Ectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1) inhibitors and methods of use thereof

Abstract

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

Description

Technical Field

[0001] The present invention generally relates to inhibitors of ectonucleotide pyrophosphatase / phosphodiesterase (ENPP1). The present invention relates to pharmaceutical compositions containing compounds of Formula 1 or Formula 2 and methods of using these compounds or compositions to treat various types of human cancers, cardiovascular, diabetes, obesity, non-alcoholic steatohepatitis, glaucoma, antiviral, antibacterial and anti-fibrotic therapeutic agents that overexpress ENPP1. The present invention also relates to methods for preparing compounds and pharmaceutical salts thereof. Background Art

[0002] The ectonucleotide pyrophosphatase / phosphodiesterase (ENPP) family of members contains seven isoforms, ENPP1-7, which are type II transmembrane glycoproteins or exoenzymes. Mass spectrometry and proteomic analysis from more than 370 protein targets showed that the exoprotein ENPP1 is one of the top genes showing 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 indicate that ENPP1 is able to hydrolyze ATP. These ectonucleases are involved in the hydrolysis of pyrophosphate (PPi) and phosphodiester bonds in extracellular nucleotides; such as triphosphates, oligonucleotides, and they produce nucleoside 5'-monophosphates. One of the key isoforms, ENPP1 (plasmacyte membrane glycoprotein-1, PC-1) is involved in many physiological processes, such as development, formation and transport, as well as pathophysiological conditions. Aberrant ENPP1 expression has been detected in breast cancer relative to normal breast epithelium, supporting its potential for development in bone metastases (occurring in approximately 80% of cases), Hodgkin's lymphoma, hepatocellular carcinoma, follicular lymphoma, glioblastoma, and other malignant tumor tissues.

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

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

[0005] There is ample evidence that ENPP1 expression is significant in human primary breast tumors relative to normal mammary epithelium, with the highest levels observed in breast-bone metastases. These data support not only a potential role for ENPP1 in breast-bone metastases, but also as a potential prognostic marker for breast cancer. Recently, ENPP1 has been shown to be upregulated in lung cancer. Knockdown of ENPP1 in lung cancer cell lines HCC827 and A549 resulted in inhibition of colon formation, anchorage-independent growth in vitro, and tumorigenicity in vivo. These results from target validation experiments clearly support the pharmacological role of ENPP1 in the development of novel cancer immunotherapies.

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

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

[0008]

[0009] in

[0010] X is N or CR 11 ;

[0011] Y is selected from -CR4R5-, -NR6-, -N(CH2) m O-, -O-, -S-, -S(O)-, -S(O)2, aryl and heteroaryl groups; wherein m is 2 or 3;

[0012] L is selected from the group consisting of C1-C5 alkyl and C1-C5 alkenyl;

[0013] Each of R1, R2 and R3 is independently selected from hydrogen, halogen, CN, OR a 、-C(=O)NR b R c 、-NR b R c 、-C(=O)R d , aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups.

[0014] Each R a are independently selected from the group consisting of hydrogen, lower alkyl, -(CH2) n -C(=O)NR b R c , aralkyl, aryl, heteroaryl, heterocycloalkyl and cycloalkyl groups;

[0015] Where n is an integer between 1 and 3

[0016] Each R b and R c independently selected from the group consisting of hydrogen, lower alkyl and lower aryl, heterocycloalkyl or cycloalkyl;

[0017] Each R d Independently selected from the group consisting of -OR e and lower alkyl groups;

[0018] Each R e independently selected from the group consisting of hydrogen, lower alkyl and lower aryl;

[0019] R 11 independently selected from the group consisting of hydrogen, halogen, COOEt, COOH and CN;

[0020] R4, R5 and R6 are independently selected from the group consisting of hydrogen and lower alkyl;

[0021] or an isomer, hydrate, solvate, polymorph, tautomer or pharmaceutically acceptable salt thereof.

[0022] The compound of formula II is as follows:

[0023]

[0024] in

[0025] X is N or CR 11 ;

[0026] Z is C or N;

[0027] W is selected from the group consisting of C1-C5 alkyl, -C(=O)-(CH2) n -, -(C1-C5 alkyl)-N-; NH and direct bond are as follows:

[0028] Each of R1, R2 and R3 is independently selected from hydrogen, halogen, CN, OR a 、-C(=O)NR b R c 、-NR b R c 、-C(=O)R d , aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups.

[0029] Each R a are independently selected from the group consisting of hydrogen, lower alkyl and -(CH2) n -C(=O)NR b R c , aralkyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl groups;

[0030] Where n is an integer between 1 and 3;

[0031] Each R b and R c independently selected from the group consisting of hydrogen, lower alkyl and lower aryl, heterocycloalkyl or cycloalkyl;

[0032] Each R d Independently selected from the group consisting of -OR e and lower alkyl groups;

[0033] Each R e independently selected from the group consisting of hydrogen, lower alkyl and lower aryl;

[0034] R 11 independently selected from the group consisting of hydrogen, halogen, COOEt, COOH and CN;

[0035] R7, R8 and R9 are independently selected from the group consisting of H, halogen and lower alkyl; and R8 and R9 may also form a bridge on a 7-membered ring having 1 or 2 atoms, as follows:

[0036] R 10 independently selected from the group consisting of hydrogen and CF3;

[0037] or an isomer, hydrate, solvate, polymorph, tautomer or pharmaceutically acceptable salt thereof.

[0038] The present invention encompasses any compound or structure comprising any combination of the above-described substituents.

[0039] In a preferred embodiment, Y in formula I is pyridyl.

[0040] In a preferred embodiment, X in Formula I or Formula II is C-CN.

[0041] In a preferred embodiment, Y in formula I is NR6.

[0042] In a preferred embodiment, in the compounds of Formula I and Formula II, R1, R2 and R3 are selected from a group including CH3O and H.

[0043] In a preferred embodiment, in the compound of formula II, Z is N.

[0044] In a preferred embodiment, in the compound of formula II, W is selected from the group consisting of -4,5-imidazole, 2-oxazole, 3-pyrrole; pyrazole and thiazole.

[0045] In a preferred embodiment, in the compound of formula II, X is N.

[0046] In a preferred embodiment, in the compound of formula II, X is C-CN.

[0047] In a preferred embodiment, in the compound of formula II, R7, R8 and R9 are independently selected from a group comprising H and halogen.

[0048] In a preferred embodiment, in the compound of formula II, R7 is halogen, more preferably F.

[0049] In a preferred embodiment,

[0050] The compound has formula I;

[0051] X is N;

[0052] Y is selected from the group consisting of pyridyl, C1-C5 alkyl, O, N and S;

[0053] L is an optionally substituted C1-C5 alkyl group; and

[0054] R1 and R2 are both CH3O.

[0055] In another preferred embodiment,

[0056] The compound has formula II;

[0057] X is N;

[0058] Z is N;

[0059] W is selected from optionally substituted groups including C1-C5 alkyl, -C(=O)-(CH2)-, -(optionally substituted C1-C5 alkyl)-N; and a direct bond; and

[0060] R1 and R2 are both CH3O.

[0061] Examples of provided compounds include:

[0062]

[0063]

[0064]

[0065]

[0066]

[0067] The present invention also includes hydrates, solvates, polymorphs, isomers, tautomers, pharmaceutically acceptable salts of the compounds, and pharmaceutically acceptable salts of the tautomers.

[0068] The present invention also provides pharmaceutical formulations, medicaments containing the compounds, methods of preparing the pharmaceutical formulations, medicaments, compounds, and methods of treating patients with the provided pharmaceutical formulations and compounds.

[0069] Compounds of the invention were identified by structure-based, computational docking and binding free energy.

[0070] Also disclosed are pharmaceutical compositions comprising a therapeutically effective amount of a disclosed compound and a pharmaceutically acceptable carrier.

[0071] Also disclosed are synthetic methods for preparing the disclosed compounds. In additional aspects, disclosed are products of the disclosed synthetic methods.

[0072] Also disclosed are methods for treating a disorder associated with ENPP1 activity dysfunction in a mammal, comprising the step of administering to the mammal a therapeutically effective amount of a disclosed compound, or a pharmaceutically acceptable salt, tautomer, isomer, hydrate, solvate or polymorph thereof.

[0073] Also disclosed is a method for inhibiting ENPP1 activity in a mammal, comprising the step of administering to the mammal a therapeutically effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt, tautomer, isomer, hydrate, solvate or polymorph thereof.

[0074] Also disclosed are methods for inhibiting ENPP1 activity of at least one cell, comprising the step of contacting the at least one cell with an effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt, tautomer, isomer, hydrate, solvate, or polymorph thereof.

[0075] Also disclosed is a method for treating a condition associated with ENPP1 activity dysfunction in a mammal by eliciting an immunotherapy response in the mammal, the method comprising administering to the mammal a therapeutically effective amount of a disclosed compound, or a pharmaceutically acceptable salt, tautomer, isomer, hydrate, solvate or polymorph thereof, wherein the compound induces an immunotherapy response that is beneficial in treating the condition associated with ENPP1 activity. Such a condition may be, but is not limited to, any type of cancer or any disease caused by bacteria and / or viruses involving ENPP1 activity. Diseases and conditions treatable by the compounds of the present invention include, but are not limited to, cancer, cardiovascular disease, diabetes, obesity, nonalcoholic steatohepatitis, glaucoma, fibrosis antiviral drugs, antibacterial and antifibrosis therapeutic agents.

[0076] Also disclosed are pharmaceutical compositions comprising a pharmaceutically acceptable carrier and an effective amount of a disclosed compound, or a pharmaceutically acceptable salt, tautomer, isomer, hydrate, solvate, or polymorph thereof.

[0077] Also disclosed are kits comprising at least one disclosed compound, or a pharmaceutically acceptable salt, tautomer, isomer, hydrate, solvate, or polymorph thereof.

[0078] Also disclosed are methods for making a medicament comprising combining at least one disclosed compound or at least one disclosed product with a pharmaceutically acceptable carrier or diluent. In a further aspect, the invention relates to the use of the disclosed compounds in the manufacture of a medicament for treating a disorder associated with ENPP1 activity dysfunction. In a further aspect, the invention relates to the use of the disclosed compounds in the manufacture of a medicament for treating an uncontrolled cell proliferation disorder.

[0079] Also disclosed is the use of a disclosed compound or a disclosed product in the manufacture of a medicament for treating a disorder associated with ENPP1 dysfunction in a mammal.

[0080] Although aspects of the invention may be described and claimed in specific statutory categories, such as the system statutory category, this is for convenience only, and those skilled in the art will understand that each aspect of the invention may be described and claimed in any statutory category. Unless expressly stated otherwise, it is not intended that any method or aspect described herein be interpreted as requiring that its steps be performed in a particular order. Therefore, in the event that a method claim does not specifically state in the claim or specification that the steps are limited to a particular order, in no way is it intended to infer an order in any respect. This applies to any possible non-express basis for interpretation, including matters regarding the logic of the arrangement of steps or operational flow, ordinary meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification. BRIEF DESCRIPTION OF THE DRAWINGS

[0081] Figure 1 A graph showing the inhibition of ENPP by compounds of the invention on transfected HEK293T cell lysates.

[0082] Figure 2 Shown are the results of immune infiltration assays in HPAC cells.

[0083] Figure 3 The PK profile of Compound 015-HCl in rats is shown.

[0084] Figure 4A Compound 015-HCl showed in vivo inhibition of tumors.

[0085] Figure 4B In vivo inhibition of tumors by Compound 015-HCl in combination with radiation therapy was shown. DETAILED DESCRIPTION

[0086] definition

[0087] As used herein, the nomenclature of compounds, including organic compounds, may be given using common names, IUPAC, IUBMB, or CAS nomenclature suggestions. When one or more stereochemical features are present, the Cahn-Ingold-Prelog rules for stereochemistry may be employed to assign stereochemical priority, E / Z specifications, etc. Given a name, one skilled in the art can readily determine the structure of the compound by systematic reduction of the compound structure using the naming convention or by commercially available software such as ChemDraw. TM (Cambridge Software Company, USA).

[0088] As used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a functional group," "an alkyl," or "a residue" includes a mixture of two or more such functional groups, alkyl groups, or residues, etc.

[0089] In this article, ranges can be expressed as from "about" a specific value and / or to "about" another specific value. When expressing such a range, additional aspects include from a specific value and / or to another specific value. Similarly, when a value is expressed as an approximation by using the antecedent "about", it should be understood that the specific value forms additional aspects. It should also be understood that the end values ​​of each range are important in relation to other end values ​​and independently of other end values. It should also be understood that multiple values ​​are disclosed herein, and each value is also disclosed herein as "about" for the specific value in addition to the value itself. For example, if the value "10" is disclosed, "about 10" is also disclosed. It should also be understood that each unit between two specific units is also disclosed. For example, if 10 and 15 are disclosed, 11, 12, 13 and 14 are also disclosed.

[0090] References in the specification and the subsequent claims to parts by weight of a particular element or component in a composition denote the weight relationship between that element or component and any other elements or components in the composition or article, expressed as parts by weight. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight of component Y, X and Y are present in a weight ratio of 2:5, and are present in this ratio regardless of whether other components are present in the compound.

[0091] Unless specifically stated to the contrary, the weight percent (wt %) of a component is based on the total weight of the formulation or composition in which the component is included.

[0092] As used herein, the term "ENPP1" refers to ectonucleotide pyrophosphatase / phosphodiesterase.

[0093] As used herein, the terms "optional" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes embodiments where said event or circumstance occurs and embodiments where it does not.

[0094] As used herein, the term "subject" can be a vertebrate, such as a mammal, fish, bird, reptile or amphibian. Therefore, the subject of the method disclosed herein can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not indicate a specific age or gender. Therefore, it is intended to cover adult and newborn subjects and fetuses, whether male or female. In one aspect, the subject is a mammal. A patient refers to a subject suffering from a disease or condition. The term "patient" includes human and livestock subjects. In some aspects of the disclosed method, prior to the administering step, the subject has been diagnosed with a need for treatment of an uncontrolled cell proliferation disorder associated with ENPP1 dysfunction. In some aspects of the disclosed method, prior to the administering step, the subject has been diagnosed with a need for inhibition of ENPP1.

[0095] As used herein, the term "treatment" refers to the medical management of a patient, intended to cure, improve, stabilize or prevent a disease, pathological condition or illness. This term includes active treatment, i.e., treatment specifically for the improvement of a disease, pathological condition or illness, and also includes etiological treatment, i.e., treatment for the removal of the cause of the disease, pathological condition or illness. In addition, this term includes palliative treatment, i.e., treatment designed to relieve symptoms rather than cure a disease, pathological condition or illness; preventive treatment, i.e., treatment for minimizing or partially or completely inhibiting the development of a disease, pathological condition or illness; and supportive treatment, i.e., treatment for another specific therapy for supplementing the improvement of a disease, pathological condition or illness. In various aspects, the term encompasses any treatment of a subject, including mammals (e.g., humans), and includes: (i) preventing the disease from occurring in a subject who may be prone to the disease but has not yet been diagnosed as having the disease; (ii) inhibiting the disease, i.e., curbing its development; or (iii) alleviating the disease, even if the disease subsides. On the one hand, the subject is a mammal, such as a primate, and in another aspect, the subject is a human. The term "subject" also includes domestic animals (eg, cats, dogs, etc.), livestock (eg, cows, horses, pigs, sheep, goats, etc.), and laboratory animals (eg, mice, rabbits, rats, guinea pigs, fruit flies, zebrafish, etc.).

[0096] As used herein, the term "prevent" or "preventing" means to exclude, avoid, eliminate, stop, stop or hinder something from happening, especially by preemptive action. It should be understood that unless otherwise expressly indicated, in the case of reducing, inhibiting or preventing as used herein, the use of the other two words is also expressly disclosed.

[0097] As used herein, the term "diagnosed" means having undergone a physical examination by a technician (e.g., a physician) and found to have a condition that can be diagnosed or treated by a compound, composition, or method disclosed herein. For example, "diagnosed with an uncontrolled cell proliferation disorder" means having undergone a physical examination by a technician (e.g., a physician) and found to have a condition that can be diagnosed or treated by a compound or composition that can inhibit ENPP1. As a further example, "diagnosed as needing to inhibit ENPP1" means having undergone a physical examination by a technician (e.g., a physician) and found to have a condition characterized by ENPP1 dysfunction. As discussed herein, such a diagnosis can refer to a condition such as uncontrolled cell proliferation, cancer, and the like. For example, "diagnosed as needing to treat one or more conditions of uncontrolled cell proliferation associated with ENPP1 dysfunction" means having undergone a physical examination by a technician (e.g., a physician) and found to have one or more conditions of uncontrolled cell proliferation associated with ENPP1 dysfunction.

[0098] As used herein, the phrase "identified as requiring treatment of a condition" and the like refers to selecting a subject based on the need for treatment of the condition. For example, based on an early diagnosis by a technician, a subject may be identified as requiring treatment of a condition (e.g., a condition associated with dysfunction of ENPP1) and thereafter undergo treatment for the condition. It is contemplated that, in one aspect, the identification may be performed by a person different from the person making the diagnosis. It is also contemplated that, in other aspects, administration may be performed by a person who subsequently performs the administration.

[0099] As used herein, the terms "administering" and "administration" refer to any method of providing a pharmaceutical formulation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, intraocular administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, oral administration, intraurethral administration, and parenteral administration, including injection, such as intravenous administration, intraarterial administration, intramuscular administration, and subcutaneous administration. Administration may be continuous or intermittent. In various aspects, the formulation may be administered therapeutically; that is, the formulation is administered to treat an existing disease or condition. In various other aspects, the formulation may be administered prophylactically; that is, it is administered to prevent a disease or condition.

[0100] The term "contacting" as used herein means bringing a disclosed compound and a cell, target receptor or other biological entity together in such a way that the compound can directly or indirectly affect the activity of the target (e.g., receptor, cell, etc.); i.e., by interacting with the target itself; i.e., by interacting with another molecule, cofactor, factor or protein on which the activity of the target depends.

[0101] As used herein, the terms "effective amount" and "amount effective" refer to an amount sufficient to achieve a desired result or have an effect on an undesirable condition. For example, a "therapeutically effective amount" refers to an amount sufficient to achieve a desired therapeutic result or have an effect on an undesirable symptom but generally not sufficient to cause adverse side effects. The specific therapeutically effective dosage level for any particular patient will depend on a variety of factors, including: the condition being treated and the severity of the condition; the specific composition being used; the patient's age, weight, general health, sex and diet; the time of administration; the route of administration; the excretion rate of the specific compound being used; the duration of treatment; the drugs used in combination or simultaneously with the specific compound being used, and similar factors well known in the medical field. For example, it is entirely within the technical scope of the art to start using a compound at a dosage level lower than the dosage level required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. If necessary, for the purpose of administration, the effective daily dose can be divided into multiple doses. Therefore, a single dosage composition may contain such an amount or a submultiple thereof to constitute a daily dose. In the case of any contraindications, the dosage may be adjusted by the individual physician. Dosages may vary and may be administered in one or more dosing administrations per day, for one day or several days. Guidance on appropriate dosages for a given class of drug products can be found in the literature. In various other aspects, the formulation may be administered in a "prophylactically effective amount"; i.e., an effective amount for preventing a disease or condition.

[0102] As used herein, “EC 50 " is intended to refer to the concentration of a substance (e.g., a compound or drug) required for 50% agonism or activation of a biological process or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc. In one aspect, EC 50 Can refer to the concentration of a substance required for 50% agonism or activation in vivo, as further defined elsewhere herein. In a further aspect, EC 50 Refers to the concentration of agonist or activator that elicits a response halfway between the baseline and maximal response.

[0103] As used herein, “IC 50" is intended to refer to the concentration of a substance (e.g., a compound or drug) required for 50% inhibition of a biological process or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc. For example, IC 50 It may refer to the concentration of a substance required for 50% inhibition in vivo or inhibition measured in vitro, as further defined elsewhere herein. Alternatively, IC 50 Refers to the half-maximal (50%) inhibitory concentration (IC) of a substance. Inhibition can be measured in cell lines such as AN3CA, BT-20, BT-549, HCT116, 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.

[0104] The term "pharmaceutically acceptable" describes a material that is not biologically or otherwise undesirable, ie, does not cause unacceptable levels of undesired biological effects or interact in a deleterious manner.

[0105] The term "stable" as used herein refers to compounds that do not substantially change when subjected to conditions that allow them to be produced, detected, and in some aspect recovered, purified, and used for one or more of the purposes disclosed herein.

[0106] As used herein, the term "derivative" refers to a compound whose structure is derived from the structure of a parent compound (e.g., a compound disclosed herein), and whose structure is sufficiently similar to that disclosed herein, and based on this similarity, a person skilled in the art would expect the compound to exhibit the same or similar activity and utility as the claimed compound, or to induce the same or similar activity and utility as a precursor to the claimed compound. Exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of the parent compound.

[0107] As used herein, the term "pharmaceutically acceptable carrier" refers to sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions before use. Embodiments of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), carboxymethyl cellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters, such as ethyl oleate. Appropriate fluidity can be maintained by maintaining the required particle size and by using a surfactant in the case of dispersions, for example, by using a coating material (such as lecithin). These compositions can also contain adjuvants, such as preservatives, wetting agents, emulsifiers and dispersants. Various antibacterial and antifungal agents can be included, such as parabens, chlorobutanol, phenol, sorbic acid, etc. to ensure the prevention of microbial effects. It can also be desirable to include isotonic agents, such as sugar, sodium chloride, etc. Prolonged absorption of injectable drug forms can be achieved by containing agents that delay absorption (such as aluminum monostearate and gelatin). Injectable reservoir forms are prepared by forming a microcapsule matrix of the drug in a biodegradable polymer, such as polylactide-polyglycolide, poly(orthoester) and poly(anhydride). According to the ratio of the drug to the polymer and the properties of the specific polymer used, the rate of drug release can be controlled. Reservoir-type injectable preparations are also prepared by trapping the drug in liposomes or microemulsions compatible with body tissues. Injectable preparations can be sterilized, for example, by filtering through a bacterial retention filter, or by incorporating a sterilizing agent in the form of a sterile solid composition, which can be dissolved or dispersed in sterile water or other sterile injectable media before use. Suitable inert carriers can include sugars, such as lactose. Desirably, the effective particle size of at least 95% of the active ingredient particles by weight is within the range of 0.01 to 10 microns.

[0108] As used in the specification and in the claims which follow, a residue of a chemical species refers to the moiety that is the resultant product of the chemical species in a particular reaction scheme or subsequent preparation or chemical product, regardless of whether the moiety is actually obtained from the chemical species. Thus, an ethylene glycol residue in a polyester refers to one or more -OCH2CH2O- units in the polyester, regardless of whether ethylene glycol was used to prepare the polyester. Similarly, a sebacic acid residue in a polyester refers to one or more -CO(CH2)8CO- moieties in the polyester, regardless of whether the residue was obtained by reacting sebacic acid or an ester thereof to obtain the polyester.

[0109] As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Illustrative substituents include, for example, those described below. For appropriate organic compounds, permissible substituents may be one or more and may be the same or different. For the purposes of this disclosure, heteroatoms (such as nitrogen) may have hydrogen substituents and / or any permissible substituents of organic compounds described herein, which will satisfy the valence of heteroatoms. This disclosure is not intended to be limited in any way to permissible substituents of organic compounds. Moreover, the term "substituted" or "substituted by ... " includes implicit conditions: this substitution is consistent with the permissible valence of the substituted atom and substituent, and the substitution results in a stable compound, such as a compound that does not spontaneously undergo transformation (such as by rearrangement, cyclization, elimination, etc.). It is also contemplated that, in certain aspects, unless explicitly stated to the contrary, individual substituents may be further optionally substituted (ie, further substituted or unsubstituted).

[0110] When defining various terms R1, R 2、 R3 etc. and R a , R b , R c , R d Used as general symbols in this article to represent various specific substituents. These symbols can be any substituent, not limited to those substituents disclosed herein, and when these symbols are defined as certain substituents in one case, they can be defined as some other substituents in another embodiment.

[0111] As used herein, term "alkyl" is a branched or unbranched saturated hydrocarbon group with 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, etc. The alkyl group can be cyclic or acyclic. The alkyl group can be branched or unbranched. The alkyl group can also be substituted or unsubstituted. For example, the alkyl group can be substituted by one or more groups, including but not limited to alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxyl, nitro, silyl, sulfo-oxo or mercaptan, as described herein. "Low alkyl group" is an alkyl group containing one to six (e.g., one to four) carbon atoms.

[0112] For example, "C1-C3 alkyl group" can be selected from methyl, ethyl, n-propyl, isopropyl and cyclopropyl, or a subset thereof. In some aspects, "C1-C3 alkyl group" can be optionally further substituted. As a further embodiment, "C1-C4 alkyl group" can be selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and cyclobutyl, or a subset thereof. In some aspects, "C1-C4 alkyl group" can be optionally further substituted. As a further embodiment, "C1-C6 alkyl group" can be selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, sec-pentyl, tert-pentyl, neopentyl, cyclopentyl, n-hexyl, isohexyl, 3-methylpentane, 2,3-dimethylbutane, neohexane and cyclohexane, or a subset thereof. In some aspects, "C1-C6 alkyl group" can be optionally further substituted. As another embodiment, "C1-C8 alkyl group" can be selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, sec-pentyl, tert-pentyl, neopentyl, cyclopentyl, n-hexyl, isohexyl, 3-methylpentane, 2,3-dimethylbutane, neohexane, cyclohexane, heptane, cycloheptane, octane and cyclooctane, or selected from its subset. In some aspects, "C1-C8 alkyl group" can be optionally further substituted. As another embodiment, "C1-C8 alkyl group" can be selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, sec-pentyl, tert-pentyl, neopentyl, cyclopentyl, n-hexyl, isohexyl, 3-methylpentane, 2,3-dimethylbutane, neohexane, cyclohexane, heptane, cycloheptane, octane and cyclooctane, or selected from its subset. As another embodiment, "C1-C12 alkyl group" can be selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, sec-pentyl, tert-pentyl, neopentyl, cyclopentyl, n-hexyl, isohexyl, 3-methylpentane, 2,3-dimethylbutane, neohexane, cyclohexane, heptane, cycloheptane, octane, cyclooctane, nonane, cyclononane, decane, cyclodecane, undecane, cycloundecane, dodecane and cyclododecane, or selected from its subset. In some aspects, "C1-C12 alkyl group" can be optionally further substituted.

[0113] Throughout this specification, "alkyl" is generally used to refer to both unsubstituted and substituted alkyl groups; however, substituted alkyl groups are also specifically mentioned herein by identifying one or more 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 halide ions (e.g., fluoride, chloride, bromide, or iodide). 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, etc., as described below. When "alkyl" is used in one case and a specific term such as "alkyl alcohol" is used in another embodiment, this does not mean to imply that the term "alkyl" also does not refer to a specific term such as "alkyl alcohol" or the like.

[0114] This practice also applies to other groups described herein. That is, although terms such as "cycloalkyl" refer to both unsubstituted and substituted cycloalkyl moieties, the substituted moieties may be otherwise specifically identified herein; for example, a specific substituted cycloalkyl may be referred to as, for example, "alkylcycloalkyl". Similarly, a substituted alkoxy may be specifically referred to as, for example, "halogenated alkoxy", a specific substituted alkenyl may be, for example, "alkenyl alcohol", etc. Again, the practice of using a general term such as "cycloalkyl" and a specific term such as "alkylcycloalkyl" is not meant to imply that the general term also does not include the specific term.

[0115] As used herein, term "cycloalkyl" is a non-aromatic carbonyl ring consisting of at least three carbon atoms. The embodiment of cycloalkyl group includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl etc. The term "heterocycloalkyl" is a type of cycloalkyl group as defined above, and is included in the meaning of term "cycloalkyl", wherein at least one carbon atom in the carbon atom of the ring is replaced by a heteroatom, such as but not limited to nitrogen, oxygen, sulfur or phosphorus. Cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted. Cycloalkyl group and heterocycloalkyl group can be substituted by one or more groups, and the group includes but is not limited to alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxyl, nitro, silyl, sulfo-oxo, nitrile, sulfonamide or thiol, as described herein.

[0116] As used herein, the term "aryl" is a group containing any carbon-based aromatic group, including but not limited to benzene, naphthalene, phenyl, biphenyl, phenoxybenzene, etc. The term "aryl" also includes "heteroaryl", which is defined as a group containing an aromatic group, and the aromatic group has at least one heteroatom incorporated into the ring of the aromatic group. The embodiment of heterocyclic atoms includes but is not limited to nitrogen, oxygen, sulfur and phosphorus. Similarly, the term "non-heteroaryl" also included in the term "aryl" defines a group containing an aromatic group that does not contain heteroatoms. The aryl group can be substituted or unsubstituted. The aryl group can be substituted by one or more groups, and the one or more groups include but are not limited to alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxyl, ketone, azide, nitro, silyl, sulfo-oxo, nitrile, sulfonamide or thiol, as described herein. The term “biaryl” is a specific type of aromatic group and is included in the definition of “aryl.” Biaryl refers to two aromatic groups bound together by a fused ring structure as in naphthalene or linked by one or more carbon-carbon bonds as in biphenyl.

[0117] As used herein, the terms "halogen", "halide" and "halo" refer to the halogens fluorine, chlorine, bromine and iodine. It is also contemplated that, in various aspects, the halogen may be selected from fluorine, chlorine, bromine and iodine. For example, the halogen may be selected from fluorine, chlorine and bromine. As a further embodiment, the halogen may be selected from fluorine and chlorine. As a further embodiment, the halogen may be selected from chlorine and bromine. As a further embodiment, the halogen may be selected from bromine and iodine. As a further embodiment, the halogen may be selected from chlorine, bromine and iodine. In one aspect, the halogen may be fluorine. In another aspect, the halogen may be chlorine. In still another aspect, the halogen is bromine. In yet another aspect, the halogen is iodine.

[0118] It is also contemplated that in some aspects, pseudo-halogens (e.g., trifluoromethanesulfonates, mesylates, toluenesulfonates, brosylates, etc.) may be used to replace halogens. For example, in some aspects, halogens may be replaced by pseudo-halogens. As further embodiments, pseudo-halogens may be selected from trifluoromethanesulfonates, mesylates, toluenesulfonates, and brosylates. On the one hand, pseudo-halogens are trifluoromethanesulfonates. In further aspects, pseudo-halogens are mesylates. In further aspects, pseudo-halogens are toluenesulfonates. In further aspects, pseudo-halogens are brosylates.

[0119] As used herein, the term "heterocycle" refers to monocyclic and polycyclic aromatic or non-aromatic ring systems in which at least one of the ring members is not carbon. The heterocyclic ring includes azetidine, dioxane, furan, imidazole, isothiazole, isoxazole, morpholine, oxazole, oxazole (including 1,2,3-oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole), piperazine, piperidine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, tetrahydrofuran, tetrahydropyran, tetrazine (including 1,2,4,5-tetrazine), tetrazole (including 1,2,3,4-tetrazole and 1,2,4,5-tetrazole), thiadiazole (including 1,2,3-thiadiazole, 1,2,5-thiadiazole and 1,3,4-thiadiazole), thiazole, thiophene, triazine (including 1,3,5-triazine and 1,2,4-triazine), triazole (including 1,2,3-triazole, 1,3,4-triazole) and the like.

[0120] The term "hydroxyl" as used herein is represented by the formula -OH.

[0121] As used herein, “R 1 ”, “R 2 ”, “R 3 ”, “R n " ”(wherein n is an integer) may independently have one or more of the groups listed above. For example, if R 1If it is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group can be optionally substituted by a hydroxyl group, an alkoxy group, an alkyl group, a halide, etc. Depending on the selected group, the first group can be incorporated into the second group, or alternatively, the first group can be a side group (i.e., connected) of the second group. For example, for the phrase "an alkyl group including an amino group", the amino group can be incorporated into the main chain of the alkyl group. Alternatively, the amino group can be connected to the main chain of the alkyl group. The properties of the selected one or more groups will determine whether the first group is embedded in the second group or connected to the second group.

[0122] As described herein, the compounds of the present invention may contain "optionally substituted" moieties. Generally, unless otherwise expressly stated, a chemical group may be substituted, whether or not it is expressly stated that it is "optionally substituted". Generally, the term "substituted", whether or not preceded by the term "optionally", means that one or more hydrogens of the specified part are replaced by suitable substituents. Unless otherwise stated, the "optionally substituted" group may have suitable substituents at each substitutable position of the group, and when more than one position in any given structure may be substituted by more than one substituent selected from a specified group, at each position, the substituents may be the same or different. The substituent combinations contemplated by the present invention are preferably substituent combinations that form stable or chemically feasible compounds. It is also contemplated that, in certain aspects, unless expressly stated to the contrary, individual substituents may be further optionally substituted (i.e., further substituted or unsubstituted).

[0123] The compounds described herein may contain one or more double bonds and may therefore give rise to cis / trans (E / Z) isomers, as well as other conformational isomers. Unless otherwise specified, the present invention encompasses all such possible isomers, as well as mixtures of such isomers.

[0124] Unless otherwise stated, formulas with chemical bonds shown only in solid lines rather than wedges or dashed lines encompass every possible isomer, such as every enantiomer and diastereomer, and mixtures of isomers, such as racemic mixtures or non-racemic mixtures. The compounds described herein may contain one or more asymmetric centers, and thus may produce diastereomers and optical isomers. Unless otherwise stated, the present invention includes all these possible diastereomers and racemic mixtures thereof, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Also included are mixtures of stereoisomers and isolated specific stereoisomers. During the course of the synthetic processes used to prepare such compounds, or during racemization or epimerization processes known to those skilled in the art, the products of these processes may be mixtures of stereoisomers.

[0125] All enantiomers were separated by SFC column and the stereochemistry remained uncertain.

[0126] Many organic compounds exist in optically active forms with the ability to rotate the plane of plane polarized light. When describing optically active compounds, prefixes D and L or R and S are used to represent the absolute configuration of the molecule around one or more chiral centers. The prefixes d and / or (+) and (-) are used to represent the rotation sign of the compound to plane polarized light, where (-) or / represent that the compound is left-handed. The compound prefixed with (+) or d is right-handed. For a given chemical structure, these compounds referred to as stereoisomers are identical, except that they are mirror images that cannot be superimposed on each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are commonly referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is referred to as a racemic mixture.

[0127] Many compounds described herein can have one or more chiral centers, and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be represented by an asterisk (*). When the bond to the chiral carbon is depicted as a straight line in the disclosed formula, it should be understood that both (R) and (S) configurations of the chiral carbon, and therefore both enantiomers and mixtures thereof are included in the formula. As used in the art, when it is desired to specify the absolute configuration about the chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (bond to the atom above the plane), and the other can be depicted as a series connection of short parallel lines or a wedge (bond to the atom below the plane). The Cahn-Inglod-Prelog system can be used to assign (R) or (S) configurations to chiral carbons.

[0128] like

[0129] The compounds described herein include atoms in both their natural isotopic abundance and in unnatural abundance. The disclosed compounds may be isotopically labeled or isotopically substituted compounds, which are identical to those described, but for the fact that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H. 3 H. 13 C. 14 C. 15 N. 18 O. 17 O. 35 S. 18 F and 36The compounds further include prodrugs thereof, and pharmaceutically acceptable salts of the compounds or prodrugs containing the above-mentioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds of the present invention (e.g., in which a radioactive isotope is incorporated, such as 3 H and 14 C) are useful in drug and / or substrate tissue distribution assays. Tritiated isotopes (i.e., 3 H) and carbon-14 isotopes (i.e., 14 C) is particularly preferred due to its ease of preparation and detectability. Further, the use of heavier isotopes, such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. Isotopically labeled compounds of the invention and prodrugs thereof can generally be prepared by carrying out the following procedure: substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0130] The compound described in the present invention can exist as a solvate. In some cases, the solvent for preparing the solvate is an aqueous solution, and therefore the solvate is generally referred to as a hydrate. The compound can exist as a hydrate, and the hydrate can be obtained, for example, by crystallization from a solvent or an aqueous solution. In this regard, one, two, three or any arbitrary number of solvates or water molecules can be combined with the compound according to the present invention to form solvates and hydrates. Unless otherwise indicated, the present invention includes all these possible solvates.

[0131] It is also understood that certain compounds described herein may exist as an equilibrium of tautomers. For example, a ketone with an α-hydrogen may exist in an equilibrium of a keto form and an enol form.

[0132]

[0133] Likewise, amides having an N-hydrogen may exist in equilibrium with the amide form and the imidic acid form. Unless stated to the contrary, the present invention encompasses all such possible tautomers.

[0134] Chemical substances are known to form solids that exist in different sequential states, which are referred to as polymorphic forms or modifications. Different modifications of polymorphic materials may differ greatly in their physical properties. Compounds according to the present invention may exist in different polymorphic forms, wherein a particular modification may be metastable. Unless otherwise indicated, the present invention encompasses all these possible polymorphic forms.

[0135] In some aspects, the structure of the compound can be represented by the following formula:

[0136]

[0137] It is understood to be equivalent to the following formula:

[0138]

[0139] where n is usually an integer. That is, R n It is understood to represent five independent substituents, R n(a) , R n(b) , R n(c) , R n(d) , R n(e) "Independent substituents" means that each R substituent can be independently defined. For example, if in one embodiment R n(a) is halogen, then in the embodiment described, R n(b) Not necessarily halogen.

[0140] Certain materials, compounds, compositions and components disclosed herein are either commercially available or readily synthesized using techniques generally known to those skilled in the art. For example, starting materials and reagents used in preparing the disclosed compounds and compositions are available from commercial suppliers such as Sigma-Aldrich Chemical Company (Milwaukee, Wisconsin), Across Organics (Morris Plains, New Jersey), Fisher Scientific (Pittsburgh, Pennsylvania), or Sigma Corporation (St. Louis, Missouri) or are prepared by methods known to those skilled in the art following the procedures set forth in references such as Fessel & Feser: Reagents for Organic Synthesis, Vols. 1-17 (John Wiley & Sons, 1991); Roche's Chemistry of Carbon Compounds, Vols. 1-5 and Supplements (Sevier Scientific Publishers, 1989); Organic Reactions, Vols. 1-40 (John Wiley & Sons, 1991); March's Advanced Organic Chemistry, (John Wiley & Sons, 4th ed.); and La Roque's Comprehensive Organic Transformations (VCH Publishers, Inc., 1989).

