2,3-Dihydroquinazoline compounds as Nav1.8 inhibitors

Abstract

The present invention relates to a method for producing a compound of formula (X): v 1.8 inhibitors 2,3-dihydroquinazoline compounds TIFF2022538588000552.tif40132(in the formula, Y', X', B', R1', R 2’ , R 3’ , R 5’ , R 6’ , R 7’ , and z 1 is as defined herein); or a pharmaceutically acceptable salt or tautomeric form thereof, the corresponding pharmaceutical composition or formulation, methods or processes for the preparation of the compounds, methods for use in the treatment of, compounds and / or pain related or associated diseases, disorders or conditions, respectively, and / or combination therapies for treating.

Description

Technical Field

[0001] The present invention relates to a Na inhibitor of formula (X), 2,3-dihydroquinazoline compound or a pharmaceutically acceptable salt or tautomeric form thereof, a corresponding pharmaceutical composition or formulation, a method or process for the preparation of the compound, a method for the treatment of each of pain-related or associated diseases, disorders or conditions, a compound for use in therapy, use in therapy and / or combination therapy. v 1.8

Background Art

[0002] Pain is a protective mechanism by which animals avoid potential tissue damage, but there are many disease symptoms in which pain persists and loses its usefulness, becoming an ineffective burden. Symptoms in which pain persists and loses its usefulness can be broadly classified into those triggered by nerve injury or damage (neuropathic pain), those in which an inflammatory response or metabolic dysregulation sensitizes the pain response (inflammatory pain), and those in which injury or surgery causes a short-term increase in the pain response (postoperative / injury pain).

[0003] Voltage-gated sodium channels underlie the transmission of electrical signals in all excitable tissues by setting the threshold and underlying the rise of the action potential. There are nine different isoforms of voltage-gated sodium channels. Na v 1.1, Na v 1.7, Na v 1.8 and Na v 1.9 are mainly expressed in the peripheral nerves where they control neuronal excitability. Na v 1.5 is the major sodium channel isoform expressed in cardiomyocytes, Na v 1.4 is expressed and functions in skeletal muscle, and Na v 1.1, Na v 1.2, Na v 1.3 and Na v1.6 is widely expressed in the central nervous system (CNS) and to some extent in the peripheral nervous system. The major role of these nine voltage-gated sodium channels is the same in that they control sodium influx into cells, but their biophysical properties are different and have a great impact on the physiological properties of their individual cell types (Catterall, 2012).

[0004] Currently, non-selective sodium channel inhibitors are in clinical use as anti-arrhythmic and anti-seizure therapies, including lidocaine, carbamazepine, amitriptyline, and mexiletine. However, because these agents show a lack of selectivity between different sodium channel isoforms, their therapeutic usefulness is greatly reduced, mostly due to adverse side effects mediated by their activity in the CNS and heart. This has prompted efforts to develop new pharmaceuticals that are selective for specific sodium channel isoforms to avoid side effects in the CNS and cardiovascular system.

[0005] Na v The Na1.8 channel is expressed in neurons of the dorsal root ganglion (DRG) and is highly expressed in the small-diameter neurons of this tissue that form pain-sensing C-fibers and Aδ-fibers (Abrahamsen, 2008; Amaya, 2000; Novakovic, 1998). Soon after this channel was first cloned from rat DRG (Akopian, 1996), it was proposed as a therapeutic target for analgesia because of its prominent physiological role and restricted expression profile in this tissue type. v Na1.8 was subsequently identified, cloned, and characterized from human DRG tissue (Rabart 1998). v The closest related molecule to Na1.8 is Na1.5, which has approximately 60% sequence homology. v Na1.5. v1.8 has been previously known as SNS (sensory neuron sodium channel), PN3 (type 3 peripheral nerve sodium channel), and is also described as a TTX-resistant sodium channel because it exhibits pharmacological properties characteristic of its resistance to blockade by tetrodotoxin.

[0006] Na as a therapeutic target for pain adaptation v The evidence for 1.8 is obtained from several sources. Na v 1.8 is shown to conduct most of the current during the rising phase of the action potential in DRG neurons (Blair & Bean, 2002), and is also important for the ability of these neurons to fire repetitively because of its repriming rate (Blair and Bean, 2003). Na v 1.8 has been reported to have increased expression and function in response to noxious stimuli such as inflammatory mediators (England 1996 & Gold 1996), nerve injury (Roza 2003 & Ruangsri 2011), and within nociceptive neuromas (Black 2008 & Coward 2000). In mice, knockout of the gene encoding Nav1.8 results in a reduction of the pain phenotype, particularly in response to inflammatory stimuli (Akopian 1999). Na v Knockdown of the mRNA encoding 1.8 also results in a reduction of the nociceptive phenotype, particularly in neuropathic models of rodent models (Lai 2002). Pharmacological intervention with selective small molecule inhibitors has been demonstrated to be effective in rodent models of inflammatory pain as well as neuropathic pain (Jarvis 2007 & Payne 2015). Na v Genetic evidence for 1.8 is also present in patients with chronic neuropathic pain (Faber 2012, Han 2014 & Eijkenboom 2018) where gain-of-function mutations have been reported to cause recurrent painful neuropathy and small fiber neuropathy.

[0007] Therefore, the novel compounds of the present invention having novel mechanisms of action and pharmacological activities, particularly, Na vThere is a need for the development of 1.8 inhibitor compounds, or pharma- ceutically acceptable salts thereof.

[0008] In view of the above, it is necessary to develop: ·Na v 1.8 Novel compounds of the present invention, or pharma- ceutically acceptable salts and / or their corresponding tautomeric forms or their corresponding pharmaceutical compositions, which exhibit pharmacological activity as inhibitors; In subjects, Na v 1.8 Methods for inhibiting voltage-gated sodium channels; Each of the following methods, compounds for use and / or uses: Treating a pain-related disease, disorder or condition, including, but not limited to, pain caused by various diseases (as defined herein); pain caused by trauma; or pain caused by iatrogenic (i.e., medical or dental) procedures; or alleviating or reducing the severity of a pain-related disease, disorder or condition as described herein; and / or Related combination therapies for treating pain caused by a pain-related disease, disorder or condition, trauma; or iatrogenic, medical or dental procedure.

[0009] The present invention is directed to overcoming these and other problems faced in the art. Summary of the Invention

[0010] Generally, the present invention provides a Na v 1.8 Inhibitors 2,3-dihydroquinazoline compounds or pharma- ceutically acceptable salts or tautomeric forms thereof, corresponding pharmaceutical compositions or formulations, methods or processes for the preparation of the compounds, methods for the treatment, compounds for use in the treatment, uses to treat and / or combination therapies of pain-related or associated diseases, disorders or conditions, respectively.

[0011] In particular, the present invention relates to any of the formulas disclosed herein including formula (X) and each of formulas (I) to (III), a novel Na v 1.8 inhibitor 2,3-dihydroquinazoline compound, or a pharmaceutically acceptable salt and / or its corresponding tautomeric form (i.e., including the partial formula as defined above), and its corresponding pharmaceutical composition or formulation.

[0012] The present invention also relates to a process for preparing a compound of any of the formulas disclosed herein, including formula (X) and formulas (I) to (III) (i.e., including the corresponding partial general formulas defined herein), or a pharmaceutically acceptable salt and / or its corresponding tautomeric form, or its corresponding pharmaceutical composition.

[0013] The present invention also relates to a method for treating pain caused by various diseases, pain-related diseases, disorders or conditions such as pain caused by trauma; or pain caused by iatrogenic (i.e., medical or dental) procedures, a compound for use in treatment, use for treatment and / or combination therapy. Detailed description of the invention

[0014] The present invention relates to a Na v 1.8 inhibitor 2,3-dihydroquinazoline compound or a pharmaceutically acceptable salt or tautomeric form thereof, the corresponding pharmaceutical composition or formulation, a method or process for preparing the compound, a method for treating each of pain and / or pain-related or associated diseases, disorders or conditions, a compound for use in treatment, use for treatment and / or combination therapy.

[0015] Compound In particular, the present invention relates to a novel Na of any of the formulas disclosed herein including formula (X) and formulas (I) to (III) (i.e., including the partial general formulas as defined herein). v1.8 relates to an inhibitor 2,3-dihydroquinazoline compound, or a pharmaceutically acceptable salt and / or its corresponding tautomeric form thereof.

[0016] In other embodiments, various embodiments of the invention as defined herein can be adapted for use with compounds of the formula as defined above herein, and are understood to include those compounds.

[0017] In one embodiment, the invention is of formula (X):

Chemical formula

[0018] Regarding the compound of formula (X), preferably, Y' is CH2.

[0019] Regarding the compound of formula (X), preferably, Y' is C=O.

[0020] Regarding the compound of formula (X), preferably, Y' is C=S.

[0021] Regarding the compound of formula (X), preferably, when Y' is C=O, R 6’ is hydrogen.

[0022] Regarding the compound of formula (X), preferably, X' is N.

[0023] Regarding the compound of formula (X), preferably, X is C-H.

[0024] Regarding the compound of formula (X), preferably, X' is C-CH3.

[0025] Regarding the compound of formula (X), preferably, X' is C-F.

[0026] Regarding the compound of formula (X), preferably, X' is C-Cl.

[0027] Regarding the compound of formula (X), preferably, X' is C-Br.

[0028] Regarding the compound of formula (X), preferably, R 1’ 、R 2’ and R 3’ are independently selected from hydrogen, fluoro, chloro, bromo, -CH3, -CF3, -CHF2, -OCH3, -OCH2CF3, -OCHF2, -OCF3, -CF2CH2OH, -N(CH3)2, -NHCH3, -C≡N, -OH, -S(O)2CH3, cyclopropyl, and oxetanyl.

[0029] Regarding the compound of formula (X), preferably, R 1’ 、R 2’ and R 3’ are independently selected from hydrogen, fluoro, chloro, bromo, -C≡N, -CH3, -CF3, -CHF2, -OCH3, -OCH2CF3, -OCHF2, -OCF3, and -CF2CH2OH.

[0030] Regarding the compound of formula (X), preferably, R 5’ is phenyl, cyclopentyl, cyclohexyl,

Chemical formula

[0031] Regarding the compound of formula (X), preferably, R 5’ is phenyl, where phenyl is -C≡N, -NR a R b , halogen, oxo, -C(O)NHR a , -C(O)NR a R b , linear or branched -(C 1-6 )-alkyl, -OR c , and (C 3-6 ) cycloalkyl may be optionally substituted with 1 to 4 substituents independently selected therefrom, wherein the linear or branched -(C 1-6 )-alkyl, when present, the alkyl chain of -OR c , and (C 3-6 )-cycloalkyl are halogen, oxo, -OH, -NH2, -NH C 1-4 alkyl, -N(C 1-4 alkyl)2, -OC 1-4 alkyl, and fluoro, oxo, -OH, -NH2, -NH C 1-4 alkyl, -N(C 1-4 alkyl)2, -OC 1-3 alkyl, and -OC 1-3 alkyl substituted with 1 to 6 substituents independently selected from fluoro, oxo, -OH, -NH2, -NH C 1-4 alkyl, and -OC

[0032] Regarding the compound of formula (X), preferably, R 5’ is phenyl, where R5’ is substituted with one or two substituents independently selected from fluoro, chloro, bromo, -CH3, -CH2CH3, -CH2CF3, -CH(CH3)2, -C(CH3)3, -CF3, -CF2CH2OH, -C(O)NH2, -OCH3, -OCH2CH3, -OCHF2, -OCF3, and -OCH2CH2OH.

[0033] Regarding the compound of formula (X), preferably, R 6’ is hydrogen, oxo or -CH3.

[0034] Regarding the compound of formula (X), preferably, R 6’ is hydrogen.

[0035] Regarding the compound of formula (X), preferably, B ’ is selected from pyridinyl, pyrimidinyl, phenyl, pyridazinyl, tetrahydrothiophenyl, pyrazolyl, piperidinyl, tetrahydrothiopyranyl, dihydropyrimidinyl, tetrahydropyridinyl, pyrazinyl, furanyl and hexahydropyrimidinyl.

[0036] Regarding the compound of formula (X), preferably, B ’ is pyridinyl.

[0037] Regarding the compound of formula (X), preferably, B’ is

Chemical formula

[0038] Regarding the compound of formula (X), preferably, each R 7’ is fluoro, chloro, bromo, -CH3, -CH2CH3, -CH2CF3, -CH(CH3)2, -C(CH3)3, -CF3, -CF2CH2OH, -C(O)NH2, -OCH3, -NH2, -OCH2CH3, -OCHF2, -OCF3, -OCH2CH2OH, -N(C 1-4 alkyl)2, -NH(C 1-4It is independently selected from alkyl, -C≡N, -OH, oxo, -C(O)OH, -C(O)CH3, -OCH2C(O)OH, -NC(O)CH3, -NHCH2CH2OH, -S(O)2CH3, -S(O)2NH2, and cyclopropyl.

[0039] Regarding the compound of formula (X), preferably, each R 7’ is independently selected from fluoro, chloro, -CH3, -CH2CH3, -CH2CF3, -CH(CH3)2, -C(CH3)3, -CF3, -CF2CH2OH, -C(O)NH2, -OCH3, -OCH2CH3, -OCHF2, -OCF3, oxo, -C(O)OH, -C(O)CH3, and -OCH2C(O)OH.

[0040] Regarding the compound of formula (X), preferably, each R 7’ is independently selected from -CH3 and oxo.

[0041] Regarding the compound of formula (X), preferably, Z 1’ is an integer from 1 to 4, preferably an integer from 1 to 3, preferably an integer selected from 1 and 2.

[0042] In one aspect, the present invention provides a compound of formula (XI):

Chemical formula

[0043] For the compound of formula (XI), preferably, Y 1’ is CH2.

[0044] For the compound of formula (XI), preferably, Y 1’ is C=O.

[0045] For the compound of formula (XI), preferably, Y 1’ is C=S.

[0046] For the compound of formula (XI), preferably, when Y 1’ is C=O, R 16’ is hydrogen.

[0047] For the compound of formula (XI), preferably, X 1’ is N.

[0048] For the compound of formula (XI), preferably, X 1’ is C-H.

[0049] For the compound of formula (XI), preferably, X 1’ is C-CH3.

[0050] For the compound of formula (XI), preferably, X 1’ is C-F.

[0051] Regarding the compound of formula (XI), preferably, X 1’ is C-Cl.

[0052] Regarding the compound of formula (XI), preferably, X 1’ is C-Br.

[0053] Regarding the compound of formula (XI), preferably, R 11’ , R 12’ and R 13’ are independently selected from hydrogen, fluoro, chloro, bromo, -CH3, -CF3, -CHF2, -OCH3, -OCH2CF3, -OCHF2, -OCF3, -CF2CH2OH, -N(CH3)2, -NHCH3, -C≡N, -OH, -S(O)2CH3, cyclopropyl, and oxetanyl.

[0054] Regarding the compound of formula (XI), preferably, R 11’ , R 12’ and R 13’ are independently selected from hydrogen, fluoro, chloro, bromo, -C≡N, -CH3, -CF3, -CHF2, -OCH3, -OCH2CF3, -OCHF2, -OCF3, and -CF2CH2OH.

[0055] Regarding the compound of formula (XI), preferably, R 15’ is phenyl, cyclopentyl, cyclohexyl,

Chemical formula

[0056] Regarding the compound of formula (XI), preferably, R 15’ is phenyl, wherein R 15’ is substituted with 1 or 2 substituents independently selected from fluoro, chloro, bromo, -CH3, -CH2CH3, -CH2CF3, -CH(CH3)2, -C(CH3)3, -CF3, -CF2CH2OH, -C(O)NH2, -OCH3, -OCH2CH3, -OCHF2, -OCF3, and -OCH2CH2OH.

[0057] Regarding the compound of formula (XI), preferably, R 16’ is hydrogen, oxo or -CH3.

[0058] Regarding the compound of formula (XI), preferably, R 16’ is hydrogen.

[0059] Regarding the compound of formula (XI), preferably, B 1’ is selected from pyridinyl, pyrimidinyl, phenyl, pyridazinyl, tetrahydrothiophenyl, pyrazolyl, piperidinyl, tetrahydrothiopyranyl, dihydropyrimidinyl, tetrahydropyridinyl, pyrazinyl, furanyl and hexahydropyrimidinyl.

[0060] Regarding the compound of formula (XI), preferably, B 1’ is pyridinyl.

[0061] Regarding the compound of formula (XI), preferably, B 1’ is [Chemical formula] is selected from.

[0062] Regarding the compound of formula (XI), preferably, each R 17’ is independently selected from fluoro, chloro, bromo, -CH3, -CH2CH3, -CH2CF3, -CH(CH3)2, -C(CH3)3, -CF3, -CF2CH2OH, -C(O)NH2, -OCH3, -NH2, -OCH2CH3, -OCHF2, -OCF3, -OCH2CH2OH, -N(C 1-4 alkyl)2, -NH(C 1-4 )alkyl, -C≡N, -OH, oxo, -C(O)OH, -C(O)CH3, -OCH2C(O)OH, -NC(O)CH3, -NHCH2CH2OH, -S(O)2CH3, -S(O)2NH2, and cyclopropyl.

[0063] Regarding the compound of formula (XI), preferably, each R 17’ is independently selected from fluoro, chloro, -CH3, -CH2CH3, -CH2CF3, -CH(CH3)2, -C(CH3)3, -CF3, -CF2CH2OH, -C(O)NH2, -OCH3, -OCH2CH3, -OCHF2, -OCF3, oxo, -C(O)OH, -C(O)CH3, and -OCH2C(O)OH.

[0064] Regarding the compound of formula (XI), preferably, each R 17’ is independently selected from -CH3 and oxo.

[0065] Regarding the compound of formula (XI), preferably, Z 11’ is an integer from 1 to 4, preferably an integer from 1 to 3, preferably an integer selected from 1 and 2.

[0066] In one aspect, the present invention relates to formula (XII): [Chemical formula] [where Y 2’is selected from CH2, C=O and C=S; X 2’ is N or C-R 24’ ; wherein R 24’ is selected from hydrogen, fluoro, chloro, bromo, and -CH3; R 21’ R 22’ and R 23’ are independently selected from hydrogen, fluoro, chloro, bromo, -CH3, -CF3, -CHF2, -OCH3, -OCH2CF3, -OCHF2, -OCF3, -CF2CH2OH, -N(CH3)2, -NHCH3, -C≡N, -OH, -S(O)2CH3, cyclopropyl, and oxetanyl; R 25’ is phenyl, cyclopentyl, cyclohexyl,

Chemical formula

[0067] Regarding the compound of formula (XII), preferably, Y 2’ is CH2.

[0068] Regarding the compound of formula (XII), preferably, Y 2’ is C=O.

[0069] Regarding the compound of formula (XII), preferably, Y 2’ is C=S.

[0070] Regarding the compound of formula (XII), preferably, when Y 2’ is C=O, R 26’ is hydrogen.

[0071] Regarding the compound of formula (XII), preferably, X 2’ is N.

[0072] Regarding the compound of formula (XII), preferably, X 2’ is C-H.

[0073] Regarding the compound of formula (XII), preferably, X 2’ is C-CH3.

[0074] Regarding the compound of formula (XII), preferably, X 2’ is C-F.

[0075] Regarding the compound of formula (XII), preferably, X 2’ is C-Cl.

[0076] Regarding the compound of formula (XII), preferably, X 2’ is C-Br.

[0077] Regarding the compound of formula (XII), preferably, R 21’ , R 22’ and R 23’ are independently selected from hydrogen, fluoro, chloro, bromo, -CH3, -CF3, -CHF2, -OCH3, -OCH2CF3, -OCHF2, -OCF3, -CF2CH2OH, -N(CH3)2, -NHCH3, -C≡N, -OH, -S(O)2CH3, cyclopropyl, and oxetanyl.

[0078] Regarding the compound of formula (XII), preferably, R 21’ , R 22’ and R 23’ are independently selected from hydrogen, fluoro, chloro, bromo, -C≡N, -CH3, -CF3, -CHF2, -OCH3, -OCH2CF3, -OCHF2, -OCF3, and -CF2CH2OH.

[0079] Regarding the compound of formula (XII), preferably, R 25’ is phenyl, cyclopentyl, cyclohexyl,

Chemical formula

[0080] Regarding the compound of formula (XII), preferably, R 25’ is phenyl, wherein R 25’ is substituted with 1 or 2 substituents independently selected from fluoro, chloro, bromo, -CH3, -CH2CH3, -CH2CF3, -CH(CH3)2, -C(CH3)3, -CF3, -CF2CH2OH, -C(O)NH2, -OCH3, -OCH2CH3, -OCHF2, -OCF3, and -OCH2CH2OH.

[0081] Regarding the compound of formula (XII), preferably, R 26’ is hydrogen, oxo or -CH3.

[0082] Regarding the compound of formula (XII), preferably, R 26’ is hydrogen.

[0083] Regarding the compound of formula (XII), preferably, B 2’ is selected from pyridinyl, pyrimidinyl, phenyl, pyridazinyl, tetrahydrothiophenyl, pyrazolyl, piperidinyl, tetrahydrothiopyranyl, dihydropyrimidinyl, tetrahydropyridinyl, pyrazinyl, furanyl and hexahydropyrimidinyl.

[0084] Regarding the compound of formula (XII), preferably, B 2’ is pyridinyl.

[0085] Regarding the compound of formula (XII), preferably, B 2’ is [Chem.] is selected from

[0086] Regarding the compound of formula (XII), preferably, each R 27’ is independently selected from fluoro, chloro, bromo, -CH3, -CH2CH3, -CH2CF3, -CH(CH3)2, -C(CH3)3, -CF3, -CF2CH2OH, -C(O)NH2, -OCH3, -NH2, -OCH2CH3, -OCHF2, -OCF3, -OCH2CH2OH, -N(C 1-4 alkyl)2, -NH(C 1-4 )alkyl, -C≡N, -OH, oxo, -C(O)OH, -C(O)CH3, -OCH2C(O)OH, -NC(O)CH3, -NHCH2CH2OH, -S(O)2CH3, -S(O)2NH2, and cyclopropyl.

[0087] Regarding the compound of formula (XII), preferably, each R 27’ is independently selected from fluoro, chloro, -CH3, -CH2CH3, -CH2CF3, -CH(CH3)2, -C(CH3)3, -CF3, -CF2CH2OH, -C(O)NH2, -OCH3, -OCH2CH3, -OCHF2, -OCF3, oxo, -C(O)OH, -C(O)CH3, and -OCH2C(O)OH.

[0088] Regarding the compound of formula (XII), preferably, each R 27’ is independently selected from -CH3 and oxo.

[0089] Regarding the compound of formula (XII), preferably, Z 21’ is an integer from 1 to 4, preferably an integer from 1 to 3, preferably an integer selected from 1 and 2.

[0090] In one aspect, the present invention relates to formula (XIII): [Chem.] [wherein, Y3’ is selected from CH2, C=O, and C=S; X 3’ is N or C-R 34’ ; wherein R 34’ is selected from hydrogen, fluoro, chloro, bromo, and -CH3; R 31’ 、R 32’ and R 33’ are independently selected from hydrogen, fluoro, chloro, bromo, -CH3, -CF3, -CHF2, -OCH3, -OCH2CF3, -OCHF2, -OCF3, -CF2CH2OH, -N(CH3)2, -NHCH3, -C≡N, -OH, -S(O)2CH3, cyclopropyl, and oxetanyl; R 35’ is phenyl, cyclopentyl, cyclohexyl,

Chemical formula

[0091] Regarding the compound of formula (XIII), preferably, Y 3’ is CH2.

[0092] Regarding the compound of formula (XIII), preferably, Y 3’ is C=O.

[0093] Regarding the compound of formula (XIII), preferably, Y 3’ is C=S.

[0094] Regarding the compound of formula (XIII), preferably, X 3’ is N.

[0095] Regarding the compound of formula (XIII), preferably, X 3’ is C-H.

[0096] Regarding the compound of formula (XIII), preferably, X 3’ is C-CH3.

[0097] Regarding the compound of formula (XIII), preferably, X 3’is C-F.

[0098] Regarding the compound of formula (XIII), preferably, X 3’ is C-Cl.

[0099] Regarding the compound of formula (XIII), preferably, X 3’ is C-Br.

[0100] Regarding the compound of formula (XIII), preferably, R 31’ , R 32’ and R 33’ are independently selected from hydrogen, fluoro, chloro, bromo, -CH3, -CF3, -CHF2, -OCH3, -OCH2CF3, -OCHF2, -OCF3, -CF2CH2OH, -N(CH3)2, -NHCH3, -C≡N, -OH, -S(O)2CH3, cyclopropyl, and oxetanyl.

[0101] Regarding the compound of formula (XIII), preferably, R 31’ , R 32’ and R 33’ are independently selected from hydrogen, fluoro, chloro, bromo, -C≡N, -CH3, -CF3, -CHF2, -OCH3, -OCH2CF3, -OCHF2, -OCF3, and -CF2CH2OH.

[0102] Regarding the compound of formula (XIII), preferably, R 31’ and R 33’ are hydrogen, and R 32’ is selected from hydrogen, fluoro, chloro, bromo, -C≡N, -CH3, -CF3, -CHF2, -OCH3, -OCH2CF3, -OCHF2, -OCF3, and -CF2CH2OH.

[0103] Regarding the compound of formula (XIII), preferably, R 35’ is phenyl, cyclopentyl, cyclohexyl,

Chemical formula

[0104] Regarding the compound of formula (XIII), preferably, R 35’ is phenyl, where R 35’ is substituted with 1 or 2 substituents independently selected from fluoro, chloro, bromo, -CH3, -CH2CH3, -CH2CF3, -CH(CH3)2, -C(CH3)3, -CF3, -CF2CH2OH, -C(O)NH2, -OCH3, -OCH2CH3, -OCHF2, -OCF3, and -OCH2CH2OH.

[0105] Regarding the compound of formula (XIII), preferably, R 35’ is phenyl, where R 35’ is substituted with 1 or 2 substituents independently selected from fluoro, -CH3, and -OCH3.

[0106] Regarding the compound of formula (XIII), preferably, R 36’ is hydrogen, oxo or -CH3.

[0107] Regarding the compound of formula (XIII), preferably, R 36’ is hydrogen.

[0108] Regarding the compound of formula (XIII), preferably, B 3’is selected from pyridinyl, pyrimidinyl, phenyl, pyridazinyl, tetrahydrothiophenyl, pyrazolyl, piperidinyl, tetrahydrothiopyranyl, dihydropyrimidinyl, tetrahydropyridinyl, pyrazinyl, furanyl and hexahydropyrimidinyl.

