Nitrogen-containing 2,3-dihydroquinazolinone compounds as NAV1.8 inhibitors

Abstract

Compounds of formula (I) are described, wherein each variable group is as defined in the specification. Pharmaceutical compositions containing compounds of formula (I) are also described, as well as the use of these compounds and pharmaceutical compositions to inhibit Na+. v 1.8 Voltage-gated sodium channels and treatment of Na+ v 1.8 Use in mediating diseases, disorders and conditions (e.g., pain and pain-related diseases, disorders and conditions, and cardiovascular diseases, disorders and conditions, such as atrial fibrillation).

Description

Technical Field

[0001] This invention relates to Na v 1.8 Inhibitor compounds or their pharmaceutically acceptable salt or tautomer forms, corresponding pharmaceutical compositions or formulations, methods or processes for preparing the compounds, methods for treating pain and pain-related disorders, impairments and conditions, and cardiovascular diseases, disorders and conditions, compounds, uses and / or combination therapies. Background Technology

[0002] Pain is a protective mechanism for animals to avoid potential tissue damage; however, there are many disease indications in which pain exceeds its usefulness and becomes an ineffective burden. Indications where pain exceeds its usefulness can be broadly classified into those induced by nerve damage or injury (neuralgic pain), those sensitized by inflammatory responses or metabolic disorders (inflammatory pain), and those where injury or surgery leads to a short-term increase in pain response (postoperative / spontaneous pain).

[0003] Voltage-gated sodium channels form the basis of electrical signal transduction in all excitable tissues by setting a threshold and raising the potential action potential. There are nine different subtypes of voltage-gated sodium channels, named Na... v 1.1, Na v 1.7, Na v 1.8 and Na v Those of 1.9 are primarily expressed in the peripheral nerves, where they control neuronal excitability. Na v 1.5 is the main sodium channel isoform expressed in cardiomyocytes, Na v 1.4 It is expressed and functions in skeletal muscle, while Na v 1.1, Na v 1.2, Na v 1.3 and Na v 1.6 These nine voltage-gated sodium channels are widely expressed in the central nervous system (CNS) and to some extent in the peripheral nervous system. While their primary functions are similar—controlling sodium inflow into cells—their different biophysical properties significantly influence the physiological characteristics of their respective cell types (Catterall, 2012).

[0004] Currently, non-selective sodium channel inhibitors are used clinically as antiarrhythmic and antiepileptic therapies; these include lidocaine, carbamazepine, amitriptyline, and mexiletine. However, because these agents exhibit a lack of selectivity among different sodium channel subtypes, their therapeutic efficacy is significantly reduced due to adverse side effects mediated primarily by their activity in the CNS and heart. This has spurred efforts to develop novel drugs that are selective against specific sodium channel subtypes 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) and is highly expressed in small-diameter neurons of this tissue that form pain-sensing C- and Aδ-neurons (Abrahamsen, 2008; Amaya, 2000; Novakocic, 1998). Due to its prominent physiological role in this tissue type and restricted expression profile, the channel was proposed as a therapeutic target for analgesia when it was initially cloned from rat DRG (Akopian, 1996). Subsequently, Na+ was identified, cloned, and characterized from human DRG tissue. v 1.8 (Rabart 1998). Na v The closest related molecule to 1.8 is Na. v 1.5, which share approximately 60% sequence homology. Na v 1.8 Formerly known as SNS (sensory neuron sodium channel), PN3 (peripheral neuron sodium channel type 3), and also described as a TTX-resistant sodium channel due to its characteristic pharmacological properties in resistance to tetrodotoxin blockade.

[0006] Na v 1.8 Support for 1.8 as a therapeutic target for pain indications comes from several sources. Na v 1.8 has been shown to conduct most of the current during the action potential rise in DRG neurons (Blair & Bean, 2002), and is also crucial for the re-firing capacity of these neurons due to its re-fire rate (Blair and Bean, 2003). Na has been reported... v Increased expression and function of Nav1.8 are responses to painful stimuli such as inflammatory mediators (England 1996 & Gold 1996), nerve damage (Roza 2003 & Ruangsri 2011), and painful neuromas (Black 2008 & Coward 2000). Knockout of the gene encoding Nav1.8 in mice resulted in a reduced pain phenotype, particularly in response to inflammatory attacks (Akopian 1999). v Knockout of 1.8 mRNA also led to a reduction in the pain phenotype in rodent models, particularly neuropathic models (Lai 2002). Pharmacological intervention via selective small molecule inhibitors has demonstrated efficacy in rodent models of inflammatory and neuropathic pain (Jarvis 2007 & Payne 2015). vSupportive genetic evidence for 1.8 also exists in patients with chronic neuropathic pain, where multiple increases in functional mutations have been reported as causes of paroxysmal painful neuropathy and small fiber neuropathy (Faber 2012, Han 2014 & Eijkenboom 2018). Invention Overview

[0008] Therefore, there is a need to develop new compounds, particularly Na for the treatment of pain and pain-related disorders, impairments and conditions, as well as cardiovascular diseases, disorders and conditions. v 1.8 Inhibitor compounds. This invention provides compounds containing Na... v 1.8 Inhibitory compounds and their use in the treatment of pain and pain-related diseases, disorders and conditions, as well as cardiovascular diseases, disorders and conditions, to meet this need.

[0009] In one aspect, the present invention relates to compounds of formula (I) or their tautomers, or pharmaceutically acceptable salts thereof:

[0010]

[0011] in:

[0012] Y is either O or S;

[0013] X 1 For nitrogen or CR 1 ,

[0014] X 2 For nitrogen or CR 2 ,

[0015] X 3 For nitrogen or CR 3 ,and

[0016] X 4 For nitrogen or CR 4 ,

[0017] The condition is X 2 X 3 and X 4 At least one of them is nitrogen;

[0018] R 1 R 2 R 3 and R 4 Each is independently hydrogen, halogen, cyano, -NR a R b -(C 1-6 )-alkyl, -(C 1-6 -Haloalkyl, -O-(C 1-6 -alkyl or -O-(C 1-6)-Haloalkyl;

[0019] Ring B is a phenyl group or a 5- or 6-membered heterocyclic group containing one or two nitrogen ring atoms;

[0020] Each R 5 Independently halogenated, 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 ;

[0021] R 6 For hydrogen, -(C 1-6 )alkyl, -O-(C 1-6 -alkyl or -NR a R b ;

[0022] Each R 7 Independently halogen, -(C 1-6 )alkyl, -O-(C 1-6 )alkyl or -O-(C 1-6 )-Haloalkyl;

[0023] Each R a and R b Independently hydrogen, -(C 1-6 )alkyl or -(C 1-6 ) Haloalkyl;

[0024] R c For hydrogen, -OH, -NR a R b -(C 1-6 )-alkyl or -(C 1-6 )-Haloalkyl;

[0025] n is 0, 1, 2, or 3;

[0026] p is 0, 1, or 2; and

[0027] z can be 0, 1, 2, or 3.

[0028] In one aspect, the present invention relates to pharmaceutical compositions comprising a compound as defined herein or a tautomer thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0029] In one aspect, the present invention relates to inhibiting Na in subjects who require this. v1.8 A method for a voltage-gated sodium channel, the method comprising administering to a subject a compound as defined herein, a tautomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0030] In one aspect, the present invention relates to a method of treating pain or pain-related diseases, disorders or conditions in a subject in need of such treatment, the method 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.

[0031] In one aspect, the present invention relates to a method of treating atrial fibrillation in a subject in need of it, the method 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.

[0032] In one aspect, the present invention relates to compounds, tautomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as defined herein, for the treatment of pain or pain-related diseases, disorders, or conditions.

[0033] In one aspect, the present invention relates to compounds as defined herein or their tautomers or pharmaceutically acceptable salts or pharmaceutical compositions as defined herein for the treatment of atrial fibrillation.

[0034] In one aspect, the present invention relates to the use of compounds as defined herein, their tautomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as defined herein, in the preparation of medicaments for treating pain or pain-related diseases, disorders, or conditions.

[0035] In one aspect, the present invention relates to the use of compounds as defined herein or their tautomers or pharmaceutically acceptable salts, or pharmaceutical compositions as defined herein, in the preparation of a medicament for the treatment of atrial fibrillation.

[0036] In one aspect, the present invention relates to compounds as defined herein or their tautomers or pharmaceutically acceptable salts or pharmaceutical compositions as defined herein for therapeutic purposes. Attached Figure Description

[0037] Figure 1 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-dihydropyridino[3,4-d]pyrimidin-4(1H)-one (form 1) is shown.

[0038] Figure 2The DSC of 1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyridino[3,4-d]pyrimidin-4(1H)-one (form 1) is shown.

[0039] Figure 3 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) is shown.

[0040] Figure 4 The DSC of 1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyridino[3,4-d]pyrimidin-4(1H)-one (form 2) is shown.

[0041] Figure 5 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-dihydropyridino[3,4-d]pyrimidin-4(1H)-one (form 3) is shown.

[0042] Figure 6 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-dihydropyridino[3,4-d]pyrimidin-4(1H)-one (form 4) is shown.

[0043] Figure 7 The DSC of 1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyridino[3,4-d]pyrimidin-4(1H)-one (form 4) is shown. Invention Details

[0045] Various publications, articles, and patents are referenced or described in the background and throughout the specification. Discussions of documents, actions, materials, devices, articles, etc., already included in this specification are for the purpose of providing context for the disclosure. Such discussions do not acknowledge that any or all of these matters constitute part of the prior art relating to this disclosure.

[0046] 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 pertains. Otherwise, certain terms used herein have the meanings specified in the specification.

[0047] It should be noted that, as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural references unless the context clearly specifies otherwise.

[0048] As used herein, the conjunction “and / or” between multiple cited elements is understood to include both individual and combined options. For example, when two elements are connected by “and / or”, the first option is to apply the first element without the second element. The second option is to apply the second element without the first element. The third option is to apply the first and second elements together. Any of these options is understood to fall within this meaning and thus satisfy the requirement of the term “and / or” as used herein. The simultaneous application of multiple options is also understood to fall within this meaning and thus satisfy the requirement of the term “and / or”.

[0049] Unless otherwise stated, any numerical value (such as concentrations or concentration ranges as described herein) should be understood to be modified by the term “about” in all cases. Therefore, numerical values ​​typically include ±10% of the referenced value. For example, the enumeration of “10-fold” includes 9-fold and 11-fold. As used herein, the use of numerical ranges explicitly includes all possible subranges, all individual numerical values ​​within that range (including integers and fractions of such values), unless the context clearly indicates otherwise.

[0050] This invention relates to Na of formula (I). v 1.8 An inhibitory compound or its pharmaceutically acceptable salt or tautomer form, the corresponding pharmaceutical composition, a method or process for preparing the compound, for the treatment of sodium-induced nausea and vomiting. v 1.8 Methods and compounds for treating Na-mediated diseases, disorders, and conditions (e.g., pain and / or pain-related diseases, disorders, or conditions, and atrial fibrillation, respectively). v 1.8 Use for mediating diseases, disorders, and conditions (e.g., pain and / or pain-related diseases, disorders, or conditions and atrial fibrillation, respectively) and / or for the treatment of Na v 1.8 Combined therapy for mediated diseases, disorders and conditions (e.g., pain and / or pain-related diseases, disorders or conditions and atrial fibrillation, respectively).

[0051] The definitions of various groups and substituents provided throughout this specification for any of the formulas disclosed herein or their pharmaceutically acceptable salts and / or corresponding tautomer forms are intended to individually and specifically describe each class of compounds disclosed herein, as well as groups of one or more classes of compounds.

[0052] As used herein, the term alkali metals are intended to refer to Group I elements, including but not limited to lithium (Li), sodium (Na), or potassium (K). The term alkaline earth metals may include, but are not limited to, calcium (Ca) or magnesium (Mg).

[0053] As used herein, the terms "alkyl" or "straight-chain or branched alkyl," etc., refer to a saturated, straight-chain or branched hydrocarbon moiety. Exemplary alkyl groups 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), etc. Alkyl groups may have a specific number of carbon atoms. When a number appears in a subscript following the symbol "C," the subscript more specifically defines the number of carbon atoms that a particular alkyl group may contain. For example, the terms "C1-C6" and "C 1-6 "" refers to alkyl groups containing 1 to 6 carbon atoms, and the terms "C1-C4" and "C" are used interchangeably. 1-4 "" refers to alkyl groups containing 1 to 4 carbon atoms.

[0054] When the term "alkyl" is used in combination with other substituents (such as "halogenated alkyl" or "hydroxyalkyl"), the term "alkyl" is intended to include divalent saturated straight-chain or branched hydrocarbon groups.

[0055] For example, the terms "haloalkyl" or "straight-chain or branched haloalkyl" are intended to denote a saturated, straight-chain or branched hydrocarbon moiety substituted with one or more halogens, wherein the halogens are independently selected from fluorine, chlorine, bromine, and iodine. Haloalkyl may have a specific number of carbon atoms. For example, the terms "(C1-C6)haloalkyl" and "(C6)haloalkyl" are used interchangeably. 1-6 "(C) haloalkyl" refers to a saturated straight-chain or branched haloalkyl group having at least one and at most six carbon atoms. Similarly, the term "(C) haloalkyl"... 1- C4) haloalkyl" and "(C 1-4 "Halogenated alkyl" refers to a saturated straight-chain or branched halogenated alkyl group having 1 to 4 carbon atoms. "Fluorinated alkyl" or "fluoroalkyl" specifically refers to any alkyl group as defined above that is substituted with at least one fluorine atom (e.g., one to three fluorine atoms, such as one, two, or three fluorine atoms). Representative halogenated alkyl groups include, but are not limited to, trifluoromethyl (-CF3), tetrafluoroethyl (-CF2CHF2), pentafluoroethyl (-CF2CF3), etc.

[0056] The term "hydroxyalkyl" refers to a saturated, straight-chain, or branched hydrocarbon moiety that is substituted with one or more hydroxyl groups.

[0057] As used herein, the terms “halogen” and “halogenated” refer to fluorine (-F), chlorine (-Cl), bromine (-Br), and iodine (-I).

[0058] The term "hydroxyl" or "hydroxyl" is intended to refer to the group -OH.

[0059] “Oxylated” refers to the oxygen moiety of a double bond; for example, if it is directly attached to a carbon atom to form a carbonyl moiety (C=O), or attached to N or S to form an oxide, such as an N-oxide, sulfone, or sulfoxide.

[0060] The term "cyano" refers to -CN.

[0061] The term "amino" refers to -NH2. One or more hydrogen atoms of an amino group can be replaced by substituents such as alkyl groups, resulting in an "alkylamino". In an alkylamino, one or two hydrogen atoms of the amino group are replaced by an alkyl group and are attached to the parent molecule via a bond on the nitrogen atom of the alkylamino group. Examples of alkylamino groups include methylamino (-NHCH3), dimethylamino (-N(CH3)2), NHCH2CH3, etc.

[0062] "Alkoxy" refers to a group containing an alkyl group linked by an oxygen atom, wherein the alkyl group is as defined above. Alkoxy groups may have a specified number of carbon atoms. For example, the terms "(C1-C6)alkoxy" and "(C6)alkoxy" are used interchangeably. 1-6 "(C)alkoxy" refers to an alkyl group having at least one and at most six carbon atoms linked by oxygen atoms. Similarly, the term "(C)alkoxy" refers to an alkyl group having at least one and at most six carbon atoms linked by oxygen atoms. 1- C4)alkoxy" and "(C 1-4 "Alkoxy" refers to an alkyl group having at least one and at most four carbon atoms connected by an oxygen atom. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, and tert-butoxy.

[0063] "Haloalkoxy" refers to an alkoxy group in which the alkyl portion is replaced by one or more halogens, wherein the halogens are independently selected from fluorine, chlorine, bromine, and iodine. Haloalkoxy groups may have a specified number of carbon atoms. For example, the term "(C1-C6)haloalkoxy" refers to a haloalkyl group having 1 to 6 carbon atoms linked by oxygen atoms. Representative haloalkoxy groups include, but are not limited to, difluoromethoxy (-OCHCF2), trifluoromethoxy (-OCF3), tetrafluoroethoxy (-OCF2CHF2), etc.

[0064] "Aryl" represents an aromatic hydrocarbon ring. An aryl group is a monocyclic, bicyclic, or tricyclic ring system having a total of five to fourteen ring member atoms, wherein at least one ring system is aromatic, and each ring in the system contains three to seven member atoms, such as phenyl, naphthalene, and tetrahydronaphthalene. Suitably, the aryl group is phenyl.

[0065] "Heteroatoms" are defined as oxygen, nitrogen, sulfur, etc. More specifically, "heteroatoms" refers to nitrogen, sulfur, or oxygen atoms.

[0066] "Heterocyclic group" includes heteroaryl and heterocyclic alkyl groups. Heterocyclic groups can be unsaturated or saturated. Unless otherwise specified, monocyclic heterocyclic groups have 3 to 7 ring atoms and contain up to 4 heteroatoms. Monocyclic or fused heterocyclic groups include substituted aromatic and non-aromatic groups.

[0067] "Heterocyclic alkyl" refers to a group or portion comprising a non-aromatic monovalent monocyclic or bicyclic group that is saturated or partially unsaturated. Unless otherwise specified, a heterocyclic alkyl contains 3 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. Typically, in the compounds of this invention, the heterocyclic alkyl is a 5-membered and / or 6-membered heterocyclic alkyl.

[0068] "Heteroaryl" means a group or portion comprising an aromatic monovalent monocyclic or bicyclic group. Unless otherwise stated, a heteroaryl contains 4 to 10 ring atoms, suitably 5 to 10 ring atoms, and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which may be unsubstituted or substituted by one or more specified substituents. "Heteroaryl" also includes bicyclic heterocyclic-aryl compounds containing an aryl ring moiety fused to a heterocyclic alkyl ring moiety, containing 4 to 10 ring atoms, suitably 5 to 10 ring atoms, and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which may be unsubstituted or substituted by one or more substituents as defined herein. Heteroaryl groups include, but are not limited to: benzimidazolyl, benzothiazolyl, benzothiophene, benzopyrazinyl, benzotriazolyl, benzotriazinyl, benzo[1,4]dioxane, benzofuranyl, 9H-α-carbolinyl, cenolinyl, furanyl, pyrazolyl, imidazolyl, indazinyl, naphthidyl, oxazolyl, oxadiazolyl, phthalazinyl, pyridyl (or pyridinyl), pyrroleyl, purinyl, pteridinyl, phenazinyl, and pyrazinyl. Pyrazolopyrimidyl, pyrazolopyrimidyl, pyrrolizinyl, pyrimidyl, isothiazolyl, furazonyl, pyrimidinyl, tetrazinyl, isoxazolyl, quinoxolinyl, quinazolinyl, quinolinyl, quinazinyl, thienyl, thiophenyl, triazolyl, triazinyl, tetrazolopyrimidyl, triazolopyrimidyl, tetrazolyl, thiazolyl, and thiazolylalkyl.

[0069] The heteroaryl groups present in the compounds of this invention are typically 5-membered and / or 6-membered monocyclic heteroaryl groups containing one or two nitrogen ring atoms. Exemplary 5-membered 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, pyrroleyl, imidazoleyl, pyrazolyl, etc.

[0070] In one embodiment, the heteroaryl group is a pyridyl group optionally substituted with one or more defined substituents (such as oxo, halogen, alkyl, etc.). For example, the pyridyl group may be oxosubstituted to form a pyridone ring moiety, which may include, but is not limited to, -3-pyridone, -4-pyridone, -5-pyridone, etc. The heteroaryl group also includes oxosubstituted pyridazinyl, pyrimidinyl, and pyrazinyl groups, including, but not limited to, those moiety shown below, which may optionally be substituted with one or more additionally specified substituents: .

[0071] According to conventions used in this field: the structural formula in this article uses... A bond used to describe the connection point between a group, part or substituent and the core, skeleton or parent molecule.

[0072] When the bond attached to a substituent crosses with the bond between two atoms in the ring, the substituent can bond to any atom in the ring.

[0073] As used herein, the term "compound of the invention" means any compound of any kind disclosed herein, in any form, i.e., any salt or non-salt form (e.g., as a free acid or base, or as a pharmaceutically acceptable salt), any tautomer form, and any physical form (e.g., including non-solid forms (e.g., liquid or semi-solid forms) and solid forms (e.g., amorphous or crystalline forms, specific polymorphic forms, solvates, including hydrates (e.g., monohydrates, dihydrates, and hemihydrates)), and mixtures of various forms.

[0074] 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 by one or more substituents as defined herein throughout. The term "substituted" as used herein for a group (e.g., alkyl, etc.) means that at least one hydrogen atom is substituted by a non-hydrogen group, provided that all normal valences are maintained and the substitution produces a stable compound. Where the group may be chosen from a number of substituents, the selected groups may be the same or different. For example, various substituents of the compound formula as defined herein may be optionally substituted, but are not limited to substituents such as halogen, cyano, amino, alkyl, haloalkyl, alkoxy, etc.

[0075] The term “independently” used in relation to substituents or heteroatoms means that when more than one substituent or heteroatom is selected from a number of possible substituents or heteroatoms, those substituents or heteroatoms may be the same or different.

[0076] compound

[0077] In particular, the present invention relates to novel Na having any of the forms disclosed herein. v 1.8 Inhibitor compounds or their pharmaceutically acceptable salts and / or corresponding tautomer forms.

[0078] In one aspect, the present invention relates to compounds of formula (I) or their tautomers, or pharmaceutically acceptable salts thereof:

[0079]

[0080] in:

[0081] Y is either O or S;

[0082] X 1 For nitrogen or CR1 ,

[0083] X 2 For nitrogen or CR 2 ,

[0084] X 3 For nitrogen or CR 3 ,and

[0085] X 4 For nitrogen or CR 4 ,

[0086] The condition is X 2 X 3 and X 4 At least one of them is nitrogen;

[0087] R 1 R 2 R 3 and R 4 Each is independently hydrogen, halogen, cyano, -NR a R b -(C 1-6 )-alkyl, -(C 1-6 -Haloalkyl, -O-(C 1-6 -alkyl or -O-(C 1-6 )-Haloalkyl;

[0088] Ring B is a phenyl group or a 5- or 6-membered heterocyclic group containing one or two nitrogen ring atoms;

[0089] Each R 5 Independently halogenated, 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 ;

[0090] R 6 For hydrogen, -(C 1-6 )alkyl, -O-(C 1-6 -alkyl or -NR a R b ;

[0091] Each R 7 Independently halogen, -(C 1-6 )alkyl, -O-(C 1-6 )alkyl or -O-(C 1-6 )-Haloalkyl;

[0092] Each R a and R b Independently hydrogen, -(C 1-6 )alkyl or -(C 1-6 ) Haloalkyl;

[0093] R c For hydrogen, -OH, -NR a R b -(C 1-6 )-alkyl or -(C 1-6 )-Haloalkyl;

[0094] n is 0, 1, 2, or 3;

[0095] p is 0, 1, or 2; and

[0096] z can be 0, 1, 2, or 3.

