2,4-pyrimidinediamine Compounds And Uses As Anti-proliferative Agents

  • Published: Aug 4, 2011
  • Earliest Priority: Aug 07 2003
  • Family: 20
  • Cited Works: 7
  • Cited by: 7
  • Cites: 7
  • Additional Info: Cited Works Full text
  *US20110190271A1*
  US20110190271A1                                 
(19)United States 
(12)Patent Application Publication(10)Pub. No.: US 2011/0190271 A1
 Argade et al.(43)Pub. Date:Aug.  4, 2011

(54)2,4-Pyrimidinediamine Compounds and Uses as Anti-Proliferative Agents 
    
(75)Inventors: Ankush Argade,  Foster City, CA (US); 
  Rajinder Singh,  Belmont, CA (US); 
  Hui Li,  Santa Clara, CA (US); 
  David Carroll,  San Francisco, CA (US); 
  Susan Catalano,  Hayward, CA (US) 
(73)Assignee:RIGEL PHARMACEUTICALS, INC.,  South San Francisco, CA (US), Type: US Company 
(21)Appl. No.: 12/981,094 
(22)Filed: Dec.  29, 2010 
 Related U.S. Application Data 
(63) .
Continuation of application No. 11/567,820, filed on Dec.  7, 2006, now Pat. No. 7,884,111 , which is a continuation of application No. 10/913,270, filed on Aug.  6, 2004, now abandoned .
 
(60)Provisional application No. 60/494,008, filed on Aug.  7, 2003.
 
 Provisional application No. 60/572,534, filed on May  18, 2004.
 
 Publication Classification 
(51)Int. Cl. A61K 031/551 (20060101); A61K 031/5377 (20060101); A61K 031/506 (20060101); A61K 031/496 (20060101); A61K 031/538 (20060101); A61K 031/5415 (20060101); A61K 031/5383 (20060101); A61P 035/00 (20060101)
(52)U.S. Cl. 514/218; 514/235.8; 514/275; 514/252.14; 514/252.18; 514/252.19; 514/230.5; 514/224.2

        

(57)

Abstract

The present invention provides 2,4-pyrimidinediamine compounds having antiproliferative activity, compositions comprising the compounds and methods of using the compounds to inhibit cellular proliferation and to treat proliferative diseases such as tumorigenic cancers.
 Claim(s),  Drawing Sheet(s), and Figure(s)
 
 

1. CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation of U.S. application Ser. No. 11/567,820, filed Dec. 7, 2006, which is a continuation of U.S. application Ser. No. 10/913,270, filed Aug. 6, 2004, now abandoned, which claims benefit to U.S. Provisional Application Ser. No. 60/494,008, filed Aug. 7, 2003 and provisional application Ser. No. 60/572,534, filed May 18, 2004.

2. FIELD

[0002] The present invention relates to 2,4 pyrimidinediamine compounds that exhibit antiproliferative activity, prodrugs of the compounds, intermediates and methods of synthesis for making the compounds and/or prodrugs, pharmaceutical compositions comprising the compounds and the use of the compounds in a variety of contexts, including for the treatment of proliferative disorders, such as, for example, tumors and cancers.

3. BACKGROUND

[0003] Cancer is a group of varied diseases characterized by uncontrolled growth and spread of abornmal cells. Generally, all types of cancers involve some abnormality in the control of cell growth and division. The pathways regulating cell division and/or cellular communication become altered in cancer cells such that the effects of these regulatory mechanisms in controlling and limiting cell growth fails or is bypassed. Through successive rounds of mutation and natural selection, a group of abnormal cells, generally originating from a single mutant cell, accumulates additional mutations that provide selective growth advantage over other cells, and thus evolves into a cell type that predominates in the cell mass. This process of mutation and natural selection is enhanced by genetic instability displayed by many types of cancer cells, an instability which is gained either from somatic mutations or by inheritance from the germ line. The enhanced mutability of cancerous cells increases the probability of their progression towards formation of malignant cells. As the cancer cells further evolve, some become locally invasive and then metastasize to colonize tissues other than the cancer cell's tissue of origin. This property along with the heterogeneity of the tumor cell population makes cancer a particularly difficult disease to treat and eradicate.
[0004] Traditional cancer treatments take advantage of the higher proliferative capacity of cancer cells and their increased sensitivity to DNA damage. Ionizing radiation, including γ-rays and x-rays, and cytotoxic agents, such as bleomycin, cis-platin, vinblastine, cyclophosphamide, 5′-fluorouracil, and methotrexate rely upon a generalized damage to DNA and destabilization of chromosomal structure which eventually lead to destruction of cancer cells. These treatments are particularly effective for those types of cancers that have defects in cell cycle checkpoint, which limits the ability of these cells to repair damaged DNA before undergoing cell division. The non-selective nature of these treatments, however, often results in severe and debilitating side effects. The systemic use of these drugs may result in damage to normally healthy organs and tissues, and compromise the long term health of the patient.
[0005] Although more selective chemotherapeutic treatments have been developed based on knowledge of how cancer cells develop, for example, the anti-estrogen compound tamoxifen, the effectiveness of all chemotherapeutic treatments are subject to development of resistance to the drugs. In particular, the increased expression of cell membrane bound transporters, such as MdrI, produces a multidrug resistance phenotype characterized by increased efflux of drugs from the cell. These types of adaptation by cancer cells severely limit the effectiveness of certain classes of chemotherapeutic agents. Consequently, identification of other chemotherapeutic agents is critical for establishing therapies effective for attacking the heterogeneous nature of proliferative disease and for overcoming any resistance that may develop over the course of therapy with other compounds. Moreover, use of combinations of chemotherapeutic agents with differing properties and cellular targets increases the effectiveness of chemotherapy and limits the generation of drug resistance.

4. SUMMARY

[0006] In one aspect, the present invention provides 2,4-pyrimidinediamine compounds that exhibit antiproliferative activity against a variety of different cell types, including a variety of different types of tumor cells. The compounds are generally 2,4-pyrimidinediamine compounds according to structural formula (I):
[see pdf for image]
[0007] including salts, hydrates, solvates and N-oxides thereof, wherein:
[0008] L1 and L2 are each, independently of one another, selected from a lower alkyldiyl linker, a lower alkylene linker and a covalent bond;
[0009] R2 is selected from the group consisting of lower alkyl optionally substituted with an Rb group,
[see pdf for image]
where Y is NH, O or CH2;
[0010] R2′ is hydrogen, methyl or lower alkyl;
[0011] R4′ is hydrogen, methyl or lower alkyl;
[0012] R4 is selected from the group consisting of lower alkyl optionally monosubstituted with an Ra or Rb group, lower cycloalkyl optionally monosubstituted with an Ra or Rb group, lower cycloheteroalkyl optionally substituted at one or more ring carbon and/or heteroatoms with an Ra or Rb group, —(CRaRa)n—Rb.
[see pdf for image]
where D is —(CR7R7)m—.
[see pdf for image]
where Z1 is N or CH and Z2 is O, S, NH, S(O) or S(O)2;
[0013] R5 is selected from the group consisting of halo, fluoro and —CF3;
[0014] R6 is hydrogen;
[0015] each R7 is independently selected from the group consisting of hydrogen, methyl, lower alkyl and halo;
[0016] each R8 is independently selected from the group consisting of hydrogen, lower alkyl, —(CH2)n—OH, —ORa, —(CH2)n—NRcRc, —O(CH2)n—Ra, —O(CH2)n—Rb, —C(O)ORa, —C(S)ORa′ halo, —CF3 and —OCF3;
[0017] each R9 is independently selected from the group consisting of hydrogen, lower alkyl, —ORa, —(CH2)n—NRcRc, —O(CH2)n—Ra, —O(CH2)n—Rb, —C(O)—NRcRc, —C(S)—NRcRc, —S(O)2—NRcRc, —NHC(O)Ra, —NHC(S)Ra, —C(O)—NH—(CH2)n—NRcRc, —C(S)—NH—(CH2)n—NRcRc, halo, —CF3, —OCF3,
[see pdf for image]
[0018] each R10 is independently selected from the group consisting of hydrogen, lower alkyl, —(CH2)n—OH, —(CH2)n—NRcRc, —ORa, —O(CH2)n—Ra, —O(CH2)n—Rb, halo, —CF3, —OCF3,
[see pdf for image]
[0019] each R11 is independently selected from the group consisting of —ORa, —NRcRc and —NRaRd;
[0020] each R12 is independently selected from the group consisting of lower alkyl, arylalkyl, —ORa, —NRcRc, —C(O)Ra, —C(O)ORa and —C(O)NRcRc;
[0021] each R13 is independently selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, methoxy, —C(O)NRcRc and —C(O)NH2;
[0022] each R15 is independently selected from the group consisting of hydrogen, lower alkyl, lower cycloakyl and phenyl;
[0023] each R16 is independently selected from the group consisting of hydrogen, methyl, lower alkyl, lower cycloalkyl, lower branched alkyl and lower cycloalkylmethyl;
[0024] each R17 is independently selected from the group consisting of hydrogen, lower alkyl, methyl and Rd or, alternatively, R17 may be taken together with R18 to form an oxo (═O) group;
[0025] each R18 is independently selected from the group consisting of hydrogen, lower alkyl and methyl or, alternatively, R18 may be taken together with R17 to form an oxo (═O) group;
[0026] each R19 is independently selected form the group consisting of hydrogen, lower alkyl, methyl and Rd;
[0027] each R20 is independently selected from the group consisting of hydrogen, lower alkyl, methyl and Rd;
[0028] each m is independently an integer from 1 to 3;
[0029] each n is independently an integer from 1 to 3;
[0030] each Ra is independently selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl, lower cycloalkylalkyl, phenyl and benzyl;
[0031] each Rb is independently selected from the group consisting of —ORa, —CF3, —OCF3, —NRcRc, —C(O)Ra, —C(S)Ra, —C(O)ORa, —C(S)ORa, —C(O)NRcRc, —C(S)NRcRc, —S(O)2NRcRc, —C(O)NRaRd, —C(S)NRaRd and —S(O)2NRaRd;
[0032] each Rc is independently selected from the group consisting of hydrogen, lower alkyl and lower cycloalkyl, or, alternatively, two Rcs may be taken together with the nitrogen atom to which they are bonded to form a 5-7 membered saturated ring which optionally includes 1-2 additional heteroatomic groups selected from O, NRa, NRa—C(O)Ra, NRa—C(O)ORa and NRa—C(O)NRa; and
[0033] each Rd is independently selected from lower mono-hydroxyalkyl and lower di-hydroxyalkyl.
[0034] In another aspect, the present invention provides prodrugs of the 2,4-pyrimidinediamine compounds. Such prodrugs may be active in their prodrug form, or may be inactive until converted under physiological or other conditions of use to an active drug form. In the prodrugs, one or more functional groups of the 2,4-pyrimidinediamine compounds are included in promoieties that cleave from the molecule under the conditions of use, typically by way of hydrolysis, enzymatic cleavage or some other cleavage mechanism, to yield the functional groups. For example, primary or secondary amino groups may be included in an amide promoiety that cleaves under conditions of use to generate the primary or secondary amino group. Thus, the prodrugs include special types of protecting groups, termed “progroups,” masking one or more functional groups of the 2,4-pyrimidinediamine compounds that cleave under the conditions of use to yield an active 2,4-pyrimidinediamine drug compound. Functional groups within the 2,4-pyrimidinediamine compounds that may be masked with progroups for inclusion in a promoiety include, but are not limited to, amines (primary and secondary), hydroxyls, sulfanyls (thiols), carboxyls, carbonyls, phenols, catechols, diols, alkynes, phosphates, etc. Myriad progroups suitable for masking such functional groups to yield promoieties that are cleavable under the desired conditions of use are known in the art. All of these progroups, alone or in combinations, may be included in the prodrugs. Specific examples of promoieties that yield primary or secondary amine groups that can be included in the prodrugs include, but are not limited to amides, carbamates, imines, ureas, phosphenyls, phosphoryls and sulfenyls. Specific examples of promoieties that yield sulfanyl groups that can be included in the prodrugs include, but are not limited to, thioethers, for example S-methyl derivatives (monothio, dithio, oxythio, aminothio acetals), silyl thioethers, thioesters, thiocarbonates, thiocarbamates, asymmetrical disulfides, etc. Specific examples of promoieties that cleave to yield hydroxyl groups that can be included in the prodrugs include, but are not limited to, sulfonates, esters and carbonates. Specific examples of promoieties that yield carboxyl groups that can be included in the prodrugs include, but are not limited to, esters (including silyl esters, oxamic acid esters and thioesters), amides and hydrazides.
[0035] In another aspect, the present invention provides compositions comprising one or more 2,4-pyrimidinediamine compounds and/or prodrugs and an appropriate carrier, excipient and/or diluent. The exact nature of the carrier, excipient and/or diluent will depend upon the desired use for the composition, and may range from being suitable or acceptable for veterinary uses to being suitable or acceptable for human use.
[0036] The 2,4-pyrimidinediamine compounds are potent inhibitors of proliferation abnormal cells, such as tumor cell proliferation, in in vitro assays. Thus, in still another aspect, the present invention provides methods of inhibiting proliferation of abnormal cells, in particular tumor cells. The method generally involves contacting an abnormal cell such as a tumor cells with an amount of a 2,4-pyrimidinediamine compound or prodrug, or an acceptable salt, hydrate, solvate, N-oxide and/or composition thereof, effective to inhibit its proliferation. The method may be practiced in in vitro contexts or in in vivo contexts as a therapeutic approach towards the treatment or prevention of proliferative disorders, such as tumorigenic cancers.
[0037] In still another aspect, the present invention provides methods of treating proliferative disorders. The methods may be practiced in animals in veterinary contexts or in humans. The methods generally involve administering to an animal or human subject an amount of a 2,4-pyrimidinediamine compound or prodrug, or an acceptable salt, hydrate, solvate, N-oxide and/or composition thereof, effective to treat the disorder. Proliferative disorders that can be treated according to the methods include, but are not limited to, tumorigenic cancers.
[0038] Other aspects of the present invention include, but are not limited to, intermediates and methods useful for synthesizing the compound and prodrugs, as will be described in more detail herein below.