[0109] Regarding the compound of formula (XIII), preferably, B 3’ is pyridinyl.

[0110] Regarding the compound of formula (XIII), preferably, B 3’ is

Chemical formula

[0111] Regarding the compound of formula (XIII), preferably, each R 37’ is independently selected from fluoro, chloro, bromo, -CH3, -CH2CH3, -CH2CF3, -CH(CH3)2, -C(CH3)3, -CF3, -CF2CH2OH, -C(O)NH2, -OCH3, -NH2, -OCH2CH3, -OCHF2, -OCF3, -OCH2CH2OH, -N(C 1-4 alkyl)2, -NH(C 1-4 )alkyl, -C≡N, -OH, oxo, -C(O)OH, -C(O)CH3, -OCH2C(O)OH, -NC(O)CH3, -NHCH2CH2OH, -S(O)2CH3, -S(O)2NH2, and cyclopropyl.

[0112] Regarding the compound of formula (XIII), preferably, each R 37’ is independently selected from fluoro, chloro, -CH3, -CH2CH3, -CH2CF3, -CH(CH3)2, -C(CH3)3, -CF3, -CF2CH2OH, -C(O)NH2, -OCH3, -OCH2CH3, -OCHF2, -OCF3, oxo, -C(O)OH, -C(O)CH3, and -OCH2C(O)OH.

[0113] Regarding the compound of formula (XIII), preferably, each R37’ is independently selected from -CH3 and oxo.

[0114] Regarding the compound of formula (XIII), preferably, Z 31’ is an integer from 1 to 4, preferably an integer from 1 to 3, preferably an integer selected from 1 and 2.

[0115] In one aspect, the present invention relates to formula (XIV):

Chemical formula

Chemical formula

Chem.

[0116] Regarding the compound of formula (XIV), preferably, X 4’ is N.

[0117] Regarding the compound of formula (XIV), preferably, X 4’ is C-H.

[0118] Regarding the compound of formula (XIV), preferably, X 4’ is C-CH3.

[0119] Regarding the compound of formula (XIV), preferably, X 4’ is C-F.

[0120] Regarding the compound of formula (XIV), preferably, X 4’ is C-Cl.

[0121] Regarding the compound of formula (XIV), preferably, X 4’ is C-Br.

[0122] Regarding the compound of formula (XIV), preferably, R 41’ , R 42’ and R 43’ are independently selected from hydrogen, fluoro, chloro, bromo, -CH3, -CF3, -CHF2, -OCH3, -OCH2CF3, -OCHF2, -OCF3, -CF2CH2OH, -N(CH3)2, -NHCH3, -C≡N, -OH, -S(O)2CH3, cyclopropyl, and oxetanyl.

[0123] Regarding the compound of formula (XIV), preferably, R 41’ , R 42’ and R 43’ are independently selected from hydrogen, fluoro, chloro, bromo, -C≡N, -CH3, -CF3, -CHF2, -OCH3, -OCH2CF3, -OCHF2, -OCF3, and -CF2CH2OH.

[0124] Regarding the compound of formula (XIV), preferably, R 41’ and R 43’ are hydrogen, and R 42’ is selected from hydrogen, -CH3, fluoro, chloro, bromo, -C≡N, -CF3, -CHF2, -OCH3, -OCH2CF3, -OCHF2, -OCF3, and -CF2CH2OH.

[0125] Regarding the compound of formula (XIV), preferably, R 45’ is phenyl, cyclopentyl, cyclohexyl,

Chemical formula

[0126] Regarding the compound of formula (XIV), preferably, R 45’ is phenyl, wherein R 45’ is substituted with 1 or 2 substituents independently selected from fluoro, chloro, bromo, -CH3, -CH2CH3, -CH2CF3, -CH(CH3)2, -C(CH3)3, -CF3, -CF2CH2OH, -C(O)NH2, -OCH3, -OCH2CH3, -OCHF2, -OCF3, and -OCH2CH2OH.

[0127] Regarding the compound of formula (XIV), preferably, R 55’ is

Chemical formula

[0128] Regarding the compound of formula (XIV), preferably, R 55’ is

Chem.

[0129] In one aspect, the present invention relates to formula (I):

Chem.

Chemical formula

[0130] In another aspect, the present invention relates to formula (IA):

Chemical formula

Chemical formula

[0131] In another aspect, the present invention relates to a compound in which X is N or X is C - R 4 or a pharmaceutically acceptable salt thereof.

[0132] In another aspect, the present invention relates to X is C - R 4 and here, R4 is - hydrogen, - halogen, - C≡N, - OH, - NHR a , - NR a R b , - straight - chain or branched - (C 1-6 ) - alkyl or - straight - chain or branched - (C 1-6 ) - haloalkyl, -(CF2) n (CH2) o OH, - OR c or - S(O) p R d ; wherein R 4 is - hydrogen, - halogen, - C≡N, NR a R b , - straight - chain or branched - (C 1-6 ) - alkyl, - straight - chain or branched - (C 1-6 ) - haloalkyl or - OR c and may optionally be substituted; wherein R a , R b or R c is - hydrogen, - straight - chain or branched - (C 1-6 ) - alkyl, - straight - chain or branched - (C 1-6 ) - haloalkyl or - (C 3-6 ) - cycloalkyl; wherein R a may optionally be further substituted with - OH; R d is - hydrogen, - OH, NHR a , NR a R b , - straight - chain or branched - (C 1-6 ) - alkyl, - straight - chain or branched - (C 1-6 ) - haloalkyl or - (C 3-6 ) - cycloalkyl; wherein R d as defined for NHR a or NR a R b of R a or Rb is each, -hydrogen, -linear or branched-chain -(C 1-6 )-alkyl, -linear or branched-chain -(C 1-6 )-haloalkyl or -(C 3-6 )-cycloalkyl, relates to a compound of formula (I) or formula (IA).

[0133] In another aspect, the present invention relates to any compound of the present invention or a pharmaceutically acceptable salt thereof, wherein the halogen is selected from bromo, chloro, fluoro or iodo.

[0134] In another aspect, the present invention

[0135] [Table 1] relates to a compound that is TIFF0007701880000026.tif242146TIFF0007701880000027.tif220143TIFF0007701880000028.tif239146TIFF0007701880000029.tif235143TIFF0007701880000030.tif227146TIFF0007701880000031.tif162144; or a pharmaceutically acceptable salt and / or corresponding tautomeric form thereof.

[0136] In another aspect, the present invention

[0137] [Table 2] relates to a compound that is TIFF0007701880000033.tif98150; or a pharmaceutically acceptable salt and / or corresponding tautomeric form thereof.

[0138] In another aspect, the present invention is formula (IB): [Chemical formula] [wherein, X is N or C-R 4 ; R 1 is - hydrogen, - halogen, - straight-chain or branched-chain -(C 1-6 )-alkyl or - straight-chain or branched-chain -(C 1-6 )-haloalkyl; R 2 or R 3 is - hydrogen, - halogen, - C≡N, - OH, - NHR a , - NR a R b , - straight-chain or branched-chain -(C 1-6 )-alkyl, -(CF2) n (CH2) o OH, - OR c or - S(O) p R d ; wherein R 4 is - hydrogen, - halogen, - straight-chain or branched-chain -(C 1-6 )-alkyl or - straight-chain or branched-chain -(C 1-6 )-haloalkyl; R 1 , R 2 or R 3 is - hydrogen, - halogen, - C≡N, - NHR a , - NR a R b , - straight-chain or branched-chain -(C 1-6 )-alkyl, - straight-chain or branched-chain -(C 1-6 )-haloalkyl or - OR c and may optionally be substituted; wherein R 4 is - hydrogen, - halogen, - C≡N, - NHR a , - NR a R b , - straight-chain or branched-chain -(C 1-6 )-alkyl, - straight-chain or branched-chain -(C 1-6 )-haloalkyl or - OR c and may optionally be substituted; R 5is an unsaturated or saturated carbocyclic ring, an unsaturated or saturated heterocyclic ring or a heteroaryl ring; wherein R 5 's unsaturated or saturated heterocyclic ring or R 5 's heteroaryl ring each contains at least one heteroatom selected from nitrogen, oxygen or sulfur; wherein R 5 is - hydrogen, halogen, - C≡N, - NHR a , - NR a R b , - O(CH2) n OH, - straight-chain or branched-chain - (C 1-6 ) - alkyl, - straight-chain or branched-chain - (C 1-6 ) - haloalkyl, - OR c or - (C 3-6 ) - cycloalkyl, which may be optionally substituted; R 6 is - hydrogen, - straight-chain or branched-chain - (C 1-6 ) - alkyl or - straight-chain or branched-chain - (C 1-6 ) - haloalkyl; R 7 is

Chemical formula

[0139] In another aspect, the present invention relates to formula (II):

Chemical formula

Chemical formula

[0140] In another aspect, the present invention relates to formula (II):

Chemical formula

Chem.

[0141] In another aspect, the present invention provides a compound of formula (IIA): [Chemical formula] [wherein, R 1 is -hydrogen, -halogen, -linear or branched -(C 1-6 )-alkyl or -linear or branched -(C 1-6 )-haloalkyl; R 2 or R 3 is -hydrogen, -halogen, -C≡N, -OH, -NHR a , -NR a R b , -linear or branched -(C 1-6 )-alkyl, -(CF2) n (CH2) o OH, -OR c or -S(O) p R d ; wherein, R 1 , R 2 or R 3 is -hydrogen, -halogen, -C≡N, -NHR a , -NR a R b, a straight-chain or branched-chain -(C 1-6 )-alkyl, a straight-chain or branched-chain -(C 1-6 )-haloalkyl or -OR c may optionally be substituted; R 5 is an unsaturated or saturated carbocyclic ring, an unsaturated or saturated heterocyclic ring or a heteroaryl ring; where R 5 's unsaturated or saturated heterocyclic ring or R 5 's heteroaryl ring each contains at least 1 heteroatom selected from nitrogen, oxygen or sulfur; where R 5 is hydrogen, halogen, -C≡N, -NHR a , -NR a R b , -O(CH2) n OH, a straight-chain or branched-chain -(C 1-6 )-alkyl, a straight-chain or branched-chain -(C 1-6 )-haloalkyl, -OR c or -(C 3-6 )-cycloalkyl may optionally be substituted; R 6 is hydrogen, a straight-chain or branched-chain -(C 1-6 )-alkyl or a straight-chain or branched-chain -(C 1-6 )-haloalkyl; R 8 , R 9 or R 12 is hydrogen, halogen, -C≡N, NHR a , NR a R b , -OR c , a straight-chain or branched-chain (C 1-6 )alkyl, a straight-chain or branched-chain (C 1-6 )haloalkyl or -(C 3-6 )-cycloalkyl; R 10 or R 11 is hydrogen or a straight-chain or branched-chain (C 1-6 )alkyl; Here, R as defined above 1 R 2 R 3 R 4 R 8 R 9 R 10 R 11 or R 12 each R of a R b or R c is hydrogen, - straight - chain or branched - chain -(C 1-6 ) - alkyl, - straight - chain or branched - chain -(C 1-6 ) - haloalkyl or -(C 3-6 ) - cycloalkyl; Here, R a may optionally be further substituted with - OH; R d is hydrogen, - OH, NHR a NR a R b - straight - chain or branched - chain -(C 1-6 ) - alkyl, - straight - chain or branched - chain -(C 1-6 ) - haloalkyl or -(C 3-6 ) - cycloalkyl; Here, R d NHR as defined for a or NR a R b each R of a or R b is hydrogen, - straight - chain or branched - chain -(C 1-6 ) - alkyl, - straight - chain or branched - chain -(C 1-6 ) - haloalkyl or -(C 3-6 ) - cycloalkyl; n, o or p is an integer of 0 or 1 - 5] for the compound; or a pharmaceutically acceptable salt and / or its corresponding tautomeric form thereof.

[0142] In another aspect, the present invention relates to formula (IIB):

Chemical formula

[0143] In another aspect, the present invention relates to 1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one: [Chemical formula] of the compound; or a pharmaceutically acceptable salt and / or its corresponding tautomeric form thereof.

[0144] In another aspect, the present invention relates to formula (III): [Chemical formula] [wherein, R 1 or R 4 is - hydrogen, - halogen, - straight-chain or branched-chain -(C 1-6 )-alkyl or - straight-chain or branched-chain -(C1-6 ) - is a haloalkyl; R 2 or R 3 is - hydrogen, - halogen, - C≡N, - OH, - NHR a , - NR a R b , - straight - chain or branched - (C 1-6 ) - alkyl, -(CF2) n (CH2) o OH, - OR c or - S(O) p R d ; wherein, R 1 , R 2 , R 3 or R 4 is - hydrogen, - halogen, - C≡N, - NHR a , - NR a R b , - straight - chain or branched - (C 1-6 ) - alkyl, - straight - chain or branched - (C 1-6 ) - haloalkyl or - OR c and may be optionally substituted; R 5 is an unsaturated or saturated carbocyclic ring, - CH2 - unsaturated carbocyclic ring, unsaturated or saturated heterocyclic ring or heteroaryl ring; wherein, R 5 's unsaturated or saturated heterocyclic ring or R 5 's heteroaryl ring each contains at least 1 heteroatom selected from nitrogen, oxygen or sulfur; wherein, R 5 is hydrogen, halogen, - C≡N, - NHR a , - NR a R b , - O(CH2) n OH, - straight - chain or branched - (C 1-6 ) - alkyl, - straight - chain or branched - (C 1-6 ) - haloalkyl, - OR c or - (C 3-6 ) - cycloalkyl and may be optionally substituted; R 6 is - hydrogen, - linear or branched - (C 1-6 ) - alkyl or - linear or branched - (C 1-6 ) - haloalkyl; R 7 is

Chemical formula

[0145] In other aspects, the present invention is 1-(4-fluoro-2-methylphenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-fluoro-2-methylphenyl)-3-(pyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-fluoro-2-methylphenyl)-3-(2-methoxypyrimidin-5-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-fluoro-2-methylphenyl)-3-(1-methyl-1H-pyrazol-5-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; N-(3-(1-(4-Fluoro-2-methylphenyl)-4-oxo-7-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)-yl)phenyl)acetamide; N-(4-(1-(4-Fluoro-2-methylphenyl)-4-oxo-7-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)-yl)phenyl)acetamide; 5-(6-Chloro-5-fluoro-1-(4-fluoro-2-methylphenyl)-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)picolylamide; 4-(6-Chloro-5-fluoro-1-(4-fluoro-2-methylphenyl)-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)picolylamide; 1-(2-Bromo-4-fluorophenyl)-3-(6-methoxy-2-methylpyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(6-methoxypyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-7-fluoro-1-(2-methyl-4-(trifluoromethoxy)phenyl)-3-(3-methylpyridin-4-yl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-1-(2-ethyl-4-fluorophenyl)-7-fluoro-3-(3-methylpyridin-4-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(4-(methylsulfonyl)phenyl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(3-(methylsulfonyl)phenyl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(1,1-Dioxidotetrahydrothiophen-3-yl)-1-(4-fluoro-2-methylphenyl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(3-methylpyridin-4-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)-1-(4-fluoro-2-methylphenyl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(1H-pyrazol-4-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(6-methoxy-2-methylpyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(4-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(2-Methyl-4-(trifluoromethoxy)phenyl)-3-(3-methylpyridin-4-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(6-Chloro-4-methylpyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-7-(difluoromethyl)-1-(4-fluoro-2-methylphenyl)-3-(3-methylpyridin-4-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(pyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(4-methylpyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(3-methylpyridazin-4-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 7-Chloro-6-fluoro-1-(4-fluoro-2-methylphenyl)-3-(6-methoxy-2-methylpyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(3-methyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(1-Acetylpiperidin-4-yl)-1-(4-fluoro-2-methylphenyl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(pyridazin-4-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(5-methylpyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-methylpyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-((2R,3S)-2-methyl-6-oxopiperidin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(1-(4-Fluoro-2-methylphenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)-yl)piperidine-2,6-dione; 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-Cyclohexyl-3-(6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2,6-dimethylphenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-2-methyl-3-(6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(2-Chloro-4-fluorophenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-(2-hydroxyethoxy)phenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(2,4-Difluorophenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(2-Ethyl-4-fluorophenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 8-Chloro-1-(4-fluoro-2-methylphenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-8-methyl-3-(6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2-Methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-isopropylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluorophenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2-Methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(o-tolyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-6-methyl-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(6-methyl-2-oxo-1,2-dihydropyridin-4-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(5-methyl-2-oxo-1,2-dihydropyridin-4-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(3-methyl-2-oxo-1,2-dihydropyridin-4-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethoxy)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-7-methyl-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(3-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 6-(1-(4-Fluoro-2-methylphenyl)-4-oxo-7-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)-yl)pyrimidine-2,4(1H,3H)-dione; 1-(2-Ethyl-4-fluorophenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-1-(4-fluoro-2-methylphenyl)-3-(4-methyl-2-oxo-1,2-dihydropyrimidin-5-yl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2,4-Dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-isopropylphenyl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-isopropylphenyl)-3-(6-methoxy-2,4-dimethylpyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2-Ethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 7-(Dimethylamino)-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 7-Chloro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(methylamino)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-1-(2-ethoxy-4-fluorophenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-isopropylphenyl)-7-methyl-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 7-(Difluoromethyl)-6-fluoro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 6-Fluoro-1-(4-fluoro-2-methylphenyl)-7-methyl-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 6-Chloro-1-(4-fluoro-2-methylphenyl)-7-methyl-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 6,7-Dichloro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 6-Chloro-5-fluoro-1-(2-methyl-4-(trifluoromethoxy)phenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile; 6-Chloro-1-(4-fluoro-2-isopropylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-3-hydroxy-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-5-fluoro-1-(4-fluoro-2-methylphenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-5-fluoro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(methylsulfonyl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-1-(2-ethyl-4-fluorophenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-3-(2,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-isopropylphenyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2-Ethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-isopropylphenyl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(5-oxo-4,5-dihydropyrazin-2-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 6-Fluoro-1-(4-fluoro-2-methylphenyl)-7-methyl-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2-Methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-phenyl-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2-Methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(o-tolyl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 5-Chloro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-5-methyl-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2-Cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-1-(4-fluoro-2-methoxyphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-5-oxo-2,5-dihydro-1H-pyrazol-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 7-Fluoro-1-(4-fluoro-2-isopropylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 3-(4,6-Dimethyl-2-oxo-1,2-dihydropyrimidin-5-yl)-1-(4-fluoro-2-methylphenyl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(2-(tert-Butyl)-4-fluorophenyl)-6-chloro-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(3,4-Difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-1-(4-fluoro-2-isopropylphenyl)-5-methyl-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-7-fluoro-1-(4-fluoro-2-isopropylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-7-methoxy-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-6-hydroxy-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-6-methoxy-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 1-(4-Fluoro-2-isopropylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethoxy)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-7-fluoro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-1,2,3,4-tetrahydroquinazoline-7-carbonitrile; 6-Chloro-3-(2-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-2,3-dihydroquinazolin-4(1H)-one; 7-Fluoro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 5-Fluoro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 7-Chloro-6-fluoro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 6-Fluoro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-7-carbonitrile; 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-7-(trifluoromethoxy)-1,2,3,4-tetrahydroquinazoline-6-carbonitrile; 1-(4,5-Difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(2-(tert-Butyl)-4-fluorophenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(6-methyl-2-oxo-1,2-dihydropyrimidin-5-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(2-Ethyl-4-fluorophenyl)-6-fluoro-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 4-(6-Chloro-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-1(2H)-yl)-3-methylbenzonitrile; 1-(5-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(2-Methyl-4-(trifluoromethoxy)phenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 1-(3-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(2,4-Difluoro-6-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 7-(Difluoromethyl)-1-(4-fluoro-2-isopropylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 3-Methyl-4-(3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-6-(trifluoromethoxy)-3,4-dihydroquinazolin-1(2H)-yl)benzonitrile; 8-Chloro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-8-methyl-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Methoxy-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Hydroxy-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(6-Chloro-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-1(2H)-yl)-2-methylbenzonitrile; 6-Fluoro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethoxy)-2,3-dihydroquinazolin-4(1H)-one; 5-(Difluoromethyl)-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 3-(5-Fluoro-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 6,7-Difluoro-1-(4-fluoro-2-methoxyphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-1-(2-hydroxy-4-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-1-(2-methoxy-4-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(2-Fluoro-6-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-5-fluoro-1-(4-fluoro-2-methylphenyl)-3-(2-oxo-1,2-dihydropyridin-4-yl)-2,3-dihydroquinazolin-4(1H)-one; 7-(Difluoromethyl)-1-(4-fluoro-2-isopropylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 7-(Difluoromethyl)-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-3-(2-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-isopropylphenyl)-2,3-dihydroquinazolin-4(1H)-one; 6-Fluoro-2-methyl-3-(3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-6-(trifluoromethyl)-3,4-dihydroquinazolin-1(2H)-yl)benzonitrile; 6-Fluoro-1-(4-fluoro-2-isopropylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 1-(2-Bromo-4-fluorophenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 6-Fluoro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluorophenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-oxo-1,2-dihydropyrimidin-5-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Bromo-2-methylphenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluorophenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-Methyl-4-(3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-7-(trifluoromethyl)-3,4-dihydroquinazolin-1(2H)-yl)benzonitrile; 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 3-(2-Ethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2-Chloro-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 7-Bromo-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-1,2,3,4-tetrahydroquinazoline-7-carbonitrile; 3-(1-(4-Fluoro-2-methylphenyl)-4-oxo-7-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)-yl)-6-oxo-1,6-dihydropyridine-2-carbonitrile; 1-(2,4-Difluorophenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Ethoxyphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-oxo-1,2-dihydropyridin-4-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 6,7-Difluoro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 6,7-Difluoro-1-(4-fluoro-2-isopropylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2-Methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-((1S,2R)-2-methylcyclohexyl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-isopropylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-1,2,3,4-tetrahydroquinazoline-7-carbonitrile; 3-(2-Methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-((1R,2S)-2-methylcyclohexyl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; N-(3-(1-(4-Fluoro-2-methylphenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)-yl)-6-oxo-1,6-dihydropyridin-2-yl)acetamide; 3-(2-Bromo-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 6-Fluoro-1-(4-fluoro-2-methylphenyl)-7-methoxy-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-6-carbonitrile; 6-Chloro-7-(difluoromethoxy)-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-7-(difluoromethyl)-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 3-(4-Amino-2-oxo-1,2-dihydropyrimidin-5-yl)-1-(4-fluoro-2-methylphenyl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-1-(2-methyl-4-(trifluoromethoxy)phenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-7-carbonitrile; 6-Chloro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-7-carbonitrile; 6-Chloro-1-(2-methyl-4-(trifluoromethoxy)phenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-1,2,3,4-tetrahydroquinazoline-7-carbonitrile; 6-Chloro-1-(4-fluoro-2-methylphenyl)-3-(6-methyl-2-oxo-1,2-dihydropyrimidin-5-yl)-4-oxo-1,2,3,4-tetrahydroquinazoline-7-carbonitrile; 1-(2-Methyl-3-(trifluoromethyl)phenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 1-(3-Chloro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 1-(2-Ethyl-4-fluorophenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 1-(3,4-Difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 1-(4-Fluoro-2-isopropylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(4-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 6-Fluoro-1-(4-fluoro-2-isopropylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(2-Cyclopropyl-4-fluorophenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(2-Cyclopropyl-4-fluorophenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 5-Fluoro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(2-Ethyl-4-fluorophenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 7-(Difluoromethoxy)-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione; 7-Cyclopropyl-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethoxy)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-(Difluoromethoxy)-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2-Ethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-7-(trifluoromethoxy)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-1-(2-ethyl-4-fluorophenyl)-7-fluoro-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-1-(2-ethyl-4-fluorophenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-1,2,3,4-tetrahydroquinazoline-7-carbonitrile; 6-Chloro-5,7-difluoro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-5-fluoro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-1,2,3,4-tetrahydroquinazoline-7-carbonitrile; 1-(2-Methyl-4-(trifluoromethyl)phenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 1-(4-Chloro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 7-(1,1-Difluoro-2-hydroxyethyl)-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-((2-hydroxyethyl)amino)-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-1-(2-(dimethylamino)-4-fluorophenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-1-(4-fluoro-2-(methylamino)phenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-(1,1-Difluoro-2-hydroxyethyl)-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(2,4-Dimethylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-oxo-1,2-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(6-methyl-2-oxo-1,2-dihydropyrimidin-5-yl)-7-(trifluoromethoxy)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-7-methyl-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 6-Chloro-1-(2-ethyl-4-fluorophenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-7-carbonitrile; 1-((1S,3S)-3-Fluorocyclopentyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-((1R,3R)-3-Fluorocyclopentyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(1,2-Dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2-Chloro-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2-Bromo-4-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-isopropylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 6-Chloro-1-(4-fluoro-2-isopropylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 5-(1-(4-Fluoro-2-methylphenyl)-4-thioxo-7-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)-yl)-6-methylpyridin-2(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methoxyphenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-5-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(6-oxo-1,6-dihydropyridazin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluorobenzyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(4-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-4-oxo-3-(6-oxo-1,6-dihydropyridin-3-yl)-1,2,3,4-tetrahydroquinazoline-7-carbonitrile; 1-(4-Fluoro-2-methoxyphenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-5-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2-Methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-methylthiazol-5-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(2,4-Dimethoxyphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methoxyphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 7-Chloro-6-fluoro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 3-(2-Methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(3-methylthiophen-2-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methoxyphenyl)-4-oxo-3-(6-oxo-1,6-dihydropyridin-3-yl)-1,2,3,4-tetrahydroquinazoline-7-carbonitrile; 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(2,2,2-trifluoroethoxy)-2,3-dihydroquinazolin-4(1H)-one; 1-(2-Methyl-4-(trifluoromethoxy)phenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-3-(4-chloro-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-2,3-dihydroquinazolin-4(1H)-one; 7-Chloro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile; 6-Chloro-1-(4-fluoro-2-methylphenyl)-5-methyl-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(3,5-Difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-isopropylphenyl)-5-methoxy-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(Bicyclo[1.1.1]pentan-1-yl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(3-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 5-(1-(4-Fluoro-2-methylphenyl)-6-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)-yl)-6-methylpyridin-2(1H)-one; 3-(2-Methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(2,2,2-trifluoroethyl)phenyl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 7-(Difluoromethoxy)-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 6-Fluoro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-1,2,3,4-tetrahydroquinazoline-7-carbonitrile; 6-Chloro-1-(2-ethyl-4-fluorophenyl)-3-(3-methylpyridin-4-yl)-4-oxo-1,2,3,4-tetrahydroquinazoline-7-carbonitrile; 4-(6-Chloro-7-(difluoromethyl)-1-(4-fluoro-2-methylphenyl)-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)-3-methylpyridine 1-oxide; 4-(6-Chloro-1-(2-ethyl-4-fluorophenyl)-7-fluoro-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)-3-methylpyridine 1-oxide; 4-(6-Chloro-7-fluoro-1-(2-methyl-4-(trifluoromethoxy)phenyl)-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)-3-methylpyridine 1-oxide; 4-(6-Chloro-7-cyano-1-(2-ethyl-4-fluorophenyl)-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)-3-methylpyridine 1-oxide; 2-Carbamoyl-5-(6-chloro-5-fluoro-1-(4-fluoro-2-methylphenyl)-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)pyridine 1-oxide; 3-(1-(4-Fluoro-2-methylphenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)-yl)pyridine 1-oxide; 3-(1-(4-Fluoro-2-methylphenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)-yl)-4-methylpyridine 1-oxide; 5-(1-(4-Fluoro-2-methylphenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)-yl)pyridazine 1-oxide; 4-(1-(4-Fluoro-2-methylphenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)-yl)pyridazine 1-oxide; 3-(1-(4-Fluoro-2-methylphenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)-yl)-2-methylpyridine 1-oxide; 4-(1-(4-Fluoro-2-methylphenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)-yl)-3-methylpyridine 1-oxide; 3-(1-(4-Fluoro-2-methylphenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)-yl)-5-methylpyridine 1-oxide; 3-Methyl-4-(1-(2-methyl-4-(trifluoromethoxy)phenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)-yl)pyridine 1-oxide; 3-(2-Amino-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(6-Amino-2-methylpyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 2-((5-(6-Chloro-1-(4-fluoro-2-methylphenyl)-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)-6-methylpyridin-2-yl)oxy)acetic acid; 1-(4-Fluoro-2-methylphenyl)-3-(2-methoxy-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(6-Aminopyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 4-(1-(4-Fluoro-2-methylphenyl)-4-oxo-7-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)-yl)benzoic acid; 3-(1-(4-Fluoro-2-methylphenyl)-4-oxo-7-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)-yl)benzoic acid; 1-(4-Fluoro-2-methylphenyl)-3-(2-hydroxy-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(oxetan-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(4-hydroxy-2-methylphenyl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(4-hydroxy-2-methylphenyl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluorophenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,4,5,6-tetrahydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-oxohexahydropyrimidin-5-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidin-5-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(1-(4-Fluoro-2-methylphenyl)-4-oxo-7-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)-yl)benzamide; 3-(6-Chloro-1-(4-fluoro-2-methylphenyl)-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)furan-2-carboxamide; 4-Methyl-3-(3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-6-(trifluoromethyl)-3,4-dihydroquinazolin-1(2H)-yl)benzamide; 4-(6-Chloro-1-(4-fluoro-2-methylphenyl)-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)furan-2-carboxamide; 3-(1-(4-Fluoro-2-methylphenyl)-4-oxo-7-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)-yl)benzenesulfonamide; 3-(6-Amino-4-methylpyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2-Methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-((1S,2S)-2-methylcyclohexyl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2-Methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-((1R,2R)-2-methylcyclohexyl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2-Methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-((3S,4S)-3-methyltetrahydro-2H-pyran-4-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2-Methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-((3R,4R)-3-methyltetrahydro-2H-pyran-4-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2-Methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-((3R,4S)-3-methyltetrahydro-2H-pyran-4-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2-Methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; rel-(R)-1-(4-Fluoro-2-methylphenyl)-2-methyl-3-(6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; rel-(R)-1-(4-Fluoro-2-methylphenyl)-2-methyl-3-(6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-((2S,3S)-2-methyl-6-oxopiperidin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-((2R,3R)-2-methyl-6-oxopiperidin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2,4-Dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-isopropylphenyl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2,4-Dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-isopropylphenyl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-3-(2,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-isopropylphenyl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-3-(2,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-isopropylphenyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(2-(tert-Butyl)-4-fluorophenyl)-6-chloro-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(2-(tert-Butyl)-4-fluorophenyl)-6-chloro-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(2-Methyl-4-(trifluoromethoxy)phenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; and 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one relates to a compound selected from or a pharmaceutically acceptable salt and / or its corresponding tautomeric form thereof.

