US20130029942A1

US20130029942A1 - Compounds and therapeutical uses thereof

Info

Publication number: US20130029942A1
Application number: US13/644,419
Authority: US
Inventors: Mark B. Anderson; J. Adam Willardsen; Warren S. Weiner; Ashantai Yungai; Robert J. Halter; Yevgeniya Klimova; Suzuki Kazuyuki; Matthew Reeder
Original assignee: Myrexis Inc
Current assignee: Myrexis Inc
Priority date: 2003-07-03
Filing date: 2012-10-04
Publication date: 2013-01-31
Also published as: US20100069383A1; US8309562B2

Abstract

Disclosed are 4-arylamino-quinazolines and analogs thereof that are effective as activators of caspases and inducers of apoptosis. The compounds of this invention are useful in the treatment of a variety of clinical conditions in which uncontrolled growth and spread of abnormal cells occurs.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of prior U.S. application Ser. No. 12/500,863, filed Jul. 10, 2009, which is a continuation-in-part of prior U.S. application Ser. No. 10/885,903, filed Jul. 6, 2004; U.S. application Ser. No. 12/500,863 claims the benefit of U.S. Provisional Application No. 61/079,889, filed Jul. 11, 2008; and U.S. application Ser. No. 10/885,903 claims the benefit of U.S. Provisional Application No. 60/484,325, filed Jul. 3, 2003, U.S. Provisional Application No. 60/493,006, filed Aug. 7, 2003, U.S. Provisional Application No. 60/557,556, filed Mar. 29, 2004, and U.S. Provisional Application No. 60/571,288, filed May 14, 2004; the contents of all of which are hereby incorporated by reference herein in their entirety.

FIELD OF THE INVENTION

This invention is in the field of medicinal chemistry. In particular, the invention relates to compounds that are activators of caspases and inducers of apoptosis. The invention also relates to the use of these compounds as therapeutically effective anti-cancer agents.

TECHNICAL BACKGROUND

Organisms eliminate unwanted cells by a process variously known as regulated cell death, programmed cell death or apoptosis. Such cell death occurs as a normal aspect of animal development, as well as in tissue homeostasis and aging (Glucksmann, A., Biol. Rev. Cambridge Philos. Soc. 26:59-86 (1951); Glucksmann, 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, facilitates morphogenesis, removes harmful or otherwise abnormal cells and eliminates cells that have already performed their function. Additionally, apoptosis occurs in response to various physiological stresses, such as hypoxia or ischemia (PCT published application WO96/20721).
There are a number of morphological changes shared by cells experiencing regulated cell death, including plasma and nuclear membrane blebbing, cell shrinkage (condensation of nucleoplasm and cytoplasm), organelle relocalization and compaction, chromatin condensation and production of apoptotic bodies (membrane enclosed particles containing intracellular material) (Orrenius, S., J. Internal Medicine 237:529-536 (1995)).
Apoptosis is achieved through an endogenous mechanism of cellular suicide (Wyllie, A. H., in Cell Death in Biology and Pathology, Bowen and Lockshin, eds., Chapman and Hall (1981), pp. 9-34). A cell activates its internally encoded suicide program as a result of either internal or external signals. The suicide program is executed through the activation of a carefully regulated genetic program (Wyllie, et al., Int. Rev. Cyt. 68:251 (1980); Ellis, et al., Ann. Rev. Cell Bio. 7:663 (1991)). Apoptotic cells and bodies are usually recognized and cleared by neighboring cells or macrophages before lysis. Because of this clearance mechanism, inflammation is not induced despite the clearance of great numbers of cells (Orrenius, S., J. Internal Medicine 237:529-536 (1995)).
It has been found that a group of proteases are a key element in apoptosis (see, e.g., Thornberry, Chemistry and Biology 5:R97-R103 (1998); Thornberry, British Med. Bull. 53:478-490 (1996)). Genetic studies in the nematode Caenorhabditis elegans revealed that apoptotic cell death involves at least 14 genes, 2 of which are the pro-apoptotic (death-promoting) ced (for cell death abnormal) genes, ced-3 and ced-4. CED-3 is homologous to interleukin 1 beta-converting enzyme, a cysteine protease, which is now called caspase-1. When these data were ultimately applied to mammals, and upon further extensive investigation, it was found that the mammalian apoptosis system appears to involve a cascade of caspases, or a system that behaves like a cascade of caspases. At present, the caspase family of cysteine proteases comprises 14 different members, and more may be discovered in the future. All known caspases are synthesized as zymogens that require cleavage at an aspartyl residue prior to forming the active enzyme. Thus, caspases are capable of activating other caspases, in the manner of an amplifying cascade.
Apoptosis and caspases are thought to be crucial in the development of cancer (Apoptosis and Cancer Chemotherapy, Hickman and Dive, eds., Humana Press (1999)). There is mounting evidence that cancer cells, while containing caspases, lack parts of the molecular machinery that activates the caspase cascade. This makes the cancer cells lose their capacity to undergo cellular suicide and the cells become cancerous. In the case of the apoptosis process, Control points are known to exist that represent points for intervention leading to activation. These control points include the CED-9-BCL-like and CED-3-ICE-like gene family products, which are intrinsic proteins regulating the decision of a cell to survive or die and executing part of the cell death process itself, respectively (see, Schmitt, et al., Biochem. Cell. Biol. 75:301-314 (1997)). BCL-like proteins include BCL-xL and BAX-alpha, which appear to function upstream of caspase activation. BCL-xL appears to prevent activation of the apoptotic protease cascade, whereas BAX-alpha accelerates activation of the apoptotic protease cascade.
It has been shown that chemotherapeutic (anti-cancer) drugs can trigger cancer cells to undergo suicide by activating the dormant caspase cascade. This may be a crucial aspect of the mode of action of most, if not all, known anticancer drugs (Los, et al., Blood 90:3118-3129 (1997); Friesen, et al., Nat. Med. 2:574 (1996)). The mechanism of action of current antineoplastic drugs frequently involves an attack at specific phases of the cell cycle. In brief, the cell cycle refers to the stages through which cells normally progress during their lifetime. Normally, cells exist in a resting phase termed G_o. During multiplication, cells progress to a stage in which DNA synthesis occurs, termed S. Later, cell division, or mitosis occurs, in a phase called M. Antineoplastic drugs, such as cytosine arabinoside, hydroxyurea, 6-mercaptopurine, and methotrexate are S phase specific, whereas antineoplastic drugs, such as vincristine, vinblastine, and paclitaxel are M phase specific. M phase specific antineoplastic drugs, such as vinblastine and paclitaxel, are known to affect tubulin polymerization. The ability of cells to appropriately polymerize and depolymerize tubulin is thought to be an important activity for M phase cell division.
Many slow growing tumors, e.g. colon cancers, exist primarily in the G_ophase, whereas rapidly proliferating normal tissues, for example bone marrow, exist primarily in the S or M phase. Thus, a drug like 6-mercaptopurine can cause bone marrow toxicity while remaining ineffective for a slow growing tumor. Further aspects of the chemotherapy of neoplastic diseases are known to those skilled in the art (see, e.g., Hardman, et al., eds., Goodman and Gilman's The Pharmacological Basis of Therapeutics, Ninth Edition, McGraw-Hill, New York (1996), pp. 1225-1287). Thus, it is clear that the possibility exists for the activation of the caspase cascade, although the exact mechanisms for doing so are not clear at this point. It is equally clear that insufficient activity of the caspase cascade and consequent apoptotic events are implicated in various types of cancer. The development of caspase cascade activators and inducers of apoptosis is a highly desirable goal in the development of therapeutically effective antineoplastic agents. Moreover, since autoimmune disease and certain degenerative diseases also involve the proliferation of abnormal cells, therapeutic treatment for these diseases could also involve the enhancement of the apoptotic process through the administration of appropriate caspase cascade activators and inducers of apoptosis.
EP520722 discloses derivatives of 4-anilino-quinazolines as inhibitors of the EGFR tyrosine kinase with antitumor activity:
wherein, for example, R^ais hydrogen, trifluoromethyl, or nitro, n is 1; and R^bis halogen, trifluoromethyl or nitro.
EP602851 discloses quinazolines as inhibitors of the EGFR tyrosine kinase:
wherein, for example R^ais hydroxy, amino, ureido, or trifluoromethoxy, m is 1, 2 or 3; Q is a 9 or 10-membered bicyclic heterocyclic moiety.
EP635498 discloses 4-anilino-quinazolines as inhibitors of the EGFR tyrosine kinase:
wherein, for example R₁includes hydroxy, amino or C_1-4alkoxy, R₂is hydrogen, hydroxy, or halogen, R₃is halogen, n is 1, 2 or 3.
EP635507 discloses tricyclic derivatives as inhibitors of the EGFR tyrosine kinase:
wherein, R₁and R₂together form an optionally substituted 5 or 6 membered ring containing at least one heteroatom; R₃includes hydrogen, hydroxy, or halogen, m is 1, 2 or 3.
WO9609294 discloses substituted heteroaromatic compounds as inhibitors of protein tyrosine kinase:
wherein, for example X is N or CH; Y is O, S, or NR^awherein R^ais H or C_1-8alkyl; R₁, R₂, R₃and R₃′ includes amino, hydrogen, hydroxy, or halogen; R₄includes amino, hydrogen, hydroxy, or halogen; n is 1, 2 or 3; R₅is selected from the group comprising hydrogen, halogen, trifluoromethyl, C_1-4alkyl and C_1-4alkoxy; R₆is a group ZR₇wherein Z includes O, S or NH and R₇is an optionally substituted C_3-6cycloalkyl, or an optionally substituted 5,6,7,8,9,10-membered carbocyclic or heterocyclic moiety.
WO9713771 discloses substituted heteroaromatic compounds as inhibitors of protein tyrosine kinase:
wherein, for example X is N or CH; U represents a fused 5,6,7-membered heterocyclic ring; Y is O, S, or NR^awherein R^ais H or C_1-8alkyl; R₁included 5,6-membered heterocyclic ring, or amino, hydrogen, hydroxy, or halogen; n is 0, 1, 2 or 3. R₂is selected from the group comprising hydrogen, halogen, trifluoromethyl, C_1-4alkyl and C_1-4alkoxy; R₃is a group ZR₄wherein Z includes O, S or NH and R₄is an optionally substituted C_3-6cycloalkyl, or an optionally substituted 5,6,7,8,9,10-membered carbocyclic or heterocyclic moiety. R₅includes hydrogen, hydroxy, or halogen; n is 1, 2 or 3.
WO9802438 discloses bicyclic heteroaromatic compounds as inhibitors of protein tyrosine kinase:
wherein, for example X is N or CH; Y is O, S, or NR^awherein R^ais H or C_1-8alkyl; R″ represents a phenyl group or a 5- or 6-membered heterocyclic ring, or amino, hydrogen, hydroxy, or halogen; n is 0 or 1. R₁includes amino, hydrogen, hydroxy, or halogen; p is 0 to 3. R₂is selected from the group comprising hydrogen, halogen, trifluoromethyl, C_1-4alkyl and C_1-4alkoxy; U represents a 5 to 10-membered mono or bicyclic ring system; A represents a fused 5, 6, or 7-membered heterocyclic ring.
Myers et al. (Bioorg. Med. Chem. Lett. 7:421-424 (1997)) reported 4-(N-methyl-N-phenyl)amino-6,7-dimethoxyquinazoline as inhibitor of CSF-1R tyrosine kinase. It was reported that substitutions on the phenyl ring resulted in reduced activity. Replacement of the 6,7-dimethoxy groups by hydrogen resulted in more than 40-fold reduction in potency. Substitution in the 2-position of quinazoline by a Cl or methoxy group resulted in inactive compounds (IC₅₀>50 μM).
Rewcastle et al. (J. Med. Chem. 38:3482-3487 (1995)) reported 4-(phenylamino)-quinazolines as inhibitors of tyrosine kinase of Epidermal Growth Factor Receptor. It was reported that N-methylation of the amino group (R₁=Me, R₂═R₃═R₄═H) completely abolished activity (IC₅₀>100,000 nM). The 6,7-dimethoxy compound (R₁═H, R₂═R₃═OMe, R₄=Br, IC₅₀=0.029 nM) was almost 1000-fold more potent than the corresponding non-substituted analog (R₁═H, R₂═R₃═H, R₄═Br, IC₅₀=27 nM).
Bridges et al. (J. Med. Chem. 39:267-276 (1996)) reported analogs of 4-(3-bromoanilino)-6,7-dimethoxyquinazoline as inhibitors of tyrosine kinase of Epidermal Growth Factor Receptor. It was reported that introduction of a methyl group to the 2-position (R₁=Me, R₂=3′-Br, R₃═H) resulted in at least 400,000-fold loss of potency (IC₅₀>10,000 nM) vs the hydrogen analog. Introduction of an amino group to the 2-position (R₁═NH₂, R₂=3′-Br, R₃═H) also resulted in over 18,000-fold loss of potency (IC₅₀>10,000 nM). Methylation of the anilino nitrogen (R₃=Me) led to 6,000-fold drop in activity. The 4′-Br analog (IC₅₀=0.96 nM) was almost 40-fold less active than the 3′-Br analog (IC₅₀=0.025 nM), and the 2′-Br analog (IC₅₀=128 nM) was at least 5,000-fold less active than the 3′-Br analog.

SUMMARY OF THE INVENTION

The present invention is related to the discovery that 4-arylamino-quinazolines and analogs, as represented in Formula I-VIb below, are potent tubulin inhibitors and active in inhibiting topoisomerase, particularly topoisomerase II. They are activators of the caspase cascade leading to the activation of caspase-3 and inducers or promoters of apoptosis. Thus, they are useful in treating or delaying the onset of diseases and disorders that are responsive to the inhibition of tubulin or topoisomerase, or to the induction of apoptosis.
Accordingly, one aspect of the present invention is directed to the use of compounds of the present invention in inhibiting tubulin, in inducing capase activities, particularly caspase-3 activities, in inhibiting topoisomerase I or II, and inducing or promoting apoptosis, by administering the compounds to cells in vitro or in vivo in warm-blood animals, particularly mammals.
Another aspect of the present invention is to provide a method for treating or delaying the onset of diseases and disorders that are responsive to inhibition of tubulin or topoisomerase II, including but not limited to neoplastic diseases (such as cancer), psoriasis, autoimmune diseases, and fungi infection. The method comprises administering to a subject mammal in need of the treatment a therapeutically effective amount of a compound of the present invention.
Many of the compounds as represented by Formula I-VIb below are novel compounds. Therefore, another aspect of the present invention is to provide novel compounds, and to also provide for the use of these novel compounds for treating, preventing or ameliorating neoplasia and cancer.
Yet another aspect of the present invention is to provide a pharmaceutical composition useful for treating disorders responsive to the inhibition of tubulin or topoisomerase II, and the induction of apoptosis, containing an effective amount of a compound of the present invention, preferably in admixture with one or more pharmaceutically acceptable carriers or diluents.
In yet another aspect of the present invention, methods are provided for the preparation of the novel compounds of the present invention.
The foregoing and other advantages and features of the invention, and the manner in which the same are accomplished, will become more readily apparent upon consideration of the following detailed description of the invention taken in conjunction with the accompanying examples, which illustrate preferred and exemplary embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the results of a Topoisomerase II activity assay testing Example 1 compound;

FIG. 2 shows the results of a Topoisomere I activity assay testing Example 1 compound;

FIG. 3 depicts the binding of radiolabeled Example 102 compound to Topoisomerase II.

DETAILED DESCRIPTION OF THE INVENTION

It has been discovered that compounds of the present invention are potent inhibitors of tubulin. It is also discovered that the compounds can also inhibit topoisomerase activities, such as topoisomerase II-dependent conversion of supercoiled DNA to topoisomers. The compounds are potent and highly efficacious activators of the caspase cascade particularly caspase-3, and inducers of apoptosis. Therefore, the compounds are useful for treating diseases and disorders responsive to induction of apoptosis, inhibition of tubulin and/or inhibition of topoisomerase II.
Thus, the present invention provides a method of inhibiting tubulin in cells in vitro or in warm-blood animals, particularly mammals, more particularly humans. As used herein, the term “inhibiting tubulin” means inhibiting the polymerization (or assembly) of tubulin monomers or promoting depolymerization of microtubles (i.e., tubulin disassembly). Inhibition of tubulin can be assayed, e.g., by the method described in Example 264 below. The present invention also provides a method for inhibiting topoisomerase II in cells in vitro or in warm-blood animals, particularly mammals, more particularly humans. As used herein, the term “inhibiting topoisomerase II” means inhibiting the activities of the enzyme topoisomerase II in topoisomerase II-dependent conversion of supercoiled DNA to topoisomers Inhibition of topoisomerase II activities can be assayed by, e.g., a method described in Example 270. In addition, the present invention also provides a method of activating caspase, particularly caspase-3 and inducing apoptosis in cells in vitro or in warm-blood animals, particularly mammals, more particularly humans. The term “activating caspase” as used herein means activating or enhancing the enzymatic (protease) activity of a caspase (e.g., caspase-3), which, if occurring inside cells, results in promoted apoptosis or cell death. The ability of a compound in activating caspase, particularly caspase-3, can be assayed in a method as provided in Example 262 below. The term “inducing apoptosis” as used herein means inducing apoptosis in cells so as to cause cell death. The ability of a compound to induce apoptosis can be tested in a method as described in Example 266 below. Also provided are methods for treating or delaying the onset of diseases and disorders responsive to inhibiting tubulin, inhibiting topoisomerase II, activating caspase-3, or inducing apoptosis. Specific examples of such diseases and disorders are provided in details below.
The above various methods of the present invention can be practiced by or comprise treating cells in vitro or a warm-blood animal, particularly mammal, more particularly a human with an effective amount of a compound according to the present invention. As used herein, the phrase “treating . . . with . . . a compound” means either administering the compound to cells or an animal, or administering to cells or an animal the compound or another agent to cause the presence or formation of the compound inside the cells or the animal. Preferably, the methods of the present invention comprise administering to cells in vitro or to a warm-blood animal, particularly mammal, more particularly a human a pharmaceutical composition comprising an effective amount of a compound according to the present invention.
Specifically, the methods of the present invention comprise treating cells in vitro or a warm-blood animal, particularly mammal, more particularly a human with an effective amount of a compound according to Formula I:
or pharmaceutically acceptable salts or solvates thereof, wherein:
Ar is aryl or heteroaryl; each of which is optionally substituted by one or more substituents wherein each substituent is independently halo, hydroxy, hydroxy-C_1-6alkyl-, C_1-6alkyl-C(O)O—, amino, nitro, cyano, C_1-6alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-6acylamino, C_1-6acyloxy, C_1-6alkoxy, or C_1-6alkylthiol-;
R₁is C_1-6alkyl, preferably methyl or ethyl, more preferably methyl;
A is an aromatic, heteroaromatic, heterocyclic, or carbocyclic ring; each of which is optionally substituted by one or more substituents wherein each substituent is as defined for Ar;
R₂is H, halo, nitro, cyano, azido, hydroxy, thiol, or a member of the group consisting of: amino, alkoxy, C_1-6alkyl, halo-C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, hydroxyalkyl, amino-C_1-6alkyl, carboxy-C_1-6alkyl, nitro, cyano, acylamido, acyloxy, carboxy, carbonylamido, alkylthiol; each of which is optionally substituted by one or more substituents wherein each substituent is as defined for Ar;
L is (CR₁₁R₁₂)n or NR₁₁CO wherein R₁₁and R₁₂independently are hydrogen or alkyl optionally substituted by R_1a, R_1b, or R_1c; wherein R_1a, R_1b, and R_1care as defined for Ar;
n is 0, 1 or 2;
B and D are independently nitrogen or CR₁₃, wherein R₁₃is hydrogen, halo, nitro, cyano, azido, hydroxy, thiol, or a member of the group consisting of amino, alkoxy, C_1-6alkyl, halo-C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, hydroxyalkyl, amino-C_1-6alkyl, carboxy-C_1-6alkyl, nitro, cyano, acylamido, acyloxy, carboxy, carbonylamido, alkylthiol; each of which is optionally substituted by one or more substituents wherein each substituent is as defined for Ar; and
with the proviso that at least one of B and D is nitrogen.
Preferred compounds of Formula I include compounds wherein D is nitrogen, and B is CR₁₃. Other preferred compounds of Formula I include those having Formula Ia:
or pharmaceutically acceptable salts or solvates thereof, wherein:

A ring is a 6-membered aryl, heteroaryl or carbocycle;
L is [C(R_L1)(R_L2)]_nor —N(R_L1)C(O)—, wherein R_L1and R_L2independently are H or C_1-6alkyl, n is 0, 1 or 2;
R₁is methyl or ethyl;
Ar is aryl or heteroaryl, each of which is optionally substituted by one or more substituents wherein each substituent is independently H, halo, N₃, OH, thiol, nitro, CN, NH₂, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, halo-C_1-6alkyl, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl, or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl); wherein any of the groups is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N₃, OH, thiol, nitro, CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle;

R₂-R₆, and R₁₂-R₁₇are independently H, halo, N₃, OH, thiol, nitro, CN, NH₂, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, halo-C_1-6alkyl, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl, or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl); wherein any of the groups is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N₃, OH, thiol, nitro, CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(Ra)(Rb)-C_1-6alkyl-, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle, with
the proviso that when A is aryl or heteroaryl, then there are no substituents R₁₄-R₁₇; and B, D, Q, T, U and V, are independently carbon or nitrogen, wherein at least one of B and D is nitrogen; wherein when B or D is nitrogen, then there is no substituent at the nitrogen; and wherein when A is heteroaryl and Q, T, U or V is nitrogen, then there is no substituent at the nitrogen.
Preferably, when the A ring is aryl or heteroaryl and U is carbon, then R₅is hydrogen or flourine, preferably hydrogen.
Other preferred compounds include compounds wherein ring A is benzo or fused cyclohexyl. Another group of preferred compounds include compounds wherein Ar is phenyl, naphthyl, pyridyl, pyridazyl, pyrimidyl, pyrazyl, quinolyl, isoquinolyl, isoxazolyl, pyrazolyl, imidazolyl, thienyl, furyl or pyrrolyl; each of which is optionally substituted by one or more substituents wherein each substituent is independently halo, hydroxy, hydroxyC_1-6alkyl-, C_1-6alkyl-C(O)O—, amino, nitro, cyano, C₁-C₆alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₆acylamino, C₁-C₆acyloxy, C₁-C₆alkoxy, or C_1-6alkylthiol-. More preferably, Ar is phenyl, pyridyl, pyridazyl, pyrimidyl or pyrazyl, each of which is optionally substituted by one or more substituents wherein each substituent is as defined immediately above.
Another group of preferred compounds of Formula Ia include compounds wherein R₂is H, halo, or a member of the group consisting of N₃, C_1-4alkoxy, C_1-4alkylthiol, hydroxyC_1-4alkyl, C_1-4alkyl and —N(R^a)(R^b) wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-4hydroxyalkyl, or C_1-4alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; each of the member is optionally substituted by 1-4 substituents wherein each substituent is independently halo, OH, or C_1-4alkyl.
In preferred embodiments of the compounds of Formula Ia, one or two of Q, T, U and V are nitrogen, and both B and D are nitrogen.
Other compounds of Formula I for use in the methods of the present invention include those having Formula Ib:
or pharmaceutically acceptable salts or solvates thereof,
wherein:
R₁is C_1-4alkyl, preferably methyl or ethyl, more preferably methyl;
R₂-R₁₁are independently H, halo, N₃, OH, thiol, nitro, CN, NH₂, C_1-6alkyl, C_2-6alkenyl,
C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, halo-C_1-6alkyl, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl, or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl); wherein any of the groups is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N₃, OH, thiol, nitro, CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle;
wherein optionally two adjacent R₇-R₁₁groups may together form a 3, 4, 5 or 6-membered aryl, heteroaryl, carbocycle, or heterocycle.
Preferably, R₅is H or F, more preferably H. Also preferably R₂is R₂is H, halo, or a member of the group consisting of: N₃, C_1-4alkoxy, C_1-4alkylthiol, hydroxy-C_1-4alkyl, C_1-4alkyl and —N(R^a)(R^b) wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-4hydroxyalkyl, or C_1-4alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle (e.g., morpholino); each of the member is optionally substituted by 1-4 substituents wherein each substituent is independently halo, OH, or C_1-4alkyl.
Other preferred compounds of Formula I for the methods of the invention include those having Formula Ic:
or pharmaceutically acceptable salts or solvates thereof, wherein:
R₁is C_1-4alkyl, preferably methyl or ethyl, more preferably methyl;
R₂-R₁₁are independently H, halo, N₃, OH, thiol, nitro, CN, NH₂, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, halo-C_1-6alkyl, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl, or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl); wherein any of the groups is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N₃, OH, thiol, nitro, CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; wherein optionally two adjacent R₇-R₁₁groups may together form a 3, 4, 5 or 6-membered aryl, heteroaryl, carbocycle, or heterocycle.
Preferably, R₅is H or F, more preferably H. Also preferably R₂is H, halo, or a member of the group consisting of: N₃, C_1-4alkoxy, C_1-4alkylthiol, hydroxy-C_1-4alkyl, C_1-4alkyl and —N(R^a)(R^b) wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-4hydroxyalkyl, or C_1-4alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle (e.g., morpholino); each of the member is optionally substituted by 1-4 substituents wherein each substituent is independently halo, OH, or C_1-4alkyl.
Another group of compounds useful in the various methods of the present invention are those represented by Formula II:
or pharmaceutically acceptable salts or solvates thereof, wherein:

Ar is as defined in Formula Ia above;
R₁is a C_1-3alkyl, preferably methyl or ethyl;
R₂-R₆, R₁₂and R₁₃are independently H, halo, N₃, OH, thiol, nitro, CN, NH₂, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, halo-C_1-6alkyl, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl, or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl); wherein any of the groups is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N₃, OH, thiol, nitro, CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; preferably, when U is C, R₅is H or F, preferably H; and
B, D, Q, T, U and V are independently C or N, wherein at least one of B and D is nitrogen. In some embodiments, at least one of Q, T, U and V is N. In one embodiment, D is N and B is C. In another embodiment, B is N and D is C. In another specific embodiment, both B and D are N. In all embodiments, preferably when B, D, Q, T, U or V is N, there is no substituent at the N.

Other preferred compounds include compounds wherein Ar is phenyl, naphthyl, pyridyl, pyridazyl, pyrimidyl, pyrazyl, quinolyl, isoquinolyl, isoxazolyl, pyrazolyl, thienyl, furyl or pyrrolyl; each of which is optionally substituted by one or more substituents wherein each substituent is as defined immediately above. More preferably, Ar is phenyl, pyridyl or pyridazyl, pyrimidyl, pyrazyl, each of which is optionally substituted by one or more substituents wherein each substituent is as defined immediately above. Another group of preferred compounds of Formula II include compounds wherein R₂is a member of the group consisting of H, halo, N₃, C_1-4alkoxy, C_1-4alkylthiol, hydroxyC_1-4alkyl, C_1-4alkyl, and —N(R^a)(R^b) wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-4hydroxyalkyl, or C_1-4alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; each of the member being optionally substituted by 1-4 substituents wherein each substituent is independently halo, OH, or C_1-4alkyl.
In preferred embodiments of the compounds of Formula II, one or two of Q, T, U and V are N, and both B and D are N.
Another group of preferred compounds that may be employed in the methods of the present invention are represented by Formula III:
or pharmaceutically acceptable salts or solvates thereof, wherein:

Ar is as defined above in Formula Ia and II;
R₁is a C_1-3alkyl, preferably methyl or ethyl, more preferably methyl;
R₂-R₆and R₁₂-R₁₇are independently H, halo, N₃, OH, thiol, nitro, CN, NH₂, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, halo-C_1-6alkyl, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl, or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl); wherein any of the groups is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N₃, OH, thiol, nitro, CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; and
B and D are independently C or N, wherein at least one of B and D is N, and when B or D is N, then there is no substituent at the nitrogen atom.

Other preferred compounds according to Formula III include compounds wherein Ar is phenyl, naphthyl, pyridyl, pyridazyl, pyrimidyl, pyrazyl, quinolyl, isoquinolyl, isoxazolyl, pyrazolyl, imidazolyl, thienyl, furyl or pyrrolyl; each of which is optionally substituted by one or more substituents wherein each substituent is as defined immediately above. More preferably, Ar is phenyl, pyridyl pyridazyl, pyrimidyl, or pyrazyl, each of which is optionally substituted by one or more substituents wherein each substituent is as defined immediately above. In one embodiment, Ar is pyridyl pyridazyl, pyrimidyl, or pyrazyl, each of which is optionally substituted by one or more substituents as defined above for Ar. Also preferably R₂is a member of the group consisting of H, halo, N₃, C_1-4alkoxy, C_1-4alkylthiol, hydroxyC_1-4alkyl, C_1-4alkyl, and —N(R^a)(R^b) wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-4hydroxyalkyl, or C_1-4alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; each of the member being optionally substituted by 1-4 substituents wherein each substituent is independently halo, OH, or C_1-4alkyl. In preferred embodiments of the compounds of Formula III, both B and D are N.
Preferably a compound according to Formula III is other than (5,6,7,8-tetrahydro-quinazolin-4-yl)-phenyl-ethyl-amine.
More preferably, the methods of inhibiting tubulin, inhibiting topoisomerase II, activating caspase-3, inducing apoptosis and treating or delaying the onset of diseases and disorders responsive to the inhibition of tubulin or topoisomerase II or to the activation of caspase-3 or induction of apoptosis comprise administering an effective amount of a compound or a pharmaceutical composition containing an effective amount of the compound, which compound is represented by any one of Formulae IV, IVa, IVb, V, Va, Vb, Vc, VI, VIa and VIb, and each and all embodiments thereof and salts or solvates thereof, as provided below.
Additional compounds useful in such methods, particularly the methods of inhibiting tubulin, inhibiting topoisomerase II, activating caspase-3 and inducing apoptosis, and treating diseases and disorders responsive to the inhibition of tubulin or topoisomerase II, or activating caspase-3 and inducing apoptosis include compounds according to Formula IV:
and pharmaceutically acceptable salts and solvates thereof, wherein:

R₁is methyl or ethyl, preferably methyl;
A ring is a carbocycle, aryl or heteroaryl;
R₂-R₁₇are independently H, halo, N₃, OH, thiol, nitro, CN, NH₂, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, halo-C_1-6alkyl, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl, or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl); wherein any of the groups is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N₃, OH, thiol, nitro, CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(Ra)(Rb), —C(O)N(R^a)(R^b), N(R^a)(R^b). —C_1-6alkyl-, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle, wherein optionally any two adjacent R₇-R₁₁groups together form a 3, 4, 5 or 6-membered carbocycle or heterocycle, with the proviso that when A is aryl or heteroaryl, then there are no substituents R₁₄-R₁₇; and
B, D, Q, T, U, V, W, X, Y, and Z are independently C or N, wherein at least one of B and D is N; wherein when B, D, W, X, Y, or Z is N, then there is no substituent at the N; and wherein when A is heteroaryl and Q, T, U or V is N, then there is no substituent at the N.

Preferably when the A ring is aryl or heteroaryl and U is C, R₅is not alkoxy. More preferably, when the A ring is aryl or heteroaryl and U is C, then R₅is H or F, preferably H.
In some embodiments of the compounds of Formula IV, one of W, X, Y and Z is N. In other embodiments of the compounds of Formula IV, two of W, X, Y and Z are N. In any of the embodiments, preferably one or two of Q, T, U and V are N. In preferred embodiments, B and D both are N.
Further additional compounds in addition to the compounds represented by Formulae IV, IVa, IVb, V, Va, Vb, Vc, VI, VIa and VIb, and all embodiments thereof, which are useful in the methods of the present invention, particularly the methods of inhibiting tubulin, inhibiting topoisomerase II, activating caspase-3 and inducing apoptosis, and treating diseases and disorders responsive to the inhibition of tubulin or topoisomerase II, activating caspase-3 and inducing apoptosis, include compounds according to Formula VI:
or pharmaceutically acceptable salts or solvates thereof, wherein:

R₁is methyl or ethyl, preferably methyl;
R₅is H or F, preferably H;
R₂-R₄, R₆-R₁₃are independently H, halo, N₃, OH, thiol, nitro, CN, NH₂, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, halo-C_1-6alkyl, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl, or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl); wherein any of the groups is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N₃, OH, thiol, nitro, CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle, wherein optionally any two adjacent R₇-R₁₁groups together form a 3, 4, 5 or 6-membered carbocycle or heterocycle; and
B, D, Q, T, U and V are independently C or N, provided that at least one of B and D is N; wherein when B, D, Q, T, U or V is N, then there is no substituent at the N.

In some embodiments of the compounds according to Formula VI, one or two of Q, T, U and V are N. In preferred embodiments, both B and D are N.
Further additional compounds useful in such methods, particularly the methods of inhibiting tubulin, inhibiting topoisomerase II, activating caspase-3 and inducing apoptosis, and treating diseases and disorders responsive to the inhibition of tubulin or topoisomerase II, activating caspase-3 and inducing apoptosis, include compounds according to Formula VIa:
or pharmaceutically acceptable salts or solvates thereof, wherein:

R₁is methyl or ethyl, preferably methyl;
R₅is H or F, preferably H;
R₂-R₄, R₆-R₁₁are independently H, halo, N₃, OH, thiol, nitro, CN, NH₂, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, halo-C_1-6alkyl, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl, or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl); wherein any of the groups is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N₃, OH, thiol, nitro, CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(Ra)(Rb), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle, wherein optionally any two adjacent R₇-R₁₁groups together form a 3, 4, 5 or 6-membered carbocycle or heterocycle; and
Q, T, U and V are independently C or N, wherein when Q, T, U or V is N, then there is no substituent at the N.

In some embodiments of the compounds according to Formula VIa, one or two of Q, T, U and V are N.
Still further additional compounds useful in such methods, particularly the methods of inhibiting tubulin or topoisomerase II, activating caspase-3 and inducing apoptosis, and treating diseases and disorders responsive to the inhibition of tubulin or topoisomerase II, activating caspase-3 and inducing apoptosis, include compounds according to Formula VIb:
or pharmaceutically acceptable salts or solvates thereof, wherein:

R₁is methyl or ethyl, more preferably methyl;
R₅is H or F, preferably H;
R₂-R₄, R₆-R₁₁are independently H, halo, N₃, OH, thiol, nitro, CN, NH₂, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, halo-C_1-6alkyl, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl, or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl); wherein any of the groups is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N₃, OH, thiol, nitro, CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle, wherein optionally any two adjacent R₇-R₁₁groups together form a 3, 4, 5 or 6-membered carbocycle or heterocycle.

In the various embodiments of the above methods of the present invention, preferably the compounds administered in the methods of the invention are able to induce caspase activation as determined by the method and under conditions (measurement at 24 hours) described in Example 262, preferably at an EC₅₀no greater than 1,000 nM, more preferably at an EC₅₀no greater than about 500 nM, more preferably at an EC₅₀no greater than about 200 nM, more preferably at an EC₅₀no greater than about 100 nM, even more preferably at an EC₅₀no greater than about 50 nM, and most preferably at an EC₅₀no greater than about 10 nM. Also preferred in the above methods of the invention are compounds of Formula I-VIb, and pharmaceutically acceptable salts or solvates thereof, that are able to inhibit tubulin at an IC₅₀of no greater than about 2,000 nM, more preferably no greater than about 1,000 nM, most preferably less than about 500 nM, as determined by the method and under conditions described in Example 264.
Exemplary compounds useful in the methods of the invention include, but are not limited to, compounds in Examples 1-142; and pharmaceutically acceptable salts or solvates thereof, and:

(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-nitro-phenyl)-methyl-amine;
(2-chloro-quinazolin-4-yl)-(4-trifluoromethoxy-phenyl)-methyl-amine;
(2-chloro-quinazolin-4-yl)-phenyl-methyl-amine;
N²-hydroxyl-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;
N²-(2-hydroxylethyl)-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;
N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;
N²-(3,7-dimethyl-octa-2,6-dienyl)-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;
N⁴-(4-methoxy-phenyl)-N⁴-methyl-N²-(2-morpholin-4-yl-ethyl)-quinazoline-2,4-diamine;
(4-methoxy-phenyl)-methyl-(2-morpholin-4-yl-quinazolin-4-yl)-amine;
N²-(3,7-dimethyl-octa-2,6-dienyl)-N⁴-(4-methyl-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;
(2-chloro-6,7-dimethoxyquinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
(5,6,7,8-tetrahydro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
(2-chloro-quinazolin-4-yl)-(4-methoxy-benzyl)-methyl-amine;
(4-methoxy-phenyl)-methyl-quinazolin-4-yl-amine;
(4-methyl-phenyl)-methyl-quinazolin-4-yl-amine;
(2-chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine;
(2-chloro-quinazolin-4-yl)-isopropyl-(4-methoxy-phenyl)-amine;
(2-chloro-quinazolin-4-yl)-cyclohexyl-(4-methoxy-phenyl)-amine;
(2-chloro-quinazolin-4-yl)-(2,3-dimethoxy-phenyl)-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)-(2,5-dimethoxy-phenyl)-methyl-amine;
(2-chloro-quinazolin-4-yl)-(3-methoxy-phenyl)-methyl-amine;
(2-chloro-quinazolin-4-yl)-(2-methoxy-phenyl)-methyl-amine;
4-chloro-benzoic acid N′-methyl-N-(2-methylthio-quinazolin-4-yl)-hydrazide;
benzoic acid N′-methyl-N′-(2-methylthio-quinazolin-4-yl)-hydrazide;
thiophene-2-carboxylic acid N′-methyl-N′-(2-methylthio-quinazolin-4-yl)-hydrazide;
N²-[2-(1H-imidazol-4-yl)-ethyl]-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;
N²-(3-dimethylamino-propyl)-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;
N²-(2-hydroxyethyl)-N⁴-(6-methoxypyridin-3-yl)-N⁴-methyl-quinazoline-2,4-diamine;
N⁴-(6-methoxypyridin-3-yl)-N⁴-methyl-quinazoline-2,4-diamine;
(2-chloro-quinazolin-4-yl)-(4-methylcarboxyphenyl)-methyl-amine;
(2-methoxy-quinazolin-4-yl)-(4-methoxyphenyl)-methylamine;
(2-chloro-quinazolin-4-yl)-(4-hydroxyphenyl)-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-7-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;
(2,7-dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
(5-chloro-2-isopropoxy-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
(isoquinolin-1-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-phenoxy-phenyl)-methyl-amine;
(2-chloro-quinazolin-4-yl)-(4-propoxy-phenyl)-methyl-amine;
(4-methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine;
4-methoxy-benzoic acid N′-methyl-N′-(2-trifluoromethyl-quinazolin-4-yl)-hydrazide;
3-methyl-benzoic acid N′-methyl-N′-(2-methylthio-quinazolin-4-yl)-hydrazide;
4-fluoro-benzoic acid N′-methyl-N′-(2-methylthio-quinazolin-4-yl)-hydrazide; and
2-fluoro-benzoic acid N′-methyl-N′-(2-trifluoromethyl-quinazolin-4-yl)-hydrazide;
(2-chloro-quinazolin-4-yl)-(2,5-dimethoxy-phenyl)-amine;
5-chloro-N²,N⁴-bis-(4-methoxy-phenyl)-N²,N⁴-dimethyl-quinazoline-2,4-diamine;
(2-chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
(2-ethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
(2-hydroxymethyl-quinazolin-4-yl)-4-methoxy-phenyl)-methyl-amine;
(2-dimethylaminomethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
(4-methoxy-phenyl)-(2-phenyl-quinazolin-4-yl)-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-methyl-quinazolin-4-yl)-(2,4,6-trimethoxy-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;
(5-methoxy-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
(4-methoxy-phenyl)-(2-methyl-pyrido[2,3-d]pyrimidin-4-yl)-methyl-amine;
(4-hydroxy-phenyl)-(2-methyl-quinazolin-4-yl)-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;
(2-methyl-quinazolin-4-yl)-(4-nitro-phenyl)-methyl-amine;
(4-amino-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
(4-azido-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
(4-amino-2,6-dibromo-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
(4-amino-2-bromo-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;
(4-methoxy-phenyl-2,3,5,6-d₄)-(2-methyl-quinazolin-4-yl)-methyl-amine;
(4-methoxy-phenyl)-(2-methyl-6-nitro-quinazolin-4-yl)-methyl-amine;
(6-amino-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
(6-azido-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
(7-amino-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
(7-azido-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
ethyl 4-(N-(4-Methoxy-phenyl)-N-methylamino)quinazoline-2-carboxylate;
succinimidyl 4-(N-Methyl-N-(2-methylquinazolin-4-yl)amino)benzoic acid ester;
(2-methylthio-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
(2-azido-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;
(4-fluoro-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
(6-methoxy-pyridazin-3-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
(5-methoxy-pyrazin-2-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
(2-dimethylamino-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-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;
difluoromethyl-(4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine;
(4-methoxy-phenyl)-(2-methyl-pteridin-4-yl)-methyl-amine; and
(5-methoxy-pyrimidin-2-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

and pharmaceutically acceptable salts or solvates thereof.
Additional exemplary compounds useful in the methods of the invention include, but are not limited to, compounds in Examples 143-261; and pharmaceutically acceptable salts or solvates thereof, such as:

{4-[methyl-(2-methyl-quinazolin-4-yl)-amino]-phenoxy}-acetic acid methyl ester;
{4-[methyl-(2-methyl-quinazolin-4-yl)-amino]-phenoxy}-acetic acid;
N²-(2-amino-ethyl)-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;
[2-(2-methoxy-ethoxy)-quinazolin-4-yl]-(4-methoxy-phenyl)-methyl-amine;
N⁴-(4-methoxy-phenyl)-N²,N⁴-dimethyl-N²-(2-methylamino-ethyl)-quinazoline-2,4-diamine;
N²-(2-dimethylamino-ethyl)-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;
N²-(2-dimethylamino-ethyl)-N⁴-(4-methoxy-phenyl)-N²,N⁴-dimethyl-quinazoline-2,4-diamine;
[2-(2-dimethylamino-ethoxy)-quinazolin-4-yl]-(4-methoxy-phenyl)-methyl-amine;
N²-ethoxymethyl-N⁴-(4-methoxy-phenyl)-N²,N⁴-dimethyl-quinazoline-2,4-diamine;
4-[(4-methoxy-phenyl)-methyl-amino]-quinazoline-2-carbonitrile;
methyl 2-[({4-[methyl(2-methylquinazolin-4-yl)amino]phenyl}amino)carbonyl]hydrazine carboxylate;
4-{4-[methyl-(2-methyl-quinazolin-4-yl)-amino]-phenyl}-[1,2,4]triazolidine-3,5-dione;
N-{4-[methyl-(2-methyl-quinazolin-4-yl)-amino]-phenyl}-methanesulfonamide;
(2-isopropoxy-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
(2-fluoro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
4-[methyl-(2-methyl-quinazolin-4-yl)-amino]-benzonitrile;
{4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-ylamino}-acetic acid ethyl ester;
2-{4-[(4-methoxy-phenyl)-methyl-amino]-6-methyl-quinazolin-2-ylamino}-ethanol;
N⁴-(4-methoxy-phenyl)-6,N²,N⁴-trimethyl-quinazoline-2,4-diamine;
N⁴-(4-methoxy-phenyl)-6,N²,N²,N⁴-tetramethyl-quinazoline-2,4-diamine;
6,7-N²-(2-amino-ethyl)-N⁴-(4-methoxy-phenyl)-6,N⁴-dimethyl-quinazoline-2,4-diamine;
(2-chloro-6-methoxy-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
6-methoxy-N⁴-(4-methoxy-phenyl)-N²,N²,N⁴-trimethyl-quinazoline-2,4-diamine;
6-methoxy-N⁴-(4-methoxy-phenyl)-N²,N⁴-dimethyl-quinazoline-2,4-diamine;
N⁴-(3,4-dimethoxy-phenyl)-N²,N⁴-dimethyl-quinazoline-2,4-diamine;
N⁴-(3,4-dimethoxy-phenyl)-N²,N²,N⁴-trimethyl-quinazoline-2,4-diamine;
2-{6-methoxy-4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-ylamino}-ethanol;
(2-chloro-5,6,7,8-tetrahydro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
(4-methoxy-phenyl)-methyl-(2-trifluoromethyl-quinolin-4-yl)-amine;
N-{4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-yl}-O-methyl-hydroxylamine;
2-{4-[(3,4-dimethoxy-phenyl)-methyl-amino]-quinazolin-2-ylamino}-ethanol;
2-({4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-yl}-methyl-amino)-ethanol;
N²-(2-amino-ethyl)-6-methoxy-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;
(4-methoxy-phenyl)-methyl-(2-methyl-thieno[2,3-d]pyrimidin-4-yl)-amine;
(2-chloro-quinazolin-4-yl)-(2-methoxy-benzyl)-methyl-amine;
N²-(2-chloro-ethyl)-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;
(2-chloro-quinazolin-4-yl)-(3-methoxy-benzyl)-methyl-amine;
3-{4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-ylamino}-propan-1-ol;
4-{4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-ylamino}-butan-1-ol;
(2-ethoxy-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
N²-(3-dimethylamino-propyl)-N⁴-(4-methoxy-phenyl)-N²,N⁴-dimethyl-quinazoline-2,4-diamine;
N²-(4-amino-butyl)-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;
(4-methoxy-phenyl)-methyl-(2-methyl-thieno[3,2-d]pyrimidin-4-yl)-amine;
2-{4-[(4-methoxy-phenyl)-methyl-amino]-6-nitro-quinazolin-2-ylamino}-ethanol;
({4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-yl}-methyl-amino)-acetic acid methyl ester;
(4-methoxy-phenyl)-methyl-(2-methyl-5,6,7,8-tetrahydro-quinazolin-4-yl)-amine;
2-{6-amino-4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-ylamino}-ethanol;
N-{4-[(4-methoxy-phenyl)-methyl-amino]-5,6,7,8-tetrahydro-quinazolin-2-yl}-O-methyl-hydroxylamine;
{4-[(4-methoxy-phenyl)-methyl-amino]-5,6,7,8-tetrahydro-quinazolin-2-ylamino}-acetic acid ethyl ester;
N⁴-(4-methoxy-phenyl)-N²,N⁴-dimethyl-5,6,7,8-tetrahydro-quinazoline-2,4-diamine;
N²-(2-amino-ethyl)-N⁴-(3,4-dimethoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;
2-{4-[(4-methoxy-phenyl)-methyl-amino]-5,6,7,8-tetrahydro-quinazolin-2-ylamino}-ethanol; (7-fluoro-phthalazin-1-yl)-(4-methoxy-phenyl)-methyl-amine;
(6-fluoro-phthalazin-1-yl)-(4-methoxy-phenyl)-methyl-amine;
N-{4-[(4-methoxy-phenyl)-methyl-amino]-6,7-dihydro-5H-cyclopentapyrimidin-2-yl}-O-methyl-hydroxylamine;
(5-fluoro-2-isopropoxy-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
(4-methoxy-phenyl)-methyl-(2-trifluoromethyl-quinazolin-4-yl)-amine;
N⁴-(4-methoxy-phenyl)-N²,N⁴-dimethyl-6,7-dihydro-5H-cyclopentapyrimidine-2,4-diamine;
N⁴-(4-methoxy-phenyl)-N²,N⁴-dimethyl-6,7,8,9-tetrahydro-5H-cycloheptapyrimidine-2,4-diamine;
{4-[(4-methoxy-phenyl)-methyl-amino]-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamino}-acetic acid ethyl ester;
N-{4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-acetamide;
methyl-{4-[methyl-(2-methyl-quinazolin-4-yl)-amino]-phenyl}-carbamic acid tert-butyl ester;
(2-aminomethyl-6-fluoro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
{4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-yl}-acetonitrile;
(4-ethoxy-phenyl)-methyl-(2-methyl-6-nitro-quinazolin-4-yl)-amine;
(6-bromo-2-chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
(4-difluoromethoxy-phenyl)-methyl-(2-methyl-6-nitro-quinazolin-4-yl)-amine;
(3-fluoro-4-methoxy-phenyl)-methyl-(2-methyl-6-nitro-quinazolin-4-yl)-amine;
(2-aminomethyl-quinazolin-4-yl)-(4-ethoxy-phenyl)-methyl-amine;
[2-(2-amino-ethyl)-quinazolin-4-yl]-(4-methoxy-phenyl)-methyl-amine;
2-aminomethyl-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-4,6-diamine;
N⁴-(4-ethoxy-phenyl)-2,N⁴-dimethyl-quinazoline-4,6-diamine;
N⁴-(3-fluoro-4-methoxy-phenyl)-2,N⁴-dimethyl-quinazoline-4,6-diamine;
N⁴-(4-difluoromethoxy-phenyl)-2,N⁴-dimethyl-quinazoline-4,6-diamine;
(2-aminomethyl-quinazolin-4-yl)-(4-isopropoxy-phenyl)-methyl-amine;
(2-aminomethyl-quinazolin-4-yl)-(2-fluoro-4-methoxy-phenyl)-methyl-amine;
(2-aminomethyl-6-bromo-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
2-aminomethyl-N⁴-(4-isopropoxy-phenyl)-N⁴-methyl-quinazoline-4,6-diamine;
(2-fluoro-4-methoxy-phenyl)-methyl-(2-methyl-6-nitro-quinazolin-4-yl)-amine;
N⁴-(2-fluoro-4-methoxy-phenyl)-2,N⁴-dimethyl-quinazoline-4,6-diamine;
N⁴-(3,4-dimethoxy-phenyl)-2,N⁴-dimethyl-quinazoline-4,6-diamine;
(4-isopropoxy-phenyl)-methyl-(2-methyl-6-nitro-quinazolin-4-yl)-amine;
2,N⁴-dimethyl-N⁴-(4-methylamino-phenyl)-quinazoline-4,6-diamine;
N⁴-(4-isopropoxy-phenyl)-2,N⁴-dimethyl-quinazoline-4,6-diamine;
N²-(3-amino-propyl)-N⁴-(4-methoxy-phenyl)-N²,N⁴-dimethyl-quinazoline-2,4-diamine;
N⁴-(4-methoxy-phenyl)-N⁴-methyl-N²-(3-methylamino-propyl)-quinazoline-2,4-diamine;
(2-aminomethyl-5-fluoro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
4-[(2-aminomethyl-quinazolin-4-yl)-methyl-amino]-phenol;
2-{4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-yl}-2-methyl-propionitrile;
N-{4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-succinamic acid;
(4-methoxy-phenyl)-methyl-(2-methylaminomethyl-quinazolin-4-yl)-amine;
(2-aminomethyl-quinazolin-4-yl)-(3-fluoro-4-methoxy-phenyl)-methyl-amine;
(2-aminomethyl-quinazolin-4-yl)-(4-ethoxy-3-fluoro-phenyl)-methyl-amine;
4-methoxy-N-{4-[(4-methoxy-phenyl)-methyl-amino]-2-methyl-quinazolin-6-yl}-benzenesulfonamide;
(2-aminomethyl-quinazolin-4-yl)-(4-ethoxy-2-fluoro-phenyl)-methyl-amine;
(S)-2-amino-N-{4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-propionamide;
(2-aminomethyl-5-fluoro-quinazolin-4-yl)-(4-ethoxy-phenyl)-methyl-amine;
(2-aminomethyl-quinazolin-4-yl)-(3-chloro-4-methoxy-phenyl)-methyl-amine;
[2-aminomethyl-6-(4-chloro-phenyl)-quinazolin-4-yl]-(4-methoxy-phenyl)-methyl-amine;
(3-chloro-4-methoxy-phenyl)-(2-chloromethyl-quinazolin-4-yl)-methyl-amine;
(2-aminomethyl-6-phenyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
N-{4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-nicotinamide; (6-Bromo-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
(6-bromo-2-methyl-quinazolin-4-yl)-(4-ethoxy-3-fluoro-phenyl)-methyl-amine;
(4-methoxy-phenyl)-methyl-[2-(1H-tetrazol-5-yl)-quinazolin-4-yl]-amine;
(R)-2-amino-N-{4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-propionamide;
4-[(4-methoxy-phenyl)-methyl-amino]-2-methyl-quinazoline-6-carbonitrile;
(2-aminomethyl-5-fluoro-quinazolin-4-yl)-(4-ethoxy-2-fluoro-phenyl)-methyl-amine;
(2-chloromethyl-quinazolin-4-yl)-(3,5-dichloro-4-methoxy-phenyl)-methyl-amine;
1-{4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-piperidin-2-one;
(4-ethoxy-3-fluoro-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine;
(2-aminomethyl-quinazolin-4-yl)-(3,5-dichloro-4-methoxy-phenyl)-methyl-amine bis(hydrochloride);
1-{4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-pyrrolidin-2-one;
3-({4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-amino)-propan-1-ol;
(2-chloromethyl-quinazolin-4-yl)-(3,5-dichloro-4-ethoxy-phenyl)-methyl-amine;
(3-chloro-4-ethoxy-phenyl)-(2-chloromethyl-quinazolin-4-yl)-methyl-amine;
(6-aminomethyl-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
2-{4-[(3-chloro-4-ethoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-isoindole-1,3-dione;
and (2-aminomethyl-quinazolin-4-yl)-(3-chloro-4-ethoxy-phenyl)-methyl-amine bis(hydrochloride).

The present invention also provides novel compounds, which are potent tubulin inhibitors, topoisomerase II inhibitors, caspase-3 activators and/or apoptosis inducers/promoters. Specifically, the novel compounds of the present invention are represented by Formula IV and pharmaceutically acceptable salts or solvates thereof:

wherein
R₁is methyl or ethyl, and preferably methyl;
A ring is a carbocycle, aryl or heteroaryl;
R₂-R₁₇are independently H, halo, N₃, OH, thiol, nitro, CN, NH₂, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, halo-C_1-6alkyl, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl, or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl); wherein any of the groups is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N₃, OH, thiol, nitro, CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle, wherein optionally any two adjacent R₇-R₁₁groups together form a 3, 4, 5 or 6-membered carbocycle or heterocycle, with the proviso that when A ring is aryl or heteroaryl, then there are no substituents R₁₄-R₁₇; and with the proviso that when A ring is aryl or heteroaryl and U is C, then R₅is H or F, preferably H; and
B, D, Q, T, U, V, W, X, Y and Z are independently C or N, wherein at least one of B and D is N; wherein when B, D, W, X, Y or Z is N, then there is no substituent at the N; and
wherein when A is heteroaryl and Q, T, U or V is N, then there is no substituent at the N; and
wherein when A is carbocycle and W, X, Y and Z are all carbon atoms, then the compound is not 2-amino-4-(N-ethylanilino)-5,6,7,8-tetrahydro-quinazoline; and
wherein when A is benzo and W, X, Y and Z are all C, then (1) R₉is not (C_1-3alkyl)OC(O)alkoxy-; and (2) when R₉is H, then at least one of R₈and R₁₀are not H or C_1-6alkyl, or halo; and
wherein when A is heteroaryl and W, X, Y and Z are all C, when R₉is H, then at least one of R₈and R₁₀is not H or alkyl, provided that R₈and R₁₀may be both alkyl.

Preferably when R₉is H then R₈or R₁₀or both are independently selected from the group OH; N₃; —XR_2awherein X is S or O and R_2ais C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo; —NH(R_2b) or N(R_2b)(R_2c) wherein R_2band R_2care independently C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, and wherein optionally R_2band R_2cmay together form a 3-6 membered heterocycle; and —C(O)OR_2dwherein R_2dis C_1-6alkyl (preferably C_1-3alkyl); and more preferably R₉is not H.
In some embodiments of the compounds of Formula IV, one of W, X, Y and Z is N. In other embodiments of the compounds of Formula IV, two of W, X, Y and Z are N. In any of the embodiments, preferably one or two of Q, T, U and V are N. In preferred embodiments, B and D both are N.
One group of the compounds of the present invention are represented by Formula IVa:
or a pharmaceutically acceptable salt or solvate thereof, wherein:

R₁is methyl, ethyl, preferably methyl;
R₂-R₁₇are independently H, halo, N₃, OH, thiol, nitro, CN, NH₂, C_1-6alkyl,

C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, halo-C_1-6alkyl, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl, or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl); wherein any of the groups is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N₃, OH, thiol, nitro, CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle, wherein optionally any two adjacent R₇-R₁₁groups together form a 3, 4, 5 or 6-membered carbocycle or heterocycle; and
B, D, W, X, Y, and Z are independently C or N, provided that at least one of B and D is N, at least one of W, X, Y, and Z is N, and when B, D, W, X, Y, or Z is N then there is no substituent at the N.
In some embodiments, one of X, Y, W and Z is N. In other embodiments, two of X, Y, W and Z are N. Preferably D is nitrogen, and more preferably both B and D are N.
In a preferred embodiment, compounds of the present invention have Formula IVa, or a pharmaceutically acceptable salt or solvate thereof, wherein:

R₁is methyl or ethyl, preferably methyl;
R₂is a member of the group consisting of H, halo, N₃, C_1-4alkoxy, C_1-4alkylthiol, hydroxyC_1-4alkyl, C_1-4alkyl, and —N(R^a)(R^b) wherein R^aand R^bare independently H, OH (R^aand R^bare not both OH), C_2-4hydroxyalkyl, or C_1-4alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; each of the member being optionally substituted by 1-4 substituents wherein each substituent is independently halo, OH, or C_1-4alkyl;
R₇and R₁₁are independently H, halo (preferably F), CH₃, or OCH₃;
R₈and R₁₀are independently H, halo (preferably F or Cl), C_1-3alkyl (preferably CH₃) optionally substituted with halo (preferably 1-3 F), C_1-3alkoxy (preferably OCH₃), or C_1-3alkylthiol (preferably —S—CH₃);
R₉is H, OH, C₁, N₃, C_1-4alkoxy, C_1-4alkylthiol, hydroxyC_1-4alkyl, C_1-4alkyl,
- —COOR^cwherein R^cis C_1-3alkyl, or —N(R^a)(R^b) wherein R^aand R^bare independently H, OH (R^aand R^bare not both OH), C_2-4hydroxyalkyl, or C_1-4alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; each of the member being optionally substituted by 1-4 substituents wherein each substituent is independently halo, OH, or C_1-4alkyl; and optionally two adjacent R₈, R₉, and R₁₀groups may together form a 3, 4, 5, or 6-membered carbocycle, heterocycle, preferably heterocyle; and
  B, D, W, X, Y, and Z are independently C or N, and at least one of B and D is N, at least one of W, X, Y and Z is N, and when B, D, W, X, Y, or Z is N then there is no substituent at the N. Preferably D is N. In some embodiments, both B and D are N.

In specific embodiments, only one of W, X, Y and Z is N. In other specific embodiments, two of W, X, Y and Z are N.
In preferred embodiments of the compound of Formula IVa, R₉is selected from the group:
—OR_9a, wherein R_9ais methyl, ethyl, fluoromethyl (CH₂F, CHF₂, CF₃), or fluoroethyl; —N₃; —N(CH₃)₂; —NHCH₃; and —COOR_9b, wherein R_9bis H or C_1-2alkyl.
Another group of compounds of the present invention are represented by Formula IVb:
or pharmaceutically acceptable salts or solvates thereof, wherein:

R₂-R₁₇are independently H, halo, N₃, OH, thiol, nitro, CN, NH₂, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, halo-C_1-6alkyl, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl, or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl); wherein any of the groups is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N₃, OH, thiol, nitro, CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle, wherein optionally any two adjacent R₇-R₁₁groups together form a 3, 4, 5 or 6-membered carbocycle or heterocycle; and
B and D are independently C or N, provided that at least one of B and D is N, and when B or D is N then there is no substituent at the N; with the proviso that said compound is not 2-amino-4-(N-ethylanilino)-5,6,7,8-tetrahydro-quinazoline.

Preferably, in the compounds of Formula IVb, D is N, and more preferably both B and D are N.
In preferred embodiments, when R₁is ethyl then at least one of R₈, R₉, and R₁₀is not H; preferably R₉is not H. Also preferably, when R₉is H then R₈or R₁₀or both are independently selected from the group OH; N₃; amido; N-dimethylamido; —XR_9awherein X is S or O and R_9ais C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo; C_1-3alkyl optionally substituted with halo (preferably F); —N(R^a)(R^b) wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), or C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, and wherein optionally R_2band R_2cmay together form a 3-6 membered heterocycle; and —C(O)OR^cwherein R^cis C_1-6alkyl (preferably C_1-3alkyl).
In a preferred embodiment of the compound of Formula IVb:

R₁is methyl or ethyl, preferably methyl;
R₃-R₆, R₁₂-R₁₇are as defined above;
R₂is a member of the group consisting of H, halo, N₃, C_1-4alkoxy, C_1-4alkylthiol, hydroxyC_1-4alkyl, C_1-4alkyl, and —N(R^a)(R^b) wherein R^aand R^bare independently H, OH (R^aand R^bare not both OH), C_2-4hydroxyalkyl, or C_1-4alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; each of the member being optionally substituted by 1-4 substituents wherein each substituent is independently halo, OH, or C_1-4alkyl;
R₇and R₁₁are independently H, halo (preferably F), CH₃, or OCH₃;
R₈and R₁₀are independently H, halo (preferably F or CO, C_1-3alkyl (preferably CH₃) optionally substituted with halo (preferably 1-3 F), C_1-3alkoxy (preferably OCH₃), or C_1-3alkylthiol (preferably —S—CH₃);
R₉is OH, C₁, N₃, C_1-4alkoxy, C_1-4alkylthiol, hydroxyC_1-4alkyl, C_1-4alkyl,
- —COOR^cwherein R^cis C_1-3alkyl, or —N(R^a)(R^b) wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-4hydroxyalkyl, or C_1-4alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; each of the member being optionally substituted by 1-4 substituents wherein each substituent is independently halo, OH, or C_1-4alkyl; and optionally two adjacent R₈, R₉, and R₁₀groups may together form a 3, 4, 5, or 6-membered carbocycle, heterocycle, preferably heterocyle; and
B and D are independently C or N, and at least one of B and D is N.

In more preferred embodiments of the compound of Formula IVa, R₉is selected from the group:
—OR_9a, wherein R_9ais methyl, ethyl, fluoromethyl (e.g., CH₂F, CHF₂, CF₃), fluoroethyl; —N₃; —N(CH₃)₂; —NHCH₃; and —COOR_9b, wherein R_9bis H or C_1-2alkyl.
Other novel compounds of the present invention are those represented by Formula V:
or a pharmaceutically acceptable salt or solvate thereof, wherein:

R₁is methyl or ethyl, preferably methyl;
R₅is H, F, Cl, N₃, methyl, methoxy or NH₂, with the proviso that when R₅is methoxy, R₁is methyl; Preferably R₅is H, F or N₃, more preferably H or F, and most preferably H;
R₂-R₄, and R₆-R₁₃are independently H, halo, N₃, OH, thiol, nitro, CN, NH₂, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, halo-C_1-6alkyl, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl, or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl); wherein any of the groups is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N₃, OH, thiol, nitro, CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle, wherein optionally any two adjacent R₇-R₁₁groups together form a 3, 4, 5 or 6-membered carbocycle or heterocycle; and
B, D, Q, T, U, V, W, X, Y and Z are independently C or N, provided that at least one of B and D is N, and at least one of W, X, Y and Z is N, and wherein when B, D, Q, T, U, V, W, X, Y or Z is N, then there is no substituent at the N.

In a specific embodiment, preferably when R₉is H, at least one of R₈and R₁₀is not H, more preferably R₉is other than H.
In some specific embodiments, B is C and D is N. In other specific embodiments, B is N and D is C. In preferred embodiments, both B and D are N.
In one embodiment of the compounds of Formula V,
R₂is H; halo; N₃;
C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, e.g., monofluoro, difluoro, or trifluoro);
—XR_2awherein X is S or O, and R_2ais C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, e.g., monofluoro-, difluoro-, or trifluoro-substituted);
—CO₂R^d, wherein R^dis C_1-3alkyl, preferably methyl or ethyl; or
—N(R^a)(R^b) wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_1-3alkyl (preferably CH₃), C_1-6hydroxyalkyl (preferably C_2-3hydroxyalkyl, more preferably —CH₂CH₂OH), or C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) that is optionally substituted with —N(R^e)(R^f) wherein R^eand R^fare independently H, OH(R^eand R^fare not both OH), C_1-3alkyl (preferably CH₃), or C_2-3hydroxyalkyl (preferably —CH₂CH2OH), and wherein optionally R^aand R^btogether may form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl).
In another embodiment of the compound of Formula V, R₂is H, methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C_1-3hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.
In preferred embodiment, R₂is H, methyl, Cl, —CH₂OH, —NH₂, —NHCH₃, —NHCH₂CH₂OH, —OCH₃, —SCH₃, or —CH₂F.
In one embodiment, R₉is selected from the group consisting of H; OH; Cl; N₃; C_1-3alkyl (preferably methyl or ethyl) or C_1-3haloalkyl (preferably monofluoromethyl, difluoromethyl, trifluoromethyl); —OR_9a, wherein R_9ais C_1-3alkyl (i.e., methyl, ethyl, propyl, isopropyl) or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —N(R^a)(R^b) wherein R^aand R^bare independently H or C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl); and optionally R₉and one of R₈and R₁₀together form a 3, 4, 5, or 6-membered heterocycle.
In another embodiment, R₉is —OCH₃, —OC₂H₅, —N(CH₃)₂, —CO₂CH₃, —OCHF₂, or N₃.
In yet another embodiment, when R₉is H, at least one of R₈and R₁₀is not H. In another embodiment, when R₉is alkyl, R₂is not H.
In a specific embodiment, compounds of the invention include compounds of Formula V or pharmaceutically acceptable salts or solvates thereof, wherein:

R₁is C_1-2alkyl, and preferably R₁is methyl;
R₅is H or F, preferably H;
R₂-R₄, R₆, R₈-R₁₀, R₁₂and R₁₃are independently H; halo; N₃;
- C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with 1, 2 or 3 substituents, each substituent being independently OH, halo, C_1-3alkoxy, (halo) C_1-3alkoxy, —N(R^a)(R^b) where R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle;
- —XR^cwherein X is S or O and R^cis C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with 1, 2 or 3 substituents, each substituent being independently OH, halo, C_1-3alkoxy, C₂-C₄alkenyl, C₂-C₄alkynyl, —N(R^a)(R^b) where R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle;
- —(C_0-3alkyl)CO₂R^d, wherein R^dis an C_1-6alkyl (preferably C_1-3alkyl, more preferably methyl or ethyl) optionally substituted with 1, 2 or 3 substituents, each substituent being independently OH, halo, C_1-3alkoxy (e.g., fluoroalkoxy), —N(R^a)(R^b) where R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; or
- —N(R^a)(R^b) where R^aand R^bare independently H; OH(R^aand R^bare not both OH); C_2-6hydroxyalkyl; C_1-6alkyl; or C_1-6alkyl substituted with —N(R^e)(R^f) where R^eand R^fare independently H, OH(R^eand R^fare not both OH), or C_1-3alkyl; wherein optionally R^aand R^btogether, and/or R^eand R^ftogether, with the nitrogen atom to which they are linked form a 3, 4, 5 or 6-membered heterocycle; preferably when R₉is H, at least one of R₈and R₁₀is not H, more preferably R₉is other than H.
R₇and R₁₁are independently H, halo (preferably F or Cl, more preferably F), C_1-3alkyl (preferably CH₃), or C_1-4alkoxy (preferably OCH₃); and
B, D, Q, T, U, V, W, X, Y, and Z are as defined above, provided that when B, D, Q, T, U, V, W, X, Y or Z is N there is no substituent at the N.

In another preferred embodiment of the compounds of Formula V,
R₁is methyl or ethyl, more preferably methyl;
R₂is H; halo; N₃;
C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, e.g., monofluoro, difluoro, or trifluoro);
—XR_2awherein X is S or O, and R_2ais C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, e.g., monofluoro-, difluoro-, or trifluoro-substituted);
—CO₂R^d, wherein R^dis C_1-3alkyl, preferably methyl or ethyl; or
—N(R^a)(R^b) wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_1-3alkyl (preferably CH₃), C_1-6hydroxyalkyl (preferably C_2-3hydroxyalkyl, more preferably —CH₂CH₂OH), or C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) that is optionally substituted with —N(R^e)(R^f) wherein R^eand R^fare independently H, OH(R^eand R^fare not both OH), C_1-3alkyl (preferably CH₃), or C_2-3hydroxyalkyl (preferably —CH₂CH2OH), and wherein optionally R^aand R^bwith N together may form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl);
R₃and R₁₂are independently H; halo; C_1-3alkyl; or C_1-3alkoxy;
R₄, R₆, and R₁₃are independently H; halo (preferably F or Cl); N₃; C_1-3alkyl (preferably CH₃);
C_1-3alkoxy (preferably OCH₃); or —N(R^a)(R^b) wherein R^aand R^bare independently H, OH, C_1-3alkyl, (hydroxy)C_1-3alkyl, and optionally R^aand R^btogether may form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl), and wherein R^aand R^bare not both OH;

R₅is H;

R₇and R₁₁are independently H, halo (preferably F), CH₃, or OCH₃;
R₈and R₁₀are independently H; halo (preferably F or Cl, more preferably F); C_1-3alkyl (preferably CH₃); C_1-3alkoxy (preferably OCH₃); and
R₉is selected from the group: H; OH; Cl; N₃; C_1-3alkyl (preferably methyl or ethyl) or C_1-3haloalkyl (preferably monofluoromethyl, difluoromethyl, trifluoromethyl); —OR_9a, wherein R_9ais C_1-3alkyl (i.e., methyl, ethyl, propyl, isopropyl) or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —N(R^a)(R^b) wherein R^aand R^bare independently H or C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl); and optionally R₉and one of R₈and R₁₀together form a 3, 4, 5, or 6-membered heterocycle; preferably when R₉is H, at least one of R₈and R₁₀is not H, more preferably R₉is other than H; and
B, D, Q, T, U, V, W, X, Y, and Z are independently C or N, provided that at least one of B and D is N, and at least one of W, X, Y, and Z is N, wherein when B, D, Q, T, U, V, W, X, Y, or Z is nitrogen, then there is no substituent at the N.
In more preferred embodiment, compounds of the invention include compounds of Formula V or pharmaceutically acceptable salts or solvates thereof, wherein:
R₁is methyl or ethyl, preferably methyl;
R₂is H, methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C_1-3hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅₅or SCH₃;
R₃and R₁₂are independently H, CH₃, OCH₃, F, or Cl;
R₄, R₆, and R₁₃are independently H, CH₃, NH₂, N₃, F, or Cl;

R₅is H;

R₇and R₁₁are independently H, F, or OCH₃;
R₈and R₁₀are independently H, F, Cl, or OCH₃;
R₉is selected from the group of consisting of H; OH; Cl; N₃; C_1-3alkyl (preferably methyl or ethyl); C_1-3haloalkyl (preferably monofluoromethyl, difluoromethyl, trifluoromethyl); —OR_9awhere R_9ais C_1-3alkyl (i.e., methyl, ethyl, propyl, isopropyl) or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —N(R^a)(R^b) wherein R^aand R^bare independently H or C_1-3alkyl; and —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl), and optionally R₉and one of R₈and R₁₀together form a 3, 4, 5, or 6-membered heterocycle; preferably when R₉is H, at least one of R₈and R₁₀is not H, more preferably R₉is other than H; and
B, D, Q, T, U, V, W, X, Y and Z are as defined above, provided that when B, D, Q, T, U, V, W, X, Y or Z is N, then there is no substituent at the N. Preferably in this embodiment, when R₉is alkyl, R₂not H.
In a even more preferred embodiment, compounds of the invention include compounds of Formula V or pharmaceutically acceptable salts or solvates thereof, wherein R₁is methyl; R₂is H, methyl, Cl, —CH₂OH, —NH₂, —NHCH₃, —NHCH₂CH₂OH, —OCH₃, —SCH₃, or —CH₂F; R₃and R₁₂are independently H, methyl, —OCH₃, or Cl; R₄is H, methyl, or NH₂; R₅is H; R₆and R₁₃are independently H or methyl; R₇and R₁₁are independently H or F; R₈and R₁₀are independently H, or F or OCH₃; and R₉is —OCH₃, —OC₂H₅, —N(CH₃)₂, —CO₂CH₃, —OCHF₂, or N₃; and B, D, Q, T, U, V, W, X, Y, and Z are as defined above, provided that when B, D, Q, T, U, V, W, X, Y, or Z is N, then there is no substituent at the N.
In all embodiments of the compounds of Formula V, it is preferred that one of W, X, Y and Z is N, or two of W, X, Y and Z are N. In any of the embodiments, preferably one or two of Q, T, U and V are N. For example, Q and V can be both N and T and U are C.
Other preferred compounds of the present invention are those represented by Formula V, with the proviso that Q, T, U, and V are all carbon. Specifically, such compounds are represented by Formula Va:
or pharmaceutically acceptable salts or solvates thereof, wherein:
R₁is methyl or ethyl, preferably methyl;
R₅is H, F, Cl, N₃, methyl, methoxy or NH₂, with the proviso that when R₅is methoxy, R₁is methyl; Preferably R₅is H, F or N₃, more preferably H or F, and most preferably H;
R₂-R₄, and R₆-R₁₃are independently H, halo, N₃, OH, thiol, nitro, CN, NH₂, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, halo-C_1-6alkyl, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl, or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl); wherein any of the groups is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N₃, OH, thiol, nitro, CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle, wherein optionally any two adjacent R₇-R₁₁groups together form a 3, 4, 5 or 6-membered carbocycle or heterocycle; and
B, D, W, X, Y and Z are independently C or N, provided that at least one of B and D is N, and at least one of W, X, Y and Z is N, and wherein when B, D, W, X, Y or Z is N, then there is no substituent at the N.
In a specific embodiment, preferably when R₉is H, then at least one of R₈and R₁₀is not H, more preferably R₉is other than H.
In some specific embodiments, B is C and D is N. In other specific embodiments, B is N and D is C. In preferred embodiments, both B and D are N.
In one embodiment of the compounds of Formula Va,
R₂is H; halo; N₃;
C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, e.g., monofluoro, difluoro, or trifluoro);
—XR_2awherein X is S or O, and R_2ais C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, e.g., monofluoro-, difluoro-, or trifluoro-substituted);
—CO₂R^d, wherein R^dis C_1-3alkyl, preferably methyl or ethyl; or
—N(R^a)(R^b) wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_1-3alkyl (preferably CH₃), C_1-6hydroxyalkyl (preferably C_2-3hydroxyalkyl, more preferably —CH₂CH₂OH), or C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) that is optionally substituted with —N(R^e)(R^f) wherein R^eand R^fare independently H, OH(R^eand R^fare not both OH), C_1-3alkyl (preferably CH₃), or C_2-3hydroxyalkyl (preferably —CH₂CH2OH), and wherein optionally R^aand R^btogether may form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl).
In another embodiment of the compound of Formula Va, R₂is H, methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C_1-3hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.
In preferred embodiment, R₂is H, methyl, Cl, —CH₂OH, —NH₂, —NHCH₃, —NHCH₂CH₂OH, —OCH₃, —SCH₃, or —CH₂F.
In one embodiment, R₉is selected from the group consisting of H; OH; Cl; N₃; C_1-3alkyl (preferably methyl or ethyl) or C_1-3haloalkyl (preferably monofluoromethyl, difluoromethyl, trifluoromethyl); —OR_9a, wherein R_9ais C_1-3alkyl (i.e., methyl, ethyl, propyl, isopropyl) or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —N(R^a)(R^b) wherein R^aand R^bare independently H or C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl); and optionally R₉and one of R₈and R₁₀together form a 3, 4, 5, or 6-membered heterocycle.
In another embodiment, R₉is —OCH₃, —OC₂H₅, —N(CH₃)₂, —CO₂CH₃, —OCHF₂, or N₃.
In yet another embodiment, when R₉is H, then at least one of R₈and R₁₀is not H. In another embodiment, when R₉is alkyl, then R₂is not H.
In a specific embodiment, compounds of the invention include compounds of Formula Va or pharmaceutically acceptable salts or solvates thereof, wherein:
R₁is C_1-2alkyl, and preferably R₁is methyl;
R₅is H or F, preferably H;
R₂-R₄, R₆, R₈-R₁₀, R₁₂and R₁₃are independently H; halo; N₃;

- C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with 1, 2 or 3 substituents, each substituent being independently OH, halo, C_1-3alkoxy, (halo) C_1-3alkoxy, —N(R^a)(R^b) where R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle;
- —XR^cwherein X is S or O and R^cis C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with 1, 2 or 3 substituents, each substituent being independently OH, halo, C_1-3alkoxy, C₂-C₄alkenyl, C₂-C₄alkynyl, —N(R^a)(R^b) where R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle;
- (C_0-3alkyl)CO₂R^d, wherein R^dis an C_1-6alkyl (preferably C_1-3alkyl, more preferably methyl or ethyl) optionally substituted with 1, 2 or 3 substituents, each substituent being independently OH, halo, C_1-3alkoxy (e.g., fluoroalkoxy), —N(R^a)(R^b) where R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; or
- —N(R^a)(R^b) where R^aand R^bare independently H; OH(R^aand R^bare not both OH); C_2-6hydroxyalkyl; C_1-6alkyl; or C_1-6alkyl substituted with —N(R^e)(R^f) where R^eand R^fare independently H, OH(R^eand R^fare not both OH), or C_1-3alkyl; wherein optionally R^aand R^btogether, and/or R^eand R^ftogether, with the nitrogen atom to which they are linked form a 3, 4, 5 or 6-membered heterocycle; preferably when R₉is H, at least one of R₈and R₁₀is not H, more preferably R₉is other than H.
  R₇and R₁₁are independently H, halo (preferably F or Cl, more preferably F), C_1-3alkyl (preferably CH₃), or C_1-4alkoxy (preferably OCH3); and
  B, D, W, X, Y, and Z are as defined above, provided that when B, D, W, X, Y or Z is N there is no substituent at the N.

