Quinoline and quinazoline compounds and methods of use thereof

Abstract

Compounds and methods for their preparation and their use as therapeutic or prophylactic agents, for example, for treating cancer, bacterial or viral diseases by targeting ectonucleotide pyrophosphatase / phosphodiesterase-1 (ENPP1).

Description

Technical Field

[0001] The present invention generally relates to substituted quinoline and quinazoline derivatives as ENPP1 inhibitors. The present invention relates to pharmaceutical compositions containing compounds of formula 1 and methods of using the compounds or compositions to treat various types of human cancers, cardiovascular, diabetes, obesity, antiviral, antibacterial and antifibrotic treatments with overexpression of ENPP1. The present invention also relates to methods for preparing the compounds and pharmaceutical salts thereof. Background Art

[0002] Members of the ectonucleotide pyrophosphatase / phosphodiesterase (ENPP) family include seven isoforms, ENPP1-7, which are type II transmembrane glycoproteins or ectoenzymes. Mass spectrometry and proteomic analysis from more than 370 protein targets led to the identification of the ectoprotein ENPP1 as one of the top hits showing high hydrolytic activity. ATP is the substrate of the identified ENPP1, which is hydrolyzed to AMP and PPi. CD73 converts AMP into adenosine and inorganic phosphate (Pi). Kinetic experimental data show that ENPP1 can hydrolyze ATP. These ectonucleotide enzymes participate in the hydrolysis of pyrophosphate (PPi) and phosphodiester bonds in ectonucleotides; such as triphosphates, oligonucleotides, and they produce nucleoside 5'-monophosphates. One of the key isoforms, ENPP1 (plasmacyte membrane glycoprotein-1, PC-1) is involved in many physiological processes, such as development, formation and transport, as well as pathophysiological conditions. Aberrant ENPP1 expression has been detected in breast cancer relative to normal breast epithelium, supporting its potential for development in bone metastasis (occurring in approximately 80% of cases), Hodgkin's lymphoma, hepatocellular carcinoma, follicular lymphoma, glioblastoma, and other malignant tumor tissues.

[0003] Recent reports show that cyclic dinucleotides (CDNs), substrates of ENPP1, stimulate innate immunity through STING-dependent activation of interferon genes. ENPP1 inhibition of STING pathway activation is critical for tumor control, similar to checkpoint inhibitors, such as inhibition of anti-PD-1 or PD-L1, which are promising immunotherapies for various cancers. In addition, mutations in ENPP1 are associated with several conditions, including infantile arterial calcification (generalized arterial calcification in infancy or GACI), ossification of the posterior longitudinal ligament of the spine, and insulin signaling and resistance. ENPP1 expression is high in bone and cartilage, and is involved in lung and kidney fibrosis. It is also found that the expression of ENPP1 is correlated with the grade of astrocytic tumors. Another study reported that ENPP1 is needed to maintain the undifferentiated and proliferative state of glioblastoma stem-like cells. Therefore, ENPP1 is an attractive druggable target for the development of new anticancer, cardiovascular, diabetes, obesity and anti-fibrosis therapies.

[0004] The importance of ENPP1 activity was further studied based on both direct binding assays and in vitro cell efficacy of MDA-MB231 cells. ENPP1 knockdown based on siRNA significantly reduced its catalytic activity in both cell specificity and in vivo experiments. These experiments demonstrated that ENPP1 activity was eliminated after treatment with siRNA. This further supports the effectiveness of this target in certain diseases. It has recently been shown that dithiophosphate analogs of endogenous cGAMP are resistant to hydrolysis by ENPP1 phosphodiesterase, and in particular cyclic dinucleotides (CDNs) are more effective in inducing IFN-β secretion in human THP1 cells by inhibiting ENPP1 activity and simultaneously inhibiting the mechanism of STING activation response.

[0005] There is ample evidence that ENPP1 expression is significant in human primary breast tumors relative to normal mammary epithelium, with the highest levels observed in breast-bone metastases. These data support not only a potential role for ENPP1 in breast-bone metastases, but also as a potential prognostic marker for breast cancer. These results from target validation experiments clearly support a pharmacological role for ENPP1 in the development of novel cancer immunotherapies.

[0006] Furthermore, ENPP1 activity has also been implicated in diseases caused by bacteria and / or viruses, and thus modulators of ENPP1 may be useful in treating bacterial and / or viral diseases and conditions. Summary of the invention

[0007] In one aspect, the present invention relates to compounds of formula 1:

[0008]

[0009] in

[0010] X is selected from the group consisting of -C and -N;

[0011] Freedom to choose The group composed of;

[0012] L is selected from the group consisting of:

[0013]

[0014] Y is selected from the group consisting of H and alkyl;

[0015] R1 is selected from the group consisting of: -H, alkyl, O-alkyl, -OCF3, -OP=(O)(ONa)2 and -CH2OP=(O)(ONa)2;

[0016] R2 is selected from the group consisting of: -H, alkyl, -Oalkyl, -OH, -OCF3, -OCH2CH2OH, -OCH2CH2OCH3, -OCH2OCH3, -OP=(O)(ONa)2, -CH2-OP=(O)(ONa)2; and

[0017] R3 is selected from the group consisting of -H, -NH2 and -CH3;

[0018] or an isomer, hydrate, solvate, polymorph, tautomer or pharmaceutically acceptable salt thereof.

[0019] In a preferred embodiment, R1 is selected from the group consisting of: -H, -CH3, -OCH3, -OCF3, -OP=(O)(ONa)2 and -CH2OP=(O)(ONa)2.

[0020] In a preferred embodiment, R1 is OCH3.

[0021] In another preferred embodiment, R2 is selected from the group consisting of: -H, -CH3, -OCH3, -OH, -OCF3, -OCH2CH2OH, -OCH2CH2OCH3, -OCH2OCH3, -OP=(O)(ONa)2, -CH2OP=(O)(ONa)2 and

[0022] In another preferred embodiment, Y is selected from the group consisting of H and CH3.

[0023] In a preferred embodiment, Y is H.

[0024] In a preferred embodiment, for

[0025] R1 is OCH3.

[0026] In a preferred embodiment,

[0027] X is N;

[0028] for

[0029] L choose freedom The group composed of;

[0030] Y is H;

[0031] R1 is selected from the group consisting of -H, -CH3 and -OCH3;

[0032] R2 is selected from the group consisting of: -H, -CH3, -OCH3, OP=(O)(ONa)2, -CH2-OP=(O)(ONa)2, -OH, -OCH2CH2OH, -OCH2CH2OCH3, -OCH2OCH3 and

[0033] R3 is selected from the group consisting of -H, -NH2 and -CH3.

[0034] In another preferred embodiment,

[0035] X is C;

[0036] Freedom to choose The group composed of;

[0037] L is selected from the group consisting of:

[0038]

[0039] R1 is selected from the group consisting of -H, -CH3 and -OCH3;

[0040] R2 is selected from the group consisting of: -H, -CH3, -OCH3, -OH, -OCF3, -OCH2OCH3, -OCH2CH2OH, -OCH2CH2OCH3, -OP=(O)(ONa)2, -CH2OP=(O)(ONa)2; and

[0041] R3 is selected from the group consisting of -H, -NH2 and -CH3.

[0042] Examples of provided compounds include:

[0043]

[0044]

[0045]

[0046]

[0047] The present invention also includes hydrates, solvates, polymorphs, isomers, tautomers, pharmaceutically acceptable salts of the compounds, and pharmaceutically acceptable salts of the tautomers.

[0048] The present invention also provides pharmaceutical formulations, medicaments comprising the compounds, methods of preparing the pharmaceutical formulations, medicaments, compounds, and methods of treating patients with the provided pharmaceutical formulations and compounds.

[0049] Compounds of the invention were identified by structure-based, computational docking and binding free energy.

[0050] Also disclosed are pharmaceutical compositions comprising a therapeutically effective amount of a disclosed compound and a pharmaceutically acceptable carrier.

[0051] Also disclosed are synthetic methods for preparing the disclosed compounds. In additional aspects, disclosed are products of the disclosed synthetic methods.

[0052] Also disclosed are methods for treating a disorder associated with ENPP1 activity dysfunction in a mammal, comprising the step of administering to the mammal a therapeutically effective amount of a disclosed compound, or a pharmaceutically acceptable salt, tautomer, isomer, hydrate, solvate or polymorph thereof.

[0053] Also disclosed is a method for inhibiting ENPP1 activity in a mammal, comprising the step of administering to the mammal a therapeutically effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt, tautomer, isomer, hydrate, solvate or polymorph thereof.

[0054] Also disclosed are methods for inhibiting ENPP1 activity of at least one cell, comprising the step of contacting the at least one cell with an effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt, tautomer, isomer, hydrate, solvate, or polymorph thereof.

[0055] Also disclosed is a method for treating a condition associated with ENPP1 activity dysfunction in a mammal by eliciting an immunotherapy response in the mammal, the method comprising administering to the mammal a therapeutically effective amount of a disclosed compound, or a pharmaceutically acceptable salt, tautomer, isomer, hydrate, solvate or polymorph thereof, wherein the compound induces an immunotherapy response that is beneficial in treating the condition associated with ENPP1 activity. Such a condition may be, but is not limited to, any type of cancer or any disease caused by bacteria and / or viruses involving ENPP1 activity.

[0056] Also disclosed are pharmaceutical compositions comprising a pharmaceutically acceptable carrier and an effective amount of a disclosed compound, or a pharmaceutically acceptable salt, tautomer, isomer, hydrate, solvate, or polymorph thereof.

[0057] Also disclosed are kits comprising at least one disclosed compound, or a pharmaceutically acceptable salt, tautomer, isomer, hydrate, solvate, or polymorph thereof.

[0058] Also disclosed are methods for making a medicament comprising combining at least one disclosed compound or at least one disclosed product with a pharmaceutically acceptable carrier or diluent. In a further aspect, the invention relates to the use of the disclosed compounds in the manufacture of a medicament for treating a disorder associated with ENPP1 activity dysfunction. In a further aspect, the invention relates to the use of the disclosed compounds in the manufacture of a medicament for treating an uncontrolled cell proliferation disorder.

[0059] Also disclosed is the use of a disclosed compound or a disclosed product in the manufacture of a medicament for treating a disorder associated with ENPP1 dysfunction in a mammal.

[0060] Although aspects of the invention may be described and claimed in specific statutory categories, such as the system statutory category, this is for convenience only, and those skilled in the art will understand that each aspect of the invention may be described and claimed in any statutory category. Unless expressly stated otherwise, it is not intended that any method or aspect described herein be interpreted as requiring that its steps be performed in a particular order. Therefore, in the event that a method claim does not specifically state in the claim or specification that the steps are limited to a particular order, in no way is it intended to infer an order in any respect. This applies to any possible non-express basis for interpretation, including matters regarding the logic of the arrangement of steps or operational flow, ordinary meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification. DETAILED DESCRIPTION

[0061] A. Definition

[0062] As used herein, the nomenclature of compounds, including organic compounds, may be given using common names, IUPAC, IUBMB, or CAS nomenclature suggestions. When one or more stereochemical features are present, the Cahn-Ingold-Prelog rules for stereochemistry may be employed to assign stereochemical priority, E / Z specifications, etc. Given a name, one skilled in the art can readily determine the structure of the compound by systematic reduction of the compound structure using the naming convention or by commercially available software such as ChemDraw. TM (Cambridgesoft Corporation, USA).

[0063] As used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a functional group," "an alkyl," or "a residue" includes a mixture of two or more such functional groups, alkyl groups, or residues, etc.

[0064] In this article, ranges can be expressed as from "about" a specific value and / or to "about" another specific value. When expressing such a range, additional aspects include from a specific value and / or to another specific value. Similarly, when a value is expressed as an approximation by using the antecedent "about", it should be understood that the specific value forms additional aspects. It should also be understood that the end values ​​of each range are important in relation to other end values ​​and independently of other end values. It should also be understood that multiple values ​​are disclosed herein, and each value is also disclosed herein as "about" for the specific value in addition to the value itself. For example, if the value "10" is disclosed, "about 10" is also disclosed. It should also be understood that each unit between two specific units is also disclosed. For example, if 10 and 15 are disclosed, 11, 12, 13 and 14 are also disclosed.

[0065] References in the specification and the subsequent claims to parts by weight of a particular element or component in a composition denote the weight relationship between that element or component and any other elements or components in the composition or article, expressed as parts by weight. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight of component Y, X and Y are present in a weight ratio of 2:5, and are present in this ratio regardless of whether other components are present in the compound.

[0066] Unless specifically stated to the contrary, the weight percent (wt. %) of a component is based on the total weight of the formulation or composition in which the component is included.

[0067] As used herein, the term "ENPP1" refers to ectonucleotide pyrophosphatase / phosphodiesterase.

[0068] As used herein, the terms "optional" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0069] As used herein, the term "subject" can be a vertebrate, such as a mammal, fish, bird, reptile or amphibian. Therefore, the subject of the method disclosed herein can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not indicate a specific age or gender. Therefore, it is intended to cover adult and newborn subjects and fetuses, whether male or female. In one aspect, the subject is a mammal. A patient refers to a subject suffering from a disease or condition. The term "patient" includes human and livestock subjects. In some aspects of the disclosed method, prior to the administering step, the subject has been diagnosed with a need for treatment of an uncontrolled cell proliferation disorder associated with ENPP1 dysfunction. In some aspects of the disclosed method, prior to the administering step, the subject has been diagnosed with a need for inhibition of ENPP1.

[0070] As used herein, the term "treatment" refers to the medical management of a patient, intended to cure, improve, stabilize or prevent a disease, pathological condition or illness. This term includes active treatment, i.e., treatment specifically for the improvement of a disease, pathological condition or illness, and also includes etiological treatment, i.e., treatment for the removal of the cause of the disease, pathological condition or illness. In addition, this term includes palliative treatment, i.e., treatment designed to relieve symptoms rather than cure a disease, pathological condition or illness; preventive treatment, i.e., treatment for minimizing or partially or completely inhibiting the development of a disease, pathological condition or illness; and supportive treatment, i.e., treatment for another specific therapy for supplementing the improvement of a disease, pathological condition or illness. In various aspects, the term encompasses any treatment of a subject, including mammals (e.g., humans), and includes: (i) preventing the disease from occurring in a subject who may be prone to the disease but has not yet been diagnosed as having the disease; (ii) inhibiting the disease, i.e., curbing its development; or (iii) alleviating the disease, even if the disease subsides. On the one hand, the subject is a mammal, such as a primate, and in another aspect, the subject is a human. The term "subject" also includes domestic animals (eg, cats, dogs, etc.), livestock (eg, cows, horses, pigs, sheep, goats, etc.), and laboratory animals (eg, mice, rabbits, rats, guinea pigs, fruit flies, zebrafish, etc.).

[0071] As used herein, the term "prevent" or "preventing" means to exclude, avoid, eliminate, stop, stop or hinder something from happening, especially by preemptive action. It should be understood that unless otherwise expressly indicated, in the case of reducing, inhibiting or preventing as used herein, the use of the other two words is also expressly disclosed.

[0072] As used herein, the term "diagnosed" means having undergone a physical examination by a technician (e.g., a physician) and found to have a condition that can be diagnosed or treated by a compound, composition, or method disclosed herein. For example, "diagnosed with an uncontrolled cell proliferation disorder" means having undergone a physical examination by a technician (e.g., a physician) and found to have a condition that can be diagnosed or treated by a compound or composition that can inhibit ENPP1. As another example, "diagnosed as needing to inhibit ENPP1" means having undergone a physical examination by a technician (e.g., a physician) and found to have a condition characterized by ENPP1 dysfunction. As discussed herein, such a diagnosis can refer to a condition such as uncontrolled cell proliferation, cancer, and the like. For example, "diagnosed as needing to treat one or more conditions of uncontrolled cell proliferation associated with ENPP1 dysfunction" means having undergone a physical examination by a technician (e.g., a physician) and found to have one or more conditions of uncontrolled cell proliferation associated with ENPP1 dysfunction.

[0073] As used herein, the phrase "identified as requiring treatment of a condition" and the like refers to selecting a subject based on the need for treatment of the condition. For example, based on an early diagnosis by a technician, a subject may be identified as requiring treatment of a condition (e.g., a condition associated with dysfunction of ENPP1) and thereafter undergo treatment for the condition. It is contemplated that, in one aspect, the identification may be performed by a person different from the person making the diagnosis. It is also contemplated that, in other aspects, administration may be performed by a person who subsequently performs the administration.

[0074] As used herein, the terms "administering" and "administration" refer to any method of providing a pharmaceutical formulation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, intraocular administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, oral administration, intraurethral administration, and parenteral administration, including injection, such as intravenous administration, intraarterial administration, intramuscular administration, and subcutaneous administration. Administration may be continuous or intermittent. In various aspects, the formulation may be administered therapeutically; that is, the formulation is administered to treat an existing disease or condition. In various other aspects, the formulation may be administered prophylactically; that is, it is administered to prevent a disease or condition.

[0075] The term "contacting" as used herein means bringing a disclosed compound and a cell, target receptor or other biological entity together in such a way that the compound can directly or indirectly affect the activity of the target (e.g., receptor, cell, etc.); i.e., by interacting with the target itself; i.e., by interacting with another molecule, cofactor, factor or protein on which the activity of the target depends.

[0076] As used herein, the terms "effective amount" and "amount effective" refer to an amount sufficient to achieve a desired result or have an effect on an undesirable condition. For example, a "therapeutically effective amount" refers to an amount sufficient to achieve a desired therapeutic result or have an effect on an undesirable symptom but generally insufficient to cause adverse side effects. The specific therapeutically effective dosage level for any particular patient will depend on a variety of factors, including: the condition being treated and the severity of the condition; the specific composition being used; the patient's age, weight, general health, sex and diet; the time of administration; the route of administration; the excretion rate of the specific compound being used; the duration of treatment; the drugs used in combination or concomitantly with the specific compound being used, and similar factors well known in the medical field. For example, it is entirely within the technical scope of the art to start using a compound at a dosage level lower than the dosage level required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. If necessary, for the purpose of administration, the effective daily dose can be divided into multiple doses. Therefore, a single dosage composition may contain such an amount or a submultiple thereof to make up the daily dose. In the case of any contraindications, the dosage can be adjusted by the individual physician. Dosages may vary and may be administered in one or more doses per day for one or more days. Guidance on appropriate dosages for a given class of drug products can be found in the literature. In further various aspects, the formulation may be administered in a "prophylactically effective amount"; i.e., an effective amount for preventing a disease or condition.

[0077] As used herein, “EC 50 " is intended to refer to the concentration of a substance (e.g., a compound or drug) required for 50% agonism or activation of a biological process or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc. In one aspect, EC 50 Can refer to the concentration of a substance required for 50% agonism or activation in vivo, as further defined elsewhere herein. In a further aspect, EC 50 Refers to the concentration of agonist or activator that elicits a response halfway between the baseline and maximal response.

[0078] As used herein, “IC 50" is intended to refer to the concentration of a substance (e.g., a compound or drug) required for 50% inhibition of a biological process or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc. For example, IC 50 It may refer to the concentration of a substance required for 50% inhibition in vivo or inhibition measured in vitro, as further defined elsewhere herein. Alternatively, IC 50 Refers to the half-maximal (50%) inhibitory concentration (IC) of a substance. Inhibition can be measured in cell lines such as AN3 CA, BT-20, BT-549, HCT 116, HER218, MCF7, MDA-MB-231, MDA-MB-235, MDA-MB-435S, MDA-MB-468, PANC-1, PC-3, SK-N-MC, T-47D, and U-87MG.

[0079] The term "pharmaceutically acceptable" describes a material that is not biologically or otherwise undesirable, ie, does not cause unacceptable levels of undesired biological effects or interact in a deleterious manner.

[0080] As used herein, the term "stable" refers to compounds that are not substantially altered when subjected to conditions that allow them to be produced, detected, and in some aspect recovered, purified, and used for one or more of the purposes disclosed herein.

[0081] As used herein, the term "derivative" refers to a compound whose structure is derived from the structure of a parent compound (e.g., a compound disclosed herein), and whose structure is sufficiently similar to that disclosed herein, and based on this similarity, a person skilled in the art would expect the compound to exhibit the same or similar activity and utility as the claimed compound, or to induce the same or similar activity and utility as a precursor to the claimed compound. Exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of the parent compound.

[0082] As used herein, the term "pharmaceutically acceptable carrier" refers to a sterile aqueous or non-aqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion before use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), carboxymethyl cellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters, such as ethyl oleate. Appropriate fluidity can be maintained by, for example, using a coating material (such as lecithin) in the case of a dispersion by maintaining the required particle size and by using a surfactant. These compositions can also contain adjuvants, such as preservatives, wetting agents, emulsifiers and dispersants. Various antibacterial and antifungal agents can be included, such as parabens, chlorobutanol, phenol, sorbic acid, etc. to ensure the prevention of microbial effects. It can also be desirable to include isotonic agents, such as sugar, sodium chloride, etc. Prolonged absorption of injectable drug forms can be achieved by containing agents that delay absorption (such as aluminum monostearate and gelatin). Injectable reservoir-type (depot) forms are prepared by forming a microcapsule matrix of the drug in a biodegradable polymer, such as polylactide-polyglycolide, poly(orthoester) and poly(anhydride). According to the ratio of the drug to the polymer and the properties of the specific polymer used, the rate of drug release can be controlled. Depot-type injectable formulations are also prepared by trapping the drug in liposomes or microemulsions compatible with body tissues. Injectable formulations can be sterilized, for example, by filtering through a bacterial retention filter, or by incorporating a sterilizing agent in the form of a sterile solid composition, which can be dissolved or dispersed in sterile water or other sterile injectable media before use. Suitable inert carriers can include sugars, such as lactose. Desirably, the effective particle size of at least 95% by weight of the active ingredient particles is within the range of 0.01 to 10 microns.

[0083] As used in the specification and in the claims which follow, a residue of a chemical species refers to a moiety that is the resultant product of the chemical species in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether the moiety is actually obtained from the chemical species. Thus, an ethylene glycol residue in a polyester refers to one or more -OCH2CH2O- units in the polyester, regardless of whether ethylene glycol was used to prepare the polyester. Similarly, a sebacic acid residue in a polyester refers to one or more -CO(CH2)8CO- moieties in the polyester, regardless of whether the residue was obtained by reacting sebacic acid or an ester thereof to obtain the polyester.

[0084] As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Illustrative substituents include, for example, those described below. For appropriate organic compounds, permissible substituents may be one or more and may be the same or different. For the purposes of this disclosure, heteroatoms (such as nitrogen) may have hydrogen substituents and / or any permissible substituents of organic compounds described herein, which will satisfy the valence of heteroatoms. This disclosure is not intended to be limited in any way to permissible substituents of organic compounds. Moreover, the term "substituted" or "substituted by ... " includes implicit conditions: this substitution is consistent with the permissible valence of the substituted atom and substituent, and the substitution results in a stable compound, such as a compound that does not spontaneously undergo transformation (such as by rearrangement, cyclization, elimination, etc.). It is also contemplated that, in certain aspects, unless explicitly stated to the contrary, individual substituents may be further optionally substituted (ie, further substituted or unsubstituted).

[0085] In defining various terms, “A 1 ”, “A 2 ”, “A 3 ” and “A 4 " are used herein as general symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when these symbols are defined as certain substituents in one instance, they can be defined as some other substituents in another instance.

[0086] As used herein, the term "alkyl" is a branched or unbranched saturated hydrocarbon group having 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, etc. The alkyl group can be cyclic or acyclic. The alkyl group can be branched or unbranched. The alkyl group can also be substituted or unsubstituted. For example, the alkyl group can be substituted by one or more groups, including but not limited to alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxyl, nitro, silyl, sulfo-oxo or mercaptan, as described herein. "Low alkyl" is an alkyl group containing one to six (e.g., one to four) carbon atoms.

[0087] For example, "C1-C3 alkyl" can be selected from methyl, ethyl, n-propyl, isopropyl and cyclopropyl, or a subset thereof. In some aspects, "C1-C3 alkyl" can optionally be further substituted. As another example, "C1-C4 alkyl" can be selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and cyclobutyl, or a subset thereof. In some aspects, "C1-C4 alkyl" can optionally be further substituted. As another example, "C1-C6 alkyl" can be selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, sec-pentyl, tert-pentyl, neopentyl, cyclopentyl, n-hexyl, isohexyl, 3-methylpentane, 2,3-dimethylbutane, neohexane and cyclohexane, or a subset thereof. In some aspects, "C1-C6 alkyl" can be optionally further substituted. As another example, "C1-C8 alkyl" can be selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, sec-pentyl, tert-pentyl, neopentyl, cyclopentyl, n-hexyl, isohexyl, 3-methylpentane, 2,3-dimethylbutane, neohexane, cyclohexane, heptane, cycloheptane, octane and cyclooctane, or selected from a subset thereof. In some aspects, "C1-C8 alkyl" can be optionally further substituted. As another example, "C1-C8 alkyl" can be selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, sec-pentyl, tert-pentyl, neopentyl, cyclopentyl, n-hexyl, isohexyl, 3-methylpentane, 2,3-dimethylbutane, neohexane, cyclohexane, heptane, cycloheptane, octane and cyclooctane, or selected from a subset thereof. As another example, "C1-C12 alkyl" can be selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, sec-pentyl, tert-pentyl, neopentyl, cyclopentyl, n-hexyl, isohexyl, 3-methylpentane, 2,3-dimethylbutane, neohexane, cyclohexane, heptane, cycloheptane, octane, cyclooctane, nonane, cyclononane, decane, cyclodecane, undecane, cycloundecane, dodecane and cyclododecane, or a subset thereof. In certain aspects, "C1-C12 alkyl" can optionally be further substituted.

[0088] Throughout this specification, "alkyl" is generally used to refer to both unsubstituted alkyl and substituted alkyl; however, substituted alkyl is also specifically referred to herein by identifying one or more specific substituents on the alkyl. For example, the term "halogenated alkyl" or "haloalkyl" specifically refers to an alkyl substituted with one or more halide ions (e.g., fluoride, chloride, bromide, or iodide). The term "alkoxyalkyl" specifically refers to an alkyl substituted with one or more alkoxy groups, as described below. The term "alkylamino" specifically refers to an alkyl substituted with one or more amino groups, etc., as described below. When "alkyl" is used in one case and a specific term such as "alkyl alcohol" is used in another case, this is not meant to imply that the term "alkyl" also does not refer to a specific term such as "alkyl alcohol", etc.

[0089] This practice also applies to other groups described herein. That is, although terms such as "cycloalkyl" refer to both unsubstituted and substituted cycloalkyl moieties, the substituted moieties may be specifically identified in addition herein; for example, a specific substituted cycloalkyl may be referred to as, for example, "alkylcycloalkyl". Similarly, a substituted alkoxy may be specifically referred to as, for example, "halogenated alkoxy", a specific substituted alkenyl may be, for example, "alkenyl alcohol", etc. Again, the practice of using a general term such as "cycloalkyl" and a specific term such as "alkylcycloalkyl" is not meant to imply that the general term also does not include the specific term.

[0090] As used herein, term "cycloalkyl" is a non-aromatic carbon-based ring consisting of at least three carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, etc. Term "heterocycloalkyl" is a type of cycloalkyl as defined above, and is included in the meaning of term "cycloalkyl", wherein at least one carbon atom in the carbon atom of the ring is replaced by a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur or phosphorus. Cycloalkyl and heterocycloalkyl can be substituted or unsubstituted. Cycloalkyl and heterocycloalkyl can be substituted by one or more groups, such as, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxyl, nitro, silyl, sulfo-oxo, nitrile, sulfonamide or thiol, as described herein.

[0091] As used herein, the term "aryl" is a group containing any carbon-based aromatic group, including but not limited to benzene, naphthalene, phenyl, biphenyl, phenoxybenzene, etc. The term "aryl" also includes "heteroaryl", which is defined as a group containing an aromatic group, and the aromatic group has at least one heteroatom incorporated into the ring of the aromatic group. Examples of heterocyclic atoms include but are not limited to nitrogen, oxygen, sulfur and phosphorus. Similarly, the term "non-heteroaryl" also included in the term "aryl" defines a group containing an aromatic group that does not contain a heteroatom. The aryl group can be substituted or unsubstituted. The aryl group can be substituted by one or more groups, and the one or more groups include but are not limited to alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxyl, ketone, azide, nitro, silyl, sulfo-oxo, nitrile, sulfonamide or thiol, as described herein. The term “biaryl” is a specific type of aryl group and is included in the definition of “aryl.” A biaryl group refers to two aryl groups bound together by a fused ring structure as in naphthalene or linked by one or more carbon-carbon bonds as in biphenyl.

[0092] As used herein, the terms "halogen", "halide" and "halo" refer to the halogens fluorine, chlorine, bromine and iodine. It is also contemplated that, in various aspects, the halogen may be selected from fluorine, chlorine, bromine and iodine. For example, the halogen may be selected from fluorine, chlorine and bromine. As a further example, the halogen may be selected from fluorine and chlorine. As a further example, the halogen may be selected from chlorine and bromine. As a further example, the halogen may be selected from bromine and iodine. As a further example, the halogen may be selected from chlorine, bromine and iodine. In one aspect, the halogen may be fluorine. In another aspect, the halogen may be chlorine. In still another aspect, the halogen is bromine. In yet another aspect, the halogen is iodine.

[0093] It is also contemplated that in some aspects, pseudo-halogens (e.g., trifluoromethanesulfonates, mesylates, toluenesulfonates, brosylates, etc.) may be used to replace halogens. For example, in some aspects, halogens may be replaced by pseudo-halogens. As another example, pseudo-halogens may be selected from trifluoromethanesulfonates, mesylates, toluenesulfonates, and brosylates. On the one hand, pseudo-halogens are trifluoromethanesulfonates. In another aspect, pseudo-halogens are mesylates. In another aspect, pseudo-halogens are toluenesulfonates. In another aspect, pseudo-halogens are brosylates.

[0094] As used herein, the term "heterocycle" refers to monocyclic and polycyclic aromatic or non-aromatic ring systems in which at least one of the ring members is not carbon. The heterocyclic ring includes azetidine, dioxane, furan, imidazole, isothiazole, isoxazole, morpholine, oxazole, oxazole (including 1,2,3-oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole), piperazine, piperidine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, tetrahydrofuran, tetrahydropyran, tetrazine (including 1,2,4,5-tetrazine), tetrazole (including 1,2,3,4-tetrazole and 1,2,4,5-tetrazole), thiadiazole (including 1,2,3-thiadiazole, 1,2,5-thiadiazole and 1,3,4-thiadiazole), thiazole, thiophene, triazine (including 1,3,5-triazine and 1,2,4-triazine), triazole (including 1,2,3-triazole, 1,3,4-triazole) and the like.

[0095] The term "hydroxyl" as used herein is represented by the formula -OH.

[0096] As used herein, “R 1 ”, “R 2 ”, “R 3 ”, “R n " ”(where n is an integer) may independently have one or more of the groups listed above. For example, if R 1If the first group is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group may be optionally substituted by a hydroxyl group, an alkoxy group, an alkyl group, a halide, etc. Depending on the selected group, the first group may be incorporated into the second group, or alternatively, the first group may be a side group (i.e., connected) of the second group. For example, for the phrase "an alkyl group including an amino group", the amino group may be incorporated into the main chain of the alkyl group. Alternatively, the amino group may be connected to the main chain of the alkyl group. The nature of the selected one or more groups will determine whether the first group is embedded in the second group or connected to the second group.

[0097] As described herein, the compounds of the present invention may contain "optionally substituted" moieties. In general, the term "substituted", whether or not preceded by the term "optionally", means that one or more hydrogens of the specified moiety are replaced by suitable substituents. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted by more than one substituent selected from a specified group, at each position, the substituent may be the same or different. The substituent combinations contemplated by the present invention are preferably substituent combinations that form stable or chemically feasible compounds. It is also contemplated that, in certain aspects, unless explicitly indicated to the contrary, individual substituents may be further optionally substituted (i.e., further substituted or unsubstituted).

[0098] The compounds described herein may contain one or more double bonds and may therefore give rise to cis / trans (E / Z) isomers, as well as other conformational isomers. Unless otherwise specified, the present invention encompasses all such possible isomers, as well as mixtures of such isomers.

[0099] Unless otherwise stated, formulas with chemical bonds shown only as solid lines, rather than wedges or dashed lines, encompass every possible isomer, such as every enantiomer and diastereomer, as well as mixtures of isomers, such as racemic mixtures or scalemic mixtures. The compounds described herein may contain one or more asymmetric centers, and thus may produce diastereomers and optical isomers. Unless otherwise stated, the present invention includes all of these possible diastereomers and racemic mixtures thereof, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Mixtures of stereoisomers are also included, as well as isolated specific stereoisomers. During the course of synthetic processes for preparing such compounds, or using racemization or epimerization processes known to those skilled in the art, the products of these processes may be mixtures of stereoisomers.

[0100] Many organic compounds exist in optically active forms with the ability to rotate the plane of plane polarized light. When describing optically active compounds, prefixes D and L or R and S are used to represent the absolute configuration of the molecule around one or more chiral centers. The prefixes d and / or (+) and (-) are used to represent the rotation sign of the compound to plane polarized light, where (-) or / represent that the compound is left-handed. The compound prefixed with (+) or d is right-handed. For a given chemical structure, these compounds referred to as stereoisomers are identical, except that they are mirror images that cannot be superimposed on each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are commonly referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is referred to as a racemic mixture.

[0101] Many compounds described herein can have one or more chiral centers, and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be represented by an asterisk (*). When the bond to the chiral carbon is depicted as a straight line in the disclosed formula, it should be understood that both (R) and (S) configurations of the chiral carbon, and therefore both enantiomers and mixtures thereof are included in the formula. As used in the art, when it is desired to specify the absolute configuration about the chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (bond to the atom above the plane), and the other can be depicted as a series or wedge (bond to the atom below the plane) of short parallel lines. The Cahn-Inglod-Prelog system can be used to assign (R) or (S) configurations to chiral carbons.

[0102] The compounds described herein include atoms in both their natural isotopic abundance and in unnatural abundance. The disclosed compounds may be isotopically labeled or isotopically substituted compounds, which are identical to those described, but for the fact that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H. 3 H. 13 C. 14 C. 15 N. 18 O. 17 O. 35 S. 18 F and 36 The compounds further include prodrugs thereof, and pharmaceutically acceptable salts of the compounds or prodrugs containing the above-mentioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds of the present invention (e.g., in which a radioactive isotope is incorporated, such as 3 H and14 C) are useful in drug and / or substrate tissue distribution assays. Tritiated isotopes (i.e., 3 H) and carbon-14 isotopes (i.e., 14 C) is particularly preferred due to its ease of preparation and detectability. Further, the use of heavier isotopes, such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. Isotopically labeled compounds of the invention and prodrugs thereof can generally be prepared by carrying out the following procedure: substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0103] The compounds described in the present invention can exist as solvates. In some cases, the solvent for preparing solvates is an aqueous solution, and therefore solvates are generally referred to as hydrates. Compounds can exist as hydrates, and the hydrates can be obtained, for example, by crystallization from a solvent or an aqueous solution. In this regard, one, two, three or any arbitrary number of solvates or water molecules can be combined with compounds according to the present invention to form solvates and hydrates. Unless otherwise indicated, the present invention includes all these possible solvates.

[0104] It is also understood that certain compounds described herein may exist as an equilibrium of tautomers. For example, a ketone with an α-hydrogen may exist in an equilibrium of a keto form and an enol form.

[0105]

[0106] Likewise, amides having an N-hydrogen may exist in equilibrium with the amide form and the imidic acid form. Unless stated to the contrary, the present invention encompasses all such possible tautomers.

[0107] Chemical substances are known to form solids that exist in different sequential states, which are referred to as polymorphic forms or modifications. Different modifications of polymorphic materials may differ greatly in their physical properties. Compounds according to the present invention may exist in different polymorphic forms, wherein a particular modification may be metastable. Unless otherwise indicated, the present invention encompasses all these possible polymorphic forms.

[0108] In some aspects, the structure of the compound can be represented by the following formula:

[0109]

[0110] It is understood to be equivalent to the following formula:

[0111]

[0112] where n is usually an integer. That is, R n It is understood to represent five independent substituents, R n(a) , R n(b) , R n(c) , R n(d) , R n(e) "Independent substituents" means that each R substituent can be independently defined. For example, if in one example R n(a) is halogen, then in the example described, R n(b) Not necessarily halogen.

[0113] Certain materials, compounds, compositions and components disclosed herein are either commercially available or readily synthesized using techniques generally known to those skilled in the art. For example, starting materials and reagents used in preparing the disclosed compounds and compositions are available from commercial suppliers such as Sigma-Aldrich Chemical Co. (Milwaukee, Wisconsin), Acros Organics (Morris Plains, New Jersey), Fisher Scientific (Pittsburgh, Pennsylvania), or Sigma (St. Louis, Missouri) or are prepared by methods known to those skilled in the art following the procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis, Vols. 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Vols. 1-5 and Supplements (Elsevier Science Press, 1991); Publishers, 1989); Organic Reactions, Vols. 1-40 (John Wiley & Sons, 1991); March's Advanced Organic Chemistry, (John Wiley & Sons, 4th ed.); and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0114] Unless otherwise expressly stated, it is not intended that any method described herein be construed as requiring that its steps be performed in a particular order. Therefore, in the event that a method claim does not actually recite the order in which its steps are to be followed or the steps are not otherwise specifically stated in the claims or specification to be limited to a particular order, no order is intended to be inferred in any respect. This applies to any possible non-express basis for interpretation, including: matters of logic regarding arrangement of steps or operational flow; ordinary meaning derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification.

[0115] Disclosed are components for preparing the composition of the present invention and the composition itself used in the method disclosed herein. These and other materials are disclosed herein, and it should be understood that when the combination, subset, interaction, group, etc. of these materials are disclosed, although it is impossible to explicitly disclose specific references to each of the various individual and collective combinations and arrangements of these compounds, each combination and arrangement is specifically envisioned and described herein. For example, if a specific compound is disclosed and discussed, and many modifications that may be made to multiple molecules containing the compound are discussed, then unless specifically indicated to the contrary, each combination and arrangement in the compound and possible modifications are specifically covered. Therefore, if a class of molecules A, B and C and a class of molecules D, E and F are disclosed, and an example of a combination molecule AD is disclosed, then even if each is not narrated individually, each molecule is considered individually and collectively, which means that it is considered to disclose a combination of AE, AF, BD, BE, BF, CD, CE and CF. Similarly, any subset or combination of these is also disclosed. Therefore, for example, it is considered that the subgroup of AE, BF and CE is disclosed. This concept applies to all aspects of the present application, including but not limited to steps in the method of making and using the composition of the present invention. Therefore, if there are various additional steps that can be performed, it should be understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the method of the present invention.

[0116] It is understood that the compositions disclosed herein have certain functions. Certain structural requirements for performing the disclosed functions are disclosed herein, and it is understood that there are multiple structures that can perform the same function related to the disclosed structures, and these structures will generally achieve the same result.

[0117] B. Compounds

[0118] In one aspect, the present invention relates to compounds useful as ENPP1 inhibitors. In addition, in one aspect, the compounds of the present invention are useful for treating an uncontrolled cell proliferation disorder. In a further aspect, the uncontrolled cell proliferation disorder is a cancer or a tumor. In still a further aspect, the uncontrolled cell proliferation disorder is associated with ENPP1 dysfunction, as further described herein.

[0119] In another aspect, the compounds of the invention can be used to treat diseases of bacterial or viral origin. Thus, in one aspect, the invention provides a method of treating a disease caused by bacteria or viruses, the method comprising administering to a subject a therapeutically effective amount of a compound of the invention.

[0120] It is contemplated that each disclosed derivative may optionally be further substituted. It is also contemplated that the present invention may optionally omit any one or more derivatives. It should be understood that the disclosed compounds may be provided by the disclosed methods. It should also be understood that the disclosed compounds may be used in the disclosed methods of use.

