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

Abstract

The present invention describes small molecule inhibitors of Nav1.8 voltage gated sodium ion channels, including compounds of formulae (I), (II), (III), (IV) and (V). Also disclosed are pharmaceutical compositions containing compounds of formulae (I), (II), (III), (IV), and (V), and the use of the compounds and pharmaceutical compositions for inhibiting Nav1.8 voltage gated sodium channels and treating Nav1.8 mediated diseases, such as pain and pain-related diseases, and cardiovascular diseases, such as atrial fibrillation.

Description

Technical Field

[0001] The present invention relates to Na v 1.8 Inhibitor compounds or pharmaceutically acceptable salts or tautomeric forms thereof, corresponding pharmaceutical compositions or formulations, methods or processes for preparing the compounds, methods, compounds, uses and / or combination therapies for treating pain and pain-related diseases and cardiovascular diseases. Background Art

[0002] Pain is a protective mechanism for animals to avoid potential tissue damage, however, there are many disease indications where pain exceeds its usefulness and becomes an ineffective burden. Indications where pain exceeds its usefulness can be broadly categorized as those where nerve damage or injury is the cause (neuropathic pain), those where inflammatory responses or metabolic disorders sensitize the pain response (inflammatory pain), and those where injury or surgery results in a short-term elevation of the pain response (postoperative / spontaneous pain).

[0003] Voltage-gated sodium channels form the basis of electrical signal transduction in all excitable tissues by setting the threshold and potential for action potential rise. There are nine different subtypes of voltage-gated sodium channels. v 1.1、Na v 1.7, Na v 1.8 and Na v Those at 1.9 are expressed primarily on peripheral nerves, where they control neuronal excitability. v 1.5 is the major sodium channel isoform expressed in cardiac myocytes. v 1.4 is expressed and functions in skeletal muscle, while Na v 1.1、Na v 1.2 Na v 1.3 and Na v 1.6 is widely expressed in the central nervous system (CNS) and to some extent in the peripheral nervous system. The primary role of these nine voltage-gated sodium channels is similar, as they control the influx of sodium into cells, but their biophysical properties differ, which greatly influence the physiological characteristics of their corresponding cell types (Catterall, 2012).

[0004] Currently, non-selective sodium channel inhibitors are used clinically as antiarrhythmic and antiepileptic therapies, including lidocaine, carbamazepine, amitriptyline, and mexiletine. However, because these agents exhibit a lack of selectivity between different sodium channel subtypes, their therapeutic utility is greatly reduced due to adverse side effects mediated primarily by activity in the CNS and heart. This has stimulated efforts to develop novel drugs that are selective for specific sodium channel subtypes to avoid side effects in the CNS and cardiovascular system.

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

[0006] Na v Support for 1.8 as a therapeutic target for pain indications comes from several sources. v 1.8 has been shown to conduct the majority of the current during the rise of the action potential in DRG neurons (Blair & Bean, 2002) and is also crucial for the repetitive firing ability of these neurons due to its refiring rate (Blair and Bean, 2003). v Increased expression and function of Nav1.8 is a response to painful stimuli such as inflammatory mediators (England 1996 & Gold 1996), nerve damage (Roza 2003 & Ruangsri 2011), and painful neuromas (Black 2008 & Coward 2000). Knockout of the gene encoding Nav1.8 in mice resulted in a reduced pain phenotype, particularly inflammatory challenges (Akopian 1999). v Knockdown of the mRNA for Na1.8 also resulted in a reduction in pain phenotypes in rodent models, particularly neuropathic models (Lai 2002). Pharmacological intervention via selective small molecule inhibitors has demonstrated efficacy in rodent models of inflammatory pain and neuropathic pain (Jarvis 2007 & Payne 2015). vSupportive genetic evidence for 1.8 also exists in patients with chronic neuropathic pain, where multiple gain-of-function mutations have been reported to be causative of paroxysmal painful neuropathy and small fiber neuropathy (Faber 2012, Han 2014 & Eijkenboom 2018). SUMMARY OF THE INVENTION

[0008] Therefore, it is necessary to develop new compounds, especially Na v 1.8 inhibitor compounds for treating pain and pain-related diseases and cardiovascular diseases. The present invention provides a compound having Na v 1.8 This need is met by compounds that inhibit the activity of pain and pain-related diseases and cardiovascular diseases.

[0009] In one aspect, provided are compounds of formula (Ia):

[0010] or a tautomer thereof, or a pharmaceutically acceptable salt thereof,

[0011] in:

[0012] Y is O or S;

[0013] X 1 Nitrogen or CR 1 ,

[0014] X 2 Nitrogen or CR 2 ,

[0015] X 3 Nitrogen or CR 3 ,and

[0016] X 4 Nitrogen or CR 4 ,

[0017] The premise is X 1 、X 2 、X 3 and X 4 At most two of them are nitrogen;

[0018] Ring A is:

[0019] in represents a covalent bond to the nitrogen atom of the bicyclic nucleus of formula (I), and represents a covalent bond to L of formula (I);

[0020] R 1 、R 2 、R 3 and R 4are independently hydrogen, halogen, cyano, -NR a R b , -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-;

[0021] X 5 N or CR 5 ;

[0022] R 5 and R 5a are each independently hydrogen, halogen, or -(C1-C6)alkyl;

[0023] R 6 、R 7 and R 8 are each independently hydrogen, halogen, cyano, hydroxy, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-;

[0024] R a and R b are each independently hydrogen, -(C1-C6)alkyl, or halo(C1-C6)alkyl-;

[0025] R 15 and R 16 each independently hydrogen or deuterium;

[0026] and

[0027] L is (C3-C6) alkenylene, -NHCH2CH2NHCH2-, -NHCH2CH2OCH2, a divalent linking group of formula (L-ia), or a divalent linking group of formula (L-iia):

[0028]

[0029] in:

[0030] X 8 and X 9 Each independently is -CR 9 R 10 -, where R 9 and R 10 are each independently hydrogen or -(C1-C3)alkyl;

[0031] R d is hydrogen or -(C1-C3)alkyl;

[0032] r is 1, 2, 3, or 4;

[0033] s is 1, 2, 3, or 4;

[0034] The sum of r and s is 2, 3, 4, or 5; and

[0035] represents a covalent bond to Ring A in Formula (Ia), and represents a covalent bond to the benzene ring in formula (Ia);

[0036]

[0037] in:

[0038] X 6 -NR c - or -CH2-;

[0039] X 7 -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 When it is -NH2-, X 6 is -CH2-;

[0040] Each X 10 Independently -CR 13 R 14 -, where R 13 and R 14 are each independently hydrogen or -(C1-C3)alkyl;

[0041] R c is hydrogen or -(C1-C3)alkyl;

[0042] q is 1, 2, 3, or 4;

[0043] and

[0044] represents a covalent bond to Ring A in Formula (Ia), and represents a covalent bond to the benzene ring in formula (Ia).

[0045] In another aspect, a pharmaceutical composition is provided, comprising a compound of the present invention or a tautomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0046] In another aspect, provided is a method of treating pain or a pain-related disease 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 a pharmaceutical composition of the present invention.

[0047] In another aspect, provided is a method of 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 a pharmaceutical composition of the present invention.

[0048] In another aspect, there is provided a compound of the invention or a tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the invention, for use in therapy.

[0049] In another aspect, provided is a compound of the present invention or a tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention for use in treating pain or pain-related diseases.

[0050] In another aspect, provided is a compound of the present invention or a tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention for use in treating atrial fibrillation.

[0051] In another aspect, provided is use of the compound of the present invention or its tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present invention in the preparation of a medicament for treating pain or pain-related diseases.

[0052] In another aspect, provided is use of the compound of the present invention, its tautomer, or its pharmaceutically acceptable salt, or the pharmaceutical composition of the present invention in preparing a medicament for treating atrial fibrillation. Detailed Description of the Invention

[0054] Various publications, articles, and patents are cited or described in the background and throughout the specification. The discussion of documents, acts, materials, devices, articles, and the like has been included in this specification for the purpose of providing context for the disclosure. Such discussion does not constitute an admission that any or all of these matters constitute part of the prior art relevant to the present disclosure.

[0055] 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 the invention belongs. Otherwise, certain terms used herein have the meanings defined in the specification.

[0056] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0057] The definitions of various groups and substituents of any formula disclosed herein, or tautomers or pharmaceutically acceptable salts thereof, provided throughout the specification are intended to specifically describe individually each compound species, as well as groups of one or more compound species, disclosed herein.

[0058] The term "alkyl" refers to a straight or branched chain saturated hydrocarbon group having a 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 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. In some embodiments, "Me" refers to methyl.

[0059] 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 encompass divalent straight or branched chain hydrocarbon groups in which the point of attachment is through the alkyl moiety.

[0060] 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 portion of a linear or branched carbon group having from 1 to 6 carbon atoms. 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.

[0061] The term "alkenyl" refers to a straight or branched hydrocarbon group containing the specified number of carbon atoms and at least one double bond. For example, "(C2-C6)alkenyl" contains 2 to 6 carbon atoms. Exemplary groups include, but are not limited to, ethenyl and propenyl.

[0062] The term "alkylene" refers to a divalent group derived from a straight-chain saturated hydrocarbon radical having a specified number of carbon atoms. For example, the term "(C3-C6)alkylene" refers to an alkylene radical having 3 to 6 carbon atoms, and the term "(C4-C5)alkylene" refers to an alkylene radical having 4 to 5 carbon atoms. Exemplary alkylene radicals include, but are not limited to, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, and -CH2CH2CH2CH2CH2CH2CH2-.

[0063] The term "alkenylene" refers to a divalent group having a specified number of carbon atoms and derived from a straight-chain unsaturated hydrocarbon group containing at least one carbon-carbon double bond. The carbon-carbon double bond of the alkylene group can be in a cis configuration or a trans configuration, or a mixture of cis and trans configurations. In certain instances of the present disclosure, an alkenylene group in a mixture of cis and trans configurations can be represented by 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-.

[0064] The term "alkoxy" refers to an -O-alkyl group, i.e., an alkyl group connected through an oxygen linker atom, wherein "alkyl" is as defined above. For example, the term "(C1-C6)alkoxy" refers to a straight or branched carbon group having 1 to 6 carbon atoms connected through an oxygen linker atom. Exemplary "(C1-C6)alkoxy" groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, and tert-butoxy.

[0065] The term "halo(C1-C6)alkoxy" refers to a straight or branched hydrocarbon radical having at least 1 and up to 6 carbon atoms, wherein one or more halogen atoms, which may be the same or different, are attached to the one or more carbon atoms, the radical being attached through an oxygen linking atom. Exemplary groups include, but are not limited to, -OCHF2 (difluoromethoxy), -OCF3 (trifluoromethoxy), and OCH(CF3)2 (hexafluoroisopropoxy).

[0066] The terms "halogen" and "halo" represent chloro (-Cl), fluoro (-F), bromo (-Br), or iodo (-I) substituents.

[0067] The term "cyano" refers to the group -CN.

[0068] The term "independently selected" means that when multiple substituents are selected from a plurality of possible substituents, the substituents may be the same or different. Thus, each substituent is individually selected from the entire group of possible substituents.

[0069] As used herein, the term "optionally" means that the subsequently described event may or may not occur, and includes both events that occur and events that do not occur.

[0070] The term "optionally substituted" means that the group can be unsubstituted or substituted with one or more defined substituents. The term "substituted" refers to the replacement of a hydrogen atom attached to a member atom in the group with one of the defined substituents. When a group can be selected from a plurality of alternative groups, the selected groups can be the same or different.

[0071] Compound

[0072] In one aspect, the present invention relates to compounds of formula (Ia):

[0073] or a tautomer thereof, or a pharmaceutically acceptable salt thereof,

[0074] in:

[0075] Y is O or S;

[0076] X 1 Nitrogen or CR 1 ,

[0077] X 2 Nitrogen or CR 2 ,

[0078] X 3 Nitrogen or CR 3 ,and

[0079] X 4 Nitrogen or CR 4 ,

[0080] The premise is X 1 、X 2 、X 3 and X 4 At most two of them are nitrogen;

[0081] Ring A is:

[0082] in represents a covalent bond to the nitrogen atom of the bicyclic core of formula (Ia), and represents a covalent bond to L of formula (Ia);

[0083] R 1 、R 2 、R 3 and R 4 are independently hydrogen, halogen, cyano, -NR a R b , -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-;

[0084] X 5 N or CR 5 ;

[0085] R 5 and R 5a are each independently hydrogen, halogen, or -(C1-C6)alkyl;

[0086] R 6 、R 7 and R 8are each independently hydrogen, halogen, cyano, hydroxy, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-;

[0087] R a and R b are each independently hydrogen, -(C1-C6)alkyl, or halo(C1-C6)alkyl-;

[0088] R 15 and R 16 each independently hydrogen or deuterium;

[0089] and

[0090] L is (C3-C6) alkenylene, -NHCH2CH2NHCH2-, -NHCH2CH2OCH2, a divalent linking group of formula (L-ia), or a divalent linking group of formula (L-iia):

[0091]

[0092] in:

[0093] X 8 and X 9 Each independently is -CR 9 R 10 -, where R 9 and R 10 are each independently hydrogen or -(C1-C3)alkyl;

[0094] R d is hydrogen or -(C1-C3)alkyl;

[0095] r is 1, 2, 3, or 4;

[0096] s is 1, 2, 3, or 4;

[0097] The sum of r and s is 2, 3, 4, or 5; and

[0098] represents a covalent bond to Ring A in Formula (Ia), and represents a covalent bond to the benzene ring in formula (Ia);

[0099]

[0100] in:

[0101] X 6 -NR c - or -CH2-;

[0102] X 7 -CR 11R 12 -, -O- or -NH2-, where R 11 and R 12 are each independently hydrogen or -(C1-C3)alkyl, provided that when X 7 When it is -NH2-, X 6 is -CH2-;

[0103] Each X 10 Independently -CR 13 R 14 -R 13 and R 14 are each independently hydrogen or -(C1-C3)alkyl;

[0104] R c is hydrogen or -(C1-C3)alkyl;

[0105] q is 1, 2, 3, or 4;

[0106] and

[0107] represents a covalent bond to Ring A in Formula (Ia), and represents a covalent bond to the benzene ring in formula (Ia).

[0108] In another aspect, the present invention relates to compounds of formula (I):

[0109] or a tautomer thereof, or a pharmaceutically acceptable salt thereof,

[0110] in:

[0111] Y is O or S;

[0112] X 1 Nitrogen or CR 1 ,

[0113] X 2 Nitrogen or CR 2 ,

[0114] X 3 Nitrogen or CR 3 ,and

[0115] X 4 Nitrogen or CR 4 ,

[0116] The premise is X 1 、X 2 、X 3 and X 4 At most two of them are nitrogen;

[0117] Ring A is:

[0118] in represents a covalent bond to the nitrogen atom of the bicyclic nucleus of formula (I), and represents a covalent bond to L of formula (I);

[0119] R 1 、R 2 、R 3 and R 4 are independently hydrogen, halogen, cyano, -NR a R b , -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-;

[0120] X 5 N or CR 5 ;

[0121] R 5 and R 5a are each independently hydrogen, halogen, or -(C1-C6)alkyl;

[0122] R 6 、R 7 and R 8 are each independently hydrogen, halogen, cyano, hydroxy, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-;

[0123] R a and R b are each independently hydrogen, -(C1-C6)alkyl, or halo(C1-C6)alkyl-;

[0124] and

[0125] L is (C3-C6) alkenylene, -NHCH2CH2NHCH2-, -NHCH2CH2OCH2, a divalent linking group of formula (L-ia), or a divalent linking group of formula (L-iia):

[0126]

[0127] in:

[0128] X 8 and X 9 Each independently is -CR 9 R 10 -, where R 9 and R 10 are each independently hydrogen or -(C1-C3)alkyl;

[0129] Rd is hydrogen or -(C1-C3)alkyl;

[0130] r is 1, 2, 3, or 4;

[0131] s is 1, 2, 3, or 4;

[0132] The sum of r and s is 2, 3, 4, or 5; and

[0133] represents a covalent bond to Ring A of formula (I), and represents a covalent bond to the benzene ring of formula (I);

[0134]

[0135] in:

[0136] X 6 -NR c - or -CH2-;

[0137] X 7 -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 When it is -NH2-, X 6 is -CH2-;

[0138] Each X 10 Independently -CR 13 R 14 -R 13 and R 14 are each independently hydrogen or -(C1-C3)alkyl;

[0139] R c is hydrogen or -(C1-C3)alkyl;

[0140] q is 1, 2, 3, or 4;

[0141] and

[0142] represents a covalent bond to Ring A of formula (I), and represents a covalent bond to the benzene ring of formula (I).

[0143] In another aspect, the present invention relates to compounds of formula (I):

[0144] or a tautomer thereof, or a pharmaceutically acceptable salt thereof,

[0145] in:

[0146] Y is O or S;

[0147] X 1 Nitrogen or CR 1 ,

[0148] X 2 Nitrogen or CR 2 ,

[0149] X 3 Nitrogen or CR 3 ,and

[0150] X 4 Nitrogen or CR 4 ,

[0151] The premise is X 1 、X 2 、X 3 and X 4 At most two of them are nitrogen;

[0152] Ring A is:

[0153] in represents a covalent bond to the nitrogen atom of the bicyclic nucleus of formula (I), and represents a covalent bond to L of formula (I);

[0154] R 1 、R 2 、R 3 and R 4 are independently hydrogen, halogen, cyano, -NR a R b , -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-;

[0155] X 5 N or CR 5 ;

[0156] R 5 and R 5a are each independently hydrogen, halogen, or -(C1-C6)alkyl;

[0157] R 6 、R 7 and R 8 are each independently hydrogen, halogen, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-;

[0158] R a and R bare each independently hydrogen, -(C1-C6)alkyl, or halo(C1-C6)alkyl-; and

[0159] L is a (C3-C6) alkenylene group, a divalent linking group of formula (Li), or a divalent linking group of formula (L-ii):

[0160]

[0161] in:

[0162] r is 1, 2, 3, or 4;

[0163] s is 1, 2, 3, or 4;

[0164] The sum of r and s is 2, 3, 4, or 5; and

[0165] represents a covalent bond to Ring A of formula (I), and represents a covalent bond to the benzene ring of formula (I);

[0166]

[0167] in:

[0168] X 6 -NR c - or -CH2-;

[0169] X 7 is -CH2-, -O- or -NH2-, provided that when X 7 When it is -NH2-, X 6 is -CH2-;

[0170] R c is hydrogen or -(C1-C3)alkyl;

[0171] q is 1, 2, 3, or 4; and

[0172] represents a covalent bond to Ring A of formula (I), and represents a covalent bond to the benzene ring of formula (I).

[0173] In one embodiment of the compound of Formula (Ia) or Formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, Y is O. In another embodiment, Y is S.

[0174] In one embodiment of the compound of Formula (Ia) or Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring A is where R 5 is hydrogen, halogen, or -(C1-C6)alkyl; and represents a covalent bond to the nitrogen atom of the bicyclic nucleus of formula (Ia) or formula (I), and represents a covalent bond to L of formula (Ia) or formula (I). In another embodiment, ring A is where R 5 is hydrogen, -F, or -CH3; and represents a covalent bond to the nitrogen atom of the bicyclic nucleus of formula (Ia) or formula (I), and represents a covalent bond to L of formula (Ia) or formula (I). In another embodiment, ring A is in represents a covalent bond to the nitrogen atom of the bicyclic nucleus of formula (Ia) or formula (I), and represents a covalent bond to L of formula (Ia) or formula (I).

[0175] In one embodiment of the compound of Formula (Ia) or Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Ring A is where X 5 N or CR 5 ; R 5 and R 5a are each independently hydrogen, halogen, or -(C1-C6)alkyl; and represents a covalent bond to the nitrogen atom of the bicyclic nucleus of formula (Ia) or formula (I), and represents a covalent bond to L of formula (Ia) or formula (I). In another embodiment, ring A is wherein R5 is hydrogen, halogen, or -(C1-C6)alkyl; and represents a covalent bond to the nitrogen atom of the bicyclic nucleus of formula (Ia) or formula (I), and represents a covalent bond to L of formula (Ia) or formula (I). In another embodiment, ring A is where R 5 is hydrogen or -(C1-C6)alkyl; and represents a covalent bond to the nitrogen atom of the bicyclic nucleus of formula (Ia) or formula (I), and represents a covalent bond to L of formula (Ia) or formula (I). In another embodiment, ring A is wherein R5 is hydrogen, -I, -Cl, or -CH3; and represents a covalent bond to the nitrogen atom of the bicyclic nucleus of formula (Ia) or formula (I), and represents a covalent bond to L of formula (Ia) or formula (I). In another embodiment, ring A is in represents a covalent bond to the nitrogen atom of the bicyclic nucleus of formula (Ia) or formula (I), and represents a covalent bond to L of formula (Ia) or formula (I).

[0176] In one embodiment of the compound of Formula (Ia) 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 them is nitrogen.

[0177] In one embodiment of the compound of Formula (Ia) or Formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, R 1 、R 2 、R 3 and R 4 are each independently hydrogen, halogen, 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 are each independently hydrogen, halogen, cyano, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy-. In another embodiment, R 1 、R 2 、R 3 and R 4 are each independently -F, -Cl, cyano, -CF3, or -OCF3. In another embodiment, R 1 、R 2 、R 3 and R 4 are each independently hydrogen, -F, or -CF3. In further embodiments, R 1 and R 4 is hydrogen, R 2 is -CF3, and R 3 is -F.

[0178] In one embodiment of the compound of Formula (Ia) 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 b are each independently hydrogen or -CH3.

[0179] In one embodiment of the compound of Formula (Ia) or Formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, R 6 、R 7 and R8 are each independently hydrogen, halogen, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-. In another embodiment, R 6 、R 7 and R 8 Each is independently hydrogen, -F, -CF3, or -OCF3.

[0180] In one embodiment of the compound of Formula (Ia) 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, halogen, -(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, halogen, 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 further embodiments, R 8 is hydrogen and R 6 and R 7 Each is -F.

[0181] In one embodiment of the compound of Formula (Ia) or Formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, R 6 and R 8 Each is hydrogen and R 7 is hydrogen, halogen, -(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, halogen, 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 In another embodiment, R 6 and R 8 Each is hydrogen and R7 is -F.

[0182] In one embodiment of a compound of Formula (Ia) or Formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, L is a divalent linking group of 3 to 6 atoms in length, e.g., 3, 4, 5, or 6 atoms in length. In some embodiments, L is a divalent linking group of 4 to 5 atoms in length. In some embodiments, L is a divalent linking group of 4 atoms in length. In some embodiments, L is a divalent linking group of 5 atoms in length.

[0183] In one embodiment of the compound of Formula (Ia) 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 (C5-C6)alkenylene having one carbon-carbon double bond. In some embodiments, when L is a (C3-C6) alkenylene group 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 configuration of 2:1 to 1:2, for example, a mixture of 2:1, 1:1, or 1:2. In another embodiment, L is a (C3-C6) alkenylene group selected from *-CH=CH-CH2-**, *-CH2-CH=CH-CH2-**, *-CH2CH2-CH=CH-CH2-**, and *-CH2-CH=CH-CH2CH2CH2-**, wherein "*" represents a covalent bond to ring A of formula (I), and "**" represents a covalent bond to the benzene ring of formula (I). In another embodiment, L is a (C3-C6) alkenylene group selected from: in represents a covalent bond to Ring A of formula (I), and represents a covalent bond to the benzene ring of formula (I).

[0184] In one embodiment of the compound of Formula (Ia) or Formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, L is a divalent linker of Formula (L-ia):

[0185]

[0186] in:

[0187] X 8 and X9 Each independently is -CR 9 R 10 -, where R 9 and R 10 are each independently hydrogen or -(C1-C3)alkyl;

[0188] R d is hydrogen or -(C1-C3)alkyl;

[0189] r is 1, 2, 3, or 4;

[0190] s is 1, 2, 3, or 4;

[0191] The sum of r and s is 2, 3, 4, or 5; and

[0192] represents a covalent bond to Ring A of Formula (Ia) or Formula (I), and represents a covalent bond to the benzene ring of formula (Ia) or formula (I).

[0193] In another embodiment, L is a divalent linking group of formula (L-ia), wherein the sum of r and s is 3 or 4. In another embodiment, L is a divalent linking group of formula (L-ia), wherein R 9 and R 10 are each independently hydrogen, -CH3, or -CH2CH3; and R d In another embodiment, L is a divalent linking group of formula (L-ia) selected from: in represents a covalent bond to Ring A of Formula (Ia) or Formula (I), and represents a covalent bond to the benzene ring of formula (Ia) or formula (I).

[0194] In one embodiment of the compound of Formula (Ia) or Formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, L is a divalent linking group of Formula (Li):

[0195]

[0196] in:

[0197] r is 1, 2, 3, or 4;

[0198] s is 1, 2, 3, or 4;

[0199] The sum of r and s is 2, 3, 4 or 5; and

[0200] represents a covalent bond to Ring A of Formula (Ia) or Formula (I), and represents a covalent bond to the benzene ring of formula (Ia) or formula (I).

[0201] In another embodiment, L is a divalent linking group of formula (Li), wherein the sum of r and s is 3 or 4. In another embodiment, L is a divalent linking group of formula (Li) selected from: in represents a covalent bond to Ring A of Formula (Ia) or Formula (I), and represents a covalent bond to the benzene ring of formula (Ia) or formula (I).

[0202] In one embodiment of the compound of Formula (Ia) or Formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, L is a divalent linker of Formula (L-iia):

[0203]

[0204] in:

[0205] X 6 -NR c - or -CH2-;

[0206] X 7 -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 When it is -NH2-, X 6 is -CH2-;

[0207] Each X 10 Independently -CR 13 R 14 -R 13 and R 14 are each independently hydrogen or -(C1-C3)alkyl;

[0208] R c is hydrogen or -(C1-C3)alkyl;

[0209] q is 1, 2, 3, or 4; and

[0210] represents a covalent bond to Ring A of Formula (Ia) or Formula (I), and represents a covalent bond to the benzene ring of formula (Ia) or formula (I).

[0211] In another embodiment, L is a divalent linking group of formula (L-iia) wherein X6 -NR c -;X 7 -CR 11 R 12 -;R c is hydrogen or -CH3; and R 11 and R 12 Each is independently hydrogen or -CH3. In another embodiment, L is a divalent linking group of formula (L-iia) selected from: -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2- and -CH2CH2CH2CH2CH2CH2-, wherein represents a covalent bond to Ring A of Formula (Ia) or Formula (I), and represents a covalent bond to the benzene ring of formula (Ia) or formula (I).

[0212] In one embodiment of the compound of Formula (Ia) or Formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, L is a divalent linker of Formula (L-ii):

[0213]

[0214] in:

[0215] X 6 -NR c - or -CH2-;

[0216] X 7 is -CH2-, -O- or -NH2-, provided that when X 7 When it is -NH2-, X 6 is -CH2-;

[0217] R c is hydrogen or -(C1-C3)alkyl;

[0218] q is 1, 2, 3, or 4; and

[0219] represents a covalent bond to Ring A of Formula (Ia) or Formula (I), and represents a covalent bond to the benzene ring of formula (Ia) or formula (I).

[0220] In another embodiment, L is a divalent linking group of formula (L-ii), wherein R c In another embodiment, L is a divalent linking group of formula (L-ii), wherein X 6 -NR c - and X7 In another embodiment, L is a divalent linking group of formula (L-ii), wherein X 6 -NR c - and X 7 In another embodiment, L is a divalent linking group of formula (L-ii), wherein X 6 is -CH2- and X 7 In another embodiment, L is a divalent linking group of formula (L-ii), wherein X 6 is -CH2- and X 7 In another embodiment, L is a divalent linking group of formula (L-ii), wherein X 6 is -CH2- and X 7 In another embodiment, L is a divalent linking group of formula (L-ii), wherein q is 2 or 3. In another embodiment, L is a divalent linking group of formula (L-ii), wherein q is 2. In another embodiment, L is a divalent linking group of formula (L-ii) selected from: -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2- and -CH2CH2CH2CH2CH2CH2-, wherein represents a covalent bond to Ring A of Formula (Ia) or Formula (I), and Represents a covalent bond to the phenyl ring of formula (Ia) or formula (I). In another embodiment, L is a divalent linking group of formula (L-ii) selected from: -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2- and -CH2CH2CH2CH2CH2CH2-. In another embodiment, L is a divalent linking group of formula (L-ii) selected from: in represents a covalent bond to Ring A of Formula (Ia) or Formula (I), and Represents a covalent bond to the benzene ring of formula (Ia) or formula (I). In another embodiment, L is a divalent linking group of formula (L-ii) selected from: in represents a covalent bond to Ring A of Formula (Ia) or Formula (I), and represents a covalent bond to the benzene ring of formula (Ia) or formula (I).

[0221] In one embodiment of the compound of Formula (Ia) or Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, L is a divalent linking group selected from in represents a covalent bond to Ring A of Formula (Ia) or Formula (I), and represents a covalent bond to the benzene ring of formula (Ia) or formula (I). In another embodiment, L is a divalent linking group in represents a covalent bond to Ring A of Formula (Ia) or Formula (I), and represents a covalent bond to the benzene ring of formula (Ia) or formula (I). In another embodiment, L is a divalent linking group in represents a covalent bond to Ring A of Formula (Ia) or Formula (I), and represents a covalent bond to the benzene ring of formula (Ia) or formula (I).

[0222] In one embodiment of the compound of formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof:

[0223] Y is O;

[0224] X 1 Nitrogen or CR 1 ,

[0225] X 2 Nitrogen or CR 2 ,

[0226] X 3 Nitrogen or CR 3 ,and

[0227] X 4 Nitrogen or CR 4 ,

[0228] The premise is X 1 、X 2 、X 3 and X 4 At most two of them are nitrogen;

[0229] Ring A is: in represents a covalent bond to the nitrogen atom of the bicyclic nucleus of formula (I), and represents a covalent bond to L of formula (I);

[0230] R 1 、R 2 、R 3 and R 4Each is independently hydrogen, halogen, cyano, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-;

[0231] X 5 N or CR 5 ;

[0232] R 5 and R 5a are each independently hydrogen, halogen, or -(C1-C6)alkyl;

[0233] R 6 and R 7 Each is independently hydrogen, halogen, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-;

[0234] R 8 is hydrogen; and

[0235] L is a divalent linking group of formula (Li) or a divalent linking group of formula (L-ii):

[0236]

[0237] in:

[0238] r is 1, 2, 3, or 4;

[0239] s is 1, 2, 3, or 4;

[0240] The sum of r and s is 2, 3, 4, or 5; and

[0241] represents a covalent bond to Ring A of formula (I), and represents a covalent bond to the benzene ring of formula (I);

[0242]

[0243] in:

[0244] X 6 -NR c -;

[0245] X 7 is -CH2-;

[0246] R c is hydrogen or -(C1-C3)alkyl;

[0247] q is 1, 2, 3, or 4; and

[0248] represents a covalent bond to Ring A of formula (I), and represents a covalent bond to the benzene ring of formula (I).

[0249] In one embodiment of the compound of formula (Ia) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 15 and R 16 One of them is hydrogen, R 15 and R 16 In another embodiment, R 15 and R 16 All are deuterium.

[0250] The present invention also relates to compounds of formula (II):

[0251] or a tautomer thereof, or a pharmaceutically acceptable salt thereof,

[0252] in:

[0253] Y is O or S;

[0254] R 1 、R 2 、R 3 and R 4 are independently hydrogen, halogen, cyano, -NR a R b , -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-;

[0255] R 5 is hydrogen, halogen, or -(C1-C6)alkyl;

[0256] R 6 、R 7 and R 8 are each independently hydrogen, halogen, cyano, hydroxy, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-;

[0257] R a and R b are each independently hydrogen, -(C1-C6)alkyl, or halo(C1-C6)alkyl-; and

[0258] L is (C3-C6) alkenylene, -NHCH2CH2NHCH2-, -NHCH2CH2OCH2, a divalent linking group of formula (L-ia), or a divalent linking group of formula (L-iia):

[0259]

[0260] in:

[0261] X 8 and X9 Each independently is -CR 9 R 10 -, where R 9 and R 10 are each independently hydrogen or -(C1-C3)alkyl;

[0262] R d is hydrogen or -(C1-C3)alkyl;

[0263] r is 1, 2, 3, or 4;

[0264] s is 1, 2, 3, or 4;

[0265] The sum of r and s is 2, 3, 4, or 5; and

[0266] represents a covalent bond to the pyridone ring of formula (II), and represents a covalent bond to the benzene ring of formula (II);

[0267]

[0268] in:

[0269] X 6 -NR c - or -CH2-;

[0270] X 7 -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 When it is -NH2-, X 6 is -CH2-;

[0271] Each X 10 Independently -CR 13 R 14 -R 13 and R 14 are each independently hydrogen or -(C1-C3)alkyl;

[0272] R c is hydrogen or -(C1-C3)alkyl;

[0273] q is 1, 2, 3, or 4;

[0274] and

[0275] represents a covalent bond to the pyridone ring of formula (II), and represents a covalent bond to the benzene ring of formula (II).

[0276] The present invention also relates to compounds of formula (II):

[0277] or a tautomer thereof, or a pharmaceutically acceptable salt thereof,

[0278] in:

[0279] Y is O or S;

[0280] R 1 、R 2 、R 3 and R 4 are independently hydrogen, halogen, cyano, -NR a R b , -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-;

[0281] R 5 is hydrogen, halogen, or -(C1-C6)alkyl;

[0282] R 6 、R 7 and R 8 are each independently hydrogen, halogen, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-;

[0283] R a and R b are each independently hydrogen, -(C1-C6)alkyl, or halo(C1-C6)alkyl-; and

[0284] L is a (C3-C6) alkenylene group, a divalent linking group of formula (Li), or a divalent linking group of formula (L-ii):

[0285]

[0286] in:

[0287] r is 1, 2, 3, or 4;

[0288] s is 1, 2, 3, or 4;

[0289] The sum of r and s is 2, 3, 4, or 5; and

[0290] represents a covalent bond to the pyridone ring of formula (II), and represents a covalent bond to the benzene ring of formula (II);

[0291] in:

[0292] X 6 -NR c - or -CH2-;

[0293] X 7 is -CH2-, -O- or -NH2-, provided that when X 7 When it is -NH2-, X 6 is -CH2-;

[0294] R c is hydrogen or -(C1-C3)alkyl;

[0295] q is 1, 2, 3, or 4; and

[0296] represents a covalent bond to the pyridone ring of formula (II), and represents a covalent bond to the benzene ring of formula (II).

[0297] In one embodiment of the compound of formula (II) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Y is O. In another embodiment, Y is S.

[0298] In one embodiment of the compound of formula (II) or its tautomer or pharmaceutically acceptable salt thereof, R 1 、R 2 、R 3 and R 4 are each independently hydrogen, halogen, cyano, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl, and halo(C1-C6)alkoxy-. In another embodiment, R 1 、R 2 、R 3 and R 4 are each independently hydrogen, halogen, cyano, halo(C1-C6)alkyl, and halo(C1-C6)alkoxy-. In another embodiment, R 1 、R 2 、R 3 and R 4 are each independently -F, -Cl, cyano, -CF3 and -OCF3. In another embodiment, R 1 、R 2 、R 3 and R 4 are each independently hydrogen, -F, or -CF3. In further embodiments, R 1 and R 4 is hydrogen, R 2 is -CF3, and R 3 is -F.

[0299] In one embodiment of the compound of formula (II) or its tautomer or pharmaceutically acceptable salt thereof, R 1 is hydrogen and R 2 、R 3 and R 4 are independently hydrogen, halogen, 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 R 2 、R 3 and R 4 are each independently hydrogen, halogen, cyano, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy-. In another embodiment, R 1 is hydrogen and R 2 、R 3 and R 4 Each is independently -F, -Cl, cyano, -CF3, or -OCF3.

[0300] In one embodiment of the compound of formula (II) or its tautomer or pharmaceutically acceptable salt thereof, R a and R b Each is independently hydrogen or -(C1-C6)alkyl. In another embodiment, R a and R b are each independently hydrogen or -CH3.

[0301] In one embodiment of the compound of formula (II) or its tautomer or 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 For hydrogen.

[0302] In one embodiment of the compound of formula (II) or its tautomer or pharmaceutically acceptable salt thereof, R 6 、R 7 and R 8 are each independently hydrogen, halogen, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-. In another embodiment, R 6 、R 7 and R 8 Each is independently hydrogen, -F, -CF3, or -OCF3.

[0303] In one embodiment of the compound of formula (II) or its tautomer or pharmaceutically acceptable salt thereof, R 8 is hydrogen and R 6 and R 7 are each independently hydrogen, halogen, -(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, halogen, 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 further embodiments, R 8 is hydrogen and R 6 and R 7 Each is -F.

[0304] In one embodiment of the compound of formula (II) or its tautomer or pharmaceutically acceptable salt thereof, R 6 and R 8 Each is hydrogen and R 7 is hydrogen, halogen, -(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, halogen, 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 In another embodiment, R 6 and R 8 Each is hydrogen and R 7 is -F.

[0305] In one embodiment of the compound of formula (II) or its tautomer or its pharmaceutically acceptable salt, L is a divalent linking group of 3 to 6 atoms in length, for example, 3, 4, 5 or 6 atoms in length. In some embodiments, L is a divalent linking group of 4 to 5 atoms in length. In some embodiments, L is a divalent linking group of 4 atoms in length. In some embodiments, L is a divalent linking group of 5 atoms in length.

[0306] In one embodiment of the compound of formula (II) or its tautomer or 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 (C5-C6)alkenylene having one carbon-carbon double bond. In some embodiments, when L is a (C3-C6) alkenylene group 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, cis:trans is 2:1 to 1:2, for example, a mixture of 2:1, 1:1, or 1:2. In another embodiment, L is a (C3-C6) alkenylene group selected from *-CH=CH-CH2-**, *-CH2-CH=CH-CH2-**, *-CH2CH2-CH=CH-CH2-**, and *-CH2-CH=CH-CH2CH2CH2-**, wherein "*" represents a covalent bond to the pyridone ring of formula (II), and "**" represents a covalent bond to the benzene ring of formula (II). In another embodiment, L is a (C3-C6) alkenylene group selected from: in represents a covalent bond to the pyridone ring of formula (II), and represents a covalent bond to the benzene ring of formula (II).