In another preferred embodiment of the compounds of Formula Va,
R₁is methyl or ethyl, more preferably methyl;
R₂is H; halo; N₃; C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, e.g., monofluoro, difluoro, or trifluoro); —XR_2awherein X is S or O, and R_2ais C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, e.g., monofluoro-, difluoro-, or trifluoro-substituted); —CO₂R^d, wherein R^dis C_1-3alkyl, preferably methyl or ethyl; or —N(R^a)(R^b) wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_1-3alkyl (preferably CH₃), C_1-6hydroxyalkyl (preferably C_2-3hydroxyalkyl, more preferably —CH₂CH₂OH), or C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) that is optionally substituted with —N(R^e)(R^f) wherein R^eand R^fare independently H, OH(R^eand R^fare not both OH), C_1-3alkyl (preferably CH₃), or C_2-3hydroxyalkyl (preferably —CH₂CH2OH), and wherein optionally R^aand R^btogether may form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl);
R₃and R₁₂are independently H; halo; C_1-3alkyl; or C_1-3alkoxy;
R₄, R₆, and R₁₃are independently H; halo (preferably F or CO; N₃; C_1-3alkyl (preferably CH₃); C_1-3alkoxy (preferably OCH₃); or —N(R^a)(R^b) wherein R^aand R^bare independently H, OH, C_1-3alkyl, hydroxy-C_1-3alkyl, and optionally R^aand R^btogether may form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl), and wherein R^aand R^bare not both OH;

R₅is H;

R₇and R₁₁are independently H, halo (preferably F), CH₃, or OCH₃;
R₈and R₁₀are independently H; halo (preferably F or Cl, more preferably F); C_1-3alkyl (preferably CH₃); C_1-3alkoxy (preferably OCH₃); and
R₉is selected from the group: H; OH; Cl; N₃; C_1-3alkyl (preferably methyl or ethyl) or C_1-3haloalkyl (preferably monofluoromethyl, difluoromethyl, trifluoromethyl); —OR_9a, wherein R_9ais C_1-3alkyl (i.e., methyl, ethyl, propyl, isopropyl) or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —N(R^a)(R^b) wherein R^aand R^bare independently H or C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl); and optionally R₉and one of R₈and R₁₀together form a 3, 4, 5, or 6-membered heterocycle; preferably when R₉is H, at least one of R₈and R₁₀is not H, more preferably R₉is other than H; and
B, D, W, X, Y, and Z are independently C or N, provided that at least one of B and D is N, and at least one of W, X, Y, and Z is N, wherein when B, D, W, X, Y, or Z is nitrogen, then there is no substituent at the N.
In more preferred embodiment, compounds of the invention include compounds of Formula Va or pharmaceutically acceptable salts or solvates thereof, wherein:
R₁is methyl or ethyl, preferably methyl;
R₂is H, methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C_1-3hydroxyalkyl

- (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅₅or SCH₃;
  R₃and R₁₂are independently H, CH₃, OCH₃, F, or Cl;
  R₄, R₆, and R₁₃are independently H, CH₃, NH₂, N₃, F, or Cl;

R₅is H;

R₇and R₁₁are independently H, F, or OCH₃;
R₈and R₁₀are independently H, F, Cl, or OCH₃;
R₉is selected from the group of consisting of H; OH; Cl; N₃; C_1-3alkyl (preferably methyl or ethyl); C_1-3haloalkyl (preferably monofluoromethyl, difluoromethyl, trifluoromethyl); —OR_9awhere R_9ais C_1-3alkyl (i.e., methyl, ethyl, propyl, isopropyl) or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —N(R^a)(R^b) wherein R^aand R^bare independently H or C_1-3alkyl; and —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl), and optionally R₉and one of R₈and R₁₀together form a 3, 4, 5, or 6-membered heterocycle; preferably when R₉is H, at least one of R₈and R₁₀is not H, more preferably R₉is other than H; and
B, D, W, X, Y and Z are as defined above, provided that when B, D, W, X, Y or Z is N, then there is no substituent at the N. Preferably in this embodiment, when R₉is alkyl, R₂not H.
In a even more preferred embodiment, compounds of the invention include compounds of Formula Va or pharmaceutically acceptable salts or solvates thereof, wherein R₁is methyl; R₂is H, methyl, Cl, —CH₂OH, —NH₂, —NHCH₃, —NHCH₂CH₂OH, —OCH₃, —SCH₃, or —CH₂F; R₃and R₁₂are independently H, methyl, —OCH₃, or Cl; R₄is H, methyl, or NH₂; R₅is H; R₆and R₁₃are independently H or methyl; R₇and R₁₁are independently H or F; R₈and R₁₀are independently H, or F or OCH₃; and R₉is —OCH₃, —OC₂H₅, —N(CH₃)₂, —CO₂CH₃, —OCHF₂, or N₃; and B, D, W, X, Y, and Z are as defined above, provided that when B, D, W, X, Y, or Z is N, then there is no substituent at the N.
In all embodiments of the compounds of Formula Va, it is preferred that one of W, X, Y and Z is N, or two of W, X, Y and Z are N.
Another group of preferred compounds of the present invention are those represented by Formula V with the proviso that both B and D are nitrogen. Specifically such compounds are represented by Formula Vb:
or pharmaceutically acceptable salts or solvates thereof, wherein:
R₁is methyl or ethyl, preferably methyl;
R₅is H, F, Cl, N₃, methyl, methoxy or NH₂, with the proviso that when R₅is methoxy, R₁is methyl; Preferably R₅is H, F or N₃, more preferably H or F, and most preferably H;
R₂-R₄, and R₆-R₁₁are independently H, halo, N₃, OH, thiol, nitro, CN, NH₂, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, halo-C_1-6alkyl, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl, or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl); wherein any of the groups is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N₃, OH, thiol, nitro, CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle, wherein optionally any two adjacent R₇-R₁₁groups together form a 3, 4, 5 or 6-membered carbocycle or heterocycle; and
Q, T, U, V, W, X, Y and Z are independently C or N, provided that at least one of W, X, Y and Z is N, and wherein when Q, T, U, V, W, X, Y or Z is N, then there is no substituent at the N.
In a specific embodiment, preferably when R₉is H, then at least one of R₈and R₁₀is not H, more preferably R₉is other than H.
In one embodiment of the compounds of Formula Vb,
R₂is H; halo; N₃;
C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, e.g., monofluoro, difluoro, or trifluoro);
—XR_2awherein X is S or O, and R_2ais C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, e.g., monofluoro-, difluoro-, or trifluoro-substituted);
—CO₂R^d, wherein R^dis C_1-3alkyl, preferably methyl or ethyl; or
—N(R^a)(R^b) wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_1-3alkyl (preferably CH₃), C_1-6hydroxyalkyl (preferably C_2-3hydroxyalkyl, more preferably —CH₂CH₂OH), or C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) that is optionally substituted with —N(R^e)(R^f) wherein R^eand R^fare independently H, OH(R^eand R^fare not both OH), C_1-3alkyl (preferably CH₃), or C_2-3hydroxyalkyl (preferably —CH₂CH2OH), and wherein optionally R^aand R^btogether may form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl).
In another embodiment of the compound of Formula V, R₂is H, methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C_1-3hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.
In preferred embodiment, R₂is H, methyl, Cl, —CH₂OH, —NH₂, —NHCH₃, —NHCH₂CH₂OH, —OCH₃, —SCH₃, or —CH₂F.
In one embodiment, R₉is selected from the group consisting of H; OH; Cl; N₃; C_1-3alkyl (preferably methyl or ethyl) or C_1-3haloalkyl (preferably monofluoromethyl, difluoromethyl, trifluoromethyl); —OR_9a, wherein R_9ais C_1-3alkyl (i.e., methyl, ethyl, propyl, isopropyl) or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —N(R^a)(R^b) wherein R^aand R^bare independently H or C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl); and optionally R₉and one of R₈and R₁₀together form a 3, 4, 5, or 6-membered heterocycle.
In another embodiment, R₉is —OCH₃, —OC₂H₅, —N(CH₃)₂, —CO₂CH₃, —OCHF₂, or N₃.
In yet another embodiment, when R₉is H, then at least one of R₈and R₁₀is not H. In another embodiment, when R₉is alkyl, then R₂is not H.
In a specific embodiment, compounds of the invention include compounds of Formula Vb or pharmaceutically acceptable salts or solvates thereof, wherein:
R₁is C_1-2alkyl, and preferably R₁is methyl;
R₅is H or F, preferably H;
R₂-R₄, R₆, R₈-R₁₀are independently H; halo; N₃;

- C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with 1, 2 or 3 substituents, each substituent being independently OH, halo, C_1-3alkoxy, (halo) C_1-3alkoxy, —N(R^a)(R^b) where R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle;
- —XR^cwherein X is S or O and R^cis C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with 1, 2 or 3 substituents, each substituent being independently OH, halo, C_1-3alkoxy, C₂-C₄alkenyl, C₂-C₄alkynyl, —N(R^a)(R^b) where R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle;
- (C_0-3alkyl)CO₂R^d, wherein R^dis an C_1-6alkyl (preferably C_1-3alkyl, more preferably methyl or ethyl) optionally substituted with 1, 2 or 3 substituents, each substituent being independently OH, halo, C_1-3alkoxy (e.g., fluoroalkoxy), —N(R^a)(R^b) where R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; or
- —N(R^a)(R^b) where R^aand R^bare independently H; OH(R^aand R^bare not both OH); C_2-6hydroxyalkyl; C_1-6alkyl; or C_1-6alkyl substituted with —N(R^e)(R^f) where R^eand R^fare independently H, OH(R^eand R^fare not both OH), or C_1-3alkyl; wherein optionally R^aand R^btogether, and/or R^eand R^ftogether, with the nitrogen atom to which they are linked to form a 3, 4, 5 or 6-membered heterocycle; preferably when R₉is H, at least one of R₈and R₁₀is not H, more preferably R₉is other than H.
  R₇and R₁₁are independently H, halo (preferably F or Cl, more preferably F), C_1-3alkyl (preferably CH₃), or C_1-4alkoxy (preferably OCH₃); and
  Q, T, U, V, W, X, Y, and Z are as defined above, provided that when Q, T, U, V, W, X, Y or Z is N there is no substituent at the N.

In another preferred embodiment of the compounds of Formula Vb,
R₁is methyl or ethyl, more preferably methyl;
R₂is H; halo; N₃;
C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, e.g., monofluoro, difluoro, or trifluoro);
—XR_2awherein X is S or O, and R_2ais C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, e.g., monofluoro-, difluoro-, or trifluoro-substituted);
—CO₂R^d, wherein R^dis C_1-3alkyl, preferably methyl or ethyl; or
—N(R^a)(R^b) wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_1-3alkyl (preferably CH₃), C_1-6hydroxyalkyl (preferably C_2-3hydroxyalkyl, more preferably —CH₂CH₂OH), or C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) that is optionally substituted with —N(R^e)(R^f) wherein R^eand R^fare independently H, OH(R^eand R^fare not both OH), C_1-3alkyl (preferably CH₃), or C_2-3hydroxyalkyl (preferably —CH₂CH2OH), and wherein optionally R^aand R^btogether may form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl);
R₃is H; halo; C_1-3alkyl; or C_1-3alkoxy;
R₄, and R₆are independently H; halo (preferably F or Cl); N₃; C_1-3alkyl (preferably CH₃); C_1-3alkoxy (preferably OCH₃); or —N(R^a)(R^b) wherein R^aand R^bare independently H, OH, C_1-3alkyl, hydroxy-C_1-3alkyl, and optionally R^aand R^btogether may form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl), and wherein R^aand R^bare not both OH;

R₅is H;

R₇and R₁₁are independently H, halo (preferably F), CH₃, or OCH₃;
R₈and R₁₀are independently H; halo (preferably F or Cl, more preferably F); C_1-3alkyl (preferably CH₃); C_1-3alkoxy (preferably OCH₃); and
R₉is selected from the group: H; OH; Cl; N₃; C_1-3alkyl (preferably methyl or ethyl) or C_1-3haloalkyl (preferably monofluoromethyl, difluoromethyl, trifluoromethyl); —OR_9a, wherein R_9ais C_1-3alkyl (i.e., methyl, ethyl, propyl, isopropyl) or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —N(R^a)(R^b) wherein R^aand R^bare independently H or C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl); and optionally R₉and one of R₈and R₁₀together form a 3, 4, 5, or 6-membered heterocycle; preferably when R₉is H, at least one of R₈and R₁₀is not H, more preferably R₉is other than H; and
Q, T, U, V, W, X, Y, and Z are independently C or N, provided that at least one of W, X, Y, and Z is N, wherein when Q, T, U, V, W, X, Y, or Z is nitrogen, then there is no substituent at the N.
In more preferred embodiment, compounds of the invention include compounds of Formula Vb or pharmaceutically acceptable salts or solvates thereof, wherein:
R₁is methyl or ethyl, preferably methyl;
R₂is H, methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C_1-3hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃;

R₃is H, CH₃, OCH₃, F, or Cl;

R₄, and R₆are independently H, CH₃, NH₂, N₃, F, or Cl;

R₅is H;

R₇and R₁₁are independently H, F, or OCH₃;
R₈and R₁₀are independently H, F, Cl, or OCH₃;
R₉is selected from the group of consisting of H; OH; Cl; N₃; C_1-3alkyl (preferably methyl or ethyl); C_1-3haloalkyl (preferably monofluoromethyl, difluoromethyl, trifluoromethyl); —OR_9awhere R_9ais C_1-3alkyl (i.e., methyl, ethyl, propyl, isopropyl) or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —N(R^a)(R^b) wherein R^aand R^bare independently H or C_1-3alkyl; and —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl), and optionally R₉and one of R₈and R₁₀together form a 3, 4, 5, or 6-membered heterocycle; preferably when R₉is H, at least one of R₈and R₁₀is not H, more preferably R₉is other than H; and
Q, T, U, V, W, X, Y and Z are as defined above, provided that when Q, T, U, V, W, X, Y or Z is N, then there is no substituent at the N. Preferably in this embodiment, when R₉is alkyl, then R₂is not H.
In an even more preferred embodiment, compounds of the invention include compounds of Formula Vb or pharmaceutically acceptable salts or solvates thereof, wherein R₁is methyl; R₂is H, methyl, Cl, —CH₂OH, —NH₂, —NHCH₃, —NHCH₂CH₂OH, —OCH₃, —SCH₃, or —CH₂F; R₃is H, methyl, —OCH₃, or Cl; R₄is H, methyl, or NH₂; R₅is H; R₆is H or methyl; R₇and R₁₁are independently H or F; R₈and R₁₀are independently H, or F or OCH₃; and R₉is —OCH₃, —OC₂H₅, —N(CH₃)₂, —CO₂CH₃, —OCHF₂, or N₃; and Q, T, U, V, W, X, Y, and Z are as defined above, provided that when Q, T, U, V, W, X, Y, or Z is N, then there is no substituent at the N.
In all embodiments of the compounds of Formula Vb, it is preferred that one of W, X, Y and Z is N, or two of W, X, Y and Z are N. In any of the embodiments, preferably one or two of Q, T, U and V are N. For example, Q and V can be both N, and T and U are C.
Another specifical group of compounds of Formula V include those represented by Formula Vc:
or pharmaceutically acceptable salts or solvates thereof, wherein:
R₁is methyl or ethyl, preferably methyl;
R₅is H, F, Cl, N₃, methyl, methoxy or NH₂, with the proviso that when R₅is methoxy, R₁is methyl; preferably R₅is H, F or N₃, more preferably H or F, and most preferably H;
R₂-R₄, and R₆-R₁₁are independently H, halo, N₃, OH, thiol, nitro, CN, NH₂, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, halo-C_1-6alkyl, C_2-6alkenyl-O—, C_2-6alkenyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl, or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl); wherein any of the groups is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N₃, OH, thiol, nitro, CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle, wherein optionally any two adjacent R₇-R₁₁groups together form a 3, 4, 5 or 6-membered carbocycle or heterocycle; and
W, X, Y and Z are independently C or N, provided that at least one of W, X, Y and Z is N, and wherein when W, X, Y or Z is N, then there is no substituent at the N.
In a specific embodiment, preferably when R₉is H, then at least one of R₈and R₁₀is not H, more preferably R₉is other than H.
In one embodiment of the compounds of Formula Vc,
R₂is H; halo; N₃;
C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, e.g., monofluoro, difluoro, or trifluoro);
—XR_2awherein X is S or O, and R_2ais C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, e.g., monofluoro-, difluoro-, or trifluoro-substituted);
—CO₂R^d, wherein R^dis C_1-3alkyl, preferably methyl or ethyl; or
—N(R^a)(R^b) wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_1-3alkyl (preferably CH₃), C_1-6hydroxyalkyl (preferably C_2-3hydroxyalkyl, more preferably —CH₂CH₂OH), or C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) that is optionally substituted with —N(R^e)(R^f) wherein R^eand R^fare independently H, OH(R^eand R^fare not both OH), C_1-3alkyl (preferably CH₃), or C_2-3hydroxyalkyl (preferably —CH₂CH2OH), and wherein optionally R^aand R^btogether may form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl).
In another embodiment of the compound of Formula Vc, R₂is H, methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C_1-3hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.
In preferred embodiment, R₂is H, methyl, Cl, —CH₂OH, —NH₂, —NHCH₃, —NHCH₂CH₂OH, —OCH₃, —SCH₃, or —CH₂F.
In one embodiment, R₉is selected from the group consisting of H; OH; Cl; N₃; C_1-3alkyl (preferably methyl or ethyl) or C_1-3haloalkyl (preferably monofluoromethyl, difluoromethyl, trifluoromethyl); —OR_9a, wherein R_9ais C_1-3alkyl (i.e., methyl, ethyl, propyl, isopropyl) or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —N(R^a)(R^b) wherein R^aand R^bare independently H or C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl); and optionally R₉and one of R₈and R₁₀together form a 3, 4, 5, or 6-membered heterocycle.
In another embodiment, R₉is —OCH₃, —OC₂H₅, —N(CH₃)₂, —CO₂CH₃, —OCHF₂, or N₃.
In yet another embodiment, when R₉is H, then at least one of R₈and R₁₀is not H. In another embodiment, when R₉is alkyl, then R₂is not H.
In a specific embodiment, compounds of the invention include compounds of Formula Vc or pharmaceutically acceptable salts or solvates thereof, wherein:
R₁is C_1-2alkyl, and preferably R₁is methyl;
R₅is H or F, preferably H;
R₂-R₄, R₆, R₈-R₁₀are independently H; halo; N₃;

- C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with 1, 2 or 3 substituents, each substituent being independently OH, halo, C_1-3alkoxy, (halo) C_1-3alkoxy, —N(R^a)(R^b) where R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle;
- —XR^cwherein X is S or O and R^cis C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with 1, 2 or 3 substituents, each substituent being independently OH, halo, C_1-3alkoxy, C₂-C₄alkenyl, C₂-C₄alkynyl, —N(R^a)(R^b) where R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle;
- (C_0-3alkyl)CO₂R^d, wherein R^dis an C_1-6alkyl (preferably C_1-3alkyl, more preferably methyl or ethyl) optionally substituted with 1, 2 or 3 substituents, each substituent being independently OH, halo, C_1-3alkoxy (e.g., fluoroalkoxy), —N(R^a)(R^b) where R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; or
- —N(R^a)(R^b) where R^aand R^bare independently H; OH(R^aand R^bare not both OH); C_2-6hydroxyalkyl; C_1-6alkyl; or C_1-6alkyl substituted with —N(R^e)(R^f) where R^eand R^fare independently H, OH(R^eand R^fare not both OH), or C_1-3alkyl; wherein optionally R^aand R^btogether, and/or R^eand R^ftogether, with the nitrogen atom to which they are linked form a 3, 4, 5 or 6-membered heterocycle;
- —(C_0-3alkyl)C(O)N(R^a)(R^b) wherein R^aand R^bare independently C_1-3alkyl, C_2-3hydroxyalkyl or C_1-3haloalkyl; preferably when R₉is H, then at least one of R₈and R₁₀is not H, more preferably R₉is other than H;
  R₇and R₁₁are independently H, halo (preferably F or Cl, more preferably F), C_1-3alkyl (preferably CH₃), or C_1-4alkoxy (preferably OCH3); and
  W, X, Y, and Z are as defined above, provided that when W, X, Y or Z is N there is no substituent at the N.

In another preferred embodiment of the compounds of Formula Vc,
R₁is methyl or ethyl, more preferably methyl;
R₂is H; halo; N₃;

- C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, e.g., monofluoro, difluoro, or trifluoro);
- —XR_2awherein X is S or O, and R_2ais C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, e.g., monofluoro-, difluoro-, or trifluoro-substituted);
- —CO₂R^d, wherein R^dis C_1-3alkyl, preferably methyl or ethyl; or
- —N(R^a)(R^b) wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_1-3alkyl (preferably CH₃), C_1-6hydroxyalkyl (preferably C_2-3hydroxyalkyl, more preferably —CH₂CH₂OH), or C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) that is optionally substituted with —N(R^e)(R^f) wherein R^eand R^fare independently H, OH(R^eand R^fare not both OH), C_1-3alkyl (preferably CH₃), or C_2-3hydroxyalkyl (preferably —CH₂CH2OH), and wherein optionally R^aand R^btogether may form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl);
  R₃is H; halo; C_1-3alkyl; or C_1-3alkoxy;
  R₄, R₆are independently H; halo (preferably F or Cl); N₃; C_1-3alkyl (preferably CH₃); C_1-3alkoxy (preferably OCH₃); or —N(R^a)(R^b) wherein R^aand R^bare independently H, OH, C_1-3alkyl, (hydroxy)C_1-3alkyl, and optionally R^aand R^btogether may form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl), and wherein R^aand R^bare not both OH;

R₅is H;

R₇and R₁₁are independently H, halo (preferably F), CH₃, or OCH₃;
R₈and R₁₀are independently H; halo (preferably F or Cl, more preferably F); C_1-3alkyl (preferably CH₃); C_1-3alkoxy (preferably OCH₃); and
R₉is selected from the group: H; OH; Cl; N₃; C_1-3alkyl (preferably methyl or ethyl) or C_1-3haloalkyl (preferably monofluoromethyl, difluoromethyl, trifluoromethyl); —OR_9a, wherein R_9ais C_1-3alkyl (i.e., methyl, ethyl, propyl, isopropyl) or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —N(R^a)(R^b) wherein R^aand R^bare independently H or C_1-3alkyl; —(C_0-3alkyl)COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl); or —(C_0-3alkyl)C(O)N(R^a)(R^b) wherein R^aand R^bare independently C_1-3alkyl; and optionally R₉and one of R₈and R₁₀together form a 3, 4, 5, or 6-membered heterocycle; preferably when R₉is H, then at least one of R₈and R₁₀is not H, more preferably R₉is other than H; and
W, X, Y, and Z are independently C or N, provided that at least one of W, X, Y, and Z is N, wherein when W, X, Y, or Z is nitrogen, then there is no substituent at the N.
In more preferred embodiment, compounds of the invention include compounds of Formula Vc or pharmaceutically acceptable salts or solvates thereof, wherein:
R₁is methyl or ethyl, preferably methyl;
R₂is H, methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C_1-3hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃;

R₃is H, CH₃, OCH₃, F, or Cl;

R₄and R₆are independently H, CH₃, NH₂, N₃, F, or Cl;

R₅is H;

R₇and R₁₁are independently H, F, or OCH₃;
R₈and R₁₀are independently H, F, Cl, or OCH₃;
R₉is selected from the group of consisting of H; OH; Cl; N₃; C_1-3alkyl (preferably methyl or ethyl); C_1-3haloalkyl (preferably monofluoromethyl, difluoromethyl, trifluoromethyl); —OR_9awhere R_9ais C_1-3alkyl (i.e., methyl, ethyl, propyl, isopropyl) or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —N(R^a)(R^b) wherein R^aand R^bare independently H or C_1-3alkyl; and —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl), and optionally R₉and one of R₈and R₁₀together form a 3, 4, 5, or 6-membered heterocycle; preferably when R₉is H, then at least one of R₈and R₁₀is not H, more preferably R₉is other than H; and
W, X, Y and Z are as defined above, provided that when W, X, Y or Z is N, then there is no substituent at the N. Preferably in this embodiment, when R₉is alkyl, R₂not H.
In a even more preferred embodiment, compounds of the invention include compounds of Formula Vc or pharmaceutically acceptable salts or solvates thereof, wherein R₁is methyl; R₂is H, methyl, Cl, —CH₂OH, —NH₂, —NHCH₃, —NHCH₂CH₂OH, —OCH₃, —SCH₃, or —CH₂F; R₃and R₁₂are independently H, methyl, —OCH₃, or Cl; R₄is H, methyl, or NH₂; R₅is H; R₆and R₁₃are independently H or methyl; R₇and R₁₁are independently H or F; R₈and R₁₀are independently H, or F or OCH₃; and R₉is —OCH₃, —OC₂H₅, —N(CH₃)₂, —CO₂CH₃, —OCHF₂, or N₃; and W, X, Y, and Z are as defined above, provided that when W, X, Y, or Z is N, then there is no substituent at the N.
In all embodiments of the compounds of Formula Vc, it is preferred that one of W, X, Y and Z is N, or two of W, X, Y and Z are N.
Other preferred compounds of the present invention are those represented by Formula VI:
or pharmaceutically acceptable salts or solvates thereof, wherein:
R₁is methyl or ethyl, preferably methyl;
R₅is H or F, preferably H;
R₂-R₄, and R₆-R₁₃are independently H, halo, N₃, OH, thiol, nitro, CN, NH₂, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, halo-C_1-6alkyl, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl, or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl); wherein any of the groups is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N₃, OH, thiol, nitro, CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked to form a 3, 4, 5 or 6-membered heterocycle, wherein optionally any two adjacent R₇-R₁₁groups together form a 3, 4, 5 or 6-membered carbocycle or heterocycle; and
B, D, Q, T, U and V are independently C or N, provided that at least one of B and D is N, and when B, D, Q, T, U or V is N, then there is no substituent at the N;
wherein when Q, T, U and V are all C, then R₉is not carboxyalkoxy or an ester thereof (preferably R₉is not —O(C_1-6alkyl)C(O)O(C_1-6alkyl); wherein when R₉is H then at least one of R₈and R₁₀is not H or halo or alkyl; and
wherein when R₉is alkyl, then R₂is not aryl.
In one embodiment, compounds of the invention include compounds of Formula VI or pharmaceutically acceptable salts or solvates thereof, wherein:
R₁is methyl or ethyl, preferably methyl;
R₅is H or F, preferably H;
R₂-R₄, R₆-R₁₁are independently H, halo, N₃, OH, thiol, nitro, CN, NH₂, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, halo-C_1-6alkyl, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl, or R^aand R^btogether with the nitrogen atom to which they are both linked to form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl); wherein any of the groups is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N₃, OH, thiol, nitro, CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle, wherein optionally any two adjacent R₇-R₁₁groups together form a 3, 4, 5 or 6-membered carbocycle or heterocycle;
exactly one of B and D is N; and
Q, T, U and V are independently C or N, wherein at least one of Q, T, U and V is N, and when Q, T, U or V is N there is no substituent at the N, provided that when R₉is H then R₂is not optionally substituted aryl or heteroaryl. Preferably, R₈and R₁₀are not both H, or one H and the other alkyl. Preferably when R₉is H then at least one of R₈and R₁₀is not H or alkyl. More preferably, when R₉is H then at least one of R₈and R₁₀is not H, alkyl, or halo.
In one embodiment, R₉is selected from the group consisting of H, OH, C₁, N₃;

C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with 1, 2 or 3 substituents, each substituent being independently OH, halo, C_1-3alkoxy, (halo)C_1-3alkoxy, —N(R^a)(R^b) where R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-4hydroxyalkyl, or C_1-3alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked to form a 3, 4, 5 or 6-membered heterocycle;
—XR^cwherein X is S or O and R^cis C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with 1, 2 or 3 substituents, each substituent being independently OH, halo, C_1-3alkoxy, or (halo)C_1-3alkoxy;
—(C_0-3alkyl)CO₂R^d, wherein R^dis an C_1-6alkyl (preferably C_1-3alkyl, more preferably methyl or ethyl) optionally substituted with 1, 2 or 3 substituents, each substituent being independently OH, halo, C_1-3alkoxy (e.g., fluoroalkoxy), —N(R^a)(R^b) where R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-4hydroxyalkyl, or C_1-3alkyl or R^aand R^btogether with the nitrogen atom to which they both are linked form a 3, 4, 5 or 6-membered heterocycle;
—N(R^a)(R^b) where R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-4hydroxyalkyl, C_1-3alkyl, or C_1-3alkyl substituted with —N(R^e)(R^f) where R^eand R^fare independently H, OH(R^eand R^fare not both OH), or C_1-3alkyl; wherein optionally R^aand R^btogether with the N form a 3, 4, 5 or 6-membered heterocycle, and optionally R^eand R^ftogether with the nitrogen atom to which they both are linked form a 3, 4, 5 or 6-membered heterocycle; or
—(C_0-3alkyl)C(O)N(R^a)(R^b) where R^aand R^bare independently H or C_1-3alkyl; and optionally R₉and one of R₈and R₁₀together form a 3, 4, 5, or 6-membered heterocycle; preferably R₉is selected from the group outlined above except R₉is not H and C_1-6alkyl.

In another embodiment, R₉is H; OH; Cl; N₃; C_1-3alkyl (preferably methyl; C_1-3haloalkyl (preferably monofluoromethyl, difluoromethyl, trifluoromethyl); —OR_9a, wherein R_9ais C_1-4alkyl or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —NH(R^a); —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl); and optionally R₉and one of R₈and R₁₀together form a 3, 4, 5, or 6-membered heterocycle; preferably R₉is selected from the group outlined above except R₉is not H or C_1-3alkyl.
In a preferred embodiment, R₉is N₃, —OR_9awherein R_9ais C_1-3alkyl optionally substituted with 1-7 F, —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl, —COOR_9bwhere R_9bis C_1-3alkyl.
In a more preferred embodiment, R₉is —OCH₃, —OC₂H₅, —N(CH₃)₂, —CO₂CH₃, —OCHF₂, or N₃.
In the various embodiments of the compounds according to Formula VI preferably when R₉is H, R₈or R₁₀or both are independently OH; Cl; N₃; —XR_9a, where X is O or S, and R_9ais C_1-4alkyl or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —NH(R^a) or —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl). More preferably, when R₉is H, R₈or R₁₀or both are independently N₃, —OR_9a, wherein R_9ais C_1-4alkyl or C_1-3haloalkyl; —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl). Even more preferably when R₉is H, R₈or R₁₀or both are C_1-3alkoxy or C_1-3haloalkoxy.
Also preferably in the various embodiments, when R₉is H then R₂is not H, and preferably R₂is halo; C_1-3alkyl optionally substituted with OH or halo (preferably F, e.g., monofluoro, difluoro, or trifluoro); —XR_2awherein X is S or O and R_2ais C_1-3alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with halo (preferably F, e.g., monofluoro-, difluoro-, or trifluoro-substituted); or —N(R^a)(R^b) wherein R^aand R^bare independently H, OH (R^aand R^bare not both OH), C_1-3alkyl (preferably CH₃), C_2-3hydroxyalkyl. More preferably R₂is methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C_1-3hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.
Also preferably, when R₉is C_1-6alkyl or C_1-6haloalkyl, R₂is not H, and preferably is methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C_1-3hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.
In one embodiment, R₂is H; halo; N₃; C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, e.g., monofluoro, difluoro, or trifluoro); —XR_2awherein X is S or O, and R_2ais C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, e.g., monofluoro-, difluoro-, or trifluoro-substituted); —CO₂R^d, wherein R^dis C_1-3alkyl, preferably methyl or ethyl; or —N(R^a)(R^b) wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_1-3alkyl (preferably CH₃), C_1-6hydroxyalkyl (preferably C_2-3hydroxyalkyl, more preferably —CH₂CH₂OH), or C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) that is optionally substituted with —N(R^e)(R^f) wherein R^eand R^fare independently H, OH(R^eand R^fare not both OH), C_1-3alkyl (preferably CH₃), or C_2-3hydroxyalkyl (preferably —CH₂CH2OH), and wherein optionally R^aand R^btogether with the N they are both linked to may form a 3, 4, 5 or 6-membered heterocycle.
In a preferred embodiment, R₂is H; halo; C_1-3alkyl optionally substituted with OH or halo (preferably F, e.g., monofluoro, difluoro, or trifluoro); —XR_2awherein X is S or O and R_2ais C_1-3alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with halo (preferably F, e.g., monofluoro-, difluoro-, or trifluoro-substituted); or —N(R^a)(R^b) wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_1-3alkyl (preferably CH₃), C_2-3hydroxyalkyl.
In preferred embodiments, R₂is H, methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C_1-3hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.
In more preferred embodiments, R₂is H, methyl, Cl, —CH₂OH, —NH₂, —NHCH₃, —NHCH₂CH₂OH, —OCH₃, —SCH₃, or —CH₂F.
In all embodiments of the compound of Formula VI, it is preferred that one or two of Q, T, U and V are N. For example Q and V are N and T and U are C.
In one embodiment, compounds of the invention include compounds of Formula VI or pharmaceutically acceptable salts or solvates thereof, wherein:

R₁is methyl or ethyl, preferably methyl;
R₂is H; halo; N₃;
C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, e.g., monofluoro, difluoro, or trifluoro);
—XR_2awherein X is S or O, and R_2ais C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, e.g., monofluoro-, difluoro-, or trifluoro-substituted);
—CO₂R^d, wherein R^dis C_1-3alkyl, preferably methyl or ethyl; or
—N(R^a)(R^b) wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_1-3alkyl (preferably CH₃), C_1-6hydroxyalkyl (preferably C_2-3hydroxyalkyl, more preferably —CH₂CH₂OH), or C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) that is optionally substituted with —N(R^e)(R^f) wherein R^eand R^fare independently H, OH(R^eand R^fare not both OH), C_1-3alkyl (preferably CH₃), or C_2-3hydroxyalkyl (preferably —CH₂CH2OH), and wherein optionally R^aand R^btogether with the N they are both linked to may form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl);
R₃is H; halo; C_1-3alkyl; or C_1-3alkoxy;
R₄and R₆are independently H; halo (preferably F or Cl); N₃; C_1-6alkyl (preferably C_1-3, more preferably CH₃); C_1-3alkoxy (preferably OCH₃); or —N(R_2b)(R_2c) wherein R_2band R_2care independently H, OH, C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃), C_1-6hydroxyalkyl (preferably C_2-3hydroxyalkyl, more preferably —CH₂CH2OH), or C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) that is optionally substituted with —N(R_2d)(R_2e) wherein R_2dand R_2eare independently H, OH, C_1-3alkyl (preferably CH₃) or C_2-3hydroxyalkyl (preferably —CH₂CH2OH), wherein R_2band R_2ctogether with the N they are both linked to may form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl), and wherein R_2band R_2care not both OH, R_2dand R_2eare not both OH;
R₅is H or F, preferably H;
R₇and R₁₁are independently H; halo (preferably F or Cl, more preferably F); CH₃; or OCH₃;
R₈and R₁₀are independently H; halo (preferably F or Cl, more preferably Cl); OH; N₃; C_1-3alkyl (preferably CH₃); C_1-3alkoxy (preferably OCH₃); C_1-3haloalkyl (preferably monofluoromethyl, difluoromethyl, trifluoromethyl); —XR_9a, where X is O or S, and R_9ais C_1-4alkyl or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —NH(R^a) or —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl);
R₉is selected from the group consisting of H, OH, C₁, N₃;
C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with 1, 2 or 3 substituents, each substituent being independently OH, halo, C_1-3alkoxy, (halo)C_1-3alkoxy, —N(R^a)(R^b) where R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-4hydroxyalkyl, or C_1-3alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle;
—XR^cwherein X is S or O and R^cis C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with 1, 2 or 3 substituents, each substituent being independently OH, halo, C_1-3alkoxy, or (halo)C_1-3alkoxy;
—(C_0-3alkyl)CO₂R^d, wherein R^dis an C_1-6alkyl (preferably C_1-3alkyl, more preferably methyl or ethyl) optionally substituted with 1, 2 or 3 substituents, each substituent being independently OH, halo, C_1-3alkoxy (e.g., fluoroalkoxy), —N(R^a)(R^b) where R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-4hydroxyalkyl, or C_1-3alkyl or R^aand R^btogether with the nitrogen atom to which they both are linked form a 3, 4, 5 or 6-membered heterocycle;
—N(R^a)(R^b) where R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-4hydroxyalkyl, C_1-3alkyl, or C_1-3alkyl substituted with —N(R^e)(R^f) where R^eand R^fare independently H, OH(R^eand R^fare not both OH), or C_1-3alkyl; wherein optionally R^aand R^btogether with the N form a 3, 4, 5 or 6-membered heterocycle, and optionally R^eand R^ftogether with the nitrogen atom to which they both are linked form a 3, 4, 5 or 6-membered heterocycle; or
—(C_0-3alkyl)C(O)N(R^a)(R^b) where R^aand R^bare independently H or C_1-3alkyl; and optionally

R₉and one of R₈and R₁₀together form a 3, 4, 5, or 6-membered heterocycle; provided that when R₉is H, at least one of R₈and R₁₀is not hydrogen or alkyl;

exactly one of B and D is N; and
Q, T, U and V are independently C or N, provided that at least one of Q, T, U and V is N, wherein when Q, T, U or V is N, then there is no substituent at the N. In some specific embodiments, one or two of Q, T, U and V are N.

Preferably when R₉is H, R₈or R₁₀or both are independently OH; Cl; N₃; —XR_9a, where X is O or S, and R_9ais C_1-4alkyl or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —NH(R^a) or —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl). More preferably, when R₉is H, R₈or R₁₀or both are independently N₃, —OR_9a, wherein R_9ais C_1-4alkyl or C_1-3haloalkyl, or —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl). Even more preferably when R₉is H, R₈or R₁₀or both are C_1-3alkoxy or C_1-3haloalkoxy.
Also preferably, when R₉is C_1-6alkyl or C_1-6haloalkyl, R₂is methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C_1-3hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.
In another preferred embodiment, compounds of the invention include compounds of Formula VI or pharmaceutically acceptable salts or solvates thereof, wherein:

R₁is methyl or ethyl, and preferably methyl;
R₂is H; halo; N₃;
C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, e.g., monofluoro, difluoro, or trifluoro);
—XR_2awherein X is S or O, and R_2ais C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, e.g., monofluoro-, difluoro-, or trifluoro-substituted);
—CO₂—R_2f, wherein R_2fis C_1-6alkyl (preferably C_1-3alkyl, more preferably methyl or ethyl); or —N(R_2b)(R_2c) wherein R_2band R_2care independently H, OH, C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃), C_1-6hydroxyalkyl (preferably C_2-3hydroxyalkyl, more preferably —CH₂CH2OH), or C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) that is optionally substituted with —N(R_2d)(R_2e) wherein R_2dand R_2eare independently H, OH, C_1-3alkyl (preferably CH₃), or C_2-3hydroxyalkyl (preferably —CH₂CH₂OH), and wherein optionally R_2band R_2ctogether with the N they are both linked to may form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl), and wherein R_2band R_2care not both OH, R_2dand R_2eare not both OH;
R₃is H; halo; C_1-3alkyl; or C_1-3alkoxy;
R₄and R₆are independently H; halo (preferably F or Cl); N₃; C_1-3alkyl (preferably CH₃); C_1-3alkoxy (preferably OCH₃); or —N(R_2b)(R_2c) wherein R_2band R_2care independently H, OH, CH₃, or ethyl, and optionally R_2band R_2ctogether with the N they are both linked to may form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl), and wherein R_2band R_2care not both OH;
R₅is H;
R₇and R₁₁are independently H, halo (preferably F), CH₃, or OCH₃;
R₈and R₁₀are independently H; halo (preferably F or Cl, more preferably F); C_1-3alkyl (preferably CH₃); C_1-3alkoxy (preferably OCH₃); and
R₉is selected from the group:
hydrogen; hydroxy; Cl; N₃;
C_1-3alkyl (preferably methyl or ethyl) or C_1-3haloalkyl (preferably monofluoromethyl, difluoromethyl, trifluoromethyl);
—OR_9a, wherein R_9ais C_1-3alkyl (i.e., methyl, ethyl, propyl, isopropyl) or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃);
—N(Ra)(Rb), wherein Ra and Rb are independently H, C_1-3alkyl, or haloC_1-3alkyl; or
—COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl); and optionally R₉and one of R₈and R₁₀together form a 3, 4, 5, or 6-membered carbocycle or heterocycle;
exactly one of B and D is N; and
Q, T, U and V are independently C or N, wherein at least one of Q, T, U and V are N, wherein when Q, T, U or V is N, then the there is no substituent at the N; with the proviso that when R₉is H then R₈and R₁₀are not both H or one H and the other alkyl. Preferably when R₉is H then at least one of R₈or R₁₀is not H or alkyl. More preferably when R₉is H then at least one of R₈or R₁₀is not H, alkyl, or halo.

In some specific embodiments, one or two of Q, T, U and V are N.
Preferably in this embodiment, when R₉is H, R₈or R₁₀or both are independently OH; Cl; N₃; C_1-3haloalkyl (preferably monofluoromethyl, difluoromethyl, trifluoromethyl); —XR_9a, where X is O or S, and R_9ais C_1-4alkyl or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —NH(R^a) or —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl). More preferably, when R₉is H, R₈or R₁₀or both are independently N₃, —OR_9a, wherein R_9ais C_1-4alkyl or C_1-3haloalkyl, or —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl). Even more preferably when R₉is H, R₈or R₁₀or both are C_1-3alkoxy or C_1-3halo alkoxy.
Also preferably, when R₉is C_1-6alkyl or C_1-6haloalkyl, R₂is not H and preferably R₂is halo; C_1-3alkyl optionally substituted with OH or halo (preferably F, e.g., monofluoro, difluoro, or trifluoro); —XR_2awherein X is S or O and R_2ais C_1-3alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with halo (preferably F, e.g., monofluoro-, difluoro-, or trifluoro-substituted); or —N(R^a)(R^b) wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_1-3alkyl (preferably CH₃), C_2-3hydroxyalkyl. More preferably R₂is methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C_1-3hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.
Also preferably, in this embodiment, when R₉is H, R₈or R₁₀or both are OCH₃and preferably R₇and R₁₁are H, and also preferably R₂is not hydrogen and preferably R₂is methyl or chloro. Also preferably in this embodiment, when R₉is alkyl or haloalkyl or chloro, R₂is not hydrogen and preferably R₂is methyl or chloro.
In another preferred embodiment, compounds of the invention include compounds of Formula VI or pharmaceutically acceptable salts or solvates thereof, wherein:

R₁is methyl or ethyl, preferably methyl;
R₂is H, methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C_1-3hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃; R₃is H, CH₃, OCH₃, F, or Cl; R₄and R₆are independently H, CH₃, NH₂, N₃, F, or Cl; R₅is H; R₇and R₁₁are independently H, F, or OCH₃; R₈and R₁₀are independently H, F, Cl, or OCH₃; and
R₉is selected from the group:
- hydrogen; hydroxy; Cl; C_1-3alkyl (preferably methyl or ethyl) or C_1-3haloalkyl (preferably monofluoromethyl, difluoromethyl, trifluoromethyl); —OR_9a, wherein R_9ais C_1-3alkyl (i.e., methyl, ethyl, propyl, isopropyl) or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); C_1-3alkyl substituted amino (preferably —NHCH₃or —N(CH₃)₂);
—N₃; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl), and optionally R₈and R₉together form a 3, 4, 5, or 6-membered carbocycle or heterocycle;
exactly one of B and D is N; and
Q, T, U and V are independently C or N, and at least one of Q, T, U and V is N, wherein when Q, T, U or V is N, then there is no substituent at the N. In some specific embodiments, one or two of Q, T, U and V are nitrogen.

Preferably in this embodiment, when R₉is H, R₈or R₁₀or both are independently OH; Cl; N₃; C_1-3haloalkyl (preferably monofluoromethyl, difluoromethyl, trifluoromethyl); —XR₉, where X is O or S, and R_9ais C_1-4alkyl or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —NH(R^a) or —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl). More preferably, when R₉is H, R₈or R₁₀or both are independently N₃, —OR_9a, wherein R_9ais C_1-4alkyl or C_1-3haloalkyl, or —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl). Even more preferably when R₉is H, R₈or R₁₀or both are C_1-3alkoxy or C_1-3halo alkoxy.
Also preferably, when R₉is C_1-6alkyl or C_1-6haloalkyl, R₂is not H and preferably R₂is methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C_1-3hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.
Also preferably, in this embodiment, when R₉is H, R₈or R₁₀or both are OCH₃and preferably R₇and R₁₁are H, and also preferably R₂is not hydrogen and preferably R₂is methyl or chloro. Also preferably in this embodiment, when R₉is alkyl or haloalkyl or chloro, R₂is not hydrogen and preferably R₂is methyl or chloro.
In another preferred embodiment, compounds of the invention include compounds of Formula VI or pharmaceutically acceptable salts or solvates thereof, wherein:
R₁is methyl;
R₂is H, methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), CH₂OH, NH₂, NHCH₃, N(CH₃)₂, —NHCH₂CH₂OH, OCH₃, or SCH₃; R₃is H, CH₃, OCH₃, F, or Cl; R₄and R₆are independently H, CH₃, NH₂, F, or Cl; R₅is H; R₇and R₁₁are independently H, F, or OCH₃; R₈and R₁₀are independently H, F, Cl, or OCH₃; and
R₉is selected from the group:

- —OR_9a, wherein R_9ais selected from the group of methyl, ethyl, fluoromethyl (e.g., CH₂F, CHF₂, CF₃), and fluoroethyl; —NHCH₃; —N(CH₃)₂; —N₃; and —COOR_9b, wherein R_9bis H or methyl or ethyl;
  exactly one of B and D is N; and
  Q, T, U and V are independently C or N, and at least one of Q, T, U and V is N, wherein when Q, T, U or V is N, then there is no substituent at the N. In some specific embodiments, one or two of Q, T, U and V are nitrogen.

In a more preferred embodiment, compounds of the invention include compounds of Formula VI or pharmaceutically acceptable salts or solvates thereof, wherein:

R₁is CH₃;

R₂is H, methyl, Cl, —CH₂OH, —NH₂, —NHCH₃, —NHCH₂CH₂OH, —OCH₃, —SCH₃, or —CH₂F;

R₃is H, —CH₃, —OCH₃, or Cl;

R₄is H, CH₃, or NH₂;

R₅is H;

R₆is H, or CH₃;

R₇and R₁₁are independently H, or F;
R₈and R₁₀are independently H, or F or OCH₃;

R₉is —OCH₃or —OC₂H₅, —N(CH₃)₂, —CO₂CH₃, —OCHF₂, or N₃;

exactly one of B and D is N; and
Q, T, U and V are independently C or N, and at least one of Q, T, U and V is N, wherein when Q, T, U or V is N, then there is no substituent at the N. In some specific embodiments, one or two of Q, T, U and V are nitrogen.
In a more preferred embodiment, the present invention provides compounds of Formula VI or pharmaceutically acceptable salts or solvates thereof, wherein R₁is CH₃; R₂is Cl, methyl, or CH₂F; R₃is H, CH₃, F, or Cl; R₄, R₅and R₆are H; R₇, R₈, R₁₀and R₁₁are independently H or F; R₉is —OCH₃or —N(CH₃)₂; and Q, T, U and V are independently C or N, and at least one of Q, T, U and V is N, wherein when Q, T, U or V is N, then there is no substituent at the N. In some specific embodiments, one or two of Q, T, U and V are nitrogen.
In another embodiment, compounds of the invention include compounds of Formula VI or pharmaceutically acceptable salts or solvates thereof, wherein:
R₁is methyl or ethyl, preferably methyl;
R₅is H or F, preferably H; and
R₂-R₄, R₆-R₁₁are independently H, halo, N₃, OH, thiol, nitro, CN, NH₂, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, halo-C_1-6alkyl, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl, or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl); wherein any of the groups is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N₃, OH, thiol, nitro, CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle, wherein optionally any two adjacent R₇-R₁₁groups together form a 3, 4, 5 or 6-membered carbocycle or heterocycle;
exactly one of B and D is N provided that when B or D is N there is no substituent at the N; and all of Q, T, U, and V are C;
provided that: (1) when R₉is H then R₈and R₁₀are not both H or one H and the other halo; and (2) when R₉is alkyl then R₂is not optionally substituted aryl or heteroaryl. Preferably when R₉is H then R₈and R₁₀are not both H or one H and the other halo or alkyl or haloalkyl.
In one embodiment, R₉is selected from the group consisting of H, C₁, N₃;
C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with 1, 2 or 3 substituents, each substituent being independently OH, halo, C_1-3alkoxy, (halo)C_1-3alkoxy, —N(R^a)(R^b) where R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-4hydroxyalkyl, or C_1-3alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle;
—XR^cwherein X is S or O and R^cis C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with 1, 2 or 3 substituents, each substituent being independently OH, halo, C_1-3alkoxy, or (halo)C_1-3alkoxy;
(CO_0-3alkyl)CO₂R^d, wherein R^dis an C_1-6alkyl, preferably C_1-3alkyl;
—N(R^a)(R^b) where R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-4hydroxyalkyl, C_1-3alkyl, or —N(R^e)(R^f) where R^eand R^fare independently H, OH(R^eand R^fare not both OH), or C_1-3alkyl; wherein optionally R^aand R^btogether with the N form a 3, 4, 5 or 6-membered heterocycle, and optionally R^eand R^ftogether with the nitrogen atom to which they both are linked form a 3, 4, 5 or 6-membered heterocycle; or
—(C_0-3alkyl)C(O)N(R^a)(R^b) where R^aand R^bare independently H or C_1-3alkyl; and optionally R₉and one of R₈and R₁₀together form a 3, 4, 5, or 6-membered heterocycle. Preferably R₉is selected from such groups except R₉is not H or chloro.
In another embodiment, R₉is H; OH; Cl; N₃; C_1-3alkyl (preferably methyl; C_1-3haloalkyl (preferably monofluoromethyl, difluoromethyl, trifluoromethyl); —OR_9a, wherein R_9ais C_1-4alkyl or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —NH(R^a) or —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl); and optionally R₉and one of R₈and R₁₀together form a 3, 4, 5, or 6-membered heterocycle. Preferably R₉is selected from such groups except R₉is not H or chloro.
In a preferred embodiment, R₉is N₃; —OR_9a, wherein R_9ais C_1-3alkyl optionally substituted with 1-7 F; —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl; or —COOR_9bwhere R_9bis C_1-3alkyl.
In more preferred embodiment, R₉is —OCH₃, —OC₂H₅, —N(CH₃)₂, —CO₂CH₃, —OCHF₂, or N₃.
Preferably when R₉is H, R₈or R₁₀or both are independently OH; N₃; —XR_9a, where X is O or S, and R_9ais C_1-4alkyl or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —NH(R^a) or —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl). More preferably, when R₉is H, R₈or R₁₀or both are independently N₃, —OR_9a, wherein R_9ais C_1-4alkyl or C_1-3haloalkyl, or —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl). Even more preferably when R₉is H, R₈or R₁₀or both are C_1-3alkoxy or C_1-3halo alkoxy.
Also preferably in the various embodiments, when R₉is H, R₈and R₁₀are not H or one H and the other halo, and R₂is not H, and preferably R₂is halo; N₃, C_1-3alkyl optionally substituted with OH or halo (preferably F, e.g., monofluoro, difluoro, or trifluoro); —XR_2awherein X is S or O and R_2ais C_1-3alkyl (more preferably CH₃) optionally substituted with halo (preferably F, e.g., monofluoro-, difluoro-, or trifluoro-substituted); or —N(R^a)(R^b) wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_1-3alkyl (preferably CH₃), C_2-3hydroxyalkyl. More preferably R₂is methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C_1-3hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.
Also preferably, when R₉is C_1-6alkyl, halo, or C_1-6haloalkyl, R₂is not H, and preferably R₂is halo; N₃, C_1-3alkyl optionally substituted with OH or halo (preferably F, e.g., monofluoro, difluoro, or trifluoro); —XR_2awherein X is S or O and R_2ais C_1-3alkyl (more preferably CH₃) optionally substituted with halo (preferably F, e.g., monofluoro-, difluoro-, or trifluoro-substituted); or —N(R^a)(R^b) wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_1-3alkyl (preferably CH₃), C_2-3hydroxyalkyl. More preferably R₂is methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C_1-3hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.
In one embodiment, R₂is H; halo; N₃; C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, e.g., monofluoro, difluoro, or trifluoro); —XR_2awherein X is S or O, and R_2ais C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, e.g., monofluoro-, difluoro-, or trifluoro-substituted); —CO₂R^d, wherein R^dis C_1-3alkyl, preferably methyl or ethyl; or —N(R^a)(R^b) wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_1-3alkyl (preferably CH₃), C_1-6hydroxyalkyl (preferably C_2-3hydroxyalkyl, more preferably —CH₂CH₂OH), or C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) that is optionally substituted with —N(R^e)(R^f) wherein R^eand R^fare independently H, OH(R^eand R^fare not both OH), C_1-3alkyl (preferably CH₃), or C_2-3hydroxyalkyl (preferably —CH₂CH2OH), and wherein optionally R^aand R^btogether with the nitrogen they both are linked to may form a 3, 4, 5 or 6-membered heterocycle.
In a preferred embodiment, R₂is H; halo; C_1-3alkyl optionally substituted with OH or halo (preferably F, e.g., monofluoro, difluoro, or trifluoro); —XR_2awherein X is S or O and R_2ais C_1-3alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with halo (preferably F, e.g., monofluoro-, difluoro-, or trifluoro-substituted); or —N(R^a)(R^b) wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_1-3alkyl (preferably CH₃), C_2-3hydroxyalkyl.
In preferred embodiments, R₂is H, methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C_1-3hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.
In more preferred embodiments, R₂is H, methyl, Cl, —CH₂OH, —NH₂, —NHCH₃, —NHCH₂CH₂OH, —OCH₃, —SCH₃, or —CH₂F.
In one embodiment, compounds of the invention include compounds of Formula VI or pharmaceutically acceptable salts or solvates thereof, wherein:
R₁is methyl or ethyl, preferably methyl;
R₂is H; halo; N₃;

- C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, e.g., monofluoro, difluoro, or trifluoro);
- —XR_2awherein X is S or O, and R_2ais C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, e.g., monofluoro-, difluoro-, or trifluoro-substituted);
- —CO₂R^d, wherein R^dis C_1-3alkyl, preferably methyl or ethyl; or
- —N(R^a)(R^b) wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C _1-3 alkyl (preferably CH₃), C_1-6hydroxyalkyl (preferably C_2-3hydroxyalkyl, more preferably —CH₂CH₂OH), or C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) that is optionally substituted with —N(R^e)(R^f) wherein R^eand R^fare independently H, OH(R^eand R^fare not both OH), C_1-3alkyl (preferably CH₃), or C_2-3hydroxyalkyl (preferably —CH₂CH2OH), and wherein optionally R^aand R^btogether may form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl);
  R₃is H; halo; C_1-3alkyl; or C_1-3alkoxy;
  R₄and R₆are independently H; halo (preferably F or Cl); N₃; C_1-6alkyl (preferably C_1-35more preferably CH₃); C_1-3alkoxy (preferably OCH₃); or —N(R_2b)(R_2c) wherein R_2band R_2care independently H, OH, C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃), C_1-6hydroxyalkyl (preferably C_2-3hydroxyalkyl, more preferably —CH₂CH2OH), or C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) that is optionally substituted with —N(R_2d)(R_2e) wherein R_2dand R_2eare independently H, OH, C_1-3alkyl (preferably CH₃) or C_2-3hydroxyalkyl (preferably —CH₂CH2OH), wherein R_2band R_2ctogether may form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl), and wherein R_2band R_2care not both OH, R_2dand R_2eare not both OH;
  R₅is H or F, preferably H;
  R₇and R₁₁are independently H; halo (preferably F or Cl, more preferably F); CH₃; or OCH₃;
  R₈and R₁₀are independently H; halo (preferably F or Cl, more preferably Cl); OH; N₃; C_1-3alkyl (preferably CH₃); C_1-3alkoxy (preferably OCH₃); C_1-3haloalkyl (preferably monofluoromethyl, difluoromethyl, trifluoromethyl); —XR_9a, where X is O or S, and R_9ais C_1-4alkyl or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —NH(R^a) or —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl); and
  R₉is H; OH; N₃; halo; C_1-3alkyl (preferably methyl or ethyl) or C_1-3haloalkyl (preferably monofluoromethyl, difluoromethyl, trifluoromethyl); —(C_0-3alkyl)C(O)N(R^a)(R^b) where R^aand R^bare independently H, C_2-4hydroxyalkyl, C_1-3alkyl, or C_1-3alkyl optionally substituted with —N(R^e)(R^f) where R^eand R^fare independently H, OH(R^aand R^bare not both OH), or C_1-3alkyl; wherein optionally R^aand R^btogether with the N form a 3, 4, 5 or 6-membered heterocycle, and optionally R^eand R^ftogether with the nitrogen atom to which they both are linked form a 3, 4, 5 or 6-membered heterocycle; —CO₂—R_2f, wherein R_2fis an optionally substituted C_1-6alkyl (preferably C_1-3alkyl, more preferably methyl or ethyl), the alkyl may be optionally substituted with OH, halo, C_1-3alkoxy, amino, and C_1-3alkylamino; —XR_2awherein X is S or O and R_2ais C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with a moiety selected from the group OH, halo, C_1-3alkoxy, amino, and C_1-3alkylamino; or —N(R_2b)(R_2c) wherein R_2band R_2care independently H, OH, C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃), C_1-6haloalkyl, C_1-6hydroxyalkyl (preferably C_2-3hydroxyalkyl, more preferably —CH₂CH2OH), or C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) that is optionally substituted with —N(R_2d)(R_2e) wherein R_2dand R_2eare independently H, OH, C_1-3alkyl (preferably CH₃) or C_2-3hydroxyalkyl (preferably —CH₂CH2OH), wherein optionally R_2band R_2ctogether with the nitrogen they both are linked to may form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl), and wherein R_2band R_2care not both OH, R_2dand R_2eare not both OH; optionally, R₉and one of R₈and R₁₀together form a 3, 4, 5 or 6-membered carbocycle or heterocycle;
  exactly one of B and D is N provided that when B or D is N there is no substituent at the N; and all of Q, T, U, and V are C;
  provided that when R₉is H then R₈and R₁₀are not both H or one H and the other halo.

Preferably when R₉is H, R₈or R₁₀or both are independently OH; N₃; —XR_9a, where X is O or S, and R_9ais C_1-4alkyl or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —NH(R^a) or —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl). More preferably, when R₉is H, R₈or R₁₀or both are independently N₃, —OR_9a, wherein R_9ais C_1-4alkyl or C_1-3haloalkyl, or —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl). Even more preferably when R₉is H, R₈or R₁₀or both are C_1-3alkoxy or C_1-3halo alkoxy.
Also preferably, when R₉is C_1-6alkyl, halo, or C_1-6haloalkyl, then R₂is not H and preferably R₂is methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C_1-3hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.
In another preferred embodiment, compounds of the invention include compounds of Formula VI or pharmaceutically acceptable salts or solvates thereof, wherein:
R₁is methyl or ethyl, and preferably methyl;
R₂is H; halo; N₃;

- C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with 1-4 substituents which are independently OH or halo (preferably F, e.g., monofluoro, difluoro, or trifluoro);
- —XR_2awherein X is S or O, and R_2ais C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, e.g., monofluoro-, difluoro-, or trifluoro-substituted);
- —CO₂—R_2f, wherein R_2fis C_1-6(preferably C_1-3, more preferably methyl or ethyl); or
- —N(R_2b)(R_2c) wherein R_2band R_2care independently H, OH, C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃), C_1-6hydroxyalkyl (preferably C_2-3hydroxyalkyl, more preferably —CH₂CH2OH), or C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) that is optionally substituted with —N(R_2d)(R_2e) wherein R_2dand R_2eare independently H, OH, C_1-3alkyl (preferably CH₃), or C_2-3hydroxyalkyl (preferably —CH₂CH₂OH), and wherein optionally R_2band R_2ctogether with the nitrogen they both are linked to may form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl), and wherein R_2band R_2care not both OH, R_2dand R_2eare not both OH;
  R₃is H; halo; C_1-3alkyl; or C_1-3alkoxy;
  R₄and R₆are independently H; halo (preferably F or Cl); N₃; C_1-3alkyl (preferably CH₃); C_1-3alkoxy (preferably OCH₃); or —N(R_2b)(R_2c) wherein R_2band R_2care independently H, OH, CH₃, and optionally R_2band R_2ctogether with the nitrogen they both are linked to may form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl), and wherein R_2band R_2care not both OH;

R₅is H;

R₇and R₁₁are independently H, halo (preferably F), CH₃, or OCH₃;
R₈and R₁₀are independently H; halo (preferably F or Cl, more preferably F); C_1-3alkyl (preferably CH₃); C_1-3alkoxy (preferably OCH₃); —XR_9a, where X is O or S, and R_9ais C_1-4alkyl or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl); and
R₉is selected from the group:

- hydrogen; hydroxy; N₃;
- C_1-3alkyl (preferably methyl or ethyl) or C_1-3haloalkyl (preferably monofluoromethyl, difluoromethyl, trifluoromethyl);
- —OR_9a, wherein R_9ais C_1-3alkyl (i.e., methyl, ethyl, propyl, isopropyl) or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃);
- —N(R_2b)(R_2c) wherein R_2band R_2care independently H, C_1-3alkyl, or C_1-3haloalkyl; or
- —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl); and optionally R₉and one of R₈and R₁₀together form a 3, 4, 5, or 6-membered heterocycle;
  exactly one of B and D is N provided that when B or D is N there is no substituent at the N; and all of Q, T, U, and V are C;
  provided that when R₉is H at least one of R₈and R₁₀is not H or halo, preferably at least one of R₈and R₁₀is not H or halo or C_1-3alkyl.

Preferably in this embodiment, when R₉is H, R₈or R₁₀or both are independently —XR_9a, where X is O or S, and R_9ais C_1-4alkyl or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl). More preferably, when R₉is H, R₈or R₁₀or both are independently N₃, —OR_9a, wherein R_9ais C_1-4alkyl or C_1-3haloalkyl, or —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl). Even more preferably when R₉is H, R₈or R₁₀or both are C_1-3alkoxy or C_1-3halo alkoxy.
Also preferably in this embodiment, when R₉is H then R₈and R₁₀are not both H or one H and the other halo, and R₂is not H.
Also preferably, in this embodiment, when R₉is C_1-6alkyl, halo, or C_1-6haloalkyl, then R₂is not H and preferably R₂is methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C_1-3hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.
Also preferably, in this embodiment, when R₉is H, R₈or R₁₀or both are OCH₃and preferably R₇and R₁₁are H, and also preferably R₂is not hydrogen and preferably R₂is methyl or chloro. Also preferably in this embodiment, when R₉is alkyl or haloalkyl or chloro, R₂is not hydrogen and preferably R₂is methyl or chloro.
In another preferred embodiment, compounds of the invention include compounds of Formula VI or pharmaceutically acceptable salts or solvates thereof, wherein:

R₁is methyl or ethyl, and preferably methyl;
R₂is H; halo; N₃; C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with 1-4 substituents which are OH or halo (preferably F, e.g., monofluoro, difluoro, or trifluoro); —XR_2awherein X is S or O, and R_2ais C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, e.g., monofluoro-, difluoro-, or trifluoro-substituted); or —N(R_2b)(R_2c) wherein R_2band R_2care independently H, OH, C_1-6alkyl (preferably C_1-3alkyl), C_1-6hydroxyalkyl (preferably C_2-3hydroxyalkyl, more preferably —CH₂CH2OH), or R_2band R_2ctogether form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl);
R₃is H; halo; C_1-3alkyl; or C_1-3alkoxy;
R₄and R₆are independently H; halo (preferably F or Cl); N₃; C_1-3alkyl (preferably CH₃); C_1-3alkoxy (preferably OCH₃); or —N(R_2b)(R_2c) wherein R_2band R_2care independently H, OH(R_2band R_2care not both OH), CH₃, or R_2band R_2ctogether form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl);
R₅is H or F, preferably H;
R₇and R₁₁are independently H, halo (preferably F), C_1-3alkyl (preferably CH₃), C_1-3alkoxy (preferably OCH₃), or C_1-3alkylthiol; Preferably R₇and R₁₁are independently H, halo or methoxy;
R₈and R₁₀are independently H; halo (preferably F or Cl); C_1-3alkyl (preferably CH₃); C_1-3alkoxy (preferably OCH₃) or C_1-3alkylthiol; and
R₉is selected from the group:
- hydrogen; hydroxy; Cl; N₃;
- C_1-3alkyl (preferably methyl or ethyl) or C_1-3haloalkyl (preferably monofluoromethyl, difluoromethyl, trifluoromethyl);
- —OR_9a, wherein R₁₂is C_1-3alkyl (i.e., methyl, ethyl, propyl, isopropyl) or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃);
- —N(R_2b)(R_2c) wherein R_2band R_2care independently C_1-3alkyl; or
- —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl); and optionally R₉and one of R₈and R₁₀together form a 3, 4, 5, or 6-membered heterocycle;
  exactly one of B and D is N provided that when B or D is N there is no substituent at the N; and all of Q, T, U, and V are C;
  provided that when R₉is H at least one of R₈and R₁₀is not H or halo, preferably at least one of R₈and R₁₀is not H or halo or C_1-3alkyl.

Preferably in this embodiment, when R₉is H, R₈or R₁₀or both are independently C_1-3alkoxy (preferably OCH₃) or C_1-3alkylthiol, each being optionally substituted with 1-4 F. Even more preferably when R₉is H, R₈or R₁₀or both are methoxy or ethoxy. Also preferably R₂is not H.
Also preferably, when R₉is C_1-3alkyl, halo, or C_1-3haloalkyl, then R₂is not H, preferably R₂is methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C_1-3hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.
Also preferably, in this embodiment, when R₉is H, R₈or R₁₀or both are OCH₃and preferably R₇and R₁₁are H, and also preferably R₂is not hydrogen and preferably R₂is methyl or chloro. Also preferably in this embodiment, when R₉is alkyl or haloalkyl or chloro, R₂is not hydrogen and preferably R₂is methyl or chloro.
In another preferred embodiment, compounds of the invention include compounds of Formula VI or pharmaceutically acceptable salts or solvates thereof, wherein:

R₁is methyl or ethyl, preferably methyl;
R₂is H, methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C_1-3hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃; R₃is H, CH₃, OCH₃, F, or Cl; R₄and R₆are independently H, CH₃, NH₂, N₃, F, or Cl; R₅is H; R₇and R₁₁are independently H, F, or OCH₃; R₈and R₁₀are independently H, F, Cl, or OCH₃; and
R₉is selected from the group:
- H; OH; N₃;
- C_1-3alkyl (preferably methyl or ethyl) or C_1-3haloalkyl (preferably monofluoromethyl, difluoromethyl, trifluoromethyl);
- —OR_9a, wherein R_9ais C_1-3alkyl (i.e., methyl, ethyl, propyl, isopropyl) or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃);
- —N(R_2b)(R_2c) wherein R_2band R₂, are independently C_1-3alkyl; or
- —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl), and optionally R₈and R₉together form a 3, 4, 5, or 6-membered heterocycle;
  exactly one of B and D is N provided that when B or D is N there is no substituent at the N; and all of Q, T, U, and V are C;
  provided that when R₉is H, at least one of R₈and R₁₀is OCH₃, and when R₉is C_1-3alkyl or C_1-3haloalkyl or Cl then R₂is Cl or methyl or ethyl.

