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

Abstract

Na containing compounds of formula (I), (II), (III), (IV), and (V) v 1.8 There is provided a small molecule inhibitor of voltage-gated sodium ion channels. Also provided are pharmaceutical compositions containing compounds of formula (I), (II), (III), (IV), and (V), and Na v 1.8 inhibiting voltage-gated sodium channels, for Na such as pain and pain-related diseases, and cardiovascular diseases such as atrial fibrillation v 1.8 Also described is the use of compounds and pharmaceutical compositions for treating mediated diseases.

Description

Technical Field

[0001] Field of the Invention The present invention relates to Na v 1.8 inhibitor compounds or pharmaceutically acceptable salts or tautomers thereof, corresponding pharmaceutical compositions or formulations, methods or processes for preparing the compounds, methods for use in the treatment of pain and pain-related diseases and cardiovascular diseases, compounds, uses for said treatment and / or combination therapies.

Background Art

[0002] Background of the Invention Pain is a defense mechanism by which animals avoid potential tissue damage, but there are numerous diseases in which pain loses its usefulness and becomes a burden of disability. Indications in which pain loses its usefulness can be broadly classified into those triggered by nerve damage or injury (neuropathic pain), those in which an inflammatory response or metabolic abnormality sensitizes the pain response (inflammatory pain), and those in which an injury or surgical procedure causes a short-term increase in the pain response (postoperative / walking pain).

[0003] Voltage-gated sodium channels underlie electrical signal transmission in all excitatory tissues by setting the threshold of the action potential and providing the basis for its rise. There are nine different isoforms of voltage-gated sodium channels. Na v 1.1, Na v 1.7, Na v 1.8 and Na v 1.9 are mainly expressed in peripheral nerves and control neuronal excitability. Na v 1.5 is expressed in cardiomyocytes, and Na v 1.4 is expressed and functions in skeletal muscle, and Na v 1.1, Na v 1.2, Na v 1.3 and Na v1.6 is widely expressed in the central nervous system (CNS) and to some extent in the peripheral nervous system. The main role of these nine voltage-dependent sodium channels is equivalent in terms of controlling sodium influx into the cell, but their biophysical properties are diverse and have a great impact on the physiological profile of each cell type (Catterall, 2012).

[0004] Currently, non-selective sodium channel inhibitors are clinically used as antiarrhythmic and antispasmodic therapies, including lidocaine, carbamazepine, amitriptyline, and mexiletine. However, the therapeutic usefulness of these agents is significantly reduced mainly due to the harmful side effects mediated by their activity in the CNS and heart because they lack selectivity among different sodium channel isoforms. This has driven efforts to develop new drugs selective for specific sodium channel isoforms to avoid side effects in the CNS and cardiovascular system.

[0005] Na v The Na1.8 channel is expressed in neurons of the dorsal root ganglia (DRG) and is highly expressed in the small-diameter neurons of this tissue that form pain-sensing C- and Aδ -nerve fibers (Abrahamsen, 2008; Amaya, 2000; Novakovic, 1998). This channel was proposed as a therapeutic target for analgesia soon after it was first cloned from rat DRG (Akopian, 1996) 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). The closest related molecule to Na v 1.8 is Na v 1.5, and their sequence homology is about 60%. Na v1.8 was previously known as SNS (sensory neuron sodium channel) and PN3 (peripheral nerve sodium channel type 3), and is also described as a TTX-resistant sodium channel because it exhibits pharmacological properties characteristic of resistance to blockade by tetrodotoxin.

[0006] Na v That 1.8 is a therapeutic target for pain indications is supported by several sources of information. Na v 1.8 has been shown to carry most of the current during the rising phase of the action potential in DRG neurons (Blair & Bean, 2002), and is also important for the ability of these neurons to fire repetitively because of its rate of re-priming (Blair and Bean, 2003). Na v Enhanced expression and function of 1.8 have been reported in response to noxious stimuli such as inflammatory mediators (England 1996 & Gold 1996), nerve injury (Roza 2003 & Ruangsri 2011), and within painful neuromas (Black 2008 & Coward 2000). In mice Na v Knockout of the gene encoding 1.8 resulted in a reduction of the pain phenotype, particularly in response to inflammatory stimuli (Akopian 1999). Also, Na v Knockdown of the mRNA encoding 1.8 resulted in a reduction of the pain phenotype 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). Na v Genetic evidence supporting 1.8 also exists in patients with chronic neuropathic pain, and multiple gain-of-function mutations have been reported to be the cause of episodic painful neuropathy and small fiber neuropathy (Faber 2012, Han 2014 & Eijkenboom 2018). Summary of the Invention

Problems to be Solved by the Invention

[0007] Summary of the Invention Therefore, there is a need for the development of novel compounds for use in the treatment of pain and pain-related disorders, as well as cardiovascular diseases, in particular, Na v 1.8 inhibitory compounds. The present invention meets this need by providing compounds having Na v 1.8 inhibitory activity, and the use of such compounds in the treatment of pain and pain-related disorders, as well as cardiovascular diseases.

Means for Solving the Problems

[0008] In one aspect, a compound of formula (I-a):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0009] In another aspect, a pharmaceutical composition comprising a compound of the present invention, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient is provided.

[0010] In another aspect, a method for treating pain or pain-related diseases in a human in need thereof, the method comprising administering to the human a compound of the present invention, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present invention is provided.

[0011] In another aspect, a method for treating atrial fibrillation in a human in need thereof, the method comprising administering to the human a compound of the present invention, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present invention is provided.

[0012] In another aspect, a compound of the present invention, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present invention for use in therapy is provided.

[0013] In another aspect, a compound of the present invention, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present invention for use in the treatment of pain or pain-related diseases is provided.

[0014] In another aspect, a compound of the present invention, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present invention for use in the treatment of atrial fibrillation is provided.

[0015] In another aspect, there is provided the use of a compound of the invention, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the invention, in the manufacture of a medicament for the treatment of pain or pain-related disorders.

[0016] In another aspect, there is provided the use of a compound of the invention, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the invention, in the manufacture of a medicament for the treatment of atrial fibrillation.

DETAILED DESCRIPTION OF THE INVENTION

[0017] Detailed Description of the Invention Various publications, papers and patents are cited or described in the background and throughout the specification. The discussion of documents, acts, materials, devices, articles, etc. contained in this specification is for the purpose of illustrating the content of this disclosure. Such discussion does not admit that everything of these matters forms part of the prior art relevant to this disclosure.

[0018] 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, the specific terms used herein have the meaning shown in this specification.

[0019] As used in this specification and the appended claims, the singular forms "a", "an" and "the" include the plural referents unless the context clearly dictates otherwise.

[0020] Throughout this specification, the definitions of the various groups and substituents of any formula disclosed herein, or a tautomer or pharmaceutically acceptable salt thereof, are intended to describe each individual compound species disclosed herein, as well as groups of one or more compound species in particular.

[0021] The term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group having the specified number of carbon atoms. For example, the term "(C1-C6)alkyl" refers to an alkyl group having 1 to 6 carbon atoms, and the term "(C1-C3)alkyl" refers to an alkyl group having 1 to 3 carbon atoms. Exemplary alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, pentyl, and hexyl. In some embodiments, "Me" refers to a methyl group.

[0022] When the term "alkyl" is used in combination with other substituents, such as "halo(C1-C6)alkyl" and "hydroxy(C1-C6)alkyl", the term "alkyl" is intended to include a divalent straight-chain or branched hydrocarbon group, and the point of attachment is on the alkyl portion.

[0023] The term "halo(C1-C6)alkyl" refers to a group having one or more halogen atoms, which may be the same or different, on one or more carbon atoms of an alkyl moiety having 1 to 6 carbon atoms, which is a straight-chain or branched carbon group. Examples of "halo(C1-C6)alkyl" groups include, but are not limited to, -CH2F (fluoromethyl), -CHF2 (difluoromethyl), -CF3 (trifluoromethyl), -CCl3 (trichloromethyl), 1,1-difluoroethyl, 2-fluoro-2-methylpropyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, and hexafluoroisopropyl.

[0024] The term "alkenyl" refers to a straight-chain or branched hydrocarbon group containing the specified number of carbon atoms and at least one double bond. For example, "(C2-C6)alkenyl" has 2 to 6 carbon atoms. Exemplary groups include, but are not limited to, ethenyl and propenyl.

[0025] The term "alkylene" refers to a divalent group derived from a straight-chain saturated hydrocarbon group having a specified number of carbon atoms. For example, the term "(C3-C6) alkylene" refers to an alkylene group having 3 to 6 carbon atoms, and the term "(C4-C5) alkylene" refers to an alkylene group having 4 to 5 carbon atoms. Exemplary alkylene groups include, but are not limited to, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, and -CH2CH2CH2CH2CH2CH2-.

[0026] The term "alkenylene" refers to a divalent group derived from a straight-chain unsaturated hydrocarbon group having at least one carbon-carbon double bond and having a specified number of carbon atoms. The carbon-carbon double bond of the alkylene group can be in the cis configuration, the trans configuration, or a mixture thereof. In certain cases of the present disclosure, an alkenylene group present as a mixture of the cis configuration and the trans configuration is [Chemical formula] representable as. For example, the term "(C3-C6) alkenylene" refers to an alkenylene group having 3 to 6 carbon atoms and at least one carbon-carbon double bond. The term "(C4-C5) alkenylene" refers to an alkenylene group having 4 to 5 carbon atoms and at least one carbon-carbon double bond. Exemplary alkenylene groups include, but are not limited to, -CH=CH-CH2-, -CH2-CH=CH-CH2-, -CH2CH2-CH=CH-CH2-, and -CH2-CH=CH-CH2CH2CH2-.

[0027] The term "alkoxy" refers to an -O-alkyl group, i.e., an alkyl group bonded through an oxygen bridging atom, where "alkyl" is defined as above. For example, the term "(C1-C6) alkoxy" refers to a straight or branched carbon group having 1 to 6 carbon atoms bonded through an oxygen bridging atom. Exemplary "(C1-C6) alkoxy" groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, isobutoxy, and t-butoxy.

[0028] The term "halo (C1-C6) alkoxy" refers to a straight or branched hydrocarbon group having at least 1 and up to 6 carbon atoms, together with one or more halogen atoms, which may be the same or different, bonded to one or more of the carbon atoms, and bonded through an oxygen bridging atom. Exemplary groups include, but are not limited to, -OCHF2 (difluoromethoxy), -OCF3 (trifluoromethoxy), and OCH(CF3)2 (hexafluoroisopropoxy).

[0029] The terms "halogen" and "halo" represent chloro (-Cl), fluoro (-F), bromo (-Br), or iodo (-I) substituents.

[0030] The term "cyano" refers to the group -CN.

[0031] The term "independently selected" means that when two or more substituents are selected from a plurality of possible substituents, those substituents may be the same or different. Thus, each substituent is selected separately from the entire group of possible substituents listed.

[0032] As used herein, the term "optionally" means that the subsequently described event may or may not be present, and includes both the case where the event is present and the case where the event is not present.

[0033] The term "optionally substituted" indicates that the group may be unsubstituted or substituted with one or more of the defined substituents. The term "substituted" with respect to a group indicates that a hydrogen atom bonded to a member atom within the group is replaced with one of the defined substituents. When multiple groups can be selected from multiple selection groups, the selected groups may be the same or different.

[0034] Compound In one aspect, the present invention relates to a compound of formula (I-a):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0035] In another aspect, the present invention provides a compound of formula (I):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0036] In another aspect, the present invention relates to a compound of formula (I): [Chemical formula] [In the formula, Y is O or S, X 1 is nitrogen or CR 1 and X 2is nitrogen or CR 2 and X 3 is nitrogen or CR 3 and X 4 is nitrogen or CR 4 and provided that X 1 , X 2 , X 3 , and X 4 among which two or less are nitrogen; Ring A is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0037] In certain embodiments of the compound of formula (I-a) or formula (I), or its tautomer, or its pharmaceutically acceptable salt, Y is O. In another embodiment, Y is S.

[0038] In certain embodiments of the compound of formula (I-a) or formula (I), or its tautomer, or its pharmaceutically acceptable salt, ring A is [Chemical formula] wherein, R 5 is hydrogen, halo, or -(C1-C6)alkyl; [Chemical formula] represents a covalent bond with the nitrogen atom of the bicyclic ring nucleus of formula (I-a) or formula (I), [Chemical formula] represents a covalent bond with L of formula (I-a) or formula (I). In another embodiment, ring A is [Chemical formula] wherein, R 5 is hydrogen, -F, or -CH3; [Chemical formula] represents a covalent bond with the nitrogen atom of the bicyclic ring nucleus of formula (I-a) or formula (I), [Chemical formula] represents a covalent bond with L of formula (I-a) or formula (I). In another embodiment, ring A is [Chemical formula] wherein, [Chemical formula] represents a covalent bond with the nitrogen atom of the bicyclic ring nucleus of formula (I-a) or formula (I),

Chemical formula

[0039] In certain embodiments of a compound of formula (I-a) or formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, ring A is,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0040] In certain embodiments of the compound of formula (I-a) or formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, X 1 X 2 X 3 and X 4 only one of which is nitrogen.

[0041] In certain embodiments of the compound of formula (I-a) or formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, R 1 R 2 R 3 and R 4 each is independently hydrogen, halo, cyano, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy-. In another embodiment, R 1 R 2 R 3 and R 4 each is independently hydrogen, halo, cyano, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy-. In another embodiment, R 1 R 2 R 3 and R 4 each is independently -F, -Cl, cyano, -CF3, or -OCF3. In another embodiment, R 1 R 2 R 3 and R 4 each is independently hydrogen, -F, or -CF3. In a further embodiment, R 1 and R 4 are hydrogen, R 2 is -CF3, and R 3 is -F.

[0042] In certain embodiments of the compound of formula (I-a) or formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, R a and R b each is independently hydrogen or -(C1-C6)alkyl. In another embodiment, R a and R bEach of them is, independently, hydrogen or -CH3.

[0043] In certain embodiments of the compound of formula (I-a) or formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, R 6 , R 7 and R 8 are each, independently, hydrogen, halo, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-. In another embodiment, R 6 , R 7 and R 8 are each, independently, hydrogen, -F, -CF3, or -OCF3.

[0044] In certain embodiments of the compound of formula (I-a) or formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, R 8 is hydrogen, and R 6 and R 7 are each, independently, hydrogen, halo, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-. In another embodiment, R 8 is hydrogen, and R 6 and R 7 are each, independently, hydrogen, halo, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-. In another embodiment, R 8 is hydrogen, and R 6 and R 7 are each, independently, hydrogen, -F, -CF3, or -OCF3. In a further embodiment, R 8 is hydrogen, and R 6 and R 7 are each -F.

[0045] In certain embodiments of the compound of formula (I-a) or formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, R 6 and R 8 are each hydrogen, and R 7is hydrogen, halo, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-. In another embodiment, R 6 and R 8 are each hydrogen, and R 7 is hydrogen, halo, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-. In another embodiment, R 6 and R 8 are each hydrogen, and R 7 is hydrogen, -F, -CF3, or -OCF3. In another embodiment, R 6 and R 8 are each hydrogen, and R 7 is -F, -CF3, or -OCF3. In another embodiment, R 6 and R 8 are each hydrogen, and R 7 is -F.

[0046] In certain embodiments of the compound of formula (I-a) or formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, L is a divalent linker having a length of 3 to 6 atoms, for example, 3, 4, 5, or 6 atoms in length. In some embodiments, L is a divalent linker having a length of 4 to 5 atoms. In some embodiments, L is a divalent linker having a length of 4 atoms. In some embodiments, L is a divalent linker having a length of 5 atoms.

[0047] In certain embodiments of the compound of formula (I-a) or formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, L is (C3-C6) alkenylene such as C3-alkenylene, C4-alkenylene, C5-alkenylene or C6-alkenylene. In another embodiment, L is (C3-C6) alkenylene having one carbon-carbon double bond. In another embodiment, L is (C4-C6) alkenylene. In another embodiment, L is (C4-C6) alkenylene having one carbon-carbon double bond. In another embodiment, L is (C4-C5) alkenylene. In another embodiment, L is (C4-C5) alkenylene having one carbon-carbon double bond. In some embodiments, when L is (C3-C6) alkenylene having one carbon-carbon double bond, the carbon-carbon double bond is in a cis configuration, a trans configuration, or a mixture thereof, for example, a cis:trans mixture of 2:1 to 1:2, for example, 2:1, 1:1, or 1:2. In another embodiment, L is * -CH=CH-CH2- ** , * -CH2-CH=CH-CH2- ** , * -CH2CH2-CH=CH-CH2- ** , and * -CH2-CH=CH-CH2CH2CH2- ** a (C3-C6) alkenylene selected from the group consisting of, wherein " * " represents a covalent bond with ring A of formula (I), and " ** " represents a covalent bond with the phenyl ring of formula (I). In another embodiment, L is

Chemical formula

Chemical formula

Chemical formula

[0048] In certain embodiments of a compound of formula (I-a) or formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, L is a divalent linker of formula (L-ia):

Chem.

Chem.

Chem.

[0049] In another embodiment, L is a divalent linker of formula (L-ia) where the sum of r and s is 3 or 4. In another embodiment, L is a divalent linker of formula (L-ia) where R 9 and R 10 are each independently hydrogen, -CH3, or -CH2CH3; and R d is hydrogen or -CH3. In another embodiment, L is

Chem.

Chem.

Chem.

[0050] In certain embodiments of a compound of formula (I-a) or formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, L is a divalent linker of formula (L-i):

Chem.

Chem.

Chem.

[0051] In another embodiment, L is a divalent linker of formula (L-i) wherein the sum of r and s is 3 or 4. In another embodiment, L is

Chem.

Chem.

[0052] In certain embodiments of a compound of formula (I-a) or formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, L is a divalent linker of formula (L-iia): [Chemistry] wherein X 6 is -NR c - or -CH2-; X 7 is -CR 11 R 12 -, -O- or -NH2-, where R 11 and R 12 are each independently hydrogen or -(C1-C3)alkyl, provided that when X 7 is -NH2-, X 6 is -CH2-; each X 10 is independently -CR 13 R 14 -, where R 13 and R 14 are each independently hydrogen or -(C1-C3)alkyl; R c is hydrogen or -(C1-C3)alkyl; q is 1, 2, 3, or 4; [Chemistry] represents a covalent bond with ring A of formula (I-a) or formula (I), [Chemistry] represents a covalent bond with the phenyl ring of formula (I-a) or formula (I).

[0053] In another embodiment, L is X6 is -NR c - and; X 7 is -CR 11 R 12 - and; R c is hydrogen or -CH3; R 11 and R 12 are each independently hydrogen or -CH3, and is a divalent linker of formula (L-iia). In another embodiment, L is

Chemical formula

Chemical formula

Chemical formula

[0054] In an embodiment of a compound of formula (I-a) or formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, L is a divalent linker of formula (L-ii):

Chemical formula

[0055] In another embodiment, L is a divalent linker of formula (L-ii) where R c is hydrogen or -CH3. In another embodiment, L is such that X 6 is -NR c -, and X 7 is -CH2-; a divalent linker of formula (L-ii). In another embodiment, L is such that X 6 is -NR c -, and X 7 is -O-; a divalent linker of formula (L-ii). In another embodiment, L is such that X 6 is -CH2-, and X 7 is -O-; a divalent linker of formula (L-ii). In another embodiment, L is such that X 6 is -CH2-, and X 7 is -NH2-; a divalent linker of formula (L-ii). In another embodiment, L is such that X 6 is -CH2-, and X 7 is -CH2-; a divalent linker of formula (L-ii). In another embodiment, L is a divalent linker of formula (L-ii) where q is 2 or 3. In another embodiment, L is a divalent linker of formula (L-ii) where q is 2. In another embodiment, L is [Chemical formula] a divalent linker of formula (L-ii) selected from the group consisting of -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, and -CH2CH2CH2CH2CH2CH2-, where [Chemical formula] represents a covalent bond with ring A of formula (I-a) or formula (I),

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0056] In an embodiment of a compound of formula (I-a) or formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, L is

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0057] In certain embodiments of the compound of formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, Y is O; X 1 is nitrogen or CR 1 and X 2 is nitrogen or CR 2 and X 3 is nitrogen or CR 3 and X 4 is nitrogen or CR 4 and provided that no more than two of X 1 X 2 X 3 and X 4 are nitrogen; Ring A is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0058] In an embodiment of the compound of formula (I-a), or its tautomer, or its pharmaceutically acceptable salt, one of R 15 and R 16 is hydrogen and the other of R 15 and R 16 is deuterium. In another embodiment, each of R 15 and R 16 is deuterium.

