Novel N-heteroarylbenzamide derivatives as FLT3 inhibitors

Abstract

The present invention relates to a compound of formula (I) or an acceptable salt thereof (I) JPEG2025535882000141.jpg29170 [wherein W, X, Y and Z each independently represent =CH- or -N=, provided that a maximum of two of W, X, Y and Z both represent -N= groups; R1 represents a linear or cyclic nitrogen-containing (C4-C8) alkyl group, said group being a non-aromatic (C4-C8) alkyl group which may be linear or cyclic and contains 4 to 8 carbon atoms, with at least one nitrogen atom interrupting the alkyl chain, said group being optionally interrupted by one or two oxygen atoms and optionally substituted by a (C1-C4) alkyl group or a (C3-C6) cycloalkyl group; R2 is a hydrogen atom, a halogen atom, R3 represents a hydrogen atom, a halogen atom, a (C1-C4) alkyl group, a (C1-C4) alkoxy group, a (C1-C4) fluoroalkyl group, a -CO-(C1-C4) alkyl group, a -CONH2 group, a SO2-NH2 group, or a cyano group; R3 represents a hydrogen atom, a halogen atom, a (C1-C4) alkyl group, a (C1-C4) alkoxy group, a (C1-C4) fluoroalkyl group, a cyano group, a (C1-C4) alkylsulfonyl group, or a SO2-NH2 group; and R4, R5, and R6 independently represent a hydrogen atom, a halogen atom, a -COOH group, a -COO(C1-C4) alkyl group, a (C1-C4) fluoroalkyl group, a (C1-C4) alkylsulfonyl group, or a (C1-C4) alkoxy group. The present invention further relates to pharmaceutical compositions containing the same, and to their use in the prevention and / or treatment of pain.

Description

[Technical Field]

[0001] The present invention relates to the prevention and / or treatment of pain, and more particularly to novel N-heteroarylbenzamide derivatives as FLT3 inhibitors. [Background technology]

[0002] Current treatments for chronic pain (lasting >3 months), especially neuropathic pain, are essentially symptomatic and unsatisfactory for most patients. While numerous analgesics are available on the pharmaceutical market, most were initially launched for other indications, such as epilepsy and depression. However, these drugs are only partially effective against neuropathic pain. Unfortunately, only a limited number of patients achieve a 50% reduction in pain symptoms, and some neuropathic pain syndromes are completely resistant to these drugs, significantly impacting the quality of life of these patients. Furthermore, existing drugs often have a variety of adverse effects that limit their use in patients, including dizziness, somnolence, fatigue, constipation, dry mouth, nausea, vomiting, and weight gain.

[0003] Perioperative and postoperative pain, like other forms of pain, is undertreated. Postoperative pain is primarily treated with opioids, such as morphine, which remains the unrivaled treatment for acute pain management. However, their use for chronic pain is severely limited by undesirable side effects, such as constipation, nausea, vomiting, sedation, and respiratory depression, as well as the risk of abuse, addiction, and numerous opioid-related deaths. Most importantly, subchronic or chronic administration of opioids can lead to tolerance to their analgesic effects, thereby necessitating increased doses of the opioid, exacerbating the aforementioned side effects and a hypersensitivity to pain, termed opioid-induced hyperalgesia (OIH) and subclinical pain sensitization, which cannot be overcome by increased opioid doses, leaving patients with inadequately treated pain and significantly diminishing quality of life.

[0004] Therefore, there is a need to find new strategies for treating pain.

[0005] One novel strategy to combat pain is to inhibit FLT3 (Rivat et al., Nat. Commun., 2018, 9, 1042).

[0006] Indeed, WO2011 / 083124 discloses the use of FLT3 receptor antagonists for treating pain disorders. FLT3 (fms-related tyrosine kinase 3) is a member of the class III receptor tyrosine kinase (RTK) family and comprises an extracellular domain (ECD) that interacts with its ligand FL and an intracellular domain containing a kinase domain responsible for autophosphorylation. After activation, FLT3 dimerizes and autophosphorylates tyrosine residues present in its intracellular domain. FLT3 receptor antagonists according to WO2011 / 083124 include several types of molecules that inhibit FLT3 activation, such as small organic molecules that act at intracellular or extracellular FLT3 sites, antibodies against FLT3 or its ligand FL, or inhibitors of FLT3 expression. WO2011 / 083124 lists a wide variety of pain disorders, including acute pain, chronic pain, neuropathic pain, inflammatory pain, lower back pain, postoperative pain, cancer pain, vascular headaches such as migraine, fibromyalgia, hyperalgesia such as mechanical hyperalgesia and thermal hyperalgesia, allodynia such as thermal allodynia and mechanical allodynia, and pain sensitization mechanisms in peripheral nerves and central nerves.

[0007] Recently, several FLT3 receptor antagonists that inhibit the interaction between FLT3 and FL have been described in WO2016 / 016370. According to WO2016 / 016370, antagonists that inhibit the interaction between FLT3 and FL can be used to treat various pain disorders, including acute pain, chronic pain, neuropathic pain, inflammatory pain, iatrogenic pain including cancer pain, infectious pain including herpes pain, visceral pain, central pain, pain caused by functional disorders including fibromyalgia, nociceptive pain including postoperative pain, and mixed pain involving the viscera, gastrointestinal tract, cranial structures, musculoskeletal system, spine, genitourinary system, cardiovascular system, and CNS, including cancer pain, back pain, and facial pain.

[0008] More recently, WO2018 / 211018 describes the use of FLT3 antagonists in combination with opioids. Such combinations enhance opioid analgesia, reduce tolerance to opioid analgesia, and suppress opioid-induced hyperalgesia. Therefore, FLT3 antagonists can be used to improve analgesia in pain disorders requiring treatment with opioids, such as inflammatory pain and postoperative pain. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] WO2011 / 083124 [Patent Document 2] WO2016 / 016370 [Patent Document 3] WO2018 / 211018 [Non-patent literature]

[0010] [Non-Patent Document 1] SMBerge et al., J. Pharmaceutical Sciences, 1977, 66, 1-19 [Non-patent document 2] Miyaura et al. Tetrahedron Letters, 1979, Vol. 20, pp. 3437-3440 [Non-patent document 3] Guram et al., Angew. Chem. Int. Ed Engl. 1995, 34, 1348-1350 [Non-patent document 4] Maghar et al., J. Chem. Soc. Perkin Trans. 1975, vol. 1, pp. 461-463 [Non-patent document 5] Chan et al., J. Org. Chem., 2007, 72, 8863-8869 [Non-patent document 6] Klapars et al., J. Am. Chem. Soc. 2001, 123, 7727-7729 [Non-Patent Document 7] Schotten.Ber.Deutsch.Chem.Gesell., 1884, Vol. 17, p. 2544 [Non-patent document 8] Subiros-Funosas et al., Chem.Eur.J., 2009, vol. 15, pp. 9394-9403 [Non-Patent Document 9] Baumann.Ber.Deutsch.Chem.Gesell, 1886, Vol. 19, p. 3212 [Non-Patent Document 10] Yin.Org.Lett., 2000, Vol. 2, No. 8, pp. 1101-1104 [Non-Patent Document 11] Treede et al., Neurology, 2008, 70:1630-1635 [Non-Patent Document 12] Ullmann's Encyclopedia of Industrial Chemistry, 6th Edition (various editors, 1989-1998, Marcel Dekker) [Non-Patent Document 13] "Pharmaceutical Dosage Forms and Drug Delivery Systems" (ANSEL et al., 1994, WILLIAMS & WILKINS) [Non-Patent Document 14] Degorce et al., Current Chemical Genomics, 2009, 3, 22-32 [Non-Patent Document 15] Rivat et al. (Nature Communications, 2018, Vol. 9:1042) Summary of the Invention [Problem to be solved by the invention]

[0011] It has now been found that compounds defined below as formula (I) are useful in the prevention and / or treatment of painful conditions or disorders. [Means for solving the problem]

[0012] Accordingly, there is provided herein a compound of formula (I) as defined below, or any of its acceptable salts, a process for its preparation, or a pharmaceutical composition comprising a compound of formula (I) as defined below, alone or in combination with an opioid. The opioids include alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dextropropoxyphene, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl buturate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethideine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, and meptazinol. , metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normetadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretam, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, remifentanil, sufentonil, tapentadol, tilidine and tramadol, in particular fentanyl, morphine, remifentanil and tramadol, in particular fentanyl, morphine, remifentanil and tramadol.

[0013] Thus, the present invention relates to a compound of formula (I) as defined below, or any of its acceptable salts, alone or in combination with an opioid as defined above, for use in the prevention and / or treatment of pain.

[0014] In particular, the prevention and / or treatment of pain also extends to conditions associated therewith.

[0015] The present invention further relates to the use of any of the compounds of formula (I) as defined below or an acceptable salt thereof, alone or in combination with an opioid as defined above, for the manufacture of a medicament for the prevention and / or treatment of pain.

[0016] The present invention further relates to a method for the prevention and / or treatment of pain, which comprises administering to a patient in need thereof a compound of formula (I) as defined below or any of its acceptable salts, alone or in combination with an opioid as defined above, or a pharmaceutical composition comprising same.

[0017] definition As used herein, the term "patient" refers to an animal, for example an animal of importance for breeding, rearing or conservation purposes, or preferably a human or human child who is suffering from or may be suffering from one or more of the diseases and conditions described herein.

[0018] In particular, as used in this application, the term "patient" refers to a mammal, such as a rodent, cat, dog, primate, or human; preferably, the patient is a human.

[0019] Identifying patients in need of treatment for the diseases and conditions described herein is within the ability and knowledge of one of ordinary skill in the art, and a veterinarian or person skilled in the art can readily identify patients in need of such treatment through clinical testing, physical examination, medical / family history, or the use of biological and diagnostic tests.

[0020] In the context of the present invention, the term "treat" or "treatment" means to reverse, alleviate, hinder the progression of or prevent a pain condition as described herein, particularly in the section "Pain Conditions."

[0021] As used herein, "effective amount" refers to an amount of a compound of the present invention that is effective to prevent, reduce, eliminate, treat, or control pain. The term "control" is intended to refer to any process that can slow, interrupt, inhibit, or stop the progression of pain, but does not necessarily indicate that the pain episodes are completely eliminated.

[0022] As used herein, "prevent" also encompasses "reducing the likelihood of occurrence" or "reducing the likelihood of recurrence."

[0023] The term "prophylactically effective amount" refers to a concentration of a compound of the present invention effective to inhibit, prevent or reduce the likelihood of a painful condition.

[0024] Similarly, the term "therapeutically effective amount" refers to a concentration of a compound effective to treat the pain conditions described herein.

[0025] As used herein, the term "prevent" means reducing the risk of developing a given phenomenon, i.e., in the present invention, a pain condition described herein, or delaying the onset of a pain condition.

[0026] As used herein, the term "pharmaceutically acceptable" means compounds, materials, excipients, compositions or 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, allergic response or other problem complications at a reasonable benefit / risk ratio.

[0027] As used herein, the terms "FLT3" or "FLT3 receptor" (Fms-related tyrosine kinase 3) are also known as CD135, Ly72, Flk-2, Flt-3, or B230315G04, are used interchangeably, and have their common meaning in the art. The FLT3 receptor may be derived from any animal species, but is typically a mammalian (e.g., human or non-human primate) FLT3 receptor, particularly a human FLT3 receptor. The naturally occurring human FLT3 gene has a nucleotide sequence and is designated GenBank Accession No. NM_004119.2, and the naturally occurring human FLT3 protein has an amino acid sequence and is designated GenBank Accession No. NP_004110.2. The mouse nucleotide and amino acid sequences have also been described (GenBank Accession Nos. NM_010229.2 and NP_034359.2).

[0028] As used herein, the terms "FL" or "FLT3-ligand" are used interchangeably and have their common meaning in the art. They refer to cytokines that are natural ligands for the FLT3 receptor. FL can be from any source, but is typically mammalian (e.g., human and non-human primate) FL, particularly human FL.

[0029] The term "FLT3 inhibitor" refers to any compound that inhibits or downregulates biological activity associated with activation of the FLT3 receptor by FL in a subject, including any downstream biological effects resulting from the binding of FL to the FLT3 receptor. Such FLT3 inhibitors act by occupying the FL binding site or a portion thereof, or a cavity nearby (an allosteric site), thereby rendering the FLT3 receptor inaccessible to its natural ligand, FL, and inhibiting or reducing its normal biological activity. The term FLT3 receptor inhibitor also includes any drug that can interact with FL, the natural ligand of FLT3.

[0030] The compounds of formula (I) according to the present invention are FLT3 inhibitors, more particularly, inhibitors of the interaction between FLT3 and FL. The compounds that inhibit the interaction between FLT3 and FL include compounds that bind to either or both of the FLT3 receptor and FL, provided that the binding of the compound of interest interferes with the interaction between the FLT3 receptor and FL.

[0031] As used herein, the term "analgesic effect" refers to the clinical effect resulting from the use of a substance that produces analgesia. The term "analgesia" refers to the loss of sensitivity to pain without loss of consciousness.

[0032] The terms "between" and "ranging from" should be understood to include limitations unless otherwise specified. DETAILED DESCRIPTION OF THE INVENTION

[0033] In particular, the present inventors have found that compounds of formula (I) provide inhibitory activity against FLT3.

[0034] A compound of formula (I) or an acceptable salt thereof (I)

[0035] [ka]

[0036] [In the formula, W, X, Y, and Z each independently represent =CH- or -N=, provided that a maximum of two of W, X, Y, and Z both represent -N= groups; R1 represents a linear or cyclic nitrogen-containing (C4-C8) alkyl group, which is a non-aromatic (C4-C8) alkyl group, which may be linear or cyclic, containing 4 to 8 carbon atoms and which contains at least one nitrogen atom interrupting the alkyl chain, optionally interrupted by one or two oxygen atoms and optionally substituted by a (C1-C4) alkyl group or a (C3-C6) cycloalkyl group, and R1 contains at least one primary, secondary or tertiary amine, in particular one or two secondary or tertiary amines, R2 represents a hydrogen atom, a halogen atom, a (C1-C4) alkyl group, a (C1-C4) alkoxy group, a (C1-C4) fluoroalkyl group, a —CO—(C1-C4) alkyl group, a —CONH2 group, a SO2—NH2 group, or a cyano group; R3 represents a hydrogen atom, a halogen atom, a (C1-C4) alkyl group, a (C1-C4) alkoxy group, a (C1-C4) fluoroalkyl group, a cyano group, a (C1-C4) alkylsulfonyl group, or an SO2-NH2 group; R4, R5 and R6 independently represent a hydrogen atom, a halogen atom, a -COOH group, a -COO(C1-C4)alkyl group, a (C1-C4)fluoroalkyl group, a (C1-C4)alkylsulfonyl group or a (C1-C4)alkoxy group] are provided herein.

[0037] Further provided herein is a pharmaceutical composition comprising at least one novel compound as defined above or a pharmaceutically acceptable salt thereof, or at least one of the compounds (1) to (118) as defined above or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0038] A pharmaceutical composition comprising at least one of the novel compounds defined above or a pharmaceutically acceptable salt thereof, or at least one of the compounds (1) to (118) defined above or a pharmaceutically acceptable salt thereof, an opioid, and at least one pharmaceutically acceptable excipient, wherein the opioid is alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, bromophenone ... Tolphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dextropropoxyphene, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl buturate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin, hydrocodone, hydromorphone Phenol, hydroxypetideine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, mylophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomo Provided herein are pharmaceutical compositions which may be selected from rfan, phenazocine, phenoperidine, piminodine, piritramide, propeptadine, promedol, properidine, propiram, propoxyphene, remifentanil, sufentonil, tapentadol, tilidine and tramadol, in particular fentanyl, morphine, remifentanil and tramadol, in particular fentanyl, morphine, remifentanil and tramadol.

[0039] Provided herein are any of the compounds of formula (I) as defined above or pharmaceutically acceptable salts thereof, and any of the compounds (1) to (118) as defined below or any pharmaceutically acceptable salts thereof, alone or in combination with an opioid, particularly as defined above, for use as a pharmaceutical.

[0040] Further provided herein is any of the compounds of formula (I) as defined above or a pharmaceutically acceptable salt thereof, as well as any of the compounds (1) to (118) as defined below or any pharmaceutically acceptable salt thereof, alone or in combination with an opioid, particularly one defined above, for use in the prevention and / or treatment of pain.

[0041] The compounds of the present invention may exist in the form of a free base or an addition salt with a pharmaceutically acceptable acid.

[0042] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals, within the scope of sound medical judgment, without undue toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., in particular, describe pharmaceutically acceptable salts in J. Pharmaceutical Sciences, 1977, Vol. 66, pp. 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or formed using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include benzenesulfonate, ethanesulfonate, fumarate, methanesulfonate, p-toluenesulfonate, and the like.

[0043] Suitable physiologically acceptable acid addition salts of compounds of formula (I) include hydrobromide, tartrate, citrate, trifluoroacetate, ascorbate, hydrochloride, triflate, maleate, mesylate, formate, acetate and fumarate salts.

[0044] The compounds of formula (I) and / or salts thereof may form solvates or hydrates, and the present invention includes all such solvates and hydrates.

[0045] The terms "hydrate" and "solvate" simply mean that the compound (I) according to the invention can be in the form of a hydrate or solvate, i.e., combined or associated with one or more water or solvent molecules. This is merely a chemical characteristic of such compounds and can apply to all organic compounds of this type.

[0046] The compounds of formula (I) and any of the compounds (1) to (118) defined below may contain one or more asymmetric carbon atoms. They may therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers and mixtures thereof, including racemic mixtures, are included within the scope of the present invention.

[0047] The compounds of formula (I) and any of compounds (1) to (118) defined below may be in amorphous or crystalline form, which are also encompassed within the scope of the present invention.

[0048] In the context of the present invention, the following terms: "halogen" is understood to mean a chlorine, fluorine, bromine or iodine atom, and in particular denotes a chlorine, fluorine or bromine atom; - When used in this specification, "(C1 to C x ) alkyl" are the usual C1 to C x, secondary or tertiary saturated hydrocarbons, particularly (C1-C3) alkyl or (C1-C5) alkyl, including, but not limited to, methyl, ethyl, 1-propyl, 2-propyl, butyl, pentyl, etc. - As used herein, unless otherwise stated, "cycloalkyl group" refers to a saturated or partially unsaturated and unsubstituted or substituted monocyclic alkyl group containing 3 to 7 carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutenyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl groups, etc., in particular cyclopentyl, cyclohexyl, cycloheptyl, cycloheptenyl, or cyclohexenyl; As used herein, a fluoroalkyl group refers to an alkyl group as defined above, where the alkyl group is substituted with at least one fluorine atom. In other words, at least one hydrogen atom of the alkyl group is replaced with a fluorine atom. Examples include CH2F, CHF2, CH2CHF2, -CH2CH2F, etc. When all hydrogen atoms of the alkyl group are replaced with fluorine atoms, the fluoroalkyl group can be called a perfluoroalkyl group. Examples include a trifluoromethyl group or a trifluoroethyl group; - As used herein, "alkoxy group" refers to an -O-alkyl group, wherein alkyl group is as defined above. Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, linear, sec- or tert-butoxy, isobutoxy, pentoxy or hexoxy groups, etc.; As used herein, the term "(C1-C4) alkylsulfonyl group" refers to a -SO2-alkyl group, wherein the alkyl group is as defined above. Examples include, but are not limited to, -SO2CH3, -SO2CH2CH3, etc.; "Linear or cyclic nitrogen-containing (C4-C8) alkyl group" means a non-aromatic (C4-C8) alkyl group that may be linear or cyclic and contains 4 to 8 carbon atoms, and in particular contains at least one nitrogen atom, especially one or two nitrogen atoms, interrupting the alkyl chain. If cyclic, it may be a monocyclic group, a monocyclic group connected to the rest of the structure by a (C1-C3) alkylene group, a bicyclic group, a bridged bicyclic group, a spiro bicyclic group, or a fused bicyclic group. The group may be interrupted by one or two oxygen atoms and may optionally be substituted by a (C1-C4) alkyl group or a (C3-C6) cycloalkyl group. Examples that may be mentioned include (dimethylamino)ethoxy, 1-methylpiperidinyl, 1-methylpyrrolidinyl, piperazinyl, 4-methylpiperazinyl, 4-isopropylpiperazinyl, 4-cyclobutylpiperazinyl, 4-methyl-1,4-diazepane, 1-amino-4-methylpiperidine, 3-hydroxymethyl-1-methylpyrrolidine, octahydropyrrolo[3,4-c]pyrrolyl, diazaspiro[3.5]nonanyl, 2-methyl-2,5-diazabicyclo[2.2.1]heptane and 7-methyl-2,7-diazaspiro[3.5]nonane; As used herein, "protonatable amine" means an amine with an sp3 carbon atom bond that is likely to be protonated at pH 7.4, including a primary, secondary, or tertiary aliphatic amine, especially a secondary or tertiary aliphatic amine.

[0049] According to one embodiment, a compound of formula (I) or any of its acceptable salts (I)

[0050] [ka]

[0051] [In the formula, W, X, Y, and Z each independently represent =CH- or -N=, provided that a maximum of two of W, X, Y, and Z both represent -N= groups; R1 represents a linear or cyclic nitrogen-containing (C4-C8) alkyl group, which is a non-aromatic (C4-C8) alkyl group, which may be linear or cyclic, containing 4 to 8 carbon atoms and which contains at least one nitrogen atom interrupting the alkyl chain, optionally interrupted by one or two oxygen atoms and optionally substituted by a (C1-C4) alkyl group or a (C3-C6) cycloalkyl group, and R1 contains at least one primary, secondary or tertiary amine, in particular one or two secondary or tertiary amines, R2 represents a hydrogen atom, a halogen atom, a (C1-C4) alkyl group, a (C1-C4) alkoxy group, a (C1-C4) fluoroalkyl group, a —CO—(C1-C4) alkyl group, or a cyano group; R3 represents a hydrogen atom, a halogen atom, a (C1-C4) alkyl group, a (C1-C4) alkoxy group, a (C1-C4) fluoroalkyl group, or a (C1-C4) alkylsulfonyl group; R4, R5, and R6 independently represent a hydrogen atom, a halogen atom, a —COO(C1-C4)alkyl group, a (C1-C4)fluoroalkyl group, a (C1-C4)alkylsulfonyl group, or a (C1-C4)alkoxy group. is provided.

[0052] According to one embodiment, there is provided a compound of formula (I) as defined above or any of its pharmaceutically acceptable salts, wherein W is -N=, and X, Y and Z are =CH-, or Y is -N=, and W, X and Z are =CH-, or X is -N=, and W, Y and Z are =CH-, or Z is -N=, and W, X and Y are =CH-, or W and Z are -N=, and X and Y are =CH-, or X and Y are -N=, and W and Z are =CH-.

[0053] According to one embodiment, there is provided a compound of formula (I) as defined above or any of its pharmaceutically acceptable salts, wherein R1 is

[0054] [ka]

[0055] Selected from, in detail,

[0056] [ka]

[0057] and more particularly selected from:

[0058] [ka]

[0059] is selected from.

