# Patent

## Title
Methods of treating cancer using pyridopyrimidinone inhibitors of PI3K alpha

## Abstract

The present invention provides methods of treating cancer by administering a compound of Formula I, optionally as a pharmaceutically acceptable salt, solvate and/or hydrate thereof, in combination with other cancer treatments.
(Formula I)

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a US national phase of international application PCT/US2008/04573 filed on Apr. 9, 2008, which claims priority to U.S. Provisional Patent Application Ser. No. 60/922,899 filed on Apr. 10, 2007, the disclosures of which are incorporated herein by reference.


FIELD OF THE INVENTION
This invention relates to methods of treating cancer with a compound that inhibits lipid kinase enzymatic activity and the resultant modulation of cellular activities (such as proliferation, differentiation, programmed cell death, migration, chemoinvasion and metabolism) in combination with anticancer agents.
BACKGROUND OF THE INVENTION
Improvements in the specificity of agents used to treat various disease states such as cancer, metabolic, and inflammatory diseases is of considerable interest because of the therapeutic benefits which would be realized if the side effects associated with the administration of these agents could be reduced. Traditionally, dramatic improvements in the treatment of cancer are associated with identification of therapeutic agents acting through novel mechanisms.
Phosphatidylinositol 3-kinase (PI3K or PIK3CA) is composed of an 85 kDa regulatory subunit and a 110 kDa catalytic subunit. The protein encoded by this gene represents the catalytic subunit, which uses ATP to phosphorylate PtdIns, PtdIns4P and PtdIns(4,5)P2. PTEN, a tumor suppressor which inhibits cell growth through multiple mechanisms, can dephosphorylate PIP3, the major product of PIK3CA. PIP3, in turn, is required for translocation of protein kinase B (AKT1, PKB) to the cell membrane, where it is phosphorylated and activated by upstream kinases. The effect of PTEN on cell death is mediated through the PIK3CA/AKT1 pathway.
PI3Kα has been implicated in the control of cytoskeletal reorganization, apoptosis, vesicular trafficking, proliferation and differentiation processes. Increased copy number and expression of PIK3CA or activating mutations in the p110a catalytic subunit of PIK3CA are associated with a number of malignancies such as ovarian cancer (Campbell et al., Cancer Res 2004, 64, 7678-7681; Levine et al., Clin Cancer Res 2005, 11, 2875-2878; Wang et al., Hum Mutat 2005, 25, 322; Lee et al., Gynecol Oncol 2005, 97, 26-34), cervical cancer, breast cancer (Bachman, et al. Cancer Biol Ther 2004, 3, 772-775; Levine, et al., supra; Li et al., Breast Cancer Res Treat 2006, 96, 91-95; Saal et al., Cancer Res 2005, 65, 2554-2559; Samuels and Velculescu, Cell Cycle 2004, 3, 1221-1224), colorectal cancer (Samuels, et al. Science 2004, 304, 554; Velho et al. Eur J Cancer 2005, 41, 1649-1654), endometrial cancer (Oda et al. Cancer Res. 2005, 65, 10669-10673), gastric carcinomas (Byun et al., Int J Cancer 2003, 104, 318-327; Li et al., supra; Velho et al., supra; Lee et al., Oncogene 2005, 24, 1477-1480), hepatocellular carcinoma (Lee et al., id.), small and non-small cell lung cancer (Tang et al., Lung Cancer 2006, 51, 181-191; Massion et al., Am J Respir Crit Care Med 2004, 170, 1088-1094), thyroid carcinoma (Wu et al., J Clin Endocrinol Metab 2005, 90, 4688-4693), acute myelogenous leukemia (AML) (Sujobert et al., Blood 1997, 106, 1063-1066), chronic myelogenous leukemia (CML) (Hickey and Cotter J Biol Chem 2006, 281, 2441-2450), and glioblastomas (Hartmann et al. Acta Neuropathol (Berl) 2005, 109, 639-642; Samuels et al., supra).
In view of the important role of PI3K-α in biological processes and disease states, inhibitors and/or modulators of this lipid kinase are desirable. In addition, it is well established that combining treatments with different mechanisms of action often leads to enhanced anti-tumor activity as compared to single treatments administered alone. This is true for combinations of chemotherapies (e.g. Kyrgiou M. et. al. J Natl Cancer Inst 2006, 98, 1655) and combinations of antibodies and chemotherapy (e.g. Pasetto L M et. al. Anticancer Res 2006, 26, 3973.
For example, activation of the PI3K pathway contributes to the resistance of human tumor cells to a wide variety of chemotherapeutic agents, including microtubule stabilizing agents such as taxol (Brognard, J., et. al. Cancer Res 2001, 61, 3986-3997; Clark, A. S., et. al. Mol Cancer Ther 2002, 1, 707-717; Kraus, A. C., et. al. Oncogene 2002, 21, 8683-8695; Krystal, G. W., et. al. Mol Cancer Ther 2002, 1, 913-922; and Yuan, Z. Q., et. al. J Biol Chem 2003, 278, 23432-23440). Taxol is widely used to treat advanced cancers including prostate carcinomas, which frequently harbor deletions in the PTEN gene, resulting in elevated signaling downstream of PI3K. A number of preclinical studies suggest that inhibiting signaling downstream of PI3K restores or enhances the ability of chemotherapeutic agents such as taxol to kill tumor cells (Brognard, J., et. al. Cancer Res 2001, 61, 3986-3997; Clark, A. S., et. al. Mol Cancer Ther 2002, 1, 707-717; Kraus, A. C., et. al. Oncogene 2002, 21, 8683-8695; Krystal, G. W., et. al. Mol Cancer Ther 2002, 1, 913-922; and Saga, Y., et. al. Clin Cancer Res 2002, 8, 1248-1252).
Rapamycin, another chemotherapeutic agent, is a potent inhibitor of the mTOR/Raptor complex. Inhibition of mTOR/Raptor prevents p70S6K and S6 phosphorylation, but also leads to relief of a negative feedback loop emanating from p70S6K that serves to downregulate PI3K (Sarbassov, D. D., et. al. Science 2005, 307, 1098-1101). As a result, rapamycin treatment can lead to upregulation of PI3K and increased phosphorylation of AKT (O′Donnell, A., et. al. paper presented at Proc Am Soc Clin Oncol. 2003; and O′Reilly, K. E., et. al. Cancer Res 2006, 66, 1500-1508). Thus, combining rapamycin with inhibitors of PI3K can enhance the efficacy of rapamycin (Powis, G. et. al. Clinical Cancer Research 2006, 12, 2964-2966; Sun, S.-Y., et. al. Cancer Research 2005, 65, 7052-7058).
A growing body of clinical and preclinical data indicates that activation of the PI3K pathway confers resistance to EGFR inhibitors such as erlotinib (Bianco, R., et. al. Oncogene 2003, 22, 2812-2822; Chakravarti, A., et. al. Cancer Res 2002, 62, 200-207; and Janmaat, M. L., et. al. Clin Cancer Res 2003, 9, 2316-2326). Both NSCLC patients with K-Ras mutations and glioblastoma patients with PTEN deletions fail to respond to erlotinib, potentially because of genetic activation of the PI3K pathway (Mellinghoff, I. K., et. al. N. Eng. J Med. 2006, 353, 2012-2024). Preclinical studies have shown that downregulation of PI3K signaling in EGFR-expressing tumor cells confers increased sensitivity to EGFR inhibitors (Ihle, N. T., et. al. Mol Cancer Ther 2005, 4, 1349-1357). Thus, treating cancer with a PI3K inhibitor in combination with an EGFR inhibitor, such as erlotinib, is desirable.
Activation of the PI3K pathway also contributes to the resistance of human tumor cells to DNA damaging agents, such as platins. A number of preclinical studies suggest that inhibiting signaling downstream of PI3K restores or enhances the ability of chemotherapeutic agents such as platins to kill tumor cells (Brognard, J., et. al. Cancer Res 2001, 61, 3986-3997; and Yuan, Z. Q., et. al. J Biol Chem 2003, 278, 23432-23440). Carboplatin is widely used to treat advanced cancers including non-small cell lung carcinomas (NSCLC), which frequently harbor activating mutations in the K-Ras gene, resulting in activation of PI3K (Aviel-Ronen S., et. al. Clin Lung Cancer 2006, 8, 30-38). NSCLC patients with K-Ras mutations do not respond to EGFR inhibitors such as Tarceva, and thus represent a significant unmet medical need (Janne P A, et. al. J Clin Oncology 2005, 23, 3227-3234). Thus, treating NSCLC with a DNA-damaging agent such as a platin in combination with an inhibitor of PI3K is desirable in light of the lack of efficacious treatments.
Treatments that combine an inhibitor of PI3K-α with other anti-cancer agents are desirable and needed.
SUMMARY OF THE INVENTION
The following only summarizes certain aspects of the invention and is not intended to be limiting in nature. These aspects and other aspects and embodiments are described more fully below. All references cited in this specification are hereby incorporated by reference in their entirety. In the event of a discrepancy between the express disclosure of this specification and the references incorporated by reference, the express disclosure of this specification shall control.
The compositions of the invention are used to treat diseases associated with abnormal and or unregulated cellular activities. Disease states which can be treated by the methods and compositions provided herein include cancer. The invention is directed to methods of treating these diseases by administering a Compound of Formula I or II in combination with one or more treatments.
One aspect of the Invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I:




or a single isomer thereof where the compound is optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof; or administering a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable carrier, excipient, or diluent in combination with one or more treatments independently selected from surgery, one or more chemotherapeutic agents, one or more hormone therapies, one or more antibodies, one or more immunotherapies, radioactive iodine therapy, and radiation, where the Compound of Formula I is that wherein:

    R1 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl;
    R2 is hydrogen or alkyl where the alkyl is optionally substituted with 1, 2, 3, 4, or 5 R8 groups;
    X is —NR3—;
    R3 hydrogen;
    R4 is optionally substituted alkyl;
    R5 is hydrogen; and
    R6 is phenyl, acyl, or heteroaryl wherein the phenyl and heteroaryl are optionally substituted with 1, 2, 3, 4, or 5 R9 groups;
    each R8, when present, is independently hydroxy, halo, alkoxy, haloalkoxy, amino, alkylamino, dialkylaminoalkyl, or alkoxyalkylamino; and
    each R9, when present, is independently halo, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, alkylamino, dialkylamino, alkoxyalkyl, carboxyalkyl, alkoxycarbonyl, aminoalkyl, cycloalkyl, aryl, arylalkyl, aryloxy, heterocycloalkyl, or heteroaryl and where the cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, each either alone or as part of another group within R9, are independently optionally substituted with 1, 2, 3, or 4 groups selected from halo, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino, alkylamino, and dialkylamino.


A second aspect of the Invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula II:




or a single isomer thereof where the compound is optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof; or administering a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula II and a pharmaceutically acceptable carrier, excipient, or diluent in combination with one or more treatments independently selected from surgery, one or more chemotherapeutic agents, one or more hormone therapies, one or more antibodies, one or more immunotherapies, radioactive iodine therapy, and radiation, where the Compound of Formula II is that wherein:

    R1 is hydrogen, optionally substituted alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl;
    X is S, SO2, or —NR3—;
    R2 is hydrogen, haloalkyl, optionally substituted alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkyl-aryl- or optionally substituted heteroaryl; R2 is optionally further substituted with one or more R8 groups;
    R3, R3a, and R3b are independently hydrogen, optionally substituted alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl or optionally substituted heteroaryl;
    R4 is hydrogen, halo, haloalkyl, haloalkoxy, —NR3a—, optionally substituted alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxyalkyl, optionally substituted aminoalkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
    R5 is hydrogen, halo, haloalkyl, haloalkoxy, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxyalkyl, optionally substituted aminoalkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted aryl, optionally substituted aryl C1-C6 alkyl or optionally substituted heteroaryl; and
    R6 is hydrogen, halo, haloalkyl, haloalkoxy, —NR3b—, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxyalkyl, optionally substituted acyl, optionally substituted aminoalkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl; substitutable R6 groups are optionally further substituted with 1, 2, 3, 4, or 5 R9 groups;
    each R8, when present, is independently hydroxy, halo, haloalkyl, haloalkoxy, optionally substituted alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 alkoxyalkylaminoalkyl, C1-C6 alkylcarboxyheterocycloalkyl, oxy C1-C6alkylheterocycloalkyl, optionally substituted aminoalkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted aryl, optionally substituted aryl C1-C6 alkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl;
    each R9, when present, is independently halo, haloalkyl, haloalkoxy, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 carboxyalkyl, optionally substituted alkoxycarbonyl, optionally substituted aminoalkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted aryl, optionally substituted aryl C1-C6 alkyl, optionally substituted aryloxy, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl.





BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 illustrates tumor growth inhibition after treatment with Compound A, a PI3K inhibitor, as a single agent and regression after treatment with Compound A in combination with taxol in a PC-3 prostate carcinoma tumor model.
FIG. 2 illustrates tumor growth inhibition after treatment with Compound A, a PI3K inhibitor, as a single agent and transient regression after treatment with Compound A in combination with rapamycin in a PC-3 prostate carcinoma tumor model.
FIG. 3 illustrates tumor growth inhibition after treatment with Compound A, a PI3K inhibitor, as a single agent as well as in combination with carboplatin in a Calu-6 non-small cell lung cancer tumor model.
FIG. 4a illustrates tumor growth inhibition after treatment with Compound A, a PI3K inhibitor, as a single agent as well as in combination with Compound B, an EGFR inhibitor, in an A549 non-small cell lung cancer tumor model.
FIG. 4b-1 illustrates tumor growth inhibition after treatment with Compound A, a PI3K inhibitor, as a single agent as well as in combination with Compound B, an EGFR inhibitor, in an MCF7 breast cancer tumor model (Study 1).
FIG. 4b-2 illustrates tumor growth inhibition after treatment with Compound A, a PI3K inhibitor, as a single agent as well as in combination with Compound B, an EGFR inhibitor, in an MCF7 breast cancer tumor model (Study 2).
FIG. 5 illustrates tumor growth inhibition after treatment with Compound A, a PI3K inhibitor, as a single agent as well as in combination with Erlotinib, an EGFR inhibitor, in an MDA-MB-468 breast carcinoma tumor model.
FIG. 6 illustrates the decrease in the fraction of proliferating cells after histological analysis of the tumors for Ki67, a marker of proliferation.
FIG. 7 illustrates the induction in the fraction of apoptotic cells after histological analysis of the tumors using the TUNEL method.
FIG. 8 depicts a first study of immunohistochemical analysis of proliferation, vascularity, and apoptosis in MCF7 xenograft tumors.
FIG. 9 depicts another study of immunohistochemical analysis of proliferation, vascularity, and apoptosis in MCF7 xenograft tumors.



DETAILED DESCRIPTION OF THE INVENTION
Abbreviations and Definitions
The following abbreviations and terms have the indicated meanings throughout:














Abbreviation
Meaning









Ac
acetyl



br
broad



° C.
degrees Celsius



c-
cyclo



CBZ
CarboBenZoxy = benzyloxycarbonyl



d
doublet



dd
doublet of doublet



dt
doublet of triplet



DCM
dichloromethane



DME
1,2-dimethoxyethane



DMF
N,N-dimethylformamide



DMSO
dimethyl sulfoxide



dppf
1,1′-bis(diphenylphosphano)ferrocene



EI
Electron Impact ionization



g
gram(s)



h or hr
hour(s)



HPLC
high pressure liquid chromatography



L
liter(s)



M
molar or molarity



m
Multiplet



mg
milligram(s)



MHz
megahertz (frequency)



Min
minute(s)



mL
milliliter(s)



μL
microliter(s)



μM
Micromole(s) or micromolar



mM
Millimolar



mmol
millimole(s)



mol
mole(s)



MS
mass spectral analysis



N
normal or normality



nM
Nanomolar



NMR
nuclear magnetic resonance spectroscopy



q
Quartet



RT
Room temperature



s
Singlet



t or tr
Triplet



TFA
trifluoroacetic acid



THF
tetrahydrofuran



TLC
thin layer chromatography










Definitions for a Compound of Formula I and II
The symbol “” means a single bond, “” means a double bond, “” means a triple bond, “” means a single or double bond. The symbol “” refers to a group on a double-bond as occupying either position on the terminus of a double bond to which the symbol is attached; that is, the geometry, E- or Z—, of the double bond is ambiguous. When a group is depicted removed from its parent formula, the “” symbol will be used at the end of the bond which was theoretically cleaved in order to separate the group from its parent structural formula.
When chemical structures are depicted or described, unless explicitly stated otherwise, all carbons are assumed to have hydrogen substitution to conform to a valence of four. For example, in the structure on the left-hand side of the schematic below there are nine hydrogens implied. The nine hydrogens are depicted in the right-hand structure. Sometimes a particular atom in a structure is described in textual formula as having a hydrogen or hydrogens as substitution (expressly defined hydrogen), for example, —CH2CH2—. It is understood by one of ordinary skill in the art that the aforementioned descriptive techniques are common in the chemical arts to provide brevity and simplicity to description of otherwise complex structures.




If a group “R” is depicted as “floating” on a ring system, as for example in the formula:




then, unless otherwise defined, a substituent “R” may reside on any atom of the ring system, assuming replacement of a depicted, implied, or expressly defined hydrogen from one of the ring atoms, so long as a stable structure is formed.

If a group “R” is depicted as floating on a fused ring system, as for example in the formulae:




then, unless otherwise defined, a substituent “R” may reside on any atom of the fused ring system, assuming replacement of a depicted hydrogen (for example the —NH— in the formula above), implied hydrogen (for example as in the formula above, where the hydrogens are not shown but understood to be present), or expressly defined hydrogen (for example where in the formula above, “Z” equals ═CH—) from one of the ring atoms, so long as a stable structure is formed. In the example depicted, the “R” group may reside on either the 5-membered or the 6-membered ring of the fused ring system. In the formula depicted above, when y is 2 for example, then the two “R's” may reside on any two atoms of the ring system, again assuming each replaces a depicted, implied, or expressly defined hydrogen on the ring.

When a group “R” is depicted as existing on a ring system containing saturated carbons, as for example in the formula:




where, in this example, “y” can be more than one, assuming each replaces a currently depicted, implied, or expressly defined hydrogen on the ring; then, unless otherwise defined, where the resulting structure is stable, two “R's” may reside on the same carbon. A simple example is when R is a methyl group; there can exist a geminal dimethyl on a carbon of the depicted ring (an “annular” carbon). In another example, two R's on the same carbon, including that carbon, may form a ring, thus creating a spirocyclic ring (a “spirocyclyl” group) structure with the depicted ring as for example in the formula:





“Acyl” means a —C(O)R radical where R is optionally substituted alkyl, optionally substituted alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl, as defined herein, e.g., acetyl, trifluoromethylcarbonyl, or 2-methoxyethylcarbonyl, and the like.
“Acylamino” means a —NRR′ radical where R is hydrogen, hydroxy, alkyl, or alkoxy and R′ is acyl, as defined herein.
“Acyloxy” means an —OR radical where R is acyl, as defined herein, e.g. cyanomethylcarbonyloxy, and the like.
“Administration” and variants thereof (e.g., “administering” a compound) in reference to a compound of the invention means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment. When a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., surgery, radiation, and chemotherapy, etc.), “administration” and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents.
“Alkenyl” means a means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to 6 carbon atoms which radical contains at least one double bond, e.g., ethenyl, propenyl, 1-but-3-enyl, and 1-pent-3-enyl, and the like.
“Alkoxy” means an —OR group where R is alkyl group as defined herein. Examples include methoxy, ethoxy, propoxy, isopropoxy, and the like.
“Alkoxyalkyl” means an alkyl group, as defined herein, substituted with at least one, preferably one, two, or three, alkoxy groups as defined herein. Representative examples include methoxymethyl and the like.
“Alkoxyalkylamino” means an NRR′ group where R is hydrogen, alkyl, or alkoxyalkyl and R′ is alkoxyalkyl, as defined herein.
“Alkoxyalkylaminoalkyl” means an alkyl group substituted with at least one, specifically one or two, alkoxyalkylamino groups, as defined herein.
“Alkoxycarbonyl” means a —C(O)R group where R is alkoxy, as defined herein.
“Alkyl” means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to 6 carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), or pentyl (including all isomeric forms), and the like.
“Alkylamino” means an —NHR group where R is alkyl, as defined herein.
“Alkylaminoalkyl” means an alkyl group substituted with one or two alkylamino groups, as defined herein.
“Alkylaminoalkyloxy” means an —OR group where R is alkylaminoalkyl, as defined herein.
“Alkylcarbonyl” means a —C(O)R group where R is alkyl, as defined herein.
“Alkynyl” means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to 6 carbon atoms which radical contains at least one triple bond, e.g., ethynyl, propynyl, butynyl, pentyN-2-yl and the like.
“Amino” means —NH2.
“Aminoalkyl” means an alkyl group substituted with at least one, for example one, two or three, amino groups.
“Aminoalkyloxy” means an —OR group where R is aminoalkyl, as defined herein.
“Aryl” means a monovalent six- to fourteen-membered, mono- or bi-carbocyclic ring, wherein the monocyclic ring is aromatic and at least one of the rings in the bicyclic ring is aromatic. Unless stated otherwise, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. Representative examples include phenyl, naphthyl, and indanyl, and the like.
“Arylalkyl” means an alkyl radical, as defined herein, substituted with one or two aryl groups, as defined herein, e.g., benzyl and phenethyl, and the like.
“Aryloxy” means an —OR group where R is aryl, as defined herein.
“Carboxyalkyl” means an alkyl group, as defined herein, substituted with at least one, for example one or two, —C(O)OH groups.
“Cycloalkyl” means a monocyclic or fused bicyclic, saturated or partially unsaturated (but not aromatic), monovalent hydrocarbon radical of three to ten carbon ring atoms. Fused bicyclic hydrocarbon radical includes bridged ring systems. Unless stated otherwise, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. One or two ring carbon atoms may be replaced by a —C(O)—, —C(S)—, or —C(═NH)— group. In another embodiment, the term cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl, or cyclohex-3-enyl, and the like.
“Cycloalkylalkyl” means an alkyl group substituted with at least one, for example one or two, cycloalkyl groups as defined herein.
“Dialkylamino” means a —NRR′ radical where R and R′ are alkyl as defined herein, or an N-oxide derivative, or a protected derivative thereof, e.g., dimethylamino, diethylamino, N,N-methylpropylamino or N,N-methylethylamino, and the like.
“Dialkylaminoalkyl” means an alkyl group substituted with one or two dialkylamino groups, as defined herein.
“Dialkylaminoalkyloxy” means an —OR group where R is dialkylaminoalkyl, as defined herein. Representative examples include 2-(N,N-diethylamino)-ethyloxy, and the like.
“Fused-polycyclic” or “fused ring system” means a polycyclic ring system that contains bridged or fused rings; that is, where two rings have more than one shared atom in their ring structures. In this application, fused-polycyclics and fused ring systems are not necessarily all aromatic ring systems. Typically, but not necessarily, fused-polycyclics share a vicinal set of atoms, for example naphthalene or 1,2,3,4-tetrahydro-naphthalene. A Spiro ring system is not a fused-polycyclic by this definition, but fused polycyclic ring systems of the invention may themselves have spiro rings attached thereto via a single ring atom of the fused-polycyclic. In some examples, as appreciated by one of ordinary skill in the art, two adjacent groups on an aromatic system may be fused together to form a ring structure. The fused ring structure may contain heteroatoms and may be optionally substituted with one or more groups. It should additionally be noted that saturated carbons of such fused groups (i.e. saturated ring structures) can contain two substitution groups.
“Halogen” or “halo” refers to fluorine, chlorine, bromine or iodine.
“Haloalkoxy” means an —OR′ group where R′ is haloalkyl as defined herein, e.g., trifluoromethoxy or 2,2,2-trifluoroethoxy, and the like.
“Haloalkyl” mean an alkyl group substituted with one or more halogens, for example one to five halo atoms, e.g., trifluoromethyl, 2-chloroethyl, and 2,2-difluoroethyl, and the like.
“Heteroaryl” means a monocyclic, fused bicyclic, or fused tricyclic, monovalent radical of 5 to 14 ring atoms containing one or more, for example one, two, three, or four ring heteroatoms independently selected from —O—, —S(O)N— (n is 0, 1, or 2), —N—, —N(Rx)—, and the remaining ring atoms being carbon, wherein the ring comprising a monocyclic radical is aromatic and wherein at least one of the fused rings comprising a bicyclic or tricyclic radical is aromatic. One or two ring carbon atoms of any nonaromatic rings comprising a bicyclic or tricyclic radical may be replaced by a —C(O)—, —C(S)—, or —C(═NH)— group. Rx is hydrogen, alkyl, hydroxy, alkoxy, acyl, or alkylsulfonyl. Fused bicyclic radical includes bridged ring systems. Unless stated otherwise, the valency may be located on any atom of any ring of the heteroaryl group, valency rules permitting. When the point of valency is located on the nitrogen, Rx is absent. In another embodiment, the term heteroaryl includes, but is not limited to, 1,2,4-triazolyl, 1,3,5-triazolyl, phthalimidyl, pyridinyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, 2,3-dihydro-1H-indolyl (including, for example, 2,3-dihydro-1H-indol-2-yl or 2,3-dihydro-1H-indol-5-yl, and the like), isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, benzodioxol-4-yl, benzofuranyl, cinnolinyl, indolizinyl, naphthyridiN-3-yl, phthalaziN-3-yl, phthalaziN-4-yl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, tetrazoyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isooxazolyl, oxadiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl (including, for example, tetrahydroisoquinoliN-4-yl or tetrahydroisoquinoliN-6-yl, and the like), pyrrolo[3,2-c]pyridinyl (including, for example, pyrrolo[3,2-c]pyridiN-2-yl or pyrrolo[3,2-c]pyridiN-7-yl, and the like), benzopyranyl, thiazolyl, isothiazolyl, thiadiazolyl, benzothiazolyl, benzothienyl, and the derivatives thereof, or N-oxide or a protected derivative thereof.
“Heteroarylalkyl” means an alkyl group, as defined herein, substituted with at least one, for example one or two heteroaryl groups, as defined herein.
“Heteroatom” refers to O, S, N, or P.
“Heterocycloalkyl” means a saturated or partially unsaturated (but not aromatic) monovalent monocyclic group of 3 to 8 ring atoms or a saturated or partially unsaturated (but not aromatic) monovalent fused bicyclic group of 5 to 12 ring atoms in which one or more, for example one, two, three, or four ring heteroatoms independently selected from O, S(O)n (n is 0, 1, or 2), N,N(Ry) (where Ry is hydrogen, alkyl, hydroxy, alkoxy, acyl, or alkylsulfonyl), the remaining ring atoms being carbon. One or two ring carbon atoms may be replaced by a —C(O)—, —C(S)—, or —C(═NH)— group. Fused bicyclic radical includes bridged ring systems. Unless otherwise stated, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. When the point of valency is located on a nitrogen atom, Ry is absent. In another embodiment the term heterocycloalkyl includes, but is not limited to, azetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, piperidinyl, 4-piperidonyl, morpholinyl, piperazinyl, 2-oxopiperazinyl, tetrahydropyranyl, 2-oxopiperidinyl, thiomorpholinyl, thiamorpholinyl, perhydroazepinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, oxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, quinuclidinyl, isothiazolidinyl, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl, tetrahydrofuryl, and tetrahydropyranyl, and the derivatives thereof and N-oxide or a protected derivative thereof.
“Heterocycloalkylalkyl” means an alkyl radical, as defined herein, substituted with one or two heterocycloalkyl groups, as defined herein, e.g., morpholinylmethyl, N-pyrrolidinylethyl, and 3-(N-azetidinyl)propyl, and the like.
“Heterocycloalkylalkyloxy means an —OR group where R is heterocycloalkylalkyl, as defined herein.
“Saturated bridged ring system” refers to a bicyclic or polycyclic ring system that is not aromatic. Such a system may contain isolated or conjugated unsaturation, but not aromatic or heteroaromatic rings in its core structure (but may have aromatic substitution thereon). For example, hexahydro-furo[3,2-b]furan, 2,3,3a,4,7,7a-hexahydro-1H-indene, 7-aza-bicyclo[2.2.1]heptane, and 1,2,3,4,4a,5,8,8a-octahydro-naphthalene are all included in the class “saturated bridged ring system.
“Spirocyclyl” or “spirocyclic ring” refers to a ring originating from a particular annular carbon of another ring. For example, as depicted below, a ring atom of a saturated bridged ring system (rings B and B′), but not a bridgehead atom, can be a shared atom between the saturated bridged ring system and a spirocyclyl (ring A) attached thereto. A spirocyclyl can be carbocyclic or heteroalicyclic.




“Optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. One of ordinary skill in the art would understand that with respect to any molecule described as containing one or more optional substituents, only sterically practical and/or synthetically feasible compounds are meant to be included. “Optionally substituted” refers to all subsequent modifiers in a term. So, for example, in the term “optionally substituted arylC1-8alkyl,” optional substitution may occur on both the “C1-8 alkyl” portion and the “aryl” portion of the molecule may or may not be substituted. A list of exemplary optional substitutions is presented below in the definition of “substituted.”
“Optionally substituted alkoxy” means an —OR group where R is optionally substituted alkyl, as defined herein.
“Optionally substituted alkyl” means an alkyl radical, as defined herein, optionally substituted with one or more groups, for example one, two, three, four, or five groups, independently selected from alkylcarbonyl, alkenylcarbonyl, cycloalkylcarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cyano, cyanoalkylaminocarbonyl, alkoxy, alkenyloxy, hydroxy, hydroxyalkoxy, halo, carboxy, alkylcarbonylamino, alkylcarbonyloxy, alkyl-S(O)0-2—, alkenyl-S(O)0-2—, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl-NRc— (where Rc is hydrogen, alkyl, optionally substituted alkenyl, hydroxy, alkoxy, alkenyloxy, or cyanoalkyl), alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, alkoxycarbonyl, alkenyloxycarbonyl, alkoxycarbonylamino, alkylaminocarbonylamino, dialkylaminocarbonylamino, alkoxyalkyloxy, and —C(O)NRaRb (where Ra and Rb are independently hydrogen, alkyl, optionally substituted alkenyl, hydroxy, alkoxy, alkenyloxy, or cyanoalkyl).
“Optionally substituted alkenyl” means an alkyl radical, as defined herein, optionally substituted with one or more groups, for example one, two, three, four, or five groups, independently selected from alkylcarbonyl, alkenylcarbonyl, cycloalkylcarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cyano, cyanoalkylaminocarbonyl, alkoxy, alkenyloxy, hydroxy, hydroxyalkoxy, halo, carboxy, alkylcarbonylamino, alkylcarbonyloxy, alkyl-S(O)0-2—, alkenyl-S(O)0-2—, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl-NRc— (where Rc is hydrogen, alkyl, optionally substituted alkenyl, hydroxy, alkoxy, alkenyloxy, or cyanoalkyl), alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, alkoxycarbonyl, alkenyloxycarbonyl, alkoxycarbonylamino, alkylaminocarbonylamino, dialkylaminocarbonylamino, alkoxyalkyloxy, and —C(O)NRaRb (where Ra and Rb are independently hydrogen, alkyl, optionally substituted alkenyl, hydroxy, alkoxy, alkenyloxy, or cyanoalkyl).
“Optionally substituted amino” refers to the group —N(H)R or —N(R)R where each R is independently selected from the group: optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, acyl, carboxy, alkoxycarbonyl, —S(O)2-(optionally substituted alkyl), —S(O)2-optionally substituted aryl), —S(O)2-(optionally substituted heterocycloalkyl), —S(O)2-(optionally substituted heteroaryl), and —S(O)2-(optionally substituted heteroaryl). For example, “optionally substituted amino” includes diethylamino, methylsulfonylamino, and furanyl-oxy-sulfonamino.
“Optionally substituted aminoalkyl” means an alkyl group, as defined herein, substituted with at least one, for example one or two, optionally substituted amino groups, as defined herein.
“Optionally substituted aryl” means an aryl group, as defined herein, optionally substituted with one, two, or three substituents independently selected from acyl, acylamino, acyloxy, optionally substituted alkyl, optionally substituted alkenyl, alkoxy, alkenyloxy, halo, hydroxy, alkoxycarbonyl, alkenyloxycarbonyl, amino, alkylamino, dialkylamino, nitro, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, carboxy, cyano, alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, aminoalkoxy, or aryl is pentafluorophenyl. Within the optional substituents on “aryl”, the alkyl and alkenyl, either alone or as part of another group (including, for example, the alkyl in alkoxycarbonyl), are independently optionally substituted with one, two, three, four, or five halo.
“Optionally substituted arylalkyl” means an alkyl group, as defined herein, substituted with optionally substituted aryl, as defined herein.
“Optionally substituted cycloalkyl” means a cycloalkyl group, as defined herein, substituted with one, two, or three groups independently selected from acyl, acyloxy, acylamino, optionally substituted alkyl, optionally substituted alkenyl, alkoxy, alkenyloxy, alkoxycarbonyl, alkenyloxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, halo, hydroxy, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, nitro, alkoxyalkyloxy, aminoalkoxy, alkylaminoalkoxy, dialkylaminoalkoxy, carboxy, and cyano. Within the above optional substitutents on “cycloalkyl”, the alkyl and alkenyl either alone or as part of another substituent on the cycloalkyl ring, are independently optionally substituted with one, two, three, four, or five halo, e.g. haloalkyl, haloalkoxy, haloalkenyloxy, or haloalkylsulfonyl.
“Optionally substituted cycloalkylalkyl” means an alkyl group substituted with at least one, for example one or two, optionally substituted cycloalkyl groups, as defined herein.
“Optionally substituted heteroaryl” means a heteroaryl group optionally substituted with one, two, or three substituents independently selected from acyl, acylamino, acyloxy, optionally substituted alkyl, optionally substituted alkenyl, alkoxy, alkenyloxy, halo, hydroxy, alkoxycarbonyl, alkenyloxycarbonyl, amino, alkylamino, dialkylamino, nitro, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, carboxy, cyano, alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, aminoalkoxy, alkylaminoalkoxy, and dialkylaminoalkoxy. Within the optional substituents on “heteroaryl”, the alkyl and alkenyl, either alone or as part of another group (including, for example, the alkyl in alkoxycarbonyl), are independently optionally substituted with one, two, three, four, or five halo.
“Optionally substituted heteroarylalkyl” means an alkyl group, as defined herein, substituted with at least one, for example one or two, optionally substituted heteroaryl groups, as defined herein.
“Optionally substituted heterocycloalkyl” means a heterocycloalkyl group, as defined herein, optionally substituted with one, two, or three substituents independently selected from acyl, acylamino, acyloxy, optionally substituted alkyl, optionally substituted alkenyl, alkoxy, alkenyloxy, halo, hydroxy, alkoxycarbonyl, alkenyloxycarbonyl, amino, alkylamino, dialkylamino, nitro, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, carboxy, cyano, alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, aminoalkoxy, or aryl is pentafluorophenyl. Within the optional substituents on “heterocycloalkyl”, the alkyl and alkenyl, either alone or as part of another group (including, for example, the alkyl in alkoxycarbonyl), are independently optionally substituted with one, two, three, four, or five halo.
“Optionally substituted heterocycloalkylalkyl” means an alkyl group, as defined herein, substituted with at least one, for example one or two, optionally substituted heterocycloalkyl groups as defined herein.
“Yield” for each of the reactions described herein is expressed as a percentage of the theoretical yield.
Definitions for the Compound of Formula 100
The terms used to describe the scope of formula 100 are defined in WO 2004/006846 (US Nat'l Stage application Ser. No. 10/522,004) which is herein incorporated by reference. For example “optionally substituted alkyl” for formula 100 has the meaning given in WO 2004/006846 (US Nat'l Stage application Ser. No. 10/522,004). Whenever a compound of formula 100 is described in this application, whether by structure or by use of the term “formula 100,” the terms used to describe that compound are defined by WO 2004/006846 (US Nat'l Stage application Ser. No. 10/522,004).
Other Definitions
“AKT inhibitor” includes, for example, LY294002, PKC 412, perifosine, compounds in Table 2a, compounds in Table 2b, and compounds described in WO 2006/071819 and WO05/117909. These references also describe in vitro assays that can be used to determine the inhibitory activity of AKT.
“Alkylating agent” includes, for example, one or more of the following: Chlorambucil, Chlormethine, Cyclophosphamide, Ifosfamide, Melphalan, Carmustine, Streptozocin, Fotemustine, Lomustine, Streptozocin, Carboplatin, Cisplatin, Oxaliplatin, BBR3464, Busulfan, Dacarbazine, Mechlorethamine, Procarbazine, Temozolomide, ThioTEPA, and Uramustine.
“Antibody” includes, for example, one or more of the following: an IGF1R antibody (including, for example, αIGF-1R A12 MoAb, 19D12, h7C10 and CP-751871), an EGFR antibody (including, for example, Cetuximab (Erbitux®) and Panitumumab), an ErbB2 antibody (including, for example, Trastuzumab (Herceptin®)), a VEGF antibody (including, for example, Bevacizumab (Avastin®)), an IgG1 antibody (including, for example, Ibritumomab (tiuxetan)), a CD20 antibody (including, for example, Rituximab and Tositumomab), a CD33 antibody (including, for example, Gemtuzumab and Gemtuzumab ozogamicin), and a CD52 antibody (including, for example, Alemtuzumab).
“Antimetabolite” includes, for example, methotrexate, Pemetrexed, Raltitrexed, Cladribine, Clofarabine, Fludarabine, Mercaptopurine, Thioguanine, Capecitabine, Cytarabine, fluorouracil (administered with or without leucovorin or folinic acid), and Gemcitabine.
“Antimicrotubule agent” includes, for example, Vincristine, Vinblastine, Vinorelbine, Vinflunine, and Vindesine.
“Aromatase inhibitor” includes, for example, one or more of the following: Aminoglutethimide, Anastrozole (Arimidex®), Letrozole (Femara®), Exemestane (Aromasin®), and Formestane (Lentaron®).
“Cancer” refers to cellular-proliferative disease states, including but not limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hanlartoma, inesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis defornians), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma], fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; Adrenal Glands: neuroblastoma; and breast cancer. Thus, the term “cancerous cell” as provided herein, includes a cell afflicted by any one of the above-identified conditions.
“Chemotherapeutic agent” includes, but is not limited to, an AKT inhibitor, an alkylating agent, an antimetabolite, an antimicrotubule agent, an aromatase inhibitor, a c-KIT inhibitor, a cMET inhibitor, an EGFR inhibitor, an ErbB2 inhibitor, a Flt-3 inhibitor, an HSP90 inhibitor, an IGF1R inhibitor, a platin, a Raf inhibitor, rapamycin, a Rapamycin analogue, a Receptor Tyrosine Kinase inhibitor, a taxane, a topoisomerase inhibitor, a SRC and/or ABL kinase inhibitor, and a VEGFR inhibitor. A pharmaceutically acceptable salt, solvate, and/or hydrate of a chemotherapeutic agent can be prepared by one of ordinary skill in the art and such salt, solvate, and/or hydrates thereof can be used to practice the invention.
“c-KIT inhibitor” includes, for example, imatinib, sunitinib, nilotinib, AMG 706, sorafenib, compounds in Table 3b, compounds in Table 3c, compounds in Table 8, compounds in Table 9, and compounds described in WO 2006/108059, WO/2005/020921, WO/2006/033943, and WO 2005/030140.
“cMET inhibitor” includes, for example, compounds in Table 3a, compounds in Table 3b, compounds in Table 3c, compounds described in WO06/108059, WO 2006/014325, and WO 2005/030140.
“EGFR inhibitor” includes, for example, one or more of the following: pelitinib, lapatinib (Tykerb®), gefitinib (Iressa®), erlotinib (Tarceva®), Zactima (ZD6474, vandetinib), AEE788 and HKI-272, EKB-569, CI-1033, N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, compounds in Table 4, compounds in Table 7, and compounds described in WO 2004/006846 and WO 2004/050681.
“ErbB2 inhibitor” includes, for example, lapatinib (GW572016), PKI-166, canertinib, CI-1033, HKI272, and EKB-569.
“Flt-3 inhibitor” includes, for example, CEP-701, PKC 412, MLN 518, sunitinib, sorafenib, compounds in Table 3a, compounds in Table 3b, compounds in Table 3c, compounds in Table 9, and compounds described in WO 2006/108059, WO/2006/033943, WO 2006/014325, and WO 2005/030140.
“Hormone therapy” and “hormonal therapy” include, for example, treatment with one or more of the following: steroids (e.g. dexamethasone), finasteride, tamoxifen, and an aromatase inhibitor.
“HSP90 inhibitor” includes, for example, 17-AAG, 17-DMAG, Geldanamycin, 5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-4-(4-(morpholinomethyl)phenyl)isoxazole-3-carboxamide [NVP-AUY922 (VER 52296)], 6-chloro-9-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-9H-purin-2-amine (CNF2024, also named BIIB021), compounds disclosed in WO2004072051 (which is herein incorporated by reference), compounds disclosed in WO2005028434 (which is herein incorporated by reference), compounds disclosed in WO2007035620 (which is herein incorporated by reference) and compounds disclosed in WO2006091963 (which is herein incorporated by reference).
“IGF1R inhibitor” includes, for example, Tyrphostin AG 1024, compounds in Table 5a, compounds in Table 5b, and compounds described in WO06/074057.
“Kinase-dependent diseases or conditions” refer to pathologic conditions that depend on the activity of one or more protein kinases. Kinases either directly or indirectly participate in the signal transduction pathways of a variety of cellular activities including proliferation, adhesion, migration, differentiation and invasion. Diseases associated with kinase activities include tumor growth, the pathologic neovascularization that supports solid tumor growth, and associated with other diseases where excessive local vascularization is involved such as ocular diseases (diabetic retinopathy, age-related macular degeneration, and the like) and inflammation (psoriasis, rheumatoid arthritis, and the like).
While not wishing to be bound to theory, phosphatases can also play a role in “kinase-dependent diseases or conditions” as cognates of kinases; that is, kinases phosphorylate and phosphatases dephosphorylate, for example protein substrates. Therefore compounds of the invention, while modulating kinase activity as described herein, may also modulate, either directly or indirectly, phosphatase activity. This additional modulation, if present, may be synergistic (or not) to activity of compounds of the invention toward a related or otherwise interdependent kinase or kinase family. In any case, as stated previously, the compounds of the invention are useful for treating diseases characterized in part by abnormal levels of cell proliferation (i.e. tumor growth), programmed cell death (apoptosis), cell migration and invasion and angiogenesis associated with tumor growth.
“Metabolite” refers to the break-down or end product of a compound or its salt produced by metabolism or biotransformation in the animal or human body; for example, biotransformation to a more polar molecule such as by oxidation, reduction, or hydrolysis, or to a conjugate (see Goodman and Gilman, “The Pharmacological Basis of Therapeutics” 8.sup.th Ed., Pergamon Press, Gilman et al. (eds), 1990 for a discussion of biotransformation). As used herein, the metabolite of a compound of the invention or its salt may be the biologically active form of the compound in the body. In one example, a prodrug may be used such that the biologically active form, a metabolite, is released in vivo. In another example, a biologically active metabolite is discovered serendipitously, that is, no prodrug design per se was undertaken. An assay for activity of a metabolite of a compound of the present invention is known to one of skill in the art in light of the present disclosure.
“Patient” for the purposes of the present invention includes humans and other animals, particularly mammals, and other organisms. Thus the methods are applicable to both human therapy and veterinary applications. In a preferred embodiment the patient is a mammal, and in a most preferred embodiment the patient is human.
A “pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference or S. M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977; 66:1-19 both of which are incorporated herein by reference.
Examples of pharmaceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; as well as organic acids such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, p-toluenesulfonic acid, and salicylic acid and the like.
Examples of a pharmaceutically acceptable base addition salts include those formed when an acidic proton present in the parent compound is replaced by a metal ion, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferable salts are the ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, tromethamine, N-methylglucamine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
“Platin,” and “platin-containing agent” include, for example, cisplatin, carboplatin, and oxaliplatin.
“Prodrug” refers to compounds that are transformed (typically rapidly) in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood. Common examples include, but are not limited to, ester and amide forms of a compound having an active form bearing a carboxylic acid moiety. Examples of pharmaceutically acceptable esters of the compounds of this invention include, but are not limited to, alkyl esters (for example with between about one and about six carbons) the alkyl group is a straight or branched chain. Acceptable esters also include cycloalkyl esters and arylalkyl esters such as, but not limited to benzyl. Examples of pharmaceutically acceptable amides of the compounds of this invention include, but are not limited to, primary amides, and secondary and tertiary alkyl amides (for example with between about one and about six carbons). Amides and esters of the compounds of the present invention may be prepared according to conventional methods. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference for all purposes.
“Raf inhibitor” includes, for example, sorafenib, RAF 265 (CHIR 265), compounds in Table 6, and compounds described in WO 2005/112932. These references also describe in vitro assays that can be used to determine the inhibitory activity of RAF.
“Rapamycin analogue” includes for example, CCI-779, AP 23573, RAD 001, TAFA 93, and compounds described in WO 2004/101583 and U.S. Pat. No. 7,160,867 which are each incorporated herein by reference in their entireties.
“Receptor Tyrosine Kinase inhibitor” includes, for example, inhibitors of AKT, EGFR, ErbB2, IGF1R, KIT, Met, Raf, and VEGFR2. Examples of receptor tyrosine kinase inhibitors can be found in WO 2006/108059 (US Nat'l Stage application Ser. No. 11/910,720), WO 2006/074057 (US Nat'l Stage application Ser. No. 11/722,719), WO 2006/071819 (US Nat'l Stage application Ser. No. 11/722,291), WO 2006/014325 (US Nat'l Stage application Ser. No. 11/571,140), WO 2005/117909 (US Nat'l Stage application Ser. No. 11/568,173), WO 2005/030140 (US Nat'l Stage application Ser. No. 10/573,336), WO 2004/050681 US Nat'l Stage application Ser. No. 10/533,555), WO 2005/112932 (US Nat'l Stage application Ser. No. 11/568,789), and WO 2004/006846 (US Nat'l Stage application Ser. No. 10/522,004), each of which is incorporated herein by reference for all purposes. In particular, the applications cited in this paragraph are incorporated for the purpose of providing specific examples and generic embodiments (and the definitions associated with the terms used in the embodiments) of compounds that are useful in the practice of the invention. These references also describe in vitro assays useful in the practice of this invention.
“Taxane” includes, for example, one or more of the following: Paclitaxel (Taxol®) and Docetaxel (Taxotere®).
“Therapeutically effective amount” is an amount of a compound of the invention, that when administered to a patient, ameliorates a symptom of the disease. The amount of a compound of the invention which constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the age of the patient to be treated, and the like. The therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their knowledge and to this disclosure.
“Topoisomerase inhibitor” includes, for example, one or more of the following: amsacrine, camptothecin, etoposide, etoposide phosphate, exatecan, irinotecan, lurtotecan, and teniposide, and topotecan.
“Treating” or “treatment” of a disease, disorder, or syndrome, as used herein, includes (i) preventing the disease, disorder, or syndrome from occurring in a human, i.e. causing the clinical symptoms of the disease, disorder, or syndrome not to develop in an animal that may be exposed to or predisposed to the disease, disorder, or syndrome but does not yet experience or display symptoms of the disease, disorder, or syndrome; (ii) inhibiting the disease, disorder, or syndrome, i.e., arresting its development; and (iii) relieving the disease, disorder, or syndrome, i.e., causing regression of the disease, disorder, or syndrome. As is known in the art, adjustments for systemic versus localized delivery, age, body weight, general health, sex, diet, time of administration, drug interaction and the severity of the condition may be necessary, and will be ascertainable with routine experimentation by one of ordinary skill in the art.
“SRC and/or ABL kinase inhibitor” includes, for example, dasatinib, imatinib (Gleevec®), and compounds described in WO 2006/074057.
“VEGFR inhibitor” includes, for example, one or more of the following: VEGF Trap, ZD6474 (vandetanib, Zactima), sorafenib, Angiozyme, AZD2171 (cediranib), pazopanib, sorafenib, axitinib, SU5416 (semaxanib), PTK787 (vatalanib), AEE778, RAF 265, sunitinib (Sutent), N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, compounds in Table 7, and compounds described in WO 2004/050681 and WO 2004/006846.
Embodiments of the Invention
The following paragraphs present a number of embodiments of compounds that can be used to practice the invention. In each instance, the embodiment includes both the recited compounds as well as individual isomers and mixtures of isomers. In addition, in each instance, the embodiment includes the pharmaceutically acceptable salts, hydrates, and/or solvates of the recited compounds and any individual isomers or mixture of isomers thereof.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, where growth and/or survival of tumor cells of the cancer is enhanced, at least in part, by the activity of PI3K; in combination with one or more treatments selected from surgery, one or more chemotherapeutic agents, one or more hormone therapies, one or more antibodies, one or more immunotherapies, radioactive iodine therapy, and radiation.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, one or more chemotherapeutic agents, one or more hormone therapies, one or more antibodies, one or more immunotherapies, radioactive iodine therapy, and radiation; where the cancer is selected from breast cancer, colon cancer, rectal cancer, endometrial cancer, gastric carcinoma (including gastrointestinal carcinoid tumors and gastrointestinal stromal tumors), glioblastoma, hepatocellular carcinoma, small cell lung cancer, non-small cell lung cancer (NSCLC), melanoma, ovarian cancer, cervical cancer, pancreatic cancer, prostate carcinoma, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), non-Hodgkin's lymphoma, and thyroid carcinoma. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, one or more chemotherapeutic agents, one or more hormone therapies, one or more antibodies, one or more immunotherapies, radioactive iodine therapy, and radiation; where the cancer is selected from prostate cancer, NSCLC, ovarian cancer, cervical cancer, breast cancer, colon cancer, rectal cancer, and glioblastoma. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, one or more chemotherapeutic agents, one or more hormone therapies, one or more antibodies, one or more immunotherapies, radioactive iodine therapy, and radiation; where the cancer is selected from NSCLC, breast cancer, prostate cancer, glioblastoma, and ovarian cancer.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or more chemotherapeutic agents.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents independently selected from rapamycin, a rapamycin analogue, an alkylating agent, a taxane, a platin, an EGFR inhibitor, and an ErbB2 inhibitor. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents independently selected from rapamycin, temozolomide, paclitaxel, docetaxel, carboplatin, cisplatin, oxaliplatin, gefitinib (Iressa®), erlotinib (Tarceva®), Zactima (ZD6474), HKI-272, pelitinib, canertinib, a compound selected from Table 4, a compound in Table 7, and lapatinib. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents independently selected from rapamycin, temozolomide, paclitaxel, docetaxel, carboplatin, trastuzumab, erlotinib, N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, a compound in Table 7, and lapatinib. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents independently selected from rapamycin, paclitaxel, carboplatin, erlotinib, and N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta-[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents independently selected from a platin and a taxane. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents independently selected from carboplatin, cisplatin, oxaliplatin, and paclitaxel.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agent is an AKT inhibitor. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is an AKT inhibitor selected from perifosine, PKC 412, a compound in Table 2a, and a compound in Table 2b.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is a cMET inhibitor. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is a cMET inhibitor selected from a compound in Table 3a, a compound in Table 3b, and a compound in Table 3c.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is an EGFR inhibitor. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is an EGFR inhibitor selected from lapatinib (Tykerb®), gefitinib (Iressa®), erlotinib (Tarceva®), Zactima (ZD6474), AEE788, HKI-272, EKB-569, CI 1033, a compound selected from Table 4, and a compound in Table 7. In another embodiment, In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is an EGFR inhibitor selected from lapatinib (Tykerb®), gefitinib (Iressa®), erlotinib (Tarceva®), Zactima (ZD6474), AEE788, HKI-272, EKB-569, CI 1033, N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, and N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is an ErbB2 inhibitor. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is an ErbB2 inhibitor selected from lapatinib, EKB-569, HKI272, CI 1033, PKI-166, and a compound selected from Table 4.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is an HSP90 inhibitor. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is an HSP90 inhibitor selected from 17-AAG, 17-DMAG, Geldanamycin, and CNF2024. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is an HSP90 inhibitor selected from 17-AAG, 17-DMAG, and Geldanamycin.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is an IGF1R inhibitor. In another embodiment, In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is an IGF1R inhibitor selected from Table 5a and Table 5b.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is a Raf inhibitor. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is a Raf inhibitor selected from sorafenib, RAF 265 (CHIR-265), and a compound in Table 6.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is a VEGFR inhibitor. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is a VEGFR inhibitor selected from VEGF Trap, ZD6474 (Zactima), cediranib (AZ2171), pazopanib, sunitinib, sorafenib, axitinib, AEE788, RAF 265 (CHIR-265), a compound selected from Table 4, and a compound selected from Table 7.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is a cKIT inhibitor. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is a cKIT inhibitor selected from imatinib, sunitinib, nilotinib, AMG 706, sorafenib, a compound in Table 3b, a compound in Table 3c, a compound in Table 8, and a compound in Table 9.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is a FLT3 inhibitor. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is a FLT3 inhibitor selected from CEP-701, PKC 412, sunitinib, MLN 518, sunitinib, sorafenib, a compound in Table 3a, a compound in Table 3b, a compound in Table 3c, and a compound in Table 9.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from rapamycin, a rapamycin analogue, PI103, and SF 1126. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from rapamycin, CCI-779, AP 23573, RAD 001, TAFA 93, PI103, and SF 1126. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is rapamycin.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is of formula 100:




where q is 1, 2, or 3; E is —NR9—, —O—, or absent and Y is —CH2CH2—, —CH2—, or absent provided that when E is —NR9— or —O—, then Y is —CH2CH2—; R2 is selected from halogen, trihalomethyl, —CN, —NO2, —OR3, and lower alkyl; R8 is selected from —H, lower alkyl, —C(O)OR3, —C(O)N(R3)R4, —SO2R4, and —C(O)R3; R9 is hydrogen or lower alkyl; R3 is hydrogen or R4; R4 is selected from lower alkyl, aryl, lower arylalkyl, heterocyclyl, and lower heterocyclylalkyl; or R3 and R4, when taken together with a common nitrogen to which they are attached, form a five- to seven-membered heterocyclyl, said five- to seven-membered heterocyclyl optionally containing one or more additional heteroatom selected from N, O, S, and P; or a single geometric isomer, stereoisomer, racemate, enantiomer, or diastereomer, thereof and optionally as a pharmaceutically acceptable salt, additionally optionally as a solvate, and additionally as a hydrate thereof. The terms used to describe the scope of formula 100 are defined in WO 2004/006846 (US Nat'l Stage application Ser. No. 10/522,004) which is herein incorporated by reference. Whenever a compound of formula 100 is described in this application, whether by structure or by use of the term “formula 100,” the terms used to describe that compound are defined by WO 2004/006846 (US Nat'l Stage application Ser. No. 10/522,004). In particular, “alkyl” in formula 100 is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof, inclusively; “lower alkyl” means alkyl groups of from one to six carbon atoms. “Aryl” in formula 100 means an aromatic six- to fourteen-membered carbocyclic rings which include, for example, benzene, naphthalene, indane, tetralin, fluorene and the like. “Lower arylalkyl” in formula 100 means a residue in which an aryl moiety is attached to a parent structure via one of an alkylene, alkenylene, or alkynylene radical where the “alkyl” portion of the group has one to six carbons; examples include benzyl, phenethyl, phenylvinyl, phenylallyl and the like. In formula 100, “heterocyclyl” means a stable monocyclic, bicyclic or tricyclic three- to fifteen-membered ring radical (including fused or bridged ring systems) that consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur where the nitrogen, phosphorus, carbon and sulfur atoms in the heterocyclyl radical may be optionally oxidized to various oxidation states and the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated or aromatic. “Lower heterocyclylalkyl” means a residue in which a heterocyclyl is attached to a parent structure via one of an alkylene, alkenylene, and alkynylene radical having one to six carbons.

