of "arylene" include, without limitation, phenylene, naphthylene and indanylene. Examples of heteroarylene include, without limitation, benzo[d][l,3]dioxolylene, benzothiazolylene, benzoxazolylene, thienylene, furylene, pyrrolylene, thiazolylene, indolylene, isoindolylene, morpholinylene, quinolylene, isoquinolylene, oxazolylene, pyridinylene and pyrimidinylene.
The term "(C3-Ci2)cycloalkyl" refers to non-aromatic mono or polycyclic ring system of about 3 to 12 carbon atoms, which may be optionally substituted by one or more substituents. The polycyclic ring denotes hydrocarbon systems containing two or more ring systems with one or more ring carbon atoms in common i.e. a spiro, fused or bridged structures. Typically, "(C3-Ci2)cycloalkyl" moiety is "(C3-C6)cycloalkyl". Examples include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, perhydronaphthyl, adamantyl, homoadamantyl, noradamantyl and norbornyl groups, bridged cyclic groups and spirobicyclic groups e.g spiro [4.4] non-2-yl.
The term "(Ci-C6)alkoxy" refers to an alkyl group attached via an oxygen linkage to the rest of the molecule, which may be optionally substituted by one or more substituents. Examples include, without limitation, -OCH3j -OC2Hs and -OC3H7.
The term "(C1-C6)alkylamino" refers to an alkyl group as defined above attached via amino linkage to the rest of the molecule, which may be optionally substituted by one or more substituents. Preferred alkylamino groups include, without limitation -NHCH3, -N(CH3)2 and -NHCH2CH3.
The term "(C2-C6)alkenyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched chain having about 2 to 6 carbon atoms, which may be optionally substituted by one or more substituents. Examples include, without limitation, ethenyl, 1-propenyl, 2-propenyl, iso-propenyl, 2-methyl- 1-propenyl, 1-butenyl, 2-butenyl and pentenyl.
The term "(C2-C6)alkynyl" refers to a straight or branched hydrocarbyl radicals having at least one carbon-carbon triple bond and having in the range of 2-6 carbon atoms, which may be optionally substituted by one or more substituents. Examples include, without limitation, ethynyl, propynyl, butynyl and pentynyl.
The term "halogen" refers to fluorine, chlorine, bromine and iodine.
The term "halo(C] -C6)alkyl" refers to halogen group attached via an alkyl linkage to the rest of the molecule, which may be optionally substituted by one or more substituents. Examples include, without limitation, -CH2C1, -C2H4C1, trifluoromethyl, tribromomethyl and trichloromethyl.
The term "halo(Ci-C6)alkoxy" refers to a group resulting from the replacement of one or more hydrogen atoms from an alkoxy group with one or more halogen atoms, which can be the same or different, which may be optionally substituted by one or more substituents. Examples include, without limitation, chloromethoxy, chloroethoxy, trifluoromethoxy, trifluoroethoxy and trichloromethoxy.
The term "(C6-C14)aryl(Ci-C6)alkoxy" refers to an alkoxy group attached to aryl substituent, which may be substituted by one or more substituents. Preferred arylalkoxy groups include, without limitation, benzyloxy and phenylethoxy.
The term "(C3-Ci2)cycloalkyloxy" refers to a cycloalkyl group attached via an oxygen linkage to the rest of the molecule, which may be substituted. Examples include, without limitation -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl and -O- cyclohexyl.
The term "amino(Ci-C6)alkyl" refers to an amino group attached via alkyl linkage to the rest of the molecule, which may be optionally substituted by one or more substituents. Examples include, without limitation -CH2NH2, -CH2CH2NH2, -CH2NHCH3 and -CH2N(CH3)2.
The term "(C6-Ci4)aryl(Ci-C6)alkyl" refers to an aryl group directly bonded to an alkyl group, which may be optionally substituted by one or more substituents. Examples, include, without limitation, -CH2C6H5 and -C2H4C6H5.
The term "(C6-C14)aryl(C2-C6)alkenyl" refers to an aryl group directly bonded to an alkenyl group, which may be optionally substituted by one or more substituents. Examples, include, without limitation, -C2H2C6H5 and -C3H5C6H5. The term "(C6-Ci4)aryl(C2-C6)alkynyl" refers to an aryl group directly bonded to an alkynyl group, which may be optionally substituted by one or more substituents. Examples, include, without limitation, -C2C6H5 and -C3H2C6H5.
The term "5-15 membered heteroaryl(Ci-C6)alkyl" refers to a heteroaryl group directly bonded to an alkyl group, which may be optionally substituted by one or more substituents. Examples include, without limitation, -CH2-pyridinyl and -C2H4-furyl.
The term "5-15 membered heteroaryl(C2-C6)alkenyl" refers to a heteroaryl group directly bonded to an alkenyl group, which may be optionally substituted by one or more substituents. Examples include, without limitation, -C2H2-pyridinyl and - C3H5-furyl.
The term "5-15 membered heteroaryl(C2-C6)alkynyl" refers to a heteroaryl group directly bonded to an alkynyl group, which may be optionally substituted by one or more substituents. Examples include, without limitation, -C2-pyridinyl and -C3H2- furyl.
The term "aminoaryl" refers to aryl group substituted with amino group.
The term "hydroxyaryl" refers to aryl group substituted with hydroxy group. The term substitutents as given here refers to one or more groups selected from hydroxy, nitro, cyano, azido, nitroso, oxo (=0), thioxo (=S), amino, hydrazino, formyl, (Ci-C6)alkyl, haloid -C6)alkyl, (C C6)alkoxy, halo(Ci-C6)alkoxy, (C6-Ci4)arylalkoxy, (C3-Ci2)cycloalkyl, (C3-Q2)cycloalkyloxy, (C6-Ci4)aryl, (C6-Ci4)aryloxy, 5-15 membered heterocyclyl, 5-15 membered heteroaryl, (Ci-C6)alkylamino, -COOR3, -C(0)Rb, -C(0)NRaRb, -N(Ra)SORb, -N(Ra)S02Rb, -NRaC(0)ORb, -NRaR , -NRaC(0)Rb, -NRaC(S)Rb, -SONRaRb, -S02NRaRb, -SRa, -SORa and -S02Ra, wherein Ra, Rb and R° in each of the above groups represent hydrogen, optionally substituted groups selected from (C]-C6)alkyl, (C3-Ci2)cycloalkyl, (C6-Ci4)aryl, (C6-Ci4)aryl(C1-C6)alkyl, 5-15 membered heterocyclyl, 5-15 membered heteroaryl and 5-15 membered heteroaryl(Ci-C6)alkyl. Ra, Rb or Rc can also combine to form a substituted or unsubstituted 3-10 membered heterocyclic rings including spiro-fused heterocyclic ring having 0-3 heteroatoms; the substituents are optionally further substituted by one or more substituents as defined above.
Preferably, term substitutents as given here refers to one or more groups selected from halogens, hydroxy, nitro, cyano, amino, formyl, (C]-C6)alkyl, halo(Ci- C6)alkyl, (C,-C6)alkoxy, (C6-Ci4)aryl, (C6-Ci4)aryloxy, (d-C6)alkylamino, -COOR3, -C(0)NRaRb, -SRa, -SORa and -S02R , wherein Ra, Rb or Rc in each of the above groups represent hydrogen, optionally substituted groups selected from (Ci-C6)alkyl, (C3-C12)cycloalkyl, (C6-C14)aryl; the substituents are optionally further substituted by one or more substituents as defined above.
The compounds described herein can be either E or Z geometrical isomers and in some cases mixtures can also be present. In cases where two or more double bonds are present in formula (I), then it can give rise to more than two geometrical isomers and in these cases the invention is said to cover all the isomers.
It is understood that included in the family of compounds of Formula (I) are isomeric forms including diastereomers, enantiomers, tautomers, and geometrical isomers in "E" or "Z" configuration or a mixture of E and Z isomers. It is also understood that some isomeric form such as diastereomers, enantiomers and geometrical isomers can be separated by physical and/or chemical methods by those skilled in the art.
The stereoisomers are isomers that differ in the arrangement of their atoms in space. Compounds disclosed herein may exist as single stereoisomers, racemates and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the subject matter described.
The term "solvates" includes combinations of solvent molecules with molecules or ions of the solute compound.
The term "derivatives" refers to a chemical compound or molecule made from a parent compound by one or more chemical reactions such as, by oxidation, hydrogenation, alkylation, esterification, halogenation and the like.
The term "tautomer" refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.
The term "metabolite" refers to compounds that result from a metabolic process either by breakdown or modifications of parent compound through phase I or phase II metabolism. Examples of metabolism on the compounds of the present invention include addition of -OH, hydrolysis and cleavage.
The term "analog" refers to a chemical compound that is structurally similar to another compound but differs slightly 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.
The pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, cream, suspensions, aerosols, and the like, may contain flavorants, sweeteners, excipients etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions. The compositions may be prepared by processes known in the art. Suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions. The active compound will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage. Suitable routes of administration, includes, not limited to, oral, transdermal, rectal, nasal, topical, sublingual, intrathecal, intra-articular, intracisternal, intravaginal, ophthalmic, epidural, intracerebral, intracerebroventricular, intravesical, intravitreal, intracavernous intrauterine transmucosal or parenteral administration such as subcutaneous, intramuscular, intravenous, intraperitoneal and intradermal routes. For parenteral administration, the compounds can be combined with a sterile aqueous or organic media to form injectable solutions or suspensions. For example, solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically acceptable acid addition salts or alkali or alkaline earth metal salts of the compounds. The injectable solutions prepared in this manner can then be, administered intravenously, intraperitoneally, subcutaneously or intramuscularly.
The phrase "pharmaceutically acceptable" refers to compounds or compositions that are physiologically tolerable and do not typically produce allergic or similar untoward reaction, including but not limited to gastric upset or dizziness when administered to mammal.
Pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Al, Zn and Mn salts; salts of organic bases such as N, N'-diacetylethylenediamine, glucamine, triethylamine, choline, dicyclohexylamine, benzylamine, trialkylamine, thiamine, guanidine, diethanolamine, a-phenylethylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, hydroxyethylpiperidine, ammonium, substituted ammonium salts and the like. Salts also include amino acid salts such as glycine, alanine, cystine, cysteine, lysine, arginine, phenylalanine, guanidine, etc. Salts may include acid addition salts where appropriate which are sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, tosylates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like.
The term "prodrugs" as used herein refers to any pharmacologically inactive or less active compound which, when metabolized or chemically transformed by a mammalian system is converted into a pharmacologically active compound of formula (I) of the present invention. For example, some of the prodrugs are esters of the compound of formula (I), during metabolism the ester group is cleaved to form the active compound of formula (I). A general overview of prodrug is provided in H Surya Prakash Rao, Resonance, 2003, 8, 19-27.
The compounds described herein can also be prepared in any solid or liquid physical form, for example the compound can be in a crystalline form, in amorphous form and have any particle size. Furthermore, the compound particles may be micronized or nanoized, or may be agglomerated, or in the form of particulate granules, powders, oils, oily suspensions or any other form of solid or liquid physical forms.
The compounds described herein may also exhibit polymorphism. This invention further includes different polymorphs of the compounds of the present invention. The term polymorph refers to a particular crystalline state of a substance, having particular physical properties such as X-ray diffraction, IR spectra, melting point and the like.
The term "histone deacetylase inhibitor" or "inhibitor of histone deacetylase" is used to identify a compound, which is capable of interacting with a histone deacetylase and inhibiting its activity, more particularly its enzymatic activity. Inhibiting histone deacetylase enzymatic activity means reducing the ability of a histone deacetylase to remove an acetyl group from a histone. Preferably, such inhibition is specific, i.e. the histone deacetylase inhibitor reduces the ability of histone deacetylase to remove an acetyl group from a histone at a concentration that is lower than the concentration of the inhibitor that is required to produce some other, unrelated biological effect. The terms "histone deacetylase" and "HDAC" are intended to refer to any one of a family of enzymes that remove acetyl groups from the ε-amino groups of lysine residues at the N-terminus of a histone. Unless otherwise indicated by context, the term "histone" is meant to refer to any histone protein, including HI, H2A, H2B, H3, H4 and H5, from any species. Human HDAC proteins or gene products include but are not limited to, HDAC-1, HDAC-2, HDAC-3, HDAC-4, HDAC-5, HDAC-6, HDAC-7, HDAC-8, HDAC-9, HDAC- 10 and HDAC-11. The histone deacetylase can also be derived from a protozoal or fungal source.
The term "isoform selective/specific HDAC inhibitors" are one which affects a single HDAC isoform and the term "class selective/specific HDAC inhibitors" are one which affects several isoforms within a single class.
The compounds described herein are used in the treatment or prevention of cancer. The cancer includes solid tumors or hematologic malignancies. Examples include, without limitation, multiple myeloma, lung cancer, breast cancer, prostate cancer, colon cancer and fibrosarcoma.
The present invention provides a method of treatment of a disorder caused by, associated with or accompanied by disruptions of cell proliferation and/or angiogenesis including administration of a therapeutically effective amount of a compound of formula (I).
In another aspect, described herein is the use of the compound of formula (I) for treating cancer, without limitation, tumors, sarcomas, lymphomas, carcinomas, leukemias, myelomas and melanomas.
The present invention provides a method of treatment of a disorder, disease or condition that can be treated by the inhibition of HDAC enzymes including administration of therapeutically effective amount of compound of formula (I).
Various proliferative diseases include, for example, a tumor disease and/or metastasis. In certain embodiment, the proliferative disease may furthermore be a hyperproliferative condition such as leukemia, fibrosis, angiogenesis, psoriasis, atherosclerosis and smooth muscle proliferation in the blood vessels, such as stenosis or restenosis following angioplasty.
In yet another embodiment, the compounds described herein are selectively toxic or toxic to rapidly proliferating cells than to normal cells, including, for example, human cancer cells, e.g. cancerous tumors, the compounds have significant antiproliferative effects and promotes differentiation, e.g., cell cycle arrest and apoptosis. In addition, the compounds induce p21, cyclin-CDK interacting protein, which includes either apoptosis or Gl arrest in variety of cell lines.
A method of treatment and/or prevention of inflammatory diseases which are mediated by HDAC's comprising rheumatoid arthritis (RA), inflammatory bowel disease (IBD), pelvic inflammatory disease (PID), human airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), cancer-induced bone pain (CIBP), atherosclerosis, endometriosis, granuloma, sepsis, multiple sclerosis, organ transplant rejection and other systemic inflammatory diseases, comprising administering to a subject suffering from the inflammatory diseases, a therapeutically effective amount of a compound of formula (I) (Bonfils C, et al., Expert Opinion on Drug Discovery, 2008, 3, 1041-1065).
A method of treatment and/or prevention of neurodegenerative disorders/CNS disorders including but not limited to Huntingtons's disease, Alzheimer's disease, Parkinson's disease, Friedreich's ataxia, stroke, spinal muscle atrophy, anxiety, traumatic brain injury, cerebral palsy, schizophrenia, spinocerebellar ataxia, Rett syndrome, fragile X disease, seizure disorders, depression, unipolar depression, bipolar disorder, amyotrophic lateral sclerosis, ischemia, Rubinstein-taybi syndrome, AIDS dementia, dementia, Korsakoff s syndrome, brain cancers, Wilson disease, Tay-Sach's disease, Tourette's disease, epilepsy and the like comprising administering to a subject suffering from the CNS disorder, a therapeutically effective amount of a compound of formula (I).
A method of treatment and/or prevention of CIBP, comprising administering to a subject suffering from such a disorder, a therapeutically effective dose of compound of formula (I).
The present invention provides a method of treatment of various fungal diseases by the inhibition of fungal HDAC enzymes, comprising administration of therapeutically effective amount of compound of formula (I).
Further, the present invention also provides a method of treatment and/or prevention of human immunovirus (HIV) latent disease, comprising, administering a therapeutically effective amount of a compound of formula (I). (Kelly Huber et. al., Journal of Biological Chemistry, 2011, 286(25), 22211-22218). In another aspect, the compounds described herein are also used for the treatment and/or prevention of protozoal infections such as malaria by inhibiting protozoal HDAC, comprising administering therapeutically effective amount of compound of formula (I).
Compounds disclosed herein are also used to treat Gaucher disease by inhibiting HDAC enzyme.
The term "therapeutically effective amount" or "effective amount" is an amount sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations. An effective amount is typically sufficient to palliate, ameliorate, stabilize, reverse, slow or delay the progression of the disease state.
In another aspect, the compound may be administered in combination therapy by combining the compound of formula (I) with one or more separate agents, not limited to targets such as HDAC, DNA methyltransferase, heat shock proteins (e.g. HSP90), kinase, matrix metalloproteinases, proteasome inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors or other known HDAC inhibitors.
"Combination therapy" includes the administration of the subject compounds in further combination with other biologically active ingredients (such as, but are not limited to, different antineoplastic agent) and non-drug therapies (such as, but are not limited to, surgery or radiation treatment). The compounds described herein can be used in combination with other pharmaceutically active compounds, preferably, which will enhance the effect of the compounds of the invention. The compounds can be administered simultaneously or sequentially to the other drug therapy.
The term "cytotoxic agents" are those which possesses a specific destructive action on certain cells or that may be genotoxic, oncogenic, mutagenic, teratogenic, or hazardous to cells in any way and includes most anti-cancer drugs substances. It acts by killing the cell or inhibiting the growth or proliferation of cells.
The term "non-cytotoxic agents" are substances that can be employed in treatment of cancers, which are more often cytostatic than cytotoxic (no tumor regression but inhibition of tumor progression). Examples include but not limited to tyrosine kinase inhibitors, angiogenesis inhibitors etc.,
In other aspect, the compound of formula (I) described herein may be coadministered with the other cytotoxic agents/non-cytotoxic agents, selected from but not limited to, bortezomib, disulfiram, salinosporamide A and carfilzomib, afatinib, axitinib, bevacizumab, cetuximab, crizotinib, dasatinib, erlotinib, fostamatinib, gefitinib, imatinib, lapatinib, lenvatinib, mubritinib, nilotinib, panitumumab, pazopanib, pegaptanib, ranibizumab, ruxolitinib, sorafenib, sunitinib, trastuzumab, vandetanib and vemurafenib, raloxifene, tamoxifen and related analogs, docetaxel, paclitaxel and related analogs.
In another aspect, the subject compounds may be combined with the antineoplastic agents (e.g. small molecules, monoclonal antibodies, antisense R A and fusion proteins) that inhibit one or more biological targets. Such combination may enhance therapeutic efficacy over the efficacy achieved by any of the agents alone and may prevent or delay the appearance of resistant variants.
In another aspect, described herein is inhibiting HDAC6, in a biological sample includes in vitro, in vivo, ex vivo, cell cultures, blood and other body fluids.
The term "subject" as used herein refers to animals including, not limited to mammals, and in particular humans, in need of treatment. The therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the particular compound of formula (I) chosen, the dosing regimen to be followed, timing of administration, the manner of administration and the like, all of which can readily be determined by one of ordinary skill in the art.
The term "transported across the blood-brain barrier" refers to targeting moiety that is able to cross the BBB. The permeability will be determined by the BBB uptake parameters like Kp, Kpu etc.
The term "prophylaxis" or "prevention" means preventing the disease, i.e, causing the clinical symptoms of the disease not to develop.
The term "treatment'V'treating" mean any treatment of a disease in a mammal, including: (a) Inhibiting the disease, i.e, slowing or arresting the development of clinical symptoms; and/or (b) Relieving the disease, i.e, causing the regression of clinical symptoms. A beneficial outcome of the treatment may include, but not limited to either a decrease in the severity of systems or delay in the onset of symptoms or a substantial reversal of the symptom or condition.
The term "compound(s) for use" as used herein embrace any one or more of the following: (1) use of compound(s), (2) method of use of compound(s), (3) use in the treatment of, (4) the use for the manufacture of pharmaceutical composition / medicament for treatment/treating or (5) method of treatment / treating/ preventing / reducing / inhibiting comprising administering an effective amount of the active compound to a subject in need thereof.
The present invention is provided by the examples given below, which are provided by way of illustration only, and should not be construed to limit the scope of the invention. Variation and changes, that are obvious to one skilled in the art, are intended to be within the scope and nature of the invention.
