US20100121049A1 - Indenoisoquinolinone analogs and methods of use thereof - Google Patents

Indenoisoquinolinone analogs and methods of use thereof

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Publication number
US20100121049A1
US20100121049A1 US12/529,069 US52906908A US2010121049A1 US 20100121049 A1 US20100121049 A1 US 20100121049A1 US 52906908 A US52906908 A US 52906908A US 2010121049 A1 US2010121049 A1 US 2010121049A1
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alkyl
alkylene
substituted
membered monocyclic
nitrogen
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Inventor
Prakash Jagtap
Duy-Phong Pham-Huu
Frederick Cohen
Xiaojing Wang
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Rocket Pharmaceuticals Inc
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Inotek Pharmaceuticals Corp
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Priority to US12/529,069 priority Critical patent/US20100121049A1/en
Assigned to INOTEK PHARMACEUTICALS CORPORATION reassignment INOTEK PHARMACEUTICALS CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PHAM-HUU, DUY-PHONG, JAGTAP, PRAKASH, WANG, XIAOJING, COHEN, FREDERICK
Publication of US20100121049A1 publication Critical patent/US20100121049A1/en
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    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/18—Ring systems of four or more rings
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    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/36—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings
    • A01N43/38—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings condensed with carbocyclic rings
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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
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
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    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/06—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

Definitions

  • the present invention relates to Indenoisoquinolinone Analogs, compositions comprising an effective amount of an Indenoisoquinolinone Analog and methods for treating or preventing an inflammatory disease, a reperfusion injury, diabetes mellitus, a diabetic complication, reoxygenation injury resulting from organ transplantation, an ischemic condition, a neurodegenerative disease, renal failure, a vascular disease, a cardiovascular disease, cancer, a complication of prematurity, cardiomyopathy, retinopathy, nephropathy, neuropathy, erectile dysfunction or urinary incontinence, comprising administering to a subject in need thereof an effective amount of an Indenoisoquinolinone Analog.
  • Erectile dysfunction (“ED”) is a significant male-health issue. While estimating its prevalence is difficult, estimates range from about 15 million to 30 million sufferers worldwide.
  • the etiology of erectile dysfunction can be multiple, and can include mechanical trauma to the nerves (such as during prostatectomy), or it can be due to diabetes mellitus, cardiovascular diseases, induced by radiation, certain drugs, or advanced age.
  • Urinary incontinence affects people of all ages and levels of physical health, both in health care settings and in the community at large. Persons suffering from urinary incontinence can be predisposed to also having urinary-tract infections, pressure ulcers, perineal rashes and urosepsis. Psychosocially, urinary incontinence can be associated with embarrassment, social stigmatization, depression and a risk of institutionalization (Herzo et al., Annu. Rev. Gerontol. Geriatr. 9:74 (1989)).
  • An inflammatory disease such as arthritis, colitis, and autoimmune diabetes, typically manifests itself as a disorder distinct from that associated with a reperfusion injury, e.g., stroke and heart attack, and can clinically manifest itself as a different entity.
  • a reperfusion injury e.g., stroke and heart attack
  • cytotoxic free radicals such as nitric oxide and superoxide.
  • NO and superoxide can react to form peroxynitrite (ONOO ⁇ ) (Szabo et al., Shock 6:79-88, 1996).
  • the ONOO ⁇ -induced cell necrosis observed in inflammatory disease and in reperfusion injury involves the activation of the nuclear enzyme poly (ADP-ribose) polymerase (PARP).
  • PARP nuclear enzyme poly
  • Activation of PARP is thought to be an important step in the cell-mediated death observed in inflammation and reperfusion injury (Szabo et al., Trends Pharmacol. Sci. 19:287-98, 1998).
  • Indenoisoquinolinone compounds have been previously discussed in the art. For example, cytotoxic non-camptothecin topoisomerase I inhibitors are reported in Cushman et al., J. Med. Chem., 43:3688-3698, 2300 and Cushman et al., J. Med. Chem. 42:446-57, 1999; indeno[1,2-c]isoquinolines are reported as antineoplastic agents in Cushman et al., WO 00/21537; and as neoplasm inhibitors in Hrbata et al., WO 93/05023.
  • the invention provides a compound of Formula (Ia)
  • X is —N(C 1 -C 4 alkyl)-, —CH(OH)—, —N(C(O)N(H)—(CH 2 ) p —Z)— or —N((CH 2 ) q —Z)—;
  • R 1 is —(CH 2 ) n —N(R 2 )(R 2 ) or —O—(CH 2 ) m —N(R 2 )(R 2 );
  • each R 2 is independently —H, —C 1 -C 6 alkyl, —C 3 -C 8 monocyclic cycloalkyl, C 1 -C 6 alkylene phenyl, phenyl, an N-terminal alpha amino acid residue, an N-terminal alpha amino hydroxymethyl residue, a C 1 -C 6 alkyl ester of an N-terminal alpha amino acid residue, or a nitrogen-containing 3- to 7-membered monocyclic heterocycle, each of which other than hydrogen is independently unsubstituted or substituted with one or more of -halo, —OH, —OP(O)(OH) 2 , —OS(O) 2 OH, —C 1 -C 6 alkyl, —O—C 1 -C 6 alkyl, —C 3 -C 8 monocyclic cycloalkyl, a 3- to 7-membered monocyclic heterocycle, —(C 1 -C 6 alkyl-substit
  • R 2 groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle or a nitrogen-containing 7- to 10-membered bicyclic heterocycle, each of which is unsubstituted or substituted with one or more of —C 1 -C 5 alkyl, —C 3 -C 8 monocyclic cycloalkyl, phenyl, a nitrogen-containing 3- to 7-membered monocyclic heterocycle, -(phenyl-substituted) C 1 -C 5 alkyl, -(hydroxy-substituted) C 1 -C 5 alkyl, -halo, -(halo-substituted) C 1 -C 5 alkyl, -(halo-substituted) phenyl, -phenylene-O—C 1 -C 5 alkyl, -(cyano-substituted) phenyl, —OH, —O—C 1 -C
  • Z is —CF 3 , —F, —OH or —O—CH 3 ;
  • n is an integer ranging from 1 to 10;
  • n is an integer ranging from 2 to 10;
  • p is an integer ranging from 1 to 5;
  • q is an integer ranging from 1 to 5.
  • the invention provides a compound of Formula (Ib)
  • X is —N(C 1 -C 4 alkyl)-, —CH(OH)—, —N(C(O)N(H)—(CH 2 ) p —Z)— or —N((CH 2 ) q —Z)—;
  • R 2 groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle or a nitrogen-containing 7- to 10-membered bicyclic heterocycle, each of which is unsubstituted or substituted with one or more of —C 1 -C 5 alkyl, —C 3 -C 8 monocyclic cycloalkyl, phenyl, a nitrogen-containing 3- to 7-membered monocyclic heterocycle, -(phenyl-substituted) C 1 -C 5 alkyl, -(hydroxy-substituted) C 1 -C 5 alkyl, -halo, -(halo-substituted) C 1 -C 5 alkyl, -(halo-substituted) phenyl, -phenylene-O—C 1 -C 5 alkyl, -(cyano-substituted) phenyl, —OH, —O—C 1 -C
  • Z is —CF 3 , —F, —OH or —O—CH 3 ;
  • n is an integer ranging from 1 to 10;
  • n is an integer ranging from 2 to 10;
  • p is an integer ranging from 1 to 5;
  • q is an integer ranging from 1 to 5.
  • the invention provides a compound of Formula (Ic)
  • X is —N(C 1 -C 4 alkyl)-, —CH(OH)—, —N(C(O)N(H)—(CH 2 ) p —Z)— or —N((CH 2 ) q —Z)—;
  • R 1 is —(CH 2 ) n —N(R 2 )(R 2 ) or —O—(CH 2 ) m —N(R 2 )(R 2 );
  • each R 2 is independently —H, —C 1 -C 6 alkyl, —C 3 -C 8 monocyclic cycloalkyl, C 1 -C 6 alkylene phenyl, phenyl, an N-terminal alpha amino acid residue, an N-terminal alpha amino hydroxymethyl residue, a C 1 -C 6 alkyl ester of an N-terminal alpha amino acid residue, or a nitrogen-containing 3- to 7-membered monocyclic heterocycle, each of which other than hydrogen is independently unsubstituted or substituted with one or more of -halo, —OH, —OP(O)(OH) 2 , —OS(O) 2 OH, —C 1 -C 6 alkyl, —O—C 1 -C 6 alkyl, —C 3 -C 8 monocyclic cycloalkyl, a 3- to 7-membered monocyclic heterocycle, —(C 1 -C 6 alkyl-substit
  • R 2 groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle or a nitrogen-containing 7- to 10-membered bicyclic heterocycle, each of which is unsubstituted or substituted with one or more of —C 1 -C 5 alkyl, —C 3 -C 8 monocyclic cycloalkyl, phenyl, a nitrogen-containing 3- to 7-membered monocyclic heterocycle, -(phenyl-substituted) C 1 -C 5 alkyl, -(hydroxy-substituted) C 1 -C 5 alkyl, -halo, -(halo-substituted) C 1 -C 5 alkyl, -(halo-substituted) phenyl, -phenylene-O—C 1 -C 5 alkyl, -(cyano-substituted) phenyl, —OH, —O—C 1 -C
  • Z is —CF 3 , —F, —OH or —O—CH 3 ;
  • n is an integer ranging from 1 to 10;
  • n is an integer ranging from 2 to 10;
  • p is an integer ranging from 1 to 5;
  • q is an integer ranging from 1 to 5.
  • X is —CH 2 —, —O—, —C(O)—, —CH(OH)—, —NH—, —N(C 1 -C 4 alkyl)- or —S—;
  • R 1 is —(CH 2 ) n —N(R 2 )(R 3 ) or
  • R 2 is —H, —C 1 -C 6 alkyl, or —C 3 -C 8 monocyclic cycloalkyl;
  • R 3 is —C(O)—(C 1 -C 6 alkylene)-(3- to 7-membered monocyclic heterocycle), a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one or more of —C(O)O—C 1 -C 6 alkyl, or —C 3 -C 8 monocyclic cycloalkyl which is substituted with one or more of (hydroxy-substituted) C 1 -C 5 alkyl groups;
  • R 2 and R 3 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which is substituted with one or more of —C 2 -C 6 alkenyl, —C(O)—C 1 -C 6 alkyl, —(C 1 -C 4 alkylene)-C(O)—(C 3 -C 8 monocyclic cycloalkyl), —C 2 -C 10 alkyl, —(C 1 -C 5 alkylene)C(H)(—O—C 1 -C 4 alkyl) 2 , -(cyano-substituted) C 1 -C 5 alkyl, —(C 1 -C 5 alkylene)-C(O)-(nitrogen-containing 3- to 7-membered monocyclic heterocycle) or —(C 1 -C 5 alkylene)-(3- to 7-membered monocyclic heterocycle) groups; and
  • n is an integer ranging from 1 to 10.
  • X is CH 2 —, —O—, —C(O)—, —CH(OH)—, —NH—, —N(C 1 -C 4 alkyl)- or —S—;
  • R 1 is —(CH 2 ) n —N(R 2 )(R 3 ) or
  • R 2 is —H, —C 1 -C 6 alkyl, or —C 3 -C 8 monocyclic cycloalkyl;
  • R 3 is —C(O)—(C 1 -C 6 alkylene)-(3- to 7-membered monocyclic heterocycle), a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one or more of —C(O)O—C 1 -C 6 alkyl, or —C 3 -C 8 monocyclic cycloalkyl which is substituted with one or more of (hydroxy-substituted) C 1 -C 5 alkyl groups;
  • R 2 and R 3 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which is substituted with one or more of —C 2 -C 6 alkenyl, —C(O)—C 1 -C 6 alkyl, —(C 1 -C 4 alkylene)-C(O)—(C 3 -C 8 monocyclic cycloalkyl), —C 7 -C 10 alkyl, —(C 1 -C 5 alkylene)C(H)(—O—C 1 -C 4 alkyl) 2 , -(cyano-substituted) C 1 -C 5 alkyl, —(C 1 -C 5 alkylene)-C(O)-(nitrogen-containing 3- to 7-membered monocyclic heterocycle) or —(C 1 -C 5 alkylene)-(3- to 7-membered monocyclic heterocycle) groups; and
  • n is an integer ranging from 1 to 10.
  • X is CH 2 —, —O—, —C(O)—, —CH(OH)—, —NH—, —N(C 1 -C 4 alkyl)- or —S—;
  • R 1 is —(CH 2 ) n —N(R 2 )(R 3 ) or
  • R 2 is —H, —C 1 -C 6 alkyl, or —C 3 -C 8 monocyclic cycloalkyl;
  • R 3 is —C(O)—(C 1 -C 6 alkylene)-(3- to 7-membered monocyclic heterocycle), a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one or more of —C(O)O—C 1 -C 6 alkyl, or —C 3 -C 8 monocyclic cycloalkyl which is substituted with one or more of (hydroxy-substituted) C 1 -C 5 alkyl groups;
  • R 2 and R 3 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which is substituted with one or more of —C 2 -C 6 alkenyl, —C(O)—C 1 -C 6 alkyl, —(C 1 -C 4 alkylene)-C(O)—(C 3 -C 8 monocyclic cycloalkyl), —C 2 -C 10 alkyl, —(C 1 -C 5 alkylene)C(H)(—O—C 1 -C 4 alkyl) 2 , -(cyano-substituted) C 1 -C 5 alkyl, —(C 1 -C 5 alkylene)-C(O)-(nitrogen-containing 3- to 7-membered monocyclic heterocycle) or —(C 1 -C 5 alkylene)-(3- to 7-membered monocyclic heterocycle) groups; and
  • n is an integer ranging from 1 to 10.
  • the invention provides the following Indenoisoquinolinone Analogs according to Formula (IIIa) as set forth below:
  • IIIa Compound —R 1 IIIa-1 IIIa-2 IIIa-3 IIIa-4 IIIa-5 IIIa-6 IIIa-7 IIIa-8 IIIa-9 IIIa-10 IIIa-11 IIIa-12 IIIa-13 IIIa-14 IIIa-15 IIIa-16 IIIa-17 IIIa-18 IIIa-19 IIIa-20 IIIa-21 IIIa-22 IIIa-23 IIIa-24
  • the invention provides the following Indenoisoquinolinone Analogs according to Formula (Mb) as set forth below:
  • IIIb Compound —R 1 IIIb-1 IIIb-2 IIIb-3 IIIb-4 IIIb-5 IIIb-6 IIIb-7 IIIb-8 IIIb-9 IIIb-10 IIIb-11 IIIb-12 IIIb-13 IIIb-14 IIIb-15 IIIb-16 IIIb-17 IIIb-18 IIIb-19 IIIb-20 IIIb-21 IIIb-22 IIIb-23 IIIb-24 and pharmaceutically acceptable salts thereof.
  • the invention provides a compound of Formula (IVa)
  • X is —O—, —CH 2 —, —C(O)—, —NH—, —S—, —N(C 1 -C 4 alkyl)-, —CH(OH)—, —N(C(O)N(H)—(CH 2 ) p —Z)— or —N((CH 2 ) q —Z)—;
  • R 1 is —O—C(C 1 -C 3 alkyl) 2 -(CH 2 ) n —N(R 2 )(R 2 );
  • each R 2 is independently —H, —C 1 -C 6 alkyl, —C 3 -C 8 monocyclic cycloalkyl, C 1 -C 6 alkylene phenyl, phenyl, an N-terminal alpha amino acid residue, an N-terminal alpha amino hydroxymethyl residue, a C 1 -C 6 alkyl ester of an N-terminal alpha amino acid residue, or a nitrogen-containing 3- to 7-membered monocyclic heterocycle, each of which other than hydrogen is independently unsubstituted or substituted with one or more of -halo, —OH, —OP(O)(OH) 2 , —OS(O) 2 OH, —C 1 -C 6 alkyl, —O—C 1 -C 6 alkyl, —C 3 -C 8 monocyclic cycloalkyl, a 3- to 7-membered monocyclic heterocycle, —(C 1 -C 6 alkyl-substit
  • R 2 groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle or a nitrogen-containing 7- to 10-membered bicyclic heterocycle, each of which is unsubstituted or substituted with one or more of —C 1 -C 5 alkyl, —C 3 -C 8 monocyclic cycloalkyl, phenyl, a nitrogen-containing 3- to 7-membered monocyclic heterocycle, -(phenyl-substituted) C 1 -C 5 alkyl, -(hydroxy-substituted) C 1 -C 5 alkyl, -halo, -(halo-substituted) C 1 -C 5 alkyl, -(halo-substituted) phenyl, -phenylene-O—C 1 -C 5 alkyl, -(cyano-substituted) phenyl, —OH, —O—C 1 -C
  • Z is —CF 3 , —F, —OH or —O—CH 3 ;
  • n is an integer ranging from 1 to 10;
  • p is an integer ranging from 1 to 5;
  • q is an integer ranging from 1 to 5.
  • the invention provides a compound of Formula (IVb)
  • X is —O—, —CH 2 —, —C(O)—, —NH—, —S—, —N(C 1 -C 4 alkyl)-, —CH(OH)—, —N(C(O)N(H)—(CH 2 ) p —Z)— or —N((CH 2 ) q —Z)—;
  • R 1 is —O—C(C 1 -C 3 alkyl) 2 -(CH 2 ) n —N(R 2 )(R 2 );
  • each R 2 is independently —H, —C 1 -C 6 alkyl, —C 3 -C 8 monocyclic cycloalkyl, C 1 -C 6 alkylene phenyl, phenyl, an N-terminal alpha amino acid residue, an N-terminal alpha amino hydroxymethyl residue, a C 1 -C 6 alkyl ester of an N-terminal alpha amino acid residue, or a nitrogen-containing 3- to 7-membered monocyclic heterocycle, each of which other than hydrogen is independently unsubstituted or substituted with one or more of -halo, —OH, —OP(O)(OH) 2 , —OS(O) 2 OH, —C 1 -C 6 alkyl, —O—C 1 -C 6 alkyl, —C 3 -C 8 monocyclic cycloalkyl, a 3- to 7-membered monocyclic heterocycle, —(C 1 -C 6 alkyl-substit
  • R 2 groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle or a nitrogen-containing 7- to 10-membered bicyclic heterocycle, each of which is unsubstituted or substituted with one or more of —C 1 -C 5 alkyl, —C 3 -C 8 monocyclic cycloalkyl, phenyl, a nitrogen-containing 3- to 7-membered monocyclic heterocycle, -(phenyl-substituted) C 1 -C 5 alkyl, -(hydroxy-substituted) C 1 -C 5 alkyl, -halo, -(halo-substituted) C 1 -C 5 alkyl, -(halo-substituted) phenyl, -phenylene-O—C 1 -C 5 alkyl, -(cyano-substituted) phenyl, —OH, —O—C 1 -C
  • Z is —CF 3 , —F, —OH or —O—CH 3 ;
  • n is an integer ranging from 1 to 10;
  • p is an integer ranging from 1 to 5;
  • q is an integer ranging from 1 to 5.