In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 2a. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from Table 2a.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or more chemotherapeutic agents where one of the chemotherapeutic agent is selected from a compound in Table 2b. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or more chemotherapeutic agents where one of the chemotherapeutic agent is selected from Table 2b.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or more chemotherapeutic agents where one of the chemotherapeutic agent is selected from a compound in Table 3a. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or more chemotherapeutic agents where one of the chemotherapeutic agent is selected from Table 3a.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or more chemotherapeutic agents where one of the chemotherapeutic agent is selected from a compound in Table 3b. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or more chemotherapeutic agents where one of the chemotherapeutic agent is selected from Table 3b.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or more chemotherapeutic agents where one of the chemotherapeutic agent is selected from a compound in Table 3c. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or more chemotherapeutic agents where one of the chemotherapeutic agent is selected from Table 3c.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from a compound in Table 4. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is selected from Table 4.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, or N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, or N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta-[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta-[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or more chemotherapeutic agents where one of the chemotherapeutic agent is selected from a compound in Table 5a. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or more chemotherapeutic agents where one of the chemotherapeutic agent is selected from Table 5a.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or more chemotherapeutic agents where one of the chemotherapeutic agent is selected from a compound in Table 5b. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or more chemotherapeutic agents where one of the chemotherapeutic agent is selected from Table 5b.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or more chemotherapeutic agents where one of the chemotherapeutic agent is selected from a compound in Table 6. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or more chemotherapeutic agents where one of the chemotherapeutic agent is selected from Table 6.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or more chemotherapeutic agents where one of the chemotherapeutic agent is selected from a compound in Table 7. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or more chemotherapeutic agents where one of the chemotherapeutic agent is selected from Table 7.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or more chemotherapeutic agents where one of the chemotherapeutic agent is selected from a compound in Table 8. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or more chemotherapeutic agents where one of the chemotherapeutic agent is selected from Table 8.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or more chemotherapeutic agents where one of the chemotherapeutic agent is selected from a compound in Table 9. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or more chemotherapeutic agents where one of the chemotherapeutic agent is selected from Table 9.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agent is paclitaxel.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agent is rapamycin.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agent is carboplatin.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agent is erlotinib.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agent is lapatinib.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or two antibodies where one of the antibodies is trastuzumab.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or two antibodies where one of the antibodies is cetuximab.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or two antibodies where one of the antibodies is panitumumab.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or two antibodies where one of the antibodies is bevacizumab.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is radiation. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is radiation.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two antibodies. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two antibodies independently selected from an IGF1R antibody (including, for example, αIGF-1R A12 MoAb, αIGF-1R 19D12 MoAb, αIGF-1R h7C10 MoAb and αIGF-1R CP-751871 MoAb), Alemtuzumab, Bevacizumab (Avastin®), Gemtuzumab, Gemtuzumab ozogamicin, Ibritumomab tiuxetan, Panitumumab, Rituximab, Tositumomab, Omnitarg (pertuzimab), an anti-ErbB2 antibodies (including trastuzumab (Herceptin®)), and an anti-EGFR antibodies (including, for example, cetuximab (Erbitux), panitumumab, nimotuzumab, and EMD72000)).
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or two antibodies. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or two antibodies independently selected from an IGF1R antibody (including, for example, αIGF-1R A12 MoAb, αIGF-1R 19D12 MoAb, αIGF-1R h7C10 MoAb and αIGF-1R CP-751871 MoAb), Alemtuzumab, Bevacizumab (Avastin®), Gemtuzumab, Gemtuzumab ozogamicin, Ibritumomab tiuxetan, Panitumumab, Rituximab, Tositumomab, Omnitarg (pertuzimab), an anti-ErbB2 antibodies (including trastuzumab (Herceptin®)), and an anti-EGFR antibodies (including, for example, cetuximab (Erbitux), panitumumab, nimotuzumab, and EMD72000)).
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or more chemotherapeutic agents where one of the chemotherapeutic agent is temozolomide. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or more chemotherapeutic agents where one of the chemotherapeutic agent is temozolomide.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is surgery. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is surgery.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two hormone therapies. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two hormone therapies independently selected from tamoxifen, Toremifene (Fareston), Fulvestrant (Faslodex), Megestrol acetate (Megace), ovarian ablation, Raloxifene, a luteinizing hormone-releasing hormone (LHRH) analog (including goserelin and leuprolide), Megestrol acetate (Megace), and one or more aromatase inhibitor. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two hormone therapies where one of the hormone therapies is an aromatase inhibitor selected from letrozole (Femara), anastrozole (Arimidex), and exemestane (Aromasin). In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where the treatment is one or two hormone therapies independently selected from tamoxifen and an aromatase inhibitor.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where the treatment is one or two hormone therapies. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where one of the treatments is one or two hormone therapies independently selected from tamoxifen, Toremifene (Fareston), Fulvestrant (Faslodex), Megestrol acetate (Megace), ovarian ablation, Raloxifene, a luteinizing hormone-releasing hormone (LHRH) analog (including goserelin and leuprolide), Megestrol acetate (Megace), and one or two aromatase inhibitor. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where one of the treatments is one or two hormone therapies where one of the hormone therapies is an aromatase inhibitor selected from letrozole (Femara), anastrozole (Arimidex), and exemestane (Aromasin). In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where one of the treatments is one or two hormone therapies independently selected from tamoxifen and an aromatase inhibitor.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with a treatment where one of the treatments is one antibody selected from an EGFR antibody and an ErbB2 antibody, or the treatment is one or two chemotherapeutic agents independently selected from a rapamycin, a rapamycin analogue, an alkylating agent, a taxane, a platin, an EGFR inhibitor, and an ErbB2 inhibitor. In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I selected from Table 1 in combination with a treatment where one of the treatments is one antibody selected from an EGFR antibody and an ErbB2 antibody, or the treatment is one or two chemotherapeutic agents independently selected from a rapamycin, rapamycin analogue, an alkylating agent, a taxane, a platin, an EGFR inhibitor, and an ErbB2 inhibitor.
In another embodiment, the invention is directed to a method of treating acute myelogenous leukemia (AML) which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from bone marrow or peripheral blood stem cell transplantation, radiation, one or two antibodies, and one or two chemotherapeutic agents. In another embodiment, the invention is directed to a method of treating acute myelogenous leukemia (AML) which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or two treatments where one of the treatments is one antibody selected from Gemtuzumab ozogamicin (Mylotarg), αIGF-1R A12 MoAb, αIGF-1R 19D12 MoAb, αIGF-1R h7C10 MoAb, αIGF-1R CP-751871 MoAb and trastuzumab. In another embodiment, the invention is directed to a method of treating acute myelogenous leukemia (AML) which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents selected from Imatinib (i.e. Gleevec®), PKC 412, CEP-701, daunorubicin, doxorubicin, cytarabine (ara-C), an anthracycline drug such as daunorubicin or idarubicin (Daunomycin, Idamycin), 6-thioguanine, and a granulocyte colony-stimulating factor (such as Neupogen or Leukine).
In another embodiment, the invention is directed to a method of treating chronic myelogenous leukemia (CML) which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from bone marrow or peripheral blood stem cell transplantation, radiation, one or two chemotherapeutic agents, immunotherapy, and one or two antibodies. In another embodiment, the invention is directed to a method of treating chronic myelogenous leukemia (CML) which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two of the chemotherapeutic agents selected from Imatinib (i.e. Gleevec®), PKC 412, hydroxyurea (Hydrea), cytosine, cytosine arabinoside, dasatinib, AMN107, VX680 (MK0457), and cytarabine (ara-C). In another embodiment, the invention is directed to a method of treating chronic myelogenous leukemia (CML) which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents selected from Imatinib (i.e. Gleevec®) and dasatinib. In another embodiment, the invention is directed to a method of treating chronic myelogenous leukemia (CML) which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is immunotherapy and the immunotherapy is interferon therapy such as interferon-α.
In another embodiment, the invention is directed to a method of treating prostate cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery (including cryosurgery), radiation, one or two chemotherapeutic agents, one or two antibodies, and one or two hormone therapies. In another embodiment, the invention is directed to a method of treating prostate cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is an antibody selected from αIGF-1R A12 MoAb, αIGF-1R 19D12 MoAb, αIGF-1R h7C10 MoAb, and αIGF-1R CP-751871 MoAb. In another embodiment, the invention is directed to a method of treating prostate cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two of the chemotherapeutic agents independently selected from rapamycin, mitoxantrone, prednisone, docetaxel (Taxotere), doxorubicin, etoposide, vinblastine, paclitaxel, and carboplatin. In another embodiment, the invention is directed to a method of treating prostate cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two of the hormone therapy independently selected from androgen deprivation therapy and androgen suppression therapy. In another embodiment, the invention is directed to a method of treating prostate cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents where one of the chemotherapeutic agents is a taxane. In another embodiment, the invention is directed to a method of treating prostate cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents where one of the chemotherapeutic agents is rapamycin.
In another embodiment, the invention is directed to a method of treating melanoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiation, one or two immunotherapies, one or two hormone therapies, and one or two chemotherapeutic agents. In another embodiment, the invention is directed to a method of treating melanoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from an alkylating agent, a taxane, a platin, and a Raf inhibitor. In another embodiment, the invention is directed to a method of treating melanoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from sorafenib, Paclitaxel (Taxol®), Docetaxel (Taxotere®), dacarbazine, rapamycin, imatinib mesylate (Gleevec®), sorafenib, cisplatin, carboplatin, dacarbazine (DTIC), carmustine (BCNU), vinblastine, temozolomide (Temodar), Melphalan, and imiquimod (Aldara). In another embodiment, the invention is directed to a method of treating melanoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two immunotherapies independently selected from ipilimumab, interferon-alpha and interleukin-2. In another embodiment, the invention is directed to a method of treating melanoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is hormone therapy where the hormone therapy is tamoxifen.
In another embodiment, the invention is directed to a method of treating colon or rectal cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiation, one or two antibodies, and one or two chemotherapeutic agents. In another embodiment, the invention is directed to a method of treating colon or rectal cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is surgery selected from local excision, electrofulguration, segmental colon resection, polypectomy, local transanal resection, low anterior resection, abdominoperineal resection, and pelvic exenteration. In another embodiment, the invention is directed to a method of treating colon or rectal cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from a platinum-containing compound (including cisplatin, oxaliplatin, and carboplatin), 5-fluorouracil (5-FU), leucovorin, capecitabine (Xeloda), irinotecan (Camptosar), FOLFOX (Folinic acid, 5-FU, Oxaliplatin), and leucovorin. In another embodiment, the invention is directed to a method of treating colon or rectal cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two antibodies independently selected from cetuximab (Erbitux) and bevacizumab (Avastin).
In another embodiment, the invention is directed to a method of treating pancreatic cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiation, one or two antibodies, and one or two chemotherapeutic agents. In another embodiment, the invention is directed to a method of treating pancreatic cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is selected from one or two chemotherapeutic agents independently selected from platinum-containing compound (including cisplatin, oxaliplatin, and carboplatin), 5-fluorouracil (5-FU), gemcitabine, a taxane (including paclitaxel and docetaxel), topotecan, irinotecan, capecitabine, streptozocin, erlotinib (Tarceva), leucovorin, and capecitabine (Xeloda). In another embodiment, the invention is directed to a method of treating pancreatic cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is an antibody where the antibody is cetuximab.
In another embodiment, the invention is directed to a method of treating breast cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiation, one or two chemotherapeutic agents, one or two hormone therapies, and one or two antibodies. In another embodiment, the invention is directed to a method of treating breast cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two of the chemotherapeutic agents independently selected from lapatinib (Tykerb®), Paclitaxel (Taxol®), docetaxel, capecitabine, Cyclophosphamide (Cytoxan), CMF (cyclophosphamide, fluoruracil, and methotrexate), methotrexate, fluorouracil, doxorubicin, epirubicin, gemcitabine, carboplatin (Paraplatin), cisplatin (Platinol), vinorelbine (Navelbine), capecitabine (Xeloda), pegylated liposomal doxorubicin (Doxil), albumin-bound paclitaxel (Abraxane), AC (adriamycin and Cyclophosphamide), adriamyclin, and pamidronate or zoledronic acid (to treat bone weakness). In another embodiment, the invention is directed to a method of treating breast cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two hormone therapies independently selected from tamoxifen, Toremifene (Fareston), Fulvestrant (Faslodex), Megestrol acetate (Megace), ovarian ablation, Raloxifene, a luteinizing hormone-releasing hormone (LHRH) analogs (including goserelin and leuprolide), Megestrol acetate (Megace), and one or more aromatase inhibitors. In another embodiment, the invention is directed to a method of treating breast cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two hormone therapies and one of the hormone therapies is an aromatase inhibitor selected from letrozole (Femara), anastrozole (Arimidex), and exemestane (Aromasin). In another embodiment, the invention is directed to a method of treating breast cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two antibodies independently selected from αIGF-1R A12 MoAb, αIGF-1R 19D12 MoAb, αIGF-1R h7C10 MoAb, αIGF-1R CP-751871 MoAb, bevacizumab (Avastin), and trastuzumab.
In another embodiment, the invention is directed to a method of treating breast cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents and one of the chemotherapeutic agents is erlotinib.
In another embodiment, the invention is directed to a method of treating breast cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two of the chemotherapeutic agents and one or two of the chemotherapeutic agents are independently selected from rapamycin, lapatinib, erlotinib, N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof, N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof, N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof, and N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof.
In another embodiment, the invention is directed to a method of treating breast cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two of the antibodies. In another embodiment, the invention is directed to a method of treating breast cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two antibodies and one of the antibodies is trastuzumab.
In another embodiment, the invention is directed to a method of treating breast cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two of the chemotherapeutic agents and one of the chemotherapeutic agents is selected from N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, and N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine; optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof.
In another embodiment, the invention is directed to a method of treating breast cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two of the chemotherapeutic agents and one of the chemotherapeutic agents is N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta-[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof.
In another embodiment, the invention is directed to a method of treating non-small cell lung cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiation, one or more antibodies, and one or more chemotherapeutic agents. In another embodiment, the invention is directed to a method of treating non-small cell lung cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from cisplatin, oxaliplatin, carboplatin, Zactima (ZD6474), Paclitaxel, Docetaxel (Taxotere®), Gemcitabine (Gemzar®), Vinorelbine, Irinotecan, Etoposide, Vinblastine, Erlotinib (Tarceva®), gefitinib (Iressa), and Pemetrexed. In another embodiment, the invention is directed to a method of treating non-small cell lung cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is an antibody and the antibody is Bevacizumab. In another embodiment, the invention is directed to a method of treating non-small cell lung cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from cisplatin, oxaliplatin, carboplatin, Paclitaxel, Docetaxel (Taxotere®), and erlotinib (Tarceva®).
In another embodiment, the invention is directed to a method of treating non-small cell lung cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents and one of the chemotherapeutic agents is carboplatin.
In another embodiment, the invention is directed to a method of treating non-small cell lung cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents and one of the chemotherapeutic agents is selected from N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine, and N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine; optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof. In another embodiment, the invention is directed to a method of treating non-small cell lung cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents and one of the chemotherapeutic agents is N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta-[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine optionally as a pharmaceutically acceptable salt and additionally optionally as a hydrate and additionally optionally as a solvate thereof.
In another embodiment, the invention is directed to a method of treating small cell lung cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiation, and one or two chemotherapeutic agents. In another embodiment, the invention is directed to a method of treating small cell lung cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapy agents independently selected from a platin (such as cisplatin, oxaliplatin, and carboplatin), gefitinib, vinorelbine, docetaxel, paclitaxel, etoposide, fosfamide, ifosfamide, cyclophosphamide, cyclophosphamide/doxorubicin/vincristine (CAV), doxorubicin, vincristine, gemcitabine, paclitaxel, vinorelbine, topotecan, irinotecan, methotrexate, and docetaxel.
In another embodiment, the invention is directed to a method of treating papillary or anaplastic thyroid cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiation, radioactive iodine therapy, one or two hormone therapies, and one or two chemotherapeutic agents. In another embodiment, the invention is directed to a method of treating papillary or anaplastic thyroid cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from thyroid hormone pills, Doxorubucin and a platin. In another embodiment, the invention is directed to a method of treating papillary or anaplastic thyroid cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is hormone therapy and the hormone therapy is radioiodine ablation.
In another embodiment, the invention is directed to a method of treating endometrial cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiation, one or two hormone therapies, and one or two chemotherapeutic agents. In another embodiment, the invention is directed to a method of treating endometrial cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two hormone therapies independently selected from megestrol acetate, Tamoxifen, and a progestin including medroxyprogesterone acetate (Provera) and megestrol acetate (Megace). In another embodiment, the invention is directed to a method of treating endometrial cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from a platinum-containing compound (including cisplatin, oxaliplatin, and carboplatin, more for example cisplatin), a taxane (including paclitaxel), doxorubicin (Adriamycin), cyclophosphamide, fluorouracil (5-FU), methotrexate, and vinblastine.
In another embodiment, the invention is directed to a method of treating ovarian cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiation, one or two antibodies, and one or two chemotherapeutic agents. In another embodiment, the invention is directed to a method of treating ovarian cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is an antibody and the antibody is bevacizumab. In another embodiment, the invention is directed to a method of treating ovarian cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from a platinum-containing compound (including cisplatin, oxaliplatin and carboplatin), a taxane (including paclitaxel and docetaxel), topotecan, an anthracyclines (including doxorubicin and liposomal doxorubicin), gemcitabine, cyclophosphamide, vinorelbine (Navelbine), hexamethylmelamine, ifosfamide, etoposide, bleomycin, vinblastine, ifosfamide, vincristine, and cyclophosphamide. In another embodiment, the invention is directed to a method of treating ovarian cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from a platin and a taxane. In another embodiment, the invention is directed to a method of treating ovarian cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from cisplatin, oxaliplatin, carboplatin, paclitaxel, and docetaxel.
In another embodiment, the invention is directed to a method of treating glioblastoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiation, one or two chemotherapeutic agents, one or two anti-seizure agents, and one or two agents to reduce swelling. In another embodiment, the invention is directed to a method of treating glioblastoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is radiation selected from external beam radiation, interstitial radiotherapy, and stereotactic radiosurgery. In another embodiment, the invention is directed to a method of treating glioblastoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from carmustine (BCNU), Erlotinib (Tarceva), bevacizumab, gefitinib (Iressa), rapamycin, temozolomide, cisplatin, BCNU, lomustine, procarbazine, and vincristine. In another embodiment, the invention is directed to a method of treating glioblastoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is an anti-seizure agent and the anti-seizure agent is diphenylhydantoin (Dilantin). In another embodiment, the invention is directed to a method of treating glioblastoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is an agents to reduce swelling and the agent is dexamethasone (Decadron). In another embodiment, the invention is directed to a method of treating glioblastoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents. In another embodiment, the invention is directed to a method of treating glioblastoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from erlotinib and temozolomide.
In another embodiment, the invention is directed to a method of treating cervical cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiation, and one or two chemotherapeutic agents. In another embodiment, the invention is directed to a method of treating cervical cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is surgery selected from cryosurgery, laser surgery, loop electrosurgical excision, conization, simple hysterectomy, and radical hysterectomy and pelvic lymph node dissection. In another embodiment, the invention is directed to a method of treating cervical cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is radiation selected from called external beam radiation therapy and brachytherapy. In another embodiment, the invention is directed to a method of treating cervical cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from a platinum compound (such as cisplatin, carboplatin, and oxaliplatin), paclitaxel, topotecan, ifosfamide, gemcitabine, vinorelbine, and fluorouracil.
In another embodiment, the invention is directed to a method of treating a gastrointestinal carcinoid tumor which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiation, immunotherapy, and one or two chemotherapeutic agents. In another embodiment, the invention is directed to a method of treating a gastrointestinal carcinoid tumor which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is surgery selected from excision and electrofulguration. In another embodiment, the invention is directed to a method of treating a gastrointestinal carcinoid tumor which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from cyproheptadine, SOM230, octreotide and lanreotide. In another embodiment, the invention is directed to a method of treating a gastrointestinal carcinoid tumor which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is immunotherapy and the immunotherapy is an interferon.
In another embodiment, the invention is directed to a method of treating a gastrointestinal stromal tumor which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiation, and one or two chemotherapeutic agents. In another embodiment, the invention is directed to a method of treating a gastrointestinal stromal tumor which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from imatinib mesylate (Gleevec), sunitinib (Sutent), and nilotinib (AMN107).
In another embodiment, the invention is directed to a method of treating hepatocellular carcinoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from surgery, radiofrequency ablation, ethanol ablation, cryosurgery, hepatic artery embolization, chemoembolization, radiation, and one or two chemotherapeutic agents. In another embodiment, the invention is directed to a method of treating hepatocellular carcinoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is surgery selected from resection and transplantation. In another embodiment, the invention is directed to a method of treating hepatocellular carcinoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from sorafenib, 5-fluorouracil and cisplatin.
In another embodiment, the invention is directed to a method of treating non-Hodgkin's lymphoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments independently selected from radiation, one or two chemotherapeutic agents, interferon therapy, one or two antibodies, and bone marrow or peripheral blood stem cell transplantation. In another embodiment, the invention is directed to a method of treating non-Hodgkin's lymphoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents selected from CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone), chlorambucil, fludarabine, and etoposide. In another embodiment, the invention is directed to a method of treating non-Hodgkin's lymphoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is an antibody selected from rituximab, ibritumomab tiuxetan, tositumomab, and alemtuzumab. In another embodiment, the invention is directed to a method of treating non-Hodgkin's lymphoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is an antibody and the antibody is rituximab.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is radiation and another treatment is surgery.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is radiation and another treatment is one or two chemotherapeutic agents.
In another embodiment, the invention is directed to a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined in the Summary of the Invention, in combination with one or more treatments where one of the treatments is surgery and another treatment is one or two chemotherapeutic agents.
For each of the foregoing embodiments, the Compound of Formula I is selected from any of the following embodiments, including from the Representative Compounds in Table 1.
One embodiment (A) of the Invention is directed to a Compound of Formula I where R1 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl. In another embodiment, R1 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalkyl, or optionally substituted heterocycloalkylalkyl. In another embodiment, R1 is hydrogen, alkyl, alkyl substituted with one or two hydroxy, alkyl substituted with alkoxy, cycloalkyl, arylalkyl, or heterocycloalkylalkyl. In another embodiment, R1 is hydrogen, methyl, ethyl, propyl, isopropyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-ethoxyethyl, 3-methoxypropyl, 3-ethoxypropyl, 3-isopropoxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, or 2-piperidin-1-ylethyl. In another embodiment, R1 is ethyl, isopropyl, cyclopentyl, or cyclohexyl. In another embodiment, R1 is ethyl.
Another embodiment (B) of the Invention is directed to a Compound of Formula I where R2 is hydrogen or alkyl where the alkyl is optionally substituted with 1, 2, 3, 4, or 5 R8 groups. In another embodiment, R2 is hydrogen or alkyl where the alkyl is optionally substituted with one, two, or three R8 groups. In another embodiment, R2 is hydrogen or alkyl where the alkyl is optionally substituted with one, two, or three R8 groups; and each R8, when present, is independently selected from amino, alkylamino, dialkylamino, and halo. In another embodiment, R2 is hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, 3-aminopropyl, 3-(N-methylamino)-propyl, 3-(N,N-dimethylamino)-propyl, 2-fluoroethyl, or 2,2,2-trifluoroethyl. In another embodiment, R2 is hydrogen or ethyl. Yet even more preferably, R2 is hydrogen.
In another embodiment of the Invention, R2 is hydrogen.
In another embodiment of the invention, R2 is alkyl optionally substituted with 1, 2, 3, 4, or 5, R8 groups. In another embodiment, R2 is alkyl where the alkyl is optionally substituted with one, two, or three R8 groups; and each R8, when present, is independently selected from amino, alkylamino, dialkylamino, and halo. In another embodiment, R2 is methyl, ethyl, propyl, isopropyl, tert-butyl, 3-aminopropyl, 3-(N-methylamino)-propyl, 3-(N,N-dimethylamino)-propyl, 2-fluoroethyl, or 2,2,2-trifluoroethyl. In another embodiment, R2 is ethyl.
Another embodiment (C) of the Invention is directed to a Compound of Formula I where R4 is optionally substituted alkyl. In another embodiment, R4 is methyl or ethyl. In another embodiment, R4 is methyl.
Another embodiment (D) of the Invention is directed to a Compound of Formula I where R6 is acyl. In another embodiment, R6 is alkylcarbonyl. In another embodiment, R6 is acetyl.
Another embodiment (E) of the Invention is directed to a Compound of Formula I where R6 is phenyl optionally substituted with 1, 2, 3, 4, or 5 R9 groups. In another embodiment, R6 is phenyl optionally substituted with one or two R9 groups; and each R9, when present, is independently selected from aryl, halo, alkoxy, aryloxy, and haloalkyl. In another embodiment, R6 is phenyl optionally substituted with one or two R9 groups; and each R9, when present, is independently selected from phenyl, fluoro, chloro, methoxy, phenyloxy, and trifluoromethyl. In another embodiment, R6 is phenyl, phenyl substituted with phenyl, fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, phenyl substituted with chloro and fluoro, methoxyphenyl, dimethoxyphenyl, phenyloxyphenyl, or trifluoromethylphenyl. In another embodiment, R6 is phenyl, 2-phenyl-phenyl, 3-phenyl-phenyl, 4-phenyl-phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 4-phenyloxyphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, or 4-trifluoromethylphenyl.
Another embodiment (F) of the Invention is directed to a Compound of Formula I where R6 is phenyl substituted with 1, 2, 3, 4, or 5 R9 groups.
Another embodiment (G) of the Invention is directed to a Compound of Formula I where R6 is heteroaryl optionally substituted with 1, 2, 3, 4, or 5 R9 groups.
Another embodiment (G1) of embodiment G is a Compound of Formula I where R6 is a 6-membered heteroaryl optionally substituted with one or two R9. In another embodiment, R6 is pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl each of which is optionally substituted with one R9 where R9, when present, is halo. In another embodiment, R6 is pyridiN-2-yl, pyridin-3-yl, pyridiN-4-yl, 3-fluoropyridiN-4-yl, pyrazin-2-yl, pyrazin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, or pyridazin-4-yl, each of which is optionally substituted with one or two R9.
In another embodiment (G2) of embodiment G is a Compound of Formula I where R6 is pyrazinyl, pyrimidinyl, or pyridazinyl each of which is optionally substituted with one R9 where R9, when present, is halo. In another embodiment, R6 is pyrazin-2-yl, pyrazin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, or pyridazin-4-yl.
Another embodiment (G3) of embodiment G is a Compound of Formula I where R6 is 5-membered heteroaryl optionally substituted with one or two R9. In another embodiment R6 is pyrazolyl, imidazolyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, triazolyl, or tetrazolyl, each of which is optionally substituted with one R9 where R9, when present, is alkyl, arylalkyl, cyano, aryl, alkoxycarbonyl, or halo. In another embodiment, R6 is pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, thien-2-yl, thien-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, furan-2-yl, furan-3-yl, pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, triazol-1-yl, triazol-4-yl, triazol-5-yl, tetrazol-1-yl, or tetrazol-5-yl; each of which is optionally substituted with one R9 where R9, when present, is methyl, benzyl, cyano, phenyl, N-tert-butoxycarbonyl, or chloro. In another embodiment, R6 is pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, thien-2-yl, thien-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, furan-2-yl, furan-3-yl, pyrrol-2-yl, pyrrol-3-yl, triazol-4-yl, triazol-5-yl, or tetrazol-5-yl; each of which is optionally substituted with one R9 where R9, when present, is methyl, benzyl, cyano, phenyl, N-tert-butoxycarbonyl, or chloro.
Another embodiment (G4) of embodiment G is a Compound of Formula I where R6 is thienyl, pyrrolyl, furanyl, pyrazolyl, thiazolyl, isoxazolyl, imidazolyl, triazolyl, or tetrazolyl, each of which is optionally substituted with one R9 where R9, when present, is methyl, benzyl, cyano, phenyl, N-tert-butoxycarbonyl, or chloro. In another embodiment, R6 is thien-2-yl, thien-3-yl, pyrrol-2-yl, furan-2-yl, furan-3-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, thiazol-2-yl, thiazol-5-yl, isoxazol-4-yl, imidazol-5-yl, triazol-5-yl, tetrazol-5-yl, each of which is optionally substituted with one R9 where R9, when present, is methyl, benzyl, cyano, phenyl, N-tert-butoxycarbonyl, or chloro. In another embodiment, R6 is thien-2-yl, thien-3-yl, 5-cyano-thien-2-yl, 4-methyl-thien-2-yl, 4-methyl-thien-3-yl, 5-chloro-thien-5-yl, 5-phenyl-thien-2-yl, pyrrol-2-yl, N-tert-butoxycarbonyl-pyrrol-2-yl, N-methyl-pyrrol-2-yl, furan-2-yl, furan-3-yl, pyrazol-3-yl, pyrazol-4-yl, N-benzyl-pyrazol-4-yl, pyrazol-5-yl, thiazol-2-yl, thiazol-5-yl, isoxazol-4-yl, imidazol-5-yl, triazol-5-yl, tetrazol-5-yl,
Another embodiment (G5) of embodiment G is a Compound of Formula I where R6 is thien-2-yl, thien-3-yl, pyrrol-2-yl, furan-2-yl, furan-3-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, thiazol-2-yl, thiazol-5-yl, isoxazol-4-yl, imidazol-5-yl, triazol-5-yl, or tetrazol-5-yl, each of which is optionally substituted with one R9 where R9, when present, is methyl, benzyl, cyano, phenyl, N-tert-butoxycarbonyl, or chloro.
Another embodiment (G6) of embodiment G is a Compound of Formula I where R6 is indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, or benzoisoxazolyl each of which is optionally substituted with 1, 2, 3, 4, or 5 R9 groups. In another embodiment, R6 is indol-2-yl, indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl, indol-7-yl, benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, benzofuran-2-yl, benzofuran-3-yl, benzofuran-4-yl, benzofuran-5-yl, benzofuran-6-yl, benzofuran-7-yl, benzoxazol-2-yl, benzoxazol-4-yl, benzoxazol-5-yl, benzoxazol-6-yl, benzoxazol-7-yl, benzoisoxazol-3-yl, benzoisoxazol-4-yl, benzoisoxazol-5-yl, benzoisoxazol-6-yl, or benzoisoxazol-7-yl; each of which is optionally substituted with 1, 2, 3, 4, or 5 R9 groups. In another embodiment, R6 is indol-6-yl.
Another embodiment of the Invention (H) is a Compound of Formula 1 where R′ is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkylalkyl, or optionally substituted arylalkyl; X is —NH—; R2 is hydrogen or alkyl where the alkyl is optionally substituted with one or two R8 groups; R4 is alkyl; R5 is hydrogen; R6 is phenyl or heteroaryl wherein the phenyl and heteroaryl are optionally substituted with one, two, or three R9 groups; each R8, when present, is independently amino, alkylamino, dialkylamino, or halo; and each R9, when present, is independently alkyl, arylalkyl, cyano, aryl, alkoxycarbonyl, or halo.
Another embodiment of the Invention (J) is a Compound of Formula 1 where R6 is pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, thien-2-yl, thien-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, furan-2-yl, furan-3-yl, pyrrol-2-yl, pyrrol-3-yl, triazol-4-yl, triazol-5-yl, or tetrazol-5-yl; each of which is optionally substituted with 1, 2, 3, 4, or 5 R9 groups.
Another embodiment (K) of the Invention is a Compound of Formula I where R′ is alkyl or cycloalkyl; R4 is methyl; and R6 is heteroaryl optionally substituted with one or two R9 groups. In another embodiment, each R9, when present, is independently alkyl, arylalkyl, cyano, aryl, alkoxycarbonyl, or halo. In another embodiment, R6 is pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, thien-2-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, furan-2-yl, furan-3-yl, pyrrol-2-yl, pyrrol-3-yl, triazol-4-yl, triazol-5-yl, or tetrazol-5-yl; each of which is optionally substituted with one R9 where R9, when present, is methyl, benzyl, cyano, phenyl, or N-tert-butoxycarbonyl.
Another embodiment (K1) of embodiment K is a Compound of Formula I where R2 is hydrogen.
Another embodiment (K2) of embodiment K is a Compound of Formula I where R2 is methyl or ethyl.
Another embodiment (L) of the Invention is a Compound of Formula I where R1 is alkyl or cycloalkyl; R4 is methyl; and R6 is phenyl optionally substituted with one or two R9 groups. In another embodiment each R9, when present, is independently halo, alkoxy, or haloalkyl.
Another embodiment (M) of the Invention is a Compound of Formula I where R1 is alkyl or cycloalkyl; R4 is methyl; and R2 is hydrogen.
Another embodiment (N) of the Invention is a Compound of Formula I where R1 is alkyl or cycloalkyl; R4 is methyl; and R2 is optionally substituted alkyl.
Representative Compounds
Representative compounds of Formula I and/or II are depicted below. The examples are merely illustrative and do not limit the scope of the invention in any way.
Compounds of the invention are named according to systematic application of the nomenclature rules agreed upon by the International Union of Pure and Applied Chemistry (IUPAC), International Union of Biochemistry and Molecular Biology (IUBMB), and the Chemical Abstracts Service (CAS). Names were generated using ACD/Labs naming software 8.00 release, product version 8.08.
Table 1
The Compounds in Table 1 can be prepared as pharmaceutically acceptable salts, solvates, hydrates, and/or isomers thereof. All such salt, solvate, hydrate, and isomer combinations of the Compounds in Table 1 can be used to practice the invention. In particular, the invention can be practiced with one or two pharmaceutically acceptable salts of a Compound of Table 1 which salt(s) are formed with one or two acids independently selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, p-toluenesulfonic acid, and salicylic acid. Any individual compound (and any optional salt, optional solvate, and optional hydrate thereof) in Table 1 can be used in combination with any of the above embodiments.









TABLE 1





Example
Structure
Name







1




8-ethyl-2-(ethylamino)-4-methyl-6- phenylpyrido[2,3-d]pyrimidin-7(8H)-one


 


2




6-bromo-8-ethyl-4-methyl-2-[(1- methylethyl)amino]pyrido[2,3-d]pyrimidin- 7(8H)-one


 


3




6-bromo-2-[(1,1-dimethylethyl)amino]-8- ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)- one


 


4




6-biphenyl-4-yl-8-ethyl-2-(ethylamino)-4- methylpyrido[2,3-d]pyrimidin-7(8H)-one


 


5




6-(2,4-difluorophenyl)-8-ethyl-2-(ethylamino)- 4-methylpyrido[2,3-d]pyrimidin-7(8H)-one


 


6




6-(3-chloro-4-fluorophenyl)-8-ethyl-2- (ethylamino)-4-methylpyrido[2,3-d]pyrimidin- 7(8H)-one


 


7




8-ethyl-2-(ethylamino)-4-methyl-6-[4- (methyloxy)phenyl]pyrido[2,3-d]pyrimidin- 7(8H)-one


 


8




6-(2,4-dichlorophenyl)-8-ethyl-2- (ethylamino)-4-methylpyrido[2,3-d]pyrimidin- 7(8H)-one


 


9




6-(3,4-difluorophenyl)-8-ethyl-2-(ethylamino)- 4-methylpyrido[2,3-d]pyrimidin-7(8H)-one


 


10




8-ethyl-2-(ethylamino)-4-methyl-6-[2- (methyloxy)phenyl]pyrido[2,3-d]pyrimidin- 7(8H)-one


 


11




6-bromo-2-{[3- (dimethylamino)propyl]amino}-8-ethyl-4- methylpyrido[2,3-d]pyrimidin-7(8H)-one


 


12




8-ethyl-2-(ethylamino)-4-methyl-6-[4- (phenyloxy)phenyl]pyrido[2,3-d]pyrimidin- 7(8H)-one


 


13




6-[2,4-bis(methyloxy)phenyl]-8-ethyl-2- (ethylamino)-4-methylpyrido[2,3-d]pyrimidin- 7(8H)-one


 


14




8-ethyl-2-(ethylamino)-6-(3-fluorophenyl)-4- methylpyrido[2,3-d]pyrimidin-7(8H)-one


 


15




8-ethyl-2-(ethylamino)-6-(2-fluorophenyl)-4- methylpyrido[2,3-d]pyrimidin-7(8H)-one


 


16




8-ethyl-2-(ethylamino)-4-methyl-6-[3- (trifluoromethyl)phenyl]pyrido[2,3- d]pyrimidin-7(8H)-one


 


17




8-ethyl-2-(ethylamino)-6-(4-fluorophenyl)-4- methylpyrido[2,3-d]pyrimidin-7(8H)-one


 


18




8-ethyl-2-(ethylamino)-4-methyl-6-(2- thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one


 


19




8-ethyl-2-(ethylamino)-4-methyl-6-[3- (methyloxy)phenyl]pyrido[2,3-d]pyrimidin- 7(8H)-one


 


20




6-(3-chlorophenyl)-8-ethyl-2-(ethylamino)-4- methylpyrido[2,3-d]pyrimidin-7(8H)-one


 


21




6-(4-chlorophenyl)-8-ethyl-2-(ethylamino)-4- methylpyrido[2,3-d]pyrimidin-7(8H)-one


 


22




8-ethyl-2-(ethylamino)-4-methyl-6-(3- thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one


 


23




8-ethyl-2-(ethylamino)-4-methyl-6-(4-methyl- 2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one


 


24




8-ethyl-2-(ethylamino)-4-methyl-6-(4-methyl- 3-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one


 


25




1,1-dimethylethyl 2-[8-ethyl-2-(ethylamino)-4- methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-6-yl]-1H-pyrrole-1-carboxylate


 


26




8-ethyl-2-(ethylamino)-4-methyl-6-(1H- pyrrol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one


 


27




6-(5-chloro-2-thienyl)-8-ethyl-2-(ethylamino)- 4-methylpyrido[2,3-d]pyrimidin-7(8H)-one


 


28




8-ethyl-2-(ethylamino)-4-methyl-6-pyrimidin- 5-ylpyrido[2,3-d]pyrimidin-7(8H)-one


 


29




8-ethyl-2-(ethylamino)-6-(3-fluoropyridiN-4- yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one


 


30




8-ethyl-2-(ethylamino)-6-furan-3-yl-4- methylpyrido[2,3-d]pyrimidin-7(8H)-one


 


31




8-ethyl-2-(ethylamino)-4-methyl-6-[1- (phenylmethyl)-1H-pyrazol-4-yl]pyrido[2,3- d]pyrimidin-7(8H)-one


 


32




6-bromo-2-(ethylamino)-4-methyl-8-(1- methylethyl)pyrido[2,3-d]pyrimidin-7(8H)-one


 


33




2-(ethylamino)-4-methyl-8-(1-methylethyl)-6- (2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one


 


34




8-ethyl-2-(ethylamino)-6-(1H-indol-6-yl)-4- methylpyrido[2,3-d]pyrimidin-7(8H)-one


 


35




8-ethyl-2-(ethylamino)-4-methyl-6-(5-phenyl- 2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one


 


36




2-(ethylamino)-6-furan-3-yl-4-methyl-8-(1- methylethyl)pyrido[2,3-d]pyrimidin-7(8H)-one


 


37




8-ethyl-2-(ethylamino)-4-methylpyrido[2,3- d]pyrimidin-7(8H)-one


 


38




8-ethyl-2-(ethylamino)-4-methyl-6-(1H- pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)- one


 


39




8-cyclohexyl-2-(ethylamino)-4-methyl-6-(2- thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one


 


40




6-bromo-2-(ethylamino)-4-methyl-8-[3- (methyloxy)propyl]pyrido[2,3-d]pyrimidin- 7(8H)-one


 


41




6-bromo-2-(ethylamino)-8-[2- (ethyloxy)ethyl]-4-methylpyrido[2,3- d]pyrimidin-7(8H)-one


 


42




6-bromo-2-(ethylamino)-4-methyl-8-(2- piperidin-1-ylethyl)pyrido[2,3-d]pyrimidin- 7(8H)-one


 


43




6-bromo-2-(ethylamino)-8-[3- (ethyloxy)propyl]-4-methylpyrido[2,3- d]pyrimidin-7(8H)-one


 


44




6-bromo-2-(ethylamino)-4-methyl-8-{3-[(1- methylethyl)oxy]propyl}pyrido[2,3- d]pyrimidin-7(8H)-one


 


45




6-bromo-2-(ethylamino)-8-(3-bydroxypropyl)- 4-methylpyrido[2,3-d]pyrimidin-7(8H)-one


 


46




6-bromo-2-(ethylamino)-8-(2-hydroxyethyl)- 4-methylpyrido[2,3-d]pyrimidin-7(8H)-one


 


47




6-bromo-8-cyclopropyl-2-(ethylamino)-4- methylpyrido[2,3-d]pyrimidin-7(8H)-one


 


48




8-ethyl-2-(ethylamino)-4-methyl-6-(1,3- thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one


 


49




6-bromo-8-cyclopentyl-2-(ethylamino)-4- methylpyrido[2,3-d]pyrimidin-7(8H)-one


 


50




8-cyclopentyl-2-(ethylamino)-4-methyl-6-(1H- pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)- one


 


51




2-(ethylamino)-4-methyl-8-(1-methylethyl)-6- (1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin- 7(8H)-one


 


52




8-ethyl-2-(ethylamino)-4-methyl-6-(1H- pyrazol-1-yl)pyrido[2,3-d]pyrimidin-7(8H)- one


 


53




2-(ethylamino)-4-methyl-8-(1-methylethyl)-6- (1H-pyrazol-1-yl)pyrido[2,3-d]pyrimidin- 7(8H)-one


 


54




8-cyclopentyl-2-(ethylamino)-4-methyl-6-(1H- pyrazol-1-yl)pyrido[2,3-d]pyrimidin-7(8H)- one


 


55




8-ethyl-4-methyl-6-(1H-pyrazol-5-yl)-2- [(2,2,2-trifluoroethyl)amino]pyrido[2,3- d]pyrimidin-7(8H)-one


 


56




2-amino-8-ethyl-4-methyl-6-(1H-pyrazol-5- yl)pyrido[2,3-d]pyrimidin-7(8H)-one


 


57




2-(ethylamino)-4-methyl-6-(1H-pyrazol-3- yl)pyrido[2,3-d]pyrimidin-7(8H)-one


 


58




8-ethyl-4-methyl-2-(methylamino)-6-(1H- pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)- one


 


59




2-amino-8-cyclopentyl-4-methyl-6-(1H- pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)- one


 


60




8-ethyl-2-[(2-fluoroethyl)amino]-4-methyl-6- (1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin- 7(8H)-one


 


61




2-amino-4-methyl-8-(1-methylethyl)-6-(1H- pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)- one


 


62




2-amino-8-ethyl-4-methylpyrido[2,3- d]pyrimidin-7(8H)-one


 


63




2-amino-4-methyl-8-(phenylmethyl)-6-(1H- pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)- one


 


64




2-amino-8-ethyl-4-methyl-6-(4-methyl-3- thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one


 


65




2-amino-8-ethyl-4-methyl-6-(2- thienyl)pyrido[2,3-d]pyrimidin-7(8H)one


 


66




2-amino-8-ethyl-6-(4-fluorophenyl)-4- methylpyrido[2,3-d]pyrimidin-7(8H)-one


 


67




2-amino-8-ethyl-6-(3-fluorophenyl)-4- methylpyrido[2,3-d]pyrimidin-7(8H)-one


 


68




2-amino-8-ethyl-6-(2-fluorophenyl)-4- methylpyrido[2,3-d]pyrimidin-7(8H)-one


 


69




2-amino-8-ethyl-4-methyl-6-(3- thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one


 


70




2-amino-8-ethyl-6-furan-3-yl-4- methylpyrido[2,3-d]pyrimidin-7(8H)-one


 


71




2-amino-8-ethyl-4-methyl-6-phenylpyrido[2,3- d]pyrimidin-7(8H)-one


 


72




2-amino-8-ethyl-4-methyl-6-[4- (methyloxy)phenyl]pyrido[2,3-d]pyrimidin- 7(8H)-one


 


73




2-amino-6-(4-chlorophenyl)-8-ethyl-4- methylpyrido[2,3-d]pyrimidin-7(8H)-one


 


74




2-amino-6-(3-chlorophenyl)-8-ethyl-4- methylpyrido[2,3-d]pyrimidin-7(8H)-one


 


75




2-amino-8-ethyl-6-isoxazol-4-yl-4- methylpyrido[2,3-d]pyrimidin-7(8H)-one


 


76




2-amino-8-ethyl-6-furan-2-yl-4- methylpyrido[2,3-d]pyrimidin-7(8H)-one


 


77




2-amino-6-(2,4-dichlorophenyl)-8-ethyl-4- methylpyrido[2,3-d]pyrimidin-7(8H)-one


 


78




5-(2-amino-8-ethyl-4-methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-6- yl)thiophene-2-carbonitrile


 


79




2-amino-8-ethyl-4-methyl-6-pyrimidin-5- ylpyrido[2,3-d]pyrimidin-7(8H)-one


 


80




2-amino-8-ethyl-6-(1H-imidazol-5-yl)-4- methylpyrido[2,3-d]pyrimidin-7(8H)-one


 


81




2-amino-8-ethyl-4-methyl-6-(1H-1,2,3-triazol- 5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one


 


82




2-amino-8-ethyl-4-methyl-6-(1H-pyrazol-4- yl)pyrido[2,3-d]pyrimidin-7(8H)-one


 


83




2-amino-8-ethyl-4-methyl-6-(1,3-thiazol-2- yl)pyrido[2,3-d]pyrimidin-7(8H)-one


 


84




2-amino-8-ethyl-4-methyl-6-(1H-tetrazol-5- yl)pyrido[2,3-d]pyrimidin-7(8H)-one


 


85




2-amino-8-ethyl-4-methyl-6-(1-methyl-1H- pyrrol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one


 


86




2-amino-6-bromo-8-cyclopentyl-4- methylpyrido[2,3-d]pyrimidin-7(8H)-one


 


87




2-amino-4,8-diethyl-6-(1H-pyrazol-5- yl)pyrido[2,3-d]pyrimidin-7(8H)-one


 


88




2-amino-8-cyclopentyl-4-methyl-6-(1,3- thiazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one









Table 2a
Representative AKT Inhibitors
The Compounds in Table 2a can be prepared as pharmaceutically acceptable salts, solvates, hydrates, and/or isomers thereof. All such salt, solvate, hydrate, and isomer combinations of the Compounds in Table 2a can be used to practice the invention.








TABLE 2a





Cmpd No.
Name
















1
3-(azetidin-3-ylidenemethyl)-4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-



pyrazolo[3,4-d]pyrimidine


2
4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(3-fluoropyridin-4-yl)-1H-pyrazolo[3,4-



d]pyrimidine


3
4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(3-chloropyridin-4-yl)-1H-pyrazolo[3,4-



d]pyrimidine


4
2-({5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-



methylphenyl}oxy)-N,N-dimethylethanamine


5
2-({5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-



methylphenyl}oxy)-N,N-diethylethanamine


6
4-(4-{5-chloro-2-methyl-3-[(2-pyrrolidin-1-ylethyl)oxy]phenyl}piperazin-1-yl)-3-ethyl-



1H-pyrazolo[3,4-d]pyrimidine


7
4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-piperazin-1-yl-1H-pyrazolo[3,4-



d]pyrimidine


8
N-(3-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-



yl}prop-2-yn-1-yl)acetamide


9
N,N-diethyl-2-({3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-



yl]phenyl}oxy)ethanamine


10
3-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-chloro-2-



methylphenyl}-N,N-diethylpropan-1-amine


11
3-bromo-4-{4-[5-chloro-2-methyl-3-(3-pyrrolidin-1-ylpropyl)phenyl]piperazin-1-yl}-1H-



pyrazolo[3,4-d]pyrimidine


12
3-bromo-4-(4-{5-chloro-2-methyl-3-[(2-pyrrolidin-1-ylethyl)oxy]phenyl}piperazin-1-yl)-



1H-pyrazolo[3,4-d]pyrimidine


13
2-({3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-chloro-2-



methylphenyl}oxy)-N,N-diethylethanamine


14
4-[4-(5-chloro-2-methyl-3-{[2-(1-methylpiperidin-4-yl)ethyl]oxy}phenyl)piperazin-1-yl]-



3-ethyl-1H-pyrazolo[3,4-d]pyrimidine


15
5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-N-(2-



pyrrolidin-1-ylethyl)aniline


16
4-(4-{5-chloro-2-methyl-3-[(2-morpholin-4-ylethyl)oxy]phenyl}piperazin-1-yl)-3-ethyl-



1H-pyrazolo[3,4-d]pyrimidine


17
4-(4-{5-chloro-2-methyl-3-[(2-piperidin-1-ylethyl)oxy]phenyl}piperazin-1-yl)-3-ethyl-1H-



pyrazolo[3,4-d]pyrimidine


18
3-bromo-4-{4-[5-chloro-2-methyl-3-(3-morpholin-4-ylpropyl)phenyl]piperazin-1-yl}-1H-



pyrazolo[3,4-d]pyrimidine


19
3-bromo-4-(4-{5-chloro-2-methyl-3-[3-(4-methylpiperazin-1-yl)propyl]phenyl}piperazin-



1-yl)-1H-pyrazolo[3,4-d]pyrimidine


20
3-bromo-4-(4-{5-chloro-2-methyl-3-[(2-piperidin-1-ylethyl)oxy]phenyl}piperazin-1-yl)-



1H-pyrazolo[3,4-d]pyrimidine


21
3-bromo-4-(4-{5-chloro-2-methyl-3-[(2-morpholin-4-ylethyl)oxy]phenyl}piperazin-1-yl)-



1H-pyrazolo[3,4-d]pyrimidine


22
4-{4-[5-chloro-2-methyl-3-(3-morpholin-4-ylpropyl)phenyl]piperazin-1-yl}-3-ethyl-1H-



pyrazolo[3,4-d]pyrimidine


23
N′-{5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-



methylphenyl}-N,N-diethylethane-1,2-diamine


24
4-{4-[5-chloro-2-methyl-3-(3-piperidin-1-ylpropyl)phenyl]piperazin-1-yl}-3-ethyl-1H-



pyrazolo[3,4-d]pyrimidine


25
4-[4-(5-chloro-3-{[2-(4-ethylpiperazin-1-yl)ethyl]oxy}-2-methylphenyl)piperazin-1-yl]-3-



ethyl-1H-pyrazolo[3,4-d]pyrimidine


26
4-(4-{5-chloro-2-methyl-3-[(3-morpholin-4-ylpropyl)oxy]phenyl}piperazin-1-yl)-3-ethyl-



1H-pyrazolo[3,4-d]pyrimidine


27
3-bromo-4-{4-[5-chloro-2-methyl-3-(3-piperidin-1-ylpropyl)phenyl]piperazin-1-yl}-1H-



pyrazolo[3,4-d]pyrimidine


28
N′-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-chloro-2-



methylphenyl}-N,N-diethylethane-1,2-diamine


29
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-chloro-2-methyl-N-(2-



pyrrolidin-1-ylethyl)aniline


30
4-[4-(5-chloro-2-methyl-3-{[2-(4-methylpiperazin-1-yl)ethyl]oxy}phenyl)piperazin-1-yl]-



3-ethyl-1H-pyrazolo[3,4-d]pyrimidine


31
4-[4-(5-chloro-2-methyl-3-{[(1-methylpiperidin-4-yl)methyl]oxy}phenyl)piperazin-1-yl]-3-



ethyl-1H-pyrazolo[3,4-d]pyrimidine


32
N,N-diethyl-2-({3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-



methylphenyl}oxy)ethanamine


33
2-[(5-chloro-3-{4-[1-(1,1-dimethylethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-



4-yl]piperazin-1-yl}-2-methylphenyl)oxy]-N,N-diethylethanamine


34
2-[(5-chloro-2-methyl-3-{4-[3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-



yl]piperazin-1-yl}phenyl)oxy]-N,N-diethylethanamine


35
4-(4-{5-chloro-2-methyl-3-[(3-pyrrolidin-1-ylpropyl)oxy]phenyl}piperazin-1-yl)-3-ethyl-



1H-pyrazolo[3,4-d]pyrimidine


36
4-[4-(5-chloro-2-methyl-3-{[3-(4-methylpiperazin-1-yl)propyl]oxy}phenyl)piperazin-1-yl]-



3-ethyl-1H-pyrazolo[3,4-d]pyrimidine


37
3-bromo-4-(4-{5-chloro-2-methyl-3-[(3-piperidin-1-ylpropyl)oxy]phenyl}piperazin-1-yl)-



1H-pyrazolo[3,4-d]pyrimidine


38
3-bromo-4-(4-{5-chloro-2-methyl-3-[(3-morpholin-4-ylpropyl)oxy]phenyl}piperazin-1-yl)-



1H-pyrazolo[3,4-d]pyrimidine


39
4-(4-{5-chloro-2-methyl-3-[(2-pyrrolidin-1-ylethyl)oxy]phenyl}piperazin-1-yl)-3-



(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine


40
4-(4-{5-chloro-2-methyl-3-[(3-morpholin-4-ylpropyl)oxy]phenyl}piperazin-1-yl)-3-



(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine


41
4-(4-{5-chloro-2-methyl-3-[(2-morpholin-4-ylethyl)oxy]phenyl}piperazin-1-yl)-3-



(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine


42
4-(4-{5-chloro-2-methyl-3-[(3-piperidin-1-ylpropyl)oxy]phenyl}piperazin-1-yl)-3-ethyl-



1H-pyrazolo[3,4-d]pyrimidine


43
4-[4-(5-chloro-3-{[3-(4-ethylpiperazin-1-yl)propyl]oxy}-2-methylphenyl)piperazin-1-yl]-3-



ethyl-1H-pyrazolo[3,4-d]pyrimidine


44
5-chloro-2-methyl-3-[4-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-N-(2-



pyrrolidin-1-ylethyl)aniline


45
5-chloro-2-methyl-3-[4-(3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-N-(2-



pyrrolidin-1-ylethyl)aniline


46
N′-(5-chloro-2-methyl-3-{4-[3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-



yl]piperazin-1-yl}phenyl)-N,N-dimethylethane-1,2-diamine


47
3-({5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-



methylphenyl}oxy)-N,N-diethylpropan-1-amine


48
N′-(5-chloro-2-methyl-3-{4-[3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-



yl]piperazin-1-yl}phenyl)-N,N-diethylethane-1,2-diamine


49
5-chloro-2-methyl-N-(2-pyrrolidin-1-ylethyl)-3-{4-[3-(trifluoromethyl)-1H-pyrazolo[3,4-



d]pyrimidin-4-yl]piperazin-1-yl}aniline


50
3-bromo-4-(4-{4-methyl-3-[(2-pyrrolidin-1-ylethyl)oxy]phenyl}piperazin-1-yl)-1H-



pyrazolo[3,4-d]pyrimidine


51
4-(4-{4-methyl-3-[(2-pyrrolidin-1-ylethyl)oxy]phenyl}piperazin-1-yl)-1H-pyrazolo[3,4-



d]pyrimidine


52
3-methyl-4-(4-{4-methyl-3-[(2-pyrrolidin-1-ylethyl)oxy]phenyl}piperazin-1-yl)-1H-



pyrazolo[3,4-d]pyrimidine


53
4-(4-{5-chloro-2-methyl-3-[(2-pyrrolidin-1-ylethyl)oxy]phenyl}piperazin-1-yl)-1H-



pyrazolo[3,4-d]pyrimidine


54
4-(4-{5-chloro-2-methyl-3-[(2-pyrrolidin-1-ylethyl)oxy]phenyl}piperazin-1-yl)-3-methyl-



1H-pyrazolo[3,4-d]pyrimidine


55
4-(4-{5-chloro-2-methyl-3-[(2-piperidin-1-ylethyl)oxy]phenyl}piperazin-1-yl)-3-



(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine


56
3-[(5-chloro-2-methyl-3-{4-[3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-



yl]piperazin-1-yl}phenyl)oxy]-N,N-diethylpropan-1-amine


57
5-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-N-(2-



pyrrolidin-1-ylethyl)aniline


58
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-fluoro-2-methyl-N-(2-



pyrrolidin-1-ylethyl)aniline


59
4-{4-[5-chloro-2-methyl-3-(3-pyrrolidin-1-ylpropyl)phenyl]piperazin-1-yl}-1H-



pyrazolo[3,4-d]pyrimidine


60
3-bromo-4-{4-[5-fluoro-2-methyl-3-(3-pyrrolidin-1-ylpropyl)phenyl]piperazin-1-yl}-1H-



pyrazolo[3,4-d]pyrimidine


61
4-{4-[5-chloro-2-methyl-3-(3-pyrrolidin-1-ylpropyl)phenyl]piperazin-1-yl}-3-



(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine


62
4-(4-{5-chloro-2-methyl-3-[3-(4-methylpiperazin-1-yl)propyl]phenyl}piperazin-1-yl)-3-



ethyl-1H-pyrazolo[3,4-d]pyrimidine


63
3-bromo-4-(4-pyridin-2-ylpiperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine


64
3-bromo-4-[4-(2,4-dimethylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine


65
3-bromo-4-{4-[3-(methyloxy)phenyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine


66
3-bromo-4-{4-[2-(methyloxy)phenyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine


67
3-bromo-4-{4-[4-methyl-3-(3-pyrrolidin-1-ylpropyl)phenyl]piperazin-1-yl}-1H-



pyrazolo[3,4-d]pyrimidine


68
4-(4-{5-chloro-2-methyl-3-[(3-pyrrolidin-1-ylpropyl)oxy]phenyl}piperazin-1-yl)-3-



(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine


69
4-(4-{5-chloro-2-methyl-3-[(3-piperidin-1-ylpropyl)oxy]phenyl}piperazin-1-yl)-3-



(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine


70
4-[4-(5-chloro-2-methyl-3-{[3-(4-methylpiperazin-1-yl)propyl]oxy}phenyl)piperazin-1-yl]-



3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine


71
4-[4-(5-chloro-3-{[3-(4-ethylpiperazin-1-yl)propyl]oxy}-2-methylphenyl)piperazin-1-yl]-3-



(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine


72
3-bromo-4-[4-(5-chloro-2-methyl-3-{[2-(4-methylpiperazin-1-



yl)ethyl]oxy}phenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine


73
4-[4-(5-chloro-2-methyl-3-{[2-(4-methylpiperazin-1-yl)ethyl]oxy}phenyl)piperazin-1-yl]-



3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine


74
3-bromo-4-[4-(5-chloro-3-{[2-(4-ethylpiperazin-1-yl)ethyl]oxy}-2-



methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine


75
3-bromo-4-[4-(3,4-dichlorophenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine


76
3-bromo-4-[4-(3,4-difluorophenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine


77
3-bromo-4-[4-(2,4-dichlorophenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine


78
3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-fluoro-2-methyl-N-(2-



pyrrolidin-1-ylethyl)aniline


79
5-fluoro-2-methyl-N-(2-pyrrolidin-1-ylethyl)-3-{4-[3-(trifluoromethyl)-1H-pyrazolo[3,4-



d]pyrimidin-4-yl]piperazin-1-yl}aniline


80
4-{4-[3,5-bis(methyloxy)phenyl]piperazin-1-yl}-3-bromo-1H-pyrazolo[3,4-d]pyrimidine


81
4-[4-(5-chloro-3-{[2-(4-ethylpiperazin-1-yl)ethyl]oxy}-2-methylphenyl)piperazin-1-yl]-3-



(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine


82
N-{5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-



methylphenyl}-N,N′,N′-trimethylethane-1,2-diamine


83
3-({3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-chloro-2-



methylphenyl}oxy)-N,N-diethylpropan-1-amine


84
3-bromo-4-(4-{5-chloro-2-methyl-3-[(3-pyrrolidin-1-ylpropyl)oxy]phenyl}piperazin-1-yl)-



1H-pyrazolo[3,4-d]pyrimidine


85
3-bromo-4-[4-(5-chloro-2-methyl-3-{[3-(4-methylpiperazin-1-



yl)propyl]oxy}phenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine


86
3-bromo-4-[4-(5-chloro-3-{[3-(4-ethylpiperazin-1-yl)propyl]oxy}-2-



methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine


87
3-(5-chloro-2-methyl-3-{4-[3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-



yl]piperazin-1-yl}phenyl)-N,N-diethylpropan-1-amine


88
3-bromo-4-[4-(5-chloro-2-methyl-3-{[(1-methylpiperidin-4-



yl)methyl]oxy}phenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine


89
3-bromo-4-[4-(5-chloro-2-methyl-3-{[2-(1-methylpiperidin-4-



yl)ethyl]oxy}phenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine


90
4-[4-(5-chloro-2-methyl-3-{[(1-methylpiperidin-4-yl)methyl]oxy}phenyl)piperazin-1-yl]-3-



(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine


91
4-[4-(5-chloro-2-methyl-3-{[2-(1-methylpiperidin-4-yl)ethyl]oxy}phenyl)piperazin-1-yl]-



3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine


92
4-(4-{5-chloro-2-methyl-3-[3-(4-methylpiperazin-1-yl)propyl]phenyl}piperazin-1-yl)-3-



(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine


93
3-bromo-4-[4-(3-chloro-4-fluorophenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine


94
1-{4-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]phenyl}ethanone


95
3-bromo-4-[4-(2,5-dichlorophenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine


96
3-bromo-4-[4-(3,4-dimethylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine


97
3-bromo-4-[4-(4-nitrophenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine


98
3-ethyl-4-(4-phenylpiperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine


99
3-ethyl-4-{4-[3-(methyloxy)phenyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine


100
4-{4-[5-chloro-2-methyl-3-(3-piperidin-1-ylpropyl)phenyl]piperazin-1-yl}-3-



(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine


101
4-[4-(3,6-dimethylpyrazin-2-yl)piperazin-1-yl]-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine


102
1-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]isoquinoline


103
3-bromo-4-[4-(2,6-dimethylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine


104
3-bromo-4-{4-[4-(ethyloxy)phenyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine


105
3-bromo-4-[4-(2-ethylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine


106
4-{4-[2,4-bis(methyloxy)phenyl]piperazin-1-yl}-3-bromo-1H-pyrazolo[3,4-d]pyrimidine


107
3-bromo-4-(4-pyrazin-2-ylpiperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine


108
3-bromo-4-(4-pyrimidin-2-ylpiperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine


109
4-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-



(trifluoromethyl)quinoline


110
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]pyrazine-2-carbonitrile


111
4-[4-(4,6-dimethylpyrimidin-2-yl)piperazin-1-yl]-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine


112
ethyl 4-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-



(trifluoromethyl)pyrimidine-5-carboxylate


113
4-{4-[3-chloro-5-(methyloxy)phenyl]piperazin-1-yl}-3-ethyl-1H-pyrazolo[3,4-



d]pyrimidine


114
4-[4-(3-bromo-2-chloro-5-fluorophenyl)piperazin-1-yl]-3-ethyl-1H-pyrazolo[3,4-



d]pyrimidine


115
2-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]pyridine-3-carboxamide


116
3-ethyl-4-{4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}-1H-pyrazolo[3,4-



d]pyrimidine


117
3-bromo-4-{4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}-1H-pyrazolo[3,4-



d]pyrimidine


118
3-bromo-4-{4-[4-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl}-1H-pyrazolo[3,4-



d]pyrimidine


119
2-({3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]pyrazin-2-yl}oxy)-



N,N-dimethylethanamine


120
4-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methylquinoline


121
3-bromo-4-[4-(2-nitrophenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine


122
2-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]benzonitrile


123
4-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]benzonitrile


124
3-bromo-4-{4-[4-(trifluoromethyl)phenyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine


125
3-bromo-4-(4-{4-[(phenylmethyl)oxy]phenyl}piperazin-1-yl)-1H-pyrazolo[3,4-



d]pyrimidine


126
4-{4-[5-chloro-2-methyl-3-(methyloxy)phenyl]piperazin-1-yl}-3-ethyl-1H-pyrazolo[3,4-



d]pyrimidine


127
2-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]pyridine-3-carbonitrile


128
3-bromo-4-[4-(3,5-dichlorophenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine


129
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-chloro-5-fluoro-N-(2-



pyrrolidin-1-ylethyl)aniline


130
2-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-fluoro-N-(2-



pyrrolidin-1-ylethyl)aniline


131
3-bromo-4-[4-(2,5-difluorophenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine


132
4-[4-(2,5-difluorophenyl)piperazin-1-yl]-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine


133
3-bromo-4-{4-[3-(methyloxy)pyrazin-2-yl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine


134
3-bromo-4-[4-(3-chlorophenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine


135
3-bromo-4-{4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}-1H-pyrazolo[3,4-



d]pyrimidine


136
3-bromo-4-{4-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}-1H-pyrazolo[3,4-



d]pyrimidine


137
4-(4-{5-chloro-2-methyl-3-[(2-pyrrolidin-1-ylethyl)oxy]phenyl}piperazin-1-yl)-3-(1-



methylethyl)-1H-pyrazolo[3,4-d]pyrimidine


138
5-chloro-2-methyl-3-{4-[3-(1-methylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]piperazin-1-



yl}-N-(2-pyrrolidin-1-ylethyl)aniline


139
2-({3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]phenyl}oxy)-N-



ethylacetamide


140
2-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-N,N-diethylpyrimidin-4-



amine


141
3-bromo-4-[4-(3-{[(3-methylphenyl)methyl]oxy}phenyl)piperazin-1-yl]-1H-pyrazolo[3,4-



d]pyrimidine


142
3-bromo-4-(4-{3-[(2-piperidin-1-ylethyl)oxy]phenyl}piperazin-1-yl)-1H-pyrazolo[3,4-



d]pyrimidine


143
3-bromo-4-[4-(4-furan-2-ylpyrimidin-2-yl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine


144
6-{2-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]pyrimidin-4-yl}-2H-



1,4-benzoxazin-3(4H)-one


145
3-ethyl-4-{4-[2-methyl-3-(methyloxy)phenyl]piperazin-1-yl}-1H-pyrazolo[3,4-



d]pyrimidine


146
N′-{5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-



methylphenyl}-N-methyl-N-(1-methylethyl)ethane-1,2-diamine


147
N′-{5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-



methylphenyl}-N-ethyl-N-methylethane-1,2-diamine


148
N′-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-chloro-2-



methylphenyl}-N,N-dimethylethane-1,2-diamine


149
3-({6-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-chloro-5-



methylpyrimidin-4-yl}oxy)-N,N-diethylpropan-1-amine


150
3-bromo-4-[4-(2,3-dichlorophenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine


151
3-bromo-4-{4-[2-(trifluoromethyl)phenyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine


152
3-bromo-4-(4-phenylpiperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine


153
3-bromo-4-[4-(4-fluorophenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine


154
3-bromo-4-[4-(4-chlorophenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine


155
3-bromo-4-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine


156
4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-amine


157
3-bromo-4-[4-(4-bromophenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine


158
3-bromo-4-[3-methyl-4-(3-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine


159
4-[4-(3-bromo-5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-



amine


160
4-(4-{5-chloro-2-methyl-3-[(2-pyrrolidin-1-ylethyl)oxy]phenyl}piperazin-1-yl)-3-



cyclopropyl-1H-pyrazolo[3,4-d]pyrimidine


161
5-chloro-3-[4-(3-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-



N-(2-pyrrolidin-1-ylethyl)aniline


162
5-chloro-2-methyl-3-{4-[3-(2-methylpropyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]piperazin-



1-yl}-N-(2-pyrrolidin-1-ylethyl)aniline


163
4-(4-{5-chloro-2-methyl-3-[(2-pyrrolidin-1-ylethyl)oxy]phenyl}piperazin-1-yl)-3-(2-



methylpropyl)-1H-pyrazolo[3,4-d]pyrimidine


164
3-bromo-4-[(3S)-4-(5-chloro-2-methylphenyl)-3-methylpiperazin-1-yl]-1H-pyrazolo[3,4-



d]pyrimidine


165
5-bromo-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methylaniline


166
2-({3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]phenyl}oxy)-N-



cyclopropylacetamide


167
3-bromo-4-(4-{3-[(2-piperidin-1-ylethyl)oxy]pyrazin-2-yl}piperazin-1-yl)-1H-



pyrazolo[3,4-d]pyrimidine


168
4-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-6,7-



bis(methyloxy)quinazoline


169
2-({3-chloro-5-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]phenyl}oxy)-



N,N-diethylethanamine


170
4-{4-[2-chloro-5-(trifluoromethyl)phenyl]piperazin-1-yl}-3-ethyl-1H-pyrazolo[3,4-



d]pyrimidine


171
3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-5-[(2-



methylpropyl)oxy]-N-(2-pyrrolidin-1-ylethyl)aniline


172
3-({4-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-6-chloro-5-



methylpyrimidin-2-yl}oxy)-N,N-diethylpropan-1-amine


173
3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-5-



[(phenylmethyl)oxy]-N-(2-pyrrolidin-1-ylethyl)aniline


174
3-bromo-4-[(3R)-4-(5-chloro-2-methylphenyl)-3-methylpiperazin-1-yl]-1H-pyrazolo[3,4-



d]pyrimidine


175
3-[(2S)-4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-methylpiperazin-1-yl]-4-methyl-



N-phenylbenzamide


176
3-[(2S)-4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-methylpiperazin-1-yl]-4-methyl-



N-(phenylmethyl)benzamide


177
methyl 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methylbenzoate


178
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methylbenzoic acid


179
(2E)-3-(4-{4-[5-chloro-2-methyl-3-(3-pyrrolidin-1-ylpropyl)phenyl]piperazin-1-yl}-1H-



pyrazolo[3,4-d]pyrimidin-3-yl)prop-2-enoic acid


180
3-(4-{4-[5-chloro-2-methyl-3-(3-pyrrolidin-1-ylpropyl)phenyl]piperazin-1-yl}-1H-



pyrazolo[3,4-d]pyrimidin-3-yl)prop-2-yn-1-ol


181
4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1-(5-chloro-2-methylphenyl)piperazin-2-



one


182
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-5-[(2-



methylpropyl)oxy]-N-(2-pyrrolidin-1-ylethyl)aniline


183
N′-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-5-[(2-



methylpropyl)oxy]phenyl}-N,N-diethylethane-1,2-diamine


184
methyl 3-bromo-5-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-



methylbenzoate


185
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methyl-N-



phenylbenzamide


186
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-N,4-dimethylbenzamide


187
2-({3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]phenyl}oxy)-N,N-



diethylethanamine


188
methyl 3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methyl-5-[(2-



pyrrolidin-1-ylethyl)amino]benzoate


189
3-bromo-5-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methyl-N-



phenylbenzamide


190
3-bromo-5-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methyl-N-



phenylbenzamide


191
N′-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-chloro-2-



methylphenyl}-N-methyl-N-(1-methylethyl)ethane-1,2-diamine


192
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methyl-N-phenyl-5-[(2-



pyrrolidin-1-ylethyl)amino]benzamide


193
N′-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-5-[(2-



methylpropyl)oxy]phenyl}-N,N-dimethylethane-1,2-diamine


194
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-N,N,4-



trimethylbenzamide


195
3-[4-(3-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methyl-N-(2-



methylpropyl)benzamide


196
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-N,N,4-trimethyl-5-[(2-



pyrrolidin-1-ylethyl)amino]benzamide


197
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxopiperazin-1-yl]-4-methyl-N-



phenylbenzamide


198
3-[(2R)-4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-(hydroxymethyl)piperazin-1-yl]-



4-methyl-N-phenylbenzamide


199
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-5-(pyrrolidin-1-



ylcarbonyl)-N-(2-pyrrolidin-1-ylethyl)aniline


200
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-N,4-dimethyl-5-[(2-



pyrrolidin-1-ylethyl)amino]benzamide


201
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-N-(4-chlorophenyl)-4-



methyl-5-[(2-pyrrolidin-1-ylethyl)amino]benzamide


202
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-N-(2-chlorophenyl)-4-



methyl-5-[(2-pyrrolidin-1-ylethyl)amino]benzamide


203
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-



[(cyclopropylmethyl)oxy]-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline


204
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-5-[(3-



methylbutyl)oxy]-N-(2-pyrrolidin-1-ylethyl)aniline


205
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-[(2-ethylbutyl)oxy]-2-



methyl-N-(2-pyrrolidin-1-ylethyl)aniline


206
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-(butyloxy)-2-methyl-N-



(2-pyrrolidin-1-ylethyl)aniline


207
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methyl-N-(1-



methylethyl)-5-[(2-pyrrolidin-1-ylethyl)amino]benzamide


208
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-N,4-dimethyl-N-(1-



methylethyl)-5-[(2-pyrrolidin-1-ylethyl)amino]benzamide


209
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-



[(cyclobutylmethyl)oxy]-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline


210
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-(ethyloxy)-2-methyl-N-



(2-pyrrolidin-1-ylethyl)aniline


211
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-N-[2-



(dimethylamino)ethyl]-4-methylbenzamide


212
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-N-(1,1-dimethylethyl)-4-



methyl-5-[(2-pyrrolidin-1-ylethyl)amino]benzamide


213
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methyl-N-pyridin-3-yl-



5-[(2-pyrrolidin-1-ylethyl)amino]benzamide


214
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-[(2-fluoro-2-



methylpropyl)oxy]-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline


215
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-



[(cyclohexylmethyl)oxy]-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline


216
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-



[(cyclopentylmethyl)oxy]-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline


217
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-N-ethyl-4-methyl-5-[(2-



pyrrolidin-1-ylethyl)amino]benzamide


218
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-5-[(1-



methylethyl)oxy]-N-(2-pyrrolidin-1-ylethyl)aniline


219
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-[(2,2-



dimethylpropyl)oxy]-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline


220
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-N-(2-



pyrrolidin-1-ylethyl)-5-[(tetrahydrofuran-2-ylmethyl)oxy]aniline


221
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-5-{[2-



(methyloxy)ethyl]oxy}-N-(2-pyrrolidin-1-ylethyl)aniline


222
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-5-(propyloxy)-



N-(2-pyrrolidin-1-ylethyl)aniline


223
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-{[2-



(dimethylamino)ethyl]amino}-4-methyl-N-phenylbenzamide


224
N′-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-[(2-fluoro-2-



methylpropyl)oxy]-2-methylphenyl}-N,N-dimethylethane-1,2-diamine


225
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-{[2-



(dimethylamino)ethyl]amino}-4-methyl-N-(1-methylethyl)benzamide


226
1-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methyl-5-[(2-



pyrrolidin-1-ylethyl)amino]phenyl}pentan-1-one


227
N′-(3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-{[2,3-difluoro-2-



(fluoromethyl)propyl]oxy}-2-methylphenyl)-N,N-dimethylethane-1,2-diamine


228
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-{[2,3-difluoro-2-



(fluoromethyl)propyl]oxy}-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline


229
5-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methyl-N-(2-



pyrrolidin-1-ylethyl)biphenyl-3-amine


230
1-(3-{5-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methylbiphenyl-



3-yl}propyl)pyridinium


231
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-N-(2-



pyrrolidin-1-ylethyl)-5-(1,3-thiazol-2-yl)aniline


232
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methyl-5-[(2-



pyrrolidin-1-ylethyl)amino]benzoic acid


233
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-5-



(phenylethynyl)-N-(2-pyrrolidin-1-ylethyl)aniline


234
{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methyl-5-[(2-



pyrrolidin-1-ylethyl)amino]phenyl}(phenyl)methanone


235
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-ethynyl-2-methyl-N-(2-



pyrrolidin-1-ylethyl)aniline


236
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-(3,3-dimethylbut-1-yn-



1-yl)-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline


237
3-bromo-4-{4-[5-{[2,3-difluoro-2-(fluoromethyl)propyl]oxy}-2-methyl-3-(3-pyrrolidin-1-



ylpropyl)phenyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine


238
3-bromo-4-{4-[2-methyl-5-[(2-methylpropyl)oxy]-3-(3-pyrrolidin-1-



ylpropyl)phenyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine


239
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-5-(3-phenyl-



1,2,4-oxadiazol-5-yl)-N-(2-pyrrolidin-1-ylethyl)aniline


240
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-5-(3-methyl-



1,2,4-oxadiazol-5-yl)-N-(2-pyrrolidin-1-ylethyl)aniline


241
1-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methyl-5-[(2-



pyrrolidin-1-ylethyl)amino]phenyl}propan-1-one


242
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-(3,3-dimethylbutyl)-2-



methyl-N-(2-pyrrolidin-1-ylethyl)aniline


243
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-ethyl-2-methyl-N-(2-



pyrrolidin-1-ylethyl)aniline


244
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-N-(2-



pyrrolidin-1-ylethyl)-5-[2-(trimethylsilyl)ethyl]aniline


245
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-5-(2-



phenylethyl)-N-(2-pyrrolidin-1-ylethyl)aniline


246
1-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methyl-5-[(2-



pyrrolidin-1-ylethyl)amino]phenyl}butan-1-one


247
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-N,4-dimethyl-N-



(methyloxy)-5-[(2-pyrrolidin-1-ylethyl)amino]benzamide


248
3-bromo-4-[4-(3-bromo-5-{[2,3-difluoro-2-(fluoromethyl)propyl]oxy}-2-



methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine


249
4-[4-(3-bromo-5-{[2,3-difluoro-2-(fluoromethyl)propyl]oxy}-2-methylphenyl)piperazin-1-



yl]-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine


250
1-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methyl-5-[(2-



pyrrolidin-1-ylethyl)amino]phenyl}ethanone


251
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-[(difluoromethyl)oxy]-



2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline


252
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-



{[(difluoromethyl)oxy]methyl}-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline


253
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-5-(methyloxy)-



N-(2-pyrrolidin-1-ylethyl)aniline


254
5-{[2,3-difluoro-2-(fluoromethyl)propyl]oxy}-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-



4-yl)piperazin-1-yl]-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline


255
2-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-3,5,6-trifluoro-N-(3-



methylbutyl)pyridin-4-amine


256
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-N-



[(cyclopropylmethyl)oxy]-4-methyl-5-[(2-pyrrolidin-1-ylethyl)amino]benzamide


257
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-5-(5-methyl-



1,2,4-oxadiazol-3-yl)-N-(2-pyrrolidin-1-ylethyl)aniline


258
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-(ethylsulfonyl)-2-



methyl-N-(2-pyrrolidin-1-ylethyl)aniline


259
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-5-



(methylsulfonyl)-N-(2-pyrrolidin-1-ylethyl)aniline


260
1-{3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methyl-5-[(2-



pyrrolidin-1-ylethyl)amino]phenyl}pentan-1-one


261
3-bromo-4-[4-(5-{[2,3-difluoro-2-(fluoromethyl)propyl]oxy}-2-methylphenyl)piperazin-1-



yl]-1H-pyrazolo[3,4-d]pyrimidine


262
6-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-3,5-difluoro-N~4~-(3-



methylbutyl)-N~2~-(2-pyrrolidin-1-ylethyl)pyridine-2,4-diamine


263
3-bromo-5-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-N-(2-pyrrolidin-



1-ylethyl)aniline


264
3-bromo-4-[4-(3′,4′,6-trifluoro-4-methylbiphenyl-3-yl)piperazin-1-yl]-1H-pyrazolo[3,4-



d]pyrimidine


265
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-chloro-N-(2-pyrrolidin-



1-ylethyl)aniline


266
{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methyl-5-[(2-



pyrrolidin-1-ylethyl)amino]phenyl}methanol


267
3-bromo-4-(4-{4-methyl-2′-[(2-pyrrolidin-1-ylethyl)oxy]biphenyl-3-yl}piperazin-1-yl)-1H-



pyrazolo[3,4-d]pyrimidine


268
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-{[(2,2-



difluorocyclopropyl)methyl]oxy}-2-methyl-N-(2-pyrrolidin-1-ylethyl)aniline


269
5-bromo-3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-N-(2-



pyrrolidin-1-ylethyl)aniline


270
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-[(ethyloxy)methyl]-2-



methyl-N-(2-pyrrolidin-1-ylethyl)aniline


271
3-[4-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-1-methyl-6-



(trifluoromethyl)-1H-benzimidazol-2-yl]propan-1-ol


272
1-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methyl-5-[(2-



pyrrolidin-1-ylethyl)amino]phenyl}-4,4,4-trifluorobutan-1-one


273
{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methyl-5-[(2-



pyrrolidin-1-ylethyl)amino]phenyl}(cyclopropyl)methanone


274
3-({3′-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4′-methylbiphenyl-2-



yl}oxy)-N,N-dimethylpropan-1-amine


275
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-(1,1-difluorobutyl)-2-



methyl-N-(2-pyrrolidin-1-ylethyl)aniline


276
3-bromo-4-(4-{4-methyl-2′-[(3-morpholin-4-ylpropyl)oxy]biphenyl-3-yl}piperazin-1-yl)-



1H-pyrazolo[3,4-d]pyrimidine


277
3-bromo-4-(4-{4-methyl-2′-[(2-morpholin-4-ylethyl)oxy]biphenyl-3-yl}piperazin-1-yl)-1H-



pyrazolo[3,4-d]pyrimidine


278
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-N-(2-



pyrrolidin-1-ylethyl)-5-{[(2,2,2-trifluoroethyl)oxy]methyl}aniline


279
1-[2-({3′-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4′-



methylbiphenyl-2-yl}oxy)ethyl]pyrrolidine-2,5-dione


280
3-bromo-4-(4-{3′-fluoro-4-methyl-2′-[(2-pyrrolidin-1-ylethyl)oxy]biphenyl-3-yl}piperazin-



1-yl)-1H-pyrazolo[3,4-d]pyrimidine


281
1-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-[(2-pyrrolidin-1-



ylethyl)amino]phenyl}butan-1-one


282
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-N-(2-



pyrrolidin-1-ylethyl)-5-[(3,3,3-trifluoropropyl)oxy]aniline


283
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-N-(2-



pyrrolidin-1-ylethyl)-5-[(2,2,2-trifluoroethyl)oxy]aniline


284
1-{3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-4-methyl-5-[(2-



pyrrolidin-1-ylethyl)amino]phenyl}butan-1-ol


285
3-bromo-4-(4-{4-chloro-2′-[(2-pyrrolidin-1-ylethyl)oxy]biphenyl-3-yl}piperazin-1-yl)-1H-



pyrazolo[3,4-d]pyrimidine


286
3-[4-(4-{5-{[2,3-difluoro-2-(fluoromethyl)propyl]oxy}-2-methyl-3-[(2-pyrrolidin-1-



ylethyl)amino]phenyl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]prop-2-yn-1-ol


287
3-bromo-4-(4-{4-chloro-4′-fluoro-2′-[(2-pyrrolidin-1-ylethyl)oxy]biphenyl-3-yl}piperazin-



1-yl)-1H-pyrazolo[3,4-d]pyrimidine


288
3-bromo-4-(4-{4-methyl-3′-[(2-pyrrolidin-1-ylethyl)oxy]biphenyl-3-yl}piperazin-1-yl)-1H-



pyrazolo[3,4-d]pyrimidine


289
(2E)-3-[4-(4-{5-{[2,3-difluoro-2-(fluoromethyl)propyl]oxy}-2-methyl-3-[(2-pyrrolidin-1-



ylethyl)amino]phenyl}piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]prop-2-enoic acid


290
3-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-methyl-N-(2-



pyrrolidin-1-ylethyl)-5-[4,4,4-trifluoro-1,1-bis(methyloxy)butyl]aniline


291
6-(4-phenylpiperazin-1-yl)-9H-purine


292
6-[4-(3-chlorophenyl)piperazin-1-yl]-9H-purine


293
4-(4-phenylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine


294
4-[4-(3-chlorophenyl)piperazin-1-yl]-7H-pyrrolo[2,3-d]pyrimidine


295
4-(4-phenylpiperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine


296
4-[4-(3-chlorophenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine


297
6-[4-(2-chlorophenyl)piperazin-1-yl]-9H-purine


298
6-[4-(2-fluorophenyl)piperazin-1-yl]-9H-purine


299
4-[4-(2-methylphenyl)piperazin-1-yl]-7H-pyrrolo[2,3-d]pyrimidine


300
4-{4-[2-(methyloxy)phenyl]piperazin-1-yl}-7H-pyrrolo[2,3-d]pyrimidine


301
4-{4-[3-(methyloxy)phenyl]piperazin-1-yl}-7H-pyrrolo[2,3-d]pyrimidine


302
4-{4-[4-(methyloxy)phenyl]piperazin-1-yl}-7H-pyrrolo[2,3-d]pyrimidine


303
4-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}-7H-pyrrolo[2,3-d]pyrimidine


304
6-{4-[4-(methyloxy)phenyl]piperazin-1-yl}-9H-purine


305
6-{4-[2-(methyloxy)phenyl]piperazin-1-yl}-9H-purine


306
6-[4-(4-chlorophenyl)piperazin-1-yl]-9H-purine


307
6-[4-(4-fluorophenyl)piperazin-1-yl]-9H-purine


308
4-[4-(4-chlorophenyl)piperazin-1-yl]-7H-pyrrolo[2,3-d]pyrimidine


309
4-[4-(2-chlorophenyl)piperazin-1-yl]-7H-pyrrolo[2,3-d]pyrimidine


310
4-[4-(4-fluorophenyl)piperazin-1-yl]-7H-pyrrolo[2,3-d]pyrimidine


311
4-[4-(2-fluorophenyl)piperazin-1-yl]-7H-pyrrolo[2,3-d]pyrimidine


312
6-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}-9H-purine


313
6-[4-(2-methylphenyl)piperazin-1-yl]-9H-purine


314
4-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine


315
4-[4-(2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine


316
4-[4-(3-chlorophenyl)piperazin-1-yl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidine


317
3-methyl-4-[4-(2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine


318
4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine


319
4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidine


320
4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-methyl-6-phenyl-1H-pyrazolo[3,4-



d]pyrimidine


321
4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine


322
4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-6-methyl-1H-pyrazolo[3,4-d]pyrimidine


323
4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-6-ethyl-1H-pyrazolo[3,4-d]pyrimidine


324
4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-6-(1-methylethyl)-1H-pyrazolo[3,4-



d]pyrimidine


325
4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine


326
4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-({[2-(methyloxy)ethyl]oxy}methyl)-1H-



pyrazolo[3,4-d]pyrimidine


327
3-bromo-4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine


328
4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-propyl-1H-pyrazolo[3,4-d]pyrimidine


329
4-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-



yl}phenol


330
4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-N-phenyl-1H-pyrazolo[3,4-d]pyrimidin-3-



amine


331
4-[4-(3-chlorophenyl)piperazin-1-yl]-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine


332
4-{4-[5-chloro-2-(methyloxy)phenyl]piperazin-1-yl}-3-ethyl-1H-pyrazolo[3,4-



d]pyrimidine


333
3-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-



yl}phenol


334
4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-{3-[(phenylmethyl)oxy]phenyl}-1H-



pyrazolo[3,4-d]pyrimidine


335
3-(1,3-benzodioxol-5-yl)-4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-



d]pyrimidine


336
4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(2-thienyl)-1H-pyrazolo[3,4-d]pyrimidine


337
3-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-



yl}aniline


338
3-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-



yl}benzoic acid


339
4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(4-methylphenyl)-1H-pyrazolo[3,4-



d]pyrimidine


340
N-(4-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-



yl}phenyl)acetamide


341
4-[4-(3-chlorophenyl)-1,4-diazepan-1-yl]-3-ethyl-1H-pyrazolo[3,4-d]pyrimidine


342
4-[5-(3-chlorophenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-3-ethyl-1H-pyrazolo[3,4-



d]pyrimidine


343
4-(4-{3-chloro-4-[(2-morpholin-4-ylethyl)oxy]phenyl}piperazin-1-yl)-3-ethyl-1H-



pyrazolo[3,4-d]pyrimidine


344
methyl 1-(3-chlorophenyl)-4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazine-2-



carboxylate


345
4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(3-methylbut-2-en-1-yl)-1H-pyrazolo[3,4-



d]pyrimidine


346
4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(trifluoromethyl)-1H-pyrazolo[3,4-



d]pyrimidine


347
methyl 4-(3-chlorophenyl)-1-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazine-2-



carboxylate


348
4-(4-{3-chloro-4-[(2-piperidin-1-ylethyl)oxy]phenyl}piperazin-1-yl)-3-ethyl-1H-



pyrazolo[3,4-d]pyrimidine


349
4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(1-methylethyl)-1H-pyrazolo[3,4-



d]pyrimidine


350
1-(3-chlorophenyl)-4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazine-2-carboxylic



acid


351
1-(3-chlorophenyl)-4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-methylpiperazine-2-



carboxamide


352
4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(phenylmethyl)-1H-pyrazolo[3,4-



d]pyrimidine


353
4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(2-methylpropyl)-1H-pyrazolo[3,4-



d]pyrimidine


354
4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-[4-(methyloxy)phenyl]-1H-pyrazolo[3,4-



d]pyrimidine


355
4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(4-fluorophenyl)-1H-pyrazolo[3,4-



d]pyrimidine


356
4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-[4-(phenyloxy)phenyl]-1H-pyrazolo[3,4-



d]pyrimidine


357
4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-{4-[(piperidin-4-ylmethyl)oxy]phenyl}-



1H-pyrazolo[3,4-d]pyrimidine


358
1-(3-chlorophenyl)-N-[2-(dimethylamino)ethyl]-4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-



yl)piperazine-2-carboxamide


359
4-[4-(5-chloro-2-methyl-3-morpholin-4-ylphenyl)piperazin-1-yl]-3-ethyl-1H-pyrazolo[3,4-



d]pyrimidine


360
4-(3-chlorophenyl)-1-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-methylpiperazine-2-



carboxamide


361
4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-[2-(methyloxy)phenyl]-1H-pyrazolo[3,4-



d]pyrimidine


362
4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-pyridin-4-yl-1H-pyrazolo[3,4-



d]pyrimidine


363
4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-[3-(methyloxy)phenyl]-1H-pyrazolo[3,4-



d]pyrimidine


364
4-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-



yl}benzonitrile


365
[5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-



(methyloxy)phenyl]methanol


366
methyl 5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-



(methyloxy)benzoate


367
(2E)-3-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-



yl}prop-2-enoic acid


368
3-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-



yl}propanoic acid


369
3-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-



yl}propan-1-ol


370
methyl (2E)-3-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-



d]pyrimidin-3-yl}prop-2-enoate


371
4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-{4-[(2-morpholin-4-ylethyl)oxy]phenyl}-



1H-pyrazolo[3,4-d]pyrimidine


372
5-chloro-N-[2-(dimethylamino)ethyl]-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-



yl)piperazin-1-yl]-2-(methyloxy)benzamide


373
4-(4-{5-chloro-2-(methyloxy)-3-[(4-methylpiperazin-1-yl)carbonyl]phenyl}piperazin-1-yl)-



3-ethyl-1H-pyrazolo[3,4-d]pyrimidine


374
2-(dimethylamino)ethyl 5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-



yl)piperazin-1-yl]-2-(methyloxy)benzoate


375
1-[5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-



(methyloxy)phenyl]-N,N-dimethylmethanamine


376
N′-{[5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-



(methyloxy)phenyl]methyl}-N,N-dimethylethane-1,2-diamine


377
[1-(3-chlorophenyl)-4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-2-yl]methanol


378
3-[(4-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-



yl}phenyl)oxy]-N,N-dimethylpropan-1-amine


379
2-chloro-4-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-methylphenol


380
1-(3-chlorophenyl)-4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-(1-methylpiperidin-4-



yl)piperazine-2-carboxamide


381
1-(3-chlorophenyl)-4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-(2-morpholin-4-



ylethyl)piperazine-2-carboxamide


382
2-{[5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-



(methyloxy)phenyl]oxy}-N,N-dimethylethanamine


383
3-{5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-



methylphenyl}-N,N-dimethylprop-2-yn-1-amine


384
N′-{5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-



methylphenyl}-N,N-dimethylethane-1,2-diamine


385
1,1-dimethylethyl (2E)-3-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-



pyrazolo[3,4-d]pyrimidin-3-yl}prop-2-enoate


386
3-({2-chloro-4-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-



methylphenyl}oxy)-N,N-dimethylpropan-1-amine


387
2-({2-chloro-4-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-5-



methylphenyl}oxy)-N,N-dimethylethanamine


388
4-{4-[5-chloro-2-methyl-4-(methyloxy)phenyl]piperazin-1-yl}-3-ethyl-1H-pyrazolo[3,4-



d]pyrimidine


389
4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(4-methylpiperazin-1-yl)-1H-



pyrazolo[3,4-d]pyrimidine


390
3-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-N,N-



diethylprop-2-yn-1-amine


391
3-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}prop-



2-yn-1-ol


392
4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(piperidin-4-ylmethyl)-1H-pyrazolo[3,4-



d]pyrimidine


393
phenylmethyl (3aR,6aS)-5-({4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-



pyrazolo[3,4-d]pyrimidin-3-yl}methylidene)hexahydrocyclopenta[c]pyrrole-2(1H)-



carboxylate


394
4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-[(E)-(3aR,6aS)-



hexahydrocyclopenta[c]pyrrol-5(1H)-ylidenemethyl]-1H-pyrazolo[3,4-d]pyrimidine


395
4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(3-pyrrolidin-1-ylprop-1-yn-1-yl)-1H-



pyrazolo[3,4-d]pyrimidine


396
4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-[3-(4-methylpiperazin-1-yl)prop-1-yn-1-



yl]-1H-pyrazolo[3,4-d]pyrimidine


397
3-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-N,N-



diethylpropan-1-amine


398
4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(3-pyrrolidin-1-ylpropyl)-1H-



pyrazolo[3,4-d]pyrimidine


399
4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-



pyrazolo[3,4-d]pyrimidine


400
3-{5-chloro-3-[4-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-



methylphenyl}-N,N-diethylpropan-1-amine


401
4-{4-[5-chloro-2-methyl-3-(3-pyrrolidin-1-ylpropyl)phenyl]piperazin-1-yl}-3-ethyl-1H-



pyrazolo[3,4-d]pyrimidine









Table 2b
Additional Representative AKT Inhibitors
The Compounds in Table 2b can be prepared as pharmaceutically acceptable salts, solvates, hydrates, and/or isomers thereof. All such salt, solvate, hydrate, and isomer combinations of the Compounds in Table 2b can be used to practice the invention.








TABLE 2b





Entry
Name
















1
[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-



chlorophenyl)methanol


2
2-{[[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-



chlorophenyl)methyl]oxy}-N,N-dimethylethanamine


3
3-{[[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-



chlorophenyl)methyl]oxy}-N,N-dimethylpropan-1-amine


4
3-bromo-4-{4-[(4-bromophenyl)methyl]piperazin-1-yl}-1H-pyrazolo[3,4-



d]pyrimidine


5
{4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1-[(4-



chlorophenyl)methyl]piperazin-2-yl}methanol


6
N′-[[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-



chlorophenyl)methyl]-N,N-diethylethane-1,2-diamine


7
3-bromo-4-(4-{[4-(1,1-dimethylethyl)phenyl]methyl}piperazin-1-yl)-1H-



pyrazolo[3,4-d]pyrimidine


8
4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1-[(4-



chlorophenyl)methyl]piperazin-2-one


9
2-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-(4-



chlorophenyl)-N-[2-(dimethylamino)ethyl]acetamide


10
N-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-N-(4-



chlorophenyl)-N′,N′-diethylpropane-1,3-diamine


11
3-bromo-4-(4-{[4-(trifluoromethyl)phenyl]methyl}piperazin-1-yl)-1H-



pyrazolo[3,4-d]pyrimidine


12
N-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-N-(4-



chlorophenyl)-N′-[2-(dimethylamino)ethyl]urea


13
N-[[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-



chlorophenyl)methyl]-N′-[2-(dimethylamino)ethyl]urea


14
2-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxopiperazin-1-yl]-



2-(4-chlorophenyl)-N-[2-(dimethylamino)ethyl]acetamide


15
2-(dimethylamino)ethyl [1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-



yl)piperidin-4-yl](4-chlorophenyl)carbamate


16
3-bromo-4-{4-[(4-chloro-3-fluorophenyl)methyl]piperazin-1-yl}-1H-



pyrazolo[3,4-d]pyrimidine


17
3-bromo-4-{4-[(4-chloro-2-fluorophenyl)methyl]piperazin-1-yl}-1H-



pyrazolo[3,4-d]pyrimidine


18
N-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-N-(4-



chlorophenyl)-N′,N′-diethylethane-1,2-diamine


19
3-bromo-4-{4-[(4-chlorophenyl)methyl]piperazin-1-yl}-1H-pyrazolo[3,4-



d]pyrimidine


20
[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-



fluorophenyl)methanone


21
N-[[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-



chlorophenyl)methyl]-N′,N′-diethyl-N-methylethane-1,2-diamine


22
[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-



fluorophenyl)methanol


23
3-bromo-4-(4-{[2-fluoro-4-(trifluoromethyl)phenyl]methyl}piperazin-1-



yl)-1H-pyrazolo[3,4-d]pyrimidine


24
N-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-N-(4-



chlorophenyl)-N~3~,N~3~-diethyl-beta-alaninamide


25
2-{[[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-



fluorophenyl)methyl]oxy}-N,N-dimethylethanamine


26
N-[[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-



chlorophenyl)methyl]-N~3~,N~3~-diethyl-beta-alaninamide


27
3-bromo-4-{4-[(3,4-dichlorophenyl)methyl]piperazin-1-yl}-1H-



pyrazolo[3,4-d]pyrimidine


28
N-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-N-(4-



chlorophenyl)-N′-[2-(dimethylamino)ethyl]ethanediamide


29
N-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-N-(4-



chlorophenyl)-2-(diethylamino)ethanesulfonamide


30
4-[4-(biphenyl-4-ylmethyl)piperazin-1-yl]-3-bromo-1H-pyrazolo[3,4-d]pyrimidine


31
3-bromo-4-{(3S)-4-[(4-chlorophenyl)methyl]-3-methylpiperazin-1-yl}-



1H-pyrazolo[3,4-d]pyrimidine


32
3-bromo-4-(4-{[4-(methyloxy)phenyl]methyl}piperazin-1-yl)-1H-



pyrazolo[3,4-d]pyrimidine


33
4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-[3-



(trifluoromethyl)phenyl]piperazine-1-carboxamide


34
3-bromo-4-{4-[(4-fluorophenyl)methyl]piperazin-1-yl}-1H-pyrazolo[3,4-



d]pyrimidine


35
N-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-N-(4-



chlorophenyl)pent-4-enamide


36
3-bromo-4-[4-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)piperazin-1-yl]-



1H-pyrazolo[3,4-d]pyrimidine


37
4-[4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl]-3-bromo-1H-



pyrazolo[3,4-d]pyrimidine


38
[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-



chlorophenyl)methanone


39
3-bromo-4-(4-{[4-(phenyloxy)phenyl]methyl}piperazin-1-yl)-1H-



pyrazolo[3,4-d]pyrimidine


40
3-bromo-4-{4-[(3,4-dichlorophenyl)methyl]piperidin-1-yl}-1H-



pyrazolo[3,4-d]pyrimidine


41
4-{[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-



yl]methyl}-N,N-dimethylaniline


42
methyl 4-{[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-



yl]methyl}benzoate


43
3-bromo-4-{4-[(2E)-3-phenylprop-2-enoyl]piperazin-1-yl}-1H-



pyrazolo[3,4-d]pyrimidine


44
1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-4-[(4-



chlorophenyl)methyl]-N-[3-(diethylamino)propyl]piperidine-4-



carboxamide


45
3-bromo-4-{4-[(2-bromophenyl)methyl]piperazin-1-yl}-1H-pyrazolo[3,4-



d]pyrimidine


46
3-bromo-4-{4-[(2-chlorophenyl)methyl]piperazin-1-yl}-1H-pyrazolo[3,4-



d]pyrimidine


47
3-bromo-4-{4-[(2,4-dichlorophenyl)methyl]piperazin-1-yl}-1H-



pyrazolo[3,4-d]pyrimidine


48
3-bromo-4-{4-[(2-chloro-4-fluorophenyl)methyl]piperazin-1-yl}-1H-



pyrazolo[3,4-d]pyrimidine


49
1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-4-(4-chlorophenyl)-N-[3-



(diethylamino)propyl]piperidine-4-carboxamide


50
3-bromo-4-[4-(phenylmethyl)piperazin-1-yl]-1H-pyrazolo[3,4-



d]pyrimidine


51
2-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-N-



pyridin-2-ylacetamide


52
3-bromo-4-[4-(1H-imidazol-2-ylmethyl)piperazin-1-yl]-1H-pyrazolo[3,4-



d]pyrimidine


53
3-bromo-4-(4-{[3-(phenyloxy)phenyl]methyl}piperazin-1-yl)-1H-



pyrazolo[3,4-d]pyrimidine


54
3-bromo-4-{4-[(3-methylphenyl)methyl]piperazin-1-yl}-1H-



pyrazolo[3,4-d]pyrimidine


55
3-{[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-



yl]methyl}benzonitrile


56
3-bromo-4-{4-[(2-chloro-6-fluorophenyl)methyl]piperazin-1-yl}-1H-



pyrazolo[3,4-d]pyrimidine


57
3-bromo-4-[4-(1-phenylethyl)piperazin-1-yl]-1H-pyrazolo[3,4-



d]pyrimidine


58
3-bromo-4-[4-(pyridin-4-ylmethyl)piperazin-1-yl]-1H-pyrazolo[3,4-



d]pyrimidine


59
1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-(4-



chlorophenyl)piperidin-4-amine


60
3-bromo-4-[4-(pyridin-3-ylmethyl)piperazin-1-yl]-1H-pyrazolo[3,4-



d]pyrimidine


61
3-bromo-4-(4-{[2,3,4-tris(methyloxy)phenyl]methyl}piperazin-1-yl)-1H-



pyrazolo[3,4-d]pyrimidine


62
3-bromo-4-[4-({3-[(phenylmethyl)oxy]phenyl}methyl)piperazin-1-yl]-



1H-pyrazolo[3,4-d]pyrimidine


63
3-bromo-4-[4-(naphthalen-1-ylmethyl)piperazin-1-yl]-1H-pyrazolo[3,4-



d]pyrimidine


64
3-bromo-4-(4-{[5-(4-chlorophenyl)furan-2-yl]methyl}piperazin-1-yl)-



1H-pyrazolo[3,4-d]pyrimidine


65
3-bromo-4-[4-({4-[(4-fluorophenyl)oxy]-3-nitrophenyl}methyl)piperazin-



1-yl]-1H-pyrazolo[3,4-d]pyrimidine


66
3-bromo-4-[4-(furan-2-ylcarbonyl)piperazin-1-yl]-1H-pyrazolo[3,4-



d]pyrimidine


67
3-bromo-4-[4-(1H-indol-6-ylcarbonyl)piperazin-1-yl]-1H-pyrazolo[3,4-



d]pyrimidine


68
3-bromo-4-{4-[2-(2-thienyl)ethyl]piperazin-1-yl}-1H-pyrazolo[3,4-



d]pyrimidine


69
3-bromo-4-[4-(3-pyrrolidin-1-ylpropyl)piperazin-1-yl]-1H-pyrazolo[3,4-



d]pyrimidine


70
3-bromo-4-[4-(cyclohexylmethyl)piperazin-1-yl]-1H-pyrazolo[3,4-



d]pyrimidine


71
3-bromo-4-{4-[(10-chloroanthracen-9-yl)methyl]piperazin-1-yl}-1H-



pyrazolo[3,4-d]pyrimidine


72
3-bromo-4-[4-(1-methylpropyl)piperazin-1-yl]-1H-pyrazolo[3,4-



d]pyrimidine


73
4-(4-{[4,6-bis(methyloxy)pyrimidin-2-yl]methyl}piperazin-1-yl)-3-



bromo-1H-pyrazolo[3,4-d]pyrimidine


74
3-bromo-4-{4-[2-(methyloxy)ethyl]piperazin-1-yl}-1H-pyrazolo[3,4-



d]pyrimidine


75
3-bromo-4-[4-(2-morpholin-4-yl-2-oxoethyl)piperazin-1-yl]-1H-



pyrazolo[3,4-d]pyrimidine


76
3-bromo-4-{4-[3-(methyloxy)propyl]piperazin-1-yl}-1H-pyrazolo[3,4-



d]pyrimidine


77
4-{4-[[4,6-bis(methyloxy)pyrimidin-2-yl](phenyl)methyl]piperazin-1-



yl}-3-bromo-1H-pyrazolo[3,4-d]pyrimidine


78
3-bromo-4-[4-(6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl)piperazin-1-



yl]-1H-pyrazolo[3,4-d]pyrimidine


79
3-bromo-4-[4-({4-[(phenylmethyl)oxy]phenyl}methyl)piperazin-1-yl]-



1H-pyrazolo[3,4-d]pyrimidine


80
3-bromo-4-[4-({3-chloro-4-



[(phenylmethyl)oxy]phenyl}methyl)piperazin-1-yl]-1H-pyrazolo[3,4-



d]pyrimidine


81
4-{[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-



yl]methyl}-N-(3-morpholin-4-ylpropyl)benzamide


82
4-{[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-



yl]methyl}-N-[3-(methyloxy)propyl]benzamide


83
2-[({4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1-[(4-



chlorophenyl)methyl]piperazin-2-yl}methyl)oxy]-N,N-



dimethylethanamine


84
3-bromo-4-[4-({4-[(4-chlorophenyl)oxy]-3-



nitrophenyl}methyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine


85
2-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-N,N-



dimethylacetamide


86
2-{[(R)-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-



chlorophenyl)methyl]oxy}-N,N-dimethylethanamine


87
N-(4-bromo-3-fluorophenyl)-N-[1-(3-bromo-1H-pyrazolo[3,4-



d]pyrimidin-4-yl)piperidin-4-yl]-N′-[2-(dimethylamino)ethyl]urea


88
2-({(R)-(4-chlorophenyl)[1-(3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-



yl)piperidin-4-yl]methyl}oxy)-N,N-dimethylethanamine


89
2-{[(S)-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-



chlorophenyl)methyl]oxy}-N,N-dimethylethanamine


90
3-bromo-4-(4-{(R)-(4-chlorophenyl)[(2-pyrrolidin-1-



ylethyl)oxy]methyl}piperidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine


91
1-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-1-(4-



chlorophenyl)-4-(dimethylamino)butan-1-ol


92
2-{[(R)-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-



chloro-3-fluorophenyl)methyl]oxy}-N,N-dimethylethanamine


93
3-bromo-4-(4-{(R)-(4-chlorophenyl)[(2-piperidin-1-



ylethyl)oxy]methyl}piperidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine


94
4-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-4-(4-



chlorophenyl)-N,N-dimethylbutan-1-amine


95
3-bromo-4-(4-{(R)-(4-chlorophenyl)[(2-morpholin-4-



ylethyl)oxy]methyl}piperidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine


96
1-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-1-(4-



fluorophenyl)-N-(furan-2-ylmethyl)-N-methylmethanamine


97
1-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-1-(4-



fluorophenyl)-N-methyl-N-(pyridin-2-ylmethyl)methanamine


98
4-{[{[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-



fluorophenyl)methyl}(methyl)amino]methyl}-N,N-dimethylaniline


99
[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl](1H-indol-



6-yl)methanol


100
3-bromo-4-(4-{(R)-(4-chloro-3-fluorophenyl)[(2-pyrrolidin-1-



ylethyl)oxy]methyl}piperidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine


101
3-bromo-4-{4-[(4-chlorophenyl)oxy]piperidin-1-yl}-1H-pyrazolo[3,4-



d]pyrimidine


102
2-{[(R)-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-



chlorophenyl)methyl]oxy}-N,N-diethylethanamine


103
2-{[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]oxy}-5-



chloro-N-(2-pyrrolidin-1-ylethyl)aniline









Table 3a
Representative c-MET and/or Flt-3 Inhibitors
The Compounds in Table 3a can be prepared as pharmaceutically acceptable salts, solvates, hydrates, and/or isomers thereof. All such salt, solvate, hydrate, and isomer combinations of the Compounds in Table 3a can be used to practice the invention.








TABLE 3a





Cmpd



No.
Name
















1
N-(4-fluorophenyl)-N′-[3-fluoro-4-(7H-pyrrolo[2,3-d]pyrimidin-



4-yloxy)phenyl]propanediamide


2
N-(4-fluorophenyl)-N′-[3-fluoro-4-(7H-pyrrolo[2,3-d]pyrimidin-



4-yloxy)phenyl]cyclopropane-1,1-dicarboxamide


3
N-({[3-fluoro-4-(7H-pyrrolo[2,3-d]pyrimidin-4-



yloxy)phenyl]amino}carbonothioyl)-2-phenylacetamide


4
N-(4-fluorophenyl)-N′-(4-{[1-(tetrahydro-2H-pyran-2-yl)-1H-



pyrazolo[3,4-d]pyrimidin-4-yl]oxy}phenyl)cyclopropane-1,1-



dicarboxamide


5
2-phenyl-N-{[(4-{[1-(tetrahydro-



2H-pyran-2-yl)-1H-pyrazolo[3,4-



d]pyrimidin-4-yl]oxy}phenyl)amino]carbonothioyl}acetamide


6
N-(4-fluorophenyl)-N′-[4-(1H-pyrazolo[3,4-d]pyrimidin-4-



yloxy)phenyl]cyclopropane-1,1-dicarboxamide


7
2-phenyl-N-({[4-(1H-pyrazolo[3,4-d]pyrimidin-4-



yloxy)phenyl]amino}carbonothioyl)acetamide


8
N-(4-fluorophenyl)-N′-(4-{[9-



(tetrahydro-2H-pyran-2-yl)-9H-purin-6-



yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide


9
2-phenyl-N-{[(4-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-



yl]oxy}phenyl)amino]carbonothioyl}acetamide


10
N-(4-fluorophenyl)-N′-[4-(9H-purin-



6-yloxy)phenyl]cyclopropane-1,1-



dicarboxamide


11
2-phenyl-N-({[4-(9H-purin-6-



yloxy)phenyl]amino}carbonothioyl)acetamide


12
N-{3-fluoro-4-[(6-{[(2-morpholin-4-ylethyl)amino]carbonyl}-



7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]phenyl}-N′-(4-



fluorophenyl)cyclopropane-1,1-dicarboxamide









Table 3b
Additional Representative c-MET, c-KIT, and/or Flt-3 Inhibitors
The Compounds in Table 3b can be prepared as pharmaceutically acceptable salts, solvates, hydrates, and/or isomers thereof. All such salt, solvate, hydrate, and isomer combinations of the Compounds in Table 3b can be used to practice the invention.








TABLE 3b





Entry
Name
















1
N-[({3-fluoro-4-[(6-(methyloxy)-7-{[(3aR,6aS)-



octahydrocyclopenta[c]pyrrol-5-ylmethyl]oxy}quinazolin-4-



yl)oxy]phenyl}amino)carbonothioyl]-2-phenylacetamide


2
N-{[(3-fluoro-4-{[7-({[(3aR,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-



5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-



yl]oxy}phenyl)amino]carbonothioyl}-2-phenylacetamide


3
N-{[(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-



fluorophenyl)(methyl)amino]carbonothioyl}-2-phenylacetamide


4
1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)imidazolidin-2-one


5
1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-3-



(phenylmethyl)imidazolidin-2-one


6
1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-3-



(phenylacetyl)imidazolidin-2-one


7
ethyl [(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-



fluorophenyl)amino](oxo)acetate


8
N-{[(4-{[6,7-bis(methyloxy)quinazolin-4-yl]amino}-3-



fluorophenyl)amino]carbonothioyl}-2-phenylacetamide


9
N′-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N-methyl-



N-(2-phenylethyl)sulfamide


10
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-3-



(phenylmethyl)-1,2,4-oxadiazol-5-amine


11
1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)piperidin-2-



one


12
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-



(phenylmethyl)ethanediamide


13
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-4-phenyl-1,3-thiazol-



2-amine


14
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(2-



phenylethyl)ethanediamide


15
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-1-



phenylmethanesulfonamide


16
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-2-



phenylethanesulfonamide


17
4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluoro-N-



(phenylmethyl)benzenesulfonamide


18
4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluoro-N-methyl-N-



(phenylmethyl)benzenesulfonamide


19
4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluoro-N-(2-



phenylethyl)benzenesulfonamide


20
4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluoro-N-methyl-N-(2-



phenylethyl)benzenesulfonamide


21
4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluoro-N-(3-



phenylpropyl)benzenesulfonamide


22
1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)pyrrolidin-2-



one


23
4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl (phenylmethyl)carbamate


24
4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl (2-phenylethyl)carbamate


25
4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluoro-N-methyl-N-(3-



phenylpropyl)benzenesulfonamide


26
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-



phenylethanediamide


27
N-{[(3-fluoro-4-{[7-{[(2-methyloctahydrocyclopenta[c]pyrrol-5-



yl)methyl]oxy}-6-(methyloxy)quinolin-4-



yl]oxy}phenyl)amino]carbonothioyl}-2-phenylacetamide


28
N-[(Z)-[(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-



fluorophenyl)amino](imino)methyl]-2-phenylacetamide


29
4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluoro-N-[2-



(phenyloxy)ethyl]benzenesulfonamide


30
N,N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-bis-(3-



phenylpropane-1-sulfonamide)


31
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-3-



phenylpropane-1-sulfonamide


32
N2-[(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)sulfonyl]-



N1-phenylglycinamide


33
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridin-3-yl)-2-



phenylacetamide


34
N-{[(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridin-3-



yl)amino]carbonothioyl}-2-phenylacetamide


35
6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-1,3-benzothiazol-2-amine


36
6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-1,3-benzothiazol-2-



amine


37
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-1,3-benzothiazol-2-



yl)-2-phenylacetamide


38
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(2-



morpholin-4-ylethyl)ethanediamide


39
benzyl-{[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenylcarbamoyl]-



methyl}-carbamic acid tert-butyl ester


40
N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N2-



(phenylmethyl)glycinamide


41
N2-acetyl-N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-



N2-(phenylmethyl)glycinamide


42
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-1,3-benzothiazol-2-yl)-2-



phenylacetamide


43
benzyl-{[6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-ylcarbamoyl]-



methyl}-carbamic acid tert-butyl ester


44
N1-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridin-3-yl)-N2-



(phenylmethyl)glycinamide


45
N2-acetyl-N1-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridin-3-yl)-N2-



(phenylmethyl)glycinamide


46
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridin-3-yl)-3-



phenylpropanamide


47
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridin-3-yl)-4-



phenylbutanamide


48
N1-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridin-3-yl)-N2-methyl-



N2-(phenylmethyl)glycinamide


49
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-{2-[4-



(methyloxy)phenyl]ethyl}ethanediamide


50
N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N2-



methyl-N2-(phenylmethyl)glycinamide


51
4-[(2-amino-1,3-benzothiazol-6-yl)oxy]-6,7-bis(methyloxy)-1-(2-oxo-2-



phenylethyl)quinolinium


52
N-{[(4-{[6,7-bis(methyloxy)quinolin-4-



yl]amino}phenyl)amino]carbonothioyl}-2-phenylacetamide


53
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-1,3-benzothiazol-2-



yl)-3-phenylpropanamide


54
N-{[(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-



yl)amino]carbonothioyl}-2-phenylacetamide


55
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(2,3-



dihydro-1H-inden-1-yl)ethanediamide


56
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(2,3-



dihydro-1H-inden-2-yl)ethanediamide


57
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(1,2,3,4-



tetrahydronaphthalen-1-yl)ethanediamide


58
N′-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N-(2-



phenylethyl)-N-(phenylmethyl)sulfamide


59
N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N2-



(trifluoroacetyl)glycinamide


60
N-{[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenylcarbamoyl]-



methyl}-benzamide


61
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridin-3-yl)-N′-(4-



fluorophenyl)propanediamide


62
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-[(2S)-



1,2,3,4-tetrahydronaphthalen-2-yl]ethanediamide


63
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-[2-(4-



methylphenyl)ethyl]ethanediamide


64
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(2-



phenylpropyl)ethanediamide


65
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-[2-(4-



chlorophenyl)ethyl]ethanediamide


66
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N,N′-



bis(phenylmethyl)sulfamide


67
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N,N′-bis(2-



phenylethyl)sulfamide


68
ethyl [(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-



yl)amino](oxo)acetate


69
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-N′-(2-



phenylethyl)ethanediamide


70
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-N′-(4-



fluorophenyl)propanediamide


71
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(1,2,3,4-



tetrahydronaphthalen-2-yl)ethanediamide


72
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-[2-(1-



methylpyrrolidin-2-yl)ethyl]ethanediamide


73
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-[2-



(phenyloxy)ethyl]ethanediamide


74
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-[2-



hydroxy-1-(phenylmethyl)ethyl]urea


75
1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-3-[(4-



methylphenyl)sulfonyl]-4-(phenylmethyl)imidazolidin-2-one


76
N′-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N-methyl-



N-(2-phenylethyl)ethanediamide


77
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-{[3-



(trifluoromethyl)phenyl]methyl}ethanediamide


78
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-{2-[3-



(trifluoromethyl)phenyl]ethyl}ethanediamide


79
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-3-oxo-



4-phenylbutanamide


80
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-2-[3-



(trifluoromethyl)phenyl]acetamide


81
6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-N-[2-



(phenyloxy)ethyl]-1,3-benzothiazol-2-amine


82
6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-N-(2-piperidin-1-



ylethyl)-1,3-benzothiazol-2-amine


83
6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-N-methyl-N-(2-



phenylethyl)-1,3-benzothiazol-2-amine


84
6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-N-(2-pyrrolidin-1-



ylethyl)-1,3-benzothiazol-2-amine


85
6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-N-{[3-



(trifluoromethyl)phenyl]methyl}-1,3-benzothiazol-2-amine


86
6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-N-{2-[3-



(trifluoromethyl)phenyl]ethyl}-1,3-benzothiazol-2-amine


87
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-N′-[3-



(trifluoromethyl)phenyl]propanediamide


88
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-1,3-benzothiazol-2-



yl)-2-[3-(trifluoromethyl)phenyl]acetamide


89
N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N2-{[3-



(trifluoromethyl)phenyl]methyl}glycinamide


90
N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N2-(2-



phenylethyl)glycinamide


91
N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N2-{2-[3-



(trifluoromethyl)phenyl]ethyl}glycinamide


92
benzyl-{[5-chloro-6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-



ylcarbamoyl]-methyl}-carbamic acid tert-butyl ester


93
N1-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-N2-



(phenylmethyl)glycinamide


94
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-1,3-benzothiazol-2-



yl)-2-[3,5-bis(trifluoromethyl)phenyl]acetamide


95
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-1,3-benzothiazol-2-



yl)-2-[2-chloro-5-(trifluoromethyl)phenyl]acetamide


96
N-{3-fluoro-4-[(6-(methyloxy)-7-{[(1-methylpiperidin-4-



yl)methyl]oxy}quinolin-4-yl)oxy]phenyl}-N′-(2-



phenylethyl)ethanediamide


97
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(1,2,3,4-



tetrahydroisoquinolin-1-ylmethyl)ethanediamide


98
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-[(2-



methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl]ethanediamide


99
N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N2-



methyl-N2-{[3-(trifluoromethyl)phenyl]methyl}glycinamide


100
N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N2-



methyl-N2-{2-[3-(trifluoromethyl)phenyl]ethyl}glycinamide


101
N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N2-



methyl-N2-(2-phenylethyl)glycinamide


102
1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-4-



(phenylmethyl)imidazolidin-2-one


103
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridazin-3-yl)-N′-(4-



fluorophenyl)propanediamide


104
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-N′-(2-



chlorophenyl)propanediamide


105
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-N′-(3-



chlorophenyl)propanediamide


106
N1-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-N2-



methyl-N2-(phenylmethyl)glycinamide


107
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-N′-(4-



chlorophenyl)propanediamide


108
(2E)—N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-2-



[(methyloxy)imino]propanamide


109
(2E)—N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-2-



[(ethyloxy)imino]propanamide


110
(2E)—N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-2-



{[(phenylmethyl)oxy]imino}propanamide


111
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-1-



(phenylmethyl)prolinamide


112
1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-3-[(4-



methylphenyl)sulfonyl]-4-(phenylmethyl)imidazolidin-2-one


113
1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-4-



(phenylmethyl)imidazolidin-2-one


114
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-4-(phenylmethyl)-



4,5-dihydro-1,3-oxazol-2-amine


115
6,7-bis(methyloxy)-4-({4-[4-(phenylmethyl)piperazin-1-



yl]phenyl}oxy)quinoline


116
1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-4-



(phenylmethyl)piperazin-2-one


117
N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N2-



(phenylmethyl)alaninamide


118
N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N2-methyl-N2-



(phenylmethyl)alaninamide


119
N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N2-



(phenylmethyl)leucinamide


120
N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N2-methyl-N2-



(phenylmethyl)leucinamide


121
N1-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N2-



(phenylmethyl)valinamide


122
4-(6,7-dimethoxy-quinolin-4-ylamino)-N-(3-phenyl-propyl)-benzamide


123
4-benzyl-1-[4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-tetrahydro-



pyrimidin-2-one


124
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-phenethyl-oxalamide


125
2-(Benzyl-methyl-amino)-N-[4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-



3-methyl-butyramide



(note: Alphabetic order of prefixes ignored while selecting parent chain)


126
N-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-phenyl]-2-phenoxyimino-



propionamide


127
2-Benzyloxyimino-N-[4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-2-



phenyl-acetamide


128
4-[4-(4-Benzyl-piperidin-1-yl)-phenoxy]-6,7-dimethoxy-quinoline


129
N-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-N′-(2-isopropyl-



1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)-oxalamide


130
N-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-N′-(2-ethyl-



1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)-oxalamide


131
4-(4-{3-Chloro-5-[2-(4-fluoro-phenylcarbamoyl)-acetylamino]-pyridin-2-



yloxy}-6-methoxy-quinolin-7-yloxymethyl)-piperidine-1-carboxylic acid



tert-butyl ester


132
N-{5-Chloro-6-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



pyridin-3-yl}-N′-(4-fluoro-phenyl)-malonamide


133
N-{5-Chloro-6-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinolin-



4-yloxy]-pyridin-3-yl}-N′-(4-fluoro-phenyl)-malonamide


134
N-{4-[7-(3-Diethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-



phenyl}-N′-phenethyl-oxalamide


135
N-{3-Fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-



yloxy]-phenyl}-N′-phenethyl-oxalamide


136
N-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-



yloxy]-phenyl}-N′-phenethyl-oxalamide


137
N-{4-[7-(2-Diethylamino-ethoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-



phenyl}-N′-phenethyl-oxalamide


138
N-{3-Fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinolin-



4-yloxy]-phenyl}-N′-methyl-N′-phenethyl-oxalamide


139
N-{3-Fluoro-4-[6-methoxy-7-(2-methyl-octahydro-cyclopenta[c]pyrrol-5-



ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-phenethyl-oxalamide


140
N-{3-Fluoro-4-[6-methoxy-7-(2-methyl-octahydro-cyclopenta[c]pyrrol-5-



ylmethoxy)-quinazolin-4-yloxy]-phenyl}-N′-phenethyl-oxalamide


141
2-(3,4-Dihydro-1H-isoquinolin-2-yl)-N-{3-fluoro-4-[6-methoxy-7-(1-



methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-2-oxo-



acetamide


142
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-2-oxo-2-(3-phenyl-pyrrolidin-1-yl)-acetamide


143
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-2-oxo-2-(2-phenyl-morpholin-4-yl)-acetamide


144
N-(2-Dimethylamino-2-phenyl-ethyl)-N′-{3-fluoro-4-[6-methoxy-7-



(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


145
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(2-oxo-2-phenyl-ethyl)-oxalamide


146
N-[5-Chloro-6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-yl]-2,2-



difluoro-N′-(4-fluoro-phenyl)-malonamide


147
N-Benzyl-N′-{3-fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-



quinolin-4-yloxy]-phenyl}-oxalamide


148
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-[2-(2-fluoro-phenyl)-ethyl]-oxalamide


149
N-[2-(3-Chloro-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-



ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


150
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-[2-(2-methoxy-phenyl)-ethyl]-oxalamide


151
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(2-pyridin-3-yl-ethyl)-oxalamide


152
N-Benzyl-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-



4-yloxy]-phenyl}-oxalamide


153
N-[2-(2,5-Dimethoxy-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-



(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


154
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-[2-(2-trifluoromethyl-phenyl)-ethyl]-oxalamide


155
N-[2-(2-Ethoxy-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-



ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


156
N-[2-(2,4-Dimethyl-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-



(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


157
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(1S-phenyl-2-p-tolyl-ethyl)-oxalamide


158
N-[2-(4-Chloro-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-



ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


159
N-{3-Fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinolin-



4-yloxy]-phenyl}-oxalamic acid


160
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-[2-(3-fluoro-phenyl)-ethyl]-oxalamide


161
N-[2-(2-Chloro-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-



ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


162
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-[2-(3-methoxy-phenyl)-ethyl]-oxalamide


163
N-(1,2-Diphenyl-ethyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-



ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


164
N-[2-(2,4-Dichloro-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-



4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


165
N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-



(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


166
N-[2-(4-Ethyl-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-



ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


167
N-[2-(4-Ethoxy-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-



ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


168
N-[2-(4-Ethoxy-3-methoxy-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-



(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


169
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-[2-(4-phenoxy-phenyl)-ethyl]-oxalamide


170
N-[2-(3-Ethoxy-4-methoxy-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-



(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


171
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(2-pyridin-2-yl-ethyl)-oxalamide


172
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(2-pyridin-4-yl-ethyl)-oxalamide


173
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-[2-(4-fluoro-phenyl)-ethyl]-oxalamide


174
N-[2-(2-Bromo-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-



ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


175
N-[2-(2-Chloro-6-fluoro-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-



(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


176
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(2R-phenyl-propyl)-oxalamide


177
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-indan-1-yl-oxalamide


178
N-{3-Fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinolin-



4-yloxy]-phenyl}-N′-isobutyl-oxalamide


179
N-{3-Fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinolin-



4-yloxy]-phenyl}-N′-(3-methyl-butyl)-oxalamide


180
N-{3-Fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinolin-



4-yloxy]-phenyl}-N′-(2R-phenyl-propyl)-oxalamide


181
N-{3-Fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinolin-



4-yloxy]-phenyl}-N′-(2-phenyl-propyl)-oxalamide


182
N-{3-Fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinolin-



4-yloxy]-phenyl}-N′-indan-2-yl-oxalamide


183
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(1R-phenyl-ethyl)-oxalamide


184
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(1S-phenyl-ethyl)-oxalamide


185
N-[2-(3-Bromo-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-



ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


186
N-[2-(2,6-Dichloro-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-



4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


187
N-[2-(2,4-Dichloro-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-



4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


188
N-(2-Benzo[1,3]dioxol-5-yl-ethyl)-N′-{3-fluoro-4-[6-methoxy-7-



(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


189
N-[2-(3-Bromo-4-methoxy-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-



(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


190
N-[2-(3,5-Dimethoxy-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-



(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


191
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(2-o-tolyl-ethyl)-oxalamide


192
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(2-m-tolyl-ethyl)-oxalamide


193
N-[2-(3-Ethoxy-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-



ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


194
N-[2-(3,4-Dimethyl-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-



(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


195
N-[2-(2,5-Dimethyl-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-



(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


196
N-[2-(3-Chloro-4-propoxy-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-



(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


197
N-[2-(4-Butoxy-3-chloro-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-



(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


198
N-[2-(4-tert-Butyl-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-



4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


199
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-[2-(4-sulfamoyl-phenyl)-ethyl]-oxalamide


200
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-oxalamide


201
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-[2-(3-hydroxy-4-methoxy-phenyl)-ethyl]-oxalamide


202
N-(2,4-Dichloro-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-



ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


203
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(4-fluoro-2-trifluoromethyl-benzyl)-oxalamide


204
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(1-p-tolyl-ethyl)-oxalamide


205
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(3-fluoro-4-trifluoromethyl-benzyl)-oxalamide


206
N-(3-Chloro-4-fluoro-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-



ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


207
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-[1-(3-methoxy-phenyl)-ethyl]-oxalamide


208
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(1-naphthalen-2-yl-ethyl)-oxalamide


209
N-(4-Chloro-3-trifluoromethyl-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-



(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


210
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(1-p-tolyl-ethyl)-oxalamide


211
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(6-trifluoromethyl-pyridin-3-ylmethyl)-oxalamide


212
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(2-methyl-benzyl)-oxalamide


213
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(3-methyl-benzyl)-oxalamide


214
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(4-fluoro-3-trifluoromethyl-benzyl)-oxalamide


215
N-(3,5-Dichloro-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-



ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


216
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(1R,2,3,4-tetrahydro-naphthalen-1-yl)-oxalamide


217
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(1S,2,3,4-tetrahydro-naphthalen-1-yl)-oxalamide


218
N-Cyclopentyl-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-



quinolin-4-yloxy]-phenyl}-oxalamide


219
N-[1-(4-Bromo-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-



ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


220
N-(2-Fluoro-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-



ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


221
N-[2-(3,4-Dichloro-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-



4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


222
N-(4-Fluoro-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-



ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


223
N-(2,3-Difluoro-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-



ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


224
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(2-phenoxy-ethyl)-oxalamide


225
N-(2,2-Diphenyl-ethyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-



ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


226
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-[2-(4-methoxy-phenyl)-ethyl]-oxalamide


227
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(2-phenyl-propyl)-oxalamide


228
N-[2-(4-Bromo-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-



ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


229
N-{4-[7-(1-Ethyl-piperidin-4-ylmethoxy)-6-methoxy-quinolin-4-yloxy]-3-



fluoro-phenyl}-2-oxo-2-(2-phenyl-morpholin-4-yl)-acetamide


230
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(3-fluoro-5-trifluoromethyl-benzyl)-oxalamide


231
N-(3,5-Difluoro-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-



ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


232
N-(2-Chloro-5-trifluoromethyl-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-



(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


233
N-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-N′-(2-



dimethylamino-2-phenyl-ethyl)-oxalamide


234
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(4-methoxy-benzyl)-oxalamide


235
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(4-trifluoromethyl-benzyl)-oxalamide


236
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(3-methoxy-benzyl)-oxalamide


237
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(3-trifluoromethyl-benzyl)-oxalamide


238
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(3-trifluoromethoxy-benzyl)-oxalamide


239
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(2-methoxy-benzyl)-oxalamide


240
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(2-trifluoromethyl-benzyl)-oxalamide


241
N-(3-Chloro-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-



ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


242
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(2-trifluoromethoxy-benzyl)-oxalamide


243
N-(2-Chloro-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-



ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


244
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(4-trifluoromethoxy-benzyl)-oxalamide


245
N-{3-Fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinolin-



4-yloxy]-phenyl}-N′-(4-methoxy-benzyl)-oxalamide


246
N-{3-Fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinolin-



4-yloxy]-phenyl}-N′-(4-trifluoromethyl-benzyl)-oxalamide


247
N-{4-[7-(Azetidin-3-ylmethoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-



phenyl}-N′-phenethyl-oxalamide


248
N-{3-Fluoro-4-[6-methoxy-7-(1-methyl-azetidin-3-ylmethoxy)-quinolin-4-



yloxy]-phenyl}-N′-phenethyl-oxalamide


249
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(2-hydroxy-2-phenyl-ethyl)-oxalamide


250
N-[5-Chloro-6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-yl]-N′-(2,4-



difluoro-phenyl)-malonamide


251
N-[5-Chloro-6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-yl]-N′-(4-



fluoro-phenyl)-N′-methyl-malonamide


252
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(1R-phenyl-propyl)-oxalamide


253
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(1R-phenyl-propyl)-oxalamide


254
N-(3,4-Difluoro-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-



ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


255
N-(2,6-Difluoro-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-



ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


256
N-{3-Fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinolin-



4-yloxy]-phenyl}-N′-[2-(4-fluoro-phenyl)-ethyl]-oxalamide


257
N-{3-Fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinolin-



4-yloxy]-phenyl}-N′-phenyl-oxalamide


258
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(3-fluoro-phenyl)-oxalamide


259
N-(4-Chloro-3-fluoro-phenyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-



ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


260
N-(3,4-Dimethoxy-phenyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-



ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


261
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(3-methyl-butyl)-oxalamide


262
N-(3,3-Dimethyl-butyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-



ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


263
N-{5-Chloro-6-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-



yloxy]-pyridin-3-yl}-N′-(4-fluoro-phenyl)-malonamide


264
N-{5-Chloro-6-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-



yloxy]-pyridin-3-yl}-N′-(4-fluoro-phenyl)-malonamide


265
N-{5-Chloro-6-[7-(3-diethylamino-propoxy)-6-methoxy-quinolin-4-



yloxy]-pyridin-3-yl}-N′-(4-fluoro-phenyl)-malonamide


266
N-(4-Chloro-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-



ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


267
N-(3,5-Dimethoxy-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-



ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


268
N-(4-Butyl-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-



quinolin-4-yloxy]-phenyl}-oxalamide


269
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(2-p-tolyl-ethyl)-oxalamide


270
N-(3,5-Bis-trifluoromethyl-benzyl)-N′-{3-fluoro-4-[6-methoxy-7-



(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


271
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-pyrazin-2-ylmethyl-oxalamide


272
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-pyridin-2-ylmethyl-oxalamide


273
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinazolin-4-



yloxy]-phenyl}-N′-phenethyl-oxalamide


274
N-{3-Fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-



quinazolin-4-yloxy]-phenyl}-N′-phenethyl-oxalamide


275
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(2-fluoro-3-trifluoromethyl-benzyl)-oxalamide


276
N-[2-(2-Bromo-6-methoxy-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-



(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


277
N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-



(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N-methyl-oxalamide


278
N-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-



(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


279
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(2-fluoro-5-trifluoromethyl-benzyl)-oxalamide


280
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-[1-(4-fluoro-phenyl)-ethyl]-oxalamide


281
N-(1S-Benzyl-2-oxo-2-pyrrolidin-1-yl-ethyl)-N′-{3-fluoro-4-[6-methoxy-7-



(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


282
N-{3-Fluoro-4-[6-methoxy-7-(octahydro-cyclopenta[c]pyrrol-5-



ylmethoxy)-quinazolin-4-yloxy]-phenyl}-N′-phenethyl-oxalamide


283
N-[2-(4-Amino-phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-



ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


284
2-(4-Benzyl-piperidin-1-yl)-N-{3-fluoro-4-[6-methoxy-7-(piperidin-4-



ylmethoxy)-quinolin-4-yloxy]-phenyl}-2-oxo-acetamide


285
N-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-phenyl]-N′-(4-fluoro-phenyl)-



malonamide


286
N-[5-Chloro-6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-yl]-N′-(3-



fluoro-phenyl)-malonamide


287
N-[5-Chloro-6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-yl]-N′-phenyl-



malonamide


288
N-[5-Chloro-6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-yl]-N′-(4-



fluoro-phenyl)-2,2-dimethyl-malonamide


289
N-Ethyl-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-



yloxy]-phenyl}-oxalamide


290
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-isopropyl-oxalamide


291
N-Butyl-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-



yloxy]-phenyl}-oxalamide


292
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(2-methoxy-ethyl)-oxalamide


293
N-Cyclopropylmethyl-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-



ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide


294
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-N′-(2-morpholin-4-yl-ethyl)-oxalamide


295
N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-



phenyl}-2-oxo-2-pyrrolidin-1-yl-acetamide


296
N-Ethyl-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-



yloxy]-phenyl}-N-methyl-oxalamide









Table 3c
Additional Representative c-MET, c-KIT, and/or Flt-3 Inhibitors
The Compounds in Table 3c can be prepared as pharmaceutically acceptable salts, solvates, hydrates, and/or isomers thereof. All such salt, solvate, hydrate, and isomer combinations of the Compounds in Table 3c can be used to practice the invention.








