Novel n-heteroarylbenzamide derivative as flt3 inhibitors

Abstract

The present invention relates to a compound of formula (I) or any acceptable salt thereof (I) wherein W, X, Y and Z each independently represent = CH-or-N =, with the proviso that up to two of W, X, Y and Z represent-N = groups, R1 represents a linear or cyclic nitrogen-containing (C4-C8) alkyl group, said groups being a non-aromatic (C4-C8) alkyl group, which may be linear or cyclic, comprising 4 to 8 carbon atoms, 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, and 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 invention further relates to a pharmaceutical composition comprising the same and to the use thereof in the prevention and / or treatment of pain. # imgabs0 #

Description

Technical Field

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

[0002] Current treatments for chronic pain (duration > 3 months), particularly neuropathic pain, are largely symptomatic and unsatisfactory for most patients. In fact, many painkillers available on the pharmaceutical market, most of which were initially marketed for other indications such as epilepsy and depression. However, these drugs are only partially effective against neuropathic pain: only a limited number of patients achieve a 50% reduction in their pain symptoms, and unfortunately, some neuropathic pain syndromes have been observed to be completely intractable to these drugs, thus significantly affecting the quality of life of these patients. In addition, existing drugs often produce a variety of adverse reactions that limit their use in patients: they can cause dizziness, drowsiness, fatigue, constipation, dry mouth, nausea, vomiting, and weight gain.

[0003] Perioperative and postoperative pain is another pain condition that is not satisfactorily treated. Postoperative pain is mainly treated with opioids such as morphine, which remains the best treatment for acute pain. However, their use for chronic pain is severely limited by undesirable side effects such as constipation, nausea, vomiting, sedation, and respiratory depression, and there is also a risk of abuse, addiction, and a large number of opioid-related deaths. Most importantly, the sub-chronic or chronic administration of opioids can also produce tolerance to their analgesic effects, which requires an increase in the opioid dose and exacerbates the above side effects and pain hypersensitivity reactions known as opioid-induced hyperalgesia (OIH) and potential pain sensitization, which cannot be overcome by increasing the opioid dose and prevents patients from adequately treating their pain, thus significantly reducing their quality of life.

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

[0005] One of the new strategies for combating pain lies in inhibiting FLT3 (Rivat et al., Nat. Commun., 2018, 9, 1042).

[0006] In fact, WO2011 / 083124 discloses the use of FLT3 receptor antagonists for the treatment of pain conditions. FLT3 (fms-related tyrosine kinase 3) is a member of the class III receptor tyrosine kinase (RTK) family, which contains an extracellular domain (ECD) that interacts with its ligand FL and an intracellular domain that contains a kinase domain responsible for autophosphorylation. Upon activation, FLT3 dimerizes and autophosphorylates tyrosine residues present in its intracellular domain. According to WO2011 / 083124, FLT3 receptor antagonists include various types of molecules that inhibit FLT3 activation, such as small organic molecules that act on intracellular or extracellular FLT3 sites, antibodies against FLT3 or its ligand FL, or inhibitors of FLT3 expression. WO2011 / 083124 lists a large number of pain conditions, including acute pain, chronic pain, neuropathic pain, inflammatory pain, low back pain, postoperative pain, cancer pain, vascular headache (such as migraine), fibromyalgia, hyperalgesia (such as mechanical and thermal hyperalgesia), allodynia (such as thermal and mechanical allodynia), peripheral sensitization of pain mechanisms, and central sensitization of pain mechanisms.

[0007] Recently, WO2016 / 016370 describes some FLT3 receptor antagonists that inhibit the interaction between FLT3 and FL. According to WO2016 / 016370, antagonists that inhibit the interaction between FLT3 and FL can be used to treat a variety of pain conditions, including acute pain, chronic pain, neuropathic pain, inflammatory pain, iatrogenic pain including cancer pain, infectious pain including herpes pain, visceral pain, central pain, dysfunctional pain including fibromyalgia, nociceptive pain including postoperative pain, and mixed pain types including the viscera, gastrointestinal tract, cranial structures, musculoskeletal system, spine, urogenital system, cardiovascular system, and CNS, including cancer pain, back, and orofacial pain.

[0008] Recently, WO2018 / 211018 describes the combined use of FLT3 antagonists with opioids. Such combinations enhance the analgesic effect of opioids, reduce tolerance to the analgesic effect of opioids, and inhibit opioid-induced hyperalgesia. Therefore, FLT3 antagonists can be used to improve the analgesic effect of pain conditions that require treatment with opioids, such as inflammatory pain and postoperative pain. Summary of the Invention

[0009] It has now been found that the compounds defined by the following formula (I) can be used for the prevention and / or treatment of pain conditions or disorders.

[0010] Accordingly, the present invention provides a compound of formula (I) as defined below, or any acceptable salt thereof, a process for its preparation, or a pharmaceutical composition comprising a compound of formula (I) as defined below, either alone or in combination with an opioid. The opioid may be selected from alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dextropropoxyphene, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetylbuturate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine,Norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, remifentanyl, sufentonil, tapentadol, tilidine and tramadol, especially selected from fentanyl, morphine, remifentanyl and tramadol, in particular fentanyl, morphine, remifentanyl and tramadol.

[0011] Accordingly, the present invention relates to a compound of formula (I) as defined below or any acceptable salt thereof, alone or in combination with an opioid as defined above, for the prevention and / or treatment of pain.

[0012] In particular, the prevention and / or treatment of pain extends to the conditions associated therewith.

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

[0014] The present invention also relates to a method for the prevention and / or treatment of pain, which method comprises the step of administering to a patient in need thereof a compound of formula (I) as defined below or any acceptable salt thereof or a pharmaceutical composition comprising the same, alone or in combination with an opioid as defined above.

[0015] Definition

[0016] As used herein, the term "patient" refers to an animal suffering from or likely to suffer from one or more diseases and conditions described herein, such as a valuable animal for breeding, companionship or preservation purposes, or preferably a human or a human child.

[0017] In particular, as used in the present application, the term "patient" refers to a mammal, such as a rodent, cat, dog, primate or human, preferably the patient is a human.

[0018] The identification of those patients in need of treatment for the diseases and conditions described herein is well within the capabilities and knowledge of those skilled in the art. A skilled veterinarian or physician in the art can readily identify those patients in need of such treatment by using clinical tests, physical examinations, medical / family histories or biological and diagnostic tests.

[0019] In the context of the present invention, the term "treatment" as used herein refers to reversing, alleviating, inhibiting the development of a pain condition as described herein or preventing a pain condition as described herein (particularly in the "pain condition" paragraph).

[0020] As used herein, "effective amount" refers to the amount of a compound of the present invention that is effective in preventing, alleviating, eliminating, treating or controlling pain. The term "control" is intended to refer to all processes in which the development of pain can be slowed, interrupted, blocked or stopped, but not necessarily to indicate complete elimination of all manifestations of pain.

[0021] As used herein, "prevention" also includes "reducing the likelihood of occurrence" or "reducing the likelihood of recurrence".

[0022] The term "preventive effective amount" refers to the concentration of a compound of the present invention that is effective in inhibiting, preventing, reducing the likelihood of a pain condition.

[0023] Similarly, the term "therapeutically effective amount" refers to the concentration of a compound that is effective in treating a pain condition as described herein.

[0024] The term "prevention" as used herein refers to reducing the risk of occurrence of a given phenomenon (i.e., in the present invention, a pain condition as described herein) or slowing its occurrence.

[0025] As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, excipients, compositions or dosage forms that, within the scope of reasonable medical judgment, are suitable for contact with the tissues of humans and animals without excessive toxicity, irritation, allergic reaction or other problem complications and that meet a reasonable benefit / risk ratio.

[0026] As used herein, the terms "FLT3" or "FLT3 receptor" (Fms-related tyrosine kinase 3), also known as CD135, Ly72, Flk-2, Flt-3 or B230315G04, are used interchangeably and have their general meaning in the art. The FLT3 receptor can be from any animal species, but is typically a mammalian (e.g., human and non-human primate) FLT3 receptor, particularly a human FLT3 receptor. The naturally occurring human Flt3 gene has the nucleotide sequence shown in Genbank accession number NM_004119.2, and the naturally occurring human FLT3 protein has the amino acid sequence shown in Genbank accession number NP_004110.2. Mouse nucleotide and amino acid sequences (Genbank accession numbers NM_010229.2 and NP_034359.2) are also described.

[0027] As used herein, the terms "FL" or "FLT3-ligand" are used interchangeably and have their general meaning in the art. They refer to cytokines that are the natural ligands of the FLT3 receptor. FL can be from any source, but is typically a mammalian (e.g., human and non-human primate) FL, particularly a human FL.

[0028] The term "FLT3 inhibitor" refers to any compound that inhibits or downregulates the biological activity in a subject related to the activation of the FLT3 receptor by FL (which includes any downstream biological effects resulting from the binding of FL to the FLT3 receptor). Such an FLT3 inhibitor can act by occupying the FL binding site or a part thereof, or a nearby cavity (allosteric site), such that the FLT3 receptor cannot access its natural ligand FL, in order to prevent or reduce its normal biological activity. The term FLT3 receptor inhibitor also includes any reagent that can interact with the natural ligand FL of FLT3.

[0029] The compound of formula (I) according to the present invention is an FLT3 inhibitor, and more specifically an inhibitor of the interaction between FLT3 and FL. The compounds that inhibit the interaction between FLT3 and FL include those that bind to the FLT3 receptor, FL, or both, provided that the binding of the target compound prevents the interaction between the FLT3 receptor and FL.

[0030] As used herein, the term "analgesic effect" refers to the clinical effect produced by using a substance that produces an analgesic action. The term "analgesia" refers to the loss of sensitivity to pain, but not the loss of consciousness.

[0031] Unless otherwise specified, the terms "between... and..." and "in the range from... to..." should be understood to include the limiting values. Detailed Description

[0032] The present inventors have specifically found that the compounds of formula (I) have inhibitory activity against FLT3.

[0033] The present invention provides a compound of formula (I) or any acceptable salt thereof (I)

[0034]

[0035] wherein

[0036] W, X, Y and Z each independently represent =CH- or -N=, provided that at most two of W, X, Y and Z represent -N= groups,

[0037] R1 represents a straight-chain or cyclic nitrogen-containing (C4-C8) alkyl group, said group being a non-aromatic (C4-C8) alkyl group, which may be straight-chain or cyclic, containing 4-8 carbon atoms, containing at least one nitrogen atom interrupting the alkyl chain, said group being optionally interrupted by one or two oxygen atoms and optionally substituted by (C1-C4) alkyl or (C3-C6) cycloalkyl, wherein R1 contains at least one primary, secondary or tertiary amine, especially one or two secondary amines 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,

[0038] R3 represents a hydrogen atom, a halogen atom, a (C1-C4) alkyl group, a (C1-C4) alkoxy group, a (C 1- C4) fluoroalkyl group, a cyano group, a (C1-C4) alkylsulfonyl group or a SO2-NH2 group, and

[0039] R4, R5 and R6 independently represent a hydrogen atom, a halogen atom, a -COOH group, a -COO(C1-C4) alkyl group, a (C 1- C4) fluoroalkyl group, a (C1-C4) alkylsulfonyl group or a (C1-C4) alkoxy group.

[0040] The present invention further provides a pharmaceutical composition comprising at least one novel compound as defined above or any pharmaceutically acceptable salt thereof, or at least any one of compounds (1) to (118) as defined above or any pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0041] The present invention further provides a pharmaceutical composition, which comprises at least one novel compound as defined above or any pharmaceutically acceptable salt thereof, or at least any one of compounds (1) to (118) as defined above or any pharmaceutically acceptable salt thereof, an opioid, and at least one pharmaceutically acceptable excipient, wherein the opioid is selected from alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dextropropoxyphene, dezocine, deprenylamine, dienomorphine, dihydrocodeine, dihydromorphine, dimepheptanol, dimexfadol, dimethylthiambutene, maphenthylbutyrate, dipipanone, etazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, papaverine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpethidine, opium, oxycodone, oxymorphone, opium alkaloids, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, dimethylpethidine, properidine, propiram, propoxyphene, remifentanil, sufentanil, tapentadol, tilidine, and tramadol, particularly selected from fentanyl, morphine, remifentanil, and tramadol, especially fentanyl, morphine, remifentanil, and tramadol.

[0042] The present invention further provides a compound of formula (I) as defined above or any pharmaceutically acceptable salt thereof, alone or in combination with an opioid, particularly an opioid as defined above, and any one of compounds (1) to (118) as defined below or any pharmaceutically acceptable salt thereof, for use as a medicament.

[0043] The present invention further provides a compound of formula (I) as defined above or any pharmaceutically acceptable salt thereof, alone or in combination with an opioid, particularly an opioid as defined above, and any one of compounds (1) to (118) as defined below or any pharmaceutically acceptable salt thereof, for the prevention and / or treatment of pain.

[0044] The compounds of the present invention may exist in the form of a free base or an addition salt formed with a pharmaceutically acceptable acid.

[0045] As used herein, the term "pharmaceutically acceptable salt" refers to those salts that, within the scope of reasonable medical judgment, are suitable for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and having a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. described pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 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 amino salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or amino salts formed with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or amino salts formed by using other methods such as ion exchange used in the art. Other pharmaceutically acceptable salts include benzenesulfonates, ethanesulfonates, fumarates, methanesulfonates, p-toluenesulfonates, etc.

[0046] Suitable physiologically acceptable acid addition salts of the compound of formula (I) include hydrobromide, tartrate, citrate, trifluoroacetate, ascorbate, hydrochloride, trifluoromethanesulfonate, maleate, methanesulfonate, formate, acetate, and fumarate.

[0047] The compound of formula (I) and / or its salt can form solvates or hydrates, and the present invention includes all such solvates and hydrates.

[0048] The terms "hydrate" and "solvate" simply mean that the compound (I) according to the present invention can be in the form of a hydrate or a solvate, i.e., combined or associated with one or more water or solvent molecules. This is just a chemical characteristic of such compounds, which can apply to all organic compounds of this type.

[0049] The compound of formula (I) defined herein and any one of compounds (1) to (118) can contain one or more asymmetric carbon atoms. Therefore, they can exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, and their mixtures (including racemic mixtures) are all included within the scope of the present invention.

[0050] The compound of formula (I) defined hereinafter and any one of compounds (1) to (118) can be in amorphous or crystalline form, and they are also included within the scope of the present invention.

[0051] In the context of the present invention, the terms:

[0052] - "Halogen" shall be understood as a chlorine, fluorine, bromine or iodine atom, especially a chlorine, fluorine or bromine atom.

[0053] - "(C1-C x )alkyl" as used herein respectively refers to C1-C x n-, secondary or tertiary saturated hydrocarbons, especially (C1-C3)alkyl or (C1-C5)alkyl. Examples are but not limited to methyl, ethyl, 1-propyl, 2-propyl, butyl, pentyl.

[0054] - Unless otherwise specified, "cycloalkyl" as used herein refers to a monocyclic alkyl group containing 3 to 7 carbon atoms (saturated or partially unsaturated, and unsubstituted or substituted). By way of example, mention may be made, but not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclobutenyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, etc., especially cyclopentyl, cyclohexyl, cycloheptyl, cycloheptenyl or cyclohexenyl;

[0055] - "Fluoroalkyl" as used herein refers to an alkyl group as defined above, in which the alkyl group is substituted by at least one fluorine atom. In other words, at least one hydrogen atom of the alkyl group is replaced by a fluorine atom. By way of example, mention may be made of CH2F, CHF2, CH2CHF2, -CH2CH2F, etc. When all hydrogen atoms belonging to the alkyl group are replaced by fluorine atoms, the fluoroalkyl group can be named perfluoroalkyl. By way of example, mention may be made of trifluoromethyl or trifluoroethyl, etc.;

[0056] - "Alkoxy" as used herein refers to -O-alkyl, where the alkyl group is as defined above. By way of example, mention may be made, but not limited to: methoxy, ethoxy, propoxy, isopropoxy, straight-chain, secondary or tertiary butoxy, isobutoxy, pentyloxy or hexyloxy, etc.;

[0057] - "(C1-C4)alkylsulfonyl" as used herein refers to -SO2-alkyl, where the alkyl group is as defined above. By way of example, mention may be made, but not limited to: -SO2CH3, -SO2CH2CH3, etc.