[0097] In embodiments of a compound of formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof:

[0098] Y is either O or S;

[0099] X 1 For nitrogen or CR 1 ,

[0100] X 2 For nitrogen or CR 2 ,

[0101] X 3 For nitrogen or CR 3 ,and

[0102] X 4 For nitrogen or CR 4 ,

[0103] The condition is X 2 X 3 and X 4 At least one of them is nitrogen;

[0104] R 1 R 2 R 3 and R 4 Each is independently hydrogen, halogen, cyano, -(C 1-6 )-alkyl, -(C 1-6 -Haloalkyl, -O-(C 1-6 -alkyl or -O-(C 1-6 )-Haloalkyl;

[0105] Ring B is a 5- or 6-membered heteroaryl group containing one or two nitrogen ring atoms;

[0106] Each R 5 Independently selected from halogen, oxo, -OH, -NR a R b or -(C 1-6 )alkyl;

[0107] R 6 For -(C 1-6 )alkyl;

[0108] Each R 7 Independently halogen, -(C 1-6 )alkyl, -O-(C 1-6 )alkyl or -O-(C 1-6 )-Haloalkyl; each R a and R b Independently hydrogen, -(C 1-6 )alkyl or -(C 1-6 ) Haloalkyl;

[0109] n is 0, 1, 2, or 3; and

[0110] z can be 0, 1, 2, or 3.

[0111] In embodiments of the compound of formula (I), or its tautomers, or its pharmaceutically acceptable salts, Y is O.

[0112] In embodiments of the compound of formula (I), or its tautomers, or its pharmaceutically acceptable salts, Y is S.

[0113] In an embodiment of a compound of formula (I), or its tautomer, or its pharmaceutically acceptable salt, X 1 It is nitrogen.

[0114] In an embodiment of a compound of formula (I), or its tautomer, or its pharmaceutically acceptable salt, X 2 It is nitrogen.

[0115] In an embodiment of a compound of formula (I), or its tautomer, or its pharmaceutically acceptable salt, X 3 It is nitrogen.

[0116] In an embodiment of a compound of formula (I), or its tautomer, or its pharmaceutically acceptable salt, X 4 It is nitrogen.

[0117] In an embodiment of a compound of formula (I), or its tautomer, or its pharmaceutically acceptable salt, X 1 For CR 1 .

[0118] In an embodiment of a compound of formula (I), or its tautomer, or its pharmaceutically acceptable salt, X 2 For CR 2 .

[0119] In an embodiment of a compound of formula (I), or its tautomer, or its pharmaceutically acceptable salt, X 3 For CR 3 .

[0120] In an embodiment of a compound of formula (I), or its tautomer, or its pharmaceutically acceptable salt, X 4 For CR 4 .

[0121] In an embodiment of a compound of formula (I), or its tautomer, or its pharmaceutically acceptable salt, X 2 X 3 and X 4 At least one of them is nitrogen, and X 1 X 2 X 3 and X 4 No more than two of them are nitrogen.

[0122] In an embodiment of a compound of formula (I), or its tautomer, or its pharmaceutically acceptable salt, X 1 For CR 1 And R 1 Hydrogen, halogen, cyano, -NR a R b -(C 1-6 )-alkyl, -(C 1-6 -Haloalkyl, -O-(C 1-6 -alkyl or -O-(C 1-6 )-Halogenated alkyl group.

[0123] In an embodiment of a compound of formula (I), or its tautomer, or its pharmaceutically acceptable salt, X 1 For CR 1 And R 1 It is hydrogen, halogen, cyano or -(C 1-6 )-Halogenated alkyl group.

[0124] In an embodiment of a compound of formula (I), or its tautomer, or its pharmaceutically acceptable salt, X 1 For CR 1 And R 1 For hydrogen.

[0125] In an embodiment of a compound of formula (I), or its tautomer, or its pharmaceutically acceptable salt, X 2 For CR2 And R 2 Hydrogen, halogen, cyano, -NR a R b -(C 1-6 )-alkyl, -(C 1-6 -Haloalkyl, -O-(C 1-6 -alkyl or -O-(C 1-6 )-Halogenated alkyl group.

[0126] In an embodiment of a compound of formula (I), or its tautomer, or its pharmaceutically acceptable salt, X 2 For CR 2 And R 2 It is hydrogen, halogen, cyano or -(C 1-6 )-Halogenated alkyl group.

[0127] In an embodiment of a compound of formula (I), or its tautomer, or its pharmaceutically acceptable salt, X 2 For CR 2 And R 2 It can be hydrogen, -CF3, -Cl, or cyano.

[0128] In an embodiment of a compound of formula (I), or its tautomer, or its pharmaceutically acceptable salt, X 3 For CR 3 And R 3 Hydrogen, halogen, cyano, -NR a R b -(C 1-6 )-alkyl, -(C 1-6 -Haloalkyl, -O-(C 1-6 -alkyl or -O-(C 1-6 )-Halogenated alkyl group.

[0129] In an embodiment of a compound of formula (I), or its tautomer, or its pharmaceutically acceptable salt, X 3 For CR 3 And R 3 It is hydrogen, halogen, cyano or -(C 1-6 )-Halogenated alkyl group.

[0130] In an embodiment of a compound of formula (I), or its tautomer, or its pharmaceutically acceptable salt, X 3 For CR 3 And R 3 It can be hydrogen, -CF3, -Cl, or cyano.

[0131] In an embodiment of a compound of formula (I), or its tautomer, or its pharmaceutically acceptable salt, X 4 For CR4 And R 4 Hydrogen, halogen, cyano, -NR a R b -(C 1-6 )-alkyl, -(C 1-6 -Haloalkyl, -O-(C 1-6 -alkyl or -O-(C 1-6 )-Halogenated alkyl group.

[0132] In an embodiment of a compound of formula (I), or its tautomer, or its pharmaceutically acceptable salt, X 4 For CR 4 And R 4 It is hydrogen, halogen, cyano or -(C 1-6 )-Halogenated alkyl group.

[0133] In an embodiment of a compound of formula (I), or its tautomer, or its pharmaceutically acceptable salt, X 4 For CR 4 And R 4 For hydrogen.

[0134] In an embodiment of a compound of formula (I), or its tautomer, or its pharmaceutically acceptable salt, X 1 For CR 1 X 2 For CR 2 X 3 For CR 3 And X 4 It is nitrogen.

[0135] In an embodiment of a compound of formula (I), or its tautomer, or its pharmaceutically acceptable salt, X 1 For CR 1 X 2 For nitrogen, X 3 For CR 3 And X 4 For CR 4 .

[0136] In an embodiment of a compound of formula (I), or its tautomer, or its pharmaceutically acceptable salt, X 1 For CR 1 X 2 For CR 2 X 3 It is nitrogen, and X 4 For CR 4 .

[0137] In an embodiment of a compound of formula (I), or its tautomer, or its pharmaceutically acceptable salt, X 1For nitrogen, X 2 For CR 2 X 3 It is nitrogen, and X 4 For CR 4 .

[0138] In an embodiment of a compound of formula (I), or its tautomer, or its pharmaceutically acceptable salt, X 1 For nitrogen, X 2 For CR 2 X 3 For CR 3 And X 4 It is nitrogen.

[0139] In embodiments of the compound of formula (I), or its tautomers, or its pharmaceutically acceptable salts, ring B is phenyl.

[0140] In embodiments of the compound of formula (I), or its tautomers, or its pharmaceutically acceptable salts, ring B is a 5- or 6-membered heterocyclic group containing one or two nitrogen ring atoms.

[0141] In embodiments of the compound of formula (I), or its tautomers, or its pharmaceutically acceptable salts, ring B is a 5- or 6-membered heteroaryl group containing one or two nitrogen ring atoms.

[0142] In embodiments of the compound of formula (I), or its tautomers, or its pharmaceutically acceptable salts, ring B is a 5- or 6-membered heterocyclic alkyl group containing one or two nitrogen ring atoms.

[0143] In embodiments of a compound of formula (I), or its tautomers, or its pharmaceutically acceptable salts, each R 5 Independently halogenated, oxo-, -OH, -NR a R b or -(C 1-6 )alkyl.

[0144] In embodiments of the compound of formula (I), or its tautomers, or its pharmaceutically acceptable salts, ring B is a 5- or 6-membered heteroaryl group containing one or two nitrogen ring atoms; and each R 5 Independently halogenated, oxo-, -OH, -NR a R b -(C 1-6 )alkyl or -(C 1-6 ) Haloalkyl.

[0145] In embodiments of compounds of formula (I), or their tautomers, or pharmaceutically acceptable salts thereof, ring B is pyridinyl; and each R 5 Independently halogenated, oxo-, -OH, -NRa R b or -(C 1-6 )alkyl.

[0146] In embodiments of compounds of formula (I), or their tautomers, or pharmaceutically acceptable salts thereof, ring B is pyridinyl; and each R 5 Independently oxidized or -(C 1-6 )alkyl.

[0147] In embodiments of compounds of formula (I), or their tautomers, or pharmaceutically acceptable salts thereof, ring B is pyridinyl; and each R 5 It can be independently oxo, -F, -Cl, -NH2 or -CH3.

[0148] In embodiments of compounds of formula (I), or their tautomers, or pharmaceutically acceptable salts thereof, ring B is pyridinyl; and each R 5 It can be independently oxo, -F, -NH2, or -CH3.

[0149] In embodiments of compounds of formula (I), or their tautomers, or pharmaceutically acceptable salts thereof, ring B is pyridinyl; and each R 5 It can be oxidized, -F, or -CH3 independently.

[0150] In embodiments of compounds of formula (I), or their tautomers, or pharmaceutically acceptable salts thereof, ring B is pyridinyl; and each R 5 It can be oxidized or -CH3 independently.

[0151] In embodiments of compounds of formula (I), or their tautomers, or pharmaceutically acceptable salts thereof, ring B is a pyrazolyl group; and each R 5 Independently halogenated, oxo-, -OH, -NR a R b or -(C 1-6 )alkyl.

[0152] In embodiments of compounds of formula (I), or their tautomers, or pharmaceutically acceptable salts thereof, ring B is a pyrazolyl group; and each R 5 Independently for -(C 1-6 )alkyl.

[0153] In embodiments of compounds of formula (I), or their tautomers, or pharmaceutically acceptable salts thereof, ring B is a pyrazolyl group; and each R 5 Independently -CH3.

[0154] In embodiments of the compound of formula (I), or its tautomers, or its pharmaceutically acceptable salts, z is 1, 2, or 3, and each R5 It can be -CH3, -F, -Cl, oxo, or -NH2 independently.

[0155] In embodiments of the compound of formula (I), or its tautomers, or its pharmaceutically acceptable salts, for:

[0156]

[0157] In embodiments of the compound of formula (I), or its tautomers, or its pharmaceutically acceptable salts, for:

[0158] In embodiments of the compound of formula (I), or its tautomers, or its pharmaceutically acceptable salts, for:

[0159] In an embodiment of a compound of formula (I), or its tautomer, or its pharmaceutically acceptable salt, R 6 For hydrogen.

[0160] In an embodiment of a compound of formula (I), or its tautomer, or its pharmaceutically acceptable salt, R 6 For -(C 1-6 )alkyl.

[0161] In an embodiment of a compound of formula (I), or its tautomer, or its pharmaceutically acceptable salt, R 6 It can be -CH3, -CH2CH3 or -CH(CH3)2.

[0162] In an embodiment of a compound of formula (I), or its tautomer, or its pharmaceutically acceptable salt, R 6 It is -CH3.

[0163] In an embodiment of a compound of formula (I), or its tautomer, or its pharmaceutically acceptable salt, R 6 For -NR a R b .

[0164] In an embodiment of a compound of formula (I), or its tautomer, or its pharmaceutically acceptable salt, R 6 It is -NH2.

[0165] In embodiments of a compound of formula (I), or its tautomers, or its pharmaceutically acceptable salts, each R 7 Independently halogenated or -O(C) 1-6 ) Haloalkyl.

[0166] In embodiments of a compound of formula (I), or its tautomers, or its pharmaceutically acceptable salts, each R 7 Independently -F or -OCF3.

[0167] In embodiments of a compound of formula (I), or its tautomers, or its pharmaceutically acceptable salts, n is 1 or 2; and each R 7 Independently -F or -OCF3.

[0168] In embodiments of the compound of formula (I), or its tautomers, or its pharmaceutically acceptable salts, n is 1, and R 7 It is -F.

[0169] In embodiments of the compound of formula (I), or its tautomers, or its pharmaceutically acceptable salts, n is 1, and R 7 It is -OCF3.

[0170] In embodiments of the compound of formula (I), or its tautomers, or its pharmaceutically acceptable salts, n is 2, and each R 7 It is -F.

[0171] In an embodiment of a compound of formula (I), or its tautomer, or its pharmaceutically acceptable salt, R 6 It is -CH3, -CH2CH3, or -CH(CH3)2; n is 1 or 2; and each R 7 Independently -F or -OCF3.

[0172] In embodiments of the compound of formula (I), or its tautomers, or its pharmaceutically acceptable salts, It has a structure: Each R 7a and R 7b Independently hydrogen, halogen, -(C 1-6 )alkyl, -O-(C 1-6 )alkyl or -O-(C 1-6 )-Halogenated alkyl group.

[0173] In embodiments of a compound of formula (I), or its tautomers, or its pharmaceutically acceptable salts, each R 7a and R 7b Independently hydrogen, halogen, or -O(C) 1-6 ) Haloalkyl.

[0174] In an embodiment of a compound of formula (I), or its tautomer, or its pharmaceutically acceptable salt, R 7a It can be either -F or -OCF3.

[0175] In an embodiment of a compound of formula (I), or its tautomer, or its pharmaceutically acceptable salt, R 7b It can be hydrogen or -F.

[0176] In an embodiment of a compound of formula (I), or its tautomer, or its pharmaceutically acceptable salt, R 7a It is -F or -OCF3; and R 7b It can be hydrogen or -F.

[0177] In an embodiment of a compound of formula (I), or its tautomer, or its pharmaceutically acceptable salt, R 7a It is -F; and R 7b For hydrogen.

[0178] In embodiments of the compound of formula (I), or its tautomers, or its pharmaceutically acceptable salts, for:

[0179] In embodiments of a compound of formula (I), or its tautomers, or its pharmaceutically acceptable salts, each R a and R b Independently hydrogen or -(C 1-6 )alkyl.

[0180] In embodiments of a compound of formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof:

[0181] Y is O;

[0182] X 1 X 2 X 3 and X 4 As defined by equation (I);

[0183] R 1 R 2 R 3 and R 4 Each can be independently hydrogen, -CF3, Cl, or cyano;

[0184] Ring B is a 5- or 6-membered heteroaryl group containing one or two nitrogen ring atoms;

[0185] Each R 5 Independently oxo, -F, -CH3, or -NH2;

[0186] R 6 It can be -CH3, -CH2CH3 or -CH(CH3)2;

[0187] Each R 7 Independently -F or -OCF3;

[0188] z is 0, 1, 2, or 3; and

[0189] n is 1 or 2.

[0190] In another respect, the present invention relates to compounds of formula (IA) or pharmaceutically acceptable salts or tautomers thereof:

[0191]

[0192] in:

[0193] Y is either O or S;

[0194] R 1 R 2 and R 3 Each is independently hydrogen, halogen, cyano, -NR a R b -(C 1-6 )-alkyl, -(C 1-6 -Haloalkyl, -O-(C 1-6 -alkyl or -O-(C 1-6 )-Haloalkyl;

[0195] Ring B is a phenyl group or a 5- or 6-membered heterocyclic group containing one or two nitrogen ring atoms;

[0196] Each R 5 Independently halogenated, 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 ;

[0197] R 6 For hydrogen, -(C 1-6 )alkyl, -O-(C 1-6 -alkyl or -NR a R b ;

[0198] Each R 7 Independently halogen, -(C 1-6 )alkyl, -O-(C 1-6 )alkyl or -O-(C 1-6 )-Haloalkyl;

[0199] Each R a and R bIndependently hydrogen, -(C 1-6 )alkyl or -(C 1-6 ) Haloalkyl;

[0200] R c For hydrogen, -OH, -NR a R b -(C 1-6 )-alkyl or -(C 1-6 )-Haloalkyl;

[0201] n is 0, 1, 2, or 3;

[0202] p is 0, 1, or 2; and

[0203] z can be 0, 1, 2, or 3.

[0204] In embodiments of a compound of formula (IA), or a tautomer thereof, or a pharmaceutically acceptable salt thereof,

[0205] Y is either O or S;

[0206] R 1 R 2 and R 3 Each is independently hydrogen, halogen, cyano, -NR a R b -(C 1-6 )-alkyl, -(C 1-6 -Haloalkyl, -O-(C 1-6 -alkyl or -O-(C 1-6 )-Haloalkyl;

[0207] Ring B is a 5- or 6-membered heteroaryl group containing one or two nitrogen ring atoms;

[0208] Each R 5 Independently halogenated, oxo-, -OH, -NR a R b or -(C 1-6 )alkyl;

[0209] R 6 For -(C 1-6 )alkyl;

[0210] Each R 7 Independently halogen, -(C 1-6 )alkyl, -O-(C 1-6 )alkyl or -O-(C 1-6 )-Haloalkyl;

[0211] Each R a and R b Independently hydrogen, -(C 1-6 )alkyl or -(C1-6 ) Haloalkyl;

[0212] n is 0, 1, 2, or 3; and

[0213] z can be 0, 1, 2, or 3.

[0214] In embodiments of the compound of formula (IA), or its tautomers, or its pharmaceutically acceptable salts, Y is O.

[0215] In embodiments of a compound of formula (IA), or its tautomers, or its pharmaceutically acceptable salts, Y is S.

[0216] In embodiments of a compound of formula (IA), or its tautomers, or its pharmaceutically acceptable salts, R 1 It is hydrogen, halogen, cyano or -(C 1-6 )-Halogenated alkyl group.

[0217] In embodiments of a compound of formula (IA), or its tautomers, or its pharmaceutically acceptable salts, R 1 It can be hydrogen, -CF3, -Cl, or cyano.

[0218] In embodiments of a compound of formula (IA), or its tautomers, or its pharmaceutically acceptable salts, R 1 For hydrogen.

[0219] In embodiments of a compound of formula (IA), or its tautomers, or its pharmaceutically acceptable salts, R 2 It is hydrogen, halogen, cyano or -(C 1-6 )-Halogenated alkyl group.

[0220] In embodiments of a compound of formula (IA), or its tautomers, or its pharmaceutically acceptable salts, R 2 It can be hydrogen, -CF3, -Cl, or cyano.

[0221] In embodiments of a compound of formula (IA), or its tautomers, or its pharmaceutically acceptable salts, R 3 It is hydrogen, halogen, cyano or -(C 1-6 )-Halogenated alkyl group.

[0222] In embodiments of a compound of formula (IA), or its tautomers, or its pharmaceutically acceptable salts, R 3 It can be hydrogen, -CF3, -Cl, or cyano.

[0223] In embodiments of the compound of formula (IA), or its tautomers, or its pharmaceutically acceptable salts, ring B is phenyl.

[0224] In embodiments of the compound of formula (IA), or its tautomers, or its pharmaceutically acceptable salts, ring B is a 5- or 6-membered heterocyclic group containing one or two nitrogen ring atoms.

[0225] In embodiments of the compound of formula (IA), or its tautomers, or its pharmaceutically acceptable salts, ring B is a 5- or 6-membered heteroaryl group containing one or two nitrogen ring atoms.

[0226] In embodiments of the compound of formula (IA), or its tautomers, or its pharmaceutically acceptable salts, ring B is a 5- or 6-membered heterocyclic alkyl group containing one or two nitrogen ring atoms.

[0227] In embodiments of a compound of formula (IA), or its tautomers, or its pharmaceutically acceptable salts, each R 5 Independently halogenated, oxo-, -OH, -NR a R b or -(C 1-6 )alkyl.

[0228] In embodiments of the compound of formula (IA), or its tautomers, or its pharmaceutically acceptable salts, ring B is a 5- or 6-membered heteroaryl group containing one or two nitrogen ring atoms; and each R 5 Independently halogenated, oxo-, -OH, -NR a R b -(C 1-6 )alkyl or -(C 1-6 ) Haloalkyl.

[0229] In embodiments of compounds of formula (IA), or their tautomers, or pharmaceutically acceptable salts thereof, ring B is pyridinyl; and each R 5 Independently halogenated, oxo-, -OH, -NR a R b or -(C 1-6 )alkyl.

[0230] In embodiments of compounds of formula (IA), or their tautomers, or pharmaceutically acceptable salts thereof, ring B is pyridinyl; and each R 5 Independently oxidized or -(C 1-6 )alkyl.

[0231] In embodiments of compounds of formula (IA), or their tautomers, or pharmaceutically acceptable salts thereof, ring B is pyridinyl; and each R 5 It can be independently oxo, -F, -Cl, -NH2 or -CH3.

[0232] In embodiments of compounds of formula (IA), or their tautomers, or pharmaceutically acceptable salts thereof, ring B is pyridinyl; and each R 5 It can be independently oxo, -F, -NH2, or -CH3.

[0233] In embodiments of compounds of formula (IA), or their tautomers, or pharmaceutically acceptable salts thereof, ring B is pyridinyl; and each R 5 It can be oxidized, -F, or -CH3 independently.

[0234] In embodiments of compounds of formula (IA), or their tautomers, or pharmaceutically acceptable salts thereof, ring B is pyridinyl; and each R 5 It can be oxidized or -CH3 independently.

[0235] In embodiments of the compound of formula (IA), or its tautomers, or its pharmaceutically acceptable salts, ring B is a pyrazolyl group; and each R 5 Independently halogenated, oxo-, -OH, -NR a R b or -(C 1-6 )alkyl.

[0236] In embodiments of the compound of formula (IA), or its tautomers, or its pharmaceutically acceptable salts, ring B is a pyrazolyl group; and each R 5 Independently for -(C 1-6 )alkyl.

[0237] In embodiments of the compound of formula (IA), or its tautomers, or its pharmaceutically acceptable salts, ring B is a pyrazolyl group; and each R 5 Independently -CH3.

[0238] In embodiments of a compound of formula (IA), or its tautomers, or its pharmaceutically acceptable salts, z is 1, 2, or 3, and each R 5 It can be -CH3, -F, -Cl, oxo, or -NH2 independently.

[0239] In embodiments of a compound of formula (IA), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, for:

[0240] In embodiments of a compound of formula (IA), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, for:

[0241] In embodiments of a compound of formula (IA), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, for:

[0242] In embodiments of a compound of formula (IA), or its tautomers, or its pharmaceutically acceptable salts, R 6 For hydrogen.

[0243] In embodiments of a compound of formula (IA), or its tautomers, or its pharmaceutically acceptable salts, R 6 For -(C 1-6 )alkyl.

[0244] In embodiments of a compound of formula (IA), or its tautomers, or its pharmaceutically acceptable salts, R 6 It can be -CH3, -CH2CH3 or -CH(CH3)2.

[0245] In embodiments of a compound of formula (IA), or its tautomers, or its pharmaceutically acceptable salts, R 6 It is -CH3.

[0246] In embodiments of a compound of formula (IA), or its tautomers, or its pharmaceutically acceptable salts, R 6 For -NR a R b .

[0247] In embodiments of a compound of formula (IA), or its tautomers, or its pharmaceutically acceptable salts, R 6 It is -NH2.