TABLE 3c





Entry
Name
















1
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-N′-(4-



fluorophenyl)cyclopropane-1,1-dicarboxamide


2
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-N′-(4-



fluorophenyl)cyclobutane-1,1-dicarboxamide


3
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-N′-



(phenylmethyl)cyclopropane-1,1-dicarboxamide


4
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-N′-



phenylcyclopropane-1,1-dicarboxamide


5
N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-



yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide


6
N-[3-fluoro-4-({6-(methyloxy)-7-[(3-piperidin-1-ylpropyl)oxy]quinolin-4-



yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide


7
N-[3-fluoro-4-({6-(methyloxy)-7-[(3-piperidin-1-ylpropyl)oxy]quinolin-4-



yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclobutane-1,1-dicarboxamide


8
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)-N′-(2-



phenylethyl)cyclopropane-1,1-dicarboxamide


9
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-2-methylpyridin-3-yl)-N′-(4-



fluorophenyl)cyclopropane-1,1-dicarboxamide


10
N-{4-[(7-chloroquinolin-4-yl)oxy]-3-fluorophenyl}-N′-(4-



fluorophenyl)cyclopropane-1,1-dicarboxamide


11
N-{4-[(7-chloroquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-



1,1-dicarboxamide


12
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-



fluorophenyl)cyclopropane-1,1-dicarboxamide


13
N-(4-{[6,7-bis(methyloxy)quinazolin-4-yl]oxy}phenyl)-N′-(4-



fluorophenyl)cyclopropane-1,1-dicarboxamide


14
N-(4-{[6,7-bis(methyloxy)quinazolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-



fluorophenyl)cyclopropane-1,1-dicarboxamide


15
N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinazolin-4-



yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide


16
N-{5-chloro-6-[(6-(methyloxy)-7-{[(1-methylpiperidin-4-



yl)methyl]oxy}quinolin-4-yl)oxy]pyridin-3-yl}-N′-(4-



fluorophenyl)cyclopropane-1,1-dicarboxamide


17
N-[5-chloro-6-({6-(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-



yl}oxy)pyridin-3-yl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide


18
N-[5-chloro-6-({6-(methyloxy)-7-[(phenylmethyl)oxy]quinolin-4-



yl}oxy)pyridin-3-yl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide


19
N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3-



fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide


20
N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3-



fluorophenyl)-N′-(4-fluorophenyl)cyclobutane-1,1-dicarboxamide


21
N-{3-fluoro-4-[(6-(methyloxy)-7-{[(1-methylpiperidin-4-



yl)methyl]oxy}quinazolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-



1,1-dicarboxamide


22
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-2-methylphenyl)-N′-(4-



fluorophenyl)cyclopropane-1,1-dicarboxamide


23
N-(4-fluorophenyl)-N′-[2-methyl-6-({6-(methyloxy)-7-[(3-morpholin-4-



ylpropyl)oxy]quinolin-4-yl}oxy)pyridin-3-yl]cyclopropane-1,1-dicarboxamide


24
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-



fluorophenyl)cyclopropane-1,1-dicarboxamide


25
N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloro-2-methylpyridin-3-yl)-



N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide


26
N-[3-fluoro-4-({7-(methyloxy)-6-[(3-morpholin-4-ylpropyl)oxy]quinazolin-4-



yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide


27
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3,5-difluorophenyl)-N′-(4-



fluorophenyl)cyclopropane-1,1-dicarboxamide


28
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-2,5-difluorophenyl)-N′-(4-



fluorophenyl)cyclopropane-1,1-dicarboxamide


29
N-[3-fluoro-4-({7-(methyloxy)-6-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-



yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide


30
N-{3-fluoro-4-[(6-(methyloxy)-7-(2-methyl octahydrocyclo-penta[c]pyrrol-5-



ylmethoxy)quinazolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-



dicarboxamide


31
N-{3-fluoro-4-[(7-(methyloxy)-6-{[(1-methylpiperidin-4-



yl)methyl]oxy}quinazolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-



1,1-dicarboxamide


32
N-[5-fluoro-2-methyl-4-({6-(methyloxy)-7-[(3-morpholin-4-



ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-



dicarboxamide


33
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-2,3,5-trifluorophenyl)-N′-(4-



fluorophenyl)cyclopropane-1,1-dicarboxamide


34
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-2-methylphenyl)-N′-(4-



fluorophenyl)cyclopropane-1,1-dicarboxamide


35
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-2-chloro-5-methylphenyl)-N′-(4-



fluorophenyl)cyclopropane-1,1-dicarboxamide


36
N-(3-fluoro-4-{[6-hydroxy-7-(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-



fluorophenyl)cyclopropane-1,1-dicarboxamide


37
N-(4-fluorophenyl)-N′-[2-methyl-4-({6-(methyloxy)-7-[(3-morpholin-4-



ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]cyclopropane-1,1-dicarboxamide


38
N-[3-fluoro-4-({6-(methyloxy)-7-[(3-piperazin-1-ylpropyl)oxy]quinolin-4-



yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide


39
N-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4-methylpiperazin-1-



yl)propyl]oxy}quinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-



1,1-dicarboxamide


40
N-{3-fluoro-4-[(6-(methyloxy)-7-{[(1-methylpiperidin-4-



yl)methyl]oxy}quinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-



1,1-dicarboxamide


41
N-(4-fluorophenyl)-N′-[4-({6-(methyloxy)-7-[(3-morpholin-4-



ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]cyclopropane-1,1-dicarboxamide


42
N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3-



fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide


43
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-2-chloro-5-fluorophenyl)-N′-(4-



fluorophenyl)cyclopropane-1,1-dicarboxamide


44
N-(4-{[6,7-bis(methyloxy)-2-(methylthio)quinolin-4-yl]oxy}-3-fluorophenyl)-



N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide


45
N-(4-fluorophenyl)-N′-(4-{[2-methyl-6,7-bis(methyloxy)quinazolin-4-



yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide


46
N-(4-{[2-amino-6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-



fluorophenyl)cyclopropane-1,1-dicarboxamide


47
N-(3-fluoro-4-{[2-(methylamino)-6,7-bis(methyloxy)quinolin-4-



yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide


48
(1S,2R)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-



ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2-



methylcyclopropane-1,1-dicarboxamide


49
(1R,2R)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-



ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2-



methylcyclopropane-1,1-dicarboxamide


50
N-(4-{[6-{[3-(diethylamino)propyl]oxy}-7-(methyloxy)quinolin-4-yl]oxy}-3-



fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide


51
N-(4-{[6-{[2-(diethylamino)ethyl]oxy}-7-(methyloxy)quinolin-4-yl]oxy}-3-



fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide


52
1,1-dimethylethyl 4-(3-{[4-[(2-fluoro-4-{[(1-{[(4-



fluorophenyl)amino]carbonyl}cyclopropyl)carbonyl]amino}phenyl)oxy]-6-



(methyloxy)quinolin-7-yl]oxy}propyl)piperazine-1-carboxylate


53
(1R,2R)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-



ylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2-



methylcyclopropane-1,1-dicarboxamide


54
(1R,2R)-N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinazolin-4-



yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1-



dicarboxamide


55
N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinazolin-4-yl]oxy}-3-



fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide


56
N-(4-{[7-{[3-(4-acetylpiperazin-1-yl)propyl]oxy}-6-(methyloxy)quinolin-4-



yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide


57
1,1-dimethylethyl 4-(3-{[4-[(2-fluoro-4-{[((1R,2R)-1-{[(4-



fluorophenyl)amino]carbonyl}-2-



methylcyclopropyl)carbonyl]amino}phenyl)oxy]-6-(methyloxy)quinolin-7-



yl]oxy}propyl)piperazine-1-carboxylate


58
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)-1-



(phenylmethyl)azetidine-3,3-dicarboxamide


59
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-



fluorophenyl)azetidine-3,3-dicarboxamide


60
(1R,2S)-N-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4-methylpiperazin-1-



yl)propyl]oxy}quinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)-2-



methylcyclopropane-1,1-dicarboxamide


61
(1R,2R)-N-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4-methylpiperazin-1-



yl)propyl]oxy}quinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)-2-



methylcyclopropane-1,1-dicarboxamide


62
(1R,2R)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-piperazin-1-



ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2-



methylcyclopropane-1,1-dicarboxamide


63
N-(3-fluoro-4-{[7-({3-[4-(1-methylethyl)piperazin-1-yl]propyl}oxy)-6-



(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-



dicarboxamide


64
N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinazolin-4-yl]oxy}-3-



fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide


65
(1R,2R)-N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinolin-4-



yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1-



dicarboxamide


66
(1R,2R)-N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinolin-4-



yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1-



dicarboxamide


67
(1R,2S)-N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinolin-4-



yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1-



dicarboxamide


68
(1R,2S)-N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinolin-4-



yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide


69
N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinazolin-4-yl]oxy}-3-



fluorophenyl)-N′-(4-fluorophenyl)cyclobutane-1,1-dicarboxamide


70
(1R,2S)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-piperazin-1-



ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2-



methylcyclopropane-1,1-dicarboxamide


71
(1R,2R,3S)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-



ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2,3-



dimethylcyclopropane-1,1-dicarboxamide


72
(1R,2R,3S)-N-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4-methylpiperazin-1-



yl)propyl]oxy}quinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)-2,3-



dimethylcyclopropane-1,1-dicarboxamide


73
(1R,2R,3S)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-



ylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2,3-



dimethylcyclopropane-1,1-dicarboxamide


74
(1R,2R,3S)-N-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4-methylpiperazin-1-



yl)propyl]oxy}quinazolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)-2,3-



dimethylcyclopropane-1,1-dicarboxamide


75
N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinazolin-4-



yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclobutane-1,1-dicarboxamide


76
(2R,3R)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-



ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2,3-



dimethylcyclopropane-1,1-dicarboxamide


77
(2R,3R)-N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinolin-4-



yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2,3-dimethylcyclopropane-1,1-



dicarboxamide


78
N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3-



fluorophenyl)-N′-(4-fluorophenyl)-2,2-dimethylcyclopropane-1,1-



dicarboxamide


79
N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinazolin-4-



yl}oxy)phenyl]-N′-(4-fluorophenyl)-2,2-dimethylcyclopropane-1,1-



dicarboxamide


80
(1R,2R,3S)-N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinolin-4-



yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2,3-dimethylcyclopropane-1,1-



dicarboxamide


81
N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3-



fluorophenyl)-N′-(4-fluorophenyl)-2,2-dimethylcyclopropane-1,1-



dicarboxamide


82
(1R,2R,3S)-N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinolin-4-



yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2,3-dimethylcyclopropane-1,1-



dicarboxamide


83
N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-



yl}oxy)phenyl]-N′-(4-fluorophenyl)-2,2-dimethylcyclopropane-1,1-



dicarboxamide


84
N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinazolin-4-yl]oxy}-3-



fluorophenyl)-N′-(4-fluorophenyl)-2,2-dimethylcyclopropane-1,1-



dicarboxamide


85
N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinazolin-4-yl]oxy}-3-



fluorophenyl)-N′-(4-fluorophenyl)-2,2-dimethylcyclopropane-1,1-



dicarboxamide


86
N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinazolin-4-yl]oxy}-3-



fluorophenyl)-N′-(4-fluorophenyl)cyclobutane-1,1-dicarboxamide


87
N-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4-methylpiperazin-1-



yl)propyl]oxy}quinazolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclobutane-



1,1-dicarboxamide


88
N-[3-fluoro-4-({6-(methyloxy)-7-[(3-piperazin-1-ylpropyl)oxy]quinazolin-4-



yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclobutane-1,1-dicarboxamide


89
(2R,3R)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-



ylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2,3-



dimethylcyclopropane-1,1-dicarboxamide


90
N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3-



fluorophenyl)-N′-(4-fluorophenyl)cyclobutane-1,1-dicarboxamide


91
N-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4-methylpiperazin-1-



yl)propyl]oxy}quinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclobutane-1,1-



dicarboxamide


92
(1R,2R)-N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinazolin-4-



yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1-



dicarboxamide


93
(1R,2R)-N-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4-methylpiperazin-1-



yl)propyl]oxy}quinazolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)-2-



methylcyclopropane-1,1-dicarboxamide


94
(2R,3R)-N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinazolin-4-



yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2,3-dimethylcyclopropane-1,1-



dicarboxamide


95
(2R,3R)-N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6-(methyloxy)quinazolin-4-



yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2,3-dimethylcyclopropane-1,1-



dicarboxamide


96
(1R,2R)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-piperazin-1-



ylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2-



methylcyclopropane-1,1-dicarboxamide


97
(2R,3R)-N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinolin-4-



yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2,3-dimethylcyclopropane-1,1-



dicarboxamide


98
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-[(4-



fluorophenyl)methyl]cyclopropane-1,1-dicarboxamide


99
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(2-morpholin-4-



ylethyl)cyclopropane-1,1-dicarboxamide


100
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-[2-(piperidin-1-



ylmethyl)phenyl]cyclopropane-1,1-dicarboxamide


101
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-[2-(pyrrolidin-1-



ylmethyl)phenyl]cyclopropane-1,1-dicarboxamide


102
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-[3-(morpholin-4-



ylmethyl)phenyl]cyclopropane-1,1-dicarboxamide


103
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-[2-(morpholin-4-



ylmethyl)phenyl]cyclopropane-1,1-dicarboxamide


104
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-phenylcyclopropane-



1,1-dicarboxamide


105
N-[3-(aminomethyl)phenyl]-N′-(4-{[6,7-bis(methyloxy)quinolin-4-



yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide


106
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-[3-(piperidin-1-



ylmethyl)phenyl]cyclopropane-1,1-dicarboxamide


107
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-[3-(pyrrolidin-1-



ylmethyl)phenyl]cyclopropane-1,1-dicarboxamide









Table 4
Representative EGFR, ErbB2, and/or VEGFR Inhibitors
The Compounds in Table 4 can be prepared as pharmaceutically acceptable salts, solvates, hydrates, and/or isomers thereof. All such salt, solvate, hydrate, and isomer combinations of the Compounds in Table 4 can be used to practice the invention. In particular, the invention can be practiced with one or two pharmaceutically acceptable salts of a Compound of Table 4 which salt(s) are formed with one or two acids independently selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, p-toluenesulfonic acid, and salicylic acid.








TABLE 4





Entry
Name
















1
N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-(1-



methylethyl)octahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-



(methyloxy)quinazolin-4-amine


2
N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-(1-



methylethyl)octahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-



(methyloxy)quinazolin-4-amine


3
7-({[(3aR,5r,6aS)-2-acetyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-



N-(4-bromo-3-chloro-2-fluorophenyl)-6-(methyloxy)quinazolin-4-amine


4
N-(4-bromo-3-chloro-2-fluorophenyl)-6-(methyloxy)-7-{[(3aR,5r,6aS)-



octahydrocyclopenta[c]pyrrol-5-ylmethyl]oxy}quinazolin-4-amine


5
ethyl (3aR,6aS)-5-({[4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]oxy}methyl)hexahydrocyclopenta[c]pyrrole-



2(1H)-carboxylate


6
N-(4-bromo-3-chloro-2-fluorophenyl)-6-(methyloxy)-7-({[(3aR,5r,6aS)-2-



(methylsulfonyl)octahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)quinazolin-4-amine


7
N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-



ethyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-



(methyloxy)quinazolin-4-amine


8
N-(3,4-dichloro-2-fluorophenyl)-6-(methyloxy)-7-({[(3aR,5r,6aS)-2-(2-



methylpropyl)octahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)quinazolin-4-



amine


9
N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-



methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-



(methyloxy)quinazolin-4-amine


10
N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-



methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-



(methyloxy)quinazolin-4-amine


11
N-(3-chloro-2,4-difluorophenyl)-7-({[(3aR,5s,6aS)-2-



methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-



(methyloxy)quinazolin-4-amine


12
N-(4,5-dichloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-



methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-



(methyloxy)quinazolin-4-amine


13
N-(4-bromo-5-chloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-



methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-



(methyloxy)quinazolin-4-amine


14
N-(4-bromo-2,3-dichlorophenyl)-7-({[(3aR,5s,6aS)-2-



methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-



(methyloxy)quinazolin-4-amine


15
N-(3,4-dichlorophenyl)-7-({[(3aR,5s,6aS)-2-



methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-



(methyloxy)quinazolin-4-amine


16
N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-



ethyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-



(methyloxy)quinazolin-4-amine


17
N-(4-bromo-3-chloro-2-fluorophenyl)-6-(methyloxy)-7-({[(3aR,5r,6aS)-2-



(2-(methylpropyl)octahydrocyclopenta[c]pyrrol-5-



yl]methyl}oxy)quinazolin-4-amine


18
N-(4-bromo-2,3-dichlorophenyl)-7-{[(3R,9aS)-hexahydro-1H-



[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-



4-amine


19
N-(4,5-dichloro-2-fluorophenyl)-7-{[(3R,9aS)-hexahydro-1H-



[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-



4-amine


20
N-(4-bromo-5-chloro-2-fluorophenyl)-7-{[(3R,9aS)-hexahydro-1H-



[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-



4-amine


21
N-(3-chloro-2,4-difluorophenyl)-7-{[(3R,9aS)-hexahydro-1H-



[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-



4-amine


22
N-(3,4-dichloro-2-fluorophenyl)-7-{[(3S,9aS)-hexahydro-1H-



[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-



4-amine


23
N-(4-bromo-3-chloro-2-fluorophenyl)-7-{[(3S,9aS)-hexahydro-1H-



[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-



4-amine


24
N-(3-chloro-2,4-difluorophenyl)-7-{[(3S,9aS)-hexahydro-1H-



[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-



4-amine


25
N-(3,4-dichlorophenyl)-7-[(hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-



3-ylmethyl)oxy]-6-(methyloxy)quinazolin-4-amine


26
N-(4,5-dichloro-2-fluorophenyl)-7-{[(3S,9aS)-hexahydro-1H-



[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-



4-amine


27
N-(4-bromo-2,3-dichlorophenyl)-7-{[(3S,9aS)-hexahydro-1H-



[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-



4-amine


28
N-(4-bromo-5-chloro-2-fluorophenyl)-7-{[(3S,9aS)-hexahydro-1H-



[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-



4-amine


29
N-(3,4-dichloro-2-fluorophenyl)-7-{[(3R,9aS)-hexahydro-1H-



[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-



4-amine


30
N-(4-bromo-3-chloro-2-fluorophenyl)-7-{[(3R,9aS)-hexahydro-1H-



[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-



4-amine


31
N-(3,4-dichlorophenyl)-7-{[(3R,8aR)-hexahydro-1H-pyrrolo[2,1-



c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine


32
N-(4-bromo-5-chloro-2-fluorophenyl)-7-{[(3S,8aS)-hexahydro-1H-



pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-



amine


33
N-(3,4-dichlorophenyl)-7-{[(3S,8aR)-hexahydro-1H-pyrrolo[2,1-



c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine


34
N-(3,4-dichlorophenyl)-7-{[(3S,8aS)-hexahydro-1H-pyrrolo[2,1-



c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine


35
N-(3,4-dichlorophenyl)-7-{[(3R,8aS)-hexahydro-1H-pyrrolo[2,1-



c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine


36
N-(3,4-dichloro-2-fluorophenyl)-7-{[(3S,8aS)-hexahydro-1H-pyrrolo[2,1-



c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine


37
N-(4-bromo-3-chloro-2-fluorophenyl)-7-{[(3S,8aS)-hexahydro-1H-



pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-



amine


38
N-(3-chloro-2,4-difluorophenyl)-7-{[(3S,8aS)-hexahydro-1H-pyrrolo[2,1-



c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine


39
N-(4-bromo-2,3-dichlorophenyl)-7-{[(3S,8aS)-hexahydro-1H-pyrrolo[2,1-



c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine


40
N-(4,5-dichloro-2-fluorophenyl)-7-{[(3S,8aS)-hexahydro-1H-pyrrolo[2,1-



c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine


41
1,4:3,6-dianhydro-5-({[4-[(4-bromo-5-chloro-2-fluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]oxy}methyl)-5-deoxy-2-O-methyl-D-xylo-



hexitol


42
1,4:3,6-dianhydro-5-deoxy-5-({[4-[(3,4-dichlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]oxy}methyl)-2-O-methyl-D-glucitol


43
1,4:3,6-dianhydro-5-deoxy-5-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]oxy}methyl)-2-O-methyl-D-xylo-hexitol


44
1,4:3,6-dianhydro-5-({[4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]oxy}methyl)-5-deoxy-2-O-methyl-D-xylo-



hexitol


45
1,4:3,6-dianhydro-5-({[4-[(3-chloro-2,4-difluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]oxy}methyl)-5-deoxy-2-O-methyl-D-xylo-



hexitol


46
1,4:3,6-dianhydro-5-({[4-[(4-bromo-2,3-dichlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]oxy}methyl)-5-deoxy-2-O-methyl-D-glucitol


47
1,4:3,6-dianhydro-2-deoxy-2-({[4-[(3,4-dichlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]oxy}methyl)-5-O-methyl-D-threo-hexitol


48
1,4:3,6-dianhydro-5-deoxy-5-({[4-[(4,5-dichloro-2-fluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]oxy}methyl)-2-O-methyl-D-glucitol


49
(3S,9aS)-3-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]oxy}methyl)hexahydro-2H-pyrido[1,2-



a]pyrazin-1(6H)-one


50
(3S,9aR)-3-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]oxy}methyl)hexahydro-2H-pyrido[1,2-



a]pyrazin-1(6H)-one


51
(3S,8aS)-3-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]oxy}methyl)hexahydropyrrolo[1,2-a]pyrazin-



1(2H)-one


52
(3S,8aR)-3-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]oxy}methyl)hexahydropyrrolo[1,2-a]pyrazin-



1(2H)-one


53
(3S,8aS)-3-({[4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]oxy}methyl)hexahydropyrrolo[1,2-a]pyrazin-



1(2H)-one


54
(3S,8aS)-3-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]oxy}methyl)-2-methylhexahydropyrrolo[1,2-



a]pyrazin-1(2H)-one


55
N-(3,4-dichlorophenyl)-7-({2-[(8-methyl-8-azabicyclo[3.2.1]oct-3-



yl)amino]ethyl}oxy)-6-(methyloxy)quinazolin-4-amine


56
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(8aR)-tetrahydro-1H-



[1,3]thiazolo[4,3-c][1,4]oxazin-6-ylmethyl]oxy}quinazolin-4-amine


57
N-(3,4-dichlorophenyl)-7-{[2-(8-methyl-8-azabicyclo[3.2.1]oct-3-



yl)ethyl]oxy}-6-(methyloxy)quinazolin-4-amine


58
N-(3,4-dichlorophenyl)-7-{[(8-methyl-8-azabicyclo[3.2.1]oct-3-



yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine


59
N-(3,4-dichlorophenyl)-7-{[(3aR,6aS)-2-



methyloctahydrocyclopenta[c]pyrrol-5-yl]oxy}-6-(methyloxy)quinazolin-4-



amine


60
N-(3,4-dichlorophenyl)-7-[(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)oxy]-6-



(methyloxy)quinazolin-4-amine


61
1,4:3,6-dianhydro-2-O-[4-[(4-bromo-5-chloro-2-fluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol


62
1,4:3,6-dianhydro-2-O-[4-[(3,4-dichloro-2-fluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol


63
1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol


64
1,4:3,6-dianhydro-2-O-methyl-5-O-{6-(methyloxy)-4-[(2,3,4-



trichlorophenyl)amino]quinazolin-7-yl}-L-iditol


65
1,4:3,6-dianhydro-5-O-[4-[(3,4-dichlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-O-methyl-D-xylo-hexitol


66
1,4:3,6-dianhydro-2-O-[4-[(4-bromo-2,3-dichlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol


67
1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-L-sorbose ethylene glycol acetal


68
1,4:3,6-dianhydro-2-O-[4-[(3-chloro-2,4-difluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol


69
1,4:3,6-dianhydro-2-O-[4-[(4,5-dichloro-2-fluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol


70
1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-5-O-(difluoromethyl)-L-iditol


71
1,4:3,6-dianhydro-2-O-[4-[(3-chloro-2-fluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol


72
1,4:3,6-dianhydro-2-O-[4-[(3,4-dichlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol


73
1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol


74
1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-5-O-ethyl-L-iditol


75
1,4:3,6-dianhydro-2-O-[4-[(3-bromo-2-methylphenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol


76
1,4:3,6-dianhydro-2-O-[4-[(3-chloro-2-methylphenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol


77
1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-5-deoxy-D-xylo-hexitol


78
1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-5-O-methyl-D-glucitol


79
methyl 3,6-anhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-O-methyl-alpha-L-idofuranoside


80
3,6-anhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-1,2-O-(1-methylethylidene)-beta-L-xylo-



hexofuranose


81
1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-5-deoxy-5-methylidene-D-xylo-hexitol


82
methyl 3,6-anhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-O-methyl-beta-L-idofuranoside


83
N-(3,4-dichloro-2-fluorophenyl)-6-(methyloxy)-7-[(octahydro-2H-



quinolizin-3-ylmethyl)oxy]quinazolin-4-amine


84
1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-{6-(methyloxy)-4-[(2,3,4-



trifluorophenyl)amino]quinazolin-7-yl}-D-iditol


85
1,4:3,6-dianhydro-5-O-[4-[(2-chloro-4-fluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol


86
1,4:3,6-dianhydro-5-O-[4-[(2-bromo-4-fluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol


87
1,4:3,6-dianhydro-2-deoxy-5-O-[4-[(2,6-difluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol


88
1,4:3,6-dianhydro-5-O-[4-[(3-chloro-2-fluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol


89
1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-[4-{[4-fluoro-3-



(trifluoromethyl)phenyl]amino}-6-(methyloxy)quinazolin-7-yl]-D-iditol


90
1,4:3,6-dianhydro-2-deoxy-5-O-[4-[(2,4-difluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol


91
1,4:3,6-dianhydro-2-deoxy-5-O-[4-[(2,5-difluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol


92
1,4:3,6-dianhydro-2-deoxy-5-O-[4-[(2,3-difluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol


93
1,4:3,6-dianhydro-5-O-[4-[(5-chloro-2-fluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol


94
1,4:3,6-dianhydro-2-deoxy-5-O-[4-[(3,5-difluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol


95
1,4:3,6-dianhydro-5-O-[4-[(3-chloro-4-fluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol


96
1,4:3,6-dianhydro-5-O-[4-[(4-bromo-2-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol


97
1,4:3,6-dianhydro-2-deoxy-5-O-[4-[(3,4-dichloro-2-fluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol


98
1,4:3,6-dianhydro-5-O-[4-[(4-bromo-5-chloro-2-fluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol


99
1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-{6-(methyloxy)-4-[(2,4,5-



trifluorophenyl)amino]quinazolin-7-yl}-D-iditol


100
1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-{6-(methyloxy)-4-[(2,4,6-



trifluorophenyl)amino]quinazolin-7-yl}-D-iditol


101
1,4:3,6-dianhydro-5-O-[4-({4-[(4-chlorophenyl)oxy]-3,5-



difluorophenyl}amino)-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-



iditol


102
1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol


103
1,4:3,6-dianhydro-5-O-[4-[(4-bromo-2,3-dichlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol


104
1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chloro-5-fluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol


105
1,4:3,6-dianhydro-2-deoxy-5-O-[4-[(4,5-dichloro-2-fluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol


106
1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-{6-(methyloxy)-4-[(2,3,4-



trichlorophenyl)amino]quinazolin-7-yl}-D-iditol


107
1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-{6-(methyloxy)-4-[(3,4,5-



trichlorophenyl)amino]quinazolin-7-yl}-D-iditol


108
1,4:3,6-dianhydro-5-O-[4-[(4-bromo-2-fluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol


109
1,4:3,6-dianhydro-5-O-[4-[(4-chloro-2-fluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol


110
1,4:3,6-dianhydro-5-O-[4-[(3-chloro-2-methylphenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol


111
1,4:3,6-dianhydro-2-deoxy-5-O-[4-[(3,4-difluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol


112
1,4:3,6-dianhydro-5-O-[4-[(2-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol


113
1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-[4-[(2-fluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-D-iditol


114
1,4:3,6-dianhydro-5-O-[4-[(3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol


115
1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-[4-[(4-fluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-D-iditol


116
1,4:3,6-dianhydro-5-O-[4-[(4-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol


117
1,4:3,6-dianhydro-2-deoxy-5-O-[4-[(2,4-dichlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol


118
1,4:3,6-dianhydro-2-deoxy-5-O-[4-[(2,5-dichlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol


119
1,4:3,6-dianhydro-2-deoxy-5-O-[4-[(3,4-dichlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol


120
1,4:3,6-dianhydro-5-O-[4-[(2-bromo-4,6-difluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol


121
1,4:3,6-dianhydro-5-O-[4-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol


122
1,4:3,6-dianhydro-5-O-[4-{[2-chloro-5-(trifluoromethyl)phenyl]amino}-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol


123
1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-[4-{[2-fluoro-3-



(trifluoromethyl)phenyl]amino}-6-(methyloxy)quinazolin-7-yl]-D-iditol


124
1,4:3,6-dianhydro-5-O-[4-{[2-bromo-5-(trifluoromethyl)phenyl]amino}-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol


125
1,4:3,6-dianhydro-5-O-[4-{[2-bromo-4-(trifluoromethyl)phenyl]amino}-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol


126
1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-[4-{[4-fluoro-2-



(trifluoromethyl)phenyl]amino}-6-(methyloxy)quinazolin-7-yl]-D-iditol


127
1,4:3,6-dianhydro-5-O-[4-{[3-bromo-5-(trifluoromethyl)phenyl]amino}-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol


128
1,4:3,6-dianhydro-5-O-[4-[(2-bromophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol


129
1,4:3,6-dianhydro-5-O-[4-[(3-bromophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol


130
1,4:3,6-dianhydro-5-O-[4-[(4-bromophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol


131
1,4:3,6-dianhydro-5-O-[4-[(3-bromo-4-methylphenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol


132
1,4:3,6-dianhydro-5-O-[4-[(5-chloro-2-methylphenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol


133
1,4:3,6-dianhydro-2-deoxy-5-O-[4-[(3,5-dimethylphenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol


134
1,4:3,6-dianhydro-5-O-[4-{[2,5-bis(methyloxy)phenyl]amino}-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol


135
1,4:3,6-dianhydro-5-O-[4-{[5-chloro-2,4-bis(methyloxy)phenyl]amino}-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol


136
1,4:3,6-dianhydro-5-O-[4-{[4-chloro-2,5-bis(methyloxy)phenyl]amino}-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol


137
1,4:3,6-dianhydro-5-O-[4-[(3-chloro-2,4-difluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol


138
N-(3,4-dichlorophenyl)-7-[({5-[(dimethylamino)methyl]-1,2,4-oxadiazol-3-



yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine


139
N-(3,4-dichlorophenyl)-7-[({3-[(dimethylamino)methyl]-1,2,4-oxadiazol-5-



yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine


140
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({3-[(4-methylpiperazin-1-



yl)methyl]-1,2,4-oxadiazol-5-yl}methyl)oxy]quinazolin-4-amine


141
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(5-piperidin-4-yl-1,2,4-



oxadiazol-3-yl)methyl]oxy}quinazolin-4-amine


142
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[5-(1-methylpiperidin-4-yl)-



1,2,4-oxadiazol-3-yl]methyl}oxy)quinazolin-4-amine


143
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[3-(morpholin-4-ylmethyl)-



1,2,4-oxadiazol-5-yl]methyl}oxy)quinazolin-4-amine


144
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(morpholin-2-



ylmethyl)oxy]quinazolin-4-amine


145
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(5-piperidin-2-yl-1,2,4-



oxadiazol-3-yl)methyl]oxy}quinazolin-4-amine


146
N-(3,4-dichlorophenyl)-7-[({2-[(dimethylamino)methyl]-1,3-thiazol-4-



yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine


147
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(phenylmethyl)morpholin-2-



yl]methyl}oxy)quinazolin-4-amine


148
1,1-dimethylethyl 2-({[4-[(3,4-dichlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]oxy}methyl)morpholine-4-carboxylate


149
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[2-(morpholin-4-ylmethyl)-1,3-



thiazol-4-yl]methyl}oxy)quinazolin-4-amine


150
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({2-[(4-methylpiperazin-1-



yl)methyl]-1,3-thiazol-4-yl}methyl)oxy]quinazolin-4-amine


151
N-(3,4-dichlorophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-



(methyloxy)quinazolin-4-amine


152
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(1,4-oxazepan-2-



ylmethyl)oxy]quinazolin-4-amine


153
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(5-piperidin-3-yl-1,2,4-



oxadiazol-3-yl)methyl]oxy}quinazolin-4-amine


154
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[5-(1-methylpiperidin-2-yl)-



1,2,4-oxadiazol-3-yl]methyl}oxy)quinazolin-4-amine


155
N-(3,4-dichlorophenyl)-7-{[(4-methyl-1,4-oxazepan-2-yl)methyl]oxy}-6-



(methyloxy)quinazolin-4-amine


156
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[5-(1-methylpiperidin-3-yl)-



1,2,4-oxadiazol-3-yl]methyl}oxy)quinazolin-4-amine


157
N-(3,4-dichlorophenyl)-7-({[5-(1,1-dimethylethyl)-1,2,4-oxadiazol-3-



yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine


158
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(2-phenyl-1,3-thiazol-4-



yl)methyl]oxy}quinazolin-4-amine


159
7-[(2,1,3-benzothiadiazol-4-ylmethyl)oxy]-N-(3,4-dichlorophenyl)-6-



(methyloxy)quinazolin-4-amine


160
N-(3,4-dichlorophenyl)-7-{[(5-methylisoxazol-3-yl)methyl]oxy}-6-



(methyloxy)quinazolin-4-amine


161
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(5-methyl-4-phenylisoxazol-3-



yl)methyl]oxy}quinazolin-4-amine


162
7-[(1,3-benzothiazol-2-ylmethyl)oxy]-N-(3,4-dichlorophenyl)-6-



(methyloxy)quinazolin-4-amine


163
7-[(2,1,3-benzoxadiazol-5-ylmethyl)oxy]-N-(3,4-dichlorophenyl)-6-



(methyloxy)quinazolin-4-amine


164
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[2-(2-thienyl)-1,3-thiazol-4-



yl]methyl}oxy)quinazolin-4-amine


165
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(1-phenyl-1H-pyrazol-4-



yl)methyl]oxy}quinazolin-4-amine


166
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({5-[3-(trifluoromethyl)phenyl]-



1,2,4-oxadiazol-3-yl}methyl)oxy]quinazolin-4-amine


167
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({5-[4-(trifluoromethyl)phenyl]-



1,2,4-oxadiazol-3-yl}methyl)oxy]quinazolin-4-amine


168
7-({[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]methyl}oxy)-N-(3,4-



dichlorophenyl)-6-(methyloxy)quinazolin-4-amine


169
7-({[6-bromo-2-(methyloxy)naphthalen-1-yl]methyl}oxy)-N-(3,4-



dichlorophenyl)-6-(methyloxy)quinazolin-4-amine


170
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(1,3-thiazol-4-



ylmethyl)oxy]quinazolin-4-amine


171
7-{[(6-chloropyridin-3-yl)methyl]oxy}-N-(3,4-dichlorophenyl)-6-



(methyloxy)quinazolin-4-amine


172
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(pyridin-4-



ylmethyl)oxy]quinazolin-4-amine


173
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(2-methyl-1,3-thiazol-4-



yl)methyl]oxy}quinazolin-4-amine


174
7-{[(6-chloro-4H-1,3-benzodioxin-8-yl)methyl]oxy}-N-(3,4-



dichlorophenyl)-6-(methyloxy)quinazolin-4-amine


175
7-{[(5-chloro-1-methyl-3-phenyl-1H-pyrazol-4-yl)methyl]oxy}-N-(3,4-



dichlorophenyl)-6-(methyloxy)quinazolin-4-amine


176
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[1-methyl-3-(trifluoromethyl)-



1H-thieno[2,3-c]pyrazol-5-yl]methyl}oxy)quinazolin-4-amine


177
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(3-phenylisoxazol-5-



yl)methyl]oxy}quinazolin-4-amine


178
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(2,4,6-



trimethylphenyl)methyl]oxy}quinazolin-4-amine


179
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(pyridin-3-



ylmethyl)oxy]quinazolin-4-amine


180
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({3-[4-



(methyloxy)phenyl]isoxazol-5-yl}methyl)oxy]quinazolin-4-amine


181
N-(3,4-dichlorophenyl)-7-({[5-[(2,4-dichlorophenyl)oxy]-1-methyl-3-



(trifluoromethyl)-1H-pyrazol-4-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-



amine


182
7-[(cyclopropylmethyl)oxy]-N-(3,4-dichlorophenyl)-6-



(methyloxy)quinazolin-4-amine


183
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(tetrahydrofuran-2-



ylmethyl)oxy]quinazolin-4-amine


184
7-(cyclopentyloxy)-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-



amine


185
7-[(2-cyclohexylethyl)oxy]-N-(3,4-dichlorophenyl)-6-



(methyloxy)quinazolin-4-amine


186
7-[(cyclohexylmethyl)oxy]-N-(3,4-dichlorophenyl)-6-



(methyloxy)quinazolin-4-amine


187
7-[(cyclobutylmethyl)oxy]-N-(3,4-dichlorophenyl)-6-



(methyloxy)quinazolin-4-amine


188
N-(3,4-dichlorophenyl)-7-{[2-(1,3-dioxolan-2-yl)ethyl]oxy}-6-



(methyloxy)quinazolin-4-amine


189
N-(3,4-dichlorophenyl)-7-{[2-(1,3-dioxan-2-yl)ethyl]oxy}-6-



(methyloxy)quinazolin-4-amine


190
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(2-morpholin-4-



ylethyl)oxy]quinazolin-4-amine


191
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(2-pyrrolidin-1-



ylethyl)oxy]quinazolin-4-amine


192
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(2-piperidin-1-



ylethyl)oxy]quinazolin-4-amine


193
2-(2-{[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-



yl]oxy}ethyl)-1H-isoindole-1,3(2H)-dione


194
methyl 6-O-[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-



alpha-D-glucopyranoside


195
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(2-morpholin-4-yl-2-



oxoethyl)oxy]quinazolin-4-amine


196
1,1-dimethylethyl 2-[3-({[4-[(3,4-dichlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]oxy}methyl)-1,2,4-oxadiazol-5-yl]piperidine-1-



carboxylate


197
1,1-dimethylethyl 4-[3-({[4-[(3,4-dichlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]oxy}methyl)-1,2,4-oxadiazol-5-yl]piperidine-1-



carboxylate


198
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(4-pyrrolidin-1-ylphenyl)-



1,3-thiazol-2-yl]methyl}oxy)quinazolin-4-amine


199
N-(3,4-dichlorophenyl)-7-[({4-[4-(diethylamino)phenyl]-1,3-thiazol-2-



yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine


200
5-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-



yl]oxy}methyl)-1,3-thiazol-4-yl]-2-hydroxybenzamide


201
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-pyridin-3-yl-1,3-thiazol-2-



yl)methyl]oxy}quinazolin-4-amine


202
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-pyridin-2-yl-1,3-thiazol-2-



yl)methyl]oxy}quinazolin-4-amine


203
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-pyridin-4-yl-1,3-thiazol-2-



yl)methyl]oxy}quinazolin-4-amine


204
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(2-morpholin-4-yl-1,3-thiazol-4-



yl)methyl]oxy}quinazolin-4-amine


205
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(3-morpholin-4-yl-1,2,4-



oxadiazol-5-yl)methyl]oxy}quinazolin-4-amine


206
N-(3,4-dichlorophenyl)-7-({[3-(dimethylamino)-1,2,4-oxadiazol-5-



yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine


207
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({4-[(4-methylpiperazin-1-



yl)methyl]-1,3-thiazol-2-yl}methyl)oxy]quinazolin-4-amine


208
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(4,5,6,7-



tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-ylmethyl)oxy]quinazolin-4-amine


209
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(morpholin-4-ylmethyl)-1,3-



thiazol-2-yl]methyl}oxy)quinazolin-4-amine


210
N-(3,4-dichlorophenyl)-7-[({4-[(4-methyl-1,4-diazepan-1-yl)methyl]-1,3-



thiazol-2-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine


211
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(5-



{[(phenylmethyl)oxy]methyl}-1,2,4-oxadiazol-3-yl)methyl]oxy}quinazolin-



4-amine


212
N-(3,4-dichlorophenyl)-7-{[(4-ethylmorpholin-2-yl)methyl]oxy}-6-



(methyloxy)quinazolin-4-amine


213
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(2-piperidin-4-yl-1,3-thiazol-4-



yl)methyl]oxy}quinazolin-4-amine


214
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[2-(1-methylpiperidin-4-yl)-1,3-



thiazol-4-yl]methyl}oxy)quinazolin-4-amine


215
1,1-dimethylethyl 4-[5-({[4-[(3,4-dichlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]oxy}methyl)-1,2,4-oxadiazol-3-yl]piperazine-



1-carboxylate


217
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(3-piperazin-1-yl-1,2,4-



oxadiazol-5-yl)methyl]oxy}quinazolin-4-amine


218
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[3-(4-methylpiperazin-1-yl)-



1,2,4-oxadiazol-5-yl]methyl}oxy)quinazolin-4-amine


219
N-(3,4-dichlorophenyl)-7-({[5-(1-ethylpiperidin-2-yl)-1,2,4-oxadiazol-3-



yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine


220
N-(3,4-dichlorophenyl)-7-({[3-(4-ethylpiperazin-1-yl)-1,2,4-oxadiazol-5-



yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine


221
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({5-[4-(methyloxy)phenyl]-1,2,4-



oxadiazol-3-yl}methyl)oxy]quinazolin-4-amine


222
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({2-[4-(trifluoromethyl)phenyl]-



1,3-thiazol-4-yl}methyl)oxy]quinazolin-4-amine


223
7-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}oxy)-N-(3,4-



dichlorophenyl)-6-(methyloxy)quinazolin-4-amine


224
N-(3,4-dichlorophenyl)-7-({[5-(3,5-dimethylisoxazol-4-yl)-1,2,4-oxadiazol-



3-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine


225
7-{[(5-chloro-1-benzothien-3-yl)methyl]oxy}-N-(3,4-dichlorophenyl)-6-



(methyloxy)quinazolin-4-amine


226
N-(3,4-dichlorophenyl)-7-[({3-[4-(1,1-dimethylethyl)phenyl]-1,2,4-



oxadiazol-5-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine


227
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({5-[2-(methyloxy)phenyl]-1,2,4-



oxadiazol-3-yl}methyl)oxy]quinazolin-4-amine


228
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[5-(4-methylphenyl)-1,3,4-



oxadiazol-2-yl]methyl}oxy)quinazolin-4-amine


229
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[1-(phenylmethyl)-1H-imidazol-



2-yl]methyl}oxy)quinazolin-4-amine


230
N-(3,4-dichlorophenyl)-7-({[3-(2,6-dichlorophenyl)-5-methylisoxazol-4-



yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine


231
N-(3,4-dichlorophenyl)-7-{[(6-fluoro-4H-1,3-benzodioxin-8-



yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine


232
7-{[(3,5-dibromophenyl)methyl]oxy}-N-(3,4-dichlorophenyl)-6-



(methyloxy)quinazolin-4-amine


233
N-(3,4-dichlorophenyl)-7-{[(2,6-difluorophenyl)methyl]oxy}-6-



(methyloxy)quinazolin-4-amine


234
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({3-[(pyridin-2-



ylsulfonyl)methyl]-1,2,4-oxadiazol-5-yl}methyl)oxy]quinazolin-4-amine


235
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(5-phenyl-1,2,4-oxadiazol-3-



yl)methyl]oxy}quinazolin-4-amine


236
7-({[4-chloro-2-(trifluoromethyl)quinolin-6-yl]methyl}oxy)-N-(3,4-



dichlorophenyl)-6-(methyloxy)quinazolin-4-amine


237
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[2-(1-methylpyrrolidin-2-



yl)ethyl]oxy}quinazolin-4-amine


238
N-(3,4-dichlorophenyl)-7-({[5-(1-ethylpiperidin-4-yl)-1,2,4-oxadiazol-3-



yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine


239
N-(3,4-dichlorophenyl)-7-({[5-(1-ethylpiperidin-3-yl)-1,2,4-oxadiazol-3-



yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine


240
N-(3,4-dichlorophenyl)-7-({[2-(dimethylamino)-1,3-thiazol-4-



yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine


241
N-(3,4-dichlorophenyl)-7-{[(4-ethyl-1,4-oxazepan-2-yl)methyl]oxy}-6-



(methyloxy)quinazolin-4-amine


242
N-(3,4-dichlorophenyl)-7-({[2-(1-ethylpiperidin-4-yl)-1,3-thiazol-4-



yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine


243
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({3-[(2S)-pyrrolidin-2-yl]-1,2,4-



oxadiazol-5-yl}methyl)oxy]quinazolin-4-amine


244
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({2-[(2S)-pyrrolidin-2-yl]-1,3-



thiazol-4-yl}methyl)oxy]quinazolin-4-amine


245
[4-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-



yl]oxy}methyl)-1,3-thiazol-2-yl]methyl benzoate


246
[4-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-



yl]oxy}methyl)-1,3-thiazol-2-yl]methanol


247
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(5-methyl-4,5,6,7-



tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)methyl]oxy}quinazolin-4-amine


248
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({2-[(4S)-1,3-thiazolidin-4-yl]-



1,3-thiazol-4-yl}methyl)oxy]quinazolin-4-amine


249
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(2-piperidin-2-yl-1,3-thiazol-4-



yl)methyl]oxy}quinazolin-4-amine


250
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[2-(1-methylpiperidin-2-yl)-1,3-



thiazol-4-yl]methyl}oxy)quinazolin-4-amine


251
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(2-piperidin-3-yl-1,3-thiazol-4-



yl)methyl]oxy}quinazolin-4-amine


252
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[2-(1-methylpiperidin-3-yl)-1,3-



thiazol-4-yl]methyl}oxy)quinazolin-4-amine


253
N-(3,4-dichlorophenyl)-7-({[2-(1-ethylpiperidin-2-yl)-1,3-thiazol-4-



yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine


254
N-(3,4-dichlorophenyl)-7-({[2-(1-ethylpiperidin-3-yl)-1,3-thiazol-4-



yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine


255
N-(3,4-dichlorophenyl)-7-[({3-[(2S)-1-ethylpyrrolidin-2-yl]-1,2,4-



oxadiazol-5-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine


256
N-(3,4-dichlorophenyl)-7-[({2-[(2S)-1-ethylpyrrolidin-2-yl]-1,3-thiazol-4-



yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine


257
N-(3,4-dichlorophenyl)-7-{[(5-ethyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-



c]pyridin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine


258
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-propyl-1,4-oxazepan-2-



yl)methyl]oxy}quinazolin-4-amine


259
7-({[4-(cyclopropylmethyl)-1,4-oxazepan-2-yl]methyl}oxy)-N-(3,4-



dichlorophenyl)-6-(methyloxy)quinazolin-4-amine


260
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({4-[2-(methyloxy)ethyl]-1,4-



oxazepan-2-yl}methyl)oxy]quinazolin-4-amine


261
N-(3,4-dichlorophenyl)-7-({[4-(1-methylethyl)-1,4-oxazepan-2-



yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine


262
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(2-piperazin-1-yl-1,3-thiazol-4-



yl)methyl]oxy}quinazolin-4-amine


263
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(5-pyrrolidin-2-yl-1,2,4-



oxadiazol-3-yl)methyl]oxy}quinazolin-4-amine


264
N-(3,4-dichlorophenyl)-7-({[5-(1-ethylpyrrolidin-2-yl)-1,2,4-oxadiazol-3-



yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine


265
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({3-[(2S)-1-methylpyrrolidin-2-



yl]-1,2,4-oxadiazol-5-yl}methyl)oxy]quinazolin-4-amine


266
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({2-[(2S)-1-methylpyrrolidin-2-



yl]-1,3-thiazol-4-yl}methyl)oxy]quinazolin-4-amine


267
N-(3,4-dichlorophenyl)-7-({[2-(4-ethylpiperazin-1-yl)-1,3-thiazol-4-



yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine


268
N-(3,4-dichlorophenyl)-7-{[(1,4-dimethylpiperazin-2-yl)methyl]oxy}-6-



(methyloxy)quinazolin-4-amine


269
7-{[(4-cyclopentylmorpholin-2-yl)methyl]oxy}-N-(3,4-dichlorophenyl)-6-



(methyloxy)quinazolin-4-amine


270
N-(3,4-dichlorophenyl)-7-({[4-(1-methylethyl)morpholin-2-yl]methyl}oxy)-



6-(methyloxy)quinazolin-4-amine


271
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(3-phenylpropyl)morpholin-



2-yl]methyl}oxy)quinazolin-4-amine


272
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({4-[2-



(methyloxy)ethyl]morpholin-2-yl}methyl)oxy]quinazolin-4-amine


273
ethyl 2-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-



yl]oxy}methyl)morpholin-4-yl]propanoate


274
N-(3,4-dichlorophenyl)-7-{[(4-hex-5-en-1-ylmorpholin-2-yl)methyl]oxy}-



6-(methyloxy)quinazolin-4-amine


275
2-({2-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-



yl]oxy}methyl)morpholin-4-yl]ethyl}oxy)ethanol


276
methyl 3-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-



yl]oxy}methyl)morpholin-4-yl]propanoate


277
6-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-



yl]oxy}methyl)morpholin-4-yl]hexanenitrile


278
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(tetrahydro-2H-pyran-2-



ylmethyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine


279
4-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-



yl]oxy}methyl)morpholin-4-yl]butanenitrile


280
N-(3,4-dichlorophenyl)-7-[({4-[(4-fluorophenyl)methyl]morpholin-2-



yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine


281
methyl 5-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-



yl]oxy}methyl)morpholin-4-yl]pentanoate


282
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-oct-7-en-1-ylmorpholin-2-



yl)methyl]oxy}quinazolin-4-amine


283
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-propylmorpholin-2-



yl)methyl]oxy}quinazolin-4-amine


284
6-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-



yl]oxy}methyl)morpholin-4-yl]hexan-1-ol


285
7-{[(4-acetylmorpholin-2-yl)methyl]oxy}-N-(3,4-dichlorophenyl)-6-



(methyloxy)quinazolin-4-amine


286
7-({[4-(cyclopropylmethyl)morpholin-2-yl]methyl}oxy)-N-(3,4-



dichlorophenyl)-6-(methyloxy)quinazolin-4-amine


287
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-prop-2-yn-1-ylmorpholin-2-



yl)methyl]oxy}quinazolin-4-amine


288
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-pyridin-4-ylmorpholin-2-



yl)methyl]oxy}quinazolin-4-amine


289
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(pyridin-2-



ylmethyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine


290
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-pent-2-yn-1-ylmorpholin-2-



yl)methyl]oxy}quinazolin-4-amine


291
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[2-(4-methylpiperazin-1-yl)-1,3-



thiazol-4-yl]methyl}oxy)quinazolin-4-amine


292
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[5-(1-methylpyrrolidin-2-yl)-



1,2,4-oxadiazol-3-yl]methyl}oxy)quinazolin-4-amine


293
N-(3-chloro-4-fluorophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-



(methyloxy)quinazolin-4-amine


294
7-{[(4-butyl-1,4-oxazepan-2-yl)methyl]oxy}-N-(3,4-dichlorophenyl)-6-



(methyloxy)quinazolin-4-amine


295
(3,4-dichlorophenyl)[7-(methyloxy)-6-({[4-(2-methylpropyl)-1,4-oxazepan-



2-yl]methyl}oxy)quinazolin-4-amine


296
7-{[(4-acetyl-1-ethylpiperazin-2-yl)methyl]oxy}-N-(3,4-dichlorophenyl)-6-



(methyloxy)quinazolin-4-amine


297
(3,4-dichlorophenyl)(6-(methyloxy)-7-{[(4-pentyl-1,4-oxazepan-2-



yl)methyl]oxy} quinazolin-4-amine


298
(3,4-dichlorophenyl)[6-(methyloxy)-7-({[4-(tetrahydro-2H-pyran-2-



ylmethyl)-1,4-oxazepan-2-yl]methyl}oxy)quinazolin-4-amine


299
(3,4-dichlorophenyl)[6-(methyloxy)-7-({[4-(3-thienylmethyl)-1,4-



oxazepan-2-yl]methyl}oxy) quinazolin-4-amine


300
N-[4-chloro-2,5-bis(methyloxy)phenyl]-7-{[(4-methylmorpholin-2-



yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine


301
N-(3-bromo-2-methylphenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-



(methyloxy)quinazolin-4-amine


302
7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)-N-(3,4,5-



trichlorophenyl)quinazolin-4-amine


303
N-(3-chloro-2-methylphenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-



(methyloxy)quinazolin-4-amine


304
N-(3,4-dichlorophenyl)-7-{[(4-ethanimidoyl-1,4-oxazepan-2-



yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine


305
N-(4-bromo-2-fluorophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-



(methyloxy)quinazolin-4-amine


306
N-(5-chloro-2-fluorophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-



(methyloxy)quinazolin-4-amine


307
N-(4-chloro-2-fluorophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-



(methyloxy)quinazolin-4-amine


308
N-(2,4-dichlorophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-



(methyloxy)quinazolin-4-amine


309
N-(2,4-dibromophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-



(methyloxy)quinazolin-4-amine


310
7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)-N-(2,3,4-



trichlorophenyl)quinazolin-4-amine


311
N-(3,4-dichlorophenyl)-7-{[(1-ethyl-4-methylpiperazin-2-yl)methyl]oxy}-



6-(methyloxy)quinazolin-4-amine


312
N′-cyano-2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-



yl]oxy}methyl)morpholine-4-carboximidamide


313
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[2-(pyrrolidin-1-ylmethyl)-1,3-



thiazol-4-yl]methyl}oxy)quinazolin-4-amine


314
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(tetrahydro-2H-pyran-4-



yl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine


315
N-(3,4-dichlorophenyl)-7-({[4-(2-ethylbutyl)morpholin-2-yl]methyl}oxy)-



6-(methyloxy)quinazolin-4-amine


316
7-({[4-(cyclohexylmethyl)morpholin-2-yl]methyl}oxy)-N-(3,4-



dichlorophenyl)-6-(methyloxy)quinazolin-4-amine


317
2-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-



yl]oxy}methyl)morpholin-4-yl]ethanol


318
7-{[(4-but-2-yn-1-ylmorpholin-2-yl)methyl]oxy}-N-(3,4-dichlorophenyl)-6-



(methyloxy)quinazolin-4-amine


319
7-{[(4-cyclobutylmorpholin-2-yl)methyl]oxy}-N-(3,4-dichlorophenyl)-6-



(methyloxy)quinazolin-4-amine


320
N-(3,4-dichlorophenyl)-7-[({4-[2-(1,3-dioxolan-2-yl)ethyl]morpholin-2-



yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine


321
7-({[4-(2-cyclohexylethyl)morpholin-2-yl]methyl}oxy)-N-(3,4-



dichlorophenyl)-6-(methyloxy)quinazolin-4-amine


322
N-(3,4-dichlorophenyl)-7-[({4-[2-(1,3-dioxan-2-yl)ethyl]morpholin-2-



yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine


323
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-pent-4-en-1-ylmorpholin-2-



yl)methyl]oxy}quinazolin-4-amine


324
N-(3,4-dichlorophenyl)-7-[({4-[(2R)-2-methylbutyl]morpholin-2-



yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine


325
N-(3,4-dichlorophenyl)-7-({[4-(4-fluorobutyl)morpholin-2-yl]methyl}oxy)-



6-(methyloxy)quinazolin-4-amine


326
3-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-



yl]oxy}methyl)morpholin-4-yl]butan-2-one


327
1-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-



yl]oxy}methyl)morpholin-4-yl]butan-2-one


328
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-pentylmorpholin-2-



yl)methyl]oxy}quinazolin-4-amine


329
N-(3,4-dichlorophenyl)-7-{[(4-hexylmorpholin-2-yl)methyl]oxy}-6-



(methyloxy)quinazolin-4-amine


330
N-(3,4-dichlorophenyl)-7-{[(4-heptylmorpholin-2-yl)methyl]oxy}-6-



(methyloxy)quinazolin-4-amine


331
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-octylmorpholin-2-



yl)methyl]oxy}quinazolin-4-amine


332
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(2-phenylethyl)morpholin-2-



yl]methyl}oxy)quinazolin-4-amine


333
7-{[(4-butylmorpholin-2-yl)methyl]oxy}-N-(3,4-dichlorophenyl)-6-



(methyloxy)quinazolin-4-amine


334
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-prop-2-en-1-ylmorpholin-2-



yl)methyl]oxy}quinazolin-4-amine


335
2-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-



yl]oxy}methyl)morpholin-4-yl]-1-phenylethanone


336
N-(3,4-dichlorophenyl)-7-({[4-(2-fluoroethyl)morpholin-2-yl]methyl}oxy)-



6-(methyloxy)quinazolin-4-amine


337
N-(3,4-dichlorophenyl)-7-({[4-(3-methylbut-2-en-1-yl)morpholin-2-



yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine


338
7-[({4-[(2E)-3-bromoprop-2-en-1-yl]morpholin-2-yl}methyl)oxy]-N-(3,4-



dichlorophenyl)-6-(methyloxy)quinazolin-4-amine


339
2-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-



yl]oxy}methyl)morpholin-4-yl]acetamide


340
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({4-[3-(tetrahydro-2H-pyran-2-



yloxy)propyl]-1,4-oxazepan-2-yl}methyl)oxy]quinazolin-4-amine


341
N-(3,4-dichlorophenyl)-7-({[4-(3-methylbutyl)-1,4-oxazepan-2-



yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine


342
7-({[4-(cyclohexylmethyl)-1,4-oxazepan-2-yl]methyl}oxy)-4-[(3,4-



dichlorophenyl)methyl]-6-(methyloxy)quinazoline


343
7-({[4-(2-cyclohexylethyl)-1,4-oxazepan-2-yl]methyl}oxy)-4-[(3,4-



dichlorophenyl)methyl]-6-(methyloxy)quinazoline


345
N-(3,4-dichlorophenyl)-7-({[4-(2-ethylbutyl)-1,4-oxazepan-2-



yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine


346
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(methylsulfonyl)-1,4-



oxazepan-2-yl]methyl}oxy)quinazolin-4-amine


347
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(1-methylpiperidin-4-



yl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine


348
N-(3-chloro-2-fluorophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-



(methyloxy)quinazolin-4-amine


349
N′-cyano-2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-



yl]oxy}methyl)-1,4-oxazepane-4-carboximidamide


350
N-(3-bromo-4-methylphenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-



(methyloxy)quinazolin-4-amine


351
N-(3,4-dichlorophenyl)-7-{[(1,4-diethylpiperazin-2-yl)methyl]oxy}-6-



(methyloxy)quinazolin-4-amine


352
4-({[4-[(4-bromo-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-



yl]oxy}methyl)-N′-cyanopiperidine-1-carboximidamide


353
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(methylsulfonyl)morpholin-2-



yl]methyl}oxy)quinazolin-4-amine


354
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({4-



[(phenylmethyl)sulfonyl]morpholin-2-yl}methyl)oxy]quinazolin-4-amine


355
N-(3,4-dichlorophenyl)-7-[({4-[(4-fluorophenyl)sulfonyl]morpholin-2-



yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine


356
N-(3,4-dichlorophenyl)-7-({[4-(ethylsulfonyl)morpholin-2-yl]methyl}oxy)-



6-(methyloxy)quinazolin-4-amine


357
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(phenylsulfonyl)morpholin-2-



yl]methyl}oxy)quinazolin-4-amine


358
7-[({4-[(3-chloropropyl)sulfonyl]morpholin-2-yl}methyl)oxy]-N-(3,4-



dichlorophenyl)-6-(methyloxy)quinazolin-4-amine


359
7-({[4-(butylsulfonyl)morpholin-2-yl]methyl}oxy)-N-(3,4-dichlorophenyl)-



6-(methyloxy)quinazolin-4-amine


360
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({4-[(4-



methylphenyl)sulfonyl]morpholin-2-yl}methyl)oxy]quinazolin-4-amine


361
N-(3,4-dichlorophenyl)-7-[({4-[(3,5-dimethylisoxazol-4-



yl)carbonyl]morpholin-2-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine


362
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-{[3-



(methyloxy)phenyl]acetyl}morpholin-2-yl)methyl]oxy}quinazolin-4-amine


363
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(2-



methylpentanoyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine


364
7-[({4-[(4-butylphenyl)carbonyl]morpholin-2-yl}methyl)oxy]-N-(3,4-



dichlorophenyl)-6-(methyloxy)quinazolin-4-amine


365
7-[({4-[(4-chlorophenyl)acetyl]morpholin-2-yl}methyl)oxy]-N-(3,4-



dichlorophenyl)-6-(methyloxy)quinazolin-4-amine


366
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(2-



propylpentanoyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine


367
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(4-



methylpentanoyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine


368
N-(3,4-dichlorophenyl)-7-[({4-[(2,5-difluorophenyl)carbonyl]morpholin-2-



yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine


369
7-({[4-(cyclopentylcarbonyl)morpholin-2-yl]methyl}oxy)-N-(3,4-



dichlorophenyl)-6-(methyloxy)quinazolin-4-amine


370
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(2-



phenylbutanoyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine


371
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({4-[(2,3,6-



trifluorophenyl)carbonyl]morpholin-2-yl}methyl)oxy]quinazolin-4-amine


372
N-(3,4-dichlorophenyl)-7-({[4-(furan-3-ylcarbonyl)morpholin-2-



yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine


373
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-propanoylmorpholin-2-



yl)methyl]oxy}quinazolin-4-amine


374
N-(3,4-dichlorophenyl)-7-{[(4-hexanoylmorpholin-2-yl)methyl]oxy}-6-



(methyloxy)quinazolin-4-amine


375
N-(3,4-dichlorophenyl)-7-({[4-(2-ethylhexanoyl)morpholin-2-



yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine


376
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(3-



phenylpropanoyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine


377
N-(3,4-dichlorophenyl)-7-({[4-(2,2-dimethylpropanoyl)morpholin-2-



yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine


378
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(naphthalen-1-



ylcarbonyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine


379
7-[({4-[(2-chloropyridin-3-yl)carbonyl]morpholin-2-yl}methyl)oxy]-N-



(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine


380
7-[({4-[(6-chloropyridin-3-yl)carbonyl]morpholin-2-yl}methyl)oxy]-N-



(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine


381
7-({[4-(1,3-benzodioxol-5-ylcarbonyl)morpholin-2-yl]methyl}oxy)-N-(3,4-



dichlorophenyl)-6-(methyloxy)quinazolin-4-amine


382
N-(3,4-dichlorophenyl)-6-[(1-methylethyl)oxy]-7-[(morpholin-2-



ylmethyl)oxy]quinazolin-4-amine


383
N-(3,4-dichlorophenyl)-6-{[2-(methyloxy)ethyl]oxy}-7-[(morpholin-2-



ylmethyl)oxy]quinazolin-4-amine


384
N-(3,4-dichlorophenyl)-6-(ethyloxy)-7-[(morpholin-2-



ylmethyl)oxy]quinazolin-4-amine


385
N-(3,4-dichlorophenyl)-6-(ethyloxy)-7-{[(4-methylmorpholin-2-



yl)methyl]oxy}quinazolin-4-amine


386
N-(4-bromo-2-methylphenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-



(methyloxy)quinazolin-4-amine


387
N-(4-chloro-3-methylphenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-



(methyloxy)quinazolin-4-amine


388
N′-cyano-2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-



yl]oxy}methyl)-N-methylmorpholine-4-carboximidamide


389
N-(4-bromo-3-chlorophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-



(methyloxy)quinazolin-4-amine


390
N-(3,4-dichlorophenyl)-6-[(1-methylethyl)oxy]-7-{[(4-methylmorpholin-2-



yl)methyl]oxy}quinazolin-4-amine


391
N-(3,4-dichlorophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-{[2-



(methyloxy)ethyl]oxy}quinazolin-4-amine


392
N-(4-bromo-2-chlorophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-



(methyloxy)quinazolin-4-amine


393
7-{[(4-acetyl-1,4-oxazepan-2-yl)methyl]oxy}-N-(3,4-dichlorophenyl)-6-



(methyloxy)quinazolin-4-amine


394
4-[(3,4-dichlorophenyl)amino]-7-{[(4-methylmorpholin-2-



yl)methyl]oxy}quinazolin-6-ol


395
N-(3-bromo-4-chlorophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-



(methyloxy)quinazolin-4-amine


396
3-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-



yl]oxy}methyl)morpholin-4-yl]-3-oxopropanoic acid


397
methyl 4-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-



yl]oxy}methyl)morpholin-4-yl]-4-oxobutanoate


398
N-(3,4-dichlorophenyl)-7-{[(4-methylmorpholin-3-yl)methyl]oxy}-6-



(methyloxy)quinazolin-4-amine


399
N-(3-bromo-2-chlorophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-



(methyloxy)quinazolin-4-amine


400
N′-cyano-2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-



yl]oxy}methyl)-N-[2-(methyloxy)ethyl]morpholine-4-carboximidamide


401
N′-cyano-2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-



yl]oxy}methyl)-N-ethylmorpholine-4-carboximidamide


402
[(1E)-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-



yl]oxy}methyl)morpholin-4-yl](piperidin-1-yl)methylidene]cyanamide


403
[(1E)-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-



yl]oxy}methyl)morpholin-4-yl](pyrrolidin-1-yl)methylidene]cyanamide


404
[(1E)-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-



yl]oxy}methyl)morpholin-4-yl](4-methylpiperazin-1-



yl)methylidene]cyanamide


405
N-(3,4-dichlorophenyl)-7-{[(6-ethyl-4,6-dimethylmorpholin-2-



yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine


406
N-(4-bromo-3-methylphenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-



(methyloxy)quinazolin-4-amine


407
N-(3,4-dichlorophenyl)-7-{[(6,6-dimethylmorpholin-2-yl)methyl]oxy}-6-



(methyloxy)quinazolin-4-amine


408
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4,6,6-trimethylmorpholin-2-



yl)methyl]oxy}quinazolin-4-amine


409
N-(3,4-dichlorophenyl)-7-{[2-(5,5-dimethylmorpholin-2-yl)ethyl]oxy}-6-



(methyloxy)quinazolin-4-amine


410
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[2-(4,5,5-trimethylmorpholin-2-



yl)ethyl]oxy}quinazolin-4-amine


411
1,1-dimethylethyl 2-(2-{[4-[(3,4-dichlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]oxy}ethyl)-5,5-dimethylmorpholine-4-



carboxylate


412
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4,5,5-trimethylmorpholin-2-



yl)methyl]oxy}quinazolin-4-amine


413
N-(4-bromo-2,3-dichlorophenyl)-7-{[(4-methylmorpholin-2-



yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine


414
N-(4,5-dichloro-2-fluorophenyl)-7-{[(4-methylmorpholin-2-



yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine


415
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[2-(4,6,6-trimethylmorpholin-2-



yl)ethyl]oxy}quinazolin-4-amine


416
N-(4-bromo-2,3-difluorophenyl)-7-{[(4-methylmorpholin-2-



yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine


417
N-(4-bromo-2,5-difluorophenyl)-7-{[(4-methylmorpholin-2-



yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine


418
N-(4-bromo-3,5-difluorophenyl)-7-{[(4-methylmorpholin-2-



yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine


419
N-(3,4-dichloro-2-methylphenyl)-7-{[(4-methylmorpholin-2-



yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine


420
N-(3,4-dichlorophenyl)-7-({[(2R,5S,6S)-5,6-dimethylmorpholin-2-



yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine


421
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[(2R,5S,6S)-4,5,6-



trimethylmorpholin-2-yl]methyl}oxy)quinazolin-4-amine


422
N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[(2S,5S,6S)-4,5,6-



trimethylmorpholin-2-yl]methyl}oxy)quinazolin-4-amine


423
N-(4-bromo-3-chloro-2-methylphenyl)-7-{[(4-methylmorpholin-2-



yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine


424
N-(4-bromo-5-chloro-2-fluorophenyl)-7-{[(4-methylmorpholin-2-



yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine


425
N-(4-bromo-3-chloro-2-fluorophenyl)-7-{[(4-methylmorpholin-2-



yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine


426
N-(3,4-dichloro-2-fluorophenyl)-7-{[(4-methylmorpholin-2-



yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine


427
N-(3-chloro-2,4-difluorophenyl)-7-{[(4-methylmorpholin-2-



yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine


428
N-(2,3-dichloro-4-methylphenyl)-7-{[(4-methylmorpholin-2-



yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine


429
6-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-



yl]oxy}methyl)-3,3,4-trimethylmorpholin-2-one


430
N-(4-bromo-2,3-dichlorophenyl)-6-(methyloxy)-7-{[(4,5,5-



trimethylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine


431
N-(4-bromo-5-chloro-2-fluorophenyl)-6-(methyloxy)-7-{[(4,5,5-



trimethylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine


432
N-(4,5-dichloro-2-fluorophenyl)-6-(methyloxy)-7-{[(4,5,5-



trimethylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine


433
N-(3,4-dichloro-2-fluorophenyl)-6-(methyloxy)-7-{[(4,5,5-



trimethylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine


434
N-(4-bromo-3-chloro-2-fluorophenyl)-6-(methyloxy)-7-{[(4,5,5-



trimethylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine


435
N-(3-chloro-2,4-difluorophenyl)-6-(methyloxy)-7-{[(4,5,5-



trimethylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine


436
(6S)-6-({[4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]oxy}methyl)-4-methylpiperazin-2-one


437
(6S)-6-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-



7-yl]oxy}methyl)-4-methylpiperazin-2-one


438
(6S)-6-({[4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]oxy}methyl)-1,4-dimethylpiperazin-2-one


439
(6S)-6-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-



7-yl]oxy}methyl)-1,4-dimethylpiperazin-2-one


440
N-(4-bromo-3-chlorophenyl)-7-{[(3a′S,4R,6′S,6a′R)-2,2-



dimethyltetrahydrospiro[1,3-dioxolane-4,3′-furo[3,2-b]furan]-6′-yl]oxy}-6-



(methyloxy)quinazolin-4-amine


441
1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-5-O-methyl-5-C-[(methyloxy)methyl]-L-



glucitol


442
1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-5-O-(methylsulfonyl)-L-glucitol


443
1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-L-glucitol


444
1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-5-S-methyl-5-thio-D-iditol


445
1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-morpholin-4-yl-D-iditol


446
1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-(4-methylpiperazin-1-yl)-D-iditol


447
1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-pyrrolidin-1-yl-D-iditol


448
2-O-acetyl-1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-D-iditol


449
1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-D-iditol


450
1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-(methylsulfonyl)-D-iditol


451
2-amino-1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-D-iditol


452
1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-(dimethylamino)-D-iditol


453
1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-(diethylamino)-D-iditol


454
1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-piperidin-1-yl-D-iditol


455
2-(acetylamino)-1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-



chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-D-iditol


456
1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-5-O-methyl-5-C-(trifluoromethyl)-L-glucitol


457
1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-[(methylsulfonyl)amino]-D-iditol


458
N-(4-bromo-3-chlorophenyl)-6-(methyloxy)-7-[(1-methylpyrrolidin-3-



yl)oxy]quinazolin-4-amine


459
N-(4-bromo-3-chlorophenyl)-6-(methyloxy)-7-[(3R)-tetrahydrofuran-3-



yloxy]quinazolin-4-amine


460
N-(4-bromo-3-chlorophenyl)-6-(methyloxy)-7-{[(3S,4R)-4-



(methyloxy)tetrahydrofuran-3-yl]oxy}quinazolin-4-amine


461
1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-(6-(methyloxy)-4-{[4-(4-



methylpiperazin-1-yl)phenyl]amino}quinazolin-7-yl)-D-iditol


462
1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-[4-{[3-fluoro-4-(4-



methylpiperazin-1-yl)phenyl]amino}-6-(methyloxy)quinazolin-7-yl]-D-



iditol


463
1,4:3,6-dianhydro-2-deoxy-5-O-[4-{[2,3-dichloro-4-(4-methylpiperazin-1-



yl)phenyl]amino}-6-(methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol


464
1,4:3,6-dianhydro-2-deoxy-5-O-[4-{[3,4-dichloro-2-(4-methylpiperazin-1-



yl)phenyl]amino}-6-(methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol


465
1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-5-C-(trifluoromethyl)-D-glucitol


466
(3,4-dichlorophenyl)[6-(methyloxy)-7-({[4-(tetrahydrofuran-2-ylmethyl)-



1,4-oxazepan-2-yl]methyl}oxy)quinazolin-4-amine


467
N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-



methyloctahydrocyclopenta-[c]pyrrol-5-yl]methyl}oxy)-6-



(methyloxy)quinazolin-4-amine


468
N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-



methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-



(methyloxy)quinazolin-4-amine


469
N-(3-chloro-2,4-difluorophenyl)-7-({[(3aR,5r,6aS)-2-



methyloctahydrocyclopenta-[c]pyrrol-5-yl]methyl}oxy)-6-



(methyloxy)quinazolin-4-amine


470
N-(4,5-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-



methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-



(methyloxy)quinazolin-4-amine


471
N-(4-bromo-5-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-



methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-



(methyloxy)quinazolin-4-amine


472
N-(4-bromo-2,3-dichlorophenyl)-7-({[(3aR,5r,6aS)-2-



methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-



(methyloxy)quinazolin-4-amine


473
N-(3,4-dichlorophenyl)-7-({[(3aR,5r,6aS)-2-



methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-



(methyloxy)quinazolin-4-amine


474
N-(3,4-dichlorophenyl)-7-[(2-{[(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-



3-yl]amino}ethyl)oxy]-6-(methyloxy)quinazolin-4-amine


475
N-(3,4-dichlorophenyl)-7-({2-[(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-



yl]ethyl}oxy)-6-(methyloxy)quinazolin-4-amine


476
N-(3,4-dichlorophenyl)-7-({[(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-



yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine


477
N-(3,4-dichlorophenyl)-7-{[(3-exo)-8-methyl-8-azabicyclo[3.2.1]oct-3-



yl]oxy}-6-(methyloxy)quinazolin-4-amine


478
1,4:3,6-Dianhydro-5-O-[4-[(3,4-dichlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-O-methyl-D-glucitol


479
1,4:3,6-dianhydro-5-O-{4-[(3-chloro-2-fluorophenyl)amino]-6-



(methyloxy)quin-azolin-7-yl}-2-deoxy-2-fluoro-L-iditol


480
1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-5-O-(methylsulfonyl)-D-glucitol


481
1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-D-glucitol


482
1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-5-S-methyl-5-thio-L-iditol


483
1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-morpholin-4-yl-L-iditol


484
1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-(4-methylpiperazin-1-yl)-L-iditol


485
1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-pyrrolidin-1-yl-L-iditol


486
2-O-acetyl-1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-L-iditol


487
1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-L-iditol


488
1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-(methylsulfonyl)-L-iditol


489
2-amino-1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-L-iditol


490
1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-(dimethylamino)-L-iditol


491
1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-(diethylamino)-L-iditol


492
1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-piperidin-1-yl-L-iditol


493
2-(acetylamino)-1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-



chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-L-iditol


494
1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-5-O-methyl-5-C-(trifluoromethyl)-D-glucitol


495
1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-deoxy-2-[(methylsulfonyl)amino]-L-iditol


496
1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-(6-(methyloxy)-4-{[4-(4-



methylpiperazin-1-yl)phenyl]amino}quinazolin-7-yl)-L-iditol


497
1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-[4-{[3-fluoro-4-(4-



methylpiperazin-1-yl)phenyl]amino}-6-(methyloxy)quinazolin-7-yl]-L-



iditol


498
1,4:3,6-dianhydro-2-deoxy-5-O-[4-{[2,3-dichloro-4-(4-methylpiperazin-1-



yl)phenyl]amino}-6-(methyloxy)quinazolin-7-yl]-2-fluoro-L-iditol


499
1,4:3,6-dianhydro-2-deoxy-5-O-[4-{[3,4-dichloro-2-(4-methylpiperazin-1-



yl)phenyl]amino}-6-(methyloxy)quinazolin-7-yl]-2-fluoro-L-iditol


500
1,4:3,6-Dianhydro-5-O-[4-[(3,4-dichlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-2-O-methyl-D-glucitol


501
1,4:3,6-Dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-



(methyloxy)quinazolin-7-yl]-5-O-methyl-L-glucitol









Representative IGF-1R Inhibitors
The Compounds in Table 5a can be prepared as pharmaceutically acceptable salts, solvates, hydrates, and/or isomers thereof. All such salt, solvate, hydrate, and isomer combinations of the Compounds in Table 5a can be used to practice the invention.








