Nitrogen-containing 2,3-dihydroquinazolinone compounds as Nav1.8 inhibitors

Abstract

Compounds of formula (I) are described, wherein each of the variables is as defined herein. Also described are pharmaceutical compositions containing compounds of formula (I), Na v 1.8 Inhibits voltage-gated sodium channels and inhibits the production of sodium channels in pain and pain-related diseases, disorders and pathologies, as well as cardiovascular diseases, disorders and pathologies such as atrial fibrillation. v The use of the compounds and pharmaceutical compositions for treating 1.8-mediated diseases, disorders and conditions is also described. [Case 1] JPEG2023554430000159.jpg49168

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention is v 1.8 inhibitor compounds or pharmaceutically acceptable salts or tautomers thereof, corresponding pharmaceutical compositions or formulations, methods or processes for preparing the compounds, methods, compounds, uses and / or combination therapies for use in the treatment of pain and pain-related diseases, disorders and conditions, and cardiovascular diseases, disorders and conditions. [Background technology]

[0002] Pain is a defense mechanism that allows animals to avoid potential tissue damage, but there are numerous disease indications in which pain loses its usefulness and becomes a disabling burden. Indications in which pain loses its usefulness can be broadly divided into those triggered by nerve damage or injury (neuropathic pain), those in which inflammation or metabolic abnormalities enhance pain responses (inflammatory pain), and those in which injury or surgical procedures result in a short-term increase in pain responses (postoperative / exogenous pain).

[0003] Voltage-gated sodium channels underpin electrical signal transduction in all excitable tissues by setting the threshold for action potentials and underlying their upregulation. There are nine different isoforms of voltage-gated sodium channels. v 1.1, Na v 1.7, Na v 1.8 and Na v The one called 1.9 is expressed mainly in peripheral nerves and controls neuronal excitability. v 1.5 is a fundamental sodium channel isoform expressed in cardiac myocytes, and Na v 1.4 is expressed and functions in skeletal muscle and is involved in Na v 1.1, Na v 1.2, Na v 1.3 and Na v1 and 6 are widely expressed in the central nervous system (CNS) and, to some extent, the peripheral nervous system. Although the primary role of these nine voltage-gated sodium channels is similar in that they regulate sodium influx into cells, their biophysical properties vary, significantly impacting the physiological profile of each cell type (Catterall, 2012).

[0004] Currently, nonselective sodium channel blockers are clinically available as antiarrhythmic and anticonvulsant drugs, including lidocaine, carbamazepine, amitriptyline, and mexiletine. However, because these drugs lack selectivity between different sodium channel isoforms, their therapeutic utility is greatly diminished by adverse side effects, primarily mediated by their activity in the CNS and heart. This has prompted efforts to develop novel drugs selective for specific sodium channel isoforms to avoid side effects in the CNS and cardiovascular system.

[0005] Na v The 1.8 channel is expressed in neurons of the dorsal root ganglion (DRG), with high expression in small-diameter neurons of this tissue that form the pain-sensing C and Aδ nerve fibers (Abrahamsen, 2008; Amaya, 2000; Novakovic, 1998). This channel was first cloned from rat DRG (Akopian, 1996) and was soon proposed as a therapeutic target for analgesia due to its prominent physiological role and restricted expression profile in this tissue type. Subsequently, Na v 1.8 was identified, cloned, and characterized from human DRG tissue (Rabart 1998). v The closest relative to 1.8 is Na v 1.5, and the sequence homology is about 60%. v1.8 was previously known as the sensory neuron sodium channel (SNS) and peripheral nerve sodium channel type 3 (PN3), and is also known as the TTX-resistant sodium channel because it exhibits a unique pharmacological property of resistance to blockade by tetrodotoxin.

[0006] Na v Support for 1.8 as a therapeutic target for pain indications comes from several sources. v 1.8 has been shown to carry the majority of current during the upstroke of action potentials in DRG neurons (Blair & Bean, 2002) and is also important for the ability of these neurons to fire repetitively due to its rate of repriming (Blair and Bean, 2003). v Increased expression and function of 1.8 has been reported in response to painful stimuli, including inflammatory mediators (England 1996 & Gold 1996), nerve injury (Roza 2003 & Ruangsri 2011), and painful schwannoma (Black 2008 & Coward 2000). v Knocking out the gene encoding 1.8 reduced the pain phenotype, especially in response to inflammatory antigen challenge (Akopian 1999). v Knocking down the mRNA encoding 1.8 reduced pain phenotypes in rodent models, particularly in neuropathic models (Lai 2002). Pharmacological intervention with selective small molecule inhibitors has also shown efficacy in rodent models of inflammatory and neuropathic pain (Jarvis 2007 & Payne 2015). v Genetic evidence for 1.8 also exists in patients with chronic neuropathic pain, with multiple gain-of-function mutations reported to cause episodic painful neuropathy and small fiber neuropathy (Faber 2012, Han 2014 & Eijkenboom 2018). Summary of the Invention [Problem to be solved by the invention]

[0007] Thus, novel compounds, in particular Na, for use in the treatment of pain and pain-related diseases, disorders and conditions, and cardiovascular diseases, disorders and conditions, are disclosed. v There is a need to develop Na 1.8 inhibitor compounds. v This need is met by providing compounds with 1.8 inhibitory activity and the use of such compounds in the treatment of pain and pain-related diseases, disorders and conditions, and cardiovascular diseases, disorders and conditions. [Means for solving the problem]

[0008] In one embodiment, the present invention provides a compound of formula (I): [ka] [In the formula, Y is O or S; X 1 is nitrogen or CR 1 and X 2 is nitrogen or CR 2 and X 3 is nitrogen or CR 3 and X 4 is nitrogen or CR 4 and However, X 2 , X 3 and X 4 at least one of which is nitrogen; R 1 , R 2 , R 3 and R 4 each independently represents hydrogen, halo, cyano, -NR a R b , -(C 1-6 )-alkyl, -(C 1-6 )-haloalkyl, -O-(C 1-6)-alkyl or -O-(C 1-6 )-haloalkyl; Ring B is phenyl or a 5- or 6-membered heterocyclyl containing 1 or 2 nitrogen ring atoms; Each R 5 are independently halo, oxo, -OH, -NR a R b , -(C 1-6 ) alkyl, -(C 1-6 ) haloalkyl, -COOR a , -C(O)NR a R b or -S(O) p R c and; R 6 is hydrogen, -(C 1-6 ) alkyl, -O-(C 1-6 )-Alkyl or -NR a R b and; Each R 7 are independently halo, -(C 1-6 ) alkyl, -O-(C 1-6 ) alkyl or -O-(C 1-6 )-haloalkyl; R a and R b each independently represents hydrogen, -(C 1-6 ) alkyl or -(C 1-6 ) haloalkyl; R c is hydrogen, -OH, -NR a R b , -(C 1-6 )-alkyl or -(C 1-6 )-haloalkyl; n is 0, 1, 2 or 3; p is 0, 1 or 2; and z is 0, 1, 2, or 3. or a tautomer thereof or a pharmaceutically acceptable salt thereof.

[0009] In one aspect, the invention relates to a pharmaceutical composition comprising a compound as defined herein or a tautomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0010] In one embodiment, the present invention provides a method for administering Na v 1.8 relates to a method of inhibiting voltage-gated sodium channels, comprising administering to a subject a compound as defined herein or a tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0011] In one aspect, the present invention relates to a method of treating pain or a pain-related disease, disorder or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound as defined herein or a tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0012] In one aspect, the present invention relates to a method of treating atrial fibrillation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound defined herein or a tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition defined herein.

[0013] In one aspect, the invention relates to a compound as defined herein or a tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of pain or a pain-related disease, disorder or condition.

[0014] In one aspect, the invention relates to a compound as defined herein or a tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of atrial fibrillation.

[0015] In one aspect, the invention relates to a compound as defined herein or a tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for the treatment of pain or a pain-related disease, disorder or condition.

[0016] In one aspect, the invention relates to a compound as defined herein or a tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for the treatment of atrial fibrillation.

[0017] In one aspect, the invention relates to a compound as defined herein or a tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in therapy. [Brief explanation of the drawings]

[0018] [Figure 1] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of 1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one (Form 1). [Figure 2] FIG. 2 shows the DSC of 1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one (Form 1). [Figure 3] FIG. 3 shows the X-ray powder diffraction (XRPD) pattern of 1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one (Form 2). [Figure 4]FIG. 4 shows the DSC of 1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one (Form 2). [Figure 5] FIG. 5 shows the X-ray powder diffraction (XRPD) pattern of 1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one (Form 3). [Figure 6] FIG. 6 shows the X-ray powder diffraction (XRPD) pattern of 1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one (Form 4). [Figure 7] FIG. 7 shows the DSC of 1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one (Form 4). DETAILED DESCRIPTION OF THE INVENTION

[0019] Various publications, articles, and patents are cited or described in the Background and Specification. Any discussion of documents, acts, materials, devices, articles, or the like included in the present specification is for the purpose of providing a context for the present disclosure. Such discussion is not an admission that any or all of these items form part of the prior art with respect to the present disclosure.

[0020] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Otherwise, certain terms used herein have the meanings indicated herein.

[0021] Please note that as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise.

[0022] As used herein, the conjunction "and / or" between multiple recited elements is understood to encompass both separate and combined alternatives. For example, when two elements are connected by "and / or," the first alternative refers to the applicability of the first element without the second element. The second alternative refers to the applicability of the second element without the first element. The third alternative refers to the applicability of the first element and the second element together. Any one of these alternatives is understood to be within the meaning of, and therefore satisfy the requirement of, the term "and / or" as used herein. The simultaneous applicability of two or more alternatives is also understood to be within the meaning of, and therefore satisfy the requirement of, the term "and / or."

[0023] Unless otherwise specified, any numerical value, for example, a concentration or concentration range described herein, is understood to be modified in all cases by the term "about." Thus, numerical values ​​generally include ±10% of the described value. For example, a description of "10 times" includes 9 times and 11 times. As used herein, the use of numerical ranges expressly includes all possible subranges, for example, all individual numerical values ​​within that range (including integers and fractions of that value within that range), unless the context clearly indicates otherwise.

[0024] The present invention relates to Na of formula (I) v 1.8 Inhibitor compounds or pharmaceutically acceptable salts or tautomers thereof, corresponding pharmaceutical compositions, methods or processes for preparing the compounds, and Na v1.8 relates to methods, compounds, uses therefor and / or combination therapies for use in mediated diseases, disorders and conditions, such as pain and / or pain-related diseases, disorders or conditions and atrial fibrillation, respectively.

[0025] The definitions of the various groups and substituents of any formula disclosed herein, or a pharmaceutically acceptable salt and / or corresponding tautomer thereof, provided herein are intended to describe each compound species disclosed herein separately, as well as groups of one or more compound species specifically.

[0026] 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 may include, but is not limited to, calcium (Ca) or magnesium (Mg).

[0027] As used herein, the terms "alkyl" or "straight- or branched-chain alkyl" and the like refer to a saturated, straight- or branched-chain hydrocarbon moiety. Exemplary alkyls include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like. An alkyl group can have a specified number of carbon atoms. When a number appears in a subscript after the symbol "C," the subscript more specifically defines the number of carbon atoms that a particular alkyl can contain. For example, "C1-C6" and "C 1-6 " refers to alkyl containing 1 to 6 carbon atoms, and "C1-C4" and "C 1-4 The term "alkyl" refers to alkyl containing 1 to 4 carbon atoms.

[0028] When the term "alkyl" is used in combination with other substituents, such as "haloalkyl" or "hydroxyalkyl," the term "alkyl" is intended to include a divalent saturated, straight or branched chain hydrocarbon radical.

[0029] For example, the terms "haloalkyl" or "straight- or branched-chain haloalkyl" are intended to mean a saturated, straight- or branched-chain hydrocarbon moiety substituted with one or more halogens, where the halogens are independently selected from fluoro, chloro, bromo, and iodo. The haloalkyl group can have the specified number of carbon atoms. For example, "(C1-C6)haloalkyl" and "(C 1-6 The term "(C )haloalkyl" refers to a saturated, straight- or branched-chain haloalkyl radical having 1 to 6 carbon atoms. 1- C4) haloalkyl" and "(C 1-4 The term "haloalkyl" refers to a saturated, straight- or branched-chain haloalkyl radical having 1 to 4 carbon atoms. "Fluorinated alkyl" or "fluoroalkyl" specifically refers to any alkyl group as defined above substituted with at least one fluoro atom, e.g., 1 to 3 fluoro atoms, e.g., 1, 2, or 3 fluoro atoms. Representative haloalkyls include, but are not limited to, trifluoromethyl (-CF), tetrafluoroethyl (-CFCHF), pentafluoroethyl (-CFCF), and the like.

[0030] The term "hydroxyalkyl" refers to a saturated, straight- or branched-chain hydrocarbon moiety substituted with one or more hydroxy groups.

[0031] As used herein, the terms "halogen" and "halo" mean fluoro (-F), chloro (-Cl), bromo (-Br) and iodo (-I).

[0032] "Hydroxy" or "hydroxyl" is intended to mean the radical --OH.

[0033] "Oxo" refers to a double-bonded oxygen moiety, e.g., when attached directly to a carbon atom, forming a carbonyl moiety (C=O), or when attached to an N or S, forming an oxide, e.g., an N-oxide, sulfone, or sulfoxide.

[0034] The term "cyano" refers to -CN.

[0035] The term "amino" refers to -NH2. One or more hydrogen atoms of an amino group can be replaced with a substituent such as an alkyl group, resulting in the term "alkylamino." An alkylamino group has one or both hydrogen atoms of the amino group replaced with an alkyl group and is connected to the parent molecule via a bond to the nitrogen atom of the alkylamino group. For example, alkylamino includes methylamino (-NHCH3), dimethylamino (-N(CH3)2), -NHCH2CH3, and the like.

[0036] "Alkoxy" refers to a group containing an alkyl radical attached through an oxygen linking atom, where alkyl is as defined above. The alkoxy group can have a specified number of carbon atoms. For example, "(C1-C6)alkoxy" and "(C 1-6 The term "(C1-C4)alkoxy" refers to an alkyl radical having from 1 to 6 carbon atoms attached through an oxygen linking atom. Similarly, "(C1-C4)alkoxy" and "(C 1-4 The term "alkoxy" refers to an alkyl radical having from 1 to 4 carbon atoms attached through an oxygen linking atom. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, and t-butoxy.

[0037] "Haloalkoxy" refers to an alkoxy group in which the alkyl portion is substituted with one or more halogens, where the halogens are independently selected from fluoro, chloro, bromo, and iodo. The haloalkoxy group can have a specified number of carbon atoms. For example, the term "(C1-C6)haloalkoxy" refers to a haloalkyl radical having from 1 to 6 carbon atoms attached through an oxygen linking atom. Representative haloalkoxy groups include, but are not limited to, difluoromethoxy (-OCHCF2), trifluoromethoxy (-OCF3), tetrafluoroethoxy (-OCF2CHF2), and the like.

[0038] "Aryl" refers to an aromatic hydrocarbon ring. Aryl groups refer to monocyclic, bicyclic, and tricyclic structures having a total of 5 to 14 ring atoms, in which at least one ring system is aromatic and each ring in the system contains 3 to 7 ring atoms, e.g., phenyl, naphthalene, and tetrahydronaphthalene. Preferably, the aryl is phenyl.

[0039] "Heteroatom" is defined as oxygen, nitrogen, sulfur, etc. Preferably, "heteroatom" refers to a nitrogen, sulfur, or oxygen atom.

[0040] "Heterocyclyl" includes heteroaryl and heterocycloalkyl groups. Heterocyclyl groups can be unsaturated or saturated. Unless otherwise specified, monocyclic heterocyclyl rings have 3 to 7 ring atoms, including up to 4 heteroatoms. Monocyclic or fused heterocyclyl rings include substituted aromatic and non-aromatic rings.

[0041] "Heterocycloalkyl" refers to a group or moiety comprising a non-aromatic, monovalent monocyclic or bicyclic radical that is saturated or partially unsaturated. Unless otherwise specified, a heterocycloalkyl contains 3 to 10 ring atoms, including 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and can be unsubstituted or substituted with one or more specified substituents. Typically, in compounds of the present invention, heterocycloalkyl groups are 5- and / or 6-membered heterocycloalkyl groups.

[0042] "Heteroaryl" refers to a group or moiety comprising an aromatic monovalent monocyclic or bicyclic radical. Unless otherwise specified, heteroaryl contains 4 to 10 ring atoms, preferably 5 to 10 ring atoms, including 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and may be unsubstituted or substituted with one or more specified substituents. "Heteroaryl" also encompasses bicyclic heterocyclic aryl compounds containing an aryl ring moiety fused to a heterocycloalkyl ring moiety, which contains 4 to 10 ring atoms, preferably 5 to 10 ring atoms, including 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and which may be unsubstituted or substituted with one or more of the substituents defined herein. Heteroaryl includes, but is not limited to, benzimidazolyl, benzothiazolyl, benzothiophenyl, benzopyrazinyl, benzotriazolyl, benzotriazinyl, benzo[1,4]dioxanyl, benzofuranyl, 9H-α-carbolinyl, cinnolinyl, furanyl, pyrazolyl, imidazolyl, indolizinyl, naphthyridinyl, oxazolyl, oxothiadiazolyl, oxadiazolyl, phthalazinyl, pyridyl (or pyridinyl), , pyrrolyl, purinyl, pteridinyl, phenazinyl, pyrazinyl, pyrazolopyrimidinyl, pyrazolopyridinyl, pyrrolidinyl, pyrimidyl, isothiazolyl, furazanyl, pyrimidinyl, tetrazinyl, isoxazolyl, quinoxalinyl, quinazolinyl, quinolinyl, quinolidinyl, thienyl, thiophenyl, triazolyl, triazinyl, tetrazolopyrimidinyl, triazolopyrimidinyl, tetrazolyl, thiazolyl and thiazolidinyl.

[0043] Heteroaryl groups present in the compounds of the present invention are generally 5- and / or 6-membered monocyclic heteroaryl groups containing one or two nitrogen ring atoms. Exemplary 5- and / or 6-membered monocyclic heteroaryl groups containing one or two nitrogen ring atoms include, but are not limited to, pyridyl (or pyridinyl), pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, and the like.

[0044] In one embodiment, the heteroaryl group is pyridinyl, which may be substituted with one or more of the defined substituents, such as oxo, halo, alkyl, etc. For example, pyridinyl may be substituted with oxo to form a pyridone ring moiety, which may include, but is not limited to, -3-pyridonyl, -4-pyridonyl, -5-pyridonyl, etc. Heteroaryl may also be substituted with one or more additional specified substituents, including, but not limited to, the moieties shown below: [ka] and oxo-substituted pyridazinyl, pyrimidinyl and pyrazinyl, including:

[0045] According to the conventions used in the art, [ka] is used in structural formulas herein to represent the bond that is the point of attachment of a group, moiety, or substituent to the core, backbone, or parent molecular structure.

[0046] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on that ring.

[0047] As used herein, the term "compound of the invention" means a compound of any of the formulae disclosed herein in any form, i.e., any salt or non-salt form (e.g., as a free acid or base form or as a pharmaceutically acceptable salt thereof), any tautomer thereof, and any of its physical forms (e.g., non-solid forms (e.g., liquid or semi-solid forms), and solid forms (e.g., amorphous or crystalline forms, particular polymorphic forms, solvates including hydrates (e.g., monohydrates, dihydrates, and hemihydrates))), as well as mixtures of various forms.

[0048] As used herein, the term "optionally substituted" means that a group (e.g., alkyl, etc.) may be unsubstituted or that the group may be substituted with one or more substituents as defined herein. The term "substituted," when used herein with respect to a group (e.g., alkyl, etc.), means that at least one hydrogen atom has been replaced with a non-hydrogen group, provided that all normal valences are maintained and the substitution results in a stable compound. When a group can be selected from multiple alternative groups, the selected groups may be the same or different. For example, various substituents of the compound formulas defined in this invention may be substituted, including, but not limited to, halo, cyano, amino, alkyl, haloalkyl, alkoxy, and the like.

[0049] The term "independently," as used herein with respect to substituents or heteroatoms, means that when two or more substituents or heteroatoms are selected from multiple possible substituents or heteroatoms, respectively, those substituents or heteroatoms may be the same or different.

[0050] compound In particular, the present invention provides novel Na v 1.8 inhibitor compounds or pharmaceutically acceptable salts thereof and / or corresponding tautomers thereof.

[0051] In one embodiment, the present invention provides a compound of formula (I): [ka] [In the formula, Y is O or S; X 1 is nitrogen or CR 1 and X 2 is nitrogen or CR 2 and X 3 is nitrogen or CR 3 and X 4 is nitrogen or CR 4 and However, X 2 , X 3 and X 4 at least one of which is nitrogen; R 1 , R 2 , R 3 and R 4 each independently represents hydrogen, halo, cyano, -NR a R b , -(C 1-6 )-alkyl, -(C 1-6 )-haloalkyl, -O-(C 1-6 )-alkyl or -O-(C 1-6 )-haloalkyl; Ring B is phenyl or a 5- or 6-membered heterocyclyl containing 1 or 2 nitrogen ring atoms; Each R 5 are independently halo, oxo, -OH, -NR a R b , -(C 1-6 ) alkyl, -(C 1-6 ) haloalkyl, -COOR a , -C(O)NR a R b or -S(O) p R c and; R 6 is hydrogen, -(C 1-6 ) alkyl, -O-(C 1-6 )-Alkyl or -NR a R b and; Each R 7 are independently halo, -(C 1-6 ) alkyl, -O-(C 1-6 ) alkyl or -O-(C 1-6 )-haloalkyl; R a and R b each independently represents hydrogen, -(C 1-6 ) alkyl or -(C 1-6 ) haloalkyl; R cis hydrogen, -OH, -NR a R b , -(C 1-6 )-alkyl or -(C 1-6 )-haloalkyl; n is 0, 1, 2 or 3; p is 0, 1 or 2; and z is 0, 1, 2, or 3. or a tautomer thereof or a pharmaceutically acceptable salt thereof.

[0052] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof: Y is O or S; X 1 is nitrogen or CR 1 and X 2 is nitrogen or CR 2 and X 3 is nitrogen or CR 3 and X 4 is nitrogen or CR 4 and However, X 2 , X 3 and X 4 at least one of which is nitrogen; R 1 , R 2 , R 3 and R 4 each independently represents hydrogen, halo, cyano, -(C 1-6 )-alkyl, -(C 1-6 )-haloalkyl, -O-(C 1-6 )-alkyl or -O-(C 1-6 )-haloalkyl; Ring B is a 5- or 6-membered heteroaryl containing 1 or 2 nitrogen ring atoms; Each R 5 are independently halo, oxo, -OH, -NR a R b and -(C 1-6 ) alkyl; R6 is -(C 1-6 ) alkyl; Each R 7 are independently halo, -(C 1-6 ) alkyl, -O-(C 1-6 ) alkyl or -O-(C 1-6 )-haloalkyl; R a and R b each independently represents hydrogen, -(C 1-6 ) alkyl or -(C 1-6 ) haloalkyl; n is 0, 1, 2 or 3; and z is 0, 1, 2 or 3.

