Protein kinase regulators

Abstract

The present invention provides, in part, novel compounds and pharmaceutically acceptable salts that are capable of modulating the activity of kinases including Akt, ERK and MEK. Such modulation affects biological function, for example by inhibiting cell proliferation and / or inducing apoptosis. The present invention also provides pharmaceutical compositions and medicaments comprising the compounds or salts of the present invention, used alone or in combination with other therapeutic agents or palliatives.

Description

Technical Field

[0001] The present invention relates to nitrogen-containing cyclic compounds and salts thereof, methods of using these compounds to treat diseases and disorders associated with abnormal cell proliferation (such as immune diseases and tumor diseases), and pharmaceutical compositions containing these compounds. Background Art

[0002] Kinase signaling pathways that are often upregulated in cancer have been shown to drive many hallmark phenotypes in tumor biology. See Hoeflich et al., J. Clin. Invest. 2016, 125 (5): 1780-1788, and incorporated herein by reference. Regulating kinase signaling through direct interaction of drugs with kinases has led to the approval of more than 25 tumor drugs targeting kinases. However, in a biological pathway, drug resistance often forms kinase inhibitors against a single kinase (target kinase). In most cases, drug resistance is due to an increase in variants (favorable (pro-survival) mutations in the target kinase) and through the recently discovered reprogramming phenomenon of the protein kinase group. See Johnson et al., Clin. Pham. & Thera. 2014 95 (4) 413-415, and incorporated herein by reference. Recently, the small molecule TIC10 (11-benzyl-7-[(2-methylphenyl)methyl]-2,5,7,11-tetraazatricyclo[7.4.0.0 2,6] 13-1 (9), 5-diene-8-one) inactivates kinases (Akt, ERK and MEK) and is shown to activate the transcription factor Foxo3a. See El-Deiry et al., Sci Transl Med 2013, 5 171ra117, which is incorporated herein by reference, and El-Deiry et al., Cancer Res. 2015 75 (7) 1423-1432, which is incorporated herein by reference. Foxo3a is a member of the Forkhead Box transcription factor family, which regulates Bim (BCL-like protein 11), FasL (Fas ligand / CD95L), TRAIL (TNF-related apoptosis-inducing factor), PUMA (up-regulator of p53 apoptosis), p27 (cyclin-dependent kinase inhibitor 1B) and p21 (cyclin-dependent kinase inhibitor 1). These enzymes are regulators of cell growth arrest and apoptosis, and regulating these factors is effective in treating abnormal cell proliferation and particularly in treating tumors. Therefore, small molecule regulators that activate Foxo3a are effective in the treatment of cancer by regulating the activity of Akt and ERK. See Jiang et al., Biochem. Biophys. Res. Commun. 2016 476 (4) 260-266 and incorporated herein by reference, and Taylor et al. Cancer Cell Inter. 2015 15 (1) 1-9 and incorporated herein by reference. Two recent patent publications US 2014 / 0335048 and WO 2015 / 153468 describe compounds that regulate TRAIL. Summary of the invention

[0003] The present invention provides, in part, novel compounds and pharmaceutically acceptable salts. These compounds can modulate the activity of kinases: Akt, ERK and MEK, thereby affecting biological functions, such as by inhibiting cell proliferation and / or inducing apoptosis. The present invention also provides pharmaceutical compositions and medicaments containing the compounds or salts of the present invention alone or in combination with other therapeutic agents or palliatives. The present invention also provides, in part, methods for preparing these novel compounds, their salts and compositions, and methods of using the foregoing.

[0004] One aspect of the present invention relates to a compound having a pharmacophore represented by the general structural formula (I):

[0005]

[0006] In the general structural formula (I), Q can be independently selected from the group consisting of heteroaryl groups;

[0007]

[0008] Additionally, V may be independently selected from the group consisting of:

[0009]

[0010] In addition, W may be absent or -C(R 12 R 13 )-. Y can be independently selected from oxygen, sulfur and -NR 14 R1, R2, R3, R4 and R5 can be independently selected from hydrogen, halogen, -CN, -S(O)2R 43 , -NO2, -NR 44 R 45 , -OH, -SH, -SR 46 , (C1-C3)haloalkoxy, (C1-C4)alkoxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C2-C6)alkynyl, (C2-C6)alkenyl and (C1-C6)haloalkyl; or, R1 and R2 may form a 4-6 membered ring together with the carbon atoms to which they are attached. 23 , R 24 , R 25 , R 28 , R 29 and R 30 can be independently selected from hydrogen, halogen, -CN, -S(O)2R 43 , -NO2, -NR 44 R 45 , -OH, -SH, -SR 46 , (C1-C3)haloalkoxy, (C1-C4)alkoxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C2-C6)alkynyl, (C2-C6)alkenyl and (C1-C6)haloalkyl; or, R 24 and R 25 Together with the carbon atoms to which they are attached, R 28 and R 29 Together with the carbon atoms to which they are attached, they may form a ring. 10 , R 11 , R 12 , R 13 , R 16 , R 17 , R 26 , R 27 , R 31 , R 32 , R 36 , R 37 , R 41 and R42 Each independently selected from hydrogen, halogen, -CN, -S(O)2R 43 ,-NO2,-NRR,-OH,-SH,-SR 46 , (C1-C3)haloalkoxy, (C1-C4)alkoxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C2-C6)alkynyl, (C2-C6)alkenyl and (C1-C6)haloalkyl. 14 and R 15 can be independently selected from hydrogen, halogen, -CN, -S(O)2R 43 , -NO2, -NR 44 R 45 , -OH, -SH, -SR 46 , -S(O)2R 43 , (C1-C3)haloalkoxy, (C1-C4)alkoxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C2-C6)alkynyl, (C2-C6)alkenyl and (C1-C6)haloalkyl, -C(NH)NH2, -C(O)R 43 , -C(O)OR 46 The group consisting of. 18 , R 19 , R 20 , R 21 and R 22 may be independently selected from the group consisting of hydrogen, halogen, (C1-C6) alkyl, (C3-C9) cycloalkyl, (C3-C9) cycloalkyl (C1-C6) alkyl, (C1-C6) haloalkyl, -OH, -SH, (C1-C6) alkoxy, -NR 44 R 45 , (C3-C9)cycloalkyl (C2-C6)alkynyl, (C4-C8)cycloalkenyl, (C4-C8)cycloalkenyl (C1-C6)alkyl, aryl, heteroaryl, heterocyclyl, -CN, -NO2, -SR 46 , -C(O)OH, -C(O)OR 46 , -OC(O)OR 46 , (C2-C6) alkynyl, (C2-C8) alkenyl, (C1-C6) haloalkoxy, -S(O)2OR 46 , -SO2NR 44 R 45 , -S(O)2R 43 , -NR 47 S(O)2R 43 , -C(O)NR 44 R 45 , -C(O)R 43 and-NR 47C(O)R 43 or, R 20 and R 21 Together with the carbon atoms to which they are attached, R 33 , R 34 , R 35 , R 38 , R 39 and R 40 may be independently selected from the group consisting of hydrogen, halogen, (C1-C6) alkyl, (C3-C9) cycloalkyl, (C3-C9) cycloalkyl (C1-C6) alkyl, (C1-C6) haloalkyl, -OH, -SH, (C1-C6) alkoxy, -NR 44 R 45 , (C3-C9)cycloalkyl (C2-C6)alkynyl, (C4-C8)cycloalkenyl, (C4-C8)cycloalkenyl (C1-C6)alkyl, aryl, heteroaryl, heterocyclyl, -CN, -NO2, -SR 46 , -C(O)OH, -C(O)OR 46 , -OC(O)OR 46 , (C2-C6) alkynyl, (C2-C8) alkenyl, (C1-C6) haloalkoxy, -S(O)2OR 46 , -SO2NR 44 R 45 , -S(O)2R 43 , -NR 47 S(O)2R 43 , -C(O)NR 44 R 45 , -C(O)R 43 and-NR 47 C(O)R 43 or, R 34 and R 35 Together with the carbon atoms to which they are attached, R 38 and R 39 Together with the carbon atoms to which they are attached, R 43 may be independently selected from hydrogen, (C1-C6) alkyl, (C3-C9) cycloalkyl, (C1-C6) haloalkyl, (C2-C6) alkynyl, (C2-C8) alkenyl, (C1-C6) haloalkoxy, aryl, heteroaryl, heterocyclyl and -NR 44 R 45 The group consisting of. 44 , R 45 and R 47R may be independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C9) cycloalkyl, (C1-C6) haloalkyl, (C2-C6) alkynyl, (C2-C8) alkenyl, (C1-C6) haloalkoxy, aryl, heteroaryl and heterocyclic; 44 and R 45 Together with the nitrogen atom to which they are attached, they can form a ring. 46 Can be independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C9) cycloalkyl, (C1-C6) haloalkyl, (C2-C6) alkynyl, (C2-C8) alkenyl, (C1-C6) haloalkoxy, aryl, heteroaryl and heterocyclic. Alternatively, the compound may include a pharmaceutically acceptable salt thereof.

[0011] In a first preferred embodiment of the first aspect of the present invention, the substituent Y in the general formula (I) is oxygen. In a second preferred embodiment, the substituent Q in the general formula (I) is M1; V is V1; R 15 independently selected from hydrogen, -CN, -S(O)2R 43 , -NO2, -NR 44 R 45 , -OH, -SR 46 , -S(O)2R 43 , (C1-C3)haloalkoxy, (C1)-C4)alkoxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C2-C6)alkynyl, (C2-C6)alkenyl and (C1-C6)haloalkyl, -C(NH)NH2, -C(O)R 43 , -C(O)OR 46 In a third preferred embodiment, R1 is independently selected from hydrogen, fluorine and chlorine; R2 is independently selected from chlorine, bromine and -CF3; R3 is independently selected from hydrogen and fluorine; R 15 is independently selected from -CH3 and -CH2CH3; R 20 Yes -CN; R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 16 , R 17 , R 18 , R 19 , R 21 , R 22 In a fourth preferred embodiment, the compound may be independently selected from a group of compounds consisting of:

[0012]

[0013]

[0014] In a fifth preferred embodiment, the compound may be independently selected from the group of compounds consisting of:

[0015]

[0016] In a sixth preferred embodiment, the compound may be independently selected from the group of compounds consisting of:

[0017]

[0018] Each embodiment of the invention described herein is expanded within the scope of a pharmaceutically acceptable salt of a compound of the invention. Thus, the phrase "or a pharmaceutically acceptable salt thereof" is implicit in the description of all compounds described herein.

[0019] The second aspect of the present invention relates to a method for treating cancer in a subject, comprising the step of administering an effective amount of a compound of the general formula I or a pharmaceutically acceptable salt thereof. In a first preferred embodiment of the second aspect of the present invention, the method for treating cancer in a subject comprises the step of administering an effective amount of a compound of the first preferred embodiment of the general formula I or a pharmaceutically acceptable salt thereof. In a first preferred embodiment of the second aspect of the present invention, the method for treating cancer in a subject comprises the step of administering an effective amount of a compound of the first preferred embodiment of the general formula I or a pharmaceutically acceptable salt thereof. In a second preferred embodiment of the second aspect of the present invention, the method for treating cancer in a subject comprises the step of administering an effective amount of a compound of the second preferred embodiment of the general formula I or a pharmaceutically acceptable salt thereof. In a third preferred embodiment of the second aspect of the present invention, the method for treating cancer in a subject comprises the step of administering an effective amount of a compound of the third preferred embodiment of the general formula I or a pharmaceutically acceptable salt thereof. In a fourth preferred embodiment of the second aspect of the present invention, the method for treating cancer in a subject comprises the step of administering an effective amount of a compound of the fourth preferred embodiment of the general formula I or a pharmaceutically acceptable salt thereof. In a fifth preferred embodiment of the second aspect of the present invention, the method for treating cancer in a subject comprises the step of administering an effective amount of a compound of the fifth preferred embodiment of the general formula I or a pharmaceutically acceptable salt thereof. In a sixth preferred embodiment of the second aspect of the present invention, the method for treating cancer in a subject comprises the step of administering an effective amount of a compound of the sixth preferred embodiment of structural formula I or a pharmaceutically acceptable salt thereof.

[0020] In common embodiments of the methods provided herein, the abnormal cell growth is cancer. In some embodiments, the methods provided produce one or more of the following results: (1) inhibiting cancer cell proliferation; (2) inhibiting cancer cell invasion; (3) inducing cancer cell apoptosis; (4) inhibiting cancer cell metastasis; (5) inhibiting angiogenesis.

[0021] In common embodiments, the abnormal cell growth is cancer and the subject is a human.

[0022] In some embodiments, the methods described herein further comprise administering to the subject an amount of an anti-cancer therapeutic or palliative agent in an amount effective together to treat the abnormal growth. In some embodiments, one or more anti-cancer therapeutic agents are selected from anti-tumor agents, anti-angiogenic agents, signal transduction inhibitors, and anti-proliferative agents in an amount effective together to treat the abnormal cell growth. In some such embodiments, the anti-tumor agent is selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibodies, growth factor inhibitors, radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxins, anti-hormones, and anti-androgens.

[0023] The third aspect of the present invention relates to a pharmaceutical composition comprising a compound represented by the general formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient in combination. In a first preferred embodiment of the third aspect of the present invention, the pharmaceutical composition comprises a compound of the first preferred embodiment of the general formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient in combination. In a second preferred embodiment of the third aspect of the present invention, the pharmaceutical composition comprises a compound of the second preferred embodiment of the general formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient in combination. In a third preferred embodiment of the third aspect of the present invention, the pharmaceutical composition comprises a compound of the third preferred embodiment of the general formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient in combination. In a fourth preferred embodiment of the third aspect of the present invention, the pharmaceutical composition comprises a compound of the fourth preferred embodiment of the general formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient in combination. In a fifth preferred embodiment of the third aspect of the present invention, the pharmaceutical composition comprises a compound of the fifth preferred embodiment of the general formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient in combination. In a sixth preferred embodiment of the third aspect of the present invention, the pharmaceutical composition comprises a compound of the sixth preferred embodiment of the general formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient in combination. In some embodiments, the pharmaceutical composition comprises two or more pharmaceutically acceptable carriers and / or excipients. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 Shown are graphs depicting bioactivity data for human cancer cell lines. DETAILED DESCRIPTION

[0025] The present invention may be understood more readily by reference to the following detailed description of preferred embodiments of the invention and the Examples included therein.

