Indenoisoquinolinone analogs and methods of use thereof

Information

  • Patent Grant
  • 8119654
  • Patent Number
    8,119,654
  • Date Filed
    Thursday, February 28, 2008
    17 years ago
  • Date Issued
    Tuesday, February 21, 2012
    13 years ago
Abstract
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.
Description
2. FIELD OF THE INVENTION

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.


3. BACKGROUND OF THE INVENTION

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. However, there can be common underlying mechanisms between these two types of disorders. Specifically, inflammatory disease and reperfusion injury can induce proinflammatory cytokine and chemokine synthesis which can, in turn, result in production of cytotoxic free radicals such as nitric oxide and superoxide. NO and superoxide can react to form peroxynitrite (ONOO) (Szabó 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). Activation of PARP is thought to be an important step in the cell-mediated death observed in inflammation and reperfusion injury (Szabó al, Trends Pharmacol. Sci. 19:287-98, 1998).


A number of PARP inhibitors have been described in the art. See, e.g., Banasik et al., J. Biol. Chem., 267:1569-75, 1992, and Banasik et al., Mol. Cell. Biochem., 138:185-97, 1994; WO 00/39104; WO 00/39070; WO 99/59975; WO 99/59973; WO 99/11649; WO 99/11645; WO 99/11644; WO 99/11628; WO 99/11623; WO 99/11311; WO 00/42040; Zhang et al., Biochem. Biophys. Res. Commun., 278:590-98, 2000; White et al, J. Med. Chem., 43:4084-4097, 2000; Griffin et al., J. Med. Chem., 41:5247-5256, 1998; Shinkwin et al., Bioorg. Med. Chem., 7:297-308, 1999; and Soriano et al., Nature Medicine, 7:108-113, 2001. Adverse effects associated with administration of PARP inhibitors have been discussed in Milan et al., Science, 223:589-591, 1984.


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.


Syntheses of indenoisoquinolinone compounds have been reported. For example, see Wawzonek et al., Org. Prep. Proc. Int., 14:163-8, 1982; Wawzonek et al., Can. J. Chem., 59:2833, 1981; Andoi et al, Bull. Chem. Soc. Japan, 47:1014-17, 1974; Dusemund et al., Arch. Pharm (Weinheim, Ger.), 3 17:381-2, 1984; and Lal et al., Indian J. Chem., Sect. B, 38B:33-39, 1999.


There remains, however, a need in the art for compounds useful 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.


Citation of any reference in Section 3 of this application is not an admission that the reference is prior art.


4. SUMMARY OF THE INVENTION

In one aspect the invention provides a compound of Formula (Ia)




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and pharmaceutically acceptable salts thereof,


wherein


X is —N(C1-C4 alkyl)-, —CH(OH)—, —N(C(O)N(H)—(CH2)p—Z)— or —N((CH2)q—Z)—;


R1 is —(CH2)n—N(R2)(R2) or —O—(CH2)m—N(R2)(R2);


each R2 is independently —H, —C1-C6 alkyl, —C3-C8 monocyclic cycloalkyl, —C1-C6 alkylene phenyl, phenyl, an N-terminal alpha amino acid residue, an N-terminal alpha amino hydroxymethyl residue, a C1-C6 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)2OH, —C1-C6 alkyl, —O—C1-C6 alkyl, —C3-C8 monocyclic cycloalkyl, a 3- to 7-membered monocyclic heterocycle, —(C1-C6 alkyl-substituted) 3- to 7-membered monocyclic heterocycle, or —N(Z3)(Z4), where Z3 and Z4 are independently —H, —C1-C5 alkyl, —(C1-C5 alkylene)-O—C1-C5 alkyl, benzyl, or —C3-C8 monocyclic cycloalkyl, each of which other than hydrogen is independently unsubstituted or substituted with one or more of -halo, —OH, —N(Ra)2, —(C1-C5 alkylene)-O—C1-C5 alkyl, —NH2, a nitrogen-containing 3- to 7-membered monocyclic heterocycle, or a —(C1-C6 alkyl-substituted) nitrogen-containing 3- to 7-membered monocyclic heterocycle, wherein each occurrence of Ra is independently —H, benzyl, or —C1-C10 alkyl; or N, Z3 and Z4 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one or more of —C1-C5 alkyl, phenyl, -(phenyl-substituted) C1-C5 alkyl, -(hydroxy-substituted) C1-C5 alkyl, -halo, -(halo-substituted) C1-C5 alkyl, -(halo-substituted) phenyl, -phenylene-O—C1-C5 alkyl, -(cyano-substituted) phenyl, —OH, —O—C1-C5 alkyl, —N(Ra)2, —(C1-C5 alkylene)-N(Ra)2, —(C1-C5 alkylene)-C(O)O—(C1-C5 alkylene)-N(Ra)2, —COOH, —(C1-C5 alkylene)-COOH, —OP(O)(OH)2, —OS(O)2OH, —(C1-C5 alkylene)-OP(O)(OH)2, —(C1-C5 alkylene)-OS(O)2OH, —C(O)O—C1-C5 alkyl, —OC(O)—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)O—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)NH—C1-C5 alkyl, —C(O)NH2, or —NO2, wherein each occurrence of Ra is independently —H, benzyl, or —C1-C10 alkyl; or N and both Ra groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle;


or N and both R2 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 —C1-C5 alkyl, —C3-C8 monocyclic cycloalkyl, phenyl, a nitrogen-containing 3- to 7-membered monocyclic heterocycle, -(phenyl-substituted) C1-C5 alkyl, -(hydroxy-substituted) C1-C5 alkyl, -halo, -(halo-substituted) C1-C5 alkyl, -(halo-substituted) phenyl, -phenylene-O—C1-C5 alkyl, -(cyano-substituted) phenyl, —OH, —O—C1-C5 alkyl, —N(Ra)2, —(C1-C5 alkylene)-N(Ra)2, —C1-C5 alkylene-C(O)O—(C1-C5 alkylene)-N(Ra)2, —COOH, —(C1-C5 alkylene)-O—C1-C5 alkyl, —(C1-C5 alkylene)-C3-C8 monocyclic cycloalkyl, —(C1-C5 alkylene)-COOH, —OP(O)(OH)2, —OS(O)2OH, —(C1-C5 alkylene)-OP(O)(OH)2, —(C1-C5 alkylene)-OS(O)2OH, —C(O)O—C1-C5 alkyl, —OC(O)—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)O—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)NH—C1-C5 alkyl, —C(O)NH2, or —NO2, wherein each occurrence of Ra is independently —H, -benzyl, —C1-C10 alkyl; or N and both Ra groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle;


Z is —CF3, —F, —OH or —O—CH3;


n is an integer ranging from 1 to 10;


m is an integer ranging from 2 to 10;


p is an integer ranging from 1 to 5; and


q is an integer ranging from 1 to 5.


In one aspect the invention provides a compound of Formula (Ib)




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and pharmaceutically acceptable salts thereof,


wherein


X is —N(C1-C4 alkyl)-, —CH(OH)—, —N(C(O)N(H)—(CH2)p—Z)— or —N((CH2)q—Z)—;


R1 is —(CH2)n—N(R2)(R2) or —O—(CH2)m—N(R2)(R2);


each R2 is independently —H, —C1-C6 alkyl, —C3-C8 monocyclic cycloalkyl, —C1-C6 alkylene phenyl, phenyl, an N-terminal alpha amino acid residue, an N-terminal alpha amino hydroxymethyl residue, a C1-C6 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)2OH, —C1-C6 alkyl, —O—C1-C6 alkyl, —C3-C8 monocyclic cycloalkyl, a 3- to 7-membered monocyclic heterocycle, —(C1-C6 alkyl-substituted) 3- to 7-membered monocyclic heterocycle, or —N(Z3)(Z4), where Z3 and Z4 are independently —H, —C1-C5 alkyl, —(C1-C5 alkylene)-O—C1-C5 alkyl, benzyl, or —C3-C8 monocyclic cycloalkyl, each of which other than hydrogen is independently unsubstituted or substituted with one or more of -halo, —OH, —N(Ra)2, —(C1-C5 alkylene)-O—C1-C5 alkyl, —NH2, a nitrogen-containing 3- to 7-membered monocyclic heterocycle, or a —(C1-C6 alkyl-substituted) nitrogen-containing 3- to 7-membered monocyclic heterocycle, wherein each occurrence of Ra is independently —H, benzyl, or —C1-C10 alkyl; or N, Z3 and Z4 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one or more of —C1-C5 alkyl, phenyl, -(phenyl-substituted) C1-C5 alkyl, -(hydroxy-substituted) C1-C5 alkyl, -halo, -(halo-substituted) C1-C5 alkyl, -(halo-substituted) phenyl, -phenylene-O—C1-C5 alkyl, -(cyano-substituted) phenyl, —OH, —O—C1-C5 alkyl, —N(Ra)2, —(C1-C5 alkylene)-N(Ra)2, —(C1-C5 alkylene)-C(O)O—(C1-C5 alkylene)-N(Ra)2, —COOH, —(C1-C5 alkylene)-COOH, —OP(O)(OH)2, —OS(O)2OH, —(C1-C5 alkylene)-OP(O)(OH)2, —(C1-C5 alkylene)-OS(O)2OH, —C(O)O—C1-C5 alkyl, —OC(O)—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)O—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)NH—C1-C5 alkyl, —C(O)NH2, or —NO2, wherein each occurrence of Ra is independently —H, benzyl, or —C1-C10 alkyl; or N and both Ra groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle;


or N and both R2 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 —C1-C5 alkyl, —C3-C8 monocyclic cycloalkyl, phenyl, a nitrogen-containing 3- to 7-membered monocyclic heterocycle, -(phenyl-substituted) C1-C5 alkyl, -(hydroxy-substituted) C1-C5 alkyl, -halo, -(halo-substituted) C1-C5 alkyl, -(halo-substituted) phenyl, -phenylene-O—C1-C5 alkyl, -(cyano-substituted) phenyl, —OH, —O—C1-C5 alkyl, —N(Ra)2, —(C1-C5 alkylene)-N(Ra)2, —C1-C5 alkylene-C(O)O—(C1-C5 alkylene)-N(Ra)2, —COOH, —(C1-C5 alkylene)-O—C1-C5 alkyl, —(C1-C5 alkylene)-C3-C8 monocyclic cycloalkyl, —(C1-C5 alkylene)-COOH, —OP(O)(OH)2, —OS(O)2OH, —(C1-C5 alkylene)-OP(O)(OH)2, —(C1-C5 alkylene)-OS(O)2OH, —C(O)O—C1-C5 alkyl, —OC(O)—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)O—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)NH—C1-C5 alkyl, —C(O)NH2, or —NO2, wherein each occurrence of Ra is independently —H, -benzyl, —C1-C10 alkyl; or N and both Ra groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle;


Z is —CF3, —F, —OH or —O—CH3;


n is an integer ranging from 1 to 10;


m is an integer ranging from 2 to 10;


p is an integer ranging from 1 to 5; and


q is an integer ranging from 1 to 5.


In one aspect the invention provides a compound of Formula (Ic)




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and pharmaceutically acceptable salts thereof,


wherein


X is —N(C1-C4 alkyl)-, —CH(OH)—, —N(C(O)N(H)—(CH2)p—Z)— or —N((CH2)q—Z)—;


R1 is —(CH2)n—N(R2)(R2) or —O—(CH2)m—N(R2)(R2);


each R2 is independently —H, —C1-C6 alkyl, —C3-C8 monocyclic cycloalkyl, —C1-C6 alkylene phenyl, phenyl, an N-terminal alpha amino acid residue, an N-terminal alpha amino hydroxymethyl residue, a C1-C6 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)2OH, —C1-C6 alkyl, —O—C1-C6 alkyl, —C3-C8 monocyclic cycloalkyl, a 3- to 7-membered monocyclic heterocycle, —(C1-C6 alkyl-substituted) 3- to 7-membered monocyclic heterocycle, or —N(Z3)(Z4), where Z3 and Z4 are independently —H, —C1-C5 alkyl, (C1-C5 alkylene)-O—C1-C5 alkyl, benzyl, or —C3-C8 monocyclic cycloalkyl, each of which other than hydrogen is independently unsubstituted or substituted with one or more of -halo, —OH, —N(Ra)2, —(C1-C5 alkylene)-O—C1-C5 alkyl, —NH2, a nitrogen-containing 3- to 7-membered monocyclic heterocycle, or a —(C1-C6 alkyl-substituted) nitrogen-containing 3- to 7-membered monocyclic heterocycle, wherein each occurrence of Ra is independently —H, benzyl, or —C1-C10 alkyl; or N, Z3 and Z4 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one or more of —C1-C5 alkyl, phenyl, -(phenyl-substituted) C1-C5 alkyl, -(hydroxy-substituted) C1-C5 alkyl, -halo, -(halo-substituted) C1-C5 alkyl, -(halo-substituted) phenyl, -phenylene-O—C1-C5 alkyl, -(cyano-substituted) phenyl, —OH, —O—C1-C5 alkyl, —N(Ra)2, —(C1-C5 alkylene)-N(Ra)2, —(C1-C5 alkylene)-C(O)O—(C1-C5 alkylene)-N(Ra)2, —COOH, —(C1-C5 alkylene)-COOH, —OP(O)(OH)2, —OS(O)2OH, —(C1-C5 alkylene)-OP(O)(OH)2, —(C1-C5 alkylene)-OS(O)2OH, —C(O)O—C1-C5 alkyl, —OC(O)—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)O—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)NH—C1-C5 alkyl, —C(O)NH2, or —NO2, wherein each occurrence of Ra is independently —H, benzyl, or —C1-C10 alkyl; or N and both Ra groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle;


or N and both R2 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 —C1-C5 alkyl, —C3-C8 monocyclic cycloalkyl, phenyl, a nitrogen-containing 3- to 7-membered monocyclic heterocycle, -(phenyl-substituted) C1-C5 alkyl, -(hydroxy-substituted) C1-C5 alkyl, -halo, -(halo-substituted) C1-C5 alkyl, -(halo-substituted) phenyl, -phenylene-O—C1-C5 alkyl, -(cyano-substituted) phenyl, —OH, —O—C1-C5 alkyl, —N(Ra)2, —(C1-C5 alkylene)-N(Ra)2, —C1-C5 alkylene-C(O)O—(C1-C5 alkylene)-N(Ra)2, —COOH, —(C1-C5 alkylene)-O—C1-C5 alkyl, —(C1-C5 alkylene)-C3-C8 monocyclic cycloalkyl, —(C1-C5 alkylene)-COOH, —OP(O)(OH)2, —OS(O)2OH, —(C1-C5 alkylene)-OP(O)(OH)2, —(C1-C5 alkylene)-OS(O)2OH, —C(O)O—C1-C5 alkyl, —OC(O)—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)O—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)NH—C1-C5 alkyl, —C(O)NH2, or —NO2, wherein each occurrence of Ra is independently —H, -benzyl, —C1-C10 alkyl; or N and both Ra groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle;


Z is —CF3, —F, —OH or —O—CH3;


n is an integer ranging from 1 to 10;


m is an integer ranging from 2 to 10;


p is an integer ranging from 1 to 5; and


q is an integer ranging from 1 to 5.


In another aspect the invention provides a compound of Formula (IIa)




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and pharmaceutically acceptable salts thereof;


wherein


X is —CH2—, —O—, —C(O)—, —CH(OH)—, —NH—, —N(C1-C4 alkyl)- or —S—;


R1 is —(CH2)n—N(R2)(R3) or




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R2 is —H, —C1-C6 alkyl, or —C3-C8 monocyclic cycloalkyl;


R3 is —C(O)—(C1-C6 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—C1-C6 alkyl, or —C3-C8 monocyclic cycloalkyl which is substituted with one or more of (hydroxy-substituted) C1-C5 alkyl groups;


or N, R2 and R3 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which is substituted with one or more of —C2-C6 alkenyl, —C(O)—C1-C6 alkyl, —(C1-C4 alkylene)-C(O)—(C3-C8 monocyclic cycloalkyl), —C7-C10 alkyl, —(C1-C5 alkylene)-C(H)(—O—C1-C4 alkyl)2, -(cyano-substituted) C1-C5 alkyl, —(C1-C5 alkylene)-C(O)-(nitrogen-containing 3- to 7-membered monocyclic heterocycle) or —(C1-C5 alkylene)-(3- to 7-membered monocyclic heterocycle) groups; and


an n is an integer ranging from 1 to 10.


In another aspect the invention provides a compound of Formula (IIb)




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and pharmaceutically acceptable salts thereof,


wherein


X is —CH2—, —O—, —C(O)—, —CH(OH)—, —NH—, —N(C1-C4 alkyl)- or —S—;


R1 is —(CH2)n—N(R2)(R3) or




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R2 is —H, —C1-C6 alkyl, or —C3-C8 monocyclic cycloalkyl;


R3 is —C(O)—(C1-C6 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—C1-C6 alkyl, or —C3-C8 monocyclic cycloalkyl which is substituted with one or more of (hydroxy-substituted) C1-C5 alkyl groups;


or N, R2 and R3 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which is substituted with one or more of —C2-C6 alkenyl, —C(O)—C1-C6 alkyl, —(C1-C4 alkylene)-C(O)—(C3-C8 monocyclic cycloalkyl), —C7-C10 alkyl, —(C1-C5 alkylene)-C(H)(—O—C1-C4 alkyl)2, -(cyano-substituted) C1-C5 alkyl, —(C1-C5 alkylene)-C(O)— (nitrogen-containing 3- to 7-membered monocyclic heterocycle) or —(C1-C5 alkylene)-(3- to 7-membered monocyclic heterocycle) groups; and


an n is an integer ranging from 1 to 10.


In another aspect the invention provides a compound of Formula (IIc)




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and pharmaceutically acceptable salts thereof,


wherein


X is —CH2—, —O—, —C(O)—, —CH(OH)—, —NH—, —N(C1-C4 alkyl)- or —S—;


R1 is —(CH2)n—N(R2)(R3) or




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R2 is —H, —C1-C6 alkyl, or —C3-C8 monocyclic cycloalkyl;


R3 is —C(O)—(C1-C6 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—C1-C6 alkyl, or —C3-C8 monocyclic cycloalkyl which is substituted with one or more of (hydroxy-substituted) C1-C5 alkyl groups;


or N, R2 and R3 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which is substituted with one or more of —C2-C6 alkenyl, —C(O)—C1-C6 alkyl, —(C1-C4 alkylene)-C(O)—(C3-C8 monocyclic cycloalkyl), —C7-C10 alkyl, —(C1-C5 alkylene)-C(H)(—O—C1-C4 alkyl)2, -(cyano-substituted) C1-C5 alkyl, —(C1-C5 alkylene)-C(O)— (nitrogen-containing 3- to 7-membered monocyclic heterocycle) or —(C1-C5 alkylene)-(3- to 7-membered monocyclic heterocycle) groups; and


an n is an integer ranging from 1 to 10.


In one aspect, the invention provides the following Indenoisoquinolinone Analogs according to Formula (IIIa) as set forth below:














(IIIa)




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Compound
—R1






IIIa-1


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IIIa-2


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IIIa-3


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IIIa-4


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IIIa-5


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IIIa-6


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IIIa-7


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IIIa-8


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IIIa-9


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IIIa-10


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IIIa-11


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IIIa-12


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IIIa-13


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IIIa-14


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IIIa-15


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IIIa-16


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IIIa-17


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IIIa-18


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IIIa-19


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IIIa-20


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IIIa-21


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IIIa-22


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IIIa-23


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IIIa-24


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and pharmaceutically acceptable salts thereof.


In another aspect, the invention provides the following Indenoisoquinolinone Analogs according to Formula (IIIb) as set forth below:














(IIIb)




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Compound
—R1






IIIb-1


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IIIb-2


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IIIb-3


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IIIb-4


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IIIb-5


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IIIb-6


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IIIb-7


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IIIb-8


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IIIb-9


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IIIb-10


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IIIb-11


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IIIb-12


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IIIb-13


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IIIb-14


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IIIb-15


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IIIb-16


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IIIb-17


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IIIb-18


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IIIb-19


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IIIb-20


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IIIb-21


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IIIb-22


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IIIb-23


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IIIb-24


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and pharmaceutically acceptable salts thereof.


In one aspect the invention provides a compound of Formula (IVa)




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and pharmaceutically acceptable salts thereof,


wherein


X is —O—, —CH2—, —C(O)—, —NH—, —S—, —N(C1-C4 alkyl)-, —CH(OH)—, —N(C(O)N(H)—(CH2)p—Z)— or —N((CH2)q—Z)—;


R1 is —O—C(C1-C3 alkyl)2-(CH2)n—N(R2)(R2);


each R2 is independently —H, —C1-C6 alkyl, —C3-C8 monocyclic cycloalkyl, —C1-C6 alkylene phenyl, phenyl, an N-terminal alpha amino acid residue, an N-terminal alpha amino hydroxymethyl residue, a C1-C6 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)2OH, —C1-C6 alkyl, —O—C1-C6 alkyl, —C3-C8 monocyclic cycloalkyl, a 3- to 7-membered monocyclic heterocycle, —(C1-C6 alkyl-substituted) 3- to 7-membered monocyclic heterocycle, or —N(Z3)(Z4), where Z3 and Z4 are independently —H, —C1-C5 alkyl, —(C1-C5 alkylene)-O—C1-C5 alkyl, benzyl, or —C3-C8 monocyclic cycloalkyl, each of which other than hydrogen is independently unsubstituted or substituted with one or more of -halo, —OH, —N(Ra)2, —(C1-C5 alkylene)-O—C1-C5 alkyl, —NH2, a nitrogen-containing 3- to 7-membered monocyclic heterocycle, or a —(C1-C6 alkyl-substituted) nitrogen-containing 3- to 7-membered monocyclic heterocycle, wherein each occurrence of Ra is independently —H, benzyl, or —C1-C10 alkyl; or N, Z3 and Z4 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one or more of —C1-C5 alkyl, phenyl, -(phenyl-substituted) C1-C5 alkyl, -(hydroxy-substituted) C1-C5 alkyl, -halo, -(halo-substituted) C1-C5 alkyl, -(halo-substituted) phenyl, -phenylene-O—C1-C5 alkyl, -(cyano-substituted) phenyl, —OH, —O—C1-C5 alkyl, —N(Ra)2, —(C1-C5 alkylene)-N(Ra)2, —(C1-C5 alkylene)-C(O)O—(C1-C5 alkylene)-N(Ra)2, —COOH, —(C1-C5 alkylene)-COOH, —OP(O)(OH)2, —OS(O)2OH, —(C1-C5 alkylene)-OP(O)(OH)2, —(C1-C5 alkylene)-OS(O)2OH, —C(O)O—C1-C5 alkyl, —OC(O)—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)O—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)NH—C1-C5 alkyl, —C(O)NH2, or —NO2, wherein each occurrence of Ra is independently —H, benzyl, or —C1-C10 alkyl; or N and both Ra groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle;


or N and both R2 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 —C1-C5 alkyl, —C3-C8 monocyclic cycloalkyl, phenyl, a nitrogen-containing 3- to 7-membered monocyclic heterocycle, -(phenyl-substituted) C1-C5 alkyl, -(hydroxy-substituted) C1-C5 alkyl, -halo, -(halo-substituted) C1-C5 alkyl, -(halo-substituted) phenyl, -phenylene-O—C1-C5 alkyl, -(cyano-substituted) phenyl, —OH, —O—C1-C5 alkyl, —N(Ra)2, —(C1-C5 alkylene)-N(Ra)2, —C1-C5 alkylene-C(O)O—(C1-C5 alkylene)-N(Ra)2, —COOH, —(C1-C5 alkylene)-O—C1-C5 alkyl, —(C1-C5 alkylene)-C3-C8 monocyclic cycloalkyl, —(C1-C5 alkylene)-COOH, —OP(O)(OH)2, —OS(O)2OH, —(C1-C5 alkylene)-OP(O)(OH)2, —(C1-C5 alkylene)-OS(O)2OH, —C(O)O—C1-C5 alkyl, —OC(O)—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)O—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)NH—C1-C5 alkyl, —C(O)NH2, or —NO2, wherein each occurrence of Ra is independently —H, -benzyl, —C1-C10 alkyl; or N and both Ra groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle;


Z is —CF3, —F, —OH or —O—CH3;


n is an integer ranging from 1 to 10;


p is an integer ranging from 1 to 5; and


q is an integer ranging from 1 to 5.


In one aspect the invention provides a compound of Formula (IVb)




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and pharmaceutically acceptable salts thereof,


wherein


X is —O—, —CH2—, —C(O)—, —NH—, —S—, —N(C1-C4 alkyl)-, —CH(OH)—, —N(C(O)N(H)—(CH2)p—Z)— or —N((CH2)q—Z)—;


R1 is —O—C(C1-C3 alkyl)2-(CH2)n—N(R2)(R2);


each R2 is independently —H, —C1-C6 alkyl, —C3-C8 monocyclic cycloalkyl, —C1-C6 alkylene phenyl, phenyl, an N-terminal alpha amino acid residue, an N-terminal alpha amino hydroxymethyl residue, a C1-C6 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)2OH, —C1-C6 alkyl, —O—C1-C6 alkyl, —C3-C8 monocyclic cycloalkyl, a 3- to 7-membered monocyclic heterocycle, —(C1-C6 alkyl-substituted) 3- to 7-membered monocyclic heterocycle, or —N(Z3)(Z4), where Z3 and Z4 are independently —H, —C1-C5 alkyl, —(C1-C5 alkylene)-O—C1-C5 alkyl, benzyl, or —C3-C8 monocyclic cycloalkyl, each of which other than hydrogen is independently unsubstituted or substituted with one or more of -halo, —OH, —N(Ra)2, —(C1-C5 alkylene)-O—C1-C5 alkyl, —NH2, a nitrogen-containing 3- to 7-membered monocyclic heterocycle, or a —(C1-C6 alkyl-substituted) nitrogen-containing 3- to 7-membered monocyclic heterocycle, wherein each occurrence of Ra is independently —H, benzyl, or —C1-C10 alkyl; or N, Z3 and Z4 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one or more of —C1-C5 alkyl, phenyl, -(phenyl-substituted) C1-C5 alkyl, -(hydroxy-substituted) C1-C5 alkyl, -halo, -(halo-substituted) C1-C5 alkyl, -(halo-substituted) phenyl, -phenylene-O—C1-C5 alkyl, -(cyano-substituted) phenyl, —OH, —O—C1-C5 alkyl, —N(Ra)2, —(C1-C5 alkylene)-N(Ra)2, —(C1-C5 alkylene)-C(O)O—(C1-C5 alkylene)-N(Ra)2, —COOH, —(C1-C5 alkylene)-COOH, —OP(O)(OH)2, —OS(O)2OH, —(C1-C5 alkylene)-OP(O)(OH)2, —(C1-C5 alkylene)-OS(O)2OH, —C(O)O—C1-C5 alkyl, —OC(O)—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)O—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)NH—C1-C5 alkyl, —C(O)NH2, or —NO2, wherein each occurrence of Ra is independently —H, benzyl, or —C1-C10 alkyl; or N and both Ra groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle;


or N and both R2 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 —C1-C5 alkyl, —C3-C8 monocyclic cycloalkyl, phenyl, a nitrogen-containing 3- to 7-membered monocyclic heterocycle, -(phenyl-substituted) C1-C5 alkyl, -(hydroxy-substituted) C1-C5 alkyl, -halo, -(halo-substituted) C1-C5 alkyl, -(halo-substituted) phenyl, -phenylene-O—C1-C5 alkyl, -(cyano-substituted) phenyl, —OH, —O—C1-C5 alkyl, —N(Ra)2, —(C1-C5 alkylene)-N(Ra)2, —C1-C5 alkylene-C(O)O—(C1-C5 alkylene)-N(Ra)2, —COOH, —(C1-C5 alkylene)-O—C1-C5 alkyl, —(C1-C5 alkylene)-C3-C8 monocyclic cycloalkyl, —(C1-C5 alkylene)-COOH, —OP(O)(OH)2, —OS(O)2OH, —(C1-C5 alkylene)-OP(O)(OH)2, —(C1-C5 alkylene)-OS(O)2OH, —C(O)O—C1-C5 alkyl, —OC(O)—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)O—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)NH—C1-C5 alkyl, —C(O)NH2, or —NO2, wherein each occurrence of Ra is independently —H, -benzyl, —C1-C10 alkyl; or N and both Ra groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle;


Z is —CF3, —F, —OH or —O—CH3;


n is an integer ranging from 1 to 10;


p is an integer ranging from 1 to 5; and


q is an integer ranging from 1 to 5.


In one aspect the invention provides a compound of Formula (IVc)




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and pharmaceutically acceptable salts thereof,


wherein


X is —O—, —CH2—, —C(O)—, —NH—, —S—, —N(C1-C4 alkyl)-, —CH(OH)—, —N(C(O)N(H)—(CH2)p—Z)— or —N((CH2)q—Z)—;


R1 is —O—C(C1-C3 alkyl)2-(CH2)n—N(R2)(R2);


each R2 is independently —H, —C1-C6 alkyl, —C3-C8 monocyclic cycloalkyl, —C1-C6 alkylene phenyl, phenyl, an N-terminal alpha amino acid residue, an N-terminal alpha amino hydroxymethyl residue, a C1-C6 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)2OH, —C1-C6 alkyl, —O—C1-C6 alkyl, —C3-C8 monocyclic cycloalkyl, a 3- to 7-membered monocyclic heterocycle, —(C1-C6 alkyl-substituted) 3- to 7-membered monocyclic heterocycle, or —N(Z3)(Z4), where Z3 and Z4 are independently —H, —C1-C5 alkyl, —(C1-C5 alkylene)-O—C1-C5 alkyl, benzyl, or —C3-C8 monocyclic cycloalkyl, each of which other than hydrogen is independently unsubstituted or substituted with one or more of -halo, —OH, —N(Ra)2, —(C1-C5 alkylene)-O—C1-C5 alkyl, —NH2, a nitrogen-containing 3- to 7-membered monocyclic heterocycle, or a —(C1-C6 alkyl-substituted) nitrogen-containing 3- to 7-membered monocyclic heterocycle, wherein each occurrence of Ra is independently —H, benzyl, or —C1-C10 alkyl; or N, Z3 and Z4 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one or more of —C1-C5 alkyl, phenyl, -(phenyl-substituted) C1-C5 alkyl, -(hydroxy-substituted) C1-C5 alkyl, -halo, -(halo-substituted) C1-C5 alkyl, -(halo-substituted) phenyl, -phenylene-O—C1-C5 alkyl, -(cyano-substituted) phenyl, —OH, —O—C1-C5 alkyl, —N(Ra)2, —(C1-C5 alkylene)-N(Ra)2, —(C1-C5 alkylene)-C(O)O—(C1-C5 alkylene)-N(Ra)2, —COOH, —(C1-C5 alkylene)-COOH, —OP(O)(OH)2, —OS(O)2OH, —(C1-C5 alkylene)-OP(O)(OH)2, —(C1-C5 alkylene)-OS(O)2OH, —C(O)O—C1-C5 alkyl, —OC(O)—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)O—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)NH—C1-C5 alkyl, —C(O)NH2, or —NO2, wherein each occurrence of Ra is independently —H, benzyl, or —C1-C10 alkyl; or N and both Ra groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle;


or N and both R2 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 —C1-C5 alkyl, —C3-C8 monocyclic cycloalkyl, phenyl, a nitrogen-containing 3- to 7-membered monocyclic heterocycle, -(phenyl-substituted) C1-C5 alkyl, -(hydroxy-substituted) C1-C5 alkyl, -halo, -(halo-substituted) C1-C5 alkyl, -(halo-substituted) phenyl, -phenylene-O—C1-C5 alkyl, -(cyano-substituted) phenyl, —OH, —O—C1-C5 alkyl, —N(Ra)2, —(C1-C5 alkylene)-N(Ra)2, —C1-C5 alkylene-C(O)O—(C1-C5 alkylene)-N(Ra)2, —COOH, —(C1-C5 alkylene)-O—C1-C5 alkyl, —(C1-C5 alkylene)-C3-C8 monocyclic cycloalkyl, —(C1-C5 alkylene)-COOH, —OP(O)(OH)2, —OS(O)2OH, —(C1-C5 alkylene)-OP(O)(OH)2, —(C1-C5 alkylene)-OS(O)2OH, —C(O)O—C1-C5 alkyl, —OC(O)—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)O—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)NH—C1-C5 alkyl, —C(O)NH2, or —NO2, wherein each occurrence of Ra is independently —H, -benzyl, —C1-C10 alkyl; or N and both Ra groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle;


Z is —CF3, —F, —OH or —O—CH3;


n is an integer ranging from 1 to 10;


p is an integer ranging from 1 to 5; and


q is an integer ranging from 1 to 5.


In one aspect, the invention provides a compound of Formula (Va)




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and pharmaceutically acceptable salts thereof,


wherein


R1 is —CH2NH—R2;


R2 is a —C3-C8 monocyclic cycloalkyl which is unsubstituted or substituted with one or more of -(hydroxy-substituted) C1-C5 alkyl; or a 3- to 7-membered monocyclic heterocycle;


X is halo or —H; and


Y′ is halo or —H, wherein at least one of X and Y′ is halo.


The invention provides 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 (Ia), Formula (IIb), Formula (IIc), Formula (IIIa), Formula (IIIb), Formula (IVa), Formula (IVb), Formula (IVc), Formula (Va), or a pharmaceutically acceptable salt thereof (an “Indenoisoquinolinone Analog”) 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.


The details of the invention are set forth in the accompanying description below.


All patents and publications cited in this specification are incorporated by reference in their entirety.







5. DETAILED DESCRIPTION OF THE INVENTION
5.1 Definitions and Abbreviations

The following definitions are used in connection with the Indenoisoquinolinone Analogs:


The term “—C1-C3 alkyl” as used herein, 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 —C1-C3 alkyls include -methyl, -ethyl, and -n-propyl. Representative branched —C1-C3 alkyls include -isopropyl.


The term “—C1-C4 alkyl” as used herein, 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 —C1-C4 alkyls include -methyl, -ethyl, -n-propyl, and -n-butyl. Representative branched —C1-C4 alkyls include -isopropyl, -sec-butyl, -isobutyl and -tert-butyl. In one embodiment, the —C1-C4 alkyl is substituted with one or more of -halo, —OH, —N(R3)2, —(C1-C5 alkylene)-O—C1-C5 alkyl, —NH2, a nitrogen-containing 3- to 7-membered monocyclic heterocycle, or an —(C1-C6 alkyl-substituted) nitrogen-containing 3- to 7-membered monocyclic heterocycle. Unless otherwise indicated, the —C1-C4 alkyl is unsubstituted.


A “C1-C4 alkylene” refers to a C1-C4 alkyl group, as defined above, wherein one of the C1-C4 alkyl group's hydrogen atoms has been replaced with a bond.


A “C2-C4 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 C2-C4 alkylene groups include, ethylene, n-propylene, isopropylene, n-butylene and isobutylene.


The term “—C1-C5 alkyl” as used herein, 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 —C1-C5 alkyls include -methyl, -ethyl, -n-propyl, -n-butyl and -n-pentyl. Representative branched —C1-C5 alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl and 1,2-dimethylpropyl. In one embodiment, the —C1-C5 alkyl is substituted with one or more of -halo, —OH, —N(R3)2, —C1-C5 alkylene-O—C1-C5 alkyl, —NH2, a nitrogen-containing 3- to 7-membered monocyclic heterocycle, or an —C1-C6 alkyl-substituted nitrogen-containing 3- to 7-membered monocyclic heterocycle. Unless otherwise indicated, the —C1-C5 alkyl is unsubstituted.


A “C1-C5 alkylene” refers to a C1-C5 alkyl group, as defined above, wherein one of the C1-C5 alkyl group's hydrogen atoms has been replaced with a bond.


The term “-phenyl-substituted C1-C5 alkyl” as used herein, refers to a “—C1-C5 alkyl” wherein one of the its hydrogen atoms has been replaced by a phenyl group.


The term “—C1-C6 alkyl” as used herein, 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 —C1-C6 alkyls include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl and -n-hexyl. Representative branched —C1-C6 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. In one embodiment, the —C1-C6 alkyl is substituted with one or more of -halo, —OH, —OP(O)(OH)2, —OS(O)2OH, —C1-C6 alkyl, —O—C1-C6 alkyl, —C3-C8 monocyclic cycloalkyl, a 3- to 7-membered monocyclic heterocycle, —(C1-C6 alkyl-substituted) 3- to 7-membered monocyclic heterocycle, or —N(Z3)(Z4). Unless otherwise indicated, the —C1-C6 alkyl is unsubstituted.


A “C1-C6 alkylene” refers to a C1-C6 alkyl group, as defined above, wherein one of the C1-C6 alkyl group's hydrogen atoms has been replaced with a bond.


The term “—C2-C6 alkenyl” refers to a straight or branched chain hydrocarbon containing 2-6 carbon atoms and at least one double bond. Representative C2-C6 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.


The term “—C1-C8 alkyl” as used herein, 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 —C1-C9 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.


The term “—C7-C10 alkyl” as used herein, 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 —C7-C10 alkyls include, but are not limited to, heptyl, octyl, nonyl, isohexyl, isoheptyl, isooctyl and isononyl, decyl, and isodecyl.


The term “—C1-C10 alkyl” as used herein, 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 —C1-C10 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.


The term “—C3-C8 monocyclic cycloalkyl” as used herein, refers to a saturated cyclic hydrocarbon having from 3 to 8 carbon atoms. Representative —C3-C8 monocyclic cycloalkyls include -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl and -cyclooctyl. In one embodiment, the —C3-C8 monocyclic cycloalkyl is substituted with one or more of -halo, —OH, —OP(O)(OH)2, —OS(O)2OH, —C1-C6 alkyl, —O—C1-C6 alkyl, —C3-C8 monocyclic cycloalkyl, a 3- to 7-membered monocyclic heterocycle, —C1-C6 alkyl-substituted 3- to 7-membered monocyclic heterocycle. In another embodiment, the —C3-C8 monocyclic cycloalkyl is substituted with one or more of —N(R3)2, —C1-C5 alkylene-O—C1-C5 alkyl, or —NH2. Unless otherwise indicated, the —C3-C8 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. Representative examples of 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.


In one embodiment, the nitrogen-containing 3- to 7-membered monocyclic heterocycle is fully saturated or partially saturated.


In another embodiment, the nitrogen-containing 3- to 7-membered monocyclic heterocycle is substituted with one or more of -halo, —OH, —OP(O)(OH)2, —OS(O)2OH, —C1-C6 alkyl, —O—C1-C6 alkyl, —C3-C8 monocyclic cycloalkyl, a 3- to 7-membered monocyclic heterocycle, —(C1-C6 alkyl-substituted) 3- to 7-membered monocyclic heterocycle, or —N(Z3)(Z4). Unless otherwise indicated, 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.


In one embodiment, 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. Representative examples of a 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. In one embodiment, 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 “C1-C6 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 C1-C6 alkyl, as defined above.


“Halo” is —F, —Cl, —Br or —I.


“Halo-substituted C1-C5 alkyl” refers to a C1-C5 alkyl group, as defined above, wherein one or more of the C1-C5 alkyl group's hydrogen atoms has been replaced with —F, —Cl, —Br or —I. Representative examples of a halo-substituted C1-C5 alkyl include, but are not limited to, —CH2F, —CCl3, —CF3, —CH2Cl, —CH2CH2Br, —CH2CH2I, —CH2CH2CH2F, —CH2CH2CH2Cl, —CH2CH2CH2CH2Br, —CH2CH2CH2CH2I, —CH2CH2CH2CH2CH2Br, —CH2CH2CH2CH2CH2I, —CH2CH(Br)CH3, —CH2CH(Cl)CH2CH3, —CH(F)CH2CH3 and —C(CH3)2(CH2Cl).


“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 C1-C5 alkyl” refers to a C1-C5 alkyl group, as defined above, wherein one or more of the C1-C5 alkyl group's hydrogen atoms has been replaced with —CN. Representative examples of a cyano-substituted C1-C5 alkyl include, but are not limited to, —CH2CN, —CH2CH2CN, —CH2CH2CH2CN, —CH2CH2CH2CH2CN, —CH2CH2CH2CH2CH2CN, —CH2CH(CN)CH3, —CH2CH(CN)CH2CH3, —CH(CN)CH2CH3 and —C(CH3)2(CH2CN).


A “C1-C6 alkylene phenyl” refers to a C1-C6 alkyl group, as defined above, wherein one of the C1-C6 alkyl group's hydrogen atoms has been replaced with phenyl.


“Hydroxy-substituted C1-C5 alkyl” refers to a C1-C5 alkyl group, as defined above, wherein one or more of the C1-C5 alkyl group's hydrogen atoms has been replaced with —OH. Representative examples of a hydroxy-substituted C1-C5 alkyl include, but are not limited to, —CH2OH, —CH2CH2OH, —CH2CH2CH2OH, —CH2CH2CH2CH2OH, —CH2CH2CH2CH2CH2OH, —CH2CH(OH)CH3, —CH2CH(OH)CH2CH3, —CH(OH)CH2CH3 and —C(CH3)2(CH2OH).


A “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, CH3—CH(NH2)—C(O)—, HN═C(NH2)—NH—(CH2)3—CH(NH2)—C(O)—, H2N—C(O)—CH2—CH(NH2)—C(O)—, HOOC—CH2—CH(NH2)—C(O)—, HS—CH2—CH(NH2)—C(O)—, H2N—C(O)—(CH2)2—CH(NH2)—C(O)—, HOOC—(CH2)2—CH(NH2)—C(O)—, H2N—CH2—C(O)—, CH3—CH2—CH(CH3)—CH(NH2)—C(O)—, (CH3)2—CH—CH2—CH(NH2)—C(O)—, H2N—(CH2)4—CH(NH2)—C(O)—, CH3—S—(CH2)2—CH(NH2)—C(O)—, HO—CH2—CH(NH2)—C(O)—, CH3—CH(OH)—CH(NH2)—C(O)—, (CH3)2—CH—CH(NH2)—C(O)—,




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In one embodiment, the C-terminal alpha amino acid is a natural amino acid.


In another embodiment, the C-terminal alpha amino acid is an unnatural amino acid.


In one embodiment, the C-terminal alpha amino acid is an L amino acid.


An “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. Representative examples of an N-terminal alpha amino acid residue include, but are not limited to, —CH2—COOH, —CH(CH3)COOH, —CH(CH(CH3)2)COOH, —CH(CH2CH(CH3)2)COOH, —CH(CH(CH3)(CH2CH3))COOH, —CH((CH2)4—NH2)COOH, —CH((CH2)3NH(C═NH2)—NH2)COOH, —CH(CH2—OH)COOH, —CH(CH((CH3)(OH)))COOH, —CH(CH2—COOH)COOH, —CH((CH2)2COOH)COOH, —CH((CH2)(CONH2))COOH, —CH((CH2)2(CONH2))COOH, —CH(CH2—SH)COOH, —CH((CH2)2—S—CH3)COOH,




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In one embodiment, the N-terminal alpha amino acid residue is substituted with one or more of -halo, —OH, —OP(O)(OH)2, —OS(O)2OH, —C1-C6 alkyl, —O—C1-C6 alkyl, —C3-C8 monocyclic cycloalkyl, a 3- to 7-membered monocyclic heterocycle, —C1-C6 alkyl-substituted 3- to 7-membered monocyclic heterocycle, or —N(Z3)(Z4). Unless otherwise indicated, the N-terminal alpha amino acid residue is unsubstituted.


An “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. In one embodiment, the N-terminal alpha amino hydroxymethyl residue is substituted with one or more of -halo, —OH, —OP(O)(OH)2, —OS(O)2OH, —C1-C6 alkyl, —O—C1-C6 alkyl, —C3-C8 monocyclic cycloalkyl, a 3- to 7-membered monocyclic heterocycle, —C1-C6 alkyl-substituted 3- to 7-membered monocyclic heterocycle, or —N(Z3)(Z4). In another embodiment, the hydroxyl group of the hydroxymethyl residue is substituted with —PO3H2, —P2O6H3, —P3O9H4, —SO3H, —C(O)—C1-C9 alkyl, β-D-glucuronyl, or a C-terminal alpha amino acid residue. Unless otherwise indicated, the N-terminal alpha amino hydroxymethyl residue is unsubstituted.


A “C1-C6 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 —C1-C6 alkyl group. In one embodiment, the C1-C6 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. In another embodiment, the C1-C6 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)2OH, —C1-C6 alkyl, —O—C1-C6 alkyl, —C3-C8 monocyclic cycloalkyl, a 3- to 7-membered monocyclic heterocycle, —C1-C6 alkyl-substituted 3- to 7-membered monocyclic heterocycle, or —N(Z3)(Z4). Unless otherwise indicated, the C1-C6 alkyl ester of an N-terminal alpha amino acid residue is unsubstituted.


In one embodiment, the N-terminal alpha amino acid is a natural amino acid.


In another embodiment, the N-terminal alpha amino acid is an unnatural amino acid.


In one embodiment, the N-terminal alpha amino acid is an L amino acid.


A “β-D-glucuronyl” refers to a group having the formula:




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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.


The phrase “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.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term “pharmaceutically acceptable salt” also refers to a salt of an Indenoisoquinolinone Analog having an acidic functional group, such as a carboxylic acid functional group, and a base. 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 tris-(hydroxymethyl)methylamine, N,N-di-lower alkyl-N-(hydroxyl-lower alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine, and the like. The term “pharmaceutically acceptable salt” also includes a hydrate of a compound of the invention.


In one embodiment, the pharmaceutically acceptable salt is a mesylate salt.


In another embodiment, 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.


The following abbreviations are used herein and have the indicated definitions: 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 is mass spectrometry, Ts is tosylate, Tf is triflate, Ph is phenyl, NMR is Nuclear Magnetic Resonance, Ms is mesylate, LAH is lithium aluminum hydride and tBoc is t-butyloxycarbonyl.


5.2 The Indenoisoquinolinone Analogs of Formula (Ia)

The present invention provides Indenoisoquinolinone Analogs according to Formula (Ia), below:




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and pharmaceutically acceptable salts thereof,


wherein X and R1 are as defined above for the Indenoisoquinolinone Analogs of Formula (Ia).


In one embodiment, X is —N(CH3)—. In another embodiment, X is —N(CH2CH3)—. In another embodiment, X is —N(CH2CH2CH3)—. In another embodiment, X is —N(CH2 CH2CH2CH3)—. In another embodiment, X is —N(C(H)(CH3)(CH2CH3))—. In another embodiment, X is —N(C(H)(CH3)2)—. In another embodiment, X is —N(CH2C(H)(CH3)2)—. In another embodiment, X is —N(C(CH3)3)—.


In one embodiment, R1 is —(CH2)n—N(R2)(R2) and X is —N(CH3)—.


In another embodiment, R1 is —(CH2)n—N(R2)(R2) and X is —N(CH2CH3)—.


In another embodiment, R1 is —(CH2)n—N(R2)(R2) and X is —N(CH2CH2CH3)—.


In another embodiment, R1 is —(CH2)n—N(R2)(R2) and X is —N(CH2CH2CH2CH3)—.


In another embodiment, R1 is —(CH2)n—N(R2)(R2) and X is —N(C(H)(CH3)(CH2CH3))—.


In another embodiment, R1 is —(CH2)n—N(R2)(R2) and X is —N(C(H)(CH3)2)—.


In another embodiment, R1 is —(CH2)n—N(R2)(R2) and X is —N(CH2C(H)(CH3)2)—.


In another embodiment, R1 is —(CH2)n—N(R2)(R2) and X is —N(C(CH3)3)—.


In one embodiment, R1 is —O—(CH2)m—N(R2)(R2) and X is —N(CH3)—.


In another embodiment, R1 is —O—(CH2)m—N(R2)(R2) and X is —N(CH2CH3)—.


In another embodiment, R1 is —O—(CH2)m—N(R2)(R2) and X is —N(CH2CH2CH3)—.


In another embodiment, R1 is —O—(CH2)m—N(R2)(R2) and X is —N(CH2CH2CH2CH3)—.


In another embodiment, R1 is —O—(CH2)m—N(R2)(R2) and X is —N(C(H)(CH3)(CH2CH3))—.


In another embodiment, R1 is —O—(CH2)m—N(R2)(R2) and X is —N(C(H)(CH3)2)—.


In another embodiment, R1 is —O—(CH2)m—N(R2)(R2) and X is —N(CH2C(H)(CH3)2)—.


In another embodiment, R1 is —O—(CH2)m—N(R2)(R2) and X is —N(C(CH3)3)—.


In one embodiment, one R2 is —H, and the other R2 is —C1-C6 alkyl.


In another embodiment, each R2 is —C1-C6 alkyl.


In another embodiment, each R2 is -methyl.


In one embodiment, X is —CH(OH)—.


In another embodiment, X is —CH(OH)— and R1 is —(CH2)n—N(R2)(R2).


In yet another embodiment, X is —CH(OH)— and R1 is —(CH2)—N(R2)(R2).


In another embodiment, X is —N(C(O)N(H)—(CH2)p—Z)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)—Z)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)2—Z)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—Z)— and R1 is —(CH2)n—N(R2)(R2).


In yet another embodiment, X is —N(C(O)N(H)—(CH2)p—Z)— and R1 is —(CH2)—N(R2)(R2).


In still another embodiment, X is —N(C(O)N(H)—(CH2)—Z)— and R1 is —(CH2)—N(R2)(R2).


In one embodiment, X is —N((CH2)q—Z)—.


In another embodiment, X is —N((CH2)—Z)—.


In another embodiment, X is —N((CH2)2—Z)—.


In another embodiment, X is —N((CH2)q—Z)— and R1 is —(CH2)n—N(R2)(R2).


In yet another embodiment, X is —N((CH2)q—Z)— and R1 is —(CH2)—N(R2)(R2).


In still another embodiment, X is —N((CH2)—Z)— and R1 is —(CH2)—N(R2)(R2).


In one embodiment, Z is —CF3.


In another embodiment, Z is —F.


In yet another embodiment, Z is —OH.


In still another embodiment, Z is —O—CH3.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—OH)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)2—OH)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—OH)— and R1 is —(CH2)n—N(R2)(R2).


In yet another embodiment, X is —N(C(O)N(H)—(CH2)p—OH)— and R1 is —(CH2)—N(R2)(R2).


In still another embodiment, X is —N(C(O)N(H)—(CH2)2—OH)— and R1 is —(CH2)—N(R2)(R2).


In one embodiment, X is —N((CH2)q—OH)—.


In another embodiment, X is —N((CH2)2—OH)—.


In another embodiment, X is —N((CH2)q—OH)— and R1 is —(CH2)n—N(R2)(R2).


In yet another embodiment, X is —N((CH2)q—OH)— and R1 is —(CH2)—N(R2)(R2).


In still another embodiment, X is —N((CH2)2—OH)— and R1 is —(CH2)—N(R2)(R2).


In another embodiment, X is —N(C(O)N(H)—(CH2)p—F)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)—F)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—F)— and R1 is —(CH2)n—N(R2)(R2).


In yet another embodiment, X is —N(C(O)N(H)—(CH2)p—F)— and R1 is —(CH2)—N(R2)(R2).


In still another embodiment, X is —N(C(O)N(H)—(CH2)—F)— and R1 is —(CH2)—N(R2)(R2).


In one embodiment, X is —N((CH2)q—F)—.


In another embodiment, X is —N((CH2)—F)—.


In another embodiment, X is —N((CH2)q—F)— and R1 is —(CH2)n—N(R2)(R2).


In yet another embodiment, X is —N((CH2)q—F)— and R1 is —(CH2)—N(R2)(R2).


In still another embodiment, X is —N((CH2)—F)— and R1 is —(CH2)—N(R2)(R2).


In another embodiment, X is —N(C(O)N(H)—(CH2)p—OMe)-.


In another embodiment, X is —N(C(O)N(H)—(CH2)2—OMe)-.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—OMe)- and R1 is —(CH2)n—N(R2)(R2).


In yet another embodiment, X is —N(C(O)N(H)—(CH2)p—OMe)- and R1 is —(CH2)—N(R2)(R2).


In still another embodiment, X is —N(C(O)N(H)—(CH2)2—OMe)- and R1 is —(CH2)—N(R2)(R2).


In one embodiment, X is —N((CH2)q—OMe)-.


In another embodiment, X is —N((CH2)2—OMe)-.


In another embodiment, X is —N((CH2)q—OMe)- and R1 is —(CH2)n—N(R2)(R2).


In yet another embodiment, X is —N((CH2)q—OMe)- and R1 is —(CH2)—N(R2)(R2).


In still another embodiment, X is —N((CH2)2—OMe)- and R1 is —(CH2)—N(R2)(R2).


In another embodiment, X is —N(C(O)N(H)—(CH2)p—CF3)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)—CF3)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—CF3)— and R1 is —(CH2)n—N(R2)(R2).


In yet another embodiment, X is —N(C(O)N(H)—(CH2)p—CF3)— and R1 is —(CH2)—N(R2)(R2).


In still another embodiment, X is —N(C(O)N(H)—(CH2)—CF3)— and R1 is —(CH2)—N(R2)(R2).


In one embodiment, X is —N((CH2)q—CF3)—.


In another embodiment, X is —N((CH2)—CF3)—.


In another embodiment, X is —N((CH2)q—CF3)— and R1 is —(CH2)n—N(R2)(R2).


In yet another embodiment, X is —N((CH2)q—CF3)— and R1 is —(CH2)—N(R2)(R2).


In still another embodiment, X is —N((CH2)—CF3)— and R1 is —(CH2)—N(R2)(R2).


In another embodiment, X is —N(C(O)N(H)—(CH2)p—CF3)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)—CF3)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—CF3)— and R1 is —(CH2)n—N(R1)(R2).


In yet another embodiment, X is —N(C(O)N(H)—(CH2)p—CF3)— and R1 is —(CH2)—N(R2)(R2).


In still another embodiment, X is —N(C(O)N(H)—(CH2)—CF3)— and R1 is —(CH2)—N(R2)(R2).


In one embodiment, X is —N((CH2)q—CF3)—.


In another embodiment, X is —N((CH2)—CF3)—.


In another embodiment, X is —N((CH2)q—CF3)— and R1 is —(CH2)n—N(R2)(R2).


In yet another embodiment, X is —N((CH2)q—CF3)— and R1 is —(CH2)—N(R2)(R2).


In still another embodiment, X is —N((CH2)—CF3)— and R1 is —(CH2)—N(R2)(R2).


In one embodiment, n is 1.


In another embodiment, n is 2.


In yet another embodiment, n is 3.


In a further embodiment, n is 4, 5, or 6.


In yet a further embodiment, n is 7, 8, or 9.


In still a further embodiment, n is 10.


In one embodiment, m is 2.


In another embodiment, m is 3.


In yet another embodiment, m is 4, 5, or 6.


In a further embodiment, m is 7, 8, or 9.


In yet a further embodiment, m is 10.


In one embodiment, p is 1.


In another embodiment, p is 2.


In yet another embodiment, p is an integer ranging from 2 to 5.


In one embodiment, q is 1.


In another embodiment, q is 2.


In yet another embodiment, q is an integer ranging from 2 to 5.


In various embodiments, —N(R2)(R2) is:




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In other embodiments, —N(R2)(R2) is:




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In some embodiments, —N(R2)(R2) is




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In still other embodiments, —N(R2)(R2) is

    • —N(CH2CH3)(CH3),
    • —N(CH2CH2CH3)(CH3),
    • —N(CH2CH2CH2CH3)(CH3),
    • —NH—CH2CH2CH2CH3, or
    • —NH—CH2CH2—O—CH3.


In some embodiments, —N(R2)(R2) is




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In various embodiments, —N(Z3)(Z4) is:




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In other embodiments, —N(Z3)(Z4) is:




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In some embodiments, —N(Z3)(Z4) is




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In still other embodiments, —N(Z3)(Z4) is

    • —N(CH2CH3)(CH3),
    • —N(CH2CH2CH3)(CH3),
    • —N(CH2CH2CH2CH3)(CH3),
    • —NH—CH2CH2CH2CH3, or
    • —NH—CH2CH2—O—CH3.


In some embodiments, —N(Z3)(Z4) is




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In one embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2 CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2)— or —N(C(CH3)3)—;


R1 is —(CH2)n—N(R2)(R2) or —O—(CH2)m—N(R2)(R2);


each R2 is independently —H, —C1-C6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —(C1-C6 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)2OH or —N(Z3)(Z4), where Z3 and Z4 are independently —H, —C1-C5 alkyl, or —(C1-C5 alkylene)-O—C1-C5 alkyl, each of which other than hydrogen is unsubstituted or substituted with one or more of -halo, —OH or —NH2;


or N, Z3 and Z4 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three of —C1-C5 alkyl, -phenyl, —(C1-C5 alkylene)-phenyl, -(hydroxy-substituted) C1-C5 alkyl, -halo, -(halo-substituted) C1-C5 alkyl, -(halo-substituted) phenyl, -phenylene-O—C1-C5 alkyl, -(cyano-substituted) phenyl, —OH, —O—C1-C5 alkyl, —N(Ra)2, —(C1-C5 alkylene)-N(Ra)2, —C1-C5 alkylene-C(O)O—(C1-C5 alkylene)-N(Ra)2, —COOH, —(C1-C5 alkylene)-COOH, —OP(O)(OH)2, —OS(O)2OH, —(C1-C5 alkylene)-OP(O)(OH)2, —(C1-C5 alkylene)-OS(O)2OH, —C(O)O—C1-C5 alkyl, —OC(O)—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)O—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)NH—C1-C5 alkyl, —C(O)NH2, or —NO2, wherein each occurrence of Ra is independently —H, -benzyl, or —C1-C10 alkyl;


or N and both R2 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 —C1-C5 alkyl, -phenyl, —(C1-C5 alkylene)-phenyl, -(hydroxy-substituted) C1-C5 alkyl, -halo, -(halo-substituted) C1-C5 alkyl, -(halo-substituted) phenyl, -phenylene-O—C1-C5 alkyl, -(cyano-substituted) phenyl, —OH, —O—C1-C5 alkyl, —N(Ra)2, —(C1-C5 alkylene)-N(Ra)2, —(C1-C5 alkylene)-C(O)O—(C1-C5 alkylene)-N(Ra)2, —COOH, —(C1-C5 alkylene)-COOH, —OP(O)(OH)2, —OS(O)2OH, —(C1-C5 alkylene)-OP(O)(OH)2, —(C1-C5 alkylene)-OS(O)2OH, —C(O)O—C1-C5 alkyl, —OC(O)—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)O—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)NH—C1-C5 alkyl, —C(O)NH2, or —NO2, wherein each occurrence of Ra is independently —H, -benzyl, or —C1-C10 alkyl;


n is an integer ranging from 1 to 10; and


m is an integer ranging from 2 to 10.


In one embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2 CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2)— or —N(C(CH3)3)—; R1 is —CH2—N(R2)(R2); and at least one R2 is methyl.


In another embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2 CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2)— or —N(C(CH3)3)—; R1 is —CH2—N(R2)(R2); and at least one R2 is ethyl.


In yet another embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2)— or —N(C(CH3)3)—; R1 is —CH2—N(R2)(R2); and at least one R2 is propyl.


In one embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2 CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2)— or —N(C(CH3)3)—; R1 is —CH2—N(R2)(R2); and at least one R2 is —C3-C8 monocyclic cycloalkyl.


In another embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2 CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2)— or —N(C(CH3)3)—; R1 is —CH2—N(R2)(R2); and at least one R2 is cyclohexyl.


In yet another embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2)— or —N(C(CH3)3)—; and R1 is —CH2—N(R2)(R2), wherein N and both R2 groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle.


In one embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2 CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2)— or —N(C(CH3)3)—; and R1 is —CH2—N(R2)(R2), wherein N and both R2 groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which is substituted with a hydroxyl.


In another embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2 CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2)— or —N(C(CH3)3)—; and R1 is —CH2—N(R2)(R2), wherein N and both R2 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.


Illustrative examples of the Indenoisoquinolinone Analogs include the compounds of Formula (Ia) as set forth below:
















(Ia)




embedded image
















Compound
n
—R1
X





Ia-1
1
—(CH2)n—N(CH3)2
—N(CH3)—


Ia-2
2
—(CH2)n—N(CH3)2
—N(CH3)—


Ia-3
3
—(CH2)n—N(CH3)2
—N(CH3)—


Ia-4
4
—(CH2)n—N(CH3)2
—N(CH3)—


Ia-5
5
—(CH2)n—N(CH3)2
—N(CH3)—


Ia-6
6
—(CH2)n—N(CH3)2
—N(CH3)—


Ia-7
1
—(CH2)n—N(CH3)2
—N(CH2CH3)—


Ia-8
2
—(CH2)n—N(CH3)2
—N(CH2CH3)—


Ia-9
3
—(CH2)n—N(CH3)2
—N(CH2CH3)—


Ia-10
4
—(CH2)n—N(CH3)2
—N(CH2CH3)—


Ia-11
5
—(CH2)n—N(CH3)2
—N(CH2CH3)—


Ia-12
6
—(CH2)n—N(CH3)2
—N(CH2CH3)—


Ia-13
1
—(CH2)n—N(CH3)2
—N(CH2CH2CH3)—


Ia-14
2
—(CH2)n—N(CH3)2
—N(CH2CH2CH3)—


Ia-15
3
—(CH2)n—N(CH3)2
—N(CH2CH2CH3)—


Ia-16
4
—(CH2)n—N(CH3)2
—N(CH2CH2CH3)—


Ia-17
5
—(CH2)n—N(CH3)2
—N(CH2CH2CH3)—


Ia-18
6
—(CH2)n—N(CH3)2
—N(CH2CH2CH3)—


Ia-19
1
—(CH2)n—N(CH3)2
—N(CH2CH2CH2CH3)—


Ia-20
2
—(CH2)n—N(CH3)2
—N(CH2CH2CH2CH3)—


Ia-21
3
—(CH2)n—N(CH3)2
—N(CH2CH2CH2CH3)—


Ia-22
4
—(CH2)n—N(CH3)2
—N(CH2CH2CH2CH3)—


Ia-23
5
—(CH2)n—N(CH3)2
—N(CH2CH2CH2CH3)—


Ia-24
6
—(CH2)n—N(CH3)2
—N(CH2CH2CH2CH3)—


Ia-25
1
—(CH2)n—N(CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ia-26
2
—(CH2)n—N(CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ia-27
3
—(CH2)n—N(CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ia-28
4
—(CH2)n—N(CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ia-29
5
—(CH2)n—N(CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ia-30
6
—(CH2)n—N(CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ia-31
1
—(CH2)n—N(CH3)2
—N(C(H)(CH3)2)—


Ia-32
2
—(CH2)n—N(CH3)2
—N(C(H)(CH3)2)—


Ia-33
3
—(CH2)n—N(CH3)2
—N(C(H)(CH3)2)—


Ia-34
4
—(CH2)n—N(CH3)2
—N(C(H)(CH3)2)—


Ia-35
5
—(CH2)n—N(CH3)2
—N(C(H)(CH3)2)—


Ia-36
6
—(CH2)n—N(CH3)2
—N(C(H)(CH3)2)—


Ia-37
1
—(CH2)n—N(CH3)2
—N(CH2C(H)(CH3)2)—


Ia-38
2
—(CH2)n—N(CH3)2
—N(CH2C(H)(CH3)2)—


Ia-39
3
—(CH2)n—N(CH3)2
—N(CH2C(H)(CH3)2)—


Ia-40
4
—(CH2)n—N(CH3)2
—N(CH2C(H)(CH3)2)—


Ia-41
5
—(CH2)n—N(CH3)2
—N(CH2C(H)(CH3)2)—


Ia-42
6
—(CH2)n—N(CH3)2
—N(CH2C(H)(CH3)2)—


Ia-43
1
—(CH2)n—N(CH3)2
—N(C(CH3)3)—


Ia-44
2
—(CH2)n—N(CH3)2
—N(C(CH3)3)—


Ia-45
3
—(CH2)n—N(CH3)2
—N(C(CH3)3)—


Ia-46
4
—(CH2)n—N(CH3)2
—N(C(CH3)3)—


Ia-47
5
—(CH2)n—N(CH3)2
—N(C(CH3)3)—


Ia-48
6
—(CH2)n—N(CH3)2
—N(C(CH3)3)—





Ia-49
1


embedded image


—N(CH3)—





Ia-50
2


embedded image


—N(CH3)—





Ia-51
3


embedded image


—N(CH3)—





Ia-52
4


embedded image


—N(CH3)—





Ia-53
5


embedded image


—N(CH3)—





Ia-54
6


embedded image


—N(CH3)—





Ia-55
1


embedded image


—N(CH2CH3)—





Ia-56
2


embedded image


—N(CH2CH3)—





Ia-57
3


embedded image


—N(CH2CH3)—





Ia-58
4


embedded image


—N(CH2CH3)—





Ia-59
5


embedded image


—N(CH2CH3)—





Ia-60
6


embedded image


—N(CH2CH3)—





Ia-61
1


embedded image


—N(CH2CH2CH3)—





Ia-62
2


embedded image


—N(CH2CH2CH3)—





Ia-63
3


embedded image


—N(CH2CH2CH3)—





Ia-64
4


embedded image


—N(CH2CH2CH3)—





Ia-65
5


embedded image


—N(CH2CH2CH3)—





Ia-66
6


embedded image


—N(CH2CH2CH3)—





Ia-67
1


embedded image


—N(CH2CH2CH2CH3)—





Ia-68
2


embedded image


—N(CH2CH2CH2CH3)—





Ia-69
3


embedded image


—N(CH2CH2CH2CH3)—





Ia-70
4


embedded image


—N(CH2CH2CH2CH3)—





Ia-71
5


embedded image


—N(CH2CH2CH2CH3)—





Ia-72
6


embedded image


—N(CH2CH2CH2CH3)—





Ia-73
1


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-74
2


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-75
3


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-76
4


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-77
5


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-78
6


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-79
1


embedded image


—N(C(H)(CH3)2)—





Ia-80
2


embedded image


—N(C(H)(CH3)2)—





Ia-81
3


embedded image


—N(C(H)(CH3)2)—





Ia-82
4


embedded image


—N(C(H)(CH3)2)—





Ia-83
5


embedded image


—N(C(H)(CH3)2)—





Ia-84
6


embedded image


—N(C(H)(CH3)2)—





Ia-85
1


embedded image


—N(CH2C(H)(CH3)2)—





Ia-86
2


embedded image


—N(CH2C(H)(CH3)2)—





Ia-87
3


embedded image


—N(CH2C(H)(CH3)2)—





Ia-88
4


embedded image


—N(CH2C(H)(CH3)2)—





Ia-89
5


embedded image


—N(CH2C(H)(CH3)2)—





Ia-90
6


embedded image


—N(CH2C(H)(CH3)2)—





Ia-91
1


embedded image


—N(C(CH3)3)—





Ia-92
2


embedded image


—N(C(CH3)3)—





Ia-93
3


embedded image


—N(C(CH3)3)—





Ia-94
4


embedded image


—N(C(CH3)3)—





Ia-95
5


embedded image


—N(C(CH3)3)—





Ia-96
6


embedded image


—N(C(CH3)3)—





Compound
m
—R1
X





Ia-146
2
—O—(CH2)m—N(CH3)2
—N(CH3)—


Ia-147
3
—O—(CH2)m—N(CH3)2
—N(CH3)—


Ia-148
4
—O—(CH2)m—N(CH3)2
—N(CH3)—


Ia-149
5
—O—(CH2)m—N(CH3)2
—N(CH3)—


Ia-150
6
—O—(CH2)m—N(CH3)2
—N(CH3)—


Ia-151
2
—O—(CH2)m—N(CH3)2
—N(CH3)—


Ia-152
3
—O—(CH2)m—N(CH3)2
—N(CH2CH3)—


Ia-153
4
—O—(CH2)m—N(CH3)2
—N(CH2CH3)—


Ia-154
5
—O—(CH2)m—N(CH3)2
—N(CH2CH3)—


Ia-155
6
—O—(CH2)m—N(CH3)2
—N(CH2CH3)—


Ia-156
2
—O—(CH2)m—N(CH3)2
—N(CH2CH3)—


Ia-157
3
—O—(CH2)m—N(CH3)2
—N(CH2CH3)—


Ia-158
4
—O—(CH2)m—N(CH3)2
—N(CH2CH2CH3)—


Ia-159
5
—O—(CH2)m—N(CH3)2
—N(CH2CH2CH3)—


Ia-160
6
—O—(CH2)m—N(CH3)2
—N(CH2CH2CH3)—


Ia-161
2
—O—(CH2)m—N(CH3)2
—N(CH2CH2CH3)—


Ia-162
3
—O—(CH2)m—N(CH3)2
—N(CH2CH2CH3)—


Ia-163
4
—O—(CH2)m—N(CH3)2
—N(CH2CH2CH3)—


Ia-164
5
—O—(CH2)m—N(CH3)2
—N(CH2CH2CH2CH3)—


Ia-165
6
—O—(CH2)m—N(CH3)2
—N(CH2CH2CH2CH3)—


Ia-166
2
—O—(CH2)m—N(CH3)2
—N(CH2CH2CH2CH3)—


Ia-167
3
—O—(CH2)m—N(CH3)2
—N(CH2CH2CH2CH3)—


Ia-168
4
—O—(CH2)m—N(CH3)2
—N(CH2CH2CH2CH3)—


Ia-169
5
—O—(CH2)m—N(CH3)2
—N(CH2CH2CH2CH3)—


Ia-170
6
—O—(CH2)m—N(CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ia-171
2
—O—(CH2)m—N(CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ia-172
3
—O—(CH2)m—N(CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ia-173
4
—O—(CH2)m—N(CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ia-174
5
—O—(CH2)m—N(CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ia-175
6
—O—(CH2)m—N(CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ia-176
2
—O—(CH2)m—N(CH3)2
—N(C(H)(CH3)2)—


Ia-178
3
—O—(CH2)m—N(CH3)2
—N(C(H)(CH3)2)—


Ia-179
4
—O—(CH2)m—N(CH3)2
—N(C(H)(CH3)2)—


Ia-180
5
—O—(CH2)m—N(CH3)2
—N(C(H)(CH3)2)—


Ia-181
6
—O—(CH2)m—N(CH3)2
—N(C(H)(CH3)2)—


Ia-182
2
—O—(CH2)m—N(CH3)2
—N(C(H)(CH3)2)—


Ia-183
3
—O—(CH2)m—N(CH3)2
—N(CH2C(H)(CH3)2)—


Ia-184
4
—O—(CH2)m—N(CH3)2
—N(CH2C(H)(CH3)2)—


Ia-185
5
—O—(CH2)m—N(CH3)2
—N(CH2C(H)(CH3)2)—


Ia-186
6
—O—(CH2)m—N(CH3)2
—N(CH2C(H)(CH3)2)—





Ia-187
2


embedded image


—N(CH3)—





Ia-188
3


embedded image


—N(CH3)—





Ia-189
4


embedded image


—N(CH3)—





Ia-190
5


embedded image


—N(CH3)—





Ia-191
6


embedded image


—N(CH3)—





Ia-192
2


embedded image


—N(CH3)—





Ia-193
3


embedded image


—N(CH2CH3)—





Ia-194
4


embedded image


—N(CH2CH3)—





Ia-195
5


embedded image


—N(CH2CH3)—





Ia-196
6


embedded image


—N(CH2CH3)—





Ia-197
2


embedded image


—N(CH2CH3)—





Ia-198
3


embedded image


—N(CH2CH3)—





Ia-199
4


embedded image


—N(CH2CH2CH3)—





Ia-200
5


embedded image


—N(CH2CH2CH3)—





Ia-201
6


embedded image


—N(CH2CH2CH3)—





Ia-202
2


embedded image


—N(CH2CH2CH3)—





Ia-203
3


embedded image


—N(CH2CH2CH3)—





Ia-204
4


embedded image


—N(CH2CH2CH3)—





Ia-205
5


embedded image


—N(CH2CH2CH2CH3)—





Ia-206
6


embedded image


—N(CH2CH2CH2CH3)—





Ia-207
2


embedded image


—N(CH2CH2CH2CH3)—





Ia-208
3


embedded image


—N(CH2CH2CH2CH3)—





Ia-209
4


embedded image


—N(CH2CH2CH2CH3)—





Ia-210
5


embedded image


—N(CH2CH2CH2CH3)—





Ia-211
6


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-212
2


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-213
3


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-214
4


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-215
5


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-216
6


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-217
2


embedded image


—N(C(H)(CH3)2)—





Ia-218
3


embedded image


—N(C(H)(CH3)2)—





Ia-219
4


embedded image


—N(C(H)(CH3)2)—





Ia-220
5


embedded image


—N(C(H)(CH3)2)—





Ia-221
6


embedded image


—N(C(H)(CH3)2)—





Ia-222
2


embedded image


—N(C(H)(CH3)2)—





Ia-223
3


embedded image


—N(CH2C(H)(CH3)2)—





Ia-224
4


embedded image


—N(CH2C(H)(CH3)2)—





Ia-225
5


embedded image


—N(CH2C(H)(CH3)2)—





Ia-226
6


embedded image


—N(CH2C(H)(CH3)2)—












Compound
—R1
X





Ia-267
—CH2—N(CH2—CH3)2
—N(CH3)—


Ia-268
—CH2—N(CH2—CH3)2
—N(CH2CH3)—


Ia-269
—CH2—N(CH2—CH3)2
—N(CH2CH2CH3)—


Ia-270
—CH2—N(CH2—CH3)2
—N(CH2CH2CH2CH3)—


Ia-271
—CH2—N(CH2—CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ia-272
—CH2—N(CH2—CH3)2
—N(C(H)(CH3)2)—


Ia-273
—CH2—N(CH2—CH3)2
—N(CH2C(H)(CH3)2)—


Ia-274
—CH2—N(CH2—CH3)2
—N(C(CH3)3)—


Ia-275
—CH2—N(CH2—CH2—CH3)2
—N(CH3)—


Ia-276
—CH2—N(CH2—CH2—CH3)2
—N(CH2CH3)—


Ia-277
—CH2—N(CH2—CH2—CH3)2
—N(CH2CH2CH3)—


Ia-278
—CH2—N(CH2—CH2—CH3)2
—N(CH2CH2CH2CH3)—


Ia-279
—CH2—N(CH2—CH2—CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ia-280
—CH2—N(CH2—CH2—CH3)2
—N(C(H)(CH3)2)—