[0059] The present invention also relates to a compound of formula (II):

Chem.

Chem.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0060] The present invention also relates to a compound of formula (II):

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

[0061] In certain embodiments of the compound of formula (II), or its tautomer, or its pharmaceutically acceptable salt, Y is O. In another embodiment, Y is S.

[0062] In certain embodiments of the compound of formula (II), or its tautomer, or its pharmaceutically acceptable salt, each of R 1 , R 2 , R 3 and R 4 is independently hydrogen, halo, cyano, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl, and halo(C1-C6)alkoxy-. In another embodiment, R1 , R 2 , R 3 , and R 4 each is, independently, hydrogen, halo, cyano, halo(C1-C6)alkyl, and halo(C1-C6)alkoxy-. In another embodiment, R 1 , R 2 , R 3 , and R 4 each is, independently, -F, -Cl, cyano, -CF3, and -OCF3. In another embodiment, R 1 , R 2 , R 3 , and R 4 each is, independently, hydrogen, -F, or -CF3. In a further embodiment, R 1 and R 4 are hydrogen, R 2 is -CF3, R 3 is -F.

[0063] In an embodiment of the compound of formula (II), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, R 1 is hydrogen, R 2 , R 3 , and R 4 each is, independently, hydrogen, halo, cyano, -NR a R b , -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-. In another embodiment, R 1 is hydrogen, R 2 , R 3 , and R 4 each is, independently, hydrogen, halo, cyano, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy-. In another embodiment, R 1 is hydrogen, R 2 , R 3 , and R 4 each is, independently, -F, -Cl, cyano, -CF3, or -OCF3.

[0064] In certain embodiments of the compound of formula (II), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, R a and R b are each, independently, hydrogen or -(C1-C6)alkyl. In another embodiment, R a and R b are each, independently, hydrogen or -CH3.

[0065] In certain embodiments of the compound of formula (II), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, R 5 is hydrogen or -(C1-C6)alkyl. In another embodiment, R 5 is hydrogen, -I, Cl, or -CH3. In another embodiment, R 5 is hydrogen.

[0066] In certain embodiments of the compound of formula (II), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, R 6 , R 7 and R 8 are each, independently, hydrogen, halo, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-. In another embodiment, R 6 , R 7 and R 8 are each, independently, hydrogen, -F, -CF3, or -OCF3.

[0067] In certain embodiments of the compound of formula (II), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, R 8 is hydrogen and R 6 and R 7 are each, independently, hydrogen, halo, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-. In another embodiment, R 8 is hydrogen and R 6 and R 7 are each, independently, hydrogen, halo, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-. In another embodiment, R 8is hydrogen, and R 6 and R 7 each is, independently, hydrogen, -F, -CF3, or -OCF3. In further embodiments, R 8 is hydrogen, and R 6 and R 7 each is -F.

[0068] In certain embodiments of the compound of formula (II), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, R 6 and R 8 each is hydrogen, and R 7 is hydrogen, halo, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-. In another embodiment, R 6 and R 8 each is hydrogen, and R 7 is hydrogen, halo, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-. In another embodiment, R 6 and R 8 each is hydrogen, and R 7 is hydrogen, -F, -CF3, or -OCF3. In another embodiment, R 6 and R 8 each is hydrogen, and R 7 is -F, -CF3, or -OCF3. In another embodiment, R 6 and R 8 each is hydrogen, and R 7 is -F.

[0069] In certain embodiments of the compound of formula (II), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, L is a divalent linker that is 3 to 6 atoms in length, e.g., 3, 4, 5, or 6 atoms in length. In some embodiments, L is a divalent linker that is 4 to 5 atoms in length. In some embodiments, L is a divalent linker that is 4 atoms in length. In some embodiments, L is a divalent linker that is 5 atoms in length.

[0070] In certain embodiments of the compound of formula (II), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, L is (C3-C6) alkenylene such as C3-alkenylene, C4-alkenylene, C5-alkenylene or C6-alkenylene. In another embodiment, L is (C3-C6) alkenylene having one carbon-carbon double bond. In another embodiment, L is (C4-C6) alkenylene. In another embodiment, L is (C4-C6) alkenylene having one carbon-carbon double bond. In another embodiment, L is (C4-C5) alkenylene. In another embodiment, L is (C4-C5) alkenylene having one carbon-carbon double bond. In some embodiments, when L is (C3-C6) alkenylene having one carbon-carbon double bond, the carbon-carbon double bond is in cis configuration, trans configuration, or a mixture thereof, for example, a cis:trans mixture of 2:1 to 1:2, for example, 2:1, 1:1, or 1:2. In another embodiment, L is * -CH=CH-CH2- ** , * -CH2-CH=CH-CH2- ** , * -CH2CH2-CH=CH-CH2- ** , and * -CH2-CH=CH-CH2CH2CH2- ** is (C3-C6) alkenylene selected from the group consisting of, where " * " represents a covalent bond with the pyridone ring of formula (II), and " ** " represents a covalent bond with the phenyl ring of formula (II). In another embodiment, L is

Chemical formula

Chemical formula

Chemical formula

[0071] In certain embodiments of a compound of formula (II), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, L is a divalent linker of formula (L-ia):

Chemical formula

Chemical formula

Chemical formula

[0072] In another embodiment, L is a divalent linker of formula (L-ia) where the sum of r and s is 3 or 4. In another embodiment, L is a divalent linker of formula (L-ia) where each of R 9 and R 10 is independently hydrogen, -CH3, or -CH2CH3; and R d is hydrogen or -CH3. In another embodiment, L is

Chemical formula

[0073] In certain embodiments of the compound of formula (II), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, L is a divalent linker of formula (L-i): [Chemistry] wherein, r is 1, 2, 3, or 4; s is 1, 2, 3, or 4; the sum of r and s is 2, 3, 4, or 5; [Chemistry] represents a covalent bond with the pyridone ring of formula (II), [Chemistry] represents a covalent bond with the phenyl ring of formula (II).

[0074] In another embodiment, L is a divalent linker of formula (L-i) where the sum of r and s is 3 or 4. In another embodiment, L is [Chemistry] a divalent linker of formula (L-i) selected from the group consisting of, where [Chemistry] represents a covalent bond with the pyridone ring of formula (II), [Chemistry] represents a covalent bond with the phenyl ring of formula (II).

[0075] In certain embodiments of a compound of formula (II), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, L is a divalent linker of formula (L-iia):

Chemical formula

Chemical formula

Chemical formula

[0076] In another embodiment, L is such that X 6 is -NR c -; X 7 is -CR 11 R 12 -; R cis hydrogen or -CH3; R 11 and R 12 each independently is a divalent linker of formula (L-iia) which is hydrogen or -CH3. In another embodiment, L is

Chemical formula

Chemical formula

Chemical formula

[0077] In an embodiment of the compound of formula (II), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, L is a divalent linker of formula (L-ii):

Chemical formula

Chemical formula

[0078] In another embodiment, L is a divalent linker of formula (L-ii) where R c is hydrogen or -CH3. In another embodiment, L is a divalent linker of formula (L-ii) where X 6 is -NR c -, and X 7 is -CH2-. In another embodiment, L is a divalent linker of formula (L-ii) where X 6 is -NR c -, and X 7 is -O-. In another embodiment, L is a divalent linker of formula (L-ii) where X 6 is -CH2-, and X 7 is -O-. In another embodiment, L is a divalent linker of formula (L-ii) where X 6 is -CH2-, and X 7 is -NH2-. In another embodiment, L is a divalent linker of formula (L-ii) where X 6 is -CH2-, and X 7 is -CH2-. In another embodiment, L is a divalent linker of formula (L-ii) where q is 2 or 3. In another embodiment, L is a divalent linker of formula (L-ii) where q is 2. In another embodiment, L is [Chemistry] a divalent linker of formula (L-ii) selected from the group consisting of -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, and -CH2CH2CH2CH2CH2CH2-, where [Chemistry] represents a covalent bond with the pyridone ring of formula (II), [Chemistry] represents a covalent bond with the phenyl ring of formula (II). In another embodiment, L is a divalent linker of formula (L-ii) selected from the group consisting of -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, and -CH2CH2CH2CH2CH2CH2-. In another embodiment, L is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0079] In an embodiment of the compound of formula (II), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, L is

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0080] In certain embodiments of the compound of formula (II), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, Y is O; R 1 is hydrogen, and each of R 2 R 3 and R 4 is independently hydrogen, halo, cyano, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-; R 5 is hydrogen; R 6 and R 7Each of them is independently hydrogen, halo, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-; R 8 is hydrogen; L is a divalent linker of formula (L-i) or a divalent linker of formula (L-ii):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0081] The present invention also relates to a compound of formula (III): [Chemical formula] [In the formula, Y is O or S; R 1 , R 2 and R 4 each is independently hydrogen, halo, cyano, -NR a R b , -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-; R 5 is hydrogen, halo, or -(C1-C6)alkyl; R 6 , R 7 and R 8 each is independently hydrogen, halo, cyano, hydroxy, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-; R a and R b each is independently hydrogen, -(C1-C6)alkyl, or halo(C1-C6)alkyl-; L is (C3-C6)alkenylene, -NHCH2CH2NHCH2-, -NHCH2CH2OCH2-, a divalent linker of formula (L-ia), or a divalent linker of formula (L-iia): [Chemical formula] In the formula, X 8 and X 9 each is independently -CR 9 R 10 -, where R 9 and R 10 each is independently hydrogen or -(C1-C3)alkyl; R d is hydrogen or -(C1-C3)alkyl; r is 1, 2, 3, or 4; s is 1, 2, 3, or 4; The sum of r and s is 2, 3, 4, or 5; [Chemical formula] represents a covalent bond with the pyridone ring of formula (III), [Chemical formula] represents a covalent bond with the phenyl ring of formula (III); [Chemical formula] wherein, X 6 is -NR c - or -CH2-; X 7 is -CR 11 R 12 -, -O-, or -NH2-, where R 11 and R 12 each is independently hydrogen or -(C1-C3)alkyl, provided that when X 7 is -NH2-, X 6 is -CH2-; each X 10 is independently -CR 13 R 14 -, where R 13 and R 14 each is independently hydrogen or -(C1-C3)alkyl; R c is hydrogen or -(C1-C3)alkyl; q is 1, 2, 3, or 4; [Chemical formula] represents a covalent bond with the pyridone ring of formula (III), [Chemical formula] represents a covalent bond with the phenyl ring of formula (III), is] or its tautomer, or its pharmaceutically acceptable salt.

[0082] The present invention also relates to a compound of formula (III):

Chem.

Chem.

Chem.

Chem.

Chemical formula

Chemical formula

Chemical formula

[0083] In certain embodiments of the compound of formula (III), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, Y is O. In another embodiment, Y is S.

[0084] In certain embodiments of the compound of formula (III), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, each of R 1 , R 2 and R 4 is independently hydrogen, halo, cyano, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl, and halo(C1-C6)alkoxy-. In another embodiment, each of R 1 , R 2 and R 4Each of them is, independently, hydrogen, halo, cyano, halo(C1-C6)alkyl, and halo(C1-C6)alkoxy-. In another embodiment, R 1 , R 2 , and R 4 are each, independently, -F, -Cl, cyano, -CF3, and -OCF3.

[0085] In certain embodiments of the compound of formula (III), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, R 1 is hydrogen, and each of R 2 and R 4 is, independently, hydrogen, halo, cyano, -NR a R b , -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-. In another embodiment, R 1 is hydrogen, and each of R 2 and R 4 is, independently, hydrogen, halo, cyano, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy-. In another embodiment, R 1 is hydrogen, and each of R 2 and R 4 is, independently, -F, -Cl, cyano, -CF3, or -OCF3.

[0086] In certain embodiments of the compound of formula (III), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, each of R a and R b is, independently, hydrogen or -(C1-C6)alkyl. In another embodiment, each of R a and R b is, independently, hydrogen or -CH3.

[0087] In certain embodiments of the compound of formula (III), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, R 5 is hydrogen or -(C1-C6)alkyl. In another embodiment, R 5is hydrogen, -I, Cl, or -CH3. In another embodiment, R 5 is hydrogen.

[0088] In certain embodiments of the compound of formula (III), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, R 6 , R 7 and R 8 are each, independently, hydrogen, halo, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-. In another embodiment, R 6 , R 7 and R 8 are each, independently, hydrogen, -F, -CF3, or -OCF3.

[0089] In certain embodiments of the compound of formula (III), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, R 8 is hydrogen, and R 6 and R 7 are each, independently, hydrogen, halo, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-. In another embodiment, R 8 is hydrogen, and R 6 and R 7 are each, independently, hydrogen, halo, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-. In another embodiment, R 8 is hydrogen, and R 6 and R 7 are each, independently, hydrogen, -F, -CF3, or -OCF3.

[0090] In certain embodiments of the compound of formula (III), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, R 6 and R 8 are each hydrogen, and R 7 is hydrogen, halo, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-. In another embodiment, R 6 and R8 Each of them is hydrogen, and R 7 is hydrogen, halo, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-. In another embodiment, R 6 and R 8 each is hydrogen, and R 7 is hydrogen, -F, -CF3, or -OCF3. In another embodiment, R 6 and R 8 each is hydrogen, and R 7 is -F, -CF3, or -OCF3. In another embodiment, R 6 and R 8 each is hydrogen, and R 7 is -F.

[0091] In certain embodiments of the compound of formula (III), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, L is a divalent linker that is 3 to 6 atoms in length, e.g., 3, 4, 5, or 6 atoms in length. In some embodiments, L is a divalent linker that is 4 to 5 atoms in length. In some embodiments, L is a divalent linker that is 4 atoms in length. In some embodiments, L is a divalent linker that is 5 atoms in length.

[0092] In certain embodiments of the compound of formula (III), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, L is (C3-C6) alkenylene such as C3-alkenylene, C4-alkenylene, C5-alkenylene or C6-alkenylene. In another embodiment, L is (C3-C6) alkenylene having one carbon-carbon double bond. In another embodiment, L is (C4-C6) alkenylene. In another embodiment, L is (C4-C6) alkenylene having one carbon-carbon double bond. In another embodiment, L is (C4-C5) alkenylene. In another embodiment, L is (C4-C5) alkenylene having one carbon-carbon double bond. In some embodiments, L is (C3-C6) alkenylene having one carbon-carbon double bond, and the carbon-carbon double bond is in cis configuration, trans configuration, or a mixture thereof, for example, a cis:trans mixture of 2:1 to 1:2, for example, 2:1, 1:1, or 1:2. In another embodiment, L is * -CH=CH-CH2- ** , * -CH2-CH=CH-CH2- ** , * -CH2CH2-CH=CH-CH2- ** , and * -CH2-CH=CH-CH2CH2CH2- ** selected from the group consisting of (C3-C6) alkenylene, wherein " * " represents a covalent bond with the pyridone ring of formula (III), and " ** " represents a covalent bond with the phenyl ring of formula (III). In another embodiment, L is

Chemical formula

Chemical formula

Chemical formula

[0093] In certain embodiments of the compound of formula (III), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, L is a divalent linker of formula (L-ia):

Chem.

Chem.

Chem.

[0094] In another embodiment, L is a divalent linker of formula (L-ia) where the sum of r and s is 3 or 4. In another embodiment, L is a divalent linker of formula (L-ia) where each of R 9 and R 10 is independently hydrogen, -CH3, or -CH2CH3; and R d is hydrogen or -CH3. In another embodiment, L is

Chem.

Chem.

Chem.

[0095] In certain embodiments of the compound of formula (III), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, L is a divalent linker of formula (L-i):

Chem.

Chem.

Chem.

[0096] In another embodiment, L is a divalent linker of formula (L-i) where the sum of r and s is 3 or 4. In another embodiment, L is

Chem.

Chem.

Chem.

[0097] In certain embodiments of the compound of formula (III), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, L is a bivalent linker of formula (L-iia):

Chemical formula

Chemical formula

Chemical formula

[0098] In another embodiment, L is such that X 6 is -NR c -; X 7 is -CR 11 R12 - and R c is hydrogen or -CH3; R 11 and R 12 each of which is independently a divalent linker of formula (L-iia) that is hydrogen or -CH3. In another embodiment, L is

Chemical formula

Chemical formula

Chemical formula

[0099] In an embodiment of the compound of formula (III), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, L is a divalent linker of formula (L-ii):

Chemical formula

Chemical formula

[0100] In another embodiment, L is a divalent linker of formula (L-ii) where R c is hydrogen or -CH3. In another embodiment, L is X 6 where X is -NR c - and X 7 is -CH2-, which is a divalent linker of formula (L-ii). In another embodiment, L is X 6 where X is -NR c - and X 7 is -O-, which is a divalent linker of formula (L-ii). In another embodiment, L is X 6 where X is -CH2- and X 7 is -O-, which is a divalent linker of formula (L-ii). In another embodiment, L is X 6 where X is -CH2- and X 7 is -NH2-, which is a divalent linker of formula (L-ii). In another embodiment, L is X 6 where X is -CH2- and X 7 is -CH2-, which is a divalent linker of formula (L-ii). In another embodiment, L is a divalent linker of formula (L-ii) where q is 2 or 3. In another embodiment, L is a divalent linker of formula (L-ii) where q is 2. In another embodiment, L is [Chemistry] a divalent linker of formula (L-ii) selected from the group consisting of -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, and -CH2CH2CH2CH2CH2CH2-, where [Chemistry] represents a covalent bond with the pyridone ring of formula (III), [Chemistry] represents a covalent bond with the phenyl ring of formula (III). In another embodiment, L is a divalent linker of formula (L-ii) selected from the group consisting of -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, and -CH2CH2CH2CH2CH2CH2-. In another embodiment, L is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0101] In certain embodiments of the compound of formula (III), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, L is

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0102] In certain embodiments of the compound of formula (III), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, Y is O; R 1 is hydrogen, and each of R 2 and R 4 is independently hydrogen, halo, cyano, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-; R 5 is hydrogen; R 6 and R 7Each of them is independently hydrogen, halo, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-; R 8 is hydrogen; L is a divalent linker of formula (L-i) or a divalent linker of formula (L-ii):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0103] The present invention also relates to a compound of formula (IV): [Chemical formula] [wherein, Y is O or S; R 1 , R 3 and R 4 each independently is hydrogen, halo, cyano, -NR a R b , -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-; R 5 is hydrogen, halo, or -(C1-C6)alkyl; R 6 , R 7 and R 8 each independently is hydrogen, halo, cyano, hydroxy, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-; R a and R b each independently is hydrogen, -(C1-C6)alkyl, or halo(C1-C6)alkyl-; L is (C3-C6)alkenylene, -NHCH2CH2NHCH2-, -NHCH2CH2OCH2-, a divalent linker of formula (L-ia), or a divalent linker of formula (L-iia): [Chemical formula] wherein, X 8 and X 9 each independently is -CR 9 R 10 -, where R 9 and R 10 each independently is hydrogen or -(C1-C3)alkyl; R d is hydrogen or -(C1-C3)alkyl; r is 1, 2, 3, or 4; s is 1, 2, 3, or 4; The sum of r and s is 2, 3, 4, or 5;

Chem.

Chem.

Chem.

Chem.

Chem.

[0104] The present invention also relates to a compound of formula (IV):

Chem.

Chem.

Chem.