5. DETAILED DESCRIPTION

5.1 Definitions

[0039] As used herein, the following terms are intended to have the following meanings:
[0040] “Alkyl” by itself or as part of another substituent refers to a saturated or unsaturated branched, straight-chain or cyclic monovalent hydrocarbon radical having the stated number of carbon atoms (i.e., C1-C6 means one to six carbon atoms) that is derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene or alkyne. Typical alkyl groups include, but are not limited to, methyl; ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl, propan-2-yl, cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl, prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl, but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like. Where specific levels of saturation are intended, the nomenclature “alkanyl,” “alkenyl” and/or “alkynyl” is used, as defined below. “Lower alkyl” refers to alkyl groups having from 1 to 8 carbon atoms.
[0041] “Alkanyl” by itself or as part of another substituent refers to a saturated branched, straight-chain or cyclic alkyl derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Typical alkanyl groups include, but are not limited to, methanyl; ethanyl; propanyls such as propan-1-yl, propan-2-yl (isopropyl), cyclopropan-1-yl, etc.; butanyls such as butan-1-yl, butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl), 2-methyl-propan-2-yl (t-butyl), cyclobutan-1-yl, etc.; and the like.
[0042] “Alkenyl” by itself or as part of another substituent refers to an unsaturated branched, straight-chain or cyclic alkyl having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene. The group may be in either the cis or trans conformation about the double bond(s). Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl, prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.; and the like.
[0043] “Alkynyl” by itself or as part of another substituent refers to an unsaturated branched, straight-chain or cyclic alkyl having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne. Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.
[0044] “Alkyldiyl” by itself or as part of another substituent refers to a saturated or unsaturated, branched, straight-chain or cyclic divalent hydrocarbon group having the stated number of carbon atoms (i.e., C1-C1 means from one to six carbon atoms) derived by the removal of one hydrogen atom from each of two different carbon atoms of a parent alkane, alkene or alkyne, or by the removal of two hydrogen atoms from a single carbon atom of a parent alkane, alkene or alkyne. The two monovalent radical centers or each valency of the divalent radical center can form bonds with the same or different atoms. Typical alkyldiyl groups include, but are not limited to, methandiyl; ethyldiyls such as ethan-1,1-diyl, ethan-1,2-diyl, ethen-1,1-diyl, ethen-1,2-diyl; propyldiyls such as propan-1,1-diyl, propan-1,2-diyl, propan-2,2-diyl, propan-1,3-diyl, cyclopropan-1,1-diyl, cyclopropan-1,2-diyl, prop-1-en-1,1-diyl, prop-1-en-1,2-diyl, prop-2-en-1,2-diyl, prop-1-en-1,3-diyl, cycloprop-1-en-1,2-diyl, cycloprop-2-en-1,2-diyl, cycloprop-2-en-1,1-diyl, prop-1-yn-1,3-diyl, etc.; butyldiyls such as, butan-1,1-diyl, butan-1,2-diyl, butan-1,3-diyl, butan-1,4-diyl, butan-2,2-diyl, 2-methyl-propan-1,1-diyl, 2-methyl-propan-1,2-diyl, cyclobutan-1,1-diyl; cyclobutan-1,2-diyl, cyclobutan-1,3-diyl, but-1-en-1,1-diyl, but-1-en-1,2-diyl, but-1-en-1,3-diyl, but-1-en-1,4-diyl, 2-methyl-prop-1-en-1,1-diyl, 2-methanylidene-propan-1,1-diyl, buta-1,3-dien-1,1-diyl, buta-1,3-dien-1,2-diyl, buta-1,3-dien-1,3-diyl, buta-1,3-dien-1,4-diyl, cyclobut-1-en-1,2-diyl, cyclobut-1-en-1,3-diyl, cyclobut-2-en-1,2-diyl, cyclobuta-1,3-dien-1,2-diyl, cyclobuta-1,3-dien-1,3-diyl, but-1-yn-1,3-diyl, but-1-yn-1,4-diyl, buta-1,3-diyn-1,4-diyl, etc.; and the like. Where specific levels of saturation are intended, the nomenclature alkanyldiyl, alkenyldiyl and/or alkynyldiyl is used. Where it is specifically intended that the two valencies are on the same carbon atom, the nomenclature “alkylidene” is used. A “lower alkyldiyl” is an alkyldiyl group having from 1 to 6 carbon atoms. In preferred embodiments the alkyldiyl groups are saturated acyclic alkanyldiyl groups in which the radical centers are at the terminal carbons, e.g., methandiyl (methano); ethan-1,2-diyl (ethano); propan-1,3-diyl (propano); butan-1,4-diyl (butano); and the like (also referred to as alkylenes, defined infra).
[0045] “Alkylene” by itself or as part of another substituent refers to a straight-chain saturated or unsaturated alkyldiyl group having two terminal monovalent radical centers derived by the removal of one hydrogen atom from each of the two terminal carbon atoms of straight-chain parent alkane, alkene or alkyne. The locant of a double bond or triple bond, if present, in a particular alkylene is indicated in square brackets. Typical alkylene groups include, but are not limited to, methylene (methano); ethylenes such as ethano, etheno, ethyno; propylenes such as propano, prop[1]eno, propa[1,2]dieno, prop[1]yno, etc.; butylenes such as butano, but[1]eno, but[2]eno, buta[1,3]dieno, but[1]yno, but[2]yno, buta[1,3]diyno, etc.; and the like. Where specific levels of saturation are intended, the nomenclature alkano, alkeno and/or alkyno is used. In preferred embodiments, the alkylene group is (C1-C6) or (C1-C3) alkylene. Also preferred are straight-chain saturated alkano groups, e.g., methano, ethano, propano, butano, and the like.
[0046] “Cycloalkyl” by itself or as part of another substituent refers to a cyclic version of an “alkyl” group. Typical cycloalkyl groups include, but are not limited to, cyclopropyl; cyclobutyls such as cyclobutanyl and cyclobutenyl; cyclopentyls such as cyclopentanyl and cyclopentenyl; cyclohexyls such as cyclohexanyl and cyclohexenyl; and the like. “Lower cycloalkyl” refers to a cycloalkyl group having from 3 to 8 ring carbon atoms.
[0047] “Cycloalkylalkyl” by itself or as part of another substitutent refers to an alkyl group that comprises a linear or branched portion and a cyclic portion. Typical cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, 1-cyclopropyleth-1-yl, 2-cyclopropyleth-1-yl, cyclobutylmethyl, 1-cyclobytyleth-1-yl, 2-cyclobutyleth-1-yl, cyclopentylmethyl, 1-cyclopentyleth-1-yl, 2-cyclopentyleth-1-yl, cyclohexylmethyl, 1-cyclohexyleth-1-yl, 2-cyclohexleth-1-yl, and the like. “Lower cycloalkylalkyl” refers to a cycloalkylalkyl group in which the linear or branched portion contains from 1 to 4 carbon atoms and the cyclic portion contains from 3 to 8 carbon atoms.
[0048] “Heteroalkyl” by itself or as part of another substituent refers to an alkyl group in which at least one of the carbon atoms is replaced with a heteroatom, for example, a heteroatom selected from O, S and N. In heteroalkyl groups including more than one heteroatom, the heteroatoms may be the same or they may be different. Like an alkyl group, a heteroalkyl can be linear, branched or cyclic in structure, and can be saturated or unsaturated. Typical heteralkyl groups include, but are not limited to, —CH2—O—CH2—, —CH2—S—CH2—, —CH2—NH—CH2—, —CH2—N(CH3)—CH2—,
[see pdf for image]
—CH2CH2—O—CH2—, —CH2CH2—S—CH2—, —CH2CH2—NH—CH2—, —CH2CH2—N(CH3)—CH2—,
[see pdf for image]
—CH2CH(CH3)—O—CH2—, —CH2CH(CH3)—S—CH2—, —CH2CH(CH3)—NH—CH2—, —CH2CH(CH3)—N(CH3)—CH2—,
[see pdf for image]

—CH═CH—O—CH2—, —CH═CH—S—CH2—, —CH═CH—NH—CH2—, —CH═CH—N(CH3)—CH2—,

[0049]  [see pdf for image]
—C≡C—N(CH3)—CH2—, —C≡C—S—CH2, —C≡C—N(CH3)—CH2—, and the like. Where specific levels of saturation are intended, the nomenclature “heteroalkanyl,” “heteroalkenyl,” and heteroalkynyl” is used. “Lower heteroalkyl” refers to a heteroalkyl group having from 1 to 8 carbon and heteroatoms.
[0050] “Cycloheteroalkyl” by itself or as part of another substituent refers to a cyclic version of a heteroalkyl. Typical examples of cycloheteroalkyl groups include, but are not limited to,
[see pdf for image]
and the like. “Lower cycloheteroalkyl” refers to a cycloheteroalkyl group having from 3 to 8 ring atoms.
[0051] “Parent Aromatic Ring System” refers to an unsaturated cyclic or polycyclic ring system having a conjugated it electron system. Specifically included within the definition of “parent aromatic ring system” are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, fluorene, indane, indene, phenalene, tetrahydronaphthalene, etc. Typical parent aromatic ring systems include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexylene, indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, tetrahydronaphthalene, triphenylene, trinaphthalene, and the like, as well as the various hydro isomers thereof.
[0052] “Aryl” by itself or as part of another substituent refers to a monovalent aromatic hydrocarbon group having the stated number of carbon atoms (i.e., C5-C15 means from 5 to 15 carbon atoms) derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexylene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like, as well as the various hydro isomers thereof. In preferred embodiments, the aryl group is (C5-C15) aryl, with (C5-C10) being even more preferred. Particularly preferred aryls are phenyl and naphthyl.
[0053] “Halogen” or “Halo” by themselves or as part of another substituent, unless otherwise stated, refer to fluoro, chloro, bromo and iodo.
[0054] “Haloalkyl” by itself or as part of another substituent refers to an alkyl group in which one or more of the hydrogen atoms is replaced with a halogen. Thus, the term “haloalkyl” is meant to include monohaloalkyls, dihaloalkyls, trihaloalkyls, etc. up to perhaloalkyls. For example, the expression “(C1-C2) haloalkyl” includes fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 1,1,1-trifluoroethyl, perfluoroethyl, etc.
[0055] The above-defined groups may include prefixes and/or suffixes that are commonly used in the art to create additional well-recognized substituent groups. As non-limiting examples, “alkyloxy” or “alkoxy” refers to a group of the formula —OR, “alkylamine” refers to a group of the formula —NHR and “dialkylamine” refers to a group of the formula —NRR, where each R is independently an alkyl. As another non-limiting example, “haloalkoxy” or “haloalkyloxy” refers to a group of the formula —OR′, where R′ is a haloalkyl.
[0056] “Prodrug” refers to a derivative of an active 2,4-pyrimidinediamine compound (drug) that may require a transformation under the conditions of use, such as within the body, to release the active 2,4-pyrimidinediamine drug. Prodrugs are frequently, but not necessarily, pharmacologically inactive until converted into the active drug. Prodrugs are typically obtained by masking a functional group in the 2,4-pyrimidinediamine drug believed to be in part required for activity with a progroup (defined below) to form a promoiety which undergoes a transformation, such as cleavage, under the specified conditions of use to release the functional group, and hence the active 2,4-pyrimidinediamine drug. The cleavage of the promoiety may proceed spontaneously, such as by way of a hydrolysis reaction, or it may be catalyzed or induced by another agent, such as by an enzyme, by light, by acid or base, or by a change of or exposure to a physical or environmental parameter, such as a change of temperature. The agent may be endogenous to the conditions of use, such as an enzyme present in the cells to which the prodrug is administered or the acidic conditions of the stomach, or it may be supplied exogenously.
[0057] A wide variety of progroups, as well as the resultant promoieties, suitable for masking functional groups in the active 2,4-pyrimidinediamines compounds to yield prodrugs are well-known in the art. For example, a hydroxyl functional group may be masked as a sulfonate, ester or carbonate promoiety, which may be hydrolyzed in vivo to provide the hydroxyl group. An amino functional group may be masked as an amide, carbamate, imine, urea, phosphenyl, phosphoryl or sulfenyl promoiety, which may be hydrolyzed in vivo to provide the amino group. A carboxyl group may be masked as an ester (including silyl esters and thioesters), amide or hydrazide promoiety, which may be hydrolyzed in vivo to provide the carboxyl group. Other specific examples of suitable progroups and their respective promoieties will be apparent to those of skill in the art.
[0058] “Progroup” refers to a type of protecting group that, when used to mask a functional group within an active 2,4-pyrimidinediamine drug to form a promoiety, converts the drug into a prodrug. Progroups are typically attached to the functional group of the drug via bonds that are cleavable under specified conditions of use. Thus, a progroup is that portion of a promoiety that cleaves to release the functional group under the specified conditions of use. As a specific example, an amide promoiety of the formula —NH—C(O)CH3 comprises the progroup —C(O)CH3.
[0059] “Proliferative disorder” refers to a disease or disorder characterized by aberrant cell proliferation, for example where cells divide more than their counterpart normal cells. The aberrant proliferation may be caused by any mechanism of action or combination of mechanisms of action. For example, the cell cycle of one or more cells may be affected such that cell(s) divide more frequently than their counterpart normal cells, or alternatively, one or more cells may bypass inhibitory signals which would normally limit their number of divisions. Proliferative diseases include, but are not limited to, slow or fast growing tumors and cancers.
[0060] “Antiproliferative compound” refers to a compound that inhibits the proliferation of a cell as compared to an untreated control cell of a similar type. The inhibition can be brought about by any mechanism or combination of mechanisms, and may operate to inhibit proliferation cytostatically or cytotoxically. As a specific example, inhibition as used herein includes, but is not limited to, arrest of cell division, a reduction in the rate of cell division, proliferation and/or growth and/or induction of cell death.
[0061] “Pharmaceutically effective amount” or “therapeutically effective amount” refers to an amount of a compound sufficient to treat a specified disorder or disease or one or more of its symptoms and/or to prevent the occurrence of the disease or disorder. In reference to tumorigenic proliferative disorders, a pharmaceutically or therapeutically effective amount comprises an amount sufficient to, among other things, cause the tumor to shrink or to decrease the growth rate of the tumor.