[0141] Unless otherwise expressly stated, it is not intended that any method described herein be construed as requiring that its steps be performed in a particular order. Therefore, in the event that a method claim does not actually recite the order in which its steps are to be followed or the steps are not otherwise specifically stated in the claims or specification to be limited to a particular order, no order is intended to be inferred in any respect. This applies to any possible non-express basis for interpretation, including: matters of logic regarding arrangement of steps or operational flow; ordinary meaning derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification.

[0142] Disclosed are components for preparing the composition of the present invention and the composition itself used in the method disclosed herein.These and other materials are disclosed herein, and it should be understood that when the combination, subset, interaction, group, etc. of these materials are disclosed, although it is impossible to explicitly disclose specific references to each various individual and collective combination and arrangement of these compounds, each combination and arrangement is specifically envisioned and described herein.For example, if a specific compound is disclosed and discussed, and many modifications that may be made to multiple molecules comprising the compound are discussed, then unless specifically indicated to the contrary, each combination and arrangement and possible modifications in the compound are specifically covered.Therefore, if a class of molecules A, B and C and a class of molecules D, E and F are disclosed, and an embodiment of a combination molecule AD is disclosed, then even if each is not narrated individually, each molecule is considered individually and collectively, which means that it is considered to disclose a combination of AE, AF, BD, BE, BF, CD, CE and CF.Similarly, any subset or combination of these is also disclosed.Therefore, for example, it will be considered that the subgroups of AE, BF and CE are disclosed. This concept applies to all aspects of the present application, including but not limited to steps in the method of making and using the composition of the present invention. Therefore, if there are various additional steps that can be performed, it should be understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the method of the present invention.

[0143] It is understood that the compositions disclosed herein have certain functions. Certain structural requirements for performing the disclosed functions are disclosed herein, and it is understood that there are multiple structures that can perform the same function related to the disclosed structures, and these structures will generally achieve the same result.

[0144] Compound

[0145] In one aspect, the present invention relates to compounds useful as ENPP1 inhibitors. In addition, in one aspect, the compounds of the present invention are useful for treating an uncontrolled cell proliferation disorder. In a further aspect, the uncontrolled cell proliferation disorder is a cancer or a tumor. In still a further aspect, the uncontrolled cell proliferation disorder is associated with ENPP1 dysfunction, as further described herein.

[0146] In another aspect, the compounds of the invention can be used to treat diseases of bacterial or viral origin. Thus, in one aspect, the invention provides a method of treating a disease caused by bacteria or viruses, the method comprising administering to a subject a therapeutically effective amount of a compound of the invention.

[0147] It is contemplated that each disclosed derivative may optionally be further substituted. It is also contemplated that the present invention may optionally omit any one or more derivatives. It should be understood that the disclosed compounds may be provided by the disclosed methods. It should also be understood that the disclosed compounds may be used in the disclosed methods of use.

[0148] structure

[0149] In one aspect, the present invention relates to compounds of formula I or II:

[0150]

[0151] in

[0152] X is N or CR 11 ;

[0153] Y is selected from -CR4R5-, -NR6-, -N(CH2) m O-, -O-, -S-, -S(O)-, -S(O)2, aryl and heteroaryl groups; wherein m is 2 or 3;

[0154] L is selected from the group consisting of C1-C5 alkyl and C1-C5 alkenyl;

[0155] Each of R1, R2 and R3 is independently selected from hydrogen, halogen, CN, OR a 、-C(=O)NR b R c 、-NR b R c 、-C(=O)R d , aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups.

[0156] Each R a are independently selected from the group consisting of hydrogen, lower alkyl, -(CH2) n -C(=O)NR b R c , aralkyl, aryl, heteroaryl, heterocycloalkyl and cycloalkyl groups;

[0157] Where n is an integer between 1 and 3;

[0158] Each R b and R c independently selected from the group consisting of hydrogen, lower alkyl and lower aryl, heterocycloalkyl or cycloalkyl;

[0159] Each R d Independently selected from the group consisting of -OR e and lower alkyl groups;

[0160] Each R eindependently selected from the group consisting of hydrogen, lower alkyl and lower aryl;

[0161] R 11 independently selected from the group consisting of hydrogen, halogen, COOEt, COOH and CN;

[0162] R4, R5 and R6 are independently selected from the group consisting of hydrogen and lower alkyl;

[0163] or an isomer, hydrate, solvate, polymorph, tautomer or pharmaceutically acceptable salt thereof.

[0164] The compound of formula II is as follows:

[0165]

[0166] in

[0167] X is N or CR 11 ;

[0168] Z is C or N;

[0169] W is selected from the group consisting of C1-C5 alkyl, -C(=O)-(CH2) n -, -(C1-C5 alkyl)-N-; NH and direct bond are as follows:

[0170] Each of R1, R2 and R3 is independently selected from hydrogen, halogen, CN, OR a 、-C(=O)NR b R c 、-NR b R c 、-C(=O)R d , aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups.

[0171] Each R a are independently selected from the group consisting of hydrogen, lower alkyl and -(CH2) n -C(=O)NR b R c , aralkyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl groups;

[0172] Where n is an integer between 1 and 3;

[0173] Each R b and R c independently selected from the group consisting of hydrogen, lower alkyl and lower aryl, heterocycloalkyl or cycloalkyl;

[0174] Each R d Independently selected from the group consisting of -OR e and lower alkyl groups;

[0175] Each R e independently selected from the group consisting of hydrogen, lower alkyl and lower aryl;

[0176] R 11 independently selected from the group consisting of hydrogen, halogen, COOEt, COOH and CN;

[0177] R 7、 R8 and R9 are independently selected from the group consisting of H, halogen and lower alkyl; and R8 and R9 may also form a bridge on a 7-membered ring having 1 or 2 atoms, as follows:

[0178] R 10 independently selected from the group consisting of hydrogen and CF3;

[0179] or an isomer, hydrate, solvate, polymorph, tautomer or pharmaceutically acceptable salt thereof.

[0180] The present invention encompasses any compound or structure comprising any combination of the above-described substituents.

[0181] In a preferred embodiment, Y in formula I is pyridyl.

[0182] In a preferred embodiment, X in Formula I or Formula II is C-CN.

[0183] In a preferred embodiment, Y in formula I is NR6.

[0184] In a preferred embodiment, in the compounds of Formula I and Formula II, R1, R2 and R3 are selected from a group including CH3O and H.

[0185] In a preferred embodiment, in the compound of formula II, Z is N.

[0186] In a preferred embodiment, in the compound of formula II, W is selected from the group consisting of -4,5-imidazole, 2-oxazole, 3-pyrrole; pyrazole and thiazole.

[0187] In a preferred embodiment, in the compound of formula II, X is N.

[0188] In a preferred embodiment, in the compound of formula II, X is C-CN.

[0189] In a preferred embodiment, in the compound of formula II, R 7、 R8 and R9 are independently selected from a group comprising H and halogen.

[0190] In a preferred embodiment, in the compound of formula II, R7 is halogen, more preferably F.

[0191] In a preferred embodiment, in the compound of formula II, R8 and R9 are both halogen.

[0192] In a preferred embodiment,

[0193] The compound has formula I;

[0194] X is N;

[0195] Y is selected from the group consisting of pyridyl, C1-C5 alkyl, O, N and S;

[0196] L is an optionally substituted C1-C5 alkyl group; and

[0197] R1 and R2 are both CH3O.

[0198] In another preferred embodiment,

[0199] The compound has formula II;

[0200] X is N;

[0201] Z is N;

[0202] W is selected from optionally substituted groups including C1-C5 alkyl, -C(=O)-(CH2)-, -(optionally substituted C1-C5 alkyl)-N; and a direct bond; and

[0203] R1 and R2 are both CH3O.

[0204] Examples of provided compounds include:

[0205]

[0206]

[0207]

[0208]

[0209]

[0210] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of any compound of the present invention and a pharmaceutically acceptable carrier.

[0211] The present invention also provides a method for treating an uncontrolled cell proliferation disorder in a mammal, the method comprising the step of administering to the mammal an effective amount of any of the compounds of the present invention.

[0212] The present invention also provides a method for reducing ENPP1 activity in a mammal, comprising the step of administering an effective amount of any compound of the present invention to the mammal.

[0213] The present invention also provides a method for inhibiting ENPP1 activity in a mammal, comprising the step of administering to the mammal an effective amount of any compound of the present invention.

[0214] Methods for preparing compounds

[0215] In one aspect, the present invention relates to methods of preparing compounds useful as ENPP1 inhibitors. In other aspects, the products of the disclosed methods of preparation are modulators of ENPP1 activity.

[0216] In addition to other standard operations known in the literature, exemplified in the experimental section or apparent to those skilled in the art, the compounds of the present invention can be prepared by using reactions as shown in the following schemes. For clarity, embodiments with a single substituent are shown, where multiple substituents are allowed under the definitions disclosed herein.

[0217] In addition to other standard operations known in the literature or to those skilled in the art, the reactions for producing compounds of the present invention are also prepared by using the reactions shown in the following reaction schemes. The following examples are provided so that the present invention can be more fully understood, and the examples are illustrative only and should not be construed as limiting.

[0218] In one aspect, the disclosed compounds include products of the synthetic methods described herein. In another aspect, the disclosed compounds include compounds produced by the synthetic methods described herein. In still another aspect, the present invention includes a pharmaceutical composition comprising a therapeutically effective amount of a product of the disclosed method and a pharmaceutically acceptable carrier. In still another aspect, the present invention includes a method for manufacturing a medicament comprising combining at least one compound of any disclosed compound or at least one product of the disclosed method with a pharmaceutically acceptable carrier or diluent.

[0219] In the absence of description of the reaction conditions and the amounts of the ingredients, it is believed that it is determined to be within the technical scope of the art. It is contemplated that each disclosed method may further include additional steps, operations and / or components. It is also contemplated that the present invention may optionally omit any one or more steps, operations and / or components. It should be understood that the disclosed methods can be used to provide the disclosed compounds. It should also be understood that the products of the disclosed methods can be used in the disclosed methods of use.

[0220] Pharmaceutical composition

[0221] In one aspect, the present invention relates to pharmaceutical compositions comprising the disclosed compounds. That is, a pharmaceutical composition comprising a therapeutically effective amount of at least one disclosed compound or at least one product of the disclosed method and a pharmaceutically acceptable carrier can be provided.

[0222] In another aspect, the present invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a product of the disclosed synthesis method. In another aspect, the effective amount is a therapeutically effective amount. In another aspect, the effective amount is a preventive effective amount. In another aspect, the compound is a disclosed compound.

[0223] In some aspects, the disclosed pharmaceutical composition includes the disclosed compound (including one or more pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally other therapeutic agent ingredients or adjuvants. The present composition includes those compositions suitable for oral administration, rectal administration, topical administration, and parenteral administration (including subcutaneous, intramuscular, and intravenous administration), but the most suitable approach in any given case will depend on the nature and severity of the condition of the specific host and the application of the active ingredient. The pharmaceutical composition can be conveniently presented in unit dosage form and can be prepared by any method known in the pharmaceutical field.

[0224] As used herein, the term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from a pharmaceutically acceptable non-toxic base (including inorganic bases and organic bases). Salts derived from such inorganic bases include salts such as aluminum, ammonium, calcium, copper (-ic and -ous), iron, ferrous, lithium, magnesium, manganese (-ic and -ous), potassium, sodium, zinc, etc. Particularly preferred are ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include primary amines, secondary amines and tertiary amines, as well as cyclic amines and substituted amines, such as naturally occurring and synthetic substituted amines. Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hepamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0225] As used herein, the term "pharmaceutically acceptable non-toxic acid" includes inorganic acids, organic acids and salts prepared therefrom, such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, etc. Preferred are citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid.

[0226] In practice, according to conventional pharmaceutical compounding techniques, the compounds of the present invention or pharmaceutically acceptable salts thereof of the present invention can be closely mixed with pharmaceutical carriers as active ingredients. The carrier can take a variety of forms, depending on the form of the desired preparation for administration, such as oral or parenteral (including intravenous). Therefore, the pharmaceutical composition of the present invention can be presented as discrete units suitable for oral administration, such as capsules, cachets or tablets each containing a predetermined amount of active ingredients. Further, the composition can exist as a powder, granules, solution, suspension in an aqueous liquid, non-aqueous liquid, oil-in-water emulsion or water-in-oil liquid emulsion. In addition to the common dosage forms described above, the compounds of the present invention and / or one or more pharmaceutically acceptable salts thereof can also be administered by controlled release devices and / or delivery devices. The composition can be prepared by any pharmaceutical method. Generally, such methods include the step of combining the active ingredient with a carrier constituting one or more essential ingredients. Generally, the composition is prepared by uniformly and closely mixing the active ingredient with a liquid carrier or a finely powdered solid carrier or both. The product can then be conveniently formed into the desired appearance.

[0227] Therefore, the pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier and a compound of the present invention or a pharmaceutically acceptable salt thereof. The compound of the present invention or a pharmaceutically acceptable salt thereof may also be included in a pharmaceutical composition in combination with one or more other therapeutically active compounds.

[0228] The pharmaceutical carrier used can be, for example, solid, liquid or gas. Examples of solid carriers include lactose, carclazyte, sucrose, talcum powder, gelatin, agar, pectin, gum arabic, magnesium stearate and stearic acid. Examples of liquid carriers include syrup, peanut oil, olive oil and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

[0229] In preparing compositions for oral dosage forms, any convenient pharmaceutical medium may be used. For example, water, ethylene glycol, oils, alcohols, flavoring agents, preservatives, colorants, and the like may be used to form oral liquid preparations, such as suspensions, elixirs, and solutions; and carriers such as starch, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants, and the like may be used to form oral solid preparations, such as powders, capsules, and tablets. Tablets and capsules are preferred oral dosage units because of ease of administration, and solid pharmaceutical carriers are thus employed. Optionally, tablets may be coated by standard aqueous or non-aqueous techniques.

[0230] Tablets containing the compositions of the present invention can be prepared by compression or molding, optionally with one or more auxiliary ingredients or adjuvants. Can be prepared by compressing the active ingredient (such as powder or granules) in a free-flowing form optionally mixed with a binder, lubricant, inert diluent, surfactant or dispersant in a suitable machine. Molded tablets can be manufactured by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.

[0231] The pharmaceutical composition of the present invention includes the compound of the present invention (or its pharmaceutically acceptable salt) as active ingredient, pharmaceutically acceptable carrier and optionally one or more other therapeutic agents or adjuvants. The present composition includes compositions suitable for oral administration, rectal administration, topical administration and parenteral (including subcutaneous, intramuscular and intravenous) administration, but the most suitable approach in any given case will depend on the nature and severity of the condition of the specific host and the administration of the active ingredient. The pharmaceutical composition can be conveniently presented in unit dosage form and can be prepared by any method known in the pharmaceutical field.

[0232] The pharmaceutical composition of the present invention suitable for parenteral administration can be prepared as a solution or suspension of the active compound in water. Suitable surfactants, such as hydroxypropylcellulose, can be included. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof, and in oils. Further, preservatives can be included to prevent harmful growth of microorganisms.

[0233] The pharmaceutical composition of the present invention suitable for injectable use comprises sterile aqueous solution or dispersion. In addition, the composition can be in the form of sterile powder for the temporary preparation of such sterile injectable solution or dispersion. In all cases, the final injectable form must be sterile and must be an effective fluid for easy injection. The pharmaceutical composition must be stable under manufacturing and storage conditions; therefore, it is preferably preserved against the contamination of antimicrobial agents (such as bacteria and fungi). The carrier can be a solvent or a dispersion medium containing, for example, water, ethanol, polyols (for example, glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils and suitable mixtures thereof.

[0234] The pharmaceutical composition of the present invention can be in a form suitable for topical use, such as an aerosol, cream, ointment, lotion, dusting powder, mouthwash, gargle, etc. Further, the composition can be in a form suitable for use in a transdermal device. These preparations can be prepared by conventional processing methods using the compounds of the present invention or their pharmaceutically acceptable salts. As an example, a cream or ointment is prepared by mixing a hydrophilic material and water with about 5wt% to about 10wt% of the compound to produce a cream or ointment with a desired consistency.

[0235] Pharmaceutical compositions of the present invention can be in a form suitable for rectal administration, wherein the carrier is a solid. Preferably, the mixture forms a unit dose suppository. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently formed by first mixing the composition with one or more softened or molten carriers, then cooling and molding in a mold.

[0236] In addition to the above-mentioned carrier components, the above-mentioned pharmaceutical preparations may optionally include one or more additional carrier components, such as diluents, buffers, flavoring agents, adhesives, surfactants, thickeners, lubricants, preservatives (including antioxidants), etc. In addition, other adjuvants may be included to make the preparation isotonic with the blood of the intended recipient. Compositions containing the compounds of the present invention and / or pharmaceutically acceptable salts thereof may also be prepared in the form of powders or liquid concentrates.

[0237] In the treatment of conditions requiring inhibition or negative regulation of ENPP1 protein activity, appropriate dosage levels will generally be about 0.01 to 500 mg per kg of patient body weight per day, and may be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg / kg per day; more preferably 0.5 to 100 mg / kg per day. Suitable dosage levels may be about 0.01 to 250 mg / kg per day, about 0.05 to 100 mg / kg per day, or about 0.1 to 50 mg / kg per day. Within this range, the dosage may be 0.05 to 0.5, 0.5 to 5.0, or 5.0 to 50 mg / kg per day. For oral administration, the composition is preferably provided in the form of tablets containing 1.0 to 1000 mg of active ingredient, specifically 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900 and 1000 mg of active ingredient, with the dosage of the patient to be treated adjusted symptomatically. The compound can be administered according to a regimen of 1 to 4 times per day, preferably once or twice per day. This dosage regimen can be adjusted to provide the best therapeutic response.

[0238] However, it should be understood that the specific dosage level for any particular patient will depend on a variety of factors. These factors include the patient's age, weight, general health, sex and diet. Other factors include the time and route of administration, excretion rate, drug combination, and the type and severity of the specific disease being treated.

[0239] The present invention further relates to a method for manufacturing a medicament for inhibiting or negatively regulating ENPP1 protein activity in a mammal (e.g., a human) (e.g., treating an uncontrolled cell proliferation disorder or one or more neurodegenerative disorders associated with ENPP1 dysfunction), the method comprising combining one or more disclosed compounds, products or compositions with a pharmaceutically acceptable carrier or diluent. Thus, in one aspect, the present invention relates to a method for manufacturing a medicament comprising combining at least one disclosed compound or at least one disclosed product with a pharmaceutically acceptable carrier or diluent.

[0240] The disclosed pharmaceutical compositions may further comprise other therapeutically active compounds, which are usually used to treat the above-mentioned pathological conditions.

[0241] 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.

[0242] Methods of using the compounds and compositions

[0243] The disclosed compounds can be used as a single agent or in combination with one or more other drugs for treating, preventing, controlling, improving or reducing the risk of the above-mentioned diseases, disorders and conditions, wherein the compounds of Formula I or II or other drugs have utility for these diseases, disorders and conditions, wherein the drugs are combined together safer or more effective than using any one of the drugs alone. Therefore, one or more other drugs can be administered simultaneously or sequentially with the disclosed compounds by route and in a commonly used amount. When the disclosed compounds are used simultaneously with one or more other drugs, a pharmaceutical composition containing a unit dosage form of such drugs and the disclosed compounds is preferred. However, combination therapy can also be administered according to an overlapping schedule. It is also envisioned that the combination of one or more active ingredients with the disclosed compounds will be more effective than as a single agent.

[0244] The pharmaceutical compositions and methods of the present invention may further comprise other therapeutically active compounds as described herein, which are typically used to treat the above-mentioned pathological conditions.

[0245] Treatment

[0246] The compounds disclosed herein can be used to treat, prevent, improve, control or reduce the risk of a variety of conditions in which patients or subjects would benefit from the inhibition or negative regulation of ENPP1. In one aspect, a method of treating or preventing a condition in a subject is provided, the method comprising administering to the subject at least one disclosed compound in an effective dose and in an effective amount; at least one disclosed pharmaceutical composition; and / or at least one disclosed product to treat the condition in the subject.

[0247] Also provided is a method for treating one or more conditions in a subject for which ENPP1 inhibition is predicted to be beneficial, the method comprising the step of administering to the subject at least one disclosed compound; at least one disclosed pharmaceutical composition; and / or at least one disclosed product in an effective dose and in an effective amount to treat the condition in the subject.

[0248] In one aspect, a method for treating an uncontrolled cell proliferation disorder is provided, the method comprising: administering to a subject at least one disclosed compound in an effective dose and in an effective amount; at least one disclosed pharmaceutical composition; and / or at least one disclosed product to treat the disorder in the subject. In another aspect, a method for treating or preventing a neurodegenerative disorder is provided, the method comprising: administering to a subject at least one disclosed compound in an effective dose and in an effective amount; at least one disclosed pharmaceutical composition; and / or at least one disclosed product to treat the disorder in the subject. A method for treating a disorder in a mammal is also provided, the method comprising the step of administering to the mammal at least one disclosed compound, composition, or drug.

[0249] The present invention relates to the use of chemical compositions for treating diseases or disorders in a patient, preferably a human, by administering one or more disclosed compounds or products, wherein ENPP1 inhibition is predicted to have a therapeutic effect, such as uncontrolled cell proliferation disorders (e.g., cancer) and neurodegenerative disorders, such as Alzheimer's disease, Huntington's disease and Parkinson's disease, diseases caused by bacteria and / or viruses (including DNA and RNA viruses).

[0250] The compounds of the present invention may also be used in immunotherapy. In one embodiment, the compounds of the present invention treat uncontrolled cell proliferation disorders and / or diseases caused by bacteria and / or viruses by immunotherapy, which means that the compounds elicit an immunotherapy response, which results in the treatment of these diseases.

[0251] The compounds disclosed herein can be used to treat, prevent, ameliorate, control or reduce the risk of a variety of uncontrolled cell proliferation disorders.

[0252] Also provided is a method for using the disclosed compound, composition or medicine. On the one hand, the method for using relates to the treatment of illness. In other aspects, the disclosed compound can be used as a single agent or in combination with one or more other drugs for treating, preventing, controlling, improving the above-mentioned diseases, illnesses and conditions for which the compound or other drugs have effectiveness or reducing its risk, wherein the drug combination is safer or more effective than any single drug. Therefore, one or more other drugs can be administered simultaneously or sequentially with the disclosed compound by a route and in a commonly used amount. When the disclosed compound is used simultaneously with one or more other drugs, a pharmaceutical composition in a unit dosage form containing such drugs and the disclosed compound is preferred. However, combination therapy can also be administered according to an overlapping schedule. It is also envisioned that the combination of one or more active ingredients with the disclosed compound can be more effective than as a single agent.

[0253] Examples of disorders that can be treated with provided compounds include uncontrolled cell proliferation disorders. In yet further aspects, the uncontrolled cell proliferation disorder is cancer. In yet further aspects, the cancer is a leukemia. In even further aspects, the cancer is a sarcoma. In still further aspects, the cancer is a solid tumor. In yet further aspects, the cancer is a lymphoma.

[0254] It should be understood that cancer refers to or describes a physiological condition characterized by unregulated cell growth in mammals. Cancer can have multidrug resistance (MDR) or drug sensitivity. Embodiments of cancer include but are not limited to carcinoma, lymphoma, blastoma, sarcoma and leukemia. More specific embodiments of such cancers include breast cancer, prostate cancer, colon cancer, squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, pancreatic cancer, cervical cancer, ovarian cancer, peritoneal cancer, liver cancer, such as liver cancer, bladder cancer, colorectal cancer, endometrial cancer, kidney cancer and thyroid cancer.

[0255] In various aspects, additional examples of cancer are basal cell carcinoma, biliary tract cancer; bone cancer; brain and CNS cancer; choriocarcinoma; connective tissue cancer; esophageal cancer; eye cancer; head and neck cancer; stomach cancer; intraepithelial neoplasia; laryngeal cancer; lymphoma, including Hodgkin lymphoma and non-Hodgkin lymphoma; melanoma; myeloma; neuroblastoma; oral cancer (e.g., lip, tongue, mouth and pharynx); retinoblastoma; rhabdomyosarcoma; rectal cancer; respiratory cancer; sarcoma; skin cancer; stomach cancer; testicular cancer; uterine cancer; urinary system cancer, and other cancers and sarcomas.

[0256] In other aspects, cancer is a hematological cancer. In still other aspects, hematological cancer is selected from acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, chronic myelomonocytic leukemia (CMML), childhood myelomonocytic leukemia (JMML), Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma, solitary myeloma, limited myeloma and extramedullary myeloma. In still other aspects, cancer is selected from chronic lymphocytic leukemia, small lymphocytic lymphoma, B cell non-Hodgkin's lymphoma and large B cell lymphoma.

[0257] In other aspects, cancer is brain cancer. In still other aspects, brain cancer is selected from glioma, medulloblastoma, primitive neuroectodermal tumor (PNET), acoustic neuroma, glioma, meningioma, pituitary adenoma, schwannoma, CNS lymphoma, primitive neuroectodermal tumor, craniopharyngioma, chordoma, medulloblastoma, brain neuroblastoma, central neurocytoma, pineal cell tumor, pinealoblastoma, atypical teratoid rhabdoid tumor, chondrosarcoma, chondroma, choroid plexus carcinoma, choroid plexus papilloma, craniopharyngioma, dysembryoplastic neuroepithelioma, gangliocytoma, germ cell tumor, hemangioblastoma, hemangiopericytoma and metastatic brain tumor. In yet other aspects, glioma is selected from ependymoma, astrocytoma, oligodendroglioma and oligoastrocytoma. In an even further aspect, the glioma is selected from the group consisting of juvenile pilocytic astrocytoma, subependymal giant cell astrocytoma, ganglioglioma, subependymoma, pleomorphic xanthoastrocytoma, anaplastic astrocytoma, glioblastoma multiforme, brain stem glioma, oligodendroglioma, ependymoma, oligoastrocytoma, cerebellar astrocytoma, infantile desmoplastic astrocytoma, subependymal giant cell astrocytoma, diffuse astrocytoma, mixed glioma, optic nerve glioma, brain glioma, multifocal glioma, multicentric multiforme glioblastoma, paraganglioma and ganglioglioma.

[0258] In one aspect, the cancer can be a cancer selected from the following: blood cancer, brain cancer, urogenital tract cancer, gastrointestinal cancer, colon cancer, rectal cancer, breast cancer, kidney cancer, lymphatic system cancer, gastric cancer, lung cancer, pancreatic cancer and skin cancer. In another aspect, the cancer is selected from prostate cancer, glioblastoma multiforme, endometrial cancer, breast cancer and colon cancer. In another aspect, the cancer is selected from breast cancer, ovarian cancer, prostate cancer, head cancer, neck cancer and kidney cancer. In still another aspect, the cancer is selected from blood cancer, brain cancer, urogenital tract cancer, gastrointestinal cancer, colon cancer, rectal cancer, breast cancer, liver cancer, kidney cancer, lymphatic system cancer, gastric cancer, lung cancer, pancreatic cancer and skin cancer. In yet another aspect, the cancer is selected from lung cancer and liver cancer. In even another aspect, the cancer is selected from breast cancer, ovarian cancer, testicular cancer and prostate cancer. In still another aspect, the cancer is breast cancer. In yet another aspect, the cancer is ovarian cancer. In even another aspect, the cancer is prostate cancer. In still another aspect, the cancer is testicular cancer.

[0259] In various aspects, the disorder associated with ENPP1 dysfunction comprises a neurodegenerative disorder. In further aspects, the neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease and Huntington's disease.

[0260] The compounds can be further used in methods for preventing, treating, controlling, improving or reducing the risk of the diseases, disorders and conditions described herein. The combination of the compounds with other agents can be further used in methods for preventing, treating, controlling, improving or reducing the risk of the above-mentioned diseases, disorders and conditions.

[0261] The invention further relates to the administration of ENPP1 inhibitors to improve therapeutic outcomes in the context of uncontrolled cell proliferation disorders, including cancer. That is, in one aspect, the invention relates to a co-therapeutic method comprising the step of administering to a mammal an effective amount and dosage of at least one compound of the invention relevant to cancer therapy.

[0262] In other aspects, in the context of cancer therapy, administration improves treatment outcomes. Administration related to cancer therapy can be continuous or intermittent. Administration does not need to be performed simultaneously with therapy and can be performed before, during and / or after therapy. For example, cancer therapy can be provided within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days before or after the administration of the compound. As another embodiment, cancer therapy can be provided within 1 week, 2 weeks, 3 weeks or 4 weeks before or after the administration of the compound. As still another embodiment, cognitive or behavioral therapy can be provided before or after administration within a time period of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 half-lives of the administered compound.

[0263] On the one hand, the disclosed compounds can be used in combination with one or more other drugs for treating, preventing, controlling, improving the diseases or conditions for which the disclosed compounds or other drugs can have effectiveness or reduce their risks, wherein the drugs are combined together safer or more effective than any single drug. Therefore, such one or more other drugs can be administered simultaneously or sequentially with the compounds of the present invention by way and in a commonly used amount. When the compounds of the present invention are used simultaneously with one or more other drugs, a pharmaceutical composition containing such other drugs and a unit dosage form of the disclosed compounds is preferred. However, the combination therapy may also include the therapy in which the disclosed compounds and one or more other drugs are administered according to different overlapping schedules. It is also considered that when used in combination with one or more other active ingredients, the disclosed compounds and other active ingredients can be used in a lower dose than when used alone. In one embodiment, the present invention relates to a combination therapy in which a compound of formula I or II is used together with radiotherapy. Radiotherapy can be performed simultaneously before or after the administration of the compounds of the present invention.

[0264] Accordingly, pharmaceutical compositions include those that contain one or more other active ingredients, in addition to a compound of the present invention.

[0265] The above combination not only comprises the combination of the disclosed compound and one other active compound, but also comprises the combination of the disclosed compound and two or more other active compounds. Similarly, the disclosed compound can be used in combination with other drugs, which are used to prevent, treat, control, improve the diseases or conditions to which the disclosed compound is useful or reduce its risk. Therefore, such other drugs can be used simultaneously or sequentially with the compound of the present invention by approach and in a commonly used amount. When the compound of the present invention is used simultaneously with one or more other drugs, it is preferred that the pharmaceutical composition also contains such other drugs in addition to the disclosed compound. Therefore, the pharmaceutical composition includes those that also contain one or more other active ingredients in addition to the compound of the present invention.

[0266] The weight ratio of the disclosed compound to the second active ingredient can vary and will depend on the effective dose of each ingredient. Typically, each effective dose will be used. Thus, for example, when the compound of the present invention is combined with another agent, the weight ratio of the disclosed compound to the other agent will typically range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. The combination of the compound of the present invention with other active ingredients will also typically be within the above range, but in each case, an effective dose of each active ingredient should be used.

[0267] In such combinations, the disclosed compounds and other active agents may be administered separately or in combination. In addition, the administration of one element may be prior to, simultaneously with, or after the administration of one or more other agents.

[0268] Therefore, the subject compound can be used alone or in combination with other medicaments known to be beneficial to the subject's indication or other drugs that affect receptors or enzymes, which improve the efficacy, safety, convenience or reduce its unwanted side effects or toxicity of the disclosed compounds. The subject compound and other medicaments can be co-administered in concomitant therapy or in a fixed combination.

[0269] In one aspect, the compounds can be used in combination with anti-cancer therapeutics or other known therapeutic agents.

[0270] In the treatment of conditions requiring inhibition or negative regulation of ENPP1, appropriate dosage levels will generally be about 0.01 to 1000 mg per kg of patient body weight per day, which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg / kg per day; more preferably about 0.5 to about 100 mg / kg per day. Suitable dosage levels may be about 0.01 to 250 mg / kg per day, about 0.05 to 100 mg / kg per day, or about 0.1 to 50 mg / kg per day. Within this range, the dosage may be 0.05 to 0.5, 0.5 to 5, or 5 to 50 mg / kg per day. For oral administration, the composition is preferably provided in the form of tablets containing 1.0 to 1000 mg of active ingredient, specifically 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900 and 1000 mg of active ingredient, to adjust the dosage of the patient to be treated symptomatically. The compound can be administered according to a regimen of 1 to 4 times a day, preferably once or twice a day. This dosage regimen can be adjusted to provide the best therapeutic response. However, it should be understood that the specific dosage level and dosage frequency for any particular patient can vary and will depend on a variety of factors, including the activity of the specific compound used, the metabolic stability of the compound and the length of action time, age, body weight, overall health, sex, diet, mode and time of administration, excretion rate, drug combination, severity of a specific condition and the host undergoing therapy.

[0271] Thus, in one aspect, the present invention relates to a method for inhibiting or negatively regulating ENPP1 in at least one cell in an effective amount for regulating or activating an ENPP1 activity response, for example in the at least one cell, the method comprising the step of contacting the at least one cell with at least one compound of the present invention. In a further aspect, the cell is a mammal, such as a human. In a further aspect, the cell has been isolated from a subject prior to the contacting step. In a further aspect, the contacting is performed by administering to a subject.

[0272] Treatment of uncontrolled cell proliferation disorders

[0273] In one aspect, the invention relates to a method for treating an uncontrolled cell proliferative disorder in a mammal, comprising the step of administering to the mammal an effective amount of at least one disclosed compound or a product of a disclosed process for preparing a compound, or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, thereby treating the uncontrolled cell proliferative disorder.

[0274] In still other aspects, the effective amount is a therapeutically effective amount. In still other aspects, the effective amount is a prophylactically effective amount.

[0275] In a further aspect, the mammal is a human. In yet a further aspect, the method further comprises the step of identifying a mammal in need of treatment for an uncontrolled cell proliferation disorder. In still a further aspect, prior to the administering step, the mammal has been diagnosed as being in need of treatment for an uncontrolled cell proliferation disorder.

[0276] In another aspect, the uncontrolled cell proliferation disorder is cancer. In another aspect, the cancer is leukemia. In an even further aspect, the cancer is a sarcoma. In another aspect, the cancer is a solid tumor. In another aspect, the cancer is a lymphoma. In an even further aspect, the cancer is selected from chronic lymphocytic leukemia, small lymphocytic lymphoma, B-cell non-Hodgkin lymphoma and large B-cell lymphoma. In another aspect, the cancer is selected from blood cancer, brain cancer, genitourinary tract cancer, gastrointestinal cancer, colon cancer, rectal cancer, breast cancer, liver cancer, kidney cancer, lymphatic system cancer, gastric cancer, lung cancer, pancreatic cancer and skin cancer. In another aspect, the cancer is selected from lung cancer and liver cancer. In an even further aspect, the cancer is selected from breast cancer, ovarian cancer, testicular cancer and prostate cancer. In another aspect, the cancer is breast cancer. In another aspect, the cancer is ovarian cancer. In an even further aspect, the cancer is prostate cancer. In another aspect, the cancer is testicular cancer.

[0277] Example

[0278] experiment

[0279] The following examples are presented to provide a person of ordinary skill in the art with a complete disclosure and description of how to prepare and evaluate the compounds, compositions, articles, devices and / or methods claimed herein, and are intended to be purely exemplary of the present invention and are not intended to limit the scope of the content of their invention as considered by the inventors. Although efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperatures, etc.), some errors and deviations should still be considered. Unless otherwise indicated, parts are parts by weight, temperatures are in ° C or at ambient temperature, and pressures are at or near atmospheric pressure.

[0280] Several methods for preparing compounds of the invention are illustrated in the following examples. Starting materials and necessary intermediates are in some cases commercially available or can be prepared according to literature procedures or as demonstrated herein.

[0281] The following exemplary compounds of the present invention are synthesized. Examples are provided herein to illustrate the present invention and should not be construed as limiting the present invention in any way. According to the IUPAC naming convention, the examples are generally depicted in free base form. However, some of the examples described are obtained or isolated in the form of salts.

[0282] Some embodiments in the described embodiments are obtained as a racemic mixture of one or more enantiomers or diastereomers. Those skilled in the art can separate compounds to separate individual enantiomers. Separation can be carried out by coupling the racemic mixture of the compound to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of individual diastereomers by standard methods (e.g., fractional crystallization or chromatography). The racemic or diastereomeric mixture of the compound can also be directly separated by using a chromatographic method of a chiral stationary phase.

[0283] Experimental Chemistry

[0284] Synthetic Schemes, Methods and Procedures:

[0285] Overall plan 1

[0286]

[0287] Example 1: Synthesis of (N-(3-((6,7-dimethoxyquinazolin-4-yl)oxy)propyl)sulfonamide:

[0288] Step 1: Synthesis of tert-butyl (N-(3-hydroxypropyl)sulfamoyl)carbamic acid

[0289]

[0290] At 0°C, diisopropylethylamine (1.9ml, 9999mmol) and N-(1-(N-(tert-butyloxycarbonyl)sulfamoyl)pyridine-4(1H)-ylidene)-N-methylformamide 2 (2.25g, 7.385mmol) were added to a stirred solution of 3-aminopropane-1-ol 1 (500mg, 6666mmol) in dichloromethane (20ml), and then stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After the reaction was completed, the organic solvent was completely distilled off under reduced pressure to obtain a crude compound. The crude compound was purified by 100-200 silica gel column chromatography and eluted with 3% methanol in dichloromethane to obtain a semi-pure compound. The semi-pure product was washed with 50% ethyl acetate in petroleum ether to obtain tert-butyl (N-(3-hydroxypropyl)sulfamoyl)carbamate 3 (650mg, 2.559mmol, 38% yield) as an off-white solid.

