Chemical compounds useful for inhibiting the Nav1.8 voltage-gated sodium channel and for treating Nav1.8-mediated disorders

Abstract

Compounds of formula (I) are described, in which each of the variables is as defined herein. Also described are pharmaceutical compositions containing compounds of formula (I), Na v 1.8 Inhibits voltage-gated sodium channels and inhibits the production of Na v 1.8 Use of the compounds and pharmaceutical compositions for treating mediated diseases, disorders and conditions is also described. [Formula 1] JPEG2024502231000049.jpg52170

Description

[Technical field]

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

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

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

[0004] Currently, nonselective sodium channel inhibitors are clinically utilized as antiarrhythmic and anticonvulsant drugs, including lidocaine, carbamazepine, amitriptyline, and mexiletine. However, because these drugs do not exhibit selectivity between different sodium channel isoforms, their therapeutic utility is greatly diminished due to adverse side effects, mainly mediated by their activity in the CNS and heart. This has prompted efforts to develop novel drugs selective for specific sodium channel isoforms to avoid side effects in the CNS and cardiovascular system.

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

[0006] Na v Support for Na 1.8 as a therapeutic target for pain indications comes from several sources. v Na1.8 has been shown to carry the majority of the current during the upstroke of action potentials in DRG neurons (Blair & Bean, 2002) and is also important for the ability of these neurons to fire repetitively due to its speed of repriming (Blair and Bean, 2003). v Increased expression and function of 1.8 has been reported in response to painful stimuli, including inflammatory mediators (England 1996 & Gold 1996), nerve injury (Roza 2003 & Ruangsri 2011) and painful schwannoma (Black 2008 & Coward 2000). v Knocking out the gene encoding 1.8 reduced the pain phenotype, especially in response to inflammatory antigen challenge (Akopian 1999). v Knocking down the mRNA encoding 1.8 reduced pain phenotypes in rodent models, particularly in neuropathic models (Lai 2002). Pharmacological intervention with selective small molecule inhibitors has also shown efficacy in rodent models of inflammatory and neuropathic pain (Jarvis 2007 & Payne 2015). v Genetic evidence for 1.8 also exists in patients with chronic neuropathic pain, with multiple gain-of-function mutations reported to be the cause of episodic painful neuropathy and small fiber neuropathy (Faber 2012, Han 2014 & Eijkenboom 2018). Summary of the Invention [Problem to be solved by the invention]

[0007] Summary of the Invention Thus, novel compounds, particularly Na, having improved solubility and therefore more advantageous for alternative routes of administration, such as intravenous administration, are available. v There is a need for the development of Na 1.8 inhibitor compounds. v This need is met by providing prodrugs of compounds having 1.8 inhibitory activity, and the use of such prodrugs in the treatment of pain and pain-related diseases, disorders and conditions, and in the treatment of cardiovascular diseases, disorders and conditions. The prodrugs of the present invention have improved solubility compared to their respective parent compounds and therefore may be useful for intravenous (IV) administration, and for the treatment of pain and pain-related diseases, disorders and conditions where IV administration may be beneficial or preferred, such as in the treatment of acute pain.

[0008] In one embodiment, the present invention provides a compound of formula (I): [ka] [In the formula, X 1 is N or CH; R 1 is -PO(OH)2; R 2 is hydrogen, -(C 1-6 ) alkyl, -NR a R b , halo or -(C 1-6 ) haloalkyl; R 3 and R 4 each independently represents hydrogen, halo, cyano, -NR a R b , -(C 1-6 ) alkyl, -(C 1-6 ) haloalkyl, -O-(C 1-6 ) alkyl or -O-(C 1-6 ) haloalkyl; Each R5 are independently halo, -(C 1-6 ) alkyl, -O(C 1-6 ) alkyl or -O(C 1-6 ) haloalkyl; R 6 is hydrogen or -(C 1-6 ) alkyl; R 7 is hydrogen, -(C 1-6 ) alkyl, halo or -(C 1-6 ) haloalkyl; R a and R b each independently represents hydrogen or -(C 1-6 ) alkyl; and n is 0, 1 or 2. or a pharma- ceutically acceptable salt thereof.

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

[0010] In one embodiment, the present invention provides a method for preventing and treating Na+ in a subject in need thereof. v 1.8 A method of inhibiting voltage-gated sodium channels comprising administering to a subject a compound as defined herein or a tautomer thereof or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

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

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

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

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

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

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

[0017] In one aspect, the invention relates to a compound as defined herein or a tautomer or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in therapy. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] Various publications, articles, and patents are cited or described in the Background and Specification. Any discussion of documents, acts, materials, devices, articles, and the like included in this specification is for the purpose of providing a context for the present disclosure. Such discussion is not an admission that any or all of these items form part of the prior art with respect to the present disclosure.

[0019] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Otherwise, certain terms used herein have the meanings set forth herein.

[0020] Please note that as used in this specification and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise.

[0021] As used herein, the conjunction "and / or" between multiple cited elements is understood to encompass both separate and combined options. For example, when two elements are connected by "and / or", the first option refers to the first element being applicable without the second element. The second option refers to the second element being applicable without the first element. The third option refers to the first and second elements being applicable together. Any one of these options is understood to be within the meaning of, and therefore satisfying the requirement of, the term "and / or" as used herein. The simultaneous applicability of two or more options is also understood to be within the meaning of, and therefore satisfying the requirement of, the term "and / or".

[0022] Unless otherwise stated, any numerical value, for example, any concentration or concentration range described herein, is understood to be modified in all cases by the term "about". Thus, numerical values ​​generally include ±10% of the described value. For example, the description "10 times" includes 9 times and 11 times. As used herein, the use of numerical ranges expressly includes all possible subranges, for example, all individual numerical values ​​within the range (including integers and fractions of values ​​within the range), unless the context clearly indicates otherwise.

[0023] The present invention relates to compounds of formula (I) or pharma- ceutically acceptable salts thereof, corresponding pharmaceutical compositions, methods or processes for preparing the compounds, and methods for preparing Na v 1.8 relates to methods, compounds, uses therefor and / or combination therapies for use in mediated diseases, disorders and conditions, such as pain and / or pain-related diseases, disorders or conditions and atrial fibrillation, respectively.

[0024] The definitions of the various groups and substituents of any formula disclosed herein, or a pharma- ceutically acceptable salt and / or the corresponding tautomer thereof, provided herein are intended to describe each compound species disclosed herein separately, as well as one or more of the groups of the compound species specifically.

[0025] As used herein, the term alkali metal is intended to mean Group I elements, including, but not limited to, lithium (Li), sodium (Na) or potassium (K), etc. The term alkaline earth metal may include, but is not limited to, calcium (Ca) or magnesium (Mg), etc.

[0026] As used herein, the terms "alkyl" or "straight or branched chain alkyl" and the like refer to a saturated, straight or branched chain hydrocarbon moiety. Exemplary alkyls include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like. An alkyl group may have a specified 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 may contain. For example, "C1-C6" and "C 1-6 The term "alkyl" refers to an alkyl group containing 1 to 6 carbon atoms, and "C1-C4" and "C 1-4 The term refers to an alkyl containing 1 to 4 carbon atoms.

[0027] When the term "alkyl" is used in combination with other substituents, such as "haloalkyl" or "hydroxyalkyl", the term "alkyl" is intended to include a divalent saturated, straight or branched chain hydrocarbon radical.

[0028] For example, the term "haloalkyl" or "straight- or branched-chain haloalkyl" is intended to mean a saturated, straight- or branched-chain hydrocarbon moiety substituted with one or more halogens, where the halogens are independently selected from fluoro, chloro, bromo, and iodo. The haloalkyl group can have the specified number of carbon atoms. For example, "(C1-C6)haloalkyl" and "(C 1-6 The term "(C)haloalkyl" refers to a saturated, straight or branched chain haloalkyl radical having 1 to 6 carbon atoms. 1- C4) haloalkyl" and "(C 1-4The term "haloalkyl" refers to a saturated, straight or branched chain haloalkyl radical having 1 to 4 carbon atoms. "Fluorinated alkyl" or "fluoroalkyl" specifically refers to any alkyl group as defined above substituted with at least one fluoro atom, e.g., 1 to 3 fluoro atoms, e.g., 1, 2 or 3 fluoro atoms. Representative haloalkyls include, but are not limited to, trifluoromethyl (-CF3), tetrafluoroethyl (-CF2CHF2), pentafluoroethyl (-CF2CF3), and the like.

[0029] The term "hydroxyalkyl" refers to a saturated, straight or branched chain hydrocarbon moiety substituted with one or more hydroxy groups.

[0030] As used herein, the terms "halogen" and "halo" mean fluoro (-F), chloro (-Cl), bromo (-Br) and iodo (-I).

[0031] "Hydroxy" or "hydroxyl" is intended to mean the radical --OH.

[0032] "Oxo" refers to a doubly bonded oxygen moiety, e.g., when attached directly to a carbon atom, forming a carbonyl moiety (C=O), or when attached to an N or S, forming an oxide, e.g., an N-oxide, sulfone, or sulfoxide.

[0033] The term "cyano" refers to --CN.

[0034] The term "amino" refers to -NH2. One or more hydrogen atoms of an amino group can be replaced with a substituent such as an alkyl group, and is called an "alkylamino". An alkylamino group has one or both hydrogen atoms of the amino group replaced with an alkyl group, and is attached to the parent molecule through a bond to the nitrogen atom of the alkylamino group. For example, alkylamino includes methylamino (-NHCH3), dimethylamino (-N(CH3)2), -NHCH2CH3, and the like.

[0035] "Alkoxy" refers to a group containing an alkyl radical attached through an oxygen linking atom, where alkyl is as defined above. The alkoxy group can have a specified number of carbon atoms. For example, "(C1-C6)alkoxy" and "(C 1-6 The term "(C1-C4)alkoxy" refers to an alkyl radical having one to six carbon atoms attached through an oxygen linking atom. Similarly, "(C1-C4)alkoxy" and "(C 1-4 The term "alkoxy" refers to an alkyl radical having from 1 to 4 carbon atoms attached through an oxygen linking atom. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, and t-butoxy.

[0036] "Haloalkoxy" refers to an alkoxy group in which the alkyl portion is substituted with one or more halogens, where the halogens are independently selected from fluoro, chloro, bromo, and iodo. The haloalkoxy group can have a specified number of carbon atoms. For example, the term "(C1-C6)haloalkoxy" refers to a haloalkyl radical having from 1 to 6 carbon atoms attached through an oxygen linking atom. Representative haloalkoxy groups include, but are not limited to, difluoromethoxy (-OCHCF2), trifluoromethoxy (-OCF3), tetrafluoroethoxy (-OCF2CHF2), and the like.

[0037] According to the conventions used in the art, [ka] is used in structural formulas herein to represent the bond that is the point of attachment of a group, moiety, or substituent to the core, backbone, or parent molecular structure.

[0038] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on that ring.

[0039] As used herein, the term "a compound of the invention" means a compound of any of the formulas disclosed herein in any form, i.e., any salt or non-salt form (e.g., as a free acid or base form or as a pharma- ceutically acceptable salt thereof), any tautomer thereof, and any of its physical forms (e.g., non-solid forms (e.g., liquid or semi-solid forms), and solid forms (e.g., amorphous or crystalline forms, certain polymorphic forms, solvates, including hydrates (e.g., monohydrates, dihydrates, and hemihydrates))) as well as mixtures of various forms.

[0040] As used herein, the term "optionally substituted" means that a group (e.g., alkyl, etc.) may be unsubstituted or that the group may be substituted with one or more of the specified substituents defined herein. The term "substituted" as used herein with respect to a group (e.g., alkyl, etc.) means that at least one hydrogen atom is replaced with a non-hydrogen group, provided that all normal valences are maintained and the substitution results in a stable compound. When a group can be selected from multiple alternative groups, the selected groups can be the same or different. For example, various substituents of the compound formulas defined in the present invention may be substituted, including, but not limited to, halo, cyano, amino, alkyl, haloalkyl, alkoxy, and other substituents.

[0041] The term "independently," as used herein with respect to substituents or heteroatoms, means that when two or more substituents or heteroatoms are selected from multiple possible substituents or heteroatoms, respectively, those substituents or heteroatoms may be the same or different.

[0042] compound The compound of formula (I) of the present invention is Na v 1.8 inhibitor compounds are prodrugs of their respective parent compounds. Upon administration of the prodrug, the prodrug moiety is cleaved, thereby yielding the parent compound. Thus, upon administration of the prodrug, Na v The 1.8 inhibitory activity is primarily due to cleavage of the prodrug to form the parent compound.