[0121] 1. Structure

[0122] In one aspect, the present invention relates to a compound of formula 1:

[0123]

[0124] in

[0125] X is selected from the group consisting of -C and -N;

[0126] Freedom to choose The group composed of;

[0127] L is selected from the group consisting of:

[0128]

[0129] Y is selected from the group consisting of H and alkyl;

[0130] R1 is selected from the group consisting of: -H, alkyl, O-alkyl, -OCF3, -OP=(O)(ONa)2 and -CH2OP=(O)(ONa)2;

[0131] R2 is selected from the group consisting of: -H, alkyl, -Oalkyl, -OH, -OCF3, -OCH3CH2OCH3, -OCH3CH2CH2OH, -OCH3CH2CH2OCH3, -OP=(O)(ONa)2, -CH2-OP=(O)(ONa)2 and

[0132] R3 is selected from the group consisting of -H, -NH2 and -CH3;

[0133] or an isomer, hydrate, solvate, polymorph, tautomer or pharmaceutically acceptable salt thereof.

[0134] In a preferred embodiment, R1 is selected from the group consisting of: -H, -CH3, -OCH3, -OCF3, -OP=(O)(ONa)2 and -CH2OP=(O)(ONa)2.

[0135] In a preferred embodiment, R1 is OCH3.

[0136] In another preferred embodiment, R2 is selected from the group consisting of: -H, -CH3, -OCH3, -OH, -OCF3, -OCH2CH2OH, -OCH2CH2OCH3, -OCH2OCH3, -OP=(O)(ONa)2, -CH2OP=(O)(ONa)2 and

[0137] In another preferred embodiment, Y is selected from the group consisting of H and CH3.

[0138] In a preferred embodiment, Y is H.

[0139] In a preferred embodiment,

[0140] X is N;

[0141] for

[0142] L choose freedom The group composed of;

[0143] Y is H;

[0144] R1 is selected from the group consisting of -H, -CH3 and -OCH3;

[0145] R2 is selected from the group consisting of: -H, -CH3, -OCH3, OP=(O)(ONa)2, -CH2-OP=(O)(ONa)2, -OH, -OCH2CH2OH, -OCH2CH2OCH3, -OCH2OCH3 and

[0146] R3 is selected from the group consisting of -H, -NH2 and -CH3.

[0147] In another preferred embodiment:

[0148] X is C;

[0149] Freedom to choose The group composed of;

[0150] L is selected from the group consisting of:

[0151]

[0152] R1 is selected from the group consisting of -H, -CH3 and -OCH3;

[0153] R2 is selected from the group consisting of: -H, -CH3, -OCH3, -OH, -OCF3, -OCH2CH2OH, -OCH2CH2OCH3, -OCH2OCH3, -OP=(O)(ONO)2 and -CH2OP=(O)(ONa)2; and

[0154] R3 is selected from the group consisting of -H, -NH2 and -CH3.

[0155] Examples of provided compounds include:

[0156]

[0157]

[0158]

[0159] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of any compound of the present invention and a pharmaceutically acceptable carrier.

[0160] The present invention also provides a method for treating an uncontrolled cell proliferation disorder in a mammal, the method comprising the step of administering to the mammal an effective amount of any of the compounds of the present invention.

[0161] The present invention also provides a method for reducing ENPP1 activity in a mammal, comprising the step of administering an effective amount of any compound of the present invention to the mammal.

[0162] The present invention also provides a method for inhibiting ENPP1 activity in a mammal, comprising the step of administering to the mammal an effective amount of any compound of the present invention.

[0163] C. Methods of preparing compounds

[0164] In one aspect, the present invention relates to methods of preparing compounds useful as ENPP1 inhibitors. In other aspects, the products of the disclosed methods of preparation are modulators of ENPP1 activity.

[0165] In addition to other standard operations known in the literature, exemplified in the experimental section or apparent to those skilled in the art, the compounds of the present invention can be prepared by using reactions as shown in the following schemes. For clarity, examples with a single substituent are shown, where multiple substituents are allowed under the definitions disclosed herein.

[0166] In addition to other standard operations known in the literature or to those skilled in the art, the reactions for producing compounds of the present invention are also prepared by using the reactions shown in the following reaction schemes. The following examples are provided so that the present invention can be more fully understood, and the examples are illustrative only and should not be construed as limiting.

[0167] In one aspect, the disclosed compounds include products of the synthetic methods described herein. In another aspect, the disclosed compounds include compounds produced by the synthetic methods described herein. In still another aspect, the present invention includes a pharmaceutical composition comprising a therapeutically effective amount of a product of the disclosed method and a pharmaceutically acceptable carrier. In still another aspect, the present invention includes a method for manufacturing a medicament comprising combining at least one compound of any disclosed compound or at least one product of the disclosed method with a pharmaceutically acceptable carrier or diluent.

[0168] In the absence of description of the reaction conditions and the amounts of the ingredients, it is believed to be determined to be within the technical scope of the art. It is contemplated that each disclosed method may further include additional steps, operations and / or components. It is also contemplated that the present invention may optionally omit any one or more steps, operations and / or components. It should be understood that the disclosed methods may be used to provide the disclosed compounds. It should also be understood that the products of the disclosed methods may be used in the disclosed methods of use.

[0169] D. Pharmaceutical Composition

[0170] In one aspect, the present invention relates to pharmaceutical compositions comprising the disclosed compounds. That is, a pharmaceutical composition comprising a therapeutically effective amount of at least one disclosed compound or at least one product of the disclosed method and a pharmaceutically acceptable carrier can be provided.

[0171] In another aspect, the present invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a product of the disclosed synthesis method. In another aspect, the effective amount is a therapeutically effective amount. In another aspect, the effective amount is a preventive effective amount. In another aspect, the compound is a disclosed compound.

[0172] In some aspects, the disclosed pharmaceutical composition includes the disclosed compound (including one or more pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally other therapeutic ingredients or adjuvants. The present composition includes those compositions suitable for oral administration, rectal administration, topical administration, and parenteral administration (including subcutaneous, intramuscular, and intravenous administration), but the most suitable approach in any given case will depend on the nature and severity of the condition of the specific host and the application of the active ingredient. The pharmaceutical composition can be conveniently presented in unit dosage form and can be prepared by any method known in the pharmaceutical field.

[0173] As used herein, the term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from a pharmaceutically acceptable non-toxic base (including inorganic bases and organic bases). Salts derived from such inorganic bases include salts such as aluminum, ammonium, calcium, copper (-ic and -ous), iron, ferrous, lithium, magnesium, manganese (-ic and -ous), potassium, sodium, zinc, etc. Particularly preferred are ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include primary amines, secondary amines and tertiary amines, as well as cyclic amines and substituted amines, such as naturally occurring and synthetic substituted amines. Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0174] As used herein, the term "pharmaceutically acceptable non-toxic acid" includes inorganic acids, organic acids and salts prepared therefrom, such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, etc. Preferred are citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid.

[0175] In practice, according to conventional pharmaceutical compounding techniques, the compounds of the present invention or pharmaceutically acceptable salts thereof can be closely mixed with pharmaceutical carriers as active ingredients. The carrier can take a variety of forms, depending on the form of the desired preparation for administration, such as oral or parenteral (including intravenous). Therefore, the pharmaceutical composition of the present invention can be presented as discrete units suitable for oral administration, such as capsules, cachets or tablets each containing a predetermined amount of active ingredients. Further, the composition can exist as a powder, granules, solution, suspension in an aqueous liquid, non-aqueous liquid, oil-in-water emulsion or water-in-oil liquid emulsion. In addition to the common dosage forms described above, the compounds of the present invention and / or one or more pharmaceutically acceptable salts thereof can also be administered by a controlled release device and / or a delivery device. The composition can be prepared by any pharmaceutical method. Generally, such methods include the step of combining the active ingredient with a carrier constituting one or more essential ingredients. Generally, the composition is prepared by uniformly and closely mixing the active ingredient with a liquid carrier or a finely powdered solid carrier or both. The product can then be conveniently formed into the desired appearance.

[0176] Therefore, the pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier and a compound of the present invention or a pharmaceutically acceptable salt thereof. The compound of the present invention or a pharmaceutically acceptable salt thereof may also be included in a pharmaceutical composition in combination with one or more other therapeutically active compounds.

[0177] The pharmaceutical carrier used can be, for example, solid, liquid or gas. Examples of solid carriers include lactose, terra alba, sucrose, talcum powder, gelatin, agar, pectin, gum arabic, magnesium stearate and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

[0178] In preparing compositions for oral dosage forms, any convenient pharmaceutical medium may be used. For example, water, ethylene glycol, oils, alcohols, flavoring agents, preservatives, colorants, and the like may be used to form oral liquid preparations, such as suspensions, elixirs, and solutions; and carriers such as starch, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants, and the like may be used to form oral solid preparations, such as powders, capsules, and tablets. Tablets and capsules are preferred oral dosage units because of ease of administration, and solid pharmaceutical carriers are thus employed. Optionally, tablets may be coated by standard aqueous or non-aqueous techniques.

[0179] Tablets containing the compositions of the present invention can be prepared by compression or molding, optionally with one or more auxiliary ingredients or adjuvants. Can be prepared by compressing the active ingredient (such as powder or granules) in a free-flowing form optionally mixed with a binder, lubricant, inert diluent, surfactant or dispersant in a suitable machine. Molded tablets can be manufactured by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.

[0180] The pharmaceutical composition of the present invention includes a compound of the present invention (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally one or more other therapeutic agents or adjuvants. The present composition includes compositions suitable for oral administration, rectal administration, topical administration and parenteral (including subcutaneous, intramuscular and intravenous) administration, but the most suitable approach in any given case will depend on the nature and severity of the condition of the specific host and the administration of the active ingredient. The pharmaceutical composition can be conveniently presented in unit dosage form and can be prepared by any method known to the pharmaceutical field.

[0181] The pharmaceutical composition of the present invention suitable for parenteral administration can be prepared as a solution or suspension of the active compound in water. Suitable surfactants, such as hydroxypropylcellulose, can be included. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof, and in oils. Further, preservatives can be included to prevent harmful growth of microorganisms.

[0182] The pharmaceutical composition of the present invention suitable for injectable use comprises a sterile aqueous solution or dispersion. In addition, the composition can be in the form of a sterile powder for the temporary preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be an effective fluid for easy injection. The pharmaceutical composition must be stable under manufacturing and storage conditions; therefore, it is preferably preserved against the contamination of antimicrobial agents (such as bacteria and fungi). The carrier can be a solvent or a dispersion medium containing, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol), a vegetable oil and a suitable mixture thereof.

[0183] The pharmaceutical compositions of the present invention may be in a form suitable for topical use, such as an aerosol, cream, ointment, lotion, dusting powder, mouthwash, gargle, etc. Further, the composition may be in a form suitable for use in a transdermal device. These formulations may be prepared by conventional processing methods using the compounds of the present invention or pharmaceutically acceptable salts thereof. As an example, a cream or ointment is prepared by mixing a hydrophilic material and water with about 5 wt % to about 10 wt % of the compound to produce a cream or ointment with a desired consistency.

[0184] Pharmaceutical compositions of the present invention can be in a form suitable for rectal administration, wherein the carrier is a solid. Preferably, the mixture forms a unit dose suppository. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently formed by first mixing the composition with one or more softened or molten carriers, then cooling and molding in a mold.

[0185] In addition to the above-mentioned carrier components, the above-mentioned pharmaceutical formulations may optionally include one or more additional carrier components, such as diluents, buffers, flavoring agents, adhesives, surfactants, thickeners, lubricants, preservatives (including antioxidants), etc. In addition, other adjuvants may be included to make the formulation isotonic with the blood of the intended recipient. Compositions containing the compounds of the present invention and / or pharmaceutically acceptable salts thereof may also be prepared in the form of powders or liquid concentrates.

[0186] In the treatment of conditions requiring inhibition or negative regulation of ENPP1 protein activity, appropriate dosage levels will generally be about 0.01 to 500 mg per kg of patient body weight per day, and may be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg / kg per day; more preferably 0.5 to 100 mg / kg per day. Suitable dosage levels may be about 0.01 to 250 mg / kg per day, about 0.05 to 100 mg / kg per day, or about 0.1 to 50 mg / kg per day. Within this range, the dosage may be 0.05 to 0.5, 0.5 to 5.0, or 5.0 to 50 mg / kg per day. For oral administration, the composition is preferably provided in the form of tablets containing 1.0 to 1000 mg of active ingredient, specifically 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900 and 1000 mg of active ingredient, with the dosage of the patient to be treated adjusted symptomatically. The compound can be administered according to a regimen of 1 to 4 times per day, preferably once or twice per day. This dosage regimen can be adjusted to provide the best therapeutic response.

[0187] However, it should be understood that the specific dosage level for any particular patient will depend on a variety of factors. These factors include the patient's age, weight, general health, sex and diet. Other factors include the time and route of administration, excretion rate, drug combination, and the type and severity of the specific disease being treated.

[0188] The present invention further relates to a method for manufacturing a medicament for inhibiting or negatively regulating ENPP1 protein activity in a mammal (e.g., a human) (e.g., treating an uncontrolled cell proliferation disorder or one or more neurodegenerative disorders associated with ENPP1 dysfunction), the method comprising combining one or more disclosed compounds, products or compositions with a pharmaceutically acceptable carrier or diluent. Thus, in one aspect, the present invention relates to a method for manufacturing a medicament comprising combining at least one disclosed compound or at least one disclosed product with a pharmaceutically acceptable carrier or diluent.

[0189] The disclosed pharmaceutical compositions may further include other therapeutically active compounds, which are generally applied in the treatment of the above-mentioned pathological conditions.

[0190] It is understood that the disclosed compositions can be prepared from the disclosed compounds. It is also understood that the disclosed compositions can be used in the disclosed methods of use.

[0191] E. Methods of Using Compounds and Compositions

[0192] The disclosed compounds can be used as a single agent or in combination with one or more other drugs for treating, preventing, controlling, improving the above-mentioned diseases, diseases and symptoms to which the compounds of formula I or other drugs are effective or reducing their risks, wherein the drug combination is safer or more effective than any single drug. Therefore, one or more other drugs can be used simultaneously or sequentially with the disclosed compounds by way and in a commonly used amount. When the disclosed compounds are used simultaneously with one or more other drugs, a pharmaceutical composition containing a unit dosage form of such drugs and the disclosed compounds is preferred. However, combination therapy can also be applied according to an overlapping schedule. It is also envisioned that the combination of one or more active ingredients with the disclosed compounds will be more effective than as a single agent.

[0193] The pharmaceutical compositions and methods of the present invention may further comprise other therapeutically active compounds as described herein, which are generally applied in the treatment of the above-mentioned pathological conditions.

[0194] 1. Treatment Methods

[0195] The compounds disclosed herein can be used to treat, prevent, improve, control or reduce the risk of a variety of conditions in which patients or subjects would benefit from the inhibition or negative regulation of ENPP1. In one aspect, a method of treating or preventing a condition in a subject is provided, the method comprising administering to the subject at least one disclosed compound in an effective dose and in an effective amount; at least one disclosed pharmaceutical composition; and / or at least one disclosed product to treat the condition in the subject.

[0196] Also provided is a method for treating one or more conditions in a subject for which ENPP1 inhibition is predicted to be beneficial, the method comprising the step of administering to the subject at least one disclosed compound; at least one disclosed pharmaceutical composition; and / or at least one disclosed product in an effective dose and in an effective amount to treat the condition in the subject.

[0197] In one aspect, a method for treating an uncontrolled cell proliferation disorder is provided, the method comprising: administering to a subject at least one disclosed compound in an effective dose and in an effective amount; at least one disclosed pharmaceutical composition; and / or at least one disclosed product to treat the disorder in the subject. In another aspect, a method for treating or preventing a neurodegenerative disorder is provided, the method comprising: administering to a subject at least one disclosed compound in an effective dose and in an effective amount; at least one disclosed pharmaceutical composition; and / or at least one disclosed product to treat the disorder in the subject. A method for treating a disorder in a mammal is also provided, the method comprising the step of administering to the mammal at least one disclosed compound, composition, or drug.

[0198] The present invention relates to the use of chemical compositions for treating diseases or disorders in a patient, preferably a human, by administering one or more disclosed compounds or products, wherein ENPP1 inhibition is predicted to have a therapeutic effect, such as uncontrolled cell proliferation disorders (e.g., cancer) and neurodegenerative disorders, such as Alzheimer's disease, Huntington's disease and Parkinson's disease, diseases caused by bacteria and / or viruses.

[0199] The compounds of the present invention may also be used in immunotherapy. In one embodiment, the compounds of the present invention treat uncontrolled cell proliferation disorders and / or diseases caused by bacteria and / or viruses by immunotherapy, which means that the compounds elicit an immunotherapy response, which results in the treatment of these diseases.

[0200] The compounds disclosed herein can be used to treat, prevent, ameliorate, control or reduce the risk of a variety of uncontrolled cell proliferation disorders.

[0201] Also provided is a method for using the disclosed compound, composition or medicine. On the one hand, the method for using relates to the treatment of illness. In other aspects, the disclosed compound can be used as a single agent or in combination with one or more other drugs for treating, preventing, controlling, improving the above-mentioned diseases, illnesses and symptoms for which the compound or other drugs have effectiveness or reducing its risk, wherein the drug combination is safer or more effective than any single drug. Therefore, one or more other drugs can be administered simultaneously or sequentially with the disclosed compound by a route and in a commonly used amount. When the disclosed compound is used simultaneously with one or more other drugs, a pharmaceutical composition in a unit dosage form containing such drugs and the disclosed compound is preferred. However, combination therapy can also be administered according to an overlapping schedule. It is also envisioned that the combination of one or more active ingredients with the disclosed compound can be more effective than as a single agent.

[0202] Examples of disorders that can be treated with provided compounds include uncontrolled cell proliferation disorders. In yet further aspects, the uncontrolled cell proliferation disorder is cancer. In yet further aspects, the cancer is a leukemia. In even further aspects, the cancer is a sarcoma. In still further aspects, the cancer is a solid tumor. In yet further aspects, the cancer is a lymphoma.

[0203] It should be understood that cancer refers to or describes a physiological condition characterized by unregulated cell growth in mammals. Cancer can have multidrug resistance (MDR) or drug sensitivity. Examples of cancer include but are not limited to carcinoma, lymphoma, blastoma, sarcoma and leukemia. More specific examples of such cancers include breast cancer, prostate cancer, colon cancer, squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, pancreatic cancer, cervical cancer, ovarian cancer, peritoneal cancer, liver cancer, such as liver cancer, bladder cancer, colorectal cancer, endometrial cancer, kidney cancer and thyroid cancer.

[0204] In various aspects, additional examples of cancer are basal cell carcinoma, biliary tract cancer; bone cancer; brain and CNS cancer; choriocarcinoma; connective tissue cancer; esophageal cancer; eye cancer; head and neck cancer; gastric cancer; intraepithelial neoplasia; laryngeal cancer; lymphoma, including Hodgkin's lymphoma and non-Hodgkin's lymphoma; melanoma; myeloma; neuroblastoma; oral cancer (e.g., lip, tongue, mouth and pharynx); retinoblastoma; rhabdomyosarcoma; rectal cancer; respiratory cancer; sarcoma; skin cancer; stomach cancer; testicular cancer; uterine cancer; urinary system cancer, as well as other cancers and sarcomas.

[0205] In other aspects, cancer is a hematological cancer. In still other aspects, hematological cancer is selected from acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, chronic myelomonocytic leukemia (CMML), childhood myelomonocytic leukemia (JMML), Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma, solitary myeloma, limited myeloma and extramedullary myeloma. In still other aspects, cancer is selected from chronic lymphocytic leukemia, small lymphocytic lymphoma, B cell non-Hodgkin's lymphoma and large B cell lymphoma.

[0206] In other aspects, cancer is brain cancer. In still other aspects, brain cancer is selected from glioma, medulloblastoma, primitive neuroectodermal tumor (PNET), acoustic neuroma, glioma, meningioma, pituitary adenoma, schwannoma, CNS lymphoma, primitive neuroectodermal tumor, craniopharyngioma, chordoma, medulloblastoma, brain neuroblastoma, central neurocytoma, pineal cell tumor, pinealoblastoma, atypical teratoid rhabdoid tumor (atypicalteratoid rhabdoid tumor), chondrosarcoma, chondroma, choroid plexus carcinoma, choroid plexus papilloma, craniopharyngioma, dysembryoplastic neuroepithelioma, gangliocytoma, germ cell tumor, hemangioblastoma, hemangiopercytoma (hemangiopercytoma) and metastatic brain tumor. In yet other aspects, glioma is selected from ependymoma, astrocytoma, oligodendroglioma and oligoastrocytoma. In an even further aspect, the glioma is selected from the group consisting of infantile pilocytic astrocytoma, subependymal giant cell astrocytoma, ganglioglioma, subependymoma, pleomorphic xanthoastrocytoma, anaplastic astrocytoma, glioblastoma multiforme, brain stem glioma, oligodendroglioma, ependymoma, oligoastrocytoma, cerebellar astrocytoma, infantile desmoplastic astrocytoma, subependymal giant cell astrocytoma, diffuse astrocytoma, mixed glioma, optic nerve glioma, brain glioma, multifocal gliomatous tumor, multicentric glioblastoma multiforme tumor, paraganglioma and ganglioglioma.

[0207] In one aspect, the cancer can be a cancer selected from the following: blood cancer, brain cancer, urogenital tract cancer, gastrointestinal cancer, colon cancer, rectal cancer, breast cancer, kidney cancer, lymphatic system cancer, gastric cancer, lung cancer, pancreatic cancer and skin cancer. In another aspect, the cancer is selected from prostate cancer, glioblastoma multiforme, endometrial cancer, breast cancer and colon cancer. In another aspect, the cancer is selected from breast cancer, ovarian cancer, prostate cancer, head cancer, neck cancer and kidney cancer. In still another aspect, the cancer is selected from blood cancer, brain cancer, urogenital tract cancer, gastrointestinal cancer, colon cancer, rectal cancer, breast cancer, liver cancer, kidney cancer, lymphatic system cancer, gastric cancer, lung cancer, pancreatic cancer and skin cancer. In yet another aspect, the cancer is selected from lung cancer and liver cancer. In even another aspect, the cancer is selected from breast cancer, ovarian cancer, testicular cancer and prostate cancer. In still another aspect, the cancer is breast cancer. In yet another aspect, the cancer is ovarian cancer. In even another aspect, the cancer is prostate cancer. In still another aspect, the cancer is testicular cancer.

[0208] In various aspects, the disorder associated with ENPP1 dysfunction comprises a neurodegenerative disorder. In further aspects, the neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease and Huntington's disease.

[0209] The compounds can be further used in methods for preventing, treating, controlling, improving or reducing the risk of the diseases, disorders and conditions described herein. The combination of the compounds with other agents can be further used in methods for preventing, treating, controlling, improving or reducing the risk of the above-mentioned diseases, disorders and conditions.

[0210] The invention further relates to the administration of ENPP1 inhibitors to improve therapeutic outcomes in the context of uncontrolled cell proliferation disorders, including cancer. That is, in one aspect, the invention relates to a co-therapeutic method comprising the step of administering to a mammal an effective amount and dosage of at least one compound of the invention relevant to cancer therapy.

[0211] In other aspects, in the context of cancer therapy, administration improves treatment outcomes. Administration related to cancer therapy can be continuous or intermittent. Administration does not need to be performed simultaneously with therapy and can be performed before, during and / or after therapy. For example, cancer therapy can be provided within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days before or after the administration of the compound. As another example, cancer therapy can be provided within 1 week, 2 weeks, 3 weeks or 4 weeks before or after the administration of the compound. As still another example, cognitive or behavioral therapy can be provided before or after administration within a time period of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 half-lives of the administered compound.

[0212] On the one hand, the disclosed compounds can be used in combination with one or more other drugs for treating, preventing, controlling, improving the diseases or conditions for which the disclosed compounds or other drugs can be effective or reducing their risks, wherein the drugs are combined together safer or more effective than any single drug. Therefore, such one or more other drugs can be administered simultaneously or sequentially with the compound of the present invention by way and in a commonly used amount. When the compound of the present invention is used simultaneously with one or more other drugs, a pharmaceutical composition containing a unit dosage form of such other drugs and the disclosed compound is preferred. However, combination therapy can also include the therapy in which the disclosed compounds and one or more other drugs are administered according to different overlapping schedules. It is also considered that when used in combination with one or more other active ingredients, the disclosed compounds and other active ingredients can be used in a lower dosage than when each is used alone.

[0213] Accordingly, pharmaceutical compositions include those that contain one or more other active ingredients, in addition to a compound of the present invention.

[0214] The above combination not only comprises the combination of the disclosed compound and a kind of other active compound, but also comprises the combination of the disclosed compound and two or more other active compounds. Similarly, the disclosed compound can be used in combination with other drugs, and the other drugs are used to prevent, treat, control, improve the diseases or conditions to which the disclosed compound is useful or reduce its risk. Therefore, such other drugs can be used simultaneously or sequentially with the compound of the present invention by way and in a commonly used amount. When the compound of the present invention is used simultaneously with one or more other drugs, it is preferred that the pharmaceutical composition also contains such other drugs in addition to the disclosed compound. Therefore, the pharmaceutical composition includes those that also contain one or more other active ingredients in addition to the compound of the present invention.

[0215] The weight ratio of the disclosed compound to the second active ingredient can vary and will depend on the effective dose of each ingredient. Typically, each effective dose will be used. Thus, for example, when the compound of the present invention is combined with another agent, the weight ratio of the disclosed compound to the other agent will typically range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. The combination of the compound of the present invention with other active ingredients will also typically be within the above range, but in each case, an effective dose of each active ingredient should be used.

[0216] In such combinations, the disclosed compounds and other active agents may be administered separately or in combination. In addition, the administration of one element may be prior to, simultaneously with, or after the administration of one or more other agents.

[0217] Therefore, the subject compound can be used alone or in combination with other medicaments known to be beneficial to the subject's indication or other drugs that affect receptors or enzymes, which improve the efficacy, safety, convenience or reduce its unwanted side effects or toxicity of the disclosed compounds. The subject compound and other medicaments can be co-administered in concomitant therapy or in a fixed combination.

[0218] In one aspect, the compounds can be used in combination with anti-cancer therapeutics or other known therapeutic agents.

[0219] In the treatment of conditions requiring inhibition or negative regulation of ENPP1, appropriate dosage levels will generally be about 0.01 to 1000 mg per kg of patient body weight per day, which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg / kg per day; more preferably about 0.5 to about 100 mg / kg per day. Suitable dosage levels may be about 0.01 to 250 mg / kg per day, about 0.05 to 100 mg / kg per day, or about 0.1 to 50 mg / kg per day. Within this range, the dosage may be 0.05 to 0.5, 0.5 to 5, or 5 to 50 mg / kg per day. For oral administration, the composition is preferably provided in the form of tablets containing 1.0 to 1000 mg of active ingredient, specifically 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900 and 1000 mg of active ingredient, to adjust the dosage of the patient to be treated symptomatically. The compound can be administered according to a regimen of 1 to 4 times a day, preferably once or twice a day. This dosage regimen can be adjusted to provide an optimal therapeutic response. However, it should be understood that the specific dosage level and dosage frequency for any particular patient can vary and will depend on a variety of factors, including the activity of the specific compound used, the metabolic stability of the compound and the length of action time, age, body weight, overall health, sex, diet, mode and time of administration, excretion rate, drug combination, severity of a specific condition and the host undergoing therapy.

[0220] Thus, in one aspect, the invention relates to a method for inhibiting or negatively regulating ENPP1 in at least one cell in an effective amount to modulate or activate an ENPP1 activity response, for example in the at least one cell, the method comprising the step of contacting the at least one cell with at least one compound of the invention. In a further aspect, the cell is a mammal, such as a human. In a further aspect, the cell has been isolated from a subject prior to the contacting step. In a further aspect, the contacting is performed by administering to a subject.

[0221] a. Treatment of uncontrolled cell proliferation disorders

[0222] In one aspect, the invention relates to a method for treating an uncontrolled cell proliferative disorder in a mammal, comprising the step of administering to the mammal an effective amount of at least one disclosed compound or a product of a disclosed process for preparing a compound, or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, thereby treating the uncontrolled cell proliferative disorder.

[0223] In still other aspects, the effective amount is a therapeutically effective amount. In still other aspects, the effective amount is a prophylactically effective amount.

[0224] In a further aspect, the mammal is a human. In yet a further aspect, the method further comprises the step of identifying a mammal in need of treatment for an uncontrolled cell proliferation disorder. In still a further aspect, prior to the administering step, the mammal has been diagnosed as being in need of treatment for an uncontrolled cell proliferation disorder.

[0225] In another aspect, the uncontrolled cell proliferation disorder is cancer. In another aspect, the cancer is leukemia. In an even further aspect, the cancer is a sarcoma. In another aspect, the cancer is a solid tumor. In another aspect, the cancer is a lymphoma. In an even further aspect, the cancer is selected from chronic lymphocytic leukemia, small lymphocytic lymphoma, B-cell non-Hodgkin lymphoma and large B-cell lymphoma. In another aspect, the cancer is selected from blood cancer, brain cancer, genitourinary tract cancer, gastrointestinal cancer, colon cancer, rectal cancer, breast cancer, liver cancer, kidney cancer, lymphatic system cancer, gastric cancer, lung cancer, pancreatic cancer and skin cancer. In another aspect, the cancer is selected from lung cancer and liver cancer. In an even further aspect, the cancer is selected from breast cancer, ovarian cancer, testicular cancer and prostate cancer. In another aspect, the cancer is breast cancer. In another aspect, the cancer is ovarian cancer. In an even further aspect, the cancer is prostate cancer. In another aspect, the cancer is testicular cancer.

[0226] Examples

[0227] F. Experiment

[0228] The following examples are presented to provide a person of ordinary skill in the art with a complete disclosure and description of how to prepare and evaluate the compounds, compositions, articles, devices and / or methods claimed herein, and are intended to be purely illustrative of the present invention and are not intended to limit the scope of what the inventors believe to be their inventions. Although efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperatures, etc.), some errors and deviations should still be considered. Unless otherwise indicated, parts are parts by weight, temperatures are in ° C or at ambient temperature, and pressures are at or near atmospheric pressure.

[0229] Several methods for preparing compounds of the invention are illustrated in the following examples. Starting materials and necessary intermediates are in some cases commercially available or can be prepared according to literature procedures or as demonstrated herein.

[0230] The following exemplary compounds of the present invention are synthesized. Examples are provided herein to illustrate the present invention and should not be construed as limiting the present invention in any way. According to the IUPAC naming convention, examples are generally depicted in free base form. However, some of the examples are obtained or isolated in the form of salts.

[0231] Some of the examples described are obtained as racemic mixtures of one or more enantiomers or diastereomers. One skilled in the art can separate compounds to separate individual enantiomers. Separation can be performed by coupling the racemic mixture of the compound to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods (e.g., fractional crystallization or chromatography). The racemic or diastereomeric mixture of the compound can also be directly separated by a chromatographic method using a chiral stationary phase.

[0232] Experimental Chemistry

[0233] Synthetic Schemes, Methods and Procedures:

[0234] Synthesis of N-(2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)propyl)sulfonamide urea (I-01)

[0235]

[0236] Synthesis of ethyl 2-(1-benzylpiperidin-4-ylidene) propionate (01)

[0237] 60%NaH (3.8 g, 95.1 mmol, 2 equiv) was added to a stirred solution of 1-benzylpiperidin-4-one (1) (9 g, 47.5 mmol, 1 equiv) in THF (90 mL) at 0 °C. Then a solution of ethyl 2-(diethoxyphosphoryl)propionate (2) (16.3 mL, 76 mmol, 1.6 equiv) in THF (10 mL) was added dropwise, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed by TLC, the reaction mixture was quenched with ice-cold water and extracted with EtOAc (2 × 100 mL). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography by eluting with 20% EtOAc / hexane to obtain ethyl 2-(1-benzylpiperidin-4-ylidene)propionate (01) (10 g, yield: 76%) as a light yellow liquid. TLC system: EtOAc / hexane (30:70), Rf Value: ~0.6; 1 H NMR (400MHz, CDCl3) δ7.34–7.25 (m, 5H), 4.18 (d, J = 7.2Hz, 2H), 3.51 (s, 2H), 2.64–2. 57(m,2H),2.49–2.44(m,4H),2.37–2.35(m,2H),1.85(s,3H),1.29(t,J=7.2Hz,3H).

[0238] Synthesis of tert-butyl 4-(1-ethoxy-1-oxopropan-2-yl)piperidine-1-carboxylate (02)

[0239] To a stirred solution of ethyl 2-(1-benzylpiperidin-4-ylidene)propanoate (01) (2 g, 7.06 mmol, 1 eq) in ethanol (30 mL) was added (Boc)2O (1.54 mL, 7.06 mmol, 1 eq), followed by 10% Pd / C (200 mg). The reaction mixture was stirred in a steel reactor at 55 °C under H2 (55 psi) for 6 hours. After completion of the reaction by TLC, the reaction mixture was filtered through a diatomaceous earth pad. The obtained filtrate was evaporated under reduced pressure to give tert-butyl 4-(1-ethoxy-1-oxopropan-2-yl)piperidine-1-carboxylate (02) (2 g, yield: 99%) as a light yellow liquid. TLC system: EtoAc: Hexane (10:90; KMnO4 staining), R f Value: ~0.3; 1 H NMR (400MHz, CDCl3) δ4.17–4.07(m,4H),2.66(t,J=12Hz,2H),2.26(p,J=7.2Hz,1H),1.72– 1.66(m,2H),1.64–1.52(m,3H),1.41(s,9H),1.27(t,J=7.2Hz,3H),1.09(d,J=7.2Hz,3H).

[0240] Synthesis of tert-butyl 4-(1-hydroxypropan-2-yl)piperidine-1-carboxylate (03):

[0241] NaBH4 (1.58 g, 42 mmol, 6 eq.) was added to a stirred solution of tert-butyl 4-(1-ethoxy-1-oxopropan-2-yl)piperidine-1-carboxylate (02) (2 g, 7 mmol, 1 eq.) in THF:MeOH (8:2) (20 mL) at 0 °C. The reaction mixture was stirred at 80 °C for 24 hours, after which the reaction was completed by TLC. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over sodium sulfate and concentrated to provide a crude product. The crude compound was purified by 100-200 mesh silica gel column chromatography by eluting with 20% EtOAc / hexane to obtain tert-butyl 4-(1-hydroxypropan-2-yl)piperidine-1-carboxylate (03) (1.5 g, yield: 88%) as a viscous liquid. TLC system EtoAc: hexane (30:70; KMnO4 staining), R f Value: 0.3; LCMS (m / z): 188.2 (M+H-tBu) + ; 1 HNMR(400MHz,DMSO-d6)δ4.37(t,J=5.2Hz,1H),3.97–3.94(m,2H),3.25–3.22(m,2H),2.51–2.49(m ,2H),1.55–1.52(m,2H),1.45–1.42(m,2H),1.38(s,9H),1.11–0.98(m,2H),0.78(d,J=6.8Hz,3H).

[0242] Synthesis of tert-butyl 4-(1-(toluenesulfonyloxy)propan-2-yl)piperidine-1-carboxylate (04)

[0243] TEA (2.64 mL, 18.3 mmol, 3 equiv.), p-toluenesulfonyl chloride (1.75 g, 9.2 mmol, 1.5 equiv.) were added to a stirred solution of tert-butyl 4-(1-hydroxypropane-2-yl)piperidine-1-carboxylate (03) (1.5 g, 6.1 mmol, 1 equiv.) cooled to 0 ° C. in DCM (10 mL). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was quenched with water and extracted with DCM (2×100 mL). The combined organic layers were washed with water (50 mL), brine (40 mL), dried over sodium sulfate and concentrated to provide a crude product. The crude compound was purified by eluting with 20% EtOAc / hexane through a 100-200 mesh silica gel column to obtain tert-butyl 4-(1-(tosyloxy)propane-2-yl)piperidine-1-carboxylate (04) (1.5 g, yield: 60%) as a viscous liquid. TLC system EtoAc: Hexane (30:70), Rf Value: 0.5; LCMS (m / z): 298.2 (M+H-Boc) + ; 1 HNMR(400MHz, CDCl3)δ7.79(d,J=7.6Hz,2H),7.34(d,J=7.6Hz,2H),4.07(brs,2H),3.93–3.87(m,2H),2.61–2.45( brs,2H),2.43(s,3H),1.69–1.66(m,1H),1.55–1.47(m,3H),1.45(s,9H),1.20–1.08(m,2H),0.87(d,J=6.8Hz,3H).

[0244] Synthesis of tert-butyl 4-(1-azidopropan-2-yl)piperidine-1-carboxylate (05)

[0245] To a stirred solution of tert-butyl 4-(1-(tosyloxy)propan-2-yl)piperidine-1-carboxylate (04) (1.5 g, 3.7 mmol, 1 eq.) in DMF (12 mL) was added NaN3 (1.2 g, 18.8 mmol, 5 eq.). The reaction mixture was stirred at 100 °C for 2 h. After completion of the reaction by TLC, the reaction mixture was quenched with cold water and extracted with diethyl ether (2 × 50 mL). The combined organic layers were washed with cold water (50 mL), brine (20 mL), dried over sodium sulfate and concentrated to give tert-butyl 4-(1-azidopropan-2-yl)piperidine-1-carboxylate (05) (910 mg, yield: 90%) as a viscous liquid. TLC system EtoAc: Hexane (20:80; KMnO4 staining), R f Value: 0.8; 1 HNMR(400MHz, CDCl3) δ4.14(brs,2H),3.31(ABq,J=6.8Hz,1H),3.19(ABq,J=6.8Hz,1H),2. 66–2.64(m,2H),1.63–1.57(m,2H),1.45(s,9H),1.28–1.14(m,4H),0.94(d,J=7.2Hz,3H).

[0246] Synthesis of tert-butyl 4-(1-aminopropan-2-yl)piperidine-1-carboxylate (06)

[0247] 10% Pd / C (450 mg) was added to a stirred solution of tert-butyl 4-(1-azidopropan-2-yl)piperidine-1-carboxylate (05) (900 mg, 3.35 mmol, 1 eq) in methanol (9 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered through a celite pad, and the filtrate was evaporated under reduced pressure to give tert-butyl 4-(1-aminopropan-2-yl)piperidine-1-carboxylate (06) (800 mg, yield: 98%) as a liquid. TLC system MeOH: DCM (10: 90; ninhydrin stain), R f Value: 0.2; 1 HNMR(400MHz,DMSO-d6)δ3.97–3.94(m,2H),2.66–2.49(m,3H),2.36(ABq,J=7.2H z,1H),1.53–1.44(m,5H),1.42(s,9H),1.09-0.97(m,3H),0.78(d,J=6.8Hz,3H).

[0248] Synthesis of tert-butyl 4-(1-((N-(tert-butyloxycarbonyl)sulfamoyl)amino)propan-2-yl)piperidine-1-carboxylate (07)

[0249] To a stirred solution of tert-butyl 4-(1-aminopropan-2-yl)piperidine-1-carboxylate (06) (500 mg, 2.05 mmol, 1 eq) in DCM (10 mL) cooled to 0 °C was added DIPEA (0.56 mL, 3.07 mmol, 1.5 eq) and (tert-butyloxycarbonyl)((4-(dimethylimino)pyridin-1(4H)-yl)sulfonyl)amide (3) (805 mg, 2.67 mmol, 1.3 eq). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was diluted with water and extracted with DCM (2×50 mL). The combined organic layers were washed with cold water (40 mL), brine (20 mL), dried over sodium sulfate and concentrated to give the crude product. The obtained crude product was purified by reverse phase Grace column purification to give tert-butyl 4-(1-((N-(tert-butyloxycarbonyl)sulfamoyl)amino)propan-2-yl)piperidine-1-carboxylate (07) (440 mg, yield: 50%) as a viscous liquid. TLC system: MeOH:DCM (10:90; KMnO4 staining), R f Value: 0.8; 1HNMR(400MHz, DMSO-d6)δ10.76(s,1H),7.53(t,J=5.6Hz,1H),3.97–3.94(m,2H),2.89–2.85(m,1H),2. 71–2.62(m,3H),1.52–1.46(m,4H),1.42(s,9H),1.38(s,9H),1.15-0.95(m,2H),0.79(d,J=6.8Hz,3H).

