KR20070117547A - Brain Cancer Treatment - Google Patents

Abstract

The present invention relates to 4-arylamino-quinazolin and its analogs effective as activators of caspases and inducers of apoptosis, and the use of these compounds in the treatment of brain cancer. The compounds of the present invention are useful for treating various clinical conditions in which unregulated growth and proliferation of abnormal cells occur.

Description

{Method of treating brain cancer}

Cross Reference of Related U.S. Application

This application claims the benefit of U.S. Provisional Patent Application 60 / 641,263, filed January 3, 2005, which is incorporated by reference in its entirety herein.

Field of invention

The present invention belongs to the field of medicinal chemistry. In particular, the present invention relates to compounds which are activators of caspases and inducers of apoptosis. The invention also relates to the use of the compounds as therapeutically effective anticancer agents, in particular the use of the compounds in the treatment of cancers of the brain and central nervous system (CNS).

Background of the Invention

The organism removes unwanted cells by a variety of methods known as controlled cell death, programmed cell death or apoptosis. Such cell death occurs not only as a normal aspect of animal development, but also in cell bio homeostasis and aging. Glucksmann, A., Biol. Rev. Cambridge Philos. Soc. 26: 59-86 (1951); Glucksmarxn, A., Archives de Biologie 76: 419-437 (1965); Ellis, et al., Dev. 112: 591-603 (1991); Vaux, et al., Cell 76: 777-779 (1994). Apoptosis regulates cell number, promotes morphogenesis, eliminates harmful or abnormal cells, and eliminates cells that have already functioned. Apoptosis also occurs in response to various physiological stresses such as hypoxia or ischemia. International Publication No. WO 96/20721.

Proteases have been found to be a major factor in apoptosis [see literature; Thornberry, Chemistry and Biology 5: R97-R103 (1998); Thornberry, British Med. Bull. 53: 478-490 (1996). In genetic studies of the nematode Caenorhabditis elegans, more than 14 genes are involved in apoptosis-induced cell death, two of which are caused by apoptosis (cell death-promoting) ced (abnormal cell death). For c) genes ced 3 and ced-4. CED-3 is an analog of the interleukin 1 beta-converting enzyme, cysteine protease, now called caspase-1. The extensive application of these data ultimately to mammals has shown that mammalian apoptosis systems are involved in a system that behaves like a cascade of caspases or a cascade of caspases. Currently, caspases of cysteine proteases comprise 14 different members, and more will be found in the future. All known caspases are synthesized as chemogens that require cleavage at aspartyl residues before forming active enzymes. Thus, caspases can activate other caspases in the manner of amplifying cascades.

Apoptosis and caspase are thought to be important in the progression of cancer. Apoptosis and Cancer Chemotherapy, Hickman and Dive, eds., Humana Press (1999)]. There is various evidence that cancer cells contain caspases but lack part of the molecular machinery that activates the caspase cascade. As a result, cancer cells lose their ability to cause cell death and the cells become malignant. In the case of an apoptosis processor, it is known that there is a control point indicative of the time point for the interference causing activation. These control points include the CED-9-BCL and CED-3-ICE gene family products, which are unique proteins that regulate the life and death decisions of cells and carry out part of the cell death process itself. Schmitt, et al., Biochem. Cell. Biol. 75: 301-314 (1997). BCL-type proteins include BCL-xL and BAX-alpha, which appear to have caspase activating action. BCL-xL appears to prevent activation of the protease cascade by apoptosis, while BAX-alpha promotes activation of the protease cascade by apoptosis.

Chemotherapy (anticancer) agents can cause suicide of cancer cells by activating a caspase cascade in a dormant state. This may be an important aspect of most but not all of the known anticancer agents [see literature; Los, et al., Blood 20: 3118-3129 (1997); Friesen, et al., Nat. Med. 2: 574 (1996). The mechanism of action of modern anti-neoplastic agents often involves attack at certain stages of the cell cycle. In summary, the cell cycle represents the stage in which cells progress normally during their lifetime. Typically, cells exist in a resting phase called G _o . During proliferation, cells proceed to a stage where DNA synthesis, called S, takes place. Cell differentiation, ie mitosis, then occurs in a stage called M. Anti-neoplastic agents such as cytosine arabinosides, hydroxyurea, 6-mercaptopurine and methotrexate are S phase specific, while anti-neoplastic agents such as vincristine, vinblastine and paclitaxel are M phase specific. M stage specific anti-neoplastic agents, such as vinblastine and paclitaxel, are known to affect tubulin synthesis. The ability of cells to properly polymerize and depolymerize tubulin is thought to be an important action for M stage cell differentiation.

Many slow-growing tumors, such as colon cancer, are mainly present at the G _o stage, while rapidly proliferating normal cells, such as bone marrow, are primarily at the S or M stage. Thus, agents such as 6-mercaptopurine may be ineffective against slow growing tumors and cause bone marrow toxicity. Additional aspects of chemotherapy of neoplastic diseases are known to those skilled in the art. Hardman, et al., Eds., Goodman and Gilman's The Pharmacological Basis of Therapeutics, Ninth Edition, McGraw-Hill, New York (1996), pp. 1225-1287]. Thus, while it is clear that there is a possibility for activation of the caspase cascade, it is not clear about the exact mechanism by which this is performed. It is likewise clear that the insufficient activity of the caspase cascade and thus apoptosis is involved in various types of cancer. The development of caspase cascade activators and apoptosis inducers is a very desirable goal in the development of therapeutically effective anti-neoplastic agents. In addition, because autoimmune diseases and certain degenerative diseases also include the proliferation of abnormal cells, treatment for such diseases involves the enhancement of the apoptosis process through the administration of appropriate caspase cascade activators and apoptosis inducers.

Recently, however, the use of apoptosis inducers and other anti-neoplastic agents as chemotherapy for brain tumors has been limited. Surgery removal, rather than chemotherapy, is the primary treatment for most brain tumor patients. Karim et al., Int. J. Radiat. Oncol. Biol. Phys. 52: 316-324 (2002); Patchell RA, Cancer Treat Rev 29: 533-540 (2003). Radiotherapy is also part of many brain tumor therapies because it has been shown to prolong disease-free survival in patients with low glioma [see literature; Karim et al., Int. J. Radiat. Oncol. Biol. Phys. 52: 316-324 (2002). One limitation in the use of chemotherapy for brain tumors is the difficulty in properly exposing the agent to the tumor. Carmustine was incorporated into biodegradable polymers to prolong the exposure of anti-neoplastic agents to tumors. Brem et al., Lancet 345: 1008-1012 (1995). However, administration of the drug-impregnated biodegradable polymer is administered by implantation at the tumor site during surgery. Administration of chemotherapeutic agents during surgery or by injecting medication directly into the site of the brain tumor is difficult and offensive to the patient. Thus, there is a need for chemotherapeutic agents that can achieve adequate exposure to tumors of the brain and CNS without the need for direct injection into the tumor site.

The gist of the invention

4-arylamino-quinazolin compounds and analogs thereof, as represented by formulas (I) to (III) below, are potent tubulin inhibitors. These are activators of the caspase cascade that activate caspase-3 and are inducers or promoters of apoptosis. Thus, they are useful for treating or delaying the onset of diseases and disorders that are sensitive to the inhibition of tubulin or the induction of apoptosis.

Surprisingly, the compounds of formulas (I)-(III) can be effective in treating and / or preventing diseases and disorders of the brain and CNS, such as brain and spinal cord tumors, by achieving appropriate concentrations in the brain and CNS. Turned out to be.

Thus, one aspect of the present invention is to inhibit tubulin and induce caspase activity, in particular caspase-3 activity, by administering a compound of the invention to in vivo cells or in vitro cells in a warm-blooded animal, in particular a mammal And to the use of the compounds of the invention in inducing or promoting apoptosis.

Another aspect of the invention relates to the use of a compound of the invention for the treatment and prevention of diseases and disorders of the brain and CNS. In particular, the present invention provides methods for treating cancers of the brain and CNS. The present invention also provides a method of reducing the size or slowing the growth of brain neoplasms or improving the survival of patients with tumors of the brain or CNS. The method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of the invention.

Another aspect of the present invention is a method of treating or delaying the onset of tubulin inhibition sensitive diseases and disorders, including but not limited to neoplastic disease (eg cancer), psoriasis, autoimmune diseases and fungal infections. To provide. The method comprises administering a therapeutically effective amount of a compound of the invention to a mammal in need thereof.

Another aspect of the invention is a pharmaceutical useful for treating a disease susceptible to tubulin inhibition and apoptosis induction, containing an effective amount of a compound of the invention, preferably in admixture with one or more pharmaceutically acceptable carriers or diluents. It is to provide a composition.

The above and other advantages and characteristics of the present invention, and the manner in which they are accomplished, will be more readily apparent in view of the following detailed description of the invention, in conjunction with the accompanying examples listing preferred and exemplary embodiments.

Detailed description of the invention

Compounds of the present invention are potent tubulin inhibitors and can also inhibit topoisomerase activity, for example, topoisomerase II-dependent conversion of supercoiled DNA to topoisomer. The compound is a potent yet very efficient activator of caspase cascade, in particular caspase-3, and an inducer of apoptosis. Thus, the compounds are useful for treating diseases and disorders that are sensitive to induction of apoptosis, inhibition of tubulin and / or inhibition of topo isomerase II.

It has now been surprisingly found that compounds of formulas (I)-(III) may be effective in the treatment and / or prevention of diseases and disorders of the brain and CNS by achieving appropriate concentrations in the brain and CNS. In particular, compounds of formulas (I)-(III) can treat diseases of the brain and CNS that are sensitive to treatment by inducing apoptosis, activating caspases, and inhibiting tubulin and / or topoisomerase in the brain. Such diseases include, for example, brain and spinal cord tumors.

Accordingly, the present invention provides a method of inhibiting tubulin in an in vitro cell or in a warm animal, especially a mammal, more particularly a human. As used herein, the term "inhibiting tubulin" means inhibiting polymerization (or assembly) of tubulin monomers or promoting depolymerization of microtubules (ie tubulin degradants). Inhibition of tubulin can be analyzed by methods known in the art.

The present invention also provides a method of inhibiting topoisomerase II in an in vitro cell or in a warm animal, especially a mammal, more particularly a human. The term "inhibiting topoisomerase II" as used herein means inhibiting the activity of the enzyme topoisomerase II in the topoisomerase II-dependent conversion of chocoil DNA to topoisomer. Inhibition of topoisomerase II activity can be assayed by methods known in the art.

The invention also provides a method of activating caspase, in particular caspase-3, and inducing apoptosis in in vitro cells or incubates, especially mammals, more particularly humans. As used herein, the term "activates caspase" means activating or enhancing the enzymatic (protease) activity of caspase (eg, caspase-3), where it occurs intracellularly , Apoptosis or cell death is promoted. The ability of a compound in activating caspases, in particular caspase-3, can be analyzed by the methods provided in Example 61 below. As used herein, the term "inducing apoptosis" means inducing apoptosis in a cell to induce cell death. The ability of a compound to induce apoptosis can be tested by methods known in the art. Also provided are methods for treating or delaying the onset of diseases and disorders that are sensitive to inhibiting tubulin, inhibiting topoisomerase II, activating caspase-3, or inducing apoptosis. Specific examples of such diseases and disorders are provided in detail below.

The various methods described above of the present invention may be carried out or include treatment of in vitro cells or warm-blooded animals, especially mammals, more particularly humans, with an effective amount of a compound according to the invention. As used herein, the phrase “treating with a compound…” refers to the presence or formation of a compound in a cell or animal by administering the compound to a cell or animal, or administering the compound or other agent to a cell or animal. It means to be possible. Preferably, the method comprises administering a pharmaceutical composition comprising an effective amount of a compound according to the invention to an in vitro cell or a warm-blooded animal, in particular a mammal, more particularly a human.

In particular, the methods of the present invention comprise treating an in vitro cell or a warm-blooded animal, especially a mammal, more particularly a human, with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

In Formula I above,

And R ₁ is C _{1 -3} alkyl,

R ₂ is _{halo, R 14, OR 14, SR} 14, NR 15 R 14 or _{NR 14 (C = O) C} 1-6 alkyl (wherein, R ₁₅ is C _{1 -6} alkyl, C _{2 -6} alkenyl, C _{2 -6-alkynyl,} C _{1 -6} haloalkyl, C _{3 -8} carbocycle, C _{3 -8} and heterocyclyl, C _6-10 aryl or alkyl, R ₁₄ is H, C _{1 -6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, a C _{1 -6} haloalkyl, C _{3 -8} carbocycle, C _{3 -8} heterocycle, C _{6 -10} aryl or arylalkyl), and

R ₃ , R ₄ , R ₆ to R ₈ , R ₁₀ to R ₁₃ are independently halo, R ₁₆ , NR ₁₆ R ₁₇ , OR ₁₆ or SR ₁₆ , wherein R ₁₆ and R ₁₇ are independently H, C _{1 -6} alkyl, C _{2 -6} alkenyl is, C _{2 -6-alkynyl} or C _{1 -6} haloalkyl, R ₁₆ and R ₁₇ are not both are H), and

R ₅ is H or C _{1 -3} alkyl,

R ₉ is H, _{halo, R 18, OR 18, SR} 18 or NR ₁₈ R ₁₉ (wherein, R ₁₈ and R ₁₉ are independently H, C _{1 -6} alkyl, C _{2 -6} alkenyl, C _{2 -6} alkynyl is a carbonyl or C _{1 -6} haloalkyl, R ₁₈ and R ₁₉ are both not H), or, and R ₉ optionally form a heterocycle together with one of R ₈ and R _10,

B, D, W, X, Y and Z are independently C or N, at least one of B and D is N, and one or less of W, X, Y and Z is N, B, D, W, X If, Y or Z is N, N has no substituent.

In certain embodiments of compounds of Formula (I), B is C and D is N. In certain embodiments of compounds of Formula (I), B is N and D is C. In certain embodiments of compounds of Formula (I), X or Y is N. In certain embodiments of compounds of Formula (I), W or Z is N.

In a particular embodiment of the compounds of formula (I), R ₂ is preferably C _{1 -3} alkyl, halo, C _{1 -3} alkyl, halo, -OC _1-3 alkyl, -SC _{1 -3} alkyl, C _{3 -8} heterocycle ( is morpholino), NR _2a C _{1 -3 alkyl, NR 2a (C = O)} C 1-3 alkyl or NR _2a (aryl) (wherein, R _2a is H or C _{1 -3} alkyl).

In a further particular embodiment of the compound of formula (I), R ₁ is CH ₃ . In certain embodiments of compounds of Formula (I), R ₅ is H. In a particular embodiment of the compounds of formula (I), R _3, R _4, R ₆ to R _8, R ₁₀ to R ₁₃ are independently H, C _{1 -3} alkyl, halo, NH (C _{1 -3} alkyl), N ( C _{1 -3} alkyl) ₂ or -OC _{1 -3} alkyl.

In certain embodiments of compounds of formula I, R ₉ is H, OH, C _{1 -3} alkyl, halo, C _{1 -3} haloalkyl, -OC _{1 -3} alkyl, -SC _{1 -3} alkyl, -OC _{1 -3} haloalkyl, NR _9a R _9b (wherein, R _9a and R _9b are independently H or C _{1 -3} alkyl, R _9a and R _9b are both not H), or, optionally, R ₈ and R ₉ is R C ₃ together with one of _{10 -8} to form a heterocycle (preferably 1,3-dioxolane).

In certain embodiments of compounds of Formula (I), R ₁ is CH ₂ CH ₃ or CH ₃ , preferably CH ₃ , and R ₂ is CH ₂ CH ₃ , CH ₃ , Cl, CH ₂ F, OCH ₃ , SCH ₃ , Morpholino, NHCH ₃ , NCH ₃ (C═O) CH ₃ or NHCH ₂ C ₆ H ₅ , and R ₃ , R ₄ , R ₆ , R ₁₂ and R ₁₃ are independently H, CH ₃ , Cl, NHCH ₃ , N (CH ₃ ) ₂ or OCH ₃ , R ₅ is H, R ₇ , R ₈ , R ₁₀ and R ₁₁ are independently H, F or OCH ₃ , R ₉ is H, OH, Cl, CH ₃ , CH ₂ CH ₃ , OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ , SCH ₃ , OCF ₃ , OCHF ₂ , OCH (CH ₃ ) ₂ , N (CH ₃ ) ₂ , NHCH _3, or Optionally R ₉ together with one of R ₈ and R ₁₀ form 1,3-dioxolane.

Compounds of formula (I) include compounds according to formula (II) or pharmaceutically acceptable salts or solvates thereof.

In Formula II above,

And R ₁ is C _{1 -3} alkyl,

R ₂ is _{halo, R 14, OR 14, SR} 14, NR 15 R 14 or _{NR 14 (C = O) C} 1-6 alkyl (wherein, R ₁₅ is C _{1 -6} alkyl, C _{2 -6} alkenyl, C _{2 -6-alkynyl,} C _{1 -6} haloalkyl, C _{3 -8} carbocycle, C _{3 -8} and heterocyclyl, C _6-10 aryl or alkyl, R ₁₄ is H, C _{1 -6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, a C _{1 -6} haloalkyl, C _{3 -8} carbocycle, C _{3 -8} heterocycle, C _{6 -10} aryl or arylalkyl), and

R ₃ , R ₄ , R ₆ to R ₈ , R ₁₀ and R ₁₁ are independently halo, R ₁₆ , NR ₁₆ R ₁₇ , OR ₁₆ or SR ₁₆ , wherein R ₁₆ and R ₁₇ are independently H, C _{1 -6} alkyl, C _{2 -6} alkenyl is, C _{2 -6-alkynyl} or C _{1 -6} haloalkyl, R ₁₆ and R ₁₇ are not both are H), and

R ₅ is H or C _{1 -3} alkyl,

R ₉ is H, _{halo, R 18, OR 18, SR} 18 or NR ₁₈ R ₁₉ (wherein, R ₁₈ and R ₁₉ are independently H, C _{1 -6} alkyl, C _{2 -6} alkenyl, C _{2 -6} alkynyl is a carbonyl or C _{1 -6} haloalkyl, R ₁₈ and R ₁₉ are both not H), or, and R ₉ optionally form a heterocycle together with one of R ₈ and R _10,

W, X, Y and Z are independently C or N, one or less of W, X, Y and Z is N, and there is no substituent in N when W, X, Y or Z is N.

In certain embodiments of compounds of Formula (II), X or Y is N. In certain embodiments of compounds of Formula (II), W or Z is N.

In certain embodiments of compounds of formula II, R ₂ is preferably C _{1 -3} alkyl, halo, C _{1 -3} alkyl, halo, -OC _1-3 alkyl, -SC _{1 -3} alkyl, C _{3 -8} heterocycle ( is morpholino), NR _2a C _{1 -3 alkyl, NR 2a (C = O)} C 1-3 alkyl or NR _2a (aryl) (wherein, R _2a is H or C _{1 -3} alkyl).

In a further particular embodiment of the compound of formula II, R ₁ is CH ₃ . In certain embodiments of compounds of Formula (II), R ₅ is H. In certain embodiments of compounds of formula II, R _3, R _4, R ₆ to R _8, R ₁₀ and R ₁₁ are independently H, C _{1 -3} alkyl, halo, NH (C _{1 -3} alkyl), N ( C _{1 -3} alkyl) ₂ or -OC _{1 -3} alkyl.

In certain embodiments of compounds of formula II, R ₉ is H, OH, C _{1 -3} alkyl, halo, C _{1 -3} haloalkyl, -OC _{1 -3} alkyl, -SC _{1 -3} alkyl, -OC _{1 -3} haloalkyl, NR _9a R _9b (wherein, R _9a and R _9b are independently H or C _{1 -3} alkyl, R _9a and R _9b are both not H), or, optionally, R ₈ and R ₉ is R C ₃ together with one of _{10 -8} to form a heterocycle (preferably 1,3-dioxolane).

In certain embodiments of compounds of Formula (II), R ₁ is CH ₂ CH ₃ or CH ₃ , preferably CH ₃ , and R ₂ is CH ₂ CH ₃ , CH ₃ , Cl, CH ₂ F, OCH ₃ , SCH ₃ , Morpholino, NHCH ₃ , NCH ₃ (C═O) CH ₃ or NHCH ₂ C ₆ H ₅ , R ₃ , R ₄ And R ₆ is independently H, CH ₃ , Cl, NHCH ₃ , N (CH ₃ ) ₂ or OCH ₃ , R ₅ is H, and R ₇ , R ₈ , R ₁₀ and R ₁₁ are independently H, F Or OCH ₃ , R ₉ is H, OH, Cl, CH ₃ , CH ₂ CH ₃ , OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ , SCH ₃ , OCF ₃ , OCHF ₂ , OCH (CH ₃ ) ₂ , N (CH ₃ ) ₂ , NHCH _3, or optionally R ₉ together with one of R ₈ and R ₁₀ form 1,3-dioxolane.

Another group of compounds of formula I include the compounds according to formula III or pharmaceutically acceptable salts or solvates thereof.