[0291] 1H NMR (400MHz, DMSO) δ10.77(s,1H),7.45(t,1H),4.44(t,1H),3.40(d,2H),2.91(d,2H),1.60-1.57(t,2H),1.41(s,9H)

[0292] The following compounds were synthesized by using the general procedure described above.

[0293]

[0294] Step 2: Synthesis of tert-butyl(N-(3-((6,7-dimethoxyquinazolin-4-yl)oxy)propyl)sulfamoyl)carbamic acid

[0295]

[0296] To a stirred solution of tert-butyl (N-(3-hydroxypropyl)sulfamoyl)carbamate 4 (900 mg, 3.897 mmol) in dichloromethane (20 ml) was added 60% NaH (212 mg, 5.314 mmol), followed by stirring at reflux for 30 minutes. Then 4-chloro-6,7-dimethoxyquinazoline 3 (795 mg, 3.542 mmol) was added at room temperature and stirred again at reflux for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, water (200 mL) was added to the reaction mixture and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine solution (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude compound was purified by 100-200 silica gel column chromatography, eluted with 100% ethyl acetate to give tert-butyl (N- (3- ((6,7-dimethoxyquinazolin-4-yl) oxy) propyl) sulfamoyl) carbamic acid 5 (700 mg, 1.583 mmol, 44% yield) as a light yellow solid. 1HNMR (400 MHz, DMSO) δ 10.85 (s, 1H), 8.60 (s, 1H), 7.71 (s, 1H), 7.31 (d, 2H), 4.55 (t, 2H), 3.92 (d, 6H), 3.12 (d, 2H), 2.01 (m, 2H), 1.37 (s, 9H). LC-MS: M / Z: 442.9 (M+1)

[0297] The following compounds were synthesized by using the general procedure described above.

[0298]

[0299] Step 3: Synthesis of (N-(3-((6,7-dimethoxyquinazolin-4-yl)oxy)propyl)sulfonamide)

[0300]

[0301] To a stirred solution of tert-butyl (N-(3-(6,7-dimethoxyquinazolin-4-yl)oxy)propyl)sulfamoyl)carbamate (200 mg, 0.452 mmol) in 1,4-dioxane (2 ml) at 0°C, 4M HCl was added to dioxane (8 ml), followed by stirring at room temperature for 3 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the organic solvent was completely distilled off under reduced pressure to obtain a crude compound. The crude compound was purified by a preparative prep-HPLC method to obtain a pure compound of (N-(3-(6,7-dimethoxyquinazolin-4-yl)oxy)propyl)sulfonamide) (target-12) (120 mg, 0.35 mmol, 78% yield) in the form of a pale yellow solid. 1H NMR (400MHz, DMSO) δ 8.93 (s, 1H), 7.42 (d, 2H), 6.57 (bs, 2H), 4.67 (t, 2H), 3.96 (d, 6H), 3.10 (t, 2H), 2.06 (t, 2H).

[0302] The following compounds were synthesized by using the general procedure described above.

[0303]

[0304] Compound 052 was also prepared based on the general procedure of Example 1.

[0305]

[0306] 1H NMR (400MHz, DMSO) δ 8.93 (s, 1H), 7.42 (d, 2H), 6.57 (bs, 2H), 4.67 (t, 2H), 3.96 (d, 6H), 3.10 (t, 2H), 2.06 (t, 2H). LCMS 342.9; MW 378.83.

[0307] Overall plan 2:

[0308]

[0309] Example 2: N-(3-((6,7-dimethoxyquinazolin-4-yl)amino)propylsulfonamide hydrochloride Step 1: N1-(6,7-dimethoxyquinazolin-4-yl)propane-1,3-diamine

[0310]

[0311] To a stirred solution of 4-chloro-6,7-dimethoxyquinazoline (2g, 8.9mmol) in tetrahydrofuran (20ml) was added propane-1,3-diamine (3.7ml, 44.50mmol) at room temperature, and the reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the organic solvent was completely distilled off under reduced pressure to obtain a crude compound. The crude compound was purified by Grace reverse phase chromatography, and the pure compound of N1-(6,7-dimethoxyquinazoline-4-yl)propane-1,3-diamine (500mg, 1.908mmol, 21% yield) was obtained as a light brown solid by eluting 40% acetonitrile in water. 1H NMR (400MHz, DMSO)8.3(s,1H),8.0(brs,1H),7.57(s,1H),7.05(s,1H),3.86(s,6H),3.55-3.46(m,2H),2.64(t,3H),1.75-1.68(m,2H).

[0312] 1.98(s,2H),1.15(d,9H).

[0313] The following compounds were synthesized by using the general procedure described above

[0314]

[0315]

[0316] Step 2: Synthesis of tert-butyl(N-(3-((6,7-dimethoxyquinazolin-4-yl)amino)propyl)sulfamoyl)carbamic acid

[0317]

[0318] To a stirred solution of N1-(6,7-dimethoxyquinazolin-4-yl)propane-1,3-diamine (500 mg, 1.90 mmol) in dichloromethane (40 ml) was added diisopropylethylamine (1.65 ml, 9.50 mmol) and N-(1-(N-(tert-butyloxycarbonyl)sulfamoyl)pyridine-4(1H)-ylidene)-N-methylformamide chloride (640 mg, 1.90 mmol) at room temperature, followed by stirring at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the organic solvent was completely distilled off under reduced pressure to obtain a crude compound. The crude compound was purified by eluting with 2% methanol in dichloromethane to obtain tert-butyl (N-(3-((6,7-dimethoxyquinazolin-4-yl)amino)propyl)sulfamoyl)carbamate (600 mg, 1.36 mmol, 71% yield) as a yellow solid. 1HNMR(400MHz,DMSO)10.83(s,1H),8.31(s,1H),7.89(t,1H),7.60(s,1H),7.54(s,1H), 7.06(s,1H)3.87(s,6H),3.55-3.50(m,2H),2.98-2.93(m,2H),1.82(t,2H),1.36(s,9H). LCMS:(M+H+):m / Z:441.9

[0319] The following compounds were synthesized by the above general procedure

[0320]

[0321]

[0322] Step 3: Synthesis of N-(3-((6,7-dimethoxyquinazolin-4-yl)amino)propyl)sulfonamide hydrochloride

[0323] 4M HCl in dioxane (2 ml) was added to tert-butyl (N-(3-(6,7-dimethoxyquinazolin-4-yl)amino)propyl)sulfamoyl)carbamate (200 mg, 0.453 mmol) in 1,4-dioxane (0.5 ml) and the solution was stirred at room temperature and then stirred at 50°C for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the organic solvent was completely distilled off under reduced pressure to obtain a crude compound. The crude compound was purified by preparative HPLC to give the pure compound (N-(3-((6,7-dimethoxyquinazolin-4-yl)amino)propyl)sulfonamide hydrochloride (100 mg, 0.293 mmol, 65% yield) as an off-white solid. 1H NMR (400 MHz, DMSO) 14.42 (brs, 1H), 9.99 (s, 1H), 8.79 (s, 1H), 8.02 (s, 1H), 7.23 (s, 1H), 6.61 (s, 1H), 6.53 (s, 1H), 3.94 (s, 6H), 3.73-3.71 (m, 2H), 2.97-2.96 (m, 2H), 1.90-1.86 (m, 2H). LCMS: (M+H+): m / Z: 341.9

[0324] The following compounds were synthesized by the general procedure described above:

[0325]

[0326]

[0327] Compound 055 was also synthesized by the above general procedure:

[0328]

[0329] 1H NMR 400MHz, DMSO)14.42(brs,1H),9.99(s,1H),8.79(s,1H),8.02(s,1H),7.23(s,1H),6.61( s,1H),6.53(s,1H),3.94(s,6H),3.73-3.71(m,2H),2.97-2.96(m,2H),1.90-1.86(m,2H). LCMS 341.9. MW.377.84

[0330] Synthesis of Compound 006

[0331]

[0332] Step 1: Synthesis of 4-((3-aminopropyl)amino)-6,7-dimethoxyquinoline-3-carbonitrile (3)

[0333]

[0334] To a stirred solution of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile 1 (150 mg, 0.60 mmol) in THF (15 mL) was added propane-1,3-diamine 2 (223 mg, 3.02 mmol), and the reaction mixture was stirred at 50 ° C for 20 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was completely evaporated and adsorbed on diatomaceous earth, and reversed phase grace was performed using an ACN / water system to obtain 4-((3-aminopropyl)amino)-6,7-dimethoxyquinoline-3-carbonitrile (250 mg) as a white solid.

[0335] Analyze the data: 1 H NMR (400MHz, DMSO): δ8.37(s,1H),8.19(brs,1H),7.9(brs,1H),7.78(s,1H),7.22(s,1H),3.99-3.89(m,7H),3.83(q,2H),2.87(t,2H),1.99(t,2H).

[0336] Step 2: Synthesis of tert-butyl(N-(3-((3-cyano-6,7-dimethoxyquinolin-4-yl)amino)propyl)sulfamoyl)carbamic acid (5)

[0337]

[0338] To a stirred solution of 4-(3-aminopropyl)amino)-6,7-dimethoxyquinoline-3-carbonitrile 3 (150 mg, 0.52 mmol) in DCM (10 mL) was slowly added N-(1-(N-(tert-butyloxycarbonyl)sulfamoyl)pyridine-4(1H)-ylidene)-N-methylformamide chloride 4 (193 mg, 0.57 mmol) followed by DIPEA (0.3 mL, 0.78 mmol) at the same temperature. The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. The reaction mixture was directly adsorbed on silica and converted into a slurry. The crude product was purified by combi-flash chromatography by eluting 2-3% MeOH in DCM to give tert-butyl (N-(3-((3-cyano-6,7-dimethoxyquinolin-4-yl)amino)propyl)sulfamoyl)carbamate 5 (100 mg) as a white solid.

[0339] Analytical data: LCMS: (M+H) + :m / Z:466.2

[0340] Step 3: Synthesis of Compound 006:

[0341]

[0342] To a stirred solution of tert-butyl (N-(3-(3-(3-cyano-6,7-dimethoxyquinolin-4-yl)amino)propyl)sulfamoyl)carbamate 5 (95 mg, 0.40 mmol) in dichloromethane (3 ml) at 0°C, 4M HCl was added to dioxane (2 ml), and then stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the organic solvent was completely distilled off under reduced pressure. The crude compound was purified by preparative HPLC to obtain compound 006 (10 mg) as a white solid.

[0343] Analyze the data: 1 H NMR(400MHz,DMSO)δ:8.33(s,1H),7.79(t,1H),7.59(s,1H),7.21(s,1H),6.60(b rs,2H),6.53(brs,2H),3.90-3.89(m,6H),3.78(q,2H),2.99(q,2H),1.92(p,2H).

[0344] LCMS: (M+H) + :m / Z:366.2.

[0345] Synthesis of compound 007:

[0346]

[0347] Step 1: Synthesis of 4-((4-aminobutyl)amino)-6,7-dimethoxyquinoline-3-carbonitrile 3:

[0348]

[0349] To a stirred solution of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile 1 (200 mg, 0.80 mmol) in THF (8 mL) was added butane-1,4-diamine 2 (411 mg, 4.03 mmol), and the reaction mixture was stirred at 50 ° C for 20 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was completely evaporated and adsorbed on diatomaceous earth, and reversed phase grace was performed using an ACN / water system to obtain 4-((4-aminobutyl)amino)-6,7-dimethoxyquinoline-3-carbonitrile 3 (220 mg) as a white solid.

[0350] Analyze the data: 1H NMR (400MHz, DMSO): δ8.37(s,2H),8.32(s,1H),7.67(s,1H),7.21(s,1H),3.90 -3.89(m,7H),3.76(t,2H),2.79(t,2H),1.78-1.73(m,2H),1.67-1.64(m,2H).

[0351] Step 2: Synthesis of tert-butyl(N-(4-((3-cyano-6,7-dimethoxyquinolin-4-yl)amino)butyl)sulfamoyl)carbamic acid 5:

[0352]

[0353] To a stirred solution of 4-(4-aminobutyl)amino)-6,7-dimethoxyquinoline-3-carbonitrile 3 (220 mg, 0.73 mmol) in DCM (10 mL) was slowly added N-(1-(N-(tert-butyloxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylformamide chloride 4 (296 mg, 0.88 mmol) followed by DIPEA (0.4 mL, 2.19 mmol) at the same temperature. The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. The reaction mixture was directly adsorbed on silica and converted to a slurry. The crude product was purified by combi-flash chromatography by eluting 2-3% MeOH in DCM to give tert-butyl (N-(4-((3-cyano-6,7-dimethoxyquinolin-4-yl)amino)butyl)sulfamoyl)carbamate 5 (100 mg) as a white solid.

[0354] Analyze the data: 1 H NMR (400MHz, DMSO): δ8.46-8.44(m,1H),8.31(s,1H),7.82(t,1H),7.60-7.57(m,2H),7.20(s, 1H),3.90-3.89(m,6H),3.72(q,2H),2.92-2.91(m,2H),1.73-1.70(m,2H),1.58-1.54(m,2H).

[0355] LCMS: (M+H) + :m / Z:480

[0356] Step 3: Synthesis of compound 007:

[0357]

[0358] To a stirred solution of tert-butyl (N-(4-(3-cyano-6,7-dimethoxyquinolin-4-yl)amino)sulfamoyl)carbamate (100 mg, 0.20 mmol) in dichloromethane (3 ml) at 0°C was added 4M HCl to dioxane (1 ml) and then stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the organic solvent was completely distilled off under reduced pressure. The crude compound was purified by preparative HPLC to give compound 007 (10 mg) as a white solid.

[0359] Analyze the data: 1 H NMR(400MHz,DMSO)δ:8.35-8.31(m,2H),7.86(t,1H),7.60(s,1H),7.20(s,1H),6.50(t,2H),6 .46(s,1H),3.90-3.89(m,6H),3.73(q,2H),2.90(q,2H),1.75-1.71(m,2H),1.61-1.53(m,2H).

[0360] LCMS: (M+H) + :m / Z:380.24.

[0361] Synthesis scheme of compound 008:

[0362]

[0363] Step 1: Synthesis of 4-((5-aminopentyl)amino)-6,7-dimethoxyquinoline-3-carbonitrile 3:

[0364]

[0365] To a stirred solution of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile 1 (200 mg, 0.80 mmol) in THF (8 mL) was added butane-1,4-diamine 2 (411.2 mg, 4.03 mmol), and the reaction mixture was stirred at 50 ° C for 20 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was completely evaporated and adsorbed on diatomaceous earth, and reversed phase grace was performed using an ACN / water system to obtain 4-((5-aminopentyl)amino)-6,7-dimethoxyquinoline-3-carbonitrile 3 (200 mg) as a white solid.

[0366] Analyze the data: 1H NMR (400MHz, DMSO): δ8.48(s,1H),8.30(s,1H),7.98(brs,1H),7.66(s,1H),7.19(s,1H),3. 90-3.89(m,6H),3.72-3.71(m,2H),2.60-2.56(m,2H),1.73-1.66(m,2H),1.48-1.21(m,4H).

[0367] LCMS: (M+H) + :m / Z:315.23

[0368] Step 2: Synthesis of tert-butyl(N-(5-((3-cyano-6,7-dimethoxyquinolin-4-yl)amino)pentyl)sulfamoyl)carbamic acid 5:

[0369]

[0370] To a stirred solution of 4-(5-aminopentyl)amino)-6,7-dimethoxyquinoline-3-carbonitrile 3 (220 mg, 0.63 mmol) in DCM (10 mL) was slowly added N-(1-(N-(tert-butyloxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylformamide chloride 4 (266 mg, 0.76 mmol) followed by DIPEA (0.17 mL, 0.95 mmol) at the same temperature. The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. The reaction mixture was directly adsorbed on silica and converted to a slurry. The crude product was purified by combi-flash chromatography by eluting 2-3% MeOH in DCM to give tert-butyl (N-(5-((3-cyano-6,7-dimethoxyquinolin-4-yl)amino)pentyl)sulfamoyl)carbamate 5 (130 mg) as a white solid.

[0371] Analyze the data: 1 H NMR (400MHz, DMSO): δ10.75(s,1h),8.31(s,1H),7.82(t,1H),7.60(s,1H),7.51(brs,1H),7.20(s,1 H),3.90-3.89(m,6H),3.71(q,2H),2.87(q,2H),1.72-1.64(m,2H),1.58-1.47(m,2H),1.22(m,2H).

[0372] LCMS: (M+H) + :m / Z:494.2

[0373] Step 3: Synthesis of compound 008:

[0374]

[0375] To a stirred solution of tert-butyl (N-(5-(3-cyano-6,7-dimethoxyquinolin-4-yl)amino)carbamate (130 mg, 0.20 mmol) in dichloromethane (4 ml) at 0°C, 4M HCl was added to dioxane (1.5 ml), followed by stirring at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the organic solvent was completely distilled off under reduced pressure. The crude compound was purified by preparative HPLC to obtain compound 008 (10 mg) as a white solid.

[0376] Analyze the data: 1 H NMR(400MHz,DMSO)δ:8.31(s,1H),8.12(s,1H),7.84(t,1H),7.60(s,1H),7.20(s,1H),6.45-6.44(m,3H),3.9 0-3.89(m,6H),3.72(q,2H),2.86(q,2H),3.01(t,2H),1.73-1.65(m,2H),1.55-1.48(m,2H),1.43-1.40(m,2H)

[0377] LCMS: (M+H) + :m / Z:394.2.

[0378] Synthesis scheme of compounds 009 and 010

[0379]

[0380] Synthesis of N1-(7-(Benzyloxy)-6-methoxyquinazolin-4-yl)butane-1,4-diamine (3)

[0381]

[0382] To a stirred solution of 7-(benzyloxy)-4-chloro-6-methoxyquinazoline (1) (1 g, 3.33 mmol) in tetrahydrofuran (20 mL) was added butane-1,4-diamine 2 (1.5 g, 16.66 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the organic solvent was completely distilled off under reduced pressure to obtain a crude compound. The crude compound was purified by Grace reverse phase chromatography by eluting 40% acetonitrile in water to obtain the pure compound N1-(7-(benzyloxy)-6-methoxyquinazoline-4-yl)butane-1,4-diamine (3) (1 g, 0.284 mmol, 85% yield) as a light brown viscous liquid.

[0383] Analyze the data: 1 H NMR (400MHz, DMSO) δ8.29(s,1H),7.95-7.98(m,1H),7.59(s,1H),7.32-7.48(m,5H),7.15(s,1H),5. 22(s,2H),3.87(s,3H),3.47-3.51(m,2H),2.56-2.59(m,2H),1.62-1.66(m,2H),1.41-1.44(m,2H).

[0384] LCMS: (M+H + ):m / z:353.2

[0385] Synthesis of tert-butyl(N-(4-((7-(benzyloxy)-6-methoxyquinazolin-4-yl)amino)butyl)sulfamoyl)carbamic acid (Int-5)

[0386]

[0387] To a stirred solution of N1-(7-(benzyloxy)-6-methoxyquinazolin-4-yl)butane-1,4-diamine (3) (1.0 g, 2.84 mmol) in dichloromethane (20 mL) was added diisopropylethylamine (1.5 mL, 8.52 mmol) and N-(1-(N-(tert-butyloxycarbonyl)sulfamoyl)sulfamoyl)pyridine-4(1H)-ylidene)-N-methylformamide 4 (957 mg, 2.84 mmol) at room temperature, followed by stirring at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the organic solvent was completely distilled off under reduced pressure to give a crude compound. The crude compound was purified by eluting with 10% MeOH in DCM to give (Int-5) (1.1 g, 2.07 mmol, 73% yield) as a light yellow solid.

[0388] Analyze the data: 1 H NMR(400MHz,DMSO)δ10.83(br s,1H),8.3(s,1H),7.93(brs,1H),7.59-7.561(m,2H),7.46-7.61(d,2H),7.32-7.42(m,3H),7.16(s,1H),5.226(s,2H ),4.03(s,1H),3.88(s,3H),3.46-3.50(m,2H),2.89-2.93(m,2H),1.62-1.66(m,2H),1.52-1.54(m,2H),1.38(s,9H).

[0389] LCMS: (M+H) + :m / Z:532.2

[0390] Synthesis of tert-butyl(N-(4-((7-hydroxy-6-methoxyquinazolin-4-yl)amino)butyl)sulfamoyl)carbamic acid (Int-6)

[0391]

[0392] To tert-butyl (N-(4-(7-(benzyloxy)-6-methoxyquinazoline-4-yl)amino)sulfamoyl)carbamate (5)-(1g, 1.88mmol) in methanol (15mL) and ethyl acetate (2.5mL) in a stirred solution, 10% palladium / carbon (100mg) was added, and the reaction mixture was stirred for 6 hours at room temperature under a balloon hydrogen atmosphere. The reaction process was monitored by TLC. After the reaction was completed, the reaction mixture was filtered through diatomite and the diatomite bed was washed with dichloromethane (100mL) containing 5% methanol. The filtrate was concentrated under reduced pressure, and the tert-butyl (N-(4-((7-hydroxy-6-methoxyquinazoline-4-yl)amino)butyl)sulfamoyl)carbamic acid (6) (800mg, 1.81mmol, 96% yield) obtained was a light yellow solid.

[0393] Analyze the data: 1 H NMR(400MHz,DMSO)δ10.13(br s,1H),8.24(s,1H),7.83(brs,1H),7.54-7.57(m,2H),6.92(s,1H),3.87(s,3H),3.4 5-3.50(m,2H),2.88-2.93(m,2H),1.59-1.65(m,2H),1.50-1.53(m,2H),1.38(s,9H).

[0394] LCMS: (M+H + ):m / Z:442.2

[0395] Preparation of Compound 009

[0396]

[0397] At room temperature, 4M HCl in dioxane (2.0 mL) was added to a stirred solution of Int-6 (100 mg, 0.226 mmol) in 1,4-dioxane (1.0 mL). The reaction mixture was stirred at room temperature for 6 hours. The reaction progress was monitored by TLC. After the reaction was completed, the organic solvent was completely distilled off under reduced pressure to obtain a crude compound. The crude compound was purified by preparative HPLC, and the pure compound (50 mg, 0.146 mmol, 64% yield) of compound 009 obtained was an off-white solid.

[0398] Analyze the data: 1 H NMR(400MHz,DMSO-d6)δ14.27(brs,1H),11.41(s,1H),9.80(s,1H),8.70(s,1H),7.94(s,1H),7.19(s,1H),6.47-6.5 1(m,3H),3.93(s,3H),3.61-3.68(m,2H),2.87-2.92(m,2H),1.66-1.71(m,2H),1.49-1.57(m,2H),1.23-1.28(m,2H).

[0399] LCMS: (M+H) + :m / Z:342.1

[0400] Preparation of Compound 010

[0401]

[0402] At room temperature, 4M HCl in dioxane (2.0 mL) was added to a stirred solution of Int-5 (100 mg, 0.188 mmol) in 1,4-dioxane (1.0 mL). The reaction mixture was stirred at room temperature for 6 hours. The reaction progress was monitored by TLC. After the reaction was completed, the organic solvent was completely distilled off under reduced pressure to obtain a crude compound. The crude compound was purified by preparative HPLC to obtain a pure Int-5 compound (50 mg, 1.16 mmol, 61% yield) as an off-white solid.

[0403] Analyze the data: 1H NMR(400MHz,DMSO)δ8.3(s,1H),8.14(s,2H),7.92(m,1H),7.6(s,1H),7.47-7.49(d,2H),7.39-7.41(t,2H),7.35-7.37(m,1H), 7.17(s,1H),6.45(s,1H),5.23(s,2H),3.89(s,3H),3.50-3.51(m,2H),2.89-2.94(m,2H),1.66-1.70(m,2H),1.54-1.56(m,2H).

[0404] LCMS: (M+H) + :m / Z:432.2

[0405] Synthesis scheme of compound 011

[0406]

[0407] 4-((4-((N-(tert-Butoxycarbonyl)sulfamoyl)amino)butyl)amino)-6-methoxyquinazolin-7-yl trifluoromethanesulfonate (Int-5)

[0408]

[0409] To a stirred solution of Int-6 (500 mg, 1.13 mmol) in dichloromethane (20 mL) at 0 °C, triethylamine (0.475 mL, 3.39 mmol) and 1,1,1-trifluoro-N-phenyl-N-(trifluoromethyl)sulfonyl)methanesulfonamide 2 (445 mg, 1.24 mmol) were added, followed by stirring at room temperature for 4 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the organic solvent was completely distilled off under reduced pressure, water (200 mL) was added to the crude product and partitioned with dichloromethane (2×200 mL). The combined organic layers were washed with brine solution (200 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by combi-flash chromatography eluting with 70% ethyl acetate in petroleum ether to afford 4-((4-((N-(tert-butoxycarbonyl)sulfamoyl)amino)butyl)amino)-6-methoxyquinazolin-7-yl trifluoromethanesulfonate Int-5 (450 mg, 0.785 mmol, 69% yield over two steps) as a light yellow solid.

[0410] LCMS: (M+H + ):m / Z:574.1

[0411] Preparation of Compound 011

[0412]

[0413] In a sealed tube, tert-butyl 5-(4,4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)-1-pyrazole-1-carboxylic acid (33mg, 0.113mmol) and cesium fluoride (40mg, 0.26mmol) are added to a stirred solution of 4-(4-(tert-butyloxycarbonyl)sulfamoyl)amino)butyl)amino)-6-methoxyquinazoline-7-yl trifluoromethanesulfonic acid Int-5 (50mg, 0.349mmol) in dioxane (2mL) and water (0.5mL). The reaction mixture is then degassed for 30 minutes. Then tetrakis(triphenylphosphine)palladium(0) (100mg, 0.0087mmol) is added for 5 minutes of degassed again, and the reaction mixture is stirred at 100°C for 5 hours. The reaction process is monitored by TLC. After the reaction is completed, the reaction mixture is poured into water (100mL) and filtered through diatomaceous earth. The celite bed was washed with 10% methanol in dichloromethane (100 mL) and the two layers were separated. The organic layer was washed with brine solution (200 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give (Compound 011) (10 mg, 0.127 mmol, 29%) as an off-white solid.

[0414] Analyze the data: 1 H NMR(400MHz,DMSO)δ12.96(brs,1H),8.39(s,1H),8.23(brs,1H),8.13(s,2H),7.74(s,2H),6.88(d,1H),6.49 5(t,1H),6.46(s,2H),4.0(s,3H),3.53-3.58(q,2H),2.90-2.95(q,2H),1.66-1.72(m,2H),1.55-1.59(m,2H).

[0415] LCMS: (M+H + ):m / Z:392.1

[0416] Overall plan 3

[0417]

[0418]

[0419] Example 3: N-(4-((6,7-dimethoxyquinazolin-4-yl)thio)butyl)sulfonamide hydrochloride

[0420] Step 1: Synthesis of 6,7-dimethoxyquinazoline-4-thiol

[0421]

[0422] At room temperature, thiourea (338 mg, 4.44 mmol) was added to a stirred solution of 4-chloro-6,7-dimethoxyquinazoline (500 mg, 2.2 mmol) in ethanol (5 ml), and the reaction mixture was stirred under reflux for 4 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was allowed to settle at room temperature. The solid formed was collected by filtration, which was the desired compound 6,7-dimethoxyquinazoline-4-thiol (400 mg, 1.801 mmol, 80% yield) as a light brown solid. 1H NMR (400 MHz, DMSO) δ 13.67 (s, 1H), 8.09-8.10 (s, 1H), 7.90 (s, 1H), 7.16 (s, 1H), 3.93 (s, 3H), 3.89 (s, 3H). LCMS: (M+H) +: m / Z: 222.9

[0423] Step 2: Synthesis of 2-(4-(6,7-dimethoxyquinazolin-4-yl)thio)butyl)isoindoline-1,3-dione

[0424]

[0425] To a stirred solution of 6,7-dimethoxyquinazoline-4-thiol (1 g, 4.5 mmol) in DMF (10 ml) was added potassium carbonate (684 mg, 4.95 mmol) and 2-(4-bromobutyl)isoindoline-1,3-dione (1.27 g, 4.5 mmol), followed by stirring at 90°C for 6 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured onto water and extracted with ethyl acetate. The organic layer was separated, washed with water, and concentrated under reduced pressure to give pure 2-(4-((6,7-dimethoxyquinazoline-4-yl)thio)butyl)isoindoline-1,3-dione compound (800 mg, 1.891 mmol, 42% yield) as a light brown solid. 1H NMR(400MHz,DMSO)δ8.75(s,1H),7.81-7.82(m,4H),7.26(s,1H),7.13(s,1 H),3.95(s,3H),3.91(s,3H),3.61(t,2H),3.30-3.36(m,2H),1.75(m,4H). LCMS:(M+H)+:m / Z:424.2.

[0426] The following compounds were synthesized by the above procedure

[0427]

[0428] Step 3: Synthesis of 4-(6,7-dimethoxyquinazolin-4-yl)thio)butylamine

[0429]

[0430] To a stirred solution of 2-(4-(6,7-dimethoxyquinazolin-4-yl)thiobutyl)isoindoline-1,3-dione (1.1 g, 2.60 mmol) in ethanol (30 ml) was added 90% hydrazine hydrate (0.163 ml, 5.2 mmol) at room temperature, and the reaction mixture was stirred at reflux for 2 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was cooled to room temperature to form a precipitate. The solid was collected by filtration to give 4-((6,7-dimethoxyquinazolin-4-yl)thio)butyl-1-amine (700 mg, 2.389 mmol, 92% yield) as a light brown solid. 1H NMR(400MHz,DMSO)δ8.81(s,1H),7.29(s,1H),7.16(s,1H),3.95(s,3H),3. 92(s,3H),3.35(t,2H),2.67(t,2H),1.77-1.71(m,2H),1.62-1.56(m,2H). LCMS:(M+H)+:m / Z:294.1

[0431] The following compounds were synthesized by the above procedure

[0432]

[0433] Step 4: tert-Butyl (N-(4-(6,7-dimethoxyquinazolin-4-yl)thio)butyl)sulfamoyl)carbamate

[0434]

[0435] To a stirred solution of 4-(6,7-dimethoxyquinazolin-4-yl)thio)butan-1-amine 5 (550 mg, 1.87 mmol) in dichloromethane (20 ml) was added diisopropylethylamine (1.6 ml, 9.38 mmol) and N-(1-(N-(tert-butyloxycarbonyl)sulfamoyl)pyridine-4(1H)-ethylidene)-N-methylformamide chloride 4 (337 mg, 1.87 mmol) at room temperature, followed by stirring at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the organic solvent was completely distilled off under reduced pressure to obtain a crude compound. The crude compound was purified using combined flash column chromatography eluting with 60% ethyl acetate in petroleum ether to afford tert-butyl (N-(4-(6,7-dimethoxyquinazolin-4-yl)thio)butyl)sulfamoyl)carbamate 6 (150 mg, 0.317 mmol, 17% yield) as a white solid.

[0436] Analytical data: 1H NMR (400 MHz, DMSO) δ: 10.79 (s, H), 8.82 (s, 1H), 7.62-7.59 (t, 1H), 7.30 (s, 1H), 7.17 (s, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 3.34 (t, 2H), 2.94-2.90 (m, 2H), 1.77-1.70 (m, 2H), 1.64-1.59 (m, 2H), 1.39 (s, 9H).

[0437] LCMS: (M+H)+: m / Z: 473.2

[0438]

[0439]

[0440] Step 5: N-(4-(6,7-dimethoxyquinazolin-4-yl)thio)butyl)sulfonamide hydrochloride

[0441]

[0442] To a stirred solution of tert-butyl(N-(4-((6,7-dimethoxyquinazolin-4-yl)thio)butyl)carbamate (6) (100 mg, 0.211 mmol) in 1,4-dioxane (1.0 ml) at room temperature, 4M HCl was added in dioxane (2 ml). The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the organic solvent was completely distilled off under reduced pressure to obtain a crude compound. The crude compound was purified by preparative HPLC method to obtain pure compound N-(4-((6,7-dimethoxyquinazolin-4-yl)thio)butyl)sulfonamide hydrochloride (30 mg, 0.08 mmol, 25% yield) as a white solid.

[0443] Analytical data: 1H NMR (400 MHz, DMSO) δ8.83 (s, 1H), 7.30 (s, 1H), 7.18 (s, 1H), 6.53-6.47 (m, 3H), 3.95 (s, 3H), 3.93 (s, 3H), 3.37-3.32 (m, 2H), 2.93-2.88 (m, 2H), 1.77-1.72 (m, 2H), 1.66-1.60 (m, 2H).

[0444] LCMS: (M+H)+: m / Z: 373.23

[0445] The following compounds were synthesized by the above general procedure

[0446]

[0447]

[0448] Compound 058 was also synthesized by the general procedure described above.

[0449]

[0450] 1H NMR(400MHz,DMSO)δ8.83(s,1H),7.30(s,1H),7.18(s,1H),6.53-6.47(m,3H),3.95(s,3H) ,3.93(s,3H),3.37-3.32(m,2H),2.93-2.88(m,2H),1.77-1.72(m,2H),1.66-1.60(m,2H). LCMS 373.23. MW.408.92

[0451] Compound 059 was also synthesized by the general procedure described above.

[0452]

[0453] 1H NMR(400MHz,DMSO)δ8.82(s,1H),7.30(s,1H),7.18(s,1H),6.45(s,3H),3.9 5(s,3H),3.93(s,3H),3.34(t,2H),2.86(d,2H),1.72(t,2H),1.48(brs,4H). LCMS387.1.MW.422.9

[0454] Synthesis scheme of compounds 013 and 014:

[0455]

[0456] Step 1: Synthesis of 4-mercapto-6,7-dimethoxyquinoline-3-carbonitrile 2:

[0457]

[0458] Thiourea (920 mg, 12.08 mmol) was added to a stirred solution of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile 1 (2000 mg, 8.06 mmol) in ethanol (30 mL), and then refluxed for 6 hours. The reaction progress was monitored by TLC. After the reaction was completed, the reaction mixture was completely distilled off and adsorbed on silica gel, and methanol / DCM was used for grace column chromatography analysis to obtain 4-mercapto-6,7-dimethoxyquinoline-3-carbonitrile 2 (1300 mg) as a light pink solid.

[0459] Analyze the data: 1 H NMR (400MHz, DMSO): δ13.51(brs,1H),8.57(s,1H),8.05(s,1H),7.09(s,1H),3.91-3.88(m,6H).

[0460] LCMS: (M+H) + :m / Z:247.1

[0461] Step 2: Synthesis of 4-((4-(1,3-dioxoisoindolin-2-yl)butyl)thio)-6,7-dimethoxyquinoline-3-carbonitrile 4:

[0462]

[0463] To a stirred solution of 4-mercapto-6,7-dimethoxyquinoline-3-carbonitrile 2 (450 mg, 1.8 mmol) in DMF (10 mL) was slowly added 2-(4-bromobutyl)isoindoline-1,3-dione 3 (513 mg, 1.8 mmol) followed by K2CO3 (277 mg, 2.01 mmol) at room temperature. After addition, the reaction mixture was heated to 90 °C for 6 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was poured directly into ice-cold water and stirred. The precipitated solid was filtered and washed again with water and dried without any further purification to give 4-((4-(1,3-dioxoisoindoline-2-yl)butyl)thio)-6,7-dimethoxyquinoline-3-carbonitrile 4 (600 mg) as a light brown solid.

[0464] Analyze the data: 1 H NMR(400MHz,DMSO)δ:8.86(s,1H),7.81-7.75(m,4H),7.66(s,1H),7.41(s,1H),3 .97-3.96(m,6H),3.49(t,2H),3.21(t,2H),1.72-1.65(m,2H),1.50-1.43(m,2H).

[0465] LCMS: (M+H) + :m / Z:448.26

[0466] Step 3: Synthesis of 4-((4-aminobutyl)thio)-6,7-dimethoxyquinoline-3-carbonitrile 5:

[0467]

[0468] To a stirred solution of 4-(4-(1,3-dioxoisooctanol-2-yl)butyl)thio-6,7-dimethoxyquinoline-3-carbonitrile 4 (550 mg, 1.2 mmol) in EtOH (10 mL) was added hydrazine hydrate (0.19 mL, 3.7 mmol) and then refluxed for 2 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was directly absorbed onto diatomaceous earth and converted into a slurry. The crude product was purified by reverse phase grace column chromatography, eluting with a 40% ACN / water system to give 4-((4-aminobutyl)thio)-6,7-dimethoxyquinoline-3-carbonitrile 5 (80 mg) as a light yellow liquid.

[0469] Analyze the data: 1 H NMR (400MHz, DMSO) δ: 8.91 (s, 1H), 7.71 (s, 1H), 7.50 (s, 1H), 3.99-3.96 (m, 6H), 3.20-3.15 (m, 2H), 2.45-2.44 (m, 2H), 1.53-1.41 (m, 4H).

[0470] LCMS: (M+H) + :m / Z:318.2

[0471] Step 4: Synthesis of tert-butyl(N-(4-((3-cyano-6,7-dimethoxyquinolin-4-yl)thio)butyl)sulfamoyl)carbamic acid 7:

[0472]

[0473] To a stirred solution of 4-(4-aminobutyl)thio)-6,7-dimethoxyquinoline-3-carbonitrile 5 (80 mg, 0.25 mmol) in DCM (10 mL) was slowly added N-(1-(N-(tert-butyloxycarbonyl)sulfamoyl)pyridine-4(1H)-ylidene)-N-methylformamide chloride 4 (85 mg, 0.25 mmol) and then DIPEA (0.07 mL, 0.375 mmol) was added at the same temperature. The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. The reaction mixture was directly adsorbed on silica and converted into a slurry. The crude product was purified by combi-flash chromatography by eluting 70% EtOAc in hexanes to give tert-butyl (N-(4-(3-cyano-6,7-dimethoxyquinolin-4-yl)thio)sulfamoyl)carbamate (90 mg) as a white solid.