5.2 Antiproliferative 2,4-Pyrimidinediamine Compounds

[0062] The antiproliferative compounds are generally 2,4-pyrimidinediamine compounds according to structural formula (I):
[see pdf for image]
[0063] including salts, hydrates, solvates and N-oxides thereof, wherein:
[0064] L1 and L2 are each, independently of one another, selected from a lower alkyldiyl linker, a lower alkylene linker and a covalent bond;
[0065] R2 is selected from the group consisting of lower alkyl optionally substituted with an Rb group,
[see pdf for image]
where Y is NH, O or CH2;
[0066] R2′ is hydrogen, methyl or lower alkyl;
[0067] R4′ is hydrogen, methyl or lower alkyl;
[0068] R4 is selected from the group consisting of lower alkyl optionally monosubstituted with an Ra or Rb group, lower cycloalkyl optionally monosubstituted with an Ra or Rb group, lower cycloheteroalkyl optionally substituted at one or more ring carbon and/or heteroatoms with an Ra or Rb group, —(CRaRa)n—Rb,
[see pdf for image]
where D is —(CR7R7)m—,
[see pdf for image]
where Z1 is N or CH and Z2 is O, S, NH, S(O) or S(O)2;
[0069] R5 is selected from the group consisting of halo, fluoro and —CF3;
[0070] R6 is hydrogen;
[0071] each R7 is independently selected from the group consisting of hydrogen, methyl, lower alkyl and halo;
[0072] each R8 is independently selected from the group consisting of hydrogen, lower alkyl, —(CH2)n—OH, —ORa, —(CH2)n—NRcRc, —O(CH2)n—Ra, —O(CH2)n—Rb, —C(O)ORa, —C(S)ORa′ halo, —CF3 and —OCF3;
[0073] each R9 is independently selected from the group consisting of hydrogen, lower alkyl, —ORa, —(CH2)n—NRcRc, —O(CH2)n—Ra, —O(CH2)n—Rb, —C(O)—NRcRc, —C(S)—NRcRc, —S(O)2—NRcRc, —NHC(O)Ra, —NHC(S)Ra, —C(O)—NH—(CH2)n—NRcRc, —C(S)—NH—(CH2)n—NRcRc, halo, —CF3, —OCF3,
[see pdf for image]
[0074] each R10 is independently selected from the group consisting of hydrogen, lower alkyl, —(CH2)n—OH, —(CH2)n—NRcRc, —ORa, —O(CH2)n—Ra, —O(CH2)n—Rb, halo, —CF3, —OCF3,
[see pdf for image]
[0075] each R11 is independently selected from the group consisting of —ORa, —NRcRc and —NRaRd;
[0076] each R12 is independently selected from the group consisting of lower alkyl, arylalkyl, —ORa, —NRcRc, —C(O)Ra, —C(O)ORa and —C(O)NRcRc;
[0077] each R13 is independently selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, methoxy, —C(O)NRcRc and —C(O)NH2;
[0078] each R15 is independently selected from the group consisting of hydrogen, lower alkyl, lower cycloakyl and phenyl;
[0079] each R16 is independently selected from the group consisting of hydrogen, methyl, lower alkyl, lower cycloalkyl, lower branched alkyl and lower cycloalkylmethyl;
[0080] each R17 is independently selected from the group consisting of hydrogen, lower alkyl, methyl and Rd or, alternatively, R17 may be taken together with R18 to form an oxo (═O) group;
[0081] each R18 is independently selected from the group consisting of hydrogen, lower alkyl and methyl or, alternatively, R18 may be taken together with R17 to form an oxo (═O) group;
[0082] each R19 is independently selected form the group consisting of hydrogen, lower alkyl, methyl and Rd;
[0083] each R20 is independently selected from the group consisting of hydrogen, lower alkyl, methyl and Rd;
[0084] each m is independently an integer from 1 to 3;
[0085] each n is independently an integer from 1 to 3;
[0086] each Ra is independently selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl, lower cycloalkylalkyl, phenyl and benzyl;
[0087] each Rb is independently selected from the group consisting of —ORa, —CF3, —OCF3, —NRcRc, —C(O)Ra, —C(S)Ra, —C(O)ORa, —C(S)ORa, —C(O)NRcRc, —C(S)NRcRc, —S(O)2NRcRc, —C(O)NRaRd, —C(S)NRaRd and —S(O)2NRaRd;
[0088] each Rc is independently selected from the group consisting of hydrogen, lower alkyl and lower cycloalkyl, or, alternatively, two Rcs may be taken together with the nitrogen atom to which they are bonded to form a 5-7 membered saturated ring which optionally includes 1-2 additional heteroatomic groups selected from O, NRa, NRa—C(O)Ra, NRa—C(O)ORa and NRa—C(O)NRa; and
[0089] each Rd is independently selected from lower mono-hydroxyalkyl and lower di-hydroxyalkyl.
[0090] An important class of compounds of structural formula (I) includes compounds in which L1 and L2 are each a covalent bond, such that the compound is a 2,4-pyrimidine diamine according to structural formula (II):
[see pdf for image]
[0091] including salts, hydrates, solvates and N-oxides thereof, wherein R2, R2′, R4, R4′, R5 and R6 are as previously defined for structural formula (I).
[0092] An important class of compounds of structural formulae (I) and/or (II) and the salts, hydrates, solvates and N-oxides thereof, includes compounds in which R5 is fluoro.
[0093] Another important class of compounds of structural formulae (I) and/or (II) and the salts, hydrates, solvates and N-oxides thereof, includes compounds in which R2′ is hydrogen.
[0094] Another important class of compounds of structural formulae (I) and/or (II) and the salts, hydrates, solvates and N-oxides thereof, includes compounds in which R2′ and R4′ are each, independently of one another, selected from hydrogen and methyl.
[0095] Another important class of compounds of structural formulae (I) and/or (II) and the salts, hydrates, solvates and N-oxides thereof, includes compounds in which R4′ is methyl.
[0096] Other important classes of compounds of structural formulae (I) and/or (II) include compounds according to structural formulae (III)-(V):
[see pdf for image]
[0097] and salts, hydrates, solvates and N-oxides thereof, wherein R2, R2′, R4 and R4′, are as previously defined for structural formula (I).
[0098] When R2 and/or R4 is
[see pdf for image]
in the compounds described herein, for example, the compounds of structural formulae (I)-(V), in some embodiments, R9 and R10 are not both simultaneously lower alkoxy or methoxy. In other embodiments, R8, R9 and R10 are not each simultaneously lower alkoxy or methoxy. In still other embodiments R8, R9 and R10 are each methoxy or lower alkoxy. In yet other embodiments, R8 is selected from hydrogen, lower alkyl, lower alkoxy, —ORa, halo, —CF3 and —OCF3 and one of R9 or R10 is selected from
[see pdf for image]
In a specific embodiment, the other one of R9 or R10 is other than
[see pdf for image]
In yet other embodiments, R8 is selected from hydrogen, lower alkyl, —ORa, halo, —CF3 and —OCF3 and one of R9 or R10 is selected from —OCH2C(O)Ra, —OCH2C(O)ORa, —OCH2C(O)NHRa, —OCH2C(O)NHRd and —OCH2C(O)NRcRc. In a specific embodiment, the other one of R9 or R10 is other than —OCH2C(O)Ra, OCH2C(O)ORa, —OCH2C(O)NHRa, —OCH2C(O)NHRd or —OCH2C(O)NRcRc.
[0099] In yet other embodiments, R8 and R9 are each, independently of one another, selected from hydrogen, lower alkyl, —ORa, halo, —CF3 and —ORa and R10 is
[see pdf for image]
In yet other embodiments R9 is hydrogen and R8 and R10 are each, independently of one another, selected from the group consisting of lower alkyl, methyl, lower alkoxy, methoxy, —CF3 and —OCF3. Specific combinations of R8 and R10 when R9 is hydrogen are as follows:
[0100] R8 and R10 are each the same lower alkyl or methyl;
[0101] R8 and R10 are each the same lower alkoxy or methoxy;
[0102] R8 is lower alkyl or methyl and R10 is —CF3;
[0103] R8 is lower alkoxy or methoxy and R10 is —CF3; and
[0104] R8 is lower alkyl or methyl and R10 is —OCF3.
[0105] In still other embodiments, R9 is hydroxy, methoxy or chloro and R8 and R10 are each, independently of one another, selected from the group consisting of lower alkyl, methyl, lower alkoxy, methoxy and chloro. Specific combinations of R8, R9 and R10 according to this embodiment are as follows:
[0106] R8 and R10 are each methyl and R9 is hydroxy, methoxy or chloro;
[0107] R8 and R10 are each chloro and R9 is hydroxy or methoxy; and
[0108] R8 is chloro, R10 is methyl and R9 is hydroxy or methoxy.
[0109] When R2 and R4 are each
[see pdf for image]
in the compounds described herein, such as, for example, the compounds of structural formulae (I)-(V), in some embodiments no more than one of R8, R9 and R10 of the R4 phenyl is hydrogen unless at least one of R8, R9 or R10 of the R2 phenyl is —O(CH2)n—NRcRc,
[see pdf for image]
In other embodiments, the substitution patterns of the R2 and R4 phenyl rings are different from each other such that the compound is not a N2,N4-bis(3,4,5-substituted phenyl)pyrimidinediamine.
[0110] In still other embodiments, the compound is a compound according to structural formula (VI):
[see pdf for image]
including the salts, hydrates, solvates and N-oxides thereof, wherein R4′, R8, R9 and R10 are as previously defined for structural formula (I).
[0111] In still other embodiments, the compound is a compound according to structural formula (VII):
[see pdf for image]
including the salts, hydrates, solvates and N-oxides thereof, wherein
R16 and R24 are each independently selected from hydrogen and methyl;
R8 is selected from hydrogen, lower alkyl, methyl; hydroxy, lower alkoxy, methoxy, halo, chloro, trifluoromethyl and —CH2OH;
R9 is selected from hydrogen, lower alkyl, methyl, hydroxy, lower alkoxy, methoxy, halo, chloro, trifluoromethyl, trifluoromethoxy, —OCH2C(O)NHRa.
[see pdf for image]
R10 is selected from hydrogen, lower alkyl, methyl, hydroxy, lower alkoxy, methoxy, halo, chloro, trifluoromethyl, trifluoromethoxy, —OCH2C(O)NHRa, —OCH2C(O)ORa,
[see pdf for image]
with the provisos that:
(i) when R9 is
[see pdf for image]
then R10 is other than
[see pdf for image]
and
(ii) when R10
[see pdf for image]
then R9 is other than
[see pdf for image]
and Z1, R12, R19, R20, Ra are as defined formula (I),
[0112] In still other embodiments when R2 and R4 are each
[see pdf for image]
R8, R9 and R10 are selected such that each R2 and R4 phenyl ring is mono-substituted.
[0113] In yet other embodiments when R2 and R4 are each
[see pdf for image]
R8, R9 and R10 are selected such that each R2 and R4 phenyl ring is di-substituted. In one specific embodiment, each R2 and R4 phenyl ring is substituted with an ethylenedioxy acetal group.
[0114] In still other embodiments when R2 and R4 are each
[see pdf for image]
R10 of the R2 or R4 ring is other than 1,3-oxazolyl or 1,3-oxazol-5-yl when the R8 and R9 of the same ring are each hydrogen. In one specific embodiment, R8, R9 and R10 are as defined in the preceeding sentence when R5 is fluoro and L2 is a lower alkylene. In another specific embodiment, R2 is other than 3-(1,3-oxazolyl)phenyl or 3-(1,3-oxazol-5-yl)phenyl when R4 is 2-(trifluoromethyl)benzyl. In another specific embodiment, the compound is other than N2-[3-(1,3-oxazolyl)phenyl]-N4-[2-trifluoromethy)lbenzyl]-5-fluoro-2,4-pyrimidinediamine. In compounds where R10 is an oxazolyl, the oxazolyl is not connected at the 5 position. In a specific embodiment, the oxazole is connected at the 2 position. In still another specific embodiment, the compound is not any compound described in WO 03/040141, the disclosure of which is incorporated herein by reference.
[0115] When R2 is
[see pdf for image]
in the compounds described herein, such as, for example, the compounds of structural formulae (I)-(VII), in some embodiments one of R9 or R10 is selected from
[see pdf for image]
where R12 is as previously defined for structural formula (I) and the other one of R9 or R10 is other than
[see pdf for image]
In still other embodiments, R8 is selected from hydrogen, lower alkyl, methyl, lower alkoxy, methoxy and halo and one of R9 or R10 is —OCH2—Rb, where Rb is selected from —C(O)NRa and —C(O)NHRa, and the other one of R9 or R10 is selected from hydrogen, lower alkyl, methyl, lower alkoxy, methoxy and halo. In still other embodiments R2 is
[see pdf for image]
where R8 is hydrogen, fluoro or CF3. In a specific embodiment, R2 is
[see pdf for image]
[0116] When R2 is
[see pdf for image]
in the compounds described herein, such as, for example, the compounds according to structural formulae (I)-(V), in some embodiments, R8 and R9 are each independently selected from hydrogen, lower alkyl, methyl, lower alkoxy, methoxy, halo and chloro. One specific embodiment, R8, R9 and R13 are each independently selected from halo, lower alkyl, methyl, lower alkoxy, and methoxy. In another specific embodiment, R2 is selected from
[see pdf for image]
[0117] In some embodiments of compounds in which R2 is
[see pdf for image]
including any of the above-described specific embodiments, R4 is selected from
[see pdf for image]
where D is as previously defined for structural formula (I).
[0118] When R2 is 3,4,5-trimethoxyphenyl or 3,4,5-tri(loweralkoxy)phenyl in the compounds described herein, such as, for example the compounds of structural formulae (I)-(V), in some embodiments, R4 is
[see pdf for image]
where Z1, Z2 and R16, R17, R18, R19 and R20 are as previously described for structural formula (I).
[0119] When R9 or R10 is
[see pdf for image]
in the compounds described herein, such as, for example, the compounds of structural formulae (I)-(VII), in some embodiments R12 is methyl. In other embodiments, R12 is —C(O)Ra or —C(O)ORa, where Ra is lower alkyl, ethyl or methyl.
[0120] When R2 is
[see pdf for image]
in the compounds described herein, such as, for example, the compounds of structural formulae (I)-(V), in some embodiments (i) each R13 is, independently or the other, selected from lower alkyl, methyl, hydroxy, lower alkoxy and methoxy; and/or (ii) R4 is selected from
[see pdf for image]
where Z1, Z2 and R16, R17, R18, R19 and R20 are as previously described for structural formula (I). In a specific embodiment, R4 is
[see pdf for image]
where Z1 is CH, R16 is hydrogen, R17 and R18 are taken together to form an oxo (═O) group and R19 and R20 are each hydrogen or methyl; and R2 is
[see pdf for image]
where each R13 is, independently of the other, selected from lower alkyl, methyl, hydroxy, lower alkoxy and methoxy.
[0121] When R2 is lower alkyl in the compounds described herein, such as, for example, the compounds of structural formulae (I)-(V), in some embodiments, R4 is
[see pdf for image]
where D is as previously defined for structural formula (I).
[0122] When R2 is
[see pdf for image]
in the compounds described herein, such as, for example, the compounds of structural formulae (I)-(V), in some embodiments, R11 is selected from the group consisting of hydroxy, methoxy, ethoxy, —NHCH3, —NHCH2CH2OH, —NHCH2CH(OH)CH2OH, —NHCH2CH(OH)(CH3)2, —N(CH3)CH2CH2OH and —N(CH3)C(CH3)2CH2OH and Y is as previously defined.
[0123] When R2 is
[see pdf for image]
in the compounds described herein, such as the compounds of structural formulae (I)-(V), in some embodiments the ring is connected to the remainder of the molecule at the 5-position
[see pdf for image]
In other embodiments, it is connected to the remainder of the molecule at the 6-position
[see pdf for image]
In some embodiments, R16 is selected from lower n-alkanyl, lower branched alkanyl, lower cycloalkanyl and lower cycloalkanylmethyl. In some embodiments, R4 is selected from
[see pdf for image]
[0124] When R2 is
[see pdf for image]
in the compounds described herein, such as, for example, the compound of structural formulae (I)-(V), in some embodiments, R4 is selected from lower cycloalkyl and lower cycloheteroalkyl optionally substituted at one or more ring carbon or heteroatoms with an Ra or an Rb group. In a specific embodiment, R4 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
[see pdf for image]
where Re and Rf are selected from (C1-C3) alkanyl and methyl and Rg is benzyl. In some embodiments, each Re is methyl. In some embodiments, Rf is ethyl.
[0125] When R4 is selected from lower alkyl, isopropyl, t-butyl, lower cycloalkyl,
[see pdf for image]
in the compounds described herein, such as, for example, the compounds of structural formulae (I)-(V), in some embodiments R2 is selected from
[see pdf for image]
where R8, R9, R10 and R13 are as previously defined for structural formula (I). In a specific embodiment, R2 is selected from any of the above-described embodiments of these substituted phenyls. In other embodiments, R2 is
[see pdf for image]
where R8 and R9 are a previously defined for structural formula (I).
[0126] When R4 is
[see pdf for image]
where R15 is lower branched alkyl or t-butyl, and R2 is
[see pdf for image]
in the compounds described herein, such as, for example, the compounds of structural formulae (I)-(V), in some embodiments at least one of R8 or R10 is other than hydrogen. In other embodiments, at least two of R8, R9 and R10 are other than hydrogen. In still other embodiments, at least two of R8, R9 and R13 are other than hydrogen.
[0127] In still other embodiments, either: (i) R9 is
[see pdf for image]
and R10 is other than
[see pdf for image]