In Formula III above,

And R ₁ is C _{1 -3} alkyl,

R ₂ is _{halo, R 15, OR 14, SR} 14, NR 15 R 14 or _{NR 14 (C = O) C} 1-6 alkyl (wherein, R ₁₅ is C _{1 -6} alkyl, C _{2 -6} alkenyl, C _{2 -6-alkynyl,} C _{1 -6} haloalkyl, C _{3 -8} carbocycle, C _{3 -8} and heterocyclyl, C _6-10 aryl or alkyl, R ₁₄ is H, C _{1 -6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, a C _{1 -6} haloalkyl, C _{3 -8} carbocycle, C _{3 -8} heterocycle, C _{6 -10} aryl or arylalkyl), and

R ₃ , R ₄ , R ₆ to R ₈ , R ₁₀ and R ₁₁ are independently halo, R ₁₆ , NR ₁₆ R ₁₇ , OR ₁₆ or SR ₁₆ , wherein R ₁₆ and R ₁₇ are independently H, C _{1 -6} alkyl, C _{2 -6} alkenyl is, C _{2 -6-alkynyl} or C _{1 -6} haloalkyl, R ₁₆ and R ₁₇ are not both are H), and

R ₅ is H or C _{1 -3} alkyl,

R ₉ is H, _{halo, R 18, OR 18, SR} 18 or NR ₁₈ R ₁₉ (wherein, R ₁₈ and R ₁₉ are independently H, C _{1 -6} alkyl, C _{2 -6} alkenyl, C _{2 -6} alkynyl is a carbonyl or C _{1 -6} haloalkyl, not the R ₁₈ and R ₁₉ are both H), or, R ₉ optionally may form a heterocycle together with R ₈ and R ₁₀ one.

In certain embodiments of compounds of Formula III, R ₂ is preferably C _{1 -3} alkyl, halo, C _{1 -3} alkyl, halo, -OC _1-3 alkyl, -SC _{1 -3} alkyl, C _{3 -8} heterocycle ( is morpholino), NR _2a C _{1 -3 alkyl, NR 2a (C = O)} C 1-3 alkyl or NR _2a (aryl) (wherein, R _2a is H or C _{1 -3} alkyl).

In a further particular embodiment of the compound of formula III, R ₁ is CH ₃ . In certain embodiments of compounds of Formula III, R ₅ is H. In certain embodiments of compounds of Formula III, R _3, R _4, R ₆ to R _8, R ₁₀ and R ₁₁ are independently H, C _{1 -3} alkyl, halo, NH (C _{1 -3} alkyl), N ( C _{1 -3} alkyl) ₂ or -OC _{1 -3} alkyl.

In certain embodiments of the addition of the compound of formula III, R ₉ is H, OH, C _{1 -3} alkyl, halo, C _{1 -3} haloalkyl, -OC _{1 -3} alkyl, -SC _{1 -3} alkyl, -OC _{1 -3} haloalkyl, NR _9a R _9b (wherein, R _9a and R _9b are independently H or C _{1 -3} alkyl, and not the R _9a and R _9b are both H), or, optionally, R ₉ is R ₈ and R ₁₀ forms a C _{3 -8} heterocycle (preferably 1,3-dioxolane), with one of the.

In certain embodiments of compounds of Formula III, R ₁ is CH ₂ CH ₃ or CH ₃ , preferably CH ₃ , and R ₂ is CH ₂ CH ₃ , CH ₃ , Cl, CH ₂ F, OCH ₃ , SCH ₃ , Morpholino, NHCH ₃ , NCH ₃ (C═O) CH ₃ or NHCH ₂ C ₆ H ₅ , R ₃ , R ₄ And R ₆ is independently H, CH ₃ , Cl, NHCH ₃ , N (CH ₃ ) ₂ or OCH ₃ , R ₅ is H, and R ₇ , R ₈ , R ₁₀ and R ₁₁ are independently H, F Or OCH ₃ , R ₉ is H, OH, Cl, CH ₃ , CH ₂ CH ₃ , OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ , SCH ₃ , OCF ₃ , OCHF ₂ , OCH (CH ₃ ) ₂ , N (CH ₃ ) ₂ , NHCH _3, or optionally R ₉ together with one of R ₈ and R ₁₀ form 1,3-dioxolane.

In another specific embodiment of compounds of Formula (III), R ₁ is CH ₃ , R ₂ is CH ₃ , Cl, OCH ₃ , NHCH ₃ or NCH ₃ (C═O) CH ₃ , and R ₃ to R ₆ , R ₇ , R ₈ , R ₁₀ and R ₁₁ are H and R ₉ is OCH ₃ , N (CH ₃ ) ₂ or NHCH ₃ .

In various embodiments of the method, preferably when R ₉ is H, R ₈ and R ₁₀ are not both H or one is H and the other is halo. Further, in the various embodiments described above, preferably when R ₉ is H, R ₈ and R ₁₀ are not both H or one is H and the other is halo, alkyl or haloalkyl. If the above-described various aspects, preferably, R9 is a C _1-6 alkyl, halo, or C _1-6 haloalkyl, R ₂ is not H. In addition, in the various embodiments described above, preferably when R ₉ is H, R ₈ and R ₁₀ are not both H or one is H and the other is halo and R ₂ is not H.

In various embodiments of the aforementioned methods of the invention, preferably the compounds administered by the methods of the invention are preferably at most 1,000 nM, as measured under the methods and conditions described in Example 61 (24 hour measurement) Caspase activation can be induced at an EC ₅₀ of preferably about 500 nM or less, even more preferably about 200 nM or less, more preferably about 100 nM or less, more preferably about 50 nM or less and most preferably about 10 nM or less. have. In the method of the present invention described above, tubulin can be suppressed at IC ₅₀ of about 2,000 nM or less, more preferably about 1,000 nM or less and most preferably less than about 500 nM, as measured by methods known in the art. Preferred are compounds of the formulas (I) to (III) and pharmaceutically acceptable salts or solvates thereof.

In certain embodiments of the aforementioned methods of the invention, the brain / plasma AUC measured under the methods and conditions described in Example 62 is at least about 5, preferably at least about 10, more preferably at least about 15 Preferred are compounds and pharmaceutically acceptable salts or solvates thereof.

Exemplary compounds useful in the methods of the invention are the compounds provided in Examples 1-60 and pharmaceutically acceptable salts or prodrugs thereof. Specific exemplary compounds include, but are not limited to the following compounds:

(2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine;

(2-chloro-quinazolin-4-yl)-(4-methyl-phenyl) -methyl-amine;

(2-chloro-quinazolin-4-yl)-(4-chloro-phenyl) -methyl-amine;

(2-Chloro-quinazolin-4-yl)-(4-trifluoromethoxy-phenyl) -methyl-amine;

(4-methoxy-phenyl) -methyl- (2-morpholin-4-yl-quinazolin-4-yl) -amine;

(2-Chloro-quinazolin-4-yl) -ethyl- (4-methoxy-phenyl) -amine;

(2-Chloro-quinazolin-4-yl)-(2,4-dimethoxy-phenyl) -methyl-amine;

(2-Chloro-quinazolin-4-yl)-(3-methoxy-phenyl) -methyl-amine;

(2-methoxy-quinazolin-4-yl)-(4-methoxyphenyl) -methylamine;

(2-fluoromethyl-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine;

(2-Chloro-6-methyl-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine;

(2-Chloro-5-methyl-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine;

(2-Chloro-8-methyl-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine;

(2,6-dichloro-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine;

(4-methoxy-phenyl) -methyl- (quinolin-4-yl) -amine;

(2-chloro-quinazolin-4-yl)-(3,4-methylenedioxyphenyl) -methyl-amine;

(2-Chloro-quinazolin-4-yl)-(3,4-dimethoxy-phenyl) -methyl-amine;

(2-Chloro-quinazolin-4-yl)-(4-propoxy-phenyl) -methyl-amine;

(4-methoxy-phenyl) -methyl- (2-methyl-quinazolin-4-yl) -amine hydrochloride;

(2-ethyl-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine;

(2-Chloro-quinazolin-4-yl)-(2,3-dimethoxy-phenyl) -methyl-amine;

(4-difluoromethoxy-phenyl)-(2-methyl-quinazolin-4-yl) -methyl-amine;

(3-fluoro-4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl) -methyl-amine;

(4-isopropoxy-phenyl)-(2-methyl-quinazolin-4-yl) -methyl-amine;

(4-ethyl-phenyl)-(2-methyl-quinazolin-4-yl) -methyl-amine;

(2,8-dichloro-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine;

(2,5-dichloro-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine;

(5-methoxy-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine;

(2-chloro-quinazolin-4-yl)-(4-ethoxy-phenyl) -methylamine;

(2-Methyl-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl) -methyl-amine;

(2-Fluoro-4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl) -methyl-amine;

(4-dimethylamino-phenyl)-(2-methyl-quinazolin-4-yl) -methyl-amine;

(4-ethoxy-phenyl)-(2-methyl-quinazolin-4-yl) -methyl-amine;

(2-methylthio-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine;

(2-methylamino-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine;

(2-methylamino-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl) -methyl-amine;

(5-methoxy-pyridin-2-yl)-(2-methyl-quinazolin-4-yl) -methyl-amine;

(2-benzylamino-quinazolin-4-yl)-(4-methoxyphenyl) -methylamine;

(2-methyl-quinazolin-4-yl)-(4-methylamino-phenyl) -methylamine;

(2-chloro-quinazolin-4-yl)-(4-dimethylaminophenyl) -methylamine;

(2-methylamino-quinazolin-4-yl)-(4-dimethylaminophenyl) -methylamine;

[2- (N-Methyl-acetamido) -quinazolin-4-yl]-(4-dimethylaminophenyl)-methylamine;

(4-methylthio-phenyl)-(2-methyl-quinazolin-4-yl) -methylamine;

(2-dimethylamino-pyridin-5-yl)-(2-methyl-quinazolin-4-yl) -methylamine;

(4-methoxy-phenyl)-(2-N-methylacetamido-quinazolin-4-yl) -methylamine;

(6-dimethylamino-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl) -methylamine;

(2-Chloro-quinazolin-4-yl) -phenyl-methyl-amine;

(2-Chloro-quinazolin-4-yl) -phenyl-methyl-amine;

(2-chloro-quinazolin-4-yl)-(2,5-dimethoxy-phenyl) -methyl-amine;

(2-Chloro-quinazolin-4-yl)-(2-methoxy-phenyl) -methyl-amine;

(2-chloro-quinazolin-4-yl)-(4-hydroxyphenyl) -methyl-amine;

(2,7-dichloro-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine;

(2-chloro-7-methyl-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine; And

Pharmaceutically acceptable salts or solvates thereof.

Unless stated otherwise or indicated by a line symbol (dashed or doublet), the point of connection to the mentioned group will be at the far right of the mentioned group. Thus, for example, hydroxyalkyl groups are linked to the main structure via alkyl and hydroxyl is a substituent on the alkyl.

The term "alkyl" as used herein, by itself or as part of another group, refers to both straight and branched chain radicals having up to 10 carbon atoms. Useful alkyl groups include straight chain and branched chain C _{1 -10} alkyl group, more preferably a C _{1 -6} alkyl group. Typical, and C _{1 -10} alkyl group may include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, 3-pentyl, hexyl, and octyl groups, which may optionally be substituted.

The term "alkenyl" as used herein, as such or as part of another group, refers to a straight chain of 2 to 10 carbon atoms that includes one or more double bonds between two carbon atoms of the chain, unless the chain length is limited thereto. Or branched radicals. Typical alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl.

As used herein, the term "alkynyl" refers to a straight or branched chain radical of 2 to 10 carbon atoms in which one or more triple bonds are present between two carbon atoms of the chain, unless the chain length is limited thereto. Typical alkynyl groups include ethynyl, 1-propynyl, 1-methyl-2-propynyl, 2-propynyl, 1-butynyl and 2-butynyl.

Useful alkoxy groups optionally include oxygen substituted by one of the above C _{1 -10} alkyl group which may be substituted. Alkoxy substituents include, but are not limited to, carboxy including halo, morpholino, amino, including alkylamino and dialkylamino, and esters thereof.

Useful alkylthio groups are optionally substituted by one of the sulfur a C _{1 -10} alkyl group which may be substituted. Also included are sulfoxides and sulfones of such alkylthio groups.

Useful amino groups include -NH ₂ , -NHR _x and -NR _x R _y , wherein R _x and R _y are C _1-10 alkyl or cycloalkyl groups, or R _x and R _y are ring together with N Structures, such as piperidine, or R _x and R _y together with N and other groups, form a ring, such as piperazine. Alkyl groups may be optionally substituted.

Any substituent on an alkyl, alkenyl, alkynyl, cycloalkyl, carbocyclic and heterocyclic group is one or more halo, hydroxy, carboxyl, amino, nitro, cyano, C ₁ -C ₆ acylamino, C ₁ -C ₆ acyloxy, C ₁ -C ₆ alkoxy, aryloxy, alkylthio, C ₆ -C ₁₀ aryl, C ₄ -C ₇ cycloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₆ -C ₁₀ aryl (C ₂ -C ₆ ) alkenyl, C ₆ -C ₁₀ aryl (C ₂ -C ₆ ) alkynyl, saturated and unsaturated heterocyclic or heteroaryl.

Any substituent on aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, and heteroarylalkyl phases may include one or more halo, C ₁ -C ₆ haloalkyl, C ₆ -C _1O aryl, C ₄ -C ₇ cyclo Alkyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₆ -C ₁₀ aryl (C ₁ -C ₆ ) alkyl, C ₆ -C ₁₀ aryl (C _2- C ₆ ) alkenyl, C ₆ -C ₁₀ aryl (C ₂ -C ₆ ) alkynyl, C ₁ -C ₆ hydroxyalkyl, nitro, amino, ureido, cyano, C ₁ -C ₆ acylamino, hydroxy hydroxy, thiol, C ₁ -C ₆ acyloxy, azido, C ₁ -C ₆ alkoxy, carboxy, or C _{1 -2} alkylenedioxy (e.g., methylenedioxy) includes.

The term "aryl" as used herein, by itself or as part of another group, refers to a monocyclic, bicyclic or tricyclic aromatic group having 6 to 14 carbon atoms in the ring portion.

Useful aryl groups include C _{6 -14} aryl, preferably C _{6 -10} aryl group. Typical C _{6 -14} aryl groups include phenyl, naphthyl, phenanthrenyl, anthracenyl, indenyl, azulenyl, biphenyl, biphenyl and fluorenyl alkylenyl group.

The term "carbocycle" as used herein includes cycloalkyl and partially saturated carbocyclic groups. Useful cycloalkyl groups are C _{3 -8} cycloalkyl. Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Useful saturated or partially saturated carbocyclic groups are cycloalkenyl groups, for example cyclopentenyl, cycloheptenyl and cyclooctenyl, as well as cycloalkyl groups as described above.

Useful halo or halogen groups include fluorine, chlorine, bromine and iodine.

The term "arylalkyl" as used herein means the above-mentioned C _{1 -10} alkyl group substituted by the above C _{6 -14} aryl group. Preferably, the arylalkyl group is benzyl, phenethyl or naphthylmethyl.

The term "arylalkenyl" as used herein means the aforementioned C _{2 -10} alkenyl group substituted by the above C _{6 -14} aryl group.

The term "arylalkynyl" as used herein means the aforementioned C _{2 -10} alkynyl groups substituted by the above C _{6 -14} aryl group.

As used herein, "aryloxy" refers to an oxygen substituted by the above C _{6 -14} aryl group which may be optionally substituted. Useful aryloxy groups include phenoxy and 4-methylphenoxy.

The term "arylalkoxy" as used herein optionally refers to the above-mentioned C _{1 -10} alkenyl groups substituted by the above aryl group which may be substituted. Useful arylalkoxy groups include benzyloxy and phenethyloxy.

Useful haloalkyl groups include one or more fluorine, chlorine, bromine or iodine atoms substituted C _{1 -10} alkyl group, e.g., methyl, tri-fluoro-fluoro-methyl, difluoro-methyl, pentafluoroethyl, 1, 1 -Difluoroethyl, chloromethyl, chlorofluoromethyl and trichloromethyl groups.

Useful acylamino (acyl amido) group is bonded to the amino nitrogen, C _{1 -6-acyl} (alkanoyl), for example, acetamido, chloro, acetamido, propionamide amido, amido butanoyl, pentanoyl amino road and hexanoyl amido, as well as aryl-substituted C _{1 -6} acylamino group, e.g., benzoyl-amido-pentafluoropropane and a benzoyl amido.

Useful acyloxy groups are oxy (-O-) bonded to the group C _{1 -6-acyl} (alkanoyl), for example, formyl oxy, acetoxy, propionyl Ono yloxy, oxy butanoyl, pentanoyl and hexanoyl oxy Oxy.

As used herein, the term heterocycle is a saturated or partially saturated 3-7 membered monocyclic or 7-10 membered bicyclic ring system, wherein they are independently selected from the group consisting of carbon atoms and O, N and S Consisting of 1 to 4 heteroatoms, nitrogen and sulfur heteroatoms may be optionally oxidized and nitrogen may be optionally quaternized), wherein the heterocyclic ring as defined above is a cyclic group fused to the benzene ring And an oxo substituent ("= O") in which two hydrogen atoms are replaced, so that the heterocyclic ring may be substituted on a carbon atom or a nitrogen atom when the resultant compound is stable.

Useful saturated or partially saturated heterocyclic groups include tetrahydrofuranyl, pyranyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuklye Diyl, morpholinyl, isochromenyl, chromanyl, pyrazolidinyl, pyrazolinyl, tetronoyl and tetramoyl groups.

The term "aryl" as used herein, by itself or as part of another group, refers to a monocyclic, bicyclic or tricyclic aromatic group having 6 to 14 carbon atoms in the ring portion.

Useful aryl groups include C _{6 -14} aryl, preferably C _{6 -10} aryl group. Typical C _{6 -14} aryl groups include phenyl, naphthyl, phenanthrenyl, anthracenyl, indenyl, azulenyl, biphenyl, biphenyl and fluorenyl alkylenyl group.

As used herein, "arylalkyl" means the above-mentioned C _{1 -10} alkyl group substituted by the above C _{6 -14} aryl group. Preferably the arylalkyl group is benzyl, phenethyl or naphthylmethyl.

The term "heteroaryl" as used herein has 5 to 14 ring atoms and 6, 10 or 14π electrons shared in a cyclic arrangement and contains carbon atoms and 1, 2 or 3 oxygen, nitrogen or sulfur heteroatoms. It shows a group.

Useful heteroaryl groups include thienyl (thiophenyl), benzo [b] thienyl, naphtho [2,3-b] thienyl, thianthrenyl, furyl (furanyl), isobenzofuranyl, cromenyl, Pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl and 4-pyridyl, including but not limited to, santenyl, phenoxanthyl, 2H-pyrrolyl Dill (pyridinyl), pyrazinyl, pyrimidinyl, pyridazinyl, indolinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, furinyl, 4H-quinolinzylyl, isoquinolyl, qui Nolyl, phthalinyl, naphthyridinyl, quinozalinyl, cinnolinyl, putridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridininyl, perimidinyl, phenanthrolinyl, phenazinyl, iso Thiazolyl, phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl, 1,4-dihydroquinoxaline-2,3-dione, 7-aminoisocoumarin, pyrido [1,2-a] pyrimidine -4- Pyrazolo [1,5-a] pyrimidinyl, 1,2-benzisoxazol-3-yl, benzimi, including but not limited to pyrazolo [1,5-a] pyrimidin-3-yl Dazolyl, 2-oxindoleyl and 2-oxobenzimidazolyl. If the heteroaryl group contains nitrogen atoms in the ring, these nitrogen atoms may be present in the form of N-oxides, for example pyridyl N-oxides, pyrazinyl N-oxides and pyrimidinyl N-oxides.

As used herein, the term “heteroaryloxy” refers to oxygen substituted with one of the heteroaryl groups described above, which may be optionally substituted. Useful heteroaryl oxy groups include pyridyloxy, pyrazinyloxy, pyrrolyloxy, pyrazolyloxy, imidazolyloxy and thiophenyloxy.

As used herein, "heteroaryl alkoxy" means the above-mentioned C _{1 -10} alkoxy group substituted by a, which may be optionally substituted with the above-described, a heteroaryl group.

The present invention also provides novel compounds that are potent tubulin inhibitors, topoisomerase II inhibitors, caspase-3 activators and / or apoptosis inducers / promoter. In particular, the novel compounds of the present invention are compounds of formulas (I) to (III) and pharmaceutically acceptable salts or solvates thereof.

Some of the compounds of the present invention may exist as stereoisomers, including optical isomers. The present invention encompasses all stereoisomers and racemic mixtures of such stereoisomers as well as individual enantiomers that can be separated by methods well known to those of ordinary skill in the art.

Examples of pharmaceutically acceptable addition salts of the compounds of the invention include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, phosphate, sulfates, citrate, lactates, tartrates, maleates, fumarates, Mandelate and oxalate; And inorganic and organic base addition salts with salts such as sodium hydroxy, tris (hydroxymethyl) aminomethane (TRIS, tromethane) and N-methyl-glucamine.

Simple esters of examples of prodrugs of the compounds of the invention are the carboxylic acid-containing compound (for example, the one obtained by condensation of an alcohol with C _{1 -4} according to the methods known in the art), the hydroxyl-containing compound esters (e.g., C _{1 -4-carboxylic} acid, the one obtained by the condensation of the C _{3 -6} video acid or its anhydride, e.g., succinic anhydride and fumaric anhydrides according to methods known in the art), imine of an amino containing compounds (e. g., obtained by the condensation of a C _{1 -4} aldehydes or ketones according to the methods known in the art), for a carbamate, for example, the amino-containing compound, described in reference ; Leu, et. acetal and alcohol-containing compounds as described in al., (J. Med. Chem. 42: 3623-3628 (1999) and Greenwald, et. al, (J Med. Chem. 42: 3657-3667 (1999)) and Ketals (eg, those obtained by condensation with chloromethyl methyl ether or chloromethyl ethyl ether according to methods known in the art).