[0058] - "Straight-chain or cyclic nitrogen-containing (C4-C8) alkyl" means a non-aromatic (C4-C8) alkyl which can be straight-chain or cyclic, contains 4-8 carbon atoms, contains at least one nitrogen atom interrupting the alkyl chain, especially one or two nitrogen atoms. When it is cyclic, it can be a monocyclic group, a monocyclic group linked to the rest of the structure through a (C1-C3) alkylene group, a bicyclic group, a bridged bicyclic group, a spirobicyclic group or a fused bicyclic group. The group can be interrupted by one or two oxygen atoms and is optionally substituted by a (C1-C4) alkyl or a (C3-C6) cycloalkyl. By way of example, mention may be made of (dimethylamino)ethoxy, 1-methylpiperidinyl, 1-methylpyrrolidinyl, piperazinyl, 4-methylpiperazinyl, 4-isopropylpiperazinyl, 4-cyclobutylpiperazinyl, 4-methyl-1,4-diazepan-1-yl, 1-amino-4-methylpiperidine, 3-hydroxymethyl-1-methylpyrrolidine, octahydropyrrolo[3,4-c]pyrrolyl, diazaspiro[3.5]nonyl, 2-methyl-2,5-diazabicyclo[2.2.1]heptane and 7-methyl-2,7-diazaspiro[3.5]nonane;

[0059] - "Protonable amine" as used herein means an amine bonded to an sp3 carbon atom which may be protonated at pH 7.4, including primary, secondary or tertiary aliphatic amines, especially secondary or tertiary aliphatic amines.

[0060] According to one embodiment, there is provided a compound of formula (I) or any acceptable salt thereof (I)

[0061]

[0062] wherein

[0063] W, X, Y and Z each independently represent =CH- or -N=, provided that at most two of W, X, Y and Z represent -N= groups,

[0064] R1 represents a straight-chain or cyclic nitrogen-containing (C4-C8) alkyl, said group being a non-aromatic (C4-C8) alkyl which can be straight-chain or cyclic, contains 4-8 carbon atoms, contains at least one nitrogen atom interrupting the alkyl chain, said group being optionally interrupted by one or two oxygen atoms and being optionally substituted by a (C1-C4) alkyl or a (C3-C6) cycloalkyl, wherein R1 contains at least one primary, secondary or tertiary amine, especially one or two secondary or tertiary amines, R2 represents a hydrogen atom, a halogen atom, a (C1-C4) alkyl, a (C1-C4) alkoxy, a (C1-C4) fluoroalkyl, -CO-(C1-C4) alkyl or a cyano group,

[0065] R3 represents a hydrogen atom, a halogen atom, a (C1-C4) alkyl, a (C1-C4) alkoxy, a (C1-C4) fluoroalkyl, a (C1-C4) alkylsulfonyl, and

[0066] R4, R5, and R6 independently represent a hydrogen atom, a halogen atom, -COO(C1-C4)alkyl, (C1-C4)fluoroalkyl, (C1-C4)alkylsulfonyl, or (C1-C4)alkoxy.

[0067] According to one embodiment, there is provided a compound of formula (I) as defined above or any pharmaceutically acceptable salt thereof, 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-.

[0068] According to one embodiment, there is provided a compound of formula (I) as defined above or any pharmaceutically acceptable salt thereof, wherein R1 is selected from

[0069]

[0070] Particularly selected from

[0071]

[0072] And more particularly selected from

[0073]

[0074] According to one embodiment, there is provided a compound of formula (I) as defined above or any pharmaceutically acceptable salt thereof, wherein R2 represents a hydrogen atom, a halogen atom, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)fluoroalkyl, or cyano, and particularly a hydrogen atom, a fluorine atom, a methyl group, a methoxy group, a trifluoromethyl group, or cyano.

[0075] According to one embodiment, there is provided a compound of formula (I) as defined above or any pharmaceutically acceptable salt thereof, wherein R3 represents a hydrogen atom, a halogen atom, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)fluoroalkyl, or (C1-C4)alkylsulfonyl, and particularly a hydrogen atom, a fluorine or chlorine atom, a methyl group, a methoxy group, a trifluoromethyl group, or a methanesulfonyl group.

[0076] According to one embodiment, there is provided a compound of formula (I) as defined above or any pharmaceutically acceptable salt thereof, wherein R4, R5, and R6 independently represent a hydrogen atom, a halogen atom, (C1-C4)fluoroalkyl, -COO(C1-C4)alkyl, (C1-C4)alkylsulfonyl, or (C1-C4)alkoxy, and particularly a hydrogen atom, a fluorine or chlorine atom, a trifluoromethyl group, a methoxycarbonyl group, or a methoxy group.

[0077] According to one embodiment, there is provided a compound of formula (I) as defined above or any pharmaceutically acceptable salt thereof, wherein R4 is a hydrogen atom.

[0078] According to one embodiment, there is provided a compound of formula (I) as defined above or any pharmaceutically acceptable salt thereof, wherein

[0079] R2 represents a hydrogen atom, a halogen atom, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)fluoroalkyl, -CO-(C1-C4)alkyl or cyano, especially a hydrogen atom, a halogen atom, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)fluoroalkyl or cyano, more especially a hydrogen atom, a fluorine atom, methyl, methoxy, cyano, trifluoromethyl, R3 represents a hydrogen atom, a halogen atom, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)fluoroalkyl or (C1-C4)alkylsulfonyl, especially a hydrogen atom, a halogen atom, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)fluoroalkyl or (C1-C4)alkylsulfonyl, more especially a hydrogen atom, a chlorine or fluorine atom, methyl, methoxy, trifluoromethyl or methylsulfonyl,

[0080] R4, R5 and R6 independently represent a hydrogen atom, a halogen atom, (C1-C4)fluoroalkyl, -COOH group, -COO(C1-C4)alkyl, (C1-C4)alkylsulfonyl or (C1-C4)alkoxy, especially a hydrogen atom, a halogen atom, (C1-C4)fluoroalkyl or (C1-C4)alkoxy, more especially a hydrogen atom, a chlorine or fluorine atom, trifluoromethyl, methoxycarbonyl or methoxy.

[0081] According to one embodiment, the straight-chain or cyclic nitrogen-containing (C4-C8)alkyl contains a protonatable amine. According to another embodiment, the straight-chain or cyclic nitrogen-containing (C4-C8)alkyl contains two protonatable amines. In one embodiment, the straight-chain or cyclic nitrogen-containing (C4-C8)alkyl containing a protonatable amine is cyclic. In one embodiment, the straight-chain or cyclic nitrogen-containing (C4-C8)alkyl containing a protonatable amine is straight-chain. In one embodiment, the straight-chain or cyclic nitrogen-containing (C4-C8)alkyl is interrupted by an oxygen atom.

[0082] According to one embodiment, there is provided a compound of formula (I) as defined above or any pharmaceutically acceptable salt thereof, wherein R6 represents a halogen atom, -COO(C1-C4)alkyl, (C1-C4)fluoroalkyl, (C1-C4)alkylsulfonyl or (C1-C4)alkoxy.

[0083] According to a preferred embodiment of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof, especially its hydrochloride salt, is characterized in that the compound is selected from the following compounds:

[0084] -(1) N-(5-Fluoroquinolin-8-yl)-4-(1-methylpiperidin-4-yl)benzamide,

[0085] -(2) N-(8-Fluoroisoquinolin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide,

[0086] -(3) N-(5-Fluoroisoquinolin-8-yl)-4-(1-methylpiperidin-4-yl)benzamide,

[0087] -(4) N-(8-Fluoroquinolin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide,

[0088] -(5) N-(8-Fluoroquinoxalin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide,

[0089] -(6) 4-(1-Methylpiperidin-4-yl)-N-(quinolin-5-yl)benzamide,

[0090] -(7) N-(Isoquinolin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide,

[0091] -(8) N-(Isoquinolin-8-yl)-4-(1-methylpiperidin-4-yl)benzamide,

[0092] -(9) 4-(1-Methylpiperidin-4-yl)-N-(quinolin-8-yl)benzamide,

[0093] -(10) 4-[2-(Dimethylamino)ethoxy]-N-(isoquinolin-8-yl)benzamide,

[0094] -(11) 4-[2-(Dimethylamino)ethoxy]-N-(quinolin-8-yl)benzamide,

[0095] -(12) 2-Fluoro-4-(1-methylpiperidin-4-yl)-N-(quinolin-8-yl)benzamide,

[0096] -(13) 3-Fluoro-N-(isoquinolin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide,

[0097] -(14) 4-(2-(Dimethylamino)ethoxy)-N-(isoquinolin-5-yl)benzamide,

[0098] -(15)4-(2-(Dimethylamino)ethoxy)-N-(quinolin-5-yl)benzamide,

[0099] -(16)2-Methoxy-4-(1-methylpiperidin-4-yl)-N-(quinolin-8-yl)benzamide,

[0100] -(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,

[0101] -(20)4-(2-(Dimethylamino)ethoxy)-N-(8-fluoroquinolin-5-yl)benzamide,

[0102] -(21)3-Cyano-N-(isoquinolin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide,

[0103] -(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,

[0104] -(25)N-(Isoquinolin-5-yl)-2-methylsulfonyl-4-(1-methylpiperidin-4-yl)benzamide,

[0105] -(26)4-[2-(Dimethylamino)ethoxy]-N-(5-fluoroquinolin-8-yl)benzamide,

[0106] -(27)4-(1-Methylpiperidin-4-yl)-N-(quinolin-5-yl)-3-(trifluoromethyl)benzamide,

[0107] -(28)4-(1-Methylpiperidin-4-yl)-N-(quinoxalin-5-yl)benzamide,

[0108] -(29)3-Methyl-4-(4-methylpiperazin-1-yl)-N-(quinolin-5-yl)benzamide,

[0109] -(30)N-(8-Chloroquinolin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide,

[0110] -(31)4-[2-(Dimethylamino)ethoxy]-N-(quinoxalin-5-yl)benzamide,

[0111] -(32)N-(8-Chloroquinolin-5-yl)-4-[2-(dimethylamino)ethoxy]benzamide,

[0112] -(33)4-[2-(dimethylamino)ethoxy]-N-(8-fluoroisoquinolin-5-yl)benzamide,

[0113] -(34)4-[2-(dimethylamino)ethoxy]-N-(7-methoxyisoquinolin-5-yl)benzamide, -(35)4-(4-methylpiperazin-1-yl)-N-(quinolin-8-yl)benzamide,

[0114] -(36)3-Cyano-4-(2-(dimethylamino)ethoxy)-N-(isoquinolin-8-yl)benzamide, -(37)N-(8-fluoroquinoxalin-5-yl)-4-(4-methylpiperazin-1-yl)benzamide,

[0115] -(38)N-(Isoquinolin-8-yl)-4-(4-methylpiperazin-1-yl)benzamide,

[0116] -(39)N-(Isoquinolin-5-yl)-4-(4-methylpiperazin-1-yl)benzamide,

[0117] -(40)4-(4-Methylpiperazin-1-yl)-N-(quinolin-5-yl)benzamide,

[0118] -(41)4-(4-Methylpiperazin-1-yl)-N-(quinoxalin-5-yl)benzamide,

[0119] -(42)N-(5-Fluoroquinolin-8-yl)-4-(4-methylpiperazin-1-yl)benzamide,

[0120] -(43)4-(2-(dimethylamino)ethoxy)-3-methyl-N-(quinolin-8-yl)benzamide,

[0121] -(44)N-(8-Fluoroquinolin-5-yl)-4-(4-methylpiperazin-1-yl)benzamide,

[0122] -(45)N-(Isoquinolin-5-yl)-2-methyl-4-(4-methylpiperazin-1-yl)benzamide,

[0123] -(46)N-(8-Chloroquinolin-5-yl)-4-(4-methylpiperazin-1-yl)benzamide,

[0124] -(47)4-(2-(dimethylamino)ethoxy)-2-methyl-N-(quinolin-5-yl)benzamide,

[0125] -(48) 4-(2-(Dimethylamino)ethoxy)-N-(isoquinolin-5-yl)-3-(trifluoromethyl)benzamide,

[0126] -(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,

[0127] -(51) N-(8-Chloroisoquinolin-5-yl)-4-(4-methylpiperazin-1-yl)benzamide hydrochloride,

[0128] -(52) 4-(4-Methylpiperazin-1-yl)-N-[5-(trifluoromethyl)isoquinolin-8-yl]benzamide hydrochloride,

[0129] -(53) 3-Fluoro-N-(5-fluoroisoquinolin-8-yl)-4-{5-methyl-octahydropyrrolo[3,4-c]pyrrol-2-yl}benzamide,

[0130] -(54) N-(8-Methoxyisoquinolin-5-yl)-3-methyl-4-{7-methyl-2,7-diazaspiro[3.5]nonan-2-yl}benzamide, and

[0131] -(55) 3-Methyl-4-[(1-methylpyrrolidin-3-yl)methoxy]-N-(quinolin-8-yl)benzamide,

[0132] -(56) 2-Fluoro-4-(4-methylpiperazin-1-yl)-N-(quinolin-5-yl)benzamide,

[0133] -(57) 2-Fluoro-N-(isoquinolin-8-yl)-4-[4-(propan-2-yl)piperazin-1-yl]benzamide,

[0134] -(58) N-(5-Fluoroisoquinolin-8-yl)-3-methoxy-4-[(1R,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]benzamide,

[0135] -(59) 4-(4-Cyclobutylpiperazin-1-yl)-N-(quinolin-5-yl)benzamide,

[0136] -(60) N-(7-Methoxyisoquinolin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide,

[0137] -(61) N-(5-Chloroisoquinolin-8-yl)-4-(1-methylpiperidin-4-yl)benzamide hydrochloride,

[0138] -(62)N-(6-chloroisoquinolin-8-yl)-4-(1-methylpiperidin-4-yl)benzamide,

[0139] -(63)N-(6-methoxyisoquinolin-8-yl)-4-(1-methylpiperidin-4-yl)benzamide,

[0140] -(64)N-(8-chloroisoquinolin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide,

[0141] -(65)N-(8-methoxyisoquinolin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide,

[0142] -(66)4-(1-methylpiperidin-4-yl)-N-[5-(trifluoromethyl)isoquinolin-8-yl]benzamide,

[0143] -(67)4-(1-methylpiperidin-4-yl)-N-(quinazolin-8-yl)benzamide,

[0144] -(68)4-(4-methylpiperazin-1-yl)-N-(quinazolin-8-yl)benzamide,

[0145] -(69)N-(5-fluoroisoquinolin-8-yl)-4-(4-methyl-1,4-diazepan-1-yl)benzamide hydrochloride,

[0146] -(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,

[0147] -(72)4-(1-methylpiperidin-4-yl)-N-(quinazolin-5-yl)benzamide,

[0148] -(73)N-(6-chloroisoquinolin-8-yl)-4-(4-methylpiperazin-1-yl)benzamide,

[0149] -(74)N-(8-chloroisoquinolin-5-yl)-3-methoxy-4-[(1-methylpiperidin-4-yl)amino]benzamide,

[0150] -(75)Methyl 8-[4-(1-methylpiperidin-4-yl)benzamido]quinoline-5-carboxylate,

[0151] -(76)N-(5-fluoroisoquinolin-8-yl)-4-(4-methylpiperazin-1-yl)benzamide,

[0152] -(77)N-(5-Chloroisoquinolin-8-yl)-4-(4-methylpiperazin-1-yl)benzamide,

[0153] -(78)4-(1-Methylpiperidin-4-yl)-N-(phthalazin-5-yl)benzamide,

[0154] -(79)N-(8-Fluoroisoquinolin-5-yl)-4-(4-methylpiperazin-1-yl)benzamide,

[0155] -(80)4-(4-Methylpiperazin-1-yl)-N-(quinazolin-5-yl)benzamide,

[0156] -(81)4-(4-Methylpiperazin-1-yl)-N-(phthalazin-5-yl)benzamide,

[0157] -(82)N-(7-Methoxyisoquinolin-5-yl)-4-(4-methylpiperazin-1-yl)benzamide hydrochloride, -(83)4-[2-(Dimethylamino)ethoxy]-N-(quinazolin-5-yl)benzamide,