Ia-281
—CH2—N(CH2—CH2—CH3)2
—N(CH2C(H)(CH3)2)—


Ia-282
—CH2—N(CH2—CH2—CH3)2
—N(C(CH3)3)—


Ia-283
—CH2—N(CH2—CH2OH)2
—N(CH3)—


Ia-284
—CH2—N(CH2—CH2OH)2
—N(CH2CH3)—


Ia-285
—CH2—N(CH2—CH2OH)2
—N(CH2CH2CH3)—


Ia-286
—CH2—N(CH2—CH2OH)2
—N(CH2CH2CH2CH3)—


Ia-287
—CH2—N(CH2—CH2OH)2
—N(C(H)(CH3)(CH2CH3))—


Ia-288
—CH2—N(CH2—CH2OH)2
—N(C(H)(CH3)2)—


Ia-289
—CH2—N(CH2—CH2OH)2
—N(CH2C(H)(CH3)2)—


Ia-290
—CH2—N(CH2—CH2OH)2
—N(C(CH3)3)—


Ia-291
—CH2—N(CH2—CH2—N(CH3)2)2
—N(CH3)—


Ia-292
—CH2—N(CH2—CH2—N(CH3)2)2
—N(CH2CH3)—


Ia-293
—CH2—N(CH2—CH2—N(CH3)2)2
—N(CH2CH2CH3)—


Ia-294
—CH2—N(CH2—CH2—N(CH3)2)2
—N(CH2CH2CH2CH3)—


Ia-295
—CH2—N(CH2—CH2—N(CH3)2)2
—N(C(H)(CH3)(CH2CH3))—


Ia-296
—CH2—N(CH2—CH2—N(CH3)2)2
—N(C(H)(CH3)2)—


Ia-297
—CH2—N(CH2—CH2—N(CH3)2)2
—N(CH2C(H)(CH3)2)—


Ia-298
—CH2—N(CH2—CH2—N(CH3)2)2
—N(C(CH3)3)—


Ia-299
—CH2—N(CH2—CH2—CH2—N(CH3)2)2
—N(CH3)—


Ia-300
—CH2—N(CH2—CH2—CH2—N(CH3)2)2
—N(CH2CH3)—


Ia-301
—CH2—N(CH2—CH2—CH2—N(CH3)2)2
—N(CH2CH2CH3)—


Ia-302
—CH2—N(CH2—CH2—CH2—N(CH3)2)2
—N(CH2CH2CH2CH3)—


Ia-303
—CH2—N(CH2—CH2—CH2—N(CH3)2)2
—N(C(H)(CH3)(CH2CH3))—


Ia-304
—CH2—N(CH2—CH2—CH2—N(CH3)2)2
—N(C(H)(CH3)2)—


Ia-305
—CH2—N(CH2—CH2—CH2—N(CH3)2)2
—N(CH2C(H)(CH3)2)—


Ia-306
—CH2—N(CH2—CH2—CH2—N(CH3)2)2
—N(C(CH3)3)—





Ia-307


embedded image


—N(CH3)—





Ia-308


embedded image


—N(CH2CH3)—





Ia-309


embedded image


—N(CH2CH2CH3)—





Ia-310


embedded image


—N(CH2CH2CH2CH3)—





Ia-311


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-312


embedded image


—N(C(H)(CH3)2)—





Ia-313


embedded image


—N(CH2C(H)(CH3)2)—





Ia-314


embedded image


—N(C(CH3)3)—





Ia-315


embedded image


—N(CH3)—





Ia-316


embedded image


—N(CH2CH3)—





Ia-317


embedded image


—N(CH2CH2CH3)—





Ia-318


embedded image


—N(CH2CH2CH2CH3)—





Ia-319


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-320


embedded image


—N(C(H)(CH3)2)—





Ia-321


embedded image


—N(CH2C(H)(CH3)2)—





Ia-322


embedded image


—N(C(CH3)3)—





Ia-323


embedded image


—N(CH3)—





Ia-324


embedded image


—N(CH2CH3)—





Ia-325


embedded image


—N(CH2CH2CH3)—





Ia-326


embedded image


—N(CH2CH2CH2CH3)—





Ia-327


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-328


embedded image


—N(C(H)(CH3)2)—





Ia-329


embedded image


—N(CH2C(H)(CH3)2)—





Ia-330


embedded image


—N(C(CH3)3)—





Ia-331


embedded image


—N(CH3)—





Ia-332


embedded image


—N(CH2CH3)—





Ia-333


embedded image


—N(CH2CH2CH3)—





Ia-334


embedded image


—N(CH2CH2CH2CH3)—





Ia-335


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-336


embedded image


—N(C(H)(CH3)2)—





Ia-337


embedded image


—N(CH2C(H)(CH3)2)—





Ia-338


embedded image


—N(C(CH3)3)—





Ia-339


embedded image


—N(CH3)—





Ia-340


embedded image


—N(CH2CH3)—





Ia-341


embedded image


—N(CH2CH2CH3)—





Ia-342


embedded image


—N(CH2CH2CH2CH3)—





Ia-343


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-344


embedded image


—N(C(H)(CH3)2)—





Ia-345


embedded image


—N(CH2C(H)(CH3)2)—





Ia-346


embedded image


—N(C(CH3)3)—





Ia-347


embedded image


—N(CH3)—





Ia-348


embedded image


—N(CH2CH3)—





Ia-349


embedded image


—N(CH2CH2CH3)—





Ia-350


embedded image


—N(CH2CH2CH2CH3)—





Ia-351


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-352


embedded image


—N(C(H)(CH3)2)—





Ia-353


embedded image


—N(CH2C(H)(CH3)2)—





Ia-354


embedded image


—N(C(CH3)3)—





Ia-355


embedded image


—N(CH3)—





Ia-356


embedded image


—N(CH2CH3)—





Ia-357


embedded image


—N(CH2CH2CH3)—





Ia-358


embedded image


—N(CH2CH2CH2CH3)—





Ia-359


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-360


embedded image


—N(C(H)(CH3)2)—





Ia-361


embedded image


—N(CH2C(H)(CH3)2)—





Ia-362


embedded image


—N(C(CH3)3)—





Ia-363


embedded image


—N(CH3)—





Ia-364


embedded image


—N(CH2CH3)—





Ia-365


embedded image


—N(CH2CH2CH3)—





Ia-366


embedded image


—N(CH2CH2CH2CH3)—





Ia-367


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-368


embedded image


—N(C(H)(CH3)2)—





Ia-369


embedded image


—N(CH2C(H)(CH3)2)—





Ia-370


embedded image


—N(C(CH3)3)—





Ia-371


embedded image


—N(CH3)—





Ia-372


embedded image


—N(CH2CH3)—





Ia-373


embedded image


—N(CH2CH2CH3)—





Ia-374


embedded image


—N(CH2CH2CH2CH3)—





Ia-375


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-376


embedded image


—N(C(H)(CH3)2)—





Ia-377


embedded image


—N(CH2C(H)(CH3)2)—





Ia-378


embedded image


—N(C(CH3)3)—





Ia-379


embedded image


—N(CH3)—





Ia-380


embedded image


—N(CH2CH3)—





Ia-381


embedded image


—N(CH2CH2CH3)—





Ia-382


embedded image


—N(CH2CH2CH2CH3)—





Ia-383


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-384


embedded image


—N(C(H)(CH3)2)—





Ia-385


embedded image


—N(CH2C(H)(CH3)2)—





Ia-386


embedded image


—N(C(CH3)3)—





Ia-387


embedded image


—N(CH3)—





Ia-388


embedded image


—N(CH2CH3)—





Ia-389


embedded image


—N(CH2CH2CH3)—





Ia-390


embedded image


—N(CH2CH2CH2CH3)—





Ia-391


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-392


embedded image


—N(C(H)(CH3)2)—





Ia-393


embedded image


—N(CH2C(H)(CH3)2)—





Ia-394


embedded image


—N(C(CH3)3)—





Ia-395


embedded image


—N(CH3)—





Ia-396


embedded image


—N(CH2CH3)—





Ia-397


embedded image


—N(CH2CH2CH3)—





Ia-398


embedded image


—N(CH2CH2CH2CH3)—





Ia-399


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-400


embedded image


—N(C(H)(CH3)2)—





Ia-401


embedded image


—N(CH2C(H)(CH3)2)—





Ia-402


embedded image


—N(C(CH3)3)—





Ia-403


embedded image


—N(CH3)—





Ia-404


embedded image


—N(CH2CH3)—





Ia-405


embedded image


—N(CH2CH2CH3)—





Ia-406


embedded image


—N(CH2CH2CH2CH3)—





Ia-407


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-408


embedded image


—N(C(H)(CH3)2)—





Ia-409


embedded image


—N(CH2C(H)(CH3)2)—





Ia-410


embedded image


—N(C(CH3)3)—





Ia-411


embedded image


—N(CH3)—





Ia-412


embedded image


—N(CH2CH3)—





Ia-413


embedded image


—N(CH2CH2CH3)—





Ia-414


embedded image


—N(CH2CH2CH2CH3)—





Ia-415


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-416


embedded image


—N(C(H)(CH3)2)—





Ia-417


embedded image


—N(CH2C(H)(CH3)2)—





Ia-418


embedded image


—N(C(CH3)3)—





Ia-419


embedded image


—N(CH3)—





Ia-420


embedded image


—N(CH2CH3)—





Ia-421


embedded image


—N(CH2CH2CH3)—





Ia-422


embedded image


—N(CH2CH2CH2CH3)—





Ia-423


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-424


embedded image


—N(C(H)(CH3)2)—





Ia-425


embedded image


—N(CH2C(H)(CH3)2)—





Ia-426


embedded image


—N(C(CH3)3)—





Ia-427


embedded image


—N(CH3)—





Ia-428


embedded image


—N(CH2CH3)—





Ia-429


embedded image


—N(CH2CH2CH3)—





Ia-430


embedded image


—N(CH2CH2CH2CH3)—





Ia-431


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-432


embedded image


—N(C(H)(CH3)2)—





Ia-433


embedded image


—N(CH2C(H)(CH3)2)—





Ia-434


embedded image


—N(C(CH3)3)—





Ia-435


embedded image


—N(CH3)—





Ia-436


embedded image


—N(CH2CH3)—





Ia-437


embedded image


—N(CH2CH2CH3)—





Ia-438


embedded image


—N(CH2CH2CH2CH3)—





Ia-439


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-440


embedded image


—N(C(H)(CH3)2)—





Ia-441


embedded image


—N(CH2C(H)(CH3)2)—





Ia-442


embedded image


—N(C(CH3)3)—





Ia-443


embedded image


—N(CH3)—





Ia-444


embedded image


—N(CH2CH3)—





Ia-445


embedded image


—N(CH2CH2CH3)—





Ia-446


embedded image


—N(CH2CH2CH2CH3)—





Ia-447


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-448


embedded image


—N(C(H)(CH3)2)—





Ia-449


embedded image


—N(CH2C(H)(CH3)2)—





Ia-450


embedded image


—N(C(CH3)3)—





Ia-451


embedded image


—N(CH3)—





Ia-452


embedded image


—N(CH2CH3)—





Ia-453


embedded image


—N(CH2CH2CH3)—





Ia-454


embedded image


—N(CH2CH2CH2CH3)—





Ia-455


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-456


embedded image


—N(C(H)(CH3)2)—





Ia-457


embedded image


—N(CH2C(H)(CH3)2)—





Ia-458


embedded image


—N(C(CH3)3)—





Ia-459


embedded image


—N(CH3)—





Ia-460


embedded image


—N(CH2CH3)—





Ia-461


embedded image


—N(CH2CH2CH3)—





Ia-462


embedded image


—N(CH2CH2CH2CH3)—





Ia-463


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-464


embedded image


—N(C(H)(CH3)2)—





Ia-465


embedded image


—N(CH2C(H)(CH3)2)—





Ia-466


embedded image


—N(C(CH3)3)—





Ia-467


embedded image


—N(CH3)—





Ia-468


embedded image


—N(CH2CH3)—





Ia-469


embedded image


—N(CH2CH2CH3)—





Ia-470


embedded image


—N(CH2CH2CH2CH3)—





Ia-471


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-472


embedded image


—N(C(H)(CH3)2)—





Ia-473


embedded image


—N(CH2C(H)(CH3)2)—





Ia-474


embedded image


—N(C(CH3)3)—





Ia-475


embedded image


—N(CH3)—





Ia-476


embedded image


—N(CH2CH3)—





Ia-477


embedded image


—N(CH2CH2CH3)—





Ia-478


embedded image


—N(CH2CH2CH2CH3)—





Ia-479


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-480


embedded image


—N(C(H)(CH3)2)—





Ia-481


embedded image


—N(CH2C(H)(CH3)2)—





Ia-482


embedded image


—N(C(CH3)3)—





Ia-483


embedded image


—N(CH3)—





Ia-484


embedded image


—N(CH2CH3)—





Ia-485


embedded image


—N(CH2CH2CH3)—





Ia-486


embedded image


—N(CH2CH2CH2CH3)—





Ia-487


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-488


embedded image


—N(C(H)(CH3)2)—





Ia-489


embedded image


—N(CH2C(H)(CH3)2)—





Ia-490


embedded image


—N(C(CH3)3)—





Ia-491
—CH2—CH2—CH2—OP(O)(OH)2
—N(CH3)—


Ia-492
—CH2—CH2—CH2—OP(O)(OH)2
—N(CH2CH3)—


Ia-493
—CH2—CH2—CH2—OP(O)(OH)2
—N(CH2CH2CH3)—


Ia-494
—CH2—CH2—CH2—OP(O)(OH)2
—N(CH2CH2CH2CH3)—


Ia-495
—CH2—CH2—CH2—OP(O)(OH)2
—N(C(H)(CH3)(CH2CH3))—


Ia-496
—CH2—CH2—CH2—OP(O)(OH)2
—N(C(H)(CH3)2)—


Ia-497
—CH2—CH2—CH2—OP(O)(OH)2
—N(CH2C(H)(CH3)2)—


Ia-498
—CH2—CH2—CH2—OP(O)(OH)2
—N(C(CH3)3)—


Ia-499
—CH2—CH2—CH2—OS(O)2OH
—N(CH3)—


Ia-500
—CH2—CH2—CH2—OS(O)2OH
—N(CH2CH3)—


Ia-501
—CH2—CH2—CH2—OS(O)2OH
—N(CH2CH2CH3)—


Ia-502
—CH2—CH2—CH2—OS(O)2OH
—N(CH2CH2CH2CH3)—


Ia-503
—CH2—CH2—CH2—OS(O)2OH
—N(C(H)(CH3)(CH2CH3))—


Ia-504
—CH2—CH2—CH2—OS(O)2OH
—N(C(H)(CH3)2)—


Ia-505
—CH2—CH2—CH2—OS(O)2OH
—N(CH2C(H)(CH3)2)—


Ia-506
—CH2—CH2—CH2—OS(O)2OH
—N(C(CH3)3)—





Ia-507


embedded image


—N(CH3)—





Ia-508


embedded image


—N(CH2CH3)—





Ia-509


embedded image


—N(CH2CH2CH3)—





Ia-510


embedded image


—N(CH2CH2CH2CH3)—





Ia-511


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-512


embedded image


—N(C(H)(CH3)2)—





Ia-513


embedded image


—N(CH2C(H)(CH3)2)—





Ia-514


embedded image


—N(C(CH3)3)—





Ia-515


embedded image


—N(CH3)—





Ia-516


embedded image


—N(CH2CH3)—





Ia-517


embedded image


—N(CH2CH2CH3)—





Ia-518


embedded image


—N(CH2CH2CH2CH3)—





Ia-519


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-520


embedded image


—N(C(H)(CH3)2)—





Ia-521


embedded image


—N(CH2C(H)(CH3)2)—





Ia-522


embedded image


—N(C(CH3)3)—





Ia-523
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(CH3)—


Ia-524
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(CH2CH3)—


Ia-525
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(CH2CH2CH3)—


Ia-526
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(CH2CH2CH2CH3)—


Ia-527
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ia-528
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(C(H)(CH3)2)—


Ia-529
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(CH2C(H)(CH3)2)—


Ia-530
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(C(CH3)3)—


Ia-531
—CH2—N(CH2—CH2—O—CH3)2
—N(CH3)—


Ia-532
—CH2—N(CH2—CH2—O—CH3)2
—N(CH2CH3)—


Ia-533
—CH2—N(CH2—CH2—O—CH3)2
—N(CH2CH2CH3)—


Ia-534
—CH2—N(CH2—CH2—O—CH3)2
—N(CH2CH2CH2CH3)—


Ia-535
—CH2—N(CH2—CH2—O—CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ia-536
—CH2—N(CH2—CH2—O—CH3)2
—N(C(H)(CH3)2)—


Ia-537
—CH2—N(CH2—CH2—O—CH3)2
—N(CH2C(H)(CH3)2)—


Ia-538
—CH2—N(CH2—CH2—O—CH3)2
—N(C(CH3)3)—





Ia-539


embedded image


—N(CH3)—





Ia-540


embedded image


—N(CH2CH3)—





Ia-541


embedded image


—N(CH2CH2CH3)—





Ia-542


embedded image


—N(CH2CH2CH2CH3)—





Ia-543


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-544


embedded image


—N(C(H)(CH3)2)—





Ia-545


embedded image


—N(CH2C(H)(CH3)2)—





Ia-546


embedded image


—N(C(CH3)3)—





Ia-547


embedded image


—N(CH3)—





Ia-548


embedded image


—N(CH2CH3)—





Ia-549


embedded image


—N(CH2CH2CH3)—





Ia-550


embedded image


—N(CH2CH2CH2CH3)—





Ia-551


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-552


embedded image


—N(C(H)(CH3)2)—





Ia-553


embedded image


—N(CH2C(H)(CH3)2)—





Ia-554


embedded image


—N(C(CH3)3)—





Ia-555


embedded image


—N(CH3)—





Ia-556


embedded image


—N(CH2CH3)—





Ia-557


embedded image


—N(CH2CH2CH3)—





Ia-558


embedded image


—N(CH2CH2CH2CH3)—





Ia-559


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-560


embedded image


—N(C(H)(CH3)2)—





Ia-561


embedded image


—N(CH2C(H)(CH3)2)—





Ia-562


embedded image


—N(C(CH3)3)—





Ia-563


embedded image


—N(CH3)—





Ia-564


embedded image


—N(CH2CH3)—





Ia-565


embedded image


—N(CH2CH2CH3)—





Ia-566


embedded image


—N(CH2CH2CH2CH3)—





Ia-567


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-568


embedded image


—N(C(H)(CH3)2)—





Ia-569


embedded image


—N(CH2C(H)(CH3)2)—





Ia-570


embedded image


—N(C(CH3)3)—





Ia-571


embedded image


—N(CH3)—





Ia-572


embedded image


—N(CH2CH3)—





Ia-573


embedded image


—N(CH2CH2CH3)—





Ia-574


embedded image


—N(CH2CH2CH2CH3)—





Ia-575


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-576


embedded image


—N(C(H)(CH3)2)—





Ia-577


embedded image


—N(CH2C(H)(CH3)2)—





Ia-578


embedded image


—N(C(CH3)3)—





Ia-579


embedded image


—N(CH3)—





Ia-580


embedded image


—N(CH2CH3)—





Ia-581


embedded image


—N(CH2CH2CH3)—





Ia-582


embedded image


—N(CH2CH2CH2CH3)—





Ia-583


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-584


embedded image


—N(C(H)(CH3)2)—





Ia-585


embedded image


—N(CH2C(H)(CH3)2)—





Ia-586


embedded image


—N(C(CH3)3)—





Ia-587


embedded image


—N(CH3)—





Ia-588


embedded image


—N(CH2CH3)—





Ia-589


embedded image


—N(CH2CH2CH3)—





Ia-590


embedded image


—N(CH2CH2CH2CH3)—





Ia-591


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-592


embedded image


—N(C(H)(CH3)2)—





Ia-593


embedded image


—N(CH2C(H)(CH3)2)—





Ia-594


embedded image


—N(C(CH3)3)—





Ia-595


embedded image


—N(CH3)—





Ia-596


embedded image


—N(CH2CH3)—





Ia-597


embedded image


—N(CH2CH2CH3)—





Ia-598


embedded image


—N(CH2CH2CH2CH3)—





Ia-599


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-600


embedded image


—N(C(H)(CH3)2)—





Ia-601


embedded image


—N(CH2C(H)(CH3)2)—





Ia-602


embedded image


—N(C(CH3)3)—





Ia-603


embedded image


—N(CH3)—





Ia-604


embedded image


—N(CH2CH3)—





Ia-605


embedded image


—N(CH2CH2CH3)—





Ia-606


embedded image


—N(CH2CH2CH2CH3)—





Ia-607


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-608


embedded image


—N(C(H)(CH3)2)—





Ia-609


embedded image


—N(CH2C(H)(CH3)2)—





Ia-610


embedded image


—N(C(CH3)3)—





Ia-611
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(CH3)—


Ia-612
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(CH2CH3)—


Ia-613
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(CH2CH2CH3)—


Ia-614
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(CH2CH2CH2CH3)—


Ia-615
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ia-616
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(C(H)(CH3)2)—


Ia-617
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(CH2C(H)(CH3)2)—


Ia-618
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(C(CH3)3)—





Ia-619


embedded image


—N(CH3)—





Ia-620


embedded image


—N(CH2CH3)—





Ia-621


embedded image


—N(CH2CH2CH3)—





Ia-622


embedded image


—N(CH2CH2CH2CH3)—





Ia-623


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-624


embedded image


—N(C(H)(CH3)2)—





Ia-625


embedded image


—N(CH2C(H)(CH3)2)—





Ia-626


embedded image


—N(C(CH3)3)—





Ia-627


embedded image


—N(CH3)—





Ia-628


embedded image


—N(CH2CH3)—





Ia-629


embedded image


—N(CH2CH2CH3)—





Ia-630


embedded image


—N(CH2CH2CH2CH3)—





Ia-631


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-632


embedded image


—N(C(H)(CH3)2)—





Ia-633


embedded image


—N(CH2C(H)(CH3)2)—





Ia-634


embedded image


—N(C(CH3)3)—





Ia-635


embedded image


—N(CH3)—





Ia-636


embedded image


—N(CH2CH3)—





Ia-637


embedded image


—N(CH2CH2CH3)—





Ia-638


embedded image


—N(CH2CH2CH2CH3)—





Ia-639


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-640


embedded image


—N(C(H)(CH3)2)—





Ia-641


embedded image


—N(CH2C(H)(CH3)2)—





Ia-642


embedded image


—N(C(CH3)3)—





Ia-643


embedded image


—N(CH3)—





Ia-644


embedded image


—N(CH2CH3)—





Ia-645


embedded image


—N(CH2CH2CH3)—





Ia-646


embedded image


—N(CH2CH2CH2CH3)—





Ia-647


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-648


embedded image


—N(C(H)(CH3)2)—





Ia-649


embedded image


—N(CH2C(H)(CH3)2)—





Ia-650


embedded image


—N(C(CH3)3)—





Ia-651


embedded image


—N(CH3)—





Ia-652


embedded image


—N(CH2CH3)—





Ia-653


embedded image


—N(CH2CH2CH3)—





Ia-654


embedded image


—N(CH2CH2CH2CH3)—





Ia-655


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-656


embedded image


—N(C(H)(CH3)2)—





Ia-657


embedded image


—N(CH2C(H)(CH3)2)—





Ia-658


embedded image


—N(C(CH3)3)—





Ia-659


embedded image


—N(CH3)—





Ia-660


embedded image


—N(CH2CH3)—





Ia-661


embedded image


—N(CH2CH2CH3)—





Ia-662


embedded image


—N(CH2CH2CH2CH3)—





Ia-663


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-664


embedded image


—N(C(H)(CH3)2)—





Ia-665


embedded image


—N(CH2C(H)(CH3)2)—





Ia-666


embedded image


—N(C(CH3)3)—





Ia-667


embedded image


—N(CH3)—





Ia-668


embedded image


—N(CH2CH3)—





Ia-669


embedded image


—N(CH2CH2CH3)—





Ia-670


embedded image


—N(CH2CH2CH2CH3)—





Ia-671


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-672


embedded image


—N(C(H)(CH3)2)—





Ia-673


embedded image


—N(CH2C(H)(CH3)2)—





Ia-674


embedded image


—N(C(CH3)3)—





Ia-675


embedded image


—N(CH3)—





Ia-676


embedded image


—N(CH2CH3)—





Ia-677


embedded image


—N(CH2CH2CH3)—





Ia-678


embedded image


—N(CH2CH2CH2CH3)—





Ia-679


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-680


embedded image


—N(C(H)(CH3)2)—





Ia-681


embedded image


—N(CH2C(H)(CH3)2)—





Ia-682


embedded image


—N(C(CH3)3)—





Ia-683


embedded image


—N(CH3)—





Ia-684


embedded image


—N(CH2CH3)—





Ia-685


embedded image


—N(CH2CH2CH3)—





Ia-686


embedded image


—N(CH2CH2CH2CH3)—





Ia-687


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-688


embedded image


—N(C(H)(CH3)2)—





Ia-689


embedded image


—N(CH2C(H)(CH3)2)—





Ia-690


embedded image


—N(C(CH3)3)—





Ia-691


embedded image


—N(CH3)—





Ia-692


embedded image


—N(CH2CH3)—





Ia-693


embedded image


—N(CH2CH2CH3)—





Ia-694


embedded image


—N(CH2CH2CH2CH3)—





Ia-695


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-696


embedded image


—N(C(H)(CH3)2)—





Ia-697


embedded image


—N(CH2C(H)(CH3)2)—





Ia-698


embedded image


—N(C(CH3)3)—





Ia-699


embedded image


—N(CH3)—





Ia-700


embedded image


—N(CH2CH3)—





Ia-701


embedded image


—N(CH2CH2CH3)—





Ia-702


embedded image


—N(CH2CH2CH2CH3)—





Ia-703


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-704


embedded image


—N(C(H)(CH3)2)—





Ia-705


embedded image


—N(CH2C(H)(CH3)2)—





Ia-706


embedded image


—N(C(CH3)3)—





Ia-707


embedded image


—N(CH3)—





Ia-708


embedded image


—N(CH2CH3)—





Ia-709


embedded image


—N(CH2CH2CH3)—





Ia-710


embedded image


—N(CH2CH2CH2CH3)—





Ia-711


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-712


embedded image


—N(C(H)(CH3)2)—





Ia-713


embedded image


—N(CH2C(H)(CH3)2)—





Ia-714


embedded image


—N(C(CH3)3)—





Ia-715


embedded image


—N(CH3)—





Ia-716


embedded image


—N(CH2CH3)—





Ia-717


embedded image


—N(CH2CH2CH3)—





Ia-718


embedded image


—N(CH2CH2CH2CH3)—





Ia-719


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-720


embedded image


—N(C(H)(CH3)2)—





Ia-721


embedded image


—N(CH2C(H)(CH3)2)—





Ia-722


embedded image


—N(C(CH3)3)—





Ia-723


embedded image


—N(CH3)—





Ia-724


embedded image


—N(CH2CH3)—





Ia-725


embedded image


—N(CH2CH2CH3)—





Ia-726


embedded image


—N(CH2CH2CH2CH3)—





Ia-727


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-728


embedded image


—N(C(H)(CH3)2)—





Ia-729


embedded image


—N(CH2C(H)(CH3)2)—





Ia-730


embedded image


—N(C(CH3)3)—





Ia-731


embedded image


—N(CH3)—





Ia-732


embedded image


—N(CH2CH3)—





Ia-733


embedded image


—N(CH2CH2CH3)—





Ia-734


embedded image


—N(CH2CH2CH2CH3)—





Ia-735


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-736


embedded image


—N(C(H)(CH3)2)—





Ia-737


embedded image


—N(CH2C(H)(CH3)2)—





Ia-738


embedded image


—N(C(CH3)3)—





Ia-739


embedded image


—N(CH3)—





Ia-740


embedded image


—N(CH2CH3)—





Ia-741


embedded image


—N(CH2CH2CH3)—





Ia-742


embedded image


—N(CH2CH2CH2CH3)—





Ia-743


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-744


embedded image


—N(C(H)(CH3)2)—





Ia-745


embedded image


—N(CH2C(H)(CH3)2)—





Ia-746


embedded image


—N(C(CH3)3)—





Ia-747


embedded image


—N(CH3)—





Ia-748


embedded image


—N(CH2CH3)—





Ia-749


embedded image


—N(CH2CH2CH3)—





Ia-750


embedded image


—N(CH2CH2CH2CH3)—





Ia-751


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-752


embedded image


—N(C(H)(CH3)2)—





Ia-753


embedded image


—N(CH2C(H)(CH3)2)—





Ia-754


embedded image


—N(C(CH3)3)—





Ia-755


embedded image


—N(CH3)—





Ia-756


embedded image


—N(CH2CH3)—





Ia-757


embedded image


—N(CH2CH2CH3)—





Ia-758


embedded image


—N(CH2CH2CH2CH3)—





Ia-759


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-760


embedded image


—N(C(H)(CH3)2)—





Ia-761


embedded image


—N(CH2C(H)(CH3)2)—





Ia-762


embedded image


—N(C(CH3)3)—





Ia-763


embedded image


—N(CH3)—





Ia-764


embedded image


—N(CH2CH3)—





Ia-765


embedded image


—N(CH2CH2CH3)—





Ia-766


embedded image


—N(CH2CH2CH2CH3)—





Ia-767


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-768


embedded image


—N(C(H)(CH3)2)—





Ia-769


embedded image


—N(CH2C(H)(CH3)2)—





Ia-770


embedded image


—N(C(CH3)3)—





Ia-771


embedded image


—N(CH3)—





Ia-772


embedded image


—N(CH2CH3)—





Ia-773


embedded image


—N(CH2CH2CH3)—





Ia-774


embedded image


—N(CH2CH2CH2CH3)—





Ia-775


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-776


embedded image


—N(C(H)(CH3)2)—





Ia-777


embedded image


—N(CH2C(H)(CH3)2)—





Ia-778


embedded image


—N(C(CH3)3)—





Ia-779
—CH2—NH—CH3
—N(CH3)—


Ia-780
—CH2—NH—CH3
—N(CH2CH3)—


Ia-781
—CH2—NH—CH3
—N(CH2CH2CH3)—


Ia-782
—CH2—NH—CH3
—N(CH2CH2CH2CH3)—


Ia-783
—CH2—NH—CH3
—N(C(H)(CH3)(CH2CH3))—


Ia-784
—CH2—NH—CH3
—N(C(H)(CH3)2)—


Ia-785
—CH2—NH—CH3
—N(CH2C(H)(CH3)2)—


Ia-786
—CH2—NH—CH3
—N(C(CH3)3)—


Ia-787
—CH2—NH—CH2—CH3
—N(CH3)—


Ia-788
—CH2—NH—CH2—CH3
—N(CH2CH3)—


Ia-789
—CH2—NH—CH2—CH3
—N(CH2CH2CH3)—


Ia-790
—CH2—NH—CH2—CH3
—N(CH2CH2CH2CH3)—


Ia-791
—CH2—NH—CH2—CH3
—N(C(H)(CH3)(CH2CH3))—


Ia-792
—CH2—NH—CH2—CH3
—N(C(H)(CH3)2)—


Ia-793
—CH2—NH—CH2—CH3
—N(CH2C(H)(CH3)2)—


Ia-794
—CH2—NH—CH2—CH3
—N(C(CH3)3)—


Ia-795
—CH2—NH—CH2—CH2—CH3
—N(CH3)—


Ia-796
—CH2—NH—CH2—CH2—CH3
—N(CH2CH3)—


Ia-797
—CH2—NH—CH2—CH2—CH3
—N(CH2CH2CH3)—


Ia-798
—CH2—NH—CH2—CH2—CH3
—N(CH2CH2CH2CH3)—


Ia-799
—CH2—NH—CH2—CH2—CH3
—N(C(H)(CH3)(CH2CH3))—


Ia-800
—CH2—NH—CH2—CH2—CH3
—N(C(H)(CH3)2)—


Ia-801
—CH2—NH—CH2—CH2—CH3
—N(CH2C(H)(CH3)2)—


Ia-802
—CH2—NH—CH2—CH2—CH3
—N(C(CH3)3)—





Ia-803


embedded image


—N(CH3)—





Ia-804


embedded image


—N(CH2CH3)—





Ia-805


embedded image


—N(CH2CH2CH3)—





Ia-806


embedded image


—N(CH2CH2CH2CH3)—





Ia-807


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-808


embedded image


—N(C(H)(CH3)2)—





Ia-809


embedded image


—N(CH2C(H)(CH3)2)—





Ia-810


embedded image


—N(C(CH3)3)—





Ia-811


embedded image


—N(CH3)—





Ia-812


embedded image


—N(CH2CH3)—





Ia-813


embedded image


—N(CH2CH2CH3)—





Ia-814


embedded image


—N(CH2CH2CH2CH3)—





Ia-815


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-816


embedded image


—N(C(H)(CH3)2)—





Ia-817


embedded image


—N(CH2C(H)(CH3)2)—





Ia-818


embedded image


—N(C(CH3)3)—





Ia-819


embedded image


—N(CH3)—





Ia-820


embedded image


—N(CH2CH3)—





Ia-821


embedded image


—N(CH2CH2CH3)—





Ia-822


embedded image


—N(CH2CH2CH2CH3)—





Ia-823


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-824


embedded image


—N(C(H)(CH3)2)—





Ia-825


embedded image


—N(CH2C(H)(CH3)2)—





Ia-826


embedded image


—N(C(CH3)3)—





Ia-827


embedded image


—N(CH3)—





Ia-828


embedded image


—N(CH2CH3)—





Ia-829


embedded image


—N(CH2CH2CH3)—





Ia-830


embedded image


—N(CH2CH2CH2CH3)—





Ia-831


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-832


embedded image


—N(C(H)(CH3)2)—





Ia-833


embedded image


—N(CH2C(H)(CH3)2)—





Ia-834


embedded image


—N(C(CH3)3)—





Ia-835


embedded image


—N(CH3)—





Ia-836


embedded image


—N(CH2CH3)—





Ia-837


embedded image


—N(CH2CH2CH3)—





Ia-838


embedded image


—N(CH2CH2CH2CH3)—





Ia-839


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-840


embedded image


—N(C(H)(CH3)2)—





Ia-841


embedded image


—N(CH2C(H)(CH3)2)—





Ia-842


embedded image


—N(C(CH3)3)—





Ia-843


embedded image


—N(CH3)—





Ia-844


embedded image


—N(CH2CH3)—





Ia-845


embedded image


—N(CH2CH2CH3)—





Ia-846


embedded image


—N(CH2CH2CH2CH3)—





Ia-847


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-848


embedded image


—N(C(H)(CH3)2)—





Ia-849


embedded image


—N(CH2C(H)(CH3)2)—





Ia-850


embedded image


—N(C(CH3)3)—





Ia-851


embedded image


—N(CH3)—





Ia-852


embedded image


—N(CH2CH3)—





Ia-853


embedded image


—N(CH2CH2CH3)—





Ia-854


embedded image


—N(CH2CH2CH2CH3)—





Ia-855


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-856


embedded image


—N(C(H)(CH3)2)—





Ia-857


embedded image


—N(CH2C(H)(CH3)2)—





Ia-858


embedded image


—N(C(CH3)3)—





Ia-859


embedded image


—N(CH3)—





Ia-860


embedded image


—N(CH2CH3)—





Ia-861


embedded image


—N(CH2CH2CH3)—





Ia-862


embedded image


—N(CH2CH2CH2CH3)—





Ia-863


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-864


embedded image


—N(C(H)(CH3)2)—





Ia-865


embedded image


—N(CH2C(H)(CH3)2)—





Ia-866


embedded image


—N(C(CH3)3)—





Ia-867


embedded image


—N(CH3)—





Ia-868


embedded image


—N(CH2CH3)—





Ia-869


embedded image


—N(CH2CH2CH3)—





Ia-870


embedded image


—N(CH2CH2CH2CH3)—





Ia-871


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-872


embedded image


—N(C(H)(CH3)2)—





Ia-873


embedded image


—N(CH2C(H)(CH3)2)—





Ia-874


embedded image


—N(C(CH3)3)—





Ia-875


embedded image


—N(CH3)—





Ia-876


embedded image


—N(CH2CH3)—





Ia-877


embedded image


—N(CH2CH2CH3)—





Ia-878


embedded image


—N(CH2CH2CH2CH3)—





Ia-879


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-880


embedded image


—N(C(H)(CH3)2)—





Ia-881


embedded image


—N(CH2C(H)(CH3)2)—





Ia-882


embedded image


—N(C(CH3)3)—





Ia-883


embedded image


—N(CH3)—





Ia-884


embedded image


—N(CH2CH3)—





Ia-885


embedded image


—N(CH2CH2CH3)—





Ia-886


embedded image


—N(CH2CH2CH2CH3)—





Ia-887


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-888


embedded image


—N(C(H)(CH3)2)—





Ia-889


embedded image


—N(CH2C(H)(CH3)2)—





Ia-890


embedded image


—N(C(CH3)3)—





Ia-891


embedded image


—N(CH3)—





Ia-892


embedded image


—N(CH2CH3)—





Ia-893


embedded image


—N(CH2CH2CH3)—





Ia-894


embedded image


—N(CH2CH2CH2CH3)—





Ia-895


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-896


embedded image


—N(C(H)(CH3)2)—





Ia-897


embedded image


—N(CH2C(H)(CH3)2)—





Ia-898


embedded image


—N(C(CH3)3)—





Ia-899


embedded image


—N(CH3)—





Ia-900


embedded image


—N(CH2CH3)—





Ia-901


embedded image


—N(CH2CH2CH3)—





Ia-902


embedded image


—N(CH2CH2CH2CH3)—





Ia-903


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-904


embedded image


—N(C(H)(CH3)2)—





Ia-905


embedded image


—N(CH2C(H)(CH3)2)—





Ia-906


embedded image


—N(C(CH3)3)—





Ia-907


embedded image


—N(CH3)—





Ia-908


embedded image


—N(CH2CH3)—





Ia-909


embedded image


—N(CH2CH2CH3)—





Ia-910


embedded image


—N(CH2CH2CH2CH3)—





Ia-911


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-912


embedded image


—N(C(H)(CH3)2)—





Ia-913


embedded image


—N(CH2C(H)(CH3)2)—





Ia-914


embedded image


—N(C(CH3)3)—





Ia-915


embedded image


—N(CH3)—





Ia-916


embedded image


—N(CH2CH3)—





Ia-917


embedded image


—N(CH2CH2CH3)—





Ia-918


embedded image


—N(CH2CH2CH2CH3)—





Ia-919


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-920


embedded image


—N(C(H)(CH3)2)—





Ia-921


embedded image


—N(CH2C(H)(CH3)2)—





Ia-922


embedded image


—N(C(CH3)3)—





Ia-923


embedded image


—N(CH3)—





Ia-924


embedded image


—N(CH2CH3)—





Ia-925


embedded image


—N(CH2CH2CH3)—





Ia-926


embedded image


—N(CH2CH2CH2CH3)—





Ia-927


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-928


embedded image


—N(C(H)(CH3)2)—





Ia-929


embedded image


—N(CH2C(H)(CH3)2)—





Ia-930


embedded image


—N(C(CH3)3)—





Ia-931


embedded image


—N(CH3)—





Ia-932


embedded image


—N(CH2CH3)—





Ia-933


embedded image


—N(CH2CH2CH3)—





Ia-934


embedded image


—N(CH2CH2CH2CH3)—





Ia-935


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-936


embedded image


—N(C(H)(CH3)2)—





Ia-937


embedded image


—N(CH2C(H)(CH3)2)—





Ia-938


embedded image


—N(C(CH3)3)—





Ia-939


embedded image


—N(CH3)—





Ia-940


embedded image


—N(CH2CH3)—





Ia-941


embedded image


—N(CH2CH2CH3)—





Ia-942


embedded image


—N(CH2CH2CH2CH3)—





Ia-943


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-944


embedded image


—N(C(H)(CH3)2)—





Ia-945


embedded image


—N(CH2C(H)(CH3)2)—





Ia-946


embedded image


—N(C(CH3)3)—





Ia-947


embedded image


—N(CH3)—





Ia-948


embedded image


—N(CH2CH3)—





Ia-949


embedded image


—N(CH2CH2CH3)—





Ia-950


embedded image


—N(CH2CH2CH2CH3)—





Ia-951


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-952


embedded image


—N(C(H)(CH3)2)—





Ia-953


embedded image


—N(CH2C(H)(CH3)2)—





Ia-954


embedded image


—N(C(CH3)3)—





Ia-955


embedded image


—N(CH3)—





Ia-956


embedded image


—N(CH2CH3)—





Ia-957


embedded image


—N(CH2CH2CH3)—





Ia-958


embedded image


—N(CH2CH2CH2CH3)—





Ia-959


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-960


embedded image


—N(C(H)(CH3)2)—





Ia-961


embedded image


—N(CH2C(H)(CH3)2)—





Ia-962


embedded image


—N(C(CH3)3)—





Ia-963
—CH2—N(CH2CH3)(CH3)
—N(CH3)—


Ia-964
—CH2—N(CH2CH3)(CH3)
—N(CH2CH3)—


Ia-965
—CH2—N(CH2CH3)(CH3)
—N(CH2CH2CH3)—


Ia-966
—CH2—N(CH2CH3)(CH3)
—N(CH2CH2CH2CH3)—


Ia-967
—CH2—N(CH2CH3)(CH3)
—N(C(H)(CH3)(CH2CH3))—


Ia-968
—CH2—N(CH2CH3)(CH3)
—N(C(H)(CH3)2)—


Ia-969
—CH2—N(CH2CH3)(CH3)
—N(CH2C(H)(CH3)2)—


Ia-970
—CH2—N(CH2CH3)(CH3)
—N(C(CH3)3)—


Ia-971
—CH2—N(CH2CH2CH3)(CH3)
—N(CH3)—


Ia-972
—CH2—N(CH2CH2CH3)(CH3)
—N(CH2CH3)—


Ia-973
—CH2—N(CH2CH2CH3)(CH3)
—N(CH2CH2CH3)—


Ia-974
—CH2—N(CH2CH2CH3)(CH3)
—N(CH2CH2CH2CH3)—


Ia-975
—CH2—N(CH2CH2CH3)(CH3)
—N(C(H)(CH3)(CH2CH3))—


Ia-976
—CH2—N(CH2CH2CH3)(CH3)
—N(C(H)(CH3)2)—


Ia-977
—CH2—N(CH2CH2CH3)(CH3)
—N(CH2C(H)(CH3)2)—


Ia-978
—CH2—N(CH2CH2CH3)(CH3)
—N(C(CH3)3)—


Ia-979
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(CH3)—


Ia-980
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(CH2CH3)—


Ia-981
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(CH2CH2CH3)—


Ia-982
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(CH2CH2CH2CH3)—


Ia-983
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(C(H)(CH3)(CH2CH3))—


Ia-984
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(C(H)(CH3)2)—


Ia-985
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(CH2C(H)(CH3)2)—


Ia-986
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(C(CH3)3)—


Ia-987
—CH2—NH—CH2CH2CH2CH3
—N(CH3)—


Ia-988
—CH2—NH—CH2CH2CH2CH3
—N(CH2CH3)—


Ia-989
—CH2—NH—CH2CH2CH2CH3
—N(CH2CH2CH3)—


Ia-990
—CH2—NH—CH2CH2CH2CH3
—N(CH2CH2CH2CH3)—


Ia-991
—CH2—NH—CH2CH2CH2CH3
—N(C(H)(CH3)(CH2CH3))—


Ia-992
—CH2—NH—CH2CH2CH2CH3
—N(C(H)(CH3)2)—


Ia-993
—CH2—NH—CH2CH2CH2CH3
—N(CH2C(H)(CH3)2)—


Ia-994
—CH2—NH—CH2CH2CH2CH3
—N(C(CH3)3)—


Ia-995
—CH2—NH—CH2CH2—O—CH3
—N(CH3)—


Ia-996
—CH2—NH—CH2CH2—O—CH3
—N(CH2CH3)—


Ia-997
—CH2—NH—CH2CH2—O—CH3
—N(CH2CH2CH3)—


Ia-998
—CH2—NH—CH2CH2—O—CH3
—N(CH2CH2CH2CH3)—


Ia-999
—CH2—NH—CH2CH2—O—CH3
—N(C(H)(CH3)(CH2CH3))—


Ia-1000
—CH2—NH—CH2CH2—O—CH3
—N(C(H)(CH3)2)—


Ia-1001
—CH2—NH—CH2CH2—O—CH3
—N(CH2C(H)(CH3)2)—


Ia-1002
—CH2—NH—CH2CH2—O—CH3
—N(C(CH3)3)—





Ia-1003


embedded image


—N(CH3)—





Ia-1004


embedded image


—N(CH2CH3)—





Ia-1005


embedded image


—N(CH2CH2CH3)—





Ia-1006


embedded image


—N(CH2CH2CH2CH3)—





Ia-1007


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-1008


embedded image


—N(C(H)(CH3)2)—





Ia-1009


embedded image


—N(CH2C(H)(CH3)2)—





Ia-1010


embedded image


—N(C(CH3)3)—





Ia-1011


embedded image


—N(CH3)—





Ia-1012


embedded image


—N(CH2CH3)—





Ia-1013


embedded image


—N(CH2CH2CH3)—





Ia-1014


embedded image


—N(CH2CH2CH2CH3)—





Ia-1015


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-1016


embedded image


—N(C(H)(CH3)2)—





Ia-1017


embedded image


—N(CH2C(H)(CH3)2)—





Ia-1018


embedded image


—N(C(CH3)3)—





Ia-1019


embedded image


—N(CH3)—





Ia-1020


embedded image


—N(CH2CH3)—





Ia-1021


embedded image


—N(CH2CH2CH3)—





Ia-1022


embedded image


—N(CH2CH2CH2CH3)—





Ia-1023


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-1024


embedded image


—N(C(H)(CH3)2)—





Ia-1025


embedded image


—N(CH2C(H)(CH3)2)—





Ia-1026


embedded image


—N(C(CH3)3)—





Ia-1027


embedded image


—N(CH3)—





Ia-1028


embedded image


—N(CH2CH3)—





Ia-1029


embedded image


—N(CH2CH2CH3)—





Ia-1030


embedded image


—N(CH2CH2CH2CH3)—





Ia-1031


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-1032


embedded image


—N(C(H)(CH3)2)—





Ia-1033


embedded image


—N(CH2C(H)(CH3)2)—





Ia-1034


embedded image


—N(C(CH3)3)—





Ia-1035


embedded image


—N(CH3)—





Ia-1036


embedded image


—N(CH2CH3)—





Ia-1037


embedded image


—N(CH2CH2CH3)—





Ia-1038


embedded image


—N(CH2CH2CH2CH3)—





Ia-1039


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-1040


embedded image


—N(C(H)(CH3)2)—





Ia-1041


embedded image


—N(CH2C(H)(CH3)2)—





Ia-1042


embedded image


—N(C(CH3)3)—





Ia-1043


embedded image


—N(CH3)—





Ia-1044


embedded image


—N(CH2CH3)—





Ia-1045


embedded image


—N(CH2CH2CH3)—





Ia-1046


embedded image


—N(CH2CH2CH2CH3)—





Ia-1047


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-1048


embedded image


—N(C(H)(CH3)2)—





Ia-1049


embedded image


—N(CH2C(H)(CH3)2)—





Ia-1050


embedded image


—N(C(CH3)3)—





Ia-1051


embedded image


—N(CH3)—





Ia-1052


embedded image


—N(CH2CH3)—





Ia-1053


embedded image


—N(CH2CH2CH3)—





Ia-1054


embedded image


—N(CH2CH2CH2CH3)—





Ia-1055


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ia-1056


embedded image


—N(C(H)(CH3)2)—





Ia-1057


embedded image


—N(CH2C(H)(CH3)2)—





Ia-1058


embedded image


—N(C(CH3)3)—













Compound
n
—R1
X





Ia-a1
1
—(CH2)n—N(CH3)2
—CH(OH)—


Ia-a2
2
—(CH2)n—N(CH3)2
—CH(OH)—


Ia-a3
3
—(CH2)n—N(CH3)2
—CH(OH)—


Ia-a4
4
—(CH2)n—N(CH3)2
—CH(OH)—


Ia-a5
5
—(CH2)n—N(CH3)2
—CH(OH)—


Ia-a6
6
—(CH2)n—N(CH3)2
—CH(OH)—


Ia-a7
1
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ia-a8
2
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ia-a9
3
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ia-a10
4
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ia-a11
5
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ia-a12
6
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ia-a13
1
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ia-a14
2
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ia-a15
3
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ia-a16
4
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ia-a17
5
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ia-a18
6
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ia-a19
1
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ia-a20
2
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ia-a21
3
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ia-a22
4
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ia-a23
5
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ia-a24
6
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ia-a25
1
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a26
2
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a27
3
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a28
4
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a29
5
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a30
6
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a31
1
—(CH2)n—N(CH3)2
—N(CH2—CH2—OH)—


Ia-a32
2
—(CH2)n—N(CH3)2
—N(CH2—CH2—OH)—


Ia-a33
3
—(CH2)n—N(CH3)2
—N(CH2—CH2—OH)—


Ia-a34
4
—(CH2)n—N(CH3)2
—N(CH2—CH2—OH)—


Ia-a35
5
—(CH2)n—N(CH3)2
—N(CH2—CH2—OH)—


Ia-a36
6
—(CH2)n—N(CH3)2
—N(CH2—CH2—OH)—


Ia-a37
1
—(CH2)n—N(CH3)2
—N(CH2—CH2—F)—


Ia-a38
2
—(CH2)n—N(CH3)2
—N(CH2—CH2—F)—


Ia-a39
3
—(CH2)n—N(CH3)2
—N(CH2—CH2—F)—


Ia-a40
4
—(CH2)n—N(CH3)2
—N(CH2—CH2—F)—


Ia-a41
5
—(CH2)n—N(CH3)2
—N(CH2—CH2—F)—


Ia-a42
6
—(CH2)n—N(CH3)2
—N(CH2—CH2—F)—


Ia-a43
1
—(CH2)n—N(CH3)2
—N(CH2—CH2—OCH3)—


Ia-a44
2
—(CH2)n—N(CH3)2
—N(CH2—CH2—OCH3)—


Ia-a45
3
—(CH2)n—N(CH3)2
—N(CH2—CH2—OCH3)—


Ia-a46
4
—(CH2)n—N(CH3)2
—N(CH2—CH2—OCH3)—


Ia-a47
5
—(CH2)n—N(CH3)2
—N(CH2—CH2—OCH3)—


Ia-a48
6
—(CH2)n—N(CH3)2
—N(CH2—CH2—OCH3)—





Ia-a49
1


embedded image


—CH(OH)—





Ia-a50
2


embedded image


—CH(OH)—





Ia-a51
3


embedded image


—CH(OH)—





Ia-a52
4


embedded image


—CH(OH)—





Ia-a53
5


embedded image


—CH(OH)—





Ia-a54
6


embedded image


—CH(OH)—





Ia-a55
1


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a56
2


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a57
3


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a58
4


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a59
5


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a60
6


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a61
1


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a62
2


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a63
3


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a64
4


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a65
5


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a66
6


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a67
1


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a68
2


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a69
3


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a70
4


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a71
5


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a72
6


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a73
1


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a74
2


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a75
3


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a76
4


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a77
5


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a78
6


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a79
1


embedded image


—N(CH2—CH2—OH)—





Ia-a80
2


embedded image


—N(CH2—CH2—OH)—





Ia-a81
3


embedded image


—N(CH2—CH2—OH)—





Ia-a82
4


embedded image


—N(CH2—CH2—OH)—





Ia-a83
5


embedded image


—N(CH2—CH2—OH)—





Ia-a84
6


embedded image


—N(CH2—CH2—OH)—





Ia-a85
1


embedded image


—N(CH2—CH2—F)—





Ia-a86
2


embedded image


—N(CH2—CH2—F)—





Ia-a87
3


embedded image


—N(CH2—CH2—F)—





Ia-a88
4


embedded image


—N(CH2—CH2—F)—





Ia-a89
5


embedded image


—N(CH2—CH2—F)—





Ia-a90
6


embedded image


—N(CH2—CH2—F)—





Ia-a91
1


embedded image


—N(CH2—CH2—OCH3)—





Ia-a92
2


embedded image


—N(CH2—CH2—OCH3)—





Ia-a93
3


embedded image


—N(CH2—CH2—OCH3)—





Ia-a94
4


embedded image


—N(CH2—CH2—OCH3)—





Ia-a95
5


embedded image


—N(CH2—CH2—OCH3)—





Ia-a96
6


embedded image


—N(CH2—CH2—OCH3)—





Compound
m
—R1
X





Ia-a146
2
—O—(CH2)m—N(CH3)2
—CH(OH)—


Ia-a147
3
—O—(CH2)m—N(CH3)2
—CH(OH)—


Ia-a148
4
—O—(CH2)m—N(CH3)2
—CH(OH)—


Ia-a149
5
—O—(CH2)m—N(CH3)2
—CH(OH)—


Ia-a150
6
—O—(CH2)m—N(CH3)2
—CH(OH)—


Ia-a151
2
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ia-a152
3
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ia-a153
4
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ia-a154
5
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ia-a155
6
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ia-a156
2
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ia-a157
3
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ia-a158
4
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ia-a159
5
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ia-a160
6
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ia-a161
2
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ia-a162
3
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ia-a163
4
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ia-a164
5
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ia-a165
6
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ia-a166
2
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a167
3
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a168
4
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a169
5
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a170
6
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a171
2
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—OH)—


Ia-a172
3
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—OH)—


Ia-a173
4
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—OH)—


Ia-a174
5
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—OH)—


Ia-a175
6
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—OH)—


Ia-a176
2
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—F)—


Ia-a178
3
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—F)—


Ia-a179
4
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—F)—


Ia-a180
5
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—F)—


Ia-a181
6
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—F)—


Ia-a182
2
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—OCH3)—


Ia-a183
3
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—OCH3)—


Ia-a184
4
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—OCH3)—


Ia-a185
5
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—OCH3)—


Ia-a186
6
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—OCH3)—





Ia-a187
2


embedded image


—CH(OH)—





Ia-a188
3


embedded image


—CH(OH)—





Ia-a189
4


embedded image


—CH(OH)—





Ia-a190
5


embedded image


—CH(OH)—





Ia-a191
6


embedded image


—CH(OH)—





Ia-a192
2


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a193
3


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a194
4


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a195
5


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a196
6


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a197
2


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a198
3


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a199
4


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a200
5


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a201
6


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a202
2


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a203
3


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a204
4


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a205
5


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a206
6


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a207
2


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a208
3


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a209
4


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a210
5


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a211
6


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a212
2


embedded image


—N(CH2—CH2—OH)—





Ia-a213
3


embedded image


—N(CH2—CH2—OH)—





Ia-a214
4


embedded image


—N(CH2—CH2—OH)—





Ia-a215
5


embedded image


—N(CH2—CH2—OH)—





Ia-a216
6


embedded image


—N(CH2—CH2—OH)—





Ia-a217
2


embedded image


—N(CH2—CH2—F)—





Ia-a218
3


embedded image


—N(CH2—CH2—F)—





Ia-a219
4


embedded image


—N(CH2—CH2—F)—





Ia-a220
5


embedded image


—N(CH2—CH2—F)—





Ia-a221
6


embedded image


—N(CH2—CH2—F)—





Ia-a222
2


embedded image


—N(CH2—CH2—OCH3)—





Ia-a223
3


embedded image


—N(CH2—CH2—OCH3)—





Ia-a224
4


embedded image


—N(CH2—CH2—OCH3)—





Ia-a225
5


embedded image


—N(CH2—CH2—OCH3)—





Ia-a226
6


embedded image


—N(CH2—CH2—OCH3)—












Compound
—R1
X





Ia-a267
—CH2—N(CH2—CH3)2
—CH(OH)—


Ia-a268
—CH2—N(CH2—CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ia-a269
—CH2—N(CH2—CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ia-a270
—CH2—N(CH2—CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ia-a271
—CH2—N(CH2—CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a275
—CH2—N(CH2—CH2—CH3)2
—CH(OH)—


Ia-a276
—CH2—N(CH2—CH2—CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ia-a277
—CH2—N(CH2—CH2—CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ia-a278
—CH2—N(CH2—CH2—CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ia-a279
—CH2—N(CH2—CH2—CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a283
—CH2—N(CH2—CH2OH)2
—CH(OH)—


Ia-a284
—CH2—N(CH2—CH2OH)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ia-a285
—CH2—N(CH2—CH2OH)2
—N(C(O)N(H)—CH2—CH2—F)—


Ia-a286
—CH2—N(CH2—CH2OH)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ia-a291
—CH2—N(CH2—CH2—N(CH3)2)2
—CH(OH)—


Ia-a292
—CH2—N(CH2—CH2—N(CH3)2)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ia-a293
—CH2—N(CH2—CH2—N(CH3)2)2
—N(C(O)N(H)—CH2—CH2—F)—


Ia-a294
—CH2—N(CH2—CH2—N(CH3)2)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ia-a295
—CH2—N(CH2—CH2—N(CH3)2)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a296
—CH2—N(CH2—CH2—N(CH3)2)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a297
—CH2—N(CH2—CH2—N(CH3)2)2
—N(C(O)N(H)—CH2—CF3)—


Ia-a298
—CH2—N(CH2—CH2—N(CH3)2)2
—N(C(O)N(H)—(CH2)3—OH)—


Ia-a299
—CH2—N(CH2—CH2—CH2—N(CH3)2)2
—CH(OH)—


Ia-a300
—CH2—N(CH2—CH2—CH2—N(CH3)2)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ia-a301
—CH2—N(CH2—CH2—CH2—N(CH3)2)2
—N(C(O)N(H)—CH2—CH2—F)—


Ia-a302
—CH2—N(CH2—CH2—CH2—N(CH3)2)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ia-a303
—CH2—N(CH2—CH2—CH2—N(CH3)2)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a304
—CH2—N(CH2—CH2—CH2—N(CH3)2)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a305
—CH2—N(CH2—CH2—CH2—N(CH3)2)2
—N(C(O)N(H)—CH2—CF3)—


Ia-a306
—CH2—N(CH2—CH2—CH2—N(CH3)2)2
—N(C(O)N(H)—(CH2)3—OH)—





Ia-a307


embedded image


—CH(OH)—





Ia-a308


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a309


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a310


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a311


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a312


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a313


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a314


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a315


embedded image


—CH(OH)—





Ia-a316


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a317


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a318


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a319


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a320


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a321


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a322


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a323


embedded image


—CH(OH)—





Ia-a324


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a325


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a326


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a327


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a328


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a329


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a330


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a331


embedded image


—CH(OH)—





Ia-a332


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a333


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a334


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a335


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a336


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a337


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a338


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a339


embedded image


—CH(OH)—





Ia-a340


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a341


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a342


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a343


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a344


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a345


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a346


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a347


embedded image


—CH(OH)—





Ia-a348


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a349


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a350


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a351


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a352


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a353


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a354


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a355


embedded image


—CH(OH)—





Ia-a356


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a357


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a358


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a359


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a360


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a361


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a362


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a363


embedded image


—CH(OH)—





Ia-a364


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a365


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a366


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a367


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a368


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a369


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a370


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a371


embedded image


—CH(OH)—





Ia-a372


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a373


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a374


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a375


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a376


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a377


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a378


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a379


embedded image


—CH(OH)—





Ia-a380


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a381


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a382


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a383


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a384


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a385


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a386


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a387


embedded image


—CH(OH)—





Ia-a388


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a389


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a390


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a391


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a392


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a393


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a394


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a395


embedded image


—CH(OH)—





Ia-a396


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a397


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a398


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a399


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a400


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a401


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a402


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a403


embedded image


—CH(OH)—





Ia-a404


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a405


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a406


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a407


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a408


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a409


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a410


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a411


embedded image


—CH(OH)—





Ia-a412


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a413


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a414


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a415


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a416


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a417


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a418


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a419


embedded image


—CH(OH)—





Ia-a420


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a421


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a422


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a423


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a424


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a425


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a426


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a427


embedded image


—CH(OH)—





Ia-a428


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a429


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a430


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a431


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a432


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a433


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a434


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a435


embedded image


—CH(OH)—





Ia-a436


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a437


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a438


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a439


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a440


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a441


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a442


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a443


embedded image


—CH(OH)—





Ia-a444


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a445


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a446


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a447


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a448


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a449


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a450


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a451


embedded image


—CH(OH)—





Ia-a452


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a453


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a454


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a455


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a456


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a457


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a458


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a459


embedded image


—CH(OH)—





Ia-a460


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a461


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a462


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a463


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a464


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a465


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a466


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a467


embedded image


—CH(OH)—





Ia-a468


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a469


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a470


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a471


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a472


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a473


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a474


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a475


embedded image


—CH(OH)—





Ia-a476


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a477


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a478


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a479


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a480


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a481


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a482


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a483


embedded image


—CH(OH)—





Ia-a484


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a485


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a486


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a487


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a488


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a489


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a490


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a491
—CH2—CH2—CH2—OP(O)(OH)2
—CH(OH)—


Ia-a492
—CH2—CH2—CH2—OP(O)(OH)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ia-a493
—CH2—CH2—CH2—OP(O)(OH)2
—N(C(O)N(H)—CH2—CH2—F)—


Ia-a494
—CH2—CH2—CH2—OP(O)(OH)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ia-a495
—CH2—CH2—CH2—OP(O)(OH)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a496
—CH2—CH2—CH2—OP(O)(OH)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a497
—CH2—CH2—CH2—OP(O)(OH)2
—N(C(O)N(H)—CH2—CF3)—


Ia-a498
—CH2—CH2—CH2—OP(O)(OH)2
—N(C(O)N(H)—(CH2)3—OH)—


Ia-a499
—CH2—CH2—CH2—OS(O)2OH
—CH(OH)—


Ia-a500
—CH2—CH2—CH2—OS(O)2OH
—N(C(O)N(H)—CH2—CH2—OH)—


Ia-a501
—CH2—CH2—CH2—OS(O)2OH
—N(C(O)N(H)—CH2—CH2—F)—


Ia-a502
—CH2—CH2—CH2—OS(O)2OH
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ia-a503
—CH2—CH2—CH2—OS(O)2OH
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a504
—CH2—CH2—CH2—OS(O)2OH
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a505
—CH2—CH2—CH2—OS(O)2OH
—N(C(O)N(H)—CH2—CF3)—


Ia-a506
—CH2—CH2—CH2—OS(O)2OH
—N(C(O)N(H)—(CH2)3—OH)—





Ia-a507


embedded image


—CH(OH)—





Ia-a508


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a509


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a510


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a511


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a512


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a513


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a514


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a515


embedded image


—CH(OH)—





Ia-a516


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a517


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a518


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a519


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a520


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a521


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a522


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a523
—(CH2)10—N(CH2—CH2—O—CH3)2
—CH(OH)—


Ia-a524
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ia-a525
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ia-a526
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ia-a527
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a528
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a529
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—CH2—CF3)—


Ia-a530
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—(CH2)3—OH)—


Ia-a531
—CH2—N(CH2—CH2—O—CH3)2
—CH(OH)—


Ia-a532
—CH2—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ia-a533
—CH2—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ia-a534
—CH2—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ia-a535
—CH2—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a536
—CH2—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a537
—CH2—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—CH2—CF3)—


Ia-a538
—CH2—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—(CH2)3—OH)—





Ia-a539


embedded image


—CH(OH)—





Ia-a540


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a541


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a542


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a543


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a544


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a545


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a546


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a547


embedded image


—CH(OH)—





Ia-a548


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a549


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a550


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a551


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a552


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a553


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a554


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a555


embedded image


—CH(OH)—





Ia-a556


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a557


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a558


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a559


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a560


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a561


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a562


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a563


embedded image


—CH(OH)—





Ia-a564


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a565


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a566


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a567


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a568


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a569


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a570


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a571


embedded image


—CH(OH)—





Ia-a572


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a573


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a574


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a575


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a576


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a577


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a578


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a579


embedded image


—CH(OH)—





Ia-a580


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a581


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a582


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a583


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a584


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a585


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a586


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a587


embedded image


—CH(OH)—





Ia-a588


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a589


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a590


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a591


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a592


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a593


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a594


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a595


embedded image


—CH(OH)—





Ia-a596


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a597


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a598


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a599


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a600


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a601


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a602


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a603


embedded image


—CH(OH)—





Ia-a604


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a605


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a606


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a607


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a608


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a609


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a610


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a611
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—CH(OH)—


Ia-a612
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ia-a613
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ia-a614
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ia-a615
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a616
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a617
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(C(O)N(H)—CH2—CF3)—


Ia-a618
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(C(O)N(H)—(CH2)3—OH)—





Ia-a619


embedded image


—CH(OH)—





Ia-a620


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a621


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a622


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a623


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a624


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a625


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a626


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a627


embedded image


—CH(OH)—





Ia-a628


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a629


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a630


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a631


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a632


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a633


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a634


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a635


embedded image


—CH(OH)—





Ia-a636


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a637


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a638


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a639


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a640


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a641


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a642


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a643


embedded image


—CH(OH)—





Ia-a644


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a645


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a646


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a647


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a648


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a649


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a650


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a651


embedded image


—CH(OH)—





Ia-a652


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a653


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a654


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a655


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a656


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a657


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a658


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a659


embedded image


—CH(OH)—





Ia-a660


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a661


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a662


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a663


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a664


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a665


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a666


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a667


embedded image


—CH(OH)—





Ia-a668


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a669


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a670


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a671


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a672


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a673


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a674


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a675


embedded image


—CH(OH)—





Ia-a676


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a677


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a678


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a679


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a680


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a681


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a682


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a683


embedded image


—CH(OH)—





Ia-a684


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a685


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a686


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a687


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a688


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a689


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a690


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a691


embedded image


—CH(OH)—





Ia-a692


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a693


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a694


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a695


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a696


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a697


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a698


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a699


embedded image


—CH(OH)—





Ia-a700


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a701


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a702


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a703


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a704


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a705


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a706


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a707


embedded image


—CH(OH)—





Ia-a708


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a709


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a710


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a711


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a712


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a713


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a714


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a715


embedded image


—CH(OH)—





Ia-a716


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a717


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a718


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a719


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a720


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a721


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a722


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a723


embedded image


—CH(OH)—





Ia-a724


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a725


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a726


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a727


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a728


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a729


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a730


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a731


embedded image


—CH(OH)—





Ia-a732


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a733


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a734


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a735


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a736


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a737


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a738


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a739


embedded image


—CH(OH)—





Ia-a740


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a741


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a742


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a743


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a744


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a745


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a746


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a747


embedded image


—CH(OH)—





Ia-a748


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a749


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a750


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a751


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a752


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a753


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a754


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a755


embedded image


—CH(OH)—





Ia-a756


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a757


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a758


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a759


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a760


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a761


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a762


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a763


embedded image


—CH(OH)—





Ia-a764


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a765


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a766


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a767


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a768


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a769


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a770


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a771


embedded image


—CH(OH)—





Ia-a772


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a773


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a774


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a775


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a776


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a777


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a778


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a779
—CH2—NH—CH3
—CH(OH)—


Ia-a780
—CH2—NH—CH3
—N(C(O)N(H)—CH2—CH2—OH)—


Ia-a781
—CH2—NH—CH3
—N(C(O)N(H)—CH2—CH2—F)—


Ia-a782
—CH2—NH—CH3
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ia-a783
—CH2—NH—CH3
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a784
—CH2—NH—CH3
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a785
—CH2—NH—CH3
—N(C(O)N(H)—CH2—CF3)—


Ia-a786
—CH2—NH—CH3
—N(C(O)N(H)—(CH2)3—OH)—


Ia-a787
—CH2—NH—CH2—CH3
—CH(OH)—


Ia-a788
—CH2—NH—CH2—CH3
—N(C(O)N(H)—CH2—CH2—OH)—


Ia-a789
—CH2—NH—CH2—CH3
—N(C(O)N(H)—CH2—CH2—F)—


Ia-a790
—CH2—NH—CH2—CH3
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ia-a791
—CH2—NH—CH2—CH3
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a792
—CH2—NH—CH2—CH3
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a793
—CH2—NH—CH2—CH3
—N(C(O)N(H)—CH2—CF3)—


Ia-a794
—CH2—NH—CH2—CH3
—N(C(O)N(H)—(CH2)3—OH)—


Ia-a795
—CH2—NH—CH2—CH2—CH3
—CH(OH)—


Ia-a796
—CH2—NH—CH2—CH2—CH3
—N(C(O)N(H)—CH2—CH2—OH)—


Ia-a797
—CH2—NH—CH2—CH2—CH3
—N(C(O)N(H)—CH2—CH2—F)—


Ia-a798
—CH2—NH—CH2—CH2—CH3
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ia-a799
—CH2—NH—CH2—CH2—CH3
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a800
—CH2—NH—CH2—CH2—CH3
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a801
—CH2—NH—CH2—CH2—CH3
—N(C(O)N(H)—CH2—CF3)—


Ia-a802
—CH2—NH—CH2—CH2—CH3
—N(C(O)N(H)—(CH2)3—OH)—





Ia-a803


embedded image


—CH(OH)—





Ia-a804


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a805


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a806


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a807


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a808


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a809


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a810


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a811


embedded image


—CH(OH)—





Ia-a812


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a813


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a814


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a815


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a816


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a817


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a818


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a819


embedded image


—CH(OH)—





Ia-a820


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a821


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a822


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a823


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a824


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a825


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a826


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a827


embedded image


—CH(OH)—





Ia-a828


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a829


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a830


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a831


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a832


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a833


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a834


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a835


embedded image


—CH(OH)—





Ia-a836


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a837


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a838


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a839


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a840


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a841


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a842


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a843


embedded image


—CH(OH)—





Ia-a844


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a845


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a846


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a847


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a848


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a849


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a850


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a851


embedded image


—CH(OH)—





Ia-a852


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a853


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a854


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a855


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a856


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a857


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a858


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a859


embedded image


—CH(OH)—





Ia-a860


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a861


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a862


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a863


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a864


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a865


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a866


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a867


embedded image


—CH(OH)—





Ia-a868


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a869


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a870


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a871


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a872


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a873


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a874


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a875


embedded image


—CH(OH)—





Ia-a876


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a877


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a878


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a879


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a880


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a881


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a882


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a883


embedded image


—CH(OH)—





Ia-a884


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a885


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a886


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a887


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a888


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a889


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a890


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a891


embedded image


—CH(OH)—





Ia-a892


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a893


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a894


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a895


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a896


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a897


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a898


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a899


embedded image


—CH(OH)—





Ia-a900


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a901


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a902


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a903


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a904


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a905


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a906


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a907


embedded image


—CH(OH)—





Ia-a908


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a909


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a910


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a911


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a912


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a913


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a914


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a915


embedded image


—CH(OH)—





Ia-a916


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a917


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a918


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a919


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a920


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a921


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a922


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a923


embedded image


—CH(OH)—





Ia-a924


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a925


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a926


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a927


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a928


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a929


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a930


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a931


embedded image


—CH(OH)—





Ia-a932


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a933


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a934


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a935


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a936


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a937


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a938


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a939


embedded image


—CH(OH)—





Ia-a940


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a941


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a942


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a943


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a944


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a945


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a946


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a947


embedded image


—CH(OH)—





Ia-a948


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a949


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a950


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a951


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a952


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a953


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a954


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a955


embedded image


—CH(OH)—





Ia-a956


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a957


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a958


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a959


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a960


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a961


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a962


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a963
—CH2—N(CH2CH3)(CH3)
—CH(OH)—


Ia-a964
—CH2—N(CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—OH)—


Ia-a965
—CH2—N(CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—F)—


Ia-a966
—CH2—N(CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ia-a967
—CH2—N(CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a968
—CH2—N(CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a969
—CH2—N(CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CF3)—


Ia-a970
—CH2—N(CH2CH3)(CH3)
—N(C(O)N(H)—(CH2)3—OH)—


Ia-a971
—CH2—N(CH2CH2CH3)(CH3)
—CH(OH)—


Ia-a972
—CH2—N(CH2CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—OH)—


Ia-a973
—CH2—N(CH2CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—F)—


Ia-a974
—CH2—N(CH2CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ia-a975
—CH2—N(CH2CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a976
—CH2—N(CH2CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a977
—CH2—N(CH2CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CF3)—


Ia-a978
—CH2—N(CH2CH2CH3)(CH3)
—N(C(O)N(H)—(CH2)3—OH)—


Ia-a979
—CH2—N(CH2CH2CH2CH3)(CH3)
—CH(OH)—


Ia-a980
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—OH)—


Ia-a981
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—F)—


Ia-a982
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ia-a983
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a984
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a985
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CF3)—


Ia-a986
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(C(O)N(H)—(CH2)3—OH)—


Ia-a987
—CH2—NH—CH2CH2CH2CH3
—CH(OH)—


Ia-a988
—CH2—NH—CH2CH2CH2CH3
—N(C(O)N(H)—CH2—CH2—OH)—


Ia-a989
—CH2—NH—CH2CH2CH2CH3
—N(C(O)N(H)—CH2—CH2—F)—


Ia-a990
—CH2—NH—CH2CH2CH2CH3
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ia-a991
—CH2—NH—CH2CH2CH2CH3
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a992
—CH2—NH—CH2CH2CH2CH3
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a993
—CH2—NH—CH2CH2CH2CH3
—N(C(O)N(H)—CH2—CF3)—


Ia-a994
—CH2—NH—CH2CH2CH2CH3
—N(C(O)N(H)—(CH2)3—OH)—


Ia-a995
—CH2—NH—CH2CH2—O—CH3
—CH(OH)—


Ia-a996
—CH2—NH—CH2CH2—O—CH3
—N(C(O)N(H)—CH2—CH2—OH)—


Ia-a997
—CH2—NH—CH2CH2—O—CH3
—N(C(O)N(H)—CH2—CH2—F)—


Ia-a998
—CH2—NH—CH2CH2—O—CH3
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ia-a999
—CH2—NH—CH2CH2—O—CH3
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a1000
—CH2—NH—CH2CH2—O—CH3
—N(C(O)N(H)—CH2—CH2—CF3)—


Ia-a1001
—CH2—NH—CH2CH2—O—CH3
—N(C(O)N(H)—CH2—CF3)—


Ia-a1002
—CH2—NH—CH2CH2—O—CH3
—N(C(O)N(H)—(CH2)3—OH)—





Ia-a1003


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—CH(OH)—





Ia-a1004


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—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a1005


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—N(C(O)N(H)—CH2—CH2—F)—





Ia-a1006


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a1007


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a1008


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a1009


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a1010


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a1011


embedded image


—CH(OH)—





Ia-a1012


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a1013


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a1014


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a1015


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a1016


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a1017


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a1018


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—N(C(O)N(H)—(CH2)3—OH)—





Ia-a1019


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—CH(OH)—





Ia-a1020


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—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a1021


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a1022


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a1023


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a1024


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a1025


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a1026


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a1027


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—CH(OH)—





Ia-a1028


embedded image


N(C(O)N(H)—CH2—CH2—OH)—





Ia-a1029


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N(C(O)N(H)—CH2—CH2—F)—





Ia-a1030


embedded image


N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a1031


embedded image


N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a1032


embedded image


N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a1033


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a1034


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ia-a1035


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—CH(OH)—





Ia-a1036


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a1037


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a1038


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a1039


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a1040


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a1041


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a1042


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—N(C(O)N(H)—(CH2)3—OH)—





Ia-a1043


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—CH(OH)—





Ia-a1044


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a1045


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a1046


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a1047


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a1048


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a1049


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a1050


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—N(C(O)N(H)—(CH2)3—OH)—





Ia-a1051


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—CH(OH)—





Ia-a1052


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ia-a1053


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ia-a1054


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ia-a1055


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a1056


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ia-a1057


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ia-a1058


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—N(C(O)N(H)—(CH2)3—OH)—









and pharmaceutically acceptable salts thereof.


5.3 The Indenoisoquinolinone Analogs of Formula (IIa)

The present invention provides Indenoisoquinolinone Analogs according to Formula (Ib), below:




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and pharmaceutically acceptable salts thereof,


wherein X and R1 are as defined above for the Indenoisoquinolinone Analogs of Formula (Ib).


In one embodiment, X is —N(CH3)—. In another embodiment, X is —N(CH2CH3)—. In another embodiment, X is —N(CH2CH2CH3)—. In another embodiment, X is —N(CH2 CH2CH2CH3)—. In another embodiment, X is —N(C(H)(CH3)(CH2CH3))—. In another embodiment, X is —N(C(H)(CH3)2)—. In another embodiment, X is —N(CH2C(H)(CH3)2)—. In another embodiment, X is —N(C(CH3)3)—.


In one embodiment, R1 is —(CH2)n—N(R2)(R2) and X is —N(CH3)—.


In another embodiment, R1 is —(CH2)n—N(R2)(R2) and X is —N(CH2CH3)—.


In another embodiment, R1 is —(CH2)n—N(R2)(R2) and X is —N(CH2CH2CH3)—.


In another embodiment, R1 is —(CH2)n—N(R2)(R2) and X is —N(CH2CH2CH2CH3)—.


In another embodiment, R1 is —(CH2)n—N(R2)(R2) and X is —N(C(H)(CH3)(CH2CH3))—.


In another embodiment, R1 is —(CH2)n—N(R2)(R2) and X is —N(C(H)(CH3)2)—.


In another embodiment, R1 is —(CH2)n—N(R2)(R2) and X is —N(CH2C(H)(CH3)2)—.


In another embodiment, R1 is —(CH2)n—N(R2)(R2) and X is —N(C(CH3)3)—.


In one embodiment, R1 is —O—(CH2)m—N(R2)(R2) and X is —N(CH3)—.


In another embodiment, R1 is —O—(CH2)m—N(R2)(R2) and X is —N(CH2CH3)—.


In another embodiment, R1 is —O—(CH2)m—N(R2)(R2) and X is —N(CH2CH2CH3)—.


In another embodiment, R1 is —O—(CH2)m—N(R2)(R2) and X is —N(CH2CH2CH2CH3)—.


In another embodiment, R1 is —O—(CH2)m—N(R2)(R2) and X is —N(C(H)(CH3)(CH2CH3))—.


In another embodiment, R1 is —O—(CH2)m—N(R2)(R2) and X is —N(C(H)(CH3)2)—.


In another embodiment, R1 is —O—(CH2)m—N(R2)(R2) and X is —N(CH2C(H)(CH3)2)—.


In another embodiment, R1 is —O—(CH2)m—N(R2)(R2) and X is —N(C(CH3)3)—.


In one embodiment, one R2 is —H, and the other R2 is —C1-C6 alkyl.


In another embodiment, each R2 is —C1-C6 alkyl.


In another embodiment, each R2 is -methyl.


In one embodiment, X is —CH(OH)—.


In another embodiment, X is —CH(OH)— and R1 is —(CH2)n—N(R2)(R2).


In yet another embodiment, X is —CH(OH)— and R1 is —(CH2)—N(R2)(R2).


In another embodiment, X is —N(C(O)N(H)—(CH2)p—Z)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)—Z)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)2—Z)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—Z)— and R1 is —(CH2)n—N(R2)(R2).


In yet another embodiment, X is —N(C(O)N(H)—(CH2)p—Z)— and R1 is —(CH2)—N(R2)(R2).


In still another embodiment, X is —N(C(O)N(H)—(CH2)—Z)— and R1 is —(CH2)—N(R2)(R2).


In one embodiment, X is —N((CH2)q—Z)—.


In another embodiment, X is —N((CH2)—Z)—.


In another embodiment, X is —N((CH2)2—Z)—.


In another embodiment, X is —N((CH2)q—Z)— and R1 is —(CH2)n—N(R2)(R2).


In yet another embodiment, X is —N((CH2)q—Z)— and R1 is —(CH2)—N(R2)(R2).


In still another embodiment, X is —N((CH2)—Z)— and R1 is —(CH2)—N(R2)(R2).


In one embodiment, Z is —CF3.


In another embodiment, Z is —F.


In yet another embodiment, Z is —OH.


In still another embodiment, Z is —O—CH3.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—OH)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)2—OH)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—OH)— and R1 is —(CH2)n—N(R2)(R2).


