Quinoline and quinazoline compounds and methods of use thereof

Abstract

Compounds and methods for their preparation and use as therapeutic or prophylactic agents for the treatment of, for example, 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 inhibitors of ENPP1.The present invention is directed to pharmaceutical compositions containing formula 1 compounds, and methods of using the compounds or compositions for treating various types of human cancers in which ENPP1 is overexpressed, cardiovascular, diabetes, obesity, antiviral, antibacterial, and antifibrotic therapeutic agents.The present invention is also directed to methods of making the compounds and their pharmaceutical salts. [Background technology]

[0002] Ectonucleotide pyrophosphatase / phosphodiesterase (ENPP) family members include seven isoforms, ENPP1-7, which are type II transmembrane glycoproteins or ectoenzymes. Mass spectrometry and proteomic analysis from over 370 protein targets led to the identification of the extracellular protein ENPP1 as one of the top hits that showed high hydrolytic activity. ATP is an identified substrate of ENPP1, which is hydrolyzed to AMP and PPi. CD73 converts AMP to adenosine and inorganic phosphate (Pi). Kinetic experimental data show that ENPP1 is capable of hydrolyzing ATP. These ectonucleotide enzymes are involved in the hydrolysis of pyrophosphate (PPi) and phosphodiester bonds in extracellular nucleotides such as those that generate triphosphates, oligonucleotides, and nucleoside 5'-monophosphates. One of the key isoforms, ENPP1 (plasma cell membrane glycoprotein-1, PC-1), is involved in several physiological processes such as development, formation, and transport, as well as pathophysiological conditions. Aberrant ENPP1 expression has been detected in breast cancer compared to normal mammary epithelium (evidence of the potential of ENPP1 in the development of bone metastases (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 important for tumor control, as are checkpoint inhibitors such as anti-PD-1 or PD-L1, which are promising immunotherapeutic agents for various cancers. In addition, mutations in ENPP1 have been associated with several disorders, 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 implicated in lung and kidney fibrosis. A correlation was also found between ENPP1 expression and astrocytoma grade. Another study reported that ENPP1 is required to maintain the undifferentiated and proliferative state of glioblastoma stem-like cells. Thus, ENPP1 is an attractive druggable target for the development of novel anticancer, cardiovascular, diabetes, obesity, and antifibrotic therapeutics.

[0004] The importance of ENPP1 activity was further investigated from both direct binding assays and in vitro cellular efficacy on MDA-MB231 cells. siRNA-based knockdown of ENPP1 significantly reduced its catalytic activity in both cell-specific and in vivo experiments. These experiments showed that ENPP1 activity was abolished after treatment with siRNA, further supporting the validity of this target in certain diseases. It was recently shown that bisphosphothionate analogs of endogenous cGAMP are resistant to hydrolysis by ENPP1 phosphodiesterase, and cyclic dinucleotides (CDNs) in particular are more potent in inducing IFN-β secretion in human THP1 cells by a mechanism that inhibits ENPP1 activity and the concomitant STING activation response.

[0005] There is ample evidence that ENPP1 expression is prominent in human primary breast tumors compared to normal mammary epithelium, with the highest levels observed in breast-bone metastases. These data support a potential role for ENPP1 in breast-bone metastases, as well as a potential prognostic marker for breast cancer. These results from target validation experiments clearly support a pharmacological role for ENPP1 for the development of novel immunotherapeutic agents for cancer.

[0006] Furthermore, ENPP1 activity has also been implicated in diseases caused by bacteria and / or viruses, and thus modulators of ENPP1 can be used to treat bacterial and / or viral diseases and conditions. Summary of the Invention

[0007] The present invention in one aspect relates to a compound of formula 1 [ka] (In the formula, X is selected from the group consisting of -C and -N; [ka] but, [ka] is selected from the group consisting of L, [ka] is selected from the group consisting of Y is selected from the group consisting of H and alkyl; R 1 -H, alkyl, O-alkyl, -OCF 3 , -OP=(O)(ONa) 2 , and -CH 2 OP=(O)(ONa) 2 is selected from the group consisting of R 2-H, alkyl, -O alkyl, -OH, -OCF 3 , -OCH 2 CH 2 OH, -OCH 2 CH 2 OCH 3 , -OCH 2 OCH 3 , -OP=(O)(ONa) 2 , -CH 2 -OP=(O)(ONa) 2 , and [ka] is selected from the group consisting of R 3 But, -H, -NH 2 , and -CH 3 (selected from the group consisting of or an isomer, hydrate, solvate, polymorph, tautomer, or pharma- ceutically acceptable salt thereof.

[0008] In one preferred embodiment, R 1 -H, -CH 3 , -OCH 3 , -OCF 3 , -OP=(O)(ONa) 2 , and -CH 2 OP=(O)(ONa) 2 is selected from the group consisting of:

[0009] In one preferred embodiment, R 1 is OCH 3 It is.

[0010] In another preferred embodiment, R 2 -H, -CH 3 , -OCH 3 , -OH, -OCF 3 , -OCH 2 CH 2 OH, -OCH 2 CH 2 OCH 3 , -OCH 2 OCH 3, -OP=(O)(ONa) 2 , -CH 2 OP=(O)(ONa) 2 , and [ka] is selected from the group consisting of:

[0011] In another preferred embodiment, Y is selected from the group consisting of H and CH 3 is selected from the group consisting of:

[0012] In one preferred embodiment, Y is H.

[0013] In one preferred embodiment, [ka] teeth, [ka] It is.

[0014] R 1 is OCH 3 It is.

[0015] In one preferred embodiment, X is N; [ka] teeth, [ka] and L is [ka] is selected from the group consisting of Y is H, R 1 -H, -CH 3 , and -OCH 3 is selected from the group consisting of R2 -H, -CH 3 , -OCH 3 , OP=(O)(ONa) 2 , -CH 2 -OP=(O)(ONa) 2 , -OH, -OCH 2 CH 2 OH, -OCH 2 CH 2 OCH 3 , -OCH 2 OCH 3 , and [ka] is selected from the group consisting of R 3 -H, -NH 2 , and -CH 3 is selected from the group consisting of:

[0016] In another preferred embodiment, X is C; [ka] teeth, [ka] is selected from the group consisting of L is [ka] is selected from the group consisting of R 1 -H, -CH 3 , and -OCH 3 is selected from the group consisting of R 2 -H, -CH 3 , -OCH 3 , -OH, -OCF 3 , -OCH 2 OCH 3 , -OCH 2 CH 2 OH, -OCH 2 CH 2 OCH3 , -OP=(O)(ONa) 2 , -CH 2 OP=(O)(ONa) 2 is selected from the group consisting of R 3 -H, -NH 2 , and -CH 3 is selected from the group consisting of:

[0017] Examples of compounds provided include: [ka] [ka] [ka]

[0018] The present invention also includes hydrates, solvates, polymorphs, isomers, tautomers, pharma- ceutically acceptable salts of the compounds, and pharma- ceutically acceptable salts of the tautomers.

[0019] The invention also provides pharmaceutical formulations, medicaments, pharmaceutical formulations, medicaments, methods of preparing the compounds, and methods of treating patients with the provided pharmaceutical formulations and compounds.

[0020] The compounds of the present invention were identified by structure-based computational docking and binding free energies.

[0021] Also disclosed are pharmaceutical compositions comprising a therapeutically effective amount of the disclosed compounds and a pharma- ceutically acceptable carrier.

[0022] Also disclosed are synthetic methods for making the disclosed compounds. In a further aspect, the products of the disclosed synthetic methods are disclosed.

[0023] Also disclosed is a method for the treatment of a disorder associated with dysfunctional ENPP1 activity in a mammal, comprising the step of administering to the mammal a therapeutically effective amount of a disclosed compound, or a pharma-ceutically acceptable salt, tautomer, isomer, hydrate, solvate, or polymorph thereof.

[0024] Also disclosed are methods for inhibiting ENPP1 activity in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one disclosed compound, or a pharma-ceutically acceptable salt, tautomer, isomer, hydrate, solvate, or polymorph thereof.

[0025] Also disclosed is a method for inhibiting ENPP1 activity in at least one cell, comprising contacting at least one cell with an effective amount of at least one disclosed compound, or a pharma-ceutically acceptable salt, tautomer, isomer, hydrate, solvate, or polymorph thereof.

[0026] Also disclosed is a method for treating a disorder associated with ENPP1 activity dysfunction in a mammal through inducing an immunotherapeutic response in the mammal, comprising administering to the mammal a therapeutically effective amount of the disclosed compound, or a pharma- ceutically acceptable salt, tautomer, isomer, hydrate, solvate, or polymorph thereof, which compound induces an immunotherapeutic response beneficial in treating the disorder associated with ENPP1 activity. Such a disorder may be, but is not limited to, any type of cancer or any disease caused by bacteria and / or viruses in which ENPP1 activity is implicated.

[0027] Also disclosed are pharmaceutical compositions comprising a pharma- ceutically acceptable carrier and an effective amount of the disclosed compounds, or a pharma- ceutically acceptable salt, tautomer, isomer, hydrate, solvate, or polymorph thereof.

[0028] Also disclosed are kits that include at least one disclosed compound, or a pharma- ceutically acceptable salt, tautomer, isomer, hydrate, solvate, or polymorph thereof.

[0029] Also disclosed is a method for producing a medicament, comprising combining at least one of the disclosed compounds or at least one of the disclosed products with a pharmaceutically acceptable carrier or diluent.In a further aspect, the present invention relates to the use of the disclosed compounds in the manufacture of a medicament for the treatment of disorders associated with ENPP1 activity dysfunction.In a further aspect, the present invention relates to the use of the disclosed compounds in the manufacture of a medicament for the treatment of disorders of uncontrolled cell proliferation.

[0030] Also disclosed is the use of a disclosed compound or a disclosed product in the manufacture of a medicament for the treatment of a disorder associated with ENPP1 dysfunction in a mammal.

[0031] Although aspects of the present invention may be described and claimed in a particular statutory class, such as a system statutory class, this is for convenience and one of ordinary skill in the art will understand that each aspect of the present invention may be described and claimed in any statutory class. Unless otherwise stated, it is never intended that the method or aspects described herein be interpreted as requiring that its steps be performed in a particular order. Thus, if a method claim does not specifically state in the claim or specification that the steps are limited to a particular order, it is never intended that an order be inferred in any respect. This applies to any possible non-express basis for interpretation, including questions of logic regarding the placement or operational flow of steps, simple interpretations derived from grammatical construction or punctuation, or the number or type of aspects described in the specification. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0032] A.Definition As used herein, nomenclature of compounds, including organic compounds, may be given using common names, IUPAC, IUBMB, or CAS nomenclature recommendations. When one or more stereochemical features are present, the Cahn-Ingold-Prelog rules for stereochemistry may be used to specify stereochemical priority, E / Z specifications, etc. Those skilled in the art can readily ascertain the structure of a compound when a name is given, either by systematic reduction of the compound structure using the naming rules, or by commercially available software such as ChemDraw™ (Cambridgesoft Corporation, USA).

[0033] As used in this 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, alkyls, or residues, etc.

[0034] Ranges can be expressed herein as from "about" one particular value and / or to "about" another particular value. When such a range is expressed, a further embodiment includes from one particular value and / or to the other particular value. Similarly, when values ​​are expressed as approximations, it will be understood that by use of the antecedent "about," the particular value forms a further embodiment. It will be further understood that each endpoint of the range is significant both in relation to the other endpoint, and independently of the other endpoint. There are a number of values ​​disclosed herein, and each value is also understood to be disclosed herein as "about" that particular value, in addition to the value itself. For example, if the value "10" is disclosed, then "about 10" is also disclosed. It is understood that each unit between two particular units is also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0035] References in this specification and in the concluding claims to parts by weight of a particular element or component in a composition indicate the weight relationship between the element or component and any other element or component in the composition or article for which the parts by weight are expressed. 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 such ratio regardless of whether additional components are contained in the compound.

[0036] Weight percentage (wt %) is based on the total weight of the formulation or composition in which the ingredient is included, unless specifically stated to the contrary.

[0037] As used herein, the term "ENPP1" refers to an ectonucleotide pyrophosphatase / phosphodiesterase.

[0038] As used herein, the term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes cases where the event or circumstance occurs and cases where the event or circumstance does not occur.

[0039] As used herein, the term "subject" may be a vertebrate, such as a mammal, fish, bird, reptile, or amphibian. Thus, the subject of the methods disclosed herein may be a human, a non-human primate, a horse, a pig, a rabbit, a dog, a sheep, a goat, a cow, a cat, a guinea pig, or a rodent. The term does not indicate a particular age or sex. Thus, it is intended to cover adult and newborn subjects, as well as fetuses, regardless of whether they are male or female. In one aspect, the subject is a mammal. A patient refers to a subject suffering from a disease or disorder. The term "patient" includes human and veterinary subjects. In some aspects of the disclosed methods, the subject has been diagnosed with a need for treatment of a disorder of uncontrolled cell proliferation associated with ENPP1 dysfunction prior to the administering step. In some aspects of the disclosed methods, the subject has been diagnosed with a need for inhibition of ENPP1 prior to the administering step.

[0040] As used herein, the term "treatment" refers to the medical management of a patient with the intent of curing, ameliorating, stabilizing, or preventing a disease, pathological condition, or disorder. This term includes active treatment, i.e., treatment specifically directed to ameliorating a disease, pathological condition, or disorder, and also includes causative treatment, i.e., treatment directed to removing the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, i.e., treatment designed to alleviate symptoms rather than cure the disease, pathological condition, or disorder, preventive treatment, i.e., treatment directed to minimize or partially or completely inhibit the onset of the associated disease, pathological condition, or disorder, and supportive treatment, i.e., treatment used to supplement another specific therapy directed to ameliorating the associated disease, pathological condition, or disorder. In various embodiments, the term encompasses any treatment of a subject, including a mammal (e.g., a human), including (i) preventing the development of a disease in a subject who may be susceptible to the disease but has not yet been diagnosed as having it, (ii) inhibiting the disease, i.e., arresting its progression, or (iii) alleviating the disease, i.e., causing regression of the disease. In one embodiment, the subject is a mammal, such as a primate, and in a further embodiment, the subject is a human. The term "subject" also includes domestic animals (e.g., cats, dogs, etc.), livestock animals (e.g., cows, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mice, rabbits, rats, guinea pigs, fruit flies, zebrafish, etc.).

[0041] As used herein, the term "prevent" or "preventing" refers to impeding, avoiding, removing, forestalling, ceasing, or impeding something from happening, especially by prior action. Where reduce, inhibit, or prevent are used herein, it is understood that the use of the other two words is also expressly disclosed unless specifically indicated otherwise.

[0042] As used herein, the term "diagnosed" means that one has undergone a physical examination by a person skilled in the art, e.g., a physician, and has been found to have a condition that can be diagnosed or treated by a compound, composition, or method disclosed herein. For example, "diagnosed with a disorder of uncontrolled cell proliferation" means that one has undergone a physical examination by a person skilled in the art, e.g., a physician, and has been found to have a condition that can be diagnosed or treated by a compound or composition that can inhibit ENPP1. As a further example, "diagnosed with a need for inhibition of ENPP1" refers to a person having undergone a physical examination by a person skilled in the art, e.g., a physician, and has been found to have a condition characterized by ENPP1 dysfunction. Such a diagnosis may be related to a disorder of uncontrolled cell proliferation, cancer, etc., as discussed herein. For example, "diagnosed with a need for treatment of one or more disorders of uncontrolled cell proliferation associated with ENPP1 dysfunction" means that one has undergone a physical examination by a person skilled in the art, e.g., a physician, and has been found to have one or more disorders of uncontrolled cell proliferation associated with ENPP1 dysfunction.

[0043] As used herein, phrases such as "identified as needing treatment of disorder" refer to the selection of a subject based on the need for treatment of disorder.For example, a subject can be identified as having the need for treatment of disorder (e.g., disorder related to ENPP1 dysfunction) based on early diagnosis by a person skilled in the art, and then be subjected to treatment of the disorder.It is contemplated that in one embodiment, the identification can be performed by a person different from the person who performs the diagnosis.In a further embodiment, it is also contemplated that the administration can be performed by the person who performs the administration afterwards.

[0044] As used herein, the terms "administer" and "administration" refer to any method of providing a pharmaceutical preparation 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, intranasal administration, topical administration, intravaginal administration, intraocular administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, intraurethral administration, and parenteral administration (including injections such as intravenous, intraarterial, intramuscular, and subcutaneous administration). Administration can be continuous or intermittent. In various embodiments, the preparation can be administered therapeutically, i.e., administered to treat an existing disease or condition. In further various embodiments, the preparation can be administered prophylactically, i.e., administered for the prevention of a disease or condition.

[0045] As used herein, the term "contacting" refers to bringing together a disclosed compound and a cell, target receptor, or other biological entity in such a manner that the compound can affect the activity of the target (e.g., receptor, cell, etc.) either directly, i.e., by interacting with the target itself, or indirectly, i.e., by interacting with another molecule, cofactor, factor, or protein on which the activity of the target is dependent.

[0046] As used herein, the terms "effective amount" and "effective amount" refer to an amount that is sufficient to achieve a desired outcome or to have an effect on an undesired condition. For example, a "therapeutically effective amount" refers to an amount that is sufficient to achieve a desired therapeutic outcome or to have an effect on an undesired condition, but generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the specific composition 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 used; the duration of treatment; drugs used in combination with or simultaneously with the specific compound used, as well as similar factors well known in the medical arts. For example, it is well within the skill of the artisan to start a dose of a compound at a level lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. As a result, a single dose composition can contain such an amount or about multiples thereof to make up the daily dose. In the event of any contraindications, the dosage can be adjusted by the individual physician. Dosage can vary and can be administered in one or more doses daily for one or several days.Guidance can be found in the literature for the appropriate administration of a given class of pharmaceutical product.In further various embodiments, the preparation can be administered in a "prophylactically effective amount", i.e., an amount effective for the prevention of a disease or condition.

[0047] 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 a component of the process, including a protein, subunit, organelle, ribonucleoprotein, etc. In one embodiment, EC 50 can refer to the concentration of a substance required for 50% agonism or activation in vivo, as further defined elsewhere herein. 50refers to the concentration of an agonist or activator that elicits a response halfway between the baseline and maximum response.

[0048] 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 a component of the process, including a protein, subunit, organelle, ribonucleoprotein, etc. For example, IC 50 can refer to the concentration of a substance required for 50% inhibition in vivo, as further defined elsewhere herein, or inhibition is measured in vitro. 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.

[0049] The term "pharmacologically acceptable" refers to a material that is not biologically or otherwise undesirable, i.e., does not cause unacceptable levels of undesirable biological effects or interact in a deleterious manner.

[0050] The term "stable" as used herein refers to compounds that do not substantially change when subjected to conditions that permit their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0051] As used herein, the term "derivative" refers to a compound having a structure derived from that of a parent compound (e.g., a compound disclosed herein) that is sufficiently similar to that disclosed herein that it would be expected by one of skill in the art based on that similarity to exhibit the same or similar activity and utility as the claimed compound, or to induce, as a precursor, the same or similar activity and utility as the claimed compound. Exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of the parent compound.

[0052] As used herein, the term "pharmaceutical acceptable carrier" refers to sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, as well as sterile powders for reconstitution into sterile injectables or dispersions immediately prior to use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial activity can be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of injectable pharmaceutical forms can be brought about by the inclusion of agents such as aluminum monostearate and gelatin which delay absorption. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters), and poly(anhydrides). Depending on the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. Injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining 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 medium immediately prior to use. Suitable inert carriers can include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.

[0053] A residue of a chemical species, as used herein and in the concluding claims, refers to a moiety that is a product of a chemical species obtained in a particular reaction scheme or in a subsequent formulation or chemical product, regardless of whether the moiety is actually derived from the chemical species. Thus, an ethylene glycol residue in a polyester refers to one or more -OCH 2 CH 2 Similarly, a sebacic acid residue in a polyester refers to one or more -CO(CH) units in the polyester, regardless of whether the residue is obtained by reacting sebacic acid or an ester thereof to obtain the polyester. 2 ) 8 Refers to the CO- moiety.

[0054] As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. Exemplary substituents include, for example, those described below. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, heteroatoms such as nitrogen can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valence of the heteroatom. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. The terms "substituted" or "substituted with" also include the implicit proviso that such substitution is subject to the permissible valences of the substituted atom and substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, and the like. It is also contemplated that in certain embodiments, unless expressly stated to the contrary, individual substituents can be optionally further substituted (ie, further substituted or unsubstituted).

[0055] In defining various terms,1 ","A 2 ","A 3 " and "A 4 " is used herein as a generic symbol to represent various specific substituents. These symbols can be any substituent, including but not limited to those disclosed herein, and when they are defined as specific substituents in one instance, they can be defined as some other substituents in another instance.

[0056] The term "alkyl" as used herein refers to a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. 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 with one or more groups, including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. A "lower alkyl" group is an alkyl group containing 1 to 6 (e.g., 1 to 4) carbon atoms.

[0057] For example, a "C1-C3 alkyl" group can be selected from methyl, ethyl, n-propyl, i-propyl, and cyclopropyl, or from any subset thereof. In certain embodiments, a "C1-C3 alkyl" group can be optionally further substituted. As a further example, a "C1-C4 alkyl" group can be selected from methyl, ethyl, n-propyl, i-propyl, cyclopropyl, n-butyl, i-butyl, s-butyl, t-butyl, and cyclobutyl, or from any subset thereof. In certain embodiments, a "C1-C4 alkyl" group can be optionally further substituted. As a further example, a "C1-C6 alkyl" group can be selected from methyl, ethyl, n-propyl, i-propyl, cyclopropyl, n-butyl, i-butyl, s-butyl, t-butyl, cyclobutyl, n-pentyl, i-pentyl, s-pentyl, t-pentyl, neopentyl, cyclopentyl, n-hexyl, i-hexyl, 3-methylpentane, 2,3-dimethylbutane, neohexane, and cyclohexane, or any subset thereof. In certain embodiments, a "C1-C6 alkyl" group can be optionally further substituted. As a further example, a "C1-C8 alkyl" group can be selected from methyl, ethyl, n-propyl, i-propyl, cyclopropyl, n-butyl, i-butyl, s-butyl, t-butyl, cyclobutyl, n-pentyl, i-pentyl, s-pentyl, t-pentyl, neopentyl, cyclopentyl, n-hexyl, i-hexyl, 3-methylpentane, 2,3-dimethylbutane, neohexane, cyclohexane, heptane, cycloheptane, octane, and cyclooctane, or any subset thereof. In certain embodiments, a "C1-C8 alkyl" group can be optionally further substituted.As a further example, the "C1-C12 alkyl" group can be selected from methyl, ethyl, n-propyl, i-propyl, cyclopropyl, n-butyl, i-butyl, s-butyl, t-butyl, cyclobutyl, n-pentyl, i-pentyl, s-pentyl, t-pentyl, neopentyl, cyclopentyl, n-hexyl, i-hexyl, 3-methylpentane, 2,3-dimethylbutane, neohexane, cyclohexane, heptane, cycloheptane, octane, cyclooctane, nonane, cyclononane, decane, cyclodecane, undecane, cycloundecane, dodecane, and cyclododecane, or any subset thereof. In certain embodiments, the "C1-C12 alkyl" group can be optionally further substituted.

[0058] Throughout this specification, "alkyl" is generally used to refer to both unsubstituted and substituted alkyl groups, but substituted alkyl groups are also specifically referred to herein by identifying the specific substituents on the alkyl group. For example, the term "halogenated alkyl" or "haloalkyl" specifically refers to an alkyl group substituted with one or more halides, such as fluorine, chlorine, bromine, or iodine. The term "alkoxyalkyl" specifically refers to an alkyl group substituted with one or more alkoxy groups, as described below. The term "alkylamino" specifically refers to an alkyl group substituted with one or more amino groups, as described below, and the like. When "alkyl" is used in one example and a specific term, such as "alkylalcohol", is used in another example, this does not mean that the term "alkyl" does not also refer to a specific term, such as "alkylalcohol".

[0059] This practice is also used for other groups described herein. That is, a term such as "cycloalkyl" refers to both unsubstituted and substituted cycloalkyl moieties, but substituted moieties can additionally be specifically identified herein, e.g., a particular substituted cycloalkyl can be referred to, e.g., as an "alkylcycloalkyl". Similarly, a substituted alkoxy can be specifically referred to, e.g., as a "halogenated alkoxy", a particular substituted alkenyl can be, e.g., as an "alkenylalcohol", and the like. Similarly, the practice of using a general term such as "cycloalkyl" and a specific term such as "alkylcycloalkyl" does not mean that the general term does not also include the specific term.

[0060] The term "cycloalkyl" as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. The term "heterocycloalkyl" is a type of cycloalkyl group as defined above and is included within the meaning of the term "cycloalkyl", in which at least one of the ring carbon atoms is replaced with a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. Cycloalkyl and heterocycloalkyl groups can be substituted or unsubstituted. Cycloalkyl and heterocycloalkyl groups can be substituted with one or more groups, including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, nitrile, sulfonamide, or thiol, as described herein.

[0061] The term "aryl" as used herein is a group that contains any carbon-based aromatic group, including, but not limited to, benzene, naphthalene, phenyl, biphenyl, phenoxybenzene, and the like. The term "aryl" also includes "heteroaryl," which is defined as a group that contains an aromatic group with at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms 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 that contains an aromatic group that does not contain a heteroatom. An aryl group can be substituted or unsubstituted. An aryl group can be substituted with one or more groups, including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, 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." Biaryl refers to two aryl groups that are bonded together through a fused ring structure, as in naphthalene, or through one or more carbon-carbon bonds, as in biphenyl.