[0307] In one embodiment of the compound of formula (II) or a tautomer thereof or a pharmaceutically acceptable salt thereof, L is a divalent linking group of formula (L-ia):

[0308]

[0309] in:

[0310] X 8 and X 9 Each independently is -CR 9 R 10 -, where R9 and R 10 are each independently hydrogen or -(C1-C3)alkyl;

[0311] R d is hydrogen or -(C1-C3)alkyl;

[0312] r is 1, 2, 3, or 4;

[0313] s is 1, 2, 3, or 4;

[0314] The sum of r and s is 2, 3, 4, or 5; and

[0315] represents a covalent bond to the pyridone ring of formula (II), and represents a covalent bond to the benzene ring of formula (II).

[0316] In another embodiment, L is a divalent linking group of formula (L-ia), wherein the sum of r and s is 3 or 4. In another embodiment, L is a divalent linking group of formula (L-ia), wherein R 9 and R 10 are each independently hydrogen, -CH3, or -CH2CH3; and R d In another embodiment, L is a divalent linking group of formula (L-ia) selected from: in represents a covalent bond to the pyridone ring of formula (II), and represents a covalent bond to the benzene ring of formula (II).

[0317] In one embodiment of the compound of formula (II) or its tautomer or a pharmaceutically acceptable salt thereof, L is a divalent linking group of formula (Li):

[0318]

[0319] in:

[0320] r is 1, 2, 3, or 4;

[0321] s is 1, 2, 3, or 4;

[0322] The sum of r and s is 2, 3, 4 or 5; and

[0323] represents a covalent bond to the pyridone ring of formula (II), and represents a covalent bond to the benzene ring of formula (II).

[0324] In another embodiment, L is a divalent linking group of formula (Li), wherein the sum of r and s is 3 or 4. In another embodiment, L is a divalent linking group of formula (Li) selected from: in represents a covalent bond to the pyridone ring of formula (II), and represents a covalent bond to the benzene ring of formula (II).

[0325] In one embodiment of the compound of formula (II) or a tautomer thereof or a pharmaceutically acceptable salt thereof, L is a divalent linking group of formula (L-iia):

[0326]

[0327] in:

[0328] X 6 -NR c - or -CH2-;

[0329] X 7 -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 When it is -NH2-, X 6 is -CH2-;

[0330] Each X 10 Independently -CR 13 R 14 -, where R 13 and R 14 are each independently hydrogen or -(C1-C3)alkyl;

[0331] R c is hydrogen or -(C1-C3)alkyl;

[0332] q is 1, 2, 3, or 4; and

[0333] represents a covalent bond to the pyridone ring of formula (II), and represents a covalent bond to the benzene ring of formula (II).

[0334] In another embodiment, L is a divalent linking group of formula (L-iia) wherein X 6 -NR c -;X 7 -CR 11 R 12 -;R cis hydrogen or -CH3; and R 11 and R 12 Each is independently hydrogen or -CH3. In another embodiment, L is a divalent linking group of formula (L-iia) selected from: -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2- and -CH2CH2CH2CH2CH2CH2-, wherein represents a covalent bond to the pyridone ring of formula (II), and represents a covalent bond to the benzene ring of formula (II).

[0335] In one embodiment of the compound of formula (II) or its tautomer or pharmaceutically acceptable salt thereof, L is a divalent linking group of formula (L-ii):

[0336]

[0337] in:

[0338] X 6 -NR c - or -CH2-;

[0339] X 7 is -CH2-, -O- or -NH2-, provided that when X 7 When it is -NH2-, X 6 is -CH2-;

[0340] R c is hydrogen or -(C1-C3)alkyl;

[0341] q is 1, 2, 3, or 4; and

[0342] represents a covalent bond to the pyridone ring of formula (II), and represents a covalent bond to the benzene ring of formula (II).

[0343] In another embodiment, L is a divalent linking group of formula (L-ii), wherein R c In another embodiment, L is a divalent linking group of formula (L-ii), wherein X 6 -NR c - and X 7 In another embodiment, L is a divalent linking group of formula (L-ii), wherein X 6 -NR c - and X 7In another embodiment, L is a divalent linking group of formula (L-ii), wherein X 6 is -CH2- and X 7 In another embodiment, L is a divalent linking group of formula (L-ii), wherein X 6 is -CH2- and X 7 In another embodiment, L is a divalent linking group of formula (L-ii), wherein X 6 is -CH2- and X 7 In another embodiment, L is a divalent linking group of formula (L-ii), wherein q is 2 or 3. In another embodiment, L is a divalent linking group of formula (L-ii), wherein q is 2. In another embodiment, L is a divalent linking group of formula (L-ii) selected from: -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2- and -CH2CH2CH2CH2CH2CH2-, wherein represents a covalent bond to the pyridone ring of formula (II), and Represents a covalent bond to the phenyl ring of formula (II). In another embodiment, L is a divalent linking group of formula (L-ii) selected from: -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2- and -CH2CH2CH2CH2CH2CH2-. In another embodiment, L is a divalent linking group of formula (L-ii) selected from: in represents a covalent bond to the pyridone ring of formula (II), and In another embodiment, L is a divalent linking group of formula (L-ii) selected from: in represents a covalent bond to the pyridone ring of formula (II), and represents a covalent bond to the benzene ring of formula (II).

[0344] In one embodiment of the compound of formula (II) or its tautomer or pharmaceutically acceptable salt thereof, L is a divalent linking group selected from in represents a covalent bond to the pyridone ring of formula (II), and represents a covalent bond to the phenyl ring of formula (II). In another embodiment, L is a divalent linking group in represents a covalent bond to the pyridone ring of formula (II), and represents a covalent bond to the phenyl ring of formula (II). In another embodiment, L is a divalent linking group in represents a covalent bond to the pyridone ring of formula (II), and represents a covalent bond to the benzene ring of formula (II).

[0345] In one embodiment of the compound of formula (II) or a tautomer thereof or a pharmaceutically acceptable salt thereof:

[0346] Y is O;

[0347] R 1 is hydrogen and R 2 、R 3 and R 4 Each is independently hydrogen, halogen, cyano, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-;

[0348] R 5 is hydrogen;

[0349] R 6 and R 7 Each is independently hydrogen, halogen, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-;

[0350] R 8 is hydrogen; and

[0351] L is a divalent linking group of formula (Li) or a divalent linking group of formula (L-ii):

[0352]

[0353] in:

[0354] r is 1, 2, 3, or 4;

[0355] s is 1, 2, 3, or 4;

[0356] The sum of r and s is 2, 3, 4, or 5; and

[0357] represents a covalent bond to the pyridone ring of formula (II), and represents a covalent bond to the benzene ring of formula (II);

[0358]

[0359] in:

[0360] X 6 -NRc -;

[0361] X 7 is -CH2-;

[0362] R c is hydrogen or -(C1-C3)alkyl;

[0363] q is 1, 2, 3, or 4; and

[0364] represents a covalent bond to the pyridone ring of formula (II), and represents a covalent bond to the benzene ring of formula (II).

[0365] The present invention also relates to compounds of formula (III):

[0366] or a tautomer thereof, or a pharmaceutically acceptable salt thereof,

[0367] in:

[0368] Y is O or S;

[0369] R 1 、R 2 and R 4 are independently hydrogen, halogen, cyano, -NR a R b , -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-;

[0370] R 5 is hydrogen, halogen, or -(C1-C6)alkyl;

[0371] R 6 、R 7 and R 8 are each independently hydrogen, halogen, cyano, hydroxy, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-;

[0372] R a and R b are each independently hydrogen, -(C1-C6)alkyl, or halo(C1-C6)alkyl-; and

[0373] L is (C3-C6) alkenylene, -NHCH2CH2NHCH2-, -NHCH2CH2OCH2, a divalent linking group of formula (L-ia), or a divalent linking group of formula (L-iia):

[0374]

[0375] in:

[0376] X 8 and X 9 Each independently is -CR 9 R 10 -, where R 9 and R 10 are each independently hydrogen or -(C1-C3)alkyl;

[0377] R d is hydrogen or -(C1-C3)alkyl;

[0378] r is 1, 2, 3, or 4;

[0379] s is 1, 2, 3, or 4;

[0380] The sum of r and s is 2, 3, 4, or 5; and

[0381] represents a covalent bond to the pyridone ring of formula (III), and represents a covalent bond to the benzene ring of formula (III);

[0382]

[0383] in:

[0384] X 6 -NR c - or -CH2-;

[0385] X 7 -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 When it is -NH2-, X 6 is -CH2-;

[0386] Each X 10 Independently -CR 13 R 14 -R 13 and R 14 are each independently hydrogen or -(C1-C3)alkyl;

[0387] R c is hydrogen or -(C1-C3)alkyl;

[0388] q is 1, 2, 3, or 4;

[0389] and

[0390] represents a covalent bond to the pyridone ring of formula (III), and represents a covalent bond to the benzene ring of formula (III).

[0391] The present invention also relates to compounds of formula (III):

[0392] or a tautomer thereof, or a pharmaceutically acceptable salt thereof,

[0393] in:

[0394] Y is O or S;

[0395] R 1 、R 2 and R 4 are independently hydrogen, halogen, cyano, -NR a R b , -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-;

[0396] R 5 is hydrogen, halogen, or -(C1-C6)alkyl;

[0397] R 6 、R 7 and R 8 are each independently hydrogen, halogen, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-;

[0398] R a and R b are each independently hydrogen, -(C1-C6)alkyl, or halo(C1-C6)alkyl-; and

[0399] L is a (C3-C6) alkenylene group, a divalent linking group of formula (Li), or a divalent linking group of formula (L-ii):

[0400]

[0401] in:

[0402] r is 1, 2, 3, or 4;

[0403] s is 1, 2, 3, or 4;

[0404] The sum of r and s is 2, 3, 4, or 5; and

[0405] represents a covalent bond to the pyridone ring of formula (III), and represents a covalent bond to the benzene ring of formula (III);

[0406] in:

[0407] X 6 -NR c - or -CH2-;

[0408] X 7 is -CH2-, -O- or -NH2-, provided that when X 7 When it is -NH2-, X 6 is -CH2-;

[0409] R c is hydrogen or -(C1-C3)alkyl;

[0410] q is 1, 2, 3, or 4; and represents a covalent bond to the pyridone ring of formula (III), and represents a covalent bond to the benzene ring of formula (III).

[0411] In one embodiment 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.

[0412] In one embodiment of the compound of formula (III) or its tautomer or pharmaceutically acceptable salt thereof, R 1 、R 2 and R 4 are each independently hydrogen, halogen, cyano, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl, and halo(C1-C6)alkoxy-. In another embodiment, R 1 、R 2 and R 4 are each independently hydrogen, halogen, cyano, halo(C1-C6)alkyl, and halo(C1-C6)alkoxy-. In another embodiment, R 1 、R 2 and R 4 Each is independently -F, -Cl, cyano, -CF3 and -OCF3.

[0413] In one embodiment of the compound of formula (III) or its tautomer or pharmaceutically acceptable salt thereof, R 1 is hydrogen and R 2 and R 4 are independently hydrogen, halogen, 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 R 2 and R 4 are each independently hydrogen, halogen, cyano, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy-. In another embodiment, R 1 is hydrogen and R 2 and R 4 Each is independently -F, -Cl, cyano, -CF3, or -OCF3.

[0414] In one embodiment of the compound of formula (III) or its tautomer or pharmaceutically acceptable salt thereof, R a and R b Each is independently hydrogen or -(C1-C6)alkyl. In another embodiment, R a and R b are each independently hydrogen or -CH3.

[0415] In one embodiment of the compound of formula (III) or its tautomer or 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 For hydrogen.

[0416] In one embodiment of the compound of formula (III) or its tautomer or pharmaceutically acceptable salt thereof, R 6 、R 7 and R 8 are each independently hydrogen, halogen, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-. In another embodiment, R 6 、R 7 and R 8 Each is independently hydrogen, -F, -CF3, or -OCF3.

[0417] In one embodiment of the compound of formula (III) or its tautomer or pharmaceutically acceptable salt thereof, R 8 is hydrogen and R 6 and R 7 are each independently hydrogen, halogen, -(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 7are each independently hydrogen, halogen, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-. In another embodiment, R 8 is hydrogen and R 6 and R 7 Each is independently hydrogen, -F, -CF3, or -OCF3.

[0418] In one embodiment of the compound of formula (III) or its tautomer or pharmaceutically acceptable salt thereof, R 6 and R 8 Each is hydrogen and R 7 is hydrogen, halogen, -(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, halogen, 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 In another embodiment, R 6 and R 8 Each is hydrogen and R 7 is -F.

[0419] In one embodiment of the compound of formula (III) or its tautomer or its pharmaceutically acceptable salt, L is a divalent linking group of 3 to 6 atoms in length, for example, 3, 4, 5 or 6 atoms in length. In some embodiments, L is a divalent linking group of 4 to 5 atoms in length. In some embodiments, L is a divalent linking group of 4 atoms in length. In some embodiments, L is a divalent linking group of 5 atoms in length.

[0420] In one embodiment of the compound of formula (III) or its tautomer or 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 (C5-C6)alkenylene having one carbon-carbon double bond. In some embodiments, when L is a (C3-C6)alkenylene group 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 configuration of 2:1 to 1:2, for example, a mixture of 2:1, 1:1, or 1:2. In another embodiment, L is a (C3-C6)alkenylene group selected from *-CH=CH-CH2-**, *-CH2-CH=CH-CH2-**, *-CH2CH2-CH=CH-CH2-**, and *-CH2-CH=CH-CH2CH2CH2-**, wherein "*" represents a covalent bond to the pyridone ring of formula (III), and "**" represents a covalent bond to the benzene ring of formula (III). In another embodiment, L is a (C3-C6)alkenylene group selected from: in represents a covalent bond to the pyridone ring of formula (III), and represents a covalent bond to the benzene ring of formula (III).

[0421] In one embodiment of the compound of formula (III) or a tautomer thereof or a pharmaceutically acceptable salt thereof, L is a divalent linking group of formula (L-ia):

[0422]

[0423] in:

[0424] X 8 and X 9 Each independently is -CR 9 R 10 -, where R 9 and R 10 are each independently hydrogen or -(C1-C3)alkyl;

[0425] R d is hydrogen or -(C1-C3)alkyl;

[0426] r is 1, 2, 3, or 4;

[0427] s is 1, 2, 3, or 4;

[0428] The sum of r and s is 2, 3, 4, or 5; and

[0429] represents a covalent bond to the pyridone ring of formula (III), and represents a covalent bond to the benzene ring of formula (III).

[0430] In another embodiment, L is a divalent linking group of formula (L-ia), wherein the sum of r and s is 3 or 4. In another embodiment, L is a divalent linking group of formula (L-ia), wherein R 9 and R 10 are each independently hydrogen, -CH3, or -CH2CH3; and R d In another embodiment, L is a divalent linking group of formula (L-ia) selected from: in represents a covalent bond to the pyridone ring of formula (III), and represents a covalent bond to the benzene ring of formula (III).

[0431] In one embodiment of the compound of formula (III) or a tautomer thereof or a pharmaceutically acceptable salt thereof, L is a divalent linking group of formula (Li):

[0432]

[0433] in:

[0434] r is 1, 2, 3, or 4;

[0435] s is 1, 2, 3, or 4;

[0436] The sum of r and s is 2, 3, 4 or 5; and

[0437] represents a covalent bond to the pyridone ring of formula (III), and represents a covalent bond to the benzene ring of formula (III).

[0438] In another embodiment, L is a divalent linking group of formula (Li), wherein the sum of r and s is 3 or 4. In another embodiment, L is a divalent linking group of formula (Li) selected from: in represents a covalent bond to the pyridone ring of formula (III), and represents a covalent bond to the benzene ring of formula (III).

[0439] In one embodiment of the compound of formula (III) or a tautomer thereof or a pharmaceutically acceptable salt thereof, L is a divalent linking group of formula (L-iia):

[0440]

[0441] in:

[0442] X 6 -NR c - or -CH2-;

[0443] X 7 -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 When it is -NH2-, X 6 is -CH2-;

[0444] Each X 10 Independently -CR 13 R 14 -, where R 13 and R 14 are each independently hydrogen or -(C1-C3)alkyl;

[0445] R c is hydrogen or -(C1-C3)alkyl;

[0446] q is 1, 2, 3, or 4; and

[0447] represents a covalent bond to the pyridone ring of formula (III), and represents a covalent bond to the benzene ring of formula (III).

[0448] In another embodiment, L is a divalent linking group of formula (L-iia) wherein X 6 -NR c -;X 7 -CR 11 R 12 -;R c is hydrogen or -CH3; and R 11 and R 12 Each is independently hydrogen or -CH3. In another embodiment, L is a divalent linking group of formula (L-iia) selected from: -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2- and -CH2CH2CH2CH2CH2CH2-, wherein represents a covalent bond to the pyridone ring of formula (III), and represents a covalent bond to the benzene ring of formula (III).

[0449] In one embodiment of the compound of formula (III) or its tautomer or pharmaceutically acceptable salt thereof, L is a divalent linking group of formula (L-ii):

[0450]

[0451] in:

[0452] X 6 -NR c - or -CH2-;

[0453] X 7 is -CH2-, -O- or -NH2-, provided that when X 7 When it is -NH2-, X 6 is -CH2-;

[0454] R c is hydrogen or -(C1-C3)alkyl;

[0455] q is 1, 2, 3, or 4; and

[0456] represents a covalent bond to the pyridone ring of formula (III), and represents a covalent bond to the benzene ring of formula (III).

[0457] In another embodiment, L is a divalent linking group of formula (L-ii), wherein R c In another embodiment, L is a divalent linking group of formula (L-ii), wherein X 6 -NR c - and X 7 In another embodiment, L is a divalent linking group of formula (L-ii), wherein X 6 -NR c - and X 7 In another embodiment, L is a divalent linking group of formula (L-ii), wherein X 6 is -CH2- and X 7 In another embodiment, L is a divalent linking group of formula (L-ii), wherein X 6 is -CH2- and X 7In another embodiment, L is a divalent linking group of formula (L-ii), wherein X 6 is -CH2- and X 7 In another embodiment, L is a divalent linking group of formula (L-ii), wherein q is 2 or 3. In another embodiment, L is a divalent linking group of formula (L-ii), wherein q is 2. In another embodiment, L is a divalent linking group of formula (L-ii) selected from: -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2- and -CH2CH2CH2CH2CH2CH2-, wherein represents a covalent bond to the pyridone ring of formula (III), and Represents a covalent bond to the phenyl ring of formula (III). In another embodiment, L is a divalent linking group of formula (L-ii) selected from: -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2- and -CH2CH2CH2CH2CH2CH2-. In another embodiment, L is a divalent linking group of formula (L-ii) selected from: in represents a covalent bond to the pyridone ring of formula (III), and In another embodiment, L is a divalent linking group of formula (L-ii) selected from: in represents a covalent bond to the pyridone ring of formula (III), and represents a covalent bond to the benzene ring of formula (III).

[0458] In one embodiment of the compound of formula (III) or its tautomer or pharmaceutically acceptable salt thereof, L is a divalent linking group selected from in represents a covalent bond to the pyridone ring of formula (III), and represents a covalent bond to the phenyl ring of formula (III). In another embodiment, L is a divalent linking group in represents a covalent bond to the pyridone ring of formula (III), and represents a covalent bond to the phenyl ring of formula (III). In another embodiment, L is a divalent linking group in represents a covalent bond to the pyridone ring of formula (III), and represents a covalent bond to the benzene ring of formula (III).

[0459] In one embodiment of the compound of formula (III) or a tautomer thereof or a pharmaceutically acceptable salt thereof:

[0460] Y is O;

[0461] R 1 is hydrogen and R 2 and R 4 Each is independently hydrogen, halogen, cyano, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-;

[0462] R 5 is hydrogen;

[0463] R 6 and R 7 Each is independently hydrogen, halogen, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-;

[0464] R 8 is hydrogen; and

[0465] L is a divalent linking group of formula (Li) or a divalent linking group of formula (L-ii):

[0466]

[0467] in:

[0468] r is 1, 2, 3, or 4;

[0469] s is 1, 2, 3, or 4;

[0470] The sum of r and s is 2, 3, 4, or 5; and

[0471] represents a covalent bond to Ring A of formula (III), and represents a covalent bond to the benzene ring of formula (III);

[0472]

[0473] in:

[0474] X 6 -NR c -;

[0475] X 7 is -CH2-;

[0476] R c is hydrogen or -(C1-C3)alkyl;

[0477] q is 1, 2, 3, or 4; and

[0478] represents a covalent bond to the pyridone ring of formula (III), and represents a covalent bond to the benzene ring of formula (III).

[0479] The present invention also relates to compounds of formula (IV):

[0480] or a tautomer thereof, or a pharmaceutically acceptable salt thereof,

[0481] in:

[0482] Y is O or S;

[0483] R 1 、R 3 and R 4 are independently hydrogen, halogen, cyano, -NR a R b , -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-;

[0484] R 5 is hydrogen, halogen, or -(C1-C6)alkyl;

[0485] R 6 、R 7 and R 8 are each independently hydrogen, halogen, cyano, hydroxy, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-;

[0486] R a and R b are each independently hydrogen, -(C1-C6)alkyl, or halo(C1-C6)alkyl-; and

[0487] L is (C3-C6) alkenylene, -NHCH2CH2NHCH2-, -NHCH2CH2OCH2-, a divalent linking group of formula (L-ia), or a divalent linking group of formula (L-iia):

[0488]

[0489] in:

[0490] X 8 and X 9 Each independently is -CR 9 R 10 -, where R 9 and R 10are each independently hydrogen or -(C1-C3)alkyl;

[0491] R d is hydrogen or -(C1-C3)alkyl;

[0492] r is 1, 2, 3, or 4;

[0493] s is 1, 2, 3, or 4;

[0494] The sum of r and s is 2, 3, 4, or 5; and

[0495] represents a covalent bond to the pyridone ring of formula (IV), and represents a covalent bond to the benzene ring of formula (IV);

[0496]

[0497] in:

[0498] X 6 -NR c - or -CH2-;

[0499] X 7 -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 When it is -NH2-, X 6 is -CH2-;

[0500] Each X 10 Independently -CR 13 R 14 -R 13 and R 14 are each independently hydrogen or -(C1-C3)alkyl;

[0501] R c is hydrogen or -(C1-C3)alkyl;

[0502] q is 1, 2, 3, or 4;

[0503] and

[0504] represents a covalent bond to the pyridone ring of formula (IV), and represents a covalent bond to the benzene ring of formula (IV).

[0505] The present invention also relates to compounds of formula (IV):

[0506] or a tautomer thereof, or a pharmaceutically acceptable salt thereof,

[0507] in:

[0508] Y is O or S;

[0509] R 1 、R 3 and R 4 are independently hydrogen, halogen, cyano, -NR a R b , -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-;

[0510] R 5 is hydrogen, halogen, or -(C1-C6)alkyl;

[0511] R 6 、R 7 and R 8 are each independently hydrogen, halogen, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-;

[0512] R a and R b are each independently hydrogen, -(C1-C6)alkyl, or halo(C1-C6)alkyl-; and

[0513] L is a (C3-C6) alkenylene group, a divalent linking group of formula (Li), or a divalent linking group of formula (L-ii):

[0514]

[0515] in:

[0516] r is 1, 2, 3, or 4;

[0517] s is 1, 2, 3, or 4;

[0518] The sum of r and s is 2, 3, 4, or 5; and

[0519] represents a covalent bond to the pyridone ring of formula (IV), and represents a covalent bond to the benzene ring of formula (IV);

[0520] in:

[0521] X 6 -NR c - or -CH2-;

[0522] X7 is -CH2-, -O- or -NH2-, provided that when X 7 When it is -NH2-, X 6 is -CH2-;

[0523] R c is hydrogen or -(C1-C3)alkyl;

[0524] q is 1, 2, 3, or 4; and

[0525] represents a covalent bond to the pyridone ring of formula (IV), and represents a covalent bond to the benzene ring of formula (IV).

[0526] In one embodiment 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.

[0527] In one embodiment of the compound of formula (IV) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 1 、R 3 and R 4 are each independently hydrogen, halogen, cyano, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy-. In another embodiment, R 1 、R 3 and R 4 are each independently hydrogen, halogen, cyano, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy-. In another embodiment, R 1 、R 3 and R 4 Each is independently -F, -Cl, cyano, -CF3, or -OCF3.

[0528] In one embodiment of the compound of formula (IV) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 1 is hydrogen and R 3 and R 4 are independently hydrogen, halogen, 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 R 3 and R 4 are each independently hydrogen, halogen, cyano, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy-. In another embodiment, R1 is hydrogen and R 3 and R 4 Each is independently -F, -Cl, cyano, -CF3, or -OCF3.

[0529] In one embodiment of the compound of formula (IV) 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 b are each independently hydrogen or -CH3.

[0530] In one embodiment 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 5 is hydrogen, -I, Cl, or -CH3. In another embodiment, R 5 For hydrogen.

[0531] In one embodiment of the compound of formula (IV) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 、R 7 and R 8 are each independently hydrogen, halogen, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-. In another embodiment, R 6 、R 7 and R 8 Each is independently hydrogen, -F, -CF3, or -OCF3.

[0532] In one embodiment 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 are each independently hydrogen, halogen, -(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, halogen, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-. In another embodiment, R 8 is hydrogen and R 6 and R 7 Each is independently hydrogen, -F, -CF3, or -OCF3.

[0533] In one embodiment 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, halogen, -(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, halogen, 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 In another embodiment, R 6 and R 8 Each is hydrogen and R 7 is -F.

[0534] In one embodiment of the compound of Formula (IV) or its tautomer or its pharmaceutically acceptable salt, L is a divalent linking group of 3 to 6 atoms in length, for example, 3, 4, 5 or 6 atoms in length. In some embodiments, L is a divalent linking group of 4 to 5 atoms in length. In some embodiments, L is a divalent linking group of 4 atoms in length. In some embodiments, L is a divalent linking group of 5 atoms in length.

[0535] In one embodiment 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 (C5-C6)alkenylene having one carbon-carbon double bond. In some embodiments, when L is a (C3-C6)alkenylene group 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 configuration of 2:1 to 1:2, for example, a mixture of 2:1, 1:1, or 1:2. In another embodiment, L is a (C3-C6)alkenylene group selected from *-CH=CH-CH2-**, *-CH2-CH=CH-CH2-**, *-CH2CH2-CH=CH-CH2-**, and *-CH2-CH=CH-CH2CH2CH2-**, wherein "*" represents a covalent bond to the pyridone ring of formula (IV), and "**" represents a covalent bond to the benzene ring of formula (IV). In another embodiment, L is a (C3-C6)alkenylene group selected from: in represents a covalent bond to the pyridone ring of formula (IV), and represents a covalent bond to the benzene ring of formula (IV).

[0536] In one embodiment of the compound of formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, L is a divalent linking group of formula (L-ia):

[0537]

[0538] in:

[0539] X 8 and X 9 Each independently is -CR 9 R 10 -, where R 9 and R 10 are each independently hydrogen or -(C1-C3)alkyl;

[0540] R d is hydrogen or -(C1-C3)alkyl;

[0541] r is 1, 2, 3, or 4;

[0542] s is 1, 2, 3, or 4;

[0543] The sum of r and s is 2, 3, 4, or 5; and

[0544] represents a covalent bond to the pyridone ring of formula (IV), and represents a covalent bond to the benzene ring of formula (IV).

[0545] In another embodiment, L is a divalent linking group of formula (L-ia), wherein the sum of r and s is 3 or 4. In another embodiment, L is a divalent linking group of formula (L-ia), wherein R 9 and R 10 are each independently hydrogen, -CH3, or -CH2CH3; and R d In another embodiment, L is a divalent linking group of formula (L-ia) selected from: in represents a covalent bond to the pyridone ring of formula (IV), and represents a covalent bond to the benzene ring of formula (IV).

[0546] In one embodiment of the compound of formula (IV) or a tautomer thereof or a pharmaceutically acceptable salt thereof, L is a divalent linking group of formula (Li):

[0547]

[0548] in:

[0549] r is 1, 2, 3, or 4;

[0550] s is 1, 2, 3, or 4;

[0551] The sum of r and s is 2, 3, 4 or 5; and

[0552] represents a covalent bond to the pyridone ring of formula (IV), and represents a covalent bond to the benzene ring of formula (IV).

[0553] In another embodiment, L is a divalent linking group of formula (Li), wherein the sum of r and s is 3 or 4. In another embodiment, L is a divalent linking group of formula (Li) selected from: in represents a covalent bond to the pyridone ring of formula (IV), and represents a covalent bond to the benzene ring of formula (IV).

[0554] In one embodiment of the compound of formula (IV) or a tautomer thereof or a pharmaceutically acceptable salt thereof, L is a divalent linker of formula (L-iia):

[0555]

[0556] in:

[0557] X 6 -NR c - or -CH2-;

[0558] X 7 -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 When it is -NH2-, X 6 is -CH2-;

[0559] Each X 10 Independently -CR 13 R 14 -, where R 13 and R 14 are each independently hydrogen or -(C1-C3)alkyl;

[0560] R c is hydrogen or -(C1-C3)alkyl;

[0561] q is 1, 2, 3, or 4; and

[0562] represents a covalent bond to the pyridone ring of formula (IV), and represents a covalent bond to the benzene ring of formula (IV).

[0563] In another embodiment, L is a divalent linking group of formula (L-iia) wherein X 6 -NR c -;X 7 -CR 11 R 12 -;R c is hydrogen or -CH3; and R 11 and R 12 Each is independently hydrogen or -CH3. In another embodiment, L is a divalent linking group of formula (L-iia) selected from: -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2- and -CH2CH2CH2CH2CH2CH2-, wherein represents a covalent bond to the pyridone ring of formula (IV), and represents a covalent bond to the benzene ring of formula (IV).

[0564] In one embodiment of the compound of formula (IV) or a tautomer thereof or a pharmaceutically acceptable salt thereof, L is a divalent linking group of formula (L-ii):

[0565]

[0566] in:

[0567] X 6 -NR c - or -CH2-;

[0568] X 7 is -CH2-, -O- or -NH2-, provided that when X 7 When it is -NH2-, X 6 is -CH2-;

[0569] R c is hydrogen or -(C1-C3)alkyl;

[0570] q is 1, 2, 3, or 4; and

[0571] represents a covalent bond to the pyridone ring of formula (IV), and represents a covalent bond to the benzene ring of formula (IV).

[0572] In another embodiment, L is a divalent linking group of formula (L-ii), wherein R c In another embodiment, L is a divalent linking group of formula (L-ii), wherein X 6 -NR c - and X 7 In another embodiment, L is a divalent linking group of formula (L-ii), wherein X 6 -NR c And X 7 In another embodiment, L is a divalent linking group of formula (L-ii), wherein X 6 is -CH2- and X 7 In another embodiment, L is a divalent linking group of formula (L-ii), wherein X 6 is -CH2- and X 7In another embodiment, L is a divalent linking group of formula (L-ii), wherein X 6 is -CH2- and X 7 In another embodiment, L is a divalent linking group of formula (L-ii), wherein q is 2 or 3. In another embodiment, L is a divalent linking group of formula (L-ii), wherein q is 2. In another embodiment, L is a divalent linking group of formula (L-ii) selected from: -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2- and -CH2CH2CH2CH2CH2CH2-, wherein represents a covalent bond to the pyridone ring of formula (IV), and Represents a covalent bond to the phenyl ring of formula (IV). In another embodiment, L is a divalent linking group of formula (L-ii) selected from: -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2- and -CH2CH2CH2CH2CH2CH2-. In another embodiment, L is a divalent linking group of formula (L-ii) selected from: in represents a covalent bond to the pyridone ring of formula (IV), and Represents a covalent bond to the phenyl ring of formula (IV). In another embodiment, L is a divalent linking group of formula (L-ii) selected from: in represents a covalent bond to the pyridone ring of formula (IV), and represents a covalent bond to the benzene ring of formula (IV).

[0573] In one embodiment of the compound of formula (IV) or a tautomer thereof or a pharmaceutically acceptable salt thereof, L is a divalent linking group selected from in represents a covalent bond to the pyridone ring of formula (IV), and represents a covalent bond to the phenyl ring of formula (IV). In another embodiment, L is a divalent linking group in represents a covalent bond to the pyridone ring of formula (IV), and represents a covalent bond to the phenyl ring of formula (IV). In another embodiment, L is a divalent linking group in represents a covalent bond to the pyridone ring of formula (IV), and represents a covalent bond to the benzene ring of formula (IV).

[0574] In one embodiment of the compound of formula (IV) or a tautomer thereof or a pharmaceutically acceptable salt thereof:

[0575] Y is O;

[0576] R 1 is hydrogen and R 3 and R 4 Each is independently hydrogen, halogen, cyano, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-;

[0577] R 5 is hydrogen;

[0578] R 6 and R 7 Each is independently hydrogen, halogen, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-;

[0579] R 8 is hydrogen; and

[0580] L is a divalent linking group of formula (Li) or a divalent linking group of formula (L-ii):

[0581]

[0582] in:

[0583] r is 1, 2, 3, or 4;

[0584] s is 1, 2, 3, or 4;

[0585] The sum of r and s is 2, 3, 4, or 5; and

[0586] represents a covalent bond to Ring A of formula (IV), and represents a covalent bond to the benzene ring of formula (IV);

[0587]

[0588] in:

[0589] X 6 -NR c -;

[0590] X 7 is -CH2-;

[0591] R c is hydrogen or -(C1-C3)alkyl;

[0592] q is 1, 2, 3, or 4; and

[0593] represents a covalent bond to the pyridone ring of formula (IV), and represents a covalent bond to the benzene ring of formula (IV).

[0594] The present invention also relates to compounds of formula (V):

[0595] or a tautomer thereof, or a pharmaceutically acceptable salt thereof,

[0596] in:

[0597] Y is O or S;

[0598] R 2 、R 3 and R 4 are independently hydrogen, halogen, cyano, -NR a R b , -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-;

[0599] R 5 is hydrogen, halogen, or -(C1-C6)alkyl;

[0600] R 6 、R 7 and R 8 are each independently hydrogen, halogen, cyano, hydroxy, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-;

[0601] R a and R b are each independently hydrogen, -(C1-C6)alkyl, or halo(C1-C6)alkyl-; and

[0602] L is (C3-C6) alkenylene, -NHCH2CH2NHCH2-, -NHCH2CH2OCH2-, a divalent linking group of formula (L-ia), or a divalent linking group of formula (L-iia):

[0603]

[0604] in:

[0605] X 8 and X 9 Each independently is -CR 9 R 10 -, where R 9 and R 10 are each independently hydrogen or -(C1-C3)alkyl;

[0606] R d is hydrogen or -(C1-C3)alkyl;

[0607] r is 1, 2, 3, or 4;

[0608] s is 1, 2, 3, or 4;

[0609] The sum of r and s is 2, 3, 4, or 5; and

[0610] represents a covalent bond to the pyridone ring of formula (V), and represents a covalent bond to the benzene ring of formula (V);

[0611]

[0612] in:

[0613] X 6 -NR c - or -CH2-;

[0614] X 7 -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 When it is -NH2-, X 6 is -CH2-;

[0615] Each X 10 Independently -CR 13 R 14 -R 13 and R 14 are each independently hydrogen or -(C1-C3)alkyl;

[0616] R c is hydrogen or -(C1-C3)alkyl;

[0617] q is 1, 2, 3, or 4;

[0618] and

[0619] represents a covalent bond to the pyridone ring of formula (V), and represents a covalent bond to the benzene ring of formula (V).

[0620] The present invention also relates to compounds of formula (V):

[0621] or a tautomer thereof, or a pharmaceutically acceptable salt thereof,

[0622] in:

[0623] Y is O or S;

[0624] R 2 、R 3 and R 4 are independently hydrogen, halogen, cyano, -NR a R b , -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-;

[0625] R 5 is hydrogen, halogen, or -(C1-C6)alkyl;

[0626] R 6 、R 7 and R 8 are each independently hydrogen, halogen, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-;

[0627] R a and R b are each independently hydrogen, -(C1-C6)alkyl, or halo(C1-C6)alkyl-; and

[0628] L is a (C3-C6) alkenylene group, a divalent linking group of formula (Li), or a divalent linking group of formula (L-ii):

[0629]

[0630] in:

[0631] r is 1, 2, 3, or 4;

[0632] s is 1, 2, 3, or 4;

[0633] The sum of r and s is 2, 3, 4, or 5; and

[0634] represents a covalent bond to the pyridone ring of formula (V), and represents a covalent bond to the benzene ring of formula (V);

[0635] in:

[0636] X 6 -NR c - or -CH2-;

[0637] X 7is -CH2-, -O- or -NH2-, provided that when X 7 When it is -NH2-, X 6 is -CH2-;

[0638] R c is hydrogen or -(C1-C3)alkyl;

[0639] q is 1, 2, 3, or 4; and

[0640] represents a covalent bond to the pyridone ring of formula (V), and represents a covalent bond to the benzene ring of formula (V).

[0641] In one embodiment of the compound of formula (V) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Y is O. In another embodiment, Y is S.

[0642] In one embodiment of the compound of formula (V) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 2 、R 3 and R 4 are each independently hydrogen, halogen, cyano, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy-. In another embodiment, R 2 、R 3 and R 4 are each independently hydrogen, halogen, cyano, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy-. In another embodiment, R 2 、R 3 and R 4 Each is independently -F, -Cl, cyano, -CF3, or -OCF3.

[0643] In one embodiment of the compound of formula (V) 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 b are each independently hydrogen or -CH3.

[0644] In one 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 For hydrogen.

[0645] In one 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, halogen, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-. In another embodiment, R 6 、R 7 and R 8 Each is independently hydrogen, -F, -CF3, or -OCF3.