[0474] Analyze the data: 1H NMR(400MHz,DMSO)δ:10.73(s,1H),8.92(s,1H),7.71(s,1H),7.55-7.50(m,2H),3.9 9-3.98(m,6H),3.19-3.17(m,2H),2.82-2.81(m,2H),1.53-1.52(m,4H),1.37(s,9H)

[0475] LCMS: (M+H) + :m / Z:497.2

[0476] Step 5: Synthesis of compound 013:

[0477]

[0478] To a stirred solution of tert-butyl (N-(4-(3-cyano-6,7-dimethoxyquinolin-4-yl)thio)butyl)sulfamoyl)carbamate 7 (90 mg, 0.18 mmol) in dichloromethane (3 ml) at 0 degrees Celsius was added 4M HCl to dioxane (1 ml), followed by stirring at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, the organic solvent was completely distilled off under reduced pressure. The crude compound was purified by preparative HPLC to obtain compound 013 (25 mg) as an off-white fluffy solid.

[0479] Analyze the data: 1 H NMR(400MHz,DMSO)δ:8.92(s,1H),7.72(s,1H),7.51(s,1H),6.45-6.42(m,3H),6.4 5(t,1H)3.99-3.98(m,6H),3.21-3.17(m,2H),2.82-2.77(m,2H),1.55-1.53(m,4H).

[0480] LCMS: (M+H) + :m / Z:397.1.

[0481] Step 6: Synthesis of 4-((5-(1,3-dioxoisoindolin-2-yl)pentyl)thio)-6,7-dimethoxyquinoline-3-carbonitrile 9:

[0482]

[0483] To a stirred solution of 4-mercapto-6,7-dimethoxyquinoline-3-carbonitrile 2 (450 mg, 1.8 mmol) in DMF (10 mL) was slowly added 2-(5-bromopentyl)isoindole-1,3-dione 8 (540 mg, 1.8 mmol) at room temperature, followed by K2CO3 (273 mg, 1.98 mmol). After addition, the reaction mixture was heated to 90 °C for 6 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was poured directly into ice-cold water and stirred. The precipitated solid was filtered and washed again with water and dried without any further purification to give 4-((5-(1,3-dioxoisoindolin-2-yl)pentyl)thio)-6,7-dimethoxyquinoline-3-carbonitrile 9 (600 mg) as a light brown solid.

[0484] Analyze the data: 1 H NMR(400MHz,DMSO)δ:8.89(s,1H),7.81-7.75(m,4H),7.69(s,1H),7.48(s,1H),3 .98-3.96(m,6H),3.49(t,2H),3.17(t,2H),1.56-1.46(m,4H),1.40-1.36(m,2H).

[0485] LCMS: (M+H) + :m / Z:462.1

[0486] Step 7: Synthesis of 4-((5-aminopentyl)thio)-6,7-dimethoxyquinoline-3-carbonitrile 10:

[0487]

[0488] To a stirred solution of 4-(5-(1,3-dihydroisoquinolin-2-yl)pentyl)thio)-6,7-dimethoxyquinoline-3-carbonitrile 9 (600 mg, 1.3 mmol) in DCM:MeOH (1:1) (10 mL): 1,2-diethylamine (0.43 mL, 6.5 mmol) was added and then heated at 40 °C for 16 hours. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was directly absorbed onto celite and converted to a slurry. The crude product was purified by reverse phase grace column chromatography eluting with a 30-40% ACN / water system to give 4-((5-aminopentyl)thio)-6,7-dimethoxyquinoline-3-carbonitrile 10 (200 mg) as a light yellow liquid.

[0489] Analytical data: LCMS: (M+H) + :m / Z:332.2

[0490] Step 8: Synthesis of tert-butyl(N-(5-((3-cyano-6,7-dimethoxyquinolin-4-yl)thio)pentyl)sulfamoyl)carbamic acid 11:

[0491]

[0492] To a stirred solution of 4-(5-aminopentyl)thio-6,7-dimethoxyquinoline-3-carbonitrile 10 (200 mg, 0.60 mmol) in DCM (10 mL) was slowly added N-(1-(N-(tert-butyloxycarbonyl)sulfamoyl)pyridine-4(1H)-ethylidene)-N-methylformamide chloride 4 (338 mg, 0.6 mmol) and then DIPEA (0.16 mL, 0.9 mmol) was added at the same temperature. The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. The reaction mixture was directly adsorbed on silica and converted into a slurry. The crude product was purified by combi-flash chromatography by eluting 70-80% EtOAc in hexanes to give tert-butyl (N-(5-((3-cyano-6,7-dimethoxyquinoline-4-yl)thio)pentyl)sulfamoyl)carbamate 11 (90 mg) as a white solid.

[0493] Analyze the data: 1 H NMR(400MHz,DMSO)δ:10.73(s,1H),8.92(s,1H),7.71(s,1H),7.55-7.50(m,2H),4.00 -3.98(m,6H),3.18-3.14(m,2H),2.80-2.79(m,2H),1.45-1.41(m,2H),1.37(m,13H).

[0494] LCMS: (M+H) + :m / Z:511.2

[0495] Step 9: Synthesis of compound 014:

[0496]

[0497] To a stirred solution of tert-butyl (N-(5-(3-cyano-6,7-dimethoxyquinolin-4-yl)thio)pentyl)sulfamoyl)carbamate 11 (90 mg, 0.176 mmol) in dichloromethane (2 ml) at 0 degrees Celsius, 4M HCl (1 ml) was added to dioxane (1 ml), and then stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the organic solvent was completely distilled off under reduced pressure. The crude compound was purified by preparative HPLC to obtain compound 014 (29 mg) as an off-white fluffy solid.

[0498] Analyze the data: 1 H NMR(400MHz,DMSO)δ:8.93(s,1H),7.73(s,1H),7.51(s,1H),6.41-6.39(m,3H),4.09 -3.99(m,6H),3.19(t,2H),2.80-2.78(m,2H),1.51-1.49(m,2H),1.48-1.40(m,4H).

[0499] LCMS: (M+H) + :m / Z:411.1.

[0500] Overall plan 4:

[0501]

[0502] Example 4: N-(5-((6,7-dimethoxyquinazolin-4-yl)(methyl)amino)pentyl)sulfonamide Step 1: tert-Butyl(5-(1,3-dioxoisoindol-2-yl)pentyl)carbamate

[0503]

[0504] To a stirred solution of tert-butyl (5-aminopentyl) carbamate 1 (500 mg, 2.47 mmol) in toluene (10 mL) was added isobenzofuran-1,3-dione 2 (366 mg, 2.47 mmol), and the reaction mixture was stirred at reflux for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was completely distilled off under reduced pressure to obtain a crude compound. The crude product was purified by combi-flash column chromatography by eluting with 20% ethyl acetate in petroleum ether to obtain tert-butyl (5-(1,3-dioxoisoindolin-2-yl)pentyl)carbamate (500 mg, 1.506 mmol, 61% yield) as a white solid.

[0505] Analytical data: 1H NMR (400 MHz, DMSO) δ 7.86-7.80 (m, 4H), 6.74 (t, 1H), 3.56-3.52 (t, 2H), 2.88-2.83 (m, 2H), 1.58-1.54 (m, 2H), 1.38-1.32 (m, 11H), 1.23-1.20 (m, 2H).

[0506] LCMS: (M+Na)+: m / Z: 355.41

[0507] Step 2: tert-Butyl (5-(1,3-dioxoisoindolin-2-yl)pentyl)(methyl)carbamate

[0508]

[0509] To a stirred solution of tert-butyl (5-(1,3-dioxoisoindole-2-yl)pentyl)carbamate 3 (2 g, 6024 mmol) in N,N'-dimethylformamide (20 mL), 60% NaH (723 mg, 30.12 mmol) was slowly added at 0 °C, followed by iodomethane (8.5 g, 60.24 mmol) at the same temperature. The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. The reaction mixture was poured into ice-cold water (500 mL) and extracted with ethyl acetate (2x400 mL). The combined organic layers were washed with brine solution (400 mL), dried over sodium sulfate, and concentrated under reduced pressure. . The crude product was purified by combi-flash chromatography eluting with 20% ethyl acetate in petroleum ether to afford a mixture of tert-butyl(5-(1,3-dioxoisoindolin-2-yl)pentyl)(methyl)carbamates 4 (1.44 g, 4.161 mmol, 69% yield) as a white solid.

[0510] Analytical data: 1H NMR (400 MHz, DMSO) δ 7.86-7.80 (m, 4H), 3.57-3.54 (t, 2H), 3.12-3.08 (t, 2H), 2.71 (s, 3H), 1.63-1.56 (m, 2H), 1.48-1.43 (m, 2H), 1.32 (s, 9H), 1.20-1.17 (m, 2H).

[0511] LCMS: (M-Boc)+: m / Z: 247.2

[0512] Step 3: 2-(5-(Methylamino)pentyl)isoindoline-1,3-dione hydrochloride

[0513]

[0514] To a stirred solution of tert-butyl 4-(2-(N-(tert-butoxycarbonyl)sulfamoyl)ethyl)-3,4-dihydroquinoline-1(2H)-carboxylate 4 (1.8 g, 5.202 mmol) in dichloromethane (15 ml) at 0°C was added 4M HCl in dioxane (6.75 ml) and then stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the organic solvent was completely distilled off under reduced pressure. The crude compound was purified by trituration with diethyl ether (100 mL) to give 2-(5-(methylamino)pentyl)isoindoline-1,3-dione hydrochloride 5 (1.3 g, 4.609 mmol, 89% yield) as a white solid.

[0515] Analytical data: 1H NMR (400 MHz, DMSO) δ 8.32 (brs, 2H), 7.87-7.82 (m, 4H), 3.58-3.55 (t, 2H), 2.83 (m, 2H), 1.63-1.53 ​​(m, 4H), 1.33-1.28 (m, 2H).

[0516] LCMS: (M+H)+: m / Z: 247.2

[0517] Step 4: 2-(5-(6,7-dimethoxyquinazolin-4-yl)(methyl)amino)pentyl)isoindoline-1,3-dione

[0518]

[0519] To a stirred solution of 2-(5-(methylamino)pentyl)isoindoline-1,3-dione hydrochloride 5 (1.2 g, 4.25 mmol) in acetonitrile (15 ml) was added potassium carbonate (1.76 g, 13.5 mmol) and 4-chloro-6,7-dimethoxyquinazoline 6 (953 mg, 4.25 mmol), followed by stirring at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, water (200 mL) was added and extracted with ethyl acetate (2 x 150 mL). The combined organic layers were washed with brine solution (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by combi-flash column chromatography eluting with 40% ethyl acetate in hexanes to afford 2-(5-((6,7-dimethoxyquinazolin-4-yl)(methyl)amino)pentyl)isoindoline-1,3-dione 7 (650 mg, 1.497 mmol, 44% yield) as a white solid.

[0520] Analytical data: 1H NMR (400 MHz, DMSO) δ8.35 (s, 1H), 7.84-7.79 (m, 4H), 7.21 (s, 1H), 7.11 (s, 1H), 3.89 (s, 3H), 3.82 (s, 3H), 3.60-3.54 (m, 2H), 3.21 (s, 3H), 1.78-1.75 (m, 2H), 1.65-1.59 (m, 2H), 1.34-1.28 (m, 2H).

[0521] LCMS: (M+H)+: m / Z: 435.2

[0522] Step 5: N1-(6,7-dimethoxyquinazolin-4-yl)-N1-methylpentane-1,5-diamine

[0523]

[0524] To a stirred solution of 2-(5-(6,7-dimethoxyquinazolin-4-yl)(methyl)amino)pentyl)isoindoline-1,3-dione 7 (545 mg, 1.126 mmol) in ethanol (15 ml) was added hydrazine hydrate (0.18 ml, 3.378 mmol) and the reaction mixture was stirred at 80 °C for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the precipitated solid was filtered out, the residue was washed with ethanol (20 mL) and the filtrate was concentrated to obtain the crude compound. The crude compound was purified by Grace reverse phase method by eluting 14% acetonitrile in 0.1% formic acid in water to obtain N1-(6,7-dimethoxyquinazolin-4-yl)-N1-methylpentane-1,5-diamine 8 (330 mg, 1.085 mmol, 86% yield) as a colorless colloidal liquid.

[0525] Analytical data: 1H NMR (400 MHz, DMSO) δ8.38 (s, 1H), 7.25 (s, 1H), 7.14 (s, 1H), 3.90 (s, 3H), 3.90 (s, 3H), 3.60-3.56 (t, 2H), 3.22-3.21 (s, 3H), 1.76-1.72 (m, 2H), 1.38-1.30 (m, 4H).

[0526] LCMS: (M+H)+: m / Z: 305.2

[0527] Step 6: tert-Butyl(N-(5-((6,7-dimethoxyquinazolin-4-yl)(methyl)amino)pentyl)sulfamoyl)carbamic acid

[0528]

[0529] To a stirred solution of N1-(6,7-dimethoxyquinazolin-4-yl)-N1-methylpentane-1,5-diamine 8 (360 mg, 1.2 mmol) in dichloromethane (10 ml) was added diisopropylethylamine (0.3 ml, 1.81 mmol) and N-(1-(N-(tert-butyloxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylformamide chloride 9 (491 mg, 1.45 mmol) at 0°C, followed by stirring at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the organic solvent was completely distilled off under reduced pressure to obtain a crude compound. The crude product was purified by 60-120 silica gel column chromatography eluting with 2% methanol in dichloromethane to afford tert-butyl (N-(5-((6,7-dimethoxyquinazolin-4-yl)(methyl)amino)pentyl)sulfamoyl)carbamate 10 (200 mg, 0.414 mmol, 35% yield) as a brown solid.

[0530] Analytical data: 1H NMR (400MHz, DMSO) δ 11.0-10.0 (brs, 1H), 8.38 (s, 1H), 7.25 (s, 1H), 7.22 (m, 1H), 7.14 (s, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 3.59-3.55 (t, 2H), 3.22-3.21 (s, 3H), 1.75-1.71 (m, 2H), 1.50-1.45 (m, 2H), 1.38 (s, 9H), 1.31-1.24 (m, 1H). LCMS: (M+H)+: m / Z: 484.2

[0531] Step 7: N-(5-((6,7-dimethoxyquinazolin-4-yl)(methyl)amino)pentyl)sulfonamide (Compound 061)

[0532]

[0533] To a stirred solution of tert-butyl (N-(5-(6,7-dimethoxyquinazolin-4-yl)(methyl)amino)pentyl)sulfamoyl)carbamate 10 (200 mg, 0.414 mmol) in dichloromethane (6 ml) at 0°C, 4M HCl was added to dioxane (4 ml), and then stirred at room temperature for 3 hours. The progress of the reaction was monitored by TLC. After completion, the organic solvent was completely distilled off under reduced pressure to obtain a crude compound. The crude product was purified by preparative HPLC to obtain N-(5-((6,7-dimethoxyquinazolin-4-yl)(methyl)amino)pentyl)sulfonamide (90 mg, 0.235 mmol, 57% yield) (Compound 061) as an off-white solid.

[0534] Analytical data: 1H NMR (400MHz, DMSO) δ8.39 (s, 1H), 8.14 (s, 1H), 7.26 (s, 1H), 7.14 (s, 1H), 6.44 (m, 3H), 3.90 (s, 3H), 3.88 (s, 3H), 3.60-3.56 (t, 2H), 2.88-2.83 (m, 2H), 1.77-1.71 (m, 2H), 1.52-1.46 (m, 2H), 1.37-1.31 (m, 2H). LCMS: (M+H)+: m / Z: 384.2

[0535] Overall plan 5:

[0536]

[0537] Example 5: 4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepane-1-sulfonamide hydrochloride (Compound 015)

[0538] Step 1: tert-Butyl 4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepane-1-carboxylic acid

[0539]

[0540] Potassium carbonate (2.4 g, 17.809 mmol) and tert-butyl 1,4-diazepane-1-carboxylate 2 (1.96 g, 9.795 mmol) were added to a stirred solution of 4-chloro-6,7-dimethoxyquinazoline 1 (2 g, 8.904 mmol) in acetonitrile (25 ml), and then stirred at 80 ° C for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was completely distilled off under reduced pressure. The crude product was purified by combi-flash chromatography, and tert-butyl 4-(6,7-dimethoxyquinazoline-4-yl)-1,4-diazepane-1-carboxylic acid (2.7 g, 6.958 mmol, 78% yield) was obtained as a light yellow solid by eluting 5% methanol in dichloromethane.

[0541] Analytical data: 1H NMR (400 MHz, DMSO) δ8.38 (s, 1H), 7.14 (s, 1H), 7.25 (s, 1H), 3.97-3.94 (t, 2H), 3.89-3.84 (m, 8H), 3.59 (d, 2H), 3.41 (s, 2H), 1.98 (s, 2H), 1.15 (d, 9H).

[0542] Step 2: 4-(1,4-diazepan-1-yl)-6,7-dimethoxyquinazoline hydrochloride

[0543]

[0544] 4M HCl was added to a stirred solution of tert-butyl 4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepane-1-carboxylate 3 (200 mg, 0.742 mmol) in dioxane (2 ml) at 0°C and then stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the organic solvent was completely distilled off under reduced pressure. The crude product was purified by trituration with ether (20 mL) to give 4-(1,4-diazepane-1-yl)-6,7-dimethoxyquinazoline hydrochloride 4 (115 mg, 0.355 mmol, 68% yield) as a yellow solid.

[0545] Analytical data: 1H NMR (400 MHz, DMSO) δ9.33 (s, 2H), 8.79 (s, 1H), 7.43 (s, 1H), 7.35 (s, 1H), 4.19 (s, 2H), 4.29 (s, 2H), 3.97-3.93 (m, 6H), 3.17 (d, 2H), 2.77-2.31 (m, 2H).

[0546] Step 3: tert-Butyl ((4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate

[0547]

[0548] To a stirred solution of 4-(1,4-diazepan-1-yl)-6,7-dimethoxyquinazoline hydrochloride 4 (500 mg, 1.508 mmol) in dichloromethane (10 ml) was added diisopropylethylamine (0.5 ml, 2.262 mmol) and N-(1-(N-(tert-butyloxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylformamide 5 (508 mg, 1.508 mmol) at 0°C, followed by stirring at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was completely distilled off under reduced pressure to obtain a crude compound. The crude product was purified by 100-200 silica gel column chromatography by eluting with 5% methanol in dichloromethane to obtain a semi-pure compound. The semi-pure product was purified again by trituration with 50% ethyl acetate in petroleum ether to afford tert-butyl ((4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate 6 (350 mg, 0.686 mmol, 44% yield) as an off-white solid.

[0549] Analytical data: 1H NMR (400MHz, DMSO) δ11.07 (brs, 1H), 8.18 (s, 1H), 7.21 (s, 1H), 3.88-3.95 (m, 10H), 3.65-3.68 (t, 2H), 3.42-3.45 (t, 2H), 2.06 (d, 2H), 1.33-1.36 (s, 9H). LCMS: (M+H+): m / Z: 468.15

[0550] Step 4: 4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepane-1-sulfonamide hydrochloride (Compound 015-HCl)

[0551]

[0552] To a stirred solution of tert-butyl ((4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate 6 (300 mg, 0.646 mmol) in dioxane (2 ml) at 0°C was added 4M HCl in dioxane (8 ml) and then stirred at room temperature for 6 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the organic solvent was completely distilled off under reduced pressure. The crude product was purified by trituration with 5% methanol in dichloromethane (50 mL) to give 4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-sulfonamide hydrochloride (120 mg, 0.327 mmol, 51% yield) as an off-white solid.

[0553] Analytical data: 1H NMR (400 MHz, DMSO) δ8.75 (s, 1H), 7.43 (s, 1H), 7.34 (s, 1H), 6.84 (s, 1H), 4.18-4.22 (m, 4H), 3.94 (s, 3H), 3.96 (s, 3H), 3.59 (m, 2H), 3.28-3.31 (t, 2H), 2.08 (brs, 2H).

[0554] LCMS: (M+H+): m / Z: 368.1

[0555] Synthesis scheme of compound 015-MES

[0556] 4-(6,7-Dimethoxyquinazolin-4-yl)-1,4-diazepane-1-sulfonamide methanesulfonate (015-MES)

[0557]

[0558] To a stirred solution of 4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepine-1-sulfonamide (100 mg, 0.272 mmol) (Compound 015 free base was prepared from the HCl salt by stirring with triethylamine for two hours) in acetonitrile (2 ml) was added aqueous methanesulfonic acid (26 mg, 0.272 mmol), and the reaction mixture was then kept under lyophilization for 16 hours to give 4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepine-1-sulfonamide methanesulfonate (Compound 015-MES) (115 mg, 0.248 mmol, 91% yield) as an off-white solid.

[0559] Analyze the data: 1H NMR(400MHz,DMSO)δ14.150(bs,1H),8.699(s,1H),7.401(s,1H),7.183(s,1H),6.819(s,1H),4.141-4.166 (m,4H),3.961(s,3H),3.930(s,3H),3.559-3.591(m,2H),3.320(m,2H),2.279(s,3H),2.061-2.103(m,2H).

[0560] LCMS: (M+H + ):m / Z:368.16.

[0561] Synthesis scheme of compound 016

[0562]

[0563] Synthesis of tert-butyl 4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepane-1-carboxylic acid (3)

[0564]

[0565] Potassium carbonate (834 mg, 6.0 mmol) and tert-butyl 1,4-diazacycloheptane-1-carboxylate 2 (904 mg, 4.5 mmol) were added to a stirred solution of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile 1 (750 mg, 3.0 mmol) in acetonitrile (15 ml), and then stirred at 80 ° C for 16 hours. The reaction progress was monitored by TLC. After the reaction was completed, water (100 mL) was added to the reaction mixture and extracted with ethyl acetate (2X100 mL). The combined organic layer was washed with a saline solution (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude compound was purified by combined flash chromatography, and the pure compound tert-butyl 4- (3-cyano-6,7-dimethoxyquinoline-4-yl) -1,4-diazacycloheptane-1-carboxylic acid (450 mg, 1.09 mmol, 38% yield) was obtained as a light yellow solid.

[0566] Analyze the data: 1 H NMR (400MHz, DMSO) δ8.67(s,1H),7.39(s,1H),7.31(s,1H),3.94(s,6H),3.59-3.62(m,6H),3.46-3.3.53(m,2H),2.05(s,2H),1.43(s,9H).

[0567] LCMS: (M+H) + :m / Z:413.2

[0568] Synthesis of 4-(1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile hydrochloride (4)

[0569]

[0570] To a stirred solution of tert-butyl 4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepane-1-carboxylate 3 (450 mg, 1.09 mmol) in dioxane (2 ml) at 0°C, 4M HCl was added to dioxane (3 ml), followed by stirring at room temperature for 4 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the organic solvent was completely distilled off under reduced pressure. The crude residue was washed with ether to obtain 4-(1,4-diazepane-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile hydrochloride 4 (400 mg, 1.28 mmol, 92% yield) as a yellow solid.

[0571] LCMS: (M+H) + :m / Z:313.31

[0572] Synthesis of tert-butyl ((4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate (6)

[0573]

[0574] Diisopropylethylamine (0.25 mL, 1.44 mmol) and N-(1-(tert-butyloxycarbonyl)sulfamoyl)sulfamoyl)pyridine-4(1H)-ethylidene-N-methylformamide 5 (243 mg, 0.72 mmol) were stirred for 16 hours at room temperature and added to a stirred solution of 4-(1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile hydrochloride (4) (150 mg, 0.48 mmol) in dichloromethane (3 mL). The reaction progress was monitored by TLC. After the reaction was completed, the organic solvent was completely distilled off under reduced pressure to obtain a crude compound. The crude compound was purified by eluting with 60% ethyl acetate in petroleum ether to afford tert-butyl((4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate (6) (100 mg, 0.203 mmol, 42% yield) as a yellow solid.

[0575] Analyze the data: 1H NMR (400MHz, DMSO) δ11.07(s,1H),8.69(S,1H),7.39(s,1H),7.34(s,1H),3.92-3.94(s,6H),3.58-3.68(m,8H),2.08(m,2H),1.43(s,9H).

[0576] LCMS: (M+H) + :m / Z:492.24

[0577] Preparation of Compound 016

[0578]

[0579] To a stirred solution of tert-butyl ((4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate (6) (100 mg, 0.203 mmol) in 1,4-dioxane (2.0 mL) at room temperature was added 4M HCl to dioxane (2.0 mL). The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the organic solvent was completely distilled off under reduced pressure to obtain a crude compound. The crude compound was purified by preparative HPLC to obtain a pure compound of compound 016 (35 mg, 0.089 mmol, 41% yield) as a light yellow solid.

[0580] Analyze the data: 1 H NMR (400MHz, DMSO) δ8.67(s,1H),7.37(d,2H),6.83(s,2H),3.94(s,6H),3.63-3.67(m,4H),3.44-3.51(m,4H),2.08(m,2H).

[0581] LCMS: (M+H) + :m / Z:392.2

[0582] Synthesis scheme of compound 017

[0583]

[0584] Synthesis of 4-(4-(N-(tert-Butoxycarbonyl)sulfamoyl)-1,4-diazepan-1-yl)-6-methoxyquinazoline-7-carboxylic acid methyl ester (2)

[0585]

[0586] To a stirred solution of 4-(4-(N-(tert-butyloxycarbonyl)sulfamoyl)-1,4-diazepan-1-yl)-6-methoxyquinazolin-7-yl trifluoromethylsulfonate 1 (200 mg, 0.342 mmol) in N,N'-dimethylformamide (2 mL) and methanol (10 mL) was added triethylamine (103.6 mg, 1.026 mmol), and the reaction mixture was degassed for 30 minutes. Palladium(II) acetate (3.8 mg, 0.017 mmol) and Xantphos (10 mg, 0.017 mmol) were then added again, degassed for 5 minutes, and the reaction mixture was stirred under a CO balloon pressure at 80°C for 6 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was completely distilled under reduced pressure, ethyl acetate (50 mL) was added to the crude product and filtered through celite. The celite bed was washed with excess ethyl acetate (50 mL). Water (100 mL) was then added and extracted. The organic layer was washed with brine (100 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain methyl 4-(4-(N-(tert-butyloxycarbonyl)sulfamoyl)-1,4-diazepan-1-yl)-6-methoxyquinazoline-7-carboxylate (2) (70 g, 0.141 mol, 41%) as a brown solid.

[0587] Analyze the data: 1 H NMR(400MHz,DMSO)δ8.493(s,1H),7.952(s,1H),7.392(s,1H),4.008-4.024(m,4H),3.938( s,3H),3.865(s,3H),3.691-3.718(t,2H),3.446-3.476(t,2H),2.099(m,2H),1.363(s,9H).

[0588] Synthesis of Methyl 6-Methoxy-4-(4-sulfamoyl-1,4-diazepan-1-yl)quinazoline-7-carboxylic Acid Hydrochloride (Int-4)

[0589]

[0590] A stirred solution of 4-(4-(N-(tert-butyloxycarbonyl)sulfamoyl)-1,4-diazepan-1-yl)-6-methoxyquinazoline-7-carboxylate 2 (70 mg, 0.545 mmol) and 4M HCl in dioxane (4 mL) was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After the reaction was completed, the organic solvent was completely distilled off under reduced pressure. The crude product was purified by trituration with 5% methanol in dichloromethane (5 mL) to give methyl 6-methoxy-4-(4-sulfamoyl-1,4-diazepan-1-yl)quinazoline-7-carboxylate hydrochloride Int-4 (55 mg, 0.127 mmol, 90% yield) as an off-white solid.

[0591] Analyze the data: 1 H NMR(400MHz,DMSO)δ8.486(s,1H),7.948(s,1H),7.406(s,1H),3.990-4.040(m,4H), 3.937(s,3H),3.865(s,3H),3.523-3.548(t,2H),3.274-3.293(t,2H),2.103(m,2H).

[0592] LCMS: (M+H + ):m / Z:396.1

[0593] Synthesis of 6-methoxy-4-(4-sulfamoyl-1,4-diazepan-1-yl)quinazoline-7-carboxylic acid (Compound 017)

[0594]

[0595] To a stirred solution of methyl 6-methoxy-4-(4-sulfamoyl-1,4-diazepan-1-yl)quinazoline-7-carboxylic acid hydrochloride (Int-4) (55 mg, 0.139 mmol) in tetrahydrofuran (3 ml) and water (1 ml) was added lithium hydroxide monohydrate (29 mg, 0.696 mmol) at 0 ° C, followed by stirring at room temperature for 16 hours. After the reaction was completed, the organic solvent was removed by distillation under reduced pressure. Water (20 mL) was added to the crude residue and acidified with 30% citric acid solution (10 mL). It was then extracted with 10% methanol in dichloromethane (50 mL) and concentrated under reduced pressure to obtain a crude compound. The crude compound was purified by a preparative HPLC method to obtain a pure compound 6-methoxy-4-(4-sulfamoyl-1,4-diazepan-1-yl)quinazoline-7-carboxylic acid compound 017 (10 mg, 0.03 mmol, 11% yield) as an off-white solid.

[0596] Analyze the data: 1H NMR(400MHz,DMSO)δ13.237(bs,1H),8.470(s,1H),7.848(bs,1H),7.363(s,1H),6.787(s,1H) ,3.980-4.033(m,4H),3.923(s,3H),3.522-3.547(t,2H),3.280(t,2H),2.072-2.102(m,2H).

[0597] LCMS: (M+H + ):m / Z:382

[0598] Synthesis scheme of compound 018

[0599]

[0600] Synthesis of tert-butyl 4-(7-(benzyloxy)-6-methoxyquinazolin-4-yl)-1,4-diazepane-1-carboxylic acid (3)

[0601]

[0602] To a stirred solution of 7-(benzyloxy)-4-chloro-6-methoxyquinazoline 1 (250mg, 0.831mmol) in acetonitrile (5ml), potassium carbonate (229mg, 1.66mmol) and tert-butyl 1,4-diazepane-1-carboxylate 2 (249mg, 1.24mmol) were added, and then stirred at 80°C for 16 hours. The reaction progress was monitored by TLC. After the reaction was completed, water was added to the reaction mixture and a solid was formed. The solid was collected by filtration, and the compound of pure tert-butyl 4-(7-(benzyloxy)-6-methoxyquinazoline-4-yl)-1,4-diazepane-1-carboxylic acid (3) (380mg, 0.818mmol, 98%) obtained was a white solid.

[0603] LCMS: (M+H) + :m / Z:465.3

[0604] Tert-butyl 4-(7-hydroxy-6-methoxyquinazolin-4-yl)-1,4-diazepane-1-carboxylic acid (4)

[0605]

[0606] 10% palladium / carbon (40 mg) was added to a stirred solution of tert-butyl 4-(7-(benzyloxy)-6-methoxyquinazoline-4-yl)-1,4-diazepane-1-carboxylate (3) (400 mg, 0.862 mmol) in methanol (3 mL) and EtOAc (2 mL), and the reaction mixture was stirred at room temperature under a balloon hydrogen atmosphere for 6 hours. The reaction progress was monitored by TLC. After the reaction was completed, the reaction mixture was filtered through diatomaceous earth and the diatomaceous earth bed was washed with dichloromethane (50 mL) containing 5% methanol. The filtrate was concentrated under reduced pressure, and the obtained 4-(7-hydroxy-6-methoxyquinazoline-4-yl)-1,4-diazepane-1-carboxylic acid tert-butyl (4) (300 mg, 0.802 mmol, 98% yield) was a light blue solid.

[0607] LCMS: (M+H + ):m / Z:375.2

[0608] Synthesis of tert-butyl 4-(7-(2-amino-2-oxoethoxy)-6-methoxyquinazolin-4-yl)-1,4-diazepane-1-carboxylic acid (6)

[0609]

[0610] Potassium carbonate (276 mg, 2.0 mmol) and 2-bromoacetamide 5 (184 mg, 1.33 mmol) were added to a stirred solution of 4-(7-hydroxy-6-methoxyquinazoline-4-yl)-1,4-diazepane-1-carboxylic acid tert-butyl ester 4 (250 mg, 0.668 mmol) in acetonitrile (5 mL), and then stirred at 80 ° C for 16 hours. The reaction progress was monitored by TLC. After the reaction was completed, water (100 mL) was added to the reaction mixture and extracted with ethyl acetate (2X100 mL). The combined organic layer was washed with a saline solution (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude compound was purified by combined flash chromatography to give the pure compound tert-butyl 4-(7-(2-amino-2-oxoethoxy)-6-methoxyquinazolin-4-yl)-1,4-diazepane-1-carboxylic acid 6 (200 mg, 0.462 mmol, 71% yield) as light brown syrup.

[0611] LCMS: (M+H + ):m / Z:432.3

[0612] Synthesis of 2-(4-(1,4-diazepan-1-yl)-6-methoxyquinazolin-7-yl)oxy)acetamide hydrochloride (7)

[0613]

[0614] To a stirred solution of tert-butyl 4-(7-(2-amino-2-oxyethoxy)-6-methoxyquinazolin-4-yl)-1,4-diazepane-1-carboxylate 6 (200 mg, 0.462 mmol) in dioxane (1 ml) was added 4M HCl at 0°C, followed by stirring at room temperature for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the organic solvent was completely distilled off under reduced pressure. The crude residue was washed with ether to give 2-((4-(1,4-diazepane-1-yl)-6-methoxyquinazolin-7-yl)oxy)acetamide hydrochloride 7 (150 mg, 0.451 mmol, 88% yield) as a yellow solid.

[0615] Analyze the data: 1 H NMR(400MHz,DMSO)δ9.23(br s,1H),8.77(s,1H),7.46-7.47(m,1H),7.01-7.26(m,2H),4.74(s,3H),4.19-4.26 (m,4H),3.94(s,3H),3.71(d,2H),3.45(m,2H),3.18-3.3.19(m,2H),2.24(m,2H).

[0616] Synthesis of tert-butyl ((4-(7-(2-amino-2-oxyethoxy)-6-methoxyquinazolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate (8)

[0617]

[0618] To a stirred solution of 2-(4-(1,4-diazepan-1-yl)-6-methoxyquinazolin-7-yl)oxy)acetamide hydrochloride (7) (150 mg, 0.451 mmol) in dichloromethane (3 ml) was added diisopropylethylamine (0.24 mL, 1.36 mmol) and N-(1-(N-(tert-butyloxycarbonyl)sulfamoyl)pyridine-4(1H)-ylidene)-N-methylmethanamine 5 (168 mg, 0.49 mmol) at room temperature and stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After the reaction was completed, the organic solvent was completely distilled off under reduced pressure to obtain a crude compound. The crude compound was purified by eluting with 60% ethyl acetate in petroleum ether and tert-butyl ((4-(7-(2-amino-2-oxoethoxy)-6-methoxyquinazolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate (9) (150 mg, 0.294 mmol, 65% yield) was obtained as a yellow solid by combined flash column chromatography.

[0619] LCMS: (M+H) +:m / Z:511.2

[0620] Synthesis of Compound 018

[0621]

[0622] To a stirred solution of tert-butyl ((4-(7-(2-amino-2-oxyethoxy)-6-methoxyquinazolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate (9) (150 mg, 0.294 mmol) in 1,4-dioxane (1.0 mL) was added 4M HCl to dioxane (2.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the organic solvent was completely distilled off under reduced pressure to obtain a crude compound. The crude compound was purified by preparative HPLC to obtain a pure compound of compound 018 (15 mg, 0.036 mmol, 12% yield) as an off-white solid.

[0623] Analyze the data: 1 H NMR(400MHz,DMSO)δ8.39(s,1H),7.42-7.47(dd,2H),7.26(s,1H),7.03(s,1H),6.77(s,1H ),4.63(s,2H),3.91-3.97(m,7H),3.48-3.51(m,2H),3.24-3.27(m,3H),2.05-2.08(m,2H).

[0624] LCMS: (M+H) + :m / Z:411.1

[0625] Synthesis scheme of compounds 019, 020, 021 and 022

[0626]

[0627] Synthesis of 7-(Benzyloxy)-4-(1,4-diazepan-1-yl)-6-methoxyquinazoline hydrochloride (2)

[0628]

[0629] A stirred solution of 4-(7-(benzyloxy)-6-methoxyquinazoline-4-yl)-1,4-diazepane-1-carboxylate 1 (1 g, 2.155 mmol) and 4M HCl in dioxane (10 mL) was stirred for 1 hour at room temperature. The progress of the reaction was monitored by TLC. After the reaction was completed, the organic solvent was completely distilled off under reduced pressure. The crude product was purified by trituration with pentane (50 mL) to give 7-(benzyloxy)-4-(1,4-diazepane-1-yl)-6-methoxyquinazoline hydrochloride 2 (600 mg, 1.5 mmol, 70% yield) as an off-white solid.

[0630] Analyze the data:

[0631] LCMS: (M+H + ):m / Z:365.2

[0632] Synthesis of tert-butyl((4-(7-(benzyloxy)-6-methoxyquinazolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate(6)

[0633]

[0634] To a stirred solution of 7-(benzyloxy)-4-(1,4-diazepan-1-yl)-6-methoxyquinazoline hydrochloride 2 (1 g, 2.497 mmol) in dichloromethane (20 mL) was added diisopropylethylamine (805 mg, 6.242 mmol) and N-(1-(N-(tert-butyloxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylformamide 3 (841 mg, 2.497 mmol) at 0 °C, followed by stirring at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was completely distilled off under reduced pressure to obtain a crude compound. The crude product was purified by 100-200 silica gel column chromatography by eluting with 5% methanol in dichloromethane to obtain a semi-pure compound. The semi-pure product was purified again by trituration with 50% ethyl acetate in petroleum ether to afford tert-butyl ((4-(7-(benzyloxy)-6-methoxyquinazolin-4-yl)-1,4-diazepan-1-yl))sulfonyl)carbamate 4 (1.2 g, 2.21 mmol, 89% yield) as an off-white solid.