Compounds of the present invention can be prepared using methods known to those skilled in the art or novel methods of the present invention. Specifically, compounds of formulas (I)-(III) of the present invention may be prepared as shown by the exemplary reactions of Scheme 1. Reaction of an optionally substituted quinazoline-2,4-dione with phosphorylchloride yields the corresponding 2,4-dichloroquinazolin, which is optionally substituted aniline, for example N-methyl-4-methoxy React with aniline to produce a substituted 2-chloro-4-anilino-quinazolin.

Compounds of formulas (I)-(III) of the present invention may also be prepared as shown by the exemplary reaction of Scheme 2. 2-anicleophile-substituted 4-anilino-quina by reaction of 2-chloro-4-anilino-quinazolin substituted in isopropanol heated by microwaves with a nucleophile (R ₂ ), for example hydroxylamine Sleepy, for example, substituted hydroxylamino is produced. Other nucleophiles that can be used in the reaction include NaOMe, NaN ₃ , NaSMe, NH ₃ , NH ₂ Me or NHMe ₂ , and the reaction can be carried out at room temperature or at elevated temperature.

Compounds of formulas (I)-(III) of the present invention may be prepared as shown by the exemplary reaction of Scheme 3. 2,4-dichloroquinazolin is reacted with substituted arylamines or heteroarylamines, for example substituted pyridin-3-ylamines to produce the corresponding 4-aryl / heteroarylamino substituted 2-chloro-quinazolins Resulting in alkylation with haloalkyl, for example methylation by reaction with methyl iodide in the presence of a base such as NaH to give the corresponding 4-N-methyl-aryl / heteroaryl-amino substituted 2-chloro Produces quinazoline

Alternatively, compounds of formulas (I)-(III) of the present invention may be prepared as shown by the exemplary reactions of Scheme 4. N-alkyl-arylamines or N-alkyl-heteroarylamines can be prepared by reaction of arylamines or heteroarylamines with ketones or aldehydes in the presence of a reducing agent, for example NaCNBH ₃ . N-alkyl-arylamine or N-alkyl-heteroarylamine is then reacted with an optionally substituted 2,4-dichloroquinazolin to produce the corresponding 4-substituted 2-chloro-quinazolin.

Compounds of formulas (I)-(III) of the present invention may also be prepared as shown by the exemplary reaction of Scheme 5. An optionally substituted 2-amino-benzoic acid such as 2-amino-5-methyl-benzoic acid is reacted with potassium cyanate in the presence of an acid such as acetic acid to produce the corresponding optionally substituted quinazoline-2,4-dione, For example, 6-methyl-quinazolin-2,4-dione is produced and reacted with phosphorylchloride to produce the corresponding optionally substituted 2,4-dichloroquinazolin, for example 6-methyl-2, Convert to 4-dichloroquinazoline. Optionally substituted 2,4-dichloroquinazolin, for example 6-methyl-2,4-dichloroquinazolin, substituted arylamine or heteroarylamine, for example N-methyl-4-methoxy-aniline With a corresponding 4-substituted 2-chloro-quinazolin, for example substituted 2-chloro-4-anilino-quinazolin.

Compounds of formulas (I)-(III) of the present invention, wherein R ₂ is an optionally substituted alkyl group, can be prepared as shown by the exemplary reaction of Scheme 6. 2-amino-benzoic acid methyl ester is reacted with an optionally substituted acetonitrile, such as fluoro-acetonitrile, in the presence of HCl to give the corresponding 2-substituted quinazolin-4 (3H) -one, for example To produce 2-fluoromethyl-quinazolin-4 (3H) -one, which is reacted with phosphorylchloride to give a 2-substituted 4-chloro-quinazolin, for example 4-chloro-2-fluoromethyl Convert to quinazoline. 2-substituted 4-chloro-quinazolin, for example 4-chloro-2-fluoromethyl-quinazolin, is reacted with a substituted aniline, for example N-methyl-4-methoxy-aniline To a 2-substituted 4-anilino-quinazolin, for example, 2-fluoromethyl-4-anilino-quinazolin. Other substituted acetonitriles that can be used in the reaction include chloro-acetonitrile and bromo-acetonitrile, as well as acetonitrile and propionitrile.

Compounds of formulas (I)-(III) of the present invention, wherein R ₂ is a substituted alkyl group, can be prepared as shown by the exemplary reaction of Scheme 7. Substituted 2-chloroalkyl-4- (N-alkyl-arylamine or N-alkyl-heteroarylamine) -quinazolin, for example N-methyl-2-chloromethyl-4-anilino-quinazolin Reaction with a nucleophile, such as NHMe ₂ , yields substituted 2-dimethylaminomethyl-4-anilino-quinazolin. Other nucleophiles that can be used in the reaction include NaOMe, NaN ₃ , NaSMe, NH ₃ , NH ₂ Me or NHMe ₂ , and the reaction can be carried out at room temperature and elevated temperature.

Compounds of formulas (I)-(III) of the present invention, wherein R ₂ is a substituted alkyl group, can be prepared as shown by the exemplary reaction of Scheme 8. For example, optionally substituted 4- (arylamine or heteroarylamine) -quinazolin, for example 2-methyl-4- (6-methoxy-pyridin-3-ylamino) -quinazolin, For example, by reacting with a substituted haloalkyl, for example difluoromethyl chloride in the presence of NaH, the corresponding 4- (N-alkyl-arylamine or N-alkyl-heteroarylamine) -quinazolin, eg For example, 2-methyl-N ⁴ -difluoromethyl-4- (4-methoxy-pyridin-3-ylamino) -quinazolin is produced.

Compounds of formulas (I)-(III) of the present invention, wherein R ₂ is an alkyl group, can be prepared as shown by the exemplary reaction of Scheme 9. Substituted 2-amino-benzoic acid, such as 2-amino-5-nitro-benzoic acid, is reacted with acetic anhydride to give the corresponding substituted 2-methyl-4H-benzo [d] [1,3] oxazine-4 -One, for example 2-methyl-6-nitro-4H-benzo [d] [1,3] oxazin-4-one, which is treated with ammonia in dioxane to give the corresponding quinazoline-4 (3H) -one, for example 2-methyl-6-nitro-quinazolin-4 (3H) -one. The compound is then reacted with phosphorylchloride to convert to the corresponding 4-chloro-quinazoline, for example 4-chloro-2-methyl-6-nitro-quinazoline. 4-chloro-quinazolin, for example 4-chloro-2-methyl-6-nitro-quinazolin, with substituted arylamines or heteroarylamines, for example N-methyl-4-methoxy-aniline Reaction yields the corresponding 4- (arylamino or heteroarylamino) -quinazolin, eg substituted 2-methyl-6-nitro-4-anilino-quinazolin. Other substituted 2-amino-benzoic acids that can be used in the reaction include 2-amino-4-nitro-benzoic acid, 2-amino-5-chloro-benzoic acid.

Compounds substituted with nitro groups can be reduced by hydrogenation under H ₂ with Pd to produce amino compounds, which can be diazotized and then treated with NaN ₃ to convert to azido compounds.

Additional exemplary compounds can be synthesized according to the following synthetic schemes.

Compounds of formulas I to III are activators of caspases and inducers of apoptosis. The compounds of formulas I to III are also inhibitors of tubulin polymerization. Thus, these compounds are useful for treating diseases susceptible to activating caspases, inducing apoptosis, or inhibiting tubulin. For example, these compounds are useful in various clinical conditions where there is unregulated cell growth and proliferation of abnormal cells, such as in the case of cancer.

Another important aspect of the present invention is the surprising finding that the compounds of formulas (I)-(III) may be effective in treating and / or preventing diseases and disorders of the brain and CNS by moderate exposure to the brain and CNS. In particular, the present invention includes methods for treating diseases of the brain and CNS that are sensitive to treatment by inducing apoptosis in the brain, activating caspases, and inhibiting tubulin and / or topoisomerase. Such diseases include, for example, brain and spinal cord tumors.

Brain tumors can generally be classified as primary brain tumors or metastatic brain tumors. Brain tumors are often further classified by cell type, morphology, cytogenetics, molecular genetics, immunological markers and / or combinations thereof. For example, brain tumors include neuroepitheliomas (e.g., glioma, neuronal neuronal-glial mixed tumors and non-glioma), meningiologic tumors, embryonic cell tumors, saddle tumors, primary CNS lymphomas, Tumors of peripheral nerves affecting the CNS, tissue origins can be classified as uncertain tumors and metastatic tumors. Classification of brain tumors by the World Health Organization classifies CNS tumors according to their malignancy based on the histological properties of the tumors. Kleihues et al., Brain Pathol 3: 255-268 (1993).

The most common types of primary brain tumors are anaplastic astrocytoma and glioblastoma, which account for approximately 38% of primary brain tumors, and meningiomas and other mesenchymal tumors, which account for approximately 27% of primary brain tumors. Levin et al., Neoplasms of the central nervous system. In DeVita, et al., Eds., Cancer: Principles and Practice of Oncology, Sixth Edition, Lippincott Williams & Wilkins, Philadelphia (2001), pp. 2100-2160. Other common primary brain tumors include pituitary tumors, schwannomas, CNS lymphomas, oligodendrocytes, ventricular cell tumors, low grade astrocytomas and medulloblastomas. Additional specific primary brain tumors include astocytic tumors, hematopoietic astrocytomas, diffuse astrocytomas, polymorphic astrocytomas, sub- and subcellular giant astrocytomas, oligodendrogliomas, olodendrogliomas, anaplastic Glioblastoma, oligoastrocytomas, anaplastic oligodendrocytes, myxed papillary stromal cysts, subcellular cell tumors, superplastic cell tumors, anaplastic astrocytomas, astrocytomas, tertiary ventricular gliomas, cerebral neuroglioma, ganglion Hematoma, connective tissue-forming infantile astrocytoma, connective tissue-forming infantile glioma, degenerative neuroepithelioma, central neurocytoma, cerebellar liponeurocytomas, paraneurocytomas, epidermoblastoma, medulloblastoma, primitive upper extremity nerve Ectoderm tumor, choroid plexus tumor, pineal tumor, pineal blastoma, pineal parenchymal tumor of intermediate differentiation intermediate differentiation), hemangiopericytoma, melanocyte-like lesions, embryonic cell tumors, saddle tumors, craniocytoma, capillary blastoma and primary CNS lymphoma.

Metastatic brain tumors overwhelm primary brain tumors at least 10 to 1 and typically arise as a result of primary lung cancer, breast cancer, melanoma or colon cancer metastasizing to the brain. Patchell RA, Cancer Treat. Rev. 29: 533-540 (2003). Cancer that has metastasized to the brain causes multiple brain metastases in at least 70% of cases [see literature; Patchell RA, Cancer Treat. Rev. 29: 533-540 (2003). Thus, they are typically not treated by surgery. However, chemotherapy has been shown to play a role in treating patients with brain metastases from tumors sensitive to chemotherapy. Patchell RA, Cancer Treat. Rev. 29: 533-540 (2003). Accordingly, the present invention includes a method of treating brain cancer, including primary brain neoplasia and brain metastases, comprising administering to a animal an effective amount of a compound of Formulas I-III or a pharmaceutically acceptable salt or prodrug thereof .

In one aspect, the invention provides a method of reducing the size of brain neoplasia or delaying growth. Reduction of neoplasm size and / or growth can be measured by the Response Evaluation Criteria in Solid Tumors Guidelines. Therasse et al., J. Nat. Cancer Institute 92: 205-216 (2000), which is incorporated herein by reference in its entirety. For example, the method identifies less than 5 lesions per organ and a total of 10 lesions and measures the average size of lesions in patients as measured 4 weeks after treatment by measuring the decrease in length at the longest diameter of the lesion. Can be reduced by about 30%. In another aspect, the present invention provides a method of improving survival of a patient suffering from or at risk of forming a brain tumor. The method comprises administering a therapeutically effective amount of a compound of the invention to a mammal in need thereof.

The present invention also encompasses a method of treatment comprising administering to an animal an effective amount of a compound of Formulas I-III or a pharmaceutically acceptable salt or prodrug thereof, wherein the method comprises uncontrolled growth of abnormal cells. And cancer, a group of diseases characterized by proliferation. These diseases include Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, Wilms' tumor, cervical cancer, testicular cancer, soft tissue. Sarcoma, primary megaglobulinemia, bladder cancer, chronic granulocytic leukemia, primary brain cancer, malignant melanoma, small cell lung cancer, gastric cancer, colon cancer, malignant pancreatic insulinoma, malignant carcinoid carcinoma, chorionic carcinoma, mycelial sarcoma, head or neck carcinoma, osteosarcoma , Pancreatic cancer, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary cancer, thyroid cancer, esophageal cancer, malignant hypercalcemia, endometrial hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera), essential thrombocytopenia, adrenal cortical cancer, skin cancer and prostate cancer.

In practicing the methods of treatment, an effective amount of a composition containing a therapeutically effective concentration of a compound formulated for oral, intravenous, topical, and topical use, to treat neoplastic and other conditions, is one of these diseases. Administration to patients with abnormal symptoms. The amount is an amount effective to ameliorate or eliminate one or more symptoms of the disease. An effective amount of a compound for treating a particular disease is an amount sufficient to improve or, in some way, reduce the symptoms associated with the disease. Such amounts can be made effective by administration in a single dose or by regimen. The amount may treat the disease but is typically administered to ameliorate the symptoms of the disease. Typically, repeated administration is required to achieve the desired improvement of symptoms.

In certain embodiments of the methods of treatment of the invention, the compounds of Formulas I-III have a calculated polar surface area of less than about 100 or about 80 square millimeters. As used herein, “calculated polar surface area” is a fast polar surface area two-dimensional polar surface area predictor software available from Acceleries ^R , San Diego, California. Measure with).

Another aspect of the invention is to provide a pharmaceutical composition containing an effective amount of a compound of Formulas I-II or a pharmaceutically acceptable salt thereof in a mixture with one or more pharmaceutically acceptable carriers or diluents.

In one embodiment there is provided a pharmaceutical composition comprising a compound of Formulas (I)-(II) or a pharmaceutically acceptable salt thereof described herein in combination with a pharmaceutically acceptable excipient.

Preferred pharmaceutical compositions preferably have an EC ₅₀ of 1,000 nM or less, more preferably an EC ₅₀ of 500 nM or less, more preferably an EC ₅₀ of 200 nM or less and more than 100 nM, as measured by the method described in Example 61. EC ₅₀ , most preferably compounds of formulas I-III and pharmaceutically acceptable salts, esters or prodrugs thereof, capable of inducing caspase activation at EC _{50 up} to 10 nM.

Another aspect of the invention is a compound of formulas (I) to (III) which functions together with one or more known cancer chemotherapeutic agents or pharmaceutically acceptable salts thereof, as caspase cascade active agents and inducers of apoptosis or inhibitors of tubulin polymerization or A composition effective for inhibiting neoplasia, including pharmaceutically acceptable salts or prodrugs of the compounds, is disclosed. Examples of known cancer chemotherapeutic agents that can be used in combination therapy include alkylating agents such as busulfan, cis-platin, mitomycin C and carboplatin; Antimitotic agents such as colchicine, vinblastine, paclitaxel and docetaxel; Topoisomerase I inhibitors such as camptothecin and topotecan; Topoisomerase II inhibitors such as doxorubicin and etoposide; RNA / DNA antimetabolic products such as 5-azacytidine, 5-fluorouracil and methotrexate; DNA anti metabolites such as 5-fluoro-2'-deoxy-uridine, ara-C, hydroxyurea and thioguanine; EGFR inhibitors such as Iressa ^R (gefitinib) and Tarceva ^R (erlotinib); Proteosome inhibitors; Antibodies, such as, but not limited to, camphor, Herceptin ^R (trastuzumab), Avastin ^R (bevacizumab) or Rituxan ^R (rituximab) no. Another known cancer chemotherapeutic agent that can be used in combination therapy is melphalan, chlorambucil, cyclophosphamide, ifosamide, vincristine, mitoguazone, epirubicin, aclarubicin, bleomycin, mi Toxanthrone, elliptinium, fludarabine, octreotide, retinoic acid, tamoxifen, Gleevec ^R (imatinib mesylate) and alanosine.

In practicing the present invention, the compounds of the present invention may be administered with one or more known chemotherapeutic agents as part of a single pharmaceutical composition. Alternatively, the compounds of the present invention can be administered separately from one or more known cancer chemotherapeutic agents. In one embodiment, the compounds of the invention and one or more known cancer chemotherapeutic agents are administered substantially simultaneously, i.e., as long as the compound reaches a therapeutic level in the blood, simultaneously or sequentially. In another embodiment, the compounds of the present invention and one or more known cancer chemotherapeutic agents are administered according to individual dose schedules, as long as the compound reaches therapeutic levels in the blood.

It has been reported that alpha-1-adrenergic receptor antagonists such as doxazosin, terrazosin and tamsulosin can inhibit the growth of prostate cancer cells through the induction of apoptosis [see literature; Kyprianou, N., et al., Cancer Res 60: 4550-4555, (2000). Accordingly, another aspect of the invention is described herein which functions as a caspase cascade activator and inducer of apoptosis or inhibitor of tubulin polymerization, in combination with known alpha-1-adrenergic receptor antagonists or pharmaceutically acceptable salts thereof. A composition effective for inhibiting neoplasia, comprising a compound or a pharmaceutically acceptable salt or prodrug of the compound. Examples of known alpha-1-adrenergic receptor antagonists that can be used in combination therapy include, but are not limited to doxazosin, terrazosin and tamsulosin.

Sigma-2 receptors are expressed at high density in various tumor cell types [see literature; Vilner, B. J., et al., Cancer Res. 55: 408-413 (1995)], sigma-2 receptor agonists such as CB-64D, CB-184 and haloperidol are known to enhance the effectiveness of anti-neoplastic agents and activate novel apoptosis pathways in breast tumor cell lines. Reported [see literature; Kyprianou, N., et al., Cancer Res. (52: 313-322 (2002)) Accordingly, another aspect of the invention, together with one or more known sigma-2 receptor agonists or pharmaceutically acceptable salts thereof, induces caspase cascade activators and apoptosis or A composition effective for inhibiting neoplasia, comprising a compound described herein or a pharmaceutically acceptable salt or prodrug of the compound, which functions as an inhibitor of tubulin polymerization, is known. Sigma-2 receptor agonists include, but are not limited to, CB-64D, CB-184 and haloperidol.

Combination therapy with lovastatin, HMG-CoA reductase inhibitors and butyrate, an inducer of apoptosis in Lewis lung cancer models in mice, has been reported to show effective anti-tumor effects. Giermasz, A., et al., Int. J. Cancer 97: 746-750 (2002)]. Accordingly, another aspect of the invention is herein directed to a caspase cascade activator and inducer of apoptosis or inhibitor of tubulin polymerization, in combination with one or more known HMG-CoA reductase inhibitors or pharmaceutically acceptable salts thereof. A composition effective for inhibiting neoplasia, comprising a compound described or a pharmaceutically acceptable salt or prodrug of the compound. Examples of known HMG-CoA reductase inhibitors that can be used in combination therapy include, but are not limited to, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, and cerivastatin.

HIV protease inhibitors, such as indinavir or saquinavir, have been reported to have potent antiangiogenic activity and promote relief of Kaposi's sarcoma [see literature; Sgadari, C, et al., Nat. Med. 5: 225-232 (2002). Accordingly, another aspect of the present invention relates to a compound or a compound described herein that functions as an inducer of caspase cascade activator and apoptosis or inhibitor of tubulin polymerization in combination with one or more known HIV protease inhibitors or pharmaceutically acceptable salts thereof. A composition effective for inhibiting neoplasia, comprising a pharmaceutically acceptable salt or prodrug of a compound. Examples of known HIV protease inhibitors that can be used in combination therapy are amprenavir, abakavir, CGP-73547, CGP-61755, DMP-450, indinavir, lpinavir, tipranavir, ritonavir, sa Quinavir, ABT-378, AG 1776 and BMS-232,632.

Synthetic retinoids, such as fenretinide (N- (4-hydroxyphenyl) retinamide, 4HPR), have excellent activity in combination with other chemotherapeutic agents such as cisplatin, etoposide or paclitaxel in small cell lung cancer cell lines. It has been reported to have [see literature; Kalemkerian, G. P., et al., Cancer Chemother. Pharmacol. 3: 145-150 (1999). 4HPR has also been reported to have good activity with gamma radiation in bladder cancer cell lines. Zou, C, et al., Int. J. Oncol. 73: 1037-1041 (1998). Accordingly, another aspect of the present invention provides a compound described herein that functions as a caspase cascade activator and inducer of apoptosis or inhibitor of tubulin polymerization, with one or more known retinoids and synthetic retinoids or pharmaceutically acceptable salts thereof. A composition effective for inhibiting neoplasia, including pharmaceutically acceptable salts or prodrugs of the compounds, is disclosed. Examples of known retinoids and synthetic retinoids that can be used in combination therapy are bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, α-difluoromethylornithine, ILX23-7553, penreti Amide and N-4-carboxyphenyl retinamide.