[0053] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Y is O.

[0054] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Y is S.

[0055] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, X 1 is nitrogen.

[0056] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, X 2 is nitrogen.

[0057] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, X 3 is nitrogen.

[0058] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, X 4 is nitrogen.

[0059] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, X 1is CR 1 is.

[0060] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, X 2 is CR 2 is.

[0061] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, X 3 is CR 3 is.

[0062] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, X 4 is CR 4 is.

[0063] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, X 2 , X 3 and X 4 At least one of X is nitrogen 1 , X 2 , X 3 and X 4 Up to two of these are nitrogen.

[0064] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, X 1 is CR 1 and R 1 -NR a R b , -(C 1-6 )-alkyl, -(C 1-6 )-haloalkyl, -O-(C 1-6 )-alkyl or -O-(C 1-6 )-haloalkyl.

[0065] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, X 1 is CR 1 and R 1is hydrogen, halo, cyano or -(C 1-6 )-haloalkyl.

[0066] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, X 1 is CR 1 and R 1 is hydrogen.

[0067] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, X 2 is CR 2 and R 2 -NR a R b , -(C 1-6 )-alkyl, -(C 1-6 )-haloalkyl, -O-(C 1-6 )-alkyl or -O-(C 1-6 )-haloalkyl.

[0068] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, X 2 is CR 2 and R 2 is hydrogen, halo, cyano or -(C 1-6 )-haloalkyl.

[0069] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, X 2 is CR 2 and R 2 is hydrogen, —CF3, —Cl, or cyano.

[0070] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, X 3 is CR 3 and R 3 -NR a R b , -(C 1-6 )-alkyl, -(C 1-6)-haloalkyl, -O-(C 1-6 )-alkyl or -O-(C 1-6 )-haloalkyl.

[0071] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, X 3 is CR 3 and R 3 is hydrogen, halo, cyano or -(C 1-6 )-haloalkyl.

[0072] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, X 3 is CR 3 and R 3 is hydrogen, —CF3, —Cl, or cyano.

[0073] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, X 4 is CR 4 and R 4 -NR a R b , -(C 1-6 )-alkyl, -(C 1-6 )-haloalkyl, -O-(C 1-6 )-alkyl or -O-(C 1-6 )-haloalkyl.

[0074] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, X 4 is CR 4 and R 4 is hydrogen, halo, cyano or -(C 1-6 )-haloalkyl.

[0075] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, X 4 is CR 4 and R 4 is hydrogen.

[0076] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, X 1 is CR 1 and X 2 is CR 2 and X 3 is CR 3 and X 4 is nitrogen.

[0077] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, X 1 is CR 1 and X 2 is nitrogen and X 3 is CR 3 and X 4 is CR 4 is.

[0078] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, X 1 is CR 1 and X 2 is CR 2 and X 3 is nitrogen and X 4 is CR 4 is.

[0079] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, X 1 is nitrogen and X 2 is CR 2 and X 3 is nitrogen and X 4 is CR 4 is.

[0080] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, X 1 is nitrogen and X 2 is CR 2 and X 3 is CR 3 and X 4 is nitrogen.

[0081] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is phenyl.

[0082] In certain embodiments of a compound of Formula (I) or a tautomer or a pharmaceutically acceptable salt thereof, Ring B is a 5- or 6-membered heterocyclyl containing 1 or 2 nitrogen ring atoms.

[0083] In certain embodiments of a compound of Formula (I) or a tautomer or a pharmaceutically acceptable salt thereof, Ring B is a 5- or 6-membered heteroaryl containing 1 or 2 nitrogen ring atoms.

[0084] In certain embodiments of a compound of Formula (I) or a tautomer or a pharmaceutically acceptable salt thereof, Ring B is a 5- or 6-membered heterocycloalkyl containing 1 or 2 nitrogen ring atoms.

[0085] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, each R 5 are independently halo, oxo, -OH, -NR a R b or -(C 1-6 ) alkyl.

[0086] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, ring B is a 5- or 6-membered heteroaryl containing 1 or 2 nitrogen ring atoms; 5 are independently halo, oxo, -OH, -NR a R b , -(C 1-6 ) alkyl or -(C 1-6 ) haloalkyl.

[0087] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyridinyl; 5 are independently halo, oxo, -OH, -NR a R b or -(C 1-6) alkyl.

[0088] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyridinyl and each R 5 are independently oxo or -(C 1-6 ) alkyl.

[0089] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyridinyl and each R 5 are independently oxo, -F, -Cl, -NH2, or -CH3.

[0090] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyridinyl and each R 5 are independently oxo, -F, -NH2, or -CH3.

[0091] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyridinyl and each R 5 is independently oxo, -F, or -CH3.

[0092] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyridinyl and each R 5 are independently oxo or -CH3.

[0093] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyrazolyl and each R 5 are independently halo, oxo, -OH, -NR a R b or -(C 1-6 ) alkyl.

[0094] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyrazolyl and each R 5 are independently -(C 1-6) alkyl.

[0095] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyrazolyl and each R 5 are independently -CH3.

[0096] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, z is 1, 2, or 3; and each R 5 are independently -CH3, -F, -Cl, oxo, or -NH2.

[0097] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] is.

[0098] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] is.

[0099] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] is.

[0100] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 is hydrogen.

[0101] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 Ha-(C 1-6 ) alkyl.

[0102] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 is -CH3, -CH2CH3 or -CH(CH3)2.

[0103] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 is -CH3.

[0104] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 Ha-NR a R b is.

[0105] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 is -NH2.

[0106] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, each R 7 are independently halo or -O(C 1-6 ) haloalkyl.

[0107] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, each R 7 are independently -F or -OCF3.

[0108] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, n is 1 or 2 and each R 7are independently -F or -OCF3.

[0109] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, n is 1 and R 7 is -F.

[0110] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, n is 1 and R 7 is -OCF3.

[0111] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, n is 2 and each R 7 is -F.

[0112] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 is -CH3, -CH2CH3, or -CH(CH3)2; n is 1 or 2; each R 7 are independently -F or -OCF3.

[0113] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, [ka] The structure: [ka] where R 7a and R 7b each independently represents hydrogen, halo, -(C 1-6 ) alkyl, -O-(C 1-6 ) alkyl or -O-(C 1-6 )-haloalkyl.

[0114] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 7a and R 7beach independently represents hydrogen, halo, or —O(C 1-6 ) haloalkyl.

[0115] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 7a is -F or -OCF3.

[0116] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 7b is hydrogen or -F.

[0117] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 7a is -F or -OCF3, and R 7b is hydrogen or -F.

[0118] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 7a is -F and R 7b is hydrogen.

[0119] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] is.

[0120] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R a and R b each independently represents hydrogen or -(C 1-6 ) alkyl.

[0121] In certain embodiments of a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Y is O; X 1 , X 2 , X 3 and X 4 is as defined for formula (I); R 1 , R 2 , R 3 and R 4 each is independently hydrogen, —CF3, Cl, or cyano; Ring B is a 5- or 6-membered heteroaryl containing 1 or 2 nitrogen ring atoms; Each R 5 are independently oxo, -F, -CH3, or -NH2; R 6 is -CH3, -CH2CH3 or -CH(CH3)2; Each R 7 are independently -F or -OCF3; z is 0, 1, 2 or 3; and n is 1 or 2.

[0122] In another aspect, the present invention provides a compound of formula (IA): [ka] [In the formula, Y is O or S; R 1 , R 2 and R 3 each independently represents hydrogen, halo, cyano, -NR a R b , -(C 1-6 )-alkyl, -(C 1-6 )-haloalkyl, -O-(C 1-6 )-alkyl or -O-(C 1-6 )-haloalkyl; Ring B is phenyl or a 5- or 6-membered heterocyclyl containing 1 or 2 nitrogen ring atoms; Each R 5 are independently halo, oxo, -OH, -NR a R b , -(C 1-6) alkyl, -(C 1-6 ) haloalkyl, -COOR a , -C(O)NR a R b or -S(O) p R c and; R 6 is hydrogen, -(C 1-6 ) alkyl, -O-(C 1-6 )-Alkyl or -NR a R b and; Each R 7 are independently halo, -(C 1-6 ) alkyl, -O-(C 1-6 ) alkyl or -O-(C 1-6 )-haloalkyl; R a and R b each independently represents hydrogen, -(C 1-6 ) alkyl or -(C 1-6 ) haloalkyl: R c is hydrogen, -OH, -NR a R b , -(C 1-6 )-alkyl or -(C 1-6 )-haloalkyl; n is 0, 1, 2 or 3; p is 0, 1 or 2; and z is 0, 1, 2, or 3. or a pharmaceutically acceptable salt or tautomer thereof.

[0123] In certain embodiments of a compound of Formula (IA) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Y is O or S; R 1 , R 2 and R 3 each independently represents hydrogen, halo, cyano, -NR a R b , -(C 1-6 )-alkyl, -(C 1-6 )-haloalkyl, -O-(C 1-6)-alkyl or -O-(C 1-6 )-haloalkyl; Ring B is a 5- or 6-membered heteroaryl containing 1 or 2 nitrogen ring atoms; Each R 5 are independently halo, oxo, -OH, -NR a R b or -(C 1-6 ) alkyl; R 6 Ha-(C 1-6 ) alkyl; Each R 7 are independently halo, -(C 1-6 ) alkyl, -O-(C 1-6 ) alkyl or -O-(C 1-6 )-haloalkyl; R a and R b each independently represents hydrogen, -(C 1-6 ) alkyl or -(C 1-6 ) haloalkyl; n is 0, 1, 2 or 3; and z is 0, 1, 2 or 3.

[0124] In certain embodiments of the compounds of Formula (IA) or tautomers thereof or pharmaceutically acceptable salts thereof, Y is O.

[0125] In certain embodiments of the compounds of Formula (IA) or tautomers thereof or pharmaceutically acceptable salts thereof, Y is S.

[0126] In certain embodiments of a compound of Formula (IA) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 1 is hydrogen, halo, cyano or -(C 1-6 )-haloalkyl.

[0127] In certain embodiments of a compound of Formula (IA) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 1 is hydrogen, —CF3, —Cl, or cyano.

[0128] In certain embodiments of a compound of Formula (IA) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 1 is hydrogen.

[0129] In certain embodiments of a compound of Formula (IA) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 2 is hydrogen, halo, cyano or -(C 1-6 )-haloalkyl.

[0130] In certain embodiments of a compound of Formula (IA) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 2 is hydrogen, —CF3, —Cl, or cyano.

[0131] In certain embodiments of a compound of Formula (IA) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 3 is hydrogen, halo, cyano or -(C 1-6 )-haloalkyl.

[0132] In certain embodiments of a compound of Formula (IA) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 3 is hydrogen, —CF3, —Cl, or cyano.

[0133] In certain embodiments of the compounds of Formula (IA) or tautomers thereof or pharmaceutically acceptable salts thereof, Ring B is phenyl.

[0134] In certain embodiments of the compounds of Formula (IA), or tautomers thereof, or pharmaceutically acceptable salts thereof, Ring B is a 5- or 6-membered heterocyclyl containing 1 or 2 nitrogen ring atoms.

[0135] In certain embodiments of a compound of Formula (IA), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, Ring B is a 5- or 6-membered heteroaryl containing 1 or 2 nitrogen ring atoms.

[0136] In certain embodiments of a compound of Formula (IA) or a tautomer or a pharmaceutically acceptable salt thereof, Ring B is a 5- or 6-membered heterocycloalkyl containing 1 or 2 nitrogen ring atoms.

[0137] In certain embodiments of a compound of Formula (IA) or a tautomer thereof or a pharmaceutically acceptable salt thereof, each R 5 are independently halo, oxo, -OH, -NR a R b or -(C 1-6 ) alkyl.

[0138] In certain embodiments of a compound of Formula (IA) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is a 5- or 6-membered heteroaryl containing 1 or 2 nitrogen ring atoms, and each R 5 are independently halo, oxo, -OH, -NR a R b , -(C 1-6 ) alkyl or -(C 1-6 ) haloalkyl.

[0139] In certain embodiments of a compound of Formula (IA), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, Ring B is pyridinyl and each R 5 are independently halo, oxo, -OH, -NR a R b or -(C 1-6 ) alkyl.

[0140] In certain embodiments of a compound of Formula (IA), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, Ring B is pyridinyl and each R 5 are independently oxo or -(C 1-6 ) alkyl.

[0141] In certain embodiments of a compound of Formula (IA), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, Ring B is pyridinyl and each R 5 are independently oxo, -F, -Cl, -NH2, or -CH3.

[0142] In certain embodiments of a compound of Formula (IA), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, Ring B is pyridinyl and each R 5 are independently oxo, -F, -NH2, or -CH3.

[0143] In certain embodiments of a compound of Formula (IA), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, Ring B is pyridinyl and each R 5 is independently oxo, -F, or -CH3.

[0144] In certain embodiments of a compound of Formula (IA), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, Ring B is pyridinyl and each R 5 are independently oxo or -CH3.

[0145] In certain embodiments of a compound of Formula (IA), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, Ring B is pyrazolyl, and each R 5 are independently halo, oxo, -OH, -NR a R b or -(C 1-6 ) alkyl.

[0146] In certain embodiments of a compound of Formula (IA), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, Ring B is pyrazolyl, and each R 5 are independently -(C 1-6 ) alkyl.

[0147] In certain embodiments of a compound of Formula (IA), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, Ring B is pyrazolyl, and each R 5 are independently -CH3.

[0148] In certain embodiments of a compound of Formula (IA) or a tautomer thereof or a pharmaceutically acceptable salt thereof, z is 1, 2, or 3; and each R 5 are independently -CH3, -F, -Cl, oxo, or -NH2.

[0149] In certain embodiments of a compound of Formula (IA) or a tautomer thereof or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] is.

[0150] In certain embodiments of a compound of Formula (IA) or a tautomer thereof or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] is.

[0151] In certain embodiments of a compound of Formula (IA) or a tautomer thereof or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] is.

[0152] In certain embodiments of a compound of Formula (IA) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 is hydrogen.

[0153] In certain embodiments of a compound of Formula (IA) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 Ha-(C 1-6 ) alkyl.

[0154] In certain embodiments of a compound of Formula (IA) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 is -CH3, -CH2CH3 or -CH(CH3)2.

[0155] In certain embodiments of a compound of Formula (IA) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 is -CH3.

[0156] In certain embodiments of a compound of Formula (IA) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 Ha-NR a R b is.

[0157] In certain embodiments of a compound of Formula (IA) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 is -NH2.

[0158] In certain embodiments of a compound of Formula (IA), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, each R 7 are independently halo or -O(C 1-6 ) haloalkyl.

[0159] In certain embodiments of a compound of Formula (IA) or a tautomer thereof or a pharmaceutically acceptable salt thereof, each R 7 are independently -F or -OCF3.

[0160] In certain embodiments of a compound of Formula (IA) or a tautomer thereof or a pharmaceutically acceptable salt thereof, n is 1 or 2 and each R 7 are independently -F or -OCF3.

[0161] In certain embodiments of a compound of Formula (IA) or a tautomer thereof or a pharmaceutically acceptable salt thereof, n is 1 and R 7 is -F.

[0162] In certain embodiments of a compound of Formula (IA) or a tautomer thereof or a pharmaceutically acceptable salt thereof, n is 1 and R 7 is -OCF3.

[0163] In certain embodiments of a compound of Formula (IA) or a tautomer thereof or a pharmaceutically acceptable salt thereof, n is 2 and each R 7 is -F.

[0164] In certain embodiments of a compound of Formula (IA) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 is -CH3, -CH2CH3, or -CH(CH3)2; n is 1 or 2; each R 7 are independently -F or -OCF3.

[0165] In certain embodiments of a compound of Formula (IA) or a tautomer thereof or a pharmaceutically acceptable salt thereof, [ka] The structure: [ka] where R 7a and R 7b each independently represents hydrogen, halo, -(C 1-6 ) alkyl, -O-(C 1-6 ) alkyl or -O-(C 1-6 )-haloalkyl.

[0166] In certain embodiments of a compound of Formula (IA) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 7a and R 7b each independently represents hydrogen, halo, or —O(C 1-6 ) haloalkyl.

[0167] In certain embodiments of a compound of Formula (IA) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 7a is -F or -OCF3.

[0168] In certain embodiments of a compound of Formula (IA) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 7b is hydrogen or -F.

[0169] In certain embodiments of a compound of Formula (IA) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 7a is -F or -OCF3, and R 7b is hydrogen or -F.

[0170] In certain embodiments of a compound of Formula (IA) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 7a is -F and R 7b is hydrogen.

[0171] In certain embodiments of a compound of Formula (IA) or a tautomer thereof or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] is.

[0172] In certain embodiments of a compound of Formula (IA) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R a and R b each independently represents hydrogen or -(C 1-6 ) alkyl.

[0173] In certain embodiments of a compound of Formula (IA) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Y is O; R 1 , R 2 and R 3 each is independently hydrogen, —CF3, Cl, or cyano; Ring B is a 5- or 6-membered heteroaryl containing 1 or 2 nitrogen ring atoms; Each R 5 are independently oxo, -F, -CH3, or -NH2; R 6 is -CH3, -CH2CH3 or -CH(CH3)2; Each R7 are independently -F or -OCF3; z is 0, 1, 2, or 3; and n is 1 or 2.

[0174] In another aspect, the present invention provides a compound of formula (IB): [ka] [In the formula, Y is O or S; R 1 , R 3 and R 4 each independently represents hydrogen, halo, cyano, -NR a R b , -(C 1-6 )-alkyl, -(C 1-6 )-haloalkyl, -O-(C 1-6 )-alkyl or -O-(C 1-6 )-haloalkyl; Ring B is phenyl or a 5- or 6-membered heterocyclyl containing 1 or 2 nitrogen ring atoms; Each R 5 are independently halo, oxo, -OH, -NR a R b , -(C 1-6 ) alkyl, -(C 1-6 ) haloalkyl, -COOR a , -C(O)NR a R b or -S(O) p R c and; R 6 is hydrogen, -(C 1-6 ) alkyl, -O-(C 1-6 )-Alkyl or -NR a R b and; Each R 7 are independently halo, -(C 1-6 ) alkyl, -O-(C 1-6 ) alkyl or -O-(C 1-6 )-haloalkyl; R a and Rb each independently represents hydrogen, -(C 1-6 ) alkyl or -(C 1-6 ) haloalkyl; R c is hydrogen, -OH, -NR a R b , -(C 1-6 )-alkyl or -(C 1-6 )-haloalkyl; n is 0, 1, 2 or 3; p is 0, 1 or 2; and z is 0, 1, 2, or 3. or a pharmaceutically acceptable salt or tautomer thereof.

[0175] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Y is O or S; R 1 , R 3 and R 4 each independently represents hydrogen, halo, cyano, -NR a R b , -(C 1-6 )-alkyl, -(C 1-6 )-haloalkyl, -O-(C 1-6 )-alkyl or -O-(C 1-6 )-haloalkyl; Ring B is a 5- or 6-membered heteroaryl containing 1 or 2 nitrogen ring atoms; Each R 5 are independently halo, oxo, -OH, -NR a R b or -(C 1-6 ) alkyl; R 6 Ha-(C 1-6 ) alkyl; Each R 7 are independently halo, -(C 1-6 ) alkyl, -O-(C 1-6 ) alkyl or -O-(C 1-6 )-haloalkyl; R a and Rb each independently represents hydrogen, -(C 1-6 ) alkyl or -(C 1-6 ) haloalkyl; n is 0, 1, 2 or 3; and z is 0, 1, 2 or 3.

[0176] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Y is O.

[0177] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Y is S.

[0178] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 1 is hydrogen, halo, cyano or -(C 1-6 )-haloalkyl.

[0179] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 1 is hydrogen, —CF3, —Cl, or cyano.

[0180] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 1 is hydrogen.

[0181] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 3 is hydrogen, halo, cyano or -(C 1-6 )-haloalkyl.

[0182] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 3 is hydrogen, —CF3, —Cl, or cyano.

[0183] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 4 is hydrogen, halo, cyano or -(C 1-6 )-haloalkyl.

[0184] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 4 is hydrogen, —CF3, —Cl, or cyano.

[0185] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 4 is hydrogen.

[0186] In certain embodiments of the compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is phenyl.

[0187] In certain embodiments of a compound of Formula (IB) or a tautomer or a pharmaceutically acceptable salt thereof, Ring B is a 5- or 6-membered heterocyclyl containing 1 or 2 nitrogen ring atoms.

[0188] In certain embodiments of a compound of Formula (IB) or a tautomer or a pharmaceutically acceptable salt thereof, Ring B is a 5- or 6-membered heteroaryl containing 1 or 2 nitrogen ring atoms.

[0189] In certain embodiments of a compound of Formula (IB) or a tautomer or a pharmaceutically acceptable salt thereof, Ring B is a 5- or 6-membered heterocycloalkyl containing 1 or 2 nitrogen ring atoms.

[0190] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, each R 5 are independently halo, oxo, -OH, -NR a R b or -(C 1-6 ) alkyl.

[0191] In certain embodiments of a compound of Formula (IB) or a tautomer or a pharmaceutically acceptable salt thereof, Ring B is a 5- or 6-membered heteroaryl containing 1 or 2 nitrogen ring atoms, and each R 5 are independently halo, oxo, -OH, -NR a R b , -(C 1-6 ) alkyl or -(C 1-6 ) haloalkyl.

[0192] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyridinyl and each R 5 are independently halo, oxo, -OH, -NR a R b or -(C 1-6 ) alkyl.

[0193] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyridinyl and each R 5 are independently oxo or -(C 1-6 ) alkyl.

[0194] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyridinyl and each R 5 are independently oxo, -F, -Cl, -NH2, or -CH3.

[0195] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyridinyl and each R 5 are independently oxo, -F, -NH2, or -CH3.

[0196] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyridinyl and each R 5 is independently oxo, -F, or -CH3.

[0197] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyridinyl and each R 5 are independently oxo or -CH3.

[0198] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyrazolyl and each R 5 are independently halo, oxo, -OH, -NR a R b or -(C 1-6 ) alkyl.

[0199] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyrazolyl and each R 5 are independently -(C 1-6 ) alkyl.

[0200] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyrazolyl and each R 5 are independently -CH3.

[0201] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, z is 1, 2, or 3, and each R 5 are independently -CH3, -F, -Cl, oxo, or -NH2.