TABLE 5a





Entry
Structure







 1






 


 2






 


 3






 


 4






 


 5






 


 6






 


 7






 


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 9






 


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 93






 


 94






 


 95






 


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 97






 


 98






 


 99






 


100






 


101






 


102






 


103






 


104






 


105






 


106






 


107






 


108






 


109






 


110






 


111






 


112






 


113






 


114






 


115






 


116






 


117






 


118






 


119






 


120






 


121






 


122






 


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124






 


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131






 


132






 


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134






 


135






 


136






 


137






 


138






 


139






 


140






 


141






 


142






 


143






 


144






 


145






 


146






 


147






 


148






 


149






 


150






 


151






 


152






 


153






 


154






 


155






 


156






 


157






 


158






 


159






 


160






 


161






 


162






 


163






 


164






 


165






 


166






 


167






 


168






 


169






 


170






 


171






 


172






 


173






 


174






 


175






 


176






 


177






 


178






 


179






 


180






 


181






 


182






 


183






 


184






 


185






 


186






 


187






 


188






 


189






 


190






 


191






 


192






 


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195






 


196






 


197






 


198






 


199






 


200






 


201






 


202






 


203






 


204






 


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210






 


211






 


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214






 


215






 


216






 


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218






 


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220






 


221






 


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224






 


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227






 


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232






 


233






 


234






 


235






 


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237






 


238






 


239






 


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241






 


242






 


243






 


244






 


245






 


246






 


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248






 


249






 


250






 


251






 


252






 


253






 


254






 


255






 


256






 


257






 


258






 


259






 


260






 


261






 


262






 


263






 


264






 


265






 


266






 


267






 


268






 


269






 


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283






 


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304






 


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315






 


316






 


317






 


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326






 


327






 


328






 


329






 


330






 


331






 


332






 


333






 


334






 


335






 


336






 


337






 


338






 


339






 


340






 


341






 


342






 


343






 


344






 


345






 


346






 


347






 


348






 


349






 


350






 


351






 


352






 


353






 


354






 


355






 


356






 


357






 


358






 


495






 


496






 


497






 


498






 


499






 


500






 


501






 


502






 


503






 


504






 


505






 


506






 


507






 


508






 


509






 


510






 


511






 


512






 


513






 


514






 


515






 


516






 


517






 


518






 


519






 


520






 


521






 


522






 


523






 


524






 


525






 


526






 


527






 


528






 


529






 


530






 


531






 


532






 


533






 


534






 


535






 


536






 


537






 


538






 


539






 


540






 


541






 


542






 


543






 


544






 


545






 


546






 


547






 


548






 


549






 


550






 


551






 


552






 


553






 


554






 


555






 


556






 


557






 


558






 


559






 


560






 


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570






 


571






 


572













Table 5b
Additional Representative IGF1R Inhibitors
The Compounds in Table 5b can be prepared as pharmaceutically acceptable salts, solvates, hydrates, and/or isomers thereof. All such salt, solvate, hydrate, and isomer combinations of the Compounds in Table 5b can be used to practice the invention.









TABLE 5b





Entry
Structure
Name







573




N4-(5-cyclopropyl-1H-pyrazol-3- yl)-N6-[3-(diethylamino)propyl]- N2-{[3-(1-methylethyl)isoxazol- 5-yl]methyl}pyrimidine-2,4,6- triamine


 


574




N4-(5-cyclopropyl-1H-pyrazol-3- yl)-N6-[2-(diethylamino)ethyl]- N2-{[3-(1-methylethyl)isoxazol- 5-yl]methyl}pyrimidine-2,4,6- triamine


 


575




N2-{[3-(1-methylethyl)isoxazol- 5-yl]methyl}-N4-[5-(1- methylethyl)-1H-pyrazol-3-yl]-6- [(3S)-3-methylpiperazin-1- yl]pyrimidine-2,4-diamine


 


576




N4-(5-cyclopropyl-1H-pyrazol-3- yl)-6-{[2- (dimethylamino)ethyl]oxy}-N2- {[3-(1-methylethyl)isoxazol-5- yl]methyl}pyrimidine-2,4- diamine


 


577




N4-[3-(1-methylethyl)-1H- pyrazol-5-yl]-6-[(1- methylpyrrolidin-3-yl)oxy]-N2- [(3-phenylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine


 


578




N4-(3-cyclopropyl-1H-pyrazol-5- yl)-N2-{[3-(1- methylethyl)isoxazol-5- yl]methyl}-6-[(1- methylpyrrolidin-3- yl)oxy]pyrimidine-2,4-diamine


 


579




N2-{[3-(1-methylethyl)isoxazol- 5-yl]methyl}-N4-[3-(1- methylethyl)-1H-pyrazol-5-yl]-6- [(1-methylpyrrolidin-3- yl)oxy]pyrimidine-2,4-diamine


 


580




N4-[2-(diethylamino)ethyl]-N2- {[3-(1-methylethyl)isoxazol-5- yl]methyl}-N6-[5-(1- methylethyl)-1H-pyrazol-3- yl]pyrimidine-2,4,6-triamine


 


581




N2-{[3-(1-methylethyl)isoxazol- 5-yl]methyl}-N4-[5-(1- methylethyl)-1H-pyrazol-3- yl]pyrimidine-2,4-diamine


 


582




N4-[5-(1-methylethyl)-1H- pyrazol-3-yl]-6-[(1- methylpiperidin-3-yl)oxy]-N2- [(3-phenylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine


 


583




N2-{[3-(1-methylethyl)isoxazol- 5-yl]methyl}-N4-[5-(1- methylethyl)-1H-pyrazol-3-yl]-6- [(1-methylpiperidin-3- yl)oxy]pyrimidine-2,4-diamine


 


584




N-(5-cyclopropyl-1H-pyrazol-3- yl)-6-methyl-2-{[(3- phenylisoxazol-5- yl)methyl]oxy}pyrimidin-4- amine


 


585




N4-(5-cyclopropyl-1H-pyrazol-3- yl)-6-methyl-N2-[(4-phenyl-1H- imidazol-2- yl)methyl]pyrimidine-2,4- diamine


 


586




6-{[2- (dimethylamino)ethyl]oxy}-N2- {[3-(1-methylethyl)isoxazol-5- yl]methyl}-N4-[5-(1- methylethyl)-1H-pyrazol-3- yl]pyrimidine-2,4-diamine


 


587




N2-{[3-(1-methylethyl)isoxazol- 5-yl]methyl}-N4-[5-(1- methylethyl)-1H-pyrazol-3-yl]-6- [(2-morpholin-4- ylethyl)oxy]pyrimidine-2,4- diamine


 


588




N4-[5-(1-methylethyl)-1H- pyrazol-3-yl]-6-[(2-morpholin-4- ylethyl)oxy]-N2-[(3- phenylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine


 


589




N4-[3-(1-methylethyl)-1H- pyrazol-5-yl]-N2-[(3- phenylisoxazol-5-yl)methyl]-6- [(2-piperidin-1- ylethyl)oxy]pyrimidine-2,4- diamine


 


590




N4-[3-(diethylamino)propyl]-N2- {[3-(1-methylethyl)isoxazol-5- yl]methyl}-N6-[5-(1- methylethyl)-1H-pyrazol-3- yl]pyrimidine-2,4,6-triamine


 


591




N4-[5-(1-methylethyl)-1H- pyrazol-3-yl]-6-[(3S)-3- methylpiperazin-1-yl]-N2-[(3- phenylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine


 


592




N4-[2-(diethylamino)ethyl]-N6- [5-(1-methylethyl)-1H-pyrazol-3- yl]-N2-[(3-phenylisoxazol-5- yl)methyl]pyrimidine-2,4,6- triamine


 


593




N4-[5-(1-methylethyl)-1H- pyrazol-3-yl]-6-[(1- methylpiperidin-4-yl)oxy]-N2- [(3-phenylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine


 


594




N4-(5-cyclopropyl-1H-pyrazol-3- yl)-N2-{[3-(1- methylethyl)isoxazol-5- yl]methyl}-6-[(2-morpholin-4- ylethyl)oxy]pyrimidine-2,4- diamine


 


595




N2-{[3-(1-methylethyl)isoxazol- 5-yl]methyl}-N4-[3-(1- methylethyl)-1H-pyrazol-5-yl]-6- [(2-piperidin-1- ylethyl)oxy]pyrimidine-2,4- diamine


 


596




N4-(3-cyclopropyl-1H-pyrazol-5- yl)-6-[3-(diethylamino)propyl]- N2-[(3-phenylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine


 


597




N4-(3-cyclopropyl-1H-pyrazol-5- yl)-N2-{[3-(1- methylethyl)isoxazol-5- yl]methyl}-6-[(2-piperidin-1- ylethyl)oxy]pyrimidine-2,4- diamine


 


598




N4-(5-cyclopropyl-1H-pyrazol-3- yl)-N2-{[3-(1- methylethyl)isoxazol-5- yl]methyl}-6-[(1- methylpiperidin-3- yl)oxy]pyrimidine-2,4-diamine


 


599




N2-{[3-(1-methylethyl)isoxazol- 5-yl]methyl}-N4-[3-(1- methylethyl)-1H-pyrazol-5-yl]-6- [(1-methylpiperidin-4- yl)oxy]pyrimidine-2,4-diamine


 


600




N4-(3-cyclopropyl-1H-pyrazol-5- yl)-6-methyl-N2-[(3- methylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine


 


601




N4-(3-cyclopropyl-1H-pyrazol-5- yl)-N2-[(3-methylisoxazol-5- yl)methyl]-6-morpholin-4- ylpyrimidine-2,4-diamine


 


602




N4-(3-cyclopropyl-1H-pyrazol-5- yl)-N2-[(3-methylisoxazol-5- yl)methyl]-6-(4-methylpiperazin- 1-yl)pyrimidine-2,4-diamine


 


603




N4-(5-cyclopropyl-1H-pyrazol-3- yl)-N2-{[3-(1- methylethyl)isoxazol-5- yl]methyl}-6-[(1- methylpiperidin-4- yl)oxy]pyrimidine-2,4-diamine


 


604




N4-(3-cyclopropyl-1H-pyrazol-5- yl)-N2-{[3-(4- fluorophenyl)isoxazol-5- yl]methyl}-6-morpholin-4- ylpyrimidine-2,4-diamine


 


605




N4-(3-cyclopropyl-1H-pyrazol-5- yl)-N2-{[3-(4- fluorophenyl)isoxazol-5- yl]methyl}-6-(4-methylpiperazin- 1-yl)pyrimidine-2,4-diamine


 


606




N4-(3-cyclopropyl-1H-pyrazol-5- yl)-N2-{[3-(4- fluorophenyl)isoxazol-5- yl]methyl}-6-[(2-morpholin-4- ylethyl)oxy]pyrimidine-2,4- diamine


 


607




N2-{[3-(4-fluorophenyl)isoxazol- 5-yl]methyl}-N4-[3-(1- methylethyl)-1H-pyrazol-5-yl]-6- morpholin-4-ylpyrimidine-2,4- diamine


 


608




N2-{[3-(4-fluorophenyl)isoxazol- 5-yl]methyl}-N4-[3-(1- methylethyl)-1H-pyrazol-5-yl]-6- (4-methylpiperazin-1- yl)pyrimidine-2,4-diamine


 


609




N2-{[3-(4-fluorophenyl)isoxazol- 5-yl]methyl}-N4-[3-(1- methylethyl)-1H-pyrazol-5-yl]-6- [(2-morpholin-4- ylethyl)oxy]pyrimidine-2,4- diamine


 


610




N4-(5-cyclopropyl-1H-pyrazol-3- yl)-6-methyl-N2-[(3-pyridin-3- ylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine


 


611




N4-(5-cyclopropyl-1H-pyrazol-3- yl)-6-(4-methylpiperazin-1-yl)- N2-[(3-pyridin-2-ylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine


 


612




N4-(5-cyclopropyl-1H-pyrazol-3- yl)-6-morpholin-4-yl-N2-[(3- pyridin-2-ylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine


 


613




N4-(5-cyclopropyl-1H-pyrazol-3- yl)-N2-{[3-(1- methylethyl)isoxazol-5- yl]methyl}-6-piperazin-1- ylpyrimidine-2,4-diamine


 


614




6-(4-acetylpiperazin-1-yl)-N4-(5- cyclopropyl-1H-pyrazol-3-yl)- N2-{[3-(1-methylethyl)isoxazol- 5-yl]methyl}pyrimidine-2,4- diamine


 


615




N4-(5-cyclopropyl-1H-pyrazol-3- yl)-N2-{[3-(1- methylethyl)isoxazol-5- yl]methyl}-6-[4- (methylsulfonyl)piperazin-1- yl]pyrimidine-2,4-diamine


 


616




4-{6-[(5-cyclopropyl-1H- pyrazol-3-yl)amino]-2-({[3-(1- methylethyl)isoxazol-5- yl]methyl}amino)pyrimidin-4- yl}piperazine-1-carbaldehyde


 


617




N4-(3-methyl-1H-pyrazol-5-yl)- 6-morpholin-4-yl-N2-[(3- phenylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine


 


618




6-(4-methylpiperazin-1-yl)-N4- (3-methyl-1H-pyrazol-5-yl)-N2- [(3-phenylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine


 


619




N4-(3-methyl-1H-pyrazol-5-yl)- 6-[(2-morpholin-4-ylethyl)oxy]- N2-[(3-phenylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine


 


620




N4-(5-cyclopropyl-1H-pyrazol-3- yl)-6-methyl-N2-[(3-pyridin-4- ylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine


 


621




N4-(5-cyclopropyl-1H-pyrazol-3- yl)-N2-{[3-(3,4- difluorophenyl)isoxazol-5- yl]methyl}-6-methylpyrimidine- 2,4-diamine


 


622




N4-(5-cyclopropyl-1H-pyrazol-3- yl)-N2-{[3-(2,4- difluorophenyl)isoxazol-5- yl]methyl}-6-methylpyrimidine- 2,4-diamine


 


623




N4-(5-cyclopropyl-1H-pyrazol-3- yl)-6-methyl-N2-[(3-pyrazin-2- ylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine


 


624




5-chloro-N4-(3-cyclopropyl-1H- pyrazol-5-yl)-6-morpholin-4-yl- N2-[(3-phenylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine


 


625




5-chloro-N4-(3-cyclopropyl-1H- pyrazol-5-yl)-6-(4- methylpiperazin-1-yl)-N2-[(3- phenylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine


 


626




N2-[(3-methylisoxazol-5- yl)methyl]-6-(4-methylpiperazin- 1-yl)-N4-(3-methyl-1H-pyrazol- 5-yl)pyrimidine-2,4-diamine


 


627




N2-[(3-methylisoxazol-5- yl)methyl]-N4-(3-methyl-1H- pyrazol-5-yl)-6-morpholin-4- ylpyrimidine-2,4-diamine


 


628




N4-(5-cyclopropyl-1H-pyrazol-3- yl)-6-(4-methylpiperazin-1-yl)- N2-[(3-pyrimidin-4-ylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine


 


629




N4-(5-cyclopropyl-1H-pyrazol-3- yl)-N2-[(3-furan-3-ylisoxazol-5- yl)methyl]-6-(4-methylpiperazin- 1-yl)pyrimidine-2,4-diamine


 


630




N4-(5-cyclopropyl-1H-pyrazol-3- yl)-N6-(8-methyl-8- azabicyclo[3.2.1]oct-3-yl)-N2- [(3-methylisoxazol-5- yl)methyl]pyrimidine-2,4,6- triamine


 


631




N4-(5-cyclopropyl-1H-pyrazol-3- yl)-6-(5-methyl-2,5- diazabicyclo[2.2.1]hept-2-yl)-N2- [(3-methylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine


 


632




N4-(5-cyclopropyl-1H-pyrazol-3- yl)-6-(5-methyl-2,5- diazabicyclo[2.2.1]hept-2-yl)-N2- {[3-(1-methylethyl)isoxazol-5- yl]methyl}pyrimidine-2,4- diamine


 


633




N4-bicyclo[2.2.1]hept-2-yl-N6-(5- cyclopropyl-1H-pyrazol-3-yl)- N2-{[3-(1-methylethyl)isoxazol- 5-yl]methyl}pyrimidine-2,4,6- triamine


 


634




N4-bicyclo[2.2.1]hept-2-yl-N6-(5- cyclopropyl-1H-pyrazol-3-yl)- N2-[(3-methylisoxazol-5- yl)methyl]pyrimidine-2,4,6- triamine


 


635




N4-(5-cyclopropyl-1H-pyrazol-3- yl)-N2-[(3-methylisoxazol-5- yl)methyl]-6-[(1R,4R)-5- (phenylmethyl)-2,5- diazabicyclo[2.2.1]hept-2- yl]pyrimidine-2,4-diamine


 


636




N4-(5-cyclopropyl-1H-pyrazol-3- yl)-N-{[3-(1- methylethyl)isoxazol-5- yl]methyl}-6-[(1R,4R)-5- (phenylmethyl)-2,5- diazabicyclo[2.2.1]hept-2- yl]pyrimidine-2,4-diamine


 


637




N4-(5-cyclopropyl-1H-pyrazol-3- yl)-6-morpholin-4-yl-N2-[(3- pyrimidin-4-ylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine


 


638




N4-(5-cyclopropyl-1H-pyrazol-3- yl)-6-{[2- (dimethylamino)ethyl]oxy}-N2- [(3-pyrimidin-4-ylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine


 


639




N4-(5-cyclopropyl-1H-pyrazol-3- yl)-N2-{[3-(5-fluoropyridin-2- yl)isoxazol-5-yl]methyl}-6- methylpyrimidine-2,4-diamine


 


640




N4-(5-cyclopropyl-1H-pyrazol-3- yl)-6-(4-methylpiperazin-1-yl)- N2-{[3-(2-thienyl)isoxazol-5- yl]methyl}pyrimidine-2,4- diamine


 


641




N4-(5-cyclopropyl-1H-pyrazol-3- yl)-6-{[2- (dimethylamino)ethyl]oxy}-N2- [(3-pyridin-2-ylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine


 


642




N4-(3-cyclopropyl-1H-pyrazol-5- yl)-6-(4-methylpiperazin-1-yl)- N2-[(3-pyrimidin-5-ylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine


 


643




N4-(3-cyclopropyl-1H-pyrazol-5- yl)-6-morpholin-4-yl-N2-[(3- pyrimidin-5-ylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine


 


644




N4-(5-cyclopropyl-1H-pyrazol-3- yl)-6-{[2- (diethylamino)ethyl]oxy}-N2-{[3- (1-methylethyl)isoxazol-5- yl]methyl}pyrimidine-2,4- diamine


 


645




N4-(5-cyclopropyl-1H-pyrazol-3- yl)-N2-{[3-(1- methylethyl)isoxazol-5- yl]methyl}-6-[(2-pyrrolidin-1- ylethyl)oxy]pyrimidine-2,4- diamine


 


646




N4-(5-cyclopropyl-1H-pyrazol-3- yl)-6-{[2- (diethylamino)ethyl]oxy}-N2-[(3- methylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine


 


647




N4-(5-cyclopropyl-1H-pyrazol-3- yl)-N2-[(3-methylisoxazol-5- yl)methyl}-6-[(2-pyrrolidin-1- ylethyl)oxy]pyrimidine-2,4- diamine


 


648




N4-(5-cyclopropyl-1H-pyrazol-3- yl)-6-(4-methylpiperazin-1-yl)- N2-{[3-(1,3-thiazol-2-yl)isoxazol- 5-yl]methyl}pyrimidine-2,4- diamine


 


649




N4-(3-cyclopropyl-1H-pyrazol-5- yl)-6-[2-(dimethylamino)ethoxy]- N2-[(3-methylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine


 


650




6-{[2- (dimethylamino)ethyl]oxy}-N2- [(3-methylisoxazol-5-yl)methyl]- N4-(3-methyl-1H-pyrazol-5- yl)pyrimidine-2,4-diamine


 


651




6-{[2-(diethylamino)ethyl]oxy}- N2-[(3-methylisoxazol-5- yl)methyl]-N4-(3-methyl-1H- pyrazol-5-yl)pyrimidine-2,4- diamine


 


652




N2-[(3-methylisoxazol-5- yl)methyl]-N4-(3-methyl-1H- pyrazol-5-yl)-6-[(2-pyrrolidin-1- ylethyl)oxy]pyrimidine-2,4- diamine


 


653




N4-(3-cyclopropyl-1H-pyrazol-5- yl)-6-methyl-N2-[2-(3- phenylisoxazol-5- yl)ethyl]pyrimidine-2,4-diamine


 


654




N4-(3-cyclopropyl-1H-pyrazol-5- yl)-6-methyl-N2-[1-(3- phenylisoxazol-5- yl)ethyl]pyrimidine-2,4-diamine


 


655




N4-(3-cyclopropyl-1H-pyrazol-5- yl)-N2-[(3-ethylisoxazol-5- yl)methyl]-6-(4-methylpiperazin- 1-yl)pyrimidine-2,4-diamine


 


656




N4-(3-cyclopropyl-1H-pyrazol-5- yl)-N2-[(3-ethylisoxazol-5- yl)methyl]-6-morpholin-4- ylpyrimidine-2,4-diamine


 


657




N4-(3-cyclopropyl-1H-pyrazol-5- yl)-6-{[2- (dimethylamino)ethyl]oxy}-N2- [(3-ethylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine


 


658




N4-(3-cyclopropyl-1H-pyrazol-5- yl)-6-{[2- (diethylamino)ethyl]oxy}-N2-[(3- ethylisoxazol-5- yl)methyl]pyrimidine-2,4- diamine


 


659




N4-(3-cyclopropyl-1H-pyrazol-5- yl)-N2-[(3-ethylisoxazol-5- yl)methyl]-6-[(2-pyrrolidin-1- ylethyl)oxy]pyrimidine-2,4- diamine


 


660




N2-{[3-(2-aminopyrimidin-4- yl)isoxazol-5-yl]methyl}-N4-(3- cyclopropyl-1H-pyrazol-5-yl)-6- (4-methylpiperazin-1- yl)pyrimidine-2,4-diamine


 


661




N4-(3-cyclopropyl-1H-pyrazol-5- yl)-6-(4-ethylpiperazin-1-yl)-N2- {[3-(1-methylethyl)isoxazol-5- yl]methyl}pyrimidine-2,4- diamine


 


662




2-(1-{6-[(3-cyclopropyl-1H- pyrazol-5-yl)amino]-2-({[3-(1- methylethyl)isoxazol-5- yl]methyl}amino)pyrimidin-4- yl}piperidin-4-yl)ethanol


 


663




2-(4-{6-[(3-cyclopropyl-1H- pyrazol-5-yl)amino]-2-({[3-(1- methylethyl)isoxazol-5- yl]methyl}amino)pyrimidin-4- yl}piperazin-1-yl)ethanol









Table 6
Representative Raf Inhibitors
The Compounds in Table 6 can be prepared as pharmaceutically acceptable salts, solvates, hydrates, and/or isomers thereof. All such salt, solvate, hydrate, and isomer combinations of the Compounds in Table 6 can be used to practice the invention.








TABLE 6





Entry
Name
















1
6-(2-butyl-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-2H-1,4-benzoxazin-



3(4H)-one


2
6-[1-hydroxy-3-oxo-2-(2-phenylethyl)-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-



benzoxazin-3(4H)-one


3
6-(1-hydroxy-2-{[4-(methyloxy)phenyl]methyl}-3-oxo-2,3-dihydro-1H-isoindol-



1-yl)-2H-1,4-benzoxazin-3(4H)-one


4
6-(1-hydroxy-2-{[3-(methyloxy)phenyl]methyl}-3-oxo-2,3-dihydro-1H-isoindol-



1-yl)-2H-1,4-benzoxazin-3(4H)-one


5
6-{2-[(4-fluorophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-



2H-1,4-benzoxazin-3(4H)-one


6
6-(1-hydroxy-3-oxo-2-phenyl-2,3-dihydro-1H-isoindol-1-yl)-2H-1,4-benzoxazin-



3(4H)-one


7
6-{2-[(3-bromophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-



2H-1,4-benzoxazin-3(4H)-one


8
6-{2-[(4-bromophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-



2H-1,4-benzoxazin-3(4H)-one


9
6-[1-hydroxy-3-oxo-2-(3-phenylpropyl)-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-



benzoxazin-3(4H)-one


10
6-{2-[(3,4-dichlorophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-



yl}-2H-1,4-benzoxazin-3(4H)-one


11
6-{1-hydroxy-2-[(4-methylphenyl)methyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-



2H-1,4-benzoxazin-3(4H)-one


12
6-{2-[(4-chlorophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-



2H-1,4-benzoxazin-3(4H)-one


13
6-[1-hydroxy-2-(1-methylethyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-



benzoxazin-3(4H)-one


14
methyl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-



1H-benzimidazol-2-yl}carbamate


15
6-{2-[(3,4-dimethylphenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-



yl}-2H-1,4-benzoxazin-3(4H)-one


16
6-(2-{[4-chloro-3-(trifluoromethyl)phenyl]methyl}-1-hydroxy-3-oxo-2,3-



dihydro-1H-isoindol-1-yl)-2H-1,4-benzoxazin-3(4H)-one


17
6-(2-{[4-(dimethylamino)phenyl]methyl}-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl)-2H-1,4-benzoxazin-3(4H)-one


18
6-[2-(3-chlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-



benzoxazin-3(4H)-one

















TABLE 6





Entry
Name
















19
6-[2-(4-chlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-



benzoxazin-3(4H)-one


20
6-[2-(3,4-dichlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-



1,4-benzoxazin-3(4H)-one


21
6-[1-hydroxy-2-(4-methylphenyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-



benzoxazin-3(4H)-one


22
3-(2-{[3,5-bis(methyloxy)phenyl]amino}-1H-benzimidazol-5-yl)-3-(methyloxy)-



2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-one


23
3-(2-{[3,5-bis(methyloxy)phenyl]amino}-1H-benzimidazol-5-yl)-2-(1-



methylethyl)-3-(methyloxy)-2,3-dihydro-1H-isoindol-1-one


24
3-(2-{[3,5-bis(methyloxy)phenyl]amino}-1H-benzimidazol-5-yl)-3-hydroxy-2-



phenyl-2,3-dihydro-1H-isoindol-1-one


25
3-(2-{[3,5-bis(methyloxy)phenyl]amino}-1H-benzimidazol-5-yl)-3-hydroxy-2-



(phenylmethyl)-2,3-dihydro-1H-isoindol-1-one


26
methyl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1-



methyl-1H-benzimidazol-2-yl}carbamate


27
3-(1H-benzimidazol-5-yl)-3-hydroxy-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-



1-one


28
5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-N-methyl-



1H-benzimidazole-2-carboxamide


29
3-hydroxy-3-(2-methyl-1H-benzimidazol-5-yl)-2-(phenylmethyl)-2,3-dihydro-



1H-isoindol-1-one


30
7-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-3,4-



dihydroquinoxalin-2(1H)-one


31
7-[2-(3-chlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-3,4-



dihydroquinoxalin-2(1H)-one


32
1,1-dimethylethyl 4-{[1-hydroxy-3-oxo-1-(3-oxo-3,4-dihydro-2H-1,4-



benzoxazin-6-yl)-1,3-dihydro-2H-isoindol-2-yl]methyl}piperidine-1-carboxylate


33
6-(1-hydroxy-2-{[2-(methyloxy)phenyl]methyl}-3-oxo-2,3-dihydro-1H-isoindol-



1-yl)-2H-1,4-benzoxazin-3(4H)-one


34
6-{2-[(3-chlorophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-



2H-1,4-benzoxazin-3(4H)-one


35
6-{2-[(2-chlorophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-



2H-1,4-benzoxazin-3(4H)-one


36
6-{2-[(3-fluorophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-



2H-1,4-benzoxazin-3(4H)-one


37
6-{2-[(2-bromophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-



2H-1,4-benzoxazin-3(4H)-one


38
6-{2-[(2-fluorophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-



2H-1,4-benzoxazin-3(4H)-one


39
6-[2-(3-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-



benzoxazin-3(4H)-one


40
6-[1-hydroxy-2-(3-iodophenyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-



benzoxazin-3(4H)-one


41
6-[2-(3-bromophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-



benzoxazin-3(4H)-one


42
6-[1-hydroxy-2-(3-nitrophenyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-



benzoxazin-3(4H)-one


43
6-{1-hydroxy-2-[3-(methyloxy)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-



2H-1,4-benzoxazin-3(4H)-one


44
6-[1-hydroxy-2-(3-methylphenyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-



benzoxazin-3(4H)-one


45
3-hydroxy-3-(1H-indol-5-yl)-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-one


46
methyl [6-(1-hydroxy-3-oxo-2-phenyl-2,3-dihydro-1H-isoindol-1-yl)-1H-



benzimidazol-2-yl]carbamate


47
6-[2-(2-aminophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-



benzoxazin-3(4H)-one


48
6-{[2-(3-phenyl-1,2,4-oxadiazol-5-yl)phenyl]carbonyl}-2H-1,4-benzoxazin-



3(4H)-one


49
6-{[2-(1H-benzimidazol-2-yl)phenyl]carbonyl}-2H-1,4-benzoxazin-3(4H)-one


50
6-(1-hydroxy-3-oxo-2-{[2-(trifluoromethyl)phenyl]methyl}-2,3-dihydro-1H-



isoindol-1-yl)-2H-1,4-benzoxazin-3(4H)-one


51
6-{2-[(5-bromo-2-fluorophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one


52
6-{1-hydroxy-2-[(3-nitrophenyl)methyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-



2H-1,4-benzoxazin-3(4H)-one


53
6-(1-hydroxy-3-oxo-2-{[3-(trifluoromethyl)phenyl]methyl}-2,3-dihydro-1H-



isoindol-1-yl)-2H-1,4-benzoxazin-3(4H)-one


54
6-(2-{[2,3-bis(methyloxy)phenyl]methyl}-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl)-2H-1,4-benzoxazin-3(4H)-one


55
6-{1-hydroxy-2-[(3-iodophenyl)methyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl}-



2H-1,4-benzoxazin-3(4H)-one


56
6-[1-hydroxy-3-oxo-2-({3-[(trifluoromethyl)oxy]phenyl}methyl)-2,3-dihydro-



1H-isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one


57
6-(1-hydroxy-2-{[2-(methylthio)phenyl]methyl}-3-oxo-2,3-dihydro-1H-isoindol-



1-yl)-2H-1,4-benzoxazin-3(4H)-one


58
6-[2-(3,4-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-



1,4-benzoxazin-3(4H)-one


59
6-{1-hydroxy-2-[3-(1-methylethyl)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-1-



yl}-2H-1,4-benzoxazin-3(4H)-one


60
6-(1-hydroxy-3-oxo-2-{3-[(trifluoromethyl)oxy]phenyl}-2,3-dihydro-1H-



isoindol-1-yl)-2H-1,4-benzoxazin-3(4H)-one


61
6-{1-hydroxy-3-oxo-2-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-isoindol-1-



yl}-2H-1,4-benzoxazin-3(4H)-one


62
3-[1-hydroxy-3-oxo-1-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1,3-dihydro-



2H-isoindol-2-yl]benzenesulfonamide


63
6-{2-[5-chloro-2-(methyloxy)phenyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-



1-yl}-2H-1,4-benzoxazin-3(4H)-one


64
6-{2-[4-fluoro-3-(trifluoromethyl)phenyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl}-2H-1,4-benzoxazin-3(4H)-one


65
3-hydroxy-3-(1H-indol-6-yl)-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-one


66
6-[2-(3-fluoro-5-iodophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-



2H-1,4-benzoxazin-3(4H)-one


67
6-[2-(3-aminophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-



benzoxazin-3(4H)-one


68
6-[2-(3,5-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-



1,4-benzoxazin-3(4H)-one


69
6-{1-hydroxy-2-[3-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-1-



yl}-2H-1,4-benzoxazin-3(4H)-one


70
ethyl 3-[1-hydroxy-3-oxo-1-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1,3-



dihydro-2H-isoindol-2-yl]benzoate


71
3-[1-hydroxy-3-oxo-1-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1,3-dihydro-



2H-isoindol-2-yl]benzonitrile


72
6-[2-(2-chlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-



benzoxazin-3(4H)-one


73
6-[2-(3-amino-5-chlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-



2H-1,4-benzoxazin-3(4H)-one


74
6-[2-(5-chloro-2-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-



2H-1,4-benzoxazin-3(4H)-one


75
6-[2-(3-chloro-2-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-



2H-1,4-benzoxazin-3(4H)-one


76
6-[2-(3-ethylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-



benzoxazin-3(4H)-one


77
6-[2-(3-ethynylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-



benzoxazin-3(4H)-one


78
6-[1-hydroxy-2-(3-hydroxyphenyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-



benzoxazin-3(4H)-one


79
6-{1-hydroxy-3-oxo-2-[3-(phenyloxy)phenyl]-2,3-dihydro-1H-isoindol-1-yl}-



2H-1,4-benzoxazin-3(4H)-one


80
6-(1-hydroxy-3-oxo-2-{3-[(phenylmethyl)oxy]phenyl}-2,3-dihydro-1H-isoindol-



1-yl)-2H-1,4-benzoxazin-3(4H)-one


81
3-[1-hydroxy-3-oxo-1-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1,3-dihydro-



2H-isoindol-2-yl]benzamide


82
6-{1-hydroxy-2-[3-(hydroxymethyl)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-1-



yl}-2H-1,4-benzoxazin-3(4H)-one


83
6-[2-(2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-



benzoxazin-3(4H)-one


84
3-hydroxy-3-[2-(methylamino)-1H-benzimidazol-5-yl]-2-(phenylmethyl)-2,3-



dihydro-1H-isoindol-1-one


85
6-(2-biphenyl-3-yl-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-2H-1,4-



benzoxazin-3(4H)-one


86
6-(2-{3-[(dimethylamino)methyl]phenyl}-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl)-2H-1,4-benzoxazin-3(4H)-one


87
6-[2-(3,5-dichlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-



1,4-benzoxazin-3(4H)-one


88
6-(1-hydroxy-3-oxo-2-piperidin-4-yl-2,3-dihydro-1H-isoindol-1-yl)-2H-1,4-



benzoxazin-3(4H)-one


89
6-[2-(3-{[2-(dimethylamino)ethyl]oxy}phenyl)-1-hydroxy-3-oxo-2,3-dihydro-



1H-isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one


90
6-[1-hydroxy-2-(2-methylphenyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-



benzoxazin-3(4H)-one


91
N-methyl-2-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-N-



phenylbenzamide


92
methyl {5-[1-(ethyloxy)-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-



1H-benzimidazol-2-yl}carbamate


93
phenylmethyl 2-[(2-{[(methyloxy)carbonyl]amino}-1H-benzimidazol-5-



yl)carbonyl]benzoate


94
3-hydroxy-3-(1H-indazol-5-yl)-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-one


95
3-hydroxy-3-(1H-indazol-6-yl)-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-one


96
ethyl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-



benzimidazol-2-yl}carbamate


97
2-methylpropyl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


98
methyl {5-[1-hydroxy-3-oxo-2-(2-thienylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-



1H-benzimidazol-2-yl}carbamate


99
methyl {5-[1-hydroxy-3-oxo-2-(2-phenylethyl)-2,3-dihydro-1H-isoindol-1-yl]-



1H-benzimidazol-2-yl}carbamate


100
3-[2-amino-1-(1,1-dimethylethyl)-1H-benzimidazol-5-yl]-3-hydroxy-2-



(phenylmethyl)-2,3-dihydro-1H-isoindol-1-one


101
3-(2-amino-1H-benzimidazol-5-yl)-3-hydroxy-2-(phenylmethyl)-2,3-dihydro-



1H-isoindol-1-one


102
methyl [5-(1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-1H-benzimidazol-2-



yl]carbamate


103
3-(methyloxy)butyl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


104
methyl (5-{1-hydroxy-3-oxo-2-[(1R)-1-phenylethyl]-2,3-dihydro-1H-isoindol-1-



yl}-1H-benzimidazol-2-yl)carbamate


105
methyl (5-{1-hydroxy-3-oxo-2-[(1S)-1-phenylethyl]-2,3-dihydro-1H-isoindol-1-



yl}-1H-benzimidazol-2-yl)carbamate


106
2-(methyloxy)ethyl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


107
methyl {6-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1-



methyl-1H-benzimidazol-2-yl}carbamate


108
prop-2-yn-1-yl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-



1-yl]-1H-benzimidazol-2-yl}carbamate


109
but-2-yn-1-yl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-



1-yl]-1H-benzimidazol-2-yl}carbamate


110
1-methylethyl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-



1-yl]-1H-benzimidazol-2-yl}carbamate


111
methyl {5-[2-(2,3-dihydro-1H-inden-2-yl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


112
methyl {5-[1-hydroxy-3-oxo-2-(pyridin-4-ylmethyl)-2,3-dihydro-1H-isoindol-1-



yl]-1H-benzimidazol-2-yl}carbamate


113
methyl {5-[1-hydroxy-3-oxo-2-(pyridin-3-ylmethyl)-2,3-dihydro-1H-isoindol-1-



yl]-1H-benzimidazol-2-yl}carbamate


114
methyl (6-{2-[(3-fluorophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


115
methyl {5-[1-hydroxy-2-(3-methylphenyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-



1H-benzimidazol-2-yl}carbamate


116
methyl [5-(1-hydroxy-2-{[2-(methyloxy)phenyl]methyl}-3-oxo-2,3-dihydro-1H-



isoindol-1-yl)-1H-benzimidazol-2-yl]carbamate


117
methyl [5-(1-hydroxy-2-{[3-(methyloxy)phenyl]methyl}-3-oxo-2,3-dihydro-1H-



isoindol-1-yl)-1H-benzimidazol-2-yl]carbamate


118
methyl [5-(1-hydroxy-2-{[4-(methyloxy)phenyl]methyl}-3-oxo-2,3-dihydro-1H-



isoindol-1-yl)-1H-benzimidazol-2-yl]carbamate


119
methyl (6-{2-[(4-fluorophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


120
methyl (6-{2-[(3-bromophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


121
methyl (5-{1-hydroxy-2-[(3-iodophenyl)methyl]-3-oxo-2,3-dihydro-1H-isoindol-



1-yl}-1H-benzimidazol-2-yl)carbamate


122
methyl (5-{2-[(3-chlorophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


123
methyl (5-{2-[(2-fluorophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


124
methyl {5-[1-hydroxy-3-oxo-2-(pyridin-2-ylmethyl)-2,3-dihydro-1H-isoindol-1-



yl]-1H-benzimidazol-2-yl}carbamate


125
phenylmethyl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-



1-yl]-1H-benzimidazol-2-yl}carbamate


126
2-fluoroethyl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-



yl]-1H-benzimidazol-2-yl}carbamate


127
propyl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-



1H-benzimidazol-2-yl}carbamate


128
methyl (5-{1-hydroxy-2-[4-(methyloxy)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-



1-yl}-1H-benzimidazol-2-yl)carbamate


129
methyl (5-{2-[(2-chlorophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


130
methyl (5-{2-[(2-bromophenyl)methyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


131
methyl (5-{1-hydroxy-2-[(3-methylphenyl)methyl]-3-oxo-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


132
methyl (5-{1-hydroxy-2-[(4-methylphenyl)methyl]-3-oxo-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


133
methyl (5-{1-hydroxy-2-[(2-methylphenyl)methyl]-3-oxo-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


134
methyl {5-[2-(3-bromophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-



1H-benzimidazol-2-yl}carbamate


135
methyl {5-[2-(3-chlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-



1H-benzimidazol-2-yl}carbamate


136
methyl {5-[2-(3-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-



1H-benzimidazol-2-yl}carbamate


137
methyl (5-{1-hydroxy-2-[3-(methyloxy)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-



1-yl}-1H-benzimidazol-2-yl)carbamate


138
methyl {5-[2-(4-bromophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-



1H-benzimidazol-2-yl}carbamate


139
methyl {5-[2-(4-chlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-



1H-benzimidazol-2-yl}carbamate


140
methyl {5-[2-(4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-



1H-benzimidazol-2-yl}carbamate


141
methyl {5-[2-(3,5-dimethylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-



yl]-1H-benzimidazol-2-yl}carbamate


142
methyl {5-[2-(2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-



1H-benzimidazol-2-yl}carbamate


143
methyl {5-[2-(2-chlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-



1H-benzimidazol-2-yl}carbamate


144
methyl {5-[1-hydroxy-2-(2-methylphenyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-



1H-benzimidazol-2-yl}carbamate


145
methyl (5-{1-hydroxy-2-[2-(methyloxy)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-



1-yl}-1H-benzimidazol-2-yl)carbamate


146
methyl {5-[1-hydroxy-2-(4-methylphenyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-



1H-benzimidazol-2-yl}carbamate


147
methyl (5-{1-hydroxy-3-oxo-2-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


148
but-2-yn-1-yl (5-{1-hydroxy-3-oxo-2-[(1R)-1-phenylethyl]-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


149
N-ethyl-N′-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-



yl]-1H-benzimidazol-2-yl}urea


150
phenylmethyl (5-{1-hydroxy-3-oxo-2-[(1R)-1-phenylethyl]-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


151
methyl {6-[2-(3-amino-5-chlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


152
piperidin-4-ylmethyl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


153
methyl {5-[2-(cyclopropylmethyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-



yl]-1H-benzimidazol-2-yl}carbamate


154
methyl {5-[2-(2,2-dimethylpropyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-



yl]-1H-benzimidazol-2-yl}carbamate


155
methyl {5-[2-(3,5-dichlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-



yl]-1H-benzimidazol-2-yl}carbamate


156
methyl {5-[2-(3,5-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-



yl]-1H-benzimidazol-2-yl}carbamate


157
N-ethyl-N′-(5-{1-hydroxy-3-oxo-2-[(1R)-1-phenylethyl]-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)urea


158
N′-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-



benzimidazol-2-yl}-N,N-dimethylurea


159
methyl {5-[2-(3-{[2-(dimethylamino)ethyl]oxy}phenyl)-1-hydroxy-3-oxo-2,3-



dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


160
3-(4-methylpiperazin-1-yl)propyl {6-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-



dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


161
methyl {5-[2-(cyclohexylmethyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-



yl]-1H-benzimidazol-2-yl}carbamate


162
methyl {5-[1-hydroxy-2-(2-methylpropyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-



1H-benzimidazol-2-yl}carbamate


163
methyl {5-[1-hydroxy-3-oxo-2-(1,3-thiazol-2-ylmethyl)-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


164
methyl {5-[2-(3,4-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-



yl]-1H-benzimidazol-2-yl}carbamate


165
methyl (5-{2-[1-(3,5-difluorophenyl)ethyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


166
methyl (5-{2-[1-(3-fluorophenyl)ethyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


167
methyl [5-(2-cyclohexyl-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-1H-



benzimidazol-2-yl]carbamate


168
methyl {5-[2-(2,5-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-



yl]-1H-benzimidazol-2-yl}carbamate


169
N-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-



benzimidazol-2-yl}-N′-(phenylmethyl)urea


170
piperidin-4-yl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-



1-yl]-1H-benzimidazol-2-yl}carbamate


171
N-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-



benzimidazol-2-yl}-N′-methylurea


172
methyl (5-{2-[1-(2-fluorophenyl)ethyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


173
methyl (5-{1-hydroxy-3-oxo-2-[1-(2-thienyl)ethyl]-2,3-dihydro-1H-isoindol-1-



yl}-1H-benzimidazol-2-yl)carbamate


174
methyl (5-{2-[1-(3-chlorophenyl)ethyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


175
methyl (5-{1-hydroxy-2-[3-methyl-5-(trifluoromethyl)phenyl]-3-oxo-2,3-



dihydro-1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


176
N-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-



benzimidazol-2-yl}propanamide


177
methyl {5-[2-(3,4-dichlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-



yl]-1H-benzimidazol-2-yl}carbamate


178
methyl {5-[2-(3-ethylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-



1H-benzimidazol-2-yl}carbamate


179
methyl {5-[2-(3-ethynylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-



1H-benzimidazol-2-yl}carbamate


180
methyl {5-[2-(4-chloro-3-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


181
methyl [5-(1-hydroxy-3-oxo-2-{1-[3-(trifluoromethyl)phenyl]ethyl}-2,3-dihydro-



1H-isoindol-1-yl)-1H-benzimidazol-2-yl]carbamate


182
methyl (5-{1-hydroxy-3-oxo-2-[(1R)-1-phenylpropyl]-2,3-dihydro-1H-isoindol-



1-yl}-1H-benzimidazol-2-yl)carbamate


183
methyl [5-(1-hydroxy-3-oxo-2-{2-[(trifluoromethyl)oxy]phenyl}-2,3-dihydro-



1H-isoindol-1-yl)-1H-benzimidazol-2-yl]carbamate


184
methyl {5-[2-(2,3-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-



yl]-1H-benzimidazol-2-yl}carbamate


185
cyclohexyl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-



yl]-1H-benzimidazol-2-yl}carbamate


186
tetrahydrofuran-2-ylmethyl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-



1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


187
cyclopropylmethyl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


188
N-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-



benzimidazol-2-yl}morpholine-4-carboxamide


189
methyl {5-[2-(cyclopentylmethyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-



yl]-1H-benzimidazol-2-yl}carbamate


190
methyl {5-[2-(2,3-dimethylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-



yl]-1H-benzimidazol-2-yl}carbamate


191
methyl {5-[2-(2,3-dihydro-1H-inden-1-yl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


192
methyl (2S)-cyclohexyl[1-hydroxy-1-(2-{[(methyloxy)carbonyl]amino}-1H-



benzimidazol-5-yl)-3-oxo-1,3-dihydro-2H-isoindol-2-yl]ethanoate


193
methyl {5-[2-(2,6-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-



yl]-1H-benzimidazol-2-yl}carbamate


194
methyl {5-[2-(3-chloro-4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


195
but-3-en-1-yl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-



yl]-1H-benzimidazol-2-yl}carbamate


196
2,2,2-trifluoroethyl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


197
methyl {5-[2-(5-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


198
methyl (5-{2-[1-(5-chloro-2-methylphenyl)ethyl]-1-hydroxy-3-oxo-2,3-dihydro-



1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


199
methyl (5-{1-hydroxy-3-oxo-2-[(1S)-1-phenylpropyl]-2,3-dihydro-1H-isoindol-



1-yl}-1H-benzimidazol-2-yl)carbamate


200
methyl (5-{2-[1-(3-chloro-2-methylphenyl)ethyl]-1-hydroxy-3-oxo-2,3-dihydro-



1H-isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


201
methyl (5-{1-hydroxy-2-[1-(5-methyl-2-thienyl)ethyl]-3-oxo-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


202
methyl (5-{2-[1-(5-chloro-2-thienyl)ethyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


203
methyl {5-[1-hydroxy-2-(3-iodophenyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-



1H-benzimidazol-2-yl}carbamate


204
methyl (5-{1-hydroxy-2-[3-(1-methylethyl)phenyl]-3-oxo-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


205
methyl {5-[2-(furan-2-ylmethyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-



yl]-1H-benzimidazol-2-yl}carbamate


206
methyl {5-[1-hydroxy-3-oxo-2-(3-thienylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-



1H-benzimidazol-2-yl}carbamate


207
methyl {5-[2-(cyclobutylmethyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-



yl]-1H-benzimidazol-2-yl}carbamate


208
3,3,3-trifluoro-2-hydroxy-N-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-



1H-isoindol-1-yl]-1H-benzimidazol-2-yl}-2-(trifluoromethyl)propanamide


209
methyl (5-{1-hydroxy-2-[1-(4-methyl-2-thienyl)ethyl]-3-oxo-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


210
methyl (5-{2-[1-(4-bromo-2-thienyl)ethyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


211
methyl {5-[1-hydroxy-2-(3-{[2-(methyloxy)ethyl]oxy}phenyl)-3-oxo-2,3-



dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


212
tetrahydrofuran-3-ylmethyl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-



1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


213
N-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-



benzimidazol-2-yl}piperidine-1-carboxamide


214
methyl {5-[2-(3-bromo-4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


215
2,3-dihydroxypropyl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


216
methyl {5-[1-hydroxy-3-oxo-2-(tetrahydrofuran-2-ylmethyl)-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


217
methyl (5-{2-[3-(aminocarbonyl)phenyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


218
4,4,4-trifluoro-3-hydroxy-N-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-



1H-isoindol-1-yl]-1H-benzimidazol-2-yl}-3-(trifluoromethyl)butanamide


219
methyl (5-{1-hydroxy-2-[3-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


220
methyl (5-{1-hydroxy-3-oxo-2-[3-(phenyloxy)phenyl]-2,3-dihydro-1H-isoindol-



1-yl}-1H-benzimidazol-2-yl)carbamate


221
methyl [5-(1-hydroxy-3-oxo-2-{3-[(phenylmethyl)oxy]phenyl}-2,3-dihydro-1H-



isoindol-1-yl)-1H-benzimidazol-2-yl]carbamate


222
methyl [5-(2-biphenyl-3-yl-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-1H-



benzimidazol-2-yl]carbamate


223
2,2-dimethyl-3-[(phenylmethyl)oxy]propyl {5-[1-hydroxy-3-oxo-2-



(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


224
methyl {5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


225
methyl {5-[2-(3-cyanophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-



1H-benzimidazol-2-yl}carbamate


226
methyl {5-[2-(3-ethynyl-4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


227
methyl {5-[2-(4-fluoro-3-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


228
methyl {6-[2-(3,4-dichloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


229
[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl {5-[1-hydroxy-3-oxo-2-



(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


230
methyl {5-[2-(5-bromo-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


231
methyl (5-{2-[3-(acetylamino)phenyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


232
methyl (5-{1-hydroxy-3-oxo-2-[3-(phenylmethyl)phenyl]-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


233
methyl (5-{2-[1-(4-chloro-2-thienyl)ethyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


234
methyl (5-{1-hydroxy-3-oxo-2-[3-(phenylcarbonyl)phenyl]-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


235
methyl [5-(2-{3-[(dimethylamino)methyl]phenyl}-1-hydroxy-3-oxo-2,3-dihydro-



1H-isoindol-1-yl)-1H-benzimidazol-2-yl]carbamate


236
methyl (5-{2-[3-(aminosulfonyl)phenyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


237
methyl {5-[2-(3-acetylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-



1H-benzimidazol-2-yl}carbamate


238
methyl {5-[2-(3-ethyl-4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


239
methyl {5-[2-(3-chloro-5-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


240
N-{6-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-



benzimidazol-2-yl}-2-methylpropanamide


241
methyl (5-{2-[1-(3-chloro-2-thienyl)ethyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


242
methyl [5-(1-hydroxy-3-oxo-2-pyridin-3-yl-2,3-dihydro-1H-isoindol-1-yl)-1H-



benzimidazol-2-yl]carbamate


243
methyl (5-{1-hydroxy-3-oxo-2-[3-(phenylamino)phenyl]-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


244
methyl {5-[2-(5-bromo-2,4-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


245
methyl {5-[2-(5-chloro-2,4-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


246
methyl {5-[2-(3,5-dichloro-4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


247
2,2-dimethyl-3-(methyloxy)propyl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-



dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


248
3-hydroxy-2,2-dimethylpropyl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-



dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


249
methyl (5-{2-[1-(5-bromo-2-thienyl)ethyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


250
methyl {5-[2-(4,5-dichloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


251
methyl {5-[2-(3-bromo-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


252
methyl {5-[2-(3-chloro-2,4-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


253
N-{6-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-



benzimidazol-2-yl}pent-4-ynamide


254
methyl (6-{1-methyl-3-oxo-2-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


255
methyl [5-(1-hydroxy-3-oxo-2-{3-[(1,1,2,2-tetrafluoroethyl)oxy]phenyl}-2,3-



dihydro-1H-isoindol-1-yl)-1H-benzimidazol-2-yl]carbamate


256
methyl {5-[1-hydroxy-3-oxo-2-(3-piperidin-4-ylphenyl)-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


257
methyl {5-[2-(3-ethenylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-



1H-benzimidazol-2-yl}carbamate


258
methyl (5-{2-[3-(dimethylamino)phenyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


259
2,2-difluoro-N-{6-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-



1-yl]-1H-benzimidazol-2-yl}cyclopropanecarboxamide


260
N-ethyl-N′-{6-[2-(4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-



yl]-1H-benzimidazol-2-yl}urea


261
methyl {5-[2-(3-aminophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-



1H-benzimidazol-2-yl}carbamate


262
N-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-



benzimidazol-2-yl}-4-[(phenylmethyl)oxy]butanamide


263
N-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-



benzimidazol-2-yl}-4-piperidin-1-ylbutanamide


264
N-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-



benzimidazol-2-yl}-4-(4-methylpiperazin-1-yl)butanamide


265
N-{6-[2-(4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-



benzimidazol-2-yl}butanamide


266
methyl {6-[2-(3-bromophenyl)-5,6-dichloro-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


267
methyl [5-(1-hydroxy-2-{3-[methyl(phenyl)amino]phenyl}-3-oxo-2,3-dihydro-



1H-isoindol-1-yl)-1H-benzimidazol-2-yl]carbamate


268
methyl {5-[1-hydroxy-3-oxo-2-(phenylsulfonyl)-2,3-dihydro-1H-isoindol-1-yl]-



1H-benzimidazol-2-yl}carbamate


269
methyl {5-[(2-{[(phenylamino)carbonyl]amino}phenyl)carbonyl]-1H-



benzimidazol-2-yl}carbamate


270
methyl (5-{[2-({[(phenylmethyl)oxy]carbonyl}amino)phenyl]carbonyl}-1H-



benzimidazol-2-yl)carbamate


271
methyl [5-({2-[(2-phenylhydrazino)carbonyl]phenyl}carbonyl)-1H-



benzimidazol-2-yl]carbamate


272
methyl {5-[(2-{[(phenyloxy)amino]carbonyl}phenyl)carbonyl]-1H-



benzimidazol-2-yl}carbamate


273
but-2-yn-1-yl {5-[2-(4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-



1-yl]-1H-benzimidazol-2-yl}carbamate


274
N-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-



benzimidazol-2-yl}-3-piperidin-1-ylpropanamide


275
N-{6-[2-(4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-



benzimidazol-2-yl}propanamide


276
N-(4-fluorophenyl)-2-{[2-(pent-4-ynoylamino)-1H-benzimidazol-6-



yl]carbonyl}benzamide


277
4-(diethylamino)-N-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}butanamide


278
N-{5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-



benzimidazol-2-yl}-4-pyrrolidin-1-ylbutanamide


279
3-piperidin-1-ylpropyl {6-[2-(4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


280
3-(4-methylpiperazin-1-yl)propyl {6-[2-(4-fluorophenyl)-1-hydroxy-3-oxo-2,3-



dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


281
methyl {5-[2-(3-bromophenyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-



benzimidazol-2-yl}carbamate


282
methyl {5-[2-(3-ethynyl-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


283
2-piperidin-1-ylethyl {5-[2-(4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


284
methyl {5-[2-(3-chloro-2-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


285
methyl {5-[2-(5-chloro-2-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


286
N-{6-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-



benzimidazol-2-yl}-2,2-dimethyl-3-piperidin-1-ylpropanamide


287
N-{5-[2-(4-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-



benzimidazol-2-yl}-4-piperidin-1-ylbutanamide


288
N-{5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-



yl]-1H-benzimidazol-2-yl}-4-piperidin-1-ylbutanamide


289
methyl [6-({2-[(phenylcarbonyl)amino]phenyl}carbonyl)-1H-benzimidazol-2-



yl]carbamate


290
methyl {5-[1-hydroxy-2-(3-morpholin-4-ylphenyl)-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


291
2-(dimethylamino)ethyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-



dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


292
2-(diethylamino)ethyl {5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-



dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


293
2-piperidin-1-ylethyl {5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-



dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


294
3-piperidin-1-ylpropyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-



dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


295
2-piperidin-1-ylethyl {6-[2-(3-bromophenyl)-3-oxo-2,3-dihydro-1H-isoindol-1-



yl]-1H-benzimidazol-2-yl}carbamate


296
methyl {6-[2-(3-bromophenyl)-4,7-difluoro-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


297
2-[methyl(phenylmethyl)amino]ethyl {5-[2-(3-chloro-2-fluorophenyl)-1-



hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


298
methyl {5-[1-hydroxy-3-oxo-2-(3-pyrrolidin-1-ylphenyl)-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


299
methyl {5-[2-(5-chloro-2,3-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


300
methyl {5-[1-hydroxy-3-oxo-2-(pyrrolidin-2-ylmethyl)-2,3-dihydro-1H-isoindol-



1-yl]-1H-benzimidazol-2-yl}carbamate


301
methyl {5-[1-hydroxy-3-oxo-2-(pyrrolidin-3-ylmethyl)-2,3-dihydro-1H-isoindol-



1-yl]-1H-benzimidazol-2-yl}carbamate


302
(1-methylpiperidin-2-yl)methyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-



oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


303
[(2S)-1-methylpyrrolidin-2-yl]methyl {6-[2-(3-chloro-2-fluorophenyl)-1-



hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


304
octahydro-2H-quinolizin-1-ylmethyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-



3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


305
methyl {5-[2-(5-bromo-2-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


306
5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-



1,3-dihydro-2H-benzimidazol-2-one


307
methyl {5-[2-(3-bromo-2,5-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


308
2-morpholin-4-ylethyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-



dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


309
(1-methylpiperidin-3-yl)methyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-



oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


310
methyl (5-{2-[5-chloro-2-(methyloxy)phenyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


311
methyl [5-(2-{3-[cyclohexyl(methyl)amino]phenyl}-1-hydroxy-3-oxo-2,3-



dihydro-1H-isoindol-1-yl)-1H-benzimidazol-2-yl]carbamate


312
8-azabicyclo[3.2.1]oct-3-ylmethyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-



oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


313
methyl {6-[1-(3-bromophenyl)-5-oxopyrrolidin-2-yl]-1H-benzimidazol-2-



yl}carbamate


314
(1-methylpiperidin-4-yl)methyl {5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-



dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


315
1,1-dimethylethyl 4-({[({5-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}amino)carbonyl]oxy}methyl)piperidine-1-



carboxylate


316
(1-methylpiperidin-4-yl)methyl {5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-



oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


317
2-(1-methylpiperidin-4-yl)ethyl {5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-



oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


318
methyl ({6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}amino)(oxo)acetate


319
N-(5-{1-hydroxy-3-oxo-2-[3-(phenyloxy)phenyl]-2,3-dihydro-1H-isoindol-1-yl}-



1H-benzimidazol-2-yl)-4-piperidin-1-ylbutanamide


320
methyl {6-[2-(3-bromophenyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-



1H-benzimidazol-2-yl}carbamate


321
4-(diethylamino)but-2-yn-1-yl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-



oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


322
methyl {5-[2-(3-chloro-2,6-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


323
2-(2-oxopyrrolidin-1-yl)ethyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-