[0060] According to one embodiment, there is provided a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof, wherein R2 represents a hydrogen atom, a halogen atom, a (C1-C4) alkyl group, a (C1-C4) alkoxy group, a (C1-C4) fluoroalkyl group or a cyano group, in particular a hydrogen atom, a fluorine atom, a methyl group, a methoxy group, a trifluoromethyl group or a cyano group.

[0061] According to one embodiment, there is provided a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof, wherein R3 represents a hydrogen atom, a halogen atom, a (C1-C4) alkyl group, a (C1-C4) alkoxy group, a (C1-C4) fluoroalkyl group or a (C1-C4) alkylsulfonyl group, in particular a hydrogen atom, a fluorine atom or a chlorine atom, a methyl group, a methoxy group, a trifluoromethyl group or a methylsulfonyl group.

[0062] According to one embodiment, there is provided a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof, wherein R4, R5 and R6 independently represent a hydrogen atom, a halogen atom, a (C1-C4)fluoroalkyl group, a -COO(C1-C4)alkyl group, a (C1-C4)alkylsulfonyl group or a (C1-C4)alkoxy group, in particular a hydrogen atom, a fluorine atom or a chlorine atom, a trifluoromethyl group, a methyloxycarbonyl group or a methoxy group.

[0063] According to one embodiment, there is provided a compound of formula (I) as defined above, or any of its pharmaceutically acceptable salts, wherein R4 is a hydrogen atom.

[0064] According to one embodiment, there is provided a compound of formula (I) as defined above or any of its pharmaceutically acceptable salts, R2 represents a hydrogen atom, a halogen atom, a (C1-C4) alkyl group, a (C1-C4) alkoxy group, a (C1-C4) fluoroalkyl group, a -CO-(C1-C4) alkyl group, or a cyano group, specifically a hydrogen atom, a halogen atom, a (C1-C4) alkyl group, a (C1-C4) alkoxy group, a (C1-C4) fluoroalkyl group, or a cyano group, more specifically a hydrogen atom, a fluorine atom, a methyl group, a methoxy group, a cyano group, or a trifluoromethyl group; R3 represents a hydrogen atom, a halogen atom, a (C1-C4) alkyl group, a (C1-C4) alkoxy group, a (C1-C4) fluoroalkyl group, or a (C1-C4) alkylsulfonyl group, specifically a hydrogen atom, a halogen atom, a (C1-C4) alkyl group, a (C1-C4) alkoxy group, a (C1-C4) fluoroalkyl group, or a (C1-C4) alkylsulfonyl group, more specifically a hydrogen atom, a chlorine atom, a fluorine atom, a methyl group, a methoxy group, a trifluoromethyl group, or a methylsulfonyl group; R4, R5, and R6 independently represent a hydrogen atom, a halogen atom, a (C1-C4)fluoroalkyl group, a —COOH group, a —COO(C1-C4)alkyl group, a (C1-C4)alkylsulfonyl group, or a (C1-C4)alkoxy group, specifically a hydrogen atom, a halogen atom, a (C1-C4)fluoroalkyl group, or a (C1-C4)alkoxy group, and more specifically a hydrogen atom, a chlorine atom, a fluorine atom, a trifluoromethyl group, a methyloxycarbonyl group, or a methoxy group.

[0065] According to one embodiment, the linear or cyclic nitrogen-containing (C4-C8) alkyl group comprises one protonatable amine. According to another embodiment, the linear or cyclic nitrogen-containing (C4-C8) alkyl group comprises two protonatable amines. In one embodiment, the linear or cyclic nitrogen-containing (C4-C8) alkyl group comprises one protonatable amine and is cyclic. According to one embodiment, the linear or cyclic nitrogen-containing (C4-C8) alkyl group comprises one protonatable amine and is linear. According to one embodiment, the linear or cyclic nitrogen-containing (C4-C8) alkyl group is interrupted by one oxygen atom.

[0066] According to one embodiment, there is provided a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, wherein R6 represents a halogen atom, a —COO(C1-C4)alkyl group, a (C1-C4)fluoroalkyl group, a (C1-C4)alkylsulfonyl group, or a (C1-C4)alkoxy group.

[0067] According to a preferred embodiment of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof, in particular the hydrochloride salt, is the following compound: (1) N-(5-fluoroquinolin-8-yl)-4-(1-methylpiperidin-4-yl)benzamide, (2) N-(8-fluoroisoquinolin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide, (3) N-(5-fluoroisoquinolin-8-yl)-4-(1-methylpiperidin-4-yl)benzamide, (4) N-(8-fluoroquinolin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide, (5) N-(8-fluoroquinoxalin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide, (6) 4-(1-methylpiperidin-4-yl)-N-(quinolin-5-yl)benzamide, (7) N-(isoquinolin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide, (8) N-(isoquinolin-8-yl)-4-(1-methylpiperidin-4-yl)benzamide, (9) 4-(1-methylpiperidin-4-yl)-N-(quinolin-8-yl)benzamide, (10) 4-[2-(dimethylamino)ethoxy]-N-(isoquinolin-8-yl)benzamide, (11) 4-[2-(dimethylamino)ethoxy]-N-(quinolin-8-yl)benzamide, (12) 2-fluoro-4-(1-methylpiperidin-4-yl)-N-(quinolin-8-yl)benzamide, (13) 3-fluoro-N-(isoquinolin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide, (14) 4-(2-(dimethylamino)ethoxy)-N-(isoquinolin-5-yl)benzamide, (15) 4-(2-(dimethylamino)ethoxy)-N-(quinolin-5-yl)benzamide, (16) 2-methoxy-4-(1-methylpiperidin-4-yl)-N-(quinolin-8-yl)benzamide, (17) N-(isoquinolin-5-yl)-3-methoxy-4-(1-methylpiperidin-4-yl)benzamide, (18) 4-(1-methylpiperidin-4-yl)-N-(quinolin-8-yl)-2-(trifluoromethyl)benzamide, (19) 4-[2-(dimethylamino)ethoxy]-N-(phthalazin-5-yl)benzamide, (20) 4-(2-(dimethylamino)ethoxy)-N-(8-fluoroquinolin-5-yl)benzamide, (21) 3-cyano-N-(isoquinolin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide, (22) 4-(2-(dimethylamino)ethoxy)-N-(5-fluoroisoquinolin-8-yl)benzamide, (23) 4-(2-(dimethylamino)ethoxy)-N-(8-fluoroquinoxalin-5-yl)benzamide, (24) 3-fluoro-N-(isoquinolin-5-yl)-4-(4-methylpiperazin-1-yl)benzamide, (25) N-(isoquinolin-5-yl)-2-methanesulfonyl-4-(1-methylpiperidin-4-yl)benzamide, (26) 4-[2-(dimethylamino)ethoxy]-N-(5-fluoroquinolin-8-yl)benzamide, (27) 4-(1-methylpiperidin-4-yl)-N-(quinolin-5-yl)-3-(trifluoromethyl)benzamide, (28) 4-(1-methylpiperidin-4-yl)-N-(quinoxalin-5-yl)benzamide, (29) 3-methyl-4-(4-methylpiperazin-1-yl)-N-(quinolin-5-yl)benzamide, (30) N-(8-chloroquinolin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide, (31) 4-[2-(dimethylamino)ethoxy]-N-(quinoxalin-5-yl)benzamide, (32) N-(8-chloroquinolin-5-yl)-4-[2-(dimethylamino)ethoxy]benzamide, (33) 4-[2-(dimethylamino)ethoxy]-N-(8-fluoroisoquinolin-5-yl)benzamide, (34) 4-[2-(dimethylamino)ethoxy]-N-(7-methoxyisoquinolin-5-yl)benzamide, (35) 4-(4-methylpiperazin-1-yl)-N-(quinolin-8-yl)benzamide, (36) 3-cyano-4-(2-(dimethylamino)ethoxy)-N-(isoquinolin-8-yl)benzamide, (37) N-(8-fluoroquinoxalin-5-yl)-4-(4-methylpiperazin-1-yl)benzamide, (38) N-(isoquinolin-8-yl)-4-(4-methylpiperazin-1-yl)benzamide, (39) N-(isoquinolin-5-yl)-4-(4-methylpiperazin-1-yl)benzamide, (40) 4-(4-methylpiperazin-1-yl)-N-(quinolin-5-yl)benzamide, (41) 4-(4-methylpiperazin-1-yl)-N-(quinoxalin-5-yl)benzamide, (42) N-(5-fluoroquinolin-8-yl)-4-(4-methylpiperazin-1-yl)benzamide, (43) 4-(2-(dimethylamino)ethoxy)-3-methyl-N-(quinolin-8-yl)benzamide, (44) N-(8-fluoroquinolin-5-yl)-4-(4-methylpiperazin-1-yl)benzamide, (45) N-(isoquinolin-5-yl)-2-methyl-4-(4-methylpiperazin-1-yl)benzamide, (46) N-(8-chloroquinolin-5-yl)-4-(4-methylpiperazin-1-yl)benzamide, (47) 4-(2-(dimethylamino)ethoxy)-2-methyl-N-(quinolin-5-yl)benzamide, (48) 4-(2-(dimethylamino)ethoxy)-N-(isoquinolin-5-yl)-3-(trifluoromethyl)benzamide, (49) 4-(2-(dimethylamino)ethoxy)-N-(quinolin-5-yl)-2-(trifluoromethyl)benzamide, (50) 3-methoxy-4-(4-methylpiperazin-1-yl)-N-(quinolin-5-yl)benzamide, (51) N-(8-chloroisoquinolin-5-yl)-4-(4-methylpiperazin-1-yl)benzamide hydrochloride, (52) 4-(4-methylpiperazin-1-yl)-N-[5-(trifluoromethyl)isoquinolin-8-yl]benzamide hydrochloride, (53) 3-fluoro-N-(5-fluoroisoquinolin-8-yl)-4-{5-methyl-octahydropyrrolo[3,4-c]pyrrol-2-yl}benzamide, (54) N-(8-methoxyisoquinolin-5-yl)-3-methyl-4-{7-methyl-2,7-diazaspiro[3.5]nonan-2-yl}benzamide, and (55) 3-methyl-4-[(1-methylpyrrolidin-3-yl)methoxy]-N-(quinolin-8-yl)benzamide, (56) 2-fluoro-4-(4-methylpiperazin-1-yl)-N-(quinolin-5-yl)benzamide, (57) 2-fluoro-N-(isoquinolin-8-yl)-4-[4-(propan-2-yl)piperazin-1-yl]benzamide, (58) N-(5-fluoroisoquinolin-8-yl)-3-methoxy-4-[(1R,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]benzamide, - (59 4-(4-cyclobutylpiperazin-1-yl)-N-(quinolin-5-yl)benzamide, (60) N-(7-methoxyisoquinolin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide, (61) N-(5-chloroisoquinolin-8-yl)-4-(1-methylpiperidin-4-yl)benzamide hydrochloride, (62) N-(6-chloroisoquinolin-8-yl)-4-(1-methylpiperidin-4-yl)benzamide, (63) N-(6-methoxyisoquinolin-8-yl)-4-(1-methylpiperidin-4-yl)benzamide, (64) N-(8-chloroisoquinolin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide, (65) N-(8-methoxyisoquinolin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide, (66) 4-(1-methylpiperidin-4-yl)-N-[5-(trifluoromethyl)isoquinolin-8-yl]benzamide, (67) 4-(1-methylpiperidin-4-yl)-N-(quinazolin-8-yl)benzamide, (68) 4-(4-methylpiperazin-1-yl)-N-(quinazolin-8-yl)benzamide, (69) N-(5-fluoroisoquinolin-8-yl)-4-(4-methyl-1,4-diazepan-1-yl)benzamide hydrochloride, (70) N-(8-methoxyisoquinolin-5-yl)-4-(4-methylpiperazin-1-yl)benzamide hydrochloride, (71) N-(6-methoxyisoquinolin-8-yl)-4-(4-methylpiperazin-1-yl)benzamide, (72) 4-(1-methylpiperidin-4-yl)-N-(quinazolin-5-yl)benzamide, (73) N-(6-chloroisoquinolin-8-yl)-4-(4-methylpiperazin-1-yl)benzamide, (74) N-(8-chloroisoquinolin-5-yl)-3-methoxy-4-[(1-methylpiperidin-4-yl)amino]benzamide, (75) methyl 8-[4-(1-methylpiperidin-4-yl)benzamido]quinoline-5-carboxylate, (76) N-(5-fluoroisoquinolin-8-yl)-4-(4-methylpiperazin-1-yl)benzamide, (77) N-(5-chloroisoquinolin-8-yl)-4-(4-methylpiperazin-1-yl)benzamide, (78) 4-(1-methylpiperidin-4-yl)-N-(phthalazin-5-yl)benzamide, (79) N-(8-fluoroisoquinolin-5-yl)-4-(4-methylpiperazin-1-yl)benzamide, (80) 4-(4-methylpiperazin-1-yl)-N-(quinazolin-5-yl)benzamide, (81) 4-(4-methylpiperazin-1-yl)-N-(phthalazin-5-yl)benzamide, (82) N-(7-methoxyisoquinolin-5-yl)-4-(4-methylpiperazin-1-yl)benzamide hydrochloride, (83) 4-[2-(dimethylamino)ethoxy]-N-(quinazolin-5-yl)benzamide, (84) methyl 8-[4-(4-methylpiperazin-1-yl)benzamido]quinoline-5-carboxylate hydrochloride, (85) 4-[2-(dimethylamino)ethoxy]-N-(quinazolin-8-yl)benzamide, (86) N-(6-chloroisoquinolin-8-yl)-4-(2-(dimethylamino)ethoxy)benzamide, (87) 4-[2-(dimethylamino)ethoxy]-N-(6-methoxyisoquinolin-8-yl)benzamide, (88) N-(5-chloroisoquinolin-8-yl)-4-[2-(dimethylamino)ethoxy]benzamide, (89) 4-(2-(dimethylamino)ethoxy)-N-(7-methoxyisoquinolin-5-yl)benzamide hydrochloride, (90) 4-[2-(dimethylamino)ethoxy]-N-[5-(trifluoromethyl)isoquinolin-8-yl]benzamide hydrochloride, (91) Methyl 8-{4-[2-(dimethylamino)ethoxy]benzamido}quinoline-5-carboxylate hydrochloride, (92) N-(8-chloroisoquinolin-5-yl)-4-[2-(dimethylamino)ethoxy]benzamide hydrochloride (93) N-(isoquinolin-5-yl)-3-methyl-4-(1-methylpiperidin-4-yl)benzamide hydrochloride, (94) 2-methyl-4-(1-methylpiperidin-4-yl)-N-(quinolin-8-yl)benzamide hydrochloride, (95) 2-methyl-4-(4-methyl-1,4-diazepan-1-yl)-N-(quinolin-5-yl)benzamide, (96) 3-cyano-4-[(1-methylpyrrolidin-3-yl)methoxy]-N-(quinoxalin-5-yl)benzamide, (97) 4-(piperazin-1-yl)-N-(quinolin-8-yl)benzamide hydrochloride, (98) 4-[(1-methylpiperidin-4-yl)amino]-N-(quinolin-8-yl)-2-(trifluoromethyl)benzamide hydrochloride, (99) 4-(4-cyclobutylpiperazin-1-yl)-N-(isoquinolin-5-yl)-2-methoxybenzamide hydrochloride, (100) N-(isoquinolin-8-yl)-4-[4-(propan-2-yl)piperazin-1-yl]benzamide hydrochloride, (101) 2-fluoro-4-[(1R,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-(quinolin-8-yl)benzamide, (102) 4-[4-(propan-2-yl)piperazin-1-yl]-2-(trifluoromethyl)-N-[5-(trifluoromethyl)isoquinolin-8-yl]benzamide, (103) 4-[2-(dimethylamino)ethoxy]-3-fluoro-N-(quinolin-5-yl)benzamide, (104) N-(8-fluoroquinolin-5-yl)-2-methoxy-4-{7-methyl-2,7-diazaspiro[3.5]nonan-2-yl}benzamide hydrochloride (105) 3-fluoro-N-(8-methoxyisoquinolin-5-yl)-4-(4-methyl-1,4-diazepan-1-yl)benzamide, (106) 4-[2-(dimethylamino)ethoxy]-2-fluoro-N-(quinolin-8-yl)benzamide, (107) 4-[2-(dimethylamino)ethoxy]-2-methoxy-N-(quinolin-5-yl)benzamide, (108) N-(8-fluoroquinolin-5-yl)-2-methanesulfonyl-4-{5-methyl-octahydropyrrolo[3,4-c]pyrrol-2-yl}benzamide, (109) N-(8-chloroisoquinolin-5-yl)-4-(4-cyclobutylpiperazin-1-yl)-3-fluorobenzamide hydrochloride (110) 4-[2-(dimethylamino)ethoxy]-3-methoxy-N-(quinolin-8-yl)benzamide, (111) N-(isoquinolin-5-yl)-4-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)benzamide, (112) N-(8-chloroquinolin-5-yl)-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)benzamide, (113) 2-methanesulfonyl-4-(piperazin-1-yl)-N-(quinolin-5-yl)benzamide hydrochloride, (114) N-(isoquinolin-5-yl)-4-[(1-methylpiperidin-4-yl)amino]-3-(trifluoromethyl)benzamide, (115) 4-(4-methylpiperazin-1-yl)-2-(methylsulfonyl)-N-(quinolin-5-yl)benzamide, (116) 4-(4-methylpiperazin-1-yl)-N-(quinolin-8-yl)-3-(trifluoromethyl)benzamide, (117) N-(8-chloroisoquinolin-5-yl)-3-cyano-4-(4-cyclobutylpiperazin-1-yl)benzamide, and - (118) 3-cyano-4-(4-methylpiperazin-1-yl)-N-(quinolin-5-yl)benzamide The present invention is characterized in that the compound is selected from the group consisting of:

[0068] The compounds of the present invention can be prepared by conventional methods of organic synthesis practiced by those skilled in the art. The general reaction sequences outlined below represent general methods useful for preparing the compounds of the present invention and are not meant to limit their scope or usefulness.

[0069] As used herein, the following terms have the following definitions throughout the specification, unless otherwise stated.

[0070] Carboxyl activating agents: Carboxyl activating agents can be used as additives for coupling between carboxylic acids and amines. These agents are used to create activated ester leaving groups in situ, promoting or enabling the reaction. Examples include, but are not limited to, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDCI) and N,N'-diisopropylcarbodiimide (DIC) or dicyclohexylcarbodiimide (DCC).

[0071] Racemization suppressor agent: A racemization suppressor agent that can be used in addition to a carboxyl activator to suppress racemization that may occur during the coupling of a carboxylic acid with an amine. Examples include, but are not limited to, 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-aza-benzotriazole (HOAt), and ethyl cyanohydroxyiminoacetate (e.g., commercially available under the name Oxyma® from Merck Millipore).

[0072] Alkali metals: Examples include, but are not limited to, lithium (Li), sodium (Na), potassium (K), and cesium (Cs).

[0073] Chlorinating Agent: A chemical reagent that can be used to add chlorine atoms to other chemicals. Specifically, chlorination can be used to convert carboxylic acids or carboxylates to acyl chlorides. Examples include, but are not limited to, SOCl2, PCl3, PCl5, oxalyl chloride, and propionyl chloride.

[0074] The following reactions can be carried out to obtain compounds of formula (I) as set forth in Scheme 1 below.

[0075] [ka]

[0076] According to Scheme 1, when W, X, Y, Z, R1, R2, R3, R4, R5 and R6 are as defined above, M represents an alkali metal or hydrogen, and R1 represents a cyclic nitrogen connected to a central phenyl ring by a carbon atom, compound (IV) can be converted to compound (V) in step 1 by Suzuki-Miyaura coupling, in particular by treatment with a boronic acid or ester derivative in the presence of a palladium catalyst, such as palladium acetate (Pd(OAc)2), a phosphine ligand, such as 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos), and a base, such as K2CO3, in a solvent, such as a mixture of toluene and water, and heating to 80°C. The resulting compound can then be used in a hydrogenation reaction using palladium supported on coal Pd / C as a catalyst and a polar protic solvent such as MeOH or EtOH under an H atmosphere (Method B: modified from Miyaura et al., Tetrahedron Letters, 1979, 20, 3437-3440). When R1 represents a cyclic nitrogen atom linked to a central phenyl ring by a nitrogen atom, an alternative way of preparing compound (V) from compound (IV) can be achieved using the Buchwald-Hartwig reaction with an amine in the presence of a palladium catalyst, such as tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3), a phosphine ligand, such as (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (Xantphos), and a base, such as Cs2CO3 in a solution, such as dioxane, by heating the solvent to reflux (Method C: modified from Guram et al., Angew. Chem. Int. Ed. Engl. 1995, 34, 1348-1350).

[0077] Compound (VI) can be converted to compound (V) in step 2 by nucleophilic substitution using a chloride derivative and a base such as KCO in a solution such as DMF with heating to 80° C. (Method D). An alternative method for preparing compound (V) from compound (VI) can be achieved by Mitsunobu coupling with an alcohol derivative by stirring at 0° C. in the presence of triphenylphosphine (PPh) and diisopropyl azodicarboxylate (DIAD) in a solution such as THF (Method E: modified from Maghar et al., J. Chem. Soc. Perkin Trans. 1975, 1, 461-463).

[0078] In step 3, compound (V) can be converted to compound (VII) by saponification using a base such as LiOH, NaOH, KOH, RbOH, or CsOH in a solvent mixture such as MeOH and THF (Method F: modified from Chan et al., J. Org. Chem., 2007, 72, 8863-8869). Optionally, the resulting carboxylic acid derivative can be treated with an acid to give the corresponding carboxylic acid derivative.

[0079] In step 4, compound (III) can be converted to compound (II) by treating it with sodium azide (NaN), a copper catalyst such as iodide (CuI), and a base such as trans-N,N'-dimethylcyclohexane-1,2-diamine (TMDCA) in a solution such as DMSO by heating to 105°C (Method A: modified from Klapars et al., J. Am. Chem. Soc. 2001, 123, 7727-7729).

[0080] In step 5, compounds (II) and (VII) are reacted in a solution, for example, in DMF, with a carboxyl activating agent for peptide synthesis, such as N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDCI) or N,N'-diisopropylcarbodiimide (DIC), a racemization inhibitor, such as 1-hydroxybenzotriazole (HOBt) or ethyl cyanohydroxyiminoacetate (e.g., Merck Compound (I) can be converted to compound (I) by peptide coupling using a chlorinating agent, such as SOCl, PCl, or PCl, optionally with an organic base such as triethylamine (EtN) or N,N-diisopropylethylamine (DIPEA), optionally with heating to 33° C. (Method G. Schotten. Ber. Deutsch. Chem. Gesell., 1884, vol. 17, pp. 2544; Method I: modified from Subiros-Funosas et al., Chem. Eur. J., 2009, vol. 15, pp. 9394-9403). An alternative method for preparing compound (I) from compounds (VII) and (II) can be achieved by first treating (VII) with a chlorinating agent, such as SOCl, PCl, or PCl, optionally with an organic base such as triethylamine (EtN), in an aprotic solvent such as THF to form the corresponding acyl chloride derivative. The acyl chloride derivative can then be reacted with compound (II) in a solution such as DMF or THF in the presence of an organic base such as triethylamine (EtN) (Method H: modified from Baumann. Ber. Deutsch. Chem. Gesell. 1886, 19, 3212).