In yet another embodiment, X is —N(C(O)N(H)—(CH2)p—OH)— and R1 is —(CH2)—N(R2)(R2).


In still another embodiment, X is —N(C(O)N(H)—(CH2)2—OH)— and R1 is —(CH2)—N(R2)(R2).


In one embodiment, X is —N((CH2)q—OH)—.


In another embodiment, X is —N((CH2)2—OH)—.


In another embodiment, X is —N((CH2)q—OH)— and R1 is —(CH2)n—N(R2)(R2).


In yet another embodiment, X is —N((CH2)q—OH)— and R1 is —(CH2)—N(R2)(R2).


In still another embodiment, X is —N((CH2)2—OH)— and R1 is —(CH2)—N(R2)(R2).


In another embodiment, X is —N(C(O)N(H)—(CH2)p—F)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)—F)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—F)— and R1 is —(CH2)n—N(R2)(R2).


In yet another embodiment, X is —N(C(O)N(H)—(CH2)p—F)— and R1 is —(CH2)—N(R2)(R2).


In still another embodiment, X is —N(C(O)N(H)—(CH2)—F)— and R1 is —(CH2)—N(R2)(R2).


In one embodiment, X is —N((CH2)q—F)—.


In another embodiment, X is —N((CH2)—F)—.


In another embodiment, X is —N((CH2)q—F)— and R1 is —(CH2)n—N(R2)(R2).


In yet another embodiment, X is —N((CH2)q—F)— and R1 is —(CH2)—N(R2)(R2).


In still another embodiment, X is —N((CH2)—F)— and R1 is —(CH2)—N(R2)(R2).


In another embodiment, X is —N(C(O)N(H)—(CH2)p—OMe)-.


In another embodiment, X is —N(C(O)N(H)—(CH2)2—OMe)-.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—OMe)- and R1 is —(CH2)n—N(R2)(R2).


In yet another embodiment, X is —N(C(O)N(H)—(CH2)p—OMe)- and R1 is —(CH2)—N(R2)(R2).


In still another embodiment, X is —N(C(O)N(H)—(CH2)2—OMe)- and R1 is —(CH2)—N(R2)(R2).


In one embodiment, X is —N((CH2)q—OMe)-.


In another embodiment, X is —N((CH2)2—OMe)-.


In another embodiment, X is —N((CH2)q—OMe)- and R1 is —(CH2)n—N(R2)(R2).


In yet another embodiment, X is —N((CH2)q—OMe)- and R1 is —(CH2)—N(R2)(R2).


In still another embodiment, X is —N((CH2)2—OMe)- and R1 is —(CH2)—N(R2)(R2).


In another embodiment, X is —N(C(O)N(H)—(CH2)p—CF3)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)—CF3)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—CF3)— and R1 is —(CH2)n—N(R2)(R2).


In yet another embodiment, X is —N(C(O)N(H)—(CH2)p—CF3)— and R1 is —(CH2)—N(R2)(R2).


In still another embodiment, X is —N(C(O)N(H)—(CH2)—CF3)— and R1 is —(CH2)—N(R2)(R2).


In one embodiment, X is —N((CH2)q—CF3)—.


In another embodiment, X is —N((CH2)—CF3)—.


In another embodiment, X is —N((CH2)q—CF3)— and R1 is —(CH2)n—N(R2)(R2).


In yet another embodiment, X is —N((CH2)q—CF3)— and R1 is —(CH2)—N(R2)(R2).


In still another embodiment, X is —N((CH2)—CF3)— and R1 is —(CH2)—N(R2)(R2).


In another embodiment, X is —N(C(O)N(H)—(CH2)p—CF3)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)—CF3)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—CF3)— and R1 is —(CH2)n—N(R1)(R2).


In yet another embodiment, X is —N(C(O)N(H)—(CH2)p—CF3)— and R1 is —(CH2)—N(R2)(R2).


In still another embodiment, X is —N(C(O)N(H)—(CH2)—CF3)— and R1 is —(CH2)—N(R2)(R2).


In one embodiment, X is —N((CH2)q—CF3)—.


In another embodiment, X is —N((CH2)—CF3)—.


In another embodiment, X is —N((CH2)q—CF3)— and R1 is —(CH2)n—N(R2)(R2).


In yet another embodiment, X is —N((CH2)q—CF3)— and R1 is —(CH2)—N(R2)(R2).


In still another embodiment, X is —N((CH2)—CF3)— and R1 is —(CH2)—N(R2)(R2).


In one embodiment, n is 1.


In another embodiment, n is 2.


In yet another embodiment, n is 3.


In a further embodiment, n is 4, 5, or 6.


In yet a further embodiment, n is 7, 8, or 9.


In still a further embodiment, n is 10.


In one embodiment, m is 2.


In another embodiment, m is 3.


In yet another embodiment, m is 4, 5, or 6.


In a further embodiment, m is 7, 8, or 9.


In yet a further embodiment, m is 10.


In one embodiment, p is 1.


In another embodiment, p is 2.


In yet another embodiment, p is an integer ranging from 2 to 5.


In one embodiment, q is 1.


In another embodiment, q is 2.


In yet another embodiment, q is an integer ranging from 2 to 5.


In various embodiments, —N(R2)(R2) is:




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In other embodiments, —N(R2)(R2) is:




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In some embodiments, —N(R2)(R2) is




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In still other embodiments, —N(R2)(R2) is —N(CH2CH3)(CH3),


—N(CH2CH2CH3)(CH3),


—N(CH2CH2CH2CH3)(CH3),


—NH—CH2CH2CH2CH3, or


—NH—CH2CH2—O—CH3.


In some embodiments, —N(R2)(R2) is




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In various embodiments, —N(Z3)(Z4) is:




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In other embodiments, —N(Z3)(Z4) is:




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In some embodiments, —N(Z3)(Z4) is




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In still other embodiments, —N(Z3)(Z4) is —N(CH2CH3)(CH3),


—N(CH2CH2CH3)(CH3),


—N(CH2CH2CH2CH3)(CH3),


—NH—CH2CH2CH2CH3, or


—NH—CH2CH2—O—CH3.


In some embodiments, —N(Z3)(Z4) is




embedded image


In one embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2— or —N(C(CH3)3)—;


R1 is —(CH2)n—N(R2)(R2) or —O—(CH2)m—N(R2)(R2);


each R2 is independently —H, —C1-C6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —(C1-C6 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)2OH or —N(Z3)(Z4), where Z3 and Z4 are independently —H, —C1-C5 alkyl, or —(C1-C5 alkylene)-O—C1-C5 alkyl, each of which other than hydrogen is unsubstituted or substituted with one or more of -halo, —OH or —NH2;


or N, Z3 and Z4 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three of —C1-C5 alkyl, -phenyl, —(C1-C5 alkylene)-phenyl, -(hydroxy-substituted) C1-C5 alkyl, -halo, -(halo-substituted) C1-C5 alkyl, -(halo-substituted) phenyl, -phenylene-O—C1-C5 alkyl, -(cyano-substituted) phenyl, —OH, —O—C1-C5 alkyl, —N(Ra)2, —(C1-C5 alkylene)-N(Ra)2, —C1-C5 alkylene-C(O)O—(C1-C5 alkylene)-N(Ra)2, —COOH, —(C1-C5 alkylene)-COOH, —OP(O)(OH)2, —OS(O)2OH, —(C1-C5 alkylene)-OP(O)(OH)2, —(C1-C5 alkylene)-OS(O)2OH, —C(O)O—C1-C5 alkyl, —OC(O)—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)O—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)NH—C1-C5 alkyl, —C(O)NH2, or —NO2, wherein each occurrence of Ra is independently —H, -benzyl, or —C1-C10 alkyl;


or N and both R2 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 —C1-C5 alkyl, -phenyl, —(C1-C5 alkylene)-phenyl, -(hydroxy-substituted) C1-C5 alkyl, -halo, -(halo-substituted) C1-C5 alkyl, -(halo-substituted) phenyl, -phenylene-O—C1-C5 alkyl, -(cyano-substituted) phenyl, —OH, —O—C1-C5 alkyl, —N(Ra)2, —(C1-C5 alkylene)-N(Ra)2, —(C1-C5 alkylene)-C(O)O—(C1-C5 alkylene)-N(Ra)2, —COOH, —(C1-C5 alkylene)-COOH, —OP(O)(OH)2, —OS(O)2OH, —(C1-C5 alkylene)-OP(O)(OH)2, —(C1-C5 alkylene)-OS(O)2OH, —C(O)O—C1-C5 alkyl, —OC(O)—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)O—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)NH—C1-C5 alkyl, —C(O)NH2, or —NO2, wherein each occurrence of Ra is independently —H, -benzyl, or —C1-C10 alkyl;


n is an integer ranging from 1 to 10; and


m is an integer ranging from 2 to 10.


In one embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2 CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2— or —N(C(CH3)3)—; R1 is —CH2—N(R2)(R2); and at least one R2 is methyl.


In another embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2— or —N(C(CH3)3)—; R1 is —CH2—N(R2)(R2); and at least one R2 is ethyl.


In yet another embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2— or —N(C(CH3)3)—; R1 is —CH2—N(R2)(R2); and at least one R2 is propyl.


In one embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2— or —N(C(CH3)3)—; R1 is —CH2—N(R2)(R2); and at least one R2 is —C3-C8 monocyclic cycloalkyl.


In another embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2— or —N(C(CH3)3)—; R1 is —CH2—N(R2)(R2); and at least one R2 is cyclohexyl.


In yet another embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2— or —N(C(CH3)3)—; and R1 is —CH2—N(R2)(R2), wherein N and both R2 groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle.


In one embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2— or —N(C(CH3)3)—; and R1 is —CH2—N(R2)(R2), wherein N and both R2 groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which is substituted with a hydroxyl.


In another embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2— or —N(C(CH3)3)—; and R1 is —CH2—N(R2)(R2), wherein N and both R2 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.


Illustrative examples of the Indenoisoquinolinone Analogs include the compounds of Formula (Ib) as set forth below:
















(Ib)




embedded image
















Compound
n
—R1
X





Ib-1
1
—(CH2)n—N(CH3)2
—N(CH3)—


Ib-2
2
—(CH2)n—N(CH3)2
—N(CH3)—


Ib-3
3
—(CH2)n—N(CH3)2
—N(CH3)—


Ib-4
4
—(CH2)n—N(CH3)2
—N(CH3)—


Ib-5
5
—(CH2)n—N(CH3)2
—N(CH3)—


Ib-6
6
—(CH2)n—N(CH3)2
—N(CH3)—


Ib-7
1
—(CH2)n—N(CH3)2
—N(CH2CH3)—


Ib-8
2
—(CH2)n—N(CH3)2
—N(CH2CH3)—


Ib-9
3
—(CH2)n—N(CH3)2
—N(CH2CH3)—


Ib-10
4
—(CH2)n—N(CH3)2
—N(CH2CH3)—


Ib-11
5
—(CH2)n—N(CH3)2
—N(CH2CH3)—


Ib-12
6
—(CH2)n—N(CH3)2
—N(CH2CH3)—


Ib-13
1
—(CH2)n—N(CH3)2
—N(CH2CH2CH3)—


Ib-14
2
—(CH2)n—N(CH3)2
—N(CH2CH2CH3)—


Ib-15
3
—(CH2)n—N(CH3)2
—N(CH2CH2CH3)—


Ib-16
4
—(CH2)n—N(CH3)2
—N(CH2CH2CH3)—


Ib-17
5
—(CH2)n—N(CH3)2
—N(CH2CH2CH3)—


Ib-18
6
—(CH2)n—N(CH3)2
—N(CH2CH2CH3)—


Ib-19
1
—(CH2)n—N(CH3)2
—N(CH2CH2CH2CH3)—


Ib-20
2
—(CH2)n—N(CH3)2
—N(CH2CH2CH2CH3)—


Ib-21
3
—(CH2)n—N(CH3)2
—N(CH2CH2CH2CH3)—


Ib-22
4
—(CH2)n—N(CH3)2
—N(CH2CH2CH2CH3)—


Ib-23
5
—(CH2)n—N(CH3)2
—N(CH2CH2CH2CH3)—


Ib-24
6
—(CH2)n—N(CH3)2
—N(CH2CH2CH2CH3)—


Ib-25
1
—(CH2)n—N(CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ib-26
2
—(CH2)n—N(CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ib-27
3
—(CH2)n—N(CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ib-28
4
—(CH2)n—N(CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ib-29
5
—(CH2)n—N(CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ib-30
6
—(CH2)n—N(CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ib-31
1
—(CH2)n—N(CH3)2
—N(C(H)(CH3)2)—


Ib-32
2
—(CH2)n—N(CH3)2
—N(C(H)(CH3)2)—


Ib-33
3
—(CH2)n—N(CH3)2
—N(C(H)(CH3)2)—


Ib-34
4
—(CH2)n—N(CH3)2
—N(C(H)(CH3)2)—


Ib-35
5
—(CH2)n—N(CH3)2
—N(C(H)(CH3)2)—


Ib-36
6
—(CH2)n—N(CH3)2
—N(C(H)(CH3)2)—


Ib-37
1
—(CH2)n—N(CH3)2
—N(CH2C(H)(CH3)2)—


Ib-38
2
—(CH2)n—N(CH3)2
—N(CH2C(H)(CH3)2)—


Ib-39
3
—(CH2)n—N(CH3)2
—N(CH2C(H)(CH3)2)—


Ib-40
4
—(CH2)n—N(CH3)2
—N(CH2C(H)(CH3)2)—


Ib-41
5
—(CH2)n—N(CH3)2
—N(CH2C(H)(CH3)2)—


Ib-42
6
—(CH2)n—N(CH3)2
—N(CH2C(H)(CH3)2)—


Ib-43
1
—(CH2)n—N(CH3)2
—N(C(CH3)3)—


Ib-44
2
—(CH2)n—N(CH3)2
—N(C(CH3)3)—


Ib-45
3
—(CH2)n—N(CH3)2
—N(C(CH3)3)—


Ib-46
4
—(CH2)n—N(CH3)2
—N(C(CH3)3)—


Ib-47
5
—(CH2)n—N(CH3)2
—N(C(CH3)3)—


Ib-48
6
—(CH2)n—N(CH3)2
—N(C(CH3)3)—





Ib-49
1


embedded image


—N(CH3)—





Ib-50
2


embedded image


—N(CH3)—





Ib-51
3


embedded image


—N(CH3)—





Ib-52
4


embedded image


—N(CH3)—





Ib-53
5


embedded image


—N(CH3)—





Ib-54
6


embedded image


—N(CH3)—





Ib-55
1


embedded image


—N(CH2CH3)—





Ib-56
2


embedded image


—N(CH2CH3)—





Ib-57
3


embedded image


—N(CH2CH3)—





Ib-58
4


embedded image


—N(CH2CH3)—





Ib-59
5


embedded image


—N(CH2CH3)—





Ib-60
6


embedded image


—N(CH2CH3)—





Ib-61
1


embedded image


—N(CH2CH2CH3)—





Ib-62
2


embedded image


—N(CH2CH2CH3)—





Ib-63
3


embedded image


—N(CH2CH2CH3)—





Ib-64
4


embedded image


—N(CH2CH2CH3)—





Ib-65
5


embedded image


—N(CH2CH2CH3)—





Ib-66
6


embedded image


—N(CH2CH2CH3)—





Ib-67
1


embedded image


—N(CH2CH2CH2CH3)—





Ib-68
2


embedded image


—N(CH2CH2CH2CH3)—





Ib-69
3


embedded image


—N(CH2CH2CH2CH3)—





Ib-70
4


embedded image


—N(CH2CH2CH2CH3)—





Ib-71
5


embedded image


—N(CH2CH2CH2CH3)—





Ib-72
6


embedded image


—N(CH2CH2CH2CH3)—





Ib-73
1


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-74
2


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-75
3


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-76
4


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-77
5


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-78
6


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-79
1


embedded image


—N(C(H)(CH3)2)—





Ib-80
2


embedded image


—N(C(H)(CH3)2)—





Ib-81
3


embedded image


—N(C(H)(CH3)2)—





Ib-82
4


embedded image


—N(C(H)(CH3)2)—





Ib-83
5


embedded image


—N(C(H)(CH3)2)—





Ib-84
6


embedded image


—N(C(H)(CH3)2)—





Ib-85
1


embedded image


—N(CH2C(H)(CH3)2)—





Ib-86
2


embedded image


—N(CH2C(H)(CH3)2)—





Ib-87
3


embedded image


—N(CH2C(H)(CH3)2)—





Ib-88
4


embedded image


—N(CH2C(H)(CH3)2)—





Ib-89
5


embedded image


—N(CH2C(H)(CH3)2)—





Ib-90
6


embedded image


—N(CH2C(H)(CH3)2)—





Ib-91
1


embedded image


—N(C(CH3)3)—





Ib-92
2


embedded image


—N(C(CH3)3)—





Ib-93
3


embedded image


—N(C(CH3)3)—





Ib-94
4


embedded image


—N(C(CH3)3)—





Ib-95
5


embedded image


—N(C(CH3)3)—





Ib-96
6


embedded image


—N(C(CH3)3)—





Compound
m
—R1
X





Ib-146
2
—O—(CH2)m—N(CH3)2
—N(CH3)—


Ib-147
3
—O—(CH2)m—N(CH3)2
—N(CH3)—


Ib-148
4
—O—(CH2)m—N(CH3)2
—N(CH3)—


Ib-149
5
—O—(CH2)m—N(CH3)2
—N(CH3)—


Ib-150
6
—O—(CH2)m—N(CH3)2
—N(CH3)—


Ib-151
2
—O—(CH2)m—N(CH3)2
—N(CH3)—


Ib-152
3
—O—(CH2)m—N(CH3)2
—N(CH2CH3)—


Ib-153
4
—O—(CH2)m—N(CH3)2
—N(CH2CH3)—


Ib-154
5
—O—(CH2)m—N(CH3)2
—N(CH2CH3)—


Ib-155
6
—O—(CH2)m—N(CH3)2
—N(CH2CH3)—


Ib-156
2
—O—(CH2)m—N(CH3)2
—N(CH2CH3)—


Ib-157
3
—O—(CH2)m—N(CH3)2
—N(CH2CH3)—


Ib-158
4
—O—(CH2)m—N(CH3)2
—N(CH2CH2CH3)—


Ib-159
5
—O—(CH2)m—N(CH3)2
—N(CH2CH2CH3)—


Ib-160
6
—O—(CH2)m—N(CH3)2
—N(CH2CH2CH3)—


Ib-161
2
—O—(CH2)m—N(CH3)2
—N(CH2CH2CH3)—


Ib-162
3
—O—(CH2)m—N(CH3)2
—N(CH2CH2CH3)—


Ib-163
4
—O—(CH2)m—N(CH3)2
—N(CH2CH2CH3)—


Ib-164
5
—O—(CH2)m—N(CH3)2
—N(CH2CH2CH2CH3)—


Ib-165
6
—O—(CH2)m—N(CH3)2
—N(CH2CH2CH2CH3)—


Ib-166
2
—O—(CH2)m—N(CH3)2
—N(CH2CH2CH2CH3)—


Ib-167
3
—O—(CH2)m—N(CH3)2
—N(CH2CH2CH2CH3)—


Ib-168
4
—O—(CH2)m—N(CH3)2
—N(CH2CH2CH2CH3)—


Ib-169
5
—O—(CH2)m—N(CH3)2
—N(CH2CH2CH2CH3)—


Ib-170
6
—O—(CH2)m—N(CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ib-171
2
—O—(CH2)m—N(CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ib-172
3
—O—(CH2)m—N(CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ib-173
4
—O—(CH2)m—N(CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ib-174
5
—O—(CH2)m—N(CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ib-175
6
—O—(CH2)m—N(CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ib-176
2
—O—(CH2)m—N(CH3)2
—N(C(H)(CH3)2)—


Ib-178
3
—O—(CH2)m—N(CH3)2
—N(C(H)(CH3)2)—


Ib-179
4
—O—(CH2)m—N(CH3)2
—N(C(H)(CH3)2)—


Ib-180
5
—O—(CH2)m—N(CH3)2
—N(C(H)(CH3)2)—


Ib-181
6
—O—(CH2)m—N(CH3)2
—N(C(H)(CH3)2)—


Ib-182
2
—O—(CH2)m—N(CH3)2
—N(C(H)(CH3)2)—


Ib-183
3
—O—(CH2)m—N(CH3)2
—N(CH2C(H)(CH3)2)—


Ib-184
4
—O—(CH2)m—N(CH3)2
—N(CH2C(H)(CH3)2)—


Ib-185
5
—O—(CH2)m—N(CH3)2
—N(CH2C(H)(CH3)2)—


Ib-186
6
—O—(CH2)m—N(CH3)2
—N(CH2C(H)(CH3)2)—





Ib-187
2


embedded image


—N(CH3)—





Ib-188
3


embedded image


—N(CH3)—





Ib-189
4


embedded image


—N(CH3)—





Ib-190
5


embedded image


—N(CH3)—





Ib-191
6


embedded image


—N(CH3)—





Ib-192
2


embedded image


—N(CH3)—





Ib-193
3


embedded image


—N(CH2CH3)—





Ib-194
4


embedded image


—N(CH2CH3)—





Ib-195
5


embedded image


—N(CH2CH3)—





Ib-196
6


embedded image


—N(CH2CH3)—





Ib-197
2


embedded image


—N(CH2CH3)—





Ib-198
3


embedded image


—N(CH2CH3)—





Ib-199
4


embedded image


—N(CH2CH2CH3)—





Ib-200
5


embedded image


—N(CH2CH2CH3)—





Ib-201
6


embedded image


—N(CH2CH2CH3)—





Ib-202
2


embedded image


—N(CH2CH2CH3)—





Ib-203
3


embedded image


—N(CH2CH2CH3)—





Ib-204
4


embedded image


—N(CH2CH2CH3)—





Ib-205
5


embedded image


—N(CH2CH2CH2CH3)—





Ib-206
6


embedded image


—N(CH2CH2CH2CH3)—





Ib-207
2


embedded image


—N(CH2CH2CH2CH3)—





Ib-208
3


embedded image


—N(CH2CH2CH2CH3)—





Ib-209
4


embedded image


—N(CH2CH2CH2CH3)—





Ib-210
5


embedded image


—N(CH2CH2CH2CH3)—





Ib-211
6


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-212
2


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-213
3


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-214
4


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-215
5


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-216
6


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-217
2


embedded image


—N(C(H)(CH3)2)—





Ib-218
3


embedded image


—N(C(H)(CH3)2)—





Ib-219
4


embedded image


—N(C(H)(CH3)2)—





Ib-220
5


embedded image


—N(C(H)(CH3)2)—





Ib-221
6


embedded image


—N(C(H)(CH3)2)—





Ib-222
2


embedded image


—N(C(H)(CH3)2)—





Ib-223
3


embedded image


—N(CH2C(H)(CH3)2)—





Ib-224
4


embedded image


—N(CH2C(H)(CH3)2)—





Ib-225
5


embedded image


—N(CH2C(H)(CH3)2)—





Ib-226
6


embedded image


—N(CH2C(H)(CH3)2)—












Compound
—R1
X





Ib-267
—CH2—N(CH2—CH3)2
—N(CH3)—


Ib-268
—CH2—N(CH2—CH3)2
—N(CH2CH3)—


Ib-269
—CH2—N(CH2—CH3)2
—N(CH2CH2CH3)—


Ib-270
—CH2—N(CH2—CH3)2
—N(CH2CH2CH2CH3)—


Ib-271
—CH2—N(CH2—CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ib-272
—CH2—N(CH2—CH3)2
—N(C(H)(CH3)2)—


Ib-273
—CH2—N(CH2—CH3)2
—N(CH2C(H)(CH3)2)—


Ib-274
—CH2—N(CH2—CH3)2
—N(C(CH3)3)—


Ib-275
—CH2—N(CH2—CH2—CH3)2
—N(CH3)—


Ib-276
—CH2—N(CH2—CH2—CH3)2
—N(CH2CH3)—


Ib-277
—CH2—N(CH2—CH2—CH3)2
—N(CH2CH2CH3)—


Ib-278
—CH2—N(CH2—CH2—CH3)2
—N(CH2CH2CH2CH3)—


Ib-279
—CH2—N(CH2—CH2—CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ib-280
—CH2—N(CH2—CH2—CH3)2
—N(C(H)(CH3)2)—


Ib-281
—CH2—N(CH2—CH2—CH3)2
—N(CH2C(H)(CH3)2)—


Ib-282
—CH2—N(CH2—CH2—CH3)2
—N(C(CH3)3)—


Ib-283
—CH2—N(CH2—CH2OH)2
—N(CH3)—


Ib-284
—CH2—N(CH2—CH2OH)2
—N(CH2CH3)—


Ib-285
—CH2—N(CH2—CH2OH)2
—N(CH2CH2CH3)—


Ib-286
—CH2—N(CH2—CH2OH)2
—N(CH2CH2CH2CH3)—


Ib-287
—CH2—N(CH2—CH2OH)2
—N(C(H)(CH3)(CH2CH3))—


Ib-288
—CH2—N(CH2—CH2OH)2
—N(C(H)(CH3)2)—


Ib-289
—CH2—N(CH2—CH2OH)2
—N(CH2C(H)(CH3)2)—


Ib-290
—CH2—N(CH2—CH2OH)2
—N(C(CH3)3)—


Ib-291
—CH2—N(CH2—CH2—N(CH3)2)2
—N(CH3)—


Ib-292
—CH2—N(CH2—CH2—N(CH3)2)2
—N(CH2CH3)—


Ib-293
—CH2—N(CH2—CH2—N(CH3)2)2
—N(CH2CH2CH3)—


Ib-294
—CH2—N(CH2—CH2—N(CH3)2)2
—N(CH2CH2CH2CH3)—


Ib-295
—CH2—N(CH2—CH2—N(CH3)2)2
—N(C(H)(CH3)(CH2CH3))—


Ib-296
—CH2—N(CH2—CH2—N(CH3)2)2
—N(C(H)(CH3)2)—


Ib-297
—CH2—N(CH2—CH2—N(CH3)2)2
—N(CH2C(H)(CH3)2)—


Ib-298
—CH2—N(CH2—CH2—N(CH3)2)2
—N(C(CH3)3)—


Ib-299
—CH2—N(CH2—CH2—CH2N(CH3)2)2
—N(CH3)—


Ib-300
—CH2—N(CH2—CH2—CH2N(CH3)2)2
—N(CH2CH3)—


Ib-301
—CH2—N(CH2—CH2—CH2N(CH3)2)2
—N(CH2CH2CH3)—


Ib-302
—CH2—N(CH2—CH2—CH2N(CH3)2)2
—N(CH2CH2CH2CH3)—


Ib-303
—CH2—N(CH2—CH2—CH2N(CH3)2)2
—N(C(H)(CH3)(CH2CH3))—


Ib-304
—CH2—N(CH2—CH2—CH2N(CH3)2)2
—N(C(H)(CH3)2)—


Ib-305
—CH2—N(CH2—CH2—CH2N(CH3)2)2
—N(CH2C(H)(CH3)2)—


Ib-306
—CH2—N(CH2—CH2—CH2N(CH3)2)2
—N(C(CH3)3)—





Ib-307


embedded image


—N(CH3)—





Ib-308


embedded image


—N(CH2CH3)—





Ib-309


embedded image


—N(CH2CH2CH3)—





Ib-310


embedded image


—N(CH2CH2CH2CH3)—





Ib-311


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-312


embedded image


—N(C(H)(CH3)2)—





Ib-313


embedded image


—N(CH2C(H)(CH3)2)—





Ib-314


embedded image


—N(C(CH3)3)—





Ib-315


embedded image


—N(CH3)—





Ib-316


embedded image


—N(CH2CH3)—





Ib-317


embedded image


—N(CH2CH2CH3)—





Ib-318


embedded image


—N(CH2CH2CH2CH3)—





Ib-319


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-320


embedded image


—N(C(H)(CH3)2)—





Ib-321


embedded image


—N(CH2C(H)(CH3)2)—





Ib-322


embedded image


—N(C(CH3)3)—





Ib-323


embedded image


—N(CH3)—





Ib-324


embedded image


—N(CH2CH3)—





Ib-325


embedded image


—N(CH2CH2CH3)—





Ib-326


embedded image


—N(CH2CH2CH2CH3)—





Ib-327


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-328


embedded image


—N(C(H)(CH3)2)—





Ib-329


embedded image


—N(CH2C(H)(CH3)2)—





Ib-330


embedded image


—N(C(CH3)3)—





Ib-331


embedded image


—N(CH3)—





Ib-332


embedded image


—N(CH2CH3)—





Ib-333


embedded image


—N(CH2CH2CH3)—





Ib-334


embedded image


—N(CH2CH2CH2CH3)—





Ib-335


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-336


embedded image


—N(C(H)(CH3)2)—





Ib-337


embedded image


—N(CH2C(H)(CH3)2)—





Ib-338


embedded image


—N(C(CH3)3)—





Ib-339


embedded image


—N(CH3)—





Ib-340


embedded image


—N(CH2CH3)—





Ib-341


embedded image


—N(CH2CH2CH3)—





Ib-342


embedded image


—N(CH2CH2CH2CH3)—





Ib-343


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-344


embedded image


—N(C(H)(CH3)2)—





Ib-345


embedded image


—N(CH2C(H)(CH3)2)—





Ib-346


embedded image


—N(C(CH3)3)—





Ib-347


embedded image


—N(CH3)—





Ib-348


embedded image


—N(CH2CH3)—





Ib-349


embedded image


—N(CH2CH2CH3)—





Ib-350


embedded image


—N(CH2CH2CH2CH3)—





Ib-351


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-352


embedded image


—N(C(H)(CH3)2)—





Ib-353


embedded image


—N(CH2C(H)(CH3)2)—





Ib-354


embedded image


—N(C(CH3)3)—





Ib-355


embedded image


—N(CH3)—





Ib-356


embedded image


—N(CH2CH3)—





Ib-357


embedded image


—N(CH2CH2CH3)—





Ib-358


embedded image


—N(CH2CH2CH2CH3)—





Ib-359


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-360


embedded image


—N(C(H)(CH3)2)—





Ib-361


embedded image


—N(CH2C(H)(CH3)2)—





Ib-362


embedded image


—N(C(CH3)3)—





Ib-363


embedded image


—N(CH3)—





Ib-364


embedded image


—N(CH2CH3)—





Ib-365


embedded image


—N(CH2CH2CH3)—





Ib-366


embedded image


—N(CH2CH2CH2CH3)—





Ib-367


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-368


embedded image


—N(C(H)(CH3)2)—





Ib-369


embedded image


—N(CH2C(H)(CH3)2)—





Ib-370


embedded image


—N(C(CH3)3)—





Ib-371


embedded image


—N(CH3)—





Ib-372


embedded image


—N(CH2CH3)—





Ib-373


embedded image


—N(CH2CH2CH3)—





Ib-374


embedded image


—N(CH2CH2CH2CH3)—





Ib-375


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-376


embedded image


—N(C(H)(CH3)2)—





Ib-377


embedded image


—N(CH2C(H)(CH3)2)—





Ib-378


embedded image


—N(C(CH3)3)—





Ib-379


embedded image


—N(CH3)—





Ib-380


embedded image


—N(CH2CH3)—





Ib-381


embedded image


—N(CH2CH2CH3)—





Ib-382


embedded image


—N(CH2CH2CH2CH3)—





Ib-383


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-384


embedded image


—N(C(H)(CH3)2)—





Ib-385


embedded image


—N(CH2C(H)(CH3)2)—





Ib-386


embedded image


—N(C(CH3)3)—





Ib-387


embedded image


—N(CH3)—





Ib-388


embedded image


—N(CH2CH3)—





Ib-389


embedded image


—N(CH2CH2CH3)—





Ib-390


embedded image


—N(CH2CH2CH2CH3)—





Ib-391


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-392


embedded image


—N(C(H)(CH3)2)—





Ib-393


embedded image


—N(CH2C(H)(CH3)2)—





Ib-394


embedded image


—N(C(CH3)3)—





Ib-395


embedded image


—N(CH3)—





Ib-396


embedded image


—N(CH2CH3)—





Ib-397


embedded image


—N(CH2CH2CH3)—





Ib-398


embedded image


—N(CH2CH2CH2CH3)—





Ib-399


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-400


embedded image


—N(C(H)(CH3)2)—





Ib-401


embedded image


—N(CH2C(H)(CH3)2)—





Ib-402


embedded image


—N(C(CH3)3)—





Ib-403


embedded image


—N(CH3)—





Ib-404


embedded image


—N(CH2CH3)—





Ib-405


embedded image


—N(CH2CH2CH3)—





Ib-406


embedded image


—N(CH2CH2CH2CH3)—





Ib-407


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-408


embedded image


—N(C(H)(CH3)2)—





Ib-409


embedded image


—N(CH2C(H)(CH3)2)—





Ib-410


embedded image


—N(C(CH3)3)—





Ib-411


embedded image


—N(CH3)—





Ib-412


embedded image


—N(CH2CH3)—





Ib-413


embedded image


—N(CH2CH2CH3)—





Ib-414


embedded image


—N(CH2CH2CH2CH3)—





Ib-415


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-416


embedded image


—N(C(H)(CH3)2)—





Ib-417


embedded image


—N(CH2C(H)(CH3)2)—





Ib-418


embedded image


—N(C(CH3)3)—





Ib-419


embedded image


—N(CH3)—





Ib-420


embedded image


—N(CH2CH3)—





Ib-421


embedded image


—N(CH2CH2CH3)—





Ib-422


embedded image


—N(CH2CH2CH2CH3)—





Ib-423


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-424


embedded image


—N(C(H)(CH3)2)—





Ib-425


embedded image


—N(CH2C(H)(CH3)2)—





Ib-426


embedded image


—N(C(CH3)3)—





Ib-427


embedded image


—N(CH3)—





Ib-428


embedded image


—N(CH2CH3)—





Ib-429


embedded image


—N(CH2CH2CH3)—





Ib-430


embedded image


—N(CH2CH2CH2CH3)—





Ib-431


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-432


embedded image


—N(C(H)(CH3)2)—





Ib-433


embedded image


—N(CH2C(H)(CH3)2)—





Ib-434


embedded image


—N(C(CH3)3)—





Ib-435


embedded image


—N(CH3)—





Ib-436


embedded image


—N(CH2CH3)—





Ib-437


embedded image


—N(CH2CH2CH3)—





Ib-438


embedded image


—N(CH2CH2CH2CH3)—





Ib-439


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-440


embedded image


—N(C(H)(CH3)2)—





Ib-441


embedded image


—N(CH2C(H)(CH3)2)—





Ib-442


embedded image


—N(C(CH3)3)—





Ib-443


embedded image


—N(CH3)—





Ib-444


embedded image


—N(CH2CH3)—





Ib-445


embedded image


—N(CH2CH2CH3)—





Ib-446


embedded image


—N(CH2CH2CH2CH3)—





Ib-447


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-448


embedded image


—N(C(H)(CH3)2)—





Ib-449


embedded image


—N(CH2C(H)(CH3)2)—





Ib-450


embedded image


—N(C(CH3)3)—





Ib-451


embedded image


—N(CH3)—





Ib-452


embedded image


—N(CH2CH3)—





Ib-453


embedded image


—N(CH2CH2CH3)—





Ib-454


embedded image


—N(CH2CH2CH2CH3)—





Ib-455


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-456


embedded image


—N(C(H)(CH3)2)—





Ib-457


embedded image


—N(CH2C(H)(CH3)2)—





Ib-458


embedded image


—N(C(CH3)3)—





Ib-459


embedded image


—N(CH3)—





Ib-460


embedded image


—N(CH2CH3)—





Ib-461


embedded image


—N(CH2CH2CH3)—





Ib-462


embedded image


—N(CH2CH2CH2CH3)—





Ib-463


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-464


embedded image


—N(C(H)(CH3)2)—





Ib-465


embedded image


—N(CH2C(H)(CH3)2)—





Ib-466


embedded image


—N(C(CH3)3)—





Ib-467


embedded image


—N(CH3)—





Ib-468


embedded image


—N(CH2CH3)—





Ib-469


embedded image


—N(CH2CH2CH3)—





Ib-470


embedded image


—N(CH2CH2CH2CH3)—





Ib-471


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-472


embedded image


—N(C(H)(CH3)2)—





Ib-473


embedded image


—N(CH2C(H)(CH3)2)—





Ib-474


embedded image


—N(C(CH3)3)—





Ib-475


embedded image


—N(CH3)—





Ib-476


embedded image


—N(CH2CH3)—





Ib-477


embedded image


—N(CH2CH2CH3)—





Ib-478


embedded image


—N(CH2CH2CH2CH3)—





Ib-479


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-480


embedded image


—N(C(H)(CH3)2)—





Ib-481


embedded image


—N(CH2C(H)(CH3)2)—





Ib-482


embedded image


—N(C(CH3)3)—





Ib-483


embedded image


—N(CH3)—





Ib-484


embedded image


—N(CH2CH3)—





Ib-485


embedded image


—N(CH2CH2CH3)—





Ib-486


embedded image


—N(CH2CH2CH2CH3)—





Ib-487


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-488


embedded image


—N(C(H)(CH3)2)—





Ib-489


embedded image


—N(CH2C(H)(CH3)2)—





Ib-490


embedded image


—N(C(CH3)3)—





Ib-491
—CH2—CH2—CH2—OP(O)(OH)2
—N(CH3)—


Ib-492
—CH2—CH2—CH2—OP(O)(OH)2
—N(CH2CH3)—


Ib-493
—CH2—CH2—CH2—OP(O)(OH)2
—N(CH2CH2CH3)—


Ib-494
—CH2—CH2—CH2—OP(O)(OH)2
—N(CH2CH2CH2CH3)—


Ib-495
—CH2—CH2—CH2—OP(O)(OH)2
—N(C(H)(CH3)(CH2CH3))—


Ib-496
—CH2—CH2—CH2—OP(O)(OH)2
—N(C(H)(CH3)2)—


Ib-497
—CH2—CH2—CH2—OP(O)(OH)2
—N(CH2C(H)(CH3)2)—


Ib-498
—CH2—CH2—CH2—OP(O)(OH)2
—N(C(CH3)3)—


Ib-499
—CH2—CH2—CH2—OS(O)2OH
—N(CH3)—


Ib-500
—CH2—CH2—CH2—OS(O)2OH
—N(CH2CH3)—


Ib-501
—CH2—CH2—CH2—OS(O)2OH
—N(CH2CH2CH3)—


Ib-502
—CH2—CH2—CH2—OS(O)2OH
—N(CH2CH2CH2CH3)—


Ib-503
—CH2—CH2—CH2—OS(O)2OH
—N(C(H)(CH3)(CH2CH3))—


Ib-504
—CH2—CH2—CH2—OS(O)2OH
—N(C(H)(CH3)2)—


Ib-505
—CH2—CH2—CH2—OS(O)2OH
—N(CH2C(H)(CH3)2)—


Ib-506
—CH2—CH2—CH2—OS(O)2OH
—N(C(CH3)3)—





Ib-507


embedded image


—N(CH3)—





Ib-508


embedded image


—N(CH2CH3)—





Ib-509


embedded image


—N(CH2CH2CH3)—





Ib-510


embedded image


—N(CH2CH2CH2CH3)—





Ib-511


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-512


embedded image


—N(C(H)(CH3)2)—





Ib-513


embedded image


—N(CH2C(H)(CH3)2)—





Ib-514


embedded image


—N(C(CH3)3)—





Ib-515


embedded image


—N(CH3)—





Ib-516


embedded image


—N(CH2CH3)—





Ib-517


embedded image


—N(CH2CH2CH3)—





Ib-518


embedded image


—N(CH2CH2CH2CH3)—





Ib-519


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-520


embedded image


—N(C(H)(CH3)2)—





Ib-521


embedded image


—N(CH2C(H)(CH3)2)—





Ib-522


embedded image


—N(C(CH3)3)—





Ib-523
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(CH3)—


Ib-524
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(CH2CH3)—


Ib-525
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(CH2CH2CH3)—


Ib-526
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(CH2CH2CH2CH3)—


Ib-527
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ib-528
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(C(H)(CH3)2)—


Ib-529
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(CH2C(H)(CH3)2)—


Ib-530
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(C(CH3)3)—


Ib-531
—CH2—N(CH2—CH2—O—CH3)2
—N(CH3)—


Ib-532
—CH2—N(CH2—CH2—O—CH3)2
—N(CH2CH3)—


Ib-533
—CH2—N(CH2—CH2—O—CH3)2
—N(CH2CH2CH3)—


Ib-534
—CH2—N(CH2—CH2—O—CH3)2
—N(CH2CH2CH2CH3)—


Ib-535
—CH2—N(CH2—CH2—O—CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ib-536
—CH2—N(CH2—CH2—O—CH3)2
—N(C(H)(CH3)2)—


Ib-537
—CH2—N(CH2—CH2—O—CH3)2
—N(CH2C(H)(CH3)2)—


Ib-538
—CH2—N(CH2—CH2—O—CH3)2
—N(C(CH3)3)—





Ib-539


embedded image


—N(CH3)—





Ib-540


embedded image


—N(CH2CH3)—





Ib-541


embedded image


—N(CH2CH2CH3)—





Ib-542


embedded image


—N(CH2CH2CH2CH3)—





Ib-543


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-544


embedded image


—N(C(H)(CH3)2)—





Ib-545


embedded image


—N(CH2C(H)(CH3)2)—





Ib-546


embedded image


—N(C(CH3)3)—





Ib-547


embedded image


—N(CH3)—





Ib-548


embedded image


—N(CH2CH3)—





Ib-549


embedded image


—N(CH2CH2CH3)—





Ib-550


embedded image


—N(CH2CH2CH2CH3)—





Ib-551


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-552


embedded image


—N(C(H)(CH3)2)—





Ib-553


embedded image


—N(CH2C(H)(CH3)2)—





Ib-554


embedded image


—N(C(CH3)3)—





Ib-555


embedded image


—N(CH3)—





Ib-556


embedded image


—N(CH2CH3)—





Ib-557


embedded image


—N(CH2CH2CH3)—





Ib-558


embedded image


—N(CH2CH2CH2CH3)—





Ib-559


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-560


embedded image


—N(C(H)(CH3)2)—





Ib-561


embedded image


—N(CH2C(H)(CH3)2)—





Ib-562


embedded image


—N(C(CH3)3)—





Ib-563


embedded image


—N(CH3)—





Ib-564


embedded image


—N(CH2CH3)—





Ib-565


embedded image


—N(CH2CH2CH3)—





Ib-566


embedded image


—N(CH2CH2CH2CH3)—





Ib-567


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-568


embedded image


—N(C(H)(CH3)2)—





Ib-569


embedded image


—N(CH2C(H)(CH3)2)—





Ib-570


embedded image


—N(C(CH3)3)—





Ib-571


embedded image


—N(CH3)—





Ib-572


embedded image


—N(CH2CH3)—





Ib-573


embedded image


—N(CH2CH2CH3)—





Ib-574


embedded image


—N(CH2CH2CH2CH3)—





Ib-575


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-576


embedded image


—N(C(H)(CH3)2)—





Ib-577


embedded image


—N(CH2C(H)(CH3)2)—





Ib-578


embedded image


—N(C(CH3)3)—





Ib-579


embedded image


—N(CH3)—





Ib-580


embedded image


—N(CH2CH3)—





Ib-581


embedded image


—N(CH2CH2CH3)—





Ib-582


embedded image


—N(CH2CH2CH2CH3)—





Ib-583


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-584


embedded image


—N(C(H)(CH3)2)—





Ib-585


embedded image


—N(CH2C(H)(CH3)2)—





Ib-586


embedded image


—N(C(CH3)3)—





Ib-587


embedded image


—N(CH3)—





Ib-588


embedded image


—N(CH2CH3)—





Ib-589


embedded image


—N(CH2CH2CH3)—





Ib-590


embedded image


—N(CH2CH2CH2CH3)—





Ib-591


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-592


embedded image


—N(C(H)(CH3)2)—





Ib-593


embedded image


—N(CH2C(H)(CH3)2)—





Ib-594


embedded image


—N(C(CH3)3)—





Ib-595


embedded image


—N(CH3)—





Ib-596


embedded image


—N(CH2CH3)—





Ib-597


embedded image


—N(CH2CH2CH3)—





Ib-598


embedded image


—N(CH2CH2CH2CH3)—





Ib-599


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-600


embedded image


—N(C(H)(CH3)2)—





Ib-601


embedded image


—N(CH2C(H)(CH3)2)—





Ib-602


embedded image


—N(C(CH3)3)—





Ib-603


embedded image


—N(CH3)—





Ib-604


embedded image


—N(CH2CH3)—





Ib-605


embedded image


—N(CH2CH2CH3)—





Ib-606


embedded image


—N(CH2CH2CH2CH3)—





Ib-607


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-608


embedded image


—N(C(H)(CH3)2)—





Ib-609


embedded image


—N(CH2C(H)(CH3)2)—





Ib-610


embedded image


—N(C(CH3)3)—





Ib-611
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(CH3)—


Ib-612
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(CH2CH3)—


Ib-613
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(CH2CH2CH3)—


Ib-614
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(CH2CH2CH2CH3)—


Ib-615
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ib-616
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(C(H)(CH3)2)—


Ib-617
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(CH2C(H)(CH3)2)—


Ib-618
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(C(CH3)3)—





Ib-619


embedded image


—N(CH3)—





Ib-620


embedded image


—N(CH2CH3)—





Ib-621


embedded image


—N(CH2CH2CH3)—





Ib-622


embedded image


—N(CH2CH2CH2CH3)—





Ib-623


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-624


embedded image


—N(C(H)(CH3)2)—





Ib-625


embedded image


—N(CH2C(H)(CH3)2)—





Ib-626


embedded image


—N(C(CH3)3)—





Ib-627


embedded image


—N(CH3)—





Ib-628


embedded image


—N(CH2CH3)—





Ib-629


embedded image


—N(CH2CH2CH3)—





Ib-630


embedded image


—N(CH2CH2CH2CH3)—





Ib-631


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-632


embedded image


—N(C(H)(CH3)2)—





Ib-633


embedded image


—N(CH2C(H)(CH3)2)—





Ib-634


embedded image


—N(C(CH3)3)—





Ib-635


embedded image


—N(CH3)—





Ib-636


embedded image


—N(CH2CH3)—





Ib-637


embedded image


—N(CH2CH2CH3)—





Ib-638


embedded image


—N(CH2CH2CH2CH3)—





Ib-639


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-640


embedded image


—N(C(H)(CH3)2)—





Ib-641


embedded image


—N(CH2C(H)(CH3)2)—





Ib-642


embedded image


—N(C(CH3)3)—





Ib-643


embedded image


—N(CH3)—





Ib-644


embedded image


—N(CH2CH3)—





Ib-645


embedded image


—N(CH2CH2CH3)—





Ib-646


embedded image


—N(CH2CH2CH2CH3)—





Ib-647


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-648


embedded image


—N(C(H)(CH3)2)—





Ib-649


embedded image


—N(CH2C(H)(CH3)2)—





Ib-650


embedded image


—N(C(CH3)3)—





Ib-651


embedded image


—N(CH3)—





Ib-652


embedded image


—N(CH2CH3)—





Ib-653


embedded image


—N(CH2CH2CH3)—





Ib-654


embedded image


—N(CH2CH2CH2CH3)—





Ib-655


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-656


embedded image


—N(C(H)(CH3)2)—





Ib-657


embedded image


—N(CH2C(H)(CH3)2)—





Ib-658


embedded image


—N(C(CH3)3)—





Ib-659


embedded image


—N(CH3)—





Ib-660


embedded image


—N(CH2CH3)—





Ib-661


embedded image


—N(CH2CH2CH3)—





Ib-662


embedded image


—N(CH2CH2CH2CH3)—





Ib-663


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-664


embedded image


—N(C(H)(CH3)2)—





Ib-665


embedded image


—N(CH2C(H)(CH3)2)—





Ib-666


embedded image


—N(C(CH3)3)—





Ib-667


embedded image


—N(CH3)—





Ib-668


embedded image


—N(CH2CH3)—





Ib-669


embedded image


—N(CH2CH2CH3)—





Ib-670


embedded image


—N(CH2CH2CH2CH3)—





Ib-671


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-672


embedded image


—N(C(H)(CH3)2)—





Ib-673


embedded image


—N(CH2C(H)(CH3)2)—





Ib-674


embedded image


—N(C(CH3)3)—





Ib-675


embedded image


—N(CH3)—





Ib-676


embedded image


—N(CH2CH3)—





Ib-677


embedded image


—N(CH2CH2CH3)—





Ib-678


embedded image


—N(CH2CH2CH2CH3)—





Ib-679


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-680


embedded image


—N(C(H)(CH3)2)—





Ib-681


embedded image


—N(CH2C(H)(CH3)2)—





Ib-682


embedded image


—N(C(CH3)3)—





Ib-683


embedded image


—N(CH3)—





Ib-684


embedded image


—N(CH2CH3)—





Ib-685


embedded image


—N(CH2CH2CH3)—





Ib-686


embedded image


—N(CH2CH2CH2CH3)—





Ib-687


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-688


embedded image


—N(C(H)(CH3)2)—





Ib-689


embedded image


—N(CH2C(H)(CH3)2)—





Ib-690


embedded image


—N(C(CH3)3)—





Ib-691


embedded image


—N(CH3)—





Ib-692


embedded image


—N(CH2CH3)—





Ib-693


embedded image


—N(CH2CH2CH3)—





Ib-694


embedded image


—N(CH2CH2CH2CH3)—





Ib-695


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-696


embedded image


—N(C(H)(CH3)2)—





Ib-697


embedded image


—N(CH2C(H)(CH3)2)—





Ib-698


embedded image


—N(C(CH3)3)—





Ib-699


embedded image


—N(CH3)—





Ib-700


embedded image


—N(CH2CH3)—





Ib-701


embedded image


—N(CH2CH2CH3)—





Ib-702


embedded image


—N(CH2CH2CH2CH3)—





Ib-703


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-704


embedded image


—N(C(H)(CH3)2)—





Ib-705


embedded image


—N(CH2C(H)(CH3)2)—





Ib-706


embedded image


—N(C(CH3)3)—





Ib-707


embedded image


—N(CH3)—





Ib-708


embedded image


—N(CH2CH3)—





Ib-709


embedded image


—N(CH2CH2CH3)—





Ib-710


embedded image


—N(CH2CH2CH2CH3)—





Ib-711


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-712


embedded image


—N(C(H)(CH3)2)—





Ib-713


embedded image


—N(CH2C(H)(CH3)2)—





Ib-714


embedded image


—N(C(CH3)3)—





Ib-715


embedded image


—N(CH3)—





Ib-716


embedded image


—N(CH2CH3)—





Ib-717


embedded image


—N(CH2CH2CH3)—





Ib-718


embedded image


—N(CH2CH2CH2CH3)—





Ib-719


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-720


embedded image


—N(C(H)(CH3)2)—





Ib-721


embedded image


—N(CH2C(H)(CH3)2)—





Ib-722


embedded image


—N(C(CH3)3)—





Ib-723


embedded image


—N(CH3)—





Ib-724


embedded image


—N(CH2CH3)—





Ib-725


embedded image


—N(CH2CH2CH3)—





Ib-726


embedded image


—N(CH2CH2CH2CH3)—





Ib-727


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-728


embedded image


—N(C(H)(CH3)2)—





Ib-729


embedded image


—N(CH2C(H)(CH3)2)—





Ib-730


embedded image


—N(C(CH3)3)—





Ib-731


embedded image


—N(CH3)—





Ib-732


embedded image


—N(CH2CH3)—





Ib-733


embedded image


—N(CH2CH2CH3)—





Ib-734


embedded image


—N(CH2CH2CH2CH3)—





Ib-735


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-736


embedded image


—N(C(H)(CH3)2)—





Ib-737


embedded image


—N(CH2C(H)(CH3)2)—





Ib-738


embedded image


—N(C(CH3)3)—





Ib-739


embedded image


—N(CH3)—





Ib-740


embedded image


—N(CH2CH3)—





Ib-741


embedded image


—N(CH2CH2CH3)—





Ib-742


embedded image


—N(CH2CH2CH2CH3)—





Ib-743


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-744


embedded image


—N(C(H)(CH3)2)—





Ib-745


embedded image


—N(CH2C(H)(CH3)2)—





Ib-746


embedded image


—N(C(CH3)3)—





Ib-747


embedded image


—N(CH3)—





Ib-748


embedded image


—N(CH2CH3)—





Ib-749


embedded image


—N(CH2CH2CH3)—





Ib-750


embedded image


—N(CH2CH2CH2CH3)—





Ib-751


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-752


embedded image


—N(C(H)(CH3)2)—





Ib-753


embedded image


—N(CH2C(H)(CH3)2)—





Ib-754


embedded image


—N(C(CH3)3)—





Ib-755


embedded image


—N(CH3)—





Ib-756


embedded image


—N(CH2CH3)—





Ib-757


embedded image


—N(CH2CH2CH3)—





Ib-758


embedded image


—N(CH2CH2CH2CH3)—





Ib-759


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-760


embedded image


—N(C(H)(CH3)2)—





Ib-761


embedded image


—N(CH2C(H)(CH3)2)—





Ib-762


embedded image


—N(C(CH3)3)—





Ib-763


embedded image


—N(CH3)—





Ib-764


embedded image


—N(CH2CH3)—





Ib-765


embedded image


—N(CH2CH2CH3)—





Ib-766


embedded image


—N(CH2CH2CH2CH3)—





Ib-767


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-768


embedded image


—N(C(H)(CH3)2)—





Ib-769


embedded image


—N(CH2C(H)(CH3)2)—





Ib-770


embedded image


—N(C(CH3)3)—





Ib-771


embedded image


—N(CH3)—





Ib-772


embedded image


—N(CH2CH3)—





Ib-773


embedded image


—N(CH2CH2CH3)—





Ib-774


embedded image


—N(CH2CH2CH2CH3)—





Ib-775


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-776


embedded image


—N(C(H)(CH3)2)—





Ib-777


embedded image


—N(CH2C(H)(CH3)2)—





Ib-778


embedded image


—N(C(CH3)3)—





Ib-779
—CH2—NH—CH3
—N(CH3)—


Ib-780
—CH2—NH—CH3
—N(CH2CH3)—


Ib-781
—CH2—NH—CH3
—N(CH2CH2CH3)—


Ib-782
—CH2—NH—CH3
—N(CH2CH2CH2CH3)—


Ib-783
—CH2—NH—CH3
—N(C(H)(CH3)(CH2CH3))—


Ib-784
—CH2—NH—CH3
—N(C(H)(CH3)2)—


Ib-785
—CH2—NH—CH3
—N(CH2C(H)(CH3)2)—


Ib-786
—CH2—NH—CH3
—N(C(CH3)3)—


Ib-787
—CH2—NH—CH2—CH3
—N(CH3)—


Ib-788
—CH2—NH—CH2—CH3
—N(CH2CH3)—


Ib-789
—CH2—NH—CH2—CH3
—N(CH2CH2CH3)—


Ib-790
—CH2—NH—CH2—CH3
—N(CH2CH2CH2CH3)—


Ib-791
—CH2—NH—CH2—CH3
—N(C(H)(CH3)(CH2CH3))—


Ib-792
—CH2—NH—CH2—CH3
—N(C(H)(CH3)2)—


Ib-793
—CH2—NH—CH2—CH3
—N(CH2C(H)(CH3)2)—


Ib-794
—CH2—NH—CH2—CH3
—N(C(CH3)3)—


Ib-795
—CH2—NH—CH2—CH2—CH3
—N(CH3)—


Ib-796
—CH2—NH—CH2—CH2—CH3
—N(CH2CH3)—


Ib-797
—CH2—NH—CH2—CH2—CH3
—N(CH2CH2CH3)—


Ib-798
—CH2—NH—CH2—CH2—CH3
—N(CH2CH2CH2CH3)—


Ib-799
—CH2—NH—CH2—CH2—CH3
—N(C(H)(CH3)(CH2CH3))—


Ib-800
—CH2—NH—CH2—CH2—CH3
—N(C(H)(CH3)2)—


Ib-801
—CH2—NH—CH2—CH2—CH3
—N(CH2C(H)(CH3)2)—


Ib-802
—CH2—NH—CH2—CH2—CH3
—N(C(CH3)3)—





Ib-803


embedded image


—N(CH3)—





Ib-804


embedded image


—N(CH2CH3)—





Ib-805


embedded image


—N(CH2CH2CH3)—





Ib-806


embedded image


—N(CH2CH2CH2CH3)—





Ib-807


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-808


embedded image


—N(C(H)(CH3)2)—





Ib-809


embedded image


—N(CH2C(H)(CH3)2)—





Ib-810


embedded image


—N(C(CH3)3)—





Ib-811


embedded image


—N(CH3)—





Ib-812


embedded image


—N(CH2CH3)—





Ib-813


embedded image


—N(CH2CH2CH3)—





Ib-814


embedded image


—N(CH2CH2CH2CH3)—





Ib-815


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-816


embedded image


—N(C(H)(CH3)2)—





Ib-817


embedded image


—N(CH2C(H)(CH3)2)—





Ib-818


embedded image


—N(C(CH3)3)—





Ib-819


embedded image


—N(CH3)—





Ib-820


embedded image


—N(CH2CH3)—





Ib-821


embedded image


—N(CH2CH2CH3)—





Ib-822


embedded image


—N(CH2CH2CH2CH3)—





Ib-823


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-824


embedded image


—N(C(H)(CH3)2)—





Ib-825


embedded image


—N(CH2C(H)(CH3)2)—





Ib-826


embedded image


—N(C(CH3)3)—





Ib-827


embedded image


—N(CH3)—





Ib-828


embedded image


—N(CH2CH3)—





Ib-829


embedded image


—N(CH2CH2CH3)—





Ib-830


embedded image


—N(CH2CH2CH2CH3)—





Ib-831


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-832


embedded image


—N(C(H)(CH3)2)—





Ib-833


embedded image


—N(CH2C(H)(CH3)2)—





Ib-834


embedded image


—N(C(CH3)3)—





Ib-835


embedded image


—N(CH3)—





Ib-836


embedded image


—N(CH2CH3)—





Ib-837


embedded image


—N(CH2CH2CH3)—





Ib-838


embedded image


—N(CH2CH2CH2CH3)—





Ib-839


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-840


embedded image


—N(C(H)(CH3)2)—





Ib-841


embedded image


—N(CH2C(H)(CH3)2)—





Ib-842


embedded image


—N(C(CH3)3)—





Ib-843


embedded image


—N(CH3)—





Ib-844


embedded image


—N(CH2CH3)—





Ib-845


embedded image


—N(CH2CH2CH3)—





Ib-846


embedded image


—N(CH2CH2CH2CH3)—





Ib-847


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-848


embedded image


—N(C(H)(CH3)2)—





Ib-849


embedded image


—N(CH2C(H)(CH3)2)—





Ib-850


embedded image


—N(C(CH3)3)—





Ib-851


embedded image


—N(CH3)—





Ib-852


embedded image


—N(CH2CH3)—





Ib-853


embedded image


—N(CH2CH2CH3)—





Ib-854


embedded image


—N(CH2CH2CH2CH3)—





Ib-855


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-856


embedded image


—N(C(H)(CH3)2)—





Ib-857


embedded image


—N(CH2C(H)(CH3)2)—





Ib-858


embedded image


—N(C(CH3)3)—





Ib-859


embedded image


—N(CH3)—





Ib-860


embedded image


—N(CH2CH3)—





Ib-861


embedded image


—N(CH2CH2CH3)—





Ib-862


embedded image


—N(CH2CH2CH2CH3)—





Ib-863


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-864


embedded image


—N(C(H)(CH3)2)—





Ib-865


embedded image


—N(CH2C(H)(CH3)2)—





Ib-866


embedded image


—N(C(CH3)3)—





Ib-867


embedded image


—N(CH3)—





Ib-868


embedded image


—N(CH2CH3)—





Ib-869


embedded image


—N(CH2CH2CH3)—





Ib-870


embedded image


—N(CH2CH2CH2CH3)—





Ib-871


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-872


embedded image


—N(C(H)(CH3)2)—





Ib-873


embedded image


—N(CH2C(H)(CH3)2)—





Ib-874


embedded image


—N(C(CH3)3)—





Ib-875


embedded image


—N(CH3)—





Ib-876


embedded image


—N(CH2CH3)—





Ib-877


embedded image


—N(CH2CH2CH3)—





Ib-878


embedded image


—N(CH2CH2CH2CH3)—





Ib-879


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-880


embedded image


—N(C(H)(CH3)2)—





Ib-881


embedded image


—N(CH2C(H)(CH3)2)—





Ib-882


embedded image


—N(C(CH3)3)—





Ib-883


embedded image


—N(CH3)—





Ib-884


embedded image


—N(CH2CH3)—





Ib-885


embedded image


—N(CH2CH2CH3)—





Ib-886


embedded image


—N(CH2CH2CH2CH3)—





Ib-887


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-888


embedded image


—N(C(H)(CH3)2)—





Ib-889


embedded image


—N(CH2C(H)(CH3)2)—





Ib-890


embedded image


—N(C(CH3)3)—





Ib-891


embedded image


—N(CH3)—





Ib-892


embedded image


—N(CH2CH3)—





Ib-893


embedded image


—N(CH2CH2CH3)—





Ib-894


embedded image


—N(CH2CH2CH2CH3)—





Ib-895


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-896


embedded image


—N(C(H)(CH3)2)—





Ib-897


embedded image


—N(CH2C(H)(CH3)2)—





Ib-898


embedded image


—N(C(CH3)3)—





Ib-899


embedded image


—N(CH3)—





Ib-900


embedded image


—N(CH2CH3)—





Ib-901


embedded image


—N(CH2CH2CH3)—





Ib-902


embedded image


—N(CH2CH2CH2CH3)—





Ib-903


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-904


embedded image


—N(C(H)(CH3)2)—





Ib-905


embedded image


—N(CH2C(H)(CH3)2)—





Ib-906


embedded image


—N(C(CH3)3)—





Ib-907


embedded image


—N(CH3)—





Ib-908


embedded image


—N(CH2CH3)—





Ib-909


embedded image


—N(CH2CH2CH3)—





Ib-910


embedded image


—N(CH2CH2CH2CH3)—





Ib-911


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-912


embedded image


—N(C(H)(CH3)2)—





Ib-913


embedded image


—N(CH2C(H)(CH3)2)—





Ib-914


embedded image


—N(C(CH3)3)—





Ib-915


embedded image


—N(CH3)—





Ib-916


embedded image


—N(CH2CH3)—





Ib-917


embedded image


—N(CH2CH2CH3)—





Ib-918


embedded image


—N(CH2CH2CH2CH3)—





Ib-919


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-920


embedded image


—N(C(H)(CH3)2)—





Ib-921


embedded image


—N(CH2C(H)(CH3)2)—





Ib-922


embedded image


—N(C(CH3)3)—





Ib-923


embedded image


—N(CH3)—





Ib-924


embedded image


—N(CH2CH3)—





Ib-925


embedded image


—N(CH2CH2CH3)—





Ib-926


embedded image


—N(CH2CH2CH2CH3)—





Ib-927


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-928


embedded image


—N(C(H)(CH3)2)—





Ib-929


embedded image


—N(CH2C(H)(CH3)2)—





Ib-930


embedded image


—N(C(CH3)3)—





Ib-931


embedded image


—N(CH3)—





Ib-932


embedded image


—N(CH2CH3)—





Ib-933


embedded image


—N(CH2CH2CH3)—





Ib-934


embedded image


—N(CH2CH2CH2CH3)—





Ib-935


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-936


embedded image


—N(C(H)(CH3)2)—





Ib-937


embedded image


—N(CH2C(H)(CH3)2)—





Ib-938


embedded image


—N(C(CH3)3)—





Ib-939


embedded image


—N(CH3)—





Ib-940


embedded image


—N(CH2CH3)—





Ib-941


embedded image


—N(CH2CH2CH3)—





Ib-942


embedded image


—N(CH2CH2CH2CH3)—





Ib-943


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-944


embedded image


—N(C(H)(CH3)2)—





Ib-945


embedded image


—N(CH2C(H)(CH3)2)—





Ib-946


embedded image


—N(C(CH3)3)—





Ib-947


embedded image


—N(CH3)—





Ib-948


embedded image


—N(CH2CH3)—





Ib-949


embedded image


—N(CH2CH2CH3)—





Ib-950


embedded image


—N(CH2CH2CH2CH3)—





Ib-951


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-952


embedded image


—N(C(H)(CH3)2)—





Ib-953


embedded image


—N(CH2C(H)(CH3)2)—





Ib-954


embedded image


—N(C(CH3)3)—





Ib-955


embedded image


—N(CH3)—





Ib-956


embedded image


—N(CH2CH3)—





Ib-957


embedded image


—N(CH2CH2CH3)—





Ib-958


embedded image


—N(CH2CH2CH2CH3)—





Ib-959


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-960


embedded image


—N(C(H)(CH3)2)—





Ib-961


embedded image


—N(CH2C(H)(CH3)2)—





Ib-962


embedded image


—N(C(CH3)3)—





Ib-963
—CH2—N(CH2CH3)(CH3)
—N(CH3)—


Ib-964
—CH2—N(CH2CH3)(CH3)
—N(CH2CH3)—


Ib-965
—CH2—N(CH2CH3)(CH3)
—N(CH2CH2CH3)—


Ib-966
—CH2—N(CH2CH3)(CH3)
—N(CH2CH2CH2CH3)—


Ib-967
—CH2—N(CH2CH3)(CH3)
—N(C(H)(CH3)(CH2CH3))—


Ib-968
—CH2—N(CH2CH3)(CH3)
—N(C(H)(CH3)2)—


Ib-969
—CH2—N(CH2CH3)(CH3)
—N(CH2C(H)(CH3)2)—


Ib-970
—CH2—N(CH2CH3)(CH3)
—N(C(CH3)3)—


Ib-971
—CH2—N(CH2CH2CH3)(CH3)
—N(CH3)—


Ib-972
—CH2—N(CH2CH2CH3)(CH3)
—N(CH2CH3)—


Ib-973
—CH2—N(CH2CH2CH3)(CH3)
—N(CH2CH2CH3)—


Ib-974
—CH2—N(CH2CH2CH3)(CH3)
—N(CH2CH2CH2CH3)—


Ib-975
—CH2—N(CH2CH2CH3)(CH3)
—N(C(H)(CH3)(CH2CH3))—


Ib-976
—CH2—N(CH2CH2CH3)(CH3)
—N(C(H)(CH3)2)—


Ib-977
—CH2—N(CH2CH2CH3)(CH3)
—N(CH2C(H)(CH3)2)—


Ib-978
—CH2—N(CH2CH2CH3)(CH3)
—N(C(CH3)3)—


Ib-979
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(CH3)—


Ib-980
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(CH2CH3)—


Ib-981
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(CH2CH2CH3)—


Ib-982
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(CH2CH2CH2CH3)—


Ib-983
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(C(H)(CH3)(CH2CH3))—


Ib-984
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(C(H)(CH3)2)—


Ib-985
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(CH2C(H)(CH3)2)—


Ib-986
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(C(CH3)3)—


Ib-987
—CH2—NH—CH2CH2CH2CH3
—N(CH3)—


Ib-988
—CH2—NH—CH2CH2CH2CH3
—N(CH2CH3)—


Ib-989
—CH2—NH—CH2CH2CH2CH3
—N(CH2CH2CH3)—


Ib-990
—CH2—NH—CH2CH2CH2CH3
—N(CH2CH2CH2CH3)—


Ib-991
—CH2—NH—CH2CH2CH2CH3
—N(C(H)(CH3)(CH2CH3))—


Ib-992
—CH2—NH—CH2CH2CH2CH3
—N(C(H)(CH3)2)—


Ib-993
—CH2—NH—CH2CH2CH2CH3
—N(CH2C(H)(CH3)2)—


Ib-994
—CH2—NH—CH2CH2CH2CH3
—N(C(CH3)3)—


Ib-995
—CH2—NH—CH2CH2—O—CH3
—N(CH3)—


Ib-996
—CH2—NH—CH2CH2—O—CH3
—N(CH2CH3)—


Ib-997
—CH2—NH—CH2CH2—O—CH3
—N(CH2CH2CH3)—


Ib-998
—CH2—NH—CH2CH2—O—CH3
—N(CH2CH2CH2CH3)—


Ib-999
—CH2—NH—CH2CH2—O—CH3
—N(C(H)(CH3)(CH2CH3))—


Ib-1000
—CH2—NH—CH2CH2—O—CH3
—N(C(H)(CH3)2)—


Ib-1001
—CH2—NH—CH2CH2—O—CH3
—N(CH2C(H)(CH3)2)—


Ib-1002
—CH2—NH—CH2CH2—O—CH3
—N(C(CH3)3)—





Ib-1003


embedded image


—N(CH3)—





Ib-1004


embedded image


—N(CH2CH3)—





Ib-1005


embedded image


—N(CH2CH2CH3)—





Ib-1006


embedded image


—N(CH2CH2CH2CH3)—





Ib-1007


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-1008


embedded image


—N(C(H)(CH3)2)—





Ib-1009


embedded image


—N(CH2C(H)(CH3)2)—





Ib-1010


embedded image


—N(C(CH3)3)—





Ib-1011


embedded image


—N(CH3)—





Ib-1012


embedded image


—N(CH2CH3)—





Ib-1013


embedded image


—N(CH2CH2CH3)—





Ib-1014


embedded image


—N(CH2CH2CH2CH3)—





Ib-1015


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-1016


embedded image


—N(C(H)(CH3)2)—





Ib-1017


embedded image


—N(CH2C(H)(CH3)2)—





Ib-1018


embedded image


—N(C(CH3)3)—





Ib-1019


embedded image


—N(CH3)—





Ib-1020


embedded image


—N(CH2CH3)—





Ib-1021


embedded image


—N(CH2CH2CH3)—





Ib-1022


embedded image


—N(CH2CH2CH2CH3)—





Ib-1023


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-1024


embedded image


—N(C(H)(CH3)2)—





Ib-1025


embedded image


—N(CH2C(H)(CH3)2)—





Ib-1026


embedded image


—N(C(CH3)3)—





Ib-1027


embedded image


—N(CH3)—





Ib-1028


embedded image


—N(CH2CH3)—





Ib-1029


embedded image


—N(CH2CH2CH3)—





Ib-1030


embedded image


—N(CH2CH2CH2CH3)—





Ib-1031


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-1032


embedded image


—N(C(H)(CH3)2)—





Ib-1033


embedded image


—N(CH2C(H)(CH3)2)—





Ib-1034


embedded image


—N(C(CH3)3)—





Ib-1035


embedded image


—N(CH3)—





Ib-1036


embedded image


—N(CH2CH3)—





Ib-1037


embedded image


—N(CH2CH2CH3)—





Ib-1038


embedded image


—N(CH2CH2CH2CH3)—





Ib-1039


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-1040


embedded image


—N(C(H)(CH3)2)—





Ib-1041


embedded image


—N(CH2C(H)(CH3)2)—





Ib-1042


embedded image


—N(C(CH3)3)—





Ib-1043


embedded image


—N(CH3)—





Ib-1044


embedded image


—N(CH2CH3)—





Ib-1045


embedded image


—N(CH2CH2CH3)—





Ib-1046


embedded image


—N(CH2CH2CH2CH3)—





Ib-1047


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-1048


embedded image


—N(C(H)(CH3)2)—





Ib-1049


embedded image


—N(CH2C(H)(CH3)2)—





Ib-1050


embedded image


—N(C(CH3)3)—





Ib-1051


embedded image


—N(CH3)—





Ib-1052


embedded image


—N(CH2CH3)—





Ib-1053


embedded image


—N(CH2CH2CH3)—





Ib-1054


embedded image


—N(CH2CH2CH2CH3)—





Ib-1055


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ib-1056


embedded image


—N(C(H)(CH3)2)—





Ib-1057


embedded image


—N(CH2C(H)(CH3)2)—





Ib-1058


embedded image


—N(C(CH3)3)—













Compound
n
—R1
X





Ib-b1
1
—(CH2)n—N(CH3)2
—CH(OH)—


Ib-b2
2
—(CH2)n—N(CH3)2
—CH(OH)—


Ib-b3
3
—(CH2)n—N(CH3)2
—CH(OH)—


Ib-b4
4
—(CH2)n—N(CH3)2
—CH(OH)—


Ib-b5
5
—(CH2)n—N(CH3)2
—CH(OH)—


Ib-b6
6
—(CH2)n—N(CH3)2
—CH(OH)—


Ib-b7
1
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ib-b8
2
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ib-b9
3
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ib-b10
4
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ib-b11
5
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ib-b12
6
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ib-b13
1
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ib-b14
2
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ib-b15
3
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ib-b16
4
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ib-b17
5
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ib-b18
6
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ib-b19
1
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ib-b20
2
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ib-b21
3
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ib-b22
4
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ib-b23
5
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ib-b24
6
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ib-b25
1
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b26
2
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b27
3
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b28
4
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b29
5
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b30
6
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b31
1
—(CH2)n—N(CH3)2
—N(CH2—CH2—OH)—


Ib-b32
2
—(CH2)n—N(CH3)2
—N(CH2—CH2—OH)—


Ib-b33
3
—(CH2)n—N(CH3)2
—N(CH2—CH2—OH)—


Ib-b34
4
—(CH2)n—N(CH3)2
—N(CH2—CH2—OH)—


Ib-b35
5
—(CH2)n—N(CH3)2
—N(CH2—CH2—OH)—


Ib-b36
6
—(CH2)n—N(CH3)2
—N(CH2—CH2—OH)—


Ib-b37
1
—(CH2)n—N(CH3)2
—N(CH2—CH2—F)—


Ib-b38
2
—(CH2)n—N(CH3)2
—N(CH2—CH2—F)—


Ib-b39
3
—(CH2)n—N(CH3)2
—N(CH2—CH2—F)—


Ib-b40
4
—(CH2)n—N(CH3)2
—N(CH2—CH2—F)—


Ib-b41
5
—(CH2)n—N(CH3)2
—N(CH2—CH2—F)—


Ib-b42
6
—(CH2)n—N(CH3)2
—N(CH2—CH2—F)—


Ib-b43
1
—(CH2)n—N(CH3)2
—N(CH2—CH2—OCH3)—


Ib-b44
2
—(CH2)n—N(CH3)2
—N(CH2—CH2—OCH3)—


Ib-b45
3
—(CH2)n—N(CH3)2
—N(CH2—CH2—OCH3)—


Ib-b46
4
—(CH2)n—N(CH3)2
—N(CH2—CH2—OCH3)—


Ib-b47
5
—(CH2)n—N(CH3)2
—N(CH2—CH2—OCH3)—


Ib-b48
6
—(CH2)n—N(CH3)2
—N(CH2—CH2—OCH3)—





Ib-b49
1


embedded image


—CH(OH)—





Ib-b50
2


embedded image


—CH(OH)—





Ib-b51
3


embedded image


—CH(OH)—





Ib-b52
4


embedded image


—CH(OH)—





Ib-b53
5


embedded image


—CH(OH)—





Ib-b54
6


embedded image


—CH(OH)—





Ib-b55
1


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b56
2


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b57
3


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b58
4


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b59
5


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b60
6


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b61
1


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b62
2


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b63
3


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b64
4


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b65
5


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b66
6


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b67
1


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b68
2


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b69
3


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b70
4


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b71
5


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b72
6


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b73
1


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b74
2


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b75
3


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b76
4


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b77
5


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b78
6


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b79
1


embedded image


—N(CH2—CH2—OH)—





Ib-b80
2


embedded image


—N(CH2—CH2—OH)—





Ib-b81
3


embedded image


—N(CH2—CH2—OH)—





Ib-b82
4


embedded image


—N(CH2—CH2—OH)—





Ib-b83
5


embedded image


—N(CH2—CH2—OH)—





Ib-b84
6


embedded image


—N(CH2—CH2—OH)—





Ib-b85
1


embedded image


—N(CH2—CH2—F)—





Ib-b86
2


embedded image


—N(CH2—CH2—F)—





Ib-b87
3


embedded image


—N(CH2—CH2—F)—





Ib-b88
4


embedded image


—N(CH2—CH2—F)—





Ib-b89
5


embedded image


—N(CH2—CH2—F)—





Ib-b90
6


embedded image


—N(CH2—CH2—F)—





Ib-b91
1


embedded image


—N(CH2—CH2—OCH3)—





Ib-b92
2


embedded image


—N(CH2—CH2—OCH3)—





Ib-b93
3


embedded image


—N(CH2—CH2—OCH3)—





Ib-b94
4


embedded image


—N(CH2—CH2—OCH3)—





Ib-b95
5


embedded image


—N(CH2—CH2—OCH3)—





Ib-b96
6


embedded image


—N(CH2—CH2—OCH3)—





Compound
m
—R1
X





Ib-b146
2
—O—(CH2)m—N(CH3)2
—CH(OH)—


Ib-b147
3
—O—(CH2)m—N(CH3)2
—CH(OH)—


Ib-b148
4
—O—(CH2)m—N(CH3)2
—CH(OH)—


Ib-b149
5
—O—(CH2)m—N(CH3)2
—CH(OH)—


Ib-b150
6
—O—(CH2)m—N(CH3)2
—CH(OH)—


Ib-b151
2
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ib-b152
3
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ib-b153
4
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ib-b154
5
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ib-b155
6
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ib-b156
2
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ib-b157
3
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ib-b158
4
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ib-b159
5
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ib-b160
6
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ib-b161
2
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ib-b162
3
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ib-b163
4
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ib-b164
5
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ib-b165
6
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ib-b166
2
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b167
3
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b168
4
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b169
5
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b170
6
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b171
2
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—OH)—