[0062] The terms "halogen", "halide", and "halo" as used herein refer to the halogens fluorine, chlorine, bromine, and iodine. In various aspects, it is also contemplated that the halogens may be selected from fluoro, chloro, bromo, and iodo. For example, the halogens may be selected from fluoro, chloro, and bromo. As a further example, the halogens may be selected from fluoro and chloro. As a further example, the halogens may be selected from chloro and bromo. As a further example, the halogens may be selected from bromo and iodo. As a further example, the halogens may be selected from chloro, bromo, and iodo. In one aspect, the halogens may be fluoro. In a further aspect, the halogens may be chloro. In a still further aspect, the halogens are bromo. In a still further aspect, the halogens are iodo.

[0063] It is also contemplated that in certain embodiments, pseudohalogens (e.g., triflates, mesylates, tosylates, brosylates, etc.) may be used in place of halogens. For example, in certain embodiments, halogens can be replaced by pseudohalogens. By way of further example, the pseudohalogens can be selected from triflates, mesylates, tosylates, and brosylates. In one embodiment, the pseudohalogen is a triflate. In a further embodiment, the pseudohalogen is a mesylate. In a further embodiment, the pseudohalogen is a tosylate. In a further embodiment, the pseudohalogen is a brosylate.

[0064] The term "heterocycle" as used herein refers to monocyclic and polycyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon. Heterocycles include azetidine, dioxane, furan, imidazole, isothiazole, isoxazole, morpholine, oxazole, oxadiazole 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, triazole including tetrazine including 1,2,4,5-tetrazine, 1,2,3,4-tetrazole and 1,2,4,5-tetrazole, thiadiazole including tetrazole, 1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole, thiophene, triazine including 1,3,5-triazine and 1,2,4-triazine, 1,2,3-triazole, 1,3,4-triazole, and the like.

[0065] The term "hydroxyl" as used herein is represented by the formula --OH.

[0066] As used herein, "R 1 ", "R 2 ", "R 3 ", n is an integer "R n " can independently have one or more of the groups listed above. For example, R 1When is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group can be optionally replaced with a hydroxyl group, an alkoxy group, an alkyl group, a halide, etc. Depending on the group selected, the first group can be incorporated within the second group, or the first group can be pendant (i.e., attached) to the second group. For example, in the phrase "an alkyl group comprising an amino group," the amino group can be incorporated within the backbone of the alkyl group. Alternatively, the amino group can be attached to the backbone of the alkyl group. The nature of the group selected will determine whether the first group is embedded or attached to the second group.

[0067] As described herein, the compounds of the present invention may contain "optionally substituted" moieties. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the specified moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when multiple positions in any given structure may be substituted with multiple substituents selected from a specified group, the substituents may be either the same or different at all positions. Combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. In certain embodiments, it is also contemplated that individual substituents may be further optionally substituted (i.e., further substituted or unsubstituted) unless expressly indicated to the contrary.

[0068] The compounds described herein contain one or more double bonds and can thus potentially give rise to cis / trans (E / Z) isomers, as well as other conformational isomers, and unless stated to the contrary, the present invention includes all such possible isomers, as well as mixtures of such isomers.

[0069] Unless stated to the contrary, formulas in which chemical bonds are shown only as solid lines, not as wedges or dashed lines, contemplate each possible isomer, e.g., each enantiomer and diastereomer, as well as mixtures of isomers, e.g., racemic or scalemic mixtures. The compounds described herein contain one or more asymmetric centers, and thus can potentially give rise to diastereomers and optical isomers. Unless stated to the contrary, the present invention includes all such possible diastereomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and their pharma-ceutically acceptable salts. Mixtures of stereoisomers, and isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds, or when using racemization or epimerization procedures known to those skilled in the art, the products of such procedures may be mixtures of stereoisomers.

[0070] Many organic compounds exist in optically active forms that have the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L, or R and S, are used to indicate the absolute configuration of the molecule about its chiral center. The prefixes d and l, or (+) and (-), are used to indicate the sign of rotation of plane-polarized light by the compound, with (-) or l meaning that the compound is levorotatory. Compounds preceded by (+) or d are dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are non-superimposable mirror images of one another. A particular stereoisomer may also be called an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture.

[0071] Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, chiral carbons can be indicated with an asterisk (*). When a bond to a chiral carbon is shown as a straight line in a disclosed formula, it is understood that both the (R) and (S) configurations of the chiral carbon, and therefore both enantiomers and mixtures thereof, are included within the formula. As used in the art, when it is desired to specify the absolute configuration for a chiral carbon, one of the bonds to the chiral carbon can be shown as a wedge (bond to an atom above the plane) and the other can be shown as a series of short parallel lines or a wedge (bond to an atom below the plane). The Cahn-Inglod-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.

[0072] The compounds described herein include atoms in both their natural isotopic abundance and non-natural abundance.The disclosed compounds may be the same isotopically labeled or isotopically substituted compounds as described, but due to the fact that one or more atoms are replaced by atoms with atomic mass or mass number different from the atomic mass or mass number typically found in nature.The examples of isotopes that can be incorporated into the compounds of the present invention are respectively: 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 18 F, and 36 The compounds further include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as Cl. The compounds further include prodrugs thereof, and pharma- ceutically acceptable salts of the compounds or prodrugs that contain the aforementioned 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. 3 H and 14Those in which a radioactive isotope such as C is incorporated are useful in drug and / or substrate tissue distribution assays. 3 H, and carbon-14, i.e. 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Additionally, deuterium, i.e., 2 Substitution with heavier isotopes such as H can confer certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced administration requirements, and therefore may be preferred in some circumstances. The isotopically labeled compounds of the present invention and their prodrugs can generally be prepared by carrying out the following procedure by substituting a readily available isotopically labeled reagent for the non-isotopically labeled reagent.

[0073] The compounds described in the present invention can exist as solvates.In some cases, the solvent used to prepare the solvates is an aqueous solution, and the solvates are often called hydrates.The compounds can exist as hydrates, which can be obtained, for example, by crystallization from a solvent or aqueous solution.In this regard, one, two, three, or any number of solvates or water molecules can be combined with the compounds according to the present invention to form solvates and hydrates.Unless stated to the contrary, the present invention includes all such possible solvates.

[0074] It is also understood that certain compounds described herein may exist in equilibrium of tautomers, for example, a ketone having an α-hydrogen may exist in equilibrium of the keto and enol forms. [ka]

[0075] Similarly, amides with an N-hydrogen can exist in equilibrium with the amide and imidic acid forms, and unless stated to the contrary, the invention includes all such possible tautomers.

[0076] Chemical substances are known to form solids that exist in different ordered states, called polymorphic forms or modifications. Different modifications of polymorphic substances can vary greatly in their physical properties. Compounds according to the present invention can exist in different polymorphic forms, and it is possible that certain modifications are metastable. Unless stated to the contrary, the present invention includes all such possible polymorphic forms.

[0077] In some embodiments, the structure of the compound can be represented by the following formula: [ka] , This is understood to be equivalent to the formula: [ka] , In the formula, n is typically an integer. That is, R n is a group consisting of five independent substituents R n(a) , R n(b) , R n(c) , R n(d) , R n(e) By "independent substituents" it is meant that each R substituent can be defined independently. For example, in one example R n(a) is a halogen, R n(b) is not necessarily a halogen in the examples.

[0078] The specific materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art. For example, starting materials and reagents used in preparing the disclosed compounds and compositions can be obtained from any commercial supplier, such as Sigma-Aldrich Chemical Co., (Milwaukee, WI.), Acros Organics (Morris Plains, NJ), Fisher Scientific (Pittsburgh, PA.), or Sigma (St. Louis, MO.), or can be found in other publications, such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition), and Larock's Comprehensive Organic Transformations (VCH Publishers, 1997). They can be prepared by procedures described in references such as (Inc., 1989) and by methods known to those skilled in the art.

[0079] Unless otherwise expressly stated, the methods described herein are in no way intended to be construed as requiring that its steps be performed in a particular order. Thus, unless a method claim actually recites an order to be followed by its steps or specifically states otherwise in the claim or description that the steps are 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 questions of logic regarding the placement or operational flow of steps, simple interpretations derived from grammatical construction or punctuation, and the number or type of embodiments described in the specification.

[0080] Disclosed are the components used to prepare the compositions of the present invention, and the compositions themselves used within the methods disclosed herein. These and other materials are disclosed herein, and when combinations, subsets, interactions, groups, etc. of these materials are disclosed, it is understood that each is specifically contemplated and described herein, although specific references to the various individual and collective combinations and permutations of each of these compounds cannot be explicitly disclosed. For example, when a particular compound is disclosed and discussed, and several modifications that can be made to several molecules that include the compound are discussed, any and all combinations and permutations of the compounds and possible modifications are specifically contemplated, unless specifically indicated to the contrary. Thus, when classes of molecules A, B, and C, and classes of molecules D, E, and F, and an example of a combination molecule, AD, are disclosed, each is individually and collectively contemplated, meaning that the combinations, AE, AF, BD, BE, β-F, CD, CE, and CF, are considered to be disclosed, even if each is not individually listed. Similarly, any subset or combination of these is also disclosed. Thus, for example, the subgroups AE, β-F, and CE are considered to be disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention. Thus, where there are various additional steps that can be performed, it is understood that each of these additional steps can be performed in any specific embodiment or combination of embodiments of the methods of the invention.

[0081] It is understood that the compositions disclosed herein have a specific function. Specific structural requirements for performing the disclosed function are disclosed herein, and it is understood that there are various structures that can perform the same function related to the disclosed structures, and these structures typically achieve the same result.

[0082] B. Compound In one aspect, the present invention relates to compounds useful as inhibitors of ENPP1. Also, in one aspect, the compounds of the present invention are useful in treating disorders of uncontrolled cell proliferation. In a further aspect, the disorder of uncontrolled cell proliferation is cancer or tumor. In yet a further aspect, the disorder of uncontrolled cell proliferation is associated with ENPP1 dysfunction, as further described herein.

[0083] In another aspect, the compounds of the present invention are useful in treating diseases of bacterial or viral origin. Thus, in one aspect, the present invention provides a method for treating a disease caused by bacteria or viruses, comprising administering to a subject a therapeutically effective amount of a compound of the present invention.

[0084] It is contemplated that each of the disclosed derivatives can be optionally further substituted.It is also contemplated that any one or more derivatives can be optionally omitted from the present invention.It is understood that the disclosed compounds can be provided by the disclosed methods.It is also understood that the disclosed compounds can be used in the disclosed methods of use.

[0085] 1. Structure In one aspect, the present invention provides a compound of formula 1, [ka] During the ceremony, X is selected from the group consisting of -C and -N; [ka] but, [ka] is selected from the group consisting of L, [ka] is selected from the group consisting of Y is selected from the group consisting of H and alkyl; R 1 -H, alkyl, O-alkyl, -OCF 3 , -OP=(O)(ONa) 2 , and -CH 2 OP=(O)(ONa) 2 is selected from the group consisting of R 2 -H, alkyl, -O alkyl, -OH, -OCF 3 , -OCH 3 CH 2 OCH 3 , -OCH 3 CH 2 CH 2 OH, -OCH 3 CH 2 CH 2 OCH 3 , -OP=(O)(ONa) 2 , -CH 2 -OP=(O)(ONa) 2 , and [ka] is selected from the group consisting of R 3 But, -H, -NH 2 , and -CH 3 A compound selected from the group consisting of: or an isomer, hydrate, solvate, polymorph, tautomer, or pharma- ceutically acceptable salt thereof.

[0086] In one preferred embodiment, R 1 -H, -CH 3 , -OCH 3 , -OCF 3 , -OP=(O)(ONa) 2 , and -CH 2 OP=(O)(ONa) 2 is selected from the group consisting of:

[0087] In one preferred embodiment, R 1 is OCH 3 It is.

[0088] In another preferred embodiment, R 2 -H, -CH 3 , -OCH 3 , -OH, -OCF 3 , -OCH 2 CH 2 OH, -OCH 2 CH 2 OCH 3 , -OCH 2 OCH 3 , -OP=(O)(ONa) 2 , -CH 2 OP=(O)(ONa) 2 , and [ka] is selected from the group consisting of:

[0089] In another preferred embodiment, Y is selected from the group consisting of H and CH 3 is selected from the group consisting of:

[0090] In one preferred embodiment, Y is H.

[0091] In one preferred embodiment, X is N; [ka] teeth, [ka] and L is [ka] is selected from the group consisting of Y is H, R 1 -H, -CH 3 , and -OCH 3 is selected from the group consisting of R 2 -H, -CH 3 , -OCH 3 , OP=(O)(ONa)2 , -CH 2 -OP=(O)(ONa) 2 , -OH, -OCH 2 CH 2 OH, -OCH 2 CH 2 OCH 3 , -OCH 2 OCH 3 , and [ka] is selected from the group consisting of R 3 -H, -NH 2 , and -CH 3 is selected from the group consisting of:

[0092] In another preferred embodiment, X is C; [ka] teeth, [ka] is selected from the group consisting of L is [ka] is selected from the group consisting of R 1 -H, -CH 3 , and -OCH 3 is selected from the group consisting of R 2 -H, -CH 3 , -OCH 3 , -OH, -OCF 3 , -OCH 2 CH 2 OH, -OCH 2 CH 2 OCH 3 , -OCH 2 OCH 3 , -OP=(O)(ONO) 2 , and -CH 2OP=(O)(ONa) 2 is selected from the group consisting of R 3 -H, -NH 2 , and -CH 3 is selected from the group consisting of: Examples of compounds provided are: [ka] [ka] [ka] Includes.

[0093] The present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of any of the compounds of the present invention and a pharma- ceutically acceptable carrier.

[0094] The invention also provides a method for the treatment of a disorder of uncontrolled cell proliferation in a mammal, the method comprising the step of administering to the mammal an effective amount of any of the compounds of the invention.

[0095] The invention also provides a method for reducing ENPP1 activity in a mammal, the method comprising the step of administering to the mammal an effective amount of any of the compounds of the invention.

[0096] The invention also provides a method for inhibiting ENPP1 activity in a mammal, the method comprising the step of administering to the mammal an effective amount of any of the compounds of the invention.

[0097] C. Methods for Making Compounds In one aspect, the invention relates to methods of making compounds useful as inhibitors of ENPP1, hi further aspects, the products of the disclosed methods of making are modulators of ENPP1 activity.

[0098] The compounds of the present invention can be prepared by using the reactions depicted in the following schemes, in addition to other standard manipulations known in the literature, illustrated in the experimental section, or apparent to one skilled in the art. For clarity, examples with a single substituent are shown; multiple substituents are permissible under the definitions disclosed herein.

[0099] The reactions used to produce the compounds of the present invention are prepared by using the reactions shown in the following reaction schemes, in addition to other standard procedures known in the literature or to those skilled in the art. The following examples are provided so that the invention may be more fully understood, and are illustrative only and should not be construed as limiting.

[0100] In one embodiment, the disclosed compounds include the products of the synthetic methods described herein. In a further embodiment, the disclosed compounds include the compounds produced by the synthetic methods described herein. In yet a further embodiment, the invention includes a pharmaceutical composition comprising a therapeutically effective amount of the product of the disclosed method and a pharma- ceutically acceptable carrier. In yet a further embodiment, the invention includes a method for producing a medicament, comprising combining at least one compound of any of the disclosed compounds or at least one product of the disclosed method with a pharma- ceutically acceptable carrier or diluent.

[0101] If reaction conditions and amounts of components are not described, it is considered that it is within the skill of the art to determine them.It is contemplated that each disclosed method can further include additional steps, operations, and / or components.It is also contemplated that any one or more steps, operations, and / or components can be optionally omitted from the present invention.It is understood that the disclosed method can be used to provide the disclosed compound.It is also understood that the product of the disclosed method can be used in the disclosed method of use.

[0102] D. Pharmaceutical Compositions In one aspect, the present invention relates to a pharmaceutical composition comprising the disclosed compounds. That is, a pharmaceutical composition can be provided that comprises a therapeutically effective amount of at least one of the disclosed compounds or at least one product of the disclosed methods and a pharma- ceutical acceptable carrier.

[0103] In a further aspect, the invention relates to a pharmaceutical composition comprising a pharma- ceutically acceptable carrier and an effective amount of the product of the disclosed synthetic methods. In a further aspect, the effective amount is a therapeutically effective amount. In a further aspect, the effective amount is a prophylactically effective amount. In a further aspect, the compound is a disclosed compound.

[0104] In certain embodiments, the disclosed pharmaceutical compositions comprise the disclosed compounds (including pharma- ceutically acceptable salts thereof) as active ingredients, pharma- ceutically acceptable carriers, and optionally other therapeutic ingredients or adjuvants. The compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host and the nature and severity of the condition for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and can be prepared by any of the methods well known in the art of pharmacy.

[0105] As used herein, the term "pharmaceutical acceptable salt" refers to a salt prepared from a pharmaceutical non-toxic base or acid. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from a pharmaceutical non-toxic base, including inorganic bases and organic bases. Such salts derived from inorganic bases include aluminum, ammonium, calcium, copper (-ic and -ous), ferric, ferrous, lithium, magnesium, manganese (-ic and -ous), potassium, sodium, zinc, and the like salts. Ammonium, calcium, magnesium, potassium, and sodium salts are particularly preferred. Salts derived from pharmaceutical non-toxic organic bases include salts of primary, secondary, and tertiary amines, as well as substituted amines, such as cyclic amines and naturally occurring and synthetic substituted amines. Other pharma- ceutically acceptable organic non-toxic bases which can form salts include, for example, ion exchange resins such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0106] As used herein, the term "pharmaceutically acceptable non-toxic acids" 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. Citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid are preferred.

[0107] In practice, the compounds of the present invention, or pharma- ceutically acceptable salts thereof, can be combined as active ingredients intimately admixed with pharmaceutical carriers according to conventional pharmaceutical compounding techniques. Carriers can take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions 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 the active ingredient. Furthermore, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion, or as a water-in-oil liquid emulsion. In addition to the common dosage forms described above, the compounds of the present invention, and / or pharma- ceutically acceptable salts thereof, can also be administered by sustained release means and / or delivery devices. The compositions can be prepared by any of the methods of pharmacy. In general, such methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers, or both. The product can then be conveniently shaped into the desired presentation.

[0108] Thus, the pharmaceutical compositions of the present invention can include a pharma- ceutically acceptable carrier and a compound or a pharma- ceutically acceptable salt of a compound of the present invention. The compound of the present invention, or a pharma- ceutically acceptable salt thereof, can also be included in a pharmaceutical composition in combination with one or more other therapeutically active compounds.

[0109] The pharmaceutical carrier used can be, for example, solid, liquid or gas.The examples of solid carrier include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid.The examples of liquid carrier include sugar syrup, peanut oil, olive oil and water.The examples of gaseous carrier include carbon dioxide and nitrogen.

[0110] When preparing compositions for oral dosage form, any convenient pharmaceutical medium can be used.For example, water, glycol, oil, alcohol, flavoring agent, preservative, coloring agent, etc. can be used to form oral liquid preparations such as suspension, elixir and solution, while carriers such as starch, sugar, microcrystalline cellulose, diluent, granulating agent, lubricant, binder, disintegrating agent, etc. can be used to form oral solid preparations such as powder, capsule and tablet.Because of their ease of administration, tablets and capsules are the preferred oral dosage units that use solid pharmaceutical carriers.Optionally, tablets can be coated by standard aqueous or non-aqueous techniques.

[0111] The tablet containing the composition of the present invention can be prepared by compression or molding, optionally with one or more auxiliary ingredients or adjuvants.Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surfactant, or dispersant, in a suitable machine.Molded tablets can be made by molding a mixture of powdered compound moistened with an inert liquid diluent in a suitable machine.

[0112] The pharmaceutical composition of the present invention comprises a compound of the present invention (or a pharma- ceutically acceptable salt thereof) as an active ingredient, a pharma- ceutically acceptable carrier, and optionally one or more additional therapeutic agents or adjuvants. The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host and the nature and severity of the condition for which the active ingredient is being administered. The pharmaceutical composition can be conveniently presented in unit dosage form and can be prepared by any of the methods well known in the art of pharmacy.

[0113] 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.For example, suitable surfactants such as hydroxypropylcellulose can be included.Dispersion can also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oil.In addition, preservatives can be included to prevent harmful growth of microorganisms.

[0114] The pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions.In all cases, the final injectable form must be sterile and effectively fluid for easy needle passage.The pharmaceutical compositions must be stable under the conditions of manufacture and storage, and thus should preferably be preserved against the contaminating action of microorganisms such as bacteria and fungi.The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oil, and suitable mixtures thereof.

[0115] The pharmaceutical compositions of the present invention may be in a form suitable for topical use, such as, for example, an aerosol, cream, ointment, lotion, dusting powder, mouthwash, gargle, etc. Additionally, the compositions may be in a form suitable for use in transdermal devices. These formulations may be prepared via conventional processing methods utilizing the compounds of the present invention, or pharma-ceutically acceptable salts thereof. As an example, a cream or ointment is prepared by mixing a hydrophilic material and water together with about 5% to about 10% by weight of the compound to produce a cream or ointment having a desired consistency.

[0116] The pharmaceutical composition of the present invention can be in a form suitable for rectal administration, where the carrier is solid.Preferably, the mixture forms unit-dose suppositories.Suitable carriers include cocoa butter and other materials commonly used in the art.Suppositories can be conveniently formed by first mixing the composition with softened or melted carrier, followed by cooling and shaping in a mold.

[0117] In addition to the aforementioned carrier components, the above pharmaceutical formulations may optionally contain one or more additional carrier components, such as diluents, buffers, flavorings, binders, 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. The compositions containing the compounds of the present invention, and / or their pharma-ceutically acceptable salts, may also be prepared in powder or liquid concentrate form.

[0118] In the treatment of conditions requiring inhibition or negative regulation of ENPP1 protein activity, suitable dosage levels will generally be about 0.01-500 mg / kg of patient body weight per day, which may be administered in single or multiple doses. Preferably, dosage levels will be about 0.1-250 mg / kg per day, more preferably 0.5-100 mg / kg per day. Suitable dosage levels may be about 0.01-250 mg / kg per day, about 0.05-100 mg / kg per day, or about 0.1-50 mg / kg per day. Within this range, dosages may be 0.05-0.5, 0.5-5.0, or 5.0-50 mg / kg per day. For oral administration, the composition is preferably provided in the form of a tablet containing 1.0 to 1000 milligrams of active ingredient, particularly 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of active ingredient, for symptomatic adjustment of the dosage of the patient to be treated. The compound may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. This administration regimen may be adjusted to provide the optimum therapeutic response.

[0119] However, it is understood that the specific dose level for any particular patient will depend on various factors. Such factors include the age, weight, general health condition, sex and diet of the patient. Other factors include the time and route of administration, excretion rate, drug combination, and the type and severity of the particular disease undergoing therapy.

[0120] The invention further relates to a method for producing a medicament for inhibiting or negatively modulating ENPP1 protein activity in a mammal (e.g., a human) (e.g., treating a disorder of uncontrolled cell proliferation, or one or more neurodegenerative disorders associated with ENPP1 dysfunction), comprising combining one or more of the disclosed compounds, products, or compositions with a pharma- ceutically acceptable carrier or diluent. Thus, in one aspect, the invention relates to a method for producing a medicament, comprising combining at least one of the disclosed compounds or at least one of the disclosed products with a pharma-ceutically acceptable carrier or diluent.

[0121] The disclosed pharmaceutical compositions may further comprise other therapeutically active compounds, which are usually applied in the treatment of the above mentioned pathological conditions.

[0122] 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.

[0123] E. Methods of Using the Compounds and Compositions The disclosed compounds can be used as single agents or in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of the risk of the aforementioned diseases, disorders, and conditions for which the compounds of formula I or other drugs have utility, and the combination of drugs together is safer or more effective than either drug alone. The other drugs can be administered simultaneously with the disclosed compounds or sequentially, by a route and in an amount commonly used therefor. When the disclosed compounds are used simultaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such drugs and the disclosed compounds is preferred. However, the combination therapy can also be carried out on an overlapping schedule. It is also envisioned that the combination of one or more active ingredients and the disclosed compounds will be more effective than either as a single agent.

[0124] The pharmaceutical compositions and methods of the present invention may further comprise other therapeutically active compounds as described herein, which are typically applied in the treatment of the above mentioned pathological conditions.

[0125] 1. Treatment The compounds disclosed herein are useful for treating, preventing, ameliorating, controlling, or reducing the risk of various disorders, and patients or subjects would benefit from the inhibition or negative regulation of ENPP1. In one aspect, a method of treating or preventing a disorder in a subject is provided, comprising administering to the subject at least one disclosed compound, at least one disclosed pharmaceutical composition, and / or at least one disclosed product in a dosage and amount effective to treat the disorder in the subject.

[0126] Also provided are methods for the treatment of one or more disorders in a subject for which ENPP1 inhibition is predicted to be beneficial, comprising administering to the subject at least one disclosed compound, at least one disclosed pharmaceutical composition, and / or at least one disclosed product, in a dosage and amount effective to treat the disorder in the subject.

[0127] In one aspect, a method is provided for treating a disorder of uncontrolled cell proliferation, comprising administering to a subject at least one disclosed compound, at least one disclosed pharmaceutical composition, and / or at least one disclosed product in a dosage and amount effective for treating the disorder in the subject. In a further aspect, a method is provided for treating or preventing a neurodegenerative disorder, comprising administering to a subject at least one disclosed compound, at least one disclosed pharmaceutical composition, and / or at least one disclosed product in a dosage and amount effective for treating the disorder in the subject. Also provided is a method for treating a disorder in a mammal, comprising administering to the mammal at least one disclosed compound, composition, or pharmaceutical.

[0128] The present invention relates to the use of the described chemical compositions for treating a disease or disorder in a patient (preferably a human), where ENPP1 inhibition is predicted to have therapeutic effects on disorders of uncontrolled cell proliferation (e.g., cancer), neurodegenerative disorders such as Alzheimer's disease, Huntington's disease, and Parkinson's disease, diseases caused by bacteria and / or viruses, by administering one or more of the disclosed compounds or products.

