The Applicants claim priority under 35 U.S.C. 119(e) to copending Provisional Application No. 60/923,164 filed on April 11, 2007.

This invention relates to the use in a method 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.

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. EurJ 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).

The prior art already discloses quinaxoline derivatives as PI3K inhibitors. Indeed document WO2007/023186 discloses fused-pyrazine derivatives, in particular quinaxoline derivatives as P13K inhibitors and document WO2007/044729, published in the priority period of the present disclosure, also discloses the present compounds of formula (I), as P13K inhibitors, in combination with a chemotherapeutic agent, surgery and radiation.

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 LM 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 PA, 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 P13K 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.

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. In the event of a discrepancy between the express disclosure of this specification and the references mentioned herein, the express disclosure of this specification shall control.

According to the invention, there is provided a compound which is: or a tautomer 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; for use in combination with one or more treatments independently selected from one or more chemotherapeutic agents selected from the group consisting of a platin, a taxane, rapamycin, and erlotinib for the treatment of cancer.

Also described is the use in 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:

• W¹, W², W³, and W⁴ are -C(R¹)=; or one or two of W¹, W², W³, and W⁴ are independently -N= and the remaining are -C(R¹)=; and where each R¹ is independently hydrogen, alkyl, haloalkyl, nitro, alkoxy, haloalkoxy, halo, hydroxy, cyano, amino, alkylamino, or dialkylamino;
  • R⁵¹ is hydrogen or alkyl;
  • R⁵² is hydrogen or halo;
  • R⁵⁰, R⁵³, and R⁵⁴ are independently hydrogen, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, nitro, amino, alkylamino, dialkylamino, -N(R⁵⁵)C(O)-C₁-C₆-alkylene-N(R^55a)R^55b, alkylcarbonyl, alkenylcarbonyl, carboxy, alkoxycarbonyl, cyano, alkylthio, -S(O)₂NR⁵⁵R^55a, or alkylcarbonylamino and where R⁵⁵ and R^55b are indepedently hydrogen, alkyl, or alkenyl and R^55a is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy; or R⁵³ and R⁵⁴ together with the carbons to which they are attached form a 5- or 6-membered heteroaryl or 5- or 6-membered heterocycloalkyl;
  • B is phenyl substituted with R^3a and optionally further substituted with one, two, or three R³; or
  • B is heteroaryl optionally substituted with one, two, or three R³;
  • R^3a is cyano; hydroxyamino; carboxy; alkoxycarbonyl; alkylamino; dialkylamino; alkylcarbonyl; haloalkoxy; alkylsulfonyl; aminoalkyloxy; alkylaminoalkyloxy; dialkylaminoalkyloxy; or
    • a) -N(R⁷)C(O)-C₁-C₆-alkylene-N(R^7a)(R^7b) where R⁷ is hydrogen, alkyl, or alkenyl and R^7a and R^7b are independently hydrogen, alkyl, alkenyl, hydroxyalkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, or arylalkyloxy and where the aryl, cycloalkyl, heterocycloalkyl and heteroaryl rings in R^7a and R^7b (either alone or as part of arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl) are independently optionally substituted with 1, 2, or 3 groups independently selected from alkyl, amino, alkylamino, dialkylamino, hydroxy, halo, alkoxy, alkylthio, and oxo);
    • b) -C(O)NR⁸R^8a where R⁸ is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, haloalkyl, or haloalkoxy and R^8a is hydrogen, alkyl, alkenyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, alkylthioalkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, aryl, or arylalkyl and where the aryl, cycloalkyl, heteroaryl, and heterocycloalkyl rings in R^8a (either alone or as part of arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl) are independently optionally substituted with 1, 2, or 3 groups independently selected from alkyl, alkenyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, amino, alkylamino, dialkylamino, alkylcarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, and -C(O)H;
    • c) -NR⁹C(O)R^9a where R⁹ is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, haloalkyl, or haloalkoxy and R^9a is hydrogen, C₂-C₆-alkyl, alkenyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, aryl, or arylalkyl; where the aryl, cycloalkyl, heteroaryl, and heterocycloalkyl rings in R^9a (either alone or as part of arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl) are independently optionally substituted with 1, 2, or 3 groups independently selected from alkyl, alkenyl, alkoxy, hydroxy, hydroxyalkyl, halo, haloalkyl, haloalkoxy, oxo, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, -C(O)H, aryl (optionally substituted with one or two halo), arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, cyloalkyl, cyloalkylalkyl, and cycloalkylcarbonyl;
    • d) -C(O)N(R¹⁰)-C₁-C₆-alkylene-N(R^10a)R^10b where R^10a is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or hydroxyalkyl and R¹⁰ and R^10b are independently hydrogen, alkyl, alkenyl, haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or hydroxyalkyl;
    • e) -NR¹¹C(O)NR^11aR^11b where R^11a is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy and R¹¹ and R^11b are independently hydrogen, alkyl, alkenyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl;
    • f) -C(O)R¹² where R¹² is heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from alkyl, oxo, amino, alkylamino, and heterocycloalkylalkyl;
    • g) -NR¹³C(O)OR^13a where R¹³ is hydrogen, alkyl, or alkenyl and R^13a is aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aryl, or arylalkyl;
    • h) -C(O)N(R¹⁴)N(R^14a)(R^14b) where R¹⁴, R^14a, and R^14b are independently hydrogen, alkyl, or alkenyl;
    • i) -S(O)₂N(R¹⁵)-C₁-C₆-alkylene-N(R^15a)R^15b where R¹⁵, R^15a, and R^15b are independently hydrogen, alkyl, or alkenyl;
    • j) -C(O)N(R¹⁶)-C₁-C₆-alkylene-C(O)OR^16a where R¹⁶ is hydrogen, alkyl, or alkenyl and R^16a is alkyl or alkenyl;
    • k) heteroaryl optionally substituted with one or two aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl;
    • l) -N(R¹⁷)-C(=N(R^17b)(R^17a))(NR^17cR^17d) where R¹⁷, R^17a, R^17b, R^17c, and R^17d are independently hydrogen, alkyl, or alkenyl;
    • m) -N(R¹⁸)C(O)-C₁-C₆-alkylene-N(R^18b)C(O)R^18a where R^18a is hydrogen, alkyl, alkenyl, or alkoxy and R¹⁸ and R^18b are independently hydrogen, alkyl, or alkenyl;
    • n) -C(O)N(R¹⁹)-C₁-C₆-alkylene-C(O)R^19a where R¹⁹ is hydrogen, alkyl, or alkenyl and R^19a is amino, alkylamino, dialkylamino, or heterocycloalkyl;
    • o) -N(R²⁰)C(O)-C₁-C₆-alkylene-C(O)R^20a where R²⁰ is hydrogen, alkyl, or alkenyl and R^20a is cycloalkyl or heterocycloalkyl;
    • p) -NR²¹S(O)₂-C₁-C₆-alkylene-N(R^21b)R^21a where R²¹ is hydrogen, alkyl, or alkenyl and R^21a and R^21b are independently hydrogen, alkyl, or alkenyl;
    • q) -N(R²²)C(O)-C₁-C₆-alkylene-N(R^22b)-N(R^22c)(R^22a) where R²², R^22a and R^22b are independently hydrogen, alkyl, or alkenyl;
    • r) -C₀-C₆-alkylene-N(R²³)-C₁-C₆-alkylene-N(R^23b)R^23a where R²³, R^23a and R^23b are independently hydrogen, alkyl, or alkenyl; or
    • s) -NR²⁴C(O)-C₁-C₆-alkylene-OR^24a where R²⁴ is hydrogen, alkyl, or alkenyl and R^24a is
      alkoxyalkyl or aryl optionally substituted with one or two halo or alkyl; and
      where each of the alkylene in R^3a is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from halo, hydroxy, amino, alkylamino, and dialkylamino; and each R³ (when R³ is present) is independently alkyl; alkenyl; alkynyl; halo; hydroxy; oxo;
      alkoxy; cyano; hydroxyamino; carboxy; alkoxycarbonyl; amino; alkylamino; dialkylamino; alkylcarbonyl; haloalkoxy; alkylsulfonyl; aminoalkyloxy; alkylaminoalkyloxy; dialkylaminoalkyloxy; or
    1. a) -N(R⁷)C(O)-C₁-C₆-alkylene-N(R^7a)(R^7b) where R⁷ is hydrogen, alkyl, or alkenyl and R^7a and R^7b are independently hydrogen, alkyl, alkenyl, hydroxyalkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, or arylalkyloxy and where the aryl, cycloalkyl, heterocycloalkyl and heteroaryl rings in R^7a and R^7b (either alone or as part of arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl) are independently optionally substituted with 1, 2, or 3 groups independently selected from alkyl, amino, alkylamino, dialkylamino, hydroxy, halo, alkoxy, alkylthio, and oxo);
    2. b) -C(O)NR⁸R^8a where R⁸ is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, haloalkyl, or haloalkoxy and R^8a is hydrogen, alkyl, alkenyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, alkylthioalkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, aryl, or arylalkyl and where the aryl, cycloalkyl, heteroaryl, and heterocycloalkyl rings in R^8a (either alone or as part of arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl) are independently optionally substituted with 1, 2, or 3 groups independently selected from alkyl, alkenyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, amino, alkylamino, dialkylamino, alkylcarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, and -C(O)H;
    3. c) -NR⁹C(O)R^9a where R⁹ is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, haloalkyl, or haloalkoxy and R^9a is hydrogen, C₂-C₆-alkyl, alkenyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, aryl, or arylalkyl; where the aryl, cycloalkyl, heteroaryl, and heterocycloalkyl rings in R^9a (either alone or as part of arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl) are independently optionally substituted with 1, 2, or 3 groups independently selected from alkyl, alkenyl, alkoxy, hydroxy, hydroxyalkyl, halo, haloalkyl, haloalkoxy, oxo, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, -C(O)H, aryl (optionally substituted with one or two halo), arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, cyloalkyl, cyloalkylalkyl, and cycloalkylcarbonyl;
    4. d) -C(O)N(R¹⁰)-C₁-C₆-alkylene-N(R^10a)R^10b where R^10a is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, haloalkyl, or hydroxyalkyl and R¹⁰ and R^10b are independently hydrogen, alkyl, alkenyl, haloalkyl, or hydroxyalkyl;
    5. e) -NR¹¹C(O)NR^11aR^11b where R^11a is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy and R¹¹ and R^11b are independently hydrogen, alkyl, alkenyl, aminoalkyl, alkylaminooalkyl, dialkylaminoalkyl;
    6. f) -C(O)R¹² where R¹² is heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from alkyl, oxo, amino, alkylamino, and heterocycloalkylalkyl;
    7. g) -NR¹³C(O)OR^13a where R¹³ is hydrogen, alkyl, or alkenyl and R^13a is aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aryl, or arylalkyl);
    8. h) -C(O)N(R¹⁴)N(R^14a)(R^14b) where R¹⁴, R^14a, and R^14b are independently hydrogen, alkyl, or alkenyl;
    9. i) -S(O)₂N(R¹⁵)-C₁-C₆-alkylene-N(R^15a)R^15b where R¹⁵, R^15a, and R^15b are independently hydrogen, alkyl, or alkenyl;
    10. j) -C(O)N(R¹⁶)-C₁-C₆-alkylene-C(O)OR^16a where R¹⁶ is hydrogen, alkyl, or alkenyl and R^16a is alkyl or alkenyl;
    11. k) heteroaryl optionally substituted with one or two aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl;
    12. l) -N(R¹⁷)-C(=N(R^17b)(R^17a))(NR^17cR^17d) where R¹⁷, R^17a, R^17b, R^17c, and R^17d are independently hydrogen, alkyl, or alkenyl;
    13. m) -N(R¹⁸)C(O)-C₁-C₆-alkylene-N(R^18b)C(O)R^18a where R^18a is hydrogen, alkyl, alkenyl, or alkoxy and R¹⁸ and R^18b are independently hydrogen, alkyl, or alkenyl;
    14. n) -C(O)N(R¹⁹)-C₁-C₆-alkylene-C(O)R^19a where R¹⁹ is hydrogen, alkyl, or alkenyl and R^19a is amino, alkylamino, dialkylamino, or heterocycloalkyl;
    15. o) -N(R²⁰)C(O)-C₁-C₆-alkylene-C(O)R^20a where R²⁰ is hydrogen, alkyl, or alkenyl and R^20a is cycloalkyl or heterocycloalkyl;
    16. p) -NR²¹S(O)₂-C₁-C₆-alkylene-N(R^21b)R^21a where R²¹ is hydrogen, alkyl, or alkenyl and R^21a and R^21b are independently hydrogen, alkyl, or alkenyl;
    17. q) -N(R²²)C(O)-C₁-C₆-alkylene-N(R^22b)-N(R^22c)(R^22a), where R²², R^22a and R^22b are independently hydrogen, alkyl, or alkenyl;
    18. r) -C₀-C₆-alkylene-N(R²³)-C₁-C₆-alkylene-N(R^23b)R^23a where R²³, R^23a and R^23b are independently hydrogen, alkyl, or alkenyl; or
    19. s) NR²⁴C(O)-C₁-C₆-akylene-OR^24a where R²⁴ is hydrogen, alkyl, or alkenyl and R^24a is alkoxyalkyl or aryl optionally substituted with one or two halo or alkyl;
    wherein each of the alkylene in R³ is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from halo, hydroxy, amino, alkylamino, and dialkylamino; and provided that when R⁵⁰ and R⁵² are hydrogen, R⁵¹ is hydrogen or methyl, R⁵³ is hydrogen or methoxy, and R⁵⁴ is hydrogen or methoxy, then B is not 2,3-dihydro-1,4-benzodioxinyl, thien-2-yl, or thien-2-yl substituted with one R³ where R³ is halo.

Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a compound of Formula II: or a pharmaceutically acceptable salt or 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 of the hormone therapies, one or more of the antibodies, one or more immunotherapies, radioactive iodine therapy, and radiation wherein the Compound of Formula I is that wherein: W¹, W², W³, and W⁴ are -C(R^1a)=; or one or two of W¹, W², W³, and W⁴ are independently -N= and the remaining are -C(R^1a)=;
X¹ is -N(R^5a)-;
A is aryl, -S(O)₂-aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halo, haloalkyl, haloalkoxy, alkyl, alkoxy, or -alkyl-N(R⁷)R^7a, where each of the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl and alkoxy groups, each either alone or as part of another group within A, are independently optionally substituted with one, two, three, or four R^2a; or
B¹ is aryl, arylalkyl, alkyl, heteroaryl, or heteroaryalkyl, wherein each of the aryl, heteroaryl and alkyl groups are independently optionally substituted with one, two, three, or four R^3d;
each R^1a is independently selected from hydrogen, alkoxy, alkyl, nitro, halo, cyano, and -C₀-C₆-alkyl-N(R⁷)R^7a, wherein each of the alkyl and alkoxy groups is optionally substituted with 1, 2, 3, 4, or 5 groups selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, nitro, cyano, hydroxy, -N(R⁸)R^8a, and -C(O)OR⁶;
each R^2a (when R^2a is present) is independently selected from alkyl, alkenyl, -alkenyl-C(O)OR⁶, -OR⁶, -N(R⁷)C(O)R⁶, -N(R⁷)C(O)-C₀-C₆ alkyl-N(R^7b)R^7a, -OC(O)-C₀-C₆ alkyl-N(R⁷)R^7a, -N(R⁷)C(O)-C₁-C₆ alkylC(O)OR⁶, C₀-C₆-alkyl-C(O)R⁶, oxo, dioxo, -S(O)₂-N(R⁷)R^7a, -C(O)OR⁶, -CH(R⁶)₂-C(O)OR⁶, -S(O)₂R⁶, cycloalkyl, heterocycloalkyl, heteroaryl, -C(O)N(R⁷)-alkyl-OR⁶, -C₀-C₆ alkyl-C(O)N(R⁷)-C₀-C₆-alkyl-C(O)OR⁶, -C₀-C₆-alkyl-C(O)N(R⁷)R^7a, aryl, arylalkyl, -S-(C₁-C₆ alkyl), halo, oxo, nitro, -SCN, cyano, and -C₀-C₆ alkyl-N(R⁷)R^7a, wherein each of the alkyl (including, for example the alkyl within alkoxy), aryl, cycloalkyl, heterocycloalkyl, and heteroaryl groups, either alone or as part of another group within R², is independently optionally substituted with 1, 2, 3, 4, or 5 groups selected from alkyl, halo, haloalkyl, haloalkoxy, oxo, nitro, cyano, hydroxy, -N(R⁸)R^8a, alkoxy, and -C(O)OR⁹;
each R^3d (when R^3d is present) is independently oxo, nitro, halo, cyano, alkyl, alkenyl, alkynyl, alkoxy, C₃-C₆-cycloalkyl, -C₀-C₆-alkyl-heterocycloalkyl, -C₀-C₆ alkyl-N(R⁷)C(O)-C₀-C₆-alkyl-N(R^7b)R^7a, -C₀-C₆ alkyl-N(R⁷)C(O)-C₀-C₆-alkyl-N(R^7b)C(O)R^7a, -C₀-C₆ alkyl-C(O)-C₀-C₆-alkyl-N(R⁷)R^7a, -C₀-C₆-alkyl-C(O)N(R⁷)-C₀-C₆-alkyl-N(R^7b)R^7a, -C₀-C₆-alkyl-C(O)N(R⁷)-C₁-C₆alkylC(O)OR^7a, -C₀-C₆ alkyl-N(R⁷)C(O)-C₀-C₆-alkyl-(R^7a), -C₀-C₆ alkyl-N(R⁷)-C₀-C₆-alkyl-N(R^7b)R^7a, -C₀-C₆ alkyl-N(R⁷)C(O)-C₀-C₆-alkyl-N(R^7b)-N(R^7c)R^7a, -C₀-C₆ alkyl-N(R⁷)C(O)O-C₀-C₆-alkyl-aryl, -C₀-C₆ alkyl-C(O)N(R⁷)-C₀-C₆-alkyl-N(R^7b)R^7a, -C₀-C₆ alkyl-N(R⁷)-C₀-C₆alkyl-C(=N(R^7b)(R^7a))(NR^7cR^7d), -C₀-C₆-alkyl-aryl, -C₀-C₆-alkyl-heteroaryl, -C₀-C₆ alkyl-heterocycloalkyl, -O-C₀-C₆ alkyl-N(R⁷)R^7a, -C₀-C₆ alkyl-OR₆, -C₀-C₆ alkyl-C(O)OR⁶, C₀-C₆-alkyl-N(R⁷)R^7a, -C₀-C₆ alkyl-C(O)NR₇R^7a, -C₀-C₆ alkyl-C(O)R⁷, -SR₇, -S(O)₂R₇, -S(O)₃R₇, -S(O)R⁷, -SO₂N(R⁷)R^7a, -SO₂N(R⁷)-C₀-C₆ alkyl-N(R^7b)R^7a, -C₀-C₆-alkyl-N(R⁷)-aryl, -C₀-C₆-alkyl-N(R⁷)-heteroaryl, -C₀-C₆-alkyl-N(R⁷)-heterocycloalkyl, -C₀-C₆-alkyl-C(O)N(R⁷)-C₀-C₆-alkyl-cycloalkyl, C₀-C₆-alkyl-C(O)N(R⁷)-C₀-C₆-alkyl-aryl, C₀-C₆ alkyl-C(O)N(R⁷)-C₀-C₆ alkyl-heteroaryl, C₀-C₆ alkyl-C(O)N(R⁷)-C₀-C₆-alkyl-heterocycloalkyl, -C₀-C₆-alkyl-N(R⁷)C(O)-C₀-C₆-alkyl-cycloalkyl, -C₀-C₆-alkyl-N(R⁷)C(O)-C₀-C₆-alkyl-aryl, C₀-C₆-alkyl-N(R⁷)C(O)-C₀-C₆-alkyl-heteroaryl, -C₀-C₆-alkyl-N(R⁷)C(O)-C₀-C₆-alkyl-heterocycloalkyl, C₀-C₆-alkyl-N(R⁷)C(O)-C₀-C₆-alkyl-heterocycloalkyl-aryl, -N(R⁷)C(O)OR⁶, or -NHC(O)H, wherein each of the alkyl, alkenyl, cycloalkyl, aryl, (including, for example the alkyl within alkoxy), heterocycloalkyl, and heteroaryl groups, either alone or as part of another group within R^3d, is independently optionally substituted with 1, 2, 3, 4, or 5 groups selected from alkyl, alkenyl, -C₀-C₆-alkyl-OR⁹, cycloalkyl, halo, haloalkyl, haloalkoxy, -C(O)R⁹, nitro, cyano, oxo, -C₀-C₆-alkyl-N(R⁸)R^8a, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -C(O)OR⁹, alkylthio, and hydroxyalkyl;
R⁴ is hydrogen, aryl, -C₀-C₆-alkyl-N(R⁷)R^7a, alkoxy, or C₁-C₆ alkyl, wherein each of the alkyl and aryl groups, either alone or as part of another group in R⁴, is independently optionally substituted with 1, 2, 3, 4, or 5 groups selected from alkyl, halo, haloalkyl, haloalkoxy, nitro, cyano, hydroxy, -N(R⁸)R^8a, alkoxy, and -C(O)OR⁶; or
R⁴ and X¹ together with the atoms to which they are attached form a heterocycloalkyl or heteroaryl group, wherein R^5a is absent when X is -N(R^5a)-, wherein each of the heterocycloalkyl or heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 groups selected from alkyl, halo, haloalkyl, haloalkoxy, nitro, cyano, hydroxy, -N(R⁷)R^7a, alkoxy, and -C(O)OR⁶;
R^5a is hydrogen, -C₁-C₆ alkyl-N(R⁷)R^7a, alkoxy, alkyl, or aryl, wherein each of the alkyl and aryl is optionally substituted with 1, 2, 3, 4, or 5 groups selected from alkyl, halo, haloalkyl, haloalkoxy, nitro, cyano, hydroxy, -N(R⁸)R^8a, C₁-C₆ alkoxy, or -C(O)OR⁶; or
R^5a and R⁴ together with the atoms to which they are attached form a heterocycloalkyl or heteroaryl group, wherein the heterocycloalkyl and heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 groups selected from alkyl, halo, haloalkyl, haloalkoxy, nitro, cyano, hydroxy, -N(R⁷)R^7a, C₁-C₆ alkoxy, and -C(O)OR⁶;
R⁶ and R⁹ are independently hydrogen, hydroxy, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, or aryl, each alkyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl, either alone or as part of another group within R⁶ and R⁹, is independently optionally substituted with 1, 2, 3, 4,
or 5 groups independently selected from amino, hydroxy, alkoxy, alkyl, and halo; and R⁷, R^7a R^7b, R^7c, R^7d, R⁸, and R^8a are independently hydrogen, alkyl, alkenyl, hydroxy, alkyloxy, alkenyloxy, -O-C₀-C₆ alkyl-aryl, -C₀-C₆ alkyl-C(O)OR⁶, -C₀-C₆ alkyl-C(O)R⁶, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl, wherein each of the alkyl, aryl, heteroaryl, and heterocycloalkyl, either alone or part of another group within R⁷, R^7a R^7b, R^7c, R^7d, R⁸, and R^8a is independently optionally substituted with 1, 2, 3, 4, or 5 groups selected from amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, -S-C₁-C₆ alkyl, cyano, nitro, hydroxy, C₁-C₆ alkoxy, C₁-C₆ alkyl, halo, aryl, heterocycloalkylalkyl, and heteroaryl optionally substituted with one or two C₁-C₆ alkyl.

The following abbreviations and terms have the indicated meanings throughout: Abbreviation Meaning br broad °C degrees Celsius CBZ CarboBenZoxy = benzyloxycarbonyl d doublet dd doublet of doublet dt doublet of triplet EI Electron Impact ionization Et Ethyl g gram(s) GC gas chromatography 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) 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 s- Secondary t- Tertiary t or tr Triplet TFA trifluoroacetic acid THF Tetrahydrofuran µL microliter(s) µM Micromole(s) or micromolar

The symbol "-" means a single bond, "=" means a double bond, "≡" means a triple bond, and "---" means a single bond and optionally a double bond. 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.

"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" or "lower alkenyl" means a straight or branched hydrocarbon radical having from 2 to 6 carbon atoms and at least one double bond and includes ethenyl, propenyl, 1-but-3-enyl, 1-pent-3-enyl, 1-hex-5-enyl and the like.

"Alkenylcarbonyl" means a C(O)R group where R is alkenyl, as defined herein.

"Alkenyloxy" or "lower alkenyloxy" means an -OR group where R is alkenyl, as defined herein. Representative examples include methoxy, ethoxy, 1-methoxyprop-1-en-3-yl, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like.

"Alkoxy" or "lower alkoxy" means an -OR group where R is alkyl, as defined herein. Representative examples include methoxy, ethoxy, 1-methoxyprop-1-en-3-yl, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like.

"Alkoxyalkyl" means an alkyl group, as defined herein, substituted with one, two, or three alkoxy groups, as defined herein.

"Akoxycarbonyl" means a -C(O)OR group where R is alkyl as defined herein.

"Alkoxyycarbonylalkyl" means an alkyl group, as defined herein, substituted with one, two, or three alkoxycarbonyl groups, as defined herein.

"Alkyl" or "lower alkyl" means a linear or branched hydrocarbon group having one to six carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, isobutyl, pentyl, hexyl and the like. A "C₀" alkyl (as in "C₀-C₆-alkyl") is a covalent bond. "C₆ alkyl" refers to, for example, n-hexyl, iso-hexyl, and the like.

"Alkylamino" means a -NHR radical where R is alkyl as defined herein, or an N-oxide derivative thereof, e.g., methylamino, ethylamino, n-, iso-propylamino, n-, iso-, tert-butylamino, or methylamino-N-oxide, and the like.

"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.

"Alkylcarbonylamino" means a -NRC(O)R' group where R is hydrogen or alkyl, as defiend herein, and R' is alkyl, as defiend herein.

"Alkylene" refers to straight or branched divalent hydrocarbon, containing no unsaturation and having from two to eight carbon atoms. Examples of alkylene include ethdiyl (-CH₂CH₂-), prop-1,3-diyl (-CH₂CH₂CH₂-), 2,2-dimethylprop-1,3-diyl (-CH₂C(CH₃)₂CH₂-), and the like.

"Alkylsulfonyl" means a -S(O)₂R group where R is lakyl, as defined herien.

"Alkylthio" means a -SR group where R is alkyl, as defined herein. Examples of alkylthio include methylthio and ethylthio, and the like.

"Alkylthioalkyl" means an alkyl group substituted with one or two alkylthio groups, as defined herein, e.g. 2-(methylthio)-ethyl and 2-(ethylthio)-ethyl.

"Alkynyl" or "lower alkynyl" means a straight or branched hydrocarbon radical having from 2 to 6 carbon atoms and at least one triple bond and includes ethynyl, propynyl, butynyl, pentyn-2-yl and the like.

"Amino" means a -NH₂.

"Aminoalkyl" means an alkyl group subsitutted 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. Representative examples include phenyl, naphthyl, and indanyl, and the like.

"Arylalkyl" means an alkyl group, as defined herein, subsituted with one or two aryl groups, as defined herein. Examples include benzyl, phenethyl, phenylvinyl, phenylallyl and the like.

"Aryloxy"means a -OR group where R is aryl as defined herein.

"Arylalkyloxy" means a -OR group where R is arylalkyl as defined herein.

"Arylsulfonyl" means a -SO₂R group where R is aryl as defined herein.

"Carboxyalkyl" means an alkyl group, as defined herein, substituted with one, two, or three -C(O)OH groups.

"Carboxy ester" means a -C(O)OR group where R is lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, aryl or arylalkyl, each of which is defined herein. Representative examples include methoxycarbonyl, ethoxycarbonyl, and benzyloxycarbonyl, and the like.

"Cyanoalkyl" means an alkyl, alkenyl, or alkynyl radical, as defined herein, substituted with at least one, for example one, two, or three, cyano groups.

"Cycloalkyl" means a monocyclic or polycyclic hydrocarbon radical having three to thirteen carbon atoms. The cycloalkyl can be saturated or partially unsaturated, but cannot contain an aromatic ring. Cycloalkyl includes fused, bridged, and spiro ring systems. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

"Cycloalkylalkyl" means alkyl group substituted with one or two cycloalkyl groups, as defined herein. Representative examples include cyclopropylmethyl and 2-cyclobutyl-ethyl, and the like.

"Cycloalkylcarbonyl" means a -C(O)R group where R is cycloalkyl as defined herein.

"Dialkylamino" means a -NRR' radical where R and R' are independently 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 dialkylamino groups, as defined herein.

"Dialkylaminoalkyloxy" means an -OR group where R is dialkylaminoalkyl, as defined herein.

"Fused ring system" and "fused ring" refer to 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.

"Haloalkoxy" means an -OR' group where R' is haloalkyl as defined herein, e.g., trifluoromethoxy or 2,2,2-trifluoroethoxy, and the like.