[0635] Analytical data: LCMS: (M+H + ):m / Z:544.15

[0636] Synthesis of tert-butyl ((4-(7-hydroxy-6-methoxyquinazolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate (5)

[0637]

[0638] To a stirred solution of tert-butyl ((4-(7-(benzyloxy)-6-methoxyquinazolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate 4 (1.2 g, 2.21 mmol) in ethanol (30 mL) was added 10% palladium on carbon (200 mg), and the reaction mixture was stirred at room temperature under a balloon hydrogen atmosphere for 16 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was filtered through diatomaceous earth and the diatomaceous earth bed was washed with dichloromethane (100 mL) containing 5% methanol. The filtrate was concentrated under reduced pressure to give a semi-pure compound (tert-butyl ((4-(7-hydroxy-6-methoxyquinazolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate (5) (1.1 g, crude) as an off-white solid.

[0639] Analyze the data: 1 H NMR (400MHz, DMSO) δ10.341(bs,1H),8.345(s,1H),7.205(s,1H),7.027(s,1H),4.330-4. 356(t,2H),3.890-3.924(m,5H),3.661(t,2H),2.054-2.061(m,1H),1.247-1.366(m,9H).

[0640] Synthesis of 4-(4-(N-(tert-Butyloxycarbonyl)sulfamoyl)-1,4-diazepan-1-yl)-6-methoxyquinazolin-7-yl trifluoromethanesulfonate (7)

[0641]

[0642] To a stirred solution of tert-butyl ((4-(7-hydroxy-6-methoxyquinazolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate 5 (1.1 g, 2428 mmol) in dichloromethane (15 mg) at 0°C were added triethylamine (0.85 mL, 6.07 mmol) and 1,1,1-trifluoro-N-phenyl-N-(trifluoromethyl)sulfonyl)methanesulfonamide 6 (1.3 g, 3.642 mmol), followed by stirring at room temperature for 4 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the organic solvent was completely distilled off under reduced pressure, water (200 mL) was added to the crude product and partitioned with dichloromethane (2×200 mL). The combined organic layers were washed with brine solution (200 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by combi-flash chromatography eluting with 70% ethyl acetate in petroleum ether to afford 4-(4-(N-(tert-butoxycarbonyl)sulfamoyl)-1,4-diazepan-1-yl)-6-methoxyquinazolin-7-yl trifluoromethylsulfonate 7 (750 mg, 1.282 mmol, 58% yield over two steps) as an off-white solid.

[0643] Analyze the data: 1 H NMR(400MHz,DMSO)δ11.021(s,1H),8.514(s,1H),7.847(s,1H),7.566(s,1H), 3.990-4.031(m,8H),3.707(s,2H),3.443(s,2H),2.080(bs,2H),1.342(s,9H).

[0644] Synthesis of 4-(6-methoxy-7-(1H-pyrrol-3-yl)quinazolin-4-yl)-1,4-diazepane-1-sulfonamide (Compound 019)

[0645]

[0646] In a sealed tube, to a stirred solution of 4-(4-(N-(tert-butyloxycarbonyl)sulfamoyl)-1,4-diazepan-1-yl)-6-methoxyquinazoline-7-yl trifluoromethylsulfonate 7 (200 mg, 0.342 mmol) in dioxane (7 mL) water (2 ml), (1-(triisopropylpropylsilyl)-1H-pyrrole-3-yl)boric acid (119 mg, 0.446 mmol) and cesium fluoride (104 mg, 0.684 mmol) were added, and the reaction mixture was degassed for 30 minutes. Then, tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.0017 mmol) was added for 5 minutes of degassing again and the reaction mixture was stirred at 65 ° C for 3 hours. The reaction progress was monitored by TLC. After the reaction was completed, the reaction mixture was poured into water (100 mL) and filtered through diatomaceous earth. The celite bed was washed with 10% methanol in dichloromethane (100 mL) and the two layers were separated. The organic layer was washed with brine solution (200 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain 4-(6-methoxy-7-(1H-pyrrol-3-yl)quinazolin-4-yl)-1,4-diazepane-1-sulfonamide (Compound 019) (30 mg, 0.074 mmol, 22%) as a brown solid.

[0647] Analyze the data: 1 H NMR (400MHz, DMSO) δ10.984(s,1H),8.332(s,1H),8.180(s,1H),7.832(s,1H),7.493(s,1H),7.288( s,1H),6.833(s,1H),6.650(s,1H),3.838(m,8H),3.499(t,2H),3.251-3.277(t,2H),2.068(m,2H).

[0648] LCMS: (M+H + ):m / Z:403.1

[0649] Synthesis scheme of compounds 023, 024 and 025:

[0650]

[0651] Step 1: Synthesis of ethyl 4-(4-(tert-butoxycarbonyl)-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carboxylate 3:

[0652]

[0653] To a stirred solution of 4-chloro-6,7-dimethoxyquinoline-3-carboxylic acid ethyl ester 1 (4.2 g, 4.2 mmol) in DMF (40 mL) was added 1,4-diazepane-1-carboxylic acid tert-butyl ester (4.2 mL, 4.2 mmol) and K2CO3 (3.9 g, 28 mmol), and then heated to 80 ° C and refluxed for 16 hours. The reaction progress was monitored by TLC. After the reaction was completed, the reaction mixture was directly poured into ice-cold water and stirred. The precipitated solid was filtered and washed with water again and dried without any further purification to obtain ethyl 4-(4-(tert-butoxycarbonyl)-1,4-diazepane-1-yl)-6,7-dimethoxyquinoline-3-carboxylate 3 (5.5 g) as a light yellow solid.

[0654] Analyze the data: 1 H NMR(400MHz,DMSO):8.68(s,1H),7.43(s,1H),7.37(s,1H),4.34(q,2H),3.93(s, 6H),3.59-3.54(m,4H),3.26-3.19(m,4H),1.97-1.92(m,2H),1.43-1.32(m,11H).

[0655] LCMS: (M+H) + :m / Z:247.1

[0656] Step 2: Synthesis of ethyl 4-(1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carboxylate hydrochloride 4:

[0657]

[0658] To a stirred solution of 4-(4-(tert-butyloxycarbonyl)-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carboxylate 3 (5.5 g, 1,8 mmol) in 1,4-dioxane (50 mL) at 0°C, 4.0 M HCl was slowly added to 1,4-dioxane (50 ml) and slowly allowed to reach room temperature and stirred for 2 hours. After the reaction was complete, the volatile organics were removed under reduced pressure, co-distilled with DCM three times and triturated with ether to give ethyl 4-(1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carboxylate hydrochloride 4 (4.2 g) as an off-white solid. The progress of the reaction was monitored by TLC.

[0659] Analytical data: LCMS: (M+H) + :m / Z:360

[0660] Step 3: Ethyl 4-(4-(N-(tert-butoxycarbonyl)sulfamoyl)-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carboxylate 6:

[0661]

[0662] To a stirred solution of 4-(4-aminobutyl)thio-6,7-dimethoxyquinoline-3-carbonitrile 4 (2 g, 5.56 mmol) in DCM (30 mL) was slowly added N-(1-(N-(tert-butyloxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylformamide chloride 5 (2.06 g, 6.1 mmol) followed by DIPEA (2.68 mL, 0.375 mmol) at the same temperature. The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. The reaction mixture was directly adsorbed on silica and converted into a slurry. The crude product was purified by combi-flash chromatography eluting with 90% EtOAc in hexanes to afford ethyl 4-(4-(N-(tert-butoxycarbonyl)sulfamoyl)-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carboxylate 6 (1.1 g) as a white solid.

[0663] Analyze the data: 1 H NMR(400MHz,DMSO):8.72(s,1H),7.49(s,1H),7.37(s,1H),4.36(q,2H),3.93(s,6H) ,3.59-3.52(m,4H),3.22-3.09(m,4H),1.97-1.96(m,2H),1.47(s,9H),1.36(t,3H).

[0664] LCMS: (M+H) + :m / Z:539.2

[0665] Step 4: Synthesis of 6,7-dimethoxy-4-(4-sulfamoyl-1,4-diazepan-1-yl)quinoline-3-carboxylic acid ethyl ester 7 (Compound 023)

[0666]

[0667] At 0 ° C, TFA (3 ml) was added to a stirred solution of 4-(4-(N-(tert-butyloxycarbonyl)sulfamoyl)-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carboxylic acid ethyl ester 7 (300 mg, 0.56 mmol) in dichloromethane (3 ml), and then stirred for 4 hours at the same temperature. The progress of the reaction was monitored by TLC. After the reaction was completed, TFA was neutralized with aq.NaHCO3, extracted with 10% MeOH / DCM, dried and concentrated. The obtained solid was ground to give 6,7-dimethoxy-4-(4-sulfamoyl-1,4-diazepan-1-yl)quinoline-3-carboxylic acid ethyl ester 7 compound 023 (250 mg) as a light yellow solid.

[0668] Analyze the data: 1 H NMR(400MHz,DMSO)δ:8.72(s,1H),7.54(s,1H),7.37(s,1H),6.79(s,2H),4.36(q,2H ),3.93(s,6H),3.44-3.43(m,4H),3.42-3.33(m,4H),1.97-1.96(m,2H),1.36(t,3H).

[0669] LCMS: (M+H) + :m / Z:439.2

[0670] Step 5: Synthesis of 6,7-dimethoxy-4-(4-sulfamoyl-1,4-diazepan-1-yl)quinoline-3-carboxylic acid compound 024:

[0671]

[0672] At room temperature, LiOH (119 mg, 2.85 mmol) was added to a stirred solution of ethyl 6,7-dimethoxy-4-(4-sulfamoyl-1,4-diazepan-1-yl)quinoline-3-carboxylate 7 (250 mg, 0.57 mmol) in THF:H2O (3:1). After addition, the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After the reaction was completed, the volatile organic matter was evaporated and triturated with ether to obtain 169 mg of 6,7-dimethoxy-4-(4-sulfamoyl-1,4-diazepan-1-yl)quinoline-3-carboxylic acid 7. 69 mg of 7 was submitted to preparative HPLC. After HPLC purification, the obtained 6,7-dimethoxy-4-(4-sulfamoyl-1,4-diazepan-1-yl)quinoline-3-carboxylic acid compound 024 (26 mg) was a light yellow solid.

[0673] Analyze the data: 1H NMR (400MHz, DMSO) δ: 13.36 (brs, 1H), 8.74 (s, 1H), 7.53 (s, 1H), 7.35 (s, 1H), 6.79 (s.1H), 3.93 (s, 6H), 3.45-3.38 (m, 8H), 1.95 (brs, 2H).

[0674] LCMS: (M+H) + :m / Z:411.2

[0675] Step 6: Synthesis of 6,7-dimethoxy-4-(4-sulfamoyl-1,4-diazepan-1-yl)quinoline-3-carboxamide compound 025:

[0676]

[0677] To a stirred solution of 6,7-dimethoxy-4-(4-sulfamoyl-1,4-diazepan-1-yl)quinoline-3-carboxylic acid 7 (100 mg, 0.24 mmol) in THF (3 ml) was added SOCl2 (0.026 ml, 0.36 mmol) at 0°C. After 1 hour, the reaction mixture was purged with NH3 (gas) for 10 minutes at the same temperature and stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the precipitate in the reaction mixture was washed with 10% MeOH / DCM, and the filtrate was dried and concentrated to give about 85 mg of crude product. After HPLC purification, the obtained 6,7-dimethoxy-4-(4-sulfamoyl-1,4-diazepan-1-yl)quinoline-3-carboxamide compound 025 (9 mg) was a light yellow solid.

[0678] Analyze the data: 1 H NMR(400MHz,DMSO)δ:8.50(s,1H),7.99(brs,1H),7.57(brs,1H),7.46(s,1H),7.33(s,1 H),6.77(s,2H),3.93-3.91(m,6H),3.45-3.42(m,4H),3.37-3.35(m,4H),1.95(brs,2H).

[0679] Synthesis of 4-(6-methoxy-7-(1H-pyrazol-4-yl)quinazolin-4-yl)-1,4-diazepane-1-sulfonamide (Compound 020)

[0680]

[0681] In a sealed tube, a stirred solution of 4-(4-(N-(tert-butyloxycarbonyl)sulfamoyl)-1 was added, 4-diazepan-1-yl)-6-methoxyquinazoline-7-yl trifluoromethylsulfonate 7 (100 mg, 0.171 mmol) was added to dioxane (5 mL) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)-1H-pyrazole-1-carboxylate-1-carboxylate 9 (65 mg, 0.222 mmol) and cesium fluoride (78 mg, 0.513 mmol) in water (1.5 mL) and then the reaction mixture was degassed for 30 minutes. Then tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.0017 mmol) was added for 5 minutes and the reaction mixture was stirred at 90 ° C for 6 hours. The reaction progress was monitored by TLC. After the reaction was completed, the reaction mixture was filtered through diatomaceous earth. The celite bed was washed with ethyl acetate (100 mL). Water (100 mL) was then added and extracted with excess ethyl acetate (100 mL). The organic layer was washed with brine solution (100 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 4-(6-methoxy-7-(1H-pyrazol-4-yl)quinazolin-4-yl)-1,4-diazepane-1-sulfonamide (Compound 020) (10 mg, 0.024 mmol, 15%) as a brown solid.

[0682] Analyze the data: 1 H NMR(400MHz,DMSO)δ13.134(s,1H),8.457(s,1H),8.273(s,1H),8.233(s,1H),7.751(bs,1H),7.405(s,1H) ,6.916(s,1H),6.799(s,1H),3.996-4.042(m,8H),3.534-3.555(t,2H),2.097-2.141(t,2H),2.068(m,2H).

[0683] LCMS: (M+H + ):m / Z:404.2.

[0684] Synthesis of 4-(7-hydroxy-6-methoxyquinazolin-4-yl)-1,4-diazepane-1-sulfonamide hydrochloride (Compound 021)

[0685]

[0686] A stirred solution of tert-butyl ((4-(7-hydroxy-6-methoxyquinazolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate 5 (100 mg, 0.221 mmol) and 4M HCl in dioxane (3 mL) was stirred for 16 hours at room temperature. The progress of the reaction was monitored by TLC. After the reaction was completed, the organic solvent was completely distilled off under reduced pressure. The crude product was purified by preparative HPLC to obtain 4-(7-hydroxy-6-methoxyquinazolin-4-yl)-1,4-diazepan-1-sulfonamide hydrochloride (Compound 021) (600 mg, 1.5 mmol, 70% yield) as an off-white solid.

[0687] Analyze the data: 1 H NMR(400MHz,DMSO)δ14.348(bs,1H),11.608(s,1H),8.693(s,1H),7.415(s,1H),7.245(s,1H),6.842 (s,2H),4.176-4.200(m,4H),3.933(s,3H),3.555-3.580(m,2H),3.275-3.301(t,2H),2.078(m,2H).

[0688] LCMS: (M+H + ):m / Z:354.1.

[0689] Synthesis of 4-(6-methoxyquinazolin-4-yl)-1,4-diazepane-1-sulfonamide (Compound 022)

[0690]

[0691] In a sealed tube, formic acid 9 (0.064 mL, 1.196 mmol) was added to a stirred solution of 4-(4-(N-(tert-butyloxycarbonyl)sulfamoyl)-1,4-diazepan-1-yl)-6-methoxyquinazolin-7-yltrifluoromethanesulfonic acid 7 (100 mg, 0.171 mmol) in N,N'-dimethylformamide (2 mL), and triethylamine (34 mg, 0.342 mmol) was then degassed from the reaction mixture for 30 minutes. Palladium (II) acetate (2 mg, 0.0085 mmol) and Xantphos (5 mg, 0.0085 mmol) were then added again, degassed for 5 minutes and the reaction mixture was stirred at 100 °C for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth. The diatomaceous earth bed was washed with ethyl acetate (100 mL). Water (100 mL) was then added and extracted with excess ethyl acetate (100 mL). The organic layer was washed with brine solution (100 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 4-(6-methoxyquinazolin-4-yl)-1,4-diazepane-1-sulfonamide (Compound 022) (10 mg, 0.024 mmol, 15%) as a brown solid.

[0692] Analyze the data: 1 H NMR (400MHz, DMSO) δ8.444(s,1H),7.704-7.727(d,1H),7.447-7.477(dd,1H),7.310-7.316(d,1H),6.789( s,2H),3.953-4.013(m,4H),3.891(s,3H),3.521-3.534(t,2H),3.268-3.296(t,2H),2.088-2.096(m,2H).

[0693] LCMS: (M+H + ):m / Z:338

[0694] Synthesis scheme of compounds 026 and 027

[0695]

[0696] Synthesis of Compounds of 4-(3,6-diazabicyclo[3.2.1]octan-3-yl)-6,7-dimethoxyquinazoline and 4-(3,6-diazabicyclo[3.2.1]octan-6-yl)-6,7-dimethoxyquinazoline (3 and 3A)

[0697]

[0698] Cesium carbonate (5.6 g, 17.119 mmol) and 3,6-diazabicyclo[3.2.1]octane 2 (900 mg, 4.891 mmol) were added to a stirred solution of 4-chloro-6,7-dimethoxyquinazoline 1 (1 g, 4.891 mmol) in t-BuOH (120 mL), followed by stirring at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was completely distilled off under reduced pressure. The crude product was purified by trituration with ether to give a compound of 4-(3,6-diazabicyclo[3.2.1]octan-3-yl)-6,7-dimethoxyquinazoline and 4-(3,6-diazabicyclo[3.2.1]octan-6-yl)-6,7-dimethoxyquinazoline (3 and 3A) (1.1 g crude product) as a white solid.

[0699] LCMS: (M+H + ):m / Z:301.2

[0700] tert-Butyl ((3-(6,7-dimethoxyquinazolin-4-yl)-3,6-diazabicyclo[3.2.1]octan-6-yl)sulfonyl)carbamate (5) and tert-butyl ((6-(6,7-dimethoxyquinazolin-4-yl)-3,6-diazabicyclo[3.2.1]

[0701] Synthesis of 3-octan-3-yl)sulfonyl)carbamate (5A)

[0702]

[0703] To a stirred solution of 4-(3,6-diazabicyclo[3.2.1]octan-3-yl)-6,7-dimethoxyquinazoline compound and 4-(3,6-diazabicyclo[3.2.1]octan-6-yl)-6,7-dimethoxyquinazoline (3 and 3A) (1.1 g, 3.666 mmol) in dichloromethane (20 ml) were added diisopropylethylamine (0.95 ml, 5.499 mmol) and N-(1-(tert-butyloxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene. e)-N-methylformamide 4 (1.23 g, 3.66 mmol) at 0°C, followed by stirring at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was completely distilled off under reduced pressure to obtain a crude compound. The crude product was purified by 100-200 silica gel column chromatography eluting with 3% methanol in dichloromethane to afford the isomeric tert-butyl((3-(6,7-dimethoxyquinazolin-4-yl)-3,6-diazabicyclo[3.2.1]octan-6-yl)sulfonyl)carbamate (5) (500 mg, 1.041 mmol, 28% yield) and tert-butyl((6-(6,7-dimethoxyquinazolin-4-yl)-3,6-diazabicyclo[3.2.1]octan-3-yl)sulfonyl)carbamate (5A) (150 mg, 0.312 mmol, 8% yield) pure compounds as off-white solids.

[0704] Analyze the data

[0705] Cpd-5: 1 H NMR(400MHz,DMSO)δ8.324(s,1H),8.144(s,1H),6.732-7.616(m,3H),4.853-4.920( dt,1H),4.287-4.351(m,1H),4.127-4.155(d,1H),3.961-3.989(d,1H),3.896(s,7H ),3.588-3.616(d,1H),3.413-3.439(d,1H),3.174-3.199(d,1H),2.886-3.012(dd, 1H),2.713-2.771(m,2H),2.004(m,2H),1.650-1.785(dd,1H),1.117-1.287(d,8H).

[0706] LCMS: (M+H + ):m / Z:480.2

[0707] Cpd-5B: 1H NMR(400MHz,DMSO)δ10.965-10.971(brs,1H),8.700-8.718(d,1H),7.680-7.725 (d,1H),7.211(s,1H),6.793(s,1H),5.027-5.102(d,1H),4.515-4.526(m,1H),4 .026-4.120(d,1H),3.944-3.959(d,6H),3.439-3.575(d,1H),3.102-3.251(m,3 H),2.844-2.942(m,2H),2.045-2.072(m,1H),1.757-1.912(s,1H),1.232(s,5H).

[0708] LCMS: (M+H + ):m / Z:480.2

[0709] Synthesis of 3-(6,7-dimethoxyquinazolin-4-yl)-3,6-diazabicyclo[3.2.1]octane-6-sulfonamide hydrochloride (Compound 026)

[0710]

[0711] A stirred solution of tert-butyl ((3-(6,7-dimethoxyquinazolin-4-yl)-3,6-diazabicyclo[3.2.1]octane-6-yl)sulfonyl)carbamate 5 (100 mg, 0.208 mmol) and 4M HCl in dioxane (4 mL) was stirred for 16 h at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the organic solvent was completely distilled off under reduced pressure. The crude product was purified by trituration with 5% methanol in dichloromethane (50 mL) to give 3-(6,7-dimethoxyquinazolin-4-yl)-3,6-diazabicyclo[3.2.1]octane-6-sulfonamide hydrochloride compound 026 (70 mg, 0.168 mmol, 81% yield) as an off-white solid.

[0712] Analyze the data: 1H NMR(400MHz,DMSO)δ14.287(bs,1H),8.743(s,1H),7.740(s,1H),7.26(s, 1H),6.812(s,2H),5.118(s,1H),4.483-4.536(bs,1H),4.148(s,1H),3.9 66(s,3H),3.971(s,3H),3.826-3.847(d,1H),3.441-3.470(d,1H),2.919 -2.947(d,1H),2.856(brs,2H),2.050-2.077(m,1H),1.768-1.797(d,1H).

[0713] LCMS: (M+H + ):m / Z:380.2

[0714] Synthesis of 6-(6,7-dimethoxyquinazolin-4-yl)-3,6-diazabicyclo[3.2.1]octane-3-sulfonamide hydrochloride (Compound 027)

[0715]

[0716] A stirred solution of tert-butyl ((6-(6,7-dimethoxyquinazolin-4-yl)-3,6-diazabicyclo[3.2.1]octane-3-yl)sulfonyl)carbamate 5A (100 mg, 0.208 mmol) and 4M HCl in dioxane (4 mL) was stirred for 16 h at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the organic solvent was completely distilled off under reduced pressure. The crude product was purified by trituration with 5% methanol in dichloromethane (50 mL) to give 6-(6,7-dimethoxyquinazolin-4-yl)-3,6-diazabicyclo[3.2.1]octane-3-sulfonamide hydrochloride compound 027 (70 mg, 0.168 mmol, 81% yield) as an off-white solid.

[0717] Analyze the data: 1H NMR(400MHz,DMSO)δ14.229(bs,1H),8.724(s,1H),7.733(s,1H),7.243( s,1H),6.802(s,2H),5.111(s,1H),4.498(bs,1H),4.113-4.116(d,1H), 3.971(s,6H),3.832-3.854(d,1H),3.444-3.469(d,1H),2.919-2.946(d ,1H),2.825-2.853(brs,2H),2.046-2.074(m,1H),1.764-1.793(d,1H).

[0718] LCMS: (M+H + ):m / Z:380.1

[0719] Synthesis scheme of compound 028

[0720] Synthesis of 4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepane-1-sulfonamide (Compound 028)

[0721]

[0722] 2-Chloro-2,2-difluoroacetic acid, sodium salt (335 mg, 2.207 mmol), cesium carbonate (719 mg, 2.205 mmol) and cesium carbonate (719 mg, 2.205 mmol) were added to a stirred solution of tert-butyl (4-(7-hydroxy-6-methoxyquinazolin-4-yl)-1,4-diazepane-1-sulfonyl)carbamate 1 (200 mg, 0.441 mmol) in N,N'-dimethylformamide (5 mL) and water (5 mL), and the reaction mixture was stirred at 100 °C for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, water (100 mL) was added to the reaction mixture and extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with brine solution (100 mL), dried over sodium sulfate and concentrated under reduced pressure to give a crude product. The crude product was purified by preparative HPLC to obtain 4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepane-1-sulfonamide (Compound 028) (10 mg, 0.027 mmol, 5%) as an off-white solid.

[0723] Analyze the data: 1H NMR(400MHz,DMSO)δ8.460(s,1H),7.425-7.470(m,3H),6.796(s,2H),3.979-4.0 01(m,4H),3.959(s,3H),3.509-3.535(t,2H),3.261-3.289(t,2H),2.084(m,2H).

[0724] LCMS: (M+H + ):m / Z:404.1

[0725] Synthesis scheme of compound 029

[0726]

[0727] Synthesis of 4-(6,6-difluoro-1,4-diazepan-1-yl)-6,7-dimethoxyquinazoline (3)

[0728]

[0729] To a stirred solution of 4-chloro-6,7-dimethoxyquinazoline 1 (160 mg, 0.695 mmol) in tert-butyl alcohol (25 mL) was added potassium carbonate (288 mg, 2.085 mmol) and 6,6-difluoro-1,4-diazepane 2 (218 mg, 1.043 mmol), followed by stirring at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was completely distilled off under reduced pressure. 10% methanol in dichloromethane was added to the crude product and filtered. The filtrate was concentrated under reduced pressure to give 4-(6,6-difluoro-1,4-diazepane-1-yl)-6,7-dimethoxyquinazoline (3) (180 mg, crude product) as an off-white solid.

[0730] LCMS: (M+H + ):m / Z:325.2

[0731] Synthesis of tert-butyl ((4-(6,7-dimethoxyquinazolin-4-yl)-6,6-difluoro-1,4-diazepan-1-yl)sulfonyl)carbamate (5)

[0732]

[0733] Diisopropylethylamine (90 mg, 0.694 mmol) and N-(1-(N-(tert-butyloxycarbonyl)sulfamoyl)pyridine-4(1H)-ylidene)-N-methylformamide 4 (171 mg, 0.509 mmol) were added to a stirred solution of 4-(6,6-difluoro-1,4-diazepan-1-yl)-6,7-dimethoxyquinazoline (3) (150 mg, 0.463 mmol) in dichloromethane (5 ml) at 0°C, followed by stirring at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was completely distilled off under reduced pressure to obtain a crude compound. The crude product was purified by 100-200 combi-flash chromatography eluting with 3% methanol in dichloromethane to afford tert-butyl ((4-(6,7-dimethoxyquinazolin-4-yl)-6,6-difluoro-1,4-diazepan-1-yl)sulfonyl)carbamate (5) (200 mg, 0.397 mmol, 86% yield) as an off-white solid.

[0734] LCMS: (M+H + ):m / Z:504.2

[0735] Synthesis of 4-(6,7-dimethoxyquinazolin-4-yl)-6,6-difluoro-1,4-diazepane-1-sulfonamide hydrochloride (Compound 029)

[0736]

[0737] A stirred solution of tert-butyl ((4-(6,7-dimethoxyquinazolin-4-yl)-6,6-difluoro-1,4-diazepan-1-yl)sulfonyl)carbamate 5 (170 mg, 0338 mmol) and 4M HCl in dioxane (10 mL) was stirred for 16 hours at room temperature. The progress of the reaction was monitored by TLC. After the reaction was completed, the organic solvent was completely distilled off under reduced pressure. The crude product was purified by trituration with 5% methanol in dichloromethane (5 mL) to give 4-(6,7-dimethoxyquinazolin-4-yl)-6,6-difluoro-1,4-diazepan-1-sulfonamide hydrochloride compound 029 (20 mg, 0.045 mmol, 13% yield) as an off-white solid.

[0738] Analyze the data: 1H NMR(400MHz,DMSO)δ8.558(s,1H),7.251(s,1H),7.181(s,1H),7.098(s,2H),4.388-4.4 56(t,2H),3.935(s,6H),3.878-3.903(t,3H),3.789-3.822(d,2H),3.720-3.755(m,2H).

[0739] LCMS: (M+H + ):m / Z:404.22

[0740] Synthesis scheme of compound 030

[0741]

[0742] Synthesis of 4-(1,4-diazepan-1-yl)-6,7-dimethoxyquinoline (3)

[0743]

[0744] To a stirred solution of 4-chloro-6,7-dimethoxyquinoline 1 (2 g, 8.9686 mmol) in ethanol (20 ml) was added potassium carbonate (2.4 g, 17.9372 mmol) and 1,4-diazepane 2 (2.7 g, 26.9058 mmol), followed by stirring at 90°C for 4 days. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was completely distilled off under reduced pressure. 10% methanol in dichloromethane was added to the crude product and filtered. The filtrate was concentrated under reduced pressure to give 4-(1,4-diazepane-1-yl)-6,7-dimethoxyquinoline (3) (1 g) in the form of an off-white solid.

[0745] Analyze the data:

[0746] LCMS: (M+H + ):m / Z:288.2.

[0747] Synthesis of tert-butyl ((4-(6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate (5)

[0748]

[0749] To a stirred solution of 4-(1,4-diazepan-1-yl)-6,7-dimethoxyquinoline (3) (150 mg, 0.0522 mmol) in dichloromethane (5 mL) at 0°C, diisopropylethylamine (0.13 mL, 0.7839 mmol) and N-(1-(N-(tert-butyloxycarbonyl)sulfamoyl)pyridine-4(1H)-ylidene)-N-methylformamide 4 (176 mg, 0.0522 mmol) were added, followed by stirring at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was completely distilled off under reduced pressure to obtain a crude compound. The crude product was purified by 100-200 combi-flash chromatography eluting with 3% methanol in dichloromethane to afford tert-butyl ((4-(6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate (5) (100 mg, 41% yield) as an off-white solid.

[0750] Analyze the data:

[0751] LCMS: (M+H + ):m / Z:466.13

[0752] Synthesis of 4-(6,7-dimethoxyquinolin-4-yl)-1,4-diazepane-1-sulfonamide (Compound 030)

[0753]

[0754] A stirred solution of tert-butyl ((4-(6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate 5 (90 mg, 0.1931 mmol) and 4M HCl in dioxane (5 mL) was stirred for 16 hours at room temperature. The progress of the reaction was monitored by TLC. After the reaction was completed, the organic solvent was completely distilled off under reduced pressure. The crude product was purified by trituration with 5% methanol in dichloromethane (5 mL) to give 4-(6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-sulfonamide compound 030 (40 mg, 57% yield) as an off-white solid.

[0755] Analyze the data: 1 H NMR (400MHz, DMSO) δ8.42(d,1H),7.40(s,1H),7.35(s,1H),6.98(d,1H),6.86(s,2H),3.94-3.99(m,10H),3.56(t,2H),2.13(s,2H).

[0756] LCMS: (M+H + ):m / Z:367.28

[0757] Synthesis scheme of compound 031

[0758]

[0759] Synthesis of 4-(1,4-diazepan-1-yl)-6,7-dimethoxy-2-(trifluoromethyl)quinazoline (3)

[0760]

[0761] To a stirred solution of 4-chloro-6,7-dimethoxy-2-(trifluoromethyl)quinazoline 1 (150 mg, 0.512 mmol) in tert-butyl alcohol (10 ml) was added potassium carbonate (71 mg, 0.512 mmol) and 1,4-diazepane 2 (102 mg, 1.025 mmol), followed by stirring at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was completely distilled off under reduced pressure. 10% methanol in dichloromethane was added to the crude product and filtered. The filtrate was concentrated under reduced pressure to give 4-(1,4-diazepane-1-yl)-6,7-dimethoxy-2-(trifluoromethyl)quinazoline (3) (170 mg, crude product) as an off-white solid.

[0762] Analyze the data: 1 H NMR (400MHz, DMSO) δ7.380(s,1H),7.312(s,1H),3.903-3.969(m,10H),3.044-3.069(t,2H),2.793-2.820(t,2H),1.947(bs,2H).

[0763] Synthesis of tert-butyl ((4-(6,7-dimethoxy-2-(trifluoromethyl)quinazolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate (5)

[0764]

[0765] To a stirred solution of 4-(1,4-diazepan-1-yl)-6,7-dimethoxy-2-(trifluoromethyl)quinazoline (3) (150 mg, 0.421 mmol) in dichloromethane (5 ml) at 0°C, diisopropylethylamine (81 mg, 0.632 mmol) and N-(1-(N-(tert-butyloxycarbonyl)sulfamoyl)pyridine-4(1H)-ylidene)-N-methylformamide 4 (142 mg, 0.421 mmol) were added, followed by stirring at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was completely distilled off under reduced pressure to obtain a crude compound. The crude product was purified by 100-200 combi-flash chromatography eluting with 3% methanol in dichloromethane to afford tert-butyl ((4-(6,7-dimethoxy-2-(trifluoromethyl)quinazolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate (5) (190 mg, 0.355 mmol, 84% yield) as an off-white solid.

[0766] Analyze the data: 1 H NMR(400MHz,DMSO)δ11.094(bs,1H),7.330(d,2H),4.009-4.019(m,4H),3.940(s,3 H),3.924(s,3H),3.699-3.712(t,3H),3.435(t,2H),2.072(bs,2H),1.343(s,9H).

[0767] Synthesis of 4-(6,7-dimethoxy-2-(trifluoromethyl)quinazolin-4-yl)-1,4-diazepane-1-sulfonamide hydrochloride (Compound 031)

[0768]

[0769] A stirred solution of tert-butyl ((4-(6,7-dimethoxy-2-(trifluoromethyl)quinazolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate 5 (160 mg, 0299 ​​mmol) and 4M HCl in dioxane (10 mL) was stirred for 16 hours at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the organic solvent was completely distilled off under reduced pressure. The crude product was purified by trituration with 5% methanol in dichloromethane (5 mL) to give 4-(6,7-dimethoxy-2-(trifluoromethyl)quinazolin-4-yl)-1,4-diazepan-1-sulfonamide hydrochloride compound 031 (100 mg, 0.212 mmol, 71% yield) as an off-white solid.

[0770] Analyze the data: 1H NMR(400MHz,DMSO)δ7.340(s,1H),6.802(bs,2H),3.992-4.040(m,4H),3.939(s,3 H),3.924(s,3H),3.516-3.556(t,2H),3.261-3.289(t,2H),2.063-2.090(m,2H).

[0771] LCMS: (M+H + ):m / Z:436.33

[0772] Overall Plan 6:

[0773]

[0774] Example 6: (N-(2-(4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-yl)ethyl)sulfonamide hydrochloride

[0775] Step 1A: 2-(4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-yl)acetonitrile

[0776]

[0777] To a stirred solution of 4-(1,4-diazepan-1-yl)-6,7-dimethoxyquinazoline 1 (1 g, 3.472 mmol) in N,N'-dimethylformamide (10 ml) was added potassium carbonate (1.4 g, 10.416 mmol) and 2-bromoacetonitrile (0.83 g, 6.944 mmol), followed by stirring at 90 °C for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was completely distilled off under reduced pressure. The crude product was purified by combi-flash chromatography by eluting 80% ethyl acetate in petroleum ether to give 2-(4-(6,7-dimethoxyquinazoline-4-yl)-1,4-diazepan-1-yl)acetonitrile 2 (0.93 g, 2.844 mmol, 68% yield) as a light brown solid.

[0778] Analytical data: 1H NMR (400MHz, DMSO) δ8.40 (s, 1H), 7.27 (s, 1H), 7.14 (s, 1H), 3.87 (s, 3H), 3.90 (s, 3H), 3.94-3.92 (m, 4H), 3.79 (s, 2H), 2.93 (t, 2H), 2.69-2.66 (m, 2H), 2.05-2.04 (m, 2H). LCMS: (M+H+): m / Z: 328.2

[0779] Step 1B: 3-(4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-yl)propanenitrile

[0780]

[0781] To a stirred solution of 4-(1,4-diazepan-1-yl)-6,7-dimethoxyquinazoline 1 (1 g, 3.472 mmol) in ethanol (15 ml) was added acrylonitrile (0.68 ml, 10.416 mmol), followed by stirring at 45 °C for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was completely distilled off under reduced pressure. The crude product was purified by combi-flash chromatography by eluting with 5% methanol in dichloromethane to give 3-(4-(6,7-dimethoxyquinazoline-4-yl)-1,4-diazepan-1-yl)propionitrile 3 (1 g, 2.932 mmol, 85% yield) as a reddish colloidal liquid.

[0782] Analytical data: 1H NMR (400MHz, DMSO) δ8.36 (s, 1H), 7.26 (s, 1H), 7.13 (t, 2H), 3.89-3.85 (m, 10H), 2.96-2.94 (m, 2H), 2.74-2.69 (m, 4H), 2.65-2.62 (m, 2H), 2.00 (m, 2H). LCMS: (M+H)+: m / Z: 342.2

[0783] Step 2: 2-(4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-yl)ethan-1-amine

[0784]

[0785] To a stirred solution of 2-(4-(6,7-dimethoxyquinazoline-4-yl)-1,4-diazepan-1-yl)acetonitrile 2 (900 mg, 2752 mmol) in 1,4-dioxane (18 mL) and water (10 mL) was added lithium hydroxide monohydrate (231 mg, 5504 mmol), Raney nickel (936 mg) and 10% palladium / carbon (295 mg), and the reaction mixture was stirred at room temperature under a balloon hydrogen atmosphere for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was filtered through diatomaceous earth and the diatomaceous earth bed was washed with dichloromethane (100 mL) containing 10% methanol. The filtrate was concentrated under reduced pressure to obtain a crude compound. The crude product was purified by Grace reverse phase column chromatography eluting with 20% acetonitrile in 0.1% formic acid in water to give 2-(4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-yl)ethan-1-amine 3 (100 mg, 0.302, 11%) as a reddish brown gummy liquid.

[0786] Analytical data: LCMS: (M+H+): m / Z: 332.24

[0787] The following compounds were synthesized by the general procedure described above:

[0788]

[0789] Step 3: tert-Butyl (N-(2-(4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-yl)ethyl)sulfamoyl)carbamate

[0790]

[0791] To a stirred solution of 2-(4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-ylethane-1-ethane-1-amine 3 (100 mg, 0.302 mmol) in dichloromethane (5 ml) at 0°C, diisopropylethylamine (60 mg, 0.453 mmol) and N-(1-(N-(tert-butyloxycarbonyl)sulfamoyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylformamide chloride 4 (102 mg, 0.302 mmol) were added, followed by stirring at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was completely distilled off under reduced pressure to obtain a crude compound. The crude product was purified by combi-flash column chromatography eluting with 5% methanol in dichloromethane to afford tert-butyl (N-(2-(4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-yl)ethyl)sulfamoyl)carbamate 5 (90 mg, 0.176 mmol, 58% yield) as a brown solid.