[0043] The prodrug of the present invention generally has higher aqueous solubility than the corresponding parent compound.This higher solubility helps to administer higher doses of prodrug, and increases drug loading per unit dose.Therefore, the compound of formula (I) of the present invention (i.e., prodrug) can be advantageous for intravenous (IV) formulation and intravenous (IV) administration, and thus is useful for use in treating pain and pain-related diseases, disorders and conditions where higher doses or administration by IV route can be beneficial, such as treating acute pain.

[0044] The term "prodrug" refers to a compound that is a drug precursor that undergoes metabolic processes in vivo to release the parent compound after administration and / or absorption. Generally, prodrugs have less biological activity than the parent compound. Prodrugs may also improve the physical properties and / or efficacy of the parent compound, such as lower toxicity and reduced undesired effects due to improved control of the absorption, blood levels, metabolic distribution and / or cellular uptake of the parent compound. Prodrugs may also have higher solubility than the corresponding parent compound.

[0045] The terms "parent compound" and "parent drug" refer to the biologically active entity that is released through the action of enzymes in metabolic or catabolic processes, or through chemical processes following administration of a prodrug. A parent compound can also be the starting material for preparing the corresponding prodrug.

[0046] In one embodiment, the present invention provides a compound of formula (I): [ka] [In the formula, X 1 is N or CH; R 1 is -PO(OH)2; R 2 is hydrogen, -(C 1-6 ) alkyl, -NR a R b , halo or -(C 1-6 ) haloalkyl; R 3 and R 4 each independently represents hydrogen, halo, cyano, -NR a R b , -(C 1-6 ) alkyl, -(C 1-6 ) haloalkyl, -O-(C 1-6 ) alkyl or -O-(C 1-6 ) haloalkyl; Each R 5 are independently halo, -(C 1-6 ) alkyl, -O(C 1-6 ) alkyl or -O(C 1-6 ) haloalkyl; R 6 is hydrogen or -(C 1-6 ) alkyl; R 7 is hydrogen, -(C 1-6 ) alkyl, halo or -(C 1-6 ) haloalkyl; R a and R b each independently represents hydrogen or -(C 1-6 ) alkyl; and n is 0, 1 or 2. or a pharma- ceutically acceptable salt thereof.

[0047] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, X 1 is N.

[0048] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, X 1 is CH.

[0049] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, R 2 is hydrogen.

[0050] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, R 2 Ha-(C 1-6 ) alkyl.

[0051] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, R 2 is CH3.

[0052] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, R 2 -NR a R b It is.

[0053] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, R 2 is -NH2.

[0054] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, R 3 is hydrogen, halo or -(C 1-6 ) haloalkyl.

[0055] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, R 3 is hydrogen, -Cl, or -CF3.

[0056] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, R 3 is hydrogen.

[0057] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, R 3 is -Cl.

[0058] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, R 3 is -CF3.

[0059] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, R 4 is hydrogen, halo or -(C 1-6 ) haloalkyl.

[0060] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, R 4 is hydrogen, -Cl, or -CF3.

[0061] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, R 4 is hydrogen.

[0062] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, R 4 is -Cl.

[0063] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, R 4 is -CF3.

[0064] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, R 3 and R 4 One of the groups is hydrogen, and the other is R 3 and R 4 The other is halo, cyano, -NR a R b , -(C 1-6 ) alkyl, -(C 1-6) haloalkyl, -O-(C 1-6 ) alkyl or -O-(C 1-6 ) haloalkyl.

[0065] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, R 3 and R 4 One of the groups is hydrogen, and the other is R 3 and R 4 The other is halo or -(C 1-6 ) haloalkyl.

[0066] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, R 3 and R 4 One of the groups is hydrogen, and the other is R 3 and R 4 The other is -Cl or -CF3.

[0067] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, each R 5 are independently halo or -O(C 1-6 ) haloalkyl.

[0068] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, each R 5 are independently -F or -OCF3.

[0069] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, n is 1 and R 5 is -F.

[0070] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, n is 1 and R 5 is -OCF3.

[0071] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, [ka] The structure: [ka] where R 5a , halo, -(C 1-6 ) alkyl, -O(C 1-6 ) alkyl or -O(C 1-6 ) haloalkyl.

[0072] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, R 5a is halo or -O(C 1-6 ) haloalkyl.

[0073] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, R 5a is -F or -OCF3.

[0074] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, R 5a is -F.

[0075] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, R 5a is -OCF3.

[0076] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, [ka] teeth, [ka] It is.

[0077] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, R 6 is hydrogen.

[0078] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, R 6 Ha-(C 1-6 ) alkyl.

[0079] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, R 6 is -CH3, -CH2CH3 or -CH(CH3)2.

[0080] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, R 6 is -CH3.

[0081] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, R 7 is hydrogen.

[0082] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, R 7 Ha-(C 1-6 ) alkyl.

[0083] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, R 7 is a halo.

[0084] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, R 7 is -F or -Cl.

[0085] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, X 1 is N; R 1 is -PO(OH)2; R 2 is hydrogen or -(C 1-6 ) alkyl; R 3 and R 4 One of the groups is hydrogen, and the other is R 3 and R 4 The other is halo or -(C 1-6 ) haloalkyl; R 5 is halo or -O(C 1-6 ) haloalkyl; R 6 Ha-(C 1-6) alkyl; R 7 is hydrogen; and n is 1.

[0086] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, X 1 is N; R 1 is -PO(OH)2; R 2 is -CH3; R 3 and R 4 One of the groups is hydrogen, and the other is R 3 and R 4 The other is halo or -(C 1-6 ) haloalkyl; R 5 is halo or -O(C 1-6 ) haloalkyl; R 6 Ha-(C 1-6 ) alkyl; R 7 is hydrogen; and n is 1.

[0087] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, X 1 is N; R 1 is -PO(OH)2; R 2 is -CH3; R 3 and R 4 One of the groups is hydrogen, and the other is R 3 and R 4 the other is -Cl or -CF3; R 5 is -F or -OCF3; R 6 is -CH3; R 7 is hydrogen; and n is 1.

[0088] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, X 1 is C; R 1 is -PO(OH)2; R 2 is hydrogen or -(C 1-6 ) alkyl; R 3 and R 4 One of the groups is hydrogen, and the other is R 3 and R 4 The other is halo or -(C 1-6 ) haloalkyl; R 5 is halo or -O(C 1-6 ) haloalkyl; R 6 Ha-(C 1-6 ) alkyl; R 7 is hydrogen; and n is 1.

[0089] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, X 1 is C; R 1 is -PO(OH)2; R 2 is -CH3; R 3 and R 4 One of the groups is hydrogen, and the other is R 3 and R 4 The other is halo or -(C 1-6 ) haloalkyl; R 5 is halo or -O(C 1-6 ) haloalkyl; R 6 Ha-(C 1-6 ) alkyl; R 7 is hydrogen; and n is 1.

[0090] In certain embodiments of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, X 1 is C; R 1 is -PO(OH)2; R 2 is -CH3; R 3 and R 4 One of the groups is hydrogen, and the other is R 3 and R 4 the other is -Cl or -CF3; R 5 is -F or -OCF3; R 6 is -CH3; R 7 is hydrogen; and n is 1.

[0091] In another aspect, the present invention relates to a compound selected from the following, or a pharma- ceutically acceptable salt thereof:

[0092] [Table 1]

[0093] salt The salt of any compound of the formula disclosed herein, including formula (I), is preferably a pharmaceutically acceptable salt, since they may be used in medicine. Pharmaceutically acceptable salts include, inter alia, those listed in Berge, Bighley and Monkhouse J.Pharm.Sci (1977) 66, pp 1-19, or those listed in PH Stahl and CG Wermuth, editors, Handbook of Pharmaceutical Salts; Properties, Selection and Use, Second Edition Stahl / Wermuth: Wiley-VCH / VHCA, 2011. Salts that are not pharmaceutically acceptable can also be used, for example, as intermediates in the preparation of any compound of the formula disclosed herein or its pharmaceutically acceptable salt.

[0094] Suitable pharma- ceutically acceptable salts may include acid addition salts or base addition salts. Such base addition salts may be formed by reacting any compound of the present invention, including formula (I), with a suitable base, optionally in a suitable solvent such as an organic solvent, to obtain a salt, which may be isolated by various methods, including crystallization and filtration.

[0095] Such acid addition salts can be formed by reacting a compound of any of the formulae disclosed herein, including formula (I) of the present invention, with an appropriate acid, optionally in a suitable solvent, such as an organic solvent, to obtain a salt, which can be isolated by various methods, including crystallization and filtration.

[0096] Salts may be generated in situ during the final isolation and purification of any compound of the formula disclosed herein, including formula (I) of the present invention. When a basic compound of any of the formulas disclosed herein, including formula (I) of the present invention, is isolated as a salt, the corresponding free base form of the compound can be prepared by any suitable method known in the art, including treating the salt with an inorganic or organic base. Similarly, when a compound of any of the formulas disclosed herein, including formula (I) of the present invention, that contains an acidic functional group, such as a phosphate group, is isolated as a salt, the corresponding free acid form of the compound can be prepared by any suitable method known in the art, including treating the salt with an inorganic or organic acid.

[0097] For example, if the compound of the invention is a base (contains a basic moiety), the desired salt form can be prepared by any suitable method known in the art, including treatment of the free base with an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like) or an organic acid (e.g., acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acids (e.g., glucuronic acid or galacturonic acid), α-hydroxy acids (e.g., citric acid or tartaric acid), amino acids (e.g., aspartic acid or glutamic acid), aromatic acids (e.g., benzoic acid or cinnamic acid), sulfonic acids (e.g., p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid), and the like).

[0098] If a basic compound of the invention is isolated as a salt, the corresponding free base form of the compound can be prepared by any suitable method known in the art, including treatment of the salt with an inorganic or organic base, preferably an inorganic or organic base that has a higher pKa than the free base form of the compound.

[0099] If the compound of the invention is an acid (contains an acidic moiety), the desired salt may be prepared by any suitable method known in the art, including treating the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or an alkaline earth metal hydroxide. Specific examples of suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary and tertiary amines and cyclic amines (e.g., ethylenediamine, dicyclohexylamine, ethanolamine, piperidine, morpholine and piperazine), and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[0100] Certain compounds of the present invention can form salts with one or more equivalents of acid (if the compound contains a basic moiety) or base (if the compound contains an acidic moiety). The present invention includes within its scope all possible stoichiometric and non-stoichiometric salt formations. When any compound of the formulas disclosed herein, including formula (I) as defined herein, contains two or more basic moieties, it is understood that the stoichiometry of salt formation can include one, two or more equivalents of acid. Such salts include one, two or more acid counterions, e.g., dihydrochloride salts. Stoichiometric and non-stoichiometric forms of pharma- ceutically acceptable salts of any compound of the formulas disclosed herein, including formula (I) of the present invention, are included within the scope of the present invention, including substoichiometric salts, e.g., where the counterion includes two or more acidic protons.

[0101] Since the compounds of the present invention may contain both acidic and basic moieties, pharma- ceutically acceptable salts may be prepared by treating these compounds with alkaline or acidic reagents, respectively. Thus, the present invention also provides the conversion of one pharma- ceutically acceptable salt of a compound of the present invention, e.g., a hydrochloride salt, to another pharma- ceutically acceptable salt of a compound of the present invention, e.g., a sodium salt.

[0102] Representative pharma- ceutically acceptable acid addition salts include, but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, bisulfate, bitartrate, butyrate, calcium edetate, camphorate, camphorsulfonate (camsylate), caprate (decanoate), caproate (hexanoate), caprylate (octanoate), cinnamate, citrate, cyclamate, digluconate, 2,5-dihydroxybenzoate, and disuccinate. Salt, dodecyl sulfate (estolate), edetate (ethylenediaminetetraacetate), estolate (lauryl sulfate), ethane-1,2-disulfonate (edisylate), ethanesulfonate (esylate), formate, fumarate, galactarate (mucate), gentisate (2,5-dihydroxybenzoate), glucoheptonate (glucoceptate), gluconate, glucuronate, glutamate, glutarate, glycerophosphate, glycolate, hexylresorcinate, hippurate, hydrabamine (N,N'-di(dehydroabietate) (ethyl)-ethylenediamine), hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, isobutyrate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, methanesulfonate (mesylate), methylsulfate, mucate, naphthalene-1,5-disulfonate (napadisilate), naphthalene-2-sulfonate (napsylate), nicotinate, nitrate, oleate, palmitate, p-aminobenzenesulfonate, p-aminosalicycla te), pamoate (embonate), pantothenate, pectinate, persulfate, phenylacetate, phenylethylbarbiturate, phosphate, polygalacturonate, propionate, p-toluenesulfonate (tosylate), pyroglutamate, pyruvate, salicylate, sebacate, stearate, subacetate, succinate, sulfamate, sulfate, tannate, tartrate, teoclate (8-chloroterophyllate), thiocyanate, triethiodide, undecanoate, undecylenate and valerate salts.