or (ii) R10 is

[0128]  [see pdf for image]
and R9 is other than
[see pdf for image]
In a specific embodiment of alternative (i), R10 is hydrogen. In a specific embodiment of alternative (ii), R9 is hydrogen.
[0129] In still other embodiments, when R2 is
[see pdf for image]
where R8 and R9 are each hydrogen, then R10 is other than lower branched alkyl, t-butyl or —O(CH2)nRb, where n is as previously defined for structural formula (I) and Rb is selected from —NRcRc, —C(O)ORa, —C(O)NRcRc and —C(O)NRaRd.
[0130] In still other embodiments, when R2 is
[see pdf for image]
where R9 is hydrogen and R13 is selected from hydrogen, lower alkyl and methyl, then R8 is other than —O(CH2)nRb, where n is as previously defined for structural formula (I) and Rb is —NRcRc. In still other embodiments, the compound is not any compound described in WO 01/64656, WO 03/026665 or WO 03/026666, the disclosures of which are incorporated herein by reference.
[0131] When R4 is —(CH2)n—Rb in the compounds described herein, such as, for example, the compounds of structural formulae (II)-(V), in some embodiments Rb is selected from the group consisting of —ORa, —NRcRc, —C(O)Ra and —C(O)NRcRc, where each Rc is independently selected from hydrogen and lower alkyl.
[0132] When R4 is
[see pdf for image]
in the compounds described herein, such as, for example, the compounds of structural formulae (I)-(V), in some embodiments R2 is
[see pdf for image]
where R9 is selected from the group consisting of —ORa, methoxy, isopropoxy, —OCH2C(O)ORa, —OCH2C(O)NHRa, —OCH2C(O)NRaRa and —OCH2CH2NRaRa; and R8 and R10 are as previously defined for structural formula (I). In a specific embodiment, R8 and R10 are selected from one of the following combinations:
[0133] R8 and R10 are each the same lower alkyl or methyl;
[0134] R8 is lower alkyl or methyl and R10 is halo, fluoro or chloro; and
[0135] R8 and R10 are each the same halo, fluoro or chloro.
[0136] When R4 is selected from lower alkyl optionally monosubstituted with an Rb group, a lower cycloalkyl optionally monosubstituted with an Rb group and —C(RaRa)n—Rb, where, Ra and Rb are as previously defined for structural formula (I), and/or L2 is a lower alkylene linker in the compounds described herein, in some embodiments, R2 is other than mono-substituted phenyl, 3-hydroxyphenyl, 3-halophenyl, 3-chlorophenyl, 3-bromophenyl, 4-halophenyl, 4-chlorophenyl, 4-bromophenyl, 3,4-dihalophenyl, 3,4-dichlorophenyl or 3,4-dichlorophenyl. In a specific embodiment, R2 is other than these defined groups in compounds in which R5 is —CF3. In another specific embodiment, the compound is not any compound described in US 2003/0171359 and/or WO 03/032997, the disclosures of which are incorporated herein by reference.
[0137] When R4 is
[see pdf for image]

and R2 is

[0138]  [see pdf for image]
in the compounds described herein, such as, for example, the compounds of structural formulae (I)-(V), in some embodiments, R9 and R9 are non-bulky substitutents. In a specific embodiment, R9 is other than
[see pdf for image]
and R10 is other than
[see pdf for image]
In another specific embodiment, R8, R9 and R10 are each, independently of one another, selected from hydrogen lower alkyl, methyl hydroxy, lower alkoxy, methoxy, halo, fluoro and chloro. In another specific embodiment, R8 is selected from hydrogen, lower alkyl, methyl, lower alkoxy and methoxy, R9 is selected from hydrogen, lower alkoxy and methoxy and R10 is selected from lower alkyl, methyl, lower alkoxy, methoxy, halo, fluoro and
[see pdf for image]
[0139] In all of the compounds described herein in which R4 is
[see pdf for image]
in some embodiments D is selected from the group consisting of —CH2—, —CF2—, —CH2CH2—, —CF2—CF2— and —CH2—CH2—CH2—.
[0140] In all of the compounds described herein having lower alkyl substitutents or substituents including lower alkyl groups (e.g., lower alkoxy groups, etc.), in some embodiments the lower alkyl substituent or group is a saturated straight-chained, branched or cyclic alkyl (i.e., an alkanyl).
[0141] Additional exemplary embodiments of the compounds described herein are illustrated in the following TABLES 1-14, below.
[00001] [TABLE-US-00001]
 
  TABLE 1A
  Type A   Type B
[see pdf for image] [see pdf for image]
 
  No.   Type   nR21R22R23R4′   A549   H1299
 
  101   A   1   H [see pdf for image]   H   H   +   +
 
  102   A   1   H   H [see pdf for image]   H   +   +
 
  103   A   1   H   H [see pdf for image]   H   +   +
 
  104   A   1   H [see pdf for image]   H   H   +   +
 
  105   A   1   H [see pdf for image]   H   H   +   +
 
  106   A   1   H   H [see pdf for image]   H   +   +
 
  107   A   2   H [see pdf for image]   H   H   +   +
 
  108   A   2   H [see pdf for image]   H   H   +   +
 
  109   A   2   H   H [see pdf for image]   H   +   +
 
  110   A   2   H   H [see pdf for image]   H   +   +
 
  111   A   2   H   Cl   Cl   H   +   +
  112   A   2   H   OMe   Cl   H   +   +
 
  113   A   2   H   H [see pdf for image]   H   +   +
 
  114   A   2   Cl   OMe   Cl   H   +   +
 
  115   A   2   H   H [see pdf for image]   H   +   +
 
  116   A   2   Me   H   Me   H   +   +
  117   A   2   OMe   H   OMe   H   +   +
  118   A   2   OMe   HCF3   H   −   +
 
  119   A   2   H   H [see pdf for image]   H   +   +
 
  120   A   2   H   H [see pdf for image]   H   +   +
 
  121   A   2   H [see pdf for image]   H   H   +   +
 
  122   A   2   H [see pdf for image]   H   H   +   +
 
  123   A   2   H [see pdf for image]   H   Me   +   +
 
  124   A   2   H [see pdf for image]   H   Me   +   +
 
  125   A   2   H [see pdf for image]   H   Me   +   +
 
  126 (HCl salt)   A   2   H [see pdf for image]   H   Me   +   +
 
  127   A   2   H   H [see pdf for image]   Me   +   +
 
  128   A   2   H   H [see pdf for image]   Me   +   +
 
  129   A   2   H   H [see pdf for image]   Me   +   +
 
  130   A   2   H   H [see pdf for image]   Me   +   +
 
  131   A   2   H [see pdf for image]   H   H   +   +
 
  132   A   2   H [see pdf for image]   H   H   +   +
 
  133   A   3   H [see pdf for image]   H   H   +   +
 
  134   A   3   H [see pdf for image]   H   H   +   +
 
  135   A   3   H   H [see pdf for image]   H   +   +
 
  136   A   3   H   H [see pdf for image]   H   +   +
 
  137   A   3   H   H [see pdf for image]   H   +   +
 
  138   A   3   H   H [see pdf for image]   H   +   +
 
  139   A   4   H [see pdf for image]   H   H   +   +
 
  140   A   4   H [see pdf for image]   H   H   +   +
 
  141   A   4   H [see pdf for image]   H   H   +   +
 
  142   A   4   H [see pdf for image]   H   H   +   +
 
  143   A   4   H   H [see pdf for image]   H   +   +
 
  144   A   4   H   H [see pdf for image]   H   +   +
 
  145   A   4   H   H [see pdf for image]   H   +   +
 
  146   A   4   H   H [see pdf for image]   H   +   +
 
  147   A   3   H [see pdf for image]   H   H   +   +
 
  148   A   3   H [see pdf for image]   H   H   +   +
 
  149   A   4   H [see pdf for image]   H   H   +   +
 
  150   A   4   H [see pdf for image]   H   H   +   +
 
  151   A   2   H   H [see pdf for image]   Me   +   +
 
  152   A   2   H [see pdf for image]   Cl   H   +   +
 
  153   A   4   H [see pdf for image]   Cl   H   +   +
 
  154 (HCl salt)   A   2   H [see pdf for image]   H   H   +   +
 
  155 (TsOH salt)   A   4   H [see pdf for image]   H   H   +   +
 
  156 (HCl salt)   A   4   H [see pdf for image]   H   H   +   +
 
  157   A   3   H [see pdf for image]   Cl   H   +   +
 
  158   A   2   H [see pdf for image]   Cl   H   +   +
 
  159   A   4   H [see pdf for image]   Cl   H   +   +
 
  160   A   2   H [see pdf for image]   Me   H   +   +
 
  161   A   3   H [see pdf for image]   Me   H   +   +
 
  162   A   4   H [see pdf for image]   Me   H   +   +
 
  163   A   2   H [see pdf for image] CF3   H   +   +
 
  164   A   2   H [see pdf for image] CF3   H   +   +
 
  165   A   4   H [see pdf for image] CF3   H   +   +
 
  166   A   2   H [see pdf for image]   Me   H   +   +
 
  167   B   2   H [see pdf for image]   —   H   +   +
 
  168   B   3   H [see pdf for image]   —   H   +   +
 
  169   B   4   H [see pdf for image]   —   H   +   +
 
  170   A   2   H [see pdf for image] CH2OH   H    
 
  171   B   2   Me [see pdf for image]   —   H   +   +
 
  172   B   3   Me [see pdf for image]   —   H   +   +
 
  173   B   4   Me [see pdf for image]   —   H   +   +
 
  174   A   2   H [see pdf for image] CH2OH   H   +   +
 
  175   A   3   H [see pdf for image]   H   H   +   −
 
  176   A   3   H [see pdf for image]   H   H   +   +
 
  177   A   3   H [see pdf for image]   H   H   +   +
 
  TABLE 1B
  Type A   Type B
[see pdf for image] [see pdf for image]
 
  No.   TypeR21R22R23R4′   A549   H1299
 
  178   A   H [see pdf for image]   H   H   +   +
 
  179   A   H   H [see pdf for image]   H   +   +
 
  180   A   H [see pdf for image]   Cl   H   +   +
 
  181   A   H [see pdf for image]   Me   H   +   +
 
  182   A   H [see pdf for image] CF3   H   +   +
 
  183   B   H [see pdf for image]   —   H   +   +
 
  184   B   Me [see pdf for image]   —   H   +   +
 
  TABLE 1C
  Type A   Type B
[see pdf for image] [see pdf for image]
 
  No.   TypeR21R22R23R4′A549   H1299
 
  185   A   H [see pdf for image]   H   H   +   +
 
  186   A   H   H [see pdf for image]   H   +   +
 
  187   A   H [see pdf for image]   Cl   H   +   +
 
  188   A   H [see pdf for image]   Me   H   +   +
 
  189   A   H [see pdf for image] CF3   H   +   +
 
  190   B   H [see pdf for image]   —   H   +   +
 
  TABLE 1D
  Type A   Type B
[see pdf for image] [see pdf for image]
 
  No.   TypeR21R22R23R4′   A549   H1299
 
  191   A   H [see pdf for image]   H   H    
 
  192   A   H [see pdf for image]   H   H    
 
  193   A   H [see pdf for image]   H   H    
 
  194   A   H [see pdf for image]   H   H    
 
  195   A   H   H [see pdf for image]   H    
 
  196   A   H   H [see pdf for image]   H    
 
  197   A   H   H [see pdf for image]   H    
 
  198   A   H   H [see pdf for image]   H
 
[00002] [TABLE-US-00002]
  TABLE 2
 
[see pdf for image]
 
  No.R15R21R22R23   A549   H1299
 
  199   t-butyl   H   H [see pdf for image]   +  
 
  200   t-butyl   H   H [see pdf for image]   +   +
 
  201   t-butyl   H   H [see pdf for image]   +   +
 
  202   t-butyl   H [see pdf for image]   H   +   +
 
  203   t-butyl   H [see pdf for image]   H   +   +
 
  204   t-butyl   H [see pdf for image]   H   +   +
 
  205   cyclopropyl   H   H [see pdf for image]   +   +
 
  206   cyclopropyl   H [see pdf for image]   H   +   +
 
  207   cyclopropyl   H   H [see pdf for image]   +   +
 
  208   cyclopropyl   H   H [see pdf for image]    
 
  209   cyclopropyl   H [see pdf for image]   H   +   +
 
  210   cyclopropyl   H [see pdf for image]   H   +   −
 
  211   cyclopropyl   H   H [see pdf for image]   +   +
 
  212   cyclopropyl   H [see pdf for image]   Cl   +   +
 
  213   cyclopropyl   H [see pdf for image]   Me   +   +
 
  214   cyclopropyl   H [see pdf for image] CF3   +   +
 
[00003] [TABLE-US-00003]
  TABLE 3
 
  Type A   Type B
[see pdf for image] [see pdf for image]
 
  No.   TypeR4R21R22R23   A549   H1299
 
  215   A   i-propyl   H [see pdf for image]   H   +   +
 
  216   A   i-propyl   H [see pdf for image]   Cl   +   +
 
  217   A   i-propyl   H [see pdf for image]   Me   +   +
 
  218   A   i-propyl   H [see pdf for image] CF3   +   +
 
  219   A   i-propyl   H   H [see pdf for image]   +   +
 
  220   A   t-butyl   H [see pdf for image]   H   +   +
 
  221   A   t-butyl   H   H [see pdf for image]   +   +
 
  222   A   t-butyl   H [see pdf for image]   Cl   +   +
 
  223   A   t-butyl   H [see pdf for image]   Me   +   +
 
  224   A   t-butyl   H [see pdf for image] CF3   +   +
 
  225   B   i-propyl   H [see pdf for image]   —   +   +
 
  226   B   t-butyl   H [see pdf for image]   —   +   +
 
  227   B   i-propyl   Me [see pdf for image]   —   +   +
 
[00004] [TABLE-US-00004]
  TABLE 4
 
[see pdf for image]
 
  No.Z1Z2R16R19R20R21R22
 
  228   CH   O   H   Me(R)   H   H   OMe
  229   CH   O   H   Me(S)   H   Me   H
  230   CH   O   H   Me(R)   H   Me   H
  231   CH   O   H   Me(R)   H   Cl   OMe
  232   CH   O   H   Me(R)   H   Cl   OMe
  236   CH   O   H   H   H   H   H
  237   CH   O   HCH2CH2OH   H   H   H
  238   CH   O   HCH2CH2OH   H   H   H
  239   CH   O   H   H   H   H   H
  240   CH   O   H   Me(S)   H   H   H
  241   CH   O   H   Me(R)   H   H   H
  242   CH   O   H   Me(S)   H   H   H
  243   CH   S   H   H   H   H   H
  244   CH   S   H   H   H   OMe   H
  245   CH   S   H   H   H   H   OMe
  246   CH   S   Me   H   H   H   H
  247   CH   S   Me   H   H   OMe   H
  248   CH   O   H   H   H   H   H
  249   CH   O   HCH2CH2OH   H   H   H
  250   CHS(O)2   H   Me   H   OMe   H
  251   CHS(O)2   H   Me   H   Me   H
  252   CHS(O)2   H   Me   H   OMe   OMe
  253   CH   O   H   H   H   H   H
  254   CH   O   H   H   H   H   H
  255   CH   O   Me   H   H   H   H
  256   CH   O   H   Me   H   H   H
  257   CH   O   H   Me(S)   H   Cl   OMe
  258   CH   O   H   Me(R)   H   Cl   OMe
  259   CH   O   HCH2CH2OH   H   OMe   H
  260   CH   O   HCH2CH2OH   H   Cl   OMe
  261   CH   O   H   Me(S)   H   OMe   H
  262   CH   O   H   Me(R)   H   OMe   H
  263   CHS(O)2   H   Me   Me   OMe   H
  264   CHS(O)2   H   Me   Me   Me   H
  265   CHS(O)2   H   Me   Me   OMe   OMe
  266   CH   S   H   Me   H   OMe   H
  267   CH   S   H   Me   H   Me   H
  268   CH   S   H   Me   H   OMe   OMe
  269   CHS(O)2   H   Me   Me   H   H
  270   CHS(O)2   H   Me   Me   H   OMe
  271   CH   S   H   Me   H   H   H
  272   CH   S   H   Me   H   H   OMe
  273   CH   S   H   H   H   H   H
  274   CH   S   H   Me   H   H   H
  275   CHS(O)2   H   Me   Me   H   H
  276   CHS(O)2   H   Me   H   H   H
  277   CHS(O)2   H   Me   H   H   H
  278   CHS(O)2   H   Me   H   H   OMe
  279   CH   S   H   H   H   OMe   OMe
  280   CH   S   H   Me   Me   H   OMe
  281   CH   S   H   Me   Me   OMe   H
  282   CH   S   H   Me   Me   Me   H
  283   CH   S   H   Me   Me   OMe   OMe
  284   CH   S   H   Me   Me   H   H
  285   CH   S   H   Me   Me   H   H
  286   CHS(O)2   H   Me   H   H   OMe
  287   CHS(O)2   H   Me   Me   H   OMe
  288   CH   S   H   Me   H   H   OMe
  289   CH   S   H   Me   Me   H   OMe
  290   CH   S   H   H   H   H   OMe
  291   CH   S   H   H   H   Me   O
  292   CHS(O)2   H   H   H   Me   O
  293   CHS(O)2   H   H   H   OMe   H
  294   CHS(O)2   H   H   H   H   OMe
  295   CHS(O)2   H   H   H   H   H
  296   CHS(O)2   H   H   H   OMe   OMe
  297   CHS(O)2   H   H   H   H   H
  298   CHS(O)2   H   H   H   H   OMe
  299   CH   O   Me   H   H   H   H
  300   CH   O   H   Me(S)   H   H   H
  301   CH   O   H   Me(R)   H   H   H
  302   CH   O   H   Me(S)   H   Cl   OMe
  303   CH   O   H   Me(R)   H   Cl   OMe
  304   CH   O   H   Me   Me   OMe   Me
  305   CH   O   H   Me   Me   OMe   H
  306   CH   O   H   Me   Me   Cl   Me
  307   CH   O   H   Me   Me   Cl   OMe
  308   CH   O   H   Me   Me   Cl   H
  309   CH   O   H   Me   Me   OMe   H
  310   CH   O   H   Me   Me   Me   H
  311   CH   O   H   Me   Me   OMe   H
  316   CH   O   H   Me   Me   Me   H
  318   CH   O   H   Me   Me   H   OMe
  319   CH   O   H   Me   Me   Me   Cl
  320   CH   O   H   Me   MeCH2OH   H
  321   CH   O   H   Me   Me   Cl   H
  322   CH   O   H   Me   Me   H   OMe
  323   CH   O   H   Me   Me   OMe   H
  324   CH   O   Me   Me   Me   Me   H
  325   CH   O   Me   Me   Me   H   OMe
  326   CH   O   Me   Me   Me   OMe   H
  327   CH   O   H   Me   Me   H   OMe
  328   CH   O   Me   Me   Me   Me   H
  329   CH   O   Me   Me   Me   OMe   H
  330   CH   O   H   Me   Me   H   C(O)NHMe
  331   CH   O   H   Me   Me   HS(O)2NHMe
  332   CH   O   H   Me   Me   H   H
  333   CH   O   H   Me   Me   C(O)OMe   H
  334   CH   O   H   Me   MeCF3   H
  335   N   O   H   Me   Me   Me   OMe
  338   CH   O   H   Me   Me   OMe   OMe
 