2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


324
2-(2,5-dioxopyrrolidin-1-yl)ethyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-



oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


325
2,2,3,3-tetrafluorocyclobutyl {5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-



2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


326
1-acetyl-N-{5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}piperidine-4-carboxamide


327
N-{5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-



yl]-1H-benzimidazol-2-yl}cyclobutanecarboxamide


328
methyl [5-(2-{3-[ethyl(phenyl)amino]phenyl}-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl)-1H-benzimidazol-2-yl]carbamate


329
N-{6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-



yl]-1H-benzimidazol-2-yl}-2,2-difluorocyclopropanecarboxamide


330
cyclobutyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


331
2,2-difluoroethyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-



1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


332
2-(3-chloro-2-fluorophenyl)-3-hydroxy-3-[2-(pyridin-2-ylamino)-1H-



benzimidazol-5-yl]-2,3-dihydro-1H-isoindol-1-one


333
1-methylethyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-



1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


334
cyclopropylmethyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-



dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


335
N-{5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-



yl]-1H-benzimidazol-2-yl}cyclopropanecarboxamide


336
2-(methyloxy)ethyl {5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-



dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


337
tetrahydrofuran-2-ylmethyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-



2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


338
N-{5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-



yl]-1H-benzimidazol-2-yl}-2-(2-thienyl)acetamide


339
methyl {6-[2-(3-chloro-2-fluorophenyl)-4,7-difluoro-1-hydroxy-3-oxo-2,3-



dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


340
ethyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


341
2-fluoroethyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


342
methyl (5-{1-hydroxy-3-oxo-2-[2-(phenyloxy)phenyl]-2,3-dihydro-1H-isoindol-



1-yl}-1H-benzimidazol-2-yl)carbamate


343
N′-{5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-



yl]-1H-benzimidazol-2-yl}-N,N-diethylpentanediamide


344
cyclobutylmethyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-



1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


345
2,2,2-trifluoroethyl {6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-



dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


346
methyl (5-{2-[3-(1,1-dimethylethyl)phenyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


347
methyl {6-[2-(3-chloro-2-fluorophenyl)-7-fluoro-1-hydroxy-3-oxo-2,3-dihydro-



1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


348
2-(3-chloro-2-fluorophenyl)-3-hydroxy-3-[2-(phenylamino)-1H-benzimidazol-5-



yl]-2,3-dihydro-1H-isoindol-1-one


349
methyl {6-[4,7-dichloro-2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-



dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


350
phenylmethyl 2-[(2-{[(ethyloxy)carbonyl]amino}-1,3-benzoxazol-5-



yl)carbonyl]benzoate


351
methyl {5-[2-(5-chloro-3-ethynyl-2-methylphenyl)-1-hydroxy-3-oxo-2,3-



dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


352
methyl {5-[2-(5-ethynyl-2,4-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


353
methyl {5-[2-(3-ethynyl-2,4-difluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


354
2-(3-chloro-2-fluorophenyl)-3-hydroxy-3-[2-(pyrimidin-2-ylamino)-1H-



benzimidazol-5-yl]-2,3-dihydro-1H-isoindol-1-one


355
methyl {5-[2-(3-ethynyl-2-fluorophenyl)-4,7-difluoro-1-hydroxy-3-oxo-2,3-



dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


356
2-(3-chloro-2-fluorophenyl)-3-hydroxy-3-[2-(1,3-thiazol-2-ylamino)-1H-



benzimidazol-5-yl]-2,3-dihydro-1H-isoindol-1-one


357
ethyl {5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1,3-benzoxazol-2-yl}carbamate


358
methyl {5-[2-(5-chloro-3-iodo-2-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-



1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


359
methyl {5-[2-(3-ethyl-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


360
methyl {5-[2-(5-ethynyl-2-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


361
2-(3-chloro-2-fluorophenyl)-3-hydroxy-3-[2-(pyrazin-2-ylamino)-1H-



benzimidazol-5-yl]-2,3-dihydro-1H-isoindol-1-one


362
methyl {5-[2-(2-fluoro-3-iodophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


363
methyl {6-[2-(5-ethynyl-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


364
2-(3-ethynyl-2-fluorophenyl)-3-hydroxy-3-[2-(pyrimidin-2-ylamino)-1H-



benzimidazol-5-yl]-2,3-dihydro-1H-isoindol-1-one


365
methyl {5-[2-(2,5-dimethylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-



yl]-1H-benzimidazol-2-yl}carbamate


366
methyl {5-[2-(3-ethenyl-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


367
methyl (6-{2-[2-fluoro-3-(methyloxy)phenyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


368
methyl (5-{1-hydroxy-2-[2-methyl-5-(methyloxy)phenyl]-3-oxo-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


369
methyl {5-[2-(3-ethynyl-2-fluorophenyl)-7-fluoro-1-hydroxy-3-oxo-2,3-dihydro-



1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


370
methyl {5-[2-(2-fluoro-3-prop-1-yn-1-ylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-



1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


371
methyl {5-[2-(5-chloro-2-methylphenyl)-7-fluoro-1-hydroxy-3-oxo-2,3-dihydro-



1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


372
methyl {5-[2-(3-ethynyl-2-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


373
3-hydroxy-2-[3-(methyloxy)phenyl]-3-[2-(pyrimidin-2-ylamino)-1H-



benzimidazol-6-yl]-2,3-dihydro-1H-isoindol-1-one


374
3-hydroxy-2-(3-methylphenyl)-3-[2-(pyrimidin-2-ylamino)-1H-benzimidazol-6-



yl]-2,3-dihydro-1H-isoindol-1-one


375
2-(5-chloro-2-methylphenyl)-3-hydroxy-3-[2-(pyrimidin-2-ylamino)-1H-



benzimidazol-6-yl]-2,3-dihydro-1H-isoindol-1-one


376
methyl {6-[2-(5-chloro-2-methylphenyl)-4,7-difluoro-1-hydroxy-3-oxo-2,3-



dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


377
methyl {5-[2-(3-ethynyl-2-fluorophenyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-



1H-benzimidazol-2-yl}carbamate


378
2-(3-chloro-2-fluorophenyl)-3-{2-[(6-chloropyridazin-3-yl)amino]-1H-



benzimidazol-5-yl}-3-hydroxy-2,3-dihydro-1H-isoindol-1-one


379
2-(3-chloro-2-fluorophenyl)-4,7-difluoro-3-hydroxy-3-[2-(pyrimidin-2-ylamino)-



1H-benzimidazol-5-yl]-2,3-dihydro-1H-isoindol-1-one


380
methyl {5-[2-(2-fluoro-5-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


381
methyl (5-{2-[2-fluoro-5-(methyloxy)phenyl]-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


382
methyl (5-{1-hydroxy-2-[5-methyl-2-(methyloxy)phenyl]-3-oxo-2,3-dihydro-1H-



isoindol-1-yl}-1H-benzimidazol-2-yl)carbamate


383
methyl {5-[2-(3-ethynyl-5-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


384
2-(3-chloro-2-fluorophenyl)-3-{2-[(5-chloropyrimidin-2-yl)amino]-1H-



benzimidazol-5-yl}-3-hydroxy-2,3-dihydro-1H-isoindol-1-one


385
2-(3-chloro-2-fluorophenyl)-3-hydroxy-3-{2-[(4-methylpyrimidin-2-yl)amino]-



1H-benzimidazol-5-yl}-2,3-dihydro-1H-isoindol-1-one


386
3-(2-{[4,6-bis(methyloxy)pyrimidin-2-yl]amino}-1H-benzimidazol-5-yl)-2-(3-



chloro-2-fluorophenyl)-3-hydroxy-2,3-dihydro-1H-isoindol-1-one


387
2-(3-chloro-2-fluorophenyl)-3-hydroxy-3-(2-{[4-methyl-6-



(methyloxy)pyrimidin-2-yl]amino}-1H-benzimidazol-5-yl)-2,3-dihydro-1H-



isoindol-1-one


388
3-hydroxy-2-(3-methylphenyl)-3-[2-(pyrazin-2-ylamino)-1H-benzimidazol-6-yl]-



2,3-dihydro-1H-isoindol-1-one


389
2-(5-chloro-2-methylphenyl)-3-hydroxy-3-[2-(pyrazin-2-ylamino)-1H-



benzimidazol-6-yl]-2,3-dihydro-1H-isoindol-1-one


390
methyl {6-[2-(2-fluoro-3-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-



isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate


391
3-hydroxy-2-[3-(methyloxy)phenyl]-3-[2-(pyrazin-2-ylamino)-1H-benzimidazol-



5-yl]-2,3-dihydro-1H-isoindol-1-one


392
methyl {6-[(2-{[(2-thienylmethyl)amino]carbonyl}phenyl)carbonyl]-1H-



benzimidazol-2-yl}carbamate


393
methyl {6-[(2-{[(3-methylphenyl)amino]carbonyl}phenyl)carbonyl]-1H-



benzimidazol-2-yl}carbamate


394
methyl {6-[(2-{[(3-bromophenyl)amino]carbonyl}phenyl)carbonyl]-1H-



benzimidazol-2-yl}carbamate


395
methyl {6-[(2-{[(3-chlorophenyl)amino]carbonyl}phenyl)carbonyl]-1H-



benzimidazol-2-yl}carbamate


396
methyl {6-[(2-{[(3-fluorophenyl)amino]carbonyl}phenyl)carbonyl]-1H-



benzimidazol-2-yl}carbamate


397
methyl (6-{[2-({[3-(methyloxy)phenyl]amino}carbonyl)phenyl]carbonyl}-1H-



benzimidazol-2-yl)carbamate


398
methyl (6-{[2-({[3-(trifluoromethyl)phenyl]amino}carbonyl)phenyl]carbonyl}-



1H-benzimidazol-2-yl)carbamate


399
methyl {6-[(2-{[(3-ethylphenyl)amino]carbonyl}phenyl)carbonyl]-1H-



benzimidazol-2-yl}carbamate


400
methyl {6-[(2-{[(3-ethynylphenyl)amino]carbonyl}phenyl)carbonyl]-1H-



benzimidazol-2-yl}carbamate


401
methyl {6-[(2-{[(3-chloro-4-fluorophenyl)amino]carbonyl}phenyl)carbonyl]-1H-



benzimidazol-2-yl}carbamate


402
methyl {6-[(2-{[(5-chloro-2-fluorophenyl)amino]carbonyl}phenyl)carbonyl]-1H-



benzimidazol-2-yl}carbamate


403
methyl {6-[(2-{[(3-iodophenyl)amino]carbonyl}phenyl)carbonyl]-1H-



benzimidazol-2-yl}carbamate


404
methyl (6-{[2-({[3-(1-methylethyl)phenyl]amino}carbonyl)phenyl]carbonyl}-



1H-benzimidazol-2-yl)carbamate


405
methyl {6-[(2-{[(3-thienylmethyl)amino]carbonyl}phenyl)carbonyl]-1H-



benzimidazol-2-yl}carbamate


406
methyl {6-[(2-{[(3-bromo-4-fluorophenyl)amino]carbonyl}phenyl)carbonyl]-1H-



benzimidazol-2-yl}carbamate


407
methyl {6-[(2-{[(3-chloro-2-fluorophenyl)amino]carbonyl}phenyl)carbonyl]-1H-



benzimidazol-2-yl}carbamate


408
methyl {6-[(2-{[(4-fluoro-3-methylphenyl)amino]carbonyl}phenyl)carbonyl]-



1H-benzimidazol-2-yl}carbamate


409
methyl {6-[(2-{[(5-bromo-2-fluorophenyl)amino]carbonyl}phenyl)carbonyl]-1H-



benzimidazol-2-yl}carbamate


410
methyl {6-[(2-{[(5-bromo-2,4-difluorophenyl)amino]carbonyl}phenyl)carbonyl]-



1H-benzimidazol-2-yl}carbamate


411
methyl {6-[(2-{[(5-chloro-2,4-difluorophenyl)amino]carbonyl}phenyl)carbonyl]-



1H-benzimidazol-2-yl}carbamate


412
methyl {6-[(2-{[(3-bromo-2-fluorophenyl)amino]carbonyl}phenyl)carbonyl]-1H-



benzimidazol-2-yl}carbamate


413
methyl {6-[(2-{[(3-ethenylphenyl)amino]carbonyl}phenyl)carbonyl]-1H-



benzimidazol-2-yl}carbamate


414
methyl {6-[(2-{[(3-ethynyl-2-fluorophenyl)amino]carbonyl}phenyl)carbonyl]-



1H-benzimidazol-2-yl}carbamate


415
methyl {6-[(2-{[(5-chloro-2-methylphenyl)amino]carbonyl}phenyl)carbonyl]-



1H-benzimidazol-2-yl}carbamate


416
methyl {6-[(2-{[(5-bromo-2-methylphenyl)amino]carbonyl}phenyl)carbonyl]-



1H-benzimidazol-2-yl}carbamate


417
methyl {6-[(2-{[(2-fluoro-3-iodophenyl)amino]carbonyl}phenyl)carbonyl]-1H-



benzimidazol-2-yl}carbamate


418
methyl {6-[(2-{[(3-ethenyl-2-fluorophenyl)amino]carbonyl}phenyl)carbonyl]-



1H-benzimidazol-2-yl}carbamate


419
methyl {6-[(2-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenyl)carbonyl]-



1H-benzimidazol-2-yl}carbamate









Table 7
Representative EGFR and/or VEGFR Inhibitors
The Compounds in Table 7 can be prepared as pharmaceutically acceptable salts, solvates, hydrates, and/or isomers thereof. All such salt, solvate, hydrate, and isomer combinations of the Compounds in Table 7 can be used to practice the invention.








TABLE 7





Entry
Name
















1
(3Z)-3-[[5-(methyloxy)-1H-benzimidazol-2-yl](phenyl)methylidene]-5-{[1-



(phenylmethyl)pyrrolidin-3-yl]amino}-1,3-dihydro-2H-indol-2-one


2
(3Z)-5-[(1-ethylpiperidin-3-yl)amino]-3-[[5-(methyloxy)-1H-benzimidazol-2-



yl](phenyl)methylidene]-1,3-dihydro-2H-indol-2-one


3
(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[[5-(methyloxy)-1H-benzimidazol-2-



yl](phenyl)methylidene]-1,3-dihydro-2H-indol-2-one


4
(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[1H-imidazol-2-



yl(phenyl)methylidene]-1,3-dihydro-2H-indol-2-one


5
(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-{[5-(methyloxy)-1H-benzimidazol-2-yl][4-



(methyloxy)phenyl]methylidene}-1,3-dihydro-2H-indol-2-one


6
(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[[5-(methyloxy)-1H-benzimidazol-2-



yl](4-methylphenyl)methylidene]-1,3-dihydro-2H-indol-2-one


7
(3Z)-3-[1H-benzimidazol-2-yl(4-nitrophenyl)methylidene]-5-[(1-ethylpiperidin-



4-yl)amino]-1,3-dihydro-2H-indol-2-one


8
(3Z)-3-{1H-benzimidazol-2-yl[4-(methyloxy)phenyl]methylidene}-5-[(1-



ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one


9
(3Z)-3-[1H-benzimidazol-2-yl(phenyl)methylidene]-5-[(1-ethylpiperidin-4-



yl)amino]-1,3-dihydro-2H-indol-2-one


10
(3Z)-3-[[5-(methyloxy)-1H-benzimidazol-2-yl](phenyl)methylidene]-5-



[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one


11
(3Z)-3-[(4-aminophenyl)(1H-benzimidazol-2-yl)methylidene]-5-[(1-



ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one


12
(3Z)-3-[1H-benzimidazol-2-yl(4-methylphenyl)methylidene]-5-[(1-



ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one


13
(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[1H-imidazol-2-yl(4-



methylphenyl)methylidene]-1,3-dihydro-2H-indol-2-one


14
(3Z)-5-[(1-ethylpiperidin-4-yl)oxy]-3-[[5-(methyloxy)-1H-benzimidazol-2-



yl](phenyl)methylidene]-1,3-dihydro-2H-indol-2-one


15
(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-{1H-imidazol-2-yl[4-



(methyloxy)phenyl]methylidene}-1,3-dihydro-2H-indol-2-one


16
(3Z)-3-[1H-benzimidazol-2-yl(4-fluorophenyl)methylidene]-5-[(1-



ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one


17
(3Z)-3-[1H-benzimidazol-2-yl(3,5-difluorophenyl)methylidene]-5-[(1-



ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one


18
(3Z)-3-[1H-benzimidazol-2-yl(3-fluorophenyl)methylidene]-5-[(1-



ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one


19
(3Z)-3-[1H-benzimidazol-2-yl(3-nitrophenyl)methylidene]-5-[(1-ethylpiperidin-



4-yl)amino]-1,3-dihydro-2H-indol-2-one


20
3-((Z)-1H-benzimidazol-2-yl{5-[(1-ethylpiperidin-4-yl)amino]-2-oxo-1,2-



dihydro-3H-indol-3-ylidene}methyl)benzonitrile


21
(3Z)-3-[(3-aminophenyl)(1H-benzimidazol-2-yl)methylidene]-5-[(1-



ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one


22
(3Z)-3-[1H-benzimidazol-2-yl(phenyl)methylidene]-5-(piperidin-4-ylamino)-



1,3-dihydro-2H-indol-2-one


23
3-((Z)-1H-benzimidazol-2-yl{5-[(1-ethylpiperidin-4-yl)amino]-2-oxo-1,2-



dihydro-3H-indol-3-ylidene}methyl)benzenecarboximidamide


24
(3Z)-3-[1H-benzimidazol-2-yl(phenyl)methylidene]-5-({1-[2-



(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one


25
(3Z)-3-[1H-benzimidazol-2-yl(phenyl)methylidene]-5-[(2,2,6,6-



tetramethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one


26
(3Z)-3-{1H-benzimidazol-2-yl[3-(methyloxy)phenyl]methylidene}-5-[(1-



ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one


27
(3Z)-3-[1H-benzimidazol-2-yl(3-chlorophenyl)methylidene]-5-[(1-



ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one


28
2-(2-{2-[(Z)-{5-[(1-ethylpiperidin-4-yl)amino]-2-oxo-1,2-dihydro-3H-indol-3-



ylidene}(phenyl)methyl]-1H-imidazol-4-yl}ethyl)-1H-isoindole-1,3(2H)-dione


29
(3Z)-3-[1H-benzimidazol-2-yl(phenyl)methylidene]-5-({1-[2-



(dimethylamino)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one


30
(3Z)-3-[1H-benzimidazol-2-yl(phenyl)methylidene]-5-{[1-



(methylsulfonyl)piperidin-4-yl]amino}-1,3-dihydro-2H-indol-2-one


31
(3Z)-5-(8-azabicyclo[3.2.1]oct-3-ylamino)-3-[1H-benzimidazol-2-



yl(phenyl)methylidene]-1,3-dihydro-2H-indol-2-one


32
(3Z)-3-{1H-benzimidazol-2-yl[3-(methyloxy)phenyl]methylidene}-5-[(1-



ethylpiperidin-4-yl)oxy]-1,3-dihydro-2H-indol-2-one


33
(3Z)-3-[1H-benzimidazol-2-yl(3,5-difluorophenyl)methylidene]-5-[(1-



ethylpiperidin-4-yl)oxy]-1,3-dihydro-2H-indol-2-one


34
(3Z)-3-[1H-benzimidazol-2-yl(phenyl)methylidene]-5-{[1-



(phenylmethyl)piperidin-4-yl]oxy}-1,3-dihydro-2H-indol-2-one


35
(3Z)-3-[1H-benzimidazol-2-yl(3-chlorophenyl)methylidene]-5-[(1-



ethylpiperidin-4-yl)oxy]-1,3-dihydro-2H-indol-2-one


36
(3Z)-3-[1H-benzimidazol-2-yl(3,5-difluorophenyl)methylidene]-5-({1-[2-



(methyloxy)ethyl]piperidin-4-yl}oxy)-1,3-dihydro-2H-indol-2-one


37
(3Z)-3-[1H-benzimidazol-2-yl(3-chlorophenyl)methylidene]-5-({1-[2-



(methyloxy)ethyl]piperidin-4-yl}oxy)-1,3-dihydro-2H-indol-2-one


38
(3Z)-3-[1H-benzimidazol-2-yl(3-chlorophenyl)methylidene]-5-({1-[2-



(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one


39
(3Z)-3-{1H-benzimidazol-2-yl[3-(methyloxy)phenyl]methylidene}-5-({1-[2-



(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one


40
(3Z)-3-[(3-chlorophenyl)(1H-imidazol-2-yl)methylidene]-5-({1-[2-



(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one


41
(3Z)-3-[(3-fluorophenyl)(1H-imidazol-2-yl)methylidene]-5-({1-[2-



(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one


42
(3Z)-3-[1H-benzimidazol-2-yl(3,5-difluorophenyl)methylidene]-5-({1-[2-



(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one


43
(3Z)-3-[1H-benzimidazol-2-yl(3-chlorophenyl)methylidene]-5-[(1-



ethylpiperidin-4-yl)(methyl)amino]-1,3-dihydro-2H-indol-2-one


44
(3Z)-3-[(3-chlorophenyl)(1H-imidazol-2-yl)methylidene]-5-[(1-ethylpiperidin-



4-yl)oxy]-1,3-dihydro-2H-indol-2-one


45
(3Z)-3-[1H-benzimidazol-2-yl(4-chlorophenyl)methylidene]-5-[(1-



ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one


46
(3Z)-3-[1H-benzimidazol-2-yl(3-fluorophenyl)methylidene]-5-({1-[2-



(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one


47
(3Z)-3-[1H-benzimidazol-2-yl(4-fluorophenyl)methylidene]-5-({1-[2-



(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one


48
(3Z)-3-[(3-chlorophenyl)(1H-imidazol-2-yl)methylidene]-5-[(1-ethylpiperidin-



4-yl)amino]-1,3-dihydro-2H-indol-2-one


49
(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[(3-fluorophenyl)(1H-imidazol-2-



yl)methylidene]-1,3-dihydro-2H-indol-2-one


50
(3Z)-3-[1H-benzimidazol-2-yl(3-fluoro-4-methylphenyl)methylidene]-5-[(1-



ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one


51
(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[(3-fluorophenyl)(4-methyl-1H-



imidazol-2-yl)methylidene]-1,3-dihydro-2H-indol-2-one


52
(3Z)-3-[1H-benzimidazol-2-yl(4-fluoro-3-methylphenyl)methylidene]-5-[(1-



ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one


53
(3Z)-3-[(3-chloro-4-fluorophenyl)(1H-imidazol-2-yl)methylidene]-5-[(1-



ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one


54
(3Z)-3-[(3,4-difluorophenyl)(1H-imidazol-2-yl)methylidene]-5-[(1-



ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one


55
(3Z)-3-[(5-chloro-1H-benzimidazol-2-yl)(phenyl)methylidene]-5-[(1-



ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one


56
(3Z)-3-[(5-chloro-1H-benzimidazol-2-yl)(3,5-difluorophenyl)methylidene]-5-



[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one


57
(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[(3-fluoro-4-methylphenyl)(1H-



imidazol-2-yl)methylidene]-1,3-dihydro-2H-indol-2-one


58
(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[(4-fluorophenyl)(1H-imidazol-2-



yl)methylidene]-1,3-dihydro-2H-indol-2-one


59
(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[1H-imidazol-2-yl(4-



propylphenyl)methylidene]-1,3-dihydro-2H-indol-2-one


60
(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-{1H-imidazol-2-yl[4-



(trifluoromethyl)phenyl]methylidene}-1,3-dihydro-2H-indol-2-one


61
(3E)-3-[(3,5-difluorophenyl)(5-fluoro-1H-benzimidazol-2-yl)methylidene]-5-



[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one


62
(3Z)-3-[(3,5-difluorophenyl)(5-fluoro-1H-benzimidazol-2-yl)methylidene]-5-



[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one


63
(3Z)-3-[(3-fluoro-4-methylphenyl)(1H-imidazol-2-yl)methylidene]-5-({1-[2-



(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one


64
(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[(4-methyl-1H-imidazol-2-yl)(4-



methylphenyl)methylidene]-1,3-dihydro-2H-indol-2-one


65
(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[[3-fluoro-4-



(trifluoromethyl)phenyl](1H-imidazol-2-yl)methylidene]-1,3-dihydro-2H-indol-



2-one


66
(3Z)-3-[(4-chlorophenyl)(1H-imidazol-2-yl)methylidene]-5-[(1-ethylpiperidin-



4-yl)amino]-1,3-dihydro-2H-indol-2-one


67
(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[(3-fluoro-4-methylphenyl)(4-methyl-



1H-imidazol-2-yl)methylidene]-1,3-dihydro-2H-indol-2-one


68
(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-{1H-imidazol-2-yl[6-



(trifluoromethyl)pyridin-3-yl]methylidene}-1,3-dihydro-2H-indol-2-one


69
(3Z)-3-[1H-imidazol-2-yl(4-methylphenyl)methylidene]-5-({1-[2-



(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one


70
(3Z)-3-[(3-fluorophenyl)(4-methyl-1H-imidazol-2-yl)methylidene]-5-({1-[2-



(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one


71
(3Z)-3-{1H-imidazol-2-yl[4-(trifluoromethyl)phenyl]methylidene}-5-({1-[2-



(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one


72
(3Z)-3-[(5-chloro-1H-benzimidazol-2-yl)(phenyl)methylidene]-5-({1-[2-



(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one


73
(3Z)-3-[(3,5-difluorophenyl)(1H-imidazol-2-yl)methylidene]-5-[(1-



ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one


74
(3Z)-3-[(3,5-difluorophenyl)(4-methyl-1H-imidazol-2-yl)methylidene]-5-[(1-



ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one


75
(3Z)-3-[(3,5-difluorophenyl)(1H-imidazol-2-yl)methylidene]-5-({1-[2-



(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one


76
(3Z)-3-[(3,5-difluorophenyl)(4-methyl-1H-imidazol-2-yl)methylidene]-5-({1-



[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one


77
(3Z)-3-[(4-methyl-1H-imidazol-2-yl)(4-methylphenyl)methylidene]-5-({1-[2-



(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one


78
(3Z)-3-[(4-fluorophenyl)(1H-imidazol-2-yl)methylidene]-5-({1-[2-



(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one


79
(3Z)-3-[(3,4-difluorophenyl)(1H-imidazol-2-yl)methylidene]-5-({1-[2-



(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one


80
(3Z)-3-[(3-chloro-4-fluorophenyl)(1H-imidazol-2-yl)methylidene]-5-({1-[2-



(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one


81
(3Z)-3-[(3-fluorophenyl)(1H-imidazol-2-yl)methylidene]-5-(piperidin-4-



ylamino)-1,3-dihydro-2H-indol-2-one


82
(3Z)-3-[(3-fluorophenyl)(1H-imidazol-2-yl)methylidene]-5-{[1-(2-piperidin-1-



ylethyl)piperidin-4-yl]amino}-1,3-dihydro-2H-indol-2-one


83
(3Z)-3-[(3-fluorophenyl)(1H-imidazol-2-yl)methylidene]-5-{[1-(2-morpholin-



4-ylethyl)piperidin-4-yl]amino}-1,3-dihydro-2H-indol-2-one


84
(3Z)-5-({1-[2-(diethylamino)ethyl]piperidin-4-yl}amino)-3-[(3-



fluorophenyl)(1H-imidazol-2-yl)methylidene]-1,3-dihydro-2H-indol-2-one


85
(3Z)-3-[(3-fluorophenyl)(1H-imidazol-2-yl)methylidene]-5-{[1-(2-pyrrolidin-1-



ylethyl)piperidin-4-yl]amino}-1,3-dihydro-2H-indol-2-one


86
(3Z)-3-[1H-imidazol-2-yl(4-methylphenyl)methylidene]-5-[(1-methylpiperidin-



4-yl)amino]-1,3-dihydro-2H-indol-2-one


87
(3Z)-3-[(3-fluorophenyl)(1H-1,2,4-triazol-5-yl)methylidene]-5-({1-[2-



(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one


88
ethyl 2-{(Z)-(3-fluorophenyl)[5-({1-[2-(methyloxy)ethyl]piperidin-4-



yl}amino)-2-oxo-1,2-dihydro-3H-indol-3-ylidene]methyl}-4-methyl-1H-



imidazole-5-carboxylate


89
(3Z)-3-[1H-imidazol-2-yl(phenyl)methylidene]-5-({1-[2-



(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one


90
(3Z)-3-{1H-imidazol-2-yl[4-(methyloxy)phenyl]methylidene}-5-({1-[2-



(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one


91
(3Z)-3-[(4-chlorophenyl)(1H-imidazol-2-yl)methylidene]-5-({1-[2-



(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one


92
(3Z)-3-[[3-fluoro-4-(trifluoromethyl)phenyl](1H-imidazol-2-yl)methylidene]-5-



({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one


93
(3Z)-3-[(3-fluorophenyl)(1H-imidazol-2-yl)methylidene]-5-{[1-



(methylsulfonyl)piperidin-4-yl]amino}-1,3-dihydro-2H-indol-2-one


94
(3Z)-3-[1H-imidazol-2-yl(4-propylphenyl)methylidene]-5-({1-[2-



(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one


95
(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[(3-fluorophenyl)(4-phenyl-1H-



imidazol-2-yl)methylidene]-1,3-dihydro-2H-indol-2-one


96
(3Z)-3-[(3-fluorophenyl)(4-phenyl-1H-imidazol-2-yl)methylidene]-5-({1-[2-



(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one


97
(3Z)-3-[(3-fluoro-4-methylphenyl)(4-methyl-1H-imidazol-2-yl)methylidene]-5-



({1-[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one


98
(3Z)-3-{1H-imidazol-2-yl[6-(trifluoromethyl)pyridin-3-yl]methylidene}-5-({1-



[2-(methyloxy)ethyl]piperidin-4-yl}amino)-1,3-dihydro-2H-indol-2-one


99
(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[(3-fluorophenyl)(1H-1,2,4-triazol-5-



yl)methylidene]-1,3-dihydro-2H-indol-2-one


100
(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[[2-fluoro-4-



(trifluoromethyl)phenyl](1H-imidazol-2-yl)methylidene]-1,3-dihydro-2H-indol-



2-one


101
(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-{(4-methyl-1H-imidazol-2-yl)[4-



(trifluoromethyl)phenyl]methylidene}-1,3-dihydro-2H-indol-2-one


102
(3Z)-3-[(4-chlorophenyl)(4-methyl-1H-imidazol-2-yl)methylidene]-5-[(1-



ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one


103
(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[[3-fluoro-4-



(trifluoromethyl)phenyl](4-methyl-1H-imidazol-2-yl)methylidene]-1,3-dihydro-



2H-indol-2-one


104
(3Z)-3-[(3,4-difluorophenyl)(4-methyl-1H-imidazol-2-yl)methylidene]-5-[(1-



ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one


105
(3Z)-3-[(3-chloro-4-fluorophenyl)(4-methyl-1H-imidazol-2-yl)methylidene]-5-



[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one


106
(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[(4-fluorophenyl)(4-methyl-1H-



imidazol-2-yl)methylidene]-1,3-dihydro-2H-indol-2-one


107
(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[(2-fluorophenyl)(1H-imidazol-2-



yl)methylidene]-1,3-dihydro-2H-indol-2-one


108
(3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[[2-fluoro-4-



(trifluoromethyl)phenyl](4-methyl-1H-imidazol-2-yl)methylidene]-1,3-dihydro-



2H-indol-2-one


109
(3Z)-3-[(2,3-difluorophenyl)(1H-imidazol-2-yl)methylidene]-5-[(1-



ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one


110
(3Z)-3-[(2,3-difluorophenyl)(4-methyl-1H-imidazol-2-yl)methylidene]-5-[(1-



ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one


111
(3Z)-3-[(2,4-difluorophenyl)(4-methyl-1H-imidazol-2-yl)methylidene]-5-[(1-



ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one


112
(3Z)-3-[(2,4-difluorophenyl)(1H-imidazol-2-yl)methylidene]-5-[(1-



ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one


113
(3Z)-3-[(2-fluorophenyl)(4-methyl-1H-imidazol-2-yl)methylidene]-5-[(1-



ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one


114
(3Z)-3-[(3-trifluoromethylphenyl)(1H-imidazol-2-yl)methylidene]-5-[(1-



ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one


115
(3Z)-3-[(3-trifluoromethylphenyl)(4-methyl-1H-imidazol-2-yl)methylidene]-5-



[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one


116
(3Z)-3-[(2,4-dichloro-5-fluorophenyl)(1H-imidazol-2-yl)methylidene]-5-[(1-



ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one


117
(3Z)-3-[(2,4-dichloro-5-fluorophenyl)(4-methyl-1H-imidazol-2-



yl)methylidene]-5-[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one


118
(3Z)-3-[(4-chloro-2-fluorophenyl)(4-methyl-1H-imidazol-2-yl)methylidene]-5-



[(1-ethylpiperidin-4-yl)amino]-1,3-dihydro-2H-indol-2-one









Table 8
c-KIT Inhibitors
The Compounds in Table 8 can be prepared as pharmaceutically acceptable salts, solvates, hydrates, and/or isomers thereof. All such salt, solvate, hydrate, and isomer combinations of the Compounds in Table 8 can be used to practice the invention.








TABLE 8





Entry
Name
















1
N-[5-chloro-2-(methyloxy)phenyl]-2-{[3-(1H-tetrazol-1-



yl)phenyl]oxy}acetamide


2
N-phenyl-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide


3
N-(2-methylphenyl)-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide


4
N-(2-chlorophenyl)-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide


5
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[3-(1H-tetrazol-1-



yl)phenyl]oxy}acetamide


6
ethyl 2-[({[3-(1H-tetrazol-1-yl)phenyl]oxy}acetyl)amino]-4,5,6,7-



tetrahydro-1-benzothiophene-3-carboxylate


7
N-(3-chloro-2-methylphenyl)-2-{[3-(1H-tetrazol-1-



yl)phenyl]oxy}acetamide


8
N-(3-fluorophenyl)-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide


9
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[3-(2H-tetrazol-5-



yl)phenyl]oxy}acetamide


10
N-(4-chloro-2-fluorophenyl)-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide


11
N-(4-bromo-3-methylphenyl)-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide


12
N-(4-morpholin-4-ylphenyl)-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide


13
N-[4-fluoro-3-(trifluoromethyl)phenyl]-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide


14
N-[4-bromo-3-(trifluoromethyl)phenyl]-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide


15
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[4-(1H-tetrazol-1-yl)phenyl]oxy}acetamide


16
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}propanamide


17
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[3-(5-methyl-1H-tetrazol-1-



yl)phenyl]oxy}acetamide


18
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[2-methyl-5-(1H-tetrazol-1-



yl)phenyl]oxy}acetamide


19
N-(4-chlorophenyl)-N-methyl-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide


20
N-[4-chloro-2-(trifluoromethyl)phenyl]-2-{[3-(1H-tetrazol-1-



yl)phenyl]oxy}acetamide


21
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[3-(2,5-dioxopyrrolidin-1-



yl)phenyl]oxy}acetamide


22
(2E)—N-[4-chloro-3-(trifluoromethyl)phenyl]-3-[3-(1H-tetrazol-1-



yl)phenyl]prop-2-enamide


23
N-[4-fluoro-3-(trifluoromethyl)phenyl]-2-{[4-(1H-tetrazol-1-yl)phenyl]oxy}acetamide


24
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[3-(2-methyl-2H-tetrazol-5-



yl)phenyl]oxy}acetamide


25
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[2,4-dichloro-5-(1H-



tetrazol-1-yl)phenyl]oxy}acetamide


26
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[3-(1H-tetrazol-1-yl)phenyl]thio}acetamide


27
N-[4-chloro-3-(trifluoromethyl)phenyl]-N~2~-[3-(1H-tetrazol-1-



yl)phenyl]glycinamide


28
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[2-(1H-tetrazol-1-yl)phenyl]oxy}acetamide


29
methyl 1-{3-[(2-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-2-



oxoethyl)oxy]phenyl}-1H-1,2,3-triazole-4-carboxylate


30
1,1-dimethylethyl {4-[({[3-(1H-tetrazol-1-



yl)phenyl]oxy}acetyl)amino]phenyl}carbamate


31
1,1-dimethylethyl {4-[({[4-(1H-tetrazol-1-



yl)phenyl]oxy}acetyl)amino]phenyl}carbamate


32
N-{4-[(1-ethylpiperidin-4-yl)amino]phenyl}-2-{[3-(1H-tetrazol-1-



yl)phenyl]oxy}acetamide


33
N-{4-[(1-ethylpiperidin-3-yl)amino]phenyl}-2-{[3-(1H-tetrazol-1-



yl)phenyl]oxy}acetamide


34
N-(4-aminophenyl)-2-{[4-(1H-tetrazol-1-yl)phenyl]oxy}acetamide


35
N-{4-[(1-ethylpiperidin-4-yl)amino]phenyl}-2-{[4-(1H-tetrazol-1-



yl)phenyl]oxy}acetamide


36
N-{4-[(1-ethylpiperidin-3-yl)amino]phenyl}-2-{[4-(1H-tetrazol-1-



yl)phenyl]oxy}acetamide


37
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-[(3-pyridin-4-



ylphenyl)oxy]acetamide


38
N-[4-chloro-3-(trifluoromethyl)phenyl]-N~2~-methyl-N~2~-[3-(1H-



tetrazol-1-yl)phenyl]glycinamide


39
N-1,3-benzothiazol-2-yl-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide


40
N-quinolin-8-yl-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide


41
N-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-{[3-(1H-tetrazol-1-



yl)phenyl]oxy}acetamide


42
N-isoquinolin-5-yl-2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}acetamide


43
N-{3-[(phenylmethyl)oxy]phenyl}-2-{[3-(1H-tetrazol-1-



yl)phenyl]oxy}acetamide


44
N-[5-methyl-2-(methyloxy)phenyl]-2-{[3-(1H-tetrazol-1-



yl)phenyl]oxy}acetamide


45
N-[2,5-bis(methyloxy)phenyl]-2-{[3-(1H-tetrazol-1-



yl)phenyl]oxy}acetamide


46
N-(6-fluoro-1,3-benzothiazol-2-yl)-2-{[3-(1H-tetrazol-1-



yl)phenyl]oxy}acetamide


47
methyl 3-[({[3-(1H-tetrazol-1-yl)phenyl]oxy}acetyl)amino]benzoate


48
5-chloro-2-[({[3-(1H-tetrazol-1-



yl)phenyl]oxy}acetyl)amino]benzamide


49
N-[5-chloro-2,4-bis(methyloxy)phenyl]-2-{[3-(1H-tetrazol-1-



yl)phenyl]oxy}acetamide


50
N-[2-(phenyloxy)phenyl]-2-{[3-(1H-tetrazol-1-



yl)phenyl]oxy}acetamide


51
N-[3-(aminosulfonyl)phenyl]-2-{[3-(1H-tetrazol-1-



yl)phenyl]oxy}acetamide


52
N-[2-(methyloxy)-5-(trifluoromethyl)phenyl]-2-{[3-(1H-tetrazol-1-



yl)phenyl]oxy}acetamide


53
N-(4-{[(4-methylphenyl)sulfonyl]amino}phenyl)-2-{[3-(1H-tetrazol-1-



yl)phenyl]oxy}acetamide


54
N-(5-phenyl-1H-pyrazol-3-yl)-2-{[3-(1H-tetrazol-1-



yl)phenyl]oxy}acetamide


55
N-1,3-benzothiazol-2-yl-2-{[4-(1H-tetrazol-1-yl)phenyl]oxy}acetamide


56
N-quinolin-8-yl-2-{[4-(1H-tetrazol-1-yl)phenyl]oxy}acetamide


57
1,1-dimethylethyl 2-{3-[(2-{[4-chloro-3-



(trifluoromethyl)phenyl]amino}-2-oxoethyl)oxy]phenyl}-1H-pyrrole-



1-carboxylate


58
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[3-(1H-pyrrol-2-



yl)phenyl]oxy}acetamide


59
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-[(3-pyrimidin-5-



ylphenyl)oxy]acetamide


60
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[3-(1H-1,2,3-triazol-1-



yl)phenyl]oxy}acetamide


61
4-chloro-N-(2-{[3-(1H-tetrazol-1-yl)phenyl]oxy}ethyl)-3-



(trifluoromethyl)aniline


62
N-[4-chloro-3-(trifluoromethyl)phenyl]-N-(2-{[3-(1H-tetrazol-1-



yl)phenyl]oxy}ethyl)formamide


63
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-[(3-pyridin-3-



ylphenyl)oxy]acetamide


64
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-[(3-furan-3-



ylphenyl)oxy]acetamide


65
(2E)—N-[4-fluoro-3-(trifluoromethyl)phenyl]-3-[3-(1H-tetrazol-1-



yl)phenyl]prop-2-enamide


66
N-[4-fluoro-3-(trifluoromethyl)phenyl]-3-[3-(1H-tetrazol-1-



yl)phenyl]propanamide


67
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[6-(1H-tetrazol-1-



yl)pyrimidin-4-yl]oxy}acetamide


68
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[3-(3,5-dimethylisoxazol-4-



yl)phenyl]oxy}acetamide


69
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-[(3-quinolin-7-



ylphenyl)oxy]acetamide


70
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-[(3-furan-2-



ylphenyl)oxy]acetamide


71
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-[3-(1H-tetrazol-1-



yl)phenyl]hydrazinecarboxamide


72
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-[(3-dibenzo[b,d]furan-4-



ylphenyl)oxy]acetamide


73
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-[(4-pyrimidin-5-



ylphenyl)oxy]acetamide


74
N-methyl-N-[4-(methyloxy)phenyl]-2-{[3-(1H-tetrazol-1-



yl)phenyl]oxy}acetamide


75
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-{[3-(1H-tetrazol-1-



yl)phenyl]methyl}urea


76
N-[4-chloro-3-(trifluoromethyl)phenyl]-N-methyl-2-{[3-(1H-tetrazol-1-



yl)phenyl]oxy}acetamide


77
N-[4-fluoro-3-(trifluoromethyl)phenyl]-N~2~-[3-(1H-tetrazol-1-



yl)phenyl]glycinamide


78
N-[4-fluoro-3-(trifluoromethyl)phenyl]-2-{[3-(pyridin-2-



ylamino)phenyl]oxy}acetamide


79
N-[2-fluoro-5-(trifluoromethyl)phenyl]-2-[3-(1H-tetrazol-1-



yl)phenyl]hydrazinecarboxamide


80
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-[(4-pyridin-3-



ylphenyl)oxy]acetamide


81
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-[(3-pyrimidin-5-



ylphenyl)methyl]urea


82
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-[(4-pyrimidin-5-



ylphenyl)methyl]urea


83
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-[(4-pyridin-3-



ylphenyl)methyl]urea


84
[3-(1H-tetrazol-1-yl)phenyl]methyl [4-chloro-3-



(trifluoromethyl)phenyl]carbamate


85
N-[4-fluoro-3-(trifluoromethyl)phenyl]-2-[(4-pyrimidin-5-



ylphenyl)oxy]acetamide


86
N~2~-[4-chloro-3-(trifluoromethyl)phenyl]-N-[3-(1H-tetrazol-1-



yl)phenyl]glycinamide


87
2-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-N-[3-(1H-tetrazol-1-



yl)phenyl]acetamide


88
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[3-methyl-4-(1H-tetrazol-1-



yl)phenyl]oxy}acetamide


89
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[4-(1H-1,2,3-triazol-1-



yl)phenyl]oxy}acetamide


90
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[3-fluoro-4-(1H-tetrazol-1-



yl)phenyl]oxy}acetamide


91
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[2-fluoro-4-(1H-tetrazol-1-



yl)phenyl]oxy}acetamide


92
N-({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)-3-(1H-



tetrazol-1-yl)benzenesulfonamide


93
N-({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)-N-methyl-3-



(1H-tetrazol-1-yl)benzenesulfonamide


94
N-[4-fluoro-3-(trifluoromethyl)phenyl]-2-[(4-pyridin-3-



ylphenyl)oxy]acetamide


95
2-({4-[2,4-bis(methyloxy)pyrimidin-5-yl]phenyl}oxy)-N-[4-fluoro-3-



(trifluoromethyl)phenyl]acetamide


96
2-({4-[2,4-bis(methyloxy)pyrimidin-5-yl]phenyl}oxy)-N-[4-chloro-3-



(trifluoromethyl)phenyl]acetamide


97
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-[(4-pyridin-4-



ylphenyl)oxy]acetamide


98
N-[4-chloro-3-(trifluoromethyl)phenyl]-N~2~-[3-(methyloxy)-4-(1H-



tetrazol-1-yl)phenyl]glycinamide


99
N-[4-chloro-3-(trifluoromethyl)phenyl]-N~2~-[4-(methyloxy)-3-(1H-



tetrazol-1-yl)phenyl]glycinamide


100
N-[4-chloro-3-(trifluoromethyl)phenyl]-N~2~-[4-(1H-tetrazol-1-



yl)phenyl]glycinamide


101
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-(2,3,5,6-tetrafluoro-4-



pyrimidin-5-ylphenyl)hydrazinecarboxamide


102
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-{[4-(1H-tetrazol-1-



yl)phenyl]methyl}urea


103
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-(4-pyrimidin-5-



ylphenyl)hydrazinecarboxamide


104
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-[(3-pyridin-3-



ylphenyl)methyl]urea


105
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-methyl-2-{[3-(1H-tetrazol-1-



yl)phenyl]oxy}propanamide


106
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[4-(1H-tetrazol-1-



yl)phenyl]oxy}propanamide


107
N-({4-[2,4-bis(methyloxy)pyrimidin-5-yl]phenyl}methyl)-N′-[4-



chloro-3-(trifluoromethyl)phenyl]urea


108
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-({3-[2-



(methyloxy)pyrimidin-5-yl]phenyl}methyl)urea


109
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-({3-[6-(methyloxy)pyridin-



3-yl]phenyl}methyl)urea


110
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-({4-[2-



(methyloxy)pyrimidin-5-yl]phenyl}methyl)urea


111
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-({4-[6-(methyloxy)pyridin-



3-yl]phenyl}methyl)urea


112
1,1-dimethylethyl 2-{4-[(2-{[4-chloro-3-



(trifluoromethyl)phenyl]amino}-2-oxoethyl)oxy]phenyl}-1H-indole-1-



carboxylate


113
N-({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)-4-(1H-



tetrazol-1-yl)benzenesulfonamide


114
N-[4-chloro-3-(trifluoromethyl)phenyl]-N~2~-[3-(2H-tetrazol-5-



yl)phenyl]glycinamide


115
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[2,6-difluoro-4-(1H-



tetrazol-1-yl)phenyl]oxy}acetamide


116
(3-pyridin-3-ylphenyl)methyl [4-chloro-3-



(trifluoromethyl)phenyl]carbamate


117
(3-pyrimidin-5-ylphenyl)methyl [4-chloro-3-



(trifluoromethyl)phenyl]carbamate


118
(3-pyridin-4-ylphenyl)methyl [4-chloro-3-



(trifluoromethyl)phenyl]carbamate


119
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-[4-(1H-tetrazol-1-



yl)phenyl]hydrazinecarboxamide


120
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-(4-pyridin-3-



ylphenyl)hydrazinecarboxamide


121
(4-pyridin-3-ylphenyl)methyl [4-chloro-3-



(trifluoromethyl)phenyl]carbamate


122
(4-pyridin-4-ylphenyl)methyl [4-chloro-3-



(trifluoromethyl)phenyl]carbamate


123
(4-pyrimidin-5-ylphenyl)methyl [4-chloro-3-



(trifluoromethyl)phenyl]carbamate


124
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-[(4-pyridin-4-



ylphenyl)methyl]urea


125
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-(3-pyridin-3-



ylphenyl)hydrazinecarboxamide


126
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-(3-pyrimidin-5-



ylphenyl)hydrazinecarboxamide


127
N-[5-chloro-2,4-bis(methyloxy)phenyl]-N′-[(4-pyrimidin-5-



ylphenyl)methyl]urea


128
N-[5-chloro-2,4-bis(methyloxy)phenyl]-N′-[(4-pyridin-3-



ylphenyl)methyl]urea


129
(4-pyrimidin-5-ylphenyl)methyl [5-chloro-2,4-



bis(methyloxy)phenyl]carbamate


130
(4-pyridin-3-ylphenyl)methyl [5-chloro-2,4-



bis(methyloxy)phenyl]carbamate


131
1-(4-pyridin-3-ylphenyl)ethyl [4-chloro-3-



(trifluoromethyl)phenyl]carbamate


132
1-(4-pyrimidin-5-ylphenyl)ethyl [4-chloro-3-



(trifluoromethyl)phenyl]carbamate


133
N-[5-chloro-2,4-bis(methyloxy)phenyl]-N′-[(3-pyridin-3-



ylphenyl)methyl]urea


134
N-[5-chloro-2,4-bis(methyloxy)phenyl]-N′-[(3-pyrimidin-5-



ylphenyl)methyl]urea


135
(3-pyridin-3-ylphenyl)methyl [5-chloro-2,4-



bis(methyloxy)phenyl]carbamate


136
(3-pyrimidin-5-ylphenyl)methyl [5-chloro-2,4-



bis(methyloxy)phenyl]carbamate


137
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-methyl-2-(3-pyrimidin-5-



ylphenyl)hydrazinecarboxamide


138
N-[4-fluoro-3-(trifluoromethyl)phenyl]-N′-[(4-pyridin-3-



ylphenyl)methyl]urea


139
N-{[3-(6-aminopyridin-3-yl)phenyl]methyl}-N′-[4-chloro-3-



(trifluoromethyl)phenyl]urea


140
N-{[4-(6-aminopyridin-3-yl)phenyl]methyl}-N′-[4-chloro-3-



(trifluoromethyl)phenyl]urea


141
N-{[3-(2-aminopyrimidin-5-yl)phenyl]methyl}-N′-[4-chloro-3-



(trifluoromethyl)phenyl]urea


142
N-{[4-(2-aminopyrimidin-5-yl)phenyl]methyl}-N′-[4-chloro-3-



(trifluoromethyl)phenyl]urea


143
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-[1-(4-pyridin-3-



ylphenyl)ethyl]urea


144
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-[1-(4-pyrimidin-5-



ylphenyl)ethyl]urea


145
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[4-(1H-indol-2-



yl)phenyl]oxy}acetamide


146
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-(isoquinolin-7-



yloxy)acetamide


147
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-(4-pyridin-4-



ylphenyl)hydrazinecarboxamide


148
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-(3-pyridin-4-



ylphenyl)hydrazinecarboxamide


149
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-[(3-pyridin-4-



ylphenyl)methyl]urea


150
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-[(3-quinoxalin-6-



ylphenyl)methyl]urea


151
methyl 3-amino-6-(3-{[({[4-chloro-3-



(trifluoromethyl)phenyl]amino}carbonyl)amino]methyl}phenyl)pyrazine-



2-carboxylate


152
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-[(4-quinoxalin-6-



ylphenyl)methyl]urea


153
N-{[3-(2-amino-5-methylpyridin-3-yl)phenyl]methyl}-N′-[4-chloro-3-



(trifluoromethyl)phenyl]urea


154
methyl 3-amino-6-(4-{[({[4-chloro-3-



(trifluoromethyl)phenyl]amino}carbonyl)amino]methyl}phenyl)pyrazine-



2-carboxylate


155
[3-(1H-tetrazol-1-yl)phenyl]methyl [3-chloro-4-



(methyloxy)phenyl]carbamate


156
N-[3-chloro-4-(methyloxy)phenyl]-N′-{[3-(1H-tetrazol-1-



yl)phenyl]methyl}urea


157
N-[4-chloro-3-(trifluoromethyl)phenyl]-2-{[4-(5-hydroxy-1H-tetrazol-



yl)phenyl]oxy}acetamide


158
N-{[3-(2-amino-5-chloropyridin-3-yl)phenyl]methyl}-N′-[4-chloro-3-



(trifluoromethyl)phenyl]urea


159
N-{[4-(2-amino-5-chloropyridin-3-yl)phenyl]methyl}-N′-[4-chloro-3-



(trifluoromethyl)phenyl]urea


160
N-{[3-(6-chloropyridin-3-yl)phenyl]methyl}-N′-[4-chloro-3-



(trifluoromethyl)phenyl]urea


161
N-{[4-(6-chloropyridin-3-yl)phenyl]methyl}-N′-[4-chloro-3-



(trifluoromethyl)phenyl]urea


162
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-{[4-(pyrimidin-2-



yloxy)phenyl]methyl}urea


163
N-({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)-3-(1H-



tetrazol-1-yl)benzamide


164
3-amino-6-(3-{[({[4-chloro-3-



(trifluoromethyl)phenyl]amino}carbonyl)amino]methyl}phenyl)-N-[2-



(dimethylamino)ethyl]pyrazine-2-carboxamide


165
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-{[3-(6-fluoropyridin-3-



yl)phenyl]methyl}urea


166
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-({3-[2-(methyloxy)pyridin-



3-yl]phenyl}methyl)urea


167
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-{[4-(6-fluoropyridin-3-



yl)phenyl]methyl}urea


168
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-({4-[2-(methyloxy)pyridin-



3-yl]phenyl}methyl)urea


169
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-{[4-(6-methylpyridin-3-



yl)phenyl]methyl}urea


170
N-{[4-(2-amino-5-fluoropyridin-3-yl)phenyl]methyl}-N′-[4-chloro-3-



(trifluoromethyl)phenyl]urea


171
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-{[3-(6-methylpyridin-3-



yl)phenyl]methyl}urea


172
N-{[4-(2-aminopyridin-3-yl)phenyl]methyl}-N′-[4-chloro-3-



(trifluoromethyl)phenyl]urea


173
N-{[3-(2-aminopyridin-3-yl)phenyl]methyl}-N′-[4-chloro-3-



(trifluoromethyl)phenyl]urea


174
[3-(6-methylpyridin-3-yl)phenyl]methyl [4-chloro-3-



(trifluoromethyl)phenyl]carbamate


175
[3-(2-amino-5-fluoropyridin-3-yl)phenyl]methyl [4-chloro-3-



(trifluoromethyl)phenyl]carbamate


176
[3-(2-aminopyridin-3-yl)phenyl]methyl [4-chloro-3-



(trifluoromethyl)phenyl]carbamate


177
(3-pyrazin-2-ylphenyl)methyl [4-chloro-3-



(trifluoromethyl)phenyl]carbamate


178
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-({3-[6-



(hydroxymethyl)pyridin-3-yl]phenyl}methyl)urea


179
N-{[3-(6-acetylpyridin-3-yl)phenyl]methyl}-N′-[4-chloro-3-



(trifluoromethyl)phenyl]urea


180
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-{[3-(6-cyanopyridin-3-



yl)phenyl]methyl}urea


181
1,1-dimethylethyl (3S)-3-({[3-amino-6-(3-{[({[4-chloro-3-



(trifluoromethyl)phenyl]amino}carbonyl)amino]methyl}phenyl)pyrazin-



2-yl]carbonyl}amino)piperidine-1-carboxylate


182
3-amino-6-(3-{[({[4-chloro-3-



(trifluoromethyl)phenyl]amino}carbonyl)amino]methyl}phenyl)-N-



[(3S)-piperidin-3-yl]pyrazine-2-carboxamide


183
1,1-dimethylethyl (3S)-3-({[3-amino-6-(4-{[({[4-chloro-3-



(trifluoromethyl)phenyl]amino}carbonyl)amino]methyl}phenyl)pyrazin-



2-yl]carbonyl}amino)piperidine-1-carboxylate


184
3-amino-6-(4-{[({[4-chloro-3-



(trifluoromethyl)phenyl]amino}carbonyl)amino]methyl}phenyl)-N-



[(3S)-piperidin-3-yl]pyrazine-2-carboxamide


185
[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl]methyl [4-chloro-3-



(trifluoromethyl)phenyl]carbamate


186
N-{[3-(2-amino-5-fluoropyridin-3-yl)phenyl]methyl}-N′-[4-chloro-3-



(trifluoromethyl)phenyl]urea


187
[6-(1H-tetrazol-1-yl)pyridin-2-yl]methyl [4-chloro-3-



(trifluoromethyl)phenyl]carbamate


188
[3-(1H-benzimidazol-2-yl)phenyl]methyl [4-chloro-3-



(trifluoromethyl)phenyl]carbamate


189
[3-(6-amino-2-methylpyridin-3-yl)phenyl]methyl [4-chloro-3-



(trifluoromethyl)phenyl]carbamate


190
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-({3-[5-(methylthio)pyridin-



3-yl]phenyl}methyl)urea


191
[4-(6-methylpyridin-3-yl)phenyl]methyl [4-chloro-3-



(trifluoromethyl)phenyl]carbamate


192
[4-(2-amino-5-fluoropyridin-3-yl)phenyl]methyl [4-chloro-3-



(trifluoromethyl)phenyl]carbamate


193
[4-(2-aminopyridin-3-yl)phenyl]methyl [4-chloro-3-



(trifluoromethyl)phenyl]carbamate


194
(4-pyrazin-2-ylphenyl)methyl [4-chloro-3-



(trifluoromethyl)phenyl]carbamate


195
[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl]methyl [4-chloro-3-



(trifluoromethyl)phenyl]carbamate


196
[4-(6-amino-2-methylpyridin-3-yl)phenyl]methyl [4-chloro-3-



(trifluoromethyl)phenyl]carbamate


197
[3-(1H-tetrazol-1-yl)phenyl]methyl 1,3-benzothiazol-2-ylcarbamate


198
[3-(1H-tetrazol-1-yl)phenyl]methyl (5-bromopyridin-2-yl)carbamate


199
(3-pyridin-3-ylphenyl)methyl (3,5-dimethylphenyl)carbamate


200
(3-pyridin-3-ylphenyl)methyl [5-chloro-2-



(methyloxy)phenyl]carbamate


201
[4-(1H-tetrazol-1-yl)phenyl]methyl [4-chloro-3-



(trifluoromethyl)phenyl]carbamate


202
(3-pyrimidin-5-ylphenyl)methyl [5-chloro-2-



(methyloxy)phenyl]carbamate


203
(4-pyrimidin-5-ylphenyl)methyl (3,4-dimethylphenyl)carbamate


204
(3-pyridin-3-ylphenyl)methyl (3,4-dimethylphenyl)carbamate


205
1,1-dimethylethyl 3-({[3-amino-6-(3-{[({[4-chloro-3-



(trifluoromethyl)phenyl]amino}carbonyl)amino]methyl}phenyl)pyrazin-



2-yl]carbonyl}amino)piperidine-1-carboxylate


206
1,1-dimethylethyl 3-({[3-amino-6-(4-{[({[4-chloro-3-



(trifluoromethyl)phenyl]amino}carbonyl)amino]methyl}phenyl)pyrazin-



2-yl]carbonyl}amino)piperidine-1-carboxylate


207
3-amino-6-(3-{[({[4-chloro-3-



(trifluoromethyl)phenyl]amino}carbonyl)amino]methyl}phenyl)-N-



piperidin-3-ylpyrazine-2-carboxamide


208
3-amino-6-(4-{[({[4-chloro-3-



(trifluoromethyl)phenyl]amino}carbonyl)amino]methyl}phenyl)-N-



piperidin-3-ylpyrazine-2-carboxamide


209
1,1-dimethylethyl 4-{[3-amino-6-(3-{[({[4-chloro-3-



(trifluoromethyl)phenyl]amino}carbonyl)amino]methyl}phenyl)pyrazin-



2-yl]carbonyl}piperazine-1-carboxylate


210
1,1-dimethylethyl 4-{[3-amino-6-(4-{[({[4-chloro-3-



(trifluoromethyl)phenyl]amino}carbonyl)amino]methyl}phenyl)pyrazin-



2-yl]carbonyl}piperazine-1-carboxylate


211
N-({3-[5-amino-6-(piperazin-1-ylcarbonyl)pyrazin-2-



yl]phenyl}methyl)-N′-[4-chloro-3-(trifluoromethyl)phenyl]urea


212
N-({4-[5-amino-6-(piperazin-1-ylcarbonyl)pyrazin-2-



yl]phenyl}methyl)-N′-[4-chloro-3-(trifluoromethyl)phenyl]urea


213
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-{[3-(1H-pyrazol-4-



yl)phenyl]methyl}urea


214
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-{[4-(1H-pyrazol-4-



yl)phenyl]methyl}urea


215
[3-(2-piperazin-1-ylpyrimidin-5-yl)phenyl]methyl [4-chloro-3-



(trifluoromethyl)phenyl]carbamate


216
[4-(2-piperazin-1-ylpyrimidin-5-yl)phenyl]methyl [4-chloro-3-



(trifluoromethyl)phenyl]carbamate


217
N-{[3-(2-chloropyridin-3-yl)phenyl]methyl}-N′-[4-chloro-3-



(trifluoromethyl)phenyl]urea


218
N-{[4-(2-chloropyridin-3-yl)phenyl]methyl}-N′-[4-chloro-3-



(trifluoromethyl)phenyl]urea


219
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-{[3-(2-fluoropyridin-3-



yl)phenyl]methyl}urea


220
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-{[4-(2-fluoropyridin-3-



yl)phenyl]methyl}urea


221
[3-(1H-tetrazol-1-yl)phenyl]methyl [3-



(trifluoromethyl)phenyl]carbamate


222
[3-(1H-tetrazol-1-yl)phenyl]methyl [6-(trifluoromethyl)pyridin-2-



yl]carbamate


223
[3-(1H-tetrazol-1-yl)phenyl]methyl [4-(trifluoromethyl)pyridin-2-



yl]carbamate


224
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-({3-[5-(methylthio)pyridin-



2-yl]phenyl}methyl)urea


225
[3-(2,6-dimethylpyridin-3-yl)phenyl]methyl [4-chloro-3-



(trifluoromethyl)phenyl]carbamate


226
{3-[5-(methyloxy)pyridin-3-yl]phenyl}methyl [4-chloro-3-



(trifluoromethyl)phenyl]carbamate


227
2,3′-bipyridin-6-ylmethyl [4-chloro-3-



(trifluoromethyl)phenyl]carbamate


228
(6-pyrimidin-5-ylpyridin-2-yl)methyl [4-chloro-3-



(trifluoromethyl)phenyl]carbamate


229
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-[(3-isoquinolin-4-



ylphenyl)methyl]urea


230
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-[(4-isoquinolin-4-



ylphenyl)methyl]urea


231
[6-(1H-tetrazol-1-yl)pyridin-2-yl]methyl [4-(trifluoromethyl)pyridin-2-



yl]carbamate


232
[3-(1H-pyrazol-4-yl)phenyl]methyl [4-chloro-3-



(trifluoromethyl)phenyl]carbamate


233
[4-(1H-pyrazol-4-yl)phenyl]methyl [4-chloro-3-



(trifluoromethyl)phenyl]carbamate









Table 9
c-KIT and/or Flt-3 Inhibitors
The Compounds in Table 9 can be prepared as pharmaceutically acceptable salts, solvates, hydrates, and/or isomers thereof. All such salt, solvate, hydrate, and isomer combinations of the Compounds in Table 9 can be used to practice the invention.