[0103] Representative pharma- ceutically acceptable base addition salts include, but are not limited to, aluminum, 2-amino-2-(hydroxymethyl)-1,3-propanediol (TRIS, tromethamine), arginine, benethamine (N-benzylphenethylamine), benzathine (N,N'-dibenzylethylenediamine), bis-(2-hydroxyethyl)amine, bismuth, calcium, chloroprocaine, choline, clemizole (1-chlorobenzyl-2-pyrrolidine-1'-ylmethylbenzylamine), benzoyl benzoate, ... These include: diphenylimidazole, cyclohexylamine, dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lepidine, lithium, lysine, magnesium, meglumine (N-methylglucamine), piperazine, piperidine, potassium, procaine, quinine, quinoline, sodium, strontium, t-butylamine and zinc.

[0104] In certain embodiments, the present invention provides pharma- ceutically acceptable salts of compounds of formula (I). For example, R 1 The phosphate group of (-PO(OH)2) is an acidic moiety that is particularly prone to participate in salt formation with cationic species (i.e., base addition salts). Any of the base addition salts listed above can be used to form pharma- ceutically acceptable salts of the compounds of formula (I) of the present invention. Additionally or alternatively, other functional groups of the compounds of formula (I) may participate in salt formation with acid and / or base addition salts such as those listed above.

[0105] In certain embodiments of the pharma- ceutically acceptable salt of the compound of Formula (I), R 1 is -P(O)(OH)O - M + , -PO(O - )2·2M + or -PO(O - )2·D 2+ and; Each M + are independently a pharma- ceutically acceptable monovalent cation; and D 2+ is a pharma- ceutically acceptable divalent cation.

[0106] In some embodiments, monovalent cations (M + ) includes, but is not limited to, alkali metal ions, such as lithium (Li + ), Sodium (Na + ), potassium (K + ) and the like; ammonium ions (e.g., -N(R a )4, where each R a are independently hydrogen, cyclohexyl or -(C 1-6 ) alkyl, -(C 1-6 )Alkyl may be substituted with one or more, preferably 1 to 6, -OH groups, e.g., NH4 + , ethanolamine ion: [ka] , N-methyl-D-glucamine ion, and dicyclohexylamine ion. + If present, then each M + are independently monovalent cations, and each M + are the same or different, and preferably, each M + is the same.

[0107] In one embodiment, each M + are independently an alkali metal ion.

[0108] In one embodiment, each M + Li independently + , Na + or K + It is.

[0109] In one embodiment, each M + are independently NH4 + It is.

[0110] In one embodiment, each M + is independent [ka] (ethanolamine ion).

[0111] In some embodiments, divalent cations (D 2+ ) includes, but is not limited to, alkaline earth metal ions, such as magnesium (Mg 2+ ), Calcium (Ca 2+ ), Strontium (Sr 2+ ) etc.; divalent aluminum ion etc.

[0112] In one embodiment, D 2+ is an alkaline earth metal ion.

[0113] In one embodiment, D 2+ is Mg 2+ or Ca 2+ It is.

[0114] Other monovalent and divalent cations suitable for use in the present invention include the monovalent or divalent ions of amino acids such as arginine, lysine, ornithine, etc. Monovalent and divalent cations containing basic nitrogen-containing groups can be prepared by quaternization with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, dibutyl sulfate and diamyl sulfate), etc.

[0115] Enantiomers, diastereomers and polymorphs A compound according to any of the formulae disclosed herein, including Formula (I), or a pharma- ceutically acceptable salt thereof of the present invention may contain one or more asymmetric centers (i.e., also referred to as chiral centers) and therefore may exist in optical forms (e.g., as separate enantiomers, diastereomers or other stereoisomers, or as mixtures thereof) and in racemic forms. All of these separate compounds, stereoisomers and mixtures thereof are within the scope of the present invention.

[0116] Chiral centers, such as chiral carbon atoms, may also be present in substituents, such as alkyl groups. When the stereochemistry of a chiral center present in any of the formulas disclosed herein, including formula (I), or its pharma- ceutically acceptable salts of the present invention, or any chemical structure shown herein is not specified, the structure is intended to encompass all individual stereoisomers and all mixtures thereof. Thus, the compounds of the present invention, or their pharma- ceutical acceptable salts, containing one or more chiral centers can be used as racemic mixtures, enantiomerically enriched mixtures, or enantiomerically pure individual stereoisomers.

[0117] The individual stereoisomers of a compound according to any of the formulas disclosed herein, including formula (I), or a pharma- ceutically acceptable salt thereof of the present invention, containing one or more asymmetric centers, can be resolved by methods known to those skilled in the art. For example, such resolution can be achieved by (1) Formation of diastereomeric salts, complexes or other derivatives; (2) selective reaction with a stereoisomer-specific reagent, e.g., enzymatic oxidation or reduction; or (3) Gas-liquid or liquid chromatography in a chiral environment (e.g., on a chiral support such as silica to which a chiral ligand is attached, or in the presence of a chiral solvent). Those skilled in the art will recognize that if the desired stereoisomer is converted to another chemical entity by one of the resolution procedures described above, further steps will be required to liberate the desired form.

[0118] Alternatively, specific stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.

[0119] When the disclosed compounds or salts thereof are named or depicted by structure, it should be understood that the compounds or salts thereof, including their solvates (particularly hydrates), can exist in crystalline form, non-crystalline form, or mixtures thereof. The compounds or their salts or solvates (particularly hydrates) can also exhibit polymorphism (i.e., the ability to exist in different crystalline forms). These different crystalline forms are commonly known as "polymorphs."

[0120] When named or depicted by structure, the disclosed compounds or solvates (particularly hydrates) thereof are to be understood to include all polymorphs thereof.

[0121] Polymorphs have the same chemical composition but differ in packing, geometric arrangement, and other descriptive properties of the crystalline solid state. Thus, polymorphs may differ in physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs usually exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which can be used for identification. Those skilled in the art will recognize that different polymorphs can be produced, for example, by changing or adjusting the conditions used to crystallize / recrystallize the compound.

[0122] solvate The compounds of the present invention or their pharma- ceutically acceptable salts may exist in solvated and non-solvated forms. For the solvates of the compounds of the present invention or their pharma- ceutically acceptable salts in crystalline form, those skilled in the art will recognize that pharma- ceutical acceptable solvates may be formed in which the solvent molecules are incorporated into the crystal lattice during crystallization. Solvates may include non-aqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine and ethyl acetate, or may include water as the solvent incorporated into the crystal lattice. Solvates in which water is the solvent incorporated into the crystal lattice are generally referred to as "hydrates". Hydrates include stoichiometric hydrates as well as compositions containing various amounts of water.

[0123] Deuterated Compounds The present invention also includes various deuterated forms of the compounds of any of the formulae disclosed herein, including Formula (I), or a pharma- ceutically acceptable salt thereof of the present invention. Each available hydrogen atom bonded to a carbon atom may be independently replaced with a deuterium atom.

[0124] Those skilled in the art will know how to synthesize deuterated forms of any of the compounds of the formulae disclosed herein, including formula (I), or pharma- ceutically acceptable salts thereof of the present invention. For example, deuterated materials such as alkyl groups can be prepared by conventional techniques (e.g., methyl-d3-amine available from Aldrich Chemical Co., Milwaukee, WI, catalog number 489,689-2).

[0125] Isotopes The present invention also includes isotopically labeled compounds that are identical to those recited in any of the formulas disclosed herein, including Formula (I), or a pharma- ceutically acceptable salt thereof of the present invention, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.

[0126] Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, iodine and chlorine, e.g., 3 H, 11 C. 14 C. 18 F, 123 I or 125 Contains I.

[0127] Compounds of the present invention that contain the aforementioned isotopes and / or other isotopes of other atoms and pharma- ceutically acceptable salts of such compounds are within the scope of the present invention. Isotopically labeled compounds of the present invention, e.g. 3 H or 14 Those in which a radioactive isotope, such as C, is incorporated are useful in drug and / or substrate tissue distribution assays. 3 H isotopes, and carbon-14, i.e. 14 C isotopes are particularly preferred for their ease of preparation and detectability. 11 C isotopes and 18 F isotopes are particularly useful in PET (positron emission tomography).

[0128] purity As the compounds of the present invention are intended for use in pharmaceutical compositions, it will be readily understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more preferably at least 75% pure, preferably at least 85% pure, especially at least 98% pure (percentages are on a weight to weight basis). Impure preparations of the compounds can be used to prepare the purer forms used in pharmaceutical compositions.

[0129] It will be appreciated that compounds of any of the formulae disclosed herein, including formula (I), or a pharma- ceutically acceptable salt thereof of the present invention may exist in stereoisomeric, regioisomeric or diastereoisomeric forms.

[0130] Tautomers Additionally, the compounds of the present invention may exist as tautomeric or tautomeric forms. Tautomers are conventionally understood in the chemical arts to be structural or constitutional isomers of chemical compounds that readily interconvert. This reaction generally results in the rearrangement of protons. A structural or constitutional isomer (according to IUPAC) is a type of isomer in which molecules with the same molecular formula have different bonding patterns and atomic configurations, as opposed to stereoisomers, in which the molecular bonds are always in the same order and differ only in their spatial arrangement. The concept of tautomerization is called tautomerism. The chemical reaction that interconverts the two is called tautomerization. Care should be taken not to confuse tautomers with the depiction of "contributing structures" in chemical resonance. Tautomers are distinct chemical species and therefore can be distinguished by differences in spectroscopic data, whereas resonance structures are merely a convenient depiction and do not exist physically.

[0131] Synthetic schemes and general methods of preparation The present invention also relates to a process for making a compound of any of the formulae disclosed herein, including Formula (I), or a pharma- ceutically acceptable salt thereof of the present invention.

[0132] Compounds of any of the formulas disclosed herein or pharma- ceutically acceptable salts thereof of the present invention can be made in any number of steps using conventional organic synthesis as described in the schemes below, and more particularly as illustrated by the exemplary compounds according to the Examples section of this specification, or by utilizing the knowledge of an organic chemist. A suitable synthetic route is depicted in the following general reaction scheme:

[0133] The syntheses shown in these schemes can be adapted to produce compounds of the invention defined by any of the formulas disclosed herein with a variety of different functional groups as defined, using appropriate precursors that are appropriately protected if necessary to be compatible with the reactions outlined herein. Although these schemes are shown only with compounds defined therein, they are illustrative of the processes that can be used to make the compounds of the invention.

[0134] Intermediates (compounds used in the preparation of compounds of the invention) may also exist as salts. Thus, with respect to an intermediate, the phrase "a compound of formula (number)" means a compound having that structural formula or a pharma- ceutically acceptable salt thereof.

[0135] The compounds of the present invention can be obtained using the procedures depicted in the following schemes, or by application of appropriate synthetic organic chemistry procedures and methodology known to those skilled in the art.

[0136] The methods illustrated in these schemes can be used to synthesize a variety of different X 1 , R 1 , R 2 , R 3 , R 4 , R 5 and R 6 can be used to prepare compounds of the invention containing groups (explanation given above in relation to compounds of formula (I)).

[0137] Those skilled in the art will recognize that in the preparation of the compounds of the present invention (e.g., a compound of formula (I) or a pharma- ceutically acceptable salt thereof), it may be necessary and / or desirable to protect one or more sensitive groups of the molecule or suitable intermediates to avoid undesired side reactions. Those skilled in the art will recognize that if a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to those reaction conditions. The protecting group may be removed at a suitable point in the reaction sequence to provide the desired intermediate or target compound. Protecting groups suitable for use according to the present invention are well known to those skilled in the art and may be used in conventional manner. For example, see "Protective Groups in Organic Synthesis" by TW Green and PGM Wets (Wiley & Sons, 1991) or "Protecting Groups" by PJ Kocienski (Georg Thieme Verlag, 1994). If necessary, deprotection then generally provides compounds of the disclosed nature.

[0138] In some cases, a substituent can be specifically selected to be reactive under the reaction conditions employed, which, under these circumstances, convert the selected substituent into another substituent that is either useful as an intermediate compound or is a desired substituent in a target compound.