[0081] Finally, in step 6, compound (I) can be obtained by converting benzoyl chloride (VIII) to a carboxamide by first reacting it with ammonia, followed by coupling the amide with aryl bromide (IX) via a palladium-catalyzed Buchwald cross-coupling in the presence of [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (Xantphos Pd G3) (method modified from J. Yin. Org. Lett., 2000, Vol. 2, No. 8, pp. 1101-1104).

[0082] Accordingly, the present invention provides a synthetic process for preparing a compound of formula (I) as defined above or any one of its pharmaceutically acceptable salts, comprising at least the following steps: - Formula (II):

[0083] [ka]

[0084] wherein R, R, R, W, X, Y, and Z are as defined above. The compound Formula (VII):

[0085] [ka]

[0086] [wherein R1, R2, and R3 are as defined above, and M represents an alkali metal or hydrogen] and a compound of (i) by peptide synthesis using a carboxyl activating agent, specifically N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDCI) or N,N'-diisopropylcarbodiimide (DIC), together with a racemization inhibitor, specifically 1-hydroxybenzotriazole (HOBt) or ethyl cyanohydroxyiminoacetate, and together with an organic base in an aprotic polar solvent; or (ii) relates to a synthetic process comprising first separately treating a compound of formula (VII) in the presence of a chlorinating agent, particularly SOCl, optionally in the presence of an organic base in an aprotic solvent, to form the corresponding acyl chloride derivative, and then reacting said acyl chloride derivative by nucleophilic substitution with an organic base in an aprotic solvent to obtain a compound of formula (I).

[0087] According to another embodiment, the present invention provides a synthetic process for preparing a compound of formula (I) as defined above or any one of its pharmaceutically acceptable salts, comprising at least the following steps: - Formula (VIII)

[0088] [ka]

[0089] wherein R2 and R3 are as defined above. The compound Formula (IX)

[0090] [ka]

[0091] wherein R, R, R, W, X, Y, and Z are as defined above. via a first reaction with ammonia to convert the acyl chloride to a carboxamide, and a second reaction via a palladium-catalyzed Buchwald cross-coupling.

[0092] All reactions were carried out under normal atmosphere unless otherwise noted. Chemicals and solvents were purchased from multiple suppliers and used without further purification.

[0093] Analytical TLC was performed using silica gel plates Merck 60F254, and plates were visualized by exposure to UV light. Compounds were purified on silica gel VWR (particle size 0.040-0.063 nm) or using Buchi flash chromatography (normal phase column: Buchi silica 40 μm, irregular shape, 4 g or 12 g).

[0094] HPLC was performed on an Agilent 1260 Infinity II with the following parameters: flow rate 1.5 mL / min, column temperature: 40 °C (InfinityLab Poroshell 120 EC-C18, 4.6 × 100 mm, 2.7 microns), solvent system: A (0.05% TFA in water) and B (acetonitrile), t = 0 min to 1 min: A 95%, B 5%, then t = 1 min to t = 7 min: B 5% to 60%, t = 7 min to t = 8.5 min: B 60% to 100%, t = 8.5 min to t = 9 min: 100%, and finally t = 9 min to t = 9.5 min: 100% to 5%. 1 H, 19 F and 13 C NMR spectra were recorded on a Bruker Avance Spectrometer and run at 400, 500, 700, 376, and 101, 125, or 176 MHz, respectively. All chemical shift values ​​δ and coupling constants J are given in ppm and Hz, respectively, and indicate peak multiplicities (s = singlet, d = doublet, t = triplet, q = quartet, quin = quintet, sex = sexlet, m = multiplet, br = broad). All spectra were evaluated using MestreNova 14.1.1 (MestreLab Research SSL).

[0095] RP-HPLC-MS analysis was performed using an Agilent LC 1200 (Agilent Accurate Mass QToF 6520) quadrupole time-of-flight mass spectrometer (QTOF) equipped with a Zorbax Agilent C18 column (C18, 50 mm × 2.1 mm; 1.8 μm) using the following parameters: 1) Solvent system: A (acetonitrile + 0.5% formic acid) and B (HO + 0.05% formic acid). 2) Gradient: t = 0-8 min: 98% B to 0%; t = 8-12.5 min: 0% B; t = 12.5-12.6 min: 0-98% B, and t = 12.6-13 min: 98% B. 3) Flow rate: 0.5 mL / min. 4) Column temperature: 40 °C. 5) DAD scan from 190 nm to 700 nm. 6) Ionization mode: ESI+.

[0096] The chemical structures and spectroscopic data of some compounds of formula (I) of the present invention are illustrated in the following Tables I and II, respectively.

[0097] [Table 1A]

[0098] [Table 1B]

[0099] [Table 1C]

[0100] [Table 1D]

[0101] [Table 1E]

[0102] [Table 1F]

[0103]

Table 1G

[0104] Table 1H

[0105]

Table 1I

[0106]

Table 1J

[0107] Table 1K

[0108]

Table 1L

[0109]

Table 1M

[0110] Table 2-1

[0111] Table 2-2

[0112] Table 2-3

[0113] Table 2-4

[0114] Table 2-5

[0115] Table 2-6

[0116] Table 2-7

[0117] Table 2-8

[0118] Table 2-9

[0119] Table 2-10

[0120] Table 2-11

[0121] Table 2-12

[0122] Table 2-13

[0123] Table 2-14

[0124] Table 2-15

[0125] Table 2-16

[0126] Table 2-17

[0127] Table 2-18

[0128] Table 2-19

[0129] Table 2-20

[0130] Table 2-21

[0131] Table 2-22

[0132] Table 2-23

[0133] Table 2-24

[0134] Table 2-25

[0135] Table 2-26

[0136] Table 2-27

[0137] Table 2-28

[0138] Table 2-29

[0139] Table 2-30

[0140] Table 2-31

[0141] Table 2-32

[0142] Table 2-33

[0143] Table 2-34

[0144] Table 2-35

[0145] Table 2-36

[0146] Table 2-37

[0147] Table 2-38

[0148] Table 2-39

[0149] Table 2-40

[0150] Table 2-41

[0151] Table 2-42

[0152] Table 2-43

[0153] Table 2-44

[0154] [Table 2-45]

[0155] [Table 2-46]

[0156] Pain conditions or pain disorders All compounds disclosed in this application are specifically contemplated herein for the prevention and / or treatment of pain conditions or pain disorders.

[0157] Different pain disorders may proceed by distinct mechanisms.

[0158] Chronic pain means pain that lasts for more than three months, and acute pain means pain that lasts for less than three months.

[0159] Among the pain disorders that can be prevented and / or treated by the compounds of formula (I) according to the present invention, there can be mentioned a wide variety of pain disorders including the following: acute pain, chronic pain, neuropathic pain, inflammatory pain, low back pain, postoperative pain, cancer pain, vascular headaches such as migraine, fibromyalgia, hyperalgesia such as mechanical hyperalgesia and thermal hyperalgesia, allodynia such as thermal allodynia and mechanical allodynia, and pain sensitization mechanisms in the peripheral nerves and pain sensitization mechanisms in the central nerves.

[0160] Neuropathic pain refers to pain resulting from nerve injury or disease of the somatosensory system. It is a debilitating, chronic clinical condition, one of whose prominent symptoms is tactile hypersensitivity to pain. According to the definition by the International Association for the Study of Pain (Treede et al., Neurology, 2008, Vol. 70:1630-1635), the term "neuropathic pain" refers to a chronic or persistent pain disorder that occurs as a direct result of a lesion or disease affecting the somatosensory system, including the nociceptive system and its ascending and descending pathways. The term "lesion" is generally used when diagnostic studies (e.g., clinical investigations, imaging, neurophysiological testing, biopsy, laboratory tests) reveal abnormalities or when there is obvious trauma. The term "disease" is generally used when the underlying cause of the lesion (e.g., stroke, vasculitis, diabetes, genetic abnormality) is known. The condition includes hyperalgesia, ie, pain from stimuli that normally cause pain, and allodynia, ie, pain from stimuli that normally do not cause pain.

[0161] Neuropathic pain can be either peripheral or central, depending on the anatomical location of the lesion or disease. However, the distribution of pain or hyperalgesia is not necessarily the same as the innervation area of ​​the organ affected by the disease.

[0162] According to certain embodiments of the invention, the neuropathic pain, which may also be referred to as neuropathic pain syndrome, is selected from pain resulting from metabolic diseases, such as painful diabetic peripheral neuropathy, infectious diseases, such as post-herpetic neuralgia, trigeminal neuralgia, post-traumatic neuropathic pain, lumbosacral radiculopathy pain, post-operative neuropathic pain, iatrogenic neuropathic pain, such as cancer chemotherapy-induced neuropathic pain, and central neuropathic pain.

[0163] Neuropathic pain differs from inflammatory pain in that it results from a localized response following injury to tissues other than the sensory system, such as joints, ligaments, tendons, bones, muscles, blood vessels, or visceral structures.

[0164] Different types of pain may coexist, i.e., neuropathic pain may coexist with other types of pain, especially in chronic pain, for example, neuropathic pain may coexist with inflammatory pain or nociceptive pain, e.g., in low back pain or cancer pain.

[0165] According to certain embodiments of the present invention, the compounds of formula (I) according to the present invention or any of their pharmaceutically acceptable salts may be useful in the prevention and / or treatment of low back pain, osteoarthritic pain, cancer pain and sciatica.

[0166] Pharmaceutical Compositions and Uses Pharmaceutical compositions according to the present invention may contain one or more compounds of the present invention in any of the forms described herein.

[0167] The compounds can be administered by any mode of administration, such as by topical, intramuscular, intravenous, intranasal or oral routes of administration.

[0168] In one embodiment, the pharmaceutical composition according to the invention is selected from oral compositions; topical compositions; inhalation compositions; injectable compositions, in particular subcutaneous, intramuscular or intravenous compositions, and oral, injectable or surgical sustained release compositions.

[0169] The compositions of the present invention may further comprise one or more additives, such as excipients, additives, stabilizers, and preservatives. Such additives are well known to those skilled in the art and are described, inter alia, in "Ullmann's Encyclopedia of Industrial Chemistry, 6th Edition (Various editors, 1989-1998, Marcel Dekker) and "Pharmaceutical Dosage Forms and Drug Delivery Systems" (ANSEL et al., 1994, WILLIAMS & WILKINS).

[0170] The additives mentioned above are selected according to the dosage form and the desired mode of administration. The additives are selected from the usual additives known to those skilled in the art according to the pharmaceutical form and the desired mode of administration.

[0171] The compositions of the present invention can be administered orally, parenterally, transdermally, transmucosally, topically, rectally, by inhalation spray, nasally, intranasally via inhalation, bucally, sublingually, vaginally, or via an implanted reservoir. As used herein, the term "parenterally" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, topical, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, transdermally, or intravenously. Sterile injectable solutions of the compositions of the present invention may be aqueous or oily suspensions. These suspensions can be formulated using suitable dispersing or wetting agents and suspending agents according to techniques known in the art. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0172] In a particular embodiment, the compounds of formula (I) according to the present invention or any one of its pharmaceutically acceptable salts are administered orally.

[0173] Within the framework of the present invention, immediate-release, delayed-release, controlled-release or sustained-release galenic formulations may be selected, in particular sustained-release galenic formulations.

[0174] The treatment by administration of the compounds of formula (I) according to the present invention may be continuous. By "continuous treatment" is meant long-term treatment, which may be carried out at various administration frequencies, including preferably twice a day, more preferably once a day.

[0175] The compounds of formula (I) according to the invention can alternatively be administered repeatedly over the course of several sequences or cycles according to a protocol that depends on the nature and intensity of the pain to be treated and the patient to be treated (age, weight, previous treatments, etc.), which can be determined by any physician specializing in pain.

[0176] In a more particular embodiment, the compound of formula (I) according to the present invention is administered before the onset of predictable pain. For example, it is well known that moderately or highly invasive surgical procedures, such as cardiac surgery, joint replacement, tumor removal, digestive tract partial ablation, transplantation, or amputation, cause pain of various intensities for a period of several hours to several days or longer after the procedure. Under such conditions and according to certain embodiments, the compound of formula (I) according to the present invention can be administered before the subject undergoing the surgical procedure regains consciousness, or if the surgical procedure is performed while the subject is anesthetized, and more generally before the initiation of opioid therapy during postoperative care.

[0177] For example, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be present in any pharmaceutical form suitable for enteral or parenteral administration, in association with suitable excipients, such as in the form of plain or coated tablets, hard gelatin capsules, soft shell capsules and other capsules, suppositories, or suspensions, drinkable syrups, or injectable solutions or suspensions, allowing a daily administration of 0.1 to 1000 mg of active substance, in particular in dosages ranging from 0.1 to 10 mg, for example from 10 to 200 mg, for example from 200 to 1000 mg.

[0178] There may be special cases in which higher or lower doses are appropriate. According to usual practice, the dose appropriate for each patient is determined by the physician according to the mode of administration and the weight and response of said patient.

[0179] In a further embodiment, the compounds of formula (I) are used as single agents or in combination with other drugs such as opioids, for example, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dextropropoxyphene, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl buturate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin, hydrocodone, hydromorphone, hydroxypetideine, isomethadone, ketobemidone, levallorphan, levorphanol, levophen ... It may be selected from the group consisting of nasylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretam, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propeptadine, promedol, properidine, propiram, propoxyphene, remifentanil, sufentonil, tapentadol, tilidine and tramadol, and in particular may be selected from fentanyl, morphine, remifentanil and tramadol.

[0180] Thus, there is further provided herein a pharmaceutical composition comprising at least one compound of formula (I) or a pharmaceutically acceptable salt thereof, an opioid, and at least one pharmaceutically acceptable excipient, wherein the opioid is as defined above.

[0181] In a further embodiment, any one of the compounds of formula (I) or a pharmaceutically acceptable salt thereof is used as a medicine, either alone or in combination with an opioid as defined above.

[0182] In a further embodiment, any one of the compounds of formula (I) or a pharmaceutically acceptable salt thereof, alone or in combination with an opioid as defined above, is used for the prevention and / or treatment of pain.

[0183] The examples set forth herein are intended to be illustrative only; those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific compounds, materials, and procedures. All such equivalents are considered to be within the scope of this invention and encompassed by the appended claims. [Example]

[0184] In the example, the following terms have the following meanings: - TMDCA: trans-N,N'-dimethylcyclohexane-1,2-diamine - DMSO: Dimethyl sulfoxide - TLC: Thin Layer Chromatography - RuPhos: 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl - Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0) - XantPhos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene - DCM: dichloromethane - rt: room temperature - O / N: All night - DIAD: Diisopropyl azodicarboxylate - eq.: equivalent - EtOAc: ethyl acetate - EtO2: Diethyl ether - HPLC: High-Performance Liquid Chromatography - DMF: Dimethylformamide - THF: Tetrahydrofuran - EDCI: N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide - HOBt: 1-hydroxybenzotriazole - Oxyma®: ethyl cyanohydroxyiminoacetate - DIC: N,N'-diisopropylcarbodiimide - DIPEA: N,N-diisopropylethylamine - MeOH: Methanol - EtOH: Ethanol -h:hour - pH: Hydrogen ion concentration - Net33 or Et3N: Triethylamine - Xphos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0185] General Procedure Method A. Amination of Aryl Bromides (Scheme 2)

[0186] [ka]

[0187] A 10 mL microwave-safe vial was charged with aryl bromide (1 eq.), sodium azide (2 eq.), copper iodide (1 eq.), and TMDCA (1.3 eq.). The vial was flushed with argon, and then dry DMSO was added while flushing with argon. The reaction mixture was then appropriately capped and placed in a preheated oil bath at 105 °C for 2–3 h until complete conversion of the starting material was achieved (TLC using a 1:1 mixture of heptane and EtOAc as the eluent). The mixture was quenched with EtOAc and water, filtered through a pad of Celite®, and the product was extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and the solvent was evaporated under reduced pressure. The crude product was then purified by flash column chromatography.

[0188] Method B. Suzuki-Miyaura Coupling (Scheme 3)

[0189] [ka]

[0190] Suzuki-Miyaura coupling In a microwave-safe vial under argon, commercially available bromobenzoic acid (1 eq.), boronic ester or boronic acid (1.1 eq.), K2CO3 (3 eq.) in toluene, and water were added. The mixture was degassed, and palladium diacetate (0.02 eq.) and commercially available RuPhos (0.04 eq.) were added. The reaction mixture was capped and heated to 80 °C overnight. The flask was allowed to cool to room temperature, then diluted with EtOAc and filtered through a pad of Celite®. The solvent was evaporated, and the crude product was purified by flash column chromatography.

[0191] Hydrogenation To a solution of methyl 4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)benzoate derivative (1 eq.) in previously degassed EtOH or MeOH was added Pd / C (0.46 eq.). The mixture was degassed again, and the flask was then placed under an H atmosphere overnight. The reaction was monitored by HPLC or TLC (10% MeOH / DCM). The mixture was filtered through Celite®, and the solvent was evaporated. The crude product was purified by flash column chromatography.

[0192] Method C. Buchwald-Hartwig Coupling (Scheme 4)

[0193] [ka]

[0194] The methyl bromobenzoate derivative (1 eq.), Pd2(dba)3 (3 mol%), and Xantphos (8 mol%) were dissolved in dry 1,4-dioxane (0.53 mmol / mL), and the solution was degassed with argon for 10 min. Amine (1.2 eq.) was added to the mixture, followed by Cs2CO3 (1.4 eq.), and the reaction mixture was stirred at 120 °C overnight. The reaction mixture was allowed to cool to room temperature, then diluted with EtOAc, filtered through a Celite® pad, and washed with EtOAc. The solvent was removed under reduced pressure, and the product was purified by flash chromatography.

[0195] Method D. Nucleophilic Substitution (Scheme 5)

[0196] [ka]

[0197] To a stirred solution of commercially available 2-dimethylaminoethyl chloride hydrochloride (1 eq.) in dry DMF under an argon atmosphere, K2CO3 (4 eq.) was added. After stirring at room temperature for 10 min, the 4-hydroxybenzoic acid derivative (1 eq.) was added in one portion. The vial was stirred at 80 °C for 48 h. The reaction was quenched with saturated NaHCO3 solution and extracted with Et2O or EtOAc. The organic phase was washed with saturated NaCl solution and then dried over Na2SO4. The crude product was purified by flash column chromatography.

[0198] Method E. Mitsunobu Coupling (Scheme 6)

[0199] [ka]

[0200] To the stirred solution, the alcohol derivative (1 eq.), triphenylphosphine (1.1 eq.), and 4-hydroxybenzoic acid derivative (1.1 eq.) were dissolved in dry THF under argon, and the solution was cooled to 0 °C. DIAD (1 eq.) was added slowly over 5 min. The mixture was stirred at 0 °C for 2 h and then warmed to room temperature overnight. The solvent was evaporated, and the resulting yellow oil was dissolved in 50 mL of EtOAc and extracted three times with HCl 4N. The aqueous phase was then cooled to 0 °C and basified with solid NaOH to a pH of at least 10. The basic phase was extracted three times with DCM, dried over MgSO4, and filtered. The crude product was purified by flash column chromatography.

[0201] Method F. Hydrolysis of Benzoic Acid Methyl Ester (Scheme 7)

[0202] [ka]

[0203] To a solution of the benzoate derivative (1 eq.) in MeOH (14.94 eq.) and THF (29.55 eq.) was added a solution of lithium hydroxide monohydrate (1.05 eq.) in HO (33.60 eq.). The reaction was stirred overnight at room temperature. If the reaction was not complete, additional aqueous LiOH solution could be added and the reaction mixture stirred at room temperature for several days. The reaction was evaporated under reduced pressure, dissolved in EtOAc, and evaporated again.

[0204] Method G. Synthesis of Benzamide Derivatives (Scheme 8)

[0205] [ka]

[0206] To a solution of benzoic acid or its lithium salt (1 eq.) and arylamine (1.1 eq.) in dry DMF (31.28 eq.) was added HOBt (1.2 eq.), EDCI (1.2 eq.), and NEt (2 eq.) successively at 0 °C under an argon atmosphere. The reaction was then stirred at 33 °C overnight. The reaction was monitored by HPLC. If the reaction was not complete, EDCI could be added and the reaction mixture could be stirred at 40-50 °C for several days. The mixture was quenched with saturated aqueous NaHCO and then extracted with EtOAc. The combined organic phases were washed with saturated NaCl, dried over anhydrous NaSO, and evaporated under reduced pressure. The crude residue was purified by flash column chromatography.

[0207] Method H. Synthesis of Benzamide Derivatives (Scheme 9)

[0208] [ka]

[0209] Preparation of benzoyl chloride After preparing the lithium benzoate salt (see general procedure F), SOCl (30 eq.) was slowly added to a stirred solution of the lithium salt (1 eq.) in dry DCM (3.4 mL), and the reaction mixture was heated at 40 °C for 1 h. The excess thionyl chloride was then evaporated under reduced pressure. The crude residue was used directly in the next step without further purification.

[0210] Amide bond formation The benzoyl chloride derivative (1 eq.) was dissolved in anhydrous THF (0.35 mmol / mL), and the resulting solution was cooled to 0 °C. The amine derivative (1.1 eq.) and NEt (1.2 eq.) were added, and the resulting mixture was stirred at room temperature overnight. Saturated aqueous NaHCO and EtOAc were added, and the phases were separated. The aqueous phase was further extracted three times with EtOAc. The combined organic phases were then washed with brine, dried over MgSO, filtered, evaporated under reduced pressure, and purified by flash chromatography.

[0211] Method I. Synthesis of benzamide derivatives (Scheme 10)

[0212] [ka]

[0213] The lithium salt (1.1 eq.), Oxyma® (1.1 eq.), and DIC (1.1 eq.) were mixed in dry DMF (0.18 mmol / mL) at 0°C. The reaction mixture was stirred at 0°C for 5 minutes to preactivate the carboxylic acid salt or its acid to form the active ester. DIPEA (1.1 eq.) was then added, followed by the amine derivative (1 eq.). The reaction mixture was then stirred at 0°C for 20 minutes and then at room temperature overnight. [If the reaction is not complete, additional DIC can be added and the reaction mixture can be stirred at 40°C for several days.] Saturated aqueous NaHCO3 and EtOAc were added, and the phases were separated. The aqueous phase was extracted three times with EtOAc. The combined organic phase was then washed with brine, dried over MgSO4, filtered, evaporated under reduced pressure, and purified by flash chromatography.

[0214] General Method J: Synthesis of Benzamide Derivatives (Scheme 11)

[0215] [ka]

[0216] Preparation of amides Benzoyl chloride was added in small portions to 28% ammonia (105 eq.) at 0°C. 1 mL of 28% ammonia was added after 5 min, and the reaction mixture was stirred at room temperature (19-20°C) for 1 h. The mixture was filtered through a sintered glass funnel, and the white solid was washed three times with 2 mL of water and three times with ether. The white solid was placed in a round-bottom flask, and the sintered glass funnel was rinsed with methanol, followed by concentration under reduced pressure.