  339   CH   O   H   Me   Me   Me [see pdf for image]
 
  340   N   O   H   Me   Me   OMe   OMe
  350   N   O   H   Me   Me   Me   Cl
  352   N   O   H   Me   Me   Cl   OH
  353   N   O   Me   Me   Me   OMe   OMe
 
  354   N   O   H   Me   Me   OMe [see pdf for image]
 
  355   CH   O   H   Me   Me   H   H
  356   CH   O   H   Me   Me   H   H
  357   N   O   H   Me   Me   H   H
  358   CH   O   H   Me   Me   Me   OH
  359   CH   O   H   Me   Me   Me   OMe
  360   N   O   H   Me   Me   H   H
  362   N   O   H   Me   Me   H   OMe
  363   N   O   H   Me   Me   OMe   H
  364   N   O   H   Me   Me   H   Cl
  365 (HCl salt)   N   O   H   Me   Me   H   H
  366 (bis HCl salt)   N   O   H   Me   Me   H   H
  367 (nitrate salt)   N   O   H   Me   Me   H   H
  368 (bis nitrate salt)   N   O   H   Me   Me   H   H
  369 (mesylate salt)   N   O   H   Me   Me   H   H
  370   N   O   H   Me   Me   H   H
  371   N   O   H   Me   Me   H   H
  372   N   O   H   Me   Me   H   H
  374   N   O   H   Me   Me   H   OMe
  375   N   O   H   Me   Me   H   H
  376   N   O   H   Me   Me   Cl   H
  377   CH   O   H   Me   Me   Me   OMe
  378   N   O   H   Me   Me   HOCF3
  379   N   O   H   Me   Me   Me   OMe
  380   N   O   H   Me   Me   H   H
  381   N   O   H   Me   Me   Me   OH
  382   N   O   H   Me   Me   Me   OMe
  383   N   O   H   Me   Me   H   H
  385   CH   O   H   Me   Me   Cl   OEt
  386   N   O   Me   Me   Me   Me   OMe
  387   N   O   H   Me   Me   Cl   OEt
  388   N   O   Me   Me   Me   H   H
 
  389   CH   O   H   Me   Me   Me [see pdf for image]
 
  390   N   O   Me   Me   Me   H   H
  391   CH   O   H   Me   Me   H   H
  392   N   O   Me   Me   Me   H   H
 
  393   CH   O   H   Me   Me   Me [see pdf for image]
 
  394   CH   O   Me   Me   Me   H   H
  395   CH   O   H   Me   Me   H   H
  396   CH   O   H   Me   Me   H   H
  397   CH   O   Me   Me   Me   H   H
 
  398   N   O   H   Me   Me   Me [see pdf for image]
 
  399   N   O   H   Me   Me   H   H
  400   N   O   H   Me   Me   H   H
  401   CH   O   Me   Me   Me   H   H
  402   CH   O   Me   Me   Me   Me   OMe
 
  403   CH   O   Me   Me   Me   Me [see pdf for image]
 
  404   N   O   Me   Me   Me   Me   OMe
 
 
  405   N   O   Me   Me   Me   Me [see pdf for image]
 
  406   N   O   H   Me   Me   H   H
  407   CH   O   H   Me   Me   H   H
 
  408   N   O   H   Me   Me   Me [see pdf for image]
 
  409   N   O   H   Me   Me   Me [see pdf for image]
 
  410   CH   O   H   Me   Me   Me   i-propoxy
  411   N   O   H   Me   Me   Me   i-propoxy
 
  412   N   O   H   Me   Me   Me [see pdf for image]
 
  413   N   O   H   Me   Me   Me [see pdf for image]
 
  414   N   O   H   Me   Me   Me [see pdf for image]
 
  415   N   O   H   Me   Me   Me [see pdf for image]
 
  416   CH   O   H   Me   Me   H   H
  417   N   O   H   Me   Me   H   C(O)NHMe
  418   N   O   H   H   H   H   H
 
  419   N   O   H   H   H   H [see pdf for image]
 
  421   N   O   H   H   H   H   Cl
  422   N   O   H   H   H   H   OMe
  423   N   O   H   H   H   Cl   OMe
  424   N   O   H   H   H   OMe   H
  425   N   O   H   H   H   H   OMe
  426   N   O   H   H   H   H   OMe
  427   N   O   H   H   H   HOCF3
  428   N   O   H   H   H   H   OEt
  429   N   O   H   H   H   H   OBu
 
  430   N   O   H   H   H   H [see pdf for image]
 
  431   N   O   H   H   H   H   O-iPr
 
  432   N   O   H   Me   Me   H [see pdf for image]
 
  433   N   O   H   H   H   H   OMe
 
  434   N   O   H   Me   Me   H [see pdf for image]
 
  435   N   O   H   H   H   H [see pdf for image]
 
  436   N   O   H   Me   Me   H [see pdf for image]
 
  437   N   O   H   H   H   Me   H
  438   N   O   H   Me   Me   Me   H
  439   N   O   H   H   H   H   H
  440   N   O   H   H   H   H   Me
  441   N   O   H   H   HCF3   H
  442   N   O   H   H   H   Cl   H
  443   N   O   H   H   H   H   H
  444   N   O   H   H   H   H   H
  445   N   O   H   H   H   OMe   OMe
  446   N   O   H   H   H   H   F
  447   N   O   H   H   H   Me   OMe
  448   N   O   H   H   H   Me   OH
  449   N   O   H   H   H   H   H
  450   N   O   H   H   H   H   H
 
  451   N   O   H   H   H   H [see pdf for image]
 
  452   N   O   H   H   H   H   H
  453   N   O   H   H   H   H   H
  454   N   O   H   Me   Me   H   H
  455   N   O   H   Me   Me   H   H
 
  456   N   O   H   Me   Me   H [see pdf for image]
 
  457   N   O   H   Me   Me   H   H
  458   N   O   H   Me   Me   H   H
  459   N   O   H   Me(S)   H   H   OMe
  460   N   O   H   Me(S)   H   OMe   OMe
  461   N   O   H   Me(S)   H   Me   H
  462   CH   O   H   Me(R)   H   HC(O)NH2
  463   CH   O   H   Me(S)   HCH2NHBOC   H
  464   CH   O   H   Me(R)   HCH2NHBOC   H
  465   CH   O   H   Me(S)   HCH2NH2   H
  466   CH   O   H   Me(R)   HCH2NH2   H
  467   CH   O   H   Me   Me   H   H
  468   CH   O   H   Me(S)   H   H   H
  469   CH   O   H   Me(R)   H   H   H
 
  470   CH   O   H   Me   Me   H [see pdf for image]
 
  471   CH   O   H   Me(S)   H   H [see pdf for image]
 
  472   N   O   H   Me   Me   HC(O)NH2
  473   N → O   O   H   Me   Me   OMe   OMe
 
  [see pdf for image]
 
    No.R23   R4′   A549   H1299
 
    228   Cl   H    
    229   Me   H   +   +
    230   Me   H   −   +
    231   H   H   −   −
    232   H   H   +   −
 
    236 [see pdf for image]   H   +   +
 
    237 [see pdf for image]   H   +   +
 
 
    238 [see pdf for image]   H   +   +
 
    239 [see pdf for image]   H   −   +
 
    240 [see pdf for image]   H   +   −
 
    241 [see pdf for image]   H    
 
    242 [see pdf for image]   H    
 
    243 [see pdf for image]   H    
 
    244   OMe   H    
    245   Cl   H    
 
    246 [see pdf for image]   H    
 
    247   OMe   H    
    248C(S)NH2   H    
    249C(S)NH2   H    
    250   OMe   H   +   +
    251   Me   H   +   +
    252   OMe   H    
 
    253 [see pdf for image]   H    
 
    254   OH   H   +  
    255   OH   H   +   +
 
    256 [see pdf for image]   H   +  
 
    257   Cl   H    
    258   Cl   H    
    259   OMe   H    
    260   H   H    
    261   OMe   H    
    262   OMe   H    
    263   OMe   H   −   −
    264   Me   H   −   +
    265   OMe   H   +   +
    266   OMe      
    267   Me   H    
    268   OMe   H    
 
    269 [see pdf for image]   H    
 
    270   Cl   H    
 
    271 [see pdf for image]   H    
 
    272   Cl   H    
    273   OH   H    
    274   OH   H    
    275   OH   H    
    276   OH   H    
 
    277 [see pdf for image]   H    
 
    278   Cl   H    
    279   OMe   H    
    280   Cl   H    
    281   OMe   H    
    282   Me   H    
    283   OMe   H    
    284   OH   H    
 
    285 [see pdf for image]   H    
 
    286   F   H    
    287   F   H   +   +
    288   F   H   +   +
    289   F   H   +   +
    290   F   H   +   +
    291   Me   H   −   +
    292   Me   H    
    293   OMe   H    
    294   Cl   H    
 
    295 [see pdf for image]   H    
 
    296   OMe   H    
    297   OH   H    
    298   F   H    
 
    299 [see pdf for image]   H   +   −
 
    300 [see pdf for image]   H   +  
 
    301 [see pdf for image]   H    
 
    302   H   H    
    303   H   H    
    304   Me   H    
    305   OMe   H   +  
    306   Cl   H   +   +
    307   Cl   H   +  
    308   Cl   H   +  
    309CF3   H   +  
    310   Me   H   +  
    311   OMe   H   +  
    316   Me   H    
    318   Cl   H    
    319   Me   H    
    320CH2OH   H   +   +
    321   OMe   H   +   +
    322   Cl   H    
    323   OMe   Me   +   +
    324   Me   Me   +   −
    325   Cl   Me   +   +
    326   OMe   Me   +   +
    327   Cl   Me   +   +
    328   Me   H    
    329   OMe   H    
    330   Cl   H    
    331   OMe   H    
 
    332 [see pdf for image]   H    
 
    333 [see pdf for image]   H   −   −
 
    334 [see pdf for image]   H   +   −
 
    335   Me   H    
    338   OMe   H   +   +
    339   Me   H   +   +
    340   OMe   H    
    350   Me   H    
    352   Cl   H   +   +
    353   OMe   H    
    354   OMe   H   +   +
 
    355 [see pdf for image]   H   +   +
 
    356   OH   H   +   −
 
    357 [see pdf for image]   H    
 
    358   Cl   H   +  
    359   Cl   H   +   +
 
    360 [see pdf for image]   H    
 
    362   Cl   H    
    363   OMe   H    
    364   Cl   H    
 
    365 (HCl salt) [see pdf for image]   H    
 
    366 (bis HCl salt) [see pdf for image]   H    
 
    367 (nitrate salt) [see pdf for image]   H    
 
    368 (bis nitrate salt) [see pdf for image]   H    
 
    369 (mesylate salt) [see pdf for image]   H    
 
    370 [see pdf for image]   H    
 
    371   t-butyl   H   +   +
    372   OH   H    
    374   F   H   −   −
    375   Cl   H   −   −
    376   Cl   H   +   +
    377   Cl   H    
    378   Cl   H   −   −
    379   Cl   H    
 
    380 [see pdf for image]      
 
    381   Cl   H    
    382   Me   H   −   −
    383   i-propyl   H    
    385   Me   H   +   −
    386   Cl   H    
    387   Me   H   −   −
 
    388 [see pdf for image]   H   +   +
 
    389   Cl   H    
 
    390 [see pdf for image]   H    
 
    391 [see pdf for image]   H   +   +
 
    392 [see pdf for image]   H    
 
    393   Cl   H    
 
    394 [see pdf for image]   H   +   −
 
    395 [see pdf for image]   Me   −   +
 
    396 [see pdf for image]   H    
 
    397 [see pdf for image]   Me   +   +
 
    398   Cl   H   −   −
 
    399 [see pdf for image]   H    
 
    400 [see pdf for image]   H    
 
    401 [see pdf for image]   Me   +   +
 
    402   Me   Me   +   −
    403   Cl   Me   +   −
    404   Me   H    
    405   Cl   H   +   +
 
    406 [see pdf for image]   H    
 
    407 [see pdf for image]   H   +   +
 
    408   Cl   H    
    409   Me   H    
    410   Cl   H    
    411   Cl   H    
    412   Me   H    
    413   Cl   H    
    414   Cl   H   −   −
    415   Me   H    
 
    416 [see pdf for image]   H    
 
    417   Cl   H    
 
    418 [see pdf for image]   H    
 
    419   H   H    
    421   Cl   H    
    422   Cl   H    
    423   Cl   H    
    424   OMe   H    
    425   F   H    
    426   H   H    
    427   H   H    
    428   H   H    
    429   H   H    
    430   H   H    
    431   H   H    
    432   H   H    
    433   OMe   H    
    434   H   H    
    435   H   H   +   +
    436   H   H   +  
    437   Me   M    
    438   Me   H    
    439   i-propyl   H   −   −
    440   Cl   H   −   −
    441   OMe   H   −   −
    442   Cl   H   −   −
    443   Br   H   −   −
    444   t-butyl   H   −   −
    445   OMe   H    
    446   F   H   −   −
    447   Me   H    
    448   Me   H   +   +
 
    449 [see pdf for image]   H   +   +
 
    450 [see pdf for image]   H   +   +
 
    451   H   H   −   −
 
    452 [see pdf for image]   H    
 
    453 [see pdf for image]   H   +   +
 
    454 [see pdf for image]   H   −   −
 
    455 [see pdf for image]   H   +   +
 
    456   H   H   +   +
 
    457 [see pdf for image]   H    
 
    458 [see pdf for image]   H   +   +
 
    459   Cl   H    
    460   OMe   H    
    461   Me   H    
    462   H   H   −   +
    463   H   H    
    464   H   H    
    465   H   H    
    466   H   H    
 