[0026] Definitions of various terms

[0027] The terms used herein have their ordinary meanings, and the meanings of these terms are independent at each occurrence. Nevertheless, unless otherwise stated, the following definitions apply to the entire description and claims. Chemical names, common names, and chemical structures can be used interchangeably to describe structures. If there is an ambiguity between a chemical structure and a chemical name, and between a structure and a name, the structure shall prevail. Unless otherwise stated, these definitions apply to any term, whether used alone or in combination with other terms. Thus, the definition of "alkyl" applies to the "alkyl" portion of "hydroxyalkyl", "fluoroalkyl", "-O-alkyl", etc.

[0028] As used herein, and throughout the present disclosure, unless otherwise indicated, the following terms shall be understood to have the following meanings:

[0029] A "patient" or "subject" is a human or non-human mammal. In one embodiment, the patient or subject is a human. In another embodiment, the patient or subject is a chimpanzee.

[0030] The term "therapeutically effective amount" as used herein refers to the amount of the compound of formula (I) and / or other additional therapeutic agents or their combination that can produce the desired effective therapeutic effect, ameliorative effect, inhibitory effect or preventive effect when administered to a patient suffering from cancer or other undesirable malignant cell proliferative diseases or conditions. In the combination therapy of the present invention, the therapeutically effective amount can refer to each individual agent or the combination as a whole. Among them, the amounts of all agents administered are effective together, but the component agents of the composition may not exist alone in an effective amount. With regard to the treatment of cancer, a therapeutically effective amount refers to an amount having the following effects: (1) reducing the size of the tumor, (2) inhibiting (slowing down to some extent, especially preventing) tumor metastasis, (3) inhibiting (especially preventing) tumor growth or tumor invasiveness to a certain extent (4) alleviating (or especially eliminating) one or more signs or symptoms associated with cancer to a certain extent.

[0031] As used herein, the term "preventing" or "preventing" a disease or condition involving cancer or unwanted cell proliferation refers to reducing the likelihood or rate at which the disease or condition will progress.

[0032] The use of dashed or dotted lines indicates a single bond between a molecular fragment and another specific molecular fragment. For example, selecting V1 as V in the general structural formula (I) yields the following structure:

[0033]

[0034] In another example, in the general structural formula (I), M1 is selected as Q to obtain the following structure:

[0035]

[0036] The term "alkyl" as used herein refers to an aliphatic hydrocarbon group in which one hydrogen atom is replaced by a group having a specified number of carbon atoms. The alkyl group can be a straight chain or branched chain group. In addition to the term "alkyl", the alkyl group can be further defined by the number of carbon atoms. The alkyl substituent typically contains 1-20 carbon atoms "(C1-C20) alkyl", preferably 1-12 carbon atoms "(C1-C12) alkyl", more preferably 1-8 carbon atoms "(C1-C8) alkyl", or 1-6 carbon atoms "(C1-C6) alkyl", or 1-4 carbon atoms "(C1-C4) alkyl". In different embodiments, the alkyl group contains 7-12 carbon atoms "(C7-C12) alkyl" or 7-20 carbon atoms "(C7-C20) alkyl". The non-limiting example of alkyl comprises methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl and neohexyl.All alkyl described here can be optionally substituted by one or more substituents, and unless otherwise indicated, these substituents are independently selected.Alkyl referred to as substituted alkyl ("substituted alkyl") herein will be substituted by one or more substituents, and unless otherwise indicated, these substituents are independently selected.The total number of substituents can be equal to the total number of hydrogen atoms on the alkyl part, and this replacement is chemically reasonable and has chemical meaning.Optionally substituted alkyl usually contains 1 to 6 optional substituents, preferably 1 to 4 optional substituents, more preferably 1 to 3 optional substituents.For example, the optionally substituted ethylene is "optionally substituted (C2) alkyl", and the substituted ethylene is "substituted (C2) alkyl".

[0037] Suitable substituents for “alkyl”, “optionally substituted alkyl” and “substituted alkyl” include, but are not limited to, (C3-C8)cycloalkyl, 3-12 membered heterocyclyl, (C6-C12)aryl, 5-12 membered heteroaryl, halogen, =O (oxo), =S (thio), =N-CN, =N-OR X , =NR X , -CN, -C(O)R X , -CO2R X , -C(O)NR X R Y , -SR X , -SOR X , -SO2R X , -SO2NR XR Y , -NO2, -NR X R Y , -NR X C(O)R Y , -NR X C(O)NR X R Y , -NR X C(O)OR X , -NR X SO 2 R Y , -NR X SO2NR X R Y , -OR X , -OC(O)R X and -OC(O)NR X R Y ; where each R X and R Y is independently hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C6) cycloalkyl, 3-12 membered heterocyclyl, (C6-C12) aryl, or 5-12 membered heteroaryl, or R X and R Y Together with the nitrogen atom to which they are attached, they may form a 3-12 membered heterocyclyl or 5-12 membered heteroaryl system, each optionally containing 0, 1 or 2 heteroatoms; each R X and R Y Optionally substituted with 1-3 substituents independently selected from halogen, =O, -CN, -C(O)R', -CO2R', -C(O)NR'2, -SO2R', -NR'2, -OR', wherein each R' is independently hydrogen, (C1-C6) alkyl, (C3-C6) cycloalkyl or 3-12 membered heterocyclyl. However, suitable substituents for "substituted alkyl" do not include hydrogen.

[0038] "Alkenyl" refers to an alkyl group as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon double bond. Typically, alkenyl groups have 2 to 20 carbon atoms "(C2-C20)alkenyl", preferably 2 to 12 carbon atoms "(C2-C12)alkenyl", more preferably 2 to 8 carbon atoms "(C2-C8)alkenyl", or 2 to 6 carbon atoms "(C2-C6)alkenyl", or 2 to 4 carbon atoms "(C2-C4)alkenyl". Representative examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like. Alkenyl groups may be optionally substituted. Suitable substituents for alkenyl groups are as described herein, "optionally substituted alkyl", "substituted alkyl" and alkyl.

[0039] "Alkynyl" refers to an alkyl group as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon triple bond. Alkynyl groups have 2 to 20 carbon atoms "(C2-C20)alkynyl", preferably 2 to 12 carbon atoms "(C2-C12)alkynyl", more preferably 2 to 8 carbon atoms "(C2-C8)alkynyl", or 2 to 6 carbon atoms "(C2-C6)alkynyl", or 2 to 4 carbon atoms "(C2-C4)alkynyl". Representative examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, etc. Any alkynyl group may be optionally substituted. Suitable alkynyl substituents are described herein, "optionally substituted alkyl", "substituted alkyl" and alkyl.

[0040] The term "fluoroalkyl" as used herein refers to an alkyl group as defined above, wherein one or more of the hydrogen atoms of the alkyl group have been replaced by fluorine. In one embodiment, the fluoroalkyl group has 1 to 6 carbon atoms. In another embodiment, the fluoroalkyl group has 1 to 3 carbon atoms. In another embodiment, the fluoroalkyl group is substituted by 1-3 fluorine atoms. Non-limiting examples of fluoroalkyl groups include -CH2F, -CHF2 and -CF3. The term "(C1-C3)fluoroalkyl" refers to a fluoroalkyl group having 1 to 3 carbon atoms. The term "(C1)fluoroalkyl" refers to -CH2F, -CHF2 and -CF3.

[0041] The term "aryl" as used herein refers to an aromatic monocyclic or polycyclic ring system containing 6 to about 14 carbon atoms. In one embodiment, the aryl group contains about 6 to 10 carbon atoms (C6-C10) aryl. In another embodiment, the aryl group is phenyl. Non-limiting examples of aryl groups include phenyl and naphthyl. The aryl group may be optionally substituted. Suitable aryl substituents are as described herein, "optionally substituted alkyl", "substituted alkyl" and alkyl.

[0042] The term "cycloalkyl" as used herein refers to a saturated ring containing a specified number of ring carbon atoms and no heteroatoms. Cycloalkyl substituents typically contain 3 to 8 carbon atoms "(C3-C8)cycloalkyl", preferably 3-7 carbon atoms "(C3-C7)cycloalkyl", more preferably 3 to 6 carbon atoms "(C3-C6)cycloalkyl", or 3 to 5 carbon atoms "(C3-C5)cycloalkyl". Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. All cycloalkyls described herein may be optionally substituted with one or more substituents, which are independently selected unless otherwise stated. The optionally substituted cycloalkyls described herein ("optionally substituted cycloalkyls") may be substituted with one or more substituents, which are independently selected unless otherwise stated. Cycloalkyls described herein as substituted cycloalkyls ("substituted cycloalkyls") will be substituted with one or more substituents, which are independently selected unless otherwise stated. The total number of substituents may be equal to the total number of hydrogen atoms on the cycloalkyl moiety, and such substitutions should have chemical meaning. Optionally substituted cycloalkyl groups typically contain 1 to 6 optional substituents, preferably 1 to 4 optional substituents, and more preferably 1 to 3 optional substituents. For example, an optionally substituted cyclopropyl group is an "optionally substituted (C3) cyclopropyl group" and a substituted cyclopropyl group is a "substituted (C3) cycloalkyl group". In one embodiment, the cycloalkyl group contains 3 to 9 carbon atoms, a "(C3-C9) cycloalkyl group". In another embodiment, a substituted cycloalkyl group contains 3 to 9 carbon atoms, a "substituted (C3-C9) cycloalkyl group". Suitable cycloalkyl substituents are described herein as "optionally substituted alkyl", "substituted alkyl" and alkyl.

[0043] The term "cycloalkenyl" as used herein refers to a partially unsaturated carbocyclic ring system containing a specified number of carbon atoms. Cycloalkenyl substituents typically contain 4-8 carbon atoms "(C4-C8)cycloalkenyl", preferably 5-6 carbon atoms "(C5-C6)cycloalkenyl". Non-limiting examples of monocyclic cycloalkenyls include cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl. Cycloalkenyl as described herein may be optionally substituted with one or more substituents, which are independently selected unless otherwise indicated. The total number of substituents may be equal to the total number of hydrogen atoms on the cycloalkenyl moiety, and this substitution is to have chemical significance. Optionally substituted cycloalkenyls typically contain 1 to 6 optional substituents, preferably 1 to 4 optional substituents, more preferably 1 to 3 optional substituents. For example, cyclopentenyl is "(C5)cycloalkenyl", and an optionally substituted cyclopentenyl is "optionally substituted (C5)cycloalkenyl". In one embodiment, the cycloalkenyl group contains 4-8 carbon atoms, "(C4-C8)cycloalkenyl". Suitable cycloalkenyl substituents are as described herein, "optionally substituted alkyl", "substituted alkyl" and alkyl.

[0044] The term "cycloalkylalkyl" as used herein refers to a cycloalkyl ring, typically (C3-C9)cycloalkyl, which is connected to the base molecule through an alkylene linker of "(C1-C6)alkylene" of 1 to 6 carbon atoms. Cycloalkylalkyl is described by the number of carbon atoms in the carbon ring and the number of carbon atoms in the linker. The cycloalkylalkyl described herein may be optionally substituted with one or more substituents, which are independently selected unless otherwise stated. The optionally substituted cycloalkylalkyl described herein ("optionally substituted cycloalkylalkyl") may be substituted with one or more substituents, which are independently selected unless otherwise stated. The cycloalkylalkyl described herein as substituted cycloalkylalkyl ("substituted cycloalkylalkyl") will be substituted with one or more substituents, which are independently selected unless otherwise stated. The total number of substituents may be equal to the total number of hydrogen atoms on the cycloalkylalkyl portion, and such substitutions should have chemical meaning. The optionally substituted cycloalkylalkyl typically contains 1 to 6 optional substituents, preferably 1 to 4 optional substituents, and more preferably 1 to 3 optional substituents. In one embodiment, the cycloalkyl group contains 3 to 9 carbon atoms and the linker alkyl group contains 1 to 6 carbon atoms, "(C3-C9)cycloalkyl(C1-C6)alkyl". For example, cyclopropylethyl is "(C3)cycloalkyl(C2)alkyl", and optionally substituted cyclopropylethyl is "optionally substituted (C3)cycloalkyl(C2)alkyl". In addition, substituted cyclopropylethyl is "substituted (C3)cycloalkyl(C2)alkyl". Suitable substituents for cycloalkylalkyl are as described herein, "optionally substituted alkyl", "substituted alkyl" and alkyl.

[0045] The term "cycloalkenylalkyl" as used herein refers to a cycloalkenyl ring, typically (C4-C8)cycloalkenyl, which is connected to the base molecule by an alkylene linker of "(C1-C6)alkylene" of 1 to 6 carbon atoms. Cycloalkenylalkyl is described by the number of carbon atoms in the carbocyclic ring and the number of carbon atoms in the linker. Therefore, "(C5)cycloalkenyl (C1) alkyl" is a cyclopentenyl group connected to the base molecule by a methylene group (-CH2-). The cycloalkenylalkyl described herein may be optionally substituted with one or more substituents, which are independently selected unless otherwise indicated. The total number of substituents may be equal to the total number of hydrogen atoms on the cycloalkenylalkyl portion to the extent that such substituents have chemical significance. Optionally substituted cycloalkenylalkyl typically contains 1 to 6 optional substituents, preferably 1 to 4 optional substituents, and more preferably 1 to 3 optional substituents. In one embodiment, the cycloalkenyl group contains 4-8 carbon atoms and the linker alkyl group contains 1-6 carbon atoms, "(C4-C8)cycloalkenyl(C1-C6)alkyl". For example, cyclopentenylethyl is "(C5)cycloalkenyl(C2)alkyl", and optionally substituted cyclopentenylethyl is "optionally substituted (C5)cycloalkenyl(C2)alkyl". Suitable substituents for cycloalkenylalkyl are as described herein, "optionally substituted alkyl", "substituted alkyl" and alkyl.

[0046] In some cases, the substituted alkyl group can be specifically named with reference to the substituent. For example, "haloalkyl" refers to an alkyl group with a specified number of carbon atoms, which is substituted by one or more halogen substituents, and generally contains 1 to 6 carbon atoms and 1, 2 or 3 halogen atoms (i.e., "(C1-C6) haloalkyl"). Therefore, (C1-C4) haloalkyl includes trifluoromethyl (-CF3) and difluoromethyl (-CF2H). The haloalkyl group described herein may be optionally substituted by one or more substituents, which are independently selected unless otherwise stated. The total number of substituents (the sum of halogen and any other substituents defined herein) can be equal to the total number of hydrogen atoms on the unsubstituted parent alkyl moiety to the extent that such substituents have chemical significance. For example, for -CH2CH2CH(OH)CH2CF3, the parent alkyl moiety is N-pentyl (-(CH2)4CH3), with 11 positions available for substitution. This example is not meant to be limited to this. The haloalkyl described herein as optionally substituted ("optionally substituted haloalkyl") may be substituted by one or more substituents, unless otherwise stated, these substituents are independently selected. The haloalkyl described herein as substituted haloalkyl ("substituted haloalkyl") will be substituted by one or more substituents, unless otherwise stated, these substituents are independently selected. The total number of substituents can be equal to the total number of hydrogen atoms on the haloalkyl portion, to the extent that such substituents have chemical significance. The haloalkyl optionally substituted generally contains 1 to 6 optional substituents, preferably 1 to 4 optional substituents, more preferably 1 to 3 optional substituents. For example, the halopropyl optionally substituted is "optionally substituted (C3) haloalkyl", and the substituted halopropyl is "substituted (C3) haloalkyl". In one embodiment, the cycloalkyl contains 1 to 6 carbon atoms, "(C1-C6) haloalkyl". In another embodiment, the substituted haloalkyl contains 1 to 6 carbon atoms, "substituted (C1-C6) haloalkyl". Suitable substituents for haloalkyl are as described herein, "optionally substituted alkyl" and "substituted alkyl".