[0248] In embodiments of a compound of formula (IA), or its tautomers, or its pharmaceutically acceptable salts, each R 7 Independently halogenated or -O(C) 1-6 ) Haloalkyl.

[0249] In embodiments of a compound of formula (IA), or its tautomers, or its pharmaceutically acceptable salts, each R 7 Independently -F or -OCF3.

[0250] In embodiments of a compound of formula (IA), or its tautomers, or its pharmaceutically acceptable salts, n is 1 or 2; and each R 7 Independently -F or -OCF3.

[0251] In embodiments of the compound of formula (IA), or its tautomers, or its pharmaceutically acceptable salts, n is 1, and R 7 It is -F.

[0252] In embodiments of the compound of formula (IA), or its tautomers, or its pharmaceutically acceptable salts, n is 1, and R 7 It is -OCF3.

[0253] In embodiments of the compound of formula (IA), or its tautomers, or its pharmaceutically acceptable salts, n is 2, and each R 7 It is -F.

[0254] In embodiments of a compound of formula (IA), or its tautomers, or its pharmaceutically acceptable salts, R 6 It is -CH3, -CH2CH3, or -CH(CH3)2; n is 1 or 2; and each R 7 Independently -F or -OCF3.

[0255] In embodiments of a compound of formula (IA), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, It has a structure: Each R 7a and R 7b Independently hydrogen, halogen, -(C 1-6 )alkyl, -O-(C 1-6 )alkyl or -O-(C 1-6 )-Halogenated alkyl group.

[0256] In embodiments of a compound of formula (IA), or its tautomers, or its pharmaceutically acceptable salts, each R 7a and R 7b Independently hydrogen, halogen, or -O(C) 1-6 ) Haloalkyl.

[0257] In embodiments of a compound of formula (IA), or its tautomers, or its pharmaceutically acceptable salts, R 7a It can be either -F or -OCF3.

[0258] In embodiments of a compound of formula (IA), or its tautomers, or its pharmaceutically acceptable salts, R 7b It can be hydrogen or -F.

[0259] In embodiments of a compound of formula (IA), or its tautomers, or its pharmaceutically acceptable salts, R 7a It is -F or -OCF3; and R 7b It can be hydrogen or -F.

[0260] In embodiments of a compound of formula (IA), or its tautomers, or its pharmaceutically acceptable salts, R 7a It is -F; and R7b For hydrogen.

[0261] In embodiments of a compound of formula (IA), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, for:

[0262] In embodiments of a compound of formula (IA), or its tautomers, or its pharmaceutically acceptable salts, each R a and R b Independently hydrogen or -(C 1-6 )alkyl.

[0263] In embodiments of a compound of formula (IA), or its tautomers, or its pharmaceutically acceptable salts:

[0264] Y is O;

[0265] R 1 R 2 and R 3 Each can be independently hydrogen, -CF3, Cl, or cyano;

[0266] Ring B is a 5- or 6-membered heteroaryl group containing one or two nitrogen ring atoms;

[0267] Each R 5 Independently oxo, -F, -CH3, or -NH2;

[0268] R 6 It can be -CH3, -CH2CH3 or -CH(CH3)2;

[0269] Each R 7 Independently -F or -OCF3;

[0270] z is 0, 1, 2, or 3; and

[0271] n is 1 or 2.

[0272] In another respect, the present invention relates to compounds of formula (IB) or pharmaceutically acceptable salts or tautomers thereof:

[0273]

[0274] in:

[0275] Y is either O or S;

[0276] R 1 R 3 and R 4 Each is independently hydrogen, halogen, cyano, -NR a R b -(C1-6 )-alkyl, -(C 1-6 -Haloalkyl, -O-(C 1-6 -alkyl or -O-(C 1-6 )-Haloalkyl;

[0277] Ring B is a phenyl group or a 5- or 6-membered heterocyclic group containing one or two nitrogen ring atoms;

[0278] Each R 5 Independently halogenated, 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 ;

[0279] R 6 For hydrogen, -(C 1-6 )alkyl, -O-(C 1-6 -alkyl or -NR a R b ;

[0280] Each R 7 Independently halogen, -(C 1-6 )alkyl, -O-(C 1-6 )alkyl or -O-(C 1-6 )-Haloalkyl;

[0281] Each R a and R b Independently hydrogen, -(C 1-6 )alkyl or -(C 1-6 ) Haloalkyl;

[0282] R c For hydrogen, -OH, -NR a R b -(C 1-6 )-alkyl or -(C 1-6 )-Haloalkyl;

[0283] n is 0, 1, 2, or 3;

[0284] p is 0, 1, or 2; and

[0285] z can be 0, 1, 2, or 3.

[0286] In embodiments of a compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts,

[0287] Y is either O or S;

[0288] R 1 R 3 and R 4 Each is independently hydrogen, halogen, cyano, -NR a R b -(C 1-6 )-alkyl, -(C 1-6 -Haloalkyl, -O-(C 1-6 -alkyl or -O-(C 1-6 )-Haloalkyl;

[0289] Ring B is a 5- or 6-membered heteroaryl group containing one or two nitrogen ring atoms;

[0290] Each R 5 Independently halogenated, oxo-, -OH, -NR a R b or -(C 1-6 )alkyl;

[0291] R 6 For -(C 1-6 )alkyl;

[0292] Each R 7 Independently halogen, -(C 1-6 )alkyl, -O-(C 1-6 )alkyl or -O-(C 1-6 )-Haloalkyl;

[0293] Each R a and R b Independently hydrogen, -(C 1-6 )alkyl or -(C 1-6 ) Haloalkyl;

[0294] n is 0, 1, 2, or 3; and

[0295] z can be 0, 1, 2, or 3.

[0296] In embodiments of the compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, Y is O.

[0297] In an embodiment of a compound of formula (IB), or its tautomer, or its pharmaceutically acceptable salt, Y is S.

[0298] In embodiments of a compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, R 1 It is hydrogen, halogen, cyano or -(C 1-6 )-Halogenated alkyl group.

[0299] In embodiments of a compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, R 1 It can be hydrogen, -CF3, -Cl, or cyano.

[0300] In embodiments of a compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, R 1 For hydrogen.

[0301] In embodiments of a compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, R 3 It is hydrogen, halogen, cyano or -(C 1-6 )-Halogenated alkyl group.

[0302] In embodiments of a compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, R 3 It can be hydrogen, -CF3, -Cl, or cyano.

[0303] In embodiments of a compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, R 4 It is hydrogen, halogen, cyano or -(C 1-6 )-Halogenated alkyl group.

[0304] In embodiments of a compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, R 4 It can be hydrogen, -CF3, -Cl, or cyano.

[0305] In embodiments of a compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, R 4 For hydrogen.

[0306] In embodiments of the compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, ring B is phenyl.

[0307] In embodiments of the compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, ring B is a 5- or 6-membered heterocyclic group containing one or two nitrogen ring atoms.

[0308] In embodiments of the compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, ring B is a 5- or 6-membered heteroaryl group containing one or two nitrogen ring atoms.

[0309] In embodiments of the compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, ring B is a 5- or 6-membered heterocyclic alkyl group containing one or two nitrogen ring atoms.

[0310] In embodiments of a compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, each R 5 Independently halogenated, oxo-, -OH, -NR a R b or -(C 1-6 )alkyl.

[0311] In embodiments of the compound of formula (IB), its tautomers, or its pharmaceutically acceptable salts, ring B is a 5- or 6-membered heteroaryl group containing one or two nitrogen ring atoms; and each R 5 Independently halogenated, oxo-, -OH, -NR a R b -(C 1-6 )alkyl or -(C 1-6 ) Haloalkyl.

[0312] In embodiments of the compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, ring B is pyridinyl; and each R 5 Independently halogenated, oxo-, -OH, -NR a R b or -(C 1-6 )alkyl.

[0313] In embodiments of the compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, ring B is pyridinyl; and each R 5 Independently oxidized or -(C 1-6 )alkyl.

[0314] In embodiments of the compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, ring B is pyridinyl; and each R 5 It can be independently oxo, -F, -Cl, -NH2 or -CH3.

[0315] In embodiments of the compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, ring B is pyridinyl; and each R 5 It can be independently oxo, -F, -NH2, or -CH3.

[0316] In embodiments of the compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, ring B is pyridinyl; and each R 5 It can be oxidized, -F, or -CH3 independently.

[0317] In embodiments of the compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, ring B is pyridinyl; and each R 5 It can be oxidized or -CH3 independently.

[0318] In embodiments of the compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, ring B is a pyrazolyl group; and each R 5 Independently halogenated, oxo-, -OH, -NR a R b or -(C 1-6 )alkyl.

[0319] In embodiments of the compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, ring B is a pyrazolyl group; and each R 5 Independently for -(C 1-6 )alkyl.

[0320] In embodiments of the compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, ring B is a pyrazolyl group; and each R 5 Independently -CH3.

[0321] In embodiments of the compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, z is 1, 2, or 3, and each R 5 It can be -CH3, -F, -Cl, oxo, or -NH2 independently.

[0322] In embodiments of a compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, for:

[0323]

[0324] In embodiments of a compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, for:

[0325] In embodiments of a compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, for:

[0326] In embodiments of a compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, R 6 For hydrogen.

[0327] In embodiments of a compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, R 6 For -(C 1-6 )alkyl.

[0328] In embodiments of a compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, R 6 It can be -CH3, -CH2CH3 or -CH(CH3)2.

[0329] In embodiments of a compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, R 6 It is -CH3.

[0330] In embodiments of a compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, R 6 For -NR a R b .

[0331] In embodiments of a compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, R 6 It is -NH2.

[0332] In embodiments of a compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, each R 7 Independently halogenated or -O(C) 1-6 ) Haloalkyl.

[0333] In embodiments of a compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, each R 7 Independently -F or -OCF3.

[0334] In embodiments of the compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, n is 1 or 2; and each R 7 Independently -F or -OCF3.

[0335] In embodiments of the compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, n is 1, and R 7 It is -F.

[0336] In embodiments of the compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, n is 1, and R 7 It is -OCF3.

[0337] In embodiments of the compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, n is 2, and each R 7 It is -F.

[0338] In embodiments of a compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, R 6It is -CH3, -CH2CH3, or -CH(CH3)2; n is 1 or 2; and each R 7 Independently -F or -OCF3.

[0339] In embodiments of a compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, It has a structure: Each R 7a and R 7b Independently hydrogen, halogen, -(C 1-6 )alkyl, -O-(C 1-6 )alkyl or -O-(C 1-6 )-Halogenated alkyl group.

[0340] In embodiments of a compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, each R 7a and R 7b Independently hydrogen, halogen, or -O(C) 1-6 ) Haloalkyl.

[0341] In embodiments of a compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, R 7a It can be either -F or -OCF3.

[0342] In embodiments of a compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, R 7b It can be hydrogen or -F.

[0343] In embodiments of a compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, R 7a It is -F or -OCF3; and R 7b It can be hydrogen or -F.

[0344] In embodiments of a compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, R 7a It is -F; and R 7b For hydrogen.

[0345] In embodiments of a compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, for:

[0346] In embodiments of a compound of formula (IB), or its tautomers, or its pharmaceutically acceptable salts, each R a and R b Independently hydrogen or -(C 1-6 )alkyl.

[0347] In an embodiment of a compound of formula (IB), or its tautomers, or a pharmaceutically acceptable salt thereof:

[0348] Y is O;

[0349] R 1 R 3 and R 4 Each can be independently hydrogen, -CF3, Cl, or cyano;

[0350] Ring B is a 5- or 6-membered heteroaryl group containing one or two nitrogen ring atoms;

[0351] Each R 5 Independently oxo, -F, -CH3, or -NH2;

[0352] R 6 It can be -CH3, -CH2CH3 or -CH(CH3)2;

[0353] Each R 7 Independently -F or -OCF3; and

[0354] n is 1 or 2.

[0355] In another respect, the present invention relates to compounds of formula (IC) or their tautomers, or pharmaceutically acceptable salts thereof:

[0356]

[0357] in:

[0358] Y is either O or S;

[0359] Each R 1 R 2 and R 4 Independently hydrogen, halogen, cyano, -NR a R b -(C 1-6 )-alkyl, -(C 1-6 -Haloalkyl, -O-(C 1-6 -alkyl or -O-(C 1-6 )-Haloalkyl;

[0360] Ring B is a phenyl group or a 5- or 6-membered heterocyclic group containing one or two nitrogen ring atoms;

[0361] Each R 5 Independently halogenated, 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 ;

[0362] R 6 For hydrogen, -(C 1-6 )alkyl, -O-(C 1-6 -alkyl or -NR a R b ;

[0363] Each R 7 Independently halogen, -(C 1-6 )alkyl, -O-(C 1-6 )alkyl or -O-(C 1-6 )-Haloalkyl;

[0364] Each R a and R b Independently hydrogen, -(C 1-6 )alkyl or -(C 1-6 ) Haloalkyl;

[0365] R c For hydrogen, -OH, -NR a R b -(C 1-6 )-alkyl or -(C 1-6 )-Haloalkyl;

[0366] n is 0, 1, 2, or 3;

[0367] p is 0, 1, or 2; and

[0368] z can be 0, 1, 2, or 3.

[0369] In embodiments of a compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts,

[0370] Y is either O or S;

[0371] Each R 1 R 2 and R 4 Independently hydrogen, halogen, cyano, -NR a R b -(C 1-6 )-alkyl, -(C 1-6 -Haloalkyl, -O-(C 1-6 -alkyl or -O-(C 1-6 )-Haloalkyl;

[0372] Ring B is a 5- or 6-membered heteroaryl group containing one or two nitrogen ring atoms;

[0373] Each R 5 Independently halogenated, oxo-, -OH, -NR a R b or -(C 1-6 )alkyl;

[0374] R 6 For -(C 1-6 )alkyl;

[0375] Each R 7 Independently halogen, -(C 1-6 )alkyl, -O-(C 1-6 )alkyl or -O-(C 1-6 )-Haloalkyl;

[0376] Each R a and R b Independently hydrogen, -(C 1-6 )alkyl or -(C 1-6 ) Haloalkyl;

[0377] n is 0, 1, 2, or 3; and

[0378] z can be 0, 1, 2, or 3.

[0379] In embodiments of a compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, R 1 It is hydrogen, halogen, cyano or -(C 1-6 )-Halogenated alkyl group.

[0380] In embodiments of a compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, R 1 It can be hydrogen, -CF3, -Cl, or cyano.

[0381] In embodiments of a compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, R 1 For hydrogen.

[0382] In embodiments of a compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, R 2 It is hydrogen, halogen, cyano or -(C 1-6 )-Halogenated alkyl group.

[0383] In embodiments of a compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, R 2 It can be hydrogen, -CF3, -Cl, or cyano.

[0384] In embodiments of a compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, R 4It is hydrogen, halogen, cyano or -(C 1-6 )-Halogenated alkyl group.

[0385] In embodiments of a compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, R 4 It can be hydrogen, -CF3, -Cl, or cyano.

[0386] In embodiments of a compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, R 4 For hydrogen.

[0387] In embodiments of the compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, ring B is phenyl.

[0388] In embodiments of the compound of formula (IC), its tautomers, or its pharmaceutically acceptable salts, ring B is a 5- or 6-membered heterocyclic group containing one or two nitrogen ring atoms.

[0389] In embodiments of the compound of formula (IC), its tautomers, or its pharmaceutically acceptable salts, ring B is a 5- or 6-membered heteroaryl group containing one or two nitrogen ring atoms.

[0390] In embodiments of the compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, ring B is a 5- or 6-membered heterocyclic alkyl group containing one or two nitrogen ring atoms.

[0391] In embodiments of the compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, each R 5 Independently halogenated, oxo-, -OH, -NR a R b or -(C 1-6 )alkyl.

[0392] In embodiments of the compound of formula (IC), its tautomers, or pharmaceutically acceptable salts thereof, ring B is a 5- or 6-membered heteroaryl group containing one or two nitrogen ring atoms; and each R 5 Independently halogenated, oxo-, -OH, -NR a R b -(C 1-6 )alkyl or -(C 1-6 ) Haloalkyl.

[0393] In embodiments of the compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, ring B is pyridinyl; and each R 5 Independently halogenated, oxo-, -OH, -NR a R b or -(C1-6 )alkyl.

[0394] In embodiments of the compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, ring B is pyridinyl; and each R 5 Independently oxidized or -(C 1-6 )alkyl.

[0395] In embodiments of the compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, ring B is pyridinyl; and each R 5 It can be independently oxo, -F, -Cl, -NH2 or -CH3.

[0396] In embodiments of the compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, ring B is pyridinyl; and each R 5 It can be independently oxo, -F, -NH2, or -CH3.

[0397] In embodiments of the compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, ring B is pyridinyl; and each R 5 It can be oxidized, -F, or -CH3 independently.

[0398] In embodiments of the compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, ring B is pyridinyl; and each R 5 It can be oxidized or -CH3 independently.

[0399] In embodiments of the compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, ring B is a pyrazolyl group; and each R 5 Independently halogenated, oxo-, -OH, -NR a R b or -(C 1-6 )alkyl.

[0400] In embodiments of the compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, ring B is a pyrazolyl group; and each R 5 Independently for -(C 1-6 )alkyl.

[0401] In embodiments of the compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, ring B is a pyrazolyl group; and each R 5 Independently -CH3.

[0402] In embodiments of the compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, z is 1, 2, or 3, and each R 5It can be -CH3, -F, -Cl, oxo, or -NH2 independently.

[0403] In embodiments of a compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, for:

[0404] In embodiments of a compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, for:

[0405] In embodiments of a compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, for:

[0406] In embodiments of a compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, R 6 For hydrogen.

[0407] In embodiments of a compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, R 6 For -(C 1-6 )alkyl.

[0408] In embodiments of a compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, R 6 It can be -CH3, -CH2CH3 or -CH(CH3)2.

[0409] In embodiments of a compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, R 6 It is -CH3.

[0410] In embodiments of a compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, R 6 For -NR a R b .

[0411] In embodiments of a compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, R 6 It is -NH2.

[0412] In embodiments of the compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, each R 7 Independently halogenated or -O(C) 1-6 ) Haloalkyl.

[0413] In embodiments of the compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, each R 7 Independently -F or -OCF3.

[0414] In embodiments of the compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, n is 1 or 2; and each R 7 Independently -F or -OCF3.

[0415] In embodiments of the compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, n is 1, and R 7 It is -F.

[0416] In embodiments of the compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, n is 1, and R 7 It is -OCF3.

[0417] In embodiments of the compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, n is 2, and each R 7 It is -F.

[0418] In embodiments of a compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, R 6 It is -CH3, -CH2CH3, or -CH(CH3)2; n is 1 or 2; and each R 7 Independently -F or -OCF3.

[0419] In embodiments of a compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, It has a structure: Each R 7a and R 7b Independently hydrogen, halogen, -(C 1-6 )alkyl, -O-(C 1-6 )alkyl or -O-(C 1-6 )-Halogenated alkyl group.

[0420] In embodiments of the compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, each R 7a and R 7b Independently hydrogen, halogen, or -O(C) 1-6 ) Haloalkyl.

[0421] In embodiments of a compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, R 7a It can be either -F or -OCF3.

[0422] In embodiments of a compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, R 7b It can be hydrogen or -F.

[0423] In embodiments of a compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, R 7a It is -F or -OCF3; and R 7b It can be hydrogen or -F.

[0424] In embodiments of a compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, R 7a It is -F; and R 7b For hydrogen.

[0425] In embodiments of a compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, for:

[0426] In embodiments of the compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, each R a and R b Independently hydrogen or -(C 1-6 )alkyl.

[0427] In embodiments of the compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts:

[0428] Y is O;

[0429] R 1 R 2 and R 3 Each can be independently hydrogen, -CF3, Cl, or cyano;

[0430] Ring B is a 5- or 6-membered heteroaryl group containing one or two nitrogen ring atoms;

[0431] Each R 5 Independently oxo, -F, -CH3, or -NH2;

[0432] R 6 It can be -CH3, -CH2CH3 or -CH(CH3)2;

[0433] Each R 7 Independently -F or -OCF3;

[0434] z is 0, 1, 2, or 3; and

[0435] n is 1 or 2.

[0436] In another respect, the present invention relates to compounds of formula (ID) or pharmaceutically acceptable salts or tautomers thereof:

[0437]

[0438] in:

[0439] Y is either O or S;

[0440] Each R 2 and R 4 Independently hydrogen, halogen, cyano, -NR a R b -(C 1-6 )-alkyl, -(C 1-6 -Haloalkyl, -O-(C 1-6 -alkyl or -O-(C 1-6 )-Haloalkyl;

[0441] Ring B is a phenyl group or a 5- or 6-membered heterocyclic group containing one or two nitrogen ring atoms;

[0442] Each R 5 Independently halogenated, 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 ;

[0443] R 6 For hydrogen, -(C 1-6 )alkyl, -O-(C 1-6 -alkyl or -NR a R b ;

[0444] Each R 7 Independently halogen, -(C 1-6 )alkyl, -O-(C 1-6 )alkyl or -O-(C 1-6 )-Haloalkyl;

[0445] Each R a and R b Independently hydrogen, -(C 1-6 )alkyl or -(C 1-6 ) Haloalkyl;

[0446] R c For hydrogen, -OH, -NR a Rb -(C 1-6 )-alkyl or -(C 1-6 )-Haloalkyl;

[0447] n is 0, 1, 2, or 3;

[0448] p is 0, 1, or 2; and

[0449] z can be 0, 1, 2, or 3.

[0450] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts,

[0451] Y is either O or S;

[0452] Each R 2 and R 4 Independently hydrogen, halogen, cyano, -NR a R b -(C 1-6 )-alkyl, -(C 1-6 -Haloalkyl, -O-(C 1-6 -alkyl or -O-(C 1-6 )-Haloalkyl;

[0453] Ring B is a 5- or 6-membered heteroaryl group containing one or two nitrogen ring atoms;

[0454] Each R 5 Independently halogenated, oxo-, -OH, -NR a R b or -(C 1-6 )alkyl;

[0455] R 6 For -(C 1-6 )alkyl;

[0456] Each R 7 Independently halogen, -(C 1-6 )alkyl, -O-(C 1-6 )alkyl or -O-(C 1-6 )-Haloalkyl;

[0457] Each R a and R b Independently hydrogen, -(C 1-6 )alkyl or -(C 1-6 ) Haloalkyl;

[0458] n is 0, 1, 2, or 3; and

[0459] z can be 0, 1, 2, or 3.

[0460] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, Y is O.

[0461] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, Y is S.

[0462] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, R 2 It is hydrogen, halogen, cyano or -(C 1-6 )-Halogenated alkyl group.

[0463] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, R 2 It can be hydrogen, -CF3, -Cl, or cyano.

[0464] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, R 2 It can be hydrogen, -CF3, -Cl, or cyano.

[0465] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, R 4 It is hydrogen, halogen, cyano or -(C 1-6 )-Halogenated alkyl group.

[0466] In embodiments of a compound of formula (IC), or its tautomers, or its pharmaceutically acceptable salts, R 4 It can be hydrogen, -CF3, -Cl, or cyano.