[0646] In one 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 7 are each independently hydrogen, halogen, -(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, halogen, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-. In another embodiment, R 8 is hydrogen and R 6 and R 7 Each is independently hydrogen, -F, -CF3, or -OCF3.

[0647] In one embodiment of the compound of formula (V) or a tautomer thereof or a pharmaceutically acceptable salt thereof, R 6 and R 8 Each is hydrogen and R 7 is hydrogen, halogen, -(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, halogen, 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 In another embodiment, R 6 and R 8 Each is hydrogen and R7 is -F.

[0648] In one embodiment of the compound of formula (V) or its tautomer or its pharmaceutically acceptable salt, L is a divalent linking group of 3 to 6 atoms in length, for example, 3, 4, 5 or 6 atoms in length. In some embodiments, L is a divalent linking group of 4 to 5 atoms in length. In some embodiments, L is a divalent linking group of 4 atoms in length. In some embodiments, L is a divalent linking group of 5 atoms in length.

[0649] In one embodiment 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 (C5-C6)alkenylene having one carbon-carbon double bond. In some embodiments, when L is a (C3-C6)alkenylene group 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, cis:trans is 2:1 to 1:2, for example, a mixture of 2:1, 1:1, or 1:2. In another embodiment, L is a (C3-C6)alkenylene group selected from *-CH=CH-CH2-**, *-CH2-CH=CH-CH2-**, *-CH2CH2-CH=CH-CH2-**, and *-CH2-CH=CH-CH2CH2CH2-**, wherein "*" represents a covalent bond to the pyridone ring of formula (V), and "**" represents a covalent bond to the benzene ring of formula (V). In another embodiment, L is a (C3-C6)alkenylene group selected from: in represents a covalent bond to the pyridone ring of formula (V), and represents a covalent bond to the benzene ring of formula (V).

[0650] In one embodiment of the compound of formula (V) or a tautomer thereof or a pharmaceutically acceptable salt thereof, L is a divalent linking group of formula (L-ia):

[0651]

[0652] in:

[0653] X 8 and X 9 Each independently is -CR9 R 10 -, where R 9 and R 10 are each independently hydrogen or -(C1-C3)alkyl;

[0654] R d is hydrogen or -(C1-C3)alkyl;

[0655] r is 1, 2, 3, or 4;

[0656] s is 1, 2, 3, or 4;

[0657] The sum of r and s is 2, 3, 4, or 5; and

[0658] represents a covalent bond to the pyridone ring of formula (V), and represents a covalent bond to the benzene ring of formula (V).

[0659] In another embodiment, L is a divalent linking group of formula (L-ia), wherein the sum of r and s is 3 or 4. In another embodiment, L is a divalent linking group of formula (L-ia), wherein R 9 and R 10 are each independently hydrogen, -CH3, or -CH2CH3; and R d In another embodiment, L is a divalent linking group of formula (L-ia) selected from: in represents a covalent bond to the pyridone ring of formula (V), and represents a covalent bond to the benzene ring of formula (V).

[0660] In one embodiment of the compound of formula (V) or a tautomer thereof or a pharmaceutically acceptable salt thereof, L is a divalent linking group of formula (Li):

[0661]

[0662] in:

[0663] r is 1, 2, 3, or 4;

[0664] s is 1, 2, 3, or 4;

[0665] The sum of r and s is 2, 3, 4 or 5; and

[0666] represents a covalent bond to the pyridone ring of formula (V), and represents a covalent bond to the benzene ring of formula (V).

[0667] In another embodiment, L is a divalent linking group of formula (Li), wherein the sum of r and s is 3 or 4. In another embodiment, L is a divalent linking group of formula (Li) selected from: in represents a covalent bond to the pyridone ring of formula (V), and represents a covalent bond to the benzene ring of formula (V).

[0668] In one 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-iia):

[0669]

[0670] in:

[0671] X 6 -NR c - or -CH2-;

[0672] X 7 -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 When it is -NH2-, X 6 is -CH2-;

[0673] Each X 10 Independently -CR 13 R 14 -, where R 13 and R 14 are each independently hydrogen or -(C1-C3)alkyl;

[0674] R c is hydrogen or -(C1-C3)alkyl;

[0675] q is 1, 2, 3, or 4; and

[0676] represents a covalent bond to the pyridone ring of formula (V), and represents a covalent bond to the benzene ring of formula (V).

[0677] In another embodiment, L is a divalent linking group of formula (L-iia) wherein X 6 -NR c -;X 7 -CR 11 R 12 -;R cis hydrogen or -CH3; and R 11 and R 12 Each is independently hydrogen or -CH3. In another embodiment, L is a divalent linking group of formula (L-iia) selected from: -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2- and -CH2CH2CH2CH2CH2CH2-, wherein represents a covalent bond to the benzene ring of formula (V), and represents a covalent bond to the benzene ring of formula (V).

[0678] In one embodiment of the compound of formula (V) or a tautomer thereof or a pharmaceutically acceptable salt thereof, L is a divalent linking group of formula (L-ii):

[0679]

[0680] in:

[0681] X 6 -NR c - or -CH2-;

[0682] X 7 is -CH2-, -O- or -NH2-, provided that when X 7 When it is -NH2-, X 6 is -CH2-;

[0683] R c is hydrogen or -(C1-C3)alkyl;

[0684] q is 1, 2, 3, or 4; and

[0685] represents a covalent bond to the pyridone ring of formula (V), and represents a covalent bond to the benzene ring of formula (V).

[0686] In another embodiment, L is a divalent linking group of formula (L-ii), wherein R c In another embodiment, L is a divalent linking group of formula (L-ii), wherein X 6 -NR c - and X 7 In another embodiment, L is a divalent linking group of formula (L-ii), wherein X 6 -NR c And X 7In another embodiment, L is a divalent linking group of formula (L-ii), wherein X 6 is -CH2- and X 7 In another embodiment, L is a divalent linking group of formula (L-ii), wherein X 6 is -CH2- and X 7 In another embodiment, L is a divalent linking group of formula (L-ii), wherein X 6 is -CH2- and X 7 In another embodiment, L is a divalent linking group of formula (L-ii), wherein q is 2 or 3. In another embodiment, L is a divalent linking group of formula (L-iii), wherein q is 2. In another embodiment, L is a divalent linking group of formula (L-iii) selected from: -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2- and -CH2CH2CH2CH2CH2CH2-, wherein represents a covalent bond to the pyridone ring of formula (V), and Represents a covalent bond to the phenyl ring of formula (V). In another embodiment, L is a divalent linking group of formula (L-ii) selected from: -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2- and -CH2CH2CH2CH2CH2CH2-. In another embodiment, L is a divalent linking group of formula (L-ii) selected from: in represents a covalent bond to the pyridone ring of formula (V), and Represents a covalent bond to the benzene ring of formula (V). In another embodiment, L is a divalent linking group of formula (L-ii) selected from: in represents a covalent bond to the pyridone ring of formula (V), and represents a covalent bond to the benzene ring of formula (V).

[0687] In one embodiment of the compound of formula (V) or its tautomer or pharmaceutically acceptable salt thereof, L is a divalent linking group selected from in represents a covalent bond to the pyridone ring of formula (V), and represents a covalent bond to the phenyl ring of formula (V). In another embodiment, L is a divalent linking group in represents a covalent bond to the pyridone ring of formula (V), and represents a covalent bond to the phenyl ring of formula (V). In another embodiment, L is a divalent linking group in represents a covalent bond to the pyridone ring of formula (V), and represents a covalent bond to the benzene ring of formula (V).

[0688] In one embodiment of the compound of formula (V) or a tautomer thereof or a pharmaceutically acceptable salt thereof:

[0689] Y is O;

[0690] R 2 、R 3 and R 4 Each is independently hydrogen, halogen, cyano, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-;

[0691] R 5 is hydrogen;

[0692] R 6 and R 7 Each is independently hydrogen, halogen, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-;

[0693] R 8 is hydrogen; and

[0694] L is a divalent linking group of formula (Li) or a divalent linking group of formula (L-ii):

[0695]

[0696] in:

[0697] r is 1, 2, 3, or 4;

[0698] s is 1, 2, 3, or 4;

[0699] The sum of r and s is 2, 3, 4, or 5; and

[0700] represents a covalent bond to Ring A in Formula (V), and represents a covalent bond to the benzene ring of formula (V);

[0701]

[0702] in:

[0703] X 6 -NR c -;

[0704] X 7 is -CH2-;

[0705] R c is hydrogen or -(C1-C3)alkyl;

[0706] q is 1, 2, 3, or 4; and

[0707] represents a covalent bond to the pyridone ring of formula (V), and represents a covalent bond to the benzene ring of formula (V).

[0708]

[0709]

[0710]

[0711]

[0712]

[0713]

[0714]

[0715] or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0716] The present invention also relates to compounds selected from the group consisting of:

[0717]

[0718]

[0719]

[0720] or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0721] In one embodiment, there is provided a compound selected from the group consisting of:

[0722] or a tautomer thereof, or a pharmaceutically acceptable salt thereof. In another embodiment, a compound selected from the group consisting of:

[0723] or a tautomer thereof, or a pharmaceutically acceptable salt thereof. In another embodiment, a compound is provided, which is: or a tautomer thereof, or a pharmaceutically acceptable salt thereof. In another embodiment, a compound is provided, which is: or a tautomer thereof, or a pharmaceutically acceptable salt thereof. In another embodiment, a compound is provided, which is: or a tautomer thereof, or a pharmaceutically acceptable salt thereof. In a further embodiment, a compound is provided, which is: or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0724] It should be understood that references herein to compounds of Formula (Ia), (I), (II), (III), (IV) or (V) and / or their corresponding tautomeric forms or salts thereof include references to compounds of Formula (Ia), (I), (II), (III), (IV) and / or their corresponding tautomeric forms as free bases or acids, or as salts thereof, for example as pharmaceutically acceptable salts thereof. Thus, in one embodiment, the present invention relates to compounds of Formula (Ia), (I), (II), (III), (IV) or (V) and / or their corresponding tautomeric forms. In another embodiment, the present invention relates to salts of compounds of Formula (Ia), (I), (II), (III), (IV) or (V) and / or their corresponding tautomeric forms. In a further embodiment, the present invention relates to pharmaceutically acceptable salts of compounds of Formula (Ia), (I), (II), (III), (IV) or (V) and / or their corresponding tautomeric forms. In another embodiment, the present invention relates to a compound of formula (Ia), (I), (II), (III), (IV) or (V) and / or its corresponding tautomeric form, or a salt thereof. In another embodiment, the present invention relates to a compound of formula (Ia), (I), (II), (III), (IV) or (V) and / or its corresponding tautomeric form, or a pharmaceutically acceptable salt thereof

[0725] Due to their potential use in medicine, it will be appreciated that the salts of the compounds of Formula (Ia), (I), (II), (III), (IV) or (V) and / or their corresponding tautomeric forms are preferably pharmaceutically acceptable.

[0726] The term "pharmaceutically acceptable" refers to those compounds (including salts), materials, compositions and dosage forms that are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation or other problems or complications, and at a reasonable benefit / risk ratio.

[0727] The term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the target compound and exhibits minimal adverse 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 its free acid or free base form with a suitable base or acid, respectively. In addition, pharmaceutically acceptable salts of the compounds of Formula (I)-(V) and / or their corresponding tautomer forms can be prepared during further processing of the free acid or base form, for example, in situ during manufacture of a pharmaceutical formulation.

[0728] Pharmaceutically acceptable salts include, but are not limited to, those listed in Berge, J. Pharm. Sci., 1977, 66, 1-19, or in PH Stahl and CG Wermuth, editors, Handbook of Pharmaceutical Salts; Properties, Selection and Use, Second Edition Stahl / Wermuth: Wiley-VCH / VHCA, 2011.

[0729] Non-pharmaceutically acceptable salts are useful, for example, as intermediates in the preparation of compounds of Formula (Ia), (I), (II), (III), (IV) or (V) and / or their corresponding tautomeric forms or pharmaceutically acceptable salts thereof.

[0730] Suitable pharmaceutically acceptable salts can include acid or base addition salts. Such base addition salts can be formed by reaction with a suitable base by a compound of formula (Ia), (I), (II), (III), (IV) or (V) and / or its corresponding tautomeric form (for example, it contains carboxylic acid or other acidic functional groups), optionally in a suitable solvent, such as an organic solvent, to produce a salt that can be separated by a variety of methods (including crystallization and filtration). Such acid addition salts can be formed by reaction with a suitable acid by a compound of formula (Ia), (I), (II), (III), (IV) or (V) and / or its corresponding tautomeric form (for example, it contains basic amine or other basic functional groups), optionally in a suitable solvent, such as an organic solvent, to produce a salt that can be separated by a variety of methods (including crystallization and filtration).

[0731] Salts can be prepared in situ during the final separation and purification process of a compound of formula (Ia), (I), (II), (III), (IV) or (V) and / or its corresponding tautomeric form. If the basic compound of formula (Ia), (I), (II), (III), (IV) or (V) and / or its corresponding tautomeric form separate 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, if the compound containing carboxylic acid or other acidic functional groups of formula (Ia), (I), (II), (III), (IV) or (V) and / or its corresponding tautomeric form separate 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.

[0732] It will be understood that if a compound of Formula (Ia), (I), (II), (III), (IV) or (V) and / or its corresponding tautomeric form contains two or more basic moieties, the stoichiometry of salt formation may include 1, 2 or more equivalents of acid. Such salts will contain 1, 2 or more acid counterions, for example, dihydrochloride.

[0733] The scope of the present invention includes stoichiometric and non-stoichiometric forms of the pharmaceutically acceptable salts of the compounds of Formula (Ia), (I), (II), (III), (IV) or (V) and / or their corresponding tautomeric forms, including substoichiometric salts, for example, wherein the counterion contains more than one acidic proton.

[0734] 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 (dextrorotatory camphorsulfonate), caprate (decanoate), caproate (hexanoate), caprylate (octanoate), cinnamate , citrate, cyclamate, digluconate, 2,5-dihydroxybenzoate, disuccinate, lauryl sulfate (propionate lauryl sulfate), edetate (ethylenediaminetetraacetate), propionate lauryl sulfate (lauryl sulfate), ethane-1,2-disulfonate (edisylate), ethanesulfonate (ethanesulfonate), formate, fumarate, galactarate (mucates), gentisate (2,5-dihydroxybenzoate), glucoheptonate (gluceptate), gluconate, glucuronide aqua, glutamate, glutarate, glycerophosphorate, glycolate, hexylresorcinate, hippurate, hydrabamine (N,N'-di(dehydroabietyl)-ethylenediamine), hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, isobutyrate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, methanesulfonate (mesylate), methylsulfate, mucate, naphthalene-1,5-disulfonate (

[0014] Examples of the present invention include benzoic acid salts, anhydrous benzoate ...

[0735] Representative pharmaceutically acceptable base addition salts include, but are not limited to, aluminum, 2-amino-2-(hydroxymethyl)-1,3-propanediol (TRIS, tromethamine), arginine, phenethamine (N-benzylphenethylamine), benzathine (N,N'-dibenzylethylenediamine), bis-(2-hydroxyethyl)amine, bismuth, calcium, chloroprocaine, choline, clemizole (1-p-chlorobenzyl-2-pyrrolidin-1'-ylmethylbenzimidazole), cyclohexylamine, dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lepidin, lithium, lysine, magnesium, meglumine (N-methylglucamine), piperazine, piperidine, potassium, procaine, quinine, quinoline, sodium, strontium, tert-butylamine, and zinc.

[0736] It should be appreciated that many organic compounds can form complexes with solvents in which they react or precipitate or crystallize from the solvent. These complexes are referred to as "solvates." For example, complexes with water are referred to as "hydrates." Solvents with high boiling points and / or solvents that are prone to hydrogen bonding (such as water, ethanol, isopropanol, and N-methylpyrrolidone) can be used to form solvates. Methods for identifying solvates include, but are not limited to, NMR and microanalysis. Compounds of formula (Ia), (I), (II), (III), (IV), or (V) and / or their corresponding tautomeric forms or salts thereof can exist in solvated and unsolvated forms.

[0737] The compounds of the present invention may be in crystalline or amorphous form. The thermodynamically most stable crystalline forms of the compounds of the present invention are of particular interest.

[0738] The crystalline forms of the compounds of the invention can be characterized and distinguished by a variety of 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).

[0739] Compounds of Formula (Ia), (I), (II), (III), (IV) or (V) and / or their corresponding tautomeric forms and pharmaceutically acceptable salts thereof may contain one or more asymmetric centers (also referred to as chiral centers) and, therefore, may exist as individual enantiomers, diastereomers or other stereoisomeric forms or mixtures thereof. Chiral centers (e.g., chiral carbon atoms) may also be present in substituents (e.g., alkyl groups). When the stereochemistry of a chiral center present in a compound of Formula (Ia), (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 (Ia), (I), (II), (III), (IV) or (V) containing one or more chiral centers and / or their corresponding tautomeric forms and pharmaceutically acceptable salts thereof may be used as racemic mixtures, enantiomerically enriched mixtures or enantiomerically pure individual stereoisomers.

[0740] Individual stereoisomers of the compounds of Formula (Ia), (I), (II), (III), (IV) or (V) and / or their corresponding tautomeric forms or pharmaceutically acceptable salts thereof, which contain one or more asymmetric centers, may be resolved by methods known to those skilled in the art. For example, such resolution may be performed: (1) by formation of diastereomeric salts, complexes or other derivatives; (2) by selective reaction with stereoisomer-specific reagents, for example, by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent. The skilled person will appreciate that where the desired stereoisomer is converted to another chemical entity by one of the above separation procedures, additional steps may be required to liberate the desired form. Alternatively, specific stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.

[0741] The present invention also includes all suitable isotopic variations of the compounds of formula (Ia), (I), (II), (III), (IV) or (V) and / or their corresponding tautomeric forms or pharmaceutically acceptable salts thereof. An isotopic variation of a compound of formula (Ia), (I), (II), (III), (IV) or (V) and / or their corresponding tautomeric forms or pharmaceutically acceptable salts thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, for example, 2 H.3 H. 13 C. 14 C. 15 N. 17 O. 18 O. 18 F and 36 Certain isotopic variations of the compounds of formula (Ia), (I), (II), (III), (IV) or (V) and / or their corresponding tautomeric forms or their salts or solvates, for example, wherein a radioactive isotope such as 3 H or 14 C, can be used for drug and / or substrate tissue distribution studies. Tritiated isotopes, i.e. 3 H, and carbon-14 isotopes, i.e. 14 C is particularly preferred because of its ease of preparation and detectability. In addition, isotopes such as deuterium, i.e. 2 H substitution may provide certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and may therefore be preferred in certain circumstances. Isotopic variations of the compounds of Formula (Ia), (I), (II), (III), (IV) or (V) and / or their corresponding tautomeric forms or pharmaceutically salts thereof can generally be prepared by conventional procedures, for example, by the illustrative methods or as described in the Examples hereinafter, using appropriate isotopic variations of suitable reagents.

[0742] In addition, the compounds of the present invention may exist as tautomers or in tautomeric forms. It should be understood that any reference to a named compound or a structural description compound is intended to encompass all tautomers of such a compound. In the chemical field, it is generally understood that tautomers are structural or compositional isomers of compounds that are easily converted to each other. This reaction usually results in the relocation of protons. Structural isomers or compositional isomers (according to IUPAC) are isomers in which molecules with the same molecular formula have different bonding patterns and atomic structures, in contrast to stereoisomers in which the molecular bonds are always in the same order and only the spatial arrangement is different. The concept of tautomerism is called tautomerism. The chemical reaction in which the two are converted to each other is called tautomerization. It should be noted that tautomers should not be confused with the description of "contributing structures" in chemical resonance. Tautomers are different chemical substances that can be identified by their different spectral data, while resonance structures are just convenient descriptions and do not actually exist. For example, the 2-pyridone ring exhibits tautomerism, where the proton attached to the nitrogen can move to the oxygen, forming the tautomeric form 2-hydroxypyridine:

[0743]

[0744] Pharmaceutical composition

[0745] In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (Ia), (I), (II), (III), (IV) or (V) according to any embodiment disclosed herein, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient (also referred to as a carrier and / or diluent in the pharmaceutical art). An excipient is acceptable in the sense that it is compatible with the other ingredients in the formulation and is not harmful to the recipient thereof (i.e., the patient).

[0746] Pharmaceutically acceptable excipients are non-toxic and should not interfere with the efficacy of the active ingredient. Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form selected, route of administration, etc. Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, carriers, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavorings, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants and buffers. Examples of pharmaceutically acceptable excipients are described, for example, in Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited),and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

[0747] The pharmaceutical composition can be suitable for administration by any appropriate or suitable route, such as by systemic administration (e.g., oral administration, parenteral administration, transdermal administration, rectal administration, inhalation), topical administration, etc. Parenteral administration is typically by injection or infusion, including intravenous, intramuscular, and subcutaneous injection or infusion. Inhalation refers to administration to the patient's lungs, whether through the mouth or by inhalation through the nasal passages. Typically, administration is by oral or parenteral routes.

[0748] Pharmaceutical compositions suitable for oral administration can be in the form of solid dosage forms such as tablets, capsules, caplets, lozenges, pills; powders; or liquid dosage forms such as solutions, suspensions, syrups, elixirs or emulsions, etc. Pharmaceutical compositions suitable for parenteral administration can be in the form of solutions, suspensions and powders for reconstitution.

[0749] In general, the pharmaceutical compositions of the present invention are prepared using conventional materials and techniques (eg, mixing, blending, etc.). Pharmaceutical SciencesSome methods commonly used in the art are described in SEQ ID NO: 1 (Mack Publishing Company).

[0750] Solid oral dosage forms (e.g., tablets and capsules) can be prepared by mixing the compound of the present invention with excipients such as diluents and fillers (e.g., starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.), binders (e.g., starch, gum arabic, carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, etc.), lubricants (e.g., magnesium stearate, talc, etc.). Pharmaceutical compositions suitable for parenteral administration can be injections prepared by mixing powders, granules, or tablets with a carrier (e.g., distilled water, physiological saline, etc.), and the pH value can be adjusted with an alkali, etc.

[0751] The present invention also provides a pharmaceutical composition comprising 0.5 to 1,000 mg of a compound of the present invention and 0.5 to 1,000 mg of a pharmaceutically acceptable excipient.

[0752] The compounds and pharmaceutical compositions of the present invention as defined herein can be administered once or according to a dosing regimen in which multiple doses are administered at different time intervals over a given period of time. For example, a dose can be administered one, two, three, or four times a day. The dose can 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 can be in the range of 0.001 mg / kg to 100 mg / kg, for example 0.001 mg / kg to 50 mg / kg. Preferably, the dose selected is oral or parenteral.

[0753] According to another aspect of the present invention, there is provided a method for preparing a pharmaceutical composition, comprising mixing (or blending) a compound of Formula (Ia), (I), (II), (III), (IV) or (V) or a tautomer thereof or a salt thereof (e.g., a pharmaceutically acceptable salt thereof) with at least one pharmaceutically acceptable excipient.

[0754] Synthetic scheme and general preparation

[0755] The present invention also relates to methods for preparing the compounds of the present invention disclosed herein. The compounds of the present invention can be prepared by a variety of methods using conventional organic synthesis methods as described in the following schemes, more specifically as illustrated by the exemplary compounds in the Examples section herein, or utilizing the knowledge of a skilled organic chemist. Suitable synthetic routes are described in the following general reaction schemes. The synthetic procedures provided in the following schemes are suitable for producing the compounds of the present invention disclosed herein having various functional groups defined using appropriate precursors.

[0756] It will be understood by those skilled in the art that, when preparing 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 intermediate to prevent undesirable side reactions. It will be understood by those skilled in the art that, in the preparation of the compounds of the present invention (e.g., compounds of formula (I) or pharmaceutically acceptable salts thereof), it may be necessary and / or desirable to protect one or more sensitive groups in the molecule or appropriate intermediate to prevent undesirable side reactions. It will be understood by those skilled in the art that if the substituents described herein are incompatible with the synthetic methods described herein, the substituents can be protected with suitable protecting groups that are stable to the reaction conditions. The protecting groups can be removed at a suitable point in the reaction sequence to provide the desired intermediate or target compound. The suitable protecting groups used according to the present invention are well known to those skilled in the art and can be used in a conventional manner. For example, see " Protective Groups in Organic Synthesis " by T.W.Green and PGM Wets (Wiley & Sons, 1991) or " Protecting Groups " by PJ Kocienski (Georg Thieme Verlag, 1994). If desired, subsequent deprotection obtains compounds of generally disclosed properties. In some cases, a substituent can be specifically selected to be reactive under the reaction conditions employed. In these cases, the reaction conditions convert the selected substituent into another substituent that can serve as the desired substituent in an intermediate compound or target compound.

[0757] Although the schemes shown below represent methods for preparing the compounds of the present invention, they are intended only to illustrate methods for making the compounds of the present invention. Intermediates (compounds used to prepare the compounds of the present invention) may also exist in the form of salts. Therefore, when referring to intermediates, the phrase "compound of formula (number)" refers to a compound having the structural formula or a pharmaceutically acceptable salt thereof. Compound names are generated using the software naming program ChemDraw 5Ultra v12.0, which can be purchased from Perkin Elmer, 940 Winter Street, Waltham, Massachusetts, 02451, USA.

[0758] The following schemes and examples illustrate several methods for preparing the compounds of this invention. Starting materials are commercially available or can be prepared according to known methods in the literature or as illustrated.

[0759] General synthetic scheme

[0760] In the following general schemes (including general schemes 1-16), each R 1 are independently hydrogen, halogen, cyano, -NR a Rb , -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-; each R 2 are independently hydrogen, halogen, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-; and represents an alkenylene group that exists as a mixture of cis and trans isomers.

[0761] General Solution 1

[0762]

[0763] Compounds of general structures 1 and 2 exemplified herein can be prepared by the general sequence outlined in General Scheme 1. Cross-coupling of a vinylboronic acid substrate (e.g., vinyldioxaborolane, boric acid, or potassium trifluoroborate) with 2-bromo-6-methoxypyridin-3-amine at elevated temperature using a palladium catalyst (e.g., Pd(PPh3)4) and an inorganic base (e.g., sodium carbonate) in an organic solvent (e.g., dioxane or toluene) affords intermediate G1-A. In the presence of a coupling agent (e.g., HATU, pyoxim, or T3P) and an organic base (e.g., DIEA, TEA, or NMM), G1-A reacts with R 1 Substituted 2-fluorobenzoic acid undergoes amide coupling to generate G1-B. At elevated temperature, an inorganic base (such as cesium carbonate) is used with R 2 Substituted 2-bromoanilines undergo nucleophilic displacement to afford structure G1-C, which, using diiodomethane or chloroiodomethane as the formaldehyde equivalent, undergoes dihydropyrimidinone formation. In this cyclization variant, a base (typically Cs2CO3 or NaH) can be used in a suitable solvent (typically acetonitrile or DMF) at elevated temperature to yield G1-D. Stille cross-coupling at elevated temperature using a catalyst (e.g., Pd(PPh3)4) yields diene G1-E, which undergoes Grubbs-catalyzed cyclization at elevated temperature to form the macrocycle G1-F. This compound can be converted to general structure 1 by treatment with an alkali metal (e.g., lithium chloride) in the presence of a strong organic acid (e.g., p-toluenesulfonic acid) at elevated temperature, or by hydrogenation using a palladium source (e.g., Pd(OH)2) and a hydrogen atmosphere in an alcoholic solvent (e.g., methanol or ethanol), followed by conversion to the pyridone general structure 2.

[0764] General Solution 2

[0765]

[0766] Compounds of general structures 3 and 4 can be prepared according to the general sequence outlined in General Scheme 2. R can be esterified using a strong organic acid (e.g., sulfuric acid) with a suitable alcohol (e.g., methanol). 1Substituted o-bromoaryl carbonates give G2-A. This ester can be catalyzed by reacting it with an inorganic base (usually NaO) in the presence of a catalyst (e.g., Pd2(dba)3 or Pd(OAc)2) and a suitable ligand (e.g., BINAP or Xantphos). f Bu, Cs2CO3 or K3PO4) in the presence of an appropriate solvent (such as 1,4-dioxane, toluene or DMSO) at high temperature with R 2 Substituted bromoanilines undergo a catalytically mediated Buchwald coupling to afford intermediate G2-B, which is subsequently hydrolyzed under alkaline conditions. Saponification of the ester G2-B to the corresponding acid G2-C is typically achieved under standard alkaline conditions using a base (e.g., LiOH, KOH, or NaOH) in a suitable solvent or solvent system (e.g., methanol / H2O, ethanol / H2O, THF / H2O, or THF / MeOH / H2O). G2-C undergoes an amide coupling with 2-bromo-6-methoxypyridin-3-amine to afford the dibromo structure G2-D. For example, standard coupling reagents (e.g., EDC / HOBT, HATU, HBTU, or T3P) can be used in the presence of an amine base (e.g., triethylamine) or Huinig's base (diisopropylethylamine) in a suitable solvent (typically DMF, DMA, or acetonitrile). Dihydropyrimidinone formation is followed by a double Stille cross-coupling using the conditions described above in General Scheme 1 to afford intermediate G2-F. In a typical Stille coupling, a palladium source (e.g., Pd(PPh3)4 (tetrakis(triphenylphosphine)palladium)) and an organostannane (e.g., allyltributyltin) are placed in a suitable solvent (e.g., DMF or toluene) at elevated temperature. Grubbs-catalyzed cyclization using a Hoveyda-Grubbs catalyst produces the macrocycle G2-G, which upon demethylation produces the general structure 3. Preferred methods for achieving this transformation include utilizing a mixture of p-toluenesulfonic acid and LiCl in a solvent (e.g., DMF) at elevated temperature or utilizing TMS-iodide in a neutral solvent (e.g., acetonitrile) at elevated temperature to produce the intermediate G2-I. G2-I can be treated with a non-nucleophilic base (e.g., DBU) in a solvent (e.g., DMF) and then hydrogenated using the conditions described above to produce the general structure 4. Alternatively, G2-G can be hydrogenated to the pyridone general structure 4 using the conditions described above prior to demethylation.

[0767] General Solution 3

[0768]

[0769]

[0770] Compounds of general structure 5 can be prepared by the general sequence outlined in general scheme 3. Suzuki cross-linking reaction is carried out by allyl borane (such as allyl dioxaborolane, boric acid or potassium trifluoroborate) with 2-bromo-6-methoxypyridin-3-amine to provide intermediate G3-A. Such reactions are usually carried out using a palladium catalyst (such as Pd(PPh3)4), an inorganic base (such as cesium fluoride) in an organic solvent (such as THF, dioxane or toluene) at elevated temperature. Simultaneously, in a suitable alcohol solvent (such as MeOH), a strong protic acid (such as HCl or H2SO4) is used to convert R 2 Substituted o-nitrophenylacetic acid is esterified and alkylated under mild alkaline conditions using an inorganic base (e.g., NaH, K2CO3, or Cs2CO3) in the presence of a crown ether and a neutral solvent (e.g., MeCN) to afford G3-C. Subsequent ester hydrolysis is carried out using an organic base (e.g., sodium hydroxide) in a suitable solvent (e.g., dioxane), followed by decarboxylation of this intermediate (not shown) using an inorganic base (e.g., potassium carbonate) at elevated temperature to afford G3-D. Reduction of the nitro group using a metal source (e.g., zinc or iron) in the presence of an acid source (e.g., acetic acid) at elevated temperature in an alcoholic solvent (e.g., ethanol) affords G3-E. Aniline G3-E reacts with R 1 Substituted bromoaryl carbonates underwent Buchwald cross-coupling followed by ester hydrolysis under the conditions described above to provide G3-G. Amide coupling with G3-A followed by dihydropyrimidinone ring formation under the conditions outlined previously provided G3-I, which underwent Grubbs-catalyzed cyclization to form the macrocycle G3-J. Using the above procedure, the general structure 5 was formed after catalytic reduction and demethylation to the pyridinone ring.

[0771] Alternatively, using the method cited previously, R 2 Substituted o-bromoanilines can undergo Suzuki cross-coupling to form G3-L, which can then react with R 1 Substituted bromoaryl carbonates undergo Buchwald coupling to generate G3-M. Subsequent base-mediated hydrolysis using previously described conditions forms G3-N and amide formation with G9-C (see below) yields the diene G3-O. Dihydropyrimidinone formation is followed by Grubbs-catalyzed cyclization to form the macrocycle G3-Q. Grubbs borohydride reduction of the bound olefin yields the intermediate G3-K, which is converted to general structure 5 as previously described.

[0772] Another method is to convert R 2Substituted o-iodoaniline reacts with 5-hydroxypentyne to produce G3-R. Typical conditions are the use of a palladium / ligand source, such as bis(triphenylphosphine)palladium(II) dichloride / triphenylphosphine ([Pd(PPh3)2Cl2]) / PPh3) or Pd(PPh3)4, and a copper(I) halide salt cocatalyst, such as copper(I)I, in the presence of an organic base, such as TEA DEA or DIEA, in an appropriate solvent, such as DMF and a terminal alkyne, at elevated temperature. The above catalytic hydrogenation (G3-S) and Buchwald cross-coupling to R 1 Conditions for the substituted chloroaryl carbonate step can provide G3-T. Triphenylphosphine-mediated conversion to the terminal bromide with tetramethyl bromide, followed by negishi coupling to BOC-modified 2-bromo-3-amino-6-methoxypyridine, provides G3-V. Typical conditions utilize a metal catalyst (e.g., zinc), a metal halide (e.g., nickel(II) chloride), in the presence of an inorganic salt (e.g., sodium iodide), and a ligand (e.g., 2-amidinopyridine) in an appropriate solvent (e.g., dimethylacetamide (DMA)) at elevated temperature. Ester hydrolysis (G3-W), amine deprotection using a strong acid (e.g., TFA or HCl) (G3-X), and intramolecular amide coupling using the conditions described above, form the macrocycle G3-Y. Formation of the dihydropyrimidinone provides G3-K, which is demethylated to the general structure 5 using the conditions outlined previously.

[0773] General Solution 4

[0774]

[0775]

[0776] Compounds of general structure 6 can be prepared according to the general sequence outlined in general scheme 4. Benzyl halides (such as R 1 Substituted o-bromobenzyl bromide) undergoes cross-coupling with the desired Grignard reagent to form G4-A. Buchwald cross-coupling (G4-B), ester hydrolysis (G4-C), amide coupling (G4-D), and dihydropyrimidinone formation described above provide intermediate G4-E. Stille cross-coupling (G4-F) followed by cyclization using previously described methods provides G4-G. General structure 6 was prepared using the conditions described in the general scheme above for the catalytic hydrogenation and demethylation steps.

[0777] General Solution 5

[0778]

[0779]

[0780] Compounds of general structures 7, 8 and 9 can be prepared according to the general sequence outlined in General Scheme 5. 2 Substituted o-iodoanilines can be Sonogashira coupled with terminal alkynes (e.g., BOC-modified 4-aminobutyne) to afford G5-A. Typical conditions are the use of a palladium / ligand source (e.g., bis(triphenylphosphine)palladium(II) chloride / triphenylphosphine ([Pd(PPh3)2Cl2]) / PPh3) or Pd(PPh3)4 and a copper(I) halide salt cocatalyst (e.g., copper(I)I) in the presence of an organic base (e.g., TEA, DIA, or DIEA) in an appropriate solvent (e.g., diethyl ether or acetonitrile). The reaction is then carried out under the above conditions with R 1 Substituted bromophenyl esters undergo Buchwald coupling to provide G5-B. Catalytic hydrogenation of the alkyne (G5-C) using a palladium source (e.g., Pd-C) in a suitable solvent (e.g., EtOAc, EtOAc / EtOH) under a hydrogen atmosphere, followed by ester hydrolysis under previously described conditions, provides G5-D. Amide coupling (G5-E) and dihydropyrimidinone ring closure using the above conditions provide G5-F. Acid deprotection using a strong organic acid (e.g., TFA or HCl) in a suitable solvent (e.g., dichloromethane or dioxane) provides G5-G, which undergoes intramolecular ring closure to provide G5-H. Typical conditions employ a catalyst-ligand system (e.g., Pd2(dba)2 / BINAP) with a base (e.g., NaO t Bu) and a solvent (e.g., dioxane or toluene) at elevated temperature to produce G5-H. This macrocycle can be converted to general structure 7 using previously described methods, or N-alkylated with an alkylating agent (e.g., iodomethane) after treatment with an inorganic base (e.g., sodium hydride) to produce G5-I. The latter intermediate produces general structure 8 using sodium iodide in the presence of trimethylsilyl chloride. Alternatively, G5-I can be demethylated with HBr in acetic acid to form general structure 9.

[0781] General Solution 6

[0782]

[0783] Compounds of general structure 10 can be prepared by the general sequence outlined in general scheme 6. R can be appropriately protected. 2 Substituted o-bromophenols, for example, using a benzyl protecting group, are installed using a base (such as potassium carbonate), a solvent (such as acetone), and benzyl bromide at elevated temperature, followed by Buchwald cross-coupling conditions with R 1Substituted anthranilates are coupled to generate G6-B. Phenol is deprotected by catalytic hydrogenation conditions using a palladium catalyst (e.g., Pd-C or Pd(OH)2) and an appropriate solvent (e.g., ethanol) to provide G6-C. Phenol is Mitsunobu-coupled with N-BOC-conjugated 2-aminoethanol using an azodicarboxylate (e.g., DEAD, DIAD, etc.) in the presence of triphenylphosphine and an appropriate solvent (e.g., THF or toluene) to form intermediate G6-D. Ester hydrolysis (G6-E), amide coupling with 2-bromo-3-amino-6-methoxypyridine (G6-F), and dihydropyrimidinone ring formation are performed using the methods described above to provide G6-G. Subsequent amine deprotection (G6-H), intramolecular ring closure (G6-I), and demethylation using the procedures described above provide general structure 10.