Chem.

Chemical formula

Chemical formula

Chemical formula

[0105] In certain embodiments of the compound of formula (IV), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, Y is O. In another embodiment, Y is S.

[0106] In certain embodiments of the compound of formula (IV), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, each of R 1 , R 3 and R 4 is independently hydrogen, halo, cyano, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy-. In another embodiment, each of R 1 , R 3 and R 4Each of them is independently hydrogen, halo, cyano, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy-. In another embodiment, R 1 , R 3 , and R 4 are each independently -F, -Cl, cyano, -CF3, or -OCF3.

[0107] In certain embodiments of the compound of formula (IV), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, R 1 is hydrogen, and each of R 3 and R 4 is independently hydrogen, halo, cyano, -NR a R b , -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-. In another embodiment, R 1 is hydrogen, and each of R 3 and R 4 is independently hydrogen, halo, cyano, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy-. In another embodiment, R 1 is hydrogen, and each of R 3 and R 4 is independently -F, -Cl, cyano, -CF3, or -OCF3.

[0108] In certain embodiments of the compound of formula (IV), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, each of R a and R b is independently hydrogen or -(C1-C6)alkyl. In another embodiment, each of R a and R b is independently hydrogen or -CH3.

[0109] In certain embodiments of the compound of formula (IV), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, R 5 is hydrogen or -(C1-C6)alkyl. In another embodiment, R 5is hydrogen, -I, Cl, or -CH3. In another embodiment, R 5 is hydrogen.

[0110] In certain embodiments of the compound of formula (IV), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, R 6 , R 7 and R 8 each independently is hydrogen, halo, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-. In another embodiment, R 6 , R 7 and R 8 each independently is hydrogen, -F, -CF3, or -OCF3.

[0111] In certain embodiments of the compound of formula (IV), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, R 8 is hydrogen, and R 6 and R 7 each independently is hydrogen, halo, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-. In another embodiment, R 8 is hydrogen, and R 6 and R 7 each independently is hydrogen, halo, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-. In another embodiment, R 8 is hydrogen, and R 6 and R 7 each independently is hydrogen, -F, -CF3, or -OCF3.

[0112] In certain embodiments of the compound of formula (IV), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, R 6 and R 8 each is hydrogen, and R 7 is hydrogen, halo, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-. In another embodiment, R 6 and R8 Each of them is hydrogen, and R 7 is hydrogen, halo, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-. In another embodiment, R 6 and R 8 each is hydrogen, and R 7 is hydrogen, -F, -CF3, or -OCF3. In another embodiment, R 6 and R 8 each is hydrogen, and R 7 is -F, -CF3, or -OCF3. In another embodiment, R 6 and R 8 each is hydrogen, and R 7 is -F.

[0113] In certain embodiments of the compound of formula (IV), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, L is a bivalent linker having a length of 3 to 6 atoms, for example, a bivalent linker having a length of 3, 4, 5, or 6 atoms. In some embodiments, L is a bivalent linker having a length of 4 to 5 atoms. In some embodiments, L is a bivalent linker having a length of 4 atoms. In some embodiments, L is a bivalent linker having a length of 5 atoms.

[0114] In certain embodiments of the compound of formula (IV), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, L is (C3-C6) alkenylene such as C3-alkenylene, C4-alkenylene, C5-alkenylene or C6-alkenylene. In another embodiment, L is (C3-C6) alkenylene having one carbon-carbon double bond. In another embodiment, L is (C4-C6) alkenylene. In another embodiment, L is (C4-C6) alkenylene having one carbon-carbon double bond. In another embodiment, L is (C4-C5) alkenylene. In another embodiment, L is (C4-C5) alkenylene having one carbon-carbon double bond. In some embodiments, when L is (C3-C6) alkenylene having one carbon-carbon double bond, the carbon-carbon double bond is in the cis configuration, the trans configuration, or a mixture thereof, such as a cis:trans mixture of 2:1 to 1:2, such as 2:1, 1:1, or 1:2. In another embodiment, L is * -CH=CH-CH2- ** , * -CH2-CH=CH-CH2- ** , * -CH2CH2-CH=CH-CH2- ** , and * -CH2-CH=CH-CH2CH2CH2- ** a (C3-C6) alkenylene selected from the group consisting of, wherein " * " represents a covalent bond with the pyridone ring of formula (IV), and " ** " represents a covalent bond with the phenyl ring of formula (IV). In another embodiment, L is

Chemical formula

Chemical formula

Chemical formula

[0115] In certain embodiments of the compound of formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, L is a bivalent linker of formula (L-ia):

Chem.

Chem.

Chem.

[0116] In another embodiment, L is a bivalent linker of formula (L-ia) where the sum of r and s is 3 or 4. In another embodiment, L is a bivalent linker of formula (L-ia), where R 9 and R 10 each independently is hydrogen, -CH3, or -CH2CH3; R d is hydrogen or -CH3. In another embodiment, L is

Chem.

Chem.

Chem.

[0117] In certain embodiments of the compound of formula (IV), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, L is a divalent linker of formula (L-i):

Chem.

Chem.

Chem.

[0118] In another embodiment, L is a divalent linker of formula (L-i) wherein the sum of r and s is 3 or 4. In another embodiment, L is

Chem.

Chem.

Chem.

[0119] In certain embodiments of a compound of formula (IV), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, L is a bivalent linker of formula (L-iia):

Chemical formula

Chemical formula

Chemical formula

[0120] In another embodiment, L is a bivalent linker of formula (L-iia), wherein X 6 is -NR c -; X 7is -CR 11 R 12 - and; R c is hydrogen or -CH3; R 11 and R 12 each of which is, independently, hydrogen or -CH3. In another embodiment, L is

Chemical formula

Chemical formula

Chemical formula

[0121] In an embodiment of a compound of formula (IV), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, L is a divalent linker of formula (L-ii):

Chemical formula

Chemical formula

[0122] In another embodiment, L is a divalent linker of formula (L-ii) where R c is hydrogen or -CH3. In another embodiment, L is X 6 where X is -NR c - and X 7 is -CH2-, which is a divalent linker of formula (L-ii). In another embodiment, L is X 6 where X is -NR c and X 7 is -O-, which is a divalent linker of formula (L-ii). In another embodiment, L is X 6 where X is -CH2- and X 7 is -O-, which is a divalent linker of formula (L-ii). In another embodiment, L is X 6 where X is -CH2- and X 7 is -NH2-, which is a divalent linker of formula (L-ii). In another embodiment, L is X 6 where X is -CH2- and X 7 is -CH2-, which is a divalent linker of formula (L-ii). In another embodiment, L is a divalent linker of formula (L-ii) where q is 2 or 3. In another embodiment, L is a divalent linker of formula (L-ii) where q is 2. In another embodiment, L is [Chemical formula] a divalent linker of formula (L-ii) selected from the group consisting of -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, and -CH2CH2CH2CH2CH2CH2-, where [Chemical formula] represents a covalent bond with the pyridone ring of formula (IV), [Chemical formula] represents a covalent bond with the phenyl ring of formula (IV). In another embodiment, L is a divalent linker of formula (L-ii) selected from the group consisting of -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, and -CH2CH2CH2CH2CH2CH2-. In another embodiment, L is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0123] In certain embodiments of the compound of formula (IV), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, L is

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0124] In certain embodiments of the compound of formula (IV), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, Y is O; R 1 is hydrogen, and each of R 3 and R 4 is independently hydrogen, halo, cyano, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-; R 5 is hydrogen; R 6 and R 7Each of them is independently hydrogen, halo, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-; R 8 is hydrogen; L is a divalent linker of formula (L-i) or a divalent linker of formula (L-ii):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0125] The present invention also relates to a compound of formula (V):

Chemical formula

[0126] The present invention also relates to a compound of formula (V): [Chemical formula] [wherein, Y is O or S; R 2 , R 3 , and R 4 each independently is hydrogen, halo, cyano, -NR a R b , -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-; R 5 is hydrogen, halo, or -(C1-C6)alkyl; R 6 , R 7 and R 8 each independently is hydrogen, halo, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-; R a and R b each independently is hydrogen, -(C1-C6)alkyl, or halo(C1-C6)alkyl-; L is (C3-C6)alkenylene, a divalent linker of formula (L-i), or a divalent linker of formula (L-ii): [Chemical formula] wherein, r is 1, 2, 3, or 4; s is 1, 2, 3, or 4; the sum of r and s is 2, 3, 4, or 5; [Chemical formula] represents a covalent bond with the pyridone ring of formula (V), [Chemical formula] represents a covalent bond with the phenyl ring of formula (V);

Chemical formula

Chemical formula

Chemical formula

[0127] In certain embodiments of the compound of formula (V), or its tautomer, or its pharmaceutically acceptable salt, Y is O. In another embodiment, Y is S.

[0128] In certain embodiments of the compound of formula (V), or its tautomer, or its pharmaceutically acceptable salt, each of R 2 , R 3 and R 4 is independently hydrogen, halo, cyano, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy-. In another embodiment, each of R 2 , R 3 and R 4Each of them is, independently, hydrogen, halo, cyano, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy-. In another embodiment, R 2 , R 3 , and R 4 are each, independently, -F, -Cl, cyano, -CF3, or -OCF3.

[0129] In an embodiment of the compound of formula (V), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, R a and R b are each, independently, hydrogen or -(C1-C6)alkyl. In another embodiment, R a and R b are each, independently, hydrogen or -CH3.

[0130] In an embodiment of the compound of formula (V), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, R 5 is hydrogen or -(C1-C6)alkyl. In another embodiment, R 5 is hydrogen, -I, Cl, or -CH3. In another embodiment, R 5 is hydrogen.

[0131] In an embodiment of the compound of formula (V), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, R 6 , R 7 and R 8 are each, independently, hydrogen, halo, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-. In another embodiment, R 6 , R 7 and R 8 are each, independently, hydrogen, -F, -CF3, or -OCF3.

[0132] In an embodiment of the compound of formula (V), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, R 8 is hydrogen, and R 6 and R 7Each of them is, independently, hydrogen, halo, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-. In another embodiment, R 8 is hydrogen, and each of R 6 and R 7 is, independently, hydrogen, halo, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-. In another embodiment, R 8 is hydrogen, and each of R 6 and R 7 is, independently, hydrogen, -F, -CF3, or -OCF3.

[0133] In certain embodiments of the compound of formula (V), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, each of R 6 and R 8 is hydrogen, and R 7 is hydrogen, halo, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-. In another embodiment, each of R 6 and R 8 is hydrogen, and R 7 is hydrogen, halo, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-. In another embodiment, each of R 6 and R 8 is hydrogen, and R 7 is hydrogen, -F, -CF3, or -OCF3. In another embodiment, each of R 6 and R 8 is hydrogen, and R 7 is -F, -CF3, or -OCF3. In another embodiment, each of R 6 and R 8 is hydrogen, and R 7 is -F.

[0134] In certain embodiments of the compound of formula (V), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, L is a divalent linker having a length of 3 to 6 atoms, for example, 3, 4, 5, or 6 atoms in length. In some embodiments, L is a divalent linker having a length of 4 to 5 atoms. In some embodiments, L is a divalent linker having a length of 4 atoms. In some embodiments, L is a divalent linker having a length of 5 atoms.

[0135] In certain embodiments of the compound of formula (V), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, L is (C3-C6) alkenylene such as C3-alkenylene, C4-alkenylene, C5-alkenylene or C6-alkenylene. In another embodiment, L is (C3-C6) alkenylene having one carbon-carbon double bond. In another embodiment, L is (C4-C6) alkenylene. In another embodiment, L is (C4-C6) alkenylene having one carbon-carbon double bond. In another embodiment, L is (C4-C5) alkenylene. In another embodiment, L is (C4-C5) alkenylene having one carbon-carbon double bond. In some embodiments, when L is (C3-C6) alkenylene having one carbon-carbon double bond, the carbon-carbon double bond is in cis configuration, trans configuration, or a mixture thereof, for example, a cis:trans mixture of 2:1 to 1:2, for example, 2:1, 1:1, or 1:2. In another embodiment, L is * -CH=CH-CH2- ** 、 * -CH2-CH=CH-CH2- ** 、 * -CH2CH2-CH=CH-CH2- ** 、および * -CH2-CH=CH-CH2CH2CH2- ** a (C3-C6) alkenylene selected from the group consisting of, wherein " * " represents a covalent bond with the pyridone ring of formula (V), and " ** " represents a covalent bond with the phenyl ring of formula (V). In another embodiment, L is

Chemical formula

Chemical formula

Chemical formula

[0136] In certain embodiments of the compound of formula (V), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, L is a divalent linker of formula (L-ia):

Chemical formula

Chemical formula

Chemical formula

[0137] In another embodiment, L is a divalent linker of formula (L-ia) where the sum of r and s is 3 or 4. In another embodiment, L is R 9and R 10 each of which is independently hydrogen, -CH3, or -CH2CH3; R d is a divalent linker of formula (L-ia) wherein R is hydrogen or -CH3. In another embodiment, L is

Chemical formula

Chemical formula

Chemical formula

[0138] In an embodiment of a compound of formula (V), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, L is a divalent linker of formula (L-i):

Chemical formula

Chemical formula

Chemical formula

[0139] In another embodiment, L is a divalent linker of formula (L-i) wherein the sum of r and s is 3 or 4. In another embodiment, L is

Chemical formula

Chem.

Chem.

[0140] In certain embodiments of the compound of formula (V), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, L is a divalent linker of formula (L-iia):

Chem.

Chem.

Chem.

[0141] In another embodiment, L is X 6 is -NR c -; X 7 is -CR 11 R 12 -; R c is hydrogen or -CH3; R 11 and R 12 each independently is hydrogen or -CH3, and is a divalent linker of formula (L-iia). In another embodiment, L is

Chemical formula

Chemical formula

Chemical formula

[0142] In an embodiment of the compound of formula (V), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, L is a divalent linker of formula (L-ii):

Chemical formula

Chemical formula

Chemical formula

[0143] In another embodiment, L is a divalent linker of formula (L-ii) where R c is hydrogen or -CH3. In another embodiment, L is a divalent linker of formula (L-ii) where X 6 is -NR c - and X 7 is -CH2-. In another embodiment, L is a divalent linker of formula (L-ii) where X 6 is -NR c and X 7 is -O-. In another embodiment, L is a divalent linker of formula (L-ii) where X 6 is -CH2- and X 7 is -O-. In another embodiment, L is a divalent linker of formula (L-ii) where X 6 is -CH2- and X 7 is -NH2-. In another embodiment, L is a divalent linker of formula (L-ii) where X 6 is -CH2- and X 7 is -CH2-. In another embodiment, L is a divalent linker of formula (L-ii) where q is 2 or 3. In another embodiment, L is a divalent linker of formula (L-iii) where q is 2. In another embodiment, L is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0144] In certain embodiments of the compound of formula (V), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, L is

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0145] In certain embodiments of the compound of formula (V), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, Y is O; R 2 、R 3 およびR 4 Each of R R 5 is hydrogen; R 6 およびR 7 Each of R R 8 is hydrogen; L is a divalent linker of formula (L-i) or a divalent linker of formula (L-ii):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0146] as follows: [Chemical formula] JPEG2025522369000366.jpg207170 JPEG2025522369000367.jpg199170 JPEG2025522369000368.jpg228170 JPEG2025522369000369.jpg219170 JPEG2025522369000370.jpg232170 JPEG2025522369000371.jpg197170 JPEG2025522369000372.jpg129170 or its tautomer, or a pharmaceutically acceptable salt thereof.

[0147] The present invention further provides the following: [Chemical formula] relates to a compound selected from the group consisting of JPEG2025522369000374.jpg211170, or its tautomer, or a pharmaceutically acceptable salt thereof.

[0148] In certain embodiments, the following: [Chemical formula] a compound selected from the group consisting of, or its tautomer, or a pharmaceutically acceptable salt thereof is provided. In another embodiment, the following: [Chemical formula] A compound selected from the group consisting of, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, is provided. In another embodiment, the following:

Chem.

Chem.

Chem.

Chem.

[0149] As used herein, when referring to a compound of formula (I-a), (I), (II), (III), (IV), or (V) and / or its corresponding tautomeric form or a salt thereof, it is to be understood that the compound of formula (I-a), (I), (II), (III), (IV), or (V) and / or its corresponding tautomeric form is included as the free base or acid, or as its salt, for example, as its pharmaceutically acceptable salt. Thus, in one embodiment, the present invention is directed to a compound of formula (I-a), (I), (II), (III), (IV), or (V) and / or its corresponding tautomeric form. In another embodiment, the present invention is directed to a salt of a compound of formula (I-a), (I), (II), (III), (IV), or (V) and / or its corresponding tautomeric form. In a further embodiment, the present invention is directed to a pharmaceutically acceptable salt of a compound of formula (I-a), (I), (II), (III), (IV), or (V) and / or its corresponding tautomeric form. In another embodiment, the present invention is directed to a compound of formula (I-a), (I), (II), (III), (IV), or (V) and / or its corresponding tautomeric form, or a salt thereof. In another embodiment, the present invention is directed to a compound of formula (I-a), (I), (II), (III), (IV), or (V) and / or its corresponding tautomeric form, or a pharmaceutically acceptable salt thereof.

[0150] For their potential use in medicine, it will be understood that the salts of the compounds of formula (I-a), (I), (II), (III), (IV), or (V) and / or their corresponding tautomeric forms are preferably pharmaceutically acceptable.

[0151] The term "pharmaceutically acceptable" refers to compounds (including salts), materials, compositions, and dosage forms that are suitable for use in contact with the tissues of humans and animals within the scope of sound medical judgment, without excessive toxicity, irritation, or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0152] The term "pharmaceutically acceptable salt" refers to salts that retain the desired biological activity of the subject compound and minimize undesired toxicological effects. These pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compound or by reacting the purified compound in the form of the free acid or free base separately with a suitable base or acid, respectively. Furthermore, pharmaceutically acceptable salts of the compounds of formulas (I)-(V) and / or their corresponding tautomeric forms can be prepared in situ during further processing in the free acid or base form, for example, during manufacture into pharmaceutical formulations.

[0153] Pharmaceutically acceptable salts include, inter alia, those described in Berge, J. Pharm. Sci., 1977, 66, 1-19, or those listed in P H Stahl and C G Wermuth, editors, Handbook of Pharmaceutical Salts; Properties, Selection and Use, Second Edition Stahl / Wermuth: Wiley-VCH / VHCA, 2011.

[0154] Non-pharmaceutically acceptable salts can also be used, for example, as intermediates in the preparation of the compounds of formulas (I-a), (I), (II), (III), (IV), or (V) and / or their corresponding tautomeric forms or their pharmaceutically acceptable salts.

[0155] Suitable pharmaceutically acceptable salts may include acid or base addition salts. Such base addition salts can be formed by reacting a compound of formula (I-a), (I), (II), (III), (IV), or (V) and / or its corresponding tautomeric form (e.g., containing a carboxylic acid or other acidic functional group) with a suitable base, optionally in a suitable solvent such as an organic solvent, to obtain a salt, which can be isolated by various methods including crystallization and filtration. Such acid addition salts can be formed by reacting a compound of formula (I-a), (I), (II), (III), (IV), or (V) and / or its corresponding tautomeric form (e.g., containing a basic amine or other basic functional group) with a suitable 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.

[0156] The salts may be prepared in situ during the final isolation and purification of the compounds of formula (I-a), (I), (II), (III), (IV), or (V) and / or their corresponding tautomeric forms. When a basic compound of formula (I-a), (I), (II), (III), (IV), or (V) and / or its corresponding tautomeric form 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 formula (I-a), (I), (II), (III), (IV), or (V) and / or its corresponding tautomeric form containing a carboxylic acid or other acidic functional group is isolated as a salt, the corresponding free acid form of the compound can be prepared by any suitable method known in the art, including treating the salt with an inorganic or organic acid.