[0047] "Alkoxy" refers to a monovalent -O-alkyl group in which the alkyl portion has a specified number of carbon atoms. The alkyl portion of the alkoxy group can be a straight or branched group. Alkoxy groups typically contain 1-8 carbon atoms "(C1-C8) alkoxy", or 1-6 carbon atoms "(C1-C6) alkoxy" or 1-4 carbon atoms "(C1-C4) alkoxy". Non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy. All alkoxy groups described herein may be optionally substituted with one or more substituents, which are independently selected unless otherwise stated. The optionally substituted alkoxy groups described herein ("optionally substituted alkoxy") may be substituted with one or more substituents, which are independently selected unless otherwise stated. The alkoxy groups described herein as substituted alkoxy groups ("substituted alkoxy") will be substituted with one or more substituents, which are independently selected unless otherwise stated. The total number of substituents may be equal to the total number of hydrogen atoms on the alkoxy moiety to the extent that such substituents have chemical significance. Optionally substituted alkoxy groups typically contain 1 to 6 optional substituents, preferably 1 to 4 optional substituents, and more preferably 1 to 3 optional substituents. For example, optionally substituted ethoxy is an "optionally substituted (C2) alkoxy" and substituted butoxy is a "substituted (C4) alkoxy". In one embodiment, the alkoxy group contains 1 to 6 carbon atoms, a "(C1-C6) alkoxy". In another embodiment, the substituted alkoxy group contains 1 to 6 carbon atoms, a "substituted (C1-C6) alkoxy". Suitable substituents for alkoxy are as described herein, "optionally substituted alkyl", "substituted alkyl" and alkyl.

[0048] "Oxiranyl" refers to a monovalent -O-cycloalkyl group in which the cycloalkyl portion has a specified number of carbon atoms. The cycloalkyl portion of the alkoxy group typically contains 3 to 9 carbon atoms "(C3-C9) cycloalkyl", or 3 to 6 carbon atoms "(C3-C6) cycloalkyl". Non-limiting examples of cycloalkyl groups include glycidyl, glycidyl and glycidyl. All cycloalkyl groups described herein may be optionally substituted with one or more substituents, which are independently selected unless otherwise stated. The total number of substituents may be equal to the total number of hydrogen atoms on the cycloalkyl portion to the extent that such substituents have chemical significance. Optionally substituted cycloalkyl groups typically contain 1 to 6 optional substituents, preferably 1 to 4 optional substituents, and more preferably 1 to 3 optional substituents. Suitable cycloalkyl substituents are as described herein, "optionally substituted alkyl", "substituted alkyl" and alkyl.

[0049] The term "haloalkoxy" refers to a monovalent -O-haloalkyl group in which the alkyl portion has a specified number of carbon atoms and is substituted with one or more halogen substituents, and typically contains 1 to 6 carbon atoms and 1, 2 or 3 halogen atoms (i.e., "(C1-C6)haloalkoxy"). In some cases, the substituted alkyl group may be specifically named with reference to the substituent. For example, "haloalkoxy" refers to an alkyl group having a specified number of carbon atoms. Thus, (C1-C4)haloalkoxy includes trifluoromethoxy (-OCF3). The haloalkoxy groups described herein may be substituted with one or more substituents, which are independently selected unless otherwise specified. The total number of substituents may be equal to the total number of hydrogen atoms on the haloalkyl portion to the extent that such substituents have chemical significance. Optionally substituted haloalkoxy groups typically contain 1 to 3 optional substituents, preferably 1 to 2 optional substituents. In one embodiment, the haloalkoxy group contains 1 to 6 carbon atoms, "(C1-C6)haloalkoxy". Examples of substituted haloalkoxy groups contain 1 to 6 carbon atoms, "(C1-C6)haloalkoxy". Suitable substituents for haloalkoxy are as described herein, "optionally substituted alkyl" and "substituted alkyl".

[0050] As used herein, the term "halo" refers to -F, -Cl, -Br or -I. In one embodiment, the halogen group is -Cl. In another embodiment, the halogen group is -Br.

[0051] As used herein, the term "halogen" refers to -F, -Cl, -Br or -I. In one embodiment, the halogen group is -Cl. In another embodiment, the halogen group is -Br.

[0052] The term "acyl" as used herein refers to -C(O)alkyl or -C(O)cycloalkyl. The alkyl group may be a straight chain or branched chain group. The alkyl substituent of the acyl group typically contains 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 8 carbon atoms, 1 to 6 carbon atoms or 1 to 4 carbon atoms. The cycloalkyl substituent of the acyl group typically contains 3 to 8 carbon atoms, preferably 3-7 carbon atoms, more preferably 3 to 6 carbon atoms, or 3 to 5 carbon atoms. The alkyl and cycloalkyl portions of the acyl group may be substituted. Suitable substituents are described herein, "optionally substituted alkyl", "substituted alkyl" and alkyl.

[0053] The term "aryl" or "aromatic" refers to an optionally substituted monocyclic diaryl or fused bicyclic ring system having the well-known aromatic character in which at least one ring contains a completely conjugated π electron system. Typically, aryl contains 6 to 20 carbon atoms, "(C6-C20)aryl" as ring members, preferably 6 to 14 carbon atoms "(C6-C14)aryl" or more preferably 6 to 12 carbon atoms "(C6-C12)aryl". Fused aryl groups may include an aryl ring (e.g., a benzene ring) fused to another aryl ring, or an aryl ring fused to a saturated or partially unsaturated carbocyclic or heterocyclic ring. The point of attachment to the base molecule on such a fused aryl ring system may be a carbon atom of the aromatic portion or a carbon or nitrogen atom of the non-aromatic portion of the ring system. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl and tetrahydronaphthyl. The aryl groups described herein may be optionally substituted with one or more substituents, which are independently selected unless otherwise stated. Suitable substituents for aryl groups are further described herein.

[0054] The terms "heteroaryl" or "heteroaromatic" are used interchangeably herein and refer to an aromatic monocyclic or polycyclic ring system containing from about 5 to about 14 ring atoms, wherein 1 to 4 of the ring atoms are independently N, O or S and the remaining ring atoms are carbon atoms. These systems have well-known aromatic properties. The heteroaryl ring is attached to the base molecule through the ring atoms of the heteroaromatic ring, thereby maintaining the aromatic property. The inclusion of heteroatoms allows aromaticity in 5-membered rings as well as 6-membered rings. In one embodiment, the heteroaryl has 5 to 10 ring atoms. In another embodiment, the heteroaryl is a monocyclic ring system and has 5 to 6 ring atoms. In another embodiment, the heteroaryl group is a bicyclic system. The term "heteroaryl" also includes a heteroaryl as defined above fused to a heterocyclyl as defined below. The term "heteroaryl" also includes a heteroaryl as defined above fused to a heterocyclyl as defined below. "Aryl" also includes heteroaryl as defined above, which is fused to a benzene, cyclohexadiene or cyclohexane ring. Non-limiting examples of heteroaryl include pyridinyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridine (including N-substituted pyridines), isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, furanyl, pyrrolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, indolyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, and the like. The heteroaryl or heteroaromatic groups described herein may be optionally substituted with one or more substituents, which are independently selected unless otherwise stated. Suitable substituents for heteroaryl or heteroaromatic groups are further described herein.

[0055] The terms "heterocyclyl", "heterocyclic group" or "heteroalicyclic group" are used interchangeably herein and refer to a non-aromatic saturated or partially saturated monocyclic or polycyclic ring system containing 3 to 11 ring atoms, wherein 1 to 4 ring atoms are independently O, S or N, and the remaining ring atoms are carbon atoms. In one embodiment, the heterocyclic group is monocyclic and has 6 ring atoms, a "6-membered heterocycle". In another embodiment, the heterocyclic group is monocyclic and has 6 ring atoms, wherein 1 or 2 ring atoms are heteroatoms, a "6-membered heterocycle containing 1 or 2 heteroatoms". In another embodiment, the heterocyclic group is monocyclic and has 4 or 5 ring atoms, a "4- or 5-membered heterocycle". In another embodiment, the heterocyclic group has 7, 8 or 9 ring atoms, a "7-, 8- or 9-membered heterocycle". In another embodiment, the heterocyclic group is bicyclic. The heterocyclic group may be attached to the rest of the molecule via a ring carbon or ring nitrogen atom. The nitrogen or sulfur atom of the heterocyclic group may be optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. Non-limiting examples of monocyclic heterocycles include oxetane, piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, dihydropyranyl, pyran, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothienyl, δ-lactam, δ-lactone, etc. The heterocyclic groups described herein may be optionally substituted with one or more substituents, which are independently selected unless otherwise stated. Suitable substituents for heterocyclic groups are further described herein. The heterocyclic group may be unsubstituted or substituted with the same group suitable for alkyl, aryl or heteroaryl. In one embodiment, the heterocyclic ring contains 6 atoms and is substituted with 1-4 groups as defined herein, "a 6-membered heterocyclic ring substituted with 1-4 groups". In addition, when specified, the ring nitrogen atoms may be optionally substituted with groups suitable for amines, such as alkyl, acyl, carbamoyl, sulfonyl substituents, and the like, and the ring S atoms may be optionally substituted with 1 or 2 oxo groups (i.e., S(O) q , wherein q is 0, 1 or 2). In one embodiment, as described above, a 4- or 5-membered heterocycle is optionally substituted, "an optionally substituted 4- or 5-membered heterocycle". In another embodiment, as described above, a 7-, 8- or 9-membered heterocycle is optionally substituted, "an optionally substituted 7-, 8- or 9-membered heterocycle".

[0056] Aryl, heteroaryl and heterocyclic groups described herein as optionally substituted ("optionally substituted") may be partially substituted with one or more substituents, which are independently selected unless otherwise specified. The substituted ("substituted") aryl, heteroaryl and heterocyclic groups described herein are partially substituted with one or more substituents, which are independently selected unless otherwise specified. The optionally substituted aryl, heteroaryl or heterocyclic group typically contains 1 to 5 optional substituents, sometimes 1 to 4 optional substituents, preferably 1 to 3 optional substituents, or more preferably 1-2 optional substituents. The substituted aryl, heteroaryl or heterocyclic group contains at least one substituent as described herein, and may optionally contain up to a total of 5 substituents, each of which is independently selected.

[0057] Suitable substituents for aryl, heteroaryl and heterocycle include, but are not limited to: (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C8) cycloalkyl, 3-12 membered heterocyclyl, (C6-C12) aryl, 5-12 membered heteroaryl, halogen, =O (oxo), =S (thio), =N-CN, =N-OR X , =NR X , -CN, -C(O)R X , -CO2R X , -C(O)NR X R Y , -SR X , -SOR X , -SO2R X , -SO2NR X R Y , -NO2, -NR X R Y , -NR X C(O)R Y , -NR X C(O)NR X R Y , -NR X C(O)OR X , -NR X S02R Y , -NR X SO2NR X R Y , -OR X , -OC(O)R X and -OC(O)NR X R Y ; where each R X and R Yis independently hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C6) cycloalkyl, 3-12 membered heterocyclyl, (C6-C12) aryl, or 5-12 membered heteroaryl, or R X and R Y Together with the nitrogen atom to which they are attached, they may form a 3-12 membered heterocyclyl or 5-12 membered heteroaryl system, each optionally containing 0, 1 or 2 heteroatoms; each R X and R Y Optionally substituted with 1-3 substituents independently selected from halogen, =O, -CN, -C(O)R', -CO2R', -C(O)NR'2, -SO2R', -NR'2, -OR', wherein each R' is independently hydrogen, (C1-C6) alkyl, (C3-C6) cycloalkyl or 3-12 membered heterocyclyl. However, suitable substituents for "substituted alkyl" do not include hydrogen.

[0058] "Unsubstituted amino" refers to the group -NH2. When amino is described as substituted or optionally substituted, the term includes -NR X R Y A group of the form, where each R X and R Y is independently selected from hydrogen, (C1-C8) alkyl, (C3-C9) cycloalkyl, alkynyl, heterocyclyl, acyl, aryl, heteroaryl, thioacyl, cycloalkylalkyl, arylalkyl or heteroalkylalkyl, in each case having the indicated number of atoms and optionally substituted as described herein. Typically, the alkyl substituents on the amine contain 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, or more preferably 1 to 4 carbon atoms. The term also includes forms wherein R X and R Y Together with the nitrogen to which they are attached they form a 3-12 membered heterocyclyl or 5-12 membered heteroaryl ring, each of which may be optionally substituted as described herein for heterocyclyl or heteroaryl. The rings may contain 1 to 3 additional heteroatoms selected from N, O and S as ring members, provided that these rings do not contain consecutive oxygen atoms or consecutive sulfur atoms. As mentioned above, the term extends to an amino residue of another functional group (e.g., -C(O)NR X R Y , -S(O)2NR X R Y In one embodiment, -NR X R Y R X and R Y ;-C(O)NR X R YTogether with the nitrogen to which they are attached, they may form a ring (3-12 membered heterocyclyl or 5-12 membered heteroaryl ring, each of which may be optionally substituted as described herein. The heterocyclyl or heteroaryl ring may contain 1-3 additional heteroatoms selected from N, O and S as ring members, provided that these rings do not contain consecutive oxygen atoms or consecutive sulfur atoms). In another embodiment, -NR X R Y R X and R Y ; -S(O)2NR X R Y Together with the nitrogen to which they are attached, they may form a ring (a 3-12 membered heterocyclyl or a 5-12 membered heteroaryl ring, each of which may be optionally substituted as described herein). The heterocyclyl or heteroaryl ring may contain 1-3 additional heteroatoms selected from N, O and S as ring members, provided that these rings do not contain consecutive oxygen atoms or consecutive sulfur atoms).

