Tetracyclic derivatives, compositions and methods thereof

Abstract

The invention provides novel tetracyclic compounds and derivatives thereof, and pharmaceutical compositions thereof and methods for treating diseases and disorders, such as various types of cancer.

Description

Patent ApplicationAtty. Docket No. ENTX-035PCTTETRACYCLIC DERIVATIVES, COMPOSITIONS AND METHODS THEREOFPriority Claims and Related Applications

[0001] This application claims the benefit of priority to U.S. Provisional Application Nos. 63 / 701,035, filed September 30, 2024; 63 / 728,809, filed December 6, 2024; and 63 / 775,617, filed March 21, 2025, the entire content of each of which is incorporated herein by reference for all purposes.Technical Fields of the Invention

[0002] The invention generally relates to novel compounds and therapeutic uses thereof. More particularly, the invention provides novel tetracyclic compounds and derivatives thereof that are shown to be potent and selective inhibitors of KRas, in particular KRas G12D and G12V. The invention also provides pharmaceutical compositions comprising compounds of the invention and methods for treating diseases and disorders associated with or related to KRas activities, such as various types of cancer.Background of the Invention

[0003] KRAS (Kirsten rat sarcoma virus) is a gene that provides instructions for making a protein called KRas, a part of the RAS / MAPK pathway. The protein relays signal from outside the cell to the cell's nucleus instructing the cell to grow and divide (proliferate) or to mature and take on specialized functions (differentiate). KRas serves as a molecular switch cycling between inactive (GDP-bound) and active (GTP -bound) states to transduce upstream cellular signals received from multiple tyrosine kinases to downstream effectors to regulate a wide variety of processes, such as cellular proliferation. The role of activated KRas in malignancy was first observed over thirty years ago. (Santos et al. 1984 Science 223:661-664; Alamgeer et al. 2013 Current Opin Pharmcol.13:394-401.)

[0004] KRas mutation occurs in nearly 30% of human cancers. For example, mutations of KRas are observed in pancreatic ductal adenocarcinomas, colon and rectal carcinomas, and nonsmall cell lung carcinomas. RAS mutations are dominated by single-base missense mutations. The replacement of the amino acid glycine at position 12 is by far the most prevalent mutationPatent ApplicationAtty. Docket No. ENTX-035PCT and are referred to as G12D, G12V, G12C, G12R and others, depending on which amino acid replaces the glycine. G12D is the most prevalent (35%) followed by G12V (29%) and G12C (21%). (Zhu, et al. 2022 Molecular Cancer 21, 159; Punekar, et al. 2022 Nat Rev Clin Oncol. 19(10): 637-655; Huang, et al. 2021 Signal Transd. and Targeted Ther. 6, 386.)

[0005] Despite extensive efforts over the past thirty years to develop inhibitors of KRas to treat cancer, only two G12C inhibitors Sotorasib and Adagrasib and approved. No KRas G12D or G12V inhibitor has been clinically demonstrated with sufficient safety and / or efficacy to warrant regulatory approval. (Oya, et al. 2023 Tr ansi Lung Cancer Res. 12(5): 940-943;McCormick 2015 Clin Cancer Res. 21 (8): 1797-1801 ; Sun et al. 2012 Agnew Chem Int Ed Engl. 51(25):6140-6143; Ostrem et al. 2013 Nature 503:548-551; Fell et al. 2018 ACSMed. Chem. Lett. 9: 1230-1234; Cox, et al. 2014 Nature Rev Drug Discov. 13 (11), 828-51; Patricelli et al. 2016 Cancer Discov. 6(3), 316-29; Hunter et al. 2015 Mol Cancer Res. 13(9), 1325-35.)

[0006] There remains an urgent need for potent and selective KRas inhibitors, in particular, inhibitors of KRas mutants, especially G12D and G12V, that are safe and effective in treating diseases and conditions associated with aberrant expression of KRAS, such as various types of cancer ( .g., ductal cancer, colorectal cancer, rectal cancer, cell lung cancer).Summary of the Invention

[0007] The invention provides novel quinazoline and aza-quinazoline derivatives as pan- KRas inhibitors, in particular Kras G12D, Kras G12V, Kras G12C and wild-type amplified inhibitors, which have been shown to exhibit favorable potency and selectivity profiles over known KRas inhibitors. These novel compounds selectively target, bind to, inhibit and / or modulate the activity of KRas. Compounds of the invention are orally available with pharmacokinetic profiles suitable for development into an orally administered therapeutic agent for treating various diseases and disorders associated with or related to KRas activities, such as various types of cancer.

[0008] In one aspect, the invention generally relates to a compound having the structural formula (I):Patent ApplicationAtty. Docket No. ENTX-035PCTor a pharmaceutically acceptable form or an isotope derivative thereof, wherein n is 0, 1 or 2;X is O or CRX1RX2, wherein each of RX1and RX2is independently selected from H, halo and unsubstituted or substituted C1.3 alkyl;Y is O, S, NRY1, C=O, C=N-OR, CRY2RY3or S(O)2, whereinRY1is R, CN, C(O)RY4or C(O)ORY5, and each of RY2and RY3is independently selected from halo, CN, R, OR and NRC(O)NR', each of RY4and RY5is H, unsubstituted or substituted C1-6 alkyl or unsubstituted or substituted 3- to 6-membered carbocyclic ring;Z is CR6or N;R2is (CH2)iR2or (CD2)iR2, wherein 7 is an integer selected from 1-6, and (CH2)i is optionally substituted, wherein R2’ is selected from the group consisting of H, halogen, CN, OH, C(O)NRR’, unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted 3- to 6-membered carbocyclic ring, unsubstituted or substituted 4- to 6-membered heterocyclic ring and unsubstituted or substituted 7- to 10-membered bicyclic heterocyclic ring;R6is selected from the group consisting of H, halogen, CN, OR, unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted C1-6 alkoxy, C(O)NRR’, NRR’, S(O)2CHs, unsubstituted or substituted 3- to 6-membered carbocyclic or heterocyclic ring, and unsubstituted or substituted 5- to 6-membered heteroaryl;R7is an unsubstituted or substituted 6- to 14-membered unsaturated monocyclic, bicyclic or multi-cyclic ring, comprising 0-5 heteroatoms selected from N, O and S;Patent ApplicationAtty. Docket No. ENTX-035PCTR8is H, halo, unsubstituted or substituted Ci-6 alkyl, CN, OR or NRR’; each R10aand R10bis independently halo, CN, R or OR; or R10aand R10b, together with the carbon atom they are bonded to, form a cyclopropyl, cyclobutyl or oxetane group; and each R12aand R12bis independently selected from halo, CN, R or OR, or CR12aR12bis C=O; or R12aand R12b, together with the carbon atom they are bonded to, form a cyclopropyl, cyclobutyl or oxetane group; each R14aand R14bis independently selected from halo, CN, R or OR, or CR14aR14bis C=O; or R14aand R14b, together with the carbon atom they are bonded to, form a cyclopropyl, cyclobutyl or oxetane group; each R15aand R15bis independently selected from halo, CN, R or OR, or CR15aR15bis C=O or C=N-OR; or R15aand R13b, together with the carbon atom they are bonded to, form a cyclopropyl, cyclobutyl or oxetane group; each R16aand R16bis independently selected from halo, CN, R or OR; or R16aand R16b, together with the carbon atom they are bonded to, form a cyclopropyl or cyclobutyl group; provided that one of R12aand R12b, together with one of R14aand R14b, one of R15aand R15b, or one of R16aand R16b, may form a 4- to 7-membered carbocyclic or heterocyclic ring; one of R14aand R14b, together with one of R15aand R15b, or one of R16aand R16b, may form a 3- to 7-membered carbocyclic or heterocyclic ring; one of R1?aand R1?b, together with one of R16aand R16b, may form a 3- to 7- membered carbocyclic or heterocyclic ring; and each of R and R’ is independently selected from H, D, unsubstituted or substituted Ci-6 alkyl, or unsubstituted or substituted 3- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom, together form an unsubstituted or substituted 4- to 7-membered heterocyclic ring.

[0009] In another aspect, the invention generally relates to a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, or diluent.

[0010] In yet another aspect, the invention generally relates to a unit dosage form comprising a pharmaceutical composition disclosed herein.Patent ApplicationAtty. Docket No. ENTX-035PCT

[0011] In yet another aspect, the invention generally relates to a method for inhibiting cell proliferation in vitro or in vivo, comprising contacting a cell with an effective amount of a compound disclosed herein.

[0012] In yet another aspect, the invention generally relates to a method for modulating (e.g., inhibiting or reducing) a KRas activity in a cell, comprising contacting the cell with a compound disclosed herein.

[0013] In yet another aspect, the invention generally relates to a method for treating a disease or disorder mediated by a Ras mutant protein, comprising administering to a subject in need thereof a therapeutically effective amount of the compound disclosed herein.

[0014] In yet another aspect, the invention generally relates to a method for treating or reducing cancer, or a related disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of the compound disclosed herein.

[0015] In yet another aspect, the invention generally relates to a method for treating or reducing cancer, or a related disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of the compound disclosed herein.

[0016] In yet another aspect, the invention generally relates to use of a compound disclosed herein, and a pharmaceutically acceptable excipient, carrier, or diluent, in preparation of a medicament for treating a disease or disorder.Definitions

[0017] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. General principles of organic chemistry, as well as specific functional moieties and reactivity, are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 2006.

[0018] As used herein, “at least” a specific value is understood to be that value and all values greater than that value.

[0019] The term “comprising”, when used to define compositions and methods, is intended to mean that the compositions and methods include the recited elements, but do not exclude other elements. The term “consisting essentially of’, when used to define compositions and methods, shall mean that the compositions and methods include the recited elements and exclude other elements of any essential significance to the compositions and methods. For example,Patent ApplicationAtty. Docket No. ENTX-035PCT“consisting essentially of’ refers to administration of the pharmacologically active agents expressly recited and excludes pharmacologically active agents not expressly recited. The term consisting essentially of does not exclude pharmacologically inactive or inert agents, e.g., pharmaceutically acceptable excipients, carriers or diluents. The term “consisting of’, when used to define compositions and methods, shall mean excluding trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention.

[0020] Unless specifically stated or obvious from context, as used herein, the term “about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. About can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from context, all numerical values provided herein can be modified by the term about.

[0021] As used herein, the terms “administration” of or “administering” a disclosed compound encompasses the delivery to a subject of a compound as described herein, or a prodrug or other pharmaceutically acceptable form thereof, using any suitable formulation or route of administration, as discussed herein.

[0022] As used herein, the term “co-administer” refers to the presence of two pharmacological agents in a subject’s body (e.g., in the blood) at the same time. The two pharmacological agents can be administered concurrently or sequentially.

[0023] The terms “disease”, “disorder” and “condition” are used interchangeably unless indicated otherwise.

[0024] As used herein, the terms "effective amount" or "therapeutically effective amount" refer to that amount of a compound or pharmaceutical composition described herein that is sufficient to achieve the intended application including, but not limited to, disease treatment, as illustrated below.

[0025] In some embodiments, the amount is that is sufficient to negatively modulate or inhibit the activity of KRas (G12D). In some embodiments, the amount is that is sufficient to negatively modulate or inhibit the activity of KRas (G12V). In some embodiments, the amount is that is sufficient to negatively modulate or inhibit the activity of KRas (G12C). In some embodiments, the amount is that is sufficient to negatively modulate or inhibit the activity of KRas (G12R). In some embodiments, the amount is that effective for reduction or ameliorationPatent Application Atty. Docket No. ENTX-035PCT of a symptom to stop or reversion of progression of a disease or disorder such as cancer. In some embodiments, the amount is that effective for detectable killing or inhibition of the growth or spread of cancer cells; the size or number of tumors; or other measure of the level, stage, progression or severity of the cancer.

[0026] The therapeutically effective amount can vary depending upon the intended application, or the subject and disease condition being treated, e.g., the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the weight and age of the patient, which can readily be determined by one of ordinary skill in the art. Such amount may be administered as a single dosage or according to a regimen. The term also applies to a dose that will induce a particular response in target cells, e.g., reduction of cell migration. The specific dose will vary depending on, for example, the particular compounds chosen, the species of subject and their age / existing health conditions or risk for health conditions, the dosing regimen to be followed, the severity of the disease, whether it is administered in combination with other agents, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

[0027] As used herein, the terms “KRas(G12#)” or “KRas G12#” (# being D, V, C, etc.) are used interchangeably and refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of an aspartic acid for a glycine at amino acid position 12. The assignment of amino acid codon and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P011 16: Variantp.Glyl2Asp.

[0028] As used herein, an “inhibitor” of “KRas(G12#)” or “KRas G12#” (# being D, V, C, etc.) refers to a compound of the invention capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of KRas G12#. A "Pan-" KRas inhibitor refers to a compound that is active with regard to two or more G12 variants.

[0029] As used herein, a “KRas G12#-associated” (# being D, V, C, etc.) disease or disorder refers to diseases or disorders associated with or mediated by or having a corresponding KRas G12 mutation. Examples of KRas G12#-associated diseases or disorders include various KRas G12#-associated cancer types.

[0030] As used herein, the term “contacting” refers to the bringing together of indicated moielies in vitro or in vivo. For example, “contacting” a KRas G12# (# being D, V, C, etc with a compound disclosed herein includes the administration of the compound to a subject havingPatent ApplicationAty. Docket No. ENTX-035PCTKRas (312#, as well as, for example, introducing the compound into a sample containing a cellular or purified preparation containing the KRas G12#. In some embodiments, a cell in which inhibition of KRas G12# activity is desired is contacted with an effective amount of a compound disclosed herein or pharmaceutically acceptable form thereof to negatively modulate the activity of KRas G12#. By negatively modulating the activity of KRas G12#, the methods disclosed herein are designed to inhibit undesired cellular proliferation resulting from enhanced KRas G 12# activity within the cell. The cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to achieve the desired negative modulation of KRas G12#. The ability of compounds to bind KRas G12# may be monitored in vitro using methods known in the art. The inhibitory activity of exemplary compounds in cells may be monitored, for example, by measuring the inhibition of KRas G12# activity using methods known in the art.

[0031] As used herein, the terms “unsubstituted or substituted” and “optionally substituted” are used interchangeably and refer to where a given chemical moiety (e.g., an alkyl group) can (but is not required to) be bonded to other substituents (e.g., heteroatoms). For instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (e.g., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents different from hydrogen. For instance, it can, at any point along the chain be bounded to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term “optionally substituted” means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any further functional groups. Suitable substituents used in the optional substitution of the described groups include, without limitation, halogen, oxo, CN, - COOH, -CH2CN, -O-CI-C6alkyl, Ci-C6alkyl, -OCi-C6alkenyl, -OCi-C6alkynyl, -Ci-C6alkenyl, -Ci-C6alkynyl, -OH, -OP(O)(OH)2, -OC(O)Ci-C6alkyl, -C(O)Ci-C6alkyl, -OC(O)OCi- C6alkyl, NH2, NH(CI-C6alkyl), N(CI-C6alkyl)2, -NHC(O)CI-C6alkyl, -C(O)NHCI-C6alkyl, - S(O)2-Ci-C6alkyl, -S(O)NHCI-C6alkyl, and S(O)N(CI-C6alkyl)2.

[0032] As used herein, a “pharmaceutically acceptable form” of a disclosed compound includes, but is not limited to, pharmaceutically acceptable salts, esters, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives of disclosed compounds. In one embodiment, a "pharmaceutically acceptable form" includes, but is not limited to, pharmaceutically acceptable salts, esters, isomers, prodrugs and isotopically labeled derivativesPatent Application Atty. Docket No. ENTX-035PCT of disclosed compounds. In some embodiments, a "pharmaceutically acceptable form" includes, but is not limited to, pharmaceutically acceptable salts, esters, stereoisomers, prodrugs and isotopically labeled derivatives of disclosed compounds.

[0033] In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. In some embodiments, organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, trifluoracetic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[0034] The salts can be prepared in situ during the isolation and purification of the disclosed compounds, or separately, such as by reacting the free base or free acid of a parent compoundPatent ApplicationAtty. Docket No. ENTX-035PCT with a suitable base or acid, respectively. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Ci-4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, such as isopropyl amine, trimethylamine, diethylamine, tri ethyl amine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt can be chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[0035] In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable ester. As used herein, the term "pharmaceutically acceptable ester" refers to esters that hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Such esters can act as a prodrug as defined herein. Pharmaceutically acceptable esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl esters of acidic groups, including, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfinic acids, sulfonic acids and boronic acids. Examples of esters include formates, acetates, propionates, butyrates, acrylates and ethylsuccinates. The esters can be formed with a hydroxy or carboxylic acid group of the parent compound.

[0036] In certain embodiments, the pharmaceutically acceptable form is a “solvate” (e. ., a hydrate). As used herein, the term “solvate” refers to compounds that further include a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. The solvate can be of a disclosed compound or a pharmaceutically acceptable salt thereof. Where the solvent is water, the solvate is a "hydrate". Pharmaceutically acceptable solvates and hydrates are complexes that, for example, can include 1 to about 100, or 1 to about 10, or 1 to about 2, about 3 or about 4, solvent or water molecules. It will be understood that the term "compound" as used herein encompasses the compound and solvates of the compound, as well as mixtures thereof.Patent ApplicationAtty. Docket No. ENTX-035PCT

[0037] In certain embodiments, the pharmaceutically acceptable form is a prodrug. As used herein, the term “prodrug” (or “pro-drug”) refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable form of the compound. A prodrug can be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis (e.g., hydrolysis in blood). In certain cases, a prodrug has improved physical and / or delivery properties over the parent compound. Prodrugs can increase the bioavailability of the compound when administered to a subject (e.g., by permitting enhanced absorption into the blood following oral administration) or which enhance delivery to a biological compartment of interest (e.g., the brain or lymphatic system) relative to the parent compound. Exemplary prodrugs include derivatives of a disclosed compound with enhanced aqueous solubility or active transport through the gut membrane, relative to the parent compound.

[0038] The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7- 9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein. Exemplary advantages of a prodrug can include, but are not limited to, its physical properties, such as enhanced water solubility for parenteral administration at physiological pH compared to the parent compound, or it can enhance absorption from the digestive tract, or it can enhance drug stability for long-term storage.

[0039] As used herein, the term “pharmaceutically acceptable excipient, carrier, or diluent” refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth;Patent ApplicationAtty. Docket No. ENTX-035PCT malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polypropylene oxide copolymer as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0040] As used herein, the term “subject” refers to any animal (c. ., a mammal), including, but not limited to humans, non-human primates, rodents, and the like, which is to be the recipient of a particular treatment. Typically, the terms “subject” and “patient” are used interchangeably herein in reference to a human subject.

[0041] In some embodiments, the subject has experienced and / or exhibited at least one symptom of the disease or disorder to be treated with a compound disclosed herein and / or according to a herein disclosed method. In some embodiments, the subject has been identified or diagnosed as having a cancer having a KRas G12# (# being D, V, C, etc.) mutation. In some embodiments, the subject has a cancer that is positive for a KRas G12# mutation. In some embodiments, the subject is suspected of having a KRas G12# gene-associated cancer.

[0042] In some embodiments of any of the methods or uses described herein, an assay is used to determine whether the subject has KRas G12# (# being D, V, C, etc.) mutation using a sample (e g., a biological sample or a biopsy sample (e g , a paraffin-embedded biopsy sample) from a subject. Various techniques may be employed, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, break apart FISH analysis, Southern blotting. Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR).

[0043] As used herein, the terms “treatment” or “treating” a disease or disorder refers to a method of reducing, delaying or ameliorating such a condition before or after it has occurred. Treatment may be directed at one or more effects or symptoms of a disease and / or the underlying pathology. Treatment is aimed to obtain beneficial or desired results including, but not limited to,Patent ApplicationAtty. Docket No. ENTX-035PCT therapeutic benefit and / or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient can still be afflicted with the underlying disorder. For prophylactic benefit, the pharmaceutical compounds and / or compositions can be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. The treatment can be any reduction and can be, but is not limited to, the complete ablation of the disease or the symptoms of the disease. As compared with an equivalent untreated control, such reduction or degree of prevention is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100% as measured by any standard technique.

[0044] As used herein, the term "therapeutic effect" refers to a therapeutic benefit and / or a prophylactic benefit as described herein. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0045] Compounds of the present invention are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 95% (“substantially pure”), which is then used or formulated as described herein. In certain embodiments, the compounds of the present invention are more than 99% pure.

[0046] Solvates and polymorphs of the compounds of the invention are also contemplated herein. Solvates of the compounds of the present invention include, for example, hydrates.

[0047] As used herein, the term an “isolated” or “substantially isolated” molecule (such as a polypeptide or polynucleotide) is one that has been manipulated to exist in a higher concentration than in nature or has been removed from its native environment. For example, a subject antibody is isolated, purified, substantially isolated, or substantially purified when at least 10%, or 20%, or 40%, or 50%, or 70%, or 90% of non-subject-antibody materials with which it is associated in nature have been removed. For example, a polynucleotide or a polypeptide naturally present in a living animal is not "isolated," but the same polynucleotide or polypeptide separated from the coexisting materials of its natural state is "isolated." Further, recombinant DNA moleculesPatent ApplicationAtty. Docket No. ENTX-035PCT contained in a vector are considered isolated for the purposes of the present invention. Isolated RNA molecules include in vivo or in vitro RNA replication products of DNA and RNA molecules. Isolated nucleic acid molecules further include synthetically produced molecules. Additionally, vector molecules contained in recombinant host cells are also isolated. Thus, not all “isolated” molecules need be “purified.”

[0048] As used herein, the term “purified” when used in reference to a molecule, it means that the concentration of the molecule being purified has been increased relative to molecules associated with it in its natural environment, or environment in which it was produced, found or synthesized. Naturally associated molecules include proteins, nucleic acids, lipids and sugars but generally do not include water, buffers, and reagents added to maintain the integrity or facilitate the purification of the molecule being purified. According to this definition, a substance may be 5% or more, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, 98% or more, 99% or more, or 100% pure when considered relative to its contaminants.

[0049] Definitions of specific functional groups and chemical terms are described in more detail below. When a range of values is listed, it is intended to encompass each value and subrange within the range. For example, “Ci-4 alkyl” is intended to encompass, Ci, C2, C3, C4, C1-3, C1-2, C2-4, C3-4 and C2-3 alkyl groups.

[0050] As used herein, the term “alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms (e.g., C1-10 alkyl). Whenever it appears herein, a numerical range such as “1 to 10” refers to each integer in the given range; e.g. “1 to 10 carbon atoms” means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated. In some embodiments, “alkyl” can be a C1-6 alkyl group. In some embodiments, alkyl groups have 1 to 10, 1 to 8, 1 to 6, or 1 to 3 carbon atoms. Representative saturated straight chain alkyls include, but are not limited to, -methyl, - ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; while saturated branched alkyls include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, 3- methylbutyl, 2-m ethylpentyl, 3 -methylpentyl, 4-m ethylpentyl, 2-methylhexyl, 3 -methylhexyl, 4- methylhexyl, 5-methylhexyl, 2,3 -dimethylbutyl, and the like. The alkyl is attached to the parentPatent ApplicationAtty. Docket No. ENTX-035PCT molecule by a single bond. Unless stated otherwise in the specification, an alkyl group is optionally substituted by one or more of substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(Rx).3 , -ORX, -SRX, -OC(O)-RX, -N(RX)2, - C(O)RX, -C(O)ORX, -OC(O)N(RX)2, -C(O)N(RX)2, -N(RX)C(O)ORX, -N(RX)C(O)RX, - N(RX)C(O)N(RX)2, -N(RX)C(NRX)N(RX)2, -N(Rx)S(O)tN(Rx)2(where t is 1 or 2), -P(=O)(RX)(RX), or -O-P(=O)(ORX)2wherein each Rxis independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein. In a non-limiting embodiment, a substituted alkyl can be selected from fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3 -fluoropropyl, hydroxymethyl, 2-hydroxy ethyl, 3- hydroxypropyl, benzyl, and phenethyl.

[0051] Unless otherwise specifically defined, the term “aromatic” or “aryl” refers to cyclic, aromatic hydrocarbon groups that have 1 to 2 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. Exemplary substituents include, but are not limited to, H, halogen, -O-Ci-Ce alkyl, Ci-Ce alkyl, -Ci-Ce alkenyl, -OCi-Ce alkynyl, -Ci-Ce alkenyl, -Ci-C6alkynyl, -OH, -OP(O)(OH)2, -OC(O)Ci-C6alkyl, -C(O)Ci-C6alkyl, -OC(O)OCi- C6alkyl, NH2, NH(CI-C6alkyl), N(CI-C6alkyl)2, -S(O)2-Ci-C6alkyl, -S(O)NHCi-C6alkyl, and S(O)N(Ci-Ce alkyl)2. The substituents can themselves be optionally substituted. Furthermore, when containing two fused rings the aryl groups herein defined may have an unsaturated or partially saturated ring fused with a fully unsaturated ring. Exemplary ring systems of these aryl groups include indanyl, indenyl, tetrahydronaphthal enyl, and tetrahydrobenzoannulenyl.

[0052] The term “halogen” or “halo” refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).Patent ApplicationAty. Docket No. ENTX-035PCT

[0053] As used herein, the terms “heteroaryl” or “hetero-aromatic” refer to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 p electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to three heteroatoms per ring selected from the group consisting of N, O, and S. Examples of heteroaryl groups include acridtnyl, azoc-i nyl, benz.imidaz.olyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyL 6,7-dihydro-5H-pyrrolo[l,2- ajimidazole, furanyl, furazanyl, imidazolinyl, imidazolyl, 1H- indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiaz.olyL 1,2,5-oxadiaz.olyl, 1,3,4-oxadiazolyl, oxazolidinyL oxazolyl, oxazolidinyL pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl. pyranyl, pyrazinyL pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1 ,2,5- thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3- triazoiyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.“Heteroaryl” also refers to bicyclic ring systems having, in addition to carbon atoms, from one to three heteroatoms per ring selected from the group consisting of N, O, and S in which one ring system may be saturated or partially saturated.

[0054] Heteroaryl groups may be substituted with 0, 1 , 2, 3, or 4 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalky], mercapto, nitro, -NZJZJ, and (NZ;Z?)carbonyl The term "NZ1Z2" as used herein, means two groups, Zi and Z2, which are appended to the parent molecular moiety through a nitrogen atom. Zi arid Z2 are each independently selected front the group consisting of hydrogen.Patent Application Atty. Docket No. ENTX-035PCT alkyl, alkylcarbonyl, and formyl. Representative examples of NZjZj include, but are not limited to, amino, methylamino, acetylamino, and acetylmethylamino.

[0055] As used herein, the term “alkoxy” refers to an -O-alkyl radical.