[0139] The schemes depicted below are representative methods for preparing compounds of formula (I), but they are intended only to be illustrative of processes that can be used to make the compounds of the invention.

[0140] Compound names were generated using the software naming program ChemDraw Ultra v12.0 available from Perkin Elmer, 940 Winter Street, Waltham, MA (http: / / www.perkinelmer.com / ).

[0141] [ka]

[0142] The preparation of the compounds of the invention generally begins with the synthesis of the N-substituted 2-amino aromatic acid derivative I-4 (Scheme I). An appropriately substituted 2-halo aromatic acid is esterified under standard conditions to give the corresponding ester I-2. Generally, the esterification reaction is carried out in the presence of an alcohol under acidic conditions or in the presence of a suitable alkyl halide under basic conditions. The 2-halo aromatic ester I-2 (X 2 =Cl, Br or I) to the appropriate aniline or amine (R 5’ -NH2, where R 5’ is a substituted phenyl group) to give the corresponding N-substituted 2-amino aromatic ester I-3. Typically, this reaction is carried out at elevated temperature using standard heating or microwave irradiation in a suitable solvent (e.g., 1,4-dioxane, toluene or 2-ethoxyethanol) in the presence of a catalyst (e.g., Pd2(dba)3 or Cu / CuO), a suitable ligand (e.g., BINAP or Xantphos) and an inorganic base (typically Cs2CO3 or K2CO3).

[0143] Saponification of esters I-3 to the corresponding N-substituted 2-amino aromatic acid derivatives I-4 is generally carried out under standard basic conditions using a base such as LiOH, KOH or NaOH in a suitable solvent or solvent system, e.g., methanol / HO, ethanol / HO, or THF / HO. Such conditions are well known to those skilled in the art.

[0144] [ka]

[0145] The intermediate N-substituted-2-amino aromatic acid derivative I-4 prepared as shown in Scheme I can be converted to compound II-2 as outlined in Scheme II. Coupling of I-4 with substituted methoxypyridylamine II-3 under various amide coupling conditions known to those skilled in the art gives the corresponding amide II-1. For example, standard coupling reagents such as EDC / HOBT, HATU, HBTU or T3P can be used in the presence of an amine base such as triethylamine or Hunig's base (diisopropylethylamine) in a suitable solvent, typically DMF, DMA or acetonitrile. Alternatively, the acid can be converted to the corresponding acid chloride using a reagent such as thionyl chloride or oxalyl chloride, which can then be reacted with the substituted methoxypyridylamine II-3 in a suitable solvent such as dichloromethane or pyridine in the presence of an acid scavenger or base such as pyridine, 2,6-lutidine, triethylamine or Hunig's base to give the desired coupling product II-1.

[0146] As in the case of intermediate II-2, the formation of the dihydroquinazolinone ring system involves the reaction of intermediate II-1 with formaldehyde or a suitable equivalent. For example, the reaction can be carried out with formaldehyde, paraformaldehyde or s-trioxane as gaseous formaldehyde in the presence of an acid, preferably PTSA or sulfuric acid. Alternatively, the dihydroquinazolinone ring system can be formed by the reaction of II-1 with diiodomethane or chloroiodomethane as formaldehyde equivalent. This variation of the cyclization reaction uses a base, typically Cs2CO3 or NaH, in a suitable solvent, often acetonitrile or DMF. The choice of using formaldehyde or diiodomethane depends on the specific reactivity characteristics of intermediate II-1.

[0147] [ka]

[0148] ' In a variation of the methods described in Schemes I and II, compounds of the invention can be prepared as shown in Scheme III. Coupling of intermediate III-1 (generally obtained from commercial sources) with substituted methoxypyridylamine II-3 under a variety of amide coupling conditions known to those skilled in the art gives the corresponding amide III-2. General conditions for forming amides are described in Scheme II. Amide III-2 can then be reacted with an appropriate aniline or amine (R 5’ —NH2) to give intermediate II-1, which can then be converted to compound II-2 according to the methods shown in Scheme II.

[0149] [ka]

[0150] As shown in Scheme IV, the conversion of compound II-2 to pyridone IV-1 can be achieved by reacting compound II-2 with a mixture of TMS-chloride and NaI or TMS-iodide solution in a neutral solvent such as acetonitrile at elevated temperature. Compound IV-1 can be reacted with chloromethyl chloroformate in a suitable solvent such as EtOAc and DMF in the presence of an organic base such as DABCO to give chloromethyl pyridone IV-2. Compound IV-2 can be reacted with potassium di-tert-butyl phosphate in the presence of a phase transfer catalyst such as TBAI in the solvent DMF at elevated temperature to give compound IV-3. Removal of the tert-butyl protecting group under acidic conditions such as acetic acid in acetonitrile and water gives the prodrug compound of the invention.

[0151] Pharmaceutical Compositions, Routes of Administration and Dosages The compound of the present invention can be formulated into a pharmaceutical composition before being administered to a subject. According to one aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention (i.e., a compound defined by any of the formulas disclosed herein, including formula (I), or a pharma- ceutically acceptable salt thereof of the present invention) and one or more pharma- ceutical acceptable excipients. According to one aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention (i.e., a compound defined by any of the formulas disclosed herein, including formula (I), or a pharma- ceutical acceptable salt thereof) and a pharma- ceutical acceptable excipient.

[0152] In another aspect, the present invention relates to a pharmaceutical composition or formulation comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof of the present invention; a pharma- ceutically acceptable excipient; and, optionally, one or more other therapeutic ingredients.

[0153] The pharmaceutical composition or preparation defined herein generally contains one compound of the present invention.However, in certain embodiments, the pharmaceutical composition may contain two or more compounds of the present invention.In addition, the pharmaceutical composition of the present invention may optionally further comprise one or more additional pharmacologic active compounds.

[0154] Pharmaceutically acceptable excipients should be non-toxic and not interfere with the efficacy of the active ingredient. Suitable pharma-ceutically acceptable excipients vary depending on the particular dosage form, route of administration, etc. selected. Suitable pharma-ceutically acceptable excipients include the following types of excipients: diluents, carriers, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, cosolvents, suspending agents, emulsifying agents, sweeteners, flavoring agents, flavoring agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, thickening agents, antioxidants, preservatives, stabilizers, surfactants, and buffers. Examples of pharma-ceutically acceptable excipients are described, for example, in Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

[0155] The pharmaceutical composition can be adapted for administration by any suitable or appropriate route, such as systemic administration (e.g., oral administration, parenteral administration, transdermal administration, rectal administration, inhalation), topical administration, etc. Parenteral administration is generally administration by injection or infusion, including intravenous, intramuscular and subcutaneous injection or infusion. Inhalation refers to administration into the patient's lungs, whether inhaled through the oral cavity or through the nasal passages. Generally, administration is via oral or parenteral routes.

[0156] Pharmaceutical compositions adapted for oral administration can be provided as solid dosage forms such as tablets, capsules, caplets, lozenges, pills, etc.; powders; or liquid dosage forms such as solutions, suspensions, syrups, elixirs, or emulsions. Pharmaceutical compositions adapted for parenteral administration (e.g., intravenous administration) can be provided as solutions, suspensions, and powders for reconstitution.

[0157] In general, the pharmaceutical compositions of the present invention are prepared using conventional ingredients and techniques of mixing, blending, etc. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

[0158] Solid oral dosage forms such as tablets and capsules can be prepared by mixing the compounds of the present invention with excipients such as diluents and fillers (e.g., starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.), binders (e.g., starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, etc.), lubricants (e.g., magnesium stearate, talc, etc.), etc.

[0159] Pharmaceutical compositions suitable for parenteral administration may be injection solutions prepared from powders, granules, or tablets by mixing with carriers such as distilled water, physiological saline, etc., and a base or the like may be used to adjust the pH.

[0160] In one embodiment, a pharmaceutical composition of the present invention is formulated for oral administration.

[0161] In another embodiment, the pharmaceutical compositions of the present invention are formulated for parenteral administration, particularly intravenous administration.

[0162] The present invention also provides a pharmaceutical composition comprising 0.5 to 1,000 mg of a compound of the present invention (i.e., a compound of any of the formulae disclosed herein, including formula (I), or a pharma- ceutically acceptable salt thereof of the present invention) and 0.5 to 1,000 mg of a pharma- ceutically acceptable excipient.

[0163] The compounds and pharmaceutical compositions of the present invention as defined herein can be administered once or according to a dosing regimen in which multiple doses are administered at various time intervals for a given period of time. For example, doses can be administered once, twice, three times or four times a day. Doses can be administered until a desired therapeutic effect is achieved or to maintain a desired therapeutic effect indefinitely. The dose of the compound of the present invention can be from 0.001 mg / kg to 100 mg / kg, for example, from 0.001 mg / kg to 50 mg / kg. Preferably, the selected dose is administered orally or intravenously.

[0164] Methods, Uses, Compounds for the Production and / or Use in the Treatment of Diseases In general, the present invention also relates to the compounds and / or pharmaceutical compositions of the invention as defined herein for use as a medicine or for use in therapy.

[0165] The compounds of the invention as defined herein are intended to inhibit voltage-gated sodium ion channels, in particular the voltage-gated sodium ion channel Na v It is an inhibitor of 1.8. v The activity of a compound utilized in this invention as an inhibitor of 1.8 may be assayed generally according to the methods described in the Examples herein, or according to methods available to one of skill in the art.

[0166] Thus, in one embodiment, the present invention provides a method for detecting voltage-gated sodium ion channels, particularly Na v The present invention relates to compounds and pharmaceutical compositions as inhibitors of 1.8.

[0167] In one embodiment, the present invention relates to a method for inhibiting a voltage-gated sodium ion channel in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the present invention or a pharmaceutical composition of the present invention as described herein. In one embodiment, the voltage-gated sodium channel is Na v It's 1.8.

[0168] In an embodiment, the present invention relates to a compound of the present invention or a pharmaceutical composition of the present invention for use in inhibiting a voltage-gated sodium ion channel. In one embodiment, the voltage-gated sodium channel is Na v It's 1.8.

[0169] In one embodiment, the invention relates to a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for inhibiting a voltage-gated sodium ion channel. In one embodiment, the voltage-gated sodium channel is Na v It's 1.8.

[0170] Without being bound to any particular theory, the compounds and compositions of the present invention are v It is particularly useful for treating diseases, conditions or disorders in which activation or hyperactivity of Na1.8 is implicated in the disease, condition or disorder. v When activation or hyperactivity of Na 1.8 is involved in a particular disease, condition, or disorder, the disease, condition, or disorder is v 1.8 Interventional Diseases, Conditions, or Disorders. v 1.8 Mediated diseases, disorders and conditions include pain and pain-related diseases, disorders and conditions, and cardiovascular diseases, disorders and conditions, such as atrial fibrillation.

[0171] Thus, in another aspect, the present invention relates to the use of the compounds and pharmaceutical compositions of the present invention in methods and medicaments for treating pain or a pain-related disease, disorder or condition, and / or for treating cardiovascular diseases, disorders and conditions.

[0172] As used herein, a "patient" or "subject" in need thereof refers to a human or mammal. The term "mammal" as used herein includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, and non-human primates (NHPs), such as monkeys or apes, humans, and the like. Preferably, the subject to be treated is a human.

[0173] As used herein, the term "treat", "treating", and / or "treatment" in reference to a disease, disorder, or condition means ameliorating or preventing one or more of the pathology or biological manifestations of the condition; interfering with one or more points in the biological cascade that leads to or causes the pathology; alleviating one or more of the symptoms or effects associated with the condition; slowing the progression of one or more of the pathology or biological manifestations of the condition; or lessening the severity of one or more of the symptoms or effects associated with the condition. As stated above, "treatment" of a disease, disorder, or condition includes prevention of the condition. Those skilled in the art will recognize that "prevention" is not an absolute term. In medicine, "prevention" is understood to refer to the prophylactic administration of a drug to substantially reduce the likelihood or severity of a condition or its biological manifestations, or to delay the onset of such a condition or its biological manifestations.

[0174] As used herein, "effective amount" and "therapeutically effective amount" are used interchangeably. With respect to the compounds of the present invention, an effective amount means an amount of the compound that is sufficient to treat the condition of a patient within the scope of sound medical judgment, but low enough to avoid significant side effects (at a reasonable benefit / risk ratio). The effective amount of a compound or its pharmacologic acceptable salt of the present invention and / or its corresponding tautomer or its corresponding pharmaceutical composition will vary depending on factors such as the specific compound selected (e.g., taking into account the potency, efficacy and half-life of the compound); the route of administration selected; the condition being treated; the severity of the condition being treated; the age, size, weight and physical condition of the patient or subject being treated; the medical history of the patient or subject being treated; the duration of treatment; the nature of the combination therapy; the desired therapeutic effect, etc.