[0784] General Solution 7

[0785]

[0786] Compounds of general structure 11 can be prepared according to the general sequence outlined in general scheme 7. Intermediate G6-C can be alkylated using an inorganic base (e.g., potassium carbonate) and an alkyl halide (e.g., allyl bromide) in an appropriate solvent (e.g., THF, acetone, or DMF) at elevated temperature, followed by ester hydrolysis (G7-B) and amide coupling with G1-A to generate G7-C using the above-described chemical reactions. Similarly, using the previously described conditions, dihydropyrimidinone ring formation (G7-D), Grubbs-catalyzed cyclization (G7-E), catalytic hydrogenation (G7-F), and demethylation to the pyridinone ring generate general structure 11.

[0787] General Solution 8

[0788]

[0789] Compounds of general structure 12 can be prepared according to the general sequence outlined in general scheme 8. Using the sequence of reaction conditions described previously, carboxylic acid G7-B can be coupled with amine G3-A to give G8-A, followed by dihydropyrimidinone ring formation (G8-B), Grubbs-catalyzed cyclization (G8-C), catalytic hydrogenation (G8-D), and a demethylation procedure to give general structure 12.

[0790] General Solution 9

[0791]

[0792] Compounds of general structure 13 can be prepared by the general sequence outlined in general scheme 9. 2-Bromo-3-amino-6-methoxypyridine is protected with a carbamate protecting group such as tert-butyloxycarbonyl (Boc), which is installed using boc-anhydride in a suitable solvent such as acetonitrile at elevated temperature, followed by cross-coupling with butenylboronic acid to yield G9-B. Using the above chemistry, the amine is deprotected (G9-C), followed by amide coupling (G9-D), dihydropyrimidinone ring closure (G9-E), Grubbs-catalyzed cyclization (G9-F), catalytic hydrogenation (G9-G), and demethylation to yield general structure 13.

[0793] General Solution 10

[0794]

[0795] Compounds of general structure 14 can be prepared according to the general sequence outlined in general scheme 10, wherein intermediate G3-Q is demethylated with NaI / TMSCl in a suitable solvent such as acetonitrile at elevated temperature to yield general structure 14.

[0796] General Solution 11

[0797]

[0798]

[0799] Compounds of general structure 15 can be prepared according to the general sequence outlined in general scheme 11. Aminobutyne (G11-A) undergoes carbamate protection followed by Sonogashira cross-coupling with 2-iodo-3-nitro-6-methoxypyridine to form G11-B. Reduction of the nitro group with a metal such as zinc or iron in the presence of a weak acid such as ammonium chloride (G11-C) followed by amide coupling with the carboxylic acid G2-C using previously described procedures provides G11-D. Using the procedures mentioned above, catalytic hydrogenation of the alkyne (G11-E) to form the dihydropyrimidinone (G11-F), deprotection of the amine (G11-G), Buchwald cross-coupling to the macrocycle (G11-H), and demethylation to the pyridinone ring provide general structure 15.

[0800] General Solution 12

[0801]

[0802] Compounds of general structure 16 can be prepared according to the general sequence outlined in general scheme 12. Suzuki cross-coupling of 3-iodo-4-aminopyridine with propylene pinacol borane followed by N-BOC protection using previously described methods provides G12-A. Deprotection of the amine (G12-B) and amide coupling with the carboxylic acid G3-G provides G12-C, which is treated with paraformaldehyde and sulfuric acid to form the dihydropyrimidinone ring of G12-D using the above procedure. Cyclization to the macrocycle (G12-D) can be achieved in an appropriate solvent such as acetonitrile at low temperature using conditions such as hydrazine / p-nitrobenzenesulfonyl chloride, followed by olefin reduction to provide G12-F. This can be oxidized to the N-oxide using an oxidizing agent such as m-CPBA in a chlorinated solvent such as dichloromethane or dichloroethane at low temperature to provide general structure 16.

[0803] General Solution 13

[0804]

[0805] Compounds of general structure 17 can be prepared by the general sequence outlined in general scheme 13. Nucleophilic displacement of 2-chloro-6-methoxy-3-nitropyridine with an aminopropargyl group in a solvent such as DMF, NMP, or DMSO in the presence of a base such as TEA or DIEA at elevated temperature affords G13-A. N-BOC protection (G13-B) is then followed by reaction with R using the methods described above. 2 Sonogashira cross-coupling of substituted o-iodoanilines afforded G13-C. 1 Substituted o-bromoaryl carbonates underwent Buchwald cross-coupling to generate G13-D, followed by saponification (G13-E), 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, yielding the general structure 17.

[0806] Alternatively, using previously described methods, R 2 Substituted o-iodoanilines can undergo sonogashira cross-coupling with Boc-protected aminopropargyl groups to afford G13-I, which can then be reacted with R 1 Substituted o-bromoaryl carboxylates (G13-J) underwent Buchwald cross-coupling, followed by hydrolysis (G13-K), alkyne-catalyzed hydrogenation (G13-L), amide coupling (G13-M), dihydropyrimidinone formation (G13-N), amine deprotection (G13-O), intramolecular Buchwald cross-coupling (G13-P), and demethylation to pyridinone to afford general structure 17.

[0807] Alternatively, the triple bond of G13-I can be hydrogenated to the alkane with Pd(OH)2, and the protocol is continued, omitting the subsequent hydrogenation reaction.

[0808] General Solution 14

[0809]

[0810] Compounds of general structure 18 can be prepared according to the general sequence outlined in general scheme 14, where G13-P is demethylated and then chlorinated at elevated temperature to afford general structure 18.

[0811] General Solution 15

[0812]

[0813] Compounds of general structure 19 can be prepared according to the general sequence outlined in general scheme 15. Intermediate G13-P is alkylated using an alkyl halide (e.g., iodomethane) and a base (e.g., sodium hydride) in an appropriate solvent (e.g., DMF or THF), followed by demethylation as previously described to produce general structure 19.

[0814] General Solution 16

[0815]

[0816] Compounds of general structure 20 can be prepared according to the general sequence outlined in general scheme 16. Using the above procedure, 2-bromo-3-nitro-6-methoxypyridine can be Suzuki coupled with BOC amine-protected aminoethyl borate (G16-A) and then deprotected to give G16-B. 2 Substituted o-aminobenzyl alcohols can be oxidized to the corresponding aldehydes (G16-C) and then reacted with R via the Buchwald cross-coupling method. 1 Substituted o-bromoaryl carbonates are coupled to G16-D, which can then undergo reductive amination with G16-B and Boc amine protection to afford G16-E. Ester hydrolysis (G16-F) and reduction of the nitro group as previously described yield G16-G, which can undergo intramolecular amide coupling to form the macrocycle G16-H. Treatment with diiodomethane under mild basic conditions yields the dihydropyrimidinone G16-I. Demethylation under acidic conditions deprotects the amine and forms the pyridone ring of general structure 20.

[0817] General Solution 17

[0818]

[0819] Compounds of general structure 21 can be prepared according to the general sequence outlined in general scheme 17. tert-Butyl (2-bromo-6-methoxypyridin-3-yl)carbamate can be formylated by treatment with butyllithium and DMF to afford aldehyde G17-A. 1 Substituted anthranilate with R 2 Buchwald coupling of substituted 2-bromoiodobenzenes (G17-B) followed by Suzuki coupling with boc-amine-protected aminoethyl boronate afforded G17-C. Boc deprotection, reductive amination with G17-A, and p-nitrobenzenesulfonyl protection produced G17-D. Ester hydrolysis and boc deprotection (G17-E) using previously described methods enabled intramolecular amide coupling to afford G17-F. Dihydropyrimidinone formation (G17-G), p-nitrobenzenesulfonyl deprotection (G17-H), and demethylation to the pyridinone yielded the general structure 21.

[0820] General Solution 18

[0821]

[0822] Compounds of general structure 22 can be prepared by the general sequence outlined in general scheme 18. 2 The substituted o-iodoaniline was subjected to Sonagashira coupling with tert-butyl prop-2-yn-1-ylcarbamate to form G18-A, which was then catalytically hydrogenated to G18-B. Simultaneously, 3-amino-6-methoxy-2-picolinic acid methyl ester was reduced with LAH to alcohol G18-C, which was protected with phthalimide to G18-D, and finally oxidized to aldehyde G18-E via Dess-Martin reaction. 1 Buchwald coupling of the substituted o-bromobenzoate with G18-B followed by boc deprotection afforded the amine G18-F, which underwent reductive amination with G18-E to generate G18-G. Utilizing previously discussed chemistry, hydrolysis of the ester group followed by hydrazine deprotection of the phthalimide afforded G18-H, which was then subjected to intramolecular amide coupling (G18-I), dihydropyrimidinone formation (G18-J), and finally HCl-induced boc deprotection and pyridinone demethylation to yield the general structure 22.

[0823] General Solution 19

[0824]

[0825] Compounds of general structure 23 can be prepared according to the general sequence outlined in general scheme 19. 2-Bromo-6-methoxy-3-nitropyridine and (2-(trifluoro-λ 4Suzuki coupling with tert-butyl (-boryl)propyl)carbamate potassium salt yields G19-A, which undergoes boc deprotection to yield the amine G19-B. Simultaneously, G16-D can be reductively aminated with G19-B, followed by boc amine protection, to yield G19-C. Ester hydrolysis (G19-D) and reduction of the nitro group as previously described yield G19-E, which can undergo intramolecular amide coupling to yield the macrocycle G19-F. Treatment with diiodomethane under mildly basic conditions yields the dihydropyrimidinone G19-G, which undergoes demethylation under acidic conditions, leading to amine deprotection and formation of the pyridinone ring of general structure 23.

[0826] General Solution 20

[0827]

[0828] Compounds of general structure 24 can be prepared according to the general sequence outlined in general scheme 20. 2 Substituted 2-(2-bromophenyl)acetaldehyde can be reductively aminated with G16-B, followed by boc protection, to afford G20-A. 1 Substituted anthranilates were subjected to Buchwald coupling to afford G20-B. Ester hydrolysis (G20-C) and reduction of the nitro group as previously described afforded G20-D, which underwent intramolecular amide coupling to form the macrocycle G20-E. Treatment with diiodomethane under mild basic conditions afforded the dihydropyrimidinone G20-F, which underwent acidic demethylation, resulting in amine deprotection and formation of the pyridone ring of general structure 24.

[0829] General Solution 21

[0830]

[0831]

[0832] Compounds of general structure 25 can be prepared according to the general sequence outlined in general scheme 21. Under the conditions previously described, R 2 Substituted o-bromobenzyl bromide can undergo nucleophilic displacement with tert-butyl (2-hydroxyethyl)carbamate to give G21-A. 1 Buchwald coupling of the substituted anthranilate afforded G21-B. Using the same chemistry as previously described, ester hydrolysis (G21-C) and amide coupling with 2-bromo-6-methoxypyridin-3-amine (G21-D) followed by dihydropyrimidinone ring formation afforded G21-E. Subsequent amine deprotection (G21-F), intramolecular ring closure (G21-G), and demethylation using previously described procedures afforded the general structure 25.

[0833] General Solution 22

[0834]

[0835]

[0836] Compounds of general structure 26 can be prepared according to the general sequence outlined in general scheme 22. Nucleophilic displacement of 2-bromo-6-methoxypyridin-3-amine with diethyl malonate in a solvent such as THF or DMF in the presence of a base such as NaH affords G22-A. Decarboxylation at elevated temperature in DMSO / H2O in the presence of LiCl affords G22-B. 3 Dialkylation of the halide (G22-C) followed by reduction of the ester with a reducing agent such as LAH affords the alcohol G22-D. Aldehyde G22-E can be formed with a mild oxidizing agent such as Dess-Martin reagent and can then be reacted with R 2 Substituted (2-bromophenyl)methanamines (G22-F) were subjected to reductive amination followed by boc protection to generate G22-G. 1 -substituted o-bromoaniline carbonates undergo Buchwald cross-coupling to generate G22-H. Reduction of the nitro group using previously described methods yields G22-I, which is then treated with a base (e.g., LiHMDS) to effect macrocyclization to generate G22-J. Treatment with diiodomethane under mild basic conditions yields the dihydropyrimidinone G22-K, which is then treated with TMSI at elevated temperature in a solvent (e.g., acetonitrile) to deprotect the boc group and form the pyridone ring of general structure 26.

[0837] General Solution 23

[0838]

[0839] Compounds of general structure 27 can be prepared according to the general sequence outlined in general scheme 23. G16-D is acetal protected (G23-A) by treatment with p-toluenesulfonic acid (tosic acid) and ethylene glycol, followed by hydrolysis (G23-B) and amide coupling with 2-bromo-6-methoxypyridin-3-amine (G23-C) using the chemistry discussed previously. Treatment with diiodomethane under mild basic conditions generates the dihydropyrimidinone G23-D, which is acetal deprotected by treatment with HCl in dioxane (G23-E), followed by reductive amination with 2-(2-aminoethyl)isoindoline-1,3-dione (G23-F), and then boc protection to provide G23-G. Removal of the phthalimide protecting group (G23-H) allowed macrocyclization via the previously discussed Buchwald chemistry (G23-H), followed by demethylation under acidic conditions, resulting in amine deprotection and formation of the pyridone ring of general structure 27.

[0840] Method / Purpose

[0841] In general, the present invention also relates to the compounds and / or pharmaceutical compositions described herein for use as medicaments or in therapy.

[0842] The compounds of the present invention as defined herein are voltage-gated sodium ion channels, in particular voltage-gated sodium ion channels Na v 1.8 inhibitor. v 1.8 The activity of a compound as an inhibitor can be determined according to the methods generally described in the Examples herein or according to methods available to those of ordinary skill in the art.

[0843] In one aspect, the present invention relates to compounds and pharmaceutical compositions as described herein as regulators of voltage-gated sodium channels (particularly Na v 1.8) Use of inhibitors.

[0844] In one embodiment, the present invention relates to a method of inhibiting a voltage-gated sodium ion channel in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the present invention or a pharmaceutical composition of the present invention as described herein. In another embodiment, the voltage-gated sodium channel is Na v 1.8.

[0845] In one embodiment, the present invention relates to a compound of the present invention or a pharmaceutical composition of the present invention for inhibiting voltage-gated sodium ion channels. In another embodiment, the voltage-gated sodium channel is Na v 1.8.

[0846] 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 preparation of a medicament for inhibiting voltage-gated sodium ion channels. In another embodiment, the voltage-gated sodium channel is Na v 1.8.

[0847] Without wishing to be bound by any particular theory, the compounds and compositions of the present invention are particularly useful in the treatment of diseases related to Na v 1.8 Diseases, conditions or disorders related to activation or overactivity of v When activation or overactivity of 1.8 is associated with a specific disease, condition, or disorder, the disease, condition, or disorder may also be referred to as "Na v 1.8-mediated diseases, conditions or disorders". Exemplary Na v 1.8-mediated diseases, disorders and conditions include pain and pain-related diseases as well as cardiovascular diseases, such as atrial fibrillation.

[0848] According to an embodiment of the present invention, a pain-related disease is pain caused by any of a variety of diseases of different etiologies described throughout this 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.

[0849] In some embodiments, the pain or pain-related disease is neuropathic pain or chronic neuropathic pain. In some embodiments, the pain or pain-related disease 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.

[0850] In some embodiments, the pain or pain-related disorder is neuropathic pain selected from post-herpetic neuralgia, diabetic neuropathy, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma, traumatic neuroma, Morton's neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, drug 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 headache.

[0851] In some embodiments, the pain or pain-related disorder is neuropathic pain or chronic neuropathic pain selected from diabetic peripheral neuropathy, pain caused by neuropathy, nervous system or neuronal damage, pain-related nerve damage, neuropathic pain and related acute or chronic pain, post-herpetic neuralgia, pain-related nerve root avulsion, painful traumatic mononeuropathy, painful polyneuropathy, erythromelalgia, paroxysmal extreme pain disorder (PEPD), burning mouth syndrome, central pain syndrome caused by injury at the level of the nervous system, traumatic nerve injury, nerve compression or entrapment, congenital indolence (CIP), dysmenorrhea, primary erythromelalgia, HIV peripheral sensory neuropathy, pudendal neuralgia, spinal nerve injury, chronic inflammatory demyelinating polyneuropathy (CIDP), carpal tunnel syndrome and vasculitic neuropathy.

[0852] In some embodiments, the pain or pain-related disorder is visceral pain, wherein the visceral pain is inflammatory bowel disease pain, Crohn's disease pain, or interstitial cystitis pain.

[0853] In some embodiments, the pain or pain-related disorder is musculoskeletal pain, wherein the musculoskeletal pain is osteoarthritis pain, back pain, cold pain, burn pain, or dental pain.

[0854] In some embodiments, the pain or pain-related disorder is idiopathic pain, wherein the idiopathic pain is fibromyalgia.

[0855] In some embodiments, the pain or pain-related disease is chronic or acute preoperative pain or chronic or acute postoperative pain. Postoperative pain includes pain after outpatient surgery. Non-hospital surgery (also known as outpatient surgery) refers to surgery on the same day that does not require an overnight stay in a hospital or other medical institution. In some embodiments, the pain associated with preoperative pain is selected from neuropathic pain or chronic neuropathic pain, chronic osteoarthritis pain, dental pain, or inflammatory pain. In some embodiments, the pain associated with postoperative pain is selected from bunionectomy pain, hernia repair pain, breast surgery pain, or cosmetic surgery pain.

[0856] In some embodiments, pain or pain-related diseases are pain caused by trauma or iatrogenic medical or dental procedures. As used herein, the term "iatrogenic" refers to pain that is unintentionally induced by medical or dental personnel (such as a surgeon or dentist) during a medical or dental treatment or diagnostic procedure, including but not limited to pain caused by preoperative (i.e., "before"), perioperative (i.e., "during" or medically induced pain during non-surgical or surgical treatment), and postoperative (i.e., post-operative, post-operative, or surgically induced) medical or dental procedures.

[0857] In some embodiments, the pain or pain-related disorder is nociceptive pain, wherein the nociceptive pain is postoperative pain, cancer pain, back and craniofacial pain, osteoarthritis pain, dental pain, or diabetic peripheral neuropathy.

[0858] In some embodiments, the pain or pain-related disease is inflammatory pain. Inflammatory pain can be pain of various physiological causes. In some embodiments, the inflammatory pain is selected from pain associated with osteoarthritis, rheumatoid arthritis, rheumatism, tenosynovitis and gout, shoulder tendinitis or bursitis, gouty arthritis and polymyalgia rheumatica, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, or other pain caused by central sensitization; complex regional pain syndrome, chronic arthritis pain and related neuropathic pain 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, rheumatism, gout, shoulder 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 arthritic pain, and related neuropathic pain. In some embodiments, the inflammatory pain is rheumatoid arthritis pain or vulvodynia.

[0859] In some embodiments, the inflammatory pain is osteoarthritis, chronic osteoarthritis pain (eg, hip or knee), or chronic inflammatory demyelinating polyneuropathy.

[0860] 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 pain and neck pain, or pain caused by physical trauma or amputation. 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 pain and neck pain, sprains, strains, or pain caused by physical trauma or amputation.

[0861] In some embodiments, the pain or pain-related disease is a pain disorder associated or related to nerve or neuronal damage caused by a disease selected from the group consisting of: neuropathy, pain-related nerve injury, pain-related root avulsion, painful traumatic mononeuropathy, painful polyneuropathy, erythromelalgia, paroxysmal excruciating pain syndrome (PEPD), burning mouth syndrome; central pain syndrome caused by injury at the level of the nervous system, traumatic nerve injury, nerve compression or entrapment, congenital indolence (CIP), dysmenorrhea, primary erythromelalgia; HIV peripheral sensory neuropathy, pudendal neuralgia, spinal nerve injury, chronic inflammatory demyelinating polyneuropathy (CIDP), carpal tunnel syndrome, or vasculitic neuropathy.

[0862] In some embodiments, the pain or pain-related disorder is pain resulting from trauma, or pain resulting from iatrogenic, medical, or dental procedures.

[0863] 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 associated phantom limb pain, postoperative medical or dental procedure or treatment pain, or HIV-related pain or HIV treatment-induced pain.

[0864] In some embodiments, the pain or pain-related disease is neuropathic pain or other pain-related disease is selected from peripheral neuropathic pain, central neuropathic pain, hereditary erythromelalgia (IEM), small fiber neuralgia (SFN), paroxysmal excruciating 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, vulvodynia, pain caused by physical trauma, post-amputation pain, neuroma pain, phantom limb pain, cancer, toxins or chronic inflammatory conditions.

[0865] 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 zoster neuralgia, generalized neuralgia, epilepsy, epilepsy, neurodegenerative disease, psychiatric disorder, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorder, neuroendocrine disorder, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache, neck pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postoperative pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or gastrointestinal motility disorders.

[0866] 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 headaches, migraines, tension headaches (including cluster headaches), 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 and distal discharges, radiculopathy, chemotherapy-induced neuropathic pain, radiation-induced neuropathic pain, post-mastectomy pain, central pain, spinal cord injury pain, post-stroke pain, thalamic pain, complex regional pain syndrome, phantom pain, intractable pain, acute pain, acute postoperative pain, acute musculoskeletal pain, joint pain, mechanical low back pain, neck pain, Tendonitis, injury / sports pain, acute visceral pain, pyelonephritis, appendicitis, cholecystitis, intestinal obstruction, hernia, chest pain, heart pain, pelvic pain, renal colic, acute labor 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, maxillofacial pain, including sinusitis pain, toothache, multiple sclerosis (MS) pain, depression pain, leprosy pain, Behçet's disease pain, adiposity dolorosa, phlebitis pain, Guillain-Barré pain, leg pain and dysphagia syndrome, Haglaud's syndrome, erythromelalgia pain, Fabry's disease pain, bladder and genitourinary disorders including urinary incontinence, overactive bladder, painful bladder syndrome, interstitial cystitis (IC), prostatitis, complex regional pain syndrome (CRPS) (types I and II), widespread pain, paroxysmal excruciating pain, pruritus, tinnitus, or angina-induced pain.

[0867] In another aspect, the present invention relates to the use of the compounds and pharmaceutical compositions of the present invention in methods and medicines for the treatment of cardiovascular diseases, disorders and conditions, including atrial fibrillation and cardiac arrhythmias.

[0868] In some embodiments, the cardiovascular disease is atrial fibrillation that is idiopathic in nature or caused by a disease as defined herein. Atrial fibrillation can be paroxysmal atrial fibrillation, persistent atrial fibrillation, chronic atrial fibrillation, atrial fibrillation with heart failure, atrial fibrillation with valvular heart disease, or atrial fibrillation with chronic kidney disease. In specific embodiments, atrial fibrillation is selected from paroxysmal, persistent, or chronic atrial fibrillation.

[0869] In some embodiments, the cardiovascular disease comprises arrhythmia.

[0870] Thus, in another aspect, the present invention also provides methods of treating a subject, particularly a human. Disease states that can be treated by the methods and compositions provided herein include, but are not limited to, pain and pain-related diseases and cardiovascular disease.

[0871] The term "treat" refers to alleviating a particular disorder, eliminating or alleviating one or more symptoms of a disorder, slowing or eliminating the progression of a disorder, and delaying the recurrence of a disorder in a patient or subject previously suffering from the disorder.

[0872] As used herein, "effective amount" and "therapeutically effective amount" are used interchangeably. The term "therapeutically effective amount" refers to an amount of a compound of Formula (Ia), (I), (II), (III), (IV) or (V) or a tautomer thereof, or a pharmaceutically acceptable salt thereof, that will elicit the desired biological response in humans. It may vary depending on the compound, the disease and its severity, and the age and weight of the subject to be treated.

[0873] The term "subject" refers to a human body.

[0874] In one aspect, the invention relates to a method of treating pain or a pain-related disorder as defined herein in a human in need thereof, comprising administering to said human a compound of the invention or a pharmaceutical composition of the invention as described herein.

[0875] In one embodiment, there is provided a method of treating acute pain or chronic pain in a human in need thereof, comprising administering to the human a compound of the invention or a pharmaceutical composition of the invention as described herein.

[0876] In one embodiment, a method of treating pain caused by trauma, pain caused by iatrogenic medical or dental procedures, or pain associated with pre- or post-operative surgery in a human in need thereof is provided, comprising administering to the human a compound of the invention or a pharmaceutical composition of the invention as described herein.

[0877] In one embodiment, there is provided a method of 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 invention or a pharmaceutical composition of the invention as described herein.

[0878] In one embodiment, there is provided a method of treating neuropathic pain or chronic neuropathic pain selected from small fiber neuropathy, small fiber-mediated diabetic neuropathy, idiopathic small fiber neuropathy, painful diabetic neuropathy, and polyneuropathy in a human in need thereof, comprising administering to the human a compound of the invention or a pharmaceutical composition of the invention as described herein.

[0879] In one embodiment, there is provided a method of treating inflammatory pain selected from osteoarthritis, chronic osteoarthritis pain, and chronic inflammatory demyelinating polyneuropathy in a human in need thereof, comprising administering to the human a compound of the invention or a pharmaceutical composition of the invention as described herein.

[0880] In one embodiment, there is provided a method of treating pain or a pain-related disease in a person in need thereof, the pain or pain-related disease being selected from neuropathic pain, post-operative pain in an outpatient clinic, and osteoarthritis, comprising administering to the person a compound of the invention or a pharmaceutical composition of the invention as described herein. In some embodiments, the pain or pain-related disease is neuropathic pain. In some embodiments, the pain or pain-related disease is chronic neuropathic pain. In some embodiments, the pain or pain-related disease is small fiber neuropathy. In some embodiments, the pain or pain-related disease is post-operative pain in an outpatient clinic. In some embodiments, the pain or pain-related disease is osteoarthritis. In some embodiments, the pain or pain-related disease is knee osteoarthritis and / or hip osteoarthritis.

[0881] In another aspect, the present 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.

[0882] In one embodiment, there is provided a compound of the invention or a pharmaceutical composition of the invention for use in the treatment of acute pain or chronic pain.

[0883] In one embodiment, there is provided a compound of the invention or a pharmaceutical composition of the invention for use in treating pain resulting from trauma, pain resulting from iatrogenic medical or dental procedures, or pain associated with pre- or post-operative surgery.

[0884] 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.

[0885] In one embodiment, a compound of the invention or a pharmaceutical composition of the invention is provided for use in the treatment of neuropathic pain or chronic neuropathic pain selected from small fiber neuropathy, small fiber-mediated diabetic neuropathy, idiopathic small fiber neuropathy, painful diabetic neuropathy, and polyneuropathy.

[0886] In one embodiment, there is provided a compound of the invention or a pharmaceutical composition of the invention for use in the treatment of inflammatory pain selected from osteoarthritis, chronic osteoarthritis pain and chronic inflammatory demyelinating polyneuropathy.

[0887] In one embodiment, a compound of the present invention or a pharmaceutical composition of the present invention is provided for use in treating pain or a pain-related disease selected from neuropathic pain, postoperative pain in ambulatory surgery, and osteoarthritis. In some embodiments, the pain or pain-related disease is neuropathic pain. In some embodiments, the pain or pain-related disease is chronic neuropathic pain. In some embodiments, the pain or pain-related disease is small fiber neuropathy. In some embodiments, the pain or pain-related disease is postoperative pain in ambulatory surgery. In some embodiments, the pain or pain-related disease is osteoarthritis. In some embodiments, the pain or pain-related disease is knee osteoarthritis and / or hip osteoarthritis.

[0888] In another aspect, the present invention also provides 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 treating pain and pain-related diseases as described herein.

[0889] In one embodiment, there is provided the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of acute pain or chronic pain.

[0890] In one embodiment, there is provided the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for treating pain resulting from trauma, pain resulting from iatrogenic medical or dental procedures, or pain associated with pre- or post-operative surgery.

[0891] In one embodiment, there is provided the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of neuropathic pain, nociceptive pain, inflammatory pain, musculoskeletal pain, visceral pain or idiopathic pain.

[0892] In one embodiment, there is provided the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of neuropathic pain or chronic neuropathic pain, wherein the neuropathic pain or chronic neuropathic pain is selected from small fiber neuropathy, small fiber-mediated diabetic neuropathy, idiopathic small fiber neuropathy, painful diabetic neuropathy, and polyneuropathy.

[0893] In one embodiment, there is provided the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of inflammatory pain selected from osteoarthritis, chronic osteoarthritis pain and chronic inflammatory demyelinating polyneuropathy.

[0894] In one embodiment, there is provided a compound of the invention or a pharmaceutical composition of the invention for use in the manufacture of a medicament for treating pain or a pain-related disease selected from neuropathic pain, postoperative pain in ambulatory surgery, and osteoarthritis. In some embodiments, the pain or pain-related disease is neuropathic pain. In some embodiments, the pain or pain-related disease is chronic neuropathic pain. In some embodiments, the pain or pain-related disease is small fiber neuropathy. In some embodiments, the pain or pain-related disease is postoperative pain in ambulatory surgery. In some embodiments, the pain or pain-related disease is osteoarthritis. In some embodiments, the pain or pain-related disease is knee osteoarthritis and / or hip osteoarthritis.

[0895] In one aspect, the present invention relates to a method of treating atrial fibrillation as defined herein in a human in need thereof, comprising administering to the human a compound of the invention or a pharmaceutical composition of the invention as described herein. In some embodiments, atrial fibrillation is selected from paroxysmal atrial fibrillation, persistent atrial fibrillation, chronic atrial fibrillation, atrial fibrillation with heart failure, atrial fibrillation with valvular heart disease, and atrial fibrillation with chronic kidney disease.

[0896] 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 treating atrial fibrillation. In some embodiments, atrial fibrillation is selected from paroxysmal atrial fibrillation, persistent atrial fibrillation, chronic atrial fibrillation, atrial fibrillation with heart failure, atrial fibrillation with valvular heart disease, and atrial fibrillation with chronic kidney disease.

[0897] 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 in the preparation of a medicament for treating atrial fibrillation. In some embodiments, atrial fibrillation is selected from paroxysmal atrial fibrillation, persistent atrial fibrillation, chronic atrial fibrillation, atrial fibrillation with heart failure, atrial fibrillation with valvular heart disease, and atrial fibrillation with chronic kidney disease.

[0898] In another aspect, the present invention relates to a compound of the invention or a pharmaceutical composition of the invention for use in therapy.

[0899] Combination therapy

[0900] The compounds and pharmaceutical compositions of the present invention disclosed herein can be combined or co-administered with other therapeutic agents, particularly agents that enhance the activity or distribution time of the compounds. The combination therapies of the present invention comprise administering at least one compound of the present invention and using at least one other treatment method, including administering one or more other therapeutic agents.

[0901] As used herein, the term "co-administration" and its derivatives refer to the simultaneous administration or separate sequential administration of the Na v1.8 Inhibitory Compound and Additional Active Ingredient. Additional active ingredients include any known compound or therapeutic agent, or a compound or therapeutic agent that exhibits advantageous properties when administered to a human in need of treatment. Generally, if administration is not simultaneous, the compounds are administered at close times to each other. Furthermore, the compounds may be administered in the same or separate dosage forms, e.g., one compound may be administered orally and the other compound may be administered intravenously.

[0902] 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., such as but not limited to duloxetine or amitriptyline), anticonvulsants (i.e., such as but not limited to pregabalin and gabapentin), opioids (i.e., such as but not limited to hydrocodone, codeine, morphine, oxycodone, oxymorphone, fentanyl, etc.), etc.; and wherein the above-mentioned administration is also determined by one of ordinary skill in the art. In one aspect, suitable Nav1.7 inhibitors or Nav1.9 inhibitors for use in the present invention include, but are not limited to, those Nav1.7 inhibitors or Nav1.9 inhibitors known in the chemical literature.

[0903] Each component of the combination for therapeutic purposes (e.g., a compound or pharmaceutical composition of the 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 a combination of routes of administration. In certain embodiments, each of the same or different routes of administration or a combination of routes of administration is selected from oral, intravenous, or parenteral administration. Example

[0904] The following examples illustrate the present invention. These examples are not intended to limit the scope of the present invention, but rather provide guidance to the skilled person on preparing and using the compounds, compositions, and methods of the present invention. Although embodiments of the present invention have been described, it will be appreciated by the skilled person that various changes and modifications may be made without departing from the spirit and scope of the present invention.

[0905] The skilled artisan will appreciate that purification methods (using acidic or basic modifiers) or compound workup procedures (using acidic or basic conditions) may result in the formation of salts of the title compound (e.g., hydrobromic, formic, hydrochloric, trifluoroacetic, or ammonia salts of the title compound). The present invention is intended to encompass such salts.

[0906] The final compound was characterized by LCMS (conditions listed below) and NMR. 1 H NMR or 19FNMR 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. CDCl is deuterated chloroform, DMSOd is hexadeuterated dimethyl sulfoxide, and CDOD is tetradeuterated methanol. Chemical shifts are reported in parts per million (ppm) downfield from internal standard tetramethylsilane (TMS) or NMR solvents. The 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 peak. J represents the NMR coupling constant measured in Hertz.

[0907] Unless otherwise stated, all starting materials were obtained from commercial suppliers and used without further purification. Unless otherwise stated, all temperatures are expressed in degrees Celsius. Unless otherwise stated, all reactions were carried out under an inert atmosphere at ambient temperature. All temperatures are expressed in degrees Celsius, all solvents were of the highest purity, and all reactions were carried out under anhydrous conditions under an argon (Ar) or nitrogen (N2) atmosphere (where necessary).

[0908] instrument

[0909] Recorded using a Bruker Avance III 400 MHz spectrometer and a Bruker Avance NEO NanoBay V4-3400 MHz spectrometer 1 H NMR spectra. CDCI3 is deuterated chloroform, DMSO-d6 is hexadeuterated dimethyl sulfoxide, and CD3OD is tetradeuterated methanol. Chemical shifts are reported in parts per million (ppm) downfield from the internal standard tetramethylsilane (TMS) or the NMR solvent. Abbreviations for NMR data are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublet, dt = triplet of doublet, app = apparent, and bR = broad. J represents the NMR coupling constant measured in Hertz.

[0910] Mass spectra were run on an open LC-MS system using a Waters Acquity QDa mass spectrometer detector. Compounds were analyzed using a reverse phase column (e.g., Xbridge-C18, Sunfire-C188, Thermo Aquasil / Aquasil C18, Acquity HPLCC18, Thermo Hypersil Gold) eluting with a gradient of acetonitrile and water containing a low percentage of an acid modifier (e.g., 0.02% TFA).

[0911] HPLC method

[0912] Method A: UPLC: Waters Acquity equipped with Acquity CSH, C18 (2.1 mm × 30 mm, 1.7 μm column) using a gradient from 1 to 100% MeCN / H2O / 0.1% TFA over 1.85 min at a flow rate of 1.3 mL / min. Mass determination was performed using an Agilent 6110 Quadrupole MS under positive ESI;

[0913] Method B: UPLC: Waters Acquity equipped with Acquity CSH, C18 (2.1 mm × 30 mm, 1.7 μm column) using a gradient from 1 to 100% MeCN / H2O / 0.1% 10 mM NH4HCO3 / water (adjusted to pH 10 with 25% aq NH4OH) over 1.85 min at a flow rate of 1.3 mL / min. Mass determination was performed using an Agilent 6110 Quadrupole MS under positive ESI;

[0914] Method C: HPLC: Agilent 1290 Infinity II equipped with a CSH, C18, 2.1 x 30 mm, 1.7 μm column, using a 3-97% CH3CN / H2O / 0.1% HCO2H gradient over 2.0 min at a flow rate of 1.0 mL / min. Mass determination was performed using an Agilent 6110 Quadrupole MS under positive ESI.

[0915] Method D: HPLC: Agilent 1290 Infinity II equipped with an XBRIDGE, C8, 4.6 x 50 mm, 3.5 μm column, using a 5-95% CH3CN / H2O / 0.1% NH4HCO3 gradient over 6.0 min at a flow rate of 1.2 mL / min. Mass determination was performed using an Agilent 6110 Quadrupole MS under positive ESI.

[0916] Method E: HPLC: Agilent 1290 Infinity II equipped with a CSH, C18, 2.1 x 30 mm, 3.5 μm column, using a 0-100% CH3CN / H2O / 0.1% HCO2H gradient over 4.0 min at a flow rate of 1.0 mL / min. Mass determination was performed using an Agilent 6110 Quadrupole MS under positive ESI;

[0917] Method F: HPLC: Agilent 1290 Infinity II equipped with a Sunfire, C18, 2.1 x 30 mm, 3.5 μm column, using a 0-100% CH3CN / H2O / 0.1% HCO2H gradient at a flow rate of 1.0 mL / min over 4.0 min. Mass determination was performed using an Agilent 6110 Quadrupole MS under positive ESI;

[0918] Method G: 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% HCO2H over 1.85 min at a flow rate of 1.3 mL / min. Mass determination was performed using an Agilent 6110 Quadrupole MS under positive ESI;

[0919] Method H: HPLC: Shimadzu LC-20AB equipped with Kinetex, C18 (2.1 mm x 50 mm, 5 μm column) using a gradient of 30-90% MeCN / H2O / 0.1% TFA over 5.4 min at a flow rate of 0.5 mL / min.

[0920] Method I: HPLC: Agilent 1260 Infinity II equipped with a Luna C18, 2.0 x 50 mm, 5 μm column, using a gradient of 5-95% CH3CN (0.02% TFA) / H2O (0.04% TFA) over 4.5 min at a flow rate of 1.0 mL / min. Mass determination was performed using an Agilent 6110 single quadrupole MS under positive ESI.

[0921] Examples Definitions and Abbreviations

[0922] In the following experimental descriptions, the following abbreviations may be used:

[0923]

[0924]

[0925]

[0926]

[0927]

[0928] intermediates

[0929]

[0930] Step A: 6-methoxy-2-vinylpyridin-3-amine Int-1

[0931]

[0932] A solution of 2-bromo-6-methoxypyridin-3-amine (13.0 g, 64.0 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (10.9 mL, 64.0 mmol) in 1,4-dioxane (160 mL) and saturated aqueous Na2CO3 (20.0 mL, 64.0 mmol) were purged with N2 for 5 min, Pd(PPh3)4 (3.70 g, 3.20 mmol) was added under N2 atmosphere, and the reaction mixture was heated at 80 ° C for 16 h. The reaction mixture was cooled to ambient temperature, quenched with H2O (300 mL), and extracted with EtOAc (2x200 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, pre-adsorbed onto silica gel, and purified by flash column chromatography on silica gel (330 g) eluting with 15-17% EtOAc-petroleum ether. Product fractions were combined and evaporated under reduced pressure to afford 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-d6,400MHz)δ7.04-7.06(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).