[0202] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] is.

[0203] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] is.

[0204] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] is.

[0205] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 is hydrogen.

[0206] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 Ha-(C 1-6 ) alkyl.

[0207] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 is -CH3, -CH2CH3 or -CH(CH3)2.

[0208] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 is -CH3.

[0209] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 Ha-NR a R b is.

[0210] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 is -NH2.

[0211] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, each R 7 are independently halo or -O(C 1-6 ) haloalkyl.

[0212] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, each R 7 are independently -F or -OCF3.

[0213] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, n is 1 or 2 and each R 7 are independently -F or -OCF3.

[0214] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, n is 1 and R 7 is -F.

[0215] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, n is 1 and R 7 is -OCF3.

[0216] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, n is 2 and each R 7 is -F.

[0217] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 is -CH3, -CH2CH3, or -CH(CH3)2; n is 1 or 2; each R 7 are independently -F or -OCF3.

[0218] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, [ka] The structure: [ka] where R 7a and R 7b each independently represents hydrogen, halo, -(C 1-6 ) alkyl, -O-(C 1-6 ) alkyl or -O-(C 1-6 )-haloalkyl.

[0219] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 7a and R 7b each independently represents hydrogen, halo, or —O(C 1-6 ) haloalkyl.

[0220] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 7a is -F or -OCF3.

[0221] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 7b is hydrogen or -F.

[0222] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 7a is -F or -OCF3, and R 7b is hydrogen or -F.

[0223] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 7a is -F and R 7b is hydrogen.

[0224] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] is.

[0225] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R a and R b each independently represents hydrogen or -(C 1-6 ) alkyl.

[0226] In certain embodiments of a compound of Formula (IB) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Y is O, R 1 , R 3 and R 4 each is independently hydrogen, —CF3, Cl, or cyano; Ring B is a 5- or 6-membered heteroaryl containing 1 or 2 nitrogen ring atoms; Each R 5 are independently oxo, -F, -CH3, or -NH2; R 6 is -CH3, -CH2CH3 or -CH(CH3)2; Each R 7 are independently -F or -OCF; and n is 1 or 2.

[0227] In another aspect, the present invention provides a compound of formula (IC): [ka] [In the formula, Y is O or S; R 1 , R 2 and R 4each independently represents hydrogen, halo, cyano, -NR a R b , -(C 1-6 )-alkyl, -(C 1-6 )-haloalkyl, -O-(C 1-6 )-alkyl or -O-(C 1-6 )-haloalkyl; Ring B is phenyl or a 5- or 6-membered heterocyclyl containing 1 or 2 nitrogen ring atoms; Each R 5 are independently halo, oxo, -OH, -NR a R b , -(C 1-6 ) alkyl, -(C 1-6 ) haloalkyl, -COOR a , -C(O)NR a R b or -S(O) p R c and; R 6 is hydrogen, -(C 1-6 ) alkyl, -O-(C 1-6 )-Alkyl or -NR a R b and; Each R 7 are independently halo, -(C 1-6 ) alkyl, -O-(C 1-6 ) alkyl or -O-(C 1-6 )-haloalkyl; R a and R b each independently represents hydrogen, -(C 1-6 ) alkyl or -(C 1-6 ) haloalkyl; R c is hydrogen, -OH, -NR a R b , -(C 1-6 )-alkyl or -(C 1-6 )-haloalkyl; n is 0, 1, 2 or 3; p is 0, 1 or 2; and z is 0, 1, 2, or 3. or a tautomer thereof or a pharmaceutically acceptable salt thereof.

[0228] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Y is O or S; R 1 , R 2 and R 4 each independently represents hydrogen, halo, cyano, -NR a R b , -(C 1-6 )-alkyl, -(C 1-6 )-haloalkyl, -O-(C 1-6 )-alkyl or -O-(C 1-6 )-haloalkyl; Ring B is a 5- or 6-membered heteroaryl containing 1 or 2 nitrogen ring atoms; Each R 5 are independently halo, oxo, -OH, -NR a R b or -(C 1-6 ) alkyl; R 6 Ha-(C 1-6 ) alkyl; Each R 7 are independently halo, -(C 1-6 ) alkyl, -O-(C 1-6 ) alkyl or -O-(C 1-6 )-haloalkyl; R a and R b each independently represents hydrogen, -(C 1-6 ) alkyl or -(C 1-6 ) haloalkyl; n is 0, 1, 2 or 3; and z is 0, 1, 2 or 3.

[0229] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 1 is hydrogen, halo, cyano or -(C 1-6 )-haloalkyl.

[0230] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 1 is hydrogen, —CF3, —Cl, or cyano.

[0231] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 1 is hydrogen.

[0232] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 2 is hydrogen, halo, cyano or -(C 1-6 )-haloalkyl.

[0233] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 2 is hydrogen, —CF3, —Cl, or cyano.

[0234] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 4 is hydrogen, halo, cyano or -(C 1-6 )-haloalkyl.

[0235] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 4 is hydrogen, —CF3, —Cl, or cyano.

[0236] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 4 is hydrogen.

[0237] In certain embodiments of the compound of Formula (IC), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, Ring B is phenyl.

[0238] In certain embodiments of a compound of Formula (IC), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, Ring B is a 5- or 6-membered heterocyclyl containing 1 or 2 nitrogen ring atoms.

[0239] In certain embodiments of a compound of Formula (IC), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, Ring B is a 5- or 6-membered heteroaryl containing 1 or 2 nitrogen ring atoms.

[0240] In certain embodiments of a compound of Formula (IC), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, Ring B is a 5- or 6-membered heterocycloalkyl containing 1 or 2 nitrogen ring atoms.

[0241] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, each R 5 are independently halo, oxo, -OH, -NR a R b or -(C 1-6 ) alkyl.

[0242] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is a 5- or 6-membered heteroaryl containing 1 or 2 nitrogen ring atoms, and each R 5 are independently halo, oxo, -OH, -NR a R b , -(C 1-6 ) alkyl or -(C 1-6 ) haloalkyl.

[0243] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyridinyl and each R 5 are independently halo, oxo, -OH, -NR a R b or -(C 1-6 ) alkyl.

[0244] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyridinyl and each R 5 are independently oxo or -(C 1-6 ) alkyl.

[0245] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyridinyl and each R 5 are independently oxo, -F, -Cl, -NH2, or -CH3.

[0246] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyridinyl and each R 5 are independently oxo, -F, -NH2, or -CH3.

[0247] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyridinyl and each R 5 is independently oxo, -F, or -CH3.

[0248] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyridinyl and each R 5 are independently oxo or -CH3.

[0249] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyrazolyl and each R 5 are independently halo, oxo, -OH, -NR a R b or -(C 1-6 ) alkyl.

[0250] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyrazolyl and each R 5 are independently -(C 1-6 ) alkyl.

[0251] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyrazolyl and each R 5 are independently -CH3.

[0252] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, z is 1, 2, or 3, and each R 5 are independently -CH3, -F, -Cl, oxo, or -NH2.

[0253] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] is.

[0254] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] is.

[0255] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] is.

[0256] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R6 is hydrogen.

[0257] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 Ha-(C 1-6 ) alkyl.

[0258] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 is -CH3, -CH2CH3 or -CH(CH3)2.

[0259] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 is -CH3.

[0260] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 Ha-NR a R b is.

[0261] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 is -NH2.

[0262] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, each R 7 are independently halo or -O(C 1-6 ) haloalkyl.

[0263] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, each R 7 are independently -F or -OCF3.

[0264] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, n is 1 or 2 and each R 7 are independently -F or -OCF3.

[0265] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, n is 1 and R 7 is -F.

[0266] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, n is 1 and R 7 is -OCF3.

[0267] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, n is 2 and each R 7 is -F.

[0268] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 is -CH3, -CH2CH3, or -CH(CH3)2; n is 1 or 2; each R 7 are independently -F or -OCF3.

[0269] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, [ka] The structure: [ka] where R 7a and R 7b each independently represents hydrogen, halo, -(C 1-6 ) alkyl, -O-(C 1-6 ) alkyl or -O-(C 1-6 )-haloalkyl.

[0270] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 7a and R 7b each independently represents hydrogen, halo, or —O(C1-6 ) haloalkyl.

[0271] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 7a is -F or -OCF3.

[0272] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 7b is hydrogen or -F.

[0273] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 7a is -F or -OCF3, and R 7b is hydrogen or -F.

[0274] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 7a is -F and R 7b is hydrogen.

[0275] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] is.

[0276] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R a and R b each independently represents hydrogen or -(C 1-6 ) alkyl.

[0277] In certain embodiments of a compound of Formula (IC) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Y is O; R 1 , R 2 and R 3 each is independently hydrogen, —CF3, Cl, or cyano; Ring B is a 5- or 6-membered heteroaryl containing 1 or 2 nitrogen ring atoms; Each R 5 are independently oxo, -F, -CH3, or -NH2; R 6 is -CH3, -CH2CH3 or -CH(CH3)2; Each R 7 are independently -F or -OCF3; z is 0, 1, 2 or 3; and n is 1 or 2.

[0278] In another aspect, the present invention provides a compound of formula (ID): [ka] [In the formula, Y is O or S; R 2 and R 4 each independently represents hydrogen, halo, cyano, -NR a R b , -(C 1-6 )-alkyl, -(C 1-6 )-haloalkyl, -O-(C 1-6 )-alkyl or -O-(C 1-6 )-haloalkyl; Ring B is phenyl or a 5- or 6-membered heterocyclyl containing 1 or 2 nitrogen ring atoms; Each R 5 are independently halo, oxo, -OH, -NR a R b , -(C 1-6 ) alkyl, -(C 1-6 ) haloalkyl, -COOR a , -C(O)NR a R b or -S(O) p R c and; R6 is hydrogen, -(C 1-6 ) alkyl, -O-(C 1-6 )-Alkyl or -NR a R b and; Each R 7 are independently halo, -(C 1-6 ) alkyl, -O-(C 1-6 ) alkyl or -O-(C 1-6 )-haloalkyl; R a and R b each independently represents hydrogen, -(C 1-6 ) alkyl or -(C 1-6 ) haloalkyl; R c is hydrogen, -OH, -NR a R b , -(C 1-6 )-alkyl or -(C 1-6 )-haloalkyl; n is 0, 1, 2 or 3; p is 0, 1 or 2; and z is 0, 1, 2, or 3. or a pharmaceutically acceptable salt or tautomer thereof.

[0279] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Y is O or S; R 2 and R 4 each independently represents hydrogen, halo, cyano, -NR a R b , -(C 1-6 )-alkyl, -(C 1-6 )-haloalkyl, -O-(C 1-6 )-alkyl or -O-(C 1-6 )-haloalkyl; Ring B is a 5- or 6-membered heteroaryl containing 1 or 2 nitrogen ring atoms; Each R 5 are independently halo, oxo, -OH, -NR a R bor -(C 1-6 ) alkyl; R 6 Ha-(C 1-6 ) alkyl; Each R 7 are independently halo, -(C 1-6 ) alkyl, -O-(C 1-6 ) alkyl or -O-(C 1-6 )-haloalkyl; R a and R b each independently represents hydrogen, -(C 1-6 ) alkyl or -(C 1-6 ) haloalkyl; n is 0, 1, 2 or 3; and z is 0, 1, 2 or 3.

[0280] In certain embodiments of the compounds of Formula (ID) or tautomers thereof or pharmaceutically acceptable salts thereof, Y is O.

[0281] In certain embodiments of the compounds of Formula (ID) or tautomers thereof or pharmaceutically acceptable salts thereof, Y is S.

[0282] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 2 is hydrogen, halo, cyano or -(C 1-6 )-haloalkyl.

[0283] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 2 is hydrogen, —CF3, —Cl, or cyano.

[0284] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 2 is hydrogen, —CF3, —Cl, or cyano.

[0285] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 4 is hydrogen, halo, cyano or -(C 1-6 )-haloalkyl.

[0286] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 4 is hydrogen, —CF3, —Cl, or cyano.

[0287] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 4 is hydrogen.

[0288] In certain embodiments of the compounds of Formula (ID) or tautomers thereof or pharmaceutically acceptable salts thereof, Ring B is phenyl.

[0289] In certain embodiments of a compound of Formula (ID) or a tautomer or a pharmaceutically acceptable salt thereof, Ring B is a 5- or 6-membered heterocyclyl containing 1 or 2 nitrogen ring atoms.

[0290] In certain embodiments of a compound of Formula (ID) or a tautomer or a pharmaceutically acceptable salt thereof, Ring B is a 5- or 6-membered heteroaryl containing 1 or 2 nitrogen ring atoms.

[0291] In certain embodiments of a compound of Formula (ID) or a tautomer or a pharmaceutically acceptable salt thereof, Ring B is a 5- or 6-membered heterocycloalkyl containing 1 or 2 nitrogen ring atoms.

[0292] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, each R 5 are independently halo, oxo, -OH, -NR a R b or -(C 1-6 ) alkyl.

[0293] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is a 5- or 6-membered heteroaryl containing 1 or 2 nitrogen ring atoms, and each R 5 are independently halo, oxo, -OH, -NR a R b , -(C 1-6 ) alkyl or -(C 1-6 ) haloalkyl.

[0294] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyridinyl and each R 5 are independently halo, oxo, -OH, -NR a R b or -(C 1-6 ) alkyl.

[0295] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyridinyl and each R 5 are independently oxo or -(C 1-6 ) alkyl.

[0296] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyridinyl and each R 5 are independently oxo, -F, -Cl, -NH2, or -CH3.

[0297] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyridinyl and each R 5 are independently oxo, -F, -NH2, or -CH3.

[0298] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyridinyl and each R 5 is independently oxo, -F, or -CH3.

[0299] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyridinyl and each R 5 are independently oxo or -CH3.

[0300] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyrazolyl and each R 5 are independently halo, oxo, -OH, -NR a R b or -(C 1-6 ) alkyl.

[0301] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyrazolyl and each R 5 are independently -(C 1-6 ) alkyl.

[0302] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyrazolyl and each R 5 are independently -CH3.

[0303] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, z is 1, 2, or 3, and each R 5 are independently -CH3, -F, -Cl, oxo, or -NH2.

[0304] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] is.

[0305] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] is.

[0306] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] is.

[0307] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 is hydrogen.

[0308] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 Ha-(C 1-6 ) alkyl.

[0309] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 is -CH3, -CH2CH3 or -CH(CH3)2.

[0310] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 is -CH3.

[0311] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 Ha-NR a R b is.

[0312] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 is -NH2.

[0313] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, each R 7 are independently halo or -O(C 1-6 ) haloalkyl.

[0314] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, each R 7 are independently -F or -OCF3.

[0315] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, n is 1 or 2 and each R 7 are independently -F or -OCF3.

[0316] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, n is 1 and R 7 is -F.

[0317] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, n is 1 and R 7 is -OCF3.

[0318] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, n is 2 and each R 7 is -F.

[0319] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 is -CH3, -CH2CH3, or -CH(CH3)2; n is 1 or 2; each R 7 are independently -F or -OCF3.

[0320] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, [ka] The structure: [ka] where R 7a and R 7b each independently represents hydrogen, halo, -(C 1-6 ) alkyl, -O-(C 1-6 ) alkyl or -O-(C 1-6 )-haloalkyl.

[0321] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 7a and R 7b each independently represents hydrogen, halo, or —O(C 1-6 ) haloalkyl.

[0322] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 7a is -F or -OCF3.

[0323] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 7b is hydrogen or -F.

[0324] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 7a is -F or -OCF3, and R 7b is hydrogen or -F.

[0325] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 7a is -F and R 7b is hydrogen.

[0326] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] is.

[0327] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R a and R b each independently represents hydrogen or -(C 1-6 ) alkyl.

[0328] In certain embodiments of a compound of Formula (ID) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Y is O; R 2 and R 4 each is independently hydrogen, —CF3, Cl, or cyano; Ring B is a 5- or 6-membered heteroaryl containing 1 or 2 nitrogen ring atoms; Each R 5 are independently oxo, -F, -CH3, or -NH2; R 6 is -CH3, -CH2CH3 or -CH(CH3)2; Each R 7 are independently -F or -OCF3; z is 0, 1, 2 or 3; and n is 1 or 2.

[0329] In another aspect, the present invention provides a compound of formula (IE): [ka] [In the formula, Y is O or S; R 2 and R 3each independently represents hydrogen, halo, cyano, -NR a R b , -(C 1-6 )-alkyl, -(C 1-6 )-haloalkyl, -O-(C 1-6 )-alkyl or -O-(C 1-6 )-haloalkyl; Ring B is phenyl or a 5- or 6-membered heterocyclyl containing 1 or 2 nitrogen ring atoms; Each R 5 are independently halo, oxo, -OH, -NR a R b , -(C 1-6 ) alkyl, -(C 1-6 ) haloalkyl, -COOR a , -C(O)NR a R b or -S(O) p R c and; R 6 is hydrogen, -(C 1-6 ) alkyl, -O-(C 1-6 )-Alkyl or -NR a R b and; Each R 7 are independently halo, -(C 1-6 ) alkyl, -O-(C 1-6 ) alkyl or -O-(C 1-6 )-haloalkyl; R a and R b each independently represents hydrogen, -(C 1-6 ) alkyl or -(C 1-6 ) haloalkyl; R c is hydrogen, -OH, -NR a R b , -(C 1-6 )-alkyl or -(C 1-6 )-haloalkyl; n is 0, 1, 2 or 3; p is 0, 1 or 2; and z is 0, 1, 2, or 3. or a tautomer thereof or a pharmaceutically acceptable salt thereof.

[0330] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Y is O or S; R 2 and R 3 each independently represents hydrogen, halo, cyano, -NR a R b , -(C 1-6 )-alkyl, -(C 1-6 )-haloalkyl, -O-(C 1-6 )-alkyl or -O-(C 1-6 )-haloalkyl; Ring B is a 5- or 6-membered heteroaryl containing 1 or 2 nitrogen ring atoms; Each R 5 are independently halo, oxo, -OH, -NR a R b or -(C 1-6 ) alkyl; R 6 Ha-(C 1-6 ) alkyl; Each R 7 are independently halo, -(C 1-6 ) alkyl, -O-(C 1-6 ) alkyl or -O-(C 1-6 )-haloalkyl; R a and R b each independently represents hydrogen, -(C 1-6 ) alkyl or -(C 1-6 ) haloalkyl; n is 0, 1, 2, or 3; and z is 0, 1, 2 or 3.

[0331] In certain embodiments of the compounds of Formula (IE) or tautomers thereof or pharmaceutically acceptable salts thereof, Y is O.

[0332] In certain embodiments of the compounds of Formula (IE) or tautomers thereof or pharmaceutically acceptable salts thereof, Y is S.

[0333] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 2 is hydrogen, halo, cyano or -(C 1-6 )-haloalkyl.

[0334] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 2 is hydrogen, —CF3, —Cl, or cyano.

[0335] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 3 is hydrogen, halo, cyano or -(C 1-6 )-haloalkyl.

[0336] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 3 is hydrogen, —CF3, —Cl, or cyano.

[0337] In certain embodiments of the compounds of Formula (IE) or tautomers thereof or pharmaceutically acceptable salts thereof, Ring B is phenyl.

[0338] In certain embodiments of a compound of Formula (IE), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, Ring B is a 5- or 6-membered heterocyclyl containing 1 or 2 nitrogen ring atoms.

[0339] In certain embodiments of a compound of Formula (IE) or a tautomer or a pharmaceutically acceptable salt thereof, Ring B is a 5- or 6-membered heteroaryl containing 1 or 2 nitrogen ring atoms.

[0340] In certain embodiments of a compound of Formula (IE) or a tautomer or a pharmaceutically acceptable salt thereof, Ring B is a 5- or 6-membered heterocycloalkyl containing 1 or 2 nitrogen ring atoms.

[0341] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, each R 5 are independently halo, oxo, -OH, -NR a R b or -(C 1-6 ) alkyl.

[0342] In certain embodiments of a compound of Formula (IE) or a tautomer or a pharmaceutically acceptable salt thereof, Ring B is a 5- or 6-membered heteroaryl containing 1 or 2 nitrogen ring atoms, and each R 5 are independently halo, oxo, -OH, -NR a R b , -(C 1-6 ) alkyl or -(C 1-6 ) haloalkyl.

[0343] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyridinyl and each R 5 are independently halo, oxo, -OH, -NR a R b or -(C 1-6 ) alkyl.

[0344] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyridinyl and each R 5 are independently oxo or -(C 1-6 ) alkyl.

[0345] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyridinyl and each R 5 are independently oxo, -F, -Cl, -NH2, or -CH3.

[0346] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyridinyl and each R 5 are independently oxo, -F, -NH2, or -CH3.

[0347] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyridinyl and each R 5 is independently oxo, -F, or -CH3.

[0348] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyridinyl and each R 5 are independently oxo or -CH3.

[0349] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyrazolyl and each R 5 are independently halo, oxo, -OH, -NR a R b or -(C 1-6 ) alkyl.

[0350] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyrazolyl and each R 5 are independently, -(C 1-6 ) alkyl.

[0351] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring B is pyrazolyl and each R 5 are independently -CH3.

[0352] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, z is 1, 2, or 3, and each R 5 are independently -CH3, -F, -Cl, oxo, or -NH2.

[0353] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] is.

[0354] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] is.

[0355] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] is.

[0356] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 is hydrogen.

[0357] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 Ha-(C 1-6 ) alkyl.

[0358] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 is -CH3, -CH2CH3 or -CH(CH3)2.

[0359] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 is -CH3.

[0360] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 Ha-NR a R b is.

[0361] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 is -NH2.

[0362] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, each R 7 are independently halo or -O(C 1-6 ) haloalkyl.

[0363] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, each R 7 are independently -F or -OCF3.

[0364] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, n is 1 or 2 and each R 7 are independently -F or -OCF3.

[0365] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, n is 1 and R 7 is -F.

[0366] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, n is 1 and R 7 is -OCF3.

[0367] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, n is 2 and each R 7 is -F.

[0368] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 is -CH3, -CH2CH3, or -CH(CH3)2; n is 1 or 2; each R 7 are independently -F or -OCF3.

[0369] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, [ka] The structure: [ka] where R 7a and R 7b each independently represents hydrogen, halo, -(C 1-6 ) alkyl, -O-(C 1-6 ) alkyl or -O-(C 1-6 )-haloalkyl.

[0370] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 7a and R 7b each independently represents hydrogen, halo, or —O(C 1-6 ) haloalkyl.

[0371] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 7a is -F or -OCF3.

[0372] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 7b is hydrogen or -F.

[0373] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 7a is -F or -OCF3, and R 7b is hydrogen or -F.

[0374] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 7a is -F and R 7b is hydrogen.

[0375] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] is.