[0175] According to embodiments of the invention, the pain-related disease, disorder or condition is pain caused by any of a variety of diseases of various etiologies as described in this disclosure. In some embodiments, the pain or pain-related disease, disorder or condition is neuropathic pain, chronic pain, acute pain, nociceptive pain, inflammatory pain, musculoskeletal pain, visceral pain, cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Tooth syndrome or incontinence.

[0176] In some embodiments, the pain or pain-related disease, disorder or condition is acute pain.

[0177] In some embodiments, the pain or pain-related disease, disorder or condition is neuropathic pain or chronic neuropathic pain.

[0178] In some embodiments, the pain or pain-related disease, disorder or condition is neuropathic pain or chronic neuropathic pain selected from small fiber neuropathy, small fiber-mediated diabetic neuropathy, idiopathic small fiber neuropathy, painful diabetic neuropathy or polyneuropathy.

[0179] In some embodiments, the pain or pain-related disease, disorder or condition is neuropathic pain selected from post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma, traumatic neuroma, Morton's nerve, nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain, nerve avulsion injury, brachial plexus avulsion, complex regional pain syndrome, medication-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia, post-spinal cord injury pain, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal autonomic cephalopathy.

[0180] In some embodiments, the pain or pain-related disease, disorder or condition is neuropathic pain or chronic neuropathic pain selected from diabetic peripheral neuropathy, neuropathy, pain caused by neurological or neuronal injury, pain-related nerve injury, neuralgia and related acute or chronic pain, post-herpetic neuralgia, pain-related nerve root avulsion, painful traumatic mononeuropathy, painful polyneuropathy, erythromelalgia, paroxysmal excruciating pain syndrome (PEPD), burning mouth syndrome, lesions at the level of the nervous system, traumatic nerve injury, central pain syndromes caused by nerve compression or entrapment, congenital insensitivity to pain (CIP), dysmenorrhea, primary erythromelalgia, HIV peripheral sensory neuropathy, pudendal neuralgia, spinal nerve injury, chronic inflammatory demyelinating polyneuropathy (CIDP), carpal tunnel syndrome and vasculitic neuropathy.

[0181] In some embodiments, the pain or pain-related disease, disorder or condition is visceral pain, and the visceral pain is inflammatory bowel disease pain, Crohn's disease pain, or interstitial cystitis pain.

[0182] In some embodiments, the pain or pain-related disease, disorder or condition is musculoskeletal pain, and the musculoskeletal pain is osteoarthritis pain, back pain, cold pain, burn pain, or toothache.

[0183] In some embodiments, the pain or pain-related disease, disorder or condition is idiopathic pain, and the idiopathic pain is fibromyalgia pain.

[0184] In some embodiments, the pain or pain-related disease, disorder or condition is chronic or acute pre-operative associated pain or chronic or acute post-operative associated pain. Post-operative associated pain includes outpatient post-operative pain. Outpatient surgery, also known as outpatient surgery, refers to surgery on the same day without the need for an overnight stay in a hospital or other medical facility. In some embodiments, the pre-operative associated pain is selected from neuropathic pain or chronic neuropathic pain, chronic osteoarthritis pain, dental pain or inflammatory pain. In some embodiments, the post-operative associated pain is selected from hallux valgus resection pain, hernia repair pair pain, breast surgery pain or cosmetic surgery pain.

[0185] In some embodiments, the pain or pain-related disease, disorder or condition is pain caused by trauma or iatrogenic medical or dental treatment.As used herein, the term "iatrogenic" refers to pain that is inadvertently induced by medical or dental practitioners, such as surgeons or dentists, during medical or dental treatment or diagnostic procedures, including, but not limited to, pain caused preoperatively (i.e., "before" medical or dental treatment), perioperatively (i.e., medically induced pain "during" medical or dental treatment, or during non-surgical or operative treatment), and postoperatively (i.e., after medical or dental treatment, or postoperatively or surgically induced pain).

[0186] In some embodiments, the pain or pain-related disease, disorder or condition is nociceptive pain, wherein the nociceptive pain is post-operative pain, cancer pain, back and craniofacial pain, osteoarthritis pain, dental pain or diabetic peripheral neuropathy.

[0187] In some embodiments, the pain or pain-related disease, disorder or condition is inflammatory pain.Inflammatory pain can be pain of various physiological origins.In some embodiments, the inflammatory pain is selected from the pain associated with osteoarthritis, rheumatoid arthritis, rheumatic disorders, tenosynovitis and gout, shoulder tendonitis or bursitis, gouty arthritis, and rheumatic polymyalgia, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, or pain caused by central sensitization; complex regional pain syndrome, chronic joint pain and associated neuralgia or acute pain.In some embodiments, the inflammatory pain is selected from the pain associated with rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis, or juvenile arthritis. In some embodiments, the inflammatory pain is selected from rheumatoid arthritis; rheumatic spondylitis; gouty arthritis; juvenile arthritis; rheumatic disorders; gout; shoulder tendonitis or bursitis; rheumatic polymyalgia; primary hyperalgesia; secondary hyperalgesia; primary allodynia; secondary allodynia; or pain caused by central sensitization, complex regional pain syndrome, chronic or acute joint pain and associated neuralgia.

[0188] In some embodiments, the inflammatory pain is selected from rheumatoid arthritis pain or vulvodynia.

[0189] In some embodiments, the inflammatory pain is selected from osteoarthritis, chronic osteoarthritic pain (eg, of the hip or knee), or chronic inflammatory demyelinating polyneuropathy.

[0190] In some embodiments, the pain or pain-related disease, disorder or condition is musculoskeletal pain.In some embodiments, the musculoskeletal pain is selected from bone and joint pain, osteoarthritis; back and neck pain; pain resulting from physical trauma or amputation.In some embodiments, the musculoskeletal pain is selected from bone and joint pain, osteoarthritis (e.g., knee, lower back), tendonitis (e.g., shoulder), bursitis (e.g., shoulder), tenosynovitis, back and neck pain, sprain, pulled muscle, or pain resulting from physical trauma or amputation.

[0191] In some embodiments, the pain or pain-related disease, disorder or condition is a pain disorder associated with neurological or neuronal damage caused by a disease selected from neuropathy, pain-related nerve injury, pain-related nerve root avulsion, painful traumatic mononeuropathy, painful polyneuropathy, erythromelalgia, paroxysmal acute pain syndrome (PEPD), burning mouth syndrome; central pain syndromes caused by lesions at the level of the nervous system; traumatic nerve injury, nerve compression or entrapment, congenital insensitivity to pain (CIP), dysmenorrhea, primary erythromelalgia; HIV peripheral secondary neuropathy; pudendal neuralgia, seminal nerve injury, chronic inflammatory demyelinating polyneuropathy (CIDP), carpal tunnel syndrome and vasculitic neuropathy.

[0192] In some embodiments, the pain or pain-related disease, disorder or condition is pain caused by trauma, or pain caused by iatrogenic, medical or dental procedures.

[0193] In some embodiments, the pain or pain-related disease, disorder, or condition is myofascial pain; myositis or muscle inflammation; repetitive motion pain; complex regional pain syndrome; sympathetically maintained pain; pain associated with cancer, toxins, and chemotherapy; post-operative pain syndrome and / or associated phantom limb pain; post-operative medical or dental procedural or treatment pain; HIV-related pain or pain caused by HIV treatment.

[0194] In some embodiments, the pain or pain-related disease, disorder or condition is neuropathic pain or other pain-related disease, disorder or condition selected from peripheral neuropathic pain, central neuropathic pain, hereditary erythromelalgia (IEM), small fiber neuralgia (SFN), paroxysmal excruciating pain syndrome (PEPD), painful diabetic neuropathy, chronic low back pain, neuropathic back pain, sciatica, non-specific low back pain, multiple sclerosis pain, HIV-associated neuropathy, post-herpetic neuralgia, trigeminal neuralgia, vulvodynia, pain resulting from physical trauma, post-amputation pain, neuroma pain, phantom limb pain, cancer, toxins, or chronic inflammatory conditions.

[0195] In some embodiments, the pain or pain-related disease, disorder or condition is acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy, epilepsy conditions, neurodegenerative diseases, psychiatric disorders, anxiety, depression, bipolar disorder, muscle tone, arrhythmia, movement disorder, neuroendocrine disorder, 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, post-operative pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension or gastrointestinal dysmotility.

[0196] In some embodiments, the pain or pain-related disease, disorder or condition is selected from the group consisting of femoral cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; pancreatic pain; IBS pain; chronic and acute headaches; migraine headaches; tension-type headaches including cluster headaches; chronic and acute neuropathic pain, post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy; peripheral nerve injury; painful neuromas; ectopic proximal and distal discharges; radiculopathy; chemotherapy-induced neuropathic pain; radiation therapy-induced neuropathic pain; breast resection. Post-operative pain;Central pain;Spinal cord injury pain;Post-stroke pain;Thalamic pain;Complex regional pain syndrome;Phantom pain;Intractable pain;Acute pain, acute post-operative pain;Acute musculoskeletal pain;Arthral pain;Mechanical back pain;Neck pain;Tendonitis;Injury / exercise pain;Acute visceral pain;Pyelonephritis;Appendicitis;Cholecystitis;Intestinal obstruction;Hernia;Chest pain, cardiac pain;Pelvic pain, renal colic, acute obstetric pain, labour pain;Caesarean section pain;Acute inflammatory, burn and trauma pain;Acute intermittent pain, endometriosis;Acute shingles pain;Sickle cell anemia;Acute pancreatitis;Breakthrough pain;Sinusitis pain, Orofacial pain including toothache;Multiple sclerosis (MS) pain;Pain in depression;Leprosy pain;Behcet's disease pain;Painful adiposity;Phlebitis pain;Guillain-Barre pain;Painful legs and moving toes syndrome legs and moving toes); Haglund syndrome; erythromelalgia pain; Fabry pain; bladder and genitourinary disorders including urinary incontinence; overactive bladder; painful bladder syndrome; interstitial cystitis (IC); prostatitis; complex regional pain syndrome types I and II (CRPS); widespread pain, paroxysmal severe pain, pruritus, tinnitus, or angina-induced pain.

[0197] In another aspect, the invention relates to the use of the compounds and pharmaceutical compositions of the invention in methods and medicaments for the treatment of cardiovascular diseases, disorders and conditions, including atrial fibrillation and cardiac arrhythmias.

[0198] In some embodiments, the cardiovascular disease is atrial fibrillation that is idiopathic in nature or caused by a disease as defined herein.The atrial fibrillation can be paroxysmal atrial fibrillation, persistent atrial fibrillation, long-term atrial fibrillation, atrial fibrillation with heart failure, atrial fibrillation with heart valve disease, or atrial fibrillation with chronic kidney disease.In certain embodiments, the atrial fibrillation is selected from paroxysmal, persistent, or long-term atrial fibrillation.

[0199] In some embodiments, the cardiovascular disease includes cardiac arrhythmia.

[0200] In one embodiment, the present invention relates to a method of treating pain or a pain-related disease, disorder or condition as defined herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the invention or a pharmaceutical composition of the invention as described herein.

[0201] In certain embodiments, there is provided a method of treating acute or chronic pain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the invention or a pharmaceutical composition of the invention described herein.

[0202] In certain embodiments, there is provided a method of treating acute pain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the invention or a pharmaceutical composition of the invention described herein.

[0203] In certain embodiments, there is provided a method of treating pain caused by trauma; pain caused by iatrogenic, medical or dental procedures; or pre- or post-operative related pain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the invention or a pharmaceutical composition of the invention described herein.

[0204] In certain embodiments, there is provided a method of treating neuropathic pain, nociceptive pain, inflammatory pain, musculoskeletal pain, visceral pain, or idiopathic pain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the invention or a pharmaceutical composition of the invention described herein.

[0205] In certain embodiments, there is provided a method of treating neuropathic pain or chronic neuropathic pain selected from small fiber neuropathy, small fiber mediated diabetic neuropathy, idiopathic small fiber neuropathy, painful diabetic neuropathy and polyneuropathy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the invention or a pharmaceutical composition of the invention as described herein.

[0206] In certain embodiments, there is provided a method of treating inflammatory pain selected from osteoarthritis, chronic osteoarthritic pain and chronic inflammatory demyelinating polyneuropathy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the invention or a pharmaceutical composition of the invention as described herein.

[0207] In one embodiment, the present invention relates to a method of treating atrial fibrillation as defined herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition of the present invention as described herein.