[0056] As used herein, the terms “cycloalkyl” and “carbocyclyl” each refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and can be saturated or partially unsaturated. Unless stated otherwise in the specification, the term is intended to include both substituted and unsubstituted cycloalkyl groups. Partially unsaturated cycloalkyl groups can be termed "cycloalkenyl" if the carbocycle contains at least one double bond, or "cycloalkynyl" if the carbocycle contains at least one triple bond. Cycloalkyl groups include groups having from 3 to 13 ring atoms (i.e., C3-13 cycloalkyl). Whenever it appears herein, a numerical range such as "3 to 10" refers to each integer in the given range; e.g., "3 to 13 carbon atoms" means that the cycloalkyl group can consist of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc., up to and including 13 carbon atoms. The term "cycloalkyl" also includes bridged and spiro-fused cyclic structures containing no heteroatoms. The term also includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of ring atoms) groups. Polycyclic aryl groups include bicycles, tricycles, tetracycles, and the like. In some embodiments, “cycloalkyl” can be a C3-8 cycloalkyl radical. In some embodiments, “cycloalkyl” can be a C3-5 cycloalkyl radical. Illustrative examples of cycloalkyl groups include, but are not limited to the following moieties: C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce) and the like. Examples of C3-7 carbocyclyl groups include norbornyl (C7). Examples of C3-8 carbocyclyl groups include the aforementioned C3-7 carbocyclyl groups as well as cycloheptyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, and the like. Examples of C3-13 carbocyclyl groups include the aforementioned C3-8 carbocyclyl groups as well as octahydro-lH indenyl, decahydronaphthalenyl, spiro[4.5]decanyl and the like. Unless stated otherwise in the specification, a cycloalkyl group can be optionally substituted by one or more substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate,Patent ApplicationAtty. Docket No. ENTX-035PCT phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(Ra)a , -ORa, - SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tN(Ra)2(where t is 1 or 2), - P(=O)(Ra)(Ra), or -O-P(=O)(ORa)2where each Rais independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein. The terms “cycloalkenyl" and "cycloalkynyl" mirror the above description of "cycloalkyl" wherein the prefix "alk" is replaced with "alken" or "alkyn" respectively, and the parent "alkenyl" or "alkynyl" terms are as described herein. For example, a cycloalkenyl group can have 3 to 13 ring atoms, such as 5 to 8 ring atoms. In some embodiments, a cycloalkynyl group can have 5 to 13 ring atoms.

[0057] As used herein, the term “heterocycloalkyl” refers to a cycloalkyl radical, which have one or more skeletal chain atoms selected from an atom other than carbon, e.g., O, N, S, P or combinations thereof. Unless stated otherwise in the specification, the term is intended to include both substituted and unsubstituted heterocycloalkyl groups. Illustrative examples of heterocycloalkyl include 2-hydroxy-aziridin-l-yl, 3-oxo-l-oxacyclobutan-2-yl, 2,2-dimethyl- tetrahydrofuran-3-yl, 3 -carboxy -morpholin-4-yl, l-cyclopropyl-4-methyl-piperazin-2-yl. 2- pyrrolinyl, 3-pyrrolinyl, dihydro-2H-pyranyl, 1,2,3,4-tetrahydropyridine, 3,4-dihydro-2H- [l,4]oxazine, etc.

[0058] As used herein, the terms “heterocycle”, “heterocyclic” or “heterocyclo” refer to fully saturated or partially unsaturated cyclic groups, for example, 3 to 7 membered monocyclic, 7 to 12 membered bicyclic, or 10 to 15 membered spirocyclic or tricyclic ring systems, which have at least one heteroatom (selected from the group consisting of N, O, and S) in at least one ring, wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and / or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system. A heterocyclic group is optionally substituted. Examples of heterocyclic groups include, but not limited to, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrol! di nonyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl.Patent Application Atty. Docket No. ENTX-035PCT dithiany I, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, quinuclidinyl, thiomorpholinyl, thiomorpholinyl 1,1 dioxide, morpholinyl, azepanyl, oxazepanyl, azabicyclohexanyls, azabicycloheptanyl, azabicyclooctanyls, azabicyclononanyls (e.g., octahydroindolizinyl), azaspiroheptanyls, dihydro-lH,3H,5H- oxazolo[3,4-c]oxazolyl, tetrahydro- 1'H,3'H- spiro[cyclopropane-l,2'-pyrrolizine], hexahydro- IH-pyrrolizinyL hexahydro- 1 H-pyrrolo[2, 1- c][l,4]oxazinyl, octahydroindolizinyl, oxaazaspirononanyls, oxaazaspirooctanyls, diazaspirononanyls, oxaazabiocycloheptanyls, hexahydropyrrolizinyl 4(IH)-oxide, and tetrahydro- 2H-thiopyranyl 1 -oxide and tetrahydro-2H- t hi opyranyl 1 , 1 -dioxide.Detailed Description of the Invention

[0059] The invention is based in part on the discovery of KRas inhibitors, in particular KRas (G12) inhibitors, that selectively target, bind to, inhibit or modulate the activity of KRas. The novel compounds exhibit favorable potency and selectivity as well as pharmacokinetics profiles suitable for development into an orally administered therapeutic agent for treating diseases and disorders associated with or related to KRas activities, such as various types of cancer.

[0060] In one aspect, the invention generally relates to a compound having the structural formula (I):or a pharmaceutically acceptable form or an isotope derivative thereof, wherein n is 0, 1 or 2;X is O or CRX1RX2, wherein each of RX1and RX2is independently selected from H, halo and unsubstituted or substituted C1.3 alkyl;Patent ApplicationAtty. Docket No. ENTX-035PCTY is O, S, NRY1, C=O, C=N-OR, CRY2RY3or S(O)2, whereinRY1is R, CN, C(O)RY4or C(O)ORY5, and each of RY2and RY3is independently selected from halo, CN, R, OR and NRC(O)NR', each of RY4and RY5is H, unsubstituted or substituted Ci-6 alkyl or unsubstituted or substituted 3- to 6-membered carbocyclic ring;Z is CR6or N;R2is (CH2)iR2or (CD2)iR2, wherein i is an integer selected from 1-6, and (CH2)i is optionally substituted, wherein R2’ is selected from the group consisting of H, halogen, CN, OH, C(O)NRR’, unsubstituted or substituted Ci-6 alkyl, unsubstituted or substituted 3- to 6-membered carbocyclic ring, unsubstituted or substituted 4- to 6-membered heterocyclic ring and unsubstituted or substituted 7- to 10-membered bicyclic heterocyclic ring;R6is selected from the group consisting of H, halogen, CN, OR, unsubstituted or substituted Ci-6 alkyl, unsubstituted or substituted Ci-6 alkoxy, C(O)NRR’, NRR’, S(O)2CHs, unsubstituted or substituted 3- to 6-membered carbocyclic or heterocyclic ring, and unsubstituted or substituted 5- to 6-membered heteroaryl;R7is an unsubstituted or substituted 6- to 14-membered unsaturated monocyclic, bicyclic or multi-cyclic ring, comprising 0-5 heteroatoms selected from N, O and S;R8is H, halo, unsubstituted or substituted Ci-6 alkyl, CN, OR or NRR’; each R10aand R10bis independently halo, CN, R or OR; or R10aand R10b, together with the carbon atom they are bonded to, form a cyclopropyl, cyclobutyl or oxetane group; and each R12aand R12bis independently selected from halo, CN, R or OR, or CR12aR12bis C=O; or R12aand R12b, together with the carbon atom they are bonded to, form a cyclopropyl, cyclobutyl or oxetane group; each R14aand R14bis independently selected from halo, CN, R or OR, or CR14aR14bis C=O; or R14aand R14b, together with the carbon atom they are bonded to, form a cyclopropyl, cyclobutyl or oxetane group; each R15aand R15bis independently selected from halo, CN, R or OR, or CR15aR13bis C=O or C=N-OR; or R13aand R15b, together with the carbon atom they are bonded to, form a cyclopropyl, cyclobutyl or oxetane group;Patent ApplicationAtty. Docket No. ENTX-035PCT each R16aand R16bis independently selected from halo, CN, R or OR; or R16aand R16b, together with the carbon atom they are bonded to, form a cyclopropyl or cyclobutyl group; provided that one of R12aand R12b, together with one of R14aand R14b, one of R15aand R1?b, or one of R16aand R16b, may form a 4- to 7-membered carbocyclic or heterocyclic ring; one of R14aand R14b, together with one of R15aand R15b, or one of R16aand R16b, may form a 3- to 7-membered carbocyclic or heterocyclic ring; one of R15aand R15b, together with one of R16aand R16b, may form a 3- to 7- membered carbocyclic or heterocyclic ring; and each of R and R’ is independently selected from H, D, unsubstituted or substituted Ci-6 alkyl, or unsubstituted or substituted 3- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom, together form an unsubstituted or substituted 4- to 7-membered heterocyclic ring.

[0061] In certain embodiments of (I), n is 1, and the compound has the structure of formula

[0062] In certain embodiments of (II), Z is CR6, and the compound has the structure of formula (IIA):Patent ApplicationAtty. Docket No. ENTX-035PCT

[0063] In certain embodiments of (II), Z is N, and the compound has the structure of formula(I ):

[0064] In certain embodiments of (I), n is 0, and the compound has the structure of formula(HI)

[0065] In certain embodiments of (III), Z is CR6, and the compound has the structural formula (IIIA):Patent ApplicationAtty. Docket No. ENTX-035PCT

[0066] In certain embodiments of (III), Z is N, and the compound has the structural formula(IIP):

[0067] In certain embodiments of (I)-(IIIB), each of R and R’ is independently H or Ci-6 alkyl optionally substituted with one or more groups selected from halo, CN, OH and substituted or unsubstituted Ci-6 alkoxy.

[0068] In certain embodiments of (I)-(IIIB), the compound is characterized by the following stereochemistry:

[0069] In certain embodiments of (I)-(IIIB), the compound is characterized by the following stereochemistry:Patent ApplicationAtty. Docket No. ENTX-035PCT

[0070] In certain embodiments of (I)-(IIIB), Y is O.

[0071] In certain embodiments of (I)-(IIIB), Y is C=N-OR.

[0072] In certain embodiments of (I)-(IIIB), Y is C=O.

[0073] In certain embodiments of (I)-(IIIB), Y is S.

[0074] In certain embodiments of (I)-(IIIB), Y is S(O)2.

[0075] In certain embodiments of (I)-(IIIB), Y is CRY2RY3.

[0076] In certain embodiments of (I)-(IIIB), Y is NRY1.

[0077] In certain embodiments, RY1is R.

[0078] In certain embodiments, K?1is C(O)ORY3.

[0079] In certain embodiments, RY1comprises:wherein each of R and R’ is selected from H or substituted or unsubstituted Ci-6 alkyl or substituted or unsubstituted 3- to 6-membered carbocycle.

[0080] In certain embodiments, RY1comprises:

[0081] In certain embodiments of (I)-(IIIB), each R10aand R10bis H.

[0082] In certain embodiments of (I)-(IIIB), R10aH and R10bis C1-3 alkyl, OR or halo.

[0083] In certain embodiments of (I)-(IIIB), each R12aand R12bis H.

[0084] In certain embodiments of (1)-(1I1B), X is CRX1RX2.

[0085] In certain embodiments of (I)-(IIIB), each of RX1and RX2is independently selected from H, F and Cl.

[0086] In certain embodiments of (I)-(IIIB), each of RX1and RX2is H.

[0087] In certain embodiments of (I)-(IIIB), one of RX1and RX2is H and the other is F or Cl.

[0088] In certain embodiments of (I)-(IIIB), each of RX1and RX2is F or Cl.Patent ApplicationAtty. Docket No. ENTX-035PCT

[0089] In certain embodiments of (I)-(IIIB), at least one of RX1and RX2is an unsubstituted or substituted C1-3 alkyl.

[0090] In certain embodiments of (I)-(IIIB), X is O.

[0091] In certain embodiments of (I)-(IIIB), R6is H.

[0092] In certain embodiments of (I)-(IIIB), R6is F.

[0093] In certain embodiments of (I)-(IIIB), R6is Cl.

[0094] In certain embodiments of (I)-(IIIB), R6is C1-3 alkyl or C3-4 cycloalkyl.

[0095] In certain embodiments of (I)-(IIIB), R6is CH2F, CHF2 or CF3.

[0096] In certain embodiments of (I)-(IIIB), R6is CN, S(O)2R, NRR’, OR or C(O)NRR’ .

[0097] In certain embodiments of (I)-(IIIB), z is 1.

[0098] In certain embodiments of (I)-(IIIB), R2is (CH2)iR2

[0099] In certain embodiments of (I)-(IIIB), R2is (CD2)iR2.

[0100] In certain embodiments of (I)-(IIIB), R2is a C3-6 carbocyclic or heterocyclic ring substituted with 0-5 R2A, wherein each R2Ais independently selected from D, halo, OC1.3 alkyl or C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with one or more of halo, OH, NRR’, CN and CONRR’.

[0101] In certain embodiments of (I)-(IIIB), R2is C3-5 carbocyclic ring substituted with 0-5 R2A.

[0102] In certain embodiments of (I)-(IIIB), R2is selected from:

[0103] In certain embodiments of (I)-(IIIB), R2is C3-5 heterocyclic ring substituted with 0-5 R2A.

[0104] In certain embodiments of (I)-(IIIB), R2is selected from:Patent ApplicationAtty. Docket No. ENTX-035PCT

[0105] In certain embodiments of (I)-(IIIB), R2is a bicyclic, unsubstituted or substituted Ce- io heterocyclic ring.

[0106] In certain embodiments of (I)-(IIIB), R2is selected from:Patent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCT

[0108] In certain embodiments of (I)-(IIIB), R2is selected from:Patent ApplicationAtty. Docket No. ENTX-035PCT

[0109] In certain embodiments of (I)-(IIIB), R7is an unsubstituted or substituted 6- membered aryl or heteroaryl ring, comprising 0-5 heteroatoms selected from N, O and S.

[0110] In certain embodiments of (I)-(IIIB), R7has the structural formula:whereinQ is N or CR7E;W is N or CR7C;R7Ais H, halo or substituted or unsubstituted C1-3 alkyl;R7Bis H, halo or substituted or unsubstituted C1-3 alkyl;R7Cis H or halo;R7Dis H, NRR’, halo or OR; andR7Eis H, halo, substituted or unsubstituted C1.3 alkyl, OR or CN.

[0111] In certain embodiments of (IV), W is CR7C, and R7has the structural formula:Patent ApplicationAtty. Docket No. ENTX-035PCT

[0112] In certain embodiments of (IV), W is N, and R7has the structural formula:

[0113] In certain embodiments

[0114] In certain embodiments of (IV)-(IVB), R7has the structural formula:

[0115] In certain embodiments of (IV)-(IVB), R7has the structural formula:

[0116] In certain embodiments of (IV)-(IVB), Q is CR7E.

[0117] In certain embodiments of (IV)-(IVB), R7Eis H.

[0118] In certain embodiments of (IV)-(IVB), R7Eis F.

[0119] In certain embodiments of (IV)-(IVB), R7Eis CN.

[0120] In certain embodiments of (IV)-(IVB), R7Dis NH2.

[0121] In certain embodiments of (IV)-(IVB), R7Dis OR.

[0122] In certain embodiments of (IV)-(IVB), R7Ais CF3.

[0123] In certain embodiments of (IV)-(IVB), R7Ais cyclopropyl.

[0124] In certain embodiments of (IV)-(IVB), R7Bis C1-3 alkyl.Patent ApplicationAtty. Docket No. ENTX-035PCT

[0125] In certain embodiments of (IV)-(IVB), R7Bis methyl

[0126] In certain embodiments of (IV)-(IVB), R7C, if present, is F.

[0127] In certain embodiments of (IV)-(IVB), R7C, if present, is H.

[0128] In certain embodiments of (I)-(IIIB), R7is selected from:

[0129] In certain embodiments of (I)-(IIIB), R7is selected from:Patent ApplicationAtty. Docket No. ENTX-035PCT

[0130] In certain embodiments of (I)-(IIIB), R7is an unsubstituted or substituted 9- to 14- membered bicyclic or multi-cyclic aryl or heteroaryl ring, comprising 0-5 heteroatoms selected from N, O and S.

[0131] In certain embodiments of (I)-(IIIB), R7has the structure formula (V):whereinRing A is a 6-membered aryl or heteroaryl ring with 0-2 N atoms;Ring B is a 5- or 6-membered carbocyclic, heterocyclic, aryl or heteroaryl ring with 0-3 heteroatoms selected from N, O and S; each of R7Fand R7Gis independently selected from the group consisting of halogen, OH, CN, NRR’, unsubstituted or substituted Ci-6 alkyl, and unsubstituted or substituted Ci-6 alkoxy, (CH2)kNRR’, (CH2)kC(=O)NRR’, (CH2)kOC(=O)R, (CH2)kOC(=O)OR; or 2 R7Gs, together with atoms they are bonded to, for a 4- or 7-membered unsubstituted or substituted carbocyclic, heterocyclic, aryl or heteroaryl group; or 2 R7Fs, together with atoms they are bonded to, for a 4- or 7-membered unsubstituted or substituted carbocyclic, heterocyclic, aryl or heteroaryl group; each of p and q is independently 0, 1, 2 or 3; and each k is independently 0, 1 or 2.

[0132] In certain embodiments of (V), Ring A is a 6-membered aryl ring.

[0133] In certain embodiments of (V), Ring A is a 6-membered heteroaryl ring.

[0134] In certain embodiments of (V), Ring B is a 5-membered heterocyclic ring.

[0135] In certain embodiments of (V), Ring B is a 6-membered heterocyclic ring.

[0136] In certain embodiments of (V), Ring B is a 5-membered heteroaryl ring.

[0137] In certain embodiments of (V), Ring B is a 6-membered heteroaryl ring.

[0138] In certain embodiments of (V), Ring B is a 6-membered aryl ring.

[0139] In certain embodiments of (1)-(II1B), R7is selected from:Patent ApplicationAtty. Docket No. ENTX-035PCT

[0140] In certain embodiments of (I)-(IIIB), R7is selected from:Patent ApplicationAtty. Docket No. ENTX-035PCT

[0141] In certain embodiments of (I)-(IIIB), R7is selected from:

[0142] In certain embodiments of (I)-(IIIB), R7has the structure of:

[0143] In certain embodim,

[0144] In certain embodiments of (I), the compound has the structural formula:Patent ApplicationAtty. Docket No. ENTX-035PCT

[0145] In certain embodiments of (I), the compound has the structural formula:

[0146] In certain embodiments of (I), the compound has the structural formula:

[0147] In certain embodiments of (I), the compound has the structural formula:Patent ApplicationAtty. Docket No. ENTX-035PCT

[0148] In certain embodiments of (I), the compound has the structural formula:

[0149] In certain embodiments of (I), the compound has the structural formula:

[0150] In certain embodiments of (I), the compound has the structural formula:Patent ApplicationAtty. Docket No. ENTX-035PCT

[0151] In certain embodiments of (I), the compound has the structural formula:

[0152] In certain embodiments of (I), the compound has the structural formula:

[0153] In certain embodiments of (I), the compound has the structural formula:Patent ApplicationAtty. Docket No. ENTX-035PCT

[0154] In certain embodiments of (I), the compound has the structural formula:

[0155] In certain embodiments of (I), the compound has the structural formula:

[0156] In certain embodiments of (I), the compound has the structural formula:Patent ApplicationAtty. Docket No. ENTX-035PCT

[0157] In certain embodiments of (I), the compound has the structural formula:

[0158] In certain embodiments of (I), the compound has the structural formula:

[0159] In certain embodiments of (I), the compound has the structural formula:Patent ApplicationAtty. Docket No. ENTX-035PCT

[0160] In certain embodiments of (I), the compound has the structural formula:

[0161] In certain embodiments of (I), the compound has the structural formula:

[0162] In certain embodiments of (I), the compound has the structural formula:Patent ApplicationAtty. Docket No. ENTX-035PCT

[0163] In certain embodiments of (I), the compound has the structural formula:

[0164] In certain embodiments of (I), the compound has the structural formula:

[0165] In certain embodiments of (I), the compound has the structural formula:Patent ApplicationAtty. Docket No. ENTX-035PCT

[0166] In certain embodiments of (I), the compound has the structural formula:

[0167] In certain embodiments of (I), the compound has the structural formula:

[0168] In certain embodiments of (I), the compound has the structural formula:Patent ApplicationAtty. Docket No. ENTX-035PCT

[0169] In certain embodiments of (I), the compound has the structural formula:

[0170] In certain embodiments of (I), the compound has the structural formula:

[0171] In certain embodiments of (I), the compound has the structural formula:Patent ApplicationAtty. Docket No. ENTX-035PCT

[0172] In certain embodiments of (IIa)-(IIx) and (IIIa)-(IIId), the compound is characterized by having the following stereochemistry:

[0173] In certain embodiments of (IIa)-(IIx) and (IIIa)-(IIId), the compound is characterized by having the following stereochemistry:

[0174] In certain embodiments of (IIa)-(IIx) and (IIIa)-(IIId), if present R6is F.

[0175] In certain embodiments of (IIa)-(IIx) and (IIIa)-(IIId), if present R6is Cl.

[0176] In certain embodiments of (IIa)-(IIx) and (IIIa)-(IIId), R8is F.

[0177] In certain embodiments of (I)-(IIId), the compound is selected from Table 1.

[0178] In certain embodiments of (I)-(IIId), the compound is selected from Table 2.

[0179] In certain embodiments of (I)-(IIId), the compound is selected from Table 3.

[0180] In certain embodiments of (I)-(IIId), the compound is selected from Table 4.

[0181] In certain embodiments of (I)-(IIId), the compound is selected from Table 5.

[0182] In certain embodiments of (l)-(IIld), the compound is selected from Table 6.

[0183] In certain embodiments of (I)-(IIId), the compound is selected from Table 7.

[0184] In certain embodiments of (I)-(IIId), the compound is selected from Table 8.Patent ApplicationAtty. Docket No. ENTX-035PCT

[0185] In certain embodiments of (I)-(IIId), the compound is selected from Table 9.

[0186] In certain embodiments of (I)-(IIId), the compound has one or more deuterium atoms in place of hydrogen.

[0187] In certain embodiments of (I)-(IIId), the compound has one deuterium atom in place of a hydrogen atom.

[0188] In another aspect, the invention generally relates to a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, or diluent.

[0189] In certain embodiments, the pharmaceutical composition is suitable for oral administration.

[0190] In yet another aspect, the invention generally relates to a unit dosage form comprising a pharmaceutical composition of the invention.

[0191] In certain embodiments, the unit dosage form is a tablet.

[0192] In certain embodiments, the unit dosage form is a capsule.

[0193] In certain embodiments, the unit dosage form is a liquid emulsion of suspension.

[0194] In yet another aspect, the invention generally relates to a method for inhibiting cell proliferation in vitro or in vivo, comprising contacting a cell with an effective amount of a compound disclosed herein.

[0195] In yet another aspect, the invention generally relates to a method for modulating KRas activity in a cell, comprising contacting the cell with a compound disclosed herein.

[0196] In yet another aspect, the invention generally relates to a method for treating a disease or disorder mediated by a Ras mutant protein, comprising administering to a subject in need thereof a therapeutically effective amount of the compound disclosed herein.

[0197] In certain embodiments, the KRas mutant is selected from mutants G12D, G12V. G12C and G12R

[0198] In yet another aspect, the invention generally relates to a method for treating or reducing cancer, or a related disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of the compound disclosed herein.

[0199] In certain embodiments, the cancer is selected from the group consisting of carcinoma, squamous carcinoma, adenocarcinoma, sarcoma, leukemia, neuroma, melanoma, and lymphoma.Patent ApplicationAtty. Docket No. ENTX-035PCT

[0200] In certain embodiments, the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, lung cancer, endometrial cancer, appendix cancer, cholangiocarcinoma, bladder urothelial cancer, ovarian cancer, gastric cancer, breast cancer, bile duct cancer, and a hematologic malignancy.

[0201] In certain embodiments, the subject has a mutation of KRAS, HRAS and / or NRAS.

[0202] In certain embodiments, the subject being treated is further administered one or more of chemotherapy, radiotherapy, targeted therapy, immunotherapy, and hormonal therapy.

[0203] In yet another aspect, the invention generally relates to use of the compound disclosed herein, and a pharmaceutically acceptable excipient, carrier, or diluent, in preparation of a medicament for treating a disease or disorder.

[0204] In certain embodiments of the use, the disease or disorder is cancer.

[0205] In certain embodiments of the use, the cancer is selected from the group consisting of carcinoma, squamous carcinoma, adenocarcinoma, sarcoma, leukemia, neuroma, melanoma, and lymphoma.

[0206] In certain embodiments of the use, the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, lung cancer, endometrial cancer, appendix cancer, cholangiocarcinoma, bladder urothelial cancer, ovarian cancer, gastric cancer, breast cancer, bile duct cancer, and a hematologic malignancy.

[0207] Non-limiting examples of compounds of the invention include those listed in Table 1.Table 1. Exemplary CompoundsPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCT

[0208] In certain embodiments, compounds of the invention are selected from Table 2.Table 2. Exemplary CompoundsPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCT

[0209] In certain embodiments, compounds of the invention are selected from Table 3.Table 3. Exemplary CompoundsPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCT

[0210] In certain embodiments, compounds of the invention are selected from Table 4.Table 4. Exemplary CompoundsPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCT

[0211] In certain embodiments, compounds of the invention are selected from Table 5.Table 5. Exemplary CompoundsPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCT

[0212] In certain embodiments, compounds of the invention are selected from Table 6.Table 6. Exemplary CompoundsPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCT

[0213] In certain embodiments, compounds of the invention are selected from Table 7.Table 7. Exemplary CompoundsPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCT

[0214] In certain embodiments, compounds of the invention are selected from Table 8.Table 8. Exemplary CompoundsPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCTPatent ApplicationAtty. Docket No. ENTX-035PCT

[0215] In certain embodiments, compounds of the invention are selected from Table 9Table 9. Exemplary CompoundsPatent ApplicationAtty. Docket No. ENTX-035PCT

[0216] In certain embodiments, compounds of the invention have one or more deuterium atoms in place of hydrogen atoms.

[0217] In certain embodiments, compounds of the invention have one deuterium atom in place of a hydrogen atom.

[0218] In another aspect, the invention generally relates to a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, or diluent.

[0219] In certain embodiments, a pharmaceutical composition of the invention is suitable for oral administration.

[0220] In yet another aspect, the invention generally relates to a unit dosage form comprising a pharmaceutical composition comprising a compound disclosed herein.

[0221] In certain embodiments, the unit dosage form is in the form of a tablet or capsule.Patent ApplicationAtty. Docket No. ENTX-035PCT

[0222] In yet another aspect, the invention generally relates to a method for inhibiting cell proliferation in vitro or in vivo, comprising contacting a cell with an effective amount of a compound disclosed herein.

[0223] In yet another aspect, the invention generally relates to a method for modulating (e.g., inhibiting or reducing) KRas(G12#) (# being D, V, C, etc.) activity in a cell, comprising contacting the cell with a compound disclosed herein.

[0224] In yet another aspect, the invention generally relates to a method for treating a disease or disorder mediated by a Ras mutant protein, comprising administering to a subject in need thereof a therapeutically effective amount of the compound disclosed herein.

[0225] In yet another aspect, the invention generally relates to a method for treating or reducing cancer, or a related disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of the compound disclosed herein.

[0226] In yet another aspect, the invention generally relates to use of a compound disclosed herein, and a pharmaceutically acceptable excipient, carrier, or diluent, in preparation of a medicament for treating a disease or disorder.