[0157] If the compounds of formula (I-a), (I), (II), (III), (IV), or (V) and / or their corresponding tautomeric forms contain two or more basic moieties, it will be understood that the stoichiometry of salt formation may involve one, two or more equivalents of acid. Such salts will include one, two or more acid counterions, for example dihydrochloride.

[0158] The stoichiometric and non-stoichiometric forms of the pharmaceutically acceptable salts of the compounds of formula (I-a), (I), (II), (III), (IV), or (V) and / or their corresponding tautomeric forms are included within the scope of the present invention, including, for example, sub-stoichiometric salts where the counterion contains two or more acidic protons.

[0159] Representative pharmaceutically acceptable acid addition salts include, but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, bisulfate, bitartrate, butyrate, calcium edetate, camphorate, camphorsulfonate (camsylate), caprinate (decanoate), caproate (hexanoate), caprylate (octanoate), cinnamate, citrate, cyclamate, digluconate, 2,5-dihydroxybenzoate, dicosuccinate, dodecyl sulfate (esterate), edetate (ethylenediaminetetraacetate), esterate (lauryl sulfate), ethane-1,2-disulfonate (edsylate), ethanesulfonate (esylate), formate, fumarate, galactarate (mucate), gentisinate (2,5-dihydroxybenzoate), glucoheptonate (glceptate), gluconate, glucuronate, glutamate, glutarate, glycerophosphate, glycolate, hexylresorcinate, hippurate, hydrabamine (N,N'-di(dehydroabietyl)-ethylenediamine), hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, isobutyrate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, methanesulfonate (mesylate), methyl sulfate, mucate, naphthalene-1,5-disulfonate (napadisylate), naphthalene-2-sulfonate (napsylate), nicotinate, nitrate, oleate, palmitate, p-aminobenzenesulfonate, p-aminosalicylate, pamoate (embonate), pantothenate, pectinate, persulfate, phenylacetate, phenylethylbarbiturate, phosphate, polygalacturonate, propionate, p-toluenesulfonate (tosylate), pyroglutamate, pyruvate, salicylate, sebacate, stearate, subacetate, succinate, sulfamate, sulfate, tannate, tartrate, theoclate (8-chlorotheophyllinate), thiocyanate, triethiodide, undecanoate, undecylenate, and valerate are included.,

[0160] Representative pharmaceutically acceptable base addition salts include, but are not limited to, aluminum, 2-amino-2-(hydroxymethyl)-1,3-propanediol (TRIS, tromethamine), arginine, benethamine (N-benzylphenethylamine), benzathine (N,N'-dibenzylethylenediamine), bis-(2-hydroxyethyl)amine, bismuth, calcium, chloroprocaine, choline, cresol (1-p-chlorobenzyl-2-pyrrolidin-1'-ylmethylbenzimidazole), cyclohexylamine, dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lepidine, lithium, lysine, magnesium, meglumine (N-methylglucamine), piperazine, piperidine, potassium, procaine, quinene, quinoline, sodium, strontium, t-butylamine, and zinc are included.,

[0161] It will be understood that many organic compounds can form complexes with solvents in which they react, precipitate, or crystallize. These complexes are known as "solvates". For example, complexes with water are known as "hydrates". Solvates may be formed using solvents with high boiling points such as water, ethanol, isopropyl alcohol, and N-methylpyrrolidinone and / or solvents that are prone to forming hydrogen bonds. Methods for identifying solvates include, but are not limited to, NMR and microanalysis. Compounds of formula (I-a), (I), (II), (III), (IV), or (V) and / or their corresponding tautomers or salts thereof may exist in solvated and non-solvated forms.

[0162] The compounds of the present invention can be in crystalline or amorphous form. Particular attention is paid to the most thermodynamically stable crystalline form of the compounds of the present invention.

[0163] The crystalline forms of the compounds of the present invention can be characterized and differentiated using several conventional analytical techniques including, but not limited to, X-ray powder diffraction (XRPD), infrared spectroscopy (IR), Raman spectroscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and solid state nuclear magnetic resonance (ssNMR).

[0164] Compounds of formula (I-a), (I), (II), (III), (IV), or (V) and / or their corresponding tautomers and pharmaceutically acceptable salts thereof may contain one or more asymmetric centers (also called chiral centers) and thus may exist as individual enantiomers, diastereomers, or other stereoisomers, or mixtures thereof. Chiral centers, such as chiral carbon atoms, may be present within substituents such as alkyl groups. When the stereochemistry of a chiral center present in a compound of formula (I-a), (I), (II), (III), (IV), or (V) or any chemical structure shown herein is not specified, the structure is intended to encompass all individual stereoisomers and all mixtures thereof. Thus, compounds of formula (I-a), (I), (II), (III), (IV), or (V) containing one or more chiral centers and / or their corresponding tautomers and pharmaceutically acceptable salts thereof can be used as racemic mixtures, enantiomerically enriched mixtures, or enantiomerically pure individual stereoisomers.

[0165] Individual stereoisomers of compounds of formula (I-a), (I), (II), (III), (IV), or (V) and / or their corresponding tautomers or pharmaceutically acceptable salts containing one or more asymmetric centers can be resolved by methods known to those skilled in the art. For example, such resolution can be accomplished by (1) formation of diastereomeric salts, complexes or other derivatives; (2) selective reaction with stereospecific reagents, for example, by enzymatic oxidation or reduction; or (3) gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support such as silica bonded to a chiral ligand or in the presence of a chiral solvent. Those skilled in the art will understand that when the desired stereoisomer is converted to another chemical entity by one of the aforementioned separation procedures, additional steps are required to liberate the desired form. Alternatively, a particular stereoisomer can be synthesized by asymmetric synthesis using an optically active reagent, substrate, catalyst or solvent, or by asymmetric transformation by converting one enantiomer to the other enantiomer.

[0166] The present invention also includes the compounds of formula (I-a), (I), (II), (III), (IV), or (V) and / or all suitable isotopic variants of the corresponding tautomeric forms or pharmaceutically acceptable salts thereof. The compounds of formula (I-a), (I), (II), (III), (IV), or (V) and / or the isotopic variants of the corresponding tautomeric forms or pharmaceutically acceptable salts thereof are defined as those in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass from that normally found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include, respectively 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F and 36 Cl and other isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine. Compounds of formula (I-a), (I), (II), (III), (IV), or (V) and specific isotopic variants / or the corresponding tautomeric forms or salts or solvates thereof, for example, 3 H or 14 C and the like incorporated with radioactive isotopes are useful for drug and / or substrate tissue distribution studies. Tritiation, that is 3 H isotope, and carbon-14, that is 14 C isotope are particularly preferred because they are easy to prepare and have high detectability. Furthermore, substitution with isotopes such as deuterium, that is 2 H and the like provides specific therapeutic advantages such as increased metabolic stability, for example, an extended in vivo half-life or a reduced dose requirement, and may therefore be preferred depending on the situation. The compounds of formula (I-a), (I), (II), (III), (IV), or (V) and / or the corresponding tautomeric forms or pharmaceutically acceptable salts thereof can generally be prepared by conventional procedures using appropriate isotopic variants of suitable reagents, such as the exemplified methods or the preparation methods described in the following examples.

[0167] Furthermore, the compounds of the present invention may exist as tautomers or in tautomeric forms. It should be understood that references to named or structurally depicted compounds are intended to encompass all tautomers of such compounds. Tautomers are structural isomers (or constitutional isomers) of chemical compounds that readily interconvert, as is conventionally understood in the art of chemistry. This reaction generally results in the rearrangement of a proton. Structural isomers (by IUPAC) are a type of isomer in which molecules with the same molecular formula have different bonding patterns and atomic constitutions, in contrast to stereoisomers where the molecular bonds are always in the same order and only the spatial arrangement is different. The concept of tautomerizations is referred to as tautomerism. The chemical reaction that interconverts these two is called tautomerization. It is necessary to be careful not to confuse tautomers with the depiction of "contributing structures" in chemical resonance. Tautomers are distinct chemical species and can thus be identified by different spectroscopic data, while resonance structures are only convenient depictions and do not physically exist. For example, the 2-pyridone ring exhibits tautomerism, and the proton bonded to nitrogen can migrate to oxygen to form the tautomeric form 2-hydroxypyridine.

Chemical formula

[0168] Pharmaceutical Composition In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I-a), (I), (II), (III), (IV), or (V) according to any one of the embodiments disclosed herein, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient (also called a carrier and / or diluent in the pharmaceutical art). An excipient is acceptable in the sense that it is compatible with the other components of the formulation and not harmful to its recipient (i.e., the patient).

[0169] Pharmaceutically acceptable excipients are non-toxic and must not interfere with the effectiveness of the active ingredient. Suitable pharmaceutically acceptable excipients vary depending on the specific dosage form selected, the route of administration, etc. Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, carriers, extenders, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, anti-precipitants, emulsifiers, sweeteners, flavoring agents, taste modifiers, coloring agents, anti-crystallization agents, humectants, chelating agents, plasticizers, thickeners, antioxidants, preservatives, stabilizers, surfactants, and buffering agents. Examples of pharmaceutically acceptable excipients are described, for example, in Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

[0170] The pharmaceutical composition can be adapted for administration by a suitable or appropriate route, such as systemic administration (e.g., oral administration, parenteral administration, transdermal administration, rectal administration, inhalation), topical administration, etc. Parenteral administration generally refers to administration by injection or infusion and includes intravenous, intramuscular, and subcutaneous injection or infusion. Inhalation refers to the administration to the patient's lungs, whether via the oral route or the nasal route. Generally, administration is via the oral route or the parenteral route.

[0171] Pharmaceutical compositions adapted for oral administration can be prepared as solids such as tablets, capsules, caplets, troches, pills, etc.; powders; or as liquids such as solutions, suspensions, syrups, elixirs, or emulsions. Pharmaceutical compositions adapted for parenteral administration may be provided as solutions, suspensions, and powders for reconstitution.

[0172] Generally, the pharmaceutical compositions of the present invention are prepared using conventional materials and techniques, such as mixing, blending, etc. Some of the methods commonly used in the art are described in Remington’s Pharmaceutical Sciences (Mack Publishing Company).

[0173] 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 extenders (e.g., starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.), binders (e.g., starch, gum arabic, carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, etc.), lubricants (e.g., magnesium stearate, talc, etc.). Pharmaceutical compositions suitable for parenteral administration may be injections prepared by mixing from powders, granules or tablets with carriers such as distilled water, physiological saline, etc., and bases etc. may be used for pH adjustment.

[0174] The present invention also provides a pharmaceutical composition comprising 0.5 to 1,000 mg of the compound of the present invention and 0.5 to 1,000 mg of a pharmaceutically acceptable excipient.

[0175] The compounds and pharmaceutical compositions of the present invention as defined herein may be administered in a single dose or according to a dosing schedule in which multiple doses are administered over a given period at various time intervals. For example, the dose may be administered once, twice, three times, or four times a day. The dose may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. The dose of the compound of the present invention may range from 0.001 mg / kg to 100 mg / kg, such as from 0.001 mg / kg to 50 mg / kg. Preferably, the selected dose is administered orally or parenterally.

[0176] According to another aspect of the present invention, there is provided a method for preparing a pharmaceutical composition comprising a compound of formula (I-a), (I), (II), (III), (IV), or (V), or a tautomer thereof or a salt thereof (e.g., a pharmaceutically acceptable salt thereof) together with at least one pharmaceutically acceptable excipient.

[0177] Synthetic Scheme and General Preparation Methods The present invention also relates to a method for preparing the compounds of the present invention disclosed herein. The compounds of the present invention can be prepared by any number of steps using conventional organic synthesis as described in the following schemes and more specifically exemplified by the exemplary compounds according to the Examples section herein, or by utilizing the knowledge of a skilled organic chemist. Suitable synthetic routes are shown in the following general reaction schemes. The synthetic procedures provided in the following schemes are applicable for preparing the compounds of the present invention disclosed herein having various different functional groups as defined, using appropriate precursors.

[0178] Those skilled in the art will recognize that in the preparation of the compounds of the present invention, it may be necessary and / or desirable to protect one or more sensitive groups in the molecule or appropriate intermediates to prevent unwanted side reactions. Those skilled in the art will also recognize that if the substituents described herein are not compatible with the synthetic methods described herein, the substituents may be protected with appropriate protecting groups that are stable to the reaction conditions. The protecting groups can be removed at an appropriate point in the reaction sequence to provide the desired intermediate or end compound. Protecting groups suitable for use in accordance with the present invention are well known to those skilled in the art and can be used by conventional methods. See, for example, "Protective Groups in Organic Synthesis" by T.W. Green and P.G.M Wets (Wiley & Sons, 1991) or "Protecting Groups" by P. J. Kocienski (Georg Thieme Verlag, 1994). Compounds of the generally disclosed nature can be obtained by subsequent deprotection, if necessary. In some cases, the substituents may be specifically selected to be reactive under the reaction conditions used. Under such circumstances, depending on the reaction conditions, the selected substituents may be useful as intermediate compounds or may be converted to another substituent that is the desired substituent in the end compound.

[0179] The schemes shown below are representative methods for preparing the compounds of the present invention, but are intended only to illustrate the steps that can be used to produce the compounds of the present invention. Intermediates (compounds used in the preparation of the compounds of the present invention) may also exist as salts. Accordingly, with respect to intermediates, the expression "compound of formula (number)" means a compound having the structural formula or a pharmaceutically acceptable salt thereof. The compound names were generated using the software ChemDraw 5 Ultra v12.0, a nomenclature program available from Perkin Elmer, 940 Winter Street, Waltham, Massachusetts 02451, USA.

[0180] Several methods for preparing the compounds of the present invention are shown in the following schemes and examples. The starting materials are either commercially available or prepared by known procedures in the literature or as shown.

[0181] General synthetic scheme In the following general schemes including General Schemes 1 to 16, each R 1 is, independently, hydrogen, halo, cyano, -NR a R b 、 -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-; each R 2 is, independently, hydrogen, halo, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-;

Chemical formula

[0182] General Scheme 1

Chemical formula

[0183] General Scheme 2

Chemical Structure

[0184] General Scheme 3

Chemical Structure

[0185] Alternatively, using the previously cited procedure, R 2 -substituted o-bromoaniline undergoes Suzuki cross-coupling to give G3-L, and then R 1- G3-M is obtained by backward coupling with a substituted bromoaryl carbonate. Subsequently, hydrolysis of G3-N with a base and amide formation with G9-C (shown below) using the previously described conditions yield bis-alkene G3-O. Formation of dihydropyrimidinone and subsequent Grubbs-catalyzed cyclization result in the formation of macrocyclic G3-Q. Reduction of the linked alkene with borohydride Grubbs gives intermediate G3-K, which is converted to general structure 5 as previously described.

[0186] As another approach, R 2 - involves performing a Sonogashira cross-coupling of a substituted o-iodoaniline with 5-hydroxypentyne to give G3-R. Under typical conditions, in a suitable solvent such as DMF and a terminal alkyne, in the presence of an organic base such as TEA, DEA, or DIEA, a palladium / ligand source such as bis[Pd(PPh3)2Cl2]) / PPh3) or Pd(PPh3)4, and a copper(I) halide salt co-catalyst such as copper(I) iodide are used. The aforementioned conditions for catalytic hydrogenation (G3-S) and R 1 - G3-T is obtained by a backward cross-coupling step with a substituted chloroaryl carbonate step. Conversion of the terminal bromide with triphenylphosphine using tetramethylammonium bromide and subsequent Negishi coupling with BOC-protected 2-bromo-3-amino-6-methoxypyridine gives G3-V. Under typical conditions, in a suitable solvent such as dimethylacetamide (DMA) at high temperature, in the presence of an inorganic salt such as sodium iodide and a ligand such as picolinimide amide, a metal catalyst such as zinc and a metal halide such as nickel(II) chloride are used. Ester hydrolysis (G3-W) with a strong acid such as TFA or HCl, amine deprotection (G3-X), and intramolecular amide coupling using the previously described conditions result in the formation of macrocyclic G3-Y. Formation of dihydropyrimidinone gives G3-K, which is demethylated using the conditions outlined previously to give general structure 5.

[0187] General Scheme 4 [Chemical Formula] Compounds having the general structure 6 can be prepared by the general procedure outlined in General Scheme 4. At low temperature, in a suitable solvent such as toluene, a copper source such as CuI, and a ligand such as 2,2'-bipyridine are used for the cross-coupling of a benzyl halide such as an R 1 -substituted o-bromobenzyl bromide with an essential Grignard to form G4-A. The intermediate G4-E is obtained by the aforementioned backward cross-coupling (G4-B), ester hydrolysis (G4-C), amide coupling (G4-D), and dihydropyrimidinone formation. G4-G is obtained by a Stille cross-coupling (G4-F) followed by cyclization using the previously described method. The general structure 6 is prepared using the conditions described in the above general scheme for the catalytic hydrogenation and demethylation steps.

[0188] General Scheme 5

Chemical Structure

[0189] General Scheme 6

Chemical Structure

[0190] General Scheme 7 [Chemical formula] Compounds having general structure 11 can be prepared by the general procedure outlined in General Scheme 7. Alkylation of intermediate G6-C can be achieved using an inorganic base such as potassium carbonate, an alkyl halide such as allyl bromide, and a suitable solvent such as THF, acetone or DMF at elevated temperature, followed by ester hydrolysis (G7-B) and amide coupling with G1-A using the aforementioned chemical methods to give G7-C. Similarly, formation of the dihydropyrimidinone ring (G7-D), Grubbs-catalyzed cyclization (G7-E), catalytic hydrogenation (G7-F) and demethylation using the previously described conditions gives rise to the pyridinone ring and general structure 11.

[0191] General Scheme 8 [Chemical formula] Compounds having the general structure 12 can be prepared by the general procedure outlined in General Scheme 8. Using a previously described series of reaction conditions, coupling of carboxylic acid G7-B with amine G3-A gives G8-A, which is then subjected to formation of the dihydropyrimidinone ring (G8-B), Grubbs-catalyzed cyclization (G8-C), catalytic hydrogenation (G8-D) and demethylation to yield the general structure 12.

[0192] General Scheme 9

Chemical Structure

[0193] General Scheme 10

Chemical Structure

[0194] General Scheme 11

Chemical Structure

[0195] General Scheme 12

Chem.

[0196] General Scheme 13

Chem.

[0197] -substituted o-bromoaryl carbonate generates G13-D, followed by saponification (G13-E), and catalytic hydrogenation (G13-F), intramolecular amide coupling (G13-G), dihydropyrimidinone ring formation (G13-H), and double deprotection / demethylation under acidic conditions to form the pyridinone moiety, generating the general structure 17. 2 Alternatively, using the previously described method, head-to-head cross-coupling of an R 1 -substituted o-iodoaniline with Boc-protected aminopropine gives G13-I, and then backward cross-coupling (G13-J) with an R

[0198] -substituted o-bromoaryl carboxylate, followed by hydrolysis (G13-K), catalytic hydrogenation of the alkyne (G13-L), amide coupling (G13-M), dihydropyrimidinone formation (G13-N), amine deprotection (G13-O), intramolecular backward cross-coupling (G13-P), and demethylation to form the pyridinone, giving the general structure 17.

[0199] General Scheme 14

Chemical Structure

[0200] General Scheme 15

Chemical formula

[0201] General Scheme 16

Chemical formula

[0202] General Scheme 17 [Chem.] [Chem.] Compounds having the general structure 21 can be prepared by the general procedure outlined in General Scheme 17. Carbamic acid (2-bromo-6-methoxypyridin-3-yl) tert-butyl can be formylated by treatment with butyllithium and DMF to give aldehyde G17-A. At the same time, using the aforementioned procedure, the backward coupling of R 1 -substituted o-aminobenzoate and R 2 -substituted 2-bromiodobenzene is carried out (G17-B), and then Suzuki coupling with boc-amine-protected aminoethylboronate is carried out to obtain G17-C. Deprotection of Boc, reductive amination with G17-A, and nosyl protection result in the formation of G17-D. Using the previously described method, intramolecular amide coupling can be carried out by ester hydrolysis and boc deprotection (G17-E) to obtain G17-F. Dihydropyrimidinone formation (G17-G), nosyl deprotection (G17-H), and demethylation give pyridinone, and the general structure 21 is formed.