[0208] In one embodiment, a method is provided for treating atrial fibrillation, where the atrial fibrillation is paroxysmal atrial fibrillation, persistent atrial fibrillation, long-term atrial fibrillation, atrial fibrillation associated with heart failure, atrial fibrillation associated with heart valve disease, or atrial fibrillation associated with chronic kidney disease.

[0209] In another aspect, the present invention provides compounds of the invention and pharmaceutical compositions of the invention as described herein for use in the treatment of pain or a pain-related disease, disorder or condition as defined herein.

[0210] In certain embodiments there is provided a compound of the invention or a pharmaceutical composition of the invention for use in the treatment of acute pain or chronic pain.

[0211] In one embodiment there is provided a compound of the invention or a pharmaceutical composition of the invention for use in the treatment of acute pain.

[0212] In certain embodiments there is provided a compound of the invention or a pharmaceutical composition of the invention for use in the treatment of pain caused by trauma; pain caused by iatrogenic medical or dental procedures; or pre- or post-operative associated pain.

[0213] In certain embodiments there is provided a compound of the invention or a pharmaceutical composition of the invention for use in the treatment of neuropathic pain, nociceptive pain, inflammatory pain, musculoskeletal pain, visceral pain, or idiopathic pain.

[0214] In one embodiment there is provided a compound of the invention or a pharmaceutical composition of the invention for use in treating neuropathic pain or chronic neuropathic pain selected from small fiber neuropathy, small fiber mediated diabetic neuropathy, idiopathic small fiber neuropathy, painful diabetic neuropathy and polyneuropathy.

[0215] In certain embodiments there is provided a compound of the invention or a pharmaceutical composition of the invention for use in treating inflammatory pain selected from osteoarthritis, chronic osteoarthritic pain and chronic inflammatory demyelinating polyneuropathy.

[0216] In another aspect, the present invention relates to a compound of the present invention or a pharmaceutical composition of the present invention for use in the treatment of atrial fibrillation.

[0217] In one embodiment there is provided a compound of the invention or a pharmaceutical composition of the invention for use in the treatment of atrial fibrillation, wherein the atrial fibrillation is paroxysmal atrial fibrillation, persistent atrial fibrillation, long-term atrial fibrillation, atrial fibrillation associated with heart failure, atrial fibrillation associated with valvular heart disease or atrial fibrillation associated with chronic kidney disease.

[0218] In another aspect, the present invention also provides the use of a compound of the invention or a pharmaceutical composition of the invention as described herein in the manufacture of a medicament for the treatment of pain and pain-related diseases, disorders or conditions described herein.

[0219] In one embodiment there is provided the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of acute pain or chronic pain.

[0220] In one embodiment there is provided the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of acute pain.

[0221] In one embodiment there is provided a use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of pain caused by trauma; pain caused by iatrogenic, medical or dental procedures; or pain associated with pre- or post-surgical procedures.

[0222] In certain embodiments there is provided the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of neuropathic pain, nociceptive pain, inflammatory pain, musculoskeletal pain, visceral pain or idiopathic pain.

[0223] In one embodiment there is provided a use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of neuropathic pain or chronic neuropathic pain selected from small fiber neuropathy, small fiber mediated diabetic neuropathy, idiopathic small fiber neuropathy, painful diabetic neuropathy and polyneuropathy.

[0224] In one embodiment there is provided a use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of inflammatory pain selected from osteoarthritis, chronic osteoarthritic pain and chronic inflammatory demyelinating polyneuropathy.

[0225] In another aspect, the present invention also provides the use of a compound of the invention or a pharmaceutical composition of the invention as described herein in the manufacture of a medicament for the treatment of atrial fibrillation.

[0226] In certain embodiments, there is provided a use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of atrial fibrillation, wherein the atrial fibrillation is paroxysmal atrial fibrillation, persistent atrial fibrillation, long-term atrial fibrillation, atrial fibrillation associated with heart failure, atrial fibrillation associated with valvular heart disease or atrial fibrillation associated with chronic kidney disease.

[0227] In another aspect, the present invention relates to a compound of the invention or a pharmaceutical composition of the invention as described herein for use in therapy.

[0228] Use for combination therapy and therapy The compounds and pharmaceutical compositions of the invention described herein can be used in combination with one or more additional therapeutic agents. Such additional therapeutic agents can be administered simultaneously with, prior to, or following treatment with the compounds or pharmaceutical compositions of the invention described herein.

[0229] In the context of this specification, the term "concurrently," when referring to simultaneous administration of a compound or therapeutic agent, means simultaneously when the compound and the additional therapeutic agent are combined in a single preparation, e.g., as in an embodiment, or when the compound and the additional therapeutic agent are administered separately, but within a short period or time.

[0230] In view of the above, the present invention also relates to combination therapy, which may consist of simultaneous or co-administration, or sequential administration, of the compound or pharmaceutical composition of the present invention in combination with one or more additional therapeutic agents. Such combination therapy can be used for the treatment of pain or any pain-related disease, disorder or condition, or cardiovascular disease, disorder or condition, as defined herein.

[0231] Suitable therapeutic agents for use in combination with the compounds and pharmaceutical compositions of the present invention include, but are not limited to, acetaminophen, acetylsalicylic acid, sodium v 1.7 Inhibitor, Na v 1.9 inhibitors, antidepressants (i.e., but not limited to, duloxetine or amitriptyline), anticonvulsants (i.e., but not limited to, pregabalin and gabapentin), opiates (i.e., but not limited to, hydrocodone, codeine, morphine, oxycodone, oxymorphone, fentanyl, etc.), each of the above dosages may be determined by one skilled in the art. v 1.7 Inhibitor or Na v 1.9 Inhibitors include, but are not limited to, Na v 1.7 Inhibitor or Na v 1.9 inhibitors.

[0232] Each component of the combination used for therapeutic purposes (e.g., a compound or pharmaceutical composition of the present invention and an additional therapeutic agent) can be administered orally, intravenously, or parenterally, or a combination thereof. Each component of the therapeutic combination can be administered, including but not limited to, simultaneously, concomitantly, or sequentially; and / or by the same or different route of administration or combination of routes of administration. In certain embodiments, each same or different route of administration or combination of routes of administration is selected from oral administration, intravenous administration, or parenteral administration. EXAMPLES

[0233] Working Example The present invention is illustrated by the following examples, which are not intended to limit the scope of the invention but are intended to provide guidance to one of ordinary skill in the art for preparing and using the compounds, compositions and methods of the present invention.

[0234] While particular aspects or embodiments of the invention have been described, those skilled in the art will recognize that various changes and modifications can be made without departing from the spirit and scope of the invention.

[0235] Synthesis Example It will be appreciated by those skilled in the art that purification methods (using acidic or basic modifiers) or compound work-up procedures (using acidic or basic conditions) may result in the formation of salts of the title compound (e.g., the hydrobromide, formate, hydrochloride, trifluoroacetate or ammonium salts of the title compound), and the present invention is intended to encompass such salts.

[0236] The final compounds were characterized by GCMS and LCMS (conditions listed below) and NMR. 1 H NMR or 19 F NMR spectra were recorded using a Bruker Avance III 500 MHz spectrometer, a Bruker Avance 400 MHz spectrometer, and a Varian Mercury Plus-300 MHz spectrometer. CDCl3 is deuteriochloroform, DMSO-d6 is hexadeuteriodimethylsulfoxide, and CD3OD is tetradeuteriomethanol. Chemical shifts are reported in parts per million (ppm) downfield from the internal standard tetramethylsilane (TMS) or the NMR solvent. Abbreviations for NMR data are as follows: s=singlet, d=d doublet, t=triplet, q=quartet, m=multiplet, dd=double doublet, dt=double triplet, app=clear, br=broad. J indicates the NMR coupling constant measured in Hertz.

[0237] Analysis method: 1) LCMS method: Electrospray positive [M+H] with a CSH C18 column (30 mm x 2.1 mm, id 1.7 μm packing diameter) eluted at 45 °C with 0.1% TFA in water (solvent A) and 0.1% TFA in acetonitrile (solvent B) using the following elution gradient: 1 to 100% (solvent B) over 1.85 min at a flow rate of 1.3 mL / min. +Acquity UPLC with Waters Acquity QDa Mass Detector using ES+ve to obtain

[0238] 2) LCMS method: Electrospray positive [M+H] with a CSH C18 column (30 mm x 2.1 mm, id 1.7 μm packing diameter) eluted at 45 °C with formic acid in water (solvent A) and formic acid in acetonitrile (solvent B) using the following elution gradient: 1 to 100% (solvent B) over 1.85 min at a flow rate of 1.3 mL / min. + Acquity UPLC with Waters Acquity QDa Mass Detector using ES+ve to obtain

[0239] 3) LCMS method: Electrospray positive [M+H] with a CSH C18 column (30 mm x 2.1 mm, id 1.7 μm packing diameter) eluted at 45 °C with 10 mM ammonium bicarbonate in water adjusted to pH = 10 with 25% ammonium hydroxide solution (solvent A) and acetonitrile (solvent B) with the following elution gradient: 1 to 100% (solvent B) over 1.85 min at a flow rate of 1.3 mL / min. + Acquity UPLC with Waters Acquity QDa Mass Detector using ES+ve to obtain

[0240] 4) LCMS method: Agilent 1290 Infinity II LC system with Agilent MSD 6125B / 6130 using multimode (ESI and APCI +ve and -ve) with a Sunfire C18 column (30 mm x 2.1 mm, id 3.5 μm packing diameter) eluted at 25 °C with 0.1% formic acid in water (solvent A) and 0.1% formic acid in acetonitrile (solvent B) with the following elution gradient: 0-100% (solvent B) over 3.1 min at a flow rate of 1.0 mL / min and a 0.8 min hold at 100%.

[0241] 5) LCMS method: Agilent 1290 Infinity II LC system equipped with Agilent MSD 6125B / 6130 using multimode (ESI and APCI +ve and -ve) with an Atlantis dC18 column (50 mm x 4.6 mm, id 5.0 μm packing diameter) eluted with 0.1% TFA in water (solvent A) and methanol (solvent B) at 25 °C with the following elution gradient: 5 to 95% (solvent B) over 5.0 min at a flow rate of 1.0 mL / min and a 1.5 min hold at 95%.

[0242] 6) LCMS method: Agilent 1290 Infinity II LC system with Agilent MSD 6125B / 6130 using multimode (ESI and APCI +ve and -ve) with a Zorbax XDB C18 column (50 mm x 4.6 mm, id 3.5 μm packing diameter) eluted with 10 mM ammonium acetate in water (solvent A) and acetonitrile (solvent B) at 25 °C with the following elution gradient: 10 to 95% (solvent B) over 3.5 min and hold at 95% for 1.0 min at a flow rate of 1.0 mL / min.

[0243] 7) LCMS method: Agilent 1290 Infinity II LC system with Agilent MSD 6125B / 6130 using multimode (ESI and APCI +ve and -ve) with an Xbridge C8 column (50 mm x 4.6 mm, id 3.5 μm packing diameter) eluted with 10 mM ammonium bicarbonate in water (solvent A) and acetonitrile (solvent B) at 25 °C with the following elution gradient: 10 to 95% (solvent B) over 4.0 min at a flow rate of 1.0 mL / min and a 1.0 min hold at 95%.

[0244] 8) GCMS method: Agilent 7890B GC system with Agilent MSD 5977B using EI with HP-5 column (30m x 0.32mm, 0.25μm film thickness) eluted with helium at 250°C, flow rate of 2mL / min and run time of 10min with the following chromatographic run conditions: 120°C for 1min, ramp to 300°C at 40°C / min, hold for 4.5min.

[0245] In the experimental description that follows, the following abbreviations may be used: [Table 2] JPEG2024502231000017.jpg249170JPEG2024502231000018.jpg241170JPEG2024502231000019.jpg65170

[0246] Intermediate 1 2-Bromo-4-(trifluoromethyl)benzoic acid ethyl ester

[0247] [ka]

[0248] To a stirred solution of 2-bromo-4-(trifluoromethyl)benzoic acid (10.0 g, 37.2 mmol) in DMF (100 mL) was added K2CO3 (5.65 g, 40.9 mmol) followed by ethyl iodide (3.60 mL, 44.6 mmol) dropwise under N2 at 25 °C. The reaction mixture was stirred at the same temperature for 3 h. Water (150 mL) was added and the reaction was extracted with EtOAc (2 x 250 mL). The combined organic extracts were washed with brine (150 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (Biotage, 100 g SNAP column, 10% EtOAc / petroleum ether over 40 min) to give the title compound as a colorless oil (9.3 g, 31.3 mmol, 84% yield). GCMS (m / z) 296.0 (M) + .