[0467] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, R 4 For hydrogen.

[0468] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, ring B is phenyl.

[0469] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, ring B is a 5- or 6-membered heterocyclic group containing one or two nitrogen ring atoms.

[0470] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, ring B is a 5- or 6-membered heteroaryl group containing one or two nitrogen ring atoms.

[0471] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, ring B is a 5- or 6-membered heterocyclic alkyl group containing one or two nitrogen ring atoms.

[0472] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, each R 5 Independently halogenated, oxo-, -OH, -NR a R b or -(C 1-6 )alkyl.

[0473] In embodiments of the compound of formula (ID), its tautomers, or its pharmaceutically acceptable salts, ring B is a 5- or 6-membered heteroaryl group containing one or two nitrogen ring atoms; and each R 5 Independently halogenated, oxo-, -OH, -NR a R b -(C 1-6 )alkyl or -(C 1-6 ) Haloalkyl.

[0474] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, ring B is pyridinyl; and each R 5 Independently halogenated, oxo-, -OH, -NR a R b or -(C 1-6 )alkyl.

[0475] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, ring B is pyridinyl; and each R 5 Independently oxidized or -(C 1-6 )alkyl.

[0476] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, ring B is pyridinyl; and each R 5 It can be independently oxo, -F, -Cl, -NH2 or -CH3.

[0477] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, ring B is pyridinyl; and each R 5 It can be independently oxo, -F, -NH2, or -CH3.

[0478] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, ring B is pyridinyl; and each R 5 It can be oxidized, -F, or -CH3 independently.

[0479] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, ring B is pyridinyl; and each R5 It can be oxidized or -CH3 independently.

[0480] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, ring B is a pyrazolyl group; and each R 5 Independently halogenated, oxo-, -OH, -NR a R b or -(C 1-6 )alkyl.

[0481] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, ring B is a pyrazolyl group; and each R 5 Independently for -(C 1-6 )alkyl.

[0482] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, ring B is a pyrazolyl group; and each R 5 Independently -CH3.

[0483] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, z is 1, 2, or 3, and each R 5 It can be -CH3, -F, -Cl, oxo, or -NH2 independently.

[0484] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, for:

[0485] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, for:

[0486] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, for:

[0487] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, R 6 For hydrogen.

[0488] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, R 6 For -(C 1-6 )alkyl.

[0489] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, R 6 It can be -CH3, -CH2CH3 or -CH(CH3)2.

[0490] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, R 6 It is -CH3.

[0491] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, R 6 For -NR a R b .

[0492] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, R 6 It is -NH2.

[0493] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, each R 7 Independently halogenated or -O(C) 1-6 ) Haloalkyl.

[0494] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, each R 7 Independently -F or -OCF3.

[0495] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, n is 1 or 2; and each R 7 Independently -F or -OCF3.

[0496] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, n is 1, and R 7 It is -F.

[0497] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, n is 1, and R 7 It is -OCF3.

[0498] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, n is 2, and each R 7 It is -F.

[0499] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, R 6It is -CH3, -CH2CH3, or -CH(CH3)2; n is 1 or 2; and each R 7 Independently -F or -OCF3.

[0500] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, It has a structure: Each R 7a and R 7b Independently hydrogen, halogen, -(C 1-6 )alkyl, -O-(C 1-6 )alkyl or -O-(C 1-6 )-Halogenated alkyl group.

[0501] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, each R 7a and R 7b Independently hydrogen, halogen, or -O(C) 1-6 ) Haloalkyl.

[0502] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, R 7a It can be either -F or -OCF3.

[0503] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, R 7b It can be hydrogen or -F.

[0504] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, R 7a It is -F or -OCF3; and R 7b It can be hydrogen or -F.

[0505] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, R 7a It is -F; and R 7b For hydrogen.

[0506] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, for:

[0507] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts, each R a and R b Independently hydrogen or -(C 1-6 )alkyl.

[0508] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts:

[0509] Y is O;

[0510] Each R 2 and R 4 It can be hydrogen, -CF3, Cl, or cyano independently;

[0511] Ring B is a 5- or 6-membered heteroaryl group containing one or two nitrogen ring atoms;

[0512] Each R 5 Independently oxo, -F, -CH3, or -NH2;

[0513] R 6 It can be -CH3, -CH2CH3 or -CH(CH3)2;

[0514] Each R 7 Independently -F or -OCF3;

[0515] z is 0, 1, 2, or 3; and

[0516] n is 1 or 2.

[0517] In another respect, the present invention relates to compounds of formula (IE) or their tautomers, or pharmaceutically acceptable salts thereof:

[0518]

[0519] in:

[0520] Y is either O or S;

[0521] Each R 2 and R 3 Independently hydrogen, halogen, cyano, -NR a R b -(C 1-6 )-alkyl, -(C 1-6 -Haloalkyl, -O-(C 1-6 -alkyl or -O-(C 1-6 )-Haloalkyl;

[0522] Ring B is a phenyl group or a 5- or 6-membered heterocyclic group containing one or two nitrogen ring atoms;

[0523] Each R 5 Independently halogenated, oxo-, -OH, -NR a R b -(C 1-6 )alkyl, -(C 1-6 ) Haloalkyl, -COORa -C(O)NR a R b or -S(O) p R c ;

[0524] R 6 For hydrogen, -(C 1-6 )alkyl, -O-(C 1-6 -alkyl or -NR a R b ;

[0525] Each R 7 Independently halogen, -(C 1-6 )alkyl, -O-(C 1-6 )alkyl or -O-(C 1-6 )-Haloalkyl;

[0526] Each R a and R b Independently hydrogen, -(C 1-6 )alkyl or -(C 1-6 ) Haloalkyl;

[0527] R c For hydrogen, -OH, -NR a R b -(C 1-6 )-alkyl or -(C 1-6 )-Haloalkyl;

[0528] n is 0, 1, 2, or 3;

[0529] p is 0, 1, or 2; and

[0530] z can be 0, 1, 2, or 3.

[0531] In embodiments of the compound of formula (ID), or its tautomers, or its pharmaceutically acceptable salts,

[0532] Y is either O or S;

[0533] Each R 2 and R 3 Independently hydrogen, halogen, cyano, -NR a R b -(C 1-6 )-alkyl, -(C 1-6 -Haloalkyl, -O-(C 1-6 -alkyl or -O-(C 1-6 )-Haloalkyl;

[0534] Ring B is a 5- or 6-membered heteroaryl group containing one or two nitrogen ring atoms;

[0535] Each R 5 Independently halogenated, oxo-, -OH, -NR a R b or -(C 1-6 )alkyl;

[0536] R 6 For -(C 1-6 )alkyl;

[0537] Each R 7 Independently halogen, -(C 1-6 )alkyl, -O-(C 1-6 )alkyl or -O-(C 1-6 )-Haloalkyl;

[0538] Each R a and R b Independently hydrogen, -(C 1-6 )alkyl or -(C 1-6 ) Haloalkyl;

[0539] n is 0, 1, 2, or 3; and

[0540] z can be 0, 1, 2, or 3.

[0541] In embodiments of the compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, Y is O.

[0542] In embodiments of the compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, Y is S.

[0543] In embodiments of a compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, R 2 It is hydrogen, halogen, cyano or -(C 1-6 )-Halogenated alkyl group.

[0544] In embodiments of a compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, R 2 It can be hydrogen, -CF3, -Cl, or cyano.

[0545] In embodiments of a compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, R 3 It is hydrogen, halogen, cyano or -(C 1-6 )-Halogenated alkyl group.

[0546] In embodiments of a compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, R 3 It can be hydrogen, -CF3, -Cl, or cyano.

[0547] In embodiments of the compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, ring B is phenyl.

[0548] In embodiments of the compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, ring B is a 5- or 6-membered heterocyclic group containing one or two nitrogen ring atoms.

[0549] In embodiments of the compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, ring B is a 5- or 6-membered heteroaryl group containing one or two nitrogen ring atoms.

[0550] In embodiments of the compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, ring B is a 5- or 6-membered heterocyclic alkyl group containing one or two nitrogen ring atoms.

[0551] In embodiments of a compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, each R 5 Independently halogenated, oxo-, -OH, -NR a R b or -(C 1-6 )alkyl.

[0552] In embodiments of the compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, ring B is a 5- or 6-membered heteroaryl group containing one or two nitrogen ring atoms; and each R 5 Independently halogenated, oxo-, -OH, -NR a R b -(C 1-6 )alkyl or -(C 1-6 ) Haloalkyl.

[0553] In embodiments of the compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, ring B is pyridinyl; and each R 5 Independently halogenated, oxo-, -OH, -NR a R b or -(C 1-6 )alkyl.

[0554] In embodiments of the compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, ring B is pyridinyl; and each R 5 Independently oxidized or -(C 1-6 )alkyl.

[0555] In embodiments of the compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, ring B is pyridinyl; and each R 5It can be independently oxo, -F, -Cl, -NH2 or -CH3.

[0556] In embodiments of the compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, ring B is pyridinyl; and each R 5 It can be independently oxo, -F, -NH2, or -CH3.

[0557] In embodiments of the compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, ring B is pyridinyl; and each R 5 It can be oxidized, -F, or -CH3 independently.

[0558] In embodiments of the compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, ring B is pyridinyl; and each R 5 It can be oxidized or -CH3 independently.

[0559] In embodiments of the compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, ring B is a pyrazolyl group; and each R 5 Independently halogenated, oxo-, -OH, -NR a R b or -(C 1-6 )alkyl.

[0560] In embodiments of the compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, ring B is a pyrazolyl group; and each R 5 Independently for -(C 1-6 )alkyl.

[0561] In embodiments of the compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, ring B is a pyrazolyl group; and each R 5 Independently -CH3.

[0562] In embodiments of the compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, z is 1, 2, or 3, and each R 5 It can be -CH3, -F, -Cl, oxo, or -NH2 independently.

[0563] In embodiments of a compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, for:

[0564] In embodiments of a compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, for:

[0565] In embodiments of a compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, for:

[0566] In embodiments of a compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, R 6 For hydrogen.

[0567] In embodiments of a compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, R 6 For -(C 1-6 )alkyl.

[0568] In embodiments of a compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, R 6 It can be -CH3, -CH2CH3 or -CH(CH3)2.

[0569] In embodiments of a compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, R 6 It is -CH3.

[0570] In embodiments of a compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, R 6 For -NR a R b .

[0571] In embodiments of a compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, R 6 It is -NH2.

[0572] In embodiments of a compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, each R 7 Independently halogenated or -O(C) 1-6 ) Haloalkyl.

[0573] In embodiments of a compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, each R 7 Independently -F or -OCF3.

[0574] In embodiments of the compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, n is 1 or 2; and each R 7 Independently -F or -OCF3.

[0575] In embodiments of the compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, n is 1, and R 7 It is -F.

[0576] In embodiments of the compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, n is 1, and R 7 It is -OCF3.

[0577] In embodiments of the compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, n is 2, and each R 7 It is -F.

[0578] In embodiments of a compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, R 6 It is -CH3, -CH2CH3, or -CH(CH3)2; n is 1 or 2; and each R 7 Independently -F or -OCF3.

[0579] In embodiments of a compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, It has a structure: Each R 7a and R 7b Independently hydrogen, halogen, -(C 1-6 )alkyl, -O-(C 1-6 )alkyl or -O-(C 1-6 )-Halogenated alkyl group.

[0580] In embodiments of a compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, each R 7a and R 7b Independently hydrogen, halogen, or -O(C) 1-6 ) Haloalkyl.

[0581] In embodiments of a compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, R 7a It can be either -F or -OCF3.

[0582] In embodiments of a compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, R 7b It can be hydrogen or -F.

[0583] In embodiments of a compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, R 7a It is -F or -OCF3; and R 7b It can be hydrogen or -F.

[0584] In embodiments of a compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, R 7a It is -F; and R 7b For hydrogen.

[0585] In embodiments of a compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, for:

[0586] In embodiments of a compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts, each R a and R b Independently hydrogen or -(C 1-6 )alkyl.

[0587] In embodiments of the compound of formula (IE), or its tautomers, or its pharmaceutically acceptable salts:

[0588] Y is O;

[0589] Each R 2 and R 3 It can be hydrogen, -CF3, Cl, or cyano independently;

[0590] Ring B is a 5- or 6-membered heteroaryl group containing one or two nitrogen ring atoms;

[0591] Each R 5 Independently oxo, -F, -CH3, or -NH2;

[0592] R 6 It can be -CH3, -CH2CH3 or -CH(CH3)2;

[0593] Each R 7 Independently -F or -OCF3;

[0594] z is 0, 1, 2, or 3; and

[0595] n is 1 or 2.

[0596] In another respect, the present invention relates to compounds selected from the following:

[0597]

[0598]

[0599]

[0600]

[0601]

[0602] Or its tautomers or its pharmaceutically acceptable salts.

[0603] In another respect, the present invention relates to the following compounds:

[0604]

[0605] Or its tautomers or its pharmaceutically acceptable salts.

[0606] Enantiomers, diastereomers and polymorphs

[0607] Compounds of any formula disclosed herein (including compounds of formulas (I) and (IA) through (IE) of the present invention, or their pharmaceutically acceptable salts and / or corresponding tautomer forms) may contain one or more asymmetric centers (i.e., also referred to as chiral centers) and thus may exist in optical form (e.g., as individual enantiomers, diastereomers, or other stereoisomers, or mixtures thereof) and racemic form. All such individual compounds, stereoisomers, and mixtures thereof are included within the scope of the present invention.

[0608] Chiral centers, such as chiral carbon atoms, may also be present in substituents such as alkyl groups. Where the stereochemistry of a chiral center present in any formula disclosed herein (including formulas (I) and (IA) through (IE) of the present invention or their pharmaceutically acceptable salts and / or corresponding tautomer forms) or any chemical structure shown herein is not specified, the structure is intended to cover all individual stereoisomers and all mixtures thereof. Therefore, compounds of the present invention containing one or more chiral centers, or their pharmaceutically acceptable salts and / or corresponding tautomer forms, may be used as racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure individual stereoisomers.

[0609] Individual stereoisomers of compounds containing one or more asymmetric centers according to any formula disclosed herein (including compounds of formulas (I) and (IA) to (IE) of the present invention, or their pharmaceutically acceptable salts and / or corresponding tautomer forms) can be resolved by methods known to those skilled in the art. For example, such resolution can be performed as follows:

[0610] (1) By forming diastereosal salts, complexes or other derivatives;

[0611] (2) By selective reaction with stereoisomer-specific reagents, for example, by enzymatic oxidation or reduction; or

[0612] (3) The separation is carried out by gas-liquid or liquid chromatography in a chiral environment, such as on a chiral support like silica with bound chiral ligands, or in the presence of a chiral solvent. Those skilled in the art will understand that in cases where the desired stereoisomer is converted to another chemical entity via one of the above separation procedures, additional steps are required to release the desired form.

[0613] Alternatively, specific stereoisomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts, or solvents, or by asymmetric transformation of one enantiomer into another.

[0614] When a disclosed compound or its salt is named or described by structure, it should be understood that the compound or salt, including its solvates (especially hydrates), can exist in crystalline, amorphous, or mixtures thereof. The compound or its salt or solvate (especially hydrates) may also exhibit polymorphism (i.e., the ability to exist in different crystalline forms). These different crystalline forms are generally referred to as "polymorphs".

[0615] It should be understood that when named or described by structure, the disclosed compound or its solvates (especially hydrates) also include all its polymorphs.

[0616] Polymorphs have the same chemical composition but differ in their packing, geometric arrangement, and other descriptive properties in the crystalline solid state. Therefore, polymorphs can possess different physical properties, such as shape, density, hardness, deformability, stability, and solubility. 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 understand that different polymorphs can be produced, for example, by changing or adjusting the conditions used to crystallize / recrystallize the compound.

[0617] In one aspect, 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 or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0618] 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-dihydropyridino[3,4-d]pyrimidine-4(1H)-one in crystalline form.

[0619] 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-dihydropyridino[3,4-d]pyrimidin-4(1H)-one, characterized in that it provides an XRPD (X-ray powder diffraction) pattern having peaks (°2θ) at about 6.3, about 7.4, about 10.0 and / or about 12.6.

[0620] 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-dihydropyridino[3,4-d]pyrimidine-4(1H)-one, characterized in that it provides XRPD form 1 comprising essentially the peaks listed in Table 1.

[0621] 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-dihydropyridino[3,4-d]pyrimidine-4(1H)-one, characterized in that it provides a combination with... Figure 1 Essentially the same XRPD Figure 1 .

[0622] 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-dihydropyridino[3,4-d]pyrimidine-4(1H)-one, characterized in that it provides an endothermic DSC initiation at about 49°C.

[0623] 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-dihydropyridino[3,4-d]pyrimidine-4(1H)-one, characterized in that it provides substantially the same as... Figure 2 Consistent DSC.

[0624] 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-dihydropyridino[3,4-d]pyrimidin-4(1H)-one, characterized in that it provides an XRPD (X-ray powder diffraction) pattern having peaks (°2θ) at about 6.9, about 8.2, about 10.8, about 13.5 and / or about 14.8.

[0625] 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-dihydropyridino[3,4-d]pyrimidine-4(1H)-one, characterized in that it provides XRPD form 2 comprising essentially the peaks listed in Table 1.

[0626] 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-dihydropyridino[3,4-d]pyrimidine-4(1H)-one, characterized in that it provides a combination with... Figure 3 Essentially the same XRPD Figure 2 .

[0627] 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-dihydropyridino[3,4-d]pyrimidine-4(1H)-one, characterized in that it provides an endothermic DSC initiation at about 41°C.

[0628] 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-dihydropyridino[3,4-d]pyrimidine-4(1H)-one, characterized in that it provides substantially the same as... Figure 4 Consistent DSC.

[0629] 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-dihydropyridino[3,4-d]pyrimidin-4(1H)-one, characterized in that it provides an XRPD (X-ray powder diffraction) pattern having peaks (°2θ) at about 7.1, about 9.3, about 10.2, about 13.8 and / or about 15.0.

[0630] 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-dihydropyridino[3,4-d]pyrimidine-4(1H)-one, characterized in that it provides XRPD form 3 comprising essentially the peaks listed in Table 1.

[0631] 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-dihydropyridino[3,4-d]pyrimidine-4(1H)-one, characterized in that it provides a combination with... Figure 5 Essentially the same XRPD Figure 3 .

[0632] 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-dihydropyridino[3,4-d]pyrimidin-4(1H)-one, characterized in that it provides an XRPD (X-ray powder diffraction) pattern having peaks (°2θ) at about 3.9, about 7.0, about 7.3, about 7.6 and / or about 9.0.

[0633] 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-dihydropyridino[3,4-d]pyrimidine-4(1H)-one, characterized in that it provides XRPD form 4 comprising essentially the peaks listed in Table 1.

[0634] 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-dihydropyridino[3,4-d]pyrimidine-4(1H)-one, characterized in that it provides a combination with... Figure 6 Essentially the same XRPD Figure 4 .

[0635] 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-dihydropyridino[3,4-d]pyrimidin-4(1H)-one, characterized in that it provides an endothermic DSC initiation at about 42°C.

[0636] 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-dihydropyridino[3,4-d]pyrimidine-4(1H)-one, characterized in that it provides substantially the same as... Figure 7 Consistent DSC.

[0637] When this document indicates the presence of a peak in the XRPD plot for a given value, it typically means that the peak is within ±0.2 (e.g., ±0.1) of the referenced value.

[0638] When this document indicates that a given temperature value exists in the DSC, it usually means that the temperature is within ±0.2°C (e.g., ±0.1°C) of the referenced value.

[0639] Salt

[0640] Salts of any of the formulas disclosed herein (including compounds of formulas (I) and (IA) through (IE) of the present invention and / or their corresponding tautomer forms) are preferably pharmaceutically acceptable salts due to their potential use in pharmaceuticals. Pharmaceutically acceptable salts include, in particular, those described in Berge, Bigley, and Monkhouse J. Pharm. Sci (1977) 66, pp. 1–19, or those listed in PH Stahl and CG Wermuth, eds., Handbook of Pharmaceutical Salts; Properties, Selection and Use, Second Edition Stahl / Wermuth: Wiley-VCH / VHCA, 2011. Non-pharmaceutically acceptable salts may be used, for example, as intermediates in the preparation of compounds of any of the formulas disclosed herein or their pharmaceutically acceptable salts.

[0641] Suitable pharmaceutically acceptable salts may include acid or base addition salts. Such base addition salts can be formed by reacting a compound of any formula disclosed herein (including compounds of formulas (I) and (IA) to (IE) of the present invention and / or their corresponding tautomer forms) with a suitable base, optionally in a suitable solvent such as an organic solvent, to obtain a salt which can be separated by a variety of methods, including crystallization and filtration.

[0642] Such acid addition salts can be formed by reacting compounds of any formula disclosed herein (including compounds of formulas (I) and (IA) to (IE) of the present invention and / or their corresponding tautomer forms) with a suitable acid, optionally in a suitable solvent such as an organic solvent, to obtain the salt, which can be separated by a variety of methods, including crystallization and filtration.

[0643] Salts can be prepared in situ during the final separation and purification of compounds of any formula disclosed herein (including compounds of formulas (I) and (IA) to (IE) of the present invention and / or their corresponding tautomer forms). If a basic compound of any formula disclosed herein (including compounds of formulas (I) and (IA) to (IE) of the present invention and / or their corresponding tautomer forms) is separated as a salt, the corresponding free basic form of the compound can be prepared by any suitable method known in the art (including treatment of the salt with an inorganic or organic base). Similarly, if a compound of any formula disclosed herein (including compounds of formulas (I) and (IA) to (IE) of the present invention and / or their corresponding tautomer forms) containing a carboxylic acid or other acidic functional group is separated as a salt, the corresponding free acidic form of the compound can be prepared by any suitable method known in the art, including treatment of the salt with an inorganic or organic acid.

[0644] For example, when the compound of the present invention is a base (containing 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 or organic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., and an organic acid such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranoside amino acids such as glucuronic acid or galacturonic acid, α-hydroxy acids such as citric acid or tartaric acid, amino acids such as aspartic acid or glutamic acid, aromatic acids such as benzoic acid or cinnamic acid, and sulfonic acids such as p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, etc.

[0645] If the basic compound of the present invention is separated as a salt, the corresponding free basic form of the compound can be prepared by any suitable method known in the art, including with inorganic or organic bases, suitably having a higher pK than the free basic form of the compound. a The salt is treated with inorganic or organic bases.

[0646] When the compounds of the present invention are acids (containing an acidic moiety), the desired salts can be prepared by any suitable method known in the art, including treatment of the free acid with inorganic or organic bases such as amines (primary, secondary, or tertiary amines), alkali metals, or alkaline earth metal hydroxides. Exemplary 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 such as ethylenediamine, dicyclohexylamine, ethanolamine, piperidine, morpholine, and piperazine, as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0647] 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 encompasses all possible stoichiometric and non-stoichiometric salt forms within its scope. It should be understood that if a compound of any formula disclosed herein (including formulas (I) and (IA) through (IE) as defined herein) contains two or more basic moieties, the stoichiometry of the salt formation may include one, two, or more equivalents of an acid. Such a salt will contain one, two, or more acid counterions, such as dihydrochlorides. Pharmaceutically acceptable stoichiometric and non-stoichiometric salts of compounds of any formula disclosed herein (including compounds of formulas (I) and (IA) through (IE) of the present invention and / or their corresponding tautomer forms) are included within the scope of the present invention, including substoichiometric salts, such as those in which the counterion contains more than one acid proton.