Ib-b172
3
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—OH)—


Ib-b173
4
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—OH)—


Ib-b174
5
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—OH)—


Ib-b175
6
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—OH)—


Ib-b176
2
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—F)—


Ib-b178
3
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—F)—


Ib-b179
4
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—F)—


Ib-b180
5
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—F)—


Ib-b181
6
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—F)—


Ib-b182
2
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—OCH3)—


Ib-b183
3
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—OCH3)—


Ib-b184
4
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—OCH3)—


Ib-b185
5
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—OCH3)—


Ib-b186
6
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—OCH3)—





Ib-b187
2


embedded image


—CH(OH)—





Ib-b188
3


embedded image


—CH(OH)—





Ib-b189
4


embedded image


—CH(OH)—





Ib-b190
5


embedded image


—CH(OH)—





Ib-b191
6


embedded image


—CH(OH)—





Ib-b192
2


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b193
3


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b194
4


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b195
5


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b196
6


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b197
2


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b198
3


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b199
4


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b200
5


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b201
6


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b202
2


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b203
3


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b204
4


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b205
5


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b206
6


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b207
2


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b208
3


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b209
4


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b210
5


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b211
6


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b212
2


embedded image


—N(CH2—CH2—OH)—





Ib-b213
3


embedded image


—N(CH2—CH2—OH)—





Ib-b214
4


embedded image


—N(CH2—CH2—OH)—





Ib-b215
5


embedded image


—N(CH2—CH2—OH)—





Ib-b216
6


embedded image


—N(CH2—CH2—OH)—





Ib-b217
2


embedded image


—N(CH2—CH2—F)—





Ib-b218
3


embedded image


—N(CH2—CH2—F)—





Ib-b219
4


embedded image


—N(CH2—CH2—F)—





Ib-b220
5


embedded image


—N(CH2—CH2—F)—





Ib-b221
6


embedded image


—N(CH2—CH2—F)—





Ib-b222
2


embedded image


—N(CH2—CH2—OCH3)—





Ib-b223
3


embedded image


—N(CH2—CH2—OCH3)—





Ib-b224
4


embedded image


—N(CH2—CH2—OCH3)—





Ib-b225
5


embedded image


—N(CH2—CH2—OCH3)—





Ib-b226
6


embedded image


—N(CH2—CH2—OCH3)—












Compound
—R1
X





Ib-b267
—CH2—N(CH2—CH3)2
—CH(OH)—


Ib-b268
—CH2—N(CH2—CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ib-b269
—CH2—N(CH2—CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ib-b270
—CH2—N(CH2—CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ib-b271
—CH2—N(CH2—CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b275
—CH2—N(CH2—CH2—CH3)2
—CH(OH)—


Ib-b276
—CH2—N(CH2—CH2—CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ib-b277
—CH2—N(CH2—CH2—CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ib-b278
—CH2—N(CH2—CH2—CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ib-b279
—CH2—N(CH2—CH2—CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b283
—CH2—N(CH2—CH2OH)2
—CH(OH)—


Ib-b284
—CH2—N(CH2—CH2OH)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ib-b285
—CH2—N(CH2—CH2OH)2
—N(C(O)N(H)—CH2—CH2—F)—


Ib-b286
—CH2—N(CH2—CH2OH)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ib-b291
—CH2—N(CH2—CH2—N(CH3)2)2
—CH(OH)—


Ib-b292
—CH2—N(CH2—CH2—N(CH3)2)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ib-b293
—CH2—N(CH2—CH2—N(CH3)2)2
—N(C(O)N(H)—CH2—CH2—F)—


Ib-b294
—CH2—N(CH2—CH2—N(CH3)2)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ib-b295
—CH2—N(CH2—CH2—N(CH3)2)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b296
—CH2—N(CH2—CH2—N(CH3)2)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b297
—CH2—N(CH2—CH2—N(CH3)2)2
—N(C(O)N(H)—CH2—CF3)—


Ib-b298
—CH2—N(CH2—CH2—N(CH3)2)2
—N(C(O)N(H)—(CH2)3—OH)—


Ib-b299
—CH2—N(CH2—CH2—CH2—N(CH3)2)2
—CH(OH)—


Ib-b300
—CH2—N(CH2—CH2—CH2—N(CH3)2)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ib-b301
—CH2—N(CH2—CH2—CH2—N(CH3)2)2
—N(C(O)N(H)—CH2—CH2—F)—


Ib-b302
—CH2—N(CH2—CH2—CH2—N(CH3)2)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ib-b303
—CH2—N(CH2—CH2—CH2—N(CH3)2)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b304
—CH2—N(CH2—CH2—CH2—N(CH3)2)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b305
—CH2—N(CH2—CH2—CH2—N(CH3)2)2
—N(C(O)N(H)—CH2—CF3)—


Ib-b306
—CH2—N(CH2—CH2—CH2—N(CH3)2)2
N(C(O)N(H)—(CH2)3—OH)—





Ib-b307


embedded image


—CH(OH)—





Ib-b308


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b309


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b310


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b311


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b312


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b313


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b314


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b315


embedded image


—CH(OH)—





Ib-b316


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b317


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b318


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b319


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b320


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b321


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b322


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b323


embedded image


—CH(OH)—





Ib-b324


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b325


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b326


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b327


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b328


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b329


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b330


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b331


embedded image


—CH(OH)—





Ib-b332


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b333


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b334


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b335


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b336


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b337


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b338


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b339


embedded image


—CH(OH)—





Ib-b340


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b341


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b342


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b343


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b344


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b345


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b346


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b347


embedded image


—CH(OH)—





Ib-b348


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b349


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b350


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b351


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b352


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b353


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b354


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b355


embedded image


—CH(OH)—





Ib-b356


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b357


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b358


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b359


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b360


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b361


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b362


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b363


embedded image


—CH(OH)—





Ib-b364


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b365


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b366


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b367


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b368


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b369


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b370


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b371


embedded image


—CH(OH)—





Ib-b372


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b373


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b374


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b375


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b376


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b377


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b378


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b379


embedded image


—CH(OH)—





Ib-b380


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b381


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b382


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b383


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b384


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b385


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b386


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b387


embedded image


—CH(OH)—





Ib-b388


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b389


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b390


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b391


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b392


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b393


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b394


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b395


embedded image


—CH(OH)—





Ib-b396


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b397


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b398


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b399


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b400


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b401


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b402


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b403


embedded image


—CH(OH)—





Ib-b404


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b405


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b406


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b407


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b408


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b409


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b410


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b411


embedded image


—CH(OH)—





Ib-b412


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b413


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b414


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b415


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b416


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b417


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b418


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b419


embedded image


—CH(OH)—





Ib-b420


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b421


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b422


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b423


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b424


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b425


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b426


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b427


embedded image


—CH(OH)—





Ib-b428


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b429


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b430


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b431


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b432


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b433


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b434


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b435


embedded image


—CH(OH)—





Ib-b436


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b437


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b438


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b439


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b440


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b441


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b442


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b443


embedded image


—CH(OH)—





Ib-b444


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b445


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b446


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b447


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b448


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b449


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b450


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b451


embedded image


—CH(OH)—





Ib-b452


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b453


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b454


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b455


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b456


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b457


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b458


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b459


embedded image


—CH(OH)—





Ib-b460


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b461


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b462


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b463


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b464


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b465


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b466


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b467


embedded image


—CH(OH)—





Ib-b468


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b469


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b470


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b471


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b472


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b473


embedded image


N(C(O)N(H)—CH2—CF3)—





Ib-b474


embedded image


N(C(O)N(H)—(CH2)3—OH)—





Ib-b475


embedded image


—CH(OH)—





Ib-b476


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b477


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b478


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b479


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b480


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b481


embedded image


N(C(O)N(H)—CH2—CF3)—





Ib-b482


embedded image


N(C(O)N(H)—(CH2)3—OH)—





Ib-b483


embedded image


—CH(OH)—





Ib-b484


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b485


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b486


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b487


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b488


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b489


embedded image


N(C(O)N(H)—CH2—CF3)—





Ib-b490


embedded image


N(C(O)N(H)—(CH2)3—OH)—





Ib-b491
—CH2—CH2—CH2—OP(O)(OH)2
—CH(OH)—


Ib-b492
—CH2—CH2—CH2—OP(O)(OH)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ib-b493
—CH2—CH2—CH2—OP(O)(OH)2
—N(C(O)N(H)—CH2—CH2—F)—


Ib-b494
—CH2—CH2—CH2—OP(O)(OH)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ib-b495
—CH2—CH2—CH2—OP(O)(OH)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b496
—CH2—CH2—CH2—OP(O)(OH)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b497
—CH2—CH2—CH2—OP(O)(OH)2
—N(C(O)N(H)—CH2—CF3)—


Ib-b498
—CH2—CH2—CH2—OP(O)(OH)2
—N(C(O)N(H)—(CH2)3—OH)—


Ib-b499
—CH2—CH2—CH2—OS(O)2OH
—CH(OH)—


Ib-b500
—CH2—CH2—CH2—OS(O)2OH
—N(C(O)N(H)—CH2—CH2—OH)—


Ib-b501
—CH2—CH2—CH2—OS(O)2OH
—N(C(O)N(H)—CH2—CH2—F)—


Ib-b502
—CH2—CH2—CH2—OS(O)2OH
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ib-b503
—CH2—CH2—CH2—OS(O)2OH
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b504
—CH2—CH2—CH2—OS(O)2OH
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b505
—CH2—CH2—CH2—OS(O)2OH
—N(C(O)N(H)—CH2—CF3)—


Ib-b506
—CH2—CH2—CH2—OS(O)2OH
—N(C(O)N(H)—(CH2)3—OH)—





Ib-b507


embedded image


—CH(OH)—





Ib-b508


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b509


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b510


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b511


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b512


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b513


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b514


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b515


embedded image


—CH(OH)—





Ib-b516


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b517


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b518


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b519


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b520


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b521


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b522


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b523
—(CH2)10—N(CH2—CH2—O—CH3)2
—CH(OH)—


Ib-b524
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ib-b525
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ib-b526
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ib-b527
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b528
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b529
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—CH2—CF3)—


Ib-b530
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—(CH2)3—OH)—


Ib-b531
—CH2—N(CH2—CH2—O—CH3)2
—CH(OH)—


Ib-b532
—CH2—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ib-b533
—CH2—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ib-b534
—CH2—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ib-b535
—CH2—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b536
—CH2—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b537
—CH2—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—CH2—CF3)—


Ib-b538
—CH2—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—(CH2)3—OH)—





Ib-b539


embedded image


—CH(OH)—





Ib-b540


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b541


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b542


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b543


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b544


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b545


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b546


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b547


embedded image


—CH(OH)—





Ib-b548


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b549


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b550


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b551


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b552


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b553


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b554


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b555


embedded image


—CH(OH)—





Ib-b556


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b557


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b558


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b559


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b560


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b561


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b562


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b563


embedded image


—CH(OH)—





Ib-b564


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b565


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b566


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b567


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b568


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b569


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b570


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b571


embedded image


—CH(OH)—





Ib-b572


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b573


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b574


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b575


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b576


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b577


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b578


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b579


embedded image


—CH(OH)—





Ib-b580


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b581


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b582


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b583


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b584


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b585


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b586


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b587


embedded image


—CH(OH)—





Ib-b588


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b589


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b590


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b591


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b592


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b593


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b594


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b595


embedded image


—CH(OH)—





Ib-b596


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b597


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b598


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b599


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b600


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b601


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b602


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b603


embedded image


—CH(OH)—





Ib-b604


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b605


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b606


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b607


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b608


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b609


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b610


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b611
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—CH(OH)—


Ib-b612
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ib-b613
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ib-b614
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ib-b615
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b616
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b617
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(C(O)N(H)—CH2—CF3)—


Ib-b618
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(C(O)N(H)—(CH2)3—OH)—





Ib-b619


embedded image


—CH(OH)—





Ib-b620


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b621


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b622


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b623


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b624


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b625


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b626


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b627


embedded image


—CH(OH)—





Ib-b628


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b629


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b630


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b631


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b632


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b633


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b634


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b635


embedded image


—CH(OH)—





Ib-b636


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b637


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b638


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b639


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b640


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b641


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b642


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b643


embedded image


—CH(OH)—





Ib-b644


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b645


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b646


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b647


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b648


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b649


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b650


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b651


embedded image


—CH(OH)—





Ib-b652


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b653


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b654


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b655


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b656


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b657


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b658


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b659


embedded image


—CH(OH)—





Ib-b660


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b661


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b662


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b663


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b664


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b665


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b666


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b667


embedded image


—CH(OH)—





Ib-b668


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b669


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b670


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b671


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b672


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b673


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b674


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b675


embedded image


—CH(OH)—





Ib-b676


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b677


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b678


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b679


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b680


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b681


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b682


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b683


embedded image


—CH(OH)—





Ib-b684


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b685


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b686


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b687


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b688


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b689


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b690


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b691


embedded image


—CH(OH)—





Ib-b692


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b693


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b694


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b695


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b696


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b697


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b698


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b699


embedded image


—CH(OH)—





Ib-b700


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b701


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b702


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b703


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b704


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b705


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b706


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b707


embedded image


—CH(OH)—





Ib-b708


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b709


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b710


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b711


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b712


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b713


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b714


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b715


embedded image


—CH(OH)—





Ib-b716


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b717


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b718


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b719


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b720


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b721


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b722


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b723


embedded image


—CH(OH)—





Ib-b724


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b725


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b726


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b727


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b728


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b729


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b730


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b731


embedded image


—CH(OH)—





Ib-b732


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b733


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b734


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b735


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b736


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b737


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b738


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b739


embedded image


—CH(OH)—





Ib-b740


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b741


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b742


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b743


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b744


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b745


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b746


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b747


embedded image


—CH(OH)—





Ib-b748


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b749


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b750


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b751


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b752


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b753


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b754


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b755


embedded image


—CH(OH)—





Ib-b756


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b757


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b758


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b759


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b760


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b761


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b762


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b763


embedded image


—CH(OH)—





Ib-b764


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b765


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b766


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b767


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b768


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b769


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b770


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b771


embedded image


—CH(OH)—





Ib-b772


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b773


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b774


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b775


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b776


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b777


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b778


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b779
—CH2—NH—CH3
—CH(OH)—


Ib-b780
—CH2—NH—CH3
—N(C(O)N(H)—CH2—CH2—OH)—


Ib-b781
—CH2—NH—CH3
—N(C(O)N(H)—CH2—CH2—F)—


Ib-b782
—CH2—NH—CH3
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ib-b783
—CH2—NH—CH3
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b784
—CH2—NH—CH3
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b785
—CH2—NH—CH3
—N(C(O)N(H)—CH2—CF3)—


Ib-b786
—CH2—NH—CH3
—N(C(O)N(H)—(CH2)3—OH)—


Ib-b787
—CH2—NH—CH2—CH3
—CH(OH)—


Ib-b788
—CH2—NH—CH2—CH3
—N(C(O)N(H)—CH2—CH2—OH)—


Ib-b789
—CH2—NH—CH2—CH3
—N(C(O)N(H)—CH2—CH2—F)—


Ib-b790
—CH2—NH—CH2—CH3
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ib-b791
—CH2—NH—CH2—CH3
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b792
—CH2—NH—CH2—CH3
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b793
—CH2—NH—CH2—CH3
—N(C(O)N(H)—CH2—CF3)—


Ib-b794
—CH2—NH—CH2—CH3
—N(C(O)N(H)—(CH2)3—OH)—


Ib-b795
—CH2—NH—CH2—CH2—CH3
—CH(OH)—


Ib-b796
—CH2—NH—CH2—CH2—CH3
—N(C(O)N(H)—CH2—CH2—OH)—


Ib-b797
—CH2—NH—CH2—CH2—CH3
—N(C(O)N(H)—CH2—CH2—F)—


Ib-b798
—CH2—NH—CH2—CH2—CH3
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ib-b799
—CH2—NH—CH2—CH2—CH3
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b800
—CH2—NH—CH2—CH2—CH3
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b801
—CH2—NH—CH2—CH2—CH3
—N(C(O)N(H)—CH2—CF3)—


Ib-b802
—CH2—NH—CH2—CH2—CH3
—N(C(O)N(H)—(CH2)3—OH)—





Ib-b803


embedded image


—CH(OH)—





Ib-b804


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b805


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b806


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b807


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b808


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b809


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b810


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b811


embedded image


—CH(OH)—





Ib-b812


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b813


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b814


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b815


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b816


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b817


embedded image


N(C(O)N(H)—CH2—CF3)—





Ib-b818


embedded image


N(C(O)N(H)—(CH2)3—OH)—





Ib-b819


embedded image


—CH(OH)—





Ib-b820


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b821


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b822


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b823


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b824


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b825


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b826


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b827


embedded image


—CH(OH)—





Ib-b828


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b829


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b830


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b831


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b832


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b833


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b834


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b835


embedded image


—CH(OH)—





Ib-b836


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b837


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b838


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b839


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b840


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b841


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b842


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b843


embedded image


—CH(OH)—





Ib-b844


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b845


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b846


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b847


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b848


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b849


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b850


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b851


embedded image


—CH(OH)—





Ib-b852


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b853


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b854


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b855


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b856


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b857


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b858


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b859


embedded image


—CH(OH)—





Ib-b860


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b861


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b862


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b863


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b864


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b865


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b866


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b867


embedded image


—CH(OH)—





Ib-b868


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b869


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b870


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b871


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b872


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b873


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b874


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b875


embedded image


—CH(OH)—





Ib-b876


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b877


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b878


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b879


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b880


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b881


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b882


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b883


embedded image


—CH(OH)—





Ib-b884


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b885


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b886


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b887


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b888


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b889


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b890


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b891


embedded image


—CH(OH)—





Ib-b892


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b893


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b894


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b895


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b896


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b897


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b898


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b899


embedded image


—CH(OH)—





Ib-b900


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b901


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b902


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b903


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b904


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b905


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b906


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b907


embedded image


—CH(OH)—





Ib-b908


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b909


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b910


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b911


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b912


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b913


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b914


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b915


embedded image


—CH(OH)—





Ib-b916


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b917


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b918


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b919


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b920


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b921


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b922


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b923


embedded image


—CH(OH)—





Ib-b924


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b925


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b926


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b927


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b928


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b929


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b930


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b931


embedded image


—CH(OH)—





Ib-b932


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b933


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b934


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b935


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b936


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b937


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b938


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b939


embedded image


—CH(OH)—





Ib-b940


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b941


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b942


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b943


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b944


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b945


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b946


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b947


embedded image


—CH(OH)—





Ib-b948


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b949


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b950


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b951


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b952


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b953


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b954


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b955


embedded image


—CH(OH)—





Ib-b956


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b957


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b958


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b959


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b960


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b961


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b962


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b963
—CH2—N(CH2CH3)(CH3)
—CH(OH)—


Ib-b964
—CH2—N(CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—OH)—


Ib-b965
—CH2—N(CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—F)—


Ib-b966
—CH2—N(CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ib-b967
—CH2—N(CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b968
—CH2—N(CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b969
—CH2—N(CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CF3)—


Ib-b970
—CH2—N(CH2CH3)(CH3)
—N(C(O)N(H)—(CH2)3—OH)—


Ib-b971
—CH2—N(CH2CH2CH3)(CH3)
—CH(OH)—


Ib-b972
—CH2—N(CH2CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—OH)—


Ib-b973
—CH2—N(CH2CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—F)—


Ib-b974
—CH2—N(CH2CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ib-b975
—CH2—N(CH2CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b976
—CH2—N(CH2CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b977
—CH2—N(CH2CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CF3)—


Ib-b978
—CH2—N(CH2CH2CH3)(CH3)
—N(C(O)N(H)—(CH2)3—OH)—


Ib-b979
—CH2—N(CH2CH2CH2CH3)(CH3)
—CH(OH)—


Ib-b980
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—OH)—


Ib-b981
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—F)—


Ib-b982
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ib-b983
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b984
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b985
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CF3)—


Ib-b986
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(C(O)N(H)—(CH2)3—OH)—


Ib-b987
—CH2—NH—CH2CH2CH2CH3
—CH(OH)—


Ib-b988
—CH2—NH—CH2CH2CH2CH3
—N(C(O)N(H)—CH2—CH2—OH)—


Ib-b989
—CH2—NH—CH2CH2CH2CH3
—N(C(O)N(H)—CH2—CH2—F)—


Ib-b990
—CH2—NH—CH2CH2CH2CH3
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ib-b991
—CH2—NH—CH2CH2CH2CH3
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b992
—CH2—NH—CH2CH2CH2CH3
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b993
—CH2—NH—CH2CH2CH2CH3
—N(C(O)N(H)—CH2—CF3)—


Ib-b994
—CH2—NH—CH2CH2CH2CH3
—N(C(O)N(H)—(CH2)3—OH)—


Ib-b995
—CH2—NH—CH2CH2—O—CH3
—CH(OH)—


Ib-b996
—CH2—NH—CH2CH2—O—CH3
—N(C(O)N(H)—CH2—CH2—OH)—


Ib-b997
—CH2—NH—CH2CH2—O—CH3
—N(C(O)N(H)—CH2—CH2—F)—


Ib-b998
—CH2—NH—CH2CH2—O—CH3
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ib-b999
—CH2—NH—CH2CH2—O—CH3
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b1000
—CH2—NH—CH2CH2—O—CH3
—N(C(O)N(H)—CH2—CH2—CF3)—


Ib-b1001
—CH2—NH—CH2CH2—O—CH3
—N(C(O)N(H)—CH2—CF3)—


Ib-b1002
—CH2—NH—CH2CH2—O—CH3
—N(C(O)N(H)—(CH2)3—OH)—





Ib-b1003


embedded image


—CH(OH)—





Ib-b1004


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b1005


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b1006


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b1007


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b1008


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b1009


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b1010


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b1011


embedded image


—CH(OH)—





Ib-b1012


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b1013


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b1014


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b1015


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b1016


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b1017


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b1018


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b1019


embedded image


—CH(OH)—





Ib-b1020


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b1021


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b1022


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b1023


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b1024


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b1025


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b1026


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b1027


embedded image


—CH(OH)—





Ib-b1028


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b1029


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b1030


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b1031


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b1032


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b1033


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b1034


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b1035


embedded image


—CH(OH)—





Ib-b1036


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b1037


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b1038


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b1039


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b1040


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b1041


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b1042


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b1043


embedded image


—CH(OH)—





Ib-b1044


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b1045


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b1046


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b1047


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b1048


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b1049


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b1050


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ib-b1051


embedded image


—CH(OH)—





Ib-b1052


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ib-b1053


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ib-b1054


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ib-b1055


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b1056


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ib-b1057


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ib-b1058


embedded image


—N(C(O)N(H)—(CH2)3—OH)—









and pharmaceutically acceptable salts thereof.


5.4 The Indenoisoquinolinone Analogs of Formula (Ic)

The present invention provides Indenoisoquinolinone Analogs according to Formula (Ic), below:




embedded image



and pharmaceutically acceptable salts thereof,


wherein X and R1 are as defined above for the Indenoisoquinolinone Analogs of Formula (Ic).


In one embodiment, X is —N(CH3)—. In another embodiment, X is —N(CH2CH3)—. In another embodiment, X is —N(CH2CH2CH3)—. In another embodiment, X is —N(CH2 CH2CH2CH3)—. In another embodiment, X is —N(C(H)(CH3)(CH2CH3))—. In another embodiment, X is —N(C(H)(CH3)2)—. In another embodiment, X is —N(CH2C(H)(CH3)2)—. In another embodiment, X is —N(C(CH3)3)—.


In one embodiment, R1 is —(CH2)n—N(R2)(R2) and X is —N(CH3)—.


In another embodiment, R1 is —(CH2)n—N(R2)(R2) and X is —N(CH2CH3)—.


In another embodiment, R1 is —(CH2)n—N(R2)(R2) and X is —N(CH2CH2CH3)—.


In another embodiment, R1 is —(CH2)n—N(R2)(R2) and X is —N(CH2CH2CH2CH3)—.


In another embodiment, R1 is —(CH2)n—N(R2)(R2) and X is —N(C(H)(CH3)(CH2CH3))—.


In another embodiment, R1 is —(CH2)n—N(R2)(R2) and X is —N(C(H)(CH3)2)—.


In another embodiment, R1 is —(CH2)n—N(R2)(R2) and X is —N(CH2C(H)(CH3)2)—.


In another embodiment, R1 is —(CH2)n—N(R2)(R2) and X is —N(C(CH3)3)—.


In one embodiment, R1 is —O—(CH2)m—N(R2)(R2) and X is —N(CH3)—.


In another embodiment, R1 is —O—(CH2)m—N(R2)(R2) and X is —N(CH2CH3)—.


In another embodiment, R1 is —O—(CH2)m—N(R2)(R2) and X is —N(CH2CH2CH3)—.


In another embodiment, R1 is —O—(CH2)m—N(R2)(R2) and X is —N(CH2CH2CH2CH3)—.


In another embodiment, R1 is —O—(CH2)m—N(R2)(R2) and X is —N(C(H)(CH3)(CH2CH3))—.


In another embodiment, R1 is —O—(CH2)m—N(R2)(R2) and X is —N(C(H)(CH3)2)—.


In another embodiment, R1 is —O—(CH2)m—N(R2)(R2) and X is —N(CH2C(H)(CH3)2)—.


In another embodiment, R1 is —O—(CH2)m—N(R2)(R2) and X is —N(C(CH3)3)—.


In one embodiment, one R2 is —H, and the other R2 is —C1-C6 alkyl.


In another embodiment, each R2 is —C1-C6 alkyl.


In another embodiment, each R2 is -methyl.


In one embodiment, X is —CH(OH)—.


In another embodiment, X is —CH(OH)— and R1 is —(CH2)n—N(R2)(R2).


In yet another embodiment, X is —CH(OH)— and R1 is —(CH2)—N(R2)(R2).


In another embodiment, X is —N(C(O)N(H)—(CH2)p—Z)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)—Z)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)2—Z)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—Z)— and R1 is —(CH2)n—N(R2)(R2).


In yet another embodiment, X is —N(C(O)N(H)—(CH2)p—Z)— and R1 is —(CH2)—N(R2)(R2).


In still another embodiment, X is —N(C(O)N(H)—(CH2)—Z)— and R1 is —(CH2)—N(R2)(R2).


In one embodiment, X is —N((CH2)q—Z)—.


In another embodiment, X is —N((CH2)—Z)—.


In another embodiment, X is —N((CH2)2—Z)—.


In another embodiment, X is —N((CH2)q—Z)— and R1 is —(CH2)n—N(R2)(R2).


In yet another embodiment, X is —N((CH2)q—Z)— and R1 is —(CH2)—N(R2)(R2).


In still another embodiment, X is —N((CH2)—Z)— and R1 is —(CH2)—N(R2)(R2).


In one embodiment, Z is —CF3.


In another embodiment, Z is —F.


In yet another embodiment, Z is —OH.


In still another embodiment, Z is —O—CH3.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—OH)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)2—OH)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—OH)— and R1 is —(CH2)n—N(R2)(R2).


In yet another embodiment, X is —N(C(O)N(H)—(CH2)p—OH)— and R1 is —(CH2)—N(R2)(R2).


In still another embodiment, X is —N(C(O)N(H)—(CH2)2—OH)— and R1 is —(CH2)—N(R2)(R2).


In one embodiment, X is —N((CH2)q—OH)—.


In another embodiment, X is —N((CH2)2—OH)—.


In another embodiment, X is —N((CH2)q—OH)— and R1 is —(CH2)n—N(R2)(R2).


In yet another embodiment, X is —N((CH2)q—OH)— and R1 is —(CH2)—N(R2)(R2).


In still another embodiment, X is —N((CH2)2—OH)— and R1 is —(CH2)—N(R2)(R2).


In another embodiment, X is —N(C(O)N(H)—(CH2)p—F)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)—F)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—F)— and R1 is —(CH2)n—N(R2)(R2).


In yet another embodiment, X is —N(C(O)N(H)—(CH2)p—F)— and R1 is —(CH2)—N(R2)(R2).


In still another embodiment, X is —N(C(O)N(H)—(CH2)—F)— and R1 is —(CH2)—N(R2)(R2).


In one embodiment, X is —N((CH2)q—F)—.


In another embodiment, X is —N((CH2)—F)—.


In another embodiment, X is —N((CH2)q—F)— and R1 is —(CH2)n—N(R2)(R2).


In yet another embodiment, X is —N((CH2)q—F)— and R1 is —(CH2)—N(R2)(R2).


In still another embodiment, X is —N((CH2)—F)— and R1 is —(CH2)—N(R2)(R2).


In another embodiment, X is —N(C(O)N(H)—(CH2)p—OMe)-.


In another embodiment, X is —N(C(O)N(H)—(CH2)2—OMe)-.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—OMe)- and R1 is —(CH2)n—N(R2)(R2).


In yet another embodiment, X is —N(C(O)N(H)—(CH2)p—OMe)- and R1 is —(CH2)—N(R2)(R2).


In still another embodiment, X is —N(C(O)N(H)—(CH2)2—OMe)- and R1 is —(CH2)— N(R2)(R2).


In one embodiment, X is —N((CH2)q—OMe)-.


In another embodiment, X is —N((CH2)2—OMe)-.


In another embodiment, X is —N((CH2)q—OMe)- and R1 is —(CH2)n—N(R2)(R2).


In yet another embodiment, X is —N((CH2)q—OMe)- and R1 is —(CH2)—N(R2)(R2).


In still another embodiment, X is —N((CH2)2—OMe)- and R1 is —(CH2)—N(R2)(R2).


In another embodiment, X is —N(C(O)N(H)—(CH2)p—CF3)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)—CF3)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—CF3)— and R1 is —(CH2)n—N(R2)(R2).


In yet another embodiment, X is —N(C(O)N(H)—(CH2)p—CF3)— and R1 is —(CH2)—N(R2)(R2).


In still another embodiment, X is —N(C(O)N(H)—(CH2)—CF3)— and R1 is —(CH2)—N(R2)(R2).


In one embodiment, X is —N((CH2)q—CF3)—.


In another embodiment, X is —N((CH2)—CF3)—.


In another embodiment, X is —N((CH2)q—CF3)— and R1 is —(CH2)n—N(R2)(R2).


In yet another embodiment, X is —N((CH2)q—CF3)— and R1 is —(CH2)—N(R2)(R2).


In still another embodiment, X is —N((CH2)—CF3)— and R1 is —(CH2)—N(R2)(R2).


In another embodiment, X is —N(C(O)N(H)—(CH2)p—CF3)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)—CF3)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—CF3)— and R1 is —(CH2)n—N(R2)(R2).


In yet another embodiment, X is —N(C(O)N(H)—(CH2)p—CF3)— and R1 is —(CH2)—N(R2)(R2).


In still another embodiment, X is —N(C(O)N(H)—(CH2)—CF3)— and R1 is —(CH2)—N(R2)(R2).


In one embodiment, X is —N((CH2)q—CF3)—.


In another embodiment, X is —N((CH2)—CF3)—.


In another embodiment, X is —N((CH2)q—CF3)— and R1 is —(CH2)n—N(R2)(R2).


In yet another embodiment, X is —N((CH2)q—CF3)— and R1 is —(CH2)—N(R2)(R2).


In still another embodiment, X is —N((CH2)—CF3)— and R1 is —(CH2)—N(R2)(R2).


In one embodiment, n is 1.


In another embodiment, n is 2.


In yet another embodiment, n is 3.


In a further embodiment, n is 4, 5, or 6.


In yet a further embodiment, n is 7, 8, or 9.


In still a further embodiment, n is 10.


In one embodiment, m is 2.


In another embodiment, m is 3.


In yet another embodiment, m is 4, 5, or 6.


In a further embodiment, m is 7, 8, or 9.


In yet a further embodiment, m is 10.


In one embodiment, p is 1.


In another embodiment, p is 2.


In yet another embodiment, p is an integer ranging from 2 to 5.


In one embodiment, q is 1.


In another embodiment, q is 2.


In yet another embodiment, q is an integer ranging from 2 to 5.


In various embodiments, —N(R2)(R2) is:




embedded image


embedded image


embedded image


In other embodiments, —N(R2)(R2) is:




embedded image


embedded image


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In some embodiments, —N(R2)(R2) is




embedded image


In still other embodiments, —N(R2)(R2) is —N(CH2CH3)(CH3),


—N(CH2CH2CH3)(CH3),


—N(CH2CH2CH2CH3)(CH3),


—NH—CH2CH2CH2CH3, or


—NH—CH2CH2—O—CH3.


In some embodiments, —N(R2)(R2) is




embedded image


In various embodiments, —N(Z3)(Z4) is:




embedded image


embedded image


embedded image


In other embodiments, —N(Z3)(Z4) is:




embedded image


embedded image


embedded image


In some embodiments, —N(Z3)(Z4) is




embedded image


In still other embodiments, —N(Z3)(Z4) is

    • —N(CH2CH3)(CH3),
    • —N(CH2CH2CH3)(CH3),
    • —N(CH2CH2CH2CH3)(CH3),
    • —NH—CH2CH2CH2CH3, or
    • —NH—CH2CH2—O—CH3.


In some embodiments, —N(Z3)(Z4) is




embedded image


In one embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2 CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2— or —N(C(CH3)3)—;


R1 is —(CH2)n—N(R2)(R2) or —O—(CH2)m—N(R2)(R2);


each R2 is independently —H, —C1-C6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —(C1-C6 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)2OH or —N(Z3)(Z4), where Z3 and Z4 are independently —H, —C1-C5 alkyl, or —(C1-C5 alkylene)-O—C1-C5 alkyl, each of which other than hydrogen is unsubstituted or substituted with one or more of -halo, —OH or —NH2;


or N, Z3 and Z4 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three of —C1-C5 alkyl, -phenyl, —(C1-C5 alkylene)-phenyl, -(hydroxy-substituted) C1-C5 alkyl, -halo, -(halo-substituted) C1-C5 alkyl, -(halo-substituted) phenyl, -phenylene-O—C1-C5 alkyl, -(cyano-substituted) phenyl, —OH, —O—C1-C5 alkyl, —N(Ra)2, —(C1-C5 alkylene)-N(Ra)2, —C1-C5 alkylene-C(O)O—(C1-C5 alkylene)-N(Ra)2, —COOH, —(C1-C5 alkylene)-COOH, —OP(O)(OH)2, —OS(O)2OH, —(C1-C5 alkylene)-OP(O)(OH)2, —(C1-C5 alkylene)-OS(O)2OH, —C(O)O—C1-C5 alkyl, —OC(O)—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)O—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)NH—C1-C5 alkyl, —C(O)NH2, or —NO2, wherein each occurrence of Ra is independently —H, -benzyl, or —C1-C10 alkyl;


or N and both R2 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 —C1-C5 alkyl, -phenyl, —(C1-C5 alkylene)-phenyl, -(hydroxy-substituted) C1-C5 alkyl, -halo, -(halo-substituted) C1-C5 alkyl, -(halo-substituted) phenyl, -phenylene-O—C1-C5 alkyl, -(cyano-substituted) phenyl, —OH, —O—C1-C5 alkyl, —N(Ra)2, —(C1-C5 alkylene)-N(Ra)2, —(C1-C5 alkylene)-C(O)O—(C1-C5 alkylene)-N(Ra)2, —COOH, —(C1-C5 alkylene)-COOH, —OP(O)(OH)2, —OS(O)2OH, —(C1-C5 alkylene)-OP(O)(OH)2, —(C1-C5 alkylene)-OS(O)2OH, —C(O)O—C1-C5 alkyl, —OC(O)—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)O—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)NH—C1-C5 alkyl, —C(O)NH2, or —NO2, wherein each occurrence of Ra is independently —H, -benzyl, or —C1-C10 alkyl;


n is an integer ranging from 1 to 10; and


m is an integer ranging from 2 to 10.


In one embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2 CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2— or —N(C(CH3)3)—; R1 is —CH2—N(R2)(R2); and at least one R2 is methyl.


In another embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2 CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2— or —N(C(CH3)3)—; R1 is —CH2—N(R2)(R2); and at least one R2 is ethyl.


In yet another embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2— or —N(C(CH3)3)—; R1 is —CH2—N(R2)(R2); and at least one R2 is propyl.


In one embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2 CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2— or —N(C(CH3)3)—; R1 is —CH2—N(R2)(R2); and at least one R2 is —C3-C8 monocyclic cycloalkyl.


In another embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2 CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2— or —N(C(CH3)3)—; R1 is —CH2—N(R2)(R2); and at least one R2 is cyclohexyl.


In yet another embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2— or —N(C(CH3)3)—; and R1 is —CH2—N(R2)(R2), wherein N and both R2 groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle.


In one embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2 CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2— or —N(C(CH3)3)—; and R1 is —CH2—N(R2)(R2), wherein N and both R2 groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which is substituted with a hydroxyl.


In another embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2 CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2— or —N(C(CH3)3)—; and R1 is —CH2—N(R2)(R2), wherein N and both R2 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.


Illustrative examples of the Indenoisoquinolinone Analogs include the compounds of Formula (Ic) as set forth below:
















(Ic)




embedded image
















Compound
n
—R1
X





Ic-1
1
—(CH2)n—N(CH3)2
—N(CH3)—


Ic-2
2
—(CH2)n—N(CH3)2
—N(CH3)—


Ic-3
3
—(CH2)n—N(CH3)2
—N(CH3)—


Ic-4
4
—(CH2)n—N(CH3)2
—N(CH3)—


Ic-5
5
—(CH2)n—N(CH3)2
—N(CH3)—


Ic-6
6
—(CH2)n—N(CH3)2
—N(CH3)—


Ic-7
1
—(CH2)n—N(CH3)2
—N(CH2CH3)—


Ic-8
2
—(CH2)n—N(CH3)2
—N(CH2CH3)—


Ic-9
3
—(CH2)n—N(CH3)2
—N(CH2CH3)—


Ic-10
4
—(CH2)n—N(CH3)2
—N(CH2CH3)—


Ic-11
5
—(CH2)n—N(CH3)2
—N(CH2CH3)—


Ic-12
6
—(CH2)n—N(CH3)2
—N(CH2CH3)—


Ic-13
1
—(CH2)n—N(CH3)2
—N(CH2CH2CH3)—


Ic-14
2
—(CH2)n—N(CH3)2
—N(CH2CH2CH3)—


Ic-15
3
—(CH2)n—N(CH3)2
—N(CH2CH2CH3)—


Ic-16
4
—(CH2)n—N(CH3)2
—N(CH2CH2CH3)—


Ic-17
5
—(CH2)n—N(CH3)2
—N(CH2CH2CH3)—


Ic-18
6
—(CH2)n—N(CH3)2
—N(CH2CH2CH3)—


Ic-19
1
—(CH2)n—N(CH3)2
—N(CH2CH2CH2CH3)—


Ic-20
2
—(CH2)n—N(CH3)2
—N(CH2CH2CH2CH3)—


Ic-21
3
—(CH2)n—N(CH3)2
—N(CH2CH2CH2CH3)—


Ic-22
4
—(CH2)n—N(CH3)2
—N(CH2CH2CH2CH3)—


Ic-23
5
—(CH2)n—N(CH3)2
—N(CH2CH2CH2CH3)—


Ic-24
6
—(CH2)n—N(CH3)2
—N(CH2CH2CH2CH3)—


Ic-25
1
—(CH2)n—N(CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ic-26
2
—(CH2)n—N(CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ic-27
3
—(CH2)n—N(CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ic-28
4
—(CH2)n—N(CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ic-29
5
—(CH2)n—N(CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ic-30
6
—(CH2)n—N(CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ic-31
1
—(CH2)n—N(CH3)2
—N(C(H)(CH3)2)—


Ic-32
2
—(CH2)n—N(CH3)2
—N(C(H)(CH3)2)—


Ic-33
3
—(CH2)n—N(CH3)2
—N(C(H)(CH3)2)—


Ic-34
4
—(CH2)n—N(CH3)2
—N(C(H)(CH3)2)—


Ic-35
5
—(CH2)n—N(CH3)2
—N(C(H)(CH3)2)—


Ic-36
6
—(CH2)n—N(CH3)2
—N(C(H)(CH3)2)—


Ic-37
1
—(CH2)n—N(CH3)2
—N(CH2C(H)(CH3)2)—


Ic-38
2
—(CH2)n—N(CH3)2
—N(CH2C(H)(CH3)2)—


Ic-39
3
—(CH2)n—N(CH3)2
—N(CH2C(H)(CH3)2)—


Ic-40
4
—(CH2)n—N(CH3)2
—N(CH2C(H)(CH3)2)—


Ic-41
5
—(CH2)n—N(CH3)2
—N(CH2C(H)(CH3)2)—


Ic-42
6
—(CH2)n—N(CH3)2
—N(CH2C(H)(CH3)2)—


Ic-43
1
—(CH2)n—N(CH3)2
—N(C(CH3)3)—


Ic-44
2
—(CH2)n—N(CH3)2
—N(C(CH3)3)—


Ic-45
3
—(CH2)n—N(CH3)2
—N(C(CH3)3)—


Ic-46
4
—(CH2)n—N(CH3)2
—N(C(CH3)3)—


Ic-47
5
—(CH2)n—N(CH3)2
—N(C(CH3)3)—


Ic-48
6
—(CH2)n—N(CH3)2
—N(C(CH3)3)—





Ic-49
1


embedded image


—N(CH3)—





Ic-50
2


embedded image


—N(CH3)—





Ic-51
3


embedded image


—N(CH3)—





Ic-52
4


embedded image


—N(CH3)—





Ic-53
5


embedded image


—N(CH3)—





Ic-54
6


embedded image


—N(CH3)—





Ic-55
1


embedded image


—N(CH2CH3)—





Ic-56
2


embedded image


—N(CH2CH3)—





Ic-57
3


embedded image


—N(CH2CH3)—





Ic-58
4


embedded image


—N(CH2CH3)—





Ic-59
5


embedded image


—N(CH2CH3)—





Ic-60
6


embedded image


—N(CH2CH3)—





Ic-61
1


embedded image


—N(CH2CH2CH3)—





Ic-62
2


embedded image


—N(CH2CH2CH3)—





Ic-63
3


embedded image


—N(CH2CH2CH3)—





Ic-64
4


embedded image


—N(CH2CH2CH3)—





Ic-65
5


embedded image


—N(CH2CH2CH3)—





Ic-66
6


embedded image


—N(CH2CH2CH3)—





Ic-67
1


embedded image


—N(CH2CH2CH2CH3)—





Ic-68
2


embedded image


—N(CH2CH2CH2CH3)—





Ic-69
3


embedded image


—N(CH2CH2CH2CH3)—





Ic-70
4


embedded image


—N(CH2CH2CH2CH3)—





Ic-71
5


embedded image


—N(CH2CH2CH2CH3)—





Ic-72
6


embedded image


—N(CH2CH2CH2CH3)—





Ic-73
1


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-74
2


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-75
3


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-76
4


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-77
5


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-78
6


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-79
1


embedded image


—N(C(H)(CH3)2)—





Ic-80
2


embedded image


—N(C(H)(CH3)2)—





Ic-81
3


embedded image


—N(C(H)(CH3)2)—





Ic-82
4


embedded image


—N(C(H)(CH3)2)—





Ic-83
5


embedded image


—N(C(H)(CH3)2)—





Ic-84
6


embedded image


—N(C(H)(CH3)2)—





Ic-85
1


embedded image


—N(CH2C(H)(CH3)2)—





Ic-86
2


embedded image


—N(CH2C(H)(CH3)2)—





Ic-87
3


embedded image


—N(CH2C(H)(CH3)2)—





Ic-88
4


embedded image


—N(CH2C(H)(CH3)2)—





Ic-89
5


embedded image


—N(CH2C(H)(CH3)2)—





Ic-90
6


embedded image


—N(CH2C(H)(CH3)2)—





Ic-91
1


embedded image


—N(C(CH3)3)—





Ic-92
2


embedded image


—N(C(CH3)3)—





Ic-93
3


embedded image


—N(C(CH3)3)—





Ic-94
4


embedded image


—N(C(CH3)3)—





Ic-95
5


embedded image


—N(C(CH3)3)—





Ic-96
6


embedded image


—N(C(CH3)3)—





Compound
m
—R1
X





Ic-146
2
—O—(CH2)m—N(CH3)2
—N(CH3)—


Ic-147
3
—O—(CH2)m—N(CH3)2
—N(CH3)—


Ic-148
4
—O—(CH2)m—N(CH3)2
—N(CH3)—


Ic-149
5
—O—(CH2)m—N(CH3)2
—N(CH3)—


Ic-150
6
—O—(CH2)m—N(CH3)2
—N(CH3)—


Ic-151
2
—O—(CH2)m—N(CH3)2
—N(CH3)—


Ic-152
3
—O—(CH2)m—N(CH3)2
—N(CH2CH3)—


Ic-153
4
—O—(CH2)m—N(CH3)2
—N(CH2CH3)—


Ic-154
5
—O—(CH2)m—N(CH3)2
—N(CH2CH3)—


Ic-155
6
—O—(CH2)m—N(CH3)2
—N(CH2CH3)—


Ic-156
2
—O—(CH2)m—N(CH3)2
—N(CH2CH3)—


Ic-157
3
—O—(CH2)m—N(CH3)2
—N(CH2CH3)—


Ic-158
4
—O—(CH2)m—N(CH3)2
—N(CH2CH2CH3)—


Ic-159
5
—O—(CH2)m—N(CH3)2
—N(CH2CH2CH3)—


Ic-160
6
—O—(CH2)m—N(CH3)2
—N(CH2CH2CH3)—


Ic-161
2
—O—(CH2)m—N(CH3)2
—N(CH2CH2CH3)—


Ic-162
3
—O—(CH2)m—N(CH3)2
—N(CH2CH2CH3)—


Ic-163
4
—O—(CH2)m—N(CH3)2
—N(CH2CH2CH3)—


Ic-164
5
—O—(CH2)m—N(CH3)2
—N(CH2CH2CH2CH3)—


Ic-165
6
—O—(CH2)m—N(CH3)2
—N(CH2CH2CH2CH3)—


Ic-166
2
—O—(CH2)m—N(CH3)2
—N(CH2CH2CH2CH3)—


Ic-167
3
—O—(CH2)m—N(CH3)2
—N(CH2CH2CH2CH3)—


Ic-168
4
—O—(CH2)m—N(CH3)2
—N(CH2CH2CH2CH3)—


Ic-169
5
—O—(CH2)m—N(CH3)2
—N(CH2CH2CH2CH3)—


Ic-170
6
—O—(CH2)m—N(CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ic-171
2
—O—(CH2)m—N(CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ic-172
3
—O—(CH2)m—N(CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ic-173
4
—O—(CH2)m—N(CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ic-174
5
—O—(CH2)m—N(CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ic-175
6
—O—(CH2)m—N(CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ic-176
2
—O—(CH2)m—N(CH3)2
—N(C(H)(CH3)2)—


Ic-178
3
—O—(CH2)m—N(CH3)2
—N(C(H)(CH3)2)—


Ic-179
4
—O—(CH2)m—N(CH3)2
—N(C(H)(CH3)2)—


Ic-180
5
—O—(CH2)m—N(CH3)2
—N(C(H)(CH3)2)—


Ic-181
6
—O—(CH2)m—N(CH3)2
—N(C(H)(CH3)2)—


Ic-182
2
—O—(CH2)m—N(CH3)2
—N(C(H)(CH3)2)—


Ic-183
3
—O—(CH2)m—N(CH3)2
—N(CH2C(H)(CH3)2)—


Ic-184
4
—O—(CH2)m—N(CH3)2
—N(CH2C(H)(CH3)2)—


Ic-185
5
—O—(CH2)m—N(CH3)2
—N(CH2C(H)(CH3)2)—


Ic-186
6
—O—(CH2)m—N(CH3)2
—N(CH2C(H)(CH3)2)—





Ic-187
2


embedded image


—N(CH3)—





Ic-188
3


embedded image


—N(CH3)—





Ic-189
4


embedded image


—N(CH3)—





Ic-190
5


embedded image


—N(CH3)—





Ic-191
6


embedded image


—N(CH3)—





Ic-192
2


embedded image


—N(CH3)—





Ic-193
3


embedded image


—N(CH2CH3)—





Ic-194
4


embedded image


—N(CH2CH3)—





Ic-195
5


embedded image


—N(CH2CH3)—





Ic-196
6


embedded image


—N(CH2CH3)—





Ic-197
2


embedded image


—N(CH2CH3)—





Ic-198
3


embedded image


—N(CH2CH3)—





Ic-199
4


embedded image


—N(CH2CH2CH3)—





Ic-200
5


embedded image


—N(CH2CH2CH3)—





Ic-201
6


embedded image


—N(CH2CH2CH3)—





Ic-202
2


embedded image


—N(CH2CH2CH3)—





Ic-203
3


embedded image


—N(CH2CH2CH3)—





Ic-204
4


embedded image


—N(CH2CH2CH3)—





Ic-205
5


embedded image


—N(CH2CH2CH2CH3)—





Ic-206
6


embedded image


—N(CH2CH2CH2CH3)—





Ic-207
2


embedded image


—N(CH2CH2CH2CH3)—





Ic-208
3


embedded image


—N(CH2CH2CH2CH3)—





Ic-209
4


embedded image


—N(CH2CH2CH2CH3)—





Ic-210
5


embedded image


—N(CH2CH2CH2CH3)—





Ic-211
6


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-212
2


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-213
3


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-214
4


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-215
5


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-216
6


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-217
2


embedded image


—N(C(H)(CH3)2)—





Ic-218
3


embedded image


—N(C(H)(CH3)2)—





Ic-219
4


embedded image


—N(C(H)(CH3)2)—





Ic-220
5


embedded image


—N(C(H)(CH3)2)—





Ic-221
6


embedded image


—N(C(H)(CH3)2)—





Ic-222
2


embedded image


—N(C(H)(CH3)2)—





Ic-223
3


embedded image


—N(CH2C(H)(CH3)2)—





Ic-224
4


embedded image


—N(CH2C(H)(CH3)2)—





Ic-225
5


embedded image


—N(CH2C(H)(CH3)2)—





Ic-226
6


embedded image


—N(CH2C(H)(CH3)2)—












Compound
—R1
X





Ic-267
—CH2—N(CH2—CH3)2
—N(CH3)—


Ic-268
—CH2—N(CH2—CH3)2
—N(CH2CH3)—


Ic-269
—CH2—N(CH2—CH3)2
—N(CH2CH2CH3)—


Ic-270
—CH2—N(CH2—CH3)2
—N(CH2CH2CH2CH3)—


Ic-271
—CH2—N(CH2—CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ic-272
—CH2—N(CH2—CH3)2
—N(C(H)(CH3)2)—


Ic-273
—CH2—N(CH2—CH3)2
—N(CH2C(H)(CH3)2)—


Ic-274
—CH2—N(CH2—CH3)2
—N(C(CH3)3)—


Ic-275
—CH2—N(CH2—CH2—CH3)2
—N(CH3)—


Ic-276
—CH2—N(CH2—CH2—CH3)2
—N(CH2CH3)—


Ic-277
—CH2—N(CH2—CH2—CH3)2
—N(CH2CH2CH3)—


Ic-278
—CH2—N(CH2—CH2—CH3)2
—N(CH2CH2CH2CH3)—


Ic-279
—CH2—N(CH2—CH2—CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ic-280
—CH2—N(CH2—CH2—CH3)2
—N(C(H)(CH3)2)—


Ic-281
—CH2—N(CH2—CH2—CH3)2
—N(CH2C(H)(CH3)2)—


Ic-282
—CH2—N(CH2—CH2—CH3)2
—N(C(CH3)3)—


Ic-283
—CH2—N(CH2—CH2OH)2
—N(CH3)—


Ic-284
—CH2—N(CH2—CH2OH)2
—N(CH2CH3)—


Ic-285
—CH2—N(CH2—CH2OH)2
—N(CH2CH2CH3)—


Ic-286
—CH2—N(CH2—CH2OH)2
—N(CH2CH2CH2CH3)—


Ic-287
—CH2—N(CH2—CH2OH)2
—N(C(H)(CH3)(CH2CH3))—


Ic-288
—CH2—N(CH2—CH2OH)2
—N(C(H)(CH3)2)—


Ic-289
—CH2—N(CH2—CH2OH)2
—N(CH2C(H)(CH3)2)—


Ic-290
—CH2—N(CH2—CH2OH)2
—N(C(CH3)3)—


Ic-291
—CH2—N(CH2—CH2—N(CH3)2)2
—N(CH3)—


Ic-292
—CH2—N(CH2—CH2—N(CH3)2)2
—N(CH2CH3)—


Ic-293
—CH2—N(CH2—CH2—N(CH3)2)2
—N(CH2CH2CH3)—


Ic-294
—CH2—N(CH2—CH2—N(CH3)2)2
—N(CH2CH2CH2CH3)—


Ic-295
—CH2—N(CH2—CH2—N(CH3)2)2
—N(C(H)(CH3)(CH2CH3))—


Ic-296
—CH2—N(CH2—CH2—N(CH3)2)2
—N(C(H)(CH3)2)—


Ic-297
—CH2—N(CH2—CH2—N(CH3)2)2
—N(CH2C(H)(CH3)2)—


Ic-298
—CH2—N(CH2—CH2—N(CH3)2)2
—N(C(CH3)3)—


Ic-299
—CH2—N(CH2—CH2—CH2—N(CH3)2)2
—N(CH3)—


Ic-300
—CH2—N(CH2—CH2—CH2—N(CH3)2)2
—N(CH2CH3)—


Ic-301
—CH2—N(CH2—CH2—CH2—N(CH3)2)2
—N(CH2CH2CH3)—


Ic-302
—CH2—N(CH2—CH2—CH2—N(CH3)2)2
—N(CH2CH2CH2CH3)—


Ic-303
—CH2—N(CH2—CH2—CH2—N(CH3)2)2
—N(C(H)(CH3)(CH2CH3))—


Ic-304
—CH2—N(CH2—CH2—CH2—N(CH3)2)2
—N(C(H)(CH3)2)—


Ic-305
—CH2—N(CH2—CH2—CH2—N(CH3)2)2
—N(CH2C(H)(CH3)2)—


Ic-306
—CH2—N(CH2—CH2—CH2—N(CH3)2)2
—N(C(CH3)3)—





Ic-307


embedded image


—N(CH3)—





Ic-308


embedded image


—N(CH2CH3)—





Ic-309


embedded image


—N(CH2CH2CH3)—





Ic-310


embedded image


—N(CH2CH2CH2CH3)—





Ic-311


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-312


embedded image


—N(C(H)(CH3)2)—





Ic-313


embedded image


—N(CH2C(H)(CH3)2)—





Ic-314


embedded image


—N(C(CH3)3)—





Ic-315


embedded image


—N(CH3)—





Ic-316


embedded image


—N(CH2CH3)—





Ic-317


embedded image


—N(CH2CH2CH3)—





Ic-318


embedded image


—N(CH2CH2CH2CH3)—





Ic-319


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-320


embedded image


—N(C(H)(CH3)2)—





Ic-321


embedded image


—N(CH2C(H)(CH3)2)—





Ic-322


embedded image


—N(C(CH3)3)—





Ic-323


embedded image


—N(CH3)—





Ic-324


embedded image


—N(CH2CH3)—





Ic-325


embedded image


—N(CH2CH2CH3)—





Ic-326


embedded image


—N(CH2CH2CH2CH3)—





Ic-327


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-328


embedded image


—N(C(H)(CH3)2)—





Ic-329


embedded image


—N(CH2C(H)(CH3)2)—





Ic-330


embedded image


—N(C(CH3)3)—





Ic-331


embedded image


—N(CH3)—





Ic-332


embedded image


—N(CH2CH3)—





Ic-333


embedded image


—N(CH2CH2CH3)—





Ic-334


embedded image


—N(CH2CH2CH2CH3)—





Ic-335


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-336


embedded image


—N(C(H)(CH3)2)—





Ic-337


embedded image


—N(CH2C(H)(CH3)2)—





Ic-338


embedded image


—N(C(CH3)3)—





Ic-339


embedded image


—N(CH3)—





Ic-340


embedded image


—N(CH2CH3)—





Ic-341


embedded image


—N(CH2CH2CH3)—





Ic-342


embedded image


—N(CH2CH2CH2CH3)—





Ic-343


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-344


embedded image


—N(C(H)(CH3)2)—





Ic-345


embedded image


—N(CH2C(H)(CH3)2)—





Ic-346


embedded image


—N(C(CH3)3)—





Ic-347


embedded image


—N(CH3)—





Ic-348


embedded image


—N(CH2CH3)—





Ic-349


embedded image


—N(CH2CH2CH3)—





Ic-350


embedded image


—N(CH2CH2CH2CH3)—





Ic-351


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-352


embedded image


—N(C(H)(CH3)2)—





Ic-353


embedded image


—N(CH2C(H)(CH3)2)—





Ic-354


embedded image


—N(C(CH3)3)—





Ic-355


embedded image


—N(CH3)—





Ic-356


embedded image


—N(CH2CH3)—





Ic-357


embedded image


—N(CH2CH2CH3)—





Ic-358


embedded image


—N(CH2CH2CH2CH3)—





Ic-359


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-360


embedded image


—N(C(H)(CH3)2)—





Ic-361


embedded image


—N(CH2C(H)(CH3)2)—





Ic-362


embedded image


—N(C(CH3)3)—





Ic-363


embedded image


—N(CH3)—





Ic-364


embedded image


—N(CH2CH3)—





Ic-365


embedded image


—N(CH2CH2CH3)—





Ic-366


embedded image


—N(CH2CH2CH2CH3)—





Ic-367


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-368


embedded image


—N(C(H)(CH3)2)—





Ic-369


embedded image


—N(CH2C(H)(CH3)2)—





Ic-370


embedded image


—N(C(CH3)3)—





Ic-371


embedded image


—N(CH3)—





Ic-372


embedded image


—N(CH2CH3)—





Ic-373


embedded image


—N(CH2CH2CH3)—





Ic-374


embedded image


—N(CH2CH2CH2CH3)—





Ic-375


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-376


embedded image


—N(C(H)(CH3)2)—





Ic-377


embedded image


—N(CH2C(H)(CH3)2)—





Ic-378


embedded image


—N(C(CH3)3)—





Ic-379


embedded image


—N(CH3)—





Ic-380


embedded image


—N(CH2CH3)—





Ic-381


embedded image


—N(CH2CH2CH3)—





Ic-382


embedded image


—N(CH2CH2CH2CH3)—





Ic-383


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-384


embedded image


—N(C(H)(CH3)2)—





Ic-385


embedded image


—N(CH2C(H)(CH3)2)—





Ic-386


embedded image


—N(C(CH3)3)—





Ic-387


embedded image


—N(CH3)—





Ic-388


embedded image


—N(CH2CH3)—





Ic-389


embedded image


—N(CH2CH2CH3)—





Ic-390


embedded image


—N(CH2CH2CH2CH3)—





Ic-391


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-392


embedded image


—N(C(H)(CH3)2)—





Ic-393


embedded image


—N(CH2C(H)(CH3)2)—





Ic-394


embedded image


—N(C(CH3)3)—





Ic-395


embedded image


—N(CH3)—





Ic-396


embedded image


—N(CH2CH3)—





Ic-397


embedded image


—N(CH2CH2CH3)—





Ic-398


embedded image


—N(CH2CH2CH2CH3)—





Ic-399


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-400


embedded image


—N(C(H)(CH3)2)—





Ic-401


embedded image


—N(CH2C(H)(CH3)2)—





Ic-402


embedded image


—N(C(CH3)3)—





Ic-403


embedded image


—N(CH3)—





Ic-404


embedded image


—N(CH2CH3)—





Ic-405


embedded image


—N(CH2CH2CH3)—





Ic-406


embedded image


—N(CH2CH2CH2CH3)—





Ic-407


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-408


embedded image


—N(C(H)(CH3)2)—





Ic-409


embedded image


—N(CH2C(H)(CH3)2)—





Ic-410


embedded image


—N(C(CH3)3)—





Ic-411


embedded image


—N(CH3)—





Ic-412


embedded image


—N(CH2CH3)—





Ic-413


embedded image


—N(CH2CH2CH3)—





Ic-414


embedded image


—N(CH2CH2CH2CH3)—





Ic-415


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-416


embedded image


—N(C(H)(CH3)2)—





Ic-417


embedded image


—N(CH2C(H)(CH3)2)—





Ic-418


embedded image


—N(C(CH3)3)—





Ic-419


embedded image


—N(CH3)—





Ic-420


embedded image


—N(CH2CH3)—





Ic-421


embedded image


—N(CH2CH2CH3)—





Ic-422


embedded image


—N(CH2CH2CH2CH3)—





Ic-423


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-424


embedded image


—N(C(H)(CH3)2)—





Ic-425


embedded image


—N(CH2C(H)(CH3)2)—





Ic-426


embedded image


—N(C(CH3)3)—





Ic-427


embedded image


—N(CH3)—





Ic-428


embedded image


—N(CH2CH3)—





Ic-429


embedded image


—N(CH2CH2CH3)—





Ic-430


embedded image


—N(CH2CH2CH2CH3)—





Ic-431


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-432


embedded image


—N(C(H)(CH3)2)—





Ic-433


embedded image


—N(CH2C(H)(CH3)2)—





Ic-434


embedded image


—N(C(CH3)3)—





Ic-435


embedded image


—N(CH3)—





Ic-436


embedded image


—N(CH2CH3)—





Ic-437


embedded image


—N(CH2CH2CH3)—





Ic-438


embedded image


—N(CH2CH2CH2CH3)—





Ic-439


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-440


embedded image


—N(C(H)(CH3)2)—





Ic-441


embedded image


—N(CH2C(H)(CH3)2)—





Ic-442


embedded image


—N(C(CH3)3)—





Ic-443


embedded image


—N(CH3)—





Ic-444


embedded image


—N(CH2CH3)—





Ic-445


embedded image


—N(CH2CH2CH3)—





Ic-446


embedded image


—N(CH2CH2CH2CH3)—





Ic-447


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-448


embedded image


—N(C(H)(CH3)2)—





Ic-449


embedded image


—N(CH2C(H)(CH3)2)—





Ic-450


embedded image


—N(C(CH3)3)—





Ic-451


embedded image


—N(CH3)—





Ic-452


embedded image


—N(CH2CH3)—





Ic-453


embedded image


—N(CH2CH2CH3)—





Ic-454


embedded image


—N(CH2CH2CH2CH3)—





Ic-455


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-456


embedded image


—N(C(H)(CH3)2)—





Ic-457


embedded image


—N(CH2C(H)(CH3)2)—





Ic-458


embedded image


—N(C(CH3)3)—





Ic-459


embedded image


—N(CH3)—





Ic-460


embedded image


—N(CH2CH3)—





Ic-461


embedded image


—N(CH2CH2CH3)—





Ic-462


embedded image


—N(CH2CH2CH2CH3)—





Ic-463


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-464


embedded image


—N(C(H)(CH3)2)—





Ic-465


embedded image


—N(CH2C(H)(CH3)2)—





Ic-466


embedded image


—N(C(CH3)3)—





Ic-467


embedded image


—N(CH3)—





Ic-468


embedded image


—N(CH2CH3)—





Ic-469


embedded image


—N(CH2CH2CH3)—





Ic-470


embedded image


—N(CH2CH2CH2CH3)—





Ic-471


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-472


embedded image


—N(C(H)(CH3)2)—





Ic-473


embedded image


—N(CH2C(H)(CH3)2)—





Ic-474


embedded image


—N(C(CH3)3)—





Ic-475


embedded image


—N(CH3)—





Ic-476


embedded image


—N(CH2CH3)—





Ic-477


embedded image


—N(CH2CH2CH3)—





Ic-478


embedded image


—N(CH2CH2CH2CH3)—





Ic-479


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-480


embedded image


—N(C(H)(CH3)2)—





Ic-481


embedded image


—N(CH2C(H)(CH3)2)—





Ic-482


embedded image


—N(C(CH3)3)—





Ic-483


embedded image


—N(CH3)—





Ic-484


embedded image


—N(CH2CH3)—





Ic-485


embedded image


—N(CH2CH2CH3)—





Ic-486


embedded image


—N(CH2CH2CH2CH3)—





Ic-487


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-488


embedded image


—N(C(H)(CH3)2)—





Ic-489


embedded image


—N(CH2C(H)(CH3)2)—





Ic-490


embedded image


—N(C(CH3)3)—





Ic-491
—CH2—CH2—CH2—OP(O)(OH)2
—N(CH3)—


Ic-492
—CH2—CH2—CH2—OP(O)(OH)2
—N(CH2CH3)—


Ic-493
—CH2—CH2—CH2—OP(O)(OH)2
—N(CH2CH2CH3)—


Ic-494
—CH2—CH2—CH2—OP(O)(OH)2
—N(CH2CH2CH2CH3)—


Ic-495
—CH2—CH2—CH2—OP(O)(OH)2
—N(C(H)(CH3)(CH2CH3))—


Ic-496
—CH2—CH2—CH2—OP(O)(OH)2
—N(C(H)(CH3)2)—


Ic-497
—CH2—CH2—CH2—OP(O)(OH)2
—N(CH2C(H)(CH3)2)—


Ic-498
—CH2—CH2—CH2—OP(O)(OH)2
—N(C(CH3)3)—


Ic-499
—CH2—CH2—CH2—OS(O)2OH
—N(CH3)—


Ic-500
—CH2—CH2—CH2—OS(O)2OH
—N(CH2CH3)—


Ic-501
—CH2—CH2—CH2—OS(O)2OH
—N(CH2CH2CH3)—


Ic-502
—CH2—CH2—CH2—OS(O)2OH
—N(CH2CH2CH2CH3)—


Ic-503
—CH2—CH2—CH2—OS(O)2OH
—N(C(H)(CH3)(CH2CH3))—


Ic-504
—CH2—CH2—CH2—OS(O)2OH
—N(C(H)(CH3)2)—


Ic-505
—CH2—CH2—CH2—OS(O)2OH
—N(CH2C(H)(CH3)2)—


Ic-506
—CH2—CH2—CH2—OS(O)2OH
—N(C(CH3)3)—





Ic-507


embedded image


—N(CH3)—





Ic-508


embedded image


—N(CH2CH3)—





Ic-509


embedded image


—N(CH2CH2CH3)—





Ic-510


embedded image


—N(CH2CH2CH2CH3)—





Ic-511


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-512


embedded image


—N(C(H)(CH3)2)—





Ic-513


embedded image


—N(CH2C(H)(CH3)2)—





Ic-514


embedded image


—N(C(CH3)3)—





Ic-515


embedded image


—N(CH3)—





Ic-516


embedded image


—N(CH2CH3)—





Ic-517


embedded image


—N(CH2CH2CH3)—





Ic-518


embedded image


—N(CH2CH2CH2CH3)—





Ic-519


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-520


embedded image


—N(C(H)(CH3)2)—





Ic-521


embedded image


—N(CH2C(H)(CH3)2)—





Ic-522


embedded image


—N(C(CH3)3)—





Ic-523
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(CH3)—


Ic-524
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(CH2CH3)—


Ic-525
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(CH2CH2CH3)—


Ic-526
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(CH2CH2CH2CH3)—


Ic-527
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ic-528
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(C(H)(CH3)2)—


Ic-529
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(CH2C(H)(CH3)2)—


Ic-530
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(C(CH3)3)—


Ic-531
—CH2—N(CH2—CH2—O—CH3)2
—N(CH3)—


Ic-532
—CH2—N(CH2—CH2—O—CH3)2
—N(CH2CH3)—


Ic-533
—CH2—N(CH2—CH2—O—CH3)2
—N(CH2CH2CH3)—


Ic-534
—CH2—N(CH2—CH2—O—CH3)2
—N(CH2CH2CH2CH3)—


Ic-535
—CH2—N(CH2—CH2—O—CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ic-536
—CH2—N(CH2—CH2—O—CH3)2
—N(C(H)(CH3)2)—