A term once described, the same meaning applies for it, throughout the patent. Particularly useful compounds include:
1. 2-(2,3-Diphenylacryloyl)-N-hydroxy-l,2,3,4-tetrahydroisoquinoline-7- carboxamide;
2. 2-(3-(4-Fluorophenyl)-2-(4-fIuorophenyl)acryloyl)-N-hydroxy-l,2,3,4
tetrahydroisoquinoline-7-carboxamide;
3. 2-(3-(3,4-Dimethoxyphenyl)-2-(4-fluorophenyl)acryloyl)-N-hydroxy-l,2,3,4 tetrahydroisoquinoline-7-carboxamide;
4. 2-(2-(2,4-Difluorophenyl)-3-phenylacryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
5. 2-(2-(4-Fluorophenyl)-3-(4-methoxyphenyl)acryloyl)-N-hydroxy-l, 2,3,4- tetrahydroisoquinoline-7-carboxamide;
6. 2-(2-(4-Fluorophenyl)-3-phenylacryloyl)-N-hydroxy-l, 2,3,4- tetrahydroisoquinoline-7-carboxamide;
7. 2-(3-(3,4-Difluorophenyl)-2-(4-methoxyphenyl)acryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
8. 2-(3-(2,4-Difluorophenyl)-2-(4-fluorophenyl)acryloyl)-N-hydroxy- 1 ,2,3,4- tetrahydroisoquinoline-7-carboxamide;
9. 2-(3-(4-Fluoro-3-methoxyphenyl)-2-(4-fluorophenyl)acryloyl)-N-hydroxy- l,2,3,4-tetrahydroisoquinoline-7-carboxamide;
10. 2-(3-(4-Fluorophenyl)-2-/j-tolylacryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
1 1. 2-(3-(3,4-Dimethoxyphenyl)-2-p-tolylacryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide; 2-(3-(3,4-Dimethoxyphenyl)-2-phenylacryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
N-Hydroxy-2-(3-(4-(methylthio)phenyl)-2-jt?-tolylacryloyl)- 1,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(3-(3,4-Dimethoxyphenyl)-2-(2-fluorophenyl)acryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(2-(3,4-Dimethoxyphenyl)-3-(3-fluorophenyl)acryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquino line-7-carboxam ide ;
2-(2,3-6w(3,4-Dimethoxyphenyl)acryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(2-(Benzo[d][l,3]dioxol-5-yl)-3-(4-fluorophenyl)acryloyl)-N-hydroxy- l,2,3,4-tetrahydroisoquinoline-7-carboxamide;
2-(2-(4-Fluorophenyl)-3-(3-phenoxyphenyl)acryloyl)-N-hydroxy- 1,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(2-(3 -Chlorophenyl)-3 -phenylacryloyl)-N-hydroxy- 1,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(2-(3-Fluorophenyl)-3-phenylacryloyl)-N-hydroxy- 1,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(2-(2-Fluorophenyl)-3-phenylacryloyl)-N-hydroxy-l ,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(2-(2-Chloro-4-fluorophenyl)-3-phenylacryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
N-Hydroxy-2-(3-phenyl-2- ?-tolylacryloyl)-l,2,3,4-tetrahydroisoquinoline-7- carboxamide;
2-(3-(4-Fluorophenyl)-2-phenylacryloyl)-N-hydroxy- 1 ,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(2-(4-Fluorophenyl)-3-(thiophen-2-yl)acryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(3-(2,4-Dimethoxyphenyl)-2-(3-fluorophenyl)acryloyl)-N-hydroxy- 1 ,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(3-(4-Chlorophenyl)-2-phenylacryloyl)-N-hydroxy- 1,2,3,4- tetrahydroisoquinoline-7-carboxamide; 2-(2-(2-Chlorophenyl)-3-phenylacryloyl)-N-hydroxy- 1,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(3-(2,4-Dimethoxyphenyl)-2-(4-fluorophenyl)acryloyl)-N-hydroxy- 1,2,3,4- tetrahydroisoquinoline-7-carboxamide;
N-Hydroxy-2-(2-(naphthalen-2-yl)-3-phenylacryloyl)-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(2-(4-(N,N-Dimethylamino)phenyl)-3-phenylacryloyl)-N-hydroxy-l ,2,3,4- tetrahydroisoquinoline-7-carboxamide;
N-Hydroxy-2-(3-(4-methoxyphenyl)-2-phenylacryloyl)- 1,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(2,3-0w(4-Methoxyphenyl)acryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(3-(2-Fluorophenyl)-2-(4-fluorophenyl)acryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(2-(4-Fluorophenyl)-3 -(5-methylthiophen-2-yl)acryloyl)-N-hydroxy- l,2,3,4-tetrahydroisoquinoline-7-carboxamide;
2-(2-(4-Fluorophenyl)-3-(3-nitrophenyl)acryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(3-(3,4-Dimethoxyphenyl)-2-(thiophen-2-yl)acryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(2-(2-Chlorophenyl)-3 -(4-fluorophenyl)acryloy l)-N-hydroxy- 1 ,2,3 ,4- tetrahydroisoquinoline-7-carboxamide;
2-(3-(4-Chlorophenyl)-2-(4-fluorophenyl)acryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
N-Hydroxy-2-(3-(4-methoxyphenyl)-2-jp-tolylacryloyl)-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(2-(2-Chlorophenyl)-3-(4-chlorophenyl)acryloyl)-N-hydroxy- 1 ,2,3,4- tetrahydroisoquinoline-7-carboxamide;
5-(2-(4-Fluorophenyl)-3-phenylacryloyl)-N-hydroxy-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-carboxamide;
5-(2-(3 -Fluorophenyl)-3 -pheny lacryloy l)-N-hydroxy-4, 5,6,7- tetrahydrothieno[3,2-c]pyridine-2-carboxamide; 2-(2-(4-Fluorophenyl)-3-(3,4,5-trimethoxyphenyl)acryloyl)-N-hydroxy- l,2,3,4-tetrahydroisoquinoline-7-carboxamide;
2-(2-(4-Fluorophenyl)-3-(pyridin-3-yl)acryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(2-(4-Fluorophenyl)-3-(pyridin-4-yl)acryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
4-(2-(4-Fluorophenyl)-3-(7-(hydroxycarbamoyl)-3,4-dihydroisoquinolin- 2( 1 H)-yl)-3 -oxoprop- 1 -enyl)benzoic acid;
2-(2-(2-Chlorophenyl)-3-(4-methoxyphenyl)acryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(3-(3,4-Difluorophenyl)-2-phenylacryloyl)-N-hydroxy- 1,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(3-(3,4-Difluorophenyl)-2-/?-tolylacryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(2-(4-Chlorophenyl)-3-phenylacryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
l-(2,3-Diphenylacryloyl)-N-hydroxyindoline-5-carboxamide;
5-(2,3-Diphenylacryloyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine- 2-carboxamide;
2-(2-(4-Fluorophenyl)-3-(4-(methylthio)phenyl)acryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
l-(2-(4-Fluorophenyl)-3-phenylacryloyl)-N-hydroxyindoline-5-carboxamide; 2-(2,3-Di- 7-tolylacryloyl)-N-hydroxy-l,2,3,4-tetrahydroisoquinoline-7- carboxamide;
N-Hydroxy-2-(2-phenyl-3-p-tolylacryloyl)-l,2,3,4-tetrahydroisoquinoline-7- carboxamide;
N-Hydroxy-2-(3-phenyl-2-(4-(trifluoromethyl)phenyl)acryloyl)- 1 ,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(4-(3-(Cyclopropylamino)-3 -oxo-2 -phenylprop-1 -enyl)benzoyl)-N- hydroxy- 1 ,2,3,4-tetrahydroisoquinoline-7-carboxamide;
2-(2-(4-Chlorophenyl)-3-(thiophen-2-yl)acryloyl)-N-hydroxy- 1 ,2,3,4- tetrahydroisoquinoline-7-carboxamide; 61. 2-(2,3-Diphenylacryloyl)-N-hydroxy-2,3,4,5-tetrahydro-lH-benzo[c]azepine- 8-carboxamide;
62. 2-(3-(2-Aminophenyl)-2-(4-fluorophenyl)acryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
63. 2-(2-(2-Chlorophenyl)-3-(thiophen-2-yl)acryloyl)-N-hydroxy- 1 ,2,3,4- tetrahydroisoquinoline-7-carboxamide;
64. 2-(2-(2-Fluorophenyl)-3-(thiophen-2-yl)acryloyl)-N-hydroxy- 1 ,2,3,4- tetrahydroisoquinoline-7-carboxamide;
65. 2-(3-(4-Chlorophenyl)-2-(4-fluorophenyl)acryloyl)-N-hydroxy-2,3,4,5- tetrahydro- 1 H-benzo[c]azepine-8-carboxamide;
66. 2-(2-(3-Chlorophenyl)-3-(4-fluorophenyl)acryloyl)-N-hydroxy-2,3,4,5- tetrahydro-lH-benzo[c]azepine-8-carboxamide;
67. 2-(4-(3-(Cyclopropylamino)-2-(4-fluorophenyl)-3-oxoprop-l-enyl)benzoyl)- N-hydroxy- 1 ,2,3,4-tetrahydroisoquinoline-7-carboxamide;
68. 2-(2-(3-Chlorophenyl)-3-phenylacryloyl)-N-hydroxy-2,3,4,5-tetrahydro-lH- benzo[c]azepine-8-carboxamide;
69. N-Hydroxy-2-(2-phenyl-3-(thiophen-2-yl)acryloyl)-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
70. 2-(2,3-Di(thiophen-2-yl)acryloyl)-N-hydroxy-l,2,3,4-tetrahydroisoquinoline- 7-carboxamide;
71. N-Hydroxy-2-(2-(4-methoxyphenyl)-3-(thiophen-2-yl)acryloyl)- 1,2,3,4- tetrahydroisoquinoline-7-carboxamide;
72. N-Hydroxy-2-(3-(thiophen-2-yl)-2-/?-tolylacryloyl)-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
73. 2-(3-(3-Fluorophenyl)-2-phenylacryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
74. N-Hydroxy-2-(3-phenyl-2-/w-tolylacryloyl)-l,2,3,4-tetrahydroisoquinoline-7- carboxamide;
75. 2-(3-(3-Fluorophenyl)-2- 7-tolylacryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
76. N-Hydroxy-2-(2-(3-methoxyphenyl)-3-phenylacryloyl)-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
77. l-(2-(3-Fluorophenyl)-3-phenylacryloyl)-N-hydroxyindoline-6-carboxamide; 78. N-Hydroxy-2-(2-(4-methoxyphenyl)-3-phenylacryloyl)- 1,2,3,4- tetrahydroisoquinoline-7-carboxamide;
79. 2-(2-(3,4-Dimethoxyphenyl)-3-phenylacryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
80. 2-(3-(4-Fluorophenyl)-2-:(3-methoxyphenyl)acryloyl)-N-hydroxy- 1,2,3,4- tetrahydroisoquinoline-7-carboxamide;
81. 1 -(3-(4-Chlorophenyl)-2-(4-fluorophenyl)acryloyl)-N-hydroxyindoline-5- carboxamide;
82. l-(2-(3-Chlorophenyl)-3-(4-fluorophenyl)acryloyl)-N-hydroxyindoline-5- carboxamide;
83. (3-(3-Fluorophenyl)-2-p-tolylacryloyl)-N-hydroxyindoline-5-carboxamide;
84. N-Hydroxy-l-(3-phenyl-2-m-tolylacryloyl)indoline-5-carboxamide;
85. l-(3-(4-Fluorophenyl)-2-phenylacryloyl)-N-hydroxyindoline-5-carboxamide;
86. 5-(3-(4-Fluorophenyl)-2-phenylacryloyl)-N-hydroxy-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-carboxamide;
87. N-Hydroxy-5-(3-phenyl-2-p-tolylacryloyl)-4,5,6,7-tetrahydrothieno[3,2- c]pyridine-2-carboxamide;
88. 5-(3-(3-Fluorophenyl)-2- )-tolylacryloyl)-N-hydroxy-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-carboxamide;
89. N-Hydroxy-2-(2-(3-chlorophenyl)-3-(quinolin-4-yl)acryloyl)-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
90. 5-(2-(4-Fluorophenyl)-3 -( 1 H-indol-3-yl)acry loyl)-N-hydroxy-4, 5 ,6, 7- tetrahydrothieno[3,2-c]pyridine-2-carboxamide;
91. 2-(2-(4-Fluorophenyl)-3-(lH-indol-3-yl)acryloyl)-N-hydroxy-l ,2,3,4- tetrahydroisoquinoline-7-carboxamide;
92. 5-(3-(4-Fluorophenyl)-2-(lH-indol-3-yl)acryloyl)-N-hydroxy-4,5,6,7- tetrahydroisoxazolo[4,5-c]pyridine-3-carboxamide;
93. 5-(2-(4-Fluorophenyl)-3-(pyridin-4-yl)acryloyl)-N-hydroxy-4,5,6,7- tetrahydroisoxazolo[4,5-c]pyridine-3-carboxamide;
94. 5-(3-(4-Fluorophenyl)-2-phenylacryloyl)-N-hydroxy-4,5,6,7- tetrahydroisoxazolo [4, 5 -c]pyridine-3 -carboxamide ;
95. N-Hydroxy-5-(2-(4-methoxyphenyl)-3-(thiophen-2-yl)acryloyl)-4,5,6,7- tetrahydroisoxazolo[4,5-c]pyridine-3-carboxamide; 96. 5-(2-(4-Fluorophenyl)-3-phenylaciyloyl)-N-hydroxy-4,5,6,7- tetrahydroisoxazolo[4,5-c]pyridine-3-carboxamide;
97. 5 -(2, 3 -Dipheny lacry loy l)-N-hydroxy-4, 5 , 6, 7-tetrahydroisoxazolo [4,5- c]pyridine-3-carboxamide;
98. N-Hydroxy-5-(3-phenyl-2-(thiophen-2-yl)acryloyl)-4,5,6,7- tetrahydroisoxazolo [4, 5 -c]pyridine-3 -carboxamide ;
99. N-Hydroxy-5-(2-(4-methoxyphenyl)-3-(thiophen-2-yl)acryloyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-carboxamide;
100. 5-(2-(4-Fluorophenyl)-3-(pyridin-4-yl)acryloyl)-N-hydroxy-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2 -carboxamide;
101. 2-(3-(4-Fluorophenyl)-2-phenylacryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-6-carboxamide;
102. 2-(3-(4-Fluorophenyl)-2-phenylacryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-8-carboxamide;
103. 5-(2-(4-Fluorophenyl)-3-phenylacryloyl)-N-hydroxy-4,5,6,7- tetrahydrofuro[3,2-c]pyridine-2 -carboxamide;
104. N-Hydroxy- 1 -(3 -phenyl-2-(thiophen-2-yl)acryloyl)indoline-4-carboxamide ;
105. 2-(2-(4-Fluorophenyl)-3-phenylacryloyl)-N-hydroxy- 1,2,3,4- tetrahydroisoquinoline-6-carboxamide;
106. 2-(2-(4-Fluorophenyl)-3-phenylacryloyl)-N-hydroxy- 1,2,3,4- tetrahydroisoquinoline-8-carboxamide;
107. 1 -(3-(4-Fluorophenyl)-2-phenylacryloyl)-N-hydroxyindoline-6-carboxamide;
108. 1 -(2-(4-Fluorophenyl)-3-phenylacryloyl)-N-hydroxyindoline-6-carboxamide;
109. l-(2-(2-Chlorophenyl)-3-phenylacryloyl)-N-hydroxyindoline-6-carboxamide;
110. N-Hydroxy- 1 -(2-(4-methoxyphenyl)-3 -(thiophen-2-yl)acryloyl)indoline-4- carboxamide;
1 11. 1 -(3-(4-Fluorophenyl)-2-phenylacryloyl)-N-hydroxyindoline-4-carboxamide;
1 12. l-(2-(4-Fluorophenyl)-3-(pyridin-4-yl)acryloyl)-N-hydroxyindoline-4- carboxamide;
1 13. N-Hydroxy- 1 -(3 -(pyridin-4-yl)-2-(thiophen-2-yl)acryloyl)indoline-4- carboxamide;
1 14. N-Hydroxy-l-(3-phenyl-2-(thiophen-2-yl)acryloyl)indoline-6-carboxamide; 1 -(2-(4-Fluorophenyl)-3-(pyridin-4-yl)acryloyl)-N-hydroxyindoline-6- carboxamide;
2-(4-(3-(3,4-Dimethoxyphenyl)-2-(4-fluorophenyl)acryloyl)piperazin-l-yl)-N- hydroxypyrimidine-5-carboxamide;
2-(4-(3-(3,4-Dimethoxyphenyl)-2-(phenyl)acryloyl)piperazin-l-yl)-N- hydroxypyrimidine-5-carboxamide;
2-(4-(3-(3,4-Dimethoxyphenyl)-2-(3-fluorophenyl)acryloyl)piperazin-l-yl)-N- hydroxypyrimidine-5-carboxamide;
2-(4-(3-(3,4-Dimethoxyphenyl)-2-(thiophen-2-yl)acryloyl)piperazin-l-yl)-N- hydroxypyrimidine-5 -carboxamide ;
2-(4-(3-(3,4-Dimethoxyphenyl)-2-(pyridin-3-yl)acryloyl)piperazin-l-yl)-N- hydroxypyrim idine-5 -carboxamide ;
2-(4-(3 -(Phenyl)-2-(4-fluorophenyl)acryloyl)piperazin- 1 -yl)-N- hydroxypyrimidine-5-carboxamide;
2-(4-(3-(3,4-Methylenedioxyphenyl)-2-(phenyl)acryloyl)piperazin-l-yl)-N- hydroxypyrimidine-5-carboxamide;
2-(4-(3 -(4-Fluorophenyl)-2-(pyridin-3-yl)acryloyl)piperazin- 1 -yl)-N- hydroxypyrimidine-5-carboxamide;
2-(4-(3-(3 -Fluorophenyl)-2-(4-fluorophenyl)acryloyl)piperazin- 1 -yl)-N- hydroxypyrimidine-5-carboxamide;
2-(4-(3-(4-Fluoro-3-methoxyphenyl)-2-(4-fluorophenyl)acryloyl)piperazin-l- yl)-N-hydroxypyrimidine-5-carboxamide;
2-(4-(3-(3,4-Dimethoxyphenyl)-2-(2-fluorophenyl)acryloyl)piperazin-l-yl)-N- hydroxypyrimidine-5-carboxamide;
2-(4-(3 -(4-Methylthiophenyl)-2-(phenyl)acryloyl)piperazin- 1 -yl)-N- hydroxypyrimidine-5 -carboxamide ;
2-(4-(3-(3,4-Difluorophenyl)-2-(4-methoxyphenyl)acryloyl)piperazin-l-yl)-N- hydroxypyrimidine-5-carboxamide;
2-(4-(3 -(Pyr idin-3 -y l)-2 -(pyridin-3 -y l)acry loy l)piperazin- 1 -y 1)-N- hydroxypyrimidine-5-carboxamide;
2-(4-(3-(4-Fluorophenyl)-2-(indol-3-yl)acryloyl)piperazin-l-yl)-N- hydroxypyrimidine-5-carboxamide; 131. 2-(4-(3-(3,4-Dimethoxyphenyl)-2-(indol-3-yl)acryloyl)piperazin-l-yl)-N- hydroxypyrimidine-5-carboxamide;
132. 2-(4-(3-(4-Methylthiophenyl)-2-(4-tolyl)acryloyl)piperazin-l-yl)-N- hydroxypyrimidine-5-carboxamide;
133. 2-(4-(3-(4-Fluorophenyl)-2-(4-methoxyphenyl)acryloyl)piperazin-l-yl)-N- hydroxypyriniidine-5-carboxamide;
134. 2-(4-(3-(Pyridin-3-yl)-2-(4-fluorophenyl)acryloyl)piperazin-l-yl)-N- hydroxypyrimidine-5-carboxamide;
135. 2-(4-(3-(3,4-Dimethoxyphenyl)-2-(3-chlorophenyl)acryloyl)piperazin-l-yl)- N-hydroxypyrimidine-5-carboxamide;
136. 2-(4-(2,3-Diphenylacryloyl)piperazin-l-yl)-N-hydroxypyrimidine-5- carboxamide;
137. 2-(4-(3-(3,4-Dimethoxyphenyl)-2-(3-methoxyphenyl)acryloyl)piperazin-l- yl)-N-hydroxypyrimidine-5-carboxamide;
138. 2-(4-(3 -(Phenyl)-2-(3,4-dimethoxyphenyl)acryloyl)piperazin- 1 -yl)-N- hydroxypyr imidine-5 -carboxam ide ;
139. 2-(4-(3-(4-Fluorophenyl)-2-(3,4-methylenedioxyphenyl)acryloyl)piperazin-l- yl)-N-hydroxypyrimidine-5-carboxamide;
140. 2-(4-(3-(4-Fluorophenyl)-2-(3 -fluorophenyl)acryloyl)piperazin- 1 -yl)-N- hydroxypyrimidine-5-carboxamide;
141. 2-(4-(3-(3,4-Methylenedioxyphenyl)-2-(4-fluorophenyl)acryloyl)piperazin-l- yl)-N-hydroxypyrimidine-5 -carboxam ide ;
142. 2-(4-(3 -(3,4-Methylenedioxyphenyl)-2-(3 -fluorophenyl)acryloyl)piperazin- 1 - yl)-N-hydroxypyrimidine-5-carboxamide;
143. 2-(4-(3-(3 -Fluorophenyl)-2-(3 ,4-dimethoxyphenyl)acryloyl)piperazin- 1 -yl)-N- hydroxypyrimidine-5-carboxamide;
144. 2-(4-(3-(3-Fluorophenyl)-2-(3,4-dimethoxyphenyl)acrylamido)piperidin- 1 - yl)-N-hydroxypyrimidine-5-carboxamide;
145. 2-(4-(3 -(Phenyl)-2-(3 ,4-dimethoxyphenyl)acrylamido)piperidin- 1 -yl)-N- hydroxypyrimidine-5 -carboxamide ;
146. 2-(4-(3-(4-Fluorophenyl)-2-(3,4-dimethoxyphenyl)acrylamido)piperidin-l- yl)-N-hydroxypyrimidine-5-carboxamide; 147. 2-(4-((3-(3,4-Dimethoxyphenyl)-2-(3-fluorophenyl)acrylamido)methyl) piperidin- 1 -yl)-N-hydroxypyrimidine-5-carboxamide;
148. 2-(4-(4-(3-(Cyclopropylamino)-2-(4-fluorophenyl)-3-oxoprop-l-enyl)
benzoyl)piperazin-l-yl)-N-hydroxypyrimidine-5-carboxamide;
149. 2-(4-(4-(3-(Cyclopropylamino)-2-(3 ,4-dimethoxyphenyl)-3 -oxoprop- 1 -eny 1) benzoyl)piperazin-l-yl)-N-hydroxypyrimidine-5-carboxamide;
150. 2-(4-(4-(3-(Cyclopropylamino)-2-(p-tolyl)-3-oxoprop-l -enyl)
benzoyl)piperazin- 1 -yl)-N-hydroxypyrimidine-5-carboxamide;
151. 2-(4-(4-(3-(Cyclopropylamino)-2-(phenyl)-3-oxoprop- 1 -enyl)
benzoyl)piperazin-l-yl)-N-hydroxypyrimidine-5-carboxamide;
152. 2-(4-(4-(3-(N,N-Dimethylamino)-2-(4-fluorophenyl)-3-oxoprop-l -enyl) benzoyl)piperazin- 1 -yl)-N-hydroxypyrimidine-5-carboxamide;
153. 2-(4-(4-(3 -(Cyclopropylamino)-2-(2-fluorophenyl)-3 -oxoprop- 1 -enyl)
benzoyl)piperazin- 1 -yl)-N-hydroxypyrimidine-5-carboxamide;
154. 2-(2-(4-Fluorophenyl)-3-phenylallyl)-N-hydroxy- 1,2,3,4- tetrahydroisoquinoline-7-carboxamide;
155. N-(2-Aminophenyl)-2-(2,3-diphenylacryloyl)-l,2,3,4-tetrahydroisoquinoline- 7-carboxamide;
156. N-(2-Aminophenyl)-2-(2-(3-fluorophenyl)-3-phenylacryloyl)-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
157. N-(2-Aminophenyl)-2-(2-phenyl-3-(thiophen-2-yl)acryloyl)-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
158. l-(2-(4-Fluorophenyl)-3-phenylacryloyl)-N-hydroxy-l,2,3,4- tetrahydroquinoline-6-carboxamide;
159. 1 -(3-(4-Fluorophenyl)-2-phenylacryloyl)-N-hydroxy- 1 ,2,3,4- tetrahydroquinoline-6-carboxamide;
160. l-(2-(4-Fluorophenyl)-3-(pyridin-4-yl)acryloyl)-N-hydroxy-l ,2,3,4- tetrahydroquinoline-6-carboxamide;
161. 1 -(2-(4-Fluorophenyl)-3-(pyridin-4-yl)acryloyl)-N-hydroxy-2 -methyl- 1 ,2,3,4- tetrahydroquinoline-6-carboxamide;
162. l-(2-(4-Fluorophenyl)-3-phenylacryloyl)-N-hydroxy-2-methyl- 1,2,3,4- tetrahydroquinoline-6-carboxamide; and 163. 1 -(3-(4-Fluorophenyl)-2-phenylacryloyl)-N-hydroxy-2 -methyl- 1 ,2,3,4- tetrahydroquinoline-6-carboxamide.