[0158] -(84)Methyl 8-[4-(4-methylpiperazin-1-yl)benzamido]quinoline-5-carboxylate hydrochloride,

[0159] -(85)4-[2-(Dimethylamino)ethoxy]-N-(quinazolin-8-yl)benzamide,

[0160] -(86)N-(6-Chloroisoquinolin-8-yl)-4-(2-(dimethylamino)ethoxy)benzamide,

[0161] -(87)4-[2-(Dimethylamino)ethoxy]-N-(6-methoxyisoquinolin-8-yl)benzamide,

[0162] -(88)N-(5-Chloroisoquinolin-8-yl)-4-[2-(dimethylamino)ethoxy]benzamide,

[0163] -(89)4-(2-(Dimethylamino)ethoxy)-N-(7-methoxyisoquinolin-5-yl)benzamide hydrochloride,

[0164] -(90)4-[2-(Dimethylamino)ethoxy]-N-[5-(trifluoromethyl)isoquinolin-8-yl]benzamide hydrochloride,

[0165] -(91)Methyl 8-{4-[2-(dimethylamino)ethoxy]benzamido}quinoline-5-carboxylate hydrochloride,

[0166] -(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,

[0167] -(94)2-Methyl-4-(1-methylpiperidin-4-yl)-N-(quinolin-8-yl)benzamide hydrochloride,

[0168] -(95)2-Methyl-4-(4-methyl-1,4-diazepan-1-yl)-N-(quinolin-5-yl)benzamide,

[0169] -(96)3-Cyano-4-[(1-methylpyrrolidin-3-yl)methoxy]-N-(quinoxalin-5-yl)benzamide,

[0170] -(97)4-(Piperazin-1-yl)-N-(quinolin-8-yl)benzamide hydrochloride,

[0171] -(98)4-[(1-Methylpiperidin-4-yl)amino]-N-(quinolin-8-yl)-2-(trifluoromethyl)benzamide hydrochloride,

[0172] -(99)4-(4-Cyclobutylpiperazin-1-yl)-N-(isoquinolin-5-yl)-2-methoxybenzamide hydrochloride,

[0173] -(100)N-(Isoquinolin-8-yl)-4-[4-(propan-2-yl)piperazin-1-yl]benzamide hydrochloride,

[0174] -(101)2-Fluoro-4-[(1R,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]-N-(quinolin-8-yl)benzamide,

[0175] -(102)4-[4-(Propan-2-yl)piperazin-1-yl]-2-(trifluoromethyl)-N-[5-(trifluoromethyl)isoquinolin-8-yl]benzamide

[0176] -(103)4-[2-(Dimethylamino)ethoxy]-3-fluoro-N-(quinolin-5-yl)benzamide,

[0177] -(104)N-(8-Fluoroquinolin-5-yl)-2-methoxy-4-{7-methyl-2,7-diazaspiro[3.5]non-2-yl}benzamide hydrochloride,

[0178] -(105)3-Fluoro-N-(8-methoxyisoquinolin-5-yl)-4-(4-methyl-1,4-diazepan-1-yl)benzamide,

[0179] -(106) 4-[2-(Dimethylamino)ethoxy]-2-fluoro-N-(quinolin-8-yl)benzamide,

[0180] -(107) 4-[2-(Dimethylamino)ethoxy]-2-methoxy-N-(quinolin-5-yl)benzamide,

[0181] -(108) N-(8-Fluoroquinolin-5-yl)-2-(methylsulfonyl)-4-{5-methyl-octahydropyrrolo[3,4-c]pyrrol-2-yl}benzamide,

[0182] -(109) N-(8-Chloroisoquinolin-5-yl)-4-(4-cyclobutylpiperazin-1-yl)-3-fluorobenzamide hydrochloride,

[0183] -(110) 4-[2-(Dimethylamino)ethoxy]-3-methoxy-N-(quinolin-8-yl)benzamide,

[0184] -(111) N-(Isoquinolin-5-yl)-4-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)benzamide,

[0185] -(112) N-(8-Chloroquinolin-5-yl)-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)benzamide,

[0186] -(113) 2-(Methylsulfonyl)-4-(piperazin-1-yl)-N-(quinolin-5-yl)benzamide hydrochloride,

[0187] -(114) N-(Isoquinolin-5-yl)-4-[(1-methylpiperidin-4-yl)amino]-3-(trifluoromethyl)benzamide,

[0188] -(115) 4-(4-Methylpiperazin-1-yl)-2-(methylsulfonyl)-N-(quinolin-5-yl)benzamide,

[0189] -(116) 4-(4-Methylpiperazin-1-yl)-N-(quinolin-8-yl)-3-(trifluoromethyl)benzamide,

[0190] -(117) N-(8-Chloroisoquinolin-5-yl)-3-cyano-4-(4-cyclobutylpiperazin-1-yl)benzamide, and

[0191] -(118) 3-Cyano-4-(4-methylpiperazin-1-yl)-N-(quinolin-5-yl)benzamide.

[0192] The compounds of the present invention can be prepared by conventional organic synthesis methods practiced by those skilled in the art. The general reaction sequences outlined below represent general methods for preparing the compounds of the present invention and are not meant to limit the scope or utility.

[0193] As used herein, unless otherwise indicated throughout the specification, the following terms have the following definitions:

[0194] Carboxyl activator: A carboxyl activator that can be used as an additive for the coupling between a carboxylic acid and an amine. This reagent is used to in-situ generate an activated ester leaving group to enhance or permit the reaction. By way of example, but not limited to: N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDCI) and N,N′-diisopropylcarbodiimide (DIC) or dicyclohexylcarbodiimide (DCC).

[0195] Racemization inhibitor: In addition to the carboxyl activator, a racemization inhibitor can also be used to inhibit the racemization that may occur during the coupling between a carboxylic acid and an amine. By way of example, but not limited to: 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt) and ethyl cyano(hydroxyimino)acetate (e.g., the product sold by Merck Millipore under the name).

[0196] Alkali metal: By way of example, but not limited to: lithium (Li), sodium (Na), potassium (K) and cesium (Cs).

[0197] Chlorinating agent: A chemical reagent that can be used to add a chlorine atom to other chemical substances, especially chlorination can be used to convert a carboxylic acid or carboxylate into an acyl chloride. By way of example, but not limited to: SOCl2, PCl3, PCl5, oxalyl chloride and propionyl chloride.

[0198] As shown in Scheme 1 below, the following reaction can be carried out to obtain the compound of formula (I):

[0199] Scheme 1

[0200]

[0201] According to Scheme 1, where W, X, Y, Z, R1, R2, R3, R4, R5 and R6 are as defined above, and M represents an alkali metal or hydrogen, when R1 represents a ring nitrogen attached to the central benzene ring through a carbon atom, compound (IV) can be converted to compound (V) in Step 1 by Suzuki-Miyaura coupling, specifically by treating with a boric acid or ester derivative in a solution of a solvent mixture (such as toluene and water) 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), and heating to 80 °C. Then, under a H2 atmosphere, the resulting compound is 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 (Method B: adapted from Miyaura et al., Tetrahedron Letters, 1979, 20, 3437–3440). When R1 represents a cyclic nitrogen attached to the central benzene ring through a nitrogen atom, an alternative method for preparing compound (V) from compound (IV) can use 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(diphenylphosphine) (Xantphos)) and a base (such as Cs2CO3) in a solution (such as in dioxane) by heating to reflux of the solvent (Method C: adapted from Guram et al., Angew. Chem. Int. Ed Engl. 1995, 34, 1348-1350).

[0202] Compound (VI) can be converted to compound (V) in Step 2 by nucleophilic substitution using a chloride derivative and a base (such as K2CO3) in a solution (such as in DMF) by heating to 80 °C (Method D). An alternative method for preparing compound (V) from compound (VI) can be accomplished by Mitsunobu coupling using an alcohol derivative in the presence of triphenylphosphine (PPh3) and diisopropyl azodicarboxylate (DIAD) in a solution (such as in THF) by stirring at 0 °C (Method E: adapted from Maghar et al., J. Chem. Soc. Perkin Trans. 1975, 1, 461–463).

[0203] Compound (V) can be converted into compound (VII) in step 3 by saponification reaction using a base (such as LiOH, NaOH, KOH, RbOH or CsOH) and water in a solution of a solvent mixture (such as methanol and THF) (Step F: adapted from Chan et al., J. Org. Chem., 2007, 72, 8863 - 8869). Optionally, the resulting carboxylate derivative can be treated with an acid to obtain the corresponding carboxylic acid derivative.

[0204] Compound (III) can be converted into compound (II) in step 4 by heating with sodium azide (NaN3), 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 in DMSO) to 105 °C (Method A: adapted from Klapars et al., J. Am. Chem. Soc. 2001, 123, 7727–7729).

[0205] Compound (II) and (VII) can be converted into compound (I) together in step 5 by using a carboxyl activator 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 cyano(hydroxyimino)acetate (e.g., the product sold by Merck Millipore under the name of)) and an organic base (such as triethylamine (Et3N) or N,N-diisopropylethylamine (DIPEA)) in a solution (such as in DMF), optionally by heating to 33 °C (Method G: adapted from Schotten. Ber. Deutsch. Chem. Gesell., 1884, 17, 2544; Method I: adapted from Subirós-Funosas et al., Chem. Eur. J., 2009, 15, 9394 - 9403). An alternative method for preparing compound (I) from compounds (VII) and (II) can be accomplished by first treating (VII) with a chlorinating agent (such as SOCl2, PCl3 or PCl5) and optionally an organic base (such as triethylamine (Et3N)) in an aprotic solvent (such as THF) to form the corresponding acyl chloride derivative. Then, the acyl chloride derivative can be reacted with compound (II) in a solution (such as in DMF or THF) in the presence of an organic base (such as triethylamine (Et3N)) (Method H: adapted from Baumann. Ber. Deutsch. Chem. Gesell, 1886, 19, 3212).

[0206] Finally, compound (I) can be obtained in Step 6 by first converting benzoyl chloride (VIII) into formamide by reaction with ammonia and then coupling the amide with aryl bromide (IX) by 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 J: adapted from Yin. Org. Lett., 2000, 2, 8, 1101–1104).

[0207] Accordingly, the present invention relates to a synthetic method for preparing a compound of formula (I) as defined above or any of its pharmaceutically acceptable salts, comprising at least the following steps:

[0208] - reacting a compound of formula (II):

[0209]

[0210] wherein R4, R5, R6, W, X, Y and Z are as defined above,

[0211] with a compound of formula (VII):

[0212]

[0213] wherein R1, R2, R3 are as defined above and M represents an alkali metal or hydrogen, to obtain a compound of formula (I),

[0214] (i) by using a carboxyl activating agent (especially N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDCI) or N,N′-diisopropylcarbodiimide (DIC)) with a racemization inhibitor (especially 1-hydroxybenzotriazole (HOBt) or ethyl cyano(hydroxyimino)acetate), and an organic base in an aprotic polar solvent for peptide synthesis; or

[0215] (ii) first, treating the compound of formula (VII) alone in an aprotic solvent in the presence of a chlorinating agent (especially SOCl2) and optionally an organic base to form the corresponding acyl chloride derivative, and then reacting the acyl chloride derivative with the compound of formula (II) by nucleophilic substitution using an organic base in an aprotic solvent.

[0216] According to another embodiment, the present invention relates to a synthetic method for preparing a compound of formula (I) as defined above or any of its pharmaceutically acceptable salts, comprising at least the following steps:

[0217] - reacting a compound of formula (VIII):

[0218]

[0219] wherein R2 and R3 are as defined above,

[0220] react with a compound of formula (IX):

[0221]

[0222] wherein R4, R5, R6, W, X, Y and Z are as defined above,

[0223] Convert the acyl chloride to a formamide by a first reaction with ammonia, and perform a palladium-catalyzed Buchwald cross-coupling by a second reaction.

[0224] Unless otherwise stated, all reactions were carried out under a normal atmosphere. Chemicals and solvents were purchased from several suppliers and used without further purification.

[0225] Analytical TLC was performed using Merck 60F254 silica gel plates, and the plates were observed by exposure to ultraviolet light. Compounds were purified on silica gel VWR (particle size 0.040 - 0.063 nm) or using Buchi flash chromatography (normal phase column: irregular Buchi silica gel 40 μm, 4 or 12 g).

[0226] HPLC was performed using an Agilent 1260Infinity II with the following parameters: flow rate of 1.5 mL / min, column temperature: 40 °C (InfinityLab Poroshell 120 EC-C18, 4.6 x 100 mm, 2.7 μm), solvent system: A (0.05% TFA in H2O) and B (acetonitrile), t = 0 min to 1 min: 95% A and 5% B, then t = 1 min to t = 7 min: 5% to 60% B, t = 7 min to t = 8.5 min: 60% to 100% B, t = 8.5 min to t = 9 min: 100% and finally t = 9 min to t = 9.5 min: 100% to 5%. Recorded separately on a Bruker Avance spectrometer operating at 400, 500 MHz or 700 MHz; 376 MHz and 101, 125 or 176 MHz 1 H, 19 F and 13 C NMR spectra. All chemical shift values δ and coupling constants J are cited in ppm and Hz respectively, and multiplicities (s = singlet, d = doublet, t = triplet, q = quartet, quin = quintet, sex = sextet, m = multiplet, br = broad). All spectra were evaluated using MestreNova 14.1.1 (MestreLabResearch SSL).

[0227] Analytical RP-HPLC-MS was performed using an LC 1200 Agilent equipped with a quadrupole time-of-flight (QTOF) (Agilent Accurate Mass QToF 6520) and a Zorbax Agilent C18 column (C18, 50 mm x 2.1 mm; 1.8 μm) with the following parameters: 1) Solvent system: A (acetonitrile + 0.5% formic acid) and B (H2O + 0.05% formic acid). 2) Gradient: t = 0 to 8 min: 98 to 0% of B, t = 8 to t = 12.5 min: 0% of B, t = 12.5 to t = 12.6 min: 0 to 98% of B and t = 12.6 to t = 13 min: 98% of B. 3) Flow rate was 0.5 mL / min. 4) Column temperature: 40 °C. 5) DAD scan from 190 nm to 700 nm. 6) Ionization mode: ESI+.

[0228] The chemical structures and spectral data of some compounds of formula (I) of the present invention are shown in Table I and Table II below, respectively.

[0229] Table I

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243] Table II

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304] Pain condition or disorder

[0305] All compounds disclosed in the present application are specifically contemplated herein for the prevention and / or treatment of pain conditions or disorders.

[0306] Different pain disorders may arise from different mechanisms.

[0307] Chronic pain refers to pain that persists for more than 3 months, whereas acute pain refers to pain that persists for less than 3 months.

[0308] Among the pain conditions that can be prevented and / or treated by the compounds of formula (I) according to the present invention, the following can be enumerated: acute pain, chronic pain, neuropathic pain, inflammatory pain, lower back pain, postoperative pain, cancer pain, vascular headache (such as migraine), fibromyalgia, hyperalgesia (such as mechanical and thermal hyperalgesia), allodynia (such as thermal and mechanical allodynia), peripheral sensitization of pain mechanisms, and central sensitization of pain mechanisms.

[0309] Neuropathic pain refers to pain that occurs after nerve injury or diseases of the somatosensory system. It is a debilitating chronic clinical condition, and one of its hallmark symptoms is tactile allodynia to pain. According to the definition of the International Association for the Study of Pain (Treede et al., Neurology, 2008, 70:1630 - 1635), the term "neuropathic pain" actually refers to chronic or persistent pain conditions that arise as a direct consequence of injury or disease affecting the somatosensory system, which includes the nociceptive system and its ascending and descending pathways. When diagnostic investigations (such as clinical examination, imaging, neurophysiology, biopsy, laboratory tests) show abnormalities or obvious trauma, the term lesion is usually used. When the underlying etiological cause of the lesion is known (such as stroke, vasculitis, diabetes, genetic abnormalities), the term disease is usually used. These symptoms include hyperalgesia, which is pain hypersensitivity caused by stimuli that normally cause pain, and allodynia, which is pain caused by stimuli that normally do not cause pain.