  • the invention provides a compound of Formula (IVc)
  • X is —O—, —CH 2 —, —C(O)—, —NH—, —S—, —N(C 1 -C 4 alkyl)-, —CH(OH)—, —N(C(O)N(H)—(CH 2 ) p —Z)— or —N((CH 2 ) q —Z)—;
  • R 1 is —O—C(C 1 -C 3 alkyl) 2 -(CH 2 ) n —N(R 2 )(R 2 );
  • each R 2 is independently —H, —C 1 -C 6 alkyl, —C 3 -C 8 monocyclic cycloalkyl, C 1 -C 6 alkylene phenyl, phenyl, an N-terminal alpha amino acid residue, an N-terminal alpha amino hydroxymethyl residue, a C 1 -C 6 alkyl ester of an N-terminal alpha amino acid residue, or a nitrogen-containing 3- to 7-membered monocyclic heterocycle, each of which other than hydrogen is independently unsubstituted or substituted with one or more of -halo, —OH, —OP(O)(OH) 2 , —OS(O) 2 OH, —C 1 -C 6 alkyl, —O—C 1 -C 6 alkyl, —C 3 -C 8 monocyclic cycloalkyl, a 3- to 7-membered monocyclic heterocycle, —(C 1 -C 6 alkyl-substit
  • R 2 groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle or a nitrogen-containing 7- to 10-membered bicyclic heterocycle, each of which is unsubstituted or substituted with one or more of —C 1 -C 5 alkyl, —C 3 -C 8 monocyclic cycloalkyl, phenyl, a nitrogen-containing 3- to 7-membered monocyclic heterocycle, -(phenyl-substituted) C 1 -C 5 alkyl, -(hydroxy-substituted) C 1 -C 5 alkyl, -halo, -(halo-substituted) C 1 -C 5 alkyl, -(halo-substituted) phenyl, -phenylene-O—C 1 -C 5 alkyl, -(cyano-substituted) phenyl, —OH, —O—C 1 -C
  • Z is —CF 3 , —F, —OH or —O—CH 3 ;
  • n is an integer ranging from 1 to 10;
  • p is an integer ranging from 1 to 5;
  • q is an integer ranging from 1 to 5.
  • the invention provides a compound of Formula (Va)
  • R 1 is —CH 2 NH—R 2 ;
  • R 2 is a —C 3 -C 8 monocyclic cycloalkyl which is unsubstituted or substituted with one or more of (hydroxy-substituted) C 1 -C 5 alkyl; or a 3- to 7-membered monocyclic heterocycle;
  • X is halo or —H
  • Y′ is halo or —H, wherein at least one of X and Y′ is halo.
  • compositions comprising an effective amount of a compound of Formula (Ia), (Ib), (Ic), (IIa), (IIb), (IIc), (IIIa), (IIIb), (IVa), (IVb), (IVc), (Va), or a pharmaceutically acceptable salt thereof and a physiologically acceptable carrier or vehicle.
  • the invention further provides methods for treating or preventing an inflammatory disease, a reperfusion injury, diabetes mellitus, a diabetic complication, reoxygenation injury resulting from organ transplantation, an ischemic condition, a neurodegenerative disease, renal failure, a vascular disease, a cardiovascular disease, cancer, a complication of prematurity, cardiomyopathy, retinopathy, nephropathy, neuropathy, erectile dysfunction or urinary incontinence (each being a “Condition”), comprising administering to a subject in need thereof an effective amount of an Indenoisoquinolinone Analog of Formula (Ia), (Ib), (Ic), (IIa), (IIb), (IIc), (IIIa), (IIIb), (IVa), (IVb), (IVc), (Va), or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (Ia), Formula (Ib), Formula (Ic), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IIIa), Formula (IIIb), Formula (IVa), Formula (IVb), Formula (IVc), Formula (Va), or a pharmaceutically acceptable salt thereof is useful for treating or preventing a Condition.
  • a composition comprising an effective amount of an Indenoisoquinolinone Analog and a physiologically acceptable carrier or vehicle is useful for treating or preventing a Condition.
  • —C 1 -C 3 alkyl refers to a straight chain or branched non-cyclic hydrocarbon having from 1 to 3 carbon atoms, wherein one of the hydrocarbon's hydrogen atoms has been replaced by a single bond.
  • Representative straight chain —C 1 -C 3 alkyls include -methyl, -ethyl, and -n-propyl.
  • Representative branched —C 1 -C 3 alkyls include isopropyl.
  • —C 1 -C 4 alkyl refers to a straight chain or branched non-cyclic hydrocarbon having from 1 to 4 carbon atoms, wherein one of the hydrocarbon's hydrogen atoms has been replaced by a single bond.
  • Representative straight chain —C 1 -C 4 alkyls include -methyl, -ethyl, -n-propyl, and -n-butyl.
  • Representative branched —C 1 -C 4 alkyls include -isopropyl, -sec-butyl, -isobutyl and -tert-butyl.
  • the —C 1 -C 4 alkyl is substituted with one or more of -halo, —OH, —N(R a ) 2 , —(C 1 -C 5 alkylene)-O—C 1 -C 5 alkyl, —NH 2 , a nitrogen-containing 3- to 7-membered monocyclic heterocycle, or an —(C 1 -C 6 alkyl-substituted) nitrogen-containing 3- to 7-membered monocyclic heterocycle. Unless otherwise indicated, the —C 1 -C 4 alkyl is unsubstituted.
  • C 1 -C 4 alkylene refers to a C 1 -C 4 alkyl group, as defined above, wherein one of the C 1 -C 4 alkyl group's hydrogen atoms has been replaced with a bond.
  • C 2 -C 4 alkylene refers to a straight or branched chain saturated hydrocarbon containing 2-4 carbon atoms, wherein two of the hydrocarbon's hydrogen atoms have been replaced by a single a bond.
  • Representative C 2 -C 4 alkylene groups include, ethylene, n-propylene, isopropylene, n-butylene and isobutylene.
  • —C 1 -C 5 alkyl refers to a straight chain or branched non-cyclic hydrocarbon having from 1 to 5 carbon atoms, wherein one of the hydrocarbon's hydrogen atoms has been replaced by a single bond.
  • Representative straight chain —C 1 -C 5 alkyls include -methyl, -ethyl, -n-propyl, -n-butyl and -n-pentyl.
  • Representative branched —C 1 -C 5 alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl and 1,2-dimethylpropyl.
  • the —C 1 -C 5 alkyl is substituted with one or more of -halo, —OH, —N(R a ) 2 , —C 1 -C 5 alkylene-O—C 1 -C 5 alkyl, —NH 2 , a nitrogen-containing 3- to 7-membered monocyclic heterocycle, or an C 1 -C 6 alkyl-substituted nitrogen-containing 3- to 7-membered monocyclic heterocycle. Unless otherwise indicated, the —C 1 -C 5 alkyl is unsubstituted.
  • C 1 -C 5 alkylene refers to a C 1 -C 5 alkyl group, as defined above, wherein one of the C 1 -C 5 alkyl group's hydrogen atoms has been replaced with a bond.
  • -phenyl-substituted C 1 -C 5 alkyl refers to a “—C 1 -C 5 alkyl” wherein one of the its hydrogen atoms has been replaced by a phenyl group.
  • —C 1 -C 6 alkyl refers to a straight chain or branched non-cyclic hydrocarbon having from 1 to 6 carbon atoms, wherein one of the hydrocarbon's hydrogen atoms has been replaced by a single bond.
  • Representative straight chain —C 1 -C 6 alkyls include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl and n-hexyl.
  • Representative branched —C 1 -C 6 alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, -1-methylbutyl, -isohexyl, -neohexyl, -2-methylbutyl, -3-methylbutyl, -1,1-dimethylpropyl and -1,2-dimethylpropyl.
  • the —C 1 -C 6 alkyl is substituted with one or more of -halo, —OH, —OP(O)(OH) 2 , —OS(O) 2 OH, —C 1 -C 6 alkyl, —O—C 1 -C 6 alkyl, —C 3 -C 8 monocyclic cycloalkyl, a 3- to 7-membered monocyclic heterocycle, —(C 1 -C 6 alkyl-substituted) 3- to 7-membered monocyclic heterocycle, or —N(Z 3 )(Z 4 ). Unless otherwise indicated, the C 1 -C 6 alkyl is unsubstituted.
  • C 1 -C 6 alkylene refers to a C 1 -C 6 alkyl group, as defined above, wherein one of the C 1 -C 6 alkyl group's hydrogen atoms has been replaced with a bond.
  • —C 2 -C 6 alkenyl refers to a straight or branched chain hydrocarbon containing 2-6 carbon atoms and at least one double bond.
  • Representative —C 2 -C 6 alkenyl groups include, but are not limited to, ethylene, propylene, 1-butylene, 2-butylene, isobutylene, sec-butylene, 1-pentene, 2-pentene, isopentene, 1-hexene, 2-hexene, 3-hexene and isohexene.
  • —C 1 -C 9 alkyl refers to a straight chain or branched non-cyclic hydrocarbon having from 1 to 9 carbon atoms, wherein one of the hydrocarbon's hydrogen atoms has been replaced by a single bond.
  • Representative —C 1 -C 9 alkyls include, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -nonyl, isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyl, neopentyl, isohexyl, isoheptyl, isooctyl and isononyl.
  • —C 7 -C 10 alkyl refers to a straight chain or branched non-cyclic hydrocarbon having from 7 to 10 carbon atoms, wherein one of the hydrocarbon's hydrogen atoms has been replaced by a single bond.
  • Representative —C 7 -C 10 alkyls include, but are not limited to, heptyl, octyl, nonyl, isohexyl, isoheptyl, isooctyl and isononyl, decyl, and isodecyl.
  • —C 1 -C 10 alkyl refers to a straight chain or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms, wherein one of the hydrocarbon's hydrogen atoms has been replaced by a single bond.
  • Representative —C 1 -C 10 alkyls include, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -nonyl, decyl, isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyl, neopentyl, isohexyl, isoheptyl, isooctyl, isononyl and isodecyl.
  • —C 3 -C 8 monocyclic cycloalkyl refers to a saturated cyclic hydrocarbon having from 3 to 8 carbon atoms.
  • Representative —C 3 -C 8 monocyclic cycloalkyls include -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl and -cyclooctyl.
  • the —C 3 -C 8 monocyclic cycloalkyl is substituted with one or more of -halo, —OH, —OP(O)(OH) 2 , —OS(O) 2 OH, —C 1 -C 6 alkyl, —O—C 1 -C 6 alkyl, —C 3 -C 8 monocyclic cycloalkyl, a 3- to 7-membered monocyclic heterocycle, —C 1 -C 6 alkyl-substituted 3- to 7-membered monocyclic heterocycle.
  • the —C 3 -C 8 monocyclic cycloalkyl is substituted with one or more of —N(R a ) 2 , —C 1 -C 5 alkylene-O —C 1 -C 5 alkyl, or —NH 2 . Unless otherwise indicated, the —C 3 -C 8 monocyclic cycloalkyl is unsubstituted.
  • a “nitrogen containing 3- to 7-membered monocyclic heterocycle” refers to a monocyclic 3- to 7-membered aromatic or non-aromatic monocyclic cycloalkyl group in which one of the cycloalkyl group's ring carbon atoms has been replaced with a nitrogen atom and 0-4 of the cycloalkyl group's remaining ring carbon atoms are independently replaced with a N, O or S atom.
  • the nitrogen containing 3- to 7-membered monocyclic heterocycles can be attached via a nitrogen, sulfur, or carbon atom.
  • nitrogen-containing 3- to 7-membered monocyclic heterocycles include, but are not limited to, piperidinyl, piperazinyl, pyrrolyl, piperidonyl, oxazinyl, thiazinyl, diazinyl, triazinyl, tetrazinyl, imidazolyl, tetrazolyl, pyrrolidinyl, isoxazolyl, pyridinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, pyrimidinyl, morpholinyl, furuzanyl, pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, pyrazolidinyl, and thiomorpholinyl.
  • the nitrogen-containing 3- to 7-membered monocyclic heterocycle is fully saturated or partially saturated.
  • the nitrogen-containing 3- to 7-membered monocyclic heterocycle is substituted with one or more of -halo, —OH, —OP(O)(OH) 2 , —OS(O) 2 OH, —C 1 -C 6 alkyl, —O—C 1 -C 6 alkyl, —C 3 -C 8 monocyclic cycloalkyl, a 3- to 7-membered monocyclic heterocycle, —(C 1 -C 6 alkyl-substituted) 3- to 7-membered monocyclic heterocycle, or —N(Z 3 )(Z 4 ).
  • the nitrogen-containing 3- to 7-membered monocyclic heterocycle is unsubstituted.
  • a “nitrogen-containing 7- to 10-membered bicyclic heterocycle” refers to a 7- to 10-membered bicyclic ring system that contains at least one ring nitrogen atom.
  • the nitrogen-containing 7- to 10-membered bicyclic heterocycles can be attached via a nitrogen, sulfur, or carbon atom.
  • Representative nitrogen-containing 7- to 10-membered bicyclic heterocycles include -quinolinyl, -isoquinolinyl, -chromonyl, -indolyl, -isoindolyl, -indolinyl, indolizinyl, -indazolyl, -purinyl, -4H-quinolizinyl, -isoquinolyl, -quinolyl, -phthalazinyl, -naphthyridinyl, benzimidazolyl, benzthiazolyl, dihydroquinolyl, dihydroisoquinolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, and pteridyl.
  • the nitrogen-containing 7- to 10-membered bicyclic heterocycle is saturated or partially saturated.
  • a “3- to 7-membered monocyclic heterocycle” refers to a monocyclic 3- to 7-membered aromatic or non-aromatic monocyclic cycloalkyl in which 1-4 of the ring carbon atoms have been independently replaced with a N, O or S atom.
  • the 3- to 7-membered monocyclic heterocycles can be attached via a nitrogen, sulfur, or carbon atom.
  • 3- to 7-membered monocyclic heterocycle group include, but are not limited to, nitrogen-containing 3- to 7-membered monocyclic heterocycles discussed above, tetrahydrofuranyl, dihydrofuranyl, pyranyl, dihydropyranyl, tetrahydropyranyl, thiopyranyl, dihydrothiopyranyl, tetrahydrothiopyranyl, dioxanyl, dithianyl, trithianyl, dioxolanyl, furanyl, and thiophenyl.
  • the 3- to 7-membered monocyclic heterocycle is a nitrogen-containing 3- to 7-membered monocyclic heterocycle. In another embodiment, the 3- to 7-membered monocyclic heterocycle is saturated or partially saturated.
  • a “C 1 -C 6 alkyl-substituted 3- to 7-membered monocyclic heterocycle” refers to a “3- to 7-membered monocyclic heterocycle,” as defined above, wherein one or more of the heterocycle's hydrogen atoms has been replaced by a C 1 -C 6 alkyl, as defined above.
  • Halo is —F, —Cl, —Br or —I.
  • Halo-substituted C 1 -C 5 alkyl refers to a C 1 -C 5 alkyl group, as defined above, wherein one or more of the C 1 -C 5 alkyl group's hydrogen atoms has been replaced with —F, —Cl, —Br or —I.
  • halo-substituted C 1 -C 5 alkyl include, but are not limited to, —CH 2 F, —CCl 3 , —CF 3 , —CH 2 Cl, —CH 2 CH 2 Br, —CH 2 CH 2 I, —CH 2 CH 2 CH 2 F, —CH 2 CH 2 CH 2 Cl, —CH 2 CH 2 CH 2 CH 2 Br, —CH 2 CH 2 CH 2 CH 2 I, —CH 2 CH 2 CH 2 CH 2 CH 2 Br, —CH 2 CH 2 CH 2 CH 2 CH 2 I, —CH 2 CH(Br)CH 3 , —CH 2 CH(Cl)CH 2 CH 3 , —CH(F)CH 2 CH 3 and —C(CH 3 ) 2 (CH 2 Cl).
  • Halo-substituted phenyl refers to a phenyl group, wherein one or more of the phenyl group's hydrogen atoms has been replaced with —F, Cl, —Br or —I.
  • Cyano-substituted phenyl refers to a phenyl group, wherein one or more of the phenyl group's hydrogen atoms has been replaced with CN.
  • Cyano-substituted C 1 -C 5 alkyl refers to a C 1 -C 5 alkyl group, as defined above, wherein one or more of the C 1 -C 5 alkyl group's hydrogen atoms has been replaced with —CN.
  • cyano-substituted C 1 -C 5 alkyl include, but are not limited to, —CH 2 CN, —CH 2 CH 2 CN, —CH 2 CH 2 CH 2 CN, —CH 2 CH 2 CH 2 CH 2 CN, —CH 2 CH 2 CH 2 CH 2 CN, —CH 2 CH(CN)CH 3 , —CH 2 CH(CN)CH 2 CH 3 , —CH(CN)CH 2 CH 3 and —C(CH 3 ) 2 (CH 2 CN).
  • C 1 -C 6 alkylene phenyl refers to a C 1 -C 6 alkyl group, as defined above, wherein one of the C 1 -C 6 alkyl group's hydrogen atoms has been replaced with phenyl.
  • Haldroxy-substituted C 1 -C 5 alkyl refers to a C 1 -C 5 alkyl group, as defined above, wherein one or more of the C 1 -C 5 alkyl group's hydrogen atoms has been replaced with —OH.
  • hydroxy-substituted C 1 -C 5 alkyl include, but are not limited to, —CH 2 OH, —CH 2 CH 2 OH, —CH 2 CH 2 CH 2 OH, —CH 2 CH 2 CH 2 CH 2 OH, —CH 2 CH 2 CH 2 CH 2 OH, —CH 2 CH(OH)CH 3 , —CH 2 CH(OH)CH 2 CH 3 , —CH(OH)CH 2 CH 3 and —C(CH 3 ) 2 (CH 2 OH).