[0250] Synthesis of N-(2-(Piperidin-4-yl)propyl)sulfonamide urea hydrochloride (08)

[0251] To a stirred solution of tert-butyl 4-(1-((N-(tert-butoxycarbonyl)sulfamoyl)amino)propan-2-yl)piperidine-1-carboxylate (07) (440 mg, 1.04 mmol, 1 eq) in 1,4-dioxane (1 mL) at 0° C. was added 4M HCl in dioxane (3 mL). The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure to give N-(2-(piperidin-4-yl)propyl)sulfonamide urea hydrochloride (08) (230 mg, yield: 85%) as a sticky solid. 1 HNMR(400MHz,DMSO-d6)δ8.91(s,1H),8.66(s,1H),6.49(s,3H),3.26–3.23(m,2H ),2.86–2.69(m,4H),1.69–1.66(m,2H),1.59–1.35(m,4H),0.81(d,J=6.8Hz,3H).

[0252] Synthesis of N-(2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)propyl)sulfonamide urea (I-01):

[0253] To a stirred solution of 4-chloro-6,7-dimethoxyquinazoline (4) (200 mg, 0.89 mmol, 1 eq) in DMF (2 mL) at 0 °C was added NaH (89 mg, 2.23 mmol, 2.5 eq) and N-(2-(piperidin-4-yl)propyl)sulfonamide urea hydrochloride (I-01) (228 mg, 0.89 mmol, 1 eq) and stirred at room temperature for 16 hours. The reaction mixture was quenched with ice-cold water and extracted with EtOAc (2×50 mL). The combined organic layers were washed with cold water (40 mL), brine (20 mL), dried over sodium sulfate and concentrated to give a crude product. The crude compound was purified by preparative HPLC to give N-(2-(1-(6,7-dimethoxyquinazoline-4-yl)piperidin-4-yl)propyl)sulfonamide urea (I-01) (80 mg, yield: 21%) as a white solid. TLC system MeOH:DCM (10:90), R f Value: 0.4; LCMS (m / z): 410.4 (M+H) + ; 1 HNMR(400MHz,DMSO-d6)δ8.51(s,1H),7.20(s,1H),7.11(s,1H),6.46(s,3H),4.21(d,J=12.8Hz,2H),3. 92(s,3H),3.91(s,3H),3.03-2.95(m,3H),2.76-2.71(m,1H),1.70-1.40(s,6H),0.88(d,J=6.8Hz,3H).

[0254] Synthesis scheme of N-(2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propyl)sulfamoylcarbamate (I-02)

[0255] Synthesis of tert-butyl 4-(1-cyanoethyl)piperidine-1-carboxylate (01)

[0256] To a stirred solution of tert-butyl 4-oxopiperidine-1-carboxylate (1) (1.5 g, 7.5 mmol, 1 equiv) in THF (15 mL) at 0 °, diethyl (1-cyanoethyl) phosphonate (2) (2.15 g, 11.3 mmol, 1.5 equiv), LiBr (0.72 g, 9 mmol, 1.2 equiv) and TEA (2 mL, 15 mmol, 2 equiv) were added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was diluted with water and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography by eluting with 20% EtOAc / hexane to obtain tert-butyl 4- (1-cyanoethyl) piperidine-1-carboxylate (01) (1.2 g, yield: 70%) as a white solid. TLC system: EtOAc / hexane (30:70; ninhydrin stain), R f Value: ~0.6; 1 H NMR (400MHz, CDCl3) δ3.51–3.45(m,4H),2.58(t,J=5.6Hz,2H),2.35(t,J=5.6Hz,2H),1.91(s,3H),1.47(s,9H).

[0257] Synthesis of tert-butyl 4-(1-cyanoethyl)piperidine-1-carboxylate (02)

[0258] Mg turnings (4.8 g, 0.2 mol, 40 equiv) were added to a stirred solution of tert-butyl 4-(1-cyanoethyl)piperidine-1-carboxylate (01) (1.2 g, 5 mmol, 1 equiv) in anhydrous methanol (70 mL). The reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction by TLC, the reaction mixture was quenched with 6N HCl and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to give tert-butyl 4-(1-cyanoethyl)piperidine-1-carboxylate (02) (1.2 g, yield: 99%) as a viscous liquid. TLC system: EtoAc: Hexane (20:80; ninhydrin staining), R f Value: ~0.5; 1 H NMR (400MHz, CDCl3) δ4.14 (brs 2H),2.67(brs,2H),2.53(p,J=6.8Hz,1H),1.88–1.83(m,1H),1.73–1.69(m, 1H),1.63-1.55(m,2H),1.46(s,9H),1.32(d,J=6.8Hz,3H),1.31–1.29(m,1H)

[0259] Synthesis of 2-(Piperidin-4-yl)propionitrile hydrochloride (03)

[0260] A solution of tert-butyl 4-(1-cyanoethyl)piperidine-1-carboxylate (02) (1.2 g, 5 mmol, 1 eq.) in dioxane (12 mL) containing 4 M HCl was stirred at room temperature for 1 hour. After completion of the reaction by TLC, the reaction mixture was concentrated under reduced pressure to give 2-(piperidin-4-yl)propionitrile hydrochloride (03) (0.88 g, yield: 99%) as a sticky solid. TLC system EtoAc (100%, KMnO4 staining), R f Value: 0.1; 1 HNMR(400MHz,DMSO-d6)δ9.22(s,1H),8.71(s,1H),3.31–3.25(m,2H),2.91–2.81(m, 3H),1.92–1.79(m,2H),1.77-1.72(m,1H),1.53–1.46(m,2H),1.22(d,J=7.2Hz,3H).

[0261] Synthesis of 2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propionitrile (04)

[0262] 2-(piperidin-4-yl)propionitrile hydrochloride (03) (0.73 g, 5.35 mmol, 1.2 equiv) was added to a stirred solution of 4-chloro-6,7-dimethoxyquinoline (3) (1 g, 4.46 mmol, 1 equiv) in 1,4-dioxane (10 mL) degassed for 10 minutes. CsCO (4.34 g, 13.3 mmol, 3 equiv), Pd(dba) (0.4 g, 0.44 mmol, 0.1 equiv), X-Phos (0.42 g, 0.89 mmol, 0.2 equiv) were added. The reaction mixture was stirred at 110 ° C in a sealed tube for 16 hours. After the reaction was completed by TLC, the reaction mixture was filtered through a celite pad and concentrated to provide a crude product. The crude compound was purified by 100-200 mesh silica gel column by eluting with 3% MeOH / DCM to give 2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propanenitrile (04) (0.5 g, yield: 34%) as a white solid. TLC system MeOH: DCM (10:90), R f Value: 0.5; LCMS (m / z): 326.3 (M+H) + ; 1HNMR (400MHz, DMSO-d6) δ8.49(d,J=5.2Hz,1H),7.31(s,1H),7.15(s,1H),6.87(d,J=5.2Hz,1H),3.91(s,6H),3.58(t,J= 11.6Hz, 2H), 2.92 (p, J = 6.8Hz, 1H), 2.76 (t, J = 11.6Hz, 2H), 2.00–1.89 (m, 2H), 1.71–1.57 (m, 3H), 1.29 (d, J = 6.8Hz, 3H).

[0263] Synthesis of 2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propan-1-amine (05)

[0264] Ra-Ni (250 mg) was added to a stirred solution of 2-(1-(6,7-dimethoxyquinoline-4-yl)piperidin-4-yl)propionitrile (04) (500 mg, 1.53 mmol, 1 eq) in methanol (10 mL) containing 7M NH. The reaction mixture was stirred at room temperature under H2 balloon pressure for 16 hours. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad and concentrated to give 2-(1-(6,7-dimethoxyquinoline-4-yl)piperidin-4-yl)propan-1-amine (05) (500 mg, yield: 99%) as an off-white solid. TLC system MeOH: DCM (10: 90), R f Value: 0.1; 1 HNMR(400MHz,DMSO-d6)δ8.48(s,1H),7.30(s,1H),7.18(s,1H),6.86(d,J=4.8Hz,1H),3.91(s,6H),3.56–3.54(m,2H),3.41 –3.37(m,2H),2.89(br,1H),2.73–2.72(m,2H),1.78–1.76(m,2H),1.55–1.53(m,3H),1.09(t,J=6.8Hz,1H),0.98(brs,3H).

[0265] Synthesis of tert-butyl N-(2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propyl)sulfamoylcarbamate (06)

[0266] To a stirred solution of 2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propan-1-amine (05) (400 mg, 1.21 mmol, 1.0 eq.) in DCM (8 mL) was added DIPEA (0.32 mL, 1.82 mmol, 1.5 eq.), acetyl((4-(dimethylimino)pyridin-1(4H)-yl)sulfonyl)amide (03) (475 mg, 1.58 mmol, 1.3 eq.). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was diluted with water and extracted with DCM (2×50 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The crude compound was purified by preparative HPLC to give tert-butyl N-(2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propyl)sulfamoylcarbamate (06) (100 mg, yield: 16%) as an off-white solid. TLC system MeOH:DCM (5:95), R f Value: 0.5; LCMS (m / z): 509.3 (M+H) + ; 1 HNMR(400MHz,DMSO-d6)δ8.48(d,J=4.4Hz,1H),8.17(s,1H),7.46(brs,1H),7.30(s,1H),7.16(s,1H),6.84(d,J=4.4Hz,1H), 3.90(s,6H),3.02–2.96(m,2H),2.78–2.72(m,4H),1.76–1.74(m,2H),1.62–1.52(m,4H),1.43(s,9H),0.92(d,J=5.2Hz,3H).

[0267] Synthesis of (I-02)

[0268] A solution of tert-butyl N-(2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propyl)sulfamoylcarbamate (06) (60 mg, 2.05 mmol, 1 eq) in dioxane (1 mL) containing 4M HCl was stirred at room temperature for 2 hours. After completion of the reaction by TLC, the reaction mixture was concentrated and triturated with pentane to give (I-02) (60 mg, yield: 75%) as an off-white solid. TLC system MeOH: DCM (10:90), R f Value: 0.3; LCMS (m / z): 409.4 (M+H) + ; 1HNMR (400MHz, DMSO-d6) δ8.51(d,J=6.8Hz,1H),7.37(s,1H),7.241(s,1H),7.1(d,J=6.8Hz,1H),6.52–6.48(m,3H),4.11(d,J=12.8Hz,2H) ,3.97,3.96(2s,6H),3.28–3.26(m,2H),2.95–2.92(m,1H),2.78–2.7 5(m,1H),1.82-1.76(m,3H),1.64-1.44(m,3H),0.89(d,J=6.8Hz,3H).

[0269] Synthesis of 7-methoxy-4-(4-(2-(sulfamoylamino)ethyl)piperidin-1-yl)quinazolin-6-yl sodium phosphate (I-03)

[0270]

[0271] Synthesis of 6,7-dimethoxyquinazoline-4-ol (01)

[0272] To a stirred solution of 4-chloro-6,7-dimethoxyquinazoline (1) (10 g, 44.64 mmol, 1 eq.) in THF (100 mL) was added H2O (50 mL) (8.2 g, 147.3 mmol, 3.3 eq.), and the reaction mixture was stirred at 75 ° C for 24 hours. After the reaction was completed by TLC, the reaction mixture was cooled to 0 ° C and acetic acid was added. The precipitated solid was filtered and dried under vacuum to obtain 6,7-dimethoxyquinazoline-4-ol (01) (7 g, yield: 76%) as a light yellow solid. TLC system: EtOAc (100), R f Value: ~0.1; LCMS (m / z): 207.1 (M+H) + ; 1 HNMR (400MHz, DMSO-d6) δ12.1(brs,1H),7.98(s,1H),7.44(s,1H),7.13(s,1H),3.9(s,3H),3.87(s,3H).

[0273] Synthesis of 4-Hydroxy-7-methoxyquinazolin-6-yl acetate (02)

[0274] DL-methionine (8.6 g, 57.9 mmol, 1.6 equiv) was added to a stirred solution of 6,7-dimethoxyquinazoline-4-ol (01) (7 g, 36.2 mmol, 1 equiv) in methanesulfonic acid (60 mL). The reaction mixture was stirred at 120 ° C for 24 hours. After the reaction was completed by TLC, the reaction mixture was cooled to 0 ° C, and 2M NaOH was added to precipitate, and the solid was filtered and dried. The resulting solid was dissolved in (Ac) 2O (24 mL) and pyridine (5.3 mL, 67.6 mmol, 2 equiv) was added. The reaction mixture was stirred at 100 ° C for 24 hours. After the reaction was completed by TLC, the reaction mixture was diluted with cold water, the filtered solid was precipitated and dried under vacuum to obtain 4-hydroxy-7-methoxyquinazoline-6-yl acetate (02) (5.5 g, yield: 69%) as an off-white solid. TLC system: EtOAc (100), R f Value: ~0.2; LCMS (m / z): 235.0 (M+H) + ; 1 HNMR (400MHz, DMSO-d6) δ12.2(brs,1H),8.08(s,1H),7.74(s,1H),7.27(s,1H),3.9(s,3H),2.29(s,3H).

[0275] Synthesis of 4-chloro-7-methoxyquinazolin-6-yl acetate (03)

[0276] Catalytic DMF (1 mL) was added to a stirred solution of 4-hydroxy-7-methoxyquinazoline-6-yl acetate (02) (2 g, 8.54 mmol, 1 equivalent) in thionyl chloride (18 mL). The reaction mixture was stirred at 80 ° C for 2 hours. After the reaction was completed by TLC, the reaction mixture was diluted with toluene and evaporated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography by eluting with 20% EtOAc / hexanes to obtain 4-chloro-7-methoxyquinazoline-6-yl acetate (03) (1.2 g, yield: 57%) as a cream-colored solid. TLC system: EtOAc / hexanes (50:50), R f Value: 0.5; LCMS (m / z): 253.1 (M+H) + ; 1 HNMR (400MHz, CDCl3) δ8.95(s,1H),7.90(s,1H),7.43(s,1H),4.02(s,3H),2.39(s,3H).

[0277] Synthesis of tert-butyl 4-(cyanomethyl)piperidine-1-carboxylate (04)

[0278] To a stirred solution of tert-butyl 4-oxopiperidin-1-carboxylate (2) (5 g, 25.1 mmol, 1 eq) in THF (50 mL) at 0 ° C., diethyl (cyanomethyl) phosphonate (3) (6.67 mL, 37.6 mmol, 1.5 eq) was added. LiBr (2.58 g, 30.1 mmol, 1.2 eq), TEA (7.2 mL, 50.2 mmol, 2 eq) were then added, and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was diluted with water and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography by eluting with 20% EtOAc / hexane to obtain tert-butyl 4- (cyanomethyl) piperidine-1-carboxylate (04) (5 g, yield: 89%) as a white solid. TLC system: EtOAc / hexane (20:80), R f Value: ∼0.6, PMA staining; 1 H NMR (400MHz, CDCl3) δ5.19 (s, 1H), 3.51 (m, 4H), 2.56 (t, J = 5.6Hz, 2H), 2.33 (t, J = 5.6Hz, 2H), 1.47 (s, 9H).

[0279] Synthesis of tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate (05)

[0280] To a stirred solution of tert-butyl 4-(cyanomethyl)piperidine-1-carboxylate (04) (5 g, 22.5 mmol, 1 eq.) in 1,4-dioxane:HO (3:1) (130 mL) was added 10% Pd / C (1.5 g), Re-Ni (5 g), LiOH HO (1.9 g, 48.3 mmol, 2.1 eq.). The reaction mixture was stirred in a steel autoclave at room temperature under H atmosphere (50 psi) for 16 h. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad, and the filtrate was concentrated under reduced pressure to give tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate (05) (5 g (crude product)) as a viscous liquid. TLC system MeOH:DCM (10:90; ninhydrin stain), R f Value: ~0.1; 1H NMR (400 MHz, DMSO-d6) δ 3.91–3.88 (m, 2H), 2.67–2.65 (m, 2H), 1.69–1.57 (m, 2H), 1.39–1.38 (m, 11H), 1.29–1.24 (m, 2H), 1.14–1.09 (m, 1H), 0.97–1.85 (m, 2H). The expected proton and impurity peaks were observed by NMR.

[0281] Synthesis of tert-butyl 4-(2-((N-(tert-butyloxycarbonyl)sulfamoyl)amino)ethyl)piperidine-1-carboxylate (06)

[0282] To a stirred solution of tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate (05) (5 g, crude product 21.9 mmol, 1 eq) in DCM (50 mL) at 0°C was added DIPEA (6 mL, 32.8 mmol, 1.5 eq), (tert-butyloxycarbonyl)((4-(dimethylimino)pyridin-1(4H)-yl)sulfonyl)amide (03) (7.9 g, 26.2 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was diluted with water and extracted with DCM (2×100 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure to give tert-butyl 4-(2-((N-(tert-butyloxycarbonyl)sulfamoyl)amino)ethyl)piperidine-1-carboxylate (06) (2.5 g, yield: 28%) as a white solid. TLC system MeOH:DCM (10:90; ninhydrin stain), R f Value: 0.6; 1 HNMR(400MHz,DMSO-d6)δ10.79(s,1H),7.54(s,1H),3.95–3.88(m,2H),2.93–2.88(m,2H),2.67– 2.50(br,2H),1.69-1.51(m,4H),1.38(s,9H),1.34(s,9H),1.11–1.07(m,1H),0.96–0.90(m,2H).

[0283] Synthesis of 4-(2-((N-(sulfamoyl)amino)ethyl)piperidine-1-carboxylate (07)

[0284] A solution of tert-butyl 4-(2-((N-(tert-butoxycarbonyl)sulfamoyl)amino)ethyl)piperidine-1-carboxylate (06) (2.5 g, 6.1 mmol, 1 eq) in dioxane (25 mL) containing 4M HCl was stirred at room temperature for 2 hours. After completion of the reaction by TLC, the reaction mixture was concentrated under reduced pressure to give 4-(2-((N-(sulfamoyl)amino)ethyl)piperidine-1-carboxylate (07) (1.4 g, yield: 99%) as a sticky solid. TLC system MeOH:DCM (10:90; ninhydrin stain), R f Value: ~0.1; 1 HNMR(400MHz,DMSO-d6)δ8.52–8.51(br,2H),6.52–6.44(m,3H),3.28-3.20(m,2H),2.91– 2.78(m,4H),1.85–1.75(m,2H),1.64–1.61(m,1H),1.45–1.38(m,2H),1.32–1.26(m,2H).

[0285] Synthesis of 7-methoxy-4-(4-(2-(sulfamoylamino)ethyl)piperidin-1-yl)quinazolin-6-yl acetate (08)

[0286] To a stirred solution of 4-chloro-7-methoxyquinazolin-6-yl acetate (03) (1 g, 3.9 mmol, 1 eq) and 4-(2-((N-(sulfamoyl)amino)ethyl)piperidine-1-carboxylate (07) (0.97 g, 4.7 mmol, 1.2 eq) in IPA (10 mL), DMF (2 mL) at 0°C was added DIPEA (1.74 mL, 9.75 mmol, 2.5 eq). The reaction mixture was stirred at 40°C for 2 h. After completion of the reaction by TLC, the reaction mixture was Diluted with water and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure to give a crude compound. The crude product was purified by silica gel column chromatography by eluting with 10% MeOH / DCM to give 7-methoxy-4-(4-(2-(sulfamoylamino)ethyl)piperidin-1-yl)quinazolin-6-yl acetate (08) (450 mg, yield: 28%) as a white solid. TLC system: MeOH / DCM (10:90), R f Value: 0.4; LCMS (m / z): 424.4 (M+H) + ; 1HNMR (400MHz, DMSO-d6) δ8.55(s,1H),7.62(s,1H),7.32(s,1H),6.48–6.44(m,3H),4.17(d,J=13.2Hz,2H),3.94(s,3 H), 3.08 (t, J = 12.4Hz, 2H), 2.97–2.92 (m, 2H), 2.32 (s, 3H), 1.79–1.75 (m, 3H), 1.49–1.46 (m, 2H), 1.34–1.31 (m, 2H).

[0287] Synthesis of (09)

[0288] A solution of 7-methoxy-4-(4-(2-(sulfamoylamino)ethyl)piperidin-1-yl)quinazolin-6-yl acetate (08) (450 mg, 1.06 mmol, 1 eq.) in methanol (5 mL) containing 7M NH was stirred at room temperature for 1 hour. After completion of the reaction by TLC, the reaction mixture was concentrated and triturated with diethyl ether to give (09) (400 mg, yield: 99%) as an off-white solid. TLC system MeOH: DCM (10: 90), R f Value: 0.3; LCMS (m / z): 382.2 (M+H) + ; 1 HNMR (400MHz, DMSO-d6) δ9.98–9.99(br,1H),8.45(s,1H),7.19(s,1H),7.16(s,1H),6.48–6.46(m,3H),4.06(t,J=13. 2Hz,2H),3.92(s,3H),2.98–2.92(m,4H),1.81–1.75(m,2H),1.70–1.68(br,1H),1.52–1.46(m,2H),1.35–1.29(m,2H).

[0289] Synthesis of (7-methoxy-4-(4-(2-(sulfamoylamino)ethyl)piperidin-1-yl)quinazolin-6-yl)diallyl phosphate (10)

[0290] To a stirred solution of (09) (400 mg, 1.04 mmol, 1 eq) in acetone (8 mL) at 0 ° C., K2CO3 (215 mg, 1.56 mmol, 1.5 eq), diallyl chlorophosphate (03) (244 mg, 1.24 mmol, 1.2 eq) were added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was quenched with water and extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate and concentrated to give (7-methoxy-4-(4-(2-(sulfamoylamino)ethyl)piperidin-1-yl)quinazolin-6-yl)diallyl phosphate (10) (400 mg (crude product)) as a viscous liquid. TLC system MeOH: DCM (10:90), R f Value: 0.5; LCMS (m / z): 542.3 (M+H) + .

[0291] Synthesis of 7-methoxy-4-(4-(2-(sulfamoylamino)ethyl)piperidin-1-yl)quinazolin-6-yl dihydrogen phosphate (11)

[0292] Phenylsilane (0.45mL, 3.65mmol, 5 equivalents), Pd(PPh3)4 (84mg, 0.073mmol, 0.1 equivalents) were added to a stirred solution of (7-methoxy-4-(4-(2-(sulfamoylamino)ethyl)piperidin-1-yl)quinazolin-6-yl)diallyl phosphate (10) (crude product) (400mg, 0.73mmol, 1 equivalent) in DCM:DMF (1:1) (10mL) degassed for 10 minutes. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was concentrated and ground with DCM to obtain a crude product. The crude compound was purified by preparative HPLC to obtain dihydrogen phosphate 7-methoxy-4-(4-(2-(sulfamoylamino)ethyl)piperidin-1-yl)quinazolin-6-yl ester (11) (30mg, yield: 9%) as a white solid. TLC system MeOH:DCM (20:80), R f Value: ~0.05; LCMS (m / z): 462.4 (M+H) + ; 1HNMR(400MHz,DMSO-d6)δ8.53(s,1H),7.95(s,1H),7.14(s,1H),6.49–6.46(m,3H),4.37–4.34(m,2H),3. 88(s,3H),3.19–3.13(m,2H),2.95–2.93(m,2H),1.84–1.76(m,3H),1.50–1.45(m,2H),1.37–1.31(m,2H).

[0293] Synthesis of 7-methoxy-4-(4-(2-(sulfamoylamino)ethyl)piperidin-1-yl)quinazolin-6-yl sodium phosphate (I-03)

[0294] To a stirred suspension of 7-methoxy-4-(4-(2-(sulfamoylamino)ethyl)piperidin-1-yl)quinazolin-6-yl dihydrogen phosphate (11) (20 mg, 0.043 mmol, 1 eq) in H2O (0.5 mL) cooled to 0°C was added NaOH solution (3.4 mg, 0.086 mmol, 2 eq). The reaction mixture was stirred at 0°C for 5 min. The reaction mixture was kept under lyophilization to give (I-03) (21 mg, yield: 99%) as a white solid. LCMS (m / z): 462.2 ([M-2Na]+H) + ; 1 HNMR(400MHz,D2O)δ8.28(s,1H),7.96(s,1H),7.11(s,1H),4.20(d,J=13.2Hz,2H),3.92(s,3H),3.16(t,J=11.6 Hz,2H),3.02(t,J=7.2Hz,2H),1.80(d,J=12.8Hz,2H),1.71–1.67(m,1H),1.53–1.48(m,2H),1.41–1.38(m,2H).

[0295] Synthesis of I-04:

[0296] Synthesis of tert-butyl (2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidinyl)ethyl)carbamate) (01)

[0297]

[0298] 4-Chloro-6,7-dimethoxyquinazoline (1) (1.96 g, 8.76 mmol, 1.0 equiv) and tert-butyl (2-(piperidin-4-yl)ethyl)carbamate (2) (2.0 g, 8.76 mmol, 1.0 equiv) were added to a stirred solution of NaH (875 mg, 21.90 mmol, 2.5 equiv) in DMF (10 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction by TLC, the reaction mixture was quenched with ice-cold water and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate and concentrated to obtain a crude product. The crude product was purified by silica gel (60-120 mesh) column chromatography [eluted with 60% ethyl acetate / hexane gradient] to give tert-butyl (2-(1-((6,7-dimethoxyquinazolin-4-yl)methyl)piperidin-4-yl)ethyl)carbamate (01) (1.8 g, yield: 47%). TLC system: EtOAc / hexane (70:30), R f Value: ~0.1; LCMS (m / z): 417.3 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) δ8.51(s,1H),7.19(s,1H),7.10(s,1H). 6.82–6.79(brs,1H),4.13(d,J=12.8Hz,2H),3.95(s,3H),3.94(s,3H),3.02 –2.96(m,4H),1.81(d,J=10.8Hz,2H),1.59–1.57(m,1H),1.42–1.31(m,13H).

[0299] Synthesis of 2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)ethan-1-amine hydrochloride (02)

[0300]

[0301] A solution of tert-butyl (2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)ethyl)carbamate (01) (1.0 g, 2.40 mmol, 1.0 equiv) in 4M HCl in dioxane (5.0 mL; 5 volumes) was stirred at room temperature under N2 for 2 h. The volatiles were evaporated and triturated with diethyl ether to give 2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)ethan-1-amine hydrochloride (02) (580 mg, yield: 76%) as an off-white solid. TLC system: MeOH:DCM (10:90), R fValue: ~0.1; (400MHz, DMSO-d6) δ8.75(s,1H),8.04(brs,3H),7.39(s,1H),7.32(s,1H),4.68(d,J=13.2Hz,2H),3.97( s,3H),3.95(s,3H),3.49–3.38(m,2H),2.87–2.82(m,2H),1.96–86(m,3H),1.60–1.56(m,2H),1.39-1.35(m,2H).

[0302] Synthesis of (tert-butyloxycarbonyl)((4-(dimethylimino)pyridin-1(4H)-yl)sulfonyl)amide (03)

[0303]

[0304] Chlorosulfonyl isocyanate (4) (1.2 mL, 13.8 mmol, 1.0 equiv) was added to a stirred solution of tBuOH (1.3 mL, 13.5 mmol, 2.0 equiv) in DCM (10 mL) at 0°C over 15 minutes. The mixture was stirred at 0°C for 10 minutes and DMAP (3) (3.45 g, 28.3 mmol, 1.0 equiv) was added. The reaction mixture was stirred at room temperature for 1 hour. The thick slurry was diluted with DCM (60 mL) and washed with water (30 mL). The organic layer was concentrated in vacuo, and the residue was crystallized from DCM (30 mL) to give (tert-butyloxycarbonyl)((4-(dimethylimino)pyridin-1(4H)-yl)sulfonyl)amide (03) (2.3 g, 55%). 1 H NMR (400MHz, DMSO-d6) δ8.22 (d, J = 7.6 Hz, 2H), 6.99 (d, J = 7.6 Hz, 2H), 3.19 (s, 6H), 1.36 (s, 9H).

[0305] Synthesis of tert-butyl (N-(2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)ethyl)sulfamoyl)carbamate (04)

[0306]

[0307] To a stirred solution of 2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)ethan-1-amine hydrochloride (02) (500 mg, 1.58 mmol, 1.0 eq) in DCM (5 mL) was added DIPEA (0.6 ml, 3.16 mmol, 2.0 eq) and (tert-butyloxycarbonyl)((4-(dimethylimino)pyridin-1(4H)-yl)sulfonyl)amide (03) (619 mg, 2.05 mmol, 1.3 eq) at room temperature and stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was diluted with water and extracted with ethyl acetate (2×60 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate and concentrated to obtain a crude product. The crude product was purified by Grace column chromatography [eluted with 10% to 15% MeOH / DCM gradient] to give tert-butyl (N-(2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)ethyl)sulfamoyl)carbamate (04) (450 mg, yield: 57%). TLC system: MeOH:DCM (10:90), R f Value: ~0.2; LCMS (m / z): 496.3 (M+H) + ; 1 H NMR (400MHz, CDCl3) δ8.65 (s, 1H), 7.25 (s, 1H), 7.08 (s, 1H), 5.11 (t, J = 6.0 Hz, 1H), 4.20–4.17 (m, 2H), 4.02 (s, 3H), 3.99 (s, 3H), 3.19–3.15 (m, 2H), 3.07–3.04 (m, 2H), 1.89–1.86 (m, 3H), 1.79–1.73 (m, 2H), 1.66–1.64 (m, 2H), 1.51 (s, 9H). The exchangeable protons are not clearly evident in the spectrum.

[0308] Synthesis of N-(2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)ethyl)sulfonamide (I-04)

[0309]

[0310] A solution of tert-butyl N-(2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)ethyl)sulfamoylcarbamate (04) (80 mg, 0.16 mmol, 1.0 equiv) in dioxane (1.0 mL; 10 volumes) containing 4M HCl was stirred at room temperature under nitrogen flushing for 2 hours. The volatiles were evaporated and triturated with diethyl ether and then lyophilized to give N-(2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)ethyl)sulfonamide (I-04) (34 mg, yield: 80%) as an off-white solid. LCMS (m / z): 396.2 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) δ8.73(s,1H),7.31(s,1H),7.28(s,1H),6.49(s,3H),4.67(d,J=12.8Hz,2H),3.98(s,3H ),3.95(s,3H),3.48–3.42(m,2H),2.95–2.94(m,2H),1.92–1.89(m,3H),1.50–1.45(m,2H),1.37–1.33(m,2H).

[0311] Synthesis of I-06:

[0312] Synthesis of 2,5-dimethoxy-N(quinolin-3-yl)benzenesulfonamide (I-06)

[0313]

[0314] At room temperature, TEA (0.3 ml, 2.08 mmol, 1.5 equivalents) and 2,5-dimethoxybenzenesulfonyl chloride (2) (394 mg, 1.66 mmol, 1.2 equivalents) were added to a stirred solution of quinoline-3-amine (1) (200 mg, 1.38 mmol, 1.0 equivalents) in DMF (2 mL), and stirred at room temperature for 3 hours. After completion of the reaction by TLC, the reaction mixture was diluted with water and extracted with ethyl acetate (2 × 50 mL). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate and concentrated to obtain a crude product. The crude compound was purified by reverse phase Grace column chromatography [eluted with 38% 0.1% FA / water and ACN gradient] to provide 150 mg of 1-06 with 89% purity, which was further purified by silica gel column chromatography [eluted with 80% ethyl acetate / hexane gradient] to give 2,5-dimethoxy-N-(quinolin-3-yl)benzenesulfonamide (I-06) (100 mg, yield: 21%). TLC system: EtOAc (100%; by one drop of TEA), R fValue: ~0.6; LCMS (m / z): 345.2 (M+H) + ; 1 H NMR (400MHz, CDCl3) δ8.54(d,J=2.8Hz,1H),8.03(d,J=2.4Hz,1H),7.99(d,J=8.0Hz,1H),7.75(d,J=8.0Hz,1H),7.65 –7.61(m,1H),7.54–7.50(m,1H),7.31(d,J=2.8Hz,1H),7.27(brs,1H),7.01–6.94(m,2H),4.03(s,3H),3.70(s,3H).

[0315] Synthesis of I-07:

[0316] Synthesis of 2-(1-(7-methoxyquinolin-4-yl)piperidin-4-yl)propionitrile (01)

[0317]

[0318] 2-(piperidin-4-yl)propionitrile hydrochloride (2) (0.85 g, 6.19 mmol, 1.2 equivalents) was added to a stirred solution of 4-chloro-7-methoxyquinoline (1) (1 g, 5.16 mmol, 1 equivalent) in 1,4-dioxane (10 mL), and degassed for 10 minutes. Then CsCO (5 g, 15.4 mmol, 3 equivalents), Pd(dba) (0.47 g, 0.51 mmol, 0.1 equivalents) and X-Phos (0.49 g, 1.0 mmol, 0.2 equivalents) were added. The reaction mixture was stirred in a sealed tube at 110 ° C for 16 hours. After the reaction was completed by TLC, the reaction mixture was filtered through a diatomaceous earth pad and concentrated to provide a crude product. The crude compound was purified by 100-200 mesh silica gel column by eluting with 3% MeOH / DCM to give 2-(1-(7-methoxyquinolin-4-yl)piperidin-4-yl)propanenitrile (01) (0.7 g, yield: 50%) as a yellow solid. TLC system MeOH:DCM (10:90), R f Value: 0.5; LCMS (m / z): 296.2 (M+H) + ; 1HNMR (400MHz, DMSO-d6) δ8.63(d,J=5.2Hz,1H),7.87(d,J=9.2Hz,1H),7.40–7.39(m,1H),7.14(dd,J=9.2Hz,2.4Hz,1H),6.73(d,J=5.2Hz,1H),3.9 4(s,3H),3.70–3.64(m,2H),2.85–2.69(m,2H),2.68–2.65(m,1H),2.09– 2.06(m,2H),1.95–1.92(m,1H),1.81–1.76(m,2H),1.40(d,J=7.2Hz,3H).

[0319] Synthesis of 2-(1-(7-methoxyquinolin-4-yl)piperidin-4-yl)propan-1-amine (02)

[0320]

[0321] To a stirred solution of 2-(1-(7-methoxyquinolin-4-yl)piperidin-4-yl)propanenitrile (01) (700 mg, 2.03 mmol, 1 eq.) in methanol (7 mL) containing NH3 was added Ra-Ni (1.4 g). The reaction mixture was stirred at room temperature under H2 balloon pressure for 16 hours. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad and concentrated to give 2-(1-(7-methoxyquinolin-4-yl)piperidin-4-yl)propan-1-amine (02) (500 mg, yield: 70%) as a viscous compound. TLC system MeOH: DCM (10:90), R f Value: 0.1; LCMS (m / z): 300.03 (M+H) + ; 1 HNMR (400MHz, DMSO-d6) δ8.57 (brs, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.30 (s, 1H), 7.17–7.15 (m, 1H), 6.83 (d, J = 4.8 Hz, 1H), 3.89 (s, 3H), 3.54–3.49 (m, 2H), 2.75–2.64 (m, 2H), 1.76–1.73 (m, 2H), 1.64–1.53 (m, 4H), 1.29–1.23 (m, 1H), 0.97–0.93 (m, 3H). The three protons can be merged with the NMR solvent peak. D2O exchange NMR is much cleaner.

[0322] Synthesis of tert-butyl N-(2-(1-(7-methoxyquinolin-4-yl)piperidin-4-yl)propyl)sulfamoylcarbamate (03)

[0323]

[0324] To a stirred solution of 2-(1-(7-methoxyquinolin-4-yl)piperidin-4-yl)propan-1-amine (02) (500 mg, 1.67 mmol, 1 eq) in DCM (14 mL) was added DIPEA (0.46 mL, 2.50 mmol, 1.5 eq), (tert-butyloxycarbonyl)((4-(dimethylimino)pyridin-1(4H)-yl)sulfonyl)amide (I-04-03) (654 mg, 2.17 mmol, 1.3 eq). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was diluted with water and extracted with DCM (2×20 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The crude compound was purified by preparative HPLC to give tert-butyl N-(2-(1-(7-methoxyquinolin-4-yl)piperidin-4-yl)propyl)sulfamoylcarbamate (03) (120 mg, yield: 15%) as an off-white solid. TLC system MeOH:DCM (5:95), R f Value: 0.5; LCMS (m / z): 479.4 (M+H) + ; 1 HNMR(400MHz,DMSO-d6)δ8.57(d,J=5.2Hz,1H),7.87(d,J=9.2Hz,1H),7.57(t ,J=5.6Hz,1H),7.29(d,J=2.4Hz,1H),7.16(dd,J=9.2Hz,2.4Hz,1H),6.83(d,J =5.2Hz,1H),3.89(s,3H),3.56–3.53(m,2H),2.99–2.96(m,1H),2.79–2.74(m ,4H),1.73–1.70(m,2H),1.62–1.57(m,4H),1.43(s,9H),0.9(d,J=6.8Hz,3H).

[0325] Synthesis of N-(2-(1-(7-methoxyquinazolin-4-yl)piperidin-4-yl)propyl)aminosulfonamide (I-07)

[0326]

[0327] A solution of tert-butyl N-(2-(1-(7-methoxyquinolin-4-yl)piperidin-4-yl)propyl)sulfamoylcarbamate (03) (120 mg, 0.25 mmol, 1 eq) in dioxane (2 mL) containing 4M HCl was stirred at room temperature for 2 hours. After completion of the reaction by TLC, the volatiles were evaporated. The crude compound was purified by preparative HPLC to give N-(2-(1-(7-methoxyquinolin-4-yl)piperidin-4-yl)propyl)sulfamoylcarbamate (I-07) (45 mg, yield: 47%) as an off-white solid. TLC system MeOH: DCM (10: 90), R f Value: 0.3; LCMS (m / z): 379.2 (M+H) + ; 1 HNMR (400 MHz, DMSO-d6) δ8.56 (d, J=5.2 Hz, 1H), 8.13 (formic acid proton), 7.91 (d, J=9.2 Hz, 1H), 7.29 (d, J=2.8 Hz, 1H), 7.19 (dd, J=9.2 Hz, 2.8 Hz, 1H), 6.88 (d, J=5.6 Hz, 1H), 6.49–6.47 (m, 3H), 3.91 (s, 3H), 3.70–3.67 (m, 2H), 2.98–2.91 (m, 3H), 2.78–2.72 (m, 1H), 1.76–1.73 (m, 2H), 1.62–1.49 (m, 4H), 0.90 (d, J=6.4 Hz, 3H).

[0328] Synthesis of I-08:

[0329] Synthesis of 2-(1-(6-methoxyquinolin-4-yl)piperidin-4-yl)propionitrile (01)

[0330]

[0331] 2- (piperidin-4-yl) propionitrile hydrochloride (2) (0.51 g, 3.73 mmol, 1.2 equiv) was added to a stirred solution of 4- chloro-7-methoxyquinoline (1) (0.6 g, 3.18 mmol, 1 equiv) in 1,4- dioxane (10 mL), and degassed for 10 minutes. Then CsCO (3.0 g, 9.32 mmol, 3 equiv), Pd(dba) (0.28 g, 0.31 mmol, 0.1 equiv) and X-Phos (0.29 g, 0.62 mmol, 0.2 equiv) were added. The reaction mixture was stirred in a sealed tube at 110 ° C for 16 hours. After the reaction was completed by TLC, the reaction mixture was filtered through a diatomaceous earth pad and concentrated to provide a crude product. The crude compound was purified by 100-200 mesh silica gel column by eluting with 3% MeOH / DCM to give 2-(1-(6-methoxyquinolin-4-yl)piperidin-4-yl)propanenitrile (01) (0.7 g, yield: 70%) as a white solid. TLC system MeOH:DCM (10:90), R f Value: 0.5; LCMS (m / z): 296.2 (M+H) + ; 1 HNMR(400MHz, DMSO-d6)δ8.60(d,J=6.0Hz,1H),7.94(d,J=9.2Hz,1H),7.56–7.49(m,1H),7.28–7.27(m,1H),7.12(d,J=6.0Hz,1H),3.94(s,3 H),3.92–3.90(m,2H),3.15–3.09(m,2H),2.96–2.89(m,1H),2.03–1.9 2(m,2H),1.85–1.83(m,1H),1.64–1.56(m,2H),1.29(d,J=6.8Hz,3H).