[0310] Depending on the anatomical location of the lesion or disease, neuropathic pain can be peripheral or central neuropathic pain. However, the distribution of pain or allodynia does not necessarily correspond to the innervation area of the organ affected by the disease.

[0311] According to a particular embodiment of the present invention, neuropathic pain may also be referred to as a neuropathic pain syndrome, which is selected from pain caused by metabolic diseases (such as painful diabetic peripheral neuropathy), infectious diseases (such as postherpetic neuralgia), trigeminal neuralgia, post-traumatic neuropathic pain, lumbosacral radicular pain, post-surgical neuropathic pain, iatrogenic neuropathic pain (such as cancer chemotherapy-induced neuropathic pain), and central neuropathic pain.

[0312] Neuropathic pain is different from inflammatory pain, which is produced by a local reaction after injury to tissues outside the sensory system (such as joints, ligaments, tendons, bones, muscles, blood vessels, or visceral structures).

[0313] Different types of pain can coexist, that is, neuropathic pain can coexist with other types of pain, especially chronic pain. For example, neuropathic pain can coexist with inflammatory pain or nociceptive pain, such as low back pain or cancer pain.

[0314] According to a particular embodiment of the present invention, the compound of formula (I) according to the present invention or any pharmaceutically acceptable salt thereof can be used for the prevention and / or treatment of low back pain, osteoarthritis pain, cancer pain, and sciatica.

[0315] Pharmaceutical composition and use

[0316] The pharmaceutical composition according to the invention may contain one or more compounds of the invention in any of the forms described herein.

[0317] The compound may be administered by any route of administration (such as local, intramuscular, intravenous, intranasal or oral route, etc.).

[0318] In one embodiment, the pharmaceutical composition according to the invention is selected from: oral compositions; topical compositions; inhalation compositions; injectable compositions, particularly subcutaneous compositions, intramuscular compositions or intravenous compositions, and oral, injectable or surgical sustained-release compositions.

[0319] The composition of the invention may further comprise one or more additives such as diluents, excipients, stabilizers and preservatives. Such additives are well known to those skilled in the art and are described in particular in "Ullmann's Encyclopedia of Industrial Chemistry, 6th Edition" (multiple editors, 1989 - 1998, Marcel Dekker) and "Pharmaceutical Dosage Forms and Drug Delivery Systems" (ANSEL et al., 1994, WILLIAMS & WILKINS).

[0320] The above excipients are selected according to the dosage form and the desired route of administration. Depending on the desired pharmaceutical form and method of administration, the excipients are selected from conventional excipients known to those skilled in the art.

[0321] The composition of the invention may be administered orally, parenterally, transdermally, transmucosally, topically, rectally, by inhalation spray, intranasally, by inhalation via the nose, buccally, sublingually, vaginally or by an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the composition is administered orally, transdermally or by intravenous injection. The sterile injectable form of the composition of the invention may be an aqueous or oily suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3 - butanediol. Acceptable carriers and solvents that may be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are commonly used as solvents or suspending media.

[0322] In a particular embodiment, the compound of formula (I) according to the invention or any pharmaceutically acceptable salt thereof is administered orally.

[0323] In the framework of the present invention, pharmaceutical forms of immediate release, delayed release, modified release or sustained release can be selected, in particular a pharmaceutical form of sustained release.

[0324] Treatment by administration of a compound of formula (I) according to the invention can also be continuous. "Continuous treatment" means a long-term treatment that can be implemented, which includes different administration frequencies, preferably twice a day, and more preferably once a day.

[0325] The compound of formula (I) according to the invention can also be administered repeatedly during a plurality of 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 treatment, etc.). This protocol can be determined by any practitioner specializing in pain.

[0326] In a more particular embodiment, the compound of formula (I) according to the invention is administered before the predictable occurrence of pain. For example, it is well known that moderately or highly invasive surgical procedures (such as cardiac surgery, joint replacement, tumor removal, partial resection of the digestive tract, transplantation or amputation) cause pain of varying intensities in the hours and days after the surgery or even for a longer period. In these cases, and according to a particular embodiment, the compound of formula (I) according to the invention can be administered before the surgical subject regains consciousness, or during the surgical procedure, when the subject is anesthetized and before the start of opioid treatment, which usually occurs during postoperative care.

[0327] For example, the compound of formula (I) or any pharmaceutically acceptable salt thereof can be combined with a suitable excipient and presented in any pharmaceutical form suitable for enteral or parenteral administration, for example in the form of: ordinary or coated tablets, hard gelatin, soft shell capsules and other capsules, suppositories or drinkable (such as suspensions, syrups or injectable solutions or suspensions, the dose of which enables the daily administration of 0.1 to 1000 mg of the active substance, in particular 0.1 to 10 mg, or for example 10 to 200 mg, or for example 200 to 1000 mg).

[0328] There may be such specific cases where higher or lower doses are appropriate. By convention, the doctor determines the dose suitable for each patient based on the mode of administration and the weight and response of the said patient.

[0329] In another embodiment, the compound of formula (I) is used as a single agent or in combination with other agents such as opioids. The opioids may be selected from the group consisting of: alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dextropropoxyphene, dezocine, diampromide, dienorphinone, dihydrocodeine, dihydromorphine, dimethadione, dimepheptanol, dimethylthiambutene, maprotiline, dipipanone, etazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, papaverine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpethidine, opium, oxycodone, oxymorphone, opium alkaloids, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, dimethylpethidine, properidine, profadol, propoxyphene, remifentanil, sufentanil, tapentadol, tilidine, and tramadol, particularly selected from fentanyl, morphine, remifentanil, and tramadol.

[0330] Accordingly, the present invention further provides a pharmaceutical composition comprising at least one compound of formula (I) or any pharmaceutically acceptable salt thereof, an opioid, and at least one pharmaceutically acceptable excipient, wherein the opioid is as defined above.

[0331] In another embodiment, the compound of formula (I) or any pharmaceutically acceptable salt thereof, alone or in combination with an opioid as defined above, is used as a medicament.

[0332] In another embodiment, the compound of formula (I) or any pharmaceutically acceptable salt thereof, alone or in combination with an opioid as defined above, is used for the prevention and / or treatment of pain.

[0333] The examples provided herein are intended to be merely exemplary, and those skilled in the art will recognize, or will be able to determine using only routine experimentation, many equivalents of specific compounds, materials, and steps. All such equivalents are considered to be within the scope of the present invention and are encompassed by the appended claims.

[0334] Example

[0335] In the examples, the meanings of the following terms are:

[0336] -TMDCA: trans-N,N′-dimethylcyclohexane-1,2-diamine

[0337] - DMSO: Dimethyl sulfoxide

[0338] - TLC: Thin layer chromatography

[0339] - RuPhos: 2 - Dicyclohexylphosphino - 2′,6′ - diisopropoxybiphenyl

[0340] - Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0)

[0341] - XantPhos: 4,5 - Bis(diphenylphosphino) - 9,9 - dimethyloxanthene

[0342] - DCM: Dichloromethane

[0343] - r.t.: Room temperature

[0344] - O / N: Overnight

[0345] - DIAD: Diisopropyl azodicarboxylate

[0346] - eq.: Equivalent

[0347] - EtOAc: Ethyl acetate

[0348] - EtO2: Diethyl ether

[0349] - HPLC: High performance liquid chromatography

[0350] - DMF: Dimethylformamide

[0351] - THF: Tetrahydrofuran

[0352] - EDCI: N-(3 - Dimethylaminopropyl)-N′-ethylcarbodiimide

[0353] - HOBt: 1 - Hydroxybenzotriazole

[0354] - Ethyl cyano(hydroxyimino)acetate

[0355] - DIC: N,N′-Diisopropylcarbodiimide

[0356] - DIPEA: N,N - Diisopropylethylamine

[0357] - MeOH: Methanol

[0358] - EtOH: Ethanol

[0359] - h: Hour

[0360] - pH: Hydrogen potential

[0361] - NEt3 or Et3N: Triethylamine

[0362] -Xphos: 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

[0363] General procedure

[0364] Method A. Amination of aryl bromides (Scheme 2)

[0365]

[0366] Charge a 10 mL microwave vial with aryl bromide (1 equiv), sodium azide (2 equiv), copper(I) iodide (1 equiv), and TMDCA (1.3 equiv). Flush the vial with argon, then add dry DMSO while flushing with argon. Then cap the reaction mixture properly and place it in a preheated oil bath at 105 °C until the starting material is completely converted (2 - 3 h) (TLC using EtOAc in 1:1 heptane as the eluent). Quench the mixture with EtOAc and water, filter on a pad, and then extract the product with EtOAc. Wash the combined organic phases with brine, dry over anhydrous Na2SO4, and evaporate the solvent under reduced pressure. Then purify the crude product by flash column chromatography.

[0367] Method B. Suzuki - Miyaura coupling (Scheme 3)

[0368]

[0369] Suzuki-Miyaura coupling

[0370] Under argon, add a commercially available bromobenzoate compound (1 equiv), boronate or acid (1.1 equiv), K2CO3 (3 equiv) to toluene and water in a microwave vial. Degas the mixture and add palladium(II) diacetate (0.02 equiv) and a commercially available RuPhos (0.04 equiv). Cap the reaction mixture and heat to 80 °C overnight. Cool the flask to room temperature, then dilute in EtOAC and filter on a pad. Evaporate the solvent and purify the crude product by flash column chromatography.

[0371] Hydrogenation

[0372] Add Pd / C (0.46 equiv) to a solution of methyl 4-(1 - methyl - 1,2,3,6 - tetrahydropyridin - 4 - yl)benzoate derivative (1 equiv) in pre - degassed EtOH or MeOH. Degas the mixture again, then place the flask under a H2 atmosphere overnight. Monitor the reaction by HPLC or TLC (10% MeOH / DCM). The mixture is filtered through a Filter and evaporate the solvent. Purify the crude product by flash column chromatography.

[0373] Method C. Buchwald-Hartwig coupling (Scheme 4)

[0374]

[0375] Dissolve methyl bromobenzoate derivative (1 equiv), Pd2(dba)3 (3 mol %), and Xantphos (8 mol %) in dry 1,4-dioxane (0.53 mmol / mL), and degas the solution with argon for 10 min. Add amine (1.2 equiv) to the mixture, then add Cs2CO3 (1.4 equiv) and stir the reaction mixture at 120 °C overnight. Cool the reaction mixture to room temperature, then dilute in EtOAC, filter through a pad, and wash with EtOAC. Remove the solvent under reduced pressure and then purify by flash chromatography. Filter through a pad and wash with EtOAC. Remove the solvent under reduced pressure and then purify by flash chromatography.

[0376] Method D. Nucleophilic substitution (Scheme 5)

[0377]

[0378] Under an argon atmosphere, add K2CO3 (4 equiv) to a stirred solution of commercially available 2-dimethylaminoethyl chloride hydrochloride (1 equiv) in dry DMF. After stirring at room temperature for 10 min, add the 4-hydroxybenzoate derivative (1 equiv) in one portion. Stir the vial at 80 °C for 48 h. Quench the reaction with saturated NaHCO3 and extract with Et2O or EtOAc. Wash the organic phase with saturated NaCl and then dry over Na2SO4. Purify the crude product by flash column chromatography.

[0379] Method E. Mitsunobu coupling (Scheme 6)

[0380]

[0381] Under argon, add to a stirred solution of alcohol derivative (1 equiv), triphenylphosphine (1.1 equiv), and 4-hydroxybenzoate derivative (1.1 equiv) dissolved in dry THF, and cool the solution to 0 °C. Slowly add DIAD (1 equiv) over 5 min. Stir the mixture at 0 °C for 2 h and then heat at room temperature overnight. Evaporate the solvent, dissolve the resulting yellow oil in 50 mL EtOAC, and extract with 4N HCl three times. Then cool the aqueous phase to 0 °C and basify with solid NaOH until the pH is at least equal to 10. Extract the basified phase three times with DCM, dry over MgSO4, and filter. Purify the crude product by flash column chromatography.

[0382] Method F. Hydrolysis of Methyl Benzoate (Scheme 7)

[0383]

[0384] To a solution of the benzoate derivative (1 equiv) in MeOH (14.94 equiv) and THF (29.55 equiv) was added a solution of lithium hydroxide monohydrate (1.05 equiv) in H2O (33.60 equiv). The reactants were stirred overnight at room temperature. If the reaction was not complete, additional LiOH in H2O could be added and the reaction mixture could be stirred at room temperature for several days. The reactants were evaporated under reduced pressure, taken up in EtOAc and evaporated again. Method G. Synthesis of Benzamide Derivatives (Scheme 8)

[0385]

[0386] At 0 °C under an argon atmosphere, HOBt (1.2 equiv), EDCI (1.2 equiv), NEt3 (2 equiv) were successively added to a solution of benzoic acid or its lithium salt (1 equiv) and arylamine (1.1 equiv) in dry DMF (31.28 equiv). The reactants were then stirred overnight at 33 °C. The reaction was followed by HPLC and if the reaction was not complete, the reaction could be continued by adding EDCI and stirring the reaction mixture at 40 - 50 °C for several days. The mixture was quenched with saturated NaHCO3 and H2O and then extracted with EtOAc. The combined organic phases were washed with saturated NaCl, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude residue was purified by flash column chromatography.

[0387] Method H. Synthesis of Benzamide Derivatives (Scheme 9)

[0388]

[0389] Preparation of benzoyl chloride After preparation of the lithium benzoate (see General Procedure F), SOCl2 (30 equiv) was slowly added to a stirred solution of the lithium salt (1 equiv) 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.

[0390] Amide bond formation

[0391] Dissolve the benzoyl chloride derivative (1 equivalent) in anhydrous THF (0.35 mmol / mL), and cool the resulting solution to 0 °C. Add the amine derivative (1.1 equivalents) and NEt3 (1.2 equivalents) and stir the resulting mixture at room temperature overnight. Add saturated aqueous NaHCO3 and EtOAc, and separate the phases. Further extract the aqueous phase with EtOAc three times. Then, wash the combined organic phases with brine, dry over MgSO4, filter, and evaporate under reduced pressure, and then purify by flash chromatography.

[0392] Method I. Synthesis of benzamide derivatives (Scheme 10)

[0393]

[0394] At 0 °C, mix the lithium salt (1.1 equivalents), (1.1 equivalents) and DIC (1.1 equivalents) in dry DMF (0.18 mmol / mL). Stir the reaction mixture at 0 °C for 5 min to preactivate the carboxylate or acid and form the active ester. Then add DIPEA (1.1 equivalents), and then add the amine derivative (1 equivalent). Stir the reaction mixture at 0 °C for 20 min, 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]. Add saturated aqueous NaHCO3 and EtOAc, and separate the phases. Further extract the aqueous phase with EtOAc three times. Then, wash the combined organic phases with brine, dry over MgSO4, filter, and evaporate under reduced pressure, and then purify by flash chromatography.

[0395] General method J: Synthesis of benzamide derivatives (Scheme 11)

[0396]

[0397] Preparation of amide

[0398] At 0 °C, add the benzoyl chloride portionwise to 28% ammonia (105 equivalents). After 5 min, add 1 mL of 28% ammonia, and stir the reaction mixture at room temperature (19 - 20 °C) for 1 h. Filter the mixture through a sintered glass funnel, and wash the white solid three times with 2 mL of water and three times with ether. Place the white solid in a round-bottom flask, rinse the sintered glass funnel with methanol, and then concentrate under reduced pressure.

[0399] Coupling reaction

[0400] Charge a microwave flask with benzamide (1 equiv), bromoquinoline (1 equiv), K2CO3 (1.5 equiv), and tert-butanol (44 equiv). Heat the mixture at 60 °C and degas with argon. Add PdG3 Xantphos (0.035 equiv) and seal the flask properly. Stir the solution at reflux (ca. 85 °C) overnight. Quench the mixture with saturated NaHCO3 solution and extract the product 3 times with EtOAc. Evaporate the solvent under reduced pressure and purify the crude product by flash column chromatography.