There is also provided the process for the preparation of compounds of the formula (I) using General Scheme- 1, wherein all the groups are as defined earlier.
General scheme- 1:
Figure imgf000038_0001
(3) (0
Y= -COOH or -S02CI or -CHO or CH2OH; RY= Methyl or ethyl
The said process for the preparation of compound of formula (I) comprises the steps of:
A) Coupling of compound of formula (la), (where Y is a carboxylic acid) with compound of formula (lb) using appropriate peptide coupling reagents viz. 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), benzotriazol-1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate (Py- BOP), etc. and 1-hydroxybenzotriazole (HOBt) in presence of an organic base such as triethylamine (TEA) or Ν,Ν-diisopropylethylamine (DIEA) and the like, to yield the compound of formula (2).
B) Coupling of compound of formula (la), (where Y is an aldehyde) with compound of formula (lb) gives the Schiff s base which on reduction using various reducing agents such as NaBR), NaB¾CN, and the like, gives compound of formula (2).
C) Reacting a compound of formula (la), (where Y is sulfonylchloride) with compound of formula (lb) in the presence of an organic base such as TEA or DIEA and the like, to yield the compound of formula (2).
D) The reaction between compound of formula (l ), (where Y is -CH2OH) and compound of formula (lb) in the presence of carbodiimidazole and a base to yield the compound of formula (2). E) Hydrolyzing the compound of formula (2) with an inorganic base such as LiOH, NaOH, KOH and the like to give the corresponding acid (3). Coupling the acid (3) with respective amine RNH2 to yield the compound of the general formula (I) or reacting the compound of formula (2) with NH2R and an inorganic base to give the compound of formula (I).
The pharmaceutically acceptable salts of the compounds of formula (I) are also prepared. Acid addition salts are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p- toluenesulfonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid, fumaric acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, tetrahydrofuran (THF), dioxane, etc. Mixture of solvents may also be used.
The examples given below are provided by the way of illustration only and therefore should not be construed to limit the scope of the invention.
Experimental Procedures:
Synthesis of Intermediates:
Intermediate 1: l,2,3,4-Tetrahydroisoquinoline-7-carboxylic acid methyl ester
Figure imgf000039_0001
Step A: 4-Cyanomethyl-benzoic acid methyl ester
To a solution of trimethylsilylcyanide (TMSCN, 12 mL, 96 mmol), tetra-M- butylammonium fluoride (TBAF, 25 g, 96 mmol) was added portion wise over a period of 30 minutes and stirred for another 30 minutes. 4-Bromethyl benzoic acid methyl ester (20 g, 87.3 mmol) dissolved in acetonitrile (100 mL) was added drop wise over a period of 30 minutes, the reaction temperature was increased to 80 °C and stirring continued for another 30 minutes. On completion of the reaction, solvent was distilled out under reduced pressure, the crude material obtained was purified by column chromatography to give the pure title compound (10 g, Yield 68.7 %).
Step B: Methyl 4-(2-aminoethyl)benzoate hydrochloride salt
To a solution of 4-cyanomethylbenzoic acid methyl ester (10 g, 48.3 mmol) in
THF (150 mL) was added 50 mL of methanolic.HCl and 5% Pd/C (3 g). The mixture was stirred under hydrogen atmosphere for 2 hours, filtered and washed with hot methanol (500 mL). The filtrate was concentrated under reduced pressure. The crude product obtained was added with dichloromethane (20 mL) and sonicated for 10 minutes. The resulting solid was filtered and dried under vacuum to give the title compound as a white solid (5.0 g, Yield 57.87 %).
Step C: Methyl 4-[2-(2,2,2-trifluoroacetylamino)ethyl]-benzoate
Methyl 4-(2-aminoethyl)benzoate (10 g, 55.86 mmol) was added portion wise to the well stirred trifluoroacetic anhydride (50 mL). The reaction mizture was stirred at room temperature for 3 hours. On completion of the reaction, the reaction mixture was poured into 100 mL of ice water and stirred for 30 minutes. The resulting solid was filtered, washed with hexane and dried under vacuum to give the pure compound '(10 g, Yield 65.10 %).
Step D: Methyl 2-(2,2,2-trifluoroacetyl)-l,2,3,4-tetrahydroisoquinoline-7-carboxylate
Methyl 4-[2-(2,2,2-trifluoroacetylamino)ethyl]benzoate (4.5 g, 16.36 mmol) was stirred at room temperature with paraformaldehyde (2.4 g, 81.8 mmol) and cone. H2S04 (38 mL) for 1 hour. The clear solution was added to cold water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The organic layer was washed with 50 mL of saturated sodium bicarbonate solution, water (200 mL) and dried over anhydrous sodium sulphate. The filtrate was concentrated under vacuum to give the title compound (2.0 g, Yield 42.46 %).
Step E: Methyl l,2,3,4-tetrahydroisoquinoline-7-carboxylate
Methyl 2-(2,2,2-trifluoroacetyl)-l,2,3,4-tetrahydroisoquinoline-7-carboxylate (2 g, 6.9 mmol) was added to potassium carbonate (1.4 g, 10.4 mmol), methanol (5 mL), water (2 mL) and stirred at room temperature for 3 hours. Methanol was removed from the reaction mixture and water (100 mL) was added, extracted with ethyl acetate (100 mL), followed by washing with water (100 mL). The organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to get colourless solid (0.8 g Yield 60.6 %). Ή NMR (DMSO-d6) 6(ppm): 2.74-2.76 (2H, t, -CH2), 2.78-2.79 (2H, brs, -CH2), 3.81 (2H, s, -CH2), 4.1 (3H, s, -OCH3), 5.02 (1H, brs, -NH), 7.14 (1H, d, -Ar-H), 7.71-7.74 (2H, m, Ar-H); MS m/z: 192.1 (M+l).
By following the above procedure, l,2,3,4-tetrahydroisoquinoline-6-carboxylic acid methyl ester and l,2,3,4-tetrahydroisoquinoline-8-carboxylic acid methyl ester were prepared.
Intermediate 2: Ethyl 4,5,6,7-tetrahydrofuro[3,2-c]pyridine-2-carboxylate
Figure imgf000041_0001
Step A: tert-Butyl 4-chloro-3-formyl-5,6-dihydropyridine-l(2H)-carboxylate
POCI3 (3.49 mL, 37.7 mmol) in DMF (4.87 mL, 62.8 mmol) was stirred at 0 °C for 15 minutes, tert-butyl-4-oxopiperidine-l-carboxylate (5 g, 25.1 mmol) was added and the stirring was continued at room temperature for 2 hours. The reaction misxture was quenched with water and extracted with dichloromethane (DCM) (2 x 100 mL). The organic layer was separated, dried over anhydrous Na2S04 and concentrated under reduced pressure to afford crude product (4.9 g, Yield 81%).
Step B: 5-tert-Butyl 2-ethyl 6,7-dihydrofuro[3,2-c]pyridine-2,5(4H)-dicarboxylate
To a solution of ethyl glycolate (2.07 mL, 19.9 mmol) in THF was added sodium hydride (1.19g, 49.9 mmol) at 0 °C and stirred at room temperature for 1 hour. tert-Butyl 4-chloro-3-formyl-5,6-dihydropyridine-l(2H)-carboxylate dissolved in THF was added at 0 °C, refluxed the reaction mixture for 2 hours. The reaction mixture was quenched with water and extracted with ethyl acetate (2 x 100 mL). The organic layer was separated, dried over anhydrous Na2S04 and concentrated under reduced pressure to afford crude product, which on purification by column chromatography yields the title compound (0.75 g, Yield 15 %).
Step C: Ethyl 4,5,6,7-tetrahydrofuro[3,2-c]pyridine-2-carboxylate
To a solution of 5-tert-Butyl 2-ethyl 6,7-dihydrofuro[3,2-c]pyridine-2,5(4H)- dicarboxylate (0.5g, 1.7 mmol) in DCM was added trifluoroacetic acid (TFA) (0.13 mL, 1.7 mmol) at 0-5 °C. After the completion of addition, the reaction mixture was allowed to stir for 6 hours. The excess solvent and reagents were evaporated under reduced pressure. The crude product was triturated with hexane to afford the title compound as TFA salt (0.5 g, Yield 95 %). 1H NMR (DMSO-d6) 5(ppm): 1.36 (3Η, t, - CH3), 2.77 (2H, brs, -CH2), 3.74 (2H, brs, -CH2), 4.32-4.38 (4H, m, -CH2), 5.02 (1H, brs, -NH), 7.02 (1H, s, Ar-H); MS m/z: 196.1 (M+l).
Intermediate 3: Ethyl 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate
Step A: 5-tert-butyl 2-ethyl
Figure imgf000041_0002
oxylate To a solution of tert-Butyl 4-chloro-5-formyl-3,6-dihydropyridine-l(2H)- carboxylate (10 g, 40.9 mmol) in DCM was added triethylamine (11.8 mL, 81.8 mmol) and ethyl mercaptoacetate (7.8 g, 65.4 mmol) at room temperature. The reaction mixture was refluxed for 2 hours, quenched with water and extracted with ethyl acetate (2 x 100 mL). The organic layer was separated, dried over anhydrous Na2S04 and concentrated under reduced pressure to afford the crude product. The crude product obtained on purification by column chromatography affords the title compound. (4.0 g, Yield 35%).
Step B: Ethyl 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate
To a solution of 5-tert-Butyl 2-ethyl 6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)- dicarboxylate (1.0 g, 3.2 mmol) in DCM was added TFA (0.5 mL, 6.4 mmol) at 0-5 °C and the reaction mixture was stirred for 3 hours. Excess solvent and reagents were evaporated under reduced pressure. Crude product on purification by column chromatography with n-hexane/ethyl acetate solvent mixture afforded the title compound (0.333 g, Yield 49 %). Ή NMR (DMSO-d6) 5(ppm): 1.35 (3Η, t, -CH3), 2.85 (2H, t, -CH2), 3.17 (2H, brs, -CH2), 3.93 (2H, s, -CH2), 4.32 (2H, q, -OCH2), 7.45 (1H, s, Ar-H); MS m/z: 212.1 (M+l).
Intermediate 4: 4,5,6,7-Tetrahydroisoxazolo[5,4-c]pyridine-3-carboxylicacid ethylester
Figure imgf000042_0001
Step A: Ethyl (2)-(hydroxyimino)acetate
Ethyl glyoxylate in toluene (10 mL, 195.9 mmol) was added drop wise to ethanol (12.5 mL) at 25 °C for 30 minutes. Aqueous hydroxylamine (13.5 g, 391.81 mmol) was added at the same temperature and reaction mixture was stirred for another
30 minutes. Reaction was quenched with water and extracted with ethyl acetate (2x 150 mL). Organic layer was separated and washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude product (7.0 g, Yield 61.13 %).
Step B: Ethyl (2)-chloro(hydroxyimino)acetate
To a solution of N-chlorosuccinimide (8.23 g, 123.2 mmol) in DMF was added ethyl (2)-(hydroxyimino)acetate (7.00 g, 123.2 mmol) at 0-5 °C. The reaction mixture was stirred at room temperature for 12 hours. Reaction was quenched with water and extracted with ethyl acetate (2x 150 mL). Organic layer was separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude product (6.95 g, Yield 74.73 %).
Step C: te -Butyl 4-(pyrrolidin-l-yl)-5,6-dihydropyridine-l(2H)-carboxylate
To a solution of N-Boc piperidone (10.0 g, 50.25 mmol) in toluene (120 mL), was added p-toluenesulphonic acid (PTSA, 0.95 g, 5.02 mmol) and pyrrolidine (4.5 mL, 55.27 mmol) at 25 °C. The reaction mixture was refluxed at 120 °C for 2 hours in presence of Dean-Stark apparatus. Solvents were then removed under reduced pressure to get the crude product (11.5 g, Yield 90.83 %).
Step D: 5-tert-Butyl 3-ethyl 7a-(pyrrolidin-l-yl)-3a,4,7,7a-tetrahydroisoxazolo[4,5- c]pyridine-3,5(6H)-dicarboxylate
To ethyl (2)-chloro(hydroxyimino)acetate (6.89 g, 91.26 mmol) in DCM was added TEA (9.5 mL, 136.91 mmol) drop wise at 0-5 °C, followed by tert-butyl 4- (pyrrolidin-l-yl)-5,6-dihydropyridine-l(2H)-carboxylate (6.75 g, 45.63 mmol) and stirred for 12 hours. Reaction was quenched with citric acid and extracted with ethyl acetate (2x 150 mL). The organic layer was separated, dried over anhydrous Na2S04 and concentrated under reduced pressure to afford crude product. On column purification using hexane/ethyl acetate solvent mixture yielded the title product (5.02 g, Yield 60.03 %).
Step E: Ethyl 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-3-carboxylate
5-tert-Butyl 3-ethyl 7a-(pyrrolidin-l-yl)-3a,4,7,7a-tetrahydroisoxazolo[4,5- c]pyridine-3,5(6H)-dicarboxylate (5 g, 27.24 mmol) was dissolved in DCM and TFA (3.15 mL, 81.74 mmol) was added. The reaction mixture was refluxed for 2 hours, quenched with aqueous sodium bicarbonate solution and extracted with ethyl acetate (2x 150 mL). The organic layer was separated, dried over anhydrous Na2S04 and concentrated under reduced pressure to afford the crude product. Further it was column purified using DCM/methanol solvent mixture to yield the title product as its TFA salt (1 g, Yield 37.73 %). 'H NMR (DMSO-d6) 5(ppm): 1.32 (3H, t, -CH3), 2.75 (2H, t, -CH2), 3.05 (2H, brs, -CH2), 3.73 (2H, s, -CH2), 4.31 (2H, q, -OCH2); MS m/z: 197.0 (M+l).
Intermediate 5: 2,3-Dihydro-lH-indole-5-carboxylic acid methyl ester
Figure imgf000044_0001
Methyl indole-5-carboxylate (1 g, 11.4 mmol) dissolved in glacial acetic acid (10 mL) was stirred at room temperature for 10 minutes. To this sodium cyanoborohydride (1.8 g, 28 mmol) was added slowly and the stirring continued for 1 hour. On completion of reaction, it was quenched by the addition of saturated sodium bicarbonate solution (150 mL) and extracted with ethyl acetate (2 x 100 mL). The organic layer was separated, dried over anhydrous Na2S04 and concentrated under reduced pressure to get the title product (0.65 g, Yield 65%). Ή NMR (DMSO-d6) 6(ppm): 3.23 (2H, t, -CH2), 3.61 (2H, t, -CH2), 4.0 (3H, s, -OCH3), 6.8 (1H, d, Ar-H), 7.6-7.65 (2H, m, Ar-H), 8.45 (1H, brs, -NH); MS m/z: 178.1 (M+l).
By following the above procedure, 2,3-Dihydro-lH-indole-6-carboxylic acid methyl ester and 2,3-Dihydro-lH-indole-4-carboxylic acid methyl ester were prepared. Intermediate 6: Methyl 2,3,4,5-tetrahydro-lH-benzo[c]azepine-8-carboxylate
Figure imgf000044_0002
Step A: (E)-3-(4-(methoxycarbonyl)phenyl)acrylic acid
Methyl 4-formyl benzoate (5.0 g, 30.5 mmol), malonic acid (9.5 g, 91.5 mmol) and piperidine (0.5 mL, mmol) were added to a solution of pyridine (30 mL) and refluxed at 100 °C for 4 hours. The reaction mixture was cooled, neutralised with concentrated HC1 and filtered to obtain the crude product (4.5 g, Yield 59 %).
Step B: (E)-Methyl 4-(3-amino-3-oxoprop-l-enyl)benzoate
(£)-3-(4-(Methoxycarbonyl)phenyl)acrylic acid (1.5g, 7.28 mmol) was dissolved in dichloromethane (5 mL) and cooled to 0 °C. Thionyl chloride (2.1 mL, 29.12 mmol) was added drop wise and the reaction mixture was allowed to stir at room temperature for 1 hour. Excess solvent and reagents were removed under reduced pressure. The residue was dissolved in diethyl ether and added drop wise to aqueous ammonia (20 mL). The resultant precipitate was filtered, washed with excess water and dried to get the title compound (0.9 g, Yield 60.1%)
Step C: (E)-Methyl 4-(2-cyanovinyl)benzoate (£}-Methyl 4-(3-amino-3-oxoprop-l-enyl)benzoate (1.0 g, 4.8 mmol) was dissolved in THF (50 mL). To this triethylamine (2.56 mL, 18.4 mmol) was added and cooled to 0 °C. Trifluoro acetic anhydride (1.2 mL, 8.8 mmol) was added slowly to the reaction mixture and stirred at room temperature for 1 hour. The reaction mixture was poured into ice mixture and the resultant precipitate was filtered which was further purified by silica column chromatography eluting with acetone/hexane solvent mixture to get the title compound (0.35 g, Yield 38.5 %).
Step D: Methyl 4-(3-aminopropyl)benzoate
(E)-Methyl 4-(2-cyanovinyl)benzoate (1.0 g, 5.34 mmol) taken in methanol (50mL). To this raney nickel (0.1 g) was added, followed by the addition of sodium borohydride (0.79 g, 21.39 mmol). The reaction mixture was stirred at room temperature for 1 hour and filtered. The filtrate was acidified with concentrated HCl and the resultant solid was filtered and dried to get the title compound (0.4 g, Yield 32.8 %).
Step E: Methyl 4-(3-(2,2,2-trifluoroacetamido)propyl)benzoate
Methyl 4-(3-aminopropyl)benzoate (10 g, 43.66 mmol) was added portion wise to the well stirred trifluoroacetic anhydride (30 mL). This was further stirred for 3 hours at room temperature. The reaction mixture was poured into 100 mL of ice cold water and stirred for another 30 minutes. The resulting solid was filtered, washed with hexane and dried under vacuum to get the title compound (9 g, Yield 71.3 %).
Step F: Methyl 2-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-lH-benzo[c]azepine-8- carboxylate
Methyl 4-(3-(2,2,2-trifluoroacetamido)propyl)benzoate (5.0 g, 18.18 mmol) was stirred at room temperature with paraformaldehyde (2.1 g, 72.7 mmol), acetic acid (25mL) and cone. H2S04 (38 mL) for 18 hours. The clear solution was added to cold water (100 mL) and extracted with ethyl acetate (2x 100 mL). The organic layer was washed with 50 mL of saturated sodium bicarbonate solution, water (200 mL) and dried over anhydrous sodium sulphate, concentrated under vacuum to get the title compound (3.0 g, Yield 52.5 %).
Step G: Methyl 2,3,4,5-tetrahydro-lH-benzo[c]azepine-8-carboxylate
Methyl 2-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-lH-benzo[c]azepine-8- carboxylate (3 g, 9.9 mmol) was dissolved in methanol (20 mL) and added to potassium carbonate (4.18 g, 29.9 mmol) and water (2 mL) and then stirred at room temperature for 3 hours. Methanol was removed from the reaction mixture and water (100 mL) was added, extracted with ethyl acetate (100 mL), followed by washing with water (100 mL). The organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to get colourless solid (1.23 g, Yield 60.6 %). lH NMR (DMSO-de) 5(ppm): 1.52 (2H, m, -CH2), 2.73-2.75 (2H, t, -CH2), 2.76-2.77 (2H, brs, -CH2), 3.8 (2H, s, -CH2), 4.01 (3H, s, -OCH3), 5.4 (1H, brs, -NH), 7.12 (1H, d, - Ar-H), 7.71-7.74 (2H, m, Ar-H); MS m/z: 205.9 (M+l).