[0648] Because the compounds of the present invention can contain both acid and base moieties, pharmaceutically acceptable salts can be prepared by treating these compounds with either a basic or acidic reagent, respectively. Therefore, the present invention also provides the conversion of one pharmaceutically acceptable salt (e.g., hydrochloride) of a compound of the present invention to another pharmaceutically acceptable salt (e.g., sodium salt) of a compound of the present invention.

[0649] Representative pharmaceutically acceptable acid addition salts include, but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, hydrogen tartrate, butyrate, calcium edetate, camphorate, camphor sulfonate (dextrose camphor sulfonate), caprate, caproate, and caprylate. Cinnamate, citrate, cyclohexylaminosulfonate, digluconate, 2,5-dihydroxybenzoate, disuccinate, dodecyl sulfate (propionate lauryl sulfate), edetate (ethylenediaminetetraacetic acid), propionate lauryl sulfate (lauryl sulfate), ethane-1,2-disulfonate (ethanedisulfonate), ethanesulfonate (ethanesulfonate), formate, fumarate, galactarate (mucates), gentianate (2,5-dihydroxybenzoate), glucoheptonate (glucoheptonate) Gluconate, gluceptate, glucuronate, glutamate, glutamate, glycerophosphate, glycolate, hexylresorcinol, hippurate, hydrabamine (N,N'-di(dehydroabi)-ethylenediamine), hydrobromide, hydrochloride, hydroiodate, hydroxynaphthylcarboxylate, isobutyrate, lactate, lacturonate, laurate, malate, maleate, malonate, mandelate, methanesulfonate, methyl sulfate, mucilage, naphthalene-1,5-disulfonate (naphthalene disulfonate), naphthalene- 2-Sulfonates (naphthalenesulfonate), nicotinate, nitrate, oleate, palmitate, p-aminobenzenesulfonate, p-aminosalicylate, dihydroxynaphthalate (siporate), pantothenate, pectate, persulfate, phenylacetate, phenethyl barbiturate, phosphate, polygalacturonate, propionate, p-toluenesulfonate (toluenesulfonate), pyroglutamate, pyruvate, salicylate, sebate, stearate, hypoacetate, succinate, aminosulfonate, sulfate, tannin, tartrate, teoclate (8-teoclate), thiocyanate, triethyliodide, undecanoate, undecenoate, and valerate.

[0650] Representative pharmaceutically acceptable base addition salts include, but are not limited to, aluminum, 2-amino-2-(hydroxymethyl)-1,3-propanediol (TRIS), arginine, phenethylbenzylamine (N-benzylphenylethylamine), benzylamine (N,N'-dibenzylethylenediamine), bis(2-hydroxyethyl)amine, bismuth, calcium, chloroprocaine, choline, crimidazole (1-p-chlorobenzyl-2-pyrrolidine-1'-ylmethylbenzimidazole), cyclohexylamine, dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lepidol, lithium, lysine, magnesium, meglumine (N-methylglucosamine), piperazine, piperidine, potassium, procaine, quinine, quinoline, sodium, strontium, tert-butylamine, and zinc.

[0651] solvates

[0652] The compounds of the present invention, or pharmaceutically acceptable salts thereof, may exist in solvated and non-solventized forms. For solvates of the compounds of the present invention, or pharmaceutically acceptable salts thereof, or tautomers thereof, in crystalline form, those skilled in the art will understand that pharmaceutically acceptable solvates can be formed, wherein solvent molecules are introduced into the crystal lattice during crystallization. Solvates may involve non-aqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethyl acetate, or they may involve water as a solvent introduced into the crystal lattice. Solvates in which water is the solvent introduced into the crystal lattice are generally referred to as "hydrates". Hydrates include stoichiometric hydrates and compositions containing a variable amount of water.

[0653] Deuterated compounds

[0654] This invention also includes compounds of any formula disclosed herein in various deuterated forms (including compounds of formulas (I) and (IA) through (IE) or their pharmaceutically acceptable salts and / or corresponding tautomer forms). Each available hydrogen atom bonded to a carbon atom may be independently replaced with a deuterium atom.

[0655] Those skilled in the art will know how to synthesize deuterated forms of any of the formulas disclosed herein (including compounds of formulas (I) and (IA) through (IE) of the present invention, or their pharmaceutically acceptable salts and / or corresponding tautomer forms). For example, deuterated materials such as alkyl groups can be prepared by conventional techniques (see, for example, methyl-d3-amine, from Aldrich Chemical Co., Milwaukee, WI, catalog 489, 689-2).

[0656] isotope

[0657] The present invention also includes isotopically labeled compounds that are identical to those listed in any of the formulas disclosed herein (including the compounds of formulas (I) and (IA) through (IE) of the present invention or their pharmaceutically acceptable salts and / or corresponding tautomer forms), but in fact one or more atoms are replaced by atoms with atomic masses or mass numbers different from those most common in nature.

[0658] Examples of isotopes that can be incorporated into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, iodine, and chlorine, for example... 3 H. 11 C 14 C 18 F, 123 I or 125 I.

[0659] Compounds of the present invention containing other isotopes of the aforementioned isotopes and / or other atoms, and pharmaceutically acceptable salts of said compounds, are within the scope of the present invention. Isotope-labeled compounds of the present invention, such as those doped with radioactive isotopes, are also included. 3 H or 14 Compounds of C can be used for drug and / or substrate tissue distribution assays. Tritium (i.e., 3 H) isotopes and carbon-14 (i.e., ... 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. 11 C and 18 F isotopes are particularly useful in PET (positron emission tomography).

[0660] purity

[0661] Because the compounds of the present invention are intended for use in pharmaceutical compositions, it is readily understood that they are each preferably provided in a substantially pure form, for example at least 60% pure, more suitably at least 75% pure, and preferably at least 85%, especially at least 98% pure (% based on weight / weight). Impure formulations of the compounds can be used to prepare purer forms for use in pharmaceutical compositions.

[0662] It should be recognized that compounds of any formula disclosed herein (including compounds of formulas (I) and (IA) through (IE) of the present invention or their pharmaceutically acceptable salts and / or corresponding tautomer forms) may exist in stereoisomer, regioisomer, or diastereomer forms.

[0663] tautomer

[0664] Furthermore, the compounds of this invention can exist as tautomers or in tautomeric form. In chemistry, tautomers are generally understood to be structural or constitutive isomers of compounds that readily interconvert. This reaction typically results in the reorientation of protons. A structural or constitutive isomer (according to IUPAC) is an isomer in which molecules with the same molecular formula have different bonding patterns and atomic structures, as opposed to stereoisomers, where the molecular bonds are always in the same order and only spatially arranged. The concept of tautomerism is called the tautomerism phenomenon. The chemical reaction that interconverts the two is called tautomerization. It should be noted that tautomers should not be confused with the description of "contributing structures" in chemical resonance. Tautomers are different chemical substances that can be identified by their different spectral data, while resonance structures are merely a convenient description and do not actually exist.

[0665] For example, the 2-pyridone ring exhibits tautomerism, in which a proton attached to nitrogen can move to oxygen to give the tautomer form of 2-hydroxypyridine:

[0666]

[0667] Synthesis scheme and general preparation method

[0668] The present invention also relates to methods for preparing compounds of any formula disclosed herein (including compounds of formulas (I) and (IA) to (IE) of the present invention, or pharmaceutically acceptable salts and / or corresponding tautomer forms thereof).

[0669] Any of the compounds of this invention disclosed herein, or their pharmaceutically acceptable salts and / or corresponding tautomer forms, can be prepared by any number of operations using conventional organic synthesis as described in the following schemes, and more specifically by the exemplary compounds in the Examples section of this document, or by utilizing the knowledge of a skilled organic chemist. Suitable synthetic routes are described in the general reaction schemes below.

[0670] The syntheses provided in these schemes are applicable to the preparation of compounds of the invention as defined herein (having a variety of different functional groups as defined) using suitable precursors, which are suitably protected as required to achieve compatibility with the reactions outlined herein. The protection is then removed as required to obtain compounds with the generally disclosed properties. Although the schemes are shown only with compounds defined therein, they are exemplary processes that can be used to prepare compounds of the invention.

[0671] Intermediates (compounds used in the preparation of the compounds of the present invention) may also exist as salts. Therefore, the phrase "compound of formula (number)" when referring to intermediates means a compound having that structural formula or a pharmaceutically acceptable salt thereof.

[0672] The compounds of the present invention can be obtained by using the operations described in the following schemes or by applying suitable synthetic organic chemical processes and methods known to those skilled in the art.

[0673] The methods provided in these schemes can be used to prepare products containing various different Y and X molecules using suitable precursors. 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 The compounds of the present invention with the group (described above as compounds of formulas (I) and (IA) to (IE)).

[0674] Those skilled in the art will understand that in the preparation of compounds of the present invention (e.g., compounds of formulas (I) and (IA) to (IE) or their pharmaceutically acceptable salts and / or corresponding tautomer forms), it may be necessary and / or desirable to protect one or more sensitive groups in the molecule or suitable intermediate to prevent undesirable side reactions. Those skilled in the art will understand that if a substituent described herein is incompatible with the synthetic method described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions. The protecting group may be removed at an appropriate point in the reaction sequence to provide the desired intermediate or target compound. Suitable protecting groups used according to the present invention are well known to those skilled in the art and can be used in a conventional manner. See, for example, “Protective Groups in Organic Synthesis” by TW Green and PGMWets (Wiley & Sons, 1991) or “Protecting Groups” by PJ Kocienski (Georg Thieme Verlag, 1994). If desired, deprotection may then be performed to obtain a compound having the generally disclosed properties.

[0675] In some cases, substituents can be specifically chosen to be reactive under the reaction conditions used. In these cases, the reaction conditions transform the selected substituent into another substituent, which can be used as an intermediate compound or as a desired substituent in the target compound.

[0676] Although the schemes shown below are representative methods for preparing compounds of formulas (I) and (IA) to (IE), they are intended only to illustrate methods that can be used to prepare the compounds of the present invention.

[0677] Compound names were generated using the software naming program ChemDraw Ultra v12.0, from Perkin Elmer, 940 Winter Street, Waltham, Massachusetts, 02451, USA. (http: / / www.perkinelmer.com / ).

[0678] Option I

[0679]

[0680] The preparation of the compounds of this invention typically begins with the synthesis of an N-substituted 2-aminoaromatic acid derivative I-4 (Scheme I). Under standard conditions, a suitably substituted 2-haloaromatic acid I-1 is esterified to give the corresponding ester I-2. Generally, the esterification reaction is carried out under acidic conditions in the presence of an alcohol, or under basic conditions in the presence of a suitable alkyl halide. The 2-haloaromatic ester I-2 (L = Cl, Br, or I) reacts with a suitable aniline or amine (R... 5' -NH2, where R 5’ The reaction of substituted phenyl groups yields the corresponding N-substituted 2-amino aromatic ester I-3. Typically, the reaction is carried out at elevated temperatures using standard heating or microwave irradiation 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) in a suitable solvent (e.g., 1,4-dioxane, toluene, or 2-ethoxyethanol).

[0681] Intermediate I-3 can also be produced by reacting 2-aminoaromatic ester I-5 with a suitable aryl halide (R 5' -X, where R 5’The substituted phenyl group is prepared by reacting under similar coupling conditions as described above. This reaction is well known to those skilled in the art. The saponification of ester I-3 to the corresponding N-substituted 2-amino aromatic acid derivative (I-4) is typically achieved under standard alkaline conditions using a base (such as LiOH, KOH, or NaOH) in a suitable solvent or solvent system (e.g., methanol / H2O, ethanol / H2O, or THF / H2O). Such conditions are well known to those skilled in the art.

[0682] Another method, which will be obvious to those skilled in the art, is to react 2-haloaromatic ester I-1 with a suitable aniline or amine (R... 5' The reaction (-NH2) directly provides 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.

[0683] Intermediate I-4 can also be prepared by reacting ester I-2 (L=Cl) with a suitable aniline or amine (R). 5' -NH2) is achieved through a coupling reaction under similar coupling conditions as described above for converting I-2 to I-3.

[0684] Option II

[0685]

[0686] The intermediate N-substituted 2-aminoaromatic acid derivative I-4, prepared as shown in Scheme I, can be converted to II-2 as outlined in Scheme II. I-4 is coupled with a suitable 2-alkoxy-azaheterocyclic B-NH2, such as 2-methoxy-4-aminopyridine, under various amide coupling conditions known to those skilled in the art, to provide the corresponding amide II-1. For example, standard coupling agents (e.g., EDC / HOBT, HATU, HBTU, or T3P) can be used in a suitable solvent (typically DMF, DMA, or acetonitrile) in the presence of an amine base (such as triethylamine or the Hünig base (diisopropylethylamine)). Alternatively, the acid can be converted to the corresponding acyl chloride using a reagent (such as thionyl chloride or oxalyl chloride), and then the acyl chloride can be reacted with a suitable 2-alkoxy-azaheterocyclic B-NH2 (such as 2-methoxy-4-aminopyridine) in the presence of an acid scavenger or a base (such as pyridine, 2,6-dimethylpyridine, triethylamine or Hünig base) in a suitable solvent (such as dichloromethane or pyridine) to give the desired coupling product II-1.

[0687] Similar to II-2, the formation of the ring system involves the reaction of II-1 with formaldehyde or a suitable equivalent. For example, this reaction can be carried out in the presence of an acid (preferably PTSA or sulfuric acid) using formaldehyde (as gaseous formaldehyde, paraformaldehyde, or triformaldehyde). Alternatively, II-1 can be reacted to form a ring system by using diiodomethane or chloroiodomethane as the formaldehyde equivalent. In variations of this cyclization reaction, a base (typically Cs₂CO₃ or NaH) can be used in a suitable solvent (typically acetonitrile or DMF). The choice of formaldehyde or diiodomethane depends on the specific reactivity of the substrate II-1.

[0688] In some embodiments, compound II-2 can be obtained as a final product, or it can be obtained by the method described in Scheme II.

[0689] When ring B in II-2 is substituted with a suitable halogen (particularly chlorine, bromine, or iodine), the halogen can be replaced by other functional groups by reacting with the corresponding coupling partner under suitable coupling reaction conditions. This coupling partner includes suitable amines, alcohols, and boric acids or esters. This type of reaction can typically be carried out at high temperatures using standard heating or microwave irradiation, in the presence of a catalyst (typically 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 (e.g., 1,4-dioxane, THF, toluene, or 2-ethoxyethanol). In some cases where ring B is substituted with fluorine, this transformation can be carried out in the presence of a base (e.g., DIPEA) in a suitable solvent (e.g., DMF) via S... N Ar reaction is achieved.

[0690] Option III

[0691]

[0692] In B=2-alkoxy-nitrogen heterocyclic rings (each X 1’ X 2’ and X 3 Independently C, N, or NH; R 7” In the case of alkyl groups, such as 6-methoxypyridine-3-amine, it may be necessary to remove the alkoxy (usually methoxy) protecting group to complete the synthesis of the compounds of the present invention. A preferred method for achieving this conversion includes reacting at high temperature with a mixture of TMS-chloride and NaI or a solution of TMS-iodide in a neutral solvent (such as acetonitrile). Alternatively, this conversion can be achieved at high temperature using a mixture of p-toluenesulfonic acid and LiCl in a solvent (such as DMF).

[0693] Option IV

[0694]

[0695] X in II-2a 1 -X 4 One method, in the case of C-Cl, is to convert chlorine to cyano by treating II-2a with zinc cyanide or cuprous cyanide (I) in a solvent (e.g., DMF) at high temperature in the presence of tetrakis to produce the final compound IV-2.

[0696] If necessary, the final compound IV-2 can be generated from IV-1 by a suitable deprotection reaction or by the appropriate method shown in Scheme III. The choice of reaction and the corresponding conditions will be apparent to those skilled in the art.

[0697] Alternatively, after the deprotection step, reaction conditions similar to those described above for converting II-2a to IV-4 can be used to achieve the conversion from the chloro group to the cyano group, in order to generate the final compound IV-2.

[0698] Option V

[0699]

[0700] In the case of B=nitrogen heterocyclic compounds such as 3-aminopyridine or 4-aminopyridine, an oxidation step may be required to generate the corresponding pyridine N-oxide analogs of the present invention. This conversion is typically achieved at 0°C or room temperature in a neutral solvent (e.g., DCM) in the presence of an oxidizing agent (e.g., mCPBA).

[0701] Certain specific instances may require further deprotection steps. Such transformations are well known to those skilled in the art. For example, in the case where the B ring is a 2-alkoxy-aza heterocycle, the alkoxy protecting group can be removed by the operation described in Scheme IV.

[0702] Drug composition, route of administration and dosage

[0703] The compounds of the present invention can be formulated into pharmaceutical compositions prior to 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 as defined by any formula disclosed herein (including compounds of formulas (I) and (IA) to (IE) of the present invention, or pharmaceutically acceptable salts and / or corresponding tautomer forms thereof)) 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 as defined by any formula disclosed herein (including compounds of formulas (I) and (IA) to (IE) of the present invention, or pharmaceutically acceptable salts and / or corresponding tautomer forms thereof)) and pharmaceutically acceptable excipients.

[0704] In another aspect, the present invention relates to pharmaceutical compositions or formulations comprising: a compound as defined by any formula disclosed herein (including compounds of formulas (I) and (IA) to (IE) of the present invention or their pharmaceutically acceptable salts and / or corresponding tautomer forms); a pharmaceutically acceptable excipient; and optionally one or more other therapeutic ingredients.

[0705] Pharmaceutical compositions or formulations as defined herein typically comprise one compound of the present invention. However, in some embodiments, a pharmaceutical composition may comprise more than one compound of the present invention. Furthermore, pharmaceutical compositions of the present invention may optionally comprise one or more additional pharmaceutically active compounds.

[0706] Pharmaceutically acceptable excipients are non-toxic and should not interfere with the efficacy of the active ingredient. Suitable pharmaceutically acceptable excipients will vary depending on the specific dosage form, route of administration, etc. Suitable pharmaceutically acceptable excipients include the following types: diluents, carriers, fillers, binders, disintegrants, lubricants, flow aids, granulators, coatings, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, thickeners, antioxidants, preservatives, stabilizers, surfactants, and buffers. Examples of pharmaceutically acceptable excipients are described in, for example... Remington's Pharmaceutical Sciences (Mack Publishing Company) The Handbook of Pharmaceutical Additives (Gower Publishing Limited),and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

[0707] Pharmaceutical compositions may be adapted to be administered via any suitable or appropriate route, such as systemic administration (e.g., oral administration, parenteral administration, transdermal administration, rectal administration, inhalation), local administration, etc. Parenteral administration is typically via injection or infusion, including intravenous, intramuscular, and subcutaneous injection or infusion. Inhalation refers to administration to the patient's lungs, whether through the mouth or nasal passages. Generally, administration is via the oral or parenteral route.

[0708] Pharmaceutical compositions suitable for oral administration may be presented in solid dosage forms such as tablets, capsules, sac-tablets, lozenges, pills; powders; or liquid dosage forms such as solutions, suspensions, syrups, elixirs, or emulsions. Pharmaceutical compositions suitable for parenteral administration may be presented in solutions, suspensions, and powders for reconstitution.

[0709] Typically, the pharmaceutical compositions of the present invention are prepared using conventional materials and techniques (e.g., mixing, blending, etc.). Remington's Pharmaceutical Sciences Some methods commonly used in this field are described in (Mack Publishing Company).

[0710] Solid oral dosage forms (e.g., 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, carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, etc.), lubricants (e.g., magnesium stearate, talc, etc.). Pharmaceutical compositions suitable for parenteral administration can be injection solutions prepared by mixing powders, granules, or tablets with a carrier (e.g., distilled water, physiological saline, etc.), and the pH can be adjusted with an alkali or the like.

[0711] The present invention also provides pharmaceutical compositions comprising 0.5 to 1,000 mg of the compound of the present invention (i.e., a compound of any formula disclosed herein (including compounds of formulas (I) and (IA) to (IE) of the present invention or their pharmaceutically acceptable salts and / or corresponding tautomer forms)) and 0.5 to 1,000 mg of a pharmaceutically acceptable excipient.

[0712] The compounds and pharmaceutical compositions of the present invention, as defined herein, can be administered once or according to a dosing regimen, wherein multiple doses are administered at different time intervals within a given time period. For example, the dose may be administered once, twice, three or four times daily. The dose may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. The dose of the compounds of the present invention may be in the range of 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.

[0713] Methods, uses, and compounds for preparing and / or treating diseases

[0714] Generally, this invention also relates to the use of the compounds and / or pharmaceutical compositions of the invention as defined herein as medicines or for treatment.

[0715] The compounds of this invention as defined herein are inhibitors of voltage-gated sodium ion channels, particularly inhibitors of the voltage-gated sodium ion channel Nav1.8. The activity of the compounds used as Nav1.8 inhibitors in this invention can be determined according to the methods generally described in the embodiments herein, or according to methods available to those skilled in the art.

[0716] Therefore, in one aspect, the present invention relates to the use of the compounds and pharmaceutical compositions of the present invention as inhibitors of voltage-gated sodium ion channels (particularly Nav1.8).

[0717] In one embodiment, the present invention relates to a method for inhibiting a voltage-gated sodium ion channel in a subject with this need, the method comprising administering to the subject an effective amount of a compound of the present invention as described herein or a pharmaceutical composition of the present invention. In one embodiment, the voltage-gated sodium channel is Nav1.8.

[0718] In one embodiment, the present invention relates to compounds or pharmaceutical compositions of the present invention for inhibiting voltage-gated sodium ion channels. In one embodiment, the voltage-gated sodium channel is Nav1.8.

[0719] In one embodiment, the present invention relates to the use of the compounds or pharmaceutical compositions of the present invention in the preparation of a medicament for inhibiting a voltage-gated sodium ion channel. In one embodiment, the voltage-gated sodium channel is Nav1.8.

[0720] Not wishing to be bound by any particular theory, the compounds and compositions of the present invention are particularly useful for treating diseases, conditions, or disorders in which activation or hyperactivity of Nav1.8 is associated with the disease, condition, or disorder. When activation or hyperactivity of Nav1.8 is associated with a specific disease, condition, or disorder, the disease, condition, or disorder may also be referred to as a "Nav1.8-mediated disease, condition, or disorder." Exemplary Nav1.8-mediated diseases, disorders, and conditions include pain and pain-related diseases, disorders, and conditions, as well as cardiovascular diseases, disorders, and conditions, such as atrial fibrillation.

[0721] Therefore, 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.

[0722] As used herein, a “patient” or “subject” in this context refers to a human or mammal. As used herein, the term “mammal” includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, and non-human primates (NHPs) such as monkeys or apes, humans, etc. Appropriately, the subject being treated is a human.