[0376] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R a and R b each independently represents hydrogen or -(C 1-6 ) alkyl.

[0377] In certain embodiments of a compound of Formula (IE) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Y is O; R 2 and R 3 each is independently hydrogen, —CF3, Cl, or cyano; Ring B is a 5- or 6-membered heteroaryl containing 1 or 2 nitrogen ring atoms; Each R 5 are independently oxo, -F, -CH3, or -NH2; R 6 is -CH3, -CH2CH3 or -CH(CH3)2; Each R 7are independently -F or -OCF3; z is 0, 1, 2 or 3; and n is 1 or 2.

[0378] In another aspect, the invention relates to a compound selected from the following, or a tautomer thereof, or a pharmaceutically acceptable salt thereof:

[0379] [Table 1] JPEG2023554430000072.jpg238169 JPEG2023554430000073.jpg239168 JPEG2023554430000074.jpg230169

[0380] In another aspect, the present invention provides a method for producing a pharmaceutical composition comprising: [ka] or a tautomer thereof or a pharmaceutically acceptable salt thereof.

[0381] Enantiomers, diastereomers and polymorphs A compound according to any of the formulae disclosed herein, including Formulas (I) and (IA)-(IE), or a pharmaceutically acceptable salt thereof and / or the corresponding tautomer of the present invention, may contain one or more asymmetric centers (i.e., also referred to as chiral centers) and therefore may exist in optical forms (e.g., as separate enantiomers, diastereomers or other stereoisomers, or as mixtures thereof) and in racemic forms. All of these separate compounds, stereoisomers and mixtures thereof are within the scope of the present invention.

[0382] Chiral centers, such as chiral carbon atoms, may also be present in substituents, such as alkyl groups. When the stereochemistry of a chiral center present in any of the formulae disclosed herein, including Formulas (I) and (IA)-(IE), or the pharmaceutically acceptable salts and / or corresponding tautomers thereof of the present invention, or any of the chemical structures shown herein, is not explicitly stated, the structure is intended to encompass all separate stereoisomers and all mixtures thereof. Thus, compounds of the present invention, or their pharmaceutically acceptable salts and / or corresponding tautomers, containing one or more chiral centers may be used as racemic mixtures, enantiomerically enriched mixtures, or enantiomerically pure separate stereoisomers.

[0383] The individual stereoisomers of a compound according to any of the formulae disclosed herein, including Formulas (I) and (IA)-(IE), or a pharmaceutically acceptable salt thereof of the present invention and / or the corresponding tautomers, which contain one or more asymmetric centers, can be resolved by methods known to those skilled in the art. For example, such resolution can be achieved by (1) Formation of diastereoisomeric salts, complexes or other derivatives; (2) selective reaction with a stereoisomer-specific reagent, e.g., enzymatic oxidation or reduction; or (3) Gas-liquid or liquid chromatography in a chiral environment (e.g., on a chiral support such as silica to which a chiral ligand is attached, or in the presence of a chiral solvent). Those skilled in the art will recognize that if the desired stereoisomer is converted to another chemical entity by one of the resolution procedures described above, further steps will be required to liberate the desired form.

[0384] Alternatively, specific stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.

[0385] When a disclosed compound or a salt thereof is named or depicted by structure, it should be understood that the compound or salt, including its solvates (particularly hydrates), can exist in crystalline form, amorphous form, or a mixture thereof. The compound or its salt or solvates (particularly hydrates) can also exhibit polymorphism (i.e., the ability to exist in different crystalline forms). These different crystalline forms are commonly known as "polymorphs."

[0386] When named or depicted by structure, the disclosed compounds or solvates (particularly hydrates) thereof are to be understood to include all polymorphs thereof.

[0387] Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Thus, polymorphs may differ in physical properties such as shape, density, hardness, deformability, stability, and dissolution characteristics. Polymorphs typically 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 to crystallize / recrystallize a compound.

[0388] In one embodiment, the present invention provides 1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, in crystalline form.

[0389] In one embodiment, the present invention provides 1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one in crystalline form.

[0390] In another embodiment, the present invention provides 1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one, characterized in that it exhibits an XRPD (X-ray powder diffraction) pattern with peaks (°2θ) at about 6.3, about 7.4, about 10.0, and / or about 12.6.

[0391] In another embodiment, the present invention provides 1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one, characterized in that it exhibits XRPD Form 1 comprising peaks substantially as shown in Table 1.

[0392] In another embodiment, the present invention provides 1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one, characterized in that it exhibits an XRPD pattern 1 substantially in accordance with FIG. 1 .

[0393] In another embodiment, the present invention provides 1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one, characterized by a DSC endotherm onset at about 49°C.

[0394] In another embodiment, the present invention provides 1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one, characterized in that it exhibits a DSC substantially in accordance with FIG.

[0395] In another embodiment, the present invention provides 1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one, characterized in that it exhibits an XRPD (X-ray powder diffraction) pattern with peaks (°2θ) at about 6.9, about 8.2, about 10.8, about 13.5, and / or about 14.8.

[0396] In another embodiment, the present invention provides 1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one, characterized in that it exhibits XRPD Form 2 comprising peaks substantially as shown in Table 1.

[0397] In another embodiment, the present invention provides 1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one, characterized in that it exhibits an XRPD pattern 2 substantially in accordance with FIG. 3 .

[0398] In another embodiment, the present invention provides 1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one, characterized by a DSC endotherm onset at about 41° C.

[0399] In another embodiment, the present invention provides 1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one, characterized in that it exhibits a DSC substantially in accordance with FIG.

[0400] In another embodiment, the present invention provides 1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one, characterized in that it exhibits an XRPD (X-ray powder diffraction) pattern with peaks (°2θ) at about 7.1, about 9.3, about 10.2, about 13.8, and / or about 15.0.

[0401] In another embodiment, the present invention provides 1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one, characterized in that it exhibits XRPD Form 3 comprising peaks substantially as shown in Table 1.

[0402] In another embodiment, the present invention provides 1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one, characterized in that it exhibits an XRPD pattern 3 substantially in accordance with FIG. 5 .

[0403] In another embodiment, the present invention provides 1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one, characterized in that it exhibits an XRPD (X-ray powder diffraction) pattern with peaks (°2θ) at about 3.9, about 7.0, about 7.3, about 7.6, and / or about 9.0.

[0404] In another embodiment, the present invention provides 1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one, characterized in that it exhibits XRPD Form 4 comprising peaks substantially as shown in Table 1.

[0405] In another embodiment, the present invention provides 1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one, characterized in that it exhibits an XRPD pattern 4 substantially in accordance with FIG. 6.

[0406] In another embodiment, the present invention provides 1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one, characterized by a DSC endotherm onset at about 42°C.

[0407] In another embodiment, the present invention provides 1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one characterized by exhibiting a DSC substantially in accordance with FIG.

[0408] As used herein, when an XRPD pattern is said to have a peak at a given value, this typically means that the peak is within ±0.2, such as within ±0.1, of the quoted value.

[0409] When a temperature is stated herein to be at a given value in a DSC, this usually means that the temperature is within ±0.2°C, for example within ±0.1°C, of ​​the quoted value.

[0410] salt Because they may be used in medicine, the salts of any of the compounds of the formulae disclosed herein, including formulae (I) and (IA)-(IE), and / or their corresponding tautomers of the present invention are preferably pharmaceutically acceptable salts. Pharmaceutically acceptable salts include, inter alia, those described in Berge, Bighley and Monkhouse J.Pharm.Sci (1977) 66, pp 1-19, or those listed in PH Stahl and CG Wermuth, editors, Handbook of Pharmaceutical Salts; Properties, Selection and Use, Second Edition, Stahl / Wermuth: Wiley-VCH / VHCA, 2011. Non-pharmaceutically acceptable salts can also be used, for example, as intermediates in the preparation of any of the compounds of the formulae disclosed herein or their pharmaceutically acceptable salts.

[0411] Suitable pharmaceutically acceptable salts may include acid addition salts or base addition salts. Such base addition salts can be formed by reacting a compound of any of the formulae disclosed herein (including formulae (I) and (IA)-(IE)) and / or its corresponding tautomer of the present invention with an appropriate base, optionally in a suitable solvent such as an organic solvent, to obtain a salt, which can be isolated by various methods, including crystallization and filtration.

[0412] Such acid addition salts can be formed by reacting a compound of any of the formulae disclosed herein (including formulae (I) and (IA)-(IE)) and / or its corresponding tautomer of the present invention with an appropriate acid, optionally in a suitable solvent such as an organic solvent, to provide a salt, which can be isolated by a variety of methods, including crystallization and filtration.

[0413] Salts may also be generated in situ during the final isolation and purification of a compound of any of the formulas disclosed herein (including Formulas (I) and (IA)-(IE)) and / or its corresponding tautomer of the present invention. When a basic compound of any of the formulas disclosed herein (including Formulas (I) and (IA)-(IE)) and / or its corresponding tautomer of the present invention is isolated as a salt, the corresponding free base form of the compound can be prepared by any suitable method known in the art, including treating the salt with an inorganic or organic base. Similarly, when a compound of any of the formulas disclosed herein (including Formulas (I) and (IA)-(IE)) and / or its corresponding tautomer of the present invention containing a carboxylic acid or other acidic functional group is isolated as a salt, the corresponding free acid form of the compound can be prepared by any suitable method known in the art, including treating the salt with an inorganic or organic acid.

[0414] For example, if a compound of the invention is a base (contains a basic moiety), the desired salt form can be prepared by any suitable method known in the art, including treating the free base with an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like) or an organic acid (e.g., acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidylic acid (e.g., glucuronic acid or galacturonic acid), an α-hydroxy acid (e.g., citric acid or tartaric acid), an amino acid (e.g., aspartic acid or glutamic acid), an aromatic acid (e.g., benzoic acid or cinnamic acid), a sulfonic acid (e.g., p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid), and the like).

[0415] If a basic compound of the invention is isolated as a salt, the corresponding free base form of the compound can 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 higher pKa than the free base form of the compound.

[0416] If the compound of the invention is an acid (contains an acidic moiety), the desired salt can 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 hydroxide, or an alkaline earth metal hydroxide. Specific examples of suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines (e.g., ethylenediamine, dicyclohexylamine, ethanolamine, piperidine, morpholine, and piperazine), and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0417] Certain compounds of the present invention can form salts with one or more equivalents of an acid (if the compound contains a basic moiety) or a base (if the compound contains an acidic moiety). The present invention includes within its scope all possible stoichiometric and non-stoichiometric salt formations. When a compound of any of the formulas disclosed herein, including formulas (I) and (IA)-(IE) as defined herein, contains two or more basic moieties, it is understood that the stoichiometry of salt formation can include one, two, or more equivalents of acid. Such salts include one, two, or more acid counterions, e.g., a dihydrochloride salt. Stoichiometric and non-stoichiometric forms of pharmaceutically acceptable salts of any of the formulas disclosed herein (including formulas (I) and (IA)-(IE)) and / or their corresponding tautomers of the present invention are included within the scope of the present invention, including substoichiometric salts, e.g., where the counterion includes two or more acidic protons.

[0418] Because the compounds of the present invention can contain both acidic and basic moieties, pharmaceutically acceptable salts can be prepared by treating these compounds with alkaline or acidic reagents, respectively. Thus, the present invention also provides for the conversion of one pharmaceutically acceptable salt of a compound of the present invention, such as a hydrochloride salt, to another pharmaceutically acceptable salt of a compound of the present invention, such as a sodium salt.

[0419] Representative pharmaceutically acceptable acid addition salts include, but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, bisulfate, bitartrate, butyrate, calcium edetate, camphorate, camphorsulfonate (camsylate), caprate (decanoate), caproate (hexanoate), caprylate (octanoate), cinnamate, citrate, cyclamate, digluconate, 2,5-dihydroxybenzoate, and disuccinate. Salt, dodecyl sulfate (estolate), edetate (ethylenediaminetetraacetate), estolate (lauryl sulfate), ethane-1,2-disulfonate (edisylate), ethanesulfonate (esylate), formate, fumarate, galactarate (mucate), gentisate (2,5-dihydroxybenzoate), glucoheptonate (gluceptonate), gluconate, glucuronate, glutamate, glutarate, glycerophosphate, glycolate, hexylresorcinol, hippurate, hydrabamine (N,N'-di(dehydroabi) (ethyl)-ethylenediamine), hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, isobutyrate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, methanesulfonate (mesylate), methylsulfate, mucate, naphthalene-1,5-disulfonate (napadisylate), naphthalene-2-sulfonate (napsylate), nicotinate, nitrate, oleate, palmitate, p-aminobenzenesulfonate, p-aminosalicyclate te), pamoate (embonate), pantothenate, pectinate, persulfate, phenylacetate, phenylethylbarbiturate, phosphate, polygalacturonate, propionate, p-toluenesulfonate (tosylate), pyroglutamate, pyruvate, salicylate, sebacate, stearate, subacetate, succinate, sulfamate, sulfate, tannate, tartrate, teoclate (8-chloroterephyllate), thiocyanate, triethiodide, undecanoate, undecylenate, and valerate salts.

[0420] Representative pharmaceutically acceptable base addition salts include, but are not limited to, aluminum, 2-amino-2-(hydroxymethyl)-1,3-propanediol (TRIS, tromethamine), arginine, benethamine (N-benzylphenethylamine), benzathine (N,N'-dibenzylethylenediamine), bis-(2-hydroxyethyl)amine, bismuth, calcium, chloroprocaine, choline, clemizole (1-chlorobenzyl-2-pyrrolizin-1'-ylmethylbenzylamine), and benzophenone (benzophenone). These include: dibenzofuran (dibenzofuran), ...

[0421] solvate The compound of the present invention or its pharmaceutically acceptable salts can exist in solvated and non-solvated forms.For the solvates of the compound of the present invention or its pharmaceutically acceptable salts or its tautomers in crystalline form, those skilled in the art will recognize that pharmaceutically acceptable solvates can be formed in which solvent molecules are incorporated into the crystal lattice during crystallization.Solvates can include non-aqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine and ethyl acetate, or can include water as the solvent incorporated into the crystal lattice.Solvates in which water is the solvent incorporated into the crystal lattice are generally referred to as "hydrates".Hydrates include stoichiometric hydrates and compositions containing various amounts of water.

[0422] Deuterated Compounds The present invention also includes various deuterated forms of the compounds of any of the formulae disclosed herein, including Formulas (I) and (IA)-(IE), or pharmaceutically acceptable salts thereof of the present invention and / or the corresponding tautomers. Each available hydrogen atom bonded to a carbon atom may be independently replaced with a deuterium atom.

[0423] Those skilled in the art will know how to synthesize deuterated forms of any of the compounds of the formulae disclosed herein, including Formulas (I) and (IA)-(IE), or their pharmaceutically acceptable salts and / or corresponding tautomers of the present invention. For example, deuterated materials such as alkyl groups can be prepared by conventional techniques (e.g., methyl-d3-amine available from Aldrich Chemical Co., Milwaukee, WI, catalog number 489,689-2).

[0424] Isotopes The present invention also includes isotopically labeled compounds that are identical to those set forth in any of the formulas disclosed herein, including Formulas (I) and (IA)-(IE), or a pharmaceutically acceptable salt thereof and / or corresponding tautomer thereof of the present invention, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.

[0425] Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, iodine, and chlorine, e.g., 3 H, 11 C. 14 C. 18 F, 123 I or 125 Contains I.

[0426] Compounds of the present invention and pharmaceutically acceptable salts of such compounds that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. Isotopically labeled compounds of the present invention, e.g., 3 H or 14Those in which a radioactive isotope such as C is incorporated are useful in drug and / or substrate tissue distribution assays. 3 H isotopes, and carbon-14, i.e., 14 C isotopes are particularly preferred for their ease of preparation and detectability. 11 C isotopes and 18 F isotopes are particularly useful in PET (positron emission tomography).

[0427] purity It will be readily understood that because the compounds of the present invention are intended for use in pharmaceutical compositions, they are each preferably provided in substantially pure form, e.g., at least 60% pure, more preferably at least 75% pure, preferably at least 85% pure, and especially at least 98% pure (percentages are on a weight to weight basis). Impure preparations of the compounds can be used to prepare purer forms for use in pharmaceutical compositions.

[0428] It will be appreciated that compounds of any of the formulae disclosed herein, including formulae (I) and (IA)-(IE), or pharmaceutically acceptable salts thereof of the present invention and / or corresponding tautomers, may exist in stereoisomeric, regioisomeric or diastereoisomeric forms.

[0429] tautomers Additionally, compounds of the present invention may exist as tautomeric or tautomeric forms. Tautomers are conventionally understood in the chemical arts to be structural or constitutional isomers of chemical compounds that readily interconvert. This reaction generally results in the rearrangement of protons. A structural or constitutional isomer (according to IUPAC) is a type of isomer in which molecules with the same molecular formula have different bonding patterns and atomic configurations, as opposed to stereoisomers, in which the molecular bonds are always in the same order but differ only in their spatial arrangement. The concept of tautomerization is called tautomerism. The chemical reaction that interconverts the two is called tautomerization. Tautomers should not be confused with the depiction of "contributing structures" in chemical resonance. Tautomers are distinct chemical species and therefore can be distinguished by differences in spectroscopic data, whereas resonance structures are merely convenient depictions and do not physically exist.

[0430] For example, the 2-pyridone ring exhibits tautomerism in which the proton attached to the nitrogen can be transferred to the oxygen to give the tautomeric form 2-hydroxypyridine.

[0431] [ka]

[0432] Synthetic schemes and general methods of preparation The present invention also relates to a process for making a compound of any of the formulae disclosed herein (including formulae (I) and (IA)-(IE)) or a pharmaceutically acceptable salt thereof of the present invention and / or the corresponding tautomer.

[0433] Compounds of any of the formulae disclosed herein or their pharmaceutically acceptable salts and / or corresponding tautomers of the present invention can be made in any number of steps using conventional organic synthesis as described in the schemes below, and more particularly as exemplified by the exemplary compounds according to the Examples section herein, or by utilizing the knowledge of an organic chemist. Suitable synthetic routes are depicted in the following general reaction schemes:

[0434] The syntheses shown in these schemes can be adapted to produce compounds of the invention defined by any of the formulas disclosed herein, bearing a variety of different functional groups as defined, using appropriate precursors that are appropriately protected if necessary to be compatible with the reactions outlined herein. While these schemes are shown only with compounds defined therein, they are illustrative of processes that can be used to make compounds of the invention.

[0435] Intermediates (compounds used in the preparation of compounds of the invention) may also exist as salts. Thus, with respect to intermediates, the phrase "a compound of formula (number)" means a compound having that structural formula or a pharmaceutically acceptable salt thereof.

[0436] The compounds of the present invention can be obtained using the procedures depicted in the following schemes, or by applying appropriate synthetic organic chemistry procedures and methodology known to those skilled in the art.

[0437] The methods shown in these schemes can be used to prepare a variety of different Y, X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R a , R b ,n,R 7a and R 7b can be used to prepare compounds of the invention containing groups (as described above for compounds of formulae (I) and (IA)-(IE)).

[0438] Those skilled in the art will recognize that in preparing the compounds of the present invention (e.g., compounds of Formulae (I) and (IA)-(IE) or pharmaceutically acceptable salts and / or corresponding tautomers thereof), it may be necessary and / or desirable to protect one or more sensitive groups of the molecule or suitable intermediates to avoid undesired side reactions. Those skilled in the art will recognize that if a substituent described herein is incompatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions. The protecting group can be removed at a suitable point in the reaction sequence to provide the desired intermediate or target compound. Protecting groups suitable for use in accordance with the present invention are well known to those skilled in the art and can be used in conventional manner, for example, see "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). Subsequent deprotection, if necessary, generally affords compounds of the disclosed nature.

[0439] In some cases, a substituent can be specifically selected to be reactive under the reaction conditions employed, which, under these circumstances, convert the selected substituent into another substituent that is useful as an intermediate compound or is a desired substituent in a target compound.

[0440] The schemes shown below are representative methods for preparing compounds of formula (I) and (IA)-(IE), but are intended only to be illustrative of processes that can be used to make the compounds of the invention.

[0441] Compound names were generated using the software naming program ChemDraw Ultra v12.0 available from Perkin Elmer, 940 Winter Street, Waltham, MA ( http: / / www.perkinelmer.com / ).

[0442] [ka]

[0443] The preparation of compounds of the present invention generally begins with the synthesis of N-substituted 2-amino aromatic acid derivatives I-4 (Scheme I). Appropriately substituted 2-halo aromatic acids I-1 are esterified under standard conditions to give the corresponding esters 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. The 2-halo aromatic ester I-2 (L = Cl, Br, or I) is reacted with an appropriate aniline or amine (R 5’ -NH2, where R 5’ is a substituted phenyl group) to afford the corresponding N-substituted-2-amino aromatic ester I-3. Generally, this reaction is carried out at elevated temperature using standard heating or microwave irradiation in a suitable solvent (e.g., 1,4-dioxane, toluene, or 2-ethoxyethanol) in the presence of a catalyst (e.g., Pd2(dba)3 or Cu / CuO), a suitable ligand (e.g., BINAP or Xantphos), and an inorganic base (typically Cs2CO3 or K2CO3).

[0444] Alternatively, intermediate I-3 can be prepared by coupling 2-amino aromatic ester I-5 with an appropriate aryl halide (R 5’ -X, where R 5’is a substituted phenyl group). Such reactions are well known to those skilled in the art. Saponification of ester I-3 to the corresponding N-substituted 2-amino aromatic 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, e.g., methanol / HO, ethanol / HO, or THF / HO. Such conditions are well known to those skilled in the art.

[0445] Another approach, which will be readily apparent to one skilled in the art, is to react 2-haloaromatic ester I-1 with an appropriate aniline or amine (R 5’ The reaction is then carried out with HCl (I-2) to afford compound I-4. The reaction conditions are similar to those described above for the conversion of I-2 to I-3. This reaction can also be carried out under acidic conditions, such as p-toluenesulfonic acid or acetic acid, at elevated temperatures.

[0446] Intermediate I-4 can also be prepared by reacting ester I-2 (L=Cl) with an appropriate aniline or amine (R 5’ It can also be obtained by coupling reaction with —NH2).

[0447] [ka]

[0448] The intermediate N-substituted 2-amino aromatic acid derivative I-4, prepared as shown in Scheme I, can be converted to II-2 as outlined in Scheme II. Coupling of I-4 with a suitable 2-alkoxy-azaheterocycle B-NH, such as 2-methoxy-4-aminopyridine, under a variety of amide coupling conditions known to those skilled in the art, affords the corresponding amide II-1. For example, standard coupling reagents such as EDC / HOBT, HATU, HBTU, or T3P can be used in the presence of an amine base such as triethylamine or Hunig's base (diisopropylethylamine) in a suitable solvent, typically DMF, DMA, or acetonitrile. Alternatively, the acid can be converted to the corresponding acid chloride using a reagent such as thionyl chloride or oxalyl chloride, and then this acid chloride can be reacted with a suitable 2-alkoxy-azaheterocycle 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 give the desired coupling product II-1.