R₁is CH₃;

R₂is H, methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), CH₂OH, NH₂, NHCH₃, N(CH₃)₂, —NHCH₂CH₂OH, OCH₃, or SCH₃; R₃is H, CH₃, OCH₃, F, or Cl; R₄and R₆are independently H, CH₃, NH₂, F, or Cl; R₅is H; R₇and R₁₁are independently H, F, or OCH₃; R₈and R₁₀are independently H, F, Cl, or OCH₃; and
R₉is selected from the group:
—OR₁₂, wherein R₁₂is selected from the group of methyl, ethyl, fluoromethyl (e.g., CH₂F, CHF₂, CF₃), and fluoroethyl; —NHCH₃; —N(CH₃)₂; —N₃; and —COOR₁₃, wherein R₁₃is methyl or ethyl;
exactly one of B and D is N provided that when B or D is N there is no substituent at the N; and all of Q, T, U, and V are C.
In a more preferred embodiment, compounds of the invention include compounds of Formula VI or pharmaceutically acceptable salts or solvates thereof, wherein:

R₁is CH₃;

R₃is H, —CH₃, —OCH₃, or Cl;

R₄is H, CH₃, or NH₂;

R₅is H;

R₆is H, or CH₃;

R₇and R₁₁are independently H, or F;
R₈and R₁₀are independently H, or F or OCH₃; and

exactly one of B and D is N provided that when B or D is N there is no substituent at the N; and all of Q, T, U, and V are C.
In a more preferred embodiment, the present invention provides compounds of Formula VI or pharmaceutically acceptable salts or solvates thereof, wherein R₁is CH₃; R₂is Cl, methyl, or CH₂F; R₃is H, CH₃, F, or Cl; R₄, R₅and R₆are H; R₇, R₈, R₁₀and R₁₁are independently H or F; and R₉is —OCH₃or —N(CH₃)₂; exactly one of B and D is N provided that when B or D is N there is no substituent at the N; and all of Q, T, U, and V are C.
Specifically, one group of the compounds of Formula VI are those represented by Formula VIa:
or pharmaceutically acceptable salts or solvates thereof, wherein:
R₁is methyl or ethyl, preferably methyl;
R₅is H or F, preferably H;
R₂-R₄, R₆-R₁₁are independently H, halo, N₃, OH, thiol, nitro, CN, NH₂, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, halo-C_1-6alkyl, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl, or R^aand R^btogether with the nitrogen atom to which they are both linked to form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl); wherein any of the groups is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N₃, OH, thiol, nitro, CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle, wherein optionally any two adjacent R₇-R₁₁groups together form a 3, 4, 5 or 6-membered carbocycle or heterocycle; and
Q, T, U and V are independently C or N, wherein at least one of Q, T, U and V is N, and when Q, T, U or V is N there is no substituent at the N, provided that when R₉is H then R₈and R₁₀are not both H, or one H and the other alkyl. Preferably when R₉is H then at least one of R₈and R₁₀is not H or alkyl. More preferably, when R₉is H then at least one of R₈and R₁₀is not H, alkyl, or halo.
In one embodiment, R₉is selected from the group consisting of H, OH, C₁, N₃; C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with 1, 2 or 3 substituents, each substituent being independently OH, halo, C_1-3alkoxy, (halo)C_1-3alkoxy, —N(R^a)(R^b) where R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-4hydroxyalkyl, or C_1-3alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked to form a 3, 4, 5 or 6-membered heterocycle;

—XR^cwherein X is S or O and R^cis C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with 1, 2 or 3 substituents, each substituent being independently OH, halo, C_1-3alkoxy, or (halo)C_1-3alkoxy;
—(C_0-3alkyl)CO₂R^d, wherein R^dis an C_1-6alkyl (preferably C_1-3alkyl, more preferably methyl or ethyl) optionally substituted with 1, 2 or 3 substituents, each substituent being independently OH, halo, C_1-3alkoxy (e.g., fluoroalkoxy), —N(R^a)(R^b) where R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-4hydroxyalkyl, or C_1-3alkyl or R^aand R^btogether with the nitrogen atom to which they both are linked form a 3, 4, 5 or 6-membered heterocycle;
—N(R^a)(R^b) where R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-4hydroxyalkyl, C_1-3alkyl, or C_1-3alkyl substituted with —N(R^e)(R^f) where R^eand R^fare independently H, OH(R^eand R^fare not both OH), or C_1-3alkyl; wherein optionally R^aand R^btogether with the N form a 3, 4, 5 or 6-membered heterocycle, and optionally R^eand R^ftogether with the nitrogen atom to which they both are linked form a 3, 4, 5 or 6-membered heterocycle; or
—(C_0-3alkyl)C(O)N(R^a)(R^b) where R^aand R^bare independently H or C_1-3alkyl; and optionally R₉and one of R₈and R₁₀together form a 3, 4, 5, or 6-membered heterocycle; preferably R₉is selected from the group outlined above except R₉is not H and C_1-6alkyl.

In another embodiment, R₉is H; OH; Cl; N₃; C_1-3alkyl (preferably methyl; C_1-3haloalkyl (preferably monofluoromethyl, difluoromethyl, trifluoromethyl); —OR_9a, wherein R_9ais C_1-4alkyl or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —NH(R^a); —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl); and optionally R₉and one of R₈and R₁₀together form a 3, 4, 5, or 6-membered heterocycle; preferably R₉is selected from the group outlined above except R₉is not H or C_1-3alkyl.
In a preferred embodiment, R₉is N₃, —OR_9awherein R_9ais C_1-3alkyl optionally substituted with 1-7 F, —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl, —COOR_9bwhere R_9bis C_1-3alkyl.
In a more preferred embodiment, R₉is —OCH₃, —OC₂H₅, —N(CH₃)₂, —CO₂CH₃, —OCHF₂, or N₃.
In the various embodiments of the compounds according to Formula VIa preferably when R₉is H, R₈or R₁₀or both are independently OH; Cl; N₃; —XR_9a, where X is O or S, and R_9ais C_1-4alkyl or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —NH(R^a) or —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl). More preferably, when R₉is H, R₈or R₁₀or both are independently N₃, —OR_9a, wherein R_9ais C_1-4alkyl or C_1-3haloalkyl; —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl). Even more preferably when R₉is H, R₈or R₁₀or both are C_1-3alkoxy or C_1-3haloalkoxy.
Also preferably in the various embodiments, when R₉is H then R₂is not H, and preferably R₂is halo; C_1-3alkyl optionally substituted with OH or halo (preferably F, e.g., monofluoro, difluoro, or trifluoro); —XR_2awherein X is S or O and R_2ais C_1-3alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with halo (preferably F, e.g., monofluoro-, difluoro-, or trifluoro-substituted); or —N(R^a)(R^b) wherein R^aand R^bare independently H, OH (R^aand R^bare not both OH), C_1-3alkyl (preferably CH₃), C_2-3hydroxyalkyl. More preferably R₂is methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C_1-3hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.
Also preferably, when R₉is C_1-6alkyl or C_1-6haloalkyl, R₂is not H, and preferably is methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C_1-3hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.
In one embodiment, R₂is H; halo; N₃; C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, e.g., monofluoro, difluoro, or trifluoro); —XR_2awherein X is S or O, and R_2ais C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, e.g., monofluoro-, difluoro-, or trifluoro-substituted); —CO₂R^d, wherein R^dis C_1-3alkyl, preferably methyl or ethyl; or —N(R^a)(R^b) wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_1-3alkyl (preferably CH₃), C_1-6hydroxyalkyl (preferably C_2-3hydroxyalkyl, more preferably —CH₂CH₂OH), or C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) that is optionally substituted with —N(R^e)(R^f) wherein R^eand R^fare independently H, OH(R^eand R^fare not both OH), C_1-3alkyl (preferably CH₃), or C_2-3hydroxyalkyl (preferably —CH₂CH2OH), and wherein optionally R^aand R^btogether with the N they are both linked to may form a 3, 4, 5 or 6-membered heterocycle.
In a preferred embodiment, R₂is H; halo; C_1-3alkyl optionally substituted with OH or halo (preferably F, e.g., monofluoro, difluoro, or trifluoro); —XR_2awherein X is S or O and R_2ais C_1-3alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with halo (preferably F, e.g., monofluoro-, difluoro-, or trifluoro-substituted); or —N(R^a)(R^b) wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_1-3alkyl (preferably CH₃), C_2-3hydroxyalkyl.
In preferred embodiments, R₂is H, methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C_1-3hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.
In more preferred embodiments, R₂is H, methyl, Cl, —CH₂OH, —NH₂, —NHCH₃, —NHCH₂CH₂OH, —OCH₃, —SCH₃, or —CH₂F.
In all embodiments of the compound of Formula VIa, it is preferred that one or two of Q, T, U and V are N. For example Q and V are N and T and U are C.
In one embodiment, compounds of the invention include compounds of Formula VIa or pharmaceutically acceptable salts or solvates thereof, wherein:

R₁is methyl or ethyl, preferably methyl;
R₂is H; halo; N₃; C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, e.g., monofluoro, difluoro, or trifluoro); —XR_2awherein X is S or O, and R_2ais C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, e.g., monofluoro-, difluoro-, or trifluoro-substituted); —CO₂R^d, wherein R^dis C_1-3alkyl, preferably methyl or ethyl; or —N(R^a)(R^b) wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_1-3alkyl (preferably CH₃), C_1-6hydroxyalkyl (preferably C_2-3hydroxyalkyl, more preferably —CH₂CH₂OH), or C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) that is optionally substituted with —N(R^e)(R^f) wherein R^eand R^fare independently H, OH(R^eand R^fare not both OH), C_1-3alkyl (preferably CH₃), or C_2-3hydroxyalkyl (preferably —CH₂CH2OH), and wherein optionally R^aand R^btogether with the N they are both linked to may form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl);
R₃is H; halo; C_1-3alkyl; or C_1-3alkoxy;
R₄and R₆are independently H; halo (preferably F or CO; N₃; C_1-6alkyl (preferably C_1-35more preferably CH₃); C_1-3alkoxy (preferably OCH₃); or —N(R_2b)(R_2c) wherein R_2band R₂are independently H, OH, C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃), C_1-6hydroxyalkyl (preferably C_2-3hydroxyalkyl, more preferably —CH₂CH2OH), or C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) that is optionally substituted with —N(R_2d)(R_2e) wherein R_2dand R_2eare independently H, OH, C_1-3alkyl (preferably CH₃) or C_2-3hydroxyalkyl (preferably —CH₂CH2OH), wherein R_2band R_2ctogether with the N they are both linked to may form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl), and wherein R_2band R_2care not both OH, R_2dand R_2eare not both OH;
R₅is H or F, preferably H;
R₇and R₁₁are independently H; halo (preferably F or Cl, more preferably F); CH₃; or OCH₃;
R₈and R₁₀are independently H; halo (preferably F or Cl, more preferably Cl); OH; N₃; C_1-3alkyl (preferably CH₃); C_1-3alkoxy (preferably OCH₃); C_1-3haloalkyl (preferably monofluoromethyl, difluoromethyl, trifluoromethyl); —XR_9a, where X is O or S, and R_9ais C_1-4alkyl or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —NH(R^a) or —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl);
R₉is selected from the group consisting of H, OH, C₁, N₃; C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with 1, 2 or 3 substituents, each substituent being independently OH, halo, C_1-3alkoxy, (halo)C_1-3alkoxy, —N(R^a)(R^b) where R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-4hydroxyalkyl, or C_1-3alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; —XR^cwherein X is S or O and R^cis C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with 1, 2 or 3 substituents, each substituent being independently OH, halo, C_1-3alkoxy, or (halo)C_1-3alkoxy; —(C_0-3alkyl)CO₂R^d, wherein R^dis an C_1-6alkyl (preferably C_1-3alkyl, more preferably methyl or ethyl) optionally substituted with 1, 2 or 3 substituents, each substituent being independently OH, halo, C_1-3alkoxy (e.g., fluoroalkoxy), —N(R^a)(R^b) where R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-4hydroxyalkyl, or C_1-3alkyl or R^aand R^btogether with the nitrogen atom to which they both are linked form a 3, 4, 5 or 6-membered heterocycle; —N(R^a)(R^b) where R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-4hydroxyalkyl, C_1-3alkyl, or C_1-3alkyl substituted with —N(R^e)(R^f) where R^eand R^fare independently H, OH(R^eand R^fare not both OH), or C_1-3alkyl; wherein optionally R^aand R^btogether with the N form a 3, 4, 5 or 6-membered heterocycle, and optionally R^eand R^ftogether with the nitrogen atom to which they both are linked form a 3, 4, 5 or 6-membered heterocycle; or —(C_0-3alkyl)C(O)N(R^a)(R^b) where R^aand R^bare independently H or C_1-3alkyl; and optionally R₉and one of R₈and R₁₀together form a 3, 4, 5, or 6-membered heterocycle; provided that when R₉is H, at least one of R₈and R₁₀is not hydrogen or alkyl; and
Q, T, U and V are independently C or N, provided that at least one of Q, T, U and V is N, wherein when Q, T, U or V is N, then there is no substituent at the N. In some specific embodiments, one or two of Q, T, U and V are N.

Preferably when R₉is H, R₈or R₁₀or both are independently OH; Cl; N₃; —XR_9a, where X is O or S, and R_9ais C_1-4alkyl or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —NH(R^a) or —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl). More preferably, when R₉is H, R₈or R₁₀or both are independently N₃, —OR_9a, wherein R_9ais C_1-4alkyl or C_1-3haloalkyl, or —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl). Even more preferably when R₉is H, R₈or R₁₀or both are C_1-3alkoxy or C_1-3haloalkoxy.
Also preferably, when R₉is C_1-6alkyl or C_1-6haloalkyl, R₂is methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C_1-3hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.
In another preferred embodiment, compounds of the invention include compounds of Formula VIa or pharmaceutically acceptable salts or solvates thereof, wherein:

R₁is methyl or ethyl, and preferably methyl;
R₂is H; halo; N₃;
- C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, e.g., monofluoro, difluoro, or trifluoro);
- —XR_2awherein X is S or O, and R_2ais C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, e.g., monofluoro-, difluoro-, or trifluoro-substituted);
- —CO₂—R_2f, wherein R_2fis C_1-6alkyl (preferably C_1-3alkyl, more preferably methyl or ethyl); or
- —N(R_2b)(R_2c) wherein R_2band R_2care independently H, OH, C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃), C_1-6hydroxyalkyl (preferably C_2-3hydroxyalkyl, more preferably —CH₂CH2OH), or C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) that is optionally substituted with —N(R_2d)(R_2e) wherein R_2dand R_2eare independently H, OH, C_1-3alkyl (preferably CH₃), or C_2-3hydroxyalkyl (preferably —CH₂CH2OH), and wherein optionally R_2band R_2ctogether with the N they are both linked to may form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl), and wherein R_2band R_2care not both OH, R_2dand R_2eare not both OH;
R₃is H; halo; C_1-3alkyl; or C_1-3alkoxy;
R₄and R₆are independently H; halo (preferably F or Cl); N₃; C_1-3alkyl (preferably CH₃); C_1-3alkoxy (preferably OCH₃); or —N(R_2b)(R_2c) wherein R_2band R_2care independently H, OH, CH₃, or ethyl, and optionally R_2band R_2ctogether with the N they are both linked to may form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl), and wherein R_2band R_2care not both OH;
R₅is H;
R₇and R₁₁are independently H, halo (preferably F), CH₃, or OCH₃;
R₈and R₁₀are independently H; halo (preferably F or Cl, more preferably F); C_1-3alkyl (preferably CH₃); C_1-3alkoxy (preferably OCH₃); and
R₉is selected from the group:
hydrogen; hydroxy; Cl; N₃; C_1-3alkyl (preferably methyl or ethyl) or C_1-3haloalkyl (preferably monofluoromethyl, difluoromethyl, trifluoromethyl); —OR_9a, wherein R_9ais C_1-3alkyl (i.e., methyl, ethyl, propyl, isopropyl) or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —N(Ra)(Rb), wherein Ra and Rb are independently H, C_1-3alkyl, or haloC_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl); and optionally R₉and one of R₈and R₁₀together form a 3, 4, 5, or 6-membered carbocycle or heterocycle;
Q, T, U and V are independently C or N, wherein at least one of, T, U and V are N, wherein when Q, T, U or V is nitrogen, then the there is no substituent at the N; with the proviso that when R₉is H then R₈and R₉are not both H or one H and the other alkyl. Preferably when R₉is H then at least one of R₈or R₁₀is not H or alkyl. More preferably when R₉is H then at least one of R₈or R₁₀is not H, alkyl, or halo.

In some specific embodiments, one or two of Q, T, U and V are N.
Preferably in this embodiment, when R₉is H, R₉or R₁₀or both are independently OH; Cl; N₃; C_1-3haloalkyl (preferably monofluoromethyl, difluoromethyl, trifluoromethyl); —XR_9a, where X is O or S, and R_9ais C_1-4alkyl or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —NH(R^a) or —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl). More preferably, when R₉is H, R₈or R₁₀or both are independently N₃, —OR_9a, wherein R_9ais C_1-4alkyl or C_1-3haloalkyl, or —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl). Even more preferably when R₉is H, R₈or R₁₀or both are C_1-3alkoxy or C_1-3halo alkoxy.
Also preferably, when R₉is C_1-6alkyl or C_1-6haloalkyl, R₂is not H and preferably R₂is halo; C_1-3alkyl optionally substituted with OH or halo (preferably F, e.g., monofluoro, difluoro, or trifluoro); —XR_2awherein X is S or O and R_2ais C_1-3alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with halo (preferably F, e.g., monofluoro-, difluoro-, or trifluoro-substituted); or —N(R^a)(R^b) wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_1-3alkyl (preferably CH₃), C_2-3hydroxyalkyl. More preferably R₂is methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C_1-3hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.
Also preferably, in this embodiment, when R₉is H, R₈or R₁₀or both are OCH₃and preferably R₇and R₁₁are H, and also preferably R₂is not hydrogen and preferably R₂is methyl or chloro. Also preferably in this embodiment, when R₉is alkyl or haloalkyl or chloro, R₂is not hydrogen and preferably R₂is methyl or chloro.
In another preferred embodiment, compounds of the invention include compounds of Formula VIa or pharmaceutically acceptable salts or solvates thereof, wherein:

R₁is methyl or ethyl, preferably methyl;
R₂is H, methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C_1-3hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃; R₃is H, CH₃, OCH₃, F, or Cl; R₄and R₆are independently H, CH₃, NH₂, N₃, F, or Cl; R₅is H; R₇and R₁₁are independently H, F, or OCH₃; R₈and R₁₀are independently H, F, Cl, or OCH₃; and
R₉is selected from the group:
hydrogen; hydroxy; Cl; C_1-3alkyl (preferably methyl or ethyl) or C_1-3haloalkyl (preferably monofluoromethyl, difluoromethyl, trifluoromethyl); —OR_9a, wherein R_9ais C_1-3alkyl (i.e., methyl, ethyl, propyl, isopropyl) or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); C_1-3alkyl substituted amino (preferably —NHCH₃or —N(CH₃)₂); —N₃; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl), and optionally R₈and R₉together form a 3, 4, 5, or 6-membered carbocycle or heterocycle; and
Q, T, U and V are independently C or N, and at least one of Q, T, U and V is N, wherein when Q, T, U or V is N, then there is no substituent at the N. In some specific embodiments, one or two of Q, T, U and V are nitrogen.

Preferably in this embodiment, when R₉is H, R₈or R₁₀or both are independently OH; Cl; N₃; C_1-3haloalkyl (preferably monofluoromethyl, difluoromethyl, trifluoromethyl); —XR_9a, where X is O or S, and R_9ais C_1-4alkyl or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —NH(R^a) or —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl). More preferably, when R₉is H, R₈or R₁₀or both are independently N₃, —OR_9a, wherein R_9ais C_1-4alkyl or C_1-3haloalkyl, or —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl). Even more preferably when R₉is H, R₈or R₁₀or both are C_1-3alkoxy or C_1-3halo alkoxy.
Also preferably, when R₉is C_1-6alkyl or C_1-6haloalkyl, R₂is not H and preferably R₂is methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C_1-3hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.
Also preferably, in this embodiment, when R₉is H, R₈or R₁₀or both are OCH₃and preferably R₇and R₁₁are H, and also preferably R₂is not hydrogen and preferably R₂is methyl or chloro. Also preferably in this embodiment, when R₉is alkyl or haloalkyl or chloro, R₂is not hydrogen and preferably R₂is methyl or chloro.
In another preferred embodiment, compounds of the invention include compounds of Formula VIa or pharmaceutically acceptable salts or solvates thereof, wherein:
R₁is methyl;
R₂is H, methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), CH₂OH, NH₂, NHCH₃, N(CH₃)₂, —NHCH₂CH₂OH, OCH₃, or SCH₃; R₃is H, CH₃, OCH₃, F, or Cl; R₄and R₆are independently H, CH₃, NH₂, F, or Cl; R₅is H; R₇and R₁₁are independently H, F, or OCH₃; R₈and R₁₀are independently H, F, Cl, or OCH₃; and
R₉is selected from the group:
—OR_9a, wherein R_9ais selected from the group of methyl, ethyl, fluoromethyl (e.g., CH₂F, CHF₂, CF₃), and fluoroethyl; —NHCH₃; —N(CH₃)₂; —N₃; and —COOR_9b, wherein R_9bis H or methyl or ethyl; and
Q, T, U and V are independently C or N, and at least one of Q, T, U and V is N, wherein when Q, T, U or V is N, then there is no substituent at the N. In some specific embodiments, one or two of Q, T, U and V are nitrogen.
In a more preferred embodiment, compounds of the invention include compounds of Formula VIa or pharmaceutically acceptable salts or solvates thereof, wherein:

R₁is CH₃;

R₃is H, —CH₃, —OCH₃, or Cl;

R₄is H, CH₃, or NH₂;

R₅is H;

R₆is H, or CH₃;

R₉is —OCH₃or —OC₂H₅, —N(CH₃)₂, —CO₂CH₃, —OCHF₂, or N₃; and

Q, T, U and V are independently C or N, and at least one of Q, T, U and V is N, wherein when Q, T, U or V is N, then there is no substituent at the N. In some specific embodiments, one or two of Q, T, U and V are nitrogen.
In a more preferred embodiment, the present invention provides compounds of Formula VIa or pharmaceutically acceptable salts or solvates thereof, wherein R₁is CH₃; R₂is Cl, methyl, or CH₂F; R₃is H, CH₃, F, or Cl; R₄, R₅and R₆are H; R₇, R₈, R₁₀and R₁₁are independently H or F; R₉is —OCH₃or —N(CH₃)₂; and Q, T, U and V are independently C or N, and at least one of Q, T, U and V is N, wherein when Q, T, U or V is N, then there is no substituent at the N. In some specific embodiments, one or two of Q, T, U and V are nitrogen.
Other compounds of the invention include those of Formula VIb:
or pharmaceutically acceptable salts, or solvates thereof, wherein:

R₁is methyl or ethyl, preferably methyl;
R₅is H or F, preferably H; and
R₂-R₄, R₆-R₁₁are independently H, halo, N₃, OH, thiol, nitro, CN, NH₂, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, halo-C_1-6alkyl, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl, or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl); wherein any of the groups is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N₃, OH, thiol, nitro, CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle, wherein optionally any two adjacent R₇-R₁₁groups together form a 3, 4, 5 or 6-membered carbocycle or heterocycle; provided that R₉is not —O(C_1-6alkyl)C(O)O(C_1-6alkyl), and when R₉is H then R₈and R₁₀are not both H or one H and the other halo. Preferably when R₉is H then R₈and R₁₀are not both H or one H and the other halo or alkyl or haloalkyl.

In one embodiment, R₄is 4-Methoxy-benzenesulfonamide.
In one embodiment, R₉is selected from the group consisting of H, C₁, N₃; C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with 1, 2 or 3 substituents, each substituent being independently OH, halo, C_1-3alkoxy, (halo)C_1-3alkoxy, —N(R^a)(R^b) where R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-4hydroxyalkyl, or C_1-3alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; —XR^cwherein X is S or O and R^cis C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with 1, 2 or 3 substituents, each substituent being independently OH, halo, C_1-3alkoxy, or (halo)C_1-3alkoxy; —(C_0-3alkyl)CO₂R^d, wherein R^dis an C_1-6alkyl, preferably C_1-3alkyl; —N(R^a)(R^b) where R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-4hydroxyalkyl, C_1-3alkyl, or —N(R^e)(R^f) where R^eand R^fare independently H, OH(R^eand R^fare not both OH), or C_1-3alkyl; wherein optionally R^aand R^btogether with the N form a 3, 4, 5 or 6-membered heterocycle, and optionally R^eand R^ftogether with the nitrogen atom to which they both are linked form a 3, 4, 5 or 6-membered heterocycle; or —(C_0-3alkyl)C(O)N(R^a)(R^b) where R^aand R^bare independently H or C_1-3alkyl; and optionally R₉and one of R₈and R₁₀together form a 3, 4, 5, or 6-membered heterocycle. Preferably R₉is selected from such groups except R₉is not H or chloro.
In another embodiment, R₉is H; OH; Cl; N₃; C_1-3alkyl (preferably methyl; C_1-3haloalkyl (preferably monofluoromethyl, difluoromethyl, trifluoromethyl); —OR_9a, wherein R_9ais C_1-4alkyl or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —NH(R^a) or —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl); and optionally R₉and one of R₈and R₁₀together form a 3, 4, 5, or 6-membered heterocycle. Preferably R₉is selected from such groups except R₉is not H or chloro.
In a preferred embodiment, R₉is N₃; —OR_9a, wherein R_9ais C_1-3alkyl optionally substituted with 1-7 F; —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl; or —COOR_9bwhere R_9bis C_1-3alkyl.
In more preferred embodiment, R₉is —OCH₃, —OC₂H₅, —N(CH₃)₂, —CO₂CH₃, —OCHF₂, or N₃.
Preferably when R₉is H, R₈or R₁₀or both are independently OH; N₃; —XR_9a, where X is O or S, and R_9ais C_1-4alkyl or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —NH(R^a) or —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl). More preferably, when R₉is H, R₈or R₁₀or both are independently N₃, —OR_9a; wherein R_9ais C_1-4alkyl or C_1-3haloalkyl, or —NH(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl). Even more preferably when R₉is H, R₈or R₁₀or both are C_1-3alkoxy or C_1-3halo alkoxy.
Also preferably in the various embodiments, when R₉is H, R₈and R₁₀are not H or one H and the other halo, and R₂is not H, and preferably R₂is halo; N₃, C_1-3alkyl optionally substituted with OH or halo (preferably F, e.g., monofluoro, difluoro, or trifluoro); —XR_2awherein X is S or O and R_2ais C_1-3alkyl (more preferably CH₃) optionally substituted with halo (preferably F, e.g., monofluoro-, difluoro-, or trifluoro-substituted); or —N(R^a)(R^b) wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_1-3alkyl (preferably CH₃), C_2-3hydroxyalkyl. More preferably R₂is methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C_1-3hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.
Also preferably, when R₉is C_1-6alkyl, halo, or C_1-6haloalkyl, R₂is not H, and preferably R₂is halo; N₃, C_1-3alkyl optionally substituted with OH or halo (preferably F, e.g., monofluoro, difluoro, or trifluoro); —XR_2awherein X is S or O and R_2ais C_1-3alkyl (more preferably CH₃) optionally substituted with halo (preferably F, e.g., monofluoro-, difluoro-, or trifluoro-substituted); or —N(R^a)(R^b) wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_1-3alkyl (preferably CH₃), C_2-3hydroxyalkyl. More preferably R₂is methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C_1-3hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.
In one embodiment, R₂is H; halo; N₃; C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, e.g., monofluoro, difluoro, or trifluoro); —XR_2awherein X is S or O, and R_2ais C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, e.g., monofluoro-, difluoro-, or trifluoro-substituted); —CO₂R^d, wherein R^dis C_1-3alkyl, preferably methyl or ethyl; or —N(R^a)(R^b) wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_1-3alkyl (preferably CH₃), C_1-6hydroxyalkyl (preferably C_2-3hydroxyalkyl, more preferably —CH₂CH₂OH), or C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) that is optionally substituted with —N(R^e)(R^f) wherein R^eand R^fare independently H, OH(R^eand R^fare not both OH), C_1-3alkyl (preferably CH₃), or C_2-3hydroxyalkyl (preferably —CH₂CH2OH), and wherein optionally R^aand R^btogether with the nitrogen they both are linked to may form a 3, 4, 5 or 6-membered heterocycle.
In a preferred embodiment, R₂is H; halo; C_1-3alkyl optionally substituted with OH or halo (preferably F, e.g., monofluoro, difluoro, or trifluoro); —XR_2awherein X is S or O and R_2ais C_1-3alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with halo (preferably F, e.g., monofluoro-, difluoro-, or trifluoro-substituted); or —N(R^a)(R^b) wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_1-3alkyl (preferably CH₃), C_2-3hydroxyalkyl.
In preferred embodiments, R₂is H, methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C_1-3hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.
In more preferred embodiments, R₂is H, methyl, Cl, —CH₂OH, —NH₂, —NHCH₃, —NHCH₂CH₂OH, —OCH₃, —SCH₃, or —CH₂F.
In one embodiment, compounds of the invention include compounds of Formula VIb or pharmaceutically acceptable salts or solvates thereof, wherein:

R₁is methyl or ethyl, preferably methyl;
R₂is H; halo; N₃; C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, e.g., monofluoro, difluoro, or trifluoro); —XR_2awherein X is S or O, and R_2ais C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, e.g., monofluoro-, difluoro-, or trifluoro-substituted); —CO₂R^d, wherein R^dis C_1-3alkyl, preferably methyl or ethyl; or —N(R^a)(R^b) wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_1-3alkyl (preferably CH₃), C_1-6hydroxyalkyl (preferably C_2-3hydroxyalkyl, more preferably —CH₂CH₂OH), or C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) that is optionally substituted with —N(R^e)(R^f) wherein R^eand R^fare independently H, OH(R^eand R^fare not both OH), C_1-3alkyl (preferably CH₃), or C_2-3hydroxyalkyl (preferably —CH₂CH2OH), and wherein optionally R^aand R^btogether may form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl);
R₃is H; halo; C_1-3alkyl; or C_1-3alkoxy;
R₄and R₆are independently H; halo (preferably F or Cl); N₃; C_1-6alkyl (preferably C_1-35more preferably CH₃); C_1-3alkoxy (preferably OCH₃); or —N(R_2b)(R_2c) wherein R_2band R₂are independently H, OH, C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃), C_1-6hydroxyalkyl (preferably C_2-3hydroxyalkyl, more preferably —CH₂CH2OH), or C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) that is optionally substituted with —N(R_2d)(R_2e) wherein R_2dand R_2eare independently H, OH, C_1-3alkyl (preferably CH₃) or C_2-3hydroxyalkyl (preferably —CH₂CH2OH), wherein R_2band R_2ctogether may form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl), and wherein R_2band R_2care not both OH, R_2dand R_2eare not both OH;
R₅is H or F, preferably H;
R₇and R₁₁are independently H; halo (preferably F or Cl, more preferably F); CH₃; or OCH₃;
R₈and R₁₀are independently H; halo (preferably F or Cl, more preferably Cl); OH; N₃; C_1-3alkyl (preferably CH₃); C_1-3alkoxy (preferably OCH₃); C_1-3haloalkyl (preferably monofluoromethyl, difluoromethyl, trifluoromethyl); —XR_9a, where X is O or S, and R_9ais C_1-4alkyl or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —NH(R^a) or —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl); and
R₉is H; OH; N₃; halo; C_1-3alkyl (preferably methyl or ethyl) or C_1-3haloalkyl (preferably monofluoromethyl, difluoromethyl, trifluoromethyl); —(C_0-3alkyl)C(O)N(R^a)(R^b) where R^aand R^bare independently H, C_2-4hydroxyalkyl, C_1-3alkyl, or C_1-3alkyl optionally substituted with —N(R^e)(R^f) where R^eand R^fare independently H, OH(R^aand R^bare not both OH), or C_1-3alkyl; wherein optionally R^aand R^btogether with the N form a 3, 4, 5 or 6-membered heterocycle, and optionally R^eand R^ftogether with the nitrogen atom to which they both are linked form a 3, 4, 5 or 6-membered heterocycle; —CO₂—R_2f, wherein R_2fis an optionally substituted C_1-6alkyl (preferably C_1-3alkyl, more preferably methyl or ethyl), the alkyl may be optionally substituted with OH, halo, C_1-3alkoxy, amino, and C_1-3alkylamino; —XR_2awherein X is S or O and R_2ais C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with a moiety selected from the group OH, halo, C_1-3alkoxy, amino, and C_1-3alkylamino; or —N(R_2b)(R_2c) wherein R_2band R_2care independently H, OH, C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃), C_1-6haloalkyl, C_1-6hydroxyalkyl (preferably C_2-3hydroxyalkyl, more preferably —CH₂CH2OH), or C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) that is optionally substituted with —N(R_2d)(R_2e) wherein R_2dand R_2eare independently H, OH, C_1-3alkyl (preferably CH₃) or C_2-3hydroxyalkyl (preferably —CH₂CH2OH), wherein optionally R_2band R₂, together with the nitrogen they both are linked to may form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl), and wherein R_2band R_2care not both OH, R_2dand R_2eare not both OH; optionally, R₉and one of R₈and R₁₀together form a 3, 4, 5 or 6-membered carbocycle or heterocycle;
provided that when R₉is H then R₉and R₁₀are not both H or one H and the other halo.

Preferably when R₉is H, R₈or R₁₀or both are independently OH; N₃; —XR_9a, where X is O or S, and R_9ais C_1-4alkyl or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —NH(R^a) or —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl). More preferably, when R₉is H, R₈or R₁₀or both are independently N₃, —OR_9a, wherein R_9ais C_1-4alkyl or C_1-3haloalkyl, or —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl). Even more preferably when R₉is H, R₈or R₁₀or both are C_1-3alkoxy or C_1-3halo alkoxy.
Also preferably, when R₉is C_1-6alkyl, halo, or C_1-6haloalkyl, then R₂is not H and preferably R₂is methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C_1-3hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.
In another preferred embodiment, compounds of the invention include compounds of Formula VIb or pharmaceutically acceptable salts or solvates thereof, wherein:

R₁is methyl or ethyl, and preferably methyl;
R₂is H; halo; N₃; C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with 1-4 substituents which are independently OH or halo (preferably F, e.g., monofluoro, difluoro, or trifluoro); —XR_2awherein X is S or O, and R_2ais C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, e.g., monofluoro-, difluoro-, or trifluoro-substituted); —CO₂—R_2f, wherein R_2fis C_1-6(preferably C_1-3, more preferably methyl or ethyl); or —N(R_2b)(R_2c) wherein R_2band R_2care independently H, OH, C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃), C_1-6hydroxyalkyl (preferably C_2-3hydroxyalkyl, more preferably —CH₂CH2OH), or C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) that is optionally substituted with —N(R_2d)(R_2e) wherein R_2dand R_2eare independently H, OH, C_1-3alkyl (preferably CH₃), or C_2-3hydroxyalkyl (preferably —CH₂CH₂OH), and wherein optionally R_2band R_2ctogether with the nitrogen they both are linked to may form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl), and wherein R_2band R_2care not both OH, R_2dand R_2eare not both OH;
R₃is H; halo; C_1-3alkyl; or C_1-3alkoxy;
R₄and R₆are independently H; halo (preferably F or Cl); N₃; C_1-3alkyl (preferably CH₃); C_1-3alkoxy (preferably OCH₃); or —N(R_2b)(R_2c) wherein R_2band R_2care independently H, OH, CH₃, and optionally R_2band R_2ctogether with the nitrogen they both are linked to may form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl), and wherein R_2band R_2care not both OH;
R₅is H;
R₇and R₁₁are independently H, halo (preferably F), CH₃, or OCH₃;
R₈and R₁₀are independently H; halo (preferably F or Cl, more preferably F); C_1-3alkyl (preferably CH₃); C_1-3alkoxy (preferably OCH₃); —XR_9a, where X is O or S, and R_9ais C_1-4alkyl or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl); and
R₉is selected from the group: hydrogen; hydroxy; N₃; C_1-3alkyl (preferably methyl or ethyl) or C_1-3haloalkyl (preferably monofluoromethyl, difluoromethyl, trifluoromethyl); —OR_9a, wherein R_9ais C_1-3alkyl (i.e., methyl, ethyl, propyl, isopropyl) or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —N(R_2b)(R_2c) wherein R_2band R_2care independently H, C_1-3alkyl, or C_1-3haloalkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl); and optionally R₉and one of R₈and R₁₀together form a 3, 4, 5, or 6-membered heterocycle;
provided that when R₉is H at least one of R₈and R₁₀is not H or halo, preferably at least one of R₈and R₁₀is not H or halo or C_1-3alkyl.

Preferably in this embodiment, when R₉is H, R₈or R₁₀or both are independently —XR_9a, where X is O or S, and R_9ais C_1-4alkyl or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl). More preferably, when R₉is H, R₈or R₁₀or both are independently N₃, —OR_9a, wherein R_9ais C_1-4alkyl or C_1-3haloalkyl, or —N(R^a)(R^b) where R^aand R^bare independently C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl). Even more preferably when R₉is H, R₈or R₁₀or both are C_1-3alkoxy or C_1-3halo alkoxy.
Also preferably in this embodiment, when R₉is H then R₈and R₁₀are not both H or one H and the other halo, and R₂is not H.
Also preferably, in this embodiment, when R₉is C_1-6alkyl, halo, or C_1-6haloalkyl, then R₂is not H and preferably R₂is methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CFA C hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.
Also preferably, in this embodiment, when R₉is H, R₈or R₁₀or both are OCH₃and preferably R₇and R₁₁are H, and also preferably R₂is not hydrogen and preferably R₂is methyl or chloro. Also preferably in this embodiment, when R₉is alkyl or haloalkyl or chloro,
R₂is not hydrogen and preferably R₂is methyl or chloro.
In another preferred embodiment, compounds of the invention include compounds of Formula VIb or pharmaceutically acceptable salts or solvates thereof, wherein:

R₁is methyl or ethyl, and preferably methyl;
R₂is H; halo; N₃; C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with 1-4 substituents which are OH or halo (preferably F, e.g., monofluoro, difluoro, or trifluoro); —XR_2awherein X is S or O, and R_2ais C_1-6alkyl (preferably C_1-3alkyl, more preferably CH₃) optionally substituted with OH or halo (preferably F, e.g., monofluoro-, difluoro-, or trifluoro-substituted); or —N(R_2b)(R_2c) wherein R_2band R_2care independently H, OH, C_1-6alkyl (preferably C_1-3alkyl), C_1-6hydroxyalkyl (preferably C_2-3hydroxyalkyl, more preferably —CH₂CH2OH), or R_2band R_2ctogether form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl);
R₃is H; halo; C_1-3alkyl; or C_1-3alkoxy;
R₄and R₆are independently H; halo (preferably F or Cl); N₃; C_1-3alkyl (preferably CH₃); C_1-3alkoxy (preferably OCH₃); or —N(R_2b)(R_2c) wherein R_2band R_2care independently H, OH(R_2band R_2care not both OH), CH₃, or R_2band R_2ctogether form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl);
R₅is H or F, preferably H;
R₇and R₁₁are independently H, halo (preferably F), C_1-3alkyl (preferably CH₃), C_1-3alkoxy (preferably OCH₃), or C_1-3alkylthiol; Preferably R₇and R₁₁are independently H, halo or methoxy;
R₈and R₁₀are independently H; halo (preferably F or Cl); C_1-3alkyl (preferably CH₃); C_1-3alkoxy (preferably OCH₃) or C_1-3alkylthiol; and
R₉is selected from the group: hydrogen; hydroxy; Cl; N₃; C_1-3alkyl (preferably methyl or ethyl) or C_1-3haloalkyl (preferably monofluoromethyl, difluoromethyl, trifluoromethyl); —OR_9a, wherein R₁₂is C_1-3alkyl (i.e., methyl, ethyl, propyl, isopropyl) or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —N(R_2b)(R_2c) wherein R_2band R_2care independently C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl); and optionally R₉and one of R₈and R₁₀together form a 3, 4, 5, or 6-membered heterocycle;
provided that when R₉is H at least one of R₈and R₁₀is not H or halo, preferably at least one of R₈and R₁₀is not H or halo or C_1-3alkyl.

Preferably in this embodiment, when R₉is H, R₈or R₁₀or both are independently C_1-3alkoxy (preferably OCH₃) or C_1-3alkylthiol, each being optionally substituted with 1-4 F. Even more preferably when R₉is H, R₈or R₁₀or both are methoxy or ethoxy. Also preferably R₂is not H.
Also preferably, when R₉is C_1-3alkyl, halo, or C_1-3haloalkyl, then R₂is not H, preferably R₂is methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C_1-3hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.
Also preferably, in this embodiment, when R₉is H, R₈or R₁₀or both are OCH₃and preferably R₇and R₁₁are H, and also preferably R₂is not hydrogen and preferably R₂is methyl or chloro. Also preferably in this embodiment, when R₉is alkyl or haloalkyl or chloro, R₂is not hydrogen and preferably R₂is methyl or chloro.
In another preferred embodiment, compounds of the invention include compounds of Formula VIb or pharmaceutically acceptable salts or solvates thereof, wherein:

R₁is methyl or ethyl, preferably methyl;
R₂is H, methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C_1-3hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃; R₃is H, CH₃, OCH₃, F, or Cl; R₄and R₆are independently H, CH₃, NH₂, N₃, F, or Cl; R₅is H; R₇and R₁₁are independently H, F, or OCH₃; R₈and R₁₀are independently H, F, Cl, or OCH₃; and
R₉is selected from the group: H; OH; N₃; C_1-3alkyl (preferably methyl or ethyl) or C_1-3haloalkyl (preferably monofluoromethyl, difluoromethyl, trifluoromethyl); —OR_9a, wherein R_9ais C_1-3alkyl (i.e., methyl, ethyl, propyl, isopropyl) or C_1-3haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —N(R_2b)(R_2c) wherein R_2band R_2care independently C_1-3alkyl; or —COOR_9b, wherein R_9bis C_1-3alkyl (preferably methyl or ethyl), and optionally R₈and R₉together form a 3, 4, 5, or 6-membered heterocycle; provided that when R₉is H, at least one of R₈and R₁₀is OCH₃, and when R₉is C_1-3alkyl or C_1-3haloalkyl or Cl then R₂is Cl or methyl or ethyl.

R₁is CH₃;

R₂is H, methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), CH₂OH, NH₂, NHCH₃, N(CH₃)₂, —NHCH₂CH₂OH, OCH₃, or SCH₃; R₃is H, CH₃, OCH₃, F, or Cl; R₄and R₆are independently H, CH₃, NH₂, F, or Cl; R₅is H; R₇and R₁₁are independently H, F, or OCH₃; R₈and R₁₀are independently H, F, Cl, or OCH₃; and
R₉is selected from the group: —OR₁₂, wherein R₁₂is selected from the group of methyl, ethyl, fluoromethyl (e.g., CH₂F, CHF₂, CF₃), and fluoroethyl; —NHCH₃; —N(CH₃)₂; —N₃; and —COOR₁₃, wherein R₁₃is methyl or ethyl.
In a more preferred embodiment, compounds of the invention include compounds of Formula VIb or pharmaceutically acceptable salts or solvates thereof, wherein:

R₁is CH₃;

R₃is H, —CH₃, —OCH₃, or Cl;

R₄is H, CH₃, or NH₂;

R₅is H;

R₆is H, or CH₃;

R₉is —OCH₃or —OC₂H₅, —N(CH₃)₂, —CO₂CH₃, —OCHF₂, or N₃.

In a more preferred embodiment, the present invention provides compounds of Formula VIb or pharmaceutically acceptable salts or solvates thereof, wherein R₁is CH₃; R₂is Cl, methyl, or CH₂F; R₃is H, CH₃, F, or Cl; R₄, R₅and R₆are H; R₇, R₈, R₁₀and R₁₁are independently H or F; and R₉is —OCH₃or —N(CH₃)₂.
In another embodiment, compounds of Formula VIb include compounds wherein:
R₁is methyl or ethyl;
R₂is methyl, ethyl, fluoromethyl, trifluoromethyl, methoxy, chloro, hydrogen, morpholino, hydroxymethane, methylthiol, or an amino optionally substituted with hydroxyethyl, or hydroxy;
R₃is hydrogen, chloro, methyl, or methoxy;
R₄and R₆are independently hydrogen, chloro, or methyl;
R₅is hydrogen;
R₇, R₈, R₁₀, and R₁₁are independently hydrogen, fluoro, methyl, or methoxy; and
R₉is methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, azido, dimethylamino, methylcarboxy, chloro, hydrogen, or hydroxyl;
or pharmaceutically acceptable salts or solvates thereof.
Preferably, the compounds of this embodiment are not selected from the group consisting of:

6-amino-4-[(N-methyl-N-phenyl)amino]quinazoline;
1-{4-[(N-methyl-N-phenyl)amino]-6-quinazolinyl}-3-methyltriazene;
1-{4-[(N-methyl-N-phenyl)amino]-6-quinazolinyl}-3,3-dimethyltriazene;
4-(N-methylanilino)-6-sulfonylquinazoline;
4-(N-methylanilino)-6-halosulfonylquinazoline;
8-chloro-4-(N-methylanilino)quinazoline;
4-(N-methylanilino)-8-trifluoromethylquinazoline;
2-butyl-N-methyl-N-phenylquinazolin-4-amine;
4-(N-methylanilino)-6,8-dimethylquinazoline;
4-(N-methylanilino)-quinazoline;
4-(N-methylanilino)-6-methoxyquinazoline;
4-(N-methylanilino)-6-chloroquinazoline;
N-(3-chlorophenyl)-N-(quinazolin-4-yl)-N-methyl-amine;
4-(N-methylanilino)-2-chloroquinazoline;
4-(N-methylanilino)-2-chloro-8-methoxyquinazoline;
4-(N-ethylanilino)-2-chloroquinazoline;
4-(N-methylanilino)-2-chloro-6-methoxyquinazoline;
4-(N-methylanilino)-2-chloro-8-fluoroquinazoline;
2-amino-4-(N-methylphenylamino)quinazoline hydrochloride; or
2-amino-4-(N-methylphenylamino)-8-methoxyquinazoline hydrochloride.
In another embodiment, compounds of Formula VIb include compounds wherein:

R₁is methyl;
R₂is methyl, chloro, fluoromethyl, hydroxymethyl, amino, hydrogen, or hydroxyethylamino;
R₃is hydrogen, methyl, methoxy, or chloro;
R₄and R₆are independently hydrogen or methyl;
R₅is hydrogen;
R₇and R₁₁are independently hydrogen or fluoro;
R₈and R₁₀are independently hydrogen or fluoro; and
R₉is methoxy, ethoxy, dimethylamino, methylcarboxy, difluoromethoxy, or azido;
or pharmaceutically acceptable salts or solvates thereof.
Among all the compounds of the present invention as disclosed above, preferred are those that can induce caspase activation as determined by the method and under conditions (measurement at 24 hours) described in Example 262, preferably at an EC₅₀of no greater than about 1,000 nM, more preferably at an EC₅₀of no greater than about 500 nM, more preferably at an EC₅₀of no greater than about 200 nM, even more preferably at an EC₅₀of no greater than about 100 nM, and most preferably at an EC₅₀of no greater than about 10 nM. Also preferred compounds are those of Formula I-VIb, and pharmaceutically acceptable salts or solvates thereof, that are able to inhibit tubulin at an IC₅₀of no greater than about 2,000 nM, preferably no greater than about 1,000 nM, more preferably less than about 500 nM, as determined by the method and under conditions described in Example 264.
Exemplary compounds of the present invention are compounds provided in Examples 1-142; and pharmaceutically acceptable salts or prodrugs thereof, including but not limited to:

(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-nitro-phenyl)-methyl-amine;
(2-chloro-quinazolin-4-yl)-(4-trifluoromethoxy-phenyl)-methyl-amine;
N²-hydroxyl-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;
N²-(2-hydroxylethyl)-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;
N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;
N²-(3,7-dimethyl-octa-2,6-dienyl)-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;
N⁴-(4-methoxy-phenyl)-N⁴-methyl-N²-(2-morpholin-4-yl-ethyl)-quinazoline-2,4-diamine;
(4-methoxy-phenyl)-methyl-(2-morpholin-4-yl-quinazolin-4-yl)-amine;
N²-(3,7-dimethyl-octa-2,6-dienyl)-N⁴-(4-methyl-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;
(2-chloro-6,7-dimethoxyquinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
(5,6,7,8-tetrahydro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
(2-chloro-quinazolin-4-yl)-(4-methoxy-benzyl)-methyl-amine;
(4-methoxy-phenyl)-methyl-quinazolin-4-yl-amine;
(4-methyl-phenyl)-methyl-quinazolin-4-yl-amine;
(2-chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine;
(2-chloro-quinazolin-4-yl)-isopropyl-(4-methoxy-phenyl)-amine;
(2-chloro-quinazolin-4-yl)-cyclohexyl-(4-methoxy-phenyl)-amine;
(2-chloro-quinazolin-4-yl)-(2,3-dimethoxy-phenyl)-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)-(2,5-dimethoxy-phenyl)-methyl-amine;
(2-chloro-quinazolin-4-yl)-(3-methoxy-phenyl)-methyl-amine;
(2-chloro-quinazolin-4-yl)-(2-methoxy-phenyl)-methyl-amine;
N²-[2-(1H-imidazol-4-yl)-ethyl]-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;
N²-(3-dimethylamino-propyl)-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;
N²-(2-hydroxyethyl)-N⁴-(6-methoxypyridin-3-yl)-N⁴-methyl-quinazoline-2,4-diamine;
N⁴-(6-methoxypyridin-3-yl)-N⁴-methyl-quinazoline-2,4-diamine;
(2-chloro-quinazolin-4-yl)-(4-methylcarboxyphenyl)-methyl-amine;
(2-methoxy-quinazolin-4-yl)-(4-methoxyphenyl)-methylamine;
(2-chloro-quinazolin-4-yl)-(4-hydroxyphenyl)-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-7-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;
(2,7-dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
(5-chloro-2-isopropoxy-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
(isoquinolin-1-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-phenoxy-phenyl)-methyl-amine;
(2-chloro-quinazolin-4-yl)-(4-propoxy-phenyl)-methyl-amine; and
(4-methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine;
(2-chloro-quinazolin-4-yl)-(2,5-dimethoxy-phenyl)-amine;
5-chloro-N²,N⁴-bis-(4-methoxy-phenyl)-N²,N⁴-dimethyl-quinazoline-2,4-diamine;
(2-chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
(2-ethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
(2-hydroxymethyl-quinazolin-4-yl)-4-methoxy-phenyl)-methyl-amine;
(2-dimethylaminomethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
(4-methoxy-phenyl)-(2-phenyl-quinazolin-4-yl)-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-methyl-quinazolin-4-yl)-(2,4,6-trimethoxy-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;
(5-methoxy-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
(4-methoxy-phenyl)-(2-methyl-pyrido[2,3-d]pyrimidin-4-yl)-methyl-amine;
(4-hydroxy-phenyl)-(2-methyl-quinazolin-4-yl)-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;
(2-methyl-quinazolin-4-yl)-(4-nitro-phenyl)-methyl-amine;
(4-amino-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
(4-azido-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
(4-amino-2,6-dibromo-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
(4-amino-2-bromo-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;
(4-methoxy-phenyl-2,3,5,6-d₄)-(2-methyl-quinazolin-4-yl)-methyl-amine;
(4-methoxy-phenyl)-(2-methyl-6-nitro-quinazolin-4-yl)-methyl-amine;
(6-amino-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
(6-azido-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
(7-amino-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
(7-azido-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
ethyl 4-(N-(4-Methoxy-phenyl)-N-methylamino)quinazoline-2-carboxylate;
succinimidyl 4-(N-Methyl-N-(2-methylquinazolin-4-yl)amino)benzoic acid ester;
(2-methylthio-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
(2-azido-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;
(4-fluoro-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
(6-methoxy-pyridazin-3-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
(5-methoxy-pyrazin-2-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
(2-dimethylamino-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-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;
difluoromethyl-(4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine;
(4-methoxy-phenyl)-(2-methyl-pteridin-4-yl)-methyl-amine;
(5-methoxy-pyrimidin-2-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

and pharmaceutically acceptable salts or prodrugs thereof.
In one embodiment, exemplary compounds of the invention include:

(2-chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine;
N²-(2-hydroxyethyl)-N⁴-(6-methoxypyridin-3-yl)-N⁴-methyl-quinazoline-2,4-diamine;
N⁴-(6-methoxypyridin-3-yl)-N⁴-methyl-quinazoline-2,4-diamine;
(2-methyl-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine;
(6-methoxy-pyridazin-3-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
(5-methoxy-pyrazin-2-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
(2-dimethylamino-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine;
(2-methylamino-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine;
(2-methyl-quinazolin-4-yl)-(pyrazin-2-yl)-methyl-amine;
(5-methoxy-pyridin-2-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine; and
(5-methoxy-pyrimidin-2-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

or a pharmaceutically acceptable salt or solvate thereof.
In another embodiment, exemplary compounds of the invention include:

(4-methoxy-phenyl)-(2-methyl-pyrido[2,3-d]pyrimidin-4-yl)-methyl-amine; and
(4-methoxy-phenyl)-(2-methyl-pteridin-4-yl)-methyl-amine;

N²-hydroxyl-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;
N²-(2-hydroxylethyl)-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;
N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;
N²-(3,7-dimethyl-octa-2,6-dienyl)-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;
N⁴-(4-methoxy-phenyl)-N⁴-methyl-N²-(2-morpholin-4-yl-ethyl)-quinazoline-2,4-diamine;
(4-methoxy-phenyl)-methyl-(2-morpholin-4-yl-quinazolin-4-yl)-amine;
N²-(3,7-dimethyl-octa-2,6-dienyl)-N⁴-(4-methyl-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;
N²-[2-(1H-imidazol-4-yl)-ethyl]-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;
N²-(3-dimethylamino-propyl)-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;
5-chloro-N²,N⁴-bis-(4-methoxy-phenyl)-N²,N⁴-dimethyl-quinazoline-2,4-diamine;
6-chloro-N²,N⁴-bis-(4-methoxy-phenyl)-N²,N⁴-dimethyl-quinazoline-2,4-diamine;
(2-dimethylamino-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine; and
(2-methylamino-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

or a pharmaceutically acceptable salt or solvate thereof.
In yet another embodiment, exemplary compounds of the invention include:

(2-fluoromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
(4-methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine; (2-Chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
(2-ethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
(4-carboxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
ethyl 4-(N-(4-methoxy-phenyl)-N-methylamino)quinazoline-2-carboxylate;
(2-hydroxymethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
(2-dimethylaminomethyl-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;
(4-hydroxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
(2-fluoro-4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
(2-methyl-quinazolin-4-yl)-(4-nitro-phenyl)-methyl-amine;
(4-amino-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
(4-azido-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
(4-amino-2,6-dibromo-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
(4-amino-2-bromo-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;
(4-methoxy-phenyl-2,3,5,6-d₄)-(2-methyl-quinazolin-4-yl)-methyl-amine;
(4-methoxy-phenyl)-(2-methyl-6-nitro-quinazolin-4-yl)-methyl-amine;
(6-amino-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
(6-azido-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
(4-methoxy-phenyl)-(2-methyl-7-nitro-quinazolin-4-yl)-methyl-amine;
(2,4,6-trimethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
(7-amino-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
(7-azido-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
(3,5-dibromo-4-methoxyphenyl)-(2-methyl-6-nitro-quinazolin-4-yl)-methyl-amine;
(4-fluoro-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine; and
difluoromethyl-(4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine;

(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-nitro-phenyl)-methyl-amine;
(2-chloro-quinazolin-4-yl)-(4-trifluoromethoxy-phenyl)-methyl-amine;
(2-chloro-6,7-dimethoxyquinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
(2-chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine;
(2-chloro-quinazolin-4-yl)-isopropyl-(4-methoxy-phenyl)-amine;
(2-chloro-quinazolin-4-yl)-cyclohexyl-(4-methoxy-phenyl)-amine;
(2-chloro-quinazolin-4-yl)-(2,3-dimethoxy-phenyl)-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)-(2,5-dimethoxy-phenyl)-methyl-amine;
(2-chloro-quinazolin-4-yl)-(3-methoxy-phenyl)-methyl-amine;
(2-chloro-quinazolin-4-yl)-(2-methoxy-phenyl)-methyl-amine;
(2-chloro-quinazolin-4-yl)-(4-methylcarboxyphenyl)-methyl-amine;
(2-chloro-quinazolin-4-yl)-(4-hydroxyphenyl)-methylamine;
(2-chloro-6-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
(2-chloro-7-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;
(2,7-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-phenoxy-phenyl)-methyl-amine;
(2-chloro-quinazolin-4-yl)-(4-propoxy-phenyl)-methyl-amine;
(2-chloro-quinazolin-4-yl)-(4-ethoxy-phenyl)-methyl-amine;
(2,8-dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine; and
(2,5-dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(4-methoxy-phenyl)-methyl-quinazolin-4-yl-amine; and
(4-methyl-phenyl)-methyl-quinazolin-4-yl-amine;

or a pharmaceutically acceptable salt or solvate thereof.
In another embodiment, exemplary compounds useful in the methods of the invention include:

(2-methoxy-quinazolin-4-yl)-(4-methoxyphenyl)-methylamine; and
(5-chloro-2-isopropoxy-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

or a pharmaceutically acceptable salt or solvate thereof.
Additional exemplary compounds of the present invention are compounds provided in Examples 143-261; and pharmaceutically acceptable salts or prodrugs thereof, including but not limited to:

The term “alkyl” as employed herein by itself or as part of another group refers to both straight and branched chain radicals of up to ten carbons. Useful alkyl groups include straight-chained and branched C_1-10alkyl groups, more preferably C_1-6alkyl groups. Typical C_1-10alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, 3-pentyl, hexyl and octyl groups, which may be optionally substituted.
The term “alkenyl” as employed herein by itself or as part of another group means a straight or branched chain radical of 2-10 carbon atoms, unless the chain length is limited thereto, including at least one double bond between two of the carbon atoms in the chain. Typical alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl.
The term “alkynyl” is used herein to mean a straight or branched chain radical of 2-10 carbon atoms, unless the chain length is limited thereto, wherein there is at least one triple bond between two of the carbon atoms in the chain. Typical alkynyl groups include ethynyl, 1-propynyl, 1-methyl-2-propynyl, 2-propynyl, 1-butyryl and 2-butyryl.
Useful alkoxy groups include oxygen substituted by one of the C_1-10alkyl groups mentioned above, which may be optionally substituted. Alkoxy substituents include, without limitation, halo, morpholino, amino including alkylamino and dialkylamino, and carboxy including esters thereof.
Useful alkylthio groups include sulfur substituted by one of the C_1-10alkyl groups mentioned above, which may be optionally substituted. Also included are the sulfoxides and sulfones of such alkylthio groups.
Useful amino groups include —NH₂, —NHR₁₈and —NR₁₈R₁₉, wherein R₁₈and R₁₈are C_1-10alkyl or cycloalkyl groups, or R₁₈and R₁₉are combined with the N to form a ring structure, such as a piperidine, or R₁₈and R₁₉are combined with the N and other group to form a ring, such as a piperazine. The alkyl group may be optionally substituted.
Optional substituents on the alkyl, alkenyl, alkynyl, cycloalkyl, carbocyclic and heterocyclic groups include one or more halo, hydroxy, carboxyl, amino, nitro, cyano, C₁-C₆acylamino, C₁-C₆acyloxy, C₁-C₆alkoxy, aryloxy, alkylthio, C₆-C₁₀aryl, C₄-C₇cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₆-C₁₀aryl(C₂-C₆)alkenyl, C₆-C₁₀aryl(C₂-C₆)alkynyl, saturated and unsaturated heterocyclic or heteroaryl.
Optional substituents on the aryl, arylalkyl, arylalkenyl, arylalkynyl and heteroaryl and heteroarylalkyl groups include one or more halo, C₁-C₆haloalkyl, C₆-C₁₀aryl, C₄-C₇cycloalkyl, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₆-C₁₀aryl(C₁-C₆)alkyl, C₆-C₁₀aryl(C₂-C₆)alkenyl, C₆-C₁₀aryl(C₂-C₆)alkynyl, C₁-C₆hydroxyalkyl, nitro, amino, ureido, cyano, C₁-C₆acylamino, hydroxy, thiol, C₁-C₆acyloxy, azido, C₁-C₆alkoxy, carboxy or C_1-2alkylenedioxy (e.g., methylenedioxy).
The term “aryl” as employed herein by itself or as part of another group refers to monocyclic, bicyclic or tricyclic aromatic groups containing from 6 to 14 carbons in the ring portion.
Useful aryl groups include C_6-14aryl, preferably C_6-10aryl. Typical C_6-14aryl groups include phenyl, naphthyl, phenanthrenyl, anthracenyl, indenyl, azulenyl, biphenyl, biphenylenyl and fluorenyl groups.
The term “carbocycle” as employed herein include cycloalkyl and partially saturated carbocyclic groups. Useful cycloalkyl groups are C_3-8cycloalkyl. Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
Useful saturated or partially saturated carbocyclic groups are cycloalkyl groups as described above, as well as cycloalkenyl groups, such as cyclopentenyl, cycloheptenyl and cyclooctenyl.
Useful halo or halogen groups include fluorine, chlorine, bromine and iodine.
The term “arylalkyl” is used herein to mean any of the above-mentioned C_1-10alkyl groups substituted by any of the above-mentioned C_6-14aryl groups. Preferably the arylalkyl group is benzyl, phenethyl or naphthylmethyl.
The term “arylalkenyl” is used herein to mean any of the above-mentioned C_2-10alkenyl groups substituted by any of the above-mentioned C_6-14aryl groups.
The term “arylalkynyl” is used herein to mean any of the above-mentioned C_2-10alkynyl groups substituted by any of the above-mentioned C_6-14aryl groups.
The term “aryloxy” is used herein to mean oxygen substituted by one of the above-mentioned C_6-14aryl groups, which may be optionally substituted. Useful aryloxy groups include phenoxy and 4-methylphenoxy.
The term “arylalkoxy” is used herein to mean any of the above mentioned C_1-10alkoxy groups substituted by any of the above-mentioned aryl groups, which may be optionally substituted. Useful arylalkoxy groups include benzyloxy and phenethyloxy.
Useful haloalkyl groups include C_1-10alkyl groups substituted by one or more fluorine, chlorine, bromine or iodine atoms, e.g., fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, chloromethyl, chlorofluoromethyl and trichloromethyl groups.
Useful acylamino (acylamido) groups are any C_1-6acyl (alkanoyl) attached to an amino nitrogen, e.g., acetamido, chloroacetamido, propionamido, butanoylamido, pentanoylamido and hexanoylamido, as well as aryl-substituted C_1-6acylamino groups, e.g., benzoylamido, and pentafluorobenzoylamido.
Useful acyloxy groups are any C_1-6acyl (alkanoyl) attached to an oxy (—O—) group, e.g., formyloxy, acetoxy, propionoyloxy, butanoyloxy, pentanoyloxy and hexanoyloxy.
The term heterocycle is used herein to mean a saturated or partially saturated 3-7 membered monocyclic, or 7-10 membered bicyclic ring system, which consists of carbon atoms and from one to four heteroatoms independently selected from the group consisting of O, N, and S, wherein the nitrogen and sulfur heteroatoms can be optionally oxidized, the nitrogen can be optionally quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring, and wherein the heterocyclic ring can be substituted on carbon or on a nitrogen atom if the resulting compound is stable.
Useful saturated or partially saturated heterocyclic groups include tetrahydrofuranyl, pyranyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, isochromanyl, chromanyl, pyrazolidinyl, pyrazolinyl, tetronoyl and tetramoyl groups.
The term “heteroaryl” as employed herein refers to groups having 5 to 14 ring atoms; 6, 10 or 14 π electrons shared in a cyclic array; and containing carbon atoms and 1, 2 or 3 oxygen, nitrogen or sulfur heteroactoms.
Useful heteroaryl groups include thienyl (thiophenyl), benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl (furanyl), isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, pyrrolyl, including without limitation 2H-pyrrolyl, imidazolyl, pyrazolyl, pyridyl (pyridinyl), including without limitation 2-pyridyl, 3-pyridyl, and 4-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalzinyl, naphthyridinyl, quinozalinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acrindinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl, 1,4-dihydroquinoxaline-2,3-dione, 7-aminoisocoumarin, pyrido[1,2-c]pyrimidin-4-one, pyrazolo[1,5-c]pyrimidinyl, including without limitation pyrazolo[1,5-c]pyrimidin-3-yl, 1,2-benzoisoxazol-3-yl, benzimidazolyl, 2-oxindolyl and 2-oxobenzimidazolyl. Where the heteroaryl group contains a nitrogen atom in a ring, such nitrogen atom may be in the form of an N-oxide, e.g., a pyridyl N-oxide, pyrazinyl N-oxide and pyrimidinyl N-oxide.
The term “heteroaryloxy” is used herein to mean oxygen substituted by one of the above-mentioned heteroaryl groups, which may be optionally substituted. Useful heteroaryloxy groups include pyridyloxy, pyrazinyloxy, pyrrolyloxy, pyrazolyloxy, imidazolyloxy and thiophenyloxy.
The term “heteroarylalkoxy” is used herein to mean any of the above-mentioned C_1-10alkoxy groups substituted by any of the above-mentioned heteroaryl groups, which may be optionally substituted.
Some of the compounds of the present invention may exist as stereoisomers including optical isomers. The invention includes all stereoisomers and both the racemic mixtures of such stereoisomers as well as the individual enantiomers that may be separated according to methods that are well known to those of ordinary skill in the art.
In the compounds of the invention, reference to any bound hydrogen atom can also encompass a deuterium atom bound at the same position. Substitution of hydrogen atoms with deuterium atoms is conventional in the art. See, e.g., U.S. Pat. Nos. 5,149,820 & 7,317,039. Such deuteration sometimes results in a compound that is functionally indistinct from its hydrogenated counterpart, but occasionally results in a compound having beneficial changes in the properties relative to the non-deuterated form. For example, in certain instances, replacement of specific bound hydrogen atoms with deuterium atoms dramatically slows the catabolism of the deuterated compound, relative to the non-deuterated compound, such that the deuterated compound exhibit a significantly longer half-life in the bodies of individuals administered such compounds. This is particularly so when the catabolism of the hydrogenated compound is mediated by cytochrome P450 systems. Kushner et al., Can. J. Physiol. Pharmacol. (1999) 77:79-88.
Examples of pharmaceutically acceptable addition salts include inorganic and organic acid addition salts, such as hydrochloride, hydrobromide, phosphate, sulphate, citrate, lactate, tartrate, maleate, fumarate, mandelate and oxalate; and inorganic and organic base addition salts with bases, such as sodium hydroxy, Tris(hydroxymethyl)aminomethane (TRIS, tromethane) and N-methyl-glucamine.
Examples of prodrugs of the compounds of the invention include the simple esters of carboxylic acid containing compounds (e.g., those obtained by condensation with a C_1-4alcohol according to methods known in the art); esters of hydroxy containing compounds (e.g., those obtained by condensation with a C_1-4carboxylic acid, C_3-6dioic acid or anhydride thereof, such as succinic and fumaric anhydrides according to methods known in the art); imines of amino containing compounds (e.g., those obtained by condensation with a C_1-4aldehyde or ketone according to methods known in the art); carbamate of amino containing compounds, such as those described by Leu, et. al., (J. Med. Chem. 42:3623-3628 (1999)) and Greenwald, et. al., (J. Med. Chem. 42:3657-3667 (1999)); and acetals and ketals of alcohol containing compounds (e.g., those obtained by condensation with chloromethyl methyl ether or chloromethyl ethyl ether according to methods known in the art).
The compounds of this invention may be prepared using methods known to those skilled in the art, or the novel methods of this invention. Specifically, the compounds of this invention with Formulae I-VIb can be prepared as illustrated by the exemplary reaction in Scheme 1. Reaction of optionally substituted quinazoline-2,4-dione with phosphorylchloride produces the corresponding 2,4-dichloroquinazoline, which is reacted with an optionally substituted aniline, such as N-methyl-4-methoxy-aniline, to produce the substituted 2-chloro-4-anilino-quinazoline.
Compounds of this invention with Formulae I-VIb also could be prepared as illustrated by the exemplary reaction in Scheme 2. Reaction of the substituted 2-chloro-4-anilino-quinazoline with a nucleophile (R₂), such as hydroxylamine, in isopropanol heated by microwave produces the 2-nucleophile substituted-4-anilino-quinazoline, such as substituted hydroxylamino. Other nucleophiles that can be used in the reaction include NaOMe, NaN₃, NaSMe, NH₃, NH₂Me, or NHMe₂, and the reaction can be run at room temperature or elevated temperature.
Compounds of this invention with Formulae I-VIb, wherein Ar is a substituted aryl or heteroaryl, could be prepared as illustrated by the exemplary reaction in Scheme 3. Reaction of 2,4-dichloroquinazoline with a substituted arylamine or heteroarylamine (Ar), such as a substituted pyridin-3-ylamine, produces the corresponding 4-Ar-amino substituted 2-chloro-quinazoline, which is alkylated with a haloalkyl, such as methylated by reaction with methyl iodide in the presence of a base such as NaH, to produce the corresponding 4-N-methyl-Ar-amino substituted 2-chloro-quinazoline.
Alternatively, compounds of this invention with Formulae I-VIb also could be prepared as illustrated by the exemplary reaction in Scheme 4. The N-alkyl-arylamine or N-alkyl-heteroarylamine could be prepared by reaction of the arylamine or heteroarylamine with a ketone or aldehyde, such as acetone, in the presence of a reducing agent, such as NaCNBH₃. The N-alkyl-arylamine or N-alkyl-heteroarylamine is then reacted with optionally substituted 2,4-dichloroquinazoline to produce the corresponding 4-substituted 2-chloro-quinazoline.
Compounds of this invention with Formulae I-VIb also could be prepared as illustrated by the exemplary reaction in Scheme 5. Reaction of optionally substituted 2-amino-benzoic acid, such as 2-amino-5-methyl-benzoic acid, with potassium cyanate in the presence of an acid, such as acetic acid, produces the corresponding optionally substituted quinazoline-2,4-dione, such as 6-methyl-quinazoline-2,4-dione, which is converted to the corresponding optionally substituted 2,4-dichloroquinazoline, such as 6-methyl-2,4-dichloroquinazoline by reaction with phosphorylchloride. Reaction of optionally substituted 2,4-dichloroquinazoline, such as 6-methyl-2,4-dichloroquinazoline with a substituted arylamine or heteroarylamine, such as N-methyl-4-methoxy-aniline, produces the corresponding 4-substituted 2-chloro-quinazoline, such as substituted 2-chloro-4-anilino-quinazoline.
Compounds of this invention with Formulae I-VIb, wherein R₂is an optionally substituted alkyl group, could be prepared as illustrated by the exemplary reaction in Scheme 6. Reaction of 2-amino-benzoic acid methyl ester with an optionally substituted acetonitrile, such as fluoro-acetonitrile, in the presence of HCl produces the corresponding 2-substituted quinazoline-4(3H)-one, such as 2-fluoromethyl-quinazoline-4(3H)-one, which is converted to 2-substituted 4-chloro-quinazoline, such as 4-chloro-2-fluoromethyl-quinazoline by reaction with phosphorylchloride. Reaction of 2-substituted 4-chloro-quinazoline, such as 4-chloro-2-fluoromethyl-quinazoline with a substituted aniline, such as N-methyl-4-methoxy-aniline, produces the corresponding 2-substituted 4-anilino-quinazoline, such as 2-fluoromethyl-4-anilino-quinazoline. Other substituted acetonitriles that can be used for the reaction include chloro-acetonitrile and bromo-acetonitrile, as well as acetonitrile and propionitrile.
Compounds of this invention with Formulae I-VIb, wherein R₂is a substituted alkyl group, could also be prepared as illustrated by the exemplary reaction in Scheme 7. Reaction of a substituted 2-chloroalkyl-4-(N-alkyl-arylamine or N-alkyl-heteroarylamine)-quinazoline, such as N-methyl-2-chloromethyl-4-anilino-quinazoline, with a nucleophile, such as NHMe₂, produces the substituted 2-dimethylaminomethyl-4-anilino-quinazoline. Other nucleophiles that can be used in the reaction include NaOMe, NaN₃, NaSMe, NH₃, NH₂Me, or NHMe₂, and the reaction can be run at room temperature and elevated temperature.
Compounds of this invention with Formulae I-VIb, wherein R₁is a substituted alkyl, could be prepared as illustrated by the exemplary reaction in Scheme 8. For example, reaction of an optionally substituted 4-(arylamine or heteroarylamine)-quinazoline, such as 2-methyl-4-(6-methoxy-pyridin-3-ylamino)-quinazoline, with a substituted haloalkyl, such as difluoromethyl chloride, in the presence of a base such as NaH, produces the corresponding 4-(N-alkyl-arylamine or N-alkyl-heteroarylamine)-quinazoline, such as 2-methyl-N⁴-difluoromethyl-4-(4-methoxy-pyridin-3-ylamino)-quinazoline.
Compounds of this invention with Formula I-VIb, wherein R₂is an alkyl group, could be prepared as illustrated by the exemplary reaction in Scheme 9. Reaction of a substituted 2-amino-benzoic acid, such as 2-amino-5-nitro-benzoic acid, with acetic anhydride, produces the corresponding substituted 2-methyl-4H-benzo[d][1,3]oxazine-4-one, such as 2-methyl-6-nitro-4H-benzo[d][1,3]oxazine-4-one, which is converted to the corresponding quinazoline-4(3H)-one, such as 2-methyl-6-nitro-quinazoline-4(3H)-one, by treatment with ammonia in dioxane. The compound is then converted to the corresponding 4-chloro-quinazoline, such as 4-chloro-2-methyl-6-nitro-quinazoline by reaction with phosphorylchloride. Reaction of the 4-chloro-quinazoline, such as 4-chloro-2-methyl-6-nitro-quinazoline with a substituted arylamine or heteroarylamine, such as N-methyl-4-methoxy-aniline, produces the corresponding 4-(arylamino or heteroarylamino)-quinazoline, such as substituted 2-methyl-6-nitro-4-anilino-quinazoline. Other substituted 2-amino-benzoic acid that can be used for the reaction include 2-amino-4-nitro-benzoic acid, 2-amino-5-chloro-benzoic acid.
Compounds substituted with a nitro group can be reduced by hydrogenation under H₂with Pd to produce the amino compound, which can be converted to the azido compounds by diazotization followed by treatment with NaN₃as exemplified below:
Compounds of this invention with Formula I-VIb, wherein ring A is a carbocycle, could be prepared as illustrated by the exemplary reaction in Scheme 10. Reaction of optionally substituted 5,6,7,8-tetrahydro-quinazoline-4(3H)-one with phosphorylchloride produces the corresponding optionally substituted 5,6,7,8-tetrahydro-4-chloroquinazoline, which is reacted with an optionally substituted N-alkyl-arylamine or N-alkyl-heteroarylamine, such as N-methyl-4-methoxy-aniline, to produce the corresponding optionally substituted 5,6,7,8-tetrahydro-4-(N-alkyl-arylamine or N-alkyl-heteroarylamine)-quinazoline.
Compounds of this invention with Formula I-VIb, wherein ring A is a heteroaryl or heterocycle, such as pyrido, could be prepared as illustrated by the exemplary reaction in Scheme 11. Reaction of an amino-nicotinic acid, such as 2-amino-nicotinic acid, with acetyl chloride, in the presence of base, such as triethylamine, produces the corresponding amide, which is treated with ammonium acetate to produce the corresponding 2-methyl-pyrido[2,3-d](heteroaryl or heterocycle)-4-ol, such as 2-methyl-pyrido[2,3-d]pyrimidin-4-ol. The resulting compound is then converted to the corresponding 4-chloro-2-methyl-pyrido[2,3-d](heteroaryl or heterocycle), such as 4-chloro-2-methyl-pyrido[2,3-d]pyrimidine by reaction with phosphorylchloride, which is treated with an optionally substituted arylamino or heteroarylamino, such as N-methyl-4-methoxy-aniline to produce the corresponding optionally substituted 4-(arylamino or heteroarylamino)-2-methyl-pyrido[2,3-d](heteroaryl or heterocycle), such as substituted 4-anilino-2-methyl-pyrido[2,3-d]pyrimidine.
Additional exemplary compounds may be synthesized according to the synthesis schemes below:
As depicted in Scheme 12 the pteridine ring system can be constructed through the condensation of a diaminopyrimidine and a dioxanediol in ethanol. The molecules can be further elaborated through nucleophilic displacement of the chloride or through palladium mediated coupling with analines, amines, sulfides, borate reagents or the like.
As shown in scheme 13, substituted 2-chloroquinazolines can be further elaborated through addition of nucleophiles; amines, analines, sulfides, alcohols, phenols and the like.
As exemplified in schemes 14 through 20, a 4-chloroquinazoline can be elaborated through the addition of a variety of heterocyclic nucleophiles. The nuclophiles can be elaborated through alkylation prior to addition of the quinazoline or after. Acylation products can also be obtained after addition of the nucleophile to the chloroquinazoline.
Scheme 14 shows that an aminopyrazine can be used to displace the 4-chloro group using sodium hydride in DMF. The methyl group can be added via methyliodide with sodium hydride in DMF as solvent.
Scheme 15 shows that the methoxy group can be installed on the pyridazine using sodium methoxide and copper. The aminopyridazine can be methylated with sodium hydride and methyl iodide. The resulting methyl aminopyridazine can also be used to displace the 4-chloro from the quinazoline with sodium hydride in DMF.
Heteroatoms can be incorporated into the quinazoline ring system as exemplified by the pyrimidopyridazine in Scheme 16. Chlorination and displacement with nucleophiles proceeds as expected.
The 3-amino-4-carboxylpyridazine can be reacted with KOCN in water at elevated temperature to give a quinazolinediol. Treatment with phosphorous oxychloride yields the dichloride. The 4-chloride on the quinazoline derivative can be displaced with anilines, alcohols, amines, phenols, sulfides or the like. Further elaboration can be accomplished by displacing the 2-chloro with similar nucleophiles.
Scheme 17 shows that a 4-bromopyrimidine can be treated with an amine in THF to yield a substituted 4-aminopyrimidine. An alcohol on a pyrimidine can be alkylated with methyl iodide, or the like, in the presence of sodium hydride. The 4-chloro of a quinazoline can be displaced with nucleophiles, alcohols, amines, phenols, sulfides or the like.
As shown in scheme 18, 2-chloro-4-nitropyrimadine can be treated with nucleophiles, alkoxides, alcohols, amines, phenols, sulfides or the like, to yield the substituted pyrimidines. The nitro substituent can be reduced with hydrogen and palladium and alkylated with an alkyl halide in the presence of sodium hydride. Again, displacement of the chloride from the quinazoline can be accomplished in the presence of sodium hydride and DMF.
Scheme 19 shows that a 4-iodopyrimadine can also be used to obtain the 2-alkoxypyrimidine through treatment with alkoxide in the presence of copper. The aminopyrimidine can be used to displace the 4-chloro on a quinazoline in the presence of sodium hydride in DMF. The amine can be further elaborated by alkylation with an alkylhalide in the presence of sodium hydride in DMF.
Substitution of the chloro groups on the quinazoline scaffold can also be accomplished through copper and/or palladium mediated couplings as exemplified in scheme 20.
As shown in schemes 21 and 22, displacement of the chloride from a quinazoline with a hydrazine derivative leads to a versatile compound which can be further elaborated via acylation, alkylation, reductive amination, or the like.
Scheme 21 shows that treatment of 2-methyl-4-chloroquinazline with methylhydrazine yields a hydrazine derivative which can be further elaborated by treatment with benzoylchloride.
As shown in scheme 22, 2,4-dichloroquinazoline can be reacted with methylhydrazine followed by acylation with benzoyl chloride. The 2-chloro can be displaced with nucleophiles, such as, alcohols, anilines, amines, phenols, sulfides or the like.
As depicted in Scheme 23, the quinazoline ring system can be directly formed through treatment of an aminobenzoic acid ester with acetonitrile under acidic conditions. The resulting quinazolinone can be chlorinated with phosphorus oxychloride. The 4-chloro can be displaced with nucleophiles such as, alcohols, amines, analines, phenols, sulfides or the like.
Quinazoline derivatives that contain substituents on the quinazoline phenyl ring can be further elaborated via alkylation, acylation, sulfanation, reductive amination or the like.
As exemplified in Scheme 24, a 6-aminoquinazoline derivative can be treated with 4-methoxybenzenesulfanylchloride to form the sulfonamide.
As shown in scheme 25, a 6-bromoquinazoline can be transformed through palladium and/or copper mediated coupling reactions to give the biphenyl like derivatives. The bromide can also be transformed to the nitrile and reduced to give the methylamine derivative.
As shown in Scheme 26, the quinazolinone can also be activated for displacement with nucleophiles, such as, alcohols, anilines, amines, phenols, sulfides or the like, via common peptide coupling reagents such as BOP, or the like.
As shown in Scheme 27, 2-ketoester compounds can be treated with urea to form substituted pyrimidine compounds which can be chlorinated with phosphorus oxychloride and displaced with nucleophiles, alcohols, amines, phenols, sulfides or the like as shown with the quinazoline derivatives.
As shown in Scheme 28, starting from heterocyclic aminoesters, thienylpyrimidines can be formed via treatment with acetonitrile under acidic conditions. The resulting pyrimadine derivatives can be chlorinated with phosphorus oxychloride in a fashion similar to the quinazoline derivatives.
As shown in scheme 29, substituted phthalic anhydrides can be transformed into phthalazindiones. Treatment of a phthalic anhydrides with hydrazine yields a phthalazindiones. Treatment of a phthalazindiones with phosphorus oxychloride yields the dichloride derivative which can be reacted with nucleophiles, alcohols, anilines, amines, phenols, sulfides or the like. The remaining chloride can be displaced removed via reduction with palladium and hydrogen.
An important aspect of the present invention is the discovery that compounds having Formulae I-VIb are activators of caspases and inducers of apoptosis. Another important aspect of the invention is the discovery that compounds having Formulae I-Vc are inhibitors of tubulin polymerization. Therefore, these compounds are useful in treating diseases that are responsive to activating caspases, inducing apoptosis, or inhibiting tubulin. For example, these compounds are useful in a variety of clinical conditions in which there is uncontrolled cell growth and spread of abnormal cells, such as in the case of cancer.
The present invention also includes a therapeutic method comprising administering to an animal an effective amount of a compound, or a pharmaceutically acceptable salt or prodrug of said compound of Formulae I-Vc, wherein said therapeutic method is useful to treat cancer, which is a group of diseases characterized by the uncontrolled growth and spread of abnormal cells. Such diseases include, but are not limited to, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast carcinoma, ovarian carcinoma, lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, soft-tissue sarcoma, primary macroglobulinemia, bladder carcinoma, chronic granulocytic leukemia, primary brain carcinoma, malignant melanoma, small-cell lung carcinoma, stomach carcinoma, colon carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, head or neck carcinoma, osteogenic sarcoma, pancreatic carcinoma, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial carcinoma, polycythemia vera, essential thrombocytosis, adrenal cortex carcinoma, skin cancer, and prostatic carcinoma.
In practicing the therapeutic methods, effective amounts of compositions containing therapeutically effective concentrations of the compounds formulated for oral, intravenous, local and topical application, for the treatment of neoplastic diseases and other diseases, are administered to an individual exhibiting the symptoms of one or more of these disorders. The amounts are effective to ameliorate or eliminate one or more symptoms of the disorders. An effective amount of a compound for treating a particular disease is an amount that is sufficient to ameliorate, or in some manner reduce, the symptoms associated with the disease. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective. The amount may cure the disease but, typically, is administered in order to ameliorate the symptoms of the disease. Typically, repeated administration is required to achieve the desired amelioration of symptoms.
Another aspect of the present invention is to provide a pharmaceutical composition, containing an effective amount of a compound of Formulae I-VIb, or a pharmaceutically acceptable salt of said compound, in admixture with one or more pharmaceutically acceptable carriers or diluents.
In one embodiment, a pharmaceutical composition comprising a compound of Formulae I-Vc disclosed herein, or a pharmaceutically acceptable salt of said compound, in combination with a pharmaceutically acceptable vehicle is provided.
Preferred pharmaceutical compositions comprise compounds of Formulae I-VIb, and pharmaceutically acceptable salts, esters, or prodrugs thereof, that are able to induce caspase activation as determined by the method described in Example 264, preferably at an EC₅₀no greater than 1,000 nM, more preferably at an EC₅₀no greater than 500 nM, more preferably at an EC₅₀no greater than 200 nM, more preferably at an EC₅₀no greater than 100, and most preferably at an EC₅₀no greater than 10 nM. Other preferred compositions comprise compounds of Formula I-VIb, and pharmaceutically acceptable salts, esters, or prodrugs thereof, that are able to inhibit tubulin polymerization as determined by the method described in Example 266.
Another embodiment of the present invention is directed to a composition effective to inhibit neoplasia comprising a compound, or a pharmaceutically acceptable salt or prodrug of said compound of Formulae I-VIb, which functions as a caspase cascade activator and inducer of apoptosis or inhibitor of tubulin polymerization, in combination with at least one known cancer chemotherapeutic agent, or a pharmaceutically acceptable salt of said agent. Examples of known cancer chemotherapeutic agents which may be used for combination therapy include, but not are limited to alkylating agents, such as busulfan, cis-platin, mitomycin C, and carboplatin; antimitotic agents, such as colchicine, vinblastine, paclitaxel, and docetaxel; topo I inhibitors, such as camptothecin and topotecan; topo II inhibitors, such as doxorubicin and etoposide; RNA/DNA antimetabolites, such as 5-azacytidine, 5-fluorouracil and methotrexate; DNA antimetabolites, such as 5-fluoro-2′-deoxy-uridine, ara-C, hydroxyurea and thioguanine; EGFR inhibitors, such as Iressa® (gefitinib) and Tarceva® (erlotinib); proteosome inhibitors; antibodies, such as campath, Herceptin® (trastuzumab), Avastin® (bevacizumab), or Rituxan® (rituximab). Other known cancer chemotherapeutic agents which may be used for combination therapy include melphalan, chlorambucil, cyclophosamide, ifosfamide, vincristine, mitoguazone, epirubicin, aclarubicin, bleomycin, mitoxantrone, elliptinium, fludarabine, octreotide, retinoic acid, tamoxifen, Gleevec® (imatinib mesylate) and alanosine.
In practicing the methods of the present invention, the compound of the invention may be administered together with at least one known chemotherapeutic agent as part of a unitary pharmaceutical composition. Alternatively, the compound of the invention may be administered apart from at least one known cancer chemotherapeutic agent. In one embodiment, the compound of the invention and at least one known cancer chemotherapeutic agent are administered substantially simultaneously, i.e. the compounds are administered at the same time or one after the other, so long as the compounds reach therapeutic levels in the blood at the same time. On another embodiment, the compound of the invention and at least one known cancer chemotherapeutic agent are administered according to their individual dose schedule, so long as the compounds reach therapeutic levels in the blood.
It has been reported that alpha-1-adrenoceptor antagonists, such as doxazosin, terazosin, and tamsulosin can inhibit the growth of prostate cancer cell via induction of apoptosis (Kyprianou, N., et al., Cancer Res 60:4550-4555, (2000)). Therefore, another embodiment of the present invention is directed to a composition effective to inhibit neoplasia comprising a compound, or a pharmaceutically acceptable salt or prodrug of a compound described herein, which functions as a caspase cascade activator and inducer of apoptosis or inhibitor of tubulin polymerization, in combination with at least one known alpha-1-adrenoceptor antagonists, or a pharmaceutically acceptable salt of said agent. Examples of known alpha-1-adrenoceptor antagonists, which can be used for combination therapy include, but are not limited to, doxazosin, terazosin, and tamsulosin.
It has been reported that sigma-2 receptors are expressed in high densities in a variety of tumor cell types (Vilner, B. J., et al., Cancer Res. 55: 408-413 (1995)) and that sigma-2 receptor agonists, such as CB-64D, CB-184 and haloperidol activate a novel apoptotic pathway and potentiate antineoplastic drugs in breast tumor cell lines. (Kyprianou, N., et al., Cancer Res. 62:313-322 (2002)). Therefore, another embodiment of the present invention is directed to a composition effective to inhibit neoplasia comprising a compound, or a pharmaceutically acceptable salt or prodrug of a compound described herein, which functions as a caspase cascade activator and inducer of apoptosis or inhibitor of tubulin polymerization, in combination with at least one known sigma-2 receptor agonist, or a pharmaceutically acceptable salt of said agonist. Examples of known sigma-2 receptor agonists which can be used for combination therapy include, but are not limited to, CB-64D, CB-184 and haloperidol.
It has been reported that combination therapy with lovastatin, a HMG-CoA reductase inhibitor, and butyrate, an inducer of apoptosis in the Lewis lung carcinoma model in mice, showed potentiating antitumor effects (Giermasz, A., et al., Int. J. Cancer 97:746-750 (2002)). Therefore, another embodiment of the present invention is directed to a composition effective to inhibit neoplasia comprising a compound, or a pharmaceutically acceptable salt or prodrug of a compound described herein, which functions as a caspase cascade activator and inducer of apoptosis or inhibitor of tubulin polymerization, in combination with at least one known HMG-CoA reductase inhibitor, or a pharmaceutically acceptable salt of said agent. Examples of known HMG-CoA reductase inhibitors, which can be used for combination therapy include, but are not limited to, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and cerivastatin.
It has been reported that HIV protease inhibitors, such as indinavir or saquinavir, have potent anti-angiogenic activities and promote regression of Kaposi sarcoma (Sgadari, C., et al., Nat. Med. 8:225-232 (2002)). Therefore, another embodiment of the present invention is directed to a composition effective to inhibit neoplasia comprising a compound, or a pharmaceutically acceptable salt or prodrug of a compound described herein, which functions as a caspase cascade activator and inducer of apoptosis or inhibitor of tubulin polymerization, in combination with at least one known HIV protease inhibitor, or a pharmaceutically acceptable salt of said agent. Examples of known HIV protease inhibitors, which can be used for combination therapy include, but are not limited to, amprenavir, abacavir, CGP-73547, CGP-61755, DMP-450, indinavir, nelfinavir, tipranavir, ritonavir, saquinavir, ABT-378, AG 1776, and BMS-232,632.
It has been reported that synthetic retinoids, such as fenretinide (N-(4-hydroxyphenyl)retinamide, 4HPR), have good activity in combination with other chemotherapeutic agents, such as cisplatin, etoposide or paclitaxel in small-cell lung cancer cell lines (Kalemkerian, G. P., et al., Cancer Chemother. Pharmacol. 43:145-150 (1999)). 4HPR also was reported to have good activity in combination with gamma-radiation on bladder cancer cell lines (Zou, C., et al., Int. J. Oncol. 13:1037-1041 (1998)). Therefore, another embodiment of the present invention is directed to a composition effective to inhibit neoplasia comprising a compound, or a pharmaceutically acceptable salt or prodrug of a compound described herein, which functions as a caspase cascade activator and inducer of apoptosis or inhibitor of tubulin polymerization, in combination with at least one known retinoid and synthetic retinoid, or a pharmaceutically acceptable salt of said agent. Examples of known retinoids and synthetic retinoids, which can be used for combination therapy include, but are not limited to, bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, α-difluoromethylornithine, ILX23-7553, fenretinide, and N-4-carboxyphenyl retinamide.
It has been reported that proteasome inhibitors, such as lactacystin, exert anti-tumor activity in vivo and in tumor cells in vitro, including those resistant to conventional chemotherapeutic agents. By inhibiting NF-kappaB transcriptional activity, proteasome inhibitors may 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)). Therefore, another embodiment of the present invention is directed to a composition effective to inhibit neoplasia comprising a compound, or a pharmaceutically acceptable salt or prodrug of a compound described herein, which functions as a caspase cascade activator and inducer of apoptosis or inhibitor of tubulin polymerization, in combination with at least one known proteasome inhibitor, or a pharmaceutically acceptable salt of said agent. Examples of known proteasome inhibitors, which can be used for combination therapy include, but are not limited to, lactacystin, MG-132, and PS-341.
It has been reported that tyrosine kinase inhibitors, such as STI571 (Gleevec® (imatinib mesylate)), have potent synergetic effect in combination with other anti-leukemic agents, such as etoposide (Liu, W. M., et al. Br. J. Cancer 86:1472-1478 (2002)). Therefore, another embodiment of the present invention is directed to a composition effective to inhibit neoplasia comprising a compound, or a pharmaceutically acceptable salt or prodrug of a compound described herein, which functions as a caspase cascade activator and inducer of apoptosis or inhibitor of tubulin polymerization, in combination with at least one known tyrosine kinase inhibitor, or a pharmaceutically acceptable salt of said agent. Examples of known tyrosine kinase inhibitors, which can be used for combination therapy include, but are not limited to, Gleevec® (imatinib mesylate), ZD1839 Iressa® (gefitinib), SH268, genistein, CEP2563, SU6668, SU11248, and EMD121974.
It has been reported that prenyl-protein transferase inhibitors, such as farnesyl protein transferase inhibitor R115777, possess preclinical antitumor activity against human breast cancer (Kelland, L. R., et. al., Clin. Cancer Res. 7:3544-3550 (2001)). Synergy of the protein farnesyltransferase inhibitor SCH66336 and cisplatin in human cancer cell lines also has been reported (Adjei, A. A., et al., Clin. Cancer. Res. 7:1438-1445 (2001)). Therefore, another embodiment of the present invention is directed to a composition effective to inhibit neoplasia comprising a compound, or a pharmaceutically acceptable salt or prodrug of a compound described herein, which functions as a caspase cascade activator and inducer of apoptosis, in combination with at least one known prenyl-protein transferase inhibitor, including farnesyl protein transferase inhibitor, inhibitors of geranylgeranyl-protein transferase type I (GGPTase-I) and geranylgeranyl-protein transferase type-II, or a pharmaceutically acceptable salt of said agent. Examples of known prenyl-protein transferase inhibitors, which can be used for combination therapy include, but are not limited to, R115777, SCH66336, L-778,123, BAL9611 and TAN-1813.
It has been reported that cyclin-dependent kinase (CDK) inhibitors, such as flavopiridol, have potent synergetic effect in combination with other anticancer agents, such as CPT-11, a DNA topoisomerase I inhibitor in human colon cancer cells (Motwani, M., et al., Clin. Cancer Res. 7:4209-4219, (2001)). Therefore, another embodiment of the present invention is directed to a composition effective to inhibit neoplasia comprising a compound, or a pharmaceutically acceptable salt or prodrug of a compound described herein, which functions as a caspase cascade activator and inducer of apoptosis or inhibitor of tubulin polymerization, in combination with at least one known cyclin-dependent kinase inhibitor, or a pharmaceutically acceptable salt of said agent. Examples of known cyclin-dependent kinase inhibitor, which can be used for combination therapy include, but are not limited to, flavopiridol, UCN-01, roscovitine and olomoucine.
It has been reported that in preclinical studies COX-2 inhibitors were found to block angiogenesis, suppress solid tumor metastases, and slow the growth of implanted gastrointestinal cancer cells (Blanke, C. D., Oncology (Huntingt) 16(No. 4 Suppl. 3):17-21 (2002)). Therefore, another embodiment of the present invention is directed to a composition effective to inhibit neoplasia comprising a compound, or a pharmaceutically acceptable salt or prodrug of a compound described herein, which functions as a caspase cascade activator and inducer of apoptosis or inhibitor of tubulin polymerization, in combination with at least one known COX-2 inhibitor, or a pharmaceutically acceptable salt of said inhibitor. Examples of known COX-2 inhibitors which can be used for combination therapy include, but are not limited to, celecoxib, valecoxib, and rofecoxib.
Another embodiment of the present invention is directed to a composition effective to inhibit neoplasia comprising a bioconjugate of a compound described herein, which functions as a caspase cascade activator and inducer of apoptosis or inhibitor of tubulin polymerization, in bioconjugation with at least one known therapeutically useful antibody, such as Herceptin® (trastuzumab) or Rituxan® (rituximab), growth factors, such as DGF, NGF; cytokines, such as IL-2, IL-4, or any molecule that binds to the cell surface. The antibodies and other molecules will deliver a compound described herein to its targets and make it an effective anticancer agent. The bioconjugates could also enhance the anticancer effect of therapeutically useful antibodies, such as Herceptin® (trastuzumab) or Rituxan® (rituximab).
Similarly, another embodiment of the present invention is directed to a composition effective to inhibit neoplasia comprising a compound, or a pharmaceutically acceptable salt or prodrug of a compound described herein, which functions as a caspase cascade activator and inducer of apoptosis or inhibitor of tubulin polymerization, in combination with radiation therapy. In this embodiment, the compound of the invention may be administered at the same time as the radiation therapy is administered or at a different time.
Yet another embodiment of the present invention is directed to a composition effective for post-surgical treatment of cancer, comprising a compound, or a pharmaceutically acceptable salt or prodrug of a compound described herein, which functions as a caspase cascade activator and inducer of apoptosis or inhibitor of tubulin polymerization. The 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 following exposure to an infectious agent. Depending on the type of infection, rapid clonal expansion of the T and B lymphocytes occurs to combat the infection. The elimination of the effector cells following an infection is one of the major mechanisms for maintaining immune homeostasis. The elimination of the effector cells has been shown to be regulated by apoptosis. Autoimmune diseases have lately been determined to occur as a consequence of deregulated cell death. In certain autoimmune diseases, the immune system directs its powerful cytotoxic effector mechanisms against specialized cells, such as oligodendrocytes in multiple sclerosis, the beta cells of the pancreas in diabetes mellitus, and thyrocytes in Hashimoto's thyroiditis (Ohsako, S. & Elkon, K. B., Cell Death Differ. 6:13-21 (1999)). Mutations of the gene encoding the lymphocyte apoptosis receptor Fas/APO-1/CD95 are reported to be associated with defective lymphocyte apoptosis and autoimmune lymphoproliferative syndrome (ALPS), which is characterized by chronic, histologically benign splenomegaly, generalized lymphadenopathy, hypergammaglobulinemia, and autoantibody formation. (Infante, A. J., et al., J. Pediatr. 133:629-633 (1998) and Vaishnaw, A. K., et al., J. Clin. Invest. 103:355-363 (1999)). It was reported that overexpression of Bcl-2, which is a member of the bcl-2 gene family of programmed cell death regulators with anti-apoptotic activity, in developing B cells of transgenic mice, in the presence of T cell dependent costimulatory signals, results in the generation of a modified B cell repertoire and in the production of pathogenic autoantibodies (Lopez-Hoyos, M., et al., Int. J. Mol. Med. 1:475-483 (1998)). It is therefore evident that many types of autoimmune disease are caused by defects of the apoptotic process. One treatment strategy for such diseases is to turn on apoptosis in the lymphocytes that are causing the autoimmune disease (O'Reilly, L. A. & Strasser, A., Inflamm. Res. 48:5-21 (1999)).
Fas-Fas ligand (FasL) interaction is known to be required for the maintenance of immune homeostasis. Experimental autoimmune thyroiditis (EAT), characterized by autoreactive T and B cell responses and a marked lymphocytic infiltration of the thyroid, is a good model to study the therapeutic effects of FasL. Batteux, F., et al., (J. Immunol. 162:603-608 (1999)) reported that by direct injection of DNA expression vectors encoding FasL into the inflamed thyroid, the development of lymphocytic infiltration of the thyroid was inhibited and induction of infiltrating T cells death was observed. These results show that FasL expression on thyrocytes may have a curative effect on ongoing EAT by inducing death of pathogenic autoreactive infiltrating T lymphocytes.
Bisindolylmaleimide VIII is known to potentiate Fas-mediated apoptosis in human astrocytoma 1321N1 cells and in Molt-4T cells; both of which were resistant to apoptosis induced by anti-Fas antibody in the absence of bisindolylmaleimide VIII. Potentiation of Fas-mediated apoptosis by bisindolylmaleimide VIII was reported to be selective for activated, rather than non-activated, T cells, and was Fas-dependent. Zhou T., et al., (Nat. Med. 5:42-48 (1999)) reported that administration of bisindolylmaleimide VIII to rats during autoantigen stimulation prevented the development of symptoms of T cell-mediated autoimmune diseases in two models, the Lewis rat model of experimental allergic encephalitis and the Lewis adjuvant arthritis model. Therefore, the application of a Fas-dependent apoptosis enhancer, such as bisindolylmaleimide VIII, may be therapeutically useful for the more effective elimination of detrimental cells and inhibition of T cell-mediated autoimmune diseases. Therefore, an effective amount of a compound, or a pharmaceutically acceptable salt or prodrug of the compound of Formulae I-Vc, which functions as a caspase cascade activator and inducer of apoptosis, is an effective treatment for autoimmune diseases.
Psoriasis is a chronic skin disease that is characterized by scaly red patches. Psoralen plus ultraviolet A (PUVA) is a widely used and effective treatment for psoriasis vulgaris. Coven, et al., Photodermatol. Photoimmunol. Photomed. 15:22-27 (1999), reported that lymphocytes treated with psoralen 8-MOP or TMP and UVA, displayed DNA degradation patterns typical of apoptotic cell death. Ozawa, et al., J. Exp. Med. 189:711-718 (1999) reported that induction of T cell apoptosis could be the main mechanism by which 312-nm UVB resolves psoriasis skin lesions. Low doses of methotrexate may be used to treat psoriasis to restore a clinically normal skin. Heenen, et al., Arch. Dermatol. Res. 290:240-245 (1998), reported that low doses of methotrexate may induce apoptosis and that this mode of action could explain the reduction in epidermal hyperplasia during treatment of psoriasis with methotrexate. Therefore, an effective amount of a compound, or a pharmaceutically acceptable salt or prodrug of the compound of Formulae I-Vc, which functions as a caspase cascade activator and inducer of apoptosis, is an effective treatment for hyperproliferative skin diseases, such as psoriasis.
Synovial cell hyperplasia is a characteristic of patients with rheumatoid arthritis (RA). It is believed that excessive proliferation of RA synovial cells, as well as defects in synovial cell death, may be responsible for synovial cell hyperplasia. Wakisaka, et al., Clin. Exp. Immunol. 114:119-128 (1998). found that although RA synovial cells could die via apoptosis through a Fas/FasL pathway, apoptosis of synovial cells was inhibited by proinflammatory cytokines present within the synovium. Wakisaka, et al. also suggested that inhibition of apoptosis by the proinflammatory cytokines may contribute to the outgrowth of synovial cells, and lead to pannus formation and the destruction of joints in patients with RA. Therefore, an effective amount of a compound, or a pharmaceutically acceptable salt or prodrug of the compound of Formulae I-Vc, which functions as a caspase cascade activator and inducer of apoptosis, is an effective treatment for rheumatoid arthritis.
There has been an accumulation of convincing evidence that apoptosis plays a major role in promoting resolution of the acute inflammatory response. Neutrophils are constitutively programmed to undergo apoptosis, thus limiting their pro-inflammatory potential and leading to rapid, specific, and non-phlogistic recognition by macrophages and semi-professional phagocytes (Savill, J., J. Leukoc. Biol. 61:375-380 (1997)). Boirivant, et al., Gastroenterology 116:557-565 (1999), reported that lamina propria T cells, isolated from areas of inflammation in Crohn's disease, ulcerative colitis, and other inflammatory states, manifest decreased CD2 pathway-induced apoptosis. In addition, studies of cells from inflamed Crohn's disease tissue indicate that this defect is accompanied by elevated Bcl-2 levels. Therefore, an effective amount of a compound, or a pharmaceutically acceptable salt or prodrug of the compound of Formulae I-Vc, which functions as a caspase cascade activator and inducer of apoptosis, is an effective treatment for inflammation.
Caspase cascade activators and inducers of apoptosis may also be a desirable therapy in the elimination of pathogens, such as HIV, Hepatitis C and other viral pathogens. The long lasting quiecence, followed by disease progression, may be explained by an anti-apoptotic mechanism of these pathogens leading to persistent cellular reservoirs of the virions. It has been reported that HIV-1infected T leukemia cells or peripheral blood mononuclear cells (PBMCs) underwent enhanced viral replication in the presence of the caspase inhibitor Z-VAD-fmk. Furthermore, Z-VAD-fmk also stimulated endogenous virus production in activated PBMCs derived from HIV-1-infected asymptomatic individuals (Chinnaiyan, A., et al., Nat. Med. 3:333 (1997)). Therefore, apoptosis serves as a beneficial host mechanism to limit the spread of HIV and new therapeutics using caspase/apoptosis activators are useful to clear viral reservoirs from the infected individuals. Similarly, HCV infection also triggers anti-apoptotic mechanisms to evade the host's immune surveillance leading to viral persistence and hepatocarcinogenesis (Tai, D. I., et al. Hepatology 3:656-64 (2000)). Therefore, apoptosis inducers are useful as therapeutics for HIV, HCV, HBV, and other infectious disease.
Stent implantation has become the new standard angioplasty procedure. However, in-stent restenosis remains the major limitation of coronary stenting. New approaches have been developed to target pharmacological modulation of local vascular biology by local administration of drugs. This allows for drug applications at the precise site and time of vessel injury. Numerous pharmacological agents with antiproliferative properties are currently under clinical investigation, including actinomycin D, rapamycin or paclitaxel coated stents (Regar E., et al., Br. Med. Bull. 59:227-248 (2001)). Therefore, apoptosis inducers, which are antiproliferative, are useful as therapeutics for the prevention or reduction of in-stent restenosis.
Another important aspect of the present invention is the surprising discovery that compounds of the present invention are potent and highly efficacious activators of caspase-3, inhibitors of tubulin polymerization, and inhibitors of topoisomerase even in drug resistant cancer cells, which enables these compounds to inhibit the growth and proliferation of drug resistant cancer cells, and to cause apoptosis and cell death in the drug resistant cancer cells. Specifically, the compounds of the present invention are not substrates for the MDR transporters such as Pgp-1 (MDR-1), MRP-1 and BCRP. This is particularly surprising in view of the fact that almost all of the commercially available tubulin-interacting chemotherapeutics are substrates for multidrug resistance transporters (MDRs).
Multidrug resistance is the major cause of chemotherapy failure. Drug resistance is typically caused by ATP-dependent efflux of drug from cells by ATP-binding cassette (ABC) transporters. In particular, the ABC transporters ABCB1 (MDR-1, P glycoprotein); ABCC1 (MRP1); and ABCG2 (BCRP, MXR) are typically over-expressed in drug resistant tumors and thus are implicated in drug resistance. In comparison to most standard anti-cancer drugs, which are not effective in killing drug resistant cancer cells, the compounds of the present invention are effective in killing drug resistant cancer cells. Therefore, compounds of this invention are useful for the treatment of drug resistant cancer.
Thus, another aspect of the present invention is the application of the methods and compounds of the present invention as described above to tumors that have acquired resistance to other anticancer drugs. In one embodiment, a compound of the present invention is administered to a cancer patient who has been treated with another anti-cancer drug. In another embodiment, a compound of the present invention is administered to a patient who has been treated with and is not responsive to another anti-cancer drug or developed resistance to such other anti-cancer compound. In another embodiment, a compound of the present invention is administered to a patient who has been treated with another anti-cancer drug and is refractory to said other anti-cancer drug. The compounds of the present invention can be used in treating cancer in a patient who is not responsive or is resistant to any other anti-cancer agent. Examples of such other anti-cancer agent may include alkylating agents, antimitotic agents, topo I inhibitors, topo II inhibitors, RNA/DNA antimetabolites, EGFR inhibitors, angiogenesis inhibitors, tubulin inhibitors (e.g., vinblastine, Taxol® (paclitaxel), and analogues thereof), proteosome inhibitors, etc., some of the exemplary compounds of which are provided above and are general known in the art, e.g., melphalan, chlorambucil, cyclophosamide, ifosfamide, vincristine, mitoguazone, epirubicin, aclarubicin, bleomycin, mitoxantrone, elliptinium, fludarabine, octreotide, retinoic acid, tamoxifen, Gleevec® (imatinib mesylate) and alanosine. The compounds can be used in treating patients having any type of diseases responsive to the inhibition of tubulin or inhibition of topoisomerase (including but not limited to the types of cancer described above) who are not responsive or become resistant to another therapeutic agent, e.g., another anti-cancer agent.
Pharmaceutical compositions within the scope of this invention include all compositions wherein the compounds of the present invention are contained in an amount that is effective to achieve its intended purpose. While individual needs vary, determination of optimal ranges of effective amounts of each component is within the skill of the art. Typically, the compounds may be administered to animals, e.g., mammals, orally at a dose of 0.0025 to 50 mg/kg of body weight, per day, or an equivalent amount of the pharmaceutically acceptable salt thereof, to a mammal being treated. Preferably, approximately 0.01 to approximately 10 mg/kg of body weight is orally administered. For intramuscular injection, the dose is generally approximately one-half of the oral dose. For example, a suitable intramuscular dose would be approximately 0.0025 to approximately 25 mg/kg of body weight, and most preferably, from approximately 0.01 to approximately 5 mg/kg of body weight. If a known cancer chemotherapeutic agent is also administered, it is administered in an amount that is effective to achieve its intended purpose. The amounts of such known cancer chemotherapeutic agents effective for cancer are well known to those skilled in the art.
The unit oral dose may comprise from approximately 0.01 to approximately 50 mg, preferably approximately 0.1 to approximately 10 mg of the compound of the invention. The unit dose may be administered one or more times daily, as one or more tablets, each containing from approximately 0.1 to approximately 10 mg, conveniently approximately 0.25 to 50 mg of the compound or its solvates.
In a topical formulation, the compound may be present at a concentration of approximately 0.01 to 100 mg per gram of carrier.
In addition to administering the compound as a raw chemical, the compounds of the invention may be administered as part of a pharmaceutical preparation containing suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the compounds into preparations that may be used pharmaceutically. Preferably, the preparations, particularly those preparations which may be administered orally and that may be used for the preferred type of administration, such as tablets, dragees, and capsules, and also preparations that may be administered rectally, such as suppositories, as well as suitable solutions for administration by injection or orally, contain from approximately 0.01 to 99 percent, preferably from approximately 0.25 to 75 percent of active compound(s), together with the excipient.
Also included within the scope of the present invention are the non-toxic pharmaceutically acceptable salts of the compounds of the present invention. Acid addition salts are formed by mixing a solution of the compounds of the present 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. Basic salts are formed by mixing a solution of the compounds 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 may be administered to any animal, which may experience the beneficial effects of the compounds of the invention. Foremost among such animals are mammals, e.g., humans and veterinary animals, although the invention is not intended to be 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, buccal, intrathecal, intracranial, intranasal or topical routes. Alternatively, or concurrently, administration may be by the oral route. The dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
The pharmaceutical preparations of the present invention are manufactured in a manner, which is itself known, e.g., by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes. Thus, pharmaceutical preparations for oral use may be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
Suitable excipients are, in particular: fillers, such as saccharides, e.g. lactose or sucrose, mannitol or sorbitol; cellulose preparations and/or calcium phosphates, e.g. tricalcium phosphate or calcium hydrogen phosphate; as well as binders, such as starch paste, using, e.g., maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, disintegrating agents may be added, such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are, above all, flow-regulating agents and lubricants, e.g., silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol. Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juices. For this purpose, concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropymethyl-cellulose phthalate, are used. Dye stuffs or pigments may be added to the tablets or dragee coatings, e.g., for identification or in order to characterize combinations of active compound doses.
Other pharmaceutical preparations, which may be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules may contain the active compounds in the form of: granules, which may be mixed with fillers, such as lactose; binders, such as starches; and/or lubricants, such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin. In addition, stabilizers may be added.
Possible pharmaceutical preparations, which may be used rectally include, e.g., suppositories, which consist of a combination of one or more of the active compounds with a suppository base. Suitable suppository bases are, e.g., natural or synthetic triglycerides, or paraffin hydrocarbons. In addition, it is also possible to use gelatin rectal capsules, which consist of a combination of the active compounds with a base. Possible base materials include, e.g., liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.
Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, e.g., 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 vehicles include fatty oils, e.g., sesame oil, or synthetic fatty acid esters, e.g., ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400), or cremophor, or cyclodextrins. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension include, e.g., sodium carboxymethyl cellulose, sorbitol, and/or dextran. Optionally, the suspension may also contain stabilizers.
In accordance with one aspect of the present invention, compounds of the invention are employed in topical and parenteral formulations and are used for the treatment of skin cancer.
The topical compositions of this invention are formulated preferably as oils, creams, lotions, ointments and the like by choice of appropriate carriers. Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohol (greater than C₁₂). The preferred carriers are those in which the active ingredient is soluble. Emulsifiers, stabilizers, humectants and antioxidants may also be included, as well as agents imparting color or fragrance, if desired. Additionally, transdermal penetration enhancers may be employed in these topical formulations. Examples of such enhancers are found in U.S. Pat. Nos. 3,989,816 and 4,444,762.
Creams are preferably formulated from a mixture of mineral oil, self-emulsifying beeswax and water in which mixture of the active ingredient, dissolved in a small amount of an oil, such as almond oil, is admixed. A typical example of such a cream is one which includes approximately 40 parts water, approximately 20 parts beeswax, approximately 40 parts mineral oil and approximately 1 part almond oil.
Ointments may be formulated by mixing a solution of the active ingredient in a vegetable oil, such as almond oil, with warm soft paraffin and allowing the mixture to cool. A typical example of such an ointment is one which includes approximately 30% almond oil and approximately 70% white soft paraffin by weight.
The following examples are illustrative, but not limiting, of the method and compositions of the present invention. Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered in clinical therapy and which are obvious to those skilled in the art are within the spirit and scope of the invention.

EXAMPLES

Example 1

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

a) 2,4-Dichloroquinazoline: A suspension of 2,4-quinazolinedione (5.0 g, 30.8 mmol) in neat phosphorylchloride (50 mL) was heated under reflux for 18 h. The reaction mixture was concentrated under vacuum. The crude product was purified by chromatography (Silica gel) using ethyl acetate and hexane (1:4) to give 2,4-dichloroquinazoline as white solid (4.8 g, 96%). ¹H NMR (CDCl₃): 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: A solution of 2,4-dichloroquinazoline (300 mg, 1.51 mmol) and 4-methoxy-N-methylaniline (248 mg, 1.81 mmol) in 5 ml isopropanol with a drop of concentrated HCl was stirred at room temperature for 8 h. White precipitates were observed in the reaction mixture. The reaction was filtered, and the solid was washed with isopropanol, and dried under vacuum to give white powder (260 mg, 87%). ¹H NMR (CDCl₃): 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

The title compound was prepared from 2,4-dichloroquinazoline (250 mg, 1.25 mmol) and 4-methyl-N-methylaniline (196 mg, 1.43 mmol) by a procedure similar to Example 1b and was isolated as white powder (210 mg, 84%). ¹H NMR (CDCl₃): 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

The title compound was prepared from 2,4-dichloroquinazoline (60 mg, 0.302 mmol) and 4-chloro-N-methylaniline (50 mg, 0.332 mmol) by a procedure similar to Example 1b and was isolated as white powder (30 mg, 50%). ¹H NMR (CDCl₃): 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-nitro-phenyl)-methyl-amine

The title compound was prepared from 2,4-dichloroquinazoline (50 mg, 0.251 mmol) and 4-nitro-N-methylaniline (46 mg, 0.302 mmol) by a procedure similar to Example 1b and was isolated as yellow powder (6 mg, 12%). ¹H NMR (CDCl₃): 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 5

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

The title compound was prepared from 2,4-dichloroquinazoline (50 mg, 0.251 mmol) and 4-trifluoromethoxy-N-methylaniline (20 μL, 0.302 mmol) by a procedure similar to Example 1b and was isolated as white powder (22 mg, 44%). ¹H NMR (CDCl₃): 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, 1H), 6.91 (d, J=8.7 Hz, 1H), 3.65 (s, 3H).

Example 6

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

The title compound was prepared from 2,4-dichloroquinazoline (50 mg, 0.251 mmol) and N-methylaniline (20 μL, 0.301 mmol) by a procedure similar to Example 1b and was isolated as white powder (40 mg, 80%). ¹H NMR (CDCl₃): 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, 1H), 6.90 (dd, J=8.7 and 1.5 Hz, 1H), 3.65 (s, 3H).

Example 7

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

The title compound was prepared from 2,4-dichloroquinazoline (50 mg, 0.251 mmol) and 4-methoxyaniline (45 mg, 0.326 mmol) by a procedure similar to Example 1b and was isolated as off white powder (55 mg, 77%). ¹H NMR (CDCl₃): 10.25 (s, 1H), 8.58 (d, J=8.4 Hz, 1H), 7.88 (t, J=7.2 Hz, 1H), 7.71-7.63 (m, 4H), 7.03-6.99 (m, 2H), 3.79 (s, 3H).

Example 8

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

The title compound was prepared from 2,4-dichloroquinazoline (50 mg, 0.251 mmol) and 4-methylaniline (32 mg, 0.30 mmol) by a procedure similar to Example 1b and was isolated as white powder (15 mg, 30%). ¹H NMR (CDCl₃): 7.97-7.89 (m, 3H), 7.71 (d, J=6.6 Hz, 2H), 7.64 (ddd, J=8.4, 6.6 and 2.1 Hz, 1H), 7.33 (d, J=6.6 Hz, 2H), 2.47 (s, 3H).

Example 9

2-Chloro-4-(5-methoxyindol-1-yl)quinazoline

The title compound was prepared from 2,4-dichloroquinazoline (50 mg, 0.251 mmol) and 5-methoxyindole (40 mg, 0.302 mmol) similar to Example 1b and was isolated as white powder (14 mg, 28%). ¹H NMR (CDCl₃): 8.91 (s, 1H), 8.70 (ddd, J=8.4, 2.8 and 1.5 Hz, 1H), 8.01 (ddd, J=8.4, 2.8 and 1.5 Hz, 1H), 7.92 (dd, J=6.9 and 1.5 Hz, 1H), 7.87 (m, 1H), 7.74 (d, J=2.4 Hz, 1H), 7.61 (ddd, J=8.4, 6.9 and 1.2 Hz, 1H), 7.37 (d, J=9.0 Hz, 1H), 6.97 (dd, J=9.0 and 2.4 Hz, 1H), 3.88 (s, 3H).

Example 10

N²-Hydroxyl-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine

A mixture of (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (15 mg, 0.050 mmol) and hydroxylamine hydrochloride (6.7 mg, 0.10 mmol) in isopropanol was heated by microwave at 130° C. for 20 min. The solvent was evaporated under reduced pressure. The product was isolated by preparative TLC as white solid (6 mg, 40%) using acetone:hexane (1:1) as eluent. ¹H NMR (CDCl₃): 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 11

N²-(2-Hydroxylethyl)-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine

The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (15 mg, 0.050 mmol) and 2-hydroxylethylamine (20 μL) by a procedure similar to Example 10 and was isolated as white solid (12 mg, 80%). ¹H NMR (CDCl₃): 7.43 (ddd, J=8.4, 1.5 and 0.9 Hz, 1H), 7.35 (ddd, J=7.8, 3.3 and 1.5 Hz, 1H), 7.12-7.06 (m, 2H), 6.92-6.90 (m, 2H), 6.84 (dd, J=8.4 and 1.5 Hz, 1H), 6.66 (ddd, J=7.2, 6.3 and 1.5 Hz, 1H), 3.91-3.89 (m, 2H), 3.83 (s, 3H), 3.69-3.65 (m, 2H), 3.48 (s, 3H).

Example 12

N⁴-(4-Methoxy-phenyl)-methyl-quinazoline-2,4-diamine

Title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (10 mg, 0.033 mmol) and 7 M ammonia in methanol (1 mL) by a procedure similar to Example 10 (5 mg, 50%). ¹H NMR (CDCl₃): 7.44 (m, 2H), 7.16 (m, 2H), 6.96-6.95 (m, 2H), 6.88 (dd, J=8.4 and 1.5 Hz, 1H), 6.72 (ddd, J=8.7, 6.6 and 1.8 Hz, 1H), 3.86 (s, 3H), 3.72 (s, 3H).

Example 13

N²-(3,7-Dimethyl-octa-2,6-dienyl)-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine

The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (45 mg, 0.151 mmol) and 3,7-dimethyl-2,6-diene-octamine (60 μL, 0.301 mmol) by a procedure similar to Example 10 and was isolated as white powder (15 mg, 33%). ¹H NMR (CDCl₃): 7.42 (d, J=8.1 Hz, 1H), 7.32 (ddd, J=8.7, 6.6 and 1.5 Hz, 1H), 7.12-7.07 (m, 2H), 6.91-6.85 (m, 3H), 6.65 (ddd, J=8.7, 6.6 and 1.5 Hz, 1H), 5.41 (t, J=7.5 Hz, 1H), 5.11 (ddd, J=6.6, 5.1 and 1.2 Hz, 1H), 4.15 (d, J=6.9 Hz, 2H), 3.85 (s, 3H), 3.50 (s, 3H), 2.12-2.03 (m, 4H), 1.75 (s, 3H), 1.70 (s, 3H), 1.61 (s, 3H).

Example 14

N⁴-(4-Methoxy-phenyl)-N⁴-methyl-N²-(2-morpholin-4-yl-ethyl)-quinazoline-2,4-diamine

The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (10 mg, 0.033 mmol) and 2-morpholin-4-yl-ethylamine (30 μL) by a procedure similar to Example 10 and was isolated as white powder (10 mg, 100%). ¹H NMR (CDCl₃): 7.42 (dd, J=8.7 and 1.2 Hz, 1H), 7.36 (ddd, J=8.1, 6.6 and 1.5 Hz, 1H), 7.10-7.09 (m, 2H), 6.92-6.86 (m, 3H), 6.67 (ddd, J=8.1, 6.6 and 1.4 Hz, 1H), 3.82 (s, 3H), 3.75-3.62 (m, 6H), 3.52 (s, 3H), 2.55-2.44 (m, 6H).

Example 15

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

The title compound was prepared 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 10 and was isolated as white powder (10 mg, 66%). ¹H NMR (CDCl₃): 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 16

N²-(3,7-Dimethyl-octa-2,6-dienyl)-N⁴-(4-methyl-phenyl)-N⁴-methyl-quinazoline-2,4-diamine

The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methyl-phenyl)-methyl-amine (50 mg, 0.177 mmol) and 3,7-dimethyl-2,6-diene-octamine (50 μL, 0.265 mmol) by a procedure similar to Example 10 and was isolated as white powder (7 mg, 14%). ¹H NMR (CDCl₃): 7.45 (d, J=8.1 Hz, 1H), 7.35 (ddd, J=8.1, 6.6 and 1.5 Hz, 1H), 7.16 (d, J=7.8 Hz, 2H), 7.06 (d, J=7.8 Hz, 2H), 6.91 (d, J=8.4 Hz, 1H), 6.66 (ddd, J=8.1, 6.6 and 1.5 Hz, 1H), 5.41 (dd, J=6.9 and 5.7 Hz, 1H), 5.11 (dd, J=5.7 and 4.2 Hz, 1H), 4.15 (t, J=6.9 Hz, 2H), 3.50 (s, 3H), 2.36 (s, 3H), 2.12-2.03 (m, 4H), 1.75 (s, 3H), 1.68 (s, 3H), 1.61 (s, 3H).

Example 17

N⁶-(4-Methoxy-phenyl)-N⁶-methyl-9H-purine-2,6-diamine

The title compound was prepared from 2-amino-6-chloro-9H-purine (100 mg, 0.546 mmol) and 4-methoxy-N-methyl-aniline (127 mg, 0.656 mmol) by a procedure similar to Example 1b and was isolated as white powder (5 mg, 5%). ¹H NMR (CDCl₃): 7.54 (s, 1H), 7.25 (d, J=8.7 Hz, 2H), 6.98 (d, J=8.7 Hz, 2H), 3.86 (s, 3H), 3.66 (s, 3H).

Example 18

N²,N⁴-Dimethyl-N²,N⁴-diphenyl-quinazoline-2,4-diamine

The title compound was prepared from 2,4-dichloroquinazoline (50 mg, 0.251 mmol) and N-methylaniline (40 μL, 0.401 mmol) by a procedure similar to Example 1b and was isolated as white powder (33 mg, 66%). ¹H NMR (CDCl₃): 7.54 (dd, J=8.2 and 0.6 Hz, 1H), 7.45 (dd, J=8.4 and 1. Hz, 1H), 7.44-7.29 (m, 6H), 7.21-7.10 (m, 4H), 6.86 (dd, J=8.4 and 0.9 Hz, 1H), 6.67 (ddd, J=8.4, 7.2 and 1.1 Hz, 1H), 3.69 (s, 3H), 3.33 (s, 3H).

Example 19

N²,N⁴-Bis(4-chloro-phenyl)-N²,N⁴-dimethyl-quinazoline-2,4-diamine

The title compound was prepared from 2,4-dichloroquinazoline (60 mg, 0.3.02 mmol) and 4-chloro-N-methylaniline (72 mg, 0.513 mmol) by a procedure similar to Example 1b and was isolated as white powder (50 mg, 83%). ¹H NMR (CDCl₃): 8.93 (d, J=8.4 Hz, 1H), 7.56 (t, J=7.5 Hz, 1H), 7.47-7.44 (m, 4H), 7.32-7.27 (m, 2H), 7.18-7.14 (m, 2H), 6.95 (t, J=7.5 Hz, 1H), 6.67 (d, J=8.4 Hz, 1H), 4.02 (s, 3H), 3.25 (s, 3H).

Example 20

(2-Chloro-6,7-dimethoxyquinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine

A mixture of 2,4-dichloro-6,7-dimethoxyquinazoline (100 mg, 0.386 mmol), 4-methoxy-N-methylaniline (55 mg, 0.401 mmol) and sodium acetate (60 mg, 0.732 mmol) in tetrahydrofuran (5 mL) and water (2.5 mL) was stirred at room temperature for 48 h. The reaction mixture was evaporated to dryness and the residue was crystallized using ethanol/water and isolated as white solid (60 mg, 60%). ¹H NMR (CDCl₃): 8.19 (s, 1H), 7.32-7.26 (m, 2H), 7.09-7.07 (m, 2H), 6.16 (s, 1H), 4.03 (s, 3H), 3.87 (s, 3H), 3.75 (s, 3H), 3.32 (s, 3H).

Example 21

(2-Chloro-6,7-dimethoxyquinazolin-4-yl)-(4-methoxy-phenyl)-amine

The title compound was prepared from 2,4-dichloro-6,7-dimetoxyquinazoline (100 mg, 0.386 mmol) and 4-methoxyaniline (49 mg, 0.386 mmol) by a procedure similar to Example 1b and was isolated as white powder (10 mg, 10%). ¹H NMR (CDCl₃): 8.10 (s, 1H), 7.70-7.68 (m, 2H), 7.23 (s, 1H), 6.96-6.94 (m, 2H), 4.07 (s, 3H), 3.99 (s, 3H), 3.85 (s, 3H).

Example 22

(2-Chloro-6,7-dimethoxyquinazolin-4-yl)-(4-methyl-phenyl)-methyl-amine

The title compound was prepared from 2,4-dichloro-6,7-dimetoxyquinazoline (100 mg, 0.386 mmol) and N-methyl-p-tolylamine (49 mg, 0.386 mmol) by a procedure similar to Example 1b and was isolated as white powder (8 mg, 8%). ¹H NMR (CDCl₃): 7.27 (d, J=8.4 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 7.08 (s, 1H), 6.26 (s, 1H), 3.92 (s, 3H), 3.61 (s, 3H), 3.28 (s, 3H), 2.37 (s, 3H).

Example 23

6,7-Dimethoxy-N⁴-(4-methoxy-phenyl)-N⁴-methyl-N²-(2-morpholin-4-yl-ethyl)-quinazoline-2,4-diamine

The title compound was prepared from (2-chloro-6,7-dimethoxyquinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (50 mg, 0.139 mmol) and 2-morpholin-4-yl-ethylamine (25 μL, 0.167 mmol) by a procedure similar to Example 10 and was isolated as white powder (27 mg, 54%). ¹H NMR (CDCl₃): 7.21 (d, J=8.4 Hz, 2H), 7.00 (d, J=8.4 Hz, 2H), 6.93 (s, 1H), 6.13 (s, 1H), 3.95 (s, 3H), 3.84 (s, 3H), 3.77-3.74 (m, 4H), 3.71-3.66 (m, 2H), 3.60 (s, 3H), 3.25 (s, 3H), 2.70 (t, J=7.2 Hz, 2H), 2.59-2.56 (m, 4H).

Example 24

6,7-Dimethoxy-N²-(3,7-dimethyl-octa-2,6-dienyl)-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine

The title compound was prepared from (2-chloro-6,7-dimethoxyquinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (60 mg, 0.167 mmol) and 3,7-dimethyl-2,6-diene-octamine (50 mg, 0.424 mmol) by a procedure similar to Example 10 and was isolated as white powder (68 mg, 85%). ¹H NMR (CDCl₃): 7.15 (d, J=8.4 Hz, 2H), 6.91 (d, J=8.4 Hz, 2H), 6.85 (s, 1H), 6.29 (s, 1H), 5.41 (dd, J=6.9 and 6.0 Hz, 1H), 5.12 (ddd, J=6.9, 5.1 and 4.2 Hz, 1H), 4.69 (t, J=4.5 Hz, 1H), 4.12 (t, J=5.7 Hz, 2H), 3.91 (s, 3H), 3.79 (s, 3H), 3.49 (s, 3H), 3.30 (s, 3H), 2.13-2.05 (m, 4H), 1.75 (s, 3H), 1.69 (s, 3H), 1.61 (s, 3H).

Example 25

(5,6,7,8-Tetrahydro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine

a) 4-Chloro-5,6,7,8-tetrahydroquinazoline: The title compound was prepared from 5,6,7,8-tetrahydro-4-quinazolinone (50 mg, 0.301 mmol) and phosphorylchloride (5 mL) by a procedure similar to Example 1a and was isolated as off white solid (20 mg, 40%). ¹H NMR (CDCl₃): 8.60 (s, 1H), 2.75 (m, 2H), 1.76 (m, 4H), 1.53 (m, 2H).
b) (5,6,7,8-Tetrahydro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine: The title compound was prepared from 4-chloro-5,6,7,8-tetrahydroquinazoline (20 mg, 0.099 mmol) and 4-methoxy-N-methylaniline (16 mg, 0.111 mmol) by a procedure similar to Example 1b and was isolated as white powder (25 mg, 83%). ¹H NMR (CDCl₃): 8.60 (s, 1H), 7.02-6.96 (m, 2H), 6.87-6.82 (m, 2H), 3.83 (s, 3H), 3.39 (s, 3H), 2.75 (t, J=6.6 Hz, 2H), 1.76 (m, 4H), 1.53 (m, 2H).

Example 26

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

The title compound was prepared from 2,4-dichloroquinazoline (50 mg, 0.251 mmol) and N-methyl-4-methoxybenzylamine (45 mg, 0.302 mmol) by a procedure similar to Example 1b and was isolated as white powder (30 mg, 60%). ¹H NMR (CDCl₃): 7.93 (dd, J=8.4 and 1.2 Hz, 1H), 7.78 (dd, J=8.4 and 1.5 Hz, 1H), 7.68 (ddd, J=8.4, 7.5 and 1.5 Hz, 1H), 7.34-7.26 (m, 3H), 6.96-6.92 (m, 2H), 4.94 (s, 2H), 3.83 (s, 3H), 3.31 (s, 3H).

Example 27

(2-Chloro-quinazolin-4-yl)-pyridin-4-yl-amine

To a stirred suspension of 2,4-dichloroquinazoline (42 mg, 0.21 mmol) and 4-aminopyridine (21 mg, 0.22 mmol) in 3 mL of anhydrous isopropanol was added a drop of concentrated HCl and the mixture was stirred overnight. Solid precipitates were observed and the mixture was filtered. The solid was washed with cold isopropanol and dried to give the title compound as white solid (38 mg, 0.13 mmol, 61%). ¹H NMR (DMSO-d₆): 8.60 (d, J=7.5 Hz, 2H), 8.18-8.20 (m, 2H), 8.07-8.10 (m, 1H), 7.90-7.96 (m, 1H), 7.18 (d, J=7.8 Hz, 2H).

Example 28

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

A mixture of 2,4-dichloroquinazoline (61 mg, 0.31 mmol), 5-amino-2-methoxy pyridine (40 mg, 0.32 mmol) and sodium acetate (38 mg, 0.46 mmol) in 3 mL of solvent (THF:water/1:1) was stirred at 60° C. for 45 min. The reaction mixture was diluted with 25 mL of ethyl acetate. It was washed with saturated NaCl, dried over anhydrous MgSO₄, filtered and concentrated. The crude product was purified by chromatography (40% ethyl acetate/hexanes) on silica gel to give the title compound (86 mg, 0.30 mmol, 98%). ¹H NMR (CDCl₃): 8.38 (d, J=3.0 Hz, 1H), 8.07 (dd, J=8.7 and 3.0 Hz, 1H), 7.89-7.79 (d, J=8.4 Hz, 1H), 7.86 (m, 2H), 7.59-7.53 (m, 2H), 6.84 (d, J=8.7 Hz, 1H), 3.96 (s, 3H).

Example 29

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

The title compound was prepared from 2,4-dichloroquinazoline and 2,3-dimethoxyaniline by a procedure similar to Example 28 (84% yield). ¹H NMR (CDCl₃): 8.57 (s, broad, 1H), 8.38 (d, J=8.4 Hz, 1H), 7.77-7.86 (m, 3H), 7.55-7.61 (m, 1H), 7.15 (t, J=8.7 Hz, 1H), 6.73-6.75 (m, 1H), 4.00 (s, 3H), 3.91 (s, 3H).

Example 30

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

The title compound was prepared from 2,4-dichloroquinazoline and 2,4-dimethoxyaniline by a procedure similar to Example 28 (92% yield). ¹H NMR (CDCl₃): 8.59 (d, J=8.7 Hz, 1H), 8.22 (s, broad, 1H), 7.75-7.81 (m, 3H), 7.52 (ddd, J=8.4, 6.6 and 2.1 Hz, 1H), 6.52-6.59 (m, 2H), 3.95 (s, 3H), 3.82 (s, 3H).

Example 31

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

The title compound was prepared from 2,4-dichloroquinazoline and 2,5-dimethoxyaniline by a procedure similar to Example 28 (98% yield). ¹H NMR (CDCl₃): 8.59 (d, J=3.0 Hz, 1H), 8.53 (s, broad, 1H), 7.78-7.87 (m, 3H), 7.57 (ddd, J=8.4, 6.6 and 1.8 Hz, 1H), 6.88 (d, J=9.0 Hz, 1H), 6.60 (dd, J=8.7 and 3.0 Hz, 1H), 3.97 (s, 3H), 3.87 (s, 3H).

Example 32

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

The title compound was prepared from 2,4-dichloroquinazoline and 3-methoxyaniline by a procedure similar to Example 28 (80% yield). ¹H NMR (CDCl₃): 7.79-7.87 (m, 3H), 7.54-7.62 (m, 3H), 7.20-7.35 (m, 3H), 6.76 (dd, J=8.4 and 2.1 Hz, 1H), 3.87 (s, 3H).

Example 33

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

The title compound was prepared from 2,4-dichloroquinazoline and 2-methoxyaniline by a procedure similar to Example 28 (35% yield). ¹H NMR (CDCl₃): 8.76-8.79 (m, 1H), 8.50 (s, broad, 1H), 7.77-7.88 (m, 3H), 7.54-7.59 (m, 1H), 7.09-7.13 (m, 2H), 6.95-6.99 (m, 2H), 4.00 (s, 3H).

Example 34

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

The title compound was prepared from 4-chloroquinazoline and 4-methoxy-N-methylaniline by a procedure similar to Example 28 (79% yield). ¹H NMR (CDCl₃): 8.81 (s, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.57 (ddd, J=8.1, 5.4 and 2.7 Hz, 1H), 7.09-7.14 (m, 2H), 7.03-7.06 (m, 2H), 6.9-6.93 (m, 2H).

Example 35

(4-Methyl-phenyl)-methyl-quinazolin-4-yl-amine

The title compound was prepared from 4-chloroquinazoline and 4-methyl-N-methylaniline by a procedure similar to Example 28 (80% yield). ¹H NMR (CDCl₃): 8.23 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.57 (ddd, J=8.4, 6.3 and 1.8 Hz, 1H), 7.17-7.20 (m, 2H), 7.00-7.10 (m, 4H), 3.61 (s, 3H), 2.39 (s, 3H).

Example 36

(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. was added methyl iodide (100 uL, 1.61 mmol), followed by sodium hydride (60% oil suspension, 5 mg, 0.13 mmol). The mixture was stirred at 0° C. for 1 h, then allowed to warm to room temperature and stirred for 1 h. The reaction mixture was quenched by adding 50 uL of water, diluted with 25 mL of ethyl acetate, washed with water (25 mL×3), saturated NaCl, dried over anhydrous MgSO₄, 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%). ¹H NMR (CDCl₃) 8.06 (d, J=2.7 Hz, 1H), 7.57-7.79 (m, 1H), 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, 1H), 6.82 (dd, J=8.7 and 0.6 Hz, 1H), 3.97 (s, 3H), 3.61 (s, 3H).

Example 37

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

a) Isopropyl-(4-methoxy-phenyl)-amine: To a stirred solution of p-methoxy-aniline (443 mg, 3.60 mmol) and acetone (265 uL, 3.61 mmol) in 10 mL of anhydrous methanol at room temperature was added a drop of glacial acetic acid followed by NaCNBH₃(226 mg, 3.60 mmol) portion wise over 0.5 h. The reaction mixture was then stirred for 3 h at room temperature. The solvents were removed under vacuum, and the residue was dissolved in 50 mL of ethyl acetate. The solution was washed with 5% NaHCO₃, saturated NaCl, dried over anhydrous MgSO4, filtered and concentrated. The crude was purified by chromatography (10% ethyl acetate/hexanes) to give the title compound (287 mg, 1.92 mmol, 48%). ¹H NMR (CDCl₃): 6.77 (d, J=8.7 Hz, 2H), 6.57 (d, J=6.7 Hz, 2H), 3.74 (s, 3H), 3.54 (m, 1H, J=6.3), 2.94 (s, broad, 1H), 1.92 (d, J=6.3 Hz, 6H).
b) (2-Chloro-quinazolin-4-yl)-isopropyl-(4-methoxy-phenyl)-amine: The title compound was prepared from isopropyl-(4-methoxy-phenyl)-amine and 2,4-dichloroquinazoline by a procedure similar to Example 27 (51% yield). ¹H NMR (DMSO-d₆): 8.30-8.34 (m, 1H), 8.17-8.22 (m, 1H), 8.05-8.08 (m, 1H), 7.90-7.96 (m, 1H), 7.77 (d, J=8.1 Hz, 2H), 1.09 (d, J=8.4 Hz, 2H), 3.62 (m, 1H), 3.79 (s, 3H), 1.24 (d, J=6.0 Hz, 6H).

Example 38

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

a) Cyclohexyl-(4-methoxy-phenyl)-amine: The title compound was prepared from cyclohexanone and p-methoxy aniline by a procedure similar to Example 37a (60% yield). ¹H NMR (CDCl₃): 6.76 (d, J=9.0 Hz, 2H), 6.57 (d, J=9.0 Hz, 2H), 3.75 (s, 3H), 3.16 (m, 1H), 2.34 (m, 1H), 1.61-1.89 (m, 5H), 1.05-1.42 (m, 5H).
b) (2-Chloro-quinazolin-4-yl)-cyclohexyl-(4-methoxy-phenyl)-amine: The title compound was prepared from cyclohexyl-(4-methoxy-phenyl)-amine and 2,4-dichloroquinazoline by a procedure similar to Example 27 (93% yield). ¹H NMR (DMSO-d₆): 8.32 (dd, J=8.4 and 1.5 Hz, 1H), 8.22 (ddd, J=8.4, 7.5 and 1.5 Hz, 1H), 8.05-8.09 (m, 1H), 7.93 (ddd, J=8, 6.9, 0.9 Hz, 1H), 7.45 (d, J=8.7 Hz, 2H), 7.08 (d, J=8.7 Hz, 2H), 3.27-3.34 (m, 1H), 1.89-1.92 (m, 2H), 1.73-1.76 (m, 2), 1.36-1.62 (m, 3H), 1.07-1.28 (m, 3H).

Example 39

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

The title compound was prepared from (2-chloro-quinazolin-4-yl)-(2,3-dimethoxy-phenyl)-amine and methyl iodide by a procedure similar to Example 36 (71% yield). ¹H NMR (CDCl₃): 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 40

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

The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-amine and ethyl iodide by a procedure similar to Example 36 (58% yield). ¹H NMR (CDCl₃): 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, 1H), 4.13 (q, J=7.2 Hz, 2H), 3.87 (s, 1H), 1.30 (t, J=6.9 Hz, 3H).

Example 41

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

The title compound was prepared from (2-chloro-quinazolin-4-yl)-(2,4-dimethoxy-phenyl)-amine and methyl iodide by a procedure similar to Example 36 (91% yield). ¹H NMR (CDCl₃): 7.70-7.73 (m, 1H), 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 42

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

The title compound was prepared from (2-chloro-quinazolin-4-yl)-(2,5-dimethoxy-phenyl)-amine and methyl iodide by a procedure similar to Example 36 (78% yield). ¹H NMR (CDCl₃): 7.72-7.75 (m, 1H), 7.56 (ddd, J=8.4, 5.7 and 2.1 Hz, 1H), 6.98-7.00 (m, 2H), 6.92-6.92 (m, 2H), 6.78-6.79 (m, 1H), 3.75 (s, 3H), 3,58 (s, 3H), 3.56 (s, 3H).

Example 43

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

The title compound was prepared from (2-chloro-quinazolin-4-yl)-(3-methoxy-phenyl)-amine and methyl iodide by a procedure similar to Example 36 (60% yield). ¹H NMR (CDCl₃): 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 44

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

The title compound was prepared from (2-chloro-quinazolin-4-yl)-(2-methoxy-phenyl)-amine and methyl iodide by a procedure similar to Example 36 (72% yield). ¹H NMR (CDCl₃): 7.72 (d, J=8.1 Hz, 1H), 7.54 (ddd, J=8.4, 6.6 and 1.5 Hz, 1H), 7.20 (dd, J=8.4 and 1.8 Hz, 1H), 6.87-7.04 (m, 4H), 3.67 (s, 3H), 3.56 (s, 3H).

Example 45

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

a) Cyclopentyl-(4-methoxy-phenyl)-amine: The title compound was prepared from cyclopentanone and p-methoxy aniline by a procedure similar to Example 37a (68% yield). ¹H NMR (CDCl₃): 6.78 (d, J=8.7 Hz, 2H), 6.57 (d, J=8.7 Hz, 2H), 3.74 (s, 3H), 3.18 (m, 1H), 2.23 (m, 1H), 1.82-2.01 (m, 2H), 1.52-1.73 (m, 4H), 1.38-1.49 (m, 2H).
b) (2-Chloro-quinazolin-4-yl)-cyclopentyl-(4-methoxy-phenyl)-amine: The title compound was prepared from cyclopentyl-(4-methoxy-phenyl)-amine and 2,4-dichloroquinazoline by a procedure similar to Example 27 (39% yield). ¹H NMR (CDCl₃): 8.31 (dd, J=8.7 and 1.3 Hz, 1H), 8.12 (ddd, J=8.4, 7.2 and 1.3 Hz, 1H), 8.12-8.08 (m, 1H), 7.93 (ddd, J=8.3, 7.2 and 1.3 Hz, 1H), 7.41 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.7 Hz, 2H), 3.24-3.33 (m, 1H), 2.22-2.01 (m, 2H), 1.51-1.75 (m, 4H), 1.32-1.49 (m, 2H).

Example 46

N²-[2-(1H-Imidazol-4-yl)-ethyl]-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine

The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methylamine (10 mg, 0.033 mmol) and histamine hydrochloride (16 mg, 0.10) by a procedure similar to Example 10 and was isolated as white solid (7 mg, 70%). ¹H NMR (CDCl₃): 7.52 (s, 1H), 7.49 (brd, J=3.9 Hz, 2H), 7.20-7.15 (m, 2H), 7.03-6.96 (m, 3H), 6.83 (ddd, J=8.4, 4.5 and 3.9 Hz, 1H), 6.66 (d, J=8.7 Hz, 1H), 3.88 (s, 3H), 3.85 (t, J=6.6 Hz, 2H), 3.63 (s, 3H), 3.03 (t, J=6.6 Hz, 2H).

Example 47

N²-(3-Dimethylamino-propyl)-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine

The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (15 mg, 0.050 mmol) and N¹,N¹-dimethyl-propane-1,3-diamine (16 μl, 0.070 mmol) by a procedure similar to Example 10 and was isolated as white powder (11 mg, 73%). ¹H NMR (CDCl₃): 7.43 (dd, J=8.4 and 1.2 Hz, 1H), 7.34 (ddd, J=7.8, 6.6 and 1.2 Hz, 1H), 7.11-7.07 (m, 2H), 6.89-6.86 (m, 3H), 6.65 (ddd, J=8.1, 6.6 and 1.2 Hz, 1H), 3.82 (s, 3H), 3.61 (t, J=6.9 Hz, 2H), 3.49 (s, 3H), 2.41 (t, J=6.9 Hz, 2H), 2.28 (s, 6H), 1.89 (m, 2H).

Example 48

N²-(2-Hydroxyethyl)-N⁴-(6-methoxypyridin-3-yl)-N⁴-methyl-quinazoline-2,4-diamine

The title compound was prepared from (2-chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine (12 mg, 0.040 mmol) and ethanolamine (28 μl) by a procedure similar to Example 10 and was isolated as off white solid (8 mg, 66%). ¹H NMR (CDCl₃): 8.03 (brd, J=3.0 Hz, 1H), 7.47-7.35 (m, 3H), 6.91 (brd, J=8.7 Hz, 1H), 6.78-6.73 (m, 2H), 5.56 (brs, 1H), 3.94 (s, 3H), 3.93-3.90 (m, 2H), 3.70-3.56 (m, 2H), 3.48 (s, 3H).

Example 49

N⁴-(6-methoxypyridin-3-yl)-N⁴-methyl-quinazoline-2,4-diamine

The title compound was prepared from (2-chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methylamine (10 mg, 0.030 mmol) and 7 M ammonia in methanol (1 mL) by a procedure similar to Example 10 (3 mg, 30%). ¹H NMR (CDCl₃): 8.04 (dd, J=2.9, 0.6 Hz, 1H), 7.49-7.43 (m, 2H), 7.39 (dd, J=5.7 and 2.7 Hz, 1H), 6.92 (brd, J=8.4 Hz, 1H), 6.85-6.78 (m, 2H), 5.65 (s, 2H), 3.96 (s, 3H), 3.54 (s, 3H).

Example 50

N²-(2-Hydroxyethyl)-N⁴-(4-methoxy-phenyl)-N⁴-methyl-6,7-dimethoxyquinazoline-2,4-diamine

The title compound was prepared from (2-Chloro-6,7-dimethoxyquinazolin-4-yl)-(4-methoxy-phenyl)-amine (26 mg, 0.079 mmol) and ethanolamine (30 μl) by a procedure similar to Example 10 and was isolated as white powder (14 mg, 54%). ¹H NMR (CDCl₃): 7.14 (dd, J=6.6 and 2.1 Hz, 2H), 6.91 (d, J=6.6 and 2.1 Hz, 2H), 6.81 (s, 1H), 6.25 (s, 1H), 3.90 (s, 3H), 3.92-3.88 (m, 2H), 3.80 (s, 3H), 3.69-3.65 (m, 2H), 3.49 (s, 3H), 3.28 (s, 3H).