[0933]

[0934] Step A: 2-Allyl-6-methoxypyridin-3-amine Int-1a

[0935]

[0936] To a solution of 2-bromo-6-methoxypyridin-3-amine (5.0 g, 24.6 mmol) in THF (300 mL) under N2 purging was added 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.21 g, 36.9 mmol), followed by Pd(Ph3P)4 (1.99 g, 1.72 mmol) and CsF (14.9 g, 99.0 mmol), the reaction mixture was sealed and heated at 62°C for 0.5 h. Additional THF (100 mL) and H2O (50 mL) were added to the reaction mixture, and the reaction was continued to be heated at 62°C for 5 h. The reaction mixture was allowed to cool to ambient temperature, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4, filtered, and the solvent evaporated under reduced pressure. The crude residue was dissolved in DCM, pre-adsorbed onto a silica gel precolumn, and purified by silica gel flash column chromatography (220 g) with a gradient elution from 100% heptane to 60% EtOAc-heptane. Product fractions were combined and evaporated under reduced pressure to afford 2-allyl-6-methoxypyridin-3-amine Int-1a (1.50 g, 37% yield) as a red oil. HPLC / MS 0.61 min (B), [M+H]' 165.0. 1 H NMR(CDCl3,400MHz)δ3.38(dt,J=6.36,1.71Hz,2H),3.79(s,3H),5.02-5.08(m,2 H),5.89-6.01(m,1H),5.92(s,1H),6.41(d,J=8.31Hz,1H),6.87(d,J=8.80Hz,1H)

[0937]

[0938] Step A: (2-Bromo-6-methoxypyridin-3-yl)-carbamic acid tert-butyl ester Int-1b-1

[0939]

[0940] To the solution of 2-bromo-6-methoxypyridine-3-amine (5.05g, 24.9mmol) in MeCN (10mL), add boc-anhydride (23.1mL, 99.0mmol), and reactant mixture is stirred into 21h at 70 DEG C.Reactant mixture is cooled to environment temperature, is loaded in silica gel filling pre-post, by silica gel flash column chromatography (330g) with 100% heptane to 20% heptane-EtOAc gradient elution purification.Product fractions are merged, evaporated under reduced pressure, obtain yellow oil, it is further passed through silica gel flash column chromatography (330g) with 50% heptane-DCM to 100% DCM gradient elution purification.Merge product fractions and evaporate under reduced pressure, obtain (2-bromo-6-methoxypyridine-3-yl)-t-butyl carbamate Int-1b-1 (6.60g, 74% yield), is viscous yellow oil. HPLC / MS 1.07 min (A), [M+H] + 305.0. 1 H NMR (DMSO-d6, 400MHz) δ 8.5-8.8 (m, 1H), 7.71 (d, 1H, J = 8.8Hz), 6.85 (d, 1H, J = 8.3Hz), 3.84 (s, 3H), 1.5-1.5 (m, 1H), 1.45 (s, 9H).

[0941] Step B: (2-(But-en-1-yl)-6-methoxypyridin-3-yl)-carbamic acid tert-butyl ester Int-1b-2

[0942]

[0943] To (2-bromo-6-methoxypyridin-3-yl)-carbamic acid tert-butyl ester (6.57g, 21.7mmol), but-3-ene-1-yl boronic acid (4.33g, 43.3mmol), toluene (75mL) and H purged with N O (15.00mL) were added PdCl (dppf)-CH Cl adduct (1.77g, 2.17mmol) and K PO (13.8g, 65.0mmol), and the reaction mixture was heated at 80 ° C for 4h. The reaction mixture was cooled to ambient temperature, diluted with EtOAc, washed with H O, brine, dried over Na SO, filtered and the solvent was evaporated under reduced pressure. The crude residue was dissolved in DCM, supported on a silica gel-filled pre-column, and purified by silica gel chromatography (330g) eluting with a 100% heptane to 60% EtOAc-heptane gradient. The product fractions were combined and evaporated under reduced pressure to give (2-(but-en-1-yl)-6-methoxypyridin-3-yl)-carbamic acid tert-butyl ester Int-1b-2 (1.69 g, 24% yield) as a clear oil with a purity of 82%. HPLC / MS 0.99 min (A), [M+H] + 279.1. 1H NMR (DMSO-d6, 400MHz) 8.3-8.8 (m, 1H), 7.3-7.6 (m, 1H), 6.5-6.7 (m, 1H), 5.89 (tdd, 1H, J = 6.6, 10.3, 17.1Hz), 5.4-5. 7(m,1H),4.9-5.1(m,2H),3.8-3.8(m,4H),2.71(dd,2H,J=6.6,9.0Hz),2.3-2.5(m,2H),1.6-1.6(m,1H),1.44(s,9H).

[0944] Step C: 2-(But-en-1-yl)-6-methoxypyridin-3-amine Int-1b

[0945]

[0946] To a solution of (2-(but-3-ene-1-yl)-6-methoxypyridin-3-yl)-t-butyl carbamate (338 mg, 1.21 mmol) in DCM (20 mL) was added TFA (0.936 mL, 12.1 mmol), and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was evaporated under reduced pressure, and the residue was distributed and evaporated in vacuo using CHCl (3x). The oil was dissolved in EtOAc, washed with saturated NaHCO aqueous solution, H O, brine, dried over Na SO, filtered, and the solvent was evaporated under reduced pressure. The residue was dissolved in DCM, adsorbed on a pre-column filled with silica gel, and purified by flash column chromatography on silica gel (40 g) with a gradient elution of 100% heptane to 50% heptane-EtOAc. The product fractions were combined and evaporated under reduced pressure to give 2-(but-en-1-yl)-6-methoxypyridin-3-amine Int-1b (158 mg, 71% yield) as a light brown oil with a purity of 93%. HPLC / MS 0.35 min (A), [M+H] + 179.1. 1 H NMR (CD3OD, 400MHz) δ7.12 (d, 1H, J = 8.8Hz), 6.5-6.5 (m, 1H), 5.5-5.7 (m, 1H), 4.9-5.1 (m, 2H), 3.8-3.8 (m, 4H), 2.7-2.8 (m, 2H), 2.48 (br dd,2H,J=1.0,7.8Hz).

[0947]

[0948] Step A: (But-3-yn-1-yl)-carbamic acid tert-butyl ester Int-1c-1

[0949]

[0950] A stirred suspension of but-3-yn-1-amine hydrochloride (4.26 g, 40.4 mmol) in MeOH (4 mL) was treated with TEA (11.8 mL, 85.0 mmol) and the reaction mixture was stirred at room temperature until a clear solution was formed. Boc-anhydride (9.25 g, 42.4 mmol) dissolved in THF (60 mL) was added in a slow stream and the reaction mixture was stirred at room temperature for 96 h. The solvent was evaporated under reduced pressure and the crude residue was distributed between DCM and H2O, layered, and the organic phase was washed with brine, dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to give but-3-yn-1-yl-carbamic acid tert-butyl ester Int-1c-1 (6.57 g, 94% yield) as a colorless oil. 1 HNMR (CD3CN, 400MHz) δ5.44 (br s, 1H), 3.18 (q, 2H, J = 6.5Hz), 2.34 (dt, 2H, J = 2.4, 6.8Hz), 2.22 (t, 1H, J = 2.7Hz), 1.4-1.4 (m, 9H).

[0951] Step B: (4-(6-Methoxy-3-nitropyridin-2-yl)but-3-yn-1-yl)-carbamic acid tert-butyl ester Int- 1c-2

[0952]

[0953] To but-3-alkynes-1-base-t-butyl carbamate (0.500g, 2.95mmol) and 2-iodo-6-methoxyl group-3-nitropyridine (0.993g, 3.55mmol) at Et in the mixture in O (14.77ml), add diisopropylamine (2.07mL, 14.8mmol), cuprous iodide (I) (0.056g, 0.295mmol) and bis(triphenylphosphine) palladium chloride (II) (0.104g, 0.148mmol), and with reaction mixture stirring at room temperature 70min.Reaction mixture is poured into saturated NH in the Cl aqueous solution (300mL), layered, and use Et O (2x30mL) aqueous layer extracted.With the organic extract salt water washing merging, through Na SO Drying, filter and be concentrated into and carry out purifying on diatomite. The reaction mixture was purified by flash column chromatography on silica gel (40 g) with a gradient elution of 100% heptane to 20% EtOAc-heptane. The product fractions were combined and evaporated under reduced pressure to give tert-butyl (4-(6-methoxy-3-nitropyridin-2-yl)but-3-yn-1-yl)-carbamate Int-1c-2 (431 mg, 1.31 mmol, 45% yield) as a beige solid. HPLC / MS 1.05 min (A), [M- t Bu] + 266.1. 1H NMR (CD3CN, 400MHz) δ 8.3-8.4 (m, 1H), 6.88 (d, 1H, J = 8.8Hz), 5.53 (br s, 1H), 4.00 (s, 3H), 3.33 (q, 2H, J = 6.5Hz), 2.72 (t, 2H, J = 6.6Hz), 1.44 (s, 9H).

[0954] Step C: (4-(3-Amino-6-methoxypyridin-2-yl)but-3-yn-1-yl)-carbamic acid tert-butyl ester Int-1c

[0955]

[0956] To a solution of (4-(6-methoxy-3-nitropyridin-2-yl)but-3-yn-1-yl)-carbamic acid tert-butyl ester (107 mg, 0.333 mmol) in EtOH (3 mL) was added Zn (150 mg, 2.29 mmol) and NHCl (107 mg, 1.99 mmol), and the reaction mixture was heated at 60°C for 30 min. The reaction mixture was cooled to ambient temperature, the solid was filtered, washed with EtOH, and the combined organics were evaporated under reduced pressure. The residue was partitioned between EtOAc, H2O, and a saturated aqueous solution of NaHCO3. The organic phase was washed with brine, dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to give (4-(3-amino-6-methoxypyridin-2-yl)but-3-yn-1-yl)-carbamic acid tert-butyl ester Int-1c (84 mg, 82% yield) as a yellow oil. HPLC / MS 0.82 min (A), [M+H] + 292.1. 1 H NMR (CD3CN, 400MHz) δ7.10 (d, 1H, J = 8.8Hz), 6.58 (d, 1H, J = 8.8Hz), 5.59 (br s, 1H), 4.33 (br s, 2H), 3.78 (s, 3H), 3.32 (q, 2H, J = 6.4Hz), 2.67 (t, 2H, J = 6.6Hz), 1.43 (s, 9H).

[0957]

[0958] Step A: (3-Allylpyridin-4-yl)-carbamic acid tert-butyl ester Int-1d-1

[0959]

[0960] To a flask with a stir bar was added 3-iodopyridin-4-amine (2.00 g, 9.09 mmol), 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.58 g, 27.3 mmol), and DMSO (36 mL). The reaction mixture was purged with N2, and PdCl(dppf)-CH2Cl2 adduct (0.520 g, 0.636 mmol) and K2CO3 (3.14 g, 22.7 mmol) were added. The reaction mixture was heated at 80°C for 4 h. The reaction mixture was cooled to ambient temperature, filtered through celite, the celite was washed with EtOAc, and the reaction mixture was concentrated under reduced pressure. The DMSO solution was diluted with DCM (~3:1 DCM:DMSO), boc-anhydride (4.22 mL, 18.2 mmol) was added, followed by TEA (5.07 mL, 36.4 mmol), and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with DCM, washed with H o (3x), dried over Na sO, filtered and evaporated under reduced pressure. The crude residue was dissolved in DCM, pre-adsorbed on a silica gel pre-column and purified by silica gel flash column chromatography (80g) with 100% heptane to 100% 3: 1 EtOAc-EtOH-heptane gradient elution. The product fractions were combined and evaporated under reduced pressure to obtain (3-allylpyridin-4-yl)-t-butyl carbamate Int-1d-1 (896mg, 70% yield). HPLC / MS 0.93min (B), [M+H] + 235.1. 1 HNMR(DMSO-d6,400MHz)δ8.6-8.8(m,1H),8.29(s,1H),8.25(s,1H),7.66(d,1H, J=5.9Hz),5.8-6.0(m,1H),4.9-5.2(m,2H),3.45(d,2H,J=6.4Hz),1.48(s,10H).

[0961] Step B: 3-Allylpyridin-4-amine Int-1d

[0962]

[0963] To tert-butyl (3-allylpyridin-4-yl)-carbamate (896 mg, 3.82 mmol) in DCM (10 mL) cooled to 0°C was added TFA (8.84 mL, 115 mmol), and the reaction mixture was stirred at 0°C for 3 h. The reaction mixture was concentrated under reduced pressure, and the residue was azeotroped with CHCl3 (3x) and dried under vacuum to afford 3-allylpyridin-4-amine Int-1d (1.24 g, 84% yield) as a dark, viscous oil. HPLC / MS 0.43 min (B), [M+H] +135.0. 1 H NMR(DMSO-d6,400MHz)δ13.0-13.7(m,1H),8.1-8.3(m,1H),8.09(br d,1H,J=6.4Hz),8.03(s,1H),7.2-7.7(m,1H),6.84(d,1H,J=6.8Hz),5.7-6.1(m,1H),4.9-5.3(m,2H),3.28(d,2H,J=6.4Hz).

[0964]

[0965] Step A: (2-(6-methoxy-3-nitropyridin-2-yl)ethyl)-carbamic acid tert-butyl ester Int-1e-1

[0966]

[0967] To a mixture of 2-bromo-6-methoxy-3-nitropyridine (7.00 g, 30.0 mmol), toluene (130 mL) and H2O (43.3 mL) was added (2-(trifluoro-λ 4 To the product was added tert-butyl carbamate (9.05g, 36.0mmol), PdCl (dppf)-CH Cl adduct (0.491g, 0.601mmol) and Cs CO (29.4g, 90mmol), and the reaction mixture was stirred at 80°C for 21h under N. The reaction mixture was cooled to ambient temperature, diluted with EtOAc, washed with H O (2x), salt water, and dried over Na SO, filtered and the solvent was evaporated under reduced pressure. The crude residue was dissolved in DCM, adsorbed on a silica gel-filled pre-column, and purified by silica gel flash column chromatography (330g) with a 100% heptane to 50% EtOAc gradient elution. The product fractions were combined and evaporated under reduced pressure to obtain tert-butyl (2-(6-methoxy-3-nitropyridine-2-yl) ethyl)-carbamate Int-1e-1 (6.96g, 76% yield) as a yellow solid. HPLC / MS 1.02min(A),[M+H] + 298.0. 1 H NMR (DMSO-d6, 400MHz) δ8.34 (d, 1H, J = 9.3Hz), 6.7-7.0 (m, 2H), 3.98 (s, 3H), 3.4-3.5 (m, 2H), 3.17 (s, 2H), 1.33 (s, 9H).

[0968] Step B: 2-(6-methoxy-3-nitropyridin-2-yl)ethan-1-amino)carbamate trifluoroacetate Int-1e

[0969]

[0970] To a solution of tert-butyl (2-(6-methoxy-3-nitropyridin-2-yl)ethyl)carbamate (6.96 g, 23.4 mmol) in DCM (150 mL) was added TFA (54.1 mL, 702 mmol), and the reaction was stirred for 1 h. The reaction mixture was concentrated under reduced pressure, dissolved in CHCl₃, evaporated under reduced pressure (repeated 3 times), and dried under vacuum to afford 2-(6-methoxy-3-nitropyridin-2-yl)ethyl-1-amine)carbamate, TFA salt Int-1e (11.4 g, >100% yield) as a viscous oil. HPLC / MS 0.33 min (A), [M+H] + 198.0. 1 H NMR (DMSO-d6, 400MHz) δ 8.43 (d, 1H, J = 8.8Hz), 8.32 (s, 1H), 7.86 (br s, 3H), 6.97 (d, 1H, J = 9.3Hz), 4.01 (s, 3H), 3.2-3.6 (m, 4H).

[0971]

[0972] Step A: (2-Formyl-6-methoxypyridin-3-yl)-carbamic acid tert-butyl ester Int-1f

[0973]

[0974] A nitrogen-purged container containing (2-bromo-6-methoxypyridin-3-yl)-carbamic acid tert-butyl ester (2.0 g, 6.60 mmol) and THF (33.0 ml) was cooled to -78 ° C. n-Butyl lithium (6.60 mL, 16.49 mmol) was added dropwise, and DMF (3.07 mL, 39.6 mmol) was added once after 1 h. The reaction mixture was warmed to ambient temperature and quenched with saturated NH4Cl solution. The organic layer was diluted with ether, washed with water and brine, and concentrated under reduced pressure. The crude material was directly added to a silica gel column and purified by silica gel flash column chromatography with a heptane / EtOAc gradient elution to obtain (2-formyl-6-methoxypyridin-3-yl)-carbamic acid tert-butyl ester Int-1f (800 mg, 48.1% yield) as a white solid. HPLC / MS 1.21 min (G), [M+H] + 253.1. 1 H NMR (DMSO-d6, 400MHz): δ9.96 (s, 1H), 9.88 (s, 1H), 8.57 (d, J = 9.3Hz, 1H), 7.20 (d, J = 9.3Hz, 1H), 3.92 (s, 3H), 1.50 (s, 9H).

[0975]

[0976] Step A: (3-amino-6-methoxypyridin-2-yl)methanol Int-1g-1

[0977]

[0978] A solution of methyl 3-amino-6-methoxypicolinate (4.99 g, 27.4 mmol) in THF (100.00 mL) was cooled to 0 ° C. 2M LiAlH4-THF solution (27.39 mL, 54.8 mmol) was slowly added thereto. After 2 h, saturated NH4Cl aqueous solution (50 mL) was slowly added to quench the reaction mixture and filtered. The filtrate was diluted with water (100 mL) and extracted with DCM (2x150 mL). The combined organics were washed with water (75 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in DMF and purified by reverse phase Combiflash (150 g Gold C18 column) with a gradient elution of 100% H2O to 60% MeCN-H2O (0.1% NH4OH). The product fractions were combined and lyophilized to give (3-amino-6-methoxypyridin-2-yl)methanol Int-1g-1 (2.11 g, 49% yield). HPLC / MS 0.37 min (B), [M+H] + 155.0. 1 H NMR (400MHz, CD3OD) δ3.83(s,3H)4.61(s,2H)6.56(d,J=8.80Hz,1H)7.15(d,J=8.80Hz,1H).

[0979] Step B: 2-(2-(Hydroxymethyl)-6-methoxypyridin-3-yl)isoindoline-1,3-dione Int-1g-2

[0980]

[0981] To (3-amino-6-methoxypyridin-2-yl)methanol Int-1g-1 (1.066.89 mmol) in AcOH (20 mL) was added phthalic anhydride (1.02 g, 6.88 mmol). The mixture was heated to 100° C. for 1 h, concentrated, dissolved in DCM, and washed with water. The aqueous phase was extracted with DCM, and the combined organic phases were dried, filtered, and concentrated under reduced pressure. The crude residue was purified by Combiflash reverse phase chromatography (150 g C18 Gold column, 40 min run, 0-60% MeCN in H2O (all containing 0.1% formic acid) with a gradient elution from 100% H2O (0.1% formic acid) to 60% MeCN / H2O (0.1% formic acid). Product fractions were combined and lyophilized to give 2-(2-(hydroxymethyl)-6-methoxypyridin-3-yl)isoindoline-1,3-dione Int-1g-2 (1.10 g, 56% yield) as a light brown solid. HPLC / MS 0.70 min (G), [M+H]+ 285.0. 1 H NMR (400MHz, CD3OD) δ4.00 (s, 3H) 4.52 (s, 2H) 6.84 (d, J = 8.31Hz, 1H) 7.61 (d, J = 8.31Hz, 1H) 7.86-7.90 (m, 2H) 7.93-7.98 (m, 2H).

[0982] Step C: 3-(1,3-dioxoisoindolin-2-yl)-6-methoxypyridinecarboxaldehyde Int-1g

[0983]

[0984] To a solution of 2-(2-(hydroxymethyl)-6-methoxypyridin-3-yl)isoindoline-1,3-dione Int-1g-2 (1.11 g, 3.90 mmol) in DCM (40 mL) was added Dess-Martin periodinane (2.32 g, 5.47 mmol) at 0 ° C, and the reaction mixture was warmed to room temperature and stirred for 2.5 h. 1N NaOH (20 mL) was added, followed by water (30 mL) and DCM (30 mL). The mixture was stirred at room temperature for 15 min, the organic phase was separated, the aqueous phase was extracted with DCM (50 mL), and the combined organic solutions were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by Combiflash silica gel flash column chromatography (80 g) with a gradient elution of 100% heptane to 60% EtOAc. The product fractions were combined and evaporated under reduced pressure to give 3-(1,3-dioxoisoindolin-2-yl)-6-methoxypicolinaldehyde Int-1g (1.03 g, 93% yield) as a white solid. HPLC / MS 0.88 min (A), [M+H] + 283.1. 1 H NMR (400MHz, CDCl3) δ4.01-4.15(m,3H)7.03-7.17(m,1H)7.58-7.69(m,1H)7.74-7.86(m,2H)7.91-8.02(m,2H)9.87-9.96(m,1H).

[0985]

[0986] Step A: (2-(6-methoxy-3-nitropyridin-2-yl)ethyl)-carbamic acid tert-butyl ester Int-1h-1

[0987]

[0988] Following the procedure outlined in Int-1e-1, replace (2-(trifluoro-λ 4 -boryl)ethyl)-carbamic acid tert-butyl ester, potassium salt is (2-(trifluoro-λ 4-boryl)propyl)-carbamic acid tert-butyl ester, potassium salt, (3-(6-methoxy-3-nitropyridin-2-yl)propyl)-carbamic acid tert-butyl ester Int-1h-1 (352 mg, 17% yield) was prepared as a yellow solid. HPLC / MS 1.08 min (A), [M- t Bu] + 256.1. 1 H NMR (CDCl3, 400MHz) δ8.28 (d, 1H, J = 8.8Hz), 6.5-6.8 (m, 1H), 4.6-4.9 (m, 1H) ,4.06(s,3H),3.2-3.3(m,2H),3.1-3.2(m,2H),2.0-2.1(m,2H),1.49(s,9H).

[0989] Step B: 3-(6-methoxy-3-nitropyridin-2-yl)propan-1-amine hydrochloride Int-1h

[0990]

[0991] To tert-butyl (3-(6-methoxy-3-nitropyridin-2-yl)propyl)carbamate (703 mg, 2.26 mmol) in dichloromethane (5 mL) was added HCl (4M in dioxane) (16.9 mL, 67.7 mmol), and the reaction mixture was stirred for 2 h, diluted with Et2O, and the resulting solid was collected by filtration to give 3-(6-methoxy-3-nitropyridin-2-yl)propan-1-amine hydrochloride Int-1h (507.8 mg, 91% yield) as a white solid. HPLC / MS 0.40 min (A), [M+H] + 212.1. 1 H NMR (CD3OD, 400MHz) δ8.3-8.4(m,1H),6.85(d,1H,J=8.8Hz),4.06(s,3H),3.24(s,2H),3.1-3.2(m,2H),2.1-2.3(m,2H).

[0992] Step A: 1-(6-methoxy-3-nitropyridin-2-yl)propan-2-one Int-1i

[0993]

[0994] A mixture of 2-bromo-6-methoxy-3-nitropyridine (10.0 g, 42.9 mmol), 4-hydroxy-4-methylpentan-2-one (34.0 g, 292 mmol), PdOAc (482 mg, 2.15 mmol), PhP (2.25 g, 8.58 mmol) and CsCO (21.0 g, 64.3 mmol) in toluene (200 mL) was purged with N for 3 min, heated at 110° C. for 4 h, cooled, filtered through a thin pad of celite (rinsed with EtOAc), concentrated, and purified by flash column chromatography on silica gel (330 g) with a gradient elution of 100% heptane to 15% EtOAc. The product fractions were combined and evaporated under reduced pressure to give 1-(6-methoxy-3-nitropyridin-2-yl)propan-2-one Int-1i (3.95 g, 44% yield) as a yellow solid. HPLC / MS 0.71min(B),[M+H] + 211.1. 1 H NMR (DMSO-d6, 400MHz): δ 8.45 (d, 1H, J = 8.8Hz), 6.98 (d, 1H, J = 8.8Hz), 4.34 (s, 2H), 3.96 (s, 3H), 2.26 (s, 3H).

[0995]

[0996] Step A: Diethyl 2-(6-methoxy-3-nitropyridin-2-yl)malonate Int-1j-1

[0997]

[0998] To a suspension of 60% NaH (2.54 g, 63.3 mmol) in THF (48 mL) cooled to 0 ° C was added diethyl malonate (9.66 mL, 63.3 mmol). After stirring for 1 h, 2-chloro-6-methoxy-3-nitropyridine (6.00 g, 30.8 mmol) in THF (12 mL) was added. The reaction was stirred at 80 ° C for 16 h, cooled to room temperature, quenched with cold H2O (50 mL), and extracted with EtOAc (2x50 mL). The combined organic extracts were washed with H2O (50 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude diethyl 2-(6-methoxy-3-nitropyridine-2-yl) malonate Int-1j-1 (9.0 g, 84% yield) as a thick brown liquid that was used without further purification. HPLC / MS 1.039 min (C), [M+H] + 313.2.

[0999] Step B: Ethyl 2-(6-methoxy-3-nitropyridin-2-yl)acetate Int-1j-2

[1000]

[1001] To 2-(6-methoxyl group-3-nitropyridine-2-yl) diethyl malonate (9.00g, 28.8mmol) at DMSO (50mL) and H in the solution in O (10mL), add LiCl (4.89g, 115mmol), and reaction mixture is stirred to 16h at 100 ℃.Use H O (50mL) cancellation reaction, and extract with EtOAc (2x50mL).Use H O (50mL), salt solution (50mL) washing the organic extract that merges, use Na SO Drying, filter, concentrate, be dissolved in DCM (10mL) and be adsorbed on silica gel (8g).By silica gel flash column chromatography (330g), use 30% ethyl acetate-sherwood oil gradient elution purifying these slurries. The product fractions were combined and evaporated under reduced pressure to give ethyl 2-(6-methoxy-3-nitropyridin-2-yl)acetate Int-1j-2 (5.0 g, 68% yield) as a colorless liquid. HPLC / MS 0.959 min (C), [M+H] + 241.0.

[1002] Step C: Ethyl 2-(6-methoxy-3-nitropyridin-2-yl)-2-methylpropanoate Int-1j-3

[1003]

[1004] To ethyl 2-(6-methoxy-3-nitropyridin-2-yl)acetate Int-1j-2 (5.00 g, 20.8 mmol) in THF (50 mL) was added 60% NaH (2.50 g, 62.4 mmol) at 0°C. After 15 min, MeI (7.81 mL, 125 mmol) was added and the reaction mixture was stirred at RT for 16 h, quenched with H2O (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with H2O (50 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude ethyl 2-(6-methoxy-3-nitropyridin-2-yl)-2-methylpropanoate Int-1j-3 (5.90 g, 100% yield) as a brown liquid which was used without further purification. HPLC / MS 1.08 min (C), [M+H] + 269.0.

[1005] Step D: 2-(6-methoxy-3-nitropyridin-2-yl)-2-methylpropan-1-ol Int-1j-4

[1006]

[1007] A solution of ethyl 2-(6-methoxy-3-nitropyridine-2-yl)-2-methylpropanoate Int-1j-3 (4.00 g, 14.9 mmol) in Et o (40 mL) and DCM (8.00 mL) was cooled to -78 ° C, to which was added a hexane solution of 1 M DIBAL-H (52.2 mL, 52.2 mmol). The reaction mixture was stirred at 0 ° C for 3 h, quenched with H o (50 mL), and extracted with EtOAc (2x50 mL). The combined organic extracts were washed with H o (50 mL), brine (50 mL), dried over Na sO, filtered, and concentrated under reduced pressure to give crude 2-(6-methoxy-3-nitropyridine-2-yl)-2-methylpropan-1-ol Int-1j-4 (3.5 g, 76% yield) as a brown liquid that was used without further purification. HPLC / MS 0.952min(C),[M+H] + 227.0.

[1008] Step E: 2-(6-methoxy-3-nitropyridin-2-yl)-2-methylpropanal Int-1j

[1009]

[1010] Following the procedure outlined in Int-1g, stirring at RT for 2 h without purification afforded crude 2-(6-methoxy-3-nitropyridin-2-yl)-2-methylpropanal Int-1j (2.79 g, 63% yield) as a brown liquid which was used without further purification. HPLC / MS 1.109 min (C), [M+H] + 225.0.

[1011]

[1012] Step A: 2-Bromo-5-(trifluoromethyl)-benzoic acid methyl ester Int-2

[1013]

[1014] To a solution of 2-bromo-5-(trifluoromethyl)benzoic acid (20.0 g, 74.3 mmol) in MeOH (120 mL) was added SOCl2 (7.93 mL, 149 mmol) at room temperature, and the reaction mixture was stirred at 70 ° C for 3 h. The reaction mixture was cooled to 5 ° C and quenched with saturated NaHCO3 aqueous solution until the pH value was ~8, and then concentrated under reduced pressure. The aqueous phase was extracted with EtOAc (100 mL), dried over Na2SO4, filtered and evaporated under reduced pressure to give 2-bromo-5-(trifluoromethyl)-benzoic acid methyl ester Int-2 (19.0 g, 90% yield) as a clear oil. HPLC / MS 3.19 min (H). 1H NMR (400MHz, DMSO-d6) δ 8.11 (d, J = 2.0 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.86 (dd, J = 1.6 Hz, 8.4 Hz, 1H), 3.90 (s, 3H).

[1015]

[1016] Step A: Ethyl 2-bromo-4-(trifluoromethyl)benzoate Int-2a

[1017]

[1018] To a solution of 2-bromo-4-(trifluoromethyl)benzoic acid (35.0 g, 130 mmol) in DMF (250 mL) cooled to 0 ° C under N2 was added K2CO3 (25.2 g, 182 mmol) in batches within 10 min. The reaction mixture was stirred at room temperature for 10 min, iodoethane (12.6 mL, 156 mmol) was added dropwise thereto, and the reaction mixture was stirred for 4 h. The reaction mixture was quenched with ice water (500 mL), extracted with EtOAc (3x200 mL), and the combined organic extracts were washed with H2O (3x500 mL) and brine, dried over Na2SO4, filtered and evaporated under reduced pressure to give ethyl 2-bromo-4-(trifluoromethyl)benzoate Int-2a (38.0 g, 98% yield) as a yellow oil. GC / MS 3.13 min, [M+H] + 295.9. 1 H NMR (400MHz, DMSO-d6) δ8.15(s,1H),7.88-7.94(m,1H),4.34-4.40(q,2H),1.32-1.35(t,3H).

[1019] Step A: Methyl 2-chloro-5-(trifluoromethyl)nicotinate Int-2b

[1020]

[1021] Following the procedure of Int-2a, replacing iodomethane with iodoethane and 2-chloro-5-(trifluoromethyl)nicotinic acid with 2-bromo-4-(trifluoromethyl)benzoic acid, methyl 2-chloro-5-(trifluoromethyl)nicotinate Int-2b (15.0 g, 94% yield) was prepared as a brown oil. HPLC / MS 0.65 min (C), [M+H] + 240.0. 1 HNMR(DMSO-d6,400MHz)δ9.06(s,1H),8.65(s,1H),3.92(s,3H).

[1022] Step A: 2-Bromo-4-(trifluoromethyl)-benzoic acid methyl ester Int-2c

[1023]

[1024] Following the preparation of Int-2, 2-bromo-4-trifluoromethylbenzoic acid was replaced with 2-bromo-5-trifluoromethylbenzoic acid, and the reaction mixture was heated at 80°C for 12 h to isolate methyl 2-bromo-4-(trifluoromethyl)-benzoate Int-2c (10.2 g, 83% yield) as a yellow oil. HPLC / MS 1.11 min (A), [M+H] + Not ionized. 1 H NMR(DMSO-d6,400MHz)δ8.16(s,1H),7.9-8.0(m,1H),7.9-7.9(m,1H),3.91(s,3H)

[1025] 2-Bromo-4-(trifluoromethoxy)-benzoic acid methyl ester Int-2d

[1026]

[1027] Following the preparation of Int-2a, 2-bromo-4-(trifluoromethoxy)benzoic acid was substituted with 2-bromo-4-(trifluoromethoxy)benzoic acid, and the reaction mixture was stirred at room temperature for 1 h. 2-Bromo-4-(trifluoromethoxy)-benzoic acid methyl ester Int-2d (4.56 g, 83% yield) was isolated as a clear oil. HPLC / MS 1.09 min (A), [M+H] + 298.9. 1 H NMR (DMSO-d6, 400MHz) δ7.91 (d, 1H, J = 8.8Hz), 7.7-7.8 (m, 1H), 7.55 (ddd, 1H, J = 1.0, 2.9, 8.8Hz), 3.89 (s, 3H).

[1028] Step A: 2-Bromo-5-fluoro-4-(trifluoromethyl)-benzoic acid methyl ester Int-2e

[1029]

[1030] To a solution of 2-bromo-5-fluoro-4-(trifluoromethyl)benzoic acid (10.0 g, 34.8 mmol) and MeOH (14.1 mL, 348 mmol) was added H2SO4 (0.371 mL, 6.97 mmol) and the reaction mixture was stirred at 90°C for 72 h. The reaction mixture was cooled to ambient temperature and the solvent was evaporated under reduced pressure. The solution was partitioned between EtOAc and saturated aqueous NaHCO3, the layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and the solvent was evaporated under reduced pressure to give 2-bromo-5-fluoro-4-(trifluoromethyl)-benzoic acid methyl ester Int-2e (9.82 g, 94% yield) as a clear oil. HPLC / MS 1.18 min (B), [M+H] + Not ionized. 1 H NMR (CDCl3, 400MHz) δ7.89 (d, J = 6.36 Hz, 1H), 7.63 (d, J = 9.78 Hz, 1H), 3.98 (s, 3H).

[1031] Step A: 6-Bromo-2-fluoro-3-(trifluoromethyl)-benzoic acid methyl ester Int-2f

[1032]

[1033] Following the preparation of Int-2e, replacing 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid with 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid, 6-bromo-2-fluoro-3-(trifluoromethyl)-benzoic acid methyl ester Int-2f (6.59 g, 62% yield) was isolated as a yellow oil. HPLC / MS 1.15 min (B), [M+H] + Not ionized. 1 HNMR (CDCl3, 400MHz) δ7.47-7.55 (m, 2H), 3.99 (s, 3H).

[1034] Step A: 6-amino-2-fluoro-3-(trifluoromethyl)-benzoic acid methyl ester Int-2g

[1035]

[1036]

[00145] Ethyl 6-bromo-2-fluoro-3-(trifluoromethyl)benzoate Int-2f (2.0 g, 6.64 mmol), copper metal (0.422 g, 6.64 mmol), TMS-N (1.76 mL, 13.3 mmol) and 2-aminoethan-1-ol (1.00 mL, 16.6 mmol) in DMA (15 ml) were heated to 95°C for 4 h, diluted with ethyl acetate and H2O, and then filtered through a pad of celite. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The crude residue was dissolved in DCM (5 mL), adsorbed on a silica gel pre-column, and dry loaded onto a Teledyne-Isco RediSep Rf silica gold column (80 g) eluted with a gradient of 100% heptane to 100% EtOAc. The product fractions were combined and evaporated under reduced pressure to give 6-amino-2-fluoro-3-(trifluoromethyl)-benzoic acid methyl ester Int-2g (422 mg, 26% yield) as a white solid. HPLC / MS 1.01 min (B), [M+H] + 237.8. 1 H NMR (CDCl3, 400MHz) δ7.26 (s, 1H), 6.31 (d, J = 9.29Hz, 1H), 5.95 (br s, 2H), 3.79 (s, 3H).

[1037] Step A: 2-Bromo-5-(2,2,2-trifluoroethoxy)-benzoic acid methyl ester Int-2h

[1038]

[1039] A mixture of 2-bromo-5-hydroxybenzoic acid methyl ester (3.50g, 15.2mmol), 2,2,2-trifluoroethyl 4-methylbenzenesulfonate (4.24g, 16.7mmol) and Cs2CO3 (5.43g, 16.7mmol) in DMF (50mL) was stirred at 90 DEG C for 20h under nitrogen, diluted with ethyl acetate, washed with water (2x), brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (220g) with a gradient elution of 10% EtOAc-heptane to 20% EtOAc-heptane. The product fractions were combined and evaporated under reduced pressure to give 2-bromo-5-(2,2,2-trifluoroethoxy)-benzoic acid methyl ester Int-2h (3.30g, 70% yield). HPLC / MS 1.13min (A), [M+H] + 313. 1H NMR (CDCl3, 400MHz): δ7.62 (d, J = 8.8 Hz, 1H), 7.40 (d, J = 2.9 Hz, 1H), 6.95-7.01 (m, 1H), 4.39 (q, J = 8.2 Hz, 2H), 3.97 (s, 3H).

[1040] Step A: 2-Amino-5-chloro-4-(trifluoromethyl)-benzoic acid methyl ester Int-2i

[1041]

[1042] By the mixture of 2-amino-5-iodo-4-(trifluoromethyl)-benzoic acid methyl esters (2.40g, 6.96mmol) and cuprous chloride (2.40g, 24.3mmol) in NMP (6.00mL) with N2Purge, stir 1h at 150 DEG C, be cooled to environment temperature, quench with 1N HCl, extract with EtOAc (3x).By the organic extracts merged with salt water washing, use Na2SO4Drying, filter, concentrate under reduced pressure.Crude residue is dissolved in DCM, pre-adsorbed on the pre-column filled with silica gel, by normal phase silica gel flash chromatography with 100% heptane to 60% EtOAc-heptane gradient elution purification.Merge product fractions and evaporate under reduced pressure, obtain 2-amino-5-chloro-4-(trifluoromethyl)-benzoic acid methyl ester Int-2i (1.26g, 68% yield), it is light yellow solid. HPLC / MS 1.13 min (A), [M+H] + 254.0. 1 H NMR (CDCl3, 400MHz) δ8.00 (s, 1H), 7.04 (s, 1H), 5.8-6.1 (m, 2H), 3.9-4.0 (m, 3H).