[0792] Analytical data: 1H NMR (400MHz, DMSO) δ8.37 (s, 1H), 7.26 (s, 1H), 7.18 (m, 1H), 7.14 (s, 1H), 3.89-3.87 (d, 10H), 3.00-2.97 (m, 4H), 2.75-2.68 (m, 2H), 2.66-2.62 (m, 2H), 2.04-2.01 (m, 2H), 1.39 (s, 9H). LCMS: (M+H+): m / Z: 511.21

[0793] The following compounds were synthesized by the above general procedure

[0794]

[0795] Step 4: (N-(2-(4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-yl)ethyl)sulfonamide hydrochloride (Compound 063)

[0796]

[0797] To a stirred solution of tert-butyl (N-(2-(4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-yl)ethyl)sulfamoyl)carbamate 5 (90 mg, 0.176 mmol) in dioxane (2 ml) at 0°C, 4M HCl was added to dioxane (8 ml), followed by stirring at room temperature for 6 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the organic solvent was completely distilled off under reduced pressure. The crude product was purified by preparative HPLC to give (N-(2-(4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-yl)ethyl)sulfamoyl)carbamate hydrochloride (15 mg, 0.036 mmol, 72% yield) as an off-white solid.

[0798] Analytical data: 1H NMR (400MHz, DMSO) δ8.38 (s, 1H), 7.26 (s, 1H), 7.14 (s, 1H), 6.56 (brs, 2H), 6.26-6.27 (brs, 1H), 3.90-3.87 (m, 10H), 2.99-96 (m, 4H), 2.03 (m, 2H). LCMS: (M+H+): m / Z: 411.2

[0799]

[0800] Compound 062 was also prepared based on the general procedure above:

[0801]

[0802] 1H NMR(400MHz,DMSO)δ8.38(s,1H),7.26(s,1H),7.14(s,1H),6.56(brs,2H),6.26-6.27(brs,1H),3.90 -3.87(m,10H),2.99-96(m,4H),2.03(m,2H). LCMS 411.2. MW446.95.

[0803] Synthesis scheme of compound 032

[0804]

[0805] Synthesis of 4-(4-(2-(1,3-dioxoisoquinolin-2-yl)ethyl)-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile (3)

[0806]

[0807] Potassium carbonate (662 mg, 4.8 mmol) and 2-(2-bromoethyl)isoindoline-1,3-dione 2 (610 mg, 1.76 mmol) were added to a stirred solution of 4-(1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile hydrochloride 1 (500 mg, 1.6 mmol) in DMF (5 ml), and then stirred at 90 ° C for 16 hours. The reaction progress was monitored by TLC. After the reaction was completed, the reaction mixture was poured on water and extracted with ethyl acetate. The organic layer was separated and washed with water, and then the organic layer was concentrated under reduced pressure to obtain a crude product. The crude residue was purified by combi-flash chromatography to give the pure compound 4-(4-(2-(1,3-dihydroisoquinolin-2-yl)ethyl)-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile (3) (300 mg, 0.618 mmol, 38% yield) as brown syrup.

[0808] LCMS: (M+H) + :m / Z:486.2

[0809] Synthesis of 4-(4-(2-aminoethyl)-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile (4)

[0810]

[0811] To a stirred solution of 4-(4-(2-aminoethyl)-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile 3 (300 mg, 0.61 mmol) in EtOH (6 mL) was added 90% hydrazine hydrate (0.06 mL, 1.23 mmol) at room temperature, and the reaction mixture was stirred at reflux for 2 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was poured onto water and extracted with ethyl acetate. The organic layer was separated and washed with water, and the organic layer was concentrated under reduced pressure to obtain a crude product. The crude compound was purified by combi-flash chromatography to obtain the pure compound 4-(4-(2-aminoethyl)-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile (4) (100 mg, 0.281 mmol, 45% yield) as brown syrup.

[0812] LCMS: (M+H) + :m / Z:356.3

[0813] Synthesis of tert-butyl (N-(2-(4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepane-1-yl)ethyl)sulfamoyl)carbamate (6)

[0814]

[0815] To a stirred solution of 4-(4-(2-(2-aminoethyl)-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile (4) (100 mg, 0.28 mmol) in dichloromethane (2 mL) at room temperature, diisopropylethylamine (0.146 mL, 0.84 mmol) and N-(1-(N-(tert-butyloxycarbonyl)sulfamoyl)sulfamoyl)pyridine-4(1H)-ylidene)-N-methylformamide 5 (95 mg, 0.28 mmol) were added, followed by stirring at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the organic solvent was completely distilled off under reduced pressure to obtain a crude compound. The crude compound was purified by combined flash column chromatography eluting with 5% MeOH in DCM to afford tert-butyl (N-(2-(4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)ethyl)sulfamoylcarbamate (6) (80 mg, 0.225 mmol, 53% yield) as a brown thick syrup.

[0816] LCMS: (M+H) + :m / Z:535.19

[0817] Synthesis of Compound 032

[0818]

[0819] To a stirred solution of tert-butyl (N-(2-(4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)ethyl)sulfamoylcarbamate (6) (80 mg, 0.182 mmol) in 1,4-dioxane (1.0 mL) at room temperature was added 4 M HCl to dioxane (2 mL). The reaction mixture was stirred at room temperature for 6 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the organic solvent was completely distilled off under reduced pressure to obtain a crude compound. The crude compound was purified by preparative HPLC method to obtain a pure compound of compound 032 (15 mg, 0.034 mmol, 23% yield) as an off-white solid.

[0820] Analyze the data: 1 H NMR(400MHz,DMSO)δ8.62(s,1H),8.17(s,1H),7.37(s,2H),6.57(brs,2H),6.30(t,1H),3.94(d, 6H),3.71-3.7(m,4H),3.0-3.05(m,2H),2.84-2.89(m,4H),2.67-2.71(m,2H),1.98-2.01(m,2H).

[0821] LCMS: (M+H) + :m / Z:435.2

[0822] Synthesis scheme of compound 033

[0823]

[0824] Synthesis of 4-(4-(3-(1,3-dioxoisoquinolin-2-yl)propyl)-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile (3)

[0825]

[0826] Potassium carbonate (662 mg, 4.8 mmol) and 2-(3-bromopropyl)isoindoline-1,3-dione 2 (515 mg, 1.9 mmol) were added to a stirred solution of 4-(1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile hydrochloride 1 (500 mg, 1.6 mmol) in DMF (5 mL), and then stirred at 90 ° C for 16 hours. The reaction progress was monitored by TLC. After the reaction was completed, the reaction mixture was poured on water and extracted with ethyl acetate. The organic layer was separated and washed with water, and then the organic layer was concentrated under reduced pressure to obtain a crude product. The crude residue was purified by combi-flash chromatography to give the pure compound 4-(4-(3-(1,3-dihydroisoquinolin-2-yl)propyl)-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile 3 (150 mg, 0.30 mmol, 19% yield) as brown syrup.

[0827] LCMS: (M+H) + :m / Z:500.34

[0828] Synthesis of 4-(4-(3-aminopropyl)-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile (4)

[0829]

[0830] To a stirred solution of 4-(4-(3-(1,3-dihydroisoquinolin-2-yl)propyl)-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile 3 (150 mg, 0.3 mmol) in EtOH (3 mL) was added 90% hydrazine hydrate (0.03 mL, 0.6 mmol) at room temperature, and the reaction mixture was stirred at reflux for 4 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured onto water and extracted with ethyl acetate. The organic layer was separated and washed with water, and the organic layer was concentrated under reduced pressure to obtain a crude product. The crude compound was purified by combi-flash chromatography to obtain the pure compound 4-(4-(3-aminopropyl)-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile (4) (100 mg, 0.271 mmol, 90% yield) as brown syrup.

[0831] LCMS: (M+H) + :m / Z:370.2

[0832] Synthesis of tert-butyl (N-(3-(4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)propyl)sulfamoylcarbamate (6)

[0833]

[0834] To a stirred solution of 4-(4-(3-(3-aminopropyl)-1,4-diazepanazine-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile (4) (100 mg, 0.27 mmol) in dichloromethane (2 ml) at room temperature, diisopropylethylamine (0.14 ml, 0.81 mmol) and N-(1-(N-(tert-butyloxycarbonyl)sulfamoyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylformamide 5 (91 mg, 0.27 mmol) were added, followed by stirring at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the organic solvent was completely distilled off under reduced pressure to obtain a crude compound. The crude compound was purified by combined flash column chromatography eluting with 5% MeOH in DCM to afford tert-butyl (N-(3-(4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)propyl)sulfamoylcarbamate (6) (100 mg, 0.182 mmol, 67% yield) as a brown solid.

[0835] LCMS: (M+H) + :m / Z:549.31

[0836] Synthesis of compound 033

[0837]

[0838] To a stirred solution of tert-butyl (N-(3-(4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)propyl)sulfamoylcarbamate (6) (100 mg, 0.182 mmol) in 1,4-dioxane (2.0 ml) at room temperature was added 4M HCl to dioxane (2 mL). The reaction mixture was stirred at room temperature for 6 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the organic solvent was completely distilled off under reduced pressure to obtain a crude compound. The crude compound was purified by preparative HPLC method to obtain a pure compound of compound 033 (10 mg, 0.022 mmol, 12% yield) as an off-white solid.

[0839] Analyze the data: 1H NMR (400MHz, DMSO) δ8.60(s,1H),7.30(s,1H),7.36(s,2H),6.47-6.53(m,3H),3.90(d,6H),3.70-3. 72(m,4H),2.90-2.95(m,2H),2.78-2.81(m,4H),2.54-2.57(m,2H),1.98(m,2H),1.61-1.68(m,2H).

[0840] LCMS: (M+H) + :m / Z:449.2

[0841] Overall Plan 7:

[0842]

[0843]

[0844] Example 7: (N-(2-(4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-yl)-2-oxoethyl)sulfonamide hydrochloride

[0845] Step 1: Synthesis of tert-butyl (2-(4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-yl)-2-oxoethyl)carbamate

[0846]

[0847] At room temperature, dibenzo[UNK] (0.85 mL, 4.83 mmol), TBTU (531 mg, 1.65 mmol) and (tert-butyloxycarbonyl)glycine (267 mg, 1.52 mmol) were added to a stirred solution of 4-(1,4-diazepan-1-yl)-6,7-dimethoxyquinazoline (400 mg, 1.38 mmol) in DMF (5 ml). The reaction mixture was stirred for 16 hours. After the reaction was completed, the reaction mixture was poured onto water and extracted with ethyl acetate. The organic layer was separated, washed with water, and the organic layer was concentrated under reduced pressure to obtain a compound of pure tert-butyl (2-(4-(6,7-dimethoxyquinazoline-4-yl)-1,4-diazepan-1-yl)-2-oxoethyl)carbamate 20 (410 mg, 0.921 mmol, 66% yield) as a brown solid. 1H NMR (400MHz, DMSO) δ8.41(d,1H),7.21(d,1H),7.16(d,1H),6.72-6.69(m,1H),3.96-3. 87(m,10H),3.80-3.76(m,4H),3.56-3.55(m,2H),2.05-1.93(m,2H),1.36-1.33(m,9H). LCMS:(M+H)+:m / Z:446.26

[0848] The following compounds were synthesized by the general procedure described above:

[0849]

[0850]

[0851] Step 2: 2-amino-1-(4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-yl)ethan-1-one hydrochloride

[0852]

[0853] To a stirred solution of tert-butyl (2-(4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-yl)-2-oxoethyl)carbamate (3) (300 mg, 0.674 mmol) in dioxane (1 ml) at room temperature was added 4 M hydrochloric acid (3 ml), followed by stirring at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the organic solvent was distilled off under reduced pressure to give 2-amino-1-(4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-yl)ethane-1-hydrochloride (4) (250 mg, 0.656 mmol, 91% yield) as a brown solid.

[0854] Analytical data: 1H NMR (400 MHz, DMSO) δ 15.07 (brs, 1H), 8.77-8.78 (d, 1H), 8.10 (brs, 3H), 7.47-7.41 (m, 2H), 4.28-4.19 (m, 4H), 4.00-3.84 (m, 13H), 3.66-3.64 (m, 1H), 2.00-2.10 (m, 2H).

[0855]

[0856] Step 3: tert-Butyl (N-(2-(4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepanylcyclopropane-1-yl)-2-oxoethyl)sulfamoyl)carbamate

[0857]

[0858] To a stirred solution of 2-amino-1-(4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepanecyclopropane-1-yl)ethan-1-one hydrochloride (4) (250 mg, 0.724 mmol) in dichloromethane (20 ml) at room temperature, diisopropylethylamine (0.631 mL, 3.62 mmol) and N-(1-(N-(tert-butyloxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylformamide chloride 4 (293 mg, 0.869 mmol) were added, followed by stirring at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the organic solvent was completely distilled off under reduced pressure to obtain a crude compound. The crude compound was purified by eluting with 5% methanol in DCM to afford tert-butyl (N-(2-(4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-yl)-2-oxoethyl)sulfamoyl)carbamate 6 (200 mg, 0.381 mmol, 52% yield) as a brown solid. LCMS: (M+H)+: m / Z: 525.2

[0859]

[0860] Step 4: (N-(2-(4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-yl)-2-oxoethyl)sulfonamide hydrochloride (Compound 064)

[0861]

[0862] To a stirred solution of tert-butyl (N-(2-(4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-yl)-2-oxoethyl)sulfamoyl)carbamate 6 (200 mg, 0.381 mmol) in 1,4-dioxane (1.0 ml) at room temperature was added 4M HCl to dioxane (3 mL). The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, the organic solvent was completely distilled off under reduced pressure to obtain a crude compound. The crude compound was purified by preparative HPLC method to obtain the pure compound (N-(2-(4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-yl)-2-oxoethyl)sulfamoyl)carbamate hydrochloride (50 mg, 0.117 mmol, 31% yield) as an off-white solid.

[0863] Analytical data: 1H NMR (400MHz, DMSO) δ8.42 (d, 1H), 7.22-7.21 (d, 1H), 7.16 (d, 1H), 6.59-6.55 (m, 2H), 6.15-6.14 (m, 1H), 3.98-3.97 (m, 1H), 3.90-3.88 (m, 10H), 3.82-3.78 (m, 3H), 3.76-3.75 (m, 1H), 3.57-3.56 (m, 2H), 2.10-1.95 (m, 2H). LCMS: (M+H)+: m / Z: 425.2

[0864]

[0865] Compound 065 was also prepared based on the above general synthesis method:

[0866]

[0867] 1H NMR(400MHz,DMSO)δ15.07(brs,1H),8.77-8.78(d,1H),8.10(brs,3H),7.47-7.41( m,2H),4.28-4.19(m,4H),4.00-3.84(m,13H),3.66-3.64(m,1H),2.00-2.10(m,2H). LCMS 425.2.MW.460.93

[0868] Synthesis scheme of compound 034

[0869]

[0870] Synthesis of tert-butyl (2-(4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)-2-oxoethyl)carbamate (3)

[0871]

[0872] At room temperature, DIPEA (0.335 mL, 1.923 mmol), TBTU (247 mg, 0.769 mmol) and (tert-butyloxycarbonyl) glycine (123 mg, 0.705 mmol) were added to a stirred solution of 4-(1,4-diazepane-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile hydrochloride 1 (200 mg, 0.641 mmol) in DMF (4 mL). The reaction mixture was stirred for 16 hours. After the reaction was completed, the reaction mixture was poured onto water and extracted with ethyl acetate. The organic layer was separated and washed with water, and then the organic layer was concentrated under reduced pressure to obtain a crude product. The crude compound was purified by combi-flash chromatography to afford tert-butyl (2-(4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)-2-oxoethyl)carbamate (3) (200 mg, 0.426 mmol, 66% yield) as a yellow solid.

[0873] Analytical data: 1H NMR (400 MHz, DMSO) δ8.69 (s, 1H), 7.94 (s, 1H), 7.4 (d, 1H), 7.26 (s, 1H), 6.73-6.77 (m, 1H), 4.02-4.00 (m, 8H), 3.80-3.81 (m, 2H), 3.71 (m, 2H), 3.57 (m, 2H), 3.47-3.48 (m, 1H), 2.8 (s, 2H), 2.1 (m, 2H), 1.38 (s, 9H).

[0874] Synthesis of 4-(4-glycyl-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile hydrochloride (4)

[0875]

[0876] To a stirred solution of tert-butyl (2-(4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)-2-oxoethyl)carbamate 3 (300 mg, 0.639 mmol) in dioxane (2 ml) at 0°C, 4M HCl was added to dioxane (3 ml), followed by stirring at room temperature for 6 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the organic solvent was completely distilled off under reduced pressure. The crude residue was washed with ether to give 4-(4-glycyl-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile hydrochloride 4 (250 mg, 0.677 mmol, 96% yield) as a yellow solid.

[0877] LCMS: (M+H) + :m / Z:370.2

[0878] Synthesis of tert-butyl (N-(2-(4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)-2-oxoethyl)sulfamoyl)carbamate (6))

[0879]

[0880] To a stirred solution of 4-(4-glycyl-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile hydrochloride (4) (250 mg, 0.677 mmol) in dichloromethane (20 vol) at room temperature, diisopropylethylamine (0.354 mL, 2.03 mmol) and N-(1-(N-(tert-butyloxycarbonyl)sulfamoyl)pyridine-4(1H)-ylidene)-N-methylformamide 5 (251 mg, 0.745 mmol) were added, followed by stirring at room temperature for 16 hours. The reaction progress was monitored by TLC. After the reaction was completed, the organic solvent was completely distilled off under reduced pressure to obtain a crude compound. The crude compound was purified by eluting with 60% ethyl acetate in petroleum ether to afford tert-butyl (N-(2-(4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)-2-oxoethyl)sulfamoyl)carbamate (6) (200 mg, 0.364 mmol, 54% yield) as a light yellow solid.

[0881] LCMS: (M+H) + :m / Z:549.34

[0882] Preparation of Compound 034

[0883]

[0884] To a stirred solution of tert-butyl ((4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate (6) (100 mg, 0.203 mmol) in 1,4-dioxane (2.0 mL) at room temperature was added 4M HCl to dioxane (2.0 mL). The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the organic solvent was completely distilled off under reduced pressure to obtain a crude compound. The crude compound was purified by preparative HPLC to obtain pure compound 034 (35 mg, 0.089 mmol, 41% yield) as a light yellow solid.

[0885] Analytical data: 1H NMR (400 MHz, DMSO) δ8.67-8.7 (d, 1H), 7.39-7.40 (d, 1H), 7.26 (s, 1H), 6.62 (d, 2H), 6.14-6.15 (m, 1H), 3.92-3.94 (s, 6H), 3.83 (m, 2H), 3.67-3.77 (m, 3H), 3.50-3.59 (m, 3H), 2.06-2.08 (m, 2H).

[0886] LCMS: (M+H) + :m / Z:449.2

[0887] Synthesis scheme of compound 035

[0888]

[0889] Synthesis of tert-butyl 4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepane-1-carboxylic acid (3)

[0890]

[0891] Potassium carbonate (1.45g, 10.44mmol) and tert-butyl 1,4-diazacycloheptane-1-carboxylate 2 (1.57g, 7.84mmol) were added to a stirred solution of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile 1 (1.3g, 5.22mmol) in DMF (26mL), and then stirred at 80°C for 16 hours. The reaction progress was monitored by TLC. After the reaction was completed, water (100mL) was added to the reaction mixture and extracted with ethyl acetate (2X100 mL). The combined organic layer was washed with a saline solution (100mL), dried over sodium sulfate and concentrated under reduced pressure, and the compound obtained was pure 4- (3-cyano-6,7-dimethoxyquinoline-4-yl) -1,4-diazacycloheptane-1-carboxylic acid tert-butyl ester (1.5g, 3.64mmol, 69% yield) as a white solid.

[0892] LCMS: (M+H)+: m / Z: 413.2

[0893] Synthesis of 4-(1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile hydrochloride (4)

[0894]

[0895] To a stirred solution of tert-butyl 4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepane-1-carboxylate 3 (450 mg, 1.09 mmol) in dioxane (2 mL) at 0 ° C, 4M HCl was added to dioxane (3 mL), and then stirred at room temperature for 4 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the organic solvent was completely distilled off under reduced pressure. The crude residue was washed with ether to obtain 4-(1,4-diazepane-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile hydrochloride 4 (400 mg, 1.28 mmol, 92% yield) as a yellow solid.

[0896] LCMS: (M+H) + :m / Z:313.31

[0897] Synthesis of tert-butyl (3-(4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)-3-oxopropyl) carbamate (6)

[0898]

[0899] At room temperature, DIPEA (0.16ml, 0.96mmol), TBTU (124mg, 0.38mmol) and 3-(tert-butyloxycarbonyl)amino) propionic acid (66mg, 0.35mmol) were added to a stirred solution of 4-(1,4-diazepane-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile hydrochloride 4 (100mg, 0.32mmol) in DMF (2ml). The reaction mixture was stirred for 16 hours. After the reaction was completed, the reaction mixture was poured onto water and extracted with ethyl acetate. The organic layer was separated and washed with water, and then the organic layer was concentrated under reduced pressure to obtain a crude product. The crude compound was purified by combi-flash chromatography to afford tert-butyl(3-(4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)-3-oxopropyl)carbamate (6) (100 mg, 0.154 mmol, 66% yield) as a light brown solid.

[0900] LCMS: (M+H)+ :m / Z:484.3

[0901] Synthesis of 4-(4-(3-aminopropionyl)-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile hydrochloride (7)

[0902]

[0903] To a stirred solution of tert-butyl (3-(4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)-3-oxopropyl)carbamate 7 (200 mg, 0.308 mmol) in dioxane (1 mL) at 0°C, 4 M HCl was added to dioxane (2 mL), followed by stirring at room temperature for 4 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the organic solvent was completely distilled off under reduced pressure. The crude residue was washed with ether to give 4-(4-(3-aminopropanoyl)-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile hydrochloride 7 (150 mg, 0.391 mmol, 91% yield) as a brown solid.

[0904] LCMS: (M+H) + :m / Z:384.2

[0905] Synthesis of tert-butyl (N-(3-(4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)-3-oxopropyl)sulfamoylcarbamate (8)

[0906]

[0907] Diisopropylethylamine (0.2 mL, 1.17 mmol) and N-(1-(N-(tert-butyloxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylformamide (145 mg, 0.43 mmol) were added to a stirred solution of 4-(4-(3-(3-(3-aminopropanoyl)-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile hydrochloride (7) (150 mg, 0.39 mmol) in dichloromethane (3 mL) at room temperature, and then At room temperature, stir for 16 hours. Monitor the reaction progress by TLC. After the reaction is completed, the organic solvent is completely distilled off under reduced pressure to obtain a crude compound. By eluting 5% methanol in DCM, the crude compound is purified by combined flash column chromatography to obtain tert-butyl (N-(3-(4-(3-cyano-6,7-dimethoxyquinoline-4-yl)-1,4-diazepane-1-yl)-3-oxypropyl) sulfamoylcarbamate (8) (150 mg, 0.266 mmol, 68% yield) as a brown solid.

[0908] LCMS: (M+H) + :m / Z:563.3

[0909] Synthesis of Compound 035

[0910]

[0911] To a stirred solution of tert-butyl (N-(3-(4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)-3-oxopropyl)carbamate (8) (150 mg, 0.266 mmol) in 1,4-dioxane (1.0 mL) at room temperature was added 4 M HCl in dioxane (2.0 mL). The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the organic solvent was completely distilled off under reduced pressure to obtain a crude compound. The crude compound was purified by preparative HPLC method to obtain a pure compound of compound 035 (30 mg, 0.064 mmol, 24% yield) as an off-white solid.

[0912] Analytical data: 1H NMR (400MHz, DMSO) δ8.71 (d, 1H), 7.41 (d, 2H), 7.27 (s, 1H), 6.56 (d, 2H), 6.34-6.40 (m, 1H), 3.92-3.94 (m, 6H), 3.78-3.81 (m, 1H), 3.67-3.70 (m, 4H), 3.50-3.59 (m, 4H), 3.10-3.17 (m, 2H), 2.65-2.70 (m, 2H), 2.06-2.07 (m, 2H). LCMS: (M+H)+: m / Z: 463.2

[0913] Overall Plan 8

[0914]

[0915] Example 8: N-(2-(1-(6,7-dimethoxyquinazolin-4-yl)azepan-4-yl)ethyl)sulfonamide Step 1A: tert-Butyl 4-(cyanomethyl)azepane-1-carboxylic acid

[0916]

[0917] At 0 ° C, diethyl (cyanomethyl) phosphonate [UNK] (436 mg, 2464 mmol) and lithium bromide (245 mg, 2816 mmol) were added to a stirred solution of 4-oxoalkane-1-carboxylic acid tert-butyl ester [UNK] (500 mg, 2347 mmol) in tetrahydrofuran (10 mL) and triethylamine (475 mg, 4694 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction process was monitored by TLC. After completion, the reaction mixture was poured into ice-cold water (100 mL) and extracted with ethyl acetate (2x100 mL). The combined organic layer was cleaned with saline solution (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by 100-200 silica gel column chromatography, eluted by 15% ethyl acetate in petroleum ether, and the obtained 4- (cyanomethylene) azepane-1-carboxylic acid tert-butyl (510 mg, 2.161 mmol, 92% yield) was a colorless oily liquid. 1H NMR (400MHz, DMSO) δ5.57–5.42(m,1H),3.43(m,2H),3.32(m,1H),3.29(m,1 H),2.72(m,1H),2.59–2.50(m,2H),2.40(d,1H),1.61(m,2H),1.38(s,9H).

[0918] Step 1B: tert-Butyl 4-cyanoazepine-1-carboxylic acid

[0919]

[0920] At 0 ° C, to a stirred solution of tert-butyl 4-oxoalkane-1-carboxylate 1 (250 g, 1.173 mmol) in N, N'-dimethylformamide (1 ml), 1- (isocyanomethyl) sulfonyl) -4-toluene 2 (286 mg, 1.467 mmol) was added. At 0 ° C, a solution of potassium tert-butoxide (262 mg, 2.346 mmol) in tert-butanol (1 mL) and 1,2-dimethoxyethane (1 mL) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was poured into ice-cold water (50 mL) and extracted with ethyl acetate (2x30 mL). The combined organic layer was washed with saline solution (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by 100-200 silica gel column chromatography eluting with 15% ethyl acetate in petroleum ether to afford tert-butyl 4-cyanoazepine-1-carboxylic acid 3 (150 mg, 0.669 mmol, 57% yield) as a light blue gummy liquid.

[0921] Analytical data: 1H NMR (400 MHz, DMSO) δ 3.43-3.37 (m, 2H), 3.27-3.16 (m, 2H), 3.07 (brs, 1H), 1.88-1.85 (m, 2H), 1.73 (brs, 4H), 1.38 (s, 9H).

[0922] Step 2: tert-Butyl 4-(2-aminoethyl)azepane-1-carboxylic acid

[0923]

[0924] To a stirred solution of 4-(cyanomethyl)azacycloalkane-1-carboxylic acid tert-butyl ester 3 (510mg, 2.161mmol) and water (5mL) in 1,4-dioxane (15mL), lithium hydroxide monohydrate (200mg, 4.754mmol), Raney nickel (500mg) and 10% palladium / carbon (150mg) were added, and the reaction mixture was stirred at room temperature under a balloon hydrogen atmosphere for 16 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was filtered through diatomaceous earth and the diatomaceous earth bed was washed with dichloromethane (100mL) containing 5% methanol. The filtrate was concentrated under reduced pressure, and the semi-pure 4-(2-aminoethyl)azacycloheptane-1-carboxylic acid tert-butyl compound 4 (500mg, crude product) obtained was a colorless colloidal liquid.

[0925] Analytical data: 1H NMR (400 MHz, DMSO) δ 3.46–3.07 (m, 8H), 2.55–2.50 (m, 2H), 1.76–1.66 (m, 3H), 1.60 (m, 1H), 1.43 (m, 3H), 1.27–1.14 (m, 4H), 1.30–1.01 (m, 1H).

[0926]

[0927] Step 3: tert-Butyl 4-(2-(N-(tert-butyloxycarbonyl)sulfamoyl)amino)ethyl)azepane-1-carboxylic acid

[0928]

[0929] At 0 ° C, diisopropylethylamine (400mg, 3.099mmol) and N-(1-(N-(tert-butyloxycarbonyl)sulfamoyl)pyridine-4(1H)-subfoliate)-N-methylformamide 5 (696mg, 2.066mmol) were added to a stirred solution of 4-(2-aminoethyl)azacyclopentane-1-carboxylic acid tert-butyl ester 4 (500mg, 2.066mmol) in dichloromethane (10ml) at 0 ° C, and then stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After completion, water (100mL) was added to the reaction mixture and extracted with dichloromethane (2x100 mL). The combined organic layer was washed with saline solution (100mL), dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude compound. The crude product was purified by 100-200 silica gel column chromatography, eluted with 2% methanol in dichloromethane to obtain a semi-pure compound. The semi-pure product was washed with 50% ethyl acetate in petroleum ether to give tert-butyl 4-(2-(N-(tert-butoxycarbonyl)sulfamoyl)amino)ethyl)azepane-1-carboxylate 6 (600 mg, 1.425 mmol, 69% yield) as a colorless gummy liquid.

[0930] Analytical data: 1H NMR (400 MHz, DMSO) δ10.76 (s, 1H), 7.50–7.45 (m, 1H), 3.41 (m, 1H), 3.24–3.19 (m, 2H), 3.12–3.03 (m, 1H), 2.87 (d, 2H), 1.70 (m, 2H), 1.57 (m, 1H), 1.39 (m, 25H).

[0931]

[0932] Step 4: (N-(2-(aziridin-4-yl)ethyl)sulfonamide

[0933]

[0934] To a stirred solution of tert-butyl 4-(2-(N-(tert-butyloxycarbonyl)sulfamoyl)ethyl)aziridine-1-carboxylate 6 (600 mg, 1.425 mmol) in dioxane (5 ml) at 0°C, 4M HCl was added to dioxane (15 ml), followed by stirring at room temperature for 3 hours. The progress of the reaction was monitored by TLC. After completion, the organic solvent was completely distilled off under reduced pressure to give a crude product (N-(2-(aziridine-4-yl)ethyl)sulfonamide (420 mg, crude) as a light brown gummy solid.

[0935] Analytical data: 1H NMR (400 MHz, DMSO) δ8.94 (d, 2H), 6.34 (broad s, 2H), 3.07 (m, 2H), 2.96 (m, 2H), 2.86 (t, 2H), 1.76 (m, 3H), 1.64 (m, 2H), 1.52–1.44 (m, 1H), 1.41–1.32 (m, 2H), 1.22 (m, 1H).

[0936]

[0937] Step 5: N-(2-(1-(6,7-dimethoxyquinazolin-4-yl)aziridine-4-yl)ethyl)sulfonamide (Compound 060)

[0938]

[0939] Potassium carbonate (263 mg, 1909 mmol) and compound 7 (360 mg, 1,4 mmol) were added to a stirred solution of 4-chloro-6,7-dimethoxyquinazoline 8 (285 mg, 1273 mmol) in acetonitrile (15 ml), and then stirred at 90 ° C for 16 hours. The reaction progress was monitored by TLC. After the reaction was completed, water (100 mL) was added and extracted with ethyl acetate (2x100 mL). The combined organic layer was washed with a saline solution (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain N-(2-(1-(6,7-dimethoxyquinazoline-4-yl)azacyclo-4-yl)ethyl)sulfonamide (52 mg, 0.127 mmol, 10% yield) as a light orange solid.

[0940] Analytical data: 1H NMR (400 MHz, DMSO) δ8.35 (s, 1H), 7.29 (s, 1H), 7.12 (s, 1H), 6.43 (m, 3H), 3.97 (d, 2H), 3.88 (m, 6H), 3.68 (m, 2H), 2.89 (m, 2H), 1.98 (m, 2H), 1.87 (m, 1H), 1.74 (m, 1H), 1.63 (m, 2H), 1.44 (m, 2H), 1.22 (m, 1H).

[0941]

[0942]

[0943] Compound 049 was prepared based on the general procedure described above:

[0944]

[0945] MW409.51

[0946] 1H NMR (400MHz, DMSO) δ8.35(s,1H),7.29(s,1H),7.12(s,1H),6.43(m,3H),3.97(d,2H),3.88(m,6H),3. 68(m,2H),2.89(m,2H),1.98(m,2H),1.87(m,1H),1.74(m,1H),1.63(m,2H),1.44(m,2H),1.22(m,1H). LCMS 409.9

[0947] Synthesis scheme of compound 036:

[0948]

[0949] Step 1: Synthesis of 4-((2-(2-aminoethoxy)ethyl)amino)-6,7-dimethoxyquinoline-3-carbonitrile 3:

[0950]

[0951] To a stirred solution of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile 1 (150 mg, 0.68 mmol) in THF (15 mL) was added 2,2'-oxybis(ethane-1-amine) 2 (314 mg, 3.4 mmol), and the reaction mixture was stirred at 50 °C for 20 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was completely distilled out and adsorbed on diatomaceous earth, and reverse phase grace was performed using an ACN / water system to obtain 4-((2-(2-aminoethoxy)ethyl)amino)-6,7-dimethoxyquinoline-3-carbonitrile (170 mg) as a white solid.

[0952] Analytical data: 1H NMR (400 MHz, DMSO): δ8.36-8.33 (m, 3H), 8.09 (brs, 1H), 7.75 (s, 1H), 7.21 (s, 1H), 3.95-3.94 (m, 2H), 3.90 (s, 6H), 3.75 (t, 2H), 3.60 (t, 2H), 2.89 (t, 2H).

[0953] LCMS: (M+H)+: m / Z: 317.2

[0954] Step 2: Synthesis of tert-butyl (N-(2-(2-((3-cyano-6,7-dimethoxyquinolin-4-yl)amino)ethoxy)ethyl)sulfamoyl)carbamate 5:

[0955]

[0956] To a stirred solution of 4-(2-(2-aminoethoxy)ethyl)amino)-6,7-dimethoxyquinoline-3-carbonitrile 3 (170 mg, 0.54 mmol) in DCM (10 mL) was slowly added N-(1-(N-(tert-butyloxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylformamide chloride 4 (163 mg, 0.48 mmol) followed by DIPEA (0.3 mL, 1.6 mmol) at the same temperature. The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. The reaction mixture was directly adsorbed on silica and converted into a slurry. The crude product was purified by combi-flash chromatography eluting with 2-3% MeOH in DCM to afford tert-butyl (N-(2-(2-((3-cyano-6,7-dimethoxyquinolin-4-yl)amino)ethoxy))ethyl)sulfamoyl)carbamate 5 (90 mg) as a white solid.

[0957] Analytical data: 1H NMR (400 MHz, DMSO) δ: 10.84 (s, 1H), 8.34 (s, 1H), 7.81 (brs, 1H), 7.64 (s, 1H), 7.51 (t, 1H), 7.21 (s, 1H), 3.93-3.89 (m, 8H), 3.72 (t, 2H), 3.51 (t, 2H), 3.06-3.01 (m, 2H), 1.35 (s, 9H).

[0958] LCMS: (M+H)+: m / Z: 396

[0959] Step 3: Synthesis of compound 036:

[0960]

[0961] To a stirred solution of tert-butyl (N-(2-(2-((3-cyano-6,7-dimethoxyquinolin-4-yl)amino)ethoxy)ethyl)sulfamoyl)carbamate 5 (90 mg, 0.18 mmol) in dioxane (3 ml) at 0°C was added 4M HCl to dioxane (1 ml), followed by stirring at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the organic solvent was completely distilled off under reduced pressure. The crude compound was purified by preparative HPLC to obtain compound 036 (10 mg) as a white solid.

[0962] Analytical data: 1H NMR (400 MHz, DMSO) δ: 8.34 (s, 1H), 7.84 (t, 1H), 7.64 (s, 1H), 7.22 (s, 1H), 6.52 (brs, 2H), 6.45 (t, 1H) 3.94-3.89 (m, 8H), 3.72 (t, 2H), 3.54 (t, 2H), 3.06 (q, 2H).

[0963] LCMS: (M+H)+: m / Z: 396.25.

[0964] Synthesis scheme of compound 037

[0965]

[0966] Synthesis of 4-((4-((N-(tert-Butoxycarbonyl)sulfamoyl)amino)butyl)amino)-6-methoxyquinazolin-7-yl trifluoromethanesulfonate (Int-5)

[0967]

[0968] To a stirred solution of Int-6 (500 mg, 1.13 mmol) in dichloromethane (20 ml) at 0 °C, triethylamine (0.475 ml, 3.39 mmol) and 1,1,1-trifluoro-N-phenyl-N-(trifluoromethyl)sulfonyl)methanesulfonamide 2 (445 mg, 1.24 mmol) were added, followed by stirring at room temperature for 4 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the organic solvent was completely distilled off under reduced pressure, water (200 mL) was added to the crude product and partitioned with dichloromethane (2×200 mL). The combined organic layers were washed with brine solution (200 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by combi-flash chromatography eluting with 70% ethyl acetate in petroleum ether to afford 4-((4-((N-(tert-butoxycarbonyl)sulfamoyl)amino)butyl)amino)-6-methoxyquinazolin-7-yl trifluoromethanesulfonate Int-5 (450 mg, 0.785 mmol, 69% yield over two steps) as a light yellow solid.

[0969] LCMS: (M+H + ):m / Z:574.