[0203] General Scheme 18 [Chem.] [Chem.] Compounds having the general structure 22 can be prepared by the general procedure outlined in General Scheme 18. R 2 -substituted o-iodoaniline undergoes Sonogashira coupling with tert-butyl prop-2-yn-1-ylcarbamate to form G18-A, which is catalytically hydrogenated to G18-B. At the same time, methyl 3-amino-6-methoxypicolinate is reduced with LAH to give alcohol G18-C, protected with phthalimide to give G18-D, and finally, aldehyde G18-E is obtained by Dess-Martin oxidation. R 1- The backward coupling of o-bromobenzoate and G18-B followed by boc deprotection gives amine G18-F, which undergoes reductive amination with G18-E to form G18-G. Using the previously described chemical methods, G18-H is formed by ester hydrolysis and subsequent phthalimide deprotection using hydrazine, followed by intramolecular amide coupling (G18-I), dihydropyrimidinone formation (G18-J), and finally, the formation of general structure 22 by HCl-induced boc deprotection and demethylation of the pyridone.

[0204] General Scheme 19

Chemical Structure

[0205] General Scheme 20

Chemical Structure

[0206] General Scheme 21

Chemical Structure

[0207] General Scheme 22

Chemical Structure

[0208] General Scheme 23

Chemical Structure

[0209] Method / Use In general, the invention also relates to the use of the compounds and / or pharmaceutical compositions described herein for use as a medicament or for use in therapy.

[0210] The compounds of the invention as defined herein are inhibitors of voltage-dependent sodium ion channels, in particular, the voltage-dependent sodium ion channel Na v 1.8. The activity of the compounds utilized as inhibitors of Nav1.8 in the present invention can be assayed according to the methods generally described in the examples herein or according to methods available to those skilled in the art.

[0211] In one aspect, the invention relates to the use of the compounds and pharmaceutical compositions as described herein as inhibitors of voltage-dependent sodium ion channels, in particular, Na v 1.8.

[0212] In one embodiment, the present invention relates to a method of inhibiting a voltage-dependent sodium ion channel in a subject in need thereof, the method 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 another embodiment, the voltage-dependent sodium channel is Na v is 1.8.

[0213] In one 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-dependent sodium ion channel. In another embodiment, the voltage-dependent sodium channel is Nav1.8.

[0214] In one embodiment, the present invention relates to the use of a compound of the present invention or a pharmaceutical composition of the present invention in the manufacture of a medicament for inhibiting a voltage-dependent sodium ion channel. In another embodiment, the voltage-dependent sodium channel is Nav1.8.

[0215] Without being bound by a particular theory, the compounds and compositions of the present invention are particularly useful for treating diseases, conditions, or disorders in which activation or upregulation of Nav1.8 is involved. When activation or upregulation of Nav1.8 is involved in a particular disease, condition, or disorder, the disease, condition, or disorder is also referred to as a "Nav1.8-mediated disease, condition, or disorder". Exemplary Nav1.8-mediated diseases, disorders, and conditions include pain and pain-related diseases, and cardiovascular diseases such as atrial fibrillation.

[0216] According to embodiments of the present invention, a pain-related disease is pain caused by any one of a variety of diseases of various etiologies as described in the present disclosure. In some embodiments, the pain or pain-related disease 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.

[0217] In some embodiments, the pain or pain-related disorder is neuropathic pain or chronic neuropathic pain. In some embodiments, the pain or pain-related disorder 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.

[0218] In some embodiments, the pain or pain-related disorder is neuropathic pain selected from postherpetic neuralgia, diabetic neuralgia, painful HIV-related sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-traumatic pain, phantom pain, painful neuroma, traumatic neuroma, Morton's neuroma, nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica, nerve avulsion injury, brachial plexus avulsion, complex regional pain syndrome, drug therapy-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia, pain after spinal cord injury, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal autonomic cephalgia.

[0219] In some embodiments, the pain or pain-related disorder 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, postherpetic neuralgia, nerve root avulsion-related pain, painful traumatic mononeuropathy, painful polyneuropathy, erythromelalgia, paroxysmal extreme pain disorder (PEPD), burning mouth syndrome, central pain syndrome caused by lesions at the nervous system level, traumatic nerve injury, nerve compression or entrapment, congenital insensitivity to pain with anhidrosis (CIP), dysmenorrhea, primary erythromelalgia, HIV peripheral sensory neuropathy, vulvar neuralgia, spinal nerve injury, chronic inflammatory demyelinating polyneuropathy (CIDP), carpal tunnel syndrome, and vasculitic neuropathy.

[0220] In some embodiments, the pain or pain-related disorder is visceral pain, and the visceral pain is inflammatory bowel disease pain, Crohn's disease pain, or interstitial cystitis pain.

[0221] In some embodiments, the pain or pain-related disorder is musculoskeletal pain, and the musculoskeletal pain is osteoarthritis pain, back pain, cold pain, burn pain or toothache.

[0222] In some embodiments, the pain or pain-related disorder is idiopathic pain, and the idiopathic pain is fibromyalgia pain.

[0223] In some embodiments, the pain or pain-related disorder is chronic or acute pre-operative related pain or chronic or acute post-operative related pain. Post-operative related pain includes outpatient post-operative pain. An outpatient surgery, also known as a same-day surgery, refers to a surgery that does not require an overnight stay in a hospital or other medical facility. In some embodiments, the pre-operative related pain is selected from neuropathic pain or chronic neuropathic pain, chronic osteoarthritis pain, toothache or inflammatory pain. In some embodiments, the post-operative related pain is selected from hallux valgus excision pain, hernia repair pair, breast surgery pain, or cosmetic surgery pain.

[0224] In some embodiments, the pain or pain-related disorder is pain caused by trauma or iatrogenic medical or dental procedures. As used herein, the term "iatrogenic" refers to pain inadvertently induced by a medical or dental practitioner, such as a surgeon or dentist, during a medical or dental treatment or diagnostic procedure, and includes, but is not limited to, pain caused by pre-operative (i.e., "before surgery"), peri-operative (i.e., "during surgery", or pain medically induced during a non-surgical or surgical procedure), and post-operative (i.e., after surgery, post-operative, or pain induced by surgery) medical or dental procedures.

[0225] In some embodiments, the pain or pain-related disorder is nociceptive pain, and the nociceptive pain is post-operative pain, cancer pain, back and craniofacial pain, osteoarthritis pain, toothache or diabetic peripheral neuropathy.

[0226] In some embodiments, the pain or pain-related disorder is inflammatory pain. Inflammatory pain can be pain of various physiological origins. In some embodiments, the inflammatory pain is selected from osteoarthritis, rheumatoid arthritis, rheumatic disorders, tenosynovitis and gout, rotator cuff tendinitis or bursitis, gouty arthritis, and pain associated with polymyalgia rheumatica, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, or other pain caused by central sensitization, complex regional pain syndrome, chronic arthralgia and related neuralgia, or acute pain. In some embodiments, the inflammatory pain is selected from pain associated with rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis or juvenile arthritis. In some embodiments, the inflammatory pain is selected from rheumatoid arthritis, rheumatoid spondylitis, gouty arthritis, juvenile arthritis, rheumatic disorders, gout, rotator cuff tendinitis or bursitis, polymyalgia rheumatica, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, or other pain caused by central sensitization, complex regional pain syndrome, chronic or acute arthralgia and related neuralgia. In some embodiments, the inflammatory pain is rheumatoid arthritis pain or vulvodynia.

[0227] In some embodiments, the inflammatory pain is osteoarthritis, chronic osteoarthritis pain (e.g., hip or knee) or chronic inflammatory demyelinating polyneuropathy.

[0228] In some embodiments, the pain or pain-related disorder is musculoskeletal pain. In some embodiments, the musculoskeletal pain is selected from bone and joint pain, osteoarthritis, low back and neck pain, or pain due to physical trauma or laceration. In some embodiments, the musculoskeletal pain is selected from bone and joint pain, osteoarthritis (e.g., knee, hip), tendinitis (e.g., shoulder), bursitis (e.g., shoulder), tenosynovitis, low back and neck pain, sprain, strain, or pain due to physical trauma or laceration.

[0229] In some embodiments, the pain or pain-related disorder is a neurological or neuron injury-related pain disorder caused by a disease selected from neuropathy, nerve injury-related pain, nerve root avulsion-related pain, painful traumatic mononeuropathy, painful polyneuropathy, erythromelalgia, paroxysmal extreme pain disorder (PEPD), burning mouth syndrome, central pain syndrome caused by lesions at the nervous system level, traumatic nerve injury, nerve compression or nerve entrapment, congenital insensitivity to pain with anhidrosis (CIP), dysmenorrhea, primary erythromelalgia, HIV peripheral sensory neuropathy, vulvar neuralgia, spinal cord nerve injury, chronic inflammatory demyelinating polyneuropathy (CIDP), carpal tunnel syndrome, and vasculitic neuropathy.

[0230] In some embodiments, the pain or pain-related disorder is pain caused by trauma, or pain caused by iatrogenic medical or dental procedures.

[0231] In some embodiments, the pain or pain-related disorder is myofascial pain, myositis or muscle inflammation, repetitive motion pain, complex regional pain syndrome, sympathetically maintained pain, cancer, toxin and chemotherapy-related pain, postoperative pain syndrome and / or related phantom limb pain, postoperative pain of medical or dental procedures or treatments, or pain related to HIV or induced by HIV treatment.

[0232] In some embodiments, the pain or pain-related disorder, condition, or state is neuropathic pain, central neuropathic pain, inherited erythromelalgia (IEM), small fiber neuropathy (SFN), paroxysmal extreme pain disorder (PEPD), painful diabetic neuropathy, chronic low back pain, neuropathic back pain, sciatica, nonspecific low back pain, multiple sclerosis pain, HIV-related neuropathy, postherpetic neuralgia, trigeminal neuralgia, vulvar pain, pain due to physical trauma, pain after amputation, nerve tumor pain, phantom limb pain, cancer, toxin, or a neuropathic pain or other pain-related disorder selected from chronic inflammatory diseases.

[0233] In some embodiments, the pain or pain-related disorder is acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpes neuralgia, general neuralgia, epilepsy, status epilepticus, neurodegenerative disease, mental disorder, anxiety, depression, bipolar disorder, dystonia, arrhythmia, movement disorder, neuroendocrine disorder, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radiculopathy, sciatica, back pain, headache, neck pain, acute pain, intractable pain, nociceptive pain, breakthrough pain, postoperative pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or gastrointestinal motility disorder.

[0234] In some embodiments, the pain or pain-related disorder is 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 headache, migraine, tension headache (including cluster headache), chronic and acute neuropathic pain, post-herpetic neuralgia, diabetic neuropathy, HIV-related neuropathy, trigeminal neuralgia, Charcot-Marie-Tooth neuropathy, hereditary sensory neuropathy, peripheral nerve injury, painful neuroma, ectopic proximal-distal discharge, radiculopathy, chemotherapy-induced neuropathic pain, radiotherapy-induced neuropathic pain, postmastectomy pain, central pain, spinal cord injury pain, post-stroke pain, thalamic pain, complex regional pain syndrome, phantom limb pain, intractable pain, acute pain, acute postoperative pain, acute musculoskeletal pain, joint pain, mechanical low back pain, neck pain, tendinitis, injury / sports pain, acute visceral pain, pyelonephritis, appendicitis, cholecystitis, intestinal obstruction, hernia, chest pain, cardiac pain, pelvic pain, renal colic, acute obstetric pain, labor pain, cesarean section pain, acute inflammatory, burn and traumatic pain, acute intermittent pain, endometriosis, acute herpes zoster pain, sickle cell anemia, acute pancreatitis, breakthrough pain, orofacial pain including rhinosinusitis pain, toothache, multiple sclerosis (MS) pain, depression pain disorder, Lyme disease pain, Behcet's disease pain, painful lipomatosis, phlebitis pain, Guillain-Barré pain, painful moving toes syndrome, Haglund's syndrome, erythromelalgia pain, Fabry disease pain, urinary incontinence, overactive bladder, painful bladder syndrome, interstitial cystitis (IC), bladder and genitourinary disorders including prostatitis, complex regional pain syndrome (CRPS) (type I and type II), widespread pain, paroxysmal extreme pain disorder, pruritus, tinnitus, or angina-induced pain.

[0235] In another aspect, the present invention relates to methods for treating cardiovascular diseases including atrial fibrillation and cardiac arrhythmias and to the use of the compounds and pharmaceutical compositions of the present invention in medicine.

[0236] In some embodiments, the cardiovascular disease is idiopathic or atrial fibrillation caused by a disease as defined herein. The atrial fibrillation can be paroxysmal atrial fibrillation, persistent atrial fibrillation, long-standing persistent atrial fibrillation, atrial fibrillation with heart failure, atrial fibrillation with valvular heart disease, or atrial fibrillation with chronic kidney disease. In certain embodiments, the atrial fibrillation is selected from paroxysmal, persistent, or long-standing persistent atrial fibrillation.

[0237] In some embodiments, the cardiovascular disease includes cardiac arrhythmia.

[0238] Thus, in another aspect, the invention also provides a method of treatment in a subject, particularly a human. Pathologies treatable by the methods and compositions provided herein include, but are not limited to, pain and pain-related diseases, as well as cardiovascular diseases.

[0239] "Treatment" refers to alleviating a particular pathology, removing or reducing one or more symptoms of the pathology, retarding or eliminating the progression of the pathology, and delaying the recurrence of the pathology in a previously affected patient or subject.

[0240] As used herein, the terms "effective amount" and "therapeutically effective amount" are used interchangeably. The term "therapeutically effective amount" refers to an amount of a compound of formula (I-a), (I), (II), (III), (IV), or (V), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, that elicits a desired biological response in the body of a human. The amount varies depending on the compound, the disease and its severity, and the age and weight of the subject being treated.

[0241] The term "subject" refers to the human body.

[0242] In one aspect, the invention relates to a method of treating pain or a pain-related disease as defined herein in a human in need thereof, the method comprising administering to the human a compound of the invention or a pharmaceutical composition of the invention as described herein.

[0243] In one embodiment, a method for treating acute or chronic pain in a human in need thereof, comprising administering to the human a compound of the present invention or a pharmaceutical composition of the present invention as described herein, is provided.

[0244] In one embodiment, a method for treating pain caused by iatrogenic medical procedures or dental procedures, or preoperative or postoperative related pain in a human in need thereof, comprising administering to the human a compound of the present invention or a pharmaceutical composition of the present invention as described herein, is provided.

[0245] In one embodiment, a method for treating neuropathic pain, nociceptive pain, inflammatory pain, musculoskeletal pain, visceral pain, or idiopathic pain in a human in need thereof, comprising administering to the human a compound of the present invention or a pharmaceutical composition of the present invention as described herein, is provided.

[0246] In one embodiment, a method for treating neuropathic pain or chronic neuropathic pain selected from the group consisting of small fiber neuropathy, small fiber-mediated diabetic neuropathy, idiopathic small fiber neuropathy, painful diabetic neuropathy, and polyneuropathy in a human in need thereof, comprising administering to the human a compound of the present invention or a pharmaceutical composition of the present invention as described herein, is provided.

[0247] In one embodiment, a method for treating inflammatory pain selected from the group consisting of osteoarthritis, chronic osteoarthritis pain, and chronic inflammatory demyelinating polyneuropathy in a human in need thereof, comprising administering to the human a compound of the present invention or a pharmaceutical composition of the present invention as described herein, is provided.

[0248] In one embodiment, there is provided a method for treating pain or a pain-related disorder selected from the group consisting of neuropathic pain, post-operative pain in the outpatient setting, and osteoarthritis in a human in need thereof, the method comprising administering to the human a compound of the invention or a pharmaceutical composition of the invention as described herein. In some embodiments, the pain or pain-related disorder is neuropathic pain. In some embodiments, the pain or pain-related disorder is chronic neuropathic pain. In some embodiments, the pain or pain-related disorder is small fiber neuropathy. In some embodiments, the pain or pain-related disorder is post-operative pain in the outpatient setting. In some embodiments, the pain or pain-related disorder is osteoarthritis. In some embodiments, the pain or pain-related disorder is knee osteoarthritis and / or hip osteoarthritis.

[0249] In another aspect, the invention provides a compound of the invention and a pharmaceutical composition of the invention as described herein for use in the treatment of pain or a pain-related disorder as defined herein.

[0250] 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 or chronic pain.

[0251] In one embodiment, 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 related pain.

[0252] In one embodiment, 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.

[0253] In certain embodiments, provided are a compound of the present invention or a pharmaceutical composition of the present invention for use in the treatment of neuropathic pain or chronic neuropathic pain selected from the group consisting of small fiber neuropathy, small fiber-mediated diabetic neuropathy, idiopathic small fiber neuropathy, painful diabetic neuropathy, and polyneuropathy.

[0254] In certain embodiments, provided are a compound of the present invention or a pharmaceutical composition of the present invention for use in the treatment of inflammatory pain selected from the group consisting of osteoarthritis, chronic osteoarthritis pain, and chronic inflammatory demyelinating polyneuropathy.

[0255] In certain embodiments, provided are a compound of the present invention or a pharmaceutical composition of the present invention for use in the treatment of pain or pain-related disorders selected from the group consisting of neuropathic pain, postoperative pain, and osteoarthritis. In some embodiments, the pain or pain-related disorder is neuropathic pain. In some embodiments, the pain or pain-related disorder is chronic neuropathic pain. In some embodiments, the pain or pain-related disorder is small fiber neuropathy. In some embodiments, the pain or pain-related disorder is postoperative pain. In some embodiments, the pain or pain-related disorder is osteoarthritis. In some embodiments, the pain or pain-related disorder is knee osteoarthritis and / or hip osteoarthritis.

[0256] In another aspect, the present invention also provides the use of a compound of the present invention or a pharmaceutical composition of the present invention as described herein in the manufacture of a medicament for the treatment of pain and pain-related disorders as described herein.

[0257] In certain embodiments, provided is the use of a compound of the present invention or a pharmaceutical composition of the present invention in the manufacture of a medicament for the treatment of acute pain or chronic pain.

[0258] In certain embodiments, provided is the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of pain caused by trauma, pain caused by iatrogenic medical or dental procedures, or preoperative or postoperative related pain.

[0259] In certain embodiments, provided is 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.

[0260] In certain embodiments, provided is 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 or chronic neuropathic pain selected from the group consisting of small fiber neuropathy, small fiber-mediated diabetic neuropathy, idiopathic small fiber neuropathy, painful diabetic neuropathy, and polyneuropathy.

[0261] In certain embodiments, provided is 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 inflammatory pain selected from the group consisting of osteoarthritis, chronic osteoarthritis pain, and chronic inflammatory demyelinating polyneuropathy.

[0262] In certain embodiments, provided is the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of pain or pain-related disorders selected from the group consisting of neuropathic pain, outpatient postoperative pain, and osteoarthritis. In some embodiments, the pain or pain-related disorder is neuropathic pain. In some embodiments, the pain or pain-related disorder is chronic neuropathic pain. In some embodiments, the pain or pain-related disorder is small fiber neuropathy. In some embodiments, the pain or pain-related disorder is outpatient postoperative pain. In some embodiments, the pain or pain-related disorder is osteoarthritis. In some embodiments, the pain or pain-related disorder is knee osteoarthritis and / or hip osteoarthritis.

[0263] In one aspect, the present invention relates to a method for treating atrial fibrillation as defined herein in a human in need thereof, the method comprising administering to the human a compound of the present invention or a pharmaceutical composition of the present invention as described herein. In some embodiments, the atrial fibrillation is selected from the group consisting of paroxysmal atrial fibrillation, persistent atrial fibrillation, long-standing persistent atrial fibrillation, atrial fibrillation associated with heart failure, atrial fibrillation associated with valvular heart disease, and atrial fibrillation associated with chronic kidney disease.