Proteasome inhibitors, such as lactacystin, have been reported to exert antitumor activity in tumor cells in vivo and in vitro, including those resistant to conventional chemotherapeutic agents. By inhibiting NF-kappaB transcriptional activity, proteasome inhibitors can also prevent angiogenesis and metastasis in vivo and further increase the sensitivity of cancer cells to apoptosis. Almond, J. B., et al., Leukemia 16: 433-443 (2002)]. Accordingly, another aspect of the present invention relates to a compound described herein that functions as a caspase cascade active agent and an inducer of apoptosis or an inhibitor of tubulin polymerization in combination with one or more known proteasome inhibitors or pharmaceutically acceptable salts thereof. A composition effective for inhibiting neoplasia, including pharmaceutically acceptable salts or prodrugs of the compounds, is disclosed. Examples of known proteasome inhibitors that can be used in combination therapy include, but are not limited to, lactacystin, MG-32 and PS-341.

Tyrosine kinase inhibitors, such as STI571 (Gleevec ^R (imatinib mesylate)), have been reported to have strong synergistic effects in combination with other anti-leukemic agents, such as etoposide. Liu, WM, et al., J Br. J. Cancer 86: 1472-1478 (2002). Accordingly, another aspect of the present invention provides a compound described herein that functions as a caspase cascade activator and an inducer of apoptosis or an inhibitor of tubulin polymerization in combination with one or more known tyrosine kinase inhibitors or pharmaceutically acceptable salts thereof. A composition effective for inhibiting neoplasia, including pharmaceutically acceptable salts or prodrugs of the compounds, is disclosed. Examples of known tyrosine kinase inhibitors that can be used in combination therapy include, but are not limited to, Gleevec ^R (imatinib mesylate), ZDl 839 iresa ^R (gefitinib), SH268, genistein, CEP2563, SU6668, SU11248 and EMD121974 It doesn't work.

Prenyl-protein transferase inhibitors, such as the farnesyl protein transferase inhibitor R115777, have been reported to have preclinical anti-tumor activity against human breast cancer. Kelland, L. R., et al, Clin. Cancer Res. 7: 3544-3550 (2001). The synergistic action of the protein panesyltransferase inhibitor SCH65336 and cisplatin in human cancer cell lines has also been reported. Adjei, A. A., et al., Clin. Cancer. Res. 7: 1438-1445 (202). Thus, another aspect of the invention includes one comprising a farnesyl protein transferase inhibitor, a geranylgeranyl-protein transferase type I (GGPTase-I) and an inhibitor of geranylgeranyl-protein transferase type II. A compound described herein or a pharmaceutically acceptable salt or prodrug of the compound, which functions as a caspase cascade activator and inducer of apoptosis, in combination with any of the above known prenyl-protein transferase inhibitors or pharmaceutically acceptable salts thereof It relates to a composition effective to inhibit the formation of neoplasia. Examples of known prenyl-protein transferase inhibitors that can be used in combination therapy include, but are not limited to, R115777, SCH66336, L-778, 123, BAL9611 and TAN-1813.

Cyclin-dependent kinase (CDK) inhibitors such as flabopyridol have been reported to have a potent synergistic effect in human colon cancer cells in combination with other anticancer agents such as CPT-11, a DNA topoisomerase I inhibitor [See literature; Motwani, M., et al., Clin. Cancer Res. 7: 4209-4219, (2001). Accordingly, another aspect of the present invention, in combination with one or more known cyclin-dependent kinase inhibitors or pharmaceutically acceptable salts thereof, compounds described herein that function as caspase cascade active agents and inducers of apoptosis or inhibitors of tubulin polymerization Or to pharmaceutically acceptable salts or prodrugs of the compounds. Examples of known cyclin-dependent kinase inhibitors that can be used in combination therapy include, but are not limited to, flavopyridol, UCN-01, roscovitine, and olomuscin.

In preclinical studies, it has been reported that COX-2 inhibitors have been shown to block angiogenesis, inhibit solid tumor metastasis, and delay the growth of transplanted gastrointestinal cancer cells. Blanke, C. D., Oncology (Huntingt) 16 (No. 4 Suppl. 3): 17-21 (2002)]. Accordingly, another aspect of the invention relates to a compound described herein that functions as a caspase cascade activator and an inducer of apoptosis or an inhibitor of tubulin polymerization in combination with one or more known COX-2 inhibitors or pharmaceutically acceptable salts thereof. A composition effective for inhibiting neoplasia, including pharmaceutically acceptable salts or prodrugs of the compounds, is disclosed. Examples of known COX-2 inhibitors that can be used in combination therapy include, but are not limited to, selecoxib, valcoxock, and rofekkox.

Another aspect of the invention is one or more known therapeutically useful antibodies, such as Herceptin ^R (trastuzumab) or Rituxan ^R (rituximab), growth factors such as DGF, NGF; Live conjugates of cytokines such as IL-2, IL-4 or any molecule that binds to the cell surface to function as caspase cascade activators and inducers of apoptosis or inhibitors of tubulin polymerization A composition is effective for inhibiting neoplasia, including conjugates. Antibodies and other molecules will deliver the compounds described herein to their targets, making them effective anticancer agents. Bioconjugates can also enhance the anticancer effects of therapeutically useful antibodies, such as Herceptin ^R (trastuzumab) or Rituxan ^R (rituximab).

Similarly, another embodiment of the present invention, in combination with radiation therapy, acts as a caspase cascade active agent and an inducer of apoptosis or an inhibitor of tubulin polymerization or a pharmaceutically acceptable salt or prodrug of the compound It relates to a composition effective to inhibit the formation of neoplasia. In this embodiment, the compounds of the invention may be administered at the same time or at different times as the radiation therapy.

Another aspect of the present invention provides for postoperative treatment of cancer, comprising a compound described herein or a pharmaceutically acceptable salt or prodrug of the compound, which functions as a caspase cascade active agent and an inducer of apoptosis or an inhibitor of tubulin polymerization. It relates to an effective composition. The present invention also relates to a method of treating cancer by surgically removing the cancer and then treating the animal with one of the pharmaceutical compositions described herein.

A wide range of immune mechanisms operate rapidly after exposure to infectious agents. Depending on the type of infection, rapid cloning of T and B lymphocytes occurs to eradicate the infection. The removal of effector cells after infection is one of the major mechanisms for maintaining immune bioalways. Removal of effector cells has been shown to be regulated by apoptosis. Autoimmune diseases have recently been found to occur as a result of uncontrolled cell death. In certain autoimmune diseases, the immune system leads to a potent cytotoxic effector mechanism against specialized cells such as oligodendrocyte glial cells in multiple sclerosis, beta cells of the pancreas in diabetes and thyroid cells in Hashimoto's thyroiditis [ See literature; Qhsako, S. & Elkon, K.B., Cell Death Differ. (5: 13-21 (1999).) Lymphocyte apoptosis with mutations in the gene encoding the lymphocyte apoptosis receptor Fas / APO-l / CD95, and chronic histologically benign splenomegaly, generalized lymph node hypertrophy, It has been reported to be associated with autoimmune lymphoid syndrome (ALPS) characterized by hypergammaglobulinemia and autoantibody formation. See Infante, AJ, et al., J. Pediatr. 133: 629-633 ( 1998) and Vaishnaw, AK, et al., J. Clin. Invest. 103: 355-363 (1999)]. Anti-apoptosis in the development of B cells in transgenic mice in the presence of T cell dependent costimulatory signals. Overexpression of Bcl-2, a component of the bcl-2 gene system of active, programmed cell death regulators, has been reported to result in the generation of modified B-cell repertoires and the production of pathogenic autoantibodies. See Lopez-Hoyos , M., et al., JnL J. MoI Med. 7: 475-483 (1998)] It is therefore evident that several types of autoimmune diseases are caused by defects in the apoptosis process, one treatment of which acts on apoptosis in lymphocytes causing autoimmune diseases. O'Reilly, LA & Strasser, A., Inflamm. Res. 48: 5-21 (1999).

Fas-Fas ligand (FasL) interactions are known to be required for the maintenance of immune bioalways. Experimental autoimmune thyroiditis (EAT), characterized by autoreactive T and B cell responses and significant lymphocyte infiltration in the thyroid gland, is an excellent model for studying the therapeutic effect of FasL. Literature references; In Batteux, F., et al., (J. Immunol. 162: 603-608 (1999)), direct injection of a DNA expression vector encoding FasL into an inflamed thyroid inhibits the development of lymphocyte infiltration of the thyroid gland. Induction of invasive T cell death has been reported These results show that FasL expression in thyroid cells can have a therapeutic effect on ongoing EAT by inducing death of pathogenic autoreactive invasive T lymphocytes.

Bisindoleylmaleimide VIII is known to enhance the effectiveness of Fas-mediated apoptosis in human astrocytoma 1321N1 cells and Molt-4T cells; Both of these cells are resistant to apoptosis induced by anti-Fas antibodies in the absence of bisindoleylmaleimide VIII. Increased efficacy of Fas-mediated apoptosis by bisindolylmaleimide VIII has been reported to be selective and Fas-dependent on activated T cells rather than non-activated T cells. Literature references; Zhou T., et al., (Nat. Med. 5: 42-48 (1999)), two models of bisindoleylmaleimide VIII administration to rats during autoantigen stimulation, namely Lewis rats of experimental allergic encephalitis Symptomatic expression of T cell-mediated autoimmune disease has been reported to be prevented in the model and in the Lewis adjuvant arthritis model, therefore the application of Fas-dependent apoptosis enhancers, such as bisindoleylmaleimide VIII It may be therapeutically useful for more effective elimination and suppression of T cell-mediated autoimmune diseases, therefore, an effective amount of a compound of Formulas (I) to (III) or a pharmaceutical agent of the compound that functions as a caspase cascade activator and an inducer of apoptosis Acceptable salts or prodrugs are effective therapies for autoimmune diseases.

Psoriasis is a chronic skin disease characterized by red fragments that peel off like scales. Psoralen plus ultraviolet A (PUVA) is a widely used effective treatment for vulgar psoriasis. Literature references; Coven, et al., Photodermatol. Photoimmunol. Photomed. 15: 22-27 (1999), it has been reported that lymphocytes treated with Sorylene 8-MOP or TMP and UVA exhibit a DNA damage pattern typical for apoptotic cell death. See Ozawa, et al., J. Exp. Med. 189: 711-718 (1999) reported that the induction of T cell apoptosis may be the major mechanism by which 312-nm UVB dissipates psoriasis skin lesions. Low doses of methotrexate can be used to treat psoriasis to restore clinically normal skin. Literature references; Heenen, et al., Arch. Dermatol. Res. 290: 240-245 (1998) reported that low doses of methotrexate can induce apoptosis, and this mode of action may explain the reduction of epidermal hyperplasia during treatment of psoriasis with methotrexate. It was. Thus, an effective amount of a compound of Formulas I-III or a pharmaceutically acceptable salt or prodrug thereof that functions as a caspase cascade activator and an inducer of apoptosis is an effective treatment for hyperproliferative skin diseases, such as psoriasis.

Synovial cell hyperplasia is a hallmark of patients with rheumatoid arthritis (RA). It is believed that excessive proliferation of RA synovial cells and defects in synovial cell death can lead to synovial cell hyperplasia. Literature references; Wakisaka, et al., CHn. Exp. Immunol. 114: 119-128 (1998), it has been shown that RA synovial cells can die via apoptosis via the Fas / FasL pathway, but apoptosis of synovial cells is inhibited by proinflammatory cytokines present in the synovial fluid. Wakisaka et al. Also suggested that inhibition of apoptosis by proinflammatory cytokines can cause synovial cell overgrowth and cause pannus formation and joint destruction in RA patients. Thus, an effective amount of a compound of Formulas I-III, or a pharmaceutically acceptable salt or prodrug thereof, that functions as a caspase cascade activator and an inducer of apoptosis is an effective treatment for rheumatoid arthritis.

Compelling evidence is growing that apoptosis plays a major role in promoting the dissipation of acute inflammatory responses. Neutrophils are inherently programmed to perform apoptosis, limiting their proinflammatory potential and resulting in rapid, specific, non-inflammatory recognition by macrophages and semi-professional phagocytes. ; Savill ,, J., J. Leukoc. Biol. 61: 375-380 (1997). Literature references; Boirivant, et al., Gastroenterology 116: 557-565 (1999), show that the lamina propria T cells isolated from the site of inflammation in Crohn's disease, ulcerative colitis and other inflammatory diseases show a CD2 pathway-mediated reduction of apoptosis. Reported. In addition, cell studies from inflamed Crohn's disease tissue have shown that this defect is accompanied by increased Bcl-2 levels. Thus, an effective amount of a compound of Formulas I-III or a pharmaceutically acceptable salt or prodrug thereof that functions as a caspase cascade activator and an inducer of apoptosis is an effective treatment for inflammation.

Caspase cascade activators and inducers of apoptosis may also be desirable therapies for the removal of pathogens such as HIV, type C infections and other viral pathogens. Disease progression after prolonged sustained arrest can be explained by the anti-apoptotic mechanisms of these pathogens leading to sustained cell storage of virions. HIV-1 infected T leukemia cells or peripheral blood monocytes (PBMCs) have been reported to increase viral replication in the presence of caspase inhibitor Z-VAD-fmk. In addition, Z-VAD-fmk stimulates endogenous virus production in activated PBMCs derived from subjects with no symptoms of HIV-1 infection. Chinnaiyan, A., et al., Nat. Med. 5: 333 (1997). Thus, apoptosis acts as an advantageous host mechanism to limit the spread of HIV, and new therapeutics using caspase / apoptosis activators are useful for clearing the viral reservoir from infected subjects. Similarly, HCV infection also initiates anti-apoptotic mechanisms, leaving the host's immune surveillance, leading to virus persistence and patocarcinogenesis [see literature; Tai, D. L., et al., Hepatology 3: 656-64 (2000). Thus, apoptosis inducers are useful as therapeutic agents for HIV, HCV, HBV and other infectious diseases.

Stent implantation is becoming a new standard angioplasty. However, restenosis in the stent is a major limitation of coronary stent implantation. New methods have been developed to target the pharmacological adjustment of local vascular biology by topical administration of drugs. This allows the drug to be applied at the exact site and time of vascular injury. Many pharmacological agents with antiproliferative properties, including actinomycin D, rapamycin or paclitaxel coated stents, have recently been studied clinically. Regar E., et al., Br. Med. Bull. 59: 227-248 (2001). Thus, apoptosis inducers, which are antiproliferative agents, are useful as therapeutic agents for the prevention or reduction of restenosis in stents.

The compounds of the invention are potent and very effective active agents of caspase-3, inhibitors of tubulin polymerization and inhibitors of topoisomerase, even in drug resistant cancer cells. This allows these compounds to inhibit the growth and proliferation of drug resistant cancer cells and to induce apoptosis and cell death in drug resistant cancer cells. In particular, the compounds of the present invention are not substrates for MDR carriers such as Pgp-1 (MDR-1), MRP-1 and BCRP. This is particularly surprising in terms of the fact that almost all of the commercially available tubulin-interacting chemotherapeutic agents are substrates for multidrug resistance transporters (MDRs).

Multidrug resistance is a major cause of chemotherapy failure. Drug resistance is typically caused by ATP-dependent outflow of drugs from cells by ATP-binding cassette (ABC) carriers. In particular, the ABC carriers ABCB1 (MDR-1, P glycoprotein), ABCC1 (MRP1) and ABCG2 (BCRP, MXR) are typically overexpressed in drug resistant tumors and thus are involved in drug resistance. Compared to most standard anticancer drugs that are not effective in killing drug resistant cancer cells, the compounds of the present invention are effective in killing drug resistant cancer cells. Thus, the compounds of the present invention are useful for the treatment of drug resistant cancer.

Accordingly, another aspect of the present invention is the application of the methods and compounds of the present invention as described above to tumors with acquired resistance to other anticancer drugs. In one embodiment, a compound of the invention is administered to a cancer patient treated with another anticancer agent. In another embodiment, a compound of the present invention is administered to a patient who has been treated with another anticancer agent but is not reactive or has developed resistance to this other anticancer compound. In another embodiment, a compound of the present invention is administered to a patient who has been treated with another anticancer agent but not cured with this other anticancer agent. The compounds of the present invention can be used to treat cancer in patients who are not reactive or resistant to other anticancer agents. Examples of such other anticancer agents include alkylating agents, antimitotic agents, topoisomerase I inhibitors, topoisomerase II inhibitors, RNA / DNA antimetabolic products, EGFR inhibitors, angiogenic inhibitors, tubulin inhibitors (e.g., Vinblastine, Taxol ^R (paclitaxel) and analogs thereof, proteosome inhibitors and the like (some of exemplary compounds thereof are provided above and generally known in the art), for example melphalan, Chlorambucil, cyclophosphamide, phosphamide, vincristine, mitoguazone, epigubicin, aclrubicin, bleomycin, mitoxanthrone, elliptinium, fludarabine, octreotide, retinoic acid, Tamoxifen, gleevec ^R (imatinib mesylate) and alanosine. The compounds are diseases that are sensitive to inhibition of tubulin or inhibition of topoisomerase, including but not limited to the above types of cancer, which are not reactive or resistant to other therapeutic agents, such as other anticancer agents. It can be used to treat a patient with.

Pharmaceutical compositions within the scope of the present invention include all compositions in which the compound of the present invention is contained in an amount effective to achieve its intended purpose. Although the required amount varies from person to person, determination of the optimal range of effective amounts of each component is within the skill of the art. Typically, the compounds may be administered orally to animals, eg, mammals, at a dose of 0.0025-50 mg / kg / kg body weight per day to the mammal to be treated or in the same amount of a pharmaceutically acceptable salt thereof. Preferably, about 0.01 to about 10 mg / kg body weight is administered orally. For intramuscular injection, the dose is generally about half of the oral dose. For example, a suitable intramuscular dose is about 0.0025 to about 25 mg / kg body weight, most preferably about 0.01 to about 5 mg / kg body weight. If known cancer chemotherapeutic agents are also administered, they are administered in an amount effective to achieve the intended purpose. The amount of such known cancer chemotherapeutic agents effective for cancer is well known to those skilled in the art.

The unit oral dosage may comprise from about 0.01 mg to about 50 mg, preferably from about 0.1 mg to about 10 mg of a compound of the present invention. The unit dose may be administered one or more times per day as one or more tablets each containing about 0.1 to about 10 mg, typically about 0.25 to 50 mg of the compound or solvate thereof.

In topical formulations, the compound may be present at a concentration of about 0.01 to 100 mg per gram of carrier.

In addition to administering the compound as the original chemical, the compounds of the present invention contain a pharmaceutically acceptable carrier that contains a suitable pharmaceutically acceptable carrier, including excipients and auxiliaries that facilitate processing the compound into a pharmaceutically acceptable formulation. It can be administered as part of a pharmaceutical preparation. Preferably, for injection or oral administration, as well as for formulations that can be orally administered and preferred, such as formulations that can be used in tablets, dragees, and capsules, as well as formulations that can be administered straight, such as suppositories. Suitable solutions contain about 0.01 to 99%, preferably about 0.25 to 75%, of active compound (s) with excipients.

Pharmaceutically acceptable non-toxic salts of the compounds of the present invention are also included within the scope of the present invention. Acid addition salts are mixed with a solution of a compound of the invention with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, and the like. To form. Basic salts are formed by mixing a solution of a compound of the present invention with a solution of a pharmaceutically acceptable non-toxic base such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, tris, N-methyl-glucamine, and the like. .

The pharmaceutical compositions of the invention can be administered to any animal that can experience the beneficial effects of the compounds of the invention. Most important of these animals are mammals such as humans and veterinary animals, but the invention is not so limited.

The pharmaceutical compositions of the present invention may be administered by any means that achieve their intended purpose. For example, administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, nasal, intracapsular, intracranial, intranasal or topical routes. Alternatively, it may be administered by oral route at the same time. The dosage will depend on the age, health and weight of the patient, the type of concurrent treatment, the frequency of treatment and the nature of the desired effect.

The pharmaceutical formulations of the invention are prepared in a manner known per se, for example by conventional mixing, granulating, dragee-making, dissolving or lyophilizing processes. Thus, pharmaceutical preparations for oral use may be formulated with tablets or dragees by combining the active compounds with solid excipients, optionally pulverizing the resulting mixture and adding the appropriate adjuvant as appropriate or as necessary, followed by processing the mixture of granules. It can be obtained by obtaining a core.

Suitable excipients are in particular fillers such as sugars, such as lactose or sucrose, mannitol or sorbitol; Cellulose preparations and / or calcium phosphates such as tricalcium phosphate or calcium hydrogen phosphate; And binders such as starch pastes such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinyl Pyrrolidone. If desired, disintegrants, for example starch and also carboxymethyl-starch, crosslinked polyvinyl pyrrolidone, agar or alginic acid or salts thereof, for example sodium alginate can be added. Adjuvants are, among others, flow-controlling agents and lubricants such as silica, talc, stearic acid or salts thereof such as magnesium stearate or calcium stearate and / or polyethylene glycol. Dragee cores are optionally provided with suitable coatings that are resistant to gastric acid. For this purpose, thick saccharide solutions may optionally be used containing gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to prepare a film resistant to gastric acid, a solution of a suitable cellulose preparation such as acetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate is used. For example, dyes or pigments may be added to the tablets or dragee coatings for identification or to characterize the combination of active compound doses.

Still other pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin and sealed soft capsules made of gelatin and a plasticizer (eg glycerol or sorbitol). Push-fit capsules may contain the active substance in the form of granules, which may include fillers such as lactose, binders such as starch and / or lubricants such as talc or magnesium stearate and Optionally with a stabilizer. In soft capsules, the active compounds may preferably be dissolved or suspended in suitable liquids, such as fatty oils or liquid paraffin. In addition, stabilizers may be added.