[0217] Coupling Reaction A microwave-safe flask was charged with benzamide (1 eq.), bromoquinoline (1 eq.), K2CO3 (1.5 eq.), and tert-butanol (44 eq.). The mixture was heated to 60 °C and degassed with argon. PdG3 Xantphos (0.035 eq.) was added, and the flask was properly sealed. The solution was stirred at reflux (approximately 85 °C) overnight. The mixture was quenched with a stirred solution of NaHCO3, and the product was extracted three times with EtOAc. The solvent was concentrated under reduced pressure, and the crude product was purified by flash column chromatography.

[0218] Example 1 Preparation of N-(5-fluoroisoquinolin-8-yl)-4-(1-methylpiperidin-4-yl)benzamide (3) 5-Fluoroisoquinolin-8-amine

[0219] [ka]

[0220] General procedure A was applied to 8-bromo-5-fluoroisoquinoline (1.079 g, 4.77 mmol). The crude residue was purified by flash chromatography on silica gel (heptane / EtOAc 70 / 30, 50 / 50, 25 / 75 successively) to give 5-fluoroisoquinolin-8-amine (490 mg, 3.02 mmol, 63%) as a brown / green solid with an HPLC purity of 98%. NMR 1 H (400 MHz, MeOD): δ 9.39 (s, 1H), 8.40 (d, J = 6.0 Hz, 1H), 7.80 (bd, J = 6.0 Hz, 1H), 7.24 (dd, J = 10.1, 8.4 Hz, 1H), 6.79 (dd, J = 8.4, 4.1Hz, 1H). NMR 13 C (101 MHz, MeOD): δ = 150.72 (d, J = 240.0 Hz, C q), 148.39 (d, J = 2.5 Hz, CH Ar ), 143.74 (d, J = 3.0 Hz, C q ), 142.76 (d, J = 1.8 Hz, CH Ar ), 127.68 (d, J = 18.5 Hz, C q ), 119.81 (d, J = 3.9 Hz, C q ), 116.97 (d, J = 20.2 Hz, CH Ar ), 114.70 (d, J = 3.7 Hz, CH Ar ), 110.53 (d, J = 6.5 Hz, CH Ar ). NMR 19 F (376 MHz, MeOD, decoupled): δ = -141.11

[0221] N-(5-fluoroisoquinolin-8-yl)-4-(1-methylpiperidin-4-yl)benzamide (3) General procedure I was applied to commercially available 4-(1-methylpiperidin-4-yl)benzoic acid (1 eq., 93 mg, 0.424 mmol). The crude residue was purified by flash column chromatography on silica gel (using DCM / MeOH 98 / 2, then 85 / 15) to give N-(5-fluoroisoquinolin-8-yl)-4-(1-methylpiperidin-4-yl)benzamide (3) (49.5 mg, 0.136 mmol, 32%) as a pale pink / purple solid.

[0222] Example 2 Preparation of N-(8-fluoroquinoxalin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide (5) 5-Bromo-8-fluoroquinoxaline

[0223] [ka]

[0224] To a solution of 3-bromo-6-fluorobenzene-1,2-diamine (1 eq., 202 mg, 0.985 mmol) in EtOH (6 mL) under an argon atmosphere, glyoxal (4.5 eq., 257 mg, 0.214 mL, 4.43 mmol) and NEt3 (1.5 eq., 149 mg, 0.205 mL, 1.48 mmol) were added. The reaction mixture was stirred overnight at room temperature. EtOH was evaporated under reduced pressure, then water and EtOAc were added, and the phases were separated. The aqueous phase was further extracted three times with EtOAc. The combined organic phases were then washed with brine, dried over MgSO4, filtered, and evaporated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (heptane / EtOAc 100 / 0, 95 / 5, 90 / 10 successively) to afford 5-bromo-8-fluoroquinoxaline (198 mg, 0.872 mmol, 89%) as a pale yellow solid.

[0225] 8-Fluoroquinoxaline-5-amine

[0226] [ka]

[0227] General procedure A was applied to 5-bromo-8-fluoroquinoxaline (716 mg, 3.15 mmol). The crude residue was purified by flash chromatography on silica gel (heptane / EtOAc 9:1, then 7:3) to give 8-fluoroquinoxalin-5-amine (302 mg, 1.85 mmol, 59%) as a yellow / orange solid. NMR 1 H (400 MHz, MeOD): δ 8.81 (d, J = 1.9 Hz, 1H), 8.79 (d, J = 1.9 Hz, 1H), 7.34 (dd, J = 10.4, 8.5 Hz, 1H), 6.91 (dd, J = 8.6, 4.4 Hz, 1H). NMR 13 C (101 MHz, MeOD): δ = 149.59 (d, J = 245.8 Hz, Cq ), 146.01 (d, J = 2.5 Hz, CH Ar ), 143.96 (CH Ar ), 143.27 (d, J = 3.4 Hz, C q ), 134.22 (d, J = 13.4 Hz, C q ), 134.20 (C q ), 116.34 (d, J = 18.9 Hz, CH Ar ), 109.60 (d, J = 6.6 Hz, CH Ar ). NMR 19 F (376 MHz, MeOD, decoupled): δ = -144.36.

[0228] N-(8-fluoroquinoxalin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide (5) General procedure G was applied to commercially available 4-(1-methylpiperidin-4-yl)benzoic acid (55.6 mg, 0.254 mmol) and 8-fluoroquinoxalin-5-amine (41.4 mg, 0.254 mmol). The crude residue was purified by flash column chromatography on silica gel (using DCM / MeOH 98 / 2, 85 / 15, successively) and then triturated with DCM / EtOAc / Et2O to give N-(8-fluoroquinoxalin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide (5) (8 mg, 0.022 mmol, 9%) as a pale yellow solid with an HPLC purity of >99%.

[0229] Example 3 Preparation of 2-fluoro-4-(1-methylpiperidin-4-yl)-N-(quinolin-8-yl)benzamide (12) Methyl 2-fluoro-4-(1-methylpiperidin-4-yl)benzoate

[0230] [ka]

[0231] General procedure B was applied to methyl 4-bromo-2-fluorobenzoate (1 eq., 500 mg, 2.15 mmol) and 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (1.1 eq., 526.6 mg, 2.36 mmol). The crude product was purified by flash column chromatography using 0-100% EtOAc in heptane followed by 0-10% methanol in DCM as eluents to afford methyl 3-fluoro-4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)benzoate (280.8 mg, 1.13 mmol, 53%) as a pale orange solid. The resulting compound (1 eq., 280.8 mg, 1.13 mmol) was hydrogenated without further purification to give methyl 3-fluoro-4-(1-methylpiperidin-4-yl)benzoate (275.5 mg, 1.096 mmol, 97%) as a yellow oil. NMR 1 H (400 MHz, MeOD): δ 7.80 (dd, J = 8.0, 1.7 Hz, 1H), 7.65 (dd, J = 11.0, 1.7 Hz, 1H), 7.44 (t, J = 7.7 Hz, 1H), 3.90 (s, 3H), 3.03 (ddt, J = 11.4, 3.7, 1.9 Hz, 2H), 3.00 - 2.88 (m, 1H), 2.35 (s, 3H), 2.27 - 2.15 (m, 2H), 1.90 - 1.79 (m, 4H). NMR 13 C (126 MHz, MeOD ): δ 167.30 (d, J = 2.7 Hz, CO), 161.75 (d, J = 245.2 Hz, CF), 139.20 (d, J = 14.5 Hz, C q ), 131.36 (d, J = 8.0 Hz, C q ), 129.23 (d, J = 4.7 Hz, CH Ar ), 126.64 (d, J = 3.3 Hz, CH Ar ), 117.13 (d, J = 25.3 Hz, CH Ar), 56.84 (2CH2), 52.79 (CH3), 46.31 (CH3), 36.22 (d, J = 1.9 Hz, CH), 32.32 (2CH2). NMR 19 F (376 MHz, MeOD): δ -120.24.

[0232] 2-Fluoro-4-(1-methylpiperidin-4-yl)-N-(quinolin-8-yl)benzamide (12) General procedure F was applied to methyl 2-fluoro-4-(1-methylpiperidin-4-yl)benzoate (1 eq., 275.5 mg, 1.096 mmol) to quantitatively produce lithio 3-fluoro-4-(1-methylpiperidin-4-yl)benzoate (316 mg), obtained as a light beige powder. According to general procedure G, the lithium salt (1 eq., 76.68 mg, 0.32 mmol) was used for amide bond coupling with 8-quinolinamine (1.1 eq., 50 mg, 0.35 mmol), and the reaction mixture was stirred at 30 °C overnight. Three equivalents of EDCI were added, and the reaction mixture was stirred at 35 °C for 3 days. The crude product was purified by flash column chromatography using MeOH in DCM as the eluent (0-15%). 2-Fluoro-4-(1-methylpiperidin-4-yl)-N-(quinolin-8-yl)benzamide (12) was obtained as a beige powder (61.9 mg, 0.17 mmol, 54%) with an HPLC purity of 99%.

[0233] Example 4 4-(2-(dimethylamino)ethoxy)-N-(quinolin-5-yl)benzamide (15) General procedure F was applied to methyl 4-[2-(dimethylamino)ethoxy]benzoate (1.3 g, 5.82 mmol) to quantitatively produce lithio 4-[2-(dimethylamino)ethoxy]benzoate (1.25 g) as a beige solid. According to general procedure G, 1 equivalent of the lithium salt (71.3 mg, 0.332 mmol) was used for amide bond coupling with 5-quinolinamine (1 eq., 47.8 mg, 0.332 mmol). The reaction mixture was stirred at 30 °C for 2 days, followed by the addition of 1.5 equivalents of EDCI. After stirring at 40 °C for 5 days, the crude product was purified by flash column chromatography using MeOH in DCM (98 / 2, 85 / 15, successively) as the eluent. 4-[2-(dimethylamino)ethoxy]-N-(quinolin-5-yl)benzamide (15) (65 mg, 0.194 mmol, 58%) was obtained as a pale yellow solid with an HPLC purity of 93%.

[0234] Example 5 Preparation of 4-(1-methylpiperidin-4-yl)-N-(quinolin-8-yl)-2-(trifluoromethyl)benzamide (18) Methyl 4-(1-methylpiperidin-4-yl)-2-(trifluoromethyl)benzoate

[0235] [ka]

[0236] General procedure B was applied to methyl 4-bromo-2-(trifluoromethyl)benzoate (1 eq., 400 mg, 1.41 mmol) and 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (1.1 eq., 346.85 mg, 1.55 mmol). The crude product was purified by flash column chromatography using 50-100% EtOAc in heptane followed by 0-10% MeOH in DCM as eluents to give methyl 4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(trifluoromethyl)benzoate as an orange oil (404 mg, 1.35 mmol, 96%). After hydrogenation of the resulting compound, methyl 4-(1-methylpiperidin-4-yl)-2-(trifluoromethyl)benzoate was obtained as a yellow oil (390 mg, 1.29 mmol, 97%) and was used in the next step without further purification. NMR 1 H (400 MHz, MeOD): δ 7.66 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 1.7 Hz, 1H), 7.50 (dd, J = 8.0, 1.8 Hz, 1H), 2.95 - 2.87 (m, 2H), 2.61 (tt, J = 12.0, 4.0 Hz, 1H), 2.24 (s, 3H), 2.08 (td, J = 12.0, 2.8 Hz, 2H), 1.82 - 1.75 (m, 2H), 1.69 (dtd, J = 13.3, 12.0, 3.7 Hz, 2H). NMR 13 C (101 MHz, MeOD): δ 168.58 (CO), 151.60 (C q ), 131.76 (CH Ar ), 131.59 (C q ), 130.30 (CH Ar ), 129.93 - 129.61 (d, J = 31.90 Hz, C -CF3), 126.35 (d, J = 5.4 Hz, CH Ar), 126.27 - 120.846 (q, J = 273.40 Hz, CF3), 56.77 (2CH2), 53.19 (CH3), 46.36 (CH3), 42.65 (CH), 33.62 (2CH2). NMR 19 F (376 MHz, MeOD): δ -60.90.

[0237] 4-(1-methylpiperidin-4-yl)-N-(quinolin-8-yl)-2-(trifluoromethyl)benzamide (18) General procedure G was applied to methyl 4-(1-methylpiperidin-4-yl)-2-(trifluoromethyl)benzoate (1 eq., 390 mg, 1.29 mmol) to produce lithio 4-(1-methylpiperidin-4-yl)-2-(trifluoromethyl)benzoate (450 mg, 1.53 mmol, quantitative yield), obtained as a light beige powder. The previously synthesized lithium salt was used in an amide bond coupling with 8-aminoquinoline (1.1 eq., 60 mg, 0.42 mmol), and the reaction mixture was stirred at 30 °C overnight. Three equivalents of EDCI were added, and the reaction mixture was stirred at 35 °C for 3 days. The crude product was purified by flash column chromatography using MeOH in DCM (0–15%) as the eluent. 4-(1-methylpiperidin-4-yl)-N-(quinolin-8-yl)-2-(trifluoromethyl)benzamide (18) was obtained as an orange powder (76 mg, 0.18 mmol, 49%) with an HPLC purity of 97%.

[0238] Example 6 Preparation of 3-cyano-N-(isoquinolin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide (21) Methyl 3-cyano-4-(1-methylpiperidin-4-yl)benzoate

[0239] [ka]

[0240] General procedure B was applied to methyl 4-bromo-3-cyanobenzoate (1 eq., 300 mg, 1.25 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (1.063 eq., 296.37 mg, 1.33 mmol). The crude product was purified by flash column chromatography using EtOAc in heptane (50-100%) followed by methanol in DCM (0-10%) as eluents to quantitatively yield methyl 3-cyano-4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)benzoate (384.37 mg) as a pale orange oil. After hydrogenation of the resulting compound, the crude product was purified by flash column chromatography using MeOH in DCM (0-10%) as the eluent to yield methyl 3-cyano-4-(1-methylpiperidin-4-yl)benzoate (177.2 mg, 0.69 mmol, 55%) obtained as a yellow solid. NMR 1 H (400 MHz, MeOD): δ 8.28 (dd, J = 1.9, 0.5 Hz, 1H), 8.23 ​​(dd, J = 8.3, 1.9 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 3.93 (s, 3H), 3.09 - 2.99 (m, 3H, CH2+CH), 2.35 (s, 3H), 2.21 (td, J = 11.7, 3.2 Hz, 2H), 1.94 - 1.79 (m, 4H, 2CH2) NMR 13 C (101 MHz, MeOD): δ 166.48 (CO), 155.27 (C q ), 135.07 (CH Ar ), 135.04 (CH Ar ), 130.59 (C q ), 128.32 (CH Ar ), 117.92 (CN), 113.72 (C q), 56.71 (2CH2), 53.02 (CH3), 46.34 (CH3), 41.72 (CH), 32.98 (2CH2).

[0241] 3-Cyano-N-(isoquinolin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide (21) General procedure F was applied to methyl 3-cyano-4-(1-methylpiperidin-4-yl)benzoate (1 eq., 177.2 mg, 0.69 mmol) to quantitatively produce lithio 3-cyano-4-(1-methylpiperidin-4-yl)benzoate (190.3 mg) as a pale yellow powder. One equivalent of the lithium salt (58.2 mg, 0.233 mmol) previously synthesized according to general procedure I was used together with 5-isoquinolinamine (1 eq., 33.5 mg, 0.233 mmol) according to general procedure G. The crude residue was purified by flash column chromatography on silica gel (using DCM / MeOH 98 / 2, then 85 / 15) to give 3-cyano-N-(isoquinolin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide (21) (24 mg, 0.0648 mmol, 28%) as a pale orange solid with an HPLC purity of 97%.

[0242] Example 7 Preparation of N-(isoquinolin-5-yl)-2-methanesulfonyl-4-(1-methylpiperidin-4-yl)benzamide (25) Methyl 2-methanesulfonyl-4-(1-methylpiperidin-4-yl)benzoate

[0243] [ka]

[0244] General procedure B was applied to methyl 4-bromo-2-(methylsulfonyl)benzoate (1 eq., 400 mg, 1.36 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (1.1 eq., 334.91 mg, 1.501 mmol). The crude product was purified by flash column chromatography using 50-100% EtOAc in heptane followed by 0-10% MeOH in DCM as eluents to afford methylsulfonyl-4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)benzoate (410.5 mg, 1.33 mmol, 97%) as a pale orange oil. After hydrogenation of the resulting compound (1 eq., 330 mg, 1.067 mmol), the crude product was purified by flash column chromatography using MeOH in DCM (0-20%) as the eluent to yield methyl 2-methanesulfonyl-4-(1-methylpiperidin-4-yl)benzoate, obtained as a yellow oil (124.9 mg, 0.401 mmol, 37%). NMR 1 H (400 MHz, MeOD): δ 7.97 (d, J = 1.5 Hz, 1H), 7.74 - 7.61 (m, 2H), 3.92 (s, 3H), 3.09 - 2.92 (m, 2H), 2.72 (ddt, J = 11.9, 7.8, 4.0 Hz, 1H), 2.33 (s, 3H), 2.18 (td, J = 11.8, 2.6 Hz, 2H), 1.98 - 1.85 (m, 2H), 1.85 - 1.63 (m, 2H). NMR 13 C (126 MHz, MeOD): δ 168.95 (CO), 151.43, 140.46, 133.24, 132.27, 131.17, 129.31, 56.62, 53.52, 46.25, 45.01, 42.41, 33.46.

[0245] N-(isoquinolin-5-yl)-2-methanesulfonyl-4-(1-methylpiperidin-4-yl)benzamide (25) General procedure F was applied to methyl 2-methanesulfonyl-4-(1-methylpiperidin-4-yl)benzoate (1 eq., 124 mg, 0.4 mmol) to quantitatively produce lithio 2-methanesulfonyl-4-(1-methylpiperidin-4-yl)benzoate (130 mg) as a beige powder. Following general procedure G, the lithium salt (1 eq., 50 mg, 0.16 mmol) was used for amide bond coupling with 5-aminoisoquinoline (1.1 eq., 26.14 mg, 0.18 mmol). The reaction mixture was stirred overnight at 35 °C for 48 h, after which another 1 eq. of EDCI (89.8 mg) was added. The reaction was continued stirring at 35 °C for 48 h. The crude product was purified by flash column chromatography using MeOH in DCM as the eluent (0–25%). N-(isoquinolin-5-yl)-2-methanesulfonyl-4-(1-methylpiperidin-4-yl)benzamide (25) was obtained as a pale yellow powder (26.6 mg, 0.063 mmol, 38%) with an HPLC purity of 98%.

[0246] Example 8 Preparation of 4-(1-methylpiperidin-4-yl)-N-(quinolin-5-yl)-3-(trifluoromethyl)benzamide (27) Methyl 4-(1-methylpiperidin-4-yl)-3-(trifluoromethyl)benzoate

[0247] [ka]

[0248] General procedure B was applied to methyl 4-bromo-3-(trifluoromethyl)benzoate (1 eq., 400 mg, 1.41 mmol) and 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (1.1 eq., 346.85 mg, 1.55 mmol). The crude product was purified by flash column chromatography using 50-100% EtOAc in heptane followed by 0-10% methanol in DCM as eluents to afford methyl 4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-3-(trifluoromethyl)benzoate (330 mg, 1.103 mmol, 78%) as a green oil. After hydrogenation of the resulting compound (1 eq., 330 mg, 1.103 mmol), the crude product was purified by flash column chromatography using MeOH (0-10%) in DCM as eluent to give methyl 4-(1-methylpiperidin-4-yl)-3-(trifluoromethyl)benzoate (87.1 mg, 0.29 mmol, 26%) as a yellow oil. NMR 1 H (400 MHz, MeOD): δ 8.25 (d, J = 1.8 Hz, 1H), 8.21 (dd, J = 8.2, 1.9 Hz, 1H), 7.72 (d, J = 8.2 Hz, 1H), 3.93 (s, 3H), 3.09 - 3.01 (m, 2H), 2.98 (m, 1H), 2.36 (s, 3H), 2.17 (td, J = 12.0, 2.7 Hz, 2H), 1.90 (qd, J = 12.4, 3.8 Hz, 2H), 1.83 - 1.74 (m, 2H). NMR 13 C (126 MHz, MeOD): δ 167.00 (C=O), 151.41, 134.21, 130.08, 129.87, 129.78 - 128.71 (m, J = 30.26 Hz, C q-CF3), 127.85 (q, J = 6.1 Hz), 125.62 (d, J = 273.3 Hz, CF3), 56.87 (2CH2), 52.93 (CH3), 46.34 (CH3), 39.25 (d, J = 2.2 Hz, CH), 33.89 (2CH2). NMR 19 F (376 MHz, MeOD): δ -60.63.

[0249] 4-(1-methylpiperidin-4-yl)-N-(quinolin-5-yl)-3-(trifluoromethyl)benzamide (27) General procedure F was applied to methyl 4-(1-methylpiperidin-4-yl)-3-(trifluoromethyl)benzoate (1 eq., 87 mg, 0.29 mmol) to quantitatively produce lithio 4-(1-methylpiperidin-4-yl)-3-(trifluoromethyl)benzoate (96.8 mg) as a beige powder. According to general procedure G, lithium salt (1 eq., 40 mg, 0.14 mmol) was used in amide bond coupling with 5-quinolinamine (1.1 eq., 21.64 mg, 0.15 mmol), and the reaction mixture was stirred overnight at 30 °C. 34.5 mg and 37.5 mg of EDCI were added successively every 24 h, and the reaction was stirred overnight at 35 °C each time. 73.5 mg of EDCI, 40.3 mg of lithio 4-(1-methylpiperidin-4-yl)-3-(trifluoromethyl)benzoate, and 1 equivalent of EtN were added, and the reaction was stirred at 35 °C for 48 h. After extraction, the crude product was purified by flash column chromatography using MeOH (0-15%) in EtOAc as the eluent. 4-(1-methylpiperidin-4-yl)-N-(quinolin-5-yl)-3-(trifluoromethyl)benzamide (27) (30 mg, 0.073 mmol, 53%) was obtained as a yellow powder with an HPLC purity of 98%.

[0250] Example 9 Preparation of 3-methyl-4-(4-methylpiperazin-1-yl)-N-(quinolin-5-yl)benzamide (29) Methyl 3-methyl-4-(4-methylpiperazin-1-yl)benzoate

[0251] [ka]

[0252] General procedure C was applied to methyl 4-bromo-3-methylbenzoate (232 mg, 1.01 mmol). The crude residue was purified by flash column chromatography using EtOAc in heptane (90 / 10, 70 / 30, successively) and then MeOH in DCM (98 / 2, 90 / 10, successively) as eluents to yield methyl 3-methyl-4-(4-methylpiperazin-1-yl)benzoate (160 mg, 0.646 mmol, 64%) as an orange oil. NMR 1 H (400 MHz, CDCl3): δ 7.86-7.76 (m, 2H), 6.97 (d, J = 8.1 Hz, 1H), 3.85 (s, 3H), 2.98 (t, J = 4.7 Hz, 4H), 2.57 (bs, 4H), 2.35 (s, 3H), 2.30 (s, 3H). NMR 13 C (101 MHz, CDCl3): δ 167.26 (CO), 155.84 (C q ), 132.69 (CH Ar ), 131.67 (C q ), 128.51 (CH Ar ), 124.10 (C q ), 118.29 (CH Ar ), 55.44 (2CH2), 51.88 (CH3), 51.20 (2CH2), 46.20 (CH3), 18.39 (CH3).