[0449] As with II-2, the formation of this ring system involves the reaction of II-1 with formaldehyde or a suitable equivalent. For example, this reaction can be carried out using formaldehyde, paraformaldehyde, or s-trioxane as the gaseous formaldehyde in the presence of an acid, preferably PTSA or sulfuric acid. Alternatively, this ring system can be formed by the reaction of II-1 with diiodomethane or chloroiodomethane as the formaldehyde equivalent. This variation of the cyclization reaction can use a base, typically Cs2CO3 or NaH, in a suitable solvent, often acetonitrile or DMF. The choice of using formaldehyde or diiodomethane depends on the specific reactivity characteristics of the substrate II-1.

[0450] In some instances, compound II-2 can be obtained as a final product, which can also be obtained by the method described in Scheme II.

[0451] When ring B of II-2 is substituted with a suitable halogen, particularly chlorine, bromine, or iodine, the halogen can be replaced with other functional groups by reaction with the corresponding coupling partner under appropriate coupling reaction conditions. Coupling partners include suitable amines, alcohols, and boronic acids or esters. This type of reaction can typically be achieved in the presence of a catalyst (usually Pd2(dba)3), a suitable ligand (e.g., tBuXphos, XPhos, or Xantphos), and an inorganic base (typically KOH, Cs2CO3, or K2CO3) in a suitable solvent such as 1,4-dioxane, THF, toluene, or 2-ethoxyethanol, using standard heating or microwave irradiation at elevated temperature. In some cases where ring B is substituted with fluorine, the reaction can be carried out in the presence of a base, such as DIPEA, in a suitable solvent such as DMF, using S N The conversion can be achieved by Ar reaction.

[0452] [ka]

[0453] B=2-alkoxy-azaheterocycle (X 1’ , X 2’ and X 3 each independently is C or N or NH; R 7” is alkyl), for example, 6-methoxypyridin-3-amine, removal of the alkoxy (generally methoxy) protecting group may be necessary to complete the synthesis of the compounds of the invention. Preferred methods for accomplishing this transformation include reaction with a mixture of TMS-chloride and NaI or a solution of TMS-iodide in an aprotic solvent such as acetonitrile at elevated temperature. Alternatively, this transformation can be accomplished with a mixture of p-toluenesulfonic acid and LiCl in a solvent such as DMF at elevated temperature.

[0454] [ka]

[0455] II-2a, X 1 ~X 4 When one of the groups is C-Cl, conversion of the chloro group to a cyano group can be achieved by treating II-2a with zinc cyanide or copper(I) cyanide in the presence of tetrakis at elevated temperature in a solvent such as DMF to give the final compound IV-2.

[0456] If necessary, the final compound IV-2 can be produced from IV-1 by an appropriate deprotection reaction or a suitable method as shown in Scheme III. The selection of the reaction and the corresponding conditions will be apparent to those skilled in the art.

[0457] Alternatively, conversion of the chloro group to a cyano group can be achieved after a deprotection step using reaction conditions similar to those described above for the conversion of II-2a to IV-4 to yield the final compound IV-2.

[0458] [ka]

[0459] When B=an azaheterocycle such as 3-aminopyridine or 4-aminopyridine, an oxidation step may be required to generate the corresponding pyridine N-oxide analogs of the invention. This transformation is typically accomplished in the presence of an oxidizing agent, such as mCPBA, in an aprotic solvent (e.g., DCM) at 0° C. or room temperature.

[0460] In some specific cases, further deprotection steps may be required. Such transformations are well known to those skilled in the art. For example, when ring B is a 2-alkoxy-azaheterocycle, the alkoxy protecting group can be removed by the procedure described in Scheme IV.

[0461] Pharmaceutical Compositions, Routes of Administration and Dosages The compounds of the present invention can be formulated into pharmaceutical compositions before administration to a subject. According to one aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention (i.e., a compound defined by any of the formulas disclosed herein, including formulas (I) and (IA)-(IE), or a pharmaceutically acceptable salt thereof and / or corresponding tautomer thereof of the present invention) and one or more pharmaceutically acceptable excipients. According to one aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention (i.e., a compound defined by any of the formulas disclosed herein, including formulas (I) and (IA)-(IE), or a pharmaceutically acceptable salt thereof and / or corresponding tautomer thereof of the present invention) and a pharmaceutically acceptable excipient.

[0462] In another aspect, the present invention relates to a pharmaceutical composition or formulation comprising a compound defined by any of the formulae disclosed herein, including Formula (I) and (IA)-(IE), or a pharmaceutically acceptable salt and / or corresponding tautomer thereof of the present invention; a pharmaceutically acceptable excipient; and, optionally, one or more other therapeutic ingredients.

[0463] The pharmaceutical composition or preparation defined herein generally contains one compound of the present invention.However, in certain embodiments, the pharmaceutical composition may contain two or more compounds of the present invention.In addition, the pharmaceutical composition of the present invention may optionally further comprise one or more additional pharmaceutically effective compounds.

[0464] Pharmaceutically acceptable excipients should be non-toxic and not interfere with the efficacy of the active ingredient. Suitable pharmaceutically acceptable excipients vary depending on the particular dosage form, route of administration, etc. selected. Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, carriers, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, cosolvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste-masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, thickeners, antioxidants, preservatives, stabilizers, surfactants, and buffers. Examples of pharmaceutically acceptable excipients are described, for example, in 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).

[0465] The pharmaceutical composition can be adapted for administration by any appropriate or suitable route, such as systemic administration (e.g., oral administration, parenteral administration, transdermal administration, rectal administration, inhalation), topical administration, etc. Parenteral administration is generally administration by injection or infusion, and includes intravenous, intramuscular, and subcutaneous injection or infusion. Inhalation refers to administration into the patient's lungs, whether inhaled through the mouth or through the nasal passages. Generally, administration is via oral or parenteral routes.

[0466] Pharmaceutical compositions adapted for oral administration can be provided as solid dosage forms such as tablets, capsules, caplets, lozenges, pills, etc.; powders; or liquid dosage forms such as solutions, suspensions, syrups, elixirs, or emulsions. Pharmaceutical compositions adapted for parenteral administration can be provided as solutions, suspensions, and powders for reconstitution.

[0467] In general, the pharmaceutical compositions of the present invention are prepared using conventional ingredients and techniques of mixing, blending, etc. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

[0468] Solid oral dosage forms such as tablets and capsules can be prepared by mixing the compounds of the present invention with excipients such as diluents and fillers (e.g., starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.), binders (e.g., starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, etc.), lubricants (e.g., magnesium stearate, talc, etc.), etc. Pharmaceutical compositions suitable for parenteral administration can be injection solutions prepared from powders, granules, or tablets by mixing with carriers such as distilled water, physiological saline, etc., and a base or the like can be used to adjust the pH.

[0469] The present invention also provides a pharmaceutical composition comprising 0.5 to 1,000 mg of a compound of the present invention (i.e., a compound of the formulae disclosed herein, including Formulas (I) and (IA) to (IE), or a pharmaceutically acceptable salt thereof and / or corresponding tautomer of the present invention) and 0.5 to 1,000 mg of a pharmaceutically acceptable excipient.

[0470] The compounds and pharmaceutical compositions of the present invention defined herein can be administered once or according to a dosing regimen in which multiple doses are administered at various time intervals over a given period. For example, doses can be administered once, twice, three times, or four times daily. Doses can be administered until the desired therapeutic effect is achieved or to maintain the desired therapeutic effect indefinitely. The dose of the compounds of the present invention can be 0.001 mg / kg to 100 mg / kg, for example, 0.001 mg / kg to 50 mg / kg. Preferably, the selected dose is administered orally or parenterally.

[0471] Methods, Uses, Compounds for Manufacture and / or Use in Treating Diseases In general, the present invention also relates to the compounds and / or pharmaceutical compositions of the invention as defined herein for use as a medicine or for use in therapy.

[0472] The compounds of the invention as defined herein are intended to inhibit voltage-gated sodium ion channels, in particular the voltage-gated sodium ion channel Na v It is an inhibitor of 1.8. v The activity of the compounds utilized in this invention as inhibitors of 1.8 may be assayed generally according to the methods described in the Examples herein or according to methods available to one of skill in the art.

[0473] Thus, in one aspect, the present invention provides a method for detecting voltage-gated sodium ion channels, particularly Na v The present invention relates to compounds and pharmaceutical compositions of the present invention as inhibitors of 1.8.

[0474] In one embodiment, the present invention relates to a method of inhibiting a voltage-gated sodium ion channel in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the invention or a pharmaceutical composition of the invention described herein. In one embodiment, the voltage-gated sodium channel is Na v It is 1.8.

[0475] In an embodiment, the present invention relates to a compound of the present invention or a pharmaceutical composition of the present invention for use in inhibiting a voltage-gated sodium ion channel. In one embodiment, the voltage-gated sodium channel is Na v It is 1.8.

[0476] In one embodiment, the invention relates to a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for inhibiting a voltage-gated sodium ion channel. In one embodiment, the voltage-gated sodium channel is Na v It is 1.8.

[0477] Without being bound by any particular theory, the compounds and compositions of the present invention may be v It is particularly useful for treating diseases, conditions, or disorders in which activation or hyperactivity of Na 1.8 is implicated in the disease, condition, or disorder. v When activation or hyperactivity of 1.8 is involved in a particular disease, condition, or disorder, the disease, condition, or disorder is classified as "Na v 1.8 Interventional Diseases, Conditions, or Disorders. v 1.8 Interventional diseases, disorders and conditions include pain and pain-related diseases, disorders and conditions, and cardiovascular diseases, disorders and conditions, such as atrial fibrillation.

[0478] Thus, in another aspect, the present invention relates to the use of the compounds and pharmaceutical compositions of the present invention in methods and medicaments for treating pain or pain-related diseases, disorders or conditions, and / or for treating cardiovascular diseases, disorders and conditions.

[0479] As used herein, a "patient" or "subject" in need thereof refers to a human or mammal. The term "mammal" as used herein includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, and non-human primates (NHPs), such as monkeys or apes, humans, etc. Preferably, the subject to be treated is a human.

[0480] As used herein, the terms "treat," "treating," and / or "treatment" when used with respect to a disease, disorder, or condition means ameliorating or preventing the condition or one or more biological manifestations of the condition; interfering with one or more points in the biological cascade leading to or causing the condition; alleviating one or more symptoms or effects associated with the condition; slowing the progression of the condition or one or more biological manifestations of the condition; or lessening the severity of the condition or one or more symptoms or effects associated with the condition. As stated above, "treatment" of a disease, disorder, or condition includes prevention of the condition. Those skilled in the art will recognize that "prevention" is not an absolute term. In medicine, "prevention" is understood to refer to the prophylactic administration of a drug to substantially reduce the likelihood or severity of a condition or its biological manifestations, or to delay the onset of such a condition or its biological manifestations.

[0481] As used herein, "effective amount" and "therapeutically effective amount" are used interchangeably. With respect to the compounds of the present invention, an effective amount means an amount of the compound that is sufficient to treat a patient's condition within the scope of sound medical judgment, but low enough to avoid significant side effects (at a reasonable benefit / risk ratio). The effective amount of a compound or its pharmaceutically acceptable salt of the present invention and / or its corresponding tautomer or its corresponding pharmaceutical composition will vary depending on factors such as the specific compound selected (e.g., taking into account the potency, efficacy and half-life of the compound); the selected route of administration; the condition being treated; the severity of the condition being treated; the age, size, weight and physical condition of the patient or subject being treated; the medical history of the patient or subject being treated; the duration of treatment; the nature of any concurrent therapy; and the desired therapeutic effect.

[0482] According to embodiments of the present invention, the pain-related disease, disorder, or condition is pain caused by any of a variety of diseases of various etiologies, as described in this disclosure. In some embodiments, the pain or pain-related disease, disorder, or condition is neuropathic pain, chronic pain, acute pain, nociceptive pain, inflammatory pain, musculoskeletal pain, visceral pain, cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, or incontinence.

[0483] In some embodiments, the pain or pain-related disease, disorder or condition is neuropathic pain or chronic neuropathic pain.

[0484] In some embodiments, the pain or pain-related disease, disorder or condition is neuropathic pain or chronic neuropathic pain selected from small fiber neuropathy, small fiber-mediated diabetic neuropathy, idiopathic small fiber neuropathy, painful diabetic neuropathy or polyneuropathy.

[0485] In some embodiments, the pain or pain-related disease, disorder or condition is neuropathic pain selected from postherpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma, traumatic neuroma, Morton's nerve, nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain, nerve avulsion injury, brachial plexus avulsion, complex regional pain syndrome, medication-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia, post-spinal cord injury pain, idiopathic small fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic headache.

[0486] In some embodiments, the pain or pain-related disease, disorder or condition is neuropathic pain or chronic neuropathic pain selected from diabetic peripheral neuropathy, neuropathy, pain caused by neurological or neuronal injury, pain-related nerve injury, neuralgia and related acute or chronic pain, post-herpetic neuralgia, pain-related nerve root avulsion, painful traumatic mononeuropathy, painful polyneuropathy, erythromelalgia, paroxysmal excruciating pain syndrome (PEPD), burning mouth syndrome, lesions at the level of the nervous system, traumatic nerve injury, central pain syndromes caused by nerve compression or nerve entrapment, congenital insensitivity to pain (CIP), dysmenorrhea, primary erythromelalgia, HIV peripheral sensory neuropathy, pudendal neuralgia, spinal nerve injury, chronic inflammatory demyelinating polyneuropathy (CIDP), carpal tunnel syndrome and vasculitic neuropathy.

[0487] In some embodiments, the pain or pain-related disease, disorder or condition is visceral pain, and the visceral pain is inflammatory bowel disease pain, Crohn's disease pain or interstitial cystitis pain.

[0488] In some embodiments, the pain or pain-related disease, disorder or condition is musculoskeletal pain, and the musculoskeletal pain is osteoarthritis pain, back pain, cold pain, burn pain or toothache.

[0489] In some embodiments, the pain or pain-related disease, disorder or condition is idiopathic pain, and the idiopathic pain is fibromyalgia pain.

[0490] In some embodiments, the pain or pain-related disease, disorder, or condition is chronic or acute pre-operative associated pain or chronic or acute post-operative associated pain. Post-operative associated pain includes ambulatory post-operative pain. Ambulatory surgery, also known as outpatient surgery, refers to same-day surgery that does not require an overnight stay in a hospital or other medical facility. In some embodiments, the pre-operative associated pain is selected from neuropathic pain or chronic neuropathic pain, chronic osteoarthritis pain, dental pain, or inflammatory pain. In some embodiments, the post-operative associated pain is selected from hallux valgus resection pain, hernia repair pain, breast surgery pain, or cosmetic surgery pain.

[0491] In some embodiments, the pain or pain-related disease, disorder or condition is pain caused by trauma or iatrogenic medical or dental treatment. As used herein, the term "iatrogenic" refers to pain inadvertently induced by a medical or dental professional, such as a surgeon or dentist, during a medical or dental treatment or diagnostic procedure, including, but not limited to, pain caused preoperatively (i.e., "before" a medical or dental treatment), perioperatively (i.e., medically induced pain "during" a medical or dental treatment, or during a non-surgical or operative procedure), and postoperatively (i.e., after a medical or dental treatment, or postoperatively or surgically induced pain).

[0492] In some embodiments, the pain or pain-related disease, disorder or condition is nociceptive pain, and the nociceptive pain is post-operative pain, cancer pain, back and craniofacial pain, osteoarthritis pain, dental pain or diabetic peripheral neuropathy.

[0493] In some embodiments, the pain or pain-related disease, disorder, or condition is inflammatory pain. Inflammatory pain can be pain of various physiological origins. In some embodiments, the inflammatory pain is selected from the pain associated with osteoarthritis, rheumatoid arthritis, rheumatic disorders, tenosynovitis and gout, shoulder tendonitis or bursitis, gouty arthritis, and polymyalgia rheumatica, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, or pain caused by central sensitization; complex regional pain syndrome, chronic joint pain and associated neuralgia, or acute pain. In some embodiments, the inflammatory pain is selected from the pain associated with rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis, or juvenile arthritis. In some embodiments, the inflammatory pain is selected from rheumatoid arthritis; rheumatoid spondylitis; gouty arthritis; juvenile arthritis; rheumatic disorders; gout; shoulder tendonitis or bursitis; rheumatic polymyalgia; primary hyperalgesia; secondary hyperalgesia; primary allodynia; secondary allodynia; or pain caused by central sensitization, complex regional pain syndrome, chronic or acute joint pain and associated neuralgia.

[0494] In some embodiments, the inflammatory pain is selected from rheumatoid arthritis pain or vulvodynia.

[0495] In some embodiments, the inflammatory pain is selected from osteoarthritis, chronic osteoarthritic pain (eg, hip or knee), or chronic inflammatory demyelinating polyneuropathy.

[0496] In some embodiments, the pain or pain-related disease, disorder or condition is musculoskeletal pain.In some embodiments, the musculoskeletal pain is selected from bone and joint pain, osteoarthritis; low back pain and neck pain; pain resulting from physical trauma or amputation.In some embodiments, the musculoskeletal pain is selected from bone and joint pain, osteoarthritis (e.g., knee, lower back), tendonitis (e.g., shoulder), bursitis (e.g., shoulder), tenosynovitis, low back pain and neck pain, sprain, pulled muscle, or pain resulting from physical trauma or amputation.

[0497] In some embodiments, the pain or pain-related disease, disorder or condition is a pain disorder associated with or related to neurological or neuronal damage caused by a disease selected from neuropathy, pain-related nerve injury, pain-related nerve root avulsion, painful traumatic mononeuropathy, painful polyneuropathy, erythromelalgia, paroxysmal excruciating pain syndrome (PEPD), burning mouth syndrome; a central pain syndrome caused by a lesion at the level of the nervous system; traumatic nerve injury, nerve compression or entrapment, congenital insensitivity to pain (CIP), dysmenorrhea, primary erythromelalgia; HIV peripheral secondary neuropathy; pudendal neuralgia, seminal nerve injury, chronic inflammatory demyelinating polyneuropathy (CIDP), carpal tunnel syndrome and vasculitic neuropathy.

[0498] In some embodiments, the pain or pain-related disease, disorder or condition is pain caused by trauma, or pain caused by iatrogenic, medical or dental procedures.

[0499] In some embodiments, the pain or pain-related disease, disorder, or condition is myofascial pain; myositis or muscle inflammation; repetitive motion pain; complex regional pain syndrome; sympathetically maintained pain; pain associated with cancer, toxins, and chemotherapy; post-operative pain syndrome and / or associated phantom limb pain; post-operative medical or dental procedural or treatment pain; pain associated with HIV or pain caused by HIV treatment.

[0500] In some embodiments, the pain or pain-related disease, disorder or condition is neuropathic pain or other pain-related disease, disorder or condition selected from peripheral neuropathic pain, central neuropathic pain, hereditary erythromelalgia (IEM), small fiber neuralgia (SFN), paroxysmal excruciating pain syndrome (PEPD), painful diabetic neuropathy, chronic low back pain, neuropathic back pain, sciatica, non-specific low back pain, multiple sclerosis pain, HIV-associated neuropathy, post-herpetic neuralgia, trigeminal neuralgia, vulvodynia, pain resulting from physical trauma, post-amputation pain, neuroma pain, phantom limb pain, cancer, toxins, or chronic inflammatory conditions.

[0501] In some embodiments, the pain or pain-related disease, disorder or condition is acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, generalized neuralgia, epilepsy, epileptic conditions, neurodegenerative diseases, psychiatric disorders, anxiety, depression, bipolar disorder, muscle tone, cardiac arrhythmias, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritic pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache, neck pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, post-operative pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension or gastrointestinal dysmotility.

[0502] In some embodiments, the pain or pain-related disease, disorder or condition is selected from the group consisting of femoral 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 headaches; migraine; tension headaches including cluster headaches; chronic and acute neuropathic pain, post-herpetic neuralgia; diabetic neuropathy; HIV-associated 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; radiation therapy-induced neuropathic pain; mastectomy. Post-operative pain; Central pain; Spinal cord injury pain; Post-stroke pain; Thalamic pain; Complex regional pain syndrome; Phantom pain; Intractable pain; Acute pain, acute post-operative pain; Acute musculoskeletal pain; Arthral pain; Mechanical low back pain; Neck pain; Tendonitis; Injury / exercise 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 inflammatory, burn and trauma pain; Acute intermittent pain, endometriosis; Acute shingles pain; Sickle cell anemia; Acute pancreatitis; Breakthrough pain; Sinusitis pain, Orofacial pain including toothache; Multiple sclerosis (MS) pain; Pain in depression; Leprosy pain; Behçet's disease pain; Painful adiposity; Phlebitis pain; Guillain-Barré pain; Painful legs and moving toes syndrome legs and moving toes); Haglund's syndrome; erythromelalgia pain; Fabry's pain; bladder and genitourinary disorders including urinary incontinence; overactive bladder; painful bladder syndrome; interstitial cystitis (IC); prostatitis; complex regional pain syndrome types I and II (CRPS); widespread pain, paroxysmal severe pain, pruritus, tinnitus, or angina-induced pain.

[0503] In another aspect, the invention relates to the use of the compounds and pharmaceutical compositions of the invention in methods and medicaments for treating cardiovascular diseases, disorders and conditions, including atrial fibrillation and cardiac arrhythmias.

[0504] In some embodiments, the cardiovascular disease is atrial fibrillation, which is idiopathic in nature or caused by a disease as defined herein.The atrial fibrillation can be paroxysmal atrial fibrillation, persistent atrial fibrillation, long-term atrial fibrillation, atrial fibrillation associated with heart failure, atrial fibrillation associated with heart valve disease, or atrial fibrillation associated with chronic kidney disease.In certain embodiments, the atrial fibrillation is selected from paroxysmal, persistent, or long-term atrial fibrillation.

[0505] In some embodiments, the cardiovascular disease includes cardiac arrhythmia.

[0506] In one aspect, the present invention relates to a method of treating pain or a pain-related disease, disorder or condition as defined herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the invention or a pharmaceutical composition of the invention as described herein.

[0507] In certain embodiments, there is provided a method of treating acute or chronic pain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the invention or a pharmaceutical composition of the invention described herein.

[0508] In certain embodiments, there is provided a method of treating pain caused by trauma; pain caused by iatrogenic, medical, or dental procedures; or pre- or post-operative related pain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the invention or a pharmaceutical composition of the invention described herein.