[0723] As used herein, the terms “treat,” “treating,” and / or “treatment” when referring to a disease, disorder, or condition mean to improve or prevent the condition or one or more biological manifestations of the condition; to interfere with one or more points in a biological cascade that causes or is responsible for the condition; to alleviate one or more symptoms or effects associated with the condition; to slow the progression of the condition or one or more biological manifestations of the condition; or to reduce the severity of the condition or one or more symptoms or effects associated with the condition. As mentioned above, “treatment” of a disease, disorder, or condition includes prevention of the condition. Those skilled in the art will understand that “prevention” is not an absolute term. In medicine, “prevention” is understood to mean the prophylactic administration of a drug to significantly 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.

[0724] As used herein, "effective amount" and "therapeutic effective amount" are used interchangeably. When referring to compounds of the present invention, "effective amount" means an amount of compound sufficient to treat a patient's condition within a reasonable medical judgment, but low enough to avoid serious side effects (at a reasonable efficacy / risk ratio). The effective amount of compounds of the present invention, or their pharmaceutically acceptable salts and / or their corresponding tautomer forms or corresponding pharmaceutical compositions thereof, will vary depending on factors such as the specific compound chosen (e.g., considering the compound's potency, efficacy, and half-life); the chosen route of administration; the condition being treated; the severity of the condition being treated; the age, body type, weight, and physical condition of the patient or subject being treated; the patient's or subject's medical history; the duration of treatment; the nature of concurrent therapy; the desired therapeutic effect, etc.

[0725] According to embodiments of the present invention, pain-related diseases, disorders, or conditions are pain caused by any of a variety of diseases with different etiologies described throughout this disclosure. In some embodiments, the pain or pain-related diseases, disorders, or conditions are neuropathic pain, chronic pain, acute pain, nociceptive pain, inflammatory pain, musculoskeletal pain, visceral pain, cancer pain, idiopathic pain, multiple sclerosis, and Shama syndrome. Figure 3 Schizophrenia syndrome or incontinence.

[0726] In some implementations, the pain or pain-related disease, disorder, or condition is defined as neuropathic pain or chronic neuropathic pain.

[0727] In some implementations, 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.

[0728] In some implementations, pain or pain-related disorders, disorders, or conditions are defined as neuropathic pain, selected from postherpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, oral burn syndrome, post-amputation pain, phantom pain, painful neuroma, traumatic neuroma, Morton's neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, drug-induced neuropathic pain, chemotherapy-induced neuropathic pain, antiretroviral therapy-induced neuropathic pain; post-spinal cord injury pain, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal autonomic headache.

[0729] In some implementations, pain or pain-related diseases, disorders, or conditions are neuropathic pain or chronic neuropathic pain, selected from diabetic peripheral neuropathy, pain caused by neuropathy, damage to the nervous system or neurons, pain-related nerve injury, neuralgia and related acute or chronic pain, postherpetic neuralgia, pain-related nerve root avulsion, painful traumatic mononeuropathy, painful polyneuropathy, erythromelalgia, paroxysmal extreme pain disorder (PEPD), oral burn syndrome, central pain syndrome caused by damage at the nervous system level, traumatic nerve injury, nerve compression or entrapment, congenital insensitivity to pain (CIP), dysmenorrhea, primary erythromelalgia, HIV peripheral sensory neuropathy, pudendal neuralgia, spinal cord injury, chronic inflammatory demyelinating polyneuropathy (CIDP), carpal tunnel syndrome, and vasculitic neuropathy.

[0730] In some implementations, the pain or pain-related disease, disorder, or condition is defined as visceral pain, including pain associated with inflammatory bowel disease, Crohn's disease, or interstitial cystitis.

[0731] In some implementations, pain or pain-related disorders, impairments or conditions are defined as musculoskeletal pain, which includes osteoarthritis pain, back pain, cold pain, burn pain or toothache.

[0732] In some implementations, pain or pain-related diseases, disorders, or conditions are defined as idiopathic pain, where idiopathic pain is fibromyalgia.

[0733] In some implementations, pain or pain-related disorders, impairments, or conditions are chronic or acute preoperative-related pain or chronic or acute postoperative-related pain. Postoperative-related pain includes pain following outpatient surgery. Outpatient 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 implementations, preoperative-related pain is selected from neuropathic pain or chronic neuropathic pain, chronic osteoarthritis pain, toothache, or inflammatory pain. In some implementations, postoperative-related pain is selected from pain following bunion removal surgery, hernia repair surgery, breast surgery, or cosmetic surgery.

[0734] In some implementations, pain or pain-related disorders, impairments, or conditions are pain caused by trauma or iatrogenic medical or dental procedures. As used herein, the term "iatrogenic" means pain unintentionally induced by medical or dental personnel (such as surgeons or dentists) during medical or dental treatment or diagnostic procedures, including but not limited to pain medically induced before (i.e., "before"), during (i.e., "during"), or during non-surgical or surgical treatment, and after (i.e., postoperative, post-operative, or surgically induced pain) medical or dental procedures.

[0735] In some implementations, pain or pain-related diseases, disorders, or conditions are nociceptive pain, including postoperative pain, cancer pain, back pain and craniofacial pain, osteoarthritis pain, toothache, or diabetic peripheral neuropathy.

[0736] In some implementations, the pain or pain-related disease, disorder, or condition is inflammatory pain. Inflammatory pain can be pain of various physiological causes. In some implementations, inflammatory pain is selected from pain associated with: osteoarthritis, rheumatoid arthritis, rheumatism, tenosynovitis and gout, shoulder tendinitis or bursitis, gouty arthritis and polymyalgia rheumatica, primary hyperalgesia, secondary hyperalgesia, primary hyperalgesia, secondary hyperalgesia, or other pain caused by central sensitization; complex regional pain syndromes, chronic arthritic pain and associated neuropathic pain or acute pain. In some implementations, inflammatory pain is selected from pain associated with rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis, or juvenile arthritis. In some implementations, inflammatory pain is selected from rheumatoid arthritis; rheumatoid spondylitis; gouty arthritis; juvenile arthritis; rheumatism; gout; tendinitis or bursitis of the shoulder; polymyalgia rheumatica; primary hyperalgesia; secondary hyperalgesia; primary hyperalgesia; secondary hyperalgesia; or other pain caused by central sensitization, complex regional pain syndrome, chronic or acute arthritic pain and associated neuropathic pain.

[0737] In some implementations, inflammatory pain is selected from rheumatoid arthritis pain or vulvar pain.

[0738] In some implementations, the inflammatory pain is selected from osteoarthritis, chronic osteoarthritis pain (e.g., hip or knee pain), or chronic inflammatory demyelinating polyneuropathy.

[0739] In some embodiments, the pain or pain-related disorder, impairment, or condition is musculoskeletal pain. In some embodiments, musculoskeletal pain is selected from bone and joint pain, osteoarthritis; lower back pain and neck pain; pain caused by physical trauma or amputation. In some embodiments, musculoskeletal pain is selected from bone and joint pain, osteoarthritis (e.g., knee, hip), tendinitis (e.g., shoulder), bursitis (e.g., shoulder), tenosynovitis, lower back pain and neck pain, sprains, strains, or pain caused by physical trauma or amputation.

[0740] In some implementations, pain or pain-related diseases, disorders, or conditions are pain disorders related to or associated with nerve or neuronal damage caused by a condition selected from the following: neuropathy, pain-related nerve injury, pain-related radicular avulsion, painful traumatic mononeuropathy, painful polyneuropathy, erythromelalgia, paroxysmal excruciating pain syndrome (PEPD), oral burning syndrome; central pain syndrome caused by damage at the nervous system level; traumatic nerve injury, nerve compression or entrapment, congenital insensitivity to pain (CIP), dysmenorrhea, primary erythromelalgia; HIV peripheral sensory neuropathy; pudendal neuralgia, spinal cord injury, chronic inflammatory demyelinating polyneuropathy (CIDP), carpal tunnel syndrome, or vasculitic neuropathy.

[0741] In some implementations, pain or pain-related disorders, impairments, or conditions are pain caused by trauma or pain caused by iatrogenic, medical, or dental procedures.

[0742] In some implementations, pain or pain-related disorders, impairments, or conditions include myofascial pain; myositis or muscle inflammation; repetitive movement pain; complex regional pain syndrome; sympathetic maintenance pain; pain associated with cancer, toxins, and chemotherapy; postoperative pain syndrome and / or related phantom limb pain; postoperative medical or dental surgery or treatment pain; HIV-related pain or HIV treatment-induced pain.

[0743] In some implementations, pain or pain-related disorders, impairments, or conditions are neuropathic pain or other pain-related disorders, impairments, or conditions selected from peripheral neuropathic pain, central neuropathic pain, hereditary erythromelalgia (IEM), small fiber neuralgia (SFN), paroxysmal excruciating pain syndrome (PEPD), painful diabetic neuropathy, chronic lower back pain, neuropathic back pain, sciatica, nonspecific lower back pain, multiple sclerosis pain, HIV-related neuropathy, postherpetic neuralgia, trigeminal neuralgia, vulvar pain, pain caused by physical trauma, post-amputation pain, neuroma pain, phantom limb pain, cancer, toxins, or chronic inflammatory conditions.

[0744] In some implementation schemes, pain or pain-related diseases, disorders, or conditions include acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpes zoster neuralgia, generalized neuropathic pain, epilepsy, epilepsy, neurodegenerative diseases, mental disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache, neck pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postoperative pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis (ALS), stress-induced angina, exercise-induced angina, palpitations, hypertension, or gastrointestinal motility disorders.

[0745] In some implementations, pain or pain-related disorders, disorders, or conditions include: femoral cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic lower back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; pancreatic pain; IBS pain; chronic and acute headaches; migraines; tension headaches, including cluster headaches; chronic and acute neuropathic pain, postherpetic neuralgia; diabetic neuropathy; HIV-related neuropathy; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy; peripheral nerve injury; painful neuroma; ectopic proximal and distal discharges; radiculopathy; chemotherapy-induced neuropathic pain; radiotherapy-induced neuropathic pain; post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; complex regional pain syndrome; phantom pain; intractable pain; acute pain, acute postoperative pain; acute musculoskeletal pain; arthralgia; and other related conditions. Mechanical lower back pain; neck pain; tendinitis; injury / movement pain; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernia; chest pain, angina; pelvic pain, renal colic, acute labor pain, labor pain; cesarean section pain; acute inflammatory, burn and trauma pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; breakthrough pain; maxillofacial pain, including sinusitis pain, toothache; multiple sclerosis (MS) pain; depressive pain; anesthesia. Pain from wind-related diseases; pain from Behcet's disease; painful obesity; phlebitis pain; Guillain-Barré pain; leg pain and flexor toe syndrome; Haglaud syndrome; pain from erythromelalgia; pain from Fabry disease; bladder and urogenital disorders, including urinary incontinence; hyperactive bladder; painful bladder syndrome; interstitial cystitis (IC); prostatitis; complex regional pain syndrome (CRPS), type I and II; widespread pain, paroxysmal extreme pain, itching, tinnitus, or angina-induced pain.

[0746] 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 cardiovascular diseases, disorders and conditions (including atrial fibrillation and arrhythmias).

[0747] In some implementations, the cardiovascular disease is atrial fibrillation that is essentially idiopathic or caused by a disease defined herein. Atrial fibrillation can be paroxysmal atrial fibrillation, persistent atrial fibrillation, chronic atrial fibrillation, atrial fibrillation with heart failure, atrial fibrillation with valvular heart disease, or atrial fibrillation with chronic kidney disease. In specific implementations, atrial fibrillation is selected from paroxysmal, persistent, or chronic atrial fibrillation.

[0748] In some implementations, the cardiovascular disease includes arrhythmia.

[0749] In one aspect, the present invention relates to a method of treating pain or pain-related diseases, disorders or conditions as defined herein in a subject in need, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition of the present invention as described herein.

[0750] In one embodiment, a method is provided for treating acute or chronic pain in a subject who requires it, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition of the present invention as described herein.

[0751] In one embodiment, a method is provided for treating pain caused by trauma; pain caused by iatrogenic medical treatment or dental surgery; or pain associated with preoperative or postoperative procedures in a subject in need, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition of the present invention as described herein.

[0752] In one embodiment, a method is provided for treating neuropathic pain, nociceptive pain, inflammatory pain, musculoskeletal pain, visceral pain, or idiopathic pain in a subject with this need, comprising administering to the subject a therapeutically effective amount of a compound of the present invention as described herein or a pharmaceutical composition of the present invention.

[0753] In one embodiment, a method is provided for treating 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 in a subject with this need, comprising administering to the subject a therapeutically effective amount of a compound of the present invention as described herein or a pharmaceutical composition of the present invention.

[0754] In one embodiment, a method is provided for treating inflammatory pain selected from osteoarthritis, chronic osteoarthritis pain, or chronic inflammatory demyelinating polyneuropathy in a subject with this need, comprising administering to the subject a therapeutically effective amount of a compound of the present invention as described herein or a pharmaceutical composition of the present invention.

[0755] In one aspect, the present invention relates to a method of treating atrial fibrillation as defined herein in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of the present invention as described herein or a pharmaceutical composition of the present invention.

[0756] In one implementation, a method for treating atrial fibrillation is provided, wherein the atrial fibrillation is paroxysmal atrial fibrillation, persistent atrial fibrillation, long-term atrial fibrillation, atrial fibrillation with heart failure, atrial fibrillation with valvular heart disease, or atrial fibrillation with chronic kidney disease.

[0757] In another aspect, the present invention provides compounds and pharmaceutical compositions as described herein for the treatment of pain or pain-related diseases, disorders or conditions as defined herein.

[0758] In one embodiment, the compound or pharmaceutical composition of the present invention is provided for treating acute or chronic pain.

[0759] In one embodiment, the compounds or pharmaceutical compositions of the present invention are provided for treating pain caused by trauma; pain caused by iatrogenic medical treatment or dental surgery; or pre- or post-operative pain.

[0760] In one embodiment, the compounds or pharmaceutical compositions of the present invention are provided for treating neuropathic pain, nociceptive pain, inflammatory pain, musculoskeletal pain, visceral pain, or idiopathic pain.

[0761] In one embodiment, the compounds or pharmaceutical compositions of the present invention are provided for treating 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.

[0762] In one embodiment, the compounds or pharmaceutical compositions of the present invention are provided for treating inflammatory pain selected from osteoarthritis, chronic osteoarthritis pain, or chronic inflammatory demyelinating polyneuropathy.

[0763] In another aspect, the present invention relates to the compounds of the present invention or the pharmaceutical compositions of the present invention for the treatment of atrial fibrillation.

[0764] In one embodiment, the compound of the present invention or the pharmaceutical composition of the present invention is provided for treating atrial fibrillation, wherein the atrial fibrillation is paroxysmal atrial fibrillation, persistent atrial fibrillation, chronic atrial fibrillation, atrial fibrillation with heart failure, atrial fibrillation with valvular heart disease, or atrial fibrillation with chronic kidney disease.

[0765] In another aspect, the present invention also provides the use of the compounds of the present invention or the pharmaceutical compositions of the present invention as described herein in the preparation of medicaments for treating pain and pain-related diseases, disorders and conditions as described herein.

[0766] In one embodiment, the use of the compounds or pharmaceutical compositions of the present invention in the preparation of a medicament for treating acute or chronic pain is provided.

[0767] In one embodiment, the use of the compounds or pharmaceutical compositions of the present invention in the preparation of a medicament for treating pain caused by trauma; pain caused by iatrogenic medical or dental procedures; or pain associated with preoperative or postoperative procedures is provided.

[0768] In one embodiment, the use of the compounds or pharmaceutical compositions of the present invention in the preparation of a medicament for treating neuropathic pain, nociceptive pain, inflammatory pain, musculoskeletal pain, visceral pain, or idiopathic pain is provided.

[0769] In one embodiment, the use of the compounds or pharmaceutical compositions of the present invention in the preparation of a medicament for treating 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 is provided.

[0770] In one embodiment, the use of the compounds or pharmaceutical compositions of the present invention in the preparation of a medicament for treating inflammatory pain selected from osteoarthritis, chronic osteoarthritis pain, or chronic inflammatory demyelinating polyneuropathy is provided.

[0771] In another aspect, the present invention also provides the use of the compounds of the present invention or the pharmaceutical compositions of the present invention as described herein in the preparation of a medicament for the treatment of atrial fibrillation.

[0772] In one embodiment, the use of the compounds or pharmaceutical compositions of the present invention in the preparation of a medicament for treating atrial fibrillation is provided, wherein the atrial fibrillation is paroxysmal atrial fibrillation, persistent atrial fibrillation, chronic atrial fibrillation, atrial fibrillation with heart failure, atrial fibrillation with valvular heart disease, or atrial fibrillation with chronic kidney disease.

[0773] In another aspect, the present invention relates to compounds of the present invention as described herein or pharmaceutical compositions of the present invention for therapeutic purposes.

[0774] Combination therapy and its uses in therapy

[0775] The compounds and pharmaceutical compositions of the present invention as described herein can be used in combination with one or more additional therapeutic agents. These additional therapeutic agents can be administered concurrently with, before, or after treatment with the compounds or pharmaceutical compositions of the present invention as described herein.

[0776] In the context of this specification, when referring to the simultaneous administration of a compound or therapeutic agent, the term "simultaneously" means at the same time, for example, in an embodiment where the compound and an additional therapeutic agent are combined in a single formulation, or when the compound and the additional therapeutic agent are administered separately but over a short duration or period of time.

[0777] In view of the foregoing, the present invention also relates to combination therapies, which may comprise a combination of concurrent or co-administered or sequentially administered compounds or pharmaceutical compositions of the present invention with one or more additional therapeutic agents. Such combination therapies may be used to treat pain or any pain-related disorders, impairments or conditions as defined throughout this specification, or cardiovascular diseases, disorders or conditions.

[0778] Therapeutic agents suitable for use in combination with the compounds and pharmaceutical compositions of the present invention include, but are not limited to:

[0779] Acetaminophen, acetylsalicylic acid, Nav1.7 inhibitors, Nav1.9 inhibitors, antidepressants (i.e., such as, but not limited to, duloxetine or amitriptyline), anticonvulsants (i.e., such as, but not limited to, pregabalin and gabapentin), opioids (i.e., such as, but not limited to, hydrocodone, codeine, morphine, oxycodone, oxymorphone, fentanyl, etc.), etc.; and the administration of the above-mentioned drugs is determined by those skilled in the art. In one aspect, suitable Nav1.7 inhibitors or Nav1.9 inhibitors used in this invention include, but are not limited to, those Nav1.7 inhibitors or Nav1.9 inhibitors known in the chemical literature.

[0780] Each component of the combination for therapeutic purposes (e.g., the compounds or pharmaceutical compositions of the present invention and additional therapeutic agents) may be administered orally, intravenously, or parenterously, or in combination thereof. Each component of the therapeutic combination may be administered, but is not limited to, concurrent, co-administered, or sequentially; and / or via the same or different routes of administration or combinations thereof. In some embodiments, each of the same or different routes of administration or combinations thereof is selected from oral, intravenous, or parenterical administration. Example

[0781] The following examples illustrate the present invention. These examples are not intended to limit the scope of the invention, but rather to provide guidance to those skilled in the art in preparing and using the compounds, compositions, and methods of the invention.

[0782] While specific aspects or embodiments of the invention have been described, those skilled in the art will understand that various changes and modifications can be made without departing from the spirit and scope of the invention.

[0783] Synthesis Examples

[0784] Those skilled in the art will understand that purification methods (using acidic or basic modifiers) or post-treatment processes of the compound (using acidic or basic conditions) can result in the formation of salts of the title compound (e.g., hydrobromic acid, formic acid, hydrochloric acid, trifluoroacetic acid, or ammonium salts of the title compound). This invention is intended to cover such salts.

[0785] The final compounds were characterized by LCMS or GCMS (under the conditions listed below) and NMR. 1 H NMR or 19 FNMR spectra were recorded using a Bruker Avance III 500 MHz spectrometer, a Bruker Avance 400 MHz spectrometer, and a Varian MercuryPlus-300 MHz spectrometer. CDCl3 was deuterium chloroform, DMSO-d6 was hexadeuterium dimethyl sulfoxide, and CD3OD was tetradeuterium methanol. Chemical shifts were reported in parts per million (ppm) from the internal standard tetramethylsilane (TMS) or NMR solvent to a low magnetic field. NMR data abbreviations are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = double doublet, dt = double triplet, app = apparent, br = broad peak. J indicates the NMR coupling constant.

[0786] Analysis method:

[0787] 1) LCMS method: Acquity UPLC with Waters Acquity QDa mass detector, using electrospray positive ion [ES+ve] to give M+H + Equipped with a CSH C18 column (30 mm × 2.1 mm, 1.7 μm inner diameter, packed diameter), the following elution gradient was used at 45 °C, eluting with water containing 0.1% TFA (solvent A) and acetonitrile containing 0.1% TFA (solvent B): 1-100% (solvent B), for 1.85 min at a flow rate of 1.3 ml / min.

[0788] 2) LCMS method: Acquity UPLC with Waters Acquity QDa mass detector, using electrospray positive ion [ES+ve] to give M+H + Equipped with a CSH C18 column (30 mm × 2.1 mm, 1.7 μm inner diameter, packed diameter), the following elution gradient was used at 45 °C, eluting with water containing formic acid (solvent A) and acetonitrile containing formic acid (solvent B): 1-100% (solvent B), for 1.85 min, at a flow rate of 1.3 ml / min.

[0789] 3) LCMS method: Acquity UPLC with Waters Acquity QDa mass detector, using electrospray positive ion [ES+ve] to give M+H +Equipped with a CSH C18 column (30 mm × 2.1 mm, 1.7 μm inner diameter, packed diameter), the following elution gradient was used at 45 °C, eluting with water containing 10 mM ammonium bicarbonate (adjusted to pH = 10 with 25% ammonium hydroxide solution, solvent A) and acetonitrile (solvent B): 1-100% (solvent B), for 1.85 min at a flow rate of 1.3 ml / min.

[0790] 4) LCMS method: An Agilent 1290 Infinity II LC system with Agilent MSD 6125B / 6130 was used, employing multiple modes (ESI and APCI +ve and –ve), equipped with a Sunfire C18 column (30mm × 2.1mm, 3.5μm inner diameter packing diameter), using the following elution gradient at 25°C, eluted with water containing 0.1% formic acid (solvent A) and acetonitrile containing 0.1% formic acid (solvent B): 0-100% (solvent B), for 3.1 min, followed by a hold at 100% for 0.8 min, at a flow rate of 1.0 ml / min.

[0791] 5) LCMS method: An Agilent 1290 Infinity II LC system with Agilent MSD 6125B / 6130 was used, employing multiple modes (ESI and APCI +ve and –ve), equipped with an Atlantis dC18 column (50 mm × 4.6 mm, 5.0 μm inner diameter packing diameter), using the following elution gradient at 25 °C, eluted with water (solvent A) and methanol (solvent B) containing 0.1% TFA: 5-95% (solvent B), for 5.0 min, followed by a hold at 95% for 1.5 min, at a flow rate of 1.0 ml / min.