Ic-537
—CH2—N(CH2—CH2—O—CH3)2
—N(CH2C(H)(CH3)2)—


Ic-538
—CH2—N(CH2—CH2—O—CH3)2
—N(C(CH3)3)—





Ic-539


embedded image


—N(CH3)—





Ic-540


embedded image


—N(CH2CH3)—





Ic-541


embedded image


—N(CH2CH2CH3)—





Ic-542


embedded image


—N(CH2CH2CH2CH3)—





Ic-543


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-544


embedded image


—N(C(H)(CH3)2)—





Ic-545


embedded image


—N(CH2C(H)(CH3)2)—





Ic-546


embedded image


—N(C(CH3)3)—





Ic-547


embedded image


—N(CH3)—





Ic-548


embedded image


—N(CH2CH3)—





Ic-549


embedded image


—N(CH2CH2CH3)—





Ic-550


embedded image


—N(CH2CH2CH2CH3)—





Ic-551


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-552


embedded image


—N(C(H)(CH3)2)—





Ic-553


embedded image


—N(CH2C(H)(CH3)2)—





Ic-554


embedded image


—N(C(CH3)3)—





Ic-555


embedded image


—N(CH3)—





Ic-556


embedded image


—N(CH2CH3)—





Ic-557


embedded image


—N(CH2CH2CH3)—





Ic-558


embedded image


—N(CH2CH2CH2CH3)—





Ic-559


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-560


embedded image


—N(C(H)(CH3)2)—





Ic-561


embedded image


—N(CH2C(H)(CH3)2)—





Ic-562


embedded image


—N(C(CH3)3)—





Ic-563


embedded image


—N(CH3)—





Ic-564


embedded image


—N(CH2CH3)—





Ic-565


embedded image


—N(CH2CH2CH3)—





Ic-566


embedded image


—N(CH2CH2CH2CH3)—





Ic-567


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-568


embedded image


—N(C(H)(CH3)2)—





Ic-569


embedded image


—N(CH2C(H)(CH3)2)—





Ic-570


embedded image


—N(C(CH3)3)—





Ic-571


embedded image


—N(CH3)—





Ic-572


embedded image


—N(CH2CH3)—





Ic-573


embedded image


—N(CH2CH2CH3)—





Ic-574


embedded image


—N(CH2CH2CH2CH3)—





Ic-575


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-576


embedded image


—N(C(H)(CH3)2)—





Ic-577


embedded image


—N(CH2C(H)(CH3)2)—





Ic-578


embedded image


—N(C(CH3)3)—





Ic-579


embedded image


—N(CH3)—





Ic-580


embedded image


—N(CH2CH3)—





Ic-581


embedded image


—N(CH2CH2CH3)—





Ic-582


embedded image


—N(CH2CH2CH2CH3)—





Ic-583


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-584


embedded image


—N(C(H)(CH3)2)—





Ic-585


embedded image


—N(CH2C(H)(CH3)2)—





Ic-586


embedded image


—N(C(CH3)3)—





Ic-587


embedded image


—N(CH3)—





Ic-588


embedded image


—N(CH2CH3)—





Ic-589


embedded image


—N(CH2CH2CH3)—





Ic-590


embedded image


—N(CH2CH2CH2CH3)—





Ic-591


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-592


embedded image


—N(C(H)(CH3)2)—





Ic-593


embedded image


—N(CH2C(H)(CH3)2)—





Ic-594


embedded image


—N(C(CH3)3)—





Ic-595


embedded image


—N(CH3)—





Ic-596


embedded image


—N(CH2CH3)—





Ic-597


embedded image


—N(CH2CH2CH3)—





Ic-598


embedded image


—N(CH2CH2CH2CH3)—





Ic-599


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-600


embedded image


—N(C(H)(CH3)2)—





Ic-601


embedded image


—N(CH2C(H)(CH3)2)—





Ic-602


embedded image


—N(C(CH3)3)—





Ic-603


embedded image


—N(CH3)—





Ic-604


embedded image


—N(CH2CH3)—





Ic-605


embedded image


—N(CH2CH2CH3)—





Ic-606


embedded image


—N(CH2CH2CH2CH3)—





Ic-607


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-608


embedded image


—N(C(H)(CH3)2)—





Ic-609


embedded image


—N(CH2C(H)(CH3)2)—





Ic-610


embedded image


—N(C(CH3)3)—





Ic-611
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(CH3)—


Ic-612
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(CH2CH3)—


Ic-613
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(CH2CH2CH3)—


Ic-614
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(CH2CH2CH2CH3)—


Ic-615
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(C(H)(CH3)(CH2CH3))—


Ic-616
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(C(H)(CH3)2)—


Ic-617
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(CH2C(H)(CH3)2)—


Ic-618
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(C(CH3)3)—





Ic-619


embedded image


—N(CH3)—





Ic-620


embedded image


—N(CH2CH3)—





Ic-621


embedded image


—N(CH2CH2CH3)—





Ic-622


embedded image


—N(CH2CH2CH2CH3)—





Ic-623


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-624


embedded image


—N(C(H)(CH3)2)—





Ic-625


embedded image


—N(CH2C(H)(CH3)2)—





Ic-626


embedded image


—N(C(CH3)3)—





Ic-627


embedded image


—N(CH3)—





Ic-628


embedded image


—N(CH2CH3)—





Ic-629


embedded image


—N(CH2CH2CH3)—





Ic-630


embedded image


—N(CH2CH2CH2CH3)—





Ic-631


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-632


embedded image


—N(C(H)(CH3)2)—





Ic-633


embedded image


—N(CH2C(H)(CH3)2)—





Ic-634


embedded image


—N(C(CH3)3)—





Ic-635


embedded image


—N(CH3)—





Ic-636


embedded image


—N(CH2CH3)—





Ic-637


embedded image


—N(CH2CH2CH3)—





Ic-638


embedded image


—N(CH2CH2CH2CH3)—





Ic-639


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-640


embedded image


—N(C(H)(CH3)2)—





Ic-641


embedded image


—N(CH2C(H)(CH3)2)—





Ic-642


embedded image


—N(C(CH3)3)—





Ic-643


embedded image


—N(CH3)—





Ic-644


embedded image


—N(CH2CH3)—





Ic-645


embedded image


—N(CH2CH2CH3)—





Ic-646


embedded image


—N(CH2CH2CH2CH3)—





Ic-647


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-648


embedded image


—N(C(H)(CH3)2)—





Ic-649


embedded image


—N(CH2C(H)(CH3)2)—





Ic-650


embedded image


—N(C(CH3)3)—





Ic-651


embedded image


—N(CH3)—





Ic-652


embedded image


—N(CH2CH3)—





Ic-653


embedded image


—N(CH2CH2CH3)—





Ic-654


embedded image


—N(CH2CH2CH2CH3)—





Ic-655


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-656


embedded image


—N(C(H)(CH3)2)—





Ic-657


embedded image


—N(CH2C(H)(CH3)2)—





Ic-658


embedded image


—N(C(CH3)3)—





Ic-659


embedded image


—N(CH3)—





Ic-660


embedded image


—N(CH2CH3)—





Ic-661


embedded image


—N(CH2CH2CH3)—





Ic-662


embedded image


—N(CH2CH2CH2CH3)—





Ic-663


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-664


embedded image


—N(C(H)(CH3)2)—





Ic-665


embedded image


—N(CH2C(H)(CH3)2)—





Ic-666


embedded image


—N(C(CH3)3)—





Ic-667


embedded image


—N(CH3)—





Ic-668


embedded image


—N(CH2CH3)—





Ic-669


embedded image


—N(CH2CH2CH3)—





Ic-670


embedded image


—N(CH2CH2CH2CH3)—





Ic-671


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-672


embedded image


—N(C(H)(CH3)2)—





Ic-673


embedded image


—N(CH2C(H)(CH3)2)—





Ic-674


embedded image


—N(C(CH3)3)—





Ic-675


embedded image


—N(CH3)—





Ic-676


embedded image


—N(CH2CH3)—





Ic-677


embedded image


—N(CH2CH2CH3)—





Ic-678


embedded image


—N(CH2CH2CH2CH3)—





Ic-679


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-680


embedded image


—N(C(H)(CH3)2)—





Ic-681


embedded image


—N(CH2C(H)(CH3)2)—





Ic-682


embedded image


—N(C(CH3)3)—





Ic-683


embedded image


—N(CH3)—





Ic-684


embedded image


—N(CH2CH3)—





Ic-685


embedded image


—N(CH2CH2CH3)—





Ic-686


embedded image


—N(CH2CH2CH2CH3)—





Ic-687


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-688


embedded image


—N(C(H)(CH3)2)—





Ic-689


embedded image


—N(CH2C(H)(CH3)2)—





Ic-690


embedded image


—N(C(CH3)3)—





Ic-691


embedded image


—N(CH3)—





Ic-692


embedded image


—N(CH2CH3)—





Ic-693


embedded image


—N(CH2CH2CH3)—





Ic-694


embedded image


—N(CH2CH2CH2CH3)—





Ic-695


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-696


embedded image


—N(C(H)(CH3)2)—





Ic-697


embedded image


—N(CH2C(H)(CH3)2)—





Ic-698


embedded image


—N(C(CH3)3)—





Ic-699


embedded image


—N(CH3)—





Ic-700


embedded image


—N(CH2CH3)—





Ic-701


embedded image


—N(CH2CH2CH3)—





Ic-702


embedded image


—N(CH2CH2CH2CH3)—





Ic-703


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-704


embedded image


—N(C(H)(CH3)2)—





Ic-705


embedded image


—N(CH2C(H)(CH3)2)—





Ic-706


embedded image


—N(C(CH3)3)—





Ic-707


embedded image


—N(CH3)—





Ic-708


embedded image


—N(CH2CH3)—





Ic-709


embedded image


—N(CH2CH2CH3)—





Ic-710


embedded image


—N(CH2CH2CH2CH3)—





Ic-711


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-712


embedded image


—N(C(H)(CH3)2)—





Ic-713


embedded image


—N(CH2C(H)(CH3)2)—





Ic-714


embedded image


—N(C(CH3)3)—





Ic-715


embedded image


—N(CH3)—





Ic-716


embedded image


—N(CH2CH3)—





Ic-717


embedded image


—N(CH2CH2CH3)—





Ic-718


embedded image


—N(CH2CH2CH2CH3)—





Ic-719


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-720


embedded image


—N(C(H)(CH3)2)—





Ic-721


embedded image


—N(CH2C(H)(CH3)2)—





Ic-722


embedded image


—N(C(CH3)3)—





Ic-723


embedded image


—N(CH3)—





Ic-724


embedded image


—N(CH2CH3)—





Ic-725


embedded image


—N(CH2CH2CH3)—





Ic-726


embedded image


—N(CH2CH2CH2CH3)—





Ic-727


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-728


embedded image


—N(C(H)(CH3)2)—





Ic-729


embedded image


—N(CH2C(H)(CH3)2)—





Ic-730


embedded image


—N(C(CH3)3)—





Ic-731


embedded image


—N(CH3)—





Ic-732


embedded image


—N(CH2CH3)—





Ic-733


embedded image


—N(CH2CH2CH3)—





Ic-734


embedded image


—N(CH2CH2CH2CH3)—





Ic-735


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-736


embedded image


—N(C(H)(CH3)2)—





Ic-737


embedded image


—N(CH2C(H)(CH3)2)—





Ic-738


embedded image


—N(C(CH3)3)—





Ic-739


embedded image


—N(CH3)—





Ic-740


embedded image


—N(CH2CH3)—





Ic-741


embedded image


—N(CH2CH2CH3)—





Ic-742


embedded image


—N(CH2CH2CH2CH3)—





Ic-743


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-744


embedded image


—N(C(H)(CH3)2)—





Ic-745


embedded image


—N(CH2C(H)(CH3)2)—





Ic-746


embedded image


—N(C(CH3)3)—





Ic-747


embedded image


—N(CH3)—





Ic-748


embedded image


—N(CH2CH3)—





Ic-749


embedded image


—N(CH2CH2CH3)—





Ic-750


embedded image


—N(CH2CH2CH2CH3)—





Ic-751


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-752


embedded image


—N(C(H)(CH3)2)—





Ic-753


embedded image


—N(CH2C(H)(CH3)2)—





Ic-754


embedded image


—N(C(CH3)3)—





Ic-755


embedded image


—N(CH3)—





Ic-756


embedded image


—N(CH2CH3)—





Ic-757


embedded image


—N(CH2CH2CH3)—





Ic-758


embedded image


—N(CH2CH2CH2CH3)—





Ic-759


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-760


embedded image


—N(C(H)(CH3)2)—





Ic-761


embedded image


—N(CH2C(H)(CH3)2)—





Ic-762


embedded image


—N(C(CH3)3)—





Ic-763


embedded image


—N(CH3)—





Ic-764


embedded image


—N(CH2CH3)—





Ic-765


embedded image


—N(CH2CH2CH3)—





Ic-766


embedded image


—N(CH2CH2CH2CH3)—





Ic-767


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-768


embedded image


—N(C(H)(CH3)2)—





Ic-769


embedded image


—N(CH2C(H)(CH3)2)—





Ic-770


embedded image


—N(C(CH3)3)—





Ic-771


embedded image


—N(CH3)—





Ic-772


embedded image


—N(CH2CH3)—





Ic-773


embedded image


—N(CH2CH2CH3)—





Ic-774


embedded image


—N(CH2CH2CH2CH3)—





Ic-775


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-776


embedded image


—N(C(H)(CH3)2)—





Ic-777


embedded image


—N(CH2C(H)(CH3)2)—





Ic-778


embedded image


—N(C(CH3)3)—





Ic-779
—CH2—NH—CH3
—N(CH3)—


Ic-780
—CH2—NH—CH3
—N(CH2CH3)—


Ic-781
—CH2—NH—CH3
—N(CH2CH2CH3)—


Ic-782
—CH2—NH—CH3
—N(CH2CH2CH2CH3)—


Ic-783
—CH2—NH—CH3
—N(C(H)(CH3)(CH2CH3))—


Ic-784
—CH2—NH—CH3
—N(C(H)(CH3)2)—


Ic-785
—CH2—NH—CH3
—N(CH2C(H)(CH3)2)—


Ic-786
—CH2—NH—CH3
—N(C(CH3)3)—


Ic-787
—CH2—NH—CH2—CH3
—N(CH3)—


Ic-788
—CH2—NH—CH2—CH3
—N(CH2CH3)—


Ic-789
—CH2—NH—CH2—CH3
—N(CH2CH2CH3)—


Ic-790
—CH2—NH—CH2—CH3
—N(CH2CH2CH2CH3)—


Ic-791
—CH2—NH—CH2—CH3
—N(C(H)(CH3)(CH2CH3))—


Ic-792
—CH2—NH—CH2—CH3
—N(C(H)(CH3)2)—


Ic-793
—CH2—NH—CH2—CH3
—N(CH2C(H)(CH3)2)—


Ic-794
—CH2—NH—CH2—CH3
—N(C(CH3)3)—


Ic-795
—CH2—NH—CH2—CH2—CH3
—N(CH3)—


Ic-796
—CH2—NH—CH2—CH2—CH3
—N(CH2CH3)—


Ic-797
—CH2—NH—CH2—CH2—CH3
—N(CH2CH2CH3)—


Ic-798
—CH2—NH—CH2—CH2—CH3
—N(CH2CH2CH2CH3)—


Ic-799
—CH2—NH—CH2—CH2—CH3
—N(C(H)(CH3)(CH2CH3))—


Ic-800
—CH2—NH—CH2—CH2—CH3
—N(C(H)(CH3)2)—


Ic-801
—CH2—NH—CH2—CH2—CH3
—N(CH2C(H)(CH3)2)—


Ic-802
—CH2—NH—CH2—CH2—CH3
—N(C(CH3)3)—





Ic-803


embedded image


—N(CH3)—





Ic-804


embedded image


—N(CH2CH3)—





Ic-805


embedded image


—N(CH2CH2CH3)—





Ic-806


embedded image


—N(CH2CH2CH2CH3)—





Ic-807


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-808


embedded image


—N(C(H)(CH3)2)—





Ic-809


embedded image


—N(CH2C(H)(CH3)2)—





Ic-810


embedded image


—N(C(CH3)3)—





Ic-811


embedded image


—N(CH3)—





Ic-812


embedded image


—N(CH2CH3)—





Ic-813


embedded image


—N(CH2CH2CH3)—





Ic-814


embedded image


—N(CH2CH2CH2CH3)—





Ic-815


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-816


embedded image


—N(C(H)(CH3)2)—





Ic-817


embedded image


—N(CH2C(H)(CH3)2)—





Ic-818


embedded image


—N(C(CH3)3)—





Ic-819


embedded image


—N(CH3)—





Ic-820


embedded image


—N(CH2CH3)—





Ic-821


embedded image


—N(CH2CH2CH3)—





Ic-822


embedded image


—N(CH2CH2CH2CH3)—





Ic-823


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-824


embedded image


—N(C(H)(CH3)2)—





Ic-825


embedded image


—N(CH2C(H)(CH3)2)—





Ic-826


embedded image


—N(C(CH3)3)—





Ic-827


embedded image


—N(CH3)—





Ic-828


embedded image


—N(CH2CH3)—





Ic-829


embedded image


—N(CH2CH2CH3)—





Ic-830


embedded image


—N(CH2CH2CH2CH3)—





Ic-831


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-832


embedded image


—N(C(H)(CH3)2)—





Ic-833


embedded image


—N(CH2C(H)(CH3)2)—





Ic-834


embedded image


—N(C(CH3)3)—





Ic-835


embedded image


—N(CH3)—





Ic-836


embedded image


—N(CH2CH3)—





Ic-837


embedded image


—N(CH2CH2CH3)—





Ic-838


embedded image


—N(CH2CH2CH2CH3)—





Ic-839


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-840


embedded image


—N(C(H)(CH3)2)—





Ic-841


embedded image


—N(CH2C(H)(CH3)2)—





Ic-842


embedded image


—N(C(CH3)3)—





Ic-843


embedded image


—N(CH3)—





Ic-844


embedded image


—N(CH2CH3)—





Ic-845


embedded image


—N(CH2CH2CH3)—





Ic-846


embedded image


—N(CH2CH2CH2CH3)—





Ic-847


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-848


embedded image


—N(C(H)(CH3)2)—





Ic-849


embedded image


—N(CH2C(H)(CH3)2)—





Ic-850


embedded image


—N(C(CH3)3)—





Ic-851


embedded image


—N(CH3)—





Ic-852


embedded image


—N(CH2CH3)—





Ic-853


embedded image


—N(CH2CH2CH3)—





Ic-854


embedded image


—N(CH2CH2CH2CH3)—





Ic-855


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-856


embedded image


—N(C(H)(CH3)2)—





Ic-857


embedded image


—N(CH2C(H)(CH3)2)—





Ic-858


embedded image


—N(C(CH3)3)—





Ic-859


embedded image


—N(CH3)—





Ic-860


embedded image


—N(CH2CH3)—





Ic-861


embedded image


—N(CH2CH2CH3)—





Ic-862


embedded image


—N(CH2CH2CH2CH3)—





Ic-863


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-864


embedded image


—N(C(H)(CH3)2)—





Ic-865


embedded image


—N(CH2C(H)(CH3)2)—





Ic-866


embedded image


—N(C(CH3)3)—





Ic-867


embedded image


—N(CH3)—





Ic-868


embedded image


—N(CH2CH3)—





Ic-869


embedded image


—N(CH2CH2CH3)—





Ic-870


embedded image


—N(CH2CH2CH2CH3)—





Ic-871


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-872


embedded image


—N(C(H)(CH3)2)—





Ic-873


embedded image


—N(CH2C(H)(CH3)2)—





Ic-874


embedded image


—N(C(CH3)3)—





Ic-875


embedded image


—N(CH3)—





Ic-876


embedded image


—N(CH2CH3)—





Ic-877


embedded image


—N(CH2CH2CH3)—





Ic-878


embedded image


—N(CH2CH2CH2CH3)—





Ic-879


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-880


embedded image


—N(C(H)(CH3)2)—





Ic-881


embedded image


—N(CH2C(H)(CH3)2)—





Ic-882


embedded image


—N(C(CH3)3)—





Ic-883


embedded image


—N(CH3)—





Ic-884


embedded image


—N(CH2CH3)—





Ic-885


embedded image


—N(CH2CH2CH3)—





Ic-886


embedded image


—N(CH2CH2CH2CH3)—





Ic-887


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-888


embedded image


—N(C(H)(CH3)2)—





Ic-889


embedded image


—N(CH2C(H)(CH3)2)—





Ic-890


embedded image


—N(C(CH3)3)—





Ic-891


embedded image


—N(CH3)—





Ic-892


embedded image


—N(CH2CH3)—





Ic-893


embedded image


—N(CH2CH2CH3)—





Ic-894


embedded image


—N(CH2CH2CH2CH3)—





Ic-895


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-896


embedded image


—N(C(H)(CH3)2)—





Ic-897


embedded image


—N(CH2C(H)(CH3)2)—





Ic-898


embedded image


—N(C(CH3)3)—





Ic-899


embedded image


—N(CH3)—





Ic-900


embedded image


—N(CH2CH3)—





Ic-901


embedded image


—N(CH2CH2CH3)—





Ic-902


embedded image


—N(CH2CH2CH2CH3)—





Ic-903


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-904


embedded image


—N(C(H)(CH3)2)—





Ic-905


embedded image


—N(CH2C(H)(CH3)2)—





Ic-906


embedded image


—N(C(CH3)3)—





Ic-907


embedded image


—N(CH3)—





Ic-908


embedded image


—N(CH2CH3)—





Ic-909


embedded image


—N(CH2CH2CH3)—





Ic-910


embedded image


—N(CH2CH2CH2CH3)—





Ic-911


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-912


embedded image


—N(C(H)(CH3)2)—





Ic-913


embedded image


—N(CH2C(H)(CH3)2)—





Ic-914


embedded image


—N(C(CH3)3)—





Ic-915


embedded image


—N(CH3)—





Ic-916


embedded image


—N(CH2CH3)—





Ic-917


embedded image


—N(CH2CH2CH3)—





Ic-918


embedded image


—N(CH2CH2CH2CH3)—





Ic-919


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-920


embedded image


—N(C(H)(CH3)2)—





Ic-921


embedded image


—N(CH2C(H)(CH3)2)—





Ic-922


embedded image


—N(C(CH3)3)—





Ic-923


embedded image


—N(CH3)—





Ic-924


embedded image


—N(CH2CH3)—





Ic-925


embedded image


—N(CH2CH2CH3)—





Ic-926


embedded image


—N(CH2CH2CH2CH3)—





Ic-927


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-928


embedded image


—N(C(H)(CH3)2)—





Ic-929


embedded image


—N(CH2C(H)(CH3)2)—





Ic-930


embedded image


—N(C(CH3)3)—





Ic-931


embedded image


—N(CH3)—





Ic-932


embedded image


—N(CH2CH3)—





Ic-933


embedded image


—N(CH2CH2CH3)—





Ic-934


embedded image


—N(CH2CH2CH2CH3)—





Ic-935


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-936


embedded image


—N(C(H)(CH3)2)—





Ic-937


embedded image


—N(CH2C(H)(CH3)2)—





Ic-938


embedded image


—N(C(CH3)3)—





Ic-939


embedded image


—N(CH3)—





Ic-940


embedded image


—N(CH2CH3)—





Ic-941


embedded image


—N(CH2CH2CH3)—





Ic-942


embedded image


—N(CH2CH2CH2CH3)—





Ic-943


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-944


embedded image


—N(C(H)(CH3)2)—





Ic-945


embedded image


—N(CH2C(H)(CH3)2)—





Ic-946


embedded image


—N(C(CH3)3)—





Ic-947


embedded image


—N(CH3)—





Ic-948


embedded image


—N(CH2CH3)—





Ic-949


embedded image


—N(CH2CH2CH3)—





Ic-950


embedded image


—N(CH2CH2CH2CH3)—





Ic-951


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-952


embedded image


—N(C(H)(CH3)2)—





Ic-953


embedded image


—N(CH2C(H)(CH3)2)—





Ic-954


embedded image


—N(C(CH3)3)—





Ic-955


embedded image


—N(CH3)—





Ic-956


embedded image


—N(CH2CH3)—





Ic-957


embedded image


—N(CH2CH2CH3)—





Ic-958


embedded image


—N(CH2CH2CH2CH3)—





Ic-959


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-960


embedded image


—N(C(H)(CH3)2)—





Ic-961


embedded image


—N(CH2C(H)(CH3)2)—





Ic-962


embedded image


—N(C(CH3)3)—





Ic-963
—CH2—N(CH2CH3)(CH3)
—N(CH3)—


Ic-964
—CH2—N(CH2CH3)(CH3)
—N(CH2CH3)—


Ic-965
—CH2—N(CH2CH3)(CH3)
—N(CH2CH2CH3)—


Ic-966
—CH2—N(CH2CH3)(CH3)
—N(CH2CH2CH2CH3)—


Ic-967
—CH2—N(CH2CH3)(CH3)
—N(C(H)(CH3)(CH2CH3))—


Ic-968
—CH2—N(CH2CH3)(CH3)
—N(C(H)(CH3)2)—


Ic-969
—CH2—N(CH2CH3)(CH3)
—N(CH2C(H)(CH3)2)—


Ic-970
—CH2—N(CH2CH3)(CH3)
—N(C(CH3)3)—


Ic-971
—CH2—N(CH2CH2CH3)(CH3)
—N(CH3)—


Ic-972
—CH2—N(CH2CH2CH3)(CH3)
—N(CH2CH3)—


Ic-973
—CH2—N(CH2CH2CH3)(CH3)
—N(CH2CH2CH3)—


Ic-974
—CH2—N(CH2CH2CH3)(CH3)
—N(CH2CH2CH2CH3)—


Ic-975
—CH2—N(CH2CH2CH3)(CH3)
—N(C(H)(CH3)(CH2CH3))—


Ic-976
—CH2—N(CH2CH2CH3)(CH3)
—N(C(H)(CH3)2)—


Ic-977
—CH2—N(CH2CH2CH3)(CH3)
—N(CH2C(H)(CH3)2)—


Ic-978
—CH2—N(CH2CH2CH3)(CH3)
—N(C(CH3)3)—


Ic-979
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(CH3)—


Ic-980
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(CH2CH3)—


Ic-981
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(CH2CH2CH3)—


Ic-982
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(CH2CH2CH2CH3)—


Ic-983
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(C(H)(CH3)(CH2CH3))—


Ic-984
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(C(H)(CH3)2)—


Ic-985
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(CH2C(H)(CH3)2)—


Ic-986
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(C(CH3)3)—


Ic-987
—CH2—NH—CH2CH2CH2CH3
—N(CH3)—


Ic-988
—CH2—NH—CH2CH2CH2CH3
—N(CH2CH3)—


Ic-989
—CH2—NH—CH2CH2CH2CH3
—N(CH2CH2CH3)—


Ic-990
—CH2—NH—CH2CH2CH2CH3
—N(CH2CH2CH2CH3)—


Ic-991
—CH2—NH—CH2CH2CH2CH3
—N(C(H)(CH3)(CH2CH3))—


Ic-992
—CH2—NH—CH2CH2CH2CH3
—N(C(H)(CH3)2)—


Ic-993
—CH2—NH—CH2CH2CH2CH3
—N(CH2C(H)(CH3)2)—


Ic-994
—CH2—NH—CH2CH2CH2CH3
—N(C(CH3)3)—


Ic-995
—CH2—NH—CH2CH2—O—CH3
—N(CH3)—


Ic-996
—CH2—NH—CH2CH2—O—CH3
—N(CH2CH3)—


Ic-997
—CH2—NH—CH2CH2—O—CH3
—N(CH2CH2CH3)—


Ic-998
—CH2—NH—CH2CH2—O—CH3
—N(CH2CH2CH2CH3)—


Ic-999
—CH2—NH—CH2CH2—O—CH3
—N(C(H)(CH3)(CH2CH3))—


Ic-1000
—CH2—NH—CH2CH2—O—CH3
—N(C(H)(CH3)2)—


Ic-1001
—CH2—NH—CH2CH2—O—CH3
—N(CH2C(H)(CH3)2)—


Ic-1002
—CH2—NH—CH2CH2—O—CH3
—N(C(CH3)3)—





Ic-1003


embedded image


—N(CH3)—





Ic-1004


embedded image


—N(CH2CH3)—





Ic-1005


embedded image


—N(CH2CH2CH3)—





Ic-1006


embedded image


—N(CH2CH2CH2CH3)—





Ic-1007


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-1008


embedded image


—N(C(H)(CH3)2)—





Ic-1009


embedded image


—N(CH2C(H)(CH3)2)—





Ic-1010


embedded image


—N(C(CH3)3)—





Ic-1011


embedded image


—N(CH3)—





Ic-1012


embedded image


—N(CH2CH3)—





Ic-1013


embedded image


—N(CH2CH2CH3)—





Ic-1014


embedded image


—N(CH2CH2CH2CH3)—





Ic-1015


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-1016


embedded image


—N(C(H)(CH3)2)—





Ic-1017


embedded image


—N(CH2C(H)(CH3)2)—





Ic-1018


embedded image


—N(C(CH3)3)—





Ic-1019


embedded image


—N(CH3)—





Ic-1020


embedded image


—N(CH2CH3)—





Ic-1021


embedded image


—N(CH2CH2CH3)—





Ic-1022


embedded image


—N(CH2CH2CH2CH3)—





Ic-1023


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-1024


embedded image


—N(C(H)(CH3)2)—





Ic-1025


embedded image


—N(CH2C(H)(CH3)2)—





Ic-1026


embedded image


—N(C(CH3)3)—





Ic-1027


embedded image


—N(CH3)—





Ic-1028


embedded image


—N(CH2CH3)—





Ic-1029


embedded image


—N(CH2CH2CH3)—





Ic-1030


embedded image


—N(CH2CH2CH2CH3)—





Ic-1031


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-1032


embedded image


—N(C(H)(CH3)2)—





Ic-1033


embedded image


—N(CH2C(H)(CH3)2)—





Ic-1034


embedded image


—N(C(CH3)3)—





Ic-1035


embedded image


—N(CH3)—





Ic-1036


embedded image


—N(CH2CH3)—





Ic-1037


embedded image


—N(CH2CH2CH3)—





Ic-1038


embedded image


—N(CH2CH2CH2CH3)—





Ic-1039


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-1040


embedded image


—N(C(H)(CH3)2)—





Ic-1041


embedded image


—N(CH2C(H)(CH3)2)—





Ic-1042


embedded image


—N(C(CH3)3)—





Ic-1043


embedded image


—N(CH3)—





Ic-1044


embedded image


—N(CH2CH3)—





Ic-1045


embedded image


—N(CH2CH2CH3)—





Ic-1046


embedded image


—N(CH2CH2CH2CH3)—





Ic-1047


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-1048


embedded image


—N(C(H)(CH3)2)—





Ic-1049


embedded image


—N(CH2C(H)(CH3)2)—





Ic-1050


embedded image


—N(C(CH3)3)—





Ic-1051


embedded image


—N(CH3)—





Ic-1052


embedded image


—N(CH2CH3)—





Ic-1053


embedded image


—N(CH2CH2CH3)—





Ic-1054


embedded image


—N(CH2CH2CH2CH3)—





Ic-1055


embedded image


—N(C(H)(CH3)(CH2CH3))—





Ic-1056


embedded image


—N(C(H)(CH3)2)—





Ic-1057


embedded image


—N(CH2C(H)(CH3)2)—





Ic-1058


embedded image


—N(C(CH3)3)—













Compound
n
—R1
X





Ic-c1
1
—(CH2)n—N(CH3)2
—CH(OH)—


Ic-c2
2
—(CH2)n—N(CH3)2
—CH(OH)—


Ic-c3
3
—(CH2)n—N(CH3)2
—CH(OH)—


Ic-c4
4
—(CH2)n—N(CH3)2
—CH(OH)—


Ic-c5
5
—(CH2)n—N(CH3)2
—CH(OH)—


Ic-c6
6
—(CH2)n—N(CH3)2
—CH(OH)—


Ic-c7
1
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ic-c8
2
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ic-c9
3
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ic-c10
4
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ic-c11
5
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ic-c12
6
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ic-c13
1
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ic-c14
2
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ic-c15
3
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ic-c16
4
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ic-c17
5
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ic-c18
6
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ic-c19
1
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ic-c20
2
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ic-c21
3
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ic-c22
4
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ic-c23
5
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ic-c24
6
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ic-c25
1
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c26
2
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c27
3
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c28
4
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c29
5
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c30
6
—(CH2)n—N(CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c31
1
—(CH2)n—N(CH3)2
—N(CH2—CH2—OH)—


Ic-c32
2
—(CH2)n—N(CH3)2
—N(CH2—CH2—OH)—


Ic-c33
3
—(CH2)n—N(CH3)2
—N(CH2—CH2—OH)—


Ic-c34
4
—(CH2)n—N(CH3)2
—N(CH2—CH2—OH)—


Ic-c35
5
—(CH2)n—N(CH3)2
—N(CH2—CH2—OH)—


Ic-c36
6
—(CH2)n—N(CH3)2
—N(CH2—CH2—OH)—


Ic-c37
1
—(CH2)n—N(CH3)2
—N(CH2—CH2—F)—


Ic-c38
2
—(CH2)n—N(CH3)2
—N(CH2—CH2—F)—


Ic-c39
3
—(CH2)n—N(CH3)2
—N(CH2—CH2—F)—


Ic-c40
4
—(CH2)n—N(CH3)2
—N(CH2—CH2—F)—


Ic-c41
5
—(CH2)n—N(CH3)2
—N(CH2—CH2—F)—


Ic-c42
6
—(CH2)n—N(CH3)2
—N(CH2—CH2—F)—


Ic-c43
1
—(CH2)n—N(CH3)2
—N(CH2—CH2—OCH3)—


Ic-c44
2
—(CH2)n—N(CH3)2
—N(CH2—CH2—OCH3)—


Ic-c45
3
—(CH2)n—N(CH3)2
—N(CH2—CH2—OCH3)—


Ic-c46
4
—(CH2)n—N(CH3)2
—N(CH2—CH2—OCH3)—


Ic-c47
5
—(CH2)n—N(CH3)2
—N(CH2—CH2—OCH3)—


Ic-c48
6
—(CH2)n—N(CH3)2
—N(CH2—CH2—OCH3)—





Ic-c49
1


embedded image


—CH(OH)—





Ic-c50
2


embedded image


—CH(OH)—





Ic-c51
3


embedded image


—CH(OH)—





Ic-c52
4


embedded image


—CH(OH)—





Ic-c53
5


embedded image


—CH(OH)—





Ic-c54
6


embedded image


—CH(OH)—





Ic-c55
1


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c56
2


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c57
3


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c58
4


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c59
5


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c60
6


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c61
1


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c62
2


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c63
3


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c64
4


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c65
5


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c66
6


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c67
1


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c68
2


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c69
3


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c70
4


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c71
5


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c72
6


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c73
1


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c74
2


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c75
3


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c76
4


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c77
5


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c78
6


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c79
1


embedded image


—N(CH2—CH2—OH)—





Ic-c80
2


embedded image


—N(CH2—CH2—OH)—





Ic-c81
3


embedded image


—N(CH2—CH2—OH)—





Ic-c82
4


embedded image


—N(CH2—CH2—OH)—





Ic-c83
5


embedded image


—N(CH2—CH2—OH)—





Ic-c84
6


embedded image


—N(CH2—CH2—OH)—





Ic-c85
1


embedded image


—N(CH2—CH2—F)—





Ic-c86
2


embedded image


—N(CH2—CH2—F)—





Ic-c87
3


embedded image


—N(CH2—CH2—F)—





Ic-c88
4


embedded image


—N(CH2—CH2—F)—





Ic-c89
5


embedded image


—N(CH2—CH2—F)—





Ic-c90
6


embedded image


—N(CH2—CH2—F)—





Ic-c91
1


embedded image


—N(CH2—CH2—OCH3)—





Ic-c92
2


embedded image


—N(CH2—CH2—OCH3)—





Ic-c93
3


embedded image


—N(CH2—CH2—OCH3)—





Ic-c94
4


embedded image


—N(CH2—CH2—OCH3)—





Ic-c95
5


embedded image


—N(CH2—CH2—OCH3)—





Ic-c96
6


embedded image


—N(CH2—CH2—OCH3)—





Compound
m
—R1
X





Ic-c146
2
—O—(CH2)m—N(CH3)2
—CH(OH)—


Ic-c147
3
—O—(CH2)m—N(CH3)2
—CH(OH)—


Ic-c148
4
—O—(CH2)m—N(CH3)2
—CH(OH)—


Ic-c149
5
—O—(CH2)m—N(CH3)2
—CH(OH)—


Ic-c150
6
—O—(CH2)m—N(CH3)2
—CH(OH)—


Ic-c151
2
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ic-c152
3
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ic-c153
4
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ic-c154
5
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ic-c155
6
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ic-c156
2
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ic-c157
3
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ic-c158
4
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ic-c159
5
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ic-c160
6
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ic-c161
2
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ic-c162
3
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ic-c163
4
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ic-c164
5
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ic-c165
6
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ic-c166
2
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c167
3
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c168
4
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c169
5
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c170
6
—O—(CH2)m—N(CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c171
2
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—OH)—


Ic-c172
3
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—OH)—


Ic-c173
4
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—OH)—


Ic-c174
5
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—OH)—


Ic-c175
6
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—OH)—


Ic-c176
2
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—F)—


Ic-c178
3
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—F)—


Ic-c179
4
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—F)—


Ic-c180
5
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—F)—


Ic-c181
6
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—F)—


Ic-c182
2
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—OCH3)—


Ic-c183
3
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—OCH3)—


Ic-c184
4
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—OCH3)—


Ic-c185
5
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—OCH3)—


Ic-c186
6
—O—(CH2)m—N(CH3)2
—N(CH2—CH2—OCH3)—





Ic-c187
2


embedded image


—CH(OH)—





Ic-c188
3


embedded image


—CH(OH)—





Ic-c189
4


embedded image


—CH(OH)—





Ic-c190
5


embedded image


—CH(OH)—





Ic-c191
6


embedded image


—CH(OH)—





Ic-c192
2


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c193
3


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c194
4


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c195
5


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c196
6


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c197
2


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c198
3


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c199
4


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c200
5


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c201
6


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c202
2


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c203
3


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c204
4


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c205
5


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c206
6


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c207
2


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c208
3


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c209
4


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c210
5


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c211
6


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c212
2


embedded image


—N(CH2—CH2—OH)—





Ic-c213
3


embedded image


—N(CH2—CH2—OH)—





Ic-c214
4


embedded image


—N(CH2—CH2—OH)—





Ic-c215
5


embedded image


—N(CH2—CH2—OH)—





Ic-c216
6


embedded image


—N(CH2—CH2—OH)—





Ic-c217
2


embedded image


—N(CH2—CH2—F)—





Ic-c218
3


embedded image


—N(CH2—CH2—F)—





Ic-c219
4


embedded image


—N(CH2—CH2—F)—





Ic-c220
5


embedded image


—N(CH2—CH2—F)—





Ic-c221
6


embedded image


—N(CH2—CH2—F)—





Ic-c222
2


embedded image


—N(CH2—CH2—OCH3)—





Ic-c223
3


embedded image


—N(CH2—CH2—OCH3)—





Ic-c224
4


embedded image


—N(CH2—CH2—OCH3)—





Ic-c225
5


embedded image


—N(CH2—CH2—OCH3)—





Ic-c226
6


embedded image


—N(CH2—CH2—OCH3)—












Compound
—R1
X





Ic-c267
—CH2—N(CH2—CH3)2
—CH(OH)—


Ic-c268
—CH2—N(CH2—CH3)2
N(C(O)N(H)—CH2—CH2—OH)—


Ic-c269
—CH2—N(CH2—CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ic-c270
—CH2—N(CH2—CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ic-c271
—CH2—N(CH2—CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c275
—CH2—N(CH2—CH2—CH3)2
—CH(OH)—


Ic-c276
—CH2—N(CH2—CH2—CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ic-c277
—CH2—N(CH2—CH2—CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ic-c278
—CH2—N(CH2—CH2—CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ic-c279
—CH2—N(CH2—CH2—CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c283
—CH2—N(CH2—CH2OH)2
—CH(OH)—


Ic-c284
—CH2—N(CH2—CH2OH)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ic-c285
—CH2—N(CH2—CH2OH)2
—N(C(O)N(H)—CH2—CH2—F)—


Ic-c286
—CH2—N(CH2—CH2OH)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ic-c291
—CH2—N(CH2—CH2—N(CH3)2)2
—CH(OH)—


Ic-c292
—CH2—N(CH2—CH2—N(CH3)2)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ic-c293
—CH2—N(CH2—CH2—N(CH3)2)2
—N(C(O)N(H)—CH2—CH2—F)—


Ic-c294
—CH2—N(CH2—CH2—N(CH3)2)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ic-c295
—CH2—N(CH2—CH2—N(CH3)2)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c296
—CH2—N(CH2—CH2—N(CH3)2)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c297
—CH2—N(CH2—CH2—N(CH3)2)2
—N(C(O)N(H)—CH2—CF3)—


Ic-c298
—CH2—N(CH2—CH2—N(CH3)2)2
—N(C(O)N(H)—(CH2)3—OH)—


Ic-c299
—CH2—N(CH2—CH2—CH2—N(CH3)2)2
—CH(OH)—


Ic-c300
—CH2—N(CH2—CH2—CH2—N(CH3)2)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ic-c301
—CH2—N(CH2—CH2—CH2—N(CH3)2)2
—N(C(O)N(H)—CH2—CH2—F)—


Ic-c302
—CH2—N(CH2—CH2—CH2—N(CH3)2)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ic-c303
—CH2—N(CH2—CH2—CH2—N(CH3)2)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c304
—CH2—N(CH2—CH2—CH2—N(CH3)2)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c305
—CH2—N(CH2—CH2—CH2—N(CH3)2)2
—N(C(O)N(H)—CH2—CF3)—


Ic-c306
—CH2—N(CH2—CH2—CH2—N(CH3)2)2
N(C(O)N(H)—(CH2)3—OH)—





Ic-c307


embedded image


—CH(OH)—





Ic-c308


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c309


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c310


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c311


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c312


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c313


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c314


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c315


embedded image


—CH(OH)—





Ic-c316


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c317


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c318


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c319


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c320


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c321


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c322


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c323


embedded image


—CH(OH)—





Ic-c324


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c325


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c326


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c327


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c328


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c329


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c330


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c331


embedded image


—CH(OH)—





Ic-c332


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c333


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c334


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c335


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c336


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c337


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c338


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c339


embedded image


—CH(OH)—





Ic-c340


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c341


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c342


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c343


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c344


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c345


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c346


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c347


embedded image


—CH(OH)—





Ic-c348


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c349


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c350


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c351


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c352


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c353


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c354


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c355


embedded image


—CH(OH)—





Ic-c356


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c357


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c358


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c359


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c360


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c361


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c362


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c363


embedded image


—CH(OH)—





Ic-c364


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c365


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c366


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c367


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c368


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c369


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c370


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c371


embedded image


—CH(OH)—





Ic-c372


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c373


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c374


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c375


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c376


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c377


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c378


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c379


embedded image


—CH(OH)—





Ic-c380


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c381


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c382


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c383


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c384


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c385


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c386


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c387


embedded image


—CH(OH)—





Ic-c388


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c389


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c390


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c391


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c392


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c393


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c394


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c395


embedded image


—CH(OH)—





Ic-c396


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c397


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c398


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c399


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c400


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c401


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c402


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c403


embedded image


—CH(OH)—





Ic-c404


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c405


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c406


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c407


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c408


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c409


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c410


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c411


embedded image


—CH(OH)—





Ic-c412


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c413


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c414


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c415


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c416


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c417


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c418


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c419


embedded image


—CH(OH)—





Ic-c420


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c421


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c422


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c423


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c424


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c425


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c426


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c427


embedded image


—CH(OH)—





Ic-c428


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c429


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c430


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c431


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c432


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c433


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c434


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c435


embedded image


—CH(OH)—





Ic-c436


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c437


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c438


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c439


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c440


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c441


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c442


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c443


embedded image


—CH(OH)—





Ic-c444


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c445


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c446


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c447


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c448


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c449


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c450


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c451


embedded image


—CH(OH)—





Ic-c452


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c453


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c454


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c455


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c456


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c457


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c458


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c459


embedded image


—CH(OH)—





Ic-c460


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c461


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c462


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c463


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c464


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c465


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c466


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c467


embedded image


—CH(OH)—





Ic-c468


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c469


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c470


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c471


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c472


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c473


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c474


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c475


embedded image


—CH(OH)—





Ic-c476


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c477


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c478


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c479


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c480


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c481


embedded image


N(C(O)N(H)—CH2—CF3)—





Ic-c482


embedded image


N(C(O)N(H)—(CH2)3—OH)—





Ic-c483


embedded image


—CH(OH)—





Ic-c484


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c485


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c486


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c487


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c488


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c489


embedded image


N(C(O)N(H)—CH2—CF3)—





Ic-c490


embedded image


N(C(O)N(H)—(CH2)3—OH)—





Ic-c491
—CH2—CH2—CH2—OP(O)(OH)2
—CH(OH)—


Ic-c492
—CH2—CH2—CH2—OP(O)(OH)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ic-c493
—CH2—CH2—CH2—OP(O)(OH)2
—N(C(O)N(H)—CH2—CH2—F)—


Ic-c494
—CH2—CH2—CH2—OP(O)(OH)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ic-c495
—CH2—CH2—CH2—OP(O)(OH)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c496
—CH2—CH2—CH2—OP(O)(OH)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c497
—CH2—CH2—CH2—OP(O)(OH)2
—N(C(O)N(H)—CH2—CF3)—


Ic-c498
—CH2—CH2—CH2—OP(O)(OH)2
—N(C(O)N(H)—(CH2)3—OH)—


Ic-c499
—CH2—CH2—CH2—OS(O)2OH
—CH(OH)—


Ic-c500
—CH2—CH2—CH2—OS(O)2OH
—N(C(O)N(H)—CH2—CH2—OH)—


Ic-c501
—CH2—CH2—CH2—OS(O)2OH
—N(C(O)N(H)—CH2—CH2—F)—


Ic-c502
—CH2—CH2—CH2—OS(O)2OH
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ic-c503
—CH2—CH2—CH2—OS(O)2OH
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c504
—CH2—CH2—CH2—OS(O)2OH
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c505
—CH2—CH2—CH2—OS(O)2OH
—N(C(O)N(H)—CH2—CF3)—


Ic-c506
—CH2—CH2—CH2—OS(O)2OH
—N(C(O)N(H)—(CH2)3—OH)—





Ic-c507


embedded image


—CH(OH)—





Ic-c508


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c509


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c510


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c511


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c512


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c513


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c514


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c515


embedded image


—CH(OH)—





Ic-c516


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c517


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c518


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c519


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c520


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c521


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c522


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c523
—(CH2)10—N(CH2—CH2—O—CH3)2
—CH(OH)—


Ic-c524
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ic-c525
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ic-c526
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ic-c527
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c528
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c529
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—CH2—CF3)—


Ic-c530
—(CH2)10—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—(CH2)3—OH)—


Ic-c531
—CH2—N(CH2—CH2—O—CH3)2
—CH(OH)—


Ic-c532
—CH2—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ic-c533
—CH2—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ic-c534
—CH2—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ic-c535
—CH2—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c536
—CH2—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c537
—CH2—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—CH2—CF3)—


Ic-c538
—CH2—N(CH2—CH2—O—CH3)2
—N(C(O)N(H)—(CH2)3—OH)—





Ic-c539


embedded image


—CH(OH)—





Ic-c540


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c541


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c542


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c543


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c544


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c545


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c546


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c547


embedded image


—CH(OH)—





Ic-c548


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c549


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c550


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c551


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c552


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c553


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c554


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c555


embedded image


—CH(OH)—





Ic-c556


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c557


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c558


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c559


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c560


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c561


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c562


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c563


embedded image


—CH(OH)—





Ic-c564


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c565


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c566


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c567


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c568


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c569


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c570


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c571


embedded image


—CH(OH)—





Ic-c572


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c573


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c574


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c575


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c576


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c577


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c578


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c579


embedded image


—CH(OH)—





Ic-c580


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c581


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c582


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c583


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c584


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c585


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c586


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c587


embedded image


—CH(OH)—





Ic-c588


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c589


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c590


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c591


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c592


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c593


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c594


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c595


embedded image


—CH(OH)—





Ic-c596


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c597


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c598


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c599


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c600


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c601


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c602


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c603


embedded image


—CH(OH)—





Ic-c604


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c605


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c606


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c607


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c608


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c609


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c610


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c611
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—CH(OH)—


Ic-c612
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OH)—


Ic-c613
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(C(O)N(H)—CH2—CH2—F)—


Ic-c614
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ic-c615
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c616
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c617
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(C(O)N(H)—CH2—CF3)—


Ic-c618
—CH2—NH—CH2—CH2—CH2—N(CH3)2
—N(C(O)N(H)—(CH2)3—OH)—





Ic-c619


embedded image


—CH(OH)—





Ic-c620


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c621


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c622


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c623


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c624


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c625


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c626


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c627


embedded image


—CH(OH)—





Ic-c628


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c629


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c630


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c631


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c632


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c633


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c634


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c635


embedded image


—CH(OH)—





Ic-c636


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c637


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c638


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c639


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c640


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c641


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c642


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c643


embedded image


—CH(OH)—





Ic-c644


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c645


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c646


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c647


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c648


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c649


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c650


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c651


embedded image


—CH(OH)—





Ic-c652


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c653


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c654


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c655


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c656


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c657


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c658


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c659


embedded image


—CH(OH)—





Ic-c660


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c661


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c662


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c663


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c664


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c665


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c666


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c667


embedded image


—CH(OH)—





Ic-c668


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c669


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c670


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c671


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c672


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c673


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c674


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c675


embedded image


—CH(OH)—





Ic-c676


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c677


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c678


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c679


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c680


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c681


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c682


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c683


embedded image


—CH(OH)—





Ic-c684


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c685


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c686


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c687


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c688


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c689


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c690


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c691


embedded image


—CH(OH)—





Ic-c692


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c693


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c694


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c695


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c696


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c697


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c698


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c699


embedded image


—CH(OH)—





Ic-c700


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c701


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c702


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c703


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c704


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c705


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c706


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c707


embedded image


—CH(OH)—





Ic-c708


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c709


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c710


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c711


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c712


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c713


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c714


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c715


embedded image


—CH(OH)—





Ic-c716


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c717


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c718


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c719


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c720


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c721


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c722


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c723


embedded image


—CH(OH)—





Ic-c724


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c725


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c726


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c727


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c728


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c729


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c730


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c731


embedded image


—CH(OH)—





Ic-c732


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c733


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c734


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c735


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c736


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c737


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c738


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c739


embedded image


—CH(OH)—





Ic-c740


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c741


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c742


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c743


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c744


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c745


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c746


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c747


embedded image


—CH(OH)—





Ic-c748


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c749


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c750


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c751


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c752


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c753


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c754


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c755


embedded image


—CH(OH)—





Ic-c756


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c757


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c758


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c759


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c760


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c761


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c762


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c763


embedded image


—CH(OH)—





Ic-c764


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c765


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c766


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c767


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c768


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c769


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c770


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c771


embedded image


—CH(OH)—





Ic-c772


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c773


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c774


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c775


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c776


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c777


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c778


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c779
—CH2—NH—CH3
—CH(OH)—


Ic-c780
—CH2—NH—CH3
—N(C(O)N(H)—CH2—CH2—OH)—


Ic-c781
—CH2—NH—CH3
—N(C(O)N(H)—CH2—CH2—F)—


Ic-c782
—CH2—NH—CH3
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ic-c783
—CH2—NH—CH3
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c784
—CH2—NH—CH3
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c785
—CH2—NH—CH3
—N(C(O)N(H)—CH2—CF3)—


Ic-c786
—CH2—NH—CH3
—N(C(O)N(H)—(CH2)3—OH)—


Ic-c787
—CH2—NH—CH2—CH3
—CH(OH)—


Ic-c788
—CH2—NH—CH2—CH3
—N(C(O)N(H)—CH2—CH2—OH)—


Ic-c789
—CH2—NH—CH2—CH3
—N(C(O)N(H)—CH2—CH2—F)—


Ic-c790
—CH2—NH—CH2—CH3
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ic-c791
—CH2—NH—CH2—CH3
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c792
—CH2—NH—CH2—CH3
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c793
—CH2—NH—CH2—CH3
—N(C(O)N(H)—CH2—CF3)—


Ic-c794
—CH2—NH—CH2—CH3
—N(C(O)N(H)—(CH2)3—OH)—


Ic-c795
—CH2—NH—CH2—CH2—CH3
—CH(OH)—


Ic-c796
—CH2—NH—CH2—CH2—CH3
—N(C(O)N(H)—CH2—CH2—OH)—


Ic-c797
—CH2—NH—CH2—CH2—CH3
—N(C(O)N(H)—CH2—CH2—F)—


Ic-c798
—CH2—NH—CH2—CH2—CH3
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ic-c799
—CH2—NH—CH2—CH2—CH3
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c800
—CH2—NH—CH2—CH2—CH3
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c801
—CH2—NH—CH2—CH2—CH3
—N(C(O)N(H)—CH2—CF3)—


Ic-c802
—CH2—NH—CH2—CH2—CH3
—N(C(O)N(H)—(CH2)3—OH)—





Ic-c803


embedded image


—CH(OH)—





Ic-c804


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c805


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c806


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c807


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c808


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c809


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c810


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c811


embedded image


—CH(OH)—





Ic-c812


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c813


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c814


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c815


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c816


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c817


embedded image


N(C(O)N(H)—CH2—CF3)—





Ic-c818


embedded image


N(C(O)N(H)—(CH2)3—OH)—





Ic-c819


embedded image


—CH(OH)—





Ic-c820


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c821


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c822


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c823


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c824


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c825


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c826


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c827


embedded image


—CH(OH)—





Ic-c828


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c829


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c830


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c831


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c832


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c833


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c834


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c835


embedded image


—CH(OH)—





Ic-c836


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c837


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c838


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c839


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c840


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c841


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c842


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c843


embedded image


—CH(OH)—





Ic-c844


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c845


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c846


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c847


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c848


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c849


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c850


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c851


embedded image


—CH(OH)—





Ic-c852


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c853


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c854


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c855


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c856


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c857


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c858


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c859


embedded image


—CH(OH)—





Ic-c860


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c861


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c862


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c863


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c864


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c865


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c866


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c867


embedded image


—CH(OH)—





Ic-c868


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c869


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c870


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c871


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c872


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c873


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c874


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c875


embedded image


—CH(OH)—





Ic-c876


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c877


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c878


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c879


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c880


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c881


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c882


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c883


embedded image


—CH(OH)—





Ic-c884


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c885


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c886


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c887


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c888


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c889


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c890


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c891


embedded image


—CH(OH)—





Ic-c892


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c893


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c894


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c895


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c896


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c897


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c898


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c899


embedded image


—CH(OH)—





Ic-c900


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c901


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c902


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c903


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c904


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c905


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c906


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c907


embedded image


—CH(OH)—





Ic-c908


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c909


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c910


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c911


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c912


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c913


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c914


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c915


embedded image


—CH(OH)—





Ic-c916


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c917


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c918


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c919


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c920


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c921


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c922


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c923


embedded image


—CH(OH)—





Ic-c924


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c925


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c926


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c927


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c928


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c929


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c930


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c931


embedded image


—CH(OH)—





Ic-c932


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c933


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c934


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c935


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c936


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c937


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c938


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c939


embedded image


—CH(OH)—





Ic-c940


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c941


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c942


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c943


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c944


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c945


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c946


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c947


embedded image


—CH(OH)—





Ic-c948


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c949


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c950


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c951


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c952


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c953


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c954


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c955


embedded image


—CH(OH)—





Ic-c956


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c957


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c958


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c959


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c960


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c961


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c962


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c963
—CH2—N(CH2CH3)(CH3)
—CH(OH)—


Ic-c964
—CH2—N(CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—OH)—


Ic-c965
—CH2—N(CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—F)—


Ic-c966
—CH2—N(CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ic-c967
—CH2—N(CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c968
—CH2—N(CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c969
—CH2—N(CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CF3)—


Ic-c970
—CH2—N(CH2CH3)(CH3)
—N(C(O)N(H)—(CH2)3—OH)—


Ic-c971
—CH2—N(CH2CH2CH3)(CH3)
—CH(OH)—


Ic-c972
—CH2—N(CH2CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—OH)—


Ic-c973
—CH2—N(CH2CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—F)—


Ic-c974
—CH2—N(CH2CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ic-c975
—CH2—N(CH2CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c976
—CH2—N(CH2CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c977
—CH2—N(CH2CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CF3)—


Ic-c978
—CH2—N(CH2CH2CH3)(CH3)
—N(C(O)N(H)—(CH2)3—OH)—


Ic-c979
—CH2—N(CH2CH2CH2CH3)(CH3)
—CH(OH)—


Ic-c980
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—OH)—


Ic-c981
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—F)—


Ic-c982
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ic-c983
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c984
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c985
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(C(O)N(H)—CH2—CF3)—


Ic-c986
—CH2—N(CH2CH2CH2CH3)(CH3)
—N(C(O)N(H)—(CH2)3—OH)—


Ic-c987
—CH2—NH—CH2CH2CH2CH3
—CH(OH)—


Ic-c988
—CH2—NH—CH2CH2CH2CH3
—N(C(O)N(H)—CH2—CH2—OH)—


Ic-c989
—CH2—NH—CH2CH2CH2CH3
—N(C(O)N(H)—CH2—CH2—F)—


Ic-c990
—CH2—NH—CH2CH2CH2CH3
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ic-c991
—CH2—NH—CH2CH2CH2CH3
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c992
—CH2—NH—CH2CH2CH2CH3
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c993
—CH2—NH—CH2CH2CH2CH3
—N(C(O)N(H)—CH2—CF3)—


Ic-c994
—CH2—NH—CH2CH2CH2CH3
—N(C(O)N(H)—(CH2)3—OH)—


Ic-c995
—CH2—NH—CH2CH2—O—CH3
—CH(OH)—


Ic-c996
—CH2—NH—CH2CH2—O—CH3
—N(C(O)N(H)—CH2—CH2—OH)—


Ic-c997
—CH2—NH—CH2CH2—O—CH3
—N(C(O)N(H)—CH2—CH2—F)—


Ic-c998
—CH2—NH—CH2CH2—O—CH3
—N(C(O)N(H)—CH2—CH2—OCH3)—


Ic-c999
—CH2—NH—CH2CH2—O—CH3
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c1000
—CH2—NH—CH2CH2—O—CH3
—N(C(O)N(H)—CH2—CH2—CF3)—


Ic-c1001
—CH2—NH—CH2CH2—O—CH3
—N(C(O)N(H)—CH2—CF3)—


Ic-c1002
—CH2—NH—CH2CH2—O—CH3
—N(C(O)N(H)—(CH2)3—OH)—





Ic-c1003


embedded image


—CH(OH)—





Ic-c1004


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c1005


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c1006


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c1007


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c1008


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c1009


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c1010


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c1011


embedded image


—CH(OH)—





Ic-c1012


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c1013


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c1014


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c1015


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c1016


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c1017


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c1018


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c1019


embedded image


—CH(OH)—





Ic-c1020


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c1021


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c1022


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c1023


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c1024


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c1025


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c1026


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c1027


embedded image


—CH(OH)—





Ic-c1028


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c1029


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c1030


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c1031


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c1032


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c1033


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c1034


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c1035


embedded image


—CH(OH)—





Ic-c1036


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c1037


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c1038


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c1039


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c1040


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c1041


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c1042


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c1043


embedded image


—CH(OH)—





Ic-c1044


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c1045


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c1046


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c1047


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c1048


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c1049


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c1050


embedded image


—N(C(O)N(H)—(CH2)3—OH)—





Ic-c1051


embedded image


—CH(OH)—





Ic-c1052


embedded image


—N(C(O)N(H)—CH2—CH2—OH)—





Ic-c1053


embedded image


—N(C(O)N(H)—CH2—CH2—F)—





Ic-c1054


embedded image


—N(C(O)N(H)—CH2—CH2—OCH3)—





Ic-c1055


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c1056


embedded image


—N(C(O)N(H)—CH2—CH2—CF3)—





Ic-c1057


embedded image


—N(C(O)N(H)—CH2—CF3)—





Ic-c1058


embedded image


—N(C(O)N(H)—(CH2)3—OH)—









and pharmaceutically acceptable salts thereof.


5.5 The Indenoisoquinolinone Analogs of Formula (IIa)

The present invention provides Indenoisoquinolinone Analogs according to Formula (IIa), below:




embedded image



and pharmaceutically acceptable salts thereof,


wherein:


X and R1 are as defined above for the compounds of Formula (Ia).


In one embodiment, X is —CH2—. 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(C1-C4 alkyl)-. In another embodiment, X is —S—. In another embodiment, X is —CH(OH)—.


In one embodiment, n is 1. In another embodiment, n is 2.


In one embodiment, X is —CH2— and n is 1.


In one embodiment, X is —CH2— and n is 2.


In one embodiment, X is —CH(OH)— and n is 1.


In one embodiment, X is —CH(OH)— and n is 2.


In one embodiment, R2 is —C1-C6 alkyl and R3 is —C(O)—(C1-C6 alkylene)-(3- to 7-membered monocyclic heterocycle).


In one embodiment, R2 is —H and R3 is —C(O)—(C1-C6 alkylene)-(3- to 7-membered monocyclic heterocycle).


In one embodiment, n is 1 and R3 is a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one —C(O)O—C1-C6 alkyl.


In another embodiment, n is 1 and R3 is C3-C8 monocyclic cycloalkyl substituted with one hydroxy-substituted C1-C5 alkyl.


In one embodiment, n is 2 and R3 is a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one —C(O)O—C1-C6 alkyl.


In another embodiment, n is 2 and R3 is C3-C8 monocyclic cycloalkyl substituted with one hydroxy-substituted C1-C5 alkyl.


In one embodiment, N, R2 and R3 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which substituted with one of —C2-C6 alkenyl, —C(O)—C1-C6 alkyl, —(C1-C4 alkylene)-C(O)—(C3-C8 monocyclic cycloalkyl), —C7-C10 alkyl, —(C1-C5 alkylene)-C(H)(—O—C1-C4 alkyl)2, -(cyano-substituted) C1-C5 alkyl, —(C1-C5 alkylene)-C(O)-(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or —(C1-C5 alkylene)-(3- to 7-membered monocyclic heterocycle).


In one embodiment, n is 1 and N, R2 and R3 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which substituted with one of —C2-C6 alkenyl, —C(O)—C1-C6 alkyl, —(C1-C4 alkylene)-C(O)—(C3-C8 monocyclic cycloalkyl), —C7-C10 alkyl, —(C1-C5 alkylene)-C(H)(—O—C1-C4 alkyl)2, -(cyano-substituted) C1-C5 alkyl, —(C1-C5 alkylene)-C(O)-(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or —(C1-C5 alkylene)-(3- to 7-membered monocyclic heterocycle).


In one embodiment, X is —CH2—, n is 1 and N, R2 and R3 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which substituted with one of —C2-C6 alkenyl, —C(O)—C1-C6 alkyl, —(C1-C4 alkylene)-C(O)—(C3-C8 monocyclic cycloalkyl), —C7-C10 alkyl, —(C1-C5 alkylene)-C(H)(—O—C1-C4 alkyl)2, -(cyano-substituted) C1-C5 alkyl, —(C1-C5 alkylene)-C(O)-(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or —(C1-C5 alkylene)-(3- to 7-membered monocyclic heterocycle).


In one embodiment, X is —CH2—, n is 1, and R2 is C3-C8 monocyclic cycloalkyl.


In one embodiment, X is —CH2—, n is 1, and R3 is a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one —C(O)O—C1-C6 alkyl.


In one embodiment, X is —CH2—, n is 1, and R3 is C3-C8 monocyclic cycloalkyl which is substituted with one hydroxy-substituted C1-C5 alkyl.


In one embodiment, X is —CH2—, n is 1, R2 is —H, and R3 is a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one —C(O)O—C1-C6 alkyl.


In one embodiment, X is —CH2—, n is 1, R2 is —H, and R3 is C3-C8 monocyclic cycloalkyl which is substituted with one hydroxy-substituted C1-C5 alkyl.


In another embodiment, X is —CH2—, n is 1 and R3 is —C(O)—C1-C6 alkylene-(3- to 7-membered monocyclic heterocycle).


In one embodiment, X is —CH(OH)—, n is 1 and N, R2 and R3 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which substituted with one of —C2-C6 alkenyl, —C(O)—C1-C6 alkyl, —(C1-C4 alkylene)-C(O)—(C3-C8 monocyclic cycloalkyl), —C7-C10 alkyl, —(C1-C5 alkylene)-C(H)(—O—C1-C4 alkyl)2, -(cyano-substituted) C1-C5 alkyl, —(C1-C5 alkylene)-C(O)-(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or —(C1-C5 alkylene)-(3- to 7-membered monocyclic heterocycle).


In one embodiment, X is —CH(OH)—, n is 1, and R2 is C3-C8 monocyclic cycloalkyl.


In one embodiment, X is —CH(OH)—, n is 1, and R3 is a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one —C(O)O—C1-C6 alkyl.


In one embodiment, X is —CH(OH)—, n is 1, and R3 is C3-C8 monocyclic cycloalkyl which is substituted with one hydroxy-substituted C1-C5 alkyl.


In one embodiment, X is —CH(OH)—, n is 1, R2 is —H, and R3 is a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one —C(O)O—C1-C6 alkyl.


In one embodiment, X is —CH(OH)—, n is 1, R2 is —H, and R3 is C3-C8 monocyclic cycloalkyl which is substituted with one hydroxy-substituted C1-C5 alkyl.


In another embodiment, X is —CH(OH)—, n is 1 and R3 is —C(O)—C1-C6 alkylene-(3- to 7-membered monocyclic heterocycle).


In various embodiments, —R1 is:




embedded image


embedded image


Illustrative examples of the Indenoisoquinolinone Analogs include the compounds of Formula (IIa) in which n is 1 as set forth below:














(IIa)




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Compound
—R1
X





IIa-1


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—CH2





IIa-a1


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—CH(OH)—





IIa-2


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—O—





IIa-3


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—C(O)—





IIa-4


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—NH—





IIa-5


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—S—





IIa-6


embedded image


—N(CH3)—





IIa-7


embedded image


—N(CH2CH3)—





IIa-8


embedded image


—N(CH2CH2CH3)—





IIa-9


embedded image


—N(CH2CH2CH2CH3)—





IIa-10


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIa-11


embedded image


—N(C(H)(CH3)2)—





IIa-12


embedded image


—N(CH2C(H)(CH3)2)—





IIa-13


embedded image


—N(C(CH3)3)—





IIa-14


embedded image


—CH2





IIa-a14


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—CH(OH)—





IIa-15


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—O—





IIa-16


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—C(O)—





IIa-17


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—NH—





IIa-18


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—S—





IIa-19


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—N(CH3)—





IIa-20


embedded image


—N(CH2CH3)—





IIa-21


embedded image


—N(CH2CH2CH3)—





IIa-22


embedded image


—N(CH2CH2CH2CH3)—





IIa-23


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIa-24


embedded image


—N(C(H)(CH3)2)—





IIa-25


embedded image


—N(CH2C(H)(CH3)2)—





IIa-26


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—N(C(CH3)3)—





IIa-27


embedded image


—CH2





IIa-a27


embedded image


—CH(OH)—





IIa-28


embedded image


—O—





IIa-29


embedded image


—C(O)—





IIa-30


embedded image


—NH—





IIa-31


embedded image


—S—





IIa-32


embedded image


—N(CH3)—





IIa-33


embedded image


—N(CH2CH3)—





IIa-34


embedded image


—N(CH2CH2CH3)—





IIa-35


embedded image


—N(CH2CH2CH2CH3)—





IIa-36


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIa-37


embedded image


—N(C(H)(CH3)2)—





IIa-38


embedded image


—N(CH2C(H)(CH3)2)—





IIa-39


embedded image


—N(C(CH3)3)—





IIa-40


embedded image


—CH2





IIa-a40


embedded image


—CH(OH)—





IIa-41


embedded image


—O—





IIa-42


embedded image


—C(O)—





IIa-43


embedded image


—NH—





IIa-44


embedded image


—S—





IIa-45


embedded image


—N(CH3)—





IIa-46


embedded image


—N(CH2CH3)—





IIa-47


embedded image


—N(CH2CH2CH3)—





IIa-48


embedded image


—N(CH2CH2CH2CH3)—





IIa-49


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIa-50


embedded image


—N(C(H)(CH3)2)—





IIa-51


embedded image


—N(CH2C(H)(CH3)2)—





IIa-52


embedded image


—N(C(CH3)3)—





IIa-53


embedded image


—CH2





IIa-a53


embedded image


—CH(OH)—





IIa-54


embedded image


—O—





IIa-55


embedded image


—C(O)—





IIa-56


embedded image


—NH—





IIa-57


embedded image


—S—





IIa-58


embedded image


—N(CH3)—





IIa-59


embedded image


—N(CH2CH3)—





IIa-60


embedded image


—N(CH2CH2CH3)—





IIa-61


embedded image


—N(CH2CH2CH2CH3)—





IIa-62


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIa-63


embedded image


—N(C(H)(CH3)2)—





IIa-64


embedded image


—N(CH2C(H)(CH3)2)—





IIa-65


embedded image


—N(C(CH3)3)—





IIa-66


embedded image


—CH2





IIa-a66


embedded image


—CH(OH)—





IIa-67


embedded image


—O—





IIa-68


embedded image


—C(O)—





IIa-69


embedded image


—NH—





IIa-70


embedded image


—S—





IIa-71


embedded image


—N(CH3)—





IIa-72


embedded image


—N(CH2CH3)—





IIa-73


embedded image


—N(CH2CH2CH3)—





IIa-74


embedded image


—N(CH2CH2CH2CH3)—





IIa-75


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIa-76


embedded image


—N(C(H)(CH3)2)—





IIa-77


embedded image


—N(CH2C(H)(CH3)2)—





IIa-78


embedded image


—N(C(CH3)3)—





IIa-79


embedded image


—CH2





IIa-a79


embedded image


—CH(OH)—





IIa-80


embedded image


—O—





IIa-81


embedded image


—C(O)—





IIa-82


embedded image


—NH—





IIa-83


embedded image


—S—





IIa-84


embedded image


—N(CH3)—





IIa-85


embedded image


—N(CH2CH3)—





IIa-86


embedded image


—N(CH2CH2CH3)—





IIa-87


embedded image


—N(CH2CH2CH2CH3)—





IIa-88


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIa-89


embedded image


—N(C(H)(CH3)2)—





IIa-90


embedded image


—N(CH2C(H)(CH3)2)—





IIa-91


embedded image


—N(C(CH3)3)—





IIa-92


embedded image


—CH2





IIa-a92


embedded image


—CH(OH)—





IIa-93


embedded image


—O—





IIa-94


embedded image


—C(O)—





IIa-95


embedded image


—NH—





IIa-96


embedded image


—S—





IIa-97


embedded image


—N(CH3)—





IIa-98


embedded image


—N(CH2CH3)—





IIa-99


embedded image


—N(CH2CH2CH3)—





IIa-100


embedded image


—N(CH2CH2CH2CH3)—





IIa-101


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIa-102


embedded image


—N(C(H)(CH3)2)—





IIa-103


embedded image


—N(CH2C(H)(CH3)2)—





IIa-104


embedded image


—N(C(CH3)3)—





IIa-105


embedded image


—CH2





IIa-a105


embedded image


—CH(OH)—





IIa-106


embedded image


—O—





IIa-107


embedded image


—C(O)—





IIa-108


embedded image


—NH—





IIa-109


embedded image


—S—





IIa-110


embedded image


—N(CH3)—





IIa-111


embedded image


—N(CH2CH3)—





IIa-112


embedded image


—N(CH2CH2CH3)—





IIa-113


embedded image


—N(CH2CH2CH2CH3)—





IIa-114


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIa-115


embedded image


—N(C(H)(CH3)2)—





IIa-116


embedded image


—N(CH2C(H)(CH3)2)—





IIa-117


embedded image


—N(C(CH3)3)—





IIa-118


embedded image


—CH2





IIa-a118


embedded image


—CH(OH)—





IIa-119


embedded image


—O—





IIa-120


embedded image


—C(O)—





IIa-121


embedded image


—NH—





IIa-122


embedded image


—S—





IIa-123


embedded image


—N(CH3)—





IIa-124


embedded image


—N(CH2CH3)—





IIa-125


embedded image


—N(CH2CH2CH3)—





IIa-126


embedded image


—N(CH2CH2CH2CH3)—





IIa-127


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIa-128


embedded image


—N(C(H)(CH3)2)—





IIa-129


embedded image


—N(CH2C(H)(CH3)2)—





IIa-130


embedded image


—N(C(CH3)3)—





IIa-131


embedded image


—CH2





IIa-a131


embedded image


—CH(OH)—





IIa-132


embedded image


—O—





IIa-133


embedded image


—C(O)—





IIa-134


embedded image


—NH—





IIa-135


embedded image


—S—





IIa-136


embedded image


—N(CH3)—





IIa-137


embedded image


—N(CH2CH3)—





IIa-138


embedded image


—N(CH2CH2CH3)—





IIa-139


embedded image


—N(CH2CH2CH2CH3)—





IIa-140


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIa-141


embedded image


—N(C(H)(CH3)2)—





IIa-142


embedded image


—N(CH2C(H)(CH3)2)—





IIa-143


embedded image


—N(C(CH3)3)—





IIa-144


embedded image


—CH2





IIa-a144


embedded image


—CH(OH)—





IIa-145


embedded image


—O—





IIa-146


embedded image


—C(O)—





IIa-147


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—NH—





IIa-148


embedded image


—S—





IIa-149


embedded image


—N(CH3)—





IIa-150


embedded image


—N(CH2CH3)—





IIa-151


embedded image


—N(CH2CH2CH3)—





IIa-152


embedded image


—N(CH2CH2CH2CH3)—





IIa-153


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIa-154


embedded image


—N(C(H)(CH3)2)—





IIa-155


embedded image


—N(CH2C(H)(CH3)2)—





IIa-156


embedded image


—N(C(CH3)3)—





IIa-157


embedded image


—CH2





IIa-a157


embedded image


—CH(OH)—





IIa-158


embedded image


—O—





IIa-159


embedded image


—C(O)—





IIa-160


embedded image


—NH—





IIa-161


embedded image


—S—





IIa-162


embedded image


—N(CH3)—





IIa-163


embedded image


—N(CH2CH3)—





IIa-164


embedded image


—N(CH2CH2CH3)—





IIa-165


embedded image


—N(CH2CH2CH2CH3)—





IIa-166


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIa-167


embedded image


—N(C(H)(CH3)2)—





IIa-168


embedded image


—N(CH2C(H)(CH3)2)—





IIa-169


embedded image


—N(C(CH3)3)—





IIa-170


embedded image


—CH2





IIa-a170


embedded image


—CH(OH)—





IIa-171


embedded image


—O—





IIa-172


embedded image


—C(O)—





IIa-173


embedded image


—NH—





IIa-174


embedded image


—S—





IIa-175


embedded image


—N(CH3)—





IIa-176


embedded image


—N(CH2CH3)—





IIa-177


embedded image


—N(CH2CH2CH3)—





IIa-178


embedded image


—N(CH2CH2CH2CH3)—





IIa-179


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIa-180


embedded image


—N(C(H)(CH3)2)—





IIa-181


embedded image


—N(CH2C(H)(CH3)2)—





IIa-182


embedded image


—N(C(CH3)3)—





IIa-183


embedded image


—CH2





IIa-a183


embedded image


—CH(OH)—





IIa-184


embedded image


—O—





IIa-185


embedded image


—C(O)—





IIa-186


embedded image


—NH—





IIa-187


embedded image


—S—





IIa-188


embedded image


—N(CH3)—





IIa-189


embedded image


—N(CH2CH3)—





IIa-190


embedded image


—N(CH2CH2CH3)—





IIa-191


embedded image


—N(CH2CH2CH2CH3)—





IIa-192


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIa-193


embedded image


—N(C(H)(CH3)2)—





IIa-194


embedded image


—N(CH2C(H)(CH3)2)—





IIa-195


embedded image


—N(C(CH3)3)—





IIa-196


embedded image


—CH2





IIa-197


embedded image


—CH(OH)—





IIa-198


embedded image


—O—





IIa-199


embedded image


—C(O)—





IIa-200


embedded image


—NH—





IIa-201


embedded image


—S—





IIa-202


embedded image


—N(CH3)—





IIa-203


embedded image


—N(CH2CH3)—





IIa-204


embedded image


—N(CH2CH2CH3)—





IIa-205


embedded image


—N(CH2CH2CH2CH3)—





IIa-206


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIa-207


embedded image


—N(C(H)(CH3)2)—





IIa-208


embedded image


—N(CH2C(H)(CH3)2)—





IIa-209


embedded image


—N(C(CH3)3)—









and pharmaceutically acceptable salts thereof.


5.6 The Indenoisoquinolinone Analogs of Formula (IIb)

The present invention provides Indenoisoquinolinone Analogs according to Formula (IIb) below:




embedded image


and pharmaceutically acceptable salts thereof,


wherein:


X and R1 are as defined above for the compounds of Formula (IIb).


In one embodiment, X is —CH2—. 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(C1-C4 alkyl)-. In another embodiment, X is —S—. In another embodiment, X is —CH(OH)—.


In one embodiment, n is 1. In another embodiment, n is 2.


In one embodiment, X is —CH2— and n is 1.


In one embodiment, X is —CH2— and n is 2.


In one embodiment, X is —CH(OH)— and n is 1.


In one embodiment, X is —CH(OH)— and n is 2.


In one embodiment, R2 is —C1-C6 alkyl and R3 is —C(O)—(C1-C6 alkylene)-(3- to 7-membered monocyclic heterocycle).


In one embodiment, R2 is —H and R3 is —C(O)—(C1-C6 alkylene)-(3- to 7-membered monocyclic heterocycle).


In one embodiment, n is 1 and R3 is a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one —C(O)O—C1-C6 alkyl.


In another embodiment, n is 1 and R3 is C3-C8 monocyclic cycloalkyl substituted with one hydroxy-substituted C1-C5 alkyl.


In one embodiment, n is 2 and R3 is a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one —C(O)O—C1-C6 alkyl.


In another embodiment, n is 2 and R3 is C3-C8 monocyclic cycloalkyl substituted with one hydroxy-substituted C1-C5 alkyl.


In one embodiment, N, R2 and R3 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which substituted with one of —C2-C6 alkenyl, —C(O)—C1-C6 alkyl, —(C1-C4 alkylene)-C(O)—(C3-C8 monocyclic cycloalkyl), —C7-C10 alkyl, —(C1-C5 alkylene)-C(H)(—O—C1-C4 alkyl)2, -(cyano-substituted) C1-C5 alkyl, —(C1-C5 alkylene)-C(O)-(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or —(C1-C5 alkylene)-(3- to 7-membered monocyclic heterocycle).


In one embodiment, n is 1 and N, R2 and R3 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which substituted with one of —C2-C6 alkenyl, —C(O)—C1-C6 alkyl, —(C1-C4 alkylene)-C(O)—(C3-C8 monocyclic cycloalkyl), —C7-C10 alkyl, —(C1-C5 alkylene)-C(H)(—O—C1-C4 alkyl)2, -(cyano-substituted) C1-C5 alkyl, —(C1-C5 alkylene)-C(O)-(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or —(C1-C5 alkylene)-(3- to 7-membered monocyclic heterocycle).


In one embodiment, X is —CH2—, n is 1 and N, R2 and R3 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which substituted with one of —C2-C6 alkenyl, —C(O)—C1-C6 alkyl, —(C1-C4 alkylene)-C(O)—(C3-C8 monocyclic cycloalkyl), —C7-C10 alkyl, —(C1-C5 alkylene)-C(H)(—O—C1-C4 alkyl)2, -(cyano-substituted) C1-C5 alkyl, —(C1-C5 alkylene)-C(O)-(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or —(C1-C5 alkylene)-(3- to 7-membered monocyclic heterocycle).


In one embodiment, X is —CH2—, n is 1, and R2 is C3-C8 monocyclic cycloalkyl.


In one embodiment, X is —CH2—, n is 1, and R3 is a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one —C(O)O—C1-C6 alkyl.


In one embodiment, X is —CH2—, n is 1, and R3 is C3-C8 monocyclic cycloalkyl which is substituted with one hydroxy-substituted C1-C5 alkyl.


In one embodiment, X is —CH2—, n is 1, R2 is —H, and R3 is a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one —C(O)O—C1-C6 alkyl.


In one embodiment, X is —CH2—, n is 1, R2 is —H, and R3 is C3-C8 monocyclic cycloalkyl which is substituted with one hydroxy-substituted C1-C5 alkyl.


In another embodiment, X is —CH2—, n is 1 and R3 is —C(O)—C1-C6 alkylene-(3- to 7-membered monocyclic heterocycle).


In one embodiment, X is —CH(OH)—, n is 1 and N, R2 and R3 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which substituted with one of —C2-C6 alkenyl, —C(O)—C1-C6 alkyl, —(C1-C4 alkylene)-C(O)—(C3-C8 monocyclic cycloalkyl), —C7-C10 alkyl, —(C1-C5 alkylene)-C(H)(—O—C1-C4 alkyl)2, -(cyano-substituted) C1-C5 alkyl, —(C1-C5 alkylene)-C(O)-(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or —(C1-C5 alkylene)-(3- to 7-membered monocyclic heterocycle).


In one embodiment, X is —CH(OH)—, n is 1, and R2 is C3-C8 monocyclic cycloalkyl.


In one embodiment, X is —CH(OH)—, n is 1, and R3 is a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one —C(O)O—C1-C6 alkyl.


In one embodiment, X is —CH(OH)—, n is 1, and R3 is C3-C8 monocyclic cycloalkyl which is substituted with one hydroxy-substituted C1-C5 alkyl.


In one embodiment, X is —CH(OH)—, n is 1, R2 is —H, and R3 is a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one —C(O)O—C1-C6 alkyl.


In one embodiment, X is —CH(OH)—, n is 1, R2 is —H, and R3 is C3-C8 monocyclic cycloalkyl which is substituted with one hydroxy-substituted C1-C5 alkyl.


In another embodiment, X is —CH(OH)—, n is 1 and R3 is —C(O)—C1-C6 alkylene-(3- to 7-membered monocyclic heterocycle).