    467 [see pdf for image]   H    
 
    468 [see pdf for image]   H    
 
    469 [see pdf for image]   H    
 
    470   H   H   −   −
    471   H   H   +   −
    472   H   H   +   +
    473   OMe   H   +   +
 
††In TABLE 4, compounds having chirality at the carbon labeled with an asterisk (*) that, through substituent R19, designate a specified stereochemistry
  were synthesized and tested as the substantially pure enantiomer; compounds that do not designate a specified stereochemistry at this carbon atom
  were synthesized and, if tested, were tested as the racemate.
[00005] [TABLE-US-00005]
  TABLE 5
 
[see pdf for image]
 
  No.   mR7R21R22R23R4′   A549   H1299
 
  474   1   H   H [see pdf for image]   H   H   −  
 
  475   1   H   H [see pdf for image]   H   H   −  
 
  476   0   F   H   H [see pdf for image]   H    
 
  477   1   H   H   hexoxy   H   H   −  
  478   1   H   H   OEt   H   H   +  
  479   1   H   H   butoxy   H   H   −  
 
  480   1   H   H [see pdf for image]   H   H   −  
 
  481   1   H   H   H [see pdf for image]   H   −  
 
  482   1   H   H   H   OH   H   −  
  483   1   H   H   OEt   H   H   −  
  484   1   H   H   OMe   OMe   H    
  485   1   H   H   F   Cl   H   −  
  486   1   H   H   t-butyl   H   H    
  487   1   H   H   F   H   H   −  
  488   1   H   H   H   F   H    
  489   1   H   H   Et   H   H   −  
 
  490   1   H   H [see pdf for image]   H   H   −  
 
  491   1   H   H   H [see pdf for image]   H   −   +
 
  492   1   H   H   H [see pdf for image]   H   −  
 
  493   1   H   H   H [see pdf for image]   H   −/+   +
 
  494   1   H   H   H [see pdf for image]   H   +   +
 
  495   1   H   H   H [see pdf for image]   H   −/+   +
 
  496   1   H   H   H [see pdf for image]   H   +  
 
  497   1   H   H   H [see pdf for image]   H   +  
 
  498   1   H   H   H [see pdf for image]   H   −  
 
  499   1   H   H   H [see pdf for image]   H    
 
  500   1   H   H   H [see pdf for image]   H   +  
 
  501   1   H   H [see pdf for image]   H   H   −  
 
  502   1   H   H [see pdf for image]   H   H   −  
 
  503   1   F   H   H [see pdf for image]   H   −/+  
 
  504   1   H   H   H [see pdf for image]   H   +  
 
  505   1   H   H   Me [see pdf for image]   H    
 
  506   1   H   OMe   OMe   OMe   H   +  
  507   1   H   Cl   OH   Cl   H   +  
 
  508   1   H   H   H [see pdf for image]   H   −  
 
  509   1   H   H   H [see pdf for image]   H   −  
 
  510   1   H   H   H [see pdf for image]   H   −  
 
  511   1   H   H   i-propyl   H   H   −  
  512   1   H   OMe   H   OMe   H   +   +
  513   0   F   H   H   Cl   H   +   +
  514   1   H   H   HCF3   H   −  
 
  515   1   H   H   H [see pdf for image]   H   +   +
 
  516   1   H   H   H [see pdf for image]   H   +  
 
  517   1   H   H   H [see pdf for image]   H    
 
  518   1   H   H   OMe [see pdf for image]   H    
 
  519   1   H   H   H [see pdf for image]   H    
 
  520   1   H   H   H [see pdf for image]   H   +  
 
  521   1   H   Me   H   OH   H   +   −
  522   1   H   F   HCF3   H   −   −
  523   1   H   Me   HCF3   H   −   +
  524   1   H   F   H   F   H   −   −
  525   1   H   H   OMe   Cl   H    
  526   1   H   HOCF2   Cl   H   +   −
  527   1   H   Me   H   Me   H   +  
  528   1   H   Me   Cl   Me   H   +  
  529   1   HCH2OH   HCH2OH   H   +   +
  530   1   H   Cl   H   Cl   H   +   +
  531   1   H   OMe   HCF3   H   −   +
  532   1   F   OMe   H   OMe   H   +   +
  533   1   F   Me   Cl   Me   H   −   +
  534   1   FCH2OH   HCH2OH   H     +
  535   1   F   Cl   H   Cl   H   +   +
  536   1   F   OMe   HCF3   H   +   +
  537   1   F   Me   H   Me   H   +   +
  538   1   F   Me   HCF3   H   +   −
  539   1   H   Cl   H   OMe   H   +   +
  540   0   H   OMe   H   OMe   H    
  541   0   H   OMe   HCF3   H   +   +
  542   0   H   Me   HCF3   H   −   −
  543   0   H   Cl   H   Cl   H   +   +
  544   0   H   Me   H   Me   H   −   −
 
  545   0   H   H   H [see pdf for image]   Me    
 
  546   1   H   OMe   H   OMe   Me   +   −
  547   1   H   Me   H   Me   Me   +   +
 
  548   1   H   H   H [see pdf for image]   Me    
 
  549   1   H   H   H [see pdf for image]   Me   +   +
 
  550   1   H   H   H [see pdf for image]   H   +   +
 
  551   1   H   H     H   H   +   +
 
  552   1   F   H   H [see pdf for image]   H   +   +
 
  553   1   F   H [see pdf for image]   H   H   +   +
 
  554   1   H   H   C(O)NHMe   Cl   H   +   +
  555   1   H   H   C(O)NHMe   Cl   Me    
  556   1   H   HS(O)2NHMe   OMe   H    
 
  557   1   H   H   H [see pdf for image]   H    
 
  558   1   H   C(O)OMe   H [see pdf for image]   H   +   +
 
  559   1   HCF3   H [see pdf for image]   H   +   +
 
  560   0   F   OMe   OMe   OMe   H   +   +
  561   0   F   OMe   H   OMe   H   +   +
  562   0   F   Me   H   Me   H   +   +
  563   0   F   Cl   OH   Cl   H   +   +
  564   0   F   Cl   H   Cl   H   +   +
  565   0   F   Me   Cl   Me   H   −   −
  566   0   F   Me   OH   Cl   H   +   +
  567   0   F   OMe   HCF3   H   +   +
  568   0   F   Me   HCF3   H   −   +
 
  569   1   H   Me [see pdf for image]   Me   H   +   +
 
  570   0   H   Me [see pdf for image]   Me   H   +   +
 
  571   1   F   H   H [see pdf for image]   H   +   +
 
  572   1   F   H   H [see pdf for image]   Me   +   +
 
  573   1   H   Me [see pdf for image]   Me   Me   +   +
 
  574   1   F   Me [see pdf for image]   Me   Me   +   +
 
  575   1   F   Me [see pdf for image]   Me   H   +   +
 
  576   1   H   H   H [see pdf for image]   H   +  
 
  577   2   H   H [see pdf for image]   H   H    
 
  578   2   H   H [see pdf for image]   H   H    
 
  579   2   H   H [see pdf for image]   H   H    
 
  580   2   H   H   H [see pdf for image]   H   −  
 
  581   2   H   H   H [see pdf for image]   H   +  
 
  582   2   H   H   H [see pdf for image]   H    
 
  583   1   H   Me   OH   Cl   H    
  584   1   H   Me   OMe   Me   H    
  585   1   H   Me   OMe   Cl   H    
 
  586   1   H   H   H [see pdf for image]   H   −  
 
  587   1   H   H [see pdf for image]   H   H   +
 
[00006] [TABLE-US-00006]
  TABLE 6
 
[see pdf for image]
 
  No.Y1Y2Z3R17R18R19R20R21R22R23R4′   A549   H1299
 
  588   N   O   CH   Me   Me   H   H   OMe   H   OMe   H   +   +
 
  589   N   O   CH   H   H   H   H   H   H [see pdf for image]   H   +   +
 
  590   N   O   CH   Me   Me   H   H   H   H [see pdf for image]   H   +   +
 
  591   N   O   CH   H   H   H   H   H   H [see pdf for image]   H   +   +
 
  592   N   O   CH   Me   Me   H   H   H   H [see pdf for image]   H   −   −
 
  593   N   O   CH   H   H   HCH2CH2OH   OMe   H   OMe   H    
  594   N   O   CH   H   H   HCH2CH2OH   Me   H   Me   H    
 
  595   N   S   CH   H   H   H   H   H   H [see pdf for image]   H    
 
  596   N   O   CH   H   H   Me   Me   H   H [see pdf for image]   H    
 
  597   N   O   CH   H   H   Me   Me   Me   OMe   Cl   H   +   +
  598   N   O   CH   H   H   Me   Me   OMe   H   OMe   H    
 
  599   N   O   N   H   H   Me   Me   H   H [see pdf for image]   H    
 
  600   N   O   N   H   H   H   H   H   H [see pdf for image]   H    
 
  601   N   O   N   H   H   H   H   H [see pdf for image]   H   H    
 
  602   N   O   N   H   H   H   H   H   H [see pdf for image]   H    
 
  603   N   O   N   H   H   H   H   H [see pdf for image]   H   H   +   +
 
  604   N   O   N   H   H   H   H   H [see pdf for image]   H   H   −   +
 
  605   N   O   N   H   H   H   H   H   H [see pdf for image]   H   +   +
 
  606   N   O   N   H   H   H   H   H   H [see pdf for image]   H   +   +
 
  607   N   O   N   H   H   H   H   H   H [see pdf for image]   H   +   +
 
  608   N   O   N   H   H   H   H   H [see pdf for image]   H   H   +   +
 
  609   N   O   N   H   H   H   H   H   H [see pdf for image]   H   +   +
 
  610   N   O   N   H   H   H   H   H   H [see pdf for image]   H   +   +
 
  611   N   O   N   H   H   H   H   OMe   OMe   OMe   H   +   +
  612   N   O   N   H   H   H   H   H   OMe   Cl   H   −   −
 
  613   N   O   N   H   H   H   H   H   H [see pdf for image]   H   +   +
 
  614   N   O   N   H   H   H   H   H   H [see pdf for image]   H   +   +
 
  615   N   O   N   H   H   H   H   H [see pdf for image]   Cl   H   +   +
 
  616   N   O   N   H   H   H   H   H [see pdf for image]   Me   H   +   +
 
[00007] [TABLE-US-00007]
  TABLE 7
 
Type A [see pdf for image]
 
Type B [see pdf for image]
 
  No.   TypeR4′R4   YR11   A549   HTC116   H1299
 
  617   A   H [see pdf for image]   NH   OEt   −    
 
  618   A   H [see pdf for image]   NH   OEt   +    
 
  619   A   H [see pdf for image]   O   OMe   −    
 
  620   A   H [see pdf for image]   O   OMe      
 
  621   A   H [see pdf for image]   NH   OH   −    
 
  622   A   H [see pdf for image]   O   OH   −    
 
  623   A   H [see pdf for image]   O   OMe   −    
 
  624   A   H [see pdf for image]   O [see pdf for image]   −    
 
  625   A   H [see pdf for image]   O [see pdf for image]   +   +  
 
  626   A   H [see pdf for image]   O [see pdf for image]   −/+   +  
 
  627   A   H [see pdf for image]   O   NHMe   −    
 
  628   A   H [see pdf for image]   O   NHMe   −    
 
  629   A   H [see pdf for image]   O   NHMe   +   +  
 
  630   A   H [see pdf for image]   ONH(CH2)2OH   −    
 
  631   A   H [see pdf for image]   ONH(CH2)2OH   +   +  
 
  632   A   H [see pdf for image]   O [see pdf for image]   +   +  
 
  633   A   H [see pdf for image]   O [see pdf for image]   +   +  
 
  634   A   H [see pdf for image]   O [see pdf for image]   +   −  
 
  635   A   H [see pdf for image]   O [see pdf for image]   +    
 
  636   A   H [see pdf for image]   O   OMe   +   −  
 
  637   A   H [see pdf for image]   NH   OEt      
 
  638   A   H [see pdf for image]   O   OMe   −    
 
  639   A   H [see pdf for image]   O   OH   −    
 
  640   A   H [see pdf for image]   O [see pdf for image]   −    
 
  641   A   H [see pdf for image]   O   OMe   −    
 
  642   A   H [see pdf for image]   O   NHMe   +    
 
  643   A   H [see pdf for image]   ON(Me)2   −    
 
  644   A   H [see pdf for image]   O [see pdf for image]   +   +  
 
  645   A   H [see pdf for image]   O [see pdf for image]   +   +  
 
  646   B   H [see pdf for image]   NH   OEt   +   +   +
 
  647   B   H [see pdf for image]   NH   OEt   +   +  
 
  648   B   H [see pdf for image]   NH   OEt   +   +  
 
  649   B   H [see pdf for image]   NH   NHMe   +   +  
 
  650   A   H [see pdf for image]   O   OMe      
 
  651   A   H [see pdf for image]   O   OMe   −    
 
  652   A   H [see pdf for image]   O   OMe   −    
 
  653   B   H [see pdf for image]   NH   NHMe   +     +
 
  654   B   H [see pdf for image]   NH   NHMe   +     +
 
  655   B   H [see pdf for image]   NH   NHMe   +     +
 
  656   A   H [see pdf for image]   O   OMe   −     −
 
  657   A   H [see pdf for image]   O   OH   −     −
 
  658   A   H [see pdf for image]   NH   Me   −     +
 
  659   B   H [see pdf for image]   NHN(Me)CH2CH2OH   +   +   +
 
  660   B   H [see pdf for image]   NHNHC(Me)2CH2OH   +   +   +
 
  661   B   Me [see pdf for image]   O   OMe   −     −
 
  662   A   Me [see pdf for image]   O   OMe   −     +
 
  663   B   Me [see pdf for image]   NH   NHMe   +     +
 
  664   B   H [see pdf for image]   NH   OEt   +     +
 
  665   B   H [see pdf for image]   NH   NHMe   +     +
 
  666   B   Me [see pdf for image]   NH   OEt   +     +
 
  667   B   HCH2CH2OH   NH   OEt   −   −   −
 
  668   B   H [see pdf for image]   NH   NHMe   −     +
 
  669   B   H [see pdf for image]   NH   NHMe   +     +
 
  670   B   H [see pdf for image]   NH   NHMe   −     −
 
  671   A   Me [see pdf for image]   O   OMe   −     −
 
  672   A   Me [see pdf for image]   O   OMe   −     −
 
  673   A   H [see pdf for image]   O   OMe      
 
  674   A   H [see pdf for image]   O   OMe      
 
  675   A   H [see pdf for image]   O   NHMe   −    
 
  676   A   H [see pdf for image]   O   OMe   +    
 
  677   A   H [see pdf for image]   O   OMe   +   −  
 
  678   B   H [see pdf for image]   NH   OEt   −     −
 
[00008] [TABLE-US-00008]
  TABLE 8
 
[see pdf for image]
 
  No.R4'R21R22R23R31R32R33   A549   H1299
 
  679   H   Cl   H   H   Cl   H   H    
  680   H   Me   Me   H   Me   Me   H    
  681   H   H   H   Br   H   H   Br    
  682   H   Cl   H   H   Cl   H   H    
  683   H   Me   Me   H   Me   Me   H    
  684   H   H   Cl   H   H   Cl   H    
  685   H   H   OEt   H   H   OEt   H    
  686   H   H   OMe   H   H   OMe   H    
  687   H   H   H   H   H   H   H    
  688   H   Me   H   H   Me   H   H    
  689   H   H   Br   H   H   Br   H    
  690   H   H   H   H   H   H   H    
  691   H   H   H   Br   H   H   Br    
  692   H   Me   H   H   Me   H   H    
 