[0970] Preparation of Compound 037

[0971]

[0972] In a sealed tube, 3-(4,4,5,5-tetramethyl-1,3,2-dioxin-2-yl)-1-(triisopropylsilyl)-1H pyrrole (121mg, 0.453mmol) and cesium fluoride (159mg, 1047mmol) were added to a stirred solution of 4-(4-(tert-butyloxycarbonyl)sulfamoyl)butyl)butyl)-6-methoxyquinazoline-7-yl trifluoromethanesulfonic acid Int-5 (200mg, 0.349mmol) in dioxane (8mL) and water (2mL), and then the reaction mixture was degassed for 30 minutes. Then tetrakis(triphenylphosphine)palladium(0) (40mg, 0.034mmol) was added for 5 minutes and the reaction mixture was stirred at 100°C for 5 hours. The reaction process was monitored by TLC. After the reaction was completed, the reaction mixture was poured into water (100mL) and filtered through diatomaceous earth. The celite bed was washed with 10% methanol in dichloromethane (100 mL) and the two layers were separated. The organic layer was washed with brine solution (200 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give (Compound 037) (30 mg, 0.052 mmol, 23%) as a light yellow solid.

[0973] Analytical data: 1H NMR (400 MHz, DMSO) δ 11.13 (s, 1H), 8.625 (brs, 1h), 8.49 (s, 1H), 7.8 (s, 1H), 7.7 (s, 1H), 7.51 (s, 1H), 6.86-6.87 (m, 1H), 6.62-63 (m, 1H), 6.46-6.52 (m, 3H), 4.0 (s, 3H), 3.59-3.61 (q, 2H), 2.92-2.95 (q, 2H), 1.55-1.72 (m, 4H).

[0974] LCMS: (M+H + ):m / Z:391.1

[0975] Synthesis scheme of compound 038

[0976]

[0977] Potassium carbonate (83mg, 0.443mmol) and compound 2 (114mg, 0.443mmol) were added to a stirred solution of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile 1 (100mg, 0.403mmol) in N, N'-dimethylformamide (5ml), and then stirred for 3 hours at 90°C. The reaction progress was monitored by TLC. After the reaction was completed, water (100mL) was added and extracted with ethyl acetate (2X100 mL). The combined organic layer was washed with saline solution (100mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain compound 038 (29mg, 0.067mmol, 16% yield) as an off-white solid.

[0978] Analytical data: 1H NMR (400 MHz, DMSO) δ 8.618 (s, 1H), 7.365 (s, 1H), 7.330 (s, 1H), 6.450 6.467 (d, 3H), 3.94 (s, 3H), 3.931 (s, 3H), 3.671-3.689 (m, 2H), 3.554-3.587 (m, 2H), 2.903-2.953 (m, 2H), 1.820-1.926 (m, 5H), 1.437-1.582 (m, 4H).

[0979] LCMS: (M+H+): m / Z: 434.2

[0980] Compound 038 was submitted to SFC and separated into two enantiomers to give 038-Ent-1 (17 mg, 0.039 mmol) and 038-Ent-2 (17 mg, 0.039 mmol).

[0981] Analytical data of 038-Ent-1: 1H NMR (400 MHz, DMSO) δ8.628 (s, 1H), 7.376 (s, 1H), 7.343 (s, 1H), 6.456 (bs, 3H), 3.951 (s, 3H), 3.942 (s, 3H), 3.679-3.722 (t, 2H), 3.580-3.624 (m, 2H), 2.925-2.958 (t, 2H), 1.835-1.935 (m, 5H), 1.423-1.591 (m, 4H).

[0982] LCMS: (M+H+): m / Z: 434.2

[0983] Analytical data of 038-Ent-2: 1H NMR (400MHz, DMSO) δ8.627 (s, 1H), 7.376 (s, 1H), 7.342 (s, 1H), 6.462 (bs, 3H), 3.950 (s, 3H), 3.941 (s, 3H), 3.665-3.678 (m, 2H), 3.596-3.615 (m, 2H), 2.940-2.957 (t, 2H), 1.836-2.060 (m, 5H), 1.507-1.523 (m, 4H). LCMS: (M+H+): m / Z: 434.2

[0984] Synthesis scheme of compound 039

[0985]

[0986] Synthesis of Compound 039

[0987]

[0988] Potassium carbonate (250mg, 1.814mmol) and compound-7 (220mg, 0.907mmol) were added to a stirred solution of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile 8 (150mg, 0.605mmol) in N, N'-dimethylformamide (3ml), and then stirred for 6 hours at 90°C. The reaction progress was monitored by TLC. After the reaction was completed, water (100mL) was added and extracted with ethyl acetate (2X100 mL). The combined organic layer was washed with saline solution (100mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain compound 039 (170mg, 0.405mmol, 67% yield) as an off-white solid.

[0989] Analytical data: 1H NMR (400 MHz, DMSO) δ8.625 (s, 1H), 7.368 (s, 1H), 7.331 (s, 1H), 6.613-6.644 (t, 1H), 6.483 (s, 2H), 3.94 (s, 3H), 3.931 (s, 3H), 3.544-3.3.688 (m, 4H), 2.788-2.848 (m, 2H), 1.937-2.045 (m, 4H), 1.740-1.793 (m, 1H), 1.511-1.589 (m, 1H), 1.368-1.424 (m, 1H).

[0990] LCMS: (M+H+): m / Z: 420.2

[0991] Compound 039 was submitted to SFC and separated into two enantiomers to give 039-Ent-1 (25 mg, 0.059 mmol) and 039-Ent-2 (17 mg, 0.04 mmol).

[0992] Analytical data of 039-Ent-1: 1H NMR (400 MHz, DMSO) δ8.635 (s, 1H), 7.379 (s, 1H), 7.343 (s, 1H), 6.618-6.644 (t, 1H), 6.487 (s, 2H), 3.941 (s, 3H), 3.951 (s, 3H), 3.645-3.672 (m, 4H), 2.801-2.843 (m, 2H), 1.952-2.053 (m, 4H), 1.785-1.825 (m, 1H), 1.551-1.593 (m, 1H), 1.390-1.456 (m, 1H).

[0993] LCMS: (M+H+): m / Z: 420.2

[0994] Analytical data of 039-Ent-2: 1H NMR (400 MHz, DMSO) δ8.636 (s, 1H), 7.379 (s, 1H), 7.343 (s, 1H), 6.634 (bs, 1H), 6.488 (t, 1H), 6.487 (s, 2H), 3.941 (s, 3H), 3.951 (s, 3H), 3.645-3.672 (m, 4H), 2.801-2.843 (m, 2H), 1.952-2.055 (m, 4H), 1.765-1.825 (m, 1H), 1.553-1.573 (m, 1H), 1.386-1.456 (m, 1H).

[0995] LCMS: (M+H +):m / Z:420

[0996] Synthesis scheme of compound 040-Ent-1

[0997]

[0998] Synthesis of 1-(6,7-dimethoxyquinazolin-4-yl)azacycloalkane-4-sulfonamide (Compound 040-Ent-1)

[0999] To a stirred solution of 4-chloro-6,7-dimethoxyquinazoline 1 (120 mg, 0.5357 mmol) in ACN (2 mL) and K2CO3 (222 mg, 1.6071 mmol) was stirred at 90 ° C for 16 hours. After the reaction was completed, the crude residue was added to water (10 mL). It was then extracted with 10% methanol in dichloromethane (30 mL) and concentrated under reduced pressure to give a crude compound. The crude compound was purified by a preparative HPLC method to obtain the pure compound 1-(6,7-dimethoxyquinazoline-4-yl)azacycloalkane-4-sulfonamide (T-116-Ent-1) (10 mg, 5% yield) as a white solid.

[1000] Analytical data: 1H NMR (400 MHz, DMSO) δ8.40 (s, 1H), 7.26 (s, 1H), 7.15 (s, 1H), 6.74 (s, 2H), 4.09 (m, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 3.69-3.80 (m, 2H), 3.69 (m, 1H), 3.01 (p, 2H), 2.30 (m, 1H), 2.08 (p, 2H), 1.91 (m, 1H), 1.60 (m, 1H).

[1001] LCMS: (M+H + ):m / Z:367.1

[1002] Synthesis scheme of compound 040-Ent-2

[1003]

[1004] Synthesis of 1-(6,7-dimethoxyquinazolin-4-yl)azacycloalkane-4-sulfonamide (Compound 040-Ent-2)

[1005] To a stirred solution of 4-chloro-6,7-dimethoxyquinazoline 1 (120 mg, 0.5357 mmol) in ACN (2 mL) and K2CO3 (222 mg, 1.6071 mmol) was then stirred at 90 ° C for 16 hours. After the reaction was completed, the crude residue was added to water (10 mL). It was then extracted with 10% methanol in dichloromethane (30 mL) and concentrated under reduced pressure to give a crude compound. The crude compound was purified by a preparative HPLC method to give a pure compound 1-(6,7-dimethoxyquinazoline-4-yl)azacycloalkane-4-sulfonamide (T-116-Ent-2) (10 mg, 5% yield) as a white solid.

[1006] Analytical data: 1H NMR (400MHz, DMSO) δ8.50 (s, 1H), 7.34 (s, 1H), 7.18 (s, 1H), 6.78 (s, 2H), 4.18 (m, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 3.76-3.84 (m, 2H), 3.04 (m, 1H), 3.01 (p, 2H), 2.92 (m, 1H), 2.13 (m, 1H), 1.98 (m, 1H), 1.60 (m, 1H) LCMS: (M+H+): m / Z: 367.1

[1007] Synthesis scheme of compound 041

[1008]

[1009] Synthesis of tert-butyl 4-methyleneaziridine-1-carboxylic acid (2)

[1010]

[1011] 1M potassium tert-butoxide (63mg, 0.563mmol) was added to a stirred solution of methyl triphenylphosphine 2 (227mg, 0.563mmol) in ether (5mL), and the reaction turned yellow. Then tert-butyl 4-oxyethyl acetate-1-carboxylic acid 1 (100mg, 0.469mmol) was added and stirred at 50°C for 3 hours. The reaction process was monitored by TLC. After the reaction was completed, water (30mL) was added to the reaction mixture and extracted with ethyl acetate (2×20mL). The combined organic layer was washed with saline solution (40mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude compound was purified by 100-200 silica gel column chromatography, eluted by 5% ethyl acetate in petroleum ether, and the obtained 4-methylene aza-1-carboxylic acid tert-butyl 2 (60mg, 0.284mmol) was a colorless oily liquid.

[1012] Analytical data: 1H NMR (400 MHz, DMSO) δ 4.732-4.786 (m, 4H), 2.404-2.433 (m, 2H), 2.209-2.239 (t, 2H), 1.655-1.706 (m, 2H), 1.448 (s, 9H).

[1013] Synthesis of tert-butyl 4-(bromomethyl)-4-fluoroazepane-1-carboxylic acid (3)

[1014]

[1015] At 0 ℃, to the stirring solution of 4-methyleneaziridine-1-carboxylic acid tert-butyl ester 2 (1.9g, 9.005mmol) in dichloromethane (50mL), add triethylamine trihydrofluoride (3.6g, 22.52mmol) and N-bromosuccinimide (2.4g, 13.507mmol), then stir at room temperature for 2 hours. Monitor reaction process by TLC. After the completion of the reaction, reaction mixture is saturated with NaHCO solution (100mL) quenched and extracted with excessive dichloromethane (2x150 mL). The combined organic layer is washed with saline solution (150mL), at Na2SO4 upper drying, and under reduced pressure concentrated to obtain crude compound. The crude product was purified by 100-200 combi-flash chromatography eluting with 5% ethyl acetate in petroleum ether to afford tert-butyl 4-(bromomethyl)-4-fluoroazepan-1-carboxylic acid 3 (1.7 g, 5.5 mmol, 61% yield) as a colorless oily liquid.

[1016] Analytical data: 1H NMR (400 MHz, DMSO) δ 3.500-3.673 (m, 2H), 3.434-3.477 (d, 2H), 3.162-3.269 (m, 4H), 1.980-2.114 (m, 4H), 1.652-1.913 (m, 2H), 1.465 (s, 9H).

[1017] Synthesis of tert-butyl 4-(azidomethyl)-4-fluoroazepane-1-carboxylic acid (4)

[1018]

[1019] Sodium azide (473mg, 7.281mmol) and sodium iodide (1g, 7.281mmol) are added to a stirred solution of tert-butyl 4-(bromomethyl)-4-fluoroazacyclopentane-1-carboxylate 3 (1.5g, 4.854mmol) in dimethyl sulfoxide (20mL), and then stirred at 130°C for 16 hours. The reaction progress is monitored by TLC. After the reaction is completed, water (200mL) is added to the reaction mixture and extracted with ethyl acetate (2×150mL). The combined organic layer is washed with saline solution (200mL), dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude compound. The crude product is purified by combi-flash chromatography by eluting 20% ​​ethyl acetate in petroleum ether, and the obtained tert-butyl 4-(azidomethyl)-4-fluoroazaalkane-1-carboxylic acid 4 (600mg, 2.205mmol, 45% yield) is a colorless oily liquid.

[1020] Analytical data: 1H NMR (400 MHz, DMSO) δ 3.508-3.797 (m, 2H), 3.148-3.387 (m, 4H), 1.952-2.158 (m, 3H), 1.648-1.790 (m, 2H), 1.442 (s, 9H).

[1021] Synthesis of tert-butyl 4-(aminomethyl)-4-fluoroazepane-1-carboxylic acid (5)

[1022]

[1023] The stirring solution of tert-butyl 4-(azidomethyl)-4-fluoroazacycloalkane-1-carboxylic acid 5 (600mg, 2.206mmol) in methanol (20mL) was added with 10% Pd / C (60mg, 10% w / w), and then stirred for 16 hours under balloon hydrogen atmosphere. The reaction progress was monitored by TLC. After the reaction was completed, the reaction mixture was filtered through diatomite and the diatomite bed was washed with 10% methanol in dichloromethane (50mL). The filtrate was concentrated under reduced pressure to obtain a crude compound. The crude product was purified by combi-flash chromatography, and 30% ethyl acetate was eluted in petroleum ether, and the tert-butyl 4-(aminomethyl)-4-fluoroazacycloalkane-1-carboxylic acid 5 (400mg, 1.626mmol, 74% yield) obtained was a colorless oily liquid.

[1024] Analytical data: 1H NMR (400 MHz, DMSO) δ 3.106-3.503 (m, 6H), 2.618-2.625 (d, 2H), 2.570-2.576 (d, 1H), 1.490-1.912 (m, 6H), 1.380 (s, 9H).

[1025] Synthesis of tert-butyl 4-(((N-(tert-butyloxycarbonyl)sulfamoyl)amino)methyl)-4-fluoroazepine-1-carboxylic acid (7)

[1026]

[1027] At 0 ° C, diisopropylethylamine (315mg, 2.439mmol) and N-(1-(N-(tert-butyloxycarbonyl)sulfamoyl)pyridine-4(1H)-ylidene)-N-methylformamide 6 (548mg, 1.626mmol) were added to a stirred solution of 4-(aminomethyl)-4-fluoroazetidine-1-carboxylic acid tert-butyl ester 5 (400mg, 1.626mmol) in dichloromethane (10mL), and then stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After the reaction was completed, the reaction mixture was completely distilled off under reduced pressure to obtain a crude compound. The crude product was purified by 100-200 combi-flash chromatography eluting with 3% methanol in dichloromethane to afford tert-butyl 4-(((N-(tert-butoxycarbonyl)sulfamoyl)amino)methyl)-4-fluoroazepan-1-carboxylic acid 7 (350 mg, 0.823 mmol, 50% yield) as a brown solid.

[1028] Analytical data: 1H NMR (400 MHz, DMSO) δ 10.827 (s, 1H), 7.858 (bs, 1H), 3.031-3.515 (m, 4H), 1.506-1.977 (m, 6H), 1.381 (s, 9H), 1.406 (s, 9H), 1.218-1.234 (m, 1H).

[1029] Synthesis of compound 8

[1030]

[1031] A stirred solution of tert-butyl 4-(N-(tert-butyloxycarbonyl)sulfamoyl)methyl)-4-fluoroazacycloalkane-1-carboxylate 7 (350 mg, 0.823 mmol) and 4M HCl in dioxin (10 mL) was stirred for 16 hours at room temperature. The reaction progress was monitored by TLC. After the reaction was completed, the organic solvent was removed by distillation under reduced pressure, and the obtained compound 8 (250 mg, 0.958 mmol, quantitative yield) was a brown colloidal liquid.

[1032] Analytical data: 1H NMR (400 MHz, DMSO) δ 9.088 (bs, 2H), 7.147 (t, 1H), 6.880 (bs, 1H), 6.583 (bs, 1H), 2.994-3.151 (m, 6H), 2.077-2.163 (m, 2H), 1.689-1.945 (m, 4H).

[1033] Synthesis of Compound 041

[1034]

[1035] Potassium carbonate (137mg, 0.996mmol) and compound-8 (130mg, 0.498mmol) were added to a stirred solution of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile 9 (80mg, 0.332mmol) in N, N'-dimethylformamide (5ml), and then stirred for 6 hours at 90°C. The reaction progress was monitored by TLC. After the reaction was completed, water (100mL) was added and extracted with ethyl acetate (2x100 mL). The combined organic layer was washed with saline solution (100mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative HPLC method, and the obtained compound 041 (30mg, 0.068mmol, 21% yield) was an off-white solid.

[1036] Analytical data: 1H NMR (400 MHz, DMSO) δ8.651 (s, 1H), 7.377 (s, 1H), 7.319 (s, 1H), 6.860-6.895 (t, 1H), 6.567 (s, 2H), 3.945 (s, 3H), 3.937 (s, 3H), 3.811-3.856 (m, 1H), 3.549-3.639 (m, 2H), 3.462-3.500 (m, 1H), 3.073-3.3.137 (dd, 2H), 2.030-2.217 (m, 5H), 1.831-1.862 (bs, 1H).

[1037] Synthesis scheme of compounds 042 and 043

[1038]

[1039] Step 1: Synthesis of tert-butyl 4-(benzylamino)azepane-1-carboxylic acid (2)

[1040]

[1041] At 0 ° C, benzylamine (2.1 mL, 19.2 mmol) and STAB (2.1 g, 9.9 mmol) were added to a stirred solution of tert-butyl 4-oxoalkane-1-carboxylate 1 (1 g, 4.69 mmol) in DMF (7.5 mL), and AcOH (0.5 mL) was then added. The reaction mixture was then allowed to stir at room temperature for 16 h. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was poured directly into ice-cold water and stirred. The organic matter was extracted three times with EtOAc, and the combined organic matter was washed with brine, dried and concentrated. The compound was directly adsorbed on silica and combi-flash chromatography to give tert-butyl 4-(benzylamino)azepane-1-carboxylic acid 2 (1.2 g, 3.947 mmol, 85% yield)

[1042] Analytical data: (M+H)+: m / Z: 305.2

[1043] Step 2: Synthesis of tert-butyl 4-aminoazacyclopentane-1-carboxylic acid (3)

[1044]

[1045] Palladium / carbon (100mg) is added to the stirring solution of 4- (benzylamino) azepane -1- carboxylic acid tert-butyl esters 2 (1.1g, 3.6mmol) in methanol (20mL), and stirred at room temperature for 16 hours.After the completion of the reaction, the reaction mixture is filtered through a diatomaceous earth pad.The filtrate is concentrated under reduced pressure, and the tert-butyl 4-aminoaza-1-carboxylic acid 3 (600mg, 2.803mmol, 71% yield) obtained is a light yellow liquid.

[1046] Analytical data: 1H NMR (400 MHz, DMSO): 3.48-3.41 (m, 2H), 3.29-3.27 (m, 1H), 3.10-3.05 (m, 1H), 2.97-2.94 (m, 1H), 1.93-1.89 (m, 1H), 1.85-1.77 (m, 3H), 1.53-1.48 (m, 2H), 1.39 (s, 9H).

[1047] Step 3: tert-Butyl 4-((N-(tert-butoxycarbonyl)sulfamoyl)amino)azepine-1-carboxylic acid 5:

[1048]

[1049] N-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridine-4(1H)-ylidene)-N-methylformamide ammonium chloride 4(1.4g, 3.08mmol) is slowly added to a stirred solution of 4-aminoaziridine-1-carboxylic acid tert-butyl ester 3(600mg, 2.8mmol) in DCM(30mL), then DIPEA diethyl ester(1.5mL, 8.4mmol) is added at the same temperature. The reaction mixture is stirred at room temperature for 16 hours. The reaction progress is monitored by TLC. The reaction mixture is directly adsorbed onto silica, and the crude product is purified by combi-flash chromatography, and 80%EtOAc is eluted in hexane, and the 4-((N-(tert-butoxycarbonyl)sulfamoyl)amino)azepine-1-carboxylic acid tert-butyl 5(650mg, 1.65mmol, 59% yield) obtained is a white solid.

[1050] Analytical data: 1H NMR (400 MHz, DMSO): 10.77 (s, 1H), 7.68-7.63 (m, 1H), 3.32-3.30 (m, 1H), 3.20-3.10 (m, 4H), 1.89-1.74 (m, 3H), 1.58-1.48 (m, 3H), 1.41-1.38 (m, 18H).

[1051] LCMS: (MH)+: m / Z: 392.1

[1052] Step 4: Synthesis of 4-((N-sulfamoyl)amino)aziridine hydrochloride (6)

[1053]

[1054] To a stirred solution of tert-butyl 4-(N-(tert-butyloxycarbonyl)sulfamoyl)azepane-1-carboxylate 5 (650 mg, 1.6 mmol) in dichloromethane (10 ml) at 0°C, 4M HCl was added to dioxane (0.6 ml) and then stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, the organic solvent was completely distilled off under reduced pressure. The crude compound was triturated with ether to give 4-((N-sulfamoyl)amino)azepane-hydrochloride (310 mg) as a white solid.

[1055] Analytical data: 1H NMR (400MHz, DMSO) δ: 8.92 (brs, 2H), 6.72-6.70 (brs, 1H), 6.53 (brs, 1H), 3.39-3.37 (s, 1H), 3.16-3.14 (m, 1H), 3.16-3.14 (m, 1H), 3.08-3.05 (m, 1H), 3.05-2.98 (m, 2H), 2.06-2.04 (m, 1H), 1.95-1.90 (m, 1H), 1.87-1.81 (m, 2H), 1.67-1.54 (m, 2H)

[1056] Step 5: Synthesis of N-(1-(3-cyano-6,7-dimethoxyquinolin-4-yl)azacyclyl-4-yl)sulfamoylamide (Compound 042)

[1057]

[1058] At room temperature, 4-(N-sulfamoyl)aminoaziridine hydrochloride (135 mg, 0.58 mmol) was added to a stirred solution of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile 7 (146 mg, 0.65 mmol) in DMF (5 ml), followed by K2CO3 (0.270 mg, 1.96 mmol). After addition, the reaction mixture was heated to 90 ° C and stirred for 16 hours. The reaction progress was monitored by TLC. After the reaction was completed, it was quenched with water, the organic matter was extracted three times with EtOAc, the combined organic matter was washed with brine, dried, and concentrated under reduced pressure to give a crude product. The crude compound was purified by preparative HPLC to obtain N-(1-(3-cyano-6,7-dimethoxyquinoline-4-yl)azacyclo-4-yl)sulfamoylamide (compound 042) (22 mg, 0.054 mmol, 9% yield) as a light yellow fluffy solid.

[1059] Analytical data: 1H NMR (400MHz, DMSO) δ: 8.62 (s, 1H), 7.36 (s, 1H), 7.32 (s, 1H), 6.72 (d, 1H), 6.51 (s, 2H), 3.94 (s, 6H), 3.62-3.61 (m, 3H), 3.54-3.51 (m, 2H), 2.21-2.10 (m, 2H), 1.93-1.91 (m, 1H), 1.87-1.74 (m, 3H)

[1060] LCMS: (M+H) + :m / Z:406.31

[1061] Step 6: Synthesis of N-(1-(6,7-dimethoxyquinazolin-4-yl)azacyclyl-4-yl)sulfamoylamide (Compound 043)

[1062]

[1063] At room temperature, 4-(N-sulfamoyl)azepane-hydrochloride (135 mg, 0.589 mmol) was added to a stirred solution of 4-chloro-6,7-dimethoxyquinazoline 8 (146 mg, 0.65 mmol) in DMF (5 ml), followed by K2CO3 (0.270 mg, 1.96 mmol). After addition, the reaction mixture was heated to 90 ° C and stirred for 16 hours. The reaction progress was monitored by TLC. After the reaction was completed, the reaction mixture was poured onto water, extracted three times with EtOAc, the combined organic layers were washed with brine, and dried under reduced pressure to give a crude product. The crude compound was purified by preparative HPLC to obtain N-(1-(6,7-dimethoxyquinazoline-4-yl)azepine-4-yl)sulfamoylamide compound 043 (24 mg, 0.062 mmol, 9.6% yield) as an off-white solid.

[1064] Analytical data: 1H NMR (400MHz, DMSO) δ: 8.36 (s, 1H), 7.27 (s, 1H), 7.13 (s, 1H), 6.62 (d, 1H), 6.49 (s, 2H), 3.87-3.96 (m, 8H), 3.63-3.71 (m, 2H), 3.31-3.37 (m, 1H), 2.2-2.25 (m, 1H), 1.95-2.01 (m, 3H), 1.82-1.85 (m, 1H), 1.50-1.58 (m, 1H)

[1065] LCMS: (M+H) + :m / Z:382.19

[1066] Synthesis scheme of compounds 044 and 045

[1067]

[1068] Step 1: Synthesis of tert-butyl 4-((trifluoromethyl)sulfonyl)oxy)-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate (2)

[1069]

[1070] To a solution of tert-butyl 4-oxoazepine-1-carboxylic acid (1.5 g, 7.04 mmol, 1 eq.) in THF (20 mL) at -78 ° C, 1N LiHMDS (7.7 mL, 7.74 mmol) was added dropwise under nitrogen. The mixture was stirred for 20 minutes, and then a solution of PhNTf2 (2.75 g, 7.71 mmol) in THF (10 mL) was added. The mixture was heated to 0 ° C and stirred for 3 hours. The reaction was concentrated and diluted with DCM, filtered through neutral alumina and the product was eluted with 9:1 hexane / EtOAc to give 4-(((trifluoromethyl)sulfonyl)oxy)-2,3,6,7-tert-butyltetrahydro-1H-azepine-1-carboxylate (2.1 g, 6.08 mmol, 87% yield).

[1071] Analytical data: 1H NMR (400MHz, CDCl3): 5.90 (m, 1H), 3.90-3.99 (m, 2H), 3.51-3.60 (m, 2H), 2.56 (m, 1H), 1.92-1.97 (m, 2H), 1.45 (s, 9H)

[1072] Step 2: Synthesis of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate (4)

[1073]

[1074] To a stirred solution of tert-butyl 4-(trifluoromethylsulfonyl)oxy)-2,3,6,7-tetrahydro-1H-azapyridine-1-carboxylate 2 (1.5 g, 4.34 mmol) in dioxane was added bis(pyrinatocraton)diboron 3 (1.3 g, 4.9 mmol) and potassium acetate (1.28 g, 12.9 mmol) at room temperature. The mixture was degassed under nitrogen for 15 minutes, then PdCl2(PPh3)2 (300 mg, 0.43 mmol) was added at room temperature and the mixture was degassed for another 5 minutes. The reaction was stirred at 80 ° C overnight, concentrated, diluted with ethyl acetate and filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to give a crude product (3 g) which was used in the next step.

[1075] Step 3: tert-Butyl 4-(6,7-dimethoxyquinazolin-4-yl)-2,3,6,7-tetrahydro-1H-azepine-1-carboxylic acid (5)

[1076]

[1077] To a stirred solution of 4-chloro-6,7-dimethoxyquinazoline (208 mg, 0.9 mmol) in dioxane (7 mL) and water (1 mL) was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)-2,3,6,7-tetrahydro-1H-azapyridine-1-carboxylate 4 (600 mg crude, 1.8 mmol), then Na2CO3 (300 mg, 2.7 mmol) was added and degassed with argon for 30 minutes. PdCl2(dppf) was then added. DCM (76 mg, 0.09 mmol) was added and purged again with argon for 5 minutes. The reaction mixture was heated to 80 ° C for 16 hours. The reaction progress was monitored by TLC. The reaction mixture was filtered through a diatomaceous earth pad, the filtrate was quenched with water, extracted three times with EtOAc, and the combined organic layer was washed with brine and water. The organic layer was concentrated under reduced pressure to obtain a crude product. The crude compound was purified by combi-flash chromatography eluting with 90% EtOAc in hexanes to afford tert-butyl 4-(6,7-dimethoxyquinazolin-4-yl)-2,3,6,7-tetrahydro-1H-azepine-1-carboxylic acid 5 (250 mg, 0.649 mmol, 70% yield) as a light brown solid.

[1078] Analytical data: 1H NMR (400MHz, DMSO): 9.06 (s, 1H), 7.55 (s, 1H), 7.30-7.30 (m, 1H), 6.19 (t, 1H), 4.11-4.44 (m, 2H), 4.00-4.05 (m, 6H), 3.69-3.74 (m, 2H), 2.81-2.83 (m, 2H), 2.07-2.10 (m, 2H), 1.48 (s, 9H)

[1079] LCMS:(MH) + :m / Z:386.2

[1080] Step 4: 6,7-Dimethoxy-4-(2,3,6,7-tetrahydro-1H-azapyridin-4-yl)quinazoline hydrochloride (6)

[1081]

[1082] To a stirred solution of 4-(6,7-dimethoxyquinazolin-4-yl)-2,3,6,7-tetrahydro-1H-alazapine-1-carboxylic acid tert-butyl ester 5 (100 mg, 0.83 mmol) in 1,4-dioxane (10 mL) at 0°C, 4.0 M HCl was slowly added to 1,4-dioxane (1 mL) and slowly allowed to reach room temperature and stirred for 2 hours. After the reaction was complete, the volatile organics were removed under reduced pressure, co-distilled with DCM three times and triturated with ether to give 6,7-dimethoxy-4-(2,3,6,7-tetrahydro-1H-azapyridin-4-yl)quinazoline hydrochloride 6 (88 mg, 0.24 mmol, 95% yield) as an off-white solid.

[1083] Analytical data: LCMS: (MH)+: m / Z: 286.2

[1084] Step 5: tert-Butyl ((4-(6,7-dimethoxyquinazolin-4-yl)-2,3,6,7-tetrahydro-1H-azapyridin-1-yl)sulfonyl)carbamate (8)

[1085]

[1086] To a stirred solution of 6,7-dimethoxy-4-(2,3,6,7-tetrahydro-1H-azapyridin-4-yl)quinazoline hydrochloride 6 (90 mg, 0.28 mmol) in DCM was added N-(1-(N-(tert-butyloxycarbonyl)sulfamoyl)pyridine-4(1H)-ylidene)-N-methylformamide chloride 4 (95 mg, 0.28 mmol) and DIPEA (0.146 ml, 0.841 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. The reaction mixture was directly adsorbed on silica and converted into a slurry. The crude product was purified by combi-flash chromatography eluting with 90% EtOAc in hexanes to afford tert-butyl ((4-(6,7-dimethoxyquinazolin-4-yl)-2,3,6,7-tetrahydro-1H-azapyridin-1-yl)sulfonyl)carbamate 8 (120 mg, 0258 mmol, 92% yield) as an off-white solid.

[1087] Analytical data: 1H NMR (400MHz, DMSO): 11.03 (s, 1H), 8.98 (s, 1H), 7.47 (s, 1H), 7.34 (s, 1H), 6.15 (t, 1H), 4.17-4.16 (m, 2H), 3.96 (s, 3H), 3.90 (s, 3H), 3.57 (t, 2H), 2.78-2.80 (m, 2H), 2.01-2.03 (m, 2H), 1.38 (s, 9H)

[1088] LCMS:(MH) + :m / Z:465.2

[1089] Step 6: Synthesis of 4-(6,7-dimethoxyquinazolin-4-yl)-2,3,6,7-tetrahydro-1H-azepine-1-sulfonamide (Compound 044)

[1090]

[1091] To a stirred solution of tert-butyl ((4-(6,7-dimethoxyquinazolin-4-yl)-2,3,6,7-tetrahydro-1H-azapyridin-1-yl)sulfonyl)carbamate 8 (125 mg, 0.26 mmol) in dichloromethane (5 ml) at 0°C was added TFA (1.2 ml), followed by stirring at the same temperature for 4 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, TFA was neutralized with aq.NaHCO3, extracted with 10% MeOH / DCM, dried, and concentrated under reduced pressure to give a crude product. The crude compound was subjected to preparative HPLC to give 4-(6,7-dimethoxyquinazolin-4-yl)-2,3,6,7-tetrahydro-1H-aza-1-sulfonamide compound 044 (70 mg, 0.192 mmol, 70% yield) as an off-white solid.

[1092] Analytical data: 1H NMR (400MHz, DMSO): 8.97 (s, 1H), 7.52 (s, 1H), 7.32 (s, 1H), 6.82 (s, 2H), 6.16 (t, 1H), 4.02-4.00 (m, 2H), 3.96 (s, 3H), 3.98 (s, 6H), 3.51 (t, 2H), 2.82-2.79 (m, 2H), 2.02-1.98 (m, 2H)

[1093] LCMS:(MH) + :m / Z:365.1

[1094] Step 7: tert-Butyl ((4-(6,7-dimethoxyquinazolin-4-yl)azacyclyl-1-yl)sulfonyl)carbamate (9)

[1095]

[1096] 10% palladium / carbon (25 mg) was added to a stirred solution of tert-butyl ((4-(6,7-dimethoxyquinazoline-4-yl)-2,3,6,7-tetrahydro-1H-azapyridin-1-yl)sulfonyl)carbamate 8 (250 mg, 0.53 mmol) in methanol (3 mL), and stirred at room temperature for 16 hours. After the reaction was completed, the reaction mixture was filtered through a diatomaceous earth pad. The filtrate was concentrated under reduced pressure to obtain tert-butyl ((4-(6,7-dimethoxyquinazoline-4-yl)azacyclic-1-yl)sulfonyl)carbamic acid 9 (220 mg, 0.472 mmol, 87% yield) as a light yellow liquid.

[1097] Analytical data: 1H NMR (400 MHz, DMSO) δ: 11.13 (s, 1H), 8.96 (s, 1H), 7.45 (s, 1H), 7.32 (s, 1H), 6.97 (d, 2H), 3.96-3.95 (m, 6H), 3.89-3.81 (m, 1H), 3.79-3.64 (m, 1H), 3.58-3.32 (m, 3H), 2.04-1.85 (m, 6H).

[1098] LCMS: (M+H) + :m / Z:467.11

[1099] Step 8: Synthesis of 4-(6,7-dimethoxyquinazolin-4-yl)azacycloalkane-1-sulfonamide hydrochloride (Compound 045)

[1100]

[1101] To a stirred solution of tert-butyl ((4-(6,7-dimethoxyquinazolin-4-yl)azacyclo-1-yl)sulfonyl)carbamate 9 (250 mg, 0.53 mmol) in dichloromethane (2.5 mL) was added 4M HCl (2.5 mL) to dioxane (2.5 mL) at 0°C, followed by stirring at room temperature for 16 hours. The progress of the reaction was monitored by TLC. The crude reaction mixture was purified by preparative HPLC to give 4-(6,7-dimethoxyquinazolin-4-yl)aza-1-sulfonamide hydrochloride compound 045 (25 mg, 0.062 mmol, 11% yield) as an off-white solid.

[1102] Analytical data: 1H NMR (400MHz, DMSO) δ: 8.96 (s, 1H), 7.44 (s, 1H), 7.32 (s, 1H), 6.71 (s, 2H), 3.95-3.96 (m, 6H), 3.81-3.83 (m, 1H), 3.47-3.53 (m, 2H), 3.17-3.23 (m, 1H), 2.00-2.04 (m, 2H), 1.85-1.95 (m, 4H)

[1103] LCMS: (M+H) + :m / Z:367.3

[1104] Overall Plan 9

[1105]

[1106] Example 9: N-((5-(6,7-dimethoxyquinazolin-4-yl)pyridin-2-yl)methyl)sulfonamide

[1107] Step 1: 5-(6,7-dimethoxyquinazolin-4-yl)pyridinecarbonitrile

[1108]

[1109] In a sealed tube, to a stirred solution of 4-chloro-6,7-dimethoxyquinazoline 1 (1.5 g, 6.67 mmol) and water (20 mL) in dioxane (50 mL), (6-cyanopyridin-3-yl)boric acid (1.08 g, 0.72 mmol) and sodium carbonate (2.12 g, 20.0 mmol) were added, and the reaction mixture was degassed for 30 minutes. Then, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (544 mg, 0.66 mmol) was added again, degassed for 5 minutes, and the reaction mixture was stirred at 100 °C for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was poured into water (100 mL) and filtered through diatomaceous earth. The diatomaceous earth bed was washed with dichloromethane (100 mL) containing 10% methanol and the two layers were separated. The organic layer was washed with brine solution (200 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified using combi-flash column chromatography eluting with 3% methanol in dichloromethane to afford 5-(6,7-dimethoxyquinazolin-4-yl)picolinonitrile 2 (700 mg, 2.39 mmol, 37%) as a brown solid.

[1110] Analytical data: 1H NMR (400MHz, DMSO) 9.18 (d, 2H), 8.51 (d, 1H), 8.27 (d, 1H), 7.48 (s, 1H), 7.23 (s, 1H), 4.01 (s, 3H), 3.86 (s, 3H). LCMS: (M+H+): m / Z: 292.9

[1111] Step 2: (5-(6,7-dimethoxyquinazolin-4-yl)pyridin-2-yl)methanamine

[1112]

[1113] 10% palladium / carbon (300 mg) was added to a stirred solution of 5-(6,7-dimethoxyquinazoline-4-yl)pyridinecarbonitrile 2 (500 mg, 1.7 mmol) in acetic acid (30 mL), and stirred for 16 hours at room temperature under a balloon hydrogen atmosphere. The reaction progress was monitored by TLC. After the reaction was completed, the reaction mixture was passed through diatomaceous earth and the diatomaceous earth bed was washed with a 5% methanol solution in dichloromethane (100 mL). The filtrate was concentrated under reduced pressure, and the obtained (5-(6,7-dimethoxyquinazoline-4-yl)pyridine-2-yl)methylamine 3 (500 mg, 1.689 mmol, 98% yield) was a yellow solid.