[0146] In other aspects, the present invention 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(2-Methyl-4-(trifluoromethoxy)phenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 1-(4-Bromo-2-methylphenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluorophenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; and 3-Methyl-4-(3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-7-(trifluoromethyl)-3,4-dihydroquinazolin-1(2H)-yl)benzonitrile relates to a compound selected therefrom or a pharmaceutically acceptable salt thereof and / or its corresponding tautomeric form.

[0147] In another aspect, the present invention

[0148]

Table 3

[0149] In another aspect, the present invention provides a compound of formula (IIIA): [Chemical formula] [wherein, R 1 or R 4 is - hydrogen, - halogen, - straight-chain or branched-chain -(C 1-6 )-alkyl or - straight-chain or branched-chain -(C 1-6 )-haloalkyl; R 2 or R 3 is - hydrogen, - halogen, - C≡N, - OH, - NHR a , - NR a R b , - straight-chain or branched-chain -(C 1-6 )-alkyl, -(CF2) n (CH2) o OH, - OR c or - S(O) p R d ; wherein, R 1 , R 2 , R 3 or R 4 is - hydrogen, - halogen, - C≡N, - NHR a , - NR a R b , - straight-chain or branched-chain -(C 1-6 )-alkyl, - straight-chain or branched-chain -(C 1-6 )-haloalkyl or - OR cand may optionally be substituted; R 5 is an unsaturated or saturated carbocyclic ring, -CH2-unsaturated carbocyclic ring, unsaturated or saturated heterocyclic ring or heteroaryl ring; wherein R 5 's unsaturated or saturated heterocyclic ring or R 5 's heteroaryl ring each contains at least 1 heteroatom selected from nitrogen, oxygen or sulfur; wherein R 5 is hydrogen, halogen, -C≡N, -NHR a , -NR a R b , -O(CH2) n OH, - straight-chain or branched-chain -(C 1-6 )-alkyl, - straight-chain or branched-chain -(C 1-6 )-haloalkyl, -OR c or -(C 3-6 )-cycloalkyl may optionally be substituted; R 6 is - hydrogen, - straight-chain or branched-chain -(C 1-6 )-alkyl or - straight-chain or branched-chain -(C 1-6 )-haloalkyl; R 8 , R 9 or R 12 is - hydrogen, - halogen, -C≡N, NHR a , NR a R b , -OR c , - straight-chain or branched-chain (C 1-6 )alkyl, - straight-chain or branched-chain (C 1-6 )haloalkyl or -(C 3-6 )-cycloalkyl; R 11 is - hydrogen or - straight-chain or branched-chain (C 1-6 )alkyl; wherein R as defined above 1 , R 2 , R 3 , R 4 , R8 , R 9 , R 10 , R 11 or R 12 each R a , R b or R c is hydrogen, - straight - chain or branched - chain - (C 1-6 ) - alkyl, - straight - chain or branched - chain - (C 1-6 ) - haloalkyl or - (C 3-6 ) - cycloalkyl; Here, R a may optionally be further substituted with - OH; R d is - hydrogen, - OH, NHR a , NR a R b , - straight - chain or branched - chain - (C 1-6 ) - alkyl, - straight - chain or branched - chain - (C 1-6 ) - haloalkyl or - (C 3-6 ) - cycloalkyl; Here, R d as defined in NHR a or NR a R b each R a or R b is respectively - hydrogen, - straight - chain or branched - chain - (C 1-6 ) - alkyl, - straight - chain or branched - chain - (C 1-6 ) - haloalkyl or - (C 3-6 ) - cycloalkyl; n, o or p is an integer from 0 or 1 to 5] compounds; or pharmaceutically acceptable salts and / or corresponding tautomeric forms thereof.

[0150] In other embodiments, the present invention is:

[0151]

Table 4

[0152] In other aspects, the present invention relates to formula (IIIA’): [Chemical formula] [wherein, R 1 or R 4 is - hydrogen, - halogen, - straight-chain or branched-chain -(C 1-6 )-alkyl or - straight-chain or branched-chain -(C 1-6 )-haloalkyl; R 2 or R 3 is - hydrogen, - halogen, - C≡N, - OH, - NHR a , - NR a R b , - straight-chain or branched-chain -(C 1-6 )-alkyl, -(CF2) n (CH2) o OH, - OR c or - S(O) p R d ; here, R 1 , R 2 , R 3 or R 4 is - hydrogen, - halogen, - C≡N, - NHR a , - NR a R b , - straight-chain or branched-chain -(C 1-6 )-alkyl, - straight-chain or branched-chain -(C 1-6 )-haloalkyl or - OR c and may be optionally substituted; R 6is - hydrogen, - linear or branched - (C 1-6 ) - alkyl or - linear or branched - (C 1-6 ) - haloalkyl; R 8 、R 9 or R 12 is - hydrogen, - halogen, - C≡N, NHR a 、NR a R b 、 - OR c 、 - linear or branched (C 1-6 ) alkyl, - linear or branched (C 1-6 ) haloalkyl or - (C 3-6 ) - cycloalkyl; R 11 is - hydrogen or - linear or branched (C 1-6 ) alkyl; R 13 、R 14 、R 15 、R 16 or R 17 is - hydrogen, - halogen, - C≡N, - OR c 、 - linear or branched (C 1-6 ) alkyl, - linear or branched (C 1-6 ) haloalkyl, - (C 3-6 ) - cycloalkyl, aryl or heteroaryl; Here, R 13 、R 14 、R 15 、R 16 or R 17 is hydrogen, halogen, - C≡N, - NHR a 、 - NR a R b 、 - O(CH2) n OH, - linear or branched - (C 1-6 ) - alkyl, - linear or branched - (C 1-6 ) - haloalkyl, - OR c or - (C 3-6 ) - cycloalkyl may be optionally substituted; Here, R as defined above 1 、R2 , R 3 , R 4 , R 8 , R 9 , R 11 , R 13 , R 14 , R 15 , R 16 or R 17 each R of a , R b or R c is hydrogen, - straight - chain or branched - chain -(C 1-6 ), - alkyl, - straight - chain or branched - chain -(C 1-6 ), - haloalkyl or -(C 3-6 ), - cycloalkyl; Here, R a may optionally be further substituted with - OH; R d is hydrogen, - OH, NHR a , NR a R b , - straight - chain or branched - chain -(C 1-6 ), - alkyl, - straight - chain or branched - chain -(C 1-6 ), - haloalkyl or -(C 3-6 ), - cycloalkyl; Here, R d NHR or NR a as defined for a R b each R of a or R b is hydrogen, - straight - chain or branched - chain -(C 1-6 ), - alkyl, - straight - chain or branched - chain -(C 1-6 ), - haloalkyl or -(C 3-6 ), - cycloalkyl; n, o or p is an integer from 0 or 1 to 5] of the compound; or a pharmaceutically acceptable salt and / or its corresponding tautomeric form thereof.

[0153] In another aspect, the present invention relates to

[0154]

Table 5

[0155] In another aspect, the present invention relates to 1-cyclohexyl-3-(6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one:

Chemical formula

[0156] In another aspect, the present invention relates to formula (IIIA''):

Chemical formula

[0157] In another aspect, the present invention relates to 3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one: [Chemical formula] a compound; or a pharmaceutically acceptable salt and / or a corresponding tautomeric form thereof.

[0158] In another aspect, the present invention relates to formula (IIIB): [Chemical formula] [wherein, R 1 or R 4 is - hydrogen, - halogen, - straight-chain or branched-chain -(C 1-6 )-alkyl or - straight-chain or branched-chain -(C 1-6 )-haloalkyl; R 2 or R 3 is - hydrogen, - halogen, - C≡N, - OH, - NHR a , - NR a R b , - straight-chain or branched-chain -(C 1-6 )-alkyl, -(CF2) n (CH2) o OH, - OR c or - S(O) p R d ; here, R 1 , R 2 , R 3 or R 4 is - hydrogen, - halogen, - C≡N, - NHR a , - NR a R b , - straight-chain or branched-chain -(C 1-6 )-alkyl, - straight-chain or branched-chain -(C 1-6 )-haloalkyl or - OR c and may optionally be substituted; R5 is -(CH2) n unsubstituted cyclohexyl or -(CH2) n substituted cyclohexyl; -(CH2) n unsubstituted phenyl or -(CH2) n substituted phenyl; -(CH2) n unsubstituted pyridinyl or -(CH2) n substituted pyridinyl; where R 5 is hydrogen, halogen, -C≡N, NR a R b -O(CH2) n OH, - straight-chain or branched-chain -(C 1-6 )-alkyl, - straight-chain or branched-chain -(C 1-6 )-haloalkyl, -OR c or -(C 3-6 )-cycloalkyl may be further substituted; R 6 is - hydrogen, - straight-chain or branched-chain -(C 1-6 )-alkyl or - straight-chain or branched-chain -(C 1-6 )-haloalkyl; R 8 , R 9 or R 12 is - hydrogen, - halogen, -C≡N, NHR a , NR a R b , -OR c , - straight-chain or branched-chain (C 1-6 )alkyl, - straight-chain or branched-chain (C 1-6 )haloalkyl or -(C 3-6 )-cycloalkyl; R 10 is - hydrogen, - straight-chain or branched-chain (C 1-6 )alkyl; where each of the above R 1 , R 2 , R 3 , R 4 , R 8 , R 9 , R 10 or R 12 isa and R b or R c is hydrogen, linear or branched -(C 1-6 )-alkyl, linear or branched -(C 1-6 )-haloalkyl or -(C 3-6 )-cycloalkyl; wherein R a may be optionally further substituted with -OH; R d is hydrogen, -OH, NHR a , NR a R b , linear or branched -(C 1-6 )-alkyl, linear or branched -(C 1-6 )-haloalkyl or -(C 3-6 )-cycloalkyl; wherein R d as defined in NHR a or NR a R b each R a or R b is independently hydrogen, linear or branched -(C 1-6 )-alkyl, linear or branched -(C 1-6 )-haloalkyl or -(C 3-6 )-cycloalkyl; n, o or p is an integer from 0 or 1 to 5] of the compound; or a pharmaceutically acceptable salt and / or a corresponding tautomeric form thereof.

[0159] In another aspect, the present invention relates to formula (IIIB’):

Chemical formula

[0160] In another aspect, the present invention relates to

[0161]

Table 6

[0162] In another aspect, the present invention relates to formula (IIIC):

Chemical formula

[0163] In another aspect, the present invention relates to formula (IIIC’):

Chemical formula

[0164] In another aspect, the present invention relates to 1 - (4 - fluoro - 2 - methylphenyl) - 3 - (2 - oxo - 1,2 - dihydropyrimidin - 5 - yl) - 7 - (trifluoromethyl) - 2,3 - dihydroquinazolin - 4(1H) - one: [Chemical formula] relates to a compound that is; or a pharmaceutically acceptable salt and / or a corresponding tautomeric form thereof.

[0165] In another aspect, the present invention relates to formula (IIID): [Chemical formula] [wherein, R 1 or R 4 is - hydrogen, - halogen, - straight-chain or branched-chain -(C 1-6 )-alkyl or - straight-chain or branched-chain -(C 1-6 )-haloalkyl; R 2 or R 3 is - hydrogen, - halogen, - C≡N, - OH, - NHR a , - NR a R b , - straight-chain or branched-chain -(C 1-6 )-alkyl, -(CF2) n (CH2) o OH, - OR c or - S(O) p R d ; here, R 1 R 2 R 3 or R 4 is optionally substituted by - hydrogen, - halogen, - C≡N, - NHR a , - NR a R b , - straight-chain or branched-chain -(C 1-6 )-alkyl, - straight-chain or branched-chain -(C 1-6 )-haloalkyl or - OR c ; R 6 is - hydrogen, - straight-chain or branched-chain -(C 1-6 )-alkyl or - straight-chain or branched-chain -(C 1-6 )-haloalkyl; R 9 or R12 is - hydrogen, - halogen, - C≡N, NHR a , NR a R b , - OR c , - straight - chain or branched (C 1-6 ) alkyl, - straight - chain or branched (C 1-6 ) haloalkyl or -(C 3-6 ) - cycloalkyl; R 11 is - hydrogen or - straight - chain or branched (C 1-6 ) alkyl; R 13 , R 14 , R 15 , R 16 or R 17 is - hydrogen, - halogen, - C≡N, - OR c , - straight - chain or branched (C 1-6 ) alkyl, - straight - chain or branched (C 1-6 ) haloalkyl, -(C 3-6 ) - cycloalkyl, aryl or heteroaryl; wherein R 13 , R 14 , R 15 , R 16 or R 17 is hydrogen, halogen, - C≡N, - NHR a , - NR a R b , - O(CH2) n OH, - straight - chain or branched -(C 1-6 ) - alkyl, - straight - chain or branched -(C 1-6 ) - haloalkyl, - OR c or -(C 3-6 ) - cycloalkyl may be optionally substituted; wherein R as defined above 1 , R 2 , R 3 , R 4 , R 9 , R 11 , R 12 , R 13 , R 14 , R 15 , R16 or R 17 each R of a R b or R c is hydrogen, - straight - chain or branched - chain -(C 1-6 ) - alkyl, - straight - chain or branched - chain -(C 1-6 ) - haloalkyl or -(C 3-6 ) - cycloalkyl; wherein R a may optionally be further substituted with - OH; R d is hydrogen, - OH, NHR a NR a R b - straight - chain or branched - chain -(C 1-6 ) - alkyl, - straight - chain or branched - chain -(C 1-6 ) - haloalkyl or -(C 3-6 ) - cycloalkyl; wherein R d NHR as defined for a or NR a R b each R of a or R b is hydrogen, - straight - chain or branched - chain -(C 1-6 ) - alkyl, - straight - chain or branched - chain -(C 1-6 ) - haloalkyl or -(C 3-6 ) - cycloalkyl; n, o or p is an integer from 0 or 1 to 5] compound; or a pharmaceutically acceptable salt and / or its corresponding tautomeric form thereof.

[0166] In another aspect, the present invention relates to 1 - (4 - fluoro - 2 - methylphenyl) - 3 - (3 - methyl - 5 - oxo - 4,5 - dihydropyrazin - 2 - yl) - 7 - (trifluoromethyl) - 2,3 - dihydroquinazolin - 4(1H) - one:

Chemical formula

[0167] In another aspect, the present invention provides a compound of formula (IIIE):

Chemical formula

[0168] In another aspect, the present invention relates to formula (IIIE'):

Chemical formula

[0169] In another aspect, the present invention relates to 1-(4 - fluoro - 2 - methylphenyl)-3-(6 - oxo - 1,6 - dihydropyridazin - 3 - yl)-7-(trifluoromethyl)-2,3 - dihydroquinazolin - 4(1H)-one:

Chemical formula

[0170] It is recognized that each of the compounds of any of the formulas disclosed herein, including formulas (X) and (I) - (III) (i.e., including the corresponding partial general formulas defined herein), or a pharmaceutically acceptable salt thereof (i.e., as defined above and in the present application), may exist in the form of stereoisomers, positional isomers, or diastereoisomers.

[0171] These compounds of the invention have one or more asymmetric carbon atoms and may exist in racemic and optically active forms. For example, the compounds of the invention may exist as a racemic mixture of the R(+) and S(-) enantiomers or in separate optical forms (i.e., individually as either the R(+) enantiomer or the S(+) enantiomer). All of these individual compounds, their isomers, and mixtures are included within the scope of the invention.

[0172] Furthermore, the compounds of the invention may exist as tautomers or tautomeric forms. It is well understood in the chemical art that tautomers are structural or constitutional isomers of a chemical compound that readily interconvert. This reaction generally results in the movement of a proton. A structural isomer, or constitutional isomer (by the IUPAC [1] ), is a type of isomer in which molecules with the same molecular formula have different bonding patterns and atomic constitutions, as opposed to stereoisomers in which the molecular bonds are always in the same order and only the spatial arrangement is different. The concept of tautomerization is called tautomerism. The chemical reaction that interconverts the two is called tautomerization. Care should be taken not to confuse tautomers with the illustration of "contributing structures" in chemical resonance. Tautomers are distinct chemical species that can be identified by their different spectroscopic data, etc., while resonance structures are merely convenient illustrations and do not physically exist.

[0173] Definition of Substituents Generally, the present invention relates to each of the compounds of any of the formulas disclosed herein that include formula (X) and formulas (I)-(III) (i.e., including the corresponding partial general formulas defined herein), or pharmaceutically acceptable salts thereof, and the corresponding related substituents or functional groups.

[0174] Any of the formulas disclosed herein that contain formula (X) and formulas (I)-(III) (i.e., contain the corresponding partial general formulas as defined herein), or any of its pharmaceutically acceptable salts and / or its corresponding tautomeric forms provided herein (i.e., contain partial general formulas as defined above), and the definitions of various groups and substituents are intended to specifically represent each compound species individually disclosed herein, as well as groups of one or more compound species.

[0175] As used herein, the term "alkali metal" is intended to mean Group I elements including, but not limited to, lithium (Li), sodium (Na), or potassium (K). The term "alkaline earth metal" includes, but is not limited to, calcium (Ca) or magnesium (Mg).

[0176] As used herein, the term "alkyl" or "-linear or branched (C 1-6 )alkyl" and the like represent a saturated or unsaturated, linear or branched hydrocarbon moiety that may be unsubstituted or substituted with one or more substituents as defined herein. Examples of alkyl include, but are not limited to, methyl (Me), ethyl (Et), ethylene, propyl, isopropyl, butyl, butene, isobutyl, t-butyl, pentyl, and the like. By way of example, the term "C1-C6" or "C 1-6 " refers to alkyl having 1 to 6 carbon atoms, and the term "C1-C4" or "C 1-4 " refers to alkyl having 1 to 4 carbon atoms.

[0177] Preferably, the term "alkyl" or "-linear or branched (C 1-6) "Alkyl" represents a saturated, straight-chain or branched-chain hydrocarbon moiety which may be unsubstituted or substituted with one or more substituents as defined herein. Examples of alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, and the like. By way of example, the term "C1-C6" or "C 1-6 " refers to an alkyl having 1 to 6 carbon atoms, and the term "C1-C4" or "C 1-4 " refers to an alkyl having 1 to 4 carbon atoms.

[0178] When the term "alkyl" is used in combination with other substituents such as "haloalkyl" or "hydroxyalkyl", "arylalkyl", the term "alkyl" is intended to include a divalent straight-chain or branched-chain hydrocarbon group.

[0179] The terms "halogen" and "halo" represent chloro, fluoro, bromo or iodo substituents.

[0180] "Hydroxy" or "hydroxyl" is intended to mean an -OH group.

[0181] For example, the term "haloalkyl" or "- straight-chain or branched-chain (C 1-6 ) haloalkyl" is intended to mean a saturated or unsaturated, straight-chain or branched-chain hydrocarbon moiety substituted with one or more halogens, where the halogen is independently selected from fluoro, chloro, bromo and iodo. Representative haloalkyls include, but are not limited to, trifluoromethyl (-CF3), tetrafluoroethyl (-CF2CHF2), pentafluoroethyl (-CF2CF3), and the like.

[0182] For example, hydroxyalkyl is intended to mean a saturated or unsaturated, straight-chain or branched-chain hydrocarbon moiety substituted with one or more hydroxy groups.

[0183] As used herein, the term "cycloalkyl" refers to a saturated or unsaturated non-aromatic hydrocarbon ring having 3 to 7 carbon atoms, unless otherwise defined. The cycloalkyl group is a monocyclic ring system. For example, C3-C7 cycloalkyl refers to a cycloalkyl group having 3 to 7 ring atoms. Examples of cycloalkyl, as used herein, include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptyl. Preferably, the cycloalkyl is selected from cyclopropyl, cyclobutyl and cyclohexyl. Preferably, "cycloalkyl" is cyclopropyl. Preferably, "cycloalkyl" is cyclobutyl. Preferably, "cycloalkyl" is cyclopentenyl. Preferably, "cycloalkyl" is cyclohexyl.

[0184] Preferably, "cycloalkyl" refers to a non-aromatic, saturated, cyclic hydrocarbon ring. The term "-C 3-6 cycloalkyl" refers to a non-aromatic cyclic hydrocarbon ring having 3 to 6 ring carbon atoms. Examples of "-(C3-C6) cycloalkyl" or "-C 3-6 cycloalkyl" groups useful in the present invention include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Preferably, "cycloalkyl" is cyclopropyl. Preferably, "cycloalkyl" is cyclobutyl. Preferably, "cycloalkyl" is cyclopentenyl. Preferably, "cycloalkyl" is cyclohexyl.

[0185] As used herein, the term "bicycloalkyl" refers to a bridged cycloalkyl, unless otherwise defined, where cycloalkyl is as defined herein. Preferably, the bridge is a one-carbon bridge. Preferably, the bridge is a two-carbon bridge. Preferably, the bridge is a three-carbon bridge. Preferably, "bicycloalkyl" is

Chemical formula

[0186] "Alkoxy" or "-OR c " refers to a group having a group such as a defined list of "R" alkyl substituents bonded through an oxygen-linked atom. In particular, the term "-OR c " is defined when the substituent variable "R c " is selected from, but not limited to, hydrogen, - straight-chain or branched-chain -(C 1-6 )-alkyl, - straight-chain or branched-chain -(C 1-6 )-haloalkyl or -(C 3-6 )-cycloalkyl, etc. Alternatively, the term "(C1-C6) alkoxy" refers to a straight-chain or branched-chain hydrocarbon group having at least 1 to 6 carbon atoms bonded through an oxygen-linked atom. Examples of "(C1-C4)-alkoxy" groups useful in the present invention include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, and t-butoxy. Representative haloalkoxys include, but are not limited to, difluoromethoxy (-OCHCF2), trifluoromethoxy (-OCF3), tetrafluoroethoxy (-OCF2CHF2), etc.