[0332] Synthesis of 2-(1-(6-methoxyquinolin-4-yl)piperidin-4-yl)propan-1-amine (02)

[0333]

[0334] To a stirred solution of 2-(1-(6-methoxyquinolin-4-yl)piperidin-4-yl)propanenitrile (01) (600 mg, 2.03 mmol, 1 eq.) in methanol (6 mL) containing NH3 was added Re-Ni (1.4 g). The reaction mixture was stirred at room temperature under H2 balloon pressure for 16 hours. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad and concentrated to give 2-(1-(6-methoxyquinolin-4-yl)piperidin-4-yl)propan-1-amine (02) (700 mg, yield: 98%) as a viscous compound. TLC system MeOH: DCM (10:90), R f Value: 0.1; LCMS (m / z): 300.03 (M+H) + ;

[0335] Synthesis of tert-butyl N-(2-(1-(6-methoxyquinolin-4-yl)piperidin-4-yl)propyl)sulfamoylcarbamate (03)

[0336]

[0337] To a stirred solution of 2-(1-(6-methoxyquinolin-4-yl)piperidin-4-yl)propan-1-amine (02) (700 mg, 2.37 mmol, 1 eq) in DCM (14 mL) was added DIPEA (0.65 mL, 3.55 mmol, 1.5 eq), (tert-butyloxycarbonyl)((4-(dimethylimino)pyridin-1(4H)-yl)sulfonyl)amide (I-04-03) (928 mg, 3.08 mmol, 1.3 eq). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched with water and extracted with DCM (2×50 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The crude compound was purified by preparative HPLC to give tert-butyl N-(2-(1-(6-methoxyquinolin-4-yl)piperidin-4-yl)propyl)sulfamoylcarbamate (03) (100 mg, yield: 9%) as an off-white solid. TLC system MeOH:DCM (5:95), R f Value: 0.5; LCMS (m / z): 479.3 (M+H) + ; 1HNMR(400MHz,DMSO-d6)δ8.54(d,J=5.2Hz,1H),7.86(d,J=8.8Hz,1H),7.59(t, J=6.0Hz,1H),7.36(dd,J=8.8Hz,2.8Hz,1H),7.23–7.22(m,1H),6.95(d,J=5.2 Hz,1H),6.47(s,1H),3.90(s,3H),3.58–3.55(m,2H),3.02–2.96(m,1H),2.81– 2.70(m,3H),1.77–1.75(m,2H),1.64–1.53(m,4H),1.44(s,9H),0.92(d,J=6Hz 3H).

[0338] Synthesis of N-(2-(1-(6-methoxyquinazolin-4-yl)piperidin-4-yl)propyl)aminosulfonamide (I-08)

[0339]

[0340] A solution of tert-butyl N-(2-(1-(6-methoxyquinolin-4-yl)piperidin-4-yl)propyl)sulfamoylcarbamate (03) (100 mg, 0.20 mmol, 1 eq) in dioxane (2 mL) containing 4M HCl was stirred at room temperature for 2 hours. After completion of the reaction by TLC, the volatiles were evaporated, triturated with diethyl ether and dried to give N-(2-(1-(6-methoxyquinolin-4-yl)piperidin-4-yl)propyl)sulfamoylcarbamate (I-08) (50 mg, yield: 56%) as an off-white solid. TLC system MeOH:DCM (10:90), R f Value: 0.3; LCMS (m / z): 379.3 (M+H) + ; 1 HNMR(400MHz,DMSO-d6)δ14.8–14.6(br,1H),8.59(d,J=6.8Hz,1H),8.02(d,J=8.8H z,1H),7.65(dd,J=8.8Hz,2.4Hz,1H),7.31(d,J=2.4Hz,1H),7.18(d,J=6.8Hz,1H),6 .52–6.48(m,3H),4.17–4.13(m,2H),3.95(s,3H),3.31–3.29(m,2H),2.97–2.91(m, 1H), 2.79–2.73 (m, 1H), 1.83–1.79 (m, 3H), 1.66–1.47 (m, 3H), 0.89 (d, J = 6.8Hz, 3H).

[0341] Synthesis of I-09:

[0342] Synthesis of 4-chloro-7-methoxy-6-(methoxymethoxy)quinoline (01)

[0343]

[0344] To the stirred solution of 4-chloro-7-methoxyquinoline-6-ol (I-10-01) (1.2g, 5.74mmol, 1 equivalent) in DCM (15mL) cooled to 0°C, TEA (0.48mL, 34.4mmol, 6 equivalents), MOM-Cl (2.17mL, 28.7mmol, 5 equivalents) and catalytic amount of DMF were added. The reaction mixture was stirred at room temperature for 24 hours. After the reaction was completed by TLC, the reaction mixture was poured into ice water and extracted with DCM (2×80mL). The combined organic layer was washed with brine (50mL), dried over sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude compound was purified by silica gel (100-200 mesh) column purification [eluted with 2% MeOH / DCM] to obtain 4-chloro-7-methoxy-6-(methoxymethoxy)quinoline (01) (600mg, yield: 41%) as a sticky solid. TLC system EtoAc: Hexane (60:40), R f Value: 0.4; LCMS (m / z): 254.1 (M+H) + .

[0345] Synthesis of 2-(1-(7-methoxy-6-(methoxymethoxy)quinolin-4-yl)piperidin-4-yl)propionitrile (02)

[0346]

[0347] 2-(piperidin-4-yl)propionitrile hydrochloride (I-02-03) (0.49 g, 2.84 mmol, 1.2 equiv) was added to a stirred solution of 4-chloro-7-methoxy-6-(methoxymethoxy)quinoline (01) (600 mg, 2.37 mmol, 1 equiv) in 1,4-dioxane (6 mL), and degassed for 10 minutes. Then Cs2CO3 (2.3 g, 7.11 mmol, 3 equiv), Pd2(dba)3 (0.21 g, 0.23 mmol, 0.1 equiv) and X-Phos (0.21 g, 0.46 mmol, 0.2 equiv) were added. The reaction mixture was stirred in a sealed tube at 110 ° C for 16 hours. After the reaction was completed by TLC, the reaction mixture was filtered through a diatomaceous earth pad, washed with ethyl acetate and the filtrate was concentrated to provide a crude product. The crude compound was purified by silica gel (100-200 mesh) column chromatography [eluted with 2% MeOH / DCM] to give 2-(1-(7-methoxy-6-(methoxymethoxy)quinolin-4-yl)piperidin-4-yl)propanenitrile (02) (450 mg) with a purity of 66% as a sticky solid. TLC system MeOH:DCM (5:95), R f Value: 0.2; LCMS (m / z): 356.3 (M+H) + The material was used in the next step without further purification.

[0348] Synthesis of 2-(1-(7-methoxy-6-(methoxymethoxy)quinolin-4-yl)piperidin-4-yl)propan-1-amine (03)

[0349]

[0350] To a stirred solution of 2-(1-(7-methoxy-6-(methoxymethoxy)quinoline-4-yl)piperidin-4-yl)propionitrile (02) (450 mg, 2.03 mmol, 1 eq) in methanol (5 mL) containing 7M NH was added Raney Ni (1 g). The reaction mixture was stirred at room temperature under H2 balloon pressure for 16 hours. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad, washed with methanol, and the filtrate was concentrated under reduced pressure to give 2-(1-(7-methoxy-6-(methoxymethoxy)quinoline-4-yl)piperidin-4-yl)propan-1-amine (03) (450 mg) as a viscous material. TLC system MeOH: DCM (10: 90), R f Value: 0.1; LCMS (m / z): 360.3 (M+H) + .

[0351] Synthesis of tert-butyl (N-(2-(1-(7-methoxy-6-(methoxymethoxy)quinolin-4-yl)piperidin-4-yl)propyl)sulfamoyl)carbamate (04)

[0352]

[0353] To a stirred solution of 2-(1-(7-methoxy-6-(methoxymethoxy)quinolin-4-yl)piperidin-4-yl)propan-1-amine (03) (450 mg, 1.25 mmol, 1 eq) in DCM (9 mL) was added DIPEA (0.33 mL, 1.87 mmol, 1.5 eq) and (tert-butyloxycarbonyl)((4-(dimethylimino)pyridin-1(4H)-yl)sulfonyl)amide (I-04-03) (452 ​​mg, 1.50 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched with water and extracted with DCM (2×40 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The crude compound was purified by silica gel (100-200 mesh) column purification [eluted with 3% MeOH / DCM] to give tert-butyl (N-(2-(1-(7-methoxy-6-(methoxymethoxy)quinolin-4-yl)piperidin-4-yl)propyl)sulfamoyl)carbamate (04) (300 mg, yield: 44%) as an off-white solid. TLC system MeOH:DCM (5:95), R f Value: 0.5; LCMS (m / z): 539.4 (M+H) + .

[0354] Synthesis of N-(N-(2-(1-(6-hydroxy-7-methoxyquinolin-4-yl)piperidin-4-yl)propyl)thiodiamide formate (I-09)

[0355]

[0356] To a stirred solution of tert-butyl (N-(2-(1-(7-methoxy-6-(methoxymethoxy)quinolin-4-yl)piperidin-4-yl)propyl)sulfamoyl)carbamate (04) (300 mg, 0.55 mmol, 1 eq) in 1,4-dioxane (1 mL) at 0 ° C., dioxane (2 mL) containing 4M HCl was added and stirred at room temperature for 2 hours. After completion of the reaction by TLC, the volatiles were evaporated to provide a residue. The crude compound was purified by reverse phase purification [eluted with 1-15% (0.1% FA / H2O)+ACN gradient] to give N-(N-(2-(1-(6-hydroxy-7-methoxyquinolin-4-yl)piperidin-4-yl)propyl)sulfodiamide formate (I-09) (7 mg, yield: 3%) as an off-white solid. TLC system MeOH: DCM (10: 90), R f Value: 0.2; LCMS (m / z): 395.3 (M+H): 1 HNMR (400MHz, DMSO-d6) δ8.40(d,J=5.2Hz,1H),8.35(brs,2H),7.25(s,1H),7.24(s,1H),6.77(d,J=5.2Hz,1H),6.50–6.47(brs,3H),3.89(s, 3H),3.49–3.47(m,2H),3.05–2.94(m,1H),2.78–2.73(m,1H),2.71–2. 67(m,2H),1.75–1.72(m,2H),1.63–1.52(m,4H),0.92(d,J=6.8Hz,3H).

[0357] Synthesis of I-10:

[0358] Synthesis of 4-chloro-7-methoxyquinolin-6-ol (01)

[0359]

[0360] D, L-methionine (8.3 g, 56 mmol, 2.5 equiv) was added to a stirred solution of 4-chloro-6,7-dimethoxyquinoline (1) (5 g, 22.4 mmol, 1 equiv) in methanesulfonic acid (25 mL). The reaction mixture was stirred in a sealed tube at 150 ° C for 24 hours. After the reaction was completed by TLC, the reaction mixture was poured into ice water and alkalized with NH3 aqueous solution (pH-9) and extracted with EtOAc (3×100 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude compound was purified by silica gel (100-200 mesh) column [eluted with 2% MeOH / DCM] to obtain 4-chloro-7-methoxyquinoline-6-ol (01) (1.5 g, yield: 32%) as a yellow solid. TLC system EtoAc: hexane (60: 40), R f Value: 0.4 (long UV); LCMS (m / z): 210.1 (M+H) + ; 1 HNMR (400MHz, DMSO-d6) δ10.6–10.1(br,1H),8.54(d,J=4.8Hz,1H),7.49(d,J=4.8Hz,1H),7.43(s,1H),7.40(s,1H),3.97(s,3H).

[0361] Synthesis of 4-chloro-7-methoxy-6-(2-methoxyethoxy)quinoline (02)

[0362]

[0363] To a stirred solution of 4-chloro-7-methoxyquinolin-6-ol (01) (1.5 g, 7.17 mmol, 1 eq.) in DMF (15 mL) at 0 °C was added KCO (1.98 g, 14.3 mmol, 2 eq.), 1-bromo-2-methoxyethane (1.98 g, 14.3 mmol, 2 eq.). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was diluted with water and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure to give a crude product. The crude compound was purified by 100-200 mesh silica gel column by eluting with 2% MeOH / DCM to give 4-chloro-7-methoxy-6-(2-methoxyethoxy)quinoline (02) (800 mg, yield: 42%) as a sticky solid. TLC system EtoAc: Hexane (60:40), R f Value: 0.4; LCMS (m / z): 268.1 (M+H) + ; 1HNMR(400MHz, CDCl3)δ8.57(d,J=4.8Hz,1H),7.43(s,1H),7.40(s,1H),7.35(d,J= 4.8Hz, 1H), 4.34 (t, J = 4.8Hz, 2H), 4.04 (s, 3H), 3.89 (t, J = 4.8Hz, 2H), 3.49 (s, 3H).

[0364] Synthesis of 2-(1-(7-methoxy-6-(2-methoxyethoxy)quinolin-4-yl)piperidin-4-yl)propionitrile (03)

[0365]

[0366] In a sealed tube, 2- (piperidin-4-yl) propionitrile hydrochloride (I-02-03) (490 mg, 3.59 mmol, 1.2 equivalents) is added to a stirred solution of 4- chloro-7-methoxy-6- (2-methoxyethoxy) quinoline (02) (800 mg, 2.99 mmol, 1 equivalent) in 1,4- dioxane (8 mL), and degassed for 10 minutes. Then Cs2CO3 (2.9 g, 8.98 mmol, 3 equivalents), Pd2(dba)3 (0.27 g, 0.29 mmol, 0.1 equivalents), X-Phos (0.28 g, 0.59 mmol, 0.2 equivalents) are added. The reaction mixture is stirred at 110 ° C for 16 hours. After the reaction is completed by TLC, the reaction mixture is filtered through a diatomaceous earth pad and concentrated under reduced pressure to provide a crude product. The crude compound was purified by 100-200 mesh silica gel column by eluting with 3% MeOH / DCM to give 2-(1-(7-methoxy-6-(2-methoxyethoxy)quinolin-4-yl)piperidin-4-yl)propanenitrile (03) (500 mg, yield: 45%) as a yellow solid. TLC system MeOH:DCM (10:90), R f Value: 0.5; LCMS (m / z): 370.3 (M+H) + ; 1 HNMR (400MHz, DMSO-d6) δ8.49(d,J=5.2Hz,1H),7.31(s,1H),7.19(s,1H),6.87(d,J=5.2Hz,1H),4.24–4.22(m,2H),3.92(s,3H),3.76(t,J=4.8H z,2H),3.57(t,J=12.0Hz,2H),3.35(s,3H),2.91–2.90(m,1H),2.77(t,J =12Hz,2H),2.00–1.89(m,2H),1.67–1.58(m,3H),1.32(d,J=7.2Hz,3H).

[0367] Synthesis of 2-(1-(7-methoxy-6-(2-methoxyethoxy)quinolin-4-yl)piperidin-4-yl)propan-1-amine (04)

[0368]

[0369] To a stirred solution of 2-(1-(7-methoxy-6-(2-methoxyethoxy)quinolin-4-yl)piperidin-4-yl)propionitrile (03) (500 mg, 2.03 mmol, 1 eq) in methanol (5 mL) containing 7M NH3 was added Ra-Ni (1 g). The reaction mixture was stirred at room temperature under H2 balloon pressure for 16 hours. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad, and the filtrate was evaporated under reduced pressure to give 2-(1-(7-methoxy-6-(2-methoxyethoxy)quinolin-4-yl)piperidin-4-yl)propan-1-amine (04) (350 mg, yield: 69%) as a viscous compound. TLC system MeOH: DCM (10: 90), R f Value: 0.1; LCMS (m / z): 374.4 (M+H) + ; 1 HNMR (400MHz, DMSO-d6) δ8.49(d,J=5.6Hz,1H),7.90(brs,2H),7.35(s,1H),7.23(s,1H),6.92(d,J=5.2Hz,1H),4.10–4.09(m,2H),3.89( s,3H),3.77–3.68(m,4H),3.35(s,3H),2.89–2.75(m,3H),2.69–2.66(m,1H),1.78–1.75(m,3H),1.57–1.48(m,3H),0.98(d,J=7.2Hz,3H).

[0370] Synthesis of tert-butyl (N-(2-(1-(7-methoxy-6-(2-methoxyethoxy)quinolin-4-yl)piperidin-4-yl)propyl)sulfamoyl)carbamate (05)

[0371]

[0372] To a stirred solution of 2-(1-(7-methoxy-6-(2-methoxyethoxy)quinolin-4-yl)piperidin-4-yl)propan-1-amine (04) (350 mg, 0.93 mmol, 1 eq) in DCM (7 mL) was added DIPEA (0.25 mL, 1.4 mmol, 1.5 eq), (tert-butyloxycarbonyl)((4-(dimethylimino)pyridin-1(4H)-yl)sulfonyl)amide (I-04-03) (338 mg, 1.12 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched with water and extracted with DCM (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The crude compound was purified by reverse phase [eluted with 35% (0.1% FA / H2O) + ACN] to give tert-butyl (N-(2-(1-(7-methoxy-6-(2-methoxyethoxy)quinolin-4-yl)piperidin-4-yl)propyl)sulfamoyl)carbamate (05) (120 mg, yield: 23%) as an off-white solid. TLC system MeOH:DCM (5:95), R f Value: 0.5; LCMS (m / z): 553.4 (M+H) + and 453.4 (M+H-Boc) +

[0373] Synthesis of N-(2-(1-(7-methoxy-6-(2-methoxyethoxy)quinolin-4-yl)piperidin-4-yl)propyl)aminosulfonamide formate (I-10)

[0374]

[0375] To a stirred solution of tert-butyl (N-(2-(1-(7-methoxy-6-(2-methoxyethoxy)quinolin-4-yl)piperidin-4-yl)propyl)sulfamoyl)carbamate (05) (120 mg, 0.25 mmol, 1 eq) in dioxane at 0 °C was added dioxane (2 mL) containing 4M HCl and stirred at room temperature for 2 hours. After completion of the reaction by TLC, the volatiles were evaporated. The crude compound was purified by preparative HPLC to give N-(2-(1-(7-methoxy-6-(2-methoxyethoxy)quinolin-4-yl)piperidin-4-yl)propyl)sulfamoyl)carbamate (I-10) (20 mg, yield: 47%) as an off-white solid. TLC system MeOH: DCM (10: 90), R f Value: 0.3; LCMS (m / z): 453.3 (M+H), 1HNMR (400 MHz, DMSO-d6) δ8.48 (d, J=5.2 Hz, 1H), 8.14 (formate proton), 7.31 (s, 1H), 7.22 (s, 1H), 6.88 (d, J=5.2 Hz, 1H), 6.49–6.47 (m, 3H), 4.24 (t, J=4.8 Hz, 2H), 3.92 (s, 3H), 3.75 (t, J=4.8 Hz, 2H), 3.63–3.61 (m, 2H), 3.34 (s, 3H), 2.99–2.94 (m, 1H), 2.82–2.74 (m, 3H), 1.77–1.75 (m, 2H), 1.64–1.52 (m, 4H), 0.92 (d, J=6.4 Hz, 3H).

[0376] Synthesis of I-11:

[0377] Synthesis of 2-(2-bromoethoxy)tetrahydro-2H-pyran (01)

[0378]

[0379] 3,4-dihydropyran (1.7 mL, 1.93 mmol, 1.2 eq.), p-toluenesulfonic acid pyridinium salt (PPTS) (406 mg, 0.16 mmol, 0.1 eq.) were added to a stirred solution of 2-bromoethane-1-ol (1) (2 g, 1.61 mmol, 1 eq.) in THF (20 mL). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was poured into water and extracted with EtOAc (2 × 30 mL). The combined organic layer was washed with brine (30 mL), dried over sodium sulfate and concentrated to give 2-(2-bromoethoxy)tetrahydro-2H-pyran (01) (2.5 g, yield: 75%) as a yellow liquid. TLC system EtoAc: hexane (20: 80), R f Value: 0.5; 1 HNMR (400 MHz, DMSO-d6) δ 4.67 (t, J = 3.6 Hz, 1H), 4.05–3.99 (m, 1H), 3.91–3.86 (m, 2H), 3.80–3.74 (m, 1H), 3.55–3.47 (m, 4H), 1.86–1.81 (m, 2H), 1.77–1.69 (m, 2H), impurities were also observed.

[0380] Synthesis of 4-chloro-7-methoxy-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)quinoline (02)

[0381]

[0382] To a stirred solution of 4-chloro-7-methoxyquinoline-6-ol (I-10-01) (1 g, 4.78 mmol, 1 eq.) in DMF (10 mL) at 0 ° C. KCO (1.29 g, 9.56 mmol, 2 eq.) and 2-(2-bromoethoxy)tetrahydro-2H-pyran (01) (1.46 g, 7.17 mmol, 1.5 eq.) were added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was diluted with ice-cold water and extracted with EtOAc (2×40 mL). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate and concentrated under reduced pressure to give a crude product. The crude compound was purified by silica gel (100-200 mesh) column chromatography [eluted with 2% MeOH / DCM] to give 4-chloro-7-methoxy-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)quinoline (02) (800 mg, yield: 50%) as a sticky solid. TLC system EtoAc: Hexane (60:40), R f Value: 0.4; LCMS (m / z): 338.1 (M+H) + .

[0383] Synthesis of 2-(1-(7-methoxy-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)quinolin-4-yl)piperidin-4-yl)propionitrile (03)

[0384]

[0385] 2-(piperidin-4-yl)propionitrile hydrochloride (I-02-03) (0.39 g, 2.84 mmol, 1.2 eq.) was added to a stirred solution of 4-chloro-7-methoxy-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)quinoline (02) (800 mg, 2.37 mmol, 1 eq.) in 1,4-dioxane (8 mL) and degassed for 10 minutes. CsCO (2.3 g, 7.11 mmol, 3 eq.), Pd(dba) (0.22 g, 0.23 mmol, 0.1 eq.), X-Phos (0.22 g, 0.47 mmol, 0.2 eq.) were then added. The reaction mixture was stirred in a sealed tube at 110 °C for 16 hours. After completion of the reaction by TLC, the reaction mixture was filtered through a pad of celite and concentrated to provide a crude product.

[0386] The crude compound was purified by silica gel [100-200 mesh] chromatography [eluted with 3% MeOH / DCM] to give 2-(1-(7-methoxy-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)quinolin-4-yl)piperidin-4-yl)propanenitrile (03) (600 mg) as a yellow solid. TLC system MeOH:DCM (10:90), LCMS (m / z): 440.4 (M+H) + Although the purified material was not completely pure, it was used in the next step.

[0387] Synthesis of 2-(1-(7-methoxy-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)quinolin-4-yl)piperidin-4-yl)propan-1-amine (04)

[0388]

[0389] To a stirred solution of 2-(1-(7-methoxy-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)quinoline-4-yl)piperidin-4-yl)propionitrile (03) (600 mg, 60% purity, 1.36 mmol, 1 eq) in methanol (6 mL) containing 7M NH was added Ra-Ni (1.2 g). The reaction mixture was stirred at room temperature under H2 balloon pressure for 16 hours. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad and concentrated to give a crude product. The crude product was triturated with diethyl ether to give 2-(1-(7-methoxy-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)quinoline-4-yl)piperidin-4-yl)propan-1-amine (04) (400 mg, yield: 38%, two steps) as a viscous compound. TLC system MeOH:DCM (10:90), R f Value: 0.1; LCMS (m / z): 444.4 (M+H) + ; 1 HNMR(400MHz, DMSO-d6)δ8.48(d,J=4.8Hz,1H),7.30(s,1H),7.22(s,1H),6.84(d,J=4.8Hz,1H),4.71–4.70(m,1H),4.27–4.25(m,2H),4.02–3 .97(m,1H),3.91(s,3H),3.84–3.80(m,2H),3.54–3.42(m,4H),2.74–2. 67(m,3H),1.77–1.64(m,5H),1.50–1.43(m,8H),0.93(d,J=6.4Hz,3H).

[0390] Synthesis of tert-butyl N-(2-(1-(7-methoxy-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)quinolin-4-yl)piperidin-4-yl)propyl)sulfamoylcarbamate (05)

[0391]

[0392] To a stirred solution of 2-(1-(7-methoxy-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)quinolin-4-yl)piperidin-4-yl)propan-1-amine (04) (400 mg, 0.9 mmol, 1.0 equiv) in DCM (8 mL) was added DIPEA (0.21 mL, 1.17 mmol, 1.3 equiv) and (tert-butyloxycarbonyl)((4-(dimethylimino)pyridin-1(4H)-yl)sulfonyl)amide (I-04-03) (325 mg, 1.08 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched with water and extracted with DCM (2×20 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The crude compound was purified by reverse phase column [using 0.1% FA / H2O / ACN as eluent] to give tert-butyl N-(2-(1-(7-methoxy-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)quinolin-4-yl)piperidin-4-yl)propyl)sulfamoylcarbamate (05) (250 mg) as a sticky solid. TLC system MeOH:DCM (5:95), R f Value: 0.5; LCMS (m / z): 623.5 (M+H) + Although the purified material was not completely pure, it was used in the next step.

[0393] Synthesis of N-(2-(1-(6-(2-hydroxyethoxy)-7-methoxyquinolin-4-yl)piperidin-4-yl)propyl)aminosulfonamide formate (I-11)

[0394]

[0395] To a stirred solution of tert-butyl N-(2-(1-(7-methoxy-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)quinolin-4-yl)piperidin-4-yl)propyl)sulfamoylcarbamate (05) (250 mg, 0.4 mmol, 1 eq) in 1,4-dioxane at 0 °C was slowly added dioxane (2 mL) containing 4M HCl. The reaction was then stirred at room temperature for 5 hours. After completion of the reaction by TLC, the volatiles were evaporated and the crude compound was purified by preparative HPLC purification to give N-(2-(1-(6-(2-hydroxyethoxy)-7-methoxyquinolin-4-yl)piperidin-4-yl)propyl)sulfamoylcarbamate formate (I-11) (38 mg, yield: 10%, two steps) as an off-white solid. TLC system MeOH: DCM (10: 90), R f Value: 0.3; LCMS (m / z): 439.3 (M+H-HCOOH), 1 HNMR (400 MHz, DMSO-d6) δ8.47 (d, J = 4.8 Hz, 1H), 8.15 (formate proton), 7.30 (s, 1H), 7.20 (s, 1H), 6.84 (d, J = 5.2 Hz, 1H), 6.48–6.45 (m, 3H), 4.93 (brs, 1H), 4.11 (t, J = 4.8 Hz, 2H), 3.91 (s, 3H), 3.83–3.81 (m, 2H), 3.53–3.51 (m, 2H), 3.00–2.94 (m, 1H), 2.79–2.67 (m, 3H), 1.77–1.75 (m, 2H), 1.62–1.51 (m, 4H), 0.92 (d, J = 6.8 Hz, 3H)

[0396] Synthesis of I-12:

[0397] Synthesis of 4-(2-methoxy-4-nitrophenyl)morpholine (01)

[0398]

[0399] To a stirred solution of 1-fluoro-2-methoxy-4-nitrobenzene (1) (10 g, 58.44 mmol, 1 eq.) in DMF (50 mL) was added KCO (16.13 g, 116.8 mmol, 2 eq.) and morpholine (2) (10.16 g, 116.8 mmol, 2 eq.). The reaction mixture was stirred at 80 ° C for 5 hours. After the reaction was completed by TLC, the reaction mixture was poured into ice-cold water, the precipitated solid was filtered, and dried under vacuum to obtain 4- (2-methoxy-4-nitrophenyl) morpholine (01) (8 g, yield: 75%) as a yellow solid. TLC system EtoAc: hexane (30: 70), R f Value: 0.2; LCMS (m / z): 239.1 (M+H) + ; 1 HNMR (400MHz, CDCl3) δ7.87 (dd, J=8.8Hz, 2.4Hz, 1H), 7.72 (d, J=2.4Hz, 1H), 6. 89 (d, J = 8.8 Hz, 1H), 3.96 (s, 3H), 3.89 (t, J = 4.8 Hz, 4H), 3.22 (t, J = 4.8 Hz, 4H).

[0400] Synthesis of 3-methoxy-4-morpholinoaniline (02)

[0401]

[0402] To a stirred solution of 4-(2-methoxy-4-nitrophenyl)morpholine (01) (8 g, 33.5 mmol, 1 eq.) in ethanol:H2O (2: 1) (120 mL), NH4Cl (8.93 g, 167 mmol, 5 eq.), Fe powder (9.32 g, 167 mmol, 5 eq.) was added. The reaction mixture was stirred at 85 °C for 3 hours. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad and washed with EtOAc (200 mL). The filtrate was washed with brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure to give 3-methoxy-4-morpholine aniline (02) (6 g, yield: 85%) as a brown solid. TLC system MeOH: DCM (10: 90), R f Value: 0.2; LCMS (m / z): 209.2 (M+H) + ; 1HNMR(400MHz,DMSO-d6)δ6.60(d,J=8.4Hz,1H),6.23(d,J=2.4Hz,1H),6.07(dd,J=2.4 Hz, 8.0Hz, 1H), 4.72 (s, 2H), 3.68 (s, 3H), 3.66 (t, J = 4.8Hz, 4H), 2.77 (t, J = 4.8Hz, 4H).

[0403] Synthesis of 7-methoxy-6-morpholinoquinolin-4(1H)-one (03)

[0404]

[0405] A solution of Meldrum's acid (3.85 g, 3.37 mmol, 1 equivalent) and triethyl orthoformate (1.5 mL, 10.1 mmol, 3 equivalents) was stirred at 85 ° C for 3 hours. Therefore, diluted with ethanol (50 mL) and 3-methoxy-4-morpholine aniline (02) (5 g, 3.37 mmol, 1 equivalent) was added. The resulting mixture was stirred at 85 ° C for 3 hours. Subsequently, cooled to 0 ° C, a brown solid was precipitated, which was filtered and dried under vacuum. Dow's heat carrier-A (50 mL) was added to this solid and heated at 190 ° C for 5 hours. After the reaction was completed by TLC, the reaction mixture was poured into hexane (200 mL), the precipitated solid was filtered and dried under vacuum to obtain a crude product. The crude compound was purified by silica gel (60-120 mesh) column chromatography [eluted with 10%-15% MeOH / DCM gradient] to give 7-methoxy-6-morpholinoquinolin-4(1H)-one (03) (1.2 g, yield: 19%) as a brown solid. TLC system MeOH: DCM (20:80), R f Value: 0.2; LCMS (m / z): 261.1 (M+H) + ; 1 HNMR (400MHz, CDCl3) δ7.77 (s, 1H), 7.58 (d, J = 6.4Hz, 1H), 6.91 (s, 1H), 6.22 (d, J=7.2Hz, 1H), 3.88 (s, 3H), 3.86 (t, J=4.4Hz, 4H), 3.07 (t, J=4.4Hz, 4H).

[0406] Synthesis of 4-(4-chloro-7-methoxyquinolin-6-yl)morpholine (04)

[0407]

[0408] A suspension of 7-methoxy-6-morpholinequinoline-4(1H)-one (03) (1.2 g, 4.6 mmol, 1 equivalent) in POCl3 (12 mL) was stirred at 110 ° C for 3 hours. After the reaction was completed by TLC, the reaction mixture was poured into ice water and alkalized with saturated cold NaHCO3 solution [pH-8] and extracted with EtOAc (3×60 mL). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to give a crude product. The crude compound was purified by silica gel (60-120 mesh) column chromatography [eluted with 1% MeOH / DCM] to give 4-(4-chloro-7-methoxyquinoline-6-yl)morpholine (04) (1 g, yield: 78%) as a brown solid. TLC system EtoAc: Hexane (70: 30), R f Value: 0.6; LCMS (m / z): 279.1 (M+H) + ; 1 HNMR (400MHz, CDCl3) δ8.57 (d, J = 4.8Hz, 1H), 7.52 (s, 1H), 7.48 (s, 1H), 7.34 (d, J=4.8Hz, 1H), 4.03 (s, 3H), 3.95 (t, J=4.4Hz, 4H), 3.24 (t, J=4.4Hz, 4H).

[0409] Synthesis of 2-(1-(7-methoxy-6-morpholinoquinolin-4-yl)piperidin-4-yl)propionitrile (05)

[0410]

[0411] 2-(piperidin-4-yl)propionitrile is added to a stirred solution of 4-(4-chloro-7-methoxyquinoline-6-yl)morpholine (04) (1 g, 3.59 mmol, 1 equivalent) in 1,4-dioxane (10 mL). HCl (I-02-03) (0.76 g, 4.30 mmol, 1.2 equivalents), CsCO (3.5 g, 10.7 mmol, 3 equivalents) and degassed for 10 minutes. Subsequently, X-Phos (0.34 g, 0.71 mmol, 0.2 equivalents), Pd(dba) (0.32 g, 0.35 mmol, 0.1 equivalents) are added, and the reaction mixture is stirred in a sealed tube at 110 ° C for 16 hours. After the reaction is completed by TLC, the reaction mixture is filtered through a diatomaceous earth pad and concentrated to provide a crude product. The crude compound was purified by silica gel (60-120 mesh) column chromatography [eluted with 3-4% MeOH / DCM] to give 2-(1-(7-methoxy-6-morpholinoquinolin-4-yl)piperidin-4-yl)propanenitrile (05) (600 mg, yield: 44%) as a brown sticky solid. TLC system MeOH:DCM (5:95), R f Value: 0.3; LCMS (m / z): 381.3 (M+H) + ; 72% purity.

[0412] Synthesis of 2-(1-(7-methoxy-6-morpholinequinolin-4-yl)piperidin-4-yl)propan-1-amine (06)

[0413]

[0414] To a stirred solution of 2-(1-(7-methoxy-6-morpholinequinoline-4-yl)piperidin-4-yl)propionitrile (05) (600 mg, 1.57 mmol, 1 eq) in methanol (6 mL) containing 7M NH was added Raney Ni (1.2 g). The reaction mixture was stirred at room temperature under H2 balloon pressure for 16 hours. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad and concentrated to give 2-(1-(7-methoxy-6-morpholinequinoline-4-yl)piperidin-4-yl)propan-1-amine (06) (420 mg) as a viscous compound. TLC system MeOH: DCM (10: 90), R f Value: 0.1; LCMS (m / z): 385.3 (M+H) + ; 70% purity.

[0415] Synthesis of tert-butyl (N-(2-(1-(7-methoxy-6-morpholinoquinolin-4-yl)piperidin-4-yl)propyl)sulfamoyl)carbamate (07)

[0416]

[0417] To a stirred solution of 2-(1-(7-methoxy-6-morpholinoquinolin-4-yl)piperidin-4-yl)propan-1-amine (06) (400 mg, 1.0 mmol, 1 eq) in DCM (8 mL) at 0 °C was added DIPEA (0.3 mL, 1.50 mmol, 1.5 eq) and (tert-butyloxycarbonyl)((4-(dimethylimino)pyridin-1(4H)-yl)sulfonyl)amide (I-04-03) (362 mg, 1.20 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched with water and extracted with DCM (2×30 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The crude compound was purified by silica gel (60-120 mesh) column chromatography [eluted with 5% MeOH / DCM] to give tert-butyl (N-(2-(1-(7-methoxy-6-morpholinoquinolin-4-yl)piperidin-4-yl)propyl)sulfamoyl)carbamate (07) (400 mg) as a sticky solid. TLC system MeOH:DCM (5:95), R f Value: 0.5; LCMS (m / z): 564.4 (M+H) + ; 50% purity. The material was used in the next step without further improvement of purity.

[0418] Synthesis of N-(N-(2-(1-(7-methoxy-6-morpholinoquinolin-4-yl)piperidin-4-yl)propyl)sulfuramide (I-12)

[0419]

[0420] To a stirred solution of tert-butyl (N-(2-(1-(7-methoxy-6-morpholinequinolin-4-yl)piperidin-4-yl)propyl)sulfamoyl)carbamate (07) (400 mg, 50% purity) in 1,4-dioxane cooled to 0°C was added 4M HCl in dioxane (2 mL) and stirred at room temperature for 2 hours. After completion of the reaction by TLC, the volatiles were evaporated and the obtained crude compound was purified by preparative HPLC [FA method] to give N-(N-(2-(1-(7-methoxy-6-morpholinequinolin-4-yl)piperidin-4-yl)propyl)sulfamoyl)carbamate (I-12) (45 mg, yield: 3%, four steps) as a pale yellow solid. TLC system MeOH:DCM (10:90), R f Value: 0.3; LCMS (m / z): 464.3 (M+H); 1HNMR (400MHz, DMSO-d6) δ8.47(d,J=6.8Hz,1H),7.34(s,1H),7.20(s,1H),7.03(d,J=6.8Hz,1H),6.51–6.48(m,3H),4.09–4.06(m,2H),3.98(s ,3H),3.79–3.77(m,4H),3.37–3.27(m,2H),3.17–3.15(m,4H),2.97–2 .91(m,1H),2.80–2.75(m,1H),1.81–1.44(m,6H),0.89(d,J=6.8Hz,3H)

[0421] Synthesis of I-13:

[0422] Synthesis of tert-butyl 4-(cyanomethyl)piperidine-1-carboxylate (01)

[0423]

[0424] To a stirred solution of tert-butyl 4-oxopiperidine-1-carboxylate (1) (2 g, 10.05 mmol, 1 eq) in THF (20 mL) was added diethyl (cyanomethyl)phosphonate (2) (2.66 g, 15.07 mmol, 1.5 eq), LiBr (1 g, 12.06 mmol, 1.2 eq) and TEA (2.8 mL, 20.1 mmol, 2 eq) at 0 °. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was diluted with water and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography by eluting with 20% EtOAc / hexane to obtain tert-butyl 4- (cyanomethyl) piperidine-1-carboxylate (01) (2 g, yield: 90%) as a white solid. TLC system: EtOAc / hexane (30:70; ninhydrin stain), R f Value: ~0.6; 1 H NMR (400MHz, CDCl3) δ5.19 (s, 1H), 3.54–3.48 (m, 4H), 2.56 (t, J = 5.6Hz, 2H), 2.32 (t, J = 5.6Hz, 2H), 1.47 (s, 9H).