Intermediate 7: Ethyl 2-(piperazin-l-yl)pyrimidine-5-carboxylate
Figure imgf000046_0001
Step A: Ethyl 2-(methylthio)pyrimidine-5-carboxylate
Figure imgf000046_0002
Ethyl 4-chloro-2- methylthiopyrimidine-5- carboxylate (5.0 g, 21.4 mmol) and magnesium oxide (0.9 g, 21.4 mmol) was added to methanol (200 mL) in par-shaker vessel. Dry 10% Pd/C (5 g) was added and the flask was evacuated, purged with nitrogen and the contents allowed to react under 50 psi pressure hydrogen for 6 hours. The system was evacuated and purged with nitrogen. After dilution with methanol the solution was filtered through a pad of celite. The filter cake was washed with methanol and the filtrate was evaporated to get the crude material. Further on column purification using hexane/ethyl acetate solvent mixture yielded the title compound (2.2 g, Yield 52 %).
Step B: Ethyl 2-(methylsulfonyl)pyrimidine-5-carboxylate
Figure imgf000046_0003
Ethyl 2-(methylthio)pyrimidine-5-carboxylate (2.2 g, 11 mmol) was dissolved in DCM at 0 °C and stirred at room temperature for 15 minutes, followed by addition of /w-chloroperbenzoic acid (mCPBA) (5.75 g, 33 mmol). The reaction mixture was stirred for 1 hour. Saturated NaHC03 solution was added to reaction mass and extracted with DCM. The organic layer was washed with water, brine solution and dried oyer an anhydrous Na2S04. The solvent was evaporated to get the title compound (2.0 g, Yield 75 %).
Step C: Ethyl 2-(4-(tert-butoxycarbonyl)piperazin-l-yl)pyrimidine-5-carboxylate
Figure imgf000047_0001
Ethyl 2-(methylsulfonyl)pyrimidine-5-carboxylate (2 g, 8.6 mmol) was dissolved in 10 mL of DMSO. Boc protected piperazine (4.04 g, 21.7 mmol) was added to this and heated to 75-85 °C for an hour. The reaction mass was cooled to room temperature, quenched with water and extracted with DCM (2 x 100 mL). The organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was further purified by column chromatography using DCM/MeOH solvent mixture to get the pure title product (2 g, Yield 68 %).
Step D: Ethyl 2-(piperazin-l-yl)pyrimidine-5-carboxylate
Figure imgf000047_0002
Ethyl 2-(4-(tert-butoxycarbonyl)piperazin-l-yl)pyrimidine-5-carboxylate (2 g, 5.9 mmol) was dissolved in DCM and TFA (7.3 mL, 95 mmol) was added at 0 °C, and stirred for 10 minutes. Solvent was evaporated completely and diethyl ether was added drop wise. The solid thrown was filtered to get the pure title compound as its TFA salt (1.6 g, Yield 57 %). Ή NMR (DMSO-d6) 5(ppm): 1.32 (3H, t, -CH3), 3.51 (4H, brs, - CH2), 3.67 (4H, s, -CH2), 4.31 (2H, q, -OCH2), 8.64 (2H, brs, Ar-H); MS m/z: 237.1 (M+l).
By following the above procedure, ethyl 2-(4-aminopiperidin-l-yl)pyrimidine- 5-carboxylate and ethyl 2-(4-(aminomethyl)piperidin-l-yl)pyrimidine-5-carboxylate were prepared.
Example 1 : 2-(2,3-Diphenylacryloyl)-N-hydroxy- 1 ,2,3,4-tetrahydroisoquinoline-7- carboxamide
Figure imgf000047_0003
Step-I: Methyl 2-(2,3-Diphenylacryloyl)- 1 ,2,3,4-tetrahydroisoquinoline-7-carboxylate
To a solution of 2,3-Diphenylacrylic acid (0.900 g, 4.0 mmol) in 1 mL of Ν,Ν- dimethylformamide (DMF) was added DIEA (2 mL, 12 mmol), EDCI (1.5 g, 8 mmol), HOBt (0.216 g, 1.6 mmol) and finally methyl l,2,3,4-tetrahydroisoquinoline-7- carboxylate (0.925 g, 4.8 mmol). The reaction mixture was stirred at room temperature for 3 hours and cold water was added (50 mL), extracted with ethyl acetate (100 mL).
The organic layer was washed with 50 mL of water, 50 mL of brine solution, dried over anhydrous sodium sulphate and the solvent was evaporated under reduced pressure. The crude product was subjected to column chromatography on silica gel using hexane, ethyl acetate solvent system to get the title compound as solid. The resulting solid was further washed with methanol, filtered and dried under vacuum
(0.850 g, Yield 53.52 %).
Step-II: 2-(2,3-Diphenylacryloyl)-N-hydroxy- 1 ,2,3,4-tetrahydroisoquinoline-7- carboxamide
Hydroxylamine hydrochloride (0.633 g, 9.0 mmol) in methanol (5 mL) was mixed with potassium hydroxide (0.500 g, 9.0 mmol) in methanol (5 mL) at 0 °C. The resulting white precipitate was filtered and the filtrate was immediately added to a round bottom flask containing Methyl 2-(2,3-diphenylacryloyl)-l,2,3,4- tetrahydroisoquinoline-7-carboxylate (0.200 g, 0.5 mmol). The reaction mixture was stirred at room temperature for 2 hours. Methanol was evaporated under reduced pressure and diluted with ice-cold water (100 mL). The pH of the reaction mixture was adjusted to 8 using dilute acetic acid and kept in refrigerator at 10 °C for 2 hours.
The resulting solid was filtered to afford the title compound as colourless solid (0.080 g, Yield 40.20 %).
Ή NMR (DMSO-d6) 5(ppm): 2.67-2.68 (2H, m, -CH2), 3.79 (2H, t, -CH2), 4.73 (2H, brs, -CH2), 6.79 (1H, s, =CH), 7.12 (2H, d, Ar-H), 7.20-7.22 (4H, m, Ar-H), 7.30-7.33
(5H, m, Ar-H), 7.53-7.60 (2H, m, Ar-H), 9.0 (1H, s, -OH), 11.14 (1H, s, -NH); MS m/z: 399.1 (M+l).
The following compounds were prepared according to the procedure given in Example
1:
Ex. Structure Analytical Data
Ή NMR (DMSO-d6) 5(ppm): 2.74-2.84 (2H, m, -CH2), 3.79 (2H, t, -CH2), 4.73 (2H, brs, -CH2), 6.8 (1H, s,
2 =CH), 7.07-7.11 (2H, m, Ar-H), 7.14-7.18 (3H, m, Ar- H), 7.21-7.23 (2H, m, Ar-H), 7.31-7.35 (2H, m, Ar-H),
Figure imgf000048_0001
7.53-7.55 (1H, d, Ar-H), 7.6 (1H, s, Ar-H), 9.01 (1H, s, - OH), 11.14 (1H, s, -NH); MS m/z: 435,1 (M+l). !H NMR (DMSO-d6) 5(ppm): 2.74 (2H, brs, -CH2), 3.44 (3H,s, -OCH3), 3.71 (3H,s, -OCH3), 3.79 (2H, s, -CH2), 4.71 (2H, brs, -CH2), 6.63 (1H, s, =CH), 6.72-6.74 (2H, m, Ar-H), 6.83-6.85 (1H, d, Ar-H), 7.12-7.14 (1H, m,
Figure imgf000049_0001
Ar-H), 7.22-7.24 (2H, t, Ar-H), 7.35-7.39 (2H, t, Ar-H),
7.53-7.55 (2H, m, Ar-H); MS m/z: 477.1 (M+l).
!H NMR (DMSO-de) δ(ρρηι): 2.66 (2H, brs, -CH2), 3.73-3.77 (2H, s, -CH2), 4.75 (2H, s, -CH2), 6.66-6.73 (1H, s, =CH), 6.91-6.96 (1H, m, Ar-H), 7.02-7.07 (1H, m, Ar-H), 7.22-7.24 (4H, m, Ar-H), 7.27-7.32 (3H, m, o
Ar-H), 7.53-7.61 (2H, m, Ar-H), 9.02 (1H, s, -OH), 11.15 (lH, s, -NH); MS m/z: 435.1 (M+l).
1H NMR (DMSO-d6) 5(ppm): 2.67-2.84 (2H, brs, -CH2), 3.74 (3H,s, -OCH3), 3.75 (2H, s, -CH2), 4.72 (2H, s, - CH2), 6.69 (1H, s, =CH), 6.91 (2H, brs, Ar-H), 7.06-7.10 (2H, t, Ar-H), 7.17-7.21 (5H, m, Ar-H), 7.53-7.6 (2H, m, Ar-H), 9.0 (1H, s, -OH), 11.14 (1H, s, -NH); MS m/z: 447.1 (M+l).
Ή NMR (DMSO-d6) 6(ppm): 2.69-2.84 (2H, m, -CH2), 3.77-3.80 (2H, t, -CH2), 4.73 (2H, s, -CH2), 6.78 (1H, s, =CH), 7.04-7.09 (2H, t, Ar-H), 7.14-7.21 (3H, m, Ar-H), 7.28-7.34 (5H, m, Ar-H), 7.53-7.59 (2H, m, Ar-H), 9.01 (1H, s, -OH), 11.14 (1H, s, -NH); MS m/z: 417.1 (M+l).
1H NMR (DMSO-d6) 5(ppm): 2.69 (2H, brs, -CH2), 3.75 (3H,s, -OCH3), 3.76 (2H, s, -CH2), 4.72 (2H, s, -CH2), 6.68 (1H, s, =CH), 6.93-6.99 (3H, m, Ar-H), 7.13-7.21
-C (4H, m, Ar-H), 7.28-7.33 (1H, m, Ar-H), 7.53-7.6 (2H, m, Ar-H), 9.0 (1H, s, -OH), 11.14 (1H, s, -NH); MS m/z: 465.1 (M+l).
Figure imgf000050_0001
Figure imgf000051_0001
(IH, m, Ar-H), 7.07-7.12 (2H, m, Ar-H), 7.19-7.22 (3H, m, Ar-H), 7.53-7.59 (2H, m, Ar-H), 9.02 (IH, s, -OH), 11.13 (lH, s, -NH); MS m/z: 461.1 (M+l).
Ή NMR (DMSO-de) 5(ppm): 2.71-2.83 (2H, s, -CH2), 3.77 (2H, brs, -CH2), 4.7 (2H, s, -CH2), 6.61 (IH, s, =CH), 6.78 (IH, s, Ar-H), 6.84-6.86 (2H, d, Ar-H), 6.91- 6.92 (IH, s, Ar-H), 6.95-6.97 (IH, d, Ar-H), 7.09-7.13
Figure imgf000052_0001
(2H, m, Ar-H), 7.2-7.22 (3H, d, Ar-H), 7.25-7.34 (5H, m, Ar-H), 7.53-7.54 (IH, m, Ar-H), 9.0 (IH, s, -OH), 11.13 (IH, s, -NH); MS m/z: 509.1 (M+l).
Ή NMR (DMSO-d6) 6(ppm): 2.79 (2H, m, -CH2), 4.02- 4.03 (2H, t, -CH2), 4.74 (2H, s, -CH2), 6.85 (IH, s, =CH), 7.12-7.13 (2H, m, Ar-H), 7.21-7.27 (5H, m, Ar- H), 7.34 (IH, s, Ar-H), 7.39 (2H,s, Ar-H), 7.54-7.56
Figure imgf000052_0002
(IH, d, Ar-H), 7.61 (lH,s, Ar-H); MS m/z: 433 (M+l).
Ή NMR (DMSO-de) 6(ppm): 2.76-2.85 (2H, brs, -CH2), 3.81 (2H, s, -CH2), 4.74 (2H, s, -CH2), 6.85 (IH, s, =CH), 7.09-7.14 (5H, m, Ar-H), 7.22-7.27 (4H, m, Ar- H), 7.39 (IH, s, Ar-H), 7.56 (IH, s, Ar-H), 7.61 (IH, s, o o
F Ar-H), 9.01 (IH, s, -OH), 11.15 (IH, s, -NH); MS m/z:
417.1 (M+l).
Ή NMR (DMSO-d6) 6(ppm): 2.77 (2H, brs, -CH2), 3.82 (2H, s, -CH2), 4.73 (2H, s, -CH2), 7.0 (IH, s, =CH), 7.11-7.13 (2H, m, Ar-H), 7.23-7.25 (6H, m, Ar-H), 7.33- 7.40 (2H, m, Ar-H), 7.54-7.59 (2H, m, Ar-H), 9.01 (IH,
Figure imgf000052_0003
s, -OH), 11.15 (IH, s, -NH); MS m/z: 417.1 (M+l).
Ή NMR (DMSO-d6) 6(ppm): 2.88 (2H, brs, -CH2), 3.94 (2H, s, -CH2), 4.77 (2H, s, -CH2), 7.06-7.07 (IH, s, =CH), 7.08-7.09 (IH, m, Ar-H), 7.25-7.26 (5H, m, Ar- H), 7.32 (2H, m, Ar-H), 7.51 (IH, s, Ar-H), 7.56-7.58 o o
F CI (2H, m, Ar-H), 9.01 (IH, s, -OH), 11.14 (IH, s, -NH);
MS m/z: 449 (M+l). Ή NMR (DMSO-d6) 5(ppm): 2.29 (3H, s, -CH3), 2.68- 2.84 (2H, brs, -CH2), 3.75-3.78 (2H, t, -CH2), 4.72 (2H, s, -CH2), 6.73 (IH, s, =CH), 7.13-7.15 (6H, m, Ar-H), 7.21-7.23 (4H, m, Ar-H), 7.53-7.55 (IH, m, Ar-H), 7.61
Figure imgf000053_0001
(IH, m, Ar-H), 9.01 (IH, s, -OH), 11.14 (IH, s, -NH); MS m/z: 413 (M+l).
1H NMR (DMSO-d6) 5(ppm): 2.67-2.84 (2H, brs, -CH2), 3.77-3.80 (2H, t, -CH2), 4,73 (2H, s, -CH2), 6.78 (IH, s,
" =CH), 7.04-7.09 (2H, t, Ar-H), 7.14-7.21 (3H, m, Ar-H), J^OC^ H 7.28-7.29 (2H, m, Ar-H), 7.34 (3H, brs, Ar-H), 7.53-7.59 o 0
(2H, m, Ar-H), 9.01 (IH, s, -OH), 11.14 (IH, s, -NH); MS m/z: 417.1 (M+l).
Ή NMR (DMSO-d6) 5(ppm): 2.80-2.83 (2H, brs, -CH2), 3.83 (2H, brs, -CH2), 4.76 (2H, s, -CH2), 6.97-6.99 (IH, s, =CH), 7.07 (IH, s, Ar-H), 7.2-7.22 (2H, m, Ar-H), 7.26-7.3 (2H, t, Ar-H), 7.41-7.42 (IH, d, Ar-H), 7.46- 7.49 (2H, m, Ar-H), 7.54-7.56 (IH, d, Ar-H), 7.61 (IH, s, Ar-H), 9.0 (IH, s, -OH), 11.13 (IH, s, -NH); MS m/z: 423.1 (M+l).
Ή NMR (DMSO-d6) 6(ppm): 2.7-2.85 (2H, d, -CH2), 3.55 (3H, s, -OCH3), 3.75 (5H, s, -OCH3 & -CH2), 4.75 (2H, brs, -CH2), 6.7 (IH, s, =CH), 6.83 (2H, s, Ar-H), 6.94-7.08 (4H, m, Ar-H), 7.18 (IH, brs, Ar-H), 7.26-7.32
Figure imgf000053_0002
(IH, q, Ar-H), 7.53-7.59 (2H, m, Ar-H); MS m/z: 477.1
(M+l).
lR NMR (DMSO-d6) 5(ppm): 2.86-2.87 (2H, t, -CH2), 3.92 (2H, brs, -CH2), 4.74-5.02 (2H, m, -CH2), 7.042- 7.06 (3H, m, =CH & Ar-H), 7.17-7.26 (4H, m, Ar-H), 7.3-7.33 (2H, m, Ar-H), 7.36-7.41 (IH, m, Ar-H), 7.43-
Figure imgf000053_0003
7.58 (3H, m, Ar-H), 8.99 (IH, s, -OH), 11.11 (IH, brs, - NH); MS m/z: 433.1 (M+l). 'H NMR (DMSO-d6) 5(ppm): 2.86-2.87 (2H, t, -CH2), 3.92 (2H, brs, -CH2), 4.74-5.01 (2H, brs, -CH2), 7.04- 7.06 (3H, m, =CH & Ar-H), 7.2-7.24 (4H, m, Ar-H), 7.26-7.33 (2H, m, Ar-H), 7.36-7.39 (IH, m, Ar-H), 7.47 o o
(IH, brs, Ar-H), 7.56-7.58 (2H, d, Ar-H), 9.0 (IH, s, OH), 1 1.13 (IH, s, -NH); MS m/z: 433 (M+l).
Ή NMR (DMSO-d6) 5(ppm): 2.67-2.79 (2H, brs, -CH2), 3.37 (3H, s, -OCH3), 3.72 (3H, s, -OCH3), 3.81 -3.89 (2H, brs, -CH2), 4.76 (2H, brs, -CH2), 6.62 (IH, s, =CH), 6.75-6.77 (IH, d, Ar-H), 6.84-6.86 (IH, d, Ar-H), 6.92
Figure imgf000054_0001
(IH, s, Ar-H), 7.16-7.24 (3H, m, Ar-H), 7.37-7.41 (2H, m, Ar-H), 7.68-7.7 (2H, m, Ar-H), 9.04 (IH, brs, -OH), 1 1.15 (IH, brs, -NH); MS m/z: 477.1 (M+l).
1H NMR (DMSO-d6) 6(ppm): 2.67-2.85 (2H, brs, -CH2), 3.82 (2H, s, -CH2), 4.75 (2H, s, -CH2), 6.82 (IH, s, =CH), 7.15-7.2 (3H, m, Ar-H), 7.37-7.39 (3H, m, Ar-H), 7.51 (IH, m, Ar-H), 7.53-7.59 (4H, m, Ar-H), 7.88 (4H,
Figure imgf000054_0002
m, Ar-H), 9.01 (IH, s, -OH), 11.1 (IH, s, -NH); MS m/z: 449.2 (M+l).
'H NMR (DMSO-d6) 5(ppm): 2.67 (2H, brs, -CH2), 2.89-2.93 (6H, s, -CH3), 3.7-3.76 (2H, s, -CH2), 4.71 (2H, s, -CH2), 6.49-6.65 (3H, m, Ar-H & =CH), 7.06- 7.08 (2H, m, Ar-H), 7.17-7.25 (6H, m, Ar-H), 7.48-7.6 (2H, m, Ar-H), 9.06 (IH, s, -OH), 1 1.1 1 (IH, s, -NH); MS m/z: 442.2 (M+l).
Ή NMR (DMSO-d6) 5(ppm): 2.68 (2H, brs, -CH2), 3.70 (3H, s, -OCH3), 3.77 (2H, s, -CH2), 4.73 (2H, s, -CH2), 6.70 (IH, s, =CH), 6.79 (2H, brs, Ar-H), 7.04-7.06 (2H, t, Ar-H), 7.19-7.21 (IH, d, Ar-H), 7.29-7.34 (5H, m, Ar- H), 7.53-7.58 (2H, m, Ar-H), 9.0 (IH, s, -OH), 1 1.14 (IH, s, -NH); MS m/z: 429.48 (M+l).
Figure imgf000055_0001
Ή NMR (DMSO-de) 6(ppm): 2.85 (2H, s, -CH2), 3.92 (2H, brs, -CH2), 4.73 (2H, brs, -CH2), 7.08-7.10 (5H, m, =CH & Ar-H), 7.23-7.25 (2H, m, Ar-H), 7.31-7.39 (3H, m, Ar-H), 7.48 (1H, s, Ar-H), 7.55-7.57 (1H, m, Ar-H), 9.00 (1H, s, -OH), 1 1.14 (1H, s, -NH); MS m/z: 451.0 (M+l).
lH NMR (DMSO-d6) 6(ppm): 2.67-2.85 (2H, m, -CH2), 3.77-3.80 (2H, t, -CH2), 4.73 (2H, brs, -CH2), 6.8 (1H, s, =CH), 7.12-7.14 (2H, d, Ar-H), 7.21-7.23 (3H, m, Ar- H), 7.30-7.32 (4H, d, Ar-H), 7.53-7.60 (2H, d, Ar-H), o o
F 9.00 (1H, s, -OH), 11.13 (1H, s, -NH); MS m/z: 451.0
(M+l).
1H NMR (DMSO-de) 6(ppm): 2.29 (3H, s, -CH3) 2.67 (2H, brs, -CH2), 3.71 (3H, s, -OCH3), 3.74 -3.77 (2H, s, - CH2), 4.71 (2H, s, -CH2), 6.65 (1H, s, =CH), 6.77-6.80 (2H, d, Ar-H), 7.07-7.09 (2H, d, Ar-H), 7.18-7.21 (5H, m, Ar-H), 7.53-7.58 (2H, d, Ar-H), 9.0 (1H, s, -OH), 11.14 (1H, s, -NH); MS m/z: 443.1 (M+l).
Ή NMR (DMSO-d6) 6(ppm): 2.85 (2H, t, -CH2), 3.92 (2H, brs, -CH2), 4.73 (2H, brs, -CH2), 7.04-7.07 (3H, m, =CH, Ar-H), 7.23-7.48 (6H, m, Ar-H), 7.55-7.57 (3H, m, Ar-H), 8.99 (1H, s, -OH), 1 1.14 (1H, s, -NH); MS m/z: 469 (M+l).
Ή NMR (DMSO-de) 5(ppm): 2.67-2.76 (2H, t, -CH2), 3.87 (2H, s, -CH2), 4.60 (2H, s, -CH2), 6.85 (1H, s, =CH), 7.1 1-7.14 (4H, m, Ar-H), 7.24-7.25 (3H, s, Ar-H), 7.40 (3H, s, Ar-H), 9.10 (1H, s, -OH), 11.13 (1H, s, - NH); MS m/z: 423.0 (M+l).