[0129] The compound of the present invention can also be used for immunotherapy.In one embodiment, the compound of the present invention treats the disorder of uncontrolled cell proliferation and / or the disease caused by bacteria and / or viruses through immunotherapy, which means that the compound induces the immunotherapeutic response that leads to the treatment of these diseases.

[0130] The compounds disclosed herein are useful for treating, preventing, ameliorating, controlling, or reducing the risk of a variety of disorders of unregulated cell proliferation.

[0131] Methods of using the disclosed compounds, compositions, or pharmaceuticals are also provided. In one aspect, the methods of use are directed to the treatment of disorders. In a further aspect, the disclosed compounds can be used as single agents or in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of the risk of the aforementioned diseases, disorders, and conditions for which the compounds or other drugs have utility, and the combination of drugs together is safer or more effective than either drug alone. The other drugs can be administered simultaneously or sequentially with the disclosed compounds, by a route and in an amount commonly used therefor. When the disclosed compounds are used simultaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such drugs and the disclosed compounds is preferred. However, the combination therapy can also be carried out on an overlapping schedule. It is also envisioned that the combination of one or more active ingredients with the disclosed compounds may be more effective than either as a single agent.

[0132] Examples of disorders treatable with the provided compounds include disorders of uncontrolled cell proliferation. In yet a further aspect, the disorder of uncontrolled cell proliferation is cancer. In yet a further aspect, the cancer is leukemia. In yet a further aspect, the cancer is a sarcoma. In yet a further aspect, the cancer is a solid tumor. In yet a further aspect, the cancer is a lymphoma.

[0133] Cancer is understood to refer to or describe a physiological state in mammals that is typically characterized by unregulated cell proliferation. Cancer can be multidrug resistant (MDR) or drug sensitive. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia. More specific examples of such cancer 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, e.g., hepatoma, bladder cancer, colorectal cancer, endometrial cancer, kidney cancer, and thyroid cancer.

[0134] In various embodiments, further examples of cancers are basal cell carcinoma, biliary tract cancer, bone cancer, brain and CNS cancer, choriocarcinoma, connective tissue cancer, esophageal cancer, eye cancer, cancer of the head and neck, gastric cancer, intraepithelial neoplasia, laryngeal cancer, lymphoma including Hodgkin's lymphoma and non-Hodgkin's lymphoma, melanoma, myeloma, neuroblastoma, oral cancer (e.g., lips, tongue, mouth, and pharynx), retinoblastoma, rhabdomyosarcoma, rectal cancer, cancer of the respiratory system, sarcoma, skin cancer, stomach cancer, testicular cancer, uterine cancer, cancer of the urinary system, and other carcinomas and sarcomas.

[0135] In a further aspect, the cancer is a blood cancer. In yet a further aspect, the blood cancer is selected from acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma, solitary myeloma, localized myeloma, and extramedullary myeloma. In yet a further aspect, the cancer is selected from chronic lymphocytic leukemia, small lymphocytic lymphoma, B-cell non-Hodgkin's lymphoma, and large B-cell lymphoma.

[0136] In a further aspect, the cancer is brain cancer.In yet a further aspect, the 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, pineocytoma, pineoblastoma, atypical teratoid rhabdoid tumor, chondrosarcoma, chondroma, choroid plexus carcinoma, choroid plexus papilloma, craniopharyngioma, embryonal dysplastic neuroepithelial tumor, gangliocytoma, germinoma, hemangioblastoma, hemangiopericytoma and metastatic brain tumor.In yet a further aspect, the glioma is selected from ependymoma, astrocytoma, oligodendroglioma and oligoastrocytoma. In still further aspects, the glioma is selected from juvenile pilocytic astrocytoma, subependymal giant cell astrocytoma, ganglioglioma, subependymoma, polymorphic xanthoastrocytoma, anaplastic astrocytoma, glioblastoma multiforme, brain stem glioma, oligodendroglioma, ependymoma, oligoastrocytoma, cerebellar astrocytoma, desmoplastic infantile astrocytoma, subependymal giant cell astrocytoma, diffuse astrocytoma, mixed glioma, optic glioma, gliomatosis cerebri, multifocal gliomatous tumor, multicentric glioblastoma, pleomorphic tumor, paraganglioma, and ganglioglioma.

[0137] In one aspect, the cancer may be a cancer selected from cancer of the blood, brain, genitourinary system, gastrointestinal tract, colon, rectum, breast, kidney, lymphatic system, stomach, lung, pancreas, and skin. In a further aspect, the cancer is selected from prostate cancer, glioblastoma multiforme, endometrial cancer, breast cancer, and colon cancer. In a further aspect, the cancer is selected from cancer of the breast, ovary, prostate, head, neck, and kidney. In a still further aspect, the cancer is selected from cancer of the blood, brain, genitourinary system, gastrointestinal tract, colon, rectum, breast, liver, kidney, lymphatic system, stomach, lung, pancreas, and skin. In a still further aspect, the cancer is selected from cancer of the lung and liver. In a still further aspect, the cancer is selected from cancer of the breast, ovary, testis, and prostate. In a still further aspect, the cancer is cancer of the breast. In a still further aspect, the cancer is cancer of the ovary. In a still further aspect, the cancer is cancer of the prostate. In a still further aspect, the cancer is testicular cancer.

[0138] In various embodiments, the disorder associated with ENPP1 dysfunction includes a neurodegenerative disorder. In further embodiments, the neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease, and Huntington's disease.

[0139] The compounds are further useful in methods for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders, and conditions described herein.The compounds are further useful in methods for the prevention, treatment, control, amelioration, or reduction of risk of the aforementioned diseases, disorders, and conditions in combination with other agents.

[0140] The present invention further relates to the administration of ENPP1 inhibitors to improve therapeutic outcomes in the context of disorders of uncontrolled cell proliferation, including cancer. That is, in one aspect, the present invention relates to a co-therapy comprising administering to a mammal an effective amount and dosage of at least one compound of the present invention in conjunction with cancer therapy.

[0141] In a further aspect, the administration improves therapeutic outcome in the context of cancer therapy. Administration associated with cancer therapy can be continuous or intermittent. Administration does not have to be simultaneous with therapy, but can be before, during, and / or after therapy. For example, the cancer therapy can be provided within 1, 2, 3, 4, 5, 6, 7 days before or after the administration of the compound. As a further example, the cancer therapy can be provided within 1, 2, 3, or 4 weeks before or after the administration of the compound. As a further example, the cognitive or behavioral therapy can be provided before or after the administration within 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 half-lives of the compound administered.

[0142] In one embodiment, the disclosed compounds can be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of the risk of a disease or condition for which the disclosed compounds or other drugs can have utility, and the combination of drugs together is safer or more effective than either drug alone. Such other drugs can be administered simultaneously or sequentially with the compounds of the present invention, by a route and amount commonly used therefor. When the compounds of the present invention are used simultaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the disclosed compounds is preferred. However, combination therapy can also include therapy in which the disclosed compounds and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the disclosed compounds and other active ingredients can be used in lower doses than when each is used alone.

[0143] Accordingly, the pharmaceutical compositions include those that contain one or more other active ingredients, in addition to a compound of the present invention.

[0144] The above combinations include combinations of the disclosed compounds not only with one other active compound, but also with two or more other active compounds.Similarly, the disclosed compounds can be used in combination with other drugs used to prevent, treat, control, improve, or reduce the risk of diseases or conditions for which the disclosed compounds are useful.Such other drugs can be administered simultaneously or sequentially with the compounds of the present invention, by a route and in an amount commonly used therefor.When the compounds of the present invention are used simultaneously with one or more other drugs, pharmaceutical compositions containing such other drugs in addition to the disclosed compounds are preferred.Thus, pharmaceutical compositions include those that contain one or more other active ingredients in addition to the compounds of the present invention.

[0145] The weight ratio of the disclosed compound to the second active ingredient may vary and will depend on the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when the compound of the present invention is combined with another drug, the weight ratio of the disclosed compound to the other drug will generally be in the range of about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. The combination of the compound of the present invention and the other active ingredient will also generally be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.

[0146] In such combinations, the disclosed compounds and the other active agent can be administered separately or together. In addition, the administration of one element may be prior to, concurrent with, or subsequent to the administration of the other agent.

[0147] Thus, the subject compounds can be used alone or in combination with other agents known to be beneficial in the target indications, or other drugs that affect receptors or enzymes that either enhance the efficacy, safety, convenience, or reduce undesirable side effects or toxicity of the disclosed compounds. The subject compounds and other agents can be co-administered, either in combination therapy or in a fixed combination.

[0148] In one embodiment, the compounds may be used in combination with anti-cancer or other known therapeutic agents.

[0149] In the treatment of conditions requiring inhibition or negative regulation of ENPP1, suitable 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, dosage levels 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, dosages 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 a tablet containing 1.0 to 1000 milligrams of active ingredient, particularly 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of active ingredient, for symptomatic adjustment of administration to the patient being treated. The compound may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. This administration regimen may be adjusted to provide the optimum therapeutic response. However, it will be understood that the specific dose level and frequency of administration for any particular patient may vary and will depend on a variety of factors, including the activity of the particular compound employed, the metabolic stability and length of action of that compound, age, body weight, general health, sex, diet, mode and time of administration, excretion rate, drug combination, severity of the particular condition, and the host undergoing therapy.

[0150] Thus, in one aspect, the present invention relates to a method for inhibiting or negatively modulating ENPP1 in at least one cell, comprising contacting at least one cell with at least one compound of the present invention in an amount effective to modulate or activate ENPP1 activity response in at least one cell, for example.In a further aspect, the cell is a mammal, for example a human.In a further aspect, the cell is isolated from a subject before the contacting step.In a further aspect, the contacting is via administration to a subject.

[0151] a. Treatment of disorders of uncontrolled cell proliferation In one aspect, the invention relates to a method for the treatment of a disorder of uncontrolled cell proliferation in a mammal, the method comprising the step of administering to the mammal an effective amount of at least one disclosed compound or the product of the disclosed methods of making the compound, or a pharma- ceutically acceptable salt, hydrate, solvate, or polymorph thereof, thereby treating the disorder of uncontrolled cell proliferation.

[0152] In a still further aspect, the effective amount is a therapeutically effective amount. In a still yet further aspect, the effective amount is a prophylactically effective amount.

[0153] In a further aspect, the mammal is a human. In yet a further aspect, the method further comprises identifying the mammal in need of treatment for a disorder of uncontrolled cell proliferation. In yet a further aspect, the mammal has been diagnosed with a need for treatment for a disorder of uncontrolled cell proliferation prior to the administering step.

[0154] In a further aspect, the disorder of uncontrolled cell proliferation is cancer. In a still further aspect, the cancer is a leukemia. In a still further aspect, the cancer is a sarcoma. In a still further aspect, the cancer is a solid tumor. In a still further aspect, the cancer is a lymphoma. In a still further aspect, the cancer is selected from chronic lymphocytic leukemia, small lymphocytic lymphoma, B-cell non-Hodgkin's lymphoma, and large B-cell lymphoma. In a still further aspect, the cancer is selected from cancer of the blood, brain, genitourinary tract, gastrointestinal tract, colon, rectum, breast, liver, kidney, lymphatic system, stomach, lung, pancreas, and skin. In a still further aspect, the cancer is selected from cancer of the lung and liver. In a still further aspect, the cancer is selected from cancer of the breast, ovary, testis, and prostate. In a still further aspect, the cancer is cancer of the breast. In a still further aspect, the cancer is cancer of the ovary. In a still further aspect, the cancer is cancer of the prostate. In a still further aspect, the cancer is testicular cancer. EXAMPLES

[0155] F. Experiment The following examples are presented to provide one of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices, and / or methods claimed herein are made and evaluated, are intended to be purely exemplary of the invention, and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless otherwise indicated, parts are parts by weight, temperature is °C or is ambient temperature, and pressure is at or near atmospheric pressure.

[0156] Several methods for preparing the compounds of this invention are illustrated in the following examples. Starting materials and the requisite intermediates are in some cases commercially available, or can be prepared according to literature procedures or as illustrated herein.

[0157] The following exemplary compounds of the present invention have been synthesized. The examples are provided herein to illustrate the present invention, and should not be construed as limiting the present invention in any manner. The examples are typically depicted in free base form according to IUPAC naming rules. However, some of the examples have been obtained or isolated in salt form.

[0158] Some of the examples were obtained as racemic mixtures of one or more enantiomers or diastereomers. The compounds can be separated by those skilled in the art to isolate the individual enantiomers. Separation can be carried out by coupling the racemic mixture of the compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods such as fractional crystallization or chromatography. The racemic or diastereomeric mixture of the compounds can also be directly separated by chromatographic methods using chiral stationary phases.

[0159] Experimental Chemistry Synthetic schemes, methods and procedures: Synthesis of N-(2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)propyl)sulfonamide urea (I-01) [ka]

[0160] Synthesis of ethyl 2-(1-benzylpiperidin-4-ylidene)propanoate (01) To a stirred solution of 1-benzylpiperidin-4-one (1) (9 g, 47.5 mmol, 1 eq) in THF (90 mL) was added 60% NaH (3.8 g, 95.1 mmol, 2 eq) at 0° C. Then, a solution of ethyl 2-(diethoxyphosphoryl)propanoate (2) (16.3 mL, 76 mmol, 1.6 eq) in THF (10 mL) was added dropwise and the reaction mixture was allowed to stir at room temperature for 1 h. 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. The crude was purified by silica column chromatography by eluting with 20% EtOAc in hexane to give ethyl 2-(1-benzylpiperidin-4-ylidene)propanoate (01) as a pale yellow liquid (10 g, yield: 76%). TLC system: EtOAc / hexane (30:70), R f Value: about 0.6, 1 H NMR (400 MHz, CDCl 3 )δ 7.34-7.25(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).

[0161] Synthesis of tert-butyl 4-(1-ethoxy-1-oxopropan-2-yl)piperidine-1-carboxylate (02) 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) 2 O (1.54 mL, 7.06 mmol, 1 eq) was added, followed by 10% Pd / C (200 mg). The reaction mixture was diluted with H 2 The mixture was stirred at 55° C. in a steel bomb under (55 psi) for 6 h. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad. The filtrate obtained 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 pale yellow liquid. TLC system: EtoAc:Hexane (10:90, KMnO 4 staining), R f Value: about 0.3, 1 H NMR (400 MHz, CDCl 3 )δ 4.17-4.07(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).

[0162] Synthesis of tert-butyl 4-(1-hydroxypropan-2-yl)piperidine-1-carboxylate (03): 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 was added NaBH 4(1.58g, 42mmol, 6eq) was added. The reaction mixture was stirred at 80°C for 24 hours and after completion of the reaction by TLC, the reaction mixture was quenched with ice cold water and extracted with ethyl acetate (2X100mL). The combined organic layers were washed with water (50mL), brine (50mL), dried over sodium sulfate and concentrated to give the crude product. The crude compound was purified by 100-200 mesh silica gel column chromatography by eluting with 20% EtOAc in hexane to give tert-butyl 4-(1-hydroxypropan-2-yl)piperidine-1-carboxylate (03) (1.5g, yield: 88%) as a viscous liquid. TLC system EtoAc:Hexane (30:70, KMnO 4 staining), R f Value: 0.3, LCMS (m / z): 188.2 (M+H-tBu) + , 1 HNMR (400 MHz, DMSO-d 6 )δ 4.37(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).

[0163] Synthesis of tert-butyl 4-(1-(tosyloxy)propan-2-yl)piperidine-1-carboxylate (04) To a stirred solution of tert-butyl 4-(1-hydroxypropan-2-yl)piperidine-1-carboxylate (03) (1.5 g, 6.1 mmol, 1 eq) in DCM (10 mL) cooled to 0° C., TEA (2.64 mL, 18.3 mmol, 3 eq), tosyl chloride (1.75 g, 9.2 mmol, 1.5 eq) were added and 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 (2×100 mL). The combined organic layers were washed with water (50 mL), brine (40 mL), dried over sodium sulfate and concentrated to give the crude product. The crude compound was purified on a 100-200 mesh silica gel column by eluting with 20% EtOAc in hexane to give tert-butyl 4-(1-(tosyloxy)propan-2-yl)piperidine-1-carboxylate (04) (1.5 g, yield: 60%) as a viscous liquid. TLC system EtoAc:Hexane (30:70), R f Value: 0.5, LCMS (m / z): 298.2 (M+H-Boc) + , 1 HNMR (400 MHz, CDCl 3 )δ 7.79(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).

[0164] Synthesis of tert-butyl 4-(1-azidopropan-2-yl)piperidine-1-carboxylate (05) 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 NaN 3(1.2 g, 18.8 mmol, 5 eq) was added and 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, KMnO 4 staining), R f Value: 0.8, 1 HNMR (400 MHz, CDCl 3 )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).

[0165] Synthesis of tert-butyl 4-(1-aminopropan-2-yl)piperidine-1-carboxylate (06) 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) was added 10% Pd / C (450 mg). The reaction mixture was stirred at room temperature for 3 h. 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 (400 MHz, DMSO-d 6 )δ 3.97-3.94(m, 2H), 2.66-2.49(m, 3H), 2.36(ABq, J=7.2Hz, 1H), 1.53-1.44(m, 5H), 1.42(s, 9H), 1.09-0.97(m, 3H), 0.78(d, J=6.8Hz, 3H).

[0166] Synthesis of tert-butyl 4-(1-((N-(tert-butoxycarbonyl)sulfamoyl)amino)propan-2-yl)piperidine-1-carboxylate (07) 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., DIPEA (0.56 mL, 3.07 mmol, 1.5 eq), and (tert-butoxycarbonyl)((4-(dimethyliminio)pyridin-1(4H)-yl)sulfonyl)amide (3) (805 mg, 2.67 mmol, 1.3 eq) were added and the reaction mixture was stirred at room temperature for 16 h. 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 resulting crude was purified by reverse phase Grace column purification to give tert-butyl 4-(1-((N-(tert-butoxycarbonyl)sulfamoyl)amino)propan-2-yl)piperidine-1-carboxylate (07) (440 mg, yield: 50%) as a viscous liquid. TLC system MeOH:DCM (10:90, KMnO 4 staining), R f Value: 0.8, 1 HNMR (400 MHz, DMSO-d 6 )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).

[0167] Synthesis of N-(2-(piperidin-4-yl)propyl)sulfonamide urea hydrochloride (08) 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 dioxane.HCl (3 mL). The reaction mixture was stirred at room temperature for 1 h 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 (400 MHz, DMSO-d 6 )δ 8.91(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).

[0168] Synthesis of N-(2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)propyl)sulfonamide urea (I-01): 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., 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) were added and stirred at room temperature for 16 h. 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 the crude product. The crude compound was purified by preparative HPLC to give N-(2-(1-(6,7-dimethoxyquinazolin-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 (400 MHz, DMSO-d 6)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).

[0169] Scheme for the synthesis of N-(2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propyl)sulfamoylcarbamate (I-02) [ka]

[0170] Synthesis of tert-butyl 4-(1-cyanoethylidene)piperidine-1-carboxylate (01) To a stirred solution of tert-butyl 4-oxopiperidine-1-carboxylate (1) (1.5 g, 7.5 mmol, 1 eq) in THF (15 mL) at 0° C., diethyl (1-cyanoethyl)phosphonate (2) (2.15 g, 11.3 mmol, 1.5 eq), LiBr (0.72 g, 9 mmol, 1.2 eq), and TEA (2 mL, 15 mmol, 2 eq) were added. The reaction mixture was allowed to stir at room temperature for 16 h. 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 was purified by silica column chromatography by eluting with 20% EtOAc in hexane to give tert-butyl-4-(1-cyanoethylidene)piperidine-1-carboxylate (01) as a white solid (1.2 g, yield: 70%). TLC system: EtOAc / hexane (30:70, ninhydrin stain), R f Value: about 0.6, 1 H NMR (400 MHz, CDCl 3)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).

[0171] Synthesis of tert-butyl 4-(1-cyanoethyl)piperidine-1-carboxylate (02) To a stirred solution of tert-butyl 4-(1-cyanoethylidene)piperidine-1-carboxylate (01) (1.2 g, 5 mmol, 1 eq) in dry methanol (70 mL) was added Mg turnings (4.8 g, 0.2 mol, 40 eq). The reaction mixture was stirred at room temperature for 3 h. 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 stain), R f Value: about 0.5, 1 H NMR (400 MHz, CDCl 3 )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)

[0172] Synthesis of 2-(piperidin-4-yl)propanenitrile hydrochloride (03) A solution of tert-butyl 4-(1-cyanoethyl)piperidine-1-carboxylate (02) (1.2 g, 5 mmol, 1 eq) in 4M dioxane.HCl (12 mL) was stirred at room temperature for 1 h, and after completion of the reaction by TLC, the reaction mixture was concentrated under reduced pressure to give 2-(piperidin-4-yl)propanenitrile hydrochloride (03) (0.88 g, yield: 99%) as a sticky solid. TLC system EtoAc (100%, KMnO 4 staining), Rf Value: 0.1, 1 HNMR (400 MHz, DMSO-d 6 )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).

[0173] Synthesis of 2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propanenitrile (04) To a stirred solution of 4-chloro-6,7-dimethoxyquinoline (3) (1 g, 4.46 mmol, 1 eq) in 1,4 dioxane (10 mL) was added 2-(piperidin-4-yl)propanenitrile hydrochloride (03) (0.73 g, 5.35 mmol, 1.2 eq), degassed for 10 min, and cooled to 5° C. 2 CO 3 (4.34g, 13.3mmol, 3eq), Pd 2 (dba) 3 (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 in a sealed tube at 110° C. for 16 h. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad and concentrated to give the crude. The crude compound was purified by 100-200 mesh silica gel column by eluting with 3% MeOH in 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) + , 1 HNMR (400 MHz, DMSO-d 6)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).

[0174] Synthesis of 2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propan-1-amine (05) 7M methanolic NH 3 To a stirred solution of 2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propanenitrile (04) (500 mg, 1.53 mmol, 1 eq) in 10 mL of H was added Ra-Ni (250 mg). The reaction mixture was stirred at room temperature for 16 h. 2 Stirred under balloon pressure. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad and concentrated to give 2-(1-(6,7-dimethoxyquinolin-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 (400 MHz, DMSO-d 6 )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, 2 H), 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).

[0175] Synthesis of tert-butyl N-(2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propyl)sulfamoylcarbamate (06) 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-(dimethyliminio)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 h. 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 (400 MHz, DMSO-d 6 )δ 8.48(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).

[0176] Synthesis of (I-02) 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 4M dioxane.HCl (1 mL) was stirred at room temperature for 2 h. 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) + , 1 HNMR (400 MHz, DMSO-d 6 )δ 8.51(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), 2.78-2.75(m, 1H), 1.82-1.76(m, 3H), 1.64-1.44(m, 3H), 0.89(d, J=6.8Hz, 3H).

[0177] Scheme for the synthesis of 7-methoxy-4-(4-(2-(sulfamoylamino)ethyl)piperidin-1-yl)quinazolin-6-yl sodium phosphate (I-03) [ka]

[0178] Synthesis of 6,7-dimethoxyquinazolin-4-ol (01) To a stirred solution of 4-chloro-6,7-dimethoxyquinazoline (1) (10 g, 44.64 mmol, 1 eq) in THF (100 mL) was added H 2KOH (8.2 g, 147.3 mmol, 3.3 eq) in 2O (50 mL) was added and the reaction mixture was stirred at 75° C. for 24 h. After completion of the reaction by TLC, the reaction mixture was cooled to 0° C. and acetic acid was added. The precipitated solid was filtered under vacuum and dried to give 6,7-dimethoxyquinazolin-4-ol (01) as a pale yellow solid (7 g, yield: 76%). TLC system: EtOAc (100), R f Value: approx. 0.1, LCMS (m / z): 207.1 (M+H) + , 1 HNMR (400 MHz, DMSO-d 6 )δ 12.1(brs, 1H), 7.98(s, 1H), 7.44(s, 1H), 7.13(s, 1H), 3.9(s, 3H), 3.87(s, 3H).

[0179] Synthesis of 4-hydroxy-7-methoxyquinazolin-6-yl acetate (02) To a stirred solution of 6,7-dimethoxyquinazolin-4-ol (01) (7 g, 36.2 mmol, 1 eq) in methanesulfonic acid (60 mL) was added DL-methionine (8.6 g, 57.9 mmol, 1.6 eq). The reaction mixture was stirred at 120° C. for 24 h, after completion of the reaction by TLC, the reaction mixture was cooled to 0° C. and precipitated by adding 2M NaOH, the solid was filtered and dried. The resulting solid was identified as (Ac) 2 2H 2 O (24 mL) and pyridine (5.3 mL, 67.6 mmol, 2 eq) was added. The reaction mixture was stirred at 100° C. for 24 h, after completion of the reaction by TLC, the reaction mixture was diluted with cold water, the precipitated solid was filtered and dried under vacuum to give 4-hydroxy-7-methoxyquinazolin-6-yl acetate (02) (5.5 g, yield: 69%) as an off-white solid. TLC system: EtOAc (100), R f Value: approx. 0.2, LCMS (m / z): 235.0 (M+H) + , 1 HNMR (400 MHz, DMSO-d 6 )δ 12.2(brs, 1H), 8.08(s, 1H), 7.74(s, 1H), 7.27(s, 1H), 3.9(s, 3H), 2.29(s, 3H).

[0180] Synthesis of 4-chloro-7-methoxyquinazolin-6-yl acetate (03) To a stirred solution of 4-hydroxy-7-methoxyquinazolin-6-yl acetate (02) (2 g, 8.54 mmol, 1 eq) in thionyl chloride (18 mL), catalytic DMF (1 mL) was added and the reaction mixture was stirred at 80° C. for 2 h, after completion of the reaction by TLC, the reaction mixture was diluted with toluene and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica column chromatography by eluting with 20% EtOAc in hexane to obtain 4-chloro-7-methoxyquinazolin-6-yl acetate (03) (1.2 g, yield: 57%) as a cream solid. TLC system: EtOAc in hexane (50:50), R f Value: 0.5, LCMS(m / z): 253.1(M+H) + , 1 HNMR (400 MHz, CDCl 3 )δ 8.95(s, 1H), 7.90(s, 1H), 7.43(s, 1H), 4.02(s, 3H), 2.39(s, 3H).