  • C-terminal alpha amino acid residue refers to an L-, D- or racemic natural or unnatural alpha amino acid, less the hydroxyl group of the alpha amino acid's carboxyl group.
  • Representative examples of a C-terminal alpha amino acid residue include, but are not limited to, CH 3 —CH(NH 2 )—C(O)—, HN ⁇ C(NH 2 )—NH—(CH 2 ) 3 —CH(NH 2 )—C(O)—, H 2 N—C(O)—CH 2 —CH(NH 2 )—C(O)—, HOOC—CH 2 —CH(NH 2 )—C(O)—, HS—CH 2 —CH(NH 2 )—C(O)—, H 2 N—C(O)—(CH 2 ) 2 —CH(NH 2 )—C(O)—, HOOC—(CH 2 ) 2 —CH(NH 2 )—C(O)—, H 2 N—C(O)—
  • the C-terminal alpha amino acid is a natural amino acid.
  • the C-terminal alpha amino acid is an unnatural amino acid.
  • the C-terminal alpha amino acid is an L amino acid.
  • N-terminal alpha amino acid residue refers to an L-, D- or racemic natural or unnatural alpha amino acid, less the alpha amino acid's N-terminal amino group.
  • N-terminal alpha amino acid residue include, but are not limited to, —CH 2 —COOH, —CH(CH 3 )COOH, —CH(CH(CH 3 ) 2 )COOH, —CH(CH 2 CH(CH 3 ) 2 )COOH, —CH(CH(CH 3 )(CH 2 CH 3 ))COOH, —CH((CH 2 ) 4 —NH 2 )COOH, —CH((CH 2 ) 3 NH(C ⁇ NH 2 )—NH 2 )COOH, —CH(CH 2 —OH)COOH, —CH(CH((CH 3 )(OH))COOH, —CH(CH 2 —COOH)COOH, —CH((CH 2 ) 2 COOH)COOH, —CH((CH 2 )(CONH 2 ))COOH, —CH((CH 2 ) 2 (CONH 2 ))COOH, —CH(CH 2 —SH)COOH
  • the N-terminal alpha amino acid residue is substituted with one or more of -halo, —OH, —OP(O)(OH) 2 , —OS(O) 2 OH, —C 1 -C 6 alkyl, —O—C 1 -C 6 alkyl, —C 3 -C 8 monocyclic cycloalkyl, a 3- to 7-membered monocyclic heterocycle, —C 1 -C 6 alkyl-substituted 3- to 7-membered monocyclic heterocycle, or —N(Z 3 )(Z 4 ). Unless otherwise indicated, the N-terminal alpha amino acid residue is unsubstituted.
  • N-terminal alpha amino hydroxymethyl residue refers to an “N-terminal alpha amino acid residue,” wherein its C-terminal carboxyl group, a side chain's carboxyl group, or both have been replaced with a hydroxymethyl group.
  • the N-terminal alpha amino hydroxymethyl residue is substituted with one or more of -halo, —OH, —OP(O)(OH) 2 , —OS(O) 2 OH, —C 1 -C 6 alkyl, —O—C 1 -C 6 alkyl, —C 3 -C 8 monocyclic cycloalkyl, a 3- to 7-membered monocyclic heterocycle, —C 1 -C 6 alkyl-substituted 3- to 7-membered monocyclic heterocycle, or —N(Z 3 )(Z 4 ).
  • the hydroxyl group of the hydroxymethyl residue is substituted with —PO 3 H 2 , —P 2 O 6 H 3 , —P 3 O 9 H 4 , —SO 3 H, —C(O)—C 1 -C 9 alkyl, ⁇ -D-glucuronyl, or a C-terminal alpha amino acid residue. Unless otherwise indicated, the N-terminal alpha amino hydroxymethyl residue is unsubstituted.
  • a “C 1 -C 6 alkyl ester of an N-terminal alpha amino acid residue” refers to an “N-terminal alpha amino acid residue,” wherein the hydrogen atom of the amino acid's C-terminal carboxyl group, a side chain's carboxyl group, or both have been replaced by a —C 1 -C 6 alkyl group.
  • the C 1 -C 6 alkyl ester of an N-terminal alpha amino acid residue is a methyl, an ethyl, an n-propyl or an iso-propyl ester of an N-terminal alpha amino acid residue.
  • the C 1 -C 6 alkyl ester of an N-terminal alpha amino acid residue is substituted with one or more of -halo, —OH, —OP(O)(OH) 2 , —OS(O) 2 OH, —C 1 -C 6 alkyl, —O—C 1 -C 6 alkyl, —C 3 -C 8 monocyclic cycloalkyl, a 3- to 7-membered monocyclic heterocycle, —C 1 -C 6 alkyl-substituted 3- to 7-membered monocyclic heterocycle, or —N(Z 3 )(Z 4 ).
  • the C 1 -C 6 alkyl ester of an N-terminal alpha amino acid residue is unsubstituted.
  • the N-terminal alpha amino acid is a natural amino acid.
  • the N-terminal alpha amino acid is an unnatural amino acid.
  • the N-terminal alpha amino acid is an L amino acid.
  • a “ ⁇ -D-glucuronyl” refers to a group having the formula:
  • a “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or rhesus. In one embodiment, the subject is a human.
  • phrases “pharmaceutically acceptable salt,” as used herein, is a salt of an acid and a basic nitrogen atom of an Indenoisoquinolinone Analog.
  • Illustrative salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, and pamoate (i
  • Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-lower alkylamines), such as mono-; bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or
  • the pharmaceutically acceptable salt is a mesylate salt.
  • the pharmaceutically acceptable salt is a camphorsulfonate salt.
  • an “effective amount” when used in connection with an Indenoisoquinolinone Analog is an amount that is effective for treating or preventing a Condition.
  • an “effective amount” when used in connection with another anticancer agent is an amount that is effective for treating or preventing cancer alone or in combination with an Indenoisoquinolinone Analog. “In combination with” includes administration within the same composition and via separate compositions. In the latter instance, the other anticancer agent is administered during a time when the Indenoisoquinolinone Analog exerts its prophylactic or therapeutic effect, or vice versa.
  • DMF is N,N-dimethylformamide
  • THF is tetrahydrofuran
  • DMAC is dimethylacetamide.
  • DMSO is dimethylsulfoxide
  • Et is ethyl
  • Pr is n-propyl
  • i-Pr is isopropyl
  • EtOAc is ethyl acetate
  • EtOH is ethanol
  • Me is methyl
  • MS mass spectrometry
  • Ts is tosylate
  • Tf is triflate
  • Ph is phenyl
  • NMR Nuclear Magnetic Resonance
  • Ms is mesylate
  • LAH lithium aluminum hydride
  • tBoc is t-butyloxycarbonyl.
  • the present invention provides Indenoisoquinolinone Analogs according to Formula (Ia), below:
  • X is —N(CH 3 )—. In another embodiment, X is —N(CH 2 CH 3 )—. In another embodiment, X is —N(CH 2 CH 2 CH 3 )—. In another embodiment, X is —N(CH 2 CH 2 CH 2 CH 3 )—. In another embodiment, X is —N(C(H)(CH 3 )(CH 2 CH 3 ))—. In another embodiment, X is —N(C(H)(CH 3 ) 2 )—. In another embodiment, X is —N(CH 2 C(H)(CH 3 ) 2 )—. In another embodiment, X is —N(C(CH 3 ) 3 )—.
  • R 1 is —(CH 2 ) n —N(R 2 )(R 2 ) and X is —N(CH 3 )—.
  • R 1 is —(CH 2 ) n —N(R 2 )(R 2 ) and X is —N(CH 2 CH 3 )—.
  • R 1 is —(CH 2 ) n —N(R 2 )(R 2 ) and X is —N(CH 2 CH 2 CH 3 )—.
  • R 1 is —(CH 2 ) n —N(R 2 )(R 2 ) and X is —N(CH 2 CH 2 CH 2 CH 3 )—.
  • R 1 is —(CH 2 ) n —N(R 2 )(R 2 ) and X is —N(C(H)(CH 3 )(CH 2 CH 3 ))—.
  • R 1 is —(CH 2 ) n —N(R 2 )(R 2 ) and X is —N(C(H)(CH 3 ) 2 )—.
  • R 1 is —(CH 2 ) n —N(R 2 )(R 2 ) and X is —N(CH 2 C(H)(CH 3 ) 2 )—.
  • R 1 is —(CH 2 ) n —N(R 2 )(R 2 ) and X is —N(C(CH 3 ) 3 )—.
  • R 1 is —O—(CH 2 ) m —N(R 2 )(R 2 ) and X is —N(CH 3 )—.
  • R 1 is —O—(CH 2 ) m —N(R 2 )(R 2 ) and X is —N(CH 2 CH 3 )—.
  • R 1 is —O—(CH 2 ) m —N(R 2 )(R 2 ) and X is —N(CH 2 CH 2 CH 3 )—.
  • R 1 is —O—(CH 2 ) m —N(R 2 )(R 2 ) and X is —N(CH 2 CH 2 CH 2 CH 3 )—.
  • R 1 is —O—(CH 2 ) m —N(R 2 )(R 2 ) and X is —N(C(H)(CH 3 )(CH 2 CH 3 ))—.
  • R 1 is —O—(CH 2 ) m —N(R 2 )(R 2 ) and X is —N(C(H)(CH 3 ) 2 )—.
  • R 1 is —O—(CH 2 ) m —N(R 2 )(R 2 ) and X is —N(CH 2 C(H)(CH 3 ) 2 )—.
  • R 1 is —O—(CH 2 ) m —N(R 2 )(R 2 ) and X is —N(C(CH 3 ) 3 )—.
  • one R 2 is —H, and the other R 2 is —C 1 -C 6 alkyl.
  • each R 2 is —C 1 -C 6 alkyl.
  • each R 2 is -methyl.
  • X is —CH(OH)—.
  • X is —CH(OH)— and R 1 is —(CH 2 ) n —N(R 2 )(R 2 ).
  • X is —CH(OH)— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 ) p —Z)—.
  • X is —N(C(O)N(H)—(CH 2 )—Z)—.
  • X is —N(C(O)N(H)—(CH 2 ) 2 —Z)—.
  • X is —N(C(O)N(H)—(CH 2 ) p —Z)— and R 1 is —(CH 2 ) n —N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 ) p —Z)— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 )—Z)— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N((CH 2 ) q —Z)—.
  • X is —N((CH 2 )—Z)—.
  • X is —N((CH 2 ) 2 —Z)—.
  • X is —N((CH 2 ) q —Z)— and R 1 is —(CH 2 ) n —N(R 2 )(R 2 ). In yet another embodiment, X is —N((CH 2 ) q —Z)— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N((CH 2 )—Z)— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • Z is —CF 3 .
  • Z is —F.
  • Z is —OH
  • Z is O—CH 3 .
  • X is —N(C(O)N(H)—(CH 2 ) p —OH)—.
  • X is —N(C(O)N(H)—(CH 2 ) 2 —OH)—.
  • X is —N(C(O)N(H)—(CH 2 ) p —OH)— and R 1 is —(CH 2 ) n —N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 ) p —OH)— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 ) 2 —OH)— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N((CH 2 ) q —OH)—.
  • X is —N((CH 2 ) 2 —OH)—.
  • X is —N((CH 2 ) q —OH)— and R 1 is —(CH 2 ) p —N(R 2 )(R 2 ).
  • X is —N((CH 2 ) q —OH)— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N((CH 2 ) 2 —OH)— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 ) p —F)—.
  • X is —N(C(O)N(H)—(CH 2 )—F)—.
  • X is —N(C(O)N(H)—(CH 2 ) p —F)— and R 1 is —(CH 2 ) n —N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 ) p —F)— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 )—F)— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N((CH 2 ) q —F)—.
  • X is —N((CH 2 )—F)—.
  • X is —N((CH 2 ) q OH)— and R 1 is —(CH 2 ) p —N(R 2 )(R 2 ).
  • X is —N((CH 2 ) q —F)— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N((CH 2 )—F)— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 ) p —OMe)-.
  • X is —N(C(O)N(H)—(CH 2 ) 2 —OMe)-.
  • X is —N(C(O)N(H)—(CH 2 ) p —OMe)- and R 1 is —(CH 2 ) n —N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 ) p —OMe)- and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 ) 2 —OMe)- and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N((CH 2 ) q —OMe)-.
  • X is —N((CH 2 ) 2 —OMe)-.
  • X is —N((CH 2 ) q —OMe)- and R 1 is —(CH 2 ) n —N(R 2 )(R 2 ).
  • X is —N((CH 2 ) q —OMe)- and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N((CH 2 ) 2 —OMe)- and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 ) p —CF 3 )—.
  • X is —N(C(O)N(H)—(CH 2 )—CF 3 )—.
  • X is —N(C(O)N(H)—(CH 2 ) p —CF 3 )— and R 1 is —(CH 2 ) n —N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 ) p —CF 3 )— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 )—CF 3 )— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N((CH 2 ) q —CF 3 )—.
  • X is —N((CH 2 )—CF 3 )—.
  • X is —N((CH 2 ) q —CF 3 )— and R 1 is —(CH 2 ) p —N(R 2 )(R 2 ).
  • X is —N((CH 2 ) q —CF 3 )— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N((CH 2 )—CF 3 )— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 ) p —CF 3 )—.
  • X is —N(C(O)N(H)—(CH 2 )—CF 3 )—.
  • X is —N(C(O)N(H)—(CH 2 ) p —CF 3 )— and R 1 is —(CH 2 ) n —N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 ) p —CF 3 )— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 )—CF 3 )— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N((CH 2 ) q —CF 3 )—.
  • X is —N((CH 2 )—CF 3 )—.
  • X is —N((CH 2 ) q —CF 3 )— and R 1 is —(CH 2 ) p —N(R 2 )(R 2 ).
  • X is —N((CH 2 ) q —CF 3 )— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N((CH 2 )—CF 3 )— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • n 1
  • n is 2.
  • n 3.
  • n 4, 5, or 6.
  • n 7, 8, or 9.
  • n is 10.
  • n is 2.
  • m is 3.
  • m is 4, 5, or 6.
  • m is 7, 8, or 9.
  • m is 10.
  • p is 1.
  • p is 2.
  • p is an integer ranging from 2 to 5.
  • q is 1.
  • q is 2.
  • q is an integer ranging from 2 to 5.
  • —N(R 2 )(R 2 ) is:
  • —N(R 2 )(R 2 ) is:
  • —N(R 2 )(R 2 ) is
  • —N(R 2 )(R 2 ) is —N(CH 2 CH 3 )(CH 3 ),
  • —N(R 2 )(R 2 ) is
  • —N(Z 3 )(Z 4 ) is:
  • —N(Z 3 )(Z 4 ) is:
  • —N(Z 3 )(Z 4 ) is
  • —N(Z 3 )(Z 4 ) is —N(CH 2 CH 3 )(CH 3 ),
  • —N(Z 3 )(Z 4 ) is
  • X is —N(CH 3 )—, —N(CH 2 CH 3 )—, —N(CH 2 CH 2 CH 3 )—, —N(CH 2 CH 2 CH 2 CH 3 )—, —N(C(H)(CH 3 )(CH 2 CH 3 ))—, —N(C(H)(CH 3 ) 2 )—, —N(CH 2 C(H)(CH 3 ) 2 )— or —N(C(CH 3 ) 3 )—;
  • R 1 is —(CH 2 ) n —N(R 2 )(R 2 ) or —O—(CH 2 ) n —N(R 2 )(R 2 );
  • each R 2 is independently —H, —C 1 -C 6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —(C 1 -C 6 alkylene)-phenyl or -phenyl, each of which other than hydrogen is unsubstituted or substituted with one or more of -halo, —OH, —OP(O)(OH) 2 , —OS(O) 2 OH or —N(Z 3 )(Z 4 ), where Z 3 and Z 4 are independently —H, —C 1 -C 5 alkyl, or —(C 1 -C 5 alkylene)-O —C 1 -C 5 alkyl, each of which other than hydrogen is unsubstituted or substituted with one or more of -halo, —OH or —NH 2 ; or N, Z 3 and Z 4 are taken together to form a nitrogen-containing 3- to 7-membered monocycl
  • n is an integer ranging from 1 to 10;
  • n is an integer ranging from 2 to 10.
  • X is —N(CH 3 )—, —N(CH 2 CH 3 )—, —N(CH 2 CH 2 CH 3 )—, —N(CH 2 CH 2 CH 2 CH 3 )—, —N(C(H)(CH 3 )(CH 2 CH 3 ))—, —N(C(H)(CH 3 ) 2 )—, —N(CH 2 C(H)(CH 3 ) 2 )— or —N(C(CH 3 ) 3 )—;
  • R 1 is —CH 2 —N(R 2 )(R 2 ); and at least one R 2 is methyl.
  • X is —N(CH 3 )—, —N(CH 2 CH 3 )—, —N(CH 2 CH 2 CH 3 )—, —N(CH 2 CH 2 CH 2 CH 3 )—, —N(C(H)(CH 3 )(CH 2 CH 3 ))—, —N(C(H)(CH 3 ) 2 )—, —N(CH 2 C(H)(CH 3 ) 2 )— or —N(C(CH 3 ) 3 )—;
  • R 1 is —CH 2 —N(R 2 )(R 2 ); and at least one R 2 is ethyl.
  • X is —N(CH 3 )—, —N(CH 2 CH 3 )—, —N(CH 2 CH 2 CH 3 )—, —N(CH 2 CH 2 CH 2 CH 3 )—, —N(C(H)(CH 3 )(CH 2 CH 3 ))—, —N(C(H)(CH 3 ) 2 )—, —N(CH 2 C(H)(CH 3 ) 2 )— or —N(C(CH 3 ) 3 )—;
  • R 1 is —CH 2 —N(R 2 )(R 2 ); and at least one R 2 is propyl.
  • X is —N(CH 3 )—, —N(CH 2 CH 3 )—, —N(CH 2 CH 2 CH 3 )—, —N(CH 2 CH 2 CH 2 CH 3 )—, —N(C(H)(CH 3 )(CH 2 CH 3 ))—, —N(C(H)(CH 3 ) 2 )—, —N(CH 2 C(H)(CH 3 ) 2 )— or —N(C(CH 3 ) 3 )—;
  • R 1 is —CH 2 —N(R 2 )(R 2 ); and at least one R 2 is —C 3 -C 8 monocyclic cycloalkyl.