[0401] Example 1: Preparation of N-(5-fluoroisoquinolin-8-yl)-4-(1-methylpiperidin-4-yl)benzamide (3)

[0402] 5-Fluoroisoquinolin-8-amine

[0403]

[0404] Apply General Procedure A to 8-bromo-5-fluoroisoquinoline (1.079 g, 4.77 mmol). Purify the crude residue by silica gel flash chromatography (heptane / EtOAc 70 / 30 to 50 / 50 to 25 / 75) to afford 5-fluoroisoquinolin-8-amine (490 mg, 3.02 mmol, 63%) as a brown / green solid, HPLC purity 98%.

[0405] 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, 4.1 Hz, 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 ).

[0406] NMR 19F (376 MHz, MeOD, decoupled): δ = -141.11

[0407] N-(5-Fluoroisoquinolin-8-yl)-4-(1-methylpiperidin-4-yl)benzamide (3)

[0408] The 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 (DCM / MeOH 98 / 2 to 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 / violet solid.

[0409] Example 2: Preparation of N-(8-fluoroquinoxalin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide (5)

[0410] 5-Bromo-8-fluoroquinoxaline

[0411]

[0412] 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 to a solution of 3-bromo-6-fluoro-1,2-phenylenediamine (1 eq., 202 mg, 0.985 mmol) in EtOH (6 mL). 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 with EtOAc three times. Then, the combined organic phases were 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 to 95 / 5 to 90 / 10) to give 5-bromo-8-fluoroquinoxaline (198 mg, 0.872 mmol, 89%) as a pale yellow solid.

[0413] 8-Fluoroquinoxalin-5-amine

[0414]

[0415] The 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 to 7:3) to give 8-fluoroquinoxalin-5-amine (302 mg, 1.85 mmol, 59%) as a yellow / orange solid.

[0416] NMR 1H (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).

[0417] NMR 13 C (101 MHz, MeOD): δ = 149.59 (d, J = 245.8 Hz, C q ), 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 ).

[0418] NMR 19 F (376 MHz, MeOD, decoupled): δ = -144.36

[0419] N-(8-Fluoroquinoxalin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide (5)

[0420] 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 (DCM / MeOH 98 / 2 to 85 / 15), 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 and HPLC purity >99%.

[0421] Example 3: Preparation of 2-fluoro-4-(1-methylpiperidin-4-yl)-N-(quinolin-8-yl)benzamide (12)

[0422] Methyl 2-fluoro-4-(1-methylpiperidin-4-yl)benzoate

[0423]

[0424] Apply general procedure B to methyl 4-bromo-2-fluorobenzoate (1 equiv, 500 mg, 2.15 mmol) and 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (1.1 equiv, 526.6 mg, 2.36 mmol). Purify the crude product by flash column chromatography using EtOAC in heptane (0 - 100%) then methanol in DCM (0 - 10%) as eluent 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. After hydrogenation of the resulting compound (1 equiv, 280.8 mg, 1.13 mmol), methyl 3-fluoro-4-(1-methylpiperidin-4-yl)benzoate (275.5 mg, 1.096 mmol, 97%) was obtained as a yellow oil without purification.

[0425] 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).

[0426] NMR 19 F (376 MHz, MeOD): δ -120.24.

[0427] 2-Fluoro-4-(1-methylpiperidin-4-yl)-N-(quinolin-8-yl)benzamide)(12)

[0428] The general procedure F was applied to methyl 2-fluoro-4-(1-methylpiperidin-4-yl)benzoate (1 equiv, 275.5 mg, 1.096 mmol) to afford lithium 3-fluoro-4-(1-methylpiperidin-4-yl)benzoate (316 mg) as a pale beige powder in quantitative yield. According to general procedure G, amide bond coupling was carried out using this lithium salt (1 equiv, 76.68 mg, 0.32 mmol) and 8-quinolinamine (1.1 equiv, 50 mg, 0.35 mmol), and the reaction mixture was stirred at 30 °C overnight. 3 equiv of EDCI was 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) (61.9 mg, 0.17 mmol, 54%) was obtained as a beige powder with an HPLC purity of 99%.

[0429] Example 4: 4-(2-(Dimethylamino)ethoxy)-N-(quinolin-5-yl)benzamide) (15)

[0430] The general procedure F was applied to methyl 4-[2-(dimethylamino)ethoxy]benzoate (1.3 g, 5.82 mmol) to afford lithium 4-[2-(dimethylamino)ethoxy]benzoate (1.25 g) as a beige solid in quantitative yield. According to general procedure G, amide bond coupling was carried out using one equiv of this lithium salt (71.3 mg, 0.332 mmol) and 5-quinolinamine (1 equiv, 47.8 mg, 0.332 mmol), and the reaction mixture was stirred at 30 °C for 2 days, followed by the addition of 1.5 equiv 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 to 85 / 15) 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%.

[0431] 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

[0432]

[0433] General procedure B was applied to methyl 4-bromo-2-(trifluoromethyl)benzoate (1 equiv, 400 mg, 1.41 mmol) and 1-methyl-1,2,3,6-tetrahydropyridin-4-ylboronic acid pinacol ester (1.1 equiv, 346.85 mg, 1.55 mmol). The crude product was purified by flash column chromatography using EtOAc in heptane (50 - 100%) and then MeOH in DCM (0 - 10%) as eluents to afford methyl 4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(trifluoromethyl)benzoate (404 mg, 1.35 mmol, 96%) as an orange oil. After hydrogenation of the resulting compound, methyl 4-(1-methylpiperidin-4-yl)-2-(trifluoromethyl)benzoate (390 mg, 1.29 mmol, 97%) was obtained as a yellow oil and 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).

[0434] 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).

[0435] NMR 19 F (376 MHz, MeOD): δ -60.90.

[0436] 4-(1-Methylpiperidin-4-yl)-N-(quinolin-8-yl)-2-(trifluoromethyl)benzamide (18)

[0437] The general procedure G was applied to methyl 4-(1-methylpiperidin-4-yl)-2-(trifluoromethyl)benzoate (1 equiv, 390 mg, 1.29 mmol) to give lithium 4-(1-methylpiperidin-4-yl)-2-(trifluoromethyl)benzoate (450 mg, 1.53 mmol, quantitative yield), as a pale beige powder. The amide bond coupling was carried out using the previously synthesized lithium salt with 8-aminoquinoline (1.1 equiv, 60 mg, 0.42 mmol), and the reaction mixture was stirred overnight at 30 °C. 3 equiv of EDCI was 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. Methyl 4-(1-methylpiperidin-4-yl)-N-(quinolin-8-yl)-2-(trifluoromethyl)benzamide (18) (76 mg, 0.18 mmol, 49%) was obtained as an orange powder, and the HPLC purity was 97%.

[0438] Example 6: Preparation of 3-cyano-N-(isoquinolin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide (21)

[0439] Methyl 3-cyano-4-(1-methylpiperidin-4-yl)benzoate

[0440]

[0441] The general procedure B was applied to methyl 4-bromo-3-cyanobenzoate (1 equiv, 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 equiv, 296.37 mg, 1.33 mmol). The crude product was purified by flash column chromatography using EtOAc in heptane (50 - 100%) and then MeOH in DCM (0 - 10%) as the eluents to give methyl 3-cyano-4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)benzoate (384.37 mg) as a pale orange oil, quantitatively. After hydrogenating the resulting compound, the crude product was purified by flash column chromatography using MeOH in DCM (0 - 10%) as the eluent, and methyl 3-cyano-4-(1-methylpiperidin-4-yl)benzoate (177.2 mg, 0.69 mmol, 55%) was obtained as a yellow solid.

[0442] NMR 1H (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)

[0443] 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).

[0444] 3-Cyano-N-(isoquinolin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide (21)

[0445] General procedure F was applied to methyl 3-cyano-4-(1-methylpiperidin-4-yl)benzoate (1 equiv, 177.2 mg, 0.69 mmol) to afford lithium 3-cyano-4-(1-methylpiperidin-4-yl)benzoate (190.3 mg) as a pale yellow powder in quantitative yield. According to general procedure I, one equiv of the previously synthesized lithium salt (58.2 mg, 0.233 mmol) was used together with 5-isoquinolinamine (1 equiv, 33.5 mg, 0.233 mmol) according to general procedure G. The crude residue was purified by flash column chromatography on silica gel (DCM / MeOH 98 / 2 to 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 and with HPLC purity of 97%.

[0446] Example 7: Preparation of N-(isoquinolin-5-yl)-2-methylsulfonyl-4-(1-methylpiperidin-4-yl)benzamide (25) Methyl 2-methylsulfonyl-4-(1-methylpiperidin-4-yl)benzoate

[0447]

[0448] General procedure B was applied to methyl 4-bromo-2-(methylsulfonyl)benzoate (1 equiv, 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 equiv, 334.91 mg, 1.501 mmol). The crude product was purified by flash column chromatography using EtOAc in heptane (50 - 100%) and then MeOH in DCM (0 - 10%) as eluents to afford methyl 2-(methylsulfonyl)-4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)benzoate (410.5 mg, 1.33 mmol, 97%) as an orange oil. After hydrogenation of the resulting compound (1 equiv, 330 mg, 1.067 mmol), the crude product was purified by flash column chromatography using MeOH in DCM (0 - 20%) as an eluent and methyl 2-(methylsulfonyl)-4-(1-methylpiperidin-4-yl)benzoate (124.9 mg, 0.401 mmol, 37%) was obtained as a yellow oil.

[0449] 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).

[0450] 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.

[0451] N-(Isoquinolin-5-yl)-2-(methylsulfonyl)-4-(1-methylpiperidin-4-yl)benzamide (25)

[0452] The general procedure F was applied to methyl 2-(methylsulfonyl)-4-(1-methylpiperidin-4-yl)benzoate (1 equiv, 124 mg, 0.4 mmol) to afford lithium 2-(methylsulfonyl)-4-(1-methylpiperidin-4-yl)benzoate (130 mg) as a beige powder in quantitative yield. According to general procedure G, amide bond coupling was carried out using this lithium salt (1 equiv, 50 mg, 0.16 mmol) with 5-aminoisoquinoline (1.1 equiv, 26.14 mg, 0.18 mmol), and the reaction mixture was stirred at 35 °C overnight for 48 h, followed by the addition of another equivalent of EDCI (89.8 mg). The reaction was stirred at 35 °C for an additional 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-(methylsulfonyl)-4-(1-methylpiperidin-4-yl)benzamide (25) (26.6 mg, 0.063 mmol, 38%) was obtained as a pale yellow powder and had an HPLC purity of 98%.

[0453] 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

[0454]

[0455] The general procedure B was applied to methyl 4-bromo-3-(trifluoromethyl)benzoate (1 equiv, 400 mg, 1.41 mmol) and 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (1.1 equiv, 346.85 mg, 1.55 mmol). The crude product was purified by flash column chromatography using EtOAc in heptane (50 - 100%) and then MeOH in DCM (0 - 10%) as the eluent 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 equiv, 330 mg, 1.103 mmol), the crude product was purified by flash column chromatography using MeOH in DCM as the eluent (0 - 10%) to afford methyl 4-(1-methylpiperidin-4-yl)-3-(trifluoromethyl)benzoate (87.1 mg, 0.29 mmol, 26%) as a yellow oil.

[0456] NMR 1H(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).

[0457] 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).

[0458] NMR 19 F(376 MHz, MeOD): δ -60.63.

[0459] 4-(1-Methylpiperidin-4-yl)-N-(quinolin-5-yl)-3-(trifluoromethyl)benzamide (27)

[0460] The general procedure F was applied to methyl 4-(1-methylpiperidin-4-yl)-3-(trifluoromethyl)benzoate (1 equiv, 87 mg, 0.29 mmol) to afford lithium 4-(1-methylpiperidin-4-yl)-3-(trifluoromethyl)benzoate (96.8 mg) as a beige powder in quantitative yield. According to the general procedure G, amide bond coupling was carried out using this lithium salt (1 equiv, 40 mg, 0.14 mmol) with 5-quinolinamine (1.1 equiv, 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 successively added every 24 h, and each time the reaction mixture was stirred overnight at 35 °C. 73.5 mg of EDCI, 40.3 mg of lithium 4-(1-methylpiperidin-4-yl)-3-(trifluoromethyl)benzoate and 1 equiv of Et3N were added, and the reaction mixture was stirred at 35 °C for 48 h. After extraction, the crude product was purified by flash column chromatography using MeOH in EtOAc (0 - 15%) 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 HPLC purity of 98%.

[0461] Example 9: Preparation of 3-methyl-4-(4-methylpiperazin-1-yl)-N-(quinolin-5-yl)benzamide (29)

[0462] Methyl 3-methyl-4-(4-methylpiperazin-1-yl)benzoate

[0463]

[0464] The 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 to 70 / 30) and then MeOH in DCM (98 / 2 to 90 / 10) as the eluent to afford methyl 3-methyl-4-(4-methylpiperazin-1-yl)benzoate (160 mg, 0.646 mmol, 64%) as an orange oil.

[0465] 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).

[0466] 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).

[0467] 3-Methyl-4-(4-methylpiperazin-1-yl)-N-(quinolin-5-yl)benzamide (29)

[0468] General procedure F was applied to methyl 3-methyl-4-(4-methylpiperazin-1-yl)benzoate (158 mg, 0.639 mmol) to quantitatively afford lithium 3-methyl-4-(4-methylpiperazin-1-yl)benzoate (153.4 mg) as a pale orange solid. According to general procedure I, amide bond coupling was carried out using this lithium salt (1.1 equiv, 72 mg, 0.3 mmol) with 5-quinolinamine (1 equiv, 39.3 mg, 0.272 mmol). The crude residue was purified by flash column chromatography using MeOH in DCM (98 / 2 to 85 / 15) as the 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 and with HPLC purity of 92%.

[0469] Example 10: Preparation of 4-[2-(dimethylamino)ethoxy]-N-(8-methoxyisoquinolin-5-yl)benzamide (34)

[0470] According to general method G and starting from lithium 4-[2-(dimethylamino)ethoxy]benzoate (1 equiv, 50 mg, 0.23 mmol) and 8-methoxyisoquinolin-5-amine (1.1 equiv, 45 mg, 0.26 mmol), the reaction mixture was stirred at 35 °C overnight. 3 equiv of EDCI was 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) (38 mg, 0.23 mmol, 46%) was obtained as a grey powder.

[0471] Example 11: Preparation of 4-(4-methylpiperazin-1-yl)-N-(quinolin-8-yl)benzamide (35)

[0472] The general procedure H was applied to 4-(4-methylpiperazin-1-yl)benzoic acid (1 equiv, 250 mg, 1.13 mmol) to afford 4-(4-methylpiperazin-1-yl)benzoyl chloride (270.94 mg, 1.13 mmol, 100%). Then amide bond coupling was carried out using one equiv (50 mg, 0.209 mmol) of benzoyl chloride with 8-aminoquinoline (1.1 equiv, 33.22 mg, 0.23 mmol), and the crude residue was purified by flash column chromatography using a solution of 10% MeOH / DCM in pure DCM as the eluent (0 - 100%) to give 4-(4-methylpiperazin-1-yl)-N-(quinolin-8-yl)benzamide (35) (60 mg, 0.17 mmol, 83%) as an orange powder and with HPLC purity of 97%.

[0473] Example 12: Preparation of 3-cyano-4-[2-(dimethylamino)ethoxy]-N-(isoquinolin-8-yl)benzamide (36) Methyl 3-cyano-4-[2-(dimethylamino)ethoxy]benzoate

[0474]

[0475] The general procedure D was applied to commercially available methyl 3-cyano-4-hydroxybenzoate (1 equiv, 205 mg, 1.16 mmol) in acetone (8 mL). The mixture was stirred at 60 °C for 22 h and after extraction with EtOAc and H2O, methyl 3-cyano-4-[2-(dimethylamino)ethoxy]benzoate (119 mg, 0.48 mmol, 41%) was obtained as a light brown oil without further purification.

[0476] NMR 1 H (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).