Example 51

(2-Chloro-9H-purin-6-yl)-(4-methoxy-phenyl)-methyl-amine

The title compound was prepared from 2,6-dichloro-9H-purine (50 mg, 0.265) and 4-methoxy-N-methylaniline (40 mg, 0.291 mmol) by a procedure similar to Example 1b and was isolated as off white powder (10 mg, 20%). ¹H NMR (CDCl₃): 7.81 (s, 1H), 7.37 (d, J=8.4 Hz, 2H), 7.04 (d, J=8.4 Hz, 2H), 3.93 (s, 3H), 3.77 (s, 3H).

Example 52

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

The title compound was prepared from 2,4-dichloroquinazoline (30 mg, 0.152 mmol) and 4-methylamino-benzoic acid methyl ester (27 mg, 0.167 mmol) by a procedure similar to Example 1b and was isolated as off white powder (25 mg, 83%). ¹H NMR (CDCl₃): 8.08-8.04 (m, 2), 7.81 (ddd, J=8.4, 5.4 and 1.2 Hz, 1H), 7.62 (ddd, J=8.7, 3.9 and 1.8 Hz, 1H), 7.26-7.21 (m, 2H), 7.06 (ddd, J=8.4, 7.8 and 0.9 Hz, 1H), 6.99 (ddd, J=7.5, 1.2 and 0.9 Hz, 1H), 3.94 (s, 3H), 3.70 (s, 3H).

Example 53

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

To a solution of (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (50 mg, 0.167 mmol) in 2 ml methanol was added sodium methoxide (500 μl, 25% by wt. in methanol). The solution was stirred at 80° C. for 1 h, and it was diluted with 50 ml ethylacetate. The solution was washed with water, dried and concentrated. The product was purified using small silica column and isolated as off white solid (22 mg, 54%). ¹H NMR (CDCl₃): 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 54

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

To a solution of (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (100 mg, 0.334 mmol) in 30 ml dichloromethane cooled at −20° C. was added slowly 60 μl of BBr₃(0.668 mmol). The reaction mixture was stirred at −20° C. for 2 h then it was warmed to room temperature. It was stirred another 2 h at this temperature. 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 a small silica column using ethyl acetate and hexane (1:3) as eluents to give the product (57 mg, 57%). ¹H NMR (CDCl₃): 7.65-7.56 (m, 2H), 7.04-6.87 (m, 5H), 3.59 (s, 3H).

Example 55

(2-Fluoromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine
a) 2-Fluoromethyl-quinazolin-4(3H)-one: To a solution of 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 was added concentrated HCl (0.05 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 with saturated aqueous NaHCO₃to pH 7. The solution was extracted by ethyl acetate. The extracts were evaporated, and the residue was purified by column chromatography on silica gel with ethyl acetate and hexane (1:1) as eluent, yielding 70 mg (39%) of the title compound.
b) (2-Fluoromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine: A suspension of 2-fluoromethyl-quinazolin-4(3H)-one (70 mg, 0.39 mmol) in phosphoryl chloride (2 ml) and N,N-dimethylaniline (0.035 ml, 0.27 mmol) was heated under reflux for 12 hours. The reaction mixture was poured onto ice and the precipitate was collected by filtration, then washed and dried to give 4-chloro-2-fluoromethyl-quinazoline, which was used directly for the next reaction. To a solution of 4-chloro-2-fluoromethyl-quinazoline with (4-methoxy-phenyl)-methylamine (160 mg, 1.2 mmol) in isopropyl alcohol (5 ml) was added concentrated HCl (0.05 ml) and the solution was stirred at room temperature overnight. The solution was neutralized with saturated aqueous NaHCO₃, and was extracted by ethyl acetate. The extracts were evaporated, and the residue was purified by column chromatography on silica gel with ethyl acetate and hexane (1:1) as eluent, yielding 11 mg (9.5%) of the title compound. ¹H NMR (CDCl₃): 7.87-7.84 (m, 1H), 7.60-7.54 (m, 1H), 7.14-7.10 (m, 2H), 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 56

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

a) 6-Methyl-quinazoline-2,4-dione: To 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) was added acetic acid (0.5 mL). The mixture was stirred at room temperature for 24 h. A white solid was collected by vacuum filtration, washed with water, and dried in vacuo (0.736 g, 84%): ¹H NMR (DMSO-d₆) 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: The above 6-methyl-quinazoline-2,4-dione (201 mg, 1.14 mmol) and N,N-dimethylaniline (0.2 mL) were refluxed in phosphorus oxychloride (5 mL) under argon overnight. 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 at room temperature overnight. The solvent was evaporated and the residue was purified by column chromatography (SiO₂, EtOAc:hexanes 5-25%) to give the product as a light yellow solid (62 mg, 17%): ¹H NMR (CDCl₃) 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).
Compounds of EXAMPLES 57-64 were prepared in a manner similar to that of EXAMPLE 56.

Example 57

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

a) 7-Methyl-quinazoline-2,4-dione: White solid: ¹H NMR (DMSO-d₆) 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, 1H), 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: ¹H NMR (CDCl₃) 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, 3H), 2.38 (s, 3H).

Example 58

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

a) 5-Methyl-quinazoline-2,4-dione: Off-white solid: ¹H NMR (CDCl₃) 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: ¹H NMR (CDCl₃) 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 59

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

a) 8-Methyl-quinazoline-2,4-dione: Light brown solid: ¹H NMR (DMSO-d₆) 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: ¹H NMR (CDCl₃) 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 60

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

a) 6-Chloro-quinazoline-2,4-dione: white solid: ¹H NMR (DMSO-d₆) 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: ¹H NMR (CDCl₃) 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, 3H), 3.61 (s, 3H).

Example 61

6-Chloro-N²,N⁴-bis-(4-methoxy-phenyl)-N²,N⁴-dimethyl-quinazoline-2,4-diamine

The title compound was isolated from the reaction of Example 60. Yellow solid: ¹H NMR (CDCl₃) 7.41 (d, J=9.0 Hz, 1H), 7.35-7.30 (m, 2H), 7.29 (d, J=2.4 Hz, 1H), 7.26 (t, J=1.5 Hz, 1H), 7.09-7.04 (m, 2H), 6.94-6.80 (m, 5H), 6.72 (d, J=2.4 Hz, 1H), 3.84 (s, 3H), 3.83 (s, 3H), 3.62 (s, 3H), 3.27 (s, 3H).

Example 62

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

a) 7-Chloro-quinazoline-2,4-dione: White solid: ¹H NMR (DMSO-d₆) 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: ¹H NMR (CDCl₃) 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 63

5-Chloro-N²,N⁴-bis-(4-methoxy-phenyl)-N²,N⁴-dimethyl-quinazoline-2,4-diamine

a) 5-Chloro-quinazoline-2,4-dione: White solid: ¹H NMR (DMSO-d₆) 11.28 (s, 2H), 7.55 td (td, J=8.4, 0.6 Hz, 1H), 7.19 (d, J=7.8 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H).
b) 5-Chloro-N²,N⁴-bis-(4-methoxy-phenyl)-N²,N⁴-dimethyl-quinazoline-2,4-diamine: Yellow solid: ¹H NMR (CDCl₃) 7.43 (d, J=8.4 Hz, 1H), 7.32-7.26 (m, 3H), 6.93-6.88 (m, 2H), 6.81 (dd, J=1.2, 7.2 Hz, 1H), 6.75-6.65 (m, 4H), 3.83 (s, 3H), 3.73 (s, 3H), 3.61 (s, 3H), 3.33 (s, 3H).

Example 64

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

The title compound was isolated from the reaction of Example 63. White solid: ¹H NMR (CDCl₃) 7.45-7.36 (m, 2H), 7.26-7.21 (m, 2H), 7.13 (dd, J=2.1, 6.9 Hz, 1H), 6.94-6.89 (m, 2H), 5.09 (m, 1H), 3.85 (s, 3H), 3.57 (s, 3H), 1.30 (d, J=6.3 Hz, 6H).

Example 65

(Isoquinolin-1-yl)-(4-methoxy-phenyl)-methyl-amine

A mixture of 1-chloroisoquinoline (50 mg, 0.31 mmol) and (4-methoxy-phenyl)-methyl amine (300 mg, 2.2 mmol) was heated in a sealed tube at 140° C. overnight. The crude product was purified by chromatography (5-6% ethyl acetate/hexanes) on silica gel to give the title compound (46 mg, 0.17 mmol, 57%). ¹H NMR (CDCl₃): 8.22 (d, 1H, 5.7), 7.68 (d, 1H, J=8.1), 7.62 (d, 1H, J=8.7), 7.47 (ddd, 1H, J=0.9, 6.9, 8.1), 7.24 (d, 1H, J=6.0), 7.19 (ddd, 1H, J=1.5, 6.9, 8.7), 6.94 (m, 2H), 6.79 (m, 2H), 3.76 (s, 3H), 3.52 (s, 3H).

Example 66

(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 in a sealed tube at 140° C. overnight. The crude product was purified by chromatography (20-40% ethyl acetate/hexanes) on silica gel to give the title compound (60 mg, 0.23 mmol, 74%). ¹H NMR (CDCl₃): 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, 3H).

Example 67

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

a) (2-Chloro-quinazolin-4-yl)-(3,4-methylenedioxyphenyl)-amine: The title compound was prepared from 3,4-methylenedioxyphenylamine and 2,4-dichloroquinazoline by a procedure similar to Example 1b and was isolated as solids (45% yield). ¹H NMR (CDCl₃): 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, 1H, J=8.1), 6.01 (s, 2H).
b). (2-Chloro-quinazolin-4-yl)-(3,4-methylenedioxyphenyl)-methyl-amine: The title compound was prepared from (2-chloro-quinazolin-4-yl)-(3,4-methylenedioxyphenyl)-amine by a procedure similar to Example 36 and was isolated as solids (66% yield). ¹H NMR (CDCl₃): 7.73-7.76 (m, 1H), 7.58 (m, 1H), 7.07 (m, 2H), 6.82 (d, 1H, J=8.4), 6.72 (m, 1H), 6.68 (m, 1H), 6.06 (s, 2H), 3.59 (s, 3H).
Compounds of EXAMPLES 68-70 were prepared in a manner similar to that of EXAMPLE 67.

Example 68

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

a) (2-Chloro-quinazolin-4-yl)-(3,4-dimethoxy-phenyl)-amine: ¹H NMR (CDCl₃): 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: ¹H NMR (CDCl₃): 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, 3H), 3.63 (s, 3H).

Example 69

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

a) (2-Chloro-quinazolin-4-yl)-(4-phenoxy-phenyl)-amine: ¹H NMR (CDCl₃): 7.78-7.87 (m, 3H), 7.68-7.74 (m, 2H), 7.60 (s, broad, 1H), 7.56 (ddd, 1H, J=3.3, 9.9, 12.0), 7.33-7.39 (m, 2H), 7.03-7.16 (m, 5H).
b) (2-Chloro-quinazolin-4-yl)-(4-phenoxy-phenyl)-methyl amine: ¹H NMR (CDCl₃): 7.74-7.77 (m, 1H), 7.59 (ddd, 1H, J=1.5, 6.6, 8.4), 7.36-7.42 (m, 2H), 7.10-7.20 (m, 3H), 7.03-7.10 (m, 5H), 6.97-7.00 (m, 1H), 3.64 (s, 3H).

Example 70

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

a) (2-Chloro-quinazolin-4-yl)-(4-propoxy-phenyl)-amine: ¹H NMR (CDCl₃): 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: ¹H NMR (CDCl₃): 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 71

4-(4-Methoxy-phenoxy)-quinazoline

To a stirred solution of 4-methoxyphenol (75 mg, 0.60 mmol) and 4-chloro-quinazoline (125 mg, 76 mmol) in 3 mL of DMF was added sodium hydride (60% oil suspension, 30 mg, 0.75 mmol) at 0° C., then the reaction mixture was allowed to warm to room temperature and stirred for 5 h. The reaction was quenched by adding 50 uL of water and diluted with 25 mL of ethyl acetate. It was washed with water (25 mL×3), saturated NaCl, dried over anhydrous MgSO₄, filtered and concentrated. The residue was purified by chromatography (25% ethyl acetate/hexanes) to give the title compound (134 mg, 0.53 mmol, 89%). ¹H NMR (CDCl₃): 8.78 (s, 1H), 8.38 (m, 1H), 7.89-8.02 (m, 2H), 7.67 (m, 1H), 7.19 (m, 1H), 7.00 (m, 1H), 3.86 (s, 3H).

Example 72

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

a) 4-Chloro-2-methyl-quinazoline: A stirred suspension of 2-methyl-4(3H)-quinazolinone (5 g, 31.2 mmol) in POCl₃(100 mL) was heated at 120° C. for 3 h. The excess POCl₃was removed under vacuum, then to the residue was added crushed ice and 200 mL of saturated NaHCO₃, and the mixture was extracted with ethyl acetate (200 mL×2). The combined extracts were washed with water, saturated NaCl, dried over anhydrous MgSO₄, filtered and concentrated. The crude product was purified by column chromatography (5-8% ethyl acetate/hexane) to give the title compound (2.5 g, 14.0 mmol, 45%). ¹H NMR (CDCl₃): 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-quinazoline (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 and was isolated as solids (2.90 g, 9.18 mmol, 71%). ¹H NMR (CDCl₃): 8.53 (dd, 1H, J=0.6, 8.1), 7.7 (ddd, 1H, J=1.2, 7.2, 8.4), 7.22 (m, 2H), 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 73

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

a) 2-Chloromethyl-quinazolin-4(3H)-one: To a solution of 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 was added 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 with 2 N NaOH aqueous to pH 7. The precipitation was collected by filtration, then 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: A mixture of 2-chloromethyl-quinazolin-4(3H)-one (256 mg, 1.32 mmol), phosphoryl chloride (1.23 ml, 13.2 mmol) and N,N-dimethylaniline (0.34 ml, 2.64 mmol) in chloroform (10 ml) was heated under reflux for 4 h. The reaction mixture was poured onto ice and extracted by ethyl acetate. The solvent was evaporated, and the residue was purified by column chromatography on silica gel with acetate and hexane (1:1) as eluent, yielding 180 mg of 4-chloro-2-chloromethyl-quinazoline. The intermediate (170 mg, 0.80 mmol) and (4-methoxy-phenyl)-methylamine (131.7 mg, 0.96 mmol) in isopropyl alcohol (5 ml) with concentrated HCl (0.05 ml) was stirred at room temperature overnight. The precipitation was formed and collected by filtration, then washed and dried to give 231 mg (92%) of the title compound. ¹H NMR (CDCl₃): 7.82 (d, J=8.7 Hz, 1H), 7.59-7.53 (m, 1H), 7.15-7.12 (m, 2H), 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 74

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

The title compound was prepared in three steps by a procedure similar to Example 73. ¹H NMR (CDCl₃): 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 75

(2-Methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-amine

The title compound was prepared from 4-chloro-2-methyl-quinazoline (108 mg, 0.605 mmol) and 4-methoxy-phenylamine (89.4 mg, 0.73 mmol) by a procedure similar to Example 72b. ¹H NMR (DMSO-d₆): 11.28 (brs, 1H), 8.73 (d, J=8.4 Hz, 1H), 8.06 (t, J=7.5 Hz, 1H), 7.85-7.78 (m, 2H), 7.66 (d, J=9 Hz, 2H), 7.06 (d, J=8.7 Hz, 2H), 3.81 (s, 3H), 2.60 (s, 3H).

Example 76

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

To a solution of (2-chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine hydrochloride salt (67 mg, 0.19 mmol) in 1,4-dioxane (3 ml) was added 2 N NaOH aqueous (1 ml). The mixture was heated at 80° C. for 24 h and then was cooled to room temperature. The reaction mixture was diluted with ethyl acetate, then was washed with water and dried with NaSO₄. The solvent was evaporated, and the residue was purified by column chromatography on silica gel with acetate and hexane (1:1) as eluent, yielding 25 mg of title compound (44%). ¹H NMR (CDCl₃): 7.78-7.75 (m, 1H), 7.59-7.53 (m, 1H), 7.15-7.12 (m, 2H), 7.02-7.00 (m, 2H), 6.94-6.91 (m, 2H), 4.79 (s, 2H), 3.85 (s, 3H), 3.59 (s, 3H).

Example 77

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

The title compound was prepared from (2-chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine and dimethylamine by a procedure similar to Example 76. ¹H NMR (DMSO-d₆): 7.71 (d, J=8.7 Hz, 1H), 7.60 (t, J=8.4 Hz, 1H), 7.20 (d, J=8.4 Hz, 2H), 7.09 (t, J=8.1 Hz, 1H), 7.00-6.96 (m, 3H), 3.78 (s, 3H), 3.63 (s, 2H), 3.50 (s, 3H), 2.33 (s, 6H).

Example 78

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

A mixture of 4-chloro-2-methyl-quinazoline (450 mg, 2.52 mmol), 4-difluoromethoxy-phenylamine (0.32 ml, 2.52 mmol) and sodium acetate (248.07 mg, 3.02 mmol) in 6 mL of solvent (THF:water=1:1) was stirred at 70° C. for 1 h. The reaction mixture was diluted with 30 mL of ethyl acetate. It was washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated. The crude product was purified by chromatography on silica gel with acetate and hexane (1:5) as eluent, yielding 713 mg of title compound (94%). ¹H NMR (CDCl₃): 7.87-7.76 (m, 5H), 7.51 (t, J=8.4 Hz, 1H)), 7.40 (brs, 1H), 7.19 (d, J=8.7 Hz, 2H), 6.76-6.27 (three single peaks, 1H), 2.71 (s, 3H).

Example 79

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

The title compound was prepared from 4-chloro-2-methyl-quinazoline (150 mg, 0.84 mmol), 3-fluoro-4-methoxy-phenylamine (118.5 mg, 0.84 mmol) by a procedure similar to Example 78. ¹H NMR (CDCl₃): 7.89-7.75 (m, 4H), 7.53-7.48 (m, 1H)), 7.38-7.34 (m, 2H), 7.0 (t, J=8.7 Hz, 1H), 3.92 (s, 3H), 2.71 (s, 3H).

Example 80

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

The title compound was prepared from 4-chloro-2-methyl-quinazoline (100 mg, 0.56 mmol), 4-isopropoxy-phenylamine (84.66 mg, 0.56 mmol) by a procedure similar to Example 78. ¹H NMR (CDCl₃): 7.84-7.72 (m, 3H), 7.70-7.66 (m, 2H)), 7.50-7.45 (m, 1H), 7.30 (brs, 1H), 6.96-6.93 (m, 2H), 4.59-4.51 (m, 1H), 2.68 (s, 3H), 1.36 (d, J=6.3 Hz, 6H).

Example 81

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

The title compound was prepared from 4-chloro-2-methyl-quinazoline (100 mg, 0.56 mmol), 4-ethyl-phenylamine (0.07 ml, 0.56 mmol) by a procedure similar to Example 78. ¹H NMR (CDCl₃): 7.85-7.78 (m, 2H), 7.76-7.71 (m, 3H)), 7.49 (t, J=7.5 Hz, 1H), 7.36 (brs, 1H), 7.24 (s, 2H), 2.70-2.69 (m, 5H), 1.26 (t, J=7.5 Hz, 3H).

Example 82

(2-Methyl-quinazolin-4-yl)-(2,4,6-trimethoxy-phenyl)-amine

The title compound was prepared from 4-chloro-2-methyl-quinazoline (89.3 mg, 0.5 mmol), 2,4,6-trimethoxy-phenylamine (91.6 mg, 0.5 mmol) by a procedure similar to Example 78. ¹H NMR (CDCl₃): 7.86 (d, J=8.4 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.71 (t, J=6.6 Hz, 1H), 7.41 (t, J=8.1 Hz, 1H), 6.81 (brs, 1H), 6.25 (s, 2H), 3.87 (s, 3H), 3.79 (s, 6H), 2.57 (s, 3H).

Example 83

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

The title compound was prepared from (4-methoxy-phenyl)-(2-phenyl-quinazolin-4-yl)-amine (51 mg, 0.16 mmol) and methyl iodide (0.07 ml, 1.09 mmol) by a procedure similar to Example 36. ¹H NMR (CDCl₃): 8.64-8.61 (m, 2H), 7.90 (d, J=8.4 Hz, 1H), 7.59-7.48 (m, 4H), 7.18-7.14 (m, 2H), 7.08-6.98 (m, 2H), 6.94-6.91 (m, 2H), 3.85 (s, 3H), 3.73 (s, 3H).

Example 84

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

The title compound was prepared from (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 procedure similar to Example 36 (40.8% yield). ¹H NMR (CDCl₃): 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 85

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

The title compound was prepared from (3-fluoro-4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine (250 mg, 0.88 mmol) and methyl iodide (0.39 ml, 6.18 mmol) by a procedure similar to Example 36. ¹H NMR (CDCl₃): 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, 3H).

Example 86

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

The title compound was prepared from (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 procedure similar to Example 36. ¹H NMR (CDCl₃): 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=6Hz, 6H).

Example 87

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

The title compound was prepared 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 procedure similar to Example 36. ¹H NMR (CDCl₃): 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, 3H), 2.73-2.63 (m, 5H), 1.26 (d, J=7.5 Hz, 3H).

Example 88

(2-Methyl-quinazolin-4-yl)-(2,4,6-trimethoxy-phenyl)-methyl-amine

The title compound was prepared from (2-methyl-quinazolin-4-yl)-(2,4,6-trimethoxy-phenyl)-amine (56 mg, 0.17 mmol) and methyl iodide (0.1 ml, 1.6 mmol) by a procedure similar to Example 36. ¹H NMR (CDCl₃): 7.70 (d, J=8.4 Hz, 1H), 7.49 (t, J=7.8 Hz, 1H), 7.09 (d, J=8.7 Hz, 1H), 6.93 (t, J=8.1 Hz, 1H), 6.18 (s, 2H), 3.86 (s, 3H), 3.63 (s, 6H), 3.44 (s, 3H), 2.70 (s, 3H).
Compounds of EXAMPLES 89-90 were prepared by a procedure similar to that of EXAMPLE 56.

Example 89

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

a) 8-Chloro-1H-quinazoline-2,4-dione: White solid: ¹H NMR (DMSO-d₆) 11.47 (s, 1H), 10.77 (s, 1H), 7.88 (m, 1H), 7.78 (m, 1H), 7.18 (m, 1H).
b) (2,8-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine: Off-white solid: ¹H NMR (CDCl₃) 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 90

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

a) 5-Chloro-1H,3H-quinazoline-2,4-dione: White solid: ¹H NMR (DMSO-d₆) 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: ¹H NMR (CDCl₃) 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 91

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

a) 5-Methoxy-2-methyl-quinazolin-4-ol: To a suspension of 2-amino-6-methoxy-benzoic acid (305 mg, 1.82 mmol) and 4-N,N-dimethylaminopyridine (20 mg, 0.16 mmol) in DMF/toluene (2:6 mL) at 0° C. was added triethylamine (1.1 mL, 7.9 mmol) followed by 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 h. The solid was collected by filtration, washed with water, and dried to give an off-white solid (103 mg, 30%): ¹H NMR (CDCl₃) 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: The title compound was prepared by a procedure similar to that of Example 56b as white solid: ¹H NMR (CDCl₃) 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 92

(4-Methoxy-phenyl)-(2-methyl-pyrido[2,3-d]pyrimidin-4-yl)-methyl-amine

a) 2-Methyl-pyrido[2,3-d]pyrimidin-4-ol: To a solution of 2-amino-nicotinic acid (277 mg, 2 mmol), 4-N,N-dimethylaminopyridine (20 mg, 0.16 mmol), triethylamine (1.1 mL, 7.9 mmol) in DMF (2 mL) was added acetyl chloride (0.35 mL, 4.9 mmol) slowly at 0° C. under argon. The white precipitate was formed immediately. The mixture was then heated at 90° C. for 3.5 h, then ammonium acetate (0.601 g, 7.8 mmol) was added. The mixture was stirred for 1 h, cooled to rt and diluted with water (20 mL). It was extracted with EtOAc (2×50 mL), and the extracts were dried over MgSO₄, and evaporated. The crude was purified by column chromatography (SiO₂, EtOAc:MeOH/0-10%) to give an off-white solid (47 mg, 16%): ¹H NMR (DMSO-d₆) 11.40 (s, 1H), 9.01 (dd, J=2.1, 4.8 Hz, 1H), 8.61 (dd, J=2.4, 8.1 Hz, 1H), 7.44 (dd, J=4.8, 8.1 Hz, 1H), 2.66 (s, 3H).
b) (4-Methoxy-phenyl)-(2-methyl-pyrido[2,3-d]pyrimidin-4-yl)-methyl-amine: To a solution of 2-methyl-pyrido[2,3-d]pyrimidin-4-ol (47 mg, 0.32 mmol) in toluene (2 mL) was added phosphorus oxychloride (0.05 mL, 0.55 mmol) and diisopropylethyl amine (0.12 mL, 0.69 mmol). The solution was stirred at rt for 25 h, then (4-methoxy-phenyl)-methylamine (45 mg, 0.33 mmol) was added. The reaction mixture was stirred at rt for 22 h. The solvent was evaporated and the crude was purified by column chromatography (SiO₂, EtOAc:hexanes/30-100%). The product was collected as an off-white solid (6 mg, 7%): ¹H NMR (CDCl₃) 8.22 (dd, J=2.1, 4.5 Hz, 1H), 7.24 (d, J=2.1 Hz, 1H), 7.15-7.10 (m, 2H), 6.96-6.92 (m, 2H), 6.88 (dd, J=4.2, 8.4 Hz, 1H), 3.85 (s, 3H), 3.60 (s, 3H), 2.05 (s, 3H).

Example 93

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

To a solution of (4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine hydrochloride salt (106 mg, 0.336 mmol) in dichloromethane (10 mL) at −78° C. was added slowly boron tribromide (1M in CH₂Cl₂, 0.75 mL) under argon. The cold bath was removed and the reaction mixture was allowed to warm up slowly to 10° C. in 1.5 h. The reaction mixture was quenched with water (10 mL), basified with 2N NaOH to pH=10, and extracted with EtOAc (2×25 mL). The EtOAc extracts were dried and evaporated to give a light brown residue. The crude was purified by column chromatography (SiO₂, EtOAc:hexanes/15-50%) to give the product as a white solid, which was further purified by recrystallization from MeOH: ¹H NMR (acetone-d₆) 8.74 (s, 1H), 7.75 (m, 1H), 7.67 (m, 1H), 7.20-7.18 (m, 3H), 7.12 (m, 1H), 7.04-6.99 (m, 2H), 3.64 (s, 3H), 2.79 (s, 3H).

Example 94

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

The title compound was prepared from 2,4-dichloroquinazoline and 4-ethoxyaniline by a procedure similar to Example 28 (32%). ¹H NMR (CDCl₃): 7.81 (m, 1H), 7.65 (m, 1H), 7.32 (m, 2H), 7.03 (m, 1H), 6.73 (m, 3H), 4.09 (q, J=7.2, 2H), 1.49 (t, J=7.2, 3H).

Example 95

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

The title compound was prepared from 4-chloro-2-methylquinazoline and 3-amino-5-methoxypyridine by a procedure similar to Example 28 (32%). ¹H NMR (CDCl₃): 8.51 (d, J=1.8, 1H), 8.12 (m, 1H), 7.72-7.89 (m, 3H), 7.49 (m, 2H), 6.81 (d, J=8.7, 1H), 3.89 (s, 3H), 2.68 (s, 3H).

Example 96

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

The title compound was prepared from 4-chloro-2-methylquinazoline and 2-fluoro-4-methoxyaniline by a procedure similar to Example 28 (79%). ¹H NMR (CDCl₃): 8.54 (m, 1H), 7.83 (m, 2H), 7.65 (m, 1H), 7.50 (m, 1H), 7.47 (s, broad, 1H), 6.74-6.81 (m, 2H), 3.83 (s, 3H), 2.70 (s, 3H).

Example 97

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

The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-ethoxy-phenyl)-amine by a procedure similar to Example 36 (28%). ¹H NMR (CDCl₃): 7.73 (m, 1H), 7.55 (m, 1H), 7.12 (m, 2H), 7.00 (m, 1H), 6.93 (m, 3H), 4.07 (q, J=7.2, 2H), 3.61 (s, 3H), 1.46 (t, J=7.2, 3H).

Example 98

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

The title compound was prepared from (2-methyl-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-amine by a procedure similar to Example 36 (28%). ¹H NMR (CDCl₃): 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 99

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

The title compound was prepared from (2-methyl-quinazolin-4-yl)-(2-fluoro-4-methoxy-phenyl)-amine by a procedure similar to Example 36 (51%). ¹H NMR (CDCl₃): 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 100

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

To a solution of 4-chloro-2-methylquinazoline (1.4 g, 7.84 mmol) and (4-nitro-phenyl)-methylamine (1.09 g, 7.16 mmol) in 20 mL of dimethylformamide cooled to 0° C. was added sodium hydride (0.6 g, 60 oil suspension, 15 mmol). The reaction mixture was stirred at 0° C. for 1 h and quenched by adding 200 uL of water. It was diluted with 150 mL of ethyl acetate, washed with water (100 mL×3), saturated NaCl, dried over anhydrous MgSO₄, filtered and concentrated. The residue was purified by chromatography (30% ethyl acetate/hexanes) to give the title compound (1.41 g, 4.78 mmol, 67%). ¹H NMR (CDCl₃): 8.14 (m, 2H), 7.91 (m, 1H), 7.71 (ddd, J=8.4, 6.6, 1.8, 1H), 7.19-7.32 (m, 2H), 7.05 (m, 2H), 3.76 (s, 3H), 2.82 (s, 3H).

Example 101

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

A mixture of (2-methyl-quinazolin-4-yl)-(4-nitro-phenyl)-methylamine (200 mg, 0.68 mmol) in 25 mL of ethyl acetate was hydrogenated over Palladium on carbon (70 mg) at 50 psi for 4 h, and the reaction mixture was filtered through a pad of celite and concentrated. The resulting crude product was purified by chromatography (50% ethyl acetate/hexane) to obtain the title compound (140 mg, 78%). ¹H NMR (CDCl₃): 7.71 (m, 1H), 7.51 (ddd, J=8.4, 6.9, 1.5, 1H), 7.09 (m, 1H), 6.93-7.05 (m, 3H), 6.68 (m, 2H), 3.74 (s, broad, 2H), 3.56 (s, 3H), 2.71 (s, 3H).

Example 102

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

To a solution of (2-methyl-quinazolin-4-yl)-(4-amino-phenyl)-methylamine (20 mg, 0.076 mmol) in 1.2 mL of 1N HCl was added 100 uL of methanol and it was cooled 0° C. One drop of concentrated HCl was added and the solution was stirred at 0° C. for 0.25 h. To the solution was added dropwise a solution of sodium nitrite (25 mg, 0.36 mmol) in 200 uL of water. The reaction mixture was stirred for 0.5 h, then was added a solution of sodium azide (25 mg, 0.38 mmol) in 300 uL of water followed by another batch of sodium azide (25 mg, 0.38 mmol). The reaction mixture was stirred at the 0° C. for 1 h. The reaction mixture was diluted with 50 mL of ethyl acetate, washed with saturated sodium bicarbonate followed by saturated sodium chloride. The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (20-25% ethyl acetate/hexanes) on silica gel to give the title compound (19.8 mg, 0.068 mmol, 90%). ¹H NMR (CDCl₃): 7.76 (m, 1H), 7.56 (ddd, J=8.1, 6.3, 1.8, 1H), 7.13 (m, 2H), 6.98-7.13 (m, 4H), 3.61 (s, 3H), 2.74 (s, 3H).

Example 103

(4-Amino-2,6-dibromo-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine and

Example 104

(4-Amino-2-bromo-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine

To a mixture of (2-methyl-quinazolin-4-yl)-(4-amino-phenyl)-methylamine (53 mg, 0.20 mmol) in 1.8 mL of glacial acetic acid cooled at 12° C. was added dropwise a solution of Bromine (64 mg, 0.40 mmol) in 1 mL of glacial acetic acid. The mixture was stirred for 1 min and the reaction mixture was quenched by adding 1 mL of saturated sodium thiosulfate. The reaction mixture was diluted with 50 mL of ethyl acetate, and the organic layer was washed with saturated sodium bicarbonate. The organic layer was dried over anhydrous MgSO₄, filtered and concentrated. The residue was purified by chromatography (25-30% ethyl acetate/hexanes) to give the two compounds. (2-Methyl-quinazolin-4-yl)-(4-amino-2,6-dibromo-phenyl)-methyl-amine (17.5 mg, 0.041 mmol, 21%). ¹H NMR (CDCl₃): 7.78 (m, 1H), 7.58 (ddd, J=8.1, 6.6, 1.2, 1H), 7.24-7.27 (m, 2H), 7.15-7.19 (m, 1H), 7.09 (m, 1H), 4.62 (s, broad, 2H), 3.54 (s, 3H), 2.72 (s, 3H) and (2-methyl-quinazolin-4-yl)-(4-amino-2-bromo-phenyl)-methyl-amine. (15 mg, 0.045 mmol, 22%). ¹H NMR (CDCl₃): 7.75 (m, 1H), 7.55 (ddd, J=8.4, 6.9, 1.5, 1H), 7.31 (d, J=2.7, 1H), 7.13 (m, 1H), 7.03 (ddd, J=8.1, 6.9, 1.2, 1H), 6.91 (dd, J=8.1, 2.1, 1H), 6.74 (d, J=8.7, 1H), 4.18 (s, broad, 2H), 3.55 (s, 3H), 2.72 (s, 3H).

Example 105

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

To 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 of glacial acetic was added Sodium cyanoborohydride (15 mg, 0.24 mmol) and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched by adding 50 uL of 1N HCl. It was diluted with 50 mL of ethyl acetate, washed with saturated sodium bicarbonate, and followed by saturated sodium chloride. The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (25% ethyl acetate/hexanes) on silica gel to give the title compound (12.4 mg, 0.042 mmol, 80%). ¹H NMR (CDCl₃): 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 106

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

The title compound was prepared from 4-chloro-2-methylquinazoline and 4-ethoxyaniline by a procedure similar to Example 28 (93%). ¹H NMR (CDCl₃): 7.83 (m, 1H), 7.81 (m, 1H), 7.42 (m, 1H), 7.65-7.71 (m, 2H), 7.46 (ddd, J=8.4, 6.9, 1.5, 1H), 7.37 (s, broad, 1H), 6.92-6.97 (m, 2H), 4.06 (q, J=6.9, 2H), 2.68 (s, 3H), 1.43 (t, J=6.9, 3H).

Example 107

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

The title compound was prepared from (2-methyl-quinazolin-4-yl)-(4-ethoxy-phenyl)-amine by a procedure similar to Example 36 (67%). ¹H NMR (CDCl₃): 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 108

(4-Methoxy-phenyl-2,3,5,6-d4)-(2-methyl-quinazolin-4-yl)-methyl-amine

a) (4-Methoxy-phenyl-2,3,5,6-d₄)-methylacetamide. To a solution of (4-hydroxy-phenyl-2,3,5,6-d₄)-acetamide (0.410 g, 2.46 mmol) in 15 mL of dimethylformamide was added methyl iodide (1 mL, 16.1 mmol) and the solution was cooled to 0° C., then sodium hydride (0.25 g, 60% oil suspension, 6.3 mmol) was added, and the mixture was stirred for 2 h at 0° C. The reaction mixture was quenched by addition of 100 uL of water, and diluted with 100 mL of ethyl acetate. It was washed with water (100 mL×3), saturated NaCl, dried over anhydrous MgSO₄, filtered and concentrated. The residue was purified by chromatography (50% ethyl acetate/hexanes) to give the title compound (0.380 g, 1.93 mmol, 78%). ¹H NMR (CDCl₃): 3.83 (s, 3H), 3.23 (s, 3H), 1.86 (s, 3H).
b) (4-Methoxy-phenyl-2,3,5,6-d₄)-methylamine. A mixture of (4-methoxy-phenyl-2,3,5,6-d₄)-methylacetamide (280 mg, 1.41 mmol) in 15 mL of 2N HCl was refluxed for 4 h. The reaction mixture was cooled to 0° C., basified using cold 2N NaOH and extracted with ethyl acetate (50 mL×2). The combined organic extracts were washed with saturated NaCl, dried over anhydrous MgSO₄, filtered and concentrated. The residue was purified by chromatography (20% ethyl acetate/hexanes) to give the title compound (199 mg, 1.28 mmol, 90%). ¹H NMR (CDCl₃): 3.75 (s, 3H), 3.22 (s, broad, 1H), 2.80 (s, 3H).
c) (4-Methoxy-phenyl-2,3,5,6-d₄)-(2-methyl-quinazolin-4-yl)-methyl-amine. The title compound was prepared from 4-chloro-2-methylquinazoline and (4-methoxy-phenyl-2,3,5,6-d₄)-methylamine by a procedure similar to Example 28 (65%). ¹H NMR (CDCl₃): 7.73 (m, 1H), 7.52 (ddd, J=8.4, 6.3, 1.8, 1H), 6.93-7.03 (m, 2H), 3.84 (s, 3H), 3.59 (s, 3H), 2.71 (s, 3H).

Example 109

(4-Methoxy-phenyl)-(2-methyl-6-nitro-quinazolin-4-yl)-methyl-amine

a) 2-Methyl-6-nitro-4H-benzo[d][1,3]oxazin-4-one. A mixture of 2-amino-5-nitrobenzoic acid (2.0 g, 10.9 mmol) in 20 mL of acetic anhydride was refluxed for 2 h. The reaction mixture was cooled to room temperature and the resulting precipitate was collected and washed with cold diethylether and dried under vacuum to obtain the title compound (1.45 g, 7.01 mmol, 64%). ¹H NMR (CDCl₃): 9.05 (d, J=2.4, 1H), 8.61 (dd, J=9.0, 2.7, 1H), 7.71 (d, J=7.9, 1H), 2.55 (s, 3H).
b) 2-Methyl-6-nitro-quinazoline-4-one. A solution of 2-methyl-6-nitro-4H-benzo[d][1,3]oxazin-4-one (200 mg, 0.97 mmol) in a solution of ammonia in dioxane (0.5 M, 2.5 mL, 1.25 mmol) was heated at 70° C. for 4 h in a sealed tube. The reaction mixture was cooled to room temperature, and the resulting precipitate was collected and washed with cold diethylether and dried. The crude product was used for the next step.
c) 4-Chloro-2-methyl-6-nitro-quinazoline. A mixture of 2-methyl-6-nitro-quinazoline-4-one (100 mg, 0.49 mmol) and diisopropylethylamine (250 uL) in 3 mL of toluene was heated to 120° C. for 1 h, then phosphorylchloride (50 uL, 0.54 mmol) was added and the mixture was heated at 80° C. for 3 h. The reaction mixture was cooled to room temperature and poured into ice (about 15 g), basified with saturated NaHCO₃and extracted with 75 mL of ethyl acetate. The organic layer was washed with water (50 mL), 1N citric acid (50 mL), water (50 mL) and saturated NaCl, dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (15% ethyl acetate/hexanes) on silica gel to give the title compound (65.5 mg, 0.29 mmol, 60%). ¹H NMR (CDCl₃): 9.17 (d, J=2.4, 1H), 8.69 (dd, J=9.3, 2.4, 1H), 8.13 (d, J=9.3, 1H), 2.93 (s, 3H).
d) (4-Methoxy-phenyl)-(2-methyl-6-nitro-quinazolin-4-yl)-methyl-amine. The title compound was prepared from 4-chloro-2-methyl-6-nitro-quinazoline and (4-methoxy-phenyl)-methylamine by a procedure similar to Example 28 (87% yield). ¹H NMR (CDCl₃): 8.27 (dd, J=9.3, 2.7, 1H), 7.82 (d, J=2.4, 1H), 7.75 (d, J=9.0, 1H), 7.18 (m, 2H), 7.01 (m, 1H), 3.88 (s, 3H), 3.65 (s, 3H), 2.73 (s, 3H).

Example 110

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

The title compound was prepared from (4-methoxy-phenyl)-(2-methyl-6-nitro-quinazolin-4-yl)-methyl-amine by a procedure as described in Example 101 (70%). ¹H NMR (CDCl₃): 7.59 (d, J=9.0, 1H), 7.07 (m, 2H), 6.99 (dd, J=8.7, 2.4, 1H), 6.88 (m, 2H), 6.16 (d, J=2.1, 1H), 3.48 (s, broad, 2H), 3.82 (s, 3H), 3.55 (s, 3H), 2.68 (s, 3H).

Example 111

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

The title compound was prepared from (6-amino-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine by a procedure described for Example 102 (83%). ¹H NMR (CDCl₃): 7.69 (d, J=9.0, 1H), 7.10-7.18 (m, 3H), 6.95 (m, 2H), 6.62 (d, J=2.4, 1H), 3.84 (s, 3H), 3.59 (s, 3H), 2.70 (s, 3H).

Example 112

(4-Methoxy-phenyl)-methyl-(2-methyl-7-nitro-quinazolin-4-yl)-amine

The title compound was prepared from 2-amino-4-nitrobenzoic acid by a procedure similar to Example 109. ¹H NMR (CDCl₃): 8.56 (d, J=2.4, 1H), 7.68 (dd, J=9.3, 2.7, 1H), 7.08-7.14 (m, 3H), 6.92-6.97 (m, 2H), 3.86 (s, 3H), 3.61 (s, 3H), 2.73 (s, 3H).

Example 113

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

The title compound was prepared from (4-methoxy-phenyl)-(2-methyl-7-nitro-quinazolin-4-yl)-methyl-amine by a procedure as described in Example 101. ¹H NMR (CDCl₃/d₄-methanol): 7.11-7.15 (m, 2H), 6.93-6.96 (m, 2H), 6.86 (m, 1H), 6.63 (d, J=9.3, 1H), 6.35 (dd, J=9.3, 2.4, 1H), 3.86 (s, 3H), 3.60 (s, 3H), 2.65 (s, 3H).

Example 114

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

The title compound was prepared from (7-amino-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine by a procedure as described for Example 102. ¹H NMR (CDCl₃): 7.36 (d, J=2.4, 1H), 7.08-7.13 (m, 2H), 6.88-6.96 (m, 3H), 6.59 (dd, J=9.0, 2.4, 1H), 3.84 (s, 3H), 3.57 (s, 3H), 2.69 (s, 3H).

Example 115

(3,5-Dibromo-4-methoxy-phenyl)-(2-methyl-6-nitro-quinazolin-4-yl)-methyl-amine

a) N-(3,5-dibromo-4-hydroxyphenyl)acetamide: To a solution of N-(4-hydroxyphenyl)acetamide (0.50 g, 3.03 mmol) in glacial acetic acid (1 mL), methanol (1 mL) and methylene chloride (5 mL) cooled at 0° C. was added a solution of bromine (1 g, 6.25 mmol) in 1 mL of glacial acetic acid, and the mixture was stirred at 0° C. for 2 h. Additional bromine (1 g, 6.25 mmol) in 1 mL of glacial acetic acid was added and the mixture was stirred for 0.75 h at 0° C. The reaction mixture was diluted with 100 mL of ethyl acetate, washed with 1M Na₂SO₃(100 mL), water, half saturated NaHCO₃(100 mL) and saturated NaCl (100 mL). The organic layer was dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (40-45% ethyl acetate/hexanes) on silica gel to give the title compound (0.52 g, 1.61 mmol, 53%). ¹H NMR (CDCl₃): 9.96 (s, broad, 1H), 9.64 (s, broad, 1H), 7.77 (s, 2H), 2.01 (s, 3H).
b) N-(3,5-dibromo-4-methoxyphenyl)-N-methylacetamide: The title compound was prepared from N-(3,5-dibromo-4-hydroxyphenyl)acetamide (510 mg, 1.58 mmol) by a procedure similar to Example 108a (460 mg, 1.36 mmol, 86%). ¹H NMR (CDCl₃): 7.39 (s, 2H), 3.92 (s, 3H), 3.22 (s, 3H), 1.92 (s, 3H).
c) (3,5-dibromo-4-methoxy-phenyl)-methylamine: The title compound was prepared from N-(3,5-dibromo-4-methoxyphenyl)-N-methylacetamide (426 mg, 1.26 mmol) by a procedure similar to Example 108b (323 mg, 1.09 mmol, 87%). ¹H NMR (CDCl₃): 6.72 (s, 2H), 3.80 (s, 3H), 3.67 (s, broad, 1H), 2.78 (d, J=5.1, 3H).
d) (3,5-Dibromo-4-methoxy-phenyl)-(2-methyl-6-nitro-quinazolin-4-yl)-methyl-amine. The title compound was prepared from 4-chloro-2-methyl-5-nitroquinazoline and (3,5-dibromo-4-methoxy-phenyl)-methylamine by a procedure similar to Example 28 (61% yield). ¹H NMR (CDCl₃): 8.35 (dd, J=9.3, 2.4, 1H), 7.86 (d, J=2.1, 1H), 7.84 (d, J=9.0, 1H), 7.47 (m, 1H), 7.44 (s, 2H), 3.98 (s, 3H), 3.66 (s, 3H), 2.75 (s, 3H).

Example 116

4-(N-Methyl-N-(2-methylquinazolin-4-yl)amino)benzoic Acid

The title compound was prepared from 4-chloro-2-methylquinazoline and 4-(methylamino)benzoic acid by a procedure described for Example 1b. ¹H NMR (CDCl₃): 8.42-8.39 (m, 1H), 8.28 (m, 2H), 7.84 (m, 1H), 7.45 (m, 2H), 7.37 (m, 1H), 7.22 (m, 1H), 6.84 (d, J=1H, 8.4), 3.91 (s, 3H), 3.01 (s, 3H).

Example 117

Ethyl 4-(N-(4-Methoxy-phenyl)-N-methylamino)quinazoline-2-carboxylate

The title compound was prepared from ethyl 4-chloroquinazoline-2-carboxylate and (4-methoxy-phenyl)-methylamine by using the procedure described for Example 1b. ¹H NMR (CDCl₃): 7.98-8.02 (m, 1H), 7.61 (ddd, J=1H, 8.1, 6.9, 1.5), 7.08-7.17 (m, 3H), 7.01-7.05 (m, 1H), 6.91-6.96 (m, 2H), 4.56 (q, J=2H, 7.2), 3.84 (s, 3H), 3.71 (s, 3H), 1.50 (t, J=2H, 7.2).

Example 118

4-(N-(4-Methoxy-phenyl)-N-methylamino)quinazoline-2-carboxylic acid

A mixture of ethyl 4-(N-(4-methoxy-phenyl)-N-methylamino)quinazoline-2-carboxylate (560 mg, 1.66 mmol) and sodium hydroxide (126 mg, 3.15 mmol) in 25 mL of methanol and water (1:3) was stirred at room temperature for 5 h. The solvents were removed under vacuum, and the residue was dissolved in 50 mL of water and acidified to pH 3. The white precipitate was collected and washed with water and dried (380 mg, 1.23 mmol, 74%). ¹H NMR (CDCl₃): 8.02-8.05 (m, 1H), 7.68 (ddd, J=1H, 8.4, 6.9, 1.5), 7.14-7.20 (m, 3H), 7.02-7.05 (m, 1H), 6.94-6.99 (m, 2H), 3.87 (s, 3H), 3.74 (s, 3H).

Example 119

Succinimidyl 4-(N-Methyl-N-(2-methylquinazolin-4-yl)amino)benzoic acid ester

A solution of 4-(N-methyl-N-(2-methylquinazolin-4-yl)amino)benzoic acid (250 mg, 0.852 mmol), N-hydroxysuccinimide (75 mg, 0.653 mmol) and dicyclohexylcarbodiimide (135 mg, 0.653 mmol) in 50 mL of methylene chloride was refluxed overnight. The reaction mixture was cooled to room temperature and diluted with 100 mL of ethyl acetate, washed with water (3×100 mL), saturated NaCl and the organic layer was dried over Na₂SO₄, filtered and concentrated. The crude product was purified by chromatography (75% ethyl acetate/hexanes) on silica gel to give the title compound (170 mg, 0.435 mmol, 51%). ¹H NMR (CDCl₃): 8.06 (m, 2H), 7.95 (m, 1H), 7.71 (m, 1H), 7.11-7.22 (m, 4H), 3.76 (s, 3H), 2.84 (s, 3H), 2.81-2.92 (m, 4H).

Example 120

(2-Methylthio-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), sodium methanethiolate (105 mg, 1.5 mmol) in 5 mL of solvent (THF:MeOH:water=3:1:1) was stirred at 70° C. for 4 h. The reaction mixture was diluted with 30 mL of ethyl acetate and it was washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated. The crude product was purified by chromatography on silica gel with acetate and hexane (1:5) as eluent, yielding 11 mg of title compound (7%). ¹H NMR (CDCl₃): 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 121

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

The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (150 mg, 0.5 mmol), sodium azide (97.5 mg, 1.5 mmol) in 5 mL of solvent (THF:MeOH:water=3:1:1) by a procedure similar to that of Example 120 (4%). ¹H NMR (CDCl₃): 8.45 (d, J=8.4 Hz, 1H), 7.78-7.72 (m, 1H), 7.27-7.22 (m, 2H), 7.19-7.14 (m, 2H), 6.95 (d, J=8.7 Hz, 2H), 3.86 (s, 3H), 3.69 (s, 3H).

Example 122

(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 filled and the filtration was concentrated by vacuum. The residue was extracted with ethyl acetate and was washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated. The crude product was purified by chromatography on silica gel with acetate and hexane (1:9) as eluent, yielding 128 mg of title compound (83%). ¹H NMR (CDCl₃): 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, 1H), 3.82 (s, 3H), 3.51 (s, 3H), 3.30 (s, 6H).

Example 123

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

The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (150 mg, 0.5 mmol), 2.0 M methylamine in THF (2.0 ml, 4 mmol) by a procedure similar to that of Example 122 (53.7%). ¹H NMR (CDCl₃): 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 124

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

The title compound was prepared from 4-chloro-2-methyl-quinazoline (178.6 mg, 1.0 mmol) and (4-fluoro-phenyl)-methyl-amine (125 mg, 2.52 mmol) by a procedure similar to Example 28 (46.8%). ¹H NMR (CDCl₃): 7.76 (dd, J=0.9 Hz, J=8.3 Hz, 1H), 7.58-7.52 (m, 1H), 7.16-7.00 (m, 6H), 3.60 (s, 3H), 2.73 (s, 3H),

Example 125

(6-Methoxy-pyridazin-3-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine

a) 3-Amino-6-methoxy-pyridazine: A mixture of 3-amino-6-chloro-pyridazine (500 mg, 3.86 mmol), sodium methoxide (1.0 ml, 4.4 mmol, 25% w/w) and copper powder (331 mg, 5.17 mmol) in methanol (3 ml) was heated in a sealed tube at 160° C. for 24 h. After cooling, the reaction mixture was diluted with methanol (10 ml) and filtered, and the filtrate was concentrated by vacuum. The residue was purified by chromatography on silica gel with acetate and hexane (1:2) as eluent, yielding 413 mg of title compound (85.7%). ¹H NMR (CDCl₃): 6.81 (m, 2H), 4.62 (brs, 2H), 4.00 (s, 3H).
b) (6-Methoxy-pyridazin-3-yl)-methyl-amine: To a solution of 3-amino-6-methoxy-pyridazine (90 mg, 0.72 mmol) in THF (2 ml) at 0° C. was added sodium hydride (44 mg, 1.08 mmol, 60% oil dispersion), followed by methyl iodide (0.07 ml, 1.08 mmol). The mixture was stirred at 0° C. for 1 h, then allowed to warm to room temperature and stirred for another 2 h. The reaction mixture was diluted with EtOAc (10 ml), washed with saturated NaHCO₃aq., brine, dried over Na₂SO₄, filtered and concentrated by vacuum. The residue was purified by chromatography on silica gel with acetate and hexane (1:2 to 1:1) as eluent, yielding 6.0 mg of title compound (6.0%). ¹H NMR (CDCl₃): 6.79 (d, J=9.0 Hz, 1H), 6.68 (d, J=10.5 Hz, 1H), 4.29 (brs, 1H), 4.01 (s, 3H), 3.01 (d, J=4.8 Hz, 3H).
c) (6-Methoxy-pyridazin-3-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine: To a solution of (6-methoxy-pyridazin-3-yl)-methyl-amine (10 mg, 0.072 mmol) in DMF (1 ml) at 0° C. was added sodium hydride (4.3 mg, 0.11 mmol, 60% oil dispersion), followed by 4-chloro-2-methyl-quinazoline (12.9 mg, 0.072 mmol). The mixture was stirred at 0° C. for 1 h, then allowed to warm to room temperature and stirred for another 2 h. The reaction mixture was diluted with EtOAc (10 ml), washed with saturated NaHCO₃aq., brine, dried over Na₂SO₄, filtered and concentrated by vacuum. The residue was purified by chromatography on silica gel with acetate and hexane (1:2 to 1:1) as eluent, yielding 2.0 mg of title compound (10%). ¹H NMR (CDCl₃): 7.90 (d, J=8.1 Hz, 1H), 7.73 (t, J=8.4 Hz, 1H), 7.48 (d, J=8.7 Hz, 1H), 7.34-7.31 (m, 1H), 6.94 (d, J=9.3 Hz, 1H), 6.81 (d, J=9.6 Hz, 1H), 4.12 (s, 3H), 3.85 (s, 3H), 2.78 (s, 3H).

Example 126

(5-Methoxy-pyrazin-2-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine

a) 2-Amino-5-methoxy-pyrazine: The title compound was prepared from 2-amino-5-bromo-pyrazine (500 mg, 2.87 mmol) and sodium methoxide (1.0 ml, 4.4 mmol, 25% w/w) by a procedure similar to Example 125a (29%). ¹H NMR (CDCl₃): 7.76 (s, 1H), 7.56 (s, 1H), 4.20 (brs, 2H), 3.88 (s, 3H).
b) (5-Methoxy-pyrazin-2-yl)-(2-methyl-quinazolin-4-yl)-amine: The title compound was prepared from 2-amino-5-methoxy-pyrazine (105 mg, 0.84 mmol) and 4-chloro-2-methyl-quinazoline (150 mg, 0.84 mmol) by a procedure similar to Example 125c, yielding 106 mg of the title product.
c) (5-Methoxy-pyrazin-2-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine: The title compound was prepared from (5-methoxy-pyrazin-2-yl)-(2-methyl-quinazolin-4-yl)-amine (106 mg, 0.40 mmol) by a procedure similar to Example 36 (56%). ¹H NMR (CDCl₃): 8.06 (d, J=1.2 Hz, 1H), 7.85-7.81 (m, 1H), 7.74 (d, J=1.5 Hz, 1H), 7.65-7.60 (m, 1H), 7.17-7.05 (m, 2H), 3.94 (s, 3H), 3.70 (s, 3H), 2.78 (s, 3H).

Example 127

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

The title compound was prepared from 4-chloro-2-methyl-quinazoline (818 mg, 4.58 mmol), 4-hydroxy-aniline (500 mg, 4.58 mmol) by a procedure similar to Example 1b to give 498 mg (43%) of off white solids. ¹H NMR (DMSO-d₆): 9.51 (s, 1H), 9.34 (s, 1H), 8.44 (d, J=7.8 Hz, 1H), 7.77 (t, J=8.4 Hz, 1H), 7.67-7.48 (m, 4H), 6.79 (d, J=7.8 Hz, 2H), 2.45 (s, 3H).

Example 128

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

The title compound was prepared from (2-chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine (69 mg, 0.23 mmol) and 2.0 M dimethylamine in methanol (4 ml, 8 mmol) by a procedure similar to Example 122 (51%). ¹H NMR (CDCl₃): 8.02 (d, J=2.7 Hz, 1H), 7.47 (d, J=8.1 Hz, 1H), 7.38-7.34 (m, 2H), 6.93 (d, J=8.4 Hz, 1H), 6.75-6.66 (m, 2H), 3.94 (s, 3H), 3.51 (s, 3H), 3.30 (s, 6H).

Example 129

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

The title compound was prepared from (2-chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine (69 mg, 0.23 mmol) and 2.0 M methylamine in THF (4 ml, 8 mmol) by a procedure similar to Example 122 to give 20 mg (30%) of yellow solids. ¹H NMR (CDCl₃): 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 130 and 131

(2-Chloro-quinazolin-4-yl)-(cis-4-methylcyclohexyl)-amine and (2-chloro-quinazolin-4-yl)-(trans-4-methylcyclohexyl)-amine

The title compounds were prepared from 2,4-dichloro-quinazoline and 4-methylcyclohexyl-amine by a procedure similar to Example 28. The isomers were separated by chromatography (10-12% ethyl acetate/hexane). (2-Chloro-quinazolin-4-yl)-(cis-4-methylcyclohexyl)-amine. ¹H NMR (CDCl₃): 7.66-7.79 (m, 3H), 7.46 (ddd, J=1.8, 6.3, 8.4, 1H), 5.96 (d, broad, J=6.6, 1H), 4.49 (m, 1H), 1.68-1.87 (m, 7H), 1.25 (m, 2H), 0.99 (d, J=6.6, 3H). (2-Chloro-quinazolin-4-yl)-(trans-4-methylcyclohexyl)-amine. ¹H NMR (CDCl₃): 7.67-7.78 (m, 3H), 7.43 (ddd, J=1.8, 6.6, 8.4, 1H), 5.78 (d, broad, J=7.5, 1H), 4.22 (m, 1H), 2.15-2.21 (m, 2H), 1.76-1.82 (m, 2H), 1.11-1.46 (m, 5H), 0.94 (d, J=6.6, 3H).

Example 132

(2-Chloro-quinazolin-4-yl)-(cis-4-methylcyclohexyl)-methyl-amine

The title compound was prepared from (2-chloro-quinazolin-4-yl)-(cis-4-methylcyclohexyl)-amine by a procedure similar to Example 36. ¹H NMR (CDCl₃): 7.88 (m, 1H), 7.75-7.78 (m, 1H), 7.68 (ddd, J=1.5, 6.9, 8.4, 1H), 7.37 (ddd, J=1.5, 6.9, 8.4, 1H), 4.36 (m, 1H), 3.24 (s, 3H), 1.86-2.00 (m, 3H), 1.61-1.75 (m, 6H), 1.05 (d, J=7.2, 3H).

Example 133

(2-Chloro-quinazolin-4-yl)-(trans-4-methylcyclohexyl)-methyl-amine

The title compound was prepared from (2-chloro-quinazolin-4-yl)-(trans-4-methylcyclohexyl)-amine by a procedure similar to Example 36. ¹H NMR (CDCl₃): 7.89 (m, 1H), 7.74-7.78 (m, 1H), 7.68 (ddd, 0.9, 6.6, 8.1, 1H), 7.37 (ddd, J=1.2, 6.6, 8.1, 1H), 4.38 (m, 1H), 3.21 (s, 3H), 1.67-1.95 (m, 6H), 1.39 (m, 1H), 1.4-1.25 (m, 2H), 0.93 (d, J=6.3, 3H).

Example 134

(2-Methyl-quinazolin-4-yl)-(pyrazin-2-yl)-methyl-amine

The title compound was prepared from 4-chloro-2-methyl-quinazoline and 2-amino-pyrazine in two steps by a procedure similar to Examples 100 and 36. ¹H NMR (CDCl₃): 8.27 (dd, J=1.5, 2.4, 1H), 8.13-8.14 (m, 2H), 7.95 (d, J=8.4, 1H), 7.77 (ddd, J=1.5, 6.6, 8.4, 1H), 7.45-7.48 (m, 1H), 7.34 (ddd, J=0.9, 6.6, 8.1, 1H), 3.78 (s, 3H), 2.83 (s, 3H).

Example 135

(2-Methyl-quinazolin-4-yl)-(pyridin-4-yl)-amine

The title compound was prepared from 4-chloro-2-methyl-quinazoline and 4-amino-pyridine by a procedure similar to Examples 100. ¹H NMR (CDCl₃): 8.58 (m, 1H), 7.79-7.93 (m, 5H), 7.70 (s, broad, 1H), 7.55 (ddd, J=1.2, 6.9, 8.1, 1H), 2.79 (s, 3H).

Example 136

(2-Methyl-quinazolin-4-yl)-(pyridin-4-yl)-methyl-amine

The title compound was prepared from 4-chloro-2-methyl-quinazoline (0.178 g, 2.13 mmol) and (pyridin-4-yl)-methyl-amine (0.108 g, 1.84 mmol) by a procedure similar to Examples 125c (0.224 g, 49%). ¹H NMR (CDCl₃): 8.39 (m, 2H), 7.91 (d, J=8.4, 1H), 7.73 (ddd, J=1.2, 6.6, 8.4, 1H), 7.41 (m, 1H), 7.23-7.29 (m, 1H), 6.79-6.82 (m, 2H), 3.70 (s, 3H), 2.83 (s, 3H).

Example 137

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

a) 2-Amino-5-methoxy-pyridine. A mixture of 2-amino-5-iodo-pyridine (1 g, 4.54 mmol) in 20 mL of absolute methanol with 400 mg of copper powder and sodium methoxide (6 mmol) was heated at 160° C. overnight in a seal tube. The reaction mixture was cooled to room temperature, diluted with 80 mL of methanol and filtered through a pad of celite. The filtrate was concentrated and the residue was purified by chromatography (80% ethyl acetate/hexane) to give the title compound (174 mg, 31%). ¹H NMR (CDCl₃): 7.78 (d, J=2.7, 1H), 7.09 (dd, J=3.0, 9.0, 1H), 6.48 (d, J=9.0, 1H), 3.78 (s, 3H).
b) (5-M ethoxy-pyridin-2-yl)-(2-methyl-quinazolin-4-yl)-amine: The title compound was prepared from 4-chloro-2-methyl-quinazoline and 2-amino-5-methoxy-pyridine by a procedure similar to Example 28.

Example 138

(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 36. ¹H NMR (CDCl₃): 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 139

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

A solution of (4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine (100 mg, 0.35 mmol) in 3 mL of dimethylformamide in a 15 mL high pressure reaction vessel was cooled to −78° C. Difluorochloromethane (about 0.8 mL) was condensed into the solution, then cesium carbonate (160 mg, 0.49 mmol) was added. The reaction vessel was capped and heated at 80° C. overnight. The reaction mixture was cooled to room temperature and cooled to −78° C. and the seal tube was uncapped, warm to room temperature and allowed to stand for 2 h. The reaction mixture was diluted with 50 mL of ethyl acetate and the organic layer was washed with water (50 mL×3), followed by saturated aqueous NaCl. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by chromatography (30% ethyl acetate/hexane, 6 drops triethylamine/500 mL of solvent) to give the title compound (35 mg, 0.111 mmol, 32%). ¹H NMR (CDCl₃): 8.35 (dd, J=1.8, 8.1, 1H), 7.35-(m, 3H), 7.25 (t, J=72.1, 1H), 7.21-7.25 (m, 2H), 6.86-6.91 (m, 2H), 3.82 (s, 3H), 2.48 (s, 3H).

Example 140

(4-Methoxy-phenyl)-(2-methyl-pteridin-4-yl)-methyl-amine

a) 4-Chloro-2-methyl-pteridine. A mixture of 6-chloro-2-methyl-pyrimidine-4,5-diamine (37 mg, 0.233 mmol) and 1,4-dioxane-2,3-diol (32 mg, 0.266 mmol) in 0.8 mL of absolute ethanol was stirred at room temperature for 2 h. The reaction mixture was evaporated to dryness and the residue was purified by column chromatography (50% ethyl acetate/hexane) to give the title compound (41 mg, 0.227 mmol, 97%). ¹H NMR (CDCl₃): 9.24 (d, J=1.8, 1H), 9.05 (d, J=1.5, 1H), 2.99 (s, 3H).
b) (4-Methoxy-phenyl)-(2-methyl-pteridin-4-yl)-methyl-amine. The title compound was prepared from 4-chloro-2-methyl-pteridine and (4-methoxy-phenyl)-methyl-amine by a procedure similar to Example 28 (67%). ¹H NMR (CDCl₃): 8.73 (d, J=1.8, 1H), 8.22 (d, J=1.8, 1H), 7.07-7.10 (m, 2H), 6.86-6.92 (m, 2H), 3.85 (s, 3H), 3.69 (s, 3H), 2.73 (s, 3H).

Example 141

(5-Methoxy-pyrimidin-2-yl)-(2-methyl-quinazolin-4-yl)-amine

a) 2-Amino-5-methoxy-pyrimidine: The title compound was prepared from 2-amino-5-iodo-pyrimidine (2.0 g, 9.0 mmol) and sodium methoxide (10 ml, 44 mmol, 25% w/w) by a procedure similar to Example 125a (21%). ¹H NMR (CDCl₃): 8.05 (s, 2H), 4.78 (brs, 2H), 3.81 (s, 3H).
b) (5-Methoxy-pyrimidin-2-yl)-(2-methyl-quinazolin-4-yl)-amine: The title compound was prepared from 2-amino-5-methoxy-pyrimidine (240 mg, 1.92 mmol) and 4-chloro-2-methyl-quinazoline (343 mg, 1.92 mmol) by a procedure similar to Example 125c, yielding 283 mg of the title product (55%). ¹H NMR (CDCl₃): 8.69 (dd, J=1.5 Hz, J=8.1 Hz, 1H), 8.43 (s, 2H), 7.73-7.67 (m, 1H), 7.60 (d, J=7.2 Hz, 1H), 7.49-7.43 (m, 1H), 3.95 (s, 3H), 2.58 (s, 3H).

Example 142

(5-Methoxy-pyrimidin-2-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine

The title compound was prepared from (5-methoxy-pyrimidin-2-yl)-(2-methyl-quinazolin-4-yl)-amine (170 mg, 0.64 mmol) by a procedure similar to Example 36 (50%). ¹H NMR (CDCl₃): 8.12 (s, 2H), 7.91 (d, J=8.4 Hz, 1H), 7.74-7.69 (m, 1H), 7.38-7.34 (m, 1H), 7.30-7.24 (m, 1H), 3.85 (s, 3H), 3.78 (s, 3H), 2.83 (s, 3H).

Example 143

{4-[Methyl-(2-methyl-quinazolin-4-yl)-amino]phenoxy}-acetic acid methyl ester

(4-Hydroxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine (468 mg, 1.41 mmol) and K₂CO₃were dissolved in DMF (10 mL). Methyl bromoacetate (0.67 mL, 7.08 mmol) was added and the reaction was heated at 60° C. for 2 h. The mixture was cooled and diluted with EtOAc. The organics were washed with water (2×) and dried over MgSO₄. The title compound was purified by preparative RPLC. ¹H NMR (DMSO-d₆) δ 7.64 (d, 1H), 7.59 (t, 1H), 7.20 (d, 2H), 7.05 (t, 1H), 7.0-6.9 (m, 3H), 4.85 (s, 2H), 3.71 (s, 3H), 3.50 (s, 3H), 2.58 (s, 3H); LC-MS (ESI⁺; 338 ([M+H]⁺)).

Example 144

{4-[Methyl-(2-methyl-quinazolin-4-yl)-amino]phenoxy}-acetic acid

To a solution of {4-[methyl-(2-methyl-quinazolin-4-yl)-amino]-phenoxy}-acetic acid methyl ester (200 mg, 0.59 mmol) in THF (5 mL) was added potassium trimethylsilanoate (770 mg, 6 mmol). The mixture was stirred at ambient temperature for 1 h. The mixture was diluted with phosphate buffer (pH=5.5) and extracted with EtOAc (3×). The pH of the aqueous phase was raised to 6 with NaOH and was extracted with EtOAc (3×). The combined organics were dried over MgSO₄, filtered and concentrated. The title compound was used without further purification. ¹H NMR (DMSO-d₆) δ 7.64 (d, 1H), 7.59 (t, 1H), 7.20 (d, 2H), 7.03 (t, 1H), 7.0-6.9 (m, 3H), 4.85 (s, 2H), 3.50 (s, 3H), 2.60 (s, 3H); LC-MS (ESI⁺; 324 ([M+H]⁺)).

Example 145

N²-(2-Amino-ethyl)-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine

a) (2-{4-[(4-Methoxy-phenyl)-methyl-amino]-quinazolin-2-ylamino}-ethyl)-carbamic acid tert-butyl ester: A mixture of (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine 1.50 g (4.47 mmol) and (2-amino-ethyl)-carbamic acid tert-butyl ester 0.94 g (5.60 mmol) with Et₃N 2 mL in isopropanol was stirred at 85° C. for 48 h. The reaction mixture was diluted with CH₂Cl₂and directly charged to gradient column chromatography (MeOH/CH₂Cl₂, 0% to 10%) to obtain the title compound. ¹H NMR (CDCl₃, 400 MHz) δ 7.44 (d, 1H, J=8.2 Hz), 7.40-7.36 (m, 1H), 7.11 (d, 2H, J=9.0 Hz), 6.91 (d, 2H, J=9.0 Hz), 6.85 (d, 1H, J=8.6 Hz), 6.72-6.67 (m, 1H), 3.84 (s, 3H), 3.68 (q, 2H, J=5.4 Hz), 3.52 (s, 3H), 3.43 (q, 2H, J=5.4 Hz), 1.43 (s, 9H); LC-MS (ESI⁺; 424 ([M+H]⁺)).
b) N²-(2-Amino-ethyl)-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine: To a solution of (2-{4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-ylamino}-ethyl)-carbamic acid tert-butyl ester 0.422 g (1.0 mmol) in CH₂Cl₂(10 mL) was added TFA (0.55 g; 5.0 mmol) at room temperature, and the reaction mixture was stirred for 2 h. The reaction mixture was concentrated under reduced pressure, and dried in vacuo to give the title compound as the corresponding TFA salt. ¹H NMR (CD₃OD) δ 7.80-7.60 (m, 2H), 7.13 (m, 2H), 6.96 (m, 2H), 6.89 (m, 1H), 6.67 (m, 1H), 3.81 (s, 3H), 3.63 (t, J=6.0 Hz, 2H), 3.51 (s, 3H), 3.03 (t, J=6.0 Hz, 2H) (free base); LC-MS (ESI⁺; 324 ([M+H]⁺)).

Example 146

[2-(2-Methoxy-ethoxy)-quinazolin-4-yl]-(4-methoxy-phenyl)-methyl-amine

NaH (60% dispersion, 30.0 mg, 0.75 mmol, 2.5 eq.) was placed in a 25 mL roundbottom flask under a blanket of inert gas, and washed three times with hexanes. After decanting the last hexanes wash, the residue was dried with flowing N₂gas. The residue was then treated with 2 mL of di(ethylene glycol)-monomethyl ether, after which (2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine hydrochloride (100 mg, 0.3 mmol) was added in 1 mL DMF. The mixture was heated at 100° C. with stirring for two hours. The mixture was cooled, diluted with ethyl acetate (˜10 mL), and washed with water. The title compound (60%, 67 mg), was purified by preparative HPLC. ¹H NMR (CDCl₃, 400 MHz): δ 7.97 (d, 1H, J=8.4 Hz), 7.60 (t, 1H, J=7.4 Hz), 7.21 (d, 2H, J=7.0 Hz), 7.03 (d, 2H, J=7.0 Hz), 6.97 (t, 1H, J=7 Hz), 6.76 (d, 2H, J=7.0 Hz), 4.74 (t, 2H, J=4.3 Hz), 3.90 (s, 3H), 3.83 (t, 2H, J=4.1 Hz), 3.72 (s, 3H), 3.45 (s, 3H).

Example 147

N⁴-(4-Methoxy-phenyl)-N²,N⁴-dimethyl-N²-(2-methylamino-ethyl)-quinazoline-2,4-diamine

A solution of (2-chloroquinazolin-4-yl)-(4-methoxyphenyl)-methylamine hydrochloride (120 mg, 0.36 mmol) and N,N′-dimethylethylenediamine (0.14 mL, 1.26 mmol) in 2 mL of 1-butanol was heated at 100° C. overnight with stirring. The mixture was concentrated and purified by silica gel column chromatography to give the title compound (101 mg, 80%). ¹H NMR (CDCl₃, 400 MHz) δ 7.42 (d, 1H, J=8.4 Hz), 7.31 (t, 1H, J=6.8 Hz), 7.09 (d, 2H, J=8.8 Hz), 6.86 (m, 3H), 6.64 (t, 1H, J=6.8 Hz), 3.90 (t, 2H, J=6.4 Hz), 3.82 (s, 3H), 3.50 (s, 3H), 3.30 (s, 3H), 2.92 (t, 2H, J=6.4 Hz), 2.50 (s, 3H); ESI-MS m/z 352 (M+H)⁺.

Example 148

N²-(2-Dimethylamino-ethyl)-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine

The above procedure was used to prepare the title compound (105 mg, 83%). ¹H NMR (CDCl₃, 400 MHz) δ 7.42 (d, 1H, J=8.4 Hz), 7.34 (t, 1H, J=6.8 Hz), 7.10 (d, 2H, J=8.8 Hz), 6.86 (m, 3H), 6.64 (t, 1H, J=6.8 Hz), 3.82 (s, 3H), 3.62 (m, 2H), 3.49 (s, 3H), 2.57 (t, 2H, J=6.4 Hz), 2.30 (s, 6H); ESI-MS m/z 352 (M+H)⁺.