[0227] Examples of diseases or disorders that may be treated or reduced by compositions or methods of the invention include, but are not limited to, tumors, cancers, autoimmune diseases, macroglobulinemia, and the like.

[0228] In certain embodiments, the cancer is selected from the group consisting of carcinoma, squamous carcinoma, adenocarcinoma, sarcoma, leukemia, neuroma, melanoma, and lymphoma.

[0229] Examples of cancers targeted in the present invention include, but are not particularly limited to, bead and neck cancer, digestive organ cancer (esophageal cancer, stomach cancer, duodenal cancer, liver cancer, biliary cancer (e.g., gallbladder and bile duct cancer), pancreatic cancer, colorectal cancer (e.g., colon cancer, and rectal cancer), etc.), lung cancer (e.g., non- small-cell lung cancer, small -cell lung cancer, and mesothelioma), breast cancer, genital cancer (ovarian cancer, uterine cancer (e.g., cervical cancer and endometrial cancer), etc.), urological cancer (e.g., kidney cancer, bladder cancer, prostate cancer, and testicular tumor), hematopoietic tumor (e.g., leukemia, lymphoma, malignant lymphoma, and multiple myeloma), sarcoma (e.g., osteosarcoma, and soft-tissue sarcoma), skin cancer, brain tumor, a carcinoma, squamous carcinoma, adenocarcinoma, neuroma, melanoma and the like Examples include lung cancer.Patent ApplicationAty. Docket No. ENTX-035PCT pancreatic cancer, rectal cancer, colon cancer colorectal cancer and uterine cancer. In certain embodiments, squamous carcinoma is a cancer of uterine cervix, tarsus, conjunctiva, vagina, lung, oral cavity, skin, bladder, tongue, larynx or esophagus. In one embodiment, adenocarcinoma is a cancer of prostate, small intestine, endometrium, uterine cervix, large intestine, lung, pancreas, esophagus, rectum, uterus, stomach, breast or ovary. In certain embodiments, tumor is rectal cancer, colon cancer, colorectal cancer, pancreatic cancer, lung cancer, breast cancer leukemia or uterine cancer.

[0230] In certain embodiments, the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, lung cancer, endometrial cancer, appendix cancer, cholangiocarcinoma, bladder urothelial cancer, ovarian cancer, gastric cancer, breast cancer, bile duct cancer, and a hematologic malignancy.

[0231] In certain embodiments, a subject suffering from any of the disease selected from the above does not have to have KRAS G12# (# being D, V, C, etc.) mutant protein. In certain embodiments, a subject suffering from any of the disease selected from the above has KRAS G12# (# being D, V, C, etc.) mutant protein.

[0232] In certain embodiments, the subject has a mutation of KRAS, HRAS and / or NRAS.

[0233] The amount of the active compound administered will be dependent on the subject being treated, the severity of the disorder or condition, the route of administration, the disposition of the compound and the discretion of the prescribing physician. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be used without causing any harmful side effect, with such larger doses typically divided into several smaller doses for administration throughout the day.

[0234] Any appropriate route of administration can be employed, for example, oral, intramuscular, intravenous, transdermal, subcutaneous, sublingual, parenteral, nasal, pulmonary, inhalational, buccal, intraperintoneal, rectal, intrapleural, and intrathecal administration. Most suitable means of administration for a particular patient will depend on the nature and severity of the disease or condition being treated or the nature of the therapy being used and on the nature of the active compound.

[0235] In certain preferred embodiments, the compound is administered orally. Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets or tablets each containing a predeterminedPatent ApplicationAtty. Docket No. ENTX-035PCT amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion, or packed in liposomes and as a bolus, etc. Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption.

[0236] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets optionally may be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. Methods of formulating such slow or controlled release compositions of pharmaceutically active ingredients, such as those herein and other compounds known in the art, are known in the art and described in several issued US Patents, some of which include, but are not limited to, US Patent Nos. 4,369,172; and 4,842,866, and references cited therein. Coatings can be used for delivery of compounds to the intestine (see, e.g., U.S. Patent Nos. 6,638,534, 5,217,720, and 6,569,457, 6,461,631, 6,528,080, 6,800,663, and references cited therein). A useful formulation for the compounds of this invention is the form of enteric pellets of which the enteric layer comprises hydroxypropylmethylcellulose acetate succinate.

[0237] In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents may be added.

[0238] Compositions suitable for topical administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.

[0239] Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutesPatent Application Atty. Docket No. ENTX-035PCT which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

[0240] Such injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.

[0241] Compounds of the present invention may also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.Patent ApplicationAtty. Docket No. ENTX-035PCT

[0242] The pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

[0243] The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.

[0244] Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application. For application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches and iontophoretic administration are also included in this invention.

[0245] Methods of treatment disclosed herein may be employed in combination with or in addition to other therapies. In certain embodiments, the subject being treated is further administered one or more of chemotherapy, radiotherapy, targeted therapy, immunotherapy, and hormonal therapy.

[0246] Exemplary additional therapeutically active agents include, but are not limited to, small organic molecules such as drug compounds, e.g., compounds approved by the U.S. FoodPatent Application Atty. Docket No. ENTX-035PCT and Drug Administration (FDA) as provided in the Code of Federal Regulations (CFR), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins and cells.

[0247] In certain embodiments, a compound of the invention may be administered in combination with endocrine therapy, e.g., agents such as letrozole, fulvestrant, tamoxifen, exemestane, or anastrozole.

[0248] In some embodiments, a compound of the invention may be administered in combination with a chemotherapeutic agent, e.g., docetaxel, paclitaxel, cisplatin, carboplatin, capecitabine, gemcitabine or vinorelbine. In other embodiments, a compound of the invention may be administered in combination with an anti-HER2 agent, e.g., trastuzumab or pertuzumab.

[0249] In certain embodiments, the method disclosed herein is in combination with one or more of immune check point blockade, co-signaling of T cells, and tumor targeting antibody therapies.

[0250] In certain embodiments, the method further comprises administering a chemotherapeutic agent to the subject.

[0251] In certain embodiments, the method further comprises administering a radiotherapy to the subject. In certain embodiments, the method further comprises administering a targeted therapy to the subject. In certain embodiments, the method further comprises administering an immunotherapy to the subject. In certain embodiments, the method further comprises administering hormonal therapy to the subject.

[0252] As used herein, the term "chemotherapeutic agent" refers to a chemical compound useful in the treatment of cancer. Examples of chemotherapeutic agents include Erlotinib (TARCEVA®, Genentech / OSI Pharm.), Bortezomib (VELCADE®, Millennium Pharm.), Fulvestrant (FASLODEX®, AstraZeneca), Sutent (SU11248, Pfizer), Letrozole (FEMARA®, Novartis), Imatinib mesylate (GLEEVEC®, Novartis), PTK787 / ZK 222584 (Novartis), Oxaliplatin (Eloxatin®, Sanofi), 5-FU (5-fluorouracil), Leucovorin, Rapamycin (Sirolimus, RAPAMUNE®, Wyeth), Lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), Lonafarnib (SCH 66336), Sorafenib (BAY43-9006, Bayer Labs), and Gefitinib (IRESSA®, AstraZeneca), AG1478, AG1571 (SU 5271; Sugen), alkylating agents such as thiotepa and CYTOXAN®Patent ApplicationAtty. Docket No. ENTX-035PCT cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analog topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall (Angew Chem. Inti. Ed. Engl. (1994) 33: 183-186); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6- diazo-5-oxo-L- norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esonibicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5 -fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6- mercaptopurine, thiamniprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, di deoxy uridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; anPatent ApplicationAtty. Docket No. ENTX-035PCT epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK* polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N .J.), ABRAXANE® (Cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, 111.), and TAXOTERE® (doxetaxel; Rhone-Poulenc Rorer, Antony, France); chloranmbucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP- 16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylomithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above.

[0253] Examples of the second (or further) agent or therapy may include, but are not limited to, immunotherapies (e.g. PD-1 inhibitors (pembrolizumab, nivolumab, cemiplimab), PD-L1 inhibitors (atezolizumab, avelumab, durvalumab), CTLA4 antagonist, cell signal transduction inhibitors (e.g., imatinib, gefitinib, bortezomib, erlotinib, sorafenib, sunitinib, dasatinib, vorinostat, lapatinib, temsirolimus, nilotinib, everolimus, pazopanib, trastuzumab, bevacizumab, cetuximab, ranibizumab, pegaptanib, panitumumab and the like), mitosis inhibitors (e.g., paclitaxel, vincristine, vinblastine and the like), alkylating agents (e.g., cisplatin, cyclophosphamide, chromabucil, carmustine and the like), anti-metabolites (e.g., methotrexate, 5-FU and the like), intercalating anticancer agents, (e.g., actinomycin, anthracycline, bleomycin, mitomycin-C and the like), topoisomerase inhibitors (e.g., irinotecan, topotecan, teniposide and the like), immunotherapic agents (e.g., interleukin, interferon and the like) and antihormonal agents (e.g., tamoxifen, raloxifene and the like).

[0254] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis-I l lPatent ApplicationAtty. Docket No. ENTX-035PCT and trans- somers, R- and / / -enantiomers, diastereomers, (D)-isomers, (l.)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

[0255] Isomeric mixtures containing any of a variety of isomer ratios may be utilized in accordance with the present invention. For example, where only two isomers are combined, mixtures containing 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99: 1, or 100:0 isomer ratios are contemplated by the present invention. Those of ordinary skill in the art will readily appreciate that analogous ratios are contemplated for more complex isomer mixtures.

[0256] If, for instance, a particular enantiomer of a compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic methods well known in the art, and subsequent recovery of the pure enantiomers.

[0257] Isotopically-labeled compounds are also within the scope of the present disclosure. As used herein, an "isotopically-labeled compound" refers to a presently disclosed compound including pharmaceutical salts and prodrugs thereof, each as described herein, in which one or more atoms are replaced by an atom 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 compounds presently disclosed include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,170,31P,32P,35S,18F, and36C1, respectively.

[0258] By isotopically-labeling the presently disclosed compounds, the compounds may be useful in drug and / or substrate tissue distribution assays. Tritiated (3H) and carbon- 14 (14C) labeled compounds are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (2H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. IsotopicallyPatent ApplicationAtty. Docket No. ENTX-035PCT labeled compounds presently disclosed, including pharmaceutical salts, esters, and prodrugs thereof, can be prepared by any means known in the art.

[0259] Further, substitution of normally abundant hydrogen (’H) with heavier isotopes such as deuterium can afford certain therapeutic advantages, e.g., resulting from improved absorption, distribution, metabolism and / or excretion (ADME) properties, creating drugs with improved efficacy, safety, and / or tolerability. Benefits may also be obtained from replacement of normally abundant12C with13C. (See, WO 2007 / 005643, WO 2007 / 005644, WO 2007 / 016361, and WO 2007 / 016431.)

[0260] Stereoisomers (e.g., cis and trans isomers) and all optical isomers of a presently disclosed compound (e.g., R and S enantiomers), as well as racemic, diastereomeric and other mixtures of such isomers are within the scope of the present disclosure.

[0261] Compounds of the present invention are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 95% (“substantially pure”), which is then used or formulated as described herein. In certain embodiments, the compounds of the present invention are more than 99% pure.

[0262] Solvates and polymorphs of the compounds of the invention are also contemplated herein. Solvates of the compounds of the present invention include, for example, hydrates.

[0263] Any appropriate route of administration can be employed, for example, parenteral, intravenous, subcutaneous, intramuscular, intraventricular, intracorporeal, intraperitoneal, rectal, or oral administration. Most suitable means of administration for a particular patient will depend on the nature and severity of the disease or condition being treated or the nature of the therapy being used and on the nature of the active compound.

[0264] Compositions for parenteral injection comprise pharmaceutically-acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity may be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.Patent ApplicationAtty. Docket No. ENTX-035PCT

[0265] These compositions can also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paragen, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption, such as aluminum monostearate and gelatin.

[0266] Compounds of the present invention may also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically-acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.

[0267] Total daily dose of the compositions of the invention to be administered to a human or other mammal host in single or divided doses may be in amounts, for example, from 0.0001 to 300 mg / kg body weight daily and more usually 1 to 300 mg / kg body weight. The dose, from 0.0001 to 300 mg / kg body, may be given twice a day.

[0268] Materials, compositions, and components disclosed herein can be used for, can be used in conjunction with, can be used in preparation for, or are products of the disclosed methods and compositions. It is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutations of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. For example, if a method is disclosed and discussed and a number of modifications that can be made to a number of molecules including in the method are discussed, each and every combination and permutation of the method, and the modifications that are possible are specifically contemplated unless specifically indicated to the contrary. Likewise, any subset or combination of these is also specifically contemplated andPatent ApplicationAtty. Docket No. ENTX-035PCT disclosed. This concept applies to all aspects of this disclosure including, but not limited to, steps in methods using the disclosed compositions. Thus, if there are a variety of additional steps that can be performed, it is understood that each of these additional steps can be performed with any specific method steps or combination of method steps of the disclosed methods, and that each such combination or subset of combinations is specifically contemplated and should be considered disclosed.Examples

[0269] The following examples are given for the purpose of illustrating the invention, but not for limiting the scope or spirit of the invention.

[0270] Compounds of the invention, including those specifically disclosed herein above and herein below, may be prepared as described in the following schemes. Although the present invention has been described in detail with preferred embodiments, those of ordinary skill in the art should understand that modifications, variations, and equivalent replacements made to the present invention within the scope of the present invention belong to the protection of the present invention.AbbreviationsAc = AcetylAcO = AcetateAC2O = Acetic anhydrideAIBN = a,a'-AzoisobyronitrileAll = AllylAr = ArylB2Pin2 = bis(pinacolato)diboron9-BBN = 9-BorabicyclononaneBINAP = 2,2'-Bis(diphenylphosphino)-l,l'-binaphthylBMS = Borane-methylsulphide complexBn = BenzylBoc = tert-Butoxy carbonylBOP = Bis(2-oxo-3-oxazolidinyl)phosphineBu or n-Bu = n-Butyl s-Bu or sBu = sec-Butyl t-Bu or tBu = tert-Butyl t-BuOH = tert-ButanolBz = BenzoylPatent ApplicationAtty. Docket No. ENTX-035PCTBzl = BenzylCAN = Ceric ammonium nitrate cataCXium A Pd G3 = mesylate [(di(l-adamantyl)-n-butylphosphine)-2-(2’-amino- l,rbiphenyl)]palladium(II) G3CBS = Corey-Bashki-ShibatCbz = BenzyloxycarbonylCbzCl = Benzyl chloroformate oxCod = CyclooctadieneCp = CyclopentadienylCSA = Camphorsulphonic acidDABCO = 1,4-Diazabicyclo[2.2.2]octaneDAST = Diethylaminosulphur trifluoride dba = DibenzylideneacetoneDBU = l,8-Diazabyciclo[5.4.0]undec-7-eneDCC = 1,3 -DicyclohexylcarbodiimideDCM = DichloromethaneDDQ = 2,3-Dichloro-5,6-dicyano-l,4-benzoquinoneDEAD = Diethyl azodicarboxylateDIBAL = Diisobutylaluminium hydrideDIC = DiisopropylcarbodiimideDIPEA = DiisopropylethylamineDMA = N,N-DimethylacetamideDMAC = N,N-DimethylacetamideDMAP = 4-DimethylaminopyridineDME = 1,2-Dimethoxy ethaneDMF = N,N-DimethylformamideDMP = Dess-Martin periodinaneDMS = DimethylsulphideDMSO = DimethylsulphoxideDPPA = Diphenylphosphoryl azideDdpb = l,4-bis(diphenylphosphino)butaneDppe = l,2-bis(diphenylphosphino)ethaneDppf = 1 ,2-bi s(diphenylphosphino)ferrocene dppp = l,3-bis(diphenylphosphino)propaneDtbbpy = 4, 4’-di-tert-butyl-2,2’-dipyridylEDC = l-Ethyl-3-(3-dimethylaminopropy)carbodiimideEDCI = l-Ethyl-3-(3-dimethylaminopropy)carbodiimide hydrochlorideEq = equivalentESI or ES = Electrospray ionizationEt = ethylEt2O = Diethyl etherPatent ApplicationAtty. Docket No. ENTX-035PCTEtOAc = Ethyl acetateFMOC = 9-FluorenylmethoxycarbonylHATU = l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphateHMDS = HexamethyldisilazaneHMPA = HexamethylphosphoramideHOAt = 7-Aza-l-hydroxybenzotriazoleHOBt = 1-Hydroxybenzotri azoleHPLC = high pressure liquid chromatographyIP A = Isopropyl alcoholIm = ImidazoleKHMDS = Potassium bis(trimethylsilyl)amideKO Ac = Potassium acetateLAH = Lithium aluminium hydrideLDA = Lithium diisopropylamideLHMDS = Lithium bis(trimethylsilyl)amideMCPBA = meta-chloroperoxybenzoic acidMe = MethylMeCN = AcetonitrileMeOH = MethanolMOM = MethoxymethylMg = magnesiumMS = Molecular sievesMs = MethanesulphonylMTBE = Methyl tert-butyl ether m / z = mass divided by chargeNaHMDS = Sodium bis(trimethylsilyl)amideNBS = N-BromosuccinimideNCS = N-ChlorosuccinimideNIS = N-IodosuccinimideNMM = N-MethylmorpholineNMO = N-Methylmorpholine-N-oxideNMP = N-MethylpyrrolidoneNMR = Nuclear magnetic resonanceNs = p-Nitrophenyl sulphonylPd(dppf)C12 = [1, r-bis(diphenylphosphino)ferrocene]dichloropalladiumPd(PPh3)4 = tetrakis(triphenylphosphine)palladiumPCC = Pyridinium chlorochromatePE = Petroleum etherPh = PhenylPiv = Pivaloyl, 2,2-dimethylacetylPatent ApplicationAtty. Docket No. ENTX-035PCTPMB = p-MethoxybenzylPPA = Polyphosphoric acidPPTS = Pyridinium p-toluensulphonate n-Pr = n-PropylPr = Propyl i-Pr or iPr = iso-propiloPTC = Phase transfer catalystPTS A = p-Toluenesulphonic acidPv = Pivaloyl, 2,2-dimethylacetyl Py = PyridineRT = room temperatureSFC = supercritical fluid chromatography SEM = 2-(Trimethyl silyl )ethoxymethyl TBAF = Tetrabutylammonium fluoride TBDMS = tert-Butyldimethylsilyl TBDPS = tert-ButyldiphenylsilylTBHP = tert-Butylhydroperoxyde TBS = tert-Butyldimethylsilyl TEA = Tri ethylamineTES = TriethylsilylTf = TrifluoromethanesulfonylTfO = TrifluoromethanesulfonateTf2O = Trifluoromethanesulfonyl anhydride TfOH = Trifluoromethanesulfonic acid TFA = Trifluoroacetic acidTFAA = Trifluoroacetic anhydrideThexyl = 2,3-dimethyl-2-butylTHF = TetrahydrofuraneTHP = TetrahydropyranylTIPS = Triisopropyl silylTMEDA = N,N,N',N'-Tetramethylethylendiamine TMG = TetramethylguanidineTMS = Trimethyl silylTol = p-ToluylTPAP = Tetra-n-propylammonium perruthenate TPS = Tripropyl silylTr = Trityl, triphenylmethylTroc = 2,2,2-TrichloroethoxycarbonylTrt = Trityl, triphenylmethyl Ts = p-ToluenesulphonylPatent ApplicationAtty. Docket No. ENTX-035PCT p-TsOH = p-Toluenesulphonic acid UV = ultravioletZ = BenzyloxycarbonyGeneral Synthetic Schemes

[0271] Scheme 1 illustrates one procedure for preparing the compounds of disclosure using metal-catalyzed reaction to prepare the substituted aza-quinazoline by using 2,6-dichloro-5- fluoronicotinic acid I as starting material. Selective deprotonation and quenching with 1,2- di chi oro-1,1, 2, 2-tetrafluoroethane afforded fully substituted nicotinic acid intermediate II. After generation of acid chloride, coupling with methyl carbamimidothioate and cyclization gave the intermediate IV, 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one.Reaction with POC13 provided trichloro aza-quinazoline V. Displacement of 4-chloro group of the intermediate V with an (oc)-allyl amine provides 4-amine-substituted aza-quinazoline intermediate VI. Palladium-catalyzed intramolecular Heck reaction provided the tetracyclic core compound VII. Oxidation of thiomethyl group by m-CPBA gave methyl sulfone VIII, which can be replaced by alcohol to afford the 7-C1 aza-quinazoline intermediate IX. Suzuki coupling and necessary deprotection provided the desired target compound X.Scheme 1:Patent ApplicationAtty. Docket No. ENTX-035PCT

[0272] Scheme 2 illustrates another procedure for preparing the compounds of disclosure to prepare C6 substituted quinazoline. Treatment of substituted aniline I with NIS gave 2- iodoaniline intermediate II. Cyanation of iodide followed by base mediated cyclization with CO2 afforded bicyclic intermediate IV. Reaction with POC13 provided quinazoline V. Displacement of 4-chloro group of the intermediate V with an (a)-allyl amine provides 4-amine-substituted quinazoline intermediate VI. Sometime halo-exchange from 2-chloro to 2-F is necessary and gave intermediate VII. Palladium-catalyzed intramolecular Heck reaction provided the tetracyclic core compound VIII. After deprotonation and zincate formation, Pd-catalyzed Negishi coupling with a suitable aryl halide affords the desired aryl-aryl coupling product IX. After the removal of all the protecting groups, the product was purified to give the desired target compound X, which sometime can be submitted to SFC separation to provide the desired single diastereomers if necessary.Patent ApplicationAtty. Docket No. ENTX-035PCTScheme 2:Intermediate Syntheses: Intermediate 1 2,4-Dichloro-5,6,8-trifluoroquinazolineSynthetic scheme:Patent ApplicationAtty. Docket No. ENTX-035PCT

[0273] Step 1: Diisopropylamine (26.8 mL, 190 mmol) was dissolved in THF (200 mL) and the solution was cooled to -78 °C. n-Butyllithium (76.1 mL, 2.5 M in hexane) was added dropwise over 15 min at -78 °C. The mixture was stirred at -78 °C for 45 min. A solution of 2,6- dichloro-5-fluoropyridine-3-carboxylic acid (20 g, 95.2 mmol) in THF (50 mL) was added dropwise over 6 min at -78 °C. The following mixture was stirred at -78 °C for 30 min. A solution of l,2-dibromo-l,l,2,2-tetrachloroethane (46.5 g, 142.8 mmol) in THF (60 mL) was added dropwise over 10 min at -78 °C. The reaction was stirred at -78 °C for 2 h. The mixture poured into 2 N HC1 (90 mL) and extracted with EtOAc (x3). The combined organic extract was washed with brine (x2) and dried over Na2SO4 and concentrated. The residue was triturated with PE (200 mL) for 1 h. After filtration, the solid was washed with PE (3 x 50 mL), dried to afford 4-bromo-2,6-dichloro-5-fluoropyridine-3-carboxylic acid (20 g, 69.2 mmol, 72%). LCMS(ESI): m / z 287 [M+H]+.

[0274] Step 2: To a solution of 4-bromo-2,6-dichloro-5-fluoropyridine-3-carboxylic acid (10 g, 34.6 mmol) in DCM (100 mL) was added 2-chloro-2-oxoacetyl chloride (13.1 g, 103 mmol) and DMF (0.2 mL, 3.4 mmol). The reaction was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuum to give 4-bromo-2,6-dichloro-5-fluoropyridine-3- carbonyl chloride (10 g, 32.5 mmol, 94%) as a tan solid.

[0275] Step 3: To a solution of methyl carbamimidothioate sulfate (9 g, 44 mmol) in NaHCCh (30 mL) was added 4-bromo-2,6-dichloro-5-fluoropyridine-3-carbonyl chloride (9 g, 29.3 mmol) in EtOAc (20 mL). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated give crude methyl (4-bromo-2,6- dichloro-5-fluoronicotinoyl) carbamimidothioate (9 g, 24.9 mmol, 85%) as a tan solid. LCMS(ESI): m / z 360 [M+H]+.Patent ApplicationAtty. Docket No. ENTX-035PCT

[0276] Step 4: To a solution of methyl (4-bromo-2,6-dichloro-5- fluoronicotinoyl)carbamimidothioate (9 g, 24.9 mmol) in DMF (20 mb) was added DIEA (6.4 g,49.8 mmol). The reaction mixture was stirred at 90 °C for 5 h. The reaction mixture was poured into an aqueous pH 5 buffer and 100 g ice. The resulting solution was adjusted to pH=3 using 2 N HC1. After addition to the cold aqueous solution, a pale-yellow solid precipitated from solution. This precipitate was collected in a Buchner funnel and washed with water three times to afford 5,7-dichloro-8-fluoro-2-(methylsulfanyl)-3,4-dihydropyrido[4,3-d]pyrimidin-4-one (5 g,17.8 mmol, 71%) as a tan solid. LCMS(ESI): m / z 280 [M+H]+.

[0277] Step 5: To a solution of 5,7-dichloro-8-fluoro-2-(methylsulfanyl)-3,4- dihydropyrido[4,3-d]pyrimidin-4-one (500 mg, 1.7 mmol) in DIEA (346 mg, 2.6 mmol) was added POCI3 (5 mL). The reaction mixture was stirred at 90 °C for 4 h. The reaction mixture was concentrated in vacuum. The residue was purified by a silica gel column chromatography eluted with EtOAc in PE (gradient: 0—10%) to give 4,5,7-trichloro-8-fluoro-2- (methylsulfanyl)pyrido[4,3-d]pyrimidine (320 mg, 1.0 mmol, 60%) as an orange solid. LCMS(ESI): m / z 298 [M+H]+Intermediate 2 3-Allyl-l,4-oxazepane

[0278] Step 1: A mixture of prop-2-en-l-ol (7.5 mL, 109.3 mmol), tetrahydropyran-4-one (30.3 mL, 328.0 mmol), Xantphos (3.2 g, 5.5 mmol), DL-Proline (3.8 g, 32.8 mmol) and bis[chloropalladium (1+)] bis(prop-2-en-l-ide) (1 g, 2.7 mmol) in DMSO (250 mL) was heatedPatent ApplicationAtty. Docket No. ENTX-035PCT to 70 °C. The yellow suspension was cooled to room temperature and poured into water. The mixture was extracted with EtOAc (3x20mL), and the combined organic extracts were washed with brine, dried over Na2SC>4 and concentrated. The residual was purified by flash column chromatography (EtOAc in PE, 0-15%) to afford 3-(prop-l-en-3-yl) tetrahydropyran-4-one (12.4 g, 88.7 mmol, 81 %) as a light oil.1H NMR (400 MHz, DMSO-d6) 8 5.83 - 5.67 (m, 1H), 5.12 - 4.88 (m, 2H), 4.18 - 3.94 (m, 2H), 3.76 - 3.59 (m, 1H), 3.42 - 3.32 (m, 1H), 2.66 - 2.51 (m, 2H), 2.44 - 2.35 (m, 1H), 2.33 - 2.22 (m, 1H), 2.00 - 1.89 (m, 1H).