[0253] 3-Methyl-4-(4-methylpiperazin-1-yl)-N-(quinolin-5-yl)benzamide (29) General procedure F was applied to methyl 3-methyl-4-(4-methylpiperazin-1-yl)benzoate (158 mg, 0.639 mmol) to quantitatively produce lithio 3-methyl-4-(4-methylpiperazin-1-yl)benzoate (153.4 mg) as a pale orange solid. Following general procedure I, the lithium salt (1.1 eq., 72 mg, 0.3 mmol) was used in the amido-coupling with 5-quinolinamine (1 eq., 39.3 mg, 0.272 mmol). The crude residue was purified by flash column chromatography using MeOH in DCM (98 / 2, then 85 / 15) as eluent to give 3-methyl-4-(4-methylpiperazin-1-yl)-N-(quinolin-5-yl)benzamide (29) (30.5 mg, 0.0846 mmol, 31%) as a pale orange solid with an HPLC purity of 92%.

[0254] Example 10 Preparation of 4-[2-(dimethylamino)ethoxy]-N-(8-methoxyisoquinolin-5-yl)benzamide (34) Following general procedure G, starting with lithio 4-[2-(dimethylamino)ethoxy]benzoate (1 eq., 50 mg, 0.23 mmol) and 8-methoxyisoquinolin-5-amine (1.1 eq., 45 mg, 0.26 mmol), the reaction mixture was stirred at 35 °C overnight. Three equivalents of EDCI were added, and the reaction mixture was stirred at 35 °C for 2 days. The crude product was purified by flash column chromatography using MeOH in DCM as the eluent (0-15%). The title compound (34) was obtained as a gray powder (38 mg, 0.23 mmol, 46%).

[0255] Example 11 Preparation of 4-(4-methylpiperazin-1-yl)-N-(quinolin-8-yl)benzamide (35) General procedure H was applied to 4-(4-methylpiperazin-1-yl)benzoic acid (1 eq., 250 mg, 1.13 mmol) to give 4-(4-methylpiperazin-1-yl)benzoyl chloride (270.94 mg, 1.13 mmol, 100%). One equivalent of benzoyl chloride (50 mg, 0.209 mmol) was then used in an amide bond coupling with 8-aminoquinoline (1.1 eq., 33.22 mg, 0.23 mmol), and the crude residue was purified by flash column chromatography using 10% MeOH / DCM solution in pure DCM as eluent (0–100%) to afford 4-(4-methylpiperazin-1-yl)-N-(quinolin-8-yl)benzamide (35) (60 mg, 0.17 mmol, 83%) obtained as an orange powder with an HPLC purity of 97%.

[0256] Example 12 Preparation of 3-cyano-4-[2-(dimethylamino)ethoxy]-N-(isoquinolin-8-yl)benzamide (36) Methyl 3-cyano-4-[2-(dimethylamino)ethoxy]benzoate

[0257] [ka]

[0258] General procedure D was applied to commercially available methyl 3-cyano-4-hydroxybenzoate (1 eq., 205 mg, 1.16 mmol) in acetone (8 mL). The mixture was stirred at 60° C. for 22 h, and after extraction with aqueous EtOAc, methyl 3-cyano-4-[2-(dimethylamino)ethoxy]benzoate was obtained as a light brown oil (119 mg, 0.48 mmol, 41%) without further purification. NMR 1H (400 MHz, MeOD): δ 8.20 - 8.12 (m, 2H), 7.24 (d, J = 8.8 Hz, 1H), 4.33 (t, J = 5.3 Hz, 2H), 3.89 (s, 3H), 2.91 (t, J = 5.3 Hz, 2H), 2.42 (s, 6H).

[0259] 3-Cyano-4-[2-(dimethylamino)ethoxy]-N-(isoquinolin-8-yl)benzamide (36) General procedure F was applied to methyl 3-cyano-4-[2-(dimethylamino)ethoxy]benzoate (1 eq., 119 mg, 0.43 mmol) to give lithio 3-cyano-4-[2-(dimethylamino)ethoxy]benzoate as a light beige powder (73 mg, 0.304 mmol, 70%). Following general procedure G, a solution of lithio 3-cyano-4-[2-(dimethylamino)ethoxy]benzoate (1 eq., 50 mg, 0.208 mmol) and commercially available 8-aminoisoquinoline (1.1 eq., 33 mg, 0.23 mmol) was added, and the reaction mixture was stirred at 35 °C for 24 h. The crude residue was purified by flash column chromatography using MeOH (0–15%) in DCM as the eluent to give 3-cyano-4-[2-(dimethylamino)ethoxy]-N-(isoquinolin-8-yl)benzamide (36) (8 mg, 0.022 mmol, 11%) as a beige powder with an HPLC purity of 98%.

[0260] Example 13 Preparation of 4-[2-(dimethylamino)ethoxy]-3-methyl-N-(quinolin-8-yl)benzamide (43) Methyl 4-[2-(dimethylamino)ethoxy]-3-methylbenzoate

[0261] [ka]

[0262] General procedure D was applied to methyl 4-hydroxy-3-methylbenzoate (1 eq., 200 mg, 1.204 mmol) in acetone (3.5 mL). (2-Chloroethyl)dimethylamine hydrochloride (1.5 eq., 260 mg, 1.805 mmol) was added and the reaction was stirred at 60 °C overnight (21 h). Methyl 4-[2-(dimethylamino)ethoxy]-3-methylbenzoate (108 mg, 0.46 mmol, 37%) was obtained as a light brown oil without further purification. NMR 1 H (400 MHz, MeOD): δ 7.81 (dd, J = 8.6, 2.4 Hz, 2H), 7.78 - 7.72 (m, 2H), 6.91 (d, J = 8.6 Hz, 1H), 4.13 (t, J = 5.4 Hz, 2H), 3.83 (s, 2H), 2.80 (t, J = 5.4 Hz, 2H), 2.35 (s, 5H), 2.21 (s, 3H).

[0263] 4-[2-(dimethylamino)ethoxy]-3-methyl-N-(quinolin-8-yl)benzamide (43) General procedure F was applied to methyl 4-[2-(dimethylamino)ethoxy]-3-methylbenzoate (1 eq., 108 mg, 0.46 mmol) to quantitatively obtain lithio 4-[2-(dimethylamino)ethoxy]-3-methylbenzoate as a white powder (142 mg). General procedure G was applied to the lithium salt (1 eq., 92 mg, 0.401 mmol) to obtain 4-[2-(dimethylamino)ethoxy]-3-methylbenzoyl chloride as a beige powder (97 mg, 0.401 mmol). Benzoyl chloride was then used together with commercially available 8-aminoquinoline (1.1 eq., 60 mg, 0.42 mmol). The mixture was stirred at room temperature overnight, and the crude product was purified by flash column chromatography using MeOH (0–10%) in DCM as the eluent. 4-[2-(dimethylamino)ethoxy]-3-methyl-N-(quinolin-8-yl)benzamide (43) (30 mg, 0.086 mmol, 22%) was obtained as a yellow powder with an HPLC purity of 98%.

[0264] Example 14 Preparation of N-(isoquinolin-5-yl)-2-methyl-4-(4-methylpiperazin-1-yl)benzamide (45) Methyl 2-methyl-4-(4-methylpiperidin-1-yl)benzoate

[0265] [ka]

[0266] General procedure C was applied to methyl 4-bromo-2-methylbenzoate (1 eq., 204 mg, 0.893 mmol). The residue was purified by flash column chromatography using EtOAc in heptane (90 / 10, 70 / 30, successively used) and then MeOH in DCM (98 / 2, 90 / 10, successively used) to produce methyl 2-methyl-4-(4-methylpiperazin-1-yl)benzoate (211 mg, 0.853 mmol, 95%) as an orange oil. NMR 1 H (500 MHz, CDCl3) : δ 7.85 (d, J = 8.6 Hz, 1H), 6.67 (d, J = 2.7 Hz, 1H), 6.64 (d, J = 3.2 Hz, 2H), 3.79 (s, 3H), 3.36 - 3.19 (m, 4H), 2.56 (s, 3H), 2.49 (t, J = 5.1 Hz, 4H), 2.30 (s, 3H). NMR 13 C (126 MHz, CDCl3): δ 167.57 (CO), 153.31 (C q ), 142.49 (C q ), 132.66 (CH Ar ), 118.83 (C q ), 116.96 (CH Ar ), 111.42 (CH Ar ), 54.80 (2CH2), 51.25 (CH3), 47.40 (2CH2), 46.11 (CH3), 22.74 (CH3).

[0267] N-(isoquinolin-5-yl)-2-methyl-4-(4-methylpiperazin-1-yl)benzamide (45) General procedure F was applied to methyl 3-methyl-4-(4-methylpiperazin-1-yl)benzoate (1 eq., 158 mg, 0.639 mmol) to quantitatively produce lithio 3-methyl-4-(4-methylpiperazin-1-yl)benzoate (181 mg). General procedure G was applied to the lithium salt (1 eq., 100 mg, 0.42 mmol) to give 2-methyl-4-(4-methylpiperazin-1-yl)benzoyl chloride (105 mg, 0.42 mmol, 100%). Benzoyl chloride (1.1 eq., 50 mg, 0.2 mmol) was used for the amide coupling with 5-isoquinolinamine (1 eq., 25.93 mg, 0.18 mmol). The crude product was purified by flash column chromatography using 10% MeOH / DCM in pure DCM (0-100%) as the eluent. The expected N-(5-fluoroisoquinolin-8-yl)-4-(4-methylpiperazin-1-yl)benzamide (45) (8 mg, 0.022 mmol, 12%) was obtained as a yellow powder with an HPLC purity of 95%.

[0268] Example 15 Preparation of 4-[2-(dimethylamino)ethoxy]-2-methyl-N-(quinolin-5-yl)benzamide (47) Methyl 4-[2-(dimethylamino)ethoxy]-2-methylbenzoate

[0269] [ka]

[0270] General procedure D was applied to methyl 4-hydroxy-2-methylbenzoate (1 eq., 200 mg, 1.204 mmol) and (2-chloroethyl)dimethylamine hydrochloride (1.5 eq., 260 mg, 1.805 mmol). The reaction was stirred at 60 °C overnight (21 h), and the crude product was purified by flash column chromatography on silica gel using EtOAc in heptane (25 / 75) as eluent, followed by MeOH in DCM (98 / 2, 85 / 15, successively) to yield methyl 4-[2-(dimethylamino)ethoxy]-2-methylbenzoate (198 mg, 0.83 mmol, 69%) as an oil. NMR 1 H (400 MHz, MeOD): δ 7.77 (d, J = 8.4 Hz, 1H), 6.74 - 6.66 (m, 2H), 4.01 (t, J = 5.5 Hz, 2H), 3.71 (s, 3H), 2.64 (t, J = 5.5 Hz, 2H), 2.44 (s, 3H), 2.22 (s, 6H). NMR 13 C (101 MHz, MeOD): δ 132.63, 117.08, 111.22, 65.31, 57.56, 57.56, 50.61, 48.50, 44.48, 21,04

[0271] 4-[2-(dimethylamino)ethoxy]-2-methyl-N-(quinolin-5-yl)benzamide (47) General procedure F was applied to methyl 4-[2-(dimethylamino)ethoxy]-2-methylbenzoate (1 eq., 198 mg, 0.83 mmol), quantitatively obtaining lithio 4-[2-(dimethylamino)ethoxy]-2-methylbenzoate as a white powder (296 mg). General procedure G was applied to the lithium salt (1 eq., 296 mg, 1.29 mmol), obtaining 4-[2-(dimethylamino)ethoxy]-2-methylbenzoyl chloride as a white powder (312.17 mg, 0.401 mmol). Benzoyl chloride (1 eq., 298 mg, 1.23 mmol) was then used together with commercially available 5-aminoquinoline (1 eq., 177 mg, 1.23 mmol), and the mixture was stirred at room temperature overnight. The crude product was purified on silica gel using MeOH in DCM as the eluent (0–10%). The resulting fraction was triturated with ether to give 4-[2-(dimethylamino)ethoxy]-2-methyl-N-(quinolin-5-yl)benzamide (47) (30 mg, 0.086 mmol, 7%) as a yellow powder with an HPLC purity of 93.5%.

[0272] Example 16 Preparation of 4-[2-(dimethylamino)ethoxy]-N-(isoquinolin-5-yl)-3-(trifluoromethyl)benzamide (48) Methyl 4-[2-(dimethylamino)ethoxy]-3-(trifluoromethyl)benzoate

[0273] [ka]

[0274] General procedure D was applied to methyl 4-hydroxy-3-(trifluoromethyl)benzoate (1 eq., 200 mg, 0.908 mmol) and 2-dimethylaminoethyl chloride hydrochloride (1.5 eq., 196 mg, 1.36 mmol). The reaction was stirred at 60 °C overnight (21 h) to afford, without further purification, methyl 4-[2-(dimethylamino)ethoxy]-3-(trifluoromethyl)benzoate (233 mg, 0.8 mmol, 88%) as a light brown oil with an HPLC purity of 96%. NMR 1 H (400 MHz, MeOD): δ 8.57 (d, J = 2.3 Hz, 1H), 8.11 (dd, J = 8.8, 2.3 Hz, 1H), 7.23 (d, J = 8.6 Hz, 1H), 4.33 (t, J = 5.3 Hz, 2H), 3.89 (s, 3H), 2.82 (t, J = 5.3 Hz, 2H), 2.33 (s, 6H). NMR 13 C (101 MHz, MeOD): δ 171.41, 165.54, 135.09, 122.09, 112.73, 67.60, 60.08, 57.19, 51.36, 44.75, 19.51, 13.12. NMR 19 F (376 MHz, MeOD, decoupled): δ -63.85.

[0275] 4-[2-(dimethylamino)ethoxy]-N-(isoquinolin-5-yl)-3-(trifluoromethyl)benzamide (48) General procedure F (preparation of lithium salts) was applied to methyl 4-[2-(dimethylamino)ethoxy]-3-(trifluoromethyl)benzoate (1 eq., 233 mg, 0.8 mmol), yielding lithium 4-[2-(dimethylamino)ethoxy]-3-(trifluoromethyl)benzoate quantitatively as a white powder (233 mg). General procedure G was applied to the lithium salt (1 eq., 296 mg, 1.29 mmol), yielding 4-[2-(dimethylamino)ethoxy]-3-(trifluoromethyl)benzoyl chloride (243.29 mg, 0.82 mmol) as a white solid. Benzoyl chloride was then used with commercially available 5-isoquinolinamine (1.2 eq., 141 mg, 0.98 mmol), and the mixture was stirred at room temperature overnight. The crude product was purified by flash column chromatography using MeOH in DCM as the eluent (0–10%) to yield 4-[2-(dimethylamino)ethoxy]-N-(isoquinolin-5-yl)-3-(trifluoromethyl)benzamide (48) (42 mg, 0.104 mmol, 11%) obtained as a yellow powder with an HPLC purity of 99%.

[0276] Example 17 Preparation of 4-[2-(dimethylamino)ethoxy]-N-(quinolin-5-yl)-2-(trifluoromethyl)benzamide (49) Methyl 4-[2-(dimethylamino)ethoxy]-2-(trifluoromethyl)benzoate

[0277] [ka]

[0278] General procedure D was applied to methyl 4-hydroxy-2-(trifluoromethyl)benzoate (1 eq., 200 mg, 0.908 mmol) and (2-chloroethyl)dimethylamine hydrochloride (1.5 eq., 196 mg, 1.36 mmol). The reaction was stirred at 60 °C overnight (21 h) to give, without further purification, methyl 4-[2-(dimethylamino)ethoxy]-2-(trifluoromethyl)benzoate (144 mg, 0.49 mmol, 54%) with a purity of 96%. NMR 1 H (500 MHz, MeOD): δ 7.89 - 7.81 (m, 1H), 7.34 (d, J = 2.6 Hz, 1H), 7.24 (dd, J = 8.7, 2.6 Hz, 1H), 4.21 (t, J = 5.4 Hz, 2H), 3.88 (s, 3H), 2.80 (t, J = 5.4 Hz, 2H), 2.35 (s, 6H) NMR 13 C (126 MHz, MeOD): δ 166.43, 161.06, 132.93, 116.25, 113.72, 113.67, 65.93, 57.39, 51.62, 44.44. NMR 19 F (376 MHz, MeOD, decoupled): δ -60.96.

[0279] 4-[2-(dimethylamino)ethoxy]-N-(quinolin-5-yl)-2-(trifluoromethyl)benzamide (49) General procedure F was applied to methyl 4-[2-(dimethylamino)ethoxy]-2-(trifluoromethyl)benzoate (1 eq., 144 mg, 0.49 mmol) to quantitatively obtain lithio 4-[2-(dimethylamino)ethoxy]-2-(trifluoromethyl)benzoate as a white powder (160 g). General procedure G was applied to the lithium salt (1 eq., 160 mg, 0.57 mmol) to obtain 4-[2-(dimethylamino)ethoxy]-2-(trifluoromethyl)benzoyl chloride (167 mg, 0.57 mmol) as a white powder. Benzoyl chloride (1 eq., 160 mg, 0.54 mmol) was then used with commercially available 5-isoquinolinamine (1.1 eq., 141 mg, 0.98 mmol). The mixture was stirred at room temperature overnight, and the crude product was purified by flash column chromatography using MeOH in DCM as a solvent (0–10%) to give 4-[2-(dimethylamino)ethoxy]-N-(quinolin-5-yl)-2-(trifluoromethyl)benzamide (49) (22 mg, 0.055 mmol, 10%) as a yellow powder with an HPLC purity of 99%.

[0280] Example 18 Preparation of 3-fluoro-N-(5-fluoroisoquinolin-8-yl)-4-{5-methyl-octahydropyrrolo[3,4-c]pyrrol-2-yl}benzamide (53) Methyl 3-fluoro-4-{5-methyl-octahydropyrrolo[3,4-c]pyrrol-2-yl}benzoate

[0281] [ka]

[0282] General procedure C was applied to methyl 4-bromo-3-fluorobenzoate (1 eq., 200 mg, 0.86 mmol) and 2-methyl-octahydropyrrolo[3,4-c]pyrrole dihydrochloride (1.2 eq., 1.03 mmol, 205 mg). The flask was allowed to cool at room temperature. The mixture was diluted with EtOAc, filtered through a Celite® pad, and washed with EtOAc. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel (heptane / EtOAc 90 / 10, 70 / 30, then DCM / MeOH 98 / 2, 90 / 10) to produce methyl 3-fluoro-4-{5-methyl-octahydropyrrolo[3,4-c]pyrrol-2-yl}benzoate (111 mg, 0.4 mmol, 46.47%) as an orange oil. 1 H NMR (400 MHz, methanol-d4): δ 7.61 - 7.37 (m, 2H), 6.64 (t, J = 8.7 Hz, 1H), 3.72 (s, 3H), 2.81 (dt, J = 9.1, 3.4 Hz, 2H), 2.78 - 2.72 (m, 2H), 2.29 - 2.22 (m, 2H), 2.21 (s, 3H). 13 C NMR (101 MHz, methanol-d4): δ 166.39, 166.37, 152.94, 150.53, 141.31, 141.22, 126.44, 126.42, 119.75, 119.68, 116.71, 116.48, 116.40, 116.35, 62.26, 54.92, 54.86, 51.02, 41.74, 41.73, 40.57. 19 F NMR (376 MHz, methanol-d4): δ -125.33.

[0283] 3-Fluoro-N-(5-fluoroisoquinolin-8-yl)-4-{5-methyl-octahydropyrrolo[3,4-c]pyrrol-2-yl}benzamide (53) General procedure F was applied to methyl 3-fluoro-4-{5-methyl-octahydropyrrolo[3,4-c]pyrrol-2-yl}benzoate (1 eq., 111 mg, 0.4 mmol) to yield lithio 3-fluoro-4-{5-methyl-octahydropyrrolo[3,4-c]pyrrol-2-yl}benzoate (107.77 mg, 0.4 mmol, 100%) as a yellow powder.

[0284] The general procedure H was then applied to the lithium salt (1 eq., 100 mg, 0.37 mmol) to give 4-[2-(dimethylamino)ethoxy]-2-(trifluoromethyl)benzoyl chloride (100 mg, 0.35 mmol) as a white solid, which was used directly in the next step with 5-fluoroisoquinolin-8-amine (0.52 eq., 30 mg, 0.18 mmol) without further purification. The crude product was purified on silica gel using methanol in DCM as the solvent (0–10%). The expected 3-fluoro-N-(5-fluoroisoquinolin-8-yl)-4-{5-methyl-octahydropyrrolo[3,4-c]pyrrol-2-yl}benzamide (53) was obtained as a yellow powder (13.5 mg, 0.033 mmol, 18%) with an HPLC purity of 95%.

[0285] Example 19 N-(8-Methoxyisoquinolin-5-yl)-3-methyl-4-{7-methyl-2,7-diazaspiro[3.5]nonan-2-yl}benzamide (54) Methyl 3-methyl-4-{7-methyl-2,7-diazaspiro[3.5]nonan-2-yl}benzoate

[0286] [ka]

[0287] General procedure C was applied to methyl 4-bromo-3-methylbenzoate (1 eq., 200 mg, 0.87 mmol) and 7-methyl-2,7-diazaspiro[3.5]nonane dihydrochloride (1.2 eq., 223 mg, 1.048 mmol). The flask was allowed to cool at room temperature. The mixture was diluted with EtOAc, filtered through a Celite® pad, and washed with EtOAc. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel (heptane / EtOAc 90 / 10, 70 / 30, then DCM / MeOH 98 / 2, 90 / 10) to yield methyl 3-methyl-4-{7-methyl-2,7-diazaspiro[3.5]nonan-2-yl}benzoate (114 mg, 0.4 mmol, 45.28%) as a yellow oil. 1 H NMR (400 MHz, MeOD): δ 7.68 (dd, J = 8.5, 2.1 Hz, 1H), 7.62 - 7.57 (m, 1H), 6.37 (d, J = 8.5 Hz, 1H), 3.80 (s, 3H), 3.74 (s, 4H), 2.74 - 2.30 (m, 4H), 2.27 (s, 3H), 2.22 (s, 3H), 1.83 (t, J = 5.6 Hz, 4H).