[1114] Analytical data: 1H NMR (400MHz, DMSO) 9.15 (s, 1H), 8.97 (s, 1H), 8.29 (d, 1H), 7.70 (d, 1H), 7.45 (s, 1H), 7.25 (s, 1H), 4.11 (brs, 2H), 4.00 (s, 3H), 3.87 (s, 3H). LCMS: (M+H+): m / Z: 297.0

[1115] Step 3: tert-Butyl (N-(5-(6,7-dimethoxyquinazolin-4-yl)pyridin-2-yl)methyl)sulfamoylcarbamate (Int-5)

[1116]

[1117] To a stirred solution of (5-(6,7-dimethoxyquinazolin-4-yl)pyridin-2-yl)formamide 3 (500 mg, 1.689 mmol) in dichloromethane (40 ml) at room temperature, diisopropylethylamine (1.65 ml, 10.134 mmol) and N-(1-(N-(tert-butyloxycarbonyl)sulfamoyl)pyridine-4(1H)-ethylidene)-N-methylformamide chloride 4 (569 mg, 1.689 mmol) were added and allowed to stir at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the organic solvent was completely distilled off under reduced pressure to obtain a crude compound. The crude compound was purified on combined flash column chromatography eluting with 2% methanol in dichloromethane to afford tert-butyl(N-((5-(6,7-dimethoxyquinazolin-4-yl)pyridin-2-yl)methyl)sulfamoyl)carbamic acid (300 mg, 0.631 mmol, 37% yield) as a yellow solid.

[1118] Analytical data: 1H NMR (400MHz, DMSO) 9.15 (s, 1H), 8.37 (s, 1H), 8.29 (d, 1H), 7.67 (d, 1H), 7.46 (s, 1H), 7.26 (s, 1H), 4.37 (d, 2H), 4.01 (s, 3H), 3.59 (s, 3H), 1.39 (s, 9H). LCMS: (M+H+): m / Z: 475.9

[1119] Step 4: N-(5-(6,7-dimethoxyquinazolin-4-yl)pyridin-2-yl)methyl)sulfonamide (Compound 047)

[1120]

[1121] To a stirred solution of tert-butyl (N-(5-(6,7-dimethoxyquinazolin-4-yl)pyridin-2-yl)methyl)sulfamoyl)carbamate Int-5 (100 mg, 0.210 mmol) in 1,4-dioxane (1.0 ml) was added 4M HCl to dioxane (2.5 mL) at room temperature, followed by stirring at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the organic solvent was completely distilled off under reduced pressure to obtain a crude compound. The crude compound was purified by preparation. The pure compound (Compound 47) of N-((5-(6,7-dimethoxyquinazolin-4-yl)pyridin-2-yl)methyl)sulfonamide 30 mg, 0.08 mmol, 38% yield) obtained by HPLC was an off-white solid.

[1122] Analytical data: 1H NMR (400MHz, DMSO) 9.15 (s, 1H), 8.93 (s, 1H), 8.28 (d, 1H), 7.73 (d, 1H), 7.46 (s, 1H), 7.30-7.27 (m, 2H), 6.75 (s, 2H), 4.32 (d, 2H), 4.01 (s, 3H), 3.85 (s, 3H). LCMS: (M+H+): m / Z: 375.9; MW 411.86.

[1123] Synthesis scheme of compound 046

[1124]

[1125] Synthesis of tert-butyl (5-(3-cyano-6,7-dimethoxyquinolin-4-yl)pyridin-2-yl)methylcarbamate (2)

[1126]

[1127] To a stirred solution of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile (500 mg, 2.01 mmol) in 3:1 dioxane (20 mL): Na2CO3 (641 mg, 6.04 mmol) and tert-butyl ((5-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)pyridin-2-yl)methyl)carbamate Int-9 (1.3 g, 4.03 mmol) were added at room temperature, and the reaction mixture was degassed for 30 minutes. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (165 mg, 0.2 mmol) was then added again, degassed for 5 minutes, and the reaction mixture was stirred at 100 °C for 16 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was poured into water (100 mL) and filtered through celite. The celite bed was washed with 10% methanol in dichloromethane (100 mL) and the two layers were separated. The organic layer was washed with brine solution (200 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give tert-butyl((5-(3-cyano-6,7-dimethoxyquinolin-4-yl)pyridin-2-yl)methyl)carbamic acid (2) (250 mg, 0.127 mmol, 30%) as a yellow solid.

[1128] Analyze the data: 1H NMR(400MHz,DMSO)δ9.066(s,1H),8.72(s,1H),8.07-8.09(dd,1H),7.52-7.59 (m,4H),6.86(s,1H),4.38-4.41(m,2H),4.01(s,3H),3.74(s,3H),1.43(s,9H).

[1129] LCMS: (M+H + ):m / Z:421.2

[1130] Synthesis of 4-(6-(Aminomethyl)pyridin-3-yl)-6,7-dimethoxyquinoline-3-carbonitrile (3)

[1131]

[1132] To a stirred solution of tert-butyl (5-(3-cyano-6,7-dimethoxyquinolin-4-yl)pyridin-2-yl)carbamate 2 (250 mg, 0.127 mmol) in dioxane (2 mL) at 0°C was added 4M HCl to dioxane (4 mL) and then stirred at room temperature for 6 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the organic solvent was completely distilled off under reduced pressure. The crude residue was washed with ether to give 4-(6-(aminomethyl)pyridin-3-yl)-6,7-dimethoxyquinoline-3-carbonitrile (3) (150 mg, 0.451 mmol, 88% yield) as a light brown solid.

[1133] Analyze the data: 1 H NMR(400MHz,DMSO)δ9.1(s,1H),8.89(s,1H),8.45(brs,2H),8.19-8.22(dd,1H),7.76 -7.79(dd,1H),7.61(s,1H),6.82(s,1H),4.39-4.41(m,2H),4.02(s,3H),3.74(s,3H).

[1134] LCMS: (M+H + ):m / Z:321.1

[1135] Synthesis of tert-butyl(N-((5-(3-cyano-6,7-dimethoxyquinolin-4-yl)pyridin-2-yl)methyl)sulfamoyl)carbamic acid (5)

[1136]

[1137] To a stirred solution of 4-(6-(aminomethyl)pyridin-3-yl)-6,7-dimethoxyquinoline-3-carbonitrile (3) (200 mg, 0.625 mmol) in dichloromethane (4 mL) at room temperature, diisopropylethylamine (0.326 mL, 1.87 mmol) and N-(1-(N-(tert-butyloxycarbonyl)sulfamoyl)sulfamoyl)pyridine-4(1H)-ylene)-N-methylformamide 4 (210 mg, 0.625 mmol) were added, followed by stirring at room temperature for 16 hours. The reaction progress was monitored by TLC. After the reaction was completed, the organic solvent was completely distilled off under reduced pressure to obtain a crude compound. The crude compound was purified by eluting with 60% ethyl acetate in petroleum ether to afford tert-butyl (N-(5-(3-cyano-6,7-dimethoxyquinolin-4-yl)pyridin-2-yl)methyl)sulfamoylcarbamate (5) (150 mg, 0.30 mmol, 48% yield) as a yellow solid.

[1138] LCMS: (M+H) + :m / Z:499.97

[1139] Preparation of Compound 046

[1140]

[1141] To a stirred solution of tert-butyl (N-(5-(3-cyano-6,7-dimethoxyquinolin-4-yl)pyridin-2-yl)methyl)sulfamoyl)carbamate (5) (150 mg, 0.294 mmol) in 1,4-dioxane (1.0 mL) was added 4M HCl to dioxane (2.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the organic solvent was completely distilled off under reduced pressure to obtain a crude compound. The crude compound was purified by preparative HPLC to obtain a pure compound of compound 046 (85 mg, 0.213 mmol, 66% yield) as an off-white solid.

[1142] Analyze the data: 1 H NMR(400MHz,DMSO)δ9.06(s,1H),8.71-8.72(d,1H),8.08-8.11(dd,1H),7.76-7.78(dd,1H),7 .58(s,1H),7.29-7.31(t,1H),6.85(s,1H),6.77(s,1H),4.35(d,2H),4.0(s,3H),3.73(s,3H).

[1143] LCMS: (M+H) + :m / Z:400.0

[1144] Synthesis of tert-butyl((5-bromopyridin-2-yl)methyl)carbamic acid (6)

[1145]

[1146] At 0 ℃, diisopropylethylamine (2.8mL, 16.04mmol) and di-tert-butyl dicarbonate (1.28mL, 5.88mmol) were added to the stirred solution of (5-bromopyridin-2-yl)methylamine 6 (1g, 5.34mmol) in dichloromethane (20mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction process was monitored by TLC. After completion, the reaction mixture was poured into ice-cold water (500mL) and extracted with DCM (2X100 mL). The combined organic layer was washed with saline solution (200mL), dried over sodium sulfate and concentrated under reduced pressure, and the ((5-bromopyridin-2-yl)methyl)carbamic acid tert-butyl 6 (1.0g, 3.49mmol, 66% yield) obtained was a brown solid.

[1147] Analyze the data: 1 H NMR (400MHz, CDCl3) δ8.6(d,1H),8.00-8.03(dd,1H),7.45(t,1H),7.23(d,1H),4.17(d,1H),1.39(s,9H).

[1148] LCMS:(M-Boc) + :m / Z:287.0

[1149] Preparation of intermediate 9

[1150]

[1151] At room temperature, KOAc (1.02 g, 10.48 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxybenzaldehyde) (1.77 g, 6.99 mmol) were added to a stirred solution of tert-butyl((5-bromopyridin-2-yl)methyl)carbamate 6 (1 g, 3.49 mmol) in dioxane (15 ml), and the reaction mixture was degassed for 30 minutes at room temperature. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (285 mg, 0.34 mmol) was then added again, degassed for 5 minutes, and the reaction mixture was stirred at 100 ° C for 16 hours. The reaction progress was monitored by TLC. After the reaction was completed, the reaction mixture was poured into water (100 mL) and filtered through diatomaceous earth. The diatomaceous earth bed was washed with ethyl acetate (100 mL) and the two layers were separated. The organic layer was washed with brine solution (200 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude product was used directly as the raw material for the next step without purification to obtain Int-9 (1.1 g, crude) as a white solid.

[1152] Overall Plan 10:

[1153]

[1154] Example 10: (N-(2-((5-(6,7-dimethoxyquinazolin-4-yl)pyridin-2-yl)amino)ethyl)sulfonamide hydrochloride

[1155] Step 1: 5-(6,7-dimethoxyquinazolin-4-yl)pyridin-2-ol

[1156]

[1157] To a stirred solution of 4-chloro-6,7-dimethoxyquinazoline 1 (107 mg, 0.48 mmol) in dioxane (7 mL) and water (3 mL) was added (6-hydroxypyridin-3-yl)boronic acid 2 (100 mg, 0.72 mmol) and sodium carbonate (0.15 g, 1.44 mmol). The reaction mixture was then degassed for 30 minutes. Chloro[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (38 mg, 0.048 mmol) was then added, the reaction mixture was again degassed for 5 minutes, and the reaction mixture was stirred at 110°C for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was poured into water (100 mL) and filtered through celite. The celite bed was washed with 10% methanol in dichloromethane (100 mL) and the two layers were separated. The organic layer was washed with brine solution (100 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by 100-200 silica gel column chromatography and eluted with 100% ethyl acetate to give 5-(6,7-dimethoxyquinazolin-4-yl)pyridin-2-ol 3 (57 mg, 0.201 mmol, 45%) as a yellow solid.

[1158] Analytical data: 1H NMR (400MHz, DMSO) δ11.98 (brs, 1H), 9.02 (s, 1H), 7.97 (s, 1H), 7.35 (s, 1H), 7.38 (d, 2H), 6.52 (d, 1H), 3.90 (s, 3H), 3.98 (s, 3H). LCMS: (M+H+): m / Z: 283.9

[1159] Step 2: 4-(6-chloropyridin-3-yl)-6,7-dimethoxyquinazoline

[1160]

[1161] A solution of 5-(6,7-dimethoxyquinazoline-4-yl)pyridine-2-ol 3 (500 mg, 1.766 mmol) and phosphorus oxychloride (16 mL) was stirred at 110 ° C for 2 hours. The reaction progress was monitored by TLC. After the reaction was completed, the reaction mixture was slowly poured into a saturated NaHCO3 solution (100 mL) under cooling and extracted with a 5% methanol solution in dichloromethane (2x50 mL). The combined organic layer was washed with a saline solution (100 mL), dried over sodium sulfate and concentrated under reduced pressure to give 4-(6-chloropyridin-3-yl)-6,7-dimethoxyquinazoline 4 (430 mg, 0.305 mmol, 86%) as an off-white solid.

[1162] Analytical data: LCMS: (M+H+): m / Z: 301.9

[1163] Step 3: N1-(5-(6,7-dimethoxyquinazolin-4-yl)pyridin-2-yl)ethane-1,2-diamine

[1164]

[1165] A solution of 4-(6-chloropyridin-3-yl)-6,7-dimethoxyquinazoline 4 (300 mg, 0.996 mmol) and ethylenediamine (5 mL) was stirred at 100 °C for 5 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was completely distilled under reduced pressure to obtain a crude compound. The crude compound was purified by combi-flash chromatography by eluting 10% methanol in dichloromethane to obtain pure N1-(5-(6,7-dimethoxyquinazoline-4-yl)pyridin-2-yl)ethane-1,2-diamine 5 (130 mg, 0.4 mmol, 40% yield) compound as a light brown solid.

[1166] Analytical data: 1H NMR (400MHz, DMSO) δ9.01 (s, 1H), 8.51 (s, 1H), 7.91 (d, 1H), 7.37 (s, 1H), 7.38 (s, 1H), 6.65 (d, 1H), 3.87 (s, 3H), 3.98 (s, 3H), 2.69-2.72 (m, 4H). LCMS: (M+H+): m / Z: 326.0

[1167] Step 4: tert-Butyl (N-(2-(5-(6,7-dimethoxyquinazolin-4-yl)pyridin-2-yl)amino)ethyl)sulfamoylcarbamate

[1168]

[1169] To a stirred solution of N1-(5-(6,7-dimethoxyquinazolin-4-yl)pyridin-2-ylethane-1,2-diamine 5 (100 mg, 0.307 mmol) in dichloromethane (8 ml) at 0°C, diisopropylethylamine (0.1 ml, 0.461 mmol) and N-(1-(N-(tert-butyloxycarbonyl)sulfamoyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylformamide chloride 6 (156 mg, 0.461 mmol) were added, followed by stirring at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was completely distilled off under reduced pressure to obtain a crude compound. The crude product was purified by 100-200 silica gel column chromatography eluting with 3% methanol in dichloromethane to afford tert-butyl (N-(2-(5-(6,7-dimethoxyquinazolin-4-yl)pyridin-2-yl)amino)ethyl)sulfamoylamino)carboxylate 7 (140 mg, 0.277 mmol, 90% yield) as a light yellow solid.

[1170] Analytical data: 1H NMR (400MHz, DMSO) δ10.92 (bs, 1H), 9.02 (s, 1H), 8.52 (s, 1H), 7.94 (d, 1H), 7.70 (t, 1H), 7.38 (s, 2H), 7.19 (t, 1H), 6.65 (d, 1H), 3.87 (s, 3H), 3.98 (s, 3H), 3.48-3.46 (m, 2H), 3.09-3.08 (m, 2H), 1.38 (s, 9H). LCMS: (M+H+): m / Z: 504.9

[1171] Step 5: (N-(2-(5-(6,7-dimethoxyquinazolin-4-yl)pyridin-2-yl)amino)ethyl)sulfonamide hydrochloride (Compound 048)

[1172]

[1173] To a stirred solution of tert-butyl (N-(2-(5-(6,7-dimethoxyquinazolin-4-yl)pyridin-2-yl)amino)ethyl)sulfamoyl)carbamate 7 (110 mg, 0.216 mmol) in dioxane (2 ml) at 0 degrees Celsius, 4M HCl was added to dioxane (8 mL), and then stirred at room temperature for 6 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the organic solvent was completely distilled off under reduced pressure. The crude product was purified by preparative HPLC to obtain (N-(2-((5-(6,7-dimethoxyquinazolin-4-yl)pyridin-2-yl)amino)ethyl)sulfonamide hydrochloride (Compound 048).

[1174] (41 mg, 0.101 mmol, 46% yield) as a yellow solid.

[1175] Analytical data: 1H NMR (400MHz, DMSO) δ9.02 (s, 1H), 8.53 (s, 1H), 7.94 (d, 1H), 7.38 (s, 2H), 7.18-7.10 (m, 1H), 6.67-6.63 (m, 2H), 6.57 (s, 2H), 3.98 (s, 3H), 3.88 (s, 3H), 3.48-3.51 (m, 2H), 3.11-3.06 (m, 2H). LCMS: (M+H+): m / Z: 405.1

[1176] Compound 050 was prepared based on the general procedure of Example 10.

[1177]

[1178] (400MHz, DMSO) δ8.94(s,1H),7.43(s,1H),7.31(s,1H),6.44(s,3H),3.96(d,6H ),3.18(t,2H),2.85(dd,2H),1.85–1.73(m,2H),1.56–1.46(m,2H),1.42(d,2H). LCMS355.1.MW 390.88

[1179] Overall Plan 11:

[1180]

[1181]

[1182] Example 11: N-(5-(6,7-dimethoxyquinazolin-4-yl)pentyl)sulfonamide

[1183] Step 1: (E)-5-(4,4,5,5-Tetramethyl-1,3,2-dioxirane-2-yl)pent-4-enenitrile

[1184]

[1185] In a sealed tube, pentane-4-alkyne nitrile 1 (500mg, 6.329mmol) was added to a stirred solution of octane (7mL) with pyrrolidine borane (2.4g, 18.987mmol) and 4-(dimethylamino)benzoic acid (52mg, 0.316mmol), and the reaction mixture was stirred at 100°C for 16 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain (E)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pentane crude compound-4-alkene nitrile 2 (600mg, crude product) as a colorless colloidal solid.

[1186] Analytical data: 1H NMR (400 MHz, DMSO) δ7.93 (s, 1H), 6.47 (dt, 1H), 5.45 (d, 1H), 2.66–2.56 (t, 2H), 2.36 (m, 2H), 1.20 (s, 13H).

[1187]

[1188] Step 2: Potassium (E)-(4-cyano-1-en-1-yl) trifluoroborate

[1189]

[1190] Potassium bifluoride (1.35 g, 17.391 mmol) was added to a stirred solution of (E)-5-(4,4,5,5-tetramethyl-1,3,2-dioxybenzoic acid-2-yl)pent-4-enenitrile 2 (600 mg, 2.898 mmol) in methanol (6 mL) and water (6 mL), and the reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After the reaction was completed, the reaction mixture was completely distilled out under reduced pressure, acetone (10 mL) was added to the crude residue and the unwanted solid was filtered out. The filtrate was concentrated under reduced pressure to obtain a crude compound. The crude product was purified by grinding with ether (50 mL) to obtain (E)-(4-cyanobut-1-ene-1-yl)trifluoroborate potassium 3 (200 mg, crude product) as an off-white solid.

[1191] Analytical data: 1H NMR (400 MHz, DMSO) δ 5.47 (dt, 1H), 5.34 (ds, 1H), 2.43 (t, 2H), 2.13 (d, 2H).

[1192] Step 3: (E)-5-(6,7-dimethoxyquinazolin-4-yl)pent-4-enenitrile

[1193]

[1194] Potassium (E)-(4-cyano-1-ene-1-yl) trifluoroborate 3 (183mg, 0.982mmol) and potassium phosphate (946mg, 4.465mmol) were added to a stirred solution of 4-chloro-6,7-dimethoxyquinazoline 4 (200mg, 0.893mmol) in tetrahydrofuran (2.2mL) and water (1.5mL), and the reaction mixture was degassed for 30 minutes. Chloro (2-dicyclohexylphosphino-2', 4', 6'-triisopropyl-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)] palladium (II) (35mg, 0.044mmol) was then added to degas the reaction mixture for 5 minutes again, and the reaction mixture was stirred at 50°C for 16 hours. The reaction progress was monitored by TLC. After the reaction was completed, the reaction mixture was poured into water (100mL) and filtered through diatomaceous earth. The celite bed was washed with 10% methanol in dichloromethane (100 mL) and the two layers were separated. The organic layer was washed with brine solution (100 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by 100-200 silica gel column chromatography eluting with 2% methanol in dichloromethane to give (E)-5-(6,7-dimethoxyquinazolin-4-yl)pent-4-enenitrile 5 (150 mg, 0.557 mmol, 62%) as a brown solid.

[1195] Analytical data: 1H NMR (400 MHz, DMSO) δ8.97 (s, 1H), 7.61 (d, 2H), 7.32–7.22 (m, 2H), 3.98 (d, 6H), 2.83 (t, 2H), 2.72–2.63 (m, 2H).

[1196] The same reaction with the corresponding pinacol borate ester gave the following intermediate

[1197]

[1198]

[1199] Step 4: 5-(6,7-dimethoxyquinazolin-4-yl)pentan-1-amine

[1200]

[1201] To a stirred solution of (E)-5-(6,7-dimethoxyquinazolin-4-yl)pent-4-enenitrile 5 (670 mg, 2.49 mmol) in 1,4-dioxane (25 mL) and water (10 mL) was added lithium hydroxide monohydrate (230 mg, 5.48 mmol), Raney nickel (700 mg) and 10% palladium on carbon (220 mg), and the reaction mixture was stirred at room temperature under a balloon atmosphere of hydrogen for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and the celite bed was washed with 5% methanol in dichloromethane (100 mL). The filtrate was concentrated under reduced pressure. The crude compound was purified by Grace reverse phase method by eluting with 40% acetonitrile in 0.1% formic acid in water to afford 5-(6,7-dimethoxyquinazolin-4-yl)pentan-1-amine 4 (200 mg, 0.727 mmol, 29% yield) as a reddish brown gummy liquid.

[1202] Analytical data: 1H NMR (400 MHz, DMSO) δ8.94 (s, 1H), 8.46 (s, 1H), 7.43 (s, 1H), 7.31 (s, 1H), 3.95 (s, 7H), 3.23–3.17 (t, 2H), 2.64 (t, 2H), 1.79 (m, 2H), 1.51 (m, 2H), 1.40 (m, 2H).

[1203]

[1204] Step 5: tert-Butyl (N-(5-(6,7-dimethoxyquinazolin-4-yl)pentyl)sulfamoyl)carbamate

[1205]

[1206] At 0 ° C, diisopropylethylamine (140 mg, 1.091 mmol) and N-(1-(N-(tert-butyloxycarbonyl)sulfamoyl)pyridine-4(1H)-ylidene)-N-methylformamide 7 (269 mg, 0.8 mmol) were added to a stirred solution of 5-(6,7-dimethoxyquinazolin-4-yl)pentane-1-amine 6 (200 mg, 0.727 mmol) in dichloromethane (5 ml) and then stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion, water (50 mL) was added to the reaction mixture and extracted with dichloromethane (2x50 mL). The combined organic layer was washed with brine solution (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a crude compound. The crude product was purified by 100-200 silica gel column chromatography eluting with 2% methanol in dichloromethane to give tert-butyl (N-(5-(6,7-dimethoxyquinazolin-4-yl)pentyl)sulfamoyl)carbamate (200 mg, 0.44 mmol, 60% yield) as a light brown solid.

[1207] Analytical data: 1H NMR (400 MHz, DMSO) δ10.76 (s, 1H), 8.93 (s, 1H), 7.53 (bs, 1H), 7.42 (s, 1H), 7.31 (s, 1H), 3.96 (s, 6H), 3.18 (t, 2H), 2.89–2.81 (m, 2H), 1.83–1.72 (m, 2H), 1.51 (m, 2H), 1.39 (m, 11H).

[1208]

[1209] Step 6: N-(5-(6,7-dimethoxyquinazolin-4-yl)pentyl)sulfonamide (Compound 051)

[1210]

[1211] To a stirred solution of tert-butyl (N-(5-(6,7-dimethoxyquinazolin-4-yl)pentyl)sulfamoyl)carbamate Int-5 (200 mg, 0.44 mmol) in dioxane (2 ml) at 0°C, 4M HCl was added to dioxane (7 ml), followed by stirring at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the organic solvent was completely distilled off under reduced pressure. The crude product was purified by preparative HPLC to give N-(5-(6,7-dimethoxyquinazolin-4-yl)pentyl)sulfonamide (50 mg, 0.141 mmol, 29% yield) as a light yellow solid.

[1212] Analytical data: 1H NMR (400 MHz, DMSO) δ8.94 (s, 1H), 7.43 (s, 1H), 7.31 (s, 1H), 6.44 (s, 3H), 3.96 (d, 6H), 3.18 (t, 2H), 2.85 (dd, 2H), 1.85–1.73 (m, 2H), 1.56–1.46 (m, 2H), 1.42 (d, 2H).

[1213]

[1214] In vitro biology

[1215] Example 1: ENPP1 assay (TMP)

[1216] Material:

[1217] Assay buffer: 1 mM CaCl2, 0.2 mM ZnCl2, 50 mM Tris, pH 9.0

[1218] Substrate: 1.5 mM thymidine 5'-monophosphate disodium hydrate (Sigma: T4510) – Assay concentration: 150 μM

[1219] Enzyme: 1 ng / μL recombinant human ENPP-1 protein (purified in-house) - assay concentration: 5 ng / well

[1220] DMSO

[1221] 96-well transparent assay plate

[1222] protocol:

[1223] Ten point serial dilutions of the drug were prepared in 10 times of the assay buffer, and the final assay concentrations were 10 μM, 3 μM, 1 μM, 0.3 μM ... 0 μM. The dilution containing DMSO was used as a control. The assay plate was set up as follows, with duplicates for each well: 75 μL assay buffer + 10 μL ENPP1 inhibitor or DMSO dilution + 10 μL substrate + 5 μL enzyme (5 ng). Both enzyme and substrate were added to the opposite side of the well to ensure that there was no interaction until all wells had two components. The plate was then gently centrifuged for 10 seconds and then incubated at 37 ° C for 45 minutes. The reaction was quantified by measuring the absorbance at 405 nm using an Envision plate reader. Data were analyzed using GraphPad Prism8.0.

[1224] The results are shown in Table 1 below:

[1225] Table 1

[1226]

[1227]

[1228] Example 2: ENPP1 thermal shift assay

[1229] Material:

[1230] Recombinant human ENPP-1 protein (purified in-house)

[1231] Assay buffer (1 mM CaCl2, 0.2 mM ZnCl2, 50 mM Tris, pH 9.0)

[1232] 5000X SYPRO Orange (Thermo Fisher Scientific, catalog number S6651)

[1233] 384-well PCR plate

[1234] protocol:

[1235] Methods: Each drug was prepared as a 10-fold solution in assay buffer, and SYPRO Orange was diluted to a 10-fold concentration in water. Wells were set up in duplicate in a 384-well PCR plate as follows: 14 μL assay buffer, 2 μL ENPP1 inhibitor or DMSO, 2 μL (0.5 μg) ENPP1 protein. Each well was mixed and incubated on ice for 5 minutes. After incubation, 2 μL of SYPRO Orange was mixed into each well and then gently centrifuged. Protein melting reactions were run using ViiA7 software, starting at 25°C, increasing by 0.05°C / s, with a maximum temperature of 99°C.

[1236]

[1237] Example 3: ENPP2 assay

[1238] Material:

[1239] Assay buffer: 10 mM CaCl2, 5 mM MgCl2, 50 mM Tris, 0.02% Brij-35, pH 8.5 Substrate: 20 mM bis(p-nitrophenyl)phosphate sodium salt (BPNPP) (Sigma, catalog number N3002) Enzyme: 0.01 ng / μL recombinant human ENPP-2 / autophagy toxin (rhENPP-2) (R&D catalog number 5255-EN)

[1240] DMSO

[1241] PF8380(Selleck S8218)

[1242] 96-well transparent assay plate

[1243] protocol:

[1244] Eight-point serial dilutions of the drug were prepared in 10 times of the assay buffer, with the final assay concentration starting from 10 μM, 3 μM, 1 μM, 0.3 μM ... 0 μM. Dilutions containing DMSO were used as controls. The assay plate was set up as follows, with duplicates for each well: 81 μL assay buffer + 10 μL ENPP1 inhibitor or dimethyl sulfoxide + 5 μL substrate + 5 μL enzyme (0.05 ng). Both enzyme and substrate were added to the opposite side of the well to ensure that there was no interaction until all wells had two components. The plate was then gently centrifuged for 10 seconds and then incubated at 37 ° C for 10 minutes. The reaction was quantified by measuring the absorbance at 400 nm using Envision. PF8380 was used as a positive control for the assay. Data were analyzed using GraphPad Prism8.0.

[1245]

[1246] Example 4: Cell-based ENPP selectivity assay (TMP)

[1247] Material:

[1248] HEK293T cells

[1249] Culture medium: 89% DMEM, 10% FBS, 1% penicillin / streptomycin

[1250] Transfection reagent: polyethyleneimine branched chain, 1 mg / mL (Sigma: 408719)

[1251] Transfection medium: Opti-MEM low serum medium (Thermo Fisher Scientific: 31985088)

[1252] Plasmid construction:

[1253] pCMV6 empty construct (origin: PS100001)

[1254] hENPP1 (Origin: RC209222)

[1255] hENPP3 (gene script: OHu19400D)

[1256] mENPP1 (Origin: MR227498)

[1257] Assay buffer: 1mM CaCl2, 0.2mM ZnCl2, 50mM Tris, pH 9.0

[1258] Substrate: 8 mM thymidine 5'-monophosphate disodium salt hydrate (Sigma No. T7004-1G)

[1259] 6-well tissue culture treated plates

[1260] 96-well transparent assay plate

[1261] protocol:

[1262] HEK293T cells were grown at 5x10 5个 Cells were seeded in 6-well tissue culture treated plates. The transfection mixture containing 7 μL transfection reagent, 2 μg plasmid construct and 200 μL transfection medium was incubated at room temperature for 20 minutes. The transfection mixture was added dropwise to each well and incubated at 37°C / 5% CO2 for 48 hours. The transfected cells were collected by trypsin digestion, lysed and the protein concentration was determined. The drugs were prepared in 10 times the assay buffer and tested at a final assay concentration of 1 μM. The lysate (3 μg) was incubated with 10 μL ENPP1 inhibitor and 81 μL assay buffer at 4°C for 2 hours before adding 5 μL substrate. The final reaction was incubated at 37°C for 45 minutes and quantified by measuring the absorbance at 405nm using an Envision plate reader. The data was normalized to the empty construct control.

[1263] The results are as follows Figure 1 shown.

[1264] Example 5: Solubility and stability determination

[1265] Material:

[1266] PBS pH 7.4 (Catalog No. 10010-031; from Thermo Fisher Scientific),

[1267] FaSSIF (pH 6.5), FeSSIF (pH 5.0), and FaSSGF (pH 1.6) aqueous buffer (Cat. Nos. FFF01, FASBUF01, FESBUF01, FASBUF01 from biorelevant.com)

[1268] protocol:

[1269] 1 mg of powder of each compound was mixed with 1 mL of buffer to make a 1 mg / mL mixture. The samples were stirred overnight at room temperature in a magnetic stirrer with beads. The samples were then passed through a 0.45 μ PTFE syringe filter. The filtrate was diluted with the corresponding buffer before analysis. All samples were measured by UV-Vis spectrophotometry (Thermo Fisher Scientific, UV Spectrophotometer 8000) against standards. The samples were kept at room temperature (room temperature) and aliquots were subjected to UV-Vis spectrophotometric analysis at the corresponding time points to measure stability.

[1270] Example 6: Immuno-penetration assay

[1271] Material:

[1272] HPAC (ATCC catalog number: CRL-2119)

[1273] Matrigel Growth Factor Reduced (Corning Catalog Number: 354230)

[1274] 96-well spheroid microplate: ULA, round bottom, black wall plate (Corning catalog number: 10185-094)

[1275] Corning HTS Transwell 96-well Permeable Scaffold, 5 μm (Corning catalog number: 3387)

[1276] DMEM, high glucose, HEPES, without phenol red (Thermo Fisher Scientific catalog number: 21063045) Human PBMC peripheral blood mononuclear cells, cryo-amplifier (Lonza catalog number: CC-2702)

[1277] Molecular Probes CellTracker CM DiI Dye (Thermo Fisher Scientific catalog number: C7000)

[1278] 10 times drug

[1279] protocol:

[1280] HPAC cells were cultured according to ATCC guidelines. On the first day of the experiment, 5,000 cells were seeded in a 96-well spheroid microplate in 50 μL of culture medium containing 1.5% matrix gel. The cells were centrifuged at 1800 RPM for 2 minutes and then cultured at low speed on a plate stirrer at 37°C / 5% CO2 for 72 hours to allow each well to form a single sphere. After incubation, 150 μL of culture medium containing vehicle (dimethyl sulfoxide) or drug was added to each corresponding well and incubated at 37°C / 5% CO2 for 1 hour. During the incubation, human PBMCs were counted and fluorescently stained with molecular probe CellTracker CM DiI dye according to the manufacturer's protocol. After incubation with drugs for 1 hour, the transwell plate was gently placed into the spheroid plate. The PBMCs were then washed and added to each corresponding well at 400,000 cells / 100 μL of culture medium. The experiment was permeated for 48 hours at 37°C / 5% CO2 to allow immune cells to infiltrate the spheroids. After incubation, the transwell was removed and RFP fluorescence and bright field Z stack images were taken for each spheroid using Biotek Cytation5. Images were compressed and total RFP expression was assessed. Data were analyzed using GraphPad Prism 8.0.

[1281] Prophetic Pharmaceutical Composition Examples

[1282] As used throughout these examples, "active ingredient" refers to a compound of the invention, or one or more of its pharmaceutically acceptable salts, solvates, polymorphs, hydrates, and stereochemical isomers. The following examples of formulations of the compounds of the invention in tablets, suspensions, injectables, and ointments are prophetic.

[1283] Typical examples of formulations of the present invention are as follows. Various other dosage forms may be used herein, such as filled gelatin capsules, liquid emulsions / suspensions, ointments, suppositories or chewable tablet forms, using the disclosed compounds in the desired dosage according to the present invention. Predicted pharmaceutical compositions may be prepared using various conventional techniques for preparing suitable dosage forms, such as those disclosed herein and in standard reference texts, such as the Briti...

Claims

1. A compound of formula II: in X is N or C-CN; Z is C or N; W is selected from the group consisting of: C1-C5 alkyl, -C(=O)-(CH2) n -, -(C1-C5 alkyl)-NH-; NH and direct bonds; Each of R1, R2 and R3 is independently selected from the group consisting of hydrogen, CH3O, pyrazole or -OCH2C(=O)NH2, Where n is an integer between 1 and 3; R 7、 R8 and R9 are independently selected from the group consisting of H, halogen and C1-C6 alkyl, except that when Z is N, R7 is absent; or R8 and R9 are selected such that yes R 10 It is hydrogen; or an isomer or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein Z is N.

3. The compound according to claim 1, wherein R1, R2 and R3 are selected from CH3O or H.

4. The compound according to claim 1, wherein X is N.

5. The compound according to claim 1, wherein X is C-CN.

6. The compound according to claim 1, wherein R 7、 R8 and R9 are independently selected from the group consisting of H and halogen.

7. The compound according to claim 1, wherein R7 is halogen.

8. The compound according to claim 7, wherein The halogen is F.

9. The compound according to claim 1, wherein R8 and R9 are both halogen.

10. The compound according to claim 9, wherein The halogen is F.

11. The compound according to claim 1, wherein X is N; Z is N; W is selected from the group consisting of: C1-C5 alkyl, -C(=O)-(CH2)-, -(C1-C5 alkyl)-NH-; and a direct bond; and R1, R2 and R3 are selected from CH3O or H.

12. A compound selected from the group consisting of:

13. The compound according to claim 1, having the following structure: or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 1, having the following structure: or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 1, having the following structure: or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 1, having the following structure: or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 1, having the following structure: or a pharmaceutically acceptable salt thereof.

18. The compound according to claim 1, having the following structure: or a pharmaceutically acceptable salt thereof.

19. A compound having the following structure: or a pharmaceutically acceptable salt thereof.

20. The compound according to claim 1, having the following structure: or a pharmaceutically acceptable salt thereof.

21. The compound according to claim 1, having the following structure: or a pharmaceutically acceptable salt thereof.

22. A compound having the following structure: or a pharmaceutically acceptable salt thereof.

23. The compound according to claim 1, having the following structure: or a pharmaceutically acceptable salt thereof.

24. A compound having the following structure: or a pharmaceutically acceptable salt thereof.

25. A compound having the following structure: or a pharmaceutically acceptable salt thereof.

26. The compound according to claim 1, having the following structure: or a pharmaceutically acceptable salt thereof.

27. The compound according to claim 1, having the following structure: or a pharmaceutically acceptable salt thereof.

28. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 27 and a pharmaceutically acceptable carrier.

29. Use of a compound according to any one of claims 1 to 27 in the preparation of a medicament for treating an uncontrolled cell proliferation disorder in a mammal by targeting ENPP1.

30. Use of a compound according to any one of claims 1 to 27 in the preparation of a medicament for treating cancer in a mammal by targeting ENPP1.

31. The use according to claim 30, wherein The cancer is a solid tumor.

32. The use according to claim 30, wherein The cancer is a liquid tumor.

33. Use of a compound according to any one of claims 1 to 27 in the preparation of a medicament for treating an infection in a mammal by targeting ENPP1.

34. The use according to claim 33, wherein The infection is a viral infection.

35. The use according to claim 34, wherein The viral infection is caused by a DNA virus.

36. The use according to claim 34, wherein The viral infection is caused by an RNA virus.

37. The use according to claim 33, wherein The infection is a bacterial infection.

Images