TABLE 9





Entry
Name
















1
4-((E)-2-{3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-5-



yl}ethenyl)phenol


2
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-(4-{3-[5-(4-ethylpiperazin-1-yl)-1H-



benzimidazol-2-yl]-1H-pyrazol-5-yl}phenyl)urea


3
N-(3-ethylphenyl)-N′-(4-{3-[5-(4-ethylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-



pyrazol-5-yl}phenyl)urea


4
N-(4-{3-[5-(4-ethylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-5-



yl}phenyl)-N′-[3-(trifluoromethyl)phenyl]urea


5
N-(3-acetylphenyl)-N′-(4-{3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-



1H-pyrazol-5-yl}phenyl)urea


6
N-(3,4-dichlorophenyl)-N′-(4-{3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-



yl]-1H-pyrazol-5-yl}phenyl)urea


7
N-(3-bromophenyl)-N′-(4-{3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-



1H-pyrazol-5-yl}phenyl)urea


8
N-[4-fluoro-3-(trifluoromethyl)phenyl]-N′-(4-{3-[5-(4-methylpiperazin-1-yl)-1H-



benzimidazol-2-yl]-1H-pyrazol-5-yl}phenyl)urea


9
N-(4-{3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-5-



yl}phenyl)-N′-[4-(phenyloxy)phenyl]urea


10
N-(3-chlorophenyl)-N′-(4-{3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-



1H-pyrazol-5-yl}phenyl)urea


11
N-[3,5-bis(methyloxy)phenyl]-N′-(4-{3-[6-(4-methylpiperazin-1-yl)-1H-



benzimidazol-2-yl]-1H-pyrazol-5-yl}phenyl)urea


12
N-(4-{3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-5-



yl}phenyl)-N′-{4-[(trifluoromethyl)oxy]phenyl}urea


13
N-(4-{3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-5-



yl}phenyl)-N′-[4-(trifluoromethyl)phenyl]urea


14
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-(4-{3-[5-(4-methylpiperazin-1-yl)-1H-



benzimidazol-2-yl]-1H-pyrazol-5-yl}phenyl)urea


15
N-(4-{3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-5-



yl}phenyl)-N′-[3-(trifluoromethyl)phenyl]urea


16
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-(4-{3-[4-(4-methylpiperazin-1-



yl)phenyl]-1H-pyrazol-5-yl}phenyl)urea


17
N-(3,4-dimethylphenyl)-N′-(4-{5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazol-



3-yl}phenyl)urea


18
N-(4-chlorophenyl)-N′-(4-{3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-



1H-pyrazol-5-yl}phenyl)urea


19
N-(3,5-difluorophenyl)-N′-(4-{3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-



yl]-1H-pyrazol-5-yl}phenyl)urea


20
N-[3-(methyloxy)phenyl]-N′-(4-{3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-



2-yl]-1H-pyrazol-5-yl}phenyl)urea


21
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-(4-{3-[4-(4-ethylpiperazin-1-yl)phenyl]-



1H-pyrazol-5-yl}phenyl)urea


22
N-(3-fluorophenyl)-N′-(4-{3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-



1H-pyrazol-5-yl}phenyl)urea


23
N-(4-fluorophenyl)-N′-(4-{3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-



1H-pyrazol-5-yl}phenyl)urea


24
N-(3-cyanophenyl)-N′-(4-{3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-



1H-pyrazol-5-yl}phenyl)urea


25
N-(3,4-difluorophenyl)-N′-(4-{3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-



yl]-1H-pyrazol-5-yl}phenyl)urea


26
N-[3,4-bis(methyloxy)phenyl]-N′-(4-{3-[5-(4-methylpiperazin-1-yl)-1H-



benzimidazol-2-yl]-1H-pyrazol-5-yl}phenyl)urea


27
N-[5-chloro-2-(methyloxy)phenyl]-N′-(4-{5-[4-(4-methylpiperazin-1-yl)phenyl]-



1H-pyrazol-3-yl}phenyl)urea


28
N-(4-{5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazol-3-yl}phenyl)-N′-[4-



(phenyloxy)phenyl]urea


29
N-(2,4-difluorophenyl)-N′-(4-{3-[6-(4-ethylpiperazin-1-yl)-1H-benzimidazol-2-yl]-



1H-pyrazol-5-yl}phenyl)urea


30
N-{4-[3-(1H-benzimidazol-2-yl)-1H-pyrazol-5-yl]phenyl}-N′-[4-chloro-3-



(trifluoromethyl)phenyl]urea


31
N-{4-[3-(1H-benzimidazol-2-yl)-1H-pyrazol-5-yl]phenyl}-N′-[2-fluoro-5-



(trifluoromethyl)phenyl]urea


32
N-(2,4-difluorophenyl)-N′-(4-{3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-



yl]-1H-pyrazol-5-yl}phenyl)urea


33
N-{4-[3-(1H-benzimidazol-2-yl)-1H-pyrazol-5-yl]phenyl}-N′-phenylurea


34
N-[3,5-bis(trifluoromethyl)phenyl]-N′-(4-{3-[5-(4-methylpiperazin-1-yl)-1H-



benzimidazol-2-yl]-1H-pyrazol-5-yl}phenyl)urea


35
N-(2-fluorophenyl)-N′-(4-{3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-



1H-pyrazol-5-yl}phenyl)urea


36
4-((E)-2-{5-[(E)-2-phenylethenyl]-1H-pyrazol-3-yl}ethenyl)phenol


37
2-(methyloxy)-4-((E)-2-{5-[(E)-2-phenylethenyl]-1H-pyrazol-3-yl}ethenyl)phenol


38
N-(5-fluoro-2-methylphenyl)-N′-(4-{3-[6-(4-methylpiperazin-1-yl)-1H-



benzimidazol-2-yl]-1H-pyrazol-5-yl}phenyl)urea


39
N-(4-{3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-5-



yl}phenyl)-N′-phenylurea


40
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-(4-{3-[3-(4-methylpiperazin-1-



yl)phenyl]-1H-pyrazol-5-yl}phenyl)urea


41
N-(2,4-difluorophenyl)-N′-(4-{3-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazol-5-



yl}phenyl)urea


42
N-(2,3-dihydro-1,4-benzodioxin-6-yl)-N′-(4-{5-[4-(4-methylpiperazin-1-



yl)phenyl]-1H-pyrazol-3-yl}phenyl)urea


43
N-[2,4-bis(methyloxy)phenyl]-N′-(4-{5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-



pyrazol-3-yl}phenyl)urea


44
4-((E)-2-{3-[(E)-2-(4-fluorophenyl)ethenyl]-1H-pyrazol-5-yl}ethenyl)-2-



(methyloxy)phenol


45
4-{(E)-2-[3-(1-benzofuran-2-yl)-1H-pyrazol-5-yl]ethenyl}phenol


46
N-(4-{3-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazol-5-yl}phenyl)-N′-(2-



phenylethyl)ethanediamide


47
4-{(E)-2-[3-(1H-benzimidazol-2-yl)-1H-pyrazol-5-yl]ethenyl}phenol


48
4-((E)-2-{3-[(E)-2-(4-chlorophenyl)ethenyl]-1H-pyrazol-5-yl}ethenyl)-2-



(methyloxy)phenol


49
4-{(E)-2-[3-(1-benzothien-2-yl)-1H-pyrazol-5-yl]ethenyl}phenol


50
N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-[4-(3-phenyl-1H-pyrazol-5-



yl)phenyl]urea


51
4-((E)-2-{3-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazol-5-yl}ethenyl)phenol


52
1,1-dimethylethyl {4-[3-(1H-benzimidazol-2-yl)-1H-pyrazol-5-



yl]phenyl}carbamate


53
N-(5-fluoro-2-methylphenyl)-N′-(4-{5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-



pyrazol-3-yl}phenyl)urea


54
4-[(E)-2-(3-phenyl-1H-pyrazol-5-yl)ethenyl]phenol


55
2-(methyloxy)-4-[(E)-2-(5-phenyl-1H-pyrazol-3-yl)ethenyl]phenol


56
4-[(E)-2-(5-naphthalen-2-yl-1H-pyrazol-3-yl)ethenyl]phenol


57
4-{(E)-2-[5-(2-fluorophenyl)-1H-pyrazol-3-yl]ethenyl}phenol


58
4-((E)-2-{3-[3-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazol-5-yl}ethenyl)phenol


59
4-((E)-2-{3-[(E)-2-(2,4-difluorophenyl)ethenyl]-1H-pyrazol-5-yl}ethenyl)-2-



(methyloxy)phenol


60
4-{(E)-2-[5-(4-fluorophenyl)-1H-pyrazol-3-yl]ethenyl}phenol


61
4-{(E)-2-[3-(4-chlorophenyl)-1H-pyrazol-5-yl]ethenyl}phenol


62
4-[(E)-2-(5-pyridin-2-yl-1H-pyrazol-3-yl)ethenyl]phenol


63
4-{(E)-2-[3-(5-chloro-1-benzofuran-2-yl)-1H-pyrazol-5-yl]ethenyl}phenol


64
N-(1,1-dimethylethyl)-N′-(4-{3-[5-(4-ethylpiperazin-1-yl)-1H-benzimidazol-2-yl]-



1H-pyrazol-5-yl}phenyl)urea


65
4-[(E)-2-(3-pyridin-4-yl-1H-pyrazol-5-yl)ethenyl]phenol


66
4-{(E)-2-[3-(3-chlorophenyl)-1H-pyrazol-5-yl]ethenyl}phenol


67
4-((E)-2-{5-[2-(methyloxy)phenyl]-1H-pyrazol-3-yl}ethenyl)phenol


68
4-{(E)-2-[3-(2-chlorophenyl)-1H-pyrazol-5-yl]ethenyl}phenol


69
4-[(E)-2-(3-pyridin-3-yl-1H-pyrazol-5-yl)ethenyl]phenol


70
4-((E)-2-{5-[3-(methyloxy)phenyl]-1H-pyrazol-3-yl}ethenyl)phenol


71
1,1-dimethylethyl (4-{3-[(E)-2-phenylethenyl]-1H-pyrazol-5-yl}phenyl)carbamate


72
4-{(E)-2-[3-(3,4-dichlorophenyl)-1H-pyrazol-5-yl]ethenyl}phenol


73
2-{5-[(E)-2-phenylethenyl]-1H-pyrazol-3-yl}-1-benzofuran-6-ol


74
4-{(E)-2-[5-(3-fluorophenyl)-1H-pyrazol-3-yl]ethenyl}phenol


75
2-(5-phenyl-1H-pyrazol-3-yl)-1H-benzimidazole


76
N-phenyl-N′-[4-(3-phenyl-1H-pyrazol-5-yl)phenyl]urea


77
4-[3-(1H-benzimidazol-2-yl)-1H-pyrazol-5-yl]aniline


78
4-[(E)-2-(5-biphenyl-3-yl-1H-pyrazol-3-yl)ethenyl]phenol


79
4-((E)-2-{5-[5-(4-methylpiperazin-1-yl)-1H-



benzimidazol-2-yl]-1H-pyrazol-3-yl}ethenyl)phenol









General Administration
In one aspect, the invention provides pharmaceutical compositions comprising an inhibitor of PI3K according to the invention and a pharmaceutically acceptable carrier, excipient, or diluent. In certain other specific embodiments, administration is by the oral route. Administration of the compounds of the invention, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted modes of administration or agents for serving similar utilities. Thus, administration can be, for example, orally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermally, intravaginally, intravesically, intracistemally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, specifically in unit dosage forms suitable for simple administration of precise dosages.
The compositions will include a conventional pharmaceutical carrier or excipient and a compound of the invention as the/an active agent, and, in addition, may include carriers and adjuvants, etc.
Adjuvants include preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
If desired, a pharmaceutical composition of the invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, etc.
The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size. For example, U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
One specific route of administration is oral, using a convenient daily dosage regimen that can be adjusted according to the degree of severity of the disease-state to be treated.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, as for example, cellulose derivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate, (e) solution retarders, as for example paraffin, (1) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol, and glycerol monostearate, magnesium stearate and the like (h) adsorbents, as for example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms as described above can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain pacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedded compositions that can be used are polymeric substances and waxes. The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are prepared, for example, by dissolving, dispersing, etc., a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like; solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide; oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan; or mixtures of these substances, and the like, to thereby form a solution or suspension.
Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
Compositions for rectal administrations are, for example, suppositories that can be prepared by mixing the compounds of the present invention with for example suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.
Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
Compressed gases may be used to disperse a compound of this invention in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
Generally, depending on the intended mode of administration, the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient. In one example, the composition will be between about 5% and about 75% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, with the rest being suitable pharmaceutical excipients.
Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pa., 1990). The composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of a disease-state in accordance with the teachings of this invention.
The compounds of the invention, or their pharmaceutically acceptable salts or solvates, are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular disease-states, and the host undergoing therapy. The compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is an example. The specific dosage used, however, can vary. For example, the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well known to one of ordinary skill in the art.
If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described above and the other pharmaceutically active agents within its approved dosage range. Compounds of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agents when a combination formulation is inappropriate.
Representative pharmaceutical formulations containing a compound of Formula I are described below in the Pharmaceutical Composition Examples.
Utility
Certain compounds of Formula I have been tested using the assay described in Biological Example 1 and have been determined to be PI3K inhibitors. As such compounds of Formula I are useful for treating diseases, particularly cancer in which PI3K activity contributes to the pathology and/or symptomatology of the disease. For example, cancer in which PI3K activity contributes to its pathology and/or symptomatology include breast cancer, colon cancer, rectal cancer, endometrial cancer, gastric carcinoma, glioblastoma, hepatocellular carcinoma, small cell lung cancer, non-small cell lung cancer, melanoma, ovarian cancer, pancreatic cancer, prostate carcinoma, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), and thyroid carcinoma, and the like.
Suitable in vitro assays for measuring PI3K activity and the inhibition thereof by compounds are known. Typically, the assay will measure PI3K-induced ATP consumption. For further details of an in vitro assay for measuring PI3K activity see Biological Examples, Example 1 infra. Cellular activity can be determined using assays as described in Biological Examples 2, 3, and 4 infra. Suitable in vivo models of cancer are known to those of ordinary skill in the art. For further details of in vivo assays see Biological Examples 5-10, infra. Examples describing the administration of a Compound of Formula I in combination with anticancer agents are described in Biological Examples 11-14, infra. Following the examples disclosed herein, as well as that disclosed in the art, a person of ordinary skill in the art can determine what combinations of a Compound of Formula I and anti-cancer agents would be effective for treating cancer.
General Synthesis
Compounds of this invention can be made by the synthetic procedures described below. The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wis.), or Bachem (Torrance, Calif.), or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art having referred to this disclosure. The starting materials and the intermediates of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.
Unless specified to the contrary, the reactions described herein take place at atmospheric pressure and over a temperature range from about −78° C. to about 150° C., in another embodiment from about 0° C. to about 125° C. and in another embodiment at about room (or ambient) temperature, e.g., about 20° C. Unless otherwise stated (as in the case of an hydrogenation), all reactions are performed under an atmosphere of nitrogen.
Prodrugs can be prepared by techniques known to one skilled in the art. These techniques generally modify appropriate functional groups in a given compound. These modified functional groups regenerate original functional groups by routine manipulation or in vivo. Amides and esters of the compounds of the present invention may be prepared according to conventional methods. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference for all purposes.
The compounds of the invention, or their pharmaceutically acceptable salts, may have asymmetric carbon atoms or quaternized nitrogen atoms in their structure. Compounds of Formula I that may be prepared through the syntheses described herein may exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. The compounds may also exist as geometric isomers. All such single stereoisomers, racemates and mixtures thereof, and geometric isomers are intended to be within the scope of this invention. Some of the compounds of the invention may exist as tautomers. For example, where a ketone or aldehyde is present, the molecule may exist in the enol form; where an amide is present, the molecule may exist as the imidic acid; and where an enamine is present, the molecule may exist as an imine. All such tautomers are within the scope of the invention. In particular, imidazol-5-yl and pyrazol-5-yl each can also exist in their respective tautomeric forms imidazol-4-yl and pyrazol-3-yl. Regardless of which structure or which terminology is used, each tautomer is included within the scope of the Invention.
The present invention also includes N-oxide derivatives and protected derivatives of compounds of Formula I. For example, when compounds of Formula I contain an oxidizable nitrogen atom, the nitrogen atom can be converted to an N-oxide by methods well known in the art. When compounds of Formula I contain groups such as hydroxy, carboxy, thiol or any group containing a nitrogen atom(s), these groups can be protected with a suitable “protecting group” or “protective group”. A comprehensive list of suitable protective groups can be found in T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1991, the disclosure of which is incorporated herein by reference in its entirety. The protected derivatives of compounds of Formula I can be prepared by methods well known in the art.
Methods for the preparation and/or separation and isolation of single stereoisomers from racemic mixtures or non-racemic mixtures of stereoisomers are well known in the art. For example, optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Enantiomers (R- and S-isomers) may be resolved by methods known to one of ordinary skill in the art, for example by: formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which may be separated, for example, by crystallization, selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where a desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step may, be required to liberate the desired enantiomeric form. Alternatively, specific enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents or by converting on enantiomer to the other by asymmetric transformation. For a mixture of enantiomers, enriched in a particular enantiomer, the major component enantiomer may be further enriched (with concomitant loss in yield) by recrystallization.
In addition, the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
The chemistry for the preparation of the compounds of this invention is known to those skilled in the art. In fact, there may be more than one process to prepare the compounds of the invention. For specific examples, see M. Barvian et al. J. Med. Chem. 2000, 43, 4606-4616; S. N. VanderWei et al. J. Med. Chem. 2005, 48, 2371-2387; P. L. Toogood et al. J. Med. Chem. 2005, 48, 2388-2406; J. Kasparec et al. Tetrahedron Letters 2003, 44, 4567-4570; and references cited therein. See also U.S. Pre-grant publication US2004/0009993 A1 (M. Angiolini et al.), which is incorporated herein by reference, and references cited therein. The following examples illustrate but do not limit the invention. All references cited herein are incorporated by reference in their entirety.
A compound of the invention where R1 is optionally substituted alkyl, R2 is hydrogen or optionally substituted alkyl, R4 is methyl or ethyl, R6 is phenyl or heteroaryl each of which is optionally substituted with 1, 2, 3, 4, or 5 R9 groups (as defined in the Summary of the Invention), and R2 is hydrogen can be prepared according to Scheme 1.







To a solution of commercially available 2-methyl-2-thiopseudourea sulfate in a solvent such as water is added a base such as sodium carbonate and an intermediate of formula 10 at room temperature. The reaction mixture is stirred for overnight or less. After neutralizing, 11 is collected through filtration and followed by drying under vacuum. 11 is then treated with POCl3 and the reaction is heated to reflux for approximately 2 h and then concentrated under vacuum to dryness. 1 can be used directly in the next reaction without further purification.
An intermediate of formula 2 is prepared by reacting an intermediate of formula 1 with a primary amine R1NH2 in a solvent such as water and with heating. 2 is then treated with iodine monochloride in a solvent such as methanol at around 0° C. and allowed to react for approximately overnight or less as needed for the reaction to go to completion to form 3. After completion the residue is triturated with acetone. The intermediate 3 is then reacted in a solvent, such as DMA, with ethyl acrylate in the presence of a base, such as triethylamine, and in the presence of a catalyst, such as Pd(OAc)2, and (+)BINAP. The reaction is heated to approximately 100° C. and allowed to react for approximately overnight or less as needed for the reaction to go to completion to form 4. 4 is then optionally purified by column chromatography.
5 is prepared by treating 4 with DBU in the presence of a base such as DIPEA at room temperature. Then the reaction mixture is heated to reflux and reacted for approximately 15 h. After evaporation of solvent, the residue is triturated with acetone and collected by filtration to yield 5.
6 is prepared by reacting 5 with a brominating agent such as Br2 in a solvent such as DCM at room temperature. Then the reaction mixture is stirred for approximately overnight. The resulting product is filtered and then suspended in a solvent such as DCM and treated with a base such as triethylamine. The mixture is then washed with water and dried over a drying agent such as Na2SO4 to yield 6.
A Suzuki coupling is then performed using 6 reacting with a boronic acid (or ester) of formula R6B(OH)2 in a solvent such as a DME-H2O mixture, in the presence of a catalyst such as Pd(dpppf) and a base such as triethylamine at room temperature. The reaction mixture is heated to reflux for approximately 4 h. After cooling to room temperature, the reaction mixture is partitioned with water and ethyl acetate. After separation, the organic layer is dried over a drying agent such as Na2SO4 to yield 7.
The methylthio group of 7 is then oxidized with m-CPBA in a solvent such as DCM at room temperature allowing to stir for approximately 4 h. After removal of the solvent under reduced pressure, the product is treated with an amine of formula R2NH2 in a solvent such as dioxane and stirred at room temperature for approximately overnight to yield a Compound of Formula I.
Alternatively, a compound of the invention where R′ is optionally substituted alkyl, R4 is methyl or ethyl, R6 is phenyl or heteroaryl each of which is optionally substituted with 1, 2, 3, 4, or 5 R9 groups (as defined in the Summary of the Invention), and R2 is hydrogen can be prepared according to Scheme 2.




An intermediate of formula 9 is prepared by reacting an intermediate of formula 8 with neat POCl3 and heating. 9 is then treated with a primary amine R1NH2 in a solvent such as water or THF and triethylamine at 0° C. to form 10. After removal of the solvent under reduced pressure, the intermediate 10 is then reacted with lithium aluminum hydride in a solvent such as THF at 0° C. After quenching and aqueous workup, solvent removal provided crystalline 11 without further purification. Treatment of 11 with manganese (II) dioxide in a solvent such as methylene chloride or chloroform at room temperature provided aldehyde 12 upon filtration and solvent removal. A Wittig reaction with aldehyde 12 can be employed with (carbethoxymethylene)triphenylphosphorane in refluxing THF to provide the common intermediate 4. 4 can then be used to prepare a Compound of Formula I using the procedures described in Scheme 1.
A compound of the invention where R1 is optionally substituted alkyl, R4 is methyl or ethyl, R6 is phenyl or heteroaryl each of which is optionally substituted with 1, 2, 3, 4, or 5 R9 groups (as defined in the Summary of the Invention), and R2 is hydrogen can be prepared according to Scheme 3.




An intermediate of formula 14 is prepared by reacting an intermediate of formula 13 with a primary amine R1NH2 in a solvent such as water and with heating. 14 is then treated with iodine monochloride in a solvent such as methanol at around 0° C. and allowed to react for approximately overnight or less as needed for the reaction to go to completion to form 15. After completion the residue is triturated with acetone. The intermediate 15 is then reacted in a solvent, such as DMA, with ethyl acrylate in the presence of a base, such as triethylamine, and in the presence of a catalyst, such as Pd(OAc)2, and (+)BINAP. The reaction is heated to approximately 100° C. and allowed to react for approximately overnight or less as needed for the reaction to go to completion to form 16. 16 is then optionally purified by column chromatography. A Compound of Formula I can then be prepared from 16 by using the same reaction conditions as described in Scheme 1 (starting at the point of the preparation of 5 from 4).
A compound of the invention where R′ is optionally substituted alkyl, R4 is methyl or ethyl, R6 is phenyl or heteroaryl each of which is optionally substituted with 1, 2, 3, 4, or 5 R9 groups (as defined in the Summary of the Invention), and R2 is hydrogen can alternatively be prepared according to Scheme 4.




An intermediate of formula 20 is prepared by reacting an intermediate of formula 19 with neat POCl3 and heating. 20 is then treated with a primary amine R1NH2 in a solvent such as water or THF and triethylamine at 0° C. to form 21. After removal of the solvent under reduced pressure, the intermediate 21 is then reacted with lithium aluminum hydride in a solvent such as THF at 0° C. After quenching and aqueous workup, solvent removal provided crystalline 22 without further purification. Treatment of 22 with manganese (II) dioxide in a solvent such as methylene chloride or chloroform at room temperature provided aldehyde 23 upon filtration and solvent removal. A Knovenegal-type condensation with 23 and an arylacetonitrile in the presence of a base such as potassium carbonate or sodium hydroxide in a protic solvent provides the cyclized imine 24. Acetylation of the imine with acetic anhydride is required prior to hydrolysis which takes place in the presence of aqueous acid and heating to afford 25. Subsequently, 25 can be oxidized to the corresponding sulfone with m-CPBA at room temperature and displaced with ammonium to provide I.
SYNTHETIC EXAMPLES
Example 1
2-amino-8-ethyl-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one




To a solution of 2-methyl-2-thiopseudourea sulfate (Aldrich, 58.74 g, 0.422 mol) in water (1000 mL) were added sodium carbonate (81.44 g, 0.768 mol) and ethyl acetoacetate (50 g, 0.384 mol) at room temperature. The reaction mixture was stirred overnight. After neutralizing to pH=8, the solid was collected through filtration followed by drying under vacuum overnight to afford 6-methyl-2-(methylthio)pyrimidin-4(3H)-one (57.2 g, 95% yield) of product. 1H NMR (400 MHz, DMSO-d6): δ 12.47 (bs, 1H), 5.96 (bs, 1H), 2.47 (s, 3H), 2.17 (s, 3H).




To the round bottom flask containing 6-methyl-2-(methylthio)pyrimidin-4(3H)-one (19 g, 121.6 mmol) was added POCl3 (30 mL). The reaction mixture was heated to reflux for 2 h and then concentrated on a rotary evaporator to dryness. The crude 4-chloro-6-methyl-2-(methylthio)pyrimidine was used directly in the next reaction without further purification.




To the 4-chloro-6-methyl-2-(methylthio)pyrimidine from above was added 30 mL of a solution of 70% ethylamine in water. The reaction mixture was heated to 50° C. for 3 h. After completion, excess ethylamine was evaporated on rotary evaporator under vacuum. The solid was filtered and dried under vacuum to afford N-ethyl-6-methyl-2-(methylthio)pyrimidin-4-amine (20 g, 90% yield).




To the solution of N-ethyl-6-methyl-2-(methylthio)pyrimidin-4-amine (20 g, 121.6 mmol) in methanol was added iodine monochloride (26.58 g, 163.7 mmol) in small portions at 0° C. Then the reaction mixture was stirred overnight. After evaporation of solvent, the residue was triturated with acetone. The product N-ethyl-5-iodo-6-methyl-2-(methylthio)pyrimidin-4-amine (25.2 g, 75% yield) was collected by filtration. 1H NMR (400 MHz, CDCl3): δ 5.37 (bs, 1H), 3.52 (q, J=7.2 Hz, 1H), 2.50 (s, 3H), 1.26 (t, J=7.2 Hz, 3H).




To the solution of N-ethyl-5-iodo-6-methyl-2-(methylthio)pyrimidin-4-amine (25.2 g, 81.48 mmol) in DMA (260 mL) were added ethyl acrylate (12.23 g, 122.2 mmol), Pd(OAc)2 (3.65 g, 16.25 mmol), (+)BINAP and triethyl amine (24.68 g, 244.4 mmol). Then the reaction mixture was heated to 100° C. and reacted overnight. After evaporation of solvent, the residue was diluted with water and the aqueous layer was extracted with ethyl acetate. The product (E)-ethyl-3-(4-(ethylamino)-6-methyl-2-(methylthio)pyrimidin-5-yl)acrylate (16.8 g, 73% yield) was isolated by silica gel column chromatography with 6-8% ethyl acetate in hexane as eluent. 1H NMR (400 MHz, CDCl3): δ 7.65 (d, J=16.4 Hz, 1H), 6.20 (d, J=16.4 Hz, 1H), 5.15 (bs, 1H), 4.28 (q, J=7.2 Hz, 2H), 3.54 (q, J=7.2 Hz, 2H), 2.53 (s, 3H), 2.37 (s, 3H), 1.35 (t, J=7.2 Hz, 3H), 1.24 (t, J=7.2 Hz, 3H).




To a solution of (E)-ethyl-3-(4-(ethylamino)-6-methyl-2-(methylthio)pyrimidin-5-yl)acrylate (16.8 g, 59.8 mmol) in DIPEA was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 18.21 g, 119.6 mmol) at room temperature. Then the reaction mixture was heated to reflux and reacted for 15 h. After evaporation of solvent, the residue was triturated with acetone. The product 8-ethyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (10.77 g, 77% yield) was collected by filtration. NMR (400 MHz, CDCl3): δ 7.78 (d, J=9.6 Hz, 1H), 6.63 (d, J=9.6 Hz, 1H), 4.5 (q, J=7.2 Hz, 2H), 2.67 (s, 3H), 2.62 (s, 3H), 1.33 (t, J=7.2 Hz, 3H).




To a solution of 8-ethyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (6.31 g, 26.84 mmol) in DCM was added Br2 (4.79 g, 29.52 mmol) dropwise at room temperature. Then the reaction mixture was stirred at room temperature overnight. After filtration the solid was suspended in DCM (100 mL), and triethylamine (20 mL) was added. The mixture was washed with water and dried with Na2SO4, and the product 6-bromo-8-ethyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (6.96 g, 83% yield) was obtained after evaporation of DCM. 1H NMR (400 MHz, CDCl3): δ 8.22 (s, 1H), 4.56 (q, J=7.2 Hz, 2H), 2.68 (s, 3H), 2.62 (s, 3H), 1.34 (t, J=7.2 Hz, 3H).




To a solution of 6-bromo-8-ethyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (0.765 g, 2.43 mmol) in DME-H2O (10:1 11 mL) was added 1H-pyrazol-5-ylboronic acid (Frontier, 0.408 g, 3.65 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with CH2Cl2 (Pd(dpppf), 0.198 g, 0.243 mmol) and triethylamine (0.736 g, 7.29 mmol) at room temperature. Then the reaction mixture was heated to reflux and reacted for 4 h. After cooling down to room temperature, the reaction mixture was partitioned with water and ethyl acetate. After separation, the organic layer was dried with Na2SO4, and the product 8-ethyl-4-methyl-2-(methylthio)-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (0.567 g, 77% yield) was obtained by silica gel column chromatography. 1H NMR (400 MHz, CDCl3): δ 13.3 (bs, 1H), 8.54 (s, 1H), 7.82-7.07 (m, 2H), 4.45 (q, J=7.2 Hz, 2H), 2.71 (s, 3H), 2.60 (s, 3H), 1.26 (t, J=7.2 Hz, 3H).




To the solution of 8-ethyl-4-methyl-2-(methylthio)-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (0.123 g, 0.41 mmol) in DCM (2 mL) was added MCPBA (0.176 g, 77%, 0.785 mmol) in a small portion at room temperature. Then the reaction mixture was stirred for 4 h. After evaporation of DCM, dioxane (1 mL) and liquid ammonia (1 mL) were introduced. The reaction was stirred at room temperature overnight. The product 2-amino-8-ethyl-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (50.4 mg) was obtained by silica gel column chromatography. 1H NMR (400 MHz, CD3OD): δ 8.41 (s, 1H), 7.62 (d, J=2.0 Hz, 1H), 6.96 (d, J=2.0 Hz, 1H), 4.51 (q, J=7.2 Hz, 2H), 2.64 (s, 3H), 1.29 (t, J=7.2 Hz, 3H); MS (EI) for C13H14N6O: 271.3 (MH+).
Using the same or analogous synthetic techniques and substituting with appropriate reagents, the following compounds were prepared:
Example 1a
2-(amino)-8-ethyl-4-ethyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, DMSO-D6): δ 8.40 (s, 1H), 7.27 (bs, 1H), 7.00 (s, 1H), 4.40 (q, J=7.2 Hz, 2H), 2.95 (d, J=7.20 Hz, 2H), 1.14 (t, J=7.2 Hz, 3H), 1.08 (t, J=7.2 Hz, 3H), 0.89 (m, 1H), 0.24 (m, 2H), 0.01 (m, 2H); MS (EI) for C14H16N6O: 285.2 (MH+).
Example 1b
8-ethyl-4-methyl-2-(methylamino)-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CH3OH-d4): δ 8.39 (s, 1H), 7.60 (bs, 1H), 6.93 (bs, 1H), 4.53 (bs, 2H), 3.02 (s, 3H), 2.84 (bs, 3H), 1.33 (bs, 3H); MS (EI) for C14H16N6O: 285.3 (MH+).
Example 1c
8-Ethyl-2-[(2-fluoroethyl)amino]-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CH3OH-d4): δ 8.34 (bs, 1H), 7.25 (bs, 1H), 6.90 (bs, 1H), 4.60 (dt, J=5.2, 2.2 Hz, 2H), 4.49 (q, J=7.20 Hz, 2H), 3.78 (dt, J=5.2, 2.2 Hz, 2H), 2.64 (s, 3H), 1.30 (t, J=7.2 Hz, 3H); MS (EI) for C15H17FN6O: 317.3 (MH+).
Example 1d
2-Amino-8-cyclopentyl-4-methyl-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, DMSO-d6): δ 13.10 (s, 1H), 8.42 (d, 1H), 7.70 (s, 1H), 7.20 (bs, 2H), 6.01 (m, 1H), 2.61 (s, 3H), 2.30 (m, 2H), 2.10 (m, 2H), 1.80 (m, 2H), 1.60 (m, 2H); MS (EI) for C16H18N6O: 311.8 (M+H).
Intermediate 1
Alternate route to (E)-ethyl-3-(4-(ethylamino)-6-methyl-2-(methylthio)pyrimidin-5-yl)acrylate




N,N-Dimethyl acetamide dimethyl acetal (75 g, 0.56 mole) was added to a suspension of thiourea (33.0 g, 0.43 mole) in methylene chloride. The mixture was heated under reflux for 4 h. The solvent was removed and the residue was crystallized from 5% MeOH and diethyl ether affording (1E)-N′-(aminocarbonothioyl)-N,N-dimethylethanimidamide (47.8 g, 76% yield).




A suspension of (1E)-N′-(aminocarbonothioyl)-N,N-dimethylethanimidamide (47.8 g, 0.33 mole) in methyl iodide (150 mL) and THF (350 mL) was stirred for 18 h at room temperature. The mixture was evaporated under reduced pressure. After addition of 5% MeOH and diethyl ether, the compound precipitated and was collected by filtration affording (1E)-N′-[amino(methylthio)methyl]-N,N-dimethylethanimidamide hydrogen iodide salt (91.0 g, 96% yield).




To a solution of (1E)-N′-[amino(methylthio)methyl]-N,N-dimethylethanimidamide hydrogen iodide salt (73.0 g, 0.26 mole) in dry dichloromethane (900 mL), was added ethyl 3-chloro-3-oxopropanoate (44 mL, 95% Lancaster, 0.34 mole) was added under a nitrogen atmosphere. The mixture was stirred for 4 h at room temperature, cooled to 0° C. then triethylamine (107 mL, 0.78 mole) was added. The reaction mixture was stirred overnight. The solvent was removed and H2O was added. The pH was adjusted to pH=5.0 with acetic acid and extracted with ethylacetate then evaporated and crystallized from the appropriate solvent (Ethylacetate-Hexanes mixture solvent, approximately 20% ethylacetate-Hexanes). This afforded ethyl 4-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (36.5 g, 62% yield) after drying under vacuum.




A solution of ethyl 4-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (60 g, 0.26 mole) and phosphorous oxychloride (POCl3, 320 mL) was heated under reflux for 4 to 5 h (monitor reaction by TLC using 30% ethylacetate and hexanes). After completion of reaction, phosphorous oxychloride was removed on a rotary evaporator. The residue was poured on to ice water and extracted with ethylacetate several times. The combined organic layers were evaporated, on a rotary evaporator, to give crude ethyl 4-chloro-6-methyl-2-(methylthio)pyrimidine-5-carboxylate (65 g). This compound was used without purification.




To a solution of ethyl 4-chloro-6-methyl-2-(methylthio)pyrimidine-5-carboxylate (65 g) in THF (1000 mL) and triethylamine (110 mL, 0.81 mole) was added ethylamine (2.0 M in THF, 0.81 mole) at 0° C. This reaction mixture was stirred at room temperature overnight and then solvents were removed on a rotary evaporator. H2O was added and the mixture extracted with ethyl acetate several times. Solvents from the combined organic layers were removed on a rotary evaporator affording 58 g (86% yield) of ethyl 4-(ethylamino)-6-methyl-2-(methylthio)pyrimidine-5-carboxylate. This material was used as such without further purification.




To a lithium aluminum hydride solution (LAH, 1.0 M solution in THF, Aldrich, 450 mL) was added a solution of ethyl 4-(ethylamino)-6-methyl-2-(methylthio)pyrimidine-5-carboxylate (57 g) in THF (1000 mL). The reaction mixture was stirred overnight. After cooling to 0° C., the reaction mixture was cautiously quenched with a 1:9 mixture of H2O/THF until gas evolution has ceased, then diluted with H2O (500 mL) and stirred well for 2 h. The resulting slurry was extracted with ethylacetate several times. The aqueous layer was then filtered through Celite and washed with ethylacetate again. The combined organic layers were washed with brine, dried and concentrated under reduced pressure to give 41.0 g (85% yield) of [4-(ethylamino)-6-methyl-2-(methylthio)pyrimidin-5-yl]methanol as a light yellow crystal, which was used without purification in the next step.




To a solution of [4-(ethylamino)-6-methyl-2-(methylthio)pyrimidin-5-yl]methanol (41.0 g) in chloroform (4000 mL) was added manganese oxide (125 g, 1.4 mole) and stirred for 4 h at room temperature. More manganese oxide was added until the disappearance of alcohol compound was observed. The reaction mixture was filtered through Celite and washed with some chloroform and evaporated all organic solvents to give 38 g (92% yield) of 4-(ethylamino)-6-methyl-2-(methylthio)pyrimidine-5-carbaldehyde as a colorless solid, which was used without purification in the next step.




To a solution of 4-(ethylamino)-6-methyl-2-(methylthio)pyrimidine-5-carbaldehyde (38 g, 180 mmol) in THF (500 mL) was added (Carbethoxymethylene) triphenylphosphorane (95%, Aldrich, 85.18 g, 244 mmol). The reaction mixture was heated to reflux for 1.5 h and was monitored by TLC (4:1 hexanes/ethylacetate). The reaction was cooled to room temperature and was concentrated on a rotary evaporator. It was directly subjected to column chromatography (4:1 hexanes/ethylacetate) to give (E)-ethyl-3-(4-(ethylamino)-6-methyl-2-(methylthio)pyrimidin-5-yl)acrylate as a white crystal, 46.14 g (91% yield).
Example 2
2-Amino-6-bromo-8-ethyl-4-methylpyrido[2,3-c]pyrimidin-7(8H)-one




To a 3-necked 3-L flask, that was equipped with an overhead stirrer, was added in order 2-amino-4-chloro-6-methylpyrimidine (Aldrich, 100 g, 0.696 mol, 1 equiv.), ethylamine (70% ethylamine in water, Lancaster, 625 mL), 625 mL H2O, and 125 mL TEA (0.889 mol, 1.28 equiv.). The mixture was stirred and heated at reflux for 20 h, during which time the reaction turned homogeneous. The reaction was allowed to cool to room temperature. The volatile ethylamine was removed on a rotary evaporator. A precipitate formed. The aqueous mixture containing the precipitate was allowed to stand at room temperature for 2 h and then filtered. After drying under vacuum, 106 g (100% yield) of 2-amino-6-ethylaminopyrimidine was obtained as a colorless solid. This material was used as such in the following reaction.




To a solution of 2-amino-6-ethylaminopyrimidine (98 g, 0.64 mol) in methanol (1.6 L) was added ICl (115.0 g, 0.71 mol) in a small portion at 15° C. Then the reaction mixture was stirred at room temperature for 3 h (monitored by LC/MS). After evaporation of solvent by rotary evaporator, the residue was triturated with acetone. 2-amino-6-ethylamino-4-iodopyrimidine hydrochloride (188.5 g, 93% isolated yield) was obtained by vacuum filtration and drying. 1H NMR (400 MHz, CD3OD) δ 3.58 (q, 2H), 2.14 (s, 3H), 1.11 (t, 3H); MS (EI) for C7H11N4ClI: 279.1 (MH+).




To a three-neck round bottom flask equipped with over-head mechanic stirrer were added 2-amino-6-ethylamino-4-iodopyrimidine hydrochloride (188.5 g, 0.60 mol), ethyl acrylate (221 mL, 2.0 mol), triethylamine (285 mL, 2.0 mol), DMF (1.3 L), and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4, 31.3 g, 0.027 mol). The reaction mixture was heated to 95° C. and stirred for 3 h (monitored by LC/MC). After reaction completion, the reaction mixture was evaporated about to 1/10 of original volume and partitioned with 500 mL of ethyl acetate and 1000 mL of water. The aqueous layer was extracted with ethyl acetate 5 times. (E)-Ethyl 3-(2-amino-4-(ethylamino)-6-methylpyrimidin-5-yl)acrylate (100 g, 67% yield) was obtained by recrystallization from acetone after evaporation of ethyl acetate. 1H NMR (400 MHz, CD3OD) δ 7.48 (dd, J1=16.0 Hz, J2=4.0 Hz, 1H), 6.20 (dd, J1=16 Hz, J2=4 Hz, 1H), 4.25 (q, J=7.2 Hz, 2H), 3.51 (q, J=7.6 Hz, 2H), 2.39 (s, 3H), 1.3 (t, J=7.2 Hz, 3H), 1.2 (t, J=7.6 Hz, 3H). MS (EI) for C12H18N4O2: 251.3 (MH+).




(E)-Ethyl 3-(2-amino-4-(ethylamino)-6-methylpyrimidin-5-yl)acrylate (4.50 g, 18.0 mmol) was added to DBU (10.95 g, 4.0 equiv.) and the mixture was heated to 165° C. and stirred for 24 h. After that, the mixture was cooled to 70° C. followed by the addition of H2O (20 mL) to precipitate crystal and stirred for 1 h at room temperature. The crystal was collected and washed with H2O and acetone and dried under vacuum to afford 2.70 g (73.5% yield of 2-amino-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one as a light yellowish brown solid. LC/MS: Calculated for C10H12N4O (204.2). Found: 205.31 (M+1); HPLC analytical purity: 98.5%. 1H NMR (400 MHz, DMSO-d6): δ 7.9 (d, 1H), 7.20 (bs, 2H), 6.20 (m, 1H), 4.20 (q, 2H), 2.50 (s, 3H), 1.20 (t, 3H); MS (EI) for C10H12N4O: 205.11 (MH+).




2-Amino-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (2.70 g, 13.2 mmol) was added to dichloromethane (100 mL), and then bromine (0.75 mL, 1.10 equiv.) was added slowly. This reaction mixture was stirred for 3 h at room temperature. After that, the solvent was evaporated nearly 80% volume of reaction mixture under vacuum, and then acetone was added to give 3.54 g 2-Amino-6-bromo-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one as a tan solid. LC/MS: Calculated for C10H11BrN4O (283.12). Found: 285.15 (M+2). HPLC analytical purity: 97.7%.
Example 3
2-Amino-4-methyl-8-(methylethyl)-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one




To a crude solution of N-isopropyl-6-methyl-2-(methylthio)pyrimidin-4-amine (44.6 g, 224 mmol), prepared using analogous procedures as described in Example 1, in 400 mL of methanol was added ICl (40.0 g, 246 mmol) in small portions at room temperature. The reaction mixture was then stirred at for 3 h monitoring by LC/MS. After evaporation of solvent by rotary evaporator, the residue was triturated with acetone to yield 5-iodo-N-isopropyl-6-methyl-2-(methylthio)pyrimidin-4-amine. NMR (400 MHz, CDCl3) δ 6.37 (br m, 1H), 4.47 (m, 1H), 2.78 (s, 3H), 2.67 (s, 3H), 1.41 (d, J=6.4, 6H).




5-Iodo-N-isopropyl-6-methyl-2-(methylthio)pyrimidin-4-amine (8.1 g, 26.2 mmol), ethyl acrylate (5.24 g, 52.4 mmol), triethylamine (10.6 g, 105 mmol), palladium (II) acetate (1.17 g, 5.23 mmol), and tri-o-tolyl phosphine (1.59 g, 5.23 mmol) were added in that order to 10.8 mL of DMA in a pressure tube and sealed. The reaction mixture was heated to 100° C. and allowed to stir overnight. The reaction was quenched by filtration through a short silica plug washing with ACN. The solvent was evaporated and diluted with ethyl acetate then extracted with 10° A) aqueous LiCl, followed by water and brine. NOTE: Extraction is necessary to remove all DMA giving resolution in chromatography. The sample was purified by silica gel column chromatography using 20% ethyl acetate/hexane as eluent. Desired fractions were combined and reduced to afford 2.5 g (34% yield) of ethyl (2E)-3-[4-(isopropylamino)-6-methyl-2-(methylthio)pyrimidin-5-yl]acrylate as a yellow/orange oil.




(E)-Ethyl 3-(4-(isopropylamino)-6-methyl-2-(methylthio)pyrimidin-5-yl)acrylate (2.5 g, 8.46 mmol) was dissolved in acetic acid by gentle warming. Sample was placed in microwave reactor for 6 h at 180° C., 300 W, and 200 PSI. The product was purified by silica gel column chromatography eluting with 20% ethyl acetate/hexane. Desired fractions were combined and reduced into 8-isopropyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one as a yellow powder (1.20 g, 57% yield) which was then dried under heavy vacuum overnight. 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J=9.6, 1H), 6.58 (d, J=9.6, 1H), 5.84 (br s, 1H), 2.65 (s, 3H), 2.63 (s, 3H), 1.63 (d, J=6.8, 6H).




8-Isopropyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (5.38 g, 21.59 mmol) was dissolved in 100 mL DCM. To the stirring solution, m-CPBA (13.97 g, 64.78 mmol) was added. The reaction was allowed to stir for 2.5 h at room temperature. LCMS indicated reaction had gone to completion. Sample was diluted with 300 mL of DCM and 300 mL K2CO3, upon addition of base a white precipitate formed that dissolved in excess H2O. Organic layer was extracted further with H2O and brine, and then dried over Na2CO3. The solvent was evaporated to afford the product 8-isopropyl-4-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (6.0 g, 99% yield) as a light yellow oil that was used immediately in the next reaction.




8-isopropyl-4-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (approximately 3.0 g) was dissolved in 50 mL THF, in a 350 mL pressure tube. While stirring, NH3 (g) was bubbled in through solution for 1.5 minutes. A color change was observed form light yellow to olive green in about 120 seconds. The tube was sealed and stirred at room temperature overnight. A precipitate had formed. The reaction mixture, including precipitate, was reduced to near dryness, filtered and washed with a minimal volume of cold THF, affording 2.88 g of 2-amino-8-isopropyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one.




To a solution of 2-amino-8-isopropyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (2.88 g, 13.19 mmol) dissolved in 80 mL of DCM at 0° C., (4.21 g, 26.39 mmol) bromine was added. Reaction vessel was removed from ice bath and allowed to react at room temperature over night. LCMS indicated complete conversion of starting material to product. Sample was evaporated to remove DCM and excess bromine. Orange solid was diluted in ethyl acetate and extracted with 10% NaHSO3, H2O, and brine. Organic layer was dried over Na2SO4, filtered, and reduced to dryness yielding 2-amino-6-bromo-8-isopropyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one as a light yellow powder (2.2 g, 56% yield). 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 5.83 (m, 1H), 5.69 (br s, 2H), 2.60 (s, 3H), 1.58 (d, J=6.8, 6H).




In a 350 mL pressure tube 2-amino-6-bromo-8-isopropyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (1.50 g, 5.05 mmol), 1H-pyrazol-3-yl boronic acid (1.12 g, 10.09 mmol), K2CO3 (336 mg, 15.1 mmol), and tetrakis(triphenylphosphine) palladium (0) (583 mg, 0.0504 mmol) were dissolved in 50 mL dioxane and 5 mL H2O. The tube was sealed, heated to 100° C. and allowed to react overnight. A color change was observed. LCMS indicated no presence of starting material. Sample was filtered through a syringe filter and evaporated to dryness. Compound was dissolved in ethyl acetate and triturated in hexane. Light yellow powder of 2-amino-8-isopropyl-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (195 mg, 13.7% yield) was found to be 98% pure by HPLC. NMR (400 MHz, CDCl3) δ 12.97 (br s, 1H), 8.35 (s, 1H), 7.60 (br s, 1H), 7.21 (s, 2H), 6.94 (s, 1H), 5.86 (br s, 1H), 2.50 (m, 6H), 1.54 (s, 3H), MS (EI) for C14H16N6O: 285.0 (MH+).
Example 4




3-Chloroperbenzoic acid (0.565 g, 3.27 mmol) was added to a solution of 6-bromo-8-ethyl-4-methyl-2-(methylthio)pyrido[2,3-c]pyrimidin-7(8H)-one (0.308 g, 0.980 mmol) in dichloromethane (5.0 mL) at room temperature. After 30 minutes, the reaction was diluted with dichloromethane (50 mL) and washed twice with saturated NaHCO3, followed by brine. The organic phase was separated and dried over Na2SO4, filtered, and concentrated in vacuo. The residue was precipitated with ethyl acetate to provide 8-ethyl-4-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (302 mg, 89% yield) as a yellow solid.




To a stirred solution of (76.5 mg, 0.221 mmol) in 1.5 mL of CH2Cl2 was added isopropyl amine (709.9 mg, 12.0 mmol, 54 eq.) The reaction was stirred for 15 h at room temperature. The reaction was diluted with CH2Cl2 and extracted with 2N NaOH, H2O, and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified using preparative HPLC. Lyophillization of the product containing fractions afforded 19.9 mg (27.6% yield) of 6-bromo-8-ethyl-2-(isopropylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 8.08 (s, 1H), 5.30 (bs, 1H), 4.48 (bd, 2H), 4.18 (bs, 1H), 2.52 (s, 3H), 1.62 (bs, 3H), 1.29 (m, 9H), MS (EI) for C13H17BrN4O: 325.2 (MH+).
Using the same or analogous synthetic techniques and substituting with appropriate reagents, the following compounds were prepared:
Example 4b
6-bromo-2-(tert-butylamino)-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 8.08 (s, 1H), 5.47 (bs, 1H), 4.48 (m, 2H), 2.50 (s, 3H), 1.58 (bs, 3H), 1.49 (s, 9H), MS (EI) for C14H19BrN4O: 339.2 (MH+)
Example 4c
6-Bromo-2-(cyclopentylamino)-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 8.07 (s, 1H), 5.89 (bs, 1H), 4.49 (bd, 2H), 2.51 (s, 3H), 2.07 (m, 2H), 1.71 (m, 2H), 1.58 (m, 2H), 1.31 (t, 3H), MS (EI) for C15H19BrN4O: 351.2 (MH+)
Example 4d
6-Bromo-2-(cyclohexylamino)-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 8.07 (s, 1H), 5.41 (bs, 1H), 4.47 (bd, 2H), 3.84 (bs, 1H), 2.51 (s, 3H), 2.05 (d, J=12.4 Hz, 2H), 1.77 (m, 2H), 1.64 (br m, 4H), 1.39 (m, 2H), 1.30 (m, 3H), MS (EI) for C16H21BrN4O: 365.2 (MH+)
Example 4e
6-Bromo-8-ethyl-4-methyl-2-(2-morpholinoethylamino)pyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 8.08 (s, 1H), 6.22 (bs, 1H), 4.48 (q, J=6.4 Hz, 2H), 3.74 (t, J=4.4 Hz, 1H), 3.57 (q, J=4.8 Hz, 3H), 2.98 (bs, 2H), 2.63 (t, J=6.0 Hz, 2H), 2.53 (s, 3H), 1.30 (t, J=6.8 Hz, 2H), MS (EI) for C16H22BrN5O: 396.2 (MH+)
Example 4f
6-Bromo-8-ethyl-4-methyl-2-[(3-morpholino-4-ylpropyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 8.07 (s, 1H), 6.23 (bs, 1H), 4.47 (bs, 1H), 3.75 (m, 4H), 3.57 (m, 2H), 2.52 (m, 4H), 2.48 (m, 2H), 1.82 (m, 2H), 1.28 (s, 3H), MS (EI) for C17H24BrN5O: 410.2 (MH+)
Example 4g
6-Bromo-2-{[3-(dimethylamino)propyl]amino}-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 8.08 (s, 1H), 7.26 (bs, 1H), 4.47 (m, 2H), 3.54 (m, 2H), 2.78 (t, J=7.6 Hz, 2H), 2.52 (s, 3H), 2.50 (s, 3H), 2.04 (s, 3H), 2.00 (m, 2H), 1.29 (t, J=7.2 Hz, 3H), MS (EI) for C15H22BrN5O: 369.2 (MH+)
Example 4h
8-Ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 7.67 (d, J=9.2 Hz, 1H), 6.39 (d, J=9.2 Hz, 1H), 5.31 (bs, 1H), 2.54 (s, 3H), 4.32 (q, J=6.8 Hz, 2H), 3.52 (q, J=6.8 Hz, 2H), 2.53 (s, 3H), 1.15 (m, 6H); MS (EI) for C12H16N4O: 233.2 (MH+).
Example 4j
6-Bromo-2-{[2-(dimethylamino)ethyl]amino}-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, DMSO-d6): δ 8.37 (s, 1H), 7.83 (bt, J=8.0 Hz, 1H), 4.34 (q, J=8.0 Hz, 2H), 3.42 (q, J=4.0 Hz, 2H), 2.51 (s, 3H), 2.45 (t, J=4.0 Hz, 2H), 1.83 (s, 6H), 1.20 (t, J=8.0 Hz, 3H); MS (EI) for C14H20BrN5O: 354.3 (M+).
Example 4k
6-bromo-2-(ethylamino)-4-methyl-8-(1-methylethyl)pyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 8.04 (s, 1H), 6.66 (bs, 1H), 5.83 (sept, J=6.8 Hz, 1H), 3.54 (dq, J=12.8, 7.6 Hz, 2H), 2.62 (s, 3H), 1.60 (d, J=6.8 Hz, 6H), 1.34 (t, J=7.2 Hz, 3H); MS (EI) for C13H17BrN4O: 324.9 (M+).
Example 4m
6-Bromo-8-ethyl-4-methyl-2-morpholiN-4-ylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 8.09 (s, 1H), 4.45 (q, J=6.8 Hz, 2H), 3.92 (s, 3H), 3.79 (s, 3H), 2.55 (s, 3H), 1.30 (t, J=6.8 Hz, 3H); MS (EI) for C14H17BrN4O2: 355.1 (M2H+).
Example 4n
6-Bromo-8-ethyl-4-methyl-2-[(phenylmethyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 8.09 (s, 1H), 7.32 (m, 5H), 5.86 (bs, 1H), 4.68 (s, 2H), 4.43 (q, J=7.2 Hz, 2H), 2.54 (s, 3H), 1.13 (t, J=7.2 Hz, 3H); MS (EI) for C17H17BrN4O: 375.1 (M2H+).
Example 4p
6-Bromo-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 8.09 (s, 1H), 5.71 (bs, 1H), 4.48 (bs, 2H), 3.54 (q, J=6.8 Hz, 2H), 2.53 (s, 3H), 1.16 (m, 6H); MS (EI) for C12H15BrN4O: 311.9 (MH+).
Example 5
2-(Ethylamino)-4-methyl-8-(1-methylethyl)-6-(2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one




Pd(dppf) dichloromethane adduct (0.077 g, 0.095 mmol) was added to a suspension of 6-bromo-2-(ethylamino)-4-methyl-8-(1-methylethyl)pyrido[2,3-d]pyrimidin-7(8H)-one (0.154 g, 0.474 mmol), 2-thiophene boronic acid (0.079 g, 0.616 mmol), and triethylamine (165 μL, 1.19 mmol) in 10:1 DME:water (1.5 mL). The reaction was heated to 100° C. After 5 h, the reaction was cooled to room temperature, filtered though a Celite plug and concentrated in vacuo. The residue was purified on SiO2 (3:2 hexanes:ethyl acetate) to give 2-(ethylamino)-4-methyl-8-(1-methylethyl)-6-(2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one (28 mg, 18% yield) as a light yellow solid: 1H NMR (400 MHz, CDCl3): δ 8.06 (s, 1H), 7.60 (dd, J=4.0, 1.2 Hz, 1H), 7.38 (dd, J=5.2, 0.8 Hz, 1H), 7.10 (dd, J=4.8, 3.2 Hz, 1H), 5.93 (bsept, 1H), 5.13 (bs, 1H), 3.54 (pent, J=7.2 Hz, 2H), 2.61 (s, 3H), 1.66 (d, J=6.8 Hz, 6H), 1.28 (t, J=7.6 Hz, 3H); MS (EI) for C17H20N4OS: 329.0 (MH+).
Using the same or analogous synthetic techniques and substituting with appropriate reagents, the following compounds were prepared:
Example 5a
2-(Ethylamino)-6-furan-2-yl-4-methyl-8-(1-methylethyl)pyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHZ, CDCL3): δ 8.43 (S, 1H), 7.81 (S, 1H), 7.47 (T, J=2 HZ, 1H), 6.75 (DD, J=2.0, 0.8 HZ, 1H), 5.92 (BSEPT, 1H), 5.25 (BS, 1H), 3.53 (DQ, J=12.5, 7.6 HZ, 2H), 2.60 (S, 3H), 1.65 (D, J=6.8 HZ, 6H), 1.29 (T, J=7.2 HZ, 3H); MS (EI) FOR C17H20N4O2: 313.1 (MH+).
Example 5b
2-(Ethylamino)-4-methyl-8-(1-methylethyl)-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 8.08 (s, 1H), 7.61 (d, J=2.0 Hz, 1H), 6.65 (bs, 1H), 5.93 (bs, 1H), 5.44 (bs, 1H), 3.55 (dq, J=12.8, 6.4 Hz, 2H), 2.62 (s, 3H), 1.66 (d, J=6.4 Hz, 6H), 1.30 (t, J=7.6 Hz, 3H); MS (EI) for C16H20N6O: 313.3 (MH+).
Example 5c
2-(Ethylamino)-4-methyl-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, MeOH-d4:TFA-d, 10:1): δ 8.59 (s, 1H), 8.07 (s, 1H), 7.30 (s, 1H), 3.59 (q, J=8.0 Hz, 2H), 2.88 (s, 3H), 1.28 (t, J=8.0 Hz, 3H); MS (EI) for C13H14N6O: 271.0 (MH+).
Example 5e
8-Cyclopentyl-2-(ethylamino)-4-methyl-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, DMSO-d6): δ 8.32 (s, 1H), 7.80 (s, 1H), 7.59 (s, 1H), 6.916 (s, 1H), 5.95 (m, 1H), 2.35 (bs, 2H), 1.95 (bs, 2H), 1.73 (bs, 2H), 1.61 (bs, 2H), 1.12 (t, J=6.8 Hz, 3H), MS (EI) for C18H22N6O: 339.1 (MH+)
Example 5f
6-(2,4-Difluorophenyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 7.78 (d, 2H), 7.52 (m, 1H), 6.85 (m, 2H), 5.38 (bs, 1H), 4.48 (m, 2H), 3.56 (m, 2H), 2.57 (s, 3H), 1.39 (m, 6H); MS (EI) for C18H18F2N4O: 345.1 (MH+).
Example 5g
6-(3-Chloro-4-fluorophenyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 7.79 (s, 2H), 7.57 (m, 1H), 7.19 (m, 1H), 5.41 (bs, 1H), 4.45 (bs, 2H), 3.58 (m, 2H), 2.59 (m, 3H), 1.36 (m, 6H); MS (EI) for C18H18ClFN4O: 361.0 (MH+).
Example 5h
6-(2,4-Dichlorophenyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 7.75 (s, 1H), 7.42 (d, 1H), 7.38 (m, 2H), 5.38 (bs, 1H), 4.42 (m, 2H), 3.59 (m, 2H), 2.56 (s, 3H), 1.24 (m, 6H); MS (EI) for C18H18Cl2N4O: 377.0 (M+), 379.0 (M+2)
Example 5i
6-(3,4-Difluorophenyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 7.79 (s, 1H), 7.59 (m, 1H), 7.39 (m, 1H), 7.18 (m, 1H), 5.39 (bs, 1H), 4.46 (m, 2H), 3.58 (m, 2H), 2.59 (s, 3H), 1.27 (m, 6H); MS (EI) for C18H18F2N4O: 345.1 (MH+).
Example 5j
8-Ethyl-2-(ethylamino)-4-methyl-6-[4-(phenyloxy)phenyl]pyrido[2,3-c]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 7.78 (s, 1H), 7.63 (d, 2H), 7.39 (t, 2H), 7.16 (t, 1H), 7.04 (d, 4H), 5.38 (bs, 1H), 4.47 (m, 2H), 3.57 (m, 2H), 2.59 (s, 3H), 1.26 (m, 6H); MS (EI) for C24H24N4O2: 401.1 (MH+).
Example 5k
8-Ethyl-2-(ethylamino)-4-methyl-6-naphthaleN-1-ylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 7.84 (d, 2H), 7.80 (s, 1H), 7.73 (d, 1H), 7.48 (m, 4H), 539 (bs, 1H), 4.55 (bs, 2H), 3.59 (m, 2H), 2.54 (s, 3H), 1.37 (m, 6H); MS (EI) for C22H22N4O: 359.1 (MH+).
Example 5m
8-Ethyl-2-(ethylamino)-4-methyl-6-[3-(trifluoromethyl)phenyl]pyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 7.82 (m, 3H), 7.56 (m, 2H), 5.59 (bs, 1H), 4.47 (d, 2H), 3.51 (m, 2H), 2.58 (s, 3H), 1.30 (m, 6H); MS (EI) for C19H19F3N4O: 377.1 (MH+).
Example 5n
8-Ethyl-2-(ethylamino)-4-methyl-6-(2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 8.09 (s, 1H), 7.64 (dd, J=3.60, 1.20 Hz, 1H), 7.38 (dd, J=5.20, 1.20 Hz, 1H), 7.10 (dd, J=4.78, 3.60 Hz, 2H), 3.54 (qn, 2H), 2.62 (s, 3H), 1.30 (m, 6H); MS (EI) for C16H18N4OS: 315.0 (MH+).
Example 5p
6-(3-Chlorophenyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 7.78 (s, 1H), 7.65 (s, 1H), 7.56 (dd, 1H), 7.34 (m, 2H), 5.39 (bs, 1H), 4.43 (m, 2H0, 3.57 (m, 2H), 2.59 (s, 3H), 1.32 (m, 6H); MS (EI) for C18H19ClN4O: 343.0 (MH+).
Example 5q
6-(4-Chlorophenyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 7.77 (s, 1H), 7.62 (dd, 2H0, 7.40 (dd, 2H), 5.38 (bs, 1H), 4.47 (m, 2H), 3.58 (m, 2H), 2.59 (s, 3H), 1.39 (m, 6H); MS (EI) for C18H19ClN4O: 343.0 (MH+).
Example 5r
8-Ethyl-2-(ethylamino)-4-methyl-6-[4-(trifluoromethyl)phenyl]pyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 7.80 (m, 3H), 7.63 (dd, 2H), 5.39 (bs, 1H), 4.51 (m, 2H), 3.58 (m, 2H), 2.58 (s, 3H), 1.33 (m, 6H); MS (EI) for C19H19F3N4O: 343.0 (MH+).
Example 5s
8-Ethyl-2-(ethylamino)-4-methyl-6-(3-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 8.11 (dd, J=2.10, 0.90 Hz, 1H), 7.94 (s, 1H), 7.52 (dd, J=3.90, 1.20 Hz, 1H), 7.35 (qr, 1H), 5.33 (bs, 1H), 4.52 (qr, 2H), 3.54 (m, 2H), 2.58 (s, 3H), 1.28 (m, 6H); MS (EI) for C16H18N4OS: 315.0 (MH+).
Example 5t
8-Ethyl-2-(ethylamino)-4-methyl-6-(4-methyl-2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 8.01 (s, 1H), 7.52 (s, 1H), 6.93 (s, 1H), 5.38 (bs, 1H), 4.58 (qr, 2H), 3.57 (m, 2H), 2.61 (s, 1H), 2.33 (s, 1H), 1.60 (s, 3H); MS (EI) for C17H20N4OS: 329.0 (MH+).
Example 5u
8-Ethyl-2-(ethylamino)-4-methyl-6-(4-methyl-3-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 7.69 (s, 1H), 7.38 (d, 1H), 6.99 (m, 1H), 5.35 (bs, 1H), 4.51 (qr, 2H), 3.57 (m, 2H), 2.58 (s, 3H), 2.22 (s, 3H), 1.32 (m, 6H); MS (EI) for C17H20N4OS: 329.0 (MH+).
Example 5v
1,1-Dimethylethyl 2-[8-ethyl-2-(ethylamino)-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl]-1H-pyrrole-1-carboxylate: 1H NMR (400 MHz, CDCl3): δ 7.65 (s, 1H), 7.38 (d, 1H), 6.22 (m, 2H), 5.29 (bs, 1H), 4.41 (m, 2H), 3.57 (m, 2H), 2.56 (s, 3H), 1.41 (s, 9H), 1.22 (m, 6H); MS (EI) for C21H27N5O3: 398.0 (MH+).
Example 5w
8-Ethyl-2-(ethylamino)-4-methyl-6-(1H-pyrrol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 11.1 (bs, 1H), 7.99 (s, 1H), 6.85 (d, 1H), 6.62 (d, 1H), 6.29 (d, 1H), 5.28 (bs, 1H), 4.57 (m, 2H), 3.56 (m, 2H), 2.61 (s, 3H), 1.35 (m, 6H); MS (EI) for C16H19N5O: 298.1 (MH+).
Example 5x
8-Ethyl-2-(ethylamino)-6-furan-3-yl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 8.42 (s, 1H), 7.83 (s, 1H), 7.43 (s, 1H), 6.76 (s, 1H), 5.37 (bs, 1H), 4.52 (m, 2H), 3.58 (m, 2H), 2.61 (s, 3H), 1.30 (m, 6H); MS (EI) for C16H18N4O2: 299.1 (MH+).
Example 5y
8-Ethyl-2-(ethylamino)-4-methyl-6-[1-(phenylmethyl)-1H-pyrazol-4-yl]pyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 8.39 (s, 1H), 7.98 (d, 1H), 7.96 (d, 1H), 7.35 (m, 5H), 5.39 (s, 2H), 5.35 (bs, 1H), 4.52 (m, 2H), 3.58 (m, 2H), 2.62 (s, 3H), 1.35 (m, 6H); MS (EI) for C22H24N6O: 389.3 (MH+).
Example 5z
6-(3,5-Dimethylisoxazol-4-yl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 7.59 (s, 1H), 7.24 (s, 1H), 5.43 (bs, 1H), 4.47 (bs, 2H), 3.56 (m, 2H), 2.58 (s, 3H), 2.39 (s, 3H), 2.25 (s, 3H), 1.29 (m, 6H); MS (EI) for C17H21N5O2: 328.1 (MH+).
Example 5aa
8-Ethyl-2-(ethylamino)-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 8.11 (s, 1H), 7.62 (s, 1H), 6.65 (d, 1H), 5.43 (bs, 1H), 4.58 (m, 2H), 3.59 (m, 2H), 2.62 (s, 3H), 1.38 (m, 6H); MS (EI) for C15H18N6O: 299.1 (MH+).
Example 5bb
8-Ethyl-4-methyl-6-(1H-pyrazol-5-yl)-2-[(2,2,2-trifluoroethyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 8.18 (s, 1H), 7.63 (d, 1H), 6.73 (d, 1H), 5.62 (bs, 1H), 4.58 (m, 2H), 4.30 (m, 2H), 2.74 (s, 3H), 1.35 (t, 3H); MS (EI) for C15H15F3N6O: 353.0 (MH+).
Example 5cc
8-Ethyl-2-(ethylamino)-4-methyl-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 8.87 (s, 1H), 7.98 (s, 1H), 7.43 (s, 1H), 7.22 (s, 1H), 5.56 (bs, 1H), 4.58 (bs, 2H), 2.72 (s, 3H0, 1.36 (m, 6H); MS (EI) for C15H17N5OS: 316.0 (MH+).
Example 6
6-Biphenyl-4-yl-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyridimidiN-7(8H)-one




2-Ethylamino-6-bromo-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (60 mg, 0.194 mmol), K2CO3 (81.0 mg, 3.0 equiv.), biphenyl boronic acid (17.8 mg, 1.5 equiv.) and Pd(PPh3)4 (10 mol %, 225 mg) were added to dioxane/H2O (10 mL/3 mL). The reaction was heated to 95° C. and stirred for 2 h. The reaction mixture was partitioned between organic and aqueous layers with ethyl acetate (20 mL) and H2O (10 mL) and saturated aqueous NaCl (5 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated to give 6-Biphenyl-4-yl-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyridimidiN-7(8H)-one (48.42 mg, 65% yield): 1H NMR (400 MHz, CDCl3): δ 7.81 (s, 1H), 7.74 (m, 2H), 7.60 (m, 4H), 7.42 (m, 2H), 7.38 (m, 1H), 4.50 (q, 2H), 3.60 (q, 2H), 2.60 (s, 3H), 1.30 (m, 6H); MS (EI) for C24H24N4O: 385.1 (MH+).
Using the same or analogous synthetic techniques and substituting with appropriate reagents, the following compounds were prepared:
Example 6a
8-Ethyl-2-(ethylamino)-4-methyl-6-[4-(methyloxy)phenyl]pyrido[2,3-d]pyridimidiN-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 7.81 (s, 1H), 7.60 (d, 2H), 6.96 (d, 2H), 4.50 (q, 2H), 3.82 (s, 3H), 3.58 (q, 2H), 2.58 (s, 3H), 1.30 (m, 6H); MS (EI) for C19H22N4O2: 339.1 (MH+).
Example 6b
8-Ethyl-2-(ethylamino)-4-methyl-6-[2-(methyloxy)phenyl]pyrido[2,3-d]pyridimidiN-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 7.81 (s, 1H), 7.60 (d, 2H), 6.96 (d, 2H), 4.50 (q, 2H), 3.80 (s, 3H), 3.58 (q, 2H), 2.50 (s, 3H), 1.30 (m, 6H); MS (EI) for C19H22N4O2: 339.1 (MH+).
Example 6c
6-[2,4-Bis(methyloxy)phenyl]-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 7.70 (s, 1H), 7.30 (s, 1H), 6.60 (m, 2H), 4.50 (q, 2H), 3.82 (s, 3H), 3.80 (s, 3H), 3.45 (q, 2H), 2.50 (s, 3H), 1.30 (m, 6H); MS (EI) for C20H24N4O3: 369.1 (MH+).
Example 6d
8-Ethyl-2-(ethylamino)-4-methyl-643-(methyloxy)phenyl)pyrido[2,3-d]pyridimidiN-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 7.81 (s, 1H), 7.60 (d, 2H), 6.96 (d, 2H), 4.50 (q, 2H), 3.80 (s, 3H), 3.58 (q, 2H), 2.50 (s, 3H), 1.30 (m, 6H); MS (EI) for C19H22N4O2: 339.1 (MH+).
Example 6e
8-(5-Chloro-2-thienyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 8.00 (s, 1H), 7.38 (d, 2H), 6.96 (d, 2H), 4.50 (q, 2H), 3.58 (q, 2H), 2.60 (s, 3H), 1.30 (m, 6H); MS (EI) for C16H17ClN4OS: 349.2 (MH+).
Example 6f
8-Ethyl-2-(ethylamino)-4-methyl-6-pyrimidin-5-ylpyrido[2,3-d]pyridimidiN-7(8H)-one: 1H NMR (400 MHz, DMSO-d6): δ 9.19 (s, 1H), 9.16 (s, 1H), 8.23 (s, 1H), 8.00 (m, 1H), 4.38 (q, 2H), 3.40 (q, 2H), 2.50 (s, 3H), 1.30 (m, 6H); MS (EI) for C16H18N6O: 311.3 (MH+).
Example 6g
8-Ethyl-2-(ethylamino)-6-(3-fluoropyridiN-4-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 8.58 (s, 1H), 8.42 (d, 1H), 7.98 (s, 1H), 7.60 (t, 1H), 4.50 (q, 2H), 3.58 (q, 2H), 2.60 (s, 3H), 1.30 (m, 6H); MS (EI) for C17H18FN5O: 328.3 (MH+).
Example 6h
8-Ethyl-2-(ethylamino)-6-(1H-indole-6-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, DMSO-d6): δ 11.2 (s, 1H), 7.90 (s, 1H), 7.88 (s, 1H), 7.42 (s, 2H), 7.38 (s, 1H), 6.50 (s, 1H), 4.40 (q, 2H), 3.40 (q, 2H), 2.42 (s, 3H), 1.30 (m, 6H); MS (EI) for C20H21N5O: 348.3 (MH+).
Example 6i
8-Ethyl-2-(ethylamino)-4-methyl-6-(5-phenyl-2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, DMSO-d6): δ 8.40 (s, 1H), 7.81 (d, 1H), 7.70 (d, 2H), 7.50 (d, 1H), 7.42 (m, 2H), 7.30 (m, 1H), 4.40 (q, 2H), 3.40 (q, 2H), 2.42 (s, 3H), 1.30 (m, 6H); MS (EI) for C22H22N4OS: 391.3 (MH+).
Example 6j
8-Ethyl-2-(ethylamino)-4-methyl-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 7.78 (s, 1H), 7.46 (m, 5H), 5.41 (bs, 1H), 4.50 (q, J=6.8 Hz, 2H), 3.60 (m, 2H), 2.57 (s, 3H), 1.30 (m, 6H); MS (EI) for C18H20N4O: 309.2 (MH+).
Example 6k
8-Ethyl-2-(ethylamino)-6-(3-fluorophenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 7.79 (s, 1H), 7.46-7.02 (m, 4H), 5.41 (bs, 1H), 4.51 (q, J=6.4 Hz, 2H), 3.55 (q, J=6.8 Hz, 2H), 2.58 (s, 3H), 1.34 (t, J=6.80 Hz, 3H), 1.29 (t, J=6.40 Hz, 3H); MS (EI) for C18H19FN4O: 327.3 (MH+).
Example 6m
8-ethyl-2-(ethylamino)-6-(2-fluorophenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 7.80 (s, 1H), 7.52-7.12 (m, 4H), 5.33 (bs, 1H), 4.49 (q, J=6.8 Hz, 2H), 3.53 (q, J=7.2 Hz, 2H), 2.55 (s, 3H), 1.34 (t, J=7.20 Hz, 3H), 1.28 (t, J=6.80 Hz, 3H); MS (EI) for C18H19FN4O: 327.3 (MH+).
Example 6n
8-ethyl-2-(ethylamino)-6-(4-fluorophenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 7.75 (s, 1H), 7.66-7.08 (m, 4H), 5.30 (bs, 1H), 4.52 (q, J=6.4 Hz, 2H), 3.54 (q, J=6.8 Hz, 2H), 2.58 (s, 3H), 1.34 (t, J=6.80 Hz, 3H), 1.29 (t, J=6.40 Hz, 3H); MS (EI) for C18H19FN4O: 327.3 (MH+).