[0249] Intermediate 2 2-Chloro-5-(trifluoromethyl)nicotinoyl chloride

[0250] [ka]

[0251] To a stirred solution of 2-chloro-5-(trifluoromethyl)nicotinic acid (50 g, 222 mmol) in DCM (500 mL) was added oxalyl chloride (23.28 mL, 266 mmol) and DMF (1.716 mL, 22.17 mmol) at 0° C. and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was filtered under reduced pressure and dried under N2 to give the title compound as a brown gum (52 ​​g, 213 mmol, 96% yield).

[0252] Intermediate 3 2-Chloro-N-(6-methoxy-2-methylpyridin-3-yl)-5-(trifluoromethyl)nicotinamide

[0253] [ka]

[0254] A mixture of 6-methoxy-2-methylpyridin-3-amine (32.4 g, 234 mmol) and TEA (89 mL, 639 mmol) in DCM (300 mL) was added to a stirred solution of 2-chloro-5-(trifluoromethyl)nicotinoyl chloride (52 g, 213 mmol) in DCM (300 mL) at 0 °C and the reaction mixture was stirred for 2 h. The reaction mixture was quenched with ice-cold water (500 mL) and extracted with DCM (3 x 500 mL). The combined organic phase was washed with water (500 mL) and brine (500 mL), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (Biotage, 340 g SiO2 column, 0-30% EtOAc / petroleum ether over 40 min) to give the title compound as a brown solid (37 g, 106 mmol, 49.9% yield). MS (m / z) 346.0 (M+H + ).

[0255] Intermediate 4 2-((4-fluoro-2-methylphenyl)amino)-5-(trifluoromethyl)benzoic acid methyl ester

[0256] [ka]

[0257] To a solution of methyl 2-bromo-5-(trifluoromethyl)benzoate (2 g, 7.1 mmol) and 4-fluoro-2-methylaniline (1.06 g, 8.48 mmol) in 1,4-dioxane (20 mL) at room temperature under nitrogen, cesium carbonate (4.60 g, 14.13 mmol) and BINAP (0.44 g, 0.71 mmol) were added in one portion. The reaction mixture was purged with nitrogen for 10 minutes, and then Pd2(dba)3 (0.324 g, 0.353 mmol) was added to the reaction mixture. The reaction mixture was stirred at 100° C. for 16 hours. The reaction mixture was cooled to room temperature, filtered through a Celite® pad, and the filtrate was concentrated onto SiO2. Purification by flash chromatography on SiO2 (25 g) using 0-30% EtOAc in petroleum ether as eluent afforded the title compound as a colorless solid (2.3 g, 7.0 mmol, 99% yield). MS (m / z) 328.0 (M+H + ).

[0258] Intermediates 5-6 were prepared in a similar manner as described for intermediate 4 from the indicated aryl halogens and anilines.

[0259] [Table 3]

[0260] Intermediate 7 2-((4-fluoro-2-methylphenyl)amino)-5-(trifluoromethyl)benzoic acid

[0261] [ka]

[0262] To a solution of methyl 2-((4-fluoro-2-methylphenyl)amino)-5-(trifluoromethyl)benzoate (2.3 g, 7.03 mmol) in THF (20 mL) under N2 was added LiOH (1.68 g, 70.3 mmol). The reaction mixture was stirred at 80 °C for 4 h. The reaction mixture was cooled to room temperature and the filtrate was concentrated in vacuo. The crude material was extracted with 100 mL of DCM and washed with 50 mL of water. The aqueous layer was acidified with 20 mL of 1.5 N HCl and extracted twice with DCM (100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as a yellow solid (2.1 g, 6.7 mmol, 95% yield). MS (m / z) 314.0 (M+H + ).

[0263] Intermediates 8-9 were prepared from the indicated esters in a similar manner as described for intermediate 7.

[0264] [Table 4]

[0265] Intermediate 10 2-((4-fluoro-2-methylphenyl)amino)-N-(6-methoxy-2-methylpyridin-3-yl)-5-(trifluoromethyl)benzamide

[0266] [ka]

[0267] To a solution of 2-((4-fluoro-2-methylphenyl)amino)-5-(trifluoromethyl)benzoic acid (2.1 g, 6.7 mmol), DIPEA (2.34 mL, 13.4 mmol) and HATU (3.82 g, 10.1 mmol) in DMF (20 mL) at room temperature under nitrogen, 6-methoxy-2-methylpyridin-3-amine (1.02 g, 7.4 mmol) was added dropwise over 1 min. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with ice-cold water (100 mL) and the resulting solid was filtered and dried under vacuum to give the title compound as a brown solid (2.4 g, 5.5 mmol, 82% yield). MS (m / z) 434.0 (M+H + ).

[0268] Intermediates 11-12 were prepared in a similar manner as described for Intermediate 10 from the indicated amines and carboxylic acids.

[0269] [Table 5]

[0270] Intermediate 13 N-(6-Methoxy-2-methylpyridin-3-yl)-2-((2-methyl-4-(trifluoromethoxy)phenyl)amino)-5-(trifluoromethyl)nicotinamide

[0271] [ka]

[0272] A 1 L round bottom flask equipped with a magnetic stir bar was charged with 2-chloro-N-(6-methoxy-2-methylpyridin-3-yl)-5-(trifluoromethyl)nicotinamide (37 g, 107 mmol) and 2-methyl-4-(trifluoromethoxy)aniline (30.7 g, 161 mmol). Toluene (500 mL) was added followed by cesium carbonate (69.7 g, 214 mmol). The resulting reaction mixture was purged with nitrogen for 15 minutes before adding Xantphos (6.19 g, 10.70 mmol) and Pd2(dba)3 (4.90 g, 5.35 mmol). The resulting dark brown reaction mixture was stirred at 100° C. for 16 hours. The reaction mixture was allowed to cool to room temperature and filtered through a bed of Celite®, washing with EtOAc (1 L). The filtrate was concentrated in vacuo and the crude product was purified by flash column chromatography (Biotage, 330 g SiO2 column, 0-30% EtOAc / petroleum ether over 90 min) to give the title compound as a brown solid (35 g, 36.5 mmol, 34.1% yield). MS (m / z) 500.8 (M+H + ).

[0273] Intermediate 14 1-(4-Fluoro-2-methylphenyl)-3-(6-methoxy-2-methylpyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one

[0274] [ka]

[0275] To a solution of 2-((4-fluoro-2-methylphenyl)amino)-N-(6-methoxy-2-methylpyridin-3-yl)-5-(trifluoromethyl)benzamide (2.4 g, 5.5 mmol) and Cs2CO3 (7.22 g, 22.2 mmol) in acetonitrile (25 mL) at room temperature under nitrogen, diiodomethane (1.340 mL, 16.61 mmol) was added dropwise over 5 min. The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was cooled to room temperature and filtered through a Celite® pad. The filtrate was concentrated onto SiO2. Purification by flash chromatography on SiO2 (50 g) using 0-100% EtOAc / petroleum ether as eluent afforded the title compound as a colorless solid (2.0 g, 4.1 mmol, 74% yield). MS (m / z) 446.0 (M+H + ).

[0276] Intermediates 15-17 were prepared from the indicated amides in a similar manner as described for intermediate 14.

[0277] [Table 6]

[0278] Intermediate 18 1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one

[0279] [ka]

[0280] To a solution of 1-(4-fluoro-2-methylphenyl)-3-(6-methoxy-2-methylpyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one (0.6 g, 1.4 mmol) in acetonitrile (10 mL) at room temperature under nitrogen was added iodotrimethylsilane (0.54 g, 2.7 mmol) dropwise over 5 minutes. The reaction mixture was stirred at 80° C. for 12 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was dissolved in DCM (100 mL) and washed with saturated sodium thiosulfate (20 mL). The organic layer was dried over sodium sulfate and concentrated onto Celite®. Purification by reverse phase chromatography on a C18 (40 g) using a 0-100% gradient with 0.1% formic acid in acetonitrile in 0.1% formic acid in water as eluent gave clean fractions which were concentrated and the resulting precipitate was filtered, washed with water and dried to give the title compound as a colorless solid (0.21 g, 0.5 mmol, 36% yield). MS (m / z) 432.1 (M+H + ).

[0281] Intermediates 19-21 were prepared from the indicated intermediates in a similar manner as described for intermediate 18.

[0282] [Table 7]

[0283] Intermediate 22 3-(1-(chloromethyl)-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one

[0284] [ka]

[0285] To a suspension of 1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one (0.878 g, 2.035 mmol) and DABCO (0.183 g, 1.628 mmol) in ethyl acetate (16.23 mL) and DMF (1.623 mL) under N2, chloromethyl carbonochloridate (0.452 mL, 5.09 mmol) was added dropwise. The reaction was stirred at 60° C. for about 6 hours and then at room temperature for 2.5 days. The reaction was quenched with saturated NaHCO3 (20 mL) and extracted with EtOAc and DCM (2×). The combined organic extracts were dried over Na2SO4 and concentrated. The residue was triturated with a solution of 1:2 / EtOAc:heptane to give the title compound as an off-white solid (0.749 g, 1.561 mmol, 77% yield). MS (m / z) 480.3 (M+H + ).

[0286] Intermediates 23-25 ​​were prepared from the indicated amides in a similar manner as described for intermediate 22.

[0287] [Table 8]

[0288] Intermediate 26 ((5-(1-(4-fluoro-2-methylphenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl)di-tert-butyl phosphate

[0289] [ka]

[0290] DMF (7.29 mL) was added to a mixture of 3-(1-(chloromethyl)-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one (0.749 g, 1.561 mmol), potassium di-tert-butyl phosphate (0.581 g, 2.341 mmol) and tetrabutyl ammonium iodide (0.029 g, 0.078 mmol) under N2, and the reaction was stirred at 70° C. for 3 h. The reaction was cooled to room temperature and quenched slowly with ice water (40 mL). The reaction was extracted with EtOAc, washed with water (2×), dried over Na2SO4 and concentrated to give the title compound as a foam (0.846 g, 1.294 mmol, 83% yield). MS (m / z) 542.3 (M-112) + .

[0291] Intermediates 27-29 were prepared from the indicated intermediates in a similar manner as described for intermediate 26.

[0292] [Table 9]

[0293] Example 1 Dihydrogen phosphate (5-(1-(4-fluoro-2-methylphenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl

[0294] [ka]

[0295] To a suspension of di-tert-butyl phosphate ((5-(1-(4-fluoro-2-methylphenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl) (0.3 g, 0.459 mmol) in acetonitrile (1.5 mL) and water (1.5 mL) at room temperature under N2, acetic acid (0.5 mL, 8.73 mmol) was added dropwise and the reaction was stirred at 70° C. for 3 h. The reaction was cooled and concentrated. The foamy residue was rinsed with water. The residue was purified by reverse phase (EZ Prep Isco, C18 Aq 15.5 g Gold column, 30-80% gradient, 0.1% formic acid in acetonitrile / 0.1% formic acid in water, flow rate 30 mL / min, total run time 12.3 min) to give the title compound as a white solid (64.7 mg, 0.120 mmol, 26.0% yield). 1 H NMR (400 MHz, DMSO-d6) δ:11.60 (br s, 2H), 8.09 (d, J=2.4 Hz, 1H), 7.66 (br d, J=8.3 Hz, 1H), 7.52-7.38 (m, 2H), 7.37-7.28 (m, 1H), 7.26-7.15 (m, 1H), 6.43-6.30 (m, 2H), 5.80-5.60 (m, 2H), 5.55 (d, J=9.3 Hz, 0.6H), 5.1-5.2 (m, 0.8H), 4.75 (br d, J=9.3 Hz, 0.6H), 2.3-2.4 (m, 3H), 2.25 (br s, 3H). MS (m / z) 542.0 (M+H + ).

[0296] Examples 2-4 were prepared by methods similar to those described for Example 1 from the intermediates indicated.

[0297] [Table 10]

[0298] Biological assays The Na vThe 1.8 inhibitor compounds or pharma- ceutically acceptable salts thereof are each useful for the treatment of pain, a pain disorder or condition, a pain-associated disorder or condition, or pain caused by a disease, such as those defined herein.

[0299] The biological activity of the compounds of the invention is measured in assays measuring such inhibition and in vitro or in animal models of infection by the voltage-gated sodium channel Na v This can be determined using a suitable assay, such as an assay that evaluates the ability of a compound to inhibit 1.8.