[1043] Step A: 2-Amino-5-fluoro-4-(trifluoromethyl)-benzoic acid methyl ester Int-2j

[1044]

[1045] To a suspension of 2-bromo-4-fluoro-5-(trifluoromethyl)aniline (40g, 155mmol) in MeOH (400mL) was added PdCl2(dppf)-CH2Cl2 adduct (12.7g, 15.5mmol) under N2 atmosphere, degassed and purged with CO (3x), and the reaction mixture was stirred at 80°C for 12h under CO (0.5MPa). The reaction mixture was cooled to ambient temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was diluted with MTBE (300mL), the organic layer (300mL) was washed with saturated NH4Cl, and Na2SO4 was dried, filtered, and concentrated under reduced pressure. The crude product (67g) was dissolved in DCM (200mL) and 80g silica gel (100-200 mesh silica gel) was added. The resulting mixture was concentrated at 45°C to give a dry, mobile solid, which was loaded onto 180 g of silica gel (homemade column chromatography, 100-200 mesh silica gel) and eluted with a gradient of 80:1 n-heptane / EtOAc to 4:1 n-heptane / EtOAc. The desired product fractions were combined and evaporated under reduced pressure to give methyl 2-amino-5-fluoro-4-(trifluoromethyl)-benzoate Int-2j (41 g, >100% yield) as a white solid. HPLC / MS 2.69 min (I), [M+H] + 238.1. 1 H NMR (DMSO-d6, 400MHz) δ7.67-7.64(d,1H),7.19-7.21(m,1H),6.85(s,2H),3.82(s,3H).

[1046]

[1047] Step A: Methyl 2-(5-fluoro-2-nitrophenyl)acetate Int-3a-1

[1048]

[1049] To a solution of 2-(5-fluoro-2-nitrophenyl)acetic acid (10.3 g, 51.9 mmol) in MeOH (50 mL) was added dropwise H2SO4 (0.332 mL, 6.22 mmol), and the reaction mixture was stirred at 65 ° C for 21 h. The reaction mixture was cooled to ambient temperature, the solvent was evaporated under reduced pressure, and the residue was dissolved in EtOAc, dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The crude residue was dissolved in DCM, adsorbed onto a silica gel-filled pre-column, and purified by silica gel flash column chromatography (330 g) with a 100% heptane to 60% EtOAc gradient elution. The product fractions were combined and evaporated under reduced pressure to give methyl 2-(5-fluoro-2-nitrophenyl) acetate Int-3a-1 (10.8 g, 91% yield) as a yellow oil. HPLC / MS 0.75 min (A); 1H NMR (DMSO-d6, 400MHz) δ8.24 (dd, 1H, J = 5.1, 9.0Hz), 7.52 (d, 1H, J = 9.3Hz), 7.4-7.5 (m, 1H), 4.12 (s, 2H), 3.63 (s, 3H).

[1050] Step B: Methyl 2-(5-fluoro-2-nitrophenyl)pent-4-enoate Int-3a-2

[1051]

[1052] To a solution of methyl 2-(5-fluoro-2-nitrophenyl)acetate (7.92 g, 37.2 mmol) in MeCN (170 mL) was added KCO (43.1 g, 312 mmol) followed by 18-crown-6 (0.098 g, 0.372 mmol). 3-iodoprop-1-ene (4.08 mL, 44.6 mmol) was then added dropwise to the purple reaction mixture at room temperature, and the reaction mixture was stirred at room temperature for 22 h, then at 75 ° C for 21 h. The reaction mixture was diluted with EtOAc, washed with H O (2x), brine, dried over Na SO , filtered, and the solvent 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 (330 g) with a gradient elution of 100% heptane to 50% EtOAc. The product fractions were combined and evaporated under reduced pressure to give methyl 2-(5-fluoro-2-nitrophenyl)pent-4-enoate Int-3a-2 (8.02 g, 83% yield) as a clear light yellow oil. HPLC / MS 1.01 min (A), [M+H]' 254.0. 1 HNMR (DMSO-d6, 400MHz) δ8.12 (dd, 1H, J = 5.1, 9.0Hz), 7.3-7.6 (m, 2H), 5.5-5.8 (m, 1H), 4. 8-5.1(m,2H),4.31(dd,1H,J=6.4,8.8Hz),3.61(s,3H),2.8-2.9(m,1H),2.6-2.7(m,1H).

[1053] Step C: 2-(But-3-en-1-yl)-4-fluoro-1-nitrobenzene Int-3a-3

[1054]

[1055] To a solution of methyl 2-(5-fluoro-2-nitrophenyl)pent-4-enoate (16.9 g, 66.7 mmol) in 1,4-dioxane (350 mL) was added 1 M NaOH (80 mL, 80 mmol), and the reaction mixture was stirred at room temperature for 24 h. The solvent was evaporated under reduced pressure, and the residue was dissolved in water, acidified with 6 M HCl, and extracted with EtOAc. The organic phase was washed with water and brine, dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to yield a pale yellow solid. The solid was dissolved in DMF (200 mL), K2CO3 (46.1 g, 334 mmol) was added, and the reaction mixture was stirred at 50°C for 3 h. The reaction mixture was cooled, diluted with EtOAc, washed with H2O (3x), brine, dried over Na2SO4, filtered, and the solvent evaporated under reduced pressure to afford 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-d6,400MHz)δ8.07(dd,1H,J=5.1,9.0Hz),7.43(dd,1H,J=2.9,9.8Hz),7.33(ddd,1H,J= 2.9, 7.8, 8.8Hz), 5.84 (dd, 1H, J = 10.3, 17.1Hz), 4.8-5.1 (m, 2H), 2.9-3.0 (m, 2H), 2.3-2.4 (m, 2H).

[1056] Step D: 2-(But-3-en-1-yl)-4-fluoroaniline Int-3a

[1057]

[1058] To a suspension of 2-(but-3-en-1-yl)-4-fluoro-1-nitrobenzene (12.7 g, 65.1 mmol) in EtOH (300 ml) was added zinc (63.8 g, 976 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 at 0° C. for 1.5 h. The reaction mixture was filtered, the filtrate washed with EtOH, and the ethanol removed under reduced pressure. The solid was partitioned between EtOAc and 10% NaHCO 3 . The layers were separated, and the organic phase was washed with H 2 O, brine, dried over Na 2 SO 4 , filtered, and the solvent evaporated under reduced pressure to give a brown oil. The oil was dissolved in DCM, pre-adsorbed onto a silica gel pre-column, and purified by silica gel flash column chromatography (120 g) with a gradient elution 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 HNMR(DMSO-d6,400MHz)δ6.7-6.8(m,2H),6.59(dd,1H,J=5.4,8.8Hz),5.87( tdd,1H,J=6.6,10.3,17.1Hz),4.9-5.2(m,2H),4.72(s,2H),2.1-2.4(m,2H).

[1059]

[1060] Step A: 2-Allyl-4-fluoroaniline Int-3b

[1061]

[1062] Under N2, to a solution of 2-bromo-4-fluoroaniline (5.06 g, 26.6 mmol) in 1,4-dioxane (100 mL) and H2O (10.0 mL) was added 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.49 mL, 39.9 mmol), followed by the addition of Pd(PPh3)4 (3.08 g, 2.66 mmol) and CsF (16.2 g, 107 mmol), and the reaction mixture was stirred at 95 ° C for 18 h. The reaction mixture was cooled to ambient temperature, concentrated in vacuo and diluted with EtOAc (250 mL). The resulting mixture was washed with H2O, brine, dried over MgSO4, filtered, and the solvent was evaporated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (120 g) with a gradient elution from 100% heptane to 25% EtOAc-heptane. The product fractions were combined and evaporated under reduced pressure to give 2-allyl-4-fluoroaniline Int-3b (1.12 g, 26% yield) as a brown oil. HPLC / MS 0.83 min (B), [M+H] + 152.0. 1 H NMR(DMSO-d6,400MHz)δ6.7-6.8(m,2H),6.61(dd,1H,J=5.4,8.8Hz),5.93(tdd ,1H,J=6.7,10.2,16.9Hz),5.0-5.2(m,2H),4.70(s,2H),3.19(d,2H,J=6.8Hz).

[1063]

[1064] Step A: (4-(2-Amino-5-fluorophenyl)but-3-yn-1-yl)-carbamic acid tert-butyl ester Int-3c

[1065]

[1066] In N2 atmosphere, to the stirring solution of butane-3-alkynes-1-base-t-butyl carbamate (1.00g, 5.91mmol) and 4-fluoro-2-iodoaniline (1.54g, 6.50mmol) in diisopropylamine (20mL), cuprous iodide (0.113g, 0.591mmol) and Pd (Ph3)4 (0.082g, 0.071mmol).Reactant mixture is stirred at room temperature for 16h, uses H2O (100mL) dilution and is extracted with EtOAc (2x50mL).The organic extract merged is washed with salt water (50mL), uses Na2SO4 drying, filter, solvent evaporated under reduced pressure.Crude product is dissolved in DCM, is adsorbed on silica gel, is eluted with 20% ethyl acetate-petroleum ether and purified by silica gel column chromatography (40g). The product fractions were combined and evaporated under reduced pressure to give (4-(2-amino-5-fluorophenyl)but-3-yn-1-yl)-carbamic acid tert-butyl ester Int-3c (1.48 g, 82% yield) as a brown gum. HPLC / MS 1.45 min (C), [M+H]' 279.2. 1 H NMR(DMSO-d6,400MHz)δ7.06-7.09(m,1H),6.88-6.92(m,2H),6.85-6.86(d,1H),5.19(s,2H),3.14-3.19(m,2H),2.51-2.56(m,2H),1.38(s,9H).

[1067]

[1068] Step A: 1-Bromo-4-fluoro-2-(pent-4-en-1-yl)benzene Int-3d

[1069] 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) was added cuprous iodide (1.78 g, 9.33 mmol) and 2,2'-bipyridine (1.46 g, 9.33 mmol), followed by addition of a 0.5 M solution of but-3-en-1-ylmagnesium bromide in THF (560 mL, 280 mmol), and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated NH4Cl aqueous solution (250 mL) and extracted with EtOAc (2x100 mL). The combined organic extracts were washed with H2O (200 mL) and 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-(pent-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 H NMR(DMSO-d6,400MHz)δ7.59-7.62(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).

[1070]

[1071] Step A: 6-methoxy-3-nitro-N-(prop-2-yn-1-yl)pyridin-2-amine Int-3e-1

[1072]

[1073] To a solution of 2-chloro-6-methoxy-3-nitropyridine (5.60 g, 29.7 mmol) in DMF (112 ml) was added prop-2-yn-1-amine (1.90 mL, 29.7 mmol) and TEA (8.28 mL, 59.4 mmol), and the reaction mixture was stirred at 80 ° C for 4 h. Additional prop-2-yn-1-amine (0.476 mL, 7.42 mmol) was added and heated for 6 h, then stirred at room temperature for another 12 h. The reaction mixture was poured into ice (250 mL) and filtered to give 6-methoxy-3-nitro-N-(prop-2-yn-1-yl)pyridin-2-amine Int-3e-1 (5.5 g, 88% yield) as a light brown solid. HPLC / MS 0.87 min (A), [M+H] + 208.0. 1 H NMR (DMSO-d6, 400MHz) δ 8.8-9.1 (m, 1H), 8.2-8.4 (m, 1H), 6.1-6.3 (m, 1H), 4.32 (d, 2H, J = 2.4Hz), 3.99 (s, 4H), 3.10 (s, 1H).

[1074] Step B: (6-Methoxy-3-nitropyridin-2-yl)(prop-2-yn-1-yl)-carbamic acid tert-butyl ester Int-3e-2

[1075]

[1076] To a solution of 6-methoxy-3-nitro-N-(prop-2-alkynes-1-yl)pyridine-2-amine (5.40g, 26.1mmol) in MeCN (111ml), boc-anhydride (12.1mL, 52.1mmol) and DMAP (0.637g, 5.21mmol) were added, and the reaction mixture was stirred at 70°C for 30min, then stirred at ambient temperature for 18h. The solvent was evaporated under reduced pressure to give an oily substance, which was ground with EtOAc (50mL), filtered, and the filtrate was pre-adsorbed on silica gel and purified by flash column chromatography on silica gel (40g) with a gradient elution of 100% heptane to 50% EtOAc. The product fractions were combined and evaporated under reduced pressure to give tert-butyl (6-methoxy-3-nitropyridine-2-yl) (prop-2-alkynes-1-yl)-carbamate Int-3e-2 (7.38g, 92% yield), which was a yellow oil. HPLC / MS 1.12 min (A), [M-Boc] + 252.0. 1 H NMR (DMSO-d6, 400MHz) δ 8.38 (d, 1H, J = 8.8Hz), 6.87 (d, 1H, J = 8.8Hz), 4.65 (br s, 2H), 3.99 (s, 3H), 3.1-3.2 (m, 1H), 1.36 (br s, 9H).

[1077] Step C: (3-(2-amino-5-fluorophenyl)prop-2-yn-1-yl)(6-methoxy-3-nitropyridin-2-yl)-amino Tert-Butyl Formate Int-3e

[1078]

[1079] By 4- fluoro- 2- iodoaniline (5.98g, 25.2mmol) and (6- methoxy -3- nitropyridine -2- bases) (prop- 2- alkyn- 1- bases) -carbamic acid tert-butyl ester (7.38g, 24.0mmol) in Et the mixture in o (150mL) is purged with N (3x), to which cuprous iodide (I) (0.457g, 2.40mmol), bis(triphenylphosphine) palladium chloride (II) (0.843g, 1.20mmol) and diisopropylamine (16.8mL, 120mmol) are added, and the reaction is stirred at room temperature for 18h under N. The reaction mixture is quenched with NH saturated aqueous solution of Cl, diluted with EtOAc, layered, and the organic phase is saturated with NH the Cl aqueous solution, H o (2x), salt water washing, Na sO dried, filtered, and the solvent is 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 (40 g) with a gradient elution from 100% heptane to 50% EtOAc-heptane. The product fractions were combined and evaporated under reduced pressure to give (3-(2-amino-5-fluorophenyl)prop-2-yn-1-yl)(6-methoxy-3-nitropyridin-2-yl)-carbamic acid tert-butyl ester Int-3e (8.53 g, 79% yield) as a yellow foam. HPLC / MS 1.27 min (A), [M+H] + 417.1. 1 H NMR (DMSO-d6, 400MHz) δ 8.3-8.5 (m, 1H), 6.89 (d, 3H, J = 8.8Hz), 6.5-6.7 (m, 1H), 5.17 (s, 2H), 4.94 (s, 2H), 4.01 (s, 3H), 1.37 (br s, 11H).

[1080] Step A: (3-(2-Amino-5-fluorophenyl)prop-2-yn-1-yl)-carbamic acid tert-butyl ester Int-3f

[1081]

[1082] Following the procedure outlined in Scheme 11, Step A, replacing but-3-yn-1yl-carbamic acid tert-butyl ester with prop-2-yn-1-yl-carbamic acid tert-butyl ester, (3-(2-amino-5-fluorophenyl)prop-2-yn-1-yl)-carbamic acid tert-butyl ester Int-3f (0.200 g, 46% yield) was prepared as a viscous oil. HPLC / MS 0.88 min (A), [M+H] + 265.1. 1H NMR (DMSO-d6, 400MHz) δ7.37 (br s, 1H), 6.85-6.99 (m, 2H), 6.59-6.74 (m, 1H), 5.29 (s, 2H), 4.00 (d, J = 5.38Hz, 2H), 1.38-1.44 (m, 9H).

[1083]

[1084] Step A: tert-Butyl (3-(2-amino-5-fluorophenyl)propyl)carbamate Int-3g

[1085]

[1086] To a solution of (3-(2-amino-5-fluorophenyl)prop-2-yn-1-yl)-carbamic acid tert-butyl ester (3.00 g, 11.4 mmol) in MeOH (28.0 mL) was added Pd(OH)2-C (2.42 g, 3.45 mmol), and the reaction mixture was stirred under 1 atm H2 for 18 h. The reaction mixture was filtered through celite, washed with DCM, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (80 g) with a gradient elution from 100% heptane to 100% EtOAc. The product fractions were combined and the solvent was evaporated under reduced pressure to give (3-(2-amino-5-fluorophenyl)propyl)-carbamic acid tert-butyl ester Int-3g (2.10 g, 66% yield) as a white solid. HPLC / MS 0.61 min (A), [M+H] + 269.1. 1 H NMR (CD3OD, 400MHz) δ6.78 (td, 1H, J = 1.7, 9.4Hz), 6.7-6.7 (m, 2H), 3.1-3.2 (m, 2H), 2.5-2.6 (m, 2H), 1.7-1.9 (m, 2H), 1.46 (s, 9H).

[1087] Step A: (3-(6-Amino-2,3-difluorophenyl)prop-2-yn-1-yl)-carbamic acid tert-butyl ester Int-3h

[1088]

[1089] 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) in DMF (50 mL) purged with N2 was added prop-2-yn-1-yl-carbamic acid tert-butyl ester (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) with a gradient elution from 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. 1 H NMR (CDCl3, 400MHz) δ6.94 (dt, J=10.27, 8.80Hz, 1H), 6.37 (ddd, J=9.05, 3.67, 1.96Hz, 1H), 4.22 (br s, 2H), 1.49 (s, 9H).

[1090] Step B: tert-Butyl (3-(6-amino-2,3-difluorophenyl)propyl)carbamate Int-3i

[1091]

[1092] Following the procedure outlined in Scheme 14, Step A, replacing (3-(2-amino-5-fluorophenyl)prop-2-yn-1-yl)-carbamic acid tert-butyl ester with (3-(6-amino-2,3-difluoro-phenyl)prop-2-yn-1-yl)-carbamic acid tert-butyl ester, (3-(6-amino-2,3-difluorophenyl)propyl)-carbamic acid tert-butyl ester Int-3i (491 mg, 50% yield) was prepared as a light pink solid. HPLC / MS 0.79 min (A), [M+H] + 287.1. 1HNMR(CDCl3,400MHz)δ6.76-6.84(m,1H),6.35(ddd,J=8.80,3.91,1.96Hz,1H),4.91(br s,1H),3.69(br s,2H),3.14(br d,J=6.36Hz,2H),2.56-2.61(m,2H),1.71-1.79(m,2H),1.43(s,9H).

[1093]

[1094] Step A: 2-Amino-5-fluorobenzaldehyde Int-3j

[1095]

[1096] MnO2(12.3g, 142mmol) is added to a solution of (2-amino-5-fluorophenyl)methanol (10.0g, 70.8mmol) in DCM (150ml), and the reaction mixture is stirred at room temperature for 24h. The reaction mixture is filtered on a diatomaceous earth pad, the diatomaceous earth is washed with DCM, and the solvent is evaporated under reduced pressure. The crude residue is dissolved in DCM containing a minimum amount of MeOH, adsorbed on a silica gel-filled pre-column, and purified by silica gel flash column chromatography (330g) with 100% heptane to 50% EtOAc-heptane gradient elution. The product fractions are combined and evaporated under reduced pressure to obtain 2-amino-5-fluorobenzaldehyde Int-3j (3.1g, 31% yield), which is a bright yellow solid. HPLC / MS 0.55min(A), [M+H] + 139.9. 1 H NMR (DMSO-d6, 400MHz) δ9.79 (s, 1H), 7.39 (dd, 1H, J = 3.2, 9.0Hz), 7.2-7.3 (m, 1H), 7.02 (br s, 2H), 6.79 (dd, 1H, J = 4.4, 9.3Hz).

[1097]

[1098] Step A: (3-(2-amino-4,5-difluorophenyl)prop-2-yn-1-yl)(6-methoxy-3-nitropyridine-2- tert-Butyl)carbamate Int-3k

[1099] Following the procedure outlined in Scheme 13, Step C, replacing 4-fluoro-2-iodoaniline with 4,5-difluoro-2-iodoaniline (WO2011006903), (3-(2-amino-4,5-difluorophenyl)prop-2-yn-1-yl)(6-methoxy-3-nitropyridin-2-yl)-carbamic acid tert-butyl ester Int-3k (3.11 g, 74% yield) was prepared as a light orange foam. HPLC / MS 1.31 min (A), [M-t Bu] + 379.0. 1 H NMR(DMSO-d6,400MHz)δ8.3-8.5(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).

[1100] Step A: (3-(2-Bromo-5-fluorophenyl)prop-2-yn-1-yl)-carbamic acid tert-butyl ester Int-31

[1101]

[1102] Following the procedure outlined in Int-1c-2, replacing but-3-yn-1-yl-carbamic acid tert-butyl ester with prop-2-yn-1-yl-carbamic acid tert-butyl ester and 2-iodo-6-methoxy-3-nitropyridine with 1-bromo-4-fluoro-2-iodobenzene, and stirring at RT for 23 h, (3-(2-bromo-5-fluorophenyl)prop-2-yn-1-yl)-carbamic acid tert-butyl ester Int-3l (8.37 g, 77% yield) was prepared as a white solid. HPLC / MS 1.18 min (A), [M- t Bu] + 271.9. 1 H NMR (DMSO-d6, 400MHz) δ7.73 (dd, 1H, J = 5.4, 9.3Hz), 7.41 (dd, 2H, J = 2.9, 9.3Hz), 7.22 (dt, 1H, J = 2.9, 8.6Hz), 4.04 (br d, 2H, J = 5.4Hz), 1.41 (s, 9H).

[1103] Step A: (3-(6-amino-2,3-difluorophenyl)prop-2-yn-1-yl)(6-methoxy-3-nitropyridine-2- tert-Butyl)carbamate Int-3m

[1104]

[1105] Following the procedure outlined in Int-3e, replacing 4-fluoro-2-iodoaniline with 3,4-difluoro-2-iodoaniline and stirring at RT for 65 h, (3-(6-amino-2,3-difluorophenyl)prop-2-yn-1-yl)(6-methoxy-3-nitropyridin-2-yl)-carbamic acid tert-butyl ester Int-3m (12.6 g, 35% yield) was prepared as a foamy solid. HPLC / MS 1.30 min (A), [M+H] + 435.1. 1H NMR (DMSO-d6, 400MHz): δ8.40 (d, J=8.8Hz, 1H), 7.12 (dt, J=10.6, 9.1Hz, 1H), 6.89 (d, J=9. 3Hz,1H),6.44(ddd,J=9.3,4.2,1.7Hz,1H),5.47(s,2H),4.98(s,2H),4.01(s,3H),1.38(br s,9H).

[1106] Step A: tert-Butyl (2-((2-bromo-5-fluorobenzyl)oxy)ethyl)-carbamate Int-3n

[1107]

[1108] To N- (2- hydroxyethyl) -carbamic acid tert-butyl ester (2.41g, 14.3mmol) in DMF (50mL) solution, add 60% NaH (0.90g, 22.4mmol). After 10min, 1- bromo- 2- (bromomethyl) -4- fluorobenzene (2.00g, 7.46mmol), and the reaction mixture is slowly warmed to room temperature. After 1h, saturated NH4Cl aqueous solution (250mL) is used to quench the reaction mixture, and extract with EtOAc (3x100mL). The organic extracts merged are washed with salt water, used MgSO4 is dried, filtered, and concentrated under reduced pressure. The crude residue is purified by flash column chromatography on silica gel (80g) with 100% heptane to 30% EtOAc-heptane gradient elution. The product fractions were combined and evaporated under reduced pressure to give tert-butyl (2-((2-bromo-5-fluorobenzyl)oxy)ethyl)-carbamate Int-3n (1.82 g, 66% yield) as a white solid. HPLC / MS 1.15 min (A), [M+H] + 348.1. 1 H NMR (CDCl3, 400MHz): δ7.51 (dd, J=8.6, 5.1Hz, 1H), 7.24 (dd, J=9.5, 3.2Hz, 1H), 6.87-6.94 (m, 1H), 4.94 (br s, 1H), 4.56 (s, 2H), 3.66 (t, J = 5.1Hz, 2H), 3.43 (q, J = 5.4Hz, 2H), 1.48 (s, 9H).

[1109] Example

[1110]

[1111] Examples 1 and 2

[1112] (E)-8-Fluoro-2-(trifluoromethyl)-13-hydrogen-10H,18H,5,17-methanodibenzo[b,k]pyrido[3,2-f] [1,5] diazacyclododecane-14,18-dione Example 1 and 14-fluoro-8-(trifluoromethyl)-17,18-dihydro-1H,6H-5, Example 2 of 11-methanodibenzo[b,k]pyrido[3,2-f][1,5]diazacyclododecane-2,6(16H)-dione

[1113]

[1114] Step A: 2-Fluoro-N-(6-methoxy-2-vinylpyridin-3-yl)-5-(trifluoromethyl)benzamide 1a

[1115]

[1116] 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) was added DIEA (17.6 mL, 101 mmol) and HATU (19.2 g, 50.5 mmol) at room temperature, and the reaction mixture was stirred for 2 h. The reaction mixture was diluted with ice water (60 mL), the precipitate was filtered and dried under high vacuum to give 2-fluoro-N-(6-methoxy-2-vinylpyridin-3-yl)-5-(trifluoromethyl)benzamide 1a (8.2 g, 71% yield) as an off-white solid. HPLC / MS 1.20 min (C), [M+H] + 341.2. 1 H NMR(DMSO-d6,400MHz)δ10.3(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).

[1117] Step B: 2-((2-bromo-4-fluorophenyl)amino)-N-(6-methoxy-2-vinylpyridin-3-yl)-5-(trifluoro methyl)benzamide 1b

[1118]

[1119] 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 CsCO (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 water (100 mL), extracted with EtOAc (2x100 mL), and the combined organic extracts were dried with NaSO, filtered, and the solvent was evaporated under reduced pressure. The crude residue was dissolved in DCM, pre-adsorbed on silica gel, and purified by flash column chromatography on silica gel (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-d6,400MHz)δ10.4(s,1H),10.0(s,1H),8.32(s,1H),7.67-7.73(m,3H),7.55-7.58(m,1H),7.2 8-7.34(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).

[1120] Step C: 1-(2-Bromo-4-fluorophenyl)-3-(6-methoxy-2-vinylpyridin-3-yl)-6-(trifluoromethyl)- 2,3-Dihydroquinazolin-4(1H)-one 1c

[1121]

[1122] To a solution of 2-((2-bromo-4-fluorophenyl)amino)-N-(6-methoxy-2-vinylpyridin-3-yl)-5-(trifluoromethyl)benzamide (4.30 g, 8.43 mmol) in MeCN (50 mL) was added CsCO(10.9 g, 33.7 mmol) and diiodomethane (2.04 mL, 25.3 mmol), and the reaction mixture was stirred at 80 ° C for 16 h. The reaction mixture was cooled to ambient temperature, diluted with ice water (100 mL), extracted with EtOAc (2x100 mL), and the combined organic extracts were dried with NaSO, filtered, and the solvent was evaporated under reduced pressure. The crude residue was dissolved in DCM, pre-adsorbed on silica gel, and purified by flash column chromatography on silica gel (120 g) eluting with 15-17% EtOAc-petroleum ether. The product fractions were combined and evaporated under reduced pressure to give 1-(2-bromo-4-fluorophenyl)-3-(6-methoxy-2-vinylpyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one 1c (2.42 g, 53% yield) as an off-white solid. HPLC / MS 1.39 min (C), [M+H] + 524.0. 1 H NMR(DMSO-d6,400MHz)δ8.11(s,1H),7.86-7.88(m,1H),7.63-7.75(m,3H),7.45-7.48(m,1H),6.99-7.02(m,1H),6.84-6 .86(m,1H),6.36-6.44(m,2H),5.65-5.68(m,1H),5.47-5.50(m,1H),5.22-5.27(m,1H),4.79-4.81(d,1H),3.92(s,3H).

[1123] Step D: 1-(2-allyl-4-fluorophenyl)-3-(6-methoxy-2-vinylpyridin-3-yl)-6-(trifluoromethyl)- (1H)-2,3-dihydroquinazolin-4-one 1d

[1124]

[1125] To a solution of 1-(2-bromo-4-fluorophenyl)-3-(6-methoxy-2-vinylpyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one (2.32 g, 4.44 mmol) in DMF (20 mL) was added allyltributylstannane (2.75 mL, 8.88 mmol) and Pd(PPh 3 ) 4 (0.257 g, 0.222 mmol) at room temperature, and the reaction mixture was heated at 150 ° C for 1 h under microwave irradiation. The reaction mixture was cooled to ambient temperature, diluted with ice-cold water (10 mL), extracted with EtOAc (2x50 mL), and the combined organic extracts were dried over Na 2 SO 4 , filtered, and the solvent was evaporated under reduced pressure. The crude residue was dissolved in DCM, pre-adsorbed on silica gel, and purified by flash column chromatography on silica gel (120 g) eluting with 18-20% EtOAc-petroleum ether. The product fractions were combined and evaporated under reduced pressure to give 1-(2-allyl-4-fluorophenyl)-3-(6-methoxy-2-vinylpyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one 1d (1.80 g, 73% yield) as a colorless liquid. HPLC / MS 1.46 min (C), [M+H] + 483.6. 1 H NMR(DMSO-d6,400MHz)δ8.09(s,1H),7.68-7.73(m,2H),7.46-7.65(m,1H),7.27-7.29(m,1H),6.84-6.87(m,2H),6.34-6.42(m,2H) ),5.82-5.98(m,1H),5.66-5.76(m,1H),5.50-5.51(m,1H),4.97-5.07(m,3H),4.68-4.70(m,1H),3.91(s,3H),3.38-3.40(m,2H).

[1126] Step E: (E)-8-Fluoro-14-methoxy-2-(trifluoromethyl)-10H,18H,5,17-methanodibenzo[b,k]pyrrolidone Irido[3,2-f][1,5]diazacyclododecan-18-one 1e

[1127]

[1128] Under N2 atmosphere, to 1- (2-allyl -4- fluorophenyl) -3- (6- methoxy -2- vinylpyridin -3- bases) -6- (trifluoromethyl) -2,3- dihydroquinazoline -4 (1H) -one (200mg, 0.414mmol) in DCE (300mL) solution was added Hoveyda-Grubbsii (51.8mg, 0.083mmol), and the reaction mixture was heated at 80 ° C for 4h. The reaction mixture was cooled to ambient temperature, filtered through celite, washed with EtOAc (2x10mL), and the organic layer was dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The crude product was dissolved in DCM, adsorbed on silica gel and purified by silica gel flash column chromatography (10g) with 19-23% EtOAc-petroleum ether. The product fractions were combined and evaporated under reduced pressure to give (E)-8-fluoro-14-methoxy-2-(trifluoromethyl)-10H,18H,5,17-methanodibenzo[b,k]pyrido[3,2-f][1,5]diazacyclododecan-18-one 1e (140 mg, 72% yield) as a green oil. HPLC / MS 1.29 min (C), [M+H] + 456.0.

[1129] Step F: (E)-8-Fluoro-2-(trifluoromethyl)-13-hydrogen-10H,18H,-5,17-methanodibenzo[b,k]pyridinol [3,2-f][1,5]diazacyclododecane-14,18-dione Example 1

[1130]

[1131] To a solution of (E)-8-fluoro-14-methoxy-2-(trifluoromethyl)-10H,18H-5,17-methanodibenzo[b,k]pyrido[3,2-f][1,5]diazacyclododecan-18-one (100 mg, 0.220 mmol) in DMF (3 mL) were added LiCl (55.8 mg, 1.32 mmol) and p-TsOH (251 mg, 1.32 mmol), and the reaction mixture was stirred at 100° C. for 12 h. The reaction mixture was diluted with ice water (50 mL) and extracted with EtOAc (2×30 mL), and the combined organic extracts were washed with brine, dried over Na 2 SO 4 , filtered, and the solvent was evaporated under reduced pressure. The crude residue was purified by semi-preparative HPLC (Sunfire C18, 19 x 150 mm, 5 μM) eluting with 40% MeCN-H2O (0.1% HCO2H) to 100% MeCN (0.1% HCO2H) over 13 min. Product fractions were combined and evaporated under reduced pressure to afford (E)-8-fluoro-2-(trifluoromethyl)-13-hydro-10H,18H-5,17-methanodibenzo[b,k]pyrido[3,2-f][1,5]diazacyclododecane-14,18-dione (16.3 mg, 17% yield) as an off-white solid. HPLC / MS 1.02 min (C), [M+H] + 442.2. 1 H NMR(DMSO-d6,400MHz)δ11.74(bs,1H),8.08(s,1H),7.62(dd,J=1.60,8.60Hz,1H),7.55-7.43(m,3H),7.36-7.2 7(m,1H),6.67(bs,1H),6.36-6.23(m,2H),6.01(bs,1H),5.40(d,J=12.00,1H),4.85(bs,1H),3.62-3.36(m,2H).

[1132] Step G: 14-Fluoro-2-methoxy-8-(trifluoromethyl)-17,18-dihydro-6H,16H-5,11-methanodibenzoylmethane [b,k]pyrido[3,2-f][1,5]diazacyclododecane-6-dione 2a

[1133]

[1134] To a solution of (E)-8-fluoro-14-methoxy-2-(trifluoromethyl)-10H,18H-5,17-methanodibenzo[b,k]pyrido[3,2-f][1,5]diazacyclododecan-18-one (140 mg, 0.307 mmol) in MeOH (5 mL) was added PdOH2 (21.6 mg, 0.031 mmol), and the reaction mixture was stirred under H2 atmosphere (5 kg pressure) for 16 h. The reaction mixture was filtered through celite, washed with MeOH (2×30 mL), and the solvent was evaporated under reduced pressure to give 14-fluoro-2-methoxy-8-(trifluoromethyl)-17,18-dihydro-6H,16H-5,11-methanodibenzo[b,k]pyrido[3,2-f][1,5]diazacyclododecan-6-dione 2a (130 mg, 84% yield) as a brown solid. HPLC / MS 1.31 min (C), [M+H] + 457.8.

[1135] Step H: 14-Fluoro-8-(trifluoromethyl)-17,18-dihydro-1H,6H-5,11-methanodibenzo[b,k]pyrido [3,2-f][1,5]diazacyclododecane-2,6(16H)-dione Example 2

[1136]

[1137] To a solution of 14-fluoro-2-methoxy-8-(trifluoromethyl)-17,18-dihydro-6H,16H-5,11-methanodibenzo[b,k]pyrido[3,2-f][1,5]diazacyclododecan-6-one (130 mg, 0.284 mmol) in DMF (5 mL) were added LiCl (72.3 mg, 1.71 mmol) and p-TsOH (324 mg, 1.71 mmol), and the reaction mixture was stirred for 5 h at 100° C. The reaction mixture was diluted with ice water (50 mL), extracted with EtOAc (2×30 mL), and the combined extracts were washed with brine, dried over Na 2 SO 4 , filtered, and the solvent was evaporated under reduced pressure. The crude residue was purified by semi-preparative HPLC (Sunfire C18, 19x150mm, 5μM) with a gradient elution of 25% MeCN-H2O (0.1% HCO2H) to 70% MeCN-H2O (0.1% HCO2H) over 10 min, followed by elution with 97% MeCN-H2O (0.1% HCO2H) over 9 min. The product fractions were combined and evaporated under reduced pressure to afford 14-fluoro-8-(trifluoromethyl)-17,18-dihydro-1H,6H-5,11-methanodibenzo[b,k]pyrido[3,2-f][1,5]diazacyclododecane-2,6(16H)-dione (27.8 mg, 22% yield) as a white solid. HPLC / MS 1.03 min (C), [M+H] + 444.2. 1H NMR(DMSO-d6,400MHz)δ11.72(bs,1H),8.13(s,1H),7.68-7.23(m,5H),6.75-6.48(m,1H),6.28-6.13(m,1H),5.49 -5.20(m,1H),4.82(d,J=12.00Hz,1H),2.90-2.62(m,2H),2.40-2.34(m,2H),1.84-1.78(m,1H),1.39-1.24(m,1H).

[1138]

[1139] Examples 3 and 4

[1140] 8-Fluoro-2-(trifluoromethyl)-10,13-dihydro-19H-5,18-methanodibenzo[b,l]pyrido[3,2-f][1, 5] diazacyclotridecane-15,19(14H)-dione Example 3 and 8-fluoro-2-(trifluoromethyl)-10,11,12,13-tetrahydro- 19H-5,18-Methanodibenzo[b,l]pyrido[3,2-f][1,5]diazacyclotridecan-15,19(14H)-dione

[1141]

[1142] Step A: Methyl 2-((2-bromo-4-fluorophenyl)amino)-5-(trifluoromethyl)-benzoate 3a

[1143]

[1144] To a mixture of 2-bromo-5-(trifluoromethyl)-benzoic acid methyl ester Int-2 (2.50 g, 8.83 mmol), 2-bromo-4-fluoroaniline (1.68 g, 8.83 mmol) and CsCO (4.32 g, 13.3 mmol) was added toluene (60 mL) and the reaction mixture was purged with N. BINAP (0.550 g, 0.883 mmol) and Pd(dba) (0.404 g, 0.442 mmol) were added thereto. The reaction mixture was purged with N and then heated at 100°C for 16 h. The reaction mixture was cooled to ambient temperature, filtered through celite, the celite was washed with EtOAc, and the organic matter was evaporated under reduced pressure. The crude residue was dissolved in DCM, pre-adsorbed onto a silica gel pre-packed column, and purified by flash column chromatography on silica gel (100 g) eluting with 5% EtOAc-petroleum ether. The product fractions were combined and evaporated under reduced pressure to give methyl 2-((2-bromo-4-fluorophenyl)amino)-5-(trifluoromethyl)-benzoate 3a (2.0 g, 33% yield) as an off-white solid with a purity of 57%. HPLC / MS 1.44 min (C), [M+H] + 392.0.