[0509] In certain embodiments, there is provided a method of treating neuropathic pain, nociceptive pain, inflammatory pain, musculoskeletal pain, visceral pain, or idiopathic pain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the invention or a pharmaceutical composition of the invention described herein.

[0510] In certain embodiments, there is provided a method of treating neuropathic pain or chronic neuropathic pain selected from small fiber neuropathy, small fiber-mediated diabetic neuropathy, idiopathic small fiber neuropathy, painful diabetic neuropathy, and polyneuropathy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the invention or a pharmaceutical composition of the invention described herein.

[0511] In certain embodiments, there is provided a method of treating inflammatory pain selected from osteoarthritis, chronic osteoarthritic pain, and chronic inflammatory demyelinating polyneuropathy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the invention or a pharmaceutical composition of the invention as described herein.

[0512] In one embodiment, the present invention relates to a method of treating atrial fibrillation as defined herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition of the present invention as described herein.

[0513] In one embodiment, a method is provided for treating atrial fibrillation, wherein the atrial fibrillation is paroxysmal atrial fibrillation, persistent atrial fibrillation, long-term atrial fibrillation, atrial fibrillation associated with heart failure, atrial fibrillation associated with valvular heart disease, or atrial fibrillation associated with chronic kidney disease.

[0514] In another aspect, the present invention provides compounds of the invention and pharmaceutical compositions of the invention as described herein for use in the treatment of pain or a pain-related disease, disorder or condition as defined herein.

[0515] In certain embodiments, there is provided a compound of the invention or a pharmaceutical composition of the invention for use in the treatment of acute pain or chronic pain.

[0516] In certain embodiments, there is provided a compound of the invention or a pharmaceutical composition of the invention for use in the treatment of pain caused by trauma; pain caused by iatrogenic medical or dental procedures; or pain associated with pre- or post-surgical procedures.

[0517] In certain embodiments, there is provided a compound of the invention or a pharmaceutical composition of the invention for use in the treatment of neuropathic pain, nociceptive pain, inflammatory pain, musculoskeletal pain, visceral pain, or idiopathic pain.

[0518] In certain embodiments, there is provided a compound of the invention or a pharmaceutical composition of the invention for use in treating neuropathic pain or chronic neuropathic pain selected from small fiber neuropathy, small fiber-mediated diabetic neuropathy, idiopathic small fiber neuropathy, painful diabetic neuropathy, and polyneuropathy.

[0519] In certain embodiments, there is provided a compound of the invention or a pharmaceutical composition of the invention for use in treating inflammatory pain selected from osteoarthritis, chronic osteoarthritic pain, and chronic inflammatory demyelinating polyneuropathy.

[0520] In another aspect, the present invention relates to a compound of the present invention or a pharmaceutical composition of the present invention for use in the treatment of atrial fibrillation.

[0521] In one embodiment, there is provided a compound of the invention or a pharmaceutical composition of the invention for use in the treatment of atrial fibrillation, wherein the atrial fibrillation is paroxysmal atrial fibrillation, persistent atrial fibrillation, long-term atrial fibrillation, atrial fibrillation associated with heart failure, atrial fibrillation associated with valvular heart disease, or atrial fibrillation associated with chronic kidney disease.

[0522] In another aspect, the present invention also provides the use of a compound of the invention or a pharmaceutical composition of the invention as described herein in the manufacture of a medicament for the treatment of pain and pain-related diseases, disorders or conditions described herein.

[0523] In certain embodiments, there is provided the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of acute pain or chronic pain.

[0524] In certain embodiments, there is provided the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of pain caused by trauma; pain caused by iatrogenic, medical or dental procedures; or pain associated with pre- or post-surgical procedures.

[0525] In certain embodiments, there is provided the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of neuropathic pain, nociceptive pain, inflammatory pain, musculoskeletal pain, visceral pain, or idiopathic pain.

[0526] In one embodiment there is provided a use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of neuropathic pain or chronic neuropathic pain selected from small fiber neuropathy, small fiber-mediated diabetic neuropathy, idiopathic small fiber neuropathy, painful diabetic neuropathy and polyneuropathy.

[0527] In certain embodiments, there is provided a use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of inflammatory pain selected from osteoarthritis, chronic osteoarthritic pain, and chronic inflammatory demyelinating polyneuropathy.

[0528] In another aspect, the present invention also provides the use of a compound of the invention or a pharmaceutical composition of the invention described herein in the manufacture of a medicament for the treatment of atrial fibrillation.

[0529] In certain embodiments, there is provided use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of atrial fibrillation, wherein the atrial fibrillation is paroxysmal atrial fibrillation, persistent atrial fibrillation, long-term atrial fibrillation, atrial fibrillation associated with heart failure, atrial fibrillation associated with valvular heart disease, or atrial fibrillation associated with chronic kidney disease.

[0530] In another aspect, the present invention relates to a compound of the invention or a pharmaceutical composition of the invention as described herein for use in therapy.

[0531] Uses for Combination Therapies and Therapies The compounds and pharmaceutical compositions of the invention described herein can be used in combination with one or more additional therapeutic agents, which can be administered simultaneously with, prior to, or following treatment with the compounds or pharmaceutical compositions of the invention described herein.

[0532] In the context of this specification, the term "concurrently," when referring to simultaneous administration of compounds or therapeutic agents, means simultaneously when the compound and additional therapeutic agent are combined in a single preparation, e.g., as in an embodiment, or when the compound and additional therapeutic agent are administered separately, but within a short period or time.

[0533] In view of the above, the present invention also relates to combination therapy, which may consist of simultaneous, concurrent, or sequential administration of a compound or pharmaceutical composition of the present invention in combination with one or more additional therapeutic agents, which may be used for the treatment of pain or any pain-related disease, disorder, or condition, as defined herein, or a cardiovascular disease, disorder, or condition.

[0534] Suitable therapeutic agents for use in combination with the compounds and pharmaceutical compositions of the present invention include, but are not limited to, acetaminophen, acetylsalicylic acid, Na v 1.7 Inhibitor, Na v In one embodiment, the administration of NaCl, NaCl, NaCl inhibitors suitable for use in the present invention include antidepressants (i.e., but not limited to, duloxetine or amitriptyline), anticonvulsants (i.e., but not limited to, pregabalin and gabapentin), opiates (i.e., but not limited to, hydrocodone, codeine, morphine, oxycodone, oxymorphone, fentanyl, etc.), and the like, each of which can be determined by one skilled in the art. v1.7 Inhibitor or Na v 1.9 inhibitors include, but are not limited to, Na v 1.7 Inhibitor or Na v 1.9 inhibitors.

[0535] Each component of a combination used for therapeutic purposes (e.g., a compound or pharmaceutical composition of the present invention and an additional therapeutic agent) can be administered orally, intravenously, or parenterally, or a combination thereof. Each component of a therapeutic combination can be administered, including but not limited to, simultaneously, concomitantly, or sequentially; and / or by the same or different route of administration or combination of routes of administration. In certain embodiments, each of the same or different route of administration or combination of routes of administration is selected from oral administration, intravenous administration, or parenteral administration. [Example]

[0536] Example The following examples illustrate this invention and are not intended to limit the scope of the invention, but rather to provide guidance to one of ordinary skill in the art for preparing and using the compounds, compositions and methods of this invention.

[0537] While particular aspects or embodiments of the present invention have been 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 invention.

[0538] Synthesis Example It will be appreciated by those skilled in the art that purification methods (using acidic or basic modifiers) or compound work-up procedures (using acidic or basic conditions) may result in the formation of salts of the title compound (e.g., hydrobromide, formate, hydrochloride, trifluoroacetate, or ammonium salts of the title compound), and the present invention is intended to encompass such salts.

[0539] The final compounds were characterized by LCMS or GCMS (conditions listed below) and NMR.1 H NMR or 19 F 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 deuterochloroform, DMSO-d6 is hexadeuterodimethylsulfoxide, and CD3OD is tetradeuteromethanol. Chemical shifts are reported in parts per million (ppm) downfield from the internal standard tetramethylsilane (TMS) or the NMR solvent. NMR data abbreviations are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = double doublet, dt = double triplet, app = clear, br = broad. J indicates NMR coupling.

[0540] Analysis method: 1) LCMS method: Electrospray positive [M+H] analysis with a CSH C18 column (30 mm x 2.1 mm, id 1.7 μm packing diameter) eluted at 45 °C with 0.1% TFA in water (solvent A) and 0.1% TFA in acetonitrile (solvent B) using the following elution gradient: 1 to 100% (solvent B) over 1.85 min at a flow rate of 1.3 mL / min. + Acquity UPLC with Waters Acquity QDa Mass Detector using ES+ve to obtain

[0541] 2) LCMS method: Electrospray positive [M+H] analysis with a CSH C18 column (30 mm x 2.1 mm, id 1.7 μm packing diameter) eluted at 45 °C with formic acid in water (solvent A) and formic acid in acetonitrile (solvent B) using the following elution gradient: 1 to 100% (solvent B) over 1.85 min at a flow rate of 1.3 mL / min. + Acquity UPLC with Waters Acquity QDa Mass Detector using ES+ve to obtain

[0542] 3) LCMS method: Electrospray positive [M+H] analysis with a CSH C18 column (30 mm x 2.1 mm, id 1.7 μm packing diameter) eluted at 45 °C with 10 mM ammonium bicarbonate in water (solvent A) and acetonitrile (solvent B) adjusted to pH = 10 with 25% ammonium hydroxide solution, using the following elution gradient: 1 to 100% (solvent B) over 1.85 min at a flow rate of 1.3 mL / min. + Acquity UPLC with Waters Acquity QDa Mass Detector using ES+ve to obtain

[0543] 4) LCMS method: Agilent 1290 Infinity II LC system equipped with Agilent MSD 6125B / 6130 using multimode (ESI and APCI +ve and -ve) with a Sunfire C18 column (30 mm x 2.1 mm, id 3.5 μm packing diameter) eluted at 25 °C with 0.1% formic acid in water (solvent A) and 0.1% formic acid in acetonitrile (solvent B) using the following elution gradient: 0 to 100% (solvent B) over 3.1 min at a flow rate of 1.0 mL / min with a 0.8 min hold at 100%.

[0544] 5) LCMS method: Agilent 1290 Infinity II LC system equipped with Agilent MSD 6125B / 6130 using multimode (ESI and APCI +ve and -ve) with an Atlantis dC18 column (50 mm x 4.6 mm, id 5.0 μm packing diameter) eluted with 0.1% TFA in water (solvent A) and methanol (solvent B) at 25 °C using the following elution gradient: 5 to 95% (solvent B) over 5.0 min at a flow rate of 1.0 mL / min with a 1.5 min hold at 95%.

[0545] 6) LCMS method: Agilent 1290 Infinity II LC system equipped with an Agilent MSD 6125B / 6130 and multimode (ESI and APCI +ve and -ve) equipped with a Zorbax XDB C18 column (50 mm x 4.6 mm, id 3.5 μm packing diameter) eluted with 10 mM ammonium acetate in water (solvent A) and acetonitrile (solvent B) at 25 °C using the following elution gradient: 10 to 95% (solvent B) over 3.5 min with a 1.0 min hold at 95% at a flow rate of 1.0 mL / min.

[0546] 7) LCMS method: Agilent 1290 Infinity II LC system equipped with an Agilent MSD 6125B / 6130 using multimode (ESI and APCI +ve and -ve) with an Xbridge C8 column (50 mm x 4.6 mm, id 3.5 μm packing diameter) eluted with 10 mM ammonium bicarbonate in water (solvent A) and acetonitrile (solvent B) at 25 °C using the following elution gradient: 10 to 95% (solvent B) over 4.0 min at a flow rate of 1.0 mL / min with a 1.0 min hold at 95%.

[0547] 8) GCMS method: Agilent 7890B GC system equipped with an Agilent MSD 5977B using EI equipped with an HP-5 column (30 m x 0.32 mm, 0.25 μm film thickness) eluted with helium at 250 °C, with a flow rate of 2 mL / min and a run time of 10 min under the following chromatographic run conditions: 120 °C for 1 min, ramped to 300 °C at 40 °C / min, held for 4.5 min.

[0548] In the experimental description below, the following abbreviations may be used: [Table 2] JPEG2023554430000083.jpg243169 JPEG2023554430000084.jpg244169 JPEG2023554430000085.jpg98169

[0549] Intermediate 1 5-Bromo-2-chloroisonicotinic acid methyl ester

[0550] [ka]

[0551] To a stirred solution of 5-bromo-2-chloroisonicotinic acid (3 g, 12.69 mmol) in methanol (25 mL) at 0° C. was added thionyl chloride (2.78 mL, 38.1 mmol) and the reaction mixture was heated at 80° C. for 3 h. The reaction was cooled and concentrated. The resulting brown solid was diluted with water (50 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, and concentrated to give the title compound as a brown oil (1.88 g, 7.40 mmol, 58.3% yield). MS (m / z) 251.9 (M+3H). + .

[0552] Intermediate 2 Ethyl 4-bromo-6-(trifluoromethyl)nicotinate

[0553] [ka]

[0554] To a stirred solution of 4-bromo-6-(trifluoromethyl)nicotinic acid (1 g, 3.70 mmol) and ethyl iodide (0.329 mL, 4.07 mmol) in DMF (10 mL) at room temperature under N was added potassium carbonate (0.614 g, 4.44 mmol). After stirring at 27 °C for 3 h, the reaction mixture was diluted with ice-cold water (250 mL) and extracted with EtO (2 × 100 mL). The combined organic extracts were washed with ice-cold water (200 mL), dried over NaSO, and concentrated under reduced pressure to give the title compound as a brown oil (1.1 g, 3.21 mmol, 87% yield). MS (m / z) 300.0 (M+3H). + .

[0555] Intermediate 3 was prepared from the indicated carboxylic acid in a manner similar to that described for Intermediate 2.

[0556] [Table 3]

[0557] Intermediate 4 3-Bromo-6-methoxypicolinic acid

[0558] [ka]

[0559] To a stirred solution of ethyl 3-bromo-6-chloropicolinate (1.5 g, 5.67 mmol) in methanol (5 mL) was added sodium methoxide (25% in methanol) (7.78 mL, 34.0 mmol) dropwise over 2 minutes at 0 °C. After stirring at 60 °C for 6 hours, the solvent was removed in vacuo and the pH of the residue was adjusted to 5-6 with aqueous citric acid. The reaction was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were concentrated in vacuo to give the title compound as an off-white solid (1.02 g, 3.85 mmol, 67.9% yield). MS (m / z) 234.0 (M+3H). + .

[0560] Intermediate 5 Ethyl 3-bromo-6-methoxypicolinate

[0561] [ka]

[0562] This intermediate was prepared from 3-bromo-6-methoxypicolinic acid in a similar manner as described for Intermediate 2. MS (m / z) 262.0 (M+3H) + .

[0563] Intermediate 6 5-Bromo-2-(trifluoromethyl)isonicotinic acid ethyl ester

[0564] [ka]

[0565] To a suspension of 5-bromo-2-(trifluoromethyl)isonicotinic acid (500 mg, 1.852 mmol) in ethanol (3 mL) was added sulfuric acid (0.296 mL, 5.56 mmol), resulting in an exotherm. The reaction mixture was sealed, stirred, and heated to 70° C. A solution formed after approximately 5 minutes and stirring was continued for a further 4 hours. The reaction mixture was diluted with water (7 mL), basified with 2 M NaOH (aq), and then extracted into EtOAc (2×5 mL). The combined organics were dried by filtration through a hydrophobic frit and concentrated to give the title compound as a pale yellow oil / solid (443 mg, 1.486 mmol, 80% yield). MS (m / z) 299.9 (M+3H) + .

[0566] Intermediate 7 Ethyl 3-amino-3-imino-2-nitrosopropanoate

[0567] [ka]

[0568] To a stirred solution of ethyl 3-amino-3-iminopropanoate hydrochloride (10 g, 60.0 mmol) in water (30 mL) at 0° C., acetic acid (10.31 mL, 180 mmol) and sodium nitrite (12.42 g, 180 mmol) were added. After stirring at room temperature for 16 hours, the solid precipitate was filtered and dried under vacuum to give the title compound as a yellow solid (6 g, 32.4 mmol, 54.0% yield). MS (m / z) 160.2 (M+H) + .

[0569] Intermediate 8 Ethyl 2,3-diamino-3-iminopropanoate dihydrochloride

[0570] [ka]

[0571] To a stirred solution of ethyl 3-amino-3-imino-2-nitrosopropanoate (6 g, 37.7 mmol) in ethanol (120 mL) and aqueous HCl (5 M) (120 mL, 600 mmol) under N was added Pd / C (10 wt%) (1.605 g, 1.508 mmol). The reaction mixture was stirred under hydrogen (1 atm) at room temperature for 40 hours, filtered through a Celite® pad, and concentrated. The resulting off-white solid was dissolved in EtOH (60 mL) and aqueous HCl (60 mL). Pd / C (10 wt%) (0.8 g, 0.752 mmol) was added under N, and the reaction was stirred under hydrogen (1 atm) at room temperature for 16 hours. The reaction mixture was filtered through a Celite® pad and concentrated to give the title compound as an off-white solid (5.5 g, 24.97 mmol, 66.2% yield). MS (m / z) 146.1 (M+H) + .

[0572] Intermediate 9 and Intermediate 10 Ethyl 3-amino-5-(trifluoromethyl)pyrazine-2-carboxylate and Ethyl 3-amino-6-(trifluoromethyl)pyrazine-2-carboxylate

[0573] [ka]

[0574] To a stirred solution of ethyl 2,3-diamino-3-iminopropanoate (4 g, 27.6 mmol) in water (200 mL) was added 3,3,3-trifluoro-2-oxopropanal (20 wt % in water) (24.31 g, 38.6 mmol) and sodium acetate (15.82 g, 193 mmol). The reaction mixture was stirred at room temperature for 2 hours and then extracted with EtOAc (300 mL). The organic layer was washed with brine (50 mL), dried over NaSO, filtered, and concentrated. The crude product was purified by column chromatography (Biotage Isolera, 100 g SiO SNAP column, 3% EtOAc / petroleum ether over 15 min). Ethyl 3-amino-5-(trifluoromethyl)pyrazine-2-carboxylate as an off-white solid (750 mg, 3.16 mmol, 11.46% yield) MS (m / z) 236.1 (M+H) + Ethyl 3-amino-6-(trifluoromethyl)pyrazine-2-carboxylate as an off-white solid (440 mg, 1.852 mmol, 6.72% yield) MS (m / z) 236.0 (M+H) + obtained.

[0575] Intermediate 11 4-Fluoro-1-nitro-2-(prop-1-en-2-yl)benzene

[0576] [ka]

[0577] A 2.5 L four-neck round-bottom flask equipped with a magnetic stir bar and N inlet was charged with 2-chloro-4-fluoro-1-nitrobenzene (90 g, 513 mmol), 1,4-dioxane (1000 mL), sodium carbonate (65.2 g, 615 mmol), water (200 mL), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (103 g, 615 mmol), and PdCl(dppf)-CHCl adduct (20.93 g, 25.6 mmol). The flask was purged with N for 30 minutes and then stirred at 80 °C for 16 hours. The reaction mixture was cooled to room temperature, purged with N for 20 minutes, and PdCl(dppf)-CHCl adduct (2.093 g, 2.56 mmol) was added and stirred at 80 °C for an additional 16 hours. The reaction mixture was cooled to room temperature, filtered through a Celite pad, and washed with EtOAc (300 mL). The filtrate was concentrated, and the residue was washed with water (500 mL), dried over NaSO, and concentrated in vacuo to give the title compound as a brown oil (120 g, 489 mmol, 95% yield). GCMS (m / z) 181 (M) +

[0578] Intermediate 12 3,4-Difluoro-2-vinylaniline

[0579] [ka]

[0580] This intermediate was prepared in a similar manner as described for Intermediate 11, using 2-bromo-3,4-difluoroaniline and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane instead of 2-chloro-4-fluoro-1-nitrobenzene and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane. MS (m / z) 156.0 (M+H + ).

[0581] Intermediate 13 4-Fluoro-2-isopropylaniline

[0582] [ka]

[0583] A solution of 4-fluoro-1-nitro-2-(prop-1-en-2-yl)benzene (120 g, 662 mmol) in EtOAc (2 L) was hydrogenated over Pd / C (10 wt%) (30 g, 28.2 mmol) under 1 atmosphere of hydrogen pressure at room temperature for 16 h. The reaction mixture was filtered through a Celite® bed and washed with EtOAc (2 L). The filtrate was concentrated and purified by column chromatography (Biotage Isolera, 340 g SiO column, 0-20% EtOAc / petroleum ether over 4 h) to give the title compound as a brown oil (70 g, 395 mmol, 59.6% yield). MS (m / z) 154.1 (M+H). + .

[0584] Intermediates 14-15 were prepared from the indicated aryls in a similar manner as described for Intermediate 13.

[0585] [Table 4]

[0586] Intermediate 16 5-Fluoro-6-methoxy-2-methylpyridin-3-amine

[0587] [ka]

[0588] To a solution of N-(5-fluoro-6-methoxy-2-methylpyridin-3-yl)-1,1-diphenylmethanimine (24 g, 74.9 mmol) in 1,4-dioxane (120 mL) at room temperature, HCl in water (1.5 M, 200 mL, 300 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture, combined with another reaction carried out on a 25 g scale with N-(5-fluoro-6-methoxy-2-methylpyridin-3-yl)-1,1-diphenylmethanimine, was diluted with ice water (50 mL) and extracted with DCM (80 mL × 3). The combined organic extracts were slowly neutralized with solid NaHCO to pH = 8 and extracted with DCM (150 mL × 3). The combined organic extracts were dried over NaSO and concentrated under reduced pressure to give the title compound as a pale yellow solid (20 g, 126 mmol, 168% yield). MS (m / z) 157.2 (M+H) + .

[0589] Intermediate 17 Ethyl 4-((4-fluoro-2-methylphenyl)amino)-6-(trifluoromethyl)nicotinate

[0590] [ka]

[0591] A solution of ethyl 4-bromo-6-(trifluoromethyl)nicotinate (1.1 g, 3.69 mmol), 4-fluoro-2-methylaniline (0.693 g, 5.54 mmol), and cesium carbonate (2.405 g, 7.38 mmol) in 1,4-dioxane (15 mL) was purged with N for 15 minutes, after which BINAP (0.230 g, 0.369 mmol) and Pd(dba) (0.169 g, 0.185 mmol) were added. The reaction mixture was purged with N for 5 minutes and stirred at 90 °C for 15 hours. The reaction was cooled and filtered through a Celite pad, washing with EtOAc (80 mL). The filtrate was concentrated and purified by column chromatography (Biotage Isolera, 50 g SiO column, 0-20% EtOAc / petroleum ether over 1 h) to give the title compound as a pale yellow solid (850 mg, 2.128 mmol, 57.7% yield). MS (m / z) 343.1 (M+H). + .