In various embodiments, —R1 is:




embedded image


embedded image


Illustrative examples of the Indenoisoquinolinone Analogs include the compounds of Formula (IIb) in which n is 1 as set forth below:














Compound
—R1
X







IIb-1


embedded image


—CH2





IIb-b1


embedded image


—CH(OH)—





IIb-2


embedded image


—O—





IIb-3


embedded image


—C(O)—





IIb-4


embedded image


—NH—





IIb-5


embedded image


—S—





IIb-6


embedded image


—N(CH3)—





IIb-7


embedded image


—N(CH2CH3)—





IIb-8


embedded image


—N(CH2CH2CH3)—





IIb-9


embedded image


—N(CH2CH2CH2CH3)—





IIb-10


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIb-11


embedded image


—N(C(H)(CH3)2)—





IIb-12


embedded image


—N(CH2C(H)(CH3)2)—





IIb-13


embedded image


—N(C(CH3)3)—





IIb-14


embedded image


—CH2





IIb-b14


embedded image


—CH(OH)—





IIb-15


embedded image


—O—





IIb-16


embedded image


—C(O)—





IIb-17


embedded image


—NH—





IIb-18


embedded image


—S—





IIb-19


embedded image


—N(CH3)—





IIb-20


embedded image


—N(CH2CH3)—





IIb-21


embedded image


—N(CH2CH2CH3)—





IIb-22


embedded image


—N(CH2CH2CH2CH3)—





IIb-23


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIb-24


embedded image


—N(C(H)(CH3)2)—





IIb-25


embedded image


—N(CH2C(H)(CH3)2)—





IIb-26


embedded image


—N(C(CH3)3)—





IIb-27


embedded image


—CH2





IIb-b27


embedded image


—CH(OH)—





IIb-28


embedded image


—O—





IIb-29


embedded image


—C(O)—





IIb-30


embedded image


—NH—





IIb-31


embedded image


—S—





IIb-32


embedded image


—N(CH3)—





IIb-33


embedded image


—N(CH2CH3)—





IIb-34


embedded image


—N(CH2CH2CH3)—





IIb-35


embedded image


—N(CH2CH2CH2CH3)—





IIb-36


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIb-37


embedded image


—N(C(H)(CH3)2)—





IIb-38


embedded image


—N(CH2C(H)(CH3)2)—





IIb-39


embedded image


—N(C(CH3)3)—





IIb-40


embedded image


—CH2





IIb-b40


embedded image


—CH(OH)—





IIb-41


embedded image


—O—





IIb-42


embedded image


—C(O)—





IIb-43


embedded image


—NH—





IIb-44


embedded image


—S—





IIb-45


embedded image


—N(CH3)—





IIb-46


embedded image


—N(CH2CH3)—





IIb-47


embedded image


—N(CH2CH2CH3)—





IIb-48


embedded image


—N(CH2CH2CH2CH3)—





IIb-49


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIb-50


embedded image


—N(C(H)(CH3)2)—





IIb-51


embedded image


—N(CH2C(H)(CH3)2)—





IIb-52


embedded image


—N(C(CH3)3)—





IIb-53


embedded image


—CH2





IIb-b53


embedded image


—CH(OH)—





IIb-54


embedded image


—O—





IIb-55


embedded image


—C(O)—





IIb-56


embedded image


—NH—





IIb-57


embedded image


—S—





IIb-58


embedded image


—N(CH3)—





IIb-59


embedded image


—N(CH2CH3)—





IIb-60


embedded image


—N(CH2CH2CH3)—





IIb-61


embedded image


—N(CH2CH2CH2CH3)—





IIb-62


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIb-63


embedded image


—N(C(H)(CH3)2)—





IIb-64


embedded image


—N(CH2C(H)(CH3)2)—





IIb-65


embedded image


—N(C(CH3)3)—





IIb-66


embedded image


—CH2





IIb-b66


embedded image


—CH(OH)—





IIb-67


embedded image


—O—





IIb-68


embedded image


—C(O)—





IIb-69


embedded image


—NH—





IIb-70


embedded image


—S—





IIb-71


embedded image


—N(CH3)—





IIb-72


embedded image


—N(CH2CH3)—





IIb-73


embedded image


—N(CH2CH2CH3)—





IIb-74


embedded image


—N(CH2CH2CH2CH3)—





IIb-75


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIb-76


embedded image


—N(C(H)(CH3)2)—





IIb-77


embedded image


—N(CH2C(H)(CH3)2)—





IIb-78


embedded image


—N(C(CH3)3)—





IIb-79


embedded image


—CH2





IIb-b79


embedded image


—CH(OH)—





IIb-80


embedded image


—O—





IIb-81


embedded image


—C(O)—





IIb-82


embedded image


—NH—





IIb-83


embedded image


—S—





IIb-84


embedded image


—N(CH3)—





IIb-85


embedded image


—N(CH2CH3)—





IIb-86


embedded image


—N(CH2CH2CH3)—





IIb-87


embedded image


—N(CH2CH2CH2CH3)—





IIb-88


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIb-89


embedded image


—N(C(H)(CH3)2)—





IIb-90


embedded image


—N(CH2C(H)(CH3)2)—





IIb-91


embedded image


—N(C(CH3)3)—





IIb-92


embedded image


—CH2





IIb-b92


embedded image


—CH(OH)—





IIb-93


embedded image


—O—





IIb-94


embedded image


—C(O)—





IIb-95


embedded image


—NH—





IIb-96


embedded image


—S—





IIb-97


embedded image


—N(CH3)—





IIb-98


embedded image


—N(CH2CH3)—





IIb-99


embedded image


—N(CH2CH2CH3)—





IIb-100


embedded image


—N(CH2CH2CH2CH3)—





IIb-101


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIb-102


embedded image


—N(C(H)(CH3)2)—





IIb-103


embedded image


—N(CH2C(H)(CH3)2)—





IIb-104


embedded image


—N(C(CH3)3)—





IIb-105


embedded image


—CH2





IIb-b105


embedded image


—CH(OH)—





IIb-106


embedded image


—O—





IIb-107


embedded image


—C(O)—





IIb-108


embedded image


—NH—





IIb-109


embedded image


—S—





IIb-110


embedded image


—N(CH3)—





IIb-111


embedded image


—N(CH2CH3)—





IIb-112


embedded image


—N(CH2CH2CH3)—





IIb-113


embedded image


—N(CH2CH2CH2CH3)—





IIb-114


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIb-115


embedded image


—N(C(H)(CH3)2)—





IIb-116


embedded image


—N(CH2C(H)(CH3)2)—





IIb-117


embedded image


—N(C(CH3)3)—





IIb-118


embedded image


—CH2





IIb-b118


embedded image


—CH(OH)—





IIb-119


embedded image


—O—





IIb-120


embedded image


—C(O)—





IIb-121


embedded image


—NH—





IIb-122


embedded image


—S—





IIb-123


embedded image


—N(CH3)—





IIb-124


embedded image


—N(CH2CH3)—





IIb-125


embedded image


—N(CH2CH2CH3)—





IIb-126


embedded image


—N(CH2CH2CH2CH3)—





IIb-127


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIb-128


embedded image


—N(C(H)(CH3)2)—





IIb-129


embedded image


—N(CH2C(H)(CH3)2)—





IIb-130


embedded image


—N(C(CH3)3)—





IIb-131


embedded image


—CH2





IIb-b131


embedded image


—CH(OH)—





IIb-132


embedded image


—O—





IIb-133


embedded image


—C(O)—





IIb-134


embedded image


—NH—





IIb-135


embedded image


—S—





IIb-136


embedded image


—N(CH3)—





IIb-137


embedded image


—N(CH2CH3)—





IIb-138


embedded image


—N(CH2CH2CH3)—





IIb-139


embedded image


—N(CH2CH2CH2CH3)—





IIb-140


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIb-141


embedded image


—N(C(H)(CH3)2)—





IIb-142


embedded image


—N(CH2C(H)(CH3)2)—





IIb-143


embedded image


—N(C(CH3)3)—





IIb-144


embedded image


—CH2





IIb-b144


embedded image


—CH(OH)—





IIb-145


embedded image


—O—





IIb-146


embedded image


—C(O)—





IIb-147


embedded image


—NH—





IIb-148


embedded image


—S—





IIb-149


embedded image


—N(CH3)—





IIb-150


embedded image


—N(CH2CH3)—





IIb-151


embedded image


—N(CH2CH2CH3)—





IIb-152


embedded image


—N(CH2CH2CH2CH3)—





IIb-153


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIb-154


embedded image


—N(C(H)(CH3)2)—





IIb-155


embedded image


—N(CH2C(H)(CH3)2)—





IIb-156


embedded image


—N(C(CH3)3)—





IIb-157


embedded image


—CH2





IIb-b157


embedded image


—CH(OH)—





IIb-158


embedded image


—O—





IIb-159


embedded image


—C(O)—





IIb-160


embedded image


—NH—





IIb-161


embedded image


—S—





IIb-162


embedded image


—N(CH3)—





IIb-163


embedded image


—N(CH2CH3)—





IIb-164


embedded image


—N(CH2CH2CH3)—





IIb-165


embedded image


—N(CH2CH2CH2CH3)—





IIb-166


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIb-167


embedded image


—N(C(H)(CH3)2)—





IIb-168


embedded image


—N(CH2C(H)(CH3)2)—





IIb-169


embedded image


—N(C(CH3)3)—





IIb-170


embedded image


—CH2





IIb-b170


embedded image


—CH(OH)—





IIb-171


embedded image


—O—





IIb-172


embedded image


—C(O)—





IIb-173


embedded image


—NH—





IIb-174


embedded image


—S—





IIb-175


embedded image


—N(CH3)—





IIb-176


embedded image


—N(CH2CH3)—





IIb-177


embedded image


—N(CH2CH2CH3)—





IIb-178


embedded image


—N(CH2CH2CH2CH3)—





IIb-179


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIb-180


embedded image


—N(C(H)(CH3)2)—





IIb-181


embedded image


—N(CH2C(H)(CH3)2)—





IIb-182


embedded image


—N(C(CH3)3)—





IIb-183


embedded image


—CH2





IIb-b183


embedded image


—CH(OH)—





IIb-184


embedded image


—O—





IIb-185


embedded image


—C(O)—





IIb-186


embedded image


—NH—





IIb-187


embedded image


—S—





IIb-188


embedded image


—N(CH3)—





IIb-189


embedded image


—N(CH2CH3)—





IIb-190


embedded image


—N(CH2CH2CH3)—





IIb-191


embedded image


—N(CH2CH2CH2CH3)—





IIb-192


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIb-193


embedded image


—N(C(H)(CH3)2)—





IIb-194


embedded image


—N(CH2C(H)(CH3)2)—





IIb-195


embedded image


—N(C(CH3)3)—





IIb-196


embedded image


—CH2





IIb-197


embedded image


—CH(OH)—





IIb-198


embedded image


—O—





IIb-199


embedded image


—C(O)—





IIb-200


embedded image


—NH—





IIb-201


embedded image


—S—





IIb-202


embedded image


—N(CH3)—





IIb-203


embedded image


—N(CH2CH3)—





IIb-204


embedded image


—N(CH2CH2CH3)—





IIb-205


embedded image


—N(CH2CH2CH2CH3)—





IIb-206


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIb-207


embedded image


—N(C(H)(CH3)2)—





IIb-208


embedded image


—N(CH2C(H)(CH3)2)—





IIb-209


embedded image


—N(C(CH3)3)—





IIb-210


embedded image


—CH2





IIb-211


embedded image


—CH(OH)—





IIb-212


embedded image


—O—





IIb-213


embedded image


—C(O)—





IIb-214


embedded image


—NH—





IIb-215


embedded image


—S—





IIb-216


embedded image


—N(CH3)—





IIb-217


embedded image


—N(CH2CH3)—





IIb-218


embedded image


—N(CH2CH2CH3)—





IIb-219


embedded image


—N(CH2CH2CH2CH3)—





IIb-220


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIb-221


embedded image


—N(C(H)(CH3)2)—





IIb-222


embedded image


—N(CH2C(H)(CH3)2)—





IIb-223


embedded image


—N(C(CH3)3)—









and pharmaceutically acceptable salts thereof.


5.7 The Indenoisoquinolinone Analogs of Formula (IIc)

The present invention provides Indenoisoquinolinone Analogs according to Formula (IIc) below:




embedded image



and pharmaceutically acceptable salts thereof,


wherein:


X and R1 are as defined above for the compounds of Formula (IIc).


In one embodiment, X is —CH2—. 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(C1-C4 alkyl)-. In another embodiment, X is —S—. In another embodiment, X is —CH(OH)—.


In one embodiment, n is 1. In another embodiment, n is 2.


In one embodiment, X is —CH2— and n is 1.


In one embodiment, X is —CH2— and n is 2.


In one embodiment, X is —CH(OH)— and n is 1.


In one embodiment, X is —CH(OH)— and n is 2.


In one embodiment, R2 is —C1-C6 alkyl and R3 is —C(O)—(C1-C6 alkylene)-(3- to 7-membered monocyclic heterocycle).


In one embodiment, R2 is —H and R3 is —C(O)—(C1-C6 alkylene)-(3- to 7-membered monocyclic heterocycle).


In one embodiment, n is 1 and R3 is a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one —C(O)O—C1-C6 alkyl.


In another embodiment, n is 1 and R3 is C3-C8 monocyclic cycloalkyl substituted with one hydroxy-substituted C1-C5 alkyl.


In one embodiment, n is 2 and R3 is a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one —C(O)O—C1-C6 alkyl.


In another embodiment, n is 2 and R3 is C3-C8 monocyclic cycloalkyl substituted with one hydroxy-substituted C1-C5 alkyl.


In one embodiment, N, R2 and R3 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which substituted with one of —C2-C6 alkenyl, —C(O)—C1-C6 alkyl, —(C1-C4 alkylene)-C(O)—(C3-C8 monocyclic cycloalkyl), —C7-C10 alkyl, —(C1-C5 alkylene)-C(H)(—O—C1-C4 alkyl)2, -(cyano-substituted) C1-C5 alkyl, —(C1-C5 alkylene)-C(O)-(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or —(C1-C5 alkylene)-(3- to 7-membered monocyclic heterocycle).


In one embodiment, n is 1 and N, R2 and R3 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which substituted with one of —C2-C6 alkenyl, —C(O)—C1-C6 alkyl, —(C1-C4 alkylene)-C(O)—(C3-C8 monocyclic cycloalkyl), —C7-C10 alkyl, —(C1-C5 alkylene)-C(H)(—O—C1-C4 alkyl)2, -(cyano-substituted) C1-C5 alkyl, —(C1-C5 alkylene)-C(O)-(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or —(C1-C5 alkylene)-(3- to 7-membered monocyclic heterocycle).


In one embodiment, X is —CH2—, n is 1 and N, R2 and R3 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which substituted with one of —C2-C6 alkenyl, —C(O)—C1-C6 alkyl, —(C1-C4 alkylene)-C(O)—(C3-C8 monocyclic cycloalkyl), —C7-C10 alkyl, —(C1-C5 alkylene)-C(H)(—O—C1-C4 alkyl)2, -(cyano-substituted) C1-C5 alkyl, —(C1-C5 alkylene)-C(O)-(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or —(C1-C5 alkylene)-(3- to 7-membered monocyclic heterocycle).


In one embodiment, X is —CH2—, n is 1, and R2 is C3-C8 monocyclic cycloalkyl.


In one embodiment, X is —CH2—, n is 1, and R3 is a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one —C(O)O—C1-C6 alkyl.


In one embodiment, X is —CH2—, n is 21, and R3 is C3-C8 monocyclic cycloalkyl which is substituted with one hydroxy-substituted C1-C5 alkyl.


In one embodiment, X is —CH2—, n is 1, R2 is —H, and R3 is a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one —C(O)O—C1-C6 alkyl.


In one embodiment, X is —CH2—, n is 1, R2 is —H, and R3 is C3-C8 monocyclic cycloalkyl which is substituted with one hydroxy-substituted C1-C5 alkyl.


In another embodiment, X is —CH2—, n is 1 and R3 is —C(O)—C1-C6 alkylene-(3- to 7-membered monocyclic heterocycle).


In one embodiment, X is —CH(OH)—, n is 1 and N, R2 and R3 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which substituted with one of —C2-C6 alkenyl, —C(O)—C1-C6 alkyl, —(C1-C4 alkylene)-C(O)—(C3-C8 monocyclic cycloalkyl), —C7-C10 alkyl, —(C1-C5 alkylene)-C(H)(—O—C1-C4 alkyl)2, -(cyano-substituted) C1-C5 alkyl, —(C1-C5 alkylene)-C(O)-(nitrogen-containing 3- to 7-membered monocyclic heterocycle), or —(C1-C5 alkylene)-(3- to 7-membered monocyclic heterocycle).


In one embodiment, X is —CH(OH)—, n is 1, and R2 is C3-C8 monocyclic cycloalkyl.


In one embodiment, X is —CH(OH)—, n is 1, and R3 is a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one —C(O)O—C1-C6 alkyl.


In one embodiment, X is —CH(OH)—, n is 1, and R3 is C3-C8 monocyclic cycloalkyl which is substituted with one hydroxy-substituted C1-C5 alkyl.


In one embodiment, X is —CH(OH)—, n is 1, R2 is —H, and R3 is a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one —C(O)O—C1-C6 alkyl.


In one embodiment, X is —CH(OH)—, n is 1, R2 is —H, and R3 is C3-C8 monocyclic cycloalkyl which is substituted with one hydroxy-substituted C1-C5 alkyl.


In another embodiment, X is —CH(OH)—, n is 1 and R3 is —C(O)—C1-C6 alkylene-(3- to 7-membered monocyclic heterocycle).


In various embodiments, —R1 is:




embedded image


embedded image


Illustrative examples of the Indenoisoquinolinone Analogs include the compounds of Formula (IIc) in which n is 1 as set forth below:














Compound
—R1
X







IIc-1


embedded image


—CH2





IIc-c1


embedded image


—CH(OH)—





IIc-2


embedded image


—O—





IIc-3


embedded image


—C(O)—





IIc-4


embedded image


—NH—





IIc-5


embedded image


—S—





IIc-6


embedded image


—N(CH3)—





IIc-7


embedded image


—N(CH2CH3)—





IIc-8


embedded image


—N(CH2CH2CH3)—





IIc-9


embedded image


—N(CH2CH2CH2CH3)—





IIc-10


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIc-11


embedded image


—N(C(H)(CH3)2)—





IIc-12


embedded image


—N(CH2C(H)(CH3)2)—





IIc-13


embedded image


—N(C(CH3)3)—





IIc-14


embedded image


—CH2





IIc-c14


embedded image


—CH(OH)—





IIc-15


embedded image


—O—





IIc-16


embedded image


—C(O)—





IIc-17


embedded image


—NH—





IIc-18


embedded image


—S—





IIc-19


embedded image


—N(CH3)—





IIc-20


embedded image


—N(CH2CH3)—





IIc-21


embedded image


—N(CH2CH2CH3)—





IIc-22


embedded image


—N(CH2CH2CH2CH3)—





IIc-23


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIc-24


embedded image


—N(C(H)(CH3)2)—





IIc-25


embedded image


—N(CH2C(H)(CH3)2)—





IIc-26


embedded image


—N(C(CH3)3)—





IIc-27


embedded image


—CH2





IIc-c27


embedded image


—CH(OH)—





IIc-28


embedded image


—O—





IIc-29


embedded image


—C(O)—





IIc-30


embedded image


—NH—





IIc-31


embedded image


—S—





IIc-32


embedded image


—N(CH3)—





IIc-33


embedded image


—N(CH2CH3)—





IIc-34


embedded image


—N(CH2CH2CH3)—





IIc-35


embedded image


—N(CH2CH2CH2CH3)—





IIc-36


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIc-37


embedded image


—N(C(H)(CH3)2)—





IIc-38


embedded image


—N(CH2C(H)(CH3)2)—





IIc-39


embedded image


—N(C(CH3)3)—





IIc-40


embedded image


—CH2





IIc-c40


embedded image


—CH(OH)—





IIc-41


embedded image


—O—





IIc-42


embedded image


—C(O)—





IIc-43


embedded image


—NH—





IIc-44


embedded image


—S—





IIc-45


embedded image


—N(CH3)—





IIc-46


embedded image


—N(CH2CH3)—





IIc-47


embedded image


—N(CH2CH2CH3)—





IIc-48


embedded image


—N(CH2CH2CH2CH3)—





IIc-49


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIc-50


embedded image


—N(C(H)(CH3)2)—





IIc-51


embedded image


—N(CH2C(H)(CH3)2)—





IIc-52


embedded image


—N(C(CH3)3)—





IIc-53


embedded image


—CH2





IIc-c53


embedded image


—CH(OH)—





IIc-54


embedded image


—O—





IIc-55


embedded image


—C(O)—





IIc-56


embedded image


—NH—





IIc-57


embedded image


—S—





IIc-58


embedded image


—N(CH3)—





IIc-59


embedded image


—N(CH2CH3)—





IIc-60


embedded image


—N(CH2CH2CH3)—





IIc-61


embedded image


—N(CH2CH2CH2CH3)—





IIc-62


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIc-63


embedded image


—N(C(H)(CH3)2)—





IIc-64


embedded image


—N(CH2C(H)(CH3)2)—





IIc-65


embedded image


—N(C(CH3)3)—





IIc-66


embedded image


—CH2





IIc-c66


embedded image


—CH(OH)—





IIc-67


embedded image


—O—





IIc-68


embedded image


—C(O)—





IIc-69


embedded image


—NH—





IIc-70


embedded image


—S—





IIc-71


embedded image


—N(CH3)—





IIc-72


embedded image


—N(CH2CH3)—





IIc-73


embedded image


—N(CH2CH2CH3)—





IIc-74


embedded image


—N(CH2CH2CH2CH3)—





IIc-75


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIc-76


embedded image


—N(C(H)(CH3)2)—





IIc-77


embedded image


—N(CH2C(H)(CH3)2)—





IIc-78


embedded image


—N(C(CH3)3)—





IIc-79


embedded image


—CH2





IIc-c79


embedded image


—CH(OH)—





IIc-80


embedded image


—O—





IIc-81


embedded image


—C(O)—





IIc-82


embedded image


—NH—





IIc-83


embedded image


—S—





IIc-84


embedded image


—N(CH3)—





IIc-85


embedded image


—N(CH2CH3)—





IIc-86


embedded image


—N(CH2CH2CH3)—





IIc-87


embedded image


—N(CH2CH2CH2CH3)—





IIc-88


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIc-89


embedded image


—N(C(H)(CH3)2)—





IIc-90


embedded image


—N(CH2C(H)(CH3)2)—





IIc-91


embedded image


—N(C(CH3)3)—





IIc-92


embedded image


—CH2





IIc-c92


embedded image


—CH(OH)—





IIc-93


embedded image


—O—





IIc-94


embedded image


—C(O)—





IIc-95


embedded image


—NH—





IIc-96


embedded image


—S—





IIc-97


embedded image


—N(CH3)—





IIc-98


embedded image


—N(CH2CH3)—





IIc-99


embedded image


—N(CH2CH2CH3)—





IIc-100


embedded image


—N(CH2CH2CH2CH3)—





IIc-101


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIc-102


embedded image


—N(C(H)(CH3)2)—





IIc-103


embedded image


—N(CH2C(H)(CH3)2)—





IIc-104


embedded image


—N(C(CH3)3)—





IIc-105


embedded image


—CH2





IIc-c105


embedded image


—CH(OH)—





IIc-106


embedded image


—O—





IIc-107


embedded image


—C(O)—





IIc-108


embedded image


—NH—





IIc-109


embedded image


—S—





IIc-110


embedded image


—N(CH3)—





IIc-111


embedded image


—N(CH2CH3)—





IIc-112


embedded image


—N(CH2CH2CH3)—





IIc-113


embedded image


—N(CH2CH2CH2CH3)—





IIc-114


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIc-115


embedded image


—N(C(H)(CH3)2)—





IIc-116


embedded image


—N(CH2C(H)(CH3)2)—





IIc-117


embedded image


—N(C(CH3)3)—





IIc-118


embedded image


—CH2





IIc-c118


embedded image


—CH(OH)—





IIc-119


embedded image


—O—





IIc-120


embedded image


—C(O)—





IIc-121


embedded image


—NH—





IIc-122


embedded image


—S—





IIc-123


embedded image


—N(CH3)—





IIc-124


embedded image


—N(CH2CH3)—





IIc-125


embedded image


—N(CH2CH2CH3)—





IIc-126


embedded image


—N(CH2CH2CH2CH3)—





IIc-127


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIc-128


embedded image


—N(C(H)(CH3)2)—





IIc-129


embedded image


—N(CH2C(H)(CH3)2)—





IIc-130


embedded image


—N(C(CH3)3)—





IIc-131


embedded image


—CH2





IIc-c131


embedded image


—CH(OH)—





IIc-132


embedded image


—O—





IIc-133


embedded image


—C(O)—





IIc-134


embedded image


—NH—





IIc-135


embedded image


—S—





IIc-136


embedded image


—N(CH3)—





IIc-137


embedded image


—N(CH2CH3)—





IIc-138


embedded image


—N(CH2CH2CH3)—





IIc-139


embedded image


—N(CH2CH2CH2CH3)—





IIc-140


embedded image


—N(C(H)(CH3)(CH2CH3))—





IIc-141


embedded image


—N(C(H)(CH3)2)—





IIc-142


embedded image


—N(CH2C(H)(CH3)2)—





IIc-143


embedded image


—N(C(CH3)3)—





IIc-144


embedded image


—CH2





IIc-c144


embedded image


—CH(OH)—





IIc-145


embedded image


—O—





IIc-146


embedded image


—C(O)—





IIc-147


embedded image


—NH—





IIc-148


embedded image


—S—





IIc-149


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—N(CH3)—





IIc-150


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—N(CH2CH3)—





IIc-151


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—N(CH2CH2CH3)—





IIc-152


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—N(CH2CH2CH2CH3)—





IIc-153


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—N(C(H)(CH3)(CH2CH3))—





IIc-154


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—N(C(H)(CH3)2)—





IIc-155


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—N(CH2C(H)(CH3)2)—





IIc-156


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—N(C(CH3)3)—





IIc-157


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—CH2





IIc-c157


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—CH(OH)—





IIc-158


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—O—





IIc-159


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—C(O)—





IIc-160


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—NH—





IIc-161


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—S—





IIc-162


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—N(CH3)—





IIc-163


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—N(CH2CH3)—





IIc-164


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—N(CH2CH2CH3)—





IIc-165


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—N(CH2CH2CH2CH3)—





IIc-166


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—N(C(H)(CH3)(CH2CH3))—





IIc-167


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—N(C(H)(CH3)2)—





IIc-168


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—N(CH2C(H)(CH3)2)—





IIc-169


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—N(C(CH3)3)—





IIc-170


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—CH2





IIc-c170


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—CH(OH)—





IIc-171


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—O—





IIc-172


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—C(O)—





IIc-173


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—NH—





IIc-174


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—S—





IIc-175


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—N(CH3)—





IIc-176


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—N(CH2CH3)—





IIc-177


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—N(CH2CH2CH3)—





IIc-178


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—N(CH2CH2CH2CH3)—





IIc-179


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—N(C(H)(CH3)(CH2CH3))—





IIc-180


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—N(C(H)(CH3)2)—





IIc-181


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—N(CH2C(H)(CH3)2)—





IIc-182


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—N(C(CH3)3)—





IIc-183


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—CH2





IIc-c183


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—CH(OH)—





IIc-184


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—O—





IIc-185


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—C(O)—





IIc-186


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—NH—





IIc-187


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—S—





IIc-188


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—N(CH3)—





IIc-189


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—N(CH2CH3)—





IIc-190


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—N(CH2CH2CH3)—





IIc-191


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—N(CH2CH2CH2CH3)—





IIc-192


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—N(C(H)(CH3)(CH2CH3))—





IIc-193


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—N(C(H)(CH3)2)—





IIc-194


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—N(CH2C(H)(CH3)2)—





IIc-195


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—N(C(CH3)3)—





IIc-196


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—CH2





IIc-197


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—CH(OH)—





IIc-198


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—O—





IIc-199


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—C(O)—





IIc-200


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—NH—





IIc-201


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—S—





IIc-202


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—N(CH3)—





IIc-203


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—N(CH2CH3)—





IIc-204


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—N(CH2CH2CH3)—





IIc-205


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—N(CH2CH2CH2CH3)—





IIc-206


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—N(C(H)(CH3)(CH2CH3))—





IIc-207


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—N(C(H)(CH3)2)—





IIc-208


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—N(CH2C(H)(CH3)2)—





IIc-209


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—N(C(CH3)3)—









and pharmaceutically acceptable salts thereof.


5.8 The Indenoisoquinolinone Analogs of Formula (IIIa)

The present invention provides the following Indenoisoquinolinone Analogs according to Formula (IIIa) as set forth below:














(IIIa)




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Compound
—R1







IIIa-1


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IIIa-2


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IIIa-3


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IIIa-4


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IIIa-5


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IIIa-6


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IIIa-7


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IIIa-8


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IIIa-9


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IIIa-10


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IIIa-11


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IIIa-12


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IIIa-13


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IIIa-14


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IIIa-15


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IIIa-16


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IIIa-17


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IIIa-18


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IIIa-19


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IIIa-20


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IIIa-21


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IIIa-22


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IIIa-23


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IIIa-24


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and pharmaceutically acceptable salts thereof.


5.9 The Indenoisoquinolinone Analogs of Formula (IIIb)

The present invention provides the following Indenoisoquinolinone Analogs according to Formula (IIIb) as set forth below:














(IIIb)




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Compound
—R1







IIIb-1


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IIIb-2


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IIIb-3


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IIIb-4


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IIIb-5


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IIIb-6


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IIIb-7


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IIIb-8


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IIIb-9


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IIIb-10


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IIIb-11


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IIIb-12


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IIIb-13


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IIIb-14


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IIIb-15


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IIIb-16


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IIIb-17


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IIIb-18


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IIIb-19


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IIIb-20


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IIIb-21


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IIIb-22


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IIIb-23


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IIIb-24


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and pharmaceutically acceptable salts thereof.


5.10 The Indenoisoquinolinone Analogs of Formula (IVa)

The present invention provides Indenoisoquinolinone Analogs according to Formula (IVa), below:




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and pharmaceutically acceptable salts thereof,


wherein X and R1 are as defined above for the Indenoisoquinolinone Analogs of Formula (IVa).


In one embodiment, X is —N(CH3)—. In another embodiment, X is —N(CH2CH3)—. In another embodiment, X is —N(CH2CH2CH3)—. In another embodiment, X is —N(CH2CH2CH2CH3)—. In another embodiment, X is —N(C(H)(CH3)(CH2CH3))—. In another embodiment, X is —N(C(H)(CH3)2)—. In another embodiment, X is —N(CH2C(H)(CH3)2)—. In another embodiment, X is —N(C(CH3)3)—.


In one embodiment, X is —O—. In one embodiment, X is —CH2—. In one embodiment, X is —C(O)—. In one embodiment, X is —NH—. In one embodiment, X is —S—. In one embodiment, X is —CH(OH)—.


In one embodiment, each C1-C3 alkyl is independent of the other C1-C3 alkyl.


In one embodiment, each C1-C3 alkyl is methyl.


In one embodiment, each C1-C3 alkyl is methyl and X is —CH2—.


In one embodiment, each C1-C3 alkyl is methyl and X is —CH(OH)—.


In one embodiment, each C1-C3 alkyl is methyl, X is —CH2— and n is 1.


In one embodiment, each C1-C3 alkyl is methyl, X is —CH(OH)— and n is 1.


In another embodiment, X is —CH(OH)— and n is 1.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—Z)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)—Z)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)2—Z)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—Z)— and n is 1.


In yet another embodiment, X is —N(C(O)N(H)—(CH2)2—Z)— and n is 2.


In still another embodiment, X is —N(C(O)N(H)—(CH2)—Z)— and n is 1.


In one embodiment, X is —N((CH2)q—Z)—.


In another embodiment, X is —N((CH2)—Z)—.


In another embodiment, X is —N((CH2)2—Z)—.


In another embodiment, X is —N((CH2)q—Z)— and n is 1.


In yet another embodiment, X is —N((CH2)q—Z)— and n is 2.


In still another embodiment, X is —N((CH2)—Z)— and n is 1.


In still another embodiment, X is —N((CH2)—Z)— and n is 2.


In one embodiment, Z is —CF3.


In another embodiment, Z is —F.


In yet another embodiment, Z is —OH.


In still another embodiment, Z is —O—CH3.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—OH)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)2—OH)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—OH)— and n is 1.


In yet another embodiment, X is —N(C(O)N(H)—(CH2)p—OH)— and n is 2.


In still another embodiment, X is —N(C(O)N(H)—(CH2)2—OH)— and n is 1.


In still another embodiment, X is —N(C(O)N(H)—(CH2)2—OH)— and n is 2.


In one embodiment, X is —N((CH2)q—OH)—.


In another embodiment, X is —N((CH2)2—OH)—.


In another embodiment, X is —N((CH2)q—OH)— and n is 1.


In yet another embodiment, X is —N((CH2)q—OH)— and n is 2.


In still another embodiment, X is —N((CH2)2—OH)— and n is 1.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—F)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)—F)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—F)— and n is 1.


In yet another embodiment, X is —N(C(O)N(H)—(CH2)p—F)— n is 2.


In still another embodiment, X is —N(C(O)N(H)—(CH2)—F)— and n is 1.


In one embodiment, X is —N((CH2)q—F)—.


In another embodiment, X is —N((CH2)—F)—.


In another embodiment, X is —N((CH2)q—F)— and n is 1.


In yet another embodiment, X is —N((CH2)q—F)— and n is 2.


In still another embodiment, X is —N((CH2)—F)— and n is 1.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—OMe)-.


In another embodiment, X is —N(C(O)N(H)—(CH2)2—OMe)-.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—OMe)- and n is 1.


In yet another embodiment, X is —N(C(O)N(H)—(CH2)p—OMe)- and n is 2.


In still another embodiment, X is —N(C(O)N(H)—(CH2)2—OMe)- and n is 1.


In one embodiment, X is —N((CH2)q—OMe)-.


In another embodiment, X is —N((CH2)2—OMe)-.


In another embodiment, X is —N((CH2)q—OMe)- and n is 1.


In yet another embodiment, X is —N((CH2)q—OMe)- and n is 2.


In still another embodiment, X is —N((CH2)2—OMe)- and n is 1.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—CF3)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)—CF3)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—CF3)— and n is 1.


In yet another embodiment, X is —N(C(O)N(H)—(CH2)p—CF3)— and n is 2.


In still another embodiment, X is —N(C(O)N(H)—(CH2)—CF3)— and n is 1.


In one embodiment, X is —N((CH2)q—CF3)—.


In another embodiment, X is —N((CH2)—CF3)—.


In another embodiment, X is —N((CH2)q—CF3)— and n is 1.


In yet another embodiment, X is —N((CH2)q—CF3)— and n is 2.


In still another embodiment, X is —N((CH2)—CF3)— and n is 1.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—CF3)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)—CF3)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—CF3)— and n is 1.


In yet another embodiment, X is —N(C(O)N(H)—(CH2)p—CF3)— and n is 2.


In still another embodiment, X is —N(C(O)N(H)—(CH2)—CF3)— and n is 1.


In one embodiment, X is —N((CH2)q—CF3)—.


In another embodiment, X is —N((CH2)—CF3)—.


In another embodiment, X is —N((CH2)q—CF3)— and n is 1.


In yet another embodiment, X is —N((CH2)q—CF3)— and n is 2.


In still another embodiment, X is —N((CH2)—CF3)— and n is 1.


In one embodiment, n is 1.


In another embodiment, n is 2.


In yet another embodiment, n is 3.


In a further embodiment, n is 4, 5, or 6.


In yet a further embodiment, n is 7, 8, or 9.


In still a further embodiment, n is 10.


In one embodiment, p is 1.


In another embodiment, p is 2.


In yet another embodiment, p is an integer ranging from 2 to 5.


In one embodiment, q is 1.


In another embodiment, q is 2.


In yet another embodiment, q is an integer ranging from 2 to 5.


In one embodiment, n is 1 and X is —N(CH3)—.


In another embodiment, n is 1 and X is —N(CH2CH3).


In another embodiment, n is 1 and X is —N(CH2CH2CH3)—.


In another embodiment, n is 1 and X is —N(CH2CH2CH2CH3)—.


In another embodiment, n is 1 and X is —N(C(H)(CH3)(CH2CH3))—.


In another embodiment, n is 1 and X is —N(C(H)(CH3)2)—.


In another embodiment, n is 1 and X is —N(CH2C(H)(CH3)2)—.


In another embodiment, n is 1 and X is —N(C(CH3)3)—.


In one embodiment, one R2 is —H, and the other R2 is —C1-C6 alkyl.


In another embodiment, each R2 is —C1-C6 alkyl.


In another embodiment, each R2 is -methyl.


In various embodiments, —N(R2)(R2) is:




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In other embodiments, —N(R2)(R2) is:




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In some embodiments, —N(R2)(R2) is




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In still other embodiments, —N(R2)(R2) is

    • —N(CH2CH3)(CH3),
    • —N(CH2CH2CH3)(CH3),
    • —N(CH2CH2CH2CH3)(CH3),
    • —NH—CH2CH2CH2CH3, or
    • —NH—CH2CH2—O—CH3.


In some embodiments, —N(R2)(R2) is




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In various embodiments, —N(Z3)(Z4) is:




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In other embodiments, —N(Z3)(Z4) is:




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In some embodiments, —N(Z3)(Z4) is




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In still other embodiments, —N(Z3)(Z4) is

    • —N(CH2CH3)(CH3),
    • —N(CH2CH2CH3)(CH3),
    • —N(CH2CH2CH2CH3)(CH3),
    • —NH—CH2CH2CH2CH3, or
    • —NH—CH2CH2—O—CH3.


In some embodiments, —N(Z3)(Z4) is




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In one embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2)— or —N(C(CH3)3)—;


n is an integer ranging from 1 to 3;


each R2 is independently —H, —C1-C6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —(C1-C6 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)2OH or —N(Z3)(Z4), where Z3 and Z4 are independently —H, —C1-C5 alkyl, or —(C1-C5 alkylene)-O—C1-C5 alkyl, each of which other than hydrogen is unsubstituted or substituted with one or more of -halo, —OH or —NH2;


or N, Z3 and Z4 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three of —C1-C5 alkyl, -phenyl, —(C1-C5 alkylene)-phenyl, -(hydroxy-substituted) C1-C5 alkyl, -halo, -(halo-substituted) C1-C5 alkyl, -(halo-substituted) phenyl, -phenylene-O—C1-C5 alkyl, -(cyano-substituted) phenyl, —OH, —O—C1-C5 alkyl, —N(Ra)2, —(C1-C5 alkylene)-N(Ra)2, —C1-C5 alkylene-C(O)O—(C1-C5 alkylene)-N(Ra)2, —COOH, —(C1-C5 alkylene)-COOH, —OP(O)(OH)2, —OS(O)2OH, —(C1-C5 alkylene)-OP(O)(OH)2, —(C1-C5 alkylene)-OS(O)2OH, —C(O)O—C1-C5 alkyl, —OC(O)—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)O—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)NH—C1-C5 alkyl, —C(O)NH2, or —NO2, wherein each occurrence of Ra is independently —H, -benzyl, or —C1-C10 alkyl;


or N and both R2 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 —C1-C5 alkyl, -phenyl, —(C1-C5 alkylene)-phenyl, -(hydroxy-substituted) C1-C5 alkyl, -halo, -(halo-substituted) C1-C5 alkyl, -(halo-substituted) phenyl, -phenylene-O—C1-C5 alkyl, -(cyano-substituted) phenyl, —OH, —O—C1-C5 alkyl, —N(Ra)2, —(C1-C5 alkylene)-N(Ra)2, —(C1-C5 alkylene)-C(O)O—(C1-C5 alkylene)-N(Ra)2, —COOH, —(C1-C5 alkylene)-COOH, —OP(O)(OH)2, —OS(O)2OH, —(C1-C5 alkylene)-OP(O)(OH)2, —(C1-C5 alkylene)-OS(O)2OH, —C(O)O—C1-C5 alkyl, —OC(O)—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)O—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)NH—C1-C5 alkyl, —C(O)NH2, or —NO2, wherein each occurrence of Ra is independently —H, -benzyl, or —C1-C10 alkyl.


In one embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2)— or —N(C(CH3)3)—;


n is an integer ranging from 1 to 3; and


at least one C1-C3 alkyl is methyl.


In another embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2)— or —N(C(CH3)3)—; at least one C1-C3 alkyl is methyl; and at least one R2 is ethyl.


In yet another embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2)— or —N(C(CH3)3)—; at least one C1-C3 alkyl is methyl; and at least one R2 is propyl.


In one embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2)— or —N(C(CH3)3)—; at least one C1-C3 alkyl is methyl; and at least one R2 is —C3-C8 monocyclic cycloalkyl.


In another embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2)— or —N(C(CH3)3)—; at least one C1-C3 alkyl is methyl; and at least one R2 is cyclohexyl.


In yet another embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2)— or —N(C(CH3)3)—; and at least one C1-C3 alkyl is methyl, wherein N and both R2 groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle.


In one embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2)— or —N(C(CH3)3)—; and at least one C1-C3 alkyl is methyl, wherein N and both R2 groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which is substituted with a hydroxyl.


In another embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2)— or —N(C(CH3)3)—; and at least one C1-C3 alkyl is methyl, wherein N and both R2 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.


Illustrative examples of the Indenoisoquinolinone Analogs include the compounds of Formula (IVa) as set forth below:














(IVa)




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Compound
—R1
X





IVa-1
—OC(Me)(Me)—CH2—N(Et)(Et)
—O—


IVa-2
—OC(Me)(Me)—CH2—N(Et)(Et)
—CH2


IVa-3
—OC(Me)(Me)—CH2—N(Et)(Et)
—C(O)—


IVa-4
—OC(Me)(Me)—CH2—N(Et)(Et)
—NH—


IVa-5
—OC(Me)(Me)—CH2—N(Et)(Et)
—S—


IVa-6
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(CH3)—


IVa-7
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(CH2CH3)—


IVa-8
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(CH2CH2CH3)—


IVa-9
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(CH2CH2CH2CH3)—


IVa-10
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(C(H)(CH3)(CH2CH3))—


IVa-11
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(C(H)(CH3)2)—


IVa-12
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(CH2C(H)(CH3)2)—


IVa-13
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(C(CH3)3)—


IVa-14
—OC(Me)(Me)—CH2—N(Et)(Et)
—CH(OH)—


IVa-15
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(C(O)N(H)—CH2—CH2—OH)—


IVa-16
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(C(O)N(H)—CH2—CH2—F)—


IVa-17
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(CH2—CH2—OH)—


IVa-18
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(CH2—CH2—F)—


IVa-19
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(CH2—CH2—OCH3)—


IVa-20
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(CH2—CH2—CF3)—


IVa-21
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(C(O)N(H)—CH2—CH2—OCH3)—


IVa-22
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(C(O)N(H)—CH2—CH2—CF3)—


IVa-23
—OC(Me)(Et)—CH2—N(Et)(Et)
—O—


IVa-24
—OC(Me)(Et)—CH2—N(Et)(Et)
—CH2


IVa-25
—OC(Me)(Et)—CH2—N(Et)(Et)
—C(O)—


IVa-26
—OC(Me)(Et)—CH2—N(Et)(Et)
—NH—


IVa-27
—OC(Me)(Et)—CH2—N(Et)(Et)
—S—


IVa-28
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(CH3)—


IVa-29
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(CH2CH3)—


IVa-30
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(CH2CH2CH3)—


IVa-31
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(CH2CH2CH2CH3)—


IVa-32
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(C(H)(CH3)(CH2CH3))—


IVa-33
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(C(H)(CH3)2)—


IVa-34
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(CH2C(H)(CH3)2)—


IVa-35
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(C(CH3)3)—


IVa-36
—OC(Me)(Et)—CH2—N(Et)(Et)
—CH(OH)—


IVa-37
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(C(O)N(H)—CH2—CH2—OH)—


IVa-38
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(C(O)N(H)—CH2—CH2—F)—


IVa-39
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(CH2—CH2—OH)—


IVa-40
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(CH2—CH2—F)—


IVa-41
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(CH2—CH2—OCH3)—


IVa-42
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(CH2—CH2—CF3)—


IVa-43
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(C(O)N(H)—CH2—CH2—OCH3)—


IVa-44
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(C(O)N(H)—CH2—CH2—CF3)—


IVa-45
—OC(Me)(Pr)—CH2—N(Et)(Et)
—O—


IVa-46
—OC(Me)(Pr)—CH2—N(Et)(Et)
—CH2


IVa-47
—OC(Me)(Pr)—CH2—N(Et)(Et)
—C(O)—


IVa-48
—OC(Me)(Pr)—CH2—N(Et)(Et)
—NH—


IVa-49
—OC(Me)(Pr)—CH2—N(Et)(Et)
—S—


IVa-50
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(CH3)—


IVa-51
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(CH2CH3)—


IVa-52
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(CH2CH2CH3)—


IVa-53
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(CH2CH2CH2CH3)—


IVa-54
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(C(H)(CH3)(CH2CH3))—


IVa-55
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(C(H)(CH3)2)—


IVa-56
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(CH2C(H)(CH3)2)—


IVa-57
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(C(CH3)3)—


IVa-58
—OC(Me)(Pr)—CH2—N(Et)(Et)
—CH(OH)—


IVa-59
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(C(O)N(H)—CH2—CH2—OH)—


IVa-60
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(C(O)N(H)—CH2—CH2—F)—


IVa-61
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(CH2—CH2—OH)—


IVa-62
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(CH2—CH2—F)—


IVa-63
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(CH2—CH2—OCH3)—


IVa-64
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(CH2—CH2—CF3)—


IVa-65
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(C(O)N(H)—CH2—CH2—OCH3)—


IVa-66
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(C(O)N(H)—CH2—CH2—CF3)—


IVa-67
—OC(Me)(i-Pr)—CH2
—O—



N(H)(cyclopropyl)


IVa-68
—OC(Me)(i-Pr)—CH2
—CH2



N(H)(cyclopropyl)


IVa-69
—OC(Me)(i-Pr)—CH2
—C(O)—



N(H)(cyclopropyl)


IVa-70
—OC(Me)(i-Pr)—CH2
—NH—



N(H)(cyclopropyl)


IVa-71
—OC(Me)(i-Pr)—CH2
—S—



N(H)(cyclopropyl)


IVa-72
—OC(Me)(i-Pr)—CH2
—N(CH3)—



N(H)(cyclopropyl)


IVa-73
—OC(Me)(i-Pr)—CH2
—N(CH2CH3)—



N(H)(cyclopropyl)


IVa-74
—OC(Me)(i-Pr)—CH2
—N(CH2CH2CH3)—



N(H)(cyclopropyl)


IVa-75
—OC(Me)(i-Pr)—CH2
—N(CH2CH2CH2CH3)—



N(H)(cyclopropyl)


IVa-76
—OC(Me)(i-Pr)—CH2
—N(C(H)(CH3)(CH2CH3))—



N(H)(cyclopropyl)


IVa-77
—OC(Me)(i-Pr)—CH2
—N(C(H)(CH3)2)—



N(H)(cyclopropyl)


IVa-78
—OC(Me)(i-Pr)—CH2
—N(CH2C(H)(CH3)2)—



N(H)(cyclopropyl)


IVa-79
—OC(Me)(i-Pr)—CH2
—N(C(CH3)3)—



N(H)(cyclopropyl)


IVa-80
—OC(Me)(i-Pr)—CH2
—CH(OH)—



N(H)(cyclopropyl)


IVa-81
—OC(Me)(i-Pr)—CH2
—N(C(O)N(H)—CH2—CH2—OH)—



N(H)(cyclopropyl)


IVa-82
—OC(Me)(i-Pr)—CH2
—N(C(O)N(H)—CH2—CH2—F)—



N(H)(cyclopropyl)


IVa-83
—OC(Me)(i-Pr)—CH2
—N(CH2—CH2—OH)—



N(H)(cyclopropyl)


IVa-84
—OC(Me)(i-Pr)—CH2
—N(CH2—CH2—F)—



N(H)(cyclopropyl)


IVa-85
—OC(Me)(i-Pr)—CH2
—N(CH2—CH2—OCH3)—



N(H)(cyclopropyl)


IVa-86
—OC(Me)(i-Pr)—CH2
—N(CH2—CH2—CF3)—



N(H)(cyclopropyl)


IVa-87
—OC(Me)(i-Pr)—CH2
—N(C(O)N(H)—CH2—CH2—OCH3)—



N(H)(cyclopropyl)


IVa-88
—OC(Me)(i-Pr)—CH2
—N(C(O)N(H)—CH2—CH2—CF3)—



N(H)(cyclopropyl)









and pharmaceutically acceptable salts thereof.


5.11 The Indenoisoquinolinone Analogs of Formula (IVb)

The present invention provides Indenoisoquinolinone Analogs according to Formula (IVb), below:




embedded image



and pharmaceutically acceptable salts thereof,


wherein X and R1 are as defined above for the Indenoisoquinolinone Analogs of Formula (IVb).


In one embodiment, X is —N(CH3)—. In another embodiment, X is —N(CH2CH3)—. In another embodiment, X is —N(CH2CH2CH3)—. In another embodiment, X is —N(CH2CH2CH2CH3)—. In another embodiment, X is —N(C(H)(CH3)(CH2CH3))—. In another embodiment, X is —N(C(H)(CH3)2)—. In another embodiment, X is —N(CH2C(H)(CH3)2)—. In another embodiment, X is —N(C(CH3)3)—.


In one embodiment, X is —O—. In one embodiment, X is —CH2—. In one embodiment, X is —C(O)—. In one embodiment, X is —NH—. In one embodiment, X is —S—. In one embodiment, X is —CH(OH)—.


In one embodiment, each C1-C3 alkyl is independent of the other C1-C3 alkyl.


In one embodiment, each C1-C3 alkyl is methyl.


In one embodiment, each C1-C3 alkyl is methyl and X is —CH2—.


In one embodiment, each C1-C3 alkyl is methyl and X is —CH(OH)—.


In one embodiment, each C1-C3 alkyl is methyl, X is —CH2— and n is 1.


In one embodiment, each C1-C3 alkyl is methyl, X is —CH(OH)— and n is 1.


In another embodiment, X is —CH(OH)— and n is 1.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—Z)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)—Z)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)2—Z)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—Z)— and n is 1.


In yet another embodiment, X is —N(C(O)N(H)—(CH2)2—Z)— and n is 2.


In still another embodiment, X is —N(C(O)N(H)—(CH2)—Z)— and n is 1.


In one embodiment, X is —N((CH2)q—Z)—.


In another embodiment, X is —N((CH2)—Z)—.


In another embodiment, X is —N((CH2)2—Z)—.


In another embodiment, X is —N((CH2)q—Z)— and n is 1.


In yet another embodiment, X is —N((CH2)q—Z)— and n is 2.


In still another embodiment, X is —N((CH2)—Z)— and n is 1.


In still another embodiment, X is —N((CH2)—Z)— and n is 2.


In one embodiment, Z is —CF3.


In another embodiment, Z is —F.


In yet another embodiment, Z is —OH.


In still another embodiment, Z is —O—CH3.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—OH)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)2—OH)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—OH)— and n is 1.


In yet another embodiment, X is —N(C(O)N(H)—(CH2)p—OH)— and n is 2.


In still another embodiment, X is —N(C(O)N(H)—(CH2)2—OH)— and n is 1.


In still another embodiment, X is —N(C(O)N(H)—(CH2)2—OH)— and n is 2.


In one embodiment, X is —N((CH2)q—OH)—.


In another embodiment, X is —N((CH2)2—OH)—.


In another embodiment, X is —N((CH2)q—OH)— and n is 1.


In yet another embodiment, X is —N((CH2)q—OH)— and n is 2.


In still another embodiment, X is —N((CH2)2—OH)— and n is 1.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—F)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)—F)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—F)— and n is 1.


In yet another embodiment, X is —N(C(O)N(H)—(CH2)p—F)— n is 2.


In still another embodiment, X is —N(C(O)N(H)—(CH2)—F)— and n is 1.


In one embodiment, X is —N((CH2)q—F)—.


In another embodiment, X is —N((CH2)—F)—.


In another embodiment, X is —N((CH2)q—F)— and n is 1.


In yet another embodiment, X is —N((CH2)q—F)— and n is 2.


In still another embodiment, X is —N((CH2)—F)— and n is 1.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—OMe)-.


In another embodiment, X is —N(C(O)N(H)—(CH2)2—OMe)-.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—OMe)- and n is 1.


In yet another embodiment, X is —N(C(O)N(H)—(CH2)p—OMe)- and n is 2.


In still another embodiment, X is —N(C(O)N(H)—(CH2)2—OMe)- and n is 1.


In one embodiment, X is —N((CH2)q—OMe)-.


In another embodiment, X is —N((CH2)2—OMe)-.


In another embodiment, X is —N((CH2)q—OMe)- and n is 1.


In yet another embodiment, X is —N((CH2)q—OMe)- and n is 2.


In still another embodiment, X is —N((CH2)2—OMe)- and n is 1.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—CF3)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)—CF3)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—CF3)— and n is 1.


In yet another embodiment, X is —N(C(O)N(H)—(CH2)p—CF3)— and n is 2.


In still another embodiment, X is —N(C(O)N(H)—(CH2)—CF3)— and n is 1.


In one embodiment, X is —N((CH2)q—CF3)—.


In another embodiment, X is —N((CH2)—CF3)—.


In another embodiment, X is —N((CH2)q—CF3)— and n is 1.


In yet another embodiment, X is —N((CH2)q—CF3)— and n is 2.


In still another embodiment, X is —N((CH2)—CF3)— and n is 1.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—CF3)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)—CF3)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—CF3)— and n is 1.


In yet another embodiment, X is —N(C(O)N(H)—(CH2)p—CF3)— and n is 2.


In still another embodiment, X is —N(C(O)N(H)—(CH2)—CF3)— and n is 1.


In one embodiment, X is —N((CH2)q—CF3)—.


In another embodiment, X is —N((CH2)—CF3)—.


In another embodiment, X is —N((CH2)q—CF3)— and n is 1.


In yet another embodiment, X is —N((CH2)q—CF3)— and n is 2.


In still another embodiment, X is —N((CH2)—CF3)— and n is 1.


In one embodiment, n is 1.


In another embodiment, n is 2.


In yet another embodiment, n is 3.


In a further embodiment, n is 4, 5, or 6.


In yet a further embodiment, n is 7, 8, or 9.


In still a further embodiment, n is 10.


In one embodiment, p is 1.


In another embodiment, p is 2.


In yet another embodiment, p is an integer ranging from 2 to 5.


In one embodiment, q is 1.


In another embodiment, q is 2.


In yet another embodiment, q is an integer ranging from 2 to 5.


In one embodiment, n is 1 and X is —N(CH3)—.


In another embodiment, n is 1 and X is —N(CH2CH3).


In another embodiment, n is 1 and X is —N(CH2CH2CH3)—.


In another embodiment, n is 1 and X is —N(CH2CH2CH2CH3)—.


In another embodiment, n is 1 and X is —N(C(H)(CH3)(CH2CH3))—.


In another embodiment, n is 1 and X is —N(C(H)(CH3)2)—.


In another embodiment, n is 1 and X is —N(CH2C(H)(CH3)2)—.


In another embodiment, n is 1 and X is —N(C(CH3)3)—.


In one embodiment, one R2 is —H, and the other R2 is —C1-C6 alkyl.


In another embodiment, each R2 is —C1-C6 alkyl.


In another embodiment, each R2 is -methyl.


In various embodiments, —N(R2)(R2) is:




embedded image


embedded image


embedded image


In other embodiments, —N(R2)(R2) is:




embedded image


embedded image


embedded image


In some embodiments, —N(R2)(R2) is




embedded image


In still other embodiments, —N(R2)(R2) is

    • —N(CH2CH3)(CH3),
    • —N(CH2CH2CH3)(CH3),
    • —N(CH2CH2CH2CH3)(CH3),
    • —NH—CH2CH2CH2CH3, or
    • —NH—CH2CH2—O—CH3.


In some embodiments, —N(R2)(R2) is




embedded image


In various embodiments, —N(Z3)(Z4) is:




embedded image


embedded image


embedded image


In other embodiments, —N(Z3)(Z4) is:




embedded image


embedded image


embedded image


In some embodiments, —N(Z3)(Z4) is




embedded image


In still other embodiments, —N(Z3)(Z4) is

    • —N(CH2CH3)(CH3),
    • —N(CH2CH2CH3)(CH3),
    • —N(CH2CH2CH2CH3)(CH3),
    • —NH—CH2CH2CH2CH3, or
    • —NH—CH2CH2—O—CH3.


In some embodiments, —N(Z3)(Z4) is




embedded image


In one embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2— or —N(C(CH3)3)—;


n is an integer ranging from 1 to 3;


each R2 is independently —H, —C1-C6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —(C1-C6 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)2OH or —N(Z3)(Z4), where Z3 and Z4 are independently —H, —C1-C5 alkyl, or —(C1-C5 alkylene)-O—C1-C5 alkyl, each of which other than hydrogen is unsubstituted or substituted with one or more of -halo, —OH or —NH2;


or N, Z3 and Z4 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three of —C1-C5 alkyl, -phenyl, —(C1-C5 alkylene)-phenyl, -(hydroxy-substituted) C1-C5 alkyl, -halo, -(halo-substituted) C1-C5 alkyl, -(halo-substituted) phenyl, -phenylene-O—C1-C5 alkyl, -(cyano-substituted) phenyl, —OH, —O—C1-C5 alkyl, —N(Ra)2, —(C1-C5 alkylene)-N(Ra)2, —C1-C5 alkylene-C(O)O—(C1-C5 alkylene)-N(Ra)2, —COOH, —(C1-C5 alkylene)-COOH, —OP(O)(OH)2, —OS(O)2OH, —(C1-C5 alkylene)-OP(O)(OH)2, —(C1-C5 alkylene)-OS(O)2OH, —C(O)O—C1-C5 alkyl, —OC(O)—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)O—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)NH—C1-C5 alkyl, —C(O)NH2, or —NO2, wherein each occurrence of Ra is independently —H, -benzyl, or —C1-C10 alkyl;


or N and both R2 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 —C1-C5 alkyl, -phenyl, —(C1-C5 alkylene)-phenyl, -(hydroxy-substituted) C1-C5 alkyl, -halo, -(halo-substituted) C1-C5 alkyl, -(halo-substituted) phenyl, -phenylene-O—C1-C5 alkyl, -(cyano-substituted) phenyl, —OH, —O—C1-C5 alkyl, —N(Ra)2, —(C1-C5 alkylene)-N(Ra)2, —(C1-C5 alkylene)-C(O)O—(C1-C5 alkylene)-N(Ra)2, —COOH, —(C1-C5 alkylene)-COOH, —OP(O)(OH)2, —OS(O)2OH, —(C1-C5 alkylene)-OP(O)(OH)2, —(C1-C5 alkylene)-OS(O)2OH, —C(O)O—C1-C5 alkyl, —OC(O)—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)O—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)NH—C1-C5 alkyl, —C(O)NH2, or —NO2, wherein each occurrence of Ra is independently —H, -benzyl, or —C1-C10 alkyl.


In one embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2 CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2— or —N(C(CH3)3)—;


n is an integer ranging from 1 to 3; and


at least one C1-C3 alkyl is methyl.


In another embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2 CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2— or —N(C(CH3)3)—; at least one C1-C3 alkyl is methyl; and at least one R2 is ethyl.


In yet another embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2— or —N(C(CH3)3)—; at least one C1-C3 alkyl is methyl; and at least one R2 is propyl.


In one embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2 CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2— or —N(C(CH3)3)—; at least one C1-C3 alkyl is methyl; and at least one R2 is —C3-C8 monocyclic cycloalkyl.


In another embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2 CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2— or —N(C(CH3)3)—; at least one C1-C3 alkyl is methyl; and at least one R2 is cyclohexyl.


In yet another embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2— or —N(C(CH3)3)—; and at least one C1-C3 alkyl is methyl, wherein N and both R2 groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle.


In one embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2 CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2— or —N(C(CH3)3)—; and at least one C1-C3 alkyl is methyl, wherein N and both R2 groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which is substituted with a hydroxyl.


In another embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2 CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2— or —N(C(CH3)3)—; and at least one C1-C3 alkyl is methyl, wherein N and both R2 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.


Illustrative examples of the Indenoisoquinolinone Analogs include the compounds of Formula (IVb) as set forth below:














(IVb)




embedded image














Compound
—R1
X





IVb-1
—OC(Me)(Me)—CH2—N(Et)(Et)
—O—


IVb-2
—OC(Me)(Me)—CH2—N(Et)(Et)
—CH2


IVb-3
—OC(Me)(Me)—CH2—N(Et)(Et)
—C(O)—


IVb-4
—OC(Me)(Me)—CH2—N(Et)(Et)
—NH—


IVb-5
—OC(Me)(Me)—CH2—N(Et)(Et)
—S—


IVb-6
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(CH3)—


IVb-7
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(CH2CH3)—


IVb-8
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(CH2CH2CH3)—


IVb-9
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(CH2CH2CH2CH3)—


IVb-10
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(C(H)(CH3)(CH2CH3))—


IVb-11
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(C(H)(CH3)2)—


IVb-12
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(CH2C(H)(CH3)2)—


IVb-13
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(C(CH3)3)—


IVb-14
—OC(Me)(Me)—CH2—N(Et)(Et)
—CH(OH)—


IVb-15
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(C(O)N(H)—CH2—CH2—OH)—


IVb-16
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(C(O)N(H)—CH2—CH2—F)—


IVb-17
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(CH2—CH2—OH)—


IVb-18
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(CH2—CH2—F)—


IVb-19
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(CH2—CH2—OCH3)—


IVb-20
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(CH2—CH2—CF3)—


IVb-21
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(C(O)N(H)—CH2—CH2—OCH3)—


IVb-22
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(C(O)N(H)—CH2—CH2—CF3)—


IVb-23
—OC(Me)(Et)—CH2—N(Et)(Et)
—O—


IVb-24
—OC(Me)(Et)—CH2—N(Et)(Et)
—CH2


IVb-25
—OC(Me)(Et)—CH2—N(Et)(Et)
—C(O)—


IVb-26
—OC(Me)(Et)—CH2—N(Et)(Et)
—NH—


IVb-27
—OC(Me)(Et)—CH2—N(Et)(Et)
—S—


IVb-28
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(CH3)—


IVb-29
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(CH2CH3)—


IVb-30
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(CH2CH2CH3)—


IVb-31
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(CH2CH2CH2CH3)—


IVb-32
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(C(H)(CH3)(CH2CH3))—


IVb-33
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(C(H)(CH3)2)—


IVb-34
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(CH2C(H)(CH3)2)—


IVb-35
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(C(CH3)3)—


IVb-36
—OC(Me)(Et)—CH2—N(Et)(Et)
—CH(OH)—


IVb-37
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(C(O)N(H)—CH2—CH2—OH)—


IVb-38
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(C(O)N(H)—CH2—CH2—F)—


IVb-39
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(CH2—CH2—OH)—


IVb-40
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(CH2—CH2—F)—


IVb-41
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(CH2—CH2—OCH3)—


IVb-42
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(CH2—CH2—CF3)—


IVb-43
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(C(O)N(H)—CH2—CH2—OCH3)—


IVb-44
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(C(O)N(H)—CH2—CH2—CF3)—


IVb-45
—OC(Me)(Pr)—CH2—N(Et)(Et)
—O—


IVb-46
—OC(Me)(Pr)—CH2—N(Et)(Et)
—CH2


IVb-47
—OC(Me)(Pr)—CH2—N(Et)(Et)
—C(O)—


IVb-48
—OC(Me)(Pr)—CH2—N(Et)(Et)
—NH—


IVb-49
—OC(Me)(Pr)—CH2—N(Et)(Et)
—S—


IVb-50
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(CH3)—


IVb-51
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(CH2CH3)—


IVb-52
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(CH2CH2CH3)—


IVb-53
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(CH2CH2CH2CH3)—


IVb-54
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(C(H)(CH3)(CH2CH3))—


IVb-55
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(C(H)(CH3)2)—


IVb-56
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(CH2C(H)(CH3)2)—


IVb-57
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(C(CH3)3)—


IVb-58
—OC(Me)(Pr)—CH2—N(Et)(Et)
—CH(OH)—


IVb-59
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(C(O)N(H)—CH2—CH2—OH)—


IVb-60
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(C(O)N(H)—CH2—CH2—F)—


IVb-61
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(CH2—CH2—OH)—


IVb-62
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(CH2—CH2—F)—


IVb-63
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(CH2—CH2—OCH3)—


IVb-64
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(CH2—CH2—CF3)—


IVb-65
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(C(O)N(H)—CH2—CH2—OCH3)—


IVb-66
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(C(O)N(H)—CH2—CH2—CF3)—


IVb-67
—OC(Me)(i-Pr)—CH2
—O—



N(H)(cyclopropyl)


IVb-68
—OC(Me)(i-Pr)—CH2
—CH2



N(H)(cyclopropyl)


IVb-69
—OC(Me)(i-Pr)—CH2
—C(O)—



N(H)(cyclopropyl)


IVb-70
—OC(Me)(i-Pr)—CH2
—NH—



N(H)(cyclopropyl)


IVb-71
—OC(Me)(i-Pr)—CH2
—S—



N(H)(cyclopropyl)


IVb-72
—OC(Me)(i-Pr)—CH2
—N(CH3)—



N(H)(cyclopropyl)


IVb-73
—OC(Me)(i-Pr)—CH2
—N(CH2CH3)—



N(H)(cyclopropyl)


IVb-74
—OC(Me)(i-Pr)—CH2
—N(CH2CH2CH3)—



N(H)(cyclopropyl)


IVb-75
—OC(Me)(i-Pr)—CH2
—N(CH2CH2CH2CH3)—



N(H)(cyclopropyl)


IVb-76
—OC(Me)(i-Pr)—CH2
—N(C(H)(CH3)(CH2CH3))—



N(H)(cyclopropyl)


IVb-77
—OC(Me)(i-Pr)—CH2
—N(C(H)(CH3)2)—



N(H)(cyclopropyl)


IVb-78
—OC(Me)(i-Pr)—CH2
—N(CH2C(H)(CH3)2)—



N(H)(cyclopropyl)


IVb-79
—OC(Me)(i-Pr)—CH2
—N(C(CH3)3)—



N(H)(cyclopropyl)


IVb-80
—OC(Me)(i-Pr)—CH2
—CH(OH)—



N(H)(cyclopropyl)


IVb-81
—OC(Me)(i-Pr)—CH2
—N(C(O)N(H)—CH2—CH2—OH)—



N(H)(cyclopropyl)


IVb-82
—OC(Me)(i-Pr)—CH2
—N(C(O)N(H)—CH2—CH2—F)—



N(H)(cyclopropyl)


IVb-83
—OC(Me)(i-Pr)—CH2
—N(CH2—CH2—OH)—



N(H)(cyclopropyl)


IVb-84
—OC(Me)(i-Pr)—CH2
—N(CH2—CH2—F)—



N(H)(cyclopropyl)


IVb-85
—OC(Me)(i-Pr)—CH2
—N(CH2—CH2—OCH3)—



N(H)(cyclopropyl)


IVb-86
—OC(Me)(i-Pr)—CH2
—N(CH2—CH2—CF3)—



N(H)(cyclopropyl)


IVb-87
—OC(Me)(i-Pr)—CH2
—N(C(O)N(H)—CH2—CH2—OCH3)—



N(H)(cyclopropyl)


IVb-88
—OC(Me)(i-Pr)—CH2
—N(C(O)N(H)—CH2—CH2—CF3)—



N(H)(cyclopropyl)









and pharmaceutically acceptable salts thereof.


5.12 The Indenoisoquinolinone Analogs of Formula (IVc)

The present invention provides Indenoisoquinolinone Analogs according to Formula (IVc), below:




embedded image



and pharmaceutically acceptable salts thereof,


wherein X and R1 are as defined above for the Indenoisoquinolinone Analogs of Formula (IVc).


In one embodiment, X is —N(CH3)—. In another embodiment, X is —N(CH2CH3)—. In another embodiment, X is —N(CH2CH2CH3)—. In another embodiment, X is —N(CH2CH2CH2CH3)—. In another embodiment, X is —N(C(H)(CH3)(CH2CH3))—. In another embodiment, X is —N(C(H)(CH3)2)—. In another embodiment, X is —N(CH2C(H)(CH3)2)—. In another embodiment, X is —N(C(CH3)3)—.


In one embodiment, X is —O—. In one embodiment, X is —CH2—. In one embodiment,


X is —C(O)—. In one embodiment, X is —NH—. In one embodiment, X is —S—. In one embodiment, X is —CH(OH)—.


In one embodiment, each C1-C3 alkyl is independent of the other C1-C3 alkyl.


In one embodiment, each C1-C3 alkyl is methyl.


In one embodiment, each C1-C3 alkyl is methyl and X is —CH2—.


In one embodiment, each C1-C3 alkyl is methyl and X is —CH(OH)—.


In one embodiment, each C1-C3 alkyl is methyl, X is —CH2— and n is 1.


In one embodiment, each C1-C3 alkyl is methyl, X is —CH(OH)— and n is 1.


In another embodiment, X is —CH(OH)— and n is 1.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—Z)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)—Z)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)2—Z)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—Z)— and n is 1.


In yet another embodiment, X is —N(C(O)N(H)—(CH2)2—Z)— and n is 2.


In still another embodiment, X is —N(C(O)N(H)—(CH2)—Z)— and n is 1.


In one embodiment, X is —N((CH2)q—Z)—.


In another embodiment, X is —N((CH2)—Z)—.


In another embodiment, X is —N((CH2)2—Z)—.


In another embodiment, X is —N((CH2)q—Z)— and n is 1.


In yet another embodiment, X is —N((CH2)q—Z)— and n is 2.


In still another embodiment, X is —N((CH2)—Z)— and n is 1.


In still another embodiment, X is —N((CH2)—Z)— and n is 2.


In one embodiment, Z is —CF3.


In another embodiment, Z is —F.


In yet another embodiment, Z is —OH.


In still another embodiment, Z is —O—CH3.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—OH)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)2—OH)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—OH)— and n is 1.


In yet another embodiment, X is —N(C(O)N(H)—(CH2)p—OH)— and n is 2.


In still another embodiment, X is —N(C(O)N(H)—(CH2)2—OH)— and n is 1.


In still another embodiment, X is —N(C(O)N(H)—(CH2)2—OH)— and n is 2.


In one embodiment, X is —N((CH2)q—OH)—.


In another embodiment, X is —N((CH2)2—OH)—.


In another embodiment, X is —N((CH2)q—OH)— and n is 1.


In yet another embodiment, X is —N((CH2)q—OH)— and n is 2.


In still another embodiment, X is —N((CH2)2—OH)— and n is 1.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—F)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)—F)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—F)— and n is 1.


In yet another embodiment, X is —N(C(O)N(H)—(CH2)p—F)— n is 2.


In still another embodiment, X is —N(C(O)N(H)—(CH2)—F)— and n is 1.


In one embodiment, X is —N((CH2)q—F)—.


In another embodiment, X is —N((CH2)—F)—.


In another embodiment, X is —N((CH2)q—F)— and n is 1.


In yet another embodiment, X is —N((CH2)q—F)— and n is 2.


In still another embodiment, X is —N((CH2)—F)— and n is 1.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—OMe)-.


In another embodiment, X is —N(C(O)N(H)—(CH2)2—OMe)-.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—OMe)- and n is 1.


In yet another embodiment, X is —N(C(O)N(H)—(CH2)p—OMe)- and n is 2.


In still another embodiment, X is —N(C(O)N(H)—(CH2)2—OMe)- and n is 1.


In one embodiment, X is —N((CH2)q—OMe)-.


In another embodiment, X is —N((CH2)2—OMe)-.


In another embodiment, X is —N((CH2)q—OMe)- and n is 1.


In yet another embodiment, X is —N((CH2)q—OMe)- and n is 2.


In still another embodiment, X is —N((CH2)2—OMe)- and n is 1.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—CF3)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)—CF3)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—CF3)— and n is 1.


In yet another embodiment, X is —N(C(O)N(H)—(CH2)p—CF3)— and n is 2.


In still another embodiment, X is —N(C(O)N(H)—(CH2)—CF3)— and n is 1.


In one embodiment, X is —N((CH2)q—CF3)—.


In another embodiment, X is —N((CH2)—CF3)—.


In another embodiment, X is —N((CH2)q—CF3)— and n is 1.


In yet another embodiment, X is —N((CH2)q—CF3)— and n is 2.


In still another embodiment, X is —N((CH2)—CF3)— and n is 1.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—CF3)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)—CF3)—.


In another embodiment, X is —N(C(O)N(H)—(CH2)p—CF3)— and n is 1.


In yet another embodiment, X is —N(C(O)N(H)—(CH2)p—CF3)— and n is 2.


In still another embodiment, X is —N(C(O)N(H)—(CH2)—CF3)— and n is 1.


In one embodiment, X is —N((CH2)q—CF3)—.


In another embodiment, X is —N((CH2)—CF3)—.


In another embodiment, X is —N((CH2)q—CF3)— and n is 1.


In yet another embodiment, X is —N((CH2)q—CF3)— and n is 2.


In still another embodiment, X is —N((CH2)—CF3)— and n is 1.


In one embodiment, n is 1.


In another embodiment, n is 2.


In yet another embodiment, n is 3.


In a further embodiment, n is 4, 5, or 6.


In yet a further embodiment, n is 7, 8, or 9.


In still a further embodiment, n is 10.


In one embodiment, p is 1.


In another embodiment, p is 2.


In yet another embodiment, p is an integer ranging from 2 to 5.


In one embodiment, q is 1.


In another embodiment, q is 2.


In yet another embodiment, q is an integer ranging from 2 to 5.


In one embodiment, n is 1 and X is —N(CH3)—.


In another embodiment, n is 1 and X is —N(CH2CH3).


In another embodiment, n is 1 and X is —N(CH2CH2CH3)—.


In another embodiment, n is 1 and X is —N(CH2CH2CH2CH3)—.


In another embodiment, n is 1 and X is —N(C(H)(CH3)(CH2CH3))—.


In another embodiment, n is 1 and X is —N(C(H)(CH3)2)—.


In another embodiment, n is 1 and X is —N(CH2C(H)(CH3)2)—.


In another embodiment, n is 1 and X is —N(C(CH3)3)—.


In one embodiment, one R2 is —H, and the other R2 is —C1-C6 alkyl.


In another embodiment, each R2 is —C1-C6 alkyl.


In another embodiment, each R2 is -methyl.


In various embodiments, —N(R2)(R2) is:




embedded image


embedded image


embedded image


In other embodiments, —N(R2)(R2) is:




embedded image


embedded image


embedded image


In some embodiments, —N(R2)(R2) is




embedded image


In still other embodiments, —N(R2)(R2) is

    • —N(CH2CH3)(CH3),
    • —N(CH2CH2CH3)(CH3),
    • —N(CH2CH2CH2CH3)(CH3),
    • —NH—CH2CH2CH2CH3, or
    • —NH—CH2CH2—O—CH3.


In some embodiments, —N(R2)(R2) is




embedded image


In various embodiments, —N(Z3)(Z4) is:




embedded image


embedded image


embedded image


In other embodiments, —N(Z3)(Z4) is:




embedded image


embedded image


embedded image


In some embodiments, —N(Z3)(Z4) is




embedded image


In still other embodiments, —N(Z3)(Z4) is

    • —N(CH2CH3)(CH3),
    • —N(CH2CH2CH3)(CH3),
    • —N(CH2CH2CH2CH3)(CH3),
    • —NH—CH2CH2CH2CH3, or
    • —NH—CH2CH2—O—CH3.


In some embodiments, —N(Z3)(Z4) is




embedded image


In one embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2 CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2— or —N(C(CH3)3)—;


n is an integer ranging from 1 to 3;


each R2 is independently —H, —C1-C6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —(C1-C6 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)2OH or —N(Z3)(Z4), where Z3 and Z4 are independently —H, —C1-C5 alkyl, or —(C1-C5 alkylene)-O—C1-C5 alkyl, each of which other than hydrogen is unsubstituted or substituted with one or more of -halo, —OH or —NH2;


or N, Z3 and Z4 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three of —C1-C5 alkyl, -phenyl, —(C1-C5 alkylene)-phenyl, -(hydroxy-substituted) C1-C5 alkyl, -halo, -(halo-substituted) C1-C5 alkyl, -(halo-substituted) phenyl, -phenylene-O—C1-C5 alkyl, -(cyano-substituted) phenyl, —OH, —O—C1-C5 alkyl, —N(Ra)2, —(C1-C5 alkylene)-N(Ra)2, —C1-C5 alkylene-C(O)O—(C1-C5 alkylene)-N(Ra)2, —COOH, —(C1-C5 alkylene)-COOH, —OP(O)(OH)2, —OS(O)2OH, —(C1-C5 alkylene)-OP(O)(OH)2, —(C1-C5 alkylene)-OS(O)2OH, —C(O)O—C1-C5 alkyl, —OC(O)—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)O—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)NH—C1-C5 alkyl, —C(O)NH2, or —NO2, wherein each occurrence of Ra is independently —H, -benzyl, or —C1-C10 alkyl;


or N and both R2 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 —C1-C5 alkyl, -phenyl, —(C1-C5 alkylene)-phenyl, -(hydroxy-substituted) C1-C5 alkyl, -halo, -(halo-substituted) C1-C5 alkyl, -(halo-substituted) phenyl, -phenylene-O—C1-C5 alkyl, -(cyano-substituted) phenyl, —OH, —O—C1-C5 alkyl, —N(Ra)2, —(C1-C5 alkylene)-N(Ra)2, —(C1-C5 alkylene)-C(O)O—(C1-C5 alkylene)-N(Ra)2, —COOH, —(C1-C5 alkylene)-COOH, —OP(O)(OH)2, —OS(O)2OH, —(C1-C5 alkylene)-OP(O)(OH)2, —(C1-C5 alkylene)-OS(O)2OH, —C(O)O—C1-C5 alkyl, —OC(O)—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)O—C1-C5 alkyl, —(C1-C5 alkylene)-C(O)NH—C1-C5 alkyl, —C(O)NH2, or —NO2, wherein each occurrence of Ra is independently —H, -benzyl, or —C1-C10 alkyl.


In one embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2 CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2— or —N(C(CH3)3)—;


n is an integer ranging from 1 to 3; and


at least one C1-C3 alkyl is methyl.


In another embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2— or —N(C(CH3)3)—; at least one C1-C3 alkyl is methyl; and at least one R2 is ethyl.


In yet another embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2— or —N(C(CH3)3)—; at least one C1-C3 alkyl is methyl; and at least one R2 is propyl.


In one embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2 CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2— or —N(C(CH3)3)—; at least one C1-C3 alkyl is methyl; and at least one R2 is —C3-C8 monocyclic cycloalkyl.


In another embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2 CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2— or —N(C(CH3)3)—; at least one C1-C3 alkyl is methyl; and at least one R2 is cyclohexyl.


In yet another embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2— or —N(C(CH3)3)—; and at least one C1-C3 alkyl is methyl, wherein N and both R2 groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle.


In one embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2 CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2— or —N(C(CH3)3)—; and at least one C1-C3 alkyl is methyl, wherein N and both R2 groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle, which is substituted with a hydroxyl.


In another embodiment, X is —N(CH3)—, —N(CH2CH3)—, —N(CH2CH2CH3)—, —N(CH2 CH2CH2CH3)—, —N(C(H)(CH3)(CH2CH3))—, —N(C(H)(CH3)2)—, —N(CH2C(H)(CH3)2— or —N(C(CH3)3)—; and at least one C1-C3 alkyl is methyl, wherein N and both R2 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.