Example 149

N²-(2-Dimethylamino-ethyl)-N⁴-(4-methoxy-phenyl)-N²,N⁴-dimethyl-quinazoline-2,4-diamine

The above procedure was used to prepare the title compound (99 mg, 75%). ¹H NMR (CDCl₃, 400 MHz) δ 7.42 (d, 1H, J=8.4 Hz), 7.32 (t, 1H, J=6.8 Hz), 7.09 (d, 2H, J=8.8 Hz), 6.87 (m, 3H), 6.62 (t, 1H, J=6.8 Hz), 3.90 (t, 2H, J=6.4 Hz), 3.81 (s, 3H), 3.50 (s, 3H), 3.29 (s, 3H), 2.60 (t, 2H, J=6.4 Hz), 2.34 (s, 6H); ESI-MS m/z 366 (M+H)⁺.

Example 150

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

To a solution of (2-chloroquinazolin-4-yl)-(4-methoxyphenyl)-methylamine hydrochloride (120 mg, 0.36 mmol) in 2 mL of N,N-dimethylethanolamine were added potassium tert-butoxide (121 mg, 1.07 mmol) and 18-crown-6 (95 mg, 0.36 mmol). The resulting solution was heated at 100° C. overnight with stirring. The mixture was concentrated and purified by silica gel column chromatography to give the title compound (66 mg, 52%). ¹H NMR (CDCl₃, 400 MHz) δ 7.59 (d, 1H, J=8.4 Hz), 7.45 (t, 1H, J=6.8 Hz), 7.10 (d, 2H, J=8.8 Hz), 6.92 (m, 3H), 6.83 (t, 1H, J=6.8 Hz), 4.60 (t, 2H, J=6.4 Hz), 3.83 (s, 3H), 3.57 (s, 3H), 2.84 (t, 2H, J=6.4 Hz), 2.38 (s, 6H); ESI-MS m/z 353 (M+H)⁺.

Example 151

N²-Ethoxymethyl-N⁴-(4-methoxy-phenyl)-N²,N⁴-dimethyl-quinazoline-2,4-diamine

To a solution of (2-chloroquinazolin-4-yl)-(4-methoxyphenyl)-methylamine hydrochloride (0.50 g, 1.50 mmol) in 10 mL of 2-propanol was added 2.0 M solution of methylamine (3.0 mL). The mixture was heated at 100° C. overnight with stirring. The solution was diluted with 20 mL of water and 50 mL of ethyl acetate. The organic layer was washed with water, then dried and concentrated. The resulting material was dissolved in 8 mL of ethanol and then 0.22 mL of formaldehyde (37% in water), a few drops of 5% sodium hydroxide solution were added. The mixture was heated at 90° C. for 1 d with stirring, and then diluted with 10 mL of water and 30 mL of ethyl acetate. The organic layer was washed with water, then dried and concentrated. The resulting crude material was purified by silica gel column chromatography to give the title compound (0.38 mg, 72%). ¹H NMR (CDCl₃, 400 MHz) δ 7.22 (d, 1H, J=8.4 Hz), 7.18 (t, 1H, J=6.8 Hz), 7.09 (d, 2H, J=8.8 Hz), 6.98 (d, 2H, J=8.8 Hz), 6.92 (d, 1H, J=8.4 Hz), 6.67 (t, 1H, J=6.8 Hz), 5.30 (s, 2H), 3.90 (s, 3H), 3.57 (q, 2H, J=6.8 Hz), 3.49 (s, 3H), 3.22 (s, 3H), 1.17 (t, 3H, J=6.8 Hz); ESI-MS m/z 353 (M+H)⁺.

Example 152

4-[(4-Methoxy-phenyl)-methyl-amino]-quinazoline-2-carbonitrile

To a solution of (2-chloroquinazolin-4-yl)-(4-methoxyphenyl)-methylamine hydrochloride (56 mg, 0.17 mmol) in 1 mL of DMSO and 0.5 mL of 2-propanol were added sodium cyanide (16 mg, 0.34 mmol) and 1,4-diazabicyclo[2.2.2]octane (9 mg, 0.084 mmol). The mixture was heated at 35° C. for 1 d with stirring. The solution was diluted with 5 mL of water and 10 mL of ethyl acetate. The organic layer was washed with water, then dried and concentrated. The resulting crude material was purified by silica gel column chromatography to give the title compound (34 mg, 70%). ¹H NMR (CDCl₃, 400 MHz) δ 7.85 (d, 1H, J=8.4 Hz), 7.64 (t, 1H, J=6.8 Hz), 7.14 (m, 3H), 6.96 (m, 3H), 3.86 (s, 3H), 3.61 (s, 3H); ESI-MS m/z 291 (M+H)⁺.

Example 153

Methyl 2-[({4-[methyl(2-methylquinazolin-4-yl)amino]phenyl}amino)carbonyl]hydrazine carboxylate

To a mixture of N-methyl-N-(2-methylquinazolin-4-yl)benzene-1,4-diamine 0.396 g (1.5 mmol) in THF 10 mL and DMF 3 mL was added methyl hydrazine carboxylate 0.135 g (1.5 mmol), followed by addition of carbonyldiimidazole (CDI) 0.243 g (1.5 mmol) at 23° C. The reaction mixture was stirred at 23° C. for 4 h, heated under reflux for 0.5 h, and then stirred at 23° C. for another 16 h. After removal of THF, the crude product was purified with gradient column chromatography (EtOAc/hexanes, 0% to 100%) to give the titled compound in 75% yield, which was used without further purification. ¹H NMR (CD₃OD, 400 MHz): δ 7.98 (s, 1H), 7.64 (d, 1H, J=8.4 Hz), 7.59-7.54 (m, 1H), 7.52 (d, 2H, J=8.3 Hz), 7.13 (d, 2H, J=8.6 Hz), 7.05 (d, 1H, J=7.2 Hz), 7.03-6.98 (m, 1H), 3.74 (s, 3H), 3.70 (s, 1H), 2.99 (s, 3H), 2.86 (s, 3H). m/e: 381.19 (M+1), 379.03 (M−1).

Example 154

4-{4-[Methyl-(2-methyl-quinazolin-4-yl)-amino]-phenyl}-[1,2,4]triazolidine-3,5-dione

To a solution of methyl 2-[({4-[methyl(2-methylquinazolin-4-yl)amino]phenyl}amino)carbonyl]hydrazine carboxylate 0.150 g (0.4 mmol) in THF 5 mL was added K₂CO₃0.138 g (1.0 mol), and the reaction mixture was stirred for 48 h under reflux. Due to the incompletion of the reaction, the reaction was further heated under microwave irradiation at 120° C. for 20 min. The reaction mixture was filtrated with a short silica-get column using methanol, and methanol was evaporated under reduced pressure to obtain a crude product, which was purified with preparative HPLC to give the titled compound in pure form. ¹H NMR (CD₃OD, 400 MHz): δ 8.21, 8.19 (dd, 1H, J=8.0, 1.2 Hz), 7.87-7.83 (m, 2H), 7.79-7.75 (m, 1H), 7.71, 7.69 (dd, 1H, J=8.4, 0.8 Hz), 7.65-7.59 (m, 2H), 7.59-7.53 (m, 1H), 7.30-7.26 (m, 1H), 6.98 (d, 1H, J=8.4 Hz), 3.87 (s, 3H), 2.80 (s, 3H). m/e: 349.30 (M+1), 347.25 (M−1).

Example 155

N-{4-[Methyl-(2-methyl-quinazolin-4-yl)-amino]-phenyl}-methanesulfonamide

To a suspension of N-methyl-N-(2-methylquinazolin-4-yl)benzene-1,4-diamine 0.132 g (0.5 mmol) with Et₃N 0.2 mL in CH₂Cl₂10 mL was added methylsulfonyl chloride 0.115 g (1.0 mmol) at 23° C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with CH₂Cl₂30 mL, washed with water, sat. Na₂CO₃aqueous solution and dried on anhydrous MgSO₄. After removal of solvents, the crude product was subjected to gradient column chromatography (EtOAc/hexanes, 0% to 100%), but the compound was only obtained in <80% purity. Therefore, the crude compound was purified with preparative HPLC to give the titled compound in 15% yield. ¹H NMR (CD₃OD, 400 MHz): δ 7.86-7.82 (m, 1H), 7.72-7.67 (m, 1H), 7.44-7.42 (m, 4H), 7.29-7.24 (m, 1H), 6.94 (d, 1H, J=8.6 Hz), 3.84 (s, 3H), 3.07 (s, 3H), 2.78 (s, 3H). m/e: 343.1339 (M+1).

Example 156

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

A mixture of (2-chloroquinazolin-4-yl)-(4-methoxyphenyl)-methylamine 0.150 g (0.5 mmol) with NH₄F 0.500 g (13.5 mmol) in isopropanol 4 mL was stirred at reflux for 14 h. After removal of isopropanol, the residue was dissolved in dichloromethane, and the organic solution was washed with water, and dried over anhydrous MgSO₄. After removal of solvent under reduced pressure, the title compound was obtained. ¹H NMR (CD₃OD, 400 MHz) δ 7.57-7.60 (m, 1H), 7.42-7.46 (m, 1H), 7.10-7.18 (m, 2H), 6.89-6.97 (m, 3H), 6.79-6.84 (m, 1H), 5.45-5.51 (m, 1H), 3.83 (s, 3H), 3.58 (s, 3H), 1.46 (d, J=6.3 Hz, 6H); HRMS (ES) m/z calcd for C₁₉H₂₁N₃O₂(M+H) 324.1706. found 324.1954.

Example 157

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

A mixture of 2-chloro-N-(4-methoxyphenyl)-N-methylquinazolin-4-amine 0.150 g (0.5 mmol) and NH₄F 0.5 g in 1-methyl-2-pyrrolidinone 3 mL was stirred at 120° C. for 16 h. The reaction mixture was diluted with CH₂Cl₂10 mL and directly subjected to gradient column chromatography (EtOAc/hexanes, 0% to 100%) to give the crude titled compound product in 10% yield, which was further purified with preparative HPLC. ¹H NMR (CD₃OD, 400 MHz): δ 7.48-7.43 (m, 1H), 7.25-7.19 (m, 3H), 7.02 (d, 2H, J=9.0 Hz), 6.82-6.73 (m, 2H), 3.84 (s, 3H), 3.58 (s, 3H). ¹⁹F NMR (CD₃OD): −77 (s). m/e: 284.1 (M+1).

Example 158

4-[Methyl-(2-methyl-quinazolin-4-yl)-amino]-benzonitrile

To a solution of formic acid 30 mL and acetic anhydride 30 mL stirred at room temperature for 1 h was added a solution of 4-aminobenzonitrile 2.36 g (20.0 mmol) in CH₂Cl₂150 mL dropwise at 0° C. The reaction mixture was stirred at room temperature for 4 h (EMI-mass: 146 [M]⁺). After concentration, the crude intermediate was dissolved in THF 50 mL, and was added BH₃in Me₂S 15 mL. The reaction mixture was then stirred for 5 h under reflux. The crude product was extracted with EtOAc, washed with water, sat. Na₂CO₃aqueous solution and dried on anhydrous MgSO₄. After removal of solvents, 4-cyano-N-methylaniline was obtained in 80% purity based on GC/MS (EMI-mass: 132 [M]⁺). A mixture of crude 4-cyano-N-methylaniline 0.40 g (ca. 2 mmol) and 4-chloro-2-methylquinazoline 0.357 g (2.0 mmol) with NaOAc 0.2 g (2.3 mmol) in THF 20 mL and H₂O 12 mL was stirred at 23° C. for 4 days. After removing solvents, the crude product was purified with preparative HPLC to give the titled compound in 1% yield (10 mg). ¹H NMR (CD₃OD, 400 MHz): δ 7.94 (d, 2H, J=8.8 Hz), 7.91-7.86 (m, 1H), 7.76-7.73 (m, 1H), 7.65 (d, 2H, J=8.8 Hz), 7.34-7.30 (m, 1H), 6.99-6.96 (m, 1H), 3.87 (s, 3H), 2.81 (s, 3H). m/e: 275.1420 (M+1).

Example 159

{4-[(4-Methoxy-phenyl)-methyl-amino]-quinazolin-2-ylamino}-acetic acid ethyl ester

A mixture of 2-chloro-N-(4-methoxyphenyl)-N-methylquinazolin-4-amine 0.150 g (0.5 mmol) and NH₄F 0.5 g in iso-propanol 5 mL was stirred under reflux for 16 h. The reaction mixture was diluted with CH₂Cl₂20 mL, washed with water, and dried on anhydrous MgSO4. After removal of solvents, the crude product was purified with gradient column chromatography (EtOAc/hexanes, 0% to 100%) to isolate the titled compound in 80% yield. ¹H NMR (CDCl₃, 400 MHz): δ 10.70 (t, 1H, J=5.5 Hz), 7.60 (d, 1H, J=8.2 Hz), 7.59-7.47 (m, 1H), 7.19-7.14 (m, 2H), 7.02-6.99 (m, 2H), 6.85-6.81 (m, 1H), 6.64 (d, 1H, J=8.4 Hz), 4.25 (s. 2H), 4.24 (q, 2H, J=7.1 Hz), 3.89 (s, 3H), 3.59 (s, 3H), 1.29 (t, 3H, J=7.1 Hz). m/e: 367.2140 (M+1).

Example 160

2-{4-[(4-Methoxy-phenyl)-methyl-amino]-6-methyl-quinazolin-2-ylamino}-ethanol

A solution of (2-chloro-6-methyl-quinazolin-4-yl)-(4-methoxyphenyl)-methyl-amine (50.3 mg, 0.16 mmol) in ethanolamine (1.5 mL) was heated to 140° C. in the microwave for 20 min. The reaction was then concentrated onto SiO₂and purified by gradient MPLC (SiO₂, 0-100%, EtOAc/hexanes, 20 min). 19.1 mg (35%) of the title compound was isolated: ¹H NMR (DMSO-d6) δ 7.33 (d, 1H), 7.21 (dd, 1H), 7.04-7.10 (m, 2H), 6.86-6.92 (m, 2H), 6.57-6.62 (m, 1H), 5.44 (br s, 1H), 3.82-3.94 (m, 2H), 3.83 (s, 3H), 3.62-3.67 (m, 2H), 3.48 (s, 3H), 2.01 (s, 3H). HRMS (ES) calcd for C₁₉H₂₃N₄O₂[(M+H)] 339.1816. found 339.1854.

Example 161

N⁴-(4-Methoxy-phenyl)-6,N²,N⁴-trimethyl-quinazoline-2,4-diamine

A solution of (2-chloro-6-methyl-quinazolin-4-yl)-(4-methoxyphenyl)-methyl-amine (62.9 mg, 0.20 mmol), methylamine hydrochloride (145.8 mg, 2.2 mmol) and Na₂CO₃(234.5 mg, 2.2 mmol) in i-PrOH (2 mL) was heated to 100° C. overnight. After cooling to room temperature the reaction mixture was concentrated onto SiO₂and purified by gradient MPLC (SiO₂, 0 to 20% MeOH/CH₂Cl₂with 0.1% NH₄OH, 20 min). 20.3 mg (33%) of the title compound was obtained: ¹H NMR (DMSO-d6, 90° C.) δ 7.93 (br s, 1H), 7.38-7.52 (m, 2H), 7.33 (d, 2H), 7.08 (d, 2H), 6.39 (s, 1H), 3.83 (s, 3H), 3.62 (s, 3H), 3.06 (s, 3H), 1.96 (s, 3H). HRMS (ES) calcd for C₁₈H₂₁N₄O [(M+H)] 309.1710. found 309.1714.

Example 162

N⁴-(4-Methoxy-phenyl)-6,N²,N²,N⁴-tetramethyl-quinazoline-2,4-diamine

A solution of (2-chloro-6-methyl-quinazolin-4-yl)-(4-methoxyphenyl)-methyl-amine (64.4 mg, 0.21 mmol) and dimethylamine (2.0 M in THF, 1.0 mL, 2.0 mmol) in i-PrOH (2 mL) was heated to 100° C. overnight. After cooling to room temperature the reaction was concentrated onto SiO₂and purified by gradient MPLC (SiO₂, 0 to 10%, MeOH/CH₂Cl₂, 20 min). 17.9 mg (26%) of the title compound was obtained: ¹H NMR (DMSO-d6) δ 7.17-7.28 (m, 2H), 7.12-7.16 (m, 2H), 6.95-7.01 (m, 2H), 6.51-6.54 (m, 1H), 3.77 (s, 3H), 3.44 (s, 3H), 3.19 (s, 6H), 1.94 (s, 3H). HRMS (ES) calcd for C₁₉H₂₃N₄O [(M+H)] 323.1866. found 323.1951.

Example 163

6,7-N²-(2-Amino-ethyl)-N⁴-(4-methoxy-phenyl)-6,N⁴-dimethyl-quinazoline-2,4-diamine

A mixture of (2-chloro-6-methyl-quinazolin-4-yl)-(4-methoxyphenyl)-methyl-amine (220 mg, 0.70 mmol) and ethylene diamine was heated to 100° C. for 2 h. The reaction was concentrated and purified via reverse-phase MPLC. A quantitative yield of the title compound as the trifluoroacetate salt was obtained. ¹H NMR (DMSO-d6) □7.51 (d, 1H), 7.25-7.42 (m, 3 H), 7.12 (d, 2H), 6.33 (s, 1H), 3.84 (s, 3H), 3.72-3.80 (m, 2H), 3.66 (br s, 3H), 3.08-3.18 (m, 2H), 1.96 (s, 3H). HRMS (ES) calcd for C₁₉H₂₄N₅O [M+H] 338.1975. found 338.1986.

Example 164

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

A mixture of 2,4-dichloro-6-methoxy-quinazoline (0.5 g, 2.18 mmol), (4-methoxyphenyl)-methylamine (0.35 g, 2.61 mmol) and sodium acetate (0.21 g, 2.61 mmol) in 8 mL of solvent (THF:water=1:1) was stirred at 60-70° C. for 3 h. The reaction mixture was concentrated and the resulting solid was dissolved in ethyl acetate and transferred to the silica gel pad (30 mg) and washed with 40% ethyl acetate/hexane as eluent. The filtrate was concentrated under reduced pressure to give 0.7 g of the clean product (98% yield). ¹H NMR (DMSO): δ 7.6 (d, 1H), 7.36-7.31 (m, 3H), 7.08-7.05 (dd, 2H), 6.2 (d, 1H), 3.79 (s, 3H), 3.5 (s, 3H), 3.28 (s, 3H). LC/MS: 330, (M+1).

Example 165

6-Methoxy-N⁴-(4-methoxy-phenyl)-N²,N²,N⁴-trimethyl-quinazoline-2,4-diamine

A mixture of (2-chloro-6-methoxy-quinazoline-4-yl)-(4-methoxy-phenyl)-methyl-amine (0.12 g, 0.36 mmol), 2.0M dimethylamine in methanol (1.44 mL, 2.91 mmol) in sealed tube was stirred at 70-80° C. overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with sodium bicarbonate, brine, dried over anhydrous MgSO4, filtered and concentrated to give 90 mg of the titled compound (75% yield). ¹H NMR (DMSO): δ 7.28 (d, 1H), 7.20-7.18 (dd, 2H), 7.06-7.00 (d, 1H), 7.00-6.98 (dd, 2H), 6.2 (d, 1H), 3.7 (s, 3H), 3.4 (s, 3H), 3.22 (s, 3H), 3.18 (s, 6H). LC \MS: 339, (M+1).

Example 166

6-Methoxy-N⁴-(4-methoxy-phenyl)-N²,N⁴-dimethyl-quinazoline-2,4-diamine

A mixture of (2-chloro-6-methoxy-quinazoline-4-yl)-(4-methoxy-phenyl)-methyl-amine (0.15 g, 0.45 mmol), methylamine hydrochloride (0.3 g, 4.5 mmol), potassium carbonate (0.68 g, 4.4 mmol) in 4 mL of iPrOH in a sealed tube stirred at 90° C. overnight. The reaction mixture was concentrated under reduced pressure, the residue dissolved in chloroform 20 mL, washed with conc. Sodium bicarbonate, brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (CHCL3/MeOH/NH4OH=10/1/0.1 as eluent) yielding 45 mg (32%) of the title compound. ¹H NMR (DMSO): δ 7.2 (d, 1H), 7.18-7.15 (m, 2H), 7.05-7.02 (d, 1H), 6.99-6.97 (d, 2H), 6.5 (br s, 1H), 6.2 (s, 1H), 3.7 (s, 3H), 3.4 (s, 3H), 3.2 (s, 3H), 2.8 (s, 3H). LC/MS: 325, (M+1).

Example 167

N⁴-(3,4-Dimethoxy-phenyl)-N²,N⁴-dimethyl-quinazoline-2,4-diamine

a) (3,4-Dimethoxy-phenyl)-methyl-amine: A soln of 3,4-dimethoxy-phenylamine (15.318 g; 100 mmol), ethyl-diisopropyl-amine (21.0 mL; 121 mmol) and iodomethane (7.5 mL; 0.12 mol) in acetonitrile (100 mL) was stirred at 40° C. After 22 h the rxn was concd on a rotary evaporator. EtOAc (200 mL) was added and this washed with satd NaHCO₃(1×20 mL), water (3×20 mL) and satd NaCl (2×25 mL). The soln was dried (MgSO₄), filtered through a bed of silica, washed with EtOAc then adsorbed onto silica and purified by MPLC (0-60% EtOAc in hexanes gradient) yielding a pale yellow liquid which darkened upon standing (3.179 g; 19%). ¹H NMR (CDCl₃) δ 6.77 (d, J=8.4 Hz, 1H), 6.26 (d, J=2.8 Hz, 1H), 6.16 (dd, J=2.5, 8.7 Hz, 1H), 3.86 (s, 3H), 3.82 (s, 3H), 2.82 (s, 3H).
b) (2-Chloro-quinazolin-4-yl)-(3,4-dimethoxy-phenyl)-methyl-amine hydrochloride: A mixture of 2,4-dichloro-quinazoline (88 wt %, 758 mg, 3.4 mmol), (3,4-dimethoxy-phenyl)-methyl-amine (502 mg, 3.00 mmol) and 2 drops of concd HCl in i-PrOH (11 mL) was reacted for 16 h then the product was collected on a Büchner funnel, washed with i-PrOH and dried. The title compound was obtained as a pale yellow solid (792 mg; 72%). ¹H NMR (CDCl₃) δ 8.65 (m, 1H), 7.75 (m, 1H), 7.18 (m, 1H), 7.00 (d, J=8.4 Hz, 1H), 6.90 (m, 1H), 6.85-6.78 (m, 2H), 3.99 (s, 3H), 3.87 (s, 3H), 3.83 (s, 3H); LC-MS (ESI⁺; 330 ([M+H]⁺)).
c) A suspension of (2-chloro-quinazolin-4-yl)-(3,4-dimethoxy-phenyl)-methyl-amine hydrochloride (106 mg; 0.289 mmol), methylamine hydrochloride (198 mg; 2.93 mmol) and sodium carbonate (340 mg; 3.21 mmol) in i-PrOH (4 mL) was heated at 90° C. After 41 h, the suspension was concentrated then water (5 mL) was added. The product was extracted into chloroform (3×2 mL) and the combined extracts washed with water (3×2 mL) and brine (2×3 mL). This solution was dried (MgSO₄), filtered through silica and washed with 100:10:1 CHCl₃:MeOH:concentrated NH₄OH, concentrated then purified by MPLC (12 g SiO2/0-30% (20:1 MeOH:concentrated NH₄OH) in CHCl₃gradient). Product was obtained as an oil, which solidified to a pale yellow solid under high vacuum (74 mg; 79%). ¹H NMR (CDCl₃) δ 7.46 (m, 1H), 7.38 (m, 1H), 6.90 (m, 1H), 6.84 (m, 1H), 6.76-6.65 (m, 3H), 3.91 (s, 3H), 3.78 (s, 3H), 3.53 (s, 3H), 3.12 (d, 3H); LC-MS (ESI⁺; 325 ([M+H]⁺)).

Example 168

N⁴-(3,4-Dimethoxy-phenyl)-N²,N²,N⁴-trimethyl-quinazoline-2,4-diamine

A solution of (2-chloro-quinazolin-4-yl)-(3,4-dimethoxy-phenyl)-methyl-amine hydrochloride (105 mg; 0.287 mmol) and ammonium fluoride (73 mg; 1.97 mmol) in DMF (2 mL) was heated at 90° C. After 4 days the reaction was concentrated on a rotary evaporator then saturated NaHCO₃(5 mL) and water (3 mL) were added. Product was extracted into chloroform (4×2 mL) and the combined extracts washed with water (4×2 mL) and brine (3×3 mL). This solution was dried (MgSO₄), filtered through silica and washed with 100:10:1 CHCl₃:MeOH:concentrated NH₄OH, concentrated then purified by MPLC (12 g SiO₂/0-10% (20:1 MeOH:concentrated NH₄OH) in CHCl₃gradient). Product was obtained as an oil, which solidified to a tan solid under high vacuum (68 mg; 70%). ¹H NMR (CDCl₃) δ 7.45 (m, 1H), 7.35 (m, 1H), 6.89 (m, 1H), 6.83 (m, 1H), 6.75-6.68 (m, 2H), 6.64 (m, 1H), 3.90 (s, 3H), 3.77 (s, 3H), 3.54 (s, 3H), 3.31 (s, 6H); LC-MS (ESI⁺; 339 ([M+H]⁺).

Example 169

2-{6-Methoxy-4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-ylamino}-ethanol

A mixture of (2-chloro-6-methoxy-quinazoline-4-yl)-(4-methoxy-phenyl)-methyl-amine (0.2 g, 0.60 mmol), and 2-hydroxylethylamine (1.5 ml) was microwaved at 120° C. for 20 min. The excess of 2-hydroxylamine evaporated under reduced pressure. The product was isolated by preparative TLC(CH2CL2/MeOH=5/3 as eluent) yielded 35 mg (18%). ¹H NMR (DMSO): δ 7.2 (d, 2H), 7.1 (d, 2H), 7.05 (d, 1H), 6.9 (d, 2H), 6.2 (s, 1H), 3.75 (s, 3H), 3.5 (t, 2H), 3.4 (t, 2H), 3.41 (s, 3H), 3.2 (s, 3H).

Example 170

(2-Chloro-5,6,7,8-tetrahydro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine

A mixture of 2-methoxylcarbonyl cyclohexanone 5.00 g (455 mmol) and urea 6.00 g (100.0 mmol) with 2 mL of ethanol was stirred for 48 h under reflux. After cooling, the formed crude product was washed with water and dried in vacuo to give ca. 4 g of 5,6,7,8-tetrahydro-1H-quinazoline-2,4-dione. A mixture of 5,6,7,8-tetrahydro-1H-quinazoline-2,4-dione 2.00 g (12.0 mmol) and POCl ₃10 mL was stirred under reflux for 3 h. After cooling, excess of POCl₃was removed under reduced pressure, and the crude product was diluted with CHCl₃, which was poured into ice-water, washed with water, and dried on anhydrous MgSO₄. Removal of CHCl₃gave 2,4-dichloro-5,6,7,8-tetrahydro-1H-quinazoline in 95% yield. A solution of 2,4-dichloro-5,6,7,8-tetrahydro-1H-quinazoline 0.615 g (3.0 mmol) and 4-methoxy-N-methylaniline 0.411 g (1.0 mmol) with conc. HCl 0.5 mL in iso-propanol 30 mL was stirred at 23° C. for 16 h. The solution was concentrated under reduced pressure, diluted with CH₂Cl₂30 mL, washed with sat. Na₂CO₃aqueous solution, and dried on anhydrous MgSO₄. After removal of solvents, the crude product was purified with gradient column chromatography (EtOAc/hexanes, 0% to 60%) to give titled product in 50% yield, which was further purified with preparative HPLC to give the corresponding TFA salt. ¹H NMR (CDCl₃, 400 MHz): δ 7.02 (d, 2H, J=9.0 Hz), 6.86 (d, 2H, J=9.0 Hz), 3.83 (s, 3H), 3.40 (s, 3H), 2.73 (t, 2H, J=6.7 Hz), 1.62-1.68 (m, 4H), 1.44-1.49 (m, 2H). m/z: 304.1236 (M+1).

Example 171

(4-Methoxy-phenyl)-methyl-(2-trifluoromethyl-quinolin-4-yl)-amine

A mixture of 4-chloro-2-(trifluoromethyl)quinoline 0.232 g (1.0 mmol) and 4-methoxy-N-methylaniline 0.137 g (1.0 mmol) in glacial acetic acid 3 mL was stirred at 100-110° C. for 24 h. The reaction mixture was directly subjected to gradient column chromatography (EtOAc/hexanes, 0% to 50%) to give the titled compound in 70% yield. ¹H NMR (CDCl₃, 400 MHz): δ 8.11-8.08 (m, 1H), 7.62-7.58 (m, 1H), 7.58-7.55 (m, 1H), 7.27-7.22 (m, 2H), 6.97 (d, 2H, J=9.0 Hz), 6.84 (d, 2H, J=9.0 Hz), 3.79 (s, 3H), 3.49 (s, 3H). m/z: 333.2 (M+1).

Example 172

N-{4-[(4-Methoxy-phenyl)-methyl-amino]-quinazolin-2-yl}-O-methyl-hydroxylamine

A mixture of (2-chloroquinazolin-4-yl)-(4-methoxyphenyl)-methylamine 0.335 g (1.0 mmol), O-methyl-hydroxyamine hydrochloride 0.10 g (1.2 mmol) and Et₃N 0.5 mL (5.0 mmol) in isopropanol 4 mL was stirred at 85° C. for 24 h. After removal of isopropanol, the residue was purified by preparative HPLC to give the title compound as the corresponding TFA salt. ¹H NMR (CD₃OD, 400 MHz) δ 7.64-7.71 (m, 2H), 7.30-7.34 (m, 2H), 7.06-7.10 (m, 2H), 6.99-7.04 (m, 1H), 6.82-6.84 (m, 1H), 3.93 (s, 3H), 3.87 (s, 3H), 3.66 (s, 3H); LC-MS (ESI⁺; 311 ([M+H]⁺)).

Example 173

2-{4-[(3,4-Dimethoxy-phenyl)-methyl-amino]-quinazolin-2-ylamino}-ethanol

A mixture of (2-chloro-quinazolin-4-yl)-(3,4-dimethoxy-phenyl)-methyl-amine hydrochloride (63 mg; 0.172 mmol) and ethanolamine (32 μL; 0.53 mmol) in n-butanol (2 mL) was heated at 110° C. for 24 h then concd in vacuo. The material was partitioned between DCM (5 mL) and satd NaHCO₃(3 mL). The organic layer was dried (MgSO₄), filtered through silica and washed with 100:10:1 CHCl₃:MeOH:concd NH₄OH, concd then purified by pTLC (EM-13793; 100:10:1 CHCl₃:MeOH:concd NH₄OH) yielding a pale yellow glass (52 mg; 85%). ¹H NMR (CDCl₃) δ 7.44-7.34 (m, 2H), 6.88 (m, 1H), 6.84 (d, J=8.4 Hz, 1H), 6.75-6.67 (m, 3H), 5.42 (t(br), 1H), 3.91 (s, 3H), 3.91 (m, 2H), 3.79 (s, 3H), 3.68 (m, 2H), 3.50 (s, 3H); LC-MS (ESI⁺; 355 ([M+H]⁺).

Example 174

2-({4-[(4-Methoxy-phenyl)-methyl-amino]-quinazolin-2-yl}-methyl-amino)-ethanol

A mixture of (2-chloroquinazolin-4-yl)-(4-methoxyphenyl)-methylamine 0.335 g (1.0 mmol), 2-methylamino-ethanol 1.0 mL was stirred at 130° C. for 20 minutes under microwave irradiation. The crude mixture was directly charged to silica-gel, and purified by MPLC (SiO₂, EtOAc 0˜100% in hexanes) to give the title compound. ¹H NMR (CDCl₃, 400 MHz) δ 7.31-7.40 (m, 2H), 7.08-7.11 (m, 2H), 6.87-6.90 (m, 2H), 6.81-6.84 (m, 1H), 6.61-6.65 (m, 1H), 3.94-3.96 (m, 2H), 3.84-3.86 (m, 2H), 3.82 (s, 3H), 3.51 (s, 3H), 3.34 (s, 3H); HRMS (ES) m/z calcd for C₁₉H₂₂N₄O₂(M+H) 339.1815. found 339.1830.

Example 175

N²-(2-Amino-ethyl)-6-methoxy-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine

a) (2-{6-Methoxy-4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-ylamino}-ethyl)-carbamic acid tert-butyl ester: A mixture of (2-chloro-6-methoxy-quinazoline-4-yl)-(4-methoxy-phenyl)-methyl-amine (0.6 g, 1.81 mmol), (2-amino-ethyl)-carbamic acid tert-butyl ester (0.4 g, 2.54 mmol) and diisopropylethylamine (0.76 mL, 4.4 mmol) in 3 mL of n-BuOH was stirred at 130° C. for 2 days. The solvent was evaporated under reduced pressure. The title compound (0.56 g; 70%) was isolated by preparative TLC (CH₂Cl₂/MeOH=5/3 as eluent). ¹H NMR (DMSO-d₆) δ 7.3-7.28 (d, 1H), 7.2 (d, 2H), 7.11-7.08 (d, 1H), 7.02-7.00 (d, 2H), 6.2 (s, 1H), 3.7 (s, 3H), 3.46 (s, 3H), 3.42 (t, 2H), 3.23 (s, 3H), 3.17 (t, 2H), 1.37 (s, 9H); LC-MS (ESI⁺; 454 ([M+H]⁺).
b) N²-(2-Amino-ethyl)-6-methoxy-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine: 0.56 g (1.23 mmol) of (2-{6-methoxy-4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-ylamino}-ethyl)-carbamic acid tert-butyl ester in 5 mL DCM was treated with 1 mL of trifluoroacetic acid. After 2 hours the reaction mixture was quenched with satd NaHCO₃. The organics washed with water, dried over MgSO₄, filtered, concentrated. ¹H NMR (DMSO-d₆) δ 7.88-6.2 (7H), 4.1 (t, 2H), 3.79 (s, 3H), 3.24 (s, 3H), 3.16 (s, 3H), 3.09 (t, 2H); LC-MS (ESI⁺; 354 ([M+H]⁺)).

Example 176

(4-Methoxy-phenyl)-methyl-(2-methyl-thieno[2,3-d]pyrimidin-4-yl)-amine

a) 2-Methyl-3H-thieno[2,3-d]pyrimidin-4-one: A solution of methyl 2-aminothiophene-3-carboxylate 1.57 g (10.0 mmol) in acetonitrile 20 mL was heated at 50° C. and HCl gas was passed through the solution for 10 minutes. The reaction mixture was then stirred at 80° C. for 18 h. The product was extracted with ethyl acetate, washed with water, and dried on MgSO₄. The crude product was purified by MPLC (SiO₂, EtOAc 0˜100% in hexanes). LC-MS (ESI⁺; 167 ([M+H]⁺)).
b) 4-Chloro-2-methyl-thieno[2,3-d]pyrimidine: A mixture of 2-methyl-3H-thieno[2,3-d]pyrimidin-4-one 0.100 g (0.6 mmol) with POCl ₃4 mL was stirred at reflux for 4 h. After excess POCl₃was removed under reduce pressure, the residue was charged to silica-gel, and purified by MPLC (SiO₂, EtOAc 0˜100% in hexanes) to give the chlorinated intermediate. LC-MS (ESI⁺; 285 ([M+H]⁺)).
c) (4-M ethoxy-phenyl)-methyl-(2-methyl-thieno[2,3-d]pyrimidin-4-yl)-amine: 4-Chloro-2-methyl-thieno[2,3-c]pyrimidine was dissolved in THF 5 mL, and (4-methoxy-phenyl)-methyl-amine 0.137 g (1.0 mmol) was added along with Et₃N 0.2 mL (2.0 mmol). After the reaction mixture was stirred at reflux for 18 h, the crude product was charged to silica-gel, and purified by MPLC (SiO₂, EtOAc 0˜100% in hexanes) to give the title compound, which was further purified by preparative HPLC for analytical use. ¹H NMR (CD₃OD, 400 MHz) δ 7.33-7.38 (m, 2H), 7.18 (d, J=5.9 Hz, 1H), 7.11-7.14 (m, 2H), 5.55 (d, J=6.1 Hz, 1H), 3.89 (s, 3H), 3.70 (s, 3H), 2.71 (s, 3H); LC-MS (ESI⁺; 286 ([M+H]⁺)).

Example 177

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

A mixture of 2,4-dichloro-quinazoline (88 wt %, 525 mg, 2.3 mmol), (2-methoxy-benzyl)-methyl-amine (300 μL, 2.01 mmol) and 1 drop of concd HCl in i-PrOH (8 mL) was reacted for 5 days then concd in vacuo. Satd NaHCO₃(5 mL) was added then the product extracted into CHCl₃(2×4 mL). The organic portion was washed with water (1×3 mL) then dried (MgSO₄), filtered through a plug of silica with an EtOAc wash then purified by MPLC (SiO₂/0-20% i-PrOH in CHCl₃) yielding the title compound as a white solid (247 mg; 39%). ¹H NMR (CDCl₃) δ 7.83-7.77 (m, 2H), 7.67 (m, 1H), 7.40-7.32 (m, 2H), 7.26 (m, 1H), 7.01 (m, 1H), 6.95 (m, 1H), 4.96 (s, 2H), 3.81 (s, 3H), 3.31 (s, 3H); LC-MS (ESI⁺; 314 ([M+H]⁺)).

Example 178

N²-(2-Chloro-ethyl)-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine

A mixture of (2-chloroquinazolin-4-yl)-(4-methoxyphenyl)-methylamine 0.671 g (2.0 mmol), 2-chloro-ethylamine hydrochloride 0.58 g (5.0 mmol) and N-methylmorpholine 1.0 mL in DMF 1.0 mL was stirred under microwave irradiation at 130° C. for 20 minutes. The crude mixture was directly charged to silica-gel, and purified by MPLC (SiO₂, EtOAc 0˜100% in hexanes) to give the title compound. ¹H NMR (CDCl₃, 400 MHz) δ 7.44-7.46 (m, 1H), 7.34-7.38 (m, 1H), 7.08-7.11 (m, 2H), 6.85-6.91 (m, 3H), 6.65-6.70 (m, 1H), 3.92-3.94 (m, 2H), 3.82-3.84 (m, 2H), 3.82 (s, 3H), 3.50 (s, 3H).

Example 179

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

The title compound was prepared from 2,4-dichloro-quinazoline (88 wt %, 525 mg, 2.3 mmol) and (2-methoxy-benzyl)-methyl-amine (300 μL, 2.01 mmol) by a procedure similar to Example 177, with an additional MPLC purification (SiO₂/0-40% EtOAc in hexanes), yielding an off-white solid (336 mg; 53%). ¹H NMR (CDCl₃) δ 7.91 (m, 1H), 7.80 (m, 1H), 7.70 (m, 1H), 7.37-7.29 (m, 2H), 6.99-6.96 (m, 2H), 6.90 (m, 1H), 4.97 (s, 2H), 3.83 (s, 3H), 3.34 (s, 3H); LC-MS (ESI⁺; 314 ([M+H]⁺)).

Example 180

3-{4-[(4-Methoxy-phenyl)-methyl-amino]-quinazolin-2-ylamino}-propan-1-ol

A mixture of (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine hydrochloride (88 mg, 0.26 mmol) and 3-amino-propan-1-ol (62 μL, 0.82 mmol) in n-BuOH (2 mL) was heated at 115° C. for 29 h then concd in vacuo. Chloroform (5 mL) was added and this washed with satd NaHCO₃(1×2 mL); then dried (MgSO₄), filtered through silica with a wash of 100:10:1 CHCl₃:MeOH:concd NH₄OH, concd then purified by MPLC (amine column (Isco 60-2203-201)/0-100% i-PrOH in CHCl₃) yielding the title compound as a pale yellow oil (70 mg; 79%). ¹H NMR (CDCl₃) δ 7.43 (m, 1H), 7.38 (m, 1H), 7.12 (m, 2H), 6.92 (m, 2H), 6.80 (m, 1H), 6.69 (m, 1H), 3.84 (s, 3H), 3.78-3.66 (m, 4H), 3.52 (s(br), 3H), 1.81 (m, 2H); LC-MS (ESI⁺; 339 ([M+H]⁺)).

Example 181

4-{4-[(4-Methoxy-phenyl)-methyl-amino]-quinazolin-2-ylamino}-butan-1-ol

The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine hydrochloride (81 mg, 0.24 mmol) and 4-amino-butan-1-ol (69 μL, 0.75 mmol) by a procedure similar to Example 180, yielding a pale yellow oil (55 mg; 65%). ¹H NMR (CDCl₃) δ 7.48 (m, 1H), 7.38 (m, 1H), 7.12 (m, 2H), 6.91 (m, 2H), 6.81 (m, 1H), 6.69 (m, 1H), 3.84 (s, 3H), 3.78 (t, J=6Hz, 2H), 3.60 (m, 2H), 3.53 (s, 3H), 1.82 (m, 2H), 1.73 (m, 2H);

LC-MS (ESI⁺; 353 ([M+H]⁺)).

Example 182

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

A mixture of (2-chloroquinazolin-4-yl)-(4-methoxyphenyl)-methylamine 3.98 g (20.0 mmol) in ethanol 4 mL and concd HCl 3 mL was stirred at room temperature for 14 h. After removal of ethanol, the residue was dissolved in ethyl acetate, and the organic solution was washed with water, satd Na₂CO₃, and dried over anhydrous MgSO₄. After removal of solvent under reduced pressure, the crude product was purified by MPLC (SiO₂, EtOAc 0˜100% in hexanes) to give the title compound. ¹H NMR (CDCl₃, 400 MHz) δ 7.91-7.94 (m, 1H), 7.54-7.61 (m, 2H), 7.25-7.29 (m, 2H), 7.12-7.16 (m, 1H), 6.90-6.94 (m, 1H), 4.29 (q, J=7.0 Hz, 2H), 3.84 (s, 3H), 3.60 (s, 3H), 1.34 (t, J=7.0 Hz, 3H); LC-MS (ESI⁺; 310 ([M+H]⁺)).

Example 183

N²-(3-Dimethylamino-propyl)-N⁴-(4-methoxy-phenyl)-N²,N⁴-dimethyl-quinazoline-2,4-diamine

The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (200 mg, 0.67 mmol) and N,N,N-trimethyl-1,3-propane diamine (116 mg, 1.0 mmol) by a procedure similar to Example 1 and was isolated as a brown oil (112 mg, 44%). ¹H NMR (CDCl₃) δ 7.5 (d, 1H), 7.4 (m, 1H), 7.15 (d, 2H), 6.9 (m, 3H), 6.6 (m, 1H), 3.81 (s, 3H), 3.78 (t, 2H), 3.5 (s, 3H), 3.48 (s, 3H), 3.3 (s, 3H), 2.4 (m, 2H), 2.2 (s, 3H), 1.8 (m, 2H); LC-MS (ESI⁺; 380 ([M+H]⁺)).

Example 184

N²-(4-Amino-butyl)-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine

N²-(4-Aminobutyl)-N⁴-(4-methoxyphenyl)-N⁴-methylquinazoline-2,4-diamine: To a suspension of (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (300 mg, 1.0 mmol) in n-butanol (3 mL) and diisopropylethylamine (323 mg, 2.5 mmol) was added 1,4-butanediamine (132 mg, 1.5 mmol). The reaction was heated to 105° C. for 18 h, cooled to room temperature and concentrated. The crude product was purified by chromatography (amine column, i-PrOH/CHCl₃, 0-100%) to give 138 mg (39%) of the title compound. ¹H NMR (CDCl₃) δ 7.5 (d, 1H), 7.4 (t, 1H), 7.15 (d, 2H), 6.95 (d, 2H), 6.7 (m, 2H), 3.8 (s, 3H), 3.6 (s, 3H), 3.55 (t, 2H), 2.8 (t, 2H), 2.1 (s, 3H), 1.75 (pentet, 2H), 1.63 (pentet, 2H); LC-MS (ESI⁺; 352 ([M+H]⁺)).

Example 185

(4-Methoxy-phenyl)-methyl-(2-methyl-thieno[3,2-d]pyrimidin-4-yl)-amine

a) 2-Methyl-3H-thieno[3,2-d]pyrimidin-4-one: A solution of methyl 3-aminothiophene-2-carboxylate 0.79 g (5.0 mmol) in acetonitrile 10 mL was heated at 50° C. and HCl gas was passed through the solution for 10 minutes. The reaction mixture was then stirred at 80° C. for 18 h. Then, the reaction mixture was added 1 N NaOH 10 mL and heated at reflux for 1 h. The product was extracted with ethyl acetate, washed with water, and dried on MgSO₄. The crude product was purified by MPLC (SiO₂, EtOAc 0˜100% in hexanes) to give the intermediate 2-methyl-3H-thieno[3,2-d]pyrimidin-4-one. LC-MS (ESI⁺; 167 ([M+H]⁺)).
b) 4-Chloro-2-methyl-thieno[3,2-d]pyrimidine: A mixture of 2-methyl-3H-thieno[3,2-d]pyrimidin-4-one 0.100 g (0.6 mmol) with POCl ₃5 mL was stirred at reflux for 5 h. After excess POCl₃was removed under reduce pressure, the residue was charged to silica-gel, and purified by MPLC (SiO₂, EtOAc 0˜100% in hexanes) to give the chlorinated intermediate 4-chloro-2-methyl-thieno[3,2-d]pyrimidine. LC-MS (ESI⁺; 285 ([M+H]⁺)).
c) (4-M ethoxy-phenyl)-methyl-(2-methyl-thieno[3,2-c]pyrimidin-4-yl)-amine: 4-Chloro-2-methyl-thieno[3,2-d]pyrimidine was dissolved in THF 5 mL, and (4-methoxy-phenyl)-methyl-amine 0.137 g (1.0 mmol) was added along with Et₃N 0.2 mL (2.0 mmol). After the reaction mixture was stirred at reflux for 18 h, the crude product was charged to silica-gel, and purified by MPLC (SiO₂, EtOAc 0˜100% in hexanes) to give the title compound, which was further purified by preparative HPLC for analytical use. ¹H NMR (CDCl₃, 400 MHz) δ 7.68 (apparent s, 2H), 7.26-7.31 (m, 2H), 7.04-7.07 (m, 2H), 3.92 (s, 3H), 3.71 (s, 3H), 2.84 (s, 3H); LC-MS (ESI⁺; 286 ([M+H]⁺)).

Example 186

2-{4-[(4-Methoxy-phenyl)-methyl-amino]-6-nitro-quinazolin-2-ylamino}-ethanol

6-Nitro-1H-quinazoline-2,4-dione: A mixture of 5 g (27.4 mmol) of 5-nitroanthranilic acid and 22.9 g (274.0 mmol) of urea was heated to 160° C. and the melt stirred overnight. The reaction mixture was allowed to cool to 100° C. and 5 mL of water was added to dissolve the urea. The solid was filtered and suspended in 100 mL of 0.5 N NaOH and heated to boiling for 40 min to allow formation of the sodium salt. Then the mixture was cooled down and the pH was adjusted with 1 M HCl until pH=5. The precipitate was filtered off and washed with water and dried in vacuo to give 5.12 g of the title compound. ¹H NMR (DMSO-d₆) δ 11.7 (s, 2H), 8.6 (s, 1H), 8.45 (d, 1H), 7.4 (d, 1H); LC-MS (ESI⁺; 208 ([M+H]⁺)).
2,4-Dichloro-6-nitro-quinazoline: The title compound was prepared similar to Example 175. LC-MS (ESI⁺; 245 ([M+H]⁺)).
(2-Chloro-6-nitro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine: A mixture of 1.65 g (6.76 mmol) of 2,4-dichloro-6-nitro-quinazoline, 1.02 g (7.44 mmol) of (4-methoxy-phenyl)-methyl-amine, 0.6 g (7.43 mmol) of NaOAc in 6 mL of THF and 6 mL of water was stirred at ambient temperature for 18 hours. The reaction mixture extracted with EtOAc (2×15 mL) and organics were washed with NaHCO₃, dried and concentrated. Isolation done by MPLC (0-30% EtOAc/hexanes as eluent) to give 1.86 g of the title compound. ¹H NMR (DMSO-d₆) δ 8.38-7.13 (7H), 3.84 (s, 3H), 3.59 (s, 3H); LC-MS (ESI⁺; 345 ([M+H]⁺)).
2-{4-[(4-Methoxy-phenyl)-methyl-amino]-6-nitro-quinazolin-2-ylamino}-ethanol: A mixture of 77 mg (0.22 mmol) of (2-chloro-6-nitro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine and 68 mg (1.12 mmol) of ethanolamine in n-BuOH was heated at 120° C. for 18 hours. The reaction mixture concentrated and the isolation was done by preparative HPLC to give the title compound. ¹H NMR (DMSO-d₆), δ 8.2-7.1 (7H), 3.83 (3H), 3.82 (s, 2H), 3.62 (d, 3H), 3.56 (s, 2H); LC-MS (ESI⁺; 294 ([M+H]⁺)).

Example 187

({4-[(4-Methoxy-phenyl)-methyl-amino]-quinazolin-2-yl}-methyl-amino)-acetic acid methyl ester

A mixture of (2-chloroquinazolin-4-yl)-(4-methoxyphenyl)-methylamine 0.335 g (1.0 mmol), sarcosine methyl ester hydrochloride 0.139 g (1.0 mmol) with Et₃N 1.0 mL (10.0 mmol) in DMF 2 mL was stirred at 130° C. for 20 minutes under microwave irradiation. The crude mixture was directly charged to silica-gel, and purified by MPLC (SiO₂, EtOAc 0-100% in hexanes) to give the title compound, which was further purified by preparative HPLC for analytical use. ¹H NMR (CD₃OD, 400 MHz) δ 7.63-7.70 (m, 2H), 7.31 (d, J=9.0 Hz, 2H), 7.07-7.11 (m, 2H), 6.97-7.01 (m, 1H), 6.80 (d, J=8.4 Hz, 1H), 4.62 (s, 2H), 3.87 (s, 3H), 3.81 (s, 3H), 3.62 (s, 3H), 3.45 (s, 3H); HRMS (ES) m/z calcd for C₂₀H₂₂N₄O₃(M+H) 367.1764. found 367.1772.

Example 188

(4-Methoxy-phenyl)-methyl-(2-methyl-5,6,7,8-tetrahydro-quinazolin-4-yl)-amine

a) 2-Methyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one: To a solution of sodium methoxide (4.63 M solution in methanol) 5.4 mL (25.0 mmol) in methanol 50 mL was added acetamidine hydrochloride 2.4 g (25.0 mmol), and ethyl cyclohexanone-2-carboxylate 4.25 g (25.0 mmol). The reaction mixture was stirred at room temperature for overnight. After concentrated under reduced pressure, the residue was dissolved in water 100 mL and acidified by addition of 6 N HCl. The product was extracted with ethyl acetate to give the crude product 2-methyl-5,6,7,8-tetrahydro-3H-quinazolin-2-one.
b) 4-Chloro-2-methyl-5,6,7,8-tetrahydro-quinazoline: A mixture of 2-methyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one 0.300 g (2.0 mmol) and POCl₃20 mL with DMF 0.1 mL was stirred at reflux for 4 h. After removal of excess POCl₃, the residue was diluted with dichloromethane, and the solution was washed with cooled water, and dried over MgSO₄. Removal of solvents gave the crude intermediate 4-chloro-2-methyl-5,6,7,8-tetrahydro-quinazoline.
c) (4-Methoxy-phenyl)-methyl-(2-methyl-5,6,7,8-tetrahydro-quinazolin-4-yl)-amine: To a solution of the crude chlorinated intermediate in isopropanol 15 mL was added 4-methyl-N-methylaniline 0.41 g (3.0 mmol) with concd HCl 2 mL, and the reaction mixture was stirred at room temperature for 48 h. The mixture was directly charged to silica-gel, and purified by MPLC (SiO₂, EtOAc 0˜100% in hexanes) to give the title compound. ¹H NMR (CD₃OD, 400 MHz) δ 6.97-6.99 (m, 2H), 6.81-6.85 (m, 2H), 3.81 (s, 3H), 3.39 (s, 3H), 2.72 (t, J=6.5 Hz, 2H), 2.57 (s, 3H), 1.64-1.73 (m, 4H), 1.46-1.50 (m, 2H); HRMS (ES) m/z calcd for C₁₇H₂₁N₃O (M+H) 284.1757. found 284.1760.

Example 189

2-{6-Amino-4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-ylamino}-ethanol

The title compound was produced in the same manner as the compound in Example 101 from 2-{4-[(4-methoxy-phenyl)-methyl-amino]-6-nitro-quinazolin-2-ylamino}-ethanol. ¹H NMR (DMSO-d₆) δ 7.3-5.8 (7H), 5.07 (s, 2H), 3.82 (s, 3H), 3.63 (m, 2H), 3.55 (s, 3H), 3.51 (m, 2H); LC-MS (ESI⁺; 340 ([M+H]⁺)).

Example 190

N-{4-[(4-Methoxy-phenyl)-methyl-amino]-5,6,7,8-tetrahydro-quinazolin-2-yl}-O-methyl-hydroxylamine

A mixture of (2-chloro-5,6,7,8-tetrahydro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine 0.100 g (0.33 mmol), O-methyl-hydroxylamine 0.166 g (2.0 mmol) and ethyl-diisopropyl-amine 0.5 mL in isopropanol 5 mL was stirred at 100° C. for 48 h. The reaction mixture was concentrated, and the crude product was purified by preparative HPLC to give the title compound as the corresponding TFA salt. ¹H NMR (CDCl₃, 400 MHz) δ 7.08-7.11 (m, 2H), 6.91-6.93 (m, 2H), 3.89 (s, 3H), 3.86 (s, 3H), 3.54 (s, 3H), 2.71 (t, J=6.3 Hz, 2H), 1.60-1.62 (m, 2H), 1.52 (t, J=5.9 Hz, 2H), 1.41-1.45 (m, 2H); HRMS (ES) m/z calcd for C₁₇H₂₂N₄O₂(M+H) 315.1815. found 315.1865.

Example 191

{4-[(4-Methoxy-phenyl)-methyl-amino]-5,6,7,8-tetrahydro-quinazolin-2-ylamino}-acetic acid ethyl ester

A mixture of (2-chloro-5,6,7,8-tetrahydro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine 0.100 g (0.33 mmol), ethyl 2-aminoacetate 0.279 g (2.0 mmol) and ethyl-diisopropyl-amine 0.5 mL in isopropanol 5 mL was stirred at 100° C. for 48 h. The reaction mixture was concentrated, and the crude product was purified by preparative HPLC to give the title compound as the corresponding TFA salt. ¹H NMR (CDCl₃, 400 MHz) δ 9.88 (s(br), 1H), 7.04-7.08 (m, 2H), 6.89-6.92 (m, 2H), 4.22 (q, J=7.0 Hz, 2H), 4.16 (apparent d, 2H), 3.85 (s, 3H), 3.38 (s, 3H), 2.70 (t, J=6.4 Hz, 2H), 1.59-1.62 (m, 2H), 1.49 (t, J=5.9 Hz, 2H), 1.39-1.43 (m, 2H), 1.28 (t, J=7.2 Hz, 3H); HRMS (ES) m/z calcd for C₂₀H₂₆N₄O₃(M+H) 371.2077. found 371.2070.

Example 192

N⁴-(4-Methoxy-phenyl)-N²,N⁴-dimethyl-5,6,7,8-tetrahydro-quinazoline-2,4-diamine

A mixture of (2-chloro-5,6,7,8-tetrahydro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine 0.100 g (0.33 mmol), methylamine 2 M aqueous solution (2 mL, 2.0 mmol) in isopropanol 5 mL was stirred at 100° C. for 48 h. After concentration under reduced pressure, the crude product was purified with preparative HPLC to give the title compound as the corresponding TFA salt. ¹H NMR (CD₃OD, 400 MHz) δ 7.19 (d, J=8.0 Hz, 2H), 6.98 (d, J=8.0 Hz, 2H), 3.83 (s, 3H), 3.51 (s, 3H), 3.03 (s, 3H), 2.59 (t, J=6.5 Hz, 2H), 1.61-1.64 (m, 2H), 1.55-1.58 (m, 2H), 1.41-1.46 (m, 2H); HRMS (ES) m/z calcd for C₁₇H₂₂N₄O (M+H) 299.1866. found 299.1884.

Example 193

N²-(2-Amino-ethyl)-N⁴-(3,4-dimethoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine

a) (2-Chloro-quinazolin-4-yl)-(3,4-dimethoxy-phenyl)-methyl-amine: The free base of (2-chloro-quinazolin-4-yl)-(3,4-dimethoxy-phenyl)-methyl-amine hydrochloride was obtained by adding EtOAc to the solid and washing with satd NaHCO₃, water, satd NaCl; then drying (MgSO₄), filtering through silica with an EtOAc wash and concentrating in vacuo yielding an off-white solid. ¹H NMR (CDCl₃) δ 7.74 (m, 1H), 7.57 (m, 1H), 7.02 (m, 1H), 6.95 (m, 1H), 6.89 (d, J=8.4 Hz, 1H), 6.79 (dd, J=2.4, 8.4 Hz, 1H), 6.74 (d, J=2.4 Hz, 1H), 3.94 (s, 3H), 3.81 (s, 3H), 3.63 (s, 3H).
b) (2-{4-[(3,4-Dimethoxy-phenyl)-methyl-amino]-quinazolin-2-ylamino}-ethyl)-carbamic acid tert-butyl ester: A soln of (2-chloro-quinazolin-4-yl)-(3,4-dimethoxy-phenyl)-methyl-amine (440 mg, 1.33 mmol), ethyl-diisopropyl-amine (0.47 mL, 2.70 mmol) and (2-amino-ethyl)-carbamic acid tert-butyl ester (316 μL, 2.00 mmol) in n-BuOH (5 mL) was reacted at 110° C. for 29 h then concd on a rotary evaporator. The crude material was dissolved in CHCl₃(8 mL) then washed with satd NaHCO₃(2×3 mL) and water (1×3 mL). This soln was dried (MgSO₄), filtered through a plug of silica with a wash of 100:10:1 CHCl₃:MeOH:concd NH₄OH, concentrated, then purified by MPLC (amine column (Isco 68-2203-101)/0-100% i-PrOH in CHCl₃), yielding the title compound as a tan solid (550 mg; 91%). ¹H NMR (CDCl₃) δ 7.46-7.35 (m, 2H), 6.90-6.82 (m, 2H), 6.77-6.66 (m, 3H), 5.80 (s(br), 1H), 5.44 (s(br), 1H), 3.92 (s, 3H), 3.79 (s, 3H), 3.68 (m, 2H), 3.53 (s, 3H), 3.44 (m, 2H), 1.44 (s, 9H); LC-MS (ESI⁺; 454 ([M+H]⁺)).
c) N²-(2-Amino-ethyl)-N⁴-(3,4-dimethoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine: (2-{4-[(3,4-Dimethoxy-phenyl)-methyl-amino]-quinazolin-2-ylamino}-ethyl)-carbamic acid tert-butyl ester (550 mg, 1.21 mmol) was reacted with neat trifluoroacetic acid (10 mL). After 20 min the rxn was concd in vacuo then dissolved in THF (5 mL). Bicarbonate resin (Novobiochem 01-64-0419; 0.6 g; 6.2 mmol g⁻¹) was added. After 1.0 h with occasional swirling, the rxn was filtered (0.45 μm), then concd in vacuo yielding a peach-colored hard foam (412 mg; 96%). ¹H NMR (CDCl₃) δ 7.42 (m, 1H), 7.37 (m, 1H), 6.90 (m, 1H), 6.83 (s, 1H), 6.76-6.70 (m, 2H), 6.68 (m, 1H), 5.29 (s(br), 1H), 3.91 (s, 3H), 3.78 (s, 3H), 3.63 (app q, J=6.0 Hz, 2H), 3.52 (s, 3H), 3.00 (app t, J=6.0 Hz, 2H); LC-MS (ESI⁺; 354 ([M+H]⁺)).

Example 194

2-{4-[(4-Methoxy-phenyl)-methyl-amino]-5,6,7,8-tetrahydro-quinazolin-2-ylamino}-ethanol

A mixture of (2-chloro-5,6,7,8-tetrahydro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine 0.150 g (0.5 mmol), ethanolamine 0.2 mL (3.0 mmol) with Et₃N 0.2 mL in isopropanol 5 mL was stirred at 100° C. for 48 h. The reaction mixture was diluted with CH₂Cl₂, and directly charged to gradient column chromatography (MeOH/CH₂Cl₂, 0% to 20%) to give the title compound. For analytical use, it was further purified with preparative HPLC to give the corresponding TFA salt. ¹H NMR (CD₃OD, 400 MHz) δ 7.19 (d, J=8.0 Hz, 2H), 6.98 (d, J=8.0 Hz, 2H), 3.83 (s, 3H), 3.76 (t, J=5.6 Hz, 2H), 3.62 (t, J=5.6 Hz, 2H), 3.50 (s, 3H), 2.59 (t, J=6.5 Hz, 2H), 1.60-1.66 (m, 2H), 1.55-1.58 (m, 2H), 1.41-1.46 (m, 2H); HRMS (ES) m/z calcd for C₁₈H₂₄N₄O₂(M+H) 329.1972. found 329.1962.

Example 195

(7-Fluoro-phthalazin-1-yl)-(4-methoxy-phenyl)-methyl-amine

a) 6-Fluoro-2,3-dihydro-phthalazine-1,4-dione: A mixture of 2 g (12.04 mmol) of 5-fluoro-isobenzofuran-1,3-dione, 0.64 mL (13.24 mmol) of hydrazine hydrate and 12 mL of acetic acid was stirred at reflux for 3 hours. The reaction mixture was cooled down to ambient temperature and the precipitate was collected to give 1.61 g of the title compound. LC-MS (ESI⁺; 181 ([M+H]⁺)).
b) 1,4-Dichloro-6-fluoro-phthalazine: A mixture of 1.44 g (7.99 mmol) of 6-fluoro-2,3-dihydro-phthalazine-1,4-dione and 7 drops of DMF in 10 mL of POCl₃was heated at reflux for 2 hours. The reaction mixture was cooled to ambient temperature and quenched by careful dropping into ice. The precipitate was collected and washed with water, dried in vacuum to give 1.22 g of the title compound. ¹H NMR (DMSO-d₆) δ 8.5 (m, 1H), 8.2-8.16 (m, 2H); LC-MS (ESI⁺; 218 ([M+H]⁺)).
c) (4-Chloro-7-fluoro-phthalazine-1-yl)-(4-methoxy-phenyl)-methyl-amine and (4-chloro-6-fluoro-phthalazine-1-yl)-(4-methoxy-phenyl)-methyl-amine: A mixture of 1 g (4.6 mmol) of 1,4-dichloro-6-fluoro-phthalazine, 0.75 g (5.52 mmol) of (4-methoxy-phenyl)-methyl-amine in 10 mL of i-PrOH was reflux for 2 hours. The precipitate was collected and washed with i-PrOH then redissolved in MeOH, added NaHCO₃and silica gel and coevaporated and subjected to MPLC isolation to give 0.32 g of a mixture of isomers: (4-chloro-7-fluoro-phthalazine-1-yl)-(4-methoxy-phenyl)-methylamine and (4-chloro-6-fluoro-phthalazine-1-yl)-(4-methoxy-phenyl)-methylamine.
d) (7-Fluoro-phthalazin-1-yl)-(4-methoxy-phenyl)-methyl-amine: A solution of 0.32 g (1.0 mmol) of a mixture of (4-chloro-7-fluoro-phthalazine-1-yl)-(4-methoxy-phenyl)-methyl-amine and (4-chloro-6-fluoro-phthalazine-1-yl)-(4-methoxy-phenyl)-methyl-amine in 10 mL of methanol was hydrogenated over Pd/C for 18 hours. The catalyst was filtered off, washed with methanol, the filtrate concentrated. The isolation was done by preparative HPLC to give 0.1 g of the title compound (isomer). ¹H NMR (DMSO-d₆) δ 9.28-6.98 (8H), 3.8 (3H), 3.56 (3H); LC-MS (ESI⁺; 284 ([M+H]⁺)).

Example 196

(6-Fluoro-phthalazin-1-yl)-(4-methoxy-phenyl)-methyl-amine

(6-Fluoro-phthalazin-1-yl)-(4-methoxy-phenyl)-methyl-amine: The title compound was produced in the reaction of Example 195. ¹H NMR (DMSO-d₆) δ 9.38-6.81 (8H), 3.8 (3H), 3.53 (3H); LC-MS (ESI⁺; 284 ([M+H]⁺)).

Example 197

N-{4-[(4-Methoxy-phenyl)-methyl-amino]-6,7-dihydro-5H-cyclopentapyrimidin-2-yl}-O-methyl-hydroxylamine

a) 1,5,6,7-Tetrahydro-cyclopentapyrimidine-2,4-dione: A solution of 2-oxo-cyclopentanecarboxylic acid methyl ester (5 g, 35 mmol) was dissolved in ethyl alcohol (5 mL) followed by the addition of urea (6.3 g, 105 mmol). The mixture was heated to 160° C. for 48 h. Upon cooling, the formed solids were collected by filtration and dried under high vacuum. The title compound (5.3 g) was used as is.
b) 2,4-Dichloro-6,7-dihydro-5H-cyclopentapyrimidine: Crude 1,5,6,7-tetrahydro-cyclopentapyrimidine-2,4-dione (1 g) was dissolved in POCl₃(5 mL). The mixture was warmed to reflux for 18 h, cooled to ambient temperature and poured over ice. The aqueous mixture was extracted with CH₂Cl₂(2×). The combined organic layers were dried over MgSO₄, filtered and concentrated. The crude 2,4-dichloro-6,7-dihydro-5H-cyclopentapyrimidine was used as is.
c) (2-Chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-yl)-(4-methoxyphenyl)-methylamine: Crude 2,4-dichloro-6,7-dihydro-5H-cyclopentapyrimidine (1 g, 5.3 mmol) was dissolved in isopropanol (25 mL). (4-Methoxy-phenyl)-methylamine (727 mg, 5.3 mmol) was added followed by HCl (concd, 5 drops). The mixture was stirred for 18 h at ambient temperature and evaporated. The crude mixture was dissolved in CH₂Cl₂and extracted with Na₂CO₃(satd aqueous). The organics were dried over MgSO₄and concentrated. The product (2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-yl)-(4-methoxyphenyl)-methylamine was used crude in subsequent reactions.
d) The title compound was prepared from crude (2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-yl)-(4-methoxyphenyl)-methylamine in a method analogous to Example 200 ¹H NMR (CDCl₃) δ 7.18 (d, 2H), 6.96 (d, 2H), 3.95 (s, 3H), 3.90 (s, 3H), 3.68 (s, 3H), 2.85-2.75 (m, 2H), 1.95-1.82 (m, 4H); LC-MS (ESI⁺; 301 ([M+H]⁺)).

Example 198

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

a) 5-Fluoro-1H-quinazoline-2,4-dione: Synthesized using a procedure similar to that of 6-methyl-1H-quinazoline-2,4-dione in Example 56a. ¹H NMR (DMSO-d₆) δ 11.28 (s(br), 2H), 7.64 (td, 1H), 6.97 (d, 1H), 6.93 (ddd, 1H); LC-MS (ESI⁺; 181 ([M+H]⁺)) and (ESI⁻; 179 ([M−H]⁻)).
b) 2,4-Dichloro-5-fluoroquinazoline: A mixture of 5-fluoro-1H-quinazoline-2,4-dione (1.67 g, 9.3 mmol), POCl₃(10 mL) and DMF (3 drops) was heated at reflux overnight. The reaction was cooled to rt and quenched by pouring onto ice. The resulting solid was collected by vacuum filtration and purified by gradient MPLC (SiO₂, EtOAc/hexanes, 0-100%) to provide 712 mg (35%) of the title compound. ¹H NMR (DMSO-d₆) δ 8.22-8.18 (m, 1H), 7.98-7.92 (m, 1H), 7.82-7.72 (m, 1H).
c) 5-Fluoro-2-isopropoxy-N-(4-methoxyphenyl)-N-methylquinazolin-4-amine: A suspension of 2,4-dichloro-5-fluoroquinazoline (712 mg, 3.3 mmol) and (4-methoxy-phenyl)-methyl-amine (458 mg, 3.3 mmol) in i-PrOH (10 mL) was treated with HCl (12 M, 4 drops) and stirred overnight. The reaction was concentrated onto SiO₂and purified by gradient MPLC (SiO₂, MeOH/CH₂Cl₂with 1% NH₄OH, 0-20%). The major peak was concentrated, dissolved in CH₂Cl₂and washed with 5% NaOH. The organics were dried (MgSO₄), filtered and concentrated. Purification by gradient MPLC (SiO₂, EtOAc/hexanes, 0-100%) provided 147 mg of the title compound. ¹H NMR (CDCl₃) δ 7.48-7.36 (m, 2H), 6.96-6.86 (m, 2H), 6.82-6.74 (m, 2H), 6.56 (ddd, 1H), 5.41 (sept, 1H), 3.78 (s, 3H), 3.57 (s, 3H), 1.46 (d, 6H); LC-MS (ESI⁺; 342 ([M+H]⁺)).

Example 199

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

a) 4-Chloro-2-trifluoromethyl-quinazoline: A mixture of 2-trifluoromethyl-3H-quinazolin-4-one (200 mg, 0.93 mmol), N,N-dimethylaniline (0.236 uL, 1.9 mmol) and POCl₃(5 mL) was heated at reflux for 3 h. The reaction was slowly poured onto ice and extracted with CHCl₃. The volatiles were removed to give 400 mg of the crude material as a solid.
b) (4-Methoxy-phenyl)-methyl-(2-trifluoromethyl-quinazolin-4-yl)-amine: The crude material from above (200 mg, 0.86 mmol) and (4-methoxy-phenyl)-methyl-amine (142 mg, 1.0 mmol) in i-PrOH (3 mL) was treated with concd HCl (4 drops) and stirred at room temperature overnight. The precipitate was collected by filtration and purified by gradient MPLC (SiO₂, EtOAc/Hexanes, 0-100%) to provide the title compound. ¹H NMR (CDCl₃) δ 7.93 (d, 1H), 7.63 (m, 1H), 7.25-7.10 (m, 3H), 7.09-6.94 (m, 3H), 3.86 (s, 3H), 3.65 (s, 3H); LC-MS (ESI⁺; 334 ([M+H]⁺)).

Example 200

N⁴-(4-Methoxy-phenyl)-N²,N⁴-dimethyl-6,7-dihydro-5H-cyclopentapyrimidine-2,4-diamine

Crude (2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-yl)-(4-methoxyphenyl)-methylamine (100 mg, 0.32 mmol) was dissolved in isopropanol (10 mL) followed by the addition of ethyl-diisopropyl-amine (83 mg, 0.64 mmol) and alcoholic methylamine (excess, 800 μL). The mixture was stirred for 3 days at 110° C. The mixtures were evaporated and the residue was dissolved in CH₂Cl₂and extracted with HCl (1 N). The organic layer was dried with MgSO₄and concentrated. The title compound was purified by preparative RPLC. ¹H NMR (CDCl₃) δ 7.18 (d, 2H), 6.95 (d, 2H), 3.85 (S, 3H), 3.50 (s, 3H), 3.03 (d, 3H), 2.79 (m, 2H), 1.80-1.70 (m, 4H); LC-MS (ESI⁺; 285 ([M+H]⁺)).

Example 201

N4-(4-Methoxy-phenyl)-N2,N4-dimethyl-6,7,8,9-tetrahydro-5H-cycloheptapyrimidine-2,4-diamine

a) 1,5,6,7,8,9-Hexahydro-cycloheptapyrimidine-2,4-dione: A solution of 2-oxo-cycloheptanecarboxylic acid methyl ester (5 g, 27 mmol) was dissolved in ethyl alcohol (5 mL) followed by the addition of urea (4.5 g, 81 mmol). The mixture was heated to 160° C. for 48 h. Upon cooling the formed solids were collected by filtration and dried under high vacuum. The title compound was used without further purification.
b) N⁴-(4-Methoxy-phenyl)-N²,N⁴-dimethyl-6,7,8,9-tetrahydro-5H-cycloheptapyrimidine-2,4-diamine: The title compound was prepared from 1,5,6,7,8,9-hexahydro-cycloheptapyrimidine-2,4-dione in a method analogous to Example 197. ¹H NMR (DMSO-d₆) δ 7.23 (d, 2H), 7.00 (d, 2H), 3.77 (s, 3H), 3.43 (s, 3H), 2.96 (d, 3H), 2.80-2.65 (m, 2H), 2.00-1.95 (m, 2H), 1.60-1.50 (m, 4H), 1.10-1.00 (m, 2H); LC-MS (ESI⁺; 313 ([M+]⁺)).

Example 202

{4-[(4-Methoxy-phenyl)-methyl-amino]-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamino}-acetic acid ethyl ester

The title compound was prepared from crude (2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-yl)-(4-methoxyphenyl)-methylamine in a method analogous to Example 200 ¹H NMR (CD₃OD) δ 7.52 (d, 2H), 7.02 (d, 2H), 4.3-4.2 (m, 4H), 3.85 (s, 3H), 3.48 (s, 3H), 2.82-2.75 (m, 2H), 1.90-1.80 (m, 2H), 1.50-1.3 (m, 5H).