"Haloalkoxyalkyl" means an alkyl group, as defined herein, substituted with one, two, or three haloalkoxy, as defined herein.

"Halogen" or "halo" means fluoro, chloro, bromo and iodo.

"Haloalkenyl means an alkenyl group, as defined herein, substituted with one or more halogens, for example one to five halo atoms.

"Haloalkyl" means an alkyl group, as defined herein, substituted with one or more halogens, for example one to five halo atoms. Representative examples includes 2,2-difluoroethyl, trifluoromethyl, and 2-chloro-1-fluoroethyl, 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(R^x)-, 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. R^x 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. In particular, when the point of valency is located on the nitrogen, R^x 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.

"Hetereoarylalkyl" means an alkyl group substituted with one or two heteroaryl groups as defined herein.

"Heterocycloalkyl" means a saturated or partially unsaturated monovalent monocyclic group of 3 to 8 ring atoms or a saturated or partially unsaturated 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(R^y)- (where R^y 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. In particular, when the point of valency is located on a nitrogen atom, R^y 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 group, as defined herein, substituted with one or two heterocycloalkyl groups, as defined herein.

"Hydroxyalkyl" means an alkyl radical, as defined herein, substituted with at least one, for example one, two, or three, hydroxy groups, provided that if two hydroxy groups are present they are not both on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, for example 2-hydroxyethyl, 2,3-dihydroxypropyl, or 1-(hydroxymethyl)-2-hydroxyethyl, and the like.

"Hydroxyamino" means a -NH(OH) group.

"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 arylC_1-8 alkyl," both the "C_1-8 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 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, carboxy, alkylcarbonylamino, alkylcarbonyloxy, alkylS(O)_0-2-, alkenyl-S(O)_0-2-, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl-NR^c- (where R^c is hydrogen, alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, alkoxy, alkenyloxy, or cyanoalkyl), alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, alkoxycarbonyl, alkenyloxycarbonyl, alkoxycarbonylamino, alkylaminocarbonylamino, dialkylaminocarbonylamino, alkoxyalkyloxy, and -C(O)NR^aR^b (where R^a and R^b are independently hydrogen, alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, alkoxy, alkenyloxy, or cyanoalkyl).

"Optionally substituted alkenyl" means an alkenyl radical, as defined herein, optionally substituted with one or more groups, for example one, two, or three groups, independently selected from alkylcarbonyl, alkenylcarbonyl, cycloalkylcarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cyano, cyanoalkylaminocarbonyl, alkoxy, alkenyloxy, hydroxy, hydroxyalkoxy, carboxy, alkylcarbonylamino, alkylcarbonyloxy, alkyl-S(O)_0-2-, alkenyl-S(O)_0-2-, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl-NR^c- (where R^c is hydrogen, optionally substituted alkyl, optionally substituted alkynyl, hydroxy, alkoxy, or alkenyloxy), alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, alkoxycarbonyl, alkenyloxycarbonyl, alkoxycarbonylamino, alkylaminocarbonylamino, dialkylaminocarbonylamino, alkoxyalkyloxy, and -C(O)NR^aR^b (where R^a and R^b are independently hydrogen, optionally substituted alkyl, alkenyl, optionally substituted alkynyl, hydroxy, alkoxy, or alkenyloxy).

"Optionally substituted aryl" means an aryl group, as defined herein, which is optionally substituted with one, two, three, four, of five groups selected from halo, haloalkyl, haloalkoxy, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, alkoxy, carboxy, carboxy ester, amino, alkylamino, dialkylamino, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, -C(O)NR'R" (where R' is hydrogen or alkyl and R" is hydrogen, alkyl, aryl, heteroaryl, or
heterocycloalkyl), -NR'C(O)R" (where R' is hydrogen or alkyl and R" is alkyl, aryl, heteroaryl, or heterocycloalkyl), and -NHS(O)₂R' (where R' is alkyl, aryl, or heteroaryl).

"Optionally substituted heteroaryl" means a heteroaryl group, as defined herein, optionally substituted with one, two, three, four, or five groups selected from halo, haloalkyl, haloalkoxy, lower alkyl, lower alkenyl, lower alkynyl, alkoxy, hydroxy, oxo (valency rules permitting), carboxy, carboxy ester, amino, alkylamino, dialkylamino, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, heteroaryl, optionally substituted aryl, -C(O)NR'R" (where R' is hydrogen or alkyl and R" is hydrogen, alkyl, aryl, heteroaryl, or heterocycloalkyl), -NR'C(O)R" (where R' is hydrogen or alkyl and R" is alkyl, aryl, heteroaryl, or heterocycloalkyl), and -NHS(O)₂R' (where R' is alkyl, aryl, or heteroaryl).

"Optionally substituted heterocycloalkyl" means a heterocycloalkyl, as defined herein, optionally substituted with one, two, three, four, or five groups selected from halo, haloalkyl, haloalkoxy, hydroxy, oxo, lower alkyl, lower alkenyl, lower alkynyl, alkoxy, optionally substituted cycloalkyl, heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, alkylaminoalkyl, dialkylaminoalkyl, carboxy, carboxy ester, -C(O)NR'R" (where R' is hydrogen or alkyl and R" is hydrogen, alkyl, aryl, heteroaryl, or heterocycloalkyl), -NR'C(O)R" (where R' is hydrogen or alkyl and R" is alkyl, aryl, heteroaryl, or heterocycloalkyl), amino, alkylamino, dialkylamino, and -NHS(O)₂R' (where R' is alkyl, aryl, or heteroaryl).

"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 C and C'), but not a bridgehead atom, can be a shared atom between the saturated bridged ring system and a spirocyclyl (ring D) attached thereto. A spirocyclyl can be carbocyclic or heteroalicyclic.

"Yield" for each of the reactions described herein is expressed as a percentage of the theoretical yield.

The terms used to describe the scope of formula 100 are defined in WO 2004/006846 (US Nat'l Stage Application Serial 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 Serial 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 Serial No. 10/522,004).

"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" include, 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], glioblastorna 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, MLN518, 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" or "hormonal therapy" includes, 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 lipid 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 lipid 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 another embodiment the patient is a mammal, and in another 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, AP23573, RAD 001, TAFA 93, and compounds described in WO 2004/101583 and US 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 Serial No. 11/910,720), WO 2006/074057 (US Nat'l Stage Application Serial No. 11/722,719), WO 2006/071819 (US Nat'l Stage Application Serial No. 11/722,291), WO 2006/014325 (US Nat'l Stage Application Serial No. 11/571,140), WO 2005/117909 (US Nat'l Stage Application Serial No. 11/568,173), WO 2005/030140 (US Nat'l Stage Application Serial No. 10/573,336), WO 2004/050681 US Nat'l Stage Application Serial No. 10/533,555), WO 2005/112932 (US Nat'l Stage Application Serial No. 11/568,789), and WO 2004/006846 (US Nat'l Stage Application Serial 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 .

The following paragraphs present a number of options for compounds described herein. In each instance, the option includes both the recited compounds as well as individual isomers and mixtures of isomers. In addtion, in each instance, the option optionally includes the pharmaceutically acceptable salts, hydrates, and/or solvates of the recited compounds and any individual isomers or mixture of isomers thereof.

For each of the following options, the Compound of Formula I can, for example, be of Formula I(a) or be selected from a Compound in Table 1.

Also described is the use in 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.

Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, 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. Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, 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. Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, 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.

Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, in combination with a treatment where the treatment is one or more chemotherapeutic agents.

Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, 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. Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above,
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. Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, 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. Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, in combination with a treatment where the defined combination a treatment 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.

Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, in combination with a treatment where the treatment is one or two chemotherapeutic agents independently selected from a platin and a taxane. Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, in combination with a treatment where the treatment is one or two chemotherapeutic agents independently selected from carboplatin, cisplatin, oxaliplatin, and paclitaxel.

Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is an AKT inhibitor. Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, 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.

Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is a cMET inhibitor. Also described is the use in a method bf treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, 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.

Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is an EGFR inhibitor. Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above,
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. Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, 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.

Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is an ErbB2 inhibitor. Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, 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.

Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is an HSP90 inhibitor. Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, 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. Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, 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.

Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is an IGF1R inhibitor. Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, 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.

Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is a Raf inhibitor. Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, 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.

Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount ofa Compound of Formula I, as defined above, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is a VEGFR inhibitor. Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, 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.

Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is a cKIT inhibitor. Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, 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.

Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is a FLT3 inhibitor. Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above,
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, MLN518, sunitinib, sorafenib, a compound in Table 3a, a compound in Table 3b, a compound in Table 3c, and a compound in Table 9.

Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula 1, as defined above, 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. Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is select from rapamycin, CCI-779, AP23573, RAD 001, TAFA 93, PI103, and SF 1126. Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agents is rapamycin.

Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, 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 Serial 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 Serial 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.

Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, 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. Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a), 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. Also described is the use in 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 a compound in Table 2a.

Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, 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 2b. Also described is the use in a method bf treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a), 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 2b. Also described is the use in 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 a compound in Table 2b.

Also described is the use in 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 3a. Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a), 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 3a. Also described is the use in 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 a compound in Table 3a.

Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, 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 3b. Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a), 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 3b. Also described is the use in 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 m a compound in Table 3b.

Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, 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 3c. Also described is the use in a method bf treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a), 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 3c. Also described is the use in 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 a compound in Table 3c.

Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, 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. Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a), 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. Also described is the use in 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 a compound in Table 4.

Also described is the use in a method'of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, 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-methyloctahydrocyclopenta[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. Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a) 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. Also described is the use in 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 optionnally as a hydrate and additionally optionally as a solvate thereof.

Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, 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. Also described is a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a) 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. Also described is the use in 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 I 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 additionnally optionnally as a hydrate and additionally optionally as a solvate thereof.

Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, 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 5ac. Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a), 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 5a. Also described is the use in 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 a compound in Table 5a.

Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, 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 5b. Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a), 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 5b. Also described is the use in 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 a compound in Table 5b.

Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, 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 6. Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a), 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 6. Also described is the use in 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 selec from a compound in Table 6.

Also described is the use in 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 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 7. Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a), 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 7. Also described is the use in 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 a compound in Table 7.

Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, 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 8. Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a), in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the e chemotherapeutic agents is selected from a compound in Table 8. Also described is the use in 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 a compound in Table 8.

Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, 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 9. Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a), 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 9. Also described is the use in 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 a compound in Table 9.

Also described is the use in 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 I in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agent is paclitaxel.

Also described is the use in 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.

Also described is the use in 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 I in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agent is carboplatin.

Also described is the use in 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.

Also described is the use in 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 I in combination with a treatment where the treatment is one or two chemotherapeutic agents where one of the chemotherapeutic agent is lapatinib.

Also described is the use in 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.

Also described is the use in 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.

Also described is the use in 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 I in combination with a treatment where the treatment is one or two antibodies where one of the antibodies is panitumumab.

Also described is the use in 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.

Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, in combination with a treatment where the treatment is radiation. Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a) in combination with a treatment where the treatment is radiation. Also described is the use in 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.

Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, in combination with a treatment where the treatment is one or two antibodies. Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, in combination with a treatment where the treatment is one or two antibodies independently selected from an IGF1R antibody (including, for example, ^αIGF-1R A 12 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 anibodys (including trastuzumab (Herceptin®)), and an anti-EGFR antibodies (including, for example, cetuximab (Erbitux), panitumumab, nimotuzumab, and EMD72000)).

Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a) in combination with a treatment where the treatment is one or two antibodies. Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a) 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 anibodys (including trastuzumab (Herceptin®)), and an anti-EGFR antibodies (including, for example, cetuximab (Erbitux), panitumumab, nimotuzumab, and EMD72000)).

Also described is the use in 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. Also described is the use in 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 I 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 anibodys (including trastuzumab (Herceptin®)), and an anti-EGFR antibodies (including, for example, cetuximab (Erbitux), panitumumab, nimotuzumab, and EMD72000)).

Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, in combination with a treatment where the treatment is one or more chemotherapeutic agents where one of the chemotherapeutic agent is temozolomide. Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a) in combination with a treatment where the treatment is one or more chemotherapeutic agents where one of the chemotherapeutic agent is temozolomide. Also described is the use in 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 on of the chemotherapeutic agent is temozolomide.

Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, in combination with a treatment where the treatment is surgery. Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a) in combination with a treatment where the treatment is surgery. Also described is the use in 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 I in combination with a treatment where the treatment is surgery.

Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, in combination with a treatment where the treatment is one or two hormone therapies. Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I or I(a), as defined above, 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 inhibitors. Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I or I(a), as defined above, 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). Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I or I(a), as defined above, in combination with a treatment where the treatment is one or two hormone therapies independently selected from from tamoxifen and an aromatase inhibitor.

Also described is the use in 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. Also described is the use in 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 I 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 inhibitors. Also described is the use in 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 inhibitors selected from letrozole (Femara), anastrozole (Arimidex), and exemestane (Aromasin). Also described is the use in 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 setected from from tamoxifen and an aromatase inhibitor.

Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, 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. Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I according to Formula I(a) 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 rapamycin, a rapamycin analogue, an alkylating agent, a taxane, a platin, an EGFR inhibitor, and an ErbB2 inhibitor. Also described is the use in 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 rapamycin, a rapamycin analogue, an alkylating agent, a taxane, a platin an EGFR inhibitor, and an ErbB2 inhibitor.

Also described is the use in 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 above, 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. Also described is the use in 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 above, in combination with one or t 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. Also described is the use in 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 above, 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).

Also described is the use in 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 above, 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. Also described is the use in 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 above, 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). Also described is the use in 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 above, 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. Also described is the use in 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 above, in combination with one or more treatments where one of the treatments is immunotherapy and the immunotherapy is interferon therapy such as interferon-α.

Also described is the use in 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 above, 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. Also described is the use in 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 above, 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. Also described is the use in 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 above, 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. Also described is the use in 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 above, in combination with one or more treatments where one of the treatments is one or two of the hormone therapy indepependently selected from androgen deprivation therapy and androgen suppression therapy. Also described is the use in 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 above, in combination with one or more treatments where one of the treatments is one or chemotherapeutic agents where one of the chemotherapeutic agents is a taxanes. Also described is the use in 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 above, 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.

Also described is the use in a method of treating melanoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, 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. Also described is the use in a method of treating melanoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, 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. Also described is the use in a method of treating melanoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, 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). Also described is the use in a method of treating melanoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, 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. Also described is the use in a method of treating melanoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, in combination with one or more treatments where one of the treatments is hormone therapy where the hormone therapy is tamoxifen.

Also described is the use in 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 above, in combination with one or more treatments independently selected from surgery, radiation, one or two antibodies, and one or two chemotherapeutic agents. Also described is the use in 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 above, 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. Also described is the use in 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 above, 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. Also described is the use in 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 above, 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).