Ή NMR (DMSO-de) 5(ppm): 2.67-2.73 (2H, m, -CH2), 3.84-3.87 (2H, m, -CH2), 4.60 (2H, s, -CH2), 6.8 (1H, s, =CH), 7.1 1-7.13 (2H, d, Ar-H), 7.2-7.4 (8H, m, Ar-H),
Figure imgf000056_0001
9.08 (1H, s, -OH), 11.13 (1H, s, -NH); MS m/z: 423.0 (M+l).
Ή NMR (DMSO-d6) 5(ppm): 2.79 (2H, t, -CH2), 3.31 (3H, s, -OCH3), 3.33 (3H, s, -OCH3), 3.62 (3H, s, - OCH3), 3.78 (2H, brs, -CH2), 4.73 (2H, brs, -CH2), 6.44 (2H, s, =CH & Ar-H), 7.2-7.27 (3H, m, Ar-H), 7.38-7.42 (2H, m, Ar-H), 7.53-7.56 (2H, d, Ar-H), 7.6 (IH, s, Ar-
Figure imgf000057_0001
H), 9.00 (IH, s, -OH), 11.14 (IH, s, -NH); MS m/z:
507.1 (M+l).
Ή NMR (DMSO-d6) 5(ppm): 2.75-2.85 (2H, t, -CH2), 3.82 (2H, brs, -CH2), 4.74-4.82 (2H, d, -CH2), 6.79-6.84 (IH, d, =CH), 7.22-7.35 (4H, m, Ar-H), 7.42-7.45 (2H, d, Ar-H), 7.54-7.56 (2H, d, Ar-H), 7.61 (IH, s, Ar-H), o o
8.34-8.4 (2H, d, Ar-H), 9.02 (IH, s, -OH), 11.17 (IH, s, -NH); MS m/z: 418.1 (M+l).
'H NMR (DMSO-de) 6(ppm): 2.7-2.87 (2H, t, -CH2), 3.8 (2H, brs, -CH2), 4.75-4.79 (2H, d, -CH2), 6.75-6.81 (IH, d, =CH), 7.05-7.06 (2H, m, Ar-H), 7.22-7.24 (3H, d, Ar- H), 7.36 (2H, s, Ar-H), 7.54-7.56 (IH, d, Ar-H), 7.56-
Figure imgf000057_0002
7.62 (IH, s, Ar-H), 8.43-8.44 (2H, d, Ar-H), 9.02 (IH, s,
-OH), 11.17 (IH, s, -NH); MS m/z: 418.1 (M+l).
Ή NMR (DMSO-d6) 6(ppm): 2.73-2.86 (2H, t, -CH2),
O 3.80 (2H, s, -CH2), 4.73 (2H, s, -CH2), 6.85 (IH, s,
=CH), 7.16-7.23 (4H, m, Ar-H), 7.33-7.35 (3H, m, Ar- H), 7.49-7.55 (2H, m, Ar-H), 7.71-7.73 (2H, d, Ar-H),
F 7.91 (IH, s, -COOH) 9.0 (IH, s, -OH), 11.14 (IH, s, - NH); MS m/z: 461(M+1).
Ή NMR (DMSO-de) 5(ppm): 2.85 (2H, brs, -CH2), 3.71 (3H, s, -OCH3), 3.89 (2H, brs, -CH2), 4.80 (2H, brs,
/0x -CH2), 6.78-6.80 (2H, d, =CH & Ar-H) 6.97-6.99 (3H, d, ί γ Ογ Η Ar-H), 7.23-7.25 (IH, d, Ar-H), 7.29-7.38 (3H, m, Ar- H), 7.48-7.50 (IH, d, Ar-H) 7.55-7.57 (2H, d, Ar-H), 8,99 (IH, s, -OH), 11.14 (IH, s, -NH); MS m/z: 463.0 (M+l).
Ή NMR (DMSO-d6) 6(ppm): 2.70 (2H, m, -CH2), 3.79 (2H, s, -CH2), 4.72 (2H, s, -CH2), 6.78 (IH, s, =CH ), 6.97 (IH, d, Ar-H), 7.08-7.12 (IH, t, Ar-H), 7.20-7.22 on - (IH, d, Ar-H), 7.28-7.30 (3H, m, Ar-H), 7.32-7.38 (3H, o o m, Ar-H) 7.53-7.55 (IH, d, Ar-H), 7.60 (IH, s, Ar-H),
9.02 (IH, s, -OH), 11.15 (IH, s, -NH); MS m/z: 435.1 (M+l).
Ή NMR (DMSO-d6) 5(ppm): 2.30 (3H, s, -CH3) 2.70 (2H, m, -CH2), 3.78 (2H, s, -CH2), 4.72 (2H, s, -CH2), 6.72 (IH, s, =CH ), 6.98 (IH, m, Ar-H), 7.12-7.19 (6H, m, Ar-H), 7.28-7.35 (IH, q, Ar-H), 7.53-7.60 (2H, m, Ar-H) 9.02 (IH, s, -OH), 11.14 (IH, s, -NH); MS m/z: 449.0 (M+l).
Ή NMR (DMSO-d6) 5(ppm): 2.74 (2H, m, -CH2), 3.79 (2H, s, -CH2), 4.73 (2H, s, -CH2), 6.83 (IH, s, =CH), 7.12-7.14 (2H, m, Ar-H), 7.21-7.24 (4H, m, Ar-H), 7.25- 7.32 (2H, m, Ar-H), 7.41 (2H, m, Ar-H) 7.54-7.56 (IH,
Figure imgf000058_0001
d, Ar-H), 7.60 (IH, s, Ar-H), 9.01 (IH, s, -OH), 11.15
(IH, s, -NH); MS m/z: 433.1 (M+l).
Ή NMR (DMSO-d6) 5(ppm): 3.1-3.15 (2H, t, -CH2), 4.08-4.13 (2H, t, -CH2), 7.0 (IH, s, =CH), 7.14-7.16 (2H, d, Ar-H), 7.15-7.25 (3H, dd, Ar-H), 7.31-7.4 (5H, m, Ar-H), 7.62-7.65 (2H, d, Ar-H), 8.0 (IH, brs, Ar-H), 8.95 (IH, s, -OH), 11.11 (IH, s, -NH); MS m/z: 385.1
HN^OH
(M+l).
1H NMR (DMSO-d6) 5(ppm): 2.66-2.89 (2H, m, -CH2), 3.85(2H, m, -CH2), 4.59 (2H, s, -CH2), 6.79 (IH, s,
/\^S, HN OH
ΟΟ =CH), 7.12 (2H, s, Ar-H), 7.2-7.34 (5H, m, Ar-H), 7.54-
° 7.58 (4H, m, Ar-H), 9.09 (IH, s, -OH), 11.13 (IH, s, - NH); MS m/z: 405.0 (M+l). Ή NMR (DMSO-d6) δ(ρρηι): 2.43 (3Η, s, -SCH3), 2.67-2.84 (2Η, t, -CH2), 3.78 (2H, s, -CH2), 4.73 (2H, s, - CH2), 6.69 (IH, s, =CH), 7.03-7.05 (2H, d, Ar-H), 7.10- 7.12 (2H, d, Ar-H), 7.21-7.23 (3H, m, Ar-H), 7.32-7.36 (2H, m, Ar-H), 7.53-7.59 (2H, m, Ar-H) 9.0 (IH, s, - OH), 11.13 (IH, s, -NH); MS m/z: 463.0 (M+l).
!H NMR (DMSO-d6) 6(ppm): 3.14 (2H, brs, -CH2), 4.13 (2H, brs, -CH2), 7.02 (IH, s, =CH), 7.15-7.36 (8H, m, Ar-H), 7.25-7.27 (IH, d, Ar-H), 7.64 (2H, brs, Ar-H), 8.0 (IH, brs, Ar-H); MS m/z: 403.1 (M+l).
1H NMR (DMSO-d6) 5(ppm): 2.24 (6H, s, -CH3), 2.67- 2.83 (2H, t, -CH2), 3.78 (2H, s, -CH2), 4.73 (2H, s, - CH2), 6.67 (IH, s, =CH), 7.03 (4H, s, Ar-H), 7.16-7.22
° ° (5H, m, Ar-H), 7.53-7.58 (2H, m, Ar-H), 9.01 (IH, s,- OH), 11.14 (IH, s, -NH); MS m/z: 427.1 (M+l)
Ή NMR (DMSO-de) 5(ppm): 2.23 (3H, s, -CH3), 2.67- 2.83 (2H, t, -CH2), 3.78 (2H, s, -CH2), 4.73 (2H, s, - CH2), 6.73 (IH, s, =CH), 7.01 (4H, s, Ar-H), 7.21-7.33 (6H, m, Ar-H), 7.53-7.59 (2H, m, Ar-H), 9.02 (IH, s, -
Figure imgf000059_0001
OH), 11.13 (IH, s, -NH); MS m/z: 413.1 (M+l)
Ή NMR (DMSO-d6) 6(ppm): 2.78 (2H, brs, -CH2), 3.82 (2H, s, -CH2), 4.74 (2H, s, -CH2), ' 6.93 (IH, s, =CH),
/3γ00γ „ 7.11-7.13 (2H, m, Ar-H), 7.22-7.25 (4H, m, Ar-H), 7.51- 7.61 (4H, m, Ar-H), 7.51 (2H, brs, Ar-H), 9.01 (IH, s, - OH), 11.15 (IH, s, -NH); MS m/z: 467.1 (M+l).
!H NMR (DMSO-de) 5(ppm): 0.51-0.53 (2H, t, -CH2), 0.62-0.66 (2H, t, - CH2), 2.75 (IH, m, -CH), 2.85 (2H, s, -CH2), 3.80 (2H, t, -CH2), 4.7-4.73 (2H, d, -CH2), 7.05- 7.07 (2H, d, =CH & Ar-H), 7.16-7.18 (2H, m, Ar-H), 7.22-7.26 (4H, m, Ar-H), 7.37-7.39 (3H, d, Ar-H), 7.53-
Figure imgf000059_0002
7.61 (2H, d, Ar-H), 7.78-7.79 (IH, d, Ar-H), 8.99 (IH, s, -OH), 11.14 (IH, s, -NH); MS m/z: 482.1 (M+l). Ή NMR (DMSO-d6) 5(ppm): 2.81 (2H, t, -CH2), 3.83 (2H, s, -CH2), 4.75 (2H, s, -CH2), 6.68-6.69 (IH, d, =CH), 6.98-6.99 (IH, d, Ar-H), 7.00 (2Η, s, Ar-H), 7.21- 7.24 (2H, d, Ar-H), 7.42-7.45 (IH, m, Ar-H), 7.47 (2H,
Figure imgf000060_0001
d, Ar-H), 7.53-7.54 (IH, m, Ar-H), 7.56-7.61 (IH, m,
Ar-H), 9.03 (IH, s, -OH), 11.15 (IH, s, -NH); MS m/z: 439.1 (M+l).
Ή NMR (DMSO-d6) 6(ppm): 1.55- 1.77 (2H, d,- CH2), 2.95 (2H, m, -CH2), 3.84 (2H, t, -CH2), 4.63 (2H, brs, - CH2), 6.53 (IH, s, =CH), 6.96-7.15 (4H, m, Ar-H), 7.16- 7.2 (5H, m, Ar-H), 7.22-7.28 (3H, m, Ar-H), 7.54-7.73
(/ OH (IH, m, Ar-H), 8.99 (IH, s, -OH), 11.19 (IH, s, -NH);
MS m/z: 413.1 (M+l).
Ή NMR (DMSO-d6) 5(ppm): 2.66-2.67 (2H, d, -CH2), 3.73 (2H, s, -CH2), 4.73 (2H, s, -CH2), 5.19 (2H, s, - NH2), 6.27-6.30 (IH, t, Ar-H), 6.58 (IH, s, =CH), 6.66- 6.68 (IH, d, Ar-H), 6.75 (IH, s, =CH), 6.89-6.90 (IH, t, Ar-H), 7.11 (2H, brs, Ar-H), 7.20-7.24 (3H, m, Ar-H), 7.53-7.55 (IH, d, Ar-H), 7.60 (IH, s, Ar-H), 9.01 (IH, s, -OH), 11.14 (IH, s, -NH); MS m/z: 432.0 (M+l).
Ή NMR (DMSO-d6) 6(ppm): 2.84 (2H, brs, -CH2), 3.91 (2H, brs, -CH2), 4.79 (2H, brs, -CH2), 7.00-7.04 (IH, t, Ar-H), 7.11-7.13 (IH, d, =CH), 7.27 (IH, m, Ar-H), 7.33 (IH, m, Ar-H), 7.44-7.48 (4H, m, Ar-H), 7.53-7.55 (3H, m, Ar-H) 9.02 (IH, s, -OH), 11.15 (IH, s, -NH); MS m/z: 439.9 (M+l).
Ή NMR (DMSO-d6) 5(ppm): 2.78-2.81 (2H, t, -CH2), 3.82 (2H, s, -CH2), 4.74 (2H, brs, -CH2), 7.00-7.02 (IH, t, Ar-H), 7.15-7.17 (IH, d, =CH), 7.25-7.31 (4H, m, Ar- H), 7.41-7.43 (IH, m, Ar-H), 7.45-7.50 (2H, m, Ar-H), 7.54-7.55 (2H, m, Ar-H) 9.02 (IH, s, -OH), 11.15 (IH, s, -NH); MS m/z: 423.1 (M+l). Ή NMR (DMSO-d6) 5(ppm): 1.55-1.77 (2H, t,- CH2), 2.96 (2H, m, -CH2), 3.83 (2H, brs, -CH2), 4.62 (2H, brs, -CH2), 6.55 (IH, s, =CH) , 6.96-6.98 (2H, d, Ar-H), 7.12-7.21 (4Η, m, Ar-H), 7.23-7.31 (3H, m, Ar-H), 7.54-
Figure imgf000061_0001
7.72 (2H, m, Ar-H), 8.99 (IH, s, -OH), 11.18 (IH, s, - NH); MS m/z: 465.9 (M+l).
*H NMR (DMSO-de) 5(ppm): 1.55-1.77 (2H, t,- CH2), 2.96 (2H, m, -CH2), 3.83 (2H, brs, -CH2), 4.62 (2H, brs, -CH2), 6.55 (IH, s, =CH), 6.96-6.98 (2H, d, Ar-H), 7.12- 7.21 (4H, m, Ar-H), 7.23-7.31 (3H, m, Ar-H), 7.54-7.72 (2H, m, Ar-H), 8.99 (IH, s, -OH), 11.18 (IH, s, -NH);
Cl
MS m/z: 464.9 (M+l).
Ή NMR (DMSO-d6) 6(ppm): 0.51-0.57 (2H, t, -CH2), σ.63-0.67 (2H, t, - CH2) 2.75 (IH, m, -CH), 2.85 (2H, s, -CH2), 3.80 (2H, t, -CH2), 4.7-4.73 (2H, d, -CH2), 7.06- 7.08 (2H, d, =CH & Ar-H), 7.19-7.24 (5H, m, Ar-H), 7.27-7.36 (3H, m, Ar-H), 7.54-7.56 (IH, d, Ar-H), 7.82
Figure imgf000061_0002
(IH, s, Ar-H), 9.00 (IH, s, -OH), 11.13 (IH, s, -NH); MS m/z: 500.1 (M+l).
'H NMR (DMSO-d6) 5(ppm): 1.58- 1.79 (2H, t,- CH2), 2.98 (2H, m, -CH2), 3.86 (2H, brs, -CH2), 4.63 (2H, brs, -CH2), 6.61 (IH, s, =CH), 7.00-7.21 (8H, m, Ar-H), 7.32-7.35 (2H, m, Ar-H), 7.55-7.72 (2H, m, Ar-H), 8.99 (IH, s, -OH), 11.19 (IH, s, -NH); MS m/z: 446.93
Figure imgf000061_0003
(M+l).
Ή NMR (DMSO-d6) 5(ppm): 2.78-2.81 (2H, t, -CH2), 3.82 (2H, s, -CH2), 4.74 (2H, brs, -CH2), 6.96-6.98 (IH, m, Ar-H), 7.04 (IH, s, =CH), 7.17 (IH, d, Ar-H), 7.21 (IH, d, Ar-H), 7.39-7.44 (6H, m, Ar-H), 7.54-7.55 (IH,
Figure imgf000061_0004
m, Ar-H), 7.60 (IH, s, ArH), 9.07 (IH, s, -OH), 11.14
(IH, s, -NH); MS m/z: 405.9 (M+l). Ή NMR (DMSO-d6) 5(ppm): 2.82-2.85 (2H, t, -CH2), 3.82 (2H, s, -CH2), 4.74 (2H, brs, -CH2), 7.01-7.03 (IH, m, Ar-H), 7.11-7.12 (IH, s, =CH), 7.22 (IH, d, Ar-H), 7.27-7.29 (IH, t, Ar-H), 7.48-7.49 (3H, m, Ar-H), 7.54- — s o 0 7.56 (IH, m, Ar-H), 7.60 (IH, s, Ar-H), 7.68-7.69 (IH, m, Ar-H), 9.04 (IH, s, -OH), 11.14 (IH, s, -NH); MS m/z: 410.9 (M+l).
Ή NMR (DMSO-de) 5(ppm): 2.77 (2H, t, -CH2), 3.71 (3H, s, -OCH3), 3.78 (2H, s, -CH2), 4.73 (2H, brs, -CH2), 6.96-7.01 (4H, m, =CH & Ar-H), 7.17-7.18 (2H, m, Ar- H), 7.20-7.22 (2H, d, Ar-H), 7.33-7.39 (IH, d, Ar-H), 7.53-7.55 (IH, m, Ar-H), 7.60 (IH, s, Ar-H), 9.07 (IH, s, -OH), 11.14 (IH, s, -NH); MS m/z: 434.9 (M+l).
1H NMR (DMSO-d6) 6(ppm): 2.25 (3H, s, -CH3), 2.77 (2H, t, -CH2), 3.80 (2H, s, -CH2), 4.73 (2H, brs, -CH2), 6.96-6.99 (2H, m, =CH & Ar-H), 7.16-7.17 (IH, m, ArH), 7.20-7.22 (IH, d, Ar-H), 7.24-7.26 (2H, d, Ar-H),
0 0 7.30-7.32 (2H, d, Ar-H), 7.38-7.39 (IH, d, Ar-H), 7.53- 7.55 (IH, d, ArH), 7.59 (IH, s, ArH), 9.07 (IH, s, -OH), 1 1.14 (IH, s, -NH); MS m/z: 418.9 (M+l).
Ή NMR (DMSO-de) 5(ppm): 2.70-2.85 (2H, m, -CH2),
F 3.80 (2H, s, -CH2), 4.73 (2H, s, -CH2), 6.75 (IH, s,
=CH), 6.87-6.89 (IH, d,Ar-H), 6.95-6.97 (IH, d, Ar-H), 7.03-7.07 (IH, t, Ar-H), 7.20-7.21 (IH, m, Ar-H), 7.24- 7.27 (3H, m, Ar-H), 7.31-7.36 (3H, m, Ar-H), 7.53-7.55
O 0
(IH, d, Ar-H), 7.60 (IH, s, Ar-H), 9.01 (IH, s, -OH), 11.14 (IH, s, -NH); MS m/z: 417.0 (M+l).
Ή NMR (DMSO-de) 5(ppm): 2.24 (3H, s, -CH3), 2.67- 2.71 (2H, t, -CH2), 3.79 (2H, s, -CH2), 4.74 (2H, s, - CH2), 6.74 (IH, s, =CH) 7.06-7.12 (6H, m, Ar-H), 7.16-
O 0 7.21 (4H, m, Ar-H), 7.53-7.58 (2H, m, Ar-H), 9.01 (IH, s, -OH), 11.13 (IH, s, -NH); MS m/z: 413.0 (M+l).
Figure imgf000063_0001
Figure imgf000064_0001
>H NMR (DMSO-d6) 6(ppm): 3.10-3.14 (2H, t, -CH2),
4.08-4.12 (2H, t, -CH2), 7.01 (IH, s, =CH), 7.07-7.12 (2H, m, Ar-H), 7.18-7.2 (2Η, m, Ar-H), 7.32-7.34 (2H,
85
m, Ar-H), 7.36-7.41 (3H, d, Ar-H), 7.62-7.64 (2H, d, Ar- H), 8.0 (IH, s, Ar-H), 8.98 (IH, s, -OH), 11.13 (IH, s, - NH); MS m/z: 403.2 (M+l).
Ή NMR (DMSO-d6) 6(ppm): 2.67 (2H, brs, -CH2), 3.84 (2H, s, -CH2), 4.59 (2H, s, -CH2), 6.79 (IH, s,
86 =CH), 7.05-7.16 (4H, m, Ar-H), 7.29-7.36 (6H, d, Ar- H), 9.08 (IH, s, -OH), 11.13 (IH, s, -NH); MS m/z: 422.9 (M+l).
Ή NMR (DMSO-d6) 5(ppm): 2.3 (3H, s, -CH3), 2.67 (2H, brs, -CH2), 3.83 (2H, s, -CH2), 4.59 (2H, s, -CH2),
87 6.73 (IH, s, =CH), 7.16-7.21 (6H, d, Ar-H), 7.31 (3H, s,
Ar-H), 7.31 (IH, s, Ar-H), 9.08 (IH, s, -OH), 11.13 (IH, s, -NH); MS m/z: 419 (M+l).