[0288] N-(8-Methoxyisoquinolin-5-yl)-3-methyl-4-{7-methyl-2,7-diazaspiro[3.5]nonan-2-yl}benzamide (54) General procedure F was applied to methyl 3-methyl-4-{7-methyl-2,7-diazaspiro[3.5]nonan-2-yl}benzoate (1 eq., 161.5 mg, 0.56 mmol) to yield lithio 3-methyl-4-{7-methyl-2,7-diazaspiro[3.5]nonan-2-yl}benzoate (165 mg, 0.56 mmol, 100%) as a yellow powder.

[0289] The general procedure H was then applied to the lithium salt (1.28 eq., 114 mg, 0.41 mmol) to quantitatively produce 3-methyl-4-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)benzoyl chloride (100 mg, 0.34 mmol, 83%) as a white solid, which was used directly in the next step with 8-methoxyisoquinolin-5-amine (1 eq., 56.66 mg, 0.33 mmol) without further purification. The crude product was purified on silica gel using methanol in DCM as the solvent (0–10%). The expected N-(8-methoxyisoquinolin-5-yl)-3-methyl-4-{7-methyl-2,7-diazaspiro[3.5]nonan-2-yl}benzamide (54) (18 mg, 0.042 mmol, 12.85%) was obtained as a light brown powder.

[0290] Example 20 3-Methyl-4-[(1-methylpyrrolidin-3-yl)methoxy]-N-(quinolin-8-yl)benzamide (55) 3-Methyl-4-[(1-methylpyrrolidin-3-yl)methoxy]benzoic acid

[0291] [ka]

[0292] General procedure E was applied to (1-methylpyrrolidin-3-yl)methanol (1 eq., 200 mg, 0.205 mL, 1.74 mmol), triphenylphosphine (1.1 eq., 501.009 mg, 1.91 mmol) and methyl 4-hydroxy-3-methylbenzoate (1.1 eq., 317.42 mg, 1.91 mmol). The crude product was purified on silica using MeOH in DCM as eluent (0->10%) to give methyl 3-methyl-4-[(1-methylpyrrolidin-3-yl)methoxy]benzoate (150 mg, 0.57 mmol, 32.803%) as a pale yellow oil. 1H NMR (400 MHz, MeOD): δ 7.87 - 7.68 (m, 2H), 6.89 (d, J = 8.5 Hz, 1H), 4.08 - 3.87 (m, 2H), 3.83 (s, 3H), 2.86 (dd, J = 9.8, 7.9 Hz, 1H), 2.79 - 2.66 (m, 2H), 2.62 (ddd, J = 9.6, 8.1, 6.3 Hz, 1H), 2.49 (dd, J = 9.8, 6.3 Hz, 1H), 2.40 (d, J = 4.0 Hz, 3H), 2.18 (s, 3H), 2.13 - 2.01 (m, 1H), 1.67 (ddt, J = 13.7, 8.1, 5.9 Hz, 1H). 13 C NMR (101 MHz, MeOD): δ 167.10, 160.94, 131.42, 129.11, 126.31, 121.75, 110.07, 70.54, 58.62, 55.43, 50.92, 40.89, 37.40, 27.32, 15.05.

[0293] 3-Methyl-4-[(1-methylpyrrolidin-3-yl)methoxy]-N-(quinolin-8-yl)benzamide (55) General procedure F was applied to methyl 3-methyl-4-[(1-methylpyrrolidin-3-yl)methoxy]benzoate (1 eq., 150 mg, 0.57 mmol) to give lithio 3-methyl-4-[(1-methylpyrrolidin-3-yl)methoxy]benzoate (100 mg, 73%) as a yellow powder.

[0294] General procedure H was then applied to lithio({3-methyl-4-[(1-methylpyrrolidin-3-yl)methoxy]phenyl})methanone (1.31 eq., 100 mg, 0.42 mmol). The crude benzoyl chloride (white solid) was used directly in the next step without further purification to react with 8-quinolinamine (1 eq., 51.28 mg, 0.36 mmol) to yield 3-methyl-4-[(1-methylpyrrolidin-3-yl)methoxy]-N-(quinolin-8-yl)benzamide (55) (81 mg, 0.22 mmol, 60.65%) as a yellow powder.

[0295] Example 21 2-Fluoro-N-(isoquinolin-8-yl)-4-[-4-(propan-2-yl)piperazin-1-yl]benzamide (57) Methyl 2-fluoro-4-[4-(propan-2-yl)piperazin-1-yl]benzoate

[0296] [ka]

[0297] General procedure C was applied to methyl 4-bromo-2-fluorobenzoate (1 eq., 300 mg, 1.29 mmol) and 1-isopropylpiperazine (1.2 eq., 198.076 mg, 0.22 mL, 1.54 mmol). The reaction was allowed to cool at room temperature, then filtered through a Celite® pad and washed with EtOAc. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography using a solution of 10% MeOH in DCM in pure DCM (0 to 100%) to yield methyl 2-fluoro-4-[4-(propan-2-yl)piperazin-1-yl]benzoate (193.4 mg, 0.69 mmol, 53.59%) as an orange solid. 1H NMR (400 MHz, MeOD): δ 7.77 (t, J = 8.8 Hz, 1H), 6.74 (dd, J = 9.0, 2.5 Hz, 1H), 6.64 (dd, J = 15.1, 2.5 Hz, 1H), 3.83 (s, 3H), 3.46 - 3.22 (m, 4H), 2.72 (dd, J = 13.2, 6.7 Hz, 1H), 2.67 (dd, J = 6.1, 4.2 Hz, 4H), 1.12 (s, 3H), 1.10 (s, 3H). 19 F NMR (376 MHz, MeOD): δ -109.05. 13 C NMR (126 MHz, MeOD): δ 166.50 (d, J = 4.2 Hz, CO), 165.23 (d, J = 256.5 Hz, CF), 157.25 (d, J = 11.4 Hz, C q ), 134.19 (d, J = 2.8 Hz, CH Ar ), 110.35 (d, J = 2.3 Hz, CH Ar ), 107.72 (d, J = 10.1 Hz, C q ), 102.03 (d, J = 27.2 Hz, CH Ar ), 55.93 (CH), 52.12 (CH3), 49.53 (2CH2), 47.94 (2CH2), 18.64 (2CH3).

[0298] Lithio 2-fluoro-4-[4-(propan-2-yl)piperazin-1-yl]benzoate

[0299] [ka]

[0300] General procedure F was applied to methyl 2-fluoro-4-[4-(propan-2-yl)piperazin-1-yl]benzoate (1 eq., 190 mg, 0.68 mmol) to quantitatively produce lithio 2-fluoro-4-[4-(propan-2-yl)piperazin-1-yl]benzoate (202.1 mg, 0.74 mmol) as a beige powder. 1 H NMR (500 MHz, MeOD): δ 7.64 (t, J = 8.8 Hz, 1H), 6.69 (dd, J = 8.7, 2.5 Hz, 1H), 6.58 (dd, J = 14.2, 2.4 Hz, 1H), 3.29 - 3.23 (m, 4H), 2.80 - 2.61 (m, 5H, 2CH2+ CH), 1.12 (s, 3H), 1.11 (s, 3H). 19 F NMR (376 MHz, MeOD): δ -113.00. 13 C NMR (126 MHz, MeOD): δ 173.22 (d, J = 2.7 Hz, CO), 163.72 (d, J = 249.4 Hz, CF), 155.09 (d, J = 10.4 Hz, C q ), 133.40 (d, J = 4.4 Hz, CH Ar ), 118.03 (d, J = 12.4 Hz, C q ), 110.78 (d, J = 2.7 Hz, CH Ar ), 102.99 (d, J = 27.7 Hz, CH Ar ), 55.95 (CH), 49.72 (2CH2), 48.96 (2CH2), 18.68 (2CH3).

[0301] 2-Fluoro-N-(isoquinolin-8-yl)-4-[-4-(propan-2-yl)piperazin-1-yl]benzamide (57) General procedure H was applied to lithio 2-fluoro-4-[4-(propan-2-yl)piperazin-1-yl]benzoate (1.03 eq, 51.5 mg, 0.19 mmol), and the crude product was purified by flash column chromatography using methanol in DCM as the solvent (0-10%). The expected 2-fluoro-N-(isoquinolin-8-yl)-4-[4-(propan-2-yl)piperazin-1-yl]benzamide (57) (35 mg, 0.089 mmol, 51.73%) was obtained as a pink powder with an HPLC purity of 99%.

[0302] Example 22 N-(5-fluoroisoquinolin-8-yl)-3-methoxy-4-[(1R,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]benzamide (58) Methyl 3-methoxy-4-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]benzoate

[0303] [ka]

[0304] General procedure C was applied to methyl 4-bromo-3-methoxybenzoate (1 eq., 300 mg, 1.22 mmol), (1R,4R)-5-methyl-2,5-diazabicyclo-[2.2.1]heptane dihydrochloride (1.2 eq., 271.89 mg, 1.47 mmol), and CsCO (3.4 eq., 1356.072 mg, 4.16 mmol). The residue was purified by flash column chromatography using a pure DCM solution of 10% MeOH in DCM (0-100%) to yield methyl 3-methoxy-4-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]benzoate (163 mg, 0.59 mmol, 48%) as a brown oil. NMR 1H (400 MHz, MeOD): δ 7.52 (dd, J = 8.4, 1.9 Hz, 1H), 7.46 (d, J = 1.9 Hz, 1H), 6.60 (d, J = 8.5 Hz, 1H), 4.58 (d, J = 2.3 Hz, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 3.66 (dd, J = 10.5, 2.5 Hz, 1H), 3.55 - 3.46 (m, 1H), 3.41 (dd, J = 10.5, 1.7 Hz, 1H), 2.92 (dd, J = 10.1, 1.5 Hz, 1H), 2.82 (dd, J = 10.1, 2.2 Hz, 1H), 2.40 (s, 3H), 2.11 - 1.94 (m, 1H), 1.93 - 1.76 (m, 1H). NMR 13 C (126 MHz, MeOD): δ 169.01, 149.53, 143.60, 125.31, 119.65, 114.35, 113.95, 64.38, 61.27, 60.71, 56.18, 56.08, 52.16, 41.72, 35.46.

[0305] Lithio 3-methoxy-4-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]benzoate

[0306] [ka]

[0307] General method F was applied to methyl 3-methoxy-4-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]benzoate (1 eq., 156 mg, 0.56 mmol). The reaction was stirred at 25 °C for 48 h, and after evaporation, lithio 3-methoxy-4-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]benzoate was obtained quantitatively as a beige powder (189.7 mg, 0.71 mmol). NMR1 H (500 MHz, MeOD): δ 7.54 (d, J = 1.8 Hz, 1H), 7.49 (dd, J = 8.3, 1.9 Hz, 1H), 6.59 (d, J = 8.3 Hz, 1H), 4.44 (dt, J = 2.4, 1.3 Hz, 1H), 3.82 (s, 3H), 3.63 (dd, J = 10.5, 2.5 Hz, 1H), 3.48 (d, J = 2.4 Hz, 1H), 3.39 - 3.33 (m, 1H), 2.96 (dd, J = 10.2, 1.5 Hz, 1H), 2.82 (dd, J = 10.1, 2.3 Hz, 1H), 2.40 (d, J = 2.0 Hz, 3H), 1.97 - 1.93 (m, 1H), 1.88 - 1.78 (m, 1H). NMR 13 C (126 MHz, MeOD): δ 175.83, 149.81, 141.22, 128.88, 124.36, 114.80, 114.68, 64.63, 60.99, 60.08, 56.09, 55.85, 41.48, 35.42.

[0308] N-(5-fluoroisoquinolin-8-yl)-3-methoxy-4-[(1R,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]benzamide (58)

[0309] [ka]

[0310] General method H was applied to lithio 3-methoxy-4-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]benzoate (1 eq., 50 mg, 0.19 mmol). The crude product was purified by flash column chromatography using MeOH in DCM as the solvent (0-10%). The expected N-(5-fluoroisoquinolin-8-yl)-3-methoxy-4-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]benzamide (58) was obtained as a yellow powder (8.8 mg, 0.022 mmol, 13%) with an HPLC purity of 95%.

[0311] Example 23 N-(6-methoxyisoquinolin-8-yl)-4-(1-methylpiperidin-4-yl)benzamide (63)

[0312] [ka]

[0313] General procedure J was applied to 4-(1-methylpiperidin-4-yl)benzamide (1.03 eq., 58.5 mg, 0.27 mmol) and 8-bromo-6-methoxyisoquinoline (1 eq., 61.94 mg, 0.26 mmol). The crude product was pre-rinsed with a solution of ether and 5% EtN, followed by DCM, and purified by flash column chromatography using an elution gradient of 10% MeOH / DCM and pure DCM. N-(6-methoxyisoquinolin-8-yl)-4-(1-methylpiperidin-4-yl)benzamide (63) (75 mg, 0.2 mmol, 77%) was obtained as a white powder with an HPLC purity of 95%.

[0314] Example 24 N-(8-methoxyisoquinolin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide (65)

[0315] [ka]

[0316] General procedure H was applied to 4-(1-methylpiperidin-4-yl)benzoyl chloride (1.54 eq., 61.6 mg, 0.26 mmol) and 8-methoxyisoquinolin-5-amine (1.02 eq., 29.9 mg, 0.17 mmol). The crude product was purified by flash column chromatography using MeOH (0-15%) in DCM as eluent, followed by 10% MeOD in DCM with 5% EtN. N-(8-Methoxyisoquinolin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide (65) was obtained as a white powder (55.6 mg, 0.15 mmol, 86%) with an HPLC purity of 99%.

[0317] Example 25 N-(8-Methoxyisoquinolin-5-yl)-4-(4-methylpiperazin-1-yl)benzamide hydrochloride (70)

[0318] [ka]

[0319] General procedure H was applied to 4-(4-methylpiperazin-1-yl)benzoyl chloride (1.5 eq., 60 mg, 0.25 mmol) and 8-methoxyisoquinolin-5-amine (1.02 eq., 29.78 mg, 0.17 mmol). The crude product was purified by flash column chromatography using MeOH (0–20%) in DCM as eluent and repurified by reverse-phase chromatography using acetonitrile and 0.05% aqueous HCl (0–100%) to yield N-(8-methoxyisoquinolin-5-yl)-4-(4-methylpiperazin-1-yl)benzamide hydrochloride (70) (55 mg, 0.13 mmol, 78) with an HPLC purity of 99%.

[0320] Example 26 N-(6-chloroisoquinolin-8-yl)-4-(4-methylpiperazin-1-yl)benzamide (73)

[0321] [ka]

[0322] General procedure J was applied to 4-(4-methylpiperazin-1-yl)benzamide (1.03 eq., 50 mg, 0.23 mmol) and 8-bromo-6-chloroisoquinoline (1 eq., 53.68 mg, 0.22 mmol). The crude product was purified by flash column chromatography using MeOH and DCM (0–15%) as eluents. The product was repurified by reverse-phase chromatography using acetonitrile and 0.05% aqueous HCl (0–100%). The salt was washed with a basic aqueous phase (NaOH pH ca. 10–14) and extracted with EtOAc. N-(6-chloroisoquinolin-8-yl)-4-(4-methylpiperazin-1-yl)benzamide (73) (20 mg, 0.053 mmol, 24%) was obtained as a beige powder.

[0323] Example 27 Methyl 8-[4-(1-methylpiperidin-4-yl)benzamido]quinoline-5-carboxylate (75)

[0324] [ka]

[0325] General method J was applied to 4-(1-methylpiperidin-4-yl)benzamide (1.042 eq., 50.6 mg, 0.23 mmol) and methyl 8-bromoquinoline-5-carboxylate (1.026 eq., 60.7 mg, 0.23 mmol). The crude product was purified by flash column chromatography on silica gel using MeOH (0–20%) in DCM as the eluent. The obtained fraction was repurified by reverse-phase chromatography using acetonitrile and 0.05% aqueous HCl (0–100%) as the eluent. The salt was washed with a basic aqueous phase (NaOH pH ca. 10–14) and extracted with EtOAc. Methyl 8-[4-(1-methylpiperidin-4-yl)benzamido]quinoline-5-carboxylate (75) (27.5 mg, 0.068 mmol, 30%) was obtained as a yellow powder with an HPLC purity of 98%.

[0326] Example 28 4-[2-(dimethylamino)ethoxy]-N-(quinazolin-5-yl)benzamide (83)

[0327] [ka]

[0328] General procedure J was applied to 4-[2-(dimethylamino)ethoxy]benzoyl chloride (0.86 eq., 215 mg, 0.94 mmol) and 5-bromoquinazoline (1 eq., 50.19 mg, 0.24 mmol). The crude product was purified by flash column chromatography on silica gel using MeOH (0-20%) in DCM as the eluent. 4-[2-(dimethylamino)ethoxy]-N-(quinazolin-5-yl)benzamide (83) (63.3 mg, 0.19 mmol, 78%) was obtained as a beige powder with an HPLC purity of 98%.

[0329] Example 29 4-[2-(dimethylamino)ethoxy]-N-(6-methoxyisoquinolin-8-yl)benzamide (87)

[0330] [ka]

[0331] General procedure J was applied to 4-[2-(dimethylamino)ethoxy]benzamide (1.028 eq., 51.4 mg, 0.25 mmol) and 8-bromo-6-methoxyisoquinoline (1.006 eq., 57.5 mg, 0.24 mmol). The crude product was purified by flash column chromatography on silica gel using MeOH (0-20%) in DCM as the eluent. 4-[2-(dimethylamino)ethoxy]-N-(6-methoxyisoquinolin-8-yl)benzamide (87) (17.5 mg, 0.048 mmol, 20%) was obtained as a yellow powder with an HPLC purity of 98%.

[0332] Example 30 2-Methyl-4-(4-methyl-1,4-diazepan-1-yl)-N-(quinolin-5-yl)benzamide (95) Methyl 2-methyl-4-(4-methyl-1,4-diazepan-1-yl)benzoate

[0333] [ka]

[0334] General method C was applied to methyl 4-bromo-2-methylbenzoate (1.053 eq., 315.9 mg, 1.38 mmol) and 1-methyl-1,4-diazepane (1.2 eq., 179.46 mg, 195.49 μL, 1.57 mmol), and the reaction was stirred for 22 h at 120 °C. The residue was purified by flash column chromatography using 10% MeOH in DCM and pure DCM (0-100%) to yield methyl 2-methyl-4-(4-methyl-1,4-diazepan-1-yl)benzoate (250 mg, 0.95 mmol, 69%) as an orange-brown oil. NMR 1H (400 MHz, MeOD): δ 7.82 (d, J = 8.6 Hz, 1H), 6.61 - 6.46 (m, 2H), 3.79 (s, 3H), 3.70 - 3.59 (m, 2H), 3.54 (t, J = 6.3 Hz, 2H), 2.78 - 2.69 (m, 2H), 2.63 - 2.55 (m, 2H), 2.53 (s, 3H), 2.36 (s, 3H), 2.02 (p, J = 6.1 Hz, 2H). NMR 13 C (101 MHz, MeOD): δ 169.60, 153.28, 143.95, 134.18, 116.81, 114.72, 109.52, 58.58, 57.92, 51.57, 48.66, 46.55, 27.94, 23.14 (one peak hidden by solvent)

[0335] Lithio 2-methyl-4-(4-methyl-1,4-diazepan-1-yl)benzoate

[0336] [ka]

[0337] General method F was applied to methyl 2-methyl-4-(4-methyl-1,4-diazepan-1-yl)benzoate (1 eq., 233 mg, 0.89 mmol) and the reaction mixture was stirred at 35° C. for 72 h.

[0338] Lithio 2-methyl-4-(4-methyl-1,4-diazepan-1-yl)benzoate was obtained quantitatively as a beige powder (266.7 mg, 1.049 mmol). NMR 1H (400 MHz, MeOD): δ 7.54 (d, J = 8.3 Hz, 1H), 6.49 (d, J = 8.1 Hz, 2H), 3.62 - 3.56 (m, 2H), 3.50 (t, J = 6.4 Hz, 2H), 2.82 - 2.69 (m, 2H), 2.64 - 2.54 (m, 2H), 2.50 (s, 3H), 2.36 (s, 3H), 2.02 (d, J = 6.3 Hz, 2H). NMR 13 C (101 MHz, MeOD): δ 178.72, 150.87, 139.68, 131.96, 127.93, 114.27, 109.27, 58.83, 57.89, 48.67, 46.53, 28.11, 22.25, (one peak hidden by solvent).

[0339] 2-Methyl-4-(4-methyl-1,4-diazepan-1-yl)-N-(quinolin-5-yl)benzamide (95)

[0340] [ka]

[0341] General method H was applied to lithio 2-methyl-4-(4-methyl-1,4-diazepan-1-yl)benzoate (1.016 eq., 101.6 mg, 0.4 mmol). After 45 min of stirring at 40 °C, the reaction was complete. After evaporation, 2-methyl-4-(4-methyl-1,4-diazepan-1-yl)benzoyl chloride (1 eq., 105 mg, 0.39 mmol) was used together with 5-aminoquinoline (1.022 eq., 58 mg, 0.402 mmol), and the reaction was stirred overnight at room temperature. EDCI (2.092 eq., 127.8 mg, 0.82 mmol) was added, and the reaction mixture was stirred again overnight at 35 °C. The crude product was purified by flash column chromatography using MeOH in DCM as the solvent (0–20%). The expected 2-methyl-4-(4-methyl-1,4-diazepan-1-yl)-N-(quinolin-5-yl)benzamide (95) was obtained as a beige powder (48.9 mg, 0.13 mmol, 33%) with an HPLC purity of 95%.

[0342] Example 31 3-Cyano-4-[(1-methylpyrrolidin-3-yl)methoxy]-N-(quinoxalin-5-yl)benzamide (96) Methyl 3-cyano-4-[(1-methylpyrrolidin-3-yl)methoxy]benzoate

[0343] [ka]

[0344] General method E was applied to methyl 3-cyano-4-hydroxybenzoate (1.1 eq., 338.4 mg, 1.91 mmol) and (1-methylpyrrolidin-3-yl)methanol (1 eq., 200 mg, 1.74 mmol), and the reaction mixture was stirred at room temperature for 16 h. The crude product was then purified by flash column chromatography on silica gel using MeOH in DCM (0-20%) as the eluent. Methyl 3-cyano-4-[(1-methylpyrrolidin-3-yl)methoxy]benzoate (332.9 mg, 1.21 mmol, 70%) was obtained as a pale yellow solid. NMR 1 H (400 MHz, MeOD): δ 8.22 (s, 1H), 8.20 (d, J = 2.0 Hz, 1H), 7.30 - 7.18 (m, 1H), 4.23 - 4.05 (m, 2H), 3.90 (d, J = 1.1 Hz, 3H), 2.92 - 2.85 (m, 1H), 2.84 - 2.75 (m, 1H), 2.68 (td, J = 7.0, 4.2 Hz, 2H), 2.53 (dd, J = 9.7, 6.1 Hz, 1H), 2.41 (s, 3H), 2.14 (ddt, J = 13.5, 9.5, 7.1 Hz, 1H), 1.72 (dq, J = 13.1, 6.4 Hz, 1H). NMR 13 C (101 MHz, MeOD): δ 166.41, 165.12, 137.18, 136.26, 124.41, 116.27, 113.76, 103.02, 73.28, 59.70, 56.73, 52.85, 42.17, 38.45, 28.54.