[0059] Two adjacent substituents on a ring may form a ring together with the atoms to which they are attached. The term "forming a ring together with the carbon atoms to which they are attached" is defined herein to mean that two adjacent residues present on a ring may be combined with the carbon atoms to which they are attached to form a 4-6 membered heterocyclyl, 4-6 membered carbocyclyl or 4-6 membered heteroaryl ring, each of which may be optionally substituted as described herein as a heterocyclyl or heteroaryl ring. The heterocyclyl and heteroaryl rings thus formed may contain 1 to 3 additional heteroatoms selected from N, O and S as ring members (provided that these rings do not contain consecutive oxygen atoms or consecutive sulfur atoms). Representative examples of phenyl moieties derived from the phenyl moiety include, but are not limited to, benzofuranyl, benzothiophenyl, indolyl, benzimidazolyl, indazolyl, benzotriazolyl, indazolyl, quinolinyl, isoquinolinyl, quinolinyl, azaquinazoline, quinoxalinyl, 2,3-dihydro-1H-indenyl, phthaloyl 2,3-dihydrobenzofuranyl, benzodioxycarbonyl, benzodioxanyl, and the like. Representative examples of heterocyclyl rings thus formed include, but are not limited to:

[0060]

[0061] Similar structures to the above compounds. Representative examples of the carbocyclic rings thus formed include, but are not limited to:

[0062]

[0063] Similar structure to the above compounds.

[0064] The two substituents combined with a common nitrogen atom can form a ring together with the nitrogen to which they are connected. The term "forming a ring together with the nitrogen atom to which they are connected" is defined herein as indicating that two residues on the nitrogen atom can be combined together to form a 3-12-membered heterocyclic radical, a 3-7-membered carbocyclic radical or a 5-12-membered heteroaryl ring, each of which can be optionally substituted as described herein for a heterocyclic radical or a heteroaryl ring. The heterocyclic radical and heteroaryl ring thus formed can contain 1 to 3 additional heteroatoms selected from N, O and S as ring members (provided that such a ring does not contain continuous oxygen atoms or continuous sulfur atoms). Non-limiting examples derived from nitrogen atoms include the following parts: azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 1,4-azepanyl, 1,3,4-triazolyl, tetrazolyl, imidazolyl, etc.

[0065] The term "substituted" means that one or more of the designated hydrogen atoms are replaced with a selection from the indicated group, provided that the normal valence of the atom under the original conditions is not exceeded and that the substitution results in a stable compound. A "stable compound" or "stable structure" is one that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and formulation into an efficacious therapeutic agent.

[0066] When any substituent or variable occurs more than one time in any constituent or compound of formula (I), unless otherwise stated, its definition on each occurrence is independent of its definition at every other occurrence.

[0067] As used herein, the term "purified form" refers to the physical state of a compound after it has been isolated from a synthetic process (e.g., from a reaction mixture), a natural source, or a combination thereof. The term "purified form" also refers to the physical state of a compound after it has been obtained from a purification method described herein or a purification method well known to those skilled in the art (e.g., chromatography, recrystallization, etc.).

[0068] It should be noted that any carbon atom as well as heteroatom having unsatisfied valences in the text, schemes, examples and tables herein are assumed to have sufficient number of hydrogen atoms to satisfy the valences.

[0069] One or more compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the present invention embrace both solvated and unsolvated forms.

[0070] The compounds of the general structural formula (I) may contain one or more stereocenters and may therefore exist as racemates, racemic mixtures, single enantiomers, diastereoisomer mixtures and individual diastereoisomers. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomers in the mixture as well as pure or partially purified compounds are included within the scope of the present invention.

[0071] As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0072] In the compounds of the general structural formula (I), atoms may embody their natural isotopic abundance, or one or more atoms may be artificially enriched with a specific isotope having the same atomic mass, but the atomic mass or mass number is different from the atomic mass or mass number that exists in the vast majority of nature. The present invention is intended to include all suitable isotopic variants of the compounds of the general structural formula (I). Enrichment of specific isotopes may provide advantageous properties, for example, enrichment of deuterium may provide certain therapeutic advantages, such as increasing half-life in vivo or reducing dosage. In addition, isotopic enrichment may also enrich the usefulness of compounds in the characterization of biological samples. Compounds enriched in specific isotopes may be prepared by the synthetic methods described herein and methods known to those skilled in the art, by using reagents and starting materials enriched in specific isotopes.

[0073] Prodrugs of the compounds of the invention are contemplated herein. As used herein, the term "prodrug" refers to a compound that undergoes chemical transformation by metabolic or chemical processes after administration to a subject to produce a compound of the general structural formula (I). Prodrugs may have beneficial properties, such as, but not limited to, enhanced absorption and / or oral bioavailability.

[0074] Compounds of general formula (I) may also form salts in some cases, which also fall within the scope of the present invention. Unless otherwise indicated, compounds of general formula (I) mentioned herein are to be understood to include salts thereof. The term "salt" as used herein means acidic and / or basic salts formed with inorganic and / or organic acids and bases. Zwitterions (internal or inner salts) are included in the term "salt" as used herein (and may be formed, for example, where the R substituents contain acid moieties, such as carboxyl groups). Quaternary ammonium salts, such as alkyl ammonium salts, are also included herein. Pharmaceutically acceptable (i.e., nontoxic, physiologically acceptable) salts are preferred, but other salts are also useful, for example, and may be used in separation or purification steps during the preparation process. Salts of compounds of general formula (I) may be formed, for example, by reacting compounds of general formula (I) with an equal amount of acid or base in a medium such as a medium that allows salt precipitation (e.g., ether) or in an aqueous medium, and then freeze-dried.

[0075] Exemplary acid addition salts include acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate, naphthylate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, and the like. In addition, for example, by P. Stahl et al., Camille G. (ed.) Handbook of Pharmaceutical Salts, Properties, Selection and Use (2002) Zurich: Wiley-VCH. Acids that are generally considered suitable for forming pharmaceutically useful salts from basic drug compounds are discussed. This disclosure is incorporated herein by reference.

[0076] Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (e.g., organic amines) such as dicyclohexylamine, tert-butylamine and salts with amino acids such as arginine, lysine, etc. Basic nitrogen-containing groups can be quaternized with, for example, lower alkyl halides (e.g., methyl, ethyl and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl and dibutyl sulfates), long chain halides (e.g., decyl, lauryl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), etc.

[0077] The present invention also includes all compounds of the general structural formula (I) in free form.

[0078] Compounds of the present invention

[0079] In one aspect, the present invention provides a compound of the general structural formula (I):

[0080]

[0081] in

[0082] Q is independently selected from the group consisting of heteroaryl,

[0083]

[0084] V is independently selected from the group consisting of:

[0085]

[0086] W may not be included or W may be -C(R 12 R 13 )-; Y is independently selected from oxygen, sulfur and =NR 14 R1, R2, R3, R4 and R5 are independently selected from hydrogen, halogen, -CN, -S(O)2R 43, -NO2, -NR 44 R 45 , -OH, -SH, -SR 46 , (C1-C3)haloalkoxy, (C1-C4)alkoxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C2-C6)alkynyl, (C2-C6)alkenyl and (C1-C6)haloalkyl; or, R1 and R2 may form a ring together with the carbon atoms to which they are attached; R 23 , R 24 , R 25 , R 28 , R 29 and R 30 independently selected from hydrogen, halogen, -CN, -S(O)2R 43 , -NO2, -NR 44 R 45 , -OH, -SH, -SR 46 , (C1-C3)haloalkoxy, (C1-C4)alkoxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C2-C6)alkynyl, (C2-C6)alkenyl and (C1-C6)haloalkyl; or, R 24 and R 25 Together with the carbon atoms to which they are attached, they can form a ring; R 28 and R 29 can form a ring together with the carbon atoms to which they are attached; R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 16 , R 17 , R 26 , R 27 , R 31 , R 32 , R 36 , R 37 , R 41 and R 42 Each independently selected from hydrogen, halogen, -CN, -S(O)2R 43 ,-NO2,-NRR,-OH,-SH,-SR 46 , (C1-C3)haloalkoxy, (C1-C4)alkoxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C2-C6)alkynyl, (C2-C6)alkenyl and (C1-C6)haloalkyl; or, R6 and R7 together with the carbon atoms to which they are attached form a 3-membered carbocyclic ring or carbonyl moiety; R8 and R9 together with the carbon atoms to which they are attached may form a 3-membered carbocyclic ring or carbonyl moiety; R 10 and R11 Together with the carbon atom to which they are attached, they can form a 3-membered carbocyclic ring or a carbonyl moiety; R 12 and R 13 Together with the carbon atom to which they are attached, they can form a 3-membered carbocyclic ring or a carbonyl moiety; R 16 and R 17 Together with the carbon atom to which they are attached, they can form a 3-membered carbocyclic ring or a carbonyl moiety; R 26 and R 27 Together with the carbon atom to which they are attached, they can form a 3-membered carbocyclic ring or a carbonyl moiety; R 31 and R 32 Together with the carbon atom to which they are attached, they can form a 3-membered carbocyclic ring or a carbonyl moiety; R 36 and R 37 Together with the carbon atom to which they are attached, they can form a 3-membered carbocyclic ring or a carbonyl moiety; R 41 and R 42 Together with the carbon atom to which they are attached, they can form a 3-membered carbocyclic ring or a carbonyl moiety; R 14 and R 15 independently selected from hydrogen, halogen, -CN, -S(O)2R 43 , -NO2, -NR 44 R 45 , -OH, -SH, -SR 46 , -S(O)2R 43 , (C1-C3)haloalkoxy, (C1-C4)alkoxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C2-C6)alkynyl, (C2-C6)alkenyl and (C1-C6)haloalkyl, -C(NH)NH2, -C(O)R 43 , -C(O)OR 46 Group composed of 18 , R 19 , R 20 , R 21 and R 22 independently selected from the group consisting of hydrogen, halogen, (C1-C6)alkyl, (C3-C9)cycloalkyl, (C3-C9)cycloalkyl (C1-C6)alkyl, (C1-C6)haloalkyl, -OH, -SH, (C1-C6)alkoxy, -NR 44 R 45 , (C3-C9)cycloalkyl (C2-C6)alkynyl, (C4-C8)cycloalkenyl, (C4-C8)cycloalkenyl (C1-C6)alkyl, aryl, heteroaryl, heterocyclyl, -CN, -NO2, -SR 46 , -C(O)OH, -C(O)OR 46 , -OC(O)OR 46, (C2-C6) alkynyl, (C2-C8) alkenyl, (C1-C6) haloalkoxy, -S(O)2OR 46 , -SO2NR 44 R 45 , -S(O)2R 43 , -NR 47 S(O)2R 43 , -C(O)NR 44 R 45 , -C(O)R 43 and-NR 47 C(O)R 43 or, R 20 and R 21 Together with the carbon atoms to which they are attached, they can form a ring; R 33 , R 34 , R 35 , R 38 , R 39 and R 40 independently selected from the group consisting of hydrogen, halogen, (C1-C6)alkyl, (C3-C9)cycloalkyl, (C3-C9)cycloalkyl (C1-C6)alkyl, (C1-C6)haloalkyl, -OH, -SH, (C1-C6)alkoxy, -NR 44 R 45 , (C3-C9)cycloalkyl (C2-C6)alkynyl, (C4-C8)cycloalkenyl, (C4-C8)cycloalkenyl (C1-C6)alkyl, aryl, heteroaryl, heterocyclyl, -CN, -NO2, -SR 46 , -C(O)OH, -C(O)OR 46 , -OC(O)OR 46 , (C2-C6) alkynyl, (C2-C8) alkenyl, (C1-C6) haloalkoxy, -S(O)2OR 46 , -SO2NR 44 R 45 , -S(O)2R 43 , -NR 47 S(O)2R 43 , -C(O)NR 44 R 45 , -C(O)R 43 and-NR 47 C(O)R 43 or, R 34 and R 35 Together with the carbon atoms to which they are attached, they can form a ring; R 38 and R 39 Together with the carbon atoms to which they are attached, they can form a ring; R 43independently selected from hydrogen, (C1-C6) alkyl, (C3-C9) cycloalkyl, (C1-C6) haloalkyl, (C2-C6) alkynyl, (C2-C8) alkenyl, (C1-C6) haloalkoxy, aryl, heteroaryl, heterocyclyl and -NR 44 R 45 Group composed of 44 , R 45 and R 47 is independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C3-C9)cycloalkyl, (C1-C6)haloalkyl, (C2-C6)alkynyl, (C2-C8)alkenyl, (C1-C6)haloalkoxy, aryl, heteroaryl and heterocyclyl; or, R 44 and R 45 Together with the nitrogen atom to which they are attached, they form a ring; R 46 Independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C9) cycloalkyl, (C1-C6) haloalkyl, (C2-C6) alkynyl, (C2-C8) alkenyl, (C1-C6) haloalkoxy, aryl, heteroaryl and heterocyclyl; or a pharmaceutically acceptable salt thereof.

[0087] In a common embodiment of the general structure (I), R3, R4, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 It's hydrogen.

[0088] In common embodiments of the general structural formula (I), R 15 It is -CH3.

[0089] In common embodiments of the general structural formula (I), R 15 Yes -CH3

[0090] Y is oxygen.

[0091] In some embodiments of the general structural formula (I), R 15 are hydrogen, -CH2CH3 and -CH(CH3)2.

[0092] In some embodiments of structural formula (I), R2 is -Cl, -Br or -CF3.

[0093] In some embodiments of the general structure (I), R2 is -Cl and R3, R4, R6, R7, R8, R9, R 10, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 It's hydrogen.

[0094] In some embodiments of the general formula (I), R2 is -Br and R3, R4, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 It's hydrogen.

[0095] In some embodiments of the general structure (I), R2 is -CF3 and R3, R4, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 It's hydrogen.

[0096] In some embodiments of the general structural formula (I), R 22 It is a (C2-C6)alkynyl group.

[0097] In some embodiments of the general structural formula (I), R 22 is (C2)alkynyl and R2 is -CF3.

[0098] In some embodiments of the general structural formula (I), R 22 is (C2)alkynyl and R2 is -Cl.

[0099] In some embodiments of the general structural formula (I), R 22 is (C2)alkynyl and R2 is -Br.

[0100] Dosage forms and treatment regimens

[0101] Any method capable of delivering the compound to the site of action can be used to effect administration of the compounds of the present invention. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular or infusion), topical and rectal administration.

[0102] The dosage regimen can be adjusted to provide the optimal desired response. For example, a single dose may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased depending on the exigencies of the therapeutic situation. Formulating parenteral compositions in dosage unit form is particularly advantageous for ease of administration and uniformity of dosage. As used herein, dosage unit form refers to physically discrete units suitable as unit doses for mammalian subjects to be treated; each unit contains a predetermined amount of active compound calculated to produce the desired therapeutic effect together with the required pharmaceutical carrier. The specifications of the dosage unit forms of the present invention can be determined by: (a) the unique characteristics of the chemotherapeutic agent and the specific therapeutic or preventive effect to be achieved; (b) the limitations inherent in such compounds, such as the sensitivity of an active compound to individual treatments.