[0425] Synthesis of tert-butyl 4-(cyanomethyl)piperidine-1-carboxylate (02)

[0426]

[0427] Mg turnings (8.57 g, 35.7, 40 equiv) were added to a stirred solution of tert-butyl 4-(cyanomethyl)piperidine-1-carboxylate (01) (2 g, 8.9 mmol, 1 equiv) in anhydrous methanol (100 mL). The reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction by TLC, the reaction mixture was quenched with 6N HCl, evaporated and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure to give tert-butyl 4-(1-cyanoethyl)piperidine-1-carboxylate (02) (2 g, yield: 99%) as a viscous liquid. TLC system: EtoAc: Hexane (20:80; ninhydrin stain), R f Value: ~0.5; 1 H NMR (400MHz, CDCl3) δ4.16–4.12(m,2H),2.74–2.68(m,2H),2.31(d,J=6.4Hz ,2H),1.86–1.81(m,1H),1.79–1.77(m,2H),1.43(s,9H),1.31–1.21(m,2H),

[0428] Synthesis of tert-butyl 4-(1-cyanopropyl)piperidine-1-carboxylate (03)

[0429]

[0430] To a solution of tert-butyl 4-(1-cyanoethyl)piperidine-1-carboxylate (02) (2 g, 8.92 mmol, 1 eq) in dry THF (15 mL) cooled to -78 ° C, LDA (2M in THF) (4.46 mL, 8.92 mmol, 1 eq) was added and stirred for 30 minutes. Then THF (0.66 mL, 8.92 mmol, 1 eq) containing ethyl iodide was added and stirred at -40 ° C for 2.5 hours. After completion of the reaction by TLC, the reaction mixture was quenched with NH4Cl solution and extracted with EtOAc (2×30 mL). The combined organic layer was washed with brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure to obtain tert-butyl 4-(1-cyanopropyl)piperidine-1-carboxylate (03) (1.2 g, yield: 54%) as a liquid. TLC system: EtoAc: hexane (20: 80; ninhydrin staining), R f Value: 0.6; 1HNMR (400MHz, CDCl3) δ4.19–4.17(m,2H),2.68–2.66(m,2H),2.37(q,J=6.8Hz,1H),1.86 –1.81(m,1H),1.70–1.62(m,4H),1.45(s,9H),1.38–1.32(m,2H),1.21(t,J=7.2Hz,3H),

[0431] Synthesis of 2-(piperidin-4-yl)butyronitrile. HCl(04)

[0432]

[0433] A solution of tert-butyl 4-(1-cyanopropyl)piperidine-1-carboxylate (03) (1.2 g, 5 mmol, 1 eq.) in dioxane (12 mL) containing 4 M HCl was stirred at room temperature for 1 hour. After completion of the reaction by TLC, the reaction mixture was concentrated under reduced pressure to give 2-(piperidin-4-yl)propionitrile hydrochloride (04) (0.86 g, yield: 92%) as a white solid. TLC system EtoAc (100%, ninhydrin staining), Rf value: 0.1; 1 HNMR(400MHz,DMSO-d6)δ9.01–8.71(br,2H),3.28–3.25(m,2H),2.89–2.75(m,3H ),1.90–1.80(m,3H),1.61-1.55(m,2H),1.55–1.46(m,2H),0.99(t,J=7.2Hz,3H).

[0434] Synthesis of 2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)butyronitrile (05)

[0435]

[0436] 2-(piperidin-4-yl)propionitrile hydrochloride (04) (0.84 g, 4.46 mmol, 1 eq.) was added to a stirred solution of 4-chloro-6,7-dimethoxyquinoline (3) (1 g, 4.46 mmol, 1 eq.) in 1,4-dioxane (10 mL) degassed for 10 minutes. CsCO (4.34 g, 13.3 mmol, 3 eq.), Pd(dba) (0.4 g, 0.44 mmol, 0.1 eq.), X-Phos (0.42 g, 0.89 mmol, 0.2 eq.) were added. The reaction mixture was stirred at 110 °C in a sealed tube for 16 hours. After the reaction was completed by TLC, the reaction mixture was filtered through a pad of celite and concentrated to provide a crude product. The crude compound was triturated with diethyl ether to give 2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)butanenitrile (05) (0.5 g, yield: 34%) as a pale yellow solid. TLC system MeOH:DCM (10:90), R f Value: 0.5; LCMS (m / z): 340.3 (M+H) + .

[0437] Synthesis of 2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)butan-1-amine (06)

[0438]

[0439] Ra-Ni (1 g) was added to a stirred solution of 2-(1-(6,7-dimethoxyquinoline-4-yl)piperidin-4-yl)propionitrile (05) (500 mg, 1.47 mmol, 1 eq) in methanol (5 mL) containing 7M NH. The reaction mixture was stirred at room temperature under H2 balloon pressure for 16 hours. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad and concentrated to give 2-(1-(6,7-dimethoxyquinoline-4-yl)piperidin-4-yl)butan-1-amine (06) (400 mg, yield: 79%) as an off-white solid. TLC system MeOH: DCM (10: 90), R f Value: 0.1; LCMS (m / z): 344.3 (M+H) + .

[0440] Synthesis of tert-butyl (N-(2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)butyl)sulfamoyl)carbamate (07)

[0441] To a stirred solution of 2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)butan-1-amine (06) (400 mg, 1.16 mmol, 1.0 equiv) in DCM (8 mL) was added DIPEA (0.31 mL, 1.74 mmol, 1.5 equiv), (tert-butyloxycarbonyl)((4-(dimethylimino)pyridin-1(4H)-yl)sulfonyl)amide (I-04-03) (459 mg, 1.52 mmol, 1.3 equiv). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was diluted with water and extracted with DCM (2×20 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The crude compound was purified by preparative HPLC to give tert-butyl (N-(2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)butyl)sulfamoyl)carbamate (07) (100 mg, yield: 16%) as an off-white solid. TLC system MeOH:DCM (5:95), R f Value: 0.5; LCMS (m / z): 523.6 (M+H) + ; 1 HNMR(400MHz,DMSO-d6)δ8.47(d,J=4.8Hz,1H),8.14(s,1H),7.45(t,1H),7.29(s,1H),7.16(s,1H),6.84(d,J=4.8Hz,1H),3.90(s,6H),3.54–3 .52(m,2H),2.98–2.86(m,2H),2.74–2.71(m,2H),1.75–1.71(m,2H),1. 62-1.55(m,4H),1.43(s,9H),1.35-1.26(m,2H),0.88(t,J=6.8Hz,3H).

[0442] Synthesis of N-(2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)butyl)sulfuramide (I-13)

[0443]

[0444] A solution of tert-butyl (N-(2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)butyl)sulfamoyl)carbamate (07) (100 mg, 0.19 mmol, 1 eq) in dioxane (2 mL) containing 4M HCl was stirred at room temperature for 2 hours. After completion of the reaction by TLC, the reaction mixture was concentrated and diluted with ethyl acetate (10 mL) and washed with aqueous NaHCO3 solution and brine (10 mL), dried over sodium sulfate and concentrated to give N-(2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)butyl)sulfodiamide (I-13) (35 mg, yield: 43%) as an off-white solid. TLC system MeOH: DCM (10: 90), R f Value: 0.3; LCMS (m / z): 423.3 (M+H) + ; 1 HNMR (400MHz, DMSO-d6) δ8.47(d,J=4.8Hz,1H),7.29(s,1H),7.17(s,1H),6.84(d,J=4.8Hz,1H),6.47(s,2H),6.38(t,J=5.6Hz,1H),3.90(s,6H ),3.54–3.52(m,2H),2.97–2.84(m,2H),2.71(t,J=10.8Hz,2H),1.78–1 .75(m,2H),1.63–1.47(m,3H),1.38–1.29(m,3H),0.90(t,J=7.2Hz,3H).

[0445] Synthesis of I-14:

[0446] Synthesis of tert-butyl 4-(2-cyanopropan-2-yl)piperidine-1-carboxylate (01)

[0447]

[0448] To a stirred solution of tert-butyl 4-(cyanomethyl)piperidine-1-carboxylate (I-13-02) (1 g, 4.2 mmol, 1 eq.) in THF (10 mL) at 0 ° C., KHMDS (1 M in toluene) (21 mL, 21 mmol, 5 eq.) was added and stirred at 0 ° C. for 10 minutes. Then THF (2 mL) containing iodomethane (0.59 mL, 8.4 mmol, 2 eq.) was added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was diluted with water and extracted with EtOAc (3 × 30 mL). The combined organic layer was washed with brine (30 mL), dried over sodium sulfate and concentrated to give 1 g of crude product (monomethyl compound). KHMDS (1M in toluene) (21mL, 21mmol, 5 equivalents) was added to THF (10mL) containing crude product (monomethyl compound) (1g, 4.2mmol, 1 equivalent) at 0°C, stirred at 0°C for 10 minutes, and then THF containing iodomethane (2mL) (0.59mL, 8.4mmol, 2 equivalents) was added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was diluted with water and extracted with EtOAc (3×30mL). The combined organic layer was washed with brine (30mL), dried over sodium sulfate and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography by eluting with 10% EtOAc / hexane to obtain 4- (2-cyanopropane-2-yl) piperidine-1-carboxylic acid tert-butyl ester (01) (500mg, yield: 44%) as a viscous liquid. TLC system: EtOAc / hexane (20:80; ninhydrin stain), R f Value: ~0.5; 1 H NMR (400MHz, CDCl3) δ4.23(brs,2H),2.68–2.63(m,2H),1.81–1.78(m,2H),1.51–1.48(m,1H),1.45(s,9H),1.36–1.30(m,8H).

[0449] Synthesis of 2-methyl-2-(piperidin-4-yl)propionitrile hydrochloride (02)

[0450]

[0451] A solution of tert-butyl 4-(2-cyanopropan-2-yl)piperidine-1-carboxylate (01) (500 mg, 1.98 mmol, 1 eq.) in dioxane (5 mL) containing 4M HCl was stirred at room temperature for 1 hour. After completion of the reaction by TLC, the reaction mixture was concentrated under reduced pressure to give 2-methyl-2-(piperidin-4-yl)propionitrile hydrochloride (02) (410 mg, yield: 99%) as a white solid. TLC system EtoAc (100%, ninhydrin staining), Rf value: 0.1; 1 HNMR(400MHz,DMSO-d6)δ8.88(brs,1H),8.43(brs,1H),3.38–3.35(m,2H),2.85–2 .81(m,2H),1.94–1.91(m,2H),1.71–1.63(m,1H),1.53–1.43(m,2H),1.33(s,6H).

[0452] Synthesis of 2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)-2-methylpropionitrile (03)

[0453]

[0454] 4-Chloro-6,7-dimethoxyquinoline (1) (500 mg, 2.24 mmol, 1 eq.) was added to a stirred solution of 2-methyl-2-(piperidin-4-yl)propionitrile HCl (02) (408 mg, 2.24 mmol, 1 eq.) in 1,4-dioxane (10 mL) and degassed for 10 minutes. Then Cs2CO3 (2.18 g, 6.73 mmol, 3 eq.), Pd2(dba)3 (205 mg, 0.22 mmol, 0.1 eq.), X-Phos (213 mg, 0.44 mmol, 0.2 eq.) were added. The reaction mixture was stirred in a sealed tube at 110 ° C for 16 hours. After the reaction was completed by TLC, the reaction mixture was filtered through a celite pad and concentrated to provide a crude product. The crude compound was purified by silica gel chromatography [eluted with 3% MeOH / DCM] to give 2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)-2-methylpropanenitrile (03) (0.55 g, yield: 72%) as a pale yellow solid. TLC system MeOH:DCM (10:90), R f Value: 0.5; LCMS (m / z): 340.4 (M+H) + ; 1HNMR (400MHz, DMSO-d6) δ8.49(d,J=4.8Hz,1H),7.31(s,1H),7.15(s,1H),6.87(d,J=4.8Hz,1H),3.91 and 3.90(2s,6H),3.62–3.59(m,2H),2.75–2.72(m,2H),1.99–1.96(m,2H),1.67–1.62(m,3H),1.37(s,6H).

[0455] Synthesis of 2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)-2-methylpropan-1-amine (04)

[0456]

[0457] Ra-Ni (1 g) was added to a stirred solution of 2-(1-(6,7-dimethoxyquinoline-4-yl)piperidin-4-yl)-2-methylpropionitrile (03) (550 mg, 1.47 mmol, 1 eq) in methanol (5 mL) containing 7M NH. The reaction mixture was stirred at room temperature under H2 balloon pressure for 16 hours. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad and concentrated to give 2-(1-(6,7-dimethoxyquinoline-4-yl)piperidin-4-yl)-2-methylpropan-1-amine (04) (400 mg, yield: 79%) as an off-white solid. TLC system MeOH: DCM (10: 90), R f Value: 0.1; LCMS (m / z): 344.3 (M+H) + ; 68% purity. Used in the next step.

[0458] Synthesis of tert-butyl (N-(2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)-2-methylpropyl)sulfamoyl)carbamate (05)

[0459]

[0460] To a stirred solution of 2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)-2-methylpropan-1-amine (04) (400 mg, 1.16 mmol, 1.0 equiv) in DCM (8 mL) at 0 °C was added DIPEA (0.31 mL, 1.74 mmol, 1.5 equiv) and (tert-butyloxycarbonyl)((4-(dimethylimino)pyridin-1(4H)-yl)sulfonyl)amide (I-04-03) (456 mg, 1.51 mmol, 1.3 equiv). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was diluted with water and extracted with DCM (2×20 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure to provide the crude product. The crude compound was purified by preparative HPLC to give tert-butyl N-(2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)-2-methylpropyl)sulfamoylcarbamate (05) (110 mg, yield: 18%) as an off-white solid. TLC system MeOH:DCM (5:95), R f Value: 0.5; LCMS (m / z): 523.4 (M+H) + ; 1 HNMR (400MHz, DMSO-d6) δ10.81(s,1H),8.51(d,J=7.2Hz,1H),7.51(t,J=6.8Hz,1H),7.33(s,1H),7.25(s,1H),7.10(d,J=7.2Hz,1H),4.15–4.12(m ,2H),3.98 and 3.96(2s,6H),3.26–3.23(m,2H),2.81–2.79(m,2H),1.83–1.8 0(m,2H),1.70–1.64(m,1H),1.51–1.46(m,2H),1.43(s,9H),0.85(s,6H).

[0461] Synthesis of N-(2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)-2-methylpropyl)sulfuramide hydrochloride (I-14)

[0462]

[0463] A solution of tert-butyl N-(2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)-2-methylpropyl)sulfamoylcarbamate (05) (100 mg, 0.19 mmol, 1 equivalent) in dioxane (2 mL) containing 4M HCl was stirred at room temperature for 2 hours. After the reaction was completed by TLC, the reaction mixture was concentrated and then triturated with diethyl ether to give N-(2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)-2-methylpropyl)sulfodiamide hydrochloride (I-14) (40 mg, yield: 45%) as an off-white solid. TLC system MeOH: DCM (10: 90), R f Value: 0.3; LCMS (m / z): 423.3 (M+H) + ; 1 HNMR (400MHz, DMSO-d6) δ14.35(s,1H),8.50(d,J=6.8Hz,1H),7.42(s,1H),7.24(s,1H),7.10(d,J=6.8Hz,1H),6.46–6.41(m,3H),4.15–4. 12(m,2H),3.97 and 3.96(2s,6H),3.30–3.24(m,2H),2.77–2.75(m,2H), 1.86–1.83(m,2H),1.69–1.63(m,1H),1.50–1.47(m,2H),0.85(s,6H).

[0464] Synthesis of I-15:

[0465] Synthesis of N-(2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propyl)methylaminosulfonamide (I-15)

[0466]

[0467] To a stirred solution of 2-(1-(6,7-dimethoxyquinoline-4-yl)piperidin-4-yl)propan-1-amine (I-02-05) (500 mg, 1.51 mmol, 1 eq) in DCM (20 mL) at 0 ° C., TEA (0.43 mL, 3.03 mmol, 2 eq) was added, followed by methylsulfamoyl chloride (1) (294 mg, 2.27 mmol, 1.5 eq). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was concentrated and purified by reverse phase column Grace purification [eluted with 30% of 0.1% FA / H2O / ACN] to obtain N-(2-(1-(6,7-dimethoxyquinoline-4-yl)piperidin-4-yl)propyl)methylaminosulfonamide (I-15) (50 mg, yield: 8%) as an off-white solid. TLC system MeOH:DCM (10:90), R f Value: 0.6; LCMS (m / z): 423.3 (M+H) + ; 1 HNMR(400MHz,DMSO-d6)δ8.50(d,J=6.0Hz,1H),7.35(s,1H),7.21(s,1H),7.03( d, J=6.0Hz, 1H), 6.85 (t, J=6.0Hz, 1H), 6.66 (q, J=5.2Hz, 1H), 3.95 and 3.94 (2s, 6H) ,3.93–3.91(m,2H),3.14–3.05(m,2H),2.90–2.84(m,1H),2.72–2.66(m,1H),2. 43(d,J=5.2Hz,3H),1.82–1.78(m,2H),1.68–1.48(m,4H),0.91(d,J=6.8Hz,3H).

[0468] Synthesis of I-16:

[0469] Synthesis of 2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propanal (01)

[0470]

[0471] DIBAL-H (1M in hexanes) (4.92 mL, 4.92 mmol, 2 eq.) was added to a stirred solution of 2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propionitrile (I-02-04) (800 mg, 2.46 mmol, 1 eq.) in DCM (8 mL) at -78 °C. The reaction mixture was stirred at 0 °C for 3 hours. After completion of the reaction by TLC, the reaction mixture was quenched with saturated NH4Cl solution and extracted with DCM (3 × 30 mL). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography by eluting with 5% MeOH / DCM to give 2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propanal (01) (600 mg, yield: 74%) as a viscous liquid. TLC system: MeOH / DCM (10:90), R f Value: ~0.5; LCMS (m / z): 329.4 (M+H) + ; 1 H NMR (400MHz, CDCl3) δ9.74(s,1H),8.50(d,J=5.6Hz,1H),7.57(s,1H),7.17(s,1H),6.81(d,J=5.6Hz,1H),4.06 and 4.04(2s,6H),3.74–3.71(m,2H),2.96–2.91(m,2H),2.41–2.40(m,1H),1.98–1.68(m,5H),1.19(d,J=6.8Hz,3H).

[0472] Synthesis of N-(2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propyl)cyclopropylamine (02)

[0473]

[0474] Cyclopropylamine (1) (125 mg, 2.19 mmol, 1.2 eq.), molecular sieve powder (600 mg), AcOH (catalysis) were added to a stirred solution of 2-(1-(6,7-dimethoxyquinoline-4-yl)piperidin-4-yl)propanal (01) (600 mg, 1.82 mmol, 1 eq.) in methanol (6 mL) cooled to 0 ° C. The reaction mixture was stirred at room temperature for 0.5 hours, then NaCNBH3 (114 mg, 1.82 mmol, 1 eq.) was added and stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was quenched with cold water and extracted with 10% MeOH+DCM (2×30 mL). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to give a crude product. The crude compound was triturated with diethyl ether to give N-(2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propyl)cyclopropylamine (02) (400 mg, yield: 59%) as a sticky solid. TLC system: MeOH / DCM (10:90), R f Value: ~0.3; LCMS (m / z): 370.3 (M+H) + .

[0475] Synthesis of tert-butyl N-cyclopropyl-N-(2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propyl)sulfamoylcarbamate (03)

[0476]

[0477] To a stirred solution of N-(2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propyl)cyclopropylamine (02) (400 mg, 1.08 mmol, 1 eq.) in DCM (8 mL) was added DIPEA (0.29 mL, 1.62 mmol, 1.5 eq.), (tert-butyloxycarbonyl)((4-(dimethylimino)pyridin-1(4H)-yl)sulfonyl)amide (I-04-03) (422 mg, 1.4 mmol, 1.3 eq.). The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction by TLC, the reaction mixture was quenched with water and extracted with DCM (2×20 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure to provide a crude product, which was purified by preparative HPLC to give tert-butyl N-cyclopropyl-N-(2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propyl)sulfamoylcarbamate (03) (100 mg, yield: 16%) as an off-white solid. TLC system MeOH:DCM (5:95), R fValue: 0.5; LCMS (m / z): 549.4 (M+H) + , De-boc m / z was also observed.

[0478] Synthesis of N-cyclopropyl-N-(2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propyl)aminosulfonamide formate (I-16)

[0479]

[0480] A solution of tert-butyl N-cyclopropyl-N-(2-(1-(6,7-dimethoxyquinoline-4-yl)piperidin-4-yl)propyl)sulfamoylcarbamate (03) (200 mg, 0.36 mmol, 1 equivalent) in dioxane (2 mL) containing 4M HCl was stirred at room temperature for 2 hours. After completion of the reaction by TLC, the reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by preparative HPLC to give N-cyclopropyl-N-(2-(1-(6,7-dimethoxyquinoline-4-yl)piperidin-4-yl)propyl)sulfamoylcarbamate (I-16) (55 mg, yield: 35%) as a white solid. TLC system MeOH: DCM (10: 90), R f Value: 0.3; LCMS (m / z): 449.3 (M+H-HCOOH) + ; 1 HNMR(400MHz,DMSO-d6)δ8.47(d,J=5.2Hz,1H),8.14(s,1H),7.29(s,1H),7.17(s,1 H), 6.85 (d, J = 5.2Hz, 1H), 6.80 (s, 2H), 3.91 and 3.90 (2s, 6H), 3.55–3.52 (m, 2H), 3.19– 3.15(m,1H),2.88–2.83(m,1H),2.74–2.67(m,2H),2.28–2.25(m,1H),1.95–1.92(m, 1H),1.77–-1.67(m,3H),1.55–1.52(m,2H),0.88(d,J=6.8Hz,3H),0.76–0.66(m,4H)

[0481] Synthesis of I-17:

[0482] Synthesis of tert-butyl 5,6-dihydro-[3,4'-bipyridine]-1(2H)-carboxylate (01)

[0483]

[0484] To 4-bromopyridine hydrochloride (1) (2g, 10.3mmol, 1 equivalent) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-5,6-dihydropyridine-1(2H)-tert-butyl formate (2) (3.2g, 10.3mmol, 1 equivalent) in DME:HO (2: 1) 30mL stirred solution in sodium carbonate (5.4g, 51.5mmol, 5 equivalents) and Pd (PPh3) 4 (238mg, 0.20mmol, 0.02 equivalents), and degassed for 15 minutes. The reaction mixture was stirred in a sealed tube at 100 ° C for 16 hours. After the reaction was completed by TLC, the reaction mixture was filtered through a celite pad and the filtrate was concentrated to provide a crude product. The crude product was purified by silica gel (60-120 mesh) column [eluted with 20% EtOAc / hexane] to give tert-butyl 5,6-dihydro-[3,4′-bipyridine]-1(2H)-carboxylate (01) (2.2 g, yield: 84%) as a pale yellow solid. TLC system EtoAc: Hexane (50:50), R f Value: 0.2, LCMS (m / z): 261.2 (M+H) + ; 1 HNMR(400MHz,DMSO-d6)δ8.55(d,J=5.2Hz,2H),7.25(d,J=6.0Hz,2H),6.48–6 .46(m,1H),4.26(brs,2H),3.56(t,J=5.6Hz,2H),2.35(brs,2H),1.49(s,9H).

[0485] Synthesis of tert-butyl [3,4'-bipiperidinyl]-1-carboxylate (02)

[0486]

[0487] PtO2 (300 mg) was added to a stirred solution of 5,6-dihydro-[3,4'-bipyridine]-1(2H)-formic acid tert-butyl ester (01) (1 g, 3.84 mmol, 1 eq) in acetic acid (20 mL). The reaction mixture was stirred at room temperature under H2 balloon pressure for 16 hours. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad, and the filtrate was concentrated to give [3,4'-bipiperidine]-1-formic acid tert-butyl ester (02) (850 mg, yield: 85%) as a light yellow solid. TLC system MeOH: DCM (10: 90), R f Value: 0.1; 1HNMR(400MHz,DMSO-d6)δ3.81–3.72(br,2H),3.17–3.14(m,2H),2.79–2.62( m,4H),1.74–1.70(m,4H),1.61–1.57(m,1H),1.38(s,9H),1.29–1.23(m,6H).

[0488] Synthesis of tert-butyl 1'-(6,7-dimethoxyquinolin-4-yl)-[3,4'-bipiperidinyl]-1-carboxylate (03)

[0489]

[0490] To a stirred solution of 4-chloro-6,7-dimethoxyquinoline (3) (500 mg, 2.24 mmol, 1 equivalent) in 1,4-dioxane (5 mL), [3,4'-bipiperidine]-1-tert-butyl formate (02) (720 mg, 2.68 mmol, 1.2 equivalents) was added and degassed for 10 minutes. Then Cs2CO3 (2.1 g, 6.72 mmol, 3 equivalents), Pd2(dba)3 (0.20 g, 0.22 mmol, 0.1 equivalents), X-Phos (0.21 g, 0.44 mmol, 0.2 equivalents) were added. The reaction mixture was stirred in a sealed tube at 110 ° C for 16 hours. After the reaction was completed by TLC, the reaction mixture was filtered through a diatomaceous earth pad and concentrated to provide a crude product. The crude compound was purified by silica gel (60-120 mesh) column [eluted with 5% MeOH / DCM] to give tert-1'-(6, butyl 7-dimethoxyquinolin-4-yl)-[3,4'-bipiperidine]-1-carboxylate (03) (520 mg, yield: 52%) as a brown viscous liquid. TLC system MeOH: DCM (10:90), R f Value: 0.3; LCMS (m / z): 456.3 (M+H) + ; 1 HNMR (400MHz,CDCl3)δ8.55(d,J=5.2Hz,1H),7.46(s,1H),7.22(s,1H),6.78(d,J=5.2Hz,1H),4.03(s,3H),4.01(s,3H),3.98–3.93(m,2H),3.63–3.60(m,2H),2.79–2.74(m,4H),2.04–1.85(m,6H),1.47(s,9H),1.45–1.38(m,4H). The aliphatic region in the NMR spectrum is not clear.

[0491] Synthesis of 4-([3,4'-bipiperidinyl]-1'-yl)-6,7-dimethoxyquinoline hydrochloride (04)

[0492]

[0493] A solution of tert-1'-(6, butyl 7-dimethoxyquinoline-4-yl)-[3,4'-bipiperidin]-1-carboxylate (03) (520 mg, 1.14 mmol, 1 eq) in dioxane (6 mL) containing 4M HCl was stirred at 0 ° C for 15 minutes, and allowed to reach room temperature and further stirred for 2 hours. After the reaction was completed by TLC, the volatiles were evaporated. The crude product was triturated with diethyl ether to give 4-([3,4'-bipiperidin]-1'-yl)-6,7-dimethoxyquinoline hydrochloride (04) (250 mg, yield: 61%) as an off-white solid. TLC system MeOH: DCM (10: 90), R f Value: 0.1; LCMS (m / z): 356.3 (M+H) + ; 1 HNMR(400MHz,DMSO-d6)δ14.9(s,1H),9.24–9.22(m,1H),9.00–8.97(m,1H),8.53(d,J=6.4Hz,1H),7.56(s,1H),7.22(s,1H),7.11(d,J=6 .4Hz,1H),4.09–4.07(m,2H),3.97(s,6H),3.27–3.18(m,4H),2.65–2.55(m,2H),1.89–1.83(m,4H),1.68–1.60(m,3H),1.56–1.48(m,3H).

[0494] Synthesis of tert-butyl ((1'-(6,7-dimethoxyquinolin-4-yl)-[3,4'-bipiperidinyl]-1-yl)sulfonyl)carbamate (05)

[0495]

[0496] To a stirred solution of 4-([3,4'-bipiperidinyl]-1'-yl)-6,7-dimethoxyquinoline hydrochloride (04) (250 mg, 0.54 mmol, 1 eq) in DCM (5 mL) was added DIPEA (0.18 mL, 0.82 mmol, 1.5 eq) and (tert-butyloxycarbonyl)((4-(dimethylimino)pyridin-1(4H)-yl)sulfonyl)amide (I-04-03) (275 mg, 0.71 mmol, 1.3 eq). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched with water and extracted with DCM (2×20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The crude compound was purified by reverse phase C18 column [eluted with 0.1% FA / H2O / ACN] to give tert-butyl ((1'-(6,7-dimethoxyquinolin-4-yl)-[3,4'-bipiperidinyl]-1-yl)sulfonyl)carbamate (05) (150 mg, yield: 43%) as an off-white solid. TLC system MeOH:DCM (5:95), R f Value: 0.5; LCMS (m / z): 535.3 (M+H) + .

[0497] Synthesis of 6,7-dimethoxy-4-(1-(aminosulfonyl)-[3,4'-bipiperidinyl]-1'-yl)quinolinecarboxylate (I-17)

[0498]

[0499] A solution of tert-butyl ((1'-(6,7-dimethoxyquinolin-4-yl)-[3,4'-bipiperidinyl]-1-yl)sulfonyl)carbamate (05) (150 mg, 0.28 mmol, 1 eq) in dioxane (2 mL) containing 4M HCl was stirred at 0 °C for 15 min and allowed to reach room temperature for 2 h. After completion of the reaction by TLC, the volatiles were evaporated. The crude compound was purified by preparative HPLC purification to give 6,7-dimethoxy-4-(1-(aminosulfonyl)-[3,4'-bipiperidinyl]-1'-yl)quinoline as formate (I-17) (35 mg, yield: 29%) as a white solid. TLC system MeOH:DCM (10:90), R f Value: 0.2; LCMS (m / z): 435.3 (M+H-HCOOH) + ; 1HNMR (400 MHz, DMSO-d6) δ8.48 (d, J=5.2 Hz, 1H), 8.13 (formate proton), 7.30 (s, 1H), 7.17 (s, 1H), 6.86 (d, J=5.2 Hz, 1H), 6.68 (s, 2H), 3.91 (s, 6H), 3.57–3.54 (m, 2H), 3.50–3.47 (m, 2H), 3.39–3.37 (br, 1H), 2.75–2.71 (m, 2H), 2.36 (t, J=10.8 Hz, 1H), 1.90–1.75 (m, 4H), 1.56–1.47 (m, 5H), 1.11-1.08 (m, 1H).

[0500] Synthesis of I-18:

[0501] Synthesis of 1-(6,7-dimethoxyquinolin-4-yl)piperidine-4-carboxylic acid ethyl ester (01)

[0502]

[0503] To a stirred solution of 4-chloro-6,7-dimethoxyquinoline (1) (1 g, 4.46 mmol, 1 eq) in 1,4-dioxane (20 mL) degassed for 10 minutes was added piperidine-4-carboxylic acid ethyl ester (2) (0.84 g, 5.35 mmol, 1.2 eq) CsCO (4.34 g, 13.3 mmol, 3 eq), Pd(dba) (0.40 g, 0.44 mmol, 0.1 eq), X-Phos (0.42 mg, 0.89 mmol, 0.2 eq) were added. The reaction mixture was stirred at 110 °C in a sealed tube for 16 hours. After completion of the reaction by TLC, the reaction mixture was filtered through a pad of celite, washed with ethyl acetate and concentrated to provide a crude product. The crude compound was purified by 100-200 mesh silica gel column by eluting with 3% MeOH / DCM to give ethyl 1-(6,7-dimethoxyquinolin-4-yl)piperidine-4-carboxylate (01) (650 mg, yield: 45%) as a white solid. TLC system MeOH: DCM (10:90), R f Value: 0.5; LCMS (m / z): 345.4 (M+H) + ;

[0504] Synthesis of 1-(6,7-dimethoxyquinolin-4-yl)piperidine-4-carboxylic acid (02)

[0505]

[0506] LiOHH2O (193 mg, 4.59 mmol, 1 eq.) was added to a stirred solution of 1-(6,7-dimethoxyquinoline-4-yl)piperidine-4-carboxylic acid ethyl ester (01) (650 mg, 1.53 mmol, 1 eq.) in THF:H2O (2: 1) (10 mL) at 0 ° C. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was concentrated and washed with diethyl ether (50 mL). The aqueous layer was adjusted to pH-7 using 2N HCl aqueous solution and concentrated under reduced pressure to give 1-(6,7-dimethoxyquinoline-4-yl)piperidine-4-carboxylic acid (02) (590 mg, yield: 99%) as an off-white solid. TLC system MeOH: DCM (20: 80), R f Value: 0.1; LCMS (m / z): 317.4 (M+H) + ; 1 HNMR (400 MHz, DMSO-d6) δ15.38 (s, 1H), 12.45 (s, 1H), 8.53 (d, J = 6.8 Hz, 1H), 7.69 (s, 1H), 7.21 (s, 1H), 7.12 (d, J = 6.8 Hz, 1H), 3.99–3.98 (m, 2H), 3.97 and 3.96 (2s, 6H), 2.71–2.67 (m, 1H), 2.09–2.05 (m, 2H), 1.89–1.84 (m, 2H), 2 protons merged with the solvent peak.

[0507] Synthesis of N-(1-cyanocyclopropyl)-1-(6,7-dimethoxyquinolin-4-yl)piperidine-4-carboxamide (I-18)

[0508]

[0509] To a stirred solution of 1-(6,7-dimethoxyquinolin-4-yl)piperidine-4-carboxylic acid (02) (300 mg, 0.94 mmol, 1.0 equiv) in DMF (3 mL) was added 1-aminocyclopropane-1-carbonitrile hydrochloride (3) (110 mg, 0.94 mmol, 1.5 equiv), HATU (536 mg, 1.41 mmol, 1.5 equiv), DIPEA (0.78 mL, 4.7 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to give a crude product. The crude compound was purified by reverse phase Grace purification [eluted with 40% H2O / ACN gradient] to give N-(1-cyanocyclopropyl)-1-(6,7-dimethoxyquinolin-4-yl)piperidine-4-carboxamide (I-18) (36 mg, yield: 10%) as an off-white solid. TLC system MeOH: DCM (10:90), R f Value: 0.4; LCMS (m / z): 381.2 (M+H) + ; 1 HNMR (400MHz, DMSO-d6) δ 8.82 (s, 1H), 8.49 (d, J = 5.2Hz, 1H), 7.30 (s, 1H), 7.16 (s, 1H), 6.88 (d, J = 5.2Hz, 1H), 3.92 and 3.91 ( 2s,6H),3.55–3.52(m,2H),2.78–2.76(m,2H),2.35–2.33(m,1H),1.88–1.85(m,4H),1.50–1.47(m,2H),1.14–1.11(m,2H).

[0510] Synthesis of I-19:

[0511] N-(2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propyl)methanesulfonamide

[0512]

[0513] To a stirred solution of 2-(1-(6,7-dimethoxyquinoline-4-yl)piperidin-4-yl)propan-1-amine (I-02-05) (200 mg, 0.607 mmol, 1 eq.) in DCM (4 mL) at 0 ° C, TEA (0.12 mL, 0.911 mmol, 1.5 eq.) and methanesulfonyl chloride (1) (0.05 mL, 0.72 mmol, 1.5 eq.) were added. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction by TLC, the reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with brine, dried over sodium sulfate and concentrated to provide a crude product. The crude product was purified by 100-200 mesh silica gel column by eluting with 2% MeOH+DCM to give N-(2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propyl)methanesulfonamide (I-19) (60 mg, yield: 24%) as an off-white solid. TLC system MeOH: DCM (10:90), R f Value: 0.6; LCMS (m / z): 408.3 (M+H) + ; 1 HNMR (400MHz, DMSO-d6) δ8.48(d,J=5.2Hz,1H),7.29(s,1H),7.17(s,1H),6.97(t,J=6.0Hz,1H),6.86(d,J=4.8Hz,1H),3.91(s,6H),3.57–3.5 4(m,2H),3.06–3.00(m,1H),2.90(s,3H),2.85–2.82(m,1H),2.76–12. 71(m,2H),1.81–1.76(m,2H),1.59–1.55(m,4H),0.93(d,J=6.8Hz,3H).

[0514] Synthesis of I-20:

[0515] Synthesis of tert-butyl 4-(6,7-dimethoxyquinolin-4-yl)piperazine-1-carboxylate (01)

[0516]

[0517] To a stirred solution of 4-chloro-6,7-dimethoxyquinoline (1) (1 g, 4.48 mmol, 1 equivalent) in 1,4-dioxane (10 mL) was added tert-butyl piperazine-1-carboxylate (2) (1 g, 5.38 mmol, 1.2 equivalents), and degassed for 10 minutes. Subsequently, CsCO (2.91 g, 8.96 mmol, 2 equivalents), Pd(dba) (0.41 g, 0.44 mmol, 0.1 equivalents), X-Phos (0.42 mg, 0.89 mmol, 0.2 equivalents) were added. The reaction mixture was stirred in a sealed tube at 110 ° C for 16 hours. After completion of the reaction by TLC, the reaction mixture was filtered through a diatomaceous earth pad and the filtrate was concentrated to provide a crude product. The crude compound was purified by silica gel (100-200 mesh) chromatography [eluted with 3% MeOH+DCM] to give tert-butyl 4-(6,7-dimethoxyquinolin-4-yl)piperazine-1-carboxylate (01) (1.3 g, yield: 77%) as a white solid. TLC system MeOH: DCM (10:90), R f Value: 0.5; LCMS (m / z): 374.2 (M+H) + ; 1 HNMR(400MHz, CDCl3)δ8.59(d,J=5.2Hz,1H),7.40(s,1H),7.26(s,1H),6.79(d,J=5.2 Hz, 1H), 4.03 and 4.01 (2s, 6H), 3.70 (t, J = 4.8Hz, 4H), 3.15 (t, J = 4.8Hz, 4H), 1.51 (s, 9H).

[0518] Synthesis of 6,7-dimethoxy-4-(piperazin-1-yl)quinoline (02)

[0519]

[0520] A solution of tert-butyl 4-(6,7-dimethoxyquinoline-4-yl)piperazine-1-carboxylate (01) (1.3 g, 5 mmol, 1 eq.) in dioxane (13 mL) containing 4 M HCl was stirred at room temperature for 2 hours. After completion of the reaction by TLC, the reaction mixture was evaporated under reduced pressure to give a crude product. The crude compound was alkalized with saturated NaHCO3 solution and extracted with 10% MeOH+DCM (2×50 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate and concentrated to give 6,7-dimethoxy-4-(piperazine-1-yl)quinoline (02) (0.65 g, yield: 74%) as a brown solid. TLC system MeOH: DCM (10: 90), R f Value: 0.2; LCMS (m / z): 274.4 (M+H)+ .

[0521] Synthesis of tert-butyl (2-hydroxypropyl)carbamate (03)

[0522]

[0523] To a stirred solution of 1-aminopropan-2-ol (3) (5 g, 66.7 mmol, 1.0 eq) in DCM (50 mL) at 0 ° C, triethylamine (9.2 mL, 66.7 mmol, 1 eq) was added, followed by dropwise addition of (Boc)2O (14.3 mL, 66.7 mmol, 1 eq) under nitrogen flushing. The reaction was stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was diluted with ice-cold water and extracted with DCM (2×100 mL). The combined organic layers were washed with water (50 mL), brine solution (50 mL), dried over sodium sulfate and concentrated under reduced pressure to provide a crude product. The crude compound was purified by silica gel (100-200 mesh) chromatography [eluted with a 20-25% ethyl acetate / hexane gradient] to obtain tert-butyl (2-hydroxypropyl)carbamate (03) (5 g, 42%) as a yellow liquid. TLC system: EtOAc / hexane (50:50; ninhydrin stain), R f Value: ~0.4; 1 HNMR (400MHz, DMSO-d6) δ6.64 (brs, 1H), 4.55 (d, J = 4.8Hz, 1H), 3.60–3.55 (m, 1H), 2.90–2.81 (m, 2H), 1.37 (s, 9H), 0.98 (d, J = 6.4Hz, 3H).

[0524] Synthesis of tert-butyl (2-oxopropyl)carbamate (04)

[0525]

[0526] To a stirred solution of tert-butyl (2-hydroxypropyl)carbamate (03) (1.5 g, 5.71 mmol, 1 eq) in dry DCM (15 mL) at 0 ° C, Dess-Martin periodinane (4.8 g, 6.85 mmol, 1.2 eq) was added. The reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction by TLC, the reaction mixture was diluted with water and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated to provide a crude product. The crude compound was purified by silica gel (100-200 mesh chromatography [eluted with 5-10% ethyl acetate / hexane gradient] to obtain tert-butyl (2-oxopropyl)carbamate (04) (1 g, yield: 66%) as a colorless liquid. TLC system: EtoAc: Hexane (50:50; ninhydrin staining), R f Value: ~0.6; 1 H NMR (400MHz, CDCl3) δ5.25 (brs, 1H), 4.03 (d, J = 4.8Hz, 2H), 2.18 (s, 3H), 1.46 (s, 9H),

[0527] Synthesis of tert-butyl (2-(4-(6,7-dimethoxyquinolin-4-yl)piperazin-1-yl)propyl)carbamate (05)

[0528]

[0529] To a stirred solution of 6,7-dimethoxy-4-(piperazine-1-yl)quinoline (02) (650 mg, 2.38 mmol, 1 eq.) in methanol (8 mL) was added tert-butyl (2-oxopropyl)carbamate (04) (0.41 g, 2.38 mmol, 1 eq.) and titanium isopropoxide (0.69 mL, 4.76 mmol, 2 eq.). The reaction mixture was stirred at room temperature for 16 hours. Subsequently, the reaction mixture was cooled to 0 ° C, NaCNBH3 (224 mg, 3.57 mmol, 1.5 eq.) was added and stirred at room temperature for 5 hours. After the reaction was completed by TLC, the reaction mixture was quenched with water and extracted with 10% MeOH+DCM (2×50 mL). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate and concentrated. The crude compound was purified by silica gel (100-200 mesh) column chromatography [eluted with 5% MeOH+DCM] to give tert-butyl (2-(4-(6,7-dimethoxyquinolin-4-yl)piperazin-1-yl)propyl)carbamate (05) (0.2 g, yield: 20%) as a brown solid. TLC system MeOH:DCM (10:90), R fValue: 0.5; LCMS (m / z): 431.3 (M+H) + ; 1 HNMR(400MHz, DMSO-d6)δ8.49(d,J=4.8Hz,1H),7.33(s,1H),7.20(s,1H),6.84(d,J=4.8Hz,1H),6.61–6.59(m, 1H), 3.90 (s, 6H), 3.72–3.67 (m, 1H), 3.16–3.11 (m, 4H), 2.82–2.67 (m, 6H), 1.39 (s, 9H), 0.98 (d, J = 6.4Hz, 3H).