Possible pharmaceutical formulations that can be used for rectal administration include, for example, suppositories consisting of a combination of one or more active compounds with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides or paraffin hydrocarbons. It is also possible to use gelatin rectal capsules consisting of a combination of the active compound and the substrate. Possible substrate materials include, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.

Formulations suitable for parenteral administration include aqueous solutions of the active compounds in water-soluble form, such as water soluble salts and alkaline solutions. In addition, suspensions of the active compounds as appropriate oily injection suspensions may be administered. Suitable lipophilic solvents or excipients include fatty oils such as horse oil or synthetic fatty acid esters such as ethyl oleate or triglycerides or polyethylene glycol 400 or cremophors or cyclodextrins. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension and include, for example, sodium carboxymethyl cellulose, sorbitol and / or dextran. Optionally, the suspension may also contain stabilizers.

According to one embodiment of the present invention, the compounds of the present invention are used in topical and parenteral formulations and to treat skin cancer.

The topical compositions of the invention are preferably formulated as oils, creams, lotions, ointments and the like by the selection of a suitable carrier. Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched fats or oils, animal fats and high molecular weight alcohols (C ₁₂ or higher). Preferred carriers are those in which the active ingredient is soluble. If desired, emulsifiers, stabilizers, wetting agents and antioxidants as well as agents that impart color or flavor may also be included. In addition, transdermal penetration enhancers can be used in such topical formulations. Examples of such enhancers can be found in US Pat. Nos. 3,989,816 and 4,444,762.

The cream is preferably formulated from a mixture of mineral oil, self-emulsifying beeswax and water, in which a small amount of the active ingredient dissolved in a small amount of oil, for example almond oil, is mixed. Typical examples of such creams include about 40 parts water, about 20 parts beeswax, about 40 parts mineral oil and about 1 part almond oil.

Ointments can be formulated by mixing a solution of the active ingredient in vegetable oil, for example almond oil, with warmed soft paraffin and cooling the mixture. Typical examples of such ointments include about 30% by weight of almond oil and 70% by weight of white soft paraffin.

The following examples are intended to illustrate, but not limit, the methods and compositions of the present invention. Other suitable modifications and applications of the various conditions and parameters that are commonly encountered in clinical treatment and that are apparent to those skilled in the art are within the spirit and scope of the present invention.

Example 1

(2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine

a) 2,4-dichloroquinazolin: A suspension of 2,4-quinazolindione (5.0 g, 30.8 mmol) in pure phosphoryl chloride (50 mL) was heated at reflux for 18 hours. The reaction mixture was concentrated in vacuo. The crude product was purified by chromatography (silica gel) using ethyl acetate and hexanes (1: 4) to give 2,4-dichloroquinazoline as a white solid (4.8 g, 96%). ¹ H NMR (CDCl ₃ ): 8.29 (ddd, J = 8.4, 2.1 and 0.9 Hz, 1H), 8.04-8.00 (m, 2H), 7.75 (ddd, J = 8.1, 4.8 and 3.0 Hz, 1H).

b) (2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine: 2,4-dichloroquinazolin (300 mg, 1.51 mmol) in 5 mL of isopropanol with 1 drop of concentrated HCl And a solution of 4-methoxy-N-methylaniline (248 mg, 1.81 mmol) were stirred at room temperature for 8 hours. A white precipitate was observed in the reaction mixture. The reaction was filtered, the solid washed with isopropanol and dried in vacuo to yield a white powder (260 mg, 87%). ¹ H NMR (CDCl ₃ ): 8.66 (dd, J = 8.4 and 0.9 Hz, 1H), 7.75 (ddd, J = 8.1, 7.5 and 0.9 Hz, 1H), 7.26-7.19 (m, 3H), 7.14 (ddd) , J = 8.1, 7.5, 0.9 Hz, 1H), 7.06 (dd, J = 6.9 and 2.4 Hz, 2H), 6.75 (d, J = 8.7 Hz, 1H), 3.91 (s, 3H), 3.81 (s, 3H).

Example 2

(2-Chloro-quinazolin-4-yl)-(4-methyl-phenyl) -methyl-amine

A white powder (210 mg, 84%) was prepared by preparing a title compound from 2,4-dichloroquinazolin (250 mg, 1.25 mmol) and 4-methyl-N-methylaniline (196 mg, 1.43 mmol) by a similar procedure as in Example 1b. Separated as. ¹ H NMR (CDCl ₃ ): 8.69 (d, J = 8.4 Hz, 1H), 7.75 (dd, J = 8.1 and 7.5 Hz, 1H), 7.39 (d, J = 7.8 Hz, 2H), 7.25 (d, J = 7.8 Hz, 2H), 7.13 (d, J = 8.2 Hz, 1H), 6.74 (d, J = 8.7 Hz, 1H), 3.81 (s, 3H), 2.49 (s, 3H).

Example 3

(2-Chloro-quinazolin-4-yl)-(4-chloro-phenyl) -methyl-amine

A white powder (30 mg, 50%) was prepared by preparing a title compound from 2,4-dichloroquinazolin (60 mg, 0.302 mmol) and 4-chloro-N-methylaniline (50 mg, 0.332 mmol) by a procedure similar to Example 1b. Separated as. ¹ H NMR (CDCl ₃ ): 8.66 (d, J = 8.4 Hz, 1H), 7.78 (ddd, J = 8.1, 7.5 and 2.4 Hz, 1H), 7.57 (d, J = 8.7 Hz, 2H), 7.28 ( d, J = 8.7 Hz, 2H), 7.19 (ddd, J = 8.1, 7.5 and 2.4 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 3.83 (s, 3H).

Example 4

(2-Chloro-quinazolin-4-yl)-(4-trifluoromethoxy-phenyl) -methyl-amine

A white powder (22 mg) was prepared by preparing a title compound from 2,4-dichloroquinazolin (50 mg, 0.251 mmol) and 4-trifluoromethoxy-N-methylaniline (20 µl, 0.302 mmol) by a similar procedure to Example 1b. , 44%). ¹ H NMR (CDCl ₃ ): 7.93 (dd, J = 8.4, and 0.6 Hz, 1H), 7.61 (ddd, J = 8.4, 4.5 and 1.2 Hz, 1H), 7.29-7.22 (m, 4H), 7.06 ( ddd, J = 8.4, 4.5 and 1.2 Hz, 1 H), 6.91 (d, J = 8.7 Hz 3 IH), 3.65 (s, 3H).

Example 5

N ² - hydroxyl -N ⁴ - (4- methoxy-phenyl) -N ^{4-methyl-quinazoline-2,4-diamine}

A mixture of (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine (15 mg, 0.05 mmol) and hydroxylamine hydrochloride (6.7 mg, 0.10 mmol) in isopropanol was prepared. Heated with microwave at 20 ° C. for 20 minutes. The solvent was evaporated under reduced pressure. The product was isolated as a white solid (6 mg, 40%) by preparative TLC using acetone: hexane (1: 1) as eluent. ¹ H NMR (CDCl ₃ ): 7.65 (d, J = 8.4 Hz, 1H), 7.47 (ddd, J = 8.4, 6.9 and 1.8 Hz, 1H), 7.08 (d, J = 8.7 Hz, 2H), 6.94 ( d, J = 8.7 Hz, 2H), 6.88-6.75 (m, 2H), 3.86 (s, 3H), 3.48 (s, 3H):

Example 6

(4-Methoxy-phenyl) -methyl- (2-morpholin-4-yl-quinazolin-4-yl) -amine

The title compound was obtained from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine (15 mg, 0.050 mmol) and morpholine (30 μl) by a procedure similar to Example 5. Prepared and isolated as white powder (10 mg, 66%). ¹ H NMR (CDCl ₃ ): 7.46 (d, J = 8.4 Hz, 1H), 7.35 (ddd, J = 8.4, 6.6 and 1.5 Hz, 1H), 7.13-7.07 (m, 2H), 6.91-6.85 (m , 3H), 6.67 (ddd, J = 8.4, 6.6 and 1.5 Hz, 1H), 3.94-3.90 (m, 4H), 3.85-3.81 (m, 7H), 3.52 (s, 3H).

Example 7

(2-Chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl) -methyl-amine

To a solution of (2-chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl) -amine (19.4 mg, 0.068 mmol) in 1 mL of DMF cooled at 0 ° C., methyl iodide ( 100 μl, 1.61 mmol) was added followed by sodium hydride (60% oil suspension, 5 mg, 0.13 mmol). The mixture was stirred at 0 ° C. for 1 h, then warmed to rt and stirred for 1 h. The reaction mixture was quenched by addition of 50 μl of water, diluted with 25 mL of ethyl acetate, washed with water (25 mL × 3), saturated NaCl, dried over anhydrous MgSO ₄ , filtered and concentrated. The residue was purified by chromatography (20% ethyl acetate / hexanes) to give the title compound (14.3 mg, 0.048 mmol, 70%). ¹ H NMR (CDCl ₃ ): 8.06 (d, J = 2.7 Hz, 1H), 7.57-7.79 (m, IH), 7.60 (ddd, J = 8.1, 6.6 and 1.2 Hz, 1H), 7.44 (dd, J = 8.7 and 2.7 Hz, 1H), 7.09 (ddd, J = 8.1, 6.6 and 1.2 Hz, 1H), 6.99-7.02 (m, IH), 6.82 (dd, J = 8.7 and 0.6 Hz, 1H), 3.97 ( s, 3 H), 3.61 (s, 3 H).

Example 8

(2-Chloro-quinazolin-4-yl) -ethyl- (4-methoxy-phenyl) -amine

The title compound was prepared (58% yield) from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl) -amine and ethyl iodide by a procedure similar to Example 7. ¹ H NMR (CDCl ₃ ): 7.69-7.72 (m, 1H), 7.53 (ddd, J = 8.1, 6.9 and 1.5 Hz, 1H), 7.09-7.14 (m, 2H), 6.94-6.70 (m, 3H) , 6.83-6.87 (m, 1 H), 4.13 (q, J = 7.2 Hz, 2H), 3.87 (s, 1H), 1.30 (t, J = 6.9 Hz, 3H).

Example 9

(2-Chloro-quinazolin-4-yl)-(2,4-dimethoxy-phenyl) -methyl-amine

The title compound was prepared (91% yield) from (2-chloro-quinazolin-4-yl)-(2,4-dimethoxy-phenyl) -amine and methyl iodide by a procedure similar to Example 7. ¹ H NMR (CDCl ₃ ): 7.70-7.73 (m, 1 H), 7.54 (ddd, J = 8.7, 6.3 and 2.1 Hz, 1H), 7.10 (d, J = 8.7 Hz, 1H), 6.93-7.23 (m , 2H), 6.50-6.57 (m, 2H), 3.87 (s, 3H), 3.67 (s, 3H), 3.52 (s, 3H).

Example 10

(2-Chloro-quinazolin-4-yl)-(3-methoxy-phenyl) -methyl-amine

The title compound was prepared (60% yield) from (2-chloro-quinazolin-4-yl)-(3-methoxy-phenyl) -amine and methyl iodide by a procedure similar to Example 7. ¹ H NMR (CDCl ₃ ): 7.74-7.76 (m, 1H), 7.57 (ddd, J = 8.4, 6.0 and 1.8 Hz, 1H), 7.32 (t, J = 7.8 Hz, 1H), 6.98-7.03 (m , 2H), 6.89 (dd, J = 8.1 and 2.4 Hz, 1H), 6.75-6.81 (m, 2H), 3.65 (s, 3H), 3.37 (s, 3H).

Example 11

(2-methoxy-quinazolin-4-yl)-(4-methoxyphenyl) -methylamine

Sodium methoxide (50Ol, 25% by weight in methanol) in a solution of (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine (50 mg, 0.167 mmol) in 2 mL methanol Was added. The solution was stirred at 80 ° C. for 1 hour, which was diluted with 50 ml of ethyl acetate. The solution was washed with water, dried and concentrated. The product was purified using a small amount of silica column and obtained as off white solid (22 mg, 54%). ¹ H NMR (CDCl ₃ ): 7.89 (d, J = 8.4 Hz, 1H), 7.53 (ddd, J = 8.7, 5.4 and 2.4 Hz, 1H), 7.19-7.14 (m, 2H), 6.99-6.93 (m , 2H), 6.90-6.85 (m, 2H), 4.14 (s, 3H), 3.86 (s, 3H), 3.64 (s, 3H).

Example 12

(2-Fluoromethyl-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine

a) 2-fluoromethyl-quinazolin-4 (3H) -one: 2-amino-benzoic acid methyl ester (151 mg, 1 mmol) and fluoro-acetonitrile (0.14 ml, 2.5 mmol) in dioxane (5 ml) at room temperature To the solution of was concentrated HCl (0.05 ml) dropwise. The mixture was heated at 80 ° C. for 24 h and then cooled to rt. The resulting solid was collected and dissolved in water (10 ml) and the solution was neutralized to pH 7 with saturated aqueous NaHCO ₃ . The solution was extracted with ethyl acetate. The extract was evaporated and the residue was purified by column chromatography on silica gel using ethyl acetate and hexane (1: 1) as eluent to afford 70 mg (39%) of the title compound.

b) (2-fluoromethyl-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine: phosphoryl chloride (2 mL) and N, N-dimethylaniline (0.035 mL, 0.27 mmol) A suspension of 2-fluoromethyl-quinazolin-4 (3H) -one (70 mg, 0.39 mmol) in water was heated at reflux for 12 hours. The reaction mixture was poured into ice and the precipitate was collected by filtration, washed and dried to give 4-chloro-2-fluoromethyl-quinazolin, which was used directly in the next reaction. To a solution of 4-chloro-2-fluoromethyl-quinazolin (160 mg, 1.2 mmol) with (4-methoxy-phenyl) -methylamine in isopropyl alcohol (5 ml) was added concentrated HCl (0.05 ml), The solution was stirred at rt overnight. The solution was neutralized with saturated aqueous NaHCO ₃ and extracted with ethyl acetate. The extract was evaporated and the residue was purified by column chromatography on silica gel using ethyl acetate and hexanes (1: 1) as eluent to afford 11 mg (9.5%) of the title compound. ¹ H NMR (CDCl ₃ ): 7.87-7.84 (m, 1 H), 7.60-7.54 (m, 1 H), 7.14-7.10 (m, 2 H), 7.04-7.01 (m, 2H), 6.95-6.91 (m, 2H), 5.60 (s, 1H), 5.44 (s, 1H), 3.85 (s, 3H), 3.60 (s, 3H).

Example 13

(2-Chloro-6-methyl-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine

a) 6-Methyl-quinazolin-2,4-dione: In a suspension of 2-amino-5-methyl benzoic acid (0.758 g, 5 mmol) and potassium cyanate (0.673 g, 8.3 mmol) in water (20 mL) 0.5 mL) was added. The mixture was stirred at rt for 24 h. The white solid was collected by vacuum filtration, washed with water and dried in vacuo (0.736 g, 84%): ¹ H NMR (DMSO-d ₆ ) 9.90 (br s, 1H), 8.27 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 1.8 Hz, 1H), 7.29 (dd, J = 2.4, 8.7 Hz, 1H), 6.50 (br s, 1H), 2.25 (s, 3H).

b) (2-Chloro-6-methyl-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine: said 6-methyl-quinazolin-2,4-dione (201 mg, 1.14 mmol) ) And N, N-dimethylaniline (0.2 mL) were refluxed under phosphorus oxychloride (5 mL) overnight under argon. The solvent was removed by distillation under reduced pressure. The purple residue was dissolved in isopropanol (10 mL). N-methyl-p-anisidine (201 mg, 1.465 mmol) was added. The mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was purified by column chromatography (SiO ₂ , EtOAc: hexane 5-25%) to give the product as a pale yellow solid (62 mg, 17%): ¹ H NMR (CDCl ₃ ): 7.62 ( d, J = 8.7 Hz, 1H), 7.38 (dd, J = 1.8, 8.7 Hz, 1H), 7.16-7.10 (m, 2H), 6.89-6.86 (m, 2H), 6.63 (s, 1H), 3.86 (s, 3H), 3.60 (s, 3H), 2.09 (s, 3H).

The compound of Examples 14-16 was prepared similarly to Example 13.

Example 14

(2-Chloro-5-methyl-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine

a) 5-Methyl-quinazolin-2,4-dione: off-white solid: ¹ H NMR (CDCl ₃ ): 11.04 (s, 2H), 7.45 (t, J = 7.8 Hz, 1H), 7.01 (d, J = 7.8 Hz, 1H), 6.94 (d, J = 7.5 Hz, 1H), 2.65 (s, 3H).

b) (2-Chloro-5-methyl-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine: light yellow solid: ¹ H NMR (CDCl ₃ ): 7.64-7.61 (m, 1H ), 7.54 (dd, J = 7.2, 8.4 Hz, 1H), 6.99-6.96 (m, 1H), 6.75-6.68 (m, 4H), 3.75 (s, 3H), 3.63 (s, 3H), 2.11 ( s, 3H).

Example 15

(2-Chloro-8-methyl-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine

a) 8-methyl-quinazolin-2,4-dione: light brown solid: ¹ H NMR (DMSO-d ₆ ) 11.43 (s, 1H), 10.50 (s, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.58 (d, J = 7.2 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 2.43 (s, 3H).

b) (2-Chloro-8-methyl-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine: ¹ H NMR (CDCl ₃ ): 7.42-7.39 (m, 1H), 7.14 -7.04 (m, 2H), 6.94-6.87 (m, 3H), 6.84 (dd, J = 1.5, 8.4 Hz, 1H), 3.84 (s, 3H), 3.60 (s, 3H), 2.63 (s, 3H ).

Example 16

(2,6-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine

a) 6-chloro-quinazolin-2,4-dione: white solid: ¹ H NMR (DMSO-d ₆ ) 11.44 (s, 1H), 11.28 (s, 1H), 7.81 (d, J = 2.1 Hz, 1H), 7.69 (dd, J = 9.0, 2.1 Hz, 1H), 7.19 (d, J = 9.0 Hz, 1H).

b) (2,6-dichloro-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine: yellow solid: ¹ H NMR (CDCl ₃ ): 7.66 (d, J = 8.7 Hz, 1H), 7.49 (dd, J = 2.1, 8.7 Hz, 1H), 7.18-7.12 (m, 2H), 7.02-6.96 (m, 2H), 6.78 (dd, J = 0.6, 2.1 Hz, 1H), 3.88 (s, 3 H), 3.61 (s, 3 H).

Example 17

(4-methoxy-phenyl) -methyl- (quinolin-4-yl) -amine

A mixture of 4-chloroquinoline (50 mg, 0.31 mmol) and (4-methoxy-phenyl) -methyl amine (300 mg, 2.2 mmol) was heated at 140 ° C. overnight in a sealed tube. The crude product was purified by chromatography on silica gel (20-40% ethyl acetate / hexanes) to afford the title compound (60 mg, 0.23 mmol, 74%). ¹ H NMR (CDCl ₃ ): 8.77 (d, 1H, J = 5.1), 8.00-8.04 (m, 1H), 7.61-7.64 (m, 1H), 7.55 (ddd, 1H, J = 1.5, 6.9, 8.4 ), 7.22 (ddd, 1H, J = 1.5, 6.9, 8.1), 6.99 (d, 1H, J = 4.8), 6.92 (m, 2H), 6.89 (m, 2H), 3 .77 (s, 3H) , 3.43 (s, 3 H).

Example 18

(2-Chloro-quinazolin-4-yl)-(3,4-methylenedioxyphenyl) -methyl-amine

a) (2-chloro-quinazolin-4-yl)-(3,4-methylenedioxyphenyl) -amine: 3,4-methylenedioxyphenylamine and 2,4- by a similar procedure as in Example 1b The title compound was prepared from dichloroquinazoline and isolated as a solid (45% yield). ¹ H NMR (CDCl ₃ ): 7.81-7.83 (m, 3H), 7.51-7.56 (m, 2H), 7.44 (d, 1H, J = 2.1), 6.98 (dd, 1H, J = 2.1, 8.1), 6.82 (d, 1 H, J = 8.1), 6.01 (s, 2H).

b) (2-chloro-quinazolin-4-yl)-(3,4-methylenedioxyphenyl) -methyl-amine: (2-chloro-quinazolin-4-yl) by a similar procedure as in Example 36 The title compound was prepared from-(3,4-methylenedioxyphenyl) -amine, isolated as a solid (66% yield). ¹ H NMR (CDCl ₃ ): 7.73-7.76 (m, 1 H), 7.58 (m, 1 H), 7.07 (m, 2 H), 6.82 (d, 1 H, J = 8.4), 6.72 (m, 1H), 6.68 (m, 1 H), 6.06 (s, 2 H), 3.59 (s, 3 H).

The compounds of Examples 19 and 20 were prepared similar to Example 18.