  693   H   H [see pdf for image]   H   H   H   OH   +  
 
  694   H   H [see pdf for image]   H   H   H [see pdf for image]   +   +
 
  695   H   H   H [see pdf for image]   H   F   F    
 
  696   H   H   H [see pdf for image]   H   Cl   H    
 
  697   H   H   H [see pdf for image]   H   Cl   Cl   +   +
 
  698   H   H   H [see pdf for image]   H   HOCF3    
 
  699   H   H   H [see pdf for image]   HOCF3   Cl   +  
 
  700   H   H   H   Me   HOCF3   Cl    
  701   H   HCF3   H   HCF3   H   −   −
  702   H   H   OMe   H   H   OMe   H   +   +
  703   H   HCF3   F   HCF3   F   −  
  704   H   H   OEt   H   H   OEt   H   +   +
  705   H   H   HOCF3   H   HOCF3   −  
  706   H   H   ClCF3   H   ClCF3   −  
  707   H   H   H   OEt   H   H   OEt   +  
  708   H   H   H   OMe   H   H   OMe   +  
  709   H   H   OMe   OMe   H   OEt   H   −  
  710   H   H   OMe   OMe   H   OMe   OMe   +  
  711   H   H   H   OH   H   H   OH   +  
  712   H   H   OMe   OMe   H   H   OH   −  
  713   H   H   OEt   H   H   OMe   OMe   +   +
  714   H   H   H   OH   H   OEt   H   −  
  715   H   H   H   OH   H   OMe   OMe   +  
  716   H   H   Cl   H   H   Cl   H   −  
  717   H   H   H   Cl   H   H   Cl   +  
  718   H   H   t-butyl   H   H   t-butyl   H   −   −
  719   H   H   F   Cl   H   F   Cl   −   −
  720   H   H   F   H   H   F   H   +   −
  721   H   H   Me   H   H   Me   H   −   −
  722   H   H   Et   H   H   Et   H   −  
 
  723   H   H [see pdf for image]   H   H [see pdf for image]   H   +  
 
  724   H   H   H [see pdf for image]   H   H [see pdf for image]   −   +
 
  725   H   H   OMe   OH   H   OMe   OH   +  
  726   H   H   Me   OH   H   Me   OH    
 
  727   H   H [see pdf for image]   H   H [see pdf for image]   H    
 
  728   H   H [see pdf for image]   H   H   H   OH    
 
  729   H   H [see pdf for image]   H   H   H   OH   −  
 
  730   H   H   OH   H   H   OH   H   +  
  731   H   H   OH   Me   H   OH   Me   −  
 
  732   H   H   H [see pdf for image]   H   H   OH   +  
 
  733   H   H [see pdf for image]   H   H [see pdf for image]   H   −  
 
  734   H   H [see pdf for image]   H   H [see pdf for image]   H   −  
 
  735   H   H [see pdf for image]   H   H [see pdf for image]   H    
 
  736   H   H [see pdf for image]   H   H   H   Cl   −  
 
  737   H   H [see pdf for image]   H   H [see pdf for image]   H   −  
 
  738   H   H [see pdf for image]   H   H [see pdf for image]   H   −  
 
  739   H   H [see pdf for image]   H   H [see pdf for image]   H   −  
 
  740   H   H   OH   Cl   H   OH   Cl    
 
  741   H   H [see pdf for image]   Cl   H     Cl    
 
  742   H   H   OH   F   H   OH   F    
  743   H   OMe   OMe   OMe   OMe   OMe   OMe   −  
 
  744   H   H [see pdf for image]   H   H   H   OH   +  
 
  745   H   H   i-propoxy   H   H   i-propoxy   H   −  
 
  746   H   H   H   OH   H [see pdf for image]   H   −  
 
  747   H   H [see pdf for image]   H   H   t-Bu   H   −  
 
  748   H   H   H [see pdf for image]   H   t-Bu   H   −  
 
  749   H   H   H [see pdf for image]   H   t-Bu   H   −  
 
  750   H   H   H [see pdf for image]   H   t-Bu   H   −  
 
  751   H   H   H [see pdf for image]   H   i-propoxy   H   −/+  
 
  752   H   H   H [see pdf for image]   H   i-propoxy   H   −  
 
  753   H   H   H [see pdf for image]   H   OMe   OMe   −  
 
  754   H   H   H [see pdf for image]   H   OMe   OMe   −  
 
  755   H   H   H [see pdf for image]   H   H   OMe   +  
 
  756   H   H   H [see pdf for image]   H   Me   OH    
 
  757   H   H   Me [see pdf for image]   H   H   OH    
 
  758   H   H   Me [see pdf for image]   H   Me   OH    
 
  759   H   H   Me [see pdf for image]   H   Me [see pdf for image]   +   +
 
  760   H   OMe   OMe   OMe   H   H   OH   −  
 
  761   H   H   H [see pdf for image]   H   H   OH    
 
  762   H   H   H [see pdf for image]   H   H   OH   −  
 
  763   H   H   H   OH   H   H [see pdf for image]   −   +
 
  764   H   H   i-pr   H   H   H   OH   −  
  765   H   OMe   H   OMe   H   H   OH   +  
 
  766   H   H   H [see pdf for image]   OMe   H   OMe   −   +
 
  767   H   H   H [see pdf for image]   OMe   H   OMe   −  
 
  768   H   H   H   OH   OMe   H   OMe   +   +
 
  769   H   OMe   H   OMe   H   H [see pdf for image]   −   −
 
  770   H   H   H [see pdf for image]   H   HCF3   +  
 
  771   H   OMe   H   OMe   H   H [see pdf for image]   +  
 
  772   H   H   H [see pdf for image]   H   OEt   H   +   +
 
  773   H   H   OMe [see pdf for image]   H   H   OH    
 
  774   H   H   H [see pdf for image]   H   H   OH    
 
  775   H   H   H [see pdf for image]   H   H   Cl    
 
  776   H   H   H [see pdf for image] CF3   H   OMe    
 
  777   H   H   H [see pdf for image]   H   OMe   OH    
 
  778   H   H   H [see pdf for image]   H   OMeCF3    
 
  779   H   H   H [see pdf for image]   H   FCF3    
 
  780   H   H   H [see pdf for image]   H   Me   Cl    
 
  781   H   HOCF3   Cl   H   H   OH   +   +
  782   H   Br   HCF3   H   H   OH    
 
  783   H   H   H [see pdf for image]   HOCF3   H    
 
  784   H   H   H [see pdf for image]   HCF3   H    
 
  785   H   H   H [see pdf for image]   H   ClCF3    
 
  786   H   H   H   OH   H   HOCF3    
  787   H   Cl   OH   Me   H   H   OH    
 
  788   H   H   H [see pdf for image]   H   OMe   Cl   +  
 
  789   H   H   H [see pdf for image]   H   OMe   F    
 
  790   H   H   H [see pdf for image]   H   Me   OMe   +  
 
  791   H   H   H [see pdf for image]   H   H [see pdf for image]   +   +
 
  792   H   H   H [see pdf for image]   H   H     +   +
 
  793   H   H   H [see pdf for image]   H   MeCF3    
 
  794   H   H   H [see pdf for image]   H   F   Me    
 
  795   H [see pdf for image]   H [see pdf for image]   H   H   OH    
 
  796   H   OH   H [see pdf for image]   H   H   OH    
 
  797   H   OH   H [see pdf for image]   H   H   OH   +   −
 
  798   H [see pdf for image]   H [see pdf for image]   H   H   OH   −   −
 
  799   H   H   H   OH   H   OMe   Cl    
  800   H   H   OMe   Cl   H   OMe   Cl   +   −
  801   H   Me   OH   Cl   H   OMe   Cl    
  802   H   Me   OMe   Cl   H   OMe   Cl   −   −
 
  803   H   H   H [see pdf for image]   H   O-iPr   Cl    
 
  804   H   H   H [see pdf for image]   Me   OMe   Cl    
 
  805   H   OMe   H   OMe   H [see pdf for image]   Cl    
 
  806   HCF3   H   OMe   H [see pdf for image]   Cl   +   +
 
  807   H   H   H [see pdf for image]   H   OMe   Cl    
 
  808   H   Cl   H   Cl   H   OMe   Cl   +   +
  809   H   Me   H   Me   H   OMe   Cl    
  810   HCF3   H   OMe   H   OMe   Cl   +   −
  811   H   Me   Me   Me   H   OMe   Cl   +   −
  812   H   OMe   H   OMe   H   HOCF3   +   +
  813   H   Me   H   Me   H   HOCF3   −   −
  814   H   OMe   H   OMe   Me   H   Me   +   +
  815   H   OMe   HCF3   Me   H   Me   +   +
  816   H   Me   HCF3   Me   H   Me   +   +/−
  817   H   Me   H   MeCF3   H   OMe   +   +
  818   H   OMe   H   OMeCF3   H   OMe   +   +
  819   HCF3   H   OMeCF3   H   OMe   +   +
  820   H   Me   HCF3CF3   H   OMe   +/−   +
  821   H   OMe   OMe   OMeCF3   H   OMe   +   +
  822   H   Me   OH   ClCF3   H   OMe   +   +
  823   H   Cl   H   ClCF3   H   OMe   +   +
  824   HCH2OH   HCH2OHCF3   H   OMe   +   −/+
  825   H   Me   Cl   MeCF3   H   OMe   +   +
 
  826   H   H   H [see pdf for image]   H   Cl   OMe    
 
  827   H   H   H [see pdf for image]   H [see pdf for image]   Cl    
 
  828   H   Cl   OH   Cl   H   OMe   Cl   +   +
  829   H   Cl   OH   Cl   HOCF3   Cl   +   +
 
  830   H   H   H [see pdf for image]   H [see pdf for image]   Cl    
 
  831   H   Cl   OMe   Cl   H   OMe   Cl   −   −
  832   H   Cl   OMe   Cl   HOCF3   Cl   +   −
 
  833   H   H   H [see pdf for image]   Cl   OMe   Cl    
 
  834   H   Cl   OMe   Cl   H   Cl   Cl   +   +
  835   H   OMe   H   OMe   H   Cl   Cl   +   +
  836   H   OMe   H   OMe   H   OMe   Cl    
  837   H   OMe   H   OMe   HOCF3   Cl    
  838   H   Me   H   Me   H   Cl   Cl   +   −
  839   H   OMe   H   OMe   OMe   H   OMe   +  
  840   H   OMe   H   OMe   OMe   H   OMe   +   +
  841   H   Me   H   Me   Me   H   Me   +   +
  842   HCH2OH   HCH2OH   OMe   H   OMe   +   +
  843   HCH2OH   HCH2OH   H   OMe   Cl   +   +
  844   HCH2OH   HCH2OH   H   Cl   Cl   +   +
  845   H   Me   Me   Me   OMe   H   OMe   +   +
  846   H   Me   H   Me   OMe   H   OMe   +   +
  847   H   Cl   H   Cl   OMe   H   OMe   +  
  848   H   Me   HCF3   OMe   H   OMe   +  
  849   H   OMe   HCF3   OMe   H   OMe   +   +
 
  850   Me   H   H [see pdf for image]   OMe   H   OMe   −   −
 
  851   Me   Me   H   Me   OMe   H   OMe   +   +
  852   Me   OMe   H   OMe   OMe   H   OMe   +   +
  853   Me   H   OMe   Cl   OMe   H   OMe   −   −
  854   Me   H   Cl   OMe   OMe   H   OMe   −   −
  855   H   Me   H   Me   OMe   H   OMe   +   +
  856   H   OMe   H   OMe   H   OMe   OMe   +   +
 
  857   H   H   H [see pdf for image]   H   OMe   OMe    
 
  858   H   H   H [see pdf for image]   H   OMe   OMe   +   +
 
  859   H   H   H [see pdf for image]   H   OMe   OMe   +   +
 
  860   H   H   OMe   Cl   H   OMe   OMe    
 
  861   H   H   H [see pdf for image]   OMe   H   OMe   +   +
 
  862   H   H   H [see pdf for image]   H   OMe   OMe   +   +
 
  863   H   H [see pdf for image]   H   H   OMe   OMe   +   +
 
  864   Me   Me   H   Me   H   OMe   OMe   +   +
  865   Me   OMe   H   OMe   H   OMe   OMe   +   +
 
  866   H   H [see pdf for image]   H   OMe   H   OMe   +   +
 
  867   Me   H   H [see pdf for image]   H   OMe   OMe   −   +
 
  868   Me   H   H [see pdf for image]   H   OMe   OMe   +   +
 
  869   Me   H [see pdf for image]   H   H   OMe   OMe   +   +
 
  870   Me   H   H [see pdf for image]   H   OMe   OMe   −   −
 
  871   H   H   C(O)NHMe   Cl   H   OMe   OMe   +   +
  872   H   H   C(O)NHMe   Cl   OMe   H   OMe   +   +
  873   H   H   C(O)NHMe   Cl   H   OMe   Cl    
  874   H   H   C(O)NHMe   Cl   H   H   OH    
  875   Me   H   C(O)NHMe   Cl   H   OMe   OMe   +   +
  876   H   OMe   H   OMe   H   C(O)NHMe   Cl    
  877   H   Me   H   Me   H   C(O)NHMe   Cl    
 
  878   H   H   H [see pdf for image]   H   C(O)NHMe   Cl    
 
  879   H   HS(O)2NHMe   OMe   H   OMe   OMe   +   +
  880   H   HS(O)2NHMe   OMe   OMe   H   OMe   +   +
  881   H   HS(O)2NHMe   OMe   H   ClCF3    
  882   H   HS(O)2NHMe   OMe   HOCF3   Cl    
  883   H   HS(O)2NHMe   OMe   H   H   Cl    
  884   H   OMe   H   OMe   HS(O)2NHMe   OMe   +   +
 
  885   H   H   H [see pdf for image]   H   H   OH   +   +
 
  886   H   H   H [see pdf for image]   H   OMe   OMe   +   +
 
  887   H   C(O)OMe   H [see pdf for image]   H   OMe   OMe   +   +
 
  888   H   C(O)Me   H [see pdf for image]   H   H   OH   +   +
 
  889   HCF3   H [see pdf for image]   H   OMe   OMe   +   +
 
  890   H   H   H [see pdf for image]   H   H   OH   +   +
 
  891   H [see pdf for image]   H [see pdf for image] [see pdf for image]   H [see pdf for image]   −   −
 
  892   HCF3   H [see pdf for image] CF3   H [see pdf for image]   +   +
 
  893   H   Cl   OH   Cl   Cl   OMe   Cl    
 
  894   H   H [see pdf for image]   Me   H [see pdf for image]   Me   +   +
 
  895   H   OMe   OMe   OMe   Me   H   Me   +   +
  896   H   Me   Cl   Cl   Me   H   Me   +   +
  897   HCH2OH   HCH2OH   Me   H   Me   +   +
  898   H   Cl   H   Cl   Me   H   Me   −   −
  899   H   Cl   Cl   Cl   Me   H   Me   +   +
  900   H   Me   Cl   Me   Me   H   Me   −   −
 
  901   H   Me [see pdf for image]   Me   H   OMe   Cl    
 
  902   H   Me [see pdf for image]   Me   OMe   H   OMe   +   +
 
  903   Me   OMe   H   OMe   H   OMe   Cl   +   +
  904   Me   Me   OMe   Cl   H   OMe   Cl   −   −
 
  905   Me   Me [see pdf for image]   Me   H   OMe   Cl   +   +
 
  906   Me   H   H [see pdf for image]   H   OMe   Cl   +   +
 
  907   Me   H   Me   H   H   OMe   Cl   −   +
  908   Me   OMe   H   OMe   H   Cl   OMe    
  909   Me   Me   H   Me   H   Cl   OMe   +   +
 