[0477] 3-Cyano-4-[2-(dimethylamino)ethoxy]-N-(isoquinolin-8-yl)benzamide (36)

[0478] The general procedure F was applied to methyl 3-cyano-4-[2-(dimethylamino)ethoxy]benzoate (1 equiv, 119 mg, 0.43 mmol), and lithium 3-cyano-4-[2-(dimethylamino)ethoxy]benzoate (73 mg, 0.304 mmol, 70%) was obtained as a pale beige powder. According to the general procedure G, a solution of lithium 3-cyano-4-[2-(dimethylamino)ethoxy]benzoate (1 equiv, 50 mg, 0.208 mmol) and commercially available 8-aminoisoquinoline (1.1 equiv, 33 mg, 0.23 mmol) was used, and the reaction mixture was stirred at 35 °C for 24 h. The crude product was purified by flash column chromatography using MeOH in DCM (0 - 15%) 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%.

[0479] Example 13: Preparation of 4-(2-(dimethylamino)ethoxy)-3-methyl-N-(quinolin-8-yl)benzamide (43) Methyl 4-[2-(dimethylamino)ethoxy]-3-methylbenzoate

[0480]

[0481] The general procedure D was applied to methyl 4-hydroxy-3-methylbenzoate (1 equiv, 200 mg, 1.204 mmol) in acetone (3.5 mL). (2-Chloroethyl)dimethylamine hydrochloride (1.5 equiv, 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 and was used 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).

[0482] 4-(2-(Dimethylamino)ethoxy)-3-methyl-N-(quinolin-8-yl)benzamide (43)

[0483] The general procedure F was applied to methyl 4-[2-(dimethylamino)ethoxy]-3-methylbenzoate (1 equiv, 108 mg, 0.46 mmol), and lithium 4-[2-(dimethylamino)ethoxy]-3-methylbenzoate (142 mg) was obtained quantitatively as a white powder. The general procedure G was applied to this lithium salt (1 equiv, 92 mg, 0.401 mmol), and 4-[2-(dimethylamino)ethoxy]-3-methylbenzoyl chloride (97 mg, 0.401 mmol) was obtained as a beige powder. Then this benzoyl chloride was used together with commercially available 8-aminoquinoline (1.1 equiv, 60 mg, 0.42 mmol). The mixture was stirred overnight at room temperature, and the crude product was purified by flash column chromatography using MeOH in DCM as the eluent (0 - 10%). 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%.

[0484] Example 14: Preparation of N-(isoquinolin-5-yl)-2-methyl-4-(4-methylpiperazin-1-yl)benzamide (45)

[0485] Methyl 2-methyl-4-(4-methylpiperazin-1-yl)benzoate

[0486]

[0487] The general procedure C was applied to methyl 4-bromo-2-methylbenzoate (1 equiv, 204 mg, 0.893 mmol). The residue was purified by flash column chromatography using EtOAc in heptane (90 / 10 to 70 / 30), then MeOH in DCM (98 / 2 to 90 / 10), to give methyl 2-methyl-4-(4-methylpiperazin-1-yl)benzoate (211 mg, 0.853 mmol, 95%) as an orange oil.

[0488] 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).

[0489] 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).

[0490] N-(Isoquinolin-5-yl)-2-methyl-4-(4-methylpiperazin-1-yl)benzamide (45)

[0491] General procedure F was applied to methyl 3-methyl-4-(4-methylpiperazin-1-yl)benzoate (1 equiv, 158 mg, 0.639 mmol) to obtain lithium 3-methyl-4-(4-methylpiperazin-1-yl)benzoate (181 mg) quantitatively. General procedure G was applied to this lithium salt (1 equiv, 100 mg, 0.42 mmol) to give 2-methyl-4-(4-methylpiperazin-1-yl)benzoyl chloride (105 mg, 0.42 mmol, 100%). Amide coupling was carried out using this benzoyl chloride (1.1 equiv., 50 mg, 0.2 mmol) with 5-isoquinolinamine (1 equiv 25.93 mg, 0.18 mmol), and the crude product was purified by flash column chromatography using a solution of 10% MeOH / DCM in pure DCM (0 - 100%) as the eluent. The desired N-(5-fluoroisoquinolin-8-yl)-4-(4-methylpiperazin-1-yl)benzamide (45) (8 mg, 0.022 mmol, 12%) was obtained as a yellow powder and had an HPLC purity of 95%.

[0492] Example 15: Preparation of 4-[2-(dimethylamino)ethoxy]-2-methyl-N-(quinolin-5-yl)benzamide (47) Methyl 4-[2-(dimethylamino)ethoxy]-2-methylbenzoate

[0493]

[0494] General procedure D was applied to methyl 4-hydroxy-2-methylbenzoate (1 equiv, 200 mg, 1.204 mmol) and (2-chloroethyl)dimethylamine hydrochloride (1.5 equiv, 260 mg, 1.805 mmol). The reaction mixture 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), then MeOH in DCM (98 / 2 to 85 / 15) as the eluent to give methyl 4-[2-(dimethylamino)ethoxy]-2-methylbenzoate (198 mg, 0.83 mmol, 69%) as an oil.

[0495] 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

[0496] 4-[2-(Dimethylamino)ethoxy]-2-methyl-N-(quinolin-5-yl)benzamide (47)

[0497] General procedure F was applied to methyl 4-[2-(dimethylamino)ethoxy]-2-methylbenzoate (1 equiv, 198 mg, 0.83 mmol), and lithium 4-[2-(dimethylamino)ethoxy]-2-methylbenzoate (296 mg) was obtained quantitatively as a white powder. General procedure G was applied to this lithium salt (1 equiv, 296 mg, 1.29 mmol), and 4-[2-(dimethylamino)ethoxy]-2-methylbenzoyl chloride (312.17 mg, 1.29 mmol) was obtained as a white powder. Then this benzoyl chloride (1 equiv, 298 mg, 1.23 mmol) was used with commercially available 5-aminoquinoline (1 equiv, 177 mg, 1.23 mmol), and the mixture was stirred overnight at room temperature. The crude product was purified on silica gel using MeOH in DCM as the eluent (0 - 10%). The resulting fractions were triturated in diethyl ether, and 4-[2-(dimethylamino)ethoxy]-2-methyl-N-(quinolin-5-yl)benzamide (47) (30 mg, 0.086 mmol, 7%) was obtained as a yellow powder with an HPLC purity of 93.5%.

[0498] Example 16: Preparation of 4-[2-(dimethylamino)ethoxy]-N-(isoquinolin-5-yl)-3-(trifluoromethyl)benzamide (48)

[0499] Methyl 4-[2-(dimethylamino)ethoxy]-3-(trifluoromethyl)benzoate

[0500]

[0501] The general procedure D was applied to methyl 4-hydroxy-3-(trifluoromethyl)benzoate (1 equiv, 200 mg, 0.908 mmol) and 2-(dimethylamino)ethyl chloride hydrochloride (1.5 equiv, 196 mg, 1.36 mmol). The reaction mixture was stirred at 60 °C overnight (21 h) to afford methyl 4-[2-(dimethylamino)ethoxy]-3-(trifluoromethyl)benzoate (233 mg, 0.8 mmol, 88%) as a pale brown oil, which was used without further purification and had an HPLC purity of 96%.

[0502] 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).

[0503] 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.

[0504] NMR 19 F (376 MHz, MeOD, decoupled): δ -63.85.

[0505] 4-[2-(Dimethylamino)ethoxy]-N-(isoquinolin-5-yl)-3-(trifluoromethyl)benzamide (48)

[0506] The general method F (for preparing lithium salts) was applied to methyl 4-[2-(dimethylamino)ethoxy]-3-(trifluoromethyl)benzoate (1 equiv, 233 mg, 0.8 mmol), and lithium 4-[2-(dimethylamino)ethoxy]-3-(trifluoromethyl)benzoate (233 mg) was obtained quantitatively as a white powder. The general procedure G was applied to this lithium salt (1 equiv, 296 mg, 1.29 mmol), and 4-[2-(dimethylamino)ethoxy]-3-(trifluoromethyl)benzoyl chloride (243.29 mg, 0.82 mmol) was obtained as a white solid. Then this benzoyl chloride was used with commercially available 5-isoquinolinamine (1.2 equiv, 141 mg, 0.98 mmol), and the mixture was stirred overnight at room temperature. The crude product was purified by flash column chromatography using MeOH in DCM as the eluent (0 - 10%), and 4-[2-(dimethylamino)ethoxy]-N-(isoquinolin-5-yl)-3-(trifluoromethyl)benzamide (48) (42 mg, 0.104 mmol, 11%) was obtained as a yellow powder with an HPLC purity of 99%.

[0507] Example 17: Preparation of 4-[2-(dimethylamino)ethoxy]-N-(quinolin-5-yl)-2-(trifluoromethyl)ben zamide (49)

[0508] Methyl 4-[2-(dimethylamino)ethoxy]-2-(trifluoromethyl)benzoate

[0509]

[0510] The general procedure D was applied to methyl 4-hydroxy-2-(trifluoromethyl)benzoate (1 equiv, 200 mg, 0.908 mmol) and (2-chloroethyl)dimethylamine hydrochloride (1.5 equiv, 196 mg, 1.36 mmol). The reactants were stirred overnight (21 h) at 60 °C, and methyl 4-[2-(dimethylamino)ethoxy]-2-(trifluoromethyl)benzoate (144 mg, 0.49 mmol, 54%) was obtained without further purification and with a purity of 96%.

[0511] 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)

[0512] NMR 13C(126 MHz, MeOD): δ 166.43, 161.06, 132.93, 116.25, 113.72, 113.67, 65.93, 57.39, 51.62, 44.44.

[0513] NMR 19 F (376 MHz, MeOD, decoupled): δ -60.96.

[0514] 4-[2-(Dimethylamino)ethoxy]-N-(quinolin-5-yl)-2-(trifluoromethyl)benzamide (49)

[0515] General procedure F was applied to methyl 4-[2-(dimethylamino)ethoxy]-2-(trifluoromethyl)benzoate (1 equiv, 144 mg, 0.49 mmol), and lithium 4-[2-(dimethylamino)ethoxy]-2-(trifluoromethyl)benzoate (160 mg) was obtained quantitatively as a white powder. General procedure G was applied to this lithium salt (1 equiv, 160 mg, 0.57 mmol), and 4-[2-(dimethylamino)ethoxy]-2-(trifluoromethyl)benzoyl chloride (167 mg, 0.57 mmol) was obtained as a white powder. Then this benzoyl chloride (1 equiv, 160 mg, 0.54 mmol) was used together with commercially available 5-isoquinolinamine (1 equiv, 141 mg, 0.98 mmol). The mixture was stirred overnight at room temperature, and the crude product was purified by flash column chromatography using MeOH in DCM as the solvent (0 - 10%). 4-[2-(Dimethylamino)ethoxy]-N-(quinolin-5-yl)-2-(trifluoromethyl)benzamide (49) (22 mg, 0.055 mmol, 10%) was obtained as a yellow powder, and the HPLC purity was 99%.

[0516] Example 18: Preparation of 3-fluoro-N-(5-fluoroisoquinolin-8-yl)-4-{5-methyl-octahydropyrrolo[3,4-c]pyrrol-2-yl}benzamide (53)

[0517] Methyl 3-fluoro-4-{5-methyl-octahydropyrrolo[3,4-c]pyrrol-2-yl}benzoate

[0518]

[0519] General procedure C was applied to methyl 4-bromo-3-fluorobenzoate (1 equiv, 200 mg, 0.86 mmol) and 2-methyl-octahydropyrrolo[3,4-c]pyrrole dihydrochloride (1.2 equiv, 1.03 mmol, 205 mg). The reaction mixture was cooled to room temperature. The mixture was diluted in EtOAc, and in Filtered through a 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 to 70 / 30, then DCM / MeOH 98 / 2 to 90 / 10) to give 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.

[0520] 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).

[0521] 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.

[0522] 19 F NMR (376 MHz, methanol-d4): δ -125.33.

[0523] 3-Fluoro-N-(5-fluoroisoquinolin-8-yl)-4-{5-methyl-octahydropyrrolo[3,4-c]pyrrol-2-yl}benzamide (53) The general procedure F was applied to methyl 3-fluoro-4-{5-methyl-octahydropyrrolo[3,4-c]pyrrol-2-yl}benzoate (1 equiv, 111 mg, 0.4 mmol) to give lithium 3-fluoro-4-{5-methyl-octahydropyrrolo[3,4-c]pyrrol-2-yl}benzoate (107.77 mg, 0.4 mmol, 100%) as a yellow powder.

[0524] Then the general procedure H was applied to the lithium salt (1 equiv, 100 mg, 0.37 mmol) to afford 4-[2-(dimethylamino)ethoxy]-2-(trifluoromethyl)benzoyl chloride (100 mg, 0.35 mmol, 94.5%) as a white solid, which was used directly without further purification in the next step with 5-fluoroisoquinolin-8-amine (0.52 equiv, 30 mg, 0.18 mmol). The crude product was purified on silica gel using methanol in DCM as the solvent (0 - 10%). The desired 3-fluoro-N-(5-fluoroisoquinolin-8-yl)-4-{5-methyl-octahydropyrrolo[3,4-c]pyrrol-2-yl}benzamide (53) (13.5 mg, 0.033 mmol, 18%) was obtained as a yellow solid and was 95% pure by HPLC.

[0525] Example 19: N-(8-Methoxyisoquinolin-5-yl)-3-methyl-4-{7-methyl-2,7-diazaspiro[3.5]nonan-2-yl}benzamide (54)

[0526] Methyl 3-methyl-4-{7-methyl-2,7-diazaspiro[3.5]nonan-2-yl}benzoate

[0527]

[0528] The general procedure C was applied to methyl 4-bromo-3-methylbenzoate (1 equiv, 200 mg, 0.87 mmol) and 7-methyl-2,7-diazaspiro[3.5]nonane dihydrochloride (1.2 equiv, 223 mg, 1.048 mmol). The reaction mixture was cooled to room temperature. The mixture was diluted in EtOAc, filtered through a 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 to 70 / 30, then DCM / MeOH 98 / 2 to 90 / 10) to afford 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.

[0529] 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).

[0530] N-(8-Methoxyisoquinolin-5-yl)-3-methyl-4-{7-methyl-2,7-diazaspiro[3.5]nonan-2-yl}benzamide (54)

[0531] The general procedure F was applied to methyl 3-methyl-4-{7-methyl-2,7-diazaspiro[3.5]nonan-2-yl}benzoate (1 equiv, 161.5 mg, 0.56 mmol) to give lithium 3-methyl-4-{7-methyl-2,7-diazaspiro[3.5]nonan-2-yl}benzoate (165 mg, 0.56 mmol, 100%) as a yellow powder.

[0532] Then the general procedure H was applied to this lithium salt (1.28 equiv, 114 mg, 0.41 mmol) to quantitatively afford 3-methyl-4-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)benzoyl chloride (100 mg, 0.34 mmol, 83%) as a white powder, which was used directly without further purification in the next step with 8-methoxyisoquinolin-5-amine (1 equiv, 56.66 mg, 0.33 mmol). The crude product was purified on silica gel using methanol in DCM as the solvent (0 - 10%). The desired 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.

[0533] 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

[0534]

[0535] The general procedure E was applied to (1-methylpyrrolidin-3-yl)methanol (1 equiv, 200 mg, 0.205 mL, 1.74 mmol), triphenylphosphine (1.1 equiv, 501.009 mg, 1.91 mmol) and methyl 4-hydroxy-3-methylbenzoate (1.1 equiv, 317.42 mg, 1.91 mmol). The crude product was purified on silica gel using MeOH in DCM as the 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.

[0536] 11H 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).

[0537] 13 13C 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.

[0538] 3-Methyl-4-[(1-methylpyrrolidin-3-yl)methoxy]-N-(quinolin-8-yl)benzamide (55)

[0539] General procedure F was applied to methyl 3-methyl-4-[(1-methylpyrrolidin-3-yl)methoxy]benzoate (1 equiv, 150 mg, 0.57 mmol) to afford lithium 3-methyl-4-[(1-methylpyrrolidin-3-yl)methoxy]benzoate (100 mg, 73%) as a yellow powder.

[0540] Then general procedure H was applied to lithium ({3-methyl-4-[(1-methylpyrrolidin-3-yl)methoxy]phenyl})methanone (1.31 equiv, 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 equiv, 51.28 mg, 0.36 mmol) to give 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.