[0345] Lithio 3-cyano-4-[(1-methylpyrrolidin-3-yl)methoxy]benzoate

[0346] [ka]

[0347] General procedure F was applied to methyl 3-cyano-4-[(1-methylpyrrolidin-3-yl)methoxy]benzoate (1 eq., 332 mg, 1.21 mmol), and after stirring for 16 h, the crude product was triturated with ether. After evaporation, lithio 3-cyano-4-[(1-methylpyrrolidin-3-yl)methoxy]benzoate (316.1 mg, 1.19 mmol, 98%) was obtained as a beige solid. NMR 1 H (400 MHz, MeOD): δ 8.23 ​​- 8.12 (m, 2H), 7.14 (d, J = 8.7 Hz, 1H), 4.11 (qd, J = 9.1, 6.8 Hz, 2H), 2.88 (dd, J = 9.7, 7.9 Hz, 1H), 2.82 - 2.73 (m, 1H), 2.72 - 2.60 (m, 2H), 2.51 (dd, J = 9.7, 6.2 Hz, 1H), 2.40 (s, 3H), 2.13 (ddt, J = 13.7, 9.7, 7.2 Hz, 1H), 1.71 (ddt, J = 13.4, 7.8, 5.7 Hz, 1H). NMR 13 C (101 MHz, MeOD): δ 172.46, 163.34, 137.12, 135.95, 132.41, 117.22, 112.86, 101.80, 72.94, 59.80, 56.73, 42.20, 38.57, 28.60.

[0348] 3-Cyano-4-[(1-methylpyrrolidin-3-yl)methoxy]-N-(quinoxalin-5-yl)benzamide (96)

[0349] [ka]

[0350] General method H was applied to lithio 3-cyano-4-[(1-methylpyrrolidin-3-yl)methoxy]benzoate (1.026 eq., 102.6 mg, 0.39 mmol) and, after heating for 45 min, yielded 3-cyano-4-[(1-methylpyrrolidin-3-yl)methoxy]benzoyl chloride (107.42 mg, 0.39 mmol, 100%) as a white powder. The product was used together with quinoxalin-5-amine (1 eq., 55.93 mg, 0.39 mmol) and stirred at room temperature for 16 h. After stirring, EDCI (2.03 eq., 121.4 mg, 0.78 mmol) and HOBt (1 eq., 52.065 mg, 0.39 mmol) were added and the reaction was stirred at room temperature for 16 h. EDCI (2 eq., 119.63 mg, 0.77 mmol) was added, and the mixture was stirred at room temperature for 5 h. The crude product was purified by flash column chromatography on silica gel using MeOH in DCM as the eluent (0–20%). The fraction was triturated with ether and EtOAc to afford 3-cyano-4-[(1-methylpyrrolidin-3-yl)methoxy]-N-(quinoxalin-5-yl)benzamide (96) as a pale orange powder (29 mg, 0.075 mmol, 20%) with an HPLC purity of 98%.

[0351] Example 32 4-(Piperazin-1-yl)-N-(quinolin-8-yl)benzamide hydrochloride (97) 1-Boc-4-(4-methoxycarbonylphenyl)piperazine

[0352] [ka]

[0353] General method C was applied to methyl 4-bromobenzoate (1.008 eq., 504 mg, 2.34 mmol) and t-butyl 1-piperadianedicarboxylate (1.22 eq., 529.2 mg, 2.84 mmol), and the reaction mixture was stirred for 22 h at 120° C. The crude product was purified by flash column chromatography on silica gel using EtOAc (0–50%) in heptane as the eluent to yield 1-boc-4-(4-methoxycarbonylphenyl)piperazine (709 mg, 2.21 mmol, 94%) as an orange powder. NMR 1 H (400 MHz, CDCl3): δ 7.92 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 3.86 (d, J = 1.0 Hz, 3H), 3.64 - 3.50 (m, 4H), 3.29 (t, J = 5.2 Hz, 4H), 1.48 (d, J = 1.0 Hz, 9H). NMR 13 C (101 MHz, CDCl3): δ 167.15, 154.77, 154.09, 131.37, 120.34, 114.10, 80.23, 51.82, 51.79, 47.67, 28.53.

[0354] tert-Butyl 4-{4-[(lithiooxy)carbonyl]phenyl}piperazine-1-carboxylate

[0355] [ka]

[0356] General method F was applied to 1-boc-4-(4-methoxycarbonylphenyl)piperazine (1 eq., 709 mg, 2.21 mmol). The mixture was stirred at room temperature for 16 h and then at 35 °C for 6 h. The crude product was purified by flash column chromatography using MeOH in DCM (0-10%) as eluent. tert-Butyl 4-{4-[(lithioxy)carbonyl]phenyl}piperazine-1-carboxylate was obtained as a brown / beige powder (443 mg, 1.42 mmol, 64%). NMR 1 H (400 MHz, CDCl3): δ 8.00 (d, J = 8.9 Hz, 2H), 6.87 (d, J = 9.0 Hz, 2H), 3.59 (dd, J = 6.6, 3.9 Hz, 4H), 3.34 (t, J = 5.2 Hz, 4H), 1.49 (s, 9H). NMR 13 C (101 MHz, CDCl3): δ 171.94, 154.82, 154.56, 132.15, 119.27, 113.89, 80.34, 47.48, 43.14 (br), 28.55.

[0357] 4-(Piperazin-1-yl)-N-(quinolin-8-yl)benzamide hydrochloride (97)

[0358] [ka]

[0359] General method H was applied to tert-butyl 4-{4-[(lithioxy)carbonyl]phenyl}piperazine-1-carboxylate (1 eq., 150 mg, 0.48 mmol). The reaction mixture was heated at room temperature for 25 min to quantitatively obtain tert-butyl 4-[4-(carbonochloridoyl)phenyl]piperazine-1-carboxylate (163.5 mg, 0.503 mmol) as a beige powder. It was then used together with 8-aminoquinoline (1 eq., 72.57 mg, 0.503 mmol), and the reaction mixture was stirred at room temperature for 3 h. The crude product was purified by flash column chromatography on silica gel using 0-50% EtOAc in heptane as the eluent. 50 mg of the product was diluted in dioxane (1 mL), 4 M HCl in dioxane (1 eq., 0.029 mL, 0.12 mmol) was added, and the mixture was stirred for 1 h, after which the solvent was evaporated. 4-(piperazin-1-yl)-N-(quinolin-8-yl)benzamide hydrochloride (97) (50 mg, 0.14 mmol) was obtained as a yellow powder in an overall yield of 62%. The HPLC purity was 99%.

[0360] Example 33 4-[(1-methylpiperidin-4-yl)amino]-N-(quinolin-8-yl)-2-(trifluoromethyl)benzamide hydrochloride (98) Methyl 4-[(1-methylpiperidin-4-yl)amino]-2-(trifluoromethyl)benzoate

[0361] [ka]

[0362] General procedure C was applied to methyl 4-bromo-2-(trifluoromethyl)benzoate (1.083 eq., 541.3 mg, 1.91 mmol) and methylpiperidin-4-amine (1.2 eq., 242.06 mg, 266 μL, 2.12 mmol). The crude product was purified by flash column chromatography using a solution of MeOH in DCM (0-20%) to yield methyl 4-[(1-methylpiperidin-4-yl)amino]-2-(trifluoromethyl)benzoate as an orange-brown solid (436.5 mg, 1.38 mmol, 72%). NMR 1 H (400 MHz, MeOD): δ 7.76 (d, J = 8.7 Hz, 1H), 6.97 (d, J = 2.4 Hz, 1H), 6.75 (dd, J = 8.7, 2.4 Hz, 1H), 3.81 (s, 3H), 3.40 (dt, J = 8.9, 4.1 Hz, 1H), 2.86 (d, J = 11.8 Hz, 2H), 2.30 (s, 3H), 2.22 (t, J = 11.6 Hz, 2H), 2.05 - 1.95 (m, 2H), 1.61 - 1.43 (m, 2H). NMR 13 C (101 MHz, MeOD): δ 168.11 (CO), 152.31, 134.93, 132.88 - 130.02 (q, J = 31.95 Hz, C-CF3), 125.04 (d, J = 272.9 Hz, CF3), 116.45, 113.55, 112.28 (d, J = 6.2 Hz), 55.19, 52.42, 52.40, 46.18, 32.30. NMR 19 F (376 MHz, MeOD): δ -61.31.

[0363] Lithio 4-[(1-methylpiperidin-4-yl)amino]-2-(trifluoromethyl)benzoate

[0364] [ka]

[0365] General method F was applied to methyl 4-[(1-methylpiperidin-4-yl)amino]-2-(trifluoromethyl)benzoate (1 eq., 436 mg, 1.38 mmol). After stirring at 35 °C for 5 days, lithio 4-[(1-methylpiperidin-4-yl)amino]-2-(trifluoromethyl)benzoate was obtained quantitatively as a beige powder (460.8 mg, 1.49 mmol). NMR 1 H (400 MHz, MeOD): δ 7.36 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 2.3 Hz, 1H), 6.74 (dd, J = 8.5, 2.4 Hz, 1H), 3.46 - 3.30 (m, 1H), 2.87 (d, J = 11.7 Hz, 2H), 2.31 (s, 3H), 2.24 (t, J = 12.1 Hz, 2H), 2.04 - 1.99 (m, 2H), 1.60 - 1.45 (m, 2H). NMR 13 C (126 MHz, MeOD): δ 176.93, 148.94, 131.06, 129.69 - 129.31 (m), 128.79 (q), 125.80 (q, J = 545.7, 272.6 Hz), 115.64, 110.97 (d, J = 5.5 Hz), 55.26, 46.06, 32.42, 24.20.

[0366] 4-[(1-methylpiperidin-4-yl)amino]-N-(quinolin-8-yl)-2-(trifluoromethyl)benzamide hydrochloride (98) General method H was applied to lithio 4-[(1-methylpiperidin-4-yl)amino]-2-(trifluoromethyl)benzoate (1.008 eq., 100.8 mg, 0.33 mmol), and the mixture was stirred at 40 °C for 50 min. 4-[(1-methylpiperidin-4-yl)amino]-2-(trifluoromethyl)benzoyl chloride was obtained as a beige powder (104 mg). It was then used with 8-quinolinamine (1.074 eq., 50.2 mg, 0.35 mmol), and the reaction was stirred at room temperature for 16 h. The crude product was purified by flash column chromatography on silica gel using MeOH (0-20%) in DCM as the eluent and repurified by reverse-phase chromatography using acetonitrile, ultrapure water, and 0.05% HCl (0-100%) as the eluent. The expected 4-[(1-methylpiperidin-4-yl)amino]-N-(quinolin-8-yl)-2-(trifluoromethyl)benzamide hydrochloride (98) was obtained as a yellow powder (69.9 mg, 0.15 mmol, 46%) with an HPLC purity of 99%.

[0367] Example 34 4-(4-Cyclobutylpiperazin-1-yl)-N-(isoquinolin-5-yl)-2-methoxybenzamide hydrochloride (99) Methyl 4-(4-cyclobutylpiperazin-1-yl)-2-methoxybenzoate

[0368] [ka]

[0369] General method C was applied to methyl 4-bromo-2-methoxybenzoate (1 eq., 300.1 mg, 1.22 mmol) and 1-cyclobutylpiperazine (1.2 eq., 205.99 mg, 0.203 mL, 1.47 mmol), and the mixture was stirred for 22 h at 120° C. The crude product was purified by flash column chromatography using MeOH in DCM (0–10%) to yield methyl 4-(4-cyclobutylpiperazin-1-yl)-2-methoxybenzoate (269.3 mg, 0.88 mmol, 72%) as an orange-brown solid. NMR 1 H (400 MHz, MeOD): δ 7.74 (d, J = 8.8 Hz, 1H), 6.52 (d, J = 8.8 Hz, 1H), 6.50 (d, J = 2.4 Hz, 1H), 3.85 (s, 3H), 3.79 (s, 3H), 3.37 (d, J = 5.4 Hz, 4H), 2.82 (h, J = 7.4 Hz, 1H), 2.49 (t, J = 5.1 Hz, 4H), 2.18 - 2.02 (m, 2H), 2.01 - 1.86 (m, 2H), 1.81 - 1.63 (m, 2H). NMR 13 C (101 MHz, MeOD): δ 168.08, 163.03, 157.15, 134.52, 109.54, 107.27, 98.91, 61.52, 56.09, 51.83, 50.29, 47.86, 27.65, 15.08.

[0370] Lithio 4-(4-cyclobutylpiperazin-1-yl)-2-methoxybenzoate

[0371] [ka]

[0372] General method F was applied to methyl 4-(4-cyclobutylpiperazin-1-yl)-2-methoxybenzoate (1 eq., 269 mg, 0.88 mmol), and the reaction mixture was stirred overnight at 35° C. Lithio 4-(4-cyclobutylpiperazin-1-yl)-2-methoxybenzoate (255.8 mg, 0.86 mmol, 98%) was obtained as a beige solid. NMR 1 H (400 MHz, MeOD): δ 7.50 (d, J = 8.3 Hz, 1H), 6.54 - 6.43 (m, 2H), 3.82 (s, 3H), 3.25 (t, J = 5.1 Hz, 4H), 2.94 - 2.65 (m, 1H), 2.51 (t, J = 5.1 Hz, 4H), 2.25 - 2.05 (m, 2H), 1.95 (ddd, J = 11.3, 9.0, 2.2 Hz, 2H), 1.76 (td, J = 11.1, 10.1, 4.0 Hz, 2H). NMR 13 C (101 MHz, MeOD): δ 176.04, 159.87, 154.65, 132.31, 121.42, 108.12, 100.61, 61.61, 55.96, 50.47, 27.63, 15.10 (+one overlapping MeOD signal).

[0373] 4-(4-Cyclobutylpiperazin-1-yl)-N-(isoquinolin-5-yl)-2-methoxybenzamide hydrochloride (99) General procedure G was applied to lithio 4-(4-cyclobutylpiperazin-1-yl)-2-methoxybenzoate (1.035 eq., 62.1 mg, 0.21 mmol) and 5-aminoisoquinoline (1.13 eq., 33 mg, 0.23 mmol). The reaction mixture was stirred at 35 °C for 3 days. After workup, the crude residue was purified by flash column chromatography using 50-100% EtOAc in heptane as eluent, followed by reverse-phase chromatography using acetonitrile and ultrapure water mixed with 0.05% TFA (0-30%) as eluent. A third purification by flash column chromatography on silica gel using MeOH in EtOAc (0–20%) as eluent gave 4-(4-cyclobutylpiperazin-1-yl)-N-(isoquinolin-5-yl)-2-methoxybenzamide hydrochloride (99) (17 mg, 0.038 mmol, 18%) as a white powder with an HPLC purity of 99%.

[0374] Example 35 N-(isoquinolin-5-yl)-4-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)benzamide (111) Methyl 4-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)benzoate

[0375] [ka]

[0376] General method C was applied to methyl 4-bromo-2-(trifluoromethyl)benzoate (0.19 mL, 1.06 mmol, 1.1 eq.) and 1-methylpiperazine (0.11 mL, 0.96 mmol, 1 eq.), and the reaction was stirred at 120 °C for 22 h. The residue was purified by flash column chromatography on silica gel using MeOH (0-20%) in DCM as the eluent. Methyl 4-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)benzoate was obtained as a yellow oil (277 mg, 0.92 mmol, 95%). NMR 1 H (400 MHz, CDCl3) : δ 7.90 (d, J = 8.8 Hz, 1H,), 7.26 (d, J = 2.6 Hz, 1H,), 7.03 (dd, J = 8.8, 2.6 Hz, 1H, ), 3.95 (s, 3H,), 3.47 - 3.37 (m, 4H), 2.68 - 2.59 (m, 4H), 2.43 (s, 3H,). NMR 13 C (101 MHz, CDCl3): δ 166.5, 152.7, 133.1, 130.9, 130.6, 130.3, 128.6, 127.6, 124.9, 122.1, 118.9, 115.6, 112.7, 112.6, 112.5, 112.4, 54.6, 53.4, 52.2, 47.3, 46.1, 17.8.

[0377] Lithio 4-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)benzoate

[0378] [ka]

[0379] General method F was applied to methyl 4-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)benzoate (277 mg, 0.92 mmol, 1 eq.), and the reaction was stirred at 35 °C for 2 days. The crude product was triturated with EtOAc and evaporated under reduced pressure. Lithio 4-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)benzoate was obtained quantitatively as a yellow powder (300 mg, 1.02 mmol). NMR 1 H (400 MHz, MeOD): δ 7.46 (d, J = 8.5 Hz, 1H, CH Ar ), 7.13 (d, J = 7.3 Hz, 2H, CH Ar), 3.28 (t, J = 5.1 Hz, 4H, 2 x CH2), 2.63 (t, J = 5.1 Hz, 4H, 2 x CH2), 2.37 (s, 3H, NMe). NMR 13 C (101 MHz, MeOD): δ 178.9, 175.0, 168.9, 150.4, 131.6, 129.1, 126.9, 126.7, 125.7, 117.9, 112.0, 54.4, 48.2, 48.0, 47.9, 47.8, 47.6, 47.4, 47.2, 46.9, 44.7, 22.8.

[0380] N-(isoquinolin-5-yl)-4-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)benzamide (111)

[0381] [ka]

[0382] General method H was applied to lithio 4-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)benzoate (100 mg, 0.34 mmol, 1 eq.) and 5-isoquinolinamine (44 mg, 0.31 mmol, 1 eq.). The mixture was stirred at room temperature overnight. The crude product was purified by flash column chromatography on silica gel using MeOH in DCM as the solvent (0-10%). The expected N-(isoquinolin-5-yl)-4-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)benzamide (111) was obtained as a beige powder (21 mg, 0.051 mmol, 16%) with an HPLC purity of 95%.

[0383] Example 36 2-Methanesulfonyl-4-(piperazin-1-yl)-N-(quinolin-5-yl)benzamide hydrochloride (113) tert-Butyl 4-[3-methanesulfonyl-4-(methoxycarbonyl)phenyl]piperazine-1-carboxylate

[0384] [ka]

[0385] General method C was applied to methyl 4-bromo-2-methanesulfonylbenzoate (1.2 eq., 250 mg, 0.85 mmol) and t-butyl 1-piperazinecarboxylate (1 eq., 132.38 mg, 0.71 mmol) with XPhos (0.11 eq., 37.27 mg, 0.078 mmol) in dry toluene (2.36 mL). The mixture was stirred at 100 °C for 10 h overnight. The residue was purified by flash column chromatography using MeOH in DCM (0-20%) as the eluent to yield tert-butyl-4-[3-methanesulfonyl-4-(methoxycarbonyl)phenyl]piperazine-1-carboxylate (282.4 mg, 0.709 mmol, 99%) as a yellow powder. NMR 1 H (500 MHz, MeOD): δ 7.69 (d, J = 8.7 Hz, 1H), 7.57 (d, J = 2.6 Hz, 1H), 7.28 - 7.07 (m, 1H), 3.87 (s, 3H), 3.56 (d, J = 5.8 Hz, 4H), 3.39 (s, 3H), 3.38 - 3.35 (m, 4H), 1.48 (s, 9H). NMR 13 C (126 MHz, MeOD): δ 168.46, 156.25, 153.98, 142.35, 133.43, 121.66, 118.66, 116.49, 81.49, 53.08, 49.54, 48.14, 44.83, 28.66.

[0386] tert-Butyl 4-{4-[(lithiooxy)carbonyl]-3-methanesulfonylphenyl}piperazine-1-carboxylate

[0387] [ka]

[0388] General method F was applied to tert-butyl 4-[3-methanesulfonyl-4-(methoxycarbonyl)phenyl]piperazine-1-carboxylate (1 eq., 282 mg, 0.708 mmol), and the reaction was stirred at 30 °C for 4 days to quantitatively obtain tert-butyl 4-{4-[(lithioxy)carbonyl]3-methanesulfonylphenyl}piperazine-1-carboxylate as a pale yellow powder (293.1 mg, 0.75 mmol). NMR 1 H (500 MHz, MeOD): δ 7.52 (d, J = 8.5 Hz, 1H), 7.49 (d, J = 2.6 Hz, 1H), 7.21 (dd, J = 8.5, 2.7 Hz, 1H), 3.59 (t, J = 5.2 Hz, 4H), 3.41 (s, 3H), 3.26 - 3.19 (m, 4H), 1.49 (s, 9H). NMR 13 C (126 MHz, MeOD): δ 174.09, 154.99, 150.70, 137.59, 132.88, 129.89, 119.71, 114.83, 80.09, 48.85, 48.17, 43.50, 27.28.

[0389] 2-Methanesulfonyl-4-(piperazin-1-yl)-N-(quinolin-5-yl)benzamide hydrochloride (113) General method G was applied to tert-butyl 4-{4-[(lithiooxy)carbonyl]-3-methanesulfonylphenyl}piperazine-1-carboxylate (1.1 eq., 100 mg, 0.26 mmol) and 5-quinolinamine (1 eq., 33.57 mg, 0.23 mmol). The reaction mixture was stirred at 35 °C for 48 h. EDCI (2.49 eq., 89.9 mg, 0.58 mmol) was added, and the reaction mixture was stirred at 35 °C for 48 h. The crude product was purified by flash column chromatography using MeOH (0-25%) in DCM as the eluent. The fraction was diluted with dioxane (1 mL), and HCl (4 M) in dioxane (0.05 mL) was added. The reaction was stirred at room temperature for 1 h. After evaporation, 2-methanesulfonyl-4-(piperazin-1-yl)-N-(quinolin-5-yl)benzamide hydrochloride (44.25 mg, 0.099 mmol, 43%) was obtained as a pale yellow powder with an HPLC purity of 99%.

[0390] Pharmacological data The compounds of the present invention have been subjected to pharmacological testing, and as a result, they have been demonstrated to be of therapeutic value, particularly in the treatment of pain. Because the relationship between the ability to inhibit the binding of FL to FLT3 and the ability to treat pain has been established (WO2016 / 016370), the compounds of the present invention have been evaluated for their ability to inhibit the binding of FL to FLT3 (Example 10).

[0391] Example 37 Binding assay A. Principle Binding of FL to FLT3 was measured by a homogeneous time-resolved fluorescence (HTRF) assay (Degorce et al., Current Chemical Genomics, 2009, 3, 22–32), which uses resonance energy transfer between the donor Lumi4-Tb-donor-derivatized benzylguanine substrate (SNAP-Lumi4-Tb, excitation: 337 nm, emission: 630 nm, Cisbio, France) and the acceptor red-fluorescent FL (FL-d2, excitation: 620 nm, emission: 660 nm, Cisbio, France) transfected into HEK cells. Upon binding of FL-d2 to the SNAP-Lumi4-Tb-tagged FLT3 receptor, the proximity of both fluorophores generates a time-resolved Förster resonance energy transfer (TR-FRET) signal, and binding is measured as the ratio between the fluorescence emissions at 660 nm and 620 nm.