Also described is the use in 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 above, in combination with one or more treatments independently selected from surgery, radiation, one or two antibodies, and one or two chemotherapeutic agents. Also described is the use in 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 above, 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). Also described is the use in 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 above, in combination with one or more treatments where one of the treatments is an antibody wehre the antibody is cetuximab

Also described is the use in a method of treating breast cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula 1, as defined above, 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. Also described is the use in 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 above, 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). Also described is the use in 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 above, 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. Also described is the use in 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 above, 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 inhibitors selected from letrozole (Femara), anastrozole (Arimidex), and exemestane (Aromasin). Also described is the use in 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 above, 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.

Also described is the use in 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 above, 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.

Also described is the use in 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 above, 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 hydrate and additionally optionally as a solvate thereof.

Also described is the use in 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 above, in combination with one or more treatments where one of the treatments is one or two of the antibodies. Also described is the use in 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 above, in combination with one or more treatments where one of the treatments is one or two antibodies and one of the antibodies is trastuzumab.

Also described is the use in 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 above, 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

Also described is the use in 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 above, 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.

Also described is the use in 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 above, in combination with one or more treatments independently selected from surgery, radiation, one or more antibodies, and one or more chemotherapeutic agents. Also described is the use in 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 above, 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. Also described is the use in 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 above, in combination with one or more treatments where one of the treatments is an antibody and the antibody is Bevacizumab. Also described is the use in 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 above, 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®).

Also described is the use in 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 above, 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.

Also described is the use in 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 above, 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 optionnally as a hydrate and additionally optionally as a solvate thereof. Also described is the use in 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 above, 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.

Also described is the use in 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 above, in combination with one or more treatments independently selected from surgery, radiation, and one or two chemotherapeutic agents. Also described is the use in 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 above, 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.

Also described is the use in 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 above, 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. Also described is the use in 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 above, 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. Also described is the use in 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 above, in combination with one or more treatments where one of the treatments is hormone therapy and the hormone therapy is radioiodine ablation.

Also described is the use in 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 above, in combination with one or more treatments independently selected from surgery, radiation, one or two hormone therapies, and one or two chemotherapeutic agents. Also described is the use in 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 above, 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). Also described is the use in 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 above, 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.

Also described is the use in 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 above, in combination with one or more treatments independently selected from surgery, radiation, or two antibodies, and one or two chemotherapeutic agents. Also described is the use in 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 above, in combination with one or more treatments where one of the treatments is an antibody and the antibody is bevacizumab. Also described is the use in 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 above, 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. Also described is the use in 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 above, 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. Also described is the use in 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 above, 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.

Also described is the use in a method of treating glioblastoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, 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. Also described is the use in a method of treating glioblastoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, in combination with one or more treatments where one of the treatments is radiation selected from external beam radiation, interstitial radiotherapy, and stereotactic radiosurgery. Also described is the use in a method of treating glioblastoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, 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. Also described is the use in a method of treating glioblastoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, 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). Also described is the use in a method of treating glioblastoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, in combination with one or more treatments where one of the treatments is an agents to reduce swelling and the agent is dexamethasone (Decadron). Also described is the use in a method of treating glioblastoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, in combination with one or more treatements where one of the treatments is one or two chemotherapeutic agents. Also described is the use in a method of treating glioblastoma which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, in combination with one or more treatments where one of the treatments is one or two chemotherapeutic agents independently selected from erlotinib and temozolomide.

Also described is the use in 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 above, in combination with one or more treatments independently selected from surgery, radiation, and one or two chemotherapeutic agents. Also described is the use in a method of treating cervical cancer which method comprises administering to patient a therapeutically effective amount of a Compound of Formula I, as defined above, 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. Also described is the use in 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 combination with one or more treatments where one of the treatments is radiation selected from called external beam radiation therapy and brachytherapy. Also described is the use in 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 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.

Also described is the use in 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 above, in combination with one or more treatments independently selected from surgery, radiation, immunotherapy and one or two chemotherapeutic agents. Also described is 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 above, in combination with one or more treatments where one of the treatments is surgery selected from excision and electrofulguration. Also described is the use in 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 above, 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. Also described is the use in 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 above, in combination with one or more treatments where one of the treatments is immunotherapy and the immunotherapy is an interferon.

Also described is the use in 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 above, in combination with one or more treatments independently selected from surgery, radiation, and one or two chemotherapeutic agents. Also described is the use in 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 above, 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).

Also described is the use in 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 above, 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. Also described is the use in 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 above, in combination with one or more treatments where one of the treatments is surgery selected from resection and transplantation. Also described is the use in 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 above, 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.

Also described is the use in 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 above, 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. Also described is the use in 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 above, 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. Also described is the use in 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 above, in combination with one or more treatments where one of the treatments is an antibody selected from rituximab, ibritumomab tiuxetan, tositumomab, and alemtuzumab. Also described is the use in 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 above, in combination with one or more treatments where one of the treatments is an antibody and the antibody is rituximab.

Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, in combination with one or more treatments where one of the treatments is radiation and another treatment is surgery.

Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, in combination with one or more treatments where one of the treatments is radiation and another treatment is one or two chemotherapeutic agents.

Also described is the use in a method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a Compound of Formula I, as defined above, 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, the Compound of Formula I is selected from any of the following described compounds, including from the Representative Compounds in Table 1.

One described compound (A) is directed to a compound of Formula I where W¹, W², W³, and W⁴ are -C(R¹)=; or one or two of W¹, W², W³, and W⁴ are independently -N= and the remaining are -C(R¹)=; where each R¹ is independently hydrogen, alkyl, haloalkyl, nitro, alkoxy, haloalkoxy, halo, hydroxy, cyano, amino, alkylamino, or dialkylamino; and all other groups are as defined above. In another embodiment, W¹, W², W³, and W⁴ are -C(R¹)= and each R¹ is independently hydrogen or alkyl; or one of W¹ and W⁴ is -N= and the other is -C(H)=. In another , W¹, W², W³, and W⁴ are -C(R¹)= where each R¹ is independently hydrogen or alkyl. In another embodiment, R¹ is hydrogen.

Another (B) is a Compound of Formula I where R⁵⁰ is hydrogen, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, nitro, amino, alkylamino, dialkylamino, -N(R⁵⁵)C(O)-C₁-C₆-alkylene-N(R^55a)R^55b, alkylcarbonyl, alkenylcarbonyl, carboxy, alkoxycarbonyl, cyano,
alkylthio, -S(O)₂NR⁵⁵R^55a, or alkylcarbonylamino; where R⁵⁵ and R^55b are indepedently hydrogen, alkyl, or alkenyl and R^55a is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy; and all other groups are as defined above. In another, R⁵⁰ is hydrogen.

Another (C) is a Compound of formula I where R⁵¹ is hydrogen or alkyl; and all other groups are as defined above. In another, R⁵¹ is alkyl, In another, R⁵¹ is methyl.

Another (D) is a Compound of Formula I where R⁵² is hydrogen or halo; and all other groups are as defined above. In another R⁵² is hydrogen or fluoro. In another embodiment, R⁵² is hydrogen.

Another (E) is a Compound of Formula I where R⁵³ is hydrogen, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, nitro, amino, alkylamino, dialkylamino, -N(R⁵⁵)C(O)-C₁-C₆-alkylene-N(R^55a)R^55b, alkylcarbonyl, alkenylcarbonyl, carboxy, alkoxycarbonyl, cyano, alkylthio, -S(O)₂NR⁵⁵R^55a, or alkylcarbonylamino; where R⁵⁵ and R^55b are independently hydrogen, alkyl, or alkenyl and R^55a is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy; and all other groups are as defined above. In another, R⁵³ is hydrogen, alkoxy, nitro, amino, or -N(R⁵⁵)C(O)-C₁-C₆-alkylene-N(R^55a)R^55b. In another, R⁵³ is hydrogen, methoxy, nitro, amino, or -NHC(O)CH₂N(CH₃)₂. In another, R⁵³ is hydrogen or methoxy.

Another (F) is a Compound of Formula I where R⁵⁴ is hydrogen, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, nitro, amino, alkylamino, dialkylamino, -N(R⁵⁵)C(O)-C₁-C₆-alkylene-N(R^55a)R^55b, alkylcarbonyl, alkenylcarbonyl, carboxy, alkoxycarbonyl, cyano,
alkylthio, -S(O)₂NR⁵⁵R^55a, or alkylcarbonylamino; where R⁵⁵ and R^55b are indepedently hydrogen, alkyl, or alkenyl and R^55a is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy; and all other groups are as defined above. In another, R⁵⁴ is hydrogen, alkyl, alkoxy, or halo. In another, R⁵⁴ is hydrogen, methyl, methoxy, bromo, or chloro. In another, R⁵⁴ is hydrogen, methoxy, or chloro.

Another (G) is a compound of Formula I where R⁵⁰, R⁵², and R⁵³ are hydrogen and R⁵⁴ is halo or alkoxy; R⁵⁰, R⁵², and R⁵⁴ are hydrogen and R⁵³ is alkoxy; or R⁵⁰ and R⁵² are hydrogen and R⁵³ and R⁵⁴ together with the carbons to which they are attached form a 6-membered heteroaryl; and all other groups are as defined above. In another, R⁵⁰, R⁵², and R⁵³ are hydrogen and R⁵⁴ is chloro or methoxy; R⁵⁰, R⁵², and R⁵⁴ are hydrogen and R⁵³ is methoxy; or R⁵⁰ and R⁵² are hydrogen and R⁵³ and R⁵⁴ together with the carbons to which they are attached form pyridinyl. Even more speicfically, R⁵⁰, R⁵², and R⁵³ are hydrogen and R⁵⁴ is chloro or methoxy; or R⁵⁰, R⁵², and R⁵⁴ are hydrogen and R⁵³ is methoxy.

One compound of the compound of the paragraph above (G1) is a compound of formula I where R⁵¹ is methyl.

Another described compound (H) is a compound of Formula I where B is phenyl substituted with R^3a and optionally further substituted with one, two, or three R³; and all other groups are as defined above. In another, B is phenyl substituted with R^3a. In another the Compound is of Formula I(a): In another, B is phenyl substituted with R^3a as depicted in Ia and is not further substituted with R³.

Another described compound (J) a compound of Formula I where B is heteroaryl optionally substituted with one, two, or three R³. In another embodiment, B is thien-3-yl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxazolyl, isoxazolyl, pyrrolyl, imidazolyl, pyrazolyl, or thiazolyl, each of which is optionally substituted with one or two R³. In another embodiment, B is thien-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, imidazol-2-yl, pyrrol-2-yl, pyrrol-3-yl, imidazol-4-yl, imidazol-5-yl, pyrazol-3-yl, pyrazol-4-yl, or pyrazol-5-yl, each of which is optionally substituted with one or two R³. In another embodiment, B is thien-3-yl, pyridin-3-yl, pyridin-4-yl, isoxazol-4-yl, or pyrazol-4-yl, each of which is optionally substituted with one or two R³. In another, B is pyridin-3-yl, 2-hydroxy-pyridin-5-yl, isoxazol-4-yl, or pyrazol-4-yl, each of which is optionally substituted with one or two R³.

Another (K) is a compound of Formula I or Ia where R^3a is cyano; hydroxyamino; carboxy; alkylsulfonyl, aminoalkyloxy; alkylaminoalkyloxy; dialkylaminoalkyloxy; -N(R⁷)C(O)-C₁-C₆-alkylene-N(R^7a)(R^7b); -C(O)NR⁸R^8a; -NR⁹C(O)R^9a; -C(O)N(R¹⁰)-C₁-C₆-alkylene-N(R^10a)R^10b; -NR¹¹C(O)NR^11aR^11b where R^11a; -C(O)R¹²; -NR¹³C(O)OR^13a; -C(O)N(R¹⁴)N(R^14a)(R^14b); -S(O)₂N(R¹⁵)-C₁-C₆-alkylene-N(R^15a)R^15b; -C(O)N(R¹⁶)-C₁-C₆-alkylene-C(O)OR^16a; heteroaryl optionally substituted with one or two aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; -N(R¹⁷)-C(=N(R^17b)(R^17a)(NR^17cR^17d); -N(R¹⁸)C(O)-C₁-C₆-alkylene-N(R^18b)C(O)R^18a; -C(O)N(R¹⁹)-C₁-C₆-alkylene-C(O)R^19a; -N(R²²)C(O)-C₁-C₆-alkylene-N(R^22b)-N(R^22c)(R^22a); -C₀-C₆-alkylene-N(R²³)-C₁-C₆-alkylene-N(R^23b)R^23a; or -NR²⁴C(O)-C₁-C₆-alkylene-OR^24a; where each of the alkylene in R^3a is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from halo, hydroxy, amino, alkylamino, and dialkylamino; and all other groups are as defined above.