[0181] Synthesis of tert-butyl 4-(cyanomethylene)piperidine-1-carboxylate (04) To a stirred solution of tert-butyl 4-oxopiperidine-1-carboxylate (2) (5 g, 25.1 mmol, 1 eq) in THF (50 mL) was added diethyl(cyanomethyl)phosphonate (3) (6.67 mL, 37.6 mmol, 1.5 eq) at 0° C. Then LiBr (2.58 g, 30.1 mmol, 1.2 eq), TEA (7.2 mL, 50.2 mmol, 2 eq) were added and the reaction mixture was allowed to stir at room temperature for 16 h. 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 was purified by silica column chromatography by eluting with 20% EtOAc in hexane to give tert-butyl 4-(cyanomethylene)piperidine-1-carboxylate (04) as a white solid (5 g, yield: 89%). TLC system: EtOAc / hexane (20:80), R f Value: approx. 0.6, PMA staining, 1 H NMR (400 MHz, CDCl 3 )δ 5.19(s, 1H), 3.51(m, 4H), 2.56(t, J=5.6Hz, 2H), 2.33(t, J=5.6Hz, 2H), 1.47(s, 9H).

[0182] Synthesis of tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate (05) 1,4 Dioxane:H 2 To a stirred solution of tert-butyl 4-(cyanomethylene)piperidine-1-carboxylate (04) (5 g, 22.5 mmol, 1 eq) in 2H2O (3:1) (130 mL) was added 10% Pd / C (1.5 g), Re-Ni (5 g), LiOH.H 2 O (1.9 g, 48.3 mmol, 2.1 eq) was added and the reaction mixture was heated in a steel bomb with H 2The mixture was stirred at room temperature under atmosphere (50 psi) for 16 hours. After completion of the reaction by TLC, the reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to give tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate (05) (5 g (crude)) as a viscous liquid. TLC system MeOH:DCM (10:90, ninhydrin stain), R f Value: about 0.1, 1 H NMR (400 MHz, DMSO-d 6 ) 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 desired protons were observed by NMR along with impurity peaks.

[0183] Synthesis of tert-butyl 4-(2-((N-(tert-butoxycarbonyl)sulfamoyl)amino)ethyl)piperidine-1-carboxylate (06) To a stirred solution of tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate (05) (5 g, crude 21.9 mmol, 1 eq) in DCM (50 mL) was added DIPEA (6 mL, 32.8 mmol, 1.5 eq), (tert-butoxycarbonyl)((4-(dimethyliminio)pyridin-1(4H)-yl)sulfonyl)amide (03) (7.9 g, 26.2 mmol, 1.2 eq) at 0° C. 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 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-butoxycarbonyl)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 (400 MHz, DMSO-d 6)δ 10.79(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).

[0184] Synthesis of 4-(2-((N-(sulfamoyl)amino)ethyl)piperidine-1-carboxylate (07) 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 4M dioxane.HCl (25 mL) was stirred at room temperature for 2 h. 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: about 0.1, 1 HNMR (400 MHz, DMSO-d 6 )δ 8.52-8.51(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).

[0185] Synthesis of 7-methoxy-4-(4-(2-(sulfamoylamino)ethyl)piperidin-1-yl)quinazolin-6-yl acetate (08) 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., DIPEA (1.74 mL, 9.75 mmol, 2.5 eq) was added and 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 ethyl acetate ( 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 was purified by silica column chromatography by eluting with 10% MeOH in DCM to give 7-methoxy-4-(4-(2-(sulfamoylamino)ethyl)piperidin-1-yl)quinazolin-6-yl acetate (08) as a white solid (450 mg, yield: 28%). TLC system: MeOH / DCM (10:90), R f Value: 0.4, LCMS(m / z): 424.4(M+H) + , 1 HNMR (400 MHz, DMSO-d 6 )δ 8.55(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, 3H), 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).

[0186] Synthesis of (09) 7M methanolic NH 3A 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 10 mL of ethyl acetate was stirred at room temperature for 1 h. 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 (400 MHz, DMSO-d 6 )δ 9.98-9.99(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), 3.9 2(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).

[0187] Synthesis of (7-methoxy-4-(4-(2-(sulfamoylamino)ethyl)piperidin-1-yl)quinazolin-6-yl)diallyl phosphate (10) To a stirred solution of (09) (400 mg, 1.04 mmol, 1 eq) in acetone (8 mL) at 0 °C, add K 2 CO 3 (215 mg, 1.56 mmol, 1.5 eq), diallyl phosphorochloridate (03) (244 mg, 1.24 mmol, 1.2 eq) were added and 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 EtOAc (2×30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate and concentrated to give diallyl (7-methoxy-4-(4-(2-(sulfamoylamino)ethyl)piperidin-1-yl)quinazolin-6-yl)phosphate (10) (400 mg (crude)) as a viscous liquid. TLC system MeOH:DCM (10:90), R f Value: 0.5, LCMS (m / z): 542.3 (M+H)+ .

[0188] Synthesis of 7-methoxy-4-(4-(2-(sulfamoylamino)ethyl)piperidin-1-yl)quinazolin-6-yl dihydrogen phosphate (11) To a stirred solution of (7-methoxy-4-(4-(2-(sulfamoylamino)ethyl)piperidin-1-yl)quinazolin-6-yl)diallyl phosphate (10) (crude) (400 mg, 0.73 mmol, 1 eq) in DCM:DMF (1:1) (10 mL) that had been degassed for 10 min was added phenylsilane (0.45 mL, 3.65 mmol, 5 eq), Pd(PPh 3 ) 4 (84 mg, 0.073 mmol, 0.1 eq) was added and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction by TLC, the reaction mixture was concentrated and triturated with DCM to give the crude. The crude compound was purified by preparative HPLC to give 7-methoxy-4-(4-(2-(sulfamoylamino)ethyl)piperidin-1-yl)quinazolin-6-yl dihydrogen phosphate (11) (30 mg, yield: 9%) as a white solid. TLC system MeOH:DCM (20:80), R f Value: approx. 0.05, LCMS (m / z): 462.4 (M+H) + , 1 HNMR (400 MHz, DMSO-d 6 )δ 8.53(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).

[0189] Synthesis of 7-methoxy-4-(4-(2-(sulfamoylamino)ethyl)piperidin-1-yl)quinazolin-6-yl sodium phosphate (I-03) Cooled to 0°C, H 2To 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 0 (0.5 mL) 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, D 2 O)δ 8.28(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=11.6Hz, 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).

[0190] Synthesis of I-04: Synthesis of tert-butyl (2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidine)ethyl)carbamate) (01) [ka] To a stirred solution of NaH (875 mg, 21.90 mmol, 2.5 eq) in DMF (10 mL) at 0° C. was added 4-chloro-6,7-dimethoxyquinazoline (1) (1.96 g, 8.76 mmol, 1.0 eq) and tert-butyl (2-(piperidin-4-yl)ethyl)carbamate (2) (2.0 g, 8.76 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 2 h. 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 give the crude product. The crude was purified by silica (60-120 mesh) column chromatography [gradient elution with 60% ethyl acetate / hexane] 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: approx. 0.1, LCMS (m / z): 417.3 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 )δ 8.51(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).

[0191] Synthesis of 2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)ethan-1-amine hydrochloride (02) [ka] 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 eq) in 4 M HCl in dioxane (5.0 mL, 5 vol) was heated at 40° C. for 2 h at 20° C. for 1 h. 2The mixture was stirred at room temperature for 2 h under reduced pressure. 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) as an off-white solid (580 mg, yield: 76%). TLC system: MeOH:DCM (10:90), R f Value: approx. 0.1, (400MHz, DMSO-d 6 )δ 8.75(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).

[0192] Synthesis of (tert-butoxycarbonyl)((4-(dimethyliminio)pyridin-1(4H)-yl)sulfonyl)amide (03) [ka] To a stirred solution of tBuOH (1.3 mL, 13.5 mmol, 2.0 eq) in DCM (10 mL) at 0° C., chlorosulfonyl isocyanate (4) (1.2 mL, 13.8 mmol, 1.0 eq) was added over 15 min. The mixture was stirred at 0° C. for 10 min and DMAP (3) (3.45 g, 28.3 mmol, 1.0 eq) was added. The reaction mixture was stirred at room temperature for 1 h. 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-butoxycarbonyl)((4-(dimethyliminio)pyridin-1(4H)-yl)sulfonyl)amide (03) (2.3 g, 55%). 1 H NMR (400 MHz, DMSO-d 6 )δ 8.22(d, J=7.6Hz, 2H), 6.99(d, J=7.6Hz, 2H), 3.19(s, 6H), 1.36(s, 9H).

[0193] Synthesis of tert-butyl (N-(2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)ethyl)sulfamoyl)carbamate (04) [ka] 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) at room temperature, DIPEA (0.6 ml, 3.16 mmol, 2.0 eq) and (tert-butoxycarbonyl)((4-(dimethyliminio)pyridin-1(4H)-yl)sulfonyl)amide (03) (619 mg, 2.05 mmol, 1.3 eq) were added and stirred at room temperature for 16 h. 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 give the crude product. The crude was purified by Grace column chromatography [gradient elution with 10%-15% MeOH / DCM] 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: Approximately 0.2, LCMS (m / z): 496.3 (M+H) + , 1 H NMR (400 MHz, CDCl 3 ) δ 8.65(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). No exchangeable protons were evident from the spectrum.

[0194] Synthesis of N-(2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)ethyl)sulfonamide (I-04) [ka] 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 eq) in 4M HCl in dioxane (1.0 mL, 10 vol) was stirred at room temperature under nitrogen flush for 2 h. Evaporation of volatiles and trituration with diethyl ether followed by lyophilization afforded N-(2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)ethyl)sulfonamide (I-04) as an off-white solid (34 mg, yield: 80%). LCMS (m / z): 396.2 (M+H). + , 1 H NMR (400 MHz, DMSO-d 6 )δ 8.73(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, 3) H), 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).

[0195] Synthesis of I-06: Synthesis of 2,5-dimethoxy-N(quinolin-3-yl)benzenesulfonamide (I-06) [ka] To a stirred solution of quinolin-3-amine (1) (200 mg, 1.38 mmol, 1.0 eq) in DMF (2 mL) at room temperature, TEA (0.3 ml, 2.08 mmol, 1.5 eq) and 2,5-dimethoxybenzenesulfonyl chloride (2) (394 mg, 1.66 mmol, 1.2 eq) were added and stirred at room temperature for 3 h. 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 layers were washed with brine (20 mL), dried over sodium sulfate and concentrated to give the crude product. The crude compound was purified by reversed-phase Grace column chromatography [gradient elution with 0.1%% FA in 38% water and ACN] to provide 150 mg of I-06 with 89% purity, which was further purified by silica gel column chromatography [gradient elution with 80% ethyl acetate / hexane] to give 2,5-dimethoxy-N-(quinolin-3-yl)benzenesulfonamide (I-06) (100 mg, yield: 21%). TLC system: EtOAc (100%, with 1 drop of TEA), R f Value: Approximately 0.6, LCMS (m / z): 345.2 (M+H) + , 1 H NMR (400 MHz, CDCl 3 )δ 8.54(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, 1 H), 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).

[0196] Synthesis of I-07: Synthesis of 2-(1-(7-methoxyquinolin-4-yl)piperidin-4-yl)propanenitrile (01) [ka] To a stirred solution of 4-chloro-7-methoxyquinoline (1) (1 g, 5.16 mmol, 1 eq) in 1,4 dioxane (10 mL) was added 2-(piperidin-4-yl)propanenitrile hydrochloride (2) (0.85 g, 6.19 mmol, 1.2 eq) and degassed for 10 min. Cs 2 CO 3 (5g, 15.4mmol, 3eq), Pd 2 (dba) 3 (0.47 g, 0.51 mmol, 0.1 eq) and X-Phos (0.49 g, 1.0 mmol, 0.2 eq) were added. The reaction mixture was stirred in a sealed tube at 110° C. for 16 h. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad and concentrated to give the crude. The crude compound was purified by 100-200 mesh silica gel column by eluting with 3% MeOH in 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) + , 1 HNMR (400 MHz, DMSO-d 6 )δ 8.63(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), 3.94(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).

[0197] Synthesis of 2-(1-(7-methoxyquinolin-4-yl)piperidin-4-yl)propan-1-amine (02) [ka] Methanolic NH 3To a stirred solution of 2-(1-(7-methoxyquinolin-4-yl)piperidin-4-yl)propanenitrile (01) (700 mg, 2.03 mmol, 1 eq) in 10 mL of H was added Ra-Ni (1.4 g). The reaction mixture was stirred at room temperature for 16 h. 2 Stirred under balloon pressure. 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 sticky compound. TLC system MeOH:DCM (10:90), R f Value: 0.1, LCMS (m / z): 300.03 (M+H) + , 1 HNMR (400 MHz, DMSO-d 6 ) δ 8.57 (brs, 1H), 7.88 (d, J=8.8Hz, 1H), 7.30 (s, 1H), 7.17-7.15 (m, 1H), 6.83 (d, J=4.8Hz, 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). Three protons may have merged with the NMR solvent peaks. The DO exchange NMR was much cleaner.

[0198] Synthesis of tert-butyl N-(2-(1-(7-methoxyquinolin-4-yl)piperidin-4-yl)propyl)sulfamoylcarbamate (03) [ka] 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-butoxycarbonyl)((4-(dimethyliminio)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 h. 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 (400 MHz, DMSO-d 6 )δ 8.57(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).

[0199] Synthesis of N-(2-(1-(7-methoxyquinolin-4-yl)piperidin-4-yl)propyl)aminosulfonamide (I-07) [ka] 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 4M dioxane.HCl (2 mL) was stirred at room temperature for 2 h. After completion of the reaction by TLC, the volatiles were evaporated and the crude compound was purified by preparative HPLC to give N-(2-(1-(7-methoxyquinolin-4-yl)piperidin-4-yl)propyl)aminosulfonamide (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-d 6 )δ 8.56 (d, J=5.2Hz, 1H), 8.13 (formate proton), 7.91 (d, J=9.2Hz, 1H), 7.29 (d, J=2.8Hz, 1H), 7.19 (dd, J=9.2Hz, 2.8Hz, 1H), 6.88 (d, J=5.6Hz, 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=6.4Hz, 3H).

[0200] Synthesis of I-08: Synthesis of 2-(1-(6-methoxyquinolin-4-yl)piperidin-4-yl)propanenitrile (01) [ka] To a stirred solution of 4-chloro-7-methoxyquinoline (1) (0.6 g, 3.18 mmol, 1 eq) in 1,4 dioxane (10 mL) was added 2-(piperidin-4-yl)propanenitrile hydrochloride (2) (0.51 g, 3.73 mmol, 1.2 eq) and degassed for 10 min. Cs 2 CO 3 (3.0g, 9.32mmol, 3eq), Pd 2 (dba)3 (0.28 g, 0.31 mmol, 0.1 eq), and X-Phos (0.29 g, 0.62 mmol, 0.2 eq) were added. The reaction mixture was stirred at 110° C. in a sealed tube for 16 h. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad and concentrated to give the crude. The crude compound was purified by 100-200 mesh silica gel column by eluting with 3% MeOH in 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 (400 MHz, DMSO-d 6 )δ 8.60(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, 3H), 3.92-3. 90(m, 2H), 3.15-3.09(m, 2H), 2.96-2.89(m, 1H), 2.03-1.92(m, 2H), 1.85-1.83(m, 1H), 1.64-1.56(m, 2H), 1.29(d, J=6.8Hz, 3H).

[0201] Synthesis of 2-(1-(6-methoxyquinolin-4-yl)piperidin-4-yl)propan-1-amine (02) [ka] Methanolic NH 3 To a stirred solution of 2-(1-(6-methoxyquinolin-4-yl)piperidin-4-yl)propanenitrile (01) (600 mg, 2.03 mmol, 1 eq) in 10 mL of H was added Re-Ni (1.4 g). The reaction mixture was stirred at room temperature for 16 h. 2Stirred under balloon pressure. 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 sticky compound. TLC system MeOH:DCM (10:90), R f Value: 0.1, LCMS (m / z): 300.03 (M+H) + ,

[0202] Synthesis of tert-butyl N-(2-(1-(6-methoxyquinolin-4-yl)piperidin-4-yl)propyl)sulfamoylcarbamate (03) [ka] 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-butoxycarbonyl)((4-(dimethyliminio)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 h. 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) + , 1 HNMR (400 MHz, DMSO-d 6)δ 8.54(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=5.2Hz, 1H), 6.4 7(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).

[0203] Synthesis of N-(2-(1-(6-methoxyquinolin-4-yl)piperidin-4-yl)propyl)aminosulfonamide (I-08) [ka] 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 4M dioxane.HCl (2 mL) was stirred at room temperature for 2 h. 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)aminosulfonamide (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 (400 MHz, DMSO-d 6)δ 14.8-14.6(br, 1H), 8.59(d, J=6.8Hz, 1H), 8.02(d, J=8.8Hz, 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).

[0204] Synthesis of I-09: Synthesis of 4-chloro-7-methoxy-6-(methoxymethoxy)quinoline (01) [ka] To a stirred solution of 4-chloro-7-methoxyquinolin-6-ol (I-10-01) (1.2 g, 5.74 mmol, 1 eq) in DCM (15 mL) cooled to 0 °C, TEA (0.48 mL, 34.4 mmol, 6 eq), MOM-Cl (2.17 mL, 28.7 mmol, 5 eq), and catalytic amount of DMF were added. The reaction mixture was stirred at room temperature for 24 h. After completion of the reaction by TLC, the reaction mixture was poured into ice water and extracted with DCM (2 x 80 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 silica gel (100-200 mesh) column purification [eluted with 2% MeOH in DCM] to give 4-chloro-7-methoxy-6-(methoxymethoxy)quinoline (01) (600 mg, yield: 41%) as a sticky solid. TLC system: EtOAc:Hexane (60:40), R f Value: 0.4, LCMS(m / z): 254.1(M+H) + .

[0205] Synthesis of 2-(1-(7-methoxy-6-(methoxymethoxy)quinolin-4-yl)piperidin-4-yl)propanenitrile (02) [ka] To a stirred solution of 4-chloro-7-methoxy-6-(methoxymethoxy)quinoline (01) (600 mg, 2.37 mmol, 1 eq) in 1,4 dioxane (6 mL) was added 2-(piperidin-4-yl)propanenitrile hydrochloride (I-02-03) (0.49 g, 2.84 mmol, 1.2 eq) and degassed for 10 min. Cs 2 CO 3 (2.3g, 7.11mmol, 3eq), Pd 2 (dba) 3 (0.21 g, 0.23 mmol, 0.1 eq) and X-Phos (0.21 g, 0.46 mmol, 0.2 eq) were added. The reaction mixture was stirred in a sealed tube at 110° C. for 16 h. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad, washed with ethyl acetate, and the filtrate was concentrated to give the crude product. The crude compound was purified by silica gel (100-200 mesh) column chromatography [elution with 2% MeOH in DCM] to give 2-(1-(7-methoxy-6-(methoxymethoxy)quinolin-4-yl)piperidin-4-yl)propanenitrile (02) (450 mg) as a sticky solid with 66% purity. TLC system MeOH:DCM (5:95), R f Value: 0.2, LCMS (m / z): 356.3 (M+H) + The material was carried onto the next step without further purification.

[0206] Synthesis of 2-(1-(7-methoxy-6-(methoxymethoxy)quinolin-4-yl)piperidin-4-yl)propan-1-amine (03) [ka] 7M methanolic NH 3 To a stirred solution of 2-(1-(7-methoxy-6-(methoxymethoxy)quinolin-4-yl)piperidin-4-yl)propanenitrile (02) (450 mg, 2.03 mmol, 1 eq) in 1 mL of H was added Raney-Ni (1 g). The reaction mixture was stirred at room temperature for 16 h.2 Stirred under balloon pressure. 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)quinolin-4-yl)piperidin-4-yl)propan-1-amine (03) (450 mg) as a sticky material. TLC system MeOH:DCM (10:90), R f Value: 0.1, LCMS (m / z): 360.3 (M+H) + .

[0207] Synthesis of tert-butyl (N-(2-(1-(7-methoxy-6-(methoxymethoxy)quinolin-4-yl)piperidin-4-yl)propyl)sulfamoyl)carbamate (04) [ka] 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-butoxycarbonyl)((4-(dimethyliminio)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 h. 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 [elution with 3% MeOH in 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) + .

[0208] Synthesis of N-(N-(2-(1-(6-hydroxy-7-methoxyquinolin-4-yl)piperidin-4-yl)propyl)sulfuric acid diamide formate (I-09) [ka] 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, 4 M dioxane.HCl (2 mL) was added and stirred at room temperature for 2 h. After completion of the reaction by TLC, the volatiles were evaporated to give a residue. The crude compound was purified by reverse phase purification [1-15% (H 2 The mixture was purified by gradient elution with 0.1% FA in 200+ACN to give N-(N-(2-(1-(6-hydroxy-7-methoxyquinolin-4-yl)piperidin-4-yl)propyl)sulfuric acid diamide 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 (400 MHz, DMSO-d 6 )δ 8.40(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).

[0209] Synthesis of I-10: Synthesis of 4-chloro-7-methoxyquinolin-6-ol (01) [ka] To a stirred solution of 4-chloro-6,7-dimethoxyquinoline (1) (5 g, 22.4 mmol, 1 eq) in methanesulfonic acid (25 mL) was added D,L-methionine (8.3 g, 56 mmol, 2.5 eq). The reaction mixture was stirred in a sealed tube at 150° C. for 24 h. After completion of the reaction by TLC, the reaction mixture was poured onto ice and washed with aqueous NH 3 (pH-9) and extracted with EtOAc (3×100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the crude. The crude compound was purified by silica gel (100-200 mesh) column [eluted with 2% MeOH in DCM] to give 4-chloro-7-methoxyquinolin-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 (400 MHz, DMSO-d 6 )δ 10.6-10.1(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).

[0210] Synthesis of 4-chloro-7-methoxy-6-(2-methoxyethoxy)quinoline (02) [ka] 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 K 2 CO 3(1.98 g, 14.3 mmol, 2 eq), 1-bromo-2-methoxyethane (1.98 g, 14.3 mmol, 2 eq) were added and 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 EtOAc (2×50 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude compound was purified by 100-200 mesh silica gel column by eluting with 2% MeOH in DCM to obtain 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) + , 1 HNMR (400 MHz, CDCl 3 )δ 8.57(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).

[0211] Synthesis of 2-(1-(7-methoxy-6-(2-methoxyethoxy)quinolin-4-yl)piperidin-4-yl)propanenitrile (03) [ka] To a stirred solution of 4-chloro-7-methoxy-6-(2-methoxyethoxy)quinoline (02) (800 mg, 2.99 mmol, 1 eq) in 1,4 dioxane (8 mL) in a sealed tube was added 2-(piperidin-4-yl)propanenitrile hydrochloride (I-02-03) (490 mg, 3.59 mmol, 1.2 eq) and degassed for 10 min. Then, Cs 2 CO 3 (2.9g, 8.98mmol, 3eq), Pd 2 (dba) 3(0.27g, 0.29mmol, 0.1eq), X-Phos (0.28g, 0.59mmol, 0.2eq) were added. The reaction mixture was stirred at 110°C for 16 hours. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad and concentrated under reduced pressure to obtain the crude. The crude compound was purified by 100-200 mesh silica gel column by eluting with 3% MeOH in DCM to obtain 2-(1-(7-methoxy-6-(2-methoxyethoxy)quinolin-4-yl)piperidin-4-yl)propanenitrile (03) (500mg, 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 (400 MHz, DMSO-d 6 )δ 8.49(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=4.8Hz, 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).

[0212] Synthesis of 2-(1-(7-methoxy-6-(2-methoxyethoxy)quinolin-4-yl)piperidin-4-yl)propan-1-amine (04) [ka] 7M methanolic NH 3 To a stirred solution of 2-(1-(7-methoxy-6-(2-methoxyethoxy)quinolin-4-yl)piperidin-4-yl)propanenitrile (03) (500 mg, 2.03 mmol, 1 eq) in 1 mL of H was added Ra-Ni (1 g). The reaction mixture was stirred at room temperature for 16 h. 2Stirred under balloon pressure. 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 sticky compound. TLC system MeOH:DCM (10:90), R f Value: 0.1, LCMS (m / z): 374.4 (M+H) + , 1 HNMR (400 MHz, DMSO-d 6 )δ 8.49(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).

[0213] Synthesis of tert-butyl (N-(2-(1-(7-methoxy-6-(2-methoxyethoxy)quinolin-4-yl)piperidin-4-yl)propyl)sulfamoyl)carbamate (05) [ka] 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-butoxycarbonyl)((4-(dimethyliminio)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 h. 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 in HO) + 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) +

[0214] Synthesis of N-(2-(1-(7-methoxy-6-(2-methoxyethoxy)quinolin-4-yl)piperidin-4-yl)propyl)aninosulfonamide formate (I-10) [ka] 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., 4M dioxane.HCl (2 mL) was added and stirred at room temperature for 2 h. 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)aninosulfonamide formate (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), 1 HNMR (400 MHz, DMSO-d 6 )δ 8.48(d, J=5.2Hz, 1H), 8.14(formate proton), 7.31(s, 1H), 7.22(s, 1H), 6.88(d, J=5.2Hz, 1H), 6.49-6.47(m, 3H), 4.24(t, J=4.8Hz, 2H), 3.92(s, 3H), 3.75 (t, J=4.8Hz, 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=6.4Hz, 3H).