[0541] Example 21: 2-Fluoro-N-(isoquinolin-8-yl)-4-[4-(propan-2-yl)piperazin-1-yl]benzamide (57)

[0542] Methyl 2-fluoro-4-[4-(propan-2-yl)piperazin-1-yl]benzoate

[0543]

[0544] The general procedure C was applied to methyl 4-bromo-2-fluorobenzoate (1 equiv, 300 mg, 1.29 mmol) and 1-isopropylpiperazine (1.2 equiv, 198.076 mg, 0.22 mL, 1.54 mmol). The reactants were cooled at room temperature and the mixture was diluted in EtOAC, filtered over a 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 - 100%) to afford methyl 2-fluoro-4-[4-(propan-2-yl)piperazin-1-yl]benzoate (193.4 mg, 0.69 mmol, 53.59%) as an orange solid.

[0545] 1 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).

[0546] 19 19F NMR (376 MHz, MeOD): δ -109.05.

[0547] 13 13C 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).

[0548] Lithium 2-fluoro-4-[4-(propan-2-yl)piperazin-1-yl]benzoate

[0549]

[0550] The general procedure F was applied to methyl 2-fluoro-4-[4-(propan-2-yl)piperazin-1-yl]benzoate (1 equivalent, 190 mg, 0.68 mmol) to afford lithium 2-fluoro-4-[4-(propan-2-yl)piperazin-1-yl]benzoate (202.1 mg, 0.74 mmol) as a beige powder.

[0551] 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).

[0552] 19 F NMR (376 MHz, MeOD): δ -113.00.

[0553] 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).

[0554] 2-Fluoro-N-(isoquinolin-8-yl)-4-[4-(propan-2-yl)piperazin-1-yl]benzamide (57)

[0555] The general procedure H was applied to lithium 2-fluoro-4-[4-(propan-2-yl)piperazin-1-yl]benzoate (1.03 equivalents, 51.5 mg, 0.19 mmol). The crude product was purified by flash column chromatography using methanol in DCM as the solvent (0–10%). The desired 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 and had an HPLC purity of 99%.

[0556] Example 22: N-(5-fluoroisoquinolin-8-yl)-3-methoxy-4-[(1R,4S)-5-methyl-2,5-diazabicyclo N-([2.2.1]bicyclohept-2-yl)benzamide (58)

[0557] Methyl 3-methoxy-4-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]benzoate

[0558] General procedure C was applied to methyl 4-bromo-3-methoxybenzoate (1 equiv, 300 mg, 1.22 mmol), (1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptane dihydrochloride (1.2 equiv, 271.89 mg, 1.47 mmol) and Cs2CO3 (3.4 equiv, 1356.072 mg, 4.16 mmol). The residue was purified by flash column chromatography using a solution of 10% MeOH in DCM in pure DCM (0 - 100%) to afford methyl 3-methoxy-4-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]benzoate (163 mg, 0.59 mmol, 48%) as a brown oil.

[0559] NMR 1 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).

[0560] NMR 13 13C (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.

[0561] Lithium 3-methoxy-4-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]benzoate

[0562] The general method F was applied to methyl 3-methoxy-4-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]benzoate (1 equiv, 156 mg, 0.56 mmol). The reaction mixture was stirred at 25 °C for 48 h. After evaporation, lithium 3-methoxy-4-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]benzoate (189.7 mg, 0.71 mmol) was obtained quantitatively as a beige powder.

[0563] NMR 1 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).

[0564] 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.

[0565] N-(5-Fluoroisoquinolin-8-yl)-3-methoxy-4-[(1R,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]benzamide (58)

[0566]

[0567] The general method H was applied to lithium 3-methoxy-4-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]benzoate (1 equivalent, 50 mg, 0.19 mmol). The crude product was purified by flash column chromatography using MeOH in DCM as the solvent (0 - 10%). The desired N-(5-fluoroisoquinolin-8-yl)-3-methoxy-4-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]benzamide (58) (8.8 mg, 0.022 mmol, 13%) was obtained as a yellow powder with an HPLC purity of 95%.

[0568] Example 23: N-(6-Methoxyisoquinolin-8-yl)-4-(1-methylpiperidin-4-yl)benzamide (63)

[0569]

[0570] The general method J was applied to 4-(1-methylpiperidin-4-yl)benzamide (1.03 equivalents, 58.5 mg, 0.27 mmol) and 8-bromo-6-methoxyisoquinoline (1 equivalent, 61.94 mg, 0.26 mmol). The crude product was purified by flash column chromatography, pre-rinsed with diethyl ether and 5% Et3N solution, then pre-rinsed with DCM, and gradient eluted with a solution 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 and had an HPLC purity of 95%.

[0571] Example 24: N-(8-Methoxyisoquinolin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide (65)

[0572]

[0573] The general method H was applied to 4-(1-methylpiperidin-4-yl)benzoyl chloride (1.54 equivalents, 61.6 mg, 0.26 mmol) and 8-methoxyisoquinolin-5-amine (1.02 equivalents, 29.9 mg, 0.17 mmol). The crude product was purified by flash column chromatography using MeOH in DCM (0 - 15%) and then a solution of 10% MeOD in DCM with 5% Et3N as the eluent. N-(8-Methoxyisoquinolin-5-yl)-4-(1-methylpiperidin-4-yl)benzamide (65) (55.6 mg, 0.15 mmol, 86%) was obtained as a white powder and had an HPLC purity of 99%.

[0574] Example 25: N-(8-Methoxyisoquinolin-5-yl)-4-(4-methylpiperazin-1-yl)benzamide hydrochloride (70)

[0575]

[0576] The general method 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 in DCM (0 - 20%) as the eluent and re-purified in reverse phase using a solution of acetonitrile with water and 0.05% HCl (0 - 100%) to give N-(8-methoxyisoquinolin-5-yl)-4-(4-methylpiperazin-1-yl)benzamide hydrochloride (70) (55 mg, 0.13 mmol, 78%), and the HPLC purity was 99%.

[0577] Example 26: N-(6-Chloroisoquinolin-8-yl)-4-(4-methylpiperazin-1-yl)benzamide (73)

[0578]

[0579] The general method 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 in DCM (0 - 15%) as the eluent. The product was re-purified in reverse phase using a solution of acetonitrile and water + 0.05% HCl (0 to 100%). The salt was washed with basic aqueous phase (NaOH pH ~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.

[0580] Example 27: Methyl 8-[4-(1-methylpiperidin-4-yl)benzamido]quinoline-5-carboxylate (75)

[0581]

[0582] The general method J was applied to 4-(1-methylpiperidin-4-yl)benzamide (1.042 equiv., 50.6 mg, 0.23 mmol) and methyl 8-bromoquinoline-5-carboxylate (1.026 equiv., 60.7 mg, 0.23 mmol). The crude product was purified by flash column chromatography on silica gel using MeOH in DCM (0 - 20%) as the eluent. The resulting fraction was repurified by reverse phase using a solution of acetonitrile and water and 0.05% HCl (0 to 100%) as the eluent. The salt was washed with basic aqueous phase (NaOH pH ~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 and was 98% pure by HPLC.

[0583] Example 28: 4-[2-(Dimethylamino)ethoxy]-N-(quinazolin-5-yl)benzamide (83)

[0584]

[0585] The general method J was applied to 4-[2-(dimethylamino)ethoxy]benzoyl chloride (0.86 equiv., 215 mg, 0.94 mmol) and 5-bromoquinazoline (1 equiv., 50.19 mg, 0.24 mmol). The crude product was purified by flash column chromatography on silica gel using MeOH in DCM (0 - 20%) 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 and was 98% pure by HPLC.

[0586] Example 29: 4-[2-(Dimethylamino)ethoxy]-N-(6-methoxyisoquinolin-8-yl)benzamide (87)

[0587]

[0588] The general procedure J was applied to 4-[2-(dimethylamino)ethoxy]benzamide (1.028 equiv., 51.4 mg, 0.25 mmol) and 8-bromo-6-methoxyisoquinoline (1.006 equiv., 57.5 mg, 0.24 mmol). The crude product was purified by flash column chromatography on silica gel using MeOH in DCM (0 - 20%) 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 and was 98% pure by HPLC.

[0589] 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 Example 31: 3-Cyano-4-[(1-methylpyrrolidin-3-yl)methoxy]-N-(quinoxalin-5-yl)benzamide

[0590]

[0591] General method C was applied to methyl 4-bromo-2-methylbenzoate (1.053 equiv, 315.9 mg, 1.38 mmol) and 1-methyl-1,4-diazepane (1.2 equiv, 179.46 mg, 195.49 μL, 1.57 mmol), and the reactants were stirred at 120 °C for 22 h. The residue was purified by flash column chromatography using a solution of 10% MeOH in DCM and pure DCM (0 - 100%) to give methyl 2-methyl-4-(4-methyl-1,4-diazepan-1-yl)benzoate (250 mg, 0.95 mmol, 69%) as an orange-brown oil.

[0592] NMR 1 H (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).

[0593] 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 masked by solvent)

[0594] Lithium 2-methyl-4-(4-methyl-1,4-diazepan-1-yl)benzoate

[0595]

[0596] General method F was applied to methyl 2-methyl-4-(4-methyl-1,4-diazepan-1-yl)benzoate (1 equiv, 233 mg, 0.89 mmol), and the reaction mixture was stirred at 35 °C for 72 h.

[0597] Lithium 2-methyl-4-(4-methyl-1,4-diazepan-1-yl)benzoate (266.7 mg, 1.049 mmol) was obtained quantitatively as a beige powder.

[0598] 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).

[0599] 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 was masked by the solvent).

[0600] 2-Methyl-4-(4-methyl-1,4-diazepan-1-yl)-N-(quinolin-5-yl)benzamide (95)

[0601]

[0602] The general method H was applied to lithium 2-methyl-4-(4-methyl-1,4-diazepan-1-yl)benzoate (1.016 equiv, 101.6 mg, 0.4 mmol), and the reaction was completed after stirring at 40 °C for 45 min. After evaporation; 2-methyl-4-(4-methyl-1,4-diazepan-1-yl)benzoyl chloride (1 equiv, 105 mg, 0.39 mmol) and 5-aminoquinoline (1.022 equiv, 58 mg, 0.402 mmol) were used, and the reactants were stirred overnight at room temperature. EDCI (2.092 equiv, 127.8 mg, 0.82 mmol) was added and the reaction mixture was stirred overnight at 35 °C. The crude product was purified by flash column chromatography using MeOH in DCM as the solvent (0 - 20%). The desired 2-methyl-4-(4-methyl-1,4-diazepan-1-yl)-N-(quinolin-5-yl)benzamide (95) (48.9 mg, 0.13 mmol, 33%) was obtained as a beige powder and the HPLC purity was 95%.

[0603] Example 32: 4-(Piperazin-1-yl)-N-(quinolin-8-yl)benzamide hydrochloride (97) (96)

[0604] Methyl 3-cyano-4-[(1-methylpyrrolidin-3-yl)methoxy]benzoate

[0605]

[0606] The 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.

[0607] 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).

[0608] 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.

[0609] Lithium 3-cyano-4-[(1-methylpyrrolidin-3-yl)methoxy]benzoate

[0610]

[0611] The 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 in diethyl ether. After evaporation, lithium 3-cyano-4-[(1-methylpyrrolidin-3-yl)methoxy]benzoate (316.1 mg, 1.19 mmol, 98%) was obtained as an off-white powder.

[0612] NMR 1H (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).

[0613] 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.

[0614] 3-Cyano-4-[(1-methylpyrrolidin-3-yl)methoxy]-N-(quinoxalin-5-yl)benzamide (96)

[0615]

[0616] The general method H was applied to lithium 3-cyano-4-[(1-methylpyrrolidin-3-yl)methoxy]benzoate (1.026 equiv, 102.6 mg, 0.39 mmol) to afford 3-cyano-4-[(1-methylpyrrolidin-3-yl)methoxy]benzoyl chloride (107.42 mg, 0.39 mmol, 100%) as a white powder and was heated for 45 min. This product was used together with quinoxalin-5-amine (1 equiv, 55.93 mg, 0.39 mmol), stirred at room temperature for 16 h, then EDCI (2.03 equiv, 121.4 mg, 0.78 mmol) and HOBt (1 equiv, 52.065 mg, 0.39 mmol) were added, and the reaction mixture was stirred at room temperature for 16 h. EDCI (2 equiv, 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 (0–20%) in DCM as the eluent. The fraction was triturated in diethyl ether and EtOAc to afford 3-cyano-4-[(1-methylpyrrolidin-3-yl)methoxy]-N-(quinoxalin-5-yl)benzamide (96) (29 mg, 0.075 mmol, 20%) as a pale orange powder and was 98% pure by HPLC.

[0617] Example 33: 4-[(1-Methylpiperidin-4-yl)amino]-N-(quinolin-8-yl)-2-(trifluoromethyl)benzamide hydrochloride (98)

[0618] 1-Boc-4-(4-methoxycarbonylphenyl)piperazine

[0619]

[0620] General procedure C was applied to methyl 4-bromobenzoate (1.008 equiv, 504 mg, 2.34 mmol) and tert-butyl piperazine-1-carboxylate (1.22 equiv, 529.2 mg, 2.84 mmol), and the reaction mixture was stirred at 120 °C for 22 h. The crude product was purified by flash column chromatography on silica gel using EtOAc (0–50%) in heptane as the eluent to give 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).

[0621] 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.

[0622] tert-Butyl 4-{4-[(lithiooxy)carbonyl]phenyl}piperazine-1-carboxylate

[0623]

[0624] General procedure F was applied to 1-boc-4-(4-methoxycarbonylphenyl)piperazine (1 equiv, 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 (0–10%) in DCM as the eluent. tert-Butyl 4-{4-[(lithiooxy)carbonyl]phenyl}piperazine-1-carboxylate (443 mg, 1.42 mmol, 64%) was obtained as a brown / beige powder.

[0625] NMR 1H (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).

[0626] 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.

[0627] 4-(Piperazin-1-yl)-N-(quinolin-8-yl)benzamide hydrochloride (97)

[0628]

[0629] Apply the general method H to tert-butyl 4-{4-[(lithiooxy)carbonyl]phenyl}piperazine-1-carboxylate (1 equiv, 150 mg, 0.48 mmol). Heat the reaction mixture at room temperature for 25 min and quantitatively obtain tert-butyl 4-[4-(carbonylchloro)phenyl]piperazine-1-carboxylate (163.5 mg, 0.503 mmol) as a beige powder. Then use it with 8-aminoquinoline (1 equiv, 72.57 mg, 0.503 mmol) and stir the reaction mixture at room temperature for 3 h. Purify the crude product by flash column chromatography on silica gel using EtOAc (0 - 50%) in heptane as the eluent. Dilute 50 mg of the product in dioxane (1 mL), add 4 M HCl in dioxane (1 equiv, 0.029 mL, 0.12 mmol) and stir the mixture for 1 h, and then evaporate the solvent. Obtain 4-(piperazin-1-yl)-N-(quinolin-8-yl)benzamide hydrochloride (97) (50 mg, 0.14 mmol) as a yellow powder and the total yield is 62%. The HPLC purity is 99%.

[0630] Example 34: 4-(4-Cyclobutylpiperazin-1-yl)-N-(isoquinolin-5-yl)-2-methoxybenzamide hydrochloride (99) Methyl 4-(4-cyclobutylpiperazin-1-yl)-2-methoxybenzoate Example 35: N-(Isoquinolin-5-yl)-4-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)benzamide

[0631] Methyl 4-[(1-methylpiperidin-4-yl)amino]-2-(trifluoromethyl)benzoate

[0632]

[0633] The general method C was applied to methyl 4-bromo-2-(trifluoromethyl)benzoate (1.083 equiv, 541.3 mg, 1.91 mmol) and methyl piperidin-4-amine (1.2 equiv, 242.06 mg, 266 μL, 2.12 mmol). The crude product was purified by flash column chromatography using a MeOH DCM solution (0 - 20%) to give methyl 4-[(1-methylpiperidin-4-yl)amino]-2-(trifluoromethyl)benzoate (436.5 mg, 1.38 mmol, 72%) as an orange-brown oil. 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).

[0634] 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.

[0635] NMR 19 F (376 MHz, MeOD): δ -61.31.