[0530] Synthesis of 2-(4-(6,7-dimethoxyquinolin-4-yl)piperazin-1-yl)propan-1-amine hydrochloride (06)

[0531]

[0532] To a stirred solution of tert-butyl (2-(4-(6,7-dimethoxyquinolin-4-yl)piperazin-1-yl)propyl)carbamate (05) (200 mg, 0.46 mmol, 1 eq) in dioxane at 0°C was added 4M HCl in dioxane (4 mL) and stirred at room temperature for 2 hours. After completion of the reaction by TLC, the reaction mixture was concentrated under reduced pressure to give 2-(4-(6,7-dimethoxyquinolin-4-yl)piperazin-1-yl)propan-1-amine hydrochloride (06) (0.17 g) as a brown solid. TLC system MeOH:DCM (10:90), R f Value: 0.1; LCMS (m / z): 331.3 (M+H) not a molecular ion peak + 274.2 was the major ion peak of the fragment of the desired product. Neither the LCMS nor the 1H NMR spectra supported the product identification; however, the material was used in the next step and confirmed at that stage.

[0533] Synthesis of tert-butyl (N-(2-(4-(6,7-dimethoxyquinolin-4-yl)piperazin-1-yl)propyl)sulfamoyl)carbamate (07)

[0534]

[0535] To a stirred solution of 2-(4-(6,7-dimethoxyquinolin-4-yl)piperazin-1-yl)propan-1-amine hydrochloride (06) (170 mg, 0.46 mmol, 1.0 equiv) in DCM (4 mL) was added DIPEA (0.25 mL, 1.38 mmol, 3 equiv) and (tert-butyloxycarbonyl)((4-(dimethylimino)pyridin-1(4H)-yl)sulfonyl)amide (I-04-03) (181 mg, 0.60 mmol, 1.3 equiv). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was diluted with water and extracted with DCM (2×20 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The crude compound was purified by preparative HPLC to give tert-butyl (N-(2-(4-(6,7-dimethoxyquinolin-4-yl)piperazin-1-yl)propyl)sulfamoyl)carbamate (07) (150 mg, 62%, two steps) as an off-white solid. TLC system MeOH:DCM (5:95), R f Value: 0.5; LCMS (m / z): 508.3 (MH) + .

[0536] Synthesis of N-(2-(4-(6,7-dimethoxyquinolin-4-yl)piperazin-1-yl)propyl)aminosulfonamide formate (I-20)

[0537]

[0538] To a stirred solution of tert-butyl (N-(2-(4-(6,7-dimethoxyquinolin-4-yl)piperazine-1-yl)propyl)sulfamoyl)carbamate (07) (150 mg, 0.29 mmol, 1 eq) in dioxane at 0 ° C., dioxane (1 mL) containing 4M HCl was added and stirred at room temperature for 2 hours. After completion of the reaction by TLC, the reaction mixture was concentrated to give a crude product. The crude compound was purified by reverse phase purification [eluted with 0-20% (0.1% FA / H2O) + ACN gradient] to give N-(2-(4-(6,7-dimethoxyquinolin-4-yl)piperazine-1-yl)propyl)sulfamoyl)aminosulfonamide formate (I-20) (42 mg, yield: 34%) as a white solid. TLC system MeOH: DCM (20: 80), R f Value: 0.1; LCMS (m / z): 410.3 (M+H) + ; 1HNMR (400 MHz, DMSO-d6) δ8.50 (d, J=4.8 Hz, 1H), 8.14 (formate proton), 7.32 (s, 1H), 7.21 (s, 1H), 6.88 (d, J=4.8 Hz, 1H), 6.59 (brs, 2H), 6.09 (brs, 1H), 3.91 (s, 6H), 3.20–3.17 (m, 4H), 3.10–3.05 (m, 1H), 2.87–2.77 (m, 6H), 1.05 (d, J=5.6 Hz, 3H).

[0539] Synthesis of I-21:

[0540] Synthesis of (R)-tert-Butyl 4-(6,7-dimethoxyquinolin-4-yl)-2-methylpiperazine-1-carboxylate (01)

[0541]

[0542] To a stirred solution of 4-chloro-6,7-dimethoxyquinoline (1) (1 g, 4.48 mmol, 1 equivalent) in 1,4-dioxane (10 mL) was added (R)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (2) (1.0 g, 5.38 mmol, 1.2 equivalents), and degassed for 10 minutes. Then CsCO (4.2 g, 13.4 mmol, 3 equivalents), Pd(dba) (0.41 g, 0.44 mmol, 0.1 equivalents), X-Phos (0.42 g, 0.89 mmol, 0.2 equivalents) were added. The reaction mixture was stirred in a sealed tube at 110 ° C for 16 hours. After the reaction was completed by TLC, the reaction mixture was filtered through a celite pad and concentrated to provide a crude product. The crude compound was purified by silica gel (100-200 mesh) chromatography [eluted with 3% MeOH / DCM] to give (R)-tert-butyl 4-(6,7-dimethoxyquinolin-4-yl)-2-methylpiperazine-1-carboxylate (01) (1.2 g, yield: 70%) as an off-white solid. TLC system MeOH:DCM (10:90), R f Value: 0.4; LCMS (m / z): 388.3 (M+H) + ;

[0543] Synthesis of (R)-6,7-dimethoxy-4-(3-methylpiperazin-1-yl)quinoline hydrochloride (02)

[0544]

[0545] A solution of (R)-tert-butyl 4-(6,7-dimethoxyquinolin-4-yl)-2-methylpiperazine-1-carboxylate (01) (1.2 g, 3.10 mmol, 1 eq) in dioxane (15 mL) containing 4M HCl was stirred at 0°C to room temperature for 2 hours. After completion of the reaction by TLC, the volatiles were evaporated and the obtained crude product was triturated with diethyl ether to give (R)-6,7-dimethoxy-4-(3-methylpiperazin-1-yl)quinoline hydrochloride (02) (800 mg, yield: 80%) as an off-white solid. TLC system MeOH:DCM (10:90), R f Value: 0.1; LCMS (m / z): 288.2 (M+H-HCl) + ; The peak shape is not good. 1 HNMR (400 MHz, DMSO-d6) δ9.65–9.62 (brs, 2H), 8.69 (d, J=6.4 Hz, 1H), 7.53 (s, 1H), 7.31 (d, J=6.4 Hz, 1H), 7.25 (s, 1H), 4.08–4.04 (m, 2H), 4.01 (s, 3H), 3.99 (s, 3H), 3.96–3.92 (m, 1H), 3.66–3.63 (m, 2H), 1.35 (d, J=6.4 Hz, 3H), 2 protons can be merged with the DMSO-d6 peak in the spectrum.

[0546] Synthesis of tert-butyl (R)-(2-(4-(6,7-dimethoxyquinolin-4-yl)-2-methylpiperazin-1-yl)ethyl)carbamate (03)

[0547]

[0548] To a stirred solution of (R)-6,7-dimethoxy-4-(3-methylpiperazine-1-yl)quinoline hydrochloride (02) (800 mg, 2.47 mmol, 1 eq.) in DMF (8 mL) was added KCO (1.0 g, 7.43 mmol, 3 eq.) followed by tert-butyl (2-bromoethyl)carbamate (3) (1.1 g, 4.95 mmol, 2 eq.). The reaction mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was quenched with water and extracted with EtOAc (2 × 40 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to give a crude product. The crude compound was purified by silica gel (100-200 mesh) chromatography [eluted with 0-4% MeOH / DCM gradient] to give (R)-tert-butyl (2-(4-(6,7-dimethoxyquinolin-4-yl)-2-methylpiperazin-1-yl)ethyl)carbamate (03) (500 mg, yield: 50%) as an off-white solid. TLC system MeOH:DCM (10:90), R f Value: 0.4; LCMS (m / z): 431.4 (M+H) + ; 1 HNMR (400 MHz, CDCl3) δ8.57 (d, J = 4.8 Hz, 1H), 7.40 (s, 1H), 7.28 (s, 1H), 6.79 (d, J = 5.2 Hz, 1H), 4.93 (brs, 1H) 4.03 (s, 3H), 4.00 (s, 3H), 3.32–3.19 (m, 4H), 3.17–3.15 (m, 1H), 2.97–2.84 (m, 3H), 2.66–2.61 (m, 1H), 2.47–2.40 (m, 2H), 1.47 (s, 9H), 1.21 (d, J = 6 Hz, 3H). The aliphatic protons were not clean, as there were traces of compound 3 even after purification.

[0549] Synthesis of (R)-2-(4-(6,7-dimethoxyquinolin-4-yl)-2-methylpiperazin-1-yl)ethylamine hydrochloride (04)

[0550]

[0551] To a stirred solution of (R)-tert-butyl (2-(4-(6,7-dimethoxyquinolin-4-yl)-2-methylpiperazin-1-yl)ethyl)carbamate (03) (500 mg, 1.16 mmol, 1 eq) in 1,4-dioxane at 0°C was added 4M HCl in dioxane (5 mL) and stirred at room temperature for 2 hours. After completion of the reaction by TLC, the volatiles were evaporated and the crude product was triturated with diethyl ether to give (R)-2-(4-(6,7-dimethoxyquinolin-4-yl)-2-methylpiperazin-1-yl)ethanamine hydrochloride (04) (350 mg, yield: 91%) as an off-white solid. TLC system MeOH:DCM (10:90), R f Value: 0.1; LCMS (m / z): 331.3 (M+H-HCl) + ;

[0552] Synthesis of tert-butyl (R)-N-(2-(4-(6,7-dimethoxyquinolin-4-yl)-2-methylpiperazin-1-yl)ethyl)sulfamoylcarbamate (05)

[0553]

[0554] To a stirred solution of (R)-2-(4-(6,7-dimethoxyquinolin-4-yl)-2-methylpiperazin-1-yl)ethanamine hydrochloride (04) (300 mg, 0.90 mmol, 1 eq) in DCM (5 mL) was added DIPEA (0.2 mL, 1.36 mmol, 1.5 eq) and (tert-butyloxycarbonyl)((4-(dimethylimino)pyridin-1(4H)-yl)sulfonyl)amide (I-04-03) (355 mg, 1.18 mmol, 1.3 eq). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched with water and extracted with DCM (2×20 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The crude compound was purified by reverse phase column [eluted with 10-40% water / ACN gradient] to give (R)-tert-butyl N-(2-(4-(6,7-dimethoxyquinolin-4-yl)-2-methylpiperazin-1-yl)ethyl)sulfamoylcarbamate (05) (108 mg) as an off-white solid. TLC system MeOH:DCM (5:95), R f Value: 0.5; LCMS (m / z): 510.3 (M+H) + ; 60% purity.

[0555] Synthesis of (R)-N-(2-(4-(6,7-dimethoxyquinolin-4-yl)-2-methylpiperazin-1-yl)ethyl)aminosulfonamide formate (I-21)

[0556]

[0557] A solution of (R)-tert-butyl N-(2-(4-(6,7-dimethoxyquinolin-4-yl)-2-methylpiperazin-1-yl)ethyl)sulfamoylcarbamate (05) (100 mg, 0.19 mmol, 1 eq) in dioxane (3 mL) containing 4M HCl was stirred at 0 ° C to room temperature for 2 hours. After completion of the reaction by TLC, the volatiles were evaporated and washed with diethyl ether. The crude compound was purified by reverse phase column [eluted with 0-30% (0.1% FA / H2O) / ACN gradient] to give (R)-N-(2-(4-(6,7-dimethoxyquinolin-4-yl)-2-methylpiperazin-1-yl)ethyl)sulfamoylcarbamate (I-21) (20 mg, yield: 22%) as an off-white solid. TLC system MeOH: DCM (10: 90), R f Value: 0.1; LCMS (m / z): 410.3 (M+H) + ; 1 HNMR (400 MHz, DMSO-d6) δ8.50 (d, J=4.8 Hz, 1H), 8.14 (formate proton), 7.32 (s, 1H), 7.22 (s, 1H), 6.88–6.87 (m, 1H), 6.58 (brs, 2H), 6.33 (brs, 1H), 3.91 (s, 6H), 3.22–3.19 (m, 2H), 3.09–3.01 (m, 4H), 2.88–2.82 (m, 3H), 2.68–2.66 (m, 1H), 2.57–2.52 (m, 1H), 1.17 (brs, 3H).

[0558] Synthesis of I-22:

[0559] Synthesis of 1-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)cyclopropane-1-carboxylic acid ethyl ester (01)

[0560]

[0561] 1-(piperidin-4-yl)cyclopropane-1-carboxylic acid ethyl ester (I-27-02) (2.6 g, 13.41 mmol, 1.2 equiv) and CsCO (18 g, 55.9 mmol, 5 equiv) are added to a stirred solution of 4-chloro-6,7-dimethoxyquinoline (1) (2.5 g, 11.18 mmol, 1 equiv) in 1,4-dioxane (25 mL). The reaction mixture is degassed for 10 minutes. Pd(dba) (511 mg, 0.55 mmol, 0.05 equiv) and X-phos (798 mg, 1.67 mmol, 0.15 equiv) are then added and stirred in a sealed tube at 110 ° C for 16. After completion of the reaction by TLC, the reaction mixture is filtered through a pad of celite and concentrated to provide a crude product. The crude compound was purified by silica gel (100-200 mesh) column chromatography [eluted with EtOAc] to give ethyl 1-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)cyclopropane-1-carboxylate (01) (1.48 g, yield: 80%) as a brown sticky solid. TLC system: EtOAc (100), R f Value: 0.2; LCMS (m / z): 385.3 (M+H) + . 74% purity.

[0562] Synthesis of (1-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)cyclopropyl)methanol (02)

[0563]

[0564] LAH (1.0 M in THF) (18.2 mL, 18.21 mmol, 5 eq.) was added to a stirred solution of ethyl 1-(1-(6,7-dimethoxyquinoline-4-yl)piperidin-4-yl)cyclopropane-1-carboxylate (01) (1.4 g, 3.64 mmol, 1 eq.) in THF (14 mL) at -78 °C. The reaction mixture was stirred at 0 °C for 2 hours. After completion of the reaction by TLC, the reaction mixture was quenched with NH4Cl and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure to give (1-(1-(6,7-dimethoxyquinoline-4-yl)piperidin-4-yl)cyclopropyl)methanol (02) (1.2 g) as a black solid. TLC system MeOH: DCM (10: 90), R f Value: 0.3; LCMS (m / z): 343.3 (M+H) + ; 44% purity.

[0565] Synthesis of 4-(4-(1-(azidomethyl)cyclopropyl)piperidin-1-yl)-6,7-dimethoxyquinoline (03)

[0566]

[0567] DBU (2.6 mL, 17.51 ​​mmol, 5 equiv.), diphenylphosphoryl azide (3.0 mL, 14.03 mmol, 4 equiv.) were added to a stirred solution of (1-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)cyclopropyl)methanol (02) (1.2 g, 44% purity, 3.50 mmol, 1 equiv.) in THF (12 mL). The reaction mixture was stirred at room temperature for 48 hours. After completion of the reaction, the reaction mixture was quenched with NaHCO3 aqueous solution and extracted with EtOAc (2×70 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography [eluted with 3% MeOH / DCM] to give 4-(4-(1-(azidomethyl)cyclopropyl)piperidin-1-yl)-6,7-dimethoxyquinoline (03) (400 mg) as a colorless sticky solid. TLC system MeOH:DCM (10:90), R f值 :0.7; LCMS(m / z):368.3(M+H) + ; 56% purity.

[0568] Synthesis of (1-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)cyclopropyl)methylamine (04)

[0569]

[0570] 10% Pd / C (160 mg) was added to a stirred solution of 4-(4-(1-(azidomethyl)cyclopropyl)piperidin-1-yl)-6,7-dimethoxyquinoline (03) (400 mg, 56% purity, 1.08 mmol, 1 eq) in MeOH (8 mL) and the reaction mixture was stirred at room temperature under H2 balloon pressure for 16 hours. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad, and the filtrate was concentrated under reduced pressure to give (1-(1-(6,7-dimethoxyquinoline-4-yl)piperidin-4-yl)cyclopropyl)methylamine (04) (200 mg, yield: 16%, three steps) as a viscous liquid. TLC system MeOH: DCM (10: 90), R f值 :0.1; LCMS(m / z):342.3(M+H) + .

[0571] Synthesis of tert-butyl (N-((1-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)cyclopropyl)methyl)sulfamoyl)carbamate (05)

[0572]

[0573] To a stirred solution of (1-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)cyclopropyl)methanamine (04) (200 mg, 0.58 mmol, 1 eq) in DCM (2 mL) at 0 °C was added DIPEA (0.15 mL, 0.87 mmol, 1.5 eq) and (tert-butyloxycarbonyl)((4-(dimethylimino)pyridin-1(4H)-yl)sulfonyl)amide (I-04-03) (208 g, 0.69 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was quenched with water and extracted with DCM (2×30 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure to give the crude compound. The crude compound was purified by silica gel (100-200 mesh) column chromatography [eluted with 3% MeOH / DCM) to give tert-butyl (N-((1-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)cyclopropyl)methyl)sulfamoyl)carbamate (05) (180 mg). TLC system MeOH:DCM (10:90), R f Value: 0.6; LCMS (m / z): 521.4 (M+H) + ; 57% purity.

[0574] Synthesis of N-(N-((1-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)cyclopropyl)methyl)sulfamoyl)acetamide formate (I-22)

[0575]

[0576] To a stirred solution of tert-butyl (N-((1-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)cyclopropyl)methyl)sulfamoyl)carbamate (05) (180 mg, 57% purity; 0.34 mmol, 1 eq) in 1,4-dioxane (0.5 mL) at 0°C was added dioxane (2 mL) containing 4M HCl. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction by TLC, the volatiles were evaporated and the crude compound was purified by reverse phase column chromatography [eluted with a 1-16% (0.1% FA / water+ACN) gradient to give N-(N-((1-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)cyclopropyl)methyl)sulfamoyl)acetamide formate (I-22) (45 mg, yield: 19%, two steps) as a white solid. TLC system MeOH:DCM (10:90), R f Value: 0.3; LCMS (m / z): 421.3 (M+H) + ; 1 HNMR (400 MHz, DMSO-d6) δ8.47 (d, J=4.8 Hz, 1H), 8.19 (formate proton), 7.29 (s, 1H), 7.18 (s, 1H), 6.83 (d, J=5.2 Hz, 1H), 6.48–6.45 (m, 3H), 3.90 (s, 6H), 3.54–3.41 (m, 2H), 2.89 (d, J=6.4 Hz, 2H), 2.68 (t, J=11.2 Hz, 2H), 1.77–1.74 (m, 2H), 1.64–1.56 (m, 2H), 1.52–1.49 (m, 1H), 0.41 (s, 4H).

[0577] Synthesis of I-23:

[0578] Synthesis of tert-butyl (1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)carbamate (01)

[0579]

[0580] To a stirred solution of 4-chloro-6,7-dimethoxyquinoline (1) (1 g, 4.49 mmol, 1 equivalent) in 1,4-dioxanes (10 mL), piperidin-4-ylcarbamic acid tert-butyl ester (2) (1.07 g, 5.38 mmol, 1.2 equivalents) was added, and degassed for 10 minutes. Then CsCO (4.37 g, 13.4 mmol, 3 equivalents), Pd(dba) (0.41 g, 0.449 mmol, 0.1 equivalents), X-Phos (0.44 g, 0.89 mmol, 0.2 equivalents) were added. The reaction mixture was stirred in a sealed tube at 110 ° C for 16 hours. After the reaction was completed by TLC, the reaction mixture was filtered through a diatomaceous earth pad and the filtrate was concentrated to obtain a crude product. The crude compound was purified by silica gel (100-200) column chromatography [eluted with 3% MeOH / DCM] to give tert-butyl (1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)carbamate (01) (0.6 g, yield: 35%) as a yellow solid. TLC system MeOH:DCM (10:90), R f Value: 0.3; LCMS (m / z): 388.3 (M+H) + . 1 HNMR(400MHz,DMSO-d6)δ8.48(d,J=5.2Hz,1H),7.36(s,1H),7.14(s,1H),6.94–6.93(m,1H),6.72(d,J=5.2Hz,1H),3. 90(s,6H),3.46–3.43(m,2H),2.87–2.80(m,2H),2.38–2.32(m,1H),1.96–1.93(m,2H),1.74–1.71(m,2H),1.40(s,9H).

[0581] Synthesis of 1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-amine.HCl(02)

[0582]

[0583] To a solution of tert-butyl (1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)carbamate (01) (600 mg, 0.645 mmol, 1 eq) in 1,4-dioxane (2 mL) at 0°C was added 4M HCl in dioxane (6 mL) and stirred at room temperature for 2 hours. After completion of the reaction by TLC, the volatiles were evaporated and the obtained crude product was purified by trituration with diethyl ether to give 1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-amine hydrochloride (02) (400 mg) as a white solid. TLC system MeOH:DCM (10:90), Rf Value: 0.1; LCMS (m / z): 288.2 (M+H) + ; 63% purity.

[0584] Synthesis of tert-butyl (N-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)sulfamoyl)carbamate (03)

[0585]

[0586] To a stirred solution of 1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-hydrochloride amine (02) (400 mg, 1.23 mmol, 1.0 equiv) in DCM (10 mL) at 0 °C was added DIPEA (0.34 mL, 1.84 mmol, 1.5 equiv) and (tert-butyloxycarbonyl)((4-(dimethylimino)pyridin-1(4H)-yl)sulfonyl)amide (I-04-03) (444 mg, 1.47 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was diluted with water and extracted with DCM (2×25 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The crude compound was purified by reverse phase Grace purification [eluted with 0-50% (0.05% FA / H2O) / ACN gradient] to give tert-butyl (N-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)sulfamoyl)carbamate (03) (150 mg, yield: 26%) as a yellow solid. TLC system MeOH:DCM (10:90), R f Value: 0.4; LCMS (m / z): 467.3 (M+H) + .

[0587] Synthesis of N-(N-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)thiodiamide formate (I-23)

[0588]

[0589] To a solution of tert-butyl (N-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)sulfamoyl)carbamate (03) (150 mg, 0.32 mmol, 1 eq) in 1,4-dioxane (1 mL) at 0°C was added 4M dioxane in HCl (2 mL) and stirred at room temperature for 2 hours. After completion of the reaction by TLC, the volatiles were evaporated and the obtained crude compound was purified by reverse phase Grace column [eluted with 10-50% (0.01% FA / H2O) / ACN gradient] to give N-(N-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)sulfodiamide formate (I-23) (49 mg, yield: 42%) as a white solid. TLC system MeOH:DCM (10:90), R f Value: 0.2; LCMS (m / z): 367.2 (M+H) + , 1 HNMR (400 MHz, DMSO-d6) δ8.49 (d, J=5.2 Hz, 1H), 8.14 (formate proton), 7.33 (s, 1H), 7.15 (s, 1H), 6.91 (d, J=5.2 Hz, 1H), 6.70 (d, J=7.2 Hz, 1H), 6.57 (s, 2H), 3.92 (s, 6H), 3.55–3.52 (m, 2H), 3.36–3.31 (m, 1H), 2.96–2.92 (m, 2H), 2.12–2.09 (m, 2H), 1.79–1.72 (m, 2H).

[0590] Synthesis of I-24:

[0591] Synthesis of 8-(6,7-dimethoxyquinolin-4-yl)-1,4-dioxa-8-azaspiro[4.5]decane(01)

[0592]

[0593] 1,4-dioxa-8-azaspiro [4.5] decane (2) (1.5 g, 10.7 mmol, 1.2 equiv.), Cs2CO3 (8.7 g, 26.7 mmol, 3 equiv.) were added to a stirred solution of 4-chloro-6,7-dimethoxyquinoline (1) (2 g, 8.92 mmol, 1 equiv.) in 1,4-dioxane (20 mL), and degassed for 10 minutes. Subsequently, X-Phos (850 mg, 1.78 mmol, 0.2 equiv.), Pd2(dba)3 (816 mg, 0.89 mmol, 0.1 equiv.) were added. The resulting mixture was stirred in a sealed tube at 120 ° C for 16 hours. After completion of the reaction by TLC, the reaction mixture was filtered through a pad of celite, washed with ethyl acetate and concentrated to provide a crude product. The crude compound was purified by silica gel (100-200 mesh) column chromatography [eluted with 5% MeOH / DCM] to give 8-(6,7-dimethoxyquinolin-4-yl)-1,4-dioxa-8-azaspiro[4.5]decane (01) (2 g, yield: 68%) as a brown solid. TLC system: MeOH:DCM (10:90), R f Value: 0.3; LCMS (m / z): 331.3 (M+H) + ; 1 HNMR(400MHz, CDCl3)δ8.55(d,J=5.2Hz,1H),7.43(s,1H),7.24(s,1H),6.81(d,J=5.2Hz,1H ),4.04–4.01(m,4H),3.99(s,3H),3.98(s,3H),3.31(t,J=5.2Hz,4H),2.01(t,J=5.6Hz,4H).

[0594] Synthesis of 1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-one (02)

[0595]

[0596] 3N HCl aqueous solution (10 mL) was added to a stirred solution of 8-(6,7-dimethoxyquinoline-4-yl)-1,4-dioxa-8-azaspiro[4.5]decane (01) (2 g, 6.06 mmol, 1 equiv) in methanol (20 mL). The reaction mixture was stirred at 70 ° C for 16 hours. After completion of the reaction by TLC, the reaction mixture was alkalized with saturated NaHCO3 aqueous solution and extracted with EtOAc (3×60 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate and concentrated to give a crude product. The crude compound was purified by silica gel (100-200 mesh) column chromatography [eluted with 5% MeOH / DCM] to give 1-(6,7-dimethoxyquinoline-4-yl)piperidin-4-one (02) (1.2 g, yield: 70%) as a yellow solid. TLC system MeOH: DCM (10: 90), R f Value: 0.5; LCMS (m / z): 287.3 (M+H) + ; 1 HNMR(400MHz,DMSO-d6)δ8.51(d,J=4.8Hz,1H),7.34(s,1H),7.29(s,1H),6.93(d,J =4.8Hz,1H),3.94(s,3H),3.91(s,3H),3.46(t,J=6.0Hz,4H),2.0(t,J=6.0Hz,4H).

[0597] Synthesis of N-cyclopropyl-1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-amine (03)

[0598]

[0599] Cyclopropylamine (3) (0.4 mL, 6.29 mmol, 1.5 equiv) and titanium isopropoxide (2.5 mL, 8.39 mmol, 2 equiv) were added to a stirred solution of 1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-one (02) (1.2 g, 4.19 mmol, 1 equiv) in methanol (12 mL) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours. After 16 hours, sodium cyanoborohydride (394 mg, 6.29 mmol, 1.5 equiv) was added at 0 °C, and stirring was continued at room temperature for 5 hours. After completion of the reaction by TLC, the reaction mixture was diluted with ice-cold water and extracted with EtOAc (2 × 100 mL). The combined organic layer was washed with brine (80 mL), dried over sodium sulfate and concentrated to give a crude product. The crude compound was purified by silica gel (100-200 mesh) column chromatography [eluted with 8% MeOH / DCM] to give N-cyclopropyl-1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-amine (03) (350 mg, yield: 26%) as a light yellow viscous material. TLC system MeOH: DCM (10:90), R f Value: 0.3; LCMS (m / z): 328.3 (M+H) + ; 1 HNMR (400MHz, DMSO-d6) δ8.47 (d, J = 4.8 Hz, 1H), 7.29 (s, 1H), 7.16 (s, 1H), 6.85 (d, J = 5.2 Hz, 1H), 3.90 (s, 6H), 3.46–3.43 (m, 2H), 2.84–2.74 (m, 3H), 2.17–2.15 (m, 1H), 2.07–2.04 (m, 2H), 1.65–1.56 (m, 2H), 0.43–0.39 (m, 2H), 0.27–0.24 (m, 2H). The NH protons are not clearly visible in the spectrum.

[0600] Synthesis of tert-butyl (N-cyclopropyl-N-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)sulfamoyl)carbamate (04)

[0601]

[0602] To a stirred solution of N-cyclopropyl-1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-amine (03) (350 mg, 1.07 mmol, 1.0 equiv) in DCM (5 mL) at 0 °C was added DIPEA (0.2 mL, 1.60 mmol, 1.5 equiv) and (tert-butyloxycarbonyl)((4-(dimethylimino)pyridin-1(4H)-yl)sulfonyl)amide (I-04-03) (386 mg, 1.28 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was diluted with water and extracted with DCM (2×30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The crude compound was purified by silica gel (100-200 mesh) column chromatography [eluted with 5% MeOH / DCM] to give tert-butyl (N-cyclopropyl-N-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)sulfamoyl)carbamate (04) (200 mg) as an off-white solid. TLC system MeOH:DCM (5:95), R f Value: 0.5; LCMS (m / z): 507.3 (M+H) + .

[0603] Synthesis of N-(N-cyclopropyl-N-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)thiodiamide formate (I-24)

[0604]

[0605] To a stirred solution of tert-butyl (N-cyclopropyl-N-(1-(6,7-dimethoxyquinoline-4-yl)piperidin-4-yl)sulfamoyl)carbamate (04) (200 mg, 0.39 mmol, 1 eq) in 1,4-dioxane at 0 ° C, dioxane (2 mL) containing 4M HCl was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction by TLC, the reaction mixture was evaporated under reduced pressure to give a crude product. The crude product was purified by preparative HPLC to give N-(N-cyclopropyl-N-(1-(6,7-dimethoxyquinoline-4-yl)piperidin-4-yl)thiodiamide formate (I-24) (55 mg, yield: 41%) as an off-white solid. TLC system MeOH: DCM (10: 90), R f Value: 0.1; LCMS (m / z): 407.2 (M+H) + ; 1HNMR (400 MHz, DMSO-d6) δ8.53 (brs, 1H), 8.15 (formate proton), 7.33 (br, 1H), 7.19 (br, 1H), 6.95 (br, 1H), 6.90 (s, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 3.85–3.79 (m, 1H), 3.71–3.68 (m, 2H), 2.91 (t, J=12 Hz, 2H), 2.35–2.34 (m, 1H), 2.23–2.15 (m, 2H), 2.00–1.97 (m, 2H), 0.81–0.74 (m, 4H).

[0606] Synthesis of I-25:

[0607] Synthesis of 2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)butyronitrile (01)

[0608]

[0609] K2CO3 (0.98 g, 7.14 mmol, 4 equiv) and 2-(piperidin-4-yl)butyronitrile hydrochloride (I-13-04) (402 mg, 2.14 mmol, 1.2 equiv) were added to a stirred solution of 4-chloro-6,7-dimethoxyquinazoline (1) (400 mg, 1.78 mmol, 1.0 equiv) in DMF (4 mL) at 0 ° C. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was quenched with ice water and extracted with EtOAc (2 × 50 mL). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure to give a crude product. The crude compound was purified by silica gel column chromatography [eluted with 53% EtOAc / hexane] to give 2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)butanenitrile (01) (500 mg, yield: 82%) as a colorless liquid. TLC system 80% EtOAc: Hexane (80:20), R f Value: 0.5; LCMS (m / z): 341.3 (M+H) + ; 1 HNMR(400MHz, CDCl3)δ8.67(s,1H),7.25(s,1H),7.09(s,1H),4.25-4.19(m,2H),4.03(s,3H),4.00(s,3H),3.07 –3.00(m,2H),2.50-2.48(m,1H),2.05–2.04(m,1H),1.89–1.82(m,2H),1.77–1.68(m,4H),1.15(t,J=7.2Hz,3H).

[0610] Synthesis of 2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)butan-1-amine (02)

[0611]

[0612] To a stirred solution of 2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)butyronitrile (01) (500 mg, 1.64 mmol, 1 eq) in methanol (10 mL) containing 7M NH3 was added Raney Ni (1.0 g). The reaction mixture was stirred at room temperature under H2 balloon pressure for 16 hours. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad and concentrated to give 2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)butan-1-amine (02) (350 mg, yield: 69%) as an off-white solid. TLC system MeOH: DCM (10: 90), R f Value: 0.1; LCMS (m / z): 345.4 (M+H) + ; 1 HNMR(400MHz,DMSO-d6)δ8.52(s,1H),8.01–7.95(br,2H),7.20(s,1H),7.11(s,1H),4.23–4.20(m,2H),3.93(s,3H),3.91(s,3H),3.0 5–2.99(m,2H),2.88–2.83(m,1H),2.74–2.73(m,1H),1.76–1.68(m,3H),1.53–1.44(m,4H),1.35–1.33(m,1H),0.89(d,J=7.2Hz,3H).

[0613] Synthesis of tert-butyl (N-(2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)butyl)sulfamoyl)carbamate (03)

[0614]

[0615] To a stirred solution of 2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)butan-1-amine (02) (350 mg, 1.02 mmol, 1 eq.) in DCM (7 mL) was added DIPEA (0.26 mL, 1.53 mmol, 1.5 eq.), (tert-butyloxycarbonyl)((4-(dimethylimino)pyridin-1(4H)-yl)sulfonyl)amide (I-04-03) (367 mg, 1.22 mmol, 1.2 eq.). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched with water and extracted with DCM (2×30 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The crude compound was purified by silica gel (100-200 mesh) column chromatography [eluted with 3% MeOH / DCM] to give tert-butyl (N-(2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)butyl)sulfamoyl)carbamate (03) (250 mg, yield: 46%) as an off-white solid. TLC system MeOH:DCM (10:90), R f Value: 0.4; LCMS (m / z): 524.4 (M+H) + .

[0616] Synthesis of N-(N-(2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)butyl)thiodiamide formate (I-25)

[0617]

[0618] A solution of tert-butyl (N-(2-(1-(7-methoxyquinazolin-4-yl)piperidin-4-yl)butyl)sulfamoyl)carbamate (03) (250 mg, 0.48 mmol, 1 eq) in dioxane (2.5 mL) containing 4M HCl was stirred at room temperature for 2 hours and then at 0°C for 15 minutes. After completion of the reaction by TLC, the volatiles were evaporated and the crude compound was purified by reverse phase column chromatography [eluted with 23% (0.1% FA / water + ACN)] to give N-(N-(2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)butyl)sulfodiamide formate (I-25) (30 mg, yield: 27%) as an off-white solid. TLC system MeOH:DCM (10:90), R f Value: 0.3; LCMS (m / z): 424.3 (M+H) + ; 1HNMR (400 MHz, DMSO-d6) δ8.51 (s, 1H), 8.16 (formate proton), 7.19 (s, 1H), 7.12 (s, 1H), 6.46 (s, 2H), 6.38 (t, J = 6.4 Hz, 1H), 4.22–4.19 (m, 2H), 3.92 (s, 3H), 3.90 (s, 3H), 3.02–2.93 (m, 2H), 2.90–2.82 (m, 2H), 1.74–1.71 (m, 3H), 1.49–1.27 (m, 5H), 0.88 (t, J = 7.2 Hz, 3H).

[0619] Synthesis of I-26:

[0620] Synthesis of 2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)-2-methylpropionitrile (01)

[0621]

[0622] To a stirred solution of 4-chloro-6,7-dimethoxyquinazoline (1) (300 mg, 1.33 mmol, 1 eq.) in IPA (3 mL) at 0 ° C, DIPEA (0.6 mL, 3.34 mmol, 2.5 eq.), 2-methyl-2-(piperidin-4-yl)propionitrile HCl (I-14-02) (247 mg, 1.60 mmol, 1.2 eq.) and a catalytic amount of DMF were added. The reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction by TLC, the reaction mixture was diluted with ice-cold water and extracted with EtOAC (2 × 50 mL). The combined organic layer was washed with brine (30 mL), dried over sodium sulfate and concentrated to give a crude product. The crude product was purified by silica gel (100-200) column purification [eluted with 4% MeOH / DCM] to give 2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)-2-methylpropanenitrile (01) (0.45 g, yield: 90%) as an off-white solid. TLC system MeOH: DCM (10:90), R f Value: 0.4; LCMS (m / z): 341.2 (M+H) + .

[0623] Synthesis of 2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)-2-methylpropan-1-amine (02)

[0624]

[0625] Ra-Ni (1 g) was added to a stirred solution of 2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)-2-methylpropionitrile (01) (450 mg, 1.32 mmol, 1 eq) in methanol (5 mL) containing 7N NH. The reaction mixture was stirred at room temperature under H2 balloon pressure for 16 hours. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad and concentrated to give 2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)-2-methylpropan-1-amine (02) (240 mg, yield: 52%) as an off-white solid. TLC system MeOH: DCM (10: 90), R f Value: 0.1; 1 HNMR(400MHz,DMSO-d6)δ8.52(s,1H),7.83(brs,2H),7.20(s,1H),7.13(s,1H),4.25–4.22(m,2H),3.92( s,3H),3.91(s,3H),2.99(t,J=12Hz,2H),2.73(s,2H),1.75–1.73(m,2H),1.55–1.44(m,3H),0.93(s,6H).

[0626] Synthesis of tert-butyl (N-(2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)-2-methylpropyl)sulfamoyl)carbamate (03)

[0627]

[0628] To a stirred solution of 2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)-2-methylpropan-1-amine (02) (240 mg, 0.69 mmol, 1.0 equiv) in DCM (5 mL) at 0 °C was added DIPEA (0.18 mL, 1.04 mmol, 1.5 equiv) and (tert-butyloxycarbonyl)((4-(dimethylimino)pyridin-1(4H)-yl)sulfonyl)amide (I-04-03) (252 mg, 0.83 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was diluted with water and extracted with DCM (2×20 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel (100-200) column purification [eluted with 5% MeOH / DCM] to give tert-butyl (N-(2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)-2-methylpropyl)sulfamoyl)carbamate (03) (180 mg, yield: 27%) as a white solid. TLC system MeOH:DCM (5:95), R f Value: 0.5; LCMS (m / z): 524.3 (M+H) + ; 1 HNMR(400MHz,DMSO-d6)δ10.79(brs,1H),8.51(s,1H),7.43(brs,1H),7.19(s,1H),7.12(s,1H),),4.24–4.21(m,2H),3.92(s,3H),3.90 (s,3H),2.97(t,J=12Hz,2H),2.78(d,J=6.8Hz,2H),1.75–1.72(m,2H),1.57–1.54(m,1H),1.43(s,9H),1.42–1.41(m,2H),0.84(s,6H).