[0279] Step 2: A mixture of 3-(prop-l-en-3-yl) tetrahydropyran-4-one (10.4 g, 74.2 mmol) and K2CO3 (20.5 g, 148.4 mmol) in EtOH (110 mL) was added hydroxylamine hydrochloride (7.7 g, 111.3 mmol) in H2O (20 mL), and heated to 60 °C for 2h. The reaction mixture was cooled to room temperature and poured into water. The mixture was extracted with EtOAc, and the combined organic phase was washed with brine and dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (EA in PE, 0-25%) to afford [(4Z)-3- (prop-l-en-3-yl)-3,4,5,6-tetrahydro-2H-pyran-4-ylidene] hydroxylamine (6.9 g, 44.5 mmol, 60%) as a light oil. LCMS: ESI m / z 156.2 [M +H]+. ’H NMR (400 MHz, DMSO-d6) 8 10.51 (s, 1H), 5.86 - 5.67 (m, 1H), 5 12 - 4.90 (m, 2H), 3.74 - 3.66 (m, 1H), 3.65 - 3.56 (m, 2H), 3.49 - 3.40 (m, 1H), 2 61 - 2.53 (m, 1 H), 2.47 - 2.30 (m, 3H), 2.19 - 2.08 (m, 1H).

[0280] Step 3: To a stirred solution of [(4Z)-3-(prop-l-en-3-yl)-3,4,5,6-tetrahydro-2H-pyran- 4-ylidene] hydroxylamine (7.0 g, 45.1 mmol) and TEA (18.8 mL, 135.3 mmol) in DCE (80 mL) was added TsCl (12.9 g, 67.7 mmol) at room temperature and was stirred at 85°C for 4h. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica (EtOAc in PE, 0-60%) to give 3-(prop-l-en-3-yl)-l,4-oxazepan-5-one (2.1 g, 13.5 mmol, 30%) as a light brown solid. LCMS: ESI m / z 156 [M +H]+. ‘H NMR (400 MHz, DMSO-d6) 8 7.37 (s, 1H), 5.93 - 5.70 (m, 1H), 5.25 - 4.97 (m, 2H), 3.85 - 3.63 (m, 2H), 3.60 - 3.38 (m, 2H), 2.79 - 2.64 (m, 1H), 2.43 - 2.27 (m, 1H), 2.29 - 2.08 (m, 2H).

[0281] Step 4: To a solution of 3-(prop-l-en-3-yl)-l,4-oxazepan-5-one (2.1 g, 13.5 mmol) in THF (20 mL) was added LiAlH4 (16.2 mL, 40.6 mmol, 2.5N in THF) at 0 °C, the reaction mixture was stirred at 70 °C for 2h. The mixture was quenched with NazSOHOHzO at 0 °C and the mixture was added EtOAc (50 mL) and was filtered. The filtrate was washed with brine, dried and concentrated to give 3-(prop-l-en-3-yl)-l,4-oxazepane (1.6 g, 11.3 mmol, 84%) as a yellow oil and was used without further purification. LCMS-ESI (m / z): 142.1 [M + H]+. 'HPatent ApplicationAty. Docket No. ENTX-035PCTNMR (400 MHz, DMSO-d6) 5 5.91 - 5.68 (m, 1H), 5.10 - 4.93 (m, 2H), 4.43 - 4.28 (m, 2H), 3.77 - 3.66 (m, 2H), 3.65 - 3.53 (m, 2H), 3.49 - 3.42 (m, 1H), 3.14 - 3.04 (m, 1H), 3.01 - 2.90 (m, 1H), 2.75 - 2.61 (m, 2H), 1.75 - 1.68 (m, 2H), 1.63 - 1.53 (m, 1H).Intermediate 3( / ?)-3-Ally 1- 1 ,4-oxazepane

[0282] Step 1: To a solution suspension of (R)-2-aminopent-4-enoic acid (44.0 g, 0.38 mmol, 1.0 eq) in MeOH (440 mL) being cooled to 0 °C was added dropwise SOCh (90.4 g, 0.76 mmol, 2.0 eq). Then the mixture was stirred at room temperature for overnight. LCMS showed the reaction was completed. And the mixture was concentrated directly to afford the crude product methyl (R)-2-aminopent-4-enoate (50.0 g crude, yellow oil). The crude product was used for next step directly without further purification. LCMS: m / z 130.3 (M+H+).

[0283] Step 2: To a solution of methyl (7?)-2-aminopent-4-enoate (50.0 g crude, 0.38 mol, 1.0 eq) in dioxane (500 mL) was added saturated sodium bicarbonate solution (275 mL) and (BOC)2O (100.0 g, 0.46 mol, 1.2 eq) at room temperature. Then the mixture was stirred at room temperature for overnight. LCMS showed the reaction was completed. Then the mixture wasPatent ApplicationAtty. Docket No. ENTX-035PCT added to H2O (50 mL) and extracted with EtOAc (100 mL x 3). The organic layers were washed with brine (50 mL), dried over Na2SC>4, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluted with (Petroleum ether: EtOAc = 10: 1) to afford methyl (A)-2-((tert-butoxycarbonyl)amino)pent-4- enoate (46.0 g, 52.6% for two steps) as a yellow oil. LCMS: m / z 252.1 (M+Na+).

[0284] Step 3: To a solution of methyl (A)-2-((tert-butoxycarbonyl)amino)pent-4-enoate (6.5 g, 0.028 mol, 1.0 eq) in THF (65 mL) was added LiAlIL (1.0 M, 62 mL, 0.062 mol, 2.2 eq) under N2 at 0 °C. The mixture was stirred at room temperature for 2 h. TLC showed the reaction was completed. After the reaction mixture was cooled to 0 °C, the reaction mixture was quenched by addition of H2O (2.5 mL), followed by 15% aqueous NaOH (2.5 mL). After being stirred at room temperature for 15 min, H2O (7.5 mL) and Na2SC>4 was added at room temperature and the mixture was stirred for 0.5 h. The solid was removed by filtration through Celite pad. The filtrate was concentrated to dryness to give to7-butyl (R)-(l-hydroxypent-4-en-2- yl)carbamate (4.5 g, 78.9%) as a yellow oil, which was used for next step directly without further purification. LCMS: m / z 224.1 (M+Na+).

[0285] Step 4: To a solution of / ert-butyl (A)-(l-hydroxypent-4-en-2-yl)carbamate (3.6 g, 0.018 mol, 1.0 eq) in / -BuOH (36 mL) was added CS2CO3 (5.7 g, 0.018 mol, 1.0 eq) and / <77- butyl acrylate (46.1 g, 0.36 mol, 20.0 eq) at room temperature. The mixture was stirred at room temperature for overnight. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The organic layer was dried over Na2SO4 and concentrated to afford the residue. The residue was purified by column chromatography on silica gel eluted with (Petroleum ether / EtOAc = 10: 1) to give / c77-butyl (A)-3-((2-((tert-butoxycarbonyl)amino)pent- 4-en-l-yl)oxy)propanoate (4.9 g, 83.3%) as a yellow oil. LCMS: m / z 352.0 (M+Na+).

[0286] Step 5: A solution of te / 7-butyl (R)-3-((2-((tert-butoxycarbonyl)amino)pent-4-en-l- yl)oxy)propanoate (4.9 g, 0.015 mol, 1.0 eq) in HCl / dioxane (4N) (75.00 mL, 0.3 mol, 20.0 eq) was stirred at room temperature for overnight. LCMS showed the reaction was completed. The mixture was concentrated directly to afford the (R)-3-((2-aminopent-4-en-l-yl)oxy)propanoic acid (HC1 salt) (3.0 g, crude) as a yellow oil which was used for next step directly without further purification. LCMS: m / z 174.1 (M-HC1+H+).

[0287] Step 6: To a solution of (A)-3-((2-aminopent-4-en-l-yl)oxy)propanoic acid (HC1 salt) (3.0 g crude, 0.015 mol, 1.0 eq) in DMF (30 mL) was added NMM (6.1 g, 0.06 mol, 4.0 eq),Patent ApplicationAtty. Docket No. ENTX-035PCTEDCI (5.8 g, 0.03 mol, 2.0 eq) and HOBT (4.1 g, 0.03 mol, 2.0 eq). The mixture was stirred for overnight at room temperature. The reaction mixture was quenched by the addition of the saturated aqueous NaHCCL (30 mL) and extracted with EtOAc (50 mL x 3). The organic layer was dried over Na2SC>4 and concentrated to afford the crude product. The crude product was purified by column chromatography on silica gel eluted with (DCM / MeOH = 80: 1) to give (R)- 3-allyl-l,4-oxazepan-5-one (1.8 g, 78.2% for two steps) as a white solid. LCMS: m / z 156.1 (M+H+).

[0288] Step 7: To a solution of (A)-3-allyl-l,4-oxazepan-5-one (1.5 g, 0.01 mol, 1.0 eq) in THF (15 mL) was added LiAlLL (1.0 M, 20 mL, 0.02 mol, 2.0 eq) under N2 at 0 °C. The mixture was stirred at room temperature for 3h. TLC showed the reaction was completed. After the reaction mixture was cooled to 0 °C, the reaction mixture was quenched by addition of H2O (0.8 mL), followed by 15% aqueous NaOH (0.8 mL). After being stirred at room temperature for 15 min, H2O (2.4 mL) and Na2SCL was added at room temperature and the mixture was stirred for 0.5 h. The solid was removed by filtration through Celite pad. The filtrate was concentrated to dryness to give (7?)-3 -allyl- 1,4-oxazepane (1.1 g crude, 80.8%) as a yellow oil, which was used for next step directly without further purification. LCMS: m / z 142.2 (M+H+).Intermediate 4( S)-3- lly 1- 1 ,4-oxazepaneSynthetic scheme:Patent ApplicationAtty. Docket No. ENTX-035PCT

[0289] Step 1: To a solution suspension of (S)-2-aminopent-4-enoic acid (10.0 g, 0.087 mol, 1.0 eq) in MeOH being cooled to 0 °C was added dropwise SOCI2 (20.2 g, 0.17 mol, 2.0 eq). Then the mixture was stirred at room temperature overnight. LCMS showed the reaction was completed. And the mixture was concentrated directly to afford the crude product, which was used for next step directly without further purification.

[0290] Step 2: To a solution of the crude in dioxane (100 mb) was added saturated sodium bicarbonate solution (63 mL) and (Boc)2O (21.8 g, 0.10 mol, 1.2 eq) at room temperature. Then the mixture was stirred at room temperature overnight. LCMS showed the reaction was completed. Then the mixture was added to H2O (30 mL) and was extracted with EtOAc (50 mL x 3). The organic layers were washed with brine (30 mL), dried over Na2SC>4, filtered, concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluted with (petroleum ether: EtOAc = 10: 1) to afford methyl (S)- 2-((tert-butoxycarbonyl)amino)pent-4-enoate (14 g, 68.9% for two steps) as a yellow oil. LCMS: m / z 252.1 (M+Na+).Patent ApplicationAtty. Docket No. ENTX-035PCT

[0291] Step 3: To a solution of methyl (S)-2-((tert-butoxycarbonyl)amino)pent-4-enoate (16.0 g, 0.07 mol, 1.0 eq) in THF (160 mL) was added LiAlH4(1.0 M, 150 mL, 0.15 mol, 2.2 eq) under N2 at 0 °C. The mixture was stirred at room temperature for 2 h. TLC showed the reaction was completed. After the reaction mixture was cooled to 0 °C, the reaction mixture was quenched by addition of H2O (5.7 mL), followed by 15% aqueous NaOH (5.7 mL). After being stirred at room temperature for 15 min, H2O (17.1 mL) and Na2SO4were added at room temperature and stirred for 0.5 h. The solid was removed by filtration through Celite pad. The filtrate was concentrated to dryness to give / cvz-butyl (S)-(l-hydroxypent-4-en-2-yl)carbamate (13.8 g, 98.6%) as a yellow oil, which was used for next step directly without further purification. LCMS: m / z 224.1 (M+Na+).

[0292] Step 4: To a solution of / c 7-butyl (5)-(l-hydroxypent-4-en-2-yl)carbamate (8.0 g, 0.04 mol, 1.0 eq) in LBuOH (80 mL) was added CS2CO3 (13.0 g, 0.04 mol, 1.0 eq) and tert-butyl acrylate (102.5 g, 0.80 mol, 20.0 eq) at room temperature. The mixture was stirred at room temperature for overnight. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The organic layer was dried over Na2SO4. The mixture was concentrated on affording the crude product. The residue was purified by column chromatography on silica gel eluted with (petroleum ether: EtOAc = 10: 1) to give tert-butyl (5)- 3-((2-((tert-butoxycarbonyl)amino)pent-4-en-l-yl)oxy)propanoate (12.0 g, 90.0%) as a yellow oil. LCMS: m / z 352.2 (M+Na+).

[0293] Step 5: To a solution of tert-butyl (S)-3-((2-((tert-butoxycarbonyl)amino)pent-4-en-l - yl)oxy)propanoate (3.0 g, 0.009 mol, 1.0 eq) in HCl / dioxane (4N) (45.0 mL, 0.18 mol, 20.0 eq) was stirred at room temperature for overnight. LCMS showed the reaction was completed. The mixture was concentrated directly to afford (S)-3-((2-aminopent-4-en-l-yl)oxy)propanoic acid hydrochloride (2.7 g crude, yellow oil). The crude product was used for next step directly without further purification. LCMS: m / z 174.1 (M+H+).

[0294] Step 6: To a solution of (S)-3-((2-aminopent-4-en-l-yl)oxy)propanoic acid hydrochloride (2.7 g crude, ~ 0.009 mol, 1.0 eq) in DMF (20 mL) was added NMM (3.6 g, 0.036 mol, 4.0 eq), EDCI (3.5 g, 0.018 mol, 2.0 eq) and HOBT (2.4 g, 0.018 mol, 2.0 eq). The mixture was stirred at room temperature for overnight. The mixture was concentrated directly to afford the crude product. The crude product was quenched by the addition of the saturated aqueous NaHCCL (15 mL) and extracted with EtOAc (30 mL x 5). The organic layer was dried overPatent ApplicationAtty. Docket No. ENTX-035PCTNa2SO4. The mixture was concentrated to afford the crude product. The crude product was purified by silica gel column chromatography (DCM: MeOH = 80: 1) to give (5)-3 -allyl- 1,4- oxazepan-5-one (1.1 g, 77.8 % for two steps) as a white solid. LCMS: m / z 156.2 (M+H ).

[0295] Step 7: To a solution of (X)-3 -allyl- l,4-oxazepan-5-one (1.0 g, 6.5 mmol, 1.0 eq) in THF (10 mL) was added LiAlJLi (1.0 M, 13 mb, 13.0 mmol, 2.0 eq) under N2 at 0 °C. The mixture was stirred at room temperature for 3h. TLC showed the reaction was completed. After the reaction mixture was cooled to 0 °C, the reaction mixture was quenched by addition of H2O (0.5 mL), followed by 15% aqueous NaOH (0.5 mL). After being stirred at room temperature for 15 min, H2O (1.5 mL) and ISfeSCL was added at room temperature and stirred for 0.5 h. The solid was removed by fdtration through Celite pad. The fdtrate was concentrated to dryness to give (S)-3 -allyl- 1,4-oxazepane (800 mg, 87.7%) as a yellow oil, which was used for next step directly without further purification. LCMS: m / z 142.2 (M+H+).Intermediate 5 2-Chloro-l-fluoro-4-methylene-12-(methylsulfonyl)-4,5,5a,6,9,10-hexahydro-8H-7-oxa- 3,10a,ll,13-tetraazanaphtho[l,8-ab]heptaleneSynthetic scheme:Patent ApplicationAtty. Docket No. ENTX-035PCT

[0296] Step 1: To a stirred solution of 3-(prop-l-en-3-yl)-l,4-oxazepane (0.47 g, 3.3 mmol) and DIEA (1.7 mL, 10.0 mmol) in DCM (15 mL) was added 4,5,7-trichloro-8-fluoro-2- (methylsulfanyl) pyrido[4,3-d] pyrimidine (1 g, 3.4 mmol) in DCM (10 mL) at 0 °C and was stirred at 0 °C for 2h. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica (EtOAc in PE, 0-20%) to give 5,7-dichloro-8-fluoro-2- (methylsulfanyl)-4-[3-(prop-l-en-3-yl)-l,4-oxazepan-4-yl] pyrido [4, 3-d] pyrimidine (1.0 g, 2.5 mmol, 75%) as a light brown solid. LCMS: ESI m / z 403.3 [M +H]+

[0297] Step 2: To a mixture of 5,7-dichloro-8-fluoro-2-(methylsulfanyl)-4-[3-(prop-2-enyl)- l,4-oxazepan-4-yl]pyrido[4,3-d]pyrimidine (7 g, 17 mmol) in DMA (70 mL) were add Pd(OAc)2 (0.78 g, 3.4 mmol, 0.5 eq), PPhs (1 .8 g, 6.9 mmol, 1 .0 eq), and followed by KO Ac (5.11 g, 52 mmol). The reaction mixture was purged with nitrogen three times, then heated to 100 °C under nitrogen for 3 hours. The reaction was monitored by analysis of LC-MS. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with brine, and organic layer was separated. The aqueous layer was extracted with EtOAc, then the combined extracts were dried over anhydrous Na SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution with a gradient of 0-30% ethyl acetate in petroleum ether to afford 32-chloro-l-fluoro-4-methylene-12-(methylthio)-4,5,5a,6,9,10-hexahydro-8H-7-oxa- 3,10a,l l,13-tetraazanaphtho[l,8-ab]heptalene (3.8 g, 10.359 mmol, 60%) as a light yellow solid. LCMS: ESI m / z 367 [M + H]+.

[0298] Step 3: To a solution of chloro-3,6-difluoroben2-amino-4-bromo-5-3-chloro-2- fluoro-6-methylidene- 17-(methylsulfanyl)- 10-oxa-4, 14, 16,18-Patent ApplicationAtty. Docket No. ENTX-035PCT tetrazatetracyclo[13.3.1.05’19.08 14]nonadeca-l(19),2,4,15(16),17-pentaene (4 g, 10.9 mmol) in DCM (40 mL) was added m-CPBA (5.6 g, 32.7 mmol, 3 eq). The mixture was stirred at room temperature for 3 h. The reaction mixture was poured water and extracted with DCM. The organic layer was washed with brine, dried over Na2SC and concentrated. The residue was purified by a silica gel column chromatography eluted with MeOH in DCM (gradient: 0~8%) to give 2-chloro-l-fluoro-4-methylene-12-(methylsulfonyl)-4,5,5a,6,9,10-hexahydro-8H-7-oxa- 3,10a,l l,13-tetraazanaphtho[l,8-ab]heptalene (2.6 g, 6.519 mmol, 60%) as a light yellow solid. LCMS: ESI m / z 399 [M + H]+.Intermediate 62-Chloro-l-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-4- methylene-4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,ll,13-tetraazanaphtho[l,8-

[0299] Step 1: A solution of 2-chloro-l-fluoro-4-methylene-12-(methylsulfonyl)-4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,l l,13-tetraazanaphtho[l,8-ab]heptalene (150 mg, 0.4 mmol), [(2R,7aS)-2-fluoro-2,3,5,6,7,7a-hexahydro-lH-pyrrolizin-7a-yl]methanol (122 mg, 0.7 mmol) in THF (5 mL) was cooled to -30 °C, then sodium tert-butoxide (41 mg, 0.4 mmol) was added. The reaction mixture was stirred for 0.5 hour at -30 °C. Then the mixture was quenched with aq. NH4CI extracted with EtOAc. The combined organic layer was dried over anhydrousPatent ApplicationAtty. Docket No. ENTX-035PCTNa2SC>4 and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography eluted with MeOH in DCM (gradient: 0-10%) to give 2-chloro-l- fluoro-12-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-4-methylene- 4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,l l,13-tetraazanaphtho[l,8-ab]heptalene (140 mg, 0.3 mmol, 77%) LCMS(ESI): m / z 468 [M+H]+Intermediates 7 & 8Int. 7: 2-Chloro-l-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)-4-methylene-4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,ll,13- tetraazanaphtho[l,8-ab]heptaleneInt. 8: 2-Chloro-l-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5II)- yl)methoxy)-4-methylene-4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,ll,13- tetraazanaphtho[l,8-ab]heptaleneSynthetic scheme:Patent ApplicationAtty. Docket No. ENTX-035PCT

[0300] Step 1: 2-chloro-l-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)-4-m ethylene-4, 5, 5a, 6, 9, 10-hexahy dro-8H-7-oxa-3 , 10a, 11 , 13 -tetraazanaphtho [ 1,8- ab]heptalene (450 mg, 0.9 mmol) was purified by pre-SFC to give:Peak 1 : (8R)-3-chloro-2-fluoro-17-({[(2R,7aS)-2-fluoro-2,3,5,6,7,7a-hexahydro-lH-pyrrolizin- 7a-yl]methyl } oxy)-6-methylidene- 10-oxa-4, 14,16,18- tetrazatetracyclo[13.3.1.05,19.08,14]nonadeca-l(19),2,4,15(16),17-pentaene (160 mg, 0.33 mmol, 9.54%) andPeak 2: (8S)-3-chloro-2-fluoro-17-({ [(2R,7aS)-2-fluoro-2,3,5,6,7,7a-hexahydro-lH-pyrrolizin- 7a-yl]methyl } oxy)-6-methylidene- 10-oxa-4, 14,16,18- tetrazatetracyclo[13.3.1.05,19.08,14]nonadeca-l(19),2,4,15(16),17-pentaene (160 mg, 0.33 mmol, 9.54%) as a white solid.

[0301] Preparative separation methodInstrument: Waters Thar 80 preparative SFCColumn: ChiralPak IB, 250x30mm I.D., 5pmMobile phase: A for CO2 and B for MEOH( 0.1% 7mol / L NH3 in MeOH)Gradient: B 30%Flow rate: 60 mL / minBack pressure: 100 barColumn temperature: 35 °CWavelength: 220nmRun time: 12minCycle-time: 12minInjection volume: 0.8 mLNumber of injection needles: 20.Patent ApplicationAty. Docket No. ENTX-035PCTIntermediate 9 l-(4-methoxybenzyl)-6-methyl-4-(4,4,5,5-tetramethyl-l,3?2-dioxaborolan-2-yl)-5-(trifluoromethyl)-lH-indazole

[0302] Step 1: To a flask containing 3-bromo-5-fluoro-2-iodo-l -methylbenzene (4.5 g, 14.29 mmol) and Cui (23.1 g, 121 mmol) in DMF (15 mL) was added Methyl 2,2-difluoro-2- (fluorosulfonyl)acetate (23.3 g, 121 mmol). The reaction mixture was purged with nitrogen for three times, then heated to 70 °C for 18 hours under nitrogen. The reaction was monitored by analysis of LC-MS. After cooling to rt the mixture was diluted with PE, washed with brine. The aqueous layer was extracted with PE, and then the combined extracts were dried over anhydrous Na2SC>4, filtered and evaporated to afford 3-bromo-5-fluoro-l-methyl-2- (trifluoromethyl)benzene (1.8 g, 7.00 mmol, 49%) as a pale yellow solid, which was used directly without further purification. No MS. 'H NMR (400 MHz, DMSO-t / e) 8 7.77 - 7.67 (m, 1H), 7.45 - 7.36 (m, 1H), 2.52 - 2.50 (m, 3H).

[0303] Step 2: To a suspension of 3-bromo-5-fluoro-l-methyl-2-(trifluoromethyl)benzene (1.8 g, 7.00 mmol) in anhydrous LDA (7.00 mL, 17.5 mmol) was added THF (3 mL) dropwise under nitrogen at -78 °C. The white suspension was stirred at -78 °C for 0.5 hour, then DMF (1.7 mL, 21.0 mmol) was slowly added. The resulting solution was stirred at -78 °C for 0.5 h. The reaction was monitored by analysis of LC-MS. The reaction was quenched NH4CI, and thePatent ApplicationAtty. Docket No. ENTX-035PCT mixture was extracted with EtOAc. The organic extract was dried over anhydrous Na SCL, fdtered and concentrated in vacuo. The crude product was purified by flash silica chromatography, eluting with a gradient of 0-10% EtOAc in petroleum ether to afford 2-bromo- 6-fluoro-4-methyl-3-(trifluoromethyl)benzene-l-carbaldehyde (1.4 g, 4.91 mmol, 70%) as a yellow oil. No MS. ’H NMR (400 MHz, Chloroform-; / ) 5 10.41 - 10.21 (m, 1H), 7.19 - 7.02 (m, 1H), 2.63 - 2.55 (m, 3H).