  • X is —N(CH 3 )—, —N(CH 2 CH 3 )—, —N(CH 2 CH 2 CH 3 )—, —N(CH 2 CH 2 CH 2 CH 3 )—, —N(C(H)(CH 3 )(CH 2 CH 3 ))—, —N(C(H)(CH 3 ) 2 )—, —N(CH 2 C(H)(CH 3 ) 2 )— or —N(C(CH 3 ) 3 )—;
  • R 1 is —CH 2 —N(R 2 )(R 2 ); and at least one R 2 is cyclohexyl.
  • X is —N(CH 3 )—, —N(CH 2 CH 3 )—, —N(CH 2 CH 2 CH 3 )—, —N(CH 2 CH 2 CH 2 CH 3 )—, —N(C(H)(CH 3 )(CH 2 CH 3 ))—, —N(C(H)(CH 3 ) 2 )—, —N(CH 2 C(H)(CH 3 ) 2 )— or —N(C(CH 3 ) 3 )—; and R 1 is —CH 2 —N(R 2 )(R 2 ), wherein N and both R 2 groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle.
  • X is —N(CH 3 )—, —N(CH 2 CH 3 )—, —N(CH 2 CH 2 CH 3 )—, —N(CH 2 CH 2 CH 2 CH 3 )—, —N(C(H)(CH 3 )(CH 2 CH 3 ))—, —N(C(H)(CH 3 ) 2 )—, —N(CH 2 C(H)(CH 3 ) 2 )— or —N(C(CH 3 ) 3 )—; and R 1 is —CH 2 —N(R 2 )(R 2 ), wherein N and both R 2 groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which is substituted with a hydroxyl.
  • X is —N(CH 3 )—, —N(CH 2 CH 3 )—, —N(CH 2 CH 2 CH 3 )—, —N(CH 2 CH 2 CH 2 CH 3 )—, —N(C(H)(CH 3 )(CH 2 CH 3 ))—, —N(C(H)(CH 3 ) 2 )—, —N(CH 2 C(H)(CH 3 ) 2 )— or —N(C(CH 3 ) 3 )—; and R 1 is —CH 2 —N(R 2 )(R 2 ), wherein N and both R 2 groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which is substituted with a nitrogen-containing 3- to 7-membered monocyclic heterocycle.
  • Indenoisoquinolinone Analogs include the compounds of Formula (Ia) as set forth below:
  • the present invention provides Indenoisoquinolinone Analogs according to Formula (Ib), below:
  • X is —N(CH 3 )—. In another embodiment, X is —N(CH 2 CH 3 )—. In another embodiment, X is —N(CH 2 CH 2 CH 3 )—. In another embodiment, X is —N(CH 2 CH 2 CH 2 CH 3 )—. In another embodiment, X is —N(C(H)(CH 3 )(CH 2 CH 3 ))—. In another embodiment, X is —N(C(H)(CH 3 ) 2 )—. In another embodiment, X is —N(CH 2 C(H)(CH 3 ) 2 )—. In another embodiment, X is —N(C(CH 3 ) 3 )—.
  • R 1 is —(CH 2 ) n —N(R 2 )(R 2 ) and X is —N(CH 3 )—.
  • R 1 is —(CH 2 ) n —N(R 2 )(R 2 ) and X is —N(CH 2 CH 3 )—.
  • R 1 is —(CH 2 ) n —N(R 2 )(R 2 ) and X is —N(CH 2 CH 2 CH 3 )—.
  • R 1 is —(CH 2 ) n —N(R 2 )(R 2 ) and X is —N(CH 2 CH 2 CH 2 CH 3 )—.
  • R 1 is —(CH 2 ) n —N(R 2 )(R 2 ) and X is —N(C(H)(CH 3 )(CH 2 CH 3 ))—.
  • R 1 is —(CH 2 ) n —N(R 2 )(R 2 ) and X is —N(C(H)(CH 3 ) 2 )—.
  • R 1 is —(CH 2 ) n —N(R 2 )(R 2 ) and X is —N(CH 2 C(H)(CH 3 ) 2 )—.
  • R 1 is —(CH 2 ) n —N(R 2 )(R 2 ) and X is —N(C(CH 3 ) 3 )—.
  • R 1 is —O—(CH 2 ) m —N(R 2 )(R 2 ) and X is —N(CH 3 )—.
  • R 1 is —O—(CH 2 ) m —N(R 2 )(R 2 ) and X is —N(CH 2 CH 3 )—.
  • R 1 is —O—(CH 2 ) m —N(R 2 )(R 2 ) and X is —N(CH 2 CH 2 CH 3 )—.
  • R 1 is —O—(CH 2 ) m —N(R 2 )(R 2 ) and X is —N(CH 2 CH 2 CH 2 CH 3 )—.
  • R 1 is —O—(CH 2 ) m —N(R 2 )(R 2 ) and X is —N(C(H)(CH 3 )(CH 2 CH 3 ))—.
  • R 1 is —O—(CH 2 ) m —N(R 2 )(R 2 ) and X is —N(C(H)(CH 3 ) 2 )—.
  • R 1 is —O—(CH 2 ) m —N(R 2 )(R 2 ) and X is —N(CH 2 C(H)(CH 3 ) 2 )—.
  • R 1 is —O—(CH 2 ) m —N(R 2 )(R 2 ) and X is —N(C(CH 3 ) 3 )—.
  • one R 2 is —H, and the other R 2 is —C 1 -C 6 alkyl.
  • each R 2 is —C 1 -C 6 alkyl.
  • each R 2 is -methyl.
  • X is —CH(OH)—.
  • X is —CH(OH)— and R 1 is —(CH 2 ) n —N(R 2 )(R 2 ).
  • X is —CH(OH)— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 ) p —Z)—.
  • X is —N(C(O)N(H)—(CH 2 )—Z)—.
  • X is —N(C(O)N(H)—(CH 2 ) 2 —Z)—.
  • X is —N(C(O)N(H)—(CH 2 ) p —Z)— and R 1 is —(CH 2 ) n —N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 ) p —Z)— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 )—Z)— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N((CH 2 ) q —Z)—.
  • X is —N((CH 2 )—Z)—.
  • X is —N((CH 2 ) 2 —Z)—.
  • X is —N((CH 2 ) q —Z)— and R 1 is —(CH 2 ) n —N(R 2 )(R 2 ).
  • X is —N((CH 2 ) q —Z)— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N((CH 2 )—Z)— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • Z is —CF 3 .
  • Z is —F.
  • Z is —OH
  • Z is —O—CH 3 .
  • X is —N(C(O)N(H)—(CH 2 ) p —OH)—.
  • X is —N(C(O)N(H)—(CH 2 ) 2 —OH)—.
  • X is —N(C(O)N(H)—(CH 2 ) p —OH)— and R 1 is —(CH 2 ) n —N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 ) p —OH)— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 ) 2 —OH)— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N((CH 2 ) q —OH)—.
  • X is —N((CH 2 ) 2 —OH)—.
  • X is —N((CH 2 ) q —OH)— and R 1 is —(CH 2 ) p —N(R 2 )(R 2 ).
  • X is —N((CH 2 ) q —OH)— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N((CH 2 ) 2 —OH)— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 ) p —F)—.
  • X is —N(C(O)N(H)—(CH 2 )—F)—.
  • X is —N(C(O)N(H)—(CH 2 ) p —F)— and R 1 is —(CH 2 ) n —N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 ) p —F)— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 )—F)— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N((CH 2 ) q —F)—.
  • X is —N((CH 2 )—F)—.
  • X is —N((CH 2 ) q —F)— and R 1 is —(CH 2 ) p —N(R 2 )(R 2 ).
  • X is —N((CH 2 ) q —F)— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N((CH 2 )—F)— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 ) p —OMe)-.
  • X is —N(C(O)N(H)—(CH 2 ) 2 —OMe)-.
  • X is —N(C(O)N(H)—(CH 2 ) p —OMe)- and R 1 is —(CH 2 ) n —N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 ) p —OMe)- and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 ) 2 —OMe)- and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N((CH 2 ) q —OMe)-.
  • X is —N((CH 2 ) 2 —OMe)-.
  • X is —N((CH 2 ) q —OMe)- and R 1 is —(CH 2 ) n —N(R 2 )(R 2 ). In yet another embodiment, X is —N((CH 2 ) q —OMe)- and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N((CH 2 ) 2 —OMe)- and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 ) p —CF 3 )—.
  • X is —N(C(O)N(H)—(CH 2 )—CF 3 )—.
  • X is —N(C(O)N(H)—(CH 2 ) p —CF 3 )— and R 1 is —(CH 2 ) n —N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 ) p —CF 3 )— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 )—CF 3 )— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N((CH 2 ) q —CF 3 )—.
  • X is —N((CH 2 )—CF 3 )—.
  • X is —N((CH 2 ) q —CF 3 )— and R 1 is —(CH 2 ) n —N(R 2 )(R 2 ).
  • X is —N((CH 2 ) q —CF 3 )— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N((CH 2 )—CF 3 )— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 ) p —CF 3 )—.
  • X is —N(C(O)N(H)—(CH 2 )—CF 3 )—.
  • X is —N(C(O)N(H)—(CH 2 ) p —CF 3 )— and R 1 is —(CH 2 ) n —N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 ) p —CF 3 )— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 )—CF 3 )— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N((CH 2 ) q —CF 3 )—.
  • X is —N((CH 2 )—CF 3 )—.
  • X is —N((CH 2 ) q —CF 3 )— and R 1 is —(CH 2 ) n —N(R 2 )(R 2 ).
  • X is —N((CH 2 ) q —CF 3 )— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N((CH 2 )—CF 3 )— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • n 1
  • n is 2.
  • n 3.
  • n 4, 5, or 6.
  • n 7, 8, or 9.
  • n is 10.
  • n is 2.
  • m is 3.
  • m is 4, 5, or 6.
  • m is 7, 8, or 9.
  • m is 10.
  • p is 1.
  • p is 2.
  • p is an integer ranging from 2 to 5.
  • q is 1.
  • q is 2.
  • q is an integer ranging from 2 to 5.
  • —N(R 2 )(R 2 ) is:
  • —N(R 2 )(R 2 ) is:
  • —N(R 2 )(R 2 ) is
  • —N(R 2 )(R 2 ) is —N(CH 2 CH 3 )(CH 3 ),
  • —N(R 2 )(R 2 ) is
  • —N(Z 3 )(Z 4 ) is:
  • —N(Z 3 )(Z 4 ) is:
  • —N(Z 3 )(Z 4 ) is
  • —N(Z 3 )(Z 4 ) is —N(CH 2 CH 3 )(CH 3 ),
  • —N(Z 3 )(Z 4 ) is
  • X is —N(CH 3 )—, —N(CH 2 CH 3 )—, —N(CH 2 CH 2 CH 3 )—, —N(CH 2 CH 2 CH 2 CH 3 )—, —N(C(H)(CH 3 )(CH 2 CH 3 ))—, —N(C(H)(CH 3 ) 2 )—, —N(CH 2 C(H)(CH 3 ) 2 — or —N(C(CH 3 ) 3 )—;
  • R 1 is —(CH 2 ) n —N(R 2 )(R 2 ) or —O—(CH 2 ) n —N(R 2 )(R 2 );
  • each R 2 is independently —H, —C 1 -C 6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —(C 1 -C 6 alkylene)-phenyl or -phenyl, each of which other than hydrogen is unsubstituted or substituted with one or more of -halo, —OH, —OP(O)(OH) 2 , —OS(O) 2 OH or —N(Z 3 )(Z 4 ), where Z 3 and Z 4 are independently —H, —C 1 -C 5 alkyl, or —(C 1 -C 5 alkylene)-O —C 1 -C 5 alkyl, each of which other than hydrogen is unsubstituted or substituted with one or more of -halo, —OH or —NH 2 ;
  • Z 3 and Z 4 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three of —C 1 -C 5 alkyl, -phenyl, —(C 1 -C 5 alkylene)-phenyl, -(hydroxy-substituted) C 1 -C 5 alkyl, -halo, -(halo-substituted) C 1 -C 5 alkyl, -(halo-substituted) phenyl, -phenylene-O—C 1 -C 5 alkyl, -(cyano-substituted) phenyl, —OH, —O—C 1 -C 5 alkyl, —N(R a ) 2 , —(C 1 -C 5 alkylene)-N(R a ) 2 , —C 1 -C 5 alkylene-C(O)O—((O
  • R 2 groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three of —C 1 -C 5 alkyl, -phenyl, —(C 1 -C 5 alkylene) -phenyl, -(hydroxy-substituted) C 1 -C 5 alkyl, -halo, -(halo-substituted) C 1 -C 5 alkyl, -(halo-substituted) phenyl, -phenylene-O—C 1 -C 5 alkyl, -(cyano-substituted) phenyl, —OH, —O—C 1 -C 5 alkyl, —N(R a ) 2 , —(C 1 -C 5 alkylene)-N(R a ) 2 , —(C 1 -C 5 alkylene)-C(O)O
  • n is an integer ranging from 1 to 10;
  • n is an integer ranging from 2 to 10.
  • X is —N(CH 3 )—, —N(CH 2 CH 3 )—, —N(CH 2 CH 2 CH 3 )—, —N(CH 2 CH 2 CH 2 CH 3 )—, —N(C(H)(CH 3 )(CH 2 CH 3 ))—, —N(C(H)(CH 3 ) 2 )—, —N(CH 2 C(H)(CH 3 ) 2 — or —N(C(CH 3 ) 3 )—;
  • R 1 is —CH 2 —N(R 2 )(R 2 ); and at least one R 2 is methyl.
  • X is —N(CH 3 )—, —N(CH 2 CH 3 )—, —N(CH 2 CH 2 CH 3 )—, —N(CH 2 CH 2 CH 2 CH 3 )—, —N(C(H)(CH 3 )(CH 2 CH 3 ))—, —N(C(H)(CH 3 ) 2 )—, —N(CH 2 C(H)(CH 3 ) 2 — or —N(C(CH 3 ) 3 )—;
  • R 1 is —CH 2 —N(R 2 )(R 2 ); and at least one R 2 is ethyl.
  • X is —N(CH 3 )—, —N(CH 2 CH 3 )—, —N(CH 2 CH 2 CH 3 )—, —N(CH 2 CH 2 CH 2 CH 3 )—, —N(C(H)(CH 3 )(CH 2 CH 3 ))—, —N(C(H)(CH 3 ) 2 )—, —N(CH 2 C(H)(CH 3 ) 2 — or —N(C(CH 3 ) 3 )—;
  • R 1 is —CH 2 —N(R 2 )(R 2 ); and at least one R 2 is propyl.
  • X is —N(CH 3 )—, —N(CH 2 CH 3 )—, —N(CH 2 CH 2 CH 3 )—, —N(CH 2 CH 2 CH 2 CH 3 )—, —N(C(H)(CH 3 )(CH 2 CH 3 ))—, —N(C(H)(CH 3 ) 2 )—, —N(CH 2 C(H)(CH 3 ) 2 — or —N(C(CH 3 ) 3 )—;
  • R 1 is —CH 2 —N(R 2 )(R 2 ); and at least one R 2 is —C 3 -C 8 monocyclic cycloalkyl.
  • X is —N(CH 3 )—, —N(CH 2 CH 3 )—, —N(CH 2 CH 2 CH 3 )—, —N(CH 2 CH 2 CH 2 CH 3 )—, —N(C(H)(CH 3 )(CH 2 CH 3 ))—, —N(C(H)(CH 3 ) 2 )—, —N(CH 2 C(H)(CH 3 ) 2 — or —N(C(CH 3 ) 3 )—;
  • R 1 is —CH 2 —N(R 2 )(R 2 ); and at least one R 2 is cyclohexyl.
  • X is —N(CH 3 )—, —N(CH 2 CH 3 )—, —N(CH 2 CH 2 CH 3 )—, —N(CH 2 CH 2 CH 2 CH 3 )—, —N(C(H)(CH 3 )(CH 2 CH 3 ))—, —N(C(H)(CH 3 ) 2 )—, —N(CH 2 C(H)(CH 3 ) 2 — or —N(C(CH 3 ) 3 )—; and R 1 is —CH 2 —N(R 2 )(R 2 ), wherein N and both R 2 groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle.
  • X is —N(CH 3 )—, —N(CH 2 CH 3 )—, —N(CH 2 CH 2 CH 3 )—, —N(CH 2 CH 2 CH 2 CH 3 )—, —N(C(H)(CH 3 )(CH 2 CH 3 ))—, —N(C(H)(CH 3 ) 2 )—, —N(CH 2 C(H)(CH 3 ) 2 — or —N(C(CH 3 ) 3 )—; and R 1 is —CH 2 —N(R 2 )(R 2 ), wherein N and both R 2 groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which is substituted with a hydroxyl.
  • X is —N(CH 3 )—, —N(CH 2 CH 3 )—, —N(CH 2 CH 2 CH 3 )—, —N(CH 2 CH 2 CH 2 CH 3 )—, —N(C(H)(CH 3 )(CH 2 CH 3 ))—, —N(C(H)(CH 3 ) 2 )—, —N(CH 2 C(H)(CH 3 ) 2 — or —N(C(CH 3 ) 3 )—; and R 1 is —CH 2 —N(R 2 )(R 2 ), wherein N and both R 2 groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which is substituted with a nitrogen-containing 3- to 7-membered monocyclic heterocycle.
  • Indenoisoquinolinone Analogs include the compounds of Formula (Ib) as set forth below:
  • the present invention provides Indenoisoquinolinone Analogs according to Formula (Ic), below:
  • X is —N(CH 3 )—. In another embodiment, X is —N(CH 2 CH 3 )—. In another embodiment, X is —N(CH 2 CH 2 CH 3 )—. In another embodiment, X is —N(CH 2 CH 2 CH 2 CH 3 )—. In another embodiment, X is —N(C(H)(CH 3 )(CH 2 CH 3 ))—. In another embodiment, X is —N(C(H)(CH 3 ) 2 )—. In another embodiment, X is —N(CH 2 C(H)(CH 3 ) 2 )—. In another embodiment, X is —N(C(CH 3 ) 3 )—.