[0215] Synthesis of I-11: Synthesis of 2-(2-bromoethoxy)tetrahydro-2H-pyran (01) [ka] To a stirred solution of 2-bromoethan-1-ol (1) (2 g, 1.61 mmol, 1 eq) in THF (20 mL) was added 3,4 dihydropyran (1.7 mL, 1.93 mmol, 1.2 eq), p-toluenesulfonic acid pyridine salt (PPTS) (406 mg, 0.16 mmol, 0.1 eq). The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction by TLC, the reaction mixture was poured into water and extracted with EtOAc (2×30 mL). The combined organic layers were 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 pale yellow liquid. TLC system EtOAc:Hexane (20:80), R f Value: 0.5, 1 HNMR (400 MHz, DMSO-d 6 ) 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.

[0216] Synthesis of 4-chloro-7-methoxy-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)quinoline (02) [ka] To a stirred solution of 4-chloro-7-methoxyquinolin-6-ol (I-10-01) (1 g, 4.78 mmol, 1 eq) in DMF (10 mL) at 0 °C, 2 CO 3(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 h. 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 the crude product. The crude compound was purified by silica gel (100-200 mesh) column chromatography [elution with 2% MeOH in 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) + .

[0217] Synthesis of 2-(1-(7-methoxy-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)quinolin-4-yl)piperidin-4-yl)propanenitrile (03) [ka] 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) was added 2-(piperidin-4-yl)propanenitrile hydrochloride (I-02-03) (0.39 g, 2.84 mmol, 1.2 eq) and degassed for 10 min. Cs 2 CO 3 (2.3g, 7.11mmol, 3eq), Pd 2 (dba) 3 (0.22 g, 0.23 mmol, 0.1 eq), X-Phos (0.22 g, 0.47 mmol, 0.2 eq) were added. The reaction mixture was stirred in a sealed tube at 110° C. for 16 h. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad and concentrated to give the crude product.

[0218] The crude compound was purified by silica gel [100-200 mesh] chromatography [elution with 3% MeOH in 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 able to be carried forward to the next step.

[0219] 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) [ka] 7M methanolic NH 3 To a stirred solution of 2-(1-(7-methoxy-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)quinolin-4-yl)piperidin-4-yl)propanenitrile (03) (600 mg, 60% purity, 1.36 mmol, 1 eq) in 10 mL of hexane was added Ra-Ni (1.2 g). The reaction mixture was stirred at room temperature for 16 h. 2 Stirred under balloon pressure. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad and concentrated to give the crude. The crude was triturated with diethyl ether to give 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, yield: 38% for two steps) as a sticky compound. TLC system MeOH:DCM (10:90), R f Value: 0.1, LCMS(m / z): 444.4(M+H) + , 1 HNMR (400 MHz, DMSO-d 6)δ 8.48(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).

[0220] 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) [ka] 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 eq) in DCM (8 mL) was added DIPEA (0.21 mL, 1.17 mmol, 1.3 eq) and (tert-butoxycarbonyl)((4-(dimethyliminio)pyridin-1(4H)-yl)sulfonyl)amide (I-04-03) (325 mg, 1.08 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 16 h. 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 [eluent: H 2 0.1% FA in O / ACN] 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 fValue: 0.5, LCMS (m / z): 623.5 (M+H) + Although the purified material was not completely pure, it was able to be carried forward to the next step.

[0221] Synthesis of N-(2-(1-(6-(2-hydroxyethoxy)-7-methoxyquinolin-4-yl)piperidin-4-yl)propyl)aminosulfonamide formate (I-11) [ka] 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., 4M dioxane.HCl (2 mL) was added slowly. The reaction was then allowed to stir 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)aminosulfonamide formate (I-11) (38 mg, yield: 10% for 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-d 6 )δ 8.47(d, J=4.8Hz, 1H), 8.15(formate proton), 7.30(s, 1H), 7.20(s, 1H), 6.84(d , J=5.2Hz, 1H), 6.48-6.45(m, 3H), 4.93(brs, 1H), 4.11(t, J=4.8Hz, 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=6.8Hz, 3H)

[0222] Synthesis of I-12: Synthesis of 4-(2-methoxy-4-nitrophenyl)morpholine (01) [ka] 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 K 2 CO 3 (16.13 g, 116.8 mmol, 2 eq) and morpholine (2) (10.16 g, 116.8 mmol, 2 eq) were added. The reaction mixture was stirred at 80° C. for 5 h. After completion of the reaction by TLC, the reaction mixture was poured into ice-cold water and the precipitated solid was filtered and dried under vacuum to give 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 (400 MHz, CDCl 3 )δ 7.87(dd, J=8.8Hz, 2.4Hz, 1H), 7.72(d, J=2.4Hz, 1H), 6.89(d, J=8.8Hz, 1H), 3.96(s, 3H), 3.89(t, J=4.8Hz, 4H), 3.22(t, J=4.8Hz, 4H).

[0223] Synthesis of 3-methoxy-4-morpholinoaniline (02) [ka] Ethanol:H 2 To a stirred solution of 4-(2-methoxy-4-nitrophenyl)morpholine (01) (8 g, 33.5 mmol, 1 eq) in 2H2O (2:1) (120 mL) was added NH 4Cl (8.93 g, 167 mmol, 5 eq), Fe powder (9.32 g, 167 mmol, 5 eq) were added. The reaction mixture was stirred at 85° C. for 3 h. 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-morpholinoaniline (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) + , 1 HNMR (400 MHz, DMSO-d 6 )δ 6.60(d, J=8.4Hz, 1H), 6.23(d, J=2.4Hz, 1H), 6.07(dd, J=2.4Hz, 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).

[0224] Synthesis of 7-methoxy-6-morpholinoquinolin-4(1H)-one (03) [ka] A solution of Meldrum's acid (3.85 g, 3.37 mmol, 1 eq) and triethyl orthoformate (1.5 mL, 10.1 mmol, 3 eq) was stirred at 85° C. for 3 h. Thus, it was diluted with ethanol (50 mL) and 3-methoxy-4-morpholinoaniline (02) (5 g, 3.37 mmol, 1 eq) was added. The resulting mixture was stirred at 85° C. for 3 h. After cooling to 0° C., a brown solid precipitated, which was filtered and dried under vacuum. To this solid, Dowtherm-A (50 mL) was added and heated at 190° C. for 5 h. After completion of the reaction by TLC, the reaction mixture was poured into hexane (200 mL) and the precipitated solid was filtered and dried under vacuum to obtain the crude product. The crude compound was purified by silica gel (60-120 mesh) column chromatography [gradient elution with 10-15% MeOH in DCM] 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 (400 MHz, CDCl 3 )δ 7.77(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).

[0225] Synthesis of 4-(4-chloro-7-methoxyquinolin-6-yl)morpholine (04) [ka] POCl 3 A suspension of 7-methoxy-6-morpholinoquinolin-4(1H)-one (03) (1.2 g, 4.6 mmol, 1 eq) in 12 mL of ethyl acetate was stirred at 110 °C for 3 h. After completion of the reaction by TLC, the reaction mixture was poured onto ice and cooled with saturated NaHCO 3The mixture was basified with hexanes solution [pH-8] and extracted with EtOAc (3×60 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 (60-120 mesh) column chromatography [eluted with 1% MeOH in DCM] to give 4-(4-chloro-7-methoxyquinolin-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 (400 MHz, CDCl 3 )δ 8.57(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).

[0226] Synthesis of 2-(1-(7-methoxy-6-morpholinoquinolin-4-yl)piperidin-4-yl)propanenitrile (05) [ka] To a stirred solution of 4-(4-chloro-7-methoxyquinolin-6-yl)morpholine (04) (1 g, 3.59 mmol, 1 eq) in 1,4 dioxane (10 mL) was added 2-(piperidin-4-yl)propanenitrile HCl (I-02-03) (0.76 g, 4.30 mmol, 1.2 eq), Cs 2 CO 3 (3.5 g, 10.7 mmol, 3 eq) was added and degassed for 10 min. Then, X-Phos (0.34 g, 0.71 mmol, 0.2 eq), Pd 2 (dba) 3(0.32 g, 0.35 mmol, 0.1 eq) was added and the reaction mixture was stirred at 110° C. for 16 h in a sealed tube. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad and concentrated to give the crude product. The crude compound was purified by silica gel (60-120 mesh) column chromatography [elution with 3-4% MeOH in 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.

[0227] Synthesis of 2-(1-(7-methoxy-6-morpholinoquinolin-4-yl)piperidin-4-yl)propan-1-amine (06) [ka] 7M methanolic NH 3 To a stirred solution of 2-(1-(7-methoxy-6-morpholinoquinolin-4-yl)piperidin-4-yl)propanenitrile (05) (600 mg, 1.57 mmol, 1 eq) in 10 mL of H was added Raney-Ni (1.2 g). The reaction mixture was stirred at room temperature for 16 h. 2 Stirred under balloon pressure. 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-morpholinoquinolin-4-yl)piperidin-4-yl)propan-1-amine (06) (420 mg) as a sticky compound. TLC system MeOH:DCM (10:90), R f Value: 0.1, LCMS(m / z): 385.3(M+H) + , 70% purity.

[0228] Synthesis of tert-butyl (N-(2-(1-(7-methoxy-6-morpholinoquinolin-4-yl)piperidin-4-yl)propyl)sulfamoyl)carbamate (07) [ka] 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-butoxycarbonyl)((4-(dimethyliminio)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 h. 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 [elution with 5% MeOH in 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 carried on to the next step without further purification.

[0229] Synthesis of N-(N-(2-(1-(7-methoxy-6-morpholinoquinolin-4-yl)piperidin-4-yl)propyl)sulfuric acid diamide (I-12) [ka] To a stirred solution of tert-butyl (N-(2-(1-(7-methoxy-6-morpholinoquinolin-4-yl)piperidin-4-yl)propyl)sulfamoyl)carbamate (07) (400 mg, 50% purity) in 1,4 dioxane cooled to 0 °C, 4M dioxane.HCl (2 mL) was added and stirred at room temperature for 2 h. After completion of the reaction by TLC, the volatiles were evaporated and the resulting crude compound was purified by preparative HPLC [FA method] to give N-(N-(2-(1-(7-methoxy-6-morpholinoquinolin-4-yl)piperidin-4-yl)propyl)sulfuric acid diamide (I-12) (45 mg, yield: 3% for 4 steps) as a pale yellow solid. TLC system MeOH:DCM (10:90), R f Value: 0.3, LCMS (m / z): 464.3 (M+H), 1 HNMR (400 MHz, DMSO-d 6 )δ 8.47(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)

[0230] Synthesis of I-13: Synthesis of tert-butyl 4-(cyanomethylene)piperidine-1-carboxylate (01) [ka] To a stirred solution of tert-butyl 4-oxopiperidine-1-carboxylate (1) (2 g, 10.05 mmol, 1 eq) in THF (20 mL) at 0° C., 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) were added. The reaction mixture was allowed to stir at room temperature for 16 h. 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 was purified by silica column chromatography by eluting with 20% EtOAc in hexane to give tert-butyl 4-(cyanomethylene)piperidine-1-carboxylate (01) as a white solid (2 g, yield: 90%). TLC system: EtOAc / hexane (30:70, ninhydrin stain), R f Value: about 0.6, 1 H NMR (400 MHz, CDCl 3 )δ 5.19(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).

[0231] Synthesis of tert-butyl 4-(cyanomethyl)piperidine-1-carboxylate (02) [ka] To a stirred solution of tert-butyl 4-(cyanomethylene)piperidine-1-carboxylate (01) (2 g, 8.9 mmol, 1 eq) in dry methanol (100 mL) was added Mg turnings (8.57 g, 35.7, 40 eq). The reaction mixture was stirred at room temperature for 3 h. 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: about 0.5, 1 H NMR (400 MHz, CDCl 3 )δ 4.16-4.12(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),

[0232] Synthesis of tert-butyl 4-(1-cyanopropyl)piperidine-1-carboxylate (03) [ka] 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 min. Ethyl iodide (0.66 mL, 8.92 mmol, 1 eq) in THF was then added and stirred at -40°C for 2.5 h. After completion of the reaction by TLC, the reaction mixture was diluted with NH 4It was quenched with Cl solution and extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure to give tert-butyl 4-(1-cyanopropyl)piperidine-1-carboxylate (03) (1.2 g, yield: 54%) as a liquid. TLC system: EtoAc:Hexane (20:80, ninhydrin stain), R f Value: 0.6, 1 H NMR (400 MHz, CDCl 3 )δ 4.19-4.17(m, 2H), 2.68-2.66(m, 2H), 2.37(q, J=6.8Hz, 1H), 1.86-1.81(m, 1 H), 1.70-1.62(m, 4H), 1.45(s, 9H), 1.38-1.32(m, 2H), 1.21(t, J=7.2Hz, 3H),

[0233] Synthesis of 2-(piperidin-4-yl)butanenitrile.HCl (04) [ka] A solution of tert-butyl 4-(1-cyanopropyl)piperidine-1-carboxylate (03) (1.2 g, 5 mmol, 1 eq) in 4M dioxane.HCl (12 mL) was stirred at room temperature for 1 h, and after completion of the reaction by TLC, the reaction mixture was concentrated under reduced pressure to give 2-(piperidin-4-yl)propanenitrile hydrochloride (04) (0.86 g, yield: 92%) as a white solid. TLC system EtoAc (100%, ninhydrin staining), R f Value: 0.1, 1 HNMR (400 MHz, DMSO-d 6 )δ 9.01-8.71(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).

[0234] Synthesis of 2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)butanenitrile (05) [ka] To a stirred solution of 4-chloro-6,7-dimethoxyquinoline (3) (1 g, 4.46 mmol, 1 eq) in 1,4 dioxane (10 mL) was added 2-(piperidin-4-yl)propanenitrile hydrochloride (04) (0.84 g, 4.46 mmol, 1 eq), degassed for 10 min, and cooled to 50° C. 2 CO 3 (4.34g, 13.3mmol, 3eq), Pd 2 (dba) 3 (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 in a sealed tube at 110° C. for 16 h. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad and concentrated to give the 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) + .

[0235] Synthesis of 2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)butan-1-amine (06) [ka] 7M methanolic NH 3 To a stirred solution of 2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propanenitrile (05) (500 mg, 1.47 mmol, 1 eq) in 1 mL of H was added Ra-Ni (1 g). The reaction mixture was stirred at room temperature for 16 h. 2Stirred under balloon pressure. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad and concentrated to give 2-(1-(6,7-dimethoxyquinolin-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) + .

[0236] Synthesis of tert-butyl (N-(2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)butyl)sulfamoyl)carbamate (07) [ka] 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 eq) in DCM (8 mL) was added DIPEA (0.31 mL, 1.74 mmol, 1.5 eq), (tert-butoxycarbonyl)((4-(dimethyliminio)pyridin-1(4H)-yl)sulfonyl)amide (I-04-03) (459 mg, 1.52 mmol, 1.3 eq). The reaction mixture was stirred at room temperature for 16 h. 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 (400 MHz, DMSO-d 6)δ 8.47(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).

[0237] Synthesis of N-(2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)butyl)sulfuric acid diamide (I-13) [ka] 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 4M dioxane HCl (2 mL) was stirred at room temperature for 2 h. After completion of the reaction by TLC, the reaction mixture was concentrated, diluted with ethyl acetate (10 mL) and diluted with aqueous NaHCO 3 The solution was washed with brine (10 mL), dried over sodium sulfate and concentrated to give N-(2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)butyl)sulfuric acid diamide (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 (400 MHz, DMSO-d 6)δ 8.47(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).

[0238] Synthesis of I-14: Synthesis of tert-butyl 4-(2-cyanopropan-2-yl)piperidine-1-carboxylate (01) [ka] 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 (1M in toluene) (21 mL, 21 mmol, 5 eq) was added at 0° C. for 10 min. Then, iodomethane (0.59 mL, 8.4 mmol, 2 eq) in THF (2 mL) was added. The reaction mixture was allowed to stir at room temperature for 16 h. 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 to give crude 1g (monomethyl compound). To the crude (monomethyl compound) (1 g, 4.2 mmol, 1 eq) in THF (10 mL) at 0° C. was added KHMDS (1M in toluene) (21 mL, 21 mmol, 5 eq) and stirred at 0° C. for 10 min, followed by the addition of iodomethane (2 mL) in THF (0.59 mL, 8.4 mmol, 2 eq). The reaction mixture was allowed to stir at room temperature for 16 h. 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 to give the crude product. The crude product was purified by silica column chromatography by eluting with 10% EtOAc in hexane to give tert-butyl 4-(2-cyanopropan-2-yl)piperidine-1-carboxylate (01) as a viscous liquid (500 mg, yield: 44%). TLC system: EtOAc / hexane (20:80, ninhydrin stain), R f Value: about 0.5, 1 H NMR (400 MHz, CDCl 3 )δ 4.23(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).

[0239] Synthesis of 2-methyl-2-(piperidin-4-yl)propanenitrile hydrochloride (02) [ka] A solution of 4-(2-cyanopropan-2-yl)piperidine-1-carboxylate (01) (500 mg, 1.98 mmol, 1 eq) in 4M dioxane.HCl (5 mL) was stirred at room temperature for 1 h, and after completion of the reaction by TLC, the reaction mixture was concentrated under reduced pressure to give 2-methyl-2-(piperidin-4-yl)propanenitrile hydrochloride (02) (410 mg, yield: 99%) as a white solid. TLC system EtoAc (100%, ninhydrin staining), R f Value: 0.1, 1 HNMR (400 MHz, DMSO-d 6 )δ 8.88(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).

[0240] Synthesis of 2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)-2-methylpropanenitrile (03) [ka] To a stirred solution of 2-methyl-2-(piperidin-4-yl)propanenitrile HCl (02) (408 mg, 2.24 mmol, 1 eq) in 1,4 dioxane (10 mL) was added 4-chloro-6,7-dimethoxyquinoline (1) (500 mg, 2.24 mmol, 1 eq) and degassed for 10 min. Cs 2 CO 3 (2.18g, 6.73mmol, 3eq), Pd 2 (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 h. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad and concentrated to give the crude product. The crude compound was purified by silica gel chromatography [elution with 3% MeOH in 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) + , 1 HNMR (400 MHz, DMSO-d 6 )δ 8.49(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).

[0241] Synthesis of 2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)-2-methylpropan-1-amine (04) [ka] 7M methanolic NH 3 To a stirred solution of 2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)-2-methylpropanenitrile (03) (550 mg, 1.47 mmol, 1 eq) in 1 mL of H was added Ra-Ni (1 g). The reaction mixture was stirred at room temperature for 16 h. 2Stirred under balloon pressure. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad and concentrated to give 2-(1-(6,7-dimethoxyquinolin-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. Carried on to next step.

[0242] Synthesis of tert-butyl (N-(2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)-2-methylpropyl)sulfamoyl)carbamate (05) [ka] 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 eq) in DCM (8 mL) at 0° C. was added DIPEA (0.31 mL, 1.74 mmol, 1.5 eq) and (tert-butoxycarbonyl)((4-(dimethyliminio)pyridin-1(4H)-yl)sulfonyl)amide (I-04-03) (456 mg, 1.51 mmol, 1.3 eq). The reaction mixture was stirred at room temperature for 16 h. 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 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 (400 MHz, DMSO-d 6)δ 10.81(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), 1.83-1.80(m, 2H), 1.70-1.64(m, 1H), 1.51-1.46(m, 2H), 1.43(s, 9H), 0.85(s, 6H).

[0243] Synthesis of N-(2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)-2-methylpropyl)sulfuric acid diamide hydrochloride (I-14) [ka] 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 eq) in 4M dioxane.HCl (2 mL) was stirred at room temperature for 2 h. After completion of the reaction by TLC, the reaction mixture was concentrated, followed by trituration with diethyl ether to give N-(2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)-2-methylpropyl)sulfuric acid diamide 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 (400 MHz, DMSO-d 6)δ 14.35(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), 3.9 7 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).

[0244] Synthesis of I-15: Synthesis of N-(2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propyl)methylaminosulfonamide (I-15) [ka] To a stirred solution of 2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propan-1-amine (I-02-05) (500 mg, 1.51 mmol, 1 eq) in DCM (20 mL) was added TEA (0.43 mL, 3.03 mmol, 2 eq) at 0° C., followed by methylsulfamoyl chloride (1) (294 mg, 2.27 mmol, 1.5 eq). The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction by TLC, the reaction mixture was concentrated and purified by reverse phase Grace purification to give [30% H 2 Elution with 0.1% FA / ACN in 0 afforded N-(2-(1-(6,7-dimethoxyquinolin-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 (400 MHz, DMSO-d 6) δ 8.50(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), 3.93-3.9 1(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).

[0245] Synthesis of I-16: Synthesis of 2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propanal (01) [ka] To a stirred solution of 2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propanenitrile (I-02-04) (800 mg, 2.46 mmol, 1 eq) in DCM (8 mL) at -78 °C was added DIBAL-H (1 M in hexanes) (4.92 mL, 4.92 mmol, 2 eq). The reaction mixture was allowed to stir at 0 °C for 3 h. After completion of the reaction by TLC, the reaction mixture was diluted with saturated NH 4 It was quenched with Cl solution and extracted with DCM (3X30 mL). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate and concentrated. The crude was purified by silica column chromatography by eluting with 5% MeOH in DCM to give 2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propanal (01) as a viscous liquid (600 mg, yield: 74%). TLC system: MeOH / DCM (10:90), R f Value: about 0.5, LCMS (m / z): 329.4 (M+H) + , 1 H NMR (400 MHz, CDCl 3)δ 9.74(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).

[0246] Synthesis of N-(2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propyl)cyclopropanamine (02) [ka] To a stirred solution of 2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propanal (01) (600 mg, 1.82 mmol, 1 eq) in methanol (6 mL) cooled to 0° C., cyclopropanamine (1) (125 mg, 2.19 mmol, 1.2 eq), molecular sieve powder (600 mg), AcOH (catalyst) were added. The reaction mixture was stirred at room temperature for 0.5 h and then diluted with NaCNBH 3 (114 mg, 1.82 mmol, 1 eq) was added and stirred at room temperature for 16 h. After completion of the reaction by TLC, the reaction mixture was quenched with cold water and extracted with 10% MeOH+DCM (2X30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to give the crude. The crude compound was triturated with diethyl ether to give N-(2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propyl)cyclopropanamine (02) (400 mg, yield: 59%) as a sticky solid. TLC system: MeOH / DCM (10:90), R f Value: Approximately 0.3, LCMS (m / z): 370.3 (M+H) + .

[0247] Synthesis of tert-butyl N-cyclopropyl-N-(2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propyl)sulfamoylcarbamate (03) [ka] To a stirred solution of N-(2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propyl)cyclopropanamine (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-butoxycarbonyl)((4-(dimethyliminio)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 give the crude material, 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 f Value: 0.5, LCMS (m / z): 549.4 (M+H) + , De-boc m / z was also observed.

[0248] Synthesis of N-cyclopropyl-N-(2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propyl)aminosulfonamide formate (I-16) [ka] A solution of tert-butyl N-cyclopropyl-N-(2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propyl)sulfamoylcarbamate (03) (200 mg, 0.36 mmol, 1 eq) in 4M dioxane HCl (2 mL) was stirred at room temperature for 2 h. After completion of the reaction by TLC, the reaction mixture was concentrated under reduced pressure to give the crude. The crude was purified by preparative HPLC to give N-cyclopropyl-N-(2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propyl)aminosulfonamide formate (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 (400 MHz, DMSO-d 6 ) δ 8.47 (d, J = 5.2 Hz, 1H), 8.14 (s, 1H), 7.29 (s, 1H), 7.17 (s, 1H), 6.85 (d, J = 5.2 Hz, 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)

[0249] Synthesis of I-17: Synthesis of tert-butyl 5,6-dihydro-[3,4'-bipyridine]-1(2H)-carboxylate (01) [ka] DME:H 2To a stirred solution of 4-bromopyridine hydrochloride (1) (2 g, 10.3 mmol, 1 eq) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2) (3.2 g, 10.3 mmol, 1 eq) in 30 mL of HO (2:1) was added sodium carbonate (5.4 g, 51.5 mmol, 5 eq) and Pd(PPh 3 ) 4 (238 mg, 0.20 mmol, 0.02 eq) was added and degassed for 15 min. The reaction mixture was stirred at 100° C. in a sealed tube for 16 h. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad and the filtrate was concentrated to give the crude product. The crude product was purified by silica gel (60-120 mesh) column [elution with 20% EtOAc in 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 (400 MHz, DMSO-d 6 )δ 8.55(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).

[0250] Synthesis of tert-butyl[3,4'-bipiperidine]-1-carboxylate (02) [ka] To a stirred solution of tert-butyl 5,6-dihydro-[3,4'-bipyridine]-1(2H)-carboxylate (01) (1 g, 3.84 mmol, 1 eq) in acetic acid (20 mL), PtO 2 (300 mg) was added. The reaction mixture was stirred at room temperature for 16 h. 2Stirred under balloon pressure. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad and the filtrate was concentrated to give tert-butyl [3,4'-bipiperidine]-1-carboxylate (02) (850 mg, yield: 85%) as a pale yellow solid. TLC system MeOH:DCM (10:90), R f Value: 0.1, 1 HNMR (400 MHz, DMSO-d 6 )δ 3.81-3.72(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).