[0304] Step 3: A mixture of 2-bromo-6-fluoro-4-methyl-3-(trifluoromethyl)benzene-l- carbaldehyde (1.4 g, 4.91 mmol), bis[(4-methoxyphenyl)methyl]amine (1.64 g, 6.39 mmol) in DMF (20 mL) was added DIEA (1.9 g, 14.7 mmol). The reaction mixture was purged with nitrogen three times, then heated to 100 °C for 4 hours under nitrogen. The reaction was monitored by analysis of LC-MS. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with brine, and organic layer was collected. The aqueous layer was extracted with EtOAc, then the combined extracts were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash silica gel chromatography, elution with a gradient of 0 to 10% EA in PE. The desired fractions were evaporated to dryness to afford 6- {bis[(4-methoxyphenyl)methyl]amino} -2-bromo-4-methyl-3-(trifluoromethyl)benzene- 1 - carbaldehyde (2.2 g, 4.21 mmol, 85%) as a yellow oil. LCMS: ESI m / z 523 [M +H]+

[0305] Step 4: A mixture of 6-{bis[(4-methoxyphenyl)methyl]amino}-2-bromo-4-methyl-3- (trifluoromethyl)benzene-l -carbaldehyde (2.2 g, 4.21 mmol) and Hydroxylamine hydrochloride (0.38 g, 5.48 mmol) in pyridine (25 mL) was stirred to 25 °C for 16 hours under nitrogen. The reaction was monitored by analysis of LC-MS. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with brine, and organic layer was collected. The aqueous layer was extracted with EtOAc, then the combined extracts were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash silica gel chromatography, elution with a gradient of 0 to 30% EA in PE. The desired fractions were evaporated to dryness to afford (E)-(6-{bis[(4-methoxyphenyl)methyl]amino}-2-bromo-4- methyl-3-(trifluoromethyl)phenyl) methanal oxime (2 g, 3.72 mmol, 88%) as a yellow oil. LCMS: ESI m / z 537.2 [M +H]+

[0306] Step 5: To a mixture of (E)-(6-{bis[(4-methoxyphenyl)methyl]amino}-2-bromo-4- methyl-3-(trifluoromethyl)phenyl)methanal oxime (2 g, 3.72 mmol) in DCM (20 mL) were added TFAA (1.02 g, 4.84 mmol) and TEA (1.55 mL, 11.17 mmol) The reaction mixture wasPatent ApplicationAtty. Docket No. ENTX-035PCT purged with nitrogen three times, then stirred at RT for 2 hours under nitrogen. The reaction was monitored by analysis of LC-MS. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with brine, and organic layer was collected. The aqueous layer was extracted with EtOAc, then the combined extracts were dried over anhydrous Na2SO4, fdtered and concentrated. The residue was purified by flash silica gel chromatography, elution with a gradient of 0 to 30% EA in PE. The desired fractions were evaporated to dryness to afford 4- bromo-l-(4-methoxybenzyl)-6-methyl-5-(trifluoromethyl)-lH-indazole (1.3 g, 3.26 mmol, 87%) as a yellow oil. LCMS: ESI m / z 399.2 [M +H]+

[0307] Step 6: To a mixture of 4-bromo-l-(4-methoxybenzyl)-6-methyl-5-(trifluoromethyl)- IH-indazole (400 mg, 1.00 mmol), 4,4,5,5-tetramethyL2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l,3,2-dioxaborolane (381 mg, 1.50 mmol), KOAc (295 mg, 3.01 mmol) in dioxane (2 mL) was added Pd(dppf)Ch (73.3 mg, 0.10 mmol). The reaction mixture was purged with nitrogen three times, then heated to 80 °C for 5 hours under nitrogen. The reaction was monitored by analysis of LC-MS. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with brine, and organic layer was collected. The aqueous layer was extracted with EtOAc, the combined extracts were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash silica gel chromatography, elution with a gradient of 0 to 20% EA in PE. The desired fractions were evaporated to dryness to afford l-(4- methoxybenzyl)-6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)- IH-indazole (80 mg, 0.18 mmol, 17%) as a yellow oil. LCMS: ESI m / z 436 [M +H]+.Intermediate 10 (l-(4-methoxybenzyl)-6-methyl-5-(trifluoromethyl)-lH-indazol-4-yl)boronic acidSynthetic scheme:Patent ApplicationAtty. Docket No. ENTX-035PCT

[0308] Step 1. To a solution of 4-bromo-l-(4-methoxybenzyl)-6-methyl-5-(trifluoromethyl)- IH-indazole (1 g, 2.50 mmol) in EtOH (10 mL) was added hypodiboric acid (0.45 g, 5.01 mmol), potassium acetate (0.74 g, 7.51 mmol) and [2-(2-aminophenyl)phenyl]palladium(2+){6- chloro-2-[2,4,6-tri(prop-2-yl)phenyl]phenyl}dicyclohexylphosphane (0.20 g, 0.25 mmol). The reaction mixture was purged with nitrogen three times, then heated to 80 °C under nitrogen for 20 min. The reaction was monitored by analysis of LC-MS. The cooled reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SC>4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 30%] to afford (l-(4-methoxybenzyl)-6- methyl-5-(trifluoromethyl)-lH-indazol-4-yl)boronic acid (600 mg, 1.65 mmol, 65%) as a white solid. LCMS: ESI m / z 365.1 [M+H]+.Intermediate 112,6-Difluoro-3-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline

[0309] Step 1: To a solution of l,5-difluoro-4-bromo-2-methylbenzene (5 g, 24 mmol) in THF (50 mL) was added LDA (12 mL, 24.15 mmol, 2M in THF) at -78 °C. The mixture was stirred at -78 °C for 2 h and then the dry ice was added. The mixture was stirred at -78 °C for 1 h. The reaction mixture was quenched with saturated ammonium chloride aqueous solution andPatent ApplicationAtty. Docket No. ENTX-035PCT adjusted to pH=5 with IM HC1. The mixture was extracted with EtOAc. The organic was washed with brine and dried over Na2SC>4 and concentrated to give 3-bromo-2,6-difluoro-5- methylbenzoic acid (4.5 g, 17.9 mmol, 74%) as a white solid. LCMS (ESI): m / z 251 [M+H]

[0310] Step 2: To a solution of chloro-3,6-difluoroben2-amino-4-bromo-5-3-bromo-2,6- difluoro-5-methylbenzoic acid (4.5 g, 17.9 mmol) in / -BuOH (50 mL) was added DPPA (9.8 g, 35.8 mmol) and TEA (7.4 mL, 53.7 mmol). The mixture was stirred at 85 °C for 2 h. The reaction mixture was poured water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by a silica gel column chromatography eluted with EtOAc in PE (gradient: 0—3%) to give 2-methylpropan-2-yl [(3- bromo-2,6-difluoro-5-methylphenyl)amino]methanoate (4.5 g, 13.9 mmol, 77%) as a colorless oil. LCMS(ESI): m / z 322 [M+H]+.

[0311] Step 3: Chloro-3,6-difluoroben2-amino-4-bromo-5-2-methylpropan-2-yl [(3-bromo- 2,6-difluoro-5-methylphenyl)amino]methanoate (4 g, 12.4 mmol) was added into HC1 (20 ml 4M in dioxane). The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to give 3-bromo-2,6-difluoro-5-methylaniline (2.5 g, 11.2 mmol, 90%) as a yellow oil. LCMS(ESI): m / z 222 [M+H]+.

[0312] Step 4: To a solution of chloro-3,6-difluoroben2-amino-4-bromo-5-3-bromo-2,6- difluoro-5-methylaniline (1.5 g, 6.7 mmol) in dioxane (5 mL) was added 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (2.5 g, 10.1 mmol), Pd(dppf)Ch (0.49 g, 0.68 mmol) and KO Ac (1 .9 g, 20.2 mmol). The mixture was stirred at 80 °C for 16 h. The mixture was concentrated. The residue was purified by a silica gel column chromatography eluted with EtOAc in PE (gradient: 0-15%) to give2,6-difluoro-5-methyl-3- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (1.5 g, 5.5 mmol, 82%) as a colorless oil. LCMS (ESI): m / z 270 [M+H]+.Intermediate 12 2-FIuoro-N,N-bis(4-methoxybenzyl)-5-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)anilinePatent ApplicationAtty. Docket No. ENTX-035PCTSynthetic scheme:

[0313] Step 1: To a solution of 3-bromo-2-fluoro-5-methylbenzoic acid (5 g, 21.4 mmol) in / -BuOH (60 mb) and toluene (30 mb) was added TEA (9 mL, 64.3 mmol) and DPPA (8.86 g, 32.1 mmol). The reaction mixture was purged with nitrogen three times, then heated to 120 °C under nitrogen overnight. The reaction was monitored by analysis of LC-MS. The cooled reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SO i, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 1%] to afford 2-methylpropan-2-yl [(3-bromo-2-fluoro-5-methylphenyl)amino]methanoate (5 g, 16.44 mmol, 76%) as a white solid. LCMS: ESI m / z 304 [M+H]+.

[0314] Step 2: To a flask containing 2-methylpropan-2-yl [(3-bromo-2-fluoro-5- methylphenyl)amino] methanoate (5 g, 16.4 mmol) in dioxane (50 mL)was added HC1 (4 mL, 4 N in 1,4-di oxane) at room temperature. The reaction was stirred at room temperature for 2 hours. The reaction was monitored by analysis of LC-MS. The mixture was poured into a stirred solution of NaHCCL solution, extracted with EA twice. The combined extracts were dried over anhydrous MgSCU, filtered and evaporated to afford crude 3-bromo-2-fluoro-5-methylaniline (3 g, 14.70 mmol, 89%) as a colorless oil, which was used directly without further purification. LCMS: ESI m / z 204.1 [M+H]+.

[0315] Step 3: To a suspension of sodium hydride (1.41 g, 58.8 mmol) in anhydrous DMF (40 mL) was added 3-bromo-2-fluoro-5-methylaniline (4 g, 19.6 mmol) dropwise under nitrogen at 0 °C. The white suspension was stirred at 0 °C for 20 min. 4-(chl orom ethyl)- 1- methoxybenzene (9.21 g, 58.8 mmol) was added. The resulting solution was stirred at 0 °C and allowed to warm to room temperature. The reaction was monitored by analysis of LC-MS. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed withPatent ApplicationAtty. Docket No. ENTX-035PCT brine, dried by Na2SO4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 3%] to afford (3-bromo-2-fluoro-5- methylphenyl){bis[(4-methoxyphenyl)methyl] (amine (4 g, 9.00 mmol, 45%) as a white solid. LCMS: ESI m / z 444.1 [M+H]+.

[0316] Step 4: To a solution of 3-bromo-2-fluoro-N,N-bis(4-methoxybenzyl)-5- methylaniline (2 g, 4.50 mmol) in dioxane (20 mL) was added KOAc (1.33 g, 13.5 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (1.72 g, 6.76 mmol) and Pd(dppf)Ch (1.65 g, 2.25 mmol). The reaction mixture was purged with nitrogen three times, then heated to 90°C for 3 hours under nitrogen. The reaction was monitored by analysis of LC-MS. The cooled reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SC>4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 3%] to afford 2-fluoro-N,N-bis(4-methoxybenzyl)-5-methyl-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)aniline (2 g, 4.07 mmol, 90%) as a white solid. LCMS: ESI m / z 492.2 [M+H]+.. ‘HNMR (400 MHz, DMSO-d6) 8 7.20 (d, J= 8.5 Hz, 4H), 6.93 - 6.82 (m, 6H), 4.13 (s, 4H), 3.70 (s, 6H), 2.11 (s, 3H), 1.28 (s, 12H).Intermediate 13A^V-Bis(4-methoxybenzyl)-4-methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2-amine

[0317] Step 1: To a solution of 6-bromo-4-methylpyridin-2-amine (2 g, 10.6 mmol) in DMF (20 mL) was added NaH (1.03 g, 42.7 mmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 h and then PMBC1 (4.2 g, 26.7 mmol) was added. The mixture was stirred at room temperature forPatent ApplicationAtty. Docket No. ENTX-035PCT2 h. The reaction mixture was poured into NH4CI solution and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SCU and concentrated. The residue was purified by a silica gel column chromatography eluted with EtOAc in PE (gradient: 0-10%) to give 6-bromo-N,N-bis(4-methoxybenzyl)-4-methylpyridin-2-amine (4 g, 9.3 mmol, 87%) as a white solid. LCMS (ESI): m / z 427 [M+H]+.

[0318] Step 2: To a solution of 6-bromo-N,N-bis(4-methoxybenzyl)-4-methylpyridin-2- amine (2 g, 4.6 mmol) in dioxane (20 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2- dioxaborolane) (1.8 g, 7.02 mmol), Pd(dppf)Ch (0.3 g, 0.4 mmol) and KOAc (1.4 g, 14.0 mmol). The mixture was stirred at 100 °C for 5 h. The mixture was filtered, and the filtrate was concentrated to give N,N-bis(4-methoxybenzyl)-4-methyl-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-2-amine (2 g, 4.2 mmol, 90%) as a black oil. LCMS(ESI): m / z 393 [M+H]+.Intermediate 14:3-Fluoro-N,N-bis(4-methoxybenzyl)-4-methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2-amineSynthetic scheme:

[0319] Step 1: To a solution of 6-bromo-4-methylpyridin-2-amine (5 g, 26.7 mmol) in CHCI3 (150 mL) and H2O (150 mL) was added 4-(chl oromethyl)-l -fluoro- 1,4- diazabicyclo[2.2.2]octane-l,4-diium bis(tetrafhioro-X5-boranuide) (7.58 g, 21.4 mmol) inPatent ApplicationAtty. Docket No. ENTX-035PCT portions at 0 °C. The reaction was stirred at 25 °C for 16 h. The reaction mixture was extracted with DCM. The organic layer was washed with brine, dried over Na2SC and concentrated. The residue was purified using silica gel column chromatography eluting with 0-50% ethyl acetate in petroleum ether to afford 6-bromo-3-fluoro-4-methylpyridin-2-amine (1.4 g, 6.83 mmol, 26%) as a yellow solid. LCMS: ESI m / z 206.1 [M + H]+.

[0320] Step 2: To a solution of 6-bromo-3-fhioro-4-methylpyridin-2-amine (1.2 g, 5.85 mmol) in DMF (5 m ) was added NaH (0.70 g, 17.6 mmol, 60% in mineral oil) at 0 °C for 30 min. Then added 4-(chl orom ethyl)- 1 -methoxybenzene (2.02 g, 12.9 mmol). The reaction was stirred at 0 °C for overnight. The reaction mixture was diluted water, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-30%) to afford 2-{bis[(4-methoxyphenyl)methyl]amino}-6-bromo-3-fluoro-4- methylpyridine (2 g, 4.49 mmol, 77%) as a white oil. LCMS: (ESI) 447.1 [M+H]+.

[0321] Step 3: To a solution of 2-{bis[(4-methoxyphenyl)methyl]amino}-6-bromo-3-fluoro- 4-methylpyridine (500 mg, 1.12 mmol) in dioxane (3 mL) were added 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (428 mg, 1.68 mmol), Pd(dppf)C12 (82.2 mg, 0.11 mmol) and KOAc (331 mg, 3.37 mmol). The reaction was stirred at 100 °C under N2 for 5 hr. The cooled reaction mixture was filtered and concentrated to afford 2-{bis[(4-methoxyphenyl)methyl]amino]-3-fluoro-4-methyl-6-(4, 4,5, 5-tetramethyl- 1,3,2- dioxaborolan-2-yl)pyridine (500 mg, 1 .02 mmol, 90 %) as a yellow oil. LCMS: (ESI) 492.4 [M+H]+.Intermediate 152-Chloro-12-(((S)-2-(difluoromethylene)tetrahydro-lH-pyrroIizin-7a(5H)-yl)methoxy)-l- fluoro-4-methylene-4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,ll,13-tetraazanaphtho[l,8- abjheptalenePatent ApplicationAtty. Docket No. ENTX-035PCT

[0322] Step 1: To a solution of 2-chloro-l-fluoro-4-methylene-12-(methylsulfonyl)- 4,5,5a,6,7,8,9,10-octahydro-3,10a,l l,13-tetraazanaphtho[l,8-ab]heptalene (180 mg, 0.45 mmol) in THF (5 mL) and [(7aS)-2-(difluoromethylidene)-2,3,5,6,7,7a-hexahydro-lH-pyrrolizin-7a- yl]methanol (171 mg, 0.91 mmol) and was added sodium 2-methylpropan-2-olate (52 mg, 0.54 mmol). The Schlenk tube was purged with nitrogen three times and stirred at -30 °C for 1.5 hours under nitrogen. The reaction was monitored by analysis of LC-MS. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SC>4, fdtered and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 50%] to afford 2-chloro-12-(((S)-2- (difluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-l-fluoro-4-methylene- 4,5,5a,6,7,8,9,10-octahydro-3,10a,l l,13-tetraazanaphtho[l,8-ab]heptalene (160 mg, 0.32 mmol, 69%) as a white solid. LCMS: ESI m / z 506.3 [M+H]+.Intermediate 16(l?)-3-AllylmorpholinePatent ApplicationAtty. Docket No. ENTX-035PCTSynthetic scheme:

[0323] Step 1: To a solution of (R)-morpholin-3-ylmethanol hydrochloride (4 g, 26 mmol) in DCM (400 mL) was added TEA (7.22 mL, 52 mmol) and 4-methoxybenzaldehyde (3.72 g, 27.3 mmol). The mixture was stirred at 20 °C for 30 min until it became a clear solution. Then AcOH (1.79 mL, 31.2 mmol) and NaBH(OAc)3 (16.5 g, 78.1 mmol) was added into the mixture was stirred at 20 °C for 12 hours. The mixture was poured into saturatedNaHCCh and extracted with EtOAc. The combined organic phase was washed with brine, dried with NazSCL, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-5%, MeOH in DCM) to give (R)-(4-(4-methoxybenzyl)morpholin-3-yl)methanol (3.69 g, 15.5 mmol, 59%) as a pale-yellow oil. LCMS: ESI m / z 238.2 [M + H]+. 'H NMR (400 MHz, CDC13) 8 7.22 (d, J = 7.6 Hz, 2H), 6.87 (d, J = 7.2 Hz, 2H), 4.06 (d, J = 13.2 Hz, 1H), 3.97 (dd, J = 11.2, 3.6 Hz, 1H), 3.86 - 3.79 (m, 4H), 3.74 (d, J = 11.2 Hz, 1H), 3.66 (t, J = 10.4 Hz, 1H), 3.57 - 3.45 (m, 2H), 3.21 (d, J = 13.2 Hz, 1H), 2.72 (d, J = 12.0 Hz, 1H), 2.55 (s, 2H), 2.37 - 2.27 (m, 1H).

[0324] Step 2: To a solution of (R)-(4-(4-methoxybenzyl)morpholin-3-yl)methanol (3.69 g, 15.5 mmol) in DCM (140 mL) was added PPI13 (4.61 g, 17.6 mmol) and imidazole (1.59 g, 23.3 mmol) at 0 °C was stirred for 5 min. Then iodine (4.58 g, 18 mmol) was added portion wise and the mixture was stirred at 0 °C for 1 hour. The mixture was filtered and concentrated. The residue was purified by chromatography (silica gel, 0-30%, EtOAc in PE) to give (S)-3- (iodomethyl)-4-(4-methoxybenzyl)morpholine (5.04 g, 14.5 mmol, 93%) as a pale-yellow oil. LCMS: ESI m / z 348.0 [M + H]+.Patent ApplicationAtty. Docket No. ENTX-035PCT

[0325] Step 3: To a solution of Cui (4.42 g, 23.2 mmol) in THF (50 mL) was added bromo(vinyl)magnesium (43.55 mL, 43.5 mmol, 1 M) dropwise at -40 °C under N2 was stirred for 30 min, then allowed to warm to - 10 °C. The black suspension was cooled to - 40 °C and a solution of (S)-3-(iodomethyl)-4-(4-methoxybenzyl)morpholine (5.04 g, 14.5 mmol) in THF(15 mL) was added dropwise over 20 min. The thick suspension was stirred for an additional 1 hour with slow warming to 15 °C. EtOAc (100 mL) and saturated NH4CI (200 mL) were added. The mixture was stirred at room temperature for 5 min. Then 28 % aqueous NH3 (15 mL) was added. The mixture was extracted with EtOAc (3 x 300 mL). The combined organic layers were dried with Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (40 g column) using a gradient from 0 % to 40 % EtOAc in heptane which give (R)-3-allyl-4-(4-methoxybenzyl)morpholine (2.4 g, 9.70 mmol, 67%) as a colorless oil. LCMS: ESI m / z 248.1 [M + H]+.

[0326] Step 4: To a solution of (R)-3-allyl-4-(4-methoxybenzyl)morpholine (2.4 g, 9.70 mmol) in DCE (50 mL) was added 1-chloroethyl chloromethanoate (5.55 g, 38.8 mmol) and the mixture was stirred at 78 °C for 12 hours, cooled to room temperature and concentrated to remove the solvent. The residue was dissolved in MeOH (50 mL) and heated at 80 °C for 1 hour. The mixture was concentrated and co-evaporated from EtOAc (2 x 20 mL). The residue was suspended in 30 mL of a 1 : 1 mixture of EtOAc and heptane and the resultant precipitate was collected by filtration and washed with a 1 : 1 mixture of EtOAc and heptane to give (R)-3- allylmorpholine hydrochloride (1 .06 g, 6.48 mmol, 67%) as a white solid. LCMS: ESI m / z 128.2 [M + H]+.Intermediate 17 (l?)-2-Chloro-l-fluoro-4-methylene-ll-(methyIsulfonyl)-4,5,5a,6,8,9-hexahydro-7-oxa- 3,9a,10,12-tetraazabenzo[4,5]cyclohepta[l,2,3-de]naphthaleneSynthetic scheme:Patent ApplicationAtty. Docket No. ENTX-035PCT

[0327] Step 1: To a solution of (R)-3 -allylmorpholine hydrochloride (1 g, 7.86 mmol) in DCM (50 mL) was added DIEA (3.05 g, 23.6 mmol) and 4,5,7-trichloro-8-fluoro-2- (methylthio)pyrido[4,3-d]pyrimidine (2.35 g, 7.86 mmol) was stirred at 0 °C for 1 hour. The mixture was concentrated and the residue was purified by chromatography (silica gel, 0-10%, EtOAc in PE) to give (R)-3-allyl-4-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin- 4-yl)morpholine (2.6 g, 6.68 mmol, 85%) as yellow oil. LCMS: ESI m / z 389.1 [M + H]+.

[0328] Step 2: To a solution of (R)-3-allyl-4-(5,7-dichloro-8-fluoro-2- (methylthio)pyrido[4,3-d]pyrimidin-4-yl)morpholine (2.6 g, 6.68 mmol) in DMA (55 mL) was added Pd(OAc)2 (0.18 g, 0.80 mmol), PPhs (0.35 g, 1.34 mmol) and K2CO3 (2.77 g, 20.0 mmol). The mixture was stirred at 100 °C under N2 for 4 hours. The cooled mixture was poured into brine (500 mL) and extracted with EtOAc (500 mL). The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-30%, EtOAc in PE) to give (R)-2-chloro-l-fluoro-4-methylene-l 1- (methylthio)-4,5,5a,6,8,9-hexahydro-7-oxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[l,2,3- de] naphthalene (1.37 g, 3.88 mmol, 58%) as a yellow solid. LCMS: ESI m / z 353.1 [M + H]+. 1H NMR (400 MHz, DMSO-d6) 8 5.85 (d, J = 1.2 Hz, 1H), 5.49 (s, 1H), 3.98 - 3.89 (m, 3H), 2.95 (s, 2H), 2.79 (s, 2H), 2.55 (s, 3H), 1.96 (s, 2H).

[0329] Step 3: To a solution of (R)-2-chloro-l-fluoro-4-methylene-l l-(methylthio)- 4,5,5a,6,8,9-hexahydro-7-oxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[l,2,3-de]naphthalene (200 mg, 0.57 mmol) in DCM (10 mL) was added m-CPBA (293 mg, 1.70 mmol) was stirred at 20 °C for 2 hours. The mixture was concentrated and the residue was purified by chromatography (silica gel, 0-50%, EtOAc in PE) to give (R)-2-chloro-l-fluoro-4-methylene-l 1-Patent ApplicationAtty. Docket No. ENTX-035PCT (methylsulfonyl)-4,5,5a,6,8,9-hexahydro-7-oxa-3,9a, 10, 12-tetraazabenzo[4,5]cyclohepta[l ,2,3- de] naphthalene (148 mg, 0.38 mmol, 68%) as a yellow solid. LCMS: ESI m / z 385.1 [M + H]+.Intermediate 18 (l?)-2-Chloro-l-fluoro-ll-(((21?,7ai)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)- 4-methylene-4,5,5a,6,8,9-hexahydro-7-oxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[l,2,3- dejnaphthalene

[0330] Step 1: To a solution of (R)-2-chloro- l-fluoro-4-m ethylene- 1 l-(methylsulfonyl)- 4,5,5a,6,8,9-hexahydro-7-oxa-3,9a, 10,12-tetraazabenzo[4,5]cyclohepta[l,2,3-de]naphthalene (148 mg, 0.38 mmol) and ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (122 mg, 0.77 mmol) in THF (7 mL) was added sodium 2-methylpropan-2-olate (44.4 mg, 0.46 mmol) at -40 °C and the mixture was stirred under N2 for 1 hour. The mixture was concentrated and the residue was purified by chromatography (silica gel, 0-5%, MeOH in DCM) to give (R)- 2-chl oro-1 -fluoro- 1 l-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-4- methylene-4,5,5a,6,8,9-hexahydro-7-oxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[l,2,3- de] naphthalene (163 mg, 0.35 mmol, 91 %) as a brown oil. LCMS: ESI m / z 464.2 [M + H]~.Intermediate 19 (7?)-2-Chloro-ll-(((5)-2-(difluoromethylene)tetrahydro-lH-pyrrolizin-7a(5II)-yl)methoxy)- l-fluoro-4-methylene-4,5,5a,6,8,9-hexahydro-7-oxa-3,9a,10,12-tetraazabenzo[4,5] cyclohepta[l,2,3-de]naphthalenePatent ApplicationAtty. Docket No. ENTX-035PCT

[0331] Step 1: To a solution of (R)-2-chloro-l-fluoro-4-methylene-l l-(methylsulfonyl)- 4,5,5a,6,8,9-hexahydro-7-oxa-3,9a, 10,12-tetraazabenzo[4,5]cyclohepta[l,2,3-de]naphthalene (450 mg, 1.17 mmol) and (S)-(2-(difluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)- yl)methanol (443 mg, 2.34 mmol) in THF (7 mL) was added sodium 2-methylpropan-2-olate (135 mg, 1.40 mmol) at -40 °C and the mixture was stirred warmed to room temperature under N2 for 1 hour. The mixture was concentrated and the residue was purified by chromatography (silica gel, 0-50%, MeOH in DCM) to give (R)-2-chloro-l l-(((S)-2- (difluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-l-fluoro-4-methylene- 4,5,5a,6,8,9-hexahydro-7-oxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[l,2,3-de]naphthalene (414 mg, 0.84 mmol, 72 %) as a yellow solid. LCMS: ESI m / z 494.2 [M + H]+.Intermediate 20 2-AllylazepaneSynthetic scheme:Patent ApplicationAtty. Docket No. ENTX-035PCT

[0332] Step 1: To a mixture of 2-(prop-l-en-3-yl)cyclohexan-l-one (19 g, 137.47 mmol) and K2CO3 (38.00 g, 274.94 mmol) in EtOH (200 mL) was added a solution of Hydroxylamine hydrochloride (14.3 g, 206 mmol) in H2O (60 mL). The reaction mixture was stirred at 60 °C for 2 hours. The cooled reaction mixture was concentrated. The residue was diluted with water, extracted with EA. The combined organic phase was washed with brine and dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (EA in PE, 0~5%) to afford [(lE)-2-(prop-l-en-3-yl)cyclohexylidene]hydroxylamine (15 g, 97.9 mmol, 71%) as a white solid. LCMS: 154.1 [M+H]+.

[0333] Step 2: To a stirred solution of [(lE)-2-(prop-l-en-3- yl)cyclohexylidene]hydroxylamine (15 g, 97.9 mmol) and TEA (40.7 mL, 293 mmol) in DCE (150 mL) was added TsCl (27.99 g, 146 mmol) at room temperature. The reaction mixture was stirred at 85 °C for 4 hours. The cooled reaction was concentrated. The residue was purified by column chromatography on silica (EtOAc in PE, 0-30%) to give 7-(prop-l-en-3-yl)azepan-2-one (2.1 g, 13.7 mmol, 14%) as a brown solid. LCMS: 154.1 [M+H]+.

[0334] Step 3: To a solution of 7-(prop-l-en-3-yl)azepan-2-one (360 mg, 2.35 mmol) in THF (8 mL) was added lithium aluminum hydride (2.82 mL, 7.05 mmol) at 25 °C, the reaction mixture was stirred at 70 °C for 2h. The mixture was quenched with Na2SO4’10H2O at 0 °C. The following mixture was diluted with THF and filtrated. The filtrate was concentrated to give 2-(prop-l-en-3-yl)azepane (320 mg, 2.30 mmol, 98%) as a light-yellow oil and was used without further purification. LCMS: 140.1 [M+H]+.Intermediate 212-Chloro-1-fluoro-12-(((2 / ?,7aA)-2-fluorotetrahydro-lFT-pyrrolizin-7a(5H)-yl)niethoxy)-4- methylene-4,5,5a,6,7,8,9,10-octahydro-3,10a,ll,13-tetraazanaphtho[l,8-ab]heptalenePatent ApplicationAtty. Docket No. ENTX-035PCTSynthetic scheme:

[0335] Step 1: To a stirred solution of 2-(prop-l-en-3-yl)azepane (320 mg, 2.30 mmol) and DIEA (891.11 mg, 6.89 mmol) in DCM (6 mL) was added 4,5,7-trichloro-8-fluoro- 2-(methylsulfanyl)pyrido[4,3-d]pyrimidine (686 mg, 2.30 mmol) in DCM (20 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was concentrated. The residue was purified by column chromatography on silica (EtOAc in PE, 0~2%) to give 5,7-dichloro-8- fluoro-2-(methylsulfanyl)-4-[2-(prop-2-enyl)azepan-l-yl]pyrido[4,3-d]pyrimidine (370 mg, 0.92 mmol, 40%) as a yellow oil. LCMS: 401.1 [M+H]+.