[0187] "Carbocyclic ring" refers to a ring in which all ring atoms are carbon atoms and which can be unsaturated or saturated, aromatic or non-aromatic, fused or non-fused, etc. Examples of carbocyclic rings include, but are not limited to, cycloalkyl such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, etc., and aromatic rings or aryl rings containing rings such as phenyl, etc.

[0188] The "carbocyclic ring" as defined above may optionally be further substituted or may be defined as a -CH2- unsaturated carbocyclic ring. Examples of -CH2- unsaturated carbocyclic rings include, but are not limited to, benzyl (i.e., -CH2-phenyl).

[0189] "Aryl" represents an aromatic hydrocarbon ring. An aryl group has a total of 5 to 14 ring member atoms, at least one ring system is aromatic, and each ring of the ring system has 3 to 7 member atoms, and is a monocyclic, bicyclic, and tricyclic structure, such as phenyl, naphthalene, and tetrahydronaphthalene. Preferably, aryl is phenyl.

[0190] Preferably, "aryl" represents a group or moiety that is an aromatic, monovalent monocyclic or bicyclic hydrocarbon group that contains at least 6 carbocyclic atoms and may be unsubstituted or substituted by one or more of the substituents defined herein, and may be condensed with one or more cycloalkyl rings that may be unsubstituted or substituted by one or more of the substituents defined herein. Representative aryl groups suitable for use in the present invention include, but are not limited to, phenyl, benzyl, and the like.

[0191] "Heteroatom" is defined as oxygen, nitrogen, sulfur, etc. Preferably, "heteroatom" refers to a nitrogen, sulfur or oxygen atom.

[0192] "Heterocyclic" represents a heteroaryl or heterocycloalkyl group. The heterocyclic group may be unsaturated or saturated.

[0193] Each monocyclic heterocyclic ring of the present invention has 3 to 7 ring atoms and up to 4 heteroatoms. Monocyclic heterocyclic rings or fused heterocyclic rings include substituted aromatic and non-aromatic ones.

[0194] Each fused heterocyclic ring of the present invention may optionally include a carbocyclic ring or a heterocyclic ring.

[0195] "Heterocycloalkyl" refers to a saturated or unsaturated non-aromatic ring having 4 to 12 atoms, of which 1 to 11 are carbon atoms and 1 to 6 are heteroatoms independently selected from oxygen, nitrogen, and sulfur. A heterocycloalkyl group having two or more heteroatoms may have various heteroatoms. The heterocycloalkyl group is a monocyclic ring system or a monocyclic ring condensed with an aryl ring or a heteroaryl ring having 3 to 6 atoms. Examples of heterocycloalkyl include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, pyranyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothienyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, oxetanyl, thiazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl, 1,3-oxazolidin-2-one, hexahydro-1H-azepine, 4,5,6,7-tetrahydro-1H-benzimidazole, piperidinyl, 1,2,3,6-tetrahydro-pyridinyl, and azetidinyl. Preferably, examples of "heterocycloalkyl" include piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, imidazolidinyl, oxetanyl, and pyrrolidinyl. Preferably, "heterocycloalkyl" is selected from imidazolidinyl, tetrahydropyranyl, and pyrrolidinyl.

[0196] Preferably, "heterocycloalkyl" is selected from imidazolidinyl, tetrahydropyranyl, pyrrolidinyl, 1,4-dioxanyl, 1,4-oxazinyl, and oxetanyl.

[0197] Suitably, "heterocycloalkyl" has 3 to 10 ring atoms, contains 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and represents a saturated or partially unsaturated, non-aromatic, monovalent monocyclic or bicyclic group or moiety which is unsubstituted or may be substituted by one or more of the substituents defined herein. Generally, in the compounds of the present invention, the heterocycloalkyl group represents a 5-membered and / or 6-membered heterocycloalkyl group.

[0198] In one embodiment, heterocycloalkyl may include derivatives of pyridonyl substituents such as, but not limited to, -3-pyridonyl, -4-pyridonyl, -5-pyridonyl, tetrahydropyridazin-3(2H)-one, 2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one-yl ring or those shown below which may optionally be substituted, formed on a pyridone ring moiety:

Chemical formula

[0199] "Heteroaryl" refers to a group or moiety comprising an aromatic monocyclic or bicyclic group having 4 to 10 ring atoms, preferably 5 to 10 ring atoms, containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and which may be unsubstituted or substituted by one or more of the substituents defined herein. This term also encompasses bicyclic heterocyclic aryl compounds containing an aryl ring moiety fused to a heterocycloalkyl ring moiety having 4 to 10 ring atoms, preferably 5 to 10 ring atoms, and containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which may be unsubstituted or substituted by one or more of the substituents defined herein. Examples of heteroaryl include, but are not limited to, benzimidazolyl, benzothiazolyl, benzothiophenyl, benzopyrazinyl, benzotriazolyl, benzotriazinyl, benzo[1,4]dioxanyl, benzofuranyl, 9H-a-carbolinyl, cinnolinyl, furanyl, pyrazolyl, imidazolyl, indolizinyl, naphthyridinyl, oxazolyl, oxothiadiazolyl, oxadiazolyl, phthalazinyl, pyridyl, pyrrolyl, purinyl, pteridinyl, phenazinyl, pyrazinyl, pyrazolopyrimidinyl, pyrazolopyridinyl, pyrrolidinyl, pyrimidyl, isothiazolyl, phthalazinyl, pyrimidinyl, tetrazinyl, isoxazolyl, quinoxalinyl, quinazolinyl, quinolinyl, quinolidinyl, thienyl, thiophenyl, triazolyl, triazinyl, tetrazolopyrimidinyl, triazolopyrimidinyl, tetrazolyl, thiazolyl, and thiazolidinyl. Preferably, heteroaryl is selected from pyrazolyl, imidazolyl, oxazolyl, and thienyl. Preferably, heteroaryl is a pyridyl group or an imidazolyl group. Preferably, heteroaryl is pyridyl or pyrazinyl. Preferably, heteroaryl is pyridyl.

[0200] In one embodiment, the heteroaryl includes, but is not limited to, pyridyl (or pyridinyl), pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl (or furanyl), isothiazolyl, furazanyl, isoxazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazinyl, tetrazinyl, triazolyl, tetrazolyl, and the like.

[0201] Preferably, the heteroaryl is selected from pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, furanyl, thiophenyl, and thiazolyl.

[0202] Generally, the heteroaryl group present in the compounds of the present invention is a 5-membered and / or 6-membered monocyclic heteroaryl group. The selected 5-membered heteroaryl group has a nitrogen, oxygen or sulfur ring heteroatom and optionally at least 1, 2 or 3 additional nitrogen ring atoms. The selected 6-membered heteroaryl group has at least 1, 2, 3 or 4 nitrogen ring heteroatoms. The selected 5-membered or 6-membered heteroaryl group includes, but is not limited to, pyridyl (or pyridinyl), pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, pyrrolyl, imidazothienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, tetrazolyl, and the like.

[0203] "Oxo" represents a double-bonded oxygen moiety; for example, when directly bonded to a carbon atom, it forms a carbonyl moiety (C=O), or when bonded to N or S, it forms an oxide, N-oxide, sulfone or sulfoxide.

[0204] As used herein, the term "compound of the invention" refers to any form, i.e., any salt or non-salt form (e.g., as a free acid or base form, or as its pharmaceutically acceptable salt) and any physical form thereof (e.g., non-solid form (e.g., liquid or semi-solid form), and solid form (e.g., amorphous or crystalline form, specific polymorphic form, solvate including hydrates (e.g., monohydrate, dihydrate and hemihydrate)), and mixtures of various forms), of any compound of the formulas disclosed herein.

[0205] As used herein, the term "optionally substituted" means that a group which may include, but is not limited to, alkyl, aryl, heteroaryl, etc. may be unsubstituted or may be substituted with one or more substituents as defined herein. When a group may be selected from several alternative groups, the selected groups may be the same or different. For example, the various substituents in the compound formulas as defined in the present invention may include, but are not limited to, -hydrogen, -halogen, -C≡N, amino, substituted amino group, alkoxy, straight-chain or branched-chain (C 1-6 )alkyl, -straight-chain or branched-chain (C 1-6 )haloalkyl or -(C 3-6 )-cycloalkyl, etc., and may be optionally substituted.

[0206] The term "independently" means that when two or more substituents are selected from several possible substituents, those substituents may be the same or different.

[0207] Enantiomers, Diastereomers and Polymorphs A compound according to any of the formulas disclosed herein that includes Formulas (X) and (I)-(III) as defined herein (i.e., including the corresponding partial general formulas as defined herein), or a pharmaceutically acceptable salt and / or corresponding tautomeric form thereof (i.e., including the partial general formulas as defined above), may contain one or more asymmetric centers (i.e., also referred to as chiral centers), and thus may exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or mixtures thereof.

[0208] Chiral centers, such as chiral carbon atoms, may also be present in substituents such as alkyl groups. When the stereochemistry of chiral centers present in any of the formulas disclosed herein that includes Formulas (X) and (I)-(III) as defined herein (i.e., including the corresponding partial general formulas as defined herein), or a pharmaceutically acceptable salt and / or corresponding tautomeric form thereof (i.e., including the partial general formulas as defined above), or any chemical structure shown herein is not explicitly indicated, the structure is intended to encompass all individual stereoisomers and all mixtures thereof. Thus, a compound of the invention having one or more chiral centers, or a pharmaceutically acceptable salt and / or corresponding tautomeric form thereof, may be used as a racemic mixture, an enantiomerically enriched mixture, or an enantiomerically pure individual stereoisomer.

[0209] An individual stereoisomer of a compound according to the invention that contains one or more asymmetric centers and includes Formulas (X) and (I)-(III) as defined herein (i.e., including the corresponding partial general formulas as defined herein), or a pharmaceutically acceptable salt and / or corresponding tautomeric form thereof (i.e., including the partial general formulas as defined above) can be resolved by methods known to those skilled in the art. For example, such resolution can be (1) formation of diastereomeric salts, complexes or other derivatives; (2) Selective reactions with stereoisomer-specific reagents, for example, enzymatic oxidation or reduction; or (3) Gas-liquid chromatography or liquid chromatography on a chiral support such as silica to which a chiral ligand is attached or in the presence of a chiral solvent in a chiral environment It can be carried out by. Those skilled in the art will recognize that if the desired stereoisomer is converted to other chemical components by one of the above separation procedures, additional steps will be required to liberate the desired form.

[0210] Alternatively, a particular stereoisomer can be synthesized by asymmetric synthesis using an optically active reagent, substrate, catalyst or solvent, or by converting one enantiomer to another by asymmetric transformation.

[0211] When the disclosed compound or its salt is named or described by structure, it should be understood that the compound or salt, including its solvates (especially hydrates), can exist in crystalline form, amorphous form or mixtures thereof. The compound or salt, or its solvate (especially hydrate), can also exhibit polymorphism (i.e., the ability to exist in different crystalline forms). These different crystalline forms are generally known as "polymorphs".

[0212] When named or described by structure, the disclosed compound, or its solvate (especially hydrate), should also be understood to include all of its polymorphs.

[0213] Polymorphs have the same chemical composition but differ in packing, geometric arrangement, and other descriptive properties of the crystalline solid state. Thus, polymorphs can have different physical properties such as shape, density, hardness, deformability, stability, and dissolution characteristics. Polymorphs generally exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which can be used for identification. Those skilled in the art will recognize that different polymorphs can be produced, for example, by changing or adjusting the conditions used in crystallizing / recrystallizing the compound.

[0214] Salts For their potential use in medicine, salts of any of the compounds of the formulas disclosed herein, each containing the formula (X) and the formulas (I) - (III) (i.e., including the corresponding partial general formulas as defined herein), respectively (i.e., including partial general formulas as defined above), are preferably pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse J.Pharm.Sci (1977) 66, pp 1 - 19.

[0215] When the compound of the present invention is a base (having a basic moiety), the desired salt form may be prepared by any suitable method known in the art, including treating the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or an organic acid such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidic acid (e.g., glucuronic acid or galacturonic acid), α-hydroxy acid (e.g., citric acid or tartaric acid), amino acid (e.g., aspartic acid or glutamic acid), aromatic acid (e.g., benzoic acid or cinnamic acid), sulfonic acid (e.g., p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid). Examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, mandelate, and sulfonate (e.g., xylenesulfonate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, and naphthalene-2-sulfonate).

[0216] When the basic compound of the present invention is isolated as a salt, the corresponding free base form of the compound may be prepared by any suitable method known in the art, including treating the salt with an inorganic or organic base, preferably an inorganic or organic base having a pK a higher than that of the free base form of the compound.

[0217] When the compound of the present invention is an acid (including an acidic moiety), the desired salt may be prepared by any suitable method known in the art, including treating the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary), an alkali metal or alkaline earth metal hydroxide, etc. Specific examples of suitable salts include amino acids such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and organic salts derived from cyclic amines (e.g., ethylenediamine, dicyclohexylamine, ethanolamine, piperidine, morpholine, and piperazine), as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0218] Certain of the compounds of the present invention can form salts with one equivalent or more of an acid (when the compound contains a basic moiety) or a base (when the compound contains an acidic moiety). The present invention includes all possible stoichiometric and non-stoichiometric salt forms within its scope.

[0219] Since the compounds of the present invention may contain both an acid moiety and a base moiety, pharmaceutically acceptable salts can be prepared by treating these compounds with an alkali reagent or an acid reagent, respectively. Thus, the present invention also provides for the conversion of one pharmaceutically acceptable salt of a compound of the present invention, e.g., a hydrochloride salt, to another pharmaceutically acceptable salt of the compound of the present invention, e.g., a sodium salt.

[0220] Solvates Regarding the compound of the present invention in crystalline form, or a solvate of a pharmaceutically acceptable salt thereof, those skilled in the art will recognize that a pharmaceutically acceptable solvate can be formed by incorporating solvent molecules into the crystal lattice during crystallization. The solvate may include non-aqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethyl acetate as the solvent incorporated into the crystal lattice, or may include water. A solvate in which the solvent incorporated into the crystal lattice is water is generally called a "hydrate". Hydrates include stoichiometric hydrates as well as compositions containing various amounts of water. The present invention includes all such solvates.

[0221] Deuterated Compounds The present invention also includes various deuterated forms of a compound of any of the formulas disclosed herein that includes the formulas (X) and (I)-(III) respectively of the present invention (i.e., including the corresponding partial general formulas defined herein), or a pharmaceutically acceptable salt thereof and / or its corresponding tautomeric form (i.e., including the partial general formulas as defined above). Each available hydrogen atom bonded to a carbon atom may independently be replaced with a deuterium atom.

[0222] Those skilled in the art know how to synthesize the deuterated forms of a compound of any of the formulas disclosed herein that includes the formulas (X) and (I)-(III) respectively of the present invention (i.e., including the corresponding partial general formulas defined herein), or a pharmaceutically acceptable salt thereof and / or its corresponding tautomeric form (i.e., including the partial general formulas as defined above). For example, deuterated materials such as alkyl groups can be prepared by prior art techniques (see, for example, methyl-d3-amine, catalog number 489,689-2, available from Aldrich Chemical Co., Milwaukee, WI).

[0223] Isotopes The present invention also includes isotopically labeled compounds that are identical to any of the compounds of the formulas disclosed herein that include the formulas (X) and (I)-(III) (i.e., including the corresponding partial general formulas as defined herein), or pharmaceutically acceptable salts and / or corresponding tautomeric forms thereof (i.e., including partial general formulas as defined above), except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.

[0224] Examples of isotopes that can be incorporated into the compounds of the present invention include 3 H, 11 C, 14 C, 18 F, 123 I or 125 isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, iodine, and chlorine such as I.

[0225] The compounds of the present invention containing the above-mentioned isotopes and / or other isotopes of other atoms and pharmaceutically acceptable salts of said compounds are within the scope of the present invention. Isotopically labeled compounds of the present invention, for example, those incorporated with radioactive isotopes such as 3 H or 14 C, etc., are useful in drug and / or substrate tissue distribution assays. Tritium labeling, i.e., 3 H, and carbon-14, i.e., 14 C isotopes are particularly preferred because they are easy to produce and detect. 11 C and 18 F isotopes are particularly useful in PET (positron emission tomography).

[0226] Purity Since the compounds of the present invention are intended for use in pharmaceutical compositions, they are each preferably provided in a substantially pure form, for example, at least 60% purity, more preferably at least 75% purity, preferably at least 85%, particularly at least 98% purity (% is weight by weight based on the weight). It will be readily understood that impure preparations of these compounds can be used to prepare a more pure form for use in pharmaceutical compositions.

[0227] Synthetic Schemes and General Preparation Methods Any compound of a formula disclosed herein of the present invention, including formula (X) and formulas (I) to (III) respectively (i.e., including the corresponding partial general formulas defined herein), or a pharmaceutically acceptable salt and / or corresponding tautomeric form thereof (i.e., including the partial general formulas as defined above) can be prepared by using the synthetic procedures shown in the following schemes or by relying on the knowledge of a skilled organic chemist. That is, it can be produced by a process or method for producing the above-mentioned compound or a pharmaceutically acceptable salt thereof.

[0228] The syntheses provided in these schemes are carried out using appropriate precursors that are appropriately protected if necessary to achieve compatibility with the reactions outlined herein, for various different R 1 and R 2 groups to produce the compounds of the present invention. If necessary, subsequent deprotection yields compounds of the generally disclosed properties. These schemes are shown using only the compounds of the formulas disclosed herein of the present invention, including formula (X) and formulas (I) to (III) respectively (i.e., including the corresponding partial general formulas defined herein), or a pharmaceutically acceptable salt and / or corresponding tautomeric form thereof (i.e., including the partial general formulas as defined above), but they are examples of processes that can be used to produce the compounds of the present invention.

[0229] Intermediates (compounds used in the manufacture of the compounds of the present invention) may also exist as salts. Thus, when referring to an intermediate, the phrase "compound of formula (number)" means the compound having the structural formula or a pharmaceutically acceptable salt thereof.

[0230] The present invention also relates to a process for preparing a compound of any of the formulas disclosed herein, including the compounds of formula (X) and formulas (I) to (III) of the present invention (i.e., including the corresponding partial general formulas defined herein), or a pharmaceutically acceptable salt and / or corresponding tautomeric form thereof (i.e., including the partial general formulas as defined above).

[0231] The compounds of the present invention can be obtained by using the synthetic procedures shown in the following schemes or by relying on the knowledge of a skilled organic chemist.

[0232] The syntheses provided in these schemes are applicable to preparing the compounds of the present invention, including the compounds of formula (X) and formulas (I) to (III) of the present invention (i.e., including the corresponding partial general formulas defined herein), or a pharmaceutically acceptable salt and / or corresponding tautomeric form thereof (i.e., including the partial general formulas as defined above), which have various different functional groups as defined, using appropriate precursors that are protected as appropriate to achieve compatibility with the reactions outlined herein. If necessary, subsequent deprotection yields compounds of generally disclosed properties. These schemes are shown using only the compounds as defined herein, but they are illustrative of the processes that can be used to manufacture the compounds of the present invention.

[0233] Intermediates (compounds used in the manufacture of the compounds of the present invention) may also exist as salts. Thus, when referring to an intermediate, the phrase "compound of formula (number)" means the compound having the structural formula or a pharmaceutically acceptable salt thereof.

[0234] Any compound of a formula disclosed herein that includes Formula (X) and Formulas (I) to (III) respectively (i.e., including the corresponding partial general formulas defined herein), or a pharmaceutically acceptable salt and / or corresponding tautomeric form thereof (i.e., including the partial general formulas as defined above) is produced using conventional organic synthesis. Suitable synthetic routes are shown below in the following general reaction schemes.

[0235] One skilled in the art will recognize that if the substituents described herein are not compatible with the synthetic methods described herein, those substituents may be protected with suitable protecting groups that are stable under those reaction conditions. This protecting group can be removed at a suitable point in the reaction procedure to provide the desired intermediate compound or target compound. Suitable protecting groups and methods for protecting and deprotecting various substituents using such suitable protecting groups are well known to those skilled in the art, and examples thereof can be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd Edition), John Wiley & Sons, NY (1999). In some cases, substituents can also be specifically selected to be reactive under the reaction conditions used. Under these circumstances, these reaction conditions convert the selected substituents to another substituent that is useful as an intermediate compound or is the desired substituent in the target compound.

[0236] Synthetic Scheme For the convenience of the reader, the following substituents of the compounds described in the schemes represent substituents defined with respect to any compound of a formula disclosed herein that includes Formula (X) and Formulas (I) to (III) respectively (i.e., including the corresponding partial general formulas defined herein), corresponding to and / or equivalent to those.

[0237] 1. General Production Methods

Chemical formula

[0238] The compound names were assigned using the software naming program ChemDraw Ultra v12.0 available from Perkin Elmer, 940 Winter Street, Waltham, Massachusetts 02451, USA (http: / / www.perkinelmer.com / ). [Chemical formula] The production of the compounds of the present invention generally begins with the synthesis of N-substituted-2-aminoaromatic acid derivatives I-4 (Scheme I'). When appropriately substituted 2-haloaromatic acids are esterified under standard conditions, the corresponding esters I-2 are obtained. Generally, the esterification reaction can be carried out under acidic conditions, in the presence of an alcohol, or under basic conditions, in the presence of a suitable alkyl halide. 2-Haloaromatic ester I-2 (X 1 = Cl, Br or I) is reacted with a suitable aniline or amine (R 5’ -NH2) to obtain the corresponding N-substituted-2-aminoaromatic ester I-3. Generally, this reaction can be carried out at high temperature using standard heating or microwave irradiation in a suitable solvent such as 1,4-dioxane, toluene or 2-ethoxyethanol, in the presence of a catalyst such as Pd2(dba)3 or Cu / CuO, a suitable ligand such as BINAP or xantphos, and an inorganic base, generally Cs2CO3 or K2CO3. In some cases where X 1 = F, this conversion can be achieved by an S N Ar reaction in a suitable solvent such as DMF, in the presence of a base such as DIPEA.

[0239] Intermediate I-3 can also be prepared from 2-aminoaromatic acid I-5 by the same synthetic steps and reaction conditions as described above. After esterification, the resulting amino-aromatic ester I-6 is reacted with a suitable aryl halide (R 5’ -X) under similar coupling conditions to provide the corresponding I-3 where X can be Cl, Br or I. Such reactions are well known to those skilled in the art.

[0240] The saponification of ester I-3 to the corresponding N-substituted-2-aminoaromatic acid derivative (I-4) is generally achieved under standard basic conditions using a base such as LiOH, KOH or NaOH in a suitable solvent or solvent system such as methanol / H2O, ethanol / H2O, or THF / H2O. Such conditions are well known to those skilled in the art.

[0241] Alternative approaches that will be readily apparent to those skilled in the art involve reacting 2-bromo aromatic acid I-1 with a suitable aniline or amine (R 5’ -NH2) to directly obtain compound I-4. These reaction conditions are similar to those described above for the conversion from I-2 to I-3, but the use of a ligand may or may not be required.

[0242] In some cases where X’ = N, appropriately substituted 2-chloro nicotinic acid I-7 can be reacted with a suitable aniline or amine (R 5’ -NH2) under acidic conditions such as p-toluene sulfonic acid or acetic acid, at elevated temperature, with or without the use of a base such as pyridine to obtain 2-amino aromatic acid I-5. These reactions can also be carried out at ambient temperature, under basic conditions such as in the presence of LiHMDS, in a suitable solvent such as THF.

[0243] In another alternative approach, the intermediate N-substituted-2-amino aromatic acid derivative I-4 can be prepared starting from appropriately substituted 2-fluoro-aromatic nitrile I-8 using the S N Ar reaction. For example, compound I-7 can be reacted with a suitable aniline or amine (R 5’ -NH2) to effect the desired S N Ar reaction to obtain the substituted product I-9. This reaction is generally carried out in a suitable polar solvent such as DMF, in the presence of a base, often NaH or K2CO3. This reaction can be carried out at room temperature or with heating depending on the relative reactivity of the starting materials. Next, the nitrile group of I-9 is hydrolyzed by reaction with a hydroxyl base, usually LiOH, KOH, or NaOH, in a suitable solvent or solvent system, such as methanol / H2O, ethanol / H2O, or THF / H2O, to obtain the corresponding carboxylic acid I-4. I-9 can also be obtained from appropriately substituted 2-halo-aromatic nitrile I-10 (X 2 = Cl or Br) by a conventional cross-coupling reaction. These reaction conditions are similar to those described above for the conversion from I-2 to I-3. Such reactions are well known to those skilled in the art. [Chemical formula] The intermediate N-substituted-2-amino aromatic acid derivative I-4 produced as shown in Scheme I’ can be converted to II-2 as outlined in Scheme II’. Under various amide coupling conditions known to those skilled in the art, coupling I-5 with a suitable 2-alkoxy-aza heterocycle B’-NH2, such as 2-methoxy-4-aminopyridine, gives the corresponding amide II-1. For example, in a suitable solvent, generally DMF, DMA or acetonitrile, in the presence of an amine base such as triethylamine or Hunig's base (diisopropylethylamine), standard coupling reagents such as EDC / HOBT, HATU, HBTU or T3P may be used. Alternatively, a reagent such as thionyl chloride or oxalyl chloride is used to convert the acid to the corresponding acid chloride, and then the acid chloride is reacted with a suitable 2-alkoxy-aza heterocycle B’-NH2 (such as 2-methoxy-4-aminopyridine) in the presence of an acid scavenger or base, such as pyridine, 2,6-lutidine, triethylamine or Hunig's base, in a suitable solvent such as dichloromethane or pyridine to obtain the desired coupling product II-1. Alternatively, II-1 may be formed directly from the N-substituted-2-amino aromatic ester I-3 by treating a mixture of I-3 and the corresponding B’-NH2 with DABAL-Me3 at elevated temperature in a suitable solvent such as THF.

[0244] The formation of the dihydroquinazolinone ring system involves the reaction of II-1 with formaldehyde or a suitable equivalent, similar to the case of II-2. For example, this reaction can be achieved using gaseous formaldehyde, paraformaldehyde, or formaldehyde as s-trioxane in the presence of an acid, preferably PTSA or sulfuric acid. When R6’ is a carbonyl oxygen, CDI and DBU can be used. This reaction can be carried out at high temperature using chloroform, toluene, or 2,2,2-trifluoroethanol as a solvent. Alternatively, the dihydroquinazolinone ring system can be formed by the reaction of II-1 using diiodomethane or chloroiodomethane as a formaldehyde equivalent. In this variation of the cyclization reaction, a base, generally Cs2CO3 or NaH, can be used in a suitable solvent, often acetonitrile or DMF. The choice of whether to use formaldehyde or diiodomethane depends on the reaction characteristics specific to the substrate II-1.