[0392] B. Materials and Methods Detailed methods are described in Rivat et al. (Nature Communications, 2018, Vol. 9:1042). Briefly, HEK293T cells were transfected with the pCDNA3.1 SNAP-FLT3 plasmid using Lipofectamine (Invitrogen) and then labeled with SNAP-Lumi4-Tb. Plates containing attached transfected HEK293T cells were incubated with compounds of formula (I) at room temperature for 1 h. Each compound was diluted 12 times in triplicate, and experiments were performed twice. FL-d2 (0.5 nM) was then added, and the TR-FRET signal was measured after 20 h of incubation at room temperature using an HTRF-compatible reader (Envision, Perkin Elmer). Donor excitation was performed at 337 nm, and signals were collected at both 615 nm and 665 nm (20 flashes, 50 μs delay, 400 μs integration time). The HTRF ratio, calculated by dividing the acceptor signal (665 nm) by the donor signal (615 nm), was then calculated for each concentration of test substance. Nonspecific binding was measured in the presence of 50 μM BDT001 (Rivat et al., ibid.). The concentration giving 50% inhibition (IC 50 ) was calculated using nonlinear regression analysis of a one-site model with varying slope (Prism®, Graphpad software, USA).

[0393] C. Results All tested compounds inhibited FL binding to FLT3, but with varying potency (Table III). Thus, experimental evidence indicates that compounds of formula (I) according to the present invention can be used to treat pain disorders.

[0394] [Table 3A]

[0395] [Table 3B]

[0396]

Table 3C

[0397]

Table 3D

Claims

1. A compound of formula (I) or an acceptable salt thereof (I) 【Chemistry 1】 [In the formula, W, X, Y, and Z each independently represent =CH- or -N=, provided that a maximum of two of W, X, Y, and Z both represent -N= groups; R1 is a linear or cyclic nitrogen-containing (C 4 ~C 8 ) alkyl groups, which may be linear or cyclic containing 4 to 8 carbon atoms, including at least one nitrogen atom interrupting the alkyl chain. 4 ~C 8 ) alkyl groups, which are optionally interrupted by one or two oxygen atoms, (C 1 ~C 4 ) alkyl group or (C 3 ~C 6 ) optionally substituted by a cycloalkyl group, R1 containing at least one primary, secondary or tertiary amine, in particular one or two secondary or tertiary amines, R2 is a hydrogen atom, a halogen atom, or (C 1 ~C 4 ) alkyl group, (C 1 ~C 4 ) alkoxy group, (C 1 ~C 4 ) fluoroalkyl group, -CO-(C 1 ~C 4 ) alkyl group, -CONH 2 Group, SO 2 -NH 2 group or a cyano group, R3 is a hydrogen atom, a halogen atom, or (C 1 ~C 4 ) alkyl group, (C1-C4) alkoxy group, (C1-C4) fluoroalkyl group, cyano group, (C1-C4) alkylsulfonyl group or SO 2 -NH 2 represents a group, R4, R5 and R6 are independently a hydrogen atom, a halogen atom, a -COOH group, a -COO(C 1 ~C 4 ) alkyl group, (C 1 ~C 4 ) fluoroalkyl group, (C 1 ~C 4 ) alkylsulfonyl group or (C 1 ~C 4 ) represents an alkoxy group.

2. 2. A compound of formula (I) according to claim 1, wherein W is -N= and X, Y and Z are =CH-, or Y is -N= and W, X and Z are =CH-, or X is -N= and W, Y and Z are =CH-, or Z is -N= and W, X and Y are =CH-, or W and Z are -N= and X and Y are =CH-, or X and Y are -N= and W and Z are =CH-.

3. R1, 【Chemistry 2】 Selected from, in detail, 【Transformation 3】 and more particularly selected from 【Chemistry 4】 3. A compound of formula (I) according to claim 1 or 2, selected from:

5. R2 is a hydrogen atom, a halogen atom, or (C 1 ~C 4 ) alkyl group, (C 1 ~C 4 ) alkoxy group, (C 1 ~C 4 4. Compounds of formula (I) according to any one of claims 1 to 3, wherein R represents a fluoroalkyl group or a cyano group, in particular a hydrogen atom, a fluorine atom, a methyl group, a methoxy group, a trifluoromethyl group or a cyano group.

6. R3 is a hydrogen atom, a halogen atom, or (C 1 ~C 4 ) alkyl group, (C 1 ~C 4 ) alkoxy group, (C 1 ~C 4 ) fluoroalkyl group or (C 1 ~C 4 5. Compounds of formula (I) according to any one of claims 1 to 4, wherein R represents an alkylsulfonyl group, in particular a hydrogen atom, a fluorine atom or a chlorine atom, a methyl group, a methoxy group, a trifluoromethyl group or a methylsulfonyl group.

7. R4, R5 and R6 are independently a hydrogen atom, a halogen atom, (C 1 ~C 4 ) fluoroalkyl group, -COO(C 1 ~C 4 ) alkyl group, (C 1 ~C 4 ) alkylsulfonyl group or (C 1 ~C 4 6. Compounds of formula (I) according to any one of claims 1 to 5, wherein 1) represents an alkoxy group, in particular a hydrogen atom, a fluorine atom or a chlorine atom, a trifluoromethyl group, a methyloxycarbonyl group or a methoxy group.

8. R2 is a hydrogen atom, a halogen atom, or (C 1 ~C 4 ) alkyl group, (C 1 ~C 4 ) alkoxy group, (C 1 ~C 4 ) fluoroalkyl group, -CO-(C 1 ~C 4 ) alkyl group or cyano group, and specifically, a hydrogen atom, a halogen atom, (C 1 ~C 4 ) alkyl group, (C 1 ~C 4 ) alkoxy group, (C 1 ~C 4 ) represents a fluoroalkyl group or a cyano group, more specifically a hydrogen atom, a fluorine atom, a methyl group, a methoxy group, a cyano group, or a trifluoromethyl group; R3 is a hydrogen atom, a halogen atom, or (C 1 ~C 4 ) alkyl group, (C 1 ~C 4 ) alkoxy group, (C 1 ~C 4 ) a fluoroalkyl group, a cyano group, or (C 1 ~C 4 ) alkylsulfonyl group, specifically a hydrogen atom, a halogen atom, (C 1 ~C 4 ) alkyl group, (C 1 ~C 4 ) alkoxy group, (C 1 ~C 4 ) fluoroalkyl group or (C 1 ~C 4 ) an alkylsulfonyl group, more specifically a hydrogen atom, a chlorine atom, a fluorine atom, a methyl group, a methoxy group, a trifluoromethyl group, or a methylsulfonyl group; R4, R5 and R6 are independently a hydrogen atom, a halogen atom, (C 1 ~C 4 ) Fluoroalkyl group, -COOH group, -COO(C 1 ~C 4 ) alkyl group, (C 1 ~C 4 ) alkylsulfonyl group or (C 1 ~C 4 ) alkoxy group, specifically a hydrogen atom, a halogen atom, (C 1 ~C 4 ) fluoroalkyl group or (C 1 ~C 4 4. Compounds of formula (I) according to claim 1, wherein R represents an alkoxy group, more particularly a hydrogen atom, a chlorine atom or a fluorine atom, a trifluoromethyl group, a methyloxycarbonyl group or a methoxy group.

9. The compound is the following compound: (1) N-(5-fluoroquinolin-8-yl)-4-(1-methylpiperidin-4-yl)benzamide, (2) N-(8-fluoroisoquinolin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide, (3) N-(5-fluoroisoquinolin-8-yl)-4-(1-methylpiperidin-4-yl)benzamide, (4) N-(8-fluoroquinolin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide, (5) N-(8-fluoroquinoxalin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide, (6) 4-(1-methylpiperidin-4-yl)-N-(quinolin-5-yl)benzamide, (7) N-(isoquinolin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide, (8) N-(isoquinolin-8-yl)-4-(1-methylpiperidin-4-yl)benzamide, (9) 4-(1-methylpiperidin-4-yl)-N-(quinolin-8-yl)benzamide, (10) 4-[2-(dimethylamino)ethoxy]-N-(isoquinolin-8-yl)benzamide, (11) 4-[2-(dimethylamino)ethoxy]-N-(quinolin-8-yl)benzamide, (12) 2-fluoro-4-(1-methylpiperidin-4-yl)-N-(quinolin-8-yl)benzamide, (13) 3-fluoro-N-(isoquinolin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide, (14) 4-(2-(dimethylamino)ethoxy)-N-(isoquinolin-5-yl)benzamide, (15) 4-(2-(dimethylamino)ethoxy)-N-(quinolin-5-yl)benzamide, (16) 2-methoxy-4-(1-methylpiperidin-4-yl)-N-(quinolin-8-yl)benzamide, (17) N-(isoquinolin-5-yl)-3-methoxy-4-(1-methylpiperidin-4-yl)benzamide, (18) 4-(1-methylpiperidin-4-yl)-N-(quinolin-8-yl)-2-(trifluoromethyl)benzamide, (19) 4-[2-(dimethylamino)ethoxy]-N-(phthalazin-5-yl)benzamide, (20) 4-(2-(dimethylamino)ethoxy)-N-(8-fluoroquinolin-5-yl)benzamide, (21) 3-cyano-N-(isoquinolin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide, (22) 4-(2-(dimethylamino)ethoxy)-N-(5-fluoroisoquinolin-8-yl)benzamide, (23) 4-(2-(dimethylamino)ethoxy)-N-(8-fluoroquinoxalin-5-yl)benzamide, (24) 3-fluoro-N-(isoquinolin-5-yl)-4-(4-methylpiperazin-1-yl)benzamide, (25) N-(isoquinolin-5-yl)-2-methanesulfonyl-4-(1-methylpiperidin-4-yl)benzamide, (26) 4-[2-(dimethylamino)ethoxy]-N-(5-fluoroquinolin-8-yl)benzamide, (27) 4-(1-methylpiperidin-4-yl)-N-(quinolin-5-yl)-3-(trifluoromethyl)benzamide, (28) 4-(1-methylpiperidin-4-yl)-N-(quinoxalin-5-yl)benzamide, (29) 3-methyl-4-(4-methylpiperazin-1-yl)-N-(quinolin-5-yl)benzamide, (30) N-(8-chloroquinolin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide, (31) 4-[2-(dimethylamino)ethoxy]-N-(quinoxalin-5-yl)benzamide, (32) N-(8-chloroquinolin-5-yl)-4-[2-(dimethylamino)ethoxy]benzamide, (33) 4-[2-(dimethylamino)ethoxy]-N-(8-fluoroisoquinolin-5-yl)benzamide, (34) 4-[2-(dimethylamino)ethoxy]-N-(7-methoxyisoquinolin-5-yl)benzamide, (35) 4-(4-methylpiperazin-1-yl)-N-(quinolin-8-yl)benzamide, (36) 3-cyano-4-(2-(dimethylamino)ethoxy)-N-(isoquinolin-8-yl)benzamide, (37) N-(8-fluoroquinoxalin-5-yl)-4-(4-methylpiperazin-1-yl)benzamide, (38) N-(isoquinolin-8-yl)-4-(4-methylpiperazin-1-yl)benzamide, (39) N-(isoquinolin-5-yl)-4-(4-methylpiperazin-1-yl)benzamide, (40) 4-(4-methylpiperazin-1-yl)-N-(quinolin-5-yl)benzamide, (41) 4-(4-methylpiperazin-1-yl)-N-(quinoxalin-5-yl)benzamide, (42) N-(5-fluoroquinolin-8-yl)-4-(4-methylpiperazin-1-yl)benzamide, (43) 4-(2-(dimethylamino)ethoxy)-3-methyl-N-(quinolin-8-yl)benzamide, (44) N-(8-fluoroquinolin-5-yl)-4-(4-methylpiperazin-1-yl)benzamide, (45) N-(isoquinolin-5-yl)-2-methyl-4-(4-methylpiperazin-1-yl)benzamide, (46) N-(8-chloroquinolin-5-yl)-4-(4-methylpiperazin-1-yl)benzamide, (47) 4-(2-(dimethylamino)ethoxy)-2-methyl-N-(quinolin-5-yl)benzamide, (48) 4-(2-(dimethylamino)ethoxy)-N-(isoquinolin-5-yl)-3-(trifluoromethyl)benzamide, (49) 4-(2-(dimethylamino)ethoxy)-N-(quinolin-5-yl)-2-(trifluoromethyl)benzamide, (50) 3-methoxy-4-(4-methylpiperazin-1-yl)-N-(quinolin-5-yl)benzamide, (51) N-(8-chloroisoquinolin-5-yl)-4-(4-methylpiperazin-1-yl)benzamide hydrochloride, (52) 4-(4-methylpiperazin-1-yl)-N-[5-(trifluoromethyl)isoquinolin-8-yl]benzamide hydrochloride, (53) 3-fluoro-N-(5-fluoroisoquinolin-8-yl)-4-{5-methyl-octahydropyrrolo[3,4-c]pyrrol-2-yl}benzamide, (54) N-(8-methoxyisoquinolin-5-yl)-3-methyl-4-{7-methyl-2,7-diazaspiro[3.5]nonan-2-yl}benzamide, and (55) 3-methyl-4-[(1-methylpyrrolidin-3-yl)methoxy]-N-(quinolin-8-yl)benzamide, (56) 2-fluoro-4-(4-methylpiperazin-1-yl)-N-(quinolin-5-yl)benzamide, (57) 2-fluoro-N-(isoquinolin-8-yl)-4-[4-(propan-2-yl)piperazin-1-yl]benzamide, (58) N-(5-fluoroisoquinolin-8-yl)-3-methoxy-4-[(1R,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]benzamide, - (59 4-(4-cyclobutylpiperazin-1-yl)-N-(quinolin-5-yl)benzamide, (60) N-(7-methoxyisoquinolin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide, (61) N-(5-chloroisoquinolin-8-yl)-4-(1-methylpiperidin-4-yl)benzamide hydrochloride, (62) N-(6-chloroisoquinolin-8-yl)-4-(1-methylpiperidin-4-yl)benzamide, (63) N-(6-methoxyisoquinolin-8-yl)-4-(1-methylpiperidin-4-yl)benzamide, (64) N-(8-chloroisoquinolin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide, (65) N-(8-methoxyisoquinolin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide, (66) 4-(1-methylpiperidin-4-yl)-N-[5-(trifluoromethyl)isoquinolin-8-yl]benzamide, (67) 4-(1-methylpiperidin-4-yl)-N-(quinazolin-8-yl)benzamide, (68) 4-(4-methylpiperazin-1-yl)-N-(quinazolin-8-yl)benzamide, (69) N-(5-fluoroisoquinolin-8-yl)-4-(4-methyl-1,4-diazepan-1-yl)benzamide hydrochloride, (70) N-(8-methoxyisoquinolin-5-yl)-4-(4-methylpiperazin-1-yl)benzamide hydrochloride, (71) N-(6-methoxyisoquinolin-8-yl)-4-(4-methylpiperazin-1-yl)benzamide, (72) 4-(1-methylpiperidin-4-yl)-N-(quinazolin-5-yl)benzamide, (73) N-(6-chloroisoquinolin-8-yl)-4-(4-methylpiperazin-1-yl)benzamide, (74) N-(8-chloroisoquinolin-5-yl)-3-methoxy-4-[(1-methylpiperidin-4-yl)amino]benzamide, (75) methyl 8-[4-(1-methylpiperidin-4-yl)benzamido]quinoline-5-carboxylate, (76) N-(5-fluoroisoquinolin-8-yl)-4-(4-methylpiperazin-1-yl)benzamide, (77) N-(5-chloroisoquinolin-8-yl)-4-(4-methylpiperazin-1-yl)benzamide, (78) 4-(1-methylpiperidin-4-yl)-N-(phthalazin-5-yl)benzamide, (79) N-(8-fluoroisoquinolin-5-yl)-4-(4-methylpiperazin-1-yl)benzamide, (80) 4-(4-methylpiperazin-1-yl)-N-(quinazolin-5-yl)benzamide, (81) 4-(4-methylpiperazin-1-yl)-N-(phthalazin-5-yl)benzamide, (82) N-(7-methoxyisoquinolin-5-yl)-4-(4-methylpiperazin-1-yl)benzamide hydrochloride, (83) 4-[2-(dimethylamino)ethoxy]-N-(quinazolin-5-yl)benzamide, (84) methyl 8-[4-(4-methylpiperazin-1-yl)benzamido]quinoline-5-carboxylate hydrochloride, (85) 4-[2-(dimethylamino)ethoxy]-N-(quinazolin-8-yl)benzamide, (86) N-(6-chloroisoquinolin-8-yl)-4-(2-(dimethylamino)ethoxy)benzamide, (87) 4-[2-(dimethylamino)ethoxy]-N-(6-methoxyisoquinolin-8-yl)benzamide, (88) N-(5-chloroisoquinolin-8-yl)-4-[2-(dimethylamino)ethoxy]benzamide, (89) 4-(2-(dimethylamino)ethoxy)-N-(7-methoxyisoquinolin-5-yl)benzamide hydrochloride, (90) 4-[2-(dimethylamino)ethoxy]-N-[5-(trifluoromethyl)isoquinolin-8-yl]benzamide hydrochloride, (91) methyl 8-{4-[2-(dimethylamino)ethoxy]benzamido}quinoline-5-carboxylate hydrochloride, (92) N-(8-chloroisoquinolin-5-yl)-4-[2-(dimethylamino)ethoxy]benzamide hydrochloride, (93) N-(isoquinolin-5-yl)-3-methyl-4-(1-methylpiperidin-4-yl)benzamide hydrochloride, (94) 2-methyl-4-(1-methylpiperidin-4-yl)-N-(quinolin-8-yl)benzamide hydrochloride, (95) 2-methyl-4-(4-methyl-1,4-diazepan-1-yl)-N-(quinolin-5-yl)benzamide, (96) 3-cyano-4-[(1-methylpyrrolidin-3-yl)methoxy]-N-(quinoxalin-5-yl)benzamide, (97) 4-(piperazin-1-yl)-N-(quinolin-8-yl)benzamide hydrochloride, (98) 4-[(1-methylpiperidin-4-yl)amino]-N-(quinolin-8-yl)-2-(trifluoromethyl)benzamide hydrochloride, (99) 4-(4-cyclobutylpiperazin-1-yl)-N-(isoquinolin-5-yl)-2-methoxybenzamide hydrochloride, (100) N-(isoquinolin-8-yl)-4-[4-(propan-2-yl)piperazin-1-yl]benzamide hydrochloride, (101) 2-fluoro-4-[(1R,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]-N-(quinolin-8-yl)benzamide, (102) 4-[4-(propan-2-yl)piperazin-1-yl]-2-(trifluoromethyl)-N-[5-(trifluoromethyl)isoquinolin-8-yl]benzamide, (103) 4-[2-(dimethylamino)ethoxy]-3-fluoro-N-(quinolin-5-yl)benzamide, (104) N-(8-fluoroquinolin-5-yl)-2-methoxy-4-{7-methyl-2,7-diazaspiro[3.5]nonan-2-yl}benzamide hydrochloride (105) 3-fluoro-N-(8-methoxyisoquinolin-5-yl)-4-(4-methyl-1,4-diazepan-1-yl)benzamide, (106) 4-[2-(dimethylamino)ethoxy]-2-fluoro-N-(quinolin-8-yl)benzamide, (107) 4-[2-(dimethylamino)ethoxy]-2-methoxy-N-(quinolin-5-yl)benzamide, (108) N-(8-fluoroquinolin-5-yl)-2-methanesulfonyl-4-{5-methyl-octahydropyrrolo[3,4-c]pyrrol-2-yl}benzamide, (109) N-(8-chloroisoquinolin-5-yl)-4-(4-cyclobutylpiperazin-1-yl)-3-fluorobenzamide hydrochloride (110) 4-[2-(dimethylamino)ethoxy]-3-methoxy-N-(quinolin-8-yl)benzamide, (111) N-(isoquinolin-5-yl)-4-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)benzamide, (112) N-(8-chloroquinolin-5-yl)-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)benzamide, (113) 2-methanesulfonyl-4-(piperazin-1-yl)-N-(quinolin-5-yl)benzamide hydrochloride, (114) N-(isoquinolin-5-yl)-4-[(1-methylpiperidin-4-yl)amino]-3-(trifluoromethyl)benzamide, (115) 4-(4-methylpiperazin-1-yl)-2-(methylsulfonyl)-N-(quinolin-5-yl)benzamide, (116) 4-(4-methylpiperazin-1-yl)-N-(quinolin-8-yl)-3-(trifluoromethyl)benzamide, (117) N-(8-chloroisoquinolin-5-yl)-3-cyano-4-(4-cyclobutylpiperazin-1-yl)benzamide, and - (118) 3-cyano-4-(4-methylpiperazin-1-yl)-N-(quinolin-5-yl)benzamide 8. A compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, in particular its hydrochloride, characterized in that it is selected from:

10. 10. A synthetic process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, comprising at least the following steps: - Formula (II): 【Transformation 5】 wherein R4, R5, R6, W, X, Y and Z are as defined in any one of claims 1 to 7. The compound Formula (VII): 【Transformation 6】 wherein R1, R2, and R3 are as defined in any one of claims 1 to 7, and M represents an alkali metal or hydrogen. and a compound of (i) by peptide synthesis using a carboxyl activating agent, specifically N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDCI) or N,N'-diisopropylcarbodiimide (DIC), together with a racemization inhibitor, specifically 1-hydroxybenzotriazole (HOBt) or ethyl cyanohydroxyiminoacetate, and together with an organic base in an aprotic polar solvent; or (ii) First, a compound of formula (VII) is reacted with a chlorinating agent, specifically SOCl 2 , optionally in the presence of an organic base in an aprotic solvent to form the corresponding acyl chloride derivative, which is then reacted with the compound of formula (II) by nucleophilic substitution using an organic base in an aprotic solvent to obtain the compound of formula (I). A synthesis process comprising:

11. A synthetic process for producing any one of the compounds of formula (I) as defined in any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, comprising at least the following steps: Formula (VIII) 【Transformation 7】 wherein R2 and R3 are as defined in claim 1. The compound Formula (IX) 【Transformation 8】 wherein R4, R5, R6, W, X, Y and Z are as defined in claim 1. via a first reaction with ammonia to convert the acyl chloride to a carboxamide, and a second reaction by palladium-catalyzed Buchwald cross-coupling. A synthesis process comprising:

12. A pharmaceutical composition comprising at least one compound as defined in any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

13. A pharmaceutical composition comprising at least one compound defined in any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, an opioid, and at least one pharmaceutically acceptable excipient, wherein the opioid is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dextropropoxyphene, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl buturate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone hydroxypetideine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretam, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propeptadine, promedol, properidine, propiram, propoxyphene, remifentanil, sufentonil, tapentadol, tilidine and tramadol, and in particular may be selected from fentanyl, morphine, remifentanil and tramadol.

14. 13. A compound according to any one of claims 1 to 8, alone or in combination with an opioid, in particular in combination with an opioid as defined in claim 12, for use as a medicine.

15. 13. A compound according to any one of claims 1 to 8, alone or in combination with an opioid, in particular in combination with an opioid as defined in claim 12, for use in the prevention and / or treatment of pain.

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