3-Chloroperbenzoic acid (1.78 g, 10.4 mmol) was added to a solution of 6-bromo-4-methyl-8-(1-methylethyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (1.33 g, 4.14 mmol), prepared using procedures similar to those described in Example 1, in dichloromethane (30.0 mL) at room temperature. After 1, the reaction was diluted with dichloromethane (50 mL) and washed twice with saturated NaHCO3, followed by brine. The organic phase was separated and dried over Na2SO4, filtered, and concentrated in vacuo. The residue was precipitated with ethyl acetate/hexanes to provide the corresponding sulfone (1.31 g, 93% yield) as an off-white solid.
Example 8
2-Amino-4-methyl-8-(phenylmethyl)-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one




Triethylamine (3.4 mL, 24.6 mmol) was added to a suspension of 2-amino-4-chloro-6-methylpyrimidine (Aldrich, 1.77 g, 12.3 mmol) and benzylamine (1.98 g, 18.5 mmol) in anhydrous dioxane (20 mL). The reaction was heated to 80° C. and allowed to run for 12 h. Upon cooling to room temperature, a white precipitate formed which was collected by vacuum filtration. The solid was recrystallized from acetone: hexanes to afford N4-benzyl-6-methylpyrimidine-2,4-diamine (2.33 g, 89% yield) as a white solid.




Iodine (3.04 g, 12.0 mmol) was added to a solution of N4-benzyl-6-methylpyrimidine-2,4-diamine (2.33 g, 10.9 mmol) in anhydrous MeOH (50 mL) at 0° C. The reaction was allowed to warm to room temperature overnight. After 12 hours, an additional 0.5 equiv of iodine was added, and the reaction warmed to 50° C. After four hours, the reaction was cooled to room temperature and concentrated in vacuo. The residue was diluted with ethyl acetate (200 mL) and washed with 10% NaHSO3 (200 mL). The aqueous phase was separated and washed once more with ethyl acetate (200 mL). The organic phases were combined, washed with brine, separated and dried over Na2SO4, The filtrate was concentrated in vacuo to afford the product N4-benzyl-5-iodo-6-methylpyrimidine-2,4-diamine (3.14 g, 85% yield).




Triethylamine (7.60 mL, 54.5 mmol) was added to a suspension of N4-benzyl-5-iodo-6-methylpyrimidine-2,4-diamine (3.14 g, 10.9 mmol), ethyl acrylate (3.55 mL, 32.7 mmol) and Pd(PPh3)4 (629 mg, 0.545 mmol) in anhydrous DMF (20 mL). The reaction was heated to 95° C. under nitrogen. After 24 h, the reaction was allowed to cool to room temperature and concentrated in vacuo. The residue was poured into a 10% solution of LiCl and washed with ethyl acetate (100 mL). The organic phase was separated and washed with brine, separated and dried over Na2SO4. The filtrate was concentrated in vacuo and purified on SiO2 (3:2 methylene chloride:ethyl acetate) to afford (E)-ethyl-3-(2-amino-4-(benzylamino)-6-methylpyrimidin-5-yl)acrylate (0.954 g, 28% yield) as a light yellow solid.




2-amino-4-methyl-8-(phenylmethyl)pyrido[2,3-d]pyrimidin-7(8H)-one Diazabicyclo[5.4.0]undec-7-ene (DBU) (1.83 mL, 12.2 mmol) was added to a flask charged with (E)-ethyl-3-(2-amino-4-(benzylamino)-6-methylpyrimidin-5-yl)acrylate (0.954 g, 3.05 mmol) and the reaction refluxed at 160° C. under a nitrogen atmosphere. After 20 hours, the reaction was cooled to room temperature and concentrated in vacuo. Purification on SiO2 (1:1 methylene chloride:ethyl acetate) afforded the product (0.508 g, 62% yield) as an off-white solid.




Bromine (72 μL, 1.40 mmol) was added to a suspension of 2-amino-4-methyl-8-(phenylmethyl)pyrido[2,3-c]pyrimidin-7(8H)-one (0.340 g, 1.27 mmol) in methylene chloride (20 mL) at 0° C. The reaction was allowed to warm to room temperature over one hour and the resulting precipitate collected by vacuum filtration to afford 2-amino-6-bromo-4-methyl-(8-phenylmethyl)pyrido[2,3-d]pyrimidin-7(8H)-one (0.435 g, 99% yield) after drying. The yellow solid was used in the next step without further purification.




A 10:1 solution of dioxane and water (11 mL) was added to a flask charged with 2-amino-6-bromo-4-methyl-(8-phenylmethyl)pyrido[2,3-d]pyrimidin-7(8H)-one (0.435 g, 1.27 mmol), 1H-pyrazole-5-boronic acid (0.284 g, 2.54 mmol), Pd(PPh3)4 (0.073 mg, 0.063 mmol), and K2CO3 (0.527 g, 3.81 mmol). The flask was flushed with nitrogen and fitted with a reflux condenser and heated to 110° C. After 12 h the reaction was cooled to room temperature and diluted with ethyl acetate (100 mL) and washed with water. The aqueous phase was acidified to pH 1.0 and washed with ethyl acetate (100 mL). The organic phases were combined and washed with brine, separated and dried over Na2SO4, filtered and concentrated in vacuo. The residue was precipitated with ethyl acetate to give 2-Amino-4-methyl-8-(phenylmethyl)-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (0.062 g, 15% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6): δ 13.10 (bs, 1H), 12.93 (bs, 1H), 8.47 (s, 1H), 7.76 (bs, 1H), 7.51 (bs, 1H), 7.28 (m, 5H), 6.97 (s, 1H), 5.55 (s, 2H), 2.55 (bs, 3H); MS (EI) for C18H16N6O: 333.1 (MH+).
Example 9
2-Amino-8-ethyl-4-methyl-6-(4-methyl-3-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one




A 3:1 solution of dioxane and water (4 mL) was added to a flask charged with 2-amino-6-bromo-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (0.140 g, 0.495 mmol) from above, 4-methylthiophene-3-boronic acid (0.140 g, 0.989 mmol), Pd(PPh3)4 (0.057 mg, 0.050 mmol), and K2CO3 (0.205 g, 1.48 mmol). The flask was flushed with nitrogen and fitted with a reflux condenser and heated to 100° C. After 12 hours the reaction was cooled to room temperature and diluted with ethyl acetate (70 mL) and washed with water. The aqueous phase was separated and washed with an additional amount of ethyl acetate (70 mL). The organic phases were combined and washed with brine, separated and dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified on SiO2 (1:1 methylene chloride:ethyl acetate) to give 2-Amino-8-ethyl-4-methyl-6-(4-methyl-3-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one (0.081 g, 55% yield) as an off-white solid: 1H NMR (400 MHz, DMSO-d6): δ 7.84 (s, 1H), 7.46 (d, J=4.0 Hz, 1H), 7.19 (m, 3H), 4.32 (q, J=8.0 Hz, 2H), 2.52 (s, 3H), 2.11 (bs, 3H), 1.19 (t, J=8.0 Hz, 3H); MS (EI) for C15H16N4OS: 301.1 (MH+).
Using the same or analogous synthetic techniques and substituting with appropriate reagents, the following compounds were prepared:
Example 9a
2-Amino-8-ethyl-4-methyl-6-(3-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 8.11 (dd, J=2.8, 1.2 Hz, 1H), 7.95 (s, 1H), 7.51 (dd, J=5.2, 1.2 Hz, 1H), 7.37 (dd, J=4.8, 3.2 Hz, 1H), 5.21, (bs, 2H), 4.48 (q, J=6.8 Hz, 2H), 2.63 (s, 3H), 1.32 (t, J=7.2 Hz, 3H); MS (EI) for C14H14N4OS: 287.0 (MH+).
Example 9b
2-Amino-8-ethyl-6-furan-3-yl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 8.47 (bs, 1H), 7.85 (s, 1H), 7.49 (t, J=1.6 Hz, 1H), 6.77 (dd, J=2.0, 0.8 Hz, 1H), 5.19, (bs, 2H), 4.48 (q, J=6.8 Hz, 2H), 2.64 (s, 3H), 1.31 (t, J=7.2 Hz, 3H); MS (EI) for C14H14N4O2: 271.1 (MH+).
Example 9c
2-Amino-6-(3,5-dimethylisoxazol-4-yl)-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 7.62 (s, 1H), 5.27, (bs, 2H), 4.44 (q, J=7.2 Hz, 2H), 2.59 (s, 3H), 2.38 (s, 3H), 2.25 (s, 3H), 1.31 (t, J=6.8 Hz, 3H); MS (EI) for C15H17N5O2: 300.1 (MH+).
Example 9d
2-Amino-8-ethyl-6-isoxazol-4-yl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 9.36 (s, 1H), 8.71 (s, 1H), 7.91 (s, 1H), 5.30, (bs, 2H), 4.48 (q, J=7.2 Hz, 2H), 2.67 (s, 3H), 1.32 (t, J=6.8 Hz, 3H); MS (EI) for C13H13N5O2: 272.0 (MH+).
Example 9e
2-Amino-8-ethyl-6-furan-2-yl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 8.19 (s, 1H), 7.48 (d, J=0.8 Hz, 1H), 7.37 (d, J=3.6 Hz, 1H), 6.53 (dd, J=3.6, 2.0 Hz 1H), 5.21, (bs, 2H), 4.48 (q, J=7.2 Hz, 2H), 2.66 (s, 3H), 1.32 (t, J=6.8 Hz, 3H); MS (EI) for C14H14N4O2: 271.0 (MH+).
Example 9f
5-(2-Amino-8-ethyl-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)thiophene-2-carbonitrile: 1H NMR (400 MHz, CDCl3): δ 8.24 (s, 1H), 7.61 (d, J=4.4 Hz, 1H), 7.55 (d, J=4.4 Hz, 1H), 5.33, (bs, 2H), 4.48 (q, J=7.2 Hz, 2H), 2.68 (s, 3H), 1.33 (t, J=6.8 Hz, 3H); MS (EI) for C15H13N5OS: 312.0 (MH+).
Example 9g
2-Amino-8-ethyl-4-methyl-6-(1H-pyrazol-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, DMSO-d6): δ 12.88 (s, 1H), 8.38 (s, 1H), 8.17 (s, 2H), 7.10 (bs, 2H), 4.35 (q, J=7.2 Hz, 2H), 2.59 (s, 3H), 1.20 (t, J=7.2 Hz, 3H); MS (EI) for C13H14N6O: 271.0 (MH+).
Example 9h
2-Amino-8-ethyl-4-methyl-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 8.94 (s, 1H), 7.94 (d, J=3.2 Hz, 1H), 7.46 (d, J=3.2 Hz, 1H), 5.34 (bs, 2H), 4.54 (q, J=7.2 Hz, 2H), 2.73 (s, 3H), 1.35 (t, J=7.2 Hz, 3H); MS (EI) for C13H13N5OS: 288.0 (MH+).
Example 9i
2-Amino-8-ethyl-4-methyl-6-(1-methyl-1H-pyrrol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, DMSO-d6): δ 7.81 (s, 1H), 7.20 (bs, 2H), 6.81 6.11 (dd, J=3.6, 2.0 Hz, 1H), 6.02 (t, J=3.2 Hz, 1H), 4.32 (q, J=7.2 Hz, 2H), 3.49 (s, 3H), 2.52 (s, 3H), 1.19 (t, J=7.2 Hz, 3H); MS (EI) for C15H17N5O: 284.1 (MH+).
Example 9j
2-Amino-8-ethyl-4-methyl-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 7.79 (s, 1H), 7.65 (d, J=6.8 Hz, 2H), 7.43 (d, J=7.2 Hz, 2H), 7.36 (d, J=7.2 Hz, 1H), 5.24 (bs, 2H), 4.47 (q, J=7.2 Hz, 2H), 2.60 (s, 3H), 1.31 (d, J=7.2 Hz, 3H), MS (EI) for C16H16N4O: 281.2 (MH+)
Example 9k
2-Amino-8-ethyl-6-(4-methoxyphenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 7.75 (s, 1H), 7.62 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 5.17 (bs, 2H), 4.47 (q, J=6.8 Hz, 2H), 3.85 (s, 3H), 2.60 (s, 3H), 1.31 (d, J=7.2 Hz, 3H), MS (EI) for C17H18N4O2: 311.2 (MH+)
Example 9m
2-Amino-8-ethyl-6-(2-methoxyphenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 7.75 (m, 1H), 7.36 (m, 2H), 7.01 (m, 2H), 5.20 (bs, 2H), 4.45 (m, 2H), 3.82 (s, 3H), 2.56 (s, 3H), 1.31 (m, 3H), MS (EI) for C17H18N4O2: 311.2 (MH+)
Example 9n
2-Amino-6-(4-chlorophenyl)-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 7.78 (s, 1H), 7.61 (d, J=8.8 Hz, 2H), 7.39 (d, J=8.8 Hz, 2H), 5.23 (bs, 2H), 4.46 (q, J=7.2 Hz, 2H), 2.61 (s, 3H), 1.31 (d, J=6.8 Hz, 3H), MS (EI) for C16H15ClN4O: 315.1 (MH+)
Example 9p
2-Amino-6-(3-chlorophenyl)-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 7.79 (s, 1H), 7.66 (m, 1H), 7.56 (m, 1H), 7.35 (m, 2H), 5.25 (bs, 2H), 4.46 (q, J=5.6 Hz, 2H), 2.61 (s, 3H), 1.31 (d, J=7.2 Hz, 3H), MS (EI) for C16H15ClN4O: 315.1 (MH+)
Example 9q
2-Amino-6-(2-chlorophenyl)-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 7.75 (s, 1H), 7.67 (m, 1H), 7.54 (m, 2H), 7.38 (m, 1H), 7.333 (m, 1H), 5.22 (bs, 2H), 4.46 (q, J=6.8 Hz, 2H), 2.57 (s, 3H), 1.31 (d, J=6.8 Hz, 3H), MS (EI) for C16H15ClN4O: 315.1 (MH+)
Example 9r
2-Amino-6-(2,4-dichlorophenyl)-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3): δ 7.77 (s, 1H), 7.67 (m, 1H), 7.49 (m, 1H), 7.32 (m, 1H), 5.24 (bs, 2H), 4.45 (q, J=6.8 Hz, 2H), 2.58 (s, 3H), 1.30 (d, J=7.2 Hz, 3H), MS (EI) for C16H14Cl2N4O: 349.1 (MH+)
Example 9t
2-Amino-8-ethyl-4-methyl-6-(2-thienyl)pyrido[2,3-a]pyrimidin-7(8H)-one: 1H NMR (400 MHz, DMSO-d6): δ 8.39 (s, 1H), 7.85-7.13 (m, 5H), 4.37 (q, J=7.2 Hz, 2H), 2.62 (s, 3H), 1.18 (t, J=7.2 Hz, 3H); MS (EI) for C14H14N4OS: 287.1 (MH+).
Example 9u
2-Amino-8-ethyl-6-(4-fluorophenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, DMSO-d6): δ 7.99 (s, 1H), 7.76-7.22 (m, 6H), 4.34 (q, J=7.2 Hz, 2H), 2.56 (s, 3H), 1.20 (t, J=7.2 Hz, 3H); MS (EI) for C16H15FN4O: 299.2 (MH+).
Example 9v
2-Amino-8-ethyl-6-(3-fluorophenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, DMSO-d6): δ 8.06 (s, 1H), 7.61-7.44 (m, 3H), 7.29 (bs, 2H), 7.20-7.15 (m, 1H), 4.34 (q, J=7.2 Hz, 2H), 2.58 (s, 3H), 1.20 (t, J=7.2 Hz, 3H); MS (EI) for C16H15FN4O: 299.2 (MH+).
Example 9w
2-Amino-8-ethyl-6-(2-fluorophenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, DMSO-d6): δ 7.96 (s, 1H), 7.50-7.23 (m, 6H), 4.32 (q, J=6.8 Hz, 2H), 2.52 (s, 3H), 1.19 (t, J=6.8 Hz, 3H); MS (EI) for C16H15FN4O: 299.2 (MH+).
Example 9x
Methyl 3-(2-amino-8-ethyl-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)benzoate: 1H NMR (400 MHz, DMSO-d6): δ 8.34 (s, 1H), 8.06 (s, 1H), 7.95-7.55 (m, 3H), 7.28 (bs, 1H), 4.35 (q, J=6.8 Hz, 2H), 3.89 (s, 3H), 2.58 (s, 3H), 1.21 (t, J=6.8 Hz, 3H); MS (EI) for C18H18N4O3: 339.2 (MH+).
Example 9y
2-Amino-8-ethyl-4-methyl-6-pyrimidin-5-ylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, DMSO-d6): δ 8.39 (s, 1H), 7.65-7.30 (m, 5H), 4.31 (q, J=7.2 Hz, 2H), 2.50 (s, 3H), 1.17 (t, J=7.2 Hz, 3H); MS (EI) for C14H14N6O: 283.2 (MH+).
Example 10
2-Amino-8-ethyl-6-(1H-imidazol-5-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one




A solution of potassium hydroxide (0.139 g, 2.48 mmol) in absolute ethanol (3.0 mL) was added to a pressure tube charged with 4-(ethylamino)-6-methyl-2-(methylthio)pyrimidine-5-carbaldehyde (0.229 g, 1.08 mmol), prepared using procedures similar to those described for Intermediate 1, and 2-(1H-imidazol-5-yl)acetonitrile (0.174 g, 162 mmol) and heated to 70° C. After 12 h, the reaction was allowed to cool to room temperature and concentrated in vacuo affording 8-ethyl-6-(1H-imidazol-5-yl)-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-imine as a solid. The product was used in the subsequent step without further purification.




Acetic anhydride (15.0 mL) was added to a flask charged with crude 8-ethyl-6-(1H-imidazol-5-yl)-4-methyl-2-(methylthio)pyrido[2,3-c]pyrimidin-7(8H)-imine and heated to 100° C. After 30 minutes, the reaction was allowed to cool to room temperature and concentrated in vacuo. The acetylated residue was then treated with 6 N HCl (16 mL) and heated to 95° C. for 30 minutes then transferred to a large flask. A saturated solution of NaHCO3 (150 mL) was added at 0° C. to about pH=8.0. The aqueous phase was washed thrice with ethyl acetate (100 mL) and the organic layers combined, then washed with brine and dried over Na2SO4. The drying agent was filtered off and the organic layers were concentrated in vacuo to afford crude 8-ethyl-6-(1H-imidazol-5-yl)-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one which was used in the subsequent step without further purification.




3-Chloroperbenzoic acid (0.299 g, 1.73 mmol) was added to a solution of crude 8-ethyl-6-(1H-imidazol-5-yl)-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (0.260 g, 0.866 mmol) in dichloromethane (10.0 mL) at room temperature. After 1.5 h, the reaction was diluted with dichloromethane (50 mL) and washed twice with saturated NaHCO3, followed by brine. The organic phase was separated and dried over Na2SO4, filtered, and concentrated in vacuo. The corresponding sulfone was used in the subsequent step without further purification.




Concentrated aqueous ammonium hydroxide (400 μL) was added to a solution of the sulfone in dioxane (10 mL) at 0° C. The reaction flask sealed, and allowed to warm to room temperature upon standing overnight. The reaction was concentrated in vacuo and purified on reverse phase HPLC (acetonitrile: water 0.1% TFA, 20-60% gradient). The fractions containing product were collected and concentrated to one half volume and poured into saturated NaHCO3 (50 mL). The aqueous phase was washed trice with ethyl acetate (50 mL) and dried over Na2SO4, filtered, and concentrated in vacuo. The residue was triturated with methylene chloride and ethyl acetate to afford 2-amino-8-ethyl-6-(1H-imidazol-5-yl)-4-methylpyrido[2,3-c]pyrimidin-7(8H)-one (29 mg, 12% yield) as a light yellow solid: 1H NMR (400 MHz, CH3OH-d4): δ 8.52 (bs, 1H), 7.88 (bs, 1H), 7.76 (s, 1H), 4.30 (q, J=6.8 Hz, 2H), 2.65 (s, 3H), 1.29 (t, J=6.8 Hz, 3H); MS (EI) for C13H14N6O: 271.0 (MH+).
Example 11
2-Amino-8-ethyl-4-methyl-6-(1H-1,2,3-triazol-5-yl)pyrido[2,3-c]pyrimidin-7(8H)-one




Trimethylsilylethyne (1.44 mL, 10.2 mmol) was added to a pressure tube charged with 2-amino-6-bromo-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (1.58 g, 5.59 mmol) from above, CuI (0.053 g, 0.279 mmol), and PdCl2(PPh3)2 (0.211 g, 0.279 mmol) in triethylamine (20 mL). The pressure tube was sealed under nitrogen and heated to 50° C. 96 h. The reaction was cooled to room temperature and poured into a saturated solution of NaHCO3 (150 mL), then washed four times with ethyl acetate (50 mL). The organic layers were pooled and dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified on SiO2 (2:1, methylene chloride:ethyl acetate) to afford 2-amino-8-ethyl-4-methyl-6-((trimethylsilyl)ethynyl)pyrido[2,3-d]pyrimidin-7(8H)-one (1.09 g, 65% yield) as an off white solid.




Potassium carbonate (1.00 g, 7.28 mmol) was added to a flask charged with 2-amino-8-ethyl-4-methyl-6-((trimethylsilyl)ethynyl)pyrido[2,3-d]pyrimidin-7(8H)-one (1.09 g, 3.64 mmol) in anhydrous methanol (15 mL). The reaction was stirred at room temperature under nitrogen for 16 h. The reaction was concentrated to one half volume and the yellow precipitate collected by vacuum filtration to afford 2-amino-8-ethyl-6-ethynyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one.




Anhydrous DMF (5.0 mL) was added to a flask charged with 2-amino-8-ethyl-6-ethynyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (0.204 g, 0.894 mmol), sodium azide (0.070 g, 1.07 mmol), and ammonium chloride (0.057 g, 1.07 mmol). The reaction was capped under nitrogen and heated to 120° C. After 48 h, the reaction was cooled to room temperature and concentrated in vacuo. The residue was purified on reverse phase HPLC (acetonitrile: water 0.1% TFA, 20-60% gradient). The fractions containing product were collected and concentrated to one half volume and poured into saturated NaHCO3 (50 mL). The aqueous phase was washed trice with ethyl acetate (50 mL) and dried over Na2SO4, filtered, and concentrated in vacuo. The residue was triturated with methylene chloride and ethyl acetate to afford 2-amino-8-ethyl-4-methyl-6-(1H-1,2,3-triazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (14 mg, 6% yield) as a light yellow solid: 1H NMR (400 MHz, DMSO-d6): δ 8.55 (bs, 1H), 8.41 (bs, 1H), 7.32 (bs, 2H), 4.37 (q, J=7.2 Hz, 2H), 2.60 (s, 3H), 1.21 (t, J=7.2 Hz, 3H); MS (EI) for C12H13N7O: 272.0 (MH+).
Example 12
2-Amino-8-ethyl-4-methyl-6-(1H-tetrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one




Potassium carbonate (0.539 g, 3.90 mmol) was added to a suspension of 4-(ethylamino)-6-methyl-2-(methylthio)pyrimidine-5-carbaldehyde (0.413 g, 1.95 mmol) from above, and malononitrile (0.194 g, 2.93 mmol) in absolute ethanol (15.0 mL) and heated to 70° C. After one h, the reaction was allowed to cool to room temperature and concentrated in vacuo. The residue was diluted with ethyl acetate (50 mL) and washed with saturated NaHCO3 (50 mL), and brine. The organic phase was separated and concentrated in vacuo. The residue was precipitated with ethyl acetate and hexanes to give 8-ethyl-7-imino-4-methyl-2-(methylthio)-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile as a brown solid that was used in the subsequent step without further purification.




Acetic anhydride (10.0 mL) was added to a flask charged with 8-ethyl-7-imino-4-methyl-2-(methylthio)-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (0.506 g, 1.95 mmol) and heated to 100° C. After one h, the reaction was allowed to cool to room temperature and concentrated in vacuo. The acetylated residue was then treated with 6 N HCl (40 mL) and heated to 95° C. for one hour then transferred to a large flask. A saturated solution of NaHCO3 (500 mL) was added slowly at 0° C. until a  ̃pH 8.0 was achieved. The aqueous phase was washed thrice with ethyl acetate (100 mL) and the organic layers combined, then washed with brine and dried over Na2SO4. The drying agent was filtered and concentrated in vacuo to afford crude 8-ethyl-4-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile which was used in the subsequent step without further purification.




3-Chloroperbenzoic acid (1.00 g, 5.85 mmol) was added to a solution of crude 8-ethyl-4-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (0.507 g, 1.95 mmol) in dichloromethane (30.0 mL) at room temperature. After 2.5 hours, the reaction was diluted with dichloromethane (50 mL) and washed twice with saturated NaHCO3, followed by brine. The organic phase was separated and dried over Na2SO4, filtered, and concentrated in vacuo. 2-Amino-8-ethyl-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile was used in the subsequent step without further purification.
Ammonium hydroxide (500 μL) was added to a solution of the above sulfone in dioxane (10 mL) at 0° C. The reaction flask sealed, and allowed to warm to room temperature upon standing overnight. The reaction was concentrated in vacuo triturated with ethyl acetate to afford the product which was used in the subsequent step without further purification.




Tributyltin azide (660 μL, 2.41 mmol) was added to a flask charged with 2-amino-8-ethyl-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (0.184 g, 0.803 mmol) in anhydrous toluene (5.0 mL). The reaction was fitted with a reflux condenser and heated to 140° C. under a nitrogen atmosphere. After 20 h, the reaction was cooled to room temperature and the precipitate collected by vacuum filtration and washed with absolute ethanol to give 2-amino-8-ethyl-4-methyl-6-(1H-tetrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (98 mg, 45% yield) as a light brown solid: 1H NMR (400 MHz, 20% DCl in D2O): δ 6.97 (s, 1H), 2.42 (q, J=7.2 Hz, 2H), 0.953 (s, 3H), −0.73 (t, J=7.2 Hz, 3H); MS (EI) for C11H11N8O: 271.0 (MH+).
Example 13




A mixture of 8-(3-methoxypropyl)-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (0.36 g, 1.29 mmol), prepared using procedures similar to those described in Example 1, dichloromethane (10 mL), and 77% 3-chloroperbenzoic acid with water (0.723 g, 3.23 mmol) was stirred for 1 h. The mixture was diluted with dichloromethane, washed with sat. sodium bicarbonate (3 times), brine, dried over sodium sulfate, and DCM was removed under reduced pressure. The crude 8-(3-methoxypropyl)-4-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one was used without further purification for subsequent step.




8-(3-methoxypropyl)-4-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one, and a solution of 2M ethylamine in THF (20 mL) was stirred for 2 h. THF was removed under reduced pressure and the crude product was purified by flash column chromatography to give 2-(ethylamino)-8-(3-methoxypropyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (0.18 g, 50% yield over 2 steps).




To a solution of 2-(ethylamino)-8-(3-methoxypropyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (0.18 g, 0.65 mmol), acetic acid (5 mL) and dichloromethane (3 mL) was added bromine (36 ul, 0.7 mmol). The mixture was stirred for 5 minutes, and then diluted with DCM and water. The organic layer was washed with sat. sodium bicarbonate (3 times), brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography to gave 0.13 g (56% yield) of 6-bromo-2-(ethylamino)-8-(3-methoxypropyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one. 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 5.44 (Br. s, 1H), 4.55 (m, 2H), 3.54-3.47 (m, 4H), 3.33 (s, 3H), 2.53 (s, 3H), 2.05-2.00 (m, 2H), 1.30-1.23 (m, 3H); MS (EI) for C14H19BrN4O2: 355 (MH+).
Using the same or analogous synthetic techniques and substituting with appropriate reagents, the following compounds were prepared:
Example 13a
6-bromo-8-(2-ethoxyethyl)-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 5.37 (Br. s, 1H), 4.67 (m, 2H), 3.74 (m, 2H), 3.61-3.56 (t, 2H), 3.51 (m, 2H), 2.53 (s, 3H), 1.29-1.25 (t, 3H), 1.19-1.15 (t, 3H); MS (EI) for C14H19BrN4O2: 355 (MH+).
Example 13b
6-bromo-8-(3-ethoxypropyl)-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 5.37 (Br. s, 1H), 4.53 (m, 2H), 3.52 (m, 4H), 3.48-3.43 (m, 2H), 2.53 (s, 3H), 2.04-2.00 (m, 2H), 1.29-1.25 (t, 3H), 1.19-1.15 (t, 3H); MS (EI) for C15H21BrN4O2: 369 (MH+).
Example 13c
6-bromo-2-(ethylamino)-8-(3-isopropoxypropyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 5.37 (Br. s, 1H), 4.53 (m, 2H), 3.59-3.49 (m, 5H), 2.52 (s, 3H), 2.01-1.98 (m, 2H), 1.28-1.25 (t, 3H), 1.13-1.11 (t, 6H); MS (EI) for C16H23BrN4O2: 383 (MH+).
Example 14




A mixture of 2,4-dichloro-6-methylpyrimidine (Aldrich, 5 g, 30 mmol), cyclohexylamine (3 g, 30 mmol) and DIEA (10 mL) was stirred at 80° C. for 12 h. The volatile material was removed under reduced pressure. The residue was loaded on a silica gel column, and was eluted with hexanes/ethyl acetate (3:1). 8-cyclohexyl-2-(ethylamino)-4-methyl-6-(thiopheN-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one was obtained as colorless oil (2.8 g, 41% yield).




The product was reacted with a solution of ethylamine (10 equiv.) in THF at 100° C. for 12 h. The crude 2-ethylamino-4-cyclohexylamino-6-methylpyrimidine was obtained from a standard workup and was used in the next step.




To a solution of 2-ethylamino-4-cyclohexylamino-6-methylpyrimidine (600 mg, 2.56 mmol) in CH3CN (10 mL) was added N-iodosuccinimide (NIS, 658 mg, 2.92 mmol). The reaction was stirred for 2 h at room temperature. After removal of the solvent, the residue was dissolved in EtOAc. The organic phase was then washed with sodium bisulfite, brine, and dried over Na2SO4. Purification by flash column chromatography gave 660 mg (73% yield) of 2-ethylamino-4-cyclohexylamino-5-iodo-6-methylpyrimidine.




To a solution of 2-ethylamino-4-cyclohexylamino-5-iodo-6-methylpyrimidine (660 mg, 1.83 mmol) in DMA (7 mL) was added ethyl acrylate (458 mg, 4.58 mmol), Pd(OAc)2 (121 mg, 0.18 mmol), (o-Tol)3P (110 mg, 0.37 mmol), and Et3N (740 mg, 7.32 mmol). The mixture was then stirred at 100° C. for 12 h under N2. Standard workup and purification by column chromatography gave 411 mg (67% yield) of (E)-ethyl 3-(4-(cyclohexylamino)-2-(ethylamino)-6-methylpyrimidin-5-yl)acrylate




(E)-ethyl 3-(4-(cyclohexylamino)-2-(ethylamino)-6-methylpyrimidin-5-yl)acrylate (200 mg, 0.6 mmol) was dissolved in AcOH (2 mL). This solution was heated in a sealed tube at 186° C. for 17 h. Standard workup and purification by column chromatography gave 65 mg (38% yield) of 8-cyclohexyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one.




To 8-cyclohexyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one in AcOH and CH2Cl2 was added Br2 (22 uL, 0.42 mmol) at 80° C. Standard workup and purification by column chromatography gave 65 mg (0.17 mmol, 80% yield) of 6-bromo-8-cyclohexyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one.




The bromide (65 mg, 0.17 mmol) obtained above was reacted with 2-thiopheneboronic acid (45 mg, 0.36 mmol) in the presence of Pd(PPh3)4 (20 mg, 0.018 mmol) and Na2CO3 (38 mg, 0.36 mmol) in 1,4-dioxane/H2O (1:1) at 100° C. for 2 h. Removal of solvents and purification by column chromatography gave 33 mg (50% yield) of 8-cyclohexyl-2-(ethylamino)-4-methyl-6-(thiopheN-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one. 1H NMR (400 MHz, DMSO-d6)  8.01 (br s, 1H), 7.60 (m, 1H), 7.37 (m, 1H), 7.10 (m, 1H), 5.60-5.40 (m, 1H), 3.55 (m, 2H), 2.85 (m, 1H), 2.61 (s, 3H), 1.90 (m, 2H), 1.71 (m, 4H), 1.43 (m, 2H), 1.30-1.2 (m, 2H), 1.30 (t, 3H); MS (EI) for C20H24N4OS: 369 (MH+).
Using the same or analogous synthetic techniques and substituting with appropriate reagents, the following compound was prepared:
Example 14a
6-bromo-8-cyclopropyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3)  8.06 (s, 1H), 5.37 (br s, 1H), 3.54 (m, 2H), 2.94 (br s, 1H), 2.51 (s, 3H), 1.31-1.25 (m, 5H), 0.91 (br s, 2H); MS (EI) for C13H15BrN4O: 323 (MH+).
Example 15




To a solution of 6-bromo-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (100 mg, 0.35 mmol) in DMF (2 mL), prepared using procedures analogous to those described in Example 14, was added NaH (30 mg, 60%, 0.7 mmol). The mixture was stirred for 30 min at room temperature and was warmed to 70° C. 3-Bromopropanol (48 mg, 0.35 mmol) was then added. The stirring was continued for 12 h. Standard workup and purification by column chromatography gave 33 mg (27% yield) of 6-bromo-2-(ethylamino)-8-(3-hydroxypropyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one. 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 5.42 (br s, 1H), 4.59 (br s, 2H), 3.50-3.47 (m, 5H), 2.55 (s, 3H), 2.02 (br s, 2H), 1.28 (t, 3H); MS (EI) for C13H17BrN4O2: 341 (MH+).
Using the same or analogous synthetic techniques and substituting with appropriate reagents, the following compounds were prepared:
Example 15a
6-bromo-2-(ethylamino)-8-(2-hydroxyethyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 4.82 (br s, 1H), 4.40 (br s, 2H), 3.62-3.55 (m, 2H), 3.40-3.20 (m, 3H), 2.55 (s, 3H), 1.15 (t, 3H); MS (EI) for C12H15BrN4O2: 327 (MH+).
Example 15b
6-bromo-2-(ethylamino)-4-methyl-8-(2-(piperidin-1-yl)ethyl)pyrido[2,3-d]pyrimidin-7(8H)-one: 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 5.39 (br s, 1H), 4.59 (br s, 2H), 3.55-3.40 (m, 2H), 2.70-2.50 (m, 6H), 2.52 (s, 3H), 1.62-1.58 (m, 4H), 1.46-1.40 (m, 2H), 1.27 (t, 3H); MS (EI) for C17H24BrN5O: 394 (MH+).
BIOLOGICAL EXAMPLES
Biological Example 1
PI3Kalpha Luciferase-Coupled Chemiluminescence Assay Protocol
PI3Kα activity is measured as the percent of ATP consumed following the kinase reaction using luciferase-luciferiN-coupled chemiluminescence. Reactions were conducted in 384-well white, medium binding microtiter plates (Greiner). Kinase reactions were initiated by combining test compounds, ATP, substrate (PIP2), and kinase in a 20 μL volume in a buffer solution. The standard PI3Kalpha assay buffer is composed 50 mM Tris, pH 7.5, 1 mM EGTA, 10 mM MgCl2, 1 mM DTT and 0.03% CHAPS. The standard assay concentrations for enzyme, ATP, and substrate are 0.5-1.1 nM, 1 μM, and 7.5 μM, respectively. The reaction mixture was incubated at ambient temperature for approximately 2 h. Following the kinase reaction, a 10 μL aliquot of luciferase-luciferin mix (Promega Kinase-Glo) was added and the chemiluminescence signal measured using a Victor2 plate reader (Perkin Elmer). Total ATP consumption was limited to 40-60% and IC50 values of control compounds correlate well with literature references.
Certain compounds of the invention were tested in this assay and demonstrated the ability to bind to PI3K. For example, in one embodiment of the invention, the PI3K inhibitor is selected from the compounds in Table 1 having a PI3K-binding affinity of about 9 μM or less. In another embodiment, the PI3K inhibitor is selected from the compounds in Table 1 having a PI3K-binding affinity of about 5 μM or less. In another embodiment, the PI3K inhibitor is selected from the compounds in Table 1 having a PI3K-binding affinity of about 3 μM or less. In another embodiment, the PI3K inhibitor is selected from the compounds in Table 1 having a PI3K-binding affinity of about 1.5 μM or less. In another embodiment, the PI3K inhibitor is selected from the compounds in Table 1 having a PI3K-binding affinity of about 1 μM or less. In another embodiment, the PI3K inhibitor is selected from the compounds in Table 1 having a PI3K-binding affinity of about 0.6 μM or less. In another embodiment, the PI3K inhibitor is selected from the compounds in Table 1 having a PI3K-binding affinity of about 0.3 μM or less. In another embodiment, the PI3K inhibitor is selected from the compounds in Table 1 having a PI3K-binding affinity of about 0.2 μM or less. In another embodiment, the PI3K inhibitor is selected from the compounds in Table 1 having a PI3K-binding affinity of about 0.1 μM or less. In another embodiment, the PI3K inhibitor is selected from the compounds in Table 1 having a PI3K-binding affinity of about 0.04 μM or less. In another embodiment, the PI3K inhibitor is selected from the compounds in Table 1 having a PI3K-binding affinity of about 0.020 μM or less.
Biological Example 2
Phospho AKT Assay
PC-3 cells were seeded on 6-well plates at 150,000 cells/well. Cells were cultured for 3 days, then treated with compounds in serum-free medium for 3 hr. EGF (100 ng/mL) was added for the last 10 min. Cells were lysed in TENN buffer. Phospho T308 Akt and total Akt were quantified by ELISA performed according to the Biosource assay protocol. The readings of phospho Akt were normalized to total Akt readings.
Biological Example 3
Phospho S6 Assay
PC-3 cells were seeded on 96-well plates at 8,000 cells/well. For each experiment, cells were seeded and treated in duplicated plates: one plate for phospho S6 CellELISA, and one plate for total S6 CellELISA. Cells were cultured on the plates for 3 days, then treated with compounds in serum-free medium for 3 hr in triplicate. Cells were fixed with 4% formaldehyde, quenched with 0.6% H2O2, blocked with 5% BSA, incubated with either phospho S6 antibody or total S6 antibody overnight, incubated with goat-anti-rabbit-IgG-HRP for 1 hr, and developed in chemiluminescent substrate.
Biological Example 4
PIP3 Assay
MCF-7 cells grown in 10-cm dishes were starved for 3 hours in DMEM, and then treated with compounds for 20 minutes. In the last 2 minutes of the incubation with the compounds, EGF (100 ng/mL) was added to stimulate the production of PIP3. The medium was aspirated and the cells were scraped with 10% trichloroacetic acid. The lipids were extracted from the pellet after the cell lysates were centrifuged. PIP3 in the cellular lipid extraction was quantified with the AlphaScreen assay in which Grp1-PH is used as the PIP3 specific probe. The amount of cellular PIP3 was calculated from the standard curve of diC8 PI (3,4,5) P3.
Biological Example 5-10
In Vivo Models
Compound A is a Compound of Formula I. Compound B is N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta-[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine.
Female and male athymic nude mice (NCr) 5-8 weeks of age and weighing approximately 20-25 g were used in the following model. Prior to initiation of a study, the animals were allowed to acclimate for a minimum of 48 h. During these studies, animals were provided food and water ad libitum and housed in a room conditioned at 70-75° F. and 60% relative humidity. A 12 h light and 12 h dark cycle was maintained with automatic timers. All animals were examined daily for compound-induced or tumor-related deaths.
PC-3 human prostate adenocarcinoma cells were cultured in vitro in DMEM (Mediatech) supplemented with 20% Fetal Bovine Serum (Hyclone), Penicillin-Streptomycin and non-essential amino acids at 37° C. in a humidified 5% CO2 atmosphere. On day 0, cells were harvested by trypsinization and 3×106 cells (passage 13, 99% viability) in 0.1 mL of ice-cold Hank's balanced salt solution were implanted subcutaneously into the hindflank of 5-8 week old male nude mice. A transponder was implanted in each mouse for identification, and animals were monitored daily for clinical symptoms and survival. Body weights were recorded daily. Experiments were conducted with Compound A as a single agent as well as Compound A in combination with Taxol and Compound A in combination with Rapamycin. This model can be used to assess the desirability of treating with Compound A in combination with other anti-cancer agents.
U-87 MG human glioblastoma cells were cultured in vitro in DMEM (Mediatech) supplemented with 10% Fetal Bovine Serum (Hyclone), PenicilliN-Streptomycin and non-essential amino acids at 37° C. in a humidified 5% CO2 atmosphere. On day 0, cells were harvested by trypsinization and 2×106 cells (passage 5, 96% viability) in 0.1 mL of ice-cold Hank's balanced salt solution were implanted intradermally into the hindflank of 5-8 week old female nude mice. A transponder was implanted in each mouse for identification, and animals were monitored daily for clinical symptoms and survival. Body weights were recorded daily. Experiments were conducted with Compound A as a single agent and the results are not included. This model can be used to assess the desirability of treating with Compound A in combination with other anti-cancer agents.
A549 human lung carcinoma cells were cultured in vitro in DMEM (Mediatech) supplemented with 10% Fetal Bovine Serum (Hyclone), PenicilliN-Streptomycin and non-essential amino acids at 37° C. in a humidified 5% CO2 atmosphere. On day 0, cells were harvested by trypsinization and 10×106 cells (passage 12, 99% viability) in 0.1 mL of ice-cold Hank's balanced salt solution were implanted intradermally into the hindflank of 5-8 week old female nude mice. A transponder was implanted in each mouse for identification, and animals were monitored daily for clinical symptoms and survival. Body weights were recorded daily. Experiments were conducted with Compound A as a single agent as well as Compound A in combination with Compound B. This model can be used to assess the desirability of treating with Compound A in combination with other anti-cancer agents.
MDA-MB-468 human breast adenocarcinoma cells, passage number <6, were maintained and propagated in log-phase growth in Dulbecco's Modification of Eagles's Medium (DMEM; Mediatech) containing L-Glutamine supplemented with 10% Fetal Bovine Serum (Hyclone), Penicillin-Streptomycin and non-essential amino acids at 37° C. in a humidified, 5% CO2 atmosphere. On day 0, cells were harvested by trypsinization, and 10×106 cells (passage 10, 98% viability) in 50% cold Hanks balanced salt solution/50% Matrigel (100 μL total volume per mouse) were implanted subcutaneously into the mammary fat pads of female nude mice. Experiments were conducted with Compound A as a single agent as well as Compound A in combination with erlotinib. This model can be used to assess the desirability of treating with Compound A in combination with other anti-cancer agents.
Calu-6 human lung anaplastic carcinoma cells were cultured in vitro in DMEM (Mediatech) supplemented with 10% Fetal Bovine Serum (Hyclone), Penicillin-Streptomycin and non-essential amino acids at 37° C. in a humidified, 5% CO2 atmosphere. On day 0, cells were harvested by trypsinization, and 5×106 cells (passage #8, 96% viability) in 0.1 mL ice-cold Hank's balanced salt solution were implanted intradermally in the hind-flank of 5-8 week old female athymic nude mice. A transponder was implanted in each mouse for identification, and animals were monitored daily for clinical symptoms and survival. Body weights were recorded daily. Experiments were conducted with Compound A as a single agent as well as Compound A in combination with carboplatin. This model can be used to assess the desirability of treating with Compound A in combination with other anti-cancer agents.
MCF7 human mammary adenocarcinoma cells were cultured in vitro in DMEM (Cellgro) supplemented with 10% Fetal Bovine Serum (Cellgro), Penicillin-Streptomycin and non-essential amino acids at 37° C. in a humidified 5% CO2 atmosphere. On day 0, cells were harvested by trypsinization, and 5×106 cells (passage 10 and 95% viability for Study 1, passage 9 and 90% viability for Study 2) in 100 μL of a solution made of 50% cold Hanks balanced salt solution with 50% growth factor reduced matrigel (R&D Systems for Study 1 and Becton Dickinson for Study 2) implanted subcutaneously into the hindflank of female nude mice. A transponder was implanted into each mouse for identification and data tracking, and animals were monitored daily for clinical symptoms and survival. During the dosing period, the tumor weight of each animal was determined twice weekly and the body weight of each animal was measured daily. Experiments were conducted with Compound A as a single agent as well as Compound A in combination with Compound B. This model can be used to assess the desirability of treating with Compound A in combination with other anti-cancer agents.
For subcutaneous or intradermal tumors, the mean tumor weight of each animal in the respective control and treatment groups was determined twice weekly during the study. Tumor weight (TW) was determined by measuring perpendicular diameters with a caliper, using the following formula:

tumor weight (mg)=[tumor volume=length (mm)×width2 (mm2)]/2

These data were recorded and plotted on a tumor weight vs. days post-implantation line graph and presented graphically as an indication of tumor growth rates. Percent inhibition of tumor growth (TGI) is determined with the following formula:




  
    (
    
      1
      -
      
        (
        
          
            (
            
              
                X
                f
              
              -
              
                X
                0
              
            
            )
          
          
            (
            
              
                Y
                f
              
              -
              
                X
                0
              
            
            )
          
        
        )
      
    
    )
  
  *
  100




    
    
        where X0=average TW of all tumors on group day
        Xf=TW of treated group on Day f
        Yf=TW of vehicle control group on Day f

If tumors regress below their starting sizes, then the percent tumor regression is determined with the following formula:

    
    






  
    (
    
      
        (
        
          
            X
            0
          
          -
          
            X
            f
          
        
        )
      
      
        X
        0
      
    
    )
  
  *
  100




Tumor size is calculated individually for each tumor to obtain a mean±SEM value for each experimental group. Statistical significance is determined using the 2-tailed Student's t-test (significance defined as P<0.05).

Biological Examples 11-16
Compound A is a Compound of Formula I and is an inhibitor of class I PI3-kinases. Compound B is N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta-[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine.
Prostate Cancer Xenograft Model
A Compound of Formula I in Combination with Taxol
Compound A was tested alone and in combination with taxol in a prostate carcinoma tumor model. PC-3 is a human prostate carcinoma cell line that harbors a homozygous deletion mutation in PTEN, which results in constitutive activation of the PI3K pathway. In single-dose pharmacodynamic experiments, oral administration of Compound A resulted in a dose-dependent decrease in the phosphorylation of AKT, p70S6K, and S6 in PC-3 tumors grown ectopically in mice. Repeat-dose administration of Compound A also inhibited the growth of these tumors, but did not induce regressions.
Oral administration of Compound A at 100 mg/kg q2d or 30 mg/kg bid resulted in substantial tumor growth inhibition. See FIG. 1. Comparable tumor growth inhibition was achieved with 7.5 mg/kg taxol administered i.v. twice weekly. While tumor growth was inhibited substantially with Compound A alone, the combination of either dose of Compound A with taxol was superior to either agent alone and induced significant regression of the tumors. Body weight loss and dose skipping was minimal in all groups, and was not exacerbated in the combination group indicating that the combination was well tolerated. These results support the use of a Compound of Formula I in combination with taxol in tumors with constitutively activated PI3K signaling.
Prostate Cancer Xenograft Model
A Compound of Formula I in Combination with Rapamycin
Compound A was tested alone and in combination with rapamycin in a prostate carcinoma tumor model (PC-3 cell line). Oral administration of Compound A at 100 mg/kg q2d resulted in significant tumor growth inhibition. See FIG. 2. Significant tumor growth inhibition was also observed with 5 mg/kg rapamycin administered i.p. daily. While tumor growth was inhibited substantially with Compound A alone, the combination of Compound A with rapamycin was transiently superior to either agent alone and induced regression of the tumors, although the final tumor weights were similar between rapamycin alone and the combination treatment. Body weight loss and dose skipping was minimal with each agent alone, but body weight loss was exacerbated in the combination group necessitating dose skipping. The fact that tumor regression was observed despite dose skipping suggests that using an intermittent dosing schedule would maintain efficacy and improve tolerability.
At the end of the efficacy study, tumors were resected and processed for histological analysis of markers of proliferation (Ki67) and apoptosis (TUNEL). Administration of Compound A as monotherapy (100 mg/kg q2d) was associated with a significant 44% decrease in the fraction of proliferating cells. Administration of rapamycin as monotherapy was also associated with a decrease (77%) in the fraction of proliferating cells. Combined administration of Compound A and rapamycin resulted in a strong anti-proliferative effect (96% decrease) which was significantly enhanced over that seen with monotherapy (FIG. 6). Administration of Compound A as monotherapy was associated with a significant 3.6-fold induction in the fraction of apoptotic cells, whereas rapamycin administered as monotherapy did not exert significant pro-apoptotic effects. Combined administration of Compound A and rapamycin resulted in a 7-fold induction in the fraction of apoptotic cells, which was significantly enhanced over that seen with monotherapy (FIG. 7). Together, these data indicate that coadministration of Compound A and rapamycin leads to a significant decrease in tumor cell proliferation and a significant increase in tumor cell apoptosis compared to either agent administered as monotherapy. These results support the use of a Compound of Formula I in combination with rapamycin in tumors with constitutively activated PI3K signaling.
Non-Small Cell Lung Cancer Xenograft Model
A Compound of Formula I in Combination with Carboplatin
Compound A was tested both as a single agent and in combination with carboplatin in a NSCLC tumor model. Calu-6 is a human NSCLC cell line that harbors a heterozygous activating mutation in K-Ras (Q61K).
Oral administration of Compound A at 100 mg/kg q2d or 30 mg/kg bid to mice bearing Calu-6 tumors resulted in substantial tumor growth inhibition. See FIG. 3. Both dose schedules resulted in similar inhibition of tumor growth. Significant tumor growth inhibition was also observed with 50 mg/kg carboplatin administered i.v. q4d, but was not as pronounced as with Compound A. The combination of Compound A 100 mg/kg q2d and carboplatin was superior to either agent alone, however, the combination of Compound A 30 mg/kg bid with carboplatin was not significantly different from Compound A 30 mg/kg bid alone. Body weight loss and dose skipping was minimal in all groups, and was not exacerbated in the combination group indicating that the combination was well tolerated. These results support the use of a Compound of Formula I in combination with platins in tumors with activating mutations in K-Ras.
Non-Small Cell Lung Cancer Xenograft Model
A Compound of Formula I in Combination with Compound B
Compound A was tested both as a single agent and in combination with Compound B, an EGFR inhibitor, in a NSCLC tumor model. The A549 human non-small cell lung carcinoma cell line harbors a homozygous stop mutation in the gene encoding LKB1, and an activating G12S mutation in K-Ras, promoting activation of both PI3K and mTOR. A549 cells also express wild-type EGFR.
Oral single-agent administration of Compound B at 30 mg/kg qd for 18 days caused a significant tumor growth inhibition of 80%. See FIG. 4a. Compound A administered qd as a single agent at 30 mg/kg caused a significant tumor growth inhibition of 80%. Oral administration of Compound B at 30 mg/kg qd followed by administration of Compound A at 30 mg/kg qd after about six hours led to a significant TGI of 93%, which trended towards an increased anti-tumor efficacy compared to the efficacy of the single treatments, although this did not reach statistical significance in these studies. One possible explanation for the modest effect of the combination is the short duration of the dosing period (14 days), which may be too short to observe the full benefit of the combination. Longer dosing regimes may produce more significant differences, as the anticipated effect of dual inhibition of PI3K/mTOR and EGFR on cell growth and survival becomes more apparent.
As a single agent Compound B dosed at 30 mg/kg qd was generally well tolerated, with a body weight loss of 1.5 to 7% with no dose omission. Compound A dosed at 30 mg/kg qd was also well tolerated with no dose skipping and non-significant body weight loss. Co-administration of Compound B at 30 mg/kg qd with Compound A at 30 mg/kg qd was associated with a body weight loss of 3 to 12%, which was necessitated minimal dose skipping (2 doses) with no dose skipping for the last 8 days.
Breast Cancer Xenograft Model
A Compound of Formula I in Combination with Compound B
Compound A, a PI3K inhibitor, was tested both as a single agent and in combination with Compound B, an EGFR inhibitor, in a breast cancer tumor model. The MCF7 human mammary adenocarcinoma cell line harbors a heterozygous, activating mutation in PI3K (PI3KCA/E545K) and expresses wild-type EGFR.
Compound B was administered orally once-daily (qd) at 30 mg/kg, and Compound A was orally administered once-daily at 30 mg/kg. Combination therapies consisted of administering Compound B at 30 mg/kg qd followed by administration of Compound A at 30 mg/kg qd within about 6-7 hours. Single agent administration of Compound B at 30 mg/kg qd for 14 days caused a tumor growth inhibition of 38 to 61%. See FIGS. 4b-1 and 4b-2. Tumor growth inhibition of 53-76% was observed with Compound A dosed at 30 mg/kg qd. The combination of Compound B dosed at 30 mg/kg qd with Compound A dosed at 30 mg/kg qd resulted in significant tumor growth inhibition of 83-87%, which trended towards an increased anti-tumor efficacy compared to the efficacy of the single treatments, although this did not reach statistical significance in these studies. One possible explanation for the modest effect of the combination is the short duration of the dosing period (14 days), which may be too short to observe the full benefit of the combination. Longer dosing regimes may produce more significant differences, as the anticipated effect of dual inhibition of PI3K and EGFR on cell growth and survival becomes more apparent. In both studies (FIGS. 4b-1 and 4b-2) the average tumor size in the combination groups is still decreasing at the last measurement point.
At the end of the study, tumors were resected and processed for analysis of proliferating cells (Ki67 staining), determination of microvessel density (MVD) following immunostaining for CD31, and for TUNEL (apoptotic cells) analysis (see Tables 8 and 9). Administration of Compound B dosed at 30 mg/kg qd caused a significant 14 to 19% decrease in the number of viable, Ki67-positive proliferating tumor cells when compared to the vehicle control-treated group. Compound A dosed at 30 mg/kg qd did cause a significant 13% decrease in Ki67-positive cells only in Study 2. Combination of Compound B with Compound A caused a significant 23 to 37% decrease in Ki67 positive tumor cells, which was significantly more efficacious in this model than the single agent treatments (however not better than Compound B single arm in Study 1). Treatment with Compound B dosed at 30 mg/kg qd did not result in a significant induction of TUNEL-positive (apoptotic) cells compared to the vehicle control-treated group. Administration of Compound A dosed at 30 mg/kg qd did not cause a significant induction of apoptotic tumor cells. Combining Compound B with Compound A did not result in a significant induction of apoptosis compared to vehicle control. Administration of Compound B dosed at 30 mg/kg qd and Compound A dosed at 30 mg/kg qd caused a significant 31% and 32% decrease, respectively, in CD31-positive tumor vessels. The combination of Compound B with Compound A caused a 22% decrease in MVD, which was not significantly different from Compound B or Compound A single agent treatment. End-of-study immunohistochemical analyses suggest that co-administration of Compound B and Compound A may provide an additional benefit on the anti proliferative, but not the anti-angiogenic effect of the single agents in MCF-7 tumors.
As a single agent Compound B dosed at 30 mg/kg qd was generally well tolerated, with a final body weight loss of 4.5 to 6.1% (not significantly different from the vehicle-treated control group) and 7 to 13 dose omissions. The majority of the skipped doses (11 out of 13) in Study 1 came from one mouse maintaining a low body weight throughout the study from dose day 3. Administration of Compound A dosed at 30 mg/kg qd was also well tolerated with 3 to 9 doses skipped and non-significant body weight loss or gain. Co-administration of Compound B at 30 mg/kg qd with Compound A at 30 mg/kg qd was associated with a body weight loss of 0.3 to 10% throughout the study and minimal dose skipping (6 to 11 doses). By the end of the dosing period there was a non-significant loss of 0.3 to 6.2% in body weight.
Breast Cancer Xenograft Model
A Compound of Formula I in Combination with Erlotinib
Compound A was tested both as a single agent and in combination with erlotinib, in an erolitinib-resistant tumor model with elevated PI3K signaling. MDA-MB-468 is a human breast carcinoma cell line that has an increase in the copy number of the EGFR gene and a homozygous deletion of PTEN. In vitro treatment of these cells with EGFR inhibitors such as erlotinib inhibits EGFR activity but fails to downregulate the PI3K pathway.
Oral administration of erlotinib at 100 mg/kg qd to mice bearing MDA-MB-468 tumors resulted in significant but incomplete tumor growth inhibition. See FIG. 5. Oral administration of Compound A at 100 mg/kg q2d also resulted in tumor growth inhibition. The combination of the two agents was modestly superior to either agent alone. The relatively modest increase in efficacy in the combination group could improve with altering the dose and schedule for the administration of Compound A.
Mice administered Compound A at 100 mg/kg q2d exhibited a rate of body weight gain comparable to vehicle controls. Mice administered erlotinib exhibited an apparent decrease in their rate of body weight gain relative to vehicle controls. Coadministration with erlotinib resulted in a loss in body weight in mice treated with Compound A (10% body weight loss from start of dosing). Consistent with these data, only minimal dose-skipping was required when Compound A was administered as monotherapy (1-3 doses skipped), but substantial dose-skipping was required for Compound A when erlotinib was coadministered. These results support the use of a Compound of Formula I in combination with erlotinib in tumors expressing EGF receptors and harboring PTEN deletions.
The foregoing invention has been described in some detail by way of illustration and example, for purposes of clarity and understanding. The invention has been described with reference to various specific embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention. It will be obvious to one of skill in the art that changes and modifications may be practiced within the scope of the appended claims. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the invention should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled. All patents, patent applications and publications cited in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual patent, patent application or publication were so individually denoted.

## Claims

1. A method of inhibiting or relieving cancer in a patient, which method comprises administering to said patient a therapeutically effective amount of a Compound: that is:



or a single isomer thereof; in combination with one or more chemotherapeutic agents.

2. The method of claim 1 where the cancer is selected from breast cancer, colon cancer, rectal cancer, endometrial cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, glioblastoma, hepatocellular carcinoma, small cell lung cancer, non-small cell lung cancer, melanoma, ovarian cancer, cervical cancer, pancreatic cancer, prostate carcinoma, acute myelogenous leukemia, chronic myelogenous leukemia, non-Hodgkin's lymphoma, and thyroid carcinoma.

3. The method of claim 1 or 2 where the treatment one or more chemotherapeutic agents is independently selected from the group consisting of rapamycin, a rapamycin analogue, an alkylating agent a taxane, a platin, an EGFR inhibitor, and an ErbB2 inhibitor.

4. The method of claim 3 where the one or more chemotherapeutic agents is independently selected from rapamycin, paclitaxel, carboplatin, lapatinib, and erlotinib.

5. The method of claim 1 or 2 wherein the chemotherapeutic agent is erlotinib.

6. The method of claim 1 or 2 wherein the chemotherapeutic agent is lapatinib.

7. The method of claim 1 or 2 wherein the chemotherapeutic agent is carboplatin.

8. The method of claim 1 or 2 wherein the chemotherapeutic agent is paclitaxel.

9. The method of claim 1 or 2 wherein the chemotherapeutic agent is rapamycin.