In another, R^3a is -NHC(O)CH₂NH(CH₃), -NHC(O)CH₂NH(CH₂CH₃), -NHC(O)CH(CH₃)NH₂, -NHC(O)C(CH₃)₂NH₂, -NHC(O)CH₂N(CH₃)₂, -NHC(O)CH₂N(CH₃)CH₂CH₂N(CH₃)₂, -NHC (O)CH(NH₂)CH₂CH₃, -NHC(O)CH₂N(CH₃)CH₂CH₂N(CH₃)₂, -NHC(O)CH(CH₃)NH(CH₃), -NHC(O)CH₂NH₂, -NHC(O)H, -NHC(O)CH₂(azetidin-1-yl), -NHC(O)(pyrrolidin-2-yl), -NHC(O)CH(NH₂)CH₂OH, -NHC(O)(azetidin-4-yl), -NHC(O)C(CH₃)₂NH(CH₃), -NH₂, -NHC(O)CH₂NH(CH₂CH₂CH₃), -NHC(O)CH₂CH₂NH₂, -NHOH, -NHC(O)(piperidin-3-yl), -NHC(O)CH₂(4-methyl-1,4-diazepan-1-yl), -NHC(O)CH(NH₂)(CH₂CH₃), -NHC(O)CH₂NH(CH₂CH(OH)(CH₃)), -NHC(O)CH₂NHCH₂CH₂F, -NHC(O)CH₂NH(OCH₂CH(CH₃)₂), -NHC(O)(1-aminocycloprop-1-yl), -NHC(O)CH₂NH(CH₂cyclopropyl), -NHC(O)CH₂(3-(dimethylamino)-azetidin-1-yl), -NHC(O)(piperidin-2-yl), -NHC(O)(morpholin-4-yl), -NHC(O)CH₂(pyrrolidin-1-yl), -NHC(O)CH(NH₂)CH₂CH₂CH₂CH₂N(CH₃)₂, -NHC(O)CH₂N(CH₃)(CH₂CH₃), -NHC(O)CH₂(imidazol-5-yl), -NHC(O)(1-aminocyclopent-1-yl), -NHC(O)CH₂NH(CH₂CH(CH₃)₂), -NHC(O)CH₂N(CH₃)(CH₂CH₃), -NHC(O)(N-(imidazol-4-ylmethyl)-azetidin-3-yl), -NHC(O)(N-ethyl-azetidin-3-yl), -NHCH₂N(CH₃)CH₂CH₂N(CH₃)₂, -NHC(O)CH₂N(CH₃)(N-methyl-pyrrolidin-3-yl), -NHC(O)CH₂N(CH₃)(CH₂CH₂N(CH₃)₂), -NHC(O)CH₂(3-hydroxy-pyrrolidin-1-yl), -NHC(O)(1-amino-cyclobut-1-yl), -NHC(O)CH₂NH(CH₂)₃CH₃, -NHC(O)CH₂(3-piperidin-1-ylazetidin-1yl), -NHC(O)NH₂, -NHC(O)(1-hydroxycyclopropyl), -NHC(O)CH₂NHN(CH₃)₂, -NHC(O)NH(CH₂)₂N(CH₃)₂, -NHC(O)CH₂OH, -NHC(O)(pyridazin-4-yl), -NHC(O)(N-methyl-piperidin-4-yl), -NHC(O)CH₂NHCH(CH₃)₃, -NHC(O)CH₂(3-dimethylamino-pyrrolidin-lyl), -NHC(O)CH₂NH(CH₂)₂N(CH₃)₂, -NHC(O)(1-cyclopropylmethyl-azetidin-3-yl), -NHC(O)CH₂NH(CH₃)₃, -NHC(O)(imidazol-2-yl), -NHC(O)(imidazol-4-yl), -NHC(O)(1,2-oxaxol-5-yl), -NHC(O)CH₂NHCH₂CF₃, -NHC(O)CH₂CH₂(piperidin-1-yl), -NHC(O)(3-oxo-cyclopent-1-yl), -NHC(O)(2-hydroxy-pyridin-6-yl), -NHC(O)CH₂NH(3-fluoro-4-hydroxyphenyl), -NHC(O)(CH₂)₃N(CH₃)₂, -NHC(O)(1-(furan-2-ylmethyl)-azetidin-3-yl), -NHC(O)(pyrimidin-5-yl), -NHC(O)(pyrrol-2-yl), -NHC(O)CH₂N(CH₃)CH(CH₃)₂, -NHC(O)CH₂N(CH₂CH₃)₂, -NHC(O)CH₂(3-methyl-1,2-oxazol-5-yl), -NHC(O)CH₂NHCH₂(3-hydroxyphenyl), -NHC(O)(N-methyl-pyrrol-2-yl), -NHC(O)(2-amino-tetrahydropyran-2-yl), -NHC(O)CH₂(4-methylamino-piperidin-1-yl), -NHC(O)(piperidin-1-yl), -NHC(O)(N-methyl-pyrrolidin-2yl), -NHC(O)(thien-3yl), -NHC(O)(N-(cyclopropylcarbonyl)azetidin-3-yl), -NHC(O)CH₂(4-methylpiperazin-1-yl), -NHC(O)(N-benzylazetidin-3-yl), -NHC(O)(2-chloro-pyridin-3-yl), -NHC(O)CH₂(pyridin-4-yl), -NHC(O)CH₂N(CH₃)(CH₂CH=CH₂), -NHC(O)CH₂NH(benzyl), -NHC(O)CH₂OCH₃, -NHC(O)[1-(C(O)CH₂CH₃)-azetidin-3-yl], -NHC(O)(pyridin-3-yl), -NHC(O)CH₂NHCH₂CH₂OCH₃, -NHC(O)(1-[C(O)CH₃]piperidin-4-yl), -NHC(O)CH₂(2-methyl-pyrrolidin-1-yl), -NHC(O)(furan-3-yl), -NHC(O)CH₂N(CH₃)₂, -NHC(O)(2-chloro-pyridin-5-yl), -NHC(O)(2-chlorophenyl), -NHC(O)CH₂(pyridin-2-yl), -NHC(O)CH₂(3-dimethylamino-azetidin-1-yl), -NHC(O)CH₂(pyridin-3-yl), -NHC(O)CH₂(2-chlorophenyl), -NHC(O)CH₂N(CH₃)CH₂CH₂CH₂N(CH₃)₂, -NHC(O)CH₂N(CH₂CH₃)CH₂CH ₂OH, -NHC(O)CH₂(2-benzyl-pyrrolidin-1-yl), -NHC(O)(furan-2-yl, -NHC(O)(2-chloro-pyridin-4-yl), -NHC(O)CH₂NHC(O)CH₃, -NHC(O)CH₂CH₂CH₃, -NHC(O)(4-chlorophenyl), -NHC(O)(4-methyl-phenyl), -NHC(O)CH₂NHC(O)O(CH₃)₃, -NHC(O)(benzo[d][1,3]dioxol-5-yl), -NHC(O)CH₂NHOCH₂(2-methoxyphenyl), -NHC(O)(pyridin-4-yl), -NHC(O)CH₂[4-(3,4-dichlorophenyl)-piperazin-1-yl], -NHC(O)CH₂CH₂(pyridin-3-yl), -NHC(O)(tetrahydrofuran-3-yl), -NHC(O)CH₂NHCH₂(2-methylphenyl), -NHC(O)CH(CH₃)CH₂CH₃, -NHC(O)CH₂(3-fluorophenyl), -NHC(O)CH₂C(CH₃)₂phenyl, -NHC(O)(2-methyl-cycloprop-1-yl), -NHC(O)(2-methyl-4-methoxyphenyl), -NHC(O)(2-methylpyridin-3-yl), -NHC(O)(4-methoxyphenyl), -NHC(O)CH₂(4-ethylpiperazin-1-yl), -NHC(O)(thien-2-yl), -NHC(O)(3-fluoro-2-methylphenyl), -NHC(O)(2-bromo-thien-3-yl), -NHC(O)(4-fluorophenyl), -NHC(O)CH₂(3-methylpiperidin-1-yl), -NHC(O)CH(CH₃)₂, -NHC(O)(CH₂)₃CH₃, -NHC(O)CH₂OCH₂CH₃, -NHC(O)CH₂NH(2-fluorophenyl), -NHC(O)(3-dimethylaminophenyl), -NHC(O)CH₂(4-methylpiperidin-1-yl), -NHC(O)CH₂NH(2-n-propylphenyl), -NHC(O)phenyl, -NHC(O)(pyrazin2-yl), -NHC(O)(3-fluoro-4-methoxyphenyl), -NHC(O)C(CH₃)₂CH₂CH₃, -NHC(O)CH₂O(4-fluorophenyl), -NHC(O)(1-methylcarbonyl-azetidin-3-yl), -NHC(O)CH₂NH(4-methylphenyl), -NHC(O)CH₂NH(phenyl), -NHC(O)CH₂(4-allyl-piperazin-1-yl), -NHC(O)(2-methylphenyl), -NHC(O)CH₂CH₂OCH₃, -NHC(O)(3-methylfuran-2-yl), -NHC(O)C(CH₃)₃, -NHC(O)CH₂NHObenzyl, -NHC(O)CH₂NH(3-chlorophenyl), -NHC(O)cyclobutyl, -NHC(O)CH₂(3-methoxyphenyl), -NHC(O)(1-methylcycloprop-1-yl), -NHC(O)(3-flurophenyl), -NHC(O)(4-dimethylaminophenyl), -NHC(O)(3,4-dichlorophenyl), -NHC(O)CH₂NHCH₂(2-methylthiophenyl), -NHC(O)CH₂(2-fluorophenyl), -NHC(O)CH₂N(CH₂CH₃)CH(CH₃)₂, -NHC(O)(thiazol-4-yl), -NHC(O)CH₂N(CH₃)benzyl, -NHC(O)CH₂NHCH₂(thien-2-yl), -NHC(O)CH₂NHCH₂(pyridin-2-yl), -NHC(O)(3-methoxyphenyl), -NHC(O)CH₂NHCH₂(3-chloro-4-methylphenyl), -NHC(O)CH(CH₃)CH₂CH₂CH₃, -NHC(O)CH₂(4-chlorophenyl), -NHC(O)(3-fluoro-4-methylphenyl), -NHC(O)CH₂O(2-methylphenyl), -NHC(O)CH₂(cyclohexyl), -NHC(O)(2-phenyl-cycloprop-1-yl), -NHC(O)(3-chlorophenyl), -NHC(O)CH₂(2-methoxyphenyl), -NHC(O)CH₂CH₂(3-methoxyphenyl), -NHC(O)CH₂NH(2-fluoro-4-methyl-phenyl), -NHC(O)CH₂NHCH₂(3-fluoro-phenyl), -NHC(O)CH₂(4-methoxy-phenyl), -NHC(O)benzyl, -NHC(O)(2,4-dichlorophenyl), -NHC(O)(3-oxo-cyclohex-1-yl), -NHC(O)CH₂NH(3-fluorophenyl), -NHC(O)CH₂(3-chlorophenyl), -NHC(O)CH₂NHCH₂CH(CH₃)phenyl, -NHC(O)CH₂NHCH₂(2,4-dimethylphenyl), -NHC(O)CH₂(2-methyl-piperidin-1-yl), -NHC(O)CH₂NH(2-methoxyphenyl), -NHC(O)CH₂(1,2,3,4-tetrahydroisoquinolin-2-yl), -NHC(O)CH₂CH₂CH=CH₂, -NHC(O)CH₂NH(2-methylphenyl), -NHC(O)CH₂(4-oxo-piperidin-1-yl), -NHC(O)(2-fluorophenyl), -NHC(O)CH₂NHCH(CH₃)phenyl, -NHC(O)(2-fluoro-6-methoxyphenyl), -NHC(O)CH₂NH(2-isopropylphenyl), -NHC(O)CH₂CH₂(2-methoxyphenyl), -NHC(O)CH₂CH₂CH(CH₃)₂, -NHC(O)CH₂(2-phenyl-morpholin-4-yl), -NHC(O)CH₂CH₂(4-methoxyphenyl), -NHC(O)CH₂N(allyl)cyclopentyl, -NHC(O)CH₂N(CH₃)CH₂CH₂OCH₃, -NHC(O)CH₂CH₂C(O)cyclopropyl, -NHC(O)CH₂NH(3-tert-butylphenyl), -NHC(O)CH₂N(n-propyl)(cyclopropylmethyl), -NHC(O)CH₂(2-oxo-cyclopentyl), -NHC(O)CH₂NH(4-chlorophenyl), -NHC(O)CH₂(4-piperidin-1-ylpiperidin-1-yl), -NHC(O)CH₂(4-cyclopentylpiperazin-1-yl), -NHC(O)CH₂(2-methylphenyl), -NHC(O)CH₂NHCH₂(3-fluoro-6-methylphenyl), -NHC(O)CH₂C(CH₃)₃, -NHC(O)CH₂NH(2-chlorophenyl), -NHC(O)(3-fluoro-6-methylphenyl), -NHC(O)(4-fluoro-3-methylphenyl), -NHC(O)(2,3-dichlorophenyl), -NHC(O)CH₂Ophenyl, -NHC(O)CH₂NH(2,3-dimethylphenyl), -NHC(O)(2-fluoro-5-methylphenyl), -NHC(O)CH₂NHOCH₂(4-methylphenyl), -NHC(O)CH₂(4-isopropylpiperazin-1-yl), -NHC(O)CH₂(4-fluorophenyl), -NHC(O)CH₂CH(CH₃)₂, -NHC(O)(2-methoxy-4-methylphenyl), -NHC(O)CH₂(4-n-propylpiperidin-1-yl), -NHC(O)CH₂O(3-methylphenyl), -NHC(O)(tetrahydrofuran-2-yl), -NHC(O)CH₂(3-hydroxymethylpiperidin-1-yl), -NHC(O)(1-tert-butoxycarbonylpiperidin-2-yl), -NHC(O)CH₂N(CH₃)CH₂(pyridin-3-yl), -NHC(O)CH₂N(CH₂CH₃)phenyl, -NHC(O)CH₂OCH₂CH₂OCH₃, -NHC(O)CH₂CH₂(cyclopentyl), -NHC(O)(2,5-dichlorophenyl), -NHC(O)CH₂(4-methylcarbonylpiperazin-1-yl), -NHC(O)(5-fluoro-2-methoxyphenyl), -NHC(O)CH₂N(CH₂CH₃)cyclohexyl, -NHC(O)(5-methyl-1,2-oxazol-3-yl), -NHC(O)(3-methylpyridin-3-yl), -NHC(O)(2-methoxypyridin-3-yl), -NHC(O)(3,5-dichlorophenyl), -NHC(O)CH₂(thiazolidin3-yl), -NHC(O)CH₂(4-[C(O)H]-piperazin-1-yl), -NHC(O)CH₂(2-pyridin-4-ylpiperidin-1-yl), -NHC(O)(2-methoxyphenyl), -NHC(O)CH₂N(CH₃)CH₂CH(CH₃)₂, -NHC(O)CH₂(4-[C(O)H]-homopiperazin-1-yl), -NHC(O)(1-phenylcycloprop-1-yl), -NHC(O)CH₂(2,6-dimethylmorpholin-4-yl), NHC(O)CH₂(2-phenylpyrrolidin-1-yl), -NHC(O)CH₂(morpholin-4-yl), -C(O)NHCH(CH₃)CH₂N(CH₃)₂, -C(O)NHCH₂CH₂N(CH₃)₂, -C(O)NH(pyrrolidin-3-yl), -C(O)NHCH₂CH₂(pyrrolidin-1-yl), -C(O)NHCH₂CH₂NH₂, -C(O)N(CH₃)CH₂CH₂N(CH₃)₂, -C(O)NHCH₂(piperidin-2-yl), -C(O)NH(1-methylazetidin-3-yl), -C(O)NHCH₂CH₂(piperidin-1-yl), -C(O)NHCH₂CH₂N(CH₂CH₃)₂, -C(O)NH(1-methylpiperidin-3-yl), -C(O)NH(piperidin-3-yl), -C(O)NHCH₂(1-methylpiperidin-3-yl), -C(O)NHCH₂CH₂N(CH₂CH₂OH)₂, -C(O)NH(1-ethylpiperidin-3-yl), -C(O)NH₂, -C(O)(3-aminopyrrolidin-1-yl), -C(O)(3-methylaminopyrrolidin-1-yl), -C(O)OH, -C(O)NHCH₂CH₂(morpholin-4-yl), -C(O)NHCH₂(1-ethylpyrrolidin-2-yl), -C(O)(4-amino-3-oxo-pyrazolidin-1-yl), -C(O)NHCH₃, -C(O)(3-aminocyclobut-1-yl), -C(O)NHCH₂(pyridin-3-yl), -C(O)NHCH₂CH₂OH, -C(O)NH(3-oxo-pyrazolidin-4-yl), -NHCH₂CH₂(imidazol-4-yl), -C(O)(3-dimethylaminopyrrolidin-1-yl), -C(O)NHCH₂(pyridin-4-yl), -C(O)N(CH₃)(1-methyl-pyrrolidin-3-yl), -C(O)(3-diethylaminopyrrolidin-1-yl), -C(O)NH(pyrrol-1-yl), -C(O)NHCH₂CH₂CH₂(pyrrolidin-1-yl), -C(O)N(CH₃)CH₂CH₂CN, -C(O)NHCH₂CH₂OCH₃, -C(O)N(CH₂CH₃)CH₂CH₂CN, -C(O)(3-aminopiperidin-1-yl), -C(O)NHCH₂CH₂CH₂N(CH₃)₂, -C(O)NH(morpholin-4-yl), -C(O)NHN(CH₃)₂, -C(O)NHCH₂CH₂CH₂(imidazol-1-yl), -C(O)NHCH₂CH₂CH₂N(CH₂CH₃)₂, -C(O)NHCH₂CH₂CN, -C(O)NHCH₂CH₂C(O)OCH₃, -C(O)NHCH₂CH₂SCH₃, -C(O)NHCH₂CH₂SCH₂CH₃, -C(O)N(CH₂CH₃)CH₂CH₂N(CH₃)₂, -C(O)NHCH₂CH₂CH₂(2-oxo-pyrrolidin-1-yl), -C(O)NHCH₂CH₂(pyridin-4-yl), -C(O)NHCH₂CH₂CH₂OCH₂CH₃, -C(O)NHCH₂CH₂CH₂(morpholin-4-yl), -C(O)NHCH₂CH₂CH₂OCH₃, -C(O)N(CH₃)CH₂CH₂CH₂N(CH₃)₂, -C(O)NHCH₂CH₂CH₂OCH₂CH₂CH₃, -C(O)NHCH₂CH₂C(O)OCH₂CH₃, -C(O)NHCH₂CH₂CH₂OCH(CH₃)₂, -C(O)NHC(CH₃)₂CH₂(piperidin-1-yl), -C(O)N(CH₃)CH₂CH₂CH₃, -C(O)NH(piperidin-1-yl), -C(O)NHCH(CH₃)CH₂OCH₃, -C(O)NHC(CH₃)₂CH₂(morpholin-4-yl), -C(O)(2-dimethylaminomethylpiperidin-1-yl), -C(O)NH(CH₂)₃O(CH₂)₃CH₃, -C(O)NHCH(CH₃)(CH₂)₃N(CH₂CH₃)₂, -C(O)NHC(CH₃)₂C(O)(piperidin-1-yl), -C(O)(4-methylpiperazin-1-yl), -C(O)(2-piperidin-1-ylmethyl-piperidin-1-yl), cyano, -NHCH₃, -CH(CH₃)NHCH₂CH₂N(CH₃)₂, -C(O)CH₃, -S(O)₂NHCH₂CH₂N(CH₃)₂, -S( O)₂NH(CH₂)₃N(CH₃)₂, 5-(N,N-dimethylaminomethyl)-1,3,4-oxadiazol-2-yl, -NHCH₂CH₂N(CH₃)₂, -N(CH₃)₂, -OCH₂CH₂N(CH₃)₂, -NHC[N(CH₃)₂][=N(CH₃)₂], -OCH F₂, -S(O)₂CH₃, -OCF₃, or -NHC(O)CH₂(4-dimethylaminopiperidin-1-yl).