[1145] Step B: 2-((2-Bromo-4-fluorophenyl)amino)-5-(trifluoromethyl)benzoic acid 3b

[1146]

[1147] To methyl 2-((2-bromo-4-fluorophenyl)amino)-5-(trifluoromethyl)benzoate (4.10 g, 10.5 mmol) was added THF (30 mL), followed by the dropwise addition of a solution of LiOH (2.63 g, 62.7 mmol) in H2O (10 mL), and the reaction mixture was stirred at 60°C for 3 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure, and the residue was dissolved in H2O (100 mL), acidified to pH 2 with 1.5 N HCl, and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to afford 2-((2-bromo-4-fluorophenyl)amino)-5-(trifluoromethyl)benzoic acid 3b (4.0 g, 78% yield) as a yellow solid with a purity of 77%. HPLC / MS 1.37 min (C), [M+H] + 378.0. 1 H NMR(DMSO-d6,400MHz)δ13.8(br s,1H),9.92(s,1H),8.05-8.15(m,1H),7.75-7.99(m,1H),7.5 7-7.67(m,2H),7.32-7.37(m,1H),6.89-7.09(m,1H).

[1148] Step C: 2-((2-bromo-4-fluorophenyl)amino)-N-(2-bromo-6-methoxypyridin-3-yl)-5-(trifluoromethyl)- Benzamide 3c

[1149]

[1150] To 2-((2-bromo-4-fluorophenyl)amino)-5-(trifluoromethyl)benzoic acid (4.00 g, 10.6 mmol) in DMF (50 mL) was added HATU (6.03 g, 15.9 mmol) followed by DIEA (5.54 mL, 31.7 mmol) and the reaction mixture was stirred at room temperature for 20 min. 2-bromo-6-methoxypyridin-3-amine (2.58 g, 12.7 mmol) in DMF (10 mL) was added dropwise thereto and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with ice water (500 mL) and extracted with EtOAc (2 x 250 mL). The combined extracts were washed with water (250 mL), brine, dried over Na SO , filtered, and the solvent evaporated under reduced pressure. The crude residue was dissolved in DCM, adsorbed onto silica gel, and purified by flash column chromatography on silica gel (100 g) eluting with 10% EtOAc-petroleum ether. Pure product fractions were combined and evaporated under reduced pressure to give 2-((2-bromo-4-fluorophenyl)amino)-N-(2-bromo-6-methoxypyridin-3-yl)-5-(trifluoromethyl)benzamide 3c (1.75 g, 27% yield) as a yellow solid. HPLC / MS 1.45 min (C), [M+H] + 562.0. 1 H NMR(DMSO-d6,400MHz)δ10.51(s,1H),9.97(s,1H),8.30(s,1H),7.85-7.87(d,1H),7.67-7.75( m,2H),7.56-7.59(m,1H),7.29-7.34(m,1H),7.07-7.09(d,1H),6.95-6.97(d,1H),3.89(s,3H).

[1151] Step D: 1-(2-bromo-4-fluorophenyl)-3-(2-bromo-6-methoxypyridin-3-yl)-6-(trifluoromethyl)-2,3- Dihydroquinazolin-4(1H)-one 3d

[1152]

[1153] Under N to 2-((2-bromo-4-fluorophenyl) amino)-N-(2-bromo-6-methoxypyridin-3-yl)-5-(trifluoromethyl) benzamide (1.75g, 3.11mmol) in MeCN (30mL) in solution CsCO(4.05g, 12.4mmol) and diiodomethane (0.752mL, 9.32mmol), and reaction mixture is heated to 80 DEG C and kept for 20h.Reaction mixture is quenched with ice water (100mL), extracted with EtOAc (2x100mL), and use HO (100mL), salt solution, NaSOThe organic extracts merged are washed, filtered and solvent is evaporated under reduced pressure.Crude residue is dissolved in DCM, is adsorbed on silica gel and purified by silica gel flash column chromatography (100g) eluting with 10%EtOAc-petroleum ether. The pure product fractions were combined and evaporated under reduced pressure to give 1-(2-bromo-4-fluorophenyl)-3-(2-bromo-6-methoxypyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one 3d (1.4 g, 75% yield) as an off-white solid. HPLC / MS 2.55 min (E), [M+H] + 573.8. 1 H NMR(DMSO-d6,400MHz)δ8.12(s,1H),7.85-7.91(m,2H),7.63-7.72(m,2H),7.42-7. 48(m,1H),6.97-7.00(d,1H),6.41-6.53(dd,1H),4.45-5.62(ddd,2H),3.87(s,3H).

[1154] Step E: 1-(2-allyl-4-fluorophenyl)-3-(2-allyl-6-methoxypyridin-3-yl)-6-(trifluoromethyl)- (1H)-2,3-dihydroquinazolin-4-one 3e

[1155]

[1156] To a solution of 1-(2-bromo-4-fluorophenyl)-3-(2-bromo-6-methoxypyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one (0.8 g, 1.39 mmol) in DMF (10 mL) was added allyltributylstannane (1.73 mL, 5.56 mmol) and Pd(Ph3P)4 (0.241 g, 0.209 mmol) under N2, and the reaction mixture was heated at 120 ° C. for 2 h. The reaction mixture was cooled to ambient temperature, quenched with ice water (200 mL), extracted with EtOAc (2×100 mL), and 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 flash column chromatography on silica gel (100 g) eluting with 20% EtOAc-petroleum ether. Pure product fractions were combined and evaporated under reduced pressure to afford 1-(2-allyl-4-fluorophenyl)-3-(2-allyl-6-methoxypyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one 3e (0.6 g, 84% yield) as a colorless gum. HPLC / MS 1.38 min (C), [M+H] + 498.3. 1 H NMR(DMSO-d6,400MHz)δ8.09(s,1H),7.65-7.68(m,2H),7.40-7.48(m,1H),7.25-7.27(m,2H),6.76-6 .79(d,1H),6.28-6.41(dd,1H),5.81-6.12(m,2H),4.72-5.68(m,6H),3.86(s,3H),3.36-3.46(m,4H).

[1157] Step F: 8-Fluoro-15-methoxy-2-(trifluoromethyl)-10,13-dihydro-19H-5,18-methanodibenzo[b,l] Pyrido[3,2-f][1,5]diazacyclotridecan-19-one 3f

[1158]

[1159] 1-(2-allyl-4-fluorophenyl)-3-(2-allyl-6-methoxypyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one (0.3 g, 0.603 mmol), DCE (70 mL) and Hoveyda-Grubbsii (0.076 g, 0.121 mmol) were added to a 250 mL sealed tube equipped with a magnetic stir bar under N2 atmosphere and the light green reaction mixture was heated at 80 ° C for 16 h. The reaction mixture was cooled to ambient temperature, filtered through celite, washed with DCM (50 mL), and the solvent was evaporated under reduced pressure. The crude residue was dissolved in DCM, adsorbed onto silica gel, and purified by flash column chromatography on silica gel (25 g) eluting with 15% EtOAc-petroleum ether. The pure product fractions were combined and evaporated under reduced pressure to give 8-fluoro-15-methoxy-2-(trifluoromethyl)-10,11,12,13-tetrahydro-19H-5,18-methanodibenzo[b,l]pyrido[3,2-f][1,5]diazacyclotridecan-19-one 3f (200 mg, 68% yield) as a light green solid. HPLC / MS 1.36 min (C), [M+H] + 470.0. 1 H NMR(DMSO-d6,400MHz)δ8.12(s,1H),7.66-7.72(m,2H),7.48-7.57(m,2H),7.23-7.28(m,1H),6.77-6.79(d,1H),6.50-6.52(d,1H) ),5.48-5.76(m,2H),5.37-5.39(d,1H),4.28-4.32(m,2H),4.17-4.26(m,1H),3.89(s,3H),3.09-3.12(d,1H),3.01-3.04(d,1H).

[1160] Step G: 8-fluoro-2-(trifluoromethyl)-10,13-dihydro-19H-5,18-methanodibenzo[b,l]pyrido[3, 2-f][1,5]diazacyclotridecane-15,19(14H)-dione Example 3

[1161]

[1162] Following the procedure in Step F of Example 1, the reaction mixture was stirred at 100°C for 3 h to isolate 8-fluoro-2-(trifluoromethyl)-10,13-dihydro-19H-5,18-methanodibenzo[b,l]pyrido[3,2-f][1,5]diazacyclotridecan-15,19(14H)-dione (40 mg, 31% yield) as an off-white solid. HPLC / MS: 1.08 min (C), [M+H] + 456.0. 1HNMR (DMSO-d6, 400MHz) δ12.07 (s, 1H), 8.10 (s, 1H), 7.67 (d, J = 2.00Hz, 8.80Hz, 1H), 7.56 (d, J = 2. 80,9.40Hz,1H),7.50-7.43(m,2H),7.25(dd,J=2.80,8.40Hz,1H),6.51(d,J=8.80Hz,1H),6.38(d, J=9.20Hz,1H),5.52-5.44(m,2H),5.34(d,J=10.40Hz,1H),4.25(d,J=10.00Hz,1H),4.17-4.14(t ,J=12.40Hz,1H),4.11-4.02(t,J=11.20Hz,1H),3.07(d,J=14.40Hz,1H),2.93(d,J=14.00Hz,1H).

[1163] Step H: 8-Fluoro-15-methoxy-2-(trifluoromethyl)-10,11,12,13-tetrahydro-19H-5,18-methoxybenzene 1,2-diazacyclotridecan-19-one 4a

[1164]

[1165] To a solution of 8-fluoro-15-methoxy-2-(trifluoromethyl)-10,11,12,13-tetrahydro-19H-5,18-methylenedibenzo[b,l]pyrido[3,2-f][1,5]diazacyclotridecan-19-one (200mg, 0.426mmol) in MeOH (5mL) purged with N2 was added 20% Pd(OH)2(90mg, 0.128mmol), and the reaction mixture was stirred for 3h under H2 atmosphere (1atm). The reaction mixture was filtered through celite, washed with MeOH (150mL), and the solvent was evaporated under reduced pressure. The crude residue was dissolved in DCM, adsorbed onto silica gel, and purified by flash column chromatography on silica gel (25g) eluting with 20% EtOAc-petroleum ether. The pure product fractions were combined and evaporated under reduced pressure to give 8-fluoro-15-methoxy-2-(trifluoromethyl)-10,11,12,13-tetrahydro-19H-5,18-methanodibenzo[b,l]pyrido[3,2-f][1,5]diazacyclotridecan-19-one 4a (140 mg, 69% yield) as an off-white solid. HPLC / MS 1.37 min (C), [M+H] + 472.2. 1H NMR(DMSO-d6,400MHz)δ8.11(s,1H),7.66-7.69(d,2H),7.44-7.48(m,1H ),7.35-7.38(m,1H),7.19-7.24(m,1H),6.73-6.75(d,1H),6.40-6.42(d ,1H),5.67-5.69(d,1H),4.71-4.74(d,1H),3.84(s,3H),2.72-2.85(m,2 H),2.29-2.38(m,2H),1.64-1.67(m,2H),1.40-1.56(m,1H),1.32(m,1H).

[1166] Step I: 8-Fluoro-2-(trifluoromethyl)-10,11,12,13-tetrahydro-19H-5,18-methanodibenzo[b,l]pyridine Example 4 of [3,2-f][1,5]diazacyclotridecan-15,19(14H)-dione

[1167]

[1168] To a solution of 8-fluoro-15-methoxy-2-(trifluoromethyl)-10,11,12,13-tetrahydro-19H-5,18-methyldibenzo[b,l]pyrido[3,2-f][1,5]diazacyclotridecan-19-one (140mg, 0.297mmol) in MeCN (5mL) cooled to 0°C under N2 was added iodotrimethylsilane (0.121mL, 0.891mmol) dropwise, and the reaction mixture was stirred at 80°C for 3h. The reaction mixture was cooled to ambient temperature and quenched with saturated Na2S2O3 aqueous solution (20mL). The aqueous layer was extracted with EtOAc (3x25mL), the combined organic extracts were dried with Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The crude residue was dissolved in DCM, adsorbed onto silica gel, and purified by flash column chromatography on silica gel (25g) with 10% EtOAc-petroleum ether. The pure product fractions were combined and evaporated under reduced pressure. The solid was freeze-dried to give 8-fluoro-2-(trifluoromethyl)-10,11,12,13-tetrahydro-19H-5,18-methanodibenzo[b,l]pyrido[3,2-f][1,5]diazacyclotridecan-15,19(14H)-dione (80 mg, 59% yield) as a white solid. HPLC / MS 1.04 min (C), [M+H] + 458.0. 1H NMR(400MHz,DMSO-d6)δ11.85(s,1H),8.10(s,1H),7.66(dd,J=2.00,8.80Hz,1H) ,7.47-7.41(m,3H),7.26-7.21(m,1H),6.40(d,J=8.40Hz,1H),6.21(d,J=9.20Hz, 1H),5.58(d,J=11.60Hz,1H),4.71(d,J=11.60Hz,1H),2.71-2.64(m,1H),2.58-2 .51(m,1H),2.38-2.34(m,1H),2.26-2.20(m,1H),1.64-1.63(m,2H),1.42(m,2H).

[1169]

[1170] Examples 5 and 6

[1171] 8-Fluoro-3-(trifluoromethyl)-10,13-dihydro-19H-5,18-methanodibenzo[b,l]pyrido[3,2f][1, 5] diazacyclotridecane-15,19(14H)-dione Example 5 and 8-fluoro-3-(trifluoromethyl)-10,11,12,13-tetrahydro- 19H-5,18-methanodibenzo[b,l]pyrido[3,2-f][1,5]diazacyclotridecane-15,19(14H)-dione Example 6

[1172]

[1173] Step A: Ethyl 2-((2-bromo-4-fluorophenyl)amino)-4-(trifluoromethyl)benzoate 5a

[1174]

[1175] Following the procedure in Example 3, Step A, replacing Int-2 with Int-2a, ethyl 2-((2-bromo-4-fluorophenyl)amino)-4-(trifluoromethyl)benzoate 5a (2.5 g, 60% yield) was prepared as a yellow oil. HPLC / MS 3.15 min (F), [M+H] + 406.0. 1 H NMR(400MHz,DMSO-d6)δ9.45(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).

[1176] Step B: Ethyl 2-((2-allyl-4-fluorophenyl)amino)-4-(trifluoromethyl)benzoate 5b

[1177]

[1178] Under N2, to a solution of ethyl 2-((2-bromo-4-fluorophenyl) amino)-4-(trifluoromethyl) benzoate (2.50g, 6.15mmol) in DMF (30mL), allyltributylstannane (2.29mL, 7.39mmol) and Pd(PPh3)4(0.213g, 0.185mmol) were added, and the reaction mixture was stirred at 80 DEG C for 16h. The reaction mixture was cooled to ambient temperature, quenched with ice-cold water (200mL), extracted with EtOAc (2x100mL), and the organic extracts were combined with H2O (100mL), salt water washing, Na2SO4 drying, filtered, and the solvent was evaporated under reduced pressure. The crude residue was dissolved in DCM, adsorbed on silica gel, purified by flash column chromatography on silica gel (100g) eluted with 5%EtOAc-petroleum ether. Pure product fractions were combined and evaporated under reduced pressure, and the solid was freeze-dried to give ethyl 2-((2-allyl-4-fluorophenyl)amino)-4-(trifluoromethyl)benzoate 5b (2.45 g, 85% yield) as a yellow oil with a purity of 65%. HPLC / MS 3.23 min (F), [M+H] + 368.0.

[1179] Step C: 2-((2-allyl-4-fluorophenyl)amino)-4-(trifluoromethyl)benzoic acid 5c

[1180]

[1181] To a solution of ethyl 2-((2-allyl-4-fluorophenyl)amino)-4-(trifluoromethyl)benzoate (2.45 g, 6.67 mmol) in THF (18 mL) was added LiOH (1.68 g, 40.0 mmol) dissolved in H2O (6 mL) under N2, and the reaction mixture was stirred at 60 ° C for 3 h. The reaction mixture was cooled to ambient temperature and evaporated under reduced pressure. The residue was dissolved in H2O (5 mL), acidified to pH 4 with 1.5N HCl, and the aqueous layer was extracted with EtOAc (3x100 mL). The combined extracts were dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to give 2-((2-allyl-4-fluorophenyl)amino)-4-(trifluoromethyl)benzoic acid 5c (2.30 g, 83% yield) as a yellow solid with a purity of 82%. HPLC / MS 2.76 min (F), [M+H] + 338.2.

[1182] Step D: 2-((2-allyl-4-fluorophenyl)amino)-N-(2-allyl-6-methoxypyridin-3-yl)-4- (Trifluoromethyl)benzoic acid 5d

[1183]

[1184] Under N2, DIEA (3.55mL, 20.3mmol) and HATU (3.87g, 10.2mmol) are added to a solution of 2-((2-allyl-4-fluorophenyl) amino)-4-(trifluoromethyl) benzoic acid (2.30g, 6.78mmol) in DMF (25mL), and the reaction mixture is stirred for 20min. Int-1a (1.34g, 8.13mmol) dissolved in DMF (5mL) is now added dropwise, and the reaction mixture is stirred at room temperature for 2h. The reaction mixture is quenched with ice water (200mL), extracted with EtOAc (2x200mL), and the organic extracts combined are washed with H2O (200mL), salt water, and Na2SO4 is dried, filtered, and the solvent is evaporated under reduced pressure. The crude residue is dissolved in DCM, adsorbed on silica gel, purified by flash column chromatography on silica gel (75g) with 20% EtOAc-petroleum ether. Pure product fractions were combined and evaporated under reduced pressure to give 2-((2-allyl-4-fluorophenyl)amino)-N-(2-allyl-6-methoxypyridin-3-yl)-4-(trifluoromethyl)benzoic acid 5d (2.50 g, 69% yield) as a yellow solid. HPLC / MS 3.11 min (F), [M+H] + 486.2. 1 H NMR(400MHz,DMSO-d6)δ10.2(2,1H),9.27(s,1H),8.00-8.05(d,1H),7.73-7.68(d,1H),7.34-7.82(m,1H),7.12-7.19(m,3H),6.88(s ,1H),6.73-6.75(d,1H),5.92-6.08(m,1H),5.80-5.90(m,1H),4.93-5.08(m,4H),3.86(s,3H),3.49-3.51(m,2H),3.28-3.32(m,2H).

[1185] Step E: 1-(2-allyl-4-fluorophenyl)-3-(2-allyl-6-methoxy-pyridin-3-yl)-7-(trifluoromethyl)- (1H)-2,3-dihydroquinazolin-4-one 5e

[1186]

[1187] To a solution of 2-((2-allyl-4-fluorophenyl) amino)-N-(2-allyl-6-methoxypyridin-3-yl)-4-(trifluoromethyl)benzamide (1.50 g, 3.09 mmol) in MeCN (20 mL) was added CsCO(4.03 g, 12.4 mmol) and diiodomethane (0.748 mL, 9.27 mmol), and the reaction mixture was stirred at 80 ° C for 4 h. The reaction mixture was cooled to ambient temperature, quenched with ice-cold water (100 mL), extracted with EtOAc (2x200 mL), and 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 flash column chromatography on silica gel (50 g) eluting with 20% EtOAc-petroleum ether. The pure product fractions were combined and evaporated under reduced pressure. The isolated material was further purified by semi-preparative HPLC (XSELECT C18, 19x150 mm, 5 μm) with a MeCN-H2O gradient. The product fractions were combined and evaporated under reduced pressure to give 1-(2-allyl-4-fluorophenyl)-3-(2-allyl-6-methoxy-pyridin-3-yl)-7-(trifluoromethyl)2,3-dihydroquinazolin-4(1H)-one 5e (110 mg, 7% yield) as a yellow semisolid. HPLC / MS 3.05 min (F), [M+H] + 498.1. 1 H NMR(400MHz,DMSO-d6)δ8.07-8.09(d,1H),7.67-7.69(m,1H),7.44-7.46(m,1H),7.25-7.29(m,3H),6.76-6.78(d,1H),6.32-6.44(m,1 H),5.76-6.10(m,2H),5.63-5.65(d,0.5H),5.13-5.18(m,1H),4.92-5.00(m,4H),4.72-4.75(d,0.5H),3.85(s,3H),3.35-3.40(m,4H).

[1188] Step F: 8-Fluoro-15-methoxy-3-(trifluoromethyl)-10,13-dihydro-19H-5,18-methanodibenzo[b,l] Pyrido[3,2-f][1,5]diazacyclotridecan-19-one 5f

[1189]

[1190] 1-(2-allyl-4-fluorophenyl)-3-(2-allyl-6-methoxypyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one (150 mg, 0.302 mmol), DCE (35 mL) and Hoveyda-Grubbsii (51.2 mg, 0.060 mmol) were added to a 100 mL sealed tube equipped with a magnetic stir bar under N2 atmosphere, and the light brown reaction mixture was heated at 80 ° C for 16 h. The reaction mixture was cooled to ambient temperature, filtered through celite, washed with DCM (100 mL), and the solvent was evaporated under reduced pressure. The crude residue was dissolved in DCM, adsorbed onto silica gel, and purified by flash column chromatography on silica gel (25 g) eluting with 20% EtOAc-petroleum ether. The pure product fractions were combined and evaporated under reduced pressure to give 8-fluoro-15-methoxy-3-(trifluoromethyl)-10,13-dihydro-19H-5,18-methanodibenzo[b,l]pyrido[3,2-f][1,5]diazacyclotridecan-19-one 5f (75 mg, 52% yield) as an off-white solid. HPLC / MS 2.90 min (F), [M+H] + 470.2. 1 H NMR(DMSO-d6,400MHz)δ8.09-8.11(d,1H),7.70-7.72(d,1H),7.51-7.58(m,2H),7.24-7.29(m,2H),6.77-6.79 (d,1H),6.53(s,1H),5.48-5.51(m,2H),5.35-5.38(d,1H),4.19-4.33(m,3H),3.89(s,3H),3.26-3.15(m,2H).

[1191] Step G: 8-fluoro-3-(trifluoromethyl)-10,13-dihydro-19H-5,18-methanodibenzo[b,l]pyrido[3, 2f][1,5]diazacyclotridecane-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]diazacyclotridecan-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]diazacyclotridecan-15,19(14H)-dione 6a

[1192]

[1193] To a solution of 8-fluoro-15-methoxy-3-(trifluoromethyl)-10,13-dihydro-19H-5,18-methyldibenzo[b,l]pyrido[3,2-f][1,5]diazacyclotridecan-19-one (0.075 g, 0.160 mmol) in MeCN (3 mL) cooled to 0 ° C under N2 was added iodotrimethylsilane (0.065 mL, 0.479 mmol) dropwise, and the reaction mixture was stirred at 80 ° C for 1 h. The reaction mixture was concentrated under reduced pressure, the residue was quenched with saturated Na2S2O3 aqueous solution (5 mL), and extracted with EtOAc (3x10 mL). The combined organic extracts were washed with H2O (10 mL), brine, dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The crude residue was purified by semi-preparative HPLC (XSELECT, C18, 10x250mm, 5um) with a gradient elution of 70% H2O-MeCN (0.1% HCO2H) to 100% MeCN (0.1% HCO2H). Pure product fractions were combined and freeze-dried to give 8-fluoro-3-(trifluoromethyl)-10,13-dihydro-19H-5,18-methanodibenzo[b,l]pyrido[3,2f][1,5]diazacyclotridecan-15,19(14H)-dione (13 mg, 18% yield) as an off-white solid. HPLC / MS 2.19 min (F), [M+H] + 456.0. 1 H NMR (DMSO-d6, 400 MHz) δ 12.04 (brs, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.60-7.49 (m, 2H), 7.45 (d, J = 9.4 Hz, 1H), 7.32-7.14 (m, 2H), 6.52 (s, 1H), 6.26 (d, J = 9.1 Hz, 1H), 5.58-5.39 (m, 2H), 5.32 (d, J = 10.0 Hz, 1H), 4.27-4.11 (m, 2H), 4.03 (t, J = 12.1 Hz, 1H), 3.14-3.03 (m, 1H), 2.98-2.89 (m, 1H). The fractions of the second peak were combined and freeze-dried to give 8-fluoro-1-(2-nitro-1-yl)-1-nitro-2-nitropropene. 1 -iodo-3-(trifluoromethyl)-10,11,12,13-tetrahydro-19H-5,18-methanodibenzo[b,l]pyrido[3,2-f][1,5]diazacyclotridecan-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]diazacyclotridecan-15,19(14H)-dione 6a (20 mg, 6% yield). HPLC / MS 2.19 min (F), [M+H] + 584.0, purity 58%.

[1194] Step H: 8-Fluoro-3-(trifluoromethyl)-10,11,12,13-tetrahydro-19H-5,18-methanodibenzo[b,l]pyridine Example 6 of [3,2-f][1,5]diazacyclotridecan-15,19(14H)-dione

[1195]

[1196] To 8-fluoro-1 1 -iodo-3-(trifluoromethyl)-10,11,12,13-tetrahydro-19H-5,18-methanodibenzo[b,l]pyrido[3,2-f][1,5]diazacyclotridecan-15,19(14H)-dione or 8-fluoro-1 2 To a solution of -iodo-3-(trifluoromethyl)-10,11,12,13-tetrahydro-19H-5,18-methanodibenzo[b,l]pyrido[3,2-f][1,5]diazacyclotridecan-15,19(14H)-dione (25 mg, 0.043 mmol) in DMF (1 mL) was added DBU (6.46 μl, 0.043 mmol), and the reaction mixture was stirred at room temperature for 16 h, then at 60° C. for 6 h. The reaction mixture was cooled to ambient temperature, quenched with ice water (10 mL), extracted with EtOAc (2×10 mL), and the combined organic extracts were washed with H 2 O (10 mL), brine, dried over Na 2 SO 4 , filtered, and the solvent was evaporated under reduced pressure to give a white solid. The solid is dissolved in MeOH (3mL), purged with N2, 20% Pd (OH) 2 (9.25mg, 0.013mmol) is added thereto, and the reaction mixture is stirred for 16h under H2 atmosphere. The reaction mixture is filtered through diatomaceous earth, washed with MeOH (10mL), and the solvent is evaporated under reduced pressure. The crude residue is purified by semi-preparative HPLC (X-BRIDGE C18, 19x150mm, 5μm) with 95% MeCN-H2O to 100% MeCN gradient elution. The product fractions are combined, evaporated under reduced pressure, and then dried in vacuo using Genevac to obtain 8-fluoro-3- (trifluoromethyl) -10,11,12,13-tetrahydro -19H-5,18- methyl-dibenzo [b, l] pyrido [3,2-f] [1,5] diazacyclotridecane -15,19 (14H) -dione (4.5mg, 22% yield) as a pale white solid. HPLC / MS 3.12min(F),[M+H] + 457.7.1 H NMR(DMSO-d6,400MHz)δ11.84(brs,1H),8.08(d,J=8.0Hz,1H),7.48(dd,J=8.8,5.5H z,1H),7.43(d,J=9.5Hz,1H),7.36(dd,J=9.6,3.0Hz,1H),7.26-7.20(m,2H),6.40(s, 1H),6.21(d,J=9.6Hz,1H),5.57(d,J=11.6Hz,1H),4.69(d,J=11.5Hz,1H),2.75-2.6 4(m,2H),2.42-2.35(m,1H),2.29-2.20(m,1H),1.71-1.58(m,2H),1.50-1.35(m,2H).

[1197]

[1198] Example 7

[1199] 3 4 -Fluorine-2 6 -(trifluoromethyl)-1 1 ,1 2 ,1 1 ,2 2 ,2 3 ,2 4 -Hexahydro-2(3,1)-quinazolin-1(5,6)-pyridine Hetero-3(1,2)-Benzene heterocyclic octahedral-1 2 ,2 4 -dione

[1200]

[1201] Step A: Ethyl 2-((2-(but-3-en-1-yl)-4-fluorophenyl)amino)-5-(trifluoromethyl)benzoate 7a

[1202]

[1203] To ethyl 2-bromo-5-(trifluoromethyl)benzoate (8.00 g, 26.9 mmol) and 2-(but-3-en-1-yl)-4-fluoroaniline Int-3a (5.34 g, 32.3 mmol) was added toluene (80 mL) purged with N2, followed by palladium(II) acetate (0.363 g, 1.62 mmol) and BINAP (1.61 g, 2.59 mmol), the reaction mixture was further purged with N2, Cs2CO3 (12.3 g, 37.7 mmol) was added, and the reaction mixture was heated at 80°C for 24 h. The reaction mixture was cooled to ambient temperature, diluted with EtOAc, quenched and washed with H2O (2x), brine, dried over Na2SO4, filtered and the solvent evaporated under reduced pressure. The crude residue was dissolved in DCM, pre-adsorbed onto a silica gel prepacked column, and purified by silica gel flash column chromatography (330 g) with a gradient elution of 100% hexanes to 60% EtOAc-hexanes. The product fractions were combined and evaporated under reduced pressure to afford ethyl 2-((2-(but-3-en-1-yl)-4-fluorophenyl)amino)-5-(trifluoromethyl)benzoate 7a (5.55 g, 51% yield) as a light yellow oil. HPLC / MS 1.61 min (A), [M+H]+ 382.1. 1 H NMR(DMSO-d6,400MHz)δ9.3-9.6(m,1H),8.13(d,1H,J=2.0Hz),7.6-7.7(m,1H),7.3-7.4(m,1H),7.2-7.3(m,1H),7.14(d,1H,J=2.9 Hz), 6.68 (d, 1H, J = 8.8Hz), 5.7-5.8 (m, 1H), 4.90 (s, 2H), 4.38 (d, 2H, J = 6.8Hz), 2.62 (s, 2H), 2.2-2.3 (m, 2H), 1.37 (t, 3H, J = 7.1Hz).

[1204] Step B: 2-(But-3-en-1-yl)-4-fluorophenyl)amino)-5-(trifluoromethyl)benzoic acid 7b

[1205]

[1206] To ethyl 2-((2-(but-3-en-1-yl)-4-fluorophenyl)amino)-5-(trifluoromethyl)benzoate (5.55 g, 14.6 mmol) was added THF (75 mL) and H₂O (25 mL), followed by LiOH (1.39 g, 58.2 mmol), and the reaction mixture was stirred at 50°C for 24 h. The reaction mixture was cooled to ambient temperature, acidified to pH 5 with 1N HCl, extracted with EtOAc (2x), and the organic extracts were combined, washed with H₂O, brine, dried over Na₂SO₄, filtered, and the solvent evaporated under reduced pressure to afford 2-(but-3-en-1-yl)-4-fluorophenyl)amino)-5-(trifluoromethyl)benzoic acid 7b (5.34 g, 100% yield) as a beige solid. HPLC / MS 1.54 min (A), [M+H] + 354.0. 1 H NMR(DMSO-d6,400MHz)δ13.58(br s,1H),9.74(s,1H),8.13(d,1H,J=1.5Hz),7.61(dd,1H,J=2.2,9.0Hz),7.35(dd,1H,J=5.6,8.6Hz),7.26(dd,1H,J=2 .9,9.8Hz),7.1-7.2(m,1H),6.71(d,1H,J=8.8Hz),5.7-5.9(m,1H),4.6-5.1(m,2H),2.6-2.7(m,2H),2.2-2.3(m,2H).

[1207] Step C: N-(2-allyl-6-methoxypyridin-3-yl)-2-((2-(but-3-en-1-yl)-4-fluorophenyl)amine 1-(Trifluoromethyl)benzamide 7c

[1208]

[1209] To 2-((2-(but-3-ene-1-yl)-4-fluorophenyl)amino)-5-(trifluoromethyl)benzoic acid (1.10 g, 3.11 mmol) and 2-allyl-6-methoxypyridin-3-amine Int-1a (0.613 g, 3.74 mmol) in DMF (20 mL) was added HATU (1.54 g, 4.05 mmol) followed by TEA (1.30 mL, 9.34 mmol) and the reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with EtOAc, washed with H2O (3x), brine, dried over Na2SO4, filtered, and the solvent evaporated under reduced pressure. The crude residue was dissolved in DCM, adsorbed onto a silica gel-packed pre-column, and purified by flash column chromatography on silica gel (120 g) with a gradient elution of 100% heptane to 100% EtOAc. Pure product fractions were combined and evaporated under reduced pressure to give N-(2-allyl-6-methoxypyridin-3-yl)-2-((2-(but-3-en-1-yl)-4-fluorophenyl)amino)-5-(trifluoromethyl)benzamide 7c (1.24 g, 77% yield) as a yellow oil. HPLC / MS 1.55 min (A), [M+H] + 500.1. 1 H NMR(DMSO-d6,400MHz)δ10.24(s,1H),9.74(s,1H),8.22(s,1H),7.65(d,1H,J=8.8Hz),7.6-7.6(m,1H),7.3-7.4(m,1H),7.22(br d,1H,J=9.8Hz),7.11(br d,1H,J=3.4Hz),6.75(d,2H,J=8.8Hz),6.04(s,1H),5.7-5.8(m,1H),5.04(s,2H) ,4.9-5.0(m,2H),3.87(s,3H),3.5-3.5(m,2H),2.6-2.7(m,2H),2.2-2.3(m,2H).

[1210] 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

[1211]

[1212] To a solution of N-(2-allyl-6-methoxypyridin-3-yl)-2-((2-(but-3-ene-1-yl)-4-fluorophenyl)amino)-5-(trifluoromethyl)benzamide (1.24 g, 2.48 mmol) in EtOAc (100 mL) was added paraformaldehyde (1.49 g, 49.6 mmol) and then concentrated H was added dropwise SO (0.662 mL, 12.4 mmol), and the reaction mixture was stirred at ambient temperature for 4.5 h. The reaction mixture was diluted with EtOAc, quenched and washed with 10% NaHCO (2x), H O, brine, and dried over Na SO, filtered, and the solvent was evaporated under reduced pressure. The crude residue was dissolved in DCM, absorbed onto a silica gel-filled pre-column, and purified by flash column chromatography on silica gel (120 g) with a gradient elution of 100% heptane to 40% EtOAc. The pure product fractions were combined and evaporated under reduced pressure to give 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 (772.3 mg, 59% yield) as a viscous oil. HPLC / MS 1.49 min (A, [M+H] + 512.2. 1 H NMR(DMSO-d6,400MHz)δ8.10(s,1H),7.6-7.7(m,2H),7.3-7.5(m,2H),7.23(br dd,1H,J=2.7,8.6Hz),6.78(d,1H,J=8.8Hz),6.3-6.5(m,1H),5.9-6.1(m,1H),5.6-5.9(m,2H),5.3-5.3 (m,1H),4.9-5.1(m,4H),4.6-4.8(m,1H),3.86(s,3H),3.4-3.5(m,2H),2.6-2.8(m,2H),2.3-2.4(m,2H).

[1213] Step E: 3 4 -Fluorine-1 6 -Methoxy-2 6 -(trifluoromethyl)-2 1 ,2 2 ,2 3 ,2 4 -Tetrahydro-2(3,1)-quinazoline-1 (3,2)-Pyridin-3(1,2)-benzene heterocyclic octa-6-ene-2 4 -Keto 7e

[1214]

[1215] To a solution of 3-(2-allyl-6-methoxypyridin-3-yl)-1-(2-(but-3-ene-1-yl)-4-fluorophenyl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one (770 mg, 1.51 mmol) in DCE (30 mL) purged with N2 was added Hoveyda-Grubbsii (256 mg, 0.301 mmol) and the reaction mixture was stirred at 80 ° C for 18 h. The reaction mixture was cooled to ambient temperature and the solvent was evaporated under reduced pressure. The crude residue was dissolved in DCM, adsorbed onto a silica gel-filled pre-column, and the combined product fractions were purified by silica gel flash column chromatography (80 g) with a gradient elution of 100% heptane to 30% EtOAc and evaporated under reduced pressure to give 3 4 -Fluorine-1 6 -Methoxy-2 6 -(trifluoromethyl)-2 1 ,2 2 ,2 3 ,2 4 -Tetrahydro-2(3,1)-quinazoline-1(3,2)-pyridin-3(1,2)-benzene heterocycle octahydro-6-ene-2 4 -ketone 7e (506.6 mg, 67% yield) as a white solid. HPLC / MS 1.38 min (A), [M+H] + 484.1. 1 H NMR(DMSO-d6,400MHz)δ8.0-8.2(m,1H),7.6-7.8(m,2H),7.2-7.4(m,3H),6.80(d,1H,J=8.3Hz),6.3-6.5(m, 1H),5.7-6.0(m,1H),5.1-5.6(m,2H),4.36(d,1H,J=8.8Hz),3.87(d,3H,J=2.0Hz),3.4-3.8(m,1H),3.25(br s,1H),2.76(s,2H),2.4-2.5(m,1H),1.8-2.3(m,1H).