[0103] Therefore, the technical staff will refer to the disclosure provided herein and adjust the dosage and administration regimen according to the methods known in the therapeutic field. That is, the maximum tolerable dose can be determined relatively easily, and the effective dose that can achieve the therapeutic effect of the patient that can be detected can also be determined, and each agent used to achieve the time requirement of the patient having the therapeutic benefit obtained by the detection. Therefore, although certain dosages and administration regimens are illustrated herein, these implementation examples are by no means limited to the dosages and administration regimens that can be provided to the patient when implementing the present invention. It should be noted that the dosage value may vary with the type and severity of the disease to be alleviated, and may include a single dose or multiple doses. It should be further understood that for any particular subject, the specific dosage regimen should be adjusted at any time according to individual needs, and the professional judgment of the person administering the composition or supervising the administration of the composition, and the dosage range described herein is exemplary. It is only used for and is not intended to limit the scope or practice of the claimed composition. For example, the dosage can be adjusted based on pharmacokinetic or pharmacodynamic parameters, or according to clinical effects, such as toxic effects and / or experimental values. Thus, the present invention includes the use of a dose escalation schedule for patients as determined by a skilled artisan; determining the appropriate dose and schedule for administering a chemotherapeutic agent is well known in the relevant art, and once the technical disclosure is provided herein, it will be understood to be used by reference within the scope of those skilled in the art.

[0104] The amount of the compound of the present invention administered will depend on the subject being treated, the severity of the disease, the rate of administration, the disposition of the compound, and the judgment of the prescribing physician. However, in the case of a single dose or divided dose, the effective dose is about 0.001 to 100 mg per kilogram of body weight per day, preferably about 1 to about 35 mg / kg / day. For a 70kg person, the dosage is about 0.05 to about 7g / day, preferably about 0.1 to about 2.5g / day. In some cases, dosage levels below the lower limit of the above range may be more than enough, while in other cases, larger doses can be used without any harmful side effects, as long as these larger doses are first divided into several small doses for administration throughout the day.

[0105] Formulation and route of administration:

[0106] As used herein, "pharmaceutically acceptable carrier" refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the active compound.

[0107] The pharmaceutically acceptable carrier may comprise any conventional pharmaceutical carrier or excipient. The choice of carrier and / or excipient depends largely on factors such as the specific mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0108] Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents (such as hydrates and solvates). If necessary, the pharmaceutical composition may contain other ingredients, such as flavoring agents, binders, excipients, etc. Therefore, for oral administration, tablets containing various excipients such as citric acid can be used with various disintegrants such as starch, alginic acid and certain complex silicates, and with binders such as sucrose, gelatin and gum arabic. Examples of excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars and starch types, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc can generally be used for tableting purposes. Similar types of solid compositions can also be used in soft and hard filled gelatin capsules. Therefore, non-limiting examples of materials include lactose and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are administered orally, the active compound may be mixed with various sweeteners or flavoring agents, colorants or dyes, and, if desired, with emulsifiers or suspending agents, and diluents such as water, ethanol, propylene glycol, glycerol or a combination thereof.

[0109] For example, the pharmaceutical composition may be in a form suitable for oral administration such as tablets, capsules, pills, powders, sustained release formulations, solutions, suspensions or emulsions, as an ointment or cream for topical administration, or as a suppository for rectal administration.

[0110] Exemplary parenteral administration forms include solutions or suspensions of the active compound in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. These dosage forms can be suitably buffered, if necessary.

[0111] The pharmaceutical compositions may be in unit dosage form suitable for single administration of precise amounts.

[0112] Pharmaceutical compositions suitable for delivering active agents and methods for their preparation are readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in "Remington's Pharmaceutical Sciences", 19th edition (Mack Publishing Company, 1995), the disclosure of which is incorporated herein by reference in its entirety.

[0113] The compounds of the present invention can be administered orally. Oral administration may include swallowing, so that the compound enters the gastrointestinal tract; buccal or sublingual administration may also be used, where the compound enters the bloodstream directly from the oral cavity.

[0114] Formulations suitable for oral administration include solid preparations such as tablets, capsules containing granules, liquids or powders, lozenges (including liquid fillers), chewables, multi-core granules, nanoparticles, gel solid solutions, liposomes, films, ovule suppositories, sprays and liquid preparations.

[0115] Liquid preparations include suspensions, solutions, syrups and elixirs. Such preparations can be used as fillers in soft or hard capsules and typically include a carrier such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil, and one or more emulsifiers and / or suspending agents. Liquid preparations can also be prepared by reconstitution of solids, such as from sachets.

[0116] The compounds of the invention may also be used in fast dissolving, fast disintegrating dosage forms, such as those described in Expert Opinion in Therapeutic Patents, 11(6), 981-986 by Liang and Chen (2001), the disclosure of which is incorporated herein by reference in its entirety.

[0117] For tablet dosage forms, the active agent may comprise 1% (by weight) to 80% (by weight) of the dosage form, more typically 5% (by weight) to 60% (by weight) of the dosage form. In addition to the active agent, the tablet typically contains a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, crospovidone, polyvinyl pyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate. Typically, the disintegrant may comprise 1% (by weight) to 25% (by weight) of the dosage form, preferably 5% (by weight) to 20% (by weight).

[0118] Binders are often used to impart binding properties to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinyl pyrrolidone, pregelatinized starch, hydroxypropyl, cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents such as lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dehydrated calcium phosphate.

[0119] Tablets may also optionally include surfactants, such as sodium lauryl sulfate and polysorbate 80, and glidants, such as silicon dioxide and talc. If present, surfactants are generally present in amounts of 0.2% (by weight) to 5% (by weight) of the tablet, and glidants are generally present in amounts of 0.2% (by weight) to 1% (by weight) of the tablet.

[0120] Tablets generally also contain lubricants, such as magnesium stearate, calcium stearate, zinc stearate, sodium stearate fumarate, and a mixture of magnesium stearate and sodium lauryl sulfate. Lubricants are usually present in an amount from 0.25% (by weight) to 10% (by weight), preferably from 0.5% (by weight) to 3% (by weight) of the tablet.

[0121] Exemplary tablets may contain up to about 80% (by weight) of the pharmaceutically active ingredient, about 10% (by weight) to about 90% (by weight) of a binder, about 0% (by weight) to about 85% (by weight) of a diluent, about 2% (by weight) to about 10% (by weight) of a disintegrant, and about 0.25% (by weight) to about 10% (by weight) of a lubricant.

[0122] The formulation of tablets is discussed in detail in "Pharmaceutical Dosage Forms: Tablets, Vol. 1", by H. Lieberman and L. Lachman, Marcel Dekker, NY, NY, 1980 (ISBN 0-8247-6918-X), the disclosure of which is incorporated herein by reference in its entirety.

[0123] Suitable modified release formulations are described in U.S. Pat. No. 6,106,864. Details of other suitable release technologies, such as high energy dispersions and osmotic and coated particles, can be found in the article by Verma et al.: Pharmaceutical Technology On-line 25(2), 1-14 (2001). The disclosure of this reference is incorporated herein by reference in its entirety.

[0124] It will be appreciated that the compounds of general formula (I) may be formulated as double salts.

[0125] Parenteral administration:

[0126] The compounds of the invention can also be administered directly into the bloodstream, muscle or internal organs. Suitable modes for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle syringes, needle-free syringes and infusion techniques.

[0127] Parenteral formulations are usually aqueous solutions which may contain excipients such as salts, carbohydrates and buffers (preferably at pH 3 to 9), but, for some applications, they may be more appropriately formulated as sterile non-aqueous solutions or as dry forms for use with a suitable carrier such as sterile pyrogen-free water.

[0128] Parenteral formulations may readily be prepared under sterile conditions, for example, by freeze-drying, using standard pharmaceutical techniques well known to those skilled in the art.

[0129] The solubility of the compounds of the invention used in the preparation of parenteral solutions may potentially be increased by the use of appropriate formulation techniques, such as the incorporation of solubility enhancing agents.

[0130] Preparations for parenteral administration can be formulated as immediate release agents and / or modified release agents. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release. Therefore, the compounds of the present invention can potentially be formulated as solids, semisolids or thixotropic liquids for administration as implanted reservoirs, providing a modified release of the active compound. Examples of such preparations include drug-coated stents and PGLA microspheres.

[0131] The compounds of the invention can also potentially be administered topically to the skin or mucous membranes, i.e., dermally or transdermally. Typical formulations for this use include gels, hydrogels, emulsions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, wafers, implants, sponges, fiber bandages and microemulsions.

[0132] dose:

[0133] The amount of the active compound administered will depend on the subject being treated, the severity of the condition, the rate of administration, the configuration of the compound and the judgment of the prescribing physician. However, the effective dose is generally about 0.001 to about 100 mg per kg of body weight per day, preferably 0.01 to about 35 mg / kg / day, in single or divided doses. For humans, this will reach about 0.07 to about 7000 mg / day, preferably about 0.7 to about 2500 mg / day. In some cases, a dosage level below the lower limit of the above range may be sufficient, while in other cases, a larger dose may be used without causing any harmful side effects, and this larger dose is usually divided into several smaller doses for administration throughout the day.

[0134] Combination treatment:

[0135] As used herein, the term "combination therapy" refers to the sequential or simultaneous administration of a compound of the present invention together with at least one additional drug or agent (eg, anticancer agent).

[0136] As mentioned above, the compounds of this invention can potentially be used in combination with one or more other anticancer agents, which are described below. When using combination therapy, one or more other anticancer agents can be used sequentially or simultaneously with the compounds of this invention. In one embodiment, before the compounds of this invention are used, other anticancer agents are applied to mammals (subjects, patients). In another embodiment, after the compounds of this invention are used, other anticancer agents are applied to mammals. In another embodiment, while the compounds of this invention are used, other anticancer agents are applied to mammals.

[0137] The present invention also relates to a pharmaceutical composition for treating abnormal cell growth in mammals (including humans), comprising an amount of a compound of the present invention as defined herein in combination with one or more (preferably one to three) anti-cancer agents selected from the group consisting of anti-angiogenesis agents and signal transduction inhibitors and a pharmaceutically acceptable carrier, wherein the amount of the active agent and the combined anti-cancer agent is therapeutically effective for treating the abnormal cell growth when taken as a whole.

[0138] In one embodiment of the invention, the anticancer agent used in combination with the compounds of the invention and the pharmaceutical compositions described herein is an anti-angiogenic agent (e.g., an agent that prevents a tumor from developing new blood vessels). Examples of anti-angiogenic agents include, for example, VEGF inhibitors, VEGFR inhibitors, TIE-2 inhibitors, PDGFR inhibitors, angiopoietin inhibitors, PKCβ inhibitors, COX-2 inhibitors, integrins, MMP-2 (matrix metalloproteinase 2) inhibitors, and MMP-9 (matrix metalloproteinase 9) inhibitors.

[0139] Preferred anti-angiogenic agents include sunitinibTM ), bevacizumab (Avastin TM ), axitinib (AG 13736), SU 14813 (Pfizer) and AG 13958 (Pfizer).

[0140] Other antiangiogenic agents include vatalanib (CGP 79787), sorafenib (Nexavar TM ), pegaptaniboctasodium (Macugen TM ), Vandetanib (Zactima TM ), PF-0337210 (Pfizer), SU 14843 (Pfizer), AZD 2171 (AstraZeneca), Lucentis (Lucentis TM ), Neovastat TM (AE 941), tetrathiomolyb-data (Coprexa TM ), AMG 706 (Amgen), VEGF Trap (AVE0005), CEP 7055 (Sanofi-Aventis), XL880 (Exelixis), telatinib (BAY 57-9352) and CP-868,596 (Pfizer).

[0141] Other antiangiogenic agents include enzastaurin (LY 317615), midostaurin (CGP 41251), perifosine (KRX 0401), teprenone (Selbex TM ) and UCN01 (Kyowa Hakko).

[0142] Other examples of anti-angiogenic agents that can be used with the compounds of the invention and the pharmaceutical compositions described herein include: Celebrex TM ), Parecoxib (Dynastat TM ), Deracoxib (SC 59046), Lumiracoxib (Preige TM ), valdecoxic (Bextra TM ), rofecoxib (Vioxx TM ), Careram TM ), IP751 (Invedus), SC-58125 (Pharmacia) and etoricoxib (Arcoxia TM ).

[0143] Other antiangiogenic agents include exisulind (Aptosyn TM ), salsalate(Amigesic TM ), diflunisal (Dolobid TM ), ibuprofen (Motrin TM ), Ketoprofen (Orudis TM ), nabumetone (Relafen TM ), Piroxicam (Feldene TM ), naproxen (Aleve TM , Naprosyn TM ), Diclofenac (Voltarn TM ), Indomethacin TM ), Clinoril TM ), Tolectin TM ), Etodolac (Lodine TM ), Ketorolac (Toradol TM ) and oxaprozin (Day-pro TM ).

[0144] Other antiangiogenic agents include ABT 510 (Abbott), apratastat (TMI 005), AZD 8955 (AstraZeneca), incyclinide (Metastat TM ) and PCK 3145 (Procyon).

[0145] Other anti-angiogenic agents include: Acitretin (Neotigason TM ), plitidepsin (Aplidine TM ), cilengtide(EMD 121974), combretastatinA4(CA4P), fenretinide(4HPR), halofuginone(Tempostatin TM ), Panzem TM , rebimastat (BMS 275291), catumaxomab, (Removab TM ), Revlimid TM ), Squalamine (EVIZON TM ), Thalomid TM), UkrainTM (NSC 631570), VitaxinTM (MEDI 522) and zoledronic acid (Zomata TM ).

[0146] In another embodiment, the anticancer agent is a so-called signal transduction inhibitor (e.g., a means of inhibiting the intracellular transmission process of regulatory molecules that control the basic processes of cell growth, differentiation and survival). Signal transduction inhibitors include small molecules, antibodies and antisense molecules. Signal transduction inhibitors include, for example, kinase inhibitors (e.g., tyrosine kinase inhibitors or serine / threonine kinase inhibitors) and cell cycle inhibitors. More specifically, signal transduction inhibitors include such as farnesyl protein transferase inhibitors, EgF inhibitors, ErbB-1 (EGFR) inhibitors, ErbB-2 inhibitors, pan-erb inhibitors, IGF1R inhibitors, MEK (1,2) inhibitors, c-Kit inhibitors, FLT-3 inhibitors, K-Ras inhibitors, PI3 kinase inhibitors, JAK inhibitors, STAT inhibitors, Raf kinase inhibitors, Akt inhibitors, mTOR inhibitors, P70S6 kinase inhibitors, WNT pathway inhibitors and so-called multi-target kinase inhibitors.