[0592] Intermediates 18-32 were prepared from the indicated aryl halogen and aniline in a manner similar to that described for intermediate 17.

[0593] [Table 5] JPEG2023554430000102.jpg219167 JPEG2023554430000103.jpg40169

[0594] Intermediate 33 Ethyl 3-((4-fluoro-2-methylphenyl)amino)-5-(trifluoromethyl)pyrazine-2-carboxylate

[0595] [ka]

[0596] To a solution of ethyl 3-amino-5-(trifluoromethyl)pyrazine-2-carboxylate (700 mg, 2.98 mmol) in toluene (20 mL) was added 4-fluoro-1-iodo-2-methylbenzene (1054 mg, 4.46 mmol) and cesium carbonate (1455 mg, 4.46 mmol) at room temperature. The resulting reaction mixture was purged with N for 10 minutes, after which Pd(dba) (68.1 mg, 0.074 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (86 mg, 0.149 mmol) were added. The reaction mixture was stirred in a sealed tube at 90 °C for 16 hours. Ice water (20 mL) was added, and the reaction was extracted with EtOAc (2 × 50 mL). The combined organic extracts were washed with brine (10 mL), dried over NaSO, filtered, and evaporated in vacuo. The crude product was absorbed onto silica (1 g) in DCM (10 mL) and purified by flash chromatography (Isolera, 50 g SiO column, 4% EtOAc / petroleum ether) to give the title compound as a yellow solid (720 mg, 1.909 mmol, 64.1% yield). MS (m / z) 344.0 (M+H). + .

[0597] Intermediate 34 was prepared in a similar manner as described for Intermediate 33 from the indicated aryl halogen and aniline.

[0598] [Table 6]

[0599] Intermediate 35 3-((4-fluoro-2-isopropylphenyl)amino)-6-hydroxypicolinic acid ethyl ester

[0600] [ka]

[0601] To a stirred solution of ethyl 3-((4-fluoro-2-isopropylphenyl)amino)-6-methoxypicolinate (0.7 g, 2.106 mmol) in acetonitrile (10 mL) at 0 °C under N was added iodotrimethylsilane (0.717 mL, 5.27 mmol) and the reaction mixture was stirred at 80 °C for 1 h. The reaction mixture was allowed to cool to 30 °C and concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with saturated sodium thiosulfate (50 mL). The organic phase was dried over Na SO and concentrated in vacuo to give the title compound as a pale yellow solid (700 mg, 1.690 mmol, 80% yield). MS (m / z) 319.1 (M+H) + .

[0602] Intermediate 36 3-((4-fluoro-2-methylphenyl)amino)-5-(trifluoromethyl)picolinic acid

[0603] [ka]

[0604] To a stirred solution of methyl 3-chloro-5-(trifluoromethyl)picolinate (1.5 g, 6.26 mmol) in 1,4-dioxane (20 mL) was added 4-fluoro-2-methylaniline (1.567 g, 12.52 mmol), BINAP (0.390 g, 0.626 mmol), CsCO (4.08 g, 12.52 mmol), and Pddba (0.287 g, 0.313 mmol). The reaction was purged with N for 5 minutes and then stirred at 100 °C for 12 hours. After cooling the reaction, water (50 mL) was added and the reaction was washed with EtOAc (25 mL). The aqueous layer was acidified with 1.5 N HCl (5 mL) and extracted with EtOAc (75 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the title compound as a yellow solid (2 g, 4.71 mmol, 75% yield). MS (m / z) 314.9 (M+H) + .

[0605] Intermediate 37 4-((4-fluoro-2-methylphenyl)amino)-2-(trifluoromethyl)pyrimidine-5-carboxylic acid

[0606] [ka]

[0607] To a stirred solution of ethyl 4-((4-fluoro-2-methylphenyl)amino)-2-(trifluoromethyl)pyrimidine-5-carboxylate (6 g, 17.48 mmol) in THF (40.0 mL) was added a solution of LiOH (4.40 g, 105 mmol) in water (40.0 mL) dropwise over 5 minutes at room temperature. The resulting reaction mixture was stirred at 60° C. for 16 hours. The reaction mixture was allowed to cool to room temperature and concentrated. The residue was acidified with 1.5 N HCl (100 mL) to a pH of about 3-4. The yellow solid precipitate was collected by filtration and dried under reduced pressure to give the title compound as a yellow solid (4.5 g, 14.10 mmol, 81% yield). MS (m / z) 316.0 (M+H) + .

[0608] Intermediates 38-54 were prepared from the indicated esters in a similar manner as described for intermediate 37.

[0609] [Table 7] JPEG2023554430000110.jpg218167 JPEG2023554430000111.jpg67164

[0610] Intermediate 55 4-((2-ethyl-4-fluorophenyl)amino)-6-(trifluoromethyl)nicotinic acid

[0611] [ka]

[0612] A solution of 4-chloro-6-(trifluoromethyl)nicotinic acid (0.338 g, 1.499 mmol) and 2-ethyl-4-fluoroaniline (0.292 g, 2.098 mmol) in acetic acid (3.75 mL) was stirred at 100° C. for 18 hours. The reaction was cooled, water was added, and the solid precipitate was collected by filtration, washed with water, and air-dried to give the title compound as a gray solid (326 mg, 0.993 mmol, 66.3% yield). MS (m / z) 329.2 (M+H). + .

[0613] Intermediate 56 3-((4-fluoro-2-methylphenyl)amino)-N-(6-methoxy-2-methylpyridin-3-yl)-5-(trifluoromethyl)picolinamide

[0614] [ka]

[0615] To a stirred solution of 3-((4-fluoro-2-methylphenyl)amino)-5-(trifluoromethyl)picolinic acid (2 g, 6.36 mmol) in DMF (20 mL) was added 6-methoxy-2-methylpyridin-3-amine (0.879 g, 6.36 mmol), HATU (2.420 g, 6.36 mmol), and TEA (0.887 mL, 6.36 mmol). After stirring at 25 °C for 1 h, cold water (50 mL) was added and the reaction was stirred for 1 h. The solid precipitate was collected by filtration and washed with EtO (5 mL) to give the title compound as a yellow solid (1.1 g, 2.431 mmol, 38.2% yield). MS (m / z) 435.0 (M+H) + .

[0616] Intermediates 57-73 were prepared from the indicated amines and carboxylic acids in a similar manner as described for intermediate 56.

[0617] [Table 8] JPEG2023554430000115.jpg212169 JPEG2023554430000116.jpg207168

[0618] Intermediate 74 4-((4-fluoro-2-methylphenyl)amino)-N-(6-methoxy-2-methylpyridin-3-yl)-2-(trifluoromethyl)pyrimidine-5-carboxamide

[0619] [ka]

[0620] A solution of 4-((4-fluoro-2-methylphenyl)amino)-2-(trifluoromethyl)pyrimidine-5-carboxylic acid (1.5 g, 4.76 mmol) and thionyl chloride (15 mL, 206 mmol) was stirred at 80° C. for 1.5 h under N. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The resulting yellow solid residue was dissolved in DCM (10 mL) and cooled to 0° C. To this reaction solution was added a solution of triethylamine (1.990 mL, 14.28 mmol) and 6-methoxy-2-methylpyridin-3-amine (0.789 g, 5.71 mmol) in DCM (5 mL) dropwise over 5 min under N. After stirring at room temperature under N for 2 h, the reaction mixture was cooled to 0° C., quenched with water (25 mL), and extracted with DCM (3×50 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), and saturated NaHCO (25 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by column chromatography (Biotage, 50 g SiO SNAP column, 0-50% EtOAc / petroleum ether over 50 min) to give the title compound as a yellow solid (1.7 g, 3.86 mmol, 81% yield). MS (m / z) 436.1 (M+H). + .

[0621] Intermediates 75-76 were prepared from the indicated amines and carboxylic acids in a similar manner as described for Intermediate 74.

[0622] [Table 9]

[0623] Intermediate 77 1-(4-Fluoro-2-methylphenyl)-3-(6-methoxy-2-methylpyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydropyrido[3,2-d]pyrimidin-4(1H)-one

[0624] [ka]

[0625] To a stirred solution of 3-((4-fluoro-2-methylphenyl)amino)-N-(6-methoxy-2-methylpyridin-3-yl)-5-(trifluoromethyl)picolinamide (1.1 g, 2.53 mmol) in acetonitrile (15 mL) was added CsCO (3.30 g, 10.13 mmol) and diiodomethane (2.035 g, 7.60 mmol), and the reaction mixture was stirred at 90 °C for 10 h. The reaction mixture was quenched with water (50 mL), extracted with DCM (50 mL), dried over NaSO, and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage Isolera, 10 g SiO SNAP column, 2–9% EtOAc / petroleum ether over 35 min) to give the title compound as a yellow solid (430 mg, 0.954 mmol, 37.7% yield). MS (m / z) 447.0 (M+H) + .

[0626] Intermediates 78-96 were prepared from the indicated amides in a similar manner as described for intermediate 77.

[0627] [Table 10] JPEG2023554430000121.jpg213169 JPEG2023554430000122.jpg222168

[0628] Intermediate 97 1-(4-Fluoro-2-isopropylphenyl)-6-hydroxy-3-(6-methoxy-2-methylpyridin-3-yl)-2,3-dihydropyrido[3,2-d]pyrimidin-4(1H)-one

[0629] [ka]

[0630] To a stirred solution of 3-((4-fluoro-2-isopropylphenyl)amino)-6-hydroxy-N-(6-methoxy-2-methylpyridin-3-yl)picolinamide (290 mg, 0.707 mmol) in toluene (5 mL) under N was added PTSOH (134 mg, 0.707 mmol) and paraformaldehyde (849 mg, 28.3 mmol), and the reaction mixture was stirred at 100° C. for 1 h. The reaction mixture was allowed to cool to room temperature, quenched with saturated NaHCO (15 mL), and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by column chromatography (Isolera, 25 g SiO SNAP column, 2-5% MeOH / DCM over 20 min) to give the title compound as a yellow solid (180 mg, 0.418 mmol, 59.2% yield). MS (m / z) 423.2 (M+H). + .

[0631] Intermediate 98 6-chloro-1-(4-fluoro-2-isopropylphenyl)-3-(6-methoxy-2-methylpyridin-3-yl)-2,3-dihydropyrido[3,2-d]pyrimidin-4(1H)-one

[0632] [ka]

[0633] To 1-(4-fluoro-2-isopropylphenyl)-6-hydroxy-3-(6-methoxy-2-methylpyridin-3-yl)-2,3-dihydropyrido[3,2-d]pyrimidin-4(1H)-one (80 mg, 0.189 mmol) was added POCl (0.8 mL, 8.58 mmol) at 0 °C under N, and the reaction mixture was stirred at 90 °C for 18 h. The reaction was cooled to 0 °C, and additional POCl (0.1 mL, 1.073 mmol) was added. The reaction was stirred at 90 °C for 1 h and then allowed to cool to room temperature. The reaction was slowly poured into saturated NaHCO (15 mL) solution at 0 °C and extracted with EtOAc (2 × 20 mL). The combined organic extracts were dried over NaSO, filtered, and concentrated in vacuo to give the crude title compound as a pale yellow liquid (90 mg). MS (m / z) 441.1 (M+H) + .

[0634] Intermediate 99 1-(4-Fluoro-2-methylphenyl)-3-(6-methoxy-2-methylpyridin-3-yl)-4-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidine-7-carbonitrile

[0635] [ka]

[0636] To a solution of 7-chloro-1-(4-fluoro-2-methylphenyl)-3-(6-methoxy-2-methylpyridin-3-yl)-2,3-dihydropyrido[4,3-d]pyrimidin-4(1H)-one (80 mg, 0.194 mmol) in DMF (2 mL) was added dicyanozinc (45.5 mg, 0.388 mmol) and tetrakis (44.8 mg, 0.039 mmol). The reaction mixture was heated in a microwave oven at 150 °C for 1 h. The crude material was purified by column chromatography (Isco, 10-70% EtOAc / hexanes) to give the title product as an off-white solid (66 mg, 0.162 mmol, 84% yield). MS (m / z) 404.4 (M+H). + .

[0637] Intermediate 100 5-((3,4-difluoro-2-methylphenyl)amino)-2-(trifluoromethyl)isonicotinic acid hydrochloride

[0638] [ka]

[0639] To a mixture of methyl 5-bromo-2-(trifluoromethyl)isonicotinate (14 g, 49.3 mmol) and 3,4-difluoro-2-methylaniline (8.47 g, 59.1 mmol) in 1,4-dioxane (224 mL) was added cesium carbonate (32.1 g, 99 mmol), followed by Pd(dba) (2.257 g, 2.465 mmol) and 2,2'-bis(diphenylphosphaneyl)-1,1'-binaphthalene (3.07 g, 4.93 mmol). The mixture was stirred at 100 °C under nitrogen overnight. The reaction was cooled and then filtered through Celite. The crude solution was heated at 65 °C with 5 N sodium hydroxide (49.3 mL, 246 mmol) for 40 minutes. The solution was cooled, and 75 mL of 6 N HCl was added and stirred to give a yellow suspension. This was filtered to give a solid, and a second crop was also collected. These solids were combined, slurried in 100 mL of diethyl ether, sonicated, and filtered to give a lemon yellow solid, which was dried under vacuum for 18 hours to give 5-((3,4-difluoro-2-methylphenyl)amino)-2-(trifluoromethyl)isonicotinic acid hydrochloride as a yellow solid (13.25 g, 35.9 mmol yield, 72.9%). MS (m / z) 331.1 (M+H). + . 1 H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1 H) 8.06 - 8.16 (m, 1 H) 7.97 - 8.06 (m, 1 H) 7.30 - 7.41 (m, 1 H) 7.18 - 7.31 (m, 1 H) 3.37 (br s, 3 H) 2.17 (s, 3H).

[0640] Intermediate 101 5-((3,4-difluoro-2-methylphenyl)amino)-N-(6-methoxy-2-methylpyridin-3-yl)-2-(trifluoromethyl)isonicotinamide

[0641] [ka]

[0642] A mixture of 5-((3,4-difluoro-2-methylphenyl)amino)-2-(trifluoromethyl)isonicotinic acid hydrochloride (19.75 g, 53.6 mmol), 6-methoxy-2-methylpyridin-3-amine (9.84 g, 71.2 mmol), and pyridine (23.8 mL, 295 mmol) was stirred in ethyl acetate (179 mL) to give a solution at 25° C., then T3P (88 mL, 149 mmol, 50% solution in ethyl acetate) was added, and the reaction was stirred at 25° C. for 2 hours and then filtered. The filtrate was treated with 150 mL of 1 N HCl and 50 mL of EtOAc, and the organic solution was separated, washed with 150 mL of saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a light brown solid. This solid was triturated in 100 mL of MTBE at 70° C., cooled to 25° C., and filtered to give 14.21 g of crude product. The filtrate was evaporated in vacuo to give a dark oily solid, which was again triturated with approximately 30 mL of MTBE and filtered to give 4 g of white solid product. The filtrate was concentrated in vacuo and again triturated with 15 mL of MTBE to give 0.6 g of additional product, which were combined to give the title compound as a pink solid (total 19 g, 42.0 mmol, 78% yield). The remaining filtrate was evaporated in vacuo to give a dark brown gum (4.4 g) that was preabsorbed onto silica. The residue was purified by column chromatography (Isco CombiFlash Rf, 0% to 30% EtOAc in heptane gradient; 80 g RediSep column). Pure fractions were collected, and an additional 2.9 g (6.4 mmol, 12% yield) of the title product was isolated by concentration in vacuo as a pink solid. MS (m / z) 453.1 (M+H) + . 1H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1 H) 9.50 (s, 1 H) 8.23 ​​(d, J=15.16 Hz, 2 H) 7.64 (d, J=8.80 Hz, 1 H) 7.29 - 7.37 (m, 1 H) 7.16 - 7.29 (m, 1 H) 6.71 (d, J=8.31 ​​Hz, 1 H) 3.86 (s, 3 H) 2.37 (s, 3 H) 2.17 (s, 3 H).

[0643] Intermediate 102 1-(3,4-Difluoro-2-methylphenyl)-3-(6-methoxy-2-methylpyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one

[0644] [ka]

[0645] A mixture of 5-((3,4-difluoro-2-methylphenyl)amino)-N-(6-methoxy-2-methylpyridin-3-yl)-2-(trifluoromethyl)isonicotinamide (18.37 g, 40.6 mmol) and cesium carbonate (79 g, 244 mmol) in acetonitrile (625 mL) was treated with diiodomethane (32.7 mL, 406 mmol) in a 2 L flask equipped with a reflux condenser heated to Tj = 99 °C. This was stirred for 18 h. The reaction was not complete, so diiodomethane (9.81 mL, 122 mmol) was added and refluxed for an additional 4 h, then cooled, filtered through a pad of Celite, and concentrated in vacuo. The resulting solid was dissolved in dichloromethane, loaded onto 35 g of silica, and dry-loaded onto an Isco CombiFlash RF column for silica gel chromatography (0% to 30% EtOAc in heptane, 25 min gradient; 330 g RediSep column). Pure fractions were collected, and the product was isolated by vacuum concentration as a pale yellow solid (14.7 g). This powder was dissolved in 30 mL of DCM, loaded, and purified by silica gel chromatography on an Isco CombiFlash RF column (0% to 25% EtOAc in heptane gradient over 25 min; 330 g RediSep column). Pure fractions were collected, and the product was isolated by vacuum concentration to give the title compound as a tan powder (13.7 g, 29.5 mmol, 72.6% yield). MS (m / z) 465.1 (M+H). + . 1 H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 1 H) 7.84 - 8.01 (m, 1 H) 7.66 (br d, J=8.31 ​​Hz, 1 H) 7.39 - 7.53 (m, 1 H) 7.31 - 7.38 (m, 1 H) 6.75 (d, J=9.29 Hz, 1 H) 4.92 - 5.68 (m, 2 H) 3.85 (s, 3 H) 2.28 - 2.38 (m, 3 H) 2.25 (s, 3 H).

[0646] Example 1 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydropyrido[3,2-d]pyrimidin-4(1H)-one

[0647] [ka]

[0648] To a stirred solution of 1-(4-fluoro-2-methylphenyl)-3-(6-methoxy-2-methylpyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydropyrido[3,2-d]pyrimidin-4(1H)-one (430 mg, 0.963 mmol) in acetonitrile (10 mL) at room temperature under N2, iodotrimethylsilane (578 mg, 2.89 mmol) was added dropwise. The reaction mixture was stirred at 60 °C for 12 h, cooled to room temperature, and concentrated under reduced pressure. The crude product was purified by reverse-phase HPLC (Sunfire C18 (19 × 150 mm) 5 μm column, 0.1% formic acid in water / ACN) to give the title compound as a white solid (120 mg, 0.275 mmol, 28.5% yield). 1 H NMR (400MHz, DMSO-d6) δ: 11.80 (s, 1H), 8.53 (s, 1H), 7.43-7.38 (m, 2H), 7.33 (dd, J = 2.8, 9.6 Hz, 1H), 7.25-7,15 (m, 1H), 6.92-6.75 (m, 1H), 6.21 (d, J = 9.6 Hz, 1H), 5.60-4.80 (m, 2H), 2.25 (s, 3H), 2.13 (s, 3H). MS (m / z) 433.0 (M+H) + .

[0649] Examples 2-8 were prepared by methods similar to those described for Example 1 from the indicated intermediates.

[0650] [Table 11] JPEG2023554430000131.jpg218167

[0651] Example 9 6-chloro-1-(4-fluoro-2-isopropylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydropyrido[3,2-d]pyrimidin-4(1H)-one

[0652] [ka]

[0653] To a stirred solution of 6-chloro-1-(4-fluoro-2-isopropylphenyl)-3-(6-methoxy-2-methylpyridin-3-yl)-2,3-dihydropyrido[3,2-d]pyrimidin-4(1H)-one (90 mg, 0.102 mmol) in DMF (1 mL) at 0 °C under N was added p-toluenesulfonic acid monohydrate (97 mg, 0.508 mmol) and lithium chloride (21.52 mg, 0.508 mmol). The reaction mixture was stirred at 120 °C for 2 h and then cooled to 25 °C. The reaction was quenched with ice-water (15 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with brine (20 mL), dried over Na SO , filtered, and concentrated under reduced pressure. The resulting brown gum was purified by reverse-phase HPLC (X-bridge C18 (19 x 150 mm) 5 μm column, 10 mM NH4HCO3 / ACN in water) to give the title compound as an off-white solid (16 mg, 0.037 mmol, 36.5% yield). 1H NMR (400MHz, DMSO-d6) δ: 11.80 (br s, 1H), 7.43 - 7.28 (m, 4H), 7.23 - 7.15 (m, 1H), 6.76 - 6.66 (m, 1H), 6.21 (d, J = 9.3 Hz, 1H), 5.48 (d, J = 9.6 Hz, 0.6H), 5.22 (d, J = 10.4 Hz, 0.4H), 4.97 (d, J = 10.4 Hz, 0.4H), 4.72 (d, J = 9.6 Hz, 0.6H), 3.24 - 3.03 (m, 1H), 2.18 - 2.03 (m, 3H), 1.23 - 1.08 (m, 6H). MS (m / z) 427.2 (M+H) + .

[0654] Examples 10-11 were prepared from the indicated intermediates by methods similar to those described for Example 9.

[0655] [Table 12]

[0656] Example 12 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one

[0657] [ka]

[0658] To a mixture of 1-(4-fluoro-2-methylphenyl)-3-(6-methoxy-2-methylpyridin-3-yl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one (250 mg, 0.661 mmol) and sodium iodide (990 mg, 6.61 mmol) in acetonitrile (10.00 mL), chlorotrimethylsilane (0.838 mL, 6.61 mmol) was added and the reaction was stirred for 3 hours at 60° C. The reaction was diluted with DCM (30 mL), washed with aqueous NaSO, dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by MDAP (XSELECT CSH C18 (150 mm × 30 mm) 5 μm column, A = 0.1% v / v formic acid in water, B = 0.1% v / v formic acid in acetonitrile, 5–35% B, gradient time 3–12 min) to give the title compound as a white solid (76 mg, 0.198 mmol, 30.0% yield). 1 H NMR (400 MHz, DMSO-d6) δ:11.80 (br s, 1 H), 8.19 (d, J=4.89 Hz, 1 H), 7.73 (d, J=4.89 Hz, 1 H), 7.65 (br s, 1 H), 7.44 - 7.34 (m, 2 H), 7.31 (dd, J=9.29, 2.93 Hz, 1 H), 7.22 - 7.13 (m, 1 H), 6.20 (d, J=9.78 Hz, 1 H), 5.60 - 4.73 (m, 2 H), 2.27 (s, 3 H), 2.09 (br s, 3 H). MS (m / z) 365.3 (M+H) + .