[0336] Step 2: To a stirred solution of 5,7-dichloro-8-fluoro-2-(methylsulfanyl)-4-[2-(prop- 2-enyl)azepan-l-yl]pyrido[4,3-d]pyrimidine (370 mg, 0.92 mmol) and PPh (48.3 mg, 0.18 mmol) and KOAc (180 mg, 1.84 mmol) in DMA (6 mL) was added Pd(OAc)2 (20.7 mg, 0.09 mmol) at rt. The reaction mixture was stirred at 130 °C under N2 for Ih. The cooled reaction mixture was diluted with water and was extracted with EA. The organic phase was washed with brine, dried over Na2SC>4, and concentrated. The residue was purified by flash column chromatography (EA in PE= 0 ~ 5%) to afford 2-chloro- l-fluoro-4-m ethylene- 12-(methylthio)- 4,5,5a,6,7,8,9,10-octahydro-3,10a,l l,13-tetraazanaphtho[l,8-ab]heptalene (240 mg, 0.66 mmol, 71%) as a yellow oil. LCMS: 365.1 [M+H]+.

[0337] Step 3: To a stirred solution of 2-chloro-l-fluoro-4-methylene-12-(methylthio)- 4,5,5a,6,7,8,9,10-octahydro-3,10a,l l,13-tetraazanaphtho[l,8-ab]heptalene (240 mg, 0.66 mmol) in DCM (5 mL) was added m-CPBA (400 mg, 1.97 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 3h. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica (EtOAc in PE= 0~ 30%) to give 2-chloro-l -fluoroPatent ApplicationAtty. Docket No. ENTX-035PCT4-methylene-12-(methylsulfonyl)-4,5,5a,6,7,8,9,10-octahydro-3,10a,l l ,13-tetraazanaphtho[l ,8- ab]heptalene (170 mg, 0.43 mmol, 65%) as a colorless oil. LCMS: 397.1 [M+H]+.

[0338] Step 4: To a stirred solution of 2-chloro-l-fluoro-4-methylene-12-(methylsulfonyl)- 4,5,5a,6,7,8,9,10-octahydro-3,10a,l l,13-tetraazanaphtho[l,8-ab]heptalene (170 mg, 0.43 mmol) and [(2R,7aS)-2-fluoro-2,3,5,6,7,7a-hexahydro-lH-pyrrolizin-7a-yl]methanol (136 mg, 0.86 mmol) in THF (5 mL) was added sodium 2-methylpropan-2-olate (49.4 mg, 0.51 mmol) at -40 °C. The reaction mixture was stirred from -40 °C -RT. The reaction mixture was diluted with water and was extracted with EA. The organic layers were washed with brine, dried over Na2SC>4, and concentrated. The residue was purified by flash column chromatography (MeOH in DCM= 0- 3%) to afford 2-chloro-l-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-4-methylene-4,5,5a,6,7,8,9,10-octahydro-3,10a,l 1,13 -tetraazanaphtho [1,8- ab]heptalene (160 mg, 0.34 mmol, 78%) as a colorless oil. LCMS: 476.2 [M+H]+.Intermediate 22(5)-2-Allylpiperidine

[0339] Step 1: To a stirred solution of DMSO (4.2 mL, 58.9 mmol) in DCM (100 mL) was added 2-chloro-2-oxoacetyl chloride (2.5 mL, 29.4 mmol) at - 78 °C and the reaction mixture was stirred at -78 °C for 30 min. Tert-butyl (S)-2-(2-hydroxyethyl)piperidine-l -carboxylate (4.5 g, 19.6 mmol) in DCM (100 mL) was added dropwise at -78 °C and the solution was stirred at the same temperature for 1 h. EtsN (15.0 mL, 108 mmol) was then added and the reaction mixture was allowed to warm to rt and was stirred for 2h. The reaction mixture was diluted with DCM (100 mL) and the organic phase was washed with brine, dried over Na2SC>4, filtered and concentrated. The residue was purified by column chromatography on silica (EtOAc in PE, 0-30%) to give tert-butyl (S)-2-(2-oxoethyl)piperidine-l -carboxylate (4.50 g, 18.8 mmol, 96%) as a light oil. 'H NMR (400 MHz, DMSO-t / 6) 5 9.61 (t, J = 2.4 Hz, 1H), 4.76 - 4.58 (m, 1H),Patent ApplicationAtty. Docket No. ENTX-035PCT3.92 - 3.72 (m, 1H), 2.82 - 2.70 (m, 1H), 2.69 - 2.63 (m, 2H), 1.64 - 1.49 (m, 5H), 1.36 (s, 10H), 1.31 - 1.19 (m, 1H).

[0340] Step 2: To a suspension of methyltriphenylphosphanium iodide (18.4 g, 45.5 mmol) in THF (150 mL) was added w-BuLi (18.2 mL, 45.5 mmol, 2.5 N) at 0 °C. The mixture was stirred for 30 min at 0 °C. tert-butyl (S)-2-(2-oxoethyl)piperidine-l -carboxylate (4.5 g, 19.8 mmol) in THF (150 mL) was added. The reaction mixture was warmed to room temperature and stirred for 3 h. The reaction mixture was quenched with sat. NH4CI and was extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash column chromatography (hexane-EtOAc, 24: 1) to afford tert-butyl (S)-2-allylpiperidine-l -carboxylate (1.8 g, 8.0 mmol, 40%) as a light oil. 'H NMR (400 MHz, DMSO-t / 6) 8 5.78 - 5.63 (m, 1H), 5.13 - 5.01 (m, 1H), 5.00 - 4.93 (m, 1H), 4.22 - 4.10 (m, 1H), 3.90 - 3.75 (m, 1H), 2.84 - 2.66 (m, 1H), 2.43 - 2.28 (m, 1H), 2.27 - 2.15 (m, 1H), 1.63 - 1.43 (m, 5H), 1.39 (s, 9H), 1.32 - 1.21 (m, 1H).

[0341] Step 3: Tert-butyl (S)-2-allylpiperidine-l -carboxylate (1.9 g, 8.4 mmol) was dissolved in HC1 in EA (30 mL, 4N) at rt, and the reaction mixture was stirred at rt for 4h. The reaction mixture was concentrated to give the (S)-2-allylpiperidine HC1 salt (1.2 g, 5.374 mmol, 63%) as a white solid, and was used without further purification. 'H NMR (400 MHz, DMSO- d6) 8 5.91 - 5.67 (m, 1H), 5.25 - 5.03 (m, 2H), 3.23 - 3.12 (m, 1H), 3.03 (s, 1H), 2.87 - 2.74 (m, 1H), 2.48 (s, 1H), 2.35 - 2.22 (m, 1H), 1.84 - 1.55 (m, 4H), 1.50 - 1.32 (m, 2H).Intermediate 23(5)-2-Chloro-l-fluoro-ll-(((2I?,7a5)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)- 4-methylene-5,5a,6,7,8,9-hexahydro-4H-3,9a,10,12-tetraazabenzo[4,5]cycloheptafl,2,3-Synthetic scheme:Patent ApplicationAtty. Docket No. ENTX-035PCT

[0342] Step 1: To a stirred solution of (S)-2-allylpiperidine HC1 salt (0.65 g, 4.0 mmol) and DIPEA (2.8 mL, 16.1 mmol) in DCM (20 mL) was added 4,5,7-trichloro-8-fluoro-2-(methylthio) pyrido[4,3-d] pyrimidine (1.2 g, 4.1 mmol) in DCM (20 mL) at 0 °C and was stirred at 0 °C for 2h. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica (EA in PE, 0-20%) to obtain (S)-4-(2-allylpiperidin-l-yl)-5,7- dichloro-8-fhioro-2-(methylthio)pyrido[4,3-d]pyrimidine (1.6 g, 3.9 mmol, 98%) as a light brown solid. LCMS: ESI m / z 387.3 [M +H]+

[0343] Step 2: To a stirred solution of (S)-4-(2-allylpiperidin-l-yl)-5,7-dichloro-8-fluoro-2- (methylthio)pyrido[4,3-d]pyrimidine (1.6 g, 4.2 mmol) in DCM (20 mL) was added m-CPBA (2.16 g, 12.5 mmol) at 0 °C and was stirred at 0 °C for 2h. The reaction mixture was quenched with sat. NaHCCh and was extracted with EtOAc. The organic layers were washed with brine, dried over Na2SC>4, and concentrated. The residue was purified by column chromatography on silica (EA in PE= 0- 50%) to give (S)-4-(2-allylpiperidin-l-yl)-5,7-dichloro-8-fluoro-2- (methylsulfonyl)pyrido[4,3-d]pyrimidine (1 g, 2.4 mmol, 57%) as a light brown solid. LCMS: ESI m / z 419.3 [M +H]+

[0344] Step 3: To a stirred solution of (S)-4-(2-allylpiperidin-l-yl)-5,7-dichloro-8-fluoro-2- (methylsulfonyl)pyrido[4,3-d]pyrimidine (200 mg, 0.48 mmol) and [(2R,7aS)-2-fluoro- 2,3,5,6,7,7a-hexahydro-lH-pyrrolizin-7a-yl] methanol (113.9 mg, 0.72 mmol) in THF (2 mL) was added lithium bi s(trimethyl silyl) azanide in THF (1.4 mL, 1.43 mmol, IN) at -10 °C and was stirred at -10 °C for 2h. The reaction mixture was quenched with a saturated solution of NH4CI and then extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash column chromatography (MeOH in DCM=Patent ApplicationAtty. Docket No. ENTX-035PCT0~ 8%) to afford 4-((S)-2-allylpiperidin-l-yl)-5,7-dichloro-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (220 mg, 0.4 mmol, 93%) as a yellow oil. LCMS: ESI m / z 498.4 [M +H]1

[0345] Step 4: To a stirred solution of 4-((S)-2-allylpiperidin-l-yl)-5,7-dichloro-8-fluoro-2- (((2R, 7aS)-2-fluorotetrahy dro- 1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4, 3 -d]pyrimidine (170 mg, 0.3 mmol) and PPh3 (17.9 mg, 0.07 mmol) and KOAc (67 mg, 0.7 mmol) in DMA (4 mL) was added Pd(OAc)2 (7.7 mg, 0.03 mmol) at rt and was stirred at 130 °C for 2h. The reaction mixture was diluted with EA and was fdtrated. The organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash column chromatography (MeOH in DCM= 0 ~ 10%) to afford (S)-2-chloro-l -fluoro- 1 l-(((2R,7aS)-2-fluorotetrahydro- 1 H-pyrrolizin-7a(5H)-y l)methoxy)-4-methy lene-5 , 5 a, 6, 7, 8, 9-hexahy dro-4H-3 ,9a, 10,12- tetraazabenzo[4,5]cyclohepta [l,2,3-de]naphthalene (120 mg, 0.3 mmol, 76%) as a brown oil. LCMS: ESI m / z 462.1 [M +H]+Intermediate 24(R)-7-Allyl-l,4-dioxa-8-azaspiro[4.5]decane

[0346] Step 1: To a solution of 2-methylpropan-2-yl 4-oxohexahydropyridine-l -carboxylate (10 g, 50.2 mmol) in toluene (200 mL) were added 4-methylbenzenesulfonic acid (0.86 g, 5.02 mmol) and ethylene glycol (27.9 mL, 501 mmol). The reaction was stirred at rt under N2 for 18 hr. LCMS showed the reaction was completed. The reaction mixture was diluted water, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 25-40%) to afford compound 2-methylpropan-2-yl 8-aza-l,4-Patent ApplicationAtty. Docket No. ENTX-035PCT dioxaspiro[4.5]decane-8-carboxylate (12 g, 49.3 mmol, 98%) as a colorless oil. LCMS: 244.1 [M+H]+.

[0347] Step 2: To a solution of 2-methylpropan-2-yl 8-aza-l,4-dioxaspiro[4.5]decane-8- carboxylate (10 g, 41.1 mmol) in THF (200 mL) was added 2,5-dimethyl-2,5-diazahexane (9.55 g, 82 mmol) at rt. The mixture was added but-2-yllithium (5.27 g, 82.2 mmol) at -78 °C. The reaction mixture was stirred at -78 °C for another 40 min. Then 3 -bromoprop- 1-ene (24.9 g, 205 mmol) was added at -78 °C. The reaction was stirred at rt under N2 for 18 hr. LCMS showed the reaction was completed. The reaction was diluted with aqueous solution of NH4CI and EA. The organic layer was separated and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (gradient: 30-45%) to afford 2-methylpropan-2-yl 7-(prop-2-enyl)-8-aza-l,4-dioxaspiro[4.5]decane-8-carboxylate (5.6 g, 19.8 mmol, 48%) as a colorless oil. LCMS: 284.2 [M+H]+.

[0348] Step 3: To a solution of 2-methylpropan-2-yl 7-(prop-2-enyl)-8-aza-l,4- dioxaspiro[4.5]decane-8-carboxylate (2 g, 7.06 mmol) in TFA (20 mL). The reaction was stirred at rt under N2 for 1 ,5hr. LCMS showed the reaction was 90% DP. The organic layer was concentrated in vacuo afford 7-(prop-2-enyl)-8-aza-l,4-dioxaspiro[4.5]decane (1.1 g, 6 mmol, 85%) as a yellow oil. LCMS: 184.1 [M+H]+.Intermediate 25 2-Chloro-l-fluoro-ll-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-4- methylene-4,5,5a,6,8,9-hexahydro-3,9a,10,12-tetraazaspiro[benzo[4,5]cyclohepta[l,2,3- de]naphthaIene-7,2'-[l,3]dioxolan]-l(12a),2,3a,9b,ll-pentaeneSynthetic scheme:Patent ApplicationAtty. Docket No. ENTX-035PCT

[0349] Step 1: To a solution of 7-(prop-2-enyl)-8-aza-l,4-dioxaspiro[4.5]decane (1.8 g, 9.82 mmol) in DCM (20 mL) were added 4,5,7-trichloro-8-fluoro-2-(methylsulfanyl)pyrido[4,3- d]pyrimidine (3.23 g, 10.8 mmol) and DIEA (3.81 g, 29.5 mmol). The reaction was stirred at 0 °C under N2 for 1 hr. LCMS showed the reaction was 45% DP. The reaction mixture was diluted water, extracted with DCM. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether(gradi ent: 10-20%) to afford 7-allyl-8-(5,7-dichloro-8- fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-l,4-dioxa-8-azaspiro[4.5]decane (2 g, 4.5 mmol, 46%) as a colorless oil. LCMS: 445.0 [M+H]+.

[0350] Step 2: To a solution of 7-allyl-8-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3- d]pyrimidin-4-yl)-l,4-dioxa-8-azaspiro[4.5]decane (2 g, 4.49 mmol) in DMA (30 mL) were added potassium acetate (2.2 g, 22.5 mmol), PPI13 (3.54 g, 13.4 mmol) and Pd(OAc)2 (0.10 g, 0.449 mmol). The reaction was stirred at 130 °C under N2 for 30 min. LCMS showed the reaction was 40% DP. The cooled reaction mixture was diluted water, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 10- 15%) to afford 2-chloro-l-fluoro-4-methylene-l l-(methylthio)-4,5,5a,6,8,9- hexahydro-3,9a,10,12-tetraazaspiro[benzo[4,5]cyclohepta[l,2,3-de]naphthalene-7,2'- [l,3]dioxolan]-l(12a),2,3a,9b,l 1-pentaene (600 mg, 1.47 mmol, 33%) as a yellow oil. LCMS:409.0 [M+H]+.Patent ApplicationAtty. Docket No. ENTX-035PCT

[0351] Step 3: To a solution of 2-chloro-l-fluoro-4-methylene-l l-(methylthio)-4,5,5a,6,8,9- hexahydro-3,9a,10,12-tetraazaspiro[benzo[4,5]cyclohepta[l,2,3-de]naphthalene-7,2'- [l,3]dioxolan]-l(12a),2,3a,9b,l 1-pentaene (600 mg, 1.47 mmol) in DCM (10 mL) were added m-CPBA (761 mg, 4.4 mmol). The reaction was stirred at rt under N2 for 2 hr. LCMS showed the reaction was 70% DP. The reaction mixture was diluted water, extracted with DCM. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether(gradient: 15-20%) to afford 2-chloro-l-fluoro-4-methylene-l l-(methylsulfonyl)- 4,5,5a,6,8,9-hexahydro-3,9a,10,12-tetraazaspiro[benzo[4,5]cyclohepta[l,2,3-de]naphthalene- 7,2'-[l,3]dioxolan]-l(12a),2,3a,9b,l 1-pentaene (400 mg, 0.907 mmol, 62%) as a yellow oil.LCMS: 441.0 [M+H]+.

[0352] Step 4: To a stirred solution of 2-chloro-l-fluoro-4-methylene-l l-(methylsulfonyl)- 4,5,5a,6,8,9-hexahydro-3,9a,10,12-tetraazaspiro[benzo[4,5]cyclohepta[l,2,3-de]naphthalene- 7,2'-[l,3]dioxolan]-l(12a),2,3a,9b,l 1-pentaene (170 mg, 0.43 mmol) and [(2R,7aS)-2-fluoro- 2,3,5,6,7,7a-hexahydro-lH-pyrrolizin-7a-yl]methanol (136 mg, 0.86 mmol) in THF (5 mL) was added sodium 2-methylpropan-2-olate (49.4 mg, 0.51 mmol) at -40 °C. The reaction mixture was stirred from -40 °C -RT. The reaction mixture was diluted with water and was extracted with EA. The organic layers were washed with brine, dried over Na2SC>4, and concentrated. The residue was purified by flash column chromatography (MeOH in DCM= 0~ 3%) to afford 2- chloro-1 -fluoro- 1 l-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-4- methylene-4,5,5a,6,8,9-hexahydro-3,9a,10,12-tetraazaspiro[benzo[4,5]cyclohepta[l,2,3- de]naphthalene-7,2'-[l,3]dioxolan]-l(12a),2,3a,9b,l 1-pentaene (160 mg, 0.34 mmol, 78%) as a colorless oil. LCMS: 520.2 [M+H]+.Intermediate 26 (5)-8,10,12-Trifluoro-13-methylene-l,4,5,13,14,14a-hexahydro-3H- [l,4]oxazepino[4',3':l,7]azepino[2,3,4-de]quinazolinePatent ApplicationAtty. Docket No. ENTX-035PCTSynthetic scheme:

[0353] Step 1: To a solution of 5-bromo-2,4-dichloro-6,8-difluoroquinazoline (1.5 g, 0.005 mol, 1.0 eq) in DCM (15 mL) was added DIEA (5.2 g, 0.04 mol, 8.0 eq) and (7?)-3-allyl- 1 ,4- oxazepane (0.85 g, 0.006 mol, 1.2 eq) at -40 °C. The reaction was stirred at -40 °C for 2 h. The reaction was quenched with H2O (10 mL) and separated. The aqueous layer was extracted with DCM (15 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered off and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (Petroleum ether / EtOAc = 15: 1) to give (R)-3-allyl-4-(5- bromo-2-chl oro-6, 8-difluoroquinazolin-4-yl)-l,4-oxazepane (1.8 g, 90.0%) as a yellow solid. LCMS: m / z 417.8 (M+H+).

[0354] Step 2: A mixture of (7?)-3-allyl-4-(5-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)- 1,4-oxazepane (1.1 g, 0.003 mol, 1.0 eq) and KF (0.7 g, 0.012 mol, 4.0 eq) in DMSO (11 mL) was stirred at 90 °C for 5 h under N2. The mixture was quenched with H2O (40 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with H2O (10 mL x 3), brine (10 mL), dried over Na2SO4, filtered off and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (Petroleum ether / EtOAc = 15: 1) to give (R)-3-allyl-4-(5-bromo-2,6,8-trifluoroquinazolin-4-yl)-l,4-oxazepane (0.9 g, 81.8%) as a yellow solid. LCMS: m / z 401.9 (M+H+).

[0355] Step 3: To a solution of (R)-3-allyl-4-(5-bromo-2,6,8-trifluoroquinazolin-4-yl)-l,4- oxazepane (0.90 g, 2.2 mmol, 1.0 eq) in dioxane (9 mL) was added cataCxium A (0.32 g, 0.88 mmol, 0.4 eq), Pd(OAc)2 (99 mg, 0.44 mmol, 0.2 eq) and DIEA (0.85 g, 6.6 mmol, 3.0 eq). ThePatent ApplicationAtty. Docket No. ENTX-035PCT reaction mixture was stirred at 100 °C for 5 h under N2. The reaction mixture was quenched with H2O (10 mL) and extracted with EtOAc (15 mL x 3). The organic layers were washed with brine (10 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (Petroleum ether / EtOAc = 2: 1) to afford the product (450 mg (with 3 isomers)) as a yellow solid. The product was purified by prep-HPLC to give a white solid (270 mg (with 2 isomers)), which was purified by SFC to give (A)-8,10,12-trifluoro-13- methylene-l,4,5,13,14,14a-hexahydro-3H-[l,4]oxazepino[4',3': l,7]azepino[2,3,4-de]quinazoline (150 mg, 20.9%) as a white solid. LCMS: m / z 321.9 (M+H+).Intermediate 27(A)-8,10,12-Trifluoro-13-methylene-l,4,5,13,14,14a-hexahydro-3H-[l,4]oxazepino[4',3':l,7]azepino[2,3,4-de]quinazoline

[0356] Step 1: To a solution of 5-bromo-2,4-dichloro-6,8-difluoroquinazoline (1.6 g, 5.2 mmol, 1.0 eq) in DCM (15 mL) was added DIEA (5.4 g, 41.6 mmol, 8.0 eq) and (5)-3 -allyl- 1,4- oxazepane (0.8 g, 5.7 mmol, 1.1 eq) at -40 °C. The reaction was stirred at -40 °C for 2 h. The reaction was quenched with H2O (15 mL) and separated. The aqueous layer was extracted withPatent ApplicationAtty. Docket No. ENTX-035PCTDCM (20 mL x 2). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered off and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (Petroleum ether: EtOAc = 15: 1) to give (S)-3-allyl-4-(5- bromo-2-chl oro-6, 8-difluoroquinazolin-4-yl)-l,4-oxazepane (1.5 g, 69.2%) as a yellow solid. LCMS: m / z 418.0 (M+H+).

[0357] Step 2: A mixture of (5)-3-allyl-4-(5-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)- 1,4-oxazepane (1.5 g, 3.6 mmol, 1.0 eq) and KF (836.6 mg, 14.4 mmol, 4.0 eq) in DMSO (15 mL) was stirred at 90 °C for 5 h under N2. The mixture was quenched with H2O (45 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with H2O (15 mL x 3), brine (15 mL), dried over Na2SO4, filtered off and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (Petroleum ether: EtOAc = 10: 1) to give (5)-3-allyl-4-(5-bromo-2,6,8-trifluoroquinazolin-4-yl)-l,4-oxazepane (930 mg, 63.9%) as a yellow solid. LCMS: m / z 402.0 (M+H+).

[0358] Step 3: To a solution of (S)-3-allyl-4-(5-bromo-2,6,8-trifluoroquinazolin-4-yl)-l,4- oxazepane (850 mg, 2.1 mmol, 1.0 eq) in dioxane (9 mL) was added cataCxium A (301 mg, 0.84 mmol, 0.4 eq), Pd(OAc)2(95 mg, 0.42 mmol, 0.2 eq) and DIEA (814 mg, 6.3 mmol, 3.0 eq). The reaction mixture was stirred at 100 °C for 5 h under N2. The reaction mixture was quenched with H2O (10 mL) and extracted with EtOAc (15 mL x 3). The organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, concentrated under reduced pressure to give a residue. The crude product was purified by silica gel column chromatography (Petroleum ether: EtOAc = 10: 1) to afford the product (330 mg (with 3 isomers)) as a yellow solid. Then the white solid was purified by SFC to give (5’)-8,10,12-trifluoro-13-methylene-l,4,5,13,14, 14a-hexahydro-3H- [l,4]oxazepino[4',3':l,7]azepino[2,3,4-de]quinazoline (200 mg, 29.5%) as a white solid. LCMS: m / z 322.1 (M+H+).Intermediate 28(3S,5R)-3-alIyI-5-methyl-l,4-oxazepaneSynthetic scheme:Patent ApplicationAtty. Docket No. ENTX-035PCT

[0359] Step 1: To a suspension of 2-methylpropan-2-yl 3-{[(6S)-2,2-dimethyl-4-oxo-6- (prop-2-enyl)-5-aza-3-oxahept-7-yl]oxy}propanoate (58 g, 176 mmol) in THF (600 mL) at 0 °C was added LiAlf (13.4 g, 352 mmol) keeping the internal temperature at 0 to 5 °C. The mixture was stirred at 0 °C for Ih. The mixture was diluted with THF (600 mL) and cooled to 0 °C then quenched with 13 mL of water, 13 mL of 15 % aq. NaOH and 13*3 mL of water. The mixture was stirred at room temperature for 1 h, filtered and washed with THF, and the filtrate was concentrated to give 2-methylpropan-2-yl {[(2S)-l-[(3-hydroxypropyl)oxy]pent-4-en-2- yl]amino}methanoate (34 g, 131 mmol, 74%) as a colorless oil. LCMS: ESI m / z 260.2 [M+H]+.

[0360] Step 2: To a solution of 2-methylpropan-2-yl {[(2S)-l-[(3-hydroxypropyl)oxy]pent- 4-en-2-yl] amino Jmethanoate (34 g, 134 mmol) in DCM (5 mL) was added 1, 1,1 -triacetoxy- 1,3- dihydro-lX5-benzo[d][l,2]iodoxol-3-one (114 g, 268 mmol). The mixture was stirred at 0 °C for 30 min. The reaction mixture was diluted water, extracted with DCM. The organic phase was washed with brine, dried over Na2SCU and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-30%) to afford 2-methylpropan-2-yl {[(2S)-l -[(2-formylethyl)oxy]pent-4-en-2-yl]amino}methanoate (23 g, 89 mmol, 67%) as a colorless oil. LCMS: ESI m / z 258.1 [M+H]+.