[0147] Preferred signal transduction inhibitors include: gefitinib (Iressa TM ), Cetuximab (Erbitux TM ), erlotinib (Tarceva TM ), Herceptin TM ), Sunitinib TM ), imatinib (Gleevec TM ), Trametinib TM (GSK1120212) and Cobimetinib TM (XL518).

[0148] Other examples of signal transduction inhibitors that can be used in combination with the compounds of the present invention and the pharmaceutical compositions described herein include: BMS 214662, lonafarnib (Sarasar TM ), pelitrexol (AG 2037), matuzumab (EMD7200), nimotuzumab (TheraCIM h-R3 TM ), panitumumab (Vectibix TM ), Vandetanib (Zactima TM ), pazopanib (SB 786034), BIBW 2992 (Boehringer Ingelheim) and CerveneTM (TP 38).

[0149] Other examples of signal transduction inhibitors include Canertinib (CI 1033), Pertuzumab (Omnitarg TM ), Lapatinib (Tycerb TM ), pelitinib (EKB 569), Miltefosin TM ), BMS599626, Lapuleucel-T (Neuvenge TM ), NeuVax TM ), OsidemTM (IDM 1), mubritinib (TAK-165), Panitumumab (Vectibix TM ), Lapatinib (Tycerb TM ), pelitinib (EKB 569) and pertuzumab (Omnitarg TM ).

[0150] Other examples of signal transduction inhibitors include: ARRY 142886, Everolimus (Certican TM ), Zotarolimus (Endeavor TM ), Temsirolimus (Torisel TM ) and VX 680 (Vertex).

[0151] The present invention contemplates the use of the compounds of the present invention in combination with anti-tumor agents. Anti-tumor agents include, but are not limited to, hormones, anti-estrogen therapeutic agents, histone deacetylase (HDAC) inhibitors, gene silencing agents or gene activators, ribonucleases, proteomics, topoisomerase I inhibitors, camptothecin derivatives, topoisomerase II inhibitors, alkylating agents, antimetabolites, poly (ADP-ribose), polymerase-1 (PARP-1) inhibitors, tubulin inhibitors, antibiotics, spindle inhibitors, platinum coordination compounds, gene therapy agents, antisense oligonucleotides, vascular targeting agents (VTA) and statins.

[0152] Examples of antineoplastic agents useful in combination therapy with the compounds of the invention include, but are not limited to, glucocorticoids such as dexamethasone, prednisone, prednisolone, methylprednisolone, hydrocortisone and progestins such as medroxyprogesterone, megestrol acetate (Megace), mifepristone (RU-486), selective estrogen receptor modulators (SERMs, such as tamoxifen, raloxifene, lasofoxifene, afimoxifene, arzoxifene, bazedoxifene, fispemifene, ormeloxifene, ospemifene, tesmilifene, toremifene, trilostance and CHF4227 (Cheisi), selective estrogen receptor downregulators (SERDs, such as fulvestrant), exemestane (Aromasin TM ), anastrozole (Arimidex TM ), atamestane, fadrozole, letrozole (Femara), gonadotropin-releasing hormone (GnRH, also commonly called luteinizing hormone-releasing hormone [LHRH]) agonists such as buserelin (Suprefact), goserelin (Zoladex), leuprorelin (Lupron) and triptorelin (Trelstar), abarelix (Plenaxis), bicalutamide (Casodex), cyproterone, flutamide (Eulexin), megestrol acetate, nilutamide (Nilandron) and osaterone, dutasteride, epristeride, finasteride, abarelix, goserelin, leuprorelin, triptorelin, bicalutamide, tamoxifen, exemestane, anastrozole, fadrozole, fromestane, letrozole, and combinations thereof.

[0153] Other examples of antitumor agents for use in combination with the compounds of the present invention include, but are not limited to, suberolanilide hydroxamic acid (SAHA TM , Merck), depsipeptide (FR901228), G2M-777, MS-275, pivaloyloxymethylbutyrate and PXD-101 / Onconase TM (ranpimase), PS-341, Valcade TM (bortezomib), 9-aminocamptothecin, belotecan, BN-80915, camptothecin, diflomotecan, edotecarin, exatecan, gimatecan, 10-hydroxycamptothecin, irinotecan hydrochloride (CamptosarTM ), lurtotecan, orathecin TM (rubitecan), Supergen TM ), SN-38, topotecan, camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, irinotecan, aclarubicin, doxorubicin, aminadine, amrubicin, anmycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, etoposide, idarubicin, gadolinium, hydroxyurea, namomycin, novantrone (mitoxantrone), pirarubicin, pixantrone, procarbazine, rebeccamycin, sobuzoxane, tafluposide, valrubicin, Zinecard TM dexrazoxane, nitrogen mustard N-oxide, cyclophosphamide, AMD-473, altretamine, Ap-5280, apaziquone, brostallicin, bendamustine, busulfan, carboquone, carmustine, chlorambucil, dacarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine, mafosfamide, mechlorethamine, melphalan, mitobronitol, mitolactol, mitomycin C, mitoxatrone, nimustine, ranimustine, temozolomide, thiotepa, and platinum-coordinated alkylating agents such as cisplatin, Paraplatin (carboplatin), eptaplatin, lobaplatin, nedaplatin, eloxatin TM (oxaliplatin), streptozotocin, satrplatin and their combinations.

[0154] The present invention also contemplates the use of the compounds of the present invention in combination with dihydrofolate reductase inhibitors (e.g., methotrexate and NeuTrexin TM (trimethacrylate), purine antagonists (e.g., 6-mercaptopurine nucleoside, mercaptopurine, 6-thioguanine, cladribine, clofarabine TM ), fludarabine, niraparib, and raltitrexed), pyrimidine antagonists (eg, 5-fluorouracil (5-FU), Alimta TM (premethyl disodium), capecitabine (Xeloda TM ), Cytosine, Arabinoside, Gemzar TM (gemcitabine), TegafurTM (UFTOrzel TM or UForal TM , including tegafur, the TS-1 combination of gimestat and otomistat, doxifluridine, carmofur, cytarabine (including ocfosfate, phosphate stearate, sustained-release and liposomal forms), enocitabine, 5-azacitidine (Vidaza), decitabine and ethynyl-cytidine) and other antimetabolites such as eflomithine, hydroxyurea, leucovorin, nolatrexed, triapine, trimetrexate, ABT-472, Ino-1001, KU-0687 and GPI18180 and combinations thereof.

[0155] Other examples of antineoplastic agents useful in combination therapy with the compounds of the present invention, optionally with one or more other agents, include, but are not limited to, Advexin TM , Genasense (Olimersen, Genta), Combretastatin A4P (CA4P), Oxi4503, AVE-8062, ZD-6126, TZT1027, Atorvastatin (Lipitor TM ), Pravastatin TM ), lovastatin (Mevacor TM ), simvastatin (Zocor TM ), fluvastatin (Lescol TM ), cerivastatin (Baycol TM ), rosuvastatin (Crestor TM ), niacin (Advicor TM ), caduet and combinations thereof.

[0156] Another particularly interesting embodiment of the present invention relates to a method of treating a patient with breast cancer in need thereof, which method comprises administering to said patient an amount of a compound of the present invention in combination with one or more (preferably one to three) anticancer agents selected from trastuzumab, tamoxifen, docetaxel, paclitaxel, capecitabine, gemcitabine, vinorelbine, exemestane, letrozole and anastrozole.

[0157] Treatment Methods and Uses:

[0158] The present invention further provides methods and uses of treatment comprising administering a compound of the present invention alone or in combination with one or more other therapeutic agents or palliative agents.

[0159] In one aspect, the present invention provides a method of treating abnormal cell growth in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0160] In another aspect, the present invention provides a method for treating abnormal cell growth in a subject, comprising administering to the subject an amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, and an amount of an anti-tumor agent effective to treat the abnormal growth together. In some embodiments, the anti-tumor agent is selected from mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxins, anti-hormones and anti-androgens.

[0161] In another aspect, the present invention provides a method of inhibiting the proliferation of cancer cells in a subject, comprising administering to the subject a compound of the present invention or a pharmaceutically acceptable salt thereof in an amount effective to inhibit cell proliferation.

[0162] In another aspect, the present invention provides a method of inhibiting the invasiveness of cancer cells in a subject, comprising administering to the subject a compound of the present invention or a pharmaceutically acceptable salt thereof in an amount effective to inhibit cell proliferation.

[0163] In another aspect, the present invention provides a method of inducing apoptosis in cancer cells in a subject, comprising administering to the subject a compound of the present invention or a pharmaceutically acceptable salt thereof in an amount effective to inhibit cell proliferation.

[0164] In another aspect, the present invention provides a method of inducing apoptosis in a subject, comprising administering to the subject a compound of the present invention or a pharmaceutically acceptable salt thereof in an amount effective to inhibit cell proliferation.

[0165] In common embodiments of the methods provided herein, the abnormal cell growth is cancer, wherein the cancer is selected from basal cell carcinoma, medulloblastoma cancer, liver cancer, rhabdomyosarcoma, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, cancer of the adrenal glands, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney cancer or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) tumors, primary CNS lymphomas, spinal axis tumors, brain stem gliomas, pituitary adenomas, or a combination of one or more of the foregoing cancers. In some embodiments, the cell is in a tissue or a tumor, and the tissue or tumor can be in a subject, including a human.

[0166] Cancers treated using the methods and compositions described herein are characterized by abnormal cell proliferation, including but not limited to tumor metastasis, pre-neoplastic hyperproliferation, carcinoma in situ, and neoplasms or tumors. In addition to improving signs and / or symptoms of cancer, the compounds of the invention can also be used for prevention. Examples of cancers treated by the compounds of the invention include but are not limited to breast cancer, CNS cancer, colon cancer, prostate cancer, leukemia, lung cancer, and lymphoma.

[0167] Method for preparing compounds of general structural formula (I):

[0168] The compounds of the present invention can be prepared by a variety of methods, including standard chemistry. Unless otherwise indicated, any previously defined variables will continue to have the meanings previously defined. Illustrative general synthetic methods are listed below, and specific compounds of structural formula (I) are then prepared in the examples.

[0169] The compound of general formula (I) can be prepared by methods known in the field of organic synthesis, partly by the following synthesis scheme. In all schemes described below, according to the general principles of chemistry, as well-known, the protective group of sensitive or reactive groups must be used when necessary. Protective groups (TW Green and PGM Wuts (1991) Protecting Groups in Organic Synthesis, John Wiley & Sons) are used according to the standard method of organic synthesis. It will be clear whether there is a stereo center in the compound of general formula (I). Therefore, the present invention includes all possible stereoisomers, and not only includes a mixture of stereoisomers (such as racemic compounds), but also includes a single stereoisomer. When it is desired that the compound is as a single isomer, it can be obtained by various methods of separating the final product or key intermediate, or stereospecific synthesis can be carried out to give isomer purity by using the method of pure isomeric intermediates. These are known to those skilled in the art.

[0170] The following solvents, reagents, protecting groups, components and other names may be abbreviated in parentheses:

[0171] Me: methyl;

[0172] Et: ethyl;

[0173] Pr: propyl;

[0174] i-Pr: isopropyl;

[0175] Bu: butyl;

[0176] t-Bu: tert-butyl;

[0177] Ph: phenyl,

[0178] Ac:Acetyl

[0179] AcOH: acetic acid

[0180] Aq: aqueous solution

[0181] AUC: Area Under the Curve

[0182] Conc.: Concentrated

[0183] DMF: dimethylformamide

[0184] DMSO: dimethyl sulfoxide

[0185] EtOAc: ethyl acetate

[0186] EtOH: ethanol

[0187] Ex: Example

[0188] g: grams

[0189] h: hours

[0190] HPLC: High Performance Liquid Chromatography

[0191] LCMS: Liquid chromatography mass spectrometry

[0192] MeOH: Methanol

[0193] MS: Mass spectrometry

[0194] NA: Not applicable

[0195] RetTime: retention time

[0196] RT or rt: room temperature

[0197] Satd or satd.: saturated

[0198] TFA: trifluoroacetic acid

[0199] THF: Tetrahydrofuran

[0200] Preparation method:

[0201] The compounds of the present invention can be prepared according to the general synthesis schemes and exemplary methods provided herein and modifications thereof known to those skilled in the art. All references cited are incorporated herein by reference in their entirety. The starting materials can be purchased commercially or prepared in advance by those of ordinary skill in the art.

[0202] The general synthetic scheme shown in Scheme 1 is a series of reactions that can be used by those skilled in the art to prepare the compounds of the present invention. Substituents X and Y represent various substituents that can be used in this reaction sequence, and their positions on the molecule are not limited. The core of this chemical synthesis route is the use of isocyanates, which are labeled SI. In the case where A is a single chlorine atom and the remaining positions that can be substituted are hydrogens, the desired isocyanate has the chemical formula: C8H6ClNO. In addition, it is envisioned that the last step allows the isocyanate to be replaced by a chlorine atom labeled R 15 The reaction conditions shown allow the ligation of various residues labeled R 15 This embodiment is not limited to the number and type of substituents that may be used therein. The various transformations in Scheme 1 may employ alternative reaction conditions known to those skilled in the art. More clearly, X may be R 21 , Y may be R2, which is in no way intended to limit the number and type of substituents that may be used.

[0203] Solution 1

[0204]

[0205] Compounds were synthesized by Scheme 1: (a) sodium carbonate, NH3, ethanol, 70°C, 5h; (b) Et3N, toluene, reflux, 80°C, 8h; (c) RBr, K2CO3, DMF, 100°C, 12h; (d) DMF, Et3N; (e) NaBH(OAc)3, CH2Cl2, 30°C / 4h.

[0206] The general synthetic scheme shown in Scheme 2 is a series of reactions that can be used by those skilled in the art to prepare the compounds of the present invention. Substituents X and Y represent various substituents that can be used in this reaction sequence, and their positions on the molecule are not limited. More clearly, X can be R 21 , Y may be R2, which in no way limits the number and type of substituents that may be used. The compound represented by SA may be prepared from the corresponding benzyl halide (SH) and ethyl 4-oxopiperidin-3-carboxylate (SE) (C7H 11 NO3) (see Scheme 1). Alternatively, by reducing SHA with the corresponding aldehyde (see Scheme 1). The phenyl residue of SH can be substituted with a thiophene residue and optionally substituted.