!H NMR (DMSO-d6) 5(ppm): 2.31 (3H, s, -CH3), 2.69 (2H, brs, -CH2), 3.82 (2H, s, -CH2), 4.59 (2H, s, -CH2), 6.74 (IH, s, =CH), 6.91-6.98 (2H, m, Ar-H), 7.02 (IH,
88
d, Ar-H), 7.04-7.07 (4H, m, Ar-H), 7.19-7.29 (IH, m, Ar-H), 7.39 (IH, brs, Ar-H), 9.08 (IH, s, -OH), 11.13 (IH, s, -NH); MS m/z: 436.9 (M+l).
Ή NMR (DMSO-d6) 6(ppm): 2.84-2.93 (2H, t, -CH2), 3.88 (2H, s, -CH2), 4.82-4.90 (2H, d, -CH2), 7.07-7.12 JL (2H, m, =CH & Ar-H), 7.22-7.35 (6H, m, Ar-H), 7.48
89
(IH, s, Ar-H) 7.56-7.58 (3H, d, Ar-H), 7.66-7.68 (2H, m, o o Ar-H), 7.79-7.83 (IH, t, Ar-H), 9.01 (IH, s, -OH), 11.15
CI (IH, s, -NH); MS m/z: 483.1 (M+l).
Ή NMR (DMSO-d6) 5(ppm): 2.76-2.95 (2H, d, -CH2), 3.89 (2H, s, -CH2), 4.63-4.85 (2H, t, -CH2), 6.78 (IH, s,
90
=CH), 6.98-7.14 (2H, m, Ar-H), 7.18-7.26 (2H, m, Ar- H), 7.35-7.47 (3H, m, Ar-H), 7.56-7.61 (2H, brs, Ar-H),
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
s, - 3.84
3.66 Ar-
8.34
-
Figure imgf000072_0001
Figure imgf000073_0001
Ar-
3.60
-
(IH,
s, d, Ar-
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
H), 7.18-7.20 (2H, d, Ar-H), 7.23-7.27 (3H, t, Ar-H &
=CH), 7.69-7.70 (1H, d, -NH), 8.68 (2H, s, Ar-H), 9.03 (1H, s, -OH), 1 1.10 (1H, s, -NH); MS m/z: 527.2 (M+l).
Ή NMR (DMSO-d6) 6(ppm): 0.65 (2H, s, -CH2), 0.66 (2H, d, -CH2), 2.73-2.77 (1H, m, -CH), 3.39 (1H, s, -NCH2), 3.64 (2H, brs, -NCH2), 3.83-4.03 (5H, brs, -
Λ 0 Η'0Η NCH2) 7.05-7.07 (2H, d, Ar-H), 7.15-7.18 (2H, m, Ar-
151
H), 7.23-7.25 (3H, d, Ar-H), 7.38-7.40 (3H, m, Ar-H & =CH), 7.79-7.80 (1H, d, -NH) 8.68 (2H, s, Ar-H), 9.02 (1H, brs, -OH), 1 1.10 (1H, s, -NH); MS m/z: 513.2 (M+l).
1H NMR (DMSO-d6) 5(ppm): 2.92 (3H, s, -CH3), 2.99 (3H, s, -CH3), 3.39 (2H, brs, -NCH2), 3.66 (2H, brs, - NCH2), 3.85(4H, brs, -NCH2), 6.73 (1H, s, =CH), 7.13-
152
7.23 (4H, m, Ar-H), 7.30-7.32 (4H, d, Ar-H), 8.69 (2H, s, Ar-H), 9.03 (1H, s, -OH), 1 1.10 (1H, s, -NH); MS m/z: 519.1(M+1).
lH NMR (DMSO-d6) 5(ppm): 0.52-0.529 (2H, m, -CH2), 0.64-0.65 (2H, m, -CH2), 2.74-2.75 (1H, m, -CH), 2.74 (2H, brs, -CH2), 3.65 (2H, brs, -NCH2), 3.83 (4H, brs, -
153 NCH2), 7.08-7.10 (2H, d, Ar-H), 7.14-7.18 (3H, m, Ar-
Figure imgf000077_0001
H), 7.27-7.29 (2H, d, Ar-H ), 7.44 (2H, s, Ar-H), 7.98- 7.98 (1H, d, -NH) 8.65-8.68 (2H, brs, Ar-H), 9.03 (1H, s, -OH), 1 1.1 (1H, s, -NH); MS m/z: 531.1 (M+l).
Example 154: 2-(2-(4-Fluorophenyl)-3-phenylallyl)-N-hydroxy-l,2,3,4-tetrahydro isoquinoline-7-carboxamide
Figure imgf000077_0002
Step A: 2-(4-fluorophenyl)-3-phenylprop-2-en-l-ol
To a solution of 2-(4-fluorophenyl)-3-phenylacrylic acid (1.5 g, 6.1 mmol) in
THF (10 mL) was added triethylamine (1 mL, 7.4 mmol), followed by the addition of ethyl chloroformate (0.8 g, 7.4 mmol) in THF (5 mL) over a period of 30 minutes at 0 °C. The stirring was continued at same temperature. On completion of the reaction sodium borohydride (0.28 g, 7.4 mmol) was added slowly. Methanol (30 mL) was added to the reaction mixture stirred at room temperature for 1 hour. Cold water (100 mL) was added and the mixture extracted with ethyl acetate (2 x 200 mL). The organic layer was washed with 50 mL of brine solution, dried over anhydrous sodium sulphate and concentrated under vacuum to get the crude material. This was further purified by column chromatography using n-hexane and ethyl acetate solvent mixture to get the pure title compound (0.5 g, 36 %).
Step B: 2-(4-fluorophenyl)-3-phenylallyl methanesulfonate
To a solution of 2-(4-fluorophenyl)-3-phenylprop-2-en-l-ol (0.5 g, 4.3 mmol) in DCM (10 mL), triethylamine (0.6 mL, 4.4 mmol was added, followed by the slow addition of methanesulfonyl chloride (0.2 mL, 2.6 mmol) at 0-5 °C. The reaction mixture was slowly warmed to room temperature and stirring continued for 1 hour. The reaction was quenched with water and extracted with DCM. The organic layer was washed with 10% cone. HC1 solution, water, followed by saturated sodium bicarbonate solution. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to get the crude title product (0.4 g, 61 %).
Step C: Methyl 2-(2-(4-fluorophenyl)-3-phenylallyl)-l,2,3,4-tetrahydroisoquinoline-7- carboxylate
To a solution of 2-(4-fluorophenyl)-3-phenylallyl methanesulfonate (0.4 g, 1.3 mmol) in DMF (10 mL) was added K2C03 (0.53 g, 3.9 mmol) followed by methyl l,2,3,4-tetrahydroisoquinoline-7-carboxylate (0.25 g, 1.3 mmol) and the reaction mixture was stirred at room temperature for 4 hours. To this cold water (100 mL) was added and extracted with ethyl acetate (2 x 100 mL). The organic layer was washed with brine solution, dried over anhydrous sodium sulphate, and concentrated under vacuum to get the crude product, which was further purified by column chromatography using n-hexane and ethyl acetate solvent mixture to get the pure title compound (0.35 g, Yield 57 %).
Step D: 2-(2-(4-Fluorophenyl)-3-phenylallyl)-N-hydroxy-l,2,3,4-tetrahydro isoquinoline-7-carboxamide
According to procedure given in example 1, step II, Methyl 2-(2-(4- fluorophenyl)-3-phenylallyl)- 1 ,2,3,4-tetrahydroisoquinoline-7-carboxylate was converted to title compound (0.2 g, 57 %). 1H NMR (DMSO-d6) 6(ppm): 2.74-2.76 (2H, t, -CH2), 2.78-2.79 (2H, d, -CH2), 3.48 (2H, s, -CH2), 3.64 (2H, s, -CH2), 6.72 (1H, s, =CH), 6.96-6.97 (2H, d, Ar-H), 7.11-7.17 (6H, m, Ar-H), 7.24-7.28 (2H, m, Ar- H), 7.46-7.51 (2H, m, Ar-H), 8.97 (1H, s, -OH), 11.1 (1H, s, -NH); MS m/z: 403.1 (M+l).
Example 155: N-(2-Aminophenyl)-2-(2,3-diphenylacryloyl)-l,2,3,4-tetrahydro isoquinoline-7-carboxamide
Figure imgf000079_0001
Step-I: 2-(2,3-Diphenylacryloyl)-l,2,3,4-tetrahydroisoquinoline-7-carboxylic acid To a solution of 2-(2,3-Diphenylacryloyl)-l,2,3,4-tetrahydroisoquinoline-7- carboxylic acid methyl ester (0.300 g, 0.7 mmol) in methanol (15 mL) was added aqueous LiOH (0.090 g, 3.7 mmol in 2 mL of water) solution. The reaction mixture was stirred at room temperature for 4 hours and diluted with 100 mL of cold water.
The pH of the reaction mixture was adjusted to 2 with dilute aqueous HCl and allowed to stand at 4 °C for 30 minutes. The resulting precipitate was filtered and dried under vacuum to give the pure title compound as a colourless solid (0.250 g, Yield 87.10 %).
Step-II: N-(2-Aminophenyl)-2-(2,3-diphenylacryloyl)-l,2,3,4-tetrahydroisoquinoline-
7-carboxamide
To a solution of 2-(2,3-Diphenylacryloyl)-l,2,3,4-tetrahydroisoquinoline-7- carboxylic acid (0.200 g, 0.52 mmol) in DMF (5 mL) was added EDCI (0.198 g, 1.04 mmol), HOBt (0.028 g, 0.20 mmol), (9-phenylenediamine (0.109 g, 1.04 mmol), followed by DIEA (0.259 mL, 1.56 mmol). The reaction mixture was stirred for 3 hours at room temperature and added to cold water (50 mL) and extracted with ethyl acetate (2 x 150 mL). The organic layer was washed with water (2 x 80 mL), brine solution (1 x 100 mL), dried over anhydrous Na2S04 and concentrated to give crude compound. The crude yellow coloured compound was triturated with diethyl ether (20 mL) to afford the pure title compound as a colourless solid (0.080 g, yield 32.65 %). Ή NMR (DMSO-de) 5(ppm): 2.67-2.73 (2H, m, -CH2), 3.82 (2H, t, -CH2), 4.79 (4H, d, -CH2 & NH2), 6.57 (1H, s, =CH), 6.76-6.78 (2H, m, Ar-H), 6.94-6.98 (1H, m, Ar- H), 7.14-7.21 (6H, m, Ar-H), 7.31-7.34 (6H, m, Ar-H), 7.76-7.85 (2H, m, Ar-H), 9.59 (1H, s, -NH); MS m/z: 474.1 (M+l). The following compounds were prepared according to the procedure given in Example 155.
Figure imgf000080_0001
Comparative Examples:
Figure imgf000080_0002
HDAC assay and other experimental methods
HDAC 1 & 6 Assays:
The Histone Deacetylase (HDAC) inhibitory activity of molecules to specific isoforms (rhHDACl or rhHDAC6) were assayed with Boc-Lys (q-Ac)-AMC substrate, (Bachem 1-1875) which has been previously described as a small -molecule screening method for HDAC enzymes in vitro. The total HDAC assay volume was 100 /L and the assay components were diluted in HDAC buffer (50 mM Tris-HCl, 137 mM NaCl, 2.7 mM KCl and 2 mM MgCl2, pH 8.0). The reaction was carried out in black 96-well plates (Nunc). In brief, the HDAC assay mixture contained HDAC substrate (37.5 μΜ, 40 μΐ,), rhHDACl or rhHDAC6 enzymes (final concentration 30 μξ, diluted to 10 //L final volumes) and inhibitor (2X, the required assay concentration, diluted to 50 μί, final volume). For HDAC1 inhibitory activity, the assay components were incubated at 37 °C for 3 Hours, whereas for HDAC6 the components were incubated for 1 hour. Positive control termed as total activity (TA) contained all the above components except the inhibitor. The negative control or blank contained neither enzyme nor inhibitor. In each case inhibitor volumes were replaced with an equivalent volume of buffer. Following incubation, the reaction was quenched with the addition of 100 of trypsin (10 mg/mL) stop solution containing 2 μΜ Trichostatin A (TSA). The plates were incubated for 15 minutes at 37 °C to allow the fluorescence signal to develop. The fluorescent signal was detected by fluorometer (GeminiXS; Molecular Devices) at 360 nm excitation, 460 nm emission, and cut off at 435 nm for both rhHDACl and for rhHDAC6. The ICso values of the test compounds (disclosed herein) were computed by analyzing dose-response inhibition curves (Graph Pad prism, 4) (Bonfils C, et al., Clinical Cancer Research, 2008, 14, 3441 - 3449).
As detailed above, some of the test compounds were screened for HDAC6 enzyme inhibitory activity. The compounds whose IC50 values in the range of less than 1 nM to 50 nM are 1, 4, 5, 6, 7, 8, 9, 10, 12, 11, 14, 17, 19, 20, 21, 22, 23, 24, 25, 29, 32, 43, 44, 45, 46, 48, 49, 52, 53, 54, 55, 59, 62, 64, 69, 70, 71, 72, 76, 77, 78, 80, 85, 87, 88, 28, 86, 152 and 153.
A few of the compounds showed greater than 2000 fold selectivity for HDAC6 over HDAC1. In another embodiment some of the compounds showed greater than 1000 fold selectivity for HDAC6 over HDAC1. Several compounds have greater than 100 fold selectivity for HDAC6 over HDAC 1.
Anticancer Activity:
Cell Viability screening:
The test compounds were screened in ten cancer cell lines for cell viability using Sulforhodamine B (SRB) cell viability assay (Vichai V. et al., Nature Protocols, 2006, 1(3), 1112-1116) and CCK8 assay. The cell lines - MCF7 and MDA MB231 (human breast cancer cell lines), NCIH460 (human lung cancer cell line), HCT116 (human colon cancer cell line), PC3 (human prostate cancer cell line), HT1080 (human fibrosarcoma cell line) were maintained in Dulbecco's modified eagle's medium (DMEM) and the multiple myeloma cell lines (U266B 1, RPMI8226, NCIH929 & MM. IS) were maintained in RPMI 1640 medium containing 10 % foetal bovine serum. 96-well microtiter plates were inoculated with cells in 50 μΐ. of cell culture media (6 x 104 cells/mL) for 24 hours at 37 °C, 5 % C02, 95 % air and 100 % relative humidity. Separate plate with these cell lines was also inoculated to determine cell viability before the addition of the test compounds (T0). For multiple myeloma cell lines, drug addition can be performed immediately after seeding of cells.
Addition of experimental drugs:
Following 24 hours incubation, test compounds were added to the plates in triplicates with appropriate dilutions along with the cytotoxic standard and control (untreated) wells. Test compounds were dissolved in dimethyl sulfoxide (DMSO) to prepare 100 mM stock solutions on the day of drug addition and serial dilutions were carried out in complete growth medium at 5x strength such that 50 iL added to wells gave final concentrations of 0.0064, 0.032, 0.16, 0.8, 4, 20 and 100 uM in the well. The plates were then incubated for 72 hours at 37 °C, 5 % C02, 95 % air and 100 % relative humidity.
End-point measurement:
For To measurement (24 hours after seeding the cells) 100 μΐ, of ice-cold trichloroacetic acid (TCA) was added to all the wells to precipitate proteins. The plates were incubated at 4 °C for 60 minutes. The plates were washed 4 times under running tap water taking care not to dislodge the cells with a direct stream of water. The plates were tapped dry and 50 μΐ,, of 0.057 % (w/v in 1 % acetic acid) SRB solution was added to each well. The plates were incubated at room temperature for 30 minutes in dark and then rinsed four times with 200 μΜ 1 % acetic acid to remove unbound dye. The plates were blot dried on a paper towel. 200 of 10 mM Tris base was added to each well. The plates were kept on a shaker to solubilise the protein bound dye and absorbance was measured at 530 nm in a spectrophotometer. The plates treated with test compounds for 72 hours were also processed in an identical manner.
CCK8 assay for multiple myeloma:
For To measurement, 10 μ]_, of CCK8 was added to each of the wells and kept in the incubator for 90 minutes and absorbance was measured at 450 nm. The plates containing cells that were treated for 72 hours were also processed in an identical manner. Calculation of GI50, TGI and LC50:
Percent growth (PG) was calculated relative to the control and zero measurement wells (T0) as followsj.
PG = (OD530test - OD530T0) / (OD530control - OD530T0) x 100 (If OD530test > OD530T0)
PG = (OD530test - OD530T0) / (OD530T0) x 100 (If OD530test < OD530T0).
PG values were plotted against drug concentration to derive the following:
1. GI50: the concentration required to decrease PG by 50 % vs control
As detailed above, some of the compounds were screened for cell viability. The results obtained were tabulated in Table 1.
Table 1 : Cell Viability
Fibro Colon Lung Prostate
Human Myeloma Cells Breast cancer
sarcoma cancer cancer cancer
U266 RPMI NCI MDA- HCT NCIH
MM. l HT1080 MCF7 PC3 B l 8226 H929 MB-231 116 460
S (μΜ) (μΜ) (μΜ) (μΜ) (μΜ) (μΜ) (μΜ) (μΜ) (μΜ) (μΜ)
GI50 GI50 GI50 GIso GI50 GIso GIso GIso GIso GIso
16.68 23.36 21.74 — 57.7 1 1.02 7.9 - — -
5.54 21.16 18.95 - 3.7 10.04 - - - -
4.51 4.4 5.33 - 6 7.8 6.9 - - -
0.13 23.52 17.12 - 4.6 - - - - -
0.016 7.56 19.79 - 4.2 - -
4.2 5.2 21.2 - 3.4 - -
3.8 3.9 0.92 - 4.7 17 13.2 4.8 1 1 .1
0.67 13.37 19.37 - 4.3 - - - -
>100 13.93 0.002 - 5.23 - - - - -
4.77 0.105 40.03 - 12.3 - - - - -
0.89 >100 6.45 - 4.7 - - - - -
7.47 2.16 13.79 - 11.7 - - - - -
1.79 0.19 21.29 - 4.8 - - - - -
24.77 18.63 17.66 - 20.2 - - -
17.31 5.07 4.89 - 7.2 - - -
2.41 5.03 4.97 - 8.5 18.1 22.9 - - -
49.07 40.8 19.13 - 27.6 - - - - -
0.28 6.13 4.1 - 3.7 7.2 - -
0.22 10.23 4.79 - 3.5 18.7 -
0.4 4.02 1.31 - 1.4 4.5 5.8 7 4.43 2.76
0.13 0.8 0.66 - 4.5 1.1 9.7 15.8 19.6
4.22 5 1.66 1.2 6.7 3.9 4.7 4.24 8.31
0.92 0.9 1.33 1.1 7.6 5.2 5.4 4.65 8.72 9.71 7.76 13.46 - 23.5 — — — —
17.29 1.29 4.94 - 16.5 7 — — —
4.32 1.25 3.92 13.5 19.7 1.1.4 — — —
3.88 1.17 2.63 6.9 5.5 8.4 — — —
11.58 3.5 3.1 2.43 - 6.4 10.4 - — ■ —
4.32 2.8 3.51 3.28 - 5.9 11.7 — — —
7.31 3.1 5.6 3.94 — 3.9 19.1 — — —
9.34 1.5 1.9 0.01 - 4.0 9.1 — — —
21.87 2.8 3.43 2.5 - 10.0 19.9 - — .—
6.18 1.1 3.65 4.07 - 7.5 21.0 — —
34.55 1.4 3.54 11.84 - 19.0 21.5 — —
— — — - — — - 0.62 0.67 —
— — — — — — - 0.75 0.9 —
— - - - - - - 0.65 0.7 -
— — — - - - - 1.2 1 -
— — — — - 3 7 —
- - - - 9 3 -
Not done
CNS Protection: Measurement of cytotoxicity by using LDH Assay:
PC- 12 (pheochromocytoma), a semi suspension cells were seeded in Poly -D Lysine coated plate and incubated overnight at 37 °C and 5% C02. After 24 hours, the cells were treated with test compounds along with 3-Nitropropionic acid and kept for 48 hours incubation at 37 °C, 5% C02. Lactate dehydrogenase (LDH) in the cell supernatant was estimated using an LDH kit for cytotoxicity (Roche, Cat. No.11644793001). To determine the LDH activity of supematants, 100 reaction mixture was added to each well and incubated for 30 minutes at 25 °C and the absorbance of the samples measured at 490 nm. The results obtained were tabulated below.
Table 2: CNS Protection
Figure imgf000084_0001
RAW 264.7 (Macrophages) - TNF-a protocol:
RAW 264.7 cells were seeded in a 24 well plate and incubated for 48 hours. After 48 hours, the cells were treated with various concentrations of the test compounds for 24 hours followed by lipopolysaccharide (LPS) stimulation (10 ng/mL) for 3 hours. TNF-a in the cell supernatant was estimated using an ELISA kit (R&D Systems) as per manufacturer's instructions.
RAW 264.7 (Macrophages) - IL-6 protocol:
RAW 264.7 cells were seeded in a 24 well plate and incubated for 48 hours. After 48 hours the cells were treated with various concentrations of the test compounds for 24 hours followed by LPS stimulation (100 ng/mL) for 3 hours. IL-6 in the cell supernatant was estimated using an ELISA kit (R&D Systems) as per manufacturer's instructions.
THP1 (Macrophages) - TNF-a protocol:
THP1 cells were seeded in a 24 well plate along with phorbol myristate acetate (PMA) (32 nM) and incubated for 24 hours. After 24 hours, the media were changed and cells were incubated for another 24 hours. Then cells were treated with various concentrations of the test compounds for 24 hours followed by LPS stimulation (10 ng/mL) for 4 hours. TNF-a in the cell supernatant was estimated using an ELISA kit (R&D Systems) as per manufacturer's instructions.
THP1 (Macrophages) - IL-6 protocol:
THP1 cells were seeded in 24 well plates along with PMA (32 nM) and incubated for 24 hours. After 24 hours media were changed and cells were incubated for another 24 hours. Then cells were treated with various concentrations of the test compounds for 24 hours followed by LPS stimulation (100 ng/mL) for 8 hours. IL-6 in the cell supernatant was estimated using an ELISA kit (R&D Systems) as per manufacturer's instructions.