  • R 1 is —(CH 2 ) n —N(R 2 )(R 2 ) and X is —N(CH 3 )—.
  • R 1 is —(CH 2 ) n —N(R 2 )(R 2 ) and X is —N(CH 2 CH 3 )—.
  • R 1 is —(CH 2 ) n —N(R 2 )(R 2 ) and X is —N(CH 2 CH 2 CH 3 )—.
  • R 1 is —(CH 2 ) n —N(R 2 )(R 2 ) and X is —N(CH 2 CH 2 CH 2 CH 3 )—.
  • R 1 is —(CH 2 ) n —N(R 2 )(R 2 ) and X is —N(C(H)(CH 3 )(CH 2 CH 3 ))—.
  • R 1 is —(CH 2 ) n —N(R 2 )(R 2 ) and X is —N(C(H)(CH 3 ) 2 )—.
  • R 1 is —(CH 2 ) n —N(R 2 )(R 2 ) and X is —N(CH 2 C(H)(CH 3 ) 2 )—.
  • R 1 is —(CH 2 ) n —N(R 2 )(R 2 ) and X is —N(C(CH 3 ) 3 )—.
  • R 1 is —O—(CH 2 ) m —N(R 2 )(R 2 ) and X is —N(CH 3 )—.
  • R 1 is —O—(CH 2 ) n —N(R 2 )(R 2 ) and X is —N(CH 2 CH 3 )—.
  • R 1 is —O—(CH 2 ) m —N(R 2 )(R 2 ) and X is —N(CH 2 CH 2 CH 3 )—.
  • R 1 is —O—(CH 2 ) m —N(R 2 )(R 2 ) and X is —N(CH 2 CH 2 CH 2 CH 3 )—.
  • R 1 is —O—(CH 2 ) m —N(R 2 )(R 2 ) and X is —N(C(H)(CH 3 )(CH 2 CH 3 ))—.
  • R 1 is —O—(CH 2 ) m —N(R 2 )(R 2 ) and X is —N(C(H)(CH 3 ) 2 )—.
  • R 1 is —O—(CH 2 ) m —N(R 2 )(R 2 ) and X is —N(CH 2 C(H)(CH 3 ) 2 )—.
  • R 1 is —O—(CH 2 ) m —N(R 2 )(R 2 ) and X is —N(C(CH 3 ) 3 )—.
  • one R 2 is —H, and the other R 2 is —C 1 -C 6 alkyl.
  • each R 2 is —C 1 -C 6 alkyl.
  • each R 2 is -methyl.
  • X is —CH(OH)—.
  • X is —CH(OH)— and R 1 is —(CH 2 ) n —N(R 2 )(R 2 ).
  • X is —CH(OH)— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 ) p —Z)—.
  • X is —N(C(O)N(H)—(CH 2 )—Z)—.
  • X is —N(C(O)N(H)—(CH 2 ) 2 —Z)—.
  • X is —N(C(O)N(H)—(CH 2 ) p —Z)— and R 1 is —(CH 2 ) n —N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 ) p —Z)— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 )—Z)— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N((CH 2 ) q —Z)—.
  • X is —N((CH 2 )—Z)—.
  • X is —N((CH 2 ) 2 —Z)—.
  • X is —N((CH 2 ) q —Z)— and R 1 is —(CH 2 ) n —N(R 2 )(R 2 ).
  • X is —N((CH 2 ) q —Z)— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N((CH 2 )—Z)— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • Z is —CF 3 .
  • Z is —F.
  • Z is —OH
  • Z is O—CH 3 .
  • X is —N(C(O)N(H)—(CH 2 ) p —OH)—.
  • X is —N(C(O)N(H)—(CH 2 ) 2 —OH)—.
  • X is —N(C(O)N(H)—(CH 2 ) p —OH)— and R 1 is —(CH 2 ) n —N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 ) p —OH)— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 ) 2 —OH)— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N((CH 2 ) q —OH)—.
  • X is —N((CH 2 ) 2 —OH)—.
  • X is —N((CH 2 ) q —OH)— and R 1 is —(CH 2 ) n —N(R 2 )(R 2 ).
  • X is —N((CH 2 ) q —OH)— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N((CH 2 ) 2 —OH)— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 ) p —F)—.
  • X is —N(C(O)N(H)—(CH 2 )—F)—.
  • X is —N(C(O)N(H)—(CH 2 ) p —F)— and R 1 is —(CH 2 ) n —N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 ) p —F)— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 )—F)— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N((CH 2 ) q —F)—.
  • X is —N((CH 2 )—F)—.
  • X is —N((CH 2 ) q —F)— and R 1 is —(CH 2 ) n —N(R 2 )(R 2 ).
  • X is —N((CH 2 ) q —F)— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N((CH 2 )—F)— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 ) p —OMe)-.
  • X is —N(C(O)N(H)—(CH 2 ) 2 —OMe)-.
  • X is —N(C(O)N(H)—(CH 2 ) p —OMe)- and R 1 is —(CH 2 ) n —N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 ) p —OMe)- and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 ) 2 —OMe)- and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N((CH 2 ) q —OMe)-.
  • X is —N((CH 2 ) 2 —OMe)-.
  • X is —N((CH 2 ) q —OMe)- and R 1 is —(CH 2 ) n —N(R 2 )(R 2 ).
  • X is —N((CH 2 ) q —OMe)- and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N((CH 2 ) 2 —OMe)- and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 ) p —CF 3 )—.
  • X is —N(C(O)N(H)—(CH 2 )—CF 3 )—.
  • X is —N(C(O)N(H)—(CH 2 ) p —CF 3 )— and R 1 is —(CH 2 ) n —N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 ) p —CF 3 )— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 )—CF 3 )— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N((CH 2 ) q —CF 3 )—.
  • X is —N((CH 2 )—CF 3 )—.
  • X is —N((CH 2 ) q —CF 3 )— and R 1 is —(CH 2 ) p —N(R 2 )(R 2 ).
  • X is —N((CH 2 ) q —CF 3 )— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N((CH 2 )—CF 3 )— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 ) p —CF 3 )—.
  • X is —N(C(O)N(H)—(CH 2 )—CF 3 )—.
  • X is —N(C(O)N(H)—(CH 2 ) p —CF 3 )— and R 1 is —(CH 2 ) n —N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 ) p —CF 3 )— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N(C(O)N(H)—(CH 2 )—CF 3 )— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N((CH 2 ) q —CF 3 )—.
  • X is —N((CH 2 )—CF 3 )—.
  • X is —N((CH 2 ) q —CF 3 )— and R 1 is —(CH 2 ) p —N(R 2 )(R 2 ).
  • X is —N((CH 2 ) q —CF 3 )— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • X is —N((CH 2 )—CF 3 )— and R 1 is —(CH 2 )—N(R 2 )(R 2 ).
  • n 1
  • n is 2.
  • n 3.
  • n 4, 5, or 6.
  • n 7, 8, or 9.
  • n is 10.
  • n is 2.
  • m is 3.
  • m is 4, 5, or 6.
  • m is 7, 8, or 9.
  • m is 10.
  • p is 1.
  • p is 2.
  • p is an integer ranging from 2 to 5.
  • q is 1.
  • q is 2.
  • q is an integer ranging from 2 to 5.
  • —N(R 2 )(R 2 ) is:
  • —N(R 2 )(R 2 ) is:
  • —N(R 2 )(R 2 ) is
  • —N(R 2 )(R 2 ) is —N(CH 2 CH 3 )(CH 3 ),
  • —N(R 2 )(R 2 ) is
  • —N(Z 3 )(Z 4 ) is:
  • —N(Z 3 )(Z 4 ) is:
  • —N(Z 3 )(Z 4 ) is
  • —N(Z 3 )(Z 4 ) is —N(CH 2 CH 3 )(CH 3 ),
  • —N(Z 3 )(Z 4 ) is
  • X is —N(CH 3 )—, —N(CH 2 CH 3 )—, —N(CH 2 CH 2 CH 3 )—, —N(CH 2 CH 2 CH 2 CH 3 )—, —N(C(H)(CH 3 )(CH 2 CH 3 ))—, —N(C(H)(CH 3 ) 2 )—, —N(CH 2 C(H)(CH 3 ) 2 — or —N(C(CH 3 ) 3 )—;
  • R 1 is —(CH 2 ) n —N(R 2 )(R 2 ) or —O—(CH 2 ) n —N(R 2 )(R 2 );
  • each R 2 is independently —H, —C 1 -C 6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —(C 1 -C 6 alkylene)-phenyl or -phenyl, each of which other than hydrogen is unsubstituted or substituted with one or more of -halo, —OH, —OP(O)(OH) 2 , —OS(O) 2 OH or —N(Z 3 )(Z 4 ), where Z 3 and Z 4 are independently —H, —C 1 -C 5 alkyl, or —(C 1 -C 5 alkylene)-O—C 1 -C 5 alkyl, each of which other than hydrogen is unsubstituted or substituted with one or more of -halo, —OH or —NH 2 ;
  • Z 3 and Z 4 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three of —C 1 -C 5 alkyl, -phenyl, —(C 1 -C 5 alkylene)-phenyl, -(hydroxy-substituted) C 1 -C 5 alkyl, -halo, -(halo-substituted) C 1 -C 5 alkyl, -(halo-substituted) phenyl, -phenylene-O—C 1 -C 5 alkyl, -(cyano-substituted) phenyl, —OH, —O—C 1 -C 5 alkyl, —N(R a ) 2 , —(C 1 -C 5 alkylene)-N(R a ) 2 , —C 1 -C 5 alkylene-C(O)O—((O
  • R 2 groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three of —C 1 -C 5 alkyl, -phenyl, —(C 1 -C 5 alkylene) -phenyl, -(hydroxy-substituted) C 1 -C 5 alkyl, -halo, -(halo-substituted) C 1 -C 5 alkyl, -(halo-substituted) phenyl, -phenylene-O—C 1 -C 5 alkyl, -(cyano-substituted) phenyl, —OH, —O—C 1 -C 5 alkyl, —N(R a ) 2 , —(C 1 -C 5 alkylene)-N(R a ) 2 , —(C 1 -C 5 alkylene)-C(O)O
  • n is an integer ranging from 1 to 10;
  • n is an integer ranging from 2 to 10.
  • X is —N(CH 3 )—, —N(CH 2 CH 3 )—, —N(CH 2 CH 2 CH 3 )—, —N(CH 2 CH 2 CH 2 CH 3 )—, —N(C(H)(CH 3 )(CH 2 CH 3 ))—, —N(C(H)(CH 3 ) 2 )—, —N(CH 2 C(H)(CH 3 ) 2 — or —N(C(CH 3 ) 3 )—;
  • R 1 is —CH 2 —N(R 2 )(R 2 ); and at least one R 2 is methyl.
  • X is —N(CH 3 )—, —N(CH 2 CH 3 )—, —N(CH 2 CH 2 CH 3 )—, —N(CH 2 CH 2 CH 2 CH 3 )—, —N(C(H)(CH 3 )(CH 2 CH 3 ))—, —N(C(H)(CH 3 ) 2 )—, —N(CH 2 C(H)(CH 3 ) 2 — or —N(C(CH 3 ) 3 )—;
  • R 1 is —CH 2 —N(R 2 )(R 2 ); and at least one R 2 is ethyl.
  • X is —N(CH 3 )—, —N(CH 2 CH 3 )—, —N(CH 2 CH 2 CH 3 )—, —N(CH 2 CH 2 CH 2 CH 3 )—, —N(C(H)(CH 3 )(CH 2 CH 3 ))—, —N(C(H)(CH 3 ) 2 )—, —N(CH 2 C(H)(CH 3 ) 2 — or —N(C(CH 3 ) 3 )—;
  • R 1 is —CH 2 —N(R 2 )(R 2 ); and at least one R 2 is propyl.
  • X is —N(CH 3 )—, —N(CH 2 CH 3 )—, —N(CH 2 CH 2 CH 3 )—, —N(CH 2 CH 2 CH 2 CH 3 )—, —N(C(H)(CH 3 )(CH 2 CH 3 ))—, —N(C(H)(CH 3 ) 2 )—, —N(CH 2 C(H)(CH 3 ) 2 — or —N(C(CH 3 ) 3 )—;
  • R 1 is —CH 2 —N(R 2 )(R 2 ); and at least one R 2 is —C 3 -C 8 monocyclic cycloalkyl.
  • X is —N(CH 3 )—, —N(CH 2 CH 3 )—, —N(CH 2 CH 2 CH 3 )—, —N(CH 2 CH 2 CH 2 CH 3 )—, —N(C(H)(CH 3 )(CH 2 CH 3 ))—, —N(C(H)(CH 3 ) 2 )—, —N(CH 2 C(H)(CH 3 ) 2 — or —N(C(CH 3 ) 3 )—;
  • R 1 is —CH 2 —N(R 2 )(R 2 ); and at least one R 2 is cyclohexyl.
  • X is —N(CH 3 )—, —N(CH 2 CH 3 )—, —N(CH 2 CH 2 CH 3 )—, —N(CH 2 CH 2 CH 2 CH 3 )—, —N(C(H)(CH 3 )(CH 2 CH 3 ))—, —N(C(H)(CH 3 ) 2 )—, —N(CH 2 C(H)(CH 3 ) 2 — or —N(C(CH 3 ) 3 )—; and R 1 is —CH 2 —N(R 2 )(R 2 ), wherein N and both R 2 groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle.
  • X is —N(CH 3 )—, —N(CH 2 CH 3 )—, —N(CH 2 CH 2 CH 3 )—, —N(CH 2 CH 2 CH 2 CH 3 )—, —N(C(H)(CH 3 )(CH 2 CH 3 ))—, —N(C(H)(CH 3 ) 2 )—, —N(CH 2 C(H)(CH 3 ) 2 — or —N(C(CH 3 ) 3 )—; and R 1 is —CH 2 —N(R 2 )(R 2 ), wherein N and both R 2 groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which is substituted with a hydroxyl.
  • X is —N(CH 3 )—, —N(CH 2 CH 3 )—, —N(CH 2 CH 2 CH 3 )—, —N(CH 2 CH 2 CH 2 CH 3 )—, —N(C(H)(CH 3 )(CH 2 CH 3 ))—, —N(C(H)(CH 3 ) 2 )—, —N(CH 2 C(H)(CH 3 ) 2 — or —N(C(CH 3 ) 3 )—; and R 1 is —CH 2 —N(R 2 )(R 2 ), wherein N and both R 2 groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which is substituted with a nitrogen-containing 3- to 7-membered monocyclic heterocycle.
  • Indenoisoquinolinone Analogs include the compounds of Formula (Ic) as set forth below:
  • the present invention provides Indenoisoquinolinone Analogs according to Formula (IIa), below:
  • X and R 1 are as defined above for the compounds of Formula (IIa).
  • X is —CH 2 —. In another embodiment, X is —O—. In another embodiment, X is —C(O)—. In another embodiment, X is —NH—. In another embodiment, X is —N(C 1 -C 4 alkyl)-. In another embodiment, X is —S—. In another embodiment, X is —CH(OH)—.
  • n is 1. In another embodiment, n is 2.
  • X is —CH 2 — and n is 1.
  • X is —CH 2 — and n is 2.
  • X is —CH(OH)— and n is 1.
  • X is —CH(OH)— and n is 2.
  • R 2 is —C 1 -C 6 alkyl and R 3 is —C(O)—(C 1 -C 6 alkylene)-(3- to 7-membered monocyclic heterocycle).
  • R 2 is —H and R 3 is —C(O)—(C 1 -C 6 alkylene)-(3- to 7-membered monocyclic heterocycle).
  • n is 1 and R 3 is a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one —C(O)O—C 1 -C 6 alkyl.
  • n is 1 and R 3 is C 3 -C 8 monocyclic cycloalkyl substituted with one hydroxy-substituted C 1 -C 5 alkyl.
  • n is 2 and R 3 is a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one —C(O)O—C 1 -C 6 alkyl.
  • n is 2 and R 3 is C 3 -C 8 monocyclic cycloalkyl substituted with one hydroxy-substituted C 1 -C 5 alkyl.
  • N, R 2 and R 3 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which substituted with one of —C 2 -C 6 alkenyl, —C(O)—C 1 -C 6 alkyl, —(C 1 -C 4 alkylene)-C(O)—(C 3 -C 8 monocyclic cycloalkyl), —C 7 -C 10 alkyl, —(C 1 -C 5 alkylene)C(H)(—O—C 1 -C 4 alkyl) 2 , -(cyano-substituted) C 1 -C 5 alkyl, —(C 1 -C 5 alkylene)-C(O)-(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or —(C 1 -C 5 alkylene)-(3- to 7-membered monocyclic heterocycle).
  • n is 1 and N, R 2 and R 3 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which substituted with one of C 2 -C 6 alkenyl, —C(O)—C 1 -C 6 alkyl, —(C 1 -C 4 alkylene)-C(O)—(C 3 -C 8 monocyclic cycloalkyl), —C 7 -C 10 alkyl, —(C 1 -C 5 alkylene)C(H)(—O—C 1 -C 4 alkyl) 2 , -(cyano-substituted) C 1 -C 5 alkyl, —(C 1 -C 5 alkylene)-C(O)-(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or —(C 1 -C 5 alkylene)-(3- to 7-membered monocyclic heterocycle).
  • X is —CH 2 —
  • n is 1 and N
  • R 2 and R 3 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which substituted with one of —C 2 -C 6 alkenyl, —C(O)—C 1 -C 6 alkyl, —(C 1 -C 4 alkylene)-C(O)—(C 3 -C 8 monocyclic cycloalkyl), —C 7 -C 10 alkyl, —(C 1 -C 5 alkylene)C(H)(—O—C 1 -C 4 alkyl) 2 , -(cyano-substituted) C 1 -C 5 alkyl, —(C 1 -C 5 alkylene)-C(O)-(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or —(C 1 -C 5 alkylene)-(3- to 7-membered monocyclic heterocycle
  • X is —CH 2 —
  • n is 1
  • R 2 is C 3 -C 8 monocyclic cycloalkyl.
  • X is —CH 2 —
  • n is 1
  • R 3 is a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one —C(O)O—C 1 -C 6 alkyl.
  • X is —CH 2 —
  • n is 1
  • R 3 is C 3 -C 8 monocyclic cycloalkyl which is substituted with one hydroxy-substituted C 1 -C 5 alkyl.