[0245] In some examples, the final product can be the compound II-2, which can also be obtained by the methods described in Scheme III’ and Scheme IV’.

Chemical formula

[0246] VII-1 and VII-2 can also be synthesized under hydrolysis conditions as described for the reaction from I-9 to I-4 from suitably substituted aromatic nitrile II-2'.

[0247] The chemical method as shown in Scheme VII' is a typical general method, and it will be apparent to those skilled in the art that it can also be used for analogs having substituents on other aromatic rings or at other positions.

Chemical formula

[0248] For some specific examples, additional deprotection steps may be required. Such conversions are well known to those skilled in the art. For example, when the B' ring is a 2-alkoxy-aza heterocycle, the alkoxy protecting group can be removed by the procedure described in Scheme VI'.

Chemical formula

[0249] Alternatively, for compound II-2 where R 3’ is a bromo group or an iodo group, the conversion from halogen to cyano group can be achieved by treating II-2 with copper(I) cyanide in DMF at high temperature. This method is also applicable to the conversion of bromo groups at other positions on the ring, such as R 2’ to cyano groups.

[0250] If necessary, the final compound IX-2 can be produced from IX-1 by an appropriate deprotection reaction or preferably by the methods shown in Schemes V’~VIII’. The selection of the reaction and the corresponding conditions will be obvious to those skilled in the art.

Chemical formula

Chemical formula

Chemical formula

[0251]

Table 7

[0252] General Production Method

Chemical formula

[0253] The methods provided in these schemes use appropriate precursors and various different R 1 , R 2 , R3 , R 4 , R 5 , R 6 , R 7 and can be used for producing the compounds of the present invention having a G group.

[0254] Those skilled in the art will recognize that in the production of the compounds of the present invention (for example, any of the formulas disclosed herein including formulas (X) and (I)-(III) respectively (i.e., including the corresponding partial general formulas defined herein)), or pharmaceutically acceptable salts and / or corresponding tautomeric forms thereof (i.e., including partial general formulas as defined above), pharmaceutically acceptable salts, solvates, hydrates, etc.), it may be necessary and / or desirable to protect one or more sensitive groups of the molecule or appropriate intermediates to avoid unwanted side reactions.

[0255] Protecting groups suitable for use according to the present invention are well known to those skilled in the art and can be used in conventional methods. See, for example, "Protective Groups in Organic Synthesis" by T.W. Green and P.G.M Wets (Wiley & Sons, 1991) or "Protecting Groups" by P.J. Kocienski (Georg Thieme Verlag, 1994). If necessary, compounds of generally disclosed properties can be obtained by subsequent deprotection. The schemes shown below are representative methods for producing the compounds of the present invention, any of the formulas disclosed herein including formulas (X) and (I)-(III) respectively (i.e., including the corresponding partial general formulas defined herein), or pharmaceutically acceptable salts and / or corresponding tautomeric forms thereof (i.e., including partial general formulas as defined above), but they are only intended to illustrate examples of steps that can be used to produce the compounds of the present invention.

[0256] The compound names were assigned using the software naming program ChemDraw Ultra v12.0 available from Perkin Elmer, 940 Winter Street, Waltham, Massachusetts 02451, USA (http: / / www.perkinelmer.com / ). [Chem.] The preparation of the compounds of the present invention generally begins with the synthesis of N-substituted-2-aminoaromatic acid derivatives I-4 (Scheme I). Esterification of a suitably substituted 2-bromoaromatic acid under standard conditions gives the corresponding ester I-2. Generally, the esterification reaction is carried out under acidic conditions, in the presence of an alcohol, or under basic conditions, in the presence of a suitable alkyl halide. Such conditions are well known to those skilled in the art. Reaction of the 2-bromoaromatic ester I-2 with a suitable aniline or amine (G-NH2) gives the corresponding N-substituted-2-aminoaromatic ester I-3. Generally, this reaction is carried out at elevated temperature using standard heating or microwave irradiation in a suitable solvent such as 1,4-dioxane, toluene or 2-ethoxyethanol, in the presence of a catalyst such as Pd2(dba)3 or Cu / CuO, a suitable ligand such as BINAP or xantphos, and an inorganic base, generally Cs2CO3 or K2CO3. Saponification of the ester I-3 to the corresponding N-substituted-2-aminoaromatic acid derivative (I-4) is generally carried out under standard basic conditions using a base such as LiOH, KOH, or NaOH in a suitable solvent or solvent system such as methanol / H2O, ethanol / H2O, or THF / H2O. Such conditions are well known to those skilled in the art.

[0257] An alternative approach that will be readily apparent to those skilled in the art is to react the 2-bromoaromatic acid I-1 directly with a suitable aniline or amine (G-NH2) to obtain the compound I-4. These reaction conditions are similar to those described above for the conversion of I-2 to I-3, although the use of a ligand may or may not be required.

[0258] In another alternative approach, the intermediate N-substituted-2-amino aromatic acid derivative I-4 preferably starts from a suitably substituted 2-fluoro-aromatic nitrile I-5 and can be prepared using an S N Ar reaction. For example, compound I-5 can be reacted with a suitable aniline or amine (G-NH2) to effect the desired S N Ar reaction to obtain the substituted product I-6. This reaction is generally carried out in a suitable polar solvent such as DMF or DMSO, in the presence of a base, often NaH or K2CO3. This reaction can be carried out at room temperature or with heating depending on the relative reactivity of the starting materials. The nitrile group of I-6 is hydrolyzed by reaction with a hydroxyl base, usually LiOH, KOH, or NaOH, in a suitable solvent or solvent system, such as methanol / H2O, ethanol / H2O, or THF / H2O, to obtain the corresponding carboxylic acid I-4. This reaction can be carried out at room temperature or with heating. Such conditions are well known to those skilled in the art.

Chemical Structure

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0259] Pharmaceutical Compositions, Formulations, Dosage Forms The present invention relates to [a] any novel compound of a formula disclosed herein that includes formula (X) and each of formulas (I)-(III) (i.e., including the corresponding partial general formula defined herein), or a pharmaceutically acceptable salt thereof and / or its corresponding tautomeric form (i.e., including the partial general formula as defined above); and [b] at least one pharmaceutically acceptable excipient and relates to pharmaceutical compositions, formulations, dosage forms, etc. composed thereof.

[0260] The compounds of the present invention are usually, but not necessarily, formulated into pharmaceutical compositions, formulations, dosage forms, etc. before administration to patients.

[0261] Therefore, the present invention is directed to pharmaceutical compositions, formulations, dosage forms, etc. as defined herein, comprising a compound or compound species of the present invention (i.e., as defined in the present application) and a pharmaceutically acceptable excipient.

[0262] In particular, the present invention also relates to [a] a compound defined by any of the formulas disclosed herein that includes formula (X) and each of formulas (I)-(III) (i.e., including the corresponding partial general formula defined herein) of the present invention, or a pharmaceutically acceptable salt thereof and / or its corresponding tautomeric form (i.e., including the partial general formula as defined herein); [b] at least one pharmaceutically acceptable excipient; and [c] optionally, one or more other therapeutic components and relates to pharmaceutical compositions or formulations comprising the same.

[0263] The pharmaceutical compositions of the present invention may be prepared and packaged in bulk form capable of extracting an effective amount of the compound of the present invention and then administering it to patients in the form of powders, syrups, and injection solutions, etc. Alternatively, the pharmaceutical compositions of the present invention may be prepared and packaged in unit dosage form.

[0264] For oral administration, for example, one or more tablets or capsules may be administered. The dosage of the pharmaceutical composition includes at least a therapeutically effective amount of a compound of the present invention (i.e., any of the formulas disclosed herein including the compounds of formula (X) and formulas (I) to (III) (i.e., including the corresponding partial general formulas defined herein), or a pharmaceutically acceptable salt thereof and / or its corresponding tautomeric form (i.e., including the partial general formula as defined above), in particular, its pharmaceutically acceptable salt).

[0265] A pharmaceutical composition or formulation as defined herein generally contains one compound of the present invention. However, in certain embodiments, these pharmaceutical compositions may contain two or more compounds of the present invention. In addition, these pharmaceutical compositions of the present invention may optionally further contain one or more additional pharmaceutically active compounds.

[0266] As used herein, "pharmaceutically acceptable excipient" means a material, composition or vehicle included in giving form or consistency to a composition. Each excipient must be compatible with the other components of the pharmaceutical composition when mixed so as to avoid interactions that substantially reduce the effectiveness of the compounds of the present invention when administered to a patient and interactions that result in a pharmaceutically unacceptable pharmaceutical composition. In addition, each excipient must of course be of a sufficiently high purity to render it pharmaceutically acceptable.

[0267] Suitable pharmaceutically acceptable excipients vary depending on the particular dosage form selected. In addition, suitable pharmaceutically acceptable excipients can be selected for particular functions they can serve within the composition.

[0268] For example, certain pharmaceutically acceptable excipients can be selected for their ability to assist in the production of a uniform dosage form. Certain pharmaceutically acceptable excipients can be selected for their ability to assist in the production of a stable dosage form. Certain pharmaceutically acceptable excipients can be selected for their ability to assist in the transport or conveyance of one or more compounds of the present invention from one organ or body part to another organ or body part upon administration to a patient. Certain pharmaceutically acceptable excipients can be selected for their ability to improve patient compliance.

[0269] Furthermore, pharmaceutical compositions, formulations, dosage forms, etc. may conveniently be provided in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art.

[0270] All methods include the step of associating the active ingredient with a carrier composed of one or more auxiliary ingredients. In general, formulations are prepared by uniformly and intimately associating the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.

[0271] Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, extenders, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifying agents, sweetening agents, flavoring agents, buffering agents, coloring agents, anti-caking agents, wetting agents, chelating agents, plasticizers, thickening agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents. Those skilled in the art will recognize that certain pharmaceutically acceptable excipients may perform more than one function and may perform another function depending on the amount of excipient present in the formulation and what other components are present in the formulation.

[0272] A person skilled in the art has the knowledge and skill in the art to simply select an appropriate amount of a suitable pharmaceutically acceptable excipient for use in the present invention. In addition, there are several sources of information available to those skilled in the art that describe pharmaceutically acceptable excipients and may be useful in the selection of suitable pharmaceutically acceptable excipients. For example, Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press) may be mentioned.

[0273] The compounds of the present invention and one or more pharmaceutically acceptable excipients are generally formulated into dosage forms suitable for administration to a patient by the desired route of administration.

[0274] Regarding the present invention, conventional dosage forms include the following: (1) Those suitable for oral administration such as tablets, capsules, caplets, pills, lozenges, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; (2) Those suitable for parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) Those suitable for transdermal administration such as transdermal patches; (4) Those suitable for rectal administration such as suppositories; (5) Those suitable for inhalation such as aerosols and solutions; and (6) Those suitable for topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.

[0275] The pharmaceutical compositions or formulations of the present invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington’s Pharmaceutical Sciences (Mack Publishing Company).

[0276] Generally, the pharmaceutical compositions of the present invention are prepared using conventional materials and techniques such as mixing and blending.

[0277] For the purposes of the present invention, the term "active ingredient" is defined as any chemical substance or composition of the present invention that can be delivered from the device to the use environment to obtain the desired result.

[0278] Of course, the percentage of the compound in the composition can be varied as the amount of the active agent such that a suitable dosage is obtained in such therapeutically useful compositions.

[0279] In another aspect, the present invention relates to a pharmaceutical composition comprising any compound of a formula disclosed herein including formula (I), or a pharmaceutically acceptable salt and / or corresponding tautomeric form thereof, and at least one pharmaceutically acceptable excipient.

[0280] In another aspect, the present invention is any compound of a formula disclosed herein including formula (I), or a pharmaceutically acceptable salt and / or corresponding tautomeric form thereof; and at least one pharmaceutically acceptable excipient and relates to a pharmaceutical composition or formulation comprising the same.

[0281] In another aspect, the present invention is [a] a compound of the present invention according to any one of the formulas specified below (i.e., as defined in the present application): · formula (I), (IA) or (IB); · formula (II), (IIA) or (IIB); · formula (III), (IIIA) or (IIIA''); · formula (IIIB) or (IIIB'); · formula (IIIC) or (IIIC'); · formula (IIID); · formula (IIIE) or (IIIE'); or The pharmaceutically acceptable salts and / or their corresponding tautomeric forms; and [b]At least one or more pharmaceutically acceptable excipients relate to a pharmaceutical composition or formulation comprising the same.

[0282] In other aspects, the present invention relates to [a]Any of the compounds of the present invention which may comprise any of the compound intermediates, compound species or examples defined in the present application; or the pharmaceutically acceptable salts and / or their corresponding tautomeric forms thereof; and [b]At least one or more pharmaceutically acceptable excipients relate to a pharmaceutical composition or formulation comprising the same.

[0283] It will be recognized that the actual preferred dosage of the compounds used in the compositions of the present invention will vary depending on the particular composition being formulated, the mode of administration, the particular site of administration and the host being treated.

[0284] The active compounds of the present invention may be orally administered, for example, with an inert diluent or an absorbable edible carrier, or they may be enclosed in hard or soft capsules, or they may be tableted, or they may be directly incorporated with the food of the diet.

[0285] In one aspect, the present invention is directed to solid oral dosage forms such as tablets or capsules comprising a safe and effective amount of a compound of the present invention and a diluent or bulking agent. Suitable diluents and bulking agents include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g., corn starch, potato starch, and pregelatinized starch), cellulose and its derivatives (e.g., microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate. The oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g., corn starch, potato starch, and pregelatinized starch), gelatin, gum arabic, sodium alginate, alginic acid, tragacanth gum, guar gum, povidone, and cellulose and its derivatives (e.g., microcrystalline cellulose). The oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmellose, alginic acid, and sodium carboxymethyl cellulose. The oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc.

[0286] If appropriate, the unit dosage formulation for oral administration can be microencapsulated. This composition can also be prepared to extend or sustain release, for example, by coating with a polymer, wax, etc. or entrapping the particulate matter in a polymer, wax, etc.

[0287] The compounds of the present invention can also be conjugated to a soluble polymer as a targetable drug carrier. Such polymers can include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethyl aspartamide phenol, or polyethylene oxide polylysine substituted with palmitoyl residues. Further, the compounds of the present invention can be conjugated to biodegradable polymer species useful for achieving sustained drug release, such as polylactic acid, poly(ε-caprolactone), polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked block copolymers or amphiphilic block copolymers of hydrogels.

[0288] Methods, Uses, Compounds for Use in Manufacture and / or Treatment of Diseases In general, the present invention relates to, for use in the manufacture of a medicament, and / or a therapeutically effective amount of, any compound of a formula disclosed herein that includes formula (X) and each of formulas (I)-(III) (i.e., including the corresponding partial general formulas as defined herein), or a pharmaceutically acceptable salt thereof and / or its corresponding tautomeric form (i.e., including the partial general formula as defined above) or a pharmaceutically acceptable salt thereof; or its corresponding pharmaceutical composition or formulation for treating each of pain and / or pain-related diseases, disorders or conditions, for use in therapy, or relating to a compound, comprising administering the same to a patient or subject in need thereof.

[0289] As used herein, a "patient" or "subject" in need thereof refers to a human or a mammal. Preferably, the subject to be treated is a human.

[0290] In another aspect, the present invention also relates to, for use in the manufacture of a medicament, and / or Pain-related diseases, disorders or conditions such as pain caused by various diseases as defined herein in the present application; Pain caused by trauma; Pain caused by iatrogenic (i.e., medical or dental) procedures; Atrial fibrillation that is virtually idiopathic or caused by various diseases as defined herein in the present application Relates to a treatment method, use in therapy, and a compound for treating

[0291] As used herein, the term "iatrogenic" refers to pain inadvertently caused by healthcare or dental practitioners such as surgeons or dentists during medical or dental procedures or diagnostic procedures, including but not limited to pain caused by preoperative (i.e., "beforehand"), perioperative (i.e., "during", or pain medically induced during a non-surgical or surgical procedure), and postoperative (i.e., "afterwards", postoperative or pain caused by surgical induction) medical or dental procedures.

[0292] In another aspect, the present invention comprises administering to a patient or subject in need thereof a compound of the present invention, or a pharmaceutically acceptable salt and / or corresponding tautomeric form thereof, in an amount effective for treatment and / or for use in the manufacture of a medicament; or a pharmaceutical composition or formulation thereof. Pain-related diseases, disorders or conditions; Pain caused by trauma; Pain caused by iatrogenic, medical or dental procedures; or Atrial fibrillation caused by idiopathic atrial fibrillation or related diseases, disorders or conditions Relates to a treatment method, use in therapy, and a compound for treating

[0293] In another aspect, the present invention is for use in the manufacture of a medicament and / or Chronic pain; Acute pain; Neuropathic pain; Inflammatory pain of various physiological origins; Nociceptive pain; Neurological damage, neuropathic damage or neuron damage-related or associated pain disorders caused by diseases; neuralgia and related acute or chronic pain; Postherpetic neuralgia; Skeletal muscle pain; low back pain and neck pain; sprains and strains; Myofascial pain; myositis or muscle inflammation; Repetitive motion pain; Complex regional pain syndrome; Chronic or acute arthritis pain; Sympathetically maintained pain; Cancer, toxin and chemotherapy-related pain; Postoperative pain syndrome and / or related phantom limb pain; Postoperative medical treatment or dental treatment or therapeutic pain; HIV-related pain, pain induced by HIV treatment; Paroxysmal atrial fibrillation; Persistent atrial fibrillation; Permanent atrial fibrillation; Atrial fibrillation associated with heart failure; Atrial fibrillation associated with valvular heart disease; or Atrial fibrillation associated with chronic kidney disease selected from Pain-related diseases, disorders or conditions; Pain caused by trauma; Pain caused by iatrogenic, medical treatment or dental treatment respectively; or Atrial fibrillation caused by idiopathic atrial fibrillation or related diseases, disorders or conditions Relates to the use of a therapeutic method, therapy, compound for treating.

[0294] In another aspect, the present invention relates to these pain definitions as follows: Nociceptive pain is selected from postoperative pain, cancer pain, low back pain and craniofacial pain, osteoarthritis pain, toothache or diabetic peripheral neuropathy; Inflammatory pain is selected from pain associated with rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis or juvenile arthritis; Skeletal muscle pain is selected from bone and joint pain, osteoarthritis; low back pain and neck pain; pain resulting from physical trauma or amputation; Disease-induced neurological damage or neuron neuropathic damage-related or associated pain disorders are neuropathy, pain-related nerve damage, pain-related nerve root avulsion injury, painful traumatic mononeuropathy, painful polyneuropathy, erythromelalgia, paroxysmal extreme pain disorder (PEPD), burning mouth syndrome; central pain syndrome caused by lesions at the nervous system level; traumatic nerve injury, nerve compression or entrapment, congenital insensitivity to pain (CIP), dysmenorrhea, primary erythromelalgia; HIV peripheral sensory neuropathy; pudendal neuralgia, spinal cord nerve injury, chronic inflammatory demyelinating polyneuropathy (CIDP), carpal tunnel syndrome or vasculitic neuropathy; Inflammatory pain of various origins is selected from osteoarthritis, rheumatoid arthritis, rheumatic disorders, tendosynovitis and gout, shoulder tendinitis or bursitis, gouty arthritis, and polymyalgia rheumatica, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, or other pain caused by central sensitization; complex regional pain syndrome, chronic arthritis pain and related neuralgia, acute pain, or Atrial fibrillation is selected from paroxysmal atrial fibrillation, persistent atrial fibrillation, permanent atrial fibrillation, atrial fibrillation with heart failure, atrial fibrillation with valvular heart disease, or atrial fibrillation with chronic kidney disease.

[0295] In one aspect, the present invention is chronic, acute or pre-operative related pain; acute, chronic or post-operative related pain; or paroxysmal, persistent or permanent atrial fibrillation selected from pain-related diseases, disorders or conditions; pain caused by trauma; or pain caused by iatrogenic, medical treatment or dental treatment, respectively, Atrial fibrillation caused by idiopathic atrial fibrillation or related diseases, disorders or conditions relates to.

[0296] In other aspects, the present invention is for use in the manufacture of a medicament and / or chronic, acute or pre-operative related pain selected from neuropathic pain or chronic neuropathic pain, chronic degenerative joint disease pain, toothache or inflammatory pain; acute, chronic or post-operative related pain selected from bunionectomy pain, hernia repair pain, breast surgery pain or cosmetic surgery pain; or atrial fibrillation selected from paroxysmal, persistent or permanent relates to a treatment method, use in a therapy, and a compound for treating.

[0297] In other aspects, the present invention is for use in the manufacture of a medicament and / or neuropathic pain or chronic neuropathic pain selected from small fiber mediated diabetic neuropathy, small fiber neuropathy, idiopathic small fiber neuropathy, painful diabetic neuropathy or polyneuropathy; inflammatory pain selected from osteoarthritis, chronic osteoarthritis knee pain or chronic inflammatory demyelinating polyneuropathy; or atrial fibrillation selected from paroxysmal, persistent or permanent relates to a treatment method, use in a therapy, and a compound for treating.

[0298] In other aspects, the present invention is for use in the manufacture of a medicament and / or peripheral neuropathic pain, central neuropathic pain, hereditary acrodynia (IEM), small fiber neuralgia (SFN), paroxysmal extreme pain disorder (PEPD), painful diabetic neuropathy, chronic low back pain, neuropathic back pain, sciatica, non-specific low back pain, multiple sclerosis pain, HIV-associated neuropathy, postherpetic neuralgia, trigeminal neuralgia, vulvodynia, pain caused by physical trauma, pain after amputation, neural tumor pain, phantom limb pain, cancer, toxins, chronic inflammatory conditions or atrial fibrillation relates to a treatment method, use in a therapy, and a compound for treating.

[0299] In another aspect, the present invention relates to a method of treatment, use in therapy, compound for use in the manufacture of a medicament and / or in an amount effective to treat, for a patient or subject in need thereof, an inflammatory-mediated pain syndrome, comprising administering a compound of any of the formulas disclosed herein, including each of formula (X) and formulas (I)-(III) (i.e., including the corresponding partial general formulas as defined herein), or a pharmaceutically acceptable salt thereof and / or its corresponding tautomeric form (i.e., including a partial general formula as defined above) or a pharmaceutically acceptable salt thereof; or its corresponding pharmaceutical composition or formulation to a patient or subject in need thereof.

[0300] In another aspect, the present invention relates to a method of treatment, use in therapy, compound for use in the manufacture of a medicament and / or in an amount effective to treat, for a patient or subject in need thereof, a compound of any of the formulas disclosed herein, including each of formula (X) and formulas (I)-(III) (i.e., including the corresponding partial general formulas as defined herein), or a pharmaceutically acceptable salt thereof and / or its corresponding tautomeric form (i.e., including a partial general formula as defined above) or a pharmaceutically acceptable salt thereof; or its corresponding pharmaceutical composition or formulation comprising administering a pain-related disease, disorder or condition; pain caused by trauma; pain caused by iatrogenic (i.e., e.g., medical or dental) procedures, respectively; or paroxysmal, persistent or permanent atrial fibrillation to a patient or subject in need thereof for treating or reducing the severity thereof.

[0301] In another aspect, the present invention relates to a method of treatment, use in therapy, compound for use in the manufacture of a medicament and / or in an amount effective to treat, for a patient or subject in need thereof, Any compound of a formula disclosed herein that includes formula (X) and formulas (I)-(III) (i.e., including the corresponding partial general formulas defined herein), or a pharmaceutically acceptable salt thereof and / or its corresponding tautomeric form (i.e., including the partial general formula as defined above) or a pharmaceutically acceptable salt thereof; or its corresponding pharmaceutical composition or formulation A method of treatment, use in therapy, for treating or inhibiting the Nav1.8 voltage-dependent sodium channel in a subject, comprising administering to a human in need thereof.

[0302] In another aspect, the present invention relates to a compound for use in the manufacture of a medicament and / or chronic, acute or perioperative or preoperative related pain; acute, chronic or postoperative related pain; or paroxysmal, persistent or permanent atrial fibrillation A method of treatment, use in therapy, for treating each pain and / or pain-related disorder or condition selected from the above.

[0303] In another aspect, the present invention relates to a compound for use in the manufacture of a medicament and / or neuropathic pain, chronic neuropathic pain, chronic degenerative joint pain, toothache or inflammatory pain; acute, chronic or postoperative related pain selected from bunionectomy pain, hernia repair pain, breast surgery pain or cosmetic surgery pain: or paroxysmal, persistent or permanent atrial fibrillation A method of treatment, use in therapy, for treating each pain and / or pain-related disease, disorder or condition selected from the above.

[0304] In another aspect, the present invention relates to a compound for use in the manufacture of a medicament and / or Neuropathic pain or chronic neuropathic pain selected from small fiber-mediated diabetic neuropathy, small fiber neuropathy, idiopathic small fiber neuropathy, painful diabetic neuropathy or polyneuropathy; Inflammatory pain selected from osteoarthritis pain, chronic osteoarthritis knee pain or chronic inflammatory demyelinating polyneuropathy; or Atrial fibrillation selected from paroxysmal, persistent or permanent Relates to a treatment method, use in therapy, compound for treating chronic, acute or pre-operative related pain selected from

[0305] In another aspect, the present invention is for use in the manufacture of a medicament and / or A therapeutically effective amount of Any compound of the formula disclosed herein including formula (X) and formula (I)-(III) (i.e., including the corresponding partial general formula defined herein), or a pharmaceutically acceptable salt thereof and / or corresponding tautomer (i.e., including the partial general formula as defined above) or a pharmaceutically acceptable salt thereof; or Its corresponding pharmaceutical composition or formulation Comprising administering to a patient or subject in need thereof Neuropathic pain and / or pain-related diseases, disorders or conditions respectively Relates to a treatment method, use in therapy, compound for treating

[0306] In another aspect, the present invention is for use in the manufacture of a medicament and / or Peripheral neuropathic pain, central neuropathic pain, hereditary acrodynia (IEM), small fiber neuralgia (SFN), paroxysmal extreme pain disorder (PEPD), painful diabetic neuropathy, chronic low back pain, neuropathic back pain, sciatica, non-specific low back pain, multiple sclerosis pain, HIV-associated neuropathy, postherpetic neuralgia, trigeminal neuralgia, vulvodynia, pain caused by physical trauma, pain after amputation, neural tumor pain, phantom limb pain, cancer, toxins, chronic inflammatory conditions or atrial fibrillation Relates to a treatment method, use in therapy, compound for treating

[0307] In another aspect, the present invention relates to for use in the manufacture of a medicament and / or a therapeutically effective amount of any compound of a formula disclosed herein, including each of formula (X) and formulas (I) - (III) (i.e., including the corresponding partial general formula as defined herein), or a pharmaceutically acceptable salt thereof and / or corresponding tautomeric form (i.e., including the partial general formula as defined above) or a pharmaceutically acceptable salt thereof; or its corresponding pharmaceutical composition or formulation A method of treatment for treating an inflammatory pain-mediated syndrome, use in therapy, a compound, or a pain-related disease, disorder or condition such as pain caused by various diseases as defined herein in the present application; pain caused by trauma; pain caused by each iatrogenic (i.e., e.g., medical or dental) procedure; or atrial fibrillation caused by idiopathic atrial fibrillation or related diseases, disorders or conditions A method for treating and reducing the severity thereof relates to.