[0207] Central to this chemical synthesis route is the use of thioisocyanates, here labeled SSI. When Q is M1, R1, R3, R4, R5, R6 and R7 are simultaneously hydrogen and R2 is a chlorine atom, the desired thioisocyanate has the chemical formula: C7H4ClNS. In addition, the next step allows the formation of the analog SSG shown herein via a reaction that forms a guanidine residue. Treatment of SSC with primary amines or NH3 will produce the corresponding guanidine (SSG). Subsequently, SSG and SSC can be referred to for the introduction of R 15 The residue is alkylated in a similar manner as shown in Scheme 1 to form SD. This embodiment is not limited to the number and type of substituents that can be used therein. Optional reaction conditions can be used for various transformations in Scheme 2. References describing useful transformations from thiourea to guanidine are: J.Org.Chem.1986,51(10),p 1882-1884 and references therein and J.Med Chem.2010,Jan 28,53(2)734-744 and references therein. Thioisocyanates can be prepared by reacting the corresponding amines with thiophosgene, reference: J.Org.Chem.,1956,21(4)p 404-405, recent references such as J.Org.Chem.,2012,8,61-70 (Scheme 3). Precursor amines can be obtained from chemical suppliers, such as Aldrich-Aldrich, St.Louis, MO 63103. In addition, various isocyanates, such as SI, are prepared from the corresponding amines by reaction with phosgene or phosgene equivalents. There are other methods for preparing isocyanates: (1) Alkyl isocyanates are prepared in good or even excellent yields by treating alcohols, thiols and trimethylsilyl ethers with triphenylphosphine / 2,3-dichloro-5,6-dicyanobenzoquinone / Bu4NOCN in acetonitrile. This method is highly selective for converting primary alcohols to alkyl isocyanates in the presence of secondary and tertiary alcohols, thiols and trimethylsilyl ethers: Synthesis, 2005, 1955-1958, (2) Isonitriles can be quickly and efficiently oxidized to isocyanates by oxidation with DMSO using trifluoroacetic anhydride as a catalyst; the process is completed within a few minutes, forming dimethyl sulfide as the only by-product. The newly formed isocyanate can be used directly or isolated in high purity by solvent evaporation: Org. Lett., 2011, 13, 2584-2585 and (3) the acylated hydroxylamine can be converted to the corresponding isocyanate as described below: Org. Lett., 2013, 15, 602-605.

[0208] Solution 2

[0209]

[0210] Compounds were synthesized by Scheme 2: (a) Et3N, toluene, reflux, 80°C; (b) isopropanol reflux.

[0211] Solution 3

[0212]

[0213] Example

[0214] Example 1

[0215]

[0216] 6-Benzyl-1-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (1)

[0217] A mixture of 1-benzyl-4-oxopiperidine-3-methyl carboxylate hydrochloride (10.0 g, 35.2 mmol) was dissolved in ethanol (150 ml), and then urea (10.0 g, 167 mmol) and sodium methoxide (22.7 g, 118 mmol) were added, and the mixture was heated to reflux for 12 hours. After cooling to 0 ° C, crystals were formed and separated by filtration. The crystals were suspended in water, and hydrochloric acid (6.0 mol / L) was added to adjust the pH to 6.0. Stirring was continued at room temperature for 1 hour, filtered and separated, and the separated crystals were vacuum dried to obtain compound 1 (6.5 g, yield 72%). The material product can be used without further purification. 1 HNMR(DMSO_d6)δ2.42(s,2H),2.62(t,J=4.8Hz,2H),3.0(s,2H),3.62(s,2H ), 7.26-7.36 (m, 5H), 10.21 (s, 1H), 11.01 (s, 1H); LC-MS: m / z=258.1 (M+1).

[0218] Example 2

[0219]

[0220] 6-Benzyl-3-[(3-methylphenyl)benzyl]-1H,2H,3H,4H,5H,6H,7H,8H-pyrido[4,3-d]pyrimidine-2,4-dione (2)

[0221] Synthesis of 2B

[0222]

[0223] A mixture of 1-phenyl-4-oxopiperidin-3-carboxylic acid methyl ester hydrochloride (2A 8.55 g, 20.2 mmol), sodium carbonate (1.76 g) and aqueous ammonia solution (4.5 mL, 25%) were added to ethanol (70 ml), and the mixture was heated to 70°C and stirred for 5 hours. The solution was concentrated, extracted with dichloromethane (200 mL×2) and washed with brine. The extract was dried over Na2SO4 and concentrated by evaporation under reduced pressure to obtain 7.88 g of 4-amino-1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester 2B (7.88 g oil, 2B), which was used directly in the next step. 1 HNMR (400MHz, CDCl3) δ2.03(m,2H),2.52(m,2H),3.21(s,2H),3.61(s,2H),3.64(s,3H),7.29-7.36(m,5H); LC-MS: m / z=247.2(M+1).

[0224] Synthesis of compound 2

[0225]

[0226] 3-Methylbenzyl isocyanate (2C, 1.1 g, 7.5 mmol) and triethylamine (1.1 g, 10.4 mmol) were added to a toluene (20 mL) solution of methyl 4-amino-1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylate (2B, 1.7 g, 6.9 mmol). The solution was heated to 80°C and stirred for 8 hours. The reaction solution was then concentrated and cooled. The formed white solid was filtered and dissolved in methanol (20 ml). Sodium methoxide (340 mg) was added and the mixture was refluxed overnight. It was then concentrated under reduced pressure to remove about 10-15 ml of methanol and the precipitate was filtered. The desired product 6-benzyl-3-(3-methylbenzyl)-5,6,7,8-tetrahydropyridine [4,3-d] pyrimidine-2,4 (1H, 3H) -dione (2) (0.8 g, 37%) was obtained as a khaki solid. 1 HNMR(400MHz,CD3OD)δ2.29(s,3H),2.55(t,J=5.2Hz,2H),2.75(t,J=5.6Hz,2H),3.27(s,2H ), 3.72 (s, 2H), 5.02 (s, 2H), 7.04-7.15 (m, 4H), 7.29-7.39 (m, 5H); LC-MS: m / z=361.9 (M+1).

[0227] Example 3

[0228]

[0229] 6-Benzyl-1-methyl-3-[(3-methylphenyl)benzyl]-1H,2H,3H,4H,5H,6H,7H,8H-pyrido[4,3-d]pyrimidine-2,4-dione (3)

[0230] 3.1 Synthesis of compound 3

[0231]

[0232] 6-Benzyl-3-[(3-methylphenyl)benzyl]-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (3A, 200 mg) was dissolved in DMF (2 mL), and potassium carbonate (150 mg) and iodomethane (120 mg) were added. The mixture was heated and stirred at 100°C for 12 hours. After the reaction was completed, the temperature was lowered, water was added, and the solution was extracted with ethyl acetate (5 ml×3). The combined extracts were washed 3 times with brine. The product (3) (25 mg, yield 12%) was obtained by preparative chromatography. 1 HNMR(400MHz,CD3OD)δ2.14(s,3H),2.55-2.61(m,4H),3.16(s,2H),3.20(s,3H),3.56(s,2H), 4.92 (s, 2H), 6.88-6.91 (m, 1H), 6.99-7.02 (m, 3H), 7.15-7.25 (m, 5H); LC-MS: m / z=375.9 (M+1).

[0233] Example 4

[0234]

[0235] 6-Benzyl-1-isopropyl-3-(3-methylbenzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (4)

[0236] Compound 4 was prepared by referring to Example 3, except that 2-iodopropane was used instead of methyl iodide. Yield: 20%; 1 HNMR (400MHz, CD3OD) δ1.18(t,J=5.2Hz,6H),2.2(s,3H),2.55(t,J=5.2Hz,2H),2.65(t,J=5.6Hz,2H),3.29(s, 2H), 3.63 (s, 2H), 5.01 (s, 2H), 5.19-5.23 (m, 1H), 6.97-7.09 (m, 4H), 7.17-7.31 (m, 5H); LC-MS: m / z=403.9 (M).

[0237] Example 5

[0238]

[0239] 6-Benzyl-3-(4-chlorobenzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (5)

[0240] Compound 5 was prepared by referring to Example 2, except that 4-chlorobenzyl isocyanate (purity 97%) was used instead of 3-methylbenzyl isocyanate. Yield 25%; 1 HNMR (400MHz, CD3OD) δ2.53(t,J=5.2Hz,2H),2.73(t,J=5.6Hz,2H),3.3(s,2H),3.71(s,2H),5.03(s,2H),7.24-7.36(m,9H); LC-MS: m / z=382.0(M+1).

[0241] Example 6

[0242]

[0243] 6-Benzyl-3-(4-chlorobenzyl)-1-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (6)

[0244] Compound 6 was prepared by referring to Example 2 and Example 3, except that 4-chlorobenzyl isocyanate (purity 97%) was used instead of 3-methylbenzyl isocyanate, and the yield was 30%; 1 HNMR (400MHz, CD3OD) δ2.67-2.71(m,4H),3.27(s,2H),3.32(s,3H),3.67(s,2H),5.03(s,2H),7.23-7.36(m,9H); LC-MS: m / z=395.8(M+1).

[0245] Example 7

[0246]

[0247] 6-Benzyl-3-(4-chlorobenzyl)-1-isopropyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (7)

[0248] Compound 7 was prepared with reference to Example 2 and Example 3. It is worth noting that the difference is that 4-chlorobenzyl isocyanate (purity 97%) was used instead of 3-methylbenzyl isocyanate, and 2-iodopropane was used instead of methyl iodide. Yield 25%; 1HNMR (400MHz, CD3OD) δ1.29-1.3(d,J=4Hz,6H),2.66(t,J=5.6Hz,2H),2.77(t,J=5.6Hz,2H),3.37 (s,2H),3.74(s,2H),5.13(s,2H),5.29-5.35(m,1H),7.27-7.41(m,9H); LC-MS: m / z=423.8(M+1).

[0249] Example 8

[0250]

[0251] 3-(4-(Trifluoromethyl)benzyl)-6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (8)

[0252] Compound 8 was prepared in the same manner as in Example 2, except that 1-isocyanatomethyl-4-trifluoromethylbenzylbenzene was used instead of 3-methylbenzyl isocyanate, with a yield of 35%; 1 HNMR(400MHz, DMSO_d6)δ2.49(t,J=4.8Hz,2H),2.65(t,J=5.2Hz,2H),3.07(s,2H),3.63(s,2H),5.01( s, 2H), 7.27-7.35 (m, 5H), 7.44-7.46 (d, J = 8Hz, 2H), 7.65-7.67 (d, J = 8Hz, 2H); LC-MS: m / z = 416.0 (M+1).

[0253] Example 9

[0254]

[0255] 3-(4-(Trifluoromethyl)benzyl)-6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (9)

[0256] Compound 9 was prepared in the same manner as Example 3 (especially starting from Example 8) with a yield of 30%; 1 HNMR(400MHz,CD3OD)δ2.69-2.73(m,4H),3.27(s,2H),3.33(s,3H),3.68(s,2H ), 5.13 (s, 2H), 7.29-7.35 (m, 5H), 7.47-7.56 (m, 4H); LC-MS: m / z=429.8 (M+1).

[0257] Example 10

[0258]

[0259] 3-(4-(Trifluoromethyl)benzyl)-6-benzyl-5,6,7,8-tetrahydro-1-isopropylpyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (10)

[0260] Compound 10 was prepared in the same manner as in Examples 2 and 3. In particular, 2-iodopropane was used instead of iodomethane. Yield 20%; 1 HNMR(400MHz,CD3OD)δ1.14-1.16(d,J=8Hz,6H),2.55(t,J=5.6Hz,2H),2.66(t,J=5.6Hz,2H),3.26(s,2H),3.62(s,2H),5.1 1 (s, 2H), 5.18-5.21 (m, 1H), 7.17-7.29 (m, 5H), 7.33-7.35 (d, J = 8Hz, 2H), 7.49-7.51 (d, J = 8Hz, 2H); LC-MS: m / z = 457.8 (M+1).

[0261] Example 11

[0262]

[0263] 3-(4-(Trifluoromethyl)benzyl)-6-benzyl-1-ethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (11)

[0264] Compound 11 was prepared by a similar method as shown in Examples 2 and 3. In particular, iodomethane was used instead of iodoethane. Yield 25%; 1 HNMR(400MHz, CDCl3)δ1.23-1.26(m,3H),2.65-2.7(m,4H),3.37(s,2H),3.68(s,2H),3.82 -3.87(m,2H),5.15(s,2H),7.26-7.33(m,5H),7.47-7.56(m,4H); LC-MS: m / z=444.2(M+1).

[0265] Example 12

[0266]

[0267] 6-Benzyl-3-(4-chlorobenzyl)-1-ethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (12)

[0268] Compound 12 was prepared by referring to the method shown in Example 2 and Example 3, except that iodomethane was replaced by iodoethane. Yield: 25%; 1 HNMR (400MHz, CDCl3) δ1.23 (t, J = 6.8H, 3H), 2.62-2.7 (m, 4H), 3.36 (s, 2H), 3.67 (s, 2H), 3.82- 3.87 (m, 2H), 5.06 (s, 2H), 7.22-7.32 (m, 7H), 7.39-7.41 (d, J = 8Hz, 2H) LC-MS: m / z = 410.1 (M+1).

[0269] Example 13

[0270]

[0271] 3-(4-Chloromethyl)-6-benzyl-1-ethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (13)

[0272] Compound 13 was prepared by a similar method as given in Examples 2 and 3 with a yield of 25%; 1 HNMR (400MHz, CDCl3) δ2.61-2.62(d,J=4Hz,2H),2.7(t,J=4.2Hz,2H),3.35(s,3H),3.38(s,2H),3.68(s,2H),5.15(s,2H),7. 26-7.33 (m, 5H), 7.39 (t, J = 8Hz, 1H), 7.48-7.5 (d, J = 8Hz, 1H), 7.62-7.64 (d, J = 8Hz, 1H), 7.71 (s, 1H); LC-MS: m / z = 430.1 (M+1).

[0273] Example 14

[0274]

[0275] 3-(3-(Trifluoromethyl)benzyl)-6-benzyl-1-ethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (14)

[0276] Compound 14 was prepared as described in Examples 2 and 3. In particular, ethyl iodide was used instead of methyl iodide. Yield 25%; 1HNMR (400MHz, CDCl3) δ1.24(t,J=7.2H,3H),2.64-2.71(m,4H),3.38(s,2H),3.68(s,2H),3.84-3.89(m,2H),5.15(s,2H),7.2 6-7.33 (m, 5H), 7.39 (t, J = 8Hz, 1H), 7.48-7.50 (d, J = 8Hz, 1H), 7.63-7.65 (d, J = 8Hz, 1H), 7.72 (s, 1H); LC-MS: m / z = 444.2 (M+1).