[0251] Synthesis of tert-butyl 1'-(6,7-dimethoxyquinolin-4-yl)-[3,4'-bipiperidine]-1-carboxylate (03) [ka] To a stirred solution of 4-chloro-6,7-dimethoxyquinoline (3) (500 mg, 2.24 mmol, 1 eq) in 1,4 dioxane (5 mL) was added tert-butyl [3,4'-bipiperidine]-1-carboxylate (02) (720 mg, 2.68 mmol, 1.2 eq) and degassed for 10 min. Cs 2 CO 3 (2.1g, 6.72mmol, 3eq), Pd 2 (dba) 3(0.20 g, 0.22 mmol, 0.1 eq), X-Phos (0.21 g, 0.44 mmol, 0.2 eq) were added. The reaction mixture was stirred in a sealed tube at 110° C. for 16 h. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad and concentrated to give the crude product. The crude compound was purified by silica gel (60-120 mesh) column [eluted with 5% MeOH in DCM] to give tert-1′-(6,butyl 7-dimethoxyquinolin-4-yl)-[3,4′-bipiperidine]-1-carboxylate (03) (520 mg, yield: 52%) as a brown sticky liquid. TLC system MeOH:DCM (10:90), R f Value: 0.3, LCMS (m / z): 456.3 (M+H) + , 1 HNMR (400 MHz, CDCl 3 ) δ 8.55 (d, J = 5.2 Hz, 1H), 7.46 (s, 1H), 7.22 (s, 1H), 6.78 (d, J = 5.2 Hz, 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 was not evident in the NMR spectrum.

[0252] Synthesis of 4-([3,4'-bipiperidine]-1'-yl)-6,7-dimethoxyquinoline hydrochloride (04) [ka] A solution of tert-1'-(6,butyl 7-dimethoxyquinolin-4-yl)-[3,4'-bipiperidine]-1-carboxylate (03) (520 mg, 1.14 mmol, 1 eq) in 4M dioxane.HCl (6 mL) was stirred at 0°C for 15 min, allowed to reach room temperature and stirred for an additional 2 h. After completion of the reaction by TLC, the volatiles were evaporated. The crude was triturated with diethyl ether to give 4-([3,4'-bipiperidine]-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 (400 MHz, DMSO-d 6 )δ 14.9(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).

[0253] Synthesis of tert-butyl ((1'-(6,7-dimethoxyquinolin-4-yl)-[3,4'-bipiperidine]-1-yl)sulfonyl)carbamate (05) [ka] To a stirred solution of 4-([3,4'-bipiperidine]-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-butoxycarbonyl)((4-(dimethyliminio)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 h. After completion of the reaction, the reaction mixture was quenched with water and extracted with DCM (2 x 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 to give [H 2 Elution with 0.1% FA / ACN in 200 gave tert-butyl ((1'-(6,7-dimethoxyquinolin-4-yl)-[3,4'-bipiperidine]-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) + .

[0254] Synthesis of 6,7-dimethoxy-4-(1-(aminosulfonyl)-[3,4'-bipiperidine]-1'-yl)quinolin formate (I-17) [ka] A solution of tert-butyl ((1'-(6,7-dimethoxyquinolin-4-yl)-[3,4'-bipiperidine]-1'-yl)sulfonyl)carbamate (05) (150 mg, 0.28 mmol, 1 eq) in 4M dioxane.HCl (2 mL) was stirred at 0°C for 15 min, allowed to reach room temperature and continued 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'-bipiperidine]-1'-yl)quinoline formate salt (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) + , 1 HNMR (400 MHz, DMSO-d 6 )δ 8.48(d, J=5.2Hz, 1H), 8.13(formate proton), 7.30(s, 1H), 7.17(s, 1H), 6.86(d, J=5.2Hz, 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=10.8Hz, 1H), 1.90-1.75(m, 4H), 1.56-1.47(m, 5H), 1.11-1.08(m, 1H).

[0255] Synthesis of I-18: Synthesis of ethyl 1-(6,7-dimethoxyquinolin-4-yl)piperidine-4-carboxylate (01) [ka] To a stirred solution of 4-chloro-6,7-dimethoxyquinoline (1) (1 g, 4.46 mmol, 1 eq) in 1,4 dioxane (20 mL) was added ethyl piperidine-4-carboxylate (2) (0.84 g, 5.35 mmol, 1.2 eq), degassed for 10 min, and cooled to 5°C. 2 CO 3 (4.34g, 13.3mmol, 3eq), Pd 2 (dba)3 (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 in a sealed tube at 110° C. for 16 h. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad, washed with ethyl acetate, and concentrated to give the crude product. The crude compound was purified by 100-200 mesh silica gel column by eluting with 3% MeOH in 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) + ,

[0256] Synthesis of 1-(6,7-dimethoxyquinolin-4-yl)piperidine-4-carboxylic acid (02) [ka] THF:H 2 To a stirred solution of ethyl 1-(6,7-dimethoxyquinolin-4-yl)piperidine-4-carboxylate (01) (650 mg, 1.53 mmol, 1 eq) in 2H2O (2:1) (10 mL) was added LiOH.H 2 0 (193 mg, 4.59 mmol, 1 eq) was added at 0° C. The reaction mixture was stirred at room temperature for 16 h. 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 by using 2N aqueous HCl and concentrated under reduced pressure to give 1-(6,7-dimethoxyquinolin-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-d 6) δ 15.38 (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), two protons merged with the solvent peak.

[0257] Synthesis of N-(1-cyanocyclopropyl)-1-(6,7-dimethoxyquinolin-4-yl)piperidine-4-carboxamide (I-18) [ka] To a stirred solution of 1-(6,7-dimethoxyquinolin-4-yl)piperidine-4-carboxylic acid (02) (300 mg, 0.94 mmol, 1.0 eq) in DMF (3 mL) was added 1-aminocyclopropane-1-carbonitrile hydrogen chloride (3) (110 mg, 0.94 mmol, 1.5 eq), HATU (536 mg, 1.41 mmol, 1.5 eq), DIPEA (0.78 mL, 4.7 mmol, 1.5 eq) and the reaction mixture was stirred at room temperature for 16 h. 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 the crude product. The crude compound was purified by reverse phase Grace purification [40% H 2 The mixture was purified by gradient elution with 0.05% CO / ACN 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 (400 MHz, DMSO-d 6)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), 3.5 5-3.52(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).

[0258] Synthesis of I-19: N-(2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propyl)methanesulfonamide [ka] To a stirred solution of 2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)propan-1-amine (I-02-05) (200 mg, 0.607 mmol, 1 eq) in DCM (4 mL) was added TEA (0.12 mL, 0.911 mmol, 1.5 eq), methanesulfonyl chloride (1) (0.05 mL, 0.72 mmol, 1.5 eq) at 0° C. The reaction mixture was stirred at room temperature for 1 h. 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 give the crude product. The crude 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 (400 MHz, DMSO-d 6)δ 8.48(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), 3.57-3.54(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).

[0259] Synthesis of I-20: Synthesis of tert-butyl 4-(6,7-dimethoxyquinolin-4-yl)piperazine-1-carboxylate (01) [ka] To a stirred solution of 4-chloro-6,7-dimethoxyquinoline (1) (1 g, 4.48 mmol, 1 eq) in 1,4 dioxane (10 mL) was added tert-butyl piperazine-1-carboxylate (2) (1 g, 5.38 mmol, 1.2 eq) and degassed for 10 min. Cs 2 CO 3 (2.91g, 8.96mmol, 2eq), Pd 2 (dba) 3 (0.41 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 in a sealed tube at 110° C. for 16 h. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad and the filtrate was concentrated to give the 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 (400 MHz, CDCl 3)δ 8.59(d, J=5.2Hz, 1H), 7.40(s, 1H), 7.26(s, 1H), 6.79(d, J=5.2Hz, 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).

[0260] Synthesis of 6,7-dimethoxy-4-(piperazin-1-yl)quinoline (02) [ka] A solution of tert-butyl 4-(6,7-dimethoxyquinolin-4-yl)piperazine-1-carboxylate (01) (1.3 g, 5 mmol, 1 eq) in 4M dioxane.HCl (13 mL) was stirred at room temperature for 2 h. After completion of the reaction by TLC, the reaction mixture was evaporated under reduced pressure to give the crude product. The crude compound was purified by elution with saturated NaHCO 3 The mixture was basified with a solution of MeOH 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-(piperazin-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) + .

[0261] Synthesis of tert-butyl(2-hydroxypropyl)carbamate (03) [ka] 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 was added triethylamine (9.2 mL, 66.7 mmol, 1 eq), followed by (Boc) under nitrogen flush. 20 (14.3 mL, 66.7 mmol, 1 eq) was added dropwise. The reaction was stirred at room temperature for 16 h. 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 give the crude product. The crude compound was purified by silica gel (100-200 mesh) chromatography [gradient elution with 20-25% ethyl acetate / hexane] to give tert-butyl (2-hydroxypropyl)carbamate (03) as a yellow liquid (5 g, 42%). TLC system: EtOAc / hexane (50:50, ninhydrin stain), R f Value: about 0.4, 1 HNMR (400 MHz, DMSO-d 6 )δ 6.64(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).

[0262] Synthesis of tert-butyl(2-oxopropyl)carbamate (04) [ka] 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 h. After completion of the reaction by TLC, the reaction mixture was diluted with water and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, and concentrated to give the crude product. The crude compound was purified by silica gel (100-200 mesh) chromatography [gradient elution with 5-10% ethyl acetate / hexane] to give tert-butyl (2-oxopropyl)carbamate (04) (1 g, yield: 66%) as a colorless liquid. TLC system: EtoAc:Hexane (50:50, ninhydrin stain), R f Value: about 0.6,1 H NMR (400 MHz, CDCl 3 )δ 5.25(brs, 1H), 4.03(d, J=4.8Hz, 2H), 2.18(s, 3H), 1.46(s, 9H),

[0263] Synthesis of tert-butyl (2-(4-(6,7-dimethoxyquinolin-4-yl)piperazin-1-yl)propyl)carbamate (05) [ka] To a stirred solution of 6,7-dimethoxy-4-(piperazin-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 h. Afterwards, the reaction mixture was cooled to 0 °C and diluted with NaCNBH 3 (224 mg, 3.57 mmol, 1.5 eq) was added and stirred at room temperature for 5 h. After completion of the reaction by TLC, the reaction mixture was quenched with water and extracted with 10% MeOH+DCM (2X50 mL). The combined organic layers were 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 f Value: 0.5, LCMS(m / z): 431.3(M+H) + , 1 HNMR (400 MHz, DMSO-d 6)δ 8.49(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).

[0264] Synthesis of 2-(4-(6,7-dimethoxyquinolin-4-yl)piperazin-1-yl)propan-1-amine hydrochloride (06) [ka] 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., 4M dioxane.HCl (4 mL) was added and stirred at room temperature for 2 h, 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) instead of molecular ion peak + 274.2 was the major ion peak which is a fragment of the desired product. Both LCMS and 1H NMR spectra did not support the identity of the product, but the material was carried forward to the next step where it was confirmed.

[0265] Synthesis of tert-butyl (N-(2-(4-(6,7-dimethoxyquinolin-4-yl)piperazin-1-yl)propyl)sulfamoyl)carbamate (07) [ka] 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 eq) in DCM (4 mL) was added DIPEA (0.25 mL, 1.38 mmol, 3 eq) and (tert-butoxycarbonyl)((4-(dimethyliminio)pyridin-1(4H)-yl)sulfonyl)amide (I-04-03) (181 mg, 0.60 mmol, 1.3 eq). The reaction mixture was stirred at room temperature for 16 h. 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% for two steps) as an off-white solid. TLC system MeOH:DCM (5:95), R f Value: 0.5, LCMS(m / z): 508.3(MH) + .

[0266] Synthesis of N-(2-(4-(6,7-dimethoxyquinolin-4-yl)piperazin-1-yl)propyl)aminosulfonamide formate (I-20) [ka] To a stirred solution of tert-butyl (N-(2-(4-(6,7-dimethoxyquinolin-4-yl)piperazin-1-yl)propyl)sulfamoyl)carbamate (07) (150 mg, 0.29 mmol, 1 eq) in dioxane at 0 °C, 4M dioxane.HCl (1 mL) was added and stirred at room temperature for 2 h. After completion of the reaction by TLC, the reaction mixture was concentrated to give the crude product. The crude compound was purified by reverse phase purification [0-20% (H 2The mixture was purified by gradient elution with 0.1% FA in 0+ACN to give N-(2-(4-(6,7-dimethoxyquinolin-4-yl)piperazin-1-yl)propyl)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) + , 1 HNMR (400 MHz, DMSO-d 6 ) δ 8.50 (d, J = 4.8 Hz, 1H), 8.14 (formate protons), 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).

[0267] Synthesis of I-21: Synthesis of (R)-tert-butyl 4-(6,7-dimethoxyquinolin-4-yl)-2-methylpiperazine-1-carboxylate (01) [ka] To a stirred solution of 4-chloro-6,7-dimethoxyquinoline (1) (1 g, 4.48 mmol, 1 eq) in 1,4 dioxane (10 mL) was added (R)-tert-butyl 2-methylpiperazine-1-carboxylate (2) (1.0 g, 5.38 mmol, 1.2 eq) and degassed for 10 min. Cs 2 CO 3 (4.2g, 13.4mmol, 3eq), Pd 2 (dba) 3(0.41 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 in a sealed tube at 110° C. for 16 h. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad and concentrated to give the crude product. The crude compound was purified by silica gel (100-200 mesh) chromatography [eluted with 3% MeOH in 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) + ,

[0268] Synthesis of (R)-6,7-dimethoxy-4-(3-methylpiperazin-1-yl)quinoline hydrochloride (02) [ka] 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 4M dioxane.HCl (15 mL) was stirred at 0° C. for 2 h up to room temperature. After completion of the reaction by TLC, the volatiles were evaporated and the resulting crude 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 was not good. 1 HNMR (400 MHz, DMSO-d 6) δ 9.65-9.62(brs, 2H), 8.69(d, J=6.4Hz, 1H), 7.53(s, 1H), 7.31(d, J=6.4Hz, 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=6.4Hz, 3H), two protons may be merged with the DMSO-d6 peak in the spectrum.

[0269] Synthesis of (R)-tert-butyl (2-(4-(6,7-dimethoxyquinolin-4-yl)-2-methylpiperazin-1-yl)ethyl)carbamate (03) [ka] To a stirred solution of (R)-6,7-dimethoxy-4-(3-methylpiperazin-1-yl)quinoline hydrochloride (02) (800 mg, 2.47 mmol, 1 eq) in DMF (8 mL) was added K 2 CO 3 (1.0 g, 7.43 mmol, 3 eq) was added 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 h. 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 the crude product. The crude compound was purified by silica gel (100-200 mesh) chromatography [gradient elution with 0-4% MeOH in DCM] 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, CDCl 3) δ 8.57 (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 are not clean because a trace amount of compd-3 remains even after purification.

[0270] Synthesis of (R)-2-(4-(6,7-dimethoxyquinolin-4-yl)-2-methylpiperazin-1-yl)ethanamine hydrochloride (04) [ka] 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., 4M dioxane.HCl (5 mL) was added and stirred at room temperature for 2 h. After completion of the reaction by TLC, the volatiles were evaporated and the crude 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) + ,

[0271] Synthesis of (R)-tert-butyl N-(2-(4-(6,7-dimethoxyquinolin-4-yl)-2-methylpiperazin-1-yl)ethyl)sulfamoylcarbamate (05) [ka] 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-butoxycarbonyl)((4-(dimethyliminio)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 h. 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 [gradient elution with 10-40% water / ACN] 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.

[0272] Synthesis of (R)-N-(2-(4-(6,7-dimethoxyquinolin-4-yl)-2-methylpiperazin-1-yl)ethyl)aminosulfonamide formate (I-21) [ka] 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 4M dioxane.HCl (3 mL) was stirred from 0° C. to room temperature for 2 h. After completion of the reaction by TLC, the volatiles were evaporated and a diethyl ether wash was performed. The crude compound was purified by reverse phase column [0-30% (H 2The mixture was purified by gradient elution with 0.1% FA in 200 / ACN to give (R)-N-(2-(4-(6,7-dimethoxyquinolin-4-yl)-2-methylpiperazin-1-yl)ethyl)aminosulfonamide formate (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-d 6 )δ 8.50 (d, J=4.8Hz, 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), 3.9 1(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).

[0273] Synthesis of I-22: Synthesis of ethyl 1-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)cyclopropane-1-carboxylate (01) [ka] To a stirred solution of 4-chloro-6,7-dimethoxyquinoline (1) (2.5 g, 11.18 mmol, 1 eq) in 1,4 dioxane (25 mL) was added ethyl 1-(piperidin-4-yl)cyclopropane-1-carboxylate (I-27-02) (2.6 g, 13.41 mmol, 1.2 eq) and Cs 2 CO 3 (18 g, 55.9 mmol, 5 eq) was added. The reaction mixture was degassed for 10 min. Then, Pd 2 (dba) 3(511 mg, 0.55 mmol, 0.05 eq) and X-phos (798 mg, 1.67 mmol, 0.15 eq) were added and stirred at 110° C. for 16 h in a sealed tube. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad and concentrated to give the 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: Approximately 0.2, LCMS (m / z): 385.3 (M+H) + . 74% purity.

[0274] Synthesis of (1-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)cyclopropyl)methanol (02) [ka] To a stirred solution of ethyl 1-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)cyclopropane-1-carboxylate (01) (1.4 g, 3.64 mmol, 1 eq) in THF (14 mL) at -78 °C was added LAH (1.0 M in THF) (18.2 mL, 18.21 mmol, 5 eq). The reaction mixture was stirred at 0 °C for 2 h. After completion of the reaction by TLC, the reaction mixture was diluted with NH 4 The mixture was quenched with Cl 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-dimethoxyquinolin-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.

[0275] Synthesis of 4-(4-(1-(azidomethyl)cyclopropyl)piperidin-1-yl)-6,7-dimethoxyquinoline (03) [ka] 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 eq) in THF (12 mL) was added DBU (2.6 mL, 17.51 ​​mmol, 5 eq), diphenylphosphoryl azide (3.0 mL, 14.03 mmol, 4 eq). The reaction mixture was stirred at room temperature for 48 h. After completion of the reaction, the reaction mixture was washed with aqueous NaHCO 3 The mixture was quenched with ethyl acetate (2×70 mL) 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 the crude product. The crude product was purified by silica gel column chromatography [eluted with 3% MeOH in 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値 : 0.7, LCMS (m / z): 368.3 (M + H) + , 56% purity.

[0276] Synthesis of (1-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)cyclopropyl)methanamine (04) [ka] 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) was added 10% Pd / C (160 mg). The reaction mixture was stirred for 2 h at 37 °C. 2The mixture was stirred at room temperature under 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-dimethoxyquinolin-4-yl)piperidin-4-yl)cyclopropyl)methanamine (04) (200 mg, yield: 16% for three steps) as a viscous liquid. TLC system MeOH:DCM (10:90), R f値 : 0.1, LCMS (m / z): 342.3 (M + H) + .

[0277] Synthesis of tert-butyl (N-((1-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)cyclopropyl)methyl)sulfamoyl)carbamate (05) [ka] 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-butoxycarbonyl)((4-(dimethyliminio)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 h. 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 in 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.

[0278] Synthesis of N-(N-((1-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)cyclopropyl)methyl)sulfamoyl)acetamide formate (I-22) [ka] 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, 4 M HCl in dioxane (2 mL) was added. The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction by TLC, the volatiles were evaporated and the crude compound was purified by reverse phase column chromatography [gradient elution with 1-16% (0.1% FA+ACN in water)] 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% for 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-d 6 )δ 8.47(d, J=4.8Hz, 1H), 8.19(formate proton), 7.29(s, 1H), 7.18(s, 1H), 6.83(d, J=5.2Hz, 1H), 6.48-6.45(m, 3H), 3.90(s, 6H), 3.54-3 .41(m, 2H), 2.89(d, J=6.4Hz, 2H), 2.68(t, J=11.2Hz, 2H), 1.77-1.74(m, 2H), 1.64-1.56(m, 2H), 1.52-1.49(m, 1H), 0.41(s, 4H).

[0279] Synthesis of I-23: Synthesis of tert-butyl (1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)carbamate (01) [ka] To a stirred solution of 4-chloro-6,7-dimethoxyquinoline (1) (1 g, 4.49 mmol, 1 eq) in 1,4 dioxane (10 mL) was added tert-butyl piperidin-4-ylcarbamate (2) (1.07 g, 5.38 mmol, 1.2 eq) and degassed for 10 min. Cs 2 CO 3 (4.37g, 13.4mmol, 3eq), Pd 2 (dba) 3 (0.41 g, 0.449 mmol, 0.1 eq), X-Phos (0.44 g, 0.89 mmol, 0.2 eq) were added. The reaction mixture was stirred in a sealed tube at 110° C. for 16 h. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad and the filtrate was concentrated to give the crude product. The crude compound was purified by silica gel (100-200) column chromatography [eluted with 3% MeOH in 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 (400 MHz, DMSO-d 6 )δ 8.48(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).

[0280] Synthesis of 1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-amine.HCl (02) [ka] 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., 4M HCl in dioxane (6 mL) was added and stirred at room temperature for 2 h. After completion of the reaction by TLC, the volatiles were evaporated and the resulting crude 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), R f Value: 0.1, LCMS (m / z): 288.2 (M+H) + , 63% purity.

[0281] Synthesis of tert-butyl (N-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)sulfamoyl)carbamate (03) [ka] To a stirred solution of 1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-amine hydrochloride (02) (400 mg, 1.23 mmol, 1.0 eq) in DCM (10 mL) at 0° C., DIPEA (0.34 mL, 1.84 mmol, 1.5 eq) and (tert-butoxycarbonyl)((4-(dimethyliminio)pyridin-1(4H)-yl)sulfonyl)amide (I-04-03) (444 mg, 1.47 mmol, 1.2 eq) were added. 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 (2×25 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 [0-50% (H 2 The mixture was purified by gradient elution with 0.05% FA in 0 / ACN 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), Rf Value: 0.4, LCMS(m / z): 467.3(M+H) + .

[0282] Synthesis of N-(N-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)sulfuric acid diamide formate (I-23) [ka] 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, 4 M HCl in dioxane (2 mL) was added and stirred at room temperature for 2 h. After completion of the reaction by TLC, the volatiles were evaporated and the resulting crude compound was purified by reverse phase Grace column [10-50% (H 2 The mixture was purified by gradient elution with 0.01% FA in 0) / ACN to give N-(N-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)sulfuric acid diamide 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-d 6 )δ 8.49(d, J=5.2Hz, 1H), 8.14(formate proton), 7.33(s, 1H), 7.15(s, 1H), 6.91(d, J=5.2Hz, 1H), 6.70(d, J=7.2Hz, 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).

[0283] Synthesis of I-24: Synthesis of 8-(6,7-dimethoxyquinolin-4-yl)-1,4-dioxa-8-azaspiro[4.5]decane (01) [ka] To a stirred solution of 4-chloro-6,7-dimethoxyquinoline (1) (2 g, 8.92 mmol, 1 eq) in 1,4 dioxane (20 mL), 1,4-dioxa-8-azaspiro[4.5]decane (2) (1.5 g, 10.7 mmol, 1.2 eq), Cs 2 CO 3 (8.7g, 26.7mmol, 3eq) was added and degassed for 10 minutes. Then, X-Phos (850mg, 1.78mmol, 0.2eq), Pd 2 (dba) 3 (816 mg, 0.89 mmol, 0.1 eq) was added. The resulting mixture was stirred in a sealed tube at 120° C. for 16 h. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad, washed with ethyl acetate and concentrated to give the crude product. The crude compound was purified by silica gel (100-200 mesh) column chromatography [eluted with 5% MeOH in 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 (400 MHz, CDCl 3 )δ 8.55(d, J=5.2Hz, 1H), 7.43(s, 1H), 7.24(s, 1H), 6.81(d, J=5.2Hz, 1H), 4.04-4.0 1(m, 4H), 3.99(s, 3H), 3.98(s, 3H), 3.31(t, J=5.2Hz, 4H), 2.01(t, J=5.6Hz, 4H).

[0284] Synthesis of 1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-one (02) [ka] To a stirred solution of 8-(6,7-dimethoxyquinolin-4-yl)-1,4-dioxa-8-azaspiro[4.5]decane (01) (2 g, 6.06 mmol, 1 eq) in methanol (20 mL) was added 3N aqueous HCl (10 mL). The reaction mixture was stirred at 70° C. for 16 h. After completion of the reaction by TLC, the reaction mixture was diluted with saturated aqueous NaHCO 3 The mixture was basified with ethyl acetate (3×60 mL) 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 the crude product. The crude compound was purified by silica gel (100-200 mesh) column chromatography [eluted with 5% MeOH in DCM] to give 1-(6,7-dimethoxyquinolin-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 (400 MHz, DMSO-d 6 )δ 8.51(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).

[0285] Synthesis of N-cyclopropyl-1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-amine (03) [ka] To a stirred solution of 1-(6,7-dimethoxy-4-yl)piperidin-4-one (02) (1.2 g, 4.19 mmol, 1 eq) in methanol (12 mL) at 0° C., cyclopropylamine (3) (0.4 mL, 6.29 mmol, 1.5 eq) and titanium isopropoxide (2.5 mL, 8.39 mmol, 2 eq) were added. The reaction mixture was stirred at room temperature for 16 h. After 16 h, at 0° C., sodium cyanoborohydride (394 mg, 6.29 mmol, 1.5 eq) was added and stirring was continued at room temperature for 5 h. 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 layers were washed with brine (80 mL), dried over sodium sulfate and concentrated to give the crude product. The crude compound was purified by silica gel (100-200 mesh) column chromatography [eluted with 8% MeOH in DCM] to give N-cyclopropyl-1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-amine (03) (350 mg, yield: 26%) as a pale yellow sticky material. TLC system MeOH:DCM (10:90), R f Value: 0.3, LCMS(m / z): 328.3(M+H) + , 1 HNMR (400 MHz, DMSO-d 6 ) δ 8.47 (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). NH protons were not evident in the spectrum.

[0286] Synthesis of tert-butyl (N-cyclopropyl-N-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)sulfamoyl)carbamate (04) [ka] To a stirred solution of N-cyclopropyl-1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-amine (03) (350 mg, 1.07 mmol, 1.0 eq) in DCM (5 mL) at 0° C. was added DIPEA (0.2 mL, 1.60 mmol, 1.5 eq) and (tert-butoxycarbonyl)((4-(dimethyliminio)pyridin-1(4H)-yl)sulfonyl)amide (I-04-03) (386 mg, 1.28 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 16 h. 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 in 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) + .