  • X is —CH 2 —, n is 1, R 2 is —H, and R 3 is a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one —C(O)O—C 1 -C 6 alkyl.
  • X is —CH 2 —, n is 1, R 2 is —H, and R 3 is C 3 -C 8 monocyclic cycloalkyl which is substituted with one hydroxy-substituted C 1 -C 5 alkyl.
  • X is —CH 2 —, n is 1 and R 3 is —C(O)—C 1 -C 6 alkylene-(3- to 7-membered monocyclic heterocycle).
  • X is CH(OH)—
  • n is 1 and N
  • R 2 and R 3 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which substituted with one of —C 2 -C 6 alkenyl, —C(O)—C 1 -C 6 alkyl, —(C 1 -C 4 alkylene)-C(O)—(C 3 -C 8 monocyclic cycloalkyl), —C 7 -C 10 alkyl, —(C 1 -C 5 alkylene)C(H)(—O—C 1 -C 4 alkyl) 2 , -(cyano-substituted) C 1 -C 5 alkyl, —(C 1 -C 5 alkylene)-C(O)-(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or —(C 1 -C 5 alkylene)-(3- to 7-membered monocyclic heterocycle).
  • X is —CH(OH)—, n is 1, and R 2 is C 3 -C 8 monocyclic cycloalkyl.
  • X is —CH(OH)—
  • n is 1
  • R 3 is a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one —C(O)O—C 1 -C 6 alkyl.
  • X is —CH(OH)—, n is 1, and R 3 is C 3 -C 8 monocyclic cycloalkyl which is substituted with one hydroxy-substituted C 1 -C 5 alkyl.
  • X is —CH(OH)—, n is 1, R 2 is —H, and R 3 is a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one —C(O)O—C 1 -C 6 alkyl.
  • X is —CH(OH)—, n is 1, R 2 is —H, and R 3 is C 3 -C 8 monocyclic cycloalkyl which is substituted with one hydroxy-substituted C 1 -C 5 alkyl.
  • X is —CH(OH)—, n is 1 and R 3 is —C(O)—C 1 -C 6 alkylene-(3- to 7-membered monocyclic heterocycle).
  • —R 1 is:
  • Indenoisoquinolinone Analogs include the compounds of Formula (IIa) in which n is 1 as set forth below:
  • the present invention provides Indenoisoquinolinone Analogs according to Formula (IIb) below:
  • X and R 1 are as defined above for the compounds of Formula (IIb).
  • X is —CH 2 —. In another embodiment, X is —O—. In another embodiment, X is —C(O)—. In another embodiment, X is —NH—. In another embodiment, X is —N(C 1 -C 4 alkyl)-. In another embodiment, X is —S—. In another embodiment, X is —CH(OH)—.
  • n is 1. In another embodiment, n is 2.
  • X is —CH 2 — and n is 1.
  • X is —CH 2 — and n is 2.
  • X is —CH(OH)— and n is 1.
  • X is —CH(OH)— and n is 2.
  • R 2 is —C 1 -C 6 alkyl and R 3 is —C(O)—(C 1 -C 6 alkylene)-(3- to 7-membered monocyclic heterocycle).
  • R 2 is —H and R 3 is —C(O)—(C 1 -C 6 alkylene)-(3- to 7-membered monocyclic heterocycle).
  • n is 1 and R 3 is a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one —C(O)O—C 1 -C 6 alkyl.
  • n is 1 and R 3 is C 3 -C 8 monocyclic cycloalkyl substituted with one hydroxy-substituted C 1 -C 5 alkyl.
  • n is 2 and R 3 is a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one —C(O)O—C 1 -C 6 alkyl.
  • n is 2 and R 3 is C 3 -C 8 monocyclic cycloalkyl substituted with one hydroxy-substituted C 1 -C 5 alkyl.
  • N, R 2 and R 3 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which substituted with one of —C 2 -C 6 alkenyl, —C(O)—C 1 -C 6 alkyl, —(C 1 -C 4 alkylene)-C(O)—(C 3 -C 8 monocyclic cycloalkyl), —C 7 -C 10 alkyl, —(C 1 -C 5 alkylene)C(H)(—O—C 1 -C 4 alkyl) 2 , -(cyano-substituted) C 1 -C 5 alkyl, —(C 1 -C 5 alkylene)-C(O)-(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or —(C 1 -C 5 alkylene)-(3- to 7-membered monocyclic heterocycle).
  • n is 1 and N, R 2 and R 3 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which substituted with one of —C 2 -C 6 alkenyl, —C(O)—C 1 -C 6 alkyl, —(C 1 -C 4 alkylene)-C(O)—(C 3 -C 8 monocyclic cycloalkyl), —C 7 -C 10 alkyl, —(C 1 -C 5 alkylene)C(H)(—O—C 1 -C 4 alkyl) 2 , -(cyano-substituted) C 1 -C 5 alkyl, —(C 1 -C 5 alkylene)-C(O)-(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or —(C 1 -C 5 alkylene)-(3- to 7-membered monocyclic heterocycle).
  • X is —CH 2 —
  • n is 1 and N
  • R 2 and R 3 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which substituted with one of —C 2 -C 6 alkenyl, —C(O)—C 1 -C 6 alkyl, —(C 1 -C 4 alkylene)-C(O)—(C 3 -C 8 monocyclic cycloalkyl), —C 7 -C 10 alkyl, —(C 1 -C 5 alkylene)C(H)(—O—C 1 -C 4 alkyl) 2 , -(cyano-substituted) C 1 -C 5 alkyl, —(C 1 -C 5 alkylene)-C(O)-(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or —(C 1 -C 5 alkylene)-(3- to 7-membered monocyclic heterocycle
  • X is —CH 2 —
  • n is 1
  • R 2 is C 3 -C 8 monocyclic cycloalkyl.
  • X is —CH 2 —
  • n is 1
  • R 3 is a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one —C(O)O—C 1 -C 6 alkyl.
  • X is —CH 2 —
  • n is 1
  • R 3 is C 3 -C 8 monocyclic cycloalkyl which is substituted with one hydroxy-substituted C 1 -C 5 alkyl.
  • X is —CH 2 —, n is 1, R 2 is —H, and R 3 is a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one —C(O)O—C 1 -C 6 alkyl.
  • X is —CH 2 —, n is 1, R 2 is —H, and R 3 is C 3 -C 8 monocyclic cycloalkyl which is substituted with one hydroxy-substituted C 1 -C 5 alkyl.
  • X is —CH 2 —, n is 1 and R 3 is —C(O)—C 1 -C 6 alkylene-(3- to 7-membered monocyclic heterocycle).
  • X is CH(OH)—
  • n is 1 and N
  • R 2 and R 3 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which substituted with one of —C 2 -C 6 alkenyl, —C(O)—C 1 -C 6 alkyl, —(C 1 -C 4 alkylene)-C(O)—(C 3 -C 8 monocyclic cycloalkyl), —C 7 -C 10 alkyl, —(C 1 -C 5 alkylene)C(H)(—O—C 1 -C 4 alkyl) 2 , -(cyano-substituted) C 1 -C 5 alkyl, —(C 1 -C 5 alkylene)-C(O)-(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or —(C 1 -C 5 alkylene)-(3- to 7-membered monocyclic heterocycle).
  • X is —CH(OH)—, n is 1, and R 2 is C 3 -C 8 monocyclic cycloalkyl.
  • X is —CH(OH)—
  • n is 1
  • R 3 is a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one —C(O)O—C 1 -C 6 alkyl.
  • X is —CH(OH)—, n is 1, and R 3 is C 3 -C 8 monocyclic cycloalkyl which is substituted with one hydroxy-substituted C 1 -C 5 alkyl.
  • X is —CH(OH)—, n is 1, R 2 is —H, and R 3 is a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one —C(O)O—C 1 -C 6 alkyl.
  • X is —CH(OH)—, n is 1, R 2 is —H, and R 3 is C 3 -C 8 monocyclic cycloalkyl which is substituted with one hydroxy-substituted C 1 -C 5 alkyl.
  • X is —CH(OH)—, n is 1 and R 3 is —C(O)—C 1 -C 6 alkylene-(3- to 7-membered monocyclic heterocycle).
  • —R 1 is:
  • Indenoisoquinolinone Analogs include the compounds of Formula (IIb) in which n is 1 as set forth below:
  • the present invention provides Indenoisoquinolinone Analogs according to Formula (IIc) below:
  • X and R 1 are as defined above for the compounds of Formula (IIc).
  • X is —CH 2 —. In another embodiment, X is —O—. In another embodiment, X is —C(O)—. In another embodiment, X is —NH—. In another embodiment, X is —N(C 1 -C 4 alkyl)-. In another embodiment, X is —S—. In another embodiment, X is —CH(OH)—.
  • n is 1. In another embodiment, n is 2.
  • X is —CH 2 — and n is 1.
  • X is —CH 2 — and n is 2.
  • X is —CH(OH)— and n is 1.
  • X is —CH(OH)— and n is 2.
  • R 2 is —C 1 -C 6 alkyl and R 3 is —C(O)—(C 1 -C 6 alkylene)-(3- to 7-membered monocyclic heterocycle).
  • R 2 is —H and R 3 is —C(O)—(C 1 -C 6 alkylene)-(3- to 7-membered monocyclic heterocycle).
  • n is 1 and R 3 is a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one —C(O)O—C 1 -C 6 alkyl.
  • n is 1 and R 3 is C 3 -C 8 monocyclic cycloalkyl substituted with one hydroxy-substituted C 1 -C 5 alkyl.
  • n is 2 and R 3 is a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one —C(O)O—C 1 -C 6 alkyl.
  • n is 2 and R 3 is C 3 -C 8 monocyclic cycloalkyl substituted with one hydroxy-substituted C 1 -C 5 alkyl.
  • N, R 2 and R 3 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which substituted with one of —C 2 -C 6 alkenyl, —C(O)—C 1 -C 6 alkyl, —(C 1 -C 4 alkylene)-C(O)—(C 3 -C 8 monocyclic cycloalkyl), —C 7 -C 10 alkyl, —(C 1 -C 5 alkylene)C(H)(—O—C 1 -C 4 alkyl) 2 , -(cyano-substituted) C 1 -C 5 alkyl, —(C 1 -C 5 alkylene)-C(O)-(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or —(C 1 -C 5 alkylene)-(3- to 7-membered monocyclic heterocycle).
  • n is 1 and N, R 2 and R 3 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which substituted with one of —C 2 -C 6 alkenyl, —C(O)—C 1 -C 6 alkyl, —(C 1 -C 4 alkylene)-C(O)—(C 3 -C 8 monocyclic cycloalkyl), —C 7 -C 10 alkyl, —(C 1 -C 5 alkylene)C(H)(—O—C 1 -C 4 alkyl) 2 , -(cyano-substituted) C 1 -C 5 alkyl, —(C 1 -C 5 alkylene)-C(O)-(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or —(C 1 -C 5 alkylene)-(3- to 7-membered monocyclic heterocycle).
  • X is —CH 2 —
  • n is 1 and N
  • R 2 and R 3 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which substituted with one of —C 2 -C 6 alkenyl, —C(O)—C 1 -C 6 alkyl, —(C 1 -C 4 alkylene)-C(O)—(C 3 -C 8 monocyclic cycloalkyl), —C 7 -C 10 alkyl, —(C 1 -C 5 alkylene)C(H)(—O—C 1 -C 4 alkyl) 2 , -(cyano-substituted) C 1 -C 5 alkyl, —(C 1 -C 5 alkylene)-C(O)-(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or —(C 1 -C 5 alkylene)-(3- to 7-membered monocyclic heterocycle
  • X is —CH 2 —
  • n is 1
  • R 2 is C 3 -C 8 monocyclic cycloalkyl.
  • X is —CH 2 —
  • n is 1
  • R 3 is a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one —C(O)O—C 1 -C 6 alkyl.
  • X is —CH 2 —
  • n is 1
  • R 3 is C 3 -C 8 monocyclic cycloalkyl which is substituted with one hydroxy-substituted C 1 -C 5 alkyl.
  • X is —CH 2 —, n is 1, R 2 is —H, and R 3 is a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one —C(O)O—C 1 -C 6 alkyl.
  • X is —CH 2 —, n is 1, R 2 is —H, and R 3 is C 3 -C 8 monocyclic cycloalkyl which is substituted with one hydroxy-substituted C 1 -C 5 alkyl.
  • X is —CH 2 —, n is 1 and R 3 is —C(O)—C 1 -C 6 alkylene-(3- to 7-membered monocyclic heterocycle).
  • X is CH(OH)—
  • n is 1 and N
  • R 2 and R 3 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which substituted with one of —C 2 -C 6 alkenyl, —C(O)—C 1 -C 6 alkyl, —(C 1 -C 4 alkylene)-C(O)—(C 3 -C 8 monocyclic cycloalkyl), —C 7 -C 10 alkyl, —(C 1 -C 5 alkylene)C(H)(—O—C 1 -C 4 alkyl) 2 , -(cyano-substituted) C 1 -C 5 alkyl, —(C 1 -C 5 alkylene)-C(O)-(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or —(C 1 -C 5 alkylene)-(3- to 7-membered monocyclic heterocycle).
  • X is —CH(OH)—, n is 1, and R 2 is C 3 -C 8 monocyclic cycloalkyl.
  • X is —CH(OH)—
  • n is 1
  • R 3 is a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one —C(O)O—C 1 -C 6 alkyl.
  • X is —CH(OH)—, n is 1, and R 3 is C 3 -C 8 monocyclic cycloalkyl which is substituted with one hydroxy-substituted C 1 -C 5 alkyl.
  • X is —CH(OH)—, n is 1, R 2 is —H, and R 3 is a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one —C(O)O—C 1 -C 6 alkyl.
  • X is —CH(OH)—, n is 1, R 2 is —H, and R 3 is C 3 -C 8 monocyclic cycloalkyl which is substituted with one hydroxy-substituted C 1 -C 5 alkyl.
  • X is —CH(OH)—, n is 1 and R 3 is —C(O)—C 1 -C 6 alkylene-(3- to 7-membered monocyclic heterocycle).
  • —R 1 is:
  • Indenoisoquinolinone Analogs include the compounds of Formula (IIc) in which n is 1 as set forth below:
  • the present invention provides the following Indenoisoquinolinone Analogs according to Formula (IIIa) as set forth below:
  • IIIa Compound -R 1 IIIa-1 IIIa-2 IIIa-3 IIIa-4 IIIa-5 IIIa-6 IIIa-7 IIIa-8 IIIa-9 IIIa-10 IIIa-11 IIIa-12 IIIa-13 IIIa-14 IIIa-15 IIIa-16 IIIa-17 IIIa-18 IIIa-19 IIIa-20 IIIa-21 IIIa-22 IIIa-23 IIIa-24
  • the present invention provides the following Indenoisoquinolinone Analogs according to Formula (IIIb) as set forth below:
  • IIIb Compound -R 1 IIIb-1 IIIb-2 IIIb-3 IIIb-4 IIIb-5 IIIb-6 IIIb-7 IIIb-8 IIIb-9 IIIb-10 IIIb-11 IIIb-12 IIIb-13 IIIb-14 IIIb-15 IIIb-16 IIIb-17 IIIb-18 IIIb-19 IIIb-20 IIIb-21 IIIb-22 IIIb-23 IIIb-24
  • the present invention provides Indenoisoquinolinone Analogs according to Formula (IVa), below:
  • X is —N(CH 3 )—. In another embodiment, X is —N(CH 2 CH 3 )—. In another embodiment, X is —N(CH 2 CH 2 CH 3 )—. In another embodiment, X is —N(CH 2 CH 2 CH 2 CH 3 )—. In another embodiment, X is —N(C(H)(CH 3 )(CH 2 CH 3 ))—. In another embodiment, X is —N(C(H)(CH 3 ) 2 )—. In another embodiment, X is —N(CH 2 C(H)(CH 3 ) 2 )—. In another embodiment, X is —N(C(CH 3 ) 3 )—.
  • X is —O—. In one embodiment, X is CH 2 —. In one embodiment, X is C(O)—. In one embodiment, X is —NH—. In one embodiment, X is —S—.
  • X is —CH(OH)—.
  • each C 1 -C 3 alkyl is independent of the other C 1 -C 3 alkyl.
  • each C 1 -C 3 alkyl is methyl.
  • each C 1 -C 3 alkyl is methyl and X is CH 2 —.
  • each C 1 -C 3 alkyl is methyl and X is —CH(OH)—.
  • each C 1 -C 3 alkyl is methyl, X is CH 2 — and n is 1.
  • each C 1 -C 3 alkyl is methyl, X is —CH(OH)— and n is 1.
  • X is —CH(OH)— and n is 1.
  • X is —N(C(O)N(H)—(CH 2 ) p —Z)—.
  • X is —N(C(O)N(H)—(CH 2 )—Z)—.
  • X is —N(C(O)N(H)—(CH 2 ) 2 —Z)—.
  • X is —N(C(O)N(H)—(CH 2 ) p —Z)— and n is 1.
  • X is —N(C(O)N(H)—(CH 2 ) 2 —Z)— and n is 2.
  • X is —N(C(O)N(H)—(CH 2 )—Z)— and n is 1.
  • X is —N((CH 2 ) q —Z)—.
  • X is —N((CH 2 )—Z)—.
  • X is —N((CH 2 ) 2 —Z)—.
  • X is —N((CH 2 ) q —Z)— and n is 1.
  • X is —N((CH 2 ) q —Z)— and n is 2.
  • X is —N((CH 2 )—Z)— and n is 1.
  • X is —N((CH 2 )—Z)— and n is 2.
  • Z is —CF 3 .
  • Z is —F.
  • Z is —OH
  • Z is O—CH 3 .
  • X is —N(C(O)N(H)—(CH 2 ) p —OH)—.
  • X is —N(C(O)N(H)—(CH 2 ) 2 —OH)—.
  • X is —N(C(O)N(H)—(CH 2 ) p —OH)— and n is 1.
  • X is —N(C(O)N(H)—(CH 2 ) p —OH)— and n is 2.
  • X is —N(C(O)N(H)—(CH 2 ) 2 —OH)— and n is 1.
  • X is —N(C(O)N(H)—(CH 2 ) 2 —OH)— and n is 2.
  • X is —N((CH 2 ) q —OH)—.