In vitro metabolic stability in liver microsomes:
Metabolic stability is defined as the percentage of parent compound lost over time in the presence of liver microsomes, liver S9, or hepatocytes, depending on the goal of the assay. By understanding the metabolic stability of compounds early in discovery, compounds can be ranked for further studies, and the potential for a drug candidate to fail in development as a result of pharmacokinetic reasons may be reduced. The stock solutions of test compound were prepared using DMSO or water. Incubation of reaction mixture including cryopreserved mouse or human liver microsomes (1 mg/mL), test compound (50 μΜ), and nicotinamide adenine dinucleotide phosphate (NADPH) for different time points, e.g. 10, 15, 30, and 60 minutes or single time points, e.g. 60 minutes. Reaction is started by the addition of NADPH and stopped either immediately or after 60 minutes for screening assay or at 5, 15, 30 and 60 minutes for a more precise estimate of clearance by addition of ice- cold acetonitrile, followed by sample preparation. Determination of loss of parent compound (compared to zero time point control and/or no NADPH-control) was done using HPLC or LC-MS methods. Metabolism was expressed as percentage of test compound metabolized after a certain time. A marker reaction and marker substrate (e.g. testosterone) was employed as quality criteria of the metabolic capability of the microsomes. (Rodrigues, A.D., et al. Biochemical Pharmacology, 1994, 48(12): 2147- 2156). Metabolic stability was expressed as % metabolism of the compound after 30 minutes of incubation in the presence of active microsomes. Compound that had a % metabolism less than 30 % were defined as highly stable. Compound that had a metabolism between 30 % and 60 % were defined as moderately stable and compounds that showed a % metabolism higher than 60 % were defined as less stable. Some of the test compounds were found to be moderately stable.
Protein binding assay:
Dialysis membranes (Cellulose acetate membranes with 12,000-14,000 molecular weight cut-off) were charged by serially wetting in distilled water and distilled water containing 20 % ethanol for 60 and 20 minutes, respectively. Charged dialysis membranes were rinsed with distilled water three times and stored in isotonic sodium phosphate buffer until use. The 96-well dialysis apparatus was assembled by following the manufacturers instructions using the charged membranes 0.15 mL of sodium phosphate buffer (pH 7.4) was placed on the dialysate side of each well and 0.15 mL of plasma spiked with the test compound (predetermined concentrations) on the other side, and the plate was completely sealed with adhesive membrane and incubated in a shaking dry incubator preset at 100 rpm at 37 °C to equilibrate for 8 hours (as determined previously). All samples were incubated in triplicates at predetermined concentrations. At the end of equilibration time, the volume of plasma and the buffer was measured for each well. 80 of plasma and the buffer was diluted with an equal volume of acetonitrile and centrifuged for 10 minutes to precipitate the proteins. The supernatant was analyzed using HPLC. The test compound shows moderate plasma protein binding.
Pharmacokinetics and BBB permeability studies of test compounds:
Three separate sets of mice were administered orally with the test compounds at dose level of 50 mg/kg to check for its oral availability. Sample collection was staggered such that each time point resulted in n=3 to allow for minimal sampling volumes from each animal. Blood was collected at the specified time points post dosing using retro orbital bleeding method. Plasma was separated from the blood by centrifugation at 9,000 g for five minutes and processed by protein precipitation method using acidified organic solvent (0.1 % formic acid in acetonitrile). The processed samples were analyzed by the HPLC method. Following single oral administration of 50 mg/kg, some of test compounds were orally available with a Cmax of around 0.35 mg/L and the concentration was observed upto 1.5 hours.
In addition, the test compounds were administered to separate sets of two animals for each time point at 15 mg/kg dose intravenously to check for its blood-brain barrier permeability. Cerebrospinal fluid (CSF) was collected by direct cisterna-magna (CM) puncture at the specified time points from anesthetized rats.
Following CSF collection, blood was collected immediately from same animal using retro orbital bleeding method in heparinized microfuge tubes. Plasma was separated from the blood by centrifugation at 9,000 g for five minutes. Following blood collection, animals were sacrificed and brain samples were isolated and collected in labelled microfuge tubes. Brain samples were homogenized with phosphate buffered saline buffer (pH-7.4). Plasma and brain homogenate samples were processed by protein precipitation method using organic solvent (acetonitrile) and CSF samples were injected directly into HPLC.
Maximum tolerated dose determination:
Maximum tolerated dose determination was carried out using 6-7 weeks old female severe combined immunodeficient (SCID) mice. The mice were housed in individually ventilated cages (IVC), maintained in 12 hours light dark cycle with standard laboratory chow diet and water ad libitum in controlled room temperature (22 + 3 °C) and humidity (50 ± 20 %). The animals were grouped based on body weight and treated with test compound at 50 mg/kg i.p for seven days. After the treatment period, the animals were observed for 14 days, during which body weight and clinical symptoms were recorded. Mean changes in body weight was calculated as compared to the control. On the day of termination, the animals were sacrificed using C02 asphyxiation and gross pathological examination carried out. Organs of interest were collected and subjected to histopathological analysis.
Xenograft Study:
The experiment was carried out using 6-7 weeks old female SCID mice. The mice were housed in IVC, maintained in 12 hours light dark cycle with standard laboratory chow diet and water ad libitum in controlled room temperature (22 + 3 °C) and humidity (50 ± 20 %). Tumors rose from cells obtained from ATCC, USA and maintained in vivo by subcutaneous (s.c.) passage of tumor fragments (-30 mg) in healthy mice according to standard reporting procedures. Each experimental group included 6-8 mice bearing s.c tumors. Tumors were implanted into the auxiliary region using precision trochar and tumor growth was monitored by measuring diameters with a vernier caliper. Tumor volume (TV) was calculated according to the formula:
TV (mm3) = LW2 / 2
L and W are the longest diameter and shortest diameter of the tumor respectively.
The compound treatment started when tumors were palpable (-100 mm3). Test compound was administered by per oral or by intra peritoneal once daily for a period of 21 days. Control mice were administered with vehicle at equivalent volume. Tumor size was measured twice a week and body weight taken daily prior to dosing. Parameters such as survival, change in the tumor volume, body weight and clinical symptoms were observed and recorded. Test compound efficacy was assessed by calculating tumor volume with respect to vehicle control
T/C % = (1-TVtreatment / TV control) X 100
On day of termination, the animals were sacrificed and gross pathological examination was carried out. Tumor samples, organs of interest were collected and subjected to histopathological analysis and Target modulations. The tumor bearing animals (RPMI-8226 Xenograft) treated with test compound showed reduction in tumor volume as compared to untreated control. In vivo Inhibitory activity in Atopic Dermatitis Model
Oxazolone induced dermatitis in mice was performed using the protocol described in Tamura T., et al., European Journal of Pharmacology, 2005, 524, 149- 154. Balb/C mice were acclimatized to laboratory conditions five to seven days prior to the start of the experiment. They were randomly distributed to various groups based on body weight. The abdomen of animals was shaved using a small animal clipper. All the animals were sensitized with 15 % oxazolone by application to the clipped abdomen (20 μί,) 7 days before challenge. On 7th day, the animals were challenged with 2 % oxazolone at the ears (20 uL per ear). Test compounds were applied over the ears of sensitized mice 30 minutes before and 4 hours after challenge. Before challenge (0 hour) and again post-challenge at 4 and 24 hours, the ear thickness was measured using a thickness gauge. Animals were sacrificed after 24 hours and ears collected by punch biopsy for ear weight and histopathology. Percent reduction in the ear thickness and ear weight was calculated using the following equation.
Ear thickness =^ar thick*1658 in Oxazolone group - Ear thickness in Treatment group
Ear thickness in Oxazolone group - Ear thickness in Vehicle group
Ear weight in Oxazolone group - Ear weight in Treatment group % Ear Weight = "
Ear weight in Oxazolone group - Ear weight in Vehicle group Table-3: Inhibitory activity in Atopic Dermatitis
Figure imgf000089_0001
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, make various changes and modifications of the invention to adapt it to various usages and conditions.

Claims

We claim:
1. A compound of formula (I),
Figure imgf000090_0001
their derivatives, analogs, tautomeric forms, stereoisomers, geometrical isomers, diastereomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, metabolites, intermediates and prodrugs thereof;
wherein A represents
Figure imgf000090_0002
;
Ar represents substituted or unsubstituted groups selected from (C6-Cu)aryl, 5- 15 membered heterocyclyl and 5-15 membered heteroaryl;
Ar1 represents optionally substituted groups selected from (C6-Ci4)aryl, 5-15 membered heterocyclyl and 5-15 membered heteroaryl;
Ar2 represents substituted or unsubstituted groups selected from (Q- C6)alkylene, (C6-Ci4)arylene and 5-15 membered heteroarylene;
B represents hydrogen, -COOR1, -CONR'R2, -CHZNR'R2, -CH2OR', -CH2OCONR1R2, -CH^NR^OR2 or substituted or unsubstituted groups selected from (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci4)aryl and (C3-Ci2)cycloalkyl;
B1 represents hydrogen, -COOR1, -CONR'R2, -CHSN^R2, -CH20R1, -CH20C0NR1R2, -CHi-NR'COR2 or substituted or unsubstituted groups selected from (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci4)aryl and (C3-Ci2)cycloalkyl;
D represents hydrogen, -COOR1, -CONR'R2, -CH2NR1R2, -CH20R1,
-CH20C0NR'R2, -CI^NR^OR2 or substituted or unsubstituted groups selected from (C C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci4)aryl and (C3-C]2)cycloalkyl;
R1 represents hydrogen or substituted or unsubstituted groups selected from (Ci-C6)alkyl, (C3-Ci2)cycloalkyl, 5-15 membered heterocyclyl, (C6-C14)aryl, (C6- Ci4)ai l(Ci-C6)alk l, (C6-Ci4)aryl(C2-C6)alkenyl, (C6-Ci4)aryl(C2-C6)alkynyl, 5-15 membered heteroaryl, 5-15 membered heteroary^C Csialkyl, 5-15 membered heteroaryl(C2-C6)alkenyl and 5-15 membered heteroaryl(C2-Ce)alkynyl;
R2 represents hydrogen or substituted or unsubstituted groups selected from (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-Ci2)cycloalkyl, 5-15 membered heterocyclyl, (C6-C14)aryl, (C6-Ci4)aryl(Ci-C6)alkyl, (C6-Ci4)aryl(C2-C6)alkenyl, (C6- C14)aryl(C2-C6)alkynyl, 5-15 membered heteroaryl, 5-15 membered heteroaryl(Cj- C6)alkyl, 5-15 membered heteroaryl(C2-Ce)alkenyl and 5-15 membered heteroaryl(C2- C6)alkynyl;
or R1 and R2 combine together to form substituted or unsubstituted 3-7 membered ring having 0-3 heteroatoms selected from O, S and N;
when one of B1 or D is hydrogen or unsubstituted alkyl, the other is neither of hydrogen nor of unsubstituted alkyl;
X represents a bond, -CO-, -S02-, -CS-, -CH2-, -CONR3-, -CONR3CH2-, -CH2OCO-, -CONR3CO-, -CH2NR3CO, -CH2NR3- or -CH2NR3CH2-; wherein R3 represe -C6)alkyl or (C3-Ci2)cycloalkyl; bstituted or unsubstituted groups selected from,
Figure imgf000091_0001
W, W1, W2, W3 and W4 independently represents C or N;
W5 represents O, S or N; W6 represents C or N;
ring Q1 is substituted or unsubstituted 4 to 8 membered heterocyclyl ring;
R4 represents hydrogen, halogen, hydroxy, nitro, amino, cyano or substituted or unsubstituted (Ci-C6)alkyl, amino(Ci-C6)alkyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxy and halo(C l -C6)alkoxy ;
R represents -OH, ortho substituted aniline or substituted or unsubstituted group selected from aminoaryl and hydroxyaryl;
when the groups are substituted, the substituents are one or more groups, selected from halogens, hydroxy, nitro, cyano, azido, nitroso, oxo (=0), thioxo (=S), amino, hydrazino, formyl, (Ci-Ce)alkyl, halo(Ci-C6)alkyl, (CrC6)alkoxy, halo(Ci- C6)alkoxy, (C6-C14)arylalkoxy, (C3-Ci2)cycloalkyl, (C3-Ci2)cycloalkyloxy, (C6- C14)aryl, (C6-Ci )aryloxy, 5-15 membered heterocyclyl, 5-15 membered heteroaryl, (Ci-C6)alk lamino, -SONRaRb, -S02NRaRb, -SRa, -SORa, -S02Ra, -COORa, -C(0)Rb, -C(S)Ra, -C(0)NRaRb, -C(S)NRaRb, -NRaC(0)NRbRc, -NRaC(S)NRbRc, -N(Ra)SORb, -N(Ra)S02Rb, -NRaC(0)ORb, -NRaRb, -NRaC(0)Rb, -NRaC(S)Rb, -ORa, -ORaC(0)ORb, -OC(0)NRaRb, -OC(0)Ra, -RaNRbR° and -RaORb, wherein Ra, Rb and Rc in each of the above groups independently represents hydrogen or optionally substituted groups selected from (Ci-Ce)alkyl, (Ci-C6)alkylene, (C3-Ci2)cycloalkyl, (C6-C]4)aryl, (C6-Ci4)aryl(C]-C6)alkyl, 5-15 membered heterocyclyl, 5-15 membered heteroaryl and 5-15 membered heteroaryl(Ci-C6)alkyl; or Ra, Rb or Rc can also combine to form a substituted or unsubstituted 3-10 membered heterocyclic ring including spiro-fused heterocyclic ring having 0-3 heteroatoms; the substituents are optionally further substituted by one or more substituents.
2. A compound of formula (I) as claimed in claim 1, wherein the compound is selected from the compound of formula (IA),
Figure imgf000092_0001
their derivatives, analogs, tautomeric forms, stereoisomers, geometrical isomers, diastereomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, metabolites, intermediates and prodrugs thereof;
wherein:
Aa represents
Figure imgf000092_0002
or ;
Ara represents substituted or unsubstituted groups selected from (Ce-Cio)aryl, 5- 10 membered heterocyclyl and 5-10 membered heteroaryl;
Arla represents optionally substituted groups selected from (C6-Cio)aryl, 5-10 membered heterocyclyl and 5-10 membered heteroaryl;
Ar2a represents substituted or unsubstituted groups selected from (C6- Cio)arylene and 5-10 membered heteroarylene;
Ba represents hydrogen or substituted or unsubstituted groups selected from (C1-C6)alkyl and (C3-C6)cycloalkyl;
BIa represents hydrogen, -CONRlaR2a or substituted or unsubstituted groups selected from (Ci-C6)alkyl and (C3-C6)cycloalkyl;
Da represents hydrogen, -COORla, -CONR,aR2a or substituted or unsubstituted groups selected from (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Cio)aryl and
(C3-C6)cycloalkyl;
when one of Bla or Da is hydrogen or unsubstituted alkyl, the other is neither of hydrogen nor of unsubstituted alkyl; R a represents hydrogen or substituted or unsubstituted groups selected from (d-Ceialkyl and (C3-C6)cycloalkyl;
R2a represents hydrogen or substituted or unsubstituted groups selected from (Ci-C6)alkyl and (C3-C6)cycloalkyl;
or Rla and R2a combine together to form substituted or unsubstituted 3-7 membered ring having 0-3 heteroatoms selected from O, S and N;
Xa represents a bond, -CO-, -CH2-, -CONR3a-, -CONR3aCH2- or -CH2NR3a-;
3a represents hydrogen, (Ci-Ce)alkyl or (C3-C6)cycloalkyl;
Figure imgf000093_0001
T represents C, S, O or N; Wlb represents C, S, O or N; W2b represents C or N;
W3b represents C or N;
a is an integer selected from 1 and 2;
b at each occurrence is independently selected from an interger 0 and 1;
" " represents single or double bond;
R4 represents hydrogen, halogen, hydroxy, nitro, amino, cyano or substituted or unsubstituted (Ci-C6)alkyl, amino(Ci-C6)alkyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxy and halo(Ci-C6)alkoxy;
Rx represents OH or
Figure imgf000093_0002
wherein the substituents are one or more groups, selected from halogens, hydroxy, nitro, cyano, amino, formyl, (Ci-Ce)alkyl, halo(Ci-C6)alkyl, (Ci-Ce)alkoxy, (C6- C14)aryl, (C6-Ci4)aryloxy, (Q-Ce^lkylamino, -COORa, -C(0)NRaRb, -SRa, -SORa and -S02Ra, wherein Ra, Rb or Rc in each of the above groups independently represents hydrogen or optionally substituted groups selected from (C]-C6)alkyl, (C3-Ci2)cycloalkyl and (C6-Ci4)aryl; the substituents are optionally further substituted by one or more substituents.