[0287] Synthesis of N-(N-cyclopropyl-N-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)sulfuric acid diamide formate (I-24) [ka] To a stirred solution of tert-butyl (N-cyclopropyl-N-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)sulfamoyl)carbamate (04) (200 mg, 0.39 mmol, 1 eq) in 1,4 dioxane at 0° C., 4M dioxane.HCl (2 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction by TLC, the reaction mixture was evaporated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC to give N-(N-cyclopropyl-N-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)sulfuric acid diamide 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) + , 1 HNMR (400 MHz, DMSO-d 6 )δ 8.53(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=12Hz, 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).

[0288] Synthesis of I-25: Synthesis of 2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)butanenitrile (01) [ka] To a stirred solution of 4-chloro-6,7-dimethoxyquinazoline (1) (400 mg, 1.78 mmol, 1.0 eq) in DMF (4 mL) at 0 °C was added K 2 CO 3(0.98 g, 7.14 mmol, 4 eq) and 2-(piperidin-4-yl)butanenitrile hydrogen chloride (I-13-04) (402 mg, 2.14 mmol, 1.2 eq) were added. The reaction mixture was stirred at room temperature for 16 h. 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 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 silica gel column chromatography [eluted with 53% EtOAc in 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 (400 MHz, CDCl 3 )δ 8.67(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).

[0289] Synthesis of 2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)butan-1-amine (02) [ka] 7M methanolic NH 3 To a stirred solution of 2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)butanenitrile (01) (500 mg, 1.64 mmol, 1 eq) in 10 mL of H was added Raney-Ni (1.0 g). The reaction mixture was stirred at room temperature for 16 h. 2Stirred under balloon pressure. 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 (400 MHz, DMSO-d 6 )δ 8.52(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), 3.05-2.99(m, 2) H), 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).

[0290] Synthesis of tert-butyl (N-(2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)butyl)sulfamoyl)carbamate (03) [ka] 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-butoxycarbonyl)((4-(dimethyliminio)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 h. 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 [eluting with 3% MeOH in 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) + .

[0291] Synthesis of N-(N-(2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)butyl)sulfuric acid diamide formate (I-25) [ka] 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 4M HCl in dioxane (2.5 mL) at 0° C. was stirred for 15 min and then at room temperature for 2 h. 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 in water + ACN)] to give N-(N-(2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)butyl)sulfuric acid diamide 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) + , 1 HNMR (400 MHz, DMSO-d 6 )δ 8.51(s, 1H), 8.16(formate proton), 7.19(s, 1H), 7.12(s, 1H), 6.46(s, 2H), 6.38(t, J=6.4Hz, 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=7.2Hz, 3H).

[0292] Synthesis of I-26: Synthesis of 2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)-2-methylpropanenitrile (01) [ka] 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. was added DIPEA (0.6 mL, 3.34 mmol, 2.5 eq), 2-methyl-2-(piperidin-4-yl)propanenitrile HCl (I-14-02) (247 mg, 1.60 mmol, 1.2 eq) and catalytic amount of DMF. The reaction mixture was stirred at room temperature for 3 h. 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 layers were washed with brine (30 mL), dried over sodium sulfate and concentrated to give the crude product. The crude was purified by silica gel (100-200) column purification [eluted with 4% MeOH in 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) + .

[0293] Synthesis of 2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)-2-methylpropan-1-amine (02) [ka] 7N Methanolic NH 3 To a stirred solution of 2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)-2-methylpropanenitrile (01) (450 mg, 1.32 mmol, 1 eq) in 1 mL of H was added Ra-Ni (1 g). The reaction mixture was stirred at room temperature for 16 h. 2 Stirred under balloon pressure. 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 (400 MHz, DMSO-d 6 )δ 8.52(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).

[0294] Synthesis of tert-butyl (N-(2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)-2-methylpropyl)sulfamoyl)carbamate (03) [ka] 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 eq) in DCM (5 mL) at 0° C. was added DIPEA (0.18 mL, 1.04 mmol, 1.5 eq) and (tert-butoxycarbonyl)((4-(dimethyliminio)pyridin-1(4H)-yl)sulfonyl)amide (I-04-03) (252 mg, 0.83 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 16 h. 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 was purified by silica gel (100-200) column purification [eluted with 5% MeOH in 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 (400 MHz, DMSO-d 6)δ 10.79(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).

[0295] Synthesis of N-(2-(1-(6,7-dimethoxyquinazolin-4-y)piperidin-4-yl)-2-methylpropyl)sulfuric acid diamide formate (I-26) [ka] 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., 4M dioxane.HCl (3 mL) was added dropwise. The reaction was allowed to stir at room temperature for 2 hours. After completion of the reaction by TLC, the reaction mixture was concentrated to give the crude product. The crude product was purified by preparative HPLC to give N-(2-(1-(6,7-dimethoxyquinazolin-4-y)piperidin-4-yl)-2-methylpropyl)sulfuric acid diamide 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-d 6)δ 8.51(s, 1H), 8.13(formate proton), 7.19(s, 1H), 7.12(s, 1H), 6.45(s, 2H), 6.38(t, J=6.8Hz, 1H), 4.25-4.22(m, 2H), 3.92(s, 3H), 3 .91(s, 3H), 2.98(t, J=12Hz, 2H), 2.75(t, J=6.8Hz, 2H), 1.78-1.75(m, 2H), 1.56-1.53(m, 1H), 1.44-1.38(m, 2H), 0.84(s, 6H).

[0296] Synthesis of I-27: Synthesis of ethyl 1-(pyridin-4-yl)cyclopropane-1-carboxylate (01) [ka] 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 min. Then, 1,2-dibromoethane (15.7 mL, 181.68 mmol, 3 eq) was added and the mixture was allowed to warm to room temperature and continued stirring for 3.5 h. 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 layers were washed with brine (80 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 DCM] to give ethyl 1-(pyridin-4-yl)cyclopropane-1-carboxylate (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 (400 MHz, CDCl 3)δ 8.54(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).

[0297] Synthesis of ethyl 1-(piperidin-4-yl)cyclopropane-1-carboxylate (02) [ka] 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) was added PtO 2 (2g) was added and H 2 Stirred at room temperature under balloon pressure for 16 hours. 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, 1 HNMR (400 MHz, CDCl 3 )δ 4.11(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).

[0298] Synthesis of ethyl 1-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)cyclopropane-1-carboxylate (03) [ka] 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. was added ethyl 1-(piperidin-4-yl)cyclopropane-1-carboxylate (02) (3.28 g, 16.74 mmol, 1.5 eq) and K2 CO 3 (7.7 g, 55.8 mmol, 5 eq) was added. The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction by TLC, the reaction mixture was poured into ice-cold water and the precipitated solid was filtered and dried under vacuum to give ethyl 1-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)cyclopropane-1-carboxylate (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 (400 MHz, DMSO-d 6 )δ 8.51(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, 3H), 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).

[0299] Synthesis of (1-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)cyclopropyl)methanol (04) [ka] 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 from -78 °C back to 0 °C for 2 h. After completion of the reaction by TLC, the reaction mixture was diluted with saturated NH 4It was quenched with Cl 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 (400 MHz, DMSO-d 6 )δ 8.50(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).

[0300] Synthesis of 4-(4-(1-(azidomethyl)cyclopropyl)piperidin-1-yl)-6,7-dimethoxyquinazoline (05) [ka] 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 eq) in THF (13 mL) cooled to 0° C., DBU (2.2 mL, 14.8 mmol, 4 eq), DPPA (2.54 mL, 11.1 mmol, 3 eq) were added. The reaction mixture was stirred at room temperature for 48 h. After completion of the reaction, the reaction mixture was washed with aqueous NaHCO 3The mixture was quenched with ethyl acetate (2×70 mL) 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 the crude product. The crude compound was purified by silica gel (100-200 mesh) column chromatography [eluted with 2% MeOH in 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 (400 MHz, CDCl 3 )δ 8.65(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).

[0301] Synthesis of (1-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)cyclopropyl)methanamine (06) [ka] To a stirred solution of 4-(4-(1-(azidomethyl)cyclopropyl)piperidin-1-yl)-6,7-dimethoxyquinazoline (05) (900 mg, 3.35 mmol, 1 eq) in MeOH (9 mL) was added 10% Pd / C (300 mg). The reaction mixture was stirred at room temperature for 16 h. 2 Stirred under balloon pressure. After completion of the reaction by TLC, the reaction mixture was filtered through a pad of Celite, washed with methanol and concentrated under reduced pressure to give (1-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)cyclopropyl)methanamine (06) (500 mg) as a viscous liquid. TLC system MeOH:DCM (10:90), R fValue: 0.1, LCMS (m / z): 343.3 (M+H) + .

[0302] Synthesis of tert-butyl (N-((1-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)cyclopropyl)methyl)sulfamoyl)carbamate (07) [ka] 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-butoxycarbonyl)((4-(dimethyliminio)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 h. 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 in 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) + .

[0303] Synthesis of N-(N-((1-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)cyclopropyl)methyl)sulfuric acid diamide formate (I-27) [ka] 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. was added 4 M HCl in dioxane (2 mL). The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction by TLC, the volatiles were evaporated and the resulting material was purified by reverse phase column chromatography [eluted with 20% (0.1% FA+ACN in water)] to give N-(N-((1-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)cyclopropyl)methyl)sulfuric acid diamide 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-d 6 )δ 8.50(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).

[0304] Synthesis of I-28: Synthesis of 4-chloro-7-methoxyquinazolin-6-ol (01) [ka] To a stirred solution of 4-chloro-7-methoxyquinazolin-6-yl acetate (I-03-03) (700 mg, 2.77 mmol, 1 eq) in methanol (2 mL) at 0° C. was added 7M ammonia in methanol (7 mL). The reaction mixture was stirred at room temperature for 3 h. After completion of the reaction by TLC, the reaction mixture was evaporated under reduced pressure to give the crude material, which was purified by trituration with pentane to give 4-chloro-7-methoxyquinazolin-6-ol (01) (500 mg, yield: 85%) as an off-white solid. TLC system: EtOAc, R f Value: 0.5, LCMS(m / z): 211.1(M+H) + , 1 HNMR (400 MHz, DMSO-d 6 )δ 10.79-10.76(br, 1H), 8.82(s, 1H), 7.43(s, 1H), 7.41(s, 1H), 4.02(s, 3H).

[0305] Synthesis of 4-chloro-7-methoxy-6-(methoxymethoxy)quinazoline (02) [ka] To a stirred solution of 4-chloro-7-methoxyquinazolin-6-ol (01) (500 mg, 2.38 mmol, 1 eq) in DCM (5 mL) at 0° C., TEA (1.6 mL, 11.9 mmol, 5 eq) and MOM-Cl (0.7 mL, 9.52 mmol, 4 eq) were added. 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 (2×30 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the crude material, which was purified by trituration with pentane to give 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 (400 MHz, CDCl 3)δ 8.88(s, 1H), 7.78(s, 1H), 7.37(s, 1H), 5.43(s, 2H), 4.08(s, 3H), 3.58(s, 3H).

[0306] Synthesis of tert-butyl 4-(1-cyanoethyl)piperidine-1-carboxylate (03) [ka] To a stirred solution of tert-butyl 4-(cyanomethyl)piperidine-1-carboxylate (I-13-02) (6 g, 26.7 mmol, 1 eq) in dry THF (30 mL) at -78 °C was added LDA (2M in THF) (20 mL, 40.0 mmol, 1.5 eq) dropwise. The reaction was stirred at -78 °C for 30 min and methyl iodide (1.6 mL, 32.1 mmol, 1.2 eq) in THF (5 mL) was added. The reaction mixture was then stirred at 0 °C for 2.5 h. After completion of the reaction by TLC, the reaction mixture was diluted with saturated NH 4 The mixture was quenched with Cl solution and extracted with EtOAc (2×100 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 silica gel (100-200 mesh) column chromatography [eluted with 7% EtOAc in 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 (400 MHz, CDCl 3 )δ 4.19-4.13(m, 2H), 2.71-2.65(m, 2H), 2.56-2.49(m, 1H), 1.87-1.83(m, 1H), 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).

[0307] Synthesis of tert-butyl 4-(1-aminopropan-2-yl)piperidine-1-carboxylate (04) [ka] To a stirred solution of tert-butyl 4-(1-cyanoethyl)piperidine-1-carboxylate (03) (2 g, 8.36 mmol, 1 eq) in 7 M methanolic ammonia (10 mL) was added Raney-Ni (4 g). The reaction mixture was stirred at room temperature for 16 h. 2 Stirred under balloon pressure. 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-(1-aminopropan-2-yl)piperidine-1-carboxylate (04) (1.2 g, yield: 60%) as a colorless viscous liquid. TLC system EtOAc (ninhydrin stain), R f Value: 0.1, 1 HNMR (400 MHz, DMSO-d 6 ) δ 3.97-3.94(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 were not evident in the spectrum.

[0308] Synthesis of tert-butyl 4-(1-((N-(tert-butoxycarbonyl)sulfamoyl)amino)propan-2-yl)piperidine-1-carboxylate (05) [ka] 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-butoxycarbonyl)((4-(dimethyliminio)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 h. 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 [eluting with 25% EtOAc in hexane] to give tert-butyl 4-(1-((N-(tert-butoxycarbonyl)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 (400 MHz, DMSO-d 6 )δ 10.75(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).

[0309] Synthesis of N-(N-(2-(piperidin-4-yl)propyl)sulfuric acid diamide hydrochloride (06) [ka] To a stirred solution of tert-butyl 4-(1-((N-(tert-butoxycarbonyl)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., 4M dioxane.HCl (4 mL) was added dropwise. The reaction mixture was allowed to stir 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)sulfuric acid diamide 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 (400 MHz, DMSO-d 6 )δ 8.87(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).

[0310] Synthesis of N-(N-(2-(1-(7-methoxy-6-(methoxymethoxy)quinazolin-4-yl)piperidin-4-yl)propyl)sulfuric acid diamide (I-28) [ka] 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, 2 CO 3(407 mg, 2.95 mmol, 3 eq) and N-(N-(2-(piperidin-4-yl)propyl)sulfuric acid diamide hydrochloride (06) (327 mg, 1.27 mmol, 1.3 eq) were added. 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 extracted with EtOAc (2×60 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to give the crude. The crude compound was purified by reverse phase column [gradient elution with 1-19% water in ACN] to give N-(N-(2-(1-(7-methoxy-6-(methoxymethoxy)quinazolin-4-yl)piperidin-4-yl)propyl)sulfuric acid diamide (I-28) (23 mg, yield: 5%) as an off-white solid. TLC system: MeOH:DCM (10:90), R f Value: 0.4, LCMS(m / z): 440.3(M+H) + , 1 HNMR (400 MHz, DMSO-d 6 )δ 8.51(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), 3.4 3(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).

[0311] Synthesis of I-29: Synthesis of tert-butyl (1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)carbamate (01) [ka] To a stirred solution of 4-chloro-6,7-dimethoxyquinazoline (1) (1 g, 4.64 mmol, 1 eq) in DMF (10 mL) was added K 2 CO 3(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 at 0° C. 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 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 the crude product. The crude product was purified by trituration with diethyl ether to give tert-butyl (1-(6,7-dimethoxyquinazolin-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) + , 1 HNMR (400 MHz, DMSO-d 6 )δ 8.52(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).

[0312] Synthesis of 1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-amine hydrochloride (02) [ka] 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., 4M HCl in dioxane (10 mL) was added and stirred at room temperature for 2 h. After completion of the reaction by TLC, the volatiles were evaporated and the resulting crude 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 (400 MHz, DMSO-d 6 )δ 8.80(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).

[0313] Synthesis of tert-butyl (N-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)sulfamoyl)carbamate (03) [ka] To a stirred solution of 1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-amine hydrochloride (02) (500 mg, 1.54 mmol, 1.0 eq) in DCM (10 mL) at 0° C., DIPEA (0.43 mL, 2.31 mmol, 1.5 eq) and (tert-butoxycarbonyl)((4-(dimethyliminio)pyridin-1(4H)-yl)sulfonyl)amide (I-04-03) (560 mg, 1.85 mmol, 1.2 eq) were added and 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 (2×30 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) + .

[0314] Synthesis of N-(N-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)sulfuric acid diamide formate (I-29) [ka] 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., 4M HCl in dioxane (4 mL) was added and stirred at room temperature for 3 h. After completion of the reaction by TLC, the volatiles were evaporated and the resulting crude was purified by preparative HPLC [FA method] to give N-(N-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)sulfuric acid diamide 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) + , 1 HNMR (400 MHz, DMSO-d 6 )δ 8.52(s, 1H), 8.14(formate proton), 7.21(s, 1H), 7.09(s, 1H), 6.68(d, J=7.2Hz, 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).

[0315] Synthesis of I-30: Synthesis of piperidin-4-one hydrochloride (01) [ka] 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., 4M HCl in dioxane (10 mL) was added and stirred at room temperature for 2 h. After completion of the reaction by TLC, the volatiles were evaporated and the resulting crude was purified by trituration with diethyl ether to give piperidin-4-one hydrochloride (01) (500 mg, yield: 99%) as a white solid. TLC system MeOH:DCM (10:90), R f Value: 0.1, 1HNMR (400 MHz, DMSO-d 6 )δ 9.45(brs, 2H), 3.39(t, J=6.4Hz, 4H), 2.58(t, J=6.4Hz, 4H).

[0316] Synthesis of 1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-one (02) [ka] To a stirred solution of piperidin-4-one hydrochloride (01) (500 mg, 2.23 mmol, 1 eq) in DMF (5 mL) at 0 °C was added K 2 CO 3 (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 h. 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 the crude product. The crude product was purified by trituration with diethyl ether to give 1-(6,7-dimethoxyquinazolin-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 (400 MHz, DMSO-d 6 )δ 8.57(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).

[0317] Synthesis of N-cyclopropyl-1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-amine (03) [ka] To a stirred solution of 1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-one (02) (500 mg, 1.74 mmol, 1.0 eq) in MeOH (10 mL) was added cyclopropanamine (3) (100 mg, 1.74 mmol, 1 eq), molecular sieves (1 g), and acetic acid (catalyst). The reaction mixture was stirred at room temperature for 30 min and then cooled to rt with NaCNBH 3 (164 mg, 2.61 mmol, 1.5 eq) was added. The reaction mixture was stirred at room temperature for 5 h. After completion of the reaction, the reaction mixture was filtered through a celite pad and washed with 5% MeOH+DCM. The filtrate was dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was purified by trituration with diethyl ether to give N-cyclopropyl-1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-amine (03) (400 mg, yield: 70%) as a yellow sticky material. TLC system MeOH:DCM (5:95), R f Value: 0.2, LCMS (m / z): 329.3 (M+H) + .

[0318] Synthesis of tert-butyl(N-cyclopropyl-N-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)sulfamoyl) (04) [ka] To a stirred solution of N-cyclopropyl-1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-amine (03) (600 mg, 1.82 mmol, 1.0 eq) in DCM (12 mL) at 0° C. was added DIPEA (0.49 mL, 2.74 mmol, 1.5 eq) and (tert-butoxycarbonyl)((4-(dimethyliminio)pyridin-1(4H)-yl)sulfonyl)amide (I-04-03) (660 mg, 2.19 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 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 purification [gradient elution with 0-4% MeOH+DCM] 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 (400 MHz, DMSO-d 6 )δ 11.13(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).

[0319] Synthesis of N-(N-cyclopropyl-N-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)sulfuric acid diamide (I-30) [ka] 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., 4M HCl in dioxane (4 mL) was added and stirred at room temperature for 2 h. After completion of the reaction by TLC, the volatiles were evaporated and the resulting crude was purified by preparative HPLC (Method FA) to give N-(N-cyclopropyl-N-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)sulfuric acid diamide (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 (400 MHz, DMSO-d 6 )δ 8.54(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).

[0320] Synthesis of I-31: Synthesis of 1-(4-(6,7-dimethoxyquinolin-4-yl)piperazin-1-yl)cyclopropanecarbonitrile (01) [ka] In a sealed tube, a stirred solution of 4-chloro-6,7-dimethoxyquinoline (1) (600 mg, 2.67 mmol, 1.0 eq) and 1-(piperazin-1-yl)cyclopropanecarbonitrile (I-32-02) (485 mg, 3.21 mmol, 1.2 eq) in 1,4-dioxane (6 mL) was added with Cs 2 CO 3(2.6 g, 8.03 mmol, 3.0 eq) and X-Phos (255 mg, 0.53 mmol, 0.2 eq) were added and degassed for 20 min. 2 (dba) 3 (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 celite bed, washed with 10% MeOH:DCM and concentrated to give the crude product. The crude compound was purified by silica gel (60-120 mesh) column [with gradient elution of 0-2% MeOH in DCM] to give 1-(4-(6,7-dimethoxyquinolin-4-yl)piperazin-1-yl)cyclopropanecarbonitrile (01) (500 mg, yield: 55%) as a brown sticky liquid. TLC system MeOH:DCM (10:90), R f Value: 0.4, LCMS(m / z): 339.3(M+H) + , 1 HNMR (400 MHz, CDCl 3 )δ 8.57(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).

[0321] Synthesis of (1-(4-(6,7-dimethoxyquinolin-4-yl)piperazin-1-yl)cyclopropyl)methanamine (02) [ka] To a stirred solution of 1-(4-(6,7-dimethoxyquinolin-4-yl)piperazin-1-yl)cyclopropanecarbonitrile (01) (500 mg, 1.47 mmol, 1.0 eq) in 7M methanolic ammonia (5 mL) was added Ra-Ni (250 mg). The reaction mixture was stirred at room temperature under a hydrogen bladder for 16 h. 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-dimethoxyquinolin-4-yl)piperazin-1-yl)cyclopropyl)methanamine (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) + .

[0322] Synthesis of tert-butyl N-((1-(4-(6,7-dimethoxyquinolin-4-yl)piperazin-1-yl)cyclopropyl)methyl)sulfamoylcarbamate (03) [ka]

[0323] 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 eq) in DCM (5 mL) at 0° C. was added DIPEA (0.23 mL, 1.31 mmol, 1.5 eq) and (tert-butoxycarbonyl)((4-(dimethyliminio)pyridin-1(4H)-yl)sulfonyl)amide (I-04-03) (358 mg, 1.05 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 (2×40 mL). The combined organic layers were washed with Na 2 SO 4The crude was purified by Grace reverse phase column chromatography [gradient elution of 0-20% ACN in 0.1% FA in water] 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) + .

[0324] Synthesis of N-((1-(4-(6,7-dimethoxyquinolin-4-yl)piperazin-1-yl)cyclopropyl)methyl)sulfuric acid diamide (I-31 as the TFA salt) [ka] 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 eq) in 1,4-dioxane (1 mL) at 0° C., 4M HCl in dioxane (1.5 mL) was added and stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was evaporated under reduced pressure to give the crude. 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)sulfuric acid diamide as TFA salt (I-31) (11 mg, yield: 9%) as an off-white solid. TLC system MeOH:DCM (10:90), R f Value: 0.2, LCMS (m / z): 422.3 (M+H) + , 1HNMR(400MHz, DMSO)δ 8.58(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, 3 H), 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).

[0325] Synthesis of I-32: Synthesis of 1-(4-benzylpiperazin-1-yl)cyclopropanecarbonitrile (01) [ka] 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 vol), 1-aminocyclopropanecarbonitrile hydrogen chloride (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 h. After completion of the reaction by TLC, it was diluted with water (50 mL) and extracted with ethyl acetate (3×80 mL). The combined organic layers were washed with brine solution (50 mL) and extracted with Na 2 SO 4 The crude compound was purified by silica gel (60-120 mesh) column [with gradient elution of 0-10% EtOAc in hexane] to give 1-(4-benzylpiperazin-1-yl)cyclopropanecarbonitrile (01) (1.5 g, yield: 29%) as a pale yellow viscous liquid. TLC system EtOAc:Hexane (50:50), R f値 : 0.6, LCMS (m / z): 242.2 (M + H) + , 1 HNMR (400 MHz, CDCl 3)δ 7.34-7.22(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).

[0326] Synthesis of 1-(piperazin-1-yl)cyclopropanecarbonitrile (02) [ka] To a stirred solution of 1-(4-benzylpiperazin-1-yl)cyclopropanecarbonitrile (01) (1.5 g, 6.22 mmol, 1.0 eq) in acetone (15 mL), 2 CO 3 (2.5g, 18.6mmol, 3eq) and 1-chloroethyl chloroformate (2) (1mL, 9.33mmol, 1.5eq) were added. 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 (15mL) and stirred at 70°C for 1 hour. After 1 hour, the volatiles were evaporated, acidified with 2N HCl and washed with DCM (2x25mL). The aqueous layer was neutralized with 4M NaOH and extracted with DCM (2X50mL). The combined organic layers were washed with brine solution and diluted with Na 2 SO 4 The mixture was dried at 40° C. and concentrated to give 1-(piperazin-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 (400 MHz, CDCl 3 )δ 2.91(brs, 4H), 2.76(t, J=4.8Hz, 4H), 1.27-1.25(m, 2H), 0.93-0.91(m, 2H)

[0327] Synthesis of 1-(4-(6,7-dimethoxyquinazolin-4-yl)piperazin-1-yl)cyclopropanecarbonitrile (03) [ka] 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 K 2 CO 3 (924 mg, 6.69 mmol, 3.0 eq), 1-(piperazin-1-yl)cyclopropanecarbonitrile (02) (438 mg, 2.90 mmol, 1.3 eq) were added and stirred at room temperature for 16 h. 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 and diluted with Na 2 SO 4 The crude compound was purified by silica gel (60-120 mesh) column [with gradient elution of 0-1% MeOH in DCM] to give 1-(4-(6,7-dimethoxyquinazolin-4-yl)piperazin-1-yl)cyclopropanecarbonitrile (03) (350 mg, yield: 61%) as a pale green solid. TLC system EtOAc:Hexane (30:70), R f Value: 0.1, 1 HNMR (400 MHz, DMSO-d 6 )δ 8.57(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).