[0264] 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. In some embodiments, the atrial fibrillation is selected from the group consisting of paroxysmal atrial fibrillation, persistent atrial fibrillation, long-standing persistent atrial fibrillation, atrial fibrillation associated with heart failure, atrial fibrillation associated with valvular heart disease, and atrial fibrillation associated with chronic kidney disease.

[0265] In another aspect, the present invention relates to the use of a compound of the present invention or a pharmaceutical composition of the present invention as described herein in the manufacture of a medicament for the treatment of atrial fibrillation. In some embodiments, the atrial fibrillation is selected from the group consisting of paroxysmal atrial fibrillation, persistent atrial fibrillation, long-standing persistent atrial fibrillation, atrial fibrillation associated with heart failure, atrial fibrillation associated with valvular heart disease, and atrial fibrillation associated with chronic kidney disease.

[0266] In another aspect, the present invention relates to a compound of the present invention or a pharmaceutical composition of the present invention as described herein for use in therapy.

[0267] Combination Therapy The compounds and pharmaceutical compositions of the present invention disclosed herein can be used in combination or co-administration with other therapeutic agents, particularly agents that can enhance the activity or kinetic profile of the compounds. The combination therapy according to the present invention comprises the administration of at least one compound of the present invention and the use of at least one other therapeutic method comprising the administration of one or more other therapeutic agents.

[0268] As used herein, the term "co - administration" and its derivatives refer to either simultaneous administration of the Nav1.8 inhibitory compounds of the present invention and an additional active ingredient as described herein or separate sequential administration by any method. The additional active ingredient includes any compound or therapeutic agent known or shown to have advantageous properties when administered to a human in need of treatment. Usually, when the administrations are not simultaneous, the compounds are administered in temporal proximity to each other. Further, these compounds can be administered in the same dosage form or separate dosage forms; for example, one compound can be administered orally and another intravenously.

[0269] Other therapeutic agents that can be used in combination with the compounds of the present invention include, but are not limited to, acetaminophen, acetylsalicylic acid, Nav1.7 inhibitors, Nav1.9 inhibitors, antidepressants (i.e., but not limited to, duloxetine or amitriptyline, etc.), antispasmodics (i.e., but not limited to, pregabalin and gabapentin, etc.), opioids (i.e., but not limited to, hydrocodone, codeine, morphine, oxycodone, oxymorphone, fentanyl, etc.), etc. The administration of the above - mentioned agents is determined by those skilled in the art respectively. In one aspect, Nav1.7 inhibitors or Nav1.9 inhibitors suitable for use in the present invention include, but are not limited to, Nav1.7 inhibitors or Nav1.9 inhibitors known in the chemical literature.

[0270] Each component of the combination used for therapeutic purposes (e.g., the 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, but is not limited to, by simultaneous administration, co - administration, or sequential administration, and / or by the same or different routes of administration or combinations of routes of administration. In certain embodiments, each of the same or different routes of administration or combinations of routes of administration is selected from oral administration, intravenous administration or parenteral administration.

Examples

[0271] The present invention will be described below with reference to examples. These examples are not intended to limit the scope of the present invention, but rather to provide guidance for those skilled in the art to prepare and use the compounds, compositions, and methods of the present invention. Embodiments of the present invention are described, but those skilled in the art will understand that various changes and modifications can be made without departing from the spirit and scope of the present invention.

[0272] Those skilled in the art will understand that salts of the title compound (e.g., hydrobromic acid, formic acid, hydrochloric acid, trifluoroacetic acid, or ammonium salts of the title compound) can be formed by purification methods (using acidic or basic modifiers) or compound work-up procedures (using acidic or basic conditions). The present invention is intended to encompass such salts.

[0273] The final compound was characterized by LCMS (conditions shown below) and NMR. 1 1H NMR or 19 19F NMR spectra were recorded using a Bruker Avance III 500 MHz spectrometer, a Bruker Avance 400 MHz spectrometer, and a Varian Mercury Plus - 300 MHz spectrometer. CDCl3 is deuterochloroform, DMSO-d6 is hexadeuterodimethyl sulfoxide, and CD3OD is tetradeuteroethanol. Chemical shifts are reported in parts per million (ppm) from the internal standard of tetramethylsilane (TMS) or the NMR solvent towards lower magnetic field. Abbreviations for NMR data are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = double doublet, dt = double triplet, app = apparent, br = broad. J represents the NMR coupling constant measured in Hertz.

[0274] Unless otherwise specified, all starting materials were obtained from commercial suppliers and used without further purification. Unless otherwise specified, all temperatures were expressed in °C (degrees Celsius). Unless otherwise specified, all reactions were carried out at room temperature under an inert atmosphere. All temperatures were indicated in degrees Celsius, all solvents were of the highest available purity, and all reactions were carried out under anhydrous conditions in an argon (Ar) or nitrogen (N2) atmosphere as required.

[0275] Apparatus 1 1H NMR spectra were recorded using a Bruker Avance III 400 MHz spectrometer or a Bruker Avance NEO NanoBay V4-3 400 MHz spectrometer. CDCl3 is deuterochloroform, DMSO-d6 is hexadeuterodimethyl sulfoxide, and CD3OD is tetradeuteroethanol. Chemical shifts are reported in parts per million (ppm) downfield from the internal standard tetramethylsilane (TMS) or from the NMR solvent. s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = double doublet, dt = double triplet, app = apparent, br = broad. J indicates the NMR coupling constant measured in Hertz.

[0276] Mass spectra were measured using an open-access LC-MS system with a Waters Acquity QDa mass detector. Compounds were analyzed using a reverse-phase column, such as Xbridge-C18, Sunfire-C188, Thermo Aquasil / Aquasil C18, Acquity HPLC C18, Thermo Hypersil Gold, eluting with an acetonitrile and water gradient containing a low percentage acid modifier such as 0.02% TFA.

[0277] HPLC method Method A: UPLC: Waters Acquity equipped with Acquity CSH, C18 (2.1 mm × 30 mm, 1.7 μm column), using a gradient of 1 - 100% MeCN / H2O / 0.1% TFA at a flow rate of 1.3 mL / min for 1.85 minutes. Mass determination was performed using an Agilent 6110 quadrupole MS in positive ESI mode. Method B: UPLC: Waters Acquity equipped with Acquity CSH, C18 (2.1 mm × 30 mm, 1.7 μm column), using a gradient of 1 - 100% MeCN / H2O / 25% aqueous NH4OH adjusted to pH 10 with 0.1% 10 mM NH4HCO3 in water at a flow rate of 1.3 mL / min for 1.85 minutes. Mass determination was performed using an Agilent 6110 quadrupole MS in positive ESI mode. Method C: HPLC: Agilent 1290 Infinity II equipped with CSH, C18, 2.1 × 30 mm, 1.7 μ column, using a gradient of 3 - 97% CH3CN / H2O / 0.1% HCO2H at a flow rate of 1.0 mL / min for 2.0 minutes. Mass determination was performed using an Agilent 6110 quadrupole MS in positive ESI mode. Method D: HPLC: Agilent 1290 Infinity II equipped with XBRIDGE, C8, 4.6 × 50 mm, 3.5 μm column, using a gradient of 5 - 95% CH3CN / H2O / 0.1% NH4HCO3 at a flow rate of 1.2 mL / min for 6.0 minutes. Mass determination was performed using an Agilent 6110 quadrupole MS in positive ESI mode. Method E: HPLC: Agilent 1290 Infinity II equipped with CSH, C18, 2.1 × 30 mm, 3.5 μm column, using a gradient of 0 - 100% CH3CN / H2O / 0.1% HCO2H at a flow rate of 1.0 mL / min for 4.0 minutes. Mass determination was performed using an Agilent 6110 quadrupole MS in positive ESI mode. Method F: HPLC: Agilent 1290 Infinity II equipped with a Sunfire, C18, 2.1×30 mm, 3.5 μm column, using a gradient of 0 - 100% CH3CN / H2O / 0.1% HCO2H in 4.0 minutes at a flow rate of 1.0 mL / min. Mass determination was performed using an Agilent 6110 quadrupole MS in positive ESI mode. Method G: UPLC: Waters Acquity equipped with an Acquity CSH, C18 (2.1 mm×30 mm, 1.7 μm column), using a gradient of 1 - 100% MeCN / H2O / 0.1% HCO2H in 1.85 minutes at a flow rate of 1.3 mL / min. Mass determination was performed using an Agilent 6110 quadrupole MS in positive ESI mode. Method H: HPLC: Shimadzu LC-20AB equipped with a Kinetex, C18 (2.1 mm×50 mm, 5 μm column), using a gradient of 30 - 90% MeCN / H2O / 0.1% TFA in 5.4 minutes at a flow rate of 0.5 mL / min. Method I: HPLC: Agilent 1260 Infinity II equipped with a Luna, C18, 2.0×50 mm, 5 μm column, using a gradient of 5 - 95% CH3CN(0.02% TFA) / H2O(0.04% TFA) in 4.5 minutes at a flow rate of 1.0 mL / min. Mass determination was performed using an Agilent 6110 single quadrupole MS in positive ESI mode.

[0278] Definitions and Abbreviations of Examples In the following description of the experiments, the following abbreviations may be used.

Table 1

[0279] Intermediate [Chem.]

[0280] Step A: 6-Methoxy-2-vinylpyridin-3-amine Int-1 [Chem.] In 1,4 - dioxane (160 mL) and saturated aqueous Na2CO3 (20.0 mL, 64.0 mmol), a solution of 2 - bromo - 6 - methoxypyridin - 3 - amine (13.0 g, 64.0 mmol) and 4,4,5,5 - tetramethyl - 2 - vinyl - 1,3,2 - dioxaborolane (10.9 mL, 64.0 mmol) was purged with N2 for 5 minutes. Pd(PPh3)4 (3.70 g, 3.20 mmol) was added under an N2 atmosphere, and the reaction mixture was heated at 80 °C for 16 hours. The reaction mixture was allowed to cool to ambient temperature, quenched with H2O (300 mL), and extracted with EtOAc (2 × 200 mL). The combined organic extracts were washed with H2O (500 mL), brine, dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The crude residue was dissolved in DCM, adsorbed onto silica gel in advance, and purified by silica gel flash column chromatography (330 g) eluting with 15 - 17% EtOAc - petroleum ether. The product fractions were combined and evaporated under reduced pressure to give 6 - methoxy - 2 - vinylpyridin - 3 - amine Int - 1 (5.50 g, 56% yield) as a brown oil. HPLC / MS 0.371 min (C), [M + H]’ 151.2. 1 H NMR (DMSO - d6, 400 MHz) δ 7.04 - 7.06 (d, 1H), 6.94 - 7.01 (m, 1H), 6.50 - 6.52 (d, 1H), 6.06 - 6.11 (dd, 1H), 5.21 - 5.24 (dd, 1H), 4.92 (s, 2H), 3.75 (s, 3H).

[0281]

Chem.

[0282] Step A: 2-Allyl-6-methoxypyridin-3-amine Int-1a

Chem.

[0283]

Chem.

[0284] Step A: tert-Butyl (2-bromo-6-methoxypyridin-3-yl)carbamate Int-1b-1

Chem.

[0285] Step B: tert-Butyl (2-(but-1-en-1-yl)-6-methoxypyridin-3-yl)carbamate Int-1b-2

Chem.

[0286] Step C: 2-(but-1-en-1-yl)-6-methoxypyridin-3-amine Int-1b

Chem.

[0287]

Chemical Structure

[0288] Step A: tert-Butyl (but-3-yn-1-yl)carbamate Int-1c-1

Chemical Structure

[0289] Step B: tert-Butyl (4-(6-methoxy-3-nitropyridin-2-yl)but-3-yn-1-yl)carbamate Int-1c-2

Chemical formula

[0290] Step C: tert-Butyl (4-(3-amino-6-methoxypyridin-2-yl)but-3-yn-1-yl)carbamate Int-1c

Chemical Structure

[0291]

Chem.

[0292] Step A: tert-Butyl (3-allylpyridin-4-yl)carbamate Int-1d-1

Chem.

[0293] Step B: 3-Allylpyridin-4-amine Int-1d

Chemical Structure

[0294]

Chem.

[0295] Step A: tert-Butyl (2-(6-methoxy-3-nitropyridin-2-yl)ethyl)carbamate Int-1e-1

Chem.

[0296] Step B: 2-(6-Methoxy-3-nitropyridin-2-yl)ethane-1-amine trifluoroacetate Int-1e

Chemical formula

[0297]

Chem.

[0298] Step A: tert-Butyl (2-formyl-6-methoxypyridin-3-yl)carbamate Int-1f

Chem.

[0299]

Chem.

[0300] Step A: (3-Amino-6-methoxypyridin-2-yl)methanol Int-1g-1

Chem.

[0301] Step B: 2-(2-(Hydroxymethyl)-6-methoxypyridin-3-yl)isoindoline-1,3-dione Int-1g-2

Chem.

[0302] Step C: 3-(1,3-Dioxoisoindolin-2-yl)-6-methoxypicolinaldehyde Int-1g

Chem.

[0303]

Chemical formula

[0304] Step A: tert-Butyl (2-(6-methoxy-3-nitropyridin-2-yl)ethyl)carbamate Int-1h-1

Chemical formula

[0305] Step B: 3-(6-Methoxy-3-nitropyridin-2-yl)propan-1-amine hydrochloride Int-1h

Chemical formula

[0306] Step A: 1-(6-Methoxy-3-nitropyridin-2-yl)propan-2-one Int-1i

Chemical formula

[0307]

Chemical formula

[0308] Project A: Diethyl 2-(6-methoxy-3-nitropyridin-2-yl)malonate Int-1j-1

Chemical formula

[0309] Project B: Ethyl 2-(6-methoxy-3-nitropyridin-2-yl)acetate Int-1j-2

Chemical Structure

[0310] Project C: Ethyl 2-(6-methoxy-3-nitropyridin-2-yl)-2-methylpropanoate Int-1j-3

Chem.

[0311] Project D: 2-(6-methoxy-3-nitropyridin-2-yl)-2-methylpropan-1-ol Int-1j-4

Chem.

[0312] Project E: 2-(6-methoxy-3-nitropyridin-2-yl)-2-methylpropanal Int-1j

Chem.

[0313]

Chem.

[0314] Project A: Methyl 2-bromo-5-(trifluoromethyl)benzoate Int-2

Chem.

[0315]

Chem.

[0316] Project A: Ethyl 2-bromo-4-(trifluoromethyl)benzoate Int-2a

Chem.

[0317] Project A: Methyl 2-chloro-5-(trifluoromethyl)nicotinate Int-2b

Chem.

[0318] Project A: Methyl 2-bromo-4-(trifluoromethyl)benzoate Int-2c

Chemistry

[0319] Methyl 2-bromo-4-(trifluoromethoxy)benzoate Int-2d

Chemistry

[0320] Project A: Methyl 2-bromo-5-fluoro-4-(trifluoromethyl)benzoate Int-2e

Chemistry

[0321] Project A: Methyl 6-bromo-2-fluoro-3-(trifluoromethyl)benzoate Int-2f

Chemical Structure

[0322] Project A: Methyl 6-amino-2-fluoro-3-(trifluoromethyl)benzoate Int-2g

Chemical Structure

[0323] Project A: Methyl 2-bromo-5-(2,2,2-trifluoroethoxy)benzoate Int-2h

Chem.

[0324] Project A: Methyl 2-amino-5-chloro-4-(trifluoromethyl)benzoate Int-2i

Chemical Structure

[0325] Project A: Methyl 2-amino-5-fluoro-4-(trifluoromethyl)benzoate Int-2j

Chemical Structure

[0326]

Chemical Structure

[0327] Project A: Methyl 2-(5-fluoro-2-nitrophenyl)acetate Int-3a-1

Chemical Structure

[0328] Project B: Methyl 2-(5-fluoro-2-nitrophenyl)penta-4-enoate Int-3a-2 [Chemical formula] To a solution of methyl 2-(5-fluoro-2-nitrophenyl)acetate (7.92 g, 37.2 mmol) in MeCN (170 mL) was added K2CO3 (43.1 g, 312 mmol), followed by 18-crown-6 (0.098 g, 0.372 mmol). Next, 3-iodoprop-1-ene (4.08 mL, 44.6 mmol) was added dropwise to this purple reaction mixture at room temperature, and the reaction mixture was stirred at room temperature for 22 h and then at 75 °C for 21 h. The reaction mixture was diluted with EtOAc, washed with H2O (2×), brine, dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The crude residue was dissolved in DCM, adsorbed onto a silica gel-packed precolumn, and purified by silica gel flash column chromatography (330 g) eluting with a gradient of 100% heptane to 50% EtOAc. The product fractions were combined and evaporated under reduced pressure to give methyl 2-(5-fluoro-2-nitrophenyl)penta-4-enoate Int-3a-2 (8.02 g, 83% yield) as a clear pale yellow oil. HPLC / MS 1.01 min (A), [M+H]+ 254.0. 1 H NMR (DMSO-d6, 400 MHz) δ 8.12 (dd, 1H, J=5.1, 9.0 Hz), 7.3 - 7.6 (m, 2H), 5.5 - 5.8 (m, 1H), 4.8 - 5.1 (m, 2H), 4.31 (dd, 1H, J=6.4, 8.8 Hz), 3.61 (s, 3H), 2.8 - 2.9 (m, 1H), 2.6 - 2.7 (m, 1H).

[0329] Project C: 2-(But-3-en-1-yl)-4-fluoronitrobenzene Int-3a-3 [Chemical formula] In 1,4-dioxane (350 mL), 1M NaOH (80 mL, 80 mmol) was added to a solution of methyl 2-(5-fluoro-2-nitrophenyl)penta-4-enoate (16.9 g, 66.7 mmol), and the reaction mixture was stirred at room temperature for 24 h. The solvent was evaporated under reduced pressure, the residue was dissolved in H2O, acidified with 6M HCl, extracted with EtOAc, the organic phase was washed with H2O, brine, dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to give a pale yellow solid. This solid was dissolved in DMF (200 mL), K2CO3 (46.1 g, 334 mmol) was added thereto, and the reaction mixture was stirred at 50 °C for 3 h. The reaction mixture was cooled, diluted with EtOAc, washed with H2O (3×), brine, dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to give 2-(but-3-en-1-yl)-4-fluoro-1-nitrobenzene Int-3a-3 (12.7 g, 88% yield) as a light brown oil. HPLC / MS 1.10 min (A). 1 H NMR (DMSO-d6, 400 MHz) δ 8.07 (dd, 1H, J=5.1, 9.0 Hz), 7.43 (dd, 1H, J=2.9, 9.8 Hz), 7.33 (ddd, 1H, J=2.9, 7.8, 8.8 Hz), 5.84 (dd, 1H, J=10.3, 17.1 Hz), 4.8 - 5.1 (m, 2H), 2.9 - 3.0 (m, 2H), 2.3 - 2.4 (m, 2H).

[0330] Project D: 2-(But-3-en-1-yl)-4-fluoroaniline Int-3a [Chemical formula] In EtOH (300 ml), zinc (63.8 g, 976 mmol) was added to a suspension of 2-(but-3-en-1-yl)-4-fluoro-1-nitrobenzene (12.7 g, 65.1 mmol). The suspension was cooled to 0 °C in a salt-ice bath, and acetic acid (48.4 ml, 846 mmol) was slowly added dropwise thereto at 0 °C over 1.5 h. The reaction mixture was filtered, and the filter cake was washed with EtOH. Ethanol was removed under reduced pressure. The solid was partitioned between EtOAc and 10% NaHCO3. The layers were separated, and the organic phase was washed with H2O and brine, dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to give a brown oil. This oil was dissolved in DCM, pre-absorbed on a silica gel-packed pre-column, and purified by silica gel flash column chromatography (120 g) eluting with a gradient of 10% EtOAc-hexane to 100% EtOAc. The product fractions were combined and evaporated under reduced pressure to give 2-(but-3-en-1-yl)-4-fluoroaniline Int-3a (8.47 g, 71% yield) as a brown oil. HPLC / MS 0.49 min (A), [M+H]+ 166.0. 1 H NMR (DMSO-d6, 400 MHz) δ 6.7 - 6.8 (m, 2H), 6.59 (dd, 1H, J=5.4, 8.8 Hz), 5.87 (tdd, 1H, J=6.6, 10.3, 17.1 Hz), 4.9 - 5.2 (m, 2H), 4.72 (s, 2H), 2.1 - 2.4 (m, 2H).