[0308] In one aspect, the present invention also provides the use of a compound of the present invention in the manufacture of a medicament for treating the disorders described herein.

[0309] In another aspect, the present invention also provides a compound of the present invention for use in therapy as described herein or as conventionally understood in the art.

[0310] As used herein, "treatment" with respect to a condition means (1) improving or preventing the condition or one or more biological signs of the condition; (2) (a) one or more points of a biological cascade leading to or causing the condition; or (b) one or more of the biological signs of the disease state interfering with (3) alleviating one or more of the symptoms or effects associated with the disease state; or (4) slowing the progression of one or more of the disease state or the biological signs of the disease state means.

[0311] As indicated above, the "treatment" of a disease state includes the prevention of the disease state. Those skilled in the art will recognize that "prevention" is not an absolute term.

[0312] In medicine, "prevention" is understood to refer to the prophylactic administration of a drug to substantially reduce the likelihood or severity of a disease state or its biological signs, or to delay the onset of such a disease state or its biological signs.

[0313] As used herein, "effective amount" and "therapeutically effective amount" are used interchangeably. The effective amount with respect to the compounds of the present invention is an amount of the compound that is sufficient to treat the disease state of the patient within the scope of sound medical judgment, but low enough (in a reasonable benefit / risk ratio) to avoid serious side effects.

[0314] As used herein, the effective amount of a compound, pharmaceutically acceptable salt or corresponding pharmaceutical composition of the present invention depends on the particular compound selected (e.g., taking into account the potency, efficacy, and half-life of the compound); the route of administration selected; the disease state being treated; the severity of the disease state being treated; the age, size, weight, and health status of the patient being treated; the medical history of the patient being treated; the duration of treatment; the nature of combination therapy; the desired therapeutic effect; similar factors and can be determined routinely by those skilled in the art.

[0315] In another aspect, the present invention relates to a compound of the present invention that is useful as an inhibitor of voltage-dependent sodium channels, or a pharmaceutically acceptable salt thereof, or a corresponding pharmaceutical composition.

[0316] In one aspect, the compound of the present invention, or a pharmaceutically acceptable salt thereof, or a corresponding pharmaceutical composition is an inhibitor of Nav1.8. Thus, without being bound by a particular theory, the compound and composition are particularly useful for treating a disease, condition, or disorder in which activation or upregulation of Nav1.8 is associated with the disease, condition, or disorder, or for reducing the severity thereof. When activation or upregulation of Nav1.8 is associated with a particular disease, condition, or disorder, that disease, condition, or disorder is also referred to as a "disease, condition, or disorder mediated by Nav1.8".

[0317] Thus, in another aspect, the present invention provides a method for treating a disease, condition, or disorder in which activation or upregulation of Nav1.8 is associated with the disease state, or for reducing the severity thereof. The activity of the compounds used as inhibitors of Nav1.8 in the present invention can generally be assayed by the methods described in the examples herein or by methods available to those skilled in the art.

[0318] In another aspect, the present invention is for use in the manufacture of a medicament and / or in a therapeutically effective amount of any compound of the formulae disclosed herein, including formula (X) and formulae (I) - (III) (i.e., including the corresponding partial general formulae as defined herein), or a pharmaceutically acceptable salt thereof and / or a corresponding tautomeric form (i.e., including a partial general formula as defined above) or a pharmaceutically acceptable salt thereof; or a corresponding pharmaceutical composition or formulation for treating or inhibiting Nav1.8 voltage-dependent sodium channels in a subject, comprising administering to a human in need thereof.

[0319] In other aspects, the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in the treatment of chronic pain, gastrointestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence or cardiac arrhythmia in a subject or for reducing the severity thereof.

[0320] In other aspects, the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in the treatment of gastrointestinal pain in a subject or for reducing the severity thereof, wherein the gastrointestinal pain comprises inflammatory bowel disease pain, Crohn's disease pain or interstitial cystitis pain.

[0321] In other aspects, the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in the treatment of neuropathic pain in a subject or for reducing the severity thereof, wherein the neuropathic pain comprises postherpetic neuralgia, diabetic neuropathy, painful HIV-related sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, posttraumatic pain, phantom limb pain, painful neuroma, traumatic neuroma, Morton's neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica; nerve traction injury, brachial plexus traction injury; complex regional pain syndrome, drug therapy-induced neuropathy, cancer chemotherapy-induced neuropathy, antiretroviral therapy-induced neuropathy; pain after spinal cord injury, idiopathic small fiber neuropathy, idiopathic sensory neuropathy or trigeminal-autonomic cephalgia.

[0322] In other aspects, the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in the treatment of musculoskeletal pain in a subject or for reducing the severity thereof, wherein the musculoskeletal pain comprises osteoarthritis pain, back pain, cold pain, burn pain or toothache.

[0323] In another aspect, the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in the treatment of inflammatory pain in a subject or the reduction of its severity, wherein the inflammatory pain comprises rheumatoid arthritis pain or vulvodynia.

[0324] In another aspect, the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in the treatment of idiopathic pain in a subject or the reduction of its severity, wherein the idiopathic pain comprises fibromyalgia pain.

[0325] In another aspect, the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for combination with one or more additional therapeutic agents administered simultaneously with, prior to, or after treatment with the present compound or pharmaceutical composition.

[0326] In another aspect, the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in the treatment of acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpes zoster neuralgia, general neuralgia, epilepsy, status epilepticus, neurodegenerative diseases, mental disorders, anxiety, depression, bipolar disorder, muscle cramps, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache, neck pain, hyperalgesia, intractable pain, nociceptive pain, breakthrough pain, postoperative pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exertional angina, palpitations, hypertension, or abnormal gastrointestinal motility or the reduction of its severity.

[0327] In other aspects, the present invention provides for the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for treating thigh cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; pancreatic pain; IBS pain; chronic and acute headache; migraine; tension headache including cluster headache; chronic and acute neuropathic pain, postherpetic neuralgia; diabetic neuropathy; HIV-related neuropathy; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy; peripheral nerve injury; painful neuroma; ectopic proximal and distal discharges; radiculopathy; chemotherapy-induced neuropathic pain; radiotherapy-induced neuropathic pain; postmastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; complex regional pain syndrome; phantom limb pain; intractable pain; acute pain, acute postoperative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tendinitis; injury / sports pain; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernia; chest pain, cardiac pain; pelvic pain, renal colic, acute obstetric pain, labor pain; cesarean section pain; acute inflammation, burn and trauma pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; protrusion pain; maxillofacial pain including rhinitis pain, toothache; pain in multiple sclerosis (MS); pain in depression; pain in leprosy; pain in Behçet's disease; painful lipomatosis; phlebitis pain; Guillain-Barré pain; painful legs and moving toes; Haglund's syndrome; erythromelalgia pain; Fabry disease pain; bladder and urogenital disorders including urinary incontinence; overactive bladder; painful bladder syndrome; interstitial cystitis (IC); prostatitis; type I and type II complex regional pain syndrome (CRPS); for the treatment of widespread pain, paroxysmal pain, itching, tinnitus, or angina-induced pain or for reducing the severity thereof.

[0328] In another aspect, the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in the treatment of neuropathic pain or the reduction of its severity. In one aspect, the neuropathic pain is selected from postherpetic neuralgia, diabetic neuropathy, painful HIV-related sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, posttraumatic pain, phantom limb pain, painful neuroma, traumatic neuroma, Morton's neuroma, nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica, nerve avulsion injury, brachial plexus avulsion, complex regional pain syndrome, drug therapy-induced neuropathy, cancer chemotherapy-induced neuropathy, antiretroviral therapy-induced neuropathy, pain after spinal cord injury, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal-autonomic cephalalgia.

[0329] Administration A treatment plan for administration of any compound of a formula disclosed herein of the present invention, including formulas (X) and (I) - (III) respectively (i.e., including the corresponding partial general formulas as defined herein), or a pharmaceutically acceptable salt and / or corresponding tautomeric form thereof (i.e., including the partial general formulas as defined above), or the corresponding pharmaceutical composition of the present invention can also be readily determined by one of ordinary skill in the art.

[0330] The amount of the compound, pharmaceutical composition, or dosage form of the present invention to be administered can vary widely in unit dosage form and is provided in an effective amount based on the patient's body weight per day to achieve the desired effect and also based on the mode of administration.

[0331] The scope of the present invention includes any compound, pharmaceutical composition, or sustained-release formulation or dosage form included in an effective amount to achieve its intended purpose. Individual requirements vary, but determination of the optimal range of the effective amount of each component is within the scope of the skill in the art.

[0332] In one aspect, of the present invention Any compound of a formula disclosed herein that includes formula (X) and each of formulas (I) - (III) (i.e., including the corresponding partial general formulas as defined herein), or a pharmaceutically acceptable salt and / or corresponding tautomeric form thereof (i.e., including partial general formulas as defined above), or a pharmaceutically acceptable salt thereof; or its corresponding pharmaceutical composition or formulation may be administered by any suitable route of administration, including both systemic and topical administration.

[0333] Systemic administration includes oral, parenteral, transdermal, rectal, and inhalation administration.

[0334] Parenteral administration refers to routes of administration other than enteral, transdermal, or inhalation, and generally involves injection or infusion. Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion.

[0335] Inhalation refers to administration to the patient's lungs, whether by inhalation through the mouth or through the nose. In one aspect, the pharmaceutical composition, formulation, dosage, dosage form, or dosing schedule of the present invention is adapted for administration by inhalation.

[0336] Topical administration includes application to the skin as well as intraocular, intravaginal, and intranasal administration.

[0337] The present invention, as defined herein and in the present application, may be administered according to a dosing schedule in which a single dose or multiple doses are administered at various intervals over a given period. For example, the dose may be administered once, twice, three times, or four times a day. The dose may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect.

[0338] Any compound of a formula disclosed herein that includes Formula (X) and Formulas (I) to (III) (i.e., including the corresponding partial general formulas defined herein), or a pharmaceutically acceptable salt and / or corresponding tautomeric form thereof (i.e., including the partial general formulas as defined above), or a suitable dosing regimen for the corresponding pharmaceutical composition of the present invention varies depending on pharmacokinetic properties of the compound such as absorption, distribution, and half-life, which can be determined by those skilled in the art.

[0339] In addition, a suitable dosing regimen for the compounds of the present invention, including the period during which such a dosing regimen is implemented, varies depending on the condition being treated, the severity of the condition being treated, the age and health status of the patient being treated, the medical history of the patient being treated, the nature of the combination therapy, the desired therapeutic effect, and similar factors within the knowledge and expertise of those skilled in the art. It will be further understood by such skilled persons that a suitable dosing regimen may need to be adjusted over time as the response of an individual patient to the dosing regimen is obtained or as the needs of an individual patient change.

[0340] In another aspect, the present invention is directed to liquid oral dosage forms. Oral liquids such as solutions, syrups, and elixirs can be prepared in unit dosage form such that a given quantity contains a predetermined amount of a compound of the present invention. Syrups can be prepared by dissolving a compound of the present invention in an aqueous solution optionally flavored, and elixirs are prepared by the use of a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing a compound of the present invention in a non-toxic vehicle. Solubilizing and emulsifying agents (e.g., ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ethers), preservatives, flavoring agents such as peppermint oil, or natural sweeteners or saccharin or other artificial sweeteners can also be added.

[0341] In other aspects, the present invention is directed to parenteral administration. Pharmaceutical compositions suitable for parenteral administration may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and may include aqueous and non-aqueous sterile injection solutions; and aqueous and non-aqueous sterile suspensions that may contain anti-precipitants and thickening agents. The compositions may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) state that requires only the addition of a sterile liquid carrier, for example, water for injection, immediately prior to use. Immediate-preparation injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

[0342] The compounds of the present invention or pharmaceutically acceptable salts or tautomers thereof or corresponding pharmaceutical compositions as defined herein may be administered parenterally or orally as injections, capsules, tablets, and granules, and preferably are administered as injections.

[0343] When used as an injection, the carrier is, for example, distilled water, physiological saline, etc., and a base or the like may be used for pH adjustment.

[0344] When used as capsules, granules, or tablets, the carrier may be known excipients (for example, starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.), binders (for example, starch, gum arabic, carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, etc.), lubricants (for example, magnesium stearate, talc, etc.), and the like.

[0345] Furthermore, it will be recognized by those skilled in the art that the optimal amounts and intervals between each dose of the compounds of the present invention or pharmaceutically acceptable salts or tautomers thereof or corresponding pharmaceutical compositions as defined herein are determined by the nature and degree of the condition being treated, the form, route, and site of administration, and the particular patient being treated, and that such optimization can be determined by the prior art.

[0346] Those skilled in the art will also recognize that the optimal treatment course, i.e., the number of doses of a compound of any of the formulas disclosed herein that includes the formulas (X) and (I)-(III) of the present invention (i.e., including the corresponding partial general formulas as defined herein) administered per day for a given number of days, or a pharmaceutically acceptable salt and / or corresponding tautomeric form thereof (i.e., including the partial general formulas as defined above), can be determined by those skilled in the art using conventional treatment course determination tests.

[0347] The amount necessary to achieve the therapeutic effect of a compound of the present invention or a pharmaceutically acceptable salt or tautomeric form thereof or a corresponding pharmaceutical composition as defined in the present application will, of course, vary depending on the particular compound, route of administration, subject under treatment, and particular disorder or disease being treated.

[0348] Suitable dosing regimens for the compounds of the present invention vary depending on the pharmacokinetic properties of the compounds, such as absorption, distribution, and half-life, which can be determined by those skilled in the art.

[0349] In addition, suitable dosing regimens, including the period during which such dosing regimens are carried out, for the compounds of the present invention vary depending on the condition being treated, the severity of the condition being treated, the age and health status of the patient being treated, the medical history of the patient being treated, the nature of the combination therapy, the desired therapeutic effect, and similar factors within the knowledge and expertise of those skilled in the art. Such skilled persons will further understand that suitable dosing regimens may need to be adjusted over time as the response of the individual patient to the dosing regimen is obtained or as the needs of the individual patient change.

[0350] In addition, the compounds of the present invention may generally be administered as prodrugs. As used herein, a "prodrug" of a compound of the present invention is a functional derivative of a compound that will eventually release the compound of the present invention in vivo when administered to a patient. Administration of a compound of the present invention as a prodrug may enable those skilled in the art to do one or more of the following: (a) Modify the expression of the compound in vivo; (b) Modify the duration of action of the compound in vivo; (c) Modify the transport or distribution of the compound in vivo; (d) Modify the solubility of the compound in vivo; and (e) Overcome side effects or other problems associated with the compound.

[0351] Typical functional derivatives used to produce prodrugs include modifications of compounds that are cleaved chemically or enzymatically in vivo. Such modifications, including the formation of phosphates, amides, esters, thioesters, carbonates, and carbamates, are well known to those skilled in the art.

[0352] The present invention also provides compounds of the invention for use in medical therapies, particularly for diseases as defined herein, such as pain-related diseases, disorders or conditions, such as pain caused by various diseases; pain caused by trauma; or pain caused by iatrogenic (i.e., e.g., medical or dental) procedures, etc. The present invention provides compounds of the invention for use in the treatment of diseases as defined above and as defined herein.

[0353] Thus, in a further aspect, the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of the above-mentioned diseases as defined above and as defined herein.

[0354] The dosage of the pharmaceutically effective compound of the present invention in the pharmaceutical dosage unit as described above is preferably an effective non-toxic amount selected from the range of 0.001 to 100 mg / kg of the effective compound, preferably 0.001 to 50 mg / kg. When treating a human patient in need of Nav1.8 inhibition, the selected dosage is preferably administered orally or parenterally 1 to 6 times a day. Preferred forms of parenteral administration include topical, rectal, transdermal, injection and continuous infusion. Oral dosage forms for human administration preferably contain 0.05 to 3500 mg of the effective compound. Oral administration using lower dosages is preferred. However, higher dosages of parenteral administration can also be used if safe and convenient for the patient.

[0355] The present invention also provides a pharmaceutical composition comprising 0.5 to 1,000 mg of a compound of formula (X) or a pharmaceutically acceptable salt thereof and 0.5 to 1,000 mg of a pharmaceutically acceptable excipient.

[0356] Combination Therapy and Use Thereof for Therapy In general, the present invention relates to a combination therapy, method of use, compound or use, wherein a patient or subject in need thereof is treated with one or more additional therapeutic agents administered simultaneously with, prior to, or after treatment with an effective amount of a compound of any of the formulas disclosed herein that includes formulas (X) and (I)-(III) of the present invention (i.e., including the corresponding partial general formulas as defined herein), or a pharmaceutically acceptable salt and / or corresponding tautomeric form thereof (i.e., including the partial general formulas as defined above) or a corresponding pharmaceutical composition thereof.

[0357] The effective drug or therapeutic agent, when used in combination with the compound or pharmaceutical composition of the present invention, can be used or administered at dosages as indicated in the Physicians’ Desk Reference (PDR) or otherwise determined by one of ordinary skill in the art.

[0358] In the context of this specification, the term "simultaneously", when referring to the co - administration of related drugs, means exactly simultaneously, as is the case, for example, in embodiments where those drugs are combined in a single formulation. In other aspects or embodiments, "simultaneously" may mean that one drug is taken shortly after another drug, where "shortly" means a period that confers the intended synergistic effect on those drugs.

[0359] In view of the foregoing, the present invention also relates to a combination therapy that can be composed of the simultaneous or concomitant administration, or sequential administration, of a compound or pharmaceutical composition of the present invention with other active drugs or therapeutic agents including, for example, but not limited to, acetaminophen, acetylsalicylic acid, Nav1.7 inhibitors, Nav1.9 inhibitors, antidepressants (i.e., for example, but not limited to, duloxetine or amitriptyline), antispasmodics (i.e., for example, but not limited to, pregabalin and gabapentin), opioids (i.e., for example, but not limited to, hydrocodone; codeine; morphine, oxycodone, oxymorphone, fentanyl, etc.), etc., and the above - mentioned administrations are also determined by those skilled in the art respectively. In one aspect, suitable Nav1.7 inhibitors or Nav1.9 inhibitors for use in the present invention include, but are not limited to, Nav1.7 inhibitors or Nav1.9 inhibitors known in the chemical literature.

[0360] In other examples of the combination therapy of the present invention, it includes a combination of sub - therapeutic amounts of acetaminophen or acetylsalicylic acid and a sub - therapeutic amount of an oral Nav1.8 inhibitor (such as a compound of the present invention described herein), and thus, the synergistic effect of these agents provides sufficient pain relief while reducing the side - effect profile and the risks associated with the use of the therapeutic doses of these agents as monotherapies.

[0361] In other examples of the combination therapies of the present invention, it includes a combination of a sub-therapeutic oral opioid receptor antagonist and a sub-therapeutic oral Nav1.8 inhibitor. Thus, the synergistic effect of these agents provides sufficient pain relief while reducing the side effect profile and the risks associated with the use of the therapeutic doses of these agents as monotherapies.

[0362] In yet other embodiments, an example of the combination therapy of the present invention includes an initial treatment with an intravenous or parenteral Na v 1.8 inhibitor formulation to achieve rapid pain relief, followed by treatment with an oral Na v 1.8 inhibitor formulation to maintain pain relief for a longer period.

[0363] In other embodiments, the present invention relates to a pain-related disease, disorder or condition; pain caused by trauma; or pain caused by iatrogenic medical or dental procedures and relates to a combination therapy for treating, the method comprising administering to a patient or subject in need thereof components: [a] a compound of any of the formulas disclosed herein, including formula (X) including formula (I), or a pharmaceutically acceptable salt or corresponding tautomeric form thereof; or [b] its corresponding pharmaceutical composition or formulation; and [c] other active drugs or therapeutic agents selected from: acetaminophen; acetylsalicylic acid; Na v 1.7 inhibitor; Na v 1.9 inhibitor; an antidepressant; an antispasmodic; or an opiate comprising simultaneous administration, combined administration, or sequential administration of a therapeutically effective combination of.

[0364] In other aspects, the present invention relates to combination therapies in which each component of such a combination for therapeutic use can be administered orally, intravenously, parenterally, or a combination thereof.

[0365] Other aspects also indicate that each component of the above-described combination can be administered at sub-therapeutic amounts.

[0366] In other aspects, the present invention each component of the combination therapy, including but not limited to by co-administration, concomitant administration, or sequential administration; and / or administered by the same or different routes of administration or combinations of routes of administration relates to combination therapies wherein each same or different route of administration or combination of routes of administration is selected from oral administration, intravenous administration, or parenteral administration.

[0367] In other aspects, the present invention relates to combination therapies using an opioid selected from, including but not limited to, hydrocodone; codeine; morphine, oxycodone, oxymorphone, or fentanyl.

[0368] In other aspects, the present invention relates to combination therapies using an antidepressant selected from, including but not limited to, duloxetine or amitriptyline.

[0369] In other aspects, the present invention relates to combination therapies using an antispasmodic selected from, including but not limited to, pregabalin and gabapentin.

[0370] In other aspects, each active agent or therapeutic agent as defined herein is administered at sub-therapeutic amounts. For example, an active agent or therapeutic agent, such as, including but not limited to, acetaminophen or acetylsalicylic acid, is each administered at sub-therapeutic amounts.

[0371] In other aspects, the present invention is directed to the administration to a patient or subject in need thereof [a] An oral Na of the present invention below the therapeutic dose v 1.8 inhibitor, i.e., any compound of the formula disclosed herein including formula (I) or a pharmaceutically acceptable salt or corresponding tautomeric form thereof; or a corresponding pharmaceutical composition thereof; [b] An oral opioid receptor antagonist below the therapeutic dose It relates to combination therapy for the above and for the purposes as defined herein, comprising simultaneous or combined administration, or sequential administration, of a therapeutically effective combination.

[0372] In another aspect of the present invention, [a] A Na below the therapeutic dose v 1.8 inhibitor or a compound of the present invention or as defined herein; and [b] An opioid receptor antagonist below the therapeutic dose or a compound of the present invention or as defined herein The synergistic effect of the combination reduces the side effects and risks associated with using each of the above agents individually at therapeutic doses or separately as one or more monotherapies.

[0373] In another aspect, the present invention [a] For achieving rapid pain relief, an intravenous or parenteral administration of a Nav1.8 inhibitor compound or a pharmaceutically acceptable salt or corresponding tautomeric form thereof; or a corresponding pharmaceutical composition or formulation of the present invention or known in the art as an initial treatment; and v 1.8 inhibitor compound or a pharmaceutically acceptable salt or corresponding tautomeric form thereof; or a corresponding pharmaceutical composition or formulation of the present invention or known in the art as an initial treatment; and [b] Subsequently, for maintaining longer-term pain relief, treatment with the same or a different oral Nav1.8 inhibitor compound or a pharmaceutically acceptable salt and / or tautomeric form thereof or a corresponding pharmaceutical composition or formulation of the present invention or known in the art It relates to combination therapy for the above and for the purposes as defined herein, comprising sequential administration of a therapeutically effective combination.

[0374] In another aspect, the present invention [a] For achieving rapid pain relief, any compound of a formula disclosed herein including formula (I) of the present invention, or a pharmaceutically acceptable salt or corresponding tautomeric form thereof; and / or the pharmaceutical composition or formulation of the present invention for initial treatment by intravenous or parenteral administration; and [b] for subsequent maintenance of longer-term pain relief, any compound of a formula disclosed herein including formula (I) or a pharmaceutically acceptable salt or corresponding tautomeric form thereof; and / or the pharmaceutical composition or formulation of the present invention for treatment by oral administration The present invention relates to a combination therapy for the above-defined and herein-defined purposes, comprising sequential administration of a therapeutically effective combination.

[0375] In another aspect, the present invention [a] for initial treatment by intravenous or parenteral administration of the pharmaceutical composition or formulation of the present invention for achieving rapid pain relief; and [b] for subsequent treatment by oral administration of the pharmaceutical composition or formulation of the present invention for maintaining longer-term pain relief The present invention relates to a combination therapy for the above-defined and herein-defined purposes, comprising sequential administration of a therapeutically effective combination.

[0376] In another aspect, the present invention relates to any compound of a formula disclosed herein including formula (I) or a pharmaceutically acceptable salt and / or corresponding tautomeric form thereof; or its corresponding pharmaceutical composition.

[0377] In another aspect, the present invention relates to pain-related diseases, disorders or conditions; pain caused by trauma; or pain caused by iatrogenic medical or dental procedures For use in combination therapy for treating any compound of a formula disclosed herein comprising formula (I) or a pharmaceutically acceptable salt and / or corresponding tautomeric form thereof; or a corresponding pharmaceutical composition relates to.

[0378] In yet another aspect, the present invention also relates to a synergistic combination or mixture of the compounds of the present invention, which may further comprise another active agent or one or more therapeutic agents as described herein, and optionally a pharmaceutically acceptable carrier, diluent or adjuvant, a corresponding sustained release composition, a composition formed from a dosage form or formulation, a dosage form or formulation, for use in combination therapy as described herein. Further, in such above-described combination compositions, dosage forms or formulations, each active drug ingredient is contained in a therapeutically effective and synergistic dosage.

[0379] The following examples illustrate the present invention and are not intended to limit the scope of the present invention in any way.

Examples

[0380] The present invention will be described below by way of examples. These examples are not intended to limit the scope of the present invention and provide guidance for those skilled in the art to manufacture and use the compounds, compositions, and methods of the present invention.

[0381] While specific aspects or embodiments of the present invention are described, those skilled in the art will recognize that various changes and modifications can be made without departing from the spirit and scope of the present invention.