  • X is —N((CH 2 ) 2 —OH)—.
  • X is —N((CH 2 ) q —OH)— and n is 1.
  • X is —N((CH 2 ) q —OH)— and n is 2.
  • X is —N((CH 2 ) 2 —OH)— and n is 1.
  • X is —N(C(O)N(H)—(CH 2 ) p —F)—.
  • X is —N(C(O)N(H)—(CH 2 )—F)—.
  • X is —N(C(O)N(H)—(CH 2 ) p —F)— and n is 1.
  • X is —N(C(O)N(H)—(CH 2 ) p —F)— n is 2.
  • X is —N(C(O)N(H)—(CH 2 )—F)— and n is 1.
  • X is —N((CH 2 ) q —F)—.
  • X is —N((CH 2 )—F)—.
  • X is —N((CH 2 ) q —F)— and n is 1.
  • X is —N((CH 2 ) q —F)— and n is 2.
  • X is —N((CH 2 )—F)— and n is 1.
  • X is —N(C(O)N(H)—(CH 2 ) p —OMe)-.
  • X is —N(C(O)N(H)—(CH 2 ) 2 —OMe)-.
  • X is —N(C(O)N(H)—(CH 2 ) p —OMe)- and n is 1.
  • X is —N(C(O)N(H)—(CH 2 ) p —OMe)- and n is 2.
  • X is —N(C(O)N(H)—(CH 2 ) 2 —OMe)- and n is 1.
  • X is —N((CH 2 ) q —OMe)-.
  • X is —N((CH 2 ) 2 —OMe)-.
  • X is —N((CH 2 ) q —OMe)- and n is 1.
  • X is —N((CH 2 ) q —OMe)- and n is 2.
  • X is —N((CH 2 ) 2 —OMe)- and n is 1.
  • X is —N(C(O)N(H)—(CH 2 ) p —CF 3 )—.
  • X is —N(C(O)N(H)—(CH 2 )—CF 3 )—.
  • X is —N(C(O)N(H)—(CH 2 ) p —CF 3 )— and n is 1.
  • X is —N(C(O)N(H)—(CH 2 ) p —CF 3 )— and n is 2.
  • X is —N(C(O)N(H)—(CH 2 )—CF 3 )— and n is 1.
  • X is —N((CH 2 ) q —CF 3 )—.
  • X is —N((CH 2 )—CF 3 )—.
  • X is —N((CH 2 ) q —CF 3 )— and n is 1.
  • X is —N((CH 2 ) q —CF 3 )— and n is 2.
  • X is —N((CH 2 )—CF 3 )— and n is 1.
  • X is —N(C(O)N(H)—(CH 2 ) p —CF 3 )—.
  • X is —N(C(O)N(H)—(CH 2 )—CF 3 )—.
  • X is —N(C(O)N(H)—(CH 2 ) p —CF 3 )— and n is 1.
  • X is —N(C(O)N(H)—(CH 2 ) p —CF 3 )— and n is 2.
  • X is —N(C(O)N(H)—(CH 2 )—CF 3 )— and n is 1.
  • X is —N((CH 2 ) q —CF 3 )—.
  • X is —N((CH 2 )—CF 3 )—.
  • X is —N((CH 2 ) q —CF 3 )— and n is 1.
  • X is —N((CH 2 ) q —CF 3 )— and n is 2.
  • X is —N((CH 2 )—CF 3 )— and n is 1.
  • n 1
  • n is 2.
  • n 3.
  • n 4, 5, or 6.
  • n 7, 8, or 9.
  • n is 10.
  • p is 1.
  • p is 2.
  • p is an integer ranging from 2 to 5.
  • q is 1.
  • q is 2.
  • q is an integer ranging from 2 to 5.
  • n 1 and X is —N(CH 3 )—.
  • n 1 and X is —N(CH 2 CH 3 ).
  • n is 1 and X is —N(CH 2 CH 2 CH 3 )—.
  • n is 1 and X is —N(CH 2 CH 2 CH 2 CH 3 )—.
  • n is 1 and X is —N(C(H)(CH 3 )(CH 2 CH 3 ))—.
  • n is 1 and X is —N(C(H)(CH 3 ) 2 )—.
  • n is 1 and X is —N(CH 2 C(H)(CH 3 ) 2 )—.
  • n is 1 and X is —N(C(CH 3 ) 3 )—.
  • one R 2 is —H, and the other R 2 is —C 1 -C 6 alkyl.
  • each R 2 is —C 1 -C 6 alkyl.
  • each R 2 is -methyl.
  • —N(R 2 )(R 2 ) is:
  • —N(R 2 )(R 2 ) is:
  • —N(R 2 )(R 2 ) is
  • —N(R 2 )(R 2 ) is —N(CH 2 CH 3 )(CH 3 ),
  • —N(R 2 )(R 2 ) is
  • —N(Z 3 )(Z 4 ) is:
  • —N(Z 3 )(Z 4 ) is:
  • —N(Z 3 )(Z 4 ) is
  • —N(Z 3 )(Z 4 ) is —N(CH 2 CH 3 )(CH 3 ),
  • —N(Z 3 )(Z 4 ) is
  • X is —N(CH 3 )—, —N(CH 2 CH 3 )—, —N(CH 2 CH 2 CH 3 )—, —N(CH 2 CH 2 CH 2 CH 3 )—, —N(C(H)(CH 3 )(CH 2 CH 3 ))—, —N(C(H)(CH 3 ) 2 )—, —N(CH 2 C(H)(CH 3 ) 2 )— or —N(C(CH 3 ) 3 )—;
  • n is an integer ranging from 1 to 3;
  • each R 2 is independently —H, —C 1 -C 6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —(C 1 -C 6 alkylene)-phenyl or -phenyl, each of which other than hydrogen is unsubstituted or substituted with one or more of -halo, —OH, —OP(O)(OH) 2 , —OS(O) 2 OH or —N(Z 3 )(Z 4 ), where Z 3 and Z 4 are independently —H, —C 1 -C 5 alkyl, or —(C 1 -C 5 alkylene)-O—C 1 -C 5 alkyl, each of which other than hydrogen is unsubstituted or substituted with one or more of -halo, —OH or —NH 2 ;
  • Z 3 and Z 4 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three of —C 1 -C 5 alkyl, -phenyl, —(C 1 -C 5 alkylene)-phenyl, -(hydroxy-substituted) C 1 -C 5 alkyl, -halo, -(halo-substituted) C 1 -C 5 alkyl, -(halo-substituted) phenyl, -phenylene-O—C 1 -C 5 alkyl, -(cyano-substituted) phenyl, —OH, —O—C 1 -C 5 alkyl, —N(R a ) 2 , —(C 1 -C 5 alkylene)-N(R a ) 2 , —C 1 -C 5 alkylene-C(O)O—((O
  • R 2 groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three of —C 1 -C 5 alkyl, -phenyl, —(C 1 -C 5 alkylene) -phenyl, -(hydroxy-substituted) C 1 -C 5 alkyl, -halo, -(halo-substituted) C 1 -C 5 alkyl, -(halo-substituted) phenyl, -phenylene-O—C 1 -C 5 alkyl, -(cyano-substituted) phenyl, —OH, —O—C 1 -C 5 alkyl, —N(R a ) 2 , —(C 1 -C 5 alkylene)-N(R a ) 2 , —(C 1 -C 5 alkylene)-C(O)O
  • X is —N(CH 3 )—, —N(CH 2 CH 3 )—, —N(CH 2 CH 2 CH 3 )—, —N(CH 2 CH 2 CH 2 CH 3 )—, —N(C(H)(CH 3 )(CH 2 CH 3 ))—, —N(C(H)(CH 3 ) 2 )—, —N(CH 2 C(H)(CH 3 ) 2 )— or —N(C(CH 3 ) 3 )—;
  • n is an integer ranging from 1 to 3; and at least one C 1 -C 3 alkyl is methyl.
  • X is —N(CH 3 )—, —N(CH 2 CH 3 )—, —N(CH 2 CH 2 CH 3 )—, —N(CH 2 CH 2 CH 2 CH 3 )—, —N(C(H)(CH 3 )(CH 2 CH 3 ))—, —N(C(H)(CH 3 ) 2 )—, —N(CH 2 C(H)(CH 3 ) 2 )— or —N(C(CH 3 ) 3 )—; at least one C 1 -C 3 alkyl is methyl; and at least one R 2 is ethyl.
  • X is —N(CH 3 )—, —N(CH 2 CH 3 )—, —N(CH 2 CH 2 CH 3 )—, —N(CH 2 CH 2 CH 2 CH 3 )—, —N(C(H)(CH 3 )(CH 2 CH 3 ))—, —N(C(H)(CH 3 ) 2 )—, —N(CH 2 C(H)(CH 3 ) 2 )— or —N(C(CH 3 ) 3 )—; at least one C 1 -C 3 alkyl is methyl; and at least one R 2 is propyl.
  • X is —N(CH 3 )—, —N(CH 2 CH 3 )—, —N(CH 2 CH 2 CH 3 )—, —N(CH 2 CH 2 CH 2 CH 3 )—, —N(C(H)(CH 3 )(CH 2 CH 3 ))—, —N(C(H)(CH 3 ) 2 )—, —N(CH 2 C(H)(CH 3 ) 2 )— or —N(C(CH 3 ) 3 )—; at least one C 1 -C 3 alkyl is methyl; and at least one R 2 is —C 3 -C 8 monocyclic cycloalkyl.
  • X is —N(CH 3 )—, —N(CH 2 CH 3 )—, —N(CH 2 CH 2 CH 3 )—, —N(CH 2 CH 2 CH 2 CH 3 )—, —N(C(H)(CH 3 )(CH 2 CH 3 ))—, —N(C(H)(CH 3 ) 2 )—, —N(CH 2 C(H)(CH 3 ) 2 )— or —N(C(CH 3 ) 3 )—; at least one C 1 -C 3 alkyl is methyl; and at least one R 2 is cyclohexyl.
  • X is —N(CH 3 )—, —N(CH 2 CH 3 )—, —N(CH 2 CH 2 CH 3 )—, —N(CH 2 CH 2 CH 2 CH 3 )—, —N(C(H)(CH 3 )(CH 2 CH 3 ))—, —N(C(H)(CH 3 ) 2 )—, —N(CH 2 C(H)(CH 3 ) 2 )— or —N(C(CH 3 ) 3 )—; and at least one C 1 -C 3 alkyl is methyl, wherein N and both R 2 groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle.
  • X is —N(CH 3 )—, —N(CH 2 CH 3 )—, —N(CH 2 CH 2 CH 3 )—, —N(CH 2 CH 2 CH 2 CH 3 )—, —N(C(H)(CH 3 )(CH 2 CH 3 ))—, —N(C(H)(CH 3 ) 2 )—, —N(CH 2 C(H)(CH 3 ) 2 )— or —N(C(CH 3 ) 3 )—; and at least one C 1 -C 3 alkyl is methyl, wherein N and both R 2 groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which is substituted with a hydroxyl.
  • X is —N(CH 3 )—, —N(CH 2 CH 3 )—, —N(CH 2 CH 2 CH 3 )—, —N(CH 2 CH 2 CH 2 CH 3 )—, —N(C(H)(CH 3 )(CH 2 CH 3 ))—, —N(C(H)(CH 3 ) 2 )—, —N(CH 2 C(H)(CH 3 ) 2 )— or —N(C(CH 3 ) 3 )—; and at least one C 1 -C 3 alkyl is methyl, wherein N and both R 2 groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which is substituted with a nitrogen-containing 3- to 7-membered monocyclic heterocycle.
  • Indenoisoquinolinone Analogs include the compounds of Formula (IVa) as set forth below:
  • the present invention provides Indenoisoquinolinone Analogs according to Formula (IVb), below:
  • X is —N(CH 3 )—. In another embodiment, X is —N(CH 2 CH 3 )—. In another embodiment, X is —N(CH 2 CH 2 CH 3 )—. In another embodiment, X is —N(CH 2 CH 2 CH 2 CH 3 )—. In another embodiment, X is —N(C(H)(CH 3 )(CH 2 CH 3 ))—. In another embodiment, X is —N(C(H)(CH 3 ) 2 )—. In another embodiment, X is —N(CH 2 C(H)(CH 3 ) 2 )—. In another embodiment, X is —N(C(CH 3 ) 3 )—.
  • X is —O—. In one embodiment, X is CH 2 —. In one embodiment, X is C(O)—. In one embodiment, X is —NH—. In one embodiment, X is —S—.
  • X is —CH(OH)—.
  • each C 1 -C 3 alkyl is independent of the other C 1 -C 3 alkyl.
  • each C 1 -C 3 alkyl is methyl.
  • each C 1 -C 3 alkyl is methyl and X is CH 2 —.
  • each C 1 -C 3 alkyl is methyl and X is —CH(OH)—.
  • each C 1 -C 3 alkyl is methyl, X is CH 2 — and n is 1.
  • each C 1 -C 3 alkyl is methyl, X is —CH(OH)— and n is 1.
  • X is —CH(OH)— and n is 1.
  • X is —N(C(O)N(H)—(CH 2 ) p —Z)—.
  • X is —N(C(O)N(H)—(CH 2 )—Z)—.
  • X is —N(C(O)N(H)—(CH 2 ) 2 —Z)—.
  • X is —N(C(O)N(H)—(CH 2 ) p —Z)— and n is 1.
  • X is —N(C(O)N(H)—(CH 2 ) 2 —Z)— and n is 2.
  • X is —N(C(O)N(H)—(CH 2 )—Z)— and n is 1.
  • X is —N((CH 2 ) q —Z)—.
  • X is —N((CH 2 )—Z)—.
  • X is —N((CH 2 ) 2 —Z)—.
  • X is —N((CH 2 ) q —Z)— and n is 1.
  • X is —N((CH 2 ) q —Z)— and n is 2.
  • X is —N((CH 2 )—Z)— and n is 1.
  • X is —N((CH 2 )—Z)— and n is 2.
  • Z is —CF 3 .
  • Z is —F.
  • Z is —OH
  • Z is O—CH 3 .
  • X is —N(C(O)N(H)—(CH 2 ) p —OH)—.
  • X is —N(C(O)N(H)—(CH 2 ) 2 —OH)—.
  • X is —N(C(O)N(H)—(CH 2 ) p —OH)— and n is 1.
  • X is —N(C(O)N(H)—(CH 2 ) p —OH)— and n is 2.
  • X is —N(C(O)N(H)—(CH 2 ) 2 —OH)— and n is 1.
  • X is —N(C(O)N(H)—(CH 2 ) 2 —OH)— and n is 2.
  • X is —N((CH 2 ) q —OH)—.
  • X is —N((CH 2 ) 2 —OH)—.
  • X is —N((CH 2 ) q —OH)— and n is 1.
  • X is —N((CH 2 ) q —OH)— and n is 2.
  • X is —N((CH 2 ) 2 —OH)— and n is 1.
  • X is —N(C(O)N(H)—(CH 2 ) p —F)—.
  • X is —N(C(O)N(H)—(CH 2 )—F)—.
  • X is —N(C(O)N(H)—(CH 2 ) p —F)— and n is 1.
  • X is —N(C(O)N(H)—(CH 2 ) p —F)— n is 2.
  • X is —N(C(O)N(H)—(CH 2 )—F)— and n is 1.
  • X is —N((CH 2 ) q —F)—.
  • X is —N((CH 2 )—F)—.
  • X is —N((CH 2 ) q —F)— and n is 1.
  • X is —N((CH 2 ) q —F)— and n is 2.
  • X is —N((CH 2 )—F)— and n is 1.
  • X is —N(C(O)N(H)—(CH 2 ) p —OMe)-.
  • X is —N(C(O)N(H)—(CH 2 ) 2 —OMe)-.
  • X is —N(C(O)N(H)—(CH 2 ) p —OMe)- and n is 1.
  • X is —N(C(O)N(H)—(CH 2 ) p —OMe)- and n is 2.
  • X is —N(C(O)N(H)—(CH 2 ) 2 —OMe)- and n is 1.
  • X is —N((CH 2 ) q —OMe)-.
  • X is —N((CH 2 ) 2 —OMe)-.
  • X is —N((CH 2 ) q —OMe)- and n is 1.
  • X is —N((CH 2 ) q —OMe)- and n is 2.
  • X is —N((CH 2 ) 2 —OMe)- and n is 1.
  • X is —N(C(O)N(H)—(CH 2 ) p —CF 3 )—.
  • X is —N(C(O)N(H)—(CH 2 )—CF 3 )—.
  • X is —N(C(O)N(H)—(CH 2 ) p —CF 3 )— and n is 1.
  • X is —N(C(O)N(H)—(CH 2 ) p —CF 3 )— and n is 2.
  • X is —N(C(O)N(H)—(CH 2 )—CF 3 )— and n is 1.
  • X is —N((CH 2 ) q —CF 3 )—.
  • X is —N((CH 2 )—CF 3 )—.
  • X is —N((CH 2 ) q —CF 3 )— and n is 1.
  • X is —N((CH 2 ) q —CF 3 )— and n is 2.
  • X is —N((CH 2 )—CF 3 )— and n is 1.
  • X is —N(C(O)N(H)—(CH 2 ) p —CF 3 )—.
  • X is —N(C(O)N(H)—(CH 2 )—CF 3 )—.
  • X is —N(C(O)N(H)—(CH 2 ) p —CF 3 )— and n is 1.
  • X is —N(C(O)N(H)—(CH 2 ) p —CF 3 )— and n is 2.
  • X is —N(C(O)N(H)—(CH 2 )—CF 3 )— and n is 1.
  • X is —N((CH 2 ) q —CF 3 )—.
  • X is —N((CH 2 )—CF 3 )—.
  • X is —N((CH 2 ) q —CF 3 )— and n is 1.
  • X is —N((CH 2 ) q —CF 3 )— and n is 2.
  • X is —N((CH 2 )—CF 3 )— and n is 1.
  • n 1
  • n is 2.
  • n 3.
  • n 4, 5, or 6.
  • n 7, 8, or 9.
  • n is 10.
  • p is 1.
  • p is 2.
  • p is an integer ranging from 2 to 5.
  • q is 1.
  • q is 2.
  • q is an integer ranging from 2 to 5.
  • n 1 and X is —N(CH 3 )—.
  • n 1 and X is —N(CH 2 CH 3 ).
  • n is 1 and X is —N(CH 2 CH 2 CH 3 )—.