Example 19

(2-Chloro-quinazolin-4-yl)-(3,4-dimethoxy-phenyl) -methyl-amine

a) (2-Chloro-quinazolin-4-yl)-(3,4-dimethoxy-phenyl) -amine: ¹ H NMR (CDCl ₃ ): 7.77-7.86 (m, 3H), 7.51-7.60 (m , 3H), 7.12 (dd, 1H, J = 2.4, 8.4), 6.90 (d, 1H, J = 8.4), 3.94 (s, 3H), 3.91 (s, 3H).

b) (2-Chloro-quinazolin-4-yl)-(3,4-dimethoxy-phenyl) -methyl-amine: ¹ H NMR (CDCl ₃ ): 7.72-7.75 (m, 1H), 7.57 (ddd) , 1H, J = 1.5, 6.6, 8.4), 7.01 (ddd, 1H, J = 1.2, 6.9, 8.7), 6.88-6.96 (m, 2H), 6.73-6.81 (m, 2H), 3.94 (s, 3H ), 3.80 (s, 3 H), 3.63 (s, 3 H).

Example 20

(2-Chloro-quinazolin-4-yl)-(4-propoxy-phenyl) -methyl-amine

a) (2-Chloro-quinazolin-4-yl)-(4-propoxy-phenyl) -amine: ¹ H NMR (CDCl ₃ ): 7.76-7.84 (m, 3H), 7.52-7.62 (m, 4H ), 6.95 (m, 2H), 3.94 (t, 2H, J = 6.6), 1.83 (hex, 2H, J = 7.2), 1.05 (t, 3H, J = 7.5)

b) (2-Chloro-quinazolin-4-yl)-(4-propoxy-phenyl) -methyl-amine: ¹ H NMR (CDCl ₃ ): 7.71-7.74 (m, 1H), 7.55 (ddd, 1H , J = 1.5, 6.9, 8.4), 7.10-7.16 (m, 2H), 7.00 (ddd, 1H, J = 1.5, 6.9, 8.4), 6.91-6.96 (m, 3H), 3.96 (t, 2H, J = 6.6), 1.84 (hex, 2H, J = 7.5), 1.08 (t, 3H, J = 7.5).

Example 21

(4-Methoxy-phenyl) -methyl- (2-methyl-quinazolin-4-yl) -amine hydrochloride

a) 4-Chloro-2-methyl-quinazolin: A stirred suspension of 2-methyl-4 (3H) -quinazolinone (5 g, 31.2 mmol) in POCl ₃ (100 mL) was heated at 120 ° C. for 3 hours. Excess POCl ₃ was removed in vacuo, then to the residue was added 200 mL of crushed ice and saturated NaHCO ₃ and the mixture was extracted with ethyl acetate (200 mL × 2). The combined extracts were washed with water, saturated NaCl, dried over anhydrous MgSO ₄ , filtered and concentrated. The crude product was purified by column chromatography (5-8% ethyl acetate / hexanes) to give the title compound (2.5 g, 14.0 mmol, 45%). ¹ H NMR (CDCl ₃ ): 8.21-8.25 (m, 1H), 7.89-7.99 (m, 2H), 7.66 (ddd, 1H, J = 1.8, 6.6, 8.7), 2.87 (s, 3H).

b) (4-methoxy-phenyl) -methyl- (2-methyl-quinazolin-4-yl) -amine hydrochloride:

The title compound was prepared from 4-chloro-2-methyl-quinazolin (2.31 g, 12.9 mmol) and (4-methoxy phenyl) -methyl-amine (2.0 g, 14.6 mmol) by a procedure similar to Example 1b. Isolated as a solid (2.90 g, 9.18 mmol, 71%). ¹ H NMR (CDCl ₃ ): 8.53 (dd, 1H, J = 0.6, 8.1), 7.7 (ddd, 1H, J = 1.2, 7.2, 8.4), 7.22 (m, 2K), 7.13 (ddd, 1H, J = 1.2, 7.2, 8.7), 7.05 (m, 2H), 6.76 (d, 1H, J = 8.7), 3.91 (s, 3H), 3.78 (s, 3H), 2.96 (s, 3H).

Example 22

(2-Chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine

a) 2-chloromethyl-quinazolin-4 (3H) -one: 2-amino-benzoic acid methyl ester (0.26 ml, 2 mmol) and chloro-acetonitrile (0.16 ml, 4.0 mmol) in dioxane (8 ml) at room temperature To the solution of was concentrated HCl (1.0 ml) dropwise. The mixture was heated at 80 ° C. for 24 h and then cooled to room temperature. The resulting solid was collected and dissolved in water (10 ml) and the solution was neutralized to pH 7 with 2N aqueous NaOH. The precipitate was collected by filtration, washed with water and dried to give 309 mg (79.6%) of the title compound.

b) (2-Chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine: 2-chloromethyl-quinazolin-4 (3H) -one (256 mg) in chloroform (10 ml) , 1.32 mmol), phosphoryl chloride (1.23 mL, 13.2 mmol) and N, N-dimethylaniline (0.34 mL, 2.64 mmol) were heated at reflux for 4 hours. The reaction mixture was poured into ice and extracted with ethyl acetate. The solvent was evaporated and the residue was purified by column chromatography on silica gel using acetate and hexane (1: 1) as eluent to afford 180 mg of 4-chloro-2-chloromethyl-quinazolin. The intermediate (170 mg, 0.80 mmol) and (4-methoxy-phenyl) -methylamine (131.7 mg, O.96 mmol) in isopropyl alcohol (5 ml) with concentrated HCl (0.05 ml) were stirred overnight at room temperature. A precipitate formed which was collected by filtration, washed and dried to give 231 mg (92%) of the title compound. ¹ H NMR (CDCl ₃ ): 7.82 (d, J = 8.7 Hz, 1 H), 7.59-7.53 (m, 1 H), 7.15-7.12 (m, 2 H), 7.03-7.00 (m, 2H), 6.95-6.91 (m, 2H), 4.73 (s, 2H), 3.85 (s, 3H), 3.62 (s, 3H).

Example 23

(2-ethyl-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine

The title compound was prepared in three steps by a procedure similar to Example 22. ¹ H NMR (CDCl ₃ ): 7.76 (d, J = 8.4 Hz, 1H), 7.55-7.49 (m, 1H), 7.13-7.09 (m, 2H), 7.03-6.89 (m, 4H), 3.83 (s , 3H), 3.60 (s, 3H), 2.97 (q, J = 7.5 Hz, 2H), 1.44 (t, J = 7.8 Hz, 3H).

Example 24

(2-Chloro-quinazolin-4-yl)-(2,3-dimethoxy-phenyl) -methyl-amine

The title compound was prepared (71% yield) from (2-chloro-quinazolin-4-yl)-(2,3-dimethoxy-phenyl) -amine and methyl iodide by a procedure similar to Example 7. ¹ H NMR (CDCl ₃ ): 7.74 (d, J = 8.4 Hz, 1H), 7.53-7.59 (m, 1H), 7.12 (t, J = 8.4 Hz, 1H), 6.94-7.01 (m, 3H), 6.87 (dd, J = 8.1 and 1.5 Hz, 1H), 3.89 (s, 3H), 3.56 (s, 3H).

Example 25

(4-Difluoromethoxy-phenyl)-(2-methyl-quinazolin-4-yl) -methyl-amine

(4-Difluoromethoxy-phenyl)-(2-methyl-quinazolin-4-yl) -amine (710 mg, 2.36 mmol) and methyl iodide (1.03 ml, 16.52 mmol) by a similar procedure as in Example 7. ) Was prepared (40.8% yield). ¹ H NMR (CDCl ₃ ): 7.77 (dd, J = 8.4 Hz, J = 0.9 Hz, 1H), 7.59-7.53 (m, 1H), 7.17-7.10 (m, 4H), 7.06-6.99 (m, 2H ), 6.78 (d, J = 0.6 Hz, 0.25H), 6.54 (d, J = 0.9 Hz, 0.5H), 6.29 (d, J = 0.9 Hz, 0.25H), 3.62 (s, 3H), 2.75 ( s, 3H).

Example 26

(3-Fluoro-4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl) -methyl-amine

(3-Fluoro-4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl) -amine (250 mg, 0.88 mmol) and methyl iodide (0.39 ml) were prepared in a similar manner to Example 7. , 6.18 mmol) was prepared for the title compound. ¹ H NMR (CDCl ₃ ): 7.76 (d, J = 8.4 Hz, 1H), 7.59-7.53 (m, 1H), 7.09-6.82 (m, 5H), 3.91 (s, 3H), 3.58 (s, 3H ), 2.73 (s, 3 H).

Example 27

(4-isopropoxy-phenyl)-(2-methyl-quinazolin-4-yl) -methyl-amine

(4-Isopropoxy-phenyl)-(2-methyl-quinazolin-4-yl) -amine (164.3 mg, 0.56 mmol) and methyl iodide (0.25 ml, 3.92 mmol) by a similar procedure as in Example 7. The title compound was prepared. ¹ H NMR (CDCl ₃ ): 7.73 (d, J = 7.8 Hz, 1H), 7.54- 7.49 (m, 1H), 7.10-6.86 (m, 6H), 4.57-4.52 (m, 1H), 3.58 (s , 3H), 2.72 (s, 3H), 1.36 (d, J = 6 Hz, 6H).

Example 28

(4-ethyl-phenyl)-(2-methyl-quinazolin-4-yl) -methyl-amine

Titled from (4-ethyl-phenyl)-(2-methyl-quinazolin-4-yl) -amine (122 mg, 0.46 mmol) and methyl iodide (0.2 ml, 3.25 mmol) by a similar procedure as in Example 7. The compound was prepared. ¹ H NMR (CDCl ₃ ): 7.74 (d, J = 8.1 Hz, 1H), 7.54-7.49 (m, 1H), 7.19 (d, J = 8.4 Hz, 2H), 7.09-6.92 (m, 4H), 3.61 (s, 3 H), 2.73-2.63 (m, 5 H), 1.26 (d, J = 7.5 Hz, 3 H).

The compounds of Examples 29 and 30 were prepared by a similar procedure as in Example 13.

Example 29

(2,8-dichloro-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine

a) 8-chloro-1H-quinazolin-2,4-dione: white solid: ¹ H NMR (DMSO-d ₆ ) 11.47 (s, 1H), 10.77 (s, 1H), 7.88 (m, 1H), 7.78 (m, 1 H), 7.18 (m, 1 H).

b) (2,8-dichloro-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine: off-white solid: ¹ H NMR (CDCl ₃ ): 7.66 (dd, J = 2.7, 6.3 Hz, 1H), 7.14-7.10 (m, 2H), 6.97-6.89 (m, 4H), 3.86 (s, 3H), 3.62 (s, 3H).

Example 30

(2,5-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine

a) 5-Chloro-1H, 3H-quinazolin-2,4-dione: white solid: ¹ H NMR (DMSO-d ₆ ) 11.28 (s, 2H), 7.55 (m, 1H), 7.19 (d, J = 7.8 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H).

b) (2,5-dichloro-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine: yellow solid: ¹ H NMR (CDCl ₃ ): 7.67 (m, 1H), 7.52 ( m, 1H), 7.16 (m, 1H), 6.80-6.69 (m, 4H), 3.76 (s, 3H), 3.65 (s, 3H).

Example 31

(5-methoxy-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine

a) 5-methoxy-2-methyl-quinazolin-4-ol: 2-amino-6-methoxy-benzoic acid (305 mg, 1.82 mmol) and 4-N in DMF / toluene (2: 6 ml) at 0 ° C. Triethylamine (1.1 mL, 7.9 mmol) was added to a suspension of, N-dimethylaminopyridine (20 mg, 0.16 mmol), followed by the slow addition of acetyl chloride (0.40 mL, 5.6 mmol) under argon. The suspension was stirred at rt for 19 h. Ammonium acetate (0.62 g, 8.0 mmol) was added and the reaction mixture was further stirred at 90 ° C. for 5 hours. The solid was collected by filtration, washed with water and dried to give an off-white solid (103 mg, 30%): ¹ H NMR (CDCl ₃ ): 10.69 (s, 1H), 7.66 (t, J = 8.4 Hz, 1H ), 7.25 (d, J = 8.4 Hz, 1H), 6.49 (d, J = 8.4 Hz, 1H), 4.01 (s, 3H), 2.53 (s, 3H).

b) (5-methoxy-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine: similar procedure to Example 13b gave the title compound as a white solid: ¹ H NMR (CDCl ₃ ): 7.51 (t, J = 8.4 Hz, 1H), 7.35 (dd, J = 0.9, 8.4 Hz, 1H), 6.85-6.80 (m, 2H), 6.85-6.72 (m, 2H ), 6.56 (dd, J = 0.9, 7.8 Hz, 1H), 3.75 (s, 3H), 3.60 (s, 3H), 3.25 (s, 3H), 2.68 (s, 3H).

Example 32

(2-Chloro-quinazolin-4-yl)-(4-ethoxy-phenyl) -methylamine

The title compound was prepared (28%) from (2-chloro-quinazolin-4-yl)-(4-ethoxy-phenyl) -amine by a procedure similar to Example 7. ¹ H NMR (CDCl ₃ ): 7.73 (m, 1H), 7.55 (m, 1H), 7.12 (m, 2H), 7.00 (m, 1H), 6.93 (m, 3H) 5 4.07 (q, J = 7.2 , 2H), 3.61 (s, 3H), 1.46 (t, J = 7.2, 3H).

Example 33

(2-Methyl-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl) -methyl-amine

The title compound was prepared (28%) from (2-methyl-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl) -amine by a procedure similar to Example 7. ¹ H NMR (CDCl ₃ ): 8.03 (d, J = 2.7, 1H), 7.77 (m, 1H), 7.56 (ddd, J = 8.1, 6.3, 1.8, 1H), 7.38 (dd, J = 8.7, 3.0 , 1H), 7.01 (m, 2H), 6.76 (d, J = 9.0, 1H), 3.96 (s, 3H), 3.59 (s, 3H), 2.73 (s, 3H).

Example 34

(2-Fluoro-4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl) -methyl-amine

The title compound was prepared (51%) from (2-methyl-quinazolin-4-yl)-(2-fluoro-4-methoxyoxy-phenyl) -amine by a procedure similar to Example 7. ¹ H NMR (CDCl ₃ ): 7.76 (d, J = 8.1, 1H), 7.55 (ddd, J = 8.1, 6.3, 1.8, 1H), 6.98-7.11 (m, 3H), 6.66-6.76 (m, 2H ), 3.83 (s, 3H), 3.54 (s, 3H), 2.73 (s, 3H).

Example 35

(4-Dimethylamino-phenyl)-(2-methyl-1-quinazolin-4-yl) -methyl-amine

Sodium cyanoborohydride (15 mg) in a solution of (2-methyl-quinazolin-4-yl)-(4-amino-phenyl) -methylamine (14 mg, mmol) in 1.5 mL of 37% aqueous formaldehyde solution and 10 uL glacial acetic acid , 0.24 mmol) was added and the mixture was stirred at rt for 2 h. The reaction mixture was quenched by addition of 50 uL of 1N HCl. It was diluted with 50 mL of ethyl acetate, washed with saturated sodium bicarbonate and then with saturated sodium chloride. The organic layer was dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel (25% ethyl acetate / hexanes) to afford the title compound (12.4 mg, 0.042 mmol, 80%). ¹ H NMR (CDCl ₃ ): 7.71 (m, 1H), 7.50 (ddd, J = 8.4, 6.9, 1.5, 1H), 7.03-7.09 (m, 3H), 6.95 (ddd, J = 8.1, 6.6, 0.9 , 1H), 6.70 (m, 2H), 3.57 (s, 3H), 2.99 (s, 6H), 2.71 (s, 3H).

Example 36

(4-Ethoxy-phenyl)-(2-methyl-quinazolin-4-yl) -methyl-amine

The title compound was prepared (67%) from (2-methyl-quinazolin-4-yl)-(4-ethoxy-phenyl) -amine by a procedure similar to Example 7. ¹ H NMR (CDCl ₃ ): 7.71-7.74 (m, 1H), 7.51 (ddd, J = 8.1, 6.6, 1.5, 1H), 7.09 (m, 2H), 6.95-7.04 (m, 2H), 6.86 6.92 (m, 2H), 4.04 (q, J = 6.9, 2H), 3.58 (s, 3H), 2.72 (s, 3H), 1.44 (t, J = 6.9, 3H).

Example 37

(2-Methylthio-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine

(2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine (150 mg, 0.5 mmol), sodium methane in 5 mL of solvent (THF: MeOH: water = 3: 1: 1) A mixture of thioleate (105 mg, 1.5 mmol) was stirred at 70 ° C. for 4 hours. The reaction mixture was diluted with 30 mL of ethyl acetate, which was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by chromatography on silica gel using acetate and hexanes (1: 5) as eluent to afford 11 mg (7%) of the title compound. ¹ H NMR (CDCl ₃ ): 7.65 (d, J = 8.4 Hz, 1H), 7.51-7.45 (m, 1H), 7.14-7.10 (m, 2H), 6.93-6.89 (m, 4H), 3.84 (s , 3H), 3.58 (s, 3H), 2.67 (s, 3H).

Example 38

(2-Dimethylamino-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine

A mixture of (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine (150 mg, 0.5 mmol), 2.0 M dimethylamine in methanol (2.0 ml, 4 mmol) in a sealed tube Was stirred at 70-80 ° C. overnight. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by chromatography on silica gel using acetate and hexanes (1: 9) as eluent to give 128 mg (83%) of the title compound. ¹ H NMR (CDCl ₃ ): 7.44 (d, J = 7.8 Hz, 1H), 7.36-7.30 (m, 1H), 7.11-7.08 (m, 2H), 6.90-6.85 (m, 3H), 6.65-6.59 (m, 1 H), 3.82 (s, 3 H), 3.51 (s, 3 H), 3.30 (S, 6 H).

Example 39

(2-Methylamino-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine

(2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine (150 mg, 0.5 mmol), 2.0 M in THF (2.0 ml, 4 mmol) by a similar procedure as in Example 38 The title compound was prepared from methylamine (53.7%). ¹ H NMR (CDCl ₃ ): 7.45 (d, J = 7.8 Hz, 1H), 7.39-7.33 (m, 1H), 7.11-7.07 (m, 2H), 6.90-6.87 (m, 3H), 6.69-6.64 (m, 1H), 4.95 (brs, 1H), 3.82 (s, 3H), 3.50 (s, 3H), 3.11 (d, J = 5.1 Hz, 3H).

Example 40

(2-Methylamino-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl) -methyl-amine

(2-Chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl) -methyl-amine (69 mg, 0.23 mmol) in THF (4 ml, 8 mmol) by a procedure similar to Example 38. The title compound was prepared from and 2.0 M methylamine to give 20 mg (30%) of a yellow solid. ¹ H NMR (CDCl ₃ ): 8.02-8.01 (m, 1H), 7.48 (d, J = 8.1 Hz, 1H), 7.42-7.34 (m, 2H), 6.97-6.94 (m, 1H), 6.76-6.70 (m, 2H), 5.01 (brs, 1H), 3.95 (s, 3H), 3.50 (s, 3H), 3.12 (d, J = 5.1 Hz, 3H).

Example 41

(5-methoxy-pyridin-2-yl)-(2-methyl-quinazolin-4-yl) -methyl-amine

The title compound was prepared from (5-methoxy-pyridin-2-yl)-(2-methyl-quinazolin-4-yl) -amine by a procedure similar to Example 7. ¹ H NMR (CDCl ₃ ): 8.31 (d, 3.3, 1H), 7.80 (d, J = 8.4, 1H), 7.58 (ddd, J = 1.5, 6.6, 8.4, 1H), 7.13 (dd, J = 3.3 , 9.0, 1H), 6.99-7.10 (m, 2H), 6.82 (d, J = 9.0, 1H), 3.87 (s, 3H), 3.70 (s, 3H), 2.76 (s, 3H).

Example 42

(2-benzylamino-quinazolin-4-yl)-(4-methoxyphenyl) -methylamine

(2-Chloro-quinazolin-4-yl)-(4-methoxyphenyl) -methylamine (150 mg, 0.5 mmol), benzyl amine (110 uL, 1.0 mmol) and triethyl amine in 5 mL THF in a sealed tube ( 100 uL) was heated at 80 ° C. overnight. After cooling to rt, the reaction mixture was diluted with 25 mL of ethyl acetate, washed with saturated NaHCO ₃ , dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (35% ethyl acetate / hexanes) to give the title compound (25 mg, 0.067 mmol, 13%). ¹ H NMR (CDCl ₃ ): 7.24-7.46 (m, 7H), 7.10 (m, 2H), 6.84-6.92 (m, 3H), 6.68 (ddd, J = 8.1, 6.9, 1.5, 1H), 4.78 ( d, J = 6.5, 2H), 3.83 (s, 3H), 3.46 (s, 3H).

Example 43

(2-Methyl-quinazolin-4-yl)-(4-methylamino-phenyl) -methylamine

A mixture of (2-methyl-quinazolin-4-yl)-(N-methyl-4-acetamido-phenyl) -methylamine (103 mg, 0.321 mmol) in 3 mL methanol and 3 mL 2N NaOH at 4O < 0 > C for 4 hours Heated during. The reaction mixture was cooled to rt and diluted with 25 mL ethyl acetate. It was washed with saturated NaHCO ₃ , the organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (40% ethyl acetate / hexanes) to afford the title compound (28 mg, 0.10 mmol, 31%). ¹ H NMR (CDCl ₃ ): 7.71 (m, 1H), 7.50 (ddd, J = 8.4, 6.9, 1.5, 1H), 6.93-7.11 (m, 4H), 6.60 (m, 2H), 3.84 (s, broad, 1H), 3.57 (s, 3H), 2.87 (s, 3H), 2.70 (s, 3H).