In another (L), the compound of Formula I or Ia is that where R^3a is hydroxyamino, -N(R⁷)C(O)-C₁-C₆-alkylene-N(R^7a)(R^7b), -C(O)NR⁸R^8a, -NR⁹C(O)R^9a, -C(O)N(R¹⁰)-C₁-C₆-alkylene-N(R^10a)R^10b, -NR¹¹C(O)NR^11aR^11b, -N(R²²)C(O)-C₁-C₆-alkylene-N(R^22b)-N(R^22c)(R^22a), -NR¹³C(O)OR^13a, -N(R¹⁸)C(O)-C₁-C₆-alkylene-N(R^18b)C(O)R^18a, -NR²⁴C(O)-C₁-C₆-alkylene-OR^24a, or -N(R²⁰)C(O)-C₁-C₆-alkylene-C(O)R^20a; where each of the alkylene in R^3a is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from halo, hydroxy, and amino; and all other groups are as defined above. In another, R^3a is -NHC(O)CH₂NH(CH₃), -NHC(O)CH(CH₃)NH₂, -NHC(O)C(CH₃)₂NH₂, -NHC(O)CH₂N(C H₃)₂, -NHC(O)CH₂N(CH₃)CH₂CH₂N(CH₃)₂, -NHC(O)CH(NH₂)CH₂CH₃, -NHC(O)CH₂N(C H₃)CH₂CH₂N(CH₃)₂, -NHC(O)CH(CH₃)NH(CH₃), -NHC(O)H, -NHC(O)CH₂(azetidin-1-yl), -NHC(O)(pyrrolidin-2-yl), -NHC(O)CH(NH₂)CH₂OH, -NHC(O)(azetidin-4-yl), -NHC(O)C(CH₃)₂NH(CH₃), -NH₂, -NHC(O)CH₂NH(CH₂CH₂CH₃), -NHC(O)CH₂CH₂NH₂ -NHOH, or -NHC(O)(piperidin-3-yl).

In another (M) the compound is of Formula I or Ia and R^3a -N(R⁷)C(O)-C₁-C₆-alkylene-N(R^7a)(R^7b); and R⁷ is hydrogen or alkyl and R^7a and R^7b are independently hydrogen, alkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; and all other groups are as defined above. In another, R^3a is -NHC(O)CH₂NH(CH₃), -NHC(O)CH(CH₃)NH₂, -NHC(O)C(CH₃)₂NH₂, -NHC(O)CH₂N(CH₃)₂, -NHC(O)CH₂N(CH₃)CH₂CH₂N(CH₃)₂, -NHC(O)CH(NH₂)CH₂CH₃, -NHC(O)CH₂N(CH₃)CH₂CH₂N(CH₃)₂, or -NHC(O)CH(CH₃)NH(CH₃).

Another described compound (N) is a compound of Formula I where each R³ is independently halo; cyano; alkyl; alkenyl; alkoxy; hydroxyamino; carboxy; alkylsulfonyl, aminoalkyloxy; alkylaminoalkyloxy; dialkylaminoalkyloxy; -N(R⁷)C(O)-C₁-C₆-alkylene-N(R^7a)(R^7b); -C(O)NR⁸R^8a; -NR⁹C(O)R^9a; -C(O)N(R¹⁰)-C₁-C₆-alkylene- N(R^10a)R^10b; -NR¹¹C(O)NR^11aR^11b where R^11a; -C(O)R¹²; -NR¹³C(O)OR^13a; -C(O)N(R¹⁴)N(R^14a)(R^14b); -S(O)₂N(R¹⁵)-C₁-C₆-alkylene-N(R^15a)R^15b; -C(O)N(R¹⁶)-C₁-C₆-alkylene-C(O)OR^16a; heteroaryl optionally substituted with one or two aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; -N(R¹⁷)-C(=N(R^17b)(R^17a))(NR^17cR^17d); -N(R¹⁸)C(O)-C₁-C₆-alkylene-N(R^18b)C(O)R^18a; -C(O)N(R¹⁹)-C₁-C₆-alkylene-C(O)R^19a; -N(R²²)C(O)-C₁-C₆-alkylene-N(R^22b)-N(R^22c)(R^22a); -C_0-C₆-alkylene-N(R²³)-C₁-C₆-alkylene-N(R^23b)R^23a; or -NR²⁴C(O)-C₁-C₆-alkylene-OR^24a; where each of the alkylene in R³ is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from halo, hydroxy, amino, alkylamino, and dialkylamino; and all other groups are as defined above.