[0629] Synthesis of N-(2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)-2-methylpropyl)thiodiamide formate (I-26)

[0630]

[0631] To a stirred solution of tert-butyl (N-(2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)-2-methylpropyl)sulfamoyl)carbamate (03) (180 mg, 0.34 mmol, 1 eq) in 1,4-dioxane (1 mL) at 0 ° C, dioxane (3 mL) containing 4M HCl was added dropwise. The reaction was stirred at room temperature for 2 hours. After completion of the reaction by TLC, the reaction mixture was concentrated to give a crude product. The crude product was purified by preparative HPLC to give N-(2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)-2-methylpropyl)sulfodiamide formate (I-26) (33 mg, yield: 22%) as an off-white solid. TLC system MeOH: DCM (10: 90), R f Value: 0.5; LCMS (m / z): 424.3 (M+H) + ; 1 HNMR (400 MHz, DMSO-d6) δ8.51 (s, 1H), 8.13 (formate proton), 7.19 (s, 1H), 7.12 (s, 1H), 6.45 (s, 2H), 6.38 (t, J = 6.8 Hz, 1H), 4.25–4.22 (m, 2H), 3.92 (s, 3H), 3.91 (s, 3H), 2.98 (t, J = 12 Hz, 2H), 2.75 (t, J = 6.8 Hz, 2H), 1.78–1.75 (m, 2H), 1.56–1.53 (m, 1H), 1.44–1.38 (m, 2H), 0.84 (s, 6H).

[0632] Synthesis of I-27:

[0633] Synthesis of 1-(pyridin-4-yl)cyclopropane-1-carboxylic acid ethyl ester (01)

[0634]

[0635] To a stirred solution of ethyl 2-(pyridin-4-yl)acetate (1) (10 g, 60.56 mmol, 1 eq) in THF:DMF (1:1) (200 mL) cooled to 0 ° C, NaH (60%) (12.1 g, 303 mmol, 5 eq) was added and stirred at 0 ° C for 30 minutes. Subsequently, 1,2-dibromoethane (15.7 mL, 181.68 mmol, 3 eq) was added to allow it to reach room temperature and continued to stir for 3.5 hours. After completion of the reaction by TLC, the reaction mixture was quenched with ice-cold water and extracted with EtOAc (2 × 200 mL). The combined organic layer was washed with brine (80 mL), dried over sodium sulfate and concentrated under reduced pressure to give a crude product. The crude compound was purified by silica gel (100-200 mesh) column chromatography [eluted with DCM] to give ethyl 1-(pyridin-4-yl)cyclopropane-1-carbamate (01) (8.5 g, yield: 74%) as a brown solid. TLC system: EtoAc: Hexane (30:70), R f Value: 0.4; LCMS (m / z): 192.2 (M+H) + ; 1 HNMR (400MHz, CDCl3) δ8.54(dd,J=4.4Hz,1.6Hz,2H),7.25(dd,J=4.4Hz,1.6Hz,2H),4.12(q,J=7.2Hz,2H),1.66–1.63(m,2H),1.21–1.18(m,5H).

[0636] Synthesis of 1-(piperidin-4-yl)cyclopropane-1-carboxylic acid ethyl ester (02)

[0637]

[0638] PtO2 (2 g) was added to a stirred solution of ethyl 1-(pyridin-4-yl)cyclopropane-1-carboxylate (01) (8.5 g, 44.5 mmol, 1 eq) in AcOH (85 mL) and stirred at room temperature under H2 balloon pressure for 16 h. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad, washed with DCM, and concentrated under reduced pressure to give ethyl 1-(piperidin-4-yl)cyclopropane-1-carboxylate (02) (7.5 g, yield: 86%) as a black liquid. TLC system: MeOH: DCM (10: 90), R f Value: 0.1; 1HNMR (400MHz, CDCl3) δ4.11 (q, J = 7.2Hz, 2H), 3.43–3.40 (m, 2H), 2.81–2.78 (m, 2H), 1.78–1.77 (m, 4H), 1.27–1.18 (m, 6H), 0.78–0.76 (m, 2H).

[0639] Synthesis of 1-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)cyclopropane-1-carboxylic acid ethyl ester (03)

[0640]

[0641] 1-(piperidin-4-yl)cyclopropane-1-carboxylic acid ethyl ester (02) (3.28 g, 16.74 mmol, 1.5 eq) and K2CO3 (7.7 g, 55.8 mmol, 5 eq) were added to a stirred solution of 4-chloro-6,7-dimethoxyquinazoline (2) (2.5 g, 11.16 mmol, 1 eq) in DMF (25 mL) cooled to 0 ° C. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed by TLC, the reaction mixture was poured into ice-cold water, the precipitated solid was filtered, and dried under vacuum to give 1-(1-(6,7-dimethoxyquinazoline-4-yl)piperidin-4-yl)cyclopropane-1-carboxylic acid ethyl ester (03) (2 g, yield: 46%) as an off-white solid. TLC system: MeOH: DCM (10: 90), R f Value: 0.4; LCMS (m / z): 386.3 (M+H) + ; 1 HNMR(400MHz,DMSO-d6)δ8.51(s,1H),7.20(s,1H),7.10(s,1H),4.22–4.19(m,2H),4.03(q,J=7.2Hz,2H),3.92(s,3 H), 3.90 (s, 3H), 2.99–2.97 (m, 2H), 1.73–1.71 (m, 5H), 1.14 (t, J = 7.2Hz, 3H), 1.06–1.03 (m, 2H), 0.87–0.85 (m, 2H).

[0642] Synthesis of (1-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)cyclopropyl)methanol (04)

[0643]

[0644] To a stirred solution of ethyl 1-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)cyclopropane-1-carboxylate (03) (2 g, 5.19 mmol, 1 eq) in THF (20 mL) at -78 °C was added 1.0 M LAH in THF (10.3 mL, 10.3 mmol, 2 eq). The reaction mixture was stirred at -78 °C to 0 °C for 2 hours. After completion of the reaction by TLC, the reaction mixture was quenched with saturated NH4Cl solution and extracted with EtOAc (2×80 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure to give (1-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)cyclopropyl)methanol (04) (1.3 g, yield: 73%) as a colorless liquid. TLC system MeOH: DCM (10:90), R f Value: 0.3; LCMS (m / z): 344.3 (M+H) + . 1 HNMR(400MHz, DMSO-d6)δ8.50(s,1H),7.19(s,1H),7.11(s,1H),4.41(t,J=5.6Hz,1H),4.23–4.20(m,2H),3.92(s,3H),3 .90(s,3H),3.31–3.30(m,2H),2.96–2.90(m,2H),1.75–1.72(m,2H),1.59–1.52(m,2H),1.48–1.44(m,1H),0.33(m,4H).

[0645] Synthesis of 4-(4-(1-(azidomethyl)cyclopropyl)piperidin-1-yl)-6,7-dimethoxyquinazoline (05)

[0646]

[0647] DBU (2.2 mL, 14.8 mmol, 4 equiv.), DPPA (2.54 mL, 11.1 mmol, 3 equiv.) were added to a stirred solution of (1-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)cyclopropyl)methanol (04) (1.3 g, 3.70 mmol, 1 equiv.) in THF (13 mL) cooled to 0 ° C. The reaction mixture was stirred at room temperature for 48 hours. After completion of the reaction, the reaction mixture was quenched with NaHCO3 aqueous solution and extracted with EtOAc (2×70 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure to give a crude product. The crude compound was purified by silica gel (100-200 mesh) column chromatography [eluted with 2% MeOH / DCM] to give 4-(4-(1-(azidomethyl)cyclopropyl)piperidin-1-yl)-6,7-dimethoxyquinazoline (05) (900 mg, yield: 75%) as a colorless viscous liquid. TLC system MeOH:DCM (10:90), R f Value: 0.7; LCMS (m / z): 369.3 (M+H) + . 1 HNMR(400MHz, CDCl3)δ8.65(s,1H),7.23(s,1H),7.10(s,1H),4.27–4.24(m,2H),4.02(s,3H),4.00(s,3H), 3.24(s,2H),3.03–2.96(m,2H),1.86–1.83(m,2H),1.71–1.67(m,2H),1.46–1.42(m,1H),0.57-0.50(m,4H).

[0648] Synthesis of (1-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)cyclopropyl)methylamine (06)

[0649]

[0650] 10% Pd / C (300 mg) was added to a stirred solution of 4-(4-(1-(azidomethyl)cyclopropyl)piperidin-1-yl)-6,7-dimethoxyquinazoline (05) (900 mg, 3.35 mmol, 1 equivalent) in MeOH (9 mL). The reaction mixture was stirred at room temperature under H2 balloon pressure for 16 hours. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad, washed with methanol, and concentrated under reduced pressure to give (1-(1-(6,7-dimethoxyquinazoline-4-yl)piperidin-4-yl)cyclopropyl)methylamine (06) (500 mg) as a viscous liquid. TLC system MeOH: DCM (10: 90), R fValue: 0.1; LCMS (m / z): 343.3 (M+H) + .

[0651] Synthesis of tert-butyl (N-((1-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)cyclopropyl)methyl)sulfamoyl)carbamate (07)

[0652]

[0653] To a stirred solution of (1-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)cyclopropyl)methanamine (06) (300 mg, 0.87 mmol, 1 eq) in DCM (6 mL) at 0 °C was added DIPEA (0.24 mL, 1.31 mmol, 1.5 eq) and (tert-butyloxycarbonyl)((4-(dimethylimino)pyridin-1(4H)-yl)sulfonyl)amide (I-04-03) (314 mg, 1.04 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was quenched with water and extracted with DCM (2×30 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure to give the crude compound. The crude compound was purified by using silica gel (100-200 mesh) column chromatography [eluted with 5% MeOH / DCM) to give tert-butyl (N-((1-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)cyclopropyl)methyl)sulfamoyl)carbamate (07) (180 mg, yield: 39%). TLC system MeOH:DCM (10:90), R f Value: 0.5; LCMS (m / z): 522.3 (M+H) + .

[0654] Synthesis of N-(N-((1-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)cyclopropyl)methyl)thiodiamide formate (I-27)

[0655]

[0656] To a stirred solution of tert-butyl (N-((1-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)cyclopropyl)methyl)sulfamoyl)carbamate (07) (180 mg, 0.34 mmol, 1 eq) in 1,4-dioxane (0.5 mL) at 0 ° C., dioxane (2 mL) containing 4M HCl was added. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction by TLC, the volatiles were evaporated, and the obtained material was purified by reverse phase column chromatography [eluted with 20% (0.1% FA / water + ACN) to give N-(N-((1-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)cyclopropyl)methyl)sulfodiamide formate (I-27) (45 mg, yield: 31%) as a white solid. TLC system MeOH: DCM (10: 90), R f Value: 0.3; LCMS (m / z): 422.3 (M+H) + ; 1 HNMR (400 MHz, DMSO-d6) δ8.50 (s, 1H), 8.26 (formate proton), 7.19 (s, 1H), 7.11 (s, 1H), 6.49–6.46 (m, 3H), 4.22–4.19 (m, 2H), 3.92 (s, 3H), 3.91 (s, 3H), 2.96–2.90 (m, 2H), 2.86–2.85 (m, 2H), 1.74–1.72 (m, 2H), 1.60–1.45 (m, 3H), 0.39–0.37 (m, 4H).

[0657] Synthesis of I-28:

[0658] Synthesis of 4-chloro-7-methoxyquinazolin-6-ol (01)

[0659]

[0660] Methanol (7mL) containing 7M ammonia is added to a stirred solution of 4-chloro-7-methoxyquinazoline-6-yl acetate (I-03-03) (700mg, 2.77mmol, 1 equivalent) in methanol (2mL) at 0°C. The reaction mixture is stirred at room temperature for 3 hours. After the reaction is completed by TLC, the reaction mixture is evaporated under reduced pressure to obtain a crude material, which is ground with pentane to obtain 4-chloro-7-methoxyquinazoline-6-ol (01) (500mg, yield: 85%) as an off-white solid. TLC system: EtOAc, R f Value: 0.5; LCMS (m / z): 211.1 (M+H) + ; 1HNMR (400MHz, DMSO-d6) δ10.79–10.76(br,1H),8.82(s,1H),7.43(s,1H),7.41(s,1H),4.02(s,3H).

[0661] Synthesis of 4-chloro-7-methoxy-6-(methoxymethoxy)quinazoline (02)

[0662]

[0663] TEA (1.6 mL, 11.9 mmol, 5 equiv) and MOM-Cl (0.7 mL, 9.52 mmol, 4 equiv) were added to a stirred solution of 4-chloro-7-methoxyquinazoline-6-ol (01) (500 mg, 2.38 mmol, 1 equiv) in DCM (5 mL) at 0 ° C. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was diluted with water and extracted with DCM (2 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material, which was ground with pentane to obtain 4-chloro-7-methoxy-6-(methoxymethoxy)quinazoline (02) (500 mg, yield: 82%) as an off-white solid. TLC system: EtOAc, R f Value: 0.7; 1 HNMR (400MHz, CDCl3) δ8.88(s,1H),7.78(s,1H),7.37(s,1H),5.43(s,2H),4.08(s,3H),3.58(s,3H).

[0664] Synthesis of tert-butyl 4-(1-cyanoethyl)piperidine-1-carboxylate (03)

[0665]

[0666] To a stirred solution of tert-butyl 4-(cyanomethyl)piperidine-1-carboxylate (I-13-02) (6 g, 26.7 mmol, 1 equivalent) in dry THF (30 mL) was added dropwise LDA (2M in THF) (20 mL, 40.0 mmol, 1.5 equivalents) at -78 ° C. The reaction was stirred at -78 ° C for 30 minutes, and THF (5 mL) containing methyl iodide (1.6 mL, 32.1 mmol, 1.2 equivalents) was added. Subsequently, the reaction mixture was stirred at 0 ° C for 2.5 hours. After the reaction was completed by TLC, the reaction mixture was quenched with saturated NH4Cl solution and extracted with EtOAc (2 × 100 mL). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure to give a crude product. The crude compound was purified by silica gel (100-200 mesh) column chromatography [eluted with 7% EtOAc / hexane] to give tert-butyl 4-(1-cyanoethyl)piperidine-1-carboxylate (03) (2 g, yield: 31%) as a sticky solid. TLC system EtoAc: Hexane (20:80; ninhydrin stain), R f Value: 0.5; 1 HNMR (400MHz, CDCl3) δ4.19–4.13(m,2H),2.71–2.65(m,2H),2.56–2.49(m,1H),1.87–1.83(m,1 H),1.73–1.70(m,1H),1.61–1.59(m,1H),1.46(s,9H),1.31(d,J=4.0Hz,3H),1.29–1.26(m,2H).

[0667] Synthesis of tert-butyl 4-(1-aminopropan-2-yl)piperidine-1-carboxylate (04)

[0668]

[0669] Raney Ni (4 g) was added to a stirred solution of tert-butyl 4-(1-cyanoethyl)piperidine-1-formate (03) (2 g, 8.36 mmol, 1 equivalent) in methanol (10 mL) containing 7 M ammonia. The reaction mixture was stirred at room temperature under H2 balloon pressure for 16 hours. After completion of the reaction by TLC, the reaction mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated under reduced pressure to give tert-butyl 4-(1-aminopropan-2-yl)piperidine-1-formate (04) (1.2 g, yield: 60%) as a colorless viscous liquid. TLC system EtOAc (ninhydrin staining), R f Value: 0.1; 1HNMR (400MHz, DMSO-d6) δ3.97–3.94 (m, 2H), 2.61–2.50 (m, 3H), 2.38–2.34 (m, 1H), 1.54–1.49 (m, 2H), 1.45–1.43 (m, 1H), 1.38 (s, 9H), 1.28–1.22 (m, 1H), 1.13–1.02 (m, 2H), 0.80 (d, J = 6.8 Hz, 3H). NH2 protons are not clearly visible in the spectrum.

[0670] Synthesis of tert-butyl 4-(1-((N-(tert-butyloxycarbonyl)sulfamoyl)amino)propan-2-yl)piperidine-1-carboxylate (05)

[0671]

[0672] To a stirred solution of tert-butyl 4-(1-aminopropan-2-yl)piperidine-1-carboxylate (04) (1.2 g, 4.95 mmol, 1 eq) in DCM (12 mL) at 0 °C was added DIPEA (1.3 mL, 7.43 mmol, 1.5 eq) and (tert-butyloxycarbonyl)((4-(dimethylimino)pyridin-1(4H)-yl)sulfonyl)amide (I-04-03) (1.79 g, 5.95 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was quenched with water and extracted with DCM (2×50 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The crude compound was purified by silica gel (100-200 mesh) column chromatography [eluted with 25% EtOAc / hexane] to give tert-butyl 4-(1-((N-(tert-butyloxycarbonyl)sulfamoyl)amino)propan-2-yl)piperidine-1-carboxylate (05) (800 mg, yield: 40%) as a colorless viscous liquid. TLC system MeOH:DCM (5:95:ninhydrin stain), R f Value: 0.4; 1 HNMR(400MHz, DMSO-d6)δ10.75(s,1H),7.53(t,J=5.6Hz,1H),3.97–3.94(m,2H),2.89–2.86(m,1H),2.73–2.70( m,2H),2.68–2.65(m,1H),1.58–1.48(m,4H),1.42(s,9H),1.38(s,9H),1.08–0.96(m,2H),0.79(d,J=6.8Hz,3H).

[0673] Synthesis of N-(N-(2-(Piperidin-4-yl)propyl)sulfuramide hydrochloride (06)

[0674]

[0675] To a stirred solution of tert-butyl 4-(1-((N-(tert-butyloxycarbonyl)sulfamoyl)amino)propan-2-yl)piperidine-1-carboxylate (05) (800 mg, 1.90 mmol, 1 eq) in 1,4-dioxane (2 mL) at 0°C was added 4M HCl in dioxane (4 mL) dropwise. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction by TLC, the reaction mixture was concentrated under reduced pressure to give N-(N-(2-(piperidin-4-yl)propyl)sulfodiamide hydrochloride (06) (340 mg, yield: 69%) as a viscous liquid. TLC system MeOH:DCM (10:90; ninhydrin stain), R f Value: 0.1; 1 HNMR(400MHz,DMSO-d6)δ8.87(brs,1H),8.61(brs,1H),6.51–6.47(br,3H),3.26–3.23 (m,2H),2.87–2.70(m,4H),1.69–1.66(m,2H),1.55–1.37(m,4H),0.81(d,J=6.8Hz,3H).

[0676] Synthesis of N-(N-(2-(1-(7-methoxy-6-(methoxymethoxy)quinazolin-4-yl)piperidin-4-yl)propyl)sulfuramide (I-28)

[0677]

[0678] To a stirred solution of 4-chloro-7-methoxy-6-(methoxymethoxy)quinazoline (02) (250 mg, 0.98 mmol, 1 eq.) in DMF (2.5 mL) at 0°C was added KCO (407 mg, 2.95 mmol, 3 eq.) and N-(N-(2-(piperidin-4-yl)propyl)sulfodiamide hydrochloride (06) (327 mg, 1.27 mmol, 1.3 eq.). The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was quenched with ice-cold water and washed with EtOAc (2×60 mL) was extracted. The combined organic layers were washed with brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to give a crude product. The crude compound was purified by reverse phase column [eluted with 1-19% water / ACN gradient] to give N-(N-(2-(1-(7-methoxy-6-(methoxymethoxy)quinazolin-4-yl)piperidin-4-yl)propyl)sulfuramide (I-28) (23 mg, yield: 5%) as an off-white solid. TLC system: MeOH:DCM (10:90), Rf Value: 0.4; LCMS (m / z): 440.3 (M+H) + ; 1 HNMR(400MHz,DMSO-d6)δ8.51(s,1H),7.44(s,1H),7.22(s,1H),6.46–6.44(m,3H),5.31(s,2H),4.22–4.19(m,2H),3.94 (s,3H),3.43(s,3H),3.03–2.90(m,3H),2.76–2.73(m,1H),1.72–1.58(m,4H),1.51–1.35(m,2H),0.87(d,J=6.8Hz,3H).

[0679] Synthesis of I-29:

[0680] Synthesis of tert-butyl (1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)carbamate (01)

[0681]

[0682] To a stirred solution of 4-chloro-6,7-dimethoxyquinazoline (1) (1 g, 4.64 mmol, 1 eq) in DMF (10 mL) at 0 ° C. K2CO3 (1.92 g, 13.92 mmol, 3 eq) and tert-butyl piperidin-4-ylcarbamate (2) (1 g, 5.35 mmol, 1.2 eq) were added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was diluted with water and extracted with ethyl acetate (2×70 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure to give a crude product. The crude product was purified by grinding with diethyl ether to give tert-butyl (1-(6,7-dimethoxyquinazoline-4-yl) piperidin-4-yl)carbamate (01) (1.45 g, yield: 88%) as a white solid. TLC system MeOH: DCM (5: 95), R f Value: 0.25; LCMS (m / z): 389.3 (M+H) + ; 1HNMR (400MHz, DMSO-d6) δ8.52(s,1H),7.20(s,1H),7.08(s,1H),6.92(d,J=7.6Hz,1H),4.11–4.07(m,2H),3.93(s ,3H),3.91(s,3H),3.57–3.75(m,1H),3.15(t,J=11.6Hz,2H),1.91–1.89(m,2H),1.64–1.54(m,2H),1.40(s,9H).

[0683] Synthesis of 1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-amine hydrochloride (02)

[0684]

[0685] To a stirred solution of tert-butyl (1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)carbamate (01) (1.0 g, 2.58 mmol, 1 eq) in 1,4-dioxane (2 mL) at 0°C was added 4M HCl in dioxane (10 mL) and stirred at room temperature for 2 hours. After completion of the reaction by TLC, the volatiles were evaporated and the obtained crude product was purified by trituration with diethyl ether to give 1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-amine hydrochloride (02) (700 mg, yield: 84%) as a white solid. TLC system MeOH:DCM (10:90), R f Value: 0.1; LCMS (m / z): 289.2 (M+H) + ; 1 HNMR(400MHz,DMSO-d6)δ8.80(s,1H),8.39(brs,3H),7.39(s,1H),7.29(s,1H),4.69–4.65 (m,2H),3.98(s,3H),3.96(s,3H),3.62–3.56(m,3H),2.19–2.16(m,2H),1.79–1.70(m,2H).

[0686] Synthesis of tert-butyl (N-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)sulfamoyl)carbamate (03)

[0687]

[0688] To a stirred solution of 1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-hydrochloride amine (02) (500 mg, 1.54 mmol, 1.0 equiv) in DCM (10 mL) at 0 °C was added DIPEA (0.43 mL, 2.31 mmol, 1.5 equiv) and (tert-butyloxycarbonyl)((4-(dimethylimino)pyridin-1(4H)-yl)sulfonyl)amide (I-04-03) (560 mg, 1.85 mmol, 1.2 equiv) and stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was diluted with water and extracted with DCM (2×30 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The crude compound was purified by silica gel (100-200 mesh) column chromatography [eluted with 3% MeOH+DCM] to give tert-butyl (N-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)sulfamoyl)carbamate (03) (410 mg, yield: 57%) as a yellow solid. TLC system MeOH:DCM (10:90), R f Value: 0.4; LCMS (m / z): 468.3 (M+H) + .

[0689] Synthesis of N-(N-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)thiodiamide formate (I-29)

[0690]

[0691] To a stirred solution of tert-butyl (N-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)sulfamoyl)carbamate (03) (400 mg, 1.08 mmol, 1 eq) in 1,4-dioxane (2 mL) at 0 °C was added 4M HCl in dioxane (4 mL) and stirred at room temperature for 3 hours. After completion of the reaction by TLC, the volatiles were evaporated and the obtained crude product was purified by preparative HPLC [FA method] to give N-(N-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)thiodiamide formate (I-29) (44 mg, yield: 12%) as a white solid. TLC system MeOH:DCM (10:90), R f Value: 0.2; LCMS (m / z): 368.3 (M+H) + , 1HNMR (400 MHz, DMSO-d6) δ8.52 (s, 1H), 8.14 (formate proton), 7.21 (s, 1H), 7.09 (s, 1H), 6.68 (d, J=7.2 Hz, 2H), 6.55 (s, 1H), 4.10–4.07 (m, 2H), 3.93 (s, 3H) 3.91 (s, 3H), 3.42–3.40 (m, 1H), 3.20–3.14 (m, 2H), 2.05–2.03 (m, 2H), 1.68–1.63 (m, 2H).

[0692] Synthesis of I-30:

[0693] Synthesis of Piperidin-4-one Hydrochloride (01)

[0694]

[0695] To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (1) (1.0 g, 5.02 mmol, 1 eq) in 1,4-dioxane (2 mL) at 0°C was added 4M HCl in dioxane (10 mL) and stirred at room temperature for 2 hours. After completion of the reaction by TLC, the volatiles were evaporated and the obtained crude product was purified by trituration with diethyl ether to give piperidine-4-one hydrochloride (01) (500 mg, yield: 99%) as a white solid. TLC system MeOH: DCM (10:90), R f Value: 0.1; 1 HNMR (400MHz, DMSO-d6) δ9.45 (brs, 2H), 3.39 (t, J = 6.4Hz, 4H), 2.58 (t, J = 6.4Hz, 4H).

[0696] Synthesis of 1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-one (02)

[0697]

[0698] To a stirred solution of piperidine-4-one hydrochloride (01) (500 mg, 2.23 mmol, 1 eq.) in DMF (5 mL) at 0 ° C., K2CO3 (923 mg, 6.69 mmol, 3 eq.) and 4-chloro-6,7-dimethoxyquinazoline (2) (360 mg, 2.67 mmol, 1.2 eq.) were added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was diluted with water and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure to give a crude product. The crude product was purified by grinding with diethyl ether to give 1-(6,7-dimethoxyquinazoline-4-yl)piperidin-4-one (02) (500 mg, yield: 78%) as a yellow solid. TLC system MeOH: DCM (5: 95), R f Value: 0.25; LCMS (m / z): 288.3 (M+H) + ; 1 HNMR (400MHz, DMSO-d6) δ8.57(s,1H),7.24(s,1H),7.23(s,1H),3.96(t,J=6.0Hz,4H),3.94(s,3H),3.93(s,3H),2.60(t,J=6.0Hz,4H).

[0699] Synthesis of N-cyclopropyl-1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-amine (03)

[0700]

[0701] Cyclopropylamine (3) (100 mg, 1.74 mmol, 1 equivalent), molecular sieves (1 g) and acetic acid (catalysis) were added to a stirred solution of 1- (6,7-dimethoxyquinazoline-4-yl) piperidine-4-one (02) (500 mg, 1.74 mmol, 1.0 equivalent) in MeOH (10 mL). The reaction mixture was stirred at room temperature for 30 minutes, and then NaCNBH3 (164 mg, 2.61 mmol, 1.5 equivalents) was added. The reaction mixture was stirred at room temperature for 5 hours. After the reaction was completed, the reaction mixture was filtered through a diatomaceous earth pad and washed with 5% MeOH + DCM. The filtrate was dried over sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by grinding with diethyl ether to obtain yellow viscous N-cyclopropyl-1- (6,7-dimethoxyquinazoline-4-yl) piperidine-4-amine (03) (400 mg, yield: 70%). TLC system MeOH:DCM (5:95), R f Value: 0.2; LCMS (m / z): 329.3 (M+H)+ .

[0702] Synthesis of tert-butyl(N-cyclopropyl-N-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)sulfamoyl)(04)

[0703]

[0704] To a stirred solution of N-cyclopropyl-1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-amine (03) (600 mg, 1.82 mmol, 1.0 equiv) in DCM (12 mL) at 0 °C was added DIPEA (0.49 mL, 2.74 mmol, 1.5 equiv) and (tert-butyloxycarbonyl)((4-(dimethylimino)pyridin-1(4H)-yl)sulfonyl)amide (I-04-03) (660 mg, 2.19 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was diluted with water and extracted with ethyl acetate (2×40 mL). The combined organic layers were washed with brine solution (20 mL), dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The crude compound was purified by silica gel (100-200 mesh) column [eluted with 0-4% MeOH+DCM gradient] to give tert-butyl (N-cyclopropyl-N-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)sulfamoyl)carbamate (04) (410 mg, yield: 44%) as a white solid. TLC system MeOH:DCM (10:90), R f Value: 0.4; LCMS (m / z): 508.3 (M+H) + , 1 HNMR(400MHz,DMSO-d6)δ11.13(s,1H),8.54(s,1H),7.22(s,1H),7.13(s,1H),4.29–4.26(m,2H),4.06–4.03(m,1H),3.93(s,3H),3.92 (s,3H),3.10–3.04(m,2H),2.43–2.42(m,1H),2.12–2.08(m,2H),1.90–1.87(m,2H),1.44(s,9H),0.85–0.83(m,2H),0.76–0.74(m,2H).

[0705] Synthesis of N-(N-cyclopropyl-N-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)sulfuramide (I-30)

[0706]

[0707] To a stirred solution of tert-butyl (N-cyclopropyl-N-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)sulfamoyl)carbamate (04) (200 mg, 0.39 mmol, 1 eq) in 1,4-dioxane (2 mL) cooled to 0 °C was added 4M HCl in dioxane (4 mL) and stirred at room temperature for 2 hours. After completion of the reaction by TLC, the volatiles were evaporated and the obtained crude product was purified by preparative HPLC (FA method) to give N-(N-cyclopropyl-N-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)sulfodiamide (I-30) (49 mg, yield: 28%) as a white solid. TLC system MeOH:DCM (10:90), R f Value: 0.2; LCMS (m / z): 408.3 (M+H) + , 1 HNMR(400MHz,DMSO-d6)δ8.54(s,1H),7.21(s,1H),7.13(s,1H),6.88(s,2H),4.29–4.26(m,2H),3.93(s,3H),3.92(s,3H ),3.89–3.86(m,1H),3.07(t,J=12.4Hz,2H),2.32–2.30(m,1H),2.09–2.03(m,2H),1.95–1.92(m,2H),0.76–0.70(m,4H).

[0708] Synthesis of I-31:

[0709] Synthesis of 1-(4-(6,7-dimethoxyquinolin-4-yl)piperazin-1-yl)cyclopropanecarbonitrile (01)

[0710]

[0711] In a sealed tube, 4-chloro-6,7-dimethoxyquinoline (1) (600 mg, 2.67 mmol, 1.0 eq) and 1-(piperazine-1-yl)cyclopropanecarbonitrile (I-32-02) (485 mg, 3.21 mmol, 1.2 eq) were added to a stirred solution of 1,4-dioxane (6 mL) CsCO (2.6 g, 8.03 mmol, 3.0 eq) and X-Phos (255 mg, 0.53 mmol, 0.2 eq) and degassed for 20 min. Subsequently, Pd(dba) (245 mg, 0.26 mmol, 0.1 eq) was added and heated to 110 °C and stirred for 16 h. After completion of the reaction by TLC, the reaction mixture was filtered through a bed of celite, washed with 10% MeOH:DCM, and concentrated to give a crude product. The crude compound was purified by silica gel (60-120 mesh) column [eluted with 0-2% MeOH / DCM gradient] to give 1-(4-(6,7-dimethoxyquinolin-4-yl)piperazin-1-yl)cyclopropanecarbonitrile (01) (500 mg, yield: 55%) as a brown viscous liquid. TLC system MeOH: DCM (10:90), R f Value: 0.4; LCMS (m / z): 339.3 (M+H) + ; 1 HNMR(400MHz, CDCl3)δ8.57(d,J=5.2Hz,1H),7.40(s,1H),7.28(s,1H),6.77(d,J=4.8Hz,1H),4 .04 and 4.03 (2s, 6H), 3.18 (brs, 4H), 3.02 (t, J = 4.8Hz, 4H), 1.31–1.28 (m, 2H), 1.14–1.11 (m, 2H).

[0712] Synthesis of (1-(4-(6,7-dimethoxyquinolin-4-yl)piperazin-1-yl)cyclopropyl)methylamine (02)

[0713]

[0714] Ra-Ni (250 mg) was added to a stirred solution of 1-(4-(6,7-dimethoxyquinoline-4-yl)piperazine-1-yl)cyclopropanecarbonitrile (01) (500 mg, 1.47 mmol, 1.0 equiv) in 7M ammonia in methanol (5 mL). The reaction mixture was stirred at room temperature under hydrogen balloon pressure for 16 hours. After completion of the reaction by TLC, the reaction mixture was filtered through a celite bed, washed with 10% MeOH:DCM, and the filtrate was evaporated under reduced pressure to give (1-(4-(6,7-dimethoxyquinoline-4-yl)piperazine-1-yl)cyclopropyl)methylamine (02) (300 mg, yield: 59%) as a brown liquid. TLC system MeOH:DCM (10:90), R f Value: 0.1; LCMS (m / z): 343.2 (M+H) + .

[0715] Synthesis of tert-butyl N-((1-(4-(6,7-dimethoxyquinolin-4-yl)piperazin-1-yl)cyclopropyl)methyl)sulfamoylcarbamate (03)

[0716]

[0717] To a stirred solution of (1-(4-(6,7-dimethoxyquinolin-4-yl)piperazin-1-yl)cyclopropyl)methanamine (02) (300 mg, 0.87 mmol, 1.0 equiv) in DCM (5 mL) at 0 °C was added DIPEA (0.23 mL, 1.31 mmol, 1.5 equiv) and (tert-butyloxycarbonyl)((4-(dimethylimino)pyridin-1(4H)-yl)sulfonyl)amide (I-04-03) (358 mg, 1.05 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was diluted with water and extracted with DCM (2×40 mL). The combined organic layers were dried over NaSO and concentrated to give the crude product. The crude product was purified by Grace reverse phase column chromatography [eluted with 0-20% ACN / 0.1% FA / water gradient] to give tert-butyl N-((1-(4-(6,7-dimethoxyquinolin-4-yl)piperazin-1-yl)cyclopropyl)methyl)sulfamoylcarbamate (03) (150 mg, yield: 32%) as a yellow viscous liquid. TLC system MeOH:DCM (10:90), R f Value: 0.5; LCMS (m / z): 522.3 (M+H) + .

[0718] Synthesis of N-((1-(4-(6,7-dimethoxyquinolin-4-yl)piperazin-1-yl)cyclopropyl)methyl)sulfonamide (I-31 as TFA salt)

[0719]

[0720] To a stirred solution of tert-butyl N-((1-(4-(6,7-dimethoxyquinolin-4-yl)piperazin-1-yl)cyclopropyl)methyl)sulfamoylcarbamate (03) (150 mg, 0.28 mmol, 1.0 equiv) in 1,4-dioxane (1 mL) at 0 ° C., dioxane (1.5 mL) containing 4M HCl was added and stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was evaporated under reduced pressure to give a crude product. The crude material was purified by preparative HPLC [using TFA buffer] to give N-((1-(4-(6,7-dimethoxyquinolin-4-yl)piperazin-1-yl)cyclopropyl)methyl)sulfodiamide as a gray-white solid as TFA salt (I-31) (11 mg, yield: 9%). TLC system MeOH: DCM (10: 90), R f Value: 0.2; LCMS (m / z): 422.3 (M+H) + ; 1 HNMR(400MHz,DMSO)δ8.58(d,J=6.4Hz,1H),7.37(s,1H),7.26(s,1H),7.15(d,J=6.8Hz,1H),6.59 –6.54(br,3H), 3.98 and 3.97(2s,6H), 3.69–3.62(br,4H), 3.15–3.05(br,6H), 0.76–0.68(brs,4H).

[0721] Synthesis of I-32:

[0722] Synthesis of 1-(4-Benzylpiperazin-1-yl)cyclopropanecarbonitrile (01)

[0723] To a stirred solution of N-benzyl-2-chloro-N-(2-chloroethyl)ethan-1-amine (I-33-01) (5 g, 21.5 mmol, 1 eq) in ethanol (100 mL) was added DIPEA (50 mL, 10 volumes), 1-aminocyclopropanecarbonitrile hydrochloride (1) (2.8 g, 23.7 mmol, 1.1 eq) and KI (536 mg, 3.23 mmol, 0.15 eq). The reaction mixture was stirred at 80 °C for 16 hours. After completion of the reaction by TLC, it was diluted with water (50 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with brine solution (50 mL), dried over anhydrous Na2SO4 and concentrated to give the crude product. The crude compound was purified by silica gel (60-120 mesh) column [eluted with 0-10% EtOAc / hexane gradient] to give 1-(4-benzylpiperazin-1-yl)cyclopropanecarbonitrile (01) (1.5 g, yield: 29%) as a light yellow viscous liquid. TLC system EtoAc: Hexane (50:50), R f值 :0.6; LCMS(m / z):242.2(M+H) + ; 1 HNMR(400MHz, CDCl3)δ7.34–7.22(m,4H),7.28–7.24(m,1H),3.46(s,2H),2 .74(t,J=4.8Hz,4H),2.44(brs,4H),1.24–1.16(m,2H),1.02–0.99(m,2H).

[0724] Synthesis of 1-(piperazin-1-yl)cyclopropanecarbonitrile (02)

[0725]

[0726] To a stirred solution of 1-(4-benzylpiperazine-1-yl)cyclopropanecarbonitrile (01) (1.5 g, 6.22 mmol, 1.0 eq.) in acetone (15 mL) was added KCO (2.5 g, 18.6 mmol, 3 eq.) and 1-chloroethyl chloroformate (2) (1 mL, 9.33 mmol, 1.5 eq.). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was evaporated, diluted with MeOH (15 mL), and stirred at 70 ° C for 1 hour. After 1 hour, the volatiles were evaporated, acidified with 2N HCl and washed with DCM (2×25 mL). The aqueous layer was neutralized with 4M NaOH and extracted with DCM (2×50 mL). The combined organic layers were washed with brine solution, dried over NaSO and concentrated to give 1-(piperazine-1-yl)cyclopropanecarbonitrile (02) (500 mg, yield: 53%) as a brown liquid. TLC system MeOH:DCM (10:90), R f Value: 0.1; 1 HNMR(400MHz, CDCl3)δ2.91(brs,4H),2.76(t,J=4.8Hz,4H),1.27–1.25(m,2H),0.93–0.91(m,2H)

[0727] Synthesis of 1-(4-(6,7-dimethoxyquinazolin-4-yl)piperazine-1-yl)cyclopropanecarbonitrile (03)

[0728]

[0729] To a stirred solution of 4-chloro-6,7-dimethoxyquinazoline (3) (500 mg, 2.23 mmol, 1 eq.) in DMF (5 mL) at 0 °C was added KCO (924 mg, 6.69 mmol, 3.0 eq.), 1-(piperazine-1-yl)cyclopropanecarbonitrile (02) (438 mg, 2.90 mmol, 1.3 eq.) and stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was diluted with ice-cold water and extracted with EtOAc (2 × 25 mL). The combined organic layers were washed with brine solution, dried over NaSO, and concentrated to give a crude product. The crude compound was purified by silica gel (60-120 mesh) column [eluted with 0-1% MeOH / DCM gradient] to give 1-(4-(6,7-dimethoxyquinazolin-4-yl)piperazin-1-yl)cyclopropanecarbonitrile (03) (350 mg, yield: 61%) as a light green solid. TLC system EtoAc: Hexane (30:70), R f Value: 0.1; 1HNMR(400MHz,DMSO-d6)δ8.57(s,1H),7.24(s,1H),7.13(s,1H),3.93(s,6H) ,3.60(brs,4H),2.83(t,J=4.8Hz,4H),1.30–1.27(m,2H),1.14–1.09(m,2H).