[0277] Example 15

[0278]

[0279] 3-(3-Chlorobenzyl)-6-benzyl-5,6,7,8-tetrahydro-1-methylpyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (15)

[0280] Compound 15 was prepared by a similar method as given in Examples 2 and 3 with a yield of 25%; 1 HNMR(400MHz, CDCl3)δ2.68-2.75(m,4H),3.38(s,3H),3.42(s,3H),3.71(s,2H),5.26( s, 2H), 6.98-7.0 (m, 1H), 7.14-7.16 (m, 2H), 7.28-7.36 (m, 6H); LC-MS: m / z=396.2 (M+1).

[0281] Example 16

[0282]

[0283] 6-Benzyl-3-[(3-chlorophenyl)methyl]-1-ethyl-1H,2H,3H,4H,5H,6H,7H,8H-pyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (16)

[0284] Compound 16 was prepared by a similar method as shown in Examples 2 and 3 with a yield of 25%; 1 HNMR (400MHz, CDCl3) δ1.26 (t, J = 7.2H, 3H), 2.71-2.75 (m, 4H), 3.41 (s, 2H), 3.71 (s, 2H), 3.87-3.89 ( m, 2H), 5.26 (s, 2H), 6.97-6.99 (m, 1H), 7.14-7.16 (m, 2H), 7.27-7.36 (m, 6H); LC-MS: m / z=410.1 (M+1).

[0285] Example 17

[0286]

[0287] 6-Benzyl-3-(3-bromobenzyl)-1-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (17)

[0288] Compound 17 was prepared by a similar method as shown in Examples 2 and 3 with a yield of 30%; 1 HNMR (400MHz, CDCl3) δ2.62-2.63 (d, J = 4Hz, 2H), 2.71 (t, J = 5.2Hz, 2H), 3.34 (s, 3H), 3.38 (s, 2H), 3. 69 (s, 2H), 5.07 (s, 2H), 7.14 (t, J = 8Hz, 1H), 7.26-7.39 (m, 7H), 7.58 (s, 1H); LC-MS: m / z = 440.1 (M+1).

[0289] Example 18

[0290]

[0291] 6-(3-ethynylbenzyl)-1-methyl-3-(4-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (18)

[0292] Compound 18 was prepared by a similar method as shown in Examples 2 and 3 with a yield of 20%; 1 HNMR (400MHz, CDCl3) δ2.62-2.63(d,J=4Hz,2H),2.69(d,J=5.2Hz,2H),3.07(s,1H),3.35(s,5H),3.64(s,2H),5.15( s, 2H), 7.27-7.33 (m, 2H), 7.39-7.41 (d, J = 8Hz, 1H), 7.48 (s, 1H), 7.52-7.54 (d, J = 8Hz, 4H); LC-MS: m / z = 454.1 (M+1).

[0293] Example 19

[0294]

[0295] 6-(3-ethynylbenzyl)-1-methyl-3-(2-methylbenzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (19)

[0296] Compound 19 was prepared by a similar method as shown in Examples 2 and 3 with a yield of 20%; 1 HNMR (400MHz, CDCl3) δ2.44(s,3H),2.62-2.63(d,J=4Hz,2H),2.69(d,J=5.2Hz,2H),3.07(s,1H),3.34(s,3H),3.38(s,2H),3.65(s,2H),5. 13 (s, 2H), 7.01-7.02 (d, J = 4Hz, 1H), 7.08-7.12 (m, 3H), 7.26-7.32 (m, 2H), 7.39-7.41 (d, J = 8Hz, 1H), 7.48 (s, 1H); LC-MS: m / z = 400.1 (M+1).

[0297] Example 20

[0298]

[0299] 6-(3-ethynylbenzyl)-1-methyl-3-(3-methylbenzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (20)

[0300] Compound 20 was prepared by a similar method as shown in Examples 2 and 3 with a yield of 20%; 1 HNMR(400MHz, CDCl3)δ2.31(s,3H),2.62(s,2H),2.7(s,2H),3.07(s,1H),3.35(s,3H),3.38(s,2H),3.67(s,2H),5.09(s,2H), 7.04-7.06 (d, J=8Hz, 1H), 7.15-7.19 (m, 1H), 7.26-7.35 (m, 4H), 7.4-7.42 (d, J=8Hz, 1H), 7.48 (s, 1H); LC-MS: m / z=400.1 (M+1).

[0301] Example 21

[0302]

[0303] 3-(4-Chlorobenzyl)-6-(3-ethynylbenzyl)-1-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (21)

[0304] Compound 21 was prepared by a similar method as shown in Examples 2 and 3 with a yield of 20%; 1HNMR(400MHz, CDCl3)δ2.62(s,2H),2.7(s,2H),3.07(s,1H),3.35(s,5H),3.66(s,2H),5.08 (s, 2H), 7.23-7.32 (m, 4H), 7.39-7.41 (d, J = 8Hz, 3H), 7.48 (s, 1H); LC-MS: m / z = 420.1 (M+1).

[0305] Example 22

[0306]

[0307] 6-(3-Chlorobenzyl)-1-methyl-3-(4-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (22)

[0308] Compound 22 was prepared by a similar method as shown in Examples 2 and 3. Yield 20%; 1 HNMR(400MHz, CDCl3)δ2.63-2.64(d,J=4Hz,2H),2.71(t,J=5.2Hz,2H),3.36(s,5H),3.65(s, 2H), 5.16 (s, 2H), 7.19-7.26 (m, 3H), 7.35 (s, 1H), 7.52-7.57 (m, 4H); LC-MS: m / z=464.1 (M+1).

[0309] Example 23

[0310]

[0311] 3-(Benzo[d][1,3]dioxol-5-ylmethyl)-6-benzyl-1-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (23)

[0312] Compound 23 was prepared by a similar method as shown in Examples 2 and 3 with a yield of 30%; 1 HNMR (400MHz, CDCl3) δ2.58-2.59 (d, J = 4Hz, 2H), 2.68 (t, J = 5.2Hz, 2H), 3.33 (s, 3H), 3.36 (s, 2H), 3.67 (s, 2H), 5. 02 (s, 2H), 5.88 (s, 2H), 6.69-6.71 (d, J = 8Hz, 1H), 6.95-6.98 (m, 2H), 7.27-7.32 (m, 5H); LC-MS: m / z = 406.1 (M+1).

[0313] Example 24

[0314]

[0315] 3-((3-(4-bromobenzyl)-1-methyl-2,4-dioxo-1,2,3,4,7,8-hexahydropyrido[4,3-d]pyrimidin-6(5H)-yl)methyl)benzonitrile (24)

[0316] Compound 24 was prepared by a similar method as shown in Examples 2 and 3 with a yield of 25%; 1 HNMR (400MHz, CDCl3) δ2.64-2.65(d,J=4Hz,2H),2.72(t,J=5.2Hz,2H),3.33(s,2H),3.37(s,3H),3.7( s, 2H), 5.06 (s, 2H), 7.34-7.45 (m, 5H), 7.56-7.58 (d, J = 8Hz, 2H), 7.66 (s, 1H); LC-MS: m / z = 465.1 (M+1).

[0317] Example 25

[0318]

[0319] 3-((3-(4-Chlorobenzyl)-1-methyl-2,4-dioxo-1,2,3,4,7,8-hexahydropyrido[4,3-d]pyrimidin-6(5H)-yl)methyl)benzonitrile (25)

[0320] Compound 25 was prepared by a similar method as shown in Examples 2 and 3 with a yield of 20%; 1 HNMR(400MHz, CDCl3)δ2.65(s,2H),2.73(s,2H),3.34(s,2H),3.37(s,3H),3.71(s,2H),5.08(s,2H), 7.26 (t, J=8Hz, 2H), 7.4-7.46 (m, 3H), 7.57-7.59 (d, J=8Hz, 2H), 7.67 (s, 1H); LC-MS: m / z=421.1 (M+1).

[0321] Example 26

[0322]

[0323] 3-((1-methyl-2,4-dioxo-3-(4-(trifluoromethyl)benzyl)-1,2,3,4,7,8-hexahydropyrido[4,3-d]pyrimidin-6(5H)-yl)methyl)benzonitrile (26)

[0324] Compound 26 was prepared by a similar method as shown in Examples 2 and 3 with a yield of 20%; 1 HNMR (400MHz, CDCl3) δ2.66-2.67 (d, J = 4Hz, 2H), 2.73 (t, J = 5.2Hz, 2H), 3.34 (s, 2H), 3.38 (s, 3H), 3. 71 (s, 2H), 5.16 (s, 2H), 7.43 (t, J = 8Hz, 1H), 7.52-7.58 (m, 6H), 7.67 (s, 1H); LC-MS: m / z = 455.1 (M+1).

[0325] Example 27

[0326]

[0327] 3-((1-ethyl-2,4-dioxo-3-(4-(trifluoromethyl)benzyl)-1,2,3,4,7,8-hexahydropyrido[4,3-d]pyrimidin-6(5H)-yl)methyl)benzonitrile (27)

[0328] Compound 27 was prepared by a similar method as shown in Examples 2 and 3. In particular, iodoethane was used instead of iodomethyl, with a yield of 15%; 1 HNMR(400MHz, CDCl3)δ1.27(t,J=5.6Hz,3H),2.68-2.74(m,4H),3.34(s,2H),3.7(s,2H),3.86-3.9 1(m,2H),5.16(s,2H),7.44(t,J=8Hz,1H),7.52-7.58(m,6H),7.67(s,1H); LC-MS: m / z=469.1(M+1).

[0329] Example 28

[0330]

[0331] 3-((3-(4-Chlorobenzyl)-1-ethyl-2,4-dioxo-1,2,3,4,7,8-hexahydropyrido[4,3-d]pyrimidin-6(5H)-yl)methyl)benzonitrile (28)

[0332] Compound 28 was prepared by a similar method as shown in Examples 2 and 3. In particular, iodoethane was used instead of iodomethyl, with a yield of 20%; 1HNMR(400MHz, CDCl3)δ1.26(t,J=7.2Hz,3H),2.67-2.73(m,4H),3.33(s,2H),3.7(s,2H),3.85-3.9(m,2H),5.07( s, 2H), 7.25 (t, J = 8.4Hz, 2H), 7.39-7.45 (m, 3H), 7.56-7.58 (d, J = 8Hz, 2H), 7.67 (s, 1H); LC-MS: m / z = 435.2 (M+1).

[0333] Example 29

[0334]

[0335] 1-Methyl-6-(3-methylbenzyl)-3-(4-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (29)

[0336] Compound 29 was prepared by a similar method as shown in Examples 2 and 3 with a yield of 25%; 1 HNMR(400MHz,CD3OD)δ2.68-2.72(m,4H),3.27(s,2H),3.33(s,3H),3.68(s,2H ), 5.16 (s, 2H), 7.29-7.35 (m, 5H), 7.47-7.56 (m, 4H); LC–MS: m / z=444.2 (M+1).

[0337] Example 30

[0338]

[0339] 6-[(3-Chlorophenyl)methyl]-1-methyl-3-{[4-(trifluoromethyl)phenyl]methyl}-1H,2H,3H,4H,5H,6H,7H,8H-pyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (30)

[0340] Compound 29 was prepared by a similar method as shown in Examples 2 and 3 with a yield of 23%; LC-MS: m / z=464.1 (M+1).

[0341] Bioanalysis and data

[0342] The compounds of the present invention can be tested on human cancer cell lines.

[0343] Cancer cell line HCT116 (human colon cancer) or MDA-MB-231 strain (MDA231, human breast cancer) is distributed in 100ul cell suspension in 96-well plates. Plates are cultivated in a humidified incubator (37°C, 5% CO2) for 24 hours. The compounds of the present invention at appropriate test concentrations are added to the culture medium. Plates are incubated for 48 hours. CCK-8 (10 μl, see below) is added to each well. Plates are incubated for 1-4 hours under the conditions described above, and the absorbance at 450nm and 650nm is measured with a plate reader.

[0344] Cell Counting Kit-8 (CCK-8) allows for sensitive colorimetric determination of: the number of viable cells in cell proliferation and cytotoxicity assays. Cell counting by CCK-8 uses WST-8 (2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt), which produces a water-soluble formazan dye when bioreduced in the presence of the electron carrier 1-methoxy PMS. CCK-8 solution is added directly to cells. WST-8 is bioreduced by cellular dehydrogenases to an orange formazan product that is soluble in tissue culture medium. The amount of formazan produced is proportional to the number of viable cells.

[0345] The biological activities of selected examples against human cancer cells are provided in Table 1. 2,6 Compared with 13-1(9),5-diene-8-one, the compounds of the present invention unexpectedly and significantly improved their potency against human cancer cell lines.

[0346] Table 1. Bioactivity data of selected similar compounds against human cancer cell lines

[0347]

[0348]

[0349] In a similar manner to the studies on the above human cancer cell lines (HCT116 and MDA231), the compounds of the present invention were studied on the human cancer cell line SUM159 (SUM159 is derived from a primary human anaplastic breast cancer cell line and is a basal breast cancer cell line).

[0350] In Table 2 and Figure 1The biological activity of selected examples on human cancer cells is provided in . Experimental procedures with a human cancer cell line (SUM159) were similar to those described above for HCT116, where significant changes persisted for 72 hours when the compounds were incubated with the cells. 2,6 ] Compared with trideca-1(9),5-diene-8-one), the present invention shows that Example 25 and Example 26 of the compounds of the present invention unexpectedly and significantly improved the efficacy against human cancer cell lines.

[0351] Table 2. Bioactivity data of selected similar compounds against human cancer cell line (SUM159)

[0352]

[0353]

[0354] All publications and patent applications cited in this specification are incorporated herein by reference in their entirety. Although the above invention has been described in detail by way of illustration and example, it will be apparent to those skilled in the art that certain changes and modifications may be made thereto, based on the teachings of the present invention, without departing from the spirit or scope of the appended claims.

Claims

1. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof: in: Q is M1; V is V1: W is -C(R 12 R 13 )-; Y is oxygen; R1 is independently selected from hydrogen, fluorine and chlorine; R2 is independently selected from chlorine, bromine and -CF3; R3 is hydrogen; R 20 Yes-CN; R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 16 , R 17 , R 18 , R 19 , R 21 , R 22 At the same time, hydrogen R 12 and R 13 each independently is hydrogen; R 15 Independently selected from the group consisting of methyl and ethyl.

2. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is:

3. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is:

4. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating colon cancer or breast cancer in a subject, the treatment comprising administering an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.

5. Use of the compound of claim 2 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating colon cancer or breast cancer in a subject, the treatment comprising administering an effective amount of the compound of claim 2 or a pharmaceutically acceptable salt thereof.

6. Use of the compound of claim 3 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating colon cancer or breast cancer in a subject, the treatment comprising administering an effective amount of the compound of claim 3 or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

8. A pharmaceutical composition comprising the compound according to claim 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

9. A pharmaceutical composition comprising the compound according to claim 3 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

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