[0331]

Chem.

[0332] Project A: 2-Allyl-4-fluoroaniline Int-3b

Chem.

[0333]

Chem.

[0334] Project A: tert-Butyl (4-(2-amino-5-fluorophenyl)but-3-yn-1-yl)carbamate Int-3c

Chem.

[0335]

Chemical Structure

[0336] Project A: 1-Bromo-4-fluoro-2-(penta-4-en-1-yl)benzene Int-3d Under N2, at 0 °C, to a solution of 1-bromo-2-(bromomethyl)-4-fluorobenzene (25.0 g, 93.0 mmol) in toluene (250 mL), copper(I) iodide (1.78 g, 9.33 mmol) and 2,2'-bipyridine (1.46 g, 9.33 mmol) were added, followed by 0.5 M but-3-en-1-ylmagnesium bromide in THF solution (560 mL, 280 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated aqueous NH4Cl (250 mL) and extracted with EtOAc (2×100 mL). The combined organic extracts were washed with H2O (200 mL), brine, dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The crude residue was dissolved in DCM, adsorbed on silica gel, and purified by silica gel column chromatography (120 g) eluting with petroleum ether. The product fractions were combined and evaporated under reduced pressure to give 1-bromo-4-fluoro-2-(penta-4-en-1-yl)benzene Int-3d (9.0 g, 36% yield) as a clear liquid. GC / MS 3.48 min, [M+H] + 242.0。 1 1H NMR (DMSO-d6, 400 MHz) δ 7.59 - 7.62 (m, 1H), 7.22 - 7.25 (m, 1H), 7.01 - 7.06 (m, 1H), 5.79 - 5.89 (m, 1H), 4.97 - 5.07 (m, 2H), 2.66 - 2.70 (m, 2H), 2.06 - 2.12 (m, 2H), 1.61 - 1.68 (m, 2H).

[0337]

Chem.

[0338] Process A: 6-Methoxy-3-nitro-N-(prop-2-yn-1-yl)pyridin-2-amine Int-3e-1

Chem.

[0339] Process B: tert-Butyl (6-methoxy-3-nitropyridin-2-yl)(prop-2-yn-1-yl)carbamate Int-3e-2

Chemical Structure

[0340] Process C: tert-Butyl (3-(2-amino-5-fluorophenyl)prop-2-yn-1-yl)(6-methoxy-3-nitropyridin-2-yl)carbamate Int-3e

Chemical Structure

[0341] Process A: tert-Butyl (3-(2-amino-5-fluorophenyl)prop-2-yn-1-yl)carbamate Int-3f

Chem.

[0342]

Chem.

[0343] Process A: tert-Butyl (3-(2-amino-5-fluorophenyl)propyl)carbamate Int-3g

Chem.

[0344] Process A: tert-Butyl (3-(6-amino-2,3-difluorophenyl)prop-2-yn-1-yl)carbamate Int-3h [Chem.] In DMF (50 mL) purged with N2, to a solution of 3,4-difluoro-2-iodoaniline (2.50 g, 9.80 mmol), triphenylphosphine (0.514 g, 1.96 mmol), copper(I) iodide (0.373 g, 1.96 mmol), bis(triphenylphosphine)palladium(II) chloride (0.688 g, 0.980 mmol) and triethylamine (4.10 mL, 29.4 mmol) was added tert-butyl prop-2-yn-1-ylcarbamate (2.28 g, 14.7 mmol), and the reaction mixture was heated at 80 °C for 24 h. The reaction mixture was cooled to ambient temperature, diluted with EtOAc, washed with H2O, the layers were separated, the aqueous layer was extracted with EtOAc, the combined extracts were washed with brine, dried over MgSO4, filtered, and the solvent was evaporated under reduced pressure. The crude residue was dissolved in DCM, adsorbed onto a silica gel pre-column, and purified by silica gel flash column chromatography (220 g) eluting with a gradient of 100% heptane to 100% EtOAc. The product fractions were combined and evaporated under reduced pressure to give tert-butyl (3-(6-amino-2,3-difluorophenyl)prop-2-yn-1-yl)carbamate Int-3h (2.34 g, 82% yield) as a yellow solid. HPLC / MS 1.03 min (B), [M- t Bu] + 227.1. 11H NMR (CDCl3, 400 MHz) δ 6.94 (dt, J=10.27, 8.80 Hz, 1 H), 6.37 (ddd, J=9.05, 3.67, 1.96 Hz, 1 H), 4.22 (br s, 2 H), 1.49 (s, 9 H).

[0345] Process B: tert-Butyl (3-(6-amino-2,3-difluorophenyl)propyl)carbamate Int-3i

Chem.

[0346]

Chem.

[0347] Process A: 2-Amino-5-fluorobenzaldehyde Int-3j

Chem.

[0348]

Chemical Structure

[0349] Process A: tert-Butyl (3-(2-amino-4,5-difluorophenyl)prop-2-yn-1-yl)(6-methoxy-3-nitropyridin-2-yl)carbamate Int-3k Following the procedure outlined in Scheme 13, Step C, 4-fluoro-2-iodoaniline was replaced with 4,5-difluoro-2-iodoaniline (International Publication No. WO2011 / 006903), and tert-butyl (3-(2-amino-4,5-difluorophenyl)prop-2-yn-1-yl)(6-methoxy-3-nitropyridin-2-yl)carbamate Int-3k (3.11 g, 74% yield) was prepared as a pale orange foam. HPLC / MS 1.31 min (A), [M - t Bu] + 379.0。 11H NMR (DMSO-d6, 400 MHz) δ 8.3 - 8.5 (m, 1H), 7.0 - 7.2 (m, 1H), 6.8 - 7.0 (m, 1H), 6.5 - 6.7 (m, 1H), 5.44 (s, 2H), 4.93 (br s, 2H), 4.01 (s, 3H), 1.36 (br s, 12H).

[0350] Process A: tert-Butyl (3-(2-bromo-5-fluorophenyl)prop-2-yn-1-yl)carbamate Int-3l

Chem.

[0351] Process A: tert-Butyl (3-(6-amino-2,3-difluorophenyl)prop-2-yn-1-yl)(6-methoxy-3-nitropyridin-2-yl)carbamate Int-3m

Chem.

[0352] Process A: tert-Butyl (2-((2-bromo-5-fluorobenzyl)oxy)ethyl)carbamate Int-3n

Chemical Structure

[0353] Example

Chemical Structure

[0354] Examples 1 and 2 (E)-8-Fluoro-2-(trifluoromethyl)-13-hydroxy-10H,18H,5,17-methanodibenzo[b,k]pyrido[3,2-f][1,5]diazacyclododecine-14,18-dione Example 1 and 14-Fluoro-8-(trifluoromethyl)-17,18-dihydro-1H,6H-5,11-methanodibenzo[b,k]pyridino[3,2-f][1,5]diazacyclododecine-2,6(16H)-dione Example 2

Chemical Structure

[0355] Process A: 2-Fluoro-N-(6-methoxy-2-vinylpyridin-3-yl)-5-(trifluoromethyl)benzamide 1a [Chemical formula] To a solution of 2-fluoro-5-(trifluoromethyl)benzoic acid (7.00 g, 33.6 mmol) and 6-methoxy-2-vinylpyridin-3-amine Int-1 (5.56 g, 37.0 mmol) in DMF (32 mL) at room temperature, DIEA (17.6 mL, 101 mmol) and HATU (19.2 g, 50.5 mmol) were added, and the reaction mixture was stirred for 2 hours. The reaction mixture was diluted with ice-cold water (60 mL), the precipitate was filtered, and dried under high vacuum to obtain an off-white solid of 2-fluoro-N-(6-methoxy-2-vinylpyridin-3-yl)-5-(trifluoromethyl)benzamide 1a (8.2 g, 71% yield). HPLC / MS 1.20 min (C), [M+H] + 341.2. 1 H NMR (DMSO-d6, 400 MHz) δ 10.3 (s, 1H), 8.11 - 8.13 (m, 1H), 7.99 - 8.03 (m, 1H), 7.74 - 7.76 (d, 1H), 7.61 - 7.66 (t, 1H), 6.90 - 7.01 (m, 1H), 6.81 - 6.83 (d, 1H), 6.36 - 6.41 (dd, 1H), 5.49 - 5.52 (m, 1H), 3.91 (s, 3H).

[0356] Process B: 2-((2-Bromo-4-fluorophenyl)amino)-N-(6-methoxy-2-vinylpyridin-3-yl)-5-(trifluoromethyl)benzamide 1b [Chemical formula] To a solution of 2-fluoro-N-(6-methoxy-2-vinylpyridin-3-yl)-5-(trifluoromethyl)benzamide (8.20 g, 24.1 mmol) and 2-bromo-4-fluoroaniline (3.02 mL, 26.5 mmol) in DMF (50 mL) was added Cs2CO3 (15.7 g, 48.2 mmol), and the reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was cooled to ambient temperature, diluted with ice-cold water (100 mL), extracted with EtOAc (2 × 100 mL), the combined organic extracts were dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The crude residue was dissolved in DCM, absorbed onto silica gel, and purified by silica gel flash column chromatography (120 g) eluting with 5 - 6% EtOAc - petroleum ether. The product fractions were combined and evaporated under reduced pressure to give 2-((2-bromo-4-fluorophenyl)amino)-N-(6-methoxy-2-vinylpyridin-3-yl)-5-(trifluoromethyl)benzamide 1b (4.5 g, 35% yield) as an off-white solid. HPLC / MS 1.46 min (C), [M+H] + 509.6。 1 H NMR (DMSO-d6, 400 MHz) δ 10.4 (s, 1H), 10.0 (s, 1H), 8.32 (s, 1H), 7.67 - 7.73 (m, 3H), 7.55 - 7.58 (m, 1H), 7.28 - 7.34 (m, 1H), 7.07 - 7.09 (d, 1H), 6.77 - 6.96 (m, 2H), 6.36 - 6.41 (dd, 1H), 5.47 - 5.50 (m, 1H), 3.92 (s, 3H)。

[0357] Process C: 1-(2-Bromo-4-fluorophenyl)-3-(6-methoxy-2-vinylpyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one 1c

Chemical Structure

[0358] Process D: 1-(2-Allyl-4-fluorophenyl)-3-(6-methoxy-2-vinylpyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one 1d

Chem.

[0359] Process E: (E)-8-Fluoro-14-methoxy-2-(trifluoromethyl)-10H,18H,5,17-methanodibenzo[b,k]pyrido[3,2-f][1,5]diazacyclododecin-18-one 1e

Chemical Structure

[0360] Process F: (E)-8-Fluoro-2-(trifluoromethyl)-13-hydroxy-10H,18H,-5,17-methanodibenzo[b,k]pyrido[3,2-f][1,5]diazacyclododecin-14,18-dione Example 1

Chemical Structure

[0361] Process G: 14-Fluoro-2-methoxy-8-(trifluoromethyl)-17,18-dihydro-6H,16H-5,11-methanodibenzo[b,k]pyridino[3,2-f][1,5]diazacyclododecin-6-dione 2a

Chem.

[0362] Process H: 14-Fluoro-8-(trifluoromethyl)-17,18-dihydro-1H,6H-5,11-methanodibenzo[b,k]pyridino[3,2-f][1,5]diazacyclododecin-2,6(16H)-dione Example 2

Chem.

Chemical formula

[0363] Examples 3 and 4 8-Fluoro-2-(trifluoromethyl)-10,13-dihydro-19H-5,18-methanodibenzo[b,l]pyrido[3,2-f][1,5]diazacyclotridecin-15,19(14H)-dione Example 3 and 8-Fluoro-2-(trifluoromethyl)-10,11,12,13-tetrahydro-19H-5,18-methanodibenzo[b,l]pyridino[3,2-f][1,5]diazacyclotridecin-15,19(14H)-dione

Chem.

[0364] Process A: Methyl 2-((2-bromo-4-fluorophenyl)amino)-5-(trifluoromethyl)benzoate 3a

Chem.

[0365] Step B: 2-((2-Bromo-4-fluorophenyl)amino)-5-(trifluoromethyl)benzoic acid 3b

Chem.

[0366] Step C: 2-((2-Bromo-4-fluorophenyl)amino)-N-(2-bromo-6-methoxypyridin-3-yl)-5-(trifluoromethyl)benzamide 3c

Chemical Structure

[0367] Step D: 1-(2-Bromo-4-fluorophenyl)-3-(2-bromo-6-methoxypyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one 3d

Chemical Structure

[0368] Step E: 1-(2-Allyl-4-fluorophenyl)-3-(2-allyl-6-methoxypyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one 3e

Chem.

[0369] Step F: 8-Fluoro-15-methoxy-2-(trifluoromethyl)-10,13-dihydro-19H-5,18-methanodibenzo[b,l]pyrido[3,2-f][1,5]diazacyclotridecin-19-one 3f

Chemical Structure

[0370] Step G: 8-Fluoro-2-(trifluoromethyl)-10,13-dihydro-19H-5,18-methanodibenzo[b,l]pyrido[3,2-f][1,5]diazacyclotridecin-15,19(14H)-dione Example 3

Chem.

[0371] Step H: 8-Fluoro-15-methoxy-2-(trifluoromethyl)-10,11,12,13-tetrahydro-19H-5,18-methanodibenzo[b,l]pyrido[3,2-f][1,5]diazacyclotridecin-19-one 4a

Chemical Structure

[0372] Step I: 8-Fluoro-2-(trifluoromethyl)-10,11,12,13-tetrahydro-19H-5,18-methanodibenzo[b,l]pyridino[3,2-f][1,5]diazacyclotridecin-15,19(14H)-dione Example 4

Chemical Structure

[0373] [Chemical formula]

[0374] Examples 5 and 6 8-Fluoro-3-(trifluoromethyl)-10,13-dihydro-19H-5,18-methanodibenzo[b,l]pyrido[3,2 f][1,5]diazacyclotridecin-15,19(14H)-dione Example 5 and 8-Fluoro-3-(trifluoromethyl)-10,11,12,13-tetrahydro-19H-5,18-methanodibenzo[b,l]pyridino[3,2-f][1,5]diazacyclotridecin-15,19(14H)-dione Example 6 [Chemical formula]

[0375] Step A: Ethyl 2-((2-bromo-4-fluorophenyl)amino)-4-(trifluoromethyl)benzoate 5a [Chemical formula] According to the steps of Step A in Example 3, Int-2 was replaced with Int-2a, and ethyl 2-((2-bromo-4-fluorophenyl)amino)-4-(trifluoromethyl)benzoate 5a (2.5 g, yield 60%) was prepared as a yellow oil. HPLC / MS 3.15 min (F), [M+H] + 406.0。 1 H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.11 - 8.16 (m, 2H), 7.76 - 7.79 (d, 1H), 7.56 - 7.59 (m, 1H), 7.33 - 7.39 (m, 1H), 6.98 (s, 1H), 4.35 - 4.41 (q, 2H), 1.39 - 1.38 (t, 3H).

[0376] Process B: Ethyl 2-((2-allyl-4-fluorophenyl)amino)-4-(trifluoromethyl)benzoate 5b [Chemical formula] Under N2, to a solution of ethyl 2-((2-bromo-4-fluorophenyl)amino)-4-(trifluoromethyl)benzoate (2.50 g, 6.15 mmol) in DMF (30 mL), allyltributylstannane (2.29 mL, 7.39 mmol) and Pd(PPh3)4 (0.213 g, 0.185 mmol) were added, and the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was allowed to cool to ambient temperature, quenched with ice water (200 mL), extracted with EtOAc (2 × 100 mL), the combined organic extracts were washed with H2O (100 mL), brine, dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The crude residue was dissolved in DCM, adsorbed onto silica gel, and purified by silica gel flash column chromatography (100 g) eluting with 5% EtOAc - petroleum ether. The pure product fractions were combined, evaporated under reduced pressure, and the solid was lyophilized to give ethyl 2-((2-allyl-4-fluorophenyl)amino)-4-(trifluoromethyl)benzoate 5b (2.45 g, 85% yield) as a yellow oil with 65% purity. HPLC / MS 3.23 min (F), [M + H] + 368.0。

[0377] Process C: 2-((2-allyl-4-fluorophenyl)amino)-4-(trifluoromethyl)benzoic acid 5c

Chem.

[0378] Process D: 2-((2-allyl-4-fluorophenyl)amino)-N-(2-allyl-6-methoxypyridin-3-yl)-4-(trifluoromethyl)benzoic acid 5d

Chem.

[0379] Process E: 1-(2-allyl-4-fluorophenyl)-3-(2-allyl-6-methoxy-pyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one 5e

Chem.

[0380] Process F: 8-Fluoro-15-methoxy-3-(trifluoromethyl)-10,13-dihydro-19H-5,18-methanodibenzo[b,l]pyrido[3,2-f][1,5]diazacyclotridecin-19-one 5f

Chem.

[0381] Process G: 8-Fluoro-3-(trifluoromethyl)-10,13-dihydro-19H-5,18-methanodibenzo[b,l]pyrido[3,2 f][1,5]diazacyclotridecine-15,19(14H)-dione Example 5 and 8-Fluoro-1 1 -Iodo-3-(trifluoromethyl)-10,11,12,13-tetrahydro-19H-5,18-methanodibenzo[b,l]pyrido[3,2-f][1,5]diazacyclotridecine-15,19(14H)-dione or 8-Fluoro-1 2 -Iodo-3-(trifluoromethyl)-10,11,12,13-tetrahydro-19H-5,18-methanodibenzo[b,l]pyrido[3,2-f][1,5]diazacyclotridecine-15,19(14H)-dione 6a

Chem.

[0382] Process H: 8-Fluoro-3-(trifluoromethyl)-10,11,12,13-tetrahydro-19H-5,18-methanodibenzo[b,l]pyridino[3,2-f][1,5]diazacyclotridecine-15,19(14H)-dione Example 6

Chem.

[0383]

Chem.

[0384] Example 7 3 4 -Fluoro-2 6 -(Trifluoromethyl)-1 1 ,1 2 ,1 1 ,2 2 ,2 3 ,2 4 -Hexahydro-2(3,1)-quinazolina-1(5,6)-pyridina-3(1,2)-benzenacyclooctafane-1 2 ,2 4 -Dione

Chem.

[0385] Process A: Ethyl 2-((2-(buta-3-en-1-yl)-4-fluorophenyl)amino)-5-(trifluoromethyl)benzoate 7a

Chem.

[0386] Step B: 2-(But-3-en-1-yl)-4-fluorophenyl)amino)-5-(trifluoromethyl)benzoic acid 7b

Chemical formula

[0387] Step C: N-(2-Allyl-6-methoxypyridin-3-yl)-2-((2-(but-3-en-1-yl)-4-fluorophenyl)amino)-5-(trifluoromethyl)benzamide 7c

Chemical Structure

[0388] Step D: 3-(2-Allyl-6-methoxypyridin-3-yl)-1-(2-(but-3-en-1-yl)-4-fluorophenyl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one 7d

Chem.

[0389] Step E: 3 4 -Fluoro-1 6-Methoxy-2 6 -(Trifluoromethyl)-2 1 ,2 2 ,2 3 ,2 4 -Tetrahydro-2(3,1)-quinazolina-1(3,2)-pyridina-3(1,2)-benzenacyclooctafan-6-en-2 4 -One 7e

Chem.