[0792] 6) LCMS method: An Agilent 1290 Infinity II LC system with Agilent MSD 6125B / 6130 was used, employing multiple modes (ESI and APCI +ve and -ve), equipped with a Zorbax XDB C18 column (50mm × 4.6mm, 3.5μm inner diameter, packed diameter), using the following elution gradient at 25°C, eluted with water (solvent A) and acetonitrile (solvent B) containing 10mM ammonium acetate: Solvent B: 10-95% (solvent B), for 3.5 min, followed by a hold at 95% for 1.0 min, at a flow rate of 1.0 ml / min.

[0793] 7) LCMS method: An Agilent 1290 Infinity II LC system with Agilent MSD 6125B / 6130 was used, employing multiple modes (ESI and APCI +ve and -ve), equipped with an Xbridge C8 column (50mm × 4.6mm, 3.5μm inner diameter packing diameter), using the following elution gradient at 25°C, eluting with water (solvent A) and acetonitrile (solvent B) containing 10mM ammonium bicarbonate: 10-95% (solvent B), for 4.0 min, followed by a hold at 95% for 1.0 min, at a flow rate of 1.0 ml / min.

[0794] 8) GCMS method: An Agilent 7890B GC system with an Agilent MSD 5977B was used with EI and equipped with an HP-5 column (30m x 0.32mm, 0.25μm film thickness). Elution was performed at 250°C with helium at a flow rate of 2mL / min and a run time of 10 minutes under the following chromatographic run conditions: 120°C for 1 minute, ramped up to 300°C at 40°C / min and held for 4.5 min.

[0795] The following abbreviations may be used in the following experimental descriptions:

[0796]

[0797]

[0798]

[0799]

[0800]

[0801]

[0802] Intermediate 1

[0803] methyl 5-bromo-2-chloroisonicotinic acid

[0804]

[0805] Thionyl chloride (2.78 mL, 38.1 mmol) was added to a stirred methanol (25 mL) solution of 5-bromo-2-chloroisonicotinic acid (3 g, 12.69 mmol) at 0 °C, and the reaction mixture was heated at 80 °C for 3 hours. The reaction was cooled and concentrated. The resulting brown solid was diluted with water (50 mL) and extracted with EtOAc (2 x 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 (1.88 g, 7.40 mmol, 58.3% yield) as a brown oil. MS (m / z) 251.9 (M+3H) + .

[0806] Intermediate 2

[0807] 4-Bromo-6-(trifluoromethyl)nicotinic acid ethyl ester

[0808]

[0809] Under N2 atmosphere at room temperature, potassium carbonate (0.614 g, 4.44 mmol) was added to a DMF (10 mL) solution of 4-bromo-6-(trifluoromethyl)nicotinic acid (1 g, 3.70 mmol) and iodoethane (0.329 mL, 4.07 mmol) under stirring. After stirring at 27 °C for 3 hours, the reaction mixture was diluted with ice-cold water (250 mL) and extracted with Et2O (2 x 100 mL). The combined organic extracts were washed with ice-cold water (200 mL), dried over Na2SO4, and concentrated under reduced pressure to give the title compound (1.1 g, 3.21 mmol, 87% yield) as a brown oil. MS (m / z) 300.0 (M + 3H) + .

[0810] Intermediate 3 is prepared from the specified carboxylic acid by methods similar to those described for intermediate 2.

[0811]

[0812] Intermediate 4

[0813] 3-Bromo-6-methoxypyridine-2-carboxylic acid

[0814]

[0815] At 0 °C, sodium methoxide (25% wt% methanol solution) (7.78 mL, 34.0 mmol) was added dropwise over 2 minutes to a stirred solution of ethyl 3-bromo-6-chloropyridine-2-carboxylate (1.5 g, 5.67 mmol) in 5 mL of methanol. After stirring at 60 °C for 6 hours, the solvent was removed under vacuum, and the pH of the residue was adjusted to 5–6 with aqueous citric acid. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were concentrated under vacuum to give the title compound (1.02 g, 3.85 mmol, 67.9% yield) as a grayish-white solid. MS (m / z) 234.0 (M+3H) + .

[0816] Intermediate 5

[0817] ethyl 3-bromo-6-methoxypyridine-2-carboxylate

[0818]

[0819] This intermediate was prepared from 3-bromo-6-methoxypyridine-2-carboxylic acid by methods similar to those described for intermediate 2. MS (m / z) 262.0 (M+3H) + .

[0820] Intermediate 6

[0821] 5-Bromo-2-(trifluoromethyl)isonicotinic acid ethyl ester

[0822]

[0823] Sulfuric acid (0.296 mL, 5.56 mmol) was added to a suspension of 5-bromo-2-(trifluoromethyl)isonicotinic acid (500 mg, 1.852 mmol) in ethanol (3 mL), resulting in an exothermic reaction. The reaction mixture was sealed, stirred, and heated to 70 °C. After approximately 5 minutes, a solution formed, and stirring was continued for another 4 hours. The reaction mixture was diluted with water (7 mL), alkalized with 2 M NaOH (aqueous solution), and then extracted into EtOAc (2 x 5 mL). The combined organic matter was filtered through a hydrophobic glass filter, dried, and concentrated to give the title compound (443 mg, 1.486 mmol, 80% yield) as a pale yellow oil / solid. MS (m / z) 299.9 (M+3H) + .

[0824] Intermediate 7

[0825] Ethyl 3-amino-3-imino-2-nitrosopropionate

[0826]

[0827] At 0 °C, acetic acid (10.31 mL, 180 mmol) and sodium nitrite (12.42 g, 180 mmol) were added to a stirred solution of ethyl 3-amino-3-iminopropionic acid hydrochloride (10 g, 60.0 mmol) in water (30 mL). 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) + .

[0828] Intermediate 8

[0829] Ethyl 2,3-diamino-3-iminopropionic acid, 2-hydrochloride

[0830]

[0831] Under N2 atmosphere, Pd / C (10 wt%) (1.605 g, 1.508 mmol) was added to a solution of ethyl 3-amino-3-imino-2-nitrosopropionate (6 g, 37.7 mmol) in ethanol (120 mL) and HCl aqueous solution (5 M) (120 mL, 600 mmol) under stirring. The reaction mixture was stirred at room temperature under hydrogen (1 atm) for 40 hours. The mixture was filtered and concentrated. The resulting off-white solid was dissolved in EtOH (60 mL) and HCl aqueous solution (60 mL). Pd / C (10 wt%) (0.8 g, 0.752 mmol) was added under N2, and the reaction was stirred at room temperature under hydrogen (1 atm) for 16 hours. The reaction mixture was then filtered through... The solution was filtered and concentrated to give the title compound as a grayish-white solid (5.5 g, 24.97 mmol, 66.2% yield). MS (m / z) 146.1 (M+H) + .

[0832] Intermediate 9 and Intermediate 10

[0833] 3-Amino-5-(trifluoromethyl)pyrazine-2-carboxylic acid ethyl ester and 3-amino-6-(trifluoromethyl)pyrazine-2-carboxylic acid ethyl ester

[0834]

[0835] To a stirred aqueous solution of ethyl 2,3-diamino-3-iminopropionate (4 g, 27.6 mmol), 3,3,3-trifluoro-2-oxopropanal (20 wt% aqueous solution) (24.31 g, 38.6 mmol) and sodium acetate (15.82 g, 193 mmol) were added. 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 Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (Biotage Isolera, 100 g Si2O SNAP column, 3% EtOAc / petroleum ether, for 15 min) to obtain...

[0836] Ethyl 3-amino-5-(trifluoromethyl)pyrazine-2-carboxylate (750 mg, 3.16 mmol, 11.46% yield), grayish-white solid. MS (m / z) 236.1 (M+H) +

[0837] Ethyl 3-amino-6-(trifluoromethyl)pyrazine-2-carboxylate (440 mg, 1.852 mmol, 6.72% yield), off-white solid. MS (m / z) 236.0 (M+H) +

[0838] Intermediate 11

[0839] 4-Fluoro-1-nitro-2-(prop-1-en-2-yl)benzene

[0840]

[0841] A 2.5 L 4-necked round-bottom flask equipped with a magnetic stir bar and an N2 inlet contained 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-dioxaborhecyclopentane (103 g, 615 mmol), and a PdCl2(dppf)-CH2Cl2 adduct (20.93 g, 25.6 mmol). The flask was purged with N2 for 30 min, then stirred at 80 °C for 16 h. The reaction mixture was cooled to room temperature, purged with N2 for 20 min, and the PdCl2(dppf)-CH2Cl2 adduct (2.093 g, 2.56 mmol) was added, followed by stirring at 80 °C for another 16 h. The reaction mixture was cooled to room temperature and then... The sample was filtered through a pad and washed with EtOAc (300 mL). The filtrate was concentrated, and the residue was washed with water (500 mL), dried over Na₂SO₄, and concentrated under vacuum to give the title compound as a brown oil (120 g, 489 mmol, 95% yield). GCMS (m / z) 181 (M) +

[0842] Intermediate 12

[0843] 3,4-Difluoro-2-vinylaniline

[0844]

[0845] This intermediate was prepared by methods similar to those described for intermediate 11, using 2-bromo-3,4-difluoroaniline and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborhecyclopentane instead of 2-chloro-4-fluoro-1-nitrobenzene and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborhecyclopentane. MS (m / z) 156.0 (M+H) + ).

[0846] Intermediate 13

[0847] 4-Fluoro-2-isopropylaniline

[0848]

[0849] A solution of 120 g (662 mmol) of 4-fluoro-1-nitro-2-(prop-1-en-2-yl)benzene in 2 L of EtOAc was hydrogenated with Pd / C (10 wt%) (30 g, 28.2 mmol) for 16 hours at room temperature and 1 atm hydrogen pressure. The reaction mixture was then subjected to… The solution was filtered through a bed and washed with EtOAc (2 L). The filtrate was concentrated and purified by column chromatography (Biotage Isolera, 340 g Si₂O column, 0-20% EtOAc / petroleum ether, for 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) + .

[0850] Intermediates 14-15 are prepared from the specified aryl group by methods similar to those described for intermediate 13.

[0851]

[0852] Intermediate 16

[0853] 5-Fluoro-6-methoxy-2-methylpyridine-3-amine

[0854]

[0855] At room temperature, an aqueous solution of HCl (1.5 M, 200 mL, 300 mmol) was added to a solution of N-(5-fluoro-6-methoxy-2-methylpyridin-3-yl)-1,1-diphenylmethyleneimine (24 g, 74.9 mmol) in 1,4-dioxane (120 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was combined with another reaction carried out on N-(5-fluoro-6-methoxy-2-methylpyridin-3-yl)-1,1-diphenylmethyleneimine in a 25 g scale, diluted with ice-water (50 mL), and extracted with DCM (80 mL x 3). The combined organic extracts were slowly neutralized with solid NaHCO3 until pH 8 and extracted with DCM (150 mL x 3). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to give the title compound (20 g, 126 mmol, 168% yield) as a pale yellow solid. MS(m / z) 157.2(M+H) + .

[0856] Intermediate 17

[0857] 4-((4-fluoro-2-methylphenyl)amino)-6-(trifluoromethyl)nicotinic acid ethyl ester

[0858]

[0859] 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 N2 for 15 min, followed by the addition of BINAP (0.230 g, 0.369 mmol) and Pd2(dba)3 (0.169 g, 0.185 mmol). The reaction mixture was purged with N2 for 5 min and stirred at 90 °C for 15 h. The reaction was cooled and subjected to [further action]. The sample was filtered through a pad and washed with EtOAc (80 mL). The filtrate was concentrated and purified by column chromatography (Biotage Isolera, 50 g Si₂O column, 0-20% EtOAc / petroleum ether, for 1 hour) 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) + .

[0860] Intermediates 18-32 are prepared from specified aryl halides and aniline by methods similar to those described for intermediate 17.

[0861]

[0862]

[0863] Intermediate 33

[0864] ethyl 3-((4-fluoro-2-methylphenyl)amino)-5-(trifluoromethyl)pyrazine-2-carboxylate

[0865]

[0866] At room temperature, 4-fluoro-1-iodo-2-methylbenzene (1054 mg, 4.46 mmol) and cesium carbonate (1455 mg, 4.46 mmol) were added to a toluene (20 mL) solution of ethyl 3-amino-5-(trifluoromethyl)pyrazine-2-carboxylate (700 mg, 2.98 mmol). The resulting reaction mixture was purged with N2 for 10 min, and then Pd2(dba)3 (68.1 mg, 0.074 mmol) and (9,9-dimethyl-9H-xanthon-4,5-diyl)bis(diphenylphosphine) (86 mg, 0.149 mmol) were added. The reaction mixture was stirred in a sealed tube at 90 °C for 16 h. Ice water (20 mL) was added, and the reaction was extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and evaporated under vacuum. The crude product was adsorbed onto 10 mL of DCM containing 1 g of silica and purified by rapid chromatography (Isolera, 50 g Si₂O 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) + .

[0867] Intermediate 34 is prepared from a specified aryl halide and aniline by methods similar to those described for intermediate 33.

[0868]

[0869] Intermediate 35

[0870] ethyl 3-((4-fluoro-2-isopropylphenyl)amino)-6-hydroxypyridine-2-carboxylate

[0871]

[0872] At 0 °C and under N2, trimethyliodosilane (0.717 mL, 5.27 mmol) was added to a stirred solution of ethyl 3-((4-fluoro-2-isopropylphenyl)amino)-6-methoxypyridine-2-carboxylate (0.7 g, 2.106 mmol) in acetonitrile (10 mL), and the reaction mixture was stirred at 80 °C for 1 hour. The reaction mixture was cooled 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 Na2SO4 and concentrated under vacuum to give the title compound as a pale yellow solid (700 mg, 1.690 mmol, 80% yield). MS (m / z) 319.1 (M+H) + .

[0873] Intermediate 36

[0874] 3-((4-fluoro-2-methylphenyl)amino)-5-(trifluoromethyl)pyridine-2-carboxylic acid

[0875]

[0876] To a solution of methyl 3-chloro-5-(trifluoromethyl)pyridine-2-carboxylate (1.5 g, 6.26 mmol) in 1,4-dioxane (20 mL) under stirring, 4-fluoro-2-methylaniline (1.567 g, 12.52 mmol), BINAP (0.390 g, 0.626 mmol), Cs₂CO₃ (4.08 g, 12.52 mmol), and Pd₂dba₂ (0.287 g, 0.313 mmol) were added. The reaction mixture was purged with N₂ for 5 min and then stirred at 100 °C for 12 h. After cooling, water (50 mL) was added, and the mixture was washed with EtOAc (25 mL). The aqueous layer was acidified with 1.5 NHCl (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) + .

[0877] Intermediate 37

[0878] 4-((4-fluoro-2-methylphenyl)amino)-2-(trifluoromethyl)pyrimidin-5-carboxylic acid

[0879]

[0880] At room temperature, a solution of 4-((4-fluoro-2-methylphenyl)amino)-2-(trifluoromethyl)pyrimidine-5-carboxylate (6 g, 17.48 mmol) in 40.0 mL of THF was added dropwise over 5 minutes with stirring. The resulting reaction mixture was stirred at 60 °C for 16 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was acidified with 1.5 N HCl (100 mL) until pH ~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) + .

[0881] Intermediates 38-54 are prepared from the specified esters by methods similar to those described for intermediate 37.

[0882]

[0883]

[0884] Intermediate 55

[0885] 4-((2-ethyl-4-fluorophenyl)amino)-6-(trifluoromethyl)nicotinic acid

[0886]

[0887] 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. The precipitate was 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) + .

[0888] Intermediate 56

[0889] 3-((4-fluoro-2-methylphenyl)amino)-N-(6-methoxy-2-methylpyridin-3-yl)-5-(trifluoromethyl)pyridin-2-carboxamide

[0890]

[0891] To a DMF (20 mL) solution of 3-((4-fluoro-2-methylphenyl)amino)-5-(trifluoromethyl)pyridine-2-carboxylic acid (2 g, 6.36 mmol) under stirring, 6-methoxy-2-methylpyridine-3-amine (0.879 g, 6.36 mmol), HATU (2.420 g, 6.36 mmol), and TEA (0.887 mL, 6.36 mmol) were added. After stirring at 25 °C for 1 hour, cold water (50 mL) was added, and the reaction was stirred for another 1 hour. The solid precipitate was collected by filtration and washed with Et₂O (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) + .

[0892] Intermediates 57-73 are prepared from specified amines and carboxylic acids by methods similar to those described for intermediate 56.

[0893]

[0894]

[0895]

[0896]

[0897] Intermediate 74

[0898] 4-((4-fluoro-2-methylphenyl)amino)-N-(6-methoxy-2-methylpyridin-3-yl)-2-(trifluoromethyl)pyrimidin-5-carboxamide

[0899]

[0900] A solution of 4-((4-fluoro-2-methylphenyl)amino)-2-(trifluoromethyl)pyrimidin-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 N2. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting yellow solid residue was dissolved in DCM (10 mL) and cooled to 0 °C. Under N2, 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) was added dropwise over 5 minutes. After stirring at room temperature under N2 for 2 hours, the reaction mixture was cooled to 0 °C, quenched with water (25 mL), and extracted with DCM (3 x 50 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), and saturated NaHCO3 (25 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (Biotage, 50 g Si2O SNAP column, 0-50% EtOAc / petroleum ether, for 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) + .

[0901] Intermediates 75-76 are prepared from specified amines and carboxylic acids by methods similar to those described for intermediate 74.

[0902]

[0903] Intermediate 77

[0904] 1-(4-fluoro-2-methylphenyl)-3-(6-methoxy-2-methylpyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydropyrido[3,2-d]pyrimidin-4(1H)-one

[0905]

[0906] To a stirred solution of 3-((4-fluoro-2-methylphenyl)amino)-N-(6-methoxy-2-methylpyridin-3-yl)-5-(trifluoromethyl)pyridin-2-carboxamide (1.1 g, 2.53 mmol) in acetonitrile (15 mL), Cs₂CO₃ (3.30 g, 10.13 mmol) and diiodomethane (2.035 g, 7.60 mmol) were added, 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 Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage Isolera, 10 g Si₂OSNAP column, 2–9% EtOAc / petroleum ether, for 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) + .

[0907] Intermediates 78-96 are prepared from the specified amides by methods similar to those described for intermediate 77.

[0908]

[0909]

[0910]

[0911] Intermediate 97

[0912] 1-(4-fluoro-2-isopropylphenyl)-6-hydroxy-3-(6-methoxy-2-methylpyridin-3-yl)-2,3-dihydropyrido[3,2-d]pyrimidin-4(1H)-one

[0913]

[0914] Under N2 atmosphere, PTSOH (134 mg, 0.707 mmol) and paraformaldehyde (849 mg, 28.3 mmol) were added to a toluene (5 mL) solution of 3-((4-fluoro-2-isopropylphenyl)amino)-6-hydroxy-N-(6-methoxy-2-methylpyridin-3-yl)pyridine-2-carboxamide (290 mg, 0.707 mmol) under stirring, and the reaction mixture was stirred at 100 °C for 1 hour. The reaction mixture was cooled to room temperature, quenched with saturated NaHCO3 (15 mL), and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (Isolera, 25 g Si₂O SNAP column, 2-5% MeOH / DCM, for 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) + .

[0915] Intermediate 98

[0916] 6-Chloro-1-(4-fluoro-2-isopropylphenyl)-3-(6-methoxy-2-methylpyridin-3-yl)-2,3-dihydropyrido[3,2-d]pyrimidin-4(1H)-one

[0917]

[0918] Under N2 atmosphere and at 0 °C, POCl3 (0.8 mL, 8.58 mmol) was added 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), and the reaction mixture was stirred at 90 °C for 18 hours. The reaction was cooled to 0 °C, and more POCl3 (0.1 mL, 1.073 mmol) was added. The reaction was stirred at 90 °C for 1 hour, and then cooled to room temperature. At 0 °C, the reaction mixture was slowly poured into a saturated NaHCO3 solution (15 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under vacuum to give a crude title compound (90 mg) as a pale yellow liquid. MS(m / z) 441.1(M+H) + .

[0919] Intermediate 99

[0920] 1-(4-fluoro-2-methylphenyl)-3-(6-methoxy-2-methylpyridin-3-yl)-4-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidine-7-carboxynitrile

[0921]

[0922] To a DMF (2 mL) 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), zinc cyanide (45.5 mg, 0.388 mmol) and tetrakis (44.8 mg, 0.039 mmol) were added. The reaction mixture was heated in a microwave oven at 150 °C for 1 hour. The crude product was purified by column chromatography (Isco, 10-70% EtOAc / hexane) to give the title product as a grayish-white solid (66 mg, 0.162 mmol, 84% yield). MS (m / z) 404.4 (M+H) + .

[0923] Intermediate 100

[0924] 5-((3,4-difluoro-2-methylphenyl)amino)-2-(trifluoromethyl)isonicotinic acid, hydrochloride

[0925]

[0926] Cesium carbonate (32.1 g, 99 mmol) was added to a mixture of methyl 5-bromo-2-(trifluoromethyl)isonicin (14 g, 49.3 mmol) and 3,4-difluoro-2-methylaniline (8.47 g, 59.1 mmol) in 1,4-dioxane (224 mL), followed by Pd₂(dba)₃ (2.257 g, 2.465 mmol) and 2,2'-bis(diphenylphosphine)-1,1'-binaphthyl (3.07 g, 4.93 mmol). The mixture was stirred overnight at 100 °C under nitrogen. The reaction was cooled and filtered through diatomaceous earth. The crude solution was heated at 65 °C with 5N sodium hydroxide (49.3 mL, 246 mmol) for 40 minutes. The solution was cooled, and 75 mL of 6N HCl was added with stirring to give a yellow suspension. The solid was obtained by filtration, and a second batch of solids was also collected. The solids were combined and slurried with 100 mL of diethyl ether, sonicated, and filtered to obtain a lemon-yellow solid. This solid was dried under vacuum for 18 hours to provide a yellow solid of 5-((3,4-difluoro-2-methylphenyl)amino)-2-(trifluoromethyl)isonicotinic acid hydrochloride (13.25 g, 35.9 mmol, 72.9% yield). MS (m / z) 331.1 (M+H)+ . 1 H NMR(400MHz, DMSO-d6)δ9.47(s,1H)8.06-8.16(m,1H)7.97-8.06(m,1H)7.30-7.41(m,1H)7.18-7.31(m,1H)3.37(br s,3H)2.17(s,3H).

[0927] Intermediate 101

[0928] 5-((3,4-difluoro-2-methylphenyl)amino)-N-(6-methoxy-2-methylpyridin-3-yl)-2-(trifluoromethyl)isonicotinamide

[0929]

[0930] A mixture of 5-((3,4-difluoro-2-methylphenyl)amino)-2-(trifluoromethyl)isonicotinic acid salt (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 obtain a solution at 25 °C. T3P (88 mL, 149 mmol, 50% ethyl acetate solution) was then added, and the reaction was stirred at 25 °C for 2 hours, followed by filtration. The filtrate was treated with 150 mL of 1N HCl and 50 mL of LEtOAc to separate the organic matter. The solution was washed with 150 mL of saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a light brown solid. This solid was ground 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 under vacuum to give a dark oily solid, which was then ground again with about 30 mL of MTBE and filtered to give 4 g of white solid product. The filtrate was concentrated under vacuum and ground again with 15 mL of MTBE to give more than 0.6 g of product. The solids were combined to give the title compound as a pink solid (19 g total, 42.0 mmol, 78% yield). The remaining filtrate was evaporated under vacuum to give a dark brown gum-like substance (4.4 g) pre-adsorbed onto silica. The residue was purified by column chromatography (Isco CombiFlash Rf, 0% to 30% gradient of EtOAc in heptane; 80 g RediSep column). The purified fraction was collected and concentrated under vacuum to separate an additional 2.9 g (6.4 mmol, 12% yield) of the title product as a pink solid. MS (m / z) 453.1 (M+H) + . 1H NMR(400MHz, DMSO-d6)δ10.44(s,1H)9.50(s,1H)8.23(d,J=15.16Hz,2H)7.64(d,J=8.80Hz,1H) 7.29-7.37(m,1H)7.16-7.29(m,1H)6.71(d,J=8.31Hz,1H)3.86(s,3H)2.37(s,3H)2.17(s,3H).