3. The compound of formula (I) as claimed in claim 1, selected from the group consisting of:
2-(2,3-Diphenylacryloyl)-N-hydroxy-l,2,3,4-tetrahydroisoquinoline-7- carboxamide; 2-(3-(4-Fluorophenyl)-2-(4-fluorophenyl)acryloyl)-N-hydroxy-l,2,3,4 tetrahydroisoquinoline-7-carboxamide;
2-(3-(3,4-Dimethoxyphenyl)-2-(4-fluorophenyl)acryloyl)-N-hydroxy-l,2,3,4 tetrahydroisoquinoline-7-carboxamide;
2-(2-(2,4-Difluorophenyl)-3-phenylacryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(2-(4-Fluorophenyl)-3-(4-methoxyphenyl)acryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(2-(4-Fluorophenyl)-3-phenylacryloyl)-N-hydroxy- 1 ,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(3-(3,4-Difluorophenyl)-2-(4-methoxyphenyl)acryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(3-(2,4-Difluorophenyl)-2-(4-fluorophenyl)acryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxaniide;
2-(3-(4-Fluoro-3-methoxyphenyl)-2-(4-fluorophenyl)acryloyl)-N-hydroxy- l,2,3,4-tetrahydroisoquinoline-7-carboxamide;
2-(3-(4-Fluorophenyl)-2-p-tolylacryloyl)-N-hydroxy- 1,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(3-(3,4-Dimethoxyphenyl)-2- -tolylacryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(3-(3,4-Dimethoxyphenyl)-2-phenylacryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
N-Hydroxy-2-(3-(4-(methylthio)phenyl)-2-p-tolylacryloyl)-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(3-(3,4-Dimethoxyphenyl)-2-(2-fluorophenyl)acryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(2-(3,4-Dimethoxyphenyl)-3-(3-fluorophenyl)acryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(2,3-Z>/.s(3,4-Dimethoxyphenyl)acryloyl)-N-hydroxy-l, 2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(2-(Benzo[d][l,3]dioxol-5-yl)-3-(4-fluorophenyl)acryloyl)-N-hydroxy- l,2,3,4-tetrahydroisoquinoline-7-carboxamide; 2-(2-(4-Fluorophenyl)-3-(3-phenoxyphenyl)acryloyl)-N-hydroxy-l, 2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(2-(3-Chlorophenyl)-3-phenylacryloyl)-N-hydroxy- 1 ,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(2-(3-Fluorophenyl)-3-phenylacryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(2-(2-F luorophenyl)-3 -pheny lacry loy l)-N-hydroxy- 1,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(2-(2-Chloro-4-fluorophenyl)-3-phenylacryloyl)-N-hydroxy-l,2,3,4- tetrahydroi soquinoline-7-carboxam ide ;
N-Hydroxy-2-(3-phenyl-2-p-tolylacryloyl)-l,2,3,4-tetrahydroisoquinoline-7- carboxamide;
2-(3-(4-Fluorophenyl)-2-phenylacryloyl)-N-hydroxy- 1 ,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(2-(4-Fluorophenyl)-3-(thiophen-2-yl)acryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(3-(2,4-Dimethoxyphenyl)-2-(3-fluorophenyl)acryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(3-(4-Chlorophenyl)-2-phenylacryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(2-(2-Chlorophenyl)-3-phenylacryloyl)-N-hydroxy- 1,2,3,4- tetrahydroi soquinoline-7-carboxam ide ;
2-(3-(2,4-Dimethoxyphenyl)-2-(4-fluorophenyl)acryloyl)-N-hydroxy-l , 2,3,4- tetrahydroisoquinoline-7-carboxamide;
N-Hydroxy-2-(2-(naphthalen-2-yl)-3-phenylacryloyl)-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(2-(4-(N,N-Dimethylamino)phenyl)-3-phenylacryloyl)-N-hydroxy- 1 ,2,3,4- tetrahydroisoquinoline-7-carboxamide;
N-Hydroxy-2-(3-(4-methoxyphenyl)-2-phenylacryloyl)-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(2,3-6w(4-Methoxyphenyl)acryloyl)-N-hydroxy- 1 ,2,3,4- tetrahydroisoquinoline-7-carboxamide; 2-(3-(2-Fluorophenyl)-2-(4-fluorophenyl)acryloyl)-N-hydroxy-l, 2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(2-(4-Fluorophenyl)-3-(5-methylthiophen-2-yl)acryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(2-(4-Fluorophenyl)-3-(3-nitrophenyl)acryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(3-(3,4-Dimethoxyphenyl)-2-(thiophen-2-yl)acryloyl)-N-hydroxy-l,2,3,4- tetrahydroi soquinoline-7-carboxamide ;
2-(2-(2-Chlorophenyl)-3-(4-fluorophenyl)acryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(3-(4-Chlorophenyl)-2-(4-fluorophenyl)acryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
N-Hydroxy-2-(3-(4-methoxyphenyl)-2-^-tolylacryloyl)-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(2-(2-Chlorophenyl)-3 -(4-chlorophenyl)acryloyl)-N-hydroxy- 1 ,2, 3,4- tetrahydroisoquinoline-7-carboxamide;
5 -(2-(4-Fluoropheny l)-3 -pheny lacryloy l)-N-hydroxy-4, 5,6,7- tetrahydrothieno[3,2-c]pyridine-2-carboxamide;
5-(2-(3-Fluorophenyl)-3-phenylacryloyl)-N-hydroxy-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-carboxamide;
2-(2-(4-Fluorophenyl)-3-(3,4,5-trimethoxyphenyl)acryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(2-(4-Fluorophenyl)-3-(pyridin-3-yl)acryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquino line-7-carboxam ide ;
2-(2-(4-Fluorophenyl)-3-(pyridin-4-yl)acryloyl)-N-hydroxy-l , 2,3,4- tetrahydroisoquinoline-7-carboxamide;
4-(2-(4-Fluorophenyl)-3 -(7-(hydroxycarbamoyl)-3 ,4-dihydroisoquinolin-2( 1 H)- yl)-3 -oxoprop- 1 -enyl)benzoic acid;
2-(2-(2-Chlorophenyl)-3-(4-methoxyphenyl)acryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(3-(3,4-Difluorophenyl)-2-phenylacryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide; 2-(3-(3,4-Difluorophenyl)-2- 7-tolylacryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(2-(4-Chlorophenyl)-3-phenylacryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
1- (2,3-Diphenylacryloyl)-N-hydroxyindoline-5-carboxamide;
5-(2,3-Diphenylacryloyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2- carboxamide;
2- (2-(4-Fluorophenyl)-3-(4-(methylthio)phenyl)acryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
1- (2-(4-Fluorophenyl)-3-phenylacryloyl)-N-hydroxyindoline-5-carboxamide;
2- (2,3-Di- -tolylacryloyl)-N-hydroxy-l,2,3,4-tetrahydroisoquinoline-7- carboxamide;
N-Hydroxy-2-(2-phenyl-3-/7-tolylacryloyl)-l,2,3,4-tetrahydroisoquinoline-7- carboxamide;
N-Hydroxy-2-(3-phenyl-2-(4-(trifluoromethyl)phenyl)acryloyl)-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(4-(3 -(Cyclopropylamino)-3 -oxo-2-phenylprop- 1 -enyl)benzoyl)-N-hydroxy- l,2,3,4-tetrahydroisoquinoline-7-carboxamide;
2-(2-(4-Chlorophenyl)-3-(thiophen-2-yl)acryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(2,3-Diphenylacryloyl)-N-hydroxy-2,3,4,5-tetrahydro-lH-benzo[c]azepine-8- carboxamide;
2-(3-(2-Aminophenyl)-2-(4-fluorophenyl)acryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(2-(2-Chlorophenyl)-3-(thiophen-2-yl)acryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(2-(2-Fluorophenyl)-3-(thiophen-2-yl)acryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(3-(4-Chlorophenyl)-2-(4-fluorophenyl)acryloyl)-N-hydroxy-2,3,4,5- tetrahydro-lH-benzo[c]azepine-8-carboxamide;
2-(2-(3-Chlorophenyl)-3-(4-fluorophenyl)acryloyl)-N-hydroxy-2,3,4,5- tetrahydro-lH-benzo[c]azepine-8-carboxamide; 2-(4-(3-(Cyclopropylamino)-2-(4-fluorophenyl)-3-oxoprop-l-enyl)benzoyl)-N- hydroxy- 1 ,2,3,4-tetrahydroisoquinoline-7-carboxamide;
2-(2-(3 -Chlorophenyl)-3 -phenylacryloy l)-N-hydroxy-2, 3 ,4,5 -tetrahydro- 1 H- benzo[c]azepine-8-carboxamide;
N-Hydroxy-2-(2-phenyl-3-(thiophen-2-yl)acryloyl)- 1 ,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(2,3-Di(thiophen-2-yl)acryloyl)-N-hydroxy-l,2,3,4-tetrahydroisoquinoline-7- carboxamide;
N-Hydroxy-2-(2-(4-methoxyphenyl)-3-(thiophen-2-yl)acryloyl)-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
N-Hydroxy-2-(3-(thiophen-2-yl)-2- -tolylacryloyl)- 1 ,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(3-(3-Fluorophenyl)-2-phenylacryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
N-Hydroxy-2-(3-phenyl-2- w-tolylacryloyl)-l ,2,3,4-tetrahydroisoquinoline-7- carboxamide;
2-(3-(3-Fluorophenyl)-2-p-tolylacryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
N-Hydroxy-2-(2-(3-methoxyphenyl)-3-phenylacryloyl)- 1 ,2,3,4- tetrahydroi soquinoline-7-carboxamide ;
1- (2-(3-Fluorophenyl)-3-phenylacryloyl)-N-hydroxyindoline-6-carboxamide; N-Hydroxy-2-(2-(4-methoxyphenyl)-3-phenylacryloyl)- 1,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2- (2-(3,4-Dimethoxyphenyl)-3-phenylacryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
2-(3-(4-Fluorophenyl)-2-(3-methoxyphenyl)acryloyl)-N-hydroxy-l, 2,3,4- tetrahydroisoquinoline-7-carboxamide;
l-(3-(4-Chlorophenyl)-2-(4-fluorophenyl)acryloyl)-N-hydroxyindoline-5- carboxamide;
l-(2-(3-Chlorophenyl)-3-(4-fluorophenyl)acryloyl)-N-hydroxyindoline-5- carboxamide;
(3-(3-Fluorophenyl)-2- »-tolylacryloyl)-N-hydroxyindoline-5-carboxamide; N-Hydroxy-l-(3-phenyl-2-/w-tolylacryloyl)indoline-5-carboxamide; 1- (3-(4-Fluorophenyl)-2-phenylacryloyl)-N-hydroxyindoline-5-carboxamide; 5-(3-(4-Fluorophenyl)-2-phenylacryloyl)-N-hydroxy-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-carboxamide;
N-Hydroxy-5-(3-phenyl-2- j-tolylacryloyl)-4,5,6,7-tetrahydrothieno[3,2- c]pyridine-2-carboxamide;
5-(3-(3-Fluorophenyl)-2-p-tolylacryloyl)-N-hydroxy-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-carboxamide;
N-Hydroxy-2-(2-(3-chlorophenyl)-3-(quinolin-4-yl)acryloyl)-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
5-(2-(4-Fluorophenyl)-3-(lH-indol-3-yl)acryloyl)-N-hydroxy-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-carboxamide;
2- (2-(4-Fluorophenyl)-3-(lH-indol-3-yl)acryloyl)-N-hydroxy-l ,2,3,4- tetrahydroisoquinoline-7-carboxamide;
5-(3-(4-Fluorophenyl)-2-(lH-indol-3-yl)acryloyl)-N-hydroxy-4,5,6,7- tetrahydroisoxazolo[4,5-c]pyridine-3-carboxamide;
5-(2-(4-Fluorophenyl)-3-(pyridin-4-yl)acryloyl)-N-hydroxy-4,5,6,7- tetrahydroisoxazolo[4,5-c]pyridine-3-carboxamide;
5-(3-(4-Fluorophenyl)-2-phenylacryloyl)-N-hydroxy-4,5,6,7- tetrahydroisoxazolo[4,5-c]pyridine-3-carboxamide;
N-Hydroxy-5-(2-(4-methoxyphenyl)-3-(thiophen-2-yl)acryloyl)-4,5,6,7- tetrahydroisoxazolo[4,5-c]pyridine-3-carboxamide;
5 -(2-(4-Fluoropheny l)-3 -pheny lacry loyl)-N-hydroxy-4, 5,6,7- tetrahydroisoxazolo[4,5-c]pyridine-3-carboxamide;
5-(2,3-Diphenylacryloyl)-N-hydroxy-4,5,6,7-tetrahydroisoxazolo[4,5- c]pyridine-3-carboxamide;
N-Hydroxy-5-(3-phenyl-2-(thiophen-2-yl)acryloyl)-4,5,6,7- tetrahydroisoxazolo[4,5-c]pyridine-3-carboxamide;
N-Hydroxy-5-(2-(4-methoxyphenyl)-3-(thiophen-2-yl)acryloyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-carboxamide;
5-(2-(4-Fluorophenyl)-3-(pyridin-4-yl)acryloyl)-N-hydroxy-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-carboxamide;
2-(3-(4-Fluorophenyl)-2-phenylacryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-6-carboxamide; 2-(3-(4-Fluorophenyl)-2-phenylacryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-8-carboxamide;
5-(2-(4-Fluorophenyl)-3-phenylacryloyl)-N-hydroxy-4,5,6,7- tetrahydrofuro [3 ,2-c]pyridine-2-carboxam ide ;
N-Hydroxy-l-(3-phenyl-2-(thiophen-2-yl)acryloyl)indoline-4-carboxamide; 2-(2-(4-Fluorophenyl)-3-phenylacryloyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-6-carboxamide;
2-(2-(4-Fluorophenyl)-3-phenylacryloyl)-N-hydroxy- 1 ,2,3,4- tetrahydroisoquinoline-8-carboxamide;
l-(3-(4-Fluorophenyl)-2-phenylacryloyl)-N-hydroxyindoline-6-carboxamide; l-(2-(4-Fluorophenyl)-3-phenylacryloyl)-N-hydroxyindoline-6-carboxamide; l-(2-(2-Chlorophenyl)-3-phenylacryloyl)-N-hydroxyindoline-6-carboxamide;
N-Hydroxy-l-(2-(4-methoxyphenyl)-3-(thiophen-2-yl)acryloyl)indoline-4- carboxamide;
l-(3-(4-Fluorophenyl)-2-phenylacryloyl)-N-hydroxyindoline-4-carboxamide; l-(2-(4-Fluorophenyl)-3-(pyridin-4-yl)acryloyl)-N-hydroxyindoline-4- carboxamide;
N-Hydroxy-l-(3-(pyridin-4-yl)-2-(thiophen-2-yl)acryloyl)indoline-4- carboxamide;
N-Hydroxy-l-(3-phenyl-2-(thiophen-2-yl)acryloyl)indoline-6-carboxamide;
1- (2-(4-Fluorophenyl)-3-(pyridin-4-yl)acryloyl)-N-hydroxyindoline-6- carboxamide;
2- (4-(3-(3,4-Dimethoxyphenyl)-2-(4-fluorophenyl)acryloyl)piperazin-l -yl)-N- hydroxypyrimidine-5-carboxamide;
2-(4-(3-(3,4-Dimethoxyphenyl)-2-(phenyl)acryloyl)piperazin-l-yl)-N- hydroxypyrimidine-5-carboxamide;
2-(4-(3-(3,4-Dimethoxyphenyl)-2-(3-fluorophenyl)acryloyl)piperazin-l-yl)-N- hydroxypyrimidine-5-carboxamide;
2-(4-(3-(3,4-Dimethoxyphenyl)-2-(thiophen-2-yl)acryloyl)piperazin-l-yl)-N- hydroxypyrim idine-5 -carboxamide ;
2-(4-(3-(3,4-Dimethoxyphenyl)-2-(pyridin-3-yl)acryloyl)piperazin-l-yl)-N- hydroxypyrim idine-5 -carboxamide ; 2-(4-(3-(Phenyl)-2-(4-fluorophenyl)acryloyl)piperazin- 1 -yl)-N- hydroxypyrimidine-5-carboxamide;
2-(4-(3-(3,4-Methylenedioxyphenyl)-2-(phenyl)acryloyl)piperazin-l-yl)-N- hydroxypyrimidine-5-carboxamide;
2-(4-(3-(4-Fluorophenyl)-2-(pyridin-3-yl)acryloyl)piperazin-l-yl)-N- hydroxypyrimidine-5-carboxamide;
2-(4-(3-(3-Fluorophenyl)-2-(4-fluorophenyl)acryloyl)piperazin-l-yl)-N- hydroxypyrimidine-5-carboxamide;
2-(4-(3-(4-Fluoro-3-methoxyphenyl)-2-(4-fluorophenyl)acryloyl)piperazin-l- yl)-N-hydroxypyrimidine-5-carboxamide;
2-(4-(3-(3,4-Dimethoxyphenyl)-2-(2-fluorophenyl)acryloyl)piperazin-l-yl)-N- hydroxypyrimidine-5-carboxamide;
2-(4-(3 -(4-Methylthiophenyl)-2-(phenyl)acryloyl)piperazin- 1 -yl)-N- hydroxypyrimidine-5-carboxamide;
2-(4-(3-(3,4-Difluorophenyl)-2-(4-methoxyphenyl)acryloyl)piperazin-l-yl)-N- hydroxypyrimidine-5-carboxamide;
2-(4-(3-(Pyridin-3-yl)-2-(pyridin-3-yl)acryloyl)piperazin-l-yl)-N- hydroxypyrimidine-5-carboxamide;
2-(4-(3-(4-Fluorophenyl)-2-(indol-3-yl)acryloyl)piperazin-l-yl)-N- hydroxypyrimidine-5-carboxamide;
2-(4-(3-(3,4-Dimethoxyphenyl)-2-(indol-3-yl)acryloyl)piperazin-l-yl)-N- hydroxypyrimidine-5-carboxamide;
2-(4-(3-(4-Methylthiophenyl)-2-(4-tolyl)acryloyl)piperazin-l-yl)-N- hydroxypy r im idine - 5 -carboxamide ;
2-(4-(3 -(4-Fluorophenyl)-2-(4-methoxyphenyl)acryloyl)piperazin- 1 -yl)-N- hydroxypyrimidine-5-carboxamide;
2-(4-(3-(Pyridin-3-yl)-2-(4-fluorophenyl)acryloyl)piperazin-l-yl)-N- hydroxypyrimidine-5 -carboxamide ;
2-(4-(3-(3,4-Dimethoxyphenyl)-2-(3-chlorophenyl)acryloyl)piperazin-l-yl)-N- hydroxypyrimidine-5-carboxamide;
2-(4-(2,3-Diphenylacryloyl)piperazin-l-yl)-N-hydroxypyrimidine-5- carboxamide; 2-(4-(3-(3,4-Dimethoxyphenyl)-2-(3-methoxyphenyl)acryloyl)piperazin-l-yl)- N-hydroxypyrimidine-5-carboxamide;
2-(4-(3-(Phenyl)-2-(3,4-dimethoxyphenyl)acryloyl)piperazin-l-yl)-N- hydroxypyrimidine-5 -carboxamide ;
2-(4-(3-(4-Fluorophenyl)-2-(3,4-methylenedioxyphenyl)acryloyl)piperazin-l- yl)-N-hydroxypyrimidine-5-carboxamide;
2-(4-(3 -(4-Fluorophenyl)-2-(3 -fluorophenyl)acryloyl)piperazin- 1 -yl)-N- hydroxypyrimidine-5-carboxamide;
2-(4-(3-(3,4-Methylenedioxyphenyl)-2-(4-fluorophenyl)acryloyl)piperazin-l- yl)-N-hydroxypyrimidine-5-carboxamide;
2-(4-(3-(3,4-Methylenedioxyphenyl)-2-(3-fluorophenyl)acryloyl)piperazin-l- yl)-N-hydroxypyrimidine-5-carboxamide;
2-(4-(3-(3-Fluorophenyl)-2-(3,4-dimethoxyphenyl)acryloyl)piperazin-l-yl)-N- hydroxypyrimidine-5-carboxamide;
2-(4-(3-(3-Fluorophenyl)-2-(3,4-dimethoxyphenyl)acrylamido)piperidin-l-yl)- N-hy droxypy rim idine-5 -carboxamide ;
2-(4-(3-(Phenyl)-2-(3,4-dimethoxyphenyl)acrylamido)piperidin-l-yl)-N- hydroxypyrimidine-5-carboxamide;
2-(4-(3-(4-Fluorophenyl)-2-(3,4-dimethoxyphenyl)acrylamido)piperidin-l-yl)- N-hydroxypyrimidine-5-carboxamide;
2-(4-((3-(3,4-Dimethoxyphenyl)-2-(3-fluorophenyl)acrylamido)methyl) piperidin-l-yl)-N-hydroxypyrimidine-5-carboxamide;
2-(4-(4-(3-(Cyclopropylamino)-2-(4-fluorophenyl)-3-oxoprop-l-enyl) benzoyl)piperazin- 1 -yl)-N-hydroxypyrimidine-5-carboxamide;
2-(4-(4-(3-(Cyclopropylamino)-2-(3,4-dimethoxyphenyl)-3-oxoprop-l-enyl) benzoyl)piperazin-l-yl)-N-hydroxypyrimidine-5-carboxamide;
2-(4-(4-(3-(Cyclopropylamino)-2-(p-tolyl)-3-oxoprop-l-enyl)
benzoyl)piperazin-l-yl)-N-hydroxypyrimidine-5-carboxamide;
2-(4-(4-(3-(Cyclopropylamino)-2-(phenyl)-3-oxoprop- 1 -enyl)
benzoyl)piperazin- 1 -yl)-N-hydroxypyrimidine-5-carboxamide;
2-(4-(4-(3-(N,N-Dimethylamino)-2-(4-fluorophenyl)-3-oxoprop-l-enyl) benzoyl)piperazin- 1 -yl)-N-hydroxypyrimidine-5-carboxamide; 2-(4-(4-(3-(Cyclopropylamino)-2-(2-fluorophenyl)-3-oxoprop-l-enyl) benzoyl)piperazin- 1 -yl)-N-hydroxypyrimidine-5-carboxamide;
2-(2-(4-Fluorophenyl)-3-phenylallyl)-N-hydroxy-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
N-(2-Aminophenyl)-2-(2,3-diphenylacryloyl)-l,2,3,4-tetrahydroisoquinoline-7- carboxamide;
N-(2-Aminophenyl)-2-(2-(3-fluorophenyl)-3-phenylacryloyl)-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
N-(2-Aminophenyl)-2-(2-phenyl-3-(thiophen-2-yl)acryloyl)-l,2,3,4- tetrahydroisoquinoline-7-carboxamide;
l-(2-(4-Fluorophenyl)-3-phenylacryloyl)-N-hydroxy-l,2,3,4- ■
tetrahydroquinoline-6-carboxamide;
1 -(3-(4-Fluorophenyl)-2-phenylacryloyl)-N-hydroxy-l ,2,3,4- tetrahydroquinoline-6-carboxamide;
1 -(2-(4-Fluorophenyl)-3-(pyridin-4-yl)acryloyl)-N-hydroxy- 1 ,2,3,4- tetrahydroquinoline-6-carboxamide;
1 -(2-(4-Fluorophenyl)-3-(pyridin-4-yl)acryloyl)-N-hydroxy-2-methyl- 1 ,2,3,4- tetrahydroquinoline-6-carboxamide;
1 -(2-(4-Fluorophenyl)-3-phenylacryloyl)-N-hydroxy-2 -methyl- 1 ,2,3,4- tetrahydroquinoline-6-carboxamide;
1 -(3 -(4-Fluorophenyl)-2-phenylacryloyl)-N-hydroxy-2 -methyl- 1,2,3,4- tetrahydroquinoline-6-carboxamide;
their derivatives, analogs, tautomeric forms, stereoisomers, geometrical isomers, diastereomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, pharmaceutical compositions, metabolites, intermediates and prodrugs thereof.
4. A pharmaceutical composition comprising a compound of formula (I), according to claim 1, 2 or 3, as an active ingredient, along with a pharmaceutically acceptable carrier.
5. The compound of formula (I) as claimed in claim 1, 2 or 3, wherein the said compound is efficiently transported across the blood-brain barrier.
6. The compound of formula (I) as claimed in claim 1, 2 or 3, for use in inhibiting HDAC in a cell.
7. The compound of formula (I) as claimed in claim 1, 2 or 3, for use in the treatment of a condition mediated by HDAC.
8. The compound of formula (I) as claimed in claim 1, 2 or 3, for use in the treatment of proliferative conditions or cancer.
9. The compound of formula (I) as claimed in claim 1, 2 or 3, for use in the treatment of proliferative conditions or cancer in combination with other clinically relevant cytotoxic agents or non-cytotoxic agents or radiation or monoclonal antibodies.
10. The compound of formula (I) for use as claimed in claim 7 or 8, wherein the diseases are selected from lung cancer, non-small-cell lung cancer, small cell lung cancer, colon cancer, fibrosarcoma, kidney cancer, lymphoma, leukemia, skin cancer, pancreatic cancer, breast cancer, prostate cancer, bone cancer, oral cancer, multiple myeloma, brain cancer, head and neck cancer, ovarian cancer, gastric cancer, liver cancer, cervical cancer, solid tumors, cutaneous T-cell lymphoma, acute myeloid leukemia, chronic lymphocytic leukemia and acute lymphoblastic leukemia.
11. The compound of formula (I) as claimed in claim 1, 2 or 3, for use in the treatment of inflammatory diseases or autoimmune diseases.
12. The compound of formula (I) for use as claimed in claim 11, wherein the inflammatory diseases are selected from rheumatoid arthritis, inflammatory bowel disease, psoriasis, dermatitis, granuloma, uveitis, chronic obstructive pulmonary disease (COPD), ulcerative colitis, Crohn's disease, multiple sclerosis and sepsis.
13. The compound of formula (I) as claimed in claim 1, 2 or 3, for use in the treatment of Central Nervous System disorders.
14. The compound of formula (I) as claimed in claim 1, 2 or 3, for use in the treatment of neurodegenerative disorders selected from Huntington's disease, Alzheimer's disease, Friedrich's ataxia, stroke and Parkinson's disease.
15. The compound of formula (I) as claimed in claim 1, 2 or 3, for inhibiting HDAC6 in a cell.
16. The compound of formula (I) as claimed in claim 1, 2 or 3, for inhibiting HDAC6 in a subject.
17. The compound of formula (I) as claimed in claim 1, 2 or 3, for use in the treatment of malaria, fungal and HIV infections.
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