[0659] Example 17 1-(3,4-Difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one

[0660] [ka]

[0661] A solution of 1-(3,4-difluoro-2-methylphenyl)-3-(6-methoxy-2-methylpyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one (13.7 g, 29.5 mmol) and HCl (59.0 mL, 295 mmol, 5N in isopropanol) in isopropanol (73.8 mL) was heated under reflux (Tj = 91 °C) for 12 h and then at room temperature for 6 h. The mixture was concentrated in vacuo to give an orange foamy oil, which was then partitioned between 100 mL each of EtOAc and saturated aqueous sodium bicarbonate solution. The aqueous layer was back-extracted with 50 mL of EtOAc, and the combined organic solution was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a light brown foam. The foam was dissolved in 15 mL of dichloromethane, and after 30 minutes a solid precipitated and was filtered to give the title compound as a white solid (6.85 g, 15.2 mmol, 51.6% yield). The filtrate containing the crude product was collected and purified by silica gel chromatography on an Isco CombiFlash Rf (1:1 ethyl acetate:heptane to 70% 3:1 EtOAc:EtOH; 330 g RediSep column over 20 minutes). Pure fractions were collected and the product was isolated by concentration in vacuo to give additional title compound (4.1 g, 9.1 mmol, 30.9% yield) as an off-white solid after drying under high vacuum for 18 hours. MS (m / z) 451.1 (M+H) + . 1 H NMR (700 MHz, DMSO-d6) δ ppm 11.18 - 12.29 (m, 1 H) 8.00 - 8.07 (m, 1 H) 7.79 - 7.96 (m, 1 H) 7.43 - 7.51 (m, 1 H) 7.37 - 7.43 (m, 1 H) 7.29 - 7.36 (m, 1 H) 6.21 (d, J=9.47 Hz, 1 H) 4.90 - 5.55 (m, 2 H) 2.19 - 2.29 (m, 3 H) 2.02 - 2.16 (m, 3 H).

[0662] Example 17a 1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one crystalline preparation Form 1 2.0 g of 1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one was added to a 40 mL vial. To this was added 14 mL (7 volumes) of MeOH, and the contents were shaken at 25 °C and 750 rpm. The temperature was raised to 50 °C, and complete dissolution was observed in approximately 15 minutes. Approximately 10 minutes after dissolution, solids began to form. These solids were allowed to grow for approximately 10 minutes to obtain a slurry. The temperature was then raised to 63 °C and held for 4 hours. The contents were then cooled to 25 °C at a rate of 0.1 °C / min and held for 1 hour. The mixture was then heated again to 63°C at 1.0°C / min and held for 4 hours, then finally cooled again to 25°C at 0.1°C / min and held overnight to mature the crystals. The contents were filtered to remove the crystalline solid and placed in a vacuum oven at 60°C overnight to yield 1.52 g of crystalline 1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one (pattern 1—XRPD and DSC, see Table 1, Figures 1 and 2).

[0663] Form 2 70 mg of 1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one (Form 3) was added to each of 12 x 2 mL HPLC vials. To each vial was added 500 μL of various solvents. The vials were then stirred at 750 rpm starting at 25°C. The temperature was increased to 50°C. In vials that appeared to show a physical change in the input material, the solids were filtered and measured by XRPD. Solvents that showed a physical change in the input material were isopropanol, isopropyl acetate, and 1-butanol. Crystalline material isolated from these solvents appeared to produce XRPD pattern 2 (XRPD and DSC, see Table 1, Figures 3 and 4).

[0664] Form 3 To a 20 mL vial was added 1.0 g of amorphous (chromatographed and rotary evaporated) 1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one. 5 mL (5 volumes) of EtOH was added and complete dissolution of the charge was achieved at 25° C. A clarification filtration was performed and the mother liquor was added to another clean 20 mL vial. The vial was left uncapped and allowed to evaporate for 3 days. The contents were slurried with 1 mL of EtOH and filtered to recover crystalline 1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one (pattern 3—XRPD, see Table 1 and Figure 5).

[0665] Form 4 To a 20 mL vial was added 500 mg of 1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one. To this vial was added 7.5 mL of MeCN (15 volumes), and the contents were shaken at 25°C and 750 rpm. Complete dissolution of the input material was observed in approximately 5 minutes. The temperature was increased to 30°C, and solid particles began to form within 5 minutes. Mixing was continued at this temperature for an additional 30 minutes, during which time the contents became a viscous yet well-mixed slurry. The temperature was increased to 63°C at a rate of 1.0°C / min. The contents were then held at this temperature for 4 hours. After 4 hours at 63°C, the temperature was decreased to 25°C at a rate of 0.1°C / min and held for 1 hour. The temperature was then returned to 63°C at a rate of 1.0°C / min and held for 4 hours, after which it was finally cooled back to 25°C at a rate of 0.1°C / min and held overnight. The following morning, the contents were filtered and evacuated to a fine mist. The crystalline solid was then placed in a vacuum oven at 60°C overnight to yield 368 mg of crystalline 1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one (Pattern 4—XRPD and DSC, see Table 1, Figures 6 and 7).

[0666] [Table 13]

[0667] Examples 14-16 and 18-21 were prepared from the indicated intermediates by methods similar to those described for Example 12.

[0668] [Table 14] JPEG2023554430000138.jpg224170 JPEG2023554430000139.jpg55170

[0669] Example 22 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-1,2,3,4-tetrahydropyrido[3,4-d]pyrimidine-6-carbonitrile

[0670] [ka]

[0671] To a solution of 6-chloro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one (75 mg, 0.188 mmol) in DMF (2 mL) was added dicyanozinc (44.2 mg, 0.376 mmol) and tetrakis (43.5 mg, 0.038 mmol). The reaction mixture was heated at 150° C. overnight and then in a microwave at 150° C. for 1 h. The reaction mixture was cooled, filtered through Celite®, and purified by MDAP (XSELECT CSH C18 (150 mm × 30 mm) 5 μm column, A = 0.1% v / v formic acid in water, B = 0.1% v / v formic acid in acetonitrile, 15-55% B, gradient time 3-22 min) to give the title product as an off-white solid (50 mg, 0.127 mmol, 67.6% yield). 1H NMR (400 MHz, DMSO-d6) δ: 11.83 (br s, 1H), 8.19 (br s, 1H), 7.69 (br d, J = 19.6 Hz, 1H), 7.49 (dd, J = 5.4, 8.8 Hz, 1H), 7.42 - 7.32 (m, 2H), 7.29 - 7.17 (m, 1H), 6.21 (br. d, J = 9.8 Hz, 1H), 5.53 (br. d, J = 9.8 Hz, 0.5H), 5.32 - 5.16 (m, 1H), 4.93 (br. d, J = 9.8 Hz, 0.5H), 2.26 (s, 3H), 2.11 (br d, J = 7.3 Hz, 3H). MS (m / z) 390.3 (M+H) + .

[0672] Example 23 3-Methyl-4-(1-(2-methyl-4-(trifluoromethoxy)phenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridine 1-oxide

[0673] [ka]

[0674] A mixture of 1-(2-methyl-4-(trifluoromethoxy)phenyl)-3-(3-methylpyridin-4-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one (38 mg, 0.079 mmol) and mCPBA (26.5 mg, 0.118 mmol) in DCM (1.50 mL) was stirred at 0 °C for 4 h and then concentrated in vacuo. The residue was purified by MDAP (XSelect CSH Prep C18 5 μm OBD, 30-85% gradient, water / acetonitrile containing 10 mM ammonium bicarbonate and 0.075% ammonium hydroxide, flow rate 40 mL / min, total run time 17 min) to give the title product as a white solid (15 mg, 0.029 mmol, 36.3% yield). 1H NMR (400 MHz, DMSO-d6) δ: 8.34-8.33 (m, 1H), 8.21 (dd, J = 1.5, 6.8 Hz, 1H), 8.14 (s, 1H), 7.92 (br s, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 2.9 Hz, 1H), 7.47-7.42 (m, 2H), 5.55-5.30 (m, 2H), 2.37 (s, 3H), 2.16 (s, 3H). MS (m / z) 499.3 (M+H) + .

[0675] Biological assays The Na v The 1.8 inhibitor compounds or pharmaceutically acceptable salts thereof are each useful in the treatment of pain, a pain disorder or condition, a pain-related disorder or condition, or pain caused by a disease, such as those defined herein.

[0676] The biological activity of the compounds of the present invention is determined by assays measuring such inhibition and by measuring the activity of the voltage-gated sodium channel Na v This can be determined using a suitable assay, such as an assay that assesses the ability of a compound to inhibit 1.8.

[0677] Biological Assay Example 1: Human Na v 1.8, human Na v Human embryonic kidney 293 cells (HEK293) expressing β1 and human TREK1 (HEK293-Na v 1.8) to 150cm 2 HEK293-Na cells were grown in flasks at 37°C and 5% CO2. v 1.8 was subcultured into T175 cell culture flasks every 2–3 days when the confluency reached 80–90%.

[0678] Pharmacological evaluation of the compounds of the present invention was performed using assays developed in the QPatch 48 HTX electrophysiology system and HEK293-Na v1.8 was used in combination. HEK293-Na v 1.8 On the day of use, remove the culture medium, wash with DPBS, add Accutase (add 2 mL to cover the surface, then aspirate 1 mL, then incubate at 37°C for 1.5 min), then add CHO-SFM II to stop the enzymatic digestion, and add 3 x 10 6 It was prepared by obtaining a suspension of cells / mL.

[0679] The compounds were prepared in an extracellular solution containing 145 mM NaCl, 4 mM KCl, 2 mM CaCl, 2 mM MgCl, 1 mM HEPES, 10 mM glucose, and 300 mOsM / L NaOH at pH 7.4. The intracellular solution contained 115 mM CsF, 20 mM CsCl, 5 mM NaCl, 10 mM EGTA, 10 mM HEPES, 20 mM sucrose, and 310 mOsm / L CsOH at pH 7.2.

[0680] Using the voltage clamp mode of the QPatch 48HTX system, v To measure the pharmacological activity of the compounds of the present invention at 1.8 ion channels, a semi-inactivated voltage protocol (V 1 / 2 ) was used. V 1 / 2 The protocol utilized the following voltage steps: a holding voltage of -100 mV was established, followed by a 20 ms voltage step to 0 mV (P1), then an 8 s inactivating voltage step to -46 mV, followed by a 20 ms step to -100 mV, followed by a 20 ms step to 0 mV (P2), followed by a return to the holding voltage of -100 mV. This voltage protocol was repeated at a frequency of 0.07 Hz, and current magnitude was quantified during the P2 step during recording. Inhibition of the measured current amplitude by compounds of the invention was measured using a 50% inhibitory concentration (IC 50 Within the QPatch HTX software, P2 currents were normalized according to measurements taken at baseline, post-compound, and post-positive reference compound and fitted to the following equation:

number

[0681] To assess the rundown of current over the course of the experiment, vehicle-only wells were used to measure current normalized to vehicle alone.

number

number

[0682] Compounds of the present invention were tested in the above assays to determine the Na v Activity against the 1.8 sodium channel was tested in one or more experiments, and the results are shown in Table 2 below. The potency of compounds of the invention is reported as pIC50 values. The pIC50 value is the negative logarithm of the IC50 value, where the IC50 value is the half-maximal inhibitory concentration measured in molar (M). For compounds tested in more than one experiment, the pIC50 value is reported as the average value.

[0683] [Table 15]

[0684] It is to be understood that the present invention is not limited to the embodiments shown above, and the right is reserved to all modifications that come within the scope of the shown embodiments and the following claims.

Claims

1. Compounds of formula (I): [Formula 1] [In the formula, Y is O or S; X １ is nitrogen or CR １ and X ２ is nitrogen or CR ２ and X ３ is nitrogen or CR ３ and X ４ is nitrogen or CR ４ and However, X ２ , X ３ and X ４ at least one of is nitrogen; R １ , R ２ , R ３ and R ４ each independently represents hydrogen, halo, cyano, -NR ａ R ｂ , -(C １－６ )-alkyl, -(C １－６ )-haloalkyl, —O—(C １－６ )-alkyl or -O-(C １－６ )-haloalkyl; Ring B is phenyl or a 5- or 6-membered heterocyclyl containing 1 or 2 nitrogen ring atoms; Each R ５ are independently halo, oxo, -OH, -NR ａ R ｂ , -(C １－６ ) alkyl, -(C １－６ ) haloalkyl, -COOR ａ , -C(O)NR ａ R ｂ Or -S(O) ｐ R ｃ and R ６ is hydrogen, -(C １－６ ) alkyl, —O—(C １－６ )-alkyl or -NR ａ R ｂ and Each R ７ are independently halo, -(C １－６ ) alkyl, —O—(C １－６ ) alkyl or —O—(C １－６ )-haloalkyl; R ａ and R ｂ Each of the groups is independently hydrogen, -(C １－６ ) alkyl or -(C １－６ ) haloalkyl; R ｃ is hydrogen, -OH, -NR ａ R ｂ , -(C １－６ )-alkyl or -(C １－６ )-haloalkyl; n is 0, 1, 2 or 3; p is 0, 1 or 2; and z is 0, 1, 2 or 3. or a tautomer thereof or a pharma- ceutically acceptable salt thereof.

2. Compound of formula (IA): [chemical 2] [In the formula, Y is O or S; R １ , R ２ and R ３ each independently represents hydrogen, halo, cyano, -NR ａ R ｂ , -(C １－６ )-alkyl, -(C １－６ )-haloalkyl, —O—(C １－６ )-alkyl or -O-(C １－６ )-haloalkyl; Ring B is phenyl or a 5- or 6-membered heterocyclyl containing 1 or 2 nitrogen ring atoms; Each R ５ are independently halo, oxo, -OH, -NR ａ R ｂ , -(C １－６) alkyl, -(C １－６ ) haloalkyl, -COOR ａ , -C(O)NR ａ R ｂ Or -S(O) ｐ R ｃ and R ６ is hydrogen, -(C １－６ ) alkyl, —O—(C １－６ )-alkyl or -NR ａ R ｂ and Each R ７ are independently halo, -(C １－６ ) alkyl, —O—(C １－６ ) alkyl or —O—(C １－６ )-haloalkyl; R ａ and R ｂ Each of the groups is independently hydrogen, -(C １－６ ) alkyl or -(C １－６ ) haloalkyl: R ｃ is hydrogen, -OH, -NR ａ R ｂ , -(C １－６ )-alkyl or -(C １－６ )-haloalkyl; n is 0, 1, 2 or 3; p is 0, 1 or 2; and z is 0, 1, 2 or 3.

2. The compound of claim 1, which is: or a tautomer thereof, or a pharma- ceutically acceptable salt thereof.

3. Compound of formula (IB): [C3] [In the formula, Y is O or S; R １ , R ３ and R ４ each independently represents hydrogen, halo, cyano, -NR ａ R ｂ , -(C １－６ )-alkyl, -(C １－６)-haloalkyl, —O—(C １－６ )-alkyl or -O-(C １－６ )-haloalkyl; Ring B is phenyl or a 5- or 6-membered heterocyclyl containing 1 or 2 nitrogen ring atoms; Each R ５ are independently halo, oxo, -OH, -NR ａ R ｂ , -(C １－６ ) alkyl, -(C １－６ ) haloalkyl, -COOR ａ , -C(O)NR ａ R ｂ Or -S(O) ｐ R ｃ and R ６ is hydrogen, -(C １－６ ) alkyl, —O—(C １－６ )-alkyl or -NR ａ R ｂ and Each R ７ are independently halo, -(C １－６ ) alkyl, —O—(C １－６ ) alkyl or —O—(C １－６ )-haloalkyl; R ａ and R ｂ Each of the groups is independently hydrogen, -(C １－６ ) alkyl or -(C １－６ ) haloalkyl; R ｃ is hydrogen, -OH, -NR ａ R ｂ , -(C １－６ )-alkyl or -(C １－６ )-haloalkyl; n is 0, 1, 2 or 3; p is 0, 1 or 2; and z is 0, 1, 2 or 3.

2. The compound of claim 1, which is: or a tautomer thereof, or a pharma- ceutically acceptable salt thereof.

4. Compound of formula (IC): [C4] [In the formula, Y is O or S; R １ , R ２ and R ４ each independently represents hydrogen, halo, cyano, -NR ａ R ｂ , -(C １－６ )-alkyl, -(C １－６ )-haloalkyl, —O—(C １－６ )-alkyl or -O-(C １－６ )-haloalkyl; Ring B is phenyl or a 5- or 6-membered heterocyclyl containing 1 or 2 nitrogen ring atoms; Each R ５ are independently halo, oxo, -OH, -NR ａ R ｂ , -(C １－６ ) alkyl, -(C １－６ ) haloalkyl, -COOR ａ , -C(O)NR ａ R ｂ Or -S(O) ｐ R ｃ and R ６ is hydrogen, -(C １－６ ) alkyl, —O—(C １－６ )-alkyl or -NR ａ R ｂ and Each R ７ are independently halo, -(C １－６ ) alkyl, —O—(C １－６ ) alkyl or —O—(C １－６ )-haloalkyl; R ａ and R ｂ Each of the groups independently represents hydrogen, -(C １－６ ) alkyl or -(C １－６ ) haloalkyl; R ｃ is hydrogen, -OH, -NR ａ R ｂ , -(C １－６ )-alkyl or -(C １－６ )-haloalkyl; n is 0, 1, 2 or 3; p is 0, 1 or 2; and z is 0, 1, 2 or 3.

2. The compound of claim 1, which is: or a tautomer thereof, or a pharma- ceutically acceptable salt thereof.

5. Compound of formula (ID): [C5] [In the formula, Y is O or S; R ２ and R ４ each independently represents hydrogen, halo, cyano, -NR ａ R ｂ , -(C １－６ )-alkyl, -(C １－６ )-haloalkyl, —O—(C １－６ )-alkyl or -O-(C １－６ )-haloalkyl; Ring B is phenyl or a 5- or 6-membered heterocyclyl containing 1 or 2 nitrogen ring atoms; Each R ５ are independently halo, oxo, -OH, -NR ａ R ｂ , -(C １－６ ) alkyl, -(C １－６ ) haloalkyl, -COOR ａ , -C(O)NR ａ R ｂ Or -S(O) ｐ R ｃ and R ６ is hydrogen, -(C １－６ ) alkyl, —O—(C １－６ )-alkyl or -NR ａ R ｂ and Each R ７ are independently halo, -(C １－６ ) alkyl, —O—(C １－６ ) alkyl or —O—(C １－６ )-haloalkyl; R ａ and R ｂ Each of the groups is independently hydrogen, -(C １－６ ) alkyl or -(C １－６ ) haloalkyl; R ｃ is hydrogen, -OH, -NR ａ R ｂ , -(C １－６ )-alkyl or -(C １－６ )-haloalkyl; n is 0, 1, 2 or 3; p is 0, 1 or 2; and z is 0, 1, 2 or 3.

2. The compound of claim 1, which is: or a tautomer thereof, or a pharma- ceutically acceptable salt thereof.

6. Compound of formula (IE): [C6] [In the formula, Y is O or S; R ２ and R ３ each independently represents hydrogen, halo, cyano, -NR ａ R ｂ , -(C １－６ )-alkyl, -(C １－６ )-haloalkyl, —O—(C １－６ )-alkyl or -O-(C １－６ )-haloalkyl; Ring B is phenyl or a 5- or 6-membered heterocyclyl containing 1 or 2 nitrogen ring atoms; Each R ５ are independently halo, oxo, -OH, -NR ａ R ｂ , -(C １－６ ) alkyl, -(C １－６ ) haloalkyl, -COOR ａ , -C(O)NR ａ R ｂ Or -S(O) ｐ R ｃ and R ６is hydrogen, -(C １－６ ) alkyl, —O—(C １－６ )-alkyl or -NR ａ R ｂ and Each R ７ are independently halo, -(C １－６ ) alkyl, —O—(C １－６ ) alkyl or —O—(C １－６ )-haloalkyl; R ａ and R ｂ Each of the groups is independently hydrogen, -(C １－６ ) alkyl or -(C １－６ ) haloalkyl; R ｃ is hydrogen, -OH, -NR ａ R ｂ , -(C １－６ )-alkyl or -(C １－６ )-haloalkyl; n is 0, 1, 2 or 3; p is 0, 1 or 2; and z is 0, 1, 2 or 3.

2. The compound of claim 1, which is: or a tautomer thereof, or a pharma- ceutically acceptable salt thereof.

7. The compound according to any one of claims 1 to 6, wherein Y is O.

8. The following groups: [C7] but [C8] The compound according to any one of claims 1 to 7,

9. R ６ Ga-CH ３ , -CH ２ CH ３ or -CH(CH ３ ) ２ The compound according to any one of claims 1 to 8,

10. The following groups: [C9] but [C10] The compound according to any one of claims 1 to 9,

11. The following compound: 1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydropyrido[3,2-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[3,4-d]pyrimidin-4(1H)-one; 1-(2-ethyl-3,4-difluorophenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one; 1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydropyrimido[4,5-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[3,4-d]pyrimidin-4(1H)-one; 1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydropyrido[4,3-d]pyrimidin-4(1H)-one; 1-(4-fluoro-2-isopropylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one; 1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-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[3,2-d]pyrimidin-4(1H)-one; 1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydropyrido[3,4-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[3,4-d]pyrimidin-4(1H)-one; 1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydropteridin-4(1H)-one; 1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropteridin-4(1H)-one; 6-chloro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one; 1-(2-methyl-4-(trifluoromethoxy)phenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one; 1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-1,2,3,4-tetrahydropyrido[3,4-d]pyrimidine-6-carbonitrile; 7-chloro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydropyrido[4,3-d]pyrimidin-4(1H)-one; 1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidine-7-carbonitrile; 1-(2-ethyl-4-fluorophenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydropyrido[4,3-d]pyrimidin-4(1H)-one; 3-(5-fluoro-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-methyl-4-(trifluoromethoxy)phenyl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one; 3-(5-fluoro-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one; and 3-Methyl-4-(1-(2-methyl-4-(trifluoromethoxy)phenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridine 1-oxide or a tautomer thereof, or a pharma- ceutically acceptable salt thereof.

12. 12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11, or a tautomer thereof, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

13. 13. A pharmaceutical composition according to claim 12 for use in therapy.

14. The pharmaceutical composition of claim 12 for use in the treatment of a Na v 1.8 mediated disease, disorder or condition.

15. The pharmaceutical composition of claim 12 for use in inhibiting a voltage-gated sodium channel, wherein the voltage-gated sodium channel is Na v 1.8.

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