[0730] Synthesis of (1-(4-(6,7-dimethoxyquinazolin-4-yl)piperazin-1-yl)cyclopropyl)methylamine (04)

[0731]

[0732] To a stirred solution of 1-(4-(6,7-dimethoxyquinazolin-4-yl)piperazine-1-yl)cyclopropanecarbonitrile (03) (350 mg, 1.03 mmol, 1.0 equiv) in 7M ammonia in methanol (5 mL) was added Ra-Ni (150 mg) and stirred at room temperature under hydrogen balloon pressure for 16 hours. After completion of the reaction, the reaction mixture was filtered through a celite bed and washed with 10% MeOH / DCM. The filtrate was concentrated to give (1-(4-(6,7-dimethoxyquinazolin-4-yl)piperazine-1-yl)cyclopropyl)methylamine (04) (330 mg, yield: 93%) as a brown liquid. TLC system MeOH: DCM (10: 90), R f Value: 0.1; LCMS (m / z): 344.3 (M+H) +

[0733] Synthesis of tert-butyl N-((1-(4-(6,7-dimethoxyquinazolin-4-yl)piperazin-1-yl)cyclopropyl)methyl)sulfamoylcarbamate (05)

[0734]

[0735] To a stirred solution of (1-(4-(6,7-dimethoxyquinazolin-4-yl)piperazin-1-yl)cyclopropyl)methanamine (04) (330 mg, 0.96 mmol, 1.0 equiv) in DCM (5 mL) at 0 °C was added DIPEA (0.25 mL, 1.44 mmol, 1.5 equiv) and (tert-butyloxycarbonyl)((4-(dimethylimino)pyridin-1(4H)-yl)sulfonyl)amide (I-04-03) (347 mg, 1.15 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction by TLC, it was diluted with water and extracted with DCM (2×30 mL). The combined organic layers were washed with brine solution, dried over Na2SO4, and concentrated to give the crude product. The crude compound was purified by reverse phase column [eluted with 0-30% ACN / H2O gradient] to give tert-butyl N-((1-(4-(6,7-dimethoxyquinazolin-4-yl)piperazin-1-yl)cyclopropyl)methyl)sulfamoylcarbamate (05) (50 mg, yield: 17%) as a white solid. TLC system MeOH:DCM (10:90), R f Value: 0.5; LCMS (m / z): 523.4 (M+H) + .

[0736] Synthesis of N-((1-(4-(6,7-dimethoxyquinazolin-4-yl)piperazin-1-yl)cyclopropyl)methyl)sulfuramide (I-32)

[0737]

[0738] To a stirred solution of tert-butyl N-((1-(4-(6,7-dimethoxyquinazolin-4-yl)piperazin-1-yl)cyclopropyl)methyl)sulfamoylcarbamate (05) (50 mg, 0.09 mmol, 1.0 equiv) in 1,4-dioxane (0.5 mL) at 0 °C was added 4M HCl in dioxane (1 mL) and stirred at room temperature for 1 hour. After completion of the reaction by TLC, the volatiles were evaporated and the obtained crude product was purified by Grace reverse phase column chromatography [eluted with 0-30% ACN / H2O gradient] to give N-((1-(4-(6,7-dimethoxyquinazolin-4-yl)piperazin-1-yl)cyclopropyl)methyl)sulfodiamide (I-32) (35 mg, yield: 87%) as an off-white solid. TLC system MeOH:DCM (10:90), R f Value: 0.1; LCMS (m / z): 423.2 (M+H) + ; 1HNMR (400MHz, DMSO-d6) δ 8.52 (s, 1H), 7.21 (s, 1H), 7.14 (s, 1H), 6.46 (s, 2H), 6.39 (d, J = 6.4Hz, 1H), 3.92 and 3.0 1(2s,6H),3.52(brs,4H),3.07(d,J=6.4Hz,2H),2.92(t,J=4.8Hz,4H),0.66–0.64(m,2H),0.54–0.52(m,2H).

[0739] Synthesis of I-33:

[0740] Synthesis of N-benzyl-2-chloro-N-(2-chloroethyl)ethan-1-amine (01)

[0741]

[0742] To a stirred solution of bis(2-chloroethyl)amine hydrochloride (1) (50 g, 281 mmol, 1 eq.) in ACN (500 mL) was added K2CO3 (38 g, 281 mmol, 1 eq.), BnBr (33 mL, 281 mmol, 1 eq.), and stirred at 70 °C for 16 hours. After completion of the reaction by TLC, it was diluted with water (200 mL) and extracted with ethyl acetate (2×200 mL). The combined organic layers were dried over Na2SO4 and concentrated to give a crude product. The crude compound was passed through a silica gel (60-120 mesh) column and eluted in hexane to give N-benzyl-2-chloro-N-(2-chloroethyl)-1-amine (01) (20 g, yield: 33%) as a colorless liquid. TLC system hexane, R f值 : 0.8; 1 HNMR (400MHz, CDCl3) δ7.34–7.32(m,4H),7.30–7.27(m,1H),3.74(s,2H),3.50(t,J=7.2Hz,4H),2.93(t,J=7.2Hz,4H).

[0743] Synthesis of 1-(4-Benzylpiperazin-1-yl)cyclopropane-1-carboxylic acid ethyl ester (02)

[0744]

[0745] To a stirred solution of N-benzyl-2-chloro-N-(2-chloroethyl)eth-1-amine (01) (8 g, 34.4 mmol, 1 eq) in ethanol (160 mL) was added DIPEA (80 mL, 10 volumes) at room temperature, followed by 1-aminocyclopropane-1-carboxylic acid ethyl ester hydrochloride (2) (6.2 g, 37.9 mmol, 1.1 eq). The reaction mixture was stirred at 80 °C for 16 hours. After completion of the reaction by TLC, it was diluted with water (100 mL) and extracted with ethyl acetate (2 × 70 mL). The combined organic layers were dried over Na2SO4 and concentrated to give a crude product. The crude compound was purified by silica gel (60-120 mesh) column [eluted with 0-10% EtOAc / hexane gradient] to give 1-(4-benzylpiperazine-1-yl)cyclopropane-1-carboxylic acid ethyl ester (02) (5.1 g, yield: 51%) as a colorless liquid. TLC system EtoAc: Hexane (30:70), R f Value: 0.4; 1 HNMR(400MHz, CDCl3)δ7.34–7.28(m,4H),7.25–7.22(m,1H),4.13(q,J=7.2Hz,2H) ,3.49(s,2H),2.96(brs,4H),2.35(brs,4H),1.28–1.23(m,5H),0.91–0.89(m,2H).

[0746] Synthesis of 1-(piperazin-1-yl)cyclopropane-1-carboxylic acid ethyl ester (03)

[0747]

[0748] 10% Pd / C (2 g) was added to a stirred solution of ethyl 1-(4-benzylpiperazine-1-yl)cyclopropane-1-carboxylate (02) (5.1 g, 17.7 mmol, 1.0 equiv) in MeOH (50 mL) at room temperature. The reaction mixture was stirred at room temperature under hydrogen balloon pressure for 16 hours. After completion of the reaction, the reaction mixture was filtered through a celite bed and washed with ethyl acetate (2 × 50 mL). The filtrate was concentrated and dried to give ethyl 1-(piperazine-1-yl)cyclopropane-1-carboxylate (03) (3.6 g, yield: 97%) as a colorless liquid. TLC system EtoAc: Hexane (30: 70), R f Value: 0.1; LCMS (m / z): 199.2 (M+H) + ; 1HNMR (400MHz, DMSO-d6) δ4.13(q,J=7.2Hz,2H),2.97(brs,4H),2.86–2.81(m,4H),2.70(brs,1H),1.29–1.20(m,5H),0.93–0.91(m,2H).

[0749] Synthesis of tert-butyl 4-(1-(ethoxycarbonyl)cyclopropyl)piperazine-1-carboxylate (04)

[0750]

[0751] To a stirred solution of ethyl 1-(piperazine-1-yl)cyclopropane-1-carboxylate (03) (3.6 g, 18.8 mmol, 1.0 equiv) in dioxane (90 mL) and water (45 mL) at 0°C was added NaHCO (4.2 g, 54.5 mmol, 3.0 equiv) followed by Boc anhydride (3.7 mL, 18.8 mmol, 1.0 equiv). The resulting reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc (2×80 mL). The combined organic layers were dried over NaSO and concentrated to give a crude product. The crude compound was purified by silica gel (60-120 mesh) column [eluted with 0-10% EtOAc / hexane gradient] to give tert-butyl 4-(1-(ethoxycarbonyl)cyclopropyl)piperazine-1-carboxylate (04) (5 g, yield: 96%) as a colorless liquid. TLC system EtoAc: Hexane (30:70), R f Value: 0.1; 1 HNMR(400MHz, CDCl3)δ4.11(q,J=7.2Hz,2H),3.35–3.25(br,4H),2.91–2.87(br s,4H),1.46(s,9H),1.29–1.27(m,2H),1.25(t,J=7.2Hz,3H),0.95–0.92(m,2H).

[0752] Synthesis of tert-butyl 4-(1-(hydroxymethyl)cyclopropyl)piperazine-1-carboxylate (05)

[0753]

[0754] LAH (1.0M in THF) (50 mL, 50.3 mmol, 3.0 equiv) was added to a stirred solution of tert-butyl 4-(1-(ethoxycarbonyl)cyclopropyl)piperazine-1-carboxylate (04) (5 g, 16.7 mmol, 1.0 equiv) in THF (50 mL) at -78 ° C. The reaction mixture was allowed to reach 0 ° C and stirred for 2 hours. After completion of the reaction by TLC, it was quenched with saturated NH4Cl solution and filtered through a diatomaceous earth bed. The filtrate was extracted with EtOAc (3 × 60 mL), dried over Na2SO4, and concentrated under reduced pressure to give tert-butyl 4-(1-(hydroxymethyl)cyclopropyl)piperazine-1-carboxylate (05) (4 g, yield: 95%) as an off-white solid. TLC system EtoAc: Hexane (50: 50), R f Value: 0.4; LCMS (m / z): 257.2 (M+H) + ; 1 HNMR (400MHz, CDCl3) δ3.57 (d, J = 3.6 Hz, 2H), 3.35 (t, J = 5.2 Hz, 4H), 2.68 (t, J = 5.2 Hz, 4H), 1.45 (s, 9H), 0.72–0.69 (m, 2H), 0.55–0.53 (m, 2H).

[0755] Synthesis of tert-butyl 4-(1-(bromomethyl)cyclopropyl)piperazine-1-carboxylate (06)

[0756]

[0757] To a stirred solution of tert-butyl 4-(1-(hydroxymethyl)cyclopropyl)piperazine-1-carboxylate (05) (4 g, 15.6 mmol, 1.0 eq) in DCM (50 mL) at 0°C was added PPh (5.3 g, 20.3 mmol, 1.3 eq) and CBr (6.7 g, 20.3 mmol, 1.3 eq) and stirred at room temperature for 2 hours. After completion of the reaction, it was diluted with water and extracted with DCM (3×50 mL). The combined organic layers were washed with brine solution, dried over Na2SO4, and concentrated to give the crude product. The crude compound was purified by silica gel (60-120 mesh) column [eluted with 0-2% EtOAc / hexane gradient] to give tert-butyl 4-(1-(bromomethyl)cyclopropyl)piperazine-1-carboxylate (06) (1 g, yield: 20%) as a colorless liquid. TLC system EtoAc: Hexane (30:70), R f Value: 0.8; 1HNMR (400MHz, CDCl3) δ3.55 (s, 2H), 3.35–3.31 (m, 4H), 2.79 (t, J = 5.2Hz, 4H), 1.46 (s, 9H), 0.95–0.92 (m, 2H), 0.79–0.75 (m, 2H).

[0758] Synthesis of tert-butyl 4-(1-(azidomethyl)cyclopropyl)piperazine-1-carboxylate (07)

[0759]

[0760] To a stirred solution of tert-butyl 4-(1-(bromomethyl)cyclopropyl)piperazine-1-carboxylate (06) (1 g, 3.13 mmol, 1.0 equiv) in DMF (10 mL) was added NaN3 (0.244 g, 3.75 mmol, 1.2 equiv) and stirred at 100 ° C for 2 hours. After completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine solution, dried over Na2SO4, and concentrated under reduced pressure to give a crude product. The crude compound was purified by silica gel (60-120 mesh) column [eluted with 0-5% EtOAc / hexane gradient] to give tert-butyl 4-(1-(azidomethyl)cyclopropyl)piperazine-1-carboxylate (07) (650 mg, yield: 73%) as a colorless liquid. TLC system EtoAc: hexane (10: 90), R f Value: 0.4; 1 HNMR (400MHz, CDCl3) δ3.34(t,J=5.2Hz,4H),3.28(s,2H),2.70(t,J=5.2Hz,4H),1.46(s,9H),0.73–0.71(m,2H),0.63–0.61(m,2H).

[0761] Synthesis of tert-butyl 4-(1-(aminomethyl)cyclopropyl)piperazine-1-carboxylate (08)

[0762]

[0763] To a stirred solution of tert-butyl 4-(1-(azidomethyl)cyclopropyl)piperazine-1-carboxylate (07) (650 mg, 2.31 mmol, 1.0 equiv) in MeOH (6 mL) was added Pd(OH)2 (120 mg) and stirred at room temperature under hydrogen balloon pressure for 2 hours. After completion of the reaction, the reaction mixture was filtered through a celite bed and washed with ethyl acetate (2×50 mL). The filtrate was evaporated under reduced pressure to give tert-butyl 4-(1-(aminomethyl)cyclopropyl)piperazine-1-carboxylate (08) (640 mg, yield: 98%) as a brown liquid. TLC system MeOH: DCM (10: 90), R f Value: 0.1; 1 HNMR (400MHz, DMSO-d6) δ3.22–3.20(m,4H),3.17(s,2H),2.66(s,2H),2.60(t,J=5.2Hz,4H),1.39(s,9H),0.53–0.51(m,2H),0.47–0.45(m,2H).

[0764] Synthesis of tert-butyl 4-(1-(((N-(tert-butyloxycarbonyl)sulfamoyl)amino)methyl)cyclopropyl)piperazine-1-carboxylate (09)

[0765]

[0766] To a stirred solution of tert-butyl 4-(1-(aminomethyl)cyclopropyl)piperazine-1-carboxylate (08) (640 mg, 2.50 mmol, 1.0 equiv) in DCM (10 mL) at 0 °C was added DIPEA (0.6 mL, 3.76 mmol, 1.5 equiv) and (tert-butyloxycarbonyl)((4-(dimethylimino)pyridin-1(4H)-yl)sulfonyl)amide (I-04-03) (1 g, 3.01 mmol, 1.2 equiv) and stirred at room temperature for 16 hours. After completion of the reaction by TLC, it was diluted with water and extracted with DCM (3×25 mL). The combined organic layers were washed with brine solution, dried over Na2SO4, and concentrated under reduced pressure to give the crude product. The crude compound was purified by silica gel (60-120 mesh) column [eluted with 10-25% EtOAc / hexanes gradient] to give tert-butyl 4-(1-(((N-(tert-butyloxycarbonyl)sulfamoyl)amino)methyl)cyclopropyl)piperazine-1-carboxylate (09) (700 mg, yield: 70%) as a white solid. TLC system EtoAc: Hexanes (50:50), R f Value: 0.3; 1HNMR (400MHz, CDCl3) δ5.31–5.29(m,1H),3.37–3.35(m,4H),3.03(d,J=5.2Hz,2H),2 .58(t,J=5.2Hz,4H),1.49(s,9H),1.45(s,9H),0.80–0.77(m,2H),0.57–0.54(m,2H).

[0767] Synthesis of 4-(1-((sulfamoylamino)methyl)cyclopropyl)piperazine (10)

[0768]

[0769] To a stirred solution of tert-butyl 4-(1-(((N-(tert-butyloxycarbonyl)sulfamoyl)amino)methyl)cyclopropyl)piperazine-1-carboxylate (09) (700 mg, 1.61 mmol, 1.0 equiv) in dioxane (5 mL) at 0 °C was added 4M HCl in dioxane (5 mL) and stirred at room temperature for 1 hour. After completion of the reaction, the volatiles were evaporated under reduced pressure and triturated with diethyl ether (2×5 mL) to give 4-(1-((sulfamoylamino)methyl)cyclopropyl)piperazine hydrochloride (10) (350 mg, yield: 92%) as an off-white solid. TLC system MeOH:DCM (10:90), R f Value: 0.1; 1 H NMR (400 MHz, DMSO-d6) δ 8.76-8.73 (br, 2H), 6.63-6.51 (m, 3H), 3.32 (s, 2H), 3.09-2.95 (br, 8H), 0.69-0.60 (br, 4H). The NMR was not clean, however the material was used in the next step.

[0770] Synthesis of N-((1-(4-(7-methoxy-6-(methoxymethoxy)quinazolin-4-yl)piperazin-1-yl)cyclopropyl)methyl)sulfuramide (I-33)

[0771]

[0772] To a stirred solution of 4-chloro-7-methoxy-6-(methoxymethoxy)quinazoline (I-28-02) (150 mg, 0.59 mmol, 1.0 eq.) in DMF (3 mL) at 0 °C was added KCO (244 mg, 1.77 mmol, 3 eq.) and 4-(1-((sulfamoylamino)methyl)cyclopropyl)piperazine hydrochloride (10) (207 mg, 0.76 mmol, 1.3 eq.). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, it was diluted with ice-cold water and extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine solution, dried over NaSO, and concentrated to give the crude product. The crude product was purified by trituration with 2% MeOH / ACN to give N-((1-(4-(7-methoxy-6-(methoxymethoxy)quinazolin-4-yl)piperazin-1-yl)cyclopropyl)methyl)sulfonamide (I-33) (25 mg, yield: 9%) as an off-white solid. TLC system MeOH:DCM (10:90), R f Value: 0.4; LCMS (m / z): 453.3 (M+H) + ; 1 HNMR (400MHz, DMSO-d6) δ8.52(s,1H),7.44(s,1H),7.24(s,1H),6.45(s,2H),6.37(t,J=5.2Hz,1H),5.31(s,2H),3.94( s,3H),3.52(brs,4H),3.44(s,3H),3.06(d,J=5.2Hz,2H),2.90(t,J=4.8Hz,4H),0.65–0.64(m,2H),0.53–0.52(m,2H).

[0773] Synthesis of I-34:

[0774] Synthesis of 4-chloro-6-(fluoromethoxy)-7-methoxyquinazoline (01)

[0775]

[0776] To a stirred solution of 4-chloro-7-methoxyquinazoline-6-ol (I-28-01) (500 mg, 2.38 mmol, 1.0 equiv) in DMF (5 mL) at 0 ° C, NaH (60%) (86 mg, 3.57 mmol, 1.5 equiv) and ACN (1) (1.4 mL, 2.85 mmol, 1.2 equiv) containing 2M fluoroiodomethane was added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction by TLC, it was diluted with water and extracted with EtOAc (2 × 25 mL). The organic layer was dried over Na2SO4 and concentrated to provide a crude product. The crude compound was purified by silica gel column (60-120 mesh) chromatography [eluted with 0-1% MeOH / DCM gradient] to obtain 4-chloro-6-(fluoromethoxy)-7-methoxyquinazoline (01) (310 mg, yield: 53%) as an off-white solid. TLC system EtoAc: Hexane (50:50), R f Value: 0.3; LCMS (m / z): 243.0 (M+H) + ; 1 HNMR (400MHz, CDCl3) δ8.93 (s, 1H), 7.81 (s, 1H), 7.41 (s, 1H), 5.87 (d, J = 53.2Hz, 2H), 4.08 (s, 3H).

[0777] Synthesis of N-((1-(4-(6-(fluoromethoxy)-7-methoxyquinazolin-4-yl)piperazin-1-yl)cyclopropyl)methyl)sulfuramide (I-34)

[0778]

[0779] To a stirred solution of 4-chloro-6-(fluoromethoxy)-7-methoxyquinazoline (01) (150 mg, 0.61 mmol, 1.0 equiv) in DMF (3 mL) at 0 ° C. KCO (256 mg, 1.85 mmol, 3 equiv) and 4-(1-((sulfamoylamino)methyl)cyclopropyl)piperazine hydrochloride (I-33-10) (217 mg, 0.79 mmol, 1.3 equiv) were added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction by TLC, it was diluted with ice-cold water and extracted with EtOAc (2×10 mL). The organic layer was dried over NaSO and concentrated to provide a crude product. The crude compound was purified by trituration with 2% methanol / ACN to give N-((1-(4-(6-(fluoromethoxy)-7-methoxyquinazolin-4-yl)piperazin-1-yl)cyclopropyl)methyl)sulfonamide (I-34) (45 mg, yield: 16%) as an off-white solid. TLC system MeOH:DCM (10:90), R fValue: 0.4; LCMS (m / z): 441.3 (M+H) + ; 1 HNMR (400MHz, DMSO-d6) δ8.55(s,1H),7.50(s,1H),7.30(s,1H),6.45(s,2H),6.37(t,J=6.4Hz,1H),6.00(d,J=54Hz, 2H), 3.96 (s, 3H), 3.56 (brs, 4H), 3.06 (d, J = 6.4Hz, 2H), 2.90 (t, J = 4.4Hz, 4H), 0.66–0.64 (m, 2H), 0.54–0.52 (m, 2H).

[0780] Synthesis of I-35:

[0781] Synthesis of tert-butyl 4-(1-(ethoxycarbonyl)cyclopropyl)piperidine-1-carboxylate (01)

[0782]

[0783] To a stirred solution of 1-(piperidin-4-yl)cyclopropane-1-carboxylic acid ethyl ester (I-27-02) (4 g, 20.3 mmol, 1 eq.) in 1,4-dioxane and water (2: 1) cooled to 0 ° C, NaHCO (5.1 g, 60.8 mmol, 3.0 eq.) and (Boc) O (4.65 mL, 20.3 mmol, 1.0 eq.) were added. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction by TLC, the reaction mixture was diluted with water and extracted with EtOAc (2 × 80 mL). The combined organic layer was washed with a saline solution (30 mL), dried over sodium sulfate and concentrated under reduced pressure to give a crude product. The crude compound was purified by silica gel (60-120 mesh) column chromatography [eluted with 5% EtOAc / hexane] to give tert-butyl 4-(1-(ethoxycarbonyl)cyclopropyl)piperidine-1-carboxylate (01) (3.3 g, yield: 55%) as a colorless viscous liquid. TLC system: EtOAc / hexane (30:70), R f值 :0.8;Direct mass (m / z): 242.0 (M+H-tBu) + .

[0784] Synthesis of tert-butyl 4-(1-(hydroxymethyl)cyclopropyl)piperidine-1-carboxylate (02)

[0785] To a stirred solution of tert-butyl 4-(1-(ethoxycarbonyl)cyclopropyl)piperidine-1-carboxylate (01) (3.3 g, 11.1 mmol, 1 eq.) in THF (35 mL) at -78 °C was added 1.0 M LAH in THF (33 mL, 33.3 mmol, 3 eq.). The reaction mixture was allowed to reach 0 °C over 3 hours. After completion of the reaction by TLC, the reaction mixture was quenched with saturated NH4Cl solution and extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine solution (50 mL), dried over sodium sulfate and concentrated under reduced pressure to provide a crude product. The crude compound was purified by silica gel (60-120 mesh) column chromatography [eluted with a 0-30% EtOAc / hexane gradient] to give tert-butyl 4-(1-(hydroxymethyl)cyclopropyl)piperidine-1-carboxylate (02) (1.5 g, yield: 54%) as a colorless viscous liquid. TLC system: EtOAc / hexane (50:50), R f Value: 0.3; 1 HNMR (400MHz, CDCl3) δ4.19–4.17(m,2H),3.62(brs,2H),2.63–2.56(m,2H),1.64–1.58(m,4H),1.45(s,9H),1.38–1.36(m,1H),0.43–0.36(m,4H).

[0786] Synthesis of tert-butyl 4-(1-(azidomethyl)cyclopropyl)piperidine-1-carboxylate (03)

[0787]

[0788] DBU (6.6 mL, 43.9 mmol, 8 equiv) and DPPA (5.9 mL, 27.4 mmol, 5 equiv) were added to a stirred solution of tert-butyl 4-(1-(hydroxymethyl)cyclopropyl)piperidine-1-carboxylate (02) (1.4 g, 5.49 mmol, 1 equiv) in THF (14 mL) cooled to 0 ° C. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc (2×70 mL). The combined organic layers were washed with brine solution (40 mL), dried over sodium sulfate and concentrated under reduced pressure to provide a crude product. The crude compound was purified by silica gel (60-120 mesh) column chromatography [eluted with 5% EtOAc / hexane] to obtain tert-butyl 4-(1-(azidomethyl)cyclopropyl)piperidine-1-carboxylate (03) (1.9 g) as a colorless liquid. TLC system: EtOAc / hexane (50:50), R f值 :0.8;Direct mass (m / z): 225.1(M+H-tBu) + .

[0789] Synthesis of tert-butyl 4-(1-(aminomethyl)cyclopropyl)piperidine-1-carboxylate (04)

[0790]

[0791] 10% Pd / C (500mg) is added to a stirred solution of tert-butyl 4-(1-(azidomethyl)cyclopropyl)piperidine-1-formate (03) (1.9g, 6.78mmol, 1 equivalent) in MeOH (20mL), and stirred for 2 hours at room temperature under H2 capsule pressure. After the completion of the reaction by TLC, the reaction mixture is filtered through a diatomaceous earth pad and washed with ethanol. The collected filtrate is concentrated under reduced pressure to provide a crude product. The crude compound is purified by silica gel (60-120 mesh) column chromatography [eluted with 0-10% MeOH / DCM gradient] to obtain tert-butyl 4-(1-(aminomethyl)cyclopropyl)piperidine-1-formate (04) (950mg, yield: 56%) as a colorless viscous liquid. TLC system: EtOAc / hexane (50:50), R f值 :0.1;Direct mass (m / z): 255.2 (M+H) + .

[0792] Synthesis of tert-butyl 4-(1-(((N-(tert-butyloxycarbonyl)sulfamoyl)amino)methyl)cyclopropyl)piperidine-1-carboxylate (05)

[0793]

[0794] To a stirred solution of tert-butyl 4-(1-(aminomethyl)cyclopropyl)piperidine-1-carboxylate (04) (900 mg, 3.54 mmol, 1 eq.) in DCM (9 mL) at 0 °C was added DIPEA (0.95 mL, 5.31 mmol, 1.5 eq.), (tert-butyloxycarbonyl)((4-(dimethylimino)pyridin-1(4H)-yl)sulfonyl)amide (I-04-03) (1.27 g, 4.25 mmol, 1.2 eq.). The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction by TLC, the reaction mixture was diluted with water and extracted with DCM (2×50 mL). The combined organic layers were washed with brine solution (20 mL), dried over sodium sulfate and concentrated under reduced pressure to give the crude compound. The crude compound was purified by silica gel (60-120 mesh) column chromatography [eluted with 10-30% EtOAc / hexanes gradient] to give tert-butyl 4-(1-(((N-(tert-butyloxycarbonyl)sulfamoyl)amino)methyl)cyclopropyl)piperidine-1-carboxylate (05) (600 mg, yield: 40%) as a white solid. TLC system: EtOAc in hexanes (50:50), R f Value: 0.7; 1 HNMR(400MHz, CDCl3)δ6.96(s,1H),4.99(t,J=6.0Hz,1H),4.15(brs,2H),2.90(brs,2H),2.63– 6.57(m,2H),1.49(s,9H),1.45(s,9H),1.37–1.20(m,5H),0.50–0.48(m,2H),0.40–0.37(m,2H).

[0795] Synthesis of 4-(1-((sulfamoylamino)methyl)cyclopropyl)piperidine hydrochloride (06)

[0796]

[0797] To a stirred solution of tert-butyl 4-(1-(((N-(tert-butyloxycarbonyl)sulfamoyl)amino)methyl)cyclopropyl)piperidine-1-carboxylate (05) (600 mg, 1.43 mmol, 1 eq) in 1,4-dioxane (6 mL) at 0°C, 4M HCl in dioxane (2 mL) was slowly added dropwise and stirred at room temperature for 2 hours. After completion of the reaction by TLC, the reaction mixture was concentrated and triturated with n-pentane and diethyl ether to give 4-(1-((sulfamoylamino)methyl)cyclopropyl)piperidine hydrochloride (06) (300 mg, yield: 95%) as an off-white sticky solid. TLC system EtOAc (100; ninhydrin stain), R f Value: 0.1; 1HNMR(400MHz,DMSO-d6)δ8.81–8.74(m,1H),8.37–-8.35(m,1H),6.54–6.45(brs,3H),3.27–3.24(m, 2H),2.79–2.67(m,4H),1.72–1.69(m,2H),1.59–1.42(m,2H),1.24–1.21(m,1H),0.39-0.29(m,4H).

[0798] Synthesis of N-((1-(1-(7-methoxy-6-(methoxymethoxy)quinazolin-4-yl)piperidin-4-yl)cyclopropyl)methyl)sulfuramide (I-35)

[0799]

[0800] To a stirred solution of 4-chloro-7-methoxy-6-(methoxymethoxy)quinazoline (I-28-02) (150 mg, 0.59 mmol, 1 eq) in DMF (1.5 mL) at 0 °C was added KCO (244 mg, 1.77 mmol, 3 eq) and 4-(1-((sulfamoylamino)methyl)cyclopropyl)piperidine hydrochloride (06) (193 mg, 0.88 mmol, 1.5 eq) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was diluted with ice-cold water and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine solution (30 mL), dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The crude compound was purified by reverse phase (2x) column [eluted with a gradient of 10-50% ACN in 0.1% FA / water] to provide I-35 with a purity of 86%. The obtained compound was further purified by preparative HPLC to give N-((1-(1-(7-methoxy-6-(methoxymethoxy)quinazolin-4-yl)piperidin-4-yl)cyclopropyl)methyl)sulfonamide (I-35) (30 mg, yield: 11%) as a white solid. TLC system: EtOAc, R f Value: 0.2; LCMS (m / z): 452.3 (M+H) + ; 1HNMR(400MHz,DMSO-d6)δ8.50(s,1H),7.43(s,1H),7.22(s,1H),6.43(brs,3H),5.30(s,2H),4.21(d,J=8.4Hz,2H),3.94(s,3 H),3.44(s,3H),2.97–2.91(m,2H),2.85(s,2H),1.73–1.70(m,2H),1.60–1.57(m,1H),1.47–1.42(m,2H),0.39-0.36(m,4H).

[0801] Synthesis of I-36:

[0802] Synthesis of tert-butyl 4-(1-amino-2-methylpropan-2-yl)piperidine-1-carboxylate (01)

[0803]

[0804] Ra-Ni (500 mg) was added to a stirred solution of tert-butyl 4-(2-cyanopropan-2-yl)piperidine-1-carboxylate (I-14-01) (1.5 g, 5.95 mmol, 1.0 equivalent) in methanol (15 mL) containing 7 M ammonia, and stirred at room temperature under hydrogen balloon pressure for 16 hours. After the reaction was completed, the reaction mixture was filtered through a diatomaceous earth bed and washed with 10% MeOH: DCM. The filtrate was evaporated under reduced pressure to give tert-butyl 4-(1-amino-2-methylpropan-2-yl)piperidine-1-carboxylate (01) (1.4 g, yield: 93%) as a brown liquid. TLC system MeOH: DCM (10: 90), R f Value: 0.1; 1 HNMR(400MHz,DMSO-d6)δ4.01–3.98(m,2H),2.62–2.57(brs,2H),2.27–2.2 4(m,2H),1.57–1.53(m,2H),1.38(s,10H),1.05–1.02(m,2H),0.76(s,6H).

[0805] Synthesis of tert-butyl 4-(1-((N-(tert-butyloxycarbonyl)sulfamoyl)amino)-2-methylpropan-2-yl)piperidine-1-carboxylate (02)

[0806]

[0807] To a stirred solution of tert-butyl 4-(1-amino-2-methylpropan-2-yl)piperidine-1-carboxylate (01) (1.4 g, 5.46 mmol, 1.0 eq) in DCM (15 mL) at 0 °C was added DIPEA (1.5 mL, 8.20 mmol, 1.5 eq) and (tert-butyloxycarbonyl)((4-(dimethylimino)pyridin-1(4H)-yl)sulfonyl)amide (I-04-03) (1.97 g, 6.56 mmol, 1.2 eq) and stirred at room temperature for 16 hours. After completion of the reaction by TLC, it was diluted with water and extracted with DCM (3×50 mL). The combined organic layers were washed with brine solution, dried over Na2SO4, and concentrated to give the crude product. The crude product was purified by silica gel (60-120 mesh) column chromatography [eluted with 20-30% EtOAc / hexane gradient] to give tert-butyl 4-(1-((N-(tert-butyloxycarbonyl)sulfamoyl)amino)-2-methylpropan-2-yl)piperidine-1-carboxylate (02) (2.1 g, yield: 93%) as a colorless viscous liquid. TLC system EtoAc: Hexane (50:50), R f Value: 0.4; 1 HNMR(400MHz,DMSO-d6)δ10.76(s,1H),7.39(t,J=6.8Hz,1H),4.00–3.96(m,2H),2.72(d,J=6.8Hz,2H), 2.63–2.55(m,2H),1.58–1.55(m,2H),1.42(s,9H),1.37–1.35(m,10H),1.04–0.97(m,2H),0.77(s,6H).

[0808] Synthesis of 4-(2-methyl-1-(sulfamoylamino)propan-2-yl)piperidine hydrochloride (03)

[0809]

[0810] To a stirred solution of tert-butyl 4-(1-((N-(tert-butyloxycarbonyl)sulfamoyl)amino)-2-methylpropan-2-yl)piperidine-1-carboxylate (02) (1.5 g, 3.44 mmol, 1.0 equiv) in 1,4-dioxane (1 mL) was added 4M HCl in dioxane (1 mL) at 0°C and stirred at room temperature for 2 hours. After completion of the reaction by TLC, the volatiles were evaporated to give 4-(2-methyl-1-(sulfamoylamino)propan-2-yl)piperidine (03) (700 mg, yield: 86%) as a colorless viscous liquid. TLC system MeOH:DCM (10:90), R f Value: 0.1; 1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.69(s,1H),6.48–6.39(m,3H),3.27–3.24(m,2H),2 .79–2.74(m,2H),2.70(d,J=6.0Hz,2H),1.75–1.68(m,2H),1.50–1.41(m,3H),0.78(s,6H).

[0811] Synthesis of N-(2-(1-(7-methoxy-6-(methoxymethoxy)quinazolin-4-yl)piperidin-4-yl)-2-methylpropyl)sulfuramide (I-36)

[0812]

[0813] To a stirred solution of 4-chloro-7-methoxy-6-(methoxymethoxy)quinazoline (I-28-02) (250 mg, 0.98 mmol, 1.0 equiv) in DMF (5 mL) at 0 ° C, KCO (407 mg, 2.95 mmol, 3.0 equiv) was added, followed by addition of 4-(2-methyl-1-(sulfamoylamino)propan-2-yl)piperidine (03) (300 mg, 1.27 mmol, 1.3 equiv). The resulting mixture was stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was diluted with ice-cold water and stirred for 30 minutes. The precipitated solid was filtered, washed with diethyl ether, and dried under vacuum to obtain N-(2-(1-(7-methoxy-6-(methoxymethoxy)quinazoline-4-yl)piperidin-4-yl)-2-methylpropyl)sulfuramide (I-36) (42 mg, yield: 9%) as an off-white solid. TLC system MeOH:DCM (10:90), R f Value: 0.5; LCMS (m / z): 454.3 (M+H) + ; 1 HNMR(400MHz,DMSO-d6)δ8.50(s,1H),7.44(s,1H),7.22(s,1H),7.44(s,2H),6.36(s,1H),5.31(s,2H),4.25–4.22(m,2H),3.94 (s,3H),3.44(s,3H),2.97(t,J=11.6Hz,2H),2.75(s,2H),1.77–1.74(m,2H),1.57–1.54(m,1H),1.42–1.38(m,2H),0.83(s,6H).

[0814] Synthesis of I-37:

[0815] Synthesis of 4-(1-(azidomethyl)cyclopropyl)piperidine hydrochloride (01)

[0816]

[0817] To a stirred solution of tert-butyl 4-(1-(azidomethyl)cyclopropyl)piperidine-1-carboxylate (I-35-03) (1.7 g (crude product), 6.07 mmol, 1 equivalent) in 1,4-dioxane (17 mL) at 0 ° C, 4M HCl in dioxane (17 mL) was slowly added dropwise and stirred at room temperature for 2 hours. After the reaction was completed by TLC, the reaction mixture was concentrated and triturated with diethyl ether to give tert-butyl 4-(1-(azidomethyl)cyclopropyl)piperidine hydrochloride (01) (400 mg, yield: 25%) as an off-white sticky solid. TLC system EtOAc (50:50, ninhydrin staining), R f Value: 0.1; Direct mass (m / z): 181.2 (M+H) + , 1 HNMR(400MHz,DMSO-d6)δ8.92–8.57(br,2H),3.27–3.24(m,4H),2.80–2.73(m,2 H),1.75–1.71(m,2H),1.60–1.48(m,2H),1.37–1.30(m,1H),0.49–0.45(m,4H).

[0818] Synthesis of 4-chloro-6-(fluoromethoxy)-7-methoxyquinoline (02)

[0819]

[0820] To the stirring solution of 4-chloro-7-methoxyquinoline-6-ol (I-10-01) (500mg, 2.39mmol, 1 equivalent) in DMF (5mL) at 0°C, NaH (83mg, 3.58mmol, 1.5 equivalents) is added, and stirred for 15 minutes. Subsequently, iodomethane (about 2mol / L acetonitrile) (1.4mL, 2.85mmol, 1.2 equivalents) is added dropwise at 0°C for 10 minutes. The reaction mixture is stirred at room temperature for 4 hours. After the completion of the reaction by TLC, the reaction mixture is quenched with cold water and extracted with EtOAc (2 × 80mL). The combined organic layer is washed with saline solution (30mL), dried over sodium sulfate and concentrated under reduced pressure to provide a crude product. The crude compound was purified by silica gel (60-120 mesh) column chromatography [eluted with 30% EtOAc / hexane] to give 4-chloro-6-(fluoromethoxy)-7-methoxyquinoline (02) (300 mg, yield: 52%) as an off-white solid. TLC system: EtOAc (100), R f Value: 0.3; LCMS (m / z): 242 (M+H) + , 1 HNMR (400MHz, CDCl3) δ 8.65 (d, J = 4.8 Hz, 1H), 7.82 (s, 1H), 7.50 (s, 1H), 7.39 (d, J = 4.8 Hz, 1H), 5.91 (d, J = 53.6 Hz, 2H), 4.05 (s, 3H).

[0821] Synthesis of 4-(4-(1-(azidomethyl)cyclopropyl)piperidin-1-yl)-6-(fluoromethoxy)-7-methoxyquinoline (03)

[0822]

[0823] To a stirred degassed solution of 4-chloro-6-(fluoromethoxy)-7-methoxyquinoline (02) (300 mg, 1.24 mmol, 1.0 equiv) and 4-(1-(azidomethyl)cyclopropyl)piperidine hydrochloride (01) (322 mg, 1.49 mmol, 1.2 equiv) in 1,4-dioxane (3 mL) was added CsCO (1.2 g, 3.73 mmol, 3.0 equiv) and X-Phos (114 mg, 0.24 mmol, 0.2 equiv) and Pd(dba) (114 mg, 0.12 mmol, 0.1 equiv). The reaction mixture was stirred at 110 °C for 16 h. After completion of the reaction by TLC, the reaction mixture was quenched with cold water and extracted with EtOAc (2×80 mL). The combined organic layers were washed with brine solution (50 mL), dried over sodium sulfate and concentrated under reduced pressure to give 4-(4-(1-(azidomethyl)cyclopropyl)piperidin-1-yl)-6-(fluoromethoxy)-7-methoxyquinoline (03) (480 mg, 78% purity) as a brown sticky solid. TLC system MeOH:DCM (10:90), R f Value: 0.4; LCMS (m / z): 386.3 (M+H) + The material was used in the next step without purification.

[0824] Synthesis of (1-(1-(6-(fluoromethoxy)-7-methoxyquinolin-4-yl)piperidin-4-yl)cyclopropyl)methylamine (04)

[0825]

[0826] 10% Pd / C (100 mg) was added to a stirred solution of 4-(4-(1-(azidomethyl)cyclopropyl)piperidin-1-yl)-6-(fluoromethoxy)-7-methoxyquinoline (03) (480 mg, 1.24 mmol, 1 eq) in MeOH (5 mL) and stirred for 2 hours at room temperature under H2 capsule pressure. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad and concentrated under reduced pressure to give (1-(1-(6-(fluoromethoxy)-7-m...

Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

2. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 and a pharmaceutically acceptable carrier.

3. Use of the compound according to claim 1 in the preparation of a medicament for treating an uncontrolled cell proliferation disorder in a mammal.

4. Use of the compound according to claim 1 in the preparation of a medicament for treating cancer in a mammal.

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