[1216] Step F: 3 4 -Fluorine-1 6 -Methoxy-2 6 -(trifluoromethyl)-2 1 ,2 2 ,2 3 ,2 4 -Tetrahydro-2(3,1)-quinazoline-1 (3,2)-Pyridinyl-3(1,2)-Benzene Heterocyclic Bafan-2 4 -Keto 7f

[1217]

[1218] To 3 purged with N2 4 -Fluorine-1 6 -Methoxy-2 6 -(trifluoromethyl)-2 1 ,2 2 ,2 3 ,2 4-Tetrahydro-2(3,1)-quinazoline-1(3,2)-pyridin-3(1,2)-benzene heterocycle octahydro-6-ene-2 4 To the solution of -ketone (501mg, 1.04mmol) in DCE (10.0mL) and MeOH (1.0mL), add Hoveyda-Grubbsii (44.0mg, 0.052mmol), then add NaBH (78mg, 2.07mmol), and the reaction mixture is stirred to 22h at ambient temperature. Use H o quenches the reaction mixture, dilutes with DCM, and is layered, and uses Na sO dry organic phase, filters, and solvent is evaporated under reduced pressure. Crude residue is dissolved in DCM, is adsorbed on the pre-post filled with silica gel, and is purified by silica gel flash column chromatography (120g) with 100% heptane to 40% EtOAc gradient elution. Combine product fractions, evaporated under reduced pressure, and obtain a white solid, which is composed of 10% starting olefins. The solid was dissolved in EtOAc / EtOH (18:12 mL), the reaction was purged with N2 (3x), 10% Pd-C (27 mg; 0.257 mmol) was added, the reaction mixture was purged with N2, a hydrogen balloon was added, hydrogen was passed into the reaction mixture (3x), and stirred at room temperature for 23 h. The reaction mixture was purged with N2, filtered through a celite pad, the celite was washed with EtOAc, the solvent was evaporated under reduced pressure and dried under vacuum to give 3 4 -Fluorine-1 6 -Methoxy-2 6 -(trifluoromethyl)-2 1 ,2 2 ,2 3 ,2 4 -Tetrahydro-2(3,1)-quinazoline-1(3,2)-pyridin-3(1,2)-benzene heterocycle-2 4 -ketone 7f (1.21 g, 81% yield) as a white solid. HPLC / MS 1.39 min (A), [M+H] + 486.2. 1HNMR(DMSO-d6,400MHz)δ8.1-8.2(m,1H),7.66(d,2H,J=8.3Hz),7.4-7.4(m,1H),7 .28(brd,1H,J=9.8Hz),7.2-7.3(m,1H),6.74(d,1H,J=8.3Hz),6.43(d,1H,J=8.3H z),5.81(d,1H,J=10.8Hz),4.76(d,1H,J=10.8Hz),3.84(s,3H),2.6-2.8(m,1H),2 .5-2.6(m,2H),2.4-2.5(m,1H),1.7-1.9(m,2H),1.4-1.6(m,2H),1.1-1.3(m,2H).

[1219] Step G:3 4 -Fluorine-2 6 -(trifluoromethyl)-1 1 ,1 2 ,1 1 ,2 2 ,2 3 ,2 4 -Hexahydro-2(3,1)-quinazoline-1(5,6)- Pyridinyl-3(1,2)-benzene heterocyclic octahedral-1 2 ,2 4 -Diketone Example 7

[1220]

[1221] To 3 4 -Fluorine-1 6 -Methoxy-2 6 -(trifluoromethyl)-2 1 ,2 2 ,2 3 ,2 4 -Tetrahydro-2(3,1)-quinazoline-1(3,2)-pyridin-3(1,2)-benzene heterocycle-2 4 To a solution of -ketone (1.42 g, 2.49 mmol) in DMF (25 mL) was added pTsOH (2.84 g, 14.9 mmol) and LiCl (0.634 g, 14.9 mmol), and the reaction mixture was stirred at 100 ° C for 1.5 h. The reaction mixture was cooled to ambient temperature, diluted with EtOAc and washed with H2O (2x), and the precipitate was filtered, washed with EtOAc and dried under vacuum to give 3 4 -Fluorine-2 6 -(trifluoromethyl)-1 1 ,1 2 ,1 1 ,2 2 ,2 3 ,2 4 -Hexahydro-2(3,1)-quinazoline-1(5,6)-pyridin-3(1,2)-benzene heterocycle-1 2 ,2 4-dione (416.7 mg, 36% yield) as a white solid. The clear organic phase was washed with brine, dried over Na2SO4, filtered and the solvent evaporated under reduced pressure. The solid was suspended in ether, triturated, filtered and the solid washed with ether to give additional 3 4 -Fluorine-2 6 -(trifluoromethyl)-1 1 ,1 2 ,1 1 ,2 2 ,2 3 ,2 4 -Hexahydro-2(3,1)-quinazoline-1(5,6)-pyridin-3(1,2)-benzene heterocycle-1 2 ,2 4 -dione (695.5 mg, 59% yield) as a white solid. HPLC / MS 1.08 min (A), [M+H] + 472.2. 1 H NMR(DMSO-d6,400MHz)δ11.4-11.9(m,1H),8.12(d,1H,J=2.0Hz),7.68(dd,1H, J=2.0,8.8Hz),7.3-7.5(m,2H),7.2-7.3(m,2H),6.41(d,1H,J=8.3Hz),6.23(br d,1H,J=9.3Hz),5.73(d,1H,J=10.8Hz),4.76(d,1H,J=11.2Hz),2.40(br s,2H),1.80(br d,1H,J=7.3Hz),1.6-1.7(m,1H),1.3-1.5(m,2H),1.1-1.3(m,3H).

[1222] Example 8

[1223] 3 4 -Fluorine-2 7 -(trifluoromethyl)-1 1 ,1 2 ,2 1 ,2 2 ,2 3 ,2 4 -Hexahydro-2(3,1)-quinazolin-1(5,6)-pyridine Hetero-3(1,2)-Benzene heterocyclic octahedral-1 2 ,2 4 -dione

[1224]

[1225] Step A: Ethyl 2-((2-(allyl-4-fluorophenyl)amino)-4-(trifluoromethyl)benzoate 8a

[1226]

[1227] Following the procedure outlined in Example 7, Step A, replacing Int-2 with Int-2a and Int-3a with Int-3b and heating the reaction mixture at 80° C. for 4 h, ethyl 2-((2-(allyl-4-fluorophenyl)amino)-4-(trifluoromethyl)benzoate 8a (3.87 g, 59% yield) was prepared as a light yellow oil. HPLC / MS 1.56 min (A), [M+H] + 368.1. 1 H NMR(CD3OD,400MHz)δ9.2-9.5(m,1H),8.13(d,1H,J=8.3Hz),7.3-7.3(m,1H),7.0-7.2(m,2H),6.94(d,1H,J=8 .3Hz), 6.81 (d, 1H, J = 1.0Hz), 5.8-6.0 (m, 1H), 4.9-5.1 (m, 2H), 4.4-4.5 (m, 2H), 3.36 (s, 1H), 1.4-1.5 (m, 3H).

[1228] Step B: 2-((2-allyl-4-fluorophenyl)amino)-4-(trifluoromethyl)benzoic acid 8b

[1229]

[1230] Following the procedure outlined in Example 7, Step B, 2-((2-allyl-4-fluorophenyl)amino)-4-(trifluoromethyl)benzoic acid 8b (1.79 g, 95% yield) was prepared as a light off-white solid. HPLC / MS 1.36 min (A), [M+H] + 340.0. 1 H NMR(DMSO-d6,400MHz)δ12.6-14.3(m,1H),9.62(br s,1H),8.07(d,1H,J=7.8Hz),7.5-7.5(m,0.03H),7.38(dd,1H,J=5.6,8.6Hz),7.1-7.3(m,2H),6.98( dd,1H,J=1.0,8.3Hz),6.80(d,1H,J=1.0Hz),5.8-6.0(m,1H),4.9-5.1(m,2H),3.31(d,2H,J=6.4Hz).

[1231] Step C: 2-((2-allyl-4-fluorophenyl)amino)-N-(2-but-en-1-yl)-6-methoxypyridine-3-yl 4-(Trifluoromethyl)benzamide 8c

[1232]

[1233] Following the procedure outlined in Example 7, Step C, replacing Int-1a with Int-1b, and stirring the reaction mixture at room temperature for 2 h, 2-((2-allyl-4-fluorophenyl)amino)-N-(2-but-en-1-yl)-6-methoxypyridin-3-yl)-4-(trifluoromethyl)benzamide 8c (1.11 g, 57% yield) was prepared as a viscous yellow oil. HPLC / MS 1.52 min (A), [M+H] + 500.0. 1 H NMR(DMSO-d6,400MHz)δ10.21(s,1H),9.29(s,1H),8.04(d,1H,J=8.3Hz),7.62(d,1H,J=8.3Hz),7.35(dd,1H,J=5.4,8.3Hz),7.1-7.2(m,3H),6.89 (d,1H,J=1.5Hz),6.72(d,1H,J=8.3Hz),5.8-6.0(m,2H),4.9-5.1(m,4H) ,3.87(s,3H),3.30(d,2H,J=6.4Hz),2.77(dd,2H,J=6.6,9.0Hz),2.51(br d,1H,J=2.0Hz),2.4-2.5(m,1H).

[1234] 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

[1235]

[1236] Following the procedure outlined in Example 7, Step D, the reaction mixture was stirred at 65° C. for 0.5 h, and 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 (245 mg, 46% yield) was prepared as a clear, viscous oil. HPLC / MS 1.55 min (A), [M+H] + 512.1. 1H NMR(DMSO-d6,400MHz)δ8.0-8.2(m,1H),7.6-7.7(m,1H),7.4-7.5(m,1H),7.2-7.3(m,3H),6.75(d,1H,J=8.3Hz),6.47(s,1H),6. 32(s,1H),6.3-6.5(m,1H),5.76(s,2H),5.6-5.7(m,1H),5.2-5.3(m,1H),4.8-5.2(m,6H),4.6-4.7(m,1H),3.87(s,3H),3.38(br d,2H,J=6.4Hz),2.75(br s,2H),2.3-2.5(m,2H).

[1237] Step F: 3 4 -Fluorine-1 6 -Methoxy-2 7 -(trifluoromethyl)-2 1 ,2 2 ,2 3 ,2 4 -Tetrahydro-2(3,1)-quinazoline-1 (3,2)-Pyridin-3(1,2)-benzene heterocyclic octa-6-ene-2 4 -Keto 8e

[1238]

[1239] Following the procedure outlined in Example 7, Step E, the reaction mixture was stirred at 80° C. for 17 h. 4 -Fluorine-1 6 -Methoxy-2 7 -(trifluoromethyl)-2 1 ,2 2 ,2 3 ,2 4 -Tetrahydro-2(3,1)-quinazoline-1(3,2)-pyridin-3(1,2)-benzene heterocycle octahydro-6-ene-2 4 -Ketone 8e (98 mg, 41% yield) was prepared as a white solid. HPLC / MS 1.42 min (A), [M+H] + 484.0. 1H NMR(DMSO-d6,400MHz)δ8.10(dd,1H,J=7.8,17.1Hz),7.6-7.7(m,1H),7.4-7.5(m,1H),7.2-7.4( m,2H),7.18(dd,1H,J=1.2,8.1Hz),6.6-6.8(m,1H),6.43(d,1H,J=1.0Hz),6.29(d,1H,J=1.5Hz) ,6.3-6.4(m,1H),5.91(d,1H,J=8.8Hz),5.6-5.9(m,1H),5.68(d,1H,J=10.3Hz),5.2-5.5(m,2H) ,4.3-4.6(m,1H),3.86(d,3H,J=6.4Hz),3.61(dd,1H,J=10.5,13.4Hz),3.1-3.3(m,1H),2.89(br s,1H),2.6-2.8(m,2H),1.8-2.3(m,1H).

[1240] Step G:3 4 -Fluorine-1 6 -Methoxy-2 7 -(trifluoromethyl)-2 1 ,2 2 ,2 3 ,2 4 -Tetrahydro-2(3,1)-quinazoline-1 (3,2)-Pyridinyl-3(1,2)-Benzene Heterocyclic Bafan-2 4 -Keto 8f

[1241]

[1242] Following the procedure outlined in Example 7, Step F, MeOH was replaced with EtOAc and the reaction mixture was stirred for 18 h, then additional 10% Pd—C (0.1 eq) was added to the reaction and stirred under H 2 atmosphere for an additional 30 h. 4 -Fluorine-1 6 -Methoxy-2 7 -(trifluoromethyl)-2 1 ,2 2 ,2 3 ,2 4 -Tetrahydro-2(3,1)-quinazoline-1(3,2)-pyridin-3(1,2)-benzene heterocycle octahydro-6-ene-2 4 -Ketone 8f (38 mg, 67% yield) was prepared as a white solid. HPLC / MS 1.48 min (B), [M+H] + 486.3. 1H NMR (CD3OD, 400MHz) δ8.1-8.3 (m, 1H), 7.72 (d, 1H, J = 8.3Hz), 7.34 (d, 1H, J = 5.4Hz), 7. 2-7.3(m,1H),7.2-7.2(m,1H),7.1-7.2(m,1H),6.81(d,1H,J=8.8Hz),6.52(s,1H),5. 79(d,1H,J=10.8Hz),4.82(d,2H,J=10.8Hz),3.96(s,3H),2.8-2.9(m,1H),2.6-2.8(m ,2H),2.4-2.5(m,1H),1.87(dt,2H,J=6.8,13.9Hz),1.5-1.7(m,2H),1.3-1.4(m,2H).

[1243] Step H: 3 4 -Fluorine-2 7 -(trifluoromethyl)-1 1 ,1 2 ,2 1 ,2 2 ,2 3 ,2 4 -Hexahydro-2(3,1)-quinazoline-1(5,6)- Pyridinyl-3(1,2)-benzene heterocyclic octahedral-1 2 ,2 4 -Diketone Example 8

[1244]

[1245] Following the procedure outlined in Example 7, Step G, the reaction mixture was stirred at 100° C. for 2 h. 4 -Fluorine-2 7 -(trifluoromethyl)-1 1 ,1 2 ,2 1 ,2 2 ,2 3 ,2 4 -Hexahydro-2(3,1)-quinazoline-1(5,6)-pyridin-3(1,2)-benzene heterocycle-1 2 ,2 4 -dione (37 mg, 66% yield) was prepared as a white solid. HPLC / MS 1.10 min (A), [M+H] + 472.2. 1 HNMR(DMSO-d6,400MHz)δ11.4-12.1(m,1H),8.10(d,1H,J=7.8Hz),7.4-7.5(m,2H),7.1-7.3(m,3H),6.40(s,1H),6.23(d,1H, J=9.3Hz),5.72(d,1H,J=10.8Hz),4.75(d,1H,J=10.8Hz),2.3-2.5(m,4H),1.6-1.9(m,2H),1.3-1.6(m,2H),1.1-1.3(m,2H).

[1246] Example 9

[1247] 3 4 -Fluorine-1 6 -Methoxy-2 7 -(trifluoromethyl)-2 1 ,2 2 ,2 3 ,2 4 -Tetrahydro-2(3,1)-pyrido[4,3-d]pyrimidineHetero-1(3,2)-pyridine-3(1,2)-benzene heterocyclic octahedral-2 4 -ketone

[1248]

[1249] Step A: Ethyl 4-((2-allyl-4-fluorophenyl)amino)-6-(trifluoromethyl)nicotinate 9a

[1250]

[1251] To a solution of 2-allyl-4-fluoroaniline (1.74g, 11.5mmol) in EtOH (60mL) was added 4-chloro-6-(trifluoromethyl) nicotinate (3.21g, 12.7mmol), followed by concentrated HCl (2.5mL, 11.5mmol). The reaction mixture was heated at 80°C for 5 days. The reaction mixture was cooled to ambient temperature, quenched with saturated NaHCO3 aqueous solution, and extracted with EtOAc (3x). The combined organic extracts were washed with salt water, dried over MgSO4, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (120g) with a gradient elution of 100% heptane to 20% EtOAc-heptane. The product fractions were combined and evaporated under reduced pressure to give ethyl 4-((2-allyl-4-fluorophenyl)amino)-6-(trifluoromethyl)nicotinate 9a (1.83 g, 30% yield) as a pale yellow oil with a purity of 70%. HPLC / MS 1.37 min (A), [M+H] + 369.1.

[1252] Step B: 4-((2-allyl-4-fluorophenyl)amino)-6-(trifluoromethyl)nicotinic acid 9b

[1253]

[1254] Following the procedure outlined in Example 7, Step B, using a THF / MeOH / H2O solvent system and heating the reaction mixture at 50°C for 2 h, 4-((2-allyl-4-fluorophenyl)amino)-6-(trifluoromethyl)nicotinic acid was added. 9b (875 mg, 67% yield) was prepared as a light off-white solid. HPLC / MS 1.15 min (A), [M+H] + 341.1. 1 H NMR(DMSO-d6,400MHz)δ13.9(br s,1H),9.92(s,1H),8.91(s,1H),7.43(dd,J=5.4,8.3Hz,1H),7.18-7.28(m,2H),6.71 (s,1H),5.87(tdd,J=6.5,10.1,16.9Hz,1H),4.89-5.04(m,1H),3.31(d,J=6.4Hz,2H).

[1255] Step C: 4-((2-allyl-4-fluorophenyl)amino)-N-(2-(but-3-en-1-yl)-6-methoxypyridine-3-yl)- methyl)-6-(trifluoromethyl)nicotinamide 9c

[1256]

[1257] Following the procedure outlined in Example 7, Step C, replacing Int-1a with Int-1b and DMF with MeCN, and stirring the reaction mixture at room temperature for 20 h, 4-((2-allyl-4-fluorophenyl)amino)-N-(2-(but-3-en-1-yl)-6-methoxypyridin-3-yl)-6-(trifluoromethyl)nicotinamide 9c (985 mg, 74% yield) was prepared as a yellow foam with 85% purity. HPLC / MS 1.41 min (A), [M+H] + 501.1.

[1258] 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

[1259]

[1260] Following the procedure outlined in Example 1, Step C, the reaction mixture was stirred at 80°C for 23 h, and 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 (287 mg, 33% yield) was prepared as a yellow oil. HPLC / MS 1.39 min (A), [M+H] + 513.2. 1 H NMR(CD3OD,400MHz)δ8.95(s,1H),7.57-7.64(m,1H),7.45-7.50(m,1H),7. 17-7.28(m,2H),6.68-6.72(m,1H),6.45-6.49(m,1H),5.82-6.00(m,2H),5 .67-5.73(m,1H),5.21-5.36(m,1H),4.97-5.03(m,2H),4.84-4.92(m,2H), 3.89-3.96(m,3H),3.43-3.50(m,2H),2.77-2.88(m,2H),2.52-2.57(m,2H).

[1261] Step E: 3 4 -Fluorine-1 6 -Methoxy-2 7 -(trifluoromethyl)-2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-2(3,1)-pyrido[4,3- d]pyrimidin-1(3,2)-pyridin-3(1,2)-benzene heterocycle octa-ene-5-ene-2 4 -Keto 9e

[1262]

[1263] Following the procedure outlined in Example 7, Step E, the reaction mixture was stirred at 80° C. for 1 h.4 -Fluorine-1 6 -Methoxy-2 7 -(trifluoromethyl)-2 1 ,2 2 ,2 3 ,2 4 -Tetrahydro-2(3,1)-pyrido[4,3-d]pyrimidin-1(3,2)-pyridin-3(1,2)-benzeneheterocyclooctahedral-5-ene-2 4 -Ketone 9e (99 mg, 66% yield) was prepared as a clear oil. HPLC / MS 1.22 / 1.25 min (A), [M+H] + 485.1.

[1264] Step F: 3 4 -Fluorine-1 6 -Methoxy-2 7 -(trifluoromethyl)-2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-2(3,1)-pyrido[4,3- d]pyrimidin-1(3,2)-pyridin-3(1,2)-benzene heterocyclic octahedral-2 4 -Keto 9f

[1265]

[1266] Following the procedure outlined in Example 7, Step F, MeOH was replaced with EtOH and the reaction mixture was stirred for 72 h. 4 -Fluorine-1 6 -Methoxy-2 7 -(trifluoromethyl)-2 1 ,2 2 ,2 3 ,2 4 -Tetrahydro-2(3,1)-pyrido[4,3-d]pyrimidin-1(3,2)-pyridin-3(1,2)-benzene heterocycle-2 4 -ketone 9f (73 mg, 85% yield) was prepared as a colorless oil. HPLC / MS 1.25 min (A), [M+H] + 487.1. 1 H NMR (CD3OD, 400MHz) δ9.02 (s, 1H), 7.60 (d, J = 8.3Hz, 1H), 7.38 (dd, J = 5.1, 8 .6Hz,1H),7.11-7.22(m,2H),6.69(d,J=8.3Hz,1H),6.57(s,1H),5.85(d,J= 10.8Hz,1H),4.84(s,1H),3.90(s,3H),2.79(td,J=7.1,14.2Hz,1H),2.51-2 .72(m,3H),1.80-1.89(m,2H),1.51-1.69(m,2H),1.35(quin,J=6.6Hz,2H).

[1267] Step G:3 4 -Fluorine-2 7 -(trifluoromethyl)-1 1 ,1 2 ,2 1 ,2 2 ,2 3 ,2 4 -Hexahydro-2(3,1)-pyrido[4,3-d]pyrimidine Pyridin-1(5,6)-pyridin-3(1,2)-benzene heterocyclic octahedron-1 2 ,2 4 -Diketone Example 9

[1268]

[1269] To 3 4 -Fluorine-1 6 -Methoxy-2 7 -(trifluoromethyl)-2 1 ,2 2 ,2 3 ,2 4 -Tetrahydro-2(3,1)-pyrido[4,3-d]pyrimidin-1(3,2)-pyridin-3(1,2)-benzene heterocycle-2 4 To a mixture of -ketone (73.0 mg, 0.150 mmol) and NaI (225 mg, 1.50 mmol) in MeCN (2.0 mL) was added TMS-Cl (0.190 mL, 1.50 mmol), and the reaction mixture was heated at 60 ° C for 2 h. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (80 mL), washed with saturated NaHCO3 aqueous solution, Na2S2O3 aqueous solution, brine, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (40 g) with a gradient elution of 100% heptane to 80% 3: 1 EtOAc-EtOH: heptane. The product fractions were combined and evaporated under reduced pressure to give 3 4 -Fluorine-2 7 -(trifluoromethyl)-1 1 ,1 2 ,2 1 ,2 2 ,2 3 ,2 4 -Hexahydro-2(3,1)-pyrido[4,3-d]pyrimidin-1(5,6)-pyridin-3(1,2)-benzene heterocycle-1 2 ,2 4 -dione (46.6 mg, 62.4% yield) as a white solid. HPLC / MS 0.94 min (A), [M+H] + 473.1. 1 H NMR(CD3OD,400MHz)δ9.03(s,1H),7.56(d,J=9.3Hz,1H),7.39(dd,J=5.4,8.8Hz,1H),7.24-7.14(m,2H),6.56(s,1H),6.44(d,J=9.3 Hz,1H),5.82(d,J=10.8Hz,1H),4.94(d,J=10.8Hz,1H),2.68-2.47(m,4H),1.98-1.81(m,2H),1.64-1.48(m,2H),1.40-1.33(m,2H).

[1270]

[1271] Example 10

[1272] 3 4 -Fluorine-2 6 -(trifluoromethyl)-1 1 ,1 2 ,2 1 ,2 2 ,2 3 ,2 4 -Hexahydro-2(3,1)-quinazolin-1(5,6)-pyridine Hetero-3(1,2)-Benzene Heterocyclic Nine-fan-1 2 ,2 4 -dione

[1273]

[1274] Step A: Methyl 2-((4-fluoro-2-(pent-4-en-1-yl)amino)-5-(trifluoromethyl)-benzoate 10a

[1275]

[1276] To a solution of 1-bromo-4-fluoro-2-(pent-4-en-1-yl)benzene Int-3d (9.00 g, 37.0 mmol) and 2-amino-5-(trifluoromethyl)-benzoic acid methyl ester (9.74 g, 44.4 mmol) in toluene (90 mL) was added CsCO (36.2 g, 111 mmol) and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (2.31 g, 3.70 mmol) under N2, the reaction mixture was purged with N2 for 10 min, Pd(dba) (1.70 g, 1.85 mmol) was added thereto, and the reaction mixture was stirred at 100°C for 12 h. The reaction mixture was cooled to ambient temperature, filtered through celite, washed with EtOAc (2 x 50 mL), the filtrate was washed with H2O (50 mL), brine, 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 flash column chromatography on silica gel (100 g) eluting with 4% EtOAc-petroleum ether. The product fractions were combined and evaporated under reduced pressure to afford methyl 2-((4-fluoro-2-(pent-4-en-1-yl)amino)-5-(trifluoromethyl)-benzoate 10a (1.8 g, 11% yield) as a yellow oil. HPLC / MS 1.63 min (C), [M+H] + 382.0.

[1277] Step B: 2-((4-Fluoro-2-(pent-4-en-1-yl)phenyl)amino)-5-(trifluoromethyl)benzoic acid 10b

[1278]

[1279] Following the procedure outlined in Example 7, Step B, the reaction mixture was stirred at room temperature for 12 h, and 2-((4-fluoro-2-(pent-4-en-1-yl)phenyl)amino)-5-(trifluoromethyl)benzoic acid 10b (1.1 g, 56% yield) was prepared as a green solid. HPLC / MS 1.50 min (C), [M+H] + 368.2. 1H NMR(DMSO-d6,400MHz)δ13.6(br s,1H),9.75(s,1H),8.12(s,1H),7.59-7.61(d,1H),7.33-7.35(m,1H),7.23-7.26(m,1H),7.11-7.16( m,1H),6.70-6.73(m,1H),5.68-5.75(m,1H),4.88-4.96(m,2H),1.97-2.02(m,2H),1.57-1.60(m,2H).

[1280] Step C: N-(2-Bromo-6-methoxypyridin-3-yl)-2-((4-fluoro-2-(pent-4-en-1-yl)phenyl)-amino 1-(trifluoromethyl)benzamide 10c

[1281]

[1282] Following the procedure outlined in Example 3, Step C, the reaction mixture was stirred at room temperature for 2 h, and N-(2-bromo-6-methoxypyridin-3-yl)-2-((4-fluoro-2-(pent-4-en-1-yl)phenyl)amino)-5-(trifluoromethyl)benzamide 10c (1.0 g, 55% yield) was prepared as a brown gum. HPLC / MS 4.20 min (D), [M+H] + 552.0. 1 H NMR(DMSO-d6,400MHz)δ10.4(s,1H),9.74(s,1H),8.27(s,1H),7.83-7.85(d,1H),7.59-7.62(d,1H),7.31-7.35(m,1H),7.20-7.23(m,2H),7.1 0-7.14(m,1H),6.95-6.98(m,1H),6.77-6.79(d,1H),5.67-5.76(m,1H) ,4.87-4.94(m,2H),3.89(s,3H),1.95-2.00(m,2H),1.54-1.58(m,2H).

[1283] Step D: 3-(2-bromo-6-methoxypyridin-3-yl)-1-(4-fluoro-2-(pent-4-en-1-yl)phenyl)-6-(trifluoromethyl)pyridin-3-yl)-1-(4-fluoro-2-(pent-4-en-1-yl)phenyl ...6-(trifluoromethyl)pyridin-3-yl)-1 (2,3-dihydroquinazolin-4(1H)-one)10d

[1284]

[1285] Following the procedure outlined in Example 1, Step C, the reaction mixture was stirred at 80°C for 10 h, and 3-(2-bromo-6-methoxypyridin-3-yl)-1-(4-fluoro-2-(pent-4-en-1-yl)phenyl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one 10d (0.45 g, 33% yield) was prepared as a brown gum. HPLC / MS 1.50 min (C), [M+H] + 563.8.

[1286] Step E: 3-(2-allyl-6-methoxypyridin-3-yl)-1-(4-fluoro-2-(pent-4-en-1-yl)phenyl)-6- (Trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one 10e

[1287]

[1288] Following the procedure outlined in Example 3, Step E, the reaction mixture was stirred at 150° C. for 1 h, and 3-(2-allyl-6-methoxypyridin-3-yl)-1-(4-fluoro-2-(pent-4-en-1-yl)phenyl)-6-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one 10e (0.32 g) was prepared as a colorless liquid. HPLC / MS 1.53 min (C), [M+H] + 525.8.

[1289] Step F: 3 4 -Fluorine-1 6 -Methoxy-2 6 -(trifluoromethyl)-2 1 ,2 2 ,2 3 ,2 4 -Tetrahydro-2(3,1)-quinazoline-1 (3,2)-Pyridinyl-3(1,2)-benzeneheterocyclic-7-ene-2-yl 4 -Keto 10f

[1290]

[1291] Following the procedure outlined in Example 7, Step E, the reaction mixture was stirred at 80° C. for 12 h. 4 -Fluorine-1 6 -Methoxy-2 6 -(trifluoromethyl)-2 1 ,2 2 ,2 3 ,2 4 -Tetrahydro-2(3,1)-quinazoline-1(3,2)-pyridin-3(1,2)-benzeneheterocyclic-7-ene-2 4 -ketone 10f (0.200 g, 46% yield) was prepared as a green gum. HPLC / MS 1.48 min (C), [M+H] + 498.4.

[1292] Step G:3...

Claims

1. Compounds of formula (Ia): or a tautomer thereof, or a pharmaceutically acceptable salt thereof, in: Y is O or S; X 1 Nitrogen or CR 1 , X 2 Nitrogen or CR 2 , X 3 Nitrogen or CR 3 ,and X 4 Nitrogen or CR 4 , The premise is X 1 , X 2 , X 3 and X 4 At most two of them are nitrogen; Ring A is: in represents a covalent bond to the nitrogen atom of the bicyclic core of formula (Ia), and represents a covalent bond with L of formula (Ia); R 1 , R 2 , R 3 and R 4 are independently hydrogen, halogen, cyano, -NR a R b , -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-; X 5 N or CR 5 ; R 5 and R 5a Each is independently hydrogen, halogen, or -(C1-C6)alkyl; R 6 , R 7 and R 8 Each is independently hydrogen, halogen, cyano, hydroxy, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-; R a and R b are each independently hydrogen, -(C1-C6)alkyl, or halo(C1-C6)alkyl-; R 15 and R 16 each independently is hydrogen or deuterium; and L is (C3-C6) alkenylene, -NHCH2CH2NHCH2-, -NHCH2CH2OCH2-, a divalent linking group of formula (L-ia), or a divalent linking group of formula (L-iia): in: X 8 and X 9 Each independently is -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; and represents a covalent bond to Ring A in Formula (Ia), and represents a covalent bond to the benzene ring in formula (Ia); in: X 6 For-NR c - or -CH2-; X 7 For-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 When it is -NH2-, X 6 is -CH2-; Each X 10 Independently for -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; and represents a covalent bond to Ring A in Formula (Ia), and represents a covalent bond to the benzene ring in formula (Ia).

2. The compound according to claim 1, which is a compound of formula (II): or a tautomer thereof, or a pharmaceutically acceptable salt thereof, in: Y is O or S; R 1 , R 2 , R 3 and R 4 are independently hydrogen, halogen, cyano, -NR a R b , -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-; R 5 is hydrogen, halogen, or -(C1-C6)alkyl; R 6 , R 7 and R 8 Each is independently hydrogen, halogen, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-; R a and R b are each independently hydrogen, -(C1-C6)alkyl, or halo(C1-C6)alkyl-; and L is a (C3-C6) alkenylene group, a divalent linking group of formula (Li), or a divalent linking group of formula (L-ii): in: 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; and represents a covalent bond to the pyridone ring of formula (II), and represents a covalent bond to the benzene ring of formula (II); in: X 6 For-NR c - or -CH2-; X 7 is -CH2-, -O- or -NH2-, provided that when X 7 When it is -NH2-, X 6 is -CH2-; R c is hydrogen or -(C1-C3)alkyl; q is 1, 2, 3, or 4; and represents a covalent bond to the pyridone ring of formula (II), and represents a covalent bond to the benzene ring of formula (II).

3. The compound according to claim 1, which is a compound of formula (III): or a tautomer thereof, or a pharmaceutically acceptable salt thereof, in: Y is O or S; R 1 , R 2 and R 4 are independently hydrogen, halogen, cyano, -NR a R b , -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-; R 5 is hydrogen, halogen, or -(C1-C6)alkyl; R 6 , R 7 and R 8 Each is independently hydrogen, halogen, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-; R a and R b are each independently hydrogen, -(C1-C6)alkyl, or halo(C1-C6)alkyl-; and L is a (C3-C6) alkenylene group, a divalent linking group of formula (Li), or a divalent linking group of formula (L-ii): in: 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; and represents a covalent bond to the pyridone ring of formula (III), and represents a covalent bond to the benzene ring of formula (III); in: X 6 For-NR c - or -CH2-; X 7 is -CH2-, -O- or -NH2-, provided that when X 7 When it is -NH2-, X 6 is -CH2-; R c is hydrogen or -(C1-C3)alkyl; q is 1, 2, 3, or 4; and represents a covalent bond to the pyridone ring of formula (III), and represents a covalent bond to the benzene ring of formula (III).

4. The compound according to claim 1, which is a compound of formula (IV): or a tautomer thereof, or a pharmaceutically acceptable salt thereof, in: Y is O or S; R 1 , R 3 and R 4 are independently hydrogen, halogen, cyano, -NR a R b 、- (C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-; R 5 is hydrogen, halogen, or -(C1-C6)alkyl; R 6 , R 7 and R 8 Each is independently hydrogen, halogen, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-; R a and R b are each independently hydrogen, -(C1-C6)alkyl, or halo(C1-C6)alkyl-; and L is a (C3-C6) alkenylene group, a divalent linking group of formula (Li), or a divalent linking group of formula (L-ii): in: 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; and represents a covalent bond to the pyridone ring of formula (IV), and represents a covalent bond to the benzene ring of formula (IV); in: X 6 For-NR c - or -CH2-; X 7 is -CH2-, -O- or -NH2-, provided that when X 7 When it is -NH2-, X 6 is -CH2-; R c is hydrogen or -(C1-C3)alkyl; q is 1, 2, 3, or 4; and represents a covalent bond to the pyridone ring of formula (IV), and represents a covalent bond to the benzene ring of formula (IV).

5. The compound according to claim 1, which is a compound of formula (V): or a tautomer thereof, or a pharmaceutically acceptable salt thereof, in: Y is O or S; R 2 , R 3 and R 4 are independently hydrogen, halogen, cyano, -NR a R b , -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-; R 5 is hydrogen, halogen, or -(C1-C6)alkyl; R 6 , R 7 and R 8 Each is independently hydrogen, halogen, -(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkyl-, or halo(C1-C6)alkoxy-; R a and R b are each independently hydrogen, -(C1-C6)alkyl, or halo(C1-C6)alkyl-; and L is a (C3-C6) alkenylene group, a divalent linking group of formula (Li), or a divalent linking group of formula (L-ii): in: 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; and represents a covalent bond to the pyridone ring of formula (V), and represents a covalent bond to the benzene ring of formula (V); in: X 6 For-NR c - or -CH2-; X 7 is -CH2-, -O- or -NH2-, provided that when X 7 is -NH2-, X 6 is -CH2-; R c is hydrogen or -(C1-C3)alkyl; q is 1, 2, 3, or 4; and represents a covalent bond to the pyridone ring of formula (V), and represents a covalent bond to the benzene ring of formula (V). 6 . The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is O.

7. A compound according to any one of claims 1 to 6, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is a (C3-C6) alkenylene group selected from the group consisting of: *-CH=CH-CH2-**, *-CH2-CH=CH-CH2-**, *-CH2CH2-CH=CH-CH2-**, and *-CH2-CH=CH-CH2CH2CH2-**, wherein "*" represents a covalent bond to ring A or the pyridone ring of formula (Ia)-(V), and "**" represents a covalent bond to the benzene ring of formula (Ia)-(V).

8. A compound according to any one of claims 1 to 6, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is a divalent linking group of formula (Li): in: 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; and represents a covalent bond to Ring A or the pyridone ring of Formula (Ia)-(V), and represents a covalent bond to the benzene ring of formula (Ia)-(V).

9. The compound according to claim 8, or its tautomer, or a pharmaceutically acceptable salt thereof, Wherein L is a divalent linking group of formula (Li) selected from: in represents a covalent bond to Ring A or a pyridone group of Formula (Ia)-(V), and represents a covalent bond to the benzene ring of formula (Ia)-(V).

10. A compound according to any one of claims 1 to 6, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is a divalent linking group of formula (L-ii): in: X 6 For-NR c - or -CH2-; X 7 is -CH2-, -O- or -NH2-, provided that when X 7 When it is -NH2-, X 6 is -CH2-; R c is hydrogen or -(C1-C3)alkyl; q is 1, 2, 3, or 4; and represents a covalent bond to Ring A or the pyridone ring of Formula (Ia)-(V), and represents a covalent bond to the benzene ring of formula (Ia)-(V).

11. The compound according to claim 10 or its tautomer or a pharmaceutically acceptable salt thereof, wherein X 6 For-NR c - and X 7 For CH2.

12. The compound according to claim 10, or its tautomer, or its pharmaceutically acceptable salt, wherein L is a divalent linking group of formula (L-ii) selected from: -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2- and -CH2CH2CH2CH2CH2CH2-, wherein represents a covalent bond to Ring A or the pyridone ring of Formula (Ia)-(V), and represents a covalent bond to the benzene ring of formula (Ia)-(V).

13. The compound according to any one of claims 10 to 12, or its tautomer, or its pharmaceutically acceptable salt, wherein L is a divalent linking group of formula (L-ii) selected from: in represents a covalent bond to Ring A or the pyridone ring of Formula (Ia)-(V), and represents a covalent bond to the benzene ring of formula (Ia)-(V).

14. The compound according to any one of claims 1 to 6, or its tautomer, or its pharmaceutically acceptable salt, wherein L is a divalent linking group selected from and in represents a covalent bond to Ring A or the pyridone ring of Formula (Ia)-(V), and represents a covalent bond to the benzene ring of formula (Ia)-(V).

15. A compound selected from: or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

16. A compound selected from: 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 its tautomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

18. A method for treating pain or a pain-related disease in a human in need thereof, the method comprising administering to the human 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.

19. A method of treating atrial fibrillation in a human in need thereof, said method comprising administering to said human 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.

20. 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 for use in therapy.

21. 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 for use in the treatment of pain or a pain-related disease.

22. 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 for use in the treatment of atrial fibrillation.

23. Use of the compound according to any one of claims 1 to 16 or its tautomer or its pharmaceutically acceptable salt or the pharmaceutical composition according to claim 17 in the preparation of a medicament for treating pain or pain-related diseases.

24. Use of the compound according to any one of claims 1 to 16 or its tautomer or its pharmaceutically acceptable salt or the pharmaceutical composition according to claim 17 in the preparation of a medicament for treating 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, post-ambulatory surgical pain, or osteoarthritis.

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