  910   Me   H   H [see pdf for image]   H   Cl   OMe   +   −
 
  911   Me   OMe   H   OMe   Me   Cl   Me    
  912   Me   Me   H   Me   Me   Cl   Me   −   −
 
  913   Me   H   H [see pdf for image]   Me   Cl   Me   +   +
 
  914   Me   H   H [see pdf for image]   Me   Cl   Me   −   −
 
  915   H   Me   H   Me   H [see pdf for image]   Cl    
 
  916   H   OMe   H   OMe   H [see pdf for image]   Cl    
 
  917   H   H   OMe   Cl   H [see pdf for image]   Cl   +   +
 
  918   H   Me   Cl   Me   H [see pdf for image]   Cl    
 
  919   H   H   C(O)NHMe   Cl   H   Cl   OMe    
  920   H   H   C(O)NHMe   Cl   H   ClCF3    
  921   Me   H   C(O)NHMe   Cl   Me   Cl   Me   +   +
 
  922   H   Me   H   Me   H [see pdf for image]   Cl    
 
  923   H   OMe   H   OMe   H [see pdf for image]   Cl    
 
  924   H   H   OMe   Cl   H [see pdf for image]   Cl    
 
  925   H   Me   Cl   Me   H [see pdf for image]   Cl    
 
  926   H   Me   H   Me   H [see pdf for image]   Cl    
 
  927   H   OMe   H   OMe   H [see pdf for image]   Cl    
 
  928   H   OMe   Cl   H   H [see pdf for image]   Cl    
 
  929   H   Me   Cl   Me   H [see pdf for image]   Cl    
 
  930   H   H   Cl   OMe   H [see pdf for image]   Cl    
 
  931   H   Me [see pdf for image]   Me   OMe   H   OMe   +   +
 
  932   H   H   H [see pdf for image]   OMe   OMe   OMe   +   +
 
  933   H   H   H [see pdf for image]   OH   OH [see pdf for image]   +   +
 
  934   H   H [see pdf for image]   H   H   H   OH   +  
 
  935   H   H   H [see pdf for image]   H   i-pr   H   −  
 
  936   H   H [see pdf for image]   H   H   i-pr   H   −  
 
  937   H   H [see pdf for image]   H   H   i-pr   H   +  
 
  938   H   H   F   Cl   H   F   Cl   −  
 
  939   H   H   H   OH   H   H [see pdf for image]   −  
 
  940   H   H   H [see pdf for image]   OMe   H   OMe   +   +
 
  941   H   Cl   OH   Cl   Cl   OH   Cl   −  
  942   H   Me   OH   Cl   Me   OH   Cl   +   +
  943   H   Cl   OH   Me   H   H   OH   +  
  944   H   H   H   OH   Cl   OH   Me    
 
  945   H   H   OMe   OMe   H [see pdf for image]   Me   +   +
 
  946   H   Me   OH   Cl   H [see pdf for image]   H    
 
  947   H   H   H [see pdf for image]   Me   OH   Me   −   +
 
  948   H   H   H [see pdf for image]   Me   OH   Me   −  
 
  949   H   H   H [see pdf for image]   Me   OH   Me   +   +
 
  950   H   H   H [see pdf for image]   Me   OH   Me   +   +
 
  951   H   H   H   t-Bu   H   H   OH   −  
 
  952   H   H   H [see pdf for image]   Cl   OH   Me   −   +
 
  953   H   H   H   t-Bu   H   OMe   OMe   −  
 
  954   H   H   H [see pdf for image]   Cl   OH   Me   −  
 
  955   H   H   H   t-Bu   H   H [see pdf for image]   −   −
 
  956   H   H   H   t-Bu   H   H [see pdf for image]   −  
 
  957   H   H   H [see pdf for image]   Cl   OH   Me   +  
 
  958   H   H   H [see pdf for image]   H   H   t-Bu   −   −
 
  959   H   Me   OH   Cl   H   H   t-Bu   −  
 
  960   H   H   H [see pdf for image]   H   H   t-Bu   −  
 
  961   H   H   H [see pdf for image]   H   H   t-Bu   −/+  
 
  962   H   H   H [see pdf for image]   H   H   t-Bu   −   −
 
  963   H   H   H [see pdf for image]   H   H   t-Bu    
 
  964   H   H   H   OEt   H   H   i-pr   −  
 
  965   H   H   H [see pdf for image]   H   H   i-pr   −  
 
  966   H   H   H [see pdf for image]   H   H   i-pr   +  
 
  967   H   H   H [see pdf for image]   HCH2OHCH2OH   −  
 
  968   H   H   H   i-pr   H   H   i-pr   −   +
  969   H   H   OMe   OMe   H   H   OH   +   +
 
  970   H   H   H [see pdf for image]   H   HCH2NH2   +   +
 
  971   H   H [see pdf for image]   H   H [see pdf for image]   H   −  
 
  972   H   H [see pdf for image]   H   H [see pdf for image]   H    
 
  973   H   H [see pdf for image]   H   H [see pdf for image]   H   −  
 
  974   H   H   H   OH   H [see pdf for image]   H   +   +
 
  975   H   H [see pdf for image]   H   H   H   OH    
 
  976   H   H   H [see pdf for image]   H   H   OH   −  
 
  977   H   H   H [see pdf for image]   H   i-propoxy   H   −  
 
  978   H   H   H [see pdf for image]   H   H   OH   −  
 
  979   H   H   H [see pdf for image]   Me   OH   Me   −   +
 
  980   H   H   H [see pdf for image]   Me   OH   Me   +  
 
  981   H   H   H [see pdf for image]   Me   OH   Me   +  
 
  982   H   H   H [see pdf for image]   Me   OH   Me   −  
 
  983   H   H   H [see pdf for image]   Cl   OH   Me   +  
 
  984   H   H   H [see pdf for image]   Cl   OH   Me   +  
 
  985   H   H   H [see pdf for image]   Me   OMe   Me   −  
 
  986   H   H   H [see pdf for image]   Me   OMe   Me   −  
 
  987   H   H   H [see pdf for image]   Me   OMe   Me   −  
 
  988   H   H   H [see pdf for image]   H [see pdf for image]   H   +   +
 
  989   H   H   H [see pdf for image]   H [see pdf for image]   H   +   +
 
  990   H   H   H [see pdf for image]   H [see pdf for image]   H   +   +
 
  991   H   H   H [see pdf for image]   Me   OH   Cl   +  
 
  992   H   H   H [see pdf for image]   H [see pdf for image]   H   −   −
 
  993   H   H   H [see pdf for image]   H [see pdf for image]   H   +   +
 
  994   H   H   H [see pdf for image]   H   H [see pdf for image]    
 
  995   H   H   H [see pdf for image]   H   H [see pdf for image]   +   +
 
  996   H   H   OHCF3   H   OHCF3   −/+  
  997   H   H   H   Me   H   H   Me   +  
  998   H   H   Me   H   H   Me   H   −  
 
  999   H   H   H [see pdf for image]   Cl   OH   Cl   −   −
 
  1000   H   H   H [see pdf for image]   Cl   OH   Cl    
 
  1001   H   H   H [see pdf for image]   Cl   OH   Cl   −   −
 
  1002   H   H   H [see pdf for image]   H [see pdf for image]   H   −  
 
  1003   H   H   H [see pdf for image]   H [see pdf for image]   H   −  
 
  1004   H   H   H [see pdf for image]   H   OH   H   −  
 
  1005   H   H   H [see pdf for image]   H   OMeCH2OH    
 
  1006   H   H   H [see pdf for image]   H   Cl   Cl   +   +
 
  1007   Me   Me   H   Me   H   Cl   Cl   −   −
  1008   Me   H   OMe   Cl   H   Cl   Cl    
  1009   Me   OMe   H   OMe   H   Cl   Cl   −   −
  1010   Me   Cl   OMe   Cl   H   Cl   Cl    
  1011   Me   HOCF3   Cl   H   Cl   Cl    
  1012   H   HCH2NHBoc   H   HCH2NHBoc   H   +   +
  1013   H   HCH2NH2   H   HCH2NH2   H   +   +
 
  1014   H   H [see pdf for image]   H   H   Cl   Cl    
 
  1015   H   H   HCH2NHBoc   H   HCH2NHBoc   +   +
  1016   H   H   HCH2NHBoc   H   HCH2NHBoc   +   +
  1017   H   H   HCH2NHBoc   H   Cl   Cl    
  1018   H   H   HCH2NHBoc   H   Cl   Cl    
 
  1019   H   H [see pdf for image]   H   H   Cl   Cl    
 
  1020   Me   H [see pdf for image]   H   H   Cl   Cl    
 
  1021   H   H [see pdf for image]   H   H   OMe   Cl   +   +
 
  1022   H   HC(O)NH2   H   H   OMe   Cl   +   +
  1023   H   HCH2NHBoc   H   H   OMe   Cl   +   +
  1024   H   HCH2NHBoc   H   H   OMe   Cl   +   +
 
  1025   H   H [see pdf for image]   H   H   OMe   Cl   −   +
 
  1026   H   H   H   OH   HC(O)NH2   H   −   +
  1027   H   Cl   OH   Cl   HC(O)NH2   H   +   +
  1028   H   H   OMe   Cl   HC(O)NH2   H   +   +
  1029   H   HC(O)NH2   H   HC(O)NH2   H   −   −
  1030   Me   HC(O)NH2   H   H   Cl   C   +   +
 
  1031   Me   H [see pdf for image]   H   H   Cl   Cl   +   +
 
  1032   H   HC(O)NH2   H   H   Cl   OMe   −   −
  1033   H   HC(O)NH2   Cl   H   OMe   Cl   +   +
  1034   H   HC(O)NH2   Cl   H   Cl   OMe   −   +
 
  1035   H   H [see pdf for image]   H   H   Cl   OMe   +   +
 
  1036   H   HC(O)NH2   H   H   H   H   +   +
 
[00009] [TABLE-US-00009]
  TABLE 9
 
[see pdf for image]
 
    No.R4′R2′R2   A549   H1299
   
    1037   H   HCH2CH═CH2   −  
    1038   Me   H   Me   +   +
    1039   Me   Me   Me   +   +
    1040   Me   HCH2CH2OH   +   +
    1041   Me   H   i-propyl   +   +
    1042   MeCH2CH2OHCH2CH2OH   −   +
    1043   Me   HCH2CH═CH2   +   +
    1044   H   H   Me   −   −
   
[00010] [TABLE-US-00010]
  TABLE 10
 
[see pdf for image]
 
  No.R4′R40R41R42   A549   H1299
 
  1045   H   H   OMe   OMe   −  
  1046   H   H   OMe   Me   +   +
  1047   H   OMe   H   Me   +   +
  1048   H   Me   H   F   +   +
  1049   H   OMe   Cl   OMe   +   +
 
[00011] [TABLE-US-00011]
  TABLE 11
 
[see pdf for image]
 
  No.R21R22R23   A549   H1299
 
  1050   Me   OMe   Me   +   +
  1051   H   OMe   F   +   +
  1052   Me   H   Me   +   +
  1053   OMe   H   OMe   +   +
 
  1054   H   H [see pdf for image]   +   +
 
  1055   H   H [see pdf for image]   −   −
 
  1056   H [see pdf for image]   H   −   −
 
  1057   H [see pdf for image]   H   −   −
 
  1058   H [see pdf for image]   H   −   −
 
  1059   H   H [see pdf for image]   −   −
 
[00012] [TABLE-US-00012]
  TABLE 12
 
[see pdf for image]
 
  No.R13aR13bR19R20   A549   H1299
 
  1060   Me   OH   Me   Me   +   +
  1061   Me   OMe   Me   Me   +   +
  1062   Me   OMe   H   H   +   +
  1063   Me   OH   H   H   +   +
  1064   Me   OH   Me   Me   +   +
  1065   Me   OMe   Me   Me   +   −
 
[00013] [TABLE-US-00013]
  TABLE 13
 
  Type A
 
[see pdf for image]
 
  Type B
 
[see pdf for image]
 
  Type C
 
[see pdf for image]
 
  Type D
 
[see pdf for image]
 
  No.   TypeR16R31R32R33   A549   H1299
 
  1066   B   ethyl   H   OMe   Cl    
  1067   B   ethyl   H   Cl   Cl    
  1068   B   ethyl   —   —   —    
  1069   B   ethyl   H   F   OMe    
  1070   A   ethyl   H   OMe   Cl    
  1071   A   ethyl   H   Cl   Cl    
  1072   C   ethyl   —   —   —    
  1073   A   ethyl   H   F   OMe    
  1074   B   n-propyl   H   OMe   Cl   +   +
  1075   B   n-propyl   H   Cl   Cl   −   −
  1076   D   n-propyl   —   —   —   +   +
  1077   A   n-propyl   H   F   OMe   +   +
  1078   B   n-propyl   H   OMe   Cl   +   +
  1079   B   n-propyl   H   Cl   Cl   +   +
  1080   C   n-propyl   —   —   —   +   +
  1081   A   n-propyl   H   F   OMe   +   +
  1082   B   n-butyl   H   OMe   Cl   +   −
  1083   B   n-butyl   H   Cl   Cl   +   +
  1084   D   n-butyl   —   —   —   +   +
  1085   B   n-butyl   H   F   OMe   +   +
  1086   A   n-butyl   H   OMe   Cl   +   +
  1087   A   n-butyl   H   Cl   Cl   +   +
  1088   C   n-butyl   —   —   —   +   +
  1089   A   n-butyl   H   F   OMe   +   +
 
  1090   B [see pdf for image]   H   OMe   Cl   +   +
 
  1091   B [see pdf for image]   H   Cl   Cl   −   −
 
  1092   D [see pdf for image]   —   —   —   +   +
 
  1093   B [see pdf for image]   H   F   OMe   +   +
 
  1094   A [see pdf for image]   H   OMe   Cl   +   +
 
  1095   A [see pdf for image]   H   Cl   Cl   +   +
 
  1096   C [see pdf for image]   —   —   —   +   +
 
  1097   A [see pdf for image]   H   F   OMe   −   +
 
  1098   B [see pdf for image]   H   OMe   Cl   −   +
 
  1099   B [see pdf for image]   H   Cl   Cl   +   +
 
  1100   D [see pdf for image]   —   —   —   +   +
 
  1101   B [see pdf for image]   H   F   OMe   +   +
 
  1102   A [see pdf for image]   H   OMe   Cl   +   +
 
  1103   A [see pdf for image]   H   Cl   Cl     −
 
  1104   C [see pdf for image]   —   —   —   +   +
 
  1105   A [see pdf for image]   H   F   OMe   +   +
 
  1106   B [see pdf for image]   H   OMe   Cl   +   +
 
  1107   B [see pdf for image]   H   Cl   Cl   −   −
 
  1108   D [see pdf for image]   —   —   —   +   +
 
  1109   B [see pdf for image]   H   F   OMe   +   +
 
  1110   A [see pdf for image]   H   OMe   Cl   +   +
 
  1111   A [see pdf for image]   H   Cl   Cl   +   +
 
  1112   C [see pdf for image]   —   —   —   +   +
 
  1113   A [see pdf for image]   H   F   OMe   +   +
 
  1114   B [see pdf for image]   H   OMe   Cl    
 
  1115   B [see pdf for image]   H   Cl   Cl   +   +
 
  1116   D [see pdf for image]   —   —   —    
 
  1117   B [see pdf for image]   H   F   OMe   +   +
 
  1118   A [see pdf for image]   H   OMe   Cl   +   +
 
  1119   A [see pdf for image]   H   Cl   Cl   +   +
 
  1120   C [see pdf for image]   —   —   —    
 
  1121   A [see pdf for image]   H   F   OMe   +   +
 
  1124   C   methyl   —   —   —    
  1125   C   methyl   —   —   —    
  1126   C   methyl   —   —   —    
  1127   B   i-propyl   H   OMe   Cl    
  1128   B   i-propyl   H   Cl   Cl    
  1129   D   i-pr