In another described compound, each R³ is independently methyl, bromo, chloro, fluoro, -NHC(O)CH₂NH(CH₃), -NHC(O)CH₂NH(CH₂CH₃), -NHC(O)CH(CH₃)NH₂, -NHC(O)C(CH₃)₂NH₂, -NHC(O)CH₂N(CH₃)₂, -NHC(O)CH₂N(CH₃)CH₂CH₂N(CH₃)₂, -NHC(O)CH(NH₂)CH₂CH₃, -NHC(O)CH₂N(CH₃)CH₂CH₂N(CH₃)₂, -NHC(O)CH(CH₃)NH(CH₃), -NHC(O)CH₂NH₂, -NHC(O)H, -NHC(O)CH₂(azetidin-1-yl), -NHC(O)(pyrrolidin-2-yl), -NHC(O)CH(NH₂)CH₂OH, -NHC(O)(azetidin-4-yl), -NHC(O)C(CH₃)₂NH(CH₃), -NH₂, -NHC(O)CH₂NH(CH₂CH₂CH₃), -NHC(O)CH₂CH₂NH₂, -NHOH, -NHC(O)(piperidin-3-yl), -NHC(O)CH₂(4-methyl-1,4-diazepan-1-yl), -NHC(O)CH(NH₂)(CH₂CH₃), -NHC(O)CH₂NH(CH₂CH(OH)(CH₃)), -NHC(O)CH₂NHCH₂CH₂F, -NHC(O)CH₂NH(OCH₂CH(CH₃)₂), -NHC(O)(1-aminocycloprop-1-yl), -NHC(O)CH₂NH(CH₂cyclopropyl), -NHC(O)CH₂(3-(dimethylamino)-azetidin-1-yl), -NHC(O)(piperidin-2-yl), -NHC(O)(morpholin-4-yl), -NHC(O)CH₂(pyrrolidin-1-yl), -NHC(O)CH(NH₂)CH₂CH₂CH₂CH₂N(CH₃)₂, -NHC(O)CH₂N(CH₃)(CH₂CH₃), -NHC(O)CH₂(imidazol-5-yl), -NHC(O)(1-aminocyclopent-1-yl), -NHC(O)CH₂NH(CH₂CH(CH₃)₂), -NHC(O)CH₂N(CH₃)(CH₂CH₃), -NHC(O)(N-(imidazol-4-ylmethyl)-azetidin-3-yl), -NHC(O)(N-ethyl-azetidin-3-yl), -NHCH₂N(CH₃)CH₂CH₂N(CH₃)₂, -NHC(O)CH₂N(CH₃)(N-methyl-pyrrolidin-3-yl), -NHC(O)CH₂N(CH₃)(CH₂CH₂N(CH₃)₂), -NHC(O)CH₂(3-hydroxy-pyrrolidin-1-yl), -NHC(O)(1-amino-cyclobut-1-yl), -NHC(O)CH₂NH(CH₂)₃CH₃, -NHC(O)CH₂(3-piperidin-1-ylazetidin-lyl), -NHC(O)NH₂, -NHC(O)(1-hydroxycyclopropyl), -NHC(O)CH₂NHN(CH₃)₂, -NHC(O)NH(CH₂)₂N(CH₃)₂, -NHC(O)CH₂ OH, -NHC(O)(pyridazin-4-yl), -NHC(O)(N-methyl-piperidin-4-yl), -NHC(O)CH₂NHCH(CH₃)₃, -NHC(O)CH₂(3-dimethylamino-pyrrolidin-1yl), -NHC(O)CH₂NH(CH₂)₂N(CH₃)₂, -NHC(O)(1-cyclopropylmethyl-azetidin-3-yl), -NHC(O)CH₂NH(CH₃)₃, -NHC(O)(imidazol-2-yl), -NHC(O)(imidazol-4-yl), -NHC(O)(1,2-oxazol-5-yl), -NHC(O)CH₂NHCH₂CF₃, -NHC(O)CH₂CH₂(piperidin-1-yl), -NHC(O)(3-oxo-cyclopent-1-yl), -NHC(O)(2-hydroxy-pyridin-6-yl), -NHC(O)CH₂NH(3-fluoro-4-hydroxyphenyl), -NHC(O)(CH₂)₃N(CH₃)₂, -NHC(O)(1-(furan-2-ylmethyl)-azetidin-3-yl), -NHC(O)(pyrimidin-5-yl), -NHC(O)(pyrrol-2-yl), -NHC(O)CH₂N(CH₃)CH(CH₃)₂, -NHC(O)CH₂N(CH₂CH₃)₂, -NHC(O)CH₂(3-methyl-1,2-oxazol-5-yl), -NHC(O)CH₂NHCH₂(3-hydroxyphenyl), -NHC(O)(N-methyl-pyrrol-2-yl), -NHC(O)(2-amino-tetrahydropyran-2-yl), -NHC(O)CH₂(4-methylamino-piperidin-1-yl), -NHC(O)(piperidin-1-yl), -NHC(O)(N-methyl-pyrrolidin-2yl), -NHC(O)(thien-3yl), -NHC(O)(N-(cyclopropylcarbonyl)azetidin-3-yl), -NHC(O)CH₂(4-methylpiperazin-1-yl), -NHC(O)(N-benzylazetidin-3-yl), -NHC(O)(2-chloro-pyridin-3-yl), -NHC(O)CH₂(pyridin-4-yl), -NHC(O)CH₂N(CH₃)(CH₂CH=CH₂), -NHC(O)CH₂NH(benzyl), -NHC(O)CH₂OCH₃, -NHC(O)[1-(C(O)CH₂CH)-azetidin-3-yl], -NHC(O)(pyridin-3-yl), -NHC(O)CH₂NHCH₂CH₂OCH₃, -NHC(O)(1-[C(O)CH3]piperidin-4-yl), -NHC(O)CH₂(2-methyl-pyrrolidin-1-yl), -NHC(O)(furan-3-yl), -NHC(O)CH₂N(CH₃)₂, -NHC(O)(2-chloro-pyridin-5-yl), -NHC(O)(2-chlorophenyl), -NHC(O)CH₂(pyridin-2-yl), -NHC(O)CH₂(3-dimethylamino-azetidin-1-yl), -NHC(O)CH₂(pyridin-3-yl), -NHC(O)CH₂(2-chlorophenyl), -NHC(O)CH₂N(CH₃)CH₂CH₂CH₂N(CH₃)₂, -NHC(O)CH₂N(CH₂CH₃)CH₂CH₂OH, -NHC(O)CH₂(2-benzyl-pyrrolidin-1-yl), -NHC(O)(furan-2-yl, -NHC(O)(2-chloro-pyridin-4-yl), -NHC(O)CH₂NHC(O)CH₃, -NHC(O)CH₂CH₂CH₃, -NHC(O)(4-chlorophenyl), -NHC(O)(4-methylphenyl), -NHC(O)CH₂NHC(O)O(CH₃)₃, -NHC(O)(benzo[d][1,3]dioxol-5-yl), -NHC(O)CH₂NHOCH₂(2-methoxyphenyl), -NHC(O)(pyridin-4-yl), -NHC(O)CH₂[4-(3,4-dichlorophenyl)-piperazin-1-yl], -NHC(O)CH₂CH₂(pyridin-3-yl), -NHC(O)(tetrahydrofuran-3-yl), -NHC(O)CH₂NHCH₂(2-methylphenyl), -NHC(O)CH(CH₃)CH₂CH₃, -NHC(O)CH₂(3-fluorophenyl), -NHC(O)CH₂C(CH₃)₂phenyl, -NHC(O)(2-methyl-cycloprop-1-yl), -NHC(O)(2-methyl-4-methoxyphenyl), -NHC(O)(2-methylpyridin-3-yl), -NHC(O)(4-methoxyphenyl), -NHC(O)CH₂(4-ethylpiperazin-1-yl), -NHC(O)(thien-2-yl), -NHC(O)(3-fluoro-2-methylphenyl), -NHC(O)(2-bromo-thien-3-yl), -NHC(O)(4-fluorophenyl), -NHC(O)CH₂(3-methylpiperidin-1-yl), -NHC(O)CH(CH₃)₂, -NHC(O)(CH₂)₃CH₃, -NHC(O)CH₂OCH₂CH₃, -NHC(O)CH₂NH( 2-fluorophenyl), -NHC(O)(3-dimethylaminophenyl), -NHC(O)CH₂(4-methylpiperidin-1-yl), -NHC(O)CH₂NH(2-n-propylphenyl), -NHC(O)phenyl, -NHC(O)(pyrazin2-yl), -NHC(O)(3-fluoro-4-methoxyphenyl), -NHC(O)C(CH₃)₂CH₂CH₃, -NHC(O)CH₂O(4-fluorophenyl), -NHC(O)(1-methylcarbonyl-azetidin-3-yl), -NHC(O)CH₂NH(4-methylphenyl), -NHC(O)CH₂NH(phenyl), -NHC(O)CH₂(4-allyl-piperazin-I-yl), -NHC(O)(2-methylphenyl), -NHC(O)CH₂CH₂OCH₃, -NHC(O)(3-methyl-furan-2-yl), -NHC(O)C(CH₃)₃, -NHC(O)CH₂NHObenzyl, -NHC(O)CH₂NH(3-chlorophenyl), -NHC(O)cyclobutyl, -NHC(O)CH₂(3-methoxyphenyl), -NHC(O)(1-methylcycloprop-1-yl), -NHC(O)(3-flurophenyl), -NHC(O)(4-dimethylaminophenyl), -NHC(O)(3,4-dichlorophenyl), -NHC(O)CH₂NHCH₂(2-methylthiophenyl), -NHC(O)CH₂(2-fluorophenyl), -NHC(O)CH₂N(CH₂CH₃)CH(CH₃)₂, -NHC(O)(thiazol-4-yl), -NHC(O)CH₂N(CH₃)benzyl, -NHC(O)CH₂NHCH₂(thien-2-yl), -NHC(O)CH₂NHCH₂(pyridin-2-yl), -NHC(O)(3-methoxyphenyl), -NHC(O)CH₂NHCH₂(3-chloro-4-methylphenyl), -NHC(O)CH(CH₃)CH₂CH₂CH₃, -NHC(O)CH₂(4-chlorophenyl), -NHC(O)(3-fluoro-4-methylphenyl), -NHC(O)CH₂O(2-methylphenyl), -NHC(O)CH₂(cyclohexyl), -NHC(O)(2-phenyl-cycloprop-1-yl), -NHC(O)(3-chlorophenyl), -NHC(O)CH₂(2-methoxyphenyl), -NHC(O)CH₂CH₂(3-methoxyphenyl), -NHC(O)CH₂NH(2-fluoro-4-methyl-phenyl), -NHC(O)CH₂NHCH₂(3-fluoro-phenyl), -NHC(O)CH₂(4-methoxy-phenyl), -NHC(O)benzyl, -NHC(O)(2,4-dichlorophenyl), -NHC(O)(3-oxo-cyclohex-1-yl), -NHC(O)CH₂NH(3-fluorophenyl), -NHC(O)CH₂(3-chlorophenyl), -NHC(O)CH₂NHCH₂CH(CH₃)phenyl, -NHC(O)CH₂NHCH₂(2,4-dimethylphenyl), -NHC(O)CH₂(2-methyl-piperidin-1-yl), -NHC(O)CH₂NH(2-methoxyphenyl), -NHC(O)CH₂(1,2,3,4-tetrahydroisoquinolin-2-yl), -NHC(O)CH₂CH₂CH=CH₂, -NHC(O)CH₂NH(2-methylphenyl), -NHC(O)CH₂(4-oxo-piperidin-1-yl), -NHC(O)(2-fluorophenyl), -NHC(O)CH₂NHCH(CH₃)phenyl, -NHC(O)(2-fluoro-6-methoxyphenyl), -NHC(O)CH₂NH(2-isopropylphenyl), -NHC(O)CH₂CH₂(2-methoxyphenyl), -NHC(O)CH₂CH₂CH(CH₃)₂, -NHC(O)CH₂(2-phenyl-morpholin-4-yl), -NHC(O)CH₂CH₂(4-methoxyphenyl), -NHC(O)CH₂N(allyl)cyclopentyl, -NHC(O)CH₂N(CH₃)CH₂CH₂OCH₃, -NHC(O)CH₂CH₂C(O)cyclopropyl, -NHC(O)CH₂NH(3-tert-butylphenyl), -NHC(O)CH₂N(n-propyl)(cyclopropylmethyl), -NHC(O)CH₂(2-oxo-cyclopentyl), -NHC(O)CH₂NH(4-chlorophenyl), -NHC(O)CH₂(4-piperidin- 1-ylpiperidin-1-yl), -NHC(O)CH₂(4-cyclopentylpiperazin-1-yl), -NHC(O)CH₂(2-methylphenyl), -NHC(O)CH₂NHCH₂(3-fluoro-6-methylphenyl), -NHC(O)CH₂C(CH₃)₃, -NHC(O)CH₂NH(2-chlorophenyl), -NHC(O)(3-fluoro-6-methylphenyl), -NHC(O)(4-fluoro-3-methylphenyl), -NHC(O)(2,3-dichlorophenyl), -NHC(O)CH₂Ophenyl, -NHC(O)CH₂NH(2,3-dimethylphenyl), -NHC(O)(2-fluoro-5-methylphenyl), -NHC(O)CH₂NHOCH₂(4-methylphenyl), -NHC(O)CH₂(4-isopropylpiperazin-1-yl), -NHC(O)CH₂(4-fluorophenyl), -NHC(O)CH₂CH(CH₃)₂, -NHC(O)(2-methoxy-4-methylphenyl), -NHC(O)CH₂(4-n-propylpiperidin-1-yl), -NHC(O)CH₂O(3-methylphenyl), -NHC(O)(tetrahydrofuran-2-yl), -NHC(O)CH₂(3-hydroxymethylpiperidin-1-yl), -NHC(O)(1-tert-butoxycarbonylpiperidin-2-yl), -NHC(O)CH₂N(CH₃)CH₂(pyridin-3-yl), -NHC(O)CH₂N(CH₂CH₃)phenyl, -NHC(O)CH₂OCH₂CH₂OCH₃, -NHC(O)CH₂CH₂(cyclopentyl), -NHC(O)(2,5-dichlorophenyl), -NHC(O)CH₂(4-methylcarbonylpiperazin-1-yl), -NHC(O)(5-fluoro-2-methoxyphenyl), -NHC(O)CH₂N(CH₂CH₃)cyclohexyl, -NHC(O)(5-methyl-1,2-oxazol-3-yl), -NHC(O)(3-methylpyridin-3-yl), -NHC(O)(2-methoxypyridin-3-yl), -NHC(O)(3,5-dichlorophenyl), -NHC(O)CH₂(thiazolidin3-yl), -NHC(O)CH₂(4-[C(O)H]-piperazin-1-yl), -NHC(O)CH₂(2-pyridin-4-ylpiperidin-1-yl), -NHC(O)(2-methoxyphenyl), -NHC(O)CH₂N(CH₃)CH₂CH(CH₃)₂, -NHC(O)CH₂(4-[C(O)H]-homopiperazin-1-yl), -NHC(O)(1-phenylcycloprop-1-yl), -NHC(O)CH₂(2,6-dimethylmorpholin-4-yl), NHC(O)CH₂(2-phenylpyrrolidin-1-yl), -NHC(O)CH₂(morpholin-4-yl), -C(O)NHCH(CH₃)CH₂N(CH₃)₂, -C(O)NHCH₂CH₂N(CH₃)₂, -C(O)NH(pyrrolidin-3-yl), -C(O)NHCH₂CH₂(pyrrolidin-1-yl), -C(O)NHCH₂CH₂NH₂, -C(O)N(CH₃)CH₂CH₂N(CH₃)₂, -C(O)NHCH₂(piperidin-2-yl), -C(O)NH(1-methylazetidin-3-yl), -C(O)NHCH₂CH₂(piperidin-1-yl), -C(O)NHCH₂CH₂N(CH₂CH₃)₂, -C(O)NH(1-methylpiperidin-3-yl), -C(O)NH(piperidin-3-yl), -C(O)NHCH₂(1-methylpiperidin-3-yl), -C(O)NHCH₂CH₂N(CH₂CH₂OH)₂, -C(O)NH(1-ethylpiperidin-3-yl), -C(O)NH₂, -C(O)(3-aminopyrrolidin-1-yl), -C(O)(3-methylaminopyrrolidin-1-yl), -C(O)OH, -C(O)NHCH₂CH₂(morpholin-4-yl), -C(O)NHCH₂(1-ethylpyrrolidin-2-yl), -C(O)(4-amino-3-oxo-pyrazolidin-1-yl), -C(O)NHCH₃, -C(O)(3-aminocyclobut-1-yl), -C(O)NHCH₂(pyridin-3-yl), -C(O)NHCH₂CH₂OH, -C(O)NH(3-oxo-pyrazolidin-4-yl), -NHCH₂CH₂(imidazol-4-yl), -C(O)(3-dimethylaminopyrrolidin-1-yl), -C(O)NHCH₂(pyridin-4-yl), -C(O)N(CH₃)(1-methyl-pyrrolidin-3-yl), -C(O)(3-diethylaminopyrrolidin-1-yl), -C(O)NH(pyrrol-1-yl), -C(O)NHCH₂CH₂CH₂(pyrrolidin-1-yl), -C(O)N(CH₃)CH₂CH₂CN, -C(O)NHCH₂CH₂OCH₃, -C(O)N(CH₂CH₃)CH₂CH₂CN, -C(O)(3-aminopiperidin-1-yl), -C(O)NHCH₂CH₂CH₂N(CH₃)₂, -C(O)NH(morpholin-4-yl), -C(O)NHN(CH₃)₂, -C(O)NHCH₂CH₂CH₂(imidazol-1-yl), -C(O)NHCH₂CH₂CH₂N(CH₂CH₃)₂, -C(O)NHCH₂CH₂CN, -C(O)NHCH₂CH₂C(O)OCH₃, -C(O)NHCH₂CH₂SCH₃, -C(O)NHCH₂CH₂SCH₂CH₃, -C(O)N(CH₂CH₃)CH₂CH₂N(CH₃)₂, -C(O)NHCH₂CH₂CH₂(2-oxo-pyrrolidin-1-yl), -C(O)NHCH₂CH₂(pyridin-4-yl), -C(O)NHCH₂CH₂CH₂OCH₂CH₃, -C(O)NHCH₂CH₂CH₂(morpholin4-yl), -C(O)NHCH₂CH₂CH₂OCH₃, -C(O)N(CH₃)CH₂CH₂CH₂N(CH₃)₂, -C(O)NHCH₂CH₂CH₂OCH₂CH₂CH₃, -C(O)NHCH₂CH₂C(O)OCH₂CH₃, -C(O)NHCH₂CH₂CH₂OCH(CH₃)₂, -C(O)NHC(CH₃)₂CH₂(piperidin-1-yl), -C(O)N(CH₃)CH₂CH₂CH₃, -C(O)NH(piperidin-1-yl), -C(O)NHCH(CH₃)CH₂OCH₃, -C(O)NHC(CH₃)₂CH₂(morpholin-4-yl), -C(O)(2-dimethylaminomethylpiperidin-1-yl), -C(O)NH(CH₂)₃O(CH₂)₃CH₃, -C(O)NHCH(CH₃)(CH₂)₃N(CH₂CH₃)₂, -C(O)NHC(CH₃)₂C(O)(piperidin-1-yl), -C(O)(4-methylpiperazin-1-yl), -C(O)(2-piperidin-1-ylmethyl-piperidin-1-yl), cyano, -NHCH₃, -CH(CH₃)NHCH₂CH₂N(CH₃)₂, -C(O)CH₃, -S(O)₂NHCH₂CH₂N(CH₃)₂, -S( O)₂NH(CH₂)₃N(CH₃)₂, 5-(N,N-dimethylaminomethyl)-1,3,4-oxadiazol-2-yl, -NHCH₂CH₂N(CH₃)₂, -N(CH₃)₂, -OCH₂CH₂N(CH₃)₂, -NHC[N(CH₃)₂][=N(CH₃)₂], -OCH F₂, -CF₃, -S(O)₂CH₃, -OCF₃, -NHC(O)CH₂(4-dimethylaminopiperidin-1-yl), or methoxy.