[0390] Step F: 3 4 -Fluoro-1 6 -Methoxy-2 6 -(Trifluoromethyl)-2 1 ,2 2 ,2 3 ,2 4 -Tetrahydro-2(3,1)-quinazolina-1(3,2)-pyridina-3(1,2)-benzenacyclooctafan-2 4 -One 7f

Chem.

[0391] Step G: 3 4 -Fluoro-2 6 -(Trifluoromethyl)-1 1 ,1 2 ,1 1 ,2 2 ,2 3 ,2 4 -Hexahydro-2(3,1)-quinazolina-1(5,6)-pyridina-3(1,2)-benzenacyclooctafan-1 2 ,2 4 -Dione Example 7

Chem.

[0392] Example 8 3 4 -Fluoro-2 7 -(Trifluoromethyl)-1 1 ,1 2 ,2 1 ,2 2 ,2 3 ,2 4 -Hexahydro-2(3,1)-quinazolina-1(5,6)-pyridina-3(1,2)-benzenacyclooctafan-1 2 ,2 4 -Dione

Chem.

[0393] Step A: Ethyl 2-((2-(allyl-4-fluorophenyl)amino)-4-(trifluoromethyl)benzoate 8a

Chem.

[0394] Step B: 2-((2-Allyl-4-fluorophenyl)amino)-4-(trifluoromethyl)benzoic acid 8b

Chemical formula

[0395] Step C: 2-((2-Allyl-4-fluorophenyl)amino)-N-(2-but-3-en-1-yl)-6-methoxypyridin-3-yl)-4-(trifluoromethyl)benzamide 8c

Chem.

[0396] Step E: 1-(2-Allyl-4-fluorophenyl)-3-(2-(but-3-en-1-yl)-6-methoxypyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one 8d

Chem.

[0397] Step F: 3 4 -Fluoro-1 6 -Methoxy-2 7 -(Trifluoromethyl)-2 1 ,2 2 ,2 3 ,2 4 -Tetrahydro-2(3,1)-quinazolina-1(3,2)-pyridina-3(1,2)-benzenacyclooctafan-6-en-2 4 -one 8e

Chem.

[0398] Step G: 3 4 -fluoro-1 6 -methoxy-2 7 -(trifluoromethyl)-2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-2(3,1)-quinazolina-1(3,2)-pyridina-3(1,2)-benzannulenoctafan-2 4 -one 8f

Chemical Structure

[0399] Step H: 3 4 -fluoro-2 7 -(trifluoromethyl)-1 1 ,1 2 ,2 1 ,2 2 ,2 3 ,24 -hexahydro-2(3,1)-quinazolina-1(5,6)-pyridina-3(1,2)-benzannulenoctafan-1 2 ,2 4 -dione Example 8

Chem.

[0400] Example 9 3 4 -fluoro-1 6 -methoxy-2 7 -(trifluoromethyl)-2 1 ,2 2 ,2 3 ,2 4-tetrahydro-2(3,1)-pyrido[4,3-d]pyrimidine-1(3,2)-pyridina-3(1,2)-benzannulenoctafan-2 4 -one

Chem.

[0401] Step A: Ethyl 4-((2-allyl-4-fluorophenyl)amino)-6-(trifluoromethyl)nicotinate 9a

Chem.

[0402] Step B: 4-((2-allyl-4-fluorophenyl)amino)-6-(trifluoromethyl)nicotinic acid 9b

Chem.

[0403] Step C: 4-((2-allyl-4-fluorophenyl)amino)-N-(2-(but-3-en-1-yl)-6-methoxypyridin-3-yl)-6-(trifluoromethyl)nicotinamide 9c

Chem.

[0404] Step D: 1-(2-allyl-4-fluorophenyl)-3-(2-(but-3-en-1-yl)-6-methoxypyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydropyrido[4,3-d]pyrimidin-4(1H)-one 9d

Chem.

[0405] Step E: 3 4 -fluoro-1 6 -methoxy-2 7 -(trifluoromethyl)-2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-2(3,1)-pyrido[4,3-d]pyrimidine-1(3,2)-pyridina-3(1,2)-benzannulenofan-5-ene-2 4 -one 9e

Chem.

[0406] Step F: 3 4 -fluoro-1 6 -methoxy-2 7 -(trifluoromethyl)-2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-2(3,1)-pyrido[4,3-d]pyrimidine-1(3,2)-pyridina-3(1,2)-benzannulenoctafan-2 4 -one 9f [Chem.] According to the procedure ...

Claims

1. A compound of formula (I-a): 【Chemical 1】 [Wherein, Y is O or S; X １ is nitrogen or CR １ and X ２ is nitrogen or CR ２ and X ３ is nitrogen or CR ３ and X ４ is nitrogen or CR ４ and However, X １ , X ２ , X ３ , and X ４ Among them, two or less are nitrogen; Ring A is [Chemical 2] where [Chemical Formula 3] represents a covalent bond with the nitrogen atom of the bicyclic ring nucleus of formula (I-a); [Chemical Formula 4] represents a covalent bond with L of formula (I-a); R １ 、R ２ 、R ３ 、and R ４ each is, independently, hydrogen, halo, cyano, -NR ａ R ｂ 、-(C １ -C ６ )alkyl, -(C １ -C ６ )alkoxy, halo(C １ -C ６ )alkyl-, or halo(C １ -C ６ )alkoxy-; X ５ is N or CR ５ ; R ５ and R ５ａ each of which is, independently, hydrogen, halo, or -(C １ -C ６ )alkyl; R ６ 、 R ７ and R ８ each is, independently, hydrogen, halo, cyano, hydroxy, -(C １ -C ６ )alkyl, -(C １ -C ６ )alkoxy, halo(C １ -C ６ )alkyl-, or halo(C １ -C ６ )alkoxy-; R ａ and R ｂ each of which is, independently, hydrogen, -(C １ -C ６ )alkyl, or halo(C １ -C ６ )alkyl-; R １５ and R １６ each is, independently, hydrogen or deuterium; L is (C ３ -C ６ ) alkenylene, -NHCH ２ CH ２ NHCH ２ -, -NHCH ２ CH ２ OCH ２ -, a divalent linker of formula (L-ia), or a divalent linker of formula (L-iia): 【Chemical 5】 In the formula, X ８ and X ９ each of which is independently —CR ９ R １０ —, where R ９ and R １０ each of which is independently hydrogen or —(C １ —C ３ )alkyl; R ｄ is hydrogen or -(C １ -C ３ )alkyl; r is 1, 2, 3, or 4; s is 1, 2, 3, or 4; The sum of r and s is 2, 3, 4, or 5; 【Chemical Formula 6】 represents a covalent bond with ring A of formula (I-a); 【Chemical Formula 7】 represents a covalent bond with the phenyl ring of formula (I-a); 【Chemical Formula 8】 In the formula, X ６ is -NR ｃ - or -CH ２ - and; X ７ is -CR １１ R １２ -, -O- or -NH ２ -, where R １１ and R １２ each independently is hydrogen or -(C １ -C ３ )alkyl, provided that when X ７ is -NH ２ -, X ６ is -CH ２ -; Each X １０ is independently -CR １３ R １４ -, where R １３ and R １４ each of which is independently hydrogen or -(C １ -C ３ )alkyl; R ｃ is hydrogen or -(C １ -C ３ )alkyl; q is 1, 2, 3, or 4; 【Chemical Formula 9】 represents a covalent bond with ring A of formula (I-a); 【Chemical Formula 10】 represents a covalent bond with the phenyl ring of formula (I-a), is]] , or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

2. A compound of formula (II): 【Chemical Formula 11】 [Wherein, Y is O or S; R １ 、 R ２ 、 R ３ 、 and R ４ each of which is, independently, hydrogen, halo, cyano, -NR ａ R ｂ 、 -(C １ -C ６ )alkyl, -(C １ -C ６ )alkoxy, halo(C １ -C ６ )alkyl-, or halo(C １ -C ６ )alkoxy-; R ５ is hydrogen, halo, or -(C １ -C ６ )alkyl; R ６ 、 R ７ and R ８ each is, independently, hydrogen, halo, -(C １ -C ６ )alkyl, -(C １ -C ６ )alkoxy, halo(C １ -C ６ )alkyl-, or halo(C １ -C ６ )alkoxy-; R ａ and R ｂ each of which is, independently, hydrogen, -(C １ -C ６ )alkyl, or halo(C １ -C ６ )alkyl-; L is (C ３ -C ６ ) alkenylene, a divalent linker of formula (L-i), or a divalent linker of formula (L-ii): 【Chemical Formula 12】 In the formula, r is 1, 2, 3, or 4; s is 1, 2, 3, or 4; The sum of r and s is 2, 3, 4, or 5; 【Chemical 13】 represents a covalent bond with the pyridone ring of formula (II); 【Chemical Formula 14】 represents a covalent bond with the phenyl ring of formula (II); 【Chemical Formula 15】 In the formula, X ６ is -NR ｃ - or -CH ２ - and; X ７ is -CH ２ -, -O- or -NH ２ -, provided that X ７ is -NH ２ -, then X ６ is -CH ２ -; R ｃ is hydrogen or -(C １ -C ３ )alkyl; q is 1, 2, 3, or 4; 【Chemical 16】 represents a covalent bond with the pyridone ring of formula (II); 【Chemical 17】 represents a covalent bond with the phenyl ring of formula (II), is]] is the compound according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

3. A compound of formula (III): 【Chemical 18】 [Wherein, Y is O or S; R １ , R ２ and R ４ each is, independently, hydrogen, halo, cyano, -NR ａ R ｂ , -(C １ -C ６ )alkyl, -(C １ -C ６ )alkoxy, halo(C １ -C ６ )alkyl-, or halo(C １ -C ６ )alkoxy-; R ５ is hydrogen, halo, or -(C １ -C ６ )alkyl; R ６ 、 R ７ and R ８ each is, independently, hydrogen, halo, -(C １ -C ６ ), alkyl, -(C １ -C ６ ), alkoxy, halo(C １ -C ６ ), alkyl-, or halo(C １ -C ６ ), alkoxy-; R ａ and R ｂ each of which is, independently, hydrogen, -(C １ -C ６ )alkyl, or halo(C １ -C ６ )alkyl-; L is (C ３ -C ６ ) alkenylene, a divalent linker of formula (L-i), or a divalent linker of formula (L-ii): 【Chemical 19】 In the formula, r is 1, 2, 3, or 4; s is 1, 2, 3, or 4; The sum of r and s is 2, 3, 4, or 5; 【Chemical 20】 represents a covalent bond with the pyridone ring of formula (III); 【Chemical 21】 represents a covalent bond with the phenyl ring of formula (III); 【Chemical 22】 In the formula, X ６ is -NR ｃ - or -CH ２ - and; X ７ is -CH ２ -, -O- or -NH ２ -, provided that X ７ is -NH ２ -, then X ６ is -CH ２ -; R ｃ is hydrogen or -(C １ -C ３ )alkyl; q is 1, 2, 3, or 4; 【Chemical 23】 represents a covalent bond with the pyridone ring of formula (III); 【Chemical 24】 represents a covalent bond with the phenyl ring of formula (III), is]] is the compound according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

4. A compound of formula (IV): 【Chemical Formula 25】 [Wherein, Y is O or S; R １ 、 R ３ and R ４ Each of R ａ R ｂ 、 - (C １ -C ６ ) alkyl, -(C １ -C ６ ) alkoxy, halo(C １ -C ６ ) alkyl-, or halo(C １ -C ６ ) alkoxy-; R ５ is hydrogen, halo, or -(C １ -C ６ )alkyl; R ６ , R ７ and R ８ each of which is, independently, hydrogen, halo, -(C １ -C ６ )alkyl, -(C １ -C ６ )alkoxy, halo(C １ -C ６ )alkyl-, or halo(C １ -C ６ )alkoxy-; R ａ and R ｂ each of which is, independently, hydrogen, -(C １ -C ６ )alkyl, or halo(C １ -C ６ )alkyl-; L is (C ３ -C ６ ) alkenylene, a divalent linker of formula (L-i), or a divalent linker of formula (L-ii): 【Chemical 26】 In the formula, r is 1, 2, 3, or 4; s is 1, 2, 3, or 4; The sum of r and s is 2, 3, 4, or 5; 【Chemical 27】 represents a covalent bond with the pyridone ring of formula (IV); 【Chemical Formula 28】 represents a covalent bond with the phenyl ring of formula (IV); 【Chemical Formula 29】 In the formula, X ６ is -NR ｃ - or -CH ２ - and; X ７ is -CH ２ -, -O- or -NH ２ -, provided that X ７ is -NH ２ -, then X ６ is -CH ２ -; R ｃ is hydrogen or -(C １ -C ３ )alkyl; q is 1, 2, 3, or 4; 【Chemical 30】 represents a covalent bond with the pyridone ring of formula (IV); 【Chemical Formula 31】 represents a covalent bond with the phenyl ring of formula (IV), is] The compound according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

5. A compound of formula (V): 【Chemical 32】 [Wherein, Y is O or S; R ２ 、 R ３ 、 and R ４ each is, independently, hydrogen, halo, cyano, -NR ａ R ｂ 、 -(C １ -C ６ ), alkyl, -(C １ -C ６ ), alkoxy, halo(C １ -C ６ ), alkyl-, or halo(C １ -C ６ ), alkoxy-; R ５ is hydrogen, halo, or -(C １ -C ６ )alkyl; R ６ , R ７ and R ８ each is, independently, hydrogen, halo, -(C １ -C ６ ), alkyl, -(C １ -C ６ ), alkoxy, halo(C １ -C ６ ), alkyl-, or halo(C １ -C ６ ), alkoxy-; R ａ and R ｂ each of which is, independently, hydrogen, -(C １ -C ６ )alkyl, or halo(C １ -C ６ )alkyl-; L is (C ３ -C ６ ) alkenylene, a divalent linker of formula (L-i), or a divalent linker of formula (L-ii): 【Chemical 33】 Wherein, r is 1, 2, 3, or 4; s is 1, 2, 3, or 4; The sum of r and s is 2, 3, 4, or 5; 【Chemical 34】 represents a covalent bond with the pyridone ring of formula (V), 【Chemical 35】 represents a covalent bond with the phenyl ring of formula (V); 【Chemical Formula 36】 Wherein, X ６ is -NR ｃ - or -CH ２ - and; X ７ is -CH ２ -, -O- or -NH ２ -, provided that X ７ is -NH ２ -, then X ６ is -CH ２ -; R ｃ is hydrogen or -(C １ -C ３ )alkyl; q is 1, 2, 3, or 4; 【Chemical 37】 represents a covalent bond with the pyridone ring of formula (V), 【Chemical Formula 38】 represents a covalent bond with the phenyl ring of formula (V), is] The compound according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

6. The compound according to any one of claims 1 to 5, wherein Y is O, or a tautomer thereof or a pharmaceutically acceptable salt thereof.

7. L is ＊ -CH=CH-CH ２ - ＊＊ , ＊ -CH ２ -CH=CH-CH ２ - ＊＊ , ＊ -CH ２ CH ２ -CH=CH-CH ２ - ＊＊ and ＊ -CH ２ -CH=CH-CH ２ CH ２ CH ２ - ＊＊ selected from the group consisting of (C ３ -C ６ ), where " ＊ " represents a covalent bond with the ring A or pyridone ring of formula (Ia)-(V), and " ＊＊ " represents a covalent bond with the phenyl ring of formula (Ia)-(V), the compound according to any one of claims 1-6, or a tautomer thereof or a pharmaceutically acceptable salt thereof.

8. L is a divalent linker of formula (L-i): 【Chemical Formula 39】 [Wherein, r is 1, 2, 3, or 4; s is 1, 2, 3, or 4; The sum of r and s is 2, 3, 4, or 5; 【Chemical Formula 40】 represents a covalent bond with ring A or the pyridone ring of formula (Ia) to (V), 【Chemical Formula 41】 represents a covalent bond with the phenyl ring of formula (Ia) to (V)] The compound according to any one of claims 1 to 6, or a tautomer thereof or a pharmaceutically acceptable salt thereof.

9. L is 【Chemical 42】 a divalent linker of formula (L-i) selected from the group consisting of Here, 【Chemical 43】 represents a covalent bond with ring A or the pyridone group of formula (Ia) to (V), 【Chemical 44】 The compound according to claim 8, or a tautomer thereof or a pharmaceutically acceptable salt thereof, which represents a covalent bond with the phenyl ring of formula (Ia) to (V).

10. L is a divalent linker of formula (L-ii): 【Chemical 45】 [Wherein, X ６ is —NR ｃ — or —CH ２ — and; X ７ is -CH ２ -, -O- or -NH ２ -, provided that X ７ is -NH ２ -, then X ６ is -CH ２ -; R ｃ is hydrogen or -(C １ -C ３ )alkyl; q is 1, 2, 3, or 4; 【Chemical 46】 represents a covalent bond with ring A or the pyridone ring of formula (Ia) to (V), 【Chemical 47】 represents a covalent bond with the phenyl ring of formula (Ia) to (V)] The compound according to any one of claims 1 to 6, or a tautomer thereof or a pharmaceutically acceptable salt thereof.

11. X ６ is -NR ｃ -, and X ７ is CH ２ The compound according to claim 10, or a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein

12. L is 【Chemical Formula 48】 -CH ２ CH ２ CH ２ -, -CH ２ CH ２ CH ２ CH ２ -, -CH ２ CH ２ CH ２ CH ２ CH ２ - and -CH ２ CH ２ CH ２ CH ２ CH ２ CH ２ a divalent linker of formula (L-ii) selected from the group consisting of, wherein, 【Chemical 49】 represents a covalent bond with ring A or the pyridone ring of formula (Ia) to (V), 【Chemical Formula 50】 The compound according to claim 10, or a tautomer thereof or a pharmaceutically acceptable salt thereof, which represents a covalent bond with the phenyl ring of formula (Ia) to (V).

13. L is 【Chemical 51】 a divalent linker of formula (L-ii) selected from the group consisting of, where 【Chemical 52】 represents a covalent bond with ring A or the pyridone ring of formulas (Ia) to (V), 【Chemical 53】 The compound according to any one of claims 10 to 12, or a tautomer thereof or a pharmaceutically acceptable salt thereof, which represents a covalent bond with the phenyl ring of formulas (Ia) to (V).

14. L is 【Chemical 54】 a divalent linker selected from the group consisting of, where 【Chemical Formula 55】 represents a covalent bond with ring A or the pyridone ring of formulas (Ia) to (V), 【Chemical 56】 The compound according to any one of claims 1 to 6, or a tautomer thereof or a pharmaceutically acceptable salt thereof, which represents a covalent bond with the phenyl ring of formulas (Ia) to (V).

15. The following: 【Chemical 57】 【Chem.】 【Chem.】 [Chemical] 【Chem.】 [Chemical] 【Chem.】 【Chem.】 A compound selected from the group consisting of, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

16. The following: 【Chemical 58】 A compound selected from the group consisting of, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising the compound according to any one of claims 1 to 16, or a tautomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

18. A method for treating pain or pain-related diseases in a human in need thereof, comprising administering to the human the compound according to any one of claims 1 to 16, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 17.

19. A method for treating atrial fibrillation in a human in need thereof, comprising administering to the human the compound according to any one of claims 1 to 16, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 17.

20. The compound according to any one of claims 1 to 16, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 17 for use in therapy.

21. The compound according to any one of claims 1 to 16, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 17 for use in the treatment of pain or pain-related diseases.

22. The compound according to any one of claims 1 to 16, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 17 for use in the treatment of atrial fibrillation.

23. Use of a compound according to any one of claims 1 to 16, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17, in the manufacture of a medicament for the treatment of pain or a pain-related disorder.

24. Use of a compound according to any one of claims 1 to 16, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17, in the manufacture of a medicament for the treatment of atrial fibrillation.

25. The method according to claim 18, the compound for use according to claim 21, or the use according to claim 23, wherein the pain or pain-related disorder is neuropathic pain, postoperative pain in the outpatient setting, or osteoarthritis.

Images