[0382] Those skilled in the art will understand that purification methods (using acidic or basic modifiers) or post-treatment procedures of the compound (using acidic or basic conditions) can result in the formation of salts of the title compound (e.g., hydrobromide, formate, hydrochloride, trifluoroacetate, or ammonium salt of the title compound). The present invention is intended to encompass such salts.

[0383] Biology and Biological Assays Na v The 1.8 inhibitor 2,3-dihydroquinazolin-4(1H)-one compound or a pharmaceutically acceptable salt thereof is useful for the treatment of pain, pain disorder or condition, pain-related disorder or condition, or pain caused by a disease, such as those defined in the present application.

[0384] The biological activity of the compounds of the present invention can be determined using suitable assays such as those that measure such inhibition and the ability of the compound to inhibit voltage-gated sodium channel Na v 1.8 in vitro or in infected animal models.

[0385] Biological Assay Example 1: Human Na v 1.8, human Na v Human embryonic kidney 2993 cells (HEK293) expressing human Nav1.8, human Navβ1 and human TREK1 (HEK293-Na v 1.8) were grown in 150 cm 2 flasks at 37 °C and 5% CO2. HEK293-Na v 1.8 was subcultured every 2 - 3 days when the confluence reached 80 - 90% in a T175 cell culture flask.

[0386] The pharmacological evaluation of the present invention was carried out in combination with an assay developed with HEK293-Nav1.8 in a QPatch 48 HTX electrophysiological system. HEK293-Na v 1.8 was prepared on the day of use by removing the culture medium, washing with DPBS, adding Accutase (2 ml to cover the surface, 1 ml of puncture fluid, and then 1.5 minutes at 37 °C), and then stopping the enzymatic digestion and adding CHO-SFM II to obtain a suspension of 3 × 10 6 cells / mL.

[0387] The present invention was prepared in an extracellular solution having the following composition: (mM) NaCl 145, KCl 4, CaCl2 2, MgCl 2, HEPES 1, glucose 10, pH 7.4 with NaOH, and a molar osmotic concentration of 300 mOsM / L. An intracellular solution having the following composition was used: (mM) CsF 115, CsCl 20, NaCl 5, EGTA 10, HEPES 10, sucrose 20, pH 7.2 with CsOH, and a molar osmotic concentration of 310 mOsm / L.

[0388] Using the potential clamping mode with the QPatch 48 HTX system, the pharmacological activity of the present invention was determined for the Na 1 / 2 1.8 ion channel using a half inactivation state voltage protocol (V v ). The V 1 / 2 protocol was used with the following voltage steps: A holding potential of -100 mV was established, then a voltage step to 0 mV for 20 milliseconds (P1), then an inactivation voltage step at -46 mV for 8 seconds, then a step to -100 mV for 20 milliseconds, then a step to 0 mV for 20 milliseconds (P2), and then back to the holding potential of -100 mV. This voltage protocol was repeated at an amplitude of 0.07 Hz, and the magnitude of the current was quantified at the P2 step during recording. The inhibition according to the present invention of the measured current magnitude was analyzed by fitting a 6-8 point dose-response curve that enables determination of the 50% inhibitory concentration (IC 50 ). In the QPatch HTX software, the P2 current was normalized by the measured values at the baseline after the compound and after the positive control compound, and was fitted to the following formula.

Equation

[0389] To evaluate the rundown of the current during this test process, vehicle-only wells were used to determine the normalized current of the vehicle-only (n.I VEH ). To correct the compound response for rundown, the current was corrected according to the following formula.

Number

[0390] The compound of the present invention was tested for activity against Nav1.8 sodium channels in the above assay.

[0391] When the compounds of the examples were generally tested in at least one exemplary salt form or free base form by the above Nav1.8 sodium channel assay, the pIC50 value for at least one test run or the average pIC50 value for two or more test runs against Nav1.8 showed ≧5.1.

[0392] The compounds of Examples 1, 2, 3, 5, 6, 7, 8, 9, 10, 13, 14, 15, 17, 18, 19, 20, 22, 24-27, 29-32, 37, 38, 39, 41, 42, 44, 45, 46, 49, 53, 54, 55, 59, 62, 80, 84, 86, 94, 100, 124, 125, 133, 135, 136, 151, 163, 186, 195, 197, 202, 204, 208, 211, 217, 219, 220, 222, 223, 224, 229, 232, 235, 236, 237, 238, 248, 249, 250-253, 255, 258-264, 266, 267, 272-276, 282, 284, 285, 286, 287, 289, 291 and 295 were generally tested by the above Nav1.8 sodium channel assay in at least one set of test runs and showed average pIC50 values of ≧5.1 and ≦6.1 against Nav1.8.

[0393] The compounds of Examples 4, 11, 12, 16, 21, 23, 28, 34, 36, 40, 43, 50, 58, 67, 68, 71, 75, 77, 78, 82, 88, 92, 102, 113, 118, 119, 121, 127, 128, 130, 132, 134, 140, 141, 144, 145, 146, 147, 149, 154, 155, 156, 157, 164, 165, 169, 174, 175, 179, 181, 183, 196, 199, 206, 209, 210, 213, 215, 216, 218, 221, 239, 241, 243, 254, 265, 268, 270, 277, 280, 281, 283, 288, 290, 292, 293 and 299 were generally tested in at least one set of test runs by the above Nav1.8 sodium channel assay and showed mean pIC50 values of ≧6.2 and ≦6.9 against Nav1.8.

[0394] The compounds of Examples 33, 35, 47, 48, 51, 52, 56, 57, 60, 61, 63, 64, 65, 66, 69, 70, 72, 73, 74, 76, 79, 81, 83, 85, 87, 89, 90, 91, 93, 95, 96, 97, 98, 99, 101, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 114, 115, 116, 117, 120, 122, 123, 126, 129, 131, 137, 138, 139, 142, 143, 148, 150, 152, 153, 158, 159, 160, 161, 162, 166, 167, 168, 170, 171, 172, 173, 176, 177, 178, 180, 182, 184, 185, 187, 188, 189, 190, 191, 192, 193, 194, 198, 200, 201, 203, 205, 207, 212, 214, 225, 226, 227, 230, 231, 233, 234, 240, 242, 244, 245, 246, 247, 256, 257, 269, 271, 278, 279, 294, 296, 297 and 298 were generally tested in at least one set of test runs by the above Nav1.8 sodium channel assay and showed mean pIC50 values of ≧7.0 against Nav1.8.

[0395] When the compounds of the present invention were tested in at least one exemplary salt form or free base form generally according to the above Nav1.8 sodium channel assay, the pIC50 value for at least one test run or the average pIC50 value for two or more test runs against the Nav1.8 sodium channel showed the values shown in Tables 1 and 2 below.

[0396]

Table 8

[0397]

Table 9

[0398] Compound Example The present invention will be described below by way of examples. These examples are not intended to limit the scope of the present invention, but rather to provide guidance to those skilled in the art for manufacturing and using the compounds, compositions, and methods of the present invention. Although embodiments of the present invention are described, those skilled in the art will recognize that various changes and modifications can be made without departing from the spirit and scope of the present invention.

[0399] It will be understood by those skilled in the art that purification methods (using acidic or basic modifiers) or post-treatment procedures of the compounds (using acidic or basic conditions) can result in the formation of salts of the title compound (e.g., hydrobromide, formate, hydrochloride, trifluoroacetate, or ammonium salt of the title compound). The present invention is intended to encompass such salts.

[0400] The final compound was identified by LCMS (conditions listed below) and NMR. 1 1H NMR or 19 19F NMR spectra were recorded using a Bruker Avance III 500 MHz spectrometer, a Bruker Avance 400 MHz spectrometer, and a Varian Mercury Plus-300 MHz spectrometer. CDCl3 is deuterated chloroform, DMSO-d6 is deuterated dimethyl sulfoxide, and CD3OD is deuterated methanol. Chemical shifts were recorded in parts per million (ppm) from the low-field side relative to the internal standard tetramethylsilane (TMS) or the NMR solvent. Abbreviations for NMR data are as follows: s = singlet (single line), d = doublet (double line), t = triplet (triple line), q = quartet (quadruplet), m = multiplet (multiple lines), dd = doublet of doublets (double doublet), dt = triplet of doublets (double triplet), app = apparent, br = broad (wide). J represents the NMR coupling constant measured in Hertz.

[0401] Summary Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Unless otherwise noted, all temperatures are in °C (degrees Celsius). Unless otherwise noted, all reactions were carried out at ambient temperature under an inert atmosphere.

[0402] All temperatures are indicated in degrees Celsius, all solvents are of the highest available purity, and all reactions are carried out, if necessary, under anhydrous conditions in an argon (Ar) or nitrogen (N2) atmosphere.

[0403] Equipment 11H NMR spectra were recorded using a Bruker Avance III 400 MHz spectrometer and a Bruker Avance NEO NanoBay V4-3 400 MHz spectrometer. CDCl3 is deuterated chloroform, DMSO-d6 is deuterated dimethyl sulfoxide, and CD3OD is deuterated methanol. Chemical shifts were recorded in parts per million (ppm) from the internal standard tetramethylsilane (TMS) or the NMR solvent to the low magnetic field side. Abbreviations for NMR data are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets, dt = triplet of doublets, app = apparent, br = broad. J indicates the NMR coupling constant measured in Hertz.

[0404] Mass spectra were measured using an open access LC-MS system, a Waters Acquity QDa mass detector. Compounds were analyzed using a reverse phase column, such as Xbridge-C18, Sunfire-C18, Thermo Aquasil / Aquasil C18, Acquity HPLC C18, Thermo Hypersil Gold, eluting with an acetonitrile and water gradient containing a low percentage acid modifier, such as 0.02% TFA.

[0405] Analysis Method: LCMS method: A CSH C18 column (30 mm × 2.1 mm, i.d. 1.7 μm packing diameter) with an elution gradient of 1 - 100% (solvent B) for 1.85 minutes at a flow rate of 1.3 ml / min at 45 °C using 0.1% TFA in water (solvent A) and 0.1% TFA in acetonitrile (solvent B), and an electrospray positive [M+H + To obtain ES+ve] using a Waters Acquity QDa mass detector equipped with an Acquity UPLC.

[0406] LCMS method: At 45 °C, using formic acid in water (solvent A) and formic acid in acetonitrile (solvent B), with the following elution gradient: eluting with 1 - 100% (solvent B) for 1.85 minutes at a flow rate of 1.3 ml / min on a CSH C18 column (30 mm × 2.1 mm, i.d. 1.7 μm packing diameter), an Acquity UPLC equipped with a Waters Acquity QDa mass detector using electrospray positive [M+H + to obtain ES+ve].

[0407] LCMS method: At 45 °C, using 10 mM ammonium bicarbonate in water (solvent A) and acetonitrile (solvent B) adjusted to pH = 10 with 25% ammonium hydroxide solution, with the following elution gradient: eluting with 1 - 100% (solvent B) for 1.85 minutes at a flow rate of 1.3 ml / min on a CSH C18 column (30 mm × 2.1 mm, i.d. 1.7 μm packing diameter), an Acquity UPLC equipped with a Waters Acquity QDa mass detector using electrospray positive [M+H + to obtain ES+ve].

[0408] LCMS method: At 25 °C, using 0.1% formic acid in water (solvent A) and 0.1% formic acid in acetonitrile (solvent B), with the following elution gradient: eluting with 0 - 100% (solvent B) for 3.1 minutes at a flow rate of 1.0 ml / min and holding at 100% for 0.8 minutes on a Snfire C18 column (30 mm × 2.1 mm, i.d. 3.5 μm packing diameter), an Agilent 1290 Infinity II LC system equipped with an Agilent MSD 6125B / 6130 using multimode (ESI and APCI +ve and -ve).

[0409] LCMS method: Using Atlantis dC18 column (50 mm × 4.6 mm, i.d. 5.0 μm packing diameter) with the following elution gradient: held at 5 - 95% (solvent B) for 5.0 minutes and 95% for 1.5 minutes at a flow rate of 1.0 ml / min, eluting at 25°C with 0.1% TFA in water (solvent A) and methanol (solvent B), using Agilent 1290 Infinity II LC system equipped with Agilent MSD 6125B / 6130 with multimode (ESI and APCI +ve and -ve).

[0410] LCMS method: Using Zorbax XDB C18 column (50 mm × 4.6 mm, i.d. 3.5 μm packing diameter) with the following elution gradient: held at 10 - 95% (solvent B) for 3.5 minutes and 95% for 1.0 minutes at a flow rate of 1.0 ml / min, eluting at 25°C with 10 mM ammonium acetate in water (solvent A) and acetonitrile (solvent B), using Agilent 1290 Infinity II LC system equipped with Agilent MSD 6125B / 6130 with multimode (ESI and APCI +ve and -ve).

[0411] LCMS method: Using Xbridge C8 column (50 mm × 4.6 mm, i.d. 3.5 μm packing diameter) with the following elution gradient: held at 10 - 95% (solvent B) for 4.0 minutes and 95% for 1.0 minutes at a flow rate of 1.0 ml / min, eluting at 25°C with 10 mM ammonium bicarbonate in water (solvent A) and acetonitrile (solvent B), using Agilent 1290 Infinity II LC system equipped with Agilent MSD 6125B / 6130 with multimode (ESI and APCI +ve and -ve).

[0412] LCMS method: Using CSH C18 column (30 mm × 2.1 mm, i.d. 1.7 μm packing diameter) with the following elution gradient: eluting at 55°C with 0.1% formic acid in water (solvent A) and 0.1% formic acid in acetonitrile (solvent B), using 1 - 99% (solvent B) for 2.0 minutes at a flow rate of 1.0 ml / min, electrospray positive [M + H +Acquity UPLC equipped with a Waters Acquity QDa mass detector using ES+ve to obtain

[0413] Definition and Abbreviations of Examples In the following experimental descriptions, the following abbreviations may be used.

[0414]

Table 10

[0415] Intermediate Compound Example Intermediate 1 6-Amino-3-chloro-2,4-difluorobenzoic acid

Chem.

[0416] At 60 °C under N2, N-chlorosuccinimide (3.23 g, 24.21 mmol) was added dropwise to a stirred mixture of 2-amino-4,6-difluorobenzoic acid (3.81 g, 22.01 mmol). The reaction mixture was stirred at 60 °C for 2 hours. The reaction was diluted with water (200 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, concentrated, and the title compound was obtained as a yellow solid (2.3 g, 11.17 mmol, 51% yield). MS (m / z) 208.2 (M+H) + 。

[0417] Intermediate 2 was prepared from the indicated aryl aniline by the same method as described for Intermediate 1.

[0418]

Table 11

[0419] Intermediate 3 2 - Bromo - 4 - (methylsulfonyl)benzoic acid

Chem.

[0420] Intermediate 4 2 - Bromo - 5 - methoxy - 4 - (trifluoromethyl)benzoic acid

Chem.

[0421] Intermediate 5 Ethyl 2-bromo-4-(trifluoromethyl)benzoate [Chemical formula] To a stirred solution of 2-bromo-4-(trifluoromethyl)benzoic acid (10.0 g, 37.2 mmol) in DMF (100 mL) at 25 °C under N2, K2CO3 (5.65 g, 40.9 mmol) was added dropwise, followed by ethyl iodide (3.60 mL, 44.6 mmol). The reaction mixture was stirred at the same temperature for 3 hours. Water (150 mL) was added and the reaction was extracted with EtOAc (2 × 250 mL). The combined organic extracts were washed with brine (150 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (Biotage, 100 g SNAP column, 40 minutes, 10% EtOAc / petroleum ether) to give the title compound as a colorless oil (9.3 g, 31.3 mmol, 84% yield). GCMS (m / z) 296.0 (M+H) + .

[0422] Intermediates 6 - 25 were prepared from the indicated carboxylic acids by the same method as described for Intermediate 5.

[0423] [Table 12] TIFF0007701880000131.tif237170TIFF0007701880000132.tif239170TIFF0007701880000133.tif29170

[0424] Intermediate 26 Methyl 2-bromo-5-(trifluoromethyl)benzoate [Chemical formula] To a stirred solution of 2-bromo-5-(trifluoromethyl)benzoic acid (750 mg, 2.79 mmol) in methanol (3 mL) was added sulfuric acid (0.4 mL, 7.50 mmol), and the mixture exothermed. The resulting solution was heated at 70 °C for 2.5 h in a sealed vial. The cooled reaction mixture was diluted with water and then extracted with two portions of TBME. The combined organic extracts were dried by filtration through a hydrophobic frit and concentrated under a stream of nitrogen to give the title compound as a pale yellow oil (716 mg, 2.53 mmol, 91% yield). 1 H NMR (400 MHz, CDCl3) δ: 8.06 (d, J = 1.7 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.59 - 7.55 (m, 1H), 3.97 (s, 3H).

[0425] Intermediates 27 - 29 were prepared from the indicated carboxylic acids by the same method as described for Intermediate 26.

[0426] [Table 13]

[0427] Intermediate 30 Ethyl 2-bromo-4-(2,2,2-trifluoroethoxy)benzoate [Chemical Structure] Step 1: Ethyl 4-amino-2-bromobenzoate To a stirred solution of ethyl 2-bromo-4-nitrobenzoate (14.6 g, 53.3 mmol) in isopropanol (40 mL) and water (160 mL) was added ammonium chloride (3.42 g, 63.9 mmol) and iron (17.85 g, 320 mmol) at 0 °C. After stirring at 100 °C for 2 h, the reaction mixture was allowed to cool to room temperature and filtered through a Celite pad washed with EtOAc (500 mL). The filtrate was washed with water (200 mL) and brine (100 mL), dried over Na2SO4, concentrated in vacuo to afford the title compound as an off-white solid (12.4 g, 50.2 mmol, 94% yield). MS (m / z) 244.0 (M+H) + .

[0428] Step 2: Ethyl 2-bromo-4-hydroxybenzoate To a stirred solution of ethyl 4-amino-2-bromobenzoate (12.4 g, 50.8 mmol) in water (120 mL) was added sulfuric acid (12.40 mL, 233 mmol) dropwise over 5 min at 0 °C. After stirring for 5 min, a solution of sodium nitrite (3.51 g, 50.8 mmol) in water (30 mL) was added dropwise over 15 min and the reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was filtered and the filter cake was washed with water (100 mL). The filtrate was heated to reflux for 1 h and stirred at room temperature for 16 h. The reaction mixture was extracted with EtOAc (2 × 150 mL), washed with brine (100 mL), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (Biotage, 100 g SNAP column, 40 min, 0 - 50% EtOAc / petroleum ether) to afford the title compound as a red solid (7.4 g, 26.7 mmol, 52.6% yield). MS (m / z) 245.0 (M+H) + .

[0429] Step 3: Ethyl 2-bromo-4-(2,2,2-trifluoroethoxy)benzoate To a stirred solution of ethyl 2-bromo-4-hydroxybenzoate (2.0 g, 8.16 mmol) in DMSO (20 mL) was added K2CO3 (1.692 g, 12.24 mmol) at room temperature under N2. After stirring for 15 minutes, 1,1,1-trifluoro-2-iodoethane (2.413 mL, 24.48 mmol) was added dropwise, and the resulting reaction mixture was stirred at 100 °C under N2 for 22 hours. The reaction mixture was allowed to cool to room temperature, quenched with water (100 mL), and extracted with EtOAc (3 × 100 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, and concentrated. The crude product was purified by column chromatography (Isolera, 100 g SNAP column, 40 minutes, 0 - 25% EtOAc / petroleum ether) to give the title compound as a colorless liquid (1.5 g, 4.47 mmol, 54.8% yield). 1 1H NMR (400 MHz, DMSO-d6): δ 7.82 (d, J = 8.40 Hz, 1H), 7.48 (d, J = 2.80 Hz, 1H), 7.19 (dd, J = 8.80, 2.40 Hz, 1H), 4.92 (q, J = 8.80 Hz, 2H), 4.30 (q, J = 6.80 Hz, 2H), 1.32 (t, J = 7.20 Hz, 3H).

[0430] Intermediate 31 Methyl 6-bromo-3-chloro-2-methylbenzoate [Chemical formula] Step 1: Methyl 3-amino-6-bromo-2-methylbenzoate At 0 °C under N2, bromine (1.560 mL, 30.3 mmol) was added dropwise to a stirred solution of methyl 3-amino-2-methylbenzoate (5 g, 30.3 mmol) in acetic acid (100 mL) and methanol (200 mL). After stirring at 0 °C for 15 minutes, the reaction mixture was quenched with water (200 mL) and concentrated under reduced pressure. The residue was dissolved in DCM (200 mL), washed with saturated NaHCO3 solution (100 mL) and brine (100 mL), dried over Na2SO4, and concentrated in vacuo. The brown liquid residue was purified by column chromatography (Biotage, 100 g SNAP column, 60 minutes, 0 - 23% EtOAc / petroleum ether) to give the title compound as an orange gum (2.3 g, 9.23 mmol, 30.5% yield). MS (m / z) 244.0 (M+H) + 。

[0431] Step 2: Methyl 6-bromo-3-chloro-2-methylbenzoate A solution of methyl 3-amino-6-bromo-2-methylbenzoate (2.3 g, 9.42 mmol) in acetonitrile (20 mL) was added to a stirred solution of copper(II) chloride (2.53 g, 18.85 mmol) and tert-butyl nitrite (3.31 mL, 28.3 mmol) in acetonitrile (20 mL) at 0 °C under N2. The resulting reaction mixture was slowly warmed to 30 °C and stirred at the same temperature for 16 hours. The reaction was quenched with water (50 mL) and extracted with EtOAc (2 × 25 mL). The combined organic extracts were washed with water (25 mL) and brine (25 mL), dried over Na2SO4, and concentrated in vacuo. The brown liquid residue was purified by column chromatography (Biotage, 25 g SNAP column, 40 minutes, 0 - 10% EtOAc / petroleum ether) to give the title compound as an orange liquid (1.75 g, 6.49 mmol, 68.8% yield). GCMS (m / z) 264.0 (M+H) + 。

[0432] Intermediate 32 Methyl 6-amino-3-chloro-4-cyano-2-fluorobenzoate

Chemical formula

[0433] Intermediate 33 was prepared from the indicated aryl halide by a method similar to that described for Intermediate 32.

[0434]

Table 14

[0435] Intermediate 34 Ethyl 2-chloro-6-(difluoromethoxy)nicotinate

Chem.

[0436] Intermediate 35 Methyl 2-bromo-5-cyano-4-(trifluoromethyl)benzoate

Chemical formula

[0437] Intermediates 36 - 38 were prepared from the indicated carboxylic acids by the same method as described for Intermediate 35.

[0438]

Table 15

[0439] Intermediate 39 Methyl 2-chloro-5-fluoro-6-methoxynicotinate

Chem.

[0440] Step 2: Methyl 2-chloro-5-fluoro-6-methoxynicotinate To a solution of methyl 2,6-dichloro-5-fluoronicotinate (1.05 g, 4.69 mmol) in methanol (7.81 ml) was added sodium methoxide (10.31 ml, 5.16 mmol), and the solution was heated at 60 °C for 1 h. The reaction mixture was cooled and quenched with water. The solvent was concentrated, and the residue was suspended in DCM and water. The layers were separated, and the aqueous layer was extracted with DCM (3 times). The combined organic layers were washed with water and brine, and dried over MgSO4. The solvent was concentrated under reduced pressure to give the title compound (0.946 g, 4.31 mmol, 92% yield). MS (m / z) 220 (M+H) + 。

[0441] Intermediate 40 Methyl 2-bromo-5-chloro-4-formylbenzoate

Chem.

[0442] Step 1: Methyl 2-bromo-4-(bromomethyl)-5-chlorobenzoate To a solution of methyl 2-bromo-5-chloro-4-methylbenzoate (1.3 g, 4.93 mmol) in DCE (10 mL) was added NBS (1.054 g, 5.92 mmol), and the reaction mixture was heated at 80 °C overnight. The reaction mixture was diluted with DCM (50 ml), washed with aqueous NaHCO3, water and brine, and dried over Na2SO4. The solvent was removed and the crude product was purified by column chromatography (Isco, 0 - 30% EtOAc / hexane) to give the title compound as a yellow solid (1.2 g, 3.40 mmol, 68.9% yield). 1 H NMR (400 MHz, chloroform-d) δ: 7.87 (s, 1 H), 7.76 (s, 1 H), 4.53 (s, 2 H) 3.96 (s, 3 H).

[0443] Step 2: Methyl 2-bromo-5-chloro-4-formylbenzoate To a solution of methyl 2-bromo-4-(bromomethyl)-5-chlorobenzoate (200 mg, 0.467 mmol) in DCM (3 mL) was added trimethylamine oxide (140 mg, 1.869 mmol) and DMSO (1.1 ml, 15.50 mmol) at 0 °C. The reaction mixture was heated at 30 °C overnight. Water was added and the reaction was extracted with Et2O, dried over MgSO4 and concentrated. The crude product was purified by column chromatography (Isco, 0 - 20% EtOAc / hexane) to give the title compound (72 mg, 0.259 mmol, 55.5% yield). 1 H NMR (400 MHz, DMSO-d6) δ: 10.19 - 10.31 (m, 1 H) 8.09 (s, 1 H) 8.01 (s, 1 H) 3.91 (s, 3H).

[0444] Intermediate 41 Methyl 2-bromo-5-fluoro-4-formylbenzoate

Chemical Structure

[0445] This intermediate was prepared from methyl 2-bromo-5-fluoro-4-methylbenzoate by the same method as described for Intermediate 40. In Step 2, potassium bicarbonate was used instead of trimethylamine oxide. GCMS (m / z) 259.9 (M) + 。

[0446] Intermediate 42 Ethyl 2-bromo-6-formylbenzoate

Chemical formula

[0447] Step 2: Ethyl 2-bromo-6-formylbenzoate A solution of ethyl 2-bromo-6-(dibromomethyl)benzoate (2 g, 4.99 mmol) in isopropanol (20 mL) and water (4 mL) was added silver nitrate (1.695 g, 9.98 mmol) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 5 h. The reaction mixture was filtered through a Celite bed and the Celite was washed with DCM (2 × 50 ml). The filtered organic layer was washed with water (100 mL). The combined organic liquids were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage, 25 g SNAP column, 30 min, 30% EtOAc / 70% hexane) to give the title compound as a colorless oil (750 mg, 2.477 mmol, 49.6% yield). MS (m / z) 257.0 (M+H) + 。

[0448] Intermediate 43 Methyl 2-bromo-5-chloro-4-(difluoromethyl)benzoate

Chemical formula

[0449] Intermediates 44 - 46 were prepared from the indicated aldehydes by the same method as described for Intermediate 43.