  • n is 1 and X is —N(CH 2 CH 2 CH 2 CH 3 )—.
  • n is 1 and X is —N(C(H)(CH 3 )(CH 2 CH 3 ))—.
  • n is 1 and X is —N(C(H)(CH 3 ) 2 )—.
  • n is 1 and X is —N(CH 2 C(H)(CH 3 ) 2 )—.
  • n is 1 and X is —N(C(CH 3 ) 3 )—.
  • one R 2 is —H, and the other R 2 is —C 1 -C 6 alkyl.
  • each R 2 is —C 1 -C 6 alkyl.
  • each R 2 is -methyl.
  • —N(R 2 )(R 2 ) is:
  • —N(R 2 )(R 2 ) is:
  • —N(R 2 )(R 2 ) is
  • —N(R 2 )(R 2 ) is —N(CH 2 CH 3 )(CH 3 ),
  • —N(R 2 )(R 2 ) is
  • —N(Z 3 )(Z 4 ) is:
  • —N(Z 3 )(Z 4 ) is:
  • —N(Z 3 )(Z 4 ) is
  • —N(Z 3 )(Z 4 ) is
  • —N(Z 3 )(Z 4 ) is
  • X is —N(CH 3 )—, —N(CH 2 CH 3 )—, —N(CH 2 CH 2 CH 3 )—, —N(CH 2 CH 2 CH 2 CH 3 )—, —N(C(H)(CH 3 )(CH 2 CH 3 ))—, —N(C(H)(CH 3 ) 2 )—, —N(CH 2 C(H)(CH 3 ) 2 — or —N(C(CH 3 ) 3 )—;
  • n is an integer ranging from 1 to 3;
  • each R 2 is independently —H, —C 1 -C 6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —(C 1 -C 6 alkylene)-phenyl or -phenyl, each of which other than hydrogen is unsubstituted or substituted with one or more of -halo, —OH, —OP(O)(OH) 2 , —OS(O) 2 OH or —N(Z 3 )(Z 4 ), where Z 3 and Z 4 are independently —H, —C 1 -C 5 alkyl, or —(C 1 -C 5 alkylene)-O —C 1 -C 5 alkyl, each of which other than hydrogen is unsubstituted or substituted with one or more of -halo, —OH or —NH 2 ; or N, Z 3 and Z 4 are taken together to form a nitrogen-containing 3- to 7-membered monocycl
  • X is —N(CH 3 )—, —N(CH 2 CH 3 )—, —N(CH 2 CH 2 CH 3 )—, —N(CH 2 CH 2 CH 2 CH 3 )—, —N(C(H)(CH 3 )(CH 2 CH 3 ))—, —N(C(H)(CH 3 ) 2 )—, —N(CH 2 C(H)(CH 3 ) 2 — or —N(C(CH 3 ) 3 )—;
  • n is an integer ranging from 1 to 3;
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110160706A1 (en) * 2009-12-18 2011-06-30 Vysera Biomedical Limited Urological device
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US10835257B2 (en) 2007-10-17 2020-11-17 Covidien Lp Methods of managing neurovascular obstructions

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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US10518003B2 (en) * 2014-07-07 2019-12-31 Meril Life Sciences Pvt. Ltd. Method to manufacture thin strut stent from bioabsorbable polymer with high fatigue and radial strength
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WO2018118852A1 (en) * 2016-12-22 2018-06-28 Purdue Research Foundation Azaindenoisoquinoline compounds and uses thereof

Citations (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3710795A (en) * 1970-09-29 1973-01-16 Alza Corp Drug-delivery device with stretched, rate-controlling membrane
US4113731A (en) * 1975-08-27 1978-09-12 Gruppo Lepetit S.P.A. Fused isoquinoline derivatives
US4263304A (en) * 1978-06-05 1981-04-21 Sumitomo Chemical Company, Limited 7 H-indolo[2,3-c]isoquinolines
US5079246A (en) * 1988-12-09 1992-01-07 Beacham Group P. L. C. Novel indoloquinlones
US5177075A (en) * 1988-08-19 1993-01-05 Warner-Lambert Company Substituted dihydroisoquinolinones and related compounds as potentiators of the lethal effects of radiation and certain chemotherapeutic agents; selected compounds, analogs and process
US5260316A (en) * 1991-07-30 1993-11-09 Ciba-Geigy Corporation Isoquinolyl substituted hydroxylamine derivatives
US5262564A (en) * 1992-10-30 1993-11-16 Octamer, Inc. Sulfinic acid adducts of organo nitroso compounds useful as retroviral inactivating agents anti-retroviral agents and anti-tumor agents
US5597831A (en) * 1991-08-29 1997-01-28 Vufb A.S 6-[X-(2-hydroxyethyl) aminoalkyl]-5,11-dioxo-5,6-dihydro-11-H-indeno[1,2-c]isoquinolines and their use as antineoplastic agents
US5710162A (en) * 1994-05-20 1998-01-20 Taiho Pharmaceutical Co., Ltd. Condensed-indan derivatives and pharmaceutically acceptable salts thereof
US6277990B1 (en) * 1999-12-07 2001-08-21 Inotek Corporation Substituted phenanthridinones and methods of use thereof
US6346535B1 (en) * 1999-01-29 2002-02-12 American Cyanamid Company Fungicidal mixtures
US6346536B1 (en) * 1997-09-03 2002-02-12 Guilford Pharmaceuticals Inc. Poly(ADP-ribose) polymerase inhibitors and method for treating neural or cardiovascular tissue damage using the same
US20030039628A1 (en) * 1998-08-24 2003-02-27 Kristoffer Hellstrand Activation and protection of T-cells (CD4+ and CD8+) using an H2 receptor agonist and other T-cell activating agents
US6635642B1 (en) * 1997-09-03 2003-10-21 Guilford Pharmaceuticals Inc. PARP inhibitors, pharmaceutical compositions comprising same, and methods of using same
US20040039009A1 (en) * 2001-08-31 2004-02-26 Prakash Jagtap Isoquinoline derivatives and methods of use thereof
US6723733B2 (en) * 2000-05-19 2004-04-20 Guilford Pharmaceuticals, Inc. Sulfonamide and carbamide derivatives of 6(5H)phenanthridinones and their uses
US20040077667A1 (en) * 2000-12-11 2004-04-22 Nobuya Matsuoka Quinazolinone derivatives
US20040120926A1 (en) * 1999-07-16 2004-06-24 Kristoffer Hellstrand Reactive oxygen metabolite inhibitors for use in compositions and methods of treatment
US20040229895A1 (en) * 2003-02-28 2004-11-18 Inotek Pharmaceuticals Corporation Tetracyclic benzamide derivatives and methods of use thereof
US6828319B2 (en) * 2001-08-31 2004-12-07 Inotek Pharmaceuticals Corporation Substituted indeno[1,2-c]isoquinoline derivatives and methods of use thereof
US20050228007A1 (en) * 2004-02-26 2005-10-13 Prakash Jagtap Isoquinoline derivatives and methods of use thereof
US20050261288A1 (en) * 2004-02-26 2005-11-24 Prakash Jagtap Tetracyclic lactam derivatives and uses thereof
US20060019980A1 (en) * 2004-06-16 2006-01-26 Inotek Pharmaceutical, Corp. Methods for treating or preventing erectile dysfunction or urinary incontinence
US20060079510A1 (en) * 2004-09-30 2006-04-13 Kristoffer Hellstrand Use of PARP-1 inhibitors for protecting tumorcidal lymphocytes from apoptosis
US20060287311A1 (en) * 2005-02-25 2006-12-21 Inotek Pharmaceuticals Corporation Tetracyclic Sulfonamide Compounds and methods of use thereof
US20060287312A1 (en) * 2005-02-25 2006-12-21 Inotek Pharmaceuticals Corporation Tetracyclic amino and carboxamido compounds and methods of use thereof
US20060287313A1 (en) * 2005-02-25 2006-12-21 Inotek Pharmaceuticals Corporation Isoquinoline compounds and methods of use thereof
US7652028B2 (en) * 2005-08-24 2010-01-26 Inotek Pharmaceuticals Corporation Indenoisoquinolinone analogs and methods of use thereof

Family Cites Families (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2025932B (en) 1978-06-13 1982-10-27 Sumitomo Chemical Co Indoloisoquinolines and processes for producing them
ATE136786T1 (de) 1989-09-19 1996-05-15 Syntello Inc Anti-tumor-zubereitung enthaltend interleukin-2 und histamin, analoge dazu oder h2-rezeptor- agonisten
SK278794B6 (sk) 1991-08-29 1998-03-04 V�Fb 2-hydroxyetylaminosubstituované deriváty 5,11-diox
WO1999008680A1 (en) 1997-08-15 1999-02-25 The Johns Hopkins University Method of using selective parp inhibitors to prevent or treat neurotoxicity
US6250301B1 (en) 1997-08-28 2001-06-26 Hortal Harm B.V. Vaporizer for inhalation and method for extraction of active ingredients from a crude natural product or other matrix
US6197785B1 (en) 1997-09-03 2001-03-06 Guilford Pharmaceuticals Inc. Alkoxy-substituted compounds, methods, and compositions for inhibiting PARP activity
US20020028813A1 (en) 1997-09-03 2002-03-07 Paul F. Jackson Thioalkyl compounds, methods, and compositions for inhibiting parp activity
US6514983B1 (en) 1997-09-03 2003-02-04 Guilford Pharmaceuticals Inc. Compounds, methods and pharmaceutical compositions for treating neural or cardiovascular tissue damage
WO1999011644A1 (en) 1997-09-03 1999-03-11 Guilford Pharmaceuticals Inc. Di-n-heterocyclic compounds, methods, and compositions for inhibiting parp activity
CA2332279A1 (en) 1998-05-15 1999-11-25 Jia-He Li Carboxamide compounds, compositions, and methods for inhibiting parp activity
CA2332239A1 (en) 1998-05-15 1999-11-25 Guilford Pharmaceuticals Inc. Fused tricyclic compounds which inhibit parp activity
US6509344B1 (en) 1998-10-14 2003-01-21 The United States Of America As Represented By The Department Of Health And Human Services Indenoisoquinolines as antineoplastic agents
KR20010100977A (ko) 1998-11-03 2001-11-14 스타르크, 카르크 치환된 2-페닐벤즈이미다졸, 그의 제조 및 그의 용도
US6201020B1 (en) 1998-12-31 2001-03-13 Guilford Pharmaceuticals, Inc. Ortho-diphenol compounds, methods and pharmaceutical compositions for inhibiting parp
US6387902B1 (en) 1998-12-31 2002-05-14 Guilford Pharmaceuticals, Inc. Phenazine compounds, methods and pharmaceutical compositions for inhibiting PARP
SI20691B (sl) 1999-01-11 2008-10-31 Agouron Pharma Triciklični inhibitorji poli(ADP-riboza) polimeraz
US6465448B1 (en) 1999-08-13 2002-10-15 Case Western Reserve University Methoxyamine potentiation of temozolomide anti-cancer activity
GB0017508D0 (en) 2000-07-17 2000-08-30 Novartis Ag Antimicrobials
JP2003267888A (ja) 2002-03-15 2003-09-25 Seishi Yoneda 心停止液
WO2004014862A1 (en) 2002-08-09 2004-02-19 Rutgers, The State University Nitro and amino substituted heterocycles as topoisomerase i targeting agents
AU2003277674A1 (en) 2002-11-12 2004-06-03 Mochida Pharmaceutical Co., Ltd. Novel parp inhibitors
GB0317466D0 (en) 2003-07-25 2003-08-27 Univ Sheffield Use
CN102107008B (zh) 2003-12-01 2013-04-03 库多斯药物有限公司 用于治疗癌症的dna损伤修复抑制剂

Patent Citations (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3710795A (en) * 1970-09-29 1973-01-16 Alza Corp Drug-delivery device with stretched, rate-controlling membrane
US4113731A (en) * 1975-08-27 1978-09-12 Gruppo Lepetit S.P.A. Fused isoquinoline derivatives
US4263304A (en) * 1978-06-05 1981-04-21 Sumitomo Chemical Company, Limited 7 H-indolo[2,3-c]isoquinolines
US5177075A (en) * 1988-08-19 1993-01-05 Warner-Lambert Company Substituted dihydroisoquinolinones and related compounds as potentiators of the lethal effects of radiation and certain chemotherapeutic agents; selected compounds, analogs and process
US5079246A (en) * 1988-12-09 1992-01-07 Beacham Group P. L. C. Novel indoloquinlones
US5260316A (en) * 1991-07-30 1993-11-09 Ciba-Geigy Corporation Isoquinolyl substituted hydroxylamine derivatives
US5597831A (en) * 1991-08-29 1997-01-28 Vufb A.S 6-[X-(2-hydroxyethyl) aminoalkyl]-5,11-dioxo-5,6-dihydro-11-H-indeno[1,2-c]isoquinolines and their use as antineoplastic agents
US5262564A (en) * 1992-10-30 1993-11-16 Octamer, Inc. Sulfinic acid adducts of organo nitroso compounds useful as retroviral inactivating agents anti-retroviral agents and anti-tumor agents
US5710162A (en) * 1994-05-20 1998-01-20 Taiho Pharmaceutical Co., Ltd. Condensed-indan derivatives and pharmaceutically acceptable salts thereof
US5733918A (en) * 1994-05-20 1998-03-31 Taiho Pharmaceutical Co., Ltd. Condensed-Indan derivatives and pharmaceutically acceptable salts thereof
US6028079A (en) * 1994-05-20 2000-02-22 Taiho Pharmaceutical Co., Ltd Condensed-indan derivatives and pharmaceutically acceptable salts thereof
US6635642B1 (en) * 1997-09-03 2003-10-21 Guilford Pharmaceuticals Inc. PARP inhibitors, pharmaceutical compositions comprising same, and methods of using same
US6346536B1 (en) * 1997-09-03 2002-02-12 Guilford Pharmaceuticals Inc. Poly(ADP-ribose) polymerase inhibitors and method for treating neural or cardiovascular tissue damage using the same
US20030039628A1 (en) * 1998-08-24 2003-02-27 Kristoffer Hellstrand Activation and protection of T-cells (CD4+ and CD8+) using an H2 receptor agonist and other T-cell activating agents
US6498194B2 (en) * 1999-01-29 2002-12-24 Basf Aktiengsellschaft Fungicidal mixtures
US6346535B1 (en) * 1999-01-29 2002-02-12 American Cyanamid Company Fungicidal mixtures
US20020099063A1 (en) * 1999-01-29 2002-07-25 American Cyanamid Company Fungicidal mixtures
US20040120926A1 (en) * 1999-07-16 2004-06-24 Kristoffer Hellstrand Reactive oxygen metabolite inhibitors for use in compositions and methods of treatment
US6277990B1 (en) * 1999-12-07 2001-08-21 Inotek Corporation Substituted phenanthridinones and methods of use thereof
US6723733B2 (en) * 2000-05-19 2004-04-20 Guilford Pharmaceuticals, Inc. Sulfonamide and carbamide derivatives of 6(5H)phenanthridinones and their uses
US20040077667A1 (en) * 2000-12-11 2004-04-22 Nobuya Matsuoka Quinazolinone derivatives
US20040039009A1 (en) * 2001-08-31 2004-02-26 Prakash Jagtap Isoquinoline derivatives and methods of use thereof
US6828319B2 (en) * 2001-08-31 2004-12-07 Inotek Pharmaceuticals Corporation Substituted indeno[1,2-c]isoquinoline derivatives and methods of use thereof
US6956035B2 (en) * 2001-08-31 2005-10-18 Inotek Pharmaceuticals Corporation Isoquinoline derivatives and methods of use thereof
US7217709B2 (en) * 2003-02-28 2007-05-15 Inotek Pharmaceuticals Corporation Tetracyclic benzamide derivatives and methods of use thereof
US20040229895A1 (en) * 2003-02-28 2004-11-18 Inotek Pharmaceuticals Corporation Tetracyclic benzamide derivatives and methods of use thereof
US20050228007A1 (en) * 2004-02-26 2005-10-13 Prakash Jagtap Isoquinoline derivatives and methods of use thereof
US20050261288A1 (en) * 2004-02-26 2005-11-24 Prakash Jagtap Tetracyclic lactam derivatives and uses thereof
US20060019980A1 (en) * 2004-06-16 2006-01-26 Inotek Pharmaceutical, Corp. Methods for treating or preventing erectile dysfunction or urinary incontinence
US20060079510A1 (en) * 2004-09-30 2006-04-13 Kristoffer Hellstrand Use of PARP-1 inhibitors for protecting tumorcidal lymphocytes from apoptosis
US20060287311A1 (en) * 2005-02-25 2006-12-21 Inotek Pharmaceuticals Corporation Tetracyclic Sulfonamide Compounds and methods of use thereof
US20060287312A1 (en) * 2005-02-25 2006-12-21 Inotek Pharmaceuticals Corporation Tetracyclic amino and carboxamido compounds and methods of use thereof
US20060287313A1 (en) * 2005-02-25 2006-12-21 Inotek Pharmaceuticals Corporation Isoquinoline compounds and methods of use thereof
US7381722B2 (en) * 2005-02-25 2008-06-03 Inotek Pharmaceuticals Corporation Tetracyclic amino and carboxamido compounds and methods of use thereof
US7652028B2 (en) * 2005-08-24 2010-01-26 Inotek Pharmaceuticals Corporation Indenoisoquinolinone analogs and methods of use thereof

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Khadka et al. (Bioorganic & Medicinal Chemistry 19 (2011) 724-734) *
Kubinyi (3D QSAR in Drug Design: Ligand-Protein Interactions and Molecular Similarity, Vol 2-3, Springer, 1998, 800 pages), pages 243-44 provided. *
Wermuth, The Practice of Medicinal Chemsitry, 2d ed. (2003), 768 pages. Chapters 9-10 provided. *
Xiao et al. (Bioorganic & Medicinal Chemistry 12 (2004) 5147-5160) *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10835257B2 (en) 2007-10-17 2020-11-17 Covidien Lp Methods of managing neurovascular obstructions
US20110160706A1 (en) * 2009-12-18 2011-06-30 Vysera Biomedical Limited Urological device
CN102977018A (zh) * 2012-12-12 2013-03-20 中国药科大学 一类茚并异喹啉类雌激素受体β调节剂的抗乳腺癌用途

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