Example 203

N-{4-[(4-Methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-acetamide

a) 2-Chloromethyl-3H-quinazolin-4-one: A solution of 2-amino-benzoic acid methyl ester (10.0 mL, 77.3 mmol) and chloro-acetonitrile (5.5 mL, 87.1 mmol) in dioxane (150 mL) was treated with HCl (12 N, 10 mL, 120 mmol) and the resulting suspension heated at reflux overnight. The suspension was cooled to rt and the solid collected via vacuum filtration and washed with hexanes. The solid thus obtained was suspended in H₂O and neutralized with NaHCO₃. The solid was collected via vacuum filtration and dried under vacuum to yield 8.864 g (59%) of the title compound as a white solid. ¹H NMR (DMSO-d₆) δ 12.6 (s(br), 1H), 8.13 (ddd, 1H), 7.85 (ddd, 1H), 7.69 (ddd, 1H), 7.56 (ddd, 1H), 4.56 (s, 2H); LC-MS (ESI⁺; 195 ([M+H]⁺)).
b) 4-Chloro-2-chloromethyl-quinazoline: A suspension of 2-chloromethyl-3H-quinazolin-4-one (12.27 g) in toluene (200 mL) was treated with Hünig's base (19 mL, 109 mmol) and POCl₃(8.8 mL, 96.1 mmol) and heated to 65° C. overnight. The reaction was cooled to rt and the layers separated. The bottom layer was extracted with toluene. The top layers were combined and washed with cold H₂O and satd NaHCO₃, dried (MgSO₄), filtered and concentrated. Purification by gradient MPLC (SiO₂, 120 g column, EtOAc/hexanes, 0-100%) provided 9.72 g (69%) of the title compound as a white solid. ¹H NMR (DMSO-d₆) δ 8.33 (ddd, 1H), 8.05-8.22 (m, 2H), 7.93 (ddd, 1H), 4.97 (s, 2H); LC-MS (ESI⁺; 213 ([M+H]⁺)).
c) (2-Chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine hydrochloride: A suspension of 4-chloro-2-chloromethyl-quinazoline (7.383 g, 35.0 mmol) and (4-methoxy-phenyl)-methyl-amine (4.837 g, 35.3 mmol) in i-PrOH (50 mL) was treated with HCl (12 M, 1.5 mL, 18 mmol) and stirred at rt for 2 h. The resulting solid was collected by vacuum filtration, yielding 10.367 g (85%) of the title compound. ¹H NMR (DMSO-d₆) δ 7.80-7.94 (m, 2H), 7.40-7.80 (m, 2H), 7.26-7.34 (m, 1H), 7.07-7.15 (m, 2H), 6.83 (br d, 1H), 4.94 (s, 2H), 3.83 (s, 3H), 3.72 (s, 3H); LC-MS (ESI⁺; 314 ([M+H]⁺)).
d) 2-{4-[(4-Methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-isoindole-1,3-dione: A suspension of (2-chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine hydrochloride (10.367 g, 16.2 mmol) and K₂CO₃(2.25 g, 16.3 mmol) in DMF (50 mL) was heated to 70° C. for 1 h. The reaction was cooled to rt, potassium phthalimide (6.004 g, 32.5 mmol) was added and the reaction heated to 70° C. for 2 h. The reaction was cooled to rt, diluted with EtOAc, washed with H₂O and 5% NaOH, dried (MgSO₄), filtered and concentrated. The residue was purified by gradient MPLC (SiO₂, EtOAc/hexanes 0-100%) to yield 8.56 g (68%) of the title compound. ¹H NMR (DMSO-d₆) δ 7.95-8.02 (m, 2H), 7.87-7.94 (m, 2H), 7.55-7.60 (m, 2H), 7.18-7.22 (m, 2H), 7.02-7.12 (m, 1H), 6.94-7.01 (m, 2H), 6.88 (dt, 1H), 4.95 (s, 2H), 3.77 (s, 3H), 3.26 (s, 3H); HRMS (ES) calcd for C₂₅H₂₁N₄O₃(M+H) 425.1608. found 425.1604.
e) (2-Aminomethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine: A solution of 2-{4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-isoindole-1,3-dione (8.561 g, 20.2 mmol) in EtOH (100 mL) was treated with hydrazine mono-hydrate (3.0 mL, 61.8 mmol) and heated to 60° C. for 2 h. The reaction was cooled to rt, HCl (2 N, 50 mL) added and the reaction heated to 60° C. for 30 min. After cooling to rt the solid was filtered off. The filtrate was concentrated, basified with 5% NaOH and extracted with CH₂Cl₂. The organic layers were combined, dried (MgSO₄), filtered and concentrated. The residue was purified by gradient reverse phase MPLC (MeCN/H₂O with 0.1% TFA) and the free base re-extracted as above to yield 3.10 g (52%) of the title compound. ¹H NMR (CDCl₃) δ 7.76 (d, 1H), 7.54 (ddd, 1H), 7.08-7.16 (m, 2H), 6.95-7.05 (m, 2H), 6.86-6.94 (m, 2H), 4.07 (s, 2H), 3.84 (s, 3H), 3.60 (s, 3H), 2.00 (s(br), 2H); ¹³C NMR (CDCl₃) δ 165.9, 162.0, 158.2, 152.2, 141.6, 132.0, 128.2, 127.6, 126.5, 124.4, 115.5, 115.4, 55.7, 49.1, 43.0; HRMS (ES) calcd for C₁₇H₁₈N₄O (M+H) 295.1553. found 295.1506.
f) N-{4-[(4-Methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-acetamide: A solution of (2-aminomethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (113.1 mg, 0.38 mmol) and NEt₃(0.08 mL, 0.57 mmol) in CH₂Cl₂(2 mL) was treated with excess Ac₂O and stirred overnight. The reaction was concentrated onto SiO₂and purified by gradient MPLC (SiO₂, i-PrOH/CH₂Cl₂, 0-100%) to provide the title compound. ¹H NMR (DMSO-d₆) δ 8.32 (t, 1H), 7.70 (dd, 1H), 7.61 (ddd, 1H), 7.19-7.25 (m, 2H), 7.06-7.12 (m, 1H), 6.96-7.04 (m, 2H), 6.95 (dd, 1H), 4.42 (d, 2H), 3.79 (s, 3H), 3.52 (s, 3H), 1.95 (s, 3H); LC-MS (ESI⁺; 337 ([M+H]⁺)).

Example 204

Methyl-{4-[methyl-(2-methyl-quinazolin-4-yl)-amino]-phenyl}-carbamic acid tert-butyl ester

a) [4-(2-Methyl-quinazolin-4-ylamino)-phenyl]-carbamic acid tert-butyl ester: A mixture of 2-methyl-3H-quinazolin-4-one (5 g, 31.2 mmol), BOP reagent (16.5 g, 37.4 mmol) and ethyl-diisopropyl-amine (8 mL, 46.8 mmol) in DMF (100 mL) was reacted at ambient temperature for 15 min, followed by treatment with (4-amino-phenyl)-carbamic acid tert-butyl ester (10.7 g, 51.4 mmol). The reaction was run for 24 hours. The reaction mixture was diluted with EtOAc and washed with satd NaHCO₃, brine, dried (MgSO₄), filtered and concentrated. Isolation was done by MPLC (0-100% EtOAc/hexanes as eluent) to give 1 g of the title compound. ¹H NMR (DMSO-d₆) δ 8.4-7.6 (8H), 2.6 (s, 3H), 1.5 (s, 9H); LC-MS (ESI⁺; 351 ([M+H]⁺)).
b) Methyl-{4-[methyl-(2-methyl-quinazolin-4-yl)-amino]-phenyl}-carbamic acid tert-butyl ester: To a solution of 1.8 g (5.13 mmol) of [4-(2-methyl-quinazolin-4-ylamino)-phenyl]-carbamic acid tert-butyl ester in DMF (15 mL) at 0° C. was added MeI (3.2 mL, 51.3 mmol), followed by NaH (60% dispersion in oil, 0.246 g, 6.2 mmol). The reaction mixture was stirred at 0° C. for 1 hour, then allowed to warm to ambient temperature and stirred for 18 more hours. The reaction mixture was quenched by adding water, diluted with EtOAc, washed with water, brine, dried over MgSO₄, filtered, concentrated. Isolation done by MPLC (0-100% acetone/CHCl₃as eluent) to give 0.6 g of the title compound obtained. ¹H NMR (DMSO-d₆) δ 7.6-6.9 (8H), 3.5 (s, 3H), 3.1 (s, 3H), 2.6 (s, 3H), 1.4 (s, 9H); LC-MS (ESI⁺; 379 ([M+H]⁺)).

Example 205

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

a) 4-Chloro-2-chloromethyl-6-fluoro-quinazoline: A suspension of 2-chloromethyl-6-fluoro-3H-quinazolin-4-one (0.836 g, 3.9 mmol), prepared using a procedure similar to Example 203a, and NEt₃(0.60 mL, 101.19 mL) in CHCl₃(20 mL) was treated with POCl₃and heated at reflux overnight. The reaction was quenched by pouring onto ice and extracted with CH₂Cl₂. The organics were dried (MgSO₄), filtered and concentrated. The residue was purified by gradient MPLC (SiO₂, EtOAc/hexanes, 0-100%) to provide 265 mg (30%) of the title compound. ¹H NMR (DSMO-d₆) δ 8.23 (ddd, 1H), 8.15-8.06 (m, 2H), 4.97 (s, 2H); LC-MS (ESI⁺; 231 ([M+H]⁺)).
b) (2-Chloromethyl-6-fluoro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine: A suspension of 4-chloro-2-chloromethyl-6-fluoroquinazoline (265 mg, 1.15 mmol) and (4-methoxy-phenyl)-methyl-amine (175 mg, 1.26 mmol) in i-PrOH (10 mL) was treated with HCl (12 M, 4 drops) and stirred overnight at rt. The reaction was diluted with CH₂Cl₂and washed with 5% NaOH. The organics were dried (MgSO₄), concentrated and purified by gradient MPLC (SiO₂, EtOAc/hexanes, 0-100%, 20 min) to provide 258 mg (68%) of the title compound. ¹H NMR (DMSO-d₆) δ 7.83 (dd, 1H), 7.62 (ddd, 1H), 7.25-7.33 (m, 2H), 7.02-7.10 (m, 2H), 6.47 (dd, 1H), 4.75 (s, 2H), 3.81 (s, 3H), 3.54 (s, 3H); LC-MS (ESI⁺; 332 ([M+H]⁺)).
c) (2-Aminomethyl-6-fluoro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine: A suspension of (2-chloromethyl-6-fluoro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (258 mg, 0.79 mL) DMF (3 mL) was treated with potassium phthalimide (316 mg, 1.71 mmol). The reaction was heated to 70° C. for 10 min, cooled to rt, diluted with EtOAc, washed with H₂O, dried (MgSO₄) filtered and concentrated. The residue was suspended in EtOH, treated with excess hydrazine mono-hydrate and stirred overnight. The reaction was diluted with EtOAc and H₂O and the layers separated. The aqueous layer was extracted with EtOAc. The combined organics were dried (MgSO₄), filtered, concentrated and purified by gradient MPLC (SiO₂, MeOH/CH₂Cl₂with 0.1% NH₄OH, 0-20%) to provide the title compound. ¹H NMR (CDCl₃) δ 7.77 (dd, 1H), 7.27-7.37 (m, 1H), 7.08-7.15 (m, 2H), 6.90-6.97 (m, 2H), 6.60 (dd, 1H), 4.06 (s, 2H), 3.86 (s, 3H), 3.59 (s, 3H), 1.80 (s(br), 2H); HRMS (ES) m/z calcd for C₁₇H₁₈FN₄O (M+H) 313.1459. found 313.1502.
d) (2-Aminomethyl-6-fluoro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine bis(hydrochloride): A solution of (2-aminomethyl-6-fluoro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine was in MeOH was treated with excess 1.0 N HCl in Et₂O, Solvent was removed, yielding 131.3 mg (43%, 2 steps) of the title compound. ¹H NMR (DMSO-d₆) δ 8.43 (s(br), 3H), 7.82 (dd, 1H), 7.65 (td, 1H), 7.25-7.32 (m, 2H), 7.04-7.10 (m, 2H), 6.47 (dd, 1H), 4.23 (br q, 2H), 3.82 (s, 3H), 3.58 (s, 3H).

Example 206

{4-[(4-Methoxy-phenyl)-methyl-amino]-quinazolin-2-yl}-acetonitrile

A mixture of (2-chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (50 mg, 0.14 mmol) and NaCN (21 mg, 0.43 mmol) in DMSO was heated by microwave for 10 min at 120° C. The reaction was quenched with H₂O, diluted with EtOAc and the layers separated. The aqueous phase was extracted with EtOAc (2×5 mL), washed with brine, filtered over Na₂SO₄and concentrated. Purification by gradient MPLC (SiO₂, EtOAc/hexanes, 0-50%) gave the desired compound. ¹H NMR (CDCl₃) δ 7.74 (d, 1H), 7.56 (m, 1H), 7.13 (d, 2H), 7.02 (m, 1H), 6.94 (m, 3H), 4.04 (s, 2H), 3.85 (s, 3H), 3.62 (s, 3H); LC-MS (ESI⁺; 305 ([M+H]⁺)) and (ESI⁻; 303 ([M−H]⁻)).

Example 207

(4-Ethoxy-phenyl)-methyl-(2-methyl-6-nitro-quinazolin-4-yl)-amine

a) (4-Ethoxy-phenyl)-methyl-amine: A mixture of 2 g (14.57 mmol) of 4-ethoxy-phenylamine, 1.73 g (17.49 mmol) of succinimide, and 1.4 mL (17.49 mmol) of 37% aq formaldehyde in 15 mL of EtOH was heated at reflux for 18 hours. The reaction mixture cooled down and precipitate was filtered and washed with Et₂O, dried to give 2.89 g (11.27 mmol) of 1-[(4-ethoxy-phenylamino)-methyl]-pyrrolidine-2,5-dione, which was dissolved in DMSO and treated with 0.428 g (11.27 mmol) of NaBH₄. The reaction mixture was heated in a hot water bath for 15 min, then it was poured into 20 mL of cold water and extracted with Et₂O (3×15 mL), the organic extracts were combined and concentrated to give 1.7 g of the title compound. LC-MS (ESI⁺; 152 ([M+H]⁺)).
b) (4-Ethoxy-phenyl)-methyl-(2-methyl-6-nitro-quinazolin-4-yl)-amine: To the mixture of 0.2 g (0.89 mmol) of 4-chloro-2-methyl-6-nitro-quinazoline in i-PrOH (10 mL) and concd HCl (0.2 mL) was added 0.14 g (0.98 mmol) of (4-ethoxy-phenyl)-methyl-amine, and the mixture was stirring at ambient temperature for 18 hours. The precipitate was collected and washed with Et₂O to give 0.18 g of the title compound as the HCl salt. ¹H NMR (DMSO-d₆) δ 8.53-7.16 (7H), 4.14 (q, 2H), 3.75 (s, 3H), 2.74 (s, 3H), 1.37 (t, 3H); LC-MS (ESI⁺; 339 ([M+H]⁺)).

Example 208

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

a) 6-Bromo-2-chloromethyl-3H-quinazolin-4-one: Concd hydrochloric acid (3.0 mL) was added to a soln of 2-amino-5-bromo-benzoic acid methyl ester (2.264 g; 9.84 mmol) and chloro-acetonitrile (0.70 mL; 11 mmol) in dioxane (30 mL). After 24 h at a gentle reflux, additional chloro-acetonitrile (2.0 mL; 32 mmol) was added. After an additional 5 h at reflux, the rxn was cooled to rt then collected by filtration and washed with dioxane then hexanes yielding a tan solid (2.388 g).
b) 6-Bromo-4-chloro-2-chloromethyl-quinazoline: Neat phosphorus oxychloride (5.90 mL; 64.5 mmol) was added to a soln of the above tan solid (1.984 g; ca. 6.4 mmol) and Hünig's base (2.30 mL; 13.2 mmol) in choroform (80 mL). After 6.5 h at 65° C., the rxn was cooled near rt then poured slowly onto stirring ice-water (150 mL) and the layers partitioned. The organic layer was washed with satd NaHCO3 (1×50 mL) and water (1×50 mL) then dried (MgSO₄), filtered through a pad of silica and washed through with EtOAc. The soln was concd yielding a maroon solid (1.414 g; 83% over two steps). ¹H NMR (CDCl₃) δ 6.46 (d, J=2.0 Hz, 1H), 8.08 (dd, J=8.8, 2.4 Hz, 1H), 7.99 (d, J=8.8 Hz, 1H), 4.84 (s, 2H).
c) (6-Bromo-2-chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine: Concd HCl (2 drops) was added to a suspension of the above 4-chloroquinazoline (1.411 g; 4.83 mmol) and (4-methoxy-phenyl)-methyl-amine (692 mg; 5.04 mmol) in i-PrOH. After 2.6 h, the product was collected by filtration and washed with i-PrOH yielding a tan solid (1.492 g; 71% as the hydrochloride salt). ¹H NMR (CDCl₃) δ 7.67 (d, J=9.2 Hz, 1H), 7.62 (dd, J=2.0 Hz, 1H), 7.14 (m, 2H), 7.01 (m, 1H), 6.98 (m, 2H), 4.70 (s, 2H), 3.87 (s, 3H), 3.62 (s, 3H). The free base of the salt (1.414 g) was made by adding satd NaHCO₃(20 mL) then extracting into chloroform (3×5 mL). The combined organic portions were washed with satd NaHCO₃(1×5 mL) and water (1×5 mL), dried (MgSO₄), filtered through a pad of silica, washed with EtOAc and concd yielding an orange-brown microcrystalline solid (1.269 g; 67%). ¹H NMR (DMSO-d₆) δ 7.92 (dd, J=8.8, 2.0 Hz, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.40 (m, 2H), 7.13 (m, 2H), 6.82 (m, 1H), 4.85 (s, 2H), 3.83 (s, 3H), 3.66 (s, 3H); MS (ESI⁺; 392 ([M+H]⁺)).

Example 209

(4-Difluoromethoxy-phenyl)-methyl-(2-methyl-6-nitro-quinazolin-4-yl)-amine

a) (4-Difluoromethoxy-phenyl)-methyl-amine: The title compound was prepared from 4-difluoromethoxy-phenylamine in the same manner as compound in Example 207. LC-MS (ESI⁺; 174 ([M+H]⁺)).
b) (4-Difluoromethoxy-phenyl)-methyl-(2-methyl-6-nitro-quinazolin-4-yl)-amine:
To the mixture of 0.17 g (0.95 mmol) of 4-chloro-2-methyl-6-nitro-quinazoline in i-PrOH (10 mL) and concd HCl (0.2 mL) was added 0.18 g (1.04 mmol) of (4-difluoromethoxy-phenyl)-methyl-amine, and the mixture was stirring at ambient temperature for 18 hours. The precipitate occurred during the reaction was collected and washed with Et₂O. The isolation was done by preparative TLC (5% MeOH/DCM as eluent) to give 55 mg of the title compound. ¹H NMR (DMSO-d₆) δ 8.38-7.29 (8H), 3.61 (s, 3H), 2.64 (s, 3H); LC-MS (ESI⁺; 361 ([M+H]⁺)).

Example 210

(3-Fluoro-4-methoxy-phenyl)-methyl-(2-methyl-6-nitro-quinazolin-4-yl)-amine

a) (3-Fluoro-4-methoxy-phenyl)-methyl-amine: The title compound was prepared from 3-fluoro-4-methoxy-phenylamine (2.089 g, 14.8 mmol) by a procedure similar to Example 221, with MPLC purification (SiO₂/0-5% CH₃CN in CHCl₃), yielding the free base as a pale orange liquid (1.021 g; 44%). ¹H NMR (CDCl₃) δ 6.85 (dd, J=9.0, 9.0 Hz, 1H), 6.41 (dd, J=3.0, 13.4 Hz, 1H), 6.31 (ddd, J=1.4, 2.8, 8.6 Hz, 1H), 3.82 (s, 3H), 3.55 (s(br), 1H), 2.79 (s, 3H); GC-MS (EI; 155 (M⁺)). The hydrochloride salt was produced as a white solid by concentrating a soln of the aniline in HCl-i-PrOH.
b) (3-Fluoro-4-methoxy-phenyl)-methyl-(2-methyl-6-nitro-quinazolin-4-yl)-amine: To the mixture of 0.4 g (2.23 mmol) of 4-chloro-2-methyl-6-nitro-quinazoline in i-PrOH (15 mL) and concd HCl (0.2 mL) was added 0.38 g (2.46 mmol) of (3-fluoro-4-methoxy-phenyl)-methyl-amine, and the mixture was stirring at ambient temperature for 18 hours. The precipitate was collected and washed with Et₂O. The isolation was done by preparative TLC (5% MeOH/DCM as eluent) to give 0.76 g of the title compound. ¹H NMR (DMSO-d₆) δ 8.3-7.2 (6H), 3.8 (s, 3H), 3.5 (s, 3H), 2.6 (s, 3H); LC-MS (ESI⁺; 343 ([M+H]⁺)).

Example 211

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

A mixture (2-chloromethyl-quinazolin-4-yl)-(4-ethoxy-phenyl)-methyl-amine (73 mg, 0.22 mmol) and potassium phthalimide (57 mg, 0.31 mmol) in DMF (1 mL) was heated at 70° C. for 2 h. The reaction was diluted with EtOAc and washed with H₂O. The aqueous phase was extracted with EtOAc (2×10 mL). The combined organic phases were washed with brine, filtered through Na₂SO₄and concentrated. The intermediate was dissolved in EtOH (5 mL), treated with hydrazine monohydrate (81 mg, 1.62 mmol) and stirred overnight. The reaction mixture was quenched with H₂O and diluted with EtOAc. The aqueous and organic phases were separated and the aqueous phase extracted with EtOAc (2×10 mL). The combined organic phases were washed with brine, filtered over Na₂SO₄and concentrated. Purification by gradient MPLC (SiO₂, MeOH/CH₂Cl₂w/0.1% NH₄OH, 0-20%) provided 21 mg (31%) of the title compound. ¹H NMR (CDCl₃) δ 7.75 (d, 1H), 7.53 (ddd, 1H), 7.10 (d, 2H), 7.0 (m, 2H), 6.9 (d, 2H), 4.06 (s, 2H), 4.04 (q, 2H), 3.6 (s, 3H), 2.07 (s(br), 2H), 1.45 (t, 3H); LC-MS (ESI⁺; 309 ([M+H]⁺)).

Example 212

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

A mixture of {4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-yl}-acetonitrile (250 mg, 0.82 mmol), 10% Pd/C (100 mg) and HCl (12 M, 1 mL, 12 mmol) in CH₂Cl₂/MeOH (1:1, 10 mL) was treated with H₂(50 psi) and shaken for three days. The Pd/C was filtered off and the filtrate concentrated and purified to give 21 mg of the title compound as a solid. ¹H NMR (CDCl₃) δ 7.64 (d, 1H), 7.55 (ddd, 1H), 7.13 (d, 2H), 6.95 (m, 2H), 6.93 (d, 2H), 3.85 (s, 3H), 3.62 (t, 2H), 3.56 (s, 3H), 3.4 (t, 2H); LC-MS (ESI⁺; 309 ([M+H]⁺)).

Example 213

2-Aminomethyl-N4-(4-methoxy-phenyl)-N4-methyl-quinazoline-4,6-diamine

a) 2-Chloromethyl-6-nitro-3H-quinazolin-4-one: A suspension of 2-chloromethyl-3H-quinazolin-4-one (1.50 g, 7.7 mmol) in H₂SO₄(5 mL) was cooled to 0° C. and treated with HNO₃(1 mL). The reaction was stirred at 0° C. for 1 h and then poured onto ice. The solid thus obtained was collected via vacuum filtration, yielding 1.50 g (81%) of the title compound. ¹H NMR (DMSO-d₆) δ 13.11 (s(br), 1H), 8.81 (d, 1H), 8.58 (dd, 1H), 7.89 (d, 1H), 4.61 (s, 2H); LC-MS (ESI⁻; 238 ([M−H]⁻)).
b) 4-Chloro-2-chloromethyl-6-nitroquinazoline: A solution of 2-chloromethyl-6-nitro-3H-quinazolin-4-one (446 mg, 1.9 mmol), POCl₃(2.7 mL) and diethylaniline (0.64 mL, 0.933 mmol) in CHCl₃(10 mL) was heated to reflux overnight. After cooling to rt the mixture was poured onto ice and extracted with CH₂Cl₂. The organics were washed with NaHCO₃, dried (MgSO₄), filtered through SiO₂and concentrated to provide the title compound. ¹H NMR (DMSO-d₆) δ 9.02 (dd, 1H), 8.81 (dd, 1H), 8.34 (dd, 1H), 5.04 (s, 2H).
c) (2-Chloromethyl-6-nitro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine hydrochloride: Prepared using a procedure similar to (2-chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine hydrochloride in Example 203c. ¹H NMR (DMSO-d₆) δ 8.39 (dd, 1H), 7.90 (d, 1H), 7.66 (d, 1H), 7.40-7.48 (m, 2H), 7.10-7.18 (m, 2H), 4.82 (s, 2H), 3.83 (s, 3H), 3.66 (s, 3H); LC-MS (ESI⁺; 359 ([M+H]⁺)).
d) (2-Aminomethyl-6-nitro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine:
Prepared using a procedure similar to 2-(aminomethyl)-6-fluoro-N-(4-methoxyphenyl)-N-methylquinazolin-4-amine in Example 205c. ¹H NMR (DMSO-d₆) δ 8.32 (dd, 1H), 7.82 (d, 1H), 7.72 (d, 1H), 7.32-7.40 (m, 2H), 7.08-7.18 (m, 2H), 3.88 (s, 2H), 3.82 (s, 3H), 3.62 (s, 3H), 3.34 (s(br), 2H); LC-MS (ESI⁺; 340 ([M+H]⁺)).
e) 2-Aminomethyl-N⁴-(4-methoxyphenyl)-N⁴-methylquinazoline-4,6-diamine bis(hydrochloride): (2-Aminomethyl-6-nitro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (120 mg, 0.35 mmol) was hydrogenated over 10% Pd/C in AcOH (5 mL) for 1 h. The suspension was filtered through Celite, washing with MeOH, and concentrated. The residue was suspended in CH₂Cl₂and treated with Na₂CO₃. The mixture was then concentrated onto Celite and purified by gradient MPLC (amine column, MeOH/CH₂Cl₂, 0-100%). The residue was suspended in H₂O and treated with excess 2 N HCl and lypholized, yielding 69.0 mg (52%) of the title compound. ¹H NMR (DMSO-d₆) δ 7.86 (d, 1H), 7.78 (dd, 1H), 7.42-7.50 (m, 2H), 7.12-7.20 (m, 2H), 6.74 (d, 1H), 4.62 (s, 2H), 3.93 (s, 3H), 3.92 (s, 3H); HRMS (ES) m/z calcd for C₁₇H₂₀N₅O (M+H) 310.1662. found 310.1691.

Example 214

N⁴-(4-Ethoxy-phenyl)-2,N⁴-dimethyl-quinazoline-4,6-diamine

The title compound was produced in the same manner as compound in Example 101 from (4-ethoxy-phenyl)-methyl-(2-methyl-6-nitro-quinazolin-4-yl)-amine. ¹H NMR (DMSO-d₆) δ 7.4-6.1 (7H), 5.1 (2H), 4.0 (2H), 3.4 (3H), 3.38 (3H), 1.39 (3H); LC-MS (ESI⁺; 309 ([M+H]⁺)).

Example 215

N⁴-(3-Fluoro-4-methoxy-phenyl)-2,N⁴-dimethyl-quinazoline-4,6-diamine

The title compound was produced in the manner as compound in Example 101 from (3-fluoro-4-methoxy-phenyl)-methyl-(2-methyl-6-nitro-quinazolin-4-yl)-amine. ¹H NMR (DMSO-d₆) δ 7.4-6.1 (6H), 5.2 (s, 2H), 3.8 (s, 3H), 3.4 (s, 3H), 2.5 (s, 3H); LC-MS (ESI⁺; 313 ([M+H]⁺)).

Example 216

N⁴-(4-Difluoromethoxy-phenyl)-2,N⁴-dimethyl-quinazoline-4,6-diamine

The title compound was produced in the same manner as compound in Example 101 from (4-difluoromethoxy-phenyl)-methyl-(2-methyl-6-nitro-quinazolin-4-yl)-amine. ¹H NMR (DMSO-d₆) δ 7.46-6.07 (8H), 5.2 (t, 2H), 3.4 (s, 3H), 2.5 (s, 3H); LC-MS (ESI⁺; 331 ([M+H]⁺)).

Example 217

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

a) (4-Isopropoxy-phenyl)-methyl-amine: The title compound (2.7 g) was prepared from 4-isopropoxy-phenylamine (4.539 g, 30.0 mmol) by a procedure similar to Example 221, with MPLC purification (SiO₂/0-10% CH₃CN in CHCl₃). ¹H NMR (CDCl₃) δ 6.80 (m, 2H), 6.57 (m, 2H), 4.37 (heptet, J=6.1 Hz, 1H), 3.50 (s(br), 1H), 2.81 (s, 3H), 1.29 (d, J=6.0 Hz, 6H).
b) (2-Chloromethyl-quinazolin-4-yl)-(4-isopropoxy-phenyl)-methyl-amine: The title compound was prepared from 4-chloro-2-chloromethyl-quinazoline (300 mg, 1.4 mmol), 4-isopropoxy-N-methylaniline (279 mg, 1.7 mmol) and concd HCl (12 M, 10 drops) by a procedure similar to Example 203c with subsequent MPLC purification. ¹H NMR (CDCl₃) δ 7.8 (d, 1H), 7.55 (m, 1H), 7.10 (d, 2H), 7.0 (m, 2H), 6.9 (d, 2H), 4.7 (s, 2H), 4.5 (sept, 1H), 3.6 (s, 3H), 1.37 (d, 6H); LC-MS (ESI⁺; 342 ([M+H]⁺)).
c) (2-Aminomethyl-quinazolin-4-yl)-(4-isopropoxy-phenyl)-methyl-amine: The title compound was prepared from (2-chloromethyl-quinazolin-4-yl)-(4-isopropoxy-phenyl)-methyl-amine (67 mg, 0.20 mmol), potassium phthalimide (51 mg, 0.27 mmol) and hydrazine monohydrate in (74 mg, 1.5 mmol) in EtOH (4 mL) by a procedure similar to the preparation of (2-aminomethyl-quinazolin-4-yl)-(4-ethoxy-phenyl)-methyl-amine in Example 211 and was isolated as a solid. ¹H NMR (CDCl₃) δ 7.74 (d, 1H), 7.54 (ddd, 1H), 7.10 (d, 2H), 7.0 (m, 2H), 6.9 (d, 2H), 4.56 (sept, 1H), 4.15 (s, 2H), 3.6 (s, 3H), 1.36 (d, 6H); LC-MS (ESI⁺; 323 ([M+H]⁺)).

Example 218

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

a) (2-Chloromethyl-quinazolin-4-yl)-(2-fluoro-4-methoxy-phenyl)-amine hydrochloride: The title compound was prepared using a procedure similar to Example 1b. ¹H NMR (CD₃OD) δ 8.56 (d, 1H), 8.15 (t, 1H), 7.86-7.96 (m, 2H), 7.49 (t, 1H), 6.85-6.98 (m, 2H), 4.70 (s, 2H), 3.87 (s, 3H); LC-MS (ESI⁺; 318 ([M+H]⁺)).
b) (2-Chloromethyl-quinazolin-4-yl)-(2-fluoro-4-methoxy-phenyl)-methyl-amine: A solution of (2-chloromethyl-quinazolin-4-yl)-(2-fluoro-4-methoxy-phenyl)-amine hydrochloride (291 mg, 0.82 mmol) in THF (4 mL) was treated with NaH (130 mg, 3.12 mmol), followed by MeI (0.26 mL, 4.2 mmol). The reaction was stirred for 2 h, diluted with MeOH and concentrated. Purification by MPLC (SiO₂, EtOAc/hexanes, 0-100%) gave the desired compound. ¹H NMR (CDCl₃) δ 7.84 (d, 1H), 7.55-7.65 (m, 1H), 7.02-7.17 (m, 3H), 6.68-6.79 (m, 2H), 4.74 (s, 2H), 3.85 (s, 3H), 3.58 (s, 3H); LC-MS (ESI⁺; 332 ([M+H]⁺)).
c) (2-Aminomethyl-quinazolin-4-yl)-(2-fluoro-4-methoxy-phenyl)-methyl-amine: The title compound was prepared from (2-chloromethyl-quinazolin-4-yl)-(2-fluoro-4-methoxy-phenyl)-methyl-amine (28 mg, 0.08 mmol), potassium phthalimide (22 mg, 0.12 mmol) and hydrazine monohydrate in (30 mg, 0.59 mmol) in EtOH (3 mL) by a procedure similar to the preparation of (2-aminomethyl-quinazolin-4-yl)-(4-ethoxy-phenyl)-methyl-amine in Example 211 and was isolated as a solid. ¹H NMR (CDCl₃) δ 7.77 (d, 1H), 7.59-7.54 (m, 1H), 7.1 (t, 1H), 7.04-7.03 (m, 2H), 6.75-6.68 (m, 2H), 4.12 (s, 2H), 3.83 (s, 3H), 3.55 (s, 3H), 3.1 (s(br), 2H); LC-MS (ESI⁺; 313 ([M+H]⁺)).

Example 219

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

a) 2-{6-Bromo-4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-isoindole-1,3-dione: A mixture of (6-bromo-2-chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (1.266 g; 3.22 mmol) and potassium phthalimide (720 mg; 3.89 mmol) in DMF (8 mL) was heated in an oil bath (ca. 75° C.). After 3.5 h the rxn was cooled. Water (80 mL) was added with stirring and the ppt collected by filtration and washed with water. The filter cake was dissolved in CHCl₃(25 mL), dried (MgSO₄), filtered through silica and washed with EtOAc. Pure material was obtained as a tan solid (1.480 g; 91%) after MPLC (SiO₂/0 to 10% i-PrOH in CHCl₃gradient). ¹H NMR (CDCl₃) δ 7.96-7.90 (m, 2H), 7.79-7.73 (m, 2H), 7.56-7.53 (m, 2H), 7.06 (m, 2H), 6.96-6.90 (m, 3H), 5.09 (s, 2H), 3.84 (s, 3H), 3.26 (s, 3H); MS (ESI⁺; 503 ([M+H]⁺)).
b) (2-Aminomethyl-6-bromo-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine: Hydrazine monohydrate (100 μL; 2.06 mmol) was added to a suspension of the above phthalimide (129 mg; 0.256 mmol) in a mixture of absolute EtOH (3 mL) and dry THF (2 mL). After 5 h at 65° C. the rxn was concd on a rotary evaporator. The crude solid was triturated with DCM (3×5 mL) and this was filtered through a plug of glass wool in a Pasteur pipet then concd yielding the free base of the product as an orange-brown oil (95 mg; 99%).
c) The bis(hydrochloride) salt was made by adding HCl-satd i-PrOH (2 mL) to a soln of the free base in i-PrOH (2 mL), then concentrating in vacuo, yielding the salt as a yellow solid (117 mg; 96% accounting for 0.4 eq i-PrOH present by NMR). ¹H NMR (DMSO-d₆) δ 8.53 (m(br), 3H), 7.88 (dd, J=9.0, 2.2 Hz, 1H), 7.73 (d, J=8.8 Hz, 1H), 7.33 (m, 2H), 7.12 (m, 2H), 6.88 (d, J=1.6 Hz, 1H), 4.26 (q(br), J=5.6 Hz, 2H), 3.83 (s, 3H), 3.65 (s, 3H); MS (ESI⁺; 373 ([M+H]⁺)).

Example 220

2-Aminomethyl-N⁴-(4-isopropoxy-phenyl)-N⁴-methyl-quinazoline-4,6-diamine

a) (2-Chloromethyl-6-nitro-quinazolin-4-yl)-(4-isopropoxy-phenyl)-methyl-amine: A suspension of 4-chloro-2-chloromethyl-6-nitroquinazoline (200 mg, 0.77 mmol) and (4-isopropoxy-phenyl)-methyl-amine (140 mg, 0.84 mmol) in i-PrOH (1.5 mL) was treated with HCl (12 M, 6 drops) and stirred at rt overnight. CH₂Cl₂was added and the reaction washed with 5% NaOH, dried (MgSO₄), filtered and concentrated. The residue was purified by gradient MPLC (SiO₂, EtOAc/hexanes, 0-100%) to provide 203 mg (71%) of the title compound. ¹H NMR (DMSO-d₆) δ 8.35 (dd, 1H), 7.86 (dd, 1H), 7.71 (dd, 1H), 7.32-7.40 (m, 2H), 7.08-7.12 (m, 2H), 4.78 (s, 2H), 4.71 (sept, 1H), 3.63 (s, 3H), 1.31 (d, 6H); LC-MS (ESI⁺; 387 ([M+H]⁺)).
b) 2-(Aminomethyl)-N⁴-(4-isopropoxyphenyl)-N⁴-methylquinazoline-4,6-diamine: A suspension of (2-chloromethyl-6-nitro-quinazolin-4-yl)-(4-isopropoxy-phenyl)-methyl-amine (136 mg, 0.35 mmol), NEt₃(0.15 mL, 1.08 mmol) and NaN₃(31 mg, 0.48 mmol) in DMF (1 mL) was stirred at rt for 7 h. The reaction was diluted with EtOAc, washed with H₂O, dried (MgSO₄), filtered and concentrated. Purification by gradient MPLC (SiO₂, EtOAc/hexanes, 0-100%) provided the azide. The azide was hydrogenated over 10% Pd/C in AcOH for 3 h. The reaction mixture was filtered through Celite, washing with MeOH, and concentrated. The residue was suspended in CH₂Cl₂and treated with Na₂CO₃. Purification by gradient MPLC (amine column, MeOH/CH₂Cl₂, 0-100%) provided 59 mg (50%) of the title compound. ¹H NMR (CDCl₃) δ 7.62 (d, 1H), 7.04-7.10 (m, 2H), 7.01 (dd, 1H), 6.84-6.90 (m, 2H), 6.16 (d, 1H), 4.55 (sept, 1H), 4.03 (s, 2H), 3.57 (s, 3H), 3.48 (s(br), 2H), 1.36 (d, 6H); HRMS (ES) m/z calcd for C19H24N5O (M+H) 338.1975. found 338.1979.

Example 221

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

a) 2-Fluoro-4-methoxy-phenylamine: 2.5 M NaOH (3 mL, 7.5 mmol) was added to 2-fluoro-4-methoxy-phenylamine hydrochloride (1.008 g, 5.68 mmol). The free base was extracted into EtOAc (10 mL) and the organic portion was washed with satd NaCl (1×3 mL); then dried (MgSO₄), filtered through a plug of silica with an EtOAc wash and concd in vacuo to a peach-colored solid (774 mg; 97%).
b) (2-Fluoro-4-methoxy-phenyl)-methyl-amine: Formaldehyde (37 wt % in water; 0.41 mL; 5.51 mmol) was added to a soln of 2-fluoro-4-methoxy-phenylamine (774 mg, 5.48 mmol) and 1H-benzotriazole (657 mg, 5.51 mmol) in absolute EtOH (5.5 mL). After 5.8 h, dry THF was added until a soln formed (13 mL) followed by NaBH₄(210 mg, 5.55 mmol). After 19 h, 1 M NaOH (7 mL) was added then the organic volatiles removed on a rotary evaporator. The product was extracted into EtOAc (20 mL) and washed with 1 M NaOH (5 mL) and satd NaCl (2×5 mL); then dried (MgSO₄), filtered through a plug of silica with an EtOAc wash. The title compound was obtained after MPLC purification (SiO₂/0-10% i-PrOH in CHCl₃) as a dark peach-colored liquid (354 mg), which contained ca. 7% 2-fluoro-4-methoxy-phenylamine as a contaminant. ¹H NMR (CDCl₃) δ 6.68-6.58 (m, 3H), 3.74 (s, 3H), 3.61 (s(br), 1H), 2.85 (s, 3H); LC-MS (ESI⁺; 156 ([M+H]⁺)).
c) (2-Fluoro-4-methoxy-phenyl)-methyl-(2-methyl-6-nitro-quinazolin-4-yl)-amine: The title compound was prepared from 4-chloro-2-methyl-6-nitro-quinazoline (153 mg, 0.684 mmol) and (2-fluoro-4-methoxy-phenyl)-methyl-amine (119 mg, 0.77 mmol) by a procedure similar to Example 177. ¹H NMR (CDCl₃) δ 8.31 (dd, J=2.0, 9.2 Hz, 1H), 7.92 (d, J=2.4 Hz, 1H), 7.80 (d, J=9.2 Hz, 1H), 7.23 (m, 1H), 6.86-6.78 (m, 2H), 3.87 (s, 3H), 3.62 (s, 3H), 2.74 (s, 3H); LC-MS (ESI⁺; 343 ([M+H]⁺)).

Example 222

N⁴-(2-Fluoro-4-methoxy-phenyl)-2,N⁴-dimethyl-quinazoline-4,6-diamine

10% Pd—C (10 mg, 0.0094 mmol) was added to a soln of (2-fluoro-4-methoxy-phenyl)-methyl-(2-methyl-6-nitro-quinazolin-4-yl)-amine (127 mg, 0.371 mmol) in AcOH (3 mL) and this was reacted under 1 atm of hydrogen. After 3 h, the rxn was filtered through a 0.45 μm filter then concentrated. Satd NaHCO₃(10 mL) was added and the product extracted into CHCl₃(2×2 mL). The soln was dried (MgSO₄), filtered through a plug of silica with an EtOAc wash then concd to a yellow crystalline solid (104 mg; 90%). ¹H NMR (CDCl₃) δ 7.61 (d, J=8.8 Hz, 1H), 7.05-6.99 (m, 2H), 6.73 (dd, J=2.8, 12 Hz, 1H), 6.66 (ddd, J=1.2, 3.2, 8.8 Hz, 1H), 6.18 (d, J=2.4 Hz, 1H), 3.82 (s, 3H), 3.51 (s(br), 2H), 3.50 (s, 3H), 2.69 (s, 3H); LC-MS (ESI⁺; 313 ([M+H]⁺)).

Example 223

N⁴-(3,4-Dimethoxy-phenyl)-2,N⁴-dimethyl-quinazoline-4,6-diamine

a) (3,4-Dimethoxy-phenyl)-methyl-(2-methyl-6-nitro-quinazolin-4-yl)-amine: The title compound was prepared from 4-chloro-2-methyl-6-nitro-quinazoline (110 mg, 0.492 mmol) and (3,4-dimethoxy-phenyl)-methyl-amine (97 mg, 0.58 mmol) by a procedure similar to Example 177, with a final purification by MPLC (SiO₂/0-100% EtOAc in CHCl₃). LC-MS (ESI⁺; 355 ([M+H]⁺)).
b) N⁴-(3,4-Dimethoxy-phenyl)-2, N⁴-dimethyl-quinazoline-4,6-diamine: The title compound was prepared from (3,4-dimethoxy-phenyl)-methyl-(2-methyl-6-nitro-quinazolin-4-yl)-amine (52 mg, 0.15 mmol) by a procedure similar to Example 222, with a final purification by MPLC (SiO₂/0-15% i-PrOH in CHCl₃). ¹H NMR (CDCl₃) δ 7.61 (d, J=8.4 Hz, 1H), 7.00 (dd, J=2.8, 8.8 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 6.72-6.66 (m, 2H), 6.20 (d, J=2.4 Hz, 1H), 3.91 (s, 3H), 3.80 (s, 3H), 3.57 (s, 3H), 3.51 (s(br), 2H), 2.70 (s, 3H); LC-MS (ESI⁺; 325 ([M+H]⁺)).

Example 224

(4-Isopropoxy-phenyl)-methyl-(2-methyl-6-nitro-quinazolin-4-yl)-amine

The title compound was synthesized from 4-chloro-2-methyl-6-nitro-quinazoline and (4-isopropoxy-phenyl)-methyl-amine by a procedure similar to Example 1b. ¹H NMR (DMSO-d₆) δ 8.5-7.1 (7H), 4.73 (m, 1H), 3.7 (s, 3H), 2.7 (s, 3H), 1.32 (d, 6H); LC-MS (ESI⁺; 353 ([M+H]⁺)).

Example 225

2,N⁴-Dimethyl-N⁴-(4-methylamino-phenyl)-quinazoline-4,6-diamine

a) N,N′-Dimethyl-benzene-1,4-diamine: The title compound (553 mg; 8%) was prepared from benzene-1,4-diamine (5.41 g, 50.0 mmol) by a procedure similar to Example 221, with MPLC purification (SiO₂/0-15% i-PrOH in CHCl₃) followed by additional MPLC purification (SiO₂/0-100% EtOAc in hexanes). ¹H NMR (CDCl₃) δ 6.59 (s, 4H), 3.24 (s(br), 2H), 2.80 (s, 6H); LC-MS (ESI⁺; 136 ([M+H]⁺)).
b) N,N′-Dimethyl-N-(2-methyl-6-nitro-quinazolin-4-yl)-benzene-1,4-diamine: To a mixture of 0.15 g (0.67 mmol) of 4-chloro-2-methyl-6-nitro-quinazoline in i-PrOH (10 mL) and concd HCl (0.2 mL) was added 0.1 g (0.73 mmol) of N,N′-dimethyl-benzene-1,4-diamine, and the mixture was stirred at ambient temperature for 18 hours. The precipitate occurred during the reaction was collected and washed with Et₂O to give 0.19 mg of the title compound as the HCl salt. LC-MS (ESI⁺; 324 ([M+H]⁺)).
c) 2,N⁴-dimethyl-N⁴-[4-(methylamino)phenyl]quinazoline-4,6-diamine: The title compound was produced in the manner as compound in Example 101 from N,N′-dimethyl-N-(2-methyl-6-nitro-quinazolin-4-yl)-benzene-1,4-diamine. ¹H NMR (DMSO-d₆) δ 7.3-6.1 (8H), 5.03 (2H), 3.34 (s, 3H), 2.67 (d, 3H), 2.49 (s, 3H); LC-MS (ESI⁺; 294 ([M+H]⁺)).

Example 226

N⁴-(4-Isopropoxy-phenyl)-2,N⁴-dimethyl-quinazoline-4,6-diamine

The title compound was produced in the same manner as compound in Example 101 from (4-isopropoxy-phenyl)-methyl-(2-methyl-6-nitro-quinazolin-4-yl)-amine. ¹H NMR (DMSO-d₆) δ 7.5-5.9 (7H), 4.6 (m, 1H), 3.5 (s, 3H), 2.6 (s, 3H), 1.29 (d, 6H); LC-MS (ESI⁺; 323 ([M+H]⁺)).

Example 227

N²-(3-Amino-propyl)-N⁴-(4-methoxy-phenyl)-N²,N⁴-dimethyl-quinazoline-2,4-diamine

A mixture of (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine hydrochloride (203 mg, 0.604 mmol), ethyl-diisopropyl-amine (0.25 mL, 1.4 mmol) and N¹-methyl-propane-1,3-diamine (95%; 100 μL) in n-butanol (4 mL) was heated at 115° C. After 32 h, the rxn was treated with bicarbonate resin (Novabiochem 01-64-0419) then concd. The material was dissolved in CHCl₃, adsorbed onto diatomaceous earth and partially purified on an amine column (Isco 68-2203-101) eluting with a gradient of 0-100% i-PrOH in CHCl₃. Pure title compound was obtained as a pale yellow oil (23 mg; 11%) after preparative TLC (SiO₂/100:20:2 CHCl₃:MeOH:concd NH₄OH). ¹H NMR (DMSO-d₆) δ 7.38-7.27 (m, 2H), 7.16 (m, 2H), 6.97 (m, 2H), 6.79 (d, J=8.4 Hz, 1H), 6.65 (m, 1H), 3.77 (s, 3H), 3.76 (m, 2H), 3.44 (s, 3H), 3.17 (s, 3H), 2.63 (t, J=6.6 Hz, 2H), 1.75 (m, 2H); LC-MS (ESI⁺; 352 ([M+H]⁺)).

Example 228

N⁴-(4-Methoxy-phenyl)-N⁴-methyl-N²-(3-methylamino-propyl)-quinazoline-2,4-diamine

The title compound was produced in the reaction of Example 227 as a pale yellow oil (57 mg; 27%). ¹H NMR (DMSO-d₆) δ 7.39-7.25 (m, 2H), 7.15 (m, 2H), 7.00-6.93 (m, 3H), 6.82 (d, J=8.0 Hz, 1H), 6.67 (m, 1H), 3.77 (s, 3H), 3.46-3.36 (m, 5H), 2.78 (m, 2H), 2.44 (s, 3H), 1.82 (m, 2H); LC-MS (ESI⁺; 352 ([M+H]⁺)).

Example 229

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

a) (2-Chloromethyl-5-fluoro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine hydrochloride: To 4-chloro-2-chloromethyl-5-fluoro-quinazoline (205 mg, 0.96 mmol) dissolved in isopropanol (3 mL) was added (4-methoxy-phenyl)-methyl-amine (158 mg, 1.1 mmol) and HCl (12 M, 2 drops). The reaction was stirred overnight at room temperature. The resulting precipitate was filtered to give 216 mg of (2-chloromethyl-5-fluoro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine hydrochloride. ¹H NMR (CDCl₃) δ 8.24 (d, 1H), 7.8 (m, 1H), 7.06 (m, 2H), 6.8 (m, 4H), 5.00 (s, 2H), 3.84 (s, 3H), 3.8 (3H), 3.0 (s, 2H); LC-MS (ESI⁺; 328 ([M+H]⁺)).
b) (2-Aminomethyl-5-fluoro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine: The title compound was prepared from (2-chloromethyl-5-fluoro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (216 mg, 0.58 mmol), potassium phthalimide (225 mg, 1.2 mmol) and hydrazine monohydrate (167 mg, 3.3 mmol) in EtOH (3 mL) by a procedure similar to the preparation of (2-aminomethyl-quinazolin-4-yl)-(4-ethoxy-phenyl)-methyl-amine in Example 211 and was isolated as a solid. ¹H NMR (MeOH-d₄) δ 7.55 (m, 2H), 6.9 (m, 2H), 6.75 (m, 3H), 4.05 (s, 2H), 3.78 (s, 3H), 3.6 (s, 3H) 2.23 (s(br), 2H); LC-MS (ESI⁺; 313 ([M+H]⁺)).

Example 230

4-[(2-Aminomethyl-quinazolin-4-yl)-methyl-amino]-phenol

a) 4-[(2-Chloromethyl-quinazolin-4-yl)-methyl-amino]-phenol hydrochloride: To 4-chloro-2-chloromethyl-quinazoline (200 mg) suspended in isopropanol (3 ml) was added 4-methylamino-phenol (389 mg) and followed by HCl (12 M, 2 drops). The reaction was stirred overnight at room temperature. The resulting precipitate was filtered to give 391 mg of (2-chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine as the hydrochloride salt. ¹H NMR (MeOH-d₄) δ 7.28 (m, 4H), 6.90 (m, 4H), 4.8 (s, 2H), 3.8 (s, 3H); LC-MS (ESI⁺; 332 ([M+H]⁺)).
b) 4-[(2-Aminomethyl-quinazolin-4-yl)-methyl-amino]-phenol: The title compound was prepared from 4-[(2-chloromethyl-quinazolin-4-yl)-methyl-amino]-phenol (391 mg, 1.2 mmol), potassium phthalimide (452 mg, 2.4 mmol), and hydrazine monohydrate in (271 mg, 5.4 mmol) in EtOH (5 mL) by a procedure similar to the preparation of (2-aminomethyl-quinazolin-4-yl)-(4-ethoxy-phenyl)-methyl-amine in Example 211 and was isolated as a solid. ¹H NMR (MeOH-d₄) δ 7.7 (d, 1H), 7.6 (t, 1H), 7.1 (m, 4H), 6.8 (d, 2H), 4.0 (s, 2H), 3.6 (s, 3H); LC-MS (ESI⁺; 281 ([M+H]⁺)).

Example 231

2-{4-[(4-Methoxy-phenyl)-methyl-amino]-quinazolin-2-yl}-2-methyl-propionitrile

a) {4-[(4-Methoxyphenyl)methylamino]-quinazolin-2-yl}acetonitrile: A suspension of (2-chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine hydrochloride (985 mg, 2.8 mmol), Na₂CO₃(465 mg, 4.4 mmol) and NaCN (151 mg, 3.1 mmol) in DMF (10 mL) was stirred at 70° C. overnight. The reaction was cooled to rt, diluted with EtOAc and washed with H₂O. The organics were dried (MgSO₄), filtered, concentrated and purified by gradient MPLC (SiO₂, EtOAc/hexanes, 0-100%) to provide 310 mg (36%) of the title compound. ¹H NMR (CDCl₃) δ 7.75 (d, 1H), 7.57 (ddd, 1H), 7.17-7.11 (m, 2H), 7.06-6.91 (m, 4H), 4.05 (s, 2H), 3.86 (s, 3H), 3.63 (s, 3H); LC-MS (ESI⁺; 305 ([M+H]⁺)).
b) 2-{4-[(4-Methoxy-phenyl)-methyl-amino]-quinazolin-2-yl}-2-methyl-propionitrile: A solution of {4-[(4-methoxyphenyl)methylamino]-quinazolin-2-yl}acetonitrile (174 mg, 0.57 mmol) and MeI (0.08 mL, 0.80 mmol) in THF (1.5 mL) was cooled to −78° C. under N₂and treated with potassium tert-butoxide (1.0 M in t-BuOH, 1.5 mL, 1.5 mmol). The reaction was stirred at −78° C. for 1 h then allowed to warm to rt and stirred at rt for 1 h. The reaction was diluted with EtOAc, washed with H₂O, dried (MgSO₄) filtered and concentrated. Purification by gradient MPLC (SiO₂, EtOAc/hexanes, 0-100%) provided 150 mg (79%) of the title compound. ¹H NMR (CDCl₃) δ 7.81 (d, 1H), 7.56 (ddd, 1H), 7.17-7.11 (m, 2H), 7.05-6.90 (m, 4H), 3.86 (s, 3H), 3.63 (s, 3H), 1.88 (s, 6H); HRMS (ES) m/z calcd for C₂₀H₂₀N₄O (M+H) 333.1710. found 333.1696.

Example 232

N-{4-[(4-Methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-succinamic acid

A solution of (2-aminomethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (76 mg, 0.25 mmol) and succinic anhydride (25 mg, 0.25 mmol) was stirred overnight in CH₂Cl₂(1 mL). Solvent removal yielded the title compound. ¹H NMR (CDCl₃) δ 7.80-7.75 (m, 1H), 7.61 (ddd, 1H), 7.23-7.17 (m, 2H), 7.08-6.98 (m, 4H), 4.57 (s, 2H), 3.84 (s, 3H), 3.64 (s, 3H), 2.68-2.62 (m, 4H); HRMS (ES) m/z calcd for C₂₁H₂₃N₄O₄395.1714. found 395.1737.

Example 233

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

A solution of (2-aminomethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (190 mg, 0.64 mmol), NEt₃(0.17 mL, 1.22 mmol) and Boc₂O (0.16 mL, 0.75 mmol) in CH₂Cl₂(3 mL) was stirred for 45 min at rt. The mixture was concentrated onto SiO₂and purified by gradient MPLC (SiO₂, EtOAc/hexanes, 0-100%) to provide {4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-carbamic acid tert-butyl ester. The Boc protected amine was dissolved in THF and treated with MeI (0.10 mL, 1.61 mmol) and NaH (5 eq). The mixture was stirred at rt for 2 h, quenched with MeOH and concentrated onto SiO₂. Purification by MPLC (SiO₂, EtOAc/hexanes, 0-100%) provided {4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-methyl-carbamic acid tert-butyl ester. The methylated compound was dissolved in CH₂Cl₂and treated with excess TFA. After 2 h at rt the reaction was made basic with 5% NaOH and extracted with CH₂Cl₂. The combined organics were dried (MgSO₄), filtered and concentrated. Purification by gradient MPLC (SiO₂, MeOH/CH₂Cl₂w/0.1% NH₄OH, 0-20%) provided the title compound. ¹H NMR (CDCl₃) δ 7.75 (d, 1H), 7.55 (ddd, 1H), 7.16-7.08 (m, 2H), 7.04-6.88 (m, 4H), 5.75 (s(br), 1H), 4.22 (s, 2H), 3.85 (s, 3H), 3.64 (s, 3H), 2.81 (s, 3H); HRMS (ES) m/z calcd for C₁₈H₂₀N₄O (M+H) 309.1710. found 309.1646.

Example 234

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

a) (2-Chloromethyl-quinazolin-4-yl)-(3-fluoro-4-methoxy-phenyl)-amine hydrochloride: Prepared using a procedure similar to (2-chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine hydrochloride in Example 203. ¹H NMR (DMSO-d₆) δ 8.82 (d, 1H), 8.06 (t, 1H), 7.50-8.00 (m, 2H), 7.83 (t, 1H), 7.64 (d, 1H), 7.28 (t, 1H), 4.87 (s, 2H), 3.89 (s, 3H); LC-MS (ESI⁺; 318 ([M+H]⁺)) and (ESI⁻; 316 ([M−H]⁻)).
b) (2-Chloromethyl-quinazolin-4-yl)-(3-fluoro-4-methoxy-phenyl)-methyl-amine: A suspension of (2-chloromethyl-quinazolin-4-yl)-(3-fluoro-4-methoxy-phenyl)-amine hydrochloride (497 mg, 1.4 mmol) and MeI (0.18 mL, 2.9 mmol) in THF (7 mL) was treated with NaH (60% disp., 158 mg, 3.95 mmol) and stirred for 2 h at rt. The reaction was quenched by the addition of MeOH, concentrated onto SiO₂and purified by gradient MPLC (SiO₂, EtOAc/hexanes, 0-100%) to provide 281 mg (61%) of the title compound. ¹H NMR (CDCl₃) δ 7.85 (d, 1H), 7.61 (ddd, 1H), 6.97-7.13 (m, 3H), 6.86-6.97 (m, 2H), 4.75 (s, 2H), 3.93 (s, 3H), 3.62 (s, 3H); LC-MS (ESI⁺; 332 ([M+H]⁺)).
c) (2-Aminomethyl-quinazolin-4-yl)-(3-fluoro-4-methoxy-phenyl)-methyl-amine: Prepared using a procedure similar to (2-aminomethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine in Example 203e. ¹H NMR (CDCl₃) δ 7.79 (d, 1H), 7.57 (ddd, 1H), 6.82-7.16 (m, 5H), 4.08 (s, 2H), 3.91 (s, 3H), 3.59 (s, 3H), 2.67 (s(br), 2H); HRMS (ES) m/z calcd for C₁₇H₁₈FN₄O (M+H) 313.1459. found 313.1464.

Example 235

(2-Aminomethyl-quinazolin-4-yl)-(4-ethoxy-3-fluoro-phenyl)-methyl-amine

a) 1-Ethoxy-2-fluoro-4-nitro-benzene: NaOH pellets (888 mg, 22.2 mmol) were added to a soln of 1,2-difluoro-4-nitro-benzene (3.185 g, 20.0 mmol) in abs EtOH (20 mL). After 65 h, the rxn was concd on a rotary evaporator, then suspended in water, collected by filtration and washed with water yielding the title compound as a white microcrystalline solid.
b) 4-Ethoxy-3-fluoro-phenylamine: 10% Pd—C (75 mg) was added to a soln of the 1-ethoxy-2-fluoro-4-nitro-benzene collected above in AcOH (40 mL). After 46 h under hydrogen (1 atm), the rxn was filtered through silica then concd in vacuo. EtOAc (100 mL) was added and this washed with 4 M NaOH (25 mL), 1 M NaOH (25 mL), water (25 mL) and satd NaCl (2×25 mL); then dried (MgSO₄) and filtered through a pad of silica with an EtOAc wash. The title was obtained as a dark brown liquid (1.828 g; 59%) after purification by MPLC (SiO₂/0-50% EtOAc in hexanes). ¹H NMR (CDCl₃) δ 6.80 (dd, J=9.0 Hz, 1H), 6.47 (dd, J=2.6, 13.0 Hz, 1H), 6.37 (ddd, J=1.2, 2.6, 8.6 Hz, 1H), 4.02 (q, J=6.9 Hz, 2H), 3.50 (s(br), 2H), 1.39 (t, J=7.0 Hz, 3H); LC-MS (ESI⁺; 156 ([M+H]⁺)).
c) (4-Ethoxy-3-fluoro-phenyl)-methyl-amine hydrochloride: The free base of the title compound was synthesized as a clear, pale tan liquid by a procedure similar to that found in Example 221 from 4-ethoxy-3-fluoro-phenylamine (1.828 g, 11.78 mmol), 1H-benzotriazole (1.407 g, 11.8 mmol), 37 wt % aq formaldehyde (0.90 mL, 12.1 mmol) and sodium borohydride (447 mg, 11.8 mmol); with purification by MPLC (SiO₂/0-33% EtOAc in hexanes). The title compound was obtained as an off-white solid after concentrating a soln of the free base in HCl-i-PrOH in vacuo. LC-MS (ESI⁺; 170 ([M+H]⁺)).
d) (2-Chloromethyl-quinazolin-4-yl)-(4-ethoxy-3-fluoro-phenyl)-methyl-amine: Prepared using a procedure similar to (2-chloromethyl-6-fluoro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine in Example 205b. ¹H NMR (CDCl₃) δ 7.84 (d, 1H), 7.60 (t, 1H), 6.97-7.12 (m, 3H), 6.83-6.96 (m, 2H), 4.74 (s, 2H), 4.13 (q, 2H), 3.61 (s, 3H), 1.48 (t, 3H); HRMS (ES) m/z calcd for C₁₈H₁₈ClFN₃O (M+H) 346.1117. found 346.1159.
e) 2-{4-[(4-Ethoxy-3-fluoro-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-isoindole-1,3-dione: A suspension of (2-chloromethyl-quinazolin-4-yl)-(4-ethoxy-3-fluoro-phenyl)-methyl-amine (179.1 mg, 0.52 mmol) and potassium phthalimide (104 mg, 0.56 mmol) in DMF (2 mL) was heated to 70° C. for 2 h. The reaction was cooled to rt, diluted with EtOAc, washed with 5% NaOH and H₂O, dried (MgSO₄), filtered and concentrated. The residue was purified by gradient MPLC (SiO₂, EtOAc/hexanes, 0-100%) to provide 215 mg (91%) of the title compound. ¹H NMR (CDCl₃) δ 7.90-7.92 (m, 2H), 7.67-7.80 (m, 3H), 7.50-7.57 (m, 3H), 6.83-7.05 (m, 4H), 6.75-6.81 (m, 1H), 5.14 (s, 2H), 4.11 (q, 2H), 3.24 (s, 3H), 1.47 (t, 3H); LC-MS (ESI⁺; 457 ([M+H]⁺)).
f) (2-Aminomethyl-quinazolin-4-yl)-(4-ethoxy-3-fluoro-phenyl)-methyl-amine:
Prepared using a procedure similar (2-aminomethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine in Example 203e from 2-{4-[(4-ethoxy-3-fluoro-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-isoindole-1,3-dione. ¹H NMR (CDCl₃) δ 7.79 (d, 1H), 7.58 (ddd, 1H), 7.02-7.10 (m, 2H), 6.99 (dd, 1H), 6.83-6.95 (m, 2H), 4.13 (q, 2H), 4.08 (s, 2H), 3.59 (s, 3H), 2.79 (s(br), 2H), 1.48 (t, 3H); HRMS (ES) m/z calcd for C₁₈H₂₀FN₄O (M+H) 327.1616. found 327.1619.

Example 236

4-Methoxy-N-{4-[(4-methoxy-phenyl)-methyl-amino]-2-methyl-quinazolin-6-yl}-benzenesulfonamide

4-Methoxy-N-{4-[(4-methoxy-phenyl)-methyl-amino]-2-methylquinazolin-6-yl}-benzenesulfonamide: A solution of methoxybenzenesulfonyl chloride (77 mg, 0.37 mmol) in dichloromethane was added in portions to a soln of N⁴-(4-methoxy-phenyl)-2,N⁴-dimethyl-quinazolin-4,6-diamine (0.11 g, 0.37 mmol) in 5 mL of pyridine, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated and the resulting crude extracts dissolved in ethyl acetate (30 mL), washed with water, dried over MgSO₄, and concentrated. Purification was done by preparative TLC (EtOAc/hexanes=1/1 as eluent) to give 29 mg of the title compound. ¹H NMR (DMSO-d₆) δ 7.53-6.94 (m, 11H), 3.79 (s, 6H), 3.41 (s, 3H), 2.53 (s, 3H); LC-MS (ESI⁺; 465 ([M+H]⁺)).

Example 237

(2-Aminomethyl-quinazolin-4-yl)-(4-ethoxy-2-fluoro-phenyl)-methyl-amine

a) 4-Ethoxy-2-fluoro-1-nitro-benzene: Potassium carbonate (3.339 g, 24.2 mmol), followed by iodo-ethane (1.80 mL, 22.5 mmol), was added to a soln of 3-fluoro-4-nitro-phenol (3.153 g, 20.1 mmol) in acetone (20 mL). After 68 h at rt, the rxn was heated at reflux for 3.5 h, then cooled. EtOAc (100 mL) was added and this washed with water (1×25 mL), 1 M NaOH (2×15 mL), 50% satd NaCl (1×50 mL) and satd NaCl (2×25 mL). The organic portion was dried (MgSO₄), filtered through basic alumina then concentrated yielding the title compound as an off-white crystalline solid (3.55 g; 96%).
b) 4-Ethoxy-2-fluoro-phenylamine: The title compound was produced as an orange-brown liquid (948 mg; 32%) from 4-ethoxy-2-fluoro-1-nitro-benzene (3.55 g, 19.2 mmol) by a procedure similar to Example 235b. ¹H NMR (CDCl₃) δ 6.71 (m, 1H), 6.62 (m, 1H), 6.53 (m, 1H), 3.94 (q, J=6.9 Hz, 2H), 3.42 (s(br), 2H), 1.37 (t, J=7.0 Hz, 3H).
c) (2-Chloromethyl-quinazolin-4-yl)-(4-ethoxy-2-fluoro-phenyl)-amine hydrochloride: To 4-chloro-2-chloromethyl-quinazoline (500 mg, 2.3 mmol) dissolved in isopropanol (7.6 mL) was added 4-ethoxy-2-fluoro-phenylamine (540 mg, 2.8 mmol) and HCl (12 M, 1 drop). The reaction was stirred overnight at room temperature. The resulting precipitate was filtered to give 613 mg of the title compound. ¹H NMR (DMSO-d₆) δ 8.76 (d, 1H), 8.1 (t, 1H), 7.98 (d 1H), 7.85 (t, 1H), 7.47 (t 1H), 7.04 (d, 1H), 6.90 (d, 1H), 4.75 (s, 2H), 4.1 (q, 2H), 1.36 (t, 3H); LC-MS (ESI⁺; 351 ([M+H]⁺)).
d) (2-Chloromethyl-quinazolin-4-yl)-(4-ethoxy-2-fluoro-phenyl)-methyl-amine: To (2-chloromethyl-quinazolin-4-yl)-(4-ethoxy-2-fluoro-phenyl)-amine hydrochloride (531 mg, 1.5 mmol) dissolved in THF at 0° C. was added methyl iodide (1.89 mL, 30.3 mmol) and sodium hydride (363 mg, 15.1 mmol). The reaction was stirred at room temperature for 4 h then warmed to room temperature for 1 h. The reaction was quenched with H₂O and diluted with EtOAc. The aqueous phase was extracted with EtOAc (3×10 mL). The combined organic phases were washed with brine, dried (MgSO₄), concentrated and purified by gradient MPLC (0-100%, EtOAc/hexanes, SiO₂) to give 341 mg of the title compound. ¹H NMR (CDCl₃) δ 7.83 (d, 1H), 7.59 (t, 1H), 7.31-7.04 (m, 3H), 6.75-6.69 (m, 2H), 4.74 (s, 2H), 4.02 (q, 2H), 3.58 (s, 3H), 1.45 (t, 3H); LC-MS (ESI⁺; 365 ([M+H]⁺)).
e) 2-{4-[(4-Ethoxy-2-fluoro-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-isoindole-1,3-dione: To (2-chloromethyl-quinazolin-4-yl)-(4-ethoxy-2-fluoro-phenyl)-methyl-amine (341 mg 0.94 mmol) in N,N-dimethylformamide (3 mL) was added potassium phthalimide (381 mg, 2.1 mmol). The reaction was heated to 70° C. for 2.5 hours. The reaction was quenched with H₂O and diluted with EtOAc. The aqueous phase was extracted with EtOAc (3×10 mL). The combined organic phases were washed with brine, dried (MgSO₄), concentrated and purified by gradient MPLC (0-100%, EtOAc/Hexane, SiO₂) to give 380 mg (90%) of the title compound as a solid. ¹H NMR (MeOH-d₄) δ 7.95-7.93 (dd, 2H), 7.86-7.84 (dd, 2H), 7.68-7.62 (m, 2H), 7.23-7.18 (t, 1H), 7.11-7.05 (m, 2, H), 6.77 (d, 2H), 5.04 (s, 2H), 4.03 (q, 2H), 3.20 (s, 3H), 1.39 (t, 3H); LC-MS (ESI⁺; 457 ([M+H]⁺)).
f) (2-Aminomethyl-quinazolin-4-yl)-(4-ethoxy-2-fluoro-phenyl)-methyl-amine: The title compound was prepared from 2-{4-[(4-ethoxy-2-fluoro-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-isoindole-1,3-dione (297 mg, 0.65 mmol) by a procedure similar to the preparation of (2-aminomethyl-quinazolin-4-yl)-(4-ethoxy-phenyl)-methyl-amine in Example 211 and was isolated as a solid, 119 mg. ¹H NMR (CDCl₃) δ 7.74 (d, 1H), 7.66-7.62 (m, 1H), 7.3 (t, 1H), 7.12-7.08 (m, 2H), 6.88-6.87 (m, 2H), 4.07 (q, 2H), 3.99 (s, 2H), 3.6 (s, 3H), 1.41 (t, 3H); LC-MS (ESI⁺; 327 ([M+H]⁺)).

Example 238

(S)-2-Amino-N-{4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-propionamide

a) [(S)-1-({4-[(4-Methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-carbamoyl)-ethyl]-carbamic acid tert-butyl ester: To (2-aminomethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (210 mg, 0.74 mmol), Boc-L-Ala-OH (140 mg, 0.74 mmol), EDCI (170 mg, 0.89 mmol) and HOBt-hydrate (136 mg, 0.89 mmol) in DMF (3 mL) was added ethyl-diisopropyl-amine (383 μL, 2.2 mmol). The reaction was stirred at room temperature overnight, diluted with EtOAc and quenched with 10% aqueous HCl followed by saturated aqueous NaHCO₃. The aqueous phase was extracted with EtOAc (4×15 mL). The combined organic phases were washed with brine, dried (MgSO₄) and concentrated. Purification by gradient MPLC (0-20% MeOH/CH₂Cl₂with 0.1% NH₄OH) gave 285 mg (83%) of the title compound as a yellow solid. ¹H NMR (MeOH-d₄) δ 7.69 (d, 1H), 7.61-7.57 (m, 1H), 7.1 (d, 2H), 7.03-6.98 (m, 4H), 4.61-4.49 (m, 2H), 4.23 (q, 1H), 3.83 (s, 3H), 3.62 (s, 3H), 1.44 (s, 9H), 1.4 (d, 3H); LC-MS (ESI⁺; 466 ([M+H]⁺)).
b) (S)-2-Amino-N-{4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-propionamide: To [(S)-1-({4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-carbamoyl)-ethyl]-carbamic acid tert-butyl ester in MeOH (1 mL) was added HCl (12 M, 1 mL, 12 mmol). The reaction was stirred at room temperature overnight. The solvent was removed under vacuum to yield 170 mg of the title compound as a yellow solid. ¹H NMR (MeOH-d₄) δ 7.86-7.85 (m, 2H), 7.38 d, 2H), 7.27 (m, 1H), 7.13 (d, 2H), 6.92 (d, 1H), 4.75-4.72 (m, 2H), 4.19 (q, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 1.63 (d, 3H); LC-MS (ESI⁺; 366 ([M+H]⁺)).

Example 239

(2-Aminomethyl-5-fluoro-quinazolin-4-yl)-(4-ethoxy-phenyl)-methyl-amine

a) 4-Chloro-2-chloromethyl-5-fluoro-quinazoline: The title compound was prepared using a procedure similar to Example 73. ¹H NMR (CDCl₃) δ 7.88-7.97 (m, 2H), 7.36-7.46 (m, 1H), 4.82 (s, 2H).
b) (2-Chloromethyl-5-fluoro-quinazolin-4-yl)-(4-ethoxy-phenyl)-amine hydrochloride: A mixture of 4-chloro-2-chloromethyl-5-fluoro-quinazoline (310 mg, 1.34 mmol), 4-ethoxyphenylamine (0.19 mL, 1.48 mmol) and 3 drops of concd HCl was stirred for 3 h at rt in i-PrOH. The product was collected by vacuum filtration. ¹H NMR (DMSO-d₆) δ 7.85-7.95 (m, 1H), 7.60-7.72 (m, 3H), 7.45-7.54 (m, 1H), 6.92-7.02 (m, 2H), 4.66 (s, 2H), 4.05 (q, 2H), 1.35 (t, 3H).
c) (2-Chloromethyl-5-fluoro-quinazolin-4-yl)-(4-ethoxy-phenyl)-methyl-amine: NaH (60 mg, 1.5 mmol) was added to a solution of (2-chloromethyl-5-fluoro-quinazolin-4-yl)-(4-ethoxy-phenyl)-amine (184 mg, 0.5 mmol) and MeI (0.10 mL) in THF (2 mL) at rt and the reaction stirred for 2 h. MeOH and EtOAc were added. The organics were washed with brine, dried (MgSO₄), filtered and concentrated. Purification by MPLC (SiO₂, EtOAc/hexanes, 0-100%) provided the desired compound.
d) (2-Aminomethyl-5-fluoro-quinazolin-4-yl)-(4-ethoxy-phenyl)-methyl-amine: The synthesis was done in a manner similar to the synthesis of Example 205. HRMS (ES) calcd for C₁₉H₂₀FN₄O 327.1616. found 327.1626.