[0450]

Table 16

[0451] Intermediate 47 Methyl 2,5-dichloro-6-cyanonicotinate

Chem.

[0452] Step 2: Methyl 2,5-dichloro-6-cyanonicotinate To a solution containing 2,5-dichloro-3-(methoxycarbonyl)pyridine 1-oxide (5.66 g, 25.5 mmol) in acetonitrile (50 mL) was added triethylamine (5.33 mL, 38.2 mmol), and then TMS-CN (8.54 mL, 63.7 mmol). The reaction mixture was warmed to 70 °C for 20 minutes, cooled to room temperature, diluted with EtOAc, quenched with cold K2CO3 solution, and extracted with DCM. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. Purification by column chromatography on Isco, SiO2 (120 g using 0 - 50% EtOAc / heptane as eluent) gave the title compound as a colorless solid (5.33 g, 23.07 mmol, 90% yield). MS (m / z) 231.2 (M+H) + 。

[0453] Intermediate 48 5-Chloro-4-(difluoromethoxy)-2-fluorobenzonitrile

Chem.

[0454] Intermediate 49 Methyl 2-bromo-4-(dimethylamino)benzoate

Chem.

[0455] Intermediate 50 Methyl 2-chloro-5-fluoro-6-methylnicotinate

Chem.

[0456] Intermediate 51 Methyl 2,5-dichloro-6-methylnicotinate

Chem.

[0457] Intermediate 52 Methyl 6-bromo-3-chloro-2-methylbenzoate [Chemical formula] Step 1: Methyl 3-amino-6-bromo-2-methylbenzoate At 0 °C under nitrogen, bromine (1.559 mL, 30.3 mmol) was added dropwise over 1 minute to a stirred solution of methyl 3-amino-2-methylbenzoate (5.0 g, 30.3 mmol) in acetic acid (100 mL) and methanol (200 mL). The resulting reaction mixture was stirred at 0 °C for 15 minutes and then concentrated under reduced pressure to give a brown liquid residue. This residue was dissolved in DCM (200 mL), washed with saturated NaHCO3 solution (100 mL) and brine (100 mL), dried over Na2SO4 and evaporated in vacuo. The crude product was purified by column chromatography (Isolera, 100 g SNAP column, 1 hour, 0 - 50% EtOAc / petroleum ether) to give the title compound as an orange gum (2.6 g, 10.52 mmol, 34.8% yield). MS (m / z) 243.0 (M) + 。

[0458] Step 2: Methyl 6-bromo-3-chloro-2-methylbenzoate At 0 °C under nitrogen, a solution of methyl 3-amino-6-brom-2-methylbenzoate (0.2 g, 0.819 mmol) in acetonitrile (1 mL) was added dropwise to a stirred solution of copper(II) chloride (0.220 g, 1.639 mmol) and t-butyl nitrite (0.288 mL, 2.458 mmol) in acetonitrile (5 mL). The resulting reaction mixture was slowly warmed to room temperature and stirred for 2 hours. Upon completion, the reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2 × 15 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4 and evaporated in vacuo. The crude product was purified by column chromatography (Isolera, 5 g SNAP column, 30 minutes, 0 - 15% EtOAc / petroleum ether) to give the title compound as an orange gum (75 mg, 0.271 mmol, 33.1% yield). GCMS (m / z) 262.0 (M) + 。

[0459] Intermediate 53 Ethyl 2-amino-5-bromo-4-(trifluoromethoxy)benzoate

Chemical Structure

[0460] Step 2: Ethyl 2-((tert-butoxycarbonyl)amino)-4-(trifluoromethoxy)benzoate A solution of tert-Butyl (2-bromo-5-(trifluoromethoxy)phenyl)(tert-butoxycarbonyl)carbamate (6 g, 13.15 mmol) and triethylamine (3.99 g, 39.5 mmol) in ethanol (50 mL) was purged with nitrogen for 15 minutes in a stainless steel autoclave. Under nitrogen, PdCl2(dppf)-CH2Cl2 adduct (1.074 g, 1.315 mmol) was added and the resulting reaction mixture was stirred at 120 °C for 16 hours under CO gas (50 psi). The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by column chromatography (Isolera, 100 g column, 1 hour, 0 - 2% EtOAc / petroleum ether) to afford the title compound as a pale yellow oil (1.7 g, 4.53 mmol, 34.4% yield). MS (m / z) 250 (M - 99H) +

[0461] Step 3: Ethyl 2-amino-5-bromo-4-(trifluoromethoxy)benzoate To a solution of ethyl 2-((tert-butoxycarbonyl)amino)-4-(trifluoromethoxy)benzoate (1.5 g, 4.29 mmol) in DMF (10 mL) stirred at room temperature under nitrogen, a solution of N-bromosuccinimide (764 mg, 4.29 mmol) in DMF (3 mL) was added dropwise over 1 minute. The reaction mixture was stirred at 100 °C for 16 h. Ice water (50 mL) was added and the reaction mixture was extracted with EtOAc (2 × 70 mL). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered, and evaporated in vacuo. The crude product was purified by column chromatography (Isolera, 50 g SNAP column, 4% EtOAc / petroleum ether) to afford the title compound as an off-white solid (560 mg, 1.417 mmol, 33.0%). GCMS (m / z) 327.2 (M+H) + / 329.2 (M+H) + 。

[0462] Intermediate 54 Methyl 5-bromo-4-fluoro-2-nitrobenzoate

Chemical Structure

[0463] Intermediate 55 Methyl 4-fluoro-2-nitro-5-(trifluoromethyl)benzoate

Chem.

Claims

1. The following formula (XIV): 【Chemical 1】 wherein, X ４’ is N or C—R ４４’ ; here, R ４４’ is selected from hydrogen, fluoro, chloro, bromo, and -CH ３ ; R ４１’ 、 R ４２’ and R ４３’ are each independently selected from hydrogen, fluoro, chloro, bromo, -CH ３ , -CF ３ , -CHF ２ , -OCH ３ , -OCH ２ CF ３ , -OCHF ２ , -OCF ３ , -CF ２ CH ２ OH, -N(CH ３ ) ２ , -NHCH ３ , -C≡N, -OH, -S(O) ２ CH ３ and are independently selected from cyclopropyl and oxetanyl; R ４５’ is phenyl, cyclopentyl, cyclohexyl, [Chemical 2] , thiophenyl, thiazolyl, pyridyl, tetrahydropyranyl, and -CH ２ -phenyl selected from Here, R ４５’ is optionally substituted with 1 to 4 substituents independently selected from fluoro, chloro, bromo, -CH ３ , -CH ２ CH ３ , -CH ２ CF ３ , -CH(CH ３ ), ２ , -C(CH ３ ), ３ , -CF ３ , -CF ２ CH ２ OH, -C(O)NH ２ , -OCH ３ , -NH ２ , -OCH ２ CH ３ , -OCHF ２ , -OCF ３ , -OCH ２ CH ２ OH, -N(CH ３ ), ２ , -NHCH ３ , -C≡N, -OH, and cyclopropyl; and R ５５’ is [Chemical Formula 3] is selected from or its corresponding tautomeric form, Here, R ４８’ R ４９’ R ５０’ R ５１’ and R ５２’ is independently selected from hydrogen, fluoro, chloro, bromo, -CH ３ -CH ２ CH ３ -CH ２ CF ３ -CH(CH ３ ) ２ -C(CH ３ ) ３ -CF ３ -CF ２ CH ２ OH, -C(O)NH ２ -OCH ３ -NH ２ -OCH ２ CH ３ -OCHF ２ -OCF ３ -OCH ２ CH ２ OH, -N(CH ３ ) ２ -NHCH ３ -C≡N, -OH, -C(O)OH, -C(O)CH ３ -OCH ２ C(O)OH, -NC(O)CH ３ -NHCH ２ CH ２ OH, -S(O) ２ CH ３ -S(O) ２ NH ２ and is represented by a compound independently selected from cyclopropyl or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

2. X ４’ The compound according to claim 1, wherein X is N.

3. X ４’ The compound according to claim 1, wherein X is C-H.

4. 1-(4-Fluoro-2-methylphenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(4-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-Cyclohexyl-3-(6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2,6-dimethylphenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(2-Chloro-4-fluorophenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-(2-hydroxyethoxy)phenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(2,4-Difluorophenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(2-Ethyl-4-fluorophenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 8-Chloro-1-(4-fluoro-2-methylphenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-8-methyl-3-(6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2-Methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluorophenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2-Methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(o-tolyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-6-methyl-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(6-methyl-2-oxo-1,2-dihydropyridin-4-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(5-methyl-2-oxo-1,2-dihydropyridin-4-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(3-methyl-2-oxo-1,2-dihydropyridin-4-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethoxy)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-7-methyl-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(3-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(2-Ethyl-4-fluorophenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-1-(4-fluoro-2-methylphenyl)-3-(4-methyl-2-oxo-1,2-dihydropyrimidin-5-yl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2,4-Dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-isopropylphenyl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2-Ethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 7-(Dimethylamino)-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 7-Chloro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(methylamino)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-1-(2-ethoxy-4-fluorophenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-isopropylphenyl)-7-methyl-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 7-(Difluoromethyl)-6-fluoro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 6-Fluoro-1-(4-fluoro-2-methylphenyl)-7-methyl-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 6-Chloro-1-(4-fluoro-2-methylphenyl)-7-methyl-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 6,7-Dichloro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 6-Chloro-5-fluoro-1-(2-methyl-4-(trifluoromethoxy)phenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile; 6-Chloro-1-(4-fluoro-2-isopropylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-3-hydroxy-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-5-fluoro-1-(4-fluoro-2-methylphenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-5-fluoro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(methylsulfonyl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-1-(2-ethyl-4-fluorophenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-3-(2,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-isopropylphenyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2-Ethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-isopropylphenyl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(5-oxo-4,5-dihydropyrazin-2-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 6-Fluoro-1-(4-fluoro-2-methylphenyl)-7-methyl-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2-Methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-phenyl-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2-Methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(o-tolyl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 5-Chloro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-5-methyl-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2-Cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-1-(4-fluoro-2-methoxyphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 7-Fluoro-1-(4-fluoro-2-isopropylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 3-(4,6-Dimethyl-2-oxo-1,2-dihydropyrimidin-5-yl)-1-(4-fluoro-2-methylphenyl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(2-(tert-Butyl)-4-fluorophenyl)-6-chloro-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(3,4-Difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-1-(4-fluoro-2-isopropylphenyl)-5-methyl-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-7-fluoro-1-(4-fluoro-2-isopropylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-fluoro-2-methylphenyl)-7-methoxy-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-fluoro-2-methylphenyl)-6-hydroxy-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-6-methoxy-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 1-(4-Fluoro-2-isopropylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethoxy)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-7-fluoro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-1,2,3,4-tetrahydroquinazoline-7-carbonitrile; 6-Chloro-3-(2-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-2,3-dihydroquinazolin-4(1H)-one; 7-Fluoro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 5-Fluoro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 7-Chloro-6-fluoro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 6-Fluoro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-7-carbonitrile; 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-7-(trifluoromethoxy)-1,2,3,4-tetrahydroquinazoline-6-carbonitrile; 1-(4,5-Difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(2-(tert-Butyl)-4-fluorophenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(6-methyl-2-oxo-1,2-dihydropyrimidin-5-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(2-Ethyl-4-fluorophenyl)-6-fluoro-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 4-(6-Chloro-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-1(2H)-yl)-3-methylbenzonitrile; 1-(5-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(2-Methyl-4-(trifluoromethoxy)phenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 1-(3-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(2,4-Difluoro-6-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 7-(Difluoromethyl)-1-(4-fluoro-2-isopropylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 3-Methyl-4-(3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-6-(trifluoromethoxy)-3,4-dihydroquinazolin-1(2H)-yl)benzonitrile; 8-Chloro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-8-methyl-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Methoxy-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Hydroxy-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(6-Chloro-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-1(2H)-yl)-2-methylbenzonitrile; 6-Fluoro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethoxy)-2,3-dihydroquinazolin-4(1H)-one; 5-(Difluoromethyl)-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 3-(5-Fluoro-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 6,7-Difluoro-1-(4-fluoro-2-methoxyphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-1-(2-hydroxy-4-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-1-(2-methoxy-4-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(2-Fluoro-6-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-5-fluoro-1-(4-fluoro-2-methylphenyl)-3-(2-oxo-1,2-dihydropyridin-4-yl)-2,3-dihydroquinazolin-4(1H)-one; 7-(Difluoromethyl)-1-(4-fluoro-2-isopropylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 7-(Difluoromethyl)-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-3-(2-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-isopropylphenyl)-2,3-dihydroquinazolin-4(1H)-one; 6-Fluoro-2-methyl-3-(3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-6-(trifluoromethyl)-3,4-dihydroquinazolin-1(2H)-yl)benzonitrile; 6-Fluoro-1-(4-fluoro-2-isopropylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 1-(2-Bromo-4-fluorophenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 6-Fluoro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluorophenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-oxo-1,2-dihydropyrimidin-5-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Bromo-2-methylphenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluorophenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-Methyl-4-(3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-7-(trifluoromethyl)-3,4-dihydroquinazolin-1(2H)-yl)benzonitrile; 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 3-(2-Ethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2-Chloro-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 7-Bromo-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-1,2,3,4-tetrahydroquinazoline-7-carbonitrile; 3-(1-(4-Fluoro-2-methylphenyl)-4-oxo-7-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)-yl)-6-oxo-1,6-dihydropyridine-2-carbonitrile; 1-(2,4-Difluorophenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Ethoxyphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-oxo-1,2-dihydropyridin-4-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 6,7-Difluoro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 6,7-Difluoro-1-(4-fluoro-2-isopropylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2-Methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-((1S,2R)-2-methylcyclohexyl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-isopropylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-1,2,3,4-tetrahydroquinazoline-7-carbonitrile; 3-(2-Methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-((1R,2S)-2-methylcyclohexyl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; N-(3-(1-(4-Fluoro-2-methylphenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)-yl)-6-oxo-1,6-dihydropyridin-2-yl)acetamide; 3-(2-Bromo-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 6-Fluoro-1-(4-fluoro-2-methylphenyl)-7-methoxy-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-6-carbonitrile; 6-Chloro-7-(difluoromethoxy)-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-7-(difluoromethyl)-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 3-(4-Amino-2-oxo-1,2-dihydropyrimidin-5-yl)-1-(4-fluoro-2-methylphenyl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-1-(2-methyl-4-(trifluoromethoxy)phenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-7-carbonitrile; 6-Chloro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-7-carbonitrile; 6-Chloro-1-(2-methyl-4-(trifluoromethoxy)phenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-1,2,3,4-tetrahydroquinazoline-7-carbonitrile; 6-Chloro-1-(4-fluoro-2-methylphenyl)-3-(6-methyl-2-oxo-1,2-dihydropyrimidin-5-yl)-4-oxo-1,2,3,4-tetrahydroquinazoline-7-carbonitrile; 1-(2-Methyl-3-(trifluoromethyl)phenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 1-(3-Chloro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 1-(2-Ethyl-4-fluorophenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 1-(3,4-Difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 1-(4-Fluoro-2-isopropylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(4-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 6-Fluoro-1-(4-fluoro-2-isopropylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(2-Cyclopropyl-4-fluorophenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(2-Cyclopropyl-4-fluorophenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 5-Fluoro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(2-Ethyl-4-fluorophenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 7-(Difluoromethoxy)-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 7-Cyclopropyl-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethoxy)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-(Difluoromethoxy)-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2-Ethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-7-(trifluoromethoxy)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-1-(2-ethyl-4-fluorophenyl)-7-fluoro-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-1-(2-ethyl-4-fluorophenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-1,2,3,4-tetrahydroquinazoline-7-carbonitrile; 6-Chloro-5,7-difluoro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-5-fluoro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-1,2,3,4-tetrahydroquinazoline-7-carbonitrile; 1-(2-Methyl-4-(trifluoromethyl)phenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 1-(4-Chloro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 7-(1,1-Difluoro-2-hydroxyethyl)-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-((2-hydroxyethyl)amino)-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-1-(2-(dimethylamino)-4-fluorophenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-1-(4-fluoro-2-(methylamino)phenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-(1,1-Difluoro-2-hydroxyethyl)-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(2,4-Dimethylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(6-methyl-2-oxo-1,2-dihydropyrimidin-5-yl)-7-(trifluoromethoxy)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-7-methyl-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 6-Chloro-1-(2-ethyl-4-fluorophenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-7-carbonitrile; 1-((1S,3S)-3-Fluorocyclopentyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-((1R,3R)-3-Fluorocyclopentyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(1,2-Dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2-Chloro-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2-Bromo-4-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-isopropylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 6-Chloro-1-(4-fluoro-2-isopropylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methoxyphenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-5-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(6-oxo-1,6-dihydropyridazin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluorobenzyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(4-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-4-oxo-3-(6-oxo-1,6-dihydropyridin-3-yl)-1,2,3,4-tetrahydroquinazoline-7-carbonitrile; 1-(4-Fluoro-2-methoxyphenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-5-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2-Methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-methylthiazol-5-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(2,4-Dimethoxyphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methoxyphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 7-Chloro-6-fluoro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 3-(2-Methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(3-methylthiophen-2-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methoxyphenyl)-4-oxo-3-(6-oxo-1,6-dihydropyridin-3-yl)-1,2,3,4-tetrahydroquinazoline-7-carbonitrile; 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(2,2,2-trifluoroethoxy)-2,3-dihydroquinazolin-4(1H)-one; 1-(2-Methyl-4-(trifluoromethoxy)phenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-3-(4-chloro-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-2,3-dihydroquinazolin-4(1H)-one; 7-Chloro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile; 6-Chloro-1-(4-fluoro-2-methylphenyl)-5-methyl-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(3,5-Difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-isopropylphenyl)-5-methoxy-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(Bicyclo[1.1.1]pentan-1-yl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(3-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2-Methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-(2,2,2-trifluoroethyl)phenyl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 7-(Difluoromethoxy)-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 6-Fluoro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-1,2,3,4-tetrahydroquinazoline-7-carbonitrile; 4-(6-Chloro-7-(difluoromethyl)-1-(4-fluoro-2-methylphenyl)-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)-3-methylpyridine 1-oxide; 4-(6-Chloro-1-(2-ethyl-4-fluorophenyl)-7-fluoro-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)-3-methylpyridine 1-oxide; 4-(6-Chloro-7-fluoro-1-(2-methyl-4-(trifluoromethoxy)phenyl)-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)-3-methylpyridine 1-oxide; 4-(6-Chloro-7-cyano-1-(2-ethyl-4-fluorophenyl)-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)-3-methylpyridine 1-oxide; 4-(1-(4-Fluoro-2-methylphenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)-yl)-3-methylpyridine 1-oxide; 3-Methyl-4-(1-(2-methyl-4-(trifluoromethoxy)phenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)-yl)pyridine 1-oxide; 3-(2-Amino-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-methoxy-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-hydroxy-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(oxetan-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluorophenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 4-Methyl-3-(3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-6-(trifluoromethyl)-3,4-dihydroquinazolin-1(2H)-yl)benzamide; 3-(2-Methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-((1S,2S)-2-methylcyclohexyl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2-Methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-((1R,2R)-2-methylcyclohexyl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2-Methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-((3S,4S)-3-methyltetrahydro-2H-pyran-4-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2-Methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-((3R,4R)-3-methyltetrahydro-2H-pyran-4-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2-Methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-((3R,4S)-3-methyltetrahydro-2H-pyran-4-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2-Methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2,4-Dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-isopropylphenyl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 3-(2,4-Dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-isopropylphenyl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-3-(2,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-isopropylphenyl)-2,3-dihydroquinazolin-4(1H)-one; 6-Chloro-3-(2,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-isopropylphenyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(2-(tert-Butyl)-4-fluorophenyl)-6-chloro-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(2-(tert-Butyl)-4-fluorophenyl)-6-chloro-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(2-Methyl-4-(trifluoromethoxy)phenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; and 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one The compound according to claim 1 selected from the above, or its tautomer, or a pharmaceutically acceptable salt thereof.

5. 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(2-Methyl-4-(trifluoromethoxy)phenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one; 1-(4-Bromo-2-methylphenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluorophenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one; and 3-Methyl-4-(3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-7-(trifluoromethyl)-3,4-dihydroquinazolin-1(2H)-yl)benzonitrile The compound according to claim 1 selected from the above, or its tautomer, or a pharmaceutically acceptable salt thereof.

6. The following formula: 【Chemical Formula 4】 The compound according to claim 1 which is as described above, or its tautomer, or a pharmaceutically acceptable salt thereof.

7. The compound of formula (XIV) according to claim 1 or a pharmaceutically acceptable salt thereof and / or its corresponding tautomeric form, and One or more pharmaceutically acceptable excipients A pharmaceutical composition comprising the same.

8. Pain-related diseases, Pain caused by trauma, or Pain caused by iatrogenic, medical or dental procedures For treating The pharmaceutical composition according to claim 7.

9. Pain-related diseases; Pain caused by trauma; or Pain caused by each of iatrogenic, medical or dental procedures Is Chronic pain; Acute pain; Neuropathic pain; Inflammatory pain of various physiological origins; Nociceptive pain; Neurological damage, neuropathic damage or neuron damage-related or associated pain disorders caused by diseases; neuralgia and related acute or chronic pain; Postherpetic neuralgia; Skeletal muscle pain; low back pain and neck pain; sprains and muscle strains; Myofascial pain; myositis or muscle inflammation; Repetitive motion pain; Complex regional pain syndrome; Chronic or acute arthritis pain; Sympathetic nerve-dependent pain; Cancer, toxin, and chemotherapy-related pain; Postoperative pain syndrome and / or related phantom limb pain; Postoperative medical treatment or dental treatment or treatment pain; or HIV-related pain, HIV treatment-induced pain The pharmaceutical composition according to claim 8, which is selected from

10. The nociceptive pain is selected from postoperative pain, cancer pain, low back pain, craniofacial pain, osteoarthritis pain, toothache, or diabetic peripheral neuropathy; The inflammatory pain is selected from pain associated with rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis, or juvenile arthritis; The musculoskeletal pain is selected from bone and joint pain, osteoarthritis; low back pain and neck pain; pain resulting from physical trauma or amputation; Neurological injury, neuropathic injury, or neuron injury-related or associated pain disorders caused by a disease are neuropathy, pain-related nerve injury, pain-related nerve root avulsion injury, painful traumatic mononeuropathy, painful polyneuropathy, erythromelalgia, paroxysmal extreme pain disorder (PEPD), burning mouth syndrome; central pain syndrome caused by a lesion at the nervous system level; traumatic nerve injury, nerve compression or entrapment, congenital insensitivity to pain (CIP), dysmenorrhea, primary erythromelalgia; HIV peripheral sensory neuropathy; pudendal neuralgia, spinal cord nerve injury, chronic inflammatory demyelinating polyneuropathy (CIDP), carpal tunnel syndrome, or vasculitic neuropathy; Inflammatory pain of various origins is selected from rheumatic disorders, tendosynovitis and gout, rotator cuff tendinitis or bursitis, polymyalgia rheumatica, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, or other pain caused by central sensitization; complex regional pain syndrome, chronic arthritis pain, and related neuralgia or acute pain; The pharmaceutical composition according to claim 9.

11. Pain-related diseases; Pain caused by trauma; or Pain caused by each of iatrogenic, medical treatment, or dental treatment is Chronic, acute, or preoperative-related pain; or Acute, chronic, or postoperative-related pain The pharmaceutical composition according to claim 8, which is selected from

12. The chronic, acute, or preoperative-related pain is selected from neuropathic pain or chronic neuropathic pain, chronic osteoarthritis pain, toothache pain, or inflammatory pain; or The acute, chronic, or postoperative-related pain is selected from pain after vasectomy, pain after hernia repair, pain after breast surgery, or pain after cosmetic surgery. The pharmaceutical composition according to claim 11.

13. The neuropathic pain or chronic neuropathic pain is selected from small fiber-mediated diabetic neuropathy, small fiber neuropathy, idiopathic small fiber neuropathy, painful diabetic neuropathy or polyneuropathy; or The inflammatory pain is selected from osteoarthritis, chronic osteoarthritis knee pain or chronic inflammatory demyelinating polyneuropathy, The pharmaceutical composition according to claim 12.

14. For the manufacture of a medicament for treating pain and / or related diseases and for reducing their severity, The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof and / or its corresponding tautomeric form, or The pharmaceutical composition according to claim 7 Use.

15. In a patient, Na ｖ 1.8 For the production of a drug for inhibiting voltage-dependent sodium channels The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof and / or its corresponding tautomeric form, or The pharmaceutical composition according to claim 7 Use.

16. The pharmaceutical composition according to claim 7 for use in therapy.

17. Pain-related diseases such as pain caused by various diseases; Pain caused by trauma; or Pain caused by each of iatrogenic, medical or dental procedures The pharmaceutical composition according to claim 7 for the treatment of, wherein each type of pain defined above is selected from chronic, acute or pre-operative related pain is selected from neuropathic pain, chronic neuropathic pain, chronic osteoarthritis pain, toothache or inflammatory pain: or acute, chronic or post-operative related pain is selected from bunionectomy pain, hernia repair pain, breast surgery pain or cosmetic surgery pain, Pharmaceutical composition.

18. The pharmaceutical composition according to claim 7 for the treatment of each of neuropathic pain and / or diseases, wherein the neuropathic pain and / or diseases are each selected from peripheral neuropathic pain, central neuropathic pain, hereditary acrodynia (IEM), small fiber neuralgia (SFN), paroxysmal extreme pain disorder (PEPD), painful diabetic neuropathy, chronic low back pain, neuropathic back pain, sciatica, non-specific low back pain, pain in multiple sclerosis, HIV-associated neuropathy, postherpetic neuralgia, trigeminal neuralgia, vulvodynia, pain resulting from physical trauma, pain after amputation, neural tumor pain, phantom limb pain, cancer, toxins or chronic inflammatory conditions, pharmaceutical composition.

19. Na in a patient ｖ 1.8 The pharmaceutical composition according to claim 7 for inhibiting voltage-dependent sodium channels.

20. For treating pain and / or related diseases and for reducing their severity, The pharmaceutical composition according to claim 7.

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