Illustrative examples of the Indenoisoquinolinone Analogs include the compounds of Formula (IVc) as set forth below:














(IVc)




embedded image














Compound
—R1
X





IVb-1
—OC(Me)(Me)—CH2—N(Et)(Et)
—O—


IVc-2
—OC(Me)(Me)—CH2—N(Et)(Et)
—CH2


IVc-3
—OC(Me)(Me)—CH2—N(Et)(Et)
—C(O)—


IVc-4
—OC(Me)(Me)—CH2—N(Et)(Et)
—NH—


IVc-5
—OC(Me)(Me)—CH2—N(Et)(Et)
—S—


IVc-6
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(CH3)—


IVc-7
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(CH2CH3)—


IVc-8
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(CH2CH2CH3)—


IVc-9
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(CH2CH2CH2CH3)—


IVc-10
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(C(H)(CH3)(CH2CH3))—


IVc-11
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(C(H)(CH3)2)—


IVc-12
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(CH2C(H)(CH3)2)—


IVc-13
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(C(CH3)3)—


IVc-14
—OC(Me)(Me)—CH2—N(Et)(Et)
—CH(OH)—


IVc-15
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(C(O)N(H)—CH2—CH2—OH)—


IVc-16
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(C(O)N(H)—CH2—CH2—F)—


IVc-17
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(CH2—CH2—OH)—


IVc-18
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(CH2—CH2—F)—


IVc-19
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(CH2—CH2—OCH3)—


IVc-20
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(CH2—CH2—CF3)—


IVc-21
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(C(O)N(H)—CH2—CH2—OCH3)—


IVc-22
—OC(Me)(Me)—CH2—N(Et)(Et)
—N(C(O)N(H)—CH2—CH2—CF3)—


IVc-23
—OC(Me)(Et)—CH2—N(Et)(Et)
—O—


IVc-24
—OC(Me)(Et)—CH2—N(Et)(Et)
—CH2


IVc-25
—OC(Me)(Et)—CH2—N(Et)(Et)
—C(O)—


IVc-26
—OC(Me)(Et)—CH2—N(Et)(Et)
—NH—


IVc-27
—OC(Me)(Et)—CH2—N(Et)(Et)
—S—


IVc-28
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(CH3)—


IVc-29
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(CH2CH3)—


IVc-30
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(CH2CH2CH3)—


IVc-31
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(CH2CH2CH2CH3)—


IVc-32
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(C(H)(CH3)(CH2CH3))—


IVc-33
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(C(H)(CH3)2)—


IVc-34
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(CH2C(H)(CH3)2)—


IVc-35
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(C(CH3)3)—


IVc-36
—OC(Me)(Et)—CH2—N(Et)(Et)
—CH(OH)—


IVc-37
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(C(O)N(H)—CH2—CH2—OH)—


IVc-38
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(C(O)N(H)—CH2—CH2—F)—


IVc-39
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(CH2—CH2—OH)—


IVc-40
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(CH2—CH2—F)—


IVc-41
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(CH2—CH2—OCH3)—


IVc-42
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(CH2—CH2—CF3)—


IVc-43
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(C(O)N(H)—CH2—CH2—OCH3)—


IVc-44
—OC(Me)(Et)—CH2—N(Et)(Et)
—N(C(O)N(H)—CH2—CH2—CF3)—


IVc-45
—OC(Me)(Pr)—CH2—N(Et)(Et)
—O—


IVc-46
—OC(Me)(Pr)—CH2—N(Et)(Et)
—CH2


IVc-47
—OC(Me)(Pr)—CH2—N(Et)(Et)
—C(O)—


IVc-48
—OC(Me)(Pr)—CH2—N(Et)(Et)
—NH—


IVc-49
—OC(Me)(Pr)—CH2—N(Et)(Et)
—S—


IVc-50
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(CH3)—


IVc-51
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(CH2CH3)—


IVc-52
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(CH2CH2CH3)—


IVc-53
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(CH2CH2CH2CH3)—


IVc-54
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(C(H)(CH3)(CH2CH3))—


IVc-55
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(C(H)(CH3)2)—


IVc-56
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(CH2C(H)(CH3)2)—


IVc-57
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(C(CH3)3)—


IVc-58
—OC(Me)(Pr)—CH2—N(Et)(Et)
—CH(OH)—


IVc-59
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(C(O)N(H)—CH2—CH2—OH)—


IVc-60
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(C(O)N(H)—CH2—CH2—F)—


IVc-61
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(CH2—CH2—OH)—


IVc-62
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(CH2—CH2—F)—


IVc-63
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(CH2—CH2—OCH3)—


IVc-64
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(CH2—CH2—CF3)—


IVc-65
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(C(O)N(H)—CH2—CH2—OCH3)—


IVc-66
—OC(Me)(Pr)—CH2—N(Et)(Et)
—N(C(O)N(H)—CH2—CH2—CF3)—


IVc-67
—OC(Me)(i-Pr)—CH2
—O—



N(H)(cyclopropyl)


IVc-68
—OC(Me)(i-Pr)—CH2
—CH2



N(H)(cyclopropyl)


IVc-69
—OC(Me)(i-Pr)—CH2
—C(O)—



N(H)(cyclopropyl)


IVc-70
—OC(Me)(i-Pr)—CH2
—NH—



N(H)(cyclopropyl)


IVc-71
—OC(Me)(i-Pr)—CH2
—S—



N(H)(cyclopropyl)


IVc-72
—OC(Me)(i-Pr)—CH2
—N(CH3)—



N(H)(cyclopropyl)


IVc-73
—OC(Me)(i-Pr)—CH2
—N(CH2CH3)—



N(H)(cyclopropyl)


IVc-74
—OC(Me)(i-Pr)—CH2
—N(CH2CH2CH3)—



N(H)(cyclopropyl)


IVc-75
—OC(Me)(i-Pr)—CH2
—N(CH2CH2CH2CH3)—



N(H)(cyclopropyl)


IVc-76
—OC(Me)(i-Pr)—CH2
—N(C(H)(CH3)(CH2CH3))—



N(H)(cyclopropyl)


IVc-77
—OC(Me)(i-Pr)—CH2
—N(C(H)(CH3)2)—



N(H)(cyclopropyl)


IVc-78
—OC(Me)(i-Pr)—CH2
—N(CH2C(H)(CH3)2)—



N(H)(cyclopropyl)


IVc-79
—OC(Me)(i-Pr)—CH2
—N(C(CH3)3)—



N(H)(cyclopropyl)


IVc-80
—OC(Me)(i-Pr)—CH2
—CH(OH)—



N(H)(cyclopropyl)


IVc-81
—OC(Me)(i-Pr)—CH2
—N(C(O)N(H)—CH2—CH2—OH)—



N(H)(cyclopropyl)


IVc-82
—OC(Me)(i-Pr)—CH2
—N(C(O)N(H)—CH2—CH2—F)—



N(H)(cyclopropyl)


IVc-83
—OC(Me)(i-Pr)—CH2
—N(CH2—CH2—OH)—



N(H)(cyclopropyl)


IVc-84
—OC(Me)(i-Pr)—CH2
—N(CH2—CH2—F)—



N(H)(cyclopropyl)


IVc-85
—OC(Me)(i-Pr)—CH2
—N(CH2—CH2—OCH3)—



N(H)(cyclopropyl)


IVc-86
—OC(Me)(i-Pr)—CH2
—N(CH2—CH2—CF3)—



N(H)(cyclopropyl)


IVc-87
—OC(Me)(i-Pr)—CH2
—N(C(O)N(H)—CH2—CH2—OCH3)—



N(H)(cyclopropyl)


IVc-88
—OC(Me)(i-Pr)—CH2
—N(C(O)N(H)—CH2—CH2—CF3)—



N(H)(cyclopropyl)









and pharmaceutically acceptable salts thereof.


5.13 The Indenoisoquinolinone Analogs of Formula (Va)

The present invention provides Indenoisoquinolinone Analogs according to Formula (Va), below:




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and pharmaceutically acceptable salts thereof,


wherein R1, X and Y′ are as defined above for the Indenoisoquinolinone Analogs of Formula (Va).


In one embodiment, R1 is —(CH2)n—NHR2 and R2 is a —C3-C8 monocyclic cycloalkyl.


In another embodiment, R1 is —(CH2)n—NHR2 and R2 is a —C3-C8 monocyclic cycloalkyl substituted with one or more of -(hydroxy-substituted) C1-C5 alkyl.


In one embodiment, R1 is —(CH2)n—NHR2, R2 is a —C3-C8 monocyclic cycloalkyl, and X is fluoro.


In one embodiment, R1 is —(CH2)n—NHR2, R2 is a —C3-C8 monocyclic cycloalkyl, and X is chloro.


In one embodiment, R1 is —(CH2)n—NHR2 and R2 is cyclopentyl.


In another embodiment, R1 is —(CH2)n—NHR2, R2 is a —C3-C8 monocyclic cycloalkyl substituted with one or more of -(hydroxy-substituted) C1-C5 alkyl, and X is fluoro.


In another embodiment, R1 is —(CH2)n—NHR2, R2 is cyclopentyl substituted with one or more of -(hydroxy-substituted C1-C5 alkyl), and X is fluoro.


In one embodiment, R1 is —(CH2)n—NHR2, R2 is a —C3-C8 monocyclic cycloalkyl, and Y′ is fluoro.


In another embodiment, R1 is —(CH2)n—NHR2, R2 is a —C3-C8 monocyclic cycloalkyl substituted with one or more of -(hydroxy-substituted C1-C5 alkyl), and Y′ is fluoro.


In another embodiment, R1 is —(CH2)n—NHR2, R2 is a —C3-C8 monocyclic cycloalkyl substituted with one or more of -(hydroxy-substituted) C1-C5 alkyl, and X and Y′ are fluoro.


In another embodiment, R1 is —(CH2)n—NHR2, R2 is a 3- to 7-membered monocyclic heterocycle, and X is fluoro.


In another embodiment, R1 is —(CH2)n—NHR2, R2 is a 3- to 7-membered monocyclic heterocycle, and Y′ is fluoro.


In another embodiment, R1 is —(CH2)n—NHR2 and R2 is tetrahydropyranyl.


In one embodiment, R2 is tetrahydropyranyl, or cyclopentyl which is unsubstituted or substituted with one or more of -(hydroxy-substituted C1-C5 alkyl).


In another embodiment, one of X and Y′ is fluoro.


Illustrative examples of the Indenoisoquinolinone Analogs include the compounds of Formula (Va) as set forth below:














(Va)




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Compound
—R1
X
Y'





Va-1


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—Cl, at position 4
—H





Va-2


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—F, at position 2
—H





Va-3


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—F, at position 3
—H





Va-4


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—F, at position 4
—H





Va-5


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—F, at position 3
—H





Va-6


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—F, at position 1
—H





Va-7


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—F, at position 1
—H





Va-8


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—F, at position 2
—H





Va-9


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—H
—F, at position 8





Va-10


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—F, at position 3
—F, at position 8









5.14 Methods for Making Indenoisoquinolinone Analogs

Methods useful for making the Indenoisoquinolinone Analogs are set forth in the Examples below and generalized in Schemes 1-7.




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wherein n and each R2 is defined above for the Indenoisoquinolinone Analogs of Formula (IIa), (IIb), (IIc), (IIIa), (IIIb), (IVa), (IVb) or (IVc), and X is —Br, —I, —Cl, —O-Ts, —O-Ms, —O-Triflate, or —O-Acetate.


As shown in Scheme 1, a compound of formula 1 can be reacted with methanol in the presence of an acid, for example, sulphuric acid, to provide a compound of formula 2. The compound of formula 2 can then be reacted with cyanide to provide a compound of formula 3. The compound of formula 3 can be brominated using, for example, N-bromosuccinimide, to provide a compound of formula 4. The compound of formula 4 can then be reacted with homophthalic anhydride to provide a compound of formula 5. The compound of formula 5 can then be reduced, for example with lithium aluminum hydride (LAH), to provide a compound of formula 6.




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As shown in Scheme 2, an indenoisoquinolinone compound of formula 8 can be reacted with hydrochloric acid or hydrobromic acid in the presence of formaldehyde to provide a halomethyl compound of formula 9. The compound of formula 9 can then be reacted with an amine of formula NH(R2)(R3) to provide an Indenoisoquinolinone Analog of Formula (IIb), wherein R1=—(CH2)—N(R2)(R3), wherein each R2 and R3 are as defined above. Alternatively, the compound of formula 9 can be reacted with an appropriate amine to provide an Indenoisoquinolinone Analog of Formula (IIIb) or (IVb).


A compound of formula 6 can be reacted with a reagent 6a to provide a compound of formula 7 (see, e.g., Scheme 1). Suitable reagents 6a include, but are not limited to, PBr3, HBr, HI, SOCl2, Ts-Cl, pyrene, MsCl, CF3SO2Cl, acetic anhydride, acetyl chloride or NEt3. The compound of formula 7 can then be reacted with an amine of formula NH(R2)(R3) to provide an Indenoisoquinolinone Analog of Formula (IIa), (IIb) or (IIc) wherein R1=—(CH2)n—N(R2)(R3), wherein n, R2 and R3 are as defined above. Alternatively, the compound of formula 7 can be reacted with an appropriate amine to provide an Indenoisoquinolinone Analog of Formula (IIIa) or (IIIb). Using similar methods, Indenoisoquinolinone Analogs of Formula (IVa), (IVb) or (IVc) can also be obtained using an appropriate analog of the compound of formula 1, as would be apparent to one of ordinary skill in the art.




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wherein n is defined above for the Indenoisoquinolinone Analogs of Formula (Ia), (Ib), (Ic), (IIa), (IIIb) or (IIc) and X′ is —OH, —SH, —NHC(O)OMe, or —N(C1-C4 alkyl). As set forth in Scheme 3, a compound of formula 10 is reacted with a compound of formula 11 in the presence of triethylamine to provide a compound of formula 12, wherein X is —O—, —S—, —N(C(O)OMe)-, or —N(C1-C4 alkyl)-. The compound of formula 12 can then be converted to provide an Indenoisoquinolinone Analog of Formula (Ia), (Ib), (Ic), (Ia), (IIb) or (IIc), e.g., using procedures outlined in Scheme 1 and/or 2. The compound of formula 12, wherein X is —N(C(O)OMe)-, can be deprotected, for example using hydrazine, to provide a compound, wherein X is —N(H)—. Using similar methods, Indenoisoquinolinone Analogs of Formula (IVa), (IVb) or (IVc) can also be obtained using an appropriate analog of the compound of formula 1, as would be apparent to one of ordinary skill in the art.




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wherein X′ is —OH, —SH, or NHC(O)OMe or —N(C1-C4 alkyl).


As set forth in Scheme 4, a compound of formula 13 is reacted with a compound of formula 11, to provide a compound of formula 14, wherein X is —O—, —S—, —N(C(O)OMe)-, or —N(C1-C4 alkyl)-. The compound of formula 14 is then converted to provide an Indenoisoquinolinone Analog of Formula (Ia), (Ib), (Ic), wherein R1=−O—(CH2)m—N(R2)(R2) or an Indenoisoquinolinone Analog of Formula (IVa), (IVb) or (IVc), for example using methods described in Schemes 1 and/or 5.




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wherein X, m, n, each R2 and each C1-C3 alkyl is defined above for the Indenoisoquinolinone Analogs of Formula (Ia), (Ib), (Ic), (IVa), (IVb) or (IVc) and A is a halogen.


As set forth in Scheme 5, a compound of formula 14 is demethylated, for example using boron tribromide, to provide a compound of formula 15. A compound of formula 15 is then reacted in the presence of base with A(CH2)mNR2R2 to provide the compound of the general formula 15a, an Indenoisoquinolinone Analog of Formula (Ia), (Ib), or (Ic), wherein R1=—O—(CH2)m—N(R2)(R2). Alternatively, a compound of formula 15 is reacted in the presence of base with A-C(C1-C3 alkyl)2(CH2)nNR2R2 to provide the compound of the general formula 15b, an Indenoisoquinolinone Analog of Formula (IVa), (IVb), or (IVc).




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wherein R1 is as defined above for the Indenoisoquinolinone Analogs of Formula (IIa), (IIb), (IIc), (IVa), (IVb) or (IVc).


As set forth in Scheme 6, compounds of the general formula 16, which can be prepared, for example, according to Schemes 1 or 2, can be oxidized to provide a compound of the general formula 17, which is an Indenoisoquinolinone Analog of Formula (IIa), (IIb), (IIc), (IVa), (IVb) or (IVc), wherein X is —C(O)—. In one embodiment, the oxidation is achieved using O2 and dimethylsulfoxide. In one aspect, the O2 is that which is present in air. In another embodiment, the oxidation is achieved using Cerium(IV) triflate (Ce(OTf)4). Optional protecting groups can be used (Greene et al., Protective Groups in Organic Synthesis (3rd ed. 1999)). For example, where R1 is —(CH2)n—OH, protecting groups such as —SiEt3, can be used to protect the R1 hydroxyl group during the oxidation and can then be removed, for example with an acid. The compound of the general formula 17, can be reduced, for example with sodium borohydride or lithium aluminum hydride, to provide the compound of the general formula 18, which is an Indenoisoquinolinone Analog of Formula (IIa), (IIb), (IIc), (IVa), (IVb) or (IVc), wherein X is —CH(OH)—.




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As set forth in Scheme 7, Indenoisoquinolinone Analogs of Formula (Va) can be prepared, for example, as illustrated in part (1) of the scheme by reacting compound 19 with either compounds 20 or 23 to yield compounds 21 and 24, respectively. Compounds 21 and 24 can then be reacted with the selected amine to form compounds 22 and 25 respectively. Compounds 22 and 25 are representative of an Indenoisoquinolinone Analog of Formula (Va). In part (2) of the scheme, reaction of compound 26 under suitable conditions and in the presence of homophthalic anhydride and the desired amine yields compound 27, which is an Indenoisoquinolinone Analog of Formula of Formula (Va).


5.15 Treatment or Prevention of a Condition

In accordance with the invention, an Indenoisoquinolinone Analog is useful for treatment or prevention of a Condition as set forth below.


5.8.1 Treatment or Prevention of an Inflammatory Disease

The Indenoisoquinolinone Analogs are useful for treating or preventing an inflammatory disease. An inflammatory disease can arise where there is an inflammation of the body tissue. These include local inflammatory responses and systemic inflammation. Examples of inflammatory diseases include, but are not limited to, lupus; pancreatitis; macular degeneration; chronic obstructive pulmonary disease; organ transplant rejection; a chronic inflammatory disease of a joint, including arthritis, rheumatoid arthritis, osteoarthritis and a bone disease associated with increased bone resorption; an inflammatory bowel disease such as ileitis, ulcerative colitis, Barrett's syndrome, and Crohn's disease; an inflammatory lung disease such as asthma, adult respiratory distress syndrome, and chronic obstructive airway disease; an inflammatory disease of the eye including corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmitis and endophthalmitis; a chronic inflammatory disease of the gum, including gingivitis and periodontitis; tuberculosis; leprosy; an inflammatory disease of the kidney including a uremic complication, glomerulonephritis and nephrosis; an inflammatory disease of the skin including sclerodermatitis, psoriasis and eczema; an inflammatory disease of the central nervous system, including a chronic demyelinating disease of the nervous system, multiple sclerosis, AIDS-related neurodegeneration and Alzheimer's disease, infectious meningitis, encephalomyelitis, Huntington's disease, amyotrophic lateral sclerosis and viral or autoimmune encephalitis; as well as any other disease that can have a significant inflammatory component, including preeclampsia, chronic liver failure, and brain and spinal cord trauma. The inflammatory disease can also be a systemic inflammation of the body, exemplified by gram-positive or gram negative shock, hemorrhagic or anaphylactic shock, or shock induced by cancer chemotherapy in response to pro-inflammatory cytokines, e.g., shock associated with pro-inflammatory cytokines. Such shock can be induced, e.g., by a chemotherapeutic agent that is administered as a treatment for cancer.


In one embodiment, the inflammatory disease is an inflammatory disease of a joint, a chronic inflammatory disease of the gum, an inflammatory bowel disease, an inflammatory lung disease, an inflammatory disease of the central nervous system, an inflammatory disease of the eye, gram-positive shock, gram negative shock, Rickettsial shock, fungal shock, hemorrhagic shock, anaphylactic shock, traumatic shock or chemotherapeutic shock.


5.8.2 Treatment or Prevention of a Reperfusion Injury

The Indenoisoquinolinone Analogs are useful for treating or preventing a reperfusion injury. Reperfusion refers to the process whereby blood-flow in the blood vessels is resumed following ischemia, such as occurs following constriction or obstruction of the vessel. Reperfusion injury can result following a naturally occurring episode, such as a myocardial infarction, stroke, or during a surgical procedure where blood flow in vessels is intentionally or unintentionally blocked. Examples of reperfusion injuries include, but are not limited to, intestinal reperfusion injury, myocardial reperfusion injury, and reperfusion injury resulting from cardiopulmonary bypass surgery, aortic aneurysm repair surgery, carotid endarterectomy surgery, and hemorrhagic shock.


In one embodiment, the reperfusion injury results from cardiopulmonary bypass surgery, aortic aneurysm repair surgery, carotid endarterectomy surgery or hemorrhagic shock.


In another embodiment, the reperfusion injury is stroke or myocardial infarction.


5.8.3 Treatment or Prevention of Reoxygenation Injury Resulting from Organ Transplantation

The Indenoisoquinolinone Analogs are useful for treating or preventing reoxygenation injury resulting from organ transplantation. Examples of reoxygenation injuries include, but are not limited to, transplantation of one or more of the following: heart, lung, liver, kidney, pancreas, intestine and cornea.


In one embodiment, reoxygenation injury resulting from organ transplantation occurs during the organ transplantation.


The Indenoisoquinolinone Analogs are also useful for treating or preventing allograph rejection. Accordingly, the invention provides methods for treating or preventing allograph rejection, comprising administering an effective amount of an Indenoisoquinolinone Analog to a subject in need thereof. In one embodiment, the methods further comprise administering an effective amount of another agent useful for treating or preventing allograph rejection. The other agent includes, but is not limited to, SK-506 and cyclosporine.


5.8.4 Treatment or Prevention of an Ischemic Condition

The Indenoisoquinolinone Analogs are useful for treating or preventing an ischemic condition. Examples of ischemic conditions include, but are not limited to, stable angina, unstable angina, myocardial ischemia, hepatic ischemia, mesenteric artery ischemia, ischemic heart disease, intestinal ischemia, critical limb ischemia, chronic critical limb ischemia, cerebral ischemia, acute cardiac ischemia, and an ischemic disease of the central nervous system, such as stroke or cerebral ischemia.


In one embodiment, the ischemic condition is myocardial ischemia, stable angina, unstable angina, stroke, ischemic heart disease or cerebral ischemia.


5.8.5 Treatment or Prevention of Renal Failure

The Indenoisoquinolinone Analogs are useful for treating or preventing renal failure.


In one embodiment, the renal failure is chronic renal failure.


In another embodiment, the renal failure is acute renal failure.


5.8.6 Treatment or Prevention of a Vascular Disease

The Indenoisoquinolinone Analogs are useful for treating or preventing a vascular disease other than a cardiovascular disease. Examples of vascular diseases include, but are not limited to, hemorrahgic stroke, peripheral arterial occlusion, thromboangitis obliterans, Reynaud's disease and phenomenon, acrocyanosis, erythromelalgia, venous thrombosis, varicose veins, arteriovenous fistula, lymphedema, and lipedema.


In embodiment, the vascular disease is peripheral arterial occlusion, thromboangitis obliterans, Reynaud's disease and phenomenon, acrocyanosis, erythromelalgia, venous thrombosis, varicose veins, arteriovenous fistula, lymphedema or lipedema.


5.8.7 Treatment or Prevention of a Cardiovascular Disease

The Indenoisoquinolinone Analogs are useful for treating or preventing a cardiovascular disease. Examples of cardiovascular diseases include, but are not limited to, congestive heart failure (such as chronic or acute heart failure), atherosclerosis, hypercholesterolemia, circulatory shock, cardiomyopathy, cardiac transplant, myocardial infarction, and a cardiac arrhythmia, such as atrial fibrillation, supraventricular tachycardia, atrial flutter, and paroxysmal atrial tachycardia.


In one embodiment, the cardiovascular disease is chronic heart failure.


In another embodiment, the cardiovascular disease is acute heart failure.


In yet another embodiment, the cardiovascular disease is cardiac arrhythmia.


In still another embodiment, the cardiac arrhythmia is atrial fibrillation, supraventricular tachycardia, atrial flutter or paroxysmal atrial tachycardia.


In one embodiment, the cardiovascular disease is chronic heart failure, atrial fibrillation, supraventricular tachycardia, atrial flutter or paroxysmal atrial tachycardia.


5.8.8 Treatment or Prevention of Diabetes Mellitus or a Diabetic Complication

The Indenoisoquinolinone Analogs are useful for treating or preventing diabetes mellitus or one or more of its complications. Examples of diabetes mellitus include, but are not limited to, Type I diabetes (Insulin Dependent Diabetes Mellitus), Type II diabetes (Non-Insulin Dependent Diabetes Mellitus), gestational diabetes, autoimmune diabetes, insulinopathies, diabetes due to pancreatic disease, diabetes associated with other endocrine diseases (such as Cushing's Syndrome, acromegaly, pheochromocytoma, glucagonoma, primary aldosteronism or somatostatinoma), Type A insulin resistance syndrome, Type B insulin resistance syndrome, lipatrophic diabetes, and diabetes induced by β-cell toxins.


The Indenoisoquinolinone Analogs are useful for treating or preventing a complication of diabetes mellitus. Examples of complications of diabetes mellitus include, but are not limited to, diabetic cataract, glaucoma, retinopathy, nephropathy (such as microalbuminuria or progressive diabetic nephropathy), polyneuropathy, gangrene of the feet, immune-complex vasculitis, systemic lupus erythematosus (SLE), atherosclerotic coronary arterial disease, peripheral arterial disease, nonketotic hyperglycemic-hyperosmolar coma, mononeuropathies, autonomic neuropathy, foot ulcers, joint problems, and a skin or mucous membrane complication (such as an infection, a shin spot, a candidal infection or necrobiosis lipoidica diabeticorumobesity), hyperlipidemia, hypertension, syndrome of insulin resistance, coronary artery disease, retinopathy, neuropathy (such as diabetic neuropathy, polyneuropathy or mononeuropathy), autonomic neuropathy, a foot ulcer, a joint problem, a fungal infection, cardiomyopathy, and a bacterial infection.


In one embodiment diabetes mellitus is Type I diabetes mellitus or Type II diabetes mellitus.


5.8.9 Treatment or Prevention of a Neurodegenerative Disease

The Indenoisoquinolinone Analogs are useful for treating or preventing a neurodegenerative disease. Examples of neurodegenerative diseases include, but are not limited to, Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis.


5.8.10 Treatment or Prevention of Cancer

The Indenoisoquinolinone Analogs are useful for treating or preventing cancer.


Accordingly, the invention provides methods for treating or preventing cancer, comprising administering an effective amount of an Indenoisoquinolinone Analog to a subject in need thereof. In one embodiment, the methods further comprise administering an effective amount of another anticancer agent.


Examples of cancers include, but are not limited to, the cancers disclosed below in Table 1 and metastases thereof.











TABLE 1








Solid tumors, including but not limited to:




fibrosarcoma




myxosarcoma




liposarcoma




chondrosarcoma




osteogenic sarcoma




chordoma




angiosarcoma




endotheliosarcoma




lymphangiosarcoma




lymphangioendotheliosarcoma




synovioma




mesothelioma




Ewing's tumor




leiomyosarcoma




rhabdomyosarcoma




colon cancer




colorectal cancer




kidney cancer




pancreatic cancer




bone cancer




breast cancer




ovarian cancer




prostate cancer




esophageal cancer




stomach cancer




oral cancer




nasal cancer




throat cancer




squamous cell carcinoma




basal cell carcinoma




adenocarcinoma




sweat gland carcinoma




sebaceous gland carcinoma




papillary carcinoma




papillary adenocarcinomas




cystadenocarcinoma




medullary carcinoma




bronchogenic carcinoma




renal cell carcinoma




hepatoma




bile duct carcinoma




choriocarcinoma




seminoma




embryonal carcinoma




Wilms' tumor




cervical cancer




uterine cancer




testicular cancer




small cell lung carcinoma




bladder carcinoma




lung cancer




epithelial carcinoma




skin cancer




melanoma




metastatic melanoma




neuroblastoma




retinoblastoma




blood-borne cancers, including but not limited to:




acute lymphoblastic leukemia (“ALL”)




acute lymphoblastic B-cell leukemia




acute lymphoblastic T-cell leukemia




acute myeloblastic leukemia (“AML”)




acute promyelocytic leukemia (“APL”)




acute monoblastic leukemia




acute erythroleukemic leukemia




acute megakaryoblastic leukemia




acute myelomonocytic leukemia




acute nonlymphocyctic leukemia




acute undifferentiated leukemia




chronic myelocytic leukemia (“CML”)




chronic lymphocytic leukemia (“CLL”)




hairy cell leukemia




multiple myeloma




acute and chronic leukemias:




lymphoblastic




myelogenous




lymphocytic




myelocytic leukemias




Lymphomas:




Hodgkin's disease




non-Hodgkin's Lymphoma




Multiple myeloma




Waldenström's macroglobulinemia




Heavy chain disease




Polycythemia vera




Central nervous system lymphomas




CNS and Brain cancers:




glioma




pilocytic astrocytoma




astrocytoma




anaplastic astrocytoma




glioblastoma multiforme




medulloblastoma




craniopharyngioma




ependymoma




pinealoma




hemangioblastoma




acoustic neuroma




oligodendroglioma




meningioma




vestibular schwannoma




adenoma




metastatic brain tumor




meningioma




spinal tumor




medulloblastoma









In one embodiment, the cancer is lung cancer, breast cancer, colorectal cancer, prostate cancer, a leukemia, a lymphoma, non-Hodgkin's lymphoma, skin cancer, a brain cancer, a cancer of the central nervous system, ovarian cancer, uterine cancer, stomach cancer, pancreatic cancer, esophageal cancer, kidney cancer, liver cancer, or a head and neck cancer.


In another embodiment, the cancer is metastatic cancer.


In yet another embodiment, the cancer is brain cancer or melanoma.


In one embodiment, the brain cancer is metastatic brain cancer or a glioma.


In one embodiment, the glioma is pilocytic astrocytoma, astrocytoma, anaplastic astrocytoma or glioblastoma multiforme.


In one embodiment, the cancer is homologous-recombination deficient, such as BRCA-1 or BRCA-2 deficient, or is deficient in one or more proteins of the Fanconi family. In one embodiment, the deficiency is caused by a genetic mutation. In another embodiment, the phenotype resulting from the deficiency is caused by abnormally low expression of BRCA-1 or BRCA-2 protein. In another embodiment, the phenotype resulting from the deficiency is caused by abnormally low expression of one or more proteins of the Fanconi family.


In still another embodiment, the subject in need of treatment has previously undergone or is presently undergoing treatment for cancer. The treatment includes, but is not limited to, chemotherapy, radiation therapy, surgery or immunotherapy, such as administration of a cancer vaccine.


The Indenoisoquinolinone Analogs are also useful for treating or preventing a cancer caused by a virus. Such viruses include human papilloma virus, which can lead to cervical cancer (see, e.g., Hernandez-Avila et al., Archives of Medical Research (1997) 28:265-271); Epstein-Barr virus (EBV), which can lead to lymphoma (see, e.g., Herrmann et al., J Pathol (2003) 199(2):140-5); hepatitis B or C virus, which can lead to liver carcinoma (see, e.g., El-Serag, J Clin Gastroenterol (2002) 35(5 Suppl 2):S72-8); human T cell leukemia virus (HTLV)-I, which can lead to T-cell leukemia (see e.g., Mortreux et al., Leukemia (2003) 17(1):26-38); human herpesvirus-8 infection, which can lead to Kaposi's sarcoma (see, e.g., Kadow et al., Curr Opin Investig Drugs (2002) 3(11):1574-9); and Human Immune deficiency Virus (HIV) infection, which can lead to cancer as a consequence of immunodeficiency (see, e.g., Dal Maso et al., Lancet Oncol (2003) 4(2):110-9).


5.8.10.1 Prophylactic Methods for Cancer

The Indenoisoquinolinone Analogs are also useful for preventing cancer, or preventing progression of a cancer, including but not limited to the cancers listed in Table 1. Such prophylactic use includes that in which non-neoplastic cell growth such as hyperplasia, metaplasia, or most specifically, dysplasia has occurred.


Alternatively or in addition to the presence of abnormal cell growth characterized as hyperplasia, metaplasia, or dysplasia, the presence of one or more characteristics of a transformed phenotype, or of a malignant phenotype, displayed in vivo or displayed in vitro by a cell sample from a subject, can indicate the desirability of prophylactic or therapeutic administration of an Indenoisoquinolinone Analog. Such characteristics of a transformed phenotype include morphology changes, looser substratum attachment, loss of contact inhibition, loss of anchorage dependence, protease release, increased sugar transport, decreased serum requirement, expression of fetal antigens, disappearance of the 250,000 dalton cell surface protein, etc. (see also id., at pp. 84-90 for characteristics associated with a transformed or malignant phenotype).


In a specific embodiment, leukoplakia, a benign-appearing hyperplastic or dysplastic lesion of the epithelium, or Bowen's disease, a carcinoma in situ, is treatable or preventable according to the present methods.


In another embodiment, fibrocystic disease (cystic hyperplasia, mammary dysplasia, specifically adenosis (benign epithelial hyperplasia)) is treatable or preventable according to the present methods.


In other embodiments, a subject that has one or more of the following predisposing factors for malignancy can be treated by administration of an effective amount of an


Indenoisoquinolinone Analog: a chromosomal translocation associated with a malignancy (e.g., the Philadelphia chromosome for chronic myelogenous leukemia; t(14; 18) for follicular lymphoma); familial polyposis or Gardner's syndrome; benign monoclonal gammopathy; a first degree kinship with persons having a cancer or precancerous disease showing a Mendelian (genetic) inheritance pattern (e.g., familial polyposis of the colon, Gardner's syndrome, hereditary exostosis, polyendocrine adenomatosis, medullary thyroid carcinoma with amyloid production and pheochromocytoma, Peutz-Jeghers syndrome, neurofibromatosis of Von Recklinghausen, retinoblastoma, carotid body tumor, cutaneous melanocarcinoma, intraocular melanocarcinoma, xeroderma pigmentosum, ataxia telangiectasia, Chediak-Higashi syndrome, albinism, Fanconi's aplastic anemia, and Bloom's syndrome); and exposure to carcinogens (e.g., smoking, second-hand smoke exposure, and inhalation of or contacting with certain chemicals).


5.8.10.2 Combination Chemotherapy for the Treatment of Cancer

In one aspect, the present methods for treating or preventing cancer can further comprise the administration of another anticancer agent.


In one embodiment, the present invention provides methods for treating or preventing cancer, comprising the administration of an effective amount of an Indenoisoquinolinone Analog and another anticancer agent to a subject in need thereof.


The Indenoisoquinolinone Analog and another anticancer agent can be administered concurrently. In this embodiment, the Indenoisoquinolinone Analog and another anticancer agent can be administered within the same composition, or can be administered from different compositions, via the same or different routes of administration.


In another embodiment, the Indenoisoquinolinone Analog is administered during a time when the other anticancer agent exerts its prophylactic or therapeutic effect, or vice versa.


In another embodiment, the Indenoisoquinolinone Analog or other anticancer agent are administered in doses commonly employed when such agents are used as monotherapy for the treatment of cancer.


In one embodiment, the Indenoisoquinolinone Analog or other anticancer agent are administered in doses that are lower than the doses commonly employed when such agents are used as monotherapy for the treatment of cancer.


In another embodiment, the Indenoisoquinolinone Analog and other anticancer agent act synergistically and are administered in doses that are lower than the doses commonly employed when such agents are used as monotherapy for the treatment of cancer.


The dosage of the Indenoisoquinolinone Analog or other anticancer agent administered as well as the dosing schedule can depend on various parameters, including, but not limited to, the cancer being treated, the subject's general health, and the administering physician's discretion.


An Indenoisoquinolinone Analog can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concurrently with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of the other anticancer agent, to a subject in need thereof. In various embodiments an Indenoisoquinolinone Analog and the other anticancer agent are administered 1 minute apart, 10 minutes apart, 30 minutes apart, less than 1 hour apart, 1 hour apart, 1 hour to 2 hours apart, 2 hours to 3 hours apart, 3 hours to 4 hours apart, 4 hours to 5 hours apart, 5 hours to 6 hours apart, 6 hours to 7 hours apart, 7 hours to 8 hours apart, 8 hours to 9 hours apart, 9 hours to 10 hours apart, 10 hours to 11 hours apart, 11 hours to 12 hours apart, no more than 24 hours apart or no more than 48 hours apart. In one embodiment, an Indenoisoquinolinone Analog and the other anticancer agent are administered within 3 hours. In another embodiment, an Indenoisoquinolinone Analog and the other anticancer agent are administered at 1 minute to 24 hours apart.


In one embodiment, an effective amount of an Indenoisoquinolinone Analog and an effective amount of other anticancer agent are present in the same composition. In one embodiment, this composition is useful for oral administration. In another embodiment, this composition is useful for intravenous administration.


In one embodiment, the compositions comprise an amount of an Indenoisoquinolinone Analog and the other anticancer agent which together are effective to treat or prevent cancer.


In another embodiment, the compositions comprise an effective amount of temozolomide, procarbazine, dacarbazine, interleukin-2, irinotecan, or doxorubicin, a physiologically acceptable carrier or vehicle, and an effective amount of an Indenoisoquinolinone Analog.


In one embodiment, the amount of an Indenoisoquinolinone Analog and the other anticancer agent is at least about 0.01% of the combined combination chemotherapy agents by weight of the composition. When intended for oral administration, this amount can be varied from about 0.1% to about 80% by weight of the composition. Some oral compositions can comprise from about 4% to about 50% of combined amount of an Indenoisoquinolinone Analog and the other anticancer agent by weight of the composition. Other compositions of the present invention are prepared so that a parenteral dosage unit contains from about 0.01% to about 2% by weight of the composition.


Cancers that can be treated or prevented by administering an Indenoisoquinolinone Analog and the other anticancer agent include, but are not limited to, the list of cancers set forth above in Table 1.


In one embodiment, the cancer is brain cancer.


In specific embodiments, the brain cancer is pilocytic astrocytoma, astrocytoma, anaplastic astrocytoma, glioblastoma multiforme or a metastatic brain tumor.


In one embodiment, the cancer is melanoma.


In a specific embodiment, the melanoma is metastatic melanoma.


The Indenoisoquinolinone Analog and other anticancer agent can act additively or synergistically. A synergistic combination of an Indenoisoquinolinone Analog and the other anticancer agent, might allow the use of lower dosages of one or both of these agents and/or less frequent administration of the agents to a subject with cancer. The ability to utilize lower dosages of one or both of the Indenoisoquinolinone Analog and other anticancer agent and/or to administer the agents less frequently can reduce any toxicity associated with the administration of the agents to a subject without reducing the efficacy of the agents in the treatment of cancer. In addition, a synergistic effect might result in the improved efficacy of these agents in the treatment of cancer and/or the reduction of any adverse or unwanted side effects associated with the use of either agent alone.


In one embodiment, the administration of an effective amount of an Indenoisoquinolinone Analog and an effective amount of another anticancer agent inhibits the resistance of a cancer to the other anticancer agent. In one embodiment, the cancer is a tumor.


Suitable other anticancer agents useful in the methods and compositions of the present invention include, but are not limited to temozolomide, a topoisomerase I inhibitor, procarbazine, dacarbazine, gemcitabine, capecitabine, methotrexate, taxol, taxotere, mercaptopurine, thioguanine, hydroxyurea, cytarabine, cyclophosphamide, ifosfamide, nitrosoureas, cisplatin, carboplatin, mitomycin, dacarbazine, procarbizine, etoposide, teniposide, campathecins, bleomycin, doxorubicin, idarubicin, daunorubicin, dactinomycin, plicamycin, mitoxantrone, L-asparaginase, doxorubicin, epirubicin, 5-fluorouracil, taxanes such as docetaxel and paclitaxel, leucovorin, levamisole, irinotecan, estramustine, etoposide, nitrogen mustards, BCNU, nitrosoureas such as carmustine and lomustine, vinca alkaloids such as vinblastine, vincristine and vinorelbine, platinum complexes such as cisplatin, carboplatin and oxaliplatin, imatinib mesylate, hexamethylmelamine, topotecan, tyrosine kinase inhibitors, tyrphostins herbimycin A, genistein, erbstatin, and lavendustin A.


In one embodiment, the other anticancer agent is, but is not limited to, a drug listed in Table 2.










TABLE 2







Alkylating agents



Nitrogen mustards:
Cyclophosphamide



Ifosfamide



Trofosfamide



Chlorambucil


Nitrosoureas:
Carmustine (BCNU)



Lomustine (CCNU)


Alkylsulphonates:
Busulfan



Treosulfan


Triazenes:
Dacarbazine



Procarbazine



Temozolomide


Platinum containing complexes:
Cisplatin



Carboplatin



Aroplatin



Oxaliplatin


Plant Alkaloids



Vinca alkaloids:
Vincristine



Vinblastine



Vindesine



Vinorelbine


Taxoids:
Paclitaxel



Docetaxel


DNA Topoisomerase Inhibitors



Epipodophyllins:
Etoposide



Teniposide



Topotecan



9-aminocamptothecin



Camptothecin



Crisnatol


Mitomycins:
Mitomycin C



Anti-metabolites


Anti-folates:



DHFR inhibitors:
Methotrexate



Trimetrexate


IMP dehydrogenase Inhibitors:
Mycophenolic acid



Tiazofurin



Ribavirin



EICAR


Ribonuclotide reductase
Hydroxyurea


Inhibitors:
Deferoxamine


Pyrimidine Analogs:



Uracil Analogs:
5-Fluorouracil



Fluoxuridine



Doxifluridine



Ralitrexed


Cytosine Analogs:
Cytarabine (ara C)



Cytosine arabinoside



Fludarabine



Gemcitabine



Capecitabine


Purine Analogs:
Mercaptopurine



Thioguanine


DNA Antimetabolites:
3-HP



2′-deoxy-5-fluorouridine



5-HP



alpha-TGDR



aphidicolin glycinate



ara-C



5-aza-2′-deoxycytidine



beta-TGDR



cyclocytidine



guanazole



inosine glycodialdehyde



macebecin II



Pyrazoloimidazole


Hormonal therapies:



Receptor antagonists:



Anti-estrogen:
Tamoxifen



Raloxifene



Megestrol


LHRH agonists:
Goscrclin



Leuprolide acetate


Anti-androgens:
Flutamide



Bicalutamide


Retinoids/Deltoids



Vitamin A derivative:
Cis-retinoic acid



All-trans retinoic acid (ATRA-IV)


Vitamin D3 Analogs:
EB 1089



CB 1093



KH 1060


Photodynamic therapies:
Vertoporfin (BPD-MA)



Phthalocyanine



Photosensitizer Pc4



Demethoxy-hypocrellin A



(2BA-2-DMHA)


Cytokines:
Interferon-α



Interferon-β



Interferon-γ



Tumor necrosis factor



Interleukin-2


Angiogenesis Inhibitors:
Angiostatin (plasminogen



fragment)



antiangiogenic antithrombin III



Angiozyme



ABT-627



Bay 12-9566



Benefin



Bevacizumab



BMS-275291



cartilage-derived inhibitor (CDI)



CAI



CD59 complement fragment



CEP-7055



Col 3



Combretastatin A-4



Endostatin (collagen XVIII



fragment)



Fibronectin fragment



Gro-beta



Halofuginone



Heparinases



Heparin hexasaccharide fragment



HMV833



Human chorionic gonadotropin



(hCG)



IM-862



Interferon alpha/beta/gamma



Interferon inducible protein (IP-



10)



Interleukin-12



Kringle 5 (plasminogen fragment)



Marimastat



Metalloproteinase inhibitors



(TIMPs)



2-Methoxyestradiol



MMI 270 (CGS 27023A)



MoAb IMC-1C11



Neovastat



NM-3



Panzem



PI-88



Placental ribonuclease inhibitor



Plasminogen activator inhibitor



Platelet factor-4 (PF4)



Prinomastat



Prolactin 16 kD fragment



Proliferin-related protein (PRP)



PTK 787/ZK 222594



Retinoids



Solimastat



Squalamine



SS 3304



SU 5416



SU6668



SU11248



Tetrahydrocortisol-S



Tetrathiomolybdate



Thalidomide



Thrombospondin-1 (TSP-1)



TNP-470



Transforming growth factor-beta



(TGF-β)



Vasculostatin



Vasostatin (calreticulin fragment)



ZD6126



ZD 6474



farnesyl transferase inhibitors



(FTI)



Bisphosphonates


Antimitotic agents:
Allocolchicine



Halichondrin B



Colchicine



colchicine derivative



dolstatin 10



Maytansine



Rhizoxin



Thiocolchicine



trityl cysteine


Others:



Isoprenylation inhibitors:



Dopaminergic neurotoxins:
1-methyl-4-phenylpyridinium ion


Cell cycle inhibitors:
Staurosporine


Actinomycins:
Actinomycin D



Dactinomycin


Bleomycins:
Bleomycin A2



Bleomycin B2



Peplomycin


Anthracyclines:
Daunorubicin



Doxorubicin (adriamycin)



Idarubicin



Epirubicin



Pirarubicin



Zorubicin



Mitoxantrone


MDR inhibitors:
Verapamil


Ca2+ ATPase inhibitors:
Thapsigargin









Other additional anticancer agents that are useful in the compositions and methods of the present invention include, but are not limited to: acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; fluorocitabine; fosquidone; fostriecin sodium; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin-2 (including recombinant interleukin-2, or rIL2), interferon alfa-2a; interferon alfa-2β; interferon alfa-n1; interferon alfa-n3; interferon beta-Iα; interferon gamma-Iβ; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride.


Further anticancer drugs that are useful in the methods and compositions of the invention include, but are not limited to: 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta Lactam Derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene Analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin Analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-acytidine; dihydrotaxol; dioxamycin; diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine Analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine Analogue; lipophilic disaccharide peptide; lipophilic platinum complexes; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin Analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1-based therapy; mustard anticancer agents; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; 06-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel Analogues; paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum complexes; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen binding protein; sizofuran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.


In one another embodiment, the other anticancer agent is interferon-α.


In another embodiment, the other anticancer agent is interleukin-2.


In one embodiment, the other anticancer agent is an alkylating agent, such as a nitrogen mustard, a nitrosourea, an alkylsulfonate, a triazene, or a platinum-containing agent.


In one embodiment, the other anticancer agent is a triazene alkylating agent.


In another embodiment, the other anticancer agent is temozolomide, procarbazine, dacarbazine, interleukin-2, irinotecan, doxorubicin, or a combination thereof.


In a specific embodiment, the other anticancer agent is temozolomide.


Temozolomide can be administered to a subject at dosages ranging from about 60 mg/m2 (of a subject's body surface area) to about 250 mg/m2 and from about 100 mg/m2 to about 200 mg/m2. In specific embodiments, the dosages of temozolomide are about 10 mg/m2, about 1 mg/m2, about 5 mg/m2, about 10 mg/m2, about 20 mg/m2, about 30 mg/m2, about 40 mg/m2, about 50 mg/m2, about 60 mg/m2, about 70 mg/m2, about 80 mg/m2, about 90 mg/m2, about 100 mg/m2, about 110 mg/m2, about 120 mg/m2, about 130 mg/m2, about 140 mg/m2, about 150 mg/m2, about 160 mg/m2, about 170 mg/m2, about 180 mg/m2, about 190 mg/m2, about 200 mg/m2, about 210 mg/m2, about 220 mg/m2, about 230 mg/m2, about 240 mg/m2, or about 250 mg/m2.


In a specific embodiment, temozolomide is administered orally.


In one embodiment, temozolomide is administered orally to a subject at a dose ranging from about 150 mg/m2 to about 200 mg/m2.


In another embodiment, temozolomide is administered orally to a subject once per day for five consecutive days at a dose ranging from about 150 mg/m2 to about 200 mg/m2.


In a specific embodiment, temozolomide is administered orally to a subject once per day for five consecutive days at a dose ranging from about 150 mg/m2 to about 200 mg/m2 on days 1-5, then again orally once per day for five consecutive days on days 28-32 at a dose ranging from about 150 mg/m2 to about 200 mg/m2, then again orally once per day for five consecutive days on days 55-59 at a dose ranging from about 150 mg/m2 to about 200 mg/m2.


In another embodiment, temozolomide is administered orally to a subject once per day for a week, two weeks, three weeks, a month or longer at the foregoing daily dosage.


In a specific embodiment, the other anticancer agent is procarbazine.


Procarbazine can be administered to a subject at dosages ranging from about 50 mg/m2 (of a subject's body surface area) to about 100 mg/m2 and from about 60 mg/m2 to about 100 mg/m2. In specific embodiments, the dosages of procarbazine are about 10 mg/m2, about 1 mg/m2, about 5 mg/m2, about 10 mg/m2, about 20 mg/m2, about 30 mg/m2, about 40 mg/m2, about 50 mg/m2, about 60 mg/m2, about 70 mg/m2, about 80 mg/m2, about 90 mg/m2, about 100 mg/m2, about 110 mg/m2, about 120 mg/m2, about 130 mg/m2, about 140 mg/m2, about 150 mg/m2, about 160 mg/m2, about 170 mg/m2, about 180 mg/m2, about 190 mg/m2, about 200 mg/m2, about 210 mg/m2, about 220 mg/m2, about 230 mg/m2, about 240 mg/m2, about 250 mg/m2, about 260 mg/m2, about 270 mg/m2, about 280 mg/m2, about 290 mg/m2, about 300 mg/m2, about 310 mg/m2, about 320 mg/m2, about 330 mg/m2, about 340 mg/m2, about 350 mg/m2, about 360 mg/m2, about 370 mg/m2, about 380 mg/m2, about 390 mg/m2, about 400 mg/m2, about 410 mg/m2, about 420 mg/m2, about 430 mg/m2, about 440 mg/m2, about 450 mg/m2, about 460 mg/m2, about 470 mg/m2, about 480 mg/m2, about 490 mg/m2, or about 500 mg/m2.


In a specific embodiment, procarbazine is administered intravenously.


In one embodiment, procarbazine is administered intravenously to a subject at a dose ranging from about 50 mg/m2 to about 100 mg/m2.


In another embodiment, procarbazine is administered intravenously to a subject once per day for five consecutive days at a dose ranging from about 50 mg/m2 to about 100 mg/m2.


In a specific embodiment, procarbazine is administered intravenously to a subject once per day for five consecutive days at a dose ranging from about 50 mg/m2 to about 100 mg/m2 on days 1-5, then again intravenously once per day for five consecutive days on days 28-32 at a dose ranging from about 50 mg/m2 to about 100 mg/m2, then again intravenously once per day for five consecutive days on days 55-59 at a dose ranging from about 50 mg/m to about 100 mg/m2.


In another embodiment, procarbazine is administered once intravenously to a subject at a dose ranging from about 50 mg/m2 to about 100 mg/m2.


In another embodiment, procarbazine is administered intravenously to a subject once per day for a week, two weeks, three weeks, a month or longer at the foregoing daily dosage.


In a specific embodiment, the other anticancer agent is dacarbazine.


Dacarbazine can be administered to a subject at dosages ranging from about 60 mg/m2 (of a subject's body surface area) to about 250 mg/m2 and from about 150 mg/m2 to about 250 mg/m2. In specific embodiments, the dosages of dacarbazine are about 10 mg/m, about 1 mg/m2, about 5 mg/m2, about 10 mg/m2, about 20 mg/m2, about 30 mg/m2, about 40 mg/m2, about 50 mg/m2, about 60 mg/m2, about 70 mg/m2, about 80 mg/m2, about 90 mg/m2, about 100 mg/m2, about 110 mg/m2, about 120 mg/m2, about 130 mg/m2, about 140 mg/m2, about 150 mg/m2, about 160 mg/m2, about 170 mg/m2, about 180 mg/m2, about 190 mg/m2, about 200 mg/m2, about 210 mg/m2, about 220 mg/m2, about 230 mg/m2, about 240 mg/m2, about 250 mg/m2, about 260 mg/m2, about 270 mg/m2, about 280 mg/m2, about 290 mg/m2, about 300 mg/m2, about 310 mg/m2, about 320 mg/m2, about 330 mg/m2, about 340 mg/m2, about 350 mg/m2, about 360 mg/m2, about 370 mg/m2, about 380 mg/m2, about 390 mg/m2, about 400 mg/m2, about 410 mg/m2, about 420 mg/m2, about 430 mg/m2, about 440 mg/m2, about 450 mg/m2, about 460 mg/m2, about 470 mg/m2, about 480 mg/m2, about 490 mg/m2, or about 500 mg/m2.


In a specific embodiment, dacarbazine is administered intravenously.


In one embodiment, dacarbazine is administered intravenously to a subject at a dose ranging from about 150 mg/m2 to about 250 mg/m2.


In another embodiment, dacarbazine is administered intravenously to a subject once per day for five consecutive days at a dose ranging from about 150 mg/m2 to about 250 mg/m2.


In a specific embodiment, dacarbazine is administered intravenously to a subject once per day for five consecutive days at a dose ranging from about 150 mg/m2 to about 250 mg/m2 on days 1-5, then again intravenously once per day for five consecutive days on days 28-32 at a dose ranging from about 150 mg/m2 to about 250 mg/m2, then again intravenously once per day for five consecutive days on days 55-59 at a dose ranging from about 150 mg/m2 to about 250 mg/m2.


In one embodiment, dacarbazine is administered once intravenously to a subject at a dose ranging from about 150 mg/m2 to about 250 mg/m2.


In another embodiment, dacarbazine is administered intravenously to a subject once per day for a week, two weeks, three weeks, a month or longer at the foregoing daily dosage.


In a specific embodiment, the other anticancer agent is doxorubicin.


Doxorubicin can be administered to a subject at dosages ranging from about 50 mg/m2 (of a subject's body surface area) to about 100 mg/m2 and from about 60 mg/m2 to about 100 mg/m2. In specific embodiments, the dosages of doxorubicin are about 10 mg/m2, about 1 mg/m2, about 5 mg/m2, about 10 mg/m2, about 20 mg/m2, about 30 mg/m2, about 40 mg/m2, about 50 mg/m2, about 60 mg/m2, about 70 mg/m2, about 80 mg/m2, about 90 mg/m2, about 100 mg/m2, about 110 mg/m2, about 120 mg/m2, about 130 mg/m2, about 140 mg/m2, about 150 mg/m2, about 160 mg/m2, about 170 mg/m2, about 180 mg/m2, about 190 mg/m2, about 200 mg/m2, about 210 mg/m2, about 220 mg/m2, about 230 mg/m2, about 240 mg/m2, about 250 mg/m2, about 260 mg/m2, about 270 mg/m2, about 280 mg/m2, about 290 mg/m2, about 300 mg/m2, about 310 mg/m2, about 320 mg/m2, about 330 mg/m2, about 340 mg/m2, about 350 mg/m2, about 360 mg/m2, about 370 mg/m2, about 380 mg/m2, about 390 mg/m2, about 400 mg/m2, about 410 mg/m2, about 420 mg/m2, about 430 mg/m2, about 440 mg/m2, about 450 mg/m2, about 460 mg/m2, about 470 mg/m2, about 480 mg/m2, about 490 mg/m2, or about 500 mg/m2.


In a specific embodiment, doxorubicin is administered intravenously.


In one embodiment, doxorubicin is administered intravenously to a subject at a dose ranging from about 50 mg/m2 to about 100 mg/m2.


In another embodiment, doxorubicin is administered intravenously to a subject once per day for five consecutive days at a dose ranging from about 50 mg/m2 to about 100 mg/m2.


In a specific embodiment, doxorubicin is administered intravenously to a subject once per day for five consecutive days at a dose ranging from about 50 mg/m2 to about 100 mg/m2 on days 1-5, then again intravenously once per day for five consecutive days on days 28-32 at a dose ranging from about 50 mg/m2 to about 100 mg/m2, then again intravenously once per day for five consecutive days on days 55-59 at a dose ranging from about 50 mg/m2 to about 100 mg/m2.


In another embodiment, doxorubicin is administered once intravenously to a subject at a dose ranging from about 50 mg/m2 to about 100 mg/m2.


In another embodiment, doxorubicin is administered intravenously to a subject once per day for a week, two weeks, three weeks, a month or longer at the foregoing daily dosage.


In one embodiment, the other anticancer agent is a Topoisomerase I inhibitor, such as etoposide, teniposide, topotecan, irinotecan, 9-aminocamptothecin, camptothecin, or crisnatol.


In a specific embodiment, the other anticancer agent is irinotecan.


Irinotecan can be administered to a subject at dosages ranging from about 50 mg/m2 (of a subject's body surface area) to about 150 mg/m2 and from about 75 mg/m2 to about 150 mg/m2. In specific embodiments, the dosages of irinotecan are about 10 mg/m2, about 1 mg/m2, about 5 mg/m2, about 10 mg/m2, about 20 mg/m2, about 30 mg/m2, about 40 mg/m2, about 50 mg/m2, about 60 mg/m2, about 70 mg/m2, about 80 mg/m2, about 90 mg/m2, about 100 mg/m2, about 110 mg/m2, about 120 mg/m2, about 130 mg/m2, about 140 mg/m2, about 150 mg/m2, about 160 mg/m2, about 170 mg/m2, about 180 mg/m2, about 190 mg/m2, about 200 mg/m2, about 210 mg/m2, about 220 mg/m2, about 230 mg/m2, about 240 mg/m2, about 250 mg/m2, about 260 mg/m2, about 270 mg/m2, about 280 mg/m2, about 290 mg/m2, about 300 mg/m2, about 310 mg/m2, about 320 mg/m2, about 330 mg/m2, about 340 mg/m2, about 350 mg/m2, about 360 mg/m2, about 370 mg/m2, about 380 mg/m2, about 390 mg/m2, about 400 mg/m2, about 410 mg/m2, about 420 mg/m2, about 430 mg/m2, about 440 mg/m2, about 450 mg/m2, about 460 mg/m2, about 470 mg/m2, about 480 mg/m2, about 490 mg/m2, or about 500 mg/m2.


In a specific embodiment, irinotecan is administered intravenously.


In one embodiment, irinotecan is administered intravenously to a subject at a dose ranging from about 50 mg/m2 to about 150 mg/m2.


In another embodiment, irinotecan is administered intravenously to a subject once per day for five consecutive days at a dose ranging from about 50 mg/m2 to about 150 mg/m2.


In a specific embodiment, irinotecan is administered intravenously to a subject once per day for five consecutive days at a dose ranging from about 50 mg/m2 to about 150 mg/m2 on days 1-5, then again intravenously once per day for five consecutive days on days 28-32 at a dose ranging from about 50 mg/m2 to about 150 mg/m2, then again intravenously once per day for five consecutive days on days 55-59 at a dose ranging from about 50 mg/m2 to about 150 mg/m2.


In another embodiment, irinotecan is administered intravenously to a subject once per day for a week, two weeks, three weeks, a month or longer at the foregoing daily dosage.


In one embodiment, the other anticancer agent is O-6-benzylguanine.


In another embodiment, the other anticancer agent is O-6-benzylguanine and temozolomide.


In another embodiment, the other anticancer agent is O-6-benzylguanine and procarbazine.


In still another embodiment, the other anticancer agent is O-6-benzylguanine and dacarbazine.


5.8.10.3 Multi-Therapy for Cancer

The Indenoisoquinolinone Analogs can be administered to a subject that has undergone or is currently undergoing one or more additional anticancer therapies including, but not limited to, surgery, radiation therapy, or immunotherapy, such as cancer vaccines.


In one embodiment, the invention provides methods for treating or preventing cancer comprising administering to a subject in need thereof an effective amount of an Indenoisoquinolinone Analog to treat or prevent cancer and another anticancer therapy including, but not limited to, surgery, radiation therapy, or immunotherapy, such as a cancer vaccine.


In one embodiment, the other anticancer therapy is radiation therapy.


In another embodiment, the other anticancer therapy is surgery.


In still another embodiment, the other anticancer therapy is immunotherapy.


In a specific embodiment, the present methods for treating or preventing cancer comprise administering an effective amount of an Indenoisoquinolinone Analog and radiation therapy. The radiation therapy can be administered concurrently with, prior to, or subsequent to the Indenoisoquinolinone Analog, in one embodiment at least an hour, five hours, 12 hours, a day, a week, a month, in another embodiment several months (e.g., up to three months), prior or subsequent to administration of the Indenoisoquinolinone Analog.


Where the other anticancer therapy is radiation therapy, any radiation therapy protocol can be administered depending upon the type of cancer to be treated. For example, but not by way of limitation, X-ray radiation can be administered; specifically, high-energy megavoltage (radiation of greater that 1 MeV energy) can be administered for deep tumors, and electron beam and orthovoltage X-ray radiation can be administered for skin cancers. Gamma-ray emitting radioisotopes, such as radioactive isotopes of radium, cobalt and other elements, can also be administered.


Additionally, the invention provides methods of treatment of cancer comprising administering an Indenoisoquinolinone Analog as an alternative to chemotherapy or radiation therapy where the chemotherapy or the radiation therapy results in a negative side effect in the subject being treated. The subject being treated can, optionally, be treated with another anticancer therapy such as surgery, radiation therapy, or immunotherapy.


The Indenoisoquinolinone Analogs can also be administered in vitro or ex vivo, such as for the treatment of certain cancers, including, but not limited to leukemias and lymphomas, such treatment involving autologous stem cell transplants. This can involve a process in which the subject's autologous hematopoietic stem cells are harvested and purged of all cancer cells, the subject's remaining bone-marrow cell population is then eradicated via the administration of an Indenoisoquinolinone Analog and/or radiation, and the resultant stem cells are infused back into the subject. Supportive care can be subsequently provided while bone marrow function is restored and the subject recovers.


5.8.11 Treatment or Prevention of Erectile Dysfunction

The Indenoisoquinolinone Analogs are useful for treating or preventing erectile dysfunction. Erectile dysfunction includes an inability to achieve or maintain a full erection, specifically that which is sufficient to achieve or maintain sexual intercourse. The inability can be a total inability, an inconsistent ability, or a tendency to maintain only a brief erection. Erectile dysfunction includes idiopathic erectile dysfunction, as well as that which can result, for example, from trauma, including mechanical trauma, specifically that resulting from surgery, to the nerves (such as during prostatectomy); diabetes mellitus; a cardiovascular disease, including atherosclerosis; radiation; or certain drugs. The erectile dysfunction can also be age-related.


In one embodiment, the erectile dysfunction results from prostate surgery.


In a further embodiment, the erectile dysfunction results from prostate nerve injury.


5.8.12 Treatment or Prevention of Urinary Incontinence

The Indenoisoquinolinone Analogs are also useful for treating or preventing urinary incontinence. Urinary incontinence can result, for example, from trauma, including mechanical trauma, specifically during childbirth or that resulting from surgery, to the nerves (such as during prostatectomy or gynecological surgery); diabetes mellitus; a cardiovascular disease, including atherosclerosis; radiation; or certain drugs. The urinary incontinence can also be age-related.


In one embodiment, the subject in need of urinary incontinence treatment or prevention is male.


In one embodiment, the subject in need of urinary incontinence treatment or prevention is female.


5.8.13 Treatment or Prevention of a Complication of Prematurity

The Indenoisoquinolinone Analogs are also useful for treating or preventing a complication of prematurity. Examples of complications of prematurity include, but are not limited to, retinopathy, hyaline-membrane disease and necrotizing enterocolitis.


5.8.14 Treatment or Prevention of Cardiomyopathy

The Indenoisoquinolinone Analogs are also useful for treating or preventing cardiomyopathy.


5.8.15 Treatment or Prevention of Retinopathy

The Indenoisoquinolinone Analogs are also useful for treating or preventing retinopathy.


5.8.16 Treatment or Prevention of Nephropathy

The Indenoisoquinolinone Analogs are also useful for treating or preventing nephropathy.


5.8.17 Treatment or Prevention of Neuropathy

The Indenoisoquinolinone Analogs are also useful for treating or preventing neuropathy.


5.9 Therapeutic/Prophylactic Administration and Compositions of the Invention

Due to their activity, the Indenoisoquinolinone Analogs are advantageously useful in veterinary and human medicine. As described above, the Indenoisoquinolinone Analogs are useful for treating or preventing a Condition in a subject in need thereof.


The Indenoisoquinolinone Analogs can be administered in amounts that are effective to treat or prevent a Condition in a subject in need thereof.


When administered to a subject, the Indenoisoquinolinone Analogs can be administered as a component of a composition that comprises a physiologically acceptable carrier or vehicle. The present compositions, which comprise an Indenoisoquinolinone Analog, can be administered orally. The Indenoisoquinolinone Analogs can also be administered by any other convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral, rectal, or intestinal mucosa) and can be administered together with another biologically active agent. Administration can be systemic or local. Various delivery systems are known, e.g., encapsulation in liposomes, microparticles, microcapsules and capsules.


Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intracerebral, intravaginal, transdermal, rectal, by inhalation, or topical, specifically to the ears, nose, eyes, or skin. In some instances, administration will result in the release of an Indenoisoquinolinone Analog into the bloodstream.


In one embodiment, the Indenoisoquinolinone Analogs are administered orally.


In other embodiments, it can be desirable to administer the Indenoisoquinolinone Analogs locally. This can be achieved, for example, and not by way of limitation, by local infusion during surgery, topical application, e.g., in conjunction with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository or enema, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers.


In certain embodiments, it can be desirable to introduce the Indenoisoquinolinone Analogs into the central nervous system or gastrointestinal tract by any suitable route, including intraventricular, intrathecal, and epidural injection, and enema. Intraventricular injection can be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir.


Pulmonary administration can also be employed, e.g., by use of an inhaler of nebulizer, and formulation with an aerosolizing agent, or via perfusion in a fluorocarbon oar, synthetic pulmonary surfactant. In certain embodiments, the Indenoisoquinolinone Analogs can be formulated as a suppository, with traditional binders and excipients such as triglycerides.


In another embodiment Indenoisoquinolinone Analogs can be delivered in a vesicle, specifically a liposome (see Langer, Science 249:1527-1533 (1990) and Treat or prevent et al., Liposomes in Therapy of Infectious Disease and Cancer 317-327 and 353-365 (1989)).


In yet another embodiment, the Indenoisoquinolinone Analogs can be delivered in a controlled-release system or sustained-release system (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)). Other controlled or sustained-release systems discussed in the review by Langer, Science 249:1527-1533 (1990) can be used. In one embodiment a pump can be used (Langer, Science 249:1527-1533 (1990); Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); and Saudek et al., N. Engl. J. Med. 321:574 (1989)). In another embodiment polymeric materials can be used (see Medical Applications of Controlled Release (Langer and Wise eds., 1974); Controlled Drug Bioavailability, Drug Product Design and Performance (Smolen and Ball eds., 1984); Ranger and Peppas, J. Macromol. Sci. Rev. Macromol. Chem. 2:61 (1983); Levy et al., Science 228:190 (1935); During et al., Ann. Neural. 25:351 (1989); and Howard et al., J. Neurosurg. 71:105 (1989)).


In yet another embodiment a controlled- or sustained-release system can be placed in proximity of a target of the Indenoisoquinolinone Analogs, e.g., the spinal column, brain, skin, lung, or gastrointestinal tract, thus requiring only a fraction of the systemic dose.


The present compositions can optionally comprise a suitable amount of a pharmaceutically acceptable excipient so as to provide the form for proper administration to the subject.


Such pharmaceutical excipients can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical excipients can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used. In one embodiment, the pharmaceutically acceptable excipients are sterile when administered to a subject. Water is a useful excipient when the Indenoisoquinolinone Analog is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, specifically for injectable solutions. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The present compositions, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.


The present compositions can take the form of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions. aerosols, sprays, suspensions, or any other form suitable for use. In one embodiment, the composition is in the form of a capsule (see e.g. U.S. Pat. No. 5,698,155). Other examples of suitable pharmaceutical excipients are described in Remington's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro eds., 19th ed. 1995), incorporated herein by reference.


In one embodiment, the Indenoisoquinolinone Analog is formulated in accordance with routine procedures as a composition adapted for oral administration to human beings. Compositions for oral delivery can be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs for example. Orally administered compositions can contain one or more agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation. Moreover, where in tablet or pill form, the compositions can be coated to delay disintegration and absorption in the gastrointestinal tract thereby providing a sustained action over an extended period of time. Selectively permeable membranes surrounding an osmotically active driving an Indenoisoquinolinone Analog are also suitable for orally administered compositions. In these latter platforms, fluid from the environment surrounding the capsule is imbibed by the driving compound, which swells to displace the agent or agent composition through an aperture. These delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations. A time-delay material such as glycerol monostearate or glycerol stearate can also be useful. Oral compositions can include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. In one embodiment, the excipients are of pharmaceutical grade.


In another embodiment, the Indenoisoquinolinone Analogs can be formulated for intravenous administration. Typically, compositions for intravenous administration comprise sterile isotonic aqueous buffer. Where necessary, the compositions can also include a solubilizing agent. Compositions for intravenous administration can optionally include a local anesthetic such as lignocaine to lessen pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized-powder or water-free concentrate in a hermetically sealed container such as an ampule or sachette indicating the quantity of active agent. Where the Indenoisoquinolinone Analogs are to be administered by infusion, they can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the Indenoisoquinolinone Analogs are administered by injection, an ampule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.


Indenoisoquinolinone Analogs can be administered by controlled-release or sustained-release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,556, each of which is incorporated herein by reference in its entirety. Such dosage forms can be useful for providing controlled- or sustained-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled- or sustained-release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the active ingredients of the invention. The invention thus encompasses single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled- or sustained-release.


In one embodiment a controlled- or sustained-release composition comprises a minimal amount of an Indenoisoquinolinone Analog to treat or prevent the Condition over a period of time. Advantages of controlled- or sustained-release compositions include extended activity of the drug, reduced dosage frequency, and increased subject compliance. In addition, controlled- or sustained-release compositions can favorably affect the time of onset of action or other characteristics, such as blood levels of the Indenoisoquinolinone Analog, and can thus reduce the occurrence of adverse side effects.


Controlled- or sustained-release compositions can initially release an amount of an Indenoisoquinolinone Analog that promptly produces the desired therapeutic or prophylactic effect, and gradually and continually release other amounts of the Indenoisoquinolinone Analog to maintain this level of therapeutic or prophylactic effect over an extended period of time. To maintain a constant level of the Indenoisoquinolinone Analog in the body, the Indenoisoquinolinone Analog can be released from the dosage form at a rate that will replace the amount of Indenoisoquinolinone Analog being metabolized and excreted from the body. Controlled- or sustained-release of an active ingredient can be stimulated by various conditions, including but not limited to, changes in pH, changes in temperature, concentration or availability of enzymes, concentration or availability of water, or other physiological conditions or compounds.


The amount of the Indenoisoquinolinone Analog that is effective in the treatment or prevention of a Condition can be determined by standard clinical techniques. In addition, in vitro or in vivo assays can optionally be employed to help identify optimal dosage ranges. The precise dose to be employed can also depend on the route of administration, and the seriousness of the condition being treated and can be decided according to the judgment of the practitioner and each subject's circumstances in view of, e.g., published clinical studies. Suitable effective dosage amounts, however, range from about 10 micrograms to about 5 grams about every 4 hours, although they are typically about 500 mg or less per every 4 hours. In one embodiment, the effective dosage is about 0.01 mg, 0.5 mg, about 1 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1 g, about 1.2 g, about 1.4 g, about 1.6 g, about 1.8 g, about 2.0 g, about 2.2 g, about 2.4 g, about 2.6 g, about 2.8 g, about 3.0 g, about 3.2 g, about 3.4 g, about 3.6 g, about 3.8 g, about 4.0 g, about 4.2 g, about 4.4 g, about 4.6 g, about 4.8 g, and about 5.0 g, every 4 hours. Equivalent dosages can be administered over various time periods including, but not limited to, about every 2 hours, about every 6 hours, about every 8 hours, about every 12 hours, about every 24 hours, about every 36 hours, about every 48 hours, about every 72 hours, about every week, about every two weeks, about every three weeks, about every month, and about every two months. The effective dosage amounts described herein refer to total amounts administered; that is, if more than one Indenoisoquinolinone Analog is administered, the effective dosage amounts correspond to the total amount administered.


Compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present compositions can contain, in one embodiment, from about 0.1% to about 99%; and in another embodiment from about 1% to about 70% of the Indenoisoquinolinone Analog by weight or volume.


The dosage regimen utilizing the Indenoisoquinolinone Analog can be selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the subject; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the subject; and the specific Indenoisoquinolinone Analog employed. A person skilled in the art can readily determine the effective amount of the drug useful for treating or preventing the Condition.


An Indenoisoquinolinone Analog can be administered in a single daily dose, or the total daily dosage can be administered in divided doses of two, three or four times daily. Furthermore, an Indenoisoquinolinone Analog can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration can be continuous rather than intermittent throughout the dosage regimen. Other illustrative topical preparations include creams, ointments, lotions, aerosol sprays and gels, wherein the concentration of Indenoisoquinolinone Analog ranges from about 0.1% to about 15%, w/w or w/v.


The Indenoisoquinolinone Analogs can be assayed in vitro or in vivo for the desired therapeutic or prophylactic activity prior to use in humans. Animal model systems can be used to demonstrate safety and efficacy.


The present methods for treating or preventing a Condition in a subject in need thereof can further comprise administering another prophylactic or therapeutic agent to the subject being administered an Indenoisoquinolinone Analog. In one embodiment, the other prophylactic or therapeutic agent is administered in an effective amount. The other prophylactic or therapeutic agent includes, but is not limited to, an anti-inflammatory agent, an anti-renal failure agent, an anti-diabetic agent, and anti-cardiovasculare disease agent, an antiemetic agent, a hematopoietic colony stimulating factor, an anxiolytic agent, and an analgesic agent.


In one embodiment, the other prophylactic or therapeutic agent is an agent useful for reducing any potential side effect of an Indenoisoquinolinone Analog. Such potential side effects include, but are not limited to, nausea, vomiting, headache, low white blood cell count, low red blood cell count, low platelet count, headache, fever, lethargy, a muscle ache, general pain, bone pain, pain at an injection site, diarrhea, neuropathy, pruritis, a mouth sore, alopecia, anxiety or depression.


In one embodiment, the Indenoisoquinolinone Analog can be administered prior to, concurrently with, or after an anti-inflammatory agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other.


In another embodiment, the Indenoisoquinolinone Analog can be administered prior to, concurrently with, or after an anti-renal failure agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other.


In still another embodiment, the Indenoisoquinolinone Analog can be administered prior to, concurrently with, or after an anti-diabetic agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other.


In yet another embodiment, the Indenoisoquinolinone Analog can be administered prior to, concurrently with, or after an anti-cardiovascular disease agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other.


In a further embodiment, the Indenoisoquinolinone Analog can be administered prior to, concurrently with, or after an antiemetic agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other.


In another embodiment, the Indenoisoquinolinone Analog can be administered prior to, concurrently with, or after a hematopoietic colony stimulating factor, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours, 72 hours, 1 week, 2 weeks, 3 weeks or 4 weeks of each other.


In still embodiment, the Indenoisoquinolinone Analog can be administered prior to, concurrently with, or after an opioid or non-opioid analgesic agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other.


In yet another embodiment, the Indenoisoquinolinone Analog can be administered prior to, concurrently with, or after an anxiolytic agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other.


Effective amounts of the other prophylactic or therapeutic agents are well known to those skilled in the art. However, it is well within the skilled artisan's purview to determine the other prophylactic or therapeutic agent's optimal effective amount range. In one embodiment of the invention, where another prophylactic or therapeutic agent is administered to a subject, the effective amount of the Indenoisoquinolinone Analog is less than its effective amount would be where the other prophylactic or therapeutic agent is not administered. In this case, without being bound by theory, it is believed that Indenoisoquinolinone Analogs and the other prophylactic or therapeutic agent act synergistically to treat or prevent a Condition.


In one embodiment, the other therapeutic or prophylactic agent is an anti-inflammatory agent. Anti-inflammatory agents useful in the methods of the present invention include but are not limited to adrenocorticosteroids, such as cortisol, cortisone, fludrocortisone, prednisone, prednisolone, 6α-methylprednisolone, triamcinolone, betamethasone, and dexamethasone; and non-steroidal anti-inflammatory agents (NSAIDs), such as aspirin, acetaminophen, indomethacin, sulindac, tolmetin, diclofenac, ketorolac, ibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofen, oxaprozin, mefenamic acid, meclofenamic acid, piroxicam, meloxicam, nabumetone, rofecoxib, celecoxib, etodolac, and nimesulide.


In one embodiment, the other therapeutic or prophylactic agent is an anti-renal failure agent. Anti-renal failure agents useful in the methods of the present invention include include but are not limited to ACE (angiotensin-converting enzyme) inhibitors, such as captopril, enalaprilat, lisinopril, benazepril, fosinopril, trandolapril, quinapril, and ramipril; diuretics, such as mannitol, glycerin, furosemide, toresemide, tripamide, chlorothiazide, methyclothiazide, indapamide, amiloride, and spironolactone; and fibric acid agents, such as clofibrate, gemfibrozil, fenofibrate, ciprofibrate, and bezafibrate.


In one embodiment, the other therapeutic or prophylactic agent is an anti-diabetic agent. Anti-diabetic agents useful in the methods of the present invention include include but are not limited to glucagons; somatostatin; diazoxide; sulfonylureas, such as tolbutamide, acetohexamide, tolazamide, chloropropamide, glybenclamide, glipizide, gliclazide, and glimepiride; insulin secretagogues, such as repaglinide, and nateglinide; biguanides, such as metformin and phenformin; thiazolidinediones, such as pioglitazone, rosiglitazone, and troglitazone; and α-glucosidase inhibitors, such as acarbose and miglitol.