Example 44

(2-Methyl-6-nitroquinazolin-4-yl)-(4-dimethylaminophenyl) -methylamine

4-chloro-2-methyl-6-nitro-quinazolinone (160 mg, 0.72 mmol), N ¹ , N ¹ , N ⁴ -trimethylbenzene-1,4- in 5 mL of solvent (THF: water / 1: 1) A mixture of diamine (0.84 mmol) and sodium acetate (70 mg, 0.90 mmol) was stirred at room temperature for 45 minutes. The reaction mixture was diluted with 50 mL of ethyl acetate and washed with saturated NaHCO ₃ . The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated. The crude product was purified by chromatography on silica gel (40% ethyl acetate / hexanes) to afford the title compound (231 mg, 0.68 mmol, 96%). ¹ H NMR (CDCl ₃ ): 8.24 (dd, J = 9.6, 3.0, 1H), 7.82 (d, J = 2.4, 1H), 7.72 (d, J = 9.0, 1H), 7.08 (m, 2H), 6.78 (m, 2H), 3.64 (s, 3H), 3.01 (s, 6H), 2.71 (s, 3H).

Example 45

(2-Chloro-quinazolin-4-yl)-(4-dimethylaminophenyl) -methylamine

The title compound was prepared from 2,4-dichloro-6-nitro-quinazolin and N ¹ , N ¹ , N ⁴ -trimethylbenzene-1,4-diamine by similar procedures as in Example 44. ¹ H NMR (CDCl ₃ ): 7.71 (m, 1H), 7.51-7.56 (m, 1H), 7.07 (m, 2H), 6.99 (m, 2H), 6.71 (m, 2H), 3.59 (s, 3H ), 3.01 (s, 6 H).

Example 46

(2-dimethylamino-6-nitroquinazolin-4-yl)-(4-methoxyphenyl) -methylamine

A solution of (2-chloro-6-nitroquinazolin-4-yl)-(4-methoxyphenyl) -methylamine (48 mg, 0.14 mmol) in 2 mL of dimethylamine in methanol (2M, 25 mmol) was placed in a sealed tube. Heated at 70 ° C. for 48 hours. The reaction mixture was cooled to rt and concentrated in vacuo. The residue was purified by chromatography (15% ethyl acetate / hexanes) to give the title compound (39 mg, 79%). ¹ H NMR (CDCl ₃ ): 8.08 (dd, J = 9.3, 2.4, 1H), 7.71 (d, J = 2.4, 1H), 7.35 (d, J = 93, 1H), 7.14 (m, 2H), 6.97 (2H), 3.85 (s, 3H), 3.55 (s, 3H), 3.33 (s, 6H).

Example 47

(2-Methylamino-quinazolin-4-yl)-(4-dimethylaminophenyl) -methylamine

The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-dimethylaminophenyl) -methylamine and methyl amine by a procedure similar to Example 46. ¹ H NMR (CDCl ₃ ): 7.42-7.42 (m, 1H), 7.34 (ddd, J = 8.1, 6.9, 4.0, 1H), 7.04 (m, 2H), 6.94 (m, 1H), 6.63-6.71 ( m, 3H), 5. 13 (s, broad, 1H), 3.49 (s, 3H), 3.10 (d, J = 4.8, 3H), 2.97 (s, 6H).

Example 48

[2- (N-Methyl-acetamido) -quinazolin-4-yl]-(4-dimethylaminophenyl) -methylamine

Triethylamine (50 uL, 0.36 mmol) in a solution of (2-methylamino-quinazolin-4-yl)-(4-dimethylaminophenyl) -methylamine (40 mg, 0.13 mmol) in 4 mL of methylene chloride cooled to 0 ° C. ), Several crystals of dimethylaminopyridine and acetic anhydride (50 uL, 0.53 mmol) were added. The reaction mixture was stirred at 0 ° C. for 1 hour to warm to room temperature and stirred overnight. The reaction mixture was diluted with 25 mL ethyl acetate and washed with 25 mL saturated sodium bicarbonate. The organic layer was dried over anhydrous NaSO ₄ , filtered and concentrated. The residue was purified by chromatography (40% ethyl acetate / hexanes) to give the title compound (39 mg, 0.11 mmol, 85%). ¹ H NMR (CDCl ₃ ): 7.65-7.69 (m, 1H), 7.52 (ddd, J = 8.4, 6.6, 1.8, 1H), 6.93-7.12 (m, 4H), 6.72 (m, 2H), 3.56 ( s, 3H), 3.01 (s, 6H), 2.52 (s, 3H).

Example 49

(4-Methylthio-phenyl)-(2-methyl-quinazolin-4-yl) -methylamine

Sodium hydride (56.4 mg, 1.40 mmol, 60) in a solution of (4-methylthio-phenyl)-(2-methyl-quinazolin-4-yl) -amine (263 mg, 0.94 mmol) in DMF (4 ml) at 0 ° C. % Oil suspension) was added followed by methyl iodide (0.09 ml, 1.40 mmol). The mixture was stirred at 0 ° C. for 1 h and then warmed to rt and stirred for 2 h. The reaction mixture was diluted with EtOAc (15 ml), washed with saturated aqueous NaHCO ₃ , brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using acetate and hexanes (1: 2 to 1: 1) as eluent to afford 120 mg (40.7%) of the title compound. ¹ H NMR (CDCl ₃ ): 7.76 (d, J = 9.0 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.24-7.19 (m, 2H), 7.10-6.97 (m, 4H), 3.59 (s, 3 H), 2.74 (s, 3 H), 2.48 (s, 3 H).

Example 50

(2-Dimethylamino-pyridin-5-yl)-(2-methyl-quinazolin-4-yl) -methylamine

Similar to Example 49, (2-dimethylamino-pyridin-5-yl)-(2-methyl-quinazolin-4-yl) -amine (45 mg, 0.16 mmol), methyl iodide (0.016 ml, 0.24 mmol), sodium hydride (9.6 mg, 0.24 mmol, 60% oil suspension) to give the title compound to give 22 mg (47%) of a pale yellow solid. ¹ H NMR (CDCl ₃ ): 8.07 (d, J = 2.4 Hz, 1H), 7.63 (dd, J = 0.9 Hz, J = 8.4 Hz, 1H), 7.56-7.51 (m, 1H), 7.27-7.18 ( m, 2H), 7.05-7.00 (m, 1H), 6.50 (d, J = 9.3 Hz, 1H), 3.55 (s, 3H), 3.12 (s, 6H), 2.72 (s, 3H).

Example 51

(4-Methoxy-phenyl)-(2-N-methylacetamido-quinazolin-4-yl) -methylamine

To a solution of (4-methoxy-phenyl)-(2-methylamine-quinazolin-4-yl) -methylamine (100 mg, 0.34 mmol) in 5 ml of dichloromethane, triethylamine (0.071 ml, 0.51) at 0 ° C. mmol), acetyl chloride (0.036 ml, 0.51 mmol), and then 2 mg DMAP. The reaction mixture was allowed to warm to rt and stirred for 2 h. The solvent was removed by vacuum. The residue was dissolved in EtOAc (20 ml), washed with water, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel using acetate, hexane and methanol (1: 3 to 1: 1: 0.05) as eluent to afford 36 mg (31.5%) of the title compound as a white solid. ¹ H NMR (CDCl ₃ ): 7.70-7.67 (m, 1 H), 7.56-7.52 (m, 1 H), 7.17-7.14 (m, 2 H), 6.97-6.93 (m, 4 H), 3.86 (s, 3 H) , 3.57 (s, 6H), 2.52 (s, 3H).

Example 52

(6-Dimethylamino-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl) -methylamine

(6-Amino-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl) -methylamine (16 mg, 0.05 mmol), 2 ml of 37% aqueous formaldehyde solution and sodium cyanoborohydride (6.3 mg) , 0.1 mmol) was added 2N HCl (0.05 ml) at 0 ° C. The reaction mixture was stirred for 1 h at 0 ° C., then diluted with EtOAc (10 ml), washed with saturated aqueous NaHCO ₃ , brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel using acetate, hexanes (1: 3 to 1: 1) as eluent to afford 11 mg (68.8%) of the title compound as a yellow solid. ¹ H NMR (CDCl ₃ ): 7.63 (d, J = 9.0 Hz, 1H), 7.20-7.12 (m, 3H), 6.91-6.88 (m, 2H), 6.23 (d, J = 2.7 Hz, 1H), 3.80 (s, 3H), 3.57 (s, 3H), 2.69 (s, 3H), 2.62 (s, 6H).

Example 53

(3,4,5-Trimethoxy-phenyl)-(2-methyl-quinazolin-4-yl) -methylamine

Similar to Example 49 (3,4,5-trimethoxy-phenyl)-(2-methyl-quinazolin-4-yl) -amine (232 mg, 0.71 mmol), methyl iodide (0.07 ml) in DMF , 1.O8 mmol), sodium hydride (43 mg, 1.08 mmol, 60% oil suspension) to give the title compound to give 65 mg (27%) of a white solid. ¹ H NMR (CDCl ₃ ): 7.75 (d, J = 8.4 Hz, 1H), 7.58-7.53 (m, 1H), 7.11-7.00 (m, 2H), 6.39 (s, 2H), 3.88 (s, 3H ), 3.73 (s, 6H), 3.62 (s, 3H), 2.74 (s, 3H).

Example 54

(2-Chloro-quinazolin-4-yl)-(4-nitro-phenyl) -methyl-amine

By a procedure similar to Example 1b, the title compound was obtained from 2,4-dichloroquinazolin (50 mg, 0.251 mmol) and 4-nitro-N-methylaniline (46 mg, 0.302 mmol) and isolated as a yellow powder (6 mg, 12%). ¹ H NMR (CDCl ₃ ): 8.24 (d, J = 8.7 Hz, 2H), 7.81 (dd, J = 8.1, and 2.4 Hz, 1H), 7.68 (ddd ,, J = 8.1, 7.5 and 2.4 Hz, 1H ), 7.28 (d, J = 8.7 Hz, 2H), 7.18 (ddd, J = 8.1, 7.5 and 2.4 Hz, 1H), 7.07 (d, J = 7.8 Hz, 1H), 3.75 (s, 3H).

Example 55

(2-Chloro-quinazolin-4-yl) -phenyl-methyl-amine

The title compound was prepared from 2,4-dichloroquinazolin (50 mg, 0.251 mmol) and N-methylaniline (20 μl, 0.301 mmol) by a procedure similar to Example 1b to be isolated as a white solid (40 mg, 80%). . ¹ H NMR (CDCl ₃ ): 7.76 (dd, J = 8.7, and 1.5 Hz, 1H), 7.56 (ddd, J = 8. 1, 6.6 and 1.5 Hz, 1H), 7.46-7.35 (m, 3H), 7.24-7.20 (m, 2H), 6.98 (ddd, J = 8.7, 6.6 and 1.5 Hz, IH) 3 6.90 (dd, J = 8.7 and 1.5 Hz, 1H), 3.65 (s, 3H).

Example 56

(2-Chloro-quinazolin-4-yl)-(2,5-dimethoxy-phenyl) -methyl-amine

The title compound was prepared (78% yield) from (2-chloro-quinazolin-4-yl)-(2,5-dimethoxy-phenyl) -amine and methyl iodide by a procedure similar to Example 7. ¹ H NMR (CDCl ₃ ): 7.72-7.75 (m, 1 H), 7.56 (ddd, J = 8.4, 5.7 and 2.1 Hz, 1 H), 6.98-7.00 (m, 2H), 6.92-6.92 (m, 2H) , 6.78-6.79 (m, 1 H), 3.75 (s, 3 H), 3,58 (s, 3 H), 3.56 (s, 3 H).

Example 57

(2-Chloro-quinazolin-4-yl)-(2-methoxy-phenyl) -methyl-amine

The title compound was prepared (72% yield) from (2-chloro-quinazolin-4-yl)-(2-methoxy-phenyl) -amine and methyl iodide by a procedure similar to Example 7. ¹ H NMR (CDCl ₃ ): 7.72 (d, J = 8.1 Hz, 1H), 7.54 (ddd, J = 8.4, 6.6 and 1.5 Hz, 1H), 7.20 C <ld, J = 8.4 and 1.8 Hz, 1H) , 6.87-7.04 (m, 4H), 3.67 (s, 3H), 3.56 (s, 3H).

Example 58

(2-Chloro-quinazolin-4-yl)-(4-hydroxyphenyl) -methylamine

60 μl (0.668 BBr ₃ ) in a solution of (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine (100 mg, 0.334 mmol) in 30 ml of dichloromethane cooled to −20 ° C. mmol) was added slowly. The reaction mixture was stirred at -20 ° C for 2 hours and then warmed to room temperature. It was stirred at this temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with cold 5% sodium bicarbonate. The organic phase was dried and concentrated. The residue was purified by small silica column using ethyl acetate and hexane (1: 3) as eluent to afford product (57 mg, 57%). ¹ H NMR (CDCl ₃ ): 7.65-7.56 (m, 2H), 7.04-6.87 (m, 5H), 3.59 (s, 3H).

The compounds of Examples 59 and 60 were prepared similar to Example 13.

Example 59

(2,7-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine

a) 7-chloro-quinazolin-2,4-dione: white solid: ¹ H NMR (DMSO-d ₆ ) 11.42 (s, 1H), 11.26 (s, 1H), 7.88 (d, J = 8.7 Hz, 1H), 7.22 (dd, J = 1.2, 8.1 Hz, 1H), 7.18 (d, J = 2.1 Hz, 1H).

b) (2,7-dichloro-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine: light yellow solid: ¹ H NMR (CDCl ₃ ): 7.70 (d, J = 2.4 Hz, 1H), 7.16-7.11 (m, 2H), 6.98-6.92 (m, 3H), 6.80 (d, J = 9.3 Hz, 1H), 3.86 (s, 3H), 3.60 (s, 3H).

Example 60

(2-Chloro-7-methyl-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine

a) 7-methyl-quinazolin-2,4-dione: white solid: ¹ H NMR (DMSO-d ₆ ) 10.07 (br s, 1H), 8.24 (s, 1H), 7.79 (d, J = 8.1 Hz , 1H), 6.78 (dd, J = 0.6, 9.0 Hz, IH) 5 6.54 (br s, 1H), 2.30 (s, 3H).

b) (2-chloro-7-methyl-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine: light yellow solid: ¹ H NMR (CDCl ₃ ): 7.51 (m, 1H), 7.16-7.10 (m, 2H), 6.96-6.91 (m, 2H), 6.83 (dd, J = 1.8, 8.7 Hz, 1H), 6.78 (d, J = 8.7 Hz, 1H), 3.85 (s, 3H) , 3.59 (s, 3 H), 2.38 (s, 3 H).

Example 61

Identification of (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine and its analogs as caspase cascade activators and inducers of apoptosis in solid tumor cells

Human breast cancer cell lines T-47D and DLD-1 were cultured at 37 ° C. in a 5% CO ₂ -95% humidity incubator with a media component mixture designated by the American Type Culture Collection (ATCC) + 10% FCS (manufacturer; Invitrogen Corporation) Invitrogen Corporation). T-47D and DLD-1 cells were maintained at a cell density of 50-80% confluency at a cell density of 0.1-0.6 x 10 ⁶ cells / mL. Cells were harvested at 600 × g and resuspended in appropriate medium + 10% FCS at 0.65 × 10 ⁶ cells / mL. An aliquot of 22.5 μL of cells was prepared using RPMI- containing 0.16 to 100 μM of (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine or other test compound (0.016 to 10 μM final). Add wells to 384-well microtiter plates containing 2.5 μl of 10% DMSO in 1640 medium. An aliquot of 22.5 μl of cells was added to the wells of a 384-well microtiter plate containing 2.5 μl of 10% DMSO in RPMI-1640 medium without test compound as a control sample. Samples were mixed by stirring and then incubated for 48 hours at 37 ° C. in a 5% CO ₂ -95% humidity incubator. After incubation, the sample was removed from the incubator and 14 μM of N- (Ac-DEVD) -N'-ethoxycarbonyl-R11O fluorescent substrate (Cytovia, Inc .; WO99 / 18856), 20% sucrose (Sigma), 20 mM DTT (Sigma), 200 mM NaCl (Sigma), 40 mM Na PIPES buffer pH 7.2 (Sigma) and solution containing 500 μg / mL lysorecithin (Calbiocheni) Μl was added. Samples were mixed by stirring and incubated at room temperature. To determine the background fluorescence of the control sample, an initial readout (T) was performed using a fluorescence plate reader (Model SPECTRAfluor Plus, Tecan) about 1-2 minutes after addition of the substrate solution using excitation at 485 nm and emission at 530 nm. = 0). After 3 hours of incubation, the fluorescence of the sample was read as described (T = 3 h).

Calculation:

Relative Fluorescence Unit values (RFU) were used to calculate sample readings as follows:

RFU _{(T = 3h)} -control RFU _{(T = 0)} = pure RFU _{(T = 3h)}

The activity of caspase cascade activation is determined by the ratio of the RFU value of (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine or other test compound to the RFU value of the control sample. Decided. EC ₅₀ (nM) was determined by sigmoidal dose-response calculation (Prism 3.0, GraphPad Software Inc.).

Caspase activity (ratio) and efficacy (EC ₅₀ ) are summarized in Table 1:

Example 62

Determination of Brain / Plasma AUC Ratios of (2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine and its analogs

For each test compound, 45 mice received 0.10 mL of a 0.875 mg / mL solution of the test compound dissolved in a formulation consisting of 5% cremophor, 5% ethanol and 90% D5W or a modified formulation thereof via the tail vein. Injection. Five mice each were euthanized by halotan inhalation at collection points of approximately 0.05, 0.25, 0.50, 1.00, 2.00, 4.00, 8.00, 12.0 and 24.0 hours after dose administration. About 0.30 to 1.00 mL of blood from each animal was collected via cardiac puncture into a tube containing EDTA. Immediately after blood collection, whole brains from each animal were taken out. Plasma and whole brain samples were frozen separately (˜20 ° C.) until analysis. Plasma and brain samples were thawed at room temperature on the day of sample analysis. Prior to homogenization, the brain was weighed and three times the volume of sterile water was added. Plasma and homogenized brain samples were extracted using protein precipitation and filtration. Briefly, 0.20 mL of acetonitrile was added to 0.10 mL of sample in a Varian Captiva 20 μm filter plate. Vacuum was applied to the plate and the filtrate was collected. The filtrate was injected into LC-MS / MS ABI2000 QTrap LC-MS / MS equipped with reverse phase liquid chromatography inlet. The peak area of m / z product ions of the test compound was measured against the peak area of m / z internal standard product ions. The quantitative range for analysis was 1.00-1000 ng / mL for both analytes.

Pharmacodynamic parameters (PK) for the test compounds were estimated using median plasma and brain concentration using non-compartmental analysis in WinNonlin (Pharsight Corp., Mountain View, Calif.). The validity of this software program is reported in MPI-REP-P A-03.00. All values below the quantitation limit (BQL) of 1.00 ng / mL were excluded from PK analysis. The area under the concentration-time curve (AUC _{0 −∝} ) was calculated using the linear / log trapezoidal method. The furnace / plasma AUC ratios of the example compounds tested are summarized in Table 2:

Brain / Plasma AUC Ratios Example Compound Brain / Plasma AUC Ratios One 22.99 11 6.14 17 9.16 21 19.70 33 5.82 35 16.11 39 6.44 40 10.01 43 14.12 51 23.31

Example 63

Injection formulation

Excipient amount

Active compound 5mg

PEG-400 5g

TPGS 10g

0.5 g benzyl alcohol

2 g of ethanol

Add in amounts to bring 50 mL of D5W

Injectable formulations of a compound selected from Formula I (“active compound”) can be prepared according to the following methods. 5 mg of active compound are dissolved in a mixture of d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), PEG-400, ethanol and benzyl alcohol. Add D5W to a total volume of 50 mL and mix the solution. The resulting solution is filtered through a 0.2 μm disposable filter unit and stored at 25 ° C. Solutions of varying concentrations and volumes are prepared by changing the ratio of active compounds in the mixture or by changing the total amount of solution.

Example 64

Tablet formulation

100.0 mg active compound

Lactose 100.0mg

Corn Starch 50.0mg

10.0 mg hydrogenated vegetable oil

Polyvinylpyrrolidone 10.0mg

                       270.0mg

Tablet formulations of compounds selected from Formula I (“active compounds”) can be prepared according to the following methods. 100 mg of active compound is mixed with 100 mg of lactose. The mixture is dried by adding an appropriate amount of water for drying. The mixture is then blended with 50 mg corn starch, 10 mg hydrogenated vegetable oil and 10 mg polyvinylpyrrolidone. The resulting granules are compressed into tablets. Tablets of varying concentrations are prepared by changing the ratio of active compounds in the mixture or by changing the total amount of tablets.

Example 65

Capsule Formulation

100.0 mg active compound

Microcrystalline Cellulose 200.0mg

Corn Starch 100.0mg

Magnesium Stearate 400.0mg

                       800.0mg

Capsule formulations containing 100.0 mg of a compound selected from Formula I (“active compound”) can be prepared according to the following method. 100 mg of active compound are mixed with 200 mg of microcrystalline cellulose and 100 mg of corn starch. 400 mg of magnesium stearate is then blended into the mixture and the resulting blend is encapsulated in gelatin capsules. Doses of varying concentrations may be prepared by changing the ratio of the active compound to pharmaceutically acceptable carrier or by changing the size of the capsule.