[0328] Synthesis of (1-(4-(6,7-dimethoxyquinazolin-4-yl)piperazin-1-yl)cyclopropyl)methanamine (04) [ka] To a stirred solution of 1-(4-(6,7-dimethoxyquinazolin-4-yl)piperazin-1-yl)cyclopropanecarbonitrile (03) (350 mg, 1.03 mmol, 1.0 eq) in 7M methanolic ammonia (5 mL), Ra-Ni (150 mg) was added and stirred at room temperature under hydrogen bladder pressure for 16 h. After completion of the reaction, the reaction mixture was filtered through a celite bed and washed with 10% MeOH in DCM. The filtrate was concentrated to give (1-(4-(6,7-dimethoxyquinazolin-4-yl)piperazin-1-yl)cyclopropyl)methanamine (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) +

[0329] Synthesis of tert-butyl N-((1-(4-(6,7-dimethoxyquinazolin-4-yl)piperazin-1-yl)cyclopropyl)methyl)sulfamoylcarbamate (05) [ka] 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 eq) in DCM (5 mL) at 0° C. was added DIPEA (0.25 mL, 1.44 mmol, 1.5 eq) and (tert-butoxycarbonyl)((4-(dimethyliminio)pyridin-1(4H)-yl)sulfonyl)amide (I-04-03) (347 mg, 1.15 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 16 h. 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 and purified by HPLC. 2 SO 4 The crude compound was purified by reverse phase column chromatography using [H 2Purification by gradient elution of 0-30% ACN in 200 afforded 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) + .

[0330] Synthesis of N-((1-(4-(6,7-dimethoxyquinazolin-4-yl)piperazin-1-yl)cyclopropyl)methyl)sulfuric acid diamide (I-32) [ka] 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 eq) in 1,4-dioxane (0.5 mL) at 0° C., 4 M HCl in dioxane (1 mL) was added and stirred at room temperature for 1 h. After completion of the reaction by TLC, the volatiles were evaporated and the resulting crude was purified by Grace reverse phase column chromatography to give [H 2 Purification by gradient elution of 0-30% ACN in 200 afforded N-((1-(4-(6,7-dimethoxyquinazolin-4-yl)piperazin-1-yl)cyclopropyl)methyl)sulfuric acid diamide (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) + , 1 HNMR (400 MHz, DMSO-d 6)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 3.01(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).

[0331] Synthesis of I-33: Synthesis of N-benzyl-2-chloro-N-(2-chloroethyl)ethan-1-amine (01) [ka] To a stirred solution of bis(2-chloroethyl)amine hydrochloride (1) (50 g, 281 mmol, 1 eq) in ACN (500 mL) was added K 2 CO 3 (38 g, 281 mmol, 1 eq), BnBr (33 mL, 281 mmol, 1 eq) were added and stirred at 70 °C for 16 h. After completion of the reaction by TLC, it was diluted with water (200 mL) and extracted with ethyl acetate (2x200 mL). The combined organic layers were washed with Na 2 SO 4 The crude compound was purified on a silica gel (60-120 mesh) column by eluting in hexane to give N-benzyl-2-chloro-N-(2-chloroethyl)ethan-1-amine (01) (20 g, yield: 33%) as a colorless liquid. TLC system hexane, R f値 :0.8, 1 HNMR (400 MHz, CDCl 3 )δ 7.34-7.32(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).

[0332] Synthesis of ethyl 1-(4-benzylpiperazin-1-yl)cyclopropane-1-carboxylate (02) [ka] To a stirred solution of N-benzyl-2-chloro-N-(2-chloroethyl)ethan-1-amine (01) (8 g, 34.4 mmol, 1 eq) in ethanol (160 mL) at room temperature, DIPEA (80 mL, 10 vol) was added followed by ethyl 1-aminocyclopropane-1-carboxylate hydrochloride (2) (6.2 g, 37.9 mmol, 1.1 eq). The reaction mixture was stirred at 80° C. for 16 h. 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 washed with Na 2 SO 4 The crude compound was purified by silica gel (60-120 mesh) column [with gradient elution of 0-10% EtOAc in hexane] to give ethyl 1-(4-benzylpiperazin-1-yl)cyclopropane-1-carboxylate (02) (5.1 g, yield: 51%) as a colorless liquid. TLC system EtOAc:Hexane (30:70), R f Value: 0.4, 1 HNMR (400 MHz, CDCl 3 )δ 7.34-7.28(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).

[0333] Synthesis of ethyl 1-(piperazin-1-yl)cyclopropane-1-carboxylate (03) [ka] To a stirred solution of ethyl 1-(4-benzylpiperazin-1-yl)cyclopropane-1-carboxylate (02) (5.1 g, 17.7 mmol, 1.0 eq) in MeOH (50 mL) at room temperature was added 10% Pd / C (2 g). The reaction mixture was stirred at room temperature under hydrogen bladder pressure for 16 h. 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-(piperazin-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) + , 1 HNMR (400 MHz, DMSO-d 6 )δ 4.13(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).

[0334] Synthesis of tert-butyl 4-(1-(ethoxycarbonyl)cyclopropyl)piperazine-1-carboxylate (04) [ka] To a stirred solution of ethyl 1-(piperazin-1-yl)cyclopropane-1-carboxylate (03) (3.6 g, 18.8 mmol, 1.0 eq) in dioxane (90 mL) and water (45 mL) at 0 °C was added NaHCO 3 (4.2 g, 54.5 mmol, 3.0 eq) was added followed by Boc-anhydride (3.7 mL, 18.8 mmol, 1.0 eq). The resulting reaction mixture was stirred at room temperature for 4 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc (2×80 mL). The combined organic layers were washed with Na 2 SO 4The crude compound was purified by silica gel (60-120 mesh) column [with gradient elution of 0-10% EtOAc in hexane] 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 (400 MHz, CDCl 3 )δ 4.11(q, J=7.2Hz, 2H), 3.35-3.25(br, 4H), 2.91-2.87(brs, 4H), 1.46(s, 9H), 1.29-1.27(m, 2H), 1.25(t, J=7.2Hz, 3H), 0.95-0.92(m, 2H).

[0335] Synthesis of tert-butyl 4-(1-(hydroxymethyl)cyclopropyl)piperazine-1-carboxylate (05) [ka] To a stirred solution of tert-butyl 4-(1-(ethoxycarbonyl)cyclopropyl)piperazine-1-carboxylate (04) (5 g, 16.7 mmol, 1.0 eq) in THF (50 mL) at -78 °C was added LAH (1.0 M in THF) (50 mL, 50.3 mmol, 3.0 eq). The reaction mixture was allowed to reach 0 °C and stirred for 2 h. After completion of the reaction by TLC, saturated NH 4 The mixture was quenched with Cl solution and filtered through a bed of Celite. The filtrate was extracted with EtOAc (3×60 mL) and diluted with Na 2 SO 4 After drying at 40° C. and concentrating under reduced pressure, tert-butyl 4-(1-(hydroxymethyl)cyclopropyl)piperazine-1-carboxylate (05) (4 g, yield: 95%) was obtained 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 (400 MHz, CDCl 3)δ 3.57(d, J=3.6Hz, 2H), 3.35(t, J=5.2Hz, 4H), 2.68(t, J=5.2Hz, 4H), 1.45(s, 9H), 0.72-0.69(m, 2H), 0.55-0.53(m, 2H).

[0336] Synthesis of tert-butyl 4-(1-(bromomethyl)cyclopropyl)piperazine-1-carboxylate (06) [ka] 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 3 (5.3g, 20.3mmol, 1.3eq) and CBr 4 (6.7 g, 20.3 mmol, 1.3 eq) was added and stirred at room temperature for 2 h. 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 and added with Na 2 SO 4 The crude compound was purified by silica gel (60-120 mesh) column [with gradient elution of 0-2% EtOAc in hexane] 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, 1 HNMR (400 MHz, CDCl 3 )δ 3.55(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).

[0337] Synthesis of tert-butyl 4-(1-(azidomethyl)cyclopropyl)piperazine-1-carboxylate (07) [ka] To a stirred solution of tert-butyl 4-(1-(bromomethyl)cyclopropyl)piperazine-1-carboxylate (06) (1 g, 3.13 mmol, 1.0 eq) in DMF (10 mL) was added NaN 3 (0.244 g, 3.75 mmol, 1.2 eq) was added and stirred at 100° C. for 2 h. 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 and extracted with Na 2 SO 4 The crude compound was purified by silica gel (60-120 mesh) column [with gradient elution of 0-5% EtOAc in hexane] 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 (400 MHz, CDCl 3 )δ 3.34(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).

[0338] Synthesis of tert-butyl 4-(1-(aminomethyl)cyclopropyl)piperazine-1-carboxylate (08) [ka] To a stirred solution of tert-butyl 4-(1-(azidomethyl)cyclopropyl)piperazine-1-carboxylate (07) (650 mg, 2.31 mmol, 1.0 eq) in MeOH (6 mL) was added Pd(OH) 2(120 mg) was added and stirred under hydrogen bladder pressure at room temperature 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 (400 MHz, DMSO-d 6 )δ 3.22-3.20(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).

[0339] Synthesis of tert-butyl 4-(1-(((N-(tert-butoxycarbonyl)sulfamoyl)amino)methyl)cyclopropyl)piperazine-1-carboxylate (09) [ka] To a stirred solution of tert-butyl 4-(1-(aminomethyl)cyclopropyl)piperazine-1-carboxylate (08) (640 mg, 2.50 mmol, 1.0 eq) in DCM (10 mL) at 0° C., DIPEA (0.6 mL, 3.76 mmol, 1.5 eq) and (tert-butoxycarbonyl)((4-(dimethyliminio)pyridin-1(4H)-yl)sulfonyl)amide (I-04-03) (1 g, 3.01 mmol, 1.2 eq) were added and stirred at room temperature for 16 h. 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 and diluted with Na 2 SO 4The crude compound was purified by silica gel (60-120 mesh) column [gradient elution of 10-25% EtOAc in hexane] to give tert-butyl 4-(1-(((N-(tert-butoxycarbonyl)sulfamoyl)amino)methyl)cyclopropyl)piperazine-1-carboxylate (09) (700 mg, yield: 70%) as a white solid. TLC system EtOAc:Hexane (50:50), R f Value: 0.3, 1 HNMR (400 MHz, CDCl 3 )δ 5.31-5.29(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).

[0340] Synthesis of 4-(1-((sulfamoylamino)methyl)cyclopropyl)piperazine (10) [ka] To a stirred solution of tert-butyl 4-(1-(((N-(tert-butoxycarbonyl)sulfamoyl)amino)methyl)cyclopropyl)piperazine-1-carboxylate (09) (700 mg, 1.61 mmol, 1.0 eq) in dioxane (5 mL) at 0° C., 4M HCl in dioxane (5 mL) was added and stirred at room temperature for 1 h. 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 HNMR (400 MHz, DMSO-d 6) 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). NMR was not clean but the material was carried forward to the next step.

[0341] Synthesis of N-((1-(4-(7-methoxy-6-(methoxymethoxy)quinazolin-4-yl)piperazin-1-yl)cyclopropyl)methyl)sulfuric acid diamide (I-33) [ka] 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, 2 CO 3 (244 mg, 1.77 mmol, 3 eq) and 4-(1-((sulfamoylamino)methyl)cyclopropyl)piperazine hydrochloride (10) (207 mg, 0.76 mmol, 1.3 eq) were added. The reaction mixture was stirred at room temperature for 16 h. 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 and extracted with Na 2 SO 4 The crude was purified by trituration with 2% MeOH in ACN to give N-((1-(4-(7-methoxy-6-(methoxymethoxy)quinazolin-4-yl)piperazin-1-yl)cyclopropyl)methyl)sulfuric acid diamide (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 (400 MHz, DMSO-d 6)δ 8.52(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).

[0342] Synthesis of I-34: Synthesis of 4-chloro-6-(fluoromethoxy)-7-methoxyquinazoline (01) [ka] To a stirred solution of 4-chloro-7-methoxyquinazolin-6-ol (I-28-01) (500 mg, 2.38 mmol, 1.0 eq) in DMF (5 mL) at 0° C. was added NaH (60%) (86 mg, 3.57 mmol, 1.5 eq) and 2M fluoroiodomethane (1) in ACN (1.4 mL, 2.85 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction by TLC, it was diluted with water and extracted with EtOAc (2×25 mL). The organic layer was washed with Na 2 SO 4 The crude compound was purified by silica gel column (60-120 mesh) chromatography [with gradient elution of 0-1% MeOH in DCM] to give 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 (400 MHz, CDCl 3 )δ 8.93(s, 1H), 7.81(s, 1H), 7.41(s, 1H), 5.87(d, J=53.2Hz, 2H), 4.08(s, 3H).

[0343] Synthesis of N-((1-(4-(6-(fluoromethoxy)-7-methoxyquinazolin-4-yl)piperazin-1-yl)cyclopropyl)methyl)sulfuric acid diamide (I-34) [ka] To a stirred solution of 4-chloro-6-(fluoromethoxy)-7-methoxyquinazoline (01) (150 mg, 0.61 mmol, 1.0 eq) in DMF (3 mL) at 0 °C was added K 2 CO 3 (256 mg, 1.85 mmol, 3 eq) and 4-(1-((sulfamoylamino)methyl)cyclopropyl)piperazine hydrochloride (I-33-10) (217 mg, 0.79 mmol, 1.3 eq) were added. The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction by TLC, it was diluted with ice-cold water and extracted with EtOAc (2X10 mL). The organic layer was washed with Na 2 SO 4 The crude compound was purified by trituration with 2% methanol in ACN to give N-((1-(4-(6-(fluoromethoxy)-7-methoxyquinazolin-4-yl)piperazin-1-yl)cyclopropyl)methyl)sulfuric acid diamide (I-34) (45 mg, yield: 16%) as an off-white solid. TLC system MeOH:DCM (10:90), R f Value: 0.4, LCMS(m / z): 441.3(M+H) + , 1 HNMR (400 MHz, DMSO-d 6 )δ 8.55(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).

[0344] Synthesis of I-35: Synthesis of tert-butyl 4-(1-(ethoxycarbonyl)cyclopropyl)piperidine-1-carboxylate (01) [ka] To a stirred solution of ethyl 1-(piperidin-4-yl)cyclopropane-1-carboxylate (I-27-02) (4 g, 20.3 mmol, 1 eq) in 1,4-dioxane and water (2:1) cooled to 0 °C was added NaHCO 3 (5.1g, 60.8mmol, 3.0eq) and (Boc 2 )O (4.65 mL, 20.3 mmol, 1.0 eq) was added. The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction by TLC, the reaction mixture was diluted with water and extracted with EtOAc (2×80 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 silica gel (60-120 mesh) column chromatography [eluted with 5% EtOAc in 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 in hexane (30:70), R f値 :0.8, Direct mass (m / z):242.0(M+H-tBu) + .

[0345] Synthesis of tert-butyl 4-(1-(hydroxymethyl)cyclopropyl)piperidine-1-carboxylate (02) [ka] 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 in 3 h. After completion of the reaction by TLC, the reaction mixture was diluted with saturated NH 4It was quenched with Cl solution and extracted with EtOAc (3×80 mL). The combined organic layers were washed with brine solution (50 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 [with gradient elution of 0-30% EtOAc in hexane] 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 in hexane (50:50), R f Value: 0.3, 1 HNMR (400 MHz, CDCl 3 )δ 4.19-4.17(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).

[0346] Synthesis of tert-butyl 4-(1-(azidomethyl)cyclopropyl)piperidine-1-carboxylate (03) [ka] To a stirred solution of tert-butyl 4-(1-(hydroxymethyl)cyclopropyl)piperidine-1-carboxylate (02) (1.4 g, 5.49 mmol, 1 eq) in THF (14 mL) cooled to 0° C., DBU (6.6 mL, 43.9 mmol, 8 eq), and DPPA (5.9 mL, 27.4 mmol, 5 eq) were added. The reaction mixture was stirred at room temperature for 16 h. 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 give the crude product. The crude compound was purified by silica gel (60-120 mesh) column chromatography [eluting with 5% EtOAc in hexane] to give tert-butyl 4-(1-(azidomethyl)cyclopropyl)piperidine-1-carboxylate (03) (1.9 g) as a colorless liquid. TLC system: EtOAc in hexane (50:50), R f値 :0.8, Direct mass (m / z):225.1(M+H-tBu) + .

[0347] Synthesis of tert-butyl 4-(1-(aminomethyl)cyclopropyl)piperidine-1-carboxylate (04) [ka] To a stirred solution of tert-butyl 4-(1-(azidomethyl)cyclopropyl)piperidine-1-carboxylate (03) (1.9 g, 6.78 mmol, 1 eq) in MeOH (20 mL) was added 10% Pd / C (500 mg) and incubated at room temperature for 2 h with H 2Stirred under balloon pressure. After completion of the reaction by TLC, the reaction mixture was filtered through a celite pad and washed with ethanol. The collected filtrate was concentrated under reduced pressure to give the crude. The crude compound was purified by silica gel (60-120 mesh) column chromatography [with gradient elution of 0-10% MeOH in DCM] to give tert-butyl 4-(1-(aminomethyl)cyclopropyl)piperidine-1-carboxylate (04) (950 mg, yield: 56%) as a colorless viscous liquid. TLC system: EtOAc in hexane (50:50), R f値 :0.1, Direct mass (m / z):255.2(M+H) + .

[0348] Synthesis of tert-butyl 4-(1-(((N-(tert-butoxycarbonyl)sulfamoyl)amino)methyl)cyclopropyl)piperidine-1-carboxylate (05) [ka] 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. gave DIPEA (0.95 mL, 5.31 mmol, 1.5 eq), (tert-butoxycarbonyl)((4-(dimethyliminio)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 hours and 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 [with gradient elution of 10-30% EtOAc in hexanes] to give tert-butyl 4-(1-(((N-(tert-butoxycarbonyl)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 (400 MHz, CDCl 3 )δ 6.96(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).

[0349] Synthesis of 4-(1-((sulfamoylamino)methyl)cyclopropyl)piperidine hydrochloride (06) [ka] To a stirred solution of tert-butyl 4-(1-(((N-(tert-butoxycarbonyl)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 dioxane.HCl (2 ml) was slowly added dropwise and stirred at room temperature for 2 h. 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, 1 HNMR (400 MHz, DMSO-d 6 )δ 8.81-8.74(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).

[0350] Synthesis of N-((1-(1-(7-methoxy-6-(methoxymethoxy)quinazolin-4-yl)piperidin-4-yl)cyclopropyl)methyl)sulfuric acid diamide (I-35) [ka] 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, 2 CO 3(244 mg, 1.77 mmol, 3 eq) and 4-(1-((sulfamoylamino)methyl)cyclopropyl)piperidine hydrochloride (06) (193 mg, 0.88 mmol, 1.5 eq) were added and stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was diluted with ice-cold water and extracted with EtOAc (2×50 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 (twice) column [with gradient elution of 10-50% ACN in 0.1% FA in water] to provide I-35 with 86% purity. 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)sulfuric acid diamide (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) + , 1 HNMR (400 MHz, DMSO-d 6 )δ 8.50(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, 3H), 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).

[0351] Synthesis of I-36: Synthesis of tert-butyl 4-(1-amino-2-methylpropan-2-yl)piperidine-1-carboxylate (01) [ka] 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 eq) in 7M methanolic ammonia (15 mL), Ra-Ni (500 mg) was added and stirred at room temperature under hydrogen bladder pressure for 16 h. After completion of the reaction, the reaction mixture was filtered through a celite 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 (400 MHz, DMSO-d 6 )δ 4.01-3.98(m, 2H), 2.62-2.57(brs, 2H), 2.27-2.24(m, 2H), 1.57-1.53(m, 2H), 1.38(s, 10H), 1.05-1.02(m, 2H), 0.76(s, 6H).

[0352] Synthesis of tert-butyl 4-(1-((N-(tert-butoxycarbonyl)sulfamoyl)amino)-2-methylpropan-2-yl)piperidine-1-carboxylate (02) [ka] 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., DIPEA (1.5 mL, 8.20 mmol, 1.5 eq) and (tert-butoxycarbonyl)((4-(dimethyliminio)pyridin-1(4H)-yl)sulfonyl)amide (I-04-03) (1.97 g, 6.56 mmol, 1.2 eq) were added and stirred at room temperature for 16 h. 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 and diluted with Na 2 SO 4The crude was purified by silica gel (60-120 mesh) column chromatography [gradient elution of 20-30% EtOAc in hexane] to give tert-butyl 4-(1-((N-(tert-butoxycarbonyl)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 (400 MHz, DMSO-d 6 )δ 10.76(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).

[0353] Synthesis of 4-(2-methyl-1-(sulfamoylamino)propan-2-yl)piperidine hydrochloride (03) [ka] To a stirred solution of tert-butyl 4-(1-((N-(tert-butoxycarbonyl)sulfamoyl)amino)-2-methylpropan-2-yl)piperidine-1-carboxylate (02) (1.5 g, 3.44 mmol, 1.0 eq) in 1,4-dioxane (1 mL) at 0° C., 4M HCl in dioxane (1 mL) was added and stirred at room temperature for 2 h. 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, 1 HNMR (400 MHz, DMSO-d 6)δ 8.96(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).

[0354] Synthesis of N-(2-(1-(7-methoxy-6-(methoxymethoxy)quinazolin-4-yl)piperidin-4-yl)-2-methylpropyl)sulfuric acid diamide (I-36) [ka] To a stirred solution of 4-chloro-7-methoxy-6-(methoxymethoxy)quinazoline (I-28-02) (250 mg, 0.98 mmol, 1.0 eq) in DMF (5 mL) at 0 °C, 2 CO 3 (407 mg, 2.95 mmol, 3.0 eq) was added followed by 4-(2-methyl-1-(sulfamoylamino)propan-2-yl)piperidine (03) (300 mg, 1.27 mmol, 1.3 eq). The resulting mixture was stirred at room temperature for 16 h. After completion of the reaction by TLC, the reaction mixture was diluted with ice-cold water and stirred for 30 min. The precipitated solid was filtered, washed with diethyl ether and dried under vacuum to give N-(2-(1-(7-methoxy-6-(methoxymethoxy)quinazolin-4-yl)piperidin-4-yl)-2-methylpropyl)sulfuric acid diamide (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 (400 MHz, DMSO-d 6)δ 8.50(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).

[0355] Synthesis of I-37: Synthesis of 4-(1-(azidomethyl)cyclopropyl)piperidine hydrochloride (01) [ka] To a stirred solution of tert-butyl 4-(1-(azidomethyl)cyclopropyl)piperidine-1-carboxylate (I-35-03) (1.7 g (crude), 6.07 mmol, 1 eq) in 1,4 dioxane (17 mL) at 0° C., 4M dioxane.HCl (17 mL) was slowly added dropwise and stirred at room temperature for 2 h. After completion of the reaction 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 in hexane (50:50, ninhydrin stain), R f Value: 0.1, Direct mass (m / z): 181.2 (M+H) + , 1 HNMR (400 MHz, DMSO-d 6 )δ 8.92-8.57(br, 2H), 3.27-3.24(m, 4H), 2.80-2.73(m, 2H), 1.75-1.71(m, 2H), 1.60-1.48(m, 2H), 1.37-1.30(m, 1H), 0.49-0.45(m, 4H).

[0356] Synthesis of 4-chloro-6-(fluoromethoxy)-7-methoxyquinoline (02) [ka] To a stirred solution of 4-chloro-7-methoxyquinolin-6-ol (I-10-01) (500 mg, 2.39 mmol, 1 eq) in DMF (5 mL) at 0° C., NaH (83 mg, 3.58 mmol, 1.5 eq) was added and stirred for 15 min. Then fluoroiodomethane (ca. 2 mol / L in acetonitrile) (1.4 mL, 2.85 mmol, 1.2 eq) was added dropwise at 0° C. for 10 min. The reaction mixture was stirred at room temperature for 4 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 (30 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 [eluting with 30% EtOAc in 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 (400 MHz, CDCl 3 )δ 8.65(d, J=4.8Hz, 1H), 7.82(s, 1H), 7.50(s, 1H), 7.39(d, J=4.8Hz, 1H), 5.91(d, J=53.6Hz, 2H), 4.05(s, 3H).

[0357] Synthesis of 4-(4-(1-(azidomethyl)cyclopropyl)piperidin-1-yl)-6-(fluoromethoxy)-7-methoxyquinoline (03) [ka] To a stirred, degassed solution of 4-chloro-6-(fluoromethoxy)-7-methoxyquinoline (02) (300 mg, 1.24 mmol, 1.0 eq) and 4-(1-(azidomethyl)cyclopropyl)piperidine hydrochloride (01) (322 mg, 1.49 mmol, 1.2 eq) in 1,4-dioxane (3 mL) was added Cs 2 CO 3(1.2g, 3.73mmol, 3.0eq) and X-Phos (114mg, 0.24mmol, 0.2eq) and Pd 2 (dba) 3 (114 mg, 0.12 mmol, 0.1 eq) was added. 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 carried onto the next step without purification.

[0358] Synthesis of (1-(1-(6-(fluoromethoxy)-7-methoxyquinolin-4-yl)piperidin-4-yl)cyclopropyl)methanamine (04) [ka] 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) was added 10% Pd / C (100 mg) and incubat...

Claims

**Claim 1** A compound selected from the group consisting of the following compounds: 【Chemical Formula 1-1】 【Chemical 1-2】 【Chemical Formula 1-3】 A compound. **Claim 2** A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 and a pharmaceutically acceptable carrier. **Claim 3** A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 for treating disorders of uncontrolled cell proliferation in mammals. **Claim 4** A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 for treating cancer in mammals.

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