[0361] Step 3: To a solution of 2-methylpropan-2-yl {[(2S)-l-[(2-formylethyl)oxy]pent-4- en-2-yl]amino]methanoate (24 g, 93.3 mmol) in THF (240 mL) was added magnesium monobromide methanide (93.3 mL, 280 mmol). The mixture was stirred at 0 °C for Ih. The reaction mixture was quenched with aqueous NH4CI solution, extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purifiedPatent Application Atty. Docket No. ENTX-035PCT using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradientO- 30%) to afford 2-methylpropan-2-yl {[(2S)-l-[(3-hydroxybutyl)oxy]pent-4-en-2- yl]amino}methanoate (5.7 g, 20.9 mmol, 22 %) as a colorless oil. LCMS: ESI m / z 274.1 [M+H]+.

[0362] Step 4: To a solution of 2-methylpropan-2-yl {[(2S)-l-[(3-hydroxybutyl)oxy]pent-4- en-2-yl]amino}methanoate (750 mg, 2.74 mmol) in DCM (5 mb) was added 1, 1,1 -triacetoxy - l,3-dihydro-lX5-benzo[d][l,2]iodoxol-3-one (2.33 g, 5.49 mmol). The mixture was stirred at 0 °C for 30 min. The reaction mixture was diluted water, extracted with DCM. The organic phase was washed with brine, dried over NazSCh and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-30%) to afford 2-methylpropan-2-yl {[(2S)-l-[(3-oxobutyl)oxy]pent-4-en-2-yl]amino}methanoate (400 mg, 1.47 mmol, 54%) as a colorless oil. LCMS: ESI m / z 272.2 [M+H]+.

[0363] Step 5: A solution of 2-methylpropan-2-yl {[(2S)-l-[(3-oxobutyl)oxy]pent-4-en-2- yl]amino}methanoate (400 mg, 1.47 mmol) in hydrochloric acid (3 mL) was stirred at RT for ON. The reaction mixture was diluted saturated NaHCO? aqueous solution, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated to afford 4- {[(2S)-2-aminopent-4-enyl]oxy}butan-2-one (250 mg, 1.46 mmol, 99 %) as a brown oil. LCMS: ESI m / z 172.2 [M+H]+.

[0364] Step 6: To a solution of 4-{[(2S)-2-aminopent-4-enyl]oxy}butan-2-one (240 mg, 1.40 mmol) in THF (2 mL) was added AcOH (0.01 mL, 0.14 mmol) The mixture was stirred at RT for 2h. Then added sodium triacetoxyborohydride (591 mg, 2.80 mmol). The mixture was stirred at RT for 4h. The reaction mixture was diluted saturated NaHCCL solution, extracted with EA. The organic phase was washed with brine, dried over NajSO i and concentrated to afford (3S,5R)-3-allyl-5-methyl-l,4-oxazepane (200 mg, 1.29 mmol, 92%) as a yellow oil. LCMS: ESI m / z 156.2 [M+H]+.Intermediate 29(5aS,10R)-2-chloro-l-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)-10-methyl-4-methylene-4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,ll,13- tetraazanaphtho[l,8-ab]heptalenePatent ApplicationAtty. Docket No. ENTX-035PCT

[0365] Step 1: To a solution of (3S)-5-methyl-3-(prop-l-en-3-yl)-l,4-oxazepane (100 mg, 0.64 mmol) in DCM (5 mL) were added (3S)-5-methyl-3-(prop-l-en-3-yl)-l,4-oxazepane (100 mg, 0.64 mmol) and DIEA (250 mg, 1.93 mmol) slowly at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for Ih. The reaction mixture was diluted water, extracted with DCM. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-30%) to afford 5,7-dichloro-8-fhjoro-4-[(3S)-5-methyl-3-(prop-2-enyl)-l,4- oxazepan-4-yl]-2-(methylsulfanyl)pyrido[4,3-d]pyrimidine (90 mg, 0.22 mmol, 33 %)as a yellow oil. LCMS: ESI m / z 419.1 [M+H]+.

[0366] Step 2: To a solution of (3S)-3-allyl-4-(5,7-dichloro-8-fluoro-2- (methylthio)pyrido[4,3-d]pyrimidin-4-yl)-5-methyl-l,4-oxazepane (150 mg, 0.36 mmol) in DMA (3 mL) was added PPhs (37 mg, 0.14 mmol), KOAc (106 mg, 1.08 mmol) and Pd(OAc)2 (16 mg, 0.07 mmol). The reaction mixture was purged with nitrogen three timesPatent ApplicationAtty. Docket No. ENTX-035PCT and stirred at 100 °rc for 2h under nitrogen. The reaction was monitored by analysis of LC-MS. The cooled reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SC>4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 25%] to afford (5aS,10R)-2- chloro-l-fluoro-10-methyl-4-methylene-12-(methylthio)-4,5,5a,6,9,10-hexahydro-8H-7-oxa- 3,10a,l l,13-tetraazanaphtho[l,8-ab]heptalene (70 mg, 0.18 mmol, 51%) as a white solid. LCMS: ESI m / z 381 [M+H]+.

[0367] Step 3: To a stirred solution of (5aS,10R)-2-chloro-l-fluoro-10-methyl-4-methylene- 12-(methylthio)-4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,l l,13-tetraazanaphtho[l,8- ab]heptalene (70 mg, 0.18 mmol) in DCM (3 mL) was added m-CPBA (93 mg, 0.46 mmol) at 0 °C. The reaction was stirred at 0 °C for 1.5 h. The reaction was monitored by analysis of LCMS. The solvent was removed under reduced pressure. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [Gradient: 2%] to afford (5aS,10R)-2- chloro-l-fluoro-10-methyl-4-methylene-12-(methylsulfonyl)-4,5,5a,6,9, 10-hexahydro-8H-7-oxa- 3,10a,l l,13-tetraazanaphtho[l,8-ab]heptalene (70 mg, 0.17 mmol, 92%) as a colorless oil. LCMS: 412 [M+H]+.

[0368] Step 4: To a solution of (5aS,10R)-2-chloro-l-fhioro-10-methyl-4-methylene-12- (methylsulfonyl)-4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,l l,13-tetraazanaphtho[l,8- ab]heptalene (70 mg, 0.17 mmol) in THF (3 mL) was added [(2R,7aS)-2-fluoro-2,3,5,6,7,7a- hexahydro-lH-pyrrolizin-7a-yl]methanol (53 mg, 0.34 mmol) and sodium 2-methylpropan-2- olate (48mg, 0.51 mmol). The reaction mixture was purged with nitrogen three times and stirred at -30 °C for 1.5 hours under nitrogen. The reaction was monitored by analysis of LC-MS. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SC>4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with MEOH in DCM [Gradient: 5%] to afford (5aS,10R)-2- chloro-1 -fluoro- 12-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl- 4-methylene-4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,l l,13-tetraazanaphtho[l,8-ab]heptalene (70 mg, 0.14 mmol, 83%) as a white solid. LCMS: ESI m / z 492 [M+H]+.Intermediate 30Patent ApplicationAtty. Docket No. ENTX-035PCT

[0369] Step 1: To a solution of 2-chloro-l-fluoro-4-methylene-12-(methylsulfonyl)- 4,5,5a,6,7,8,9,10-octahydro-3,10a,l l,13-tetraazanaphtho[l,8-ab]heptalene (60 mg, 0.15 mmol) in THF (5mL) was added ((3S,4S)-4-(difluoromethyl)-l,3-dimethylpiperidin-3-yl)methanol (60 mg, 0.31 mmol) and sodium 2-methylpropan-2-olate (17 mg, 0.18 mmol). The Schlenk tube was purged with nitrogen three times and stirred at -30 °C for 1.5 hours under nitrogen. The reaction was monitored by analysis of LC-MS. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SO4, fdtered and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 50%] to afford 2-chloro-12-(((3S,4S)-4-(difluoromethyl)-l,3-dimethylpiperidin-3-yl)methoxy)- l-fhioro-4-methylene-4,5,5a,6,7,8,9,10-octahydro-3,10a,l l,13-tetraazanaphtho[l,8-ab]heptalene (30 mg, 0.06 mmol, 38%) as a white solid. LCMS: ESI m / z 510.3 [M+H]+.Intermediate 31 (5aS)-2-chloro-l-fluoro-4-methylene-12-((2-methylenetetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)-4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,ll,13-tetraazanaphtho[l,8- abjheptalenePatent ApplicationAtty. Docket No. ENTX-035PCT

[0370] Step 1: To a solution of (S)-2-chloro-l-fluoro-4-methylene-12-(methylsulfonyl)- 4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,l l,13-tetraazanaphtho[l,8-ab]heptalene (80 mg, 0.20 mmol) and (S)-(2-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)m ethanol (61.5 mg, 0.40 mmol) in THF (3 mL) was added sodium 2-methylpropan-2-olate (23.1 mg, 0.24 mmol) at - 40 °C. The reaction mixture was stirred at room temperature for 2 hours. The mixture was quenched with ice-water, extracted with EA. The organic phase was washed with brine, dried over ISfeSC and concentrated. The residue was purified by chromatography (silica gel, 0- 5%, MeOH in DCM) to give (S)-2-chloro-l-fluoro-4-methylene-12-(((S)-2-methylenetetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy)-4,5, 5a, 6, 9, 10-hexahydro-8H-7-oxa-3 ,10 a, 11,13- tetraazanaphtho [1, 8 -ab] heptal ene (85 mg, 0.18 mmol, 89%) as a brown oil. LCMS (ESI): 472.2 [M+H]+Intermediate 32(S)-2-chloro-12-(((3S,4S)-4-(difluoromethyl)-l,3-dimethylpiperidin-3-yl)methoxy)-l-fluoro-4-methylene-4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,ll,13-tetraazanaphtho[l,8- abjheptalenePatent ApplicationAtty. Docket No. ENTX-035PCTSynthetic scheme:

[0371] Step 1: To a solution of (8S)-13-chloro-14-fluoro-17-(methyldioxo-X6-sulfanyl)-10- methylidene-6-oxa-2,12,16,18-tetrazatetracyclo[9.7.1.015,19.02,8]nonadeca-1(18), 11(12), 13, 15(19), 16-pentaene (100 mg, 0.25 mmol) in THF (3 mL) was added [(3S,4S)-4- (difluoromethyl)-l,3-dimethylhexahydropyridin-3-yl]methanol (96 mg, 0.50 mmol) and sodium 2-methylpropan-2-olate (72 mg, 0.75 mmol) at -30 °C. The reaction mixture was purged with nitrogen three times, and stirred at -30 °C for 1 hours under nitrogen. The reaction was monitored by analysis of LC-MS. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SC>4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with MEOH in DCM [Gradient: 5%] to afford to afford (8S)-3-chloro-2-fluoro-17-({[(3R,4S)-4-(difluoromethyl)-l,3- dimethylhexahydropyridin-3-yl]methyl}oxy)-6-methylidene-10-oxa-4,14,16,18- tetrazatetracyclo[ 13.3.1.05, 19.08, 14]nonadeca-l( 18), 2, 4, 15(19), 16-pentaene (90 mg, 0.18 mmol, 70%) as a white solid. LCMS: ESI m / z 512.3 [M+H]+.Intermediate 33 (S)-2-chloro-12-(((lS,7a'S)-2,2-difluorodihydro-l'H,3'H-spiro[cyclopropane-l,2'- pyrrolizin]-7a'(5'H)-yl)methoxy)-l-fluoro-4-methylene-4,5,5a,6,9,10-hexahydro-8H-7-oxa- 3,10a,ll,13-tetraazanaphtho[l,8-ab]heptalenePatent ApplicationAtty. Docket No. ENTX-035PCT

[0372] Step 1: To a solution of (S)-2-chloro-l-fluoro-4-methylene-12-(methylsulfonyl)- 4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,l l,13-tetraazanaphtho[l,8-ab]heptalene (80 mg, 0.20 mmol) in THF (5 mL) at -40 °C was added ((lS,7a'S)-2,2-difhiorodihydro-l'H,3'H- spiro[cyclopropane-l,2'-pyrrolizin]-7a'(5'H)-yl)methanol (82 mg, 0.4 mmol) and sodium tert- butoxide (23 mg, 0.2 mmol). The reaction was stirred at -40 °C for 1 hour. The reaction was monitored by analysis of LC-MS. The reaction mixture was filtered, and the filter cake was washed with DCM. The filtrate was washed with NaHCCh solution, and dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The crude product was purified by flash silica chromatography, eluting with a gradient of 10-30% EtOAc in petroleum ether to afford (S)-2- chloro-12-(((lS,7a'S)-2,2-difluorodihydro-rH,3'H-spiro[cyclopropane-l,2'-pyrrolizin]-7a'(5'H)- yl)methoxy)- 1 -fluoro-4-methylene-4,5, 5a, 6, 9, 10-hexahy dro-8H-7-oxa-3 , 10a, 11 , 13 - tetraazanaphthofl, 8-ab]heptalene (100 mg, 0.2 mmol, 96%) as a colorless oil. LCMS: 522.0 [M+H]+.Intermediate 342-alIyIazepane-4-carbonitrilePatent ApplicationAtty. Docket No. ENTX-035PCTSynthetic scheme:

[0373] Step 1. A flask containing l,4-dioxaspiro[4.5]decan-8-one (10 g, 64 mmol) and THF (100 mL) was purged with nitrogen three times. Anhydrous LHMDS (10.7 g, 64 mmol) was added by syringe at -78 °C under nitrogen, the reaction was stirred at -78 °C for 30 minutes. 3- bromoprop-l-ene (8.5 g, 70.4 mmol) was added over a period of 5 min, and the reaction was stirred at room temperature for 18 hours. The reaction was monitored by analysis of TLC. The reaction mixture was diluted with EtOAc, washed with NaHCCh, and the organic layer was separated. The aqueous layer was extracted with EtOAc, then the combined extracts were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient of 0-30% EtOAc in petroleum ether to afford 7-allyl- l,4-dioxaspiro[4.5]decan-8-one (5000 mg, 25.5 mmol, 39%) as a colorless oil. LCMS (ESI): m / z 197.1 [M+H]+

[0374] Step 2. To a stirred mixture of 7-allyl-l,4-dioxaspiro[4.5]decan-8-one (6g, 30.6 mmol) and N-hydroxylamine hydrochloride (3.2g, 45.8 mmol) in EtOH (70 mL) and H2O (14.00 mL), was added K2CO3 (8.45g, 61.15 mmol). The reaction was stirred at 60 °C for 2 hours. The reaction was monitored by analysis of TLC. The reaction mixture was diluted with EtOAc, washed with brine, and the organic layer was separated. The aqueous layer was extracted with EtOAc, then the combined extracts were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient of 0-50%Patent ApplicationAtty. Docket No. ENTX-035PCTEtOAc in petroleum ether to afford (Z)-7-allyl-l,4-dioxaspiro[4.5]decan-8-one oxime (5000 mg, 23.67 mmol, 77%) as a white solid. LCMS (ESI): m / z 212.0 [M+H]+

[0375] Step 3. To a stirred mixture of (Z)-7-allyl-l,4-dioxaspiro[4.5]decan-8-one oxime (2000 mg, 9.47 mmol) and TsCl (2707 mg, 14.2 mmol) in DCE (20 mL), was added Na2COs (3010 mg, 28.4 mmol). The reaction was stirred at 90 °C for 2 hours. The reaction was monitored by analysis of TLC. The reaction mixture was diluted with EtOAc, washed with brine, and the organic layer was separated. The aqueous layer was extracted with EtOAc, then the combined extracts were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient of 0-50% EtOAc in petroleum ether to afford 7-allyl-l,4-dioxa-8-azaspiro[4.6]undecan-9-one (800 mg, 3.79 mmol, 40%) as a yellow solid. LCMS (ESI): m / z 212.1 [M+H]+

[0376] Step 4. To a stirred mixture of 7-allyl-l,4-dioxa-8-azaspiro[4.6]undecan-9-one (750 mg, 3.55 mmol) in acetone (5.00 mL) and H2O (5 mL), was added 4-methylbenzenesulfonic acid (122 mg, 0.71 mmol). The reaction was stirred at 60 °C for 18 hours. The reaction was monitored by analysis of TLC. The reaction mixture was diluted with EtOAc, washed with brine, and organic layer was separated. The aqueous layer was extracted with EtOAc, then the combined extracts were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient of 0-10% MeOH in DCM ether to afford 7-allylazepane-2, 5-dione (230 mg, 1.38 mmol, 38%) as a yellow oil. LCMS (ESI): m / z 168.0 [M+H]+

[0377] Step 5. A flask containing 7-allylazepane-2, 5-dione (550 mg, 3.29 mmol) and THF (3 mL) was purged with nitrogen for three times. Anhydrous LiAlH4 (9.87 mL, 9.87 mmol) was added by syringe at 0 °C under nitrogen, the reaction was stirred at 70 °C for 2 hours. The reaction was monitored by analysis of LCMS. After cooling to room temperature, the reaction mixture was quenched with Na2SC>4. IOH2O at 0 °C. The reaction mixture was filtered. The filtrate was concentrated to afford crude 2-allylazepan-4-ol (400 mg, 1.55 mmol, 47%), which was used directly without further purification. LCMS (ESI): m / z 156.1 [M+H]+

[0378] Step 6. To a stirred mixture of 2-allylazepan-4-ol (550 mg, 3.54 mmol) in THF (6 mL) was added THF (6 mL). The reaction was stirred at room temperature for 18 hours. The reaction was monitored by analysis of TLC. The reaction mixture was diluted with EtOAc, washed with brine, and the organic layer was separated. The aqueous layer was extracted withPatent Application Atty. Docket No. ENTX-035PCTEtOAc, then the combined extracts were dried over anhydrous Na2SC>4, fdtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient of 0-30% EtOAc in petroleum ether to afford tert-butyl 2-allyl-4-hydroxyazepane-l -carboxylate (298 mg, 1.17 mmol, 33%) as a yellow oil. LCMS (ESI): m / z 256.1 [M+H]+

[0379] Step 7. To a stirred mixture of tert-butyl 2-allyl-4-hydroxyazepane- 1 -carboxylate (270 mg, 1.06 mmol) and TEA (0.44 mL, 3.17 mmol) in DCM (3 mL), was added MsCl (181 mg, 1.59 mmol). The reaction was stirred at room temperature for 0.5 hours. The reaction was monitored by analysis of TLC. The reaction mixture was diluted with EtOAc, washed with brine, and the organic layer was separated. The aqueous layer was extracted with EtOAc, then the combined extracts were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient of 0-30% EtOAc in petroleum ether to afford tert-butyl 2-allyl-4-((methylsulfonyl)oxy)azepane-l -carboxylate (300 mg, 0.90 mmol, 85%) as a yellow oil. LCMS (ESI): m / z 278.0 [M+H-56]+

[0380] Step 8. To a stirred mixture of tert-butyl 2-allyl-4-((methylsulfonyl)oxy)azepane-l- carboxylate (300 mg, 0.90 mmol) in DMSO (3 mL), was added NaCN (440 mg, 9.00 mmol). The reaction was stirred at 100 °C for 4 hours. The reaction was monitored by analysis of LCMS. The reaction mixture was diluted with EtOAc, washed with brine, and the organic layer was separated. The aqueous layer was extracted with EtOAc, then the combined extracts were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient of 0-50% EtOAc in petroleum ether to afford tert-butyl 2-allyl-4-cyanoazepane-l -carboxylate (160 mg, 0.48 mmol, 53%) as a yellow oil. LCMS (ESI): m / z 209.1 [M+H-56]+

[0381] Step 9. To a stirred mixture of tert-butyl 2-allyl-4-cyanoazepane-l -carboxylate (160 mg, 0.61 mmol) in HC1 (2 mL) and dioxane (2 mL), the reaction was stirred at room temperature for 1 hour. The reaction was monitored by analysis of TLC. The reaction mixture was evaporated to afford crude 2-allylazepane-4-carbonitrile (130 mg, 0.55 mmol, 91%) as a yellow oil, which was used directly without further purification. No Ms.Intermediates 35 and 36Int. 35: crs-2-chloro-l-fluoro-4-methylene-12-(methylthio)-4,5,5a,6,7,8,9,10-octahydro- 3,10a,ll,13-tetraazanaphtho[l,8-ab]heptalene-7-carbonitrile (mixture of two cis- enantiomers)Patent ApplicationAtty. Docket No. ENTX-035PCTInt. 36: trans-2-chloro-l-fluoro-4-methylene-l 2-(methylthio)-4,5,5a,6,7,8,9, 10-octahydro- 3,10a,ll,13-tetraazanaphtho[l,8-ab]heptalene-7-carbonitrile ((mixture of two transenantiomers)Synthetic scheme:

[0382] Step 1. To a stirred mixture of 2-allylazepane-4-carbonitrile (120 mg, 0.73 mmol) and 4,5,7-trichloro-8-fluoro-2-(methylsulfanyl)pyrido[4,3-d]pyrimidine (327.16 mg, 1.10 mmol) in DCM (3 mL) was added DIEA (472.14 mg, 3.65 mmol). The reaction was stirred atPatent ApplicationAtty. Docket No. ENTX-035PCT0 °C for 1 hour. The reaction was monitored by analysis of TLC. The reaction mixture was diluted with DCM, washed with brine, and the organic layer was separated. The aqueous layer was extracted with DCM, then the combined extracts were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient of 0-50% EtOAc in petroleum ether to afford 2-allyl-l-(5,7-dichloro-8-fluoro-2- (methylthio)pyrido[4,3-d]pyrimidin-4-yl)azepane-4-carbonitrile (280 mg, 0.66 mmol, 89%) as a yellow oil. LCMS (ESI): m / z 426.2 [M+H]+

[0383] Step 2. To a stirred mixture of 2-allyl-l-(5,7-dichloro-8-fluoro-2- (methylthio)pyrido[4,3-d]pyrimidin-4-yl)azepane-4-carbonitrile (230 mg, 0.54 mmol) in DMA (5 mL), were added KO Ac (158.83 mg, 1.62 mmol), PPh (56.60 mg, 0.22 mmol) and Pd(OAc)2 (24.22 mg, 0.11 mmol). The reaction was stirred at 100 °C for 18 hours. The reaction was monitored by analysis of LCMS. The reaction mixture was diluted with EtOAc, washed with brine, and the organic layer was separated. The aqueous layer was extracted with EtOAc, then the combined extracts were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient of 0-70% EtOAc in petroleum ether to afford (5aR,7S)-2-chloro-l-fluoro-4-methylene- 12-(methylthio)-4,5,5a,6,7,8,9,10-octahydro-3,10a,l l,13-tetraazanaphtho[l,8-ab]heptalene-7- carbonitrile (Pl, cis-isomer, less polar, 30 mg, 0.08 mmol, 14 %) and (5aS,7S)-2-chloro-l- fhioro-4-methylene-12-(methylthio)-4,5,5a,6,7,8,9,10-octahydro-3,10a,l 1,13- tetraazanaphtho[l,8-ab]heptalene-7-carbonitrile (P2, trans-isomer, more polar, 45 mg, 0.09 mmol, 17%) as a yellow oil. LCMS (ESI): m / z 390.2 [M+H]+.Intermediate 37 trans-2-chloro-l-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)-4-methylene-4,5,5a,6,7,8,9,10-octahydro-3,10a,ll,13-tetraazanaphtho[l,8- ab]heptalene-7-carbonitrile (mixture of two trans- diastereomers)Patent ApplicationAtty. Docket No. ENTX-035PCT

[0384] Step 1: To a solution of (5aS,7S)-2-chloro-l-fluoro-4-methylene-12-(methylthio)- 4,5,5a,6,7,8,9,10-octahydro-3,10a,l l,13-tetraazanaphtho[l,8-ab]heptalene-7-carbonitrile (40 mg, 0.10 mmol) in DCM (4 mL) was added m-CPBA (55 mg, 0.26 mmol) at 0 °C. The reaction mixture stirred at rt for 1.5 hours under nitrogen. The reaction was monitored by analysis of LC- MS. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SO4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with MEOH in DCM [Gradient: 3%] to afford (5aS,7S)-2-chloro-l-fhioro-4-methylene-12-(methylsulfonyl)-4,5,5a,6,7,8,9,10-octahydro- 3,10a,l l,13-tetraazanaphtho[l,8-ab]heptalene-7-carbonitrile (20 mg, 0.05 mmol, 46%) as a white solid. LCMS: ESI m / z 422.1 [M+H]+.