[0636] Lithium 4-[(1-methylpiperidin-4-yl)amino]-2-(trifluoromethyl)benzoate

[0637]

[0638] The general method F was applied to methyl 4-[(1-methylpiperidin-4-yl)amino]-2-(trifluoromethyl)benzoate (1 equiv, 436 mg, 1.38 mmol). After stirring for 5 days at 35 °C, lithium 4-[(1-methylpiperidin-4-yl)amino]-2-(trifluoromethyl)benzoate (460.8 mg, 1.49 mmol) was obtained quantitatively as a beige powder.

[0639] NMR 1H (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).

[0640] 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.

[0641] 4-[(1-Methylpiperidin-4-yl)amino]-N-(quinolin-8-yl)-2-(trifluoromethyl)benzamide hydrochloride (98)

[0642] The general method H was applied to lithium 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 (104 mg) was obtained as a beige powder. Then it was used with 8-quinolinamine (1.074 eq., 50.2 mg, 0.35 mmol), and the reactants were stirred at room temperature for 16 h. The crude product was purified by flash column chromatography on silica gel using MeOH in DCM (0–20%) as the eluent and re-purified in the reverse phase using a solution of acetonitrile and 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) (69.9 mg, 0.15 mmol, 46%) was obtained as a yellow powder and had an HPLC purity of 99%.

[0643] Example 36: 2-Methanesulfonyl-4-(piperazin-1-yl)-N-(quinolin-5-yl)benzamide hydrochloride (113) Example 37: Binding assay

[0644]

[0645] The general method C was applied to methyl 4-bromo-2-methoxybenzoate (1 equiv, 300.1 mg, 1.22 mmol) and 1-cyclobutylpiperazine (1.2 equiv, 205.99 mg, 0.203 mL, 1.47 mmol), and the mixture was stirred at 120 °C for 22 h. The crude product was purified by flash column chromatography using MeOH in DCM (0 to 10%) to give methyl 4-(4-cyclobutylpiperazin-1-yl)-2-methoxybenzoate (269.3 mg, 0.88 mmol, 72%) as an orange-brown solid.

[0646] 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).

[0647] 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.

[0648] Lithium 4-(4-cyclobutylpiperazin-1-yl)-2-methoxybenzoate

[0649]

[0650] The general method F was applied to methyl 4-(4-cyclobutylpiperazin-1-yl)-2-methoxybenzoate (1 equiv, 269 mg, 0.88 mmol), and the reaction mixture was stirred at 35 °C overnight. Lithium 4-(4-cyclobutylpiperazin-1-yl)-2-methoxybenzoate (255.8 mg, 0.86 mmol, 98%) was obtained as a beige powder.

[0651] NMR 1H (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).

[0652] 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 masked by MeOD signal).

[0653] 4-(4-Cyclobutylpiperazin-1-yl)-N-(isoquinolin-5-yl)-2-methoxybenzamide hydrochloride (99)

[0654] General procedure G was applied to lithium 4-(4-cyclobutylpiperazin-1-yl)-2-methoxybenzoate (1.035 equiv, 62.1 mg, 0.21 mmol) and 5-aminoisoquinoline (1.13 equiv, 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 a solution of EtOAc in heptane (50–100%) as eluent and further purified by reverse phase using a solution of acetonitrile and ultrapure water mixed with 0.05% TFA (0–30%) as eluent. A third purification was carried out by flash column chromatography on silica gel using a solution of MeOH in EtOAc (0–20%) as eluent to afford 4-(4-cyclobutylpiperazin-1-yl)-N-(isoquinolin-5-yl)-2-methoxybenzamide hydrochloride (99) (17 mg, 0.038 mmol, 18%) as a white powder with HPLC purity of 99%.

[0655] A. Principle (111)

[0656] Methyl 4-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)benzoate

[0657]

[0658] The general method C was applied to methyl 4-bromo-2-(trifluoromethyl)benzoate (0.19 mL, 1.06 mmol, 1.1 equiv) and 1-methylpiperazine (0.11 mL, 0.96 mmol, 1 equiv), and the reactants were stirred at 120 °C for 22 h. The residue was purified by flash column chromatography on silica gel using MeOH in DCM (0 - 20%) as the eluent. Methyl 4-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)benzoate (277 mg, 0.92 mmol, 95%) was obtained as a yellow oil.

[0659] 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,).

[0660] 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.

[0661] Lithium 4-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)benzoate

[0662]

[0663] The general method F was applied to methyl 4-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)benzoate (277 mg, 0.92 mmol, 1 equiv), and the reactants were stirred at 35 °C for 2 days. The crude product was triturated with EtOAc and evaporated under reduced pressure. Lithium 4-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)benzoate (300 mg, 1.02 mmol) was obtained quantitatively as a yellow powder.

[0664] 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, 2x CH2), 2.63 (t, J = 5.1 Hz, 4H, 2x CH2), 2.37 (s, 3H, NMe).

[0665] 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.

[0666] N-(Isoquinolin-5-yl)-4-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)benzamide (111)

[0667]

[0668] The general method H was applied to lithium 4-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)benzoate (100 mg, 0.34 mmol, 1 equiv) and 5-isoquinolinamine (44 mg, 0.31 mmol, 1 equiv). The mixture was stirred overnight at room temperature. 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) (21 mg, 0.051 mmol, 16%) was obtained as a beige powder and had an HPLC purity of 95%.

[0669] B. Materials & Methods

[0670] tert-Butyl 4-[3-(methylsulfonyl)-4-(methoxycarbonyl)phenyl]piperazine-1-carboxylate

[0671]

[0672] General procedure B was applied to methyl 4-bromo-2-(methylsulfonyl)benzoate (1.2 equiv, 250 mg, 0.85 mmol) and tert-butyl piperazine-1-carboxylate (1 equiv, 132.38 mg, 0.71 mmol) using XPhos (0.11 equiv, 37.27 mg, 0.078 mmol) in dry toluene (2.36 mL). The mixture was stirred at 100 °C for 10 h. The residue was purified by flash column chromatography using MeOH (0 - 20%) in DCM as eluent to afford tert-butyl 4-[3-(methylsulfonyl)-4-(methoxycarbonyl)phenyl]piperazine-1-carboxylate (282.4 mg, 0.709 mmol, 99%) as a yellow powder.

[0673] NMR 1 ¹H (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).

[0674] NMR 13 ¹³C (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.

[0675] tert-Butyl 4-{4-[(lithiooxy)carbonyl]-3-(methylsulfonyl)phenyl}piperazine-1-carboxylate

[0676]

[0677] General procedure F was applied to tert-butyl 4-[3-(methylsulfonyl)-4-(methoxycarbonyl)phenyl]piperazine-1-carboxylate (1 equiv, 282 mg, 0.708 mmol) and the reaction mixture was stirred at 30 °C for 4 days. tert-Butyl 4-{4-[(lithiooxy)carbonyl]-3-(methylsulfonyl)phenyl}piperazine-1-carboxylate (293.1 mg, 0.75 mmol) was obtained quantitatively as a pale yellow powder.

[0678] NMR 1H(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).

[0679] 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.

[0680] 2-Methylsulfonyl-4-(piperazin-1-yl)-N-(quinolin-5-yl)benzamide hydrochloride (113)

[0681] The general method G was applied to tert-butyl 4-{4-[(lithiooxy)carbonyl]-3-methylsulfonylphenyl}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 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 in 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-methylsulfonyl-4-(piperazin-1-yl)-N-(quinolin-5-yl)benzamide hydrochloride (44.25 mg, 0.099 mmol, 43%) was obtained as a pale yellow powder and the HPLC purity was 99%.

[0682] C. Results

[0683] The compounds of the invention are the subject of pharmacological tests which have demonstrated their relevance as active substances in therapy, particularly for the treatment of pain. Since the relationship between this ability and the ability to treat pain has been established (WO2016 / 016370), their ability to inhibit the binding of FL to FLT3 has been evaluated (Example 10).

[0684] Table III

[0685] ​

[0686] The 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 involves resonance energy transfer between a donor and a receptor transfected in HEK cells. The donor is the lumi4-Tb-donor-derived benzylguanine substrate (SNAP-Lumi4-Tb, excitation: 337 nm, emission: 630 nm, Cisbio, France), and the receptor is the red fluorescent FL (FL-d2, excitation: 620 nm, emission: 660 nm, Cisbio, France). When FL-D2 binds to the SNAP-Lumi4-Tb-labeled FLT3 receptor, the proximity of the two fluorophores causes a time-resolved resonance energy transfer (TR-FRET) signal to occur, and the binding is measured as the ratio between the fluorescence emissions at 660 - 620 nm.

[0687] ​

[0688] Rivat et al. (Nature Communications, 2018, 9:1042) described the detailed method. Briefly, HEK293T cells were transfected with the pCDNA3.1 SNAP-FLT3 plasmid using Lipofectamine (Invitrogen) and then labeled with SNAP-Lumi4-Tb. Plates containing the transfected HEK293T cells were incubated with the compound of formula (I) at room temperature for 1 h. A series of 12 dilutions in triplicate were used for each compound, and the experiment was performed twice. Then FL-D2 (0.5 nM) was added, and after incubation at room temperature for 20 h, the TR-FRET signal was read using an HTRF-compatible reader (Envision, Perkin Elmer), allowing excitation of the donor at 337 nm and collection of signals at 615 nm and 665 nm (20 flashes, delay 50 μs, integration time 400 μs). Then the HTRF ratio was calculated at each test compound concentration, which was obtained by dividing the receptor signal (665 nm) by the donor signal (615 nm). Nonspecific binding was measured in the presence of 50 μM BDT001 (Rivat et al., ibid.). The concentration resulting in 50% inhibition (IC 50 ) was calculated by nonlinear regression analysis using a one-point model with variable slope ( Graphpad software, USA).

[0689] ​

[0690] All tested compounds inhibited the binding of FL to FLT3, but with different potencies (Table III). Thus, the experimental evidence indicates that the compounds of formula (I) according to the present invention can be used for treating pain conditions.

[0691] ​

[0692]

[0693]

[0694]

[0695]

[0696]

[0697]

Claims

1. A compound of formula (I) or any acceptable salt thereof (I) wherein W, X, Y and Z each independently represent =CH- or -N=, provided that at most two of W, X, Y and Z represent -N= groups, R1 represents a straight-chain or cyclic nitrogen-containing (C4-C8) alkyl group, said group being a non-aromatic (C4-C8) alkyl group, which may be straight-chain or cyclic, containing 4-8 carbon atoms, containing at least one nitrogen atom interrupting the alkyl chain, said group being optionally interrupted by one or two oxygen atoms and optionally substituted by (C1-C4) alkyl or (C3-C6) cycloalkyl, wherein R1 contains at least one primary, secondary or tertiary amine, especially one or two secondary or tertiary amines, R2 represents a hydrogen atom, a halogen atom, (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) fluoroalkyl, -CO-(C1-C4) alkyl, -CONH2 group, SO2-NH2 group or a cyano group, R3 represents a hydrogen atom, a halogen atom, (C1-C4) alkyl, (C1-C4) alkoxy, (C 1- C4) fluoroalkyl, cyano, (C1-C4) alkylsulfonyl or SO2-NH2 group, and R4, R5 and R6 independently represent a hydrogen atom, a halogen atom, -COOH group, -COO(C1-C4) alkyl, (C1-C4) fluoroalkyl, (C1-C4) alkylsulfonyl or (C1-C4) alkoxy.

2. The 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. The compound of formula (I) according to claim 1 or 2, wherein R1 is selected from in particular selected from 4. And more particularly selected from 5. The compound of formula (I) according to any one of claims 1 to 3, wherein R2 represents a hydrogen atom, a halogen atom, (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) fluoroalkyl or a cyano group, and in particular a hydrogen atom, a fluorine atom, a methyl group, a methoxy group, a trifluoromethyl group or a cyano group.

6. A compound of formula (I) according to any one of claims 1 to 4, 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, and in particular a hydrogen atom, a fluorine or chlorine atom, a methyl group, a methoxy group, a trifluoromethyl group or a methanesulfonyl group.

7. A compound of formula (I) according to any one of claims 1 to 5, wherein R4, R5 and R6 independently represent a hydrogen atom, a halogen atom, a (C1-C4) fluoroalkyl group, -COO(C1-C4) alkyl group, a (C1-C4) alkylsulfonyl group or a (C1-C4) alkoxy group, and in particular a hydrogen atom, a fluorine or chlorine atom, a trifluoromethyl group, a methoxycarbonyl group or a methoxy group.

8. A compound of formula (I) according to any one of claims 1 to 3, wherein R2 represents a hydrogen atom, a halogen atom, a (C1-C4) alkyl group, a (C1-C4) alkoxy group, a (C1-C4) fluoroalkyl group, -CO-(C1-C4) alkyl group or a cyano group, in particular 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 particularly a hydrogen atom, a fluorine atom, a methyl group, a methoxy group, a cyano group, 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, a cyano group or a (C1-C4) alkylsulfonyl group, in particular 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 particularly a hydrogen atom, a chlorine or fluorine atom, a methyl group, a methoxy group, a trifluoromethyl group or a methylsulfonyl group, and R4, R5 and R6 independently represent a hydrogen atom, a halogen atom, a (C1-C4) fluoroalkyl group, a -COOH group, -COO(C1-C4) alkyl group, a (C1-C4) alkylsulfonyl group or a (C1-C4) alkoxy group, in particular a hydrogen atom, a halogen atom, a (C1-C4) fluoroalkyl group or a (C1-C4) alkoxy group, more particularly a hydrogen atom, a chlorine or fluorine atom, a trifluoromethyl group, a methoxycarbonyl group or a methoxy group.

9. A compound of formula (I) according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, especially its hydrochloride salt, characterized in that, The compound is selected from the following compounds: -(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-methylsulfonyl-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-(methylsulfonyl)-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-(Methylsulfonyl)-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.

10. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 8, comprising at least the following steps: -Reacting a compound of formula (II): wherein R4, R5, R6, W, X, Y and Z are as defined in any one of claims 1 to 7, with a compound of formula (VII): wherein R1, R2, R3 are as defined in any one of claims 1 to 7, and M represents an alkali metal or hydrogen, to obtain a compound of formula (I), (i) by using a carboxyl activating agent, in particular N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDCI) or N,N′-diisopropylcarbodiimide (DIC), with a racemization inhibitor, in particular 1-hydroxybenzotriazole (HOBt) or ethyl cyanohydroxyiminodiacetate, and with an organic base in an aprotic polar solvent for peptide synthesis; or (ii) first, treating the compound of formula (VII) alone in an aprotic solvent in the presence of a chlorinating agent, in particular SOCl2, and optionally an organic base, to form the corresponding acyl chloride derivative, and then reacting the acyl chloride derivative with the compound of formula (II) by nucleophilic substitution using an organic base in an aprotic solvent.

11. A synthetic method for preparing a compound of formula (I) as defined in any one of claims 1 to 8 or any pharmaceutically acceptable salt thereof, comprising at least the following steps: Reacting a compound of formula (VIII): wherein R2 and R3 are as defined in claim 1, with a compound of formula (IX): wherein R4, R5, R6, W, X, Y and Z are as defined in claim 1, converting the acyl chloride to a formamide by a first reaction with ammonia and performing a palladium-catalyzed Buchwald cross-coupling by a second reaction.

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

13. A pharmaceutical composition comprising at least one compound as defined in any one of claims 1 to 8 or any pharmaceutically acceptable salt thereof, an opioid, and at least one pharmaceutically acceptable excipient, wherein the opioid is selected from alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dextropropoxyphene, dezocine, deprenylamine, dienorphinone, dihydrocodeine, dihydromorphine, dimepheptanol, dimexifene, dimethylthiambutene, maprotiline, dipipanone, etazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, papaverine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpethidine, opium, oxycodone, oxymorphone, opium alkaloids, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, dimethylpethidine, pipradrol, pirprofen, propoxyphene, remifentanil, sufentanil, tapentadol, tilidine, and tramadol, particularly selected from fentanyl, morphine, remifentanil, and tramadol.

14. The compound according to any one of claims 1 to 8, used alone as a drug or in combination with an opioid, particularly as defined in claim 12, as a drug.

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

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