In another (P), the Compound of Formula I is that where each R³ is independently halo, alkyl, hydroxyamino, -N(R⁷)C(O)-C₁-C₆-alkylene-N(R^7a)(R^7b), -C(O)NR⁸R^8a, -NR⁹C(O)R^9a, -C(O)N(R¹⁰)-C₁-C₆-alkylene-N(R^10a)R^10b-NR¹¹C(O)NR^11aR^11b, -N(R²²)C(O)-C₁-C-₆-alkylene-N(R^22b)-N(R^22c)(R^22a), -NR¹³C(O)OR^13a, -N(R¹⁸)C(O)-C₁-C₆-alkylene-N(R^18b)C(O)R^18a, -NR²⁴C(O)-C₁-C₆-alkylene-OR^24a, or -N(R²)C(O)-C₁-C₆-alkylene-C(O)R^20a; where each of the alkylene in R³ is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from halo, hydroxy, and amino; and all other groups are as defined above . In another, each R³ is independently methyl, chloro, -NHC(O)CH₂NH(CH₃), -NHC(O)CH(CH₃)NH₂, -NHC(O)C(CH₃)₂NH₂, -NHC(O)CH₂N(CH₃)₂, -NHC(O)CH₂N(CH₃)CH₂CH₂N(CH₃)₂, -NHC(O)CH(NH₂)CH₂CH₃, -NHC(O)CH₂N(CH₃)CH₂CH₂N(CH₃)₂, -NHC(O)CH(CH₃)NH(CH₃), -NHC(O)H, -NHC(O)CH₂(azetidin-1-yl), -NHC(O)(pyrrolidin-2-yl), -NHC(O)CH(NH₂)CH₂OH, -NHC(O)(azetidin-4-yl), -NHC(O)C(CH₃)₂NH(CH₃), -NH₂, -NHC(O)CH₂NH(CH₂CH₂CH₃), -NHC(O)CH₂CH₂NH₂, -NHOH, or -NHC(O)(piperidin-3-yl).

In another (Q), the Compound of Formula I is that where R³ is alkyl or -N(R⁷)C(O)-C₁-C₆-alkylene-N(R^7a)(R^7b); and R⁷ is hydrogen or alkyl and R^7a and R^7b are independently hydrogen, alkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; and all other groups are as defined above. In another, each R³ is independently methyl, -NHC(O)CH₂NH(CH₃), -NHC(O)CH(CH₃)NH₂, -NHC(O)C(CH₃)₂NH₂, -NHC(O)-CH₂N(CH₃)₂, -NHC(O)CH₂N(CH₃)CH₂CH₂N(CH₃)₂, -NHC(O)CH(NH₂)CH₂CH₃, -NHC(O) CH₂N(CH₃)CH₂CH₂N(CH₃)₂, or -NHC(O)CH(CH₃)NH(CH₃).

In another (R), the Compound of Formula I is that where B is phenyl, R³ is not present or R³ is halo, alkyl, or alkoxy; R^3a is -C(O)NR⁸R^8a, -NR⁹C(O)R^9a, -N(R⁷)C(O)-C₁-C₆-alkylene-N(R^7a)(R^7b), or -C(O)N(R¹⁰)-C₁-C₆-alkylene-N(R^10a)R^10b where each of the alkylene in R^3a is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from halo, hydroxy, and amino; and all other groups are as defined in the Summary of the Invention.

In another compound (R1) of compound R, the compound is that where R⁵⁰, R⁵², and R⁵³ are hydrogen and R⁵⁴ is halo or alkoxy; R⁵⁰, R⁵², and R⁵⁴ are hydrogen and R⁵³ is alkoxy; or R⁵⁰ and R⁵² are hydrogen and R⁵³ and R⁵⁴ together with the carbons to which they are attached form a 6-membered heteroaryl; and all other groups are as defined above . In another embodiment, R⁵⁰, R⁵², and R⁵³ are hydrogen and R⁵⁴ is halo or alkoxy; or R⁵⁰, R⁵², and R⁵⁴ are hydrogen and R⁵³ is alkoxy.

In another compound (R2) of compound R, the compound is that where R⁵¹ is methyl.

In another (S), the compound of Formula Ia: is that where R³ is not present or R³ is alkyl and R^3a is -N(R⁷)C(O)-C₁-C₆-alkylene-N(R^7a)(R^7b), -C(O)NR⁸R^8a, -NR⁹C(O)R^9a, or -C(O)N(R¹⁰)-C₁-C₆-alkylene-N(R^10a)R^10b; where each of the alkylene in R^3a is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from halo, hydroxy, and amino; and all other groups are as defined above . In another, R³ is is not present or is methyl. In another, R³ is is not present.

Another compound (S1) of compound S is that where R⁷ is hydrogen or alkyl and R^7a, and R^7b are independently hydrogen, alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; R⁸ is hydrogen or alkyl and R^8a is heterocycloalkyl or heterocycloalkylalkyl; R⁹ is hydrogen or alkyl and R^9a is hydrogen, heterocycloalkyl, or heterocycloalkylalkyl; and R¹⁰, R^10a, and R^10b are independently hydrogen, alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl.

Another compound (S2) of compound S is that where R⁵⁰, R⁵², and R⁵³ are hydrogen and R⁵⁴ is halo or alkoxy; or R⁵⁰, R⁵², and R⁵⁴ are hydrogen and R⁵³ is alkoxy; or R⁵⁰ and R⁵² are hydrogen and R⁵³ and R⁵⁴ together with the carbons to which they are attached form a 6-membered heteroaryl. In another, R⁵⁰, R⁵², and R⁵³ are hydrogen and R⁵⁴ is halo or alkoxy; or R⁵⁰, R⁵², and R⁵⁴ are hydrogen and R⁵³ is alkoxy.

In another compound of (S3) of compound S, the compound is that where R⁵¹ is methyl.

In another (T), the Compound of Formula I is that where B is heteroaryl, one R³ is halo, alkyl, or alkoxy and a second R³ is -C(O)NR⁸R^8a, -NR⁹C(O)R^9a, -N(R⁷)C(O)-C₁-C₆-alkylene-N(R^7a)(R^7b), or -C(O)N(R¹⁰)-C₁-C₆-alkylene-N(R^10a)R^10b where each of the alkylene in R³ is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from halo, hydroxy, and amino; and all other groups are as defined above.

In another compound (T1) of compound T, the compound is that where R⁷ is hydrogen or alkyl and R^7a, and R^7b are independently hydrogen, alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; R⁸ is hydrogen or alkyl and R^8a is heterocycloalkyl or heterocycloalkylalkyl; R⁹ is hydrogen or alkyl and R^9a is hydrogen, heterocycloalkyl, or heterocycloalkylalkyl; R¹⁰, R^10a, and R^10b are independently hydrogen, alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl.

In another compound U, the compound of Formula I is that where B is each R³ (when R³ is present) is independently halo, alkyl, alkoxy, aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, alkylamino, dialkylamino, -C(O)NR⁸R^8a, -NR⁹C(O)R^9a, -N(R⁷)C(O)-C₁-C₆-alkylene-N(R^7a)(R^7b), or -C(O)N(R¹⁰)-C₁-C₆-alkylene-N(R^10a)R^10b; and all other groups are as defined above.

In another compound (U1) of compound U, the compound of Formula I is that where R⁵⁰, R⁵², and R⁵³ are hydrogen and R⁵⁴ is halo or alkoxy; R⁵⁰, R⁵², and R⁵⁴ are hydrogen and R⁵³ is alkoxy; or R⁵⁰ and R⁵² are hydrogen and R⁵³ and R⁵⁴ together with the carbons to which they are attached form a 6-membered heteroaryl; and all other groups are as defined above. In another embodiment, R⁵⁰, R⁵², and R⁵³ are hydrogen and R⁵⁴ is halo or alkoxy; or R⁵⁰, R⁵², and R⁵⁴ are hydrogen and R⁵³ is alkoxy.

In another compound (U2) of compound U1, the compound of Formula I is that where R⁵¹ is methyl.

In another compound (U3) of compound U, the Compound of Formula I is that where R⁷ is hydrogen or alkyl and R^7a, and R^7b are independently hydrogen, alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; R⁸ is hydrogen or alkyl and R^8a is heterocycloalkyl or heterocycloalkylalkyl; R⁹ is hydrogen or alkyl and R^9a is hydrogen, heterocycloalkyl, or heterocycloalkylalkyl; R¹⁰, R^10a, and R^10b are independently hydrogen, alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl

In another compound (V) the Compound of Formula I is that where W¹, W², W³, and W⁴ are -C(H)=; or W² and W³ are -C(H)= and one of W¹ and W⁴ is -N= and the other is -C(H)=;
R⁵⁰ is hydrogen;
R⁵¹ is hydrogen or alkyl;
R⁵² is hydrogen;
R⁵³ is hydrogen, alkoxy, nitro, amino, or -N(R⁵⁵)C(O)-C₁-C₆-alkylene-N(R^55a)R^55b; and R⁵⁴ is hydrogen, alkyl, alkoxy, or halo; or R⁵³ and R⁵⁴ together with the carbons to which they are attached form a 6-membered heteroaryl;
B is phenyl substituted with R^3a and optionally further substituted with one R³; or
B is heteroaryl optionally substituted with one or two R³;
R^3a is cyano; hydroxyamino; carboxy; alkylsulfonyl, aminoalkyloxy; alkylaminoalkyloxy; dialkylaminoalkyloxy; -N(R⁷)C(O)-C₁-C₆-alkylene-N(R^7a)(R^7b); -C(O)NR⁸R^8a; -NR⁹C(O)R^9a; -C(O)N(R¹⁰)-C₁-C₆-alkylene-N(R^10a)R^10b; -NR¹¹C(O)NR¹¹R^11b where R^11a; -C(O)R¹²; -NR¹³C(O)OR^13a; -C(O)N(R¹⁴)N(R^14a)(R¹⁴); -S(O)₂N(R¹⁵)-C₁-C₆-alkylene-N(R^15a)R^15b; -C(O)N(R¹⁶)-C₁-C₆-alkylene-C(O)OR^16a; heteroaryl optionally substituted with one or two aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; -N(R¹⁷)-C(=N(R^17b)(R^17a))(NR^17cR^17d); -N(R¹⁸)C(O)-C₁-C₆-alkylene-N(R^18b)C(O)R^18a; -C(O)N(R¹⁹)-C₁-C₆-alkylene-C(O)R^19a; -N(R²²)C(O)-C₁-C₆-alkylene-N(R^22b)-N(R^22c)(R^22a); -C₀-C₆-alkylene-N(R²³)-C₁-C₆-alkylene-N(R^23b)R^23a; or -NR²⁴C(O)-C₁-C₆-alkylene-OR^24a; where each of the alkylene in R^3a is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from halo, hydroxy, and amino;
each R³ (when R³ is present) is independently halo; cyano; alkyl; alkenyl; alkoxy; hydroxyamino; carboxy; alkylsulfonyl, aminoalkyloxy; alkylaminoalkyloxy; dialkylaminoalkyloxy; -N(R⁷)C(O)-C₁-C₆-alkylene-N(R^7a)(R^7b); -C(O)NR⁸R^8a; -NR⁹C(O)R^9a; -C(O)N(R¹⁰)-C₁-C₆-alkylene-N(R^10a)R^10b; -NR¹¹C(O)NR^11aR^11b where R^11a; -C(O)R¹²; -NR¹³C(O)OR^13a; -C(O)N(R¹⁴)N(R^14a)(R^14b); -S(O)₂N(R¹⁵)-C₁-C₆-alkylene-N(R^15a)R^15b; -C(O)N(R¹⁶)-C₁-C₆-alkylene-C(O)OR^16a; heteroaryl optionally substituted with one or two aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; -N(R¹⁷)-C(=N(R^17b)R^17a))(NR^17cR^17d); -N(R¹⁸)C(O)-C₁-C₆-alkylene-N(R^18b)C(O)R^18a; -C(O)N(R¹⁹)-C₁-C₆-alkylene-C(O)R^19a; -N(R²²)C(O)-C₁-C₆-alkylene-N(R^22b)-N(R^22c)(R^22a); -C₀-C₆-alkylene-N(R²³)-C₁-C₆-alkylene-N(R^23b)R^23a; or -NR²⁴C(O)-C₁-C₆-alkylene-OR^24a; where each of the alkylene in R³ is independently optionally further substituted with 1, 2, 3, 4, or 5 groups selected from halo, hydroxy, and amino;
provided that when R⁵⁰ and R⁵² are hydrogen, R⁵¹ is hydrogen or methyl, R⁵³ is hydrogen or methoxy, and R⁵⁴ is hydrogen or methoxy, then B is not 2,3-dihydro-1,4-benzodioxinyl, thien-2-yl, or thien-2-yl substituted with one R³ where R³ is halo.

Another compound (W) is a Compound of Formula I where R⁵⁰, R⁵³, and R⁵⁴ are independently hydrogen, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, nitro, amino, alkylamino,
dialkylamino, -N(R⁵⁵)C(O)-C₁-C₆-alkylene-N(R^55a)R^55b, alkylcarbonyl, alkenylcarbonyl, carboxy, alkoxycarbonyl, cyano, alkylthio, -S(O)₂NR⁵⁵R^55a, or alkylcarbonylamino and where R⁵⁵ and R^55b are indepedently hydrogen, alkyl, or alkenyl and R^55a is hydrogen, alkyl, alkenyl, hydroxy, or alkoxy; or R⁵³ and R⁵⁴ together with the carbons to which they are attached form a 5- or 6-membered heteroaryl or 5- or 6-membered heterocycloalkyl.

Another compound (X) is a Compound of Formula I where R⁵³ and R⁵⁴ together with the carbons to which they are attached form a 5- or 6-membered heteroaryl or 5- or 6-membered heterocycloalkyl.

Representative compounds of Formula I and/or II are depicted below. Compounds of Table 1 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 in Table 1 were generated using ACD/Labs naming software 8.00 release, product version 8.08 with the exception of Compound 374 which was named using ChemDraw v. 9.0.1.

The Compounds in Table 1 can be prepared as pharmaceutically acceptable salts, solvates, hydrates, and/or isomers thereof. Salt, solvate, hydrate, and isomer combinations of the Compounds of Claim 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 Claim 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. In particular, the invention can be practiced with one or two pharmaceutically acceptable salts of a Compound of Claim 1 which salt(s) are formed with one or two bases independently selected from sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, 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, and N-methylglucamine. 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.

Except compound 357, all the compounds of Table 1 are to be considered as reference examples.

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. 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-promo-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-promo-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-l-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-[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-(methytoxy)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

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. 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-brorno-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)pipendin-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

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. 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

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. 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-phenylpronane-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)-N'2-(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)-N'2-(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-fluorophenyl}-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-yloxyl-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-yloxyl]-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-yloxyl-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-yloxyl-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-yloxyl-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)-quinolin4-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-yloxyl-phenyl}-oxalamide 223 N-(2,3-Difluoro-benxyl)-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-ethy)-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-Fluorl-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-fluorophenyl}-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-yloxyl-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-yloxyl-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-yloxyl-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

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. 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)pheny]-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)cycloropane-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-methyloctahydrocyclo-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-fluorl-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)quinolin4-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)cvclobutane-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