[0385] Step 2: To a solution of (5aS,7S)-2-chloro-l-fhioro-4-methylene-12- (methylsulfonyl)-4,5,5a,6,7,8,9,10-octahydro-3,10a,l l,13-tetraazanaphtho[l,8-ab]heptalene-7- carbonitrile (20 mg, 0.05 mmol) in THF (4 mL) was added [(2R,7aS)-2-fluoro-2,3,5,6,7,7a- hexahydro-lH-pyrrolizin-7a-yl]methanol (22 mg, 0.14 mmol) and sodium 2-methylpropan-2- olate (13 mg, 0.14 mmol) at -30 °C. The reaction mixture was stirred at -30 °C for 1 hour under nitrogen. The reaction was monitored by analysis of LC-MS. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SO4,Patent ApplicationAtty. Docket No. ENTX-035PCT filtered and concentrated. The residue was purified using silica gel column chromatography eluting with MEOH in DCM [Gradient: 5%] to afford (5aS,7S)-2-chloro-l-fluoro-12-(((2R,7aS)- 2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-4-methylene-4,5,5a,6,7,8,9,10-octahydro- 3,10a,l l,13-tetraazanaphtho[l,8-ab]heptalene-7-carbonitrile (15 mg, 0.03 mmol, 63%) as a white solid. LCMS: ESI m / z 501.1 [M+H]+.Intermediate 38 cis-2-chloro-l-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)- 4-methylene-4,5,5a,6,7,8,9,10-octahydro-3,10a,ll,13-tetraazanaphtho[l,8-ab]heptalene-7- carbonitrile (mixture of two cis- diastereomers)

[0386] Step 1: To a solution of 2-chloro-l-fIuoro-4-methylene-12-(methylthio)- 4,5,5a,6,7,8,9,10-octahydro-3,10a,l l,13-tetraazanaphtho[l,8-ab]heptalene-7-carbonitrile (30 mg, 0.08 mmol) in DCM (5 m ) was added / w-CPBA (26.5 mg, 0.15 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was poured water and extracted with DCM. The organic layer was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified by pre-TLC (80% EtOAc in PE) to give (5aR,7S)-2-chloro-l-fluoro-4-methylene-12- (methylsulfonyl)-4,5,5a,6,7,8,9,10-octahydro-3,10a,l l,13-tetraazanaphtho[l,8-ab]heptalene-7- carbonitrile (15 mg, 0.04 mmol, 46%) as a white solid. LCMS(ESI): m / z 422 [M+H]+Patent Application Atty. Docket No. ENTX-035PCT

[0387] Step 2: To a mixture of (5aR,7S)-2-chloro-l-fluoro-4-methylene-12- (methylsulfonyl)-4,5,5a,6,7,8,9,10-octahydro-3,10a,l l,13-tetraazanaphtho[l,8-ab]heptalene-7- carbonitrile (15 mg, 0.04 mmol) in THF (5 mb) was add ((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methanol (11.3 mg, 0.07 mmol) and followed by sodium tert-butoxide (10.2 mg, 0.11 mmol) at -40 °C then cooled to 0 °C for 1 hour under nitrogen. The reaction was monitored by analysis of LC-MS. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with brine, and organic layer was separated. The aqueous layer was extracted with EtOAc, then the combined extracts were dried over anhydrous MgSO4, fdtered and evaporated. The crude product was purified by pre-TLC (0~5% MeOH in DCM) to afford (5 aR, 7 S)-2-chloro- 1 -fluoro- 12-(((2R, 7aS)-2-fluorotetrahy dro- 1 H-pyrrolizin-7a(5H)- yl)methoxy)-4-m ethylene-4, 5, 5a, 6, 7, 8, 9, 10-octahydro-3 , 10a, 11 , 13 -tetraazanaphtho [ 1,8- ab]heptalene-7-carbonitrile (15 mg, 0.03 mmol, 84%) as a white solid. LCMS(ESI): m / z 501 [M+H]+.Intermediate 39 2-chloro-ll-(((S)-2-(difluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-l- fluoro-4-methylene-4,5,5a,6,8,9-hexahydro-3,9a,10,12- tetraazaspiro[benzo[4,5]cyclohepta[l,2,3-de]naphthalene-7,2'-[l,3]dioxolan]- l(12a),2,3a,9b,l 1-pentaeneSynthetic scheme:Patent ApplicationAtty. Docket No. ENTX-035PCT

[0388] Step 1: To a solution of 16'-chloro-17'-fluoro-3'-(methyldioxo-X6-sulfanyl)-13'- methylidenespiro[l,3-dioxolane-2,9'-2,4,6,15-tetrazatetracyclo[12.3.1.05,18.06,l l]octadeca- 1(2), 3, 5(18), 14(15), 16-pentaene] (230 mg, 0.52 mmol) in THF (7 mL) was added [(7aS)-2- (difluoromethylidene)-2,3,5,6,7,7a-hexahydro-lH-pyrrolizin-7a-yl]methanol (247 mg, 1.30 mmol) at room temperature. The mixture was added / -BuONa (100 mg, 1 .04 mmol) at -60 °C. The reaction mixture was stirred at room temperature under nitrogen for 1 hour. LCMS showed the reaction was completed. The reaction was diluted with aqueous solution of NH4CI and EA. The organic layer was separated and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with methanol in dichloroform(gradient:0-10%) to afford 3'- ({[(7aS)-2-(difluoromethylidene)-2,3,5,6,7,7a-hexahydro-lH-pyrrolizin-7a-yl]methyl}oxy)-16'- chloro-17'-fluoro-13'-methylidenespiro[l, 3-di oxolane-2, 9'-2, 4, 6, 15- tetrazatetracyclo[12.3.1.05, 18.06, 11 ]octadeca- 1 (2), 3, 5(18), 14(15), 16-pentaene] (180 mg, 0.33 mmol, 63%) as a white solid. LCMS: 550.2 [M+H]+.Intermediate 40 ((3R,6S)-l,l-difluoro-5-methyl-5-azaspiro[2.4]heptan-6-yl)methanolSynthetic scheme:

[0389] Step 1: Under nitrogen, a solution of 1 -(tert-butyl) 2-methyl (S)-4- methylenepyrrolidine-l,2-dicarboxylate (2 g, 8.3 mmol) in THF (28 mL) was added TMS-CF3Patent ApplicationAtty. Docket No. ENTX-035PCT(4.3 mL, 29 mmol) and Nal (0.7 g, 4.2 mmol) at room temperature. The resulting solution was stirred for 2 h at 60 °C. The reaction was concentrated under vacuum. The residue was diluted with water, extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and then concentrated under vacuum. The residue was purified by flash chromatography on silica gel to afford 5 -(tert-butyl) 6-methyl (3R,6S)-l,l-difluoro-5- azaspiro[2.4]heptane-5,6-dicarboxylate (2.2 g, 7.4 mmol, 89%) as yellow oil. LCMS: 292.0 [M+H]+.

[0390] Step 2: Lithium Aluminum Hydride (313 mg, 8.3 mmol) was added to a solution of 5 -(tert-butyl) 6-methyl (3R,6S)-l,l-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (800 mg, 2.8 mmol) in THF (10 mL) at 0 °C and stirred at 70 °C for 1 hour. After completion, the reaction was quenched by sodium sulfate decahydrate. After stirring at 25 °C for 20 min, the mixture was filtered. The filtrate was dried over sodium sulfate and concentrated under reduced pressure to afford ((3R,6S)-l,l-difluoro-5-methyl-5-azaspiro[2.4]heptan-6-yl)methanol (300 mg, 1.7 mmol, 62%) as a light-yellow oil. LCMS: ESI m / z 178.0 [M + H]+.Intermediate 41(S)-2-chloro-12-(((3R,6S)-l,l-difluoro-5-methyl-5-azaspiro[2.4]heptan-6-yl)methoxy)-l- fluoro-4-methylene-4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,ll,13-tetraazanaphtho[l,8- abjheptalene

[0391] Step 1: To a solution of ((3R,6S)-l,l-difluoro-5-methyl-5-azaspiro[2.4]heptan-6-Patent ApplicationAtty. Docket No. ENTX-035PCT yl)methanol (150 mg, 0.4 mmol) in THF (5 mL) at -40 °C, was added (S)-2-chloro-l-fluoro-4- methylene- 12-(methylsulfonyl)-4, 5 , 5 a, 6, 9, 10-hexahy dro-8H-7-oxa-3 , 1 Oa, 11 , 13 - tetraazanaphtho [1, 8 -ab] heptal ene and Sodium tert-butoxide (44 mg, 0.5 mmol). The reaction was stirred at -40 °C for 1 hour. The reaction was monitored by analysis of LC-MS. The reaction mixture was filtered, and the filter cake was washed with DCM. The filtrate was washed with NaHCCh solution, and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash silica chromatography, eluting with a gradient of 10-30% EtOAc in petroleum ether to afford (S)-2-chloro-12-(((3R,6S)-l,l-difluoro-5-methyl-5- azaspiro[2.4]heptan-6-yl)methoxy)-l-fluoro-4-methylene-4,5,5a,6,9,10-hexahydro-8H-7-oxa- 3,10a,l l,13-tetraazanaphtho[l,8-ab]heptalene (150 mg, 0.3 mmol, 81%) as a colorless oil. LCMS: ESI m / z 496.0 [M + H]+.Intermediate 423-allyl-l,4-diazepan-2-one

[0392] Step 1. To a stirred mixture of ethyl 2-oxoacetate (10.0 g, 97.9 mmol) and trimethyl(prop-l-en-3-yl)silane (17.9 g, 156 mmol) in DCM (100 mL) was added BF OEt2 (20.8 g, 146 mmol) at 0 °C. The reaction was stirred at room temperature for 2 hours. The reaction was monitored by analysis of TLC. The reaction mixture was diluted with DCM, washed with brine, and the organic layer was separated. The aqueous layer was extracted with DCM, then the combined extracts were dried over anhydrous Na2SO4, fdtered and evaporated. The crude product was purified by flash silica chromatography, eluting with aPatent ApplicationAtty. Docket No. ENTX-035PCT gradient of 0-30% EtOAc in petroleum ether to afford ethyl 2-hydroxypent-4-enoate (4.50 g, 31.2 mmol, 31%) as a yellow oil. LCMS (ESI): m / z 145.0 [M+H]+

[0393] Step 2. To a stirred mixture of ethyl 2-hydroxypent-4-enoate (4.50 g, 31.2 mmol) and 4-methylbenzenesulfonyl chloride (8.92 g, 46.8 mmol) in DCE (50 mL) was added TEA (12.9 mL, 93.6 mmol). The reaction was stirred at room temperature for 2 hours. The reaction was monitored by analysis of TLC. The reaction mixture was diluted with EtOAc, washed with brine, and the organic layer was separated. The aqueous layer was extracted with EtOAc, then the combined extracts were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient of 0-20% EtOAc in petroleum ether to afford ethyl 2-(tosyloxy)pent-4-enoate (4.50 g, 15.1 mmol, 48%) as a yellow oil. LCMS (ESI): m / z 299.0 [M+H]+

[0394] Step 3. To a stirred mixture of ethyl 2-(tosyloxy)pent-4-enoate (4.0 g, 13.4 mmol) and 2-methylpropan-2-yl [(3-aminopropyl)amino]methanoate (2.80 g, 16.1 mmol) in ACN (40 mL) was added Na2COa (4.26 g, 40.2 mmol). The reaction was stirred at 50 °C for 4 hours. The reaction was monitored by analysis of TLC. The reaction mixture was diluted with EtOAc, washed with brine, and the organic layer was separated. The aqueous layer was extracted with EtOAc, then the combined extracts were dried over anhydrous Na?SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient of 0-50% EtOAc in petroleum ether to afford ethyl 2-((3-((tert- butoxycarbonyl)amino)propyl)amino)pent-4-enoate (1.50 g, 4.99 mmol, 37%) as a yellow oil. LCMS (ESI): m / z 301.1 [M+H]+

[0395] Step 4. A mixture of ethyl 2-((3-((tert-butoxycarbonyl)amino)propyl)amino)pent-4- enoate (1.50 g, 4.99 mmol) in HC1 (5.00 mL) and dioxane (5 mL) was stirred at room temperature for 1 hour. The reaction was monitored by analysis of LCMS. The reaction mixture was evaporated to afford crude ethyl 2-((3-aminopropyl)amino)pent-4-enoate (1.30 g, 4.54 mmol, 90%) as a yellow oil, which was used directly without further purification. LCMS (ESI): m / z 201.2 [M+H]+

[0396] Step 5. To a stirred mixture of ethyl 2-((3-aminopropyl)amino)pent-4-enoate (1.10 g, 5.49 mmol) in EtOH (15 mL) was added Na2CC>3 (582 mg, 5.49 mmol). The reaction was stirred at 60 °C for 18 hours. The reaction was monitored by analysis of TLC. The reaction mixture was filtered and evaporated. The crude product was purified by flash silica chromatography, elutingPatent ApplicationAtty. Docket No. ENTX-035PCT with a gradient of 0~10% MeOH in DCM ether to afford 3-allyl-l ,4-diazepan-2-one (180 mg,1.17 mmol, 21%) as a white solid. LCMS (ESI): m / z 155.2 [M+H]+Intermediate 432-chloro-l-fluoro-4-methylene-12-(methylsulfonyl)-5,5a,7,8,9,10-hexahydro-3,7,10a,ll,13- pentaazanaphtho[l,8-ab]heptalen-6(4H)-oneSynthetic scheme:

[0397] Step 1. To a stirred mixture of 3-allyl-l,4-diazepan-2-one (170 mg, 1.10 mmol) and 4,5,7-trichloro-8-fluoro-2-(methylsulfanyl)pyrido[4,3-d]pyrimidine (427 mg, 1.43 mmol) in DCM (3 mb) was added DIEA (427 mg, 3.31 mmol). The reaction was stirred at 0 °C for 1 hour. The reaction was monitored by analysis of TLC. The reaction mixture was diluted with DCM, washed with brine, and the organic layer was separated. The aqueous layer was extracted with DCM, then the combined extracts were dried over anhydrous Na2SC>4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient of 0-70% EtOAc in petroleum ether to afford 3-allyl-4-(5,7-dichloro-8-fluoro-2-Patent ApplicationAtty. Docket No. ENTX-035PCT(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-l,4-diazepan-2-one (330 mg, 0.79 mmol, 71%) as a brown solid. LCMS (ESI): m / z 415.9 [M+H]+

[0398] Step 2. To a stirred mixture of 3-allyl-4-(5,7-dichloro-8-fluoro-2- (methylthio)pyrido[4,3-d]pyrimidin-4-yl)-l,4-diazepan-2-one (300 mg, 0.72 mmol) in DMA (10 mL) were added KOAc (212 mg, 2.16 mmol), PPhs (75.6 mg, 0.29 mmol) and Pd(OAc)2 (32.3 mg, 0.14 mmol). The reaction was stirred at 100 °C for 6 hours. The reaction was monitored by analysis of LCMS. The reaction mixture was diluted with EtOAc, washed with brine, and the organic layer was separated. The aqueous layer was extracted with EtOAc, then the combined extracts were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient of 0-70% EtOAc in petroleum ether to afford 2-chloro-l-fluoro-4-methylene-12-(methylthio)-5,5a,7,8,9,10-hexahydro- 3,7, 10a, 1 l,13-pentaazanaphtho[l,8-ab]heptalen-6(4H)-one (120 mg, 0.32 mmol, 43%) as a yellow oil. LCMS (ESI): m / z 380.2 [M+H]+

[0399] Step 3. To a stirred mixture of 2-chloro-l-fluoro-4-methylene-12-(methylthio)- 5,5a,7,8,9,10-hexahydro-3,7,10a,l l,13-pentaazanaphtho[l,8-ab]heptalen-6(4H)-one (80.0 mg, 0.21 mmol) in DCM (3 mL), was added m-CPBA (72.6 mg, 0.42 mmol). The reaction was stirred at room temperature for 1.5 hours. The reaction was monitored by analysis of LCMS. The reaction mixture was diluted with DCM, washed with brine, and the organic layer was separated. The aqueous layer was extracted with DCM, then the combined extracts were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient of 0-10% DCM in MeOH ether to afford 2-chl oro-1 - fhioro-4-methylene-12-(methylsulfonyl)-5,5a,7,8,9,10-hexahydro-3,7,10a,l 1,13- pentaazanaphtho[l,8-ab]heptalen-6(4H)-one (50 mg, 0.10 mmol, 46%) as a yellow oil. LCMS (ESI): m / z 412.1 [M+H]+Intermediate 442-chloro-12-(((S)-2-(difluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-l- fluoro-4-methylene-5,5a,7,8,9,10-hexahydro-3,7,10a,ll,13-pentaazanaphtho[l,8- ab] heptalen-6(4H)-onePatent ApplicationAtty. Docket No. ENTX-035PCT

[0400] Step 1. A flask containing [7aS)-2-(difhioromethylidene)-2,3,5,6,7,7a-hexahydro-lH- pyrrolizin-7a-yl]methanol (68.9 mg, 0.36 mmol) and THF (3 mL) was purged with nitrogen for three times, sodium 2-methylpropan-2-olate (21.0 mg, 0.22 mmol) was added by syringe at -40 °C under nitrogen. The reaction was stirred at -40 °C for 5 minutes, then 2-chloro-l-fluoro-4- methylene-12-(methylsulfonyl)-5,5a,7,8,9,10-hexahydro-3,7,10a,l l,13-pentaazanaphtho[l,8- ab]heptalen-6(4H)-one (30 mg, 0.07 mmol) was added by syringe at -40 °C under nitrogen. The reaction was stirred at room temperature for 1 hour. The reaction was monitored by analysis of LC-MS. The reaction mixture was diluted with EtOAc, washed with brine, and the organic layer was separated. The aqueous layer was extracted with EtOAc, then the combined extracts were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by TLC, eluting with a gradient of 0-10% DCM in MeOH ether to afford 2-chloro-12-(((S)-2- (difluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-l-fluoro-4-methylene- 5,5a,7,8,9,10-hexahydro-3,7,10a,l l,13-pentaazanaphtho[l,8-ab]heptalen-6(4H)-one (30 mg, 0.06 mmol, 79%) as a yellow oil. LCMS (ESI): m / z 521.0 [M+H]+Intermediate 45Patent ApplicationAty. Docket No. ENTX-035PCT l-(4-methoxybenzyl)-5-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6,7,8- tetrahydro-lH-benzo[f] indazole

[0401] Step 1: To a solution of (2R)-pent-4-en-2-ol (2 g, 23.2 mmol) in DCM (2 mL) was added TEA (0.05 mL, 0.40 mmol) and TsCl (6.64 g, 34.8 mmol) and the mixture was stirred at rt for 2h. The mixture was quenched with water (20 mL), extracted with DCM (15 mL x 2). The combined organic layer was dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by flash silica chromatography, eluting with a gradient of 0-15% EtOAc in petroleum ether to give 3 -bromo-4-iodo-2-m ethylaniline (1.7 g, 50%) as a brown solid. LCMS (ESI): m / z 312.2 [M + H]+.

[0402] Step 2: To a solution of 3-bromo-4-iodo-2-methylaniline (1.7 g, 5.45 mmol) in HOAc (20 mL) was added sodium nitrite (0.41 g, 5.99 mmol) in H2O (2 mL) and the mixture was stirred at rt overnight. The mixture was quenched with water (25 mL), extracted with EtOAc (25 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuoPatent ApplicationAtty. Docket No. ENTX-035PCT and purified by flash silica chromatography, eluting with a gradient of 0-20% EtOAc in petroleum ether to give 4-bromo-5-iodo-lH-indazole (0.9 g, 46%) as a brown solid. LCMS (ESI): m / z 323.2 [M + H]1.

[0403] Step 3: To a solution of 4-bromo-5-iodo-lH-indazole (0.9 g, 2.79 mmol) in THF (15 mb) was added 3,4-dihydro-2H-pyran (0.48 mL, 5.57 mmol) and 4-methylbenzenesulfonic acid (0.14 g, 0.84 mmol) and the mixture was stirred at 70 °C overnight. TLC showed the reaction was completed. The mixture was quenched with NaHCOs (aq.), extracted with EtOAc (15 mL x 2). The combined organic layer was dried over Na2SO4, filtered and the filtrate was concentrated in vacuo and purified by flash silica chromatography, eluting with a gradient of 0-15% EtOAc in petroleum ether to give 4-bromo-5-iodo-l-(3,4,5,6-tetrahydro-2H-pyran-2-yl)indazole (1.0 g, 79%) as a brown solid. LCMS (ESI): m / z 407.2 [M + H]+.

[0404] Step 4. Under nitrogen, a solution of 4-bromo-5-iodo-l-(tetrahydro-2H-pyran-2-yl)- IH-indazole (500 mg, 1.2 mmol) in THF (5 mL) was added cyclobutanone (0.5 mL, 6.1 mmol) and n-Butyllithium (0.8 mL, 2.1 mmol) at room temperature. The resulting solution was stirred for 2 h at 60 °C. The reaction was concentrated under vacuum. The residue was diluted with water, extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and then concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0-20% EtOAc / petroleum ether) to afford l-(4-bromo-l- (tetrahydro-2H-pyran-2-yl)-lH-indazol-5-yl)cyclobutan-l-ol (200 mg, 0.5 mmol, 46%) as a yellow oil. LCMS: ESI m / z 351.0 [M+H]+.

[0405] Step 5. To a stirred mixture of l-(4-bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol- 5-yl)cyclobutan-l-ol (1.50 g, 4.27 mmol) in DCM (10.0 mL), were added AgNCL (217 mg, 1.28 mmol), potassium persulfate (5.77 g, 21.3 mmol) and H2O (10.0 mL). The reaction was stirred at 35 °C for 18 hours. The reaction was monitored by analysis of LCMS. The reaction mixture was diluted with DCM, washed with brine, and the organic layer was separated. The aqueous layer was extracted with DCM, then the combined extracts were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient of 0-30% EtOAc in petroleum ether to afford 4-bromo-l-(tetrahydro-2H-pyran-2-yl)- l,6,7,8-tetrahydro-5H-benzo[f]indazol-5-one (400 mg, 1.15 mmol, 26%) as a yellow solid.LCMS: ESI m / z 348.9 [M+H]+.

[0406] Step 6. A flask containing methyltriphenylphosphanium bromide (756 mg, 2.12Patent ApplicationAtty. Docket No. ENTX-035PCT mmol) and THF (5 mL) was purged with nitrogen three times. Potassium 2-methylpropan-2- olate (237 mg, 2.12 mmol) was added by syringe at 0 °C under nitrogen. The reaction was stirred at room temperature for 10 minutes, then 4-bromo-l-(tetrahydro-2H-pyran-2-yl)-l,6,7,8- tetrahydro-5H-benzo[f]indazol-5-one (370 mg, 1.06 mmol) was added by syringe at 0 °C under nitrogen. The reaction was stirred at room temperature for 18 hours. The reaction was monitored by analysis of LCMS. The reaction mixture was diluted with EtOAc, washed with brine, and the organic layer was separated. The aqueous layer was extracted with EtOAc, then the combined extracts were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient of 0-30% EtOAc in petroleum ether to afford 4-bromo-5-methylene-l-(tetrahydro-2H-pyran-2-yl)-5,6,7,8-tetrahydro-lH- benzo[f]indazole (200 mg, 0.58 mmol, 54%) as a yellow oil. LCMS: ESI m / z 347.1 [M+H]+.

[0407] Step 7. To a stirred mixture of 4-bromo-5-methylene-l-(tetrahydro-2H-pyran-2-yl)- 5,6,7,8-tetrahydro-lH-benzo[f]indazole (250 mg, 0.72 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (274 mg, 1.08 mmol)in dioxane (3 mL), were added KO Ac (211 mg, 2.16 mmol) and Pd(dppf)C12 (52.6 mg, 0.07 mmol). The reaction was stirred at 90 °C for 2 hours. The reaction was monitored by analysis of LCMS. The reaction mixture was diluted with EtOAc, washed with brine, and the organic layer was separated. The aqueous layer was extracted with EtOAc, then the combined extracts were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient of 0-30% EtOAc in petroleum ether to afford 5- methylene-l-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6,7,8- tetrahydro- lH-benzo[f]indazole (100 mg, 0.25 mmol, 35%) as a yellow solid. LCMS: ESI m / z 395.1 [M+H]+

[0408] Step 8. To a solution of 5-methylene-l-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6,7,8-tetrahydro-lH-benzo[f]indazole (100 mg, 0.25 mmol) in MeOH (3 mL) was added Pd / C (134 mg, 1.27 mmol). The mixture was stirred at room temperature for 1 hour under H2. The reaction was monitored by analysis of LCMS. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, was triturated with DCM, filtered and dried over vaccum to afford 5-methyl-l- (tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6,7,8-tetrahydro- lH-benzo[f]indazole (80.0 mg, 0.20 mmol, 79%) as a yellow solid, which was used directlyPatent ApplicationAtty. Docket No. ENTX-035PCT without further purification. LCMS: ESI m / z 397.1 [M+H]+.Intermediate 46 l-((S)-2-chloro-l-fluoro-4-methylene-4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,ll,13- tetraazanaphtho[l,8-ab]heptalen-12-yl)-N,N,4-trimethylpyrrolidin-3-amine

[0409] Step 1. To a microwave tube containing (8S)- l 3-chloro-14-fluoro- l 7-(methyldioxo- X6-sulfanyl)-10-methylidene-6-oxa-2, 12, 16, 18-tetrazatetracyclo[9.7.1.015, 19.02,8]nonadeca- 1(18), 11(19), 12,14, 16-pentaene (100 mg, 0.25 mmol) and DIEA (0.13 mL, 0.75 mmol) in DCM (5 mL) was added 3-(dimethylamino)-4-methyltetrahydropyrrole (30 mg, 0.23 mmol) in DCM (5 mL) at 0°C. The resulting mixture was stirred at rt for 2 hours under microwave. The reaction was monitored by analysis of LC-MS. The reaction mixture was concentrated. The crude residue was purified by flash silica chromatography, eluting with a gradient 0% to 6% MeOH in DCM. The desired fractions were evaporated to dryness to afford (8S)-13-chloro-17-[4- (dimethylamino)-3-methyltetrahydro-lH-pyrrol-l-yl]-14-fluoro-10-methylidene-6-oxa- 2,12,16,18 -tetrazatetracy clo[9.7.1.015,19.02, 8]nonadeca- 1(18), 11(19), 12, 14,16-pentaene (100 mg, 0.22 mmol, 89%) as a pale yellow solid. LC / MS (ESI) m / z: 447.1 [M+H]+Intermediate 47(S)-2-chloro-l-fluoro-ll-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)- 4-methylene-4,5,5a,6,8,9-hexahydro-7-oxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[l,2,3- de]naphthalenePatent ApplicationAtty. Docket No. ENTX-035PCT

[0410] Step 1: To a solution of ((S)-2-chloro-l-fluoro-4-methylene-l l-(methylsulfonyl)- 4,5,5a,6,8,9-hexahydro-7-oxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[l,2,3-de]naphthalene (195 mg, 0.51 mmol) and ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (242 mg, 1.52 mmol) in THF (5 mL) was added / -BuONa (58 mg, 0.61 mmol) at -40 °C. The mixture was stirred and warmed to room temperature under N2 for 1 hour. The mixture was concentrated and the residue was purified by chromatography (silica gel, 0-5%, MeOH in DCM) to give (S)-2- chl oro-1 -fluoro- 1 l-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-4- methylene-4,5,5a,6,8,9-hexahydro-7-oxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[l,2,3- de] naphthalene (190 mg, 0.41 mmol, 81%) as a yellow solid. LCMS: ESI m / z 464.1 [M + H]+. !H NMR (400 MHz, CDCh) 5 6.03 (s, 1H), 5.40 (s, 1H), 5.35 - 5.13 (m, 1H), 4.76 - 4.66 (m, 1H), 4.26 (d, J= 10.4 Hz, 1H), 4.15 (d, J= 10.4 Hz, 1H), 4.03 - 3.82 (m, 3H), 3.76 - 3.66 (m, 1H), 3.56 - 3.45 (m, 1H), 3.40 - 3.31 (m, 1H), 3.30 - 3.09 (m, 3H), 3.03 - 2.91 (m, 1H), 2.89 - 2.81 (m, 1H), 2.67 - 2.56 (m, 1H), 2.31 - 2.06 (m, 3H), 2.00 - 1.83 (m, 3H).Intermediate 48 (3-(bis(4-methoxybenzyl)amino)-2-cyano-5-methyl-6-(trifluoromethyl)phenyl)boronic acidPatent ApplicationAtty. Docket No. ENTX-035PCTSynthetic scheme:

[0411] Step 1: To a mixture of 2-bromo-6-fluoro-4-methyl-3-(trifluoromethyl)benzene-l- carbaldehyde (1.5 g, 5.26 mmol) in pyridine (30 mb) was added Hydroxylamine hydrochloride (0.48 g, 6.84 mmol). The reaction mixture was purged with nitrogen and stirred at 25 °C under nitrogen for 16 hours. The reaction was monitored by analysis of LC-MS. After cooling to room temperature evaporated. The crude product was purified by flash silica gel chromatography, elution with a gradient of 0 to 25% EA in PE. The desired fractions were evaporated to dryness to afford (E)-[2-bromo-6-fluoro-4-methyl-3-(trifluoromethyl)phenyl]methanal oxime (1.4 g, 4.67 mmol, 88%) as a yellow oil. LCMS: ESI m / z 300.2 [M +H]+.

[0412] Step 2: To a mixture of (E)-2-bromo-6-fluoro-4-methyl-3- (trifluoromethyl)benzaldehyde oxime (1 g, 3.3 mmol), TEA (1.4 m , 10.0 mmol) in DCM (10 ml) was added TFAA (0.6 mb, 4.3 mmol). The reaction mixture was purged with nitrogen and then stirred at 25 °C under nitrogen for 2 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with brine, and organic layer was collected. The aqueous layer was extracted with EtOAc, then the combined extracts were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash silica gel chromatography, elution with a gradient of 0 to 30% EA in PE. The desired fractions were evaporated to dryness to afford 2-bromo-6-fluoro-4-methyl-3-(trifluoromethyl)benzonitrile (800 mg, 2.8 mmol, 85%