Example 240

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

a) 2-[4-(3-Chloro-4-methoxy-phenylamino)-quinazolin-2-ylmethyl]-isoindole-1,3-dione: The title compound was prepared from (3-chloro-4-methoxy-phenyl)-(2-chloromethyl-quinazolin-4-yl)-methyl-amine (428 mg, 1.1 mmol) and potassium phthalimide (453 mg, 2.4 mmol) in DMF (3.7 mL) by a procedure similar to Example 203d. ¹H NMR (DMSO-d₆) δ 7.98-7.90 (m, 4H), 7.62-7.60 (m, 2H), 7.48 (d, 1H), 7.2-7.13 (m, 3H), 6.96-6.93 (d, 1H), 4.96 (s, 2H), 3.87 (s, 3H), 3.28 (s, 3H); LC-MS (ESI⁺; 459 ([M+H]⁺)).
b) (2-Aminomethyl-quinazolin-4-yl)-(3-chloro-4-methoxy-phenyl)-methyl-amine: To 2-{4-[(3-chloro-4-methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-isoindole-1,3-dione (527 mg, 1.1 mmol) in EtOH (3.6 mL) was added hydrazine monohydrate (215 μL, 4.4 mmol). The reaction was heated at 70° C. for 2.5 h then cooled to room temperature. To the reaction was then added HCl (1 M, 10 mL). The reaction was heated again to 70° C. for 1 hour, cooled to room temperature, filtered and quenched with NaOH (1 M, 10 mL). The reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were washed with brine dried over MgSO₄and concentrated. Purification by MPLC ((20% MeOH with 0.1% NH₄OH) in CH₂Cl₂, SiO₂) gave 119 mg as a yellow solid. ¹H NMR (MeOH-d₄) δ 7.75-7.73 (td, 1H), 7.66-7.61 (m, 1H), 7.33 (d, 1H), 7.17-7.07 (m, 4H), 4.0 (s, 2H), 3.92 (s, 3H), 3.63 (s, 3H); LC-MS (ESI⁺; 329 ([M+H]⁺)).

Example 241

[2-Aminomethyl-6-(4-chloro-phenyl)-quinazolin-4-yl]-(4-methoxy-phenyl)-methyl-amine

a) 2-{6-(4-chloro-phenyl)-4-[(4-methoxy-phenyl)-methyl-amino]-quinazoline-2-yl-methyl}-isoindole-1,3-dione: The title compound was prepared from 2-{6-bromo-4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-isoindole-1,3-dione similar to Example 243. LC-MS (ESI⁺; 501 ([M+H]⁺)).
b) [2-Aminomethyl-6-(4-chloro-phenyl)-quinazolin-4-yl]-(4-methoxy-phenyl)-methyl-amine: To the mixture of 0.14 g (0.26 mmol) of 2-{6-(4-chloro-phenyl)-4-[(4-methoxy-phenyl)-methyl-amino]-quinazoline-2-yl-methyl}-isoindole-1,3-dione in EtOH (10 mL) and CH₂Cl₂(3 mL) was added 0.04 g (0.80 mmol) of hydrazine monohydrate. The reaction mixture was stirred at ambient temperature for 18 hours. The solvent was evaporated. The isolation was done by preparative TLC (CHCl₃/MeOH/NH₄OH=10/0.5/0.025 as eluent) to give 0.02 g of the title compound. ¹H NMR (DMSO-d₆) δ 8.08-7.08 (11H), 3.89 (s, 2H), 3.85 (s, 3H), 3.58 (s, 3H); LC-MS (ESI⁺; 405 ([M+H]⁺)).

Example 242

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

a) (3-Chloro-4-methoxy-phenyl)-(2-chloromethyl-quinazolin-4-yl)-amine hydrochloride: The title compound was prepared from 4-chloro-2-chloromethyl-quinazoline (500 mg, 2.3 mmol), 3-chloro-4-methoxy-phenylamine (444 mg, 2.8 mmol) and HCl (12 M, 7 drops) in i-PrOH (8 mL) by a procedure similar to the preparation of (2-chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine hydrochloride in Example 203c. ¹H NMR (CDCl₃) δ 8.6 (d, 1H), 8.1 (t, 1H), 7.85 (m, 3H), 7.62 (d, 1H), 7.20 (d, 1H), 4.8 (s, 2H), 3.92 (s, 3H); LC-MS (ESI⁺; 334 ([M+H]⁺)).
b) (3-Chloro-4-methoxy-phenyl)-(2-chloromethyl-quinazolin-4-yl)-methyl-amine: To (3-chloro-4-methoxy-phenyl)-(2-chloromethyl-quinazolin-4-yl)-amine hydrochloride (690 mg, 1.9 mmol) in THF (7 mL) cooled to 0° C. was added iodomethane (2.32 mL, 37 mmol) and sodium hydride (447 mg, 18.6 mmol). The reaction was stirred for 1 h at 0° C. then warmed to room temperature for 1 h. The reaction was quenched with H₂O and diluted with EtOAc. The aqueous phase was extracted with EtOAc (3×10 mL). The combined organic phases were washed with brine, dried (MgSO₄), concentrated and purified by gradient MPLC (0-100%, EtOAc/hexanes, SiO₂) to give 539 mg (81%) of the title compound as a yellow solid. ¹H NMR (CDCl₃) δ 7.85 (d, 1H), 7.63-7.59 (m, 1H), 7.30 (d, 1H), 7.12-7.01 (m, 3H), 6.90 (d, 1H), 4.74 (s, 2H), 3.94 (s, 3H), 3.62 (s, 3H); MS (EI) m/z 347.

Example 243

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

a) 2-{4-[(4-Methoxy-phenyl)-methyl-amino]-6-phenyl-quinazolin-2-ylmethyl}-isoindole-1,3-dione: A mixture of 0.2 g (0.39 mmol) of 2-{6-bromo-4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-isoindole-1,3-dione in 0.4 mL of DMF, 0.058 g (0.48 mmol) of phenylboronic acid in 0.4 mL of DMF, 0.23 mL (0.48 mmol) of 2 M aq Na₂CO₃, 2.8 mg (0.004 mmol) of dichlorobis(triphenylphosphine)palladium(II) in DME/H₂O/EtOH=2.3/1/0.66 mL, was exposed to MW irradiation at 150° C. for 2 min. The reaction mixture filtered through Celite and washed with Et₂O. The organics dried over Na₂SO₄, filtered, concentrated, to give 0.019 g of crude extract, which was used in the next reaction without further purification.
b) (2-Aminomethyl-6-phenyl-quinazoline-4-yl)-(4-methoxy-phenyl)-methyl-amine: To a solution of 0.1 g (0.2 mmol) of 2-{4-[(4-methoxy-phenyl)-methyl-amino]-6-phenyl-quinazolin-2-ylmethyl}-isoindole-1,3-dione in EtOH (15 mL) was added hydrazine monohydrate (0.029 mL, 0.60 mmol) and the mixture was stirred at ambient temperature for 18 hours. Then concd HCl (10 drops) was added to the reaction mixture and was stirred for 2 hours. The precipitate filtered off, the filtrate concentrated. Isolation was done by RPLC (water/0.1% TFA- acetonitrile/0.01% TFA) to give 70 mg of the title compound obtained as the TFA salt. ¹H NMR (DMSO-d₆) δ 8.4-7.1 (12H), 4.26 (s, 2H), 4.8 (s, 3H), 4.7 (s, 3H); LC-MS (ESI⁺; 371 ([M+H]⁺)).

Example 244

N-{4-[(4-Methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-nicotinamide

To (2-aminomethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (100 mg, 0.34 mmol) and nicotinoyl chloride hydrochloride (91 mg, 0.51 mmol) in CH₂Cl₂(3 mL) at 0° C. was added triethylamine (167 mg, 1.2 mmol). The reaction was stirred for 2 h at 0° C. The mixture was washed successively with H₂O, 0.1 M HCl, H₂O and 5% NaHCO₃. The reaction was extracted with EtOAc (3×10 mL), washed with brine, dried (MgSO₄) and concentrated providing 64 mg of the title compound. ¹H NMR (CDCl₃) δ 8.76 (s, 1H), 8.29 (d, 1H), 8.11 (s, 1H), 7.78 (d, 1H), 7.58 (t, 1H), 7.45 (t, 1H), 7.14 (d, 2H), 7.05-7.01 (m, 2H), 6.93 (d, 2H), 4.85 (s, 2H), 3.85 (s, 3H), 3.61 (s, 3H); LC-MS (ESI⁺; 400 ([M+H]⁺)).

Example 245

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

a) 6-Bromo-2-Methyl-3H-quinazoline-4-one: HCl gas was bubbled through a solution of 2 g (4.3 mmol) of 2-amino-5-bromo-benzoic acid methyl ester in 50 mL of acetonitrile for 15 min with vigorous stirring. The resulting mixture was heated at reflux for 16 hours. Then the reaction mixture was cooled down and the precipitate was collected by filtration, washed by water and dried in vacuum to give 1.7 g of the title compound. ¹H NMR (DMSO-d₆) δ 8.14 (s, 1H), 7.92 (d, 1H), 7.54 (d, 1H), 2.35 (s, 3H); LC-MS (ESI⁺; 240 ([M+H]⁺)).
b) 6-Bromo-4-chloro-2-methyl-quinazoline: The title compound was prepared from 6-bromo-2-methyl-3H-quinazoline-4-one similar to Example 109. LC-MS (ESI⁺; 258 ([M+H]⁺)).
c) (6-Bromo-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine: To the mixture of 0.5 g (1.94 mmol) of 6-bromo-4-chloro-2-methyl-quinazoline in i-PrOH (10 mL) and HCl (0.2 mL) was added 0.29 g (2.13 mmol) of (4-methoxy-phenyl)-methyl-amine, and the mixture was stirring at ambient temperature for 4 hours. The precipitate was collected and washed with Et₂O to give 0.2 g of the title compound as the HCl salt. ¹H NMR (DMSO-d₆) δ 8.32-6.7 (7H), 3.84 (s, 3H), 3.72 (s, 3H), 2.72 (s, 3H); LC-MS (ESI⁺; 359 ([M+H]⁺)).

Example 246

(6-Bromo-2-methyl-quinazolin-4-yl)-(4-ethoxy-3-fluoro-phenyl)-methyl-amine

A mixture of 0.21 g (0.82 mmol) of 6-bromo-4-chloro-2-methyl-quinazoline and 0.16 g (0.89 mmol) of (4-ethoxy-3-fluoro-phenyl)-methyl-amine in i-PrOH (20 mL) was stirred at ambient temperature for 18 hours. The precipitate was collected and washed with Et₂O to give 0.1 g of the title compound as the HCl salt. ¹H NMR (DMSO-d₆) δ 8.32-6.8 (6H), 4.23 (q, 2H), 3.72 (s, 3H), 2.73 (s, 3H), 1.39 (t, 3H); LC-MS (ESI⁺; 391 ([M+H]⁺)).

Example 247

(4-Methoxy-phenyl)-methyl-[2-(1H-tetrazol-5-yl)-quinazolin-4-yl]-amine

To 4-[(4-methoxy-phenyl)-methyl-amino]-quinazoline-2-carbonitrile (100 mg, 0.34 mmol) in DMF (3.4 mL) was added sodium azide (269 mg, 4.1 mmol) and ammonium chloride (220 mg, 4.1 mmol). The reaction was heated to 130° C. for 15 min in a microwave. The reaction was quenched with aqueous NaHCO₃and diluted with EtOAc. The aqueous phase was acidified with HCl (12 M) to pH 1 and extracted with EtOAc. The combined organic phases were washed with brine, dried (MgSO₄), filtered and concentrated. Purification via gradient MPLC gave 15 mg (13%) of the title compound as a solid. ¹H NMR (MeOH-d₄) δ 7.91 (d, 1H), 7.74-7.70 (t, 1H), 7.30 (d, 2H), 7.16 (t, 1H), 7.06 (d, 2H), 7.0 (d, 1H), 3.86 (s, 3H), 3.82 (s, 3H); LC-MS (ESI⁺; 334 ([M+H]⁺)).

Example 248

(R)-2-Amino-N-{4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-propionamide

a) [(R)-1-({4-[(4-Methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-carbamoyl)-ethyl]-carbamic acid tert-butyl ester: The title compound was prepared from (2-aminomethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (100 mg, 0.37 mmol), Boc-D-Ala-OH (70 mg, 0.37 mmol), EDCI (86 mg, 0.45 mmol), HOBt-hydrate (68 mg, 0.82 mmol) and ethyl-diisopropyl-amine (191 μL, 1.1 mmol) in DMF (1.2 mL) by a procedure similar to the preparation of Example 238a and was isolated as a yellow solid, 114 mg (67%). ¹H NMR (MeOH-d₄) δ 7.7 (d, 1H), 7.62-7.57 (m, 1H), 7.18 (d, 2H), 7.06-6.98 (m, 4H), 4.55 (m, 2H), 4.2 (q, 1H), 3.82 (s, 3H), 3.62 (s, 3H), 1.49 (s, 9H), 1.48 (d, 3H); LC-MS (ESI⁺; 466 ([M+H]⁺)).
b) (R)-2-Amino-N-{4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-propionamide: The title compound was prepared from [(R)-1-({4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-carbamoyl)-ethyl]-carbamic acid tert-butyl ester (78 mg, 0.17 mmol), methanol (1 mL) and concentrated HCl (12 M, 1 mL) by a procedure similar to the preparation of (S)-2-amino-N-{4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-propionamide in Example 238b and was isolated as a yellow solid. ¹H NMR (MeOH-d₄) δ 7.87-7.84 (m, 2H), 7.4-7.37 (d, 2H), 7.29-7.25 (m, 1H), 7.15-7.12 (d, 2H), 6.90 (d, 1H), 4.73 (d, 2H), 4.19 (q, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 1.63 (d, 3H); LC-MS (ESI⁺; 366 ([M+H]⁺)).

Example 249

4-[(4-Methoxy-phenyl)-methyl-amino]-2-methyl-quinazoline-6-carbonitrile

4-[(4-Methoxy-phenyl)-methyl-amino]-2-methyl-quinazoline-6-carbonitrile: 0.22 g (0.51 mmol) of (6-bromo-2-methyl-quinazoline-4-yl)-(4-methoxy-phenyl)methyl-amine, 0.072 g (0.61 mmol) of Zn(CN)₂, 0.021 g (0.018 mmol) of Pd(PPh₃)₄and DMF (1.5 mL) was exposed to MW irradiation at 195° C. and 300 W for 40 min. The reaction mixture was diluted with EtOAc (10 mL), and water (5 mL), the organic layer separated, dried over MgSO₄, filtered and concentrated. The isolation was done by MPLC (0-100% EtOAc/hexanes as eluent) to give 86 mg of the title compound. ¹H NMR (DMSO-d₆) δ 7.9-7.07 (7H), 3.81 (s, 3H), 3.54 (s, 3H), 2.59 (s, 3H); LC-MS (ESI⁺; 305 ([M+H]⁺)).

Example 250

(2-Aminomethyl-5-fluoro-quinazolin-4-yl)-(4-ethoxy-2-fluoro-phenyl)-methyl-amine

a) (4-Ethoxy-2-fluoro-phenyl)-methyl-amine: The title compound was produced from 4-ethoxy-2-fluoro-phenylamine as a clear, colorless liquid, which turned dark purple within hours, by a procedure similar to Example 221b, with final purification by MPLC (SiO₂/0-30% EtOAc in hexanes). ¹H NMR (CDCl₃) δ 6.68-6.60 (m, 3H), 3.95 (q, J=6.9 Hz, 2H), 3.60 (s(br), 1H), 2.84 (s, 3H), 1.37 (t, J=6.8 Hz, 3H); GC-MS (EI; 169 (M⁺)).
b) (4-Ethoxy-2-fluoro-phenyl)-methyl-amine hydrochloride: The title compound was produced as a pale purple solid (169 mg; 13% from 4-ethoxy-2-fluoro-phenylamine) by concentrating a HCl-i-PrOH soln of (4-ethoxy-2-fluoro-phenyl)-methyl-amine in vacuo.
c) (2-Chloromethyl-5-fluoro-quinazolin-4-yl)-(4-ethoxy-2-fluoro-phenyl)-methyl-amine: Prepared using a procedure similar to Example 203c, starting from 4-chloro-2-chloromethyl-5-fluoro-quinazoline and (4-ethoxy-2-fluoro-phenyl)-methyl-amine hydrochloride. ¹H NMR (MeOH-d₄) δ 7.98 (td, 1H), 7.66 (d, 1H), 7.14-7.26 (m, 2H), 6.89 (dd, 1H), 6.71 (ddd, 1H), 4.85 (s, 2H), 4.05 (q, 2H), 3.81 (s, 3H), 1.40 (t, 3H); LC-MS (ESI⁺; 364 ([M+H]⁺)).
d) (2-Aminomethyl-5-fluoro-quinazolin-4-yl)-(4-ethoxy-2-fluoro-phenyl)-methyl-amine: Prepared using a procedure similar to Example 203 starting from (2-chloromethyl-5-fluoro-quinazolin-4-yl)-(4-ethoxy-2-fluoro-phenyl)-methyl-amine hydrochloride. ¹H NMR (CDCl₃) δ 7.50-7.64 (m, 2H), 6.77 (ddd, 1H), 6.60-6.72 (m, 2H), 6.46 (ddd, 1H), 4.10 (s, 2H), 3.98 (q, 2H), 3.51 (s, 3H), 2.45 (s(br), 2H), 1.40 (t, 3H); HRMS (ES) m/z calcd for C₁₈H₁₉N₄F₂O (M+H) 345.1521. found 345.1542.

Example 251

(2-Chloromethyl-quinazolin-4-yl)-(3,5-dichloro-4-methoxy-phenyl)-methyl-amine

a) (3,5-Dichloro-4-hydroxy-phenyl)-carbamic acid ethyl ester: Neat ethyl chloroformate (2.70 mL, 28.2 mmol) was added dropwise over 4 min to a soln of 4-amino-2,6-dichloro-phenol (5.005 g, 28.1 mmol) and 10 N NaOH (2.81 mL, 28.1 mmol) in water (25 mL). After 5 min at room temperature, the reaction was heated at 80° C. for 45 min, then cooled. 1 M HCl (35 mL) was added and the ppt collected by filtration and washed with water. The product was dissolved in EtOAc (50 mL), dried (MgSO₄), filtered through a plug of silica and washed with EtOAc then purified by MPLC (SiO₂/0-50% EtOAc in hexanes), yielding the title compound as a white solid (4.924 g; 70%). LC-MS (ESI⁻; 248 ([M−H]⁻)).
b) (3,5-Dichloro-4-methoxy-phenyl)-carbamic acid ethyl ester: Neat iodomethane (0.65 mL, 10.4 mmol) was added to a suspension of (3,5-dichloro-4-hydroxy-phenyl)-carbamic acid ethyl ester (2.504 g, 10.0 mmol) and potassium carbonate (2.910 g, 21.1 mmol) in acetone. After 3 days, water (20 mL) was added, the organic volatiles removed in vacuo, then the product extracted into EtOAc (40 mL). The soln was washed with water (10 mL), aq citric acid (10 mL) and satd NaCl (2×10 mL); then dried (MgSO₄), filtered through a plug of silica with an EtOAc wash, then purified by MPLC (SiO₂/0-25% EtOAc in hexanes yielding the title compound as a white solid (2.516 g; 95%). ¹H NMR (CDCl₃) δ 7.38 (s, 2H), 6.52 (s, 1H), 4.23 (q, J=7.1 Hz, 2H), 3.86 (s, 3H), 1.31 (t, J=7.0 Hz, 3H); LC-MS (ESI⁺; 264 ([M+H]⁺)).
c) (3,5-Dichloro-4-methoxy-phenyl)-methyl-amine hydrochloride: LiAlH₄(1.0 M in THF, 4.0 mL, 4.0 mmol) was added dropwise to a soln of (3,5-dichloro-4-methoxy-phenyl)-carbamic acid ethyl ester (528 mg, 2.00 mmol) in dry THF (4 mL) at rt. After 6 min, the rxn was heated at 70° C. for 23 h, then cooled to rt. Water (152 μL) then 15% aq NaOH (152 μL) then water (456 μL) were added. MgSO₄and Celite were added and the rxn was filtered through a plug of silica with an EtOAc wash. The free base of the title compound was obtained after MPLC purification (SiO₂/0-20% EtOAc in hexanes) as a light purple liquid (250 mg; 61%). LC-MS (ESI⁺; 206 ([M+H]⁺)); GC-MS (EI; 205). The title compound was obtained as a light tan solid by dissolving the product in i-PrOH, adding HCl-satd i-PrOH, then concentraing in vacuo.
d) (2-Chloromethyl-quinazolin-4-yl)-(3,5-dichloro-4-methoxy-phenyl)-methyl-amine hydrochloride: A mixture of 4-chloro-2-chloromethyl-quinazoline (320 mg, 1.50 mmol) and (3,5-dichloro-4-methoxy-phenyl)-methyl-amine hydrochloride (401 mg, 1.65 mmol) in i-PrOH was stirred at rt for 2.8 h then collected by filtration and washed with i-PrOH, yielding the title compound as a light tan solid (529 mg; 84%). ¹H NMR (CDCl₃) δ 8.59 (m, 1H), 7.87 (m, 1H), 7.37 (m, 1H), 7.33 (s, 2H), 6.94 (m, 1H), 5.11 (s, 2H), 4.02 (s, 3H), 3.85 (s, 3H); LC-MS (ESI⁺; 382 ([M+H]⁺)).

Example 252

1-{4-[(4-Methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-piperidin-2-one

To 2-piperidone (149 mg, 1.5 mmol) in THF (1 mL) at 0° C. was added n-butyllithium (2.5 M, 0.60 mL, 1.5 mmol) followed by a solution of (2-chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (150 mg, 0.43 mmol) in THF (1.5 mL). The reaction was heated to reflux for 2 h, cooled to room temperature, quenched with H₂O and diluted with ether. The aqueous phase was extracted with ether (3×10 mL) The combined organic phases were washed with brine, dried (MgSO₄), concentrated and purified by gradient MPLC (SiO₂, 0-20% MeOH/CH₂Cl₂with 0.1% NH₄OH) to give 133 mg (82%) of the title compound as a yellow oil. ¹H NMR (MeOH-d₄) δ 7.73 (d, 1H), 7.52 (dd, 1H), 7.71 (d, 2H), 6.98-6.96 (m, 2H), 6.90 (d, 2H), 4.82 (s, 2H), 3.84 (s, 3H), 3.55 (s, 3H), 3.52 (m, 2H), 2.53 (m, 2H), 1.92-1.88 (m, 4H); LC-MS (ESI⁺; 377 ([M+H]⁺)).

Example 253

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

(4-Ethoxy-3-fluoro-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine hydrochloride: The title compound was prepared from 4-chloro-2-methyl-quinazoline (78 mg, 0.44 mmol) and (4-ethoxy-3-fluoro-phenyl)-methyl-amine hydrochloride (81 mg, 0.39 mmol) by a procedure similar to Example 251. ¹H NMR (CDCl₃) δ 8.57 (m, 1H), 7.74 (m, 1H), 7.19 (m, 1H), 7.10 (dd, J=2.6, 10.6 Hz, 1H), 7.05 (d, J=8.8 Hz, 1H), 6.98 (ddd, J=1.5, 2.8, 8.5 Hz, 1H), 6.81 (m, 1H), 4.19 (q, J=6.9 Hz, 2H), 3.77 (s, 3H), 2.98 (s, 3H), 1.53 (t, J=7.0 Hz, 3H); LC-MS (ESI⁺; 312 ([M+H]⁺)).

Example 254

(2-Aminomethyl-quinazolin-4-yl)-(3,5-dichloro-4-methoxy-phenyl)-methyl-amine bis(hydrochloride)

a) 2-{4-[(3,5-Dichloro-4-methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-isoindole-1,3-dione: A mixture of (2-chloromethyl-quinazolin-4-yl)-(3,5-dichloro-4-methoxy-phenyl)-methyl-amine hydrochloride (521 mg, 1.24 mmol), K₂CO₃(401 mg, 2.90 mmol) and potassium phthalimide (312 mg, 1.68 mmol) in DMF (7 mL) was heated at 50° C. for 4 h. EtOAc and DCM were added and this was washed with water then 50% satd NaCl then satd NaCl. The organic layer was dried (MgSO₄), filtered through a pad of silica with an EtOAc wash then most of the solvents were removed on a rotary evaporator. The remaining solvent was removed from the crystalline material that had formed and the product was washed with two portions of EtOAc then suspended in hexanes, collected by filtration and washed with hexanes. The title compound was obtained as a paleyellow microcrystalline solid (373 mg; 61%). ¹H NMR (CDCl₃) δ 7.96-7.91 (m, 2H), 7.79-7.40 (m, 3H), 7.60 (m, 1H), 7.16-7.06 (m, 2H), 7.04 (s, 2H), 5.16 (s, 2H), 3.90 (s, 3H), 3.30 (s, 3H); LC-MS (ESI⁺; 493 ([M+H]⁺)).
b) (2-Aminomethyl-quinazolin-4-yl)-(3,5-dichloro-4-methoxy-phenyl)-methyl-amine: Hydrazine monohydrate (300 μL, 6.18 mmol) was added to a suspension of 2-{4-[(3,5-dichloro-4-methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-isoindole-1,3-dione (0.37 g, 0.75 mmol) in 3:2 abs. EtOH:THF (15 mL). After 3 h at 65° C., the product was collected by filtration. The material was purified by preparative TLC (SiO₂/100:10:1 CHCl₃:i-PrOH:concd HCl) and the bis(hydrochloride) salt was obtained by adding HCl-satd i-PrOH to a soln of the product in i-PrOH then concd in vacuo (307 mg; 94%). ¹H NMR (DMSO-d₆) δ 8.55 (t(br), 3H), 7.90-7.80 (m, 2H), 7.61 (s, 2H), 7.38 (m, 1H), 7.12 (m, 1H), 4.33 (q(br), J=5.6 Hz, 2H), 3.87 (s, 3H), 3.67 (s, 3H); LC-MS (ESI⁺; 363 ([M+H]⁺)).

Example 255

1-{4-[(4-Methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-pyrrolidin-2-one

The title compound was prepared from (2-chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (150 mg, 0.43 mmol), 2-pyrrolidinone (128 mg, 1.5 mmol) and n-butyllithium (2.5 M in THF, 1.2 mL, 3 mmol) in THF (2 mL) by a procedure similar to the preparation of 1-{4-[(4-methoxyphenyl)methylamino]quinazolin-2-ylmethyl}piperidin-2-one in Example 252 and was isolated as a yellow solid. ¹H NMR (CDCl₃) δ 7.75-7.73 (m, 1H), 7.55-7.51 (m, 1H), 7.13-7.10 (d, 2H), 6.99-6.97 (m, 2H), 6.93-6.90 (d, 2H), 4.72 (s, 2H), 3.84 (s, 3H), 3.61 (t, 2H), 3.54 (s, 3H), 2.53 (t, 2H), 2.15-2.10 (pentet, 2H); LC-MS (ESI⁺; 363 ([M+H]⁺)).

Example 256

3-({4-[(4-Methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-amino)-propan-1-ol

A mixture of (2-chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine hydrochloride (100 mg, 0.286 mmol), Cs₂CO₃(201 mg, 0.617 mmol) and 3-amino-propan-1-ol (44 μL, 0.58 mmol) in DMF (1 mL) was heated at 80° C. After 18 h, EtOAc (12 mL) was added and this was washed with water (2×2 mL) and satd NaCl (2×2 mL). The soln was dried (MgSO₄), filtered through a plug of silica with a wash of 100:10:1 chloroform:methanol:concd NH₄OH then purified by preparative TLC (SiO₂/200:10:1 chloroform:2-propanol:concd NH₄OH). A band was removed from this preparative TLC plate and further purified by preparative TLC (SiO₂/100:10:1 chloroform:methanol:concd NH₄OH) yielding the title compound as a yellow oil. The bis(hydrochloride) salt was formed by adding then evaporating a soln of HCl in i-PrOH, giving an off-white solid. ¹H NMR (DMSO-d₆) δ 7.84 (m, 1H), 7.78 (m, 1H), 7.35 (m, 2H), 7.25 (m, 1H), 7.09 (m, 2H), 6.90 (m, 1H), 4.91 (t(br), 2H), 3.82 (s, 3H), 3.68 (s, 3H), 3.56 (t, J=6.2 Hz, 2H), 3.24 (m, 2H), 1.91 (m, 2H); LC-MS (ESI⁺; 353 ([M+H]⁺)).

Example 257

(2-Chloromethyl-quinazolin-4-yl)-(3,5-dichloro-4-ethoxy-phenyl)-methyl-amine

a) (3,5-Dichloro-4-ethoxy-phenyl)-carbamic acid ethyl ester: The title compound was synthesized as a pale yellow crystalline solid (2.759 g; 99%) from (3,5-dichloro-4-hydroxy-phenyl)-carbamic acid ethyl ester (2.505 g, 10.0 mmol) by a procedure similar to Example 251b. ¹H NMR (CDCl₃) δ 7.38 (s, 2H), 6.50 (s, 1H), 4.23 (q, J=6.9 Hz, 2H), 4.06 (q, J=6.9 Hz, 2H), 1.44 (t, J=7.0 Hz, 3H), 1.31 (t, J=7.2 Hz, 3H); LC-MS (ESI⁺; 278 ([M+H]⁺)).
b) (3,5-Dichloro-4-ethoxy-phenyl)-methyl-amine hydrochloride and (3-chloro-4-ethoxy-phenyl)-methyl-amine hydrochloride: LiAlH₄(1.0 M in THF, 10.0 mL, 10.0 mmol) was added dropwise to a soln of (3,5-dichloro-4-ethoxy-phenyl)-carbamic acid ethyl ester (1.509 g, 5.426 mmol) in dry THF (8 mL) at rt. After 4 min, the rxn was heated at 70° C. for 6.3 h, then cooled to rt. Water (300 μL) then 15% aq NaOH (300 μL) then water (900 μL) were added. EtOAc (25 mL), MgSO₄and Celite were added and the rxn was filtered through a plug of silica with an EtOAc wash. HPLC-MS shows this crude material to be a mixture of (3,5-dichloro-4-ethoxy-phenyl)-methyl-amine and (3-chloro-4-ethoxy-phenyl)-methyl-amine, plus an unknown compound. The hydrochloride salts of the product anilines, as a mixture, were produced by dissolving the crude mixture in i-PrOH, adding HCl-satd i-PrOH, then concentraing in vacuo.
c) (2-Chloromethyl-quinazolin-4-yl)-(3,5-dichloro-4-ethoxy-phenyl)-methyl-amine: The above mixture of (3,5-dichloro-4-ethoxy-phenyl)-methyl-amine hydrochloride and (3-chloro-4-ethoxy-phenyl)-methyl-amine hydrochloride was dissolved in hot i-PrOH (20 mL) then this was cooled to rt. 4-Chloro-2-chloromethyl-quinazoline (607 mg, 2.85 mmol) was added. After 2 h, the rxn was cooled in a freezer then the crude product mixture, as hydrochloride salts, was collected by filtration. EtOAc (20 mL) was added and this washed with satd NaHCO₃(2×5 mL) and satd NaCl (2×8 mL); then dried (MgSO₄) and filtered. The title compound was obtained as an off-white solid (229 mg; 20%) after MPLC (SiO₂/0-35% EtOAc in hexanes). This reaction also produced (3-chloro-4-ethoxy-phenyl)-(2-chloromethyl-quinazolin-4-yl)-methyl-amine. ¹H NMR (CDCl₃) δ 7.89 (m, 1H), 7.66 (m, 1H), 7.21-7.11 (m, 2H), 7.12 (s, 2H), 4.76 (s, 2H), 4.14 (q, J=6.8 Hz, 2H), 3.63 (s, 3H), 1.48 (t, J=7.0 Hz, 3H); LC-MS (ESI⁺; 396 ([M+H]⁺)).

Example 258

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

The title compound was produced in the reaction of Example 257c as a pale yellow solid (139 mg; 13%). ¹H NMR (CDCl₃) δ 7.84 (m, 1H), 7.60 (m, 1H), 7.30 (d, J=2.4 Hz, 1H), 7.12-7.04 (m, 2H), 6.99 (dd, J=2.8, 9.2 Hz, 1H), 6.89 (d, J=8.8 Hz, 1H), 4.74 (s, 2H), 4.13 (q, J=7.1 Hz, 2H), 3.61 (s, 3H), 1.51 (t, J=7.0 Hz, 3H); LC-MS (ESI⁺; 362 ([M+H]⁺)).

Example 259

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

A solution of 0.02 g of 4-[4-methoxy-phenyl]-methyl-amino]-2-methyl-quinazoline-6-carbonitrile in 2 mL of methanol was hydrogenated over Pd/C for 1.5 hours. The catalyst was filtered off, washed with methanol, the filtrate concentrated. The isolation was done by preparative RPLC (10% MeOH/DCM as eluent) to give 5 mg of the title compound as the TFA salt. ¹H NMR (DMSO-d₆) δ 7.9-6.7 (7H), 3.8 (3H), 3.77 (3H), 3.67 (2H), 2.77 (3H); LC-MS (ESI⁺; 309 ([M+H]⁺)).

Example 260

2-{4-[(3-Chloro-4-ethoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-isoindole-1,3-dione

A mixture of (3-chloro-4-ethoxy-phenyl)-(2-chloromethyl-quinazolin-4-yl)-methyl-amine (119 mg, 0.328 mmol) and potassium phthalimide (79 mg, 0.43 mmol) in DMF (2 mL) was heated at 50° C. for 3.5 h. EtOAc (25 mL) was added and this was washed with water (4×5 mL) then satd NaCl (2×5 mL). The organic layer was dried (MgSO₄), filtered through a pad of silica with an EtOAc wash then concd. The title compound was obtained as an off-white solid (124 mg; 80%) after MPLC (SiO₂/0-50% EtOAc in hexanes). ¹H NMR (CDCl₃) δ 7.96-7.90 (m, 2H), 7.78-7.73 (m, 2H), 7.72 (m, 1H), 7.53 (m, 1H), 7.22 (d, J=2.4 Hz, 1H), 7.05-6.95 (m, 2H), 6.91 (dd, J=2.4, 8.8 Hz, 1H), 6.83 (d, J=8.8 Hz, 1H), 5.14 (s, 2H), 4.10 (q, J=6.9 Hz, 2H), 3.24 (s, 3H), 1.48 (t, J=6.8 Hz, 3H); LC-MS (ESI⁺; 473 ([M+H]⁺)).

Example 261

2-Aminomethyl-quinazolin-4-yl)-(3-chloro-4-ethoxy-phenyl)-methyl-amine bis(hydrochloride)

The title compound was synthesized as a pale yellow-green solid (83 mg; 91%) in a manner analogous to that found in Example 254 from 2-{4-[(3-chloro-4-ethoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-isoindole-1,3-dione (104 mg, 0.220 mmol) and hydrazine monohydrate (85 μL, 1.8 mmol). ¹H NMR (DMSO-d₆) δ 8.62 (m(br), 3H), 7.87 (m, 1H), 7.81 (m, 1H), 7.64 (m, 1H), 7.35-7.28 (m, 2H), 7.25 (d, J=8.8 Hz, 1H), 6.96 (d, J=8.8 Hz, 1H), 4.36 (m, 2H), 4.17 (q, J=6.9 Hz, 2H), 3.69 (s, 3H), 1.39 (t, J=6.8 Hz, 3H); LC-MS (ESI⁺; 343 ([M+H]⁺)).

Example 262

Identification of (2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine and Analogs as Caspase Cascade Activators and Inducers of Apoptosis in Solid Tumor Cells

Human breast cancer cell lines T-47D and DLD-1 were grown according to media component mixtures designated by American Type Culture Collection+10% FCS (Invitrogen Corporation), in a 5% CO₂—95% humidity incubator at 37° C. T-47D and DLD-1 cells were maintained at a cell density between 50 and 80% confluency at a cell density of 0.1 to 0.6×10⁶cells/mL. Cells were harvested at 600×g and resuspended at 0.65×10⁶cells/mL into appropriate media+10% FCS. An aliquot of 22.5 μL of cells was added to a well of a 384-well microtiter plate containing 2.5 μL of a 10% DMSO in RPMI-1640 media solution 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). An aliquot of 22.5 μL of cells was added to a well of a 384-well microtiter plate containing 2.5 μL of a 10% DMSO in RPMI-1640 media solution without test compound as the control sample. The samples were mixed by agitation and then incubated at 37° C. for 48 h in a 5% CO₂-95% humidity incubator. After incubation, the samples were removed from the incubator and 25 μL of a solution containing 14 μM of N-(Ac-DEVD)-N′-ethoxycarbonyl-R110 fluorogenic 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 500 μg/mL lysolecithin (Calbiochem) was added. The samples were mixed by agitation and incubated at room temperature. Using a fluorescent plate reader (Model SPECTRAfluor Plus, Tecan), an initial reading (T=0) was made approximately 1-2 min after addition of the substrate solution, employing excitation at 485 nm and emission at 530 nm, to determine the background fluorescence of the control sample. After the 3 h incubation, the samples were read for fluorescence as above (T=3 h).
Calculation: The Relative Fluorescence Unit values (RFU) were used to calculate the sample readings as follows:
RFU_(T=3h)−Control RFU_(T=0)=Net RFU_(T=3h)
The activity of caspase cascade activation was determined by the ratio of the net RFU value for (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine or other test compounds to that of control samples. The EC₅₀(nM) was determined by a sigmoidal dose-response calculation (Prism 3.0, GraphPad Software Inc.).
The caspase activity (Ratio) and potency (EC₅₀) are summarized in Table I:

TABLE I

Caspase Activity and Potency

T-47D (24 hr)

T-47D (48 hr)

Exa. Cmpd.	Ratio	EC₅₀(nM)	Ratio	EC₅₀(nM)

1	8.7	2	NA	NA
2	6.7	31	NA	NA
3	8.1	79	NA	NA
4	7.1	872	NA	NA
5	10.3	24	NA	NA
6	6.7	219	NA	NA
7	1.2	>10000	1.0	>10000
8	1.0	>10000	NA	NA
9	NA	NA	1.8	>10000
10	NA	NA	12.8	48
11	9.0	8	12.5	10
12	5.3	8	12.8	9
13	8.9	260	NA	NA
14	9.7	1345	12.3	1326
15	5.7	56	11.5	89
16	7.6	296	NA	NA
17	3.0	7945	NA	NA
18	1.0	>10000	1.0	>10000
19	1.0	>10000	1.0	>10000
20	13.1	161	NA	NA
21	1.0	>10000	1.0	>10000
22	1.0	>10000	1.0	>10000
23	1.0	>10000	1.0	>10000
24	1.0	>10000	2.4	9460
25	NA	NA	5.8	42
26	NA	NA	15.7	178
27	NA	NA	1.0	>10000
28	1.0	>10000	1.0	>10000
29	NA	NA	1.0	>10000
30	NA	NA	1.0	>10000
31	8.0	317	14.7	563
32	NA	NA	1.0	>10000
33	NA	NA	1.0	>10000
34	7.5	7	NA	NA
35	7.2	141	NA	NA
36	6.7	6	NA	NA
37	3.3	2693	NA	NA
38	3.4	2933	NA	NA
39	4.5	693	NA	NA
40	NA	NA	6.1	47
41	NA	NA	12.4	20
42	8.6	282	14.6	265
43	NA	NA	14.7	34
44	NA	NA	14.3	501
45	NA	NA	1.0	>10000
46	12.8	2184	9.4	2272
47	NA	NA	11.5	187
48	NA	NA	12.5	137
49	7.5	29	13.4	22
50	NA	NA	1.0	>10000
51	NA	NA	0.9	>10000
52	NA	NA	10.8	6
53	8.3	5	11.4	11
54	NA	NA	12.5	46
55	NA	NA	9.0	1
56	NA	NA	4.9	5
57	NA	NA	6.2	432
58	NA	NA	10.8	1
59	NA	NA	7.1	11
60	NA	NA	6.5	13
61	NA	NA	9.2	4046
62	NA	NA	12.7	316
63	NA	NA	10.9	427
64	NA	NA	1	>10000
65	NA	NA	13.7	599
66	7.2	18	12.5	22
67	NA	NA	12.5	38
68	NA	NA	13.1	4
69	NA	NA	1	>1000
70	NA	NA	11.3	42
71	NA	NA	6.9	2265
72	9.0	2	7.4	2
73	6.2	679	5.7	543
74	6.6	15	5.3	36
75	1.5	>10000	NA	NA
76	5.6	7	14.1	8
77	5.7	700	12.3	2107
78	0.6	>10000	NA	NA
79	0.7	>10000	NA	NA
80	8.3	5752	NA	NA
81	1.9	>10000	NA	NA
82	1.0	>10000	NA	NA
83	NA	NA	10.8	168
84	6.7	8	NA	NA
85	7.6	2	NA	NA
86	6.2	41	NA	NA
87	6.3	25	NA	NA
88	7.6	556	NA	NA
89	NA	NA	7.8	24
90	10.6	2	NA	NA
91	8.3	4	NA	NA
92	10.1	16	NA	NA
93	11.3	65	NA	NA
94	NA	NA	1.0	>10000
95	1.0	>10000	NA	NA
96	1.0	>10000	NA	NA
97	NA	NA	9.0	5
98	5.4	14	12.9	8
99	6.9	4	NA	NA
100	8.9	474	NA	NA
101	9.5	175	NA	NA
102	8.8	5	11.3	16
103	9.3	552	NA	NA
104	8.6	134	NA	NA
105	8.5	2	NA	NA
106	1.1	>10000	NA	NA
107	5.2	5	NA	NA
108	4.8	1	NA	NA
109	4.6	274	NA	NA
110	8.8	7	NA	NA
111	9.4	32	NA	NA
112	1.0	>10000	NA	NA
113	3.7	735	NA	NA
114	7.2	130	NA	NA
115	1.0	>10000	NA	NA
116	1.0	>10000	NA	NA
117	7.4	134	NA	NA
118	1.0	>10000	NA	NA
119	11.8	4288	NA	NA
120	5.2	8	NA	NA
121	8.8	30	NA	NA
122	8.2	16	NA	NA
123	8.2	8	NA	NA
124	5.2	408	NA	NA
125	8.3	385	NA	NA
126	7.6	55	NA	NA
127	1.2	>10000	NA	NA
128	10	58	NA	NA
129	10	27	NA	NA
130	1.2	>10000	NA	NA
131	1.2	>10000	NA	NA
132	1.2	>10000	NA	NA
133	1.2	>10000	NA	NA
134	1.2	>10000	NA	NA
135	1.2	>10000	NA	NA
136	1.2	>10000	NA	NA
137	1.2	>10000	NA	NA
138	5.0	15	NA	NA
139	5.6	4662	NA	NA
140	7.0	27	NA	NA
141	1.2	>10000	NA	NA
142	7.5	141	NA	NA

NA = Not available

The following substituted N′-methyl-N′-(quinazolin-4-yl)benzohydrazides and analogs also are identified as potent caspase cascade activators and inducers of apoptosis and are thus useful in treating the various diseases and disorders discussed above.


	T-47D (24 hr)	T-47D (48 hr)

		EC₅₀		EC₅₀
Compound	Ratio	(Nm)	Ratio	(nM)

NA	NA	14.4	138

NA	NA	10.1	737

NA	NA	14.7	149

NA	NA	13.7	184

NA	NA	13.8	290

NA	NA	12.7	46

NA	NA	13.1	39

Thus, (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (Example 1) and analogs are identified as potent caspase cascade activators and inducers of apoptosis and are thus useful in treating the various diseases and disorders discussed above.

Example 263

Identification of (2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine and Analogs as Antineoplastic Compounds that Inhibit Cell Proliferation (GI50)

T-47D, DLD, H1299, MX-1 and SW620 cells were grown and harvested as in Example 262. An aliquot of 90 μL of cells (4.4×10⁴cells/mL) was added to a well of a 96-well microtiter plate containing 5 μL of a 10% DMSO in RPMI-1640 media solution containing 10 nM to 100 μM of (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (1 nM to 10 μM final). An aliquot of 45 μL of cells was added to a well of a 96-well microtiter plate containing 5 μL of a 10% DMSO in RPMI-1640 media solution without compound as the control sample for maximal cell proliferation (L_max). The samples were mixed by agitation and then incubated at 37° C. for 48 h in a 5% CO₂—95% humidity incubator. After incubation, the samples were removed from the incubator and 25 μL of CellTiter-Glo™ reagent (Promega) was added. The samples were mixed by agitation and incubated at room temeperature for 10-15 min. Plates were then read using a luminescent plate reader (Model SPECTRAfluor Plus, Tecan) to give L_testvalues.
Baseline for GI₅₀(dose for 50% inhibition of cell proliferation) of initial cell numbers was determined by adding an aliquot of 45 μL of cells or 45 μL of media, respectively, to wells of a 96-well microtiter plate containing 5 μL of a 10% DMSO in RPMI-1640 media solution. The samples were mixed by agitation and then incubated at 37° C. for 0.5 h in a 5% CO₂—95% humidity incubator. After incubation, the samples were removed from the incubator and 25 μL of CellTiter-Glo™ reagent (Promega) was added. The samples were mixed by agitation and incubated at 37° C. for 10-15 min at room temperature in a 5% CO₂—95% humidity incubator. Fluorescence was read as above, (L_Start) defining luminescence for initial cell number used as baseline in GI₅₀determinations.
Calculation: GI₅₀(dose for 50% inhibition of cell proliferation) is the concentration where [(L_Test−L_Start)/(L_Max−L_Start)]=0.5.
The GI₅₀(nM) are summarized in Table II:

TABLE II

GI50 in Cancer Cells

GI₅₀(nM)

Cell lines	Example 1	Example 7	Example 34	Example 36

T-47D	8	>10000	503	111
DLD	8	>10000	76	89
H1299	6	>10000	59	53
MX-1	5	>10000	73	73
SW620	3	>10000	55	70

Example 264

Identification of (2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine and Analogs as Inhibitors of Tubulin Polymerization

Lyophilized tubulin (Cytoskeleton #ML113, 1 mg, MAP-rich) was assayed for the effect of the test compound on tubulin polymerization as measured by change in fluorescence for 4′,6-diamidino-2-phenylindole (DAPI) (Barron, D. M. et al. Analytical Biochem., 2003, 315, 49-56). 1 μl of serial dilutions of each test compound (from 100×DMSO stock) was added in 96 well plate format and preincubated for 30 minutes with 94 ul of the non-GTP supplemented tubulin supernatant. 5 μl of DAPI/GTP solution was added to initiate polymerization and incubated for 30 minutes at 37° C. Fluorescence was read with excitation 350 nm, emission wavelength 485 nm on a Tecan Spectraflour Plus. Polymerized tubulin (DMSO and with the tubulin stabilizer Taxol® (paclitaxel)) gives a higher DAPI fluorescence as compared to non-polymerized tubulin (vinblastine and colchicine used to determine baseline). The IC₅₀for tubulin inhibition was the concentration found to decrease the fluorescence of DAPI by 50% as calculated with Prism 3.0. The IC50 are summarized in Table III.

TABLE III

Inhibition of Tubulin Polymerization Activity

		Inhibition of tubulin
	Caspase activation	polymerization
Example	(EC₅₀nM)	(IC₅₀, nM)

1	2	<500
2	31	3000
6	219	4000
7	>10000	>50000
12	8	2000
13	260	6000
20	161	3000
25	42	2000
31	317	10000
34	7	1000
35	141	4000
36	6	<1000
41	20	<1000
42	282	5000
43	34	2000
44	501	10000
65	599	10000
72	2	<1000

Thus, (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (Example 1) and analogs are identified as potent inhibitors of tubulin polymerization and are thus useful in treating diseases and disorders discussed above.

Example 265

Identification of (2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine as a Cytotoxic Compound in Multidrug Resistant Cells

Cytotoxicity of compounds in multidrug resistant cells can be determined by administering compounds to cell lines that overexpress the multidrug resistance pump MDR-1 and determining the viability of the cell lines. NCI-ADR/Res and P388/ADR cell lines are known to over-express the multidrug resistance pump MDR-1 (also known as P-glycoprotein-1; Pgp-1); whereas MCF-7 and P388 cell lines do not overexpress the multidrug resistance pumps MDR-1, MRP-1, or BCRP.
NCI-ADR/Res, MCF-7, P388, and P388/ADR cell lines were obtained from American Type Culture Collection (Manassas, Va.) and maintained in RPMI-1640 media supplemented with 10% FCS, 10 units/ml penicillin and streptomycin, 2 mM Glutamax and 1 mM sodium pyruvate (Invitrogen Corporation, Carlsbad, Calif.). For compound testing, cells were plated in 96 well dishes at a concentration of 1.5×10⁴cells/well. Cells were allowed to adhere to the plate overnight and then incubated with compounds at final concentrations ranging from 0.13 nM to 10 uM for 72 hours. Cell viability was then assessed using the ATP-lite reagent (Perkin Elmer, Foster City, Calif.). Plates were read on a Wallac Topcount luminescence reader (Perkin Elmer, Foster City, Calif.) and the results graphed in Prism software (Graphpad Software, Inc., San Diego, Calif.). Non-linear regression with variable slope analysis was performed to obtain IC₅₀concentration values.
Example 1 compound, docetaxel, and vinblastine were tested for their ability to kill multidrug resistant cells by administering the compounds to NCI-ADR/Res, MCF-7 cells, P388 and P388/ADR cells and determining the viability of the cells. Example 1 compound maintained nearly equal potency in all four cell lines, whereas known MDR-1 substrates vinblastine and docetaxel showed a loss of potency in the MDR-1 over-expressing cell lines as shown in Table IV below:

TABLE IV

Cytotoxicity of Exa 1 Cmpd in MDR-1 over-expressing cell lines

IC₅₀(nM)

	Exa 1
Cell Line	Cmpd	Vinblastine	Docetaxel

MCF-7	2.9	0.5	2
NCI/ADR-	1.3	3	410
RES
P388	1.1	2.6	7
P388/ADR	2.7	2.8	127

Thus, (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine is identified as a cytotoxic compound in multidrug resistant cells and is thus useful in treating diseases and disorders discussed above.

Example 266

Propidium Iodide and Annexin V Flow Cytometer-Based Assay To Detect Apoptosis

Necrotic versus apoptotic killing of human cell lines by compounds can be determined using dual annexin V-FITC and propidium iodide (PI) staining Flipping of phosphatidylserine to the outer leaflet of the plasma membrane is a characteristic of all apoptotic cells. AnnexinV is a serum protein that binds to phosphatidylserine in the presence of the divalent cations (calcium). PI is a DNA stain that is excluded from live cells and is used to discriminate between cells with intact or damaged plasma membranes.
Cells are plated at varying densities in 6 well plates and treated with varying concentrations of compounds for 18-72 hours. Cells are grown in RPMI-1640 media supplemented with 10% FCS. DMSO concentrations do not exceed 0.1% v:v in any assay. All cells in the wells are harvested and rinsed 1× with cold Hanks buffered saline solution (HBSS) containing calcium and magnesium (Invitrogen, Carlsbad Calif.). Carefully aspirate supernatant after the wash and resuspend in 100 μl Annexin V-FITC (Annexin V/PI Apoptosis Detection Kit; R & D Systems TA4638; Minneapolis, Minn.) in binding buffer (10 mM HEPES pH 7.4, 150 mM NaCl, 5 mM KCl, 1 mM MgCl₂, 1.8 mM CaCl₂and 2% bovine serum albumin w:v). Incubate in dark for 15 minutes on ice. Prior to analyzing samples, the volume is adjusted to 500 μl with 1× Binding Buffer and 25 μl PI is added per sample. Staining can be quantified on a flow cytometer (Becton-Dickenson, Franklin Lake, N.J.).

Example 267

Injection Formulation

	Excipients	Amount

Active Compound	5	mg
PEG-400	5	grams
TPGS	10	grams
Benzyl alcohol	0.5	gram
Ethanol
2	grams

	D5W	Add to make 50 mL

An injection formulation of a compound selected from Formula IV (the “Active Compound”) can be prepared according to the following method: 5 mg of the Active Compound is dissolved into a mixture of the d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), PEG-400, ethanol, and benzyl alcohol. D5W is added to make a total volume of 50 mL and the solution is mixed. The resulting solution is filtered through a 0.2 μm disposable filter unit and is stored at 25° C. Solutions of varying strengths and volumes are prepared by altering the ratio of Active Compound in the mixture or changing the total amount of the solution.

Example 268


Tablet Formulation

Active Compound	100.0	mg
Lactose	100.0	mg
Corn Starch	50.0	mg
Hydrogenated Vegetable Oil	10.0	mg
Polyvinylpyrrolidone	10.0	mg
	270.0	mg

A formulation of tablets of a compound selected from Formulae I-VIb (e.g. Example 1 compound) (the “Active Compound”) can be prepared according to the following method: 100 mg of Active Compound) is mixed with 100 mg lactose. A suitable amount of water for drying is added and the mixture is dried. The mixture is then blended with 50 mg of corn starch, 10 mg hydrogenated vegetable oil, and 10 mg polyvinylpyrrolidinone. The resulting granules are compressed into tablets. Tablets of varying strengths are prepared by altering the ratio of Active Compound in the mixture or changing the total weight of the tablet.

Example 269


Capsule Formulation

Active Compound	100.0	mg
Microcrystalline Cellulose	200.0	mg
Corn Starch	100.0	mg
Magnesium Stearate	400.0	mg
	800.0	mg

A formulation of capsules containing 100.0 mg of a compound selected from Formulae I-VIb (e.g. Example 1 compound) (the “Active Compound”) can be prepared according to the following method. 100 mg of Active Compound is 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 into a gelatin capsule. Doses of varying strengths can be prepared by altering the ratio of the Active Compound to pharmaceutically acceptable carriers or changing the size of the capsule.

Example 270

Identification of (2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine as an Inhibitor of Topoisomerase

The ability of compounds to inhibit Topoisomerase II activity in relaxing supercoiled DNA can be determined by adding compounds to DNA samples and measuring the formation of topoisomers. The addition of Topoisomerase II to DNA samples results in the formation of topoisomers, which migrate faster than open circular DNA and slower than supercoiled DNA substrate when run on a gel. Ethidium Bromide, a known intercalator, and etoposide (VP16), a known topoisomerase II inhibitor, are used as controls.
Assay reagents were obtained from TopoGEN, Inc. (Columbus, Ohio). Samples were prepared by combining 10 μl of D/W, 2 μl of 10×TOPO II assay buffer, and 1 μl (0.25 μg) pRYG DNA. 5 μl of (2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (Example 1 Compound), Ethidium Bromide, or VP16 were added to samples at varying concentrations. 2 μl of TOPO II (4 units in 20 μl reaction) was added to the samples and the samples were incubated at 37° C. in a water bath for 50 minutes. 2 μl of 10% SDS was added and 0. Proteinase K (500 μg/ml) was added and the samples were incubated again at 37° C. in a water bath for 50 minutes. Half of the reaction was loaded on a 1% gel without ethidium bromide and run in 1×TAE buffer at 20 volts/cm for 2 hours. The gel was stained with 0.5 μg/ml Ethidium Bromide for 10 seconds and destained in D/W for 30 seconds. The resulting gel image is shown in FIG. 1.
Inspection of the amount of supercoiled DNA present in the sample with 100 μM of Example 1 Compound indicates that inhibition of DNA relaxation is substantial. The results are consistent with topoisomerase II inhibition as well as with an effect of the compound not on topoisomerase II, but rather on the DNA itself, such as intercalation of the compound into the DNA substrate. In order to distinguish between direct inhibition of topoisomerase II activity and intercalation, the effect of Example 1 Compound is determined on topoisomerase I-mediated relaxation of supercoiled DNA.
Samples were prepared by combining 10 μl of D/W, 2 μl of 10×TOPO II assay buffer, and 1 μl (0.25 μg) Form I DNA. 5 μl of (2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (Example 1 Compound), Ethidium Bromide, or VP16 were added to samples at varying concentrations. 1 μl of TOPO I (5 units in 20 μl reaction) was added to the samples and the samples were incubated at 37° C. in a water bath for 50 minutes. 2 μl of 10% SDS was added and 0. Proteinase K (500 μg/ml) was added and the samples were incubated again at 37° C. in a water bath for 50 minutes. Half of the reaction was loaded on a 1% gel without ethidium bromide and run in 1×TAE buffer at 20 volts/cm for 2 hours. The gel was stained with 0.5 μg/ml Ethidium Bromide for 10 seconds and destained in D/W for 30 seconds. The resulting gel image is shown in FIG. 2.
As shown in FIG. 2, the known intercalator, Ethidium Bromide, completely eliminated topoisomerase I-dependent relaxation of supercoiled DNA, just as it eliminated topoisomerase II-dependent relaxation of supercoiled DNA (see FIG. 1). In contrast, Example 1 Compound and the known topoisomerase II inhibitor, VP-16, have no apparent effect on topoisomerase I activity.

Example 271

Identification of Radiolabeled (4-Azido-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine as an Inhibitor of Topoisomerase

30 Units (15 ul) Human Type II Topoisomerase (p170 Form) (from TopoGEN, Inc., Columbus, Ohio) was incubated with 50 nM radiolabeled Example 102 compound for 60 minutes at room temperature.

Radiolabeled Example 102 Compound

Radiolabeled Example 102 compound stock is 16.67 uM, 60 Ci/mmol, 1 mCi/ml American Radiolabeled Chemicals, Inc., St. Louis, Mo. Samples were either UV irradiated (+) with a short wavelength UV Source (254 nm) for 10 minutes at a distance of 3.5 cm or not irradiated (−). 8 ul of 5× sample buffer (150 mM Tris, pH 6.8, 50% glycerol, 1% SDS, 50 mM dithiothreitol, 62 mg/ml bromophenol blue) was added to the samples and boiled for 5 minutes. The entire sample was then loaded onto a 6% Tris-Glycine SDS-gel (10 well, 1.5 mm thickness) (Invitrogen, Carlsbad, Calif.). The gel was stained with 1% Coomassie Brilliant Blue in 40% methanol, 7.5% acetic acid for 2 hours then de-stained in several changes of de-stainer (40% methanol, 7.5% acetic acid). The gel was then incubated in Amplify (Amersham, Piscataway, N.J.) for 30 minutes at room temperature and then dried down on Whatman filter paper at 80° C. for 2 hours on a gel dryer. The dried gel was put on Hyperfilm (Amersham) in a film cassette and placed at −80° C. for 5-7 days. The resulting gel image is shown in FIG. 3. These results indicate that the compound binds sufficiently well to Topoisomerase II to crosslink to the enzyme when photoactivated.

Example 272

Identification of Cytotoxic Agents

A P388 murine leukemia cell line was obtained from NCI, Frederick, Md. P388 cells were cultured in RPMI-1640 supplemented with 10% fetal bovine serum, 2 mM Glutamax, 1 mM sodium pyruvate, 0.1 mM non-essential amino acids and 10 mM HEPES. Cells were grown at 37° C. in a humidified 5% CO₂atmosphere. Exponentially growing P388 cells were plated at 5,000 cells/well in a 96-well flat-bottomed microtiter plate (Corning, Costar #3595). Twenty-four hours later, test compound was added to cells at final concentrations of 100 nM, 33.3 nM, 11.1 nM, 3.7 nM, 1.23 nM, 0.4 nM and 0.13 nM. Cellular viability was determined 72 hours later by measuring intracellular ATP with ATP-Lite assay system. The effect of compounds on cell viability was calculated by comparing the ATP levels of cells exposed to test compound with those of cells exposed to DMSO. A semi-log plot of relative ATP levels versus compound concentration was used to calculate the compound concentration required to inhibit growth by 50% (IC₅₀). Data was analyzed by Prism software (GraphPad; San Diego, Calif.) by fitting it to a sigmoidal dose response curve.
The P388 IC₅₀data of representative compounds are summarized in Table IV:

TABLE IV

P388 IC₅₀Data

	Example Cmpd No.	P388 IC₅₀(nM)

	143	2200
	144	1700
	145	38
	156	6
	167	15
	168	45
	172	2
	174	22
	175	5000
	176	3
	177	970
	178	18
	179	1400
	180	5
	181	13
	182	2300
	183	490
	184	500
	185	7
	186	1800
	187	110
	188	2
	189	460
	190	6
	191	470
	192	19
	194	20
	195	1500
	196	330
	197	8
	198	3
	199	3
	200	7
	201	76
	202	300
	203	19
	204	460
	205	19
	206	2
	207	17
	208	27
	209	490
	210	57
	211	15
	212	250
	213	170
	214	9
	215	3
	216	20
	217	18
	218	12
	219	250
	220	870
	221	58
	222	6
	223	64
	224	170
	225	37
	226	20
	227	27
	228	900
	229	5
	230	1700
	231	37
	232	950
	233	1100
	234	11
	235	5
	236	680
	237	15
	238	12
	239	22
	240	6
	241	1435
	242	10
	243	4200
	244	58
	245	2
	246	11
	247	60
	248	222
	249	20
	250	22
	251	2077
	252	1004
	253	3
	254	5200
	255	610
	256	1800
	257	2400
	258	15
	259	773
	260	469
	261	9

Accordingly, compounds of the invention were identified as cytotoxic agents and are thus useful in treating the various diseases and disorders discussed above.
Having now fully described this invention, it will be understood by those of ordinary skill in the art that the same can be performed within a wide and equivalent range of conditions, formulations and other parameters without affecting the scope of the invention or any embodiment thereof. All patents, patent applications and publications cited herein are fully incorporated by reference herein in their entirety.

Claims

1. A compound having a structure according to Formula IVb:

or pharmaceutically-acceptable salts thereof, wherein:

R₁is methyl or ethyl;

R₂-R₁₇are independently H, halo, N₃, OH, thiol, nitro, CN, NH₂, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, halo-C_1-6alkyl, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl, or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl); wherein any of the groups is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N₃, OH, thiol, nitro, CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle, wherein optionally any two adjacent R₇-R₁₁groups together form a 3, 4, 5 or 6-membered carbocycle or heterocycle; and

B and D are independently C or N, provided that at least one of B and D is N,

and when B or D is N then there is no substituent at the N;

with the proviso that said compound is not 2-amino-4-(N-ethylanilino)-5,6,7,8-tetrahydro-quinazoline.

2. The compound of claim 1, wherein both B and D are Nitrogen.

3. The compound of claim 1, wherein when R₁is ethyl then at least one of R₈, R₉, and R₁₀is not H.

4. The compound of claim 1, wherein when R₁is ethyl then R₉is not H.

5. The compound of claim 1, wherein:

R₁is methyl or ethyl;

R₃-R₆, R₁₂-R₁₇are as defined above;

R₂is a member of the group consisting of H, halo, N₃, C_1-4alkoxy, C_1-4alkylthiol,

hydroxyC_1-4alkyl, C_1-4alkyl, and —N(R^a)(R^b) wherein R^aand R^bare independently H, OH (R^aand R^bare not both OH), C_2-4hydroxyalkyl, or C_1-4alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; each of the member being optionally substituted by 1-4 substituents wherein each substituent is independently halo, OH, or C_1-4alkyl;

R₇and R₁₁are independently H, halo (preferably F), CH₃, or OCH₃;

R₈and R₁₀are independently H, halo (preferably F or Cl), C_1-3alkyl (preferably CH₃) optionally substituted with halo (preferably 1-3 F), C_1-3alkoxy (preferably OCH₃), or C_1-3alkylthiol (preferably —S—CH₃);

R₉is OH, C₁, N₃, C_1-4alkoxy, C_1-4alkylthiol, hydroxyC_1-4alkyl, C_1-4alkyl,

—COOR^cwherein R^cis C_1-3alkyl, or —N(R^a)(R^b) wherein R^aand R^bare independently H, OH (R^aand R^bare not both OH), C_2-4hydroxyalkyl, or C_1-4alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; each of the member being optionally substituted by 1-4 substituents wherein each substituent is independently halo, OH, or C_1-4alkyl; and optionally two adjacent R₈, R₉, and R₁₀groups may together form a 3, 4, 5, or 6-membered carbocycle, heterocycle, preferably heterocyle; and

B and D are independently C or N, and at least one of B and D is N.

6. The compound of claim 1, wherein

R₉is selected from:

—OR_9a, wherein R_9ais methyl, ethyl, fluoromethyl, fluoroethyl; —N₃; —N(CH₃)₂; —NHCH₃; and —COOR_9b, wherein R_9bis H or C_1-2alkyl.

7. A compound of claim 1, wherein the compound is:

(2-Chloro-5,6,7,8-tetrahydro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(4-Methoxy-phenyl)-methyl-(2-methyl-5,6,7,8-tetrahydro-quinazolin-4-yl)-amine;

N-{4-[(4-Methoxy-phenyl)-methyl-amino]-5,6,7,8-tetrahydro-quinazolin-2-yl}-O-methyl-hydroxylamine;

{4-[(4-Methoxy-phenyl)-methyl-amino]-5,6,7,8-tetrahydro-quinazolin-2-ylamino}-acetic acid ethyl ester;

N⁴-(4-Methoxy-phenyl)-N²,N⁴-dimethyl-5,6,7,8-tetrahydro-quinazoline-2,4-diamine;

2-{4-[(4-Methoxy-phenyl)-methyl-amino]-5,6,7,8-tetrahydro-quinazolin-2-ylamino}-ethanol; or

(5,6,7,8-Tetrahydro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine.

8. A compound having a structure according to:

and pharmaceutically-acceptable salts thereof, wherein:

R₁is methyl or ethyl;

R₂-R₅and R₇-R₁₆are independently H, halo, N₃, OH, thiol, nitro, CN, NH₂, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, halo-C_1-6alkyl, C_2-6alkenyl-O—, C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl, or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; wherein any of the groups is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N₃, OH, thiol, nitro, CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkylthiol, C_2-6alkenyl-O—C_2-6alkynyl-O—, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, C_1-6acyl, C_1-6acyloxy, —C_1-6alkyl-C(O)O—C_1-6alkyl, —C(O)O—C_1-6alkyl, C_1-6alkyl-C(O)O—C_1-6alkyl-, C_1-6acylamido, —N(R^a)(R^b), —C_1-6alkyl-C(O)N(R^a)(R^b), —C(O)N(R^a)(R^b), N(R^a)(R^b)—C_1-6alkyl-, wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-6hydroxyalkyl, or C_1-6alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle, wherein optionally any two adjacent R₇-R₁₁groups together form a 3, 4, 5 or 6-membered carbocycle or heterocycle;

the bonds between Q, T, and U are single, double, or aromatic bonds, provided that both bonds are not double bonds;

T is C;

Q and U are independently C, N, or S, provided that when Q or U is S, then there are no substituents on the S and the bond with T is a single or aromatic bond, and provided that when Q or U is N and the bond with T is an aromatic bond or double bond, then there are no substituents on the N, and provided that when Q or U is N and the bond with T is a single bond, then there is one substituent on the N; and

B and D are independently C or N, provided that at least one of B and D is N, and when B or D is N then there is no substituent on the N.

9. The compound of claim 8, wherein both B and D are Nitrogen.

10. The compound of claim 8, wherein at least one of R₈, R₉, and R₁₀is not H.

11. The compound of claim 8, wherein R₉is not H.

12. The compound of claim 8, wherein when R₉is H and R₈or R₁₀or both are independently selected from the group OH; N₃; amido; N-dimethylamido; —XR_8awherein X is S or O and R_8ais C_1-6alkyl optionally substituted with OH or halo; C_1-3alkyl optionally substituted with halo; —N(R^a)(R^b) wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), or C_1-6alkyl optionally substituted with OH or halo, and wherein optionally R^aand R^bmay together form a 3-6 membered heterocycle; and —C(O)OR^cwherein R^cis C_1-6alkyl.

13. The compound of claim 8, wherein:

R₁is methyl or ethyl;

R₃-R₅, R₁₂-R₁₆are as defined above;

hydroxyC_1-4alkyl, C_1-4alkyl, and —N(R^a)(R^b) wherein R^aand R^bare independently H, OH (R^aand R^bare not both OH), C_2-4hydroxyalkyl, or C_1-4alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle;

wherein each R₂substituent is optionally substituted by 1-4 substituents wherein each substituent is independently halo, OH, or C_1-4alkyl;

R₇and R₁₁are independently H, halo (preferably F), CH₃, or OCH₃;

R₉is OH, C₁, N₃, C_1-4alkoxy, C_1-4alkylthiol, hydroxyC_1-4alkyl, C_1-4alkyl, —COOR^cwherein R^cis C_1-3alkyl, or —N(R^a)(R^b) wherein R^aand R^bare independently H, OH (R^aand R^bare not both OH), C_2-4hydroxyalkyl, or C_1-4alkyl or R^aand R^btogether with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; each of the member being optionally substituted by 1-4 substituents wherein each substituent is independently halo, OH, or C_1-4alkyl; and optionally two adjacent R₈, R₉, and R₁₀groups may together form a 3, 4, 5, or 6-membered carbocycle, heterocycle, preferably heterocyle; and

B and D are independently C or N, and at least one of B and D is N.

14. The compound of claim 8, wherein

R₉is selected from the group:

15. The compound of claim 8, wherein

R₂is selected from the group:

H, halo, N₃, C_1-4alkoxy, C_1-4alkylthiol, hydroxyC_1-4alkyl, C_1-4alkyl, and —N(R^a)(R^b) wherein R^aand R^bare independently H, OH(R^aand R^bare not both OH), C_2-4hydroxyalkyl, C_1-4alkoxy, —C_1-4alkyl-C(O)O—C_1-4alkyl, or C_1-4alkyl.

16. The compound of claim 8, wherein the compound has the structure:

17. The compound of claim 16, wherein

R₉is selected from the group:

18. The compound of claim 16, wherein

R₂is selected from the group:

19. The compound of claim 8, wherein the compound is:

N-{4-[(4-M ethoxy-phenyl)-methyl-amino]-6,7-dihydro-5H-cyclopentapyrimidin-2-yl}-O-methyl-hydroxylamine;

N⁴-(4-Methoxy-phenyl)-N²,N⁴-dimethyl-6,7-dihydro-5H-cyclopentapyrimidine-2,4-diamine;

{4-[(4-Methoxy-phenyl)-methyl-amino]-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamino}-acetic acid ethyl ester;

(4-Methoxy-phenyl)-methyl-(2-methyl-thieno[2,3-d]pyrimidin-4-yl)-amine;

(4-Methoxy-phenyl)-methyl-(2-methyl-thieno[3,2-d]pyrimidin-4-yl)-amine;

N⁶-(4-Methoxy-phenyl)-N⁶-methyl-9H-purine-2,6-diamine; or

(2-Chloro-9H-purin-6-yl)-(4-methoxy-phenyl)-methyl-amine.

20. A method of inhibiting tubulin, inhibiting topoisomerase II, activating caspase, and/or inducing apoptosis in a mammal, said method comprising administering to said mammal an effective amount of a compound according to Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

Ar is aryl or heteroaryl; each of which is optionally substituted by one or more substituents wherein each substituent is independently halo, hydroxy, hydroxy-C_1-6alkyl-, C_1-6alkyl-C(O)O—, amino, nitro, cyano, C_1-6alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-6acylamino, C_1-6acyloxy, C_1-6alkoxy, or C_1-6alkylthiol;

R₁is C_1-6alkyl;

A is an aromatic, heteroaromatic, heterocyclic, or carbocyclic ring; each of which is optionally substituted by one or more substituents wherein each substituent is as defined for Ar;

R₂is H, halo, nitro, cyano, azido, hydroxy, thiol, or a member of the group consisting of: amino, alkoxy, C_1-6alkyl, halo-C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, hydroxyalkyl, amino-C_1-6alkyl, carboxy-C_1-6alkyl, nitro, cyano, acylamido, acyloxy, carboxy, carbonylamido, alkylthiol; each of which is optionally substituted by one or more substituents wherein each substituent is as defined for Ar;

L is (CR₁₁R₁₂)_nor NR₁₁CO wherein R₁₁and R₁₂independently are hydrogen or alkyl optionally substituted by R_1a, R_1b, or R_1c; wherein R_1a, R_1b, and R_1care as defined for Ar;

n is 0, 1 or 2;

B and D are independently nitrogen or CR₁₃, wherein R₁₃is hydrogen, halo, nitro, cyano, azido, hydroxy, thiol, or a member of the group consisting of amino, alkoxy, C_1-6alkyl, halo-C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, hydroxyalkyl, amino-C_1-6alkyl, carboxy-C_1-6alkyl, nitro, cyano, acylamido, acyloxy, carboxy, carbonylamido, alkylthiol; each of which is optionally substituted by one or more substituents wherein each substituent is as defined for Ar; and

with the proviso that at least one of B and D is nitrogen.