[0300] Biological Assay Example 1: Human Na v 1.8 Human Na v Human embryonic kidney 293 cells (HEK293) expressing β1 and human TREK1 (HEK293-Na v 1.8) to 150cm 2 HEK293-Na cells were grown in flasks at 37°C and 5% CO2. v 1.8 were subcultured into T175 cell culture flasks every 2–3 days when the confluency reached 80–90%.

[0301] Pharmacological evaluation of the compounds of the present invention was performed using assays developed in the QPatch 48 HTX electrophysiological system and HEK293-Na v 1.8 was used in combination. HEK293-Na v 1.8: On the day of use, remove the culture medium, wash with DPBS, add Accutase (add 2 mL to cover the surface, then aspirate 1 mL, then 1.5 min at 37 °C), then add CHO-SFM II to stop the enzymatic digestion, and 3 × 10 6 The suspension was prepared by obtaining a suspension of cells / mL.

[0302] 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, NaOH osmolality 300 mOsM / L. The intracellular solution had the following composition: CsF (115 mM), CsCl (20 mM), NaCl (5 mM), EGTA (10 mM), HEPES (10 mM), sucrose (20 mM), pH 7.2, CsOH osmolality 310 mOsm / L.

[0303] Using the voltage clamp mode of the QPatch 48HTX system, v 1.8 To measure the pharmacological activity of the compounds of the invention at ion channels, a semi-inactivated voltage protocol (V 1 / 2 ) was used. V 1 / 2 The protocol utilized the following voltage steps: a holding voltage of -100 mV was established, followed by a 20 ms voltage step to 0 mV (P1), then an 8 sec inactivation voltage step to -46 mV, then a 20 ms step to -100 mV, then a 20 ms step to 0 mV (P2), then back to the holding voltage of -100 mV. This voltage protocol was repeated at a frequency of 0.07 Hz and the current magnitude was quantified at the P2 step during the recording. Inhibition of the measured current amplitude by the compounds of the invention was measured using a 50% inhibitory concentration (IC 50 Within the QPatch HTX software, P2 currents were normalized according to measurements taken at baseline, post-compound and post-positive reference compound and fitted to the following equation:

number

[0304] To assess the rundown of currents over the course of the experiment, vehicle-only wells were utilized to measure currents normalized to vehicle alone.

number

number

[0305] The compounds of the present invention and the corresponding parent compounds (see Table 1A for structures) were assayed using the above-mentioned assays. v The activity against 1.8 sodium channel is tested in one or more experimental runs, and the results are shown in Table 1 below. The potency of the compounds of the present invention is reported as pIC50 value. pIC50 value is the negative logarithm of IC50 value, where IC50 value is the half-maximal inhibitory concentration measured in molar (M). The potency of the compounds of the present invention is comparable to that of the parent compound. For compounds tested in more than one experiment, pIC50 value is reported as the average value.

[0306] [Table 11]

[0307] [Table 12]

[0308] Biological Assay Example 2: Kinetic solubility measurements using a Charged Aerosol Detector (CAD). Kinetic solubility in aqueous solutions at pH 7.4 was determined by measuring the concentration of solute in solution after precipitation from a DMSO stock solution. The DMSO stock solution was diluted 20-fold with phosphate buffered saline (PBS) pH 7.4, and the solubility of the compounds was measured by HPLC-CAD after equilibration at room temperature for 1 hour. Calibration standards for ketoconazole and primidone were prepared at concentrations ranging from 0.016 to 4.5 mg / mL by serial dilution in DMSO to generate calibration curves, which were used to determine the solubility of the compounds as previously described in Max W. Robinson et al, Use of Calculated Physicochemical Properties to Enhance Quantitative Response When Using Charged Aerosol Detection, Anal. Chem., 2017, 89 (3), pp 1772-1777, incorporated herein by reference.

[0309] The CAD solubilities of the compounds of the invention and the corresponding parent compounds were measured as described above and the results are shown in Table 2 below.

[0310] [Table 13]

[0311] Biological Assay Example 3: Rat IV / PO Test In order to determine whether the prodrug compounds of the present invention are converted to their respective parent compounds upon administration, an in vivo rat pharmacokinetic study was performed. The rat pharmacokinetic study was performed in a two-test day crossover design with one day recovery between each test day. Three double-catheterized (femoral vein and carotid artery) male Han Wistar rats were used in the study. Each rat was also equipped with a gastric catheter for oral dosing. The rats were dosed at 1 mg / kg by 60-minute intravenous (IV) infusion (femoral vein cannula) followed by oral dosing at 2 mg / kg via the gastric cannula with 48 hours between dosing sessions. Dosing solutions of the compound of Example 3 were prepared in 20% Cavitron / 5% DMSO / 75% water (IV) and 6% Cavitron / 5% DMSO / 89% water (PO) without pH adjustment. The dosing solutions were filtered using a 0.22μ filter. The pH of the final dosing solution was 6.0.

[0312] In the intravenous study, blood samples were collected from the carotid catheter at targeted time points 15, 30, 60 (end of infusion), 65, 75, 90, 120, 240, 360, 480, 720, and 1440 minutes after the start of the intravenous infusion of the compound of Example 3. In the oral study, blood samples were collected before dosing and at targeted time points 15, 30, 60, 90, 120, 180, 240, 360, 480, 720, and 1440 minutes after oral dosing. 100 μL of blood sample was mixed with 100 μL of phosphatase inhibitor, and 50 μL aliquots of the blood and inhibitor mixture were transferred to heparin-free tubes and stored at approximately −80° C. until analysis. The concentration of the filtered dosing solution was confirmed to reach the desired nominal concentration by preparing serial dilutions first in 50% aqueous acetonitrile containing 0.1% formic acid, then in heparinized male Wistar Han blood: inhibitor. Triplicate aliquots of 50 μL were removed and stored frozen at approximately 80°C until analysis by LC-MS / MS as described below.

[0313] LC-MS / MS was used to quantify the compound of Example 3 and the corresponding parent compound of Example 3A in biological samples generated in the in vivo studies described above. Samples were prepared by protein precipitation and then subjected to LC-MS / MS analysis using positive mode ionization against a set of calibration standards of the compound prepared in the same matrix. Pharmacokinetic parameters for this study were derived from concentration versus time profiles. For the compound of Example 3, AUC 0-∞ (Extrapolated area under the blood concentration-time curve), AUC 0-t (area under the blood concentration-time curve up to the last time point at which the drug can be measured), Cmax (maximum concentration), Tmax (time at which Cmax is achieved), CL (systemic blood clearance), Vdss (steady-state volume of distribution), MRT (mean retention time), t 1 / 2 The main pharmacokinetic parameters were determined, including AUC 0-∞ , AUC 0-t , Cmax, Tmax, MRT and t 1 / 2 Key pharmacokinetic parameters such as (half-life) were determined for the parent compound Example 3A. Descriptive statistics of the pharmacokinetic parameters, including mean and standard deviation (SD), were calculated using Microsoft Excel.

[0314] These data are presented below in Tables 3A and 3B. Data are reported as mean ± SD (N=3).

[0315] [Table 14]

[0316] [Table 15]

[0317] It is to be understood that the present invention is not limited to the embodiments shown above, but reserves the right to all modifications that come within the scope of the shown embodiments and the following claims.

Claims

1. Compounds of formula (I): [Case 1] [In the formula, X １ represents N or CH; R １ is -P(O)(OH) ２ represents; R ２ is a hydrogen atom, -(C １－６ ) an alkyl group, —NR ａ R ｂ , a halogen atom or -(C １－６ ) represents a haloalkyl group; R ３ and R ４ each independently represents a hydrogen atom, a halogen atom, a cyano group, or -NR ａ R ｂ , -(C １－６ ) alkyl group, -(C １－６ ) haloalkyl group, —O—(C １－６ ) alkyl group or —O—(C １－６ ) represents a haloalkyl group; Each R ５ are independently a halogen atom, -(C １－６ ) alkyl group, —O(C １－６ ) alkyl group or -O(C １－６ ) represents a haloalkyl group; R ６ is a hydrogen atom or -(C １－６ ) represents an alkyl group; R ７ is a hydrogen atom, -(C １－６ ) an alkyl group, a halogen atom or -(C １－６ ) represents a haloalkyl group; R ａ and R ｂ Each of the groups independently represents a hydrogen atom or -(C １－６ ) alkyl group; and n represents 0, 1 or 2. or a pharma- ceutically acceptable salt or tautomer thereof.

2. X １The compound of claim 1 , wherein represents N.

3. X １ 2. The compound of claim 1 , wherein represents CH.

4. R ２ But-(C １－６ 4. The compound according to claim 1, wherein:

5. R ３ and R ４ each independently represents a hydrogen atom, a halogen atom, or -(C １－６ 5. The compound according to claim 1, wherein the aryl group is a haloalkyl group.

6. R ３ and R ４ each of which is a hydrogen atom, -Cl or -CF ３ 6. The compound according to claim 5, wherein

7. R ３ and R ４ One of the groups represents a hydrogen atom, and R ３ and R ４ The other is a halogen atom or -(C １－６ 4. The compound according to claim 1, wherein the aryl group is a haloalkyl group.

8. R ３ and R ４ One of the groups represents a hydrogen atom, and R ３ and R ４ The other is -Cl or -CF ３ 8. The compound according to claim 7, wherein

9. Each R ５ are independently a halogen atom or -O(C １－６ 9. A compound according to any one of claims 1 to 8, wherein:

10. Each R ５ are independently -F or -OCF ３ 10. The compound according to claim 9, which represents

11. R ６ But-(C １－６ 11. The compound according to claim 1, wherein:

12. R ６ Ga-CH ３ , -CH ２ CH ３ or -CH(CH ３ ) ２ 12. The compound according to claim 11, wherein

13. X １ represents N; R １ Ga-PO(OH) ２ represents; R ２ Ga-CH ３ represents; R ３ and R ４ One of the groups represents a hydrogen atom, and R ３ and R ４ The other is a halogen atom or -(C １－６ ) represents a haloalkyl group; R ５ is a halogen atom or -O(C １－６ ) represents a haloalkyl group; R ６ But-(C １－６ ) represents an alkyl group; R ７ represents a hydrogen atom; and 2. The compound of claim 1, wherein n represents 1.

14. A compound according to any one of claims 1 to 13, which is a pharma- ceutically acceptable salt of a compound of formula (I), R １ But -P(O)(OH)O － M ＋ , -PO(O － ) 2 2M ＋ Or -PO(O － ) 2D ２＋ represents Each M ＋ independently represent a pharma- ceutically acceptable monovalent cation; and D ２＋ A compound according to any one of claims 1 to 13, wherein represents a pharma- ceutically acceptable divalent cation.

15. The following compound: (5-(1-(4-fluoro-2-methylphenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate; (5-(1-(4-fluoro-2-methylphenyl)-4-oxo-7-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate; (5-(6-chloro-1-(4-fluoro-2-methylphenyl)-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate; and (6-methyl-5-(1-(2-methyl-4-(trifluoromethoxy)phenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydropyrido[2,3-d]pyrimidin-3(2H)-yl)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate 1. A compound selected from the group consisting of: or a pharma- ceutically acceptable salt or tautomer thereof.

16. 16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15, or a pharma- ceutically acceptable salt or tautomer thereof, and a pharma- ceutically acceptable excipient.

17. 17. The pharmaceutical composition of claim 16, formulated for intravenous administration.

18. 18. A pharmaceutical composition according to claim 16 or 17 for use in therapy.

19. 18. A pharmaceutical composition according to claim 16 or 17 for use in the treatment of pain or a pain-related disease, disorder or condition.

20. 20. The pharmaceutical composition of claim 19, wherein the pain is acute pain or chronic pain.

21. 20. The pharmaceutical composition of claim 19, wherein the pain or pain-related disease, disorder or condition is pain caused by trauma; pain caused by a medical or dental procedure; or pre- or post-operative associated pain.

22. 20. The pharmaceutical composition of claim 19, wherein the pain or pain-related disease, disorder or condition is neuropathic pain, nociceptive pain, inflammatory pain, musculoskeletal pain, visceral pain or idiopathic pain.

23. 20. The pharmaceutical composition of claim 19, wherein 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 and polyneuropathy.

24. 20. The pharmaceutical composition of claim 19, wherein the pain or pain-related disease, disorder or condition is inflammatory pain selected from osteoarthritis pain, chronic osteoarthritis pain and chronic inflammatory demyelinating polyneuropathy.

25. 18. A pharmaceutical composition according to claim 16 or 17 for use in the treatment of atrial fibrillation.

26. The pharmaceutical composition of claim 16 or 17 for use in the treatment of a Na v 1.8 mediated disease, disorder or condition.

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