In one embodiment, the other therapeutic or prophylactic agent is an anti-cardiovascular agent. Anti-cardiovascular disease agents useful in the methods of the present invention include include but are not limited to carnitine; thiamine; and muscarinic receptor antagonists, such as atropine, scopolamine, homatropine, tropicamide, pirenzipine, ipratropium, tiotropium, and tolterodine.


In one embodiment, the other therapeutic or prophylactic agent is an antiemetic agent. Antiemetic agents useful in the methods of the present invention include include, but are not limited to, metoclopromide, domperidone, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetron, benzquinamide, bietanautine, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone, oxyperndyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinol, thiethylperazine, thioproperazine, tropisetron, and mixtures thereof.


In one embodiment, the other therapeutic or prophylactic agent is a hematopoietic colony stimulating factor. Hematopoietic colony stimulating factors useful in the methods of the present invention include, but are not limited to, filgrastim, sargramostim, molgramostim and epoietin alfa.


In one embodiment, the other therapeutic or prophylactic agent is an opioid analgesic agent. Opioid analgesic agents useful in the methods of the present invention include, but are not limited to, morphine, heroin, hydromorphone, hydrocodone, oxymorphone, oxycodone, metopon, apomorphine, normorphine, etorphine, buprenorphine, meperidine, lopermide, anileridine, ethoheptazine, piminidine, betaprodine, diphenoxylate, fentanil, sufentanil, alfentanil, remifentanil, levorphanol, dextromethorphan, phenazocine, pentazocine, cyclazocine, methadone, isomethadone and propoxyphene.


In one embodiment, the other therapeutic or prophylactic agent is a non-opioid analgesic agent. Non-opioid analgesic agents useful in the methods of the present invention include, but are not limited to, aspirin, celecoxib, rofecoxib, diclofinac, diflusinal, etodolac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, indomethacin, ketorolac, meclofenamate, mefanamic acid, nabumetone, naproxen, piroxicam and sulindac.


In one embodiment, the other therapeutic or prophylactic agent is an anxiolytic agent. Anxiolytic agents useful in the methods of the present invention include, but are not limited to, buspirone, and benzodiazepines such as diazepam, lorazepam, oxazapam, chlorazepate, clonazepam, chlordiazepoxide and alprazolam.


5.10 Kits

The invention encompasses kits that can simplify the administration of an Indenoisoquinolinone Analog to a subject.


A typical kit of the invention comprises a unit dosage form of an Indenoisoquinolinone Analog. In one embodiment, the unit dosage form is a container, which can be sterile, containing an effective amount of an Indenoisoquinolinone Analog and a physiologically acceptable carrier or vehicle. The kit can further comprise a label or printed instructions instructing the use of the Indenoisoquinolinone Analog to treat or prevent a Condition. The kit can also further comprise a unit dosage form of another prophylactic or therapeutic agent, for example, a container containing an effective amount of the other prophylactic or therapeutic agent. In one embodiment, the kit comprises a container containing an effective amount of an Indenoisoquinolinone Analog and an effective amount of another prophylactic or therapeutic agent. Examples of other prophylactic or therapeutic agents include, but are not limited to, those listed above.


The invention is further described in the following examples, which do not limit the scope of the invention described in the claims.


6. EXAMPLES
Example 1
Illustrative Indenoisoquinolinone Analogs

General Methods:



1H-NMR spectra were obtained using Varian 300 MHz spectrophotometer and chemical shifts (6) are reported in parts per million (ppm). 1H-NMR spectra were obtained using DMSO-d6 or CDCl3 as solvents. Analytical thin layer chromatography (TLC) was performed using TLC plates pre-coated with silica gel 60 F-254. Compounds were visualized with short wavelength UV light. All final compounds were characterized on the basis of 1H-NMR or mass-spectrometry (MS) data. Homophthalic anhydride, 2-methyl-3-bromobenzoic acid, benzonitrile, and 3-methyl-4-bromobenzoic acid were obtained commercially (Sigma-Aldrich Corp., St. Louis, Mo.).


A. Synthesis of Indenoisocquinolinone Analogs of Formula Ia and IIIa
Methyl 3-bromo-2-methylbenzoate

2 mL of concentrated sulfuric acid were added to a solution of 3-bromo-2-methylbenzoic acid (20 g, 93 mmol) in methanol (150 mL). The resultant mixture was refluxed for 6 hours. Methanol was removed under reduced pressure, and the residue was dissolved in a mixture of chloroform (100 mL) and saturated solution of Na2CO3 (100 mL). The organic layer was separated and washed with brine, dried over Na2SO4 and concentrated to provide methyl 3-bromo-2-methylbenzoate (21.1 g). 1H NMR spectrum (in DMSO-d6): δ 7.79 (d, J=8.0 Hz, 1H); 7.69 (d, J=7.9 Hz, 1H); 7.23 (t, 1H); 3.82 (s, 3H).


Methyl 3-cyano-2-methylbenzoate

To a flask was added methyl 3-bromo-2-methylbenzoate (21 g, 91.7 mmol), potassium hexacyanoferrate (II) trihydrate (9.7 g, 22.9 mmol), Na2CO3 (9.7 g, 91.7 mmol) and Pd(OAc)2 (102 mg) in N,N-dimethylacetamide (100 mL). The flask's atmosphere was evacuated and replaced with nitrogen, and the reaction mixture heated at 120° C. for 10 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (150 mL). The resultant slurry was filtered and washed thoroughly with ethyl acetate (2×50 mL). The combined filtrate was washed with brine and water, dried over Na2SO4 and evaporated under reduced pressure. The residue obtained after the concentration was purified using flash chromatography (ethyl acetate-hexanes (1:9) as the eluent) to provide methyl 3-cyano-2-methylbenzoate (11.2 g, 70% yield). 1H NMR spectrum (in DMSO-d6): δ 8.03 (d, J=8.1 Hz, 1H); 7.98 (d, J=7.9 Hz, 1H); 7.49 (t, 1H); 3.84 (s, 3H); 2.65 (s, 3H).


Methyl 2-bromomethyl-3-cyanobenzoate

A suspension of methyl 3-cyano-2-methylbenzoate (10.6 g, 60.5 mmol), NBS (16.2 g, 90.7 mmol) and azobisisobutyronitrile (AIBN) (100 mg) in tetrachloromethane (200 mL) was refluxed under nitrogen atmosphere for 6 hours. TLC analysis indicated the complete consumption of methyl 3-cyano-2-methylbenzoate (TLC solvent: 10% ethyl acetate in hexane). The reaction mixture was filtered and washed with chloroform (3×20 mL). The combined filtrate and washings were concentrated under reduced pressure. The residue was washed through a short column of silica gel using 10% ethyl acetate in hexanes as an eluent. The eluent was concentrated and the resultant product dried under vacuum overnight to provide 15.1 g of methyl 2-bromomethyl-3-cyanobenzoate (98% yield). 1H NMR spectrum (in DMSO-d6): δ 8.15 (d, J=8.0 Hz, 1H); 8.12 (d, J=7.9 Hz, 1H); 7.67 (t, 1H); 5.04 (s, 2H); 3.89 (s, 3H).


Methyl 5,6-dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline-10-carboxylate

A mixture of methyl 2-bromomethyl-3-cyanobenzoate (14.1 g, 55.5 mmol) and homophthalic anhydride (22.5 g, 138.8 mmol) in acetonitrile (150 mL) was stirred at room temperature. A solution of triethylamine (23.2 mL) in acetonitrile (100 mL) was added dropwise over the period of 1 hour. After the completion of addition, the resultant suspension was refluxed for 4 hours. The reaction mixture was then cooled to room temperature and filtered. The resultant solid was washed thoroughly with acetonitrile (100 mL) and ethanol (2×100 mL) and dried in vacuum oven at 50° C. to provide methyl 5,6-dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline-10-carboxylate was obtained in 81% yield (13.1 g). 1H NMR spectrum (in DMSO-d6): δ 12.21 (s, 1H); 8.20 (m, 2H); 7.83 (d, J=7.5 Hz, 1H); 7.71 (m, 2H); 7.47 (m, 2H); 4.07 (s, 2H); 3.89 (s, 3H).


10-Hydroxymethyl-5,6-dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline

Fine powder of methyl 5,6-dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline-10-carboxylate (11.3 g, 28.8 mmol) was suspended in THF (150 mL) and stirred at room temperature. A 2M solution of Lithium aluminium hydride (LAH) in THF (39 mL) was added slowly to the stirred suspension. After the complete addition, the mixture was stirred at room temperature for 6 hours, then cooled to 0° C. The reaction mixture was quenched with dropwise addition of ethyl acetate (50 mL). During the quenching the reaction temperature was kept below 50° C. The reaction mixture was poured into 1N HCl solution (200 mL) and stirred for 1 hour. The resultant solid was collected by filtration, washed with 1N HCl solution (20 mL) and ethyl acetate, and dried in a vacuum oven overnight to provide 10-hydroxymethyl-5,6-dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline in 93% yield (9.5 g). 1H NMR spectrum (in DMSO-d6): δ 12.28 (s, 1H); 8.23 (d, J=8.1 Hz, 1H); 7.89 (m, 1H); 7.73 (m, 2H); 7.45 (m, 1H); 7.36 (m, 2H); 5.22 (d, J=5.1 Hz, 1H), 4.68 (d, 2H); 3.85 (s, 2H).


10-Bromomethyl-5,6-dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline

Fine powder of 10-hydroxymethyl-5,6-dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline (7.3 g, 27.7 mmol) was suspended in THF (150 mL). A solution of PBr3 (83 mL, 1M in dichloromethane) was added dropwise at room temperature. After the complete addition, the resultant mixture was stirred overnight and quenched by addition of water (150 mL). The suspension was stirred for 1 hour and filtered. The resultant solid was washed with water (2×100 mL) and ethyl acetate (2×100 mL) and dried in a vacuum oven to provide 110-Bromomethyl-5,6-dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline in 81% yield. 1H NMR spectrum (in DMSO-d6): δ 12.31 (s, 1H); 8.23 d, J=7.5 Hz, 1H); 7.95 (m, 1H); 7.75 (m, 2H); 7.45 (m, 2H); 4.87 (s, 2H); 3.97 (s, 2H).


General Procedure for the Amination Reaction:


A suspension of 10-bromomethyl-5,6-dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline (0.425 g, 1.3 mmol) or a higher alkylene chain bromo-derivative, an appropriate amine in ethanol or DMF and ethanol and in the presence of base is refluxed for 2 hrs to overnight. The reaction mixture is stirred at room temperature for about 30 minutes and filtered. The resultant solid is washed with ethanol (2×20 mL) and dried in a vacuum oven to provide an Indenoisoquinolinone Analog of Formula IIa or IIIa.


Methanesulfonate or Hydrochloride Salt Formation:


Free base of an Indenoisoquinolinone Analog of Formula IIb or IIIb is suspended in ethanol. To the stirred suspension, methanesulfonic acid or hydrochloric acid is added (2 to 10 equivalents). After some time, the resultant salt starts to precipitate from the solution. The mixture is stirred at room temperature for about 2 hours, filtered and washed with ethanol (2×20 mL). The filtered solid is dissolved in water (10 mL) and filtered. The filtrate is lyophilized to provide the corresponding salt of the free base of the Indenoisoquinolinone Analog of Formula Ia or IIIa.


B. Synthesis of Indenoisoquinolinone Analogs of Formula IIb and IIIb
Methyl 4-cyano-3-methylbenzoate

Methyl 4-cyano-3-methylbenzoate was obtained in 86% yield according to the procedure used to prepare methyl 3-cyano-2-methylbenzoate, except that methyl 4-bromo-3-methylbenzoate was used in place of methyl 3-bromo-2-methylbenzoate. 1H NMR spectrum (in DMSO-d6): δ 7.96 (s, 1H); 7.85 (m, 2H); 3.85 (s, 3H); 2.46 (s, 3H).


Methyl 3-bromomethyl-4-cyanobenzoate

Methyl 3-bromomethyl-4-cyanobenzoate was obtained in 60% yield according to the procedure used to prepare methyl 2-bromomethyl-3-cyanobenzoate (supra), except that methyl 4-cyano-3-methylbenzoate was used in place of methyl 3-cyano-2-methylbenzoate. 1H NMR spectrum (in DMSO-d6): δ 8.26 (s, 1H); 8.02 (s, 2H); 4.89 (s, 2H); 3.88 (s, 3H).


Methyl 5,6-dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline-9-carboxylate

Methyl 5,6-dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline-9-carboxylate was obtained in 65% yield according to the procedure used to prepare methyl 5,6-dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline-10-carboxylate, except that methyl 3-bromomethyl-4-cyanobenzoate was used in place of methyl 2-bromomethyl-3-cyanobenzoate. 1H NMR spectrum (in DMSO-d6): δ 12.35 (s, 1H); 8.25 (d, J=8.1 Hz, 1H); 8.11 (s, 1H); 8.06 (d, J=7.8 Hz, 1H); 7.98 (d, J=8.1 Hz, 1H); 7.75 (m, 2H); 7.49 (m, 1H); 3.95 (s, 2H); 3.85 (s, 3H).


9-Hydroxymethyl-5,6-dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline

9-Hydroxymethyl-5,6-dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline was obtained in 96% yield according to the procedure used to prepare 10-hydroxymethyl-5,6-dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline, except that methyl 5,6-dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline-9-carboxylate was used in place of methyl 5,6-dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline-10-carboxylate. 1H NMR spectrum (in DMSO-d6): δ 12.26 (s, 1H); 8.22 (d, J=8.1 Hz, 1H); 7.91 (s, J=8.1 Hz, 1H); 7.70 (m, 2H); 7.54 (s, 1H); 7.42 (m, 1H); 7.30 (d, J=8.1 Hz, 1H); 5.21 (d, 1H); 4.55 (d, J=5.4 Hz, 2H); 3.89 (s, 2H).


9-Bromomethyl-5,6-dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline

9-Bromomethyl-5,6-dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline was obtained in 65% yield according to the procedure used to prepare 10-bromomethyl-5,6-dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline, except that 9-hydroxymethyl-5,6-dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline was used in place of 10-hydroxymethyl-5,6-dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline. 1H NMR spectrum (in DMSO-d6): δ 12.24 (s, 1H); 8.23 (d, J=7.5 Hz, 1H); 7.94 (d, J=7.8 Hz, 1H); 7.72 (m, 2H); 7.65 (s, 1H); 7.45 (m, 2H); 4.79 (s, 2H); 3.89 (s, 2H).


General Procedure for the Amination Reaction:


A suspension of 9-bromomethyl-5,6-dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline (0.425 g, 1.3 mmol) or a higher alkylene chain bromo-derivative, an appropriate amine in ethanol or DMF and ethanol and in the presence of base is refluxed for 2 hrs to overnight. The reaction mixture is stirred at room temperature for about 30 minutes and filtered. The resultant solid is washed with ethanol (2×20 mL) and dried in a vacuum oven to provide an Indenoisoquinolinone Analog of Formula IIb or IIIb.


Methanesulfonate or Hydrochloride Salt Formation:


Free base of an Indenoisoquinolinone Analog of Formula IIb or IIIb is suspended in ethanol. To the stirred suspension, methanesulfonic acid or hydrochloric acid is added (2 to 10 equivalents). After some time, the resultant salt starts to precipitate from the solution. The mixture is stirred at room temperature for about 2 hours, filtered and washed with ethanol (2×20 mL). The filtered solid is dissolved in water (10 mL) and filtered. The filtrate is lyophilized to provide the corresponding salt of the free base of the Indenoisoquinolinone Analog of Formula IIb or IIIb.



1H NMR data for illustrative Indenoisoquinolinone Analogs are presented below in Table 3.










TABLE 3





Com-



pound

1H NMR (DMSO-d6 or DMSO-d6 and D2O)








IIa-1
10-[1-(4-Allylpiperazino)methyl]-5,6-dihydro-5-oxo-11-H-



indeno[1,2-c]isoquinoline: 1H NMR (DMSO) δ 12.28 (s, 1H);



8.23 (d, J = 8.1 Hz, 1H); 7.89 (d, J = 7.2 Hz, 1H); 7.75 (m, 2H);



7.45 (m, 1H); 7.37 (t, J = 7.5 Hz, 1H); 7.28 (d, J = 7.5 Hz, 1H);



5.77 (m, 1H); 5.14 (d, J = 18.6 Hz, 1H); 5.08 (d, J = 10.8 Hz,



1H); 3.89 (s, 2H); 3.61 (s, 2H); 2.89 (d, J = 6.0 Hz, 2H);



2.40 (m, 8H). MS: m/z = 372 (M+ − H)


IIIa-2
10-[1-(4-Butylpiperazino)methyl]-5,6-dihydro-5-oxo-11-H-



indeno[1,2-c]isoquinoline: 1H NMR (DMSO) δ 12.28 (s, 1H);



8.24 (d, J = 7.8 Hz, 1H); 7.90 (d, J = 7.2 Hz, 1H); 7.74 (m, 2H);



7.45 (m, 1H); 7.36 (t, J = 7.5 Hz, 1H); 7.27 (d, J = 7.2 Hz, 1H);



3.90 (s, 2H); 3.64 (s, 2H); 2.38 (m, 10H); 1.41 (m, 2H); 1.24



(m, 2H); 0.85 (t, J = 7.2 Hz, 3H). MS: m/z = 388 (M+ − H).


Dihydro-
10-[1-(4-Allylpiperazino)methyl]-5,6-dihydro-5-oxo-11-H-


chloride
indeno[1,2-c]isoquinoline dihydrochloride: 1H NMR (DMSO


salt of
& D2O) δ 12.35 (s, 1H); 8.25 (d, J = 8.1 Hz, 1H); 8.04 (d, J =


IIa-1
7.5 Hz, 1H); 7.78 (t, J = 7.5 Hz, 1H); 7.72 (d, J = 7.5 Hz, 1H);



7.58 (s, 1H); 7.48 (m, 2H); 5.94 (m, 1H); 5.56 (d, J = 19.2 Hz,



1H); 5.48 (d, J = 10.5 Hz, 1H); 4.15 (s, 2H); 3.73 (s, 2H);



3.51 (m, 10H).


Dihydro-
10-[1-(4-Butylpiperazino)methyl]-5,6-dihydro-5-oxo-11-H-


chloride
indeno[1,2-c]isoquinoline dihydrochloride: 1H NMR (DMSO


salt of
& D2O) δ 12.35 (s, 1H); 8.25 (d, J = 8.1 Hz, 1H); 8.04 (d, J =


IIIa-2
7.2 Hz, 1H); 7.78 (t, J = 7.2 Hz, 1H); 7.71 (d, J = 7.2 Hz, 1H);



7.58 (s, 1H); 7.48 (m, 2H); 4.15 (s, 2H); 3.53 (m, 10H); 3.04 (s,



2H); 1.62 (m, 2H); 1.30 (m, 2H); 0.88 (t, J = 7.2 Hz, 3H). MS:



m/z = 388 (M+ − H).


IIIa-3
10-[1-(4-Cyclopropylmethylpiperazino)methyl]-5,6-dihydro-



5-oxo-11-H-indeno[1,2-c]isoquinoline: 1H NMR (DMSO) δ



12.23 (s, 1H); 8.24 (d, J = 7.8 Hz, 1H); 7.90 (d, J = 7.2 Hz, 1H);



7.74 (m, 2H); 7.44 (m, 1H); 7.35 (t, J = 7.5 Hz, 1H); 7.27 (d, J =



7.2 Hz, 1H); 3.88 (s, 2H); 3.61 (s, 2H); 2.42 (m, 8H); 2.13 (d,



J = 5.7 Hz, 2H); 0.78 (m, 2H); 0.40 (d, J = 6.6 Hz, 2H); 0.02



(m, 2H). MS: m/z = 386 (M+ − H).


IIa-14
10-[(4,4-Ethylenedioxy-piperidino)methyl]-5,6-dihydro-5-



oxo-11-H-indeno[1,2-c]isoquinoline: 1H NMR (DMSO): δ



12.28 (s, 1H); 8.24 (d, J = 7.8 Hz, 1H); 7.90 (d, J = 7.2 Hz, 1H);



7.76 (m, 2H); 7.45 (m, 1H); 7.36 (t, J = 7.5 Hz, 1H); 7.29 (d,



J = 7.2 Hz, 1H); 3.90 (s, 2H); 3.84 (s, 4H); 3.64 (s, 2H); 2.45



(m, 4H); 1.61 (m, 4H). MS: m/z 389 (M+ − H).


IIIa-5
10-[N-(2-Pyrollidinoethyl)aminomethyl}-5,6-dihydro-5-oxo-



11-H-indeno[1,2-c]isoquinoline: 1H NMR (DMSO) δ 12.23 (s,



1H); 8.23 (d, J = 8.1 Hz, 1H); 7.88 (dd, J = 2.1 Hz, 6.3 Hz, 1H);



7.74 (d, J = 3.6 Hz, 2H); 7.44 (m, 1H); 7.34 (m, 2H); 3.89 (s,



2H); 3.87 (s, 2H); 2.62 (t, J = 6.3, 2H); 2.52 (m, 2H); 2.37 (m,



4H); 1.61 (m, 4H). MS: m/z 360 (M+ − H).


IIa-27
10-{N-[1-(Hydroxymethyl)cyclopentyl]aminomethyl}-5,6-



dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline: 1H NMR



(DMSO) δ 12.28 (s, 1H); 8.23 (d, J = 7.8 Hz, 1H); 7.86 (d, J =



6.9 Hz, 1H); 7.73 (m, 2H); 7.45 (m, 1H); 7.36 (m, 2H); 4.56 (s,



1H); 3.90 (s, 2H); 3.79 (s, 2H); 3.41 (s, 2H); 1.69 (m, 2H);



1.53 (m, 4H). MS: m/z = 361 (M+ − H).


IIIa-6
10-{1-[4-(2-Pyrollidinoethyl)piperidino]methyl}-5,6-dihydro-



5-oxo-11-H-indeno[1,2-c]isoquinoline: 1H NMR (DMSO) δ



12.24 (s, 1H); 8.24 (d, J = 7.8 Hz, 1H); 7.89 (d, J = 7.2 Hz, 1H);



7.75 (m, 2H); 7.45 (m, 1H); 7.35 (t, J = 7.2 Hz, 1H); 7.28 (d, J =



7.2 Hz, 1H); 3.89 (s, 2H); 3.58 (s, 2H); 2.79 (d, J = 9.9 Hz, 2H);



2.35 (m, 6H); 1.95 (t, J = 10.6 Hz, 2H); 1.62 (m, 6H); 1.33 (m,



3H); 1.12 (m, 2H). MS: m/z = 428 (M+ − H).


IIIa-7
10-{N-[4-(1-Methylpiperidyl)]aminomethyl}-5,6-dihydro-5-



oxo-11-H-indeno[1,2-c]isoquinoline: 1H NMR (DMSO) δ



12.23 (s, 1H); 8.23 (d, J = 7.8 Hz, 1H); 7.87 (m, 1H); 7.75 (m,



2H); 7.46 (m, 1H); 7.36 (m, 2H); 3.90 (s, 2H); 3.88 (s, 2H);



2.68 (d, J = 11.7 Hz, 2H); 2.40 (m, 1H); 2.11 (s, 3H); 1.82



(m, 4H); 1.30 (m, 2H).


IIIa-9
10-[1-(4-Cyclopentylpiperazino)methyl]-5,6-dihydro-5-oxo-



11-H-indeno[1,2-c]isoquinoline: 1H NMR (DMSO) δ 12.23 (s,



1H); 8.24 (d, J = 7.8 Hz, 1H); 7.90 (d, J = 7.2 Hz, 1H); 7.74 (m,



2H); 7.44 (m, 1H); 7.35 (t, J = 7.5 Hz, 1H); 7.28 (d, J = 7.2 Hz,



1H); 3.89 (s, 2H); 3.60 (s, 2H); 2.41 (m, 9H); 1.71 (m, 2H);



1.56 (m, 2H); 1.45 (m, 2H); 1.28 (m, 2H).



MS: m/z = 400 (M+ − H).


IIIa-8
10-{1-[4-(2-Pyrimidyl)piperazino]methyl}-5,6-dihydro-5-oxo-



11-H-indeno[1,2-c]isoquinoline: 1H NMR (DMSO) δ 12.28 (s,



1H); 8.32 (d, J = 4.8, 2H); 8.24 (d, J = 7.8 Hz, 1H); 7.92 (d, J =



6.8 Hz, 1H); 7.74 (m, 2H); 7.44 (m, 1H); 7.35 (m, 2H); 6.59



(t, J = 4.8 Hz, 1H); 3.94 (s, 2H); 3.73 (m, 4H); 3.68 (s, 2H);



2.46 (m, 4H). MS: m/z = 410 (M+ − H).


IIIa-10
10-{1-[4-(2-Ethoxyethyl)piperazino]methyl}-5,6-dihydro-5-



oxo-11-H-indeno[1,2-c]isoquinoline: 1H NMR (DMSO) δ



12.28 (s, 1H); 8.23 (d, J = 7.8 Hz, 1H); 7.90 (d, J = 7.2 Hz, 1H);



7.76 (m, 2H); 7.45 (m, 1H); 7.35 (t, J = 7.5 Hz, 1H); 7.27 (d, J =



7.2 Hz, 1H); 3.89 (s, 2H); 3.60 (s, 2H); 3.38 (m, 4H); 2.40 (m,



10H); 1.06 (t, J = 6.9 Hz, 3H). MS: m/z = 404 (M+ − H).


IIb-1
9-[1-(4-Allylpiperazino)methyl]-5,6-dihydro-5-oxo-11-H-



indeno[1,2-c]isoquinoline: 1H NMR (DMSO) δ 12.23 (s, 1H);



8.22 (d, J = 7.8 Hz, 1H); 7.91 (d, J = 7.8 Hz, 1H); 7.71 (m, 2H);



7.51 (s, 1H); 7.44 (m, 1H); 7.28 (d, J = 7.5 Hz, 1H); 5.76 (m,



1H); 5.13 (d, J = 18.9 Hz, 1H); 5.08 (d, J = 11.2 Hz, 1H);



3.86 (s, 2H); 3.51 (s, 2H); 2.90 (d, J = 6.0 Hz, 2H); 2.37



(m, 8H). MS: m/z = 372 (M+ − H).


IIIb-1
9-[1-(4-iso-Propylpiperazino)methyl]-5,6-dihydro-5-oxo-11-



H-indeno[1,2-c]isoquinoline: 1H NMR (DMSO) δ 12.22 (s,



1H); 8.23 (d, J = 7.8 Hz, 1H); 7.92 (d, J = 7.8 Hz, 1H); 7.71 (m,



2H); 7.50 (s, 1H); 7.43 (m, 1H); 7.28 (d, J = 7.8 Hz, 1H);



3.86 (s, 2H); 3.50 (s, 2H); 2.60 (m, 1H); 2.46-2.35 (m, 8H); 0.94



(d, J = 6.3 Hz, 6H). MS: m/z = 374 (M+ − H).


IIIb-13
9-[1-(4-Methylhomopiperazino)methyl]-5,6-dihydro-5-oxo-



11-H-indeno[1,2-c]isoquinoline: 1H NMR (DMSO) δ 12.24 (s,



1H); 8.23 (d, J = 8.1 Hz, 1H); 7.91 (d, J = 7.8 Hz, 1H); 7.71 (m,



2H); 7.53 (s, 1H); 7.43 (m, 1H); 7.31 (d, J = 7.8 Hz, 1H);



3.86 (s, 2H); 3.65 (s, 2H); 2.66-2.50 (m, 8H); 2.25 (s, 3H); 1.71



(m, 2H). m/z = 360 (M+ − H).


Dihydro-
9-[1-(4-Cyclopropylmethylpiperazino)methyl]-5,6-dihydro-5-


chloride
oxo-11-H-indeno[1,2-c]isoquinoline dihydrochloride: 1H


salt of
NMR (DMSO & D2O) δ 8.22 (d, J = 7.8 Hz, 1H); 7.98 (t, J =


IIIb-3
7.5 Hz, 1H); 7.74 (m, 3H); 7.50 (m, 2H); 4.35 (s, 2H); 3.87 (s,



2H); 3.38 (m, 8H); 3.04 (d, J = 6.3 Hz, 2H); 1.02 (m, 1H); 0.62



(d, J = 6.3 Hz, 2H); 0.34 (m, 2H). MS: m/z = 386 (M+ − H).


Dihydro-
9-[1-(4-iso-Propylpiperazino)methyl]-5,6-dihydro-5-oxo-11-


chloride
H-indeno[1,2-c]isoquinoline dihydrochloride: 1H NMR


salt of
(DMSO) δ 12.22 (s, 1H); 8.22 (d, J = 8.1 Hz, 1H); 7.99 (d, J =


IIIb-1
7.8 Hz, 1H); 7.75 (m, 3H); 7.56 (d, J = 7.8 Hz, 1H); 7.47 (m,



1H); 4.39 (s, 2H); 3.90 (s, 2H); 3.54 (m, 9H); 1.23 (d, J =



6.0 Hz, 6H). MS: m/z = 374 (M+ − H).


IIIb-2
9-[1-(4-Butylpiperazino)methyl]-5,6-dihydro-5-oxo-11-H-



indeno[1,2-c]isoquinoline: 1H NMR (DMSO) δ 12.23 (s, 1H);



8.22 (d, J = 8.1 Hz, 1H); 7.91 (d, J = 7.8 Hz, 1H); 7.71 (m, 2H);



7.50 (s, 1H); 7.43 (m, 1H); 7.27 (d, J = 7.8 Hz, 1H); 3.86 (s,



2H); 3.50 (s, 2H); 2.35 (m, 8H); 2.22 (t, J = 6.9 Hz, 2H);



1.37-1.20 (m, 4H); 0.84 (t, J = 6.9 Hz, 3H).



MS: m/z = 388 (M+ − H).


Dihydro-
9-[1-(4-Butylpiperazino)methyl]-5,6-dihydro-5-oxo-11-H-


chloride
indeno[1,2-c]isoquinoline dihydrochloride: 1H NMR (DMSO)


salt of
δ 12.23 (s, 1H); 8.23 (d, J = 7.8 Hz, 1H); 8.00 (d, J = 8.1 Hz,


IIIb-2
1H); 7.76 (m, 3H); 7.55 (d, J = 7.5 Hz, 1H); 7.48 (m, 1H);



4.36 (s, 2H); 3.91 (s, 2H); 3.40 (m, 8H); 3.09 (t, J = 7.5 Hz, 2H);



1.58 (m, 2H); 1.28 (m, 1H); 0.86 (t, J = 7.2 Hz, 3H).



MS: m/z = 388 (M+ − H).


Dihydro-
9-[1-(4-Allylpiperazino)methyl]-5,6-dihydro-5-oxo-11-H-


chloride
indeno[1,2-c]isoquinoline dihydrochloride: 1H NMR (DMSO


salt of
& D2O) δ 8.22 (d, J = 8.1 Hz, 1H); 7.97 (d, J = 7.8 Hz, 1H);


IIb-1
7.75 (m, 3H); 7.49 (m, 2H); 5.83 (m, 1H); 5.53 (d, J = 19.5 Hz,



1H); 5.08 (d, J = 9.6 Hz, 1H); 4.29 (s, 2H); 3.91 (s, 2H); 3.71



(d, J = 6.9 Hz, 2H); 3.32 (m, 8H).


Dihydro-
9-[1-(4-Cyclohexylpiperazino)methyl]-5,6-dihydro-5-oxo-11-


chloride
H-indeno[1,2-c]isoquinoline dihydrochloride: 1H NMR


salt of
(DMSO & D2O) δ 8.21 (d, J = 8.1 Hz, 1H); 7.94 (d, J = 7.8 Hz,


IIIb-14
1H); 7.75 (d, J = 3.9 Hz, 2H); 7.70 (s, 1H); 7.48 (m, 2H);



3.92 (s, 2H); 3.57 (s, 3H); 3.27 (m, 8H); 2.05 (s, 2H); 1.79 (d,



J = 10.8 Hz, 2H); 1.57 (d, J = 11.1 Hz, 1H); 1.43-1.05 (m, 5H).


IIIb-24
9-[1-(3,5-Dimethylpiperazino)methyl]-5,6-dihydro-5-oxo-11-



H-indeno[1,2-c]isoquinoline: 1H NMR (DMSO) δ 12.22 (s,



1H); 8.22 (d, J = 7.8 Hz, 1H); 7.91 (d, J = 7.8 Hz, 1H); 7.71 (m,



2H); 7.49 (s, 1H); 7.44 (m, 1H); 7.28 (d, J = 7.8 Hz, 1H);



3.87 (s, 2H); 3.46 (s, 2H); 2.72 (m, 2H); 2.65 (d, J = 9.3 Hz,



2H); 1.49 (t, J = 10.1 Hz, 3H); 0.87 (d, J = 6.0 Hz, 6H).



MS: m/z = 360 (M+ − H).


IIIb-17
9-{1-[4-(2-Pyrollidinoethyl)piperidino]methyl}-5,6-dihydro-



5-oxo-11-H-indeno[1,2-c]isoquinoline: 1H NMR (DMSO) δ



12.23 (s, 1H); 8.22 (d, J = 8.1 Hz, 1H); 7.91 (d, J = 7.5 Hz, 1H);



7.73 (m, 2H); 7.50 (s, 1H); 7.44 (m, 1H); 7.28 (d, J = 7.8 Hz,



1H); 3.87 (s, 2H); 3.48 (s, 2H); 2.79 (d, J = 11.1 Hz, 2H);



2.35 (m, 6H); 1.90 (t, J = 10.6 Hz, 2H); 1.62 (m, 6H); 1.33



(m, 3H); 1.15 (m, 2H). MS: m/z = 428 (M+ − H).


IIb-92
9-{N-[4-(1-Boc-piperidyl)]aminomethyl}-5,6-dihydro-5-oxo-



11-H-indeno[1,2-c]isoquinoline: 1H NMR (DMSO) δ 12.23 (s,



1H); 8.23 (d, J = 7.8 Hz, 1H); 7.90 (d, J = 7.5 Hz, 1H); 7.71 (m,



2H); 7.57 (s, 1H); 7.43 (m, 1H); 7.34 (d, J = 7.5 Hz, 1H);



3.86 (s, 2H); 3.79 (m, 4H); 2.78 (m, 2H); 2.56 (m, 1H); 1.79



(d, J = 12.0 Hz, 2H); 1.37 (s, 9H); 1.15 (m, 2H).



MS: m/z = 446 (M+ − H).


IIIb-9
9-[1-(4-Cyclopentylpiperazino)methyl]-5,6-dihydro-5-oxo-11-



H-indeno[1,2-c]isoquinoline dihydrochloride: 1H NMR



(DMSO) δ 12.22 (s, 1H); 8.22 (d, J = 8.1 Hz, 1H); 7.91 (d, J =



8.1 Hz, 1H); 7.71 (m, 2H); 7.51 (s, 1H); 7.44 (m, 1H); 7.28



(d, J = 7.5 Hz, 1H); 3.87 (s, 2H); 3.50 (s, 2H); 2.83 (m, 1H);



2.38 (m, 8H); 1.71 (m, 2H); 1.51 (m, 4H); 1.27 (m, 2H).



MS: m/z = 400 (M+ − H).


IIIb-10
9-{1-[4-(2-Ethoxyethyl)piperazino]methyl}-5,6-dihydro-5-



oxo-11-H-indeno[1,2-c]isoquinoline: 1H NMR (DMSO) δ



12.28 (s, 1H); 8.23 (d, J = 7.8 Hz, 1H); 7.91 (d, J = 7.8 Hz, 1H);



7.71 (m, 2H); 7.51 (s, 1H); 7.43 (m, 1H); 7.29 (d, J = 7.8 Hz,



1H); 3.87 (s, 2H); 3.50 (s, 2H); 3.38 (m, 4H); 2.38 (m, 10H);



1.06 (t, J = 6.9 Hz, 3H). MS: m/z = 404 (M+ − H).


IIb-196
9-{1-[4-(2,2-Diethoxyethyl)piperazino]methyl}-5,6-dihydro-



5-oxo-11-H-indeno[1,2-c]isoquinoline: 1H NMR (DMSO) δ



12.29 (s, 1H); 8.22 (d, J = 7.8 Hz, 1H); 7.91 (d, J = 7.8 Hz, 1H);



7.71 (m, 2H); 7.50 (s, 1H); 7.43 (m, 1H); 7.28 (d, J = 7.8 Hz,



1H); 4.54 (t, J = 4.8 Hz, 1H); 3.87 (s, 2H); 3.50 (m, 6H); 3.38



(m, 8H); 1.07 (t, J = 7.2 Hz, 3H). MS: m/z = 448 (M+ − H).


IIb-53
9-[(1-N-Methyl-3-morpholinopropyonyl)methyl]-5,6-



dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline: 1H NMR



(DMSO) δ 12.28 (bs, 1H); 8.25 (d, J = 7.5 Hz, 1H); 7.98 (m,



1H); 7.76 (m, 2H); 7.51 (s, 1H); 7.47 (m, 1H); 7.26 (m, 1H);



4.67 (s, 1H); 4.59 (s, 1H); 3.83 (m, 2H); 3.58-3.49 (m, 4H);



2.96 (s, 2H); 2.84 (s, 1H); 2.73-2.32 (m, 8H).


IIIb-16
9-[(4-tert-Butoxycarbonyl-piperazino)methyl]-5,6-dihydro-5-



oxo-11-H-indeno[1,2-c]isoquinoline: 1H NMR (DMSO) δ



12.29 (s, 1H); 8.25 (d, J = 7.5 Hz, 1H); 7.95 (d, J = 7.8 Hz, 1H);



7.74 (m, 2H); 7.48 (m, 2H); 7.32 (d, J = 7.8, 1H); 3.89 (s, 2H);



3.56 (s, 2H); 3.32 (m, 2H); 2.50 (m, 2H); 2.33 (m, 4H); 1.39



(s, 9H).


IIb-105
9-[(4-Propionyl-piperazino)methyl]-5,6-dihydro-5-oxo-11-H-



indeno[1,2-c]isoquinoline: 1H NMR (DMSO) δ 12.32 (s, 1H);



8.25 (d, J = 7.5 Hz, 1H); 7.95 (d, J = 7.8 Hz, 1H); 7.75 (m, 2H);



7.55 (s, 1H); 7.47 (m, 1H); 7.33 (d, J = 8.1); 3.90 (s, 2H);



3.57 (s, 2H); 3.44 (m, 4H); 2.33 (m, 6H); 0.97 (t, J = 7.5, 3H).



MS: m/z = 388 (M+ − H).


IIIb-18
9-[4-(2-Hydroxy-2-methyl-propyl-piperazino)methyl]-5,6-



dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline



dihydrochloride: 1H NMR (DMSO) δ 12.37 (s, 1H); 8.27 (d,



J = 7.8 Hz, 1H); 8.05 (m, 1H); 7.78 (m, 3H); 7.50 (m, 2H);



3.96 (s, 2H); 3.72-2.73 (m, 12H); 1.20 (s, 6H).



MS: m/z = 404 (M+ − H).


IIb-118
9-[(4-Propionyl-homopiperazino)methyl]-5,6-dihydro-5-oxo-



11-H-indeno[1,2-c]isoquinoline hydrochloride: 1H NMR



(DMSO) δ 12.39 (s, 1H); 10.71 (bs, 1H); 8.27 (d, J = 8.1, 1H);



8.06 (d, J = 7.5 Hz, 1H); 7.81 (m, 3H); 7.64 (m, 1H); 7.51 (m,



1H); 4.42 (s, 2H); 4.15-2.99 (m, 14H); 0.99 (t, J = 7.2 Hz, 1H).



MS: m/z = 402 (M+ − H).


Dihydro-
9-[(1-N-Methyl-2-morpholino-aminoethyl)methyl]-5,6-


chloride
dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline


salt of
dihydrochloride: 1H NMR (DMSO) δ 12.41 (s, 1H); 11.64 (bs,


IIIb-19
1H); 11.35 (bs, 1H); 8.27 (d, J = 6.9, 1H); 8.07 (d, J = 6.9, 1H);



7.90 (s, 1H); 7.74 (m, 3H); 7.51 (m, 1H); 4.62 (m, 1H); 4.39 (m,



1H); 3.96 (s, 2H); 3.83-3.17 (m, 12H); 2.73 (s, 3H).



MS: m/z = 390 (M+ − H).


IIIa-11
10-[S-(3-Fluoropyrrolidino)methyl]-5,6-dihydro-5-oxo-11-H-



indeno[1,2-c]isoquinoline: 1H NMR (DMSO) δ 12.30 (s, 1H);



8.24 (d, J = 8.1 Hz, 1H); 7.91 (d, J = 7.5); 7.75 (m, 2H);



7.48-7.30 (m, 3H); 5.30 (m, 0.5H); 5.11 (m, 0.5H); 3.89 (s, 2H);



3.78 (s, 2H); 2.87-1.86 (m, 6H). MS: m/z = 335 (M+ − H).


IIIa-12
10-[(3,4-Dehydropiperidino)methyl]-5,6-dihydro-5-oxo-11-



H-indeno[1,2-c]isoquinoline: 1H NMR (DMSO) δ 12.29 (s,



1H); 8.26 (d, J = 7.2 Hz, 1H); 7.93 (d, J = 6.6); 7.77 (m, 2H);



7.46-7.33 (m, 3H); 5.67 (m, 2H); 3.91 (s, 2H); 3.71 (s, 2H);



2.92 (m, 2H); 2.56 (m, 2H); 2.09 (m, 2H).



MS: m/z = 329 (M+ − H).


IIIa-4
10-[N-1-(3-Hydroxypropyl)aminomethyl]-5,6-dihydro-5-oxo-



11-H-indeno[1,2-c]isoquinoline: 1H NMR (DMSO) δ 12.25 (s,



1H); 8.23 (d, J = 8.1 Hz, 1H); 7.87 (dd, J = 2.9 Hz, 5.9 Hz, 1H);



7.75 (m, 2H); 7.44 (m, 1H); 7.34 (m, 1H); 3.89 (s, 2H); 3.85 (s,



2H); 3.46 (t, J = 6.3 Hz, 2H); 2.60 (t, J = 6.9 Hz, 2H); 1.60 (m,



J = 6.3 Hz, 2H). MS: m/z = 321 (M+ − H).


IIIa-1
10-[1-(4-iso-Propylpiperazino)methyl]-5,6-dihydro-5-oxo-11-



H-indeno[1,2-c]isoquinoline: 1H NMR (DMSO) δ 12.28 (s,



1H); 8.23 (d, J = 8.1 Hz, 1H); 7.90 (d, J = 7.5 Hz, 1H); 7.75 (m,



2H); 7.44 (m, 1H); 7.35 (t, J = 7.2 Hz, 1H); 7.27 (d, J = 7.2 Hz,



1H); 3.89 (s, 2H); 3.59 (s, 2H); 2.58 (m, 1H); 2.46-2.35 (m,



8H); 0.92 (d, J = 6.3 Hz, 6H). MS: m/z = 374 (M+ − H).


IIa-40
10-{1-[4-(1-pyrrolidinocarbonylmethyl)piperazino]methyl}-



5,6-dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline: 1H NMR



(DMSO) δ 12.25 (s, 1H); 8.24 (d, J = 8.1 Hz, 1H); 7.90 (d,



J = 7.2 Hz, 1H); 7.76 (m, 2H); 7.45 (m, 1H); 7.36 (t, J = 7.8 Hz,



1H); 7.28 (d, J = 7.8 Hz, 1H); 3.90 (s, 2H); 3.62 (s, 2H); 3.44 (t,



J = 6.6 Hz, 2H); 3.24 (t, J = 6.9 Hz, 2H); 3.04 (s, 2H); 2.43 (m,



8H); 1.81 (m, 2H); 1.72 (m, 2H). MS: m/z = 443 (M+ − H).


Dihydro-
9-[1-(4-Methylhomopiperazino)methyl]-5,6-dihydro-5-oxo-


chloride
11-H-indeno[1,2-c]isoquinoline dihydrochloride: 1H NMR


salt of
(DMSO) δ 12.35 (s, 1H); 8.23 (d, J = 7.8 Hz, 1H); 8.02 (d,


IIIb-13
J = 7.8 Hz, 1H); 7.84 (s, 1H); 7.76 (d, J = 3.3 Hz, 2H); 7.65



(d, J = 7.2 Hz, 1H); 7.47 (m, 1H); 4.42 (s, 2H); 3.92 (s, 2H);



3.32 (m, 8H); 2.76 (s, 3H); 2.19 (m, 2H).



MS: m/z = 360 (M+ − H).


IIb-66
9-{1-[4-(2-Cyanoethyl)piperazino]methyl}-5,6-dihydro-5-



oxo-11-H-indeno[1,2-c]isoquinoline: 1H NMR (DMSO) δ



12.25 (s, 1H); 8.22 (d, J = 8.1 Hz, 1H); 7.92 (d, J = 7.5 Hz, 1H);



7.71 (m, 2H); 7.51 (s, 1H); 7.44 (m, 1H); 7.29 (d, J = 7.5 Hz,



1H); 3.87 (s, 2H); 3.52 (s, 2H); 2.62 (d, J = 6.1 Hz, 2H); 2.54 (d,



J = 6.1 Hz, 2H); 2.41 (m, 8H). MS: m/z = 385 (M+ − H).


Methyl-
9-[1-(4,4-Difluoropiperidino)methyl]-5,6-dihydro-5-oxo-11-


sulfonate
H-indeno[1,2-c]isoquinoline methylsulfonate: 1H NMR


salt of
(DMSO) δ 12.36 (s, 1H); 9.75 (s, 1H); 8.25 (d, J = 8.1 Hz, 1H);


IIIb-15
8.06 (d, J = 8.1 Hz, 1H); 7.77 (m, 3H); 7.51 (m, 2H); 4.47 (s,



2H); 3.96 (s, 2H); 3.42 (m, 2H); 3.19 (m, 2H); 2.32 (s, 3H);



2.29 (m, 4H). MS: m/z = 367 (M+ − H).


IIb-79
9-{N-[4-(1-Boc-piperidyl)]-N-cyclopropylaminomethyl}-5,6-



dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline: 1H NMR



(DMSO) δ 12.28 (s, 1H); 8.22 (d, J = 8.1 Hz, 1H); 7.88 (d,



J = 8.1 Hz, 1H); 7.71 (m, 2H); 7.48 (s, 1H); 7.43 (m, 1H); 7.27



(d, J = 7.8 Hz, 1H); 3.94 (m, 2H); 3.85 (s, 2H); 3.81 (s, 2H);



2.61 (m, 3H); 2.01 (m, 1H); 1.74 (m, 2H); 1.36 (m, 11H); 0.42



(m, 2H); 0.25 (m, 2H). MS: m/z = 486 (M+ − H).


IIb-131
9-{1-[4-(2-Furyl)piperazino]methyl}-5,6-dihydro-5-oxo-11-H-



indeno[1,2-c]isoquinoline: 1H NMR (DMSO) δ 12.28 (s, 1H);



8.23 (d, J = 8.1 Hz, 1H); 7.92 (d, J = 7.8 Hz, 1H); 7.72 (m, 2H);



7.51 (s, 1H); 7.44 (m, 1H); 7.29 (d, J = 8.1 Hz, 1H); 3.88 (m,



3H); 3.68 (dt, J = 6.9 Hz, 7.5 Hz, 1H); 3.55 (dt, J = 6.9 Hz,



7.5 Hz, 1H); 3.51 (s, 2H); 2.37 (m, 10H); 1.86 (m, 1H); 1.73



(m, 2H); 1.45 (m, 1H). MS: m/z = 416 (M+ − H).


IIb-157
9-{1-[4-(1-Pyrrolidinocarbonylmethyl)piperazino]methyl}-



5,6-dihydro-5-oxo-11-H-indeno[1,2-c] isoquinoline: 1H NMR



(DMSO) δ 12.27 (s, 1H); 8.23 (d, J = 7.8 Hz, 1H); 7.92 (d,



J = 8.1 Hz, 1H); 7.72 (m, 2H); 7.51 (s, 1H); 7.44 (m, 1H);



7.29 (d, J = 7.8 Hz, 1H); 3.88 (s, 2H); 3.51 (m, 2H); 3.43 (t,



J = 6.5 Hz, 2H); 3.24 (t, J = 6.6 Hz, 2H); 3.04 (s, 2H); 2.38



(m, 8H); 1.77 (m, 4H). MS: m/z = 443 (M+ − H).


IIIb-20
9-(N-4-Piperidylaminomethyl)-5,6-dihydro-5-oxo-11-H-



indeno[1,2-c]isoquinoline: 1H NMR (DMSO) δ 12.35 (s, 1H);



9.67 (s, 2H); 9.04 (s, 1H); 8.90 (s, 1H); 8.25 (d, J = 7.8 Hz, 1H);



8.01 (d, J = 7.8 Hz, 1H); 7.83 (s, 1H); 7.77 (m, 2H); 7.63 (d,



J = 7.5 Hz, 1H); 7.48 (m, 1H); 4.23 (s, 2H); 3.94 (s, 2H); 3.32



(m, 3H); 2.90 (m, 2H); 2.27 (m, 2H); 1.92 (m, 2H).



MS: m/z = 346 (M+ − H).


IIIb-8
9-{1-[4-(2-Pyrimidyl)piperazino]methyl}-5,6-dihydro-5-oxo-



11-H-indeno[1,2-c]isoquinoline: 1H NMR (DMSO) δ 12.29 (s,



1H); 8.32 (d, J = 5.1 Hz, 2H); 8.23 (d, J = 8.1 Hz, 1H); 7.94 (d,



J = 7.5 Hz, 1H); 7.72 (m, 2H); 7.57 (s, 1H); 7.45 (m, 1H); 7.34



(d, J = 7.5 Hz, 1H); 6.59 (t, J = 4.8 Hz, 1H); 3.89 (s, 2H); 3.72



(m, 4H); 3.58 (s, 2H); 2.44 (m, 4H). MS: m/z = 410 (M+ − H).


IIb-170
9-{1-[4-(Cyclopropylcarbonyl)piperazino]methyl}-5,6-



dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline: 1H NMR



(DMSO) δ 12.23 (s, 1H); 8.24 (d, J = 8.1 Hz, 1H); 7.94 (d,



J = 7.8 Hz, 1H); 7.72 (m, 2H); 7.55 (s, 1H); 7.45 (m, 1H); 7.33



(d, J = 7.2 Hz, 1H); 3.89 (s, 2H); 3.66 (m, 2H); 3.57 (s, 2H);



3.46 (m, 2H); 2.40 (m, 4H); 1.93 (m, 1H); 0.68 (m, 4H).



MS: m/z = 400 (M+ − H).


IIIb-21
9-{1-[4-(Trifluoromethyl)piperidino]methyl}-5,6-dihydro-5-



oxo-11-H-indeno[1,2-c]isoquinoline: 1H NMR (DMSO) δ



12.23 (s, 1H); 8.23 (d, J = 7.8 Hz, 1H); 7.93 (d, J = 8.1 Hz, 1H);



7.72 (m, 2H); 7.52 (s, 1H); 7.44 (m, 1H); 7.30 (d, J = 7.8 Hz,



1H); 3.87 (s, 2H); 3.54 (s, 2H); 2.89 (d, J = 11.3 Hz, 2H);



2.21 (m, 1H); 1.97 (t, J = 11.5 Hz, 2H); 1.76 (d, J = 11.6 Hz,



2H); 1.45 (m, 2H). MS: m/z = 399 (M+ − H).


IIIb-22
9-(1-Homopiperidinomethyl)-5,6-dihydro-5-oxo-11-H-



indeno[1,2-c]isoquinoline: 1H NMR (DMSO) δ 12.18 (s, 1H);



8.23 (d, J = 7.8 Hz, 1H); 7.90 (d, J = 7.8 Hz, 1H); 7.71 (m, 2H);



7.54 (s, 1H); 7.43 (m, 1H); 7.31 (d, J = 7.8 Hz, 1H); 3.86 (s,



2H); 3.65 (2, H); 2.57 (m, 4H), 1.57 (m, 8H).



MS: m/z = 345 (M+ − H).


IIb-183
9-[1-(4-Octylpiperazino)methyl]-5,6-dihydro-5-oxo-11-H-



indeno[1,2-c]isoquinoline: 1H NMR (DMSO) δ 12.28 (s, 1H);



8.23 (d, J = 8.1 Hz, 1H); 7.93 (d, J = 7.8 Hz, 1H); 7.72 (m, 2H);



7.53 (s, 1H); 7.44 (m, 1H); 7.31 (d, J = 7.2 Hz, 1H); 3.88 (s,



2H); 3.58 (s, 2H); 2.87 (m, 4H); 2.41 (m, 6H); 1.55 (m, 2H),



1.23 (m, 10H); 0.84 (t, J = 6.9 Hz, 3H).



MS: m/z = 444 (M+ − H).


IIIb-23
9-{1-[4-(3-Hydroxypropyl)piperazino]methyl}-5,6-dihydro-5-



oxo-11-H-indeno[1,2-c]isoquinoline: 1H NMR (DMSO) δ



12.27 (s, 1H); 8.22 (d, J = 7.5 Hz, 1H); 7.92 (d, J = 7.8 Hz, 1H);



7.71 (m, 2H); 7.51 (s, 1H); 7.44 (m, 1H); 7.27 (d, J = 7.8 Hz,



1H); 3.87 (s, 2H); 3.51 (s, 2H); 3.40 (t, J = 6.3 Hz, 2H); 2.37



(m, 10H); 1.53 (t, J = 6.3 Hz, 3H). MS: m/z = 390 (M+ − H).


IIb-40
9-((4-(2-oxo-2-(pyrrolidin-1-yl)ethyl)piperazin-1-



yl)methyl)-6,11-dihydro-5H-indeno[1,2-c]isoquinolin-



5-one: 1H NMR (DMSO-d6): δ 12.27



(s, 1H); 8.23 (d, J = 7.8 Hz, 1H); 7.92 (d, J = 8.1 Hz, 1H);



7.72 (m, 2H); 7.51 (s, 1H); 7.43 (t, J = 7.8 Hz, 1H); 7.29 (d,



J = 7.8 Hz, 1H); 3.87 (s, 2H); 3.51 (s, 2H); 3.43 (t,



J = 6.6 Hz, 2H); 3.24 (t, J = 6.6 Hz, 2H); 3.04 (s, 2H);



2.38 (m, 8H); 1.80 (m, 2H); 1.72 (m, 2H).


IIb-27
9-((1-(hydroxymethyl)cyclopentylamino)methyl)-



6,11-dihydro-5H-indeno[1,2-c]isoquinolin-5-one:




1H NMR (DMSO-d6): δ 12.35 (s, 1H); 8.86 (s, 2H); 8.26




(d, J = 8.1 Hz, 1H); 8.03 (d, J = 7.2 Hz, 1H); 7.78 (m,



3H); 7.55 (m, 2H); 5.74 (s, 1H); 4.19 (s, 2H); 3.97 (s, 2H);



3.58 (s, 2H); 1.76 (m, 6H); 1.58 (m, 2H).



MS: m/z 361 (M − H+).


IIb-210
9-((4-(2-(pyrrolidin-1-yl)ethyl)piperidin-1-yl)methyl)-



6,11-dihydro-5H-indeno[1,2-c]isoquinolin-5-one:




1H NMR (DMSO-d6): δ 12.24 (s, 1H);




8.22 (d, J = 8.1 Hz, 1H); 7.91 (d, J = 7.5 Hz, 1H);



7.70 (m, 2H); 7.50 (s, 1H); 7.43 (t, J = 7.8 Hz, 1H); 7.27 (d, J =



7.8 Hz, 1H); 3.86 (s, 2H); 3.48 (s, 2H); 2.78 (d, J = 11.1 Hz,



2H); 2.35 (m, 6H); 1.89 (t, J = 10.6 Hz, 2H); 1.62 (m, 6H);



1.35 (m, 3H); 1.15 (m, 2H). MS: m/z 428 (M − H+).


IIa-28
10-((1-hydroxymethyl)cyclopentylamino)methyl)benzofuro[3,2-



c]isoquinolin-5(6H)-one: 1H NMR (DMSO-d6): δ 12.52 (s, 1H);



9.16 (s, 2H); 8.35 (d, J = 8.1 Hz, 1H); 8.08 (m, 2H); 7.94 (t, J =



7.5 Hz, 1H); 7.69 (t, J = 7.2 Hz, 1H); 7.63 (d, J = 7.8 Hz, 1H);



7.46 (t, J = 7.5 Hz, 1H); 5.85 (s, 1H); 4.51 (s, 2H); 3.68 (s, 2H);



1.91 (m, 5H); 1.79 (m, 2H); 1.63 (m, 2H).


Va-1
4-chloro-10-((cyclopentylamino)methyl)-6,11-dihydro-5H-



indeno[1,2-c]isoquinolin-5-one 1H NMR (DMSO-d6).: δ 8.94



(bs, 2H), 8.13 (m, 1H), 7.85 (m, 2H), 7.51 (m, 3H), 4.39 (m,



2H), 4.10 (s, 2H), 3.67 (m, 1H), 2.07 (m, 2H), 1.65 (m, 4H),



1.54 (m, 2H). MS: m/z 365.2 (M − H+).


Va-2
10-((cyclopentylamino)methyl)-2-fluoro-6,11-dihydro-5H-



indeno[1,2-c]isoquinolin-5-one 1H NMR (DMSO-d6).: δ



12.46 (bs, 1H), 8.95 (bs, 2H), 8.32 (dd, J = 6.0,



6.0 Hz, 1H), 8.07 (dd, J = 2.0, 5.0 Hz, 1H),



7.54 (m, 3H), 7.33 (dd, J = 6.0, 6.0 Hz, 1H), 4.29 (m, 2H),



4.06 (s, 2H), 3.65 (m, 1H), 2.06 (m, 2H), 1.72 (m, 4H),



1.58 (m, 2H). MS: m/z 349.0 (M − H+).


Va-3
10-((cyclopentylamino)methyl)-3-fluoro-6,11-dihydro-5H-



indeno[1,2-c]isoquinolin-5-one 1H NMR (DMSO-d6).: δ



12.53 (bs, 1H); 8.95 (bs, 2H), 8.04 (dd, J = 6.0, 7.2 Hz,



1H), 7.98 (m, 1H), 7.73 (m, 1H), 7.51 (m, 2H), 4.31



(dd, J = 5.2, 5.2 Hz, 2H), 4.06 (s, 2H),



3.65 (m, 1H), 2.07 (m, 2H), 1.72 (m, 4H), 1.57 (m, 2H).



MS: m/z 348.9 (M − H+).


Va-4
10-((cyclopentylamino)methyl)-4-fluoro-6,11-dihydro-5H-



indeno[1,2-c]isoquinolin-5-one 1H NMR (DMSO-d6).: δ 12.37



(bs,1H), 8.86 (bs, 2H); 8.05 (dd, J = 2.0, 6.8 Hz, 1H), 7.77



(m, 1H), 7.54 (m, 3H); 7.23 (m, 1H); 4.30 (dd, J = 6.0, 6.0 Hz,



2H); 4.04 (s, 2H); 3.65 (m, 1H); 2.31 (m, 2H); 1.71 (m, 4H);



1.57 (m, 2H). MS: m/z 348.9 (M − H+)


Va-5
3-fluoro-10-((tetrahydro-2H-pyran-4-ylamino)methyl)-



6,11-dihydro-5H-indeno[1,2-c]isoquinolin-5-one




1H NMR (DMSO-d6).: δ 12.47 (bs, 1H),




8.85 (bs, 2H), 7.98 (d, J = 6.5 Hz, 2H), 7.67 (m, 1H),



7.44 (m, 3H), 4.38 (m, 2H), 4.27 (m, 2H), 3.99 (dd, J =



3.6, 11.6 Hz, 2H), 3.53 (m, 2H), 3.42 (m, 1H), 2.01 (m, 2H),



1.58 (m, 2H) MS: m/z 365.30 (M − H+).


Va-6
1-fluoro-10-((tetrahydro-2H-pyran-4-ylamino)methyl)-



6,11-dihydro-5H-indeno[1,2-c]isoquinolin-5-one




1H NMR (DMSO-d6).: δ 12.49 (bs, 1H),




8.93 (bs, 2H). 8.65 (m, 1H), 7.95 (dd, J = 2.0,



8.9 Hz, 1H), 7.89 (dd, J = 2.5, 8.9, 1H), 7.75 (m, 2H), 7.42 (dd,



J = 4.0, 8.0 Hz, 1H), 5.81 (bs, 1H), 4.28 (m, 2H), 4.07 (s, 2H),



3.65 (m, 2H), 3.49 (m, 1H), 1.84 (m, 8H).



MS: m/z 379.2 (M − H+)


Va-7
10-((cyclopentylamino)methyl)-1-fluoro-6,11-dihydro-5H-



indeno[1,2-c]isoquinolin-5-one 1H NMR (DMSO-d6).: δ 12.58



(bs, 1H), 8.94 (bs, 2H), 8.13 (d, J = 2.8, 7,6 Hz, 2H), 7.65 (m,



1H), 7.51 (m, 3H), 4.34 (dd, J = 6.0, 6.0 Hz, 2H), 4.20 (s, 2H),



3.67 (m, 1H), 2.07 (m, 2H), 1.69 (m, 4H), 1.57 (m, 2H).



MS: m/z 348.9 (M − H+).


Va-8
2-fluoro-10-((tetrahydro-2H-pyran-4-ylamino)methyl)-



6,11-dihydro-5H-indeno[1,2-c]isoquinolin-5-one




1H NMR (DMSO-d6).: δ 12.70 (bs, 1H),




9.16 (bs, 2H), 8.57 (m, 1H), 8.33 (m, 1H), 7.77 (m, 3H),



7.55 (m, 1H), 4.60 (m, 2H), 4.27 (m, 2H), 4.21 (m, 2H),



3.65 (m, 2H), 3.55 (m, 1H), 2.31 (m, 2H), 1.92 (m, 2H).



MS: m/z 365.3 (M − H+).


Va-9
8-fluoro-10-((1-(hydroxymethyl)cyclopentylamino)methyl)-



6,11-dihydro-5H-indeno[1,2-c]isoquinolin-5-one 1H NMR



(DMSO-d6).: δ 12.59 (bs, 1H), 8.90 (bs, 2H);



8.12 (d, J = 8.0 Hz, 2H), 7.65 (m, 1H), 7.52 (m, 3H),



4.38 (m, 2H), 4.20 (s, 2H), 3.97 (dd J = 2.0,



10 Hz, 2H), 3.55 (m, 2H), 3.42 (m, 1H), 2.13 (m, 2H);



1.65 (m, 2H). MS: m/z 365.3 (M − H+).


Va-10
3,8-difluoro-10-((1-(hydroxymethyl)cyclopentylamino)methyl)-



6,11-dihydro-5H-indeno[1,2-c]isoquinolin-5-one 1H NMR



(DMSO-d6).: δ 12.49 (bs, 1H); 9.12 (bs, 2H), 8.66 (m, 1H),



7.96 (m, 2H), 7.89 (m, 1H); 7.75 (m, 1H), 5.84 (bs, 1H), 4.28



(m, 2H), 4.07 (s, 2H), 3.65 (m, 2H); 3.45 (m, 1H), 1.84 (m, 4H),



1.64 (m, 4H). MS: m/z 397.2 (M − H+).









Example 2
Determination of the Effect of Indenoisoquinolinone Analogs on in vitro PARP Activity

The ability of an illustrative Indenoisoquinolinone Analog to inhibit PARP and prevent peroxynitrite induced cytotoxicity can be demonstrated using methods described in Virag et al., Br. J. Pharmacol. 1999, 126(3):769-77; and Immunology 1998, 94(3):345-55.


The potency of inhibition of purified PARP enzyme can be subsequently determined for selected Indenoisoquinolinone Analogs, and the potency is compared with that of 3-aminobenzamide, a prototypical benchmark PARP inhibitor. The assay is performed in 96 well ELISA plates according to instructions provided with a commercially available PARP inhibition assay kit (for example, from Trevigen, Gaithersburg, Md.).


Example 3
Determination of the Effect of Indenoisoquinolinone Analogs in an In Vitro Model of Cell Death

Using an in vitro, oxidant-stimulated thymocyte assay (described, in detail, in Virag et al., Immunology 94(3):345-55, 1998), an illustrative Indenoisoquinolinone Analog can be tested for its ability to prevent the oxidant-induced suppression of the viability of the cells and as such, this assay represents an in vitro model of reperfusion related cell death in ischemic organs.


Example 4
Determination of the Effect of Indenoisoquinolinone Analogs on in vivo Models of Inflammatory Diseases

The effect of an illustrative Indenoisoquinolinone Analog can be determined using a systemic inflammatory model induced by bacterial lipopolysaccharide (LPS), which is reported to be responsible for causing reperfusion injurys and inflammatory diseases such as septic shock and systemic inflammatory response syndrome in animals (see Parrillo, N. Engl. J. Med., 328:1471-1478 (1993) and Lamping, J. Clin. Invest. 101:2065-2071 (1998).


Example 5
Determination of the Effect of Indenoisoquinolinone Analogs on In Vivo Models of Reperfusion injury

The efficacy of an illustrative Indenoisoquinolinone Analog in a mouse model of ischemic and reperfused gut can be determined according to the method described in Liaudet et al., Shock 2000, 14(2):134-41.


In another set of experiments, the effect of an illustrative Indenoisoquinolinone Analog in a rat model of middle cerebral artery occlusion/reperfusion can be assayed as described in Abdelkarim et al, Int. J. Mol. Med. 2001, 7(3):255-60.


Example 6
Determination of the Effect of Indenoisoquinolinone Analogs in an In Vivo Model of Diabetes Mellitus

PARP inhibitors and PARP deficiency are known to reduce the development of diabetes mellitus and the incidence of diabetic complications. The anti-diabetic effect of an illustrative Indenoisoquinolinone Analog can be determined using a single high-dose streptozotocin model of diabetes mellitus, which can be used as conducted as described in Mabley et al., Br. J. Pharmacol. 2001, 133(6):909-9; and Soriano et al., Nat. Med. 2001, 7(1): 108-13. Briefly, 160 mg/kg streptozotocin is injected to mice treated with vehicle (control) or with an illustrative Indenoisoquinolinone Analog intraperitoneally (3 mg/kg) and 3 days later blood sugar levels are determined using a blood glucose meter.


Example 7
Determination of the Effect of Indenoisoquinolinone Analogs in an In Vivo Model of Erectile Dysfunction

Experiments are conducted in male Sprague-Dawley rats according to previously published methods for forceps-induced nerve crush injury and erectile function measurements (Rehman, J., et al., Urology 51:640-644, 1998; Sezen, S. F., et al., Int. J. Impot. Res. 14:506-12, 2002). Subjects are anesthetized with Phenobarbital. The prostate of the subjects is exposed and the cavernosal nerve is clipped on either side with a forceps to induce mechanical injury (crush). This rat model mimics the nerve injury that develops during human male prostatectomy, leading to nerve injury and subsequent erectile dysfunction. Subjects are studied 2 weeks after the injury. Two groups of subjects are used, one group treated with vehicle and one group treated with an illustrative Indenoisoquinolinone Analog. The illustrative Indenoisoquinolinone Analog is injected at 30 mg/kg i.v. immediately before the crush injury, and on the following day at the same dose. Thereafter, for 12 days, subjects are treated with 60 mg/kg of the illustrative Indenoisoquinolinone Analog intraperitoneally. At 2 weeks, subjects are re-anesthetized and measured for mean arterial blood pressure (MAP) and intracavernosal pressure (ICP). Cavernosal nerve stimulation is conducted at 5 and 7.5 V using a square pulse stimulator for 30 msec. ICP is determined as the area under curve (mmHg×sec). In addition, IPC/MAP ratios are determined.


Example 8
Effect of Indenoisoquinolinone Analogs on PARP Activity in Cultured Macrophages, Using a Whole-Cell Based Assay

Demonstration of Indenoisoquinolinone Analogs' ability to inhibit PARP and prevent peroxynitrite induced cytotoxicity was shown using methods described in Virag et al., Br. J. Pharmacol. 1999, 126(3):769-77; and Immunology 1998, 94(3):345-55. The murine RAW macrophages (ATCC, American Type Culture Collection, Manassas, Va.) were grown in RPMI 1650 (Invitrogen Life Technologies; Carlsbad, Calif.) medium supplemented with 10% heat-inactivated FBS, 2 mM L-glutamine, and 100 U/ml of penicillin and streptomycin. Cells, between passages 5 and 15, were seeded at a density of 250,000 cells/well in 12 well plates and allowed to grow 48 hours before use. Growth medium was changed on the day of use. Cells were treated with an Indenoisoquinolinone Analog diluted in a growth medium supplemented with 10% fetal bovine serum (FBS) for 1 hour prior to the addition of hydrogen peroxide (0.5 mM) for a further 25 minutes. For the measurement of PARP activity, media was removed and replaced with 0.5 ml of the assay buffer (56 mM HEPES-pH 7.5, 28 mM KCl, 28 mM NaCl, 2 mM MgCl2, 0.01% digitonin, and 0.5 μCi/ml of 3H-NAD+) for 20 minutes. After aspirating the assay buffer, cells were lysed and transferred to eppendorf tubes containing 250 μl of 50% ice-cold trichloroacetic acid (TCA), which were then placed at 4° C. for 4 hours. Samples were centrifuged at 10,000 g for 10 minutes and supernatant removed. The pellets were washed twice with 500 μl of ice-cold 5% w/v TCA. The pellets were then solubilized in 250 μl of NaOH (0.1 M) containing 2% SDS overnight at 37° C. and the PARP activity was then determined by measuring the radioactivity incorporated using a Wallac scintillation counter. The solubilized protein (250 μl) was mixed with 5 ml of scintillation fluid (ScintiSafe Plus, Fisher Scientific) before being counted for 3 minutes. EC50 values were determined from a dose-response curve.











TABLE 4






Compound
EC50 value [nM]


















IIa-1
20



IIa-14
30



IIa-27
<10



IIIa-2
25



IIIa-3
20



IIIa-4
15



IIIa-5
40



IIIa-6
50



IIIa-7
60



IIIa-8
75



IIIa-9
60



IIIa-10
60



IIIa-11
12



IIIa-12
7



IIb-1
45



IIb-53
>50



IIb-66
45



IIb-79
>60



IIb-92
>60



IIb-105
100



IIb-118
60



IIb-170
75



IIb-131
75



IIb-196
75



IIb-183
100



IIb-157
75



IIIb-1
20



IIIb-2
25



Dihydrochloride
10



salt of IIIb-3




IIIb-8
75



IIIb-9
20



IIIb-10
75



IIIb-13
25



Dihydrochloride
20



salt of IIIb-14




Methylsulfonate
55



salt of IIIb-15




IIIb-16
>100



IIIb-17
100



IIIb-18
75



IIIb-19
30



Dihydrochloride
100



salt of IIIb-20




IIIb-21
100



IIIb-22
>100



IIIb-24
>60



IIIa-1
45



IIb-23
80



Va-1
>100



Va-3
9



Va-4
4



Va-5
5



Va-7
5



Va-9
3



Va-10
3









The present invention is not to be limited in scope by the specific embodiments disclosed in the examples, which are intended as illustrations of a few aspects of the invention and any embodiments that are functionally equivalent are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims.


A number of references have been cited, the entire disclosures of which have been incorporated herein in their entirety.

Claims
  • 1. A compound having the formula:
  • 2. The compound or a pharmaceutically acceptable salt of the compound of claim 1, wherein at least one R2 is —C1-C6 alkyl or —C3-C8 monocyclic cycloalkyl.
  • 3. The compound or a pharmaceutically acceptable salt of the compound of claim 1, wherein n is 1.
  • 4. The compound or a pharmaceutically acceptable salt of the compound of claim 1, wherein each R2 is independently —C1-C6 alkyl.
  • 5. The compound or a pharmaceutically acceptable salt of the compound of claim 1, wherein one R2 is —H.
  • 6. A compound having the formula:
  • 7. The compound or a pharmaceutically acceptable salt of the compound of claim 6, wherein at least one R2 is —C1-C6 alkyl or —C3-C8 monocyclic cycloalkyl.
  • 8. The compound or a pharmaceutically acceptable salt of the compound of claim 6, wherein n is 1.
  • 9. The compound or a pharmaceutically acceptable salt of the compound of claim 6, wherein each R2 is independently —C1-C6 alkyl.
  • 10. The compound or a pharmaceutically acceptable salt of the compound of claim 6, wherein one R2 is —H.
  • 11. A compound having the formula:
  • 12. The compound or a pharmaceutically acceptable salt of the compound of claim 11, wherein at least one R2 is —C1-C6 alkyl or —C3-C8 monocyclic cycloalkyl.
  • 13. The compound or a pharmaceutically acceptable salt of the compound of claim 11, wherein n is 1.
  • 14. The compound or a pharmaceutically acceptable salt of the compound of claim 11, wherein each R2 is independently —C1-C6 alkyl.
  • 15. The compound or a pharmaceutically acceptable salt of the compound of claim 11, wherein one R2 is —H.
  • 16. A compound having the formula:
  • 17. The compound or a pharmaceutically acceptable salt of the compound of claim 16, wherein R2 is —H, and R3 is a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one or more of —C(O)O—C1-C6 alkyl groups.
  • 18. The compound or a pharmaceutically acceptable salt of the compound of claim 16, wherein R3 is —C3-C8 monocyclic cycloalkyl which is substituted with one or more of hydroxy-substituted C1-C5 alkyl groups.
  • 19. The compound or a pharmaceutically acceptable salt of the compound of claim 16, wherein R3 is —C(O)—C1-C6 alkylene-3- to 7-membered monocyclic heterocycle.
  • 20. A compound having the formula:
  • 21. The compound or a pharmaceutically acceptable salt of the compound of claim 20, wherein R2 is —H, and R3 is a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one or more of —C(O)O—C1-C6 alkyl groups.
  • 22. The compound or a pharmaceutically acceptable salt of the compound of claim 20, wherein R3 is —C3-C8 monocyclic cycloalkyl which is substituted with one or more of hydroxy-substituted C1-C5 alkyl groups.
  • 23. The compound or a pharmaceutically acceptable salt of the compound of claim 20, wherein R3 is —C(O)—C1-C6 alkylene-3- to 7-membered monocyclic heterocycle.
  • 24. A compound having the formula:
  • 25. The compound or a pharmaceutically acceptable salt of the compound of claim 24, wherein R2 is —H, and R3 is a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is substituted with one or more of —C(O)O—C1-C6 alkyl groups.
  • 26. The compound or a pharmaceutically acceptable salt of the compound of claim 24, wherein R3 is —C3-C8 monocyclic cycloalkyl which is substituted with one or more of hydroxy-substituted C1-C5 alkyl groups.
  • 27. The compound or a pharmaceutically acceptable salt of the compound of claim 24, wherein R3 is —C(O)—C1-C6 alkylene-3- to 7-membered monocyclic heterocycle.
  • 28. A composition comprising a physiologically acceptable carrier or vehicle and an effective amount of a compound or a pharmaceutically acceptable salt of a compound of claim 1.
  • 29. A composition comprising a physiologically acceptable carrier or vehicle and an effective amount of a compound or a pharmaceutically acceptable salt of a compound of claim 6.
  • 30. A composition comprising a physiologically acceptable carrier or vehicle and an effective amount of a compound or a pharmaceutically acceptable salt of a compound of claim 11.
  • 31. A composition comprising a physiologically acceptable carrier or vehicle and an effective amount of a compound or a pharmaceutically acceptable salt of a compound of claim 16.
  • 32. A composition comprising a physiologically acceptable carrier or vehicle and an effective amount of a compound or a pharmaceutically acceptable salt of a compound of claim 20.
  • 33. A composition comprising a physiologically acceptable carrier or vehicle and an effective amount of a compound or a pharmaceutically acceptable salt of a compound of claim 24.
  • 34. A compound having the formula:
  • 35. A compound having the formula:
  • 36. A compound having the formula:
  • 37. A composition comprising a physiologically acceptable carrier or vehicle and an effective amount of a compound or a pharmaceutically acceptable salt of a compound of claim 36.
  • 38. A composition comprising a physiologically acceptable carrier or vehicle and an effective amount of a compound or a pharmaceutically acceptable salt of a compound of claim 34.
  • 39. A composition comprising a physiologically acceptable carrier or vehicle and an effective amount of a compound or a pharmaceutically acceptable salt of a compound of claim 35.
  • 40. A compound having the formula:
  • 41. The compound or a pharmaceutically acceptable salt of the compound of claim 40 wherein R2 is tetrahydropyranyl; or cyclopentyl which is unsubstituted or substituted with one or more of -(hydroxyl-substituted) C1-C5 alkyl.
  • 42. The compound or a pharmaceutically acceptable salt of the compound of claim 40 wherein one of X and Y′ is fluoro.
  • 43. A composition comprising a physiologically acceptable carrier or vehicle and an effective amount of a compound or a pharmaceutically acceptable salt of a compound of claim 40.
1. REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No. 60/904,393, filed on Feb. 28, 2007, the disclosure of which is incorporated by reference herein in its entirety.

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Related Publications (1)
Number Date Country
20100004220 A1 Jan 2010 US
Provisional Applications (1)
Number Date Country
60904393 Feb 2007 US