[0931] Intermediate 102

[0932] 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

[0933]

[0934] 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) at Tj = 99 °C in a 2 L flask equipped with a reflux condenser. The mixture was stirred for 18 hours. The reaction was incomplete, so diiodomethane (9.81 ml, 122 mmol) was added and the mixture was refluxed for more than 4 hours, then cooled, filtered through a diatomaceous earth mat, and concentrated under vacuum. The resulting solid was dissolved in dichloromethane and loaded onto 35 g of silica gel, then dried and loaded onto an Isco CombiFlash Rf column for silica gel chromatography (0% to 30% EtOAc in heptane solution, 25 min gradient; 330 g RediSep column). The pure fraction was collected and the product was separated by vacuum concentration to obtain a pale yellow solid, 14.7 g. This powder was dissolved in 30 mL of DCM and purified by silica gel chromatography on an Isco CombiFlash Rf column (0% to 25% EtOAc in heptane solution, 25 min gradient; 330 g RediSep column). The pure fraction was collected and the product was separated by vacuum concentration to obtain the title compound as a brownish-yellow powder (13.7 g, 29.5 mmol, 72.6% yield). MS (m / z) 465.1 (M+H) + . 1H NMR(400MHz,DMSO-d6)δ8.07(s,1H)7.84-8.01(m,1H)7.66(br d,J=8.31Hz,1H)7.39-7.53(m,1H)7.31-7.38(m,1H)6.75(d,J=9.29Hz,1H)4.92-5.68(m,2H)3.85(s,3H)2.28-2.38(m,3H)2.25(s,3H).

[0935] Example 1

[0936] 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

[0937]

[0938] At room temperature and under N2, trimethyliodosilane (578 mg, 2.89 mmol) was added dropwise 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). 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 reversed-phase HPLC (Sunfire C18 (19 x 150 mm) 5 μm column, 0.1% formic acid in water / ACN solution) to give the title compound as a white solid (120 mg, 0.275 mmol, 28.5% yield). 1 HNMR (400MHz, DMSO-d6) δ: 11.80 (s, 1H), 8.53 (s, 1H), 7.43-7.38 (m, 2H), 7.33 (dd, J = 2.8, 9.6Hz, 1H), 7.25-7, 15 ( m,1H),6.92-6.75(m,1H),6.21(d,J=9.6Hz,1H),5.60-4.80(m,2H),2.25(s,3H),2.13(s,3H).MS(m / z)433.0(M+H) + .

[0939] Examples 2-8 were prepared from designated intermediates using methods similar to those described in Example 1.

[0940]

[0941]

[0942]

[0943] Example 9

[0944] 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

[0945]

[0946] Under N2 atmosphere at 0 °C, p-toluenesulfonic acid monohydrate (97 mg, 0.508 mmol) and lithium chloride (21.52 mg, 0.508 mmol) were added to a DMF (1 mL) 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) under stirring. The reaction mixture was stirred at 120 °C for 2 hours and then cooled to 25 °C. The reaction was quenched with ice water (15 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting brownish resinous substance was purified by reversed-phase HPLC (X-bridge C18 (19x150mm) 5μm column, 10mM NH4HCO3 in water / ACN solution) to give the title compound as a grayish-white solid (16mg, 0.037mmol, 36.5% yield). 1 H 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=9.3Hz,1H),5.48(d,J=9.6Hz,0.6H),5.22(d,J=10.4Hz,0. 4H),4.97(d,J=10.4Hz,0.4H),4.72(d,J=9.6Hz,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) + .

[0947] Examples 10-11 were prepared from designated intermediates using methods similar to those described in Example 9.

[0948]

[0949] Example 12

[0950] 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

[0951]

[0952] Trimethylchlorosilane (0.838 mL, 6.61 mmol) was added 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), and the reaction was stirred at 60 °C for 3 hours. The reaction mixture was diluted with DCM (30 mL), washed with an aqueous solution of Na₂S₂O₃, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by passing it through an MDAP (XSELECT CSH C18 (150 mm x 30 mm) 5 μm column, A = 0.1% v / v formic acid aqueous solution, B = 0.1% v / v formic acid acetonitrile solution, 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 (400MHz, DMSO-d6) δ: 11.80 (br s, 1H), 8.19 (d, J = 4.89Hz, 1H), 7.73 (d, J = 4.89Hz, 1H), 7.65 (br s,1H),7.44-7.34(m,2H),7.31(dd,J=9.29,2.93Hz,1H),7.22-7.13(m,1H),6.20(d,J=9.78Hz,1H),5.60-4.73(m,2H),2.27(s,3H),2.09(br s,3H). MS(m / z)365.3(M+H) + .

[0953] 1H NMR (400MHz, DMSO-d6) δ: 11.80 (br s, 1H), 8.19 (d, J = 4.89Hz, 1H), 7.73 (d, J = 4.89Hz, 1H), 7.65 (br s,1H),7.44-7.34(m,2H),7.31(dd,J=9.29,2.93Hz,1H),7.22-7.13(m,1H),6.20(d,J=9.78Hz,1H),5.60-4.73(m,2H),2.27(s,3H),2.09(br s,3H). MS(m / z)365.3(M+H) + .

[0954] Example 17

[0955] 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

[0956]

[0957] 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, 5 N isopropanol solution) in 73.8 mL of isopropanol was heated under reflux (Tj = 91 °C) for 12 hours, followed by heating at room temperature for 6 hours. The mixture was concentrated under vacuum to an orange foamy oil, which was then partitioned between 100 mL each of EtOAc and saturated sodium bicarbonate aqueous solution. The aqueous layer was back-extracted with 50 mL of EtOAc, and the combined organic matter was washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to a light brown foamy substance. The foamy substance was dissolved in 15 mL of dichloromethane. After 30 minutes, a solid precipitated out 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 column (1:1 ethyl acetate:heptane to 70% 3:1 EtOAc:EtOH; 330 g RediSep column, 20 min). The pure fraction was collected and the product was separated by vacuum concentration and dried under high vacuum for 18 hours to give a further amount of the title compound (4.1 g, 9.1 mmol, 30.9% yield) as a grayish-white solid. MS (m / z) 451.1 (M+H) + . 1H NMR(700MHz,DMSO-d6)δppm 11.18-12.29(m,1H)8.00-8.07(m,1H)7.79-7.96(m,1H)7.43-7.51(m,1H)7.37-7.43(m,1H)7 .29-7.36(m,1H)6.21(d,J=9.47Hz,1H)4.90-5.55(m,2H)2.19-2.29(m,3H)2.02-2.16(m,3H).

[0958] Example 17a

[0959] 1-(3,4-Difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl) Prepared in crystalline form of 2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one

[0960] Form 1

[0961] 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. 14 mL (7 volumes) of MeOH was added, and the contents were shaken at 25 °C and 750 rpm. The temperature was raised to 50 °C, and complete dissolution occurred within approximately 15 minutes. Solidification began approximately 10 minutes after dissolution. These solids were allowed to grow for approximately 10 minutes to produce 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 crystals were then matured by reheating to 63 °C at a rate of 1.0 °C / min and holding for 4 hours, and finally cooled again to 25 °C at a rate of 0.1 °C / min and held overnight. The contents were filtered to remove the crystalline solid, and the mixture was placed in a vacuum oven at 60°C overnight to give 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 - see XRPD and DSC, Table 1 and...). Figure 1 and 2 ).

[0962] Form 2

[0963] 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 12 x 2 mL HPLC vial. 500 μL of each solvent was added to each vial. The vial was then stirred at 750 rpm at 25 °C. The temperature was increased to 50 °C. In those vials that showed physical changes in the input substance, the solids were filtered off and run on XRPD. The solvents that showed physical changes in the input substance were isopropanol, isopropyl acetate, and 1-butanol. The crystalline substances separated from these solvents appeared to form XRPD of pattern 2 (see XRPD and DSC, Table 1 and...). Figure 3 and Figure 4 ).

[0964] Form 3

[0965] 1.0 g of amorphous (chromatographic, rotary evaporation) 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 20 mL vial. 5 mL (5 volumes) of EtOH was added, and complete dissolution of the input was achieved at 25 °C. The solution was clarified and filtered, and the mother liquor was added to a separate, clean 20 mL vial. The vial was opened and evaporated over three days. The contents were slurried in 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-see XRPD, Table 1 and Figure 5 ).

[0966] Form 4

[0967] 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 was added to a 20 mL vial. 7.5 mL of MeCN (15 volumes) was added to the vial, and the contents were shaken at 25 °C and 750 rpm. The input substance dissolved completely within approximately 5 minutes. The temperature was raised to 30 °C, and solid particles began to form within 5 minutes. Mixing was continued at this temperature for another 30 minutes, during which time the contents became a thicker but well-mixed slurry. The temperature was raised 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 lowered to 25 °C at a rate of 0.1 °C / min and held for 1 hour. The temperature was then cyclically increased to 63°C at a rate of 1.0°C / min and held for 4 hours, and finally cooled again to 25°C at a rate of 0.1°C / min and held overnight. The contents were filtered and aspirated until atomized the next morning. The crystalline solid was then placed in a vacuum oven at 60°C overnight to obtain 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-). See XRPD and DSC, Table 1 and... Figure 6 and 7 ).

[0968] XRPD - Characteristic peaks and d-spacing of forms 1 to 4 when using Cu Kα radiation measurements

[0969]

[0970]

[0971] Table 1

[0972] Examples 14-16 and 18-21 were prepared from designated intermediates using methods similar to those described in Example 12.

[0973]

[0974]

[0975]

[0976] Example 22

[0977] 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-carboxynitrile

[0978]

[0979] To a DMF (2 mL) 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), zinc cyanide (44.2 mg, 0.376 mmol) and tetrakis (43.5 mg, 0.038 mmol) were added. The reaction mixture was heated at 150 °C overnight, and then heated in a microwave oven at 150 °C for 1 hour. The reaction mixture was cooled and subjected to... The sample was filtered and purified by MDAP (XSELECT CSH C18 (150 mm x 30 mm) 5 μm column, A = 0.1% v / v formic acid aqueous solution, B = 0.1% v / v formic acid acetonitrile solution, 15-55% B, gradient time 3-22 min) to give the title product as a grayish-white solid (50 mg, 0.127 mmol, 67.6% yield). 1 H NMR (400MHz, DMSO-d6) δ: 11.83 (br s, 1H), 8.19 (br s, 1H), 7.69 (br d,J=19.6Hz,1H),7.49(dd,J=5.4,8.8Hz,1H),7.42-7.32(m,2H),7.29-7.17(m,1H),6.21(br.d,J=9.8H z,1H),5.53(br.d,J=9.8Hz,0.5H),5.32-5.16(m,1H),4.93(br.d,J=9.8Hz,0.5H),2.26(s,3H),2.11(br d,J=7.3Hz,3H).MS(m / z)390.3(M+H) + .

[0980] Example 23

[0981] 3-Methyl-4-(1-(2-methyl-4-(trifluoromethoxy)phenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydropyridino[3,4-d]pyrimidin-3(2H)-yl)pyridine 1-oxide

[0982]

[0983] 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, followed by vacuum concentration. The residue was purified by MDAP (XSelect CSHPrep C18 5 μm OBD, 30-85% gradient. Water containing 10 mM ammonium bicarbonate and 0.075% ammonium hydroxide / acetonitrile, 40 mL / min flow rate, total run time 17 min) to give the title product as a white solid (15 mg, 0.029 mmol, 36.3% yield). 1 H NMR (400MHz, DMSO-d6) δ: 8.34-8.33 (m, 1H), 8.21 (dd, J = 1.5, 6.8Hz, 1H), 8.14 (s, 1H), 7.92 (br s,1H),7.63(d,J=8.8Hz,1H),7.55(d,J=2.9Hz,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) + .

[0984] Bioassay

[0985] The Na of the present invention v 1.8 Inhibitor compounds or pharmaceutically acceptable salts thereof may be used to treat pain, pain disorders or conditions, pain-related disorders or conditions, or pain caused by disease, as defined herein.

[0986] The bioactivity of the compounds of the present invention can be determined using appropriate assays, such as measuring the inhibition of those compounds and evaluating their inhibitory effects on voltage-gated sodium channels Na+ in vitro or in infected animal models. v Those with 1.8 capabilities.

[0987] Bioassay Example 1:

[0988] Make the person Na express v 1.8. People Na v β1 and human TREK1 (HEK293-Na) v 1.8) Human embryonic kidney 293 cells (HEK293) at 150 cm 2 Growth was carried out in a flask at 37°C and 5% CO2. When the confluence reached 80-90%, HEK293-Na was grown every 2-3 days. v1.8 Passage in T175 cell culture flasks.

[0989] The pharmacological evaluation of this invention was performed by combining HEK293-Nav1.8 with an assay developed on the QPatch 48HTX electrophysiological system. HEK293-Nav1.8 was prepared on the day of use as follows: v 1.8: Remove the culture medium, wash with DPBS, add Accutase (2 ml to cover the surface, aspirate 1 ml, and then incubate at 37°C for 1.5 min), followed by adding CHO-SFMII to stop enzymatic digestion, in order to obtain 3 x 10⁻⁶ cells / mL. 6 A suspension of cells per mL.

[0990] The compounds were prepared in an extracellular solution with the following composition: NaCl (145 mM), KCl (4 mM), CaCl2 (2 mM), MgCl2 (2 mM), HEPES (1 mM), glucose (10 mM), pH 7.4, and NaOH permeability 300 mOsm / L. Intracellular solutions were prepared using the following composition: CsF (115 mM), CsCl (20 mM), NaCl (5 mM), EGTA (10 mM), HEPES (10 mM), sucrose (20 mM), pH 7.2, and CsOH permeability 310 mOsm / L.

[0991] Utilizing the voltage clamp mode in the QPatch 48HTX system, a semi-deactivated voltage scheme (V) is employed. 1 / 2 To determine the compound of the present invention in Na v Pharmacological activity under ion channels 1.8. Utilizing V 1 / 2 The voltage step scheme is as follows: a sustaining voltage of -100 mV is established, followed by a voltage step to 0 mV (P1) over 20 ms, then an inactivation voltage step of -46 mV for 8 seconds, followed by a step to -100 mV over 20 ms, then a step to 0 mV (P2) over 20 ms, and finally a return to the sustaining voltage of -100 mV. This voltage scheme is repeated at a frequency of 0.07 Hz, with the current intensity quantified at the P2 step throughout the recording process. The inhibition of the measured current intensity by the compound of the present invention is analyzed by fitting 4-8 point dose-response curves to determine the 50% inhibitory concentration (IC50). 50 Within the QPatch HTX software, the P2 current is normalized based on measurements taken at the baseline after the compound and after the positive reference compound, and fitted to the following equation:

[0992]

[0993] To assess the current drop during the experiment, the aperture of the medium alone was used, and the current drop of the medium alone (nI) was measured. VEH The normalized current of ). To correct for the compound's response to the decrease, the corrected current is calculated according to the following equation:

[0994]

[0995] The activity of the compounds of the present invention against the Nav1.8 sodium channel was tested in one or more experimental runs as described above, and the results are shown in Table 2 below. The potency of the compounds of the present invention is recorded as pIC50 values. The pIC50 value is the negative logarithm of the IC50 value, where the IC50 value is the half-maximum inhibitory concentration measured at molar concentration (M). For compounds tested in more than one experimental run, the pIC50 values ​​are reported as the average value.

[0996] Table 2

[0997] Example No. [Nav1.8]pIC50 1 5.9 2 6 3 7 4 6.8 5 7.2 6 7 7 5.4 8 5.1 9 5.8 10 7.5 11 6.5 12 5.3 14 7.1 15 6.6 16 7.9 17 7.2 18 6.6 19 5.4 20 7.1 21 7.4 22 5.4 23 6.7

[0998] It should be understood that the present invention is not limited to the embodiments described above, and the right to modify the described embodiments and all modifications falling within the scope of the appended claims is reserved.

Claims

1. A compound of formula (I) or its tautomer or a pharmaceutically acceptable salt thereof: in: Y is either O or S; X 1 For nitrogen or CR 1 , X 2 For nitrogen or CR 2 , X 3 For nitrogen or CR 3 ,and X 4 For nitrogen or CR 4 , The condition is X 2 X 3 and X 4 At least one of them is nitrogen; R 1 R 2 R 3 and R 4 Each is independently hydrogen, halogen, 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 phenyl group or a 5- or 6-membered heterocyclic group containing one or two nitrogen ring atoms; Each R 5 Independently halogenated, 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 ; R 6 For hydrogen, -(C 1-6 )alkyl, -O-(C 1-6 -alkyl or -NR a R b ; Each R 7 Independently halogen, -(C 1-6 )alkyl, -O-(C 1-6 )alkyl or -O-(C 1-6 )-Haloalkyl; Each R a and R b Independently hydrogen, -(C 1-6 )alkyl or -(C 1-6 ) Haloalkyl; R c For 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 can be 0, 1, 2, or 3.

2. The compound of claim 1, or its tautomer or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (IA): in: Y is either O or S; R 1 R 2 and R 3 Each is independently hydrogen, halogen, 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 phenyl group or a 5- or 6-membered heterocyclic group containing one or two nitrogen ring atoms; Each R 5 Independently halogenated, 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 ; R 6 For hydrogen, -(C 1-6 )alkyl, -O-(C 1-6 -alkyl or -NR a R b ; Each R 7 Independently halogen, -(C 1-6 )alkyl, -O-(C 1-6 )alkyl or -O-(C 1-6 )-Haloalkyl; Each R a and R b Independently hydrogen, -(C 1-6 )alkyl or -(C 1-6 ) Haloalkyl; R c For 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 can be 0, 1, 2, or 3.

3. The compound of claim 1, or its tautomer or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (IB): in: Y is either O or S; R 1 R 3 and R 4 Each is independently hydrogen, halogen, 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 phenyl group or a 5- or 6-membered heterocyclic group containing one or two nitrogen ring atoms; Each R 5 Independently halogenated, 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 ; R 6 For hydrogen, -(C 1-6 )alkyl, -O-(C 1-6 -alkyl or -NR a R b ; Each R 7 Independently halogen, -(C 1-6 )alkyl, -O-(C 1-6 )alkyl or -O-(C 1-6 )-Haloalkyl; Each R a and R b Independently hydrogen, -(C 1-6 )alkyl or -(C 1-6 ) Haloalkyl; R c For 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 can be 0, 1, 2, or 3.

4. The compound of claim 1, or its tautomer or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (IC): in: Y is either O or S; R 1 R 2 and R 4 Each is independently hydrogen, halogen, 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 phenyl group or a 5- or 6-membered heterocyclic group containing one or two nitrogen ring atoms; Each R 5 Independently halogenated, 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 ; R 6 For hydrogen, -(C 1-6 )alkyl, -O-(C 1-6 -alkyl or -NR a R b ; Each R 7 Independently halogen, -(C 1-6 )alkyl, -O-(C 1-6 )alkyl or -O-(C 1-6 )-Haloalkyl; Each R a and R b Independently hydrogen, -(C 1-6 )alkyl or -(C 1-6 ) Haloalkyl; R c For 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 can be 0, 1, 2, or 3.

5. The compound of claim 1, or its tautomer or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (ID): in: Y is either O or S; R 2 and R 4 Each is independently hydrogen, halogen, 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 phenyl group or a 5- or 6-membered heterocyclic group containing one or two nitrogen ring atoms; Each R 5 Independently halogenated, 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 ; R 6 For hydrogen, -(C 1-6 )alkyl, -O-(C 1-6 -alkyl or -NR a R b ; Each R 7 Independently halogen, -(C 1-6 )alkyl, -O-(C 1-6 )alkyl or -O-(C 1-6 )-Haloalkyl; Each R a and R b Independently hydrogen, -(C 1-6 )alkyl or -(C 1-6 ) Haloalkyl; R c For 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 can be 0, 1, 2, or 3.

6. The compound of claim 1, or its tautomer or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (IE): in: Y is either O or S; R 2 and R 3 Each is independently hydrogen, halogen, 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 phenyl group or a 5- or 6-membered heterocyclic group containing one or two nitrogen ring atoms; Each R 5 Independently halogenated, 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 ; R 6 For hydrogen, -(C 1-6 )alkyl, -O-(C 1-6 -alkyl or -NR a R b ; Each R 7 Independently halogen, -(C 1-6 )alkyl, -O-(C 1-6 )alkyl or -O-(C 1-6 )-Haloalkyl; Each R a and R b Independently hydrogen, -(C 1-6 )alkyl or -(C 1-6 ) Haloalkyl; R c For 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 can be 0, 1, 2, or 3.

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

8. The compound according to any one of claims 1-6, wherein for:

9. The compound according to claim 7, wherein for:

10. The compound according to any one of claims 1-6 and 9, wherein R 6 It can be -CH3, -CH2CH3 or -CH(CH3)2.

11. The compound according to claim 7, wherein R 6 It can be -CH3, -CH2CH3 or -CH(CH3)2.

12. The compound according to claim 8, wherein R 6 It can be -CH3, -CH2CH3 or -CH(CH3)2.

13. The compound according to any one of claims 1-6, 9 and 11-12, wherein for:

14. The compound according to claim 7, wherein for:

15. The compound according to claim 8, wherein for:

16. The compound of claim 10, wherein... for:

17. Compounds selected from: 1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydropyridino[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-dihydropyridino[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-dihydropyridino[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-dihydropyrimidino[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-dihydropyridino[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-dihydropyridino[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-dihydropyridino[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-dihydropyridino[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-dihydropyridino[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-dihydropyridino[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-dihydropyridino[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-dihydropyridino[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-tetrahydropyridino[3,4-d]pyrimidine-6-carboxynitrile; 7-Chloro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydropyridino[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-tetrahydropyridino[4,3-d]pyrimidine-7-carboxynitrile; 1-(2-ethyl-4-fluorophenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydropyridino[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-dihydropyridino[3,4-d]pyrimidin-3(2H)-yl)pyridine 1-oxide, Or its tautomers, or its pharmaceutically acceptable salts.

18. A pharmaceutical composition comprising a compound according to any one of claims 1-17, a tautomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

19. Use of a compound of any one of claims 1-17, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 18 in the preparation of a medicament for therapeutic purposes.

20. Use of a compound of any one of claims 1-17, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 18, in the preparation of a medicament for treating pain or pain-related diseases, disorders, or conditions.

21. Use of a compound of any one of claims 1-17, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 18, in the preparation of a medicament for the treatment of atrial fibrillation.

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