Although the present invention has been described in detail, those skilled in the art will understand that the invention can be carried out within a broad and equivalent range of conditions, formulations and other parameters without affecting the scope of the invention or aspects thereof. All patents, patent publications, and publications cited herein are hereby fully incorporated by reference in their entirety.

Claims (45)

Mammals in need of treatment of brain or central nervous system diseases, including administering to a mammal in need of treatment of brain or central nervous system diseases an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof Use of a compound of formula (I) to prepare a medicament useful for treating a disease of the brain or central nervous system that is sensitive to inducing apoptosis, activating caspases, inhibiting tubulin, or inhibiting topoisomerase in an animal. Formula I

In Formula I above, And R ₁ is C _{1 -3} alkyl, R ₂ is _{halo, R 14, OR 14, SR} 14, NR 15 R 14 or _{NR 14 (C = O) C} 1-6 alkyl (wherein, R ₁₅ is C _{1 -6} alkyl, C _{2 -6} alkenyl, C _{2 -6-alkynyl,} C _{1 -6} haloalkyl, C _{3 -8} carbocycle, C _{3 -8} and heterocyclyl, C _6-10 aryl or alkyl, R ₁₄ is H, C _{1 -6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1 -6} to roal keel, a C _{3 -8} carbocycle, C _{3 -8} heterocycle, C _{6 -10} aryl or arylalkyl), and R ₃ , R ₄ , R ₆ to R ₈ , R ₁₀ to R ₁₃ are independently halo, R ₁₆ , NR ₁₆ R ₁₇ , OR ₁₆ or SR ₁₆ , wherein R ₁₆ and R ₁₇ are independently H, C _{1 -6} alkyl, C _{2 -6} alkenyl is, C _{2 -6-alkynyl} or C _{1 -6} haloalkyl, R ₁₆ and R ₁₇ are not both are H), and R ₅ is H or C _{1 -3} alkyl, R ₉ is H, _{halo, R 18, OR 18, SR} 18 or NR ₁₈ R ₁₉ (wherein, R ₁₈ and R ₁₉ are independently H, C _{1 -6} alkyl, C _{2 -6} alkenyl, C _{2 -6} alkynyl is a carbonyl or C _{1 -6} haloalkyl, R ₁₈ and R ₁₉ are both not H), or, and R ₉ optionally form a heterocycle together with one of R ₈ and R _10, B, D, W, X, Y and Z are independently C or N, at least one of B and D is N, and one or less of W, X, Y and Z is N, B, D, W, X If, Y or Z is N, N has no substituent. 2. Use according to claim 1, wherein B is C and D is N. The use according to claim 1 or 2, wherein X or Y is N. The use according to any one of claims 1 to 3, wherein W or Z is N. Any one of claims 1 to 4 according to any one of wherein, R ₂ is C _{1 -3} alkyl, halo, C _{1 -3} haloalkyl, -OC _{1 -3} alkyl, -SC _{1 -3} alkyl, C _{3 -8} the use heterocycle, NR _2a C _{1 -3 alkyl, NR 2a (C = O)} C 1-3 alkyl or NR _2a (aryl) (wherein, R _2a is H or C _{1 -3} alkyl). The use according to any one of claims 1 to 5, wherein R ₁ is CH ₃ . The use according to any one of claims 1 to 6, wherein R ₅ is H. The method according to any one of claims 1 to 7 _{wherein, R 3, R 4, R} 6 to R _8, R _10, if the R ₁₁ and R _12, present, R ₁₃ is independently H, C _{1 - 3} alkyl, halo, NH (C _{1 -3} alkyl), N (C _{1 -3} alkyl) ₂ or -OC _{1 -3} alkyl purposes. Any one of claims 1 to 8 according to any one of wherein, R ₉ is H, OH, C _{1 -3} alkyl, halo, C _1-3 haloalkyl, -OC _{1 -3} alkyl, -SC _{1 -3} alkyl, -OC _{1 -3} haloalkyl, or NR _9a R _9b (wherein, R _9a and R _9b are independently H or C _{1 -3} alkyl, and not the R _9a and R _9b are both H), or, optionally, R ₉ the use to form a C _{3 -8} heterocycle with R ₈ and R ₁₀ one. The method according to any one of claims 1 to 4, R ₁ is CH ₂ CH ₃ or CH ₃ , R ₂ is CH ₂ CH ₃ , CH ₃ , Cl, CH ₂ F, OCH ₃ , SCH ₃ , morpholino, NHCH ₃ , NCH ₃ (C═O) CH ₃ or NHCH ₂ C ₆ H ₅ , R ₃ , R ₄ , R ₆ , R ₁₂ and R ₁₃ are independently H, CH ₃ , Cl, NHCH ₃ , N (CH ₃ ) ₂ or OCH ₃ , R ₅ is H, R ₇ , R ₈ , R ₁₀ and R ₁₁ are independently H, F or OCH ₃ , R ₉ is H, OH, Cl, CH ₃ , CH ₂ CH ₃ , OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ , SCH ₃ , OCF ₃ , OCHF ₂ , OCH (CH ₃ ) ₂ , N ( CH ₃ ) ₂ or NHCH _3, or optionally R ₉ forms with 1 of R ₈ and R ₁₀ a 1,3-dioxolane. 2. Use according to claim 1, wherein the compound is a compound of Formula II or a pharmaceutically acceptable salt or solvate thereof. Formula II

In Formula II above, And R ₁ is C _{1 -3} alkyl, R ₂ is _{halo, R 14, OR 14, SR} 14, NR 15 R 14 or _{NR 14 (C = O) C} 1-6 alkyl (wherein, R ₁₅ is C _{1 -6} alkyl, C _{2 -6} alkenyl, C _{2 -6-alkynyl,} C _{1 -6} haloalkyl, C _{3 -8} carbocycle, C _{3 -8} and heterocyclyl, C _6-10 aryl or alkyl, R ₁₄ is H, C _{1 -6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, a C _{1 -6} haloalkyl, C _{3 -8} carbocycle, C _{3 -8} heterocycle, C _{6 -10} aryl or arylalkyl), and R ₃ , R ₄ , R ₆ to R ₈ , R ₁₀ and R ₁₁ are independently halo, R ₁₆ , NR ₁₆ R ₁₇ , OR ₁₆ or SR ₁₆ , wherein R ₁₆ and R ₁₇ are independently H, C _{1 -6} alkyl, C _{2 -6} alkenyl is, C _{2 -6-alkynyl} or C _{1 -6} haloalkyl, R ₁₆ and R ₁₇ are not both are H), and R ₅ is H or C _{1 -3} alkyl, R ₉ is H, _{halo, R 18, OR 18, SR} 18 or NR ₁₈ R ₁₉ (wherein, R ₁₈ and R ₁₉ are independently H, C _{1 -6} alkyl, C _{2 -6} alkenyl, C _{2 -6} alkynyl is a carbonyl or C _{1 -6} haloalkyl, R ₁₈ and R ₁₉ are both not H), or, and R ₉ optionally form a heterocycle together with one of R ₈ and R _10, W, X, Y and Z are independently C or N, one or less of W, X, Y and Z is N, and there is no substituent in N when W, X, Y or Z is N. Use according to claim 11, wherein X or Y is N. 13. Use according to claim 11 or 12, wherein W or Z is N. Claim 11 to 13 according to any one of wherein, R ₂ is C _{1 -3} alkyl, halo, C _{1 -3} haloalkyl, -OC _{1 -3} alkyl, -SC _{1 -3} alkyl, C _{3 -8} the use heterocycle, NR _2a C _{1 -3 alkyl, NR 2a (C = O)} C 1-3 alkyl or NR _2a (aryl) (wherein, R _2a is H or C _{1 -3} alkyl). The use according to any one of claims 11 to 14, wherein R ₁ is CH ₃ . Use according to any one of claims 11 to 15, wherein R ₅ is H. 12. The method of claim 11 to any one of claim 16, wherein, R _3, R _4, R ₆ to R _8, R ₁₀ and R ₁₁ are independently H, C _{1 -3} alkyl, halo, NH (C _{1 -3} alkyl), N (C _{1 -3} alkyl) ₂ or -OC _{1 -3} alkyl purposes. Claim 11 to 17 according to any one of wherein, R ₉ is H, OH, C _{1 -3} alkyl, halo, C _{1 -3} haloalkyl, -OC _{1 -3} alkyl, -SC _{1 -3} alkyl, -OC _{1 -3} haloalkyl, or NR _9a R _9b (wherein, R _9a and R _9b are independently H or C _{1 -3} alkyl, and not the R _9a and R _9b are both H), or, optionally, R ₉ the use to form a C _{3 -8} heterocycle with R ₈ and R ₁₀ one. The method according to any one of claims 11 to 13, R ₁ is CH ₂ CH ₃ or CH ₃ , R ₂ is CH ₂ CH ₃ , CH ₃ , Cl, CH ₂ F, OCH ₃ , SCH ₃ , morpholino, NHCH ₃ , NCH ₃ (C═O) CH ₃ or NHCH ₂ C ₆ H ₅ , R ₃ , R ₄ and R ₆ are independently H, CH ₃ , Cl, NHCH ₃ , N (CH ₃ ) ₂ or OCH ₃ , R ₅ is H, R ₇ , R ₈ , R ₁₀ and R ₁₁ are independently H, F or OCH ₃ , R ₉ is H, OH, Cl, CH ₃ , CH ₂ CH ₃ , OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ , SCH ₃ , OCF ₃ , OCHF ₂ , OCH (CH ₃ ) ₂ , N ( CH ₃ ) ₂ or NHCH _3, or optionally R ₉ forms with 1 of R ₈ and R ₁₀ a 1,3-dioxolane. Use according to claim 1, wherein the compound is a compound of Formula III or a pharmaceutically acceptable salt or solvate thereof. Formula III

In Formula III above, And R ₁ is C _{1 -3} alkyl, R ₂ is _{halo, R 15, OR 14, SR} 14, NR 15 R 14 or _{NR 14 (C = O) C} 1-6 alkyl (wherein, R ₁₅ is C _{1 -6} alkyl, C _{2 -6} alkenyl, C _{2 -6-alkynyl,} C _{1 -6} haloalkyl, C _{3 -8} carbocycle, C _{3 -8} and heterocyclyl, C _6-10 aryl or alkyl, R ₁₄ is H, C _{1 -6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, a C _{1 -6} haloalkyl, C _{3 -8} carbocycle, C _{3 -8} heterocycle, C _{6 -10} aryl or arylalkyl), and R ₃ , R ₄ , R ₆ to R ₈ , R ₁₀ and R ₁₁ are independently halo, R ₁₆ , NR ₁₆ R ₁₇ , OR ₁₆ or SR ₁₆ , wherein R ₁₆ and R ₁₇ are independently H, C _{1 -6} alkyl, C _{2 -6} alkenyl is, C _{2 -6-alkynyl} or C _{1 -6} haloalkyl, R ₁₆ and R ₁₇ are not both are H), and R ₅ is H or C _{1 -3} alkyl, R ₉ is H, _{halo, R 18, OR 18, SR} 18 or NR ₁₈ R ₁₉ (wherein, R ₁₈ and R ₁₉ are independently H, C _{1 -6} alkyl, C _{2 -6} alkenyl, C _{2 -6} alkynyl is a carbonyl or C _{1 -6} haloalkyl, not the R ₁₈ and R ₁₉ are both H), or, R ₉ optionally may form a heterocycle together with R ₈ and R ₁₀ one. 21. The method of claim 20 wherein, R ₂ is C _{1 -3} alkyl, halo, C _{1 -3} haloalkyl, -OC _{1 -3} alkyl, -SC _{1 -3} alkyl, C _{3 -8} heterocycle, NR _2a C _{1 - 3 alkyl, NR 2a (C = O)} C 1-3 alkyl or NR _2a (aryl) (wherein, R _2a is H or C _{1 -3} alkyl) purposes. 22. The use of claim 20 or 21, wherein R ₁ is CH ₃ . 23. The use of any one of claims 20 to 22, wherein R ₅ is H. 21. The method of claim 20 to any one of claim 23, wherein, R _3, R _4, R ₆ to R _8, R ₁₀ and R ₁₁ are independently H, C _{1 -3} alkyl, halo, NH (C _{1 -3} alkyl), N (C _{1 -3} alkyl) ₂ or -OC _{1 -3} alkyl purposes. Of claim 20 to claim 24 according to any one of wherein, R ₉ is H, OH, C _{1 -3} alkyl, halo, C _{1 -3} haloalkyl, -OC _{1 -3} alkyl, -SC _{1 -3} alkyl, -OC _{1 -3} haloalkyl, or NR _9a R _9b (wherein, R _9a and R _9b are independently H or C _{1 -3} alkyl, and not the R _9a and R _9b are both H), or, optionally, R ₉ the use to form a C _{3 -8} heterocycle with R ₈ and R ₁₀ one. The method of claim 20, R ₁ is CH ₂ CH ₃ or CH ₃ , R ₂ is CH ₂ CH ₃ , CH ₃ , Cl, CH ₂ F, OCH ₃ , SCH ₃ , morpholino, NHCH ₃ , NCH ₃ (C═O) CH ₃ or NHCH ₂ C ₆ H ₅ , R ₃ , R ₄ and R ₆ are independently H, CH ₃ , Cl, NHCH ₃ , N (CH ₃ ) ₂ or OCH ₃ , R ₅ is H, R ₇ , R ₈ , R ₁₀ and R ₁₁ are independently H, F or OCH ₃ , R ₉ is H, OH, Cl, CH ₃ , CH ₂ CH ₃ , OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ , SCH ₃ , OCF ₃ , OCHF ₂ , OCH (CH ₃ ) ₂ , N ( CH ₃ ) ₂ or NHCH _3, or optionally R ₉ forms with 1 of R ₈ and R ₁₀ a 1,3-dioxolane. The method of claim 20, R ₁ is CH ₃ , R ₂ is CH ₃ , Cl, OCH ₃ , NHCH ₃ or NCH ₃ (C═O) CH ₃ , R ₃ to R ₆ , R ₇ , R ₈ , R ₁₀ and R ₁₁ are H, R ₉ is OCH ₃ , N (CH ₃ ) ₂ or NHCH ₃ . 27. The use of any one of claims 1 to 26, wherein when R ₉ is H, both R ₈ and R ₁₀ are not H or one is H and the other is halo. 27. The use of any one of claims 1 to 26, wherein when R ₉ is H, both R ₈ and R ₁₀ are not H or one is H and the other is halo, alkyl or haloalkyl. Claim 1 to claim 26 according to any one of wherein, if R ₉ is a C _1-6 alkyl, halo, or C _1-6 haloalkyl, R ₂ is not H purpose. 27. The use according to any one of claims 1 to 26, wherein when R ₉ is H, both R ₈ and R ₁₀ are not H or one is H and the other is halo and R ₂ is not H. The compound of claim 1 wherein the compound is (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine, (2-methoxy-quinazolin-4-yl)-(4-methoxyphenyl) -methylamine, (4-methoxy-phenyl) -methyl- (quinolin-4-yl) -amine, (4-methoxy-phenyl) -methyl- (2-methyl-quinazolin-4-yl) -amine hydrochloride, (2-methyl-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl) -methyl-amine, (4-dimethylamino-phenyl)-(2-methyl-quinazolin-4-yl) -methyl-amine, (2-methylamino-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine, (2-methylamino-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl) -methyl-amine, (2-methyl-quinazolin-4-yl)-(4-methylamino-phenyl) -methylamine, (4-methoxy-phenyl)-(2-N-methylacetamido-quinazolin-4-yl) -methylamine and a pharmaceutically acceptable salt or solvate thereof. The compound of claim 1 wherein the compound is (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine, (2-chloro-quinazolin-4-yl)-(4-methyl-phenyl) -methyl-amine, (2-chloro-quinazolin-4-yl)-(4-chloro-phenyl) -methyl-amine, (2-chloro-quinazolin-4-yl)-(4-trifluoromethoxy-phenyl) -methyl-amine, (2-chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl) -methyl-amine, (2-chloro-quinazolin-4-yl) -ethyl- (4-methoxy-phenyl) -amine, (2-chloro-quinazolin-4-yl)-(2,4-dimethoxy-phenyl) -methyl-amine, (2-chloro-quinazolin-4-yl)-(3-methoxy-phenyl) -methyl-amine, (2-chloro-6-methyl-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine, (2-chloro-5-methyl-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine, (2-chloro-8-methyl-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine, (2,6-dichloro-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine, (2-chloro-quinazolin-4-yl)-(3,4-methylenedioxyphenyl) -methyl-amine, (2-chloro-quinazolin-4-yl)-(3,4-dimethoxy-phenyl) -methyl-amine, (2-chloro-quinazolin-4-yl)-(4-propoxy-phenyl) -methyl-amine, (2-chloro-quinazolin-4-yl)-(2,3-dimethoxy-phenyl) -methyl-amine, (2,8-dichloro-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine, (2,5-dichloro-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine, (2-chloro-quinazolin-4-yl)-(4-ethoxy-phenyl) -methylamine, (2-chloro-quinazolin-4-yl)-(4-dimethylaminophenyl) -methylamine, (2-chloro-quinazolin-4-yl)-(4-nitro-phenyl) -methyl-amine, (2-chloro-quinazolin-4-yl) -phenyl-methyl-amine, (2-chloro-quinazolin-4-yl)-(2,5-dimethoxy-phenyl) -methyl-amine, (2-chloro-quinazolin-4-yl)-(2-methoxy-phenyl) -methyl-amine, (2-chloro-quinazolin-4-yl)-(4-hydroxyphenyl) -methylamine, (2,7-dichloro-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine, (2-chloro-7-methyl-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine and pharmaceutically acceptable salts or solvates thereof. The compound of claim 1 wherein the compound is (2-fluoromethyl-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine, (4-methoxy-phenyl) -methyl- (2-methyl-quinazolin-4-yl) -amine hydrochloride, (2-chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine, (2-ethyl-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine, (4-difluoromethoxy-phenyl)-(2-methyl-quinazolin-4-yl) -methyl-amine, (3-fluoro-4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl) -methyl-amine, (4-isopropoxy-phenyl)-(2-methyl-quinazolin-4-yl) -methyl-amine, (4-ethyl-phenyl)-(2-methyl-quinazolin-4-yl) -methyl-amine, (5-methoxy-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine, (2-methyl-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl) -methyl-amine, (2-fluoro-4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl) -methyl-amine, (4-dimethylamino-phenyl)-(2-methyl-quinazolin-4-yl) -methyl-amine, (4-ethoxy-phenyl)-(2-methyl-quinazolin-4-yl) -methyl-amine, (5-methoxy-pyridin-2-yl)-(2-methyl-quinazolin-4-yl) -methyl-amine, (2-methyl-quinazolin-4-yl)-(4-methylamino-phenyl) -methylamine, (2-methyl-6-nitroquinazolin-4-yl)-(4-dimethylaminophenyl) -methylamine, (4-methylthio-phenyl)-(2-methyl-quinazolin-4-yl) -methylamine, (2-dimethylamino-pyridin-5-yl)-(2-methyl-quinazolin-4-yl) -methylamine, (6-dimethylamino-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl) -methylamine, (3,4,5-trimethoxy-phenyl)-(2-methyl-quinazolin-4-yl) -methylamine and a pharmaceutically acceptable salt or solvate thereof. The compound of claim 1 wherein the compound is N ² - hydroxyl -N ⁴ - (4- methoxy-phenyl) -N ^{4-methyl-quinazoline-2,4-diamine,} (4-methoxy-phenyl) -methyl- (2-morpholin-4-yl-quinazolin-4-yl) -amine, (2-methoxy-quinazolin-4-yl)-(4-methoxyphenyl) -methylamine, (4-methoxy-phenyl) -methyl- (quinolin-4-yl) -amine, (2-methylthio-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine, (2-dimethylamino-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine, (2-methylamino-quinazolin-4-yl)-(4-methoxy-phenyl) -methyl-amine, (2-methylamino-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl) -methyl-amine, (2-benzylamino-quinazolin-4-yl)-(4-methoxyphenyl) -methylamine, (2-dimethylamino-6-nitroquinazolin-4-yl)-(4-methoxyphenyl) -methylamine, (2-methylamino-quinazolin-4-yl)-(4-dimethylaminophenyl) -methylamine, [2- (N-Methyl-acetamido) -quinazolin-4-yl]-(4-dimethylaminophenyl) -methylamine, (4-methoxy-phenyl)-(2-N-methylacetamido-quinazolin-4-yl) -methylamine and a pharmaceutically acceptable salt or solvate thereof. 36. The use of any one of claims 1 to 35, wherein the disease is a neoplasm of the brain or central nervous system. 37. The use of claim 36, wherein the disease is brain cancer. 37. The use of claim 36, wherein the disease is metastatic brain cancer. 37. The use of claim 36, wherein the disease is primary brain cancer. The use of claim 36, wherein the disease is anaplastic astrocytoma, glioblastoma, meningioma or other mesenchymal tumor. 41. The use of any one of claims 1-40, wherein the brain / plasma AUC ratio is at least about 5. 41. The use of any of claims 1-40, wherein the brain / plasma AUC ratio is at least about 10. 41. The use of any of claims 1-40, wherein the brain / plasma AUC ratio is at least about 15. 44. The use of any one of claims 1-43, wherein the calculated polar surface area of the compound is less than about 100 square millimeters. The use of any one of claims 1-43, wherein the calculated polar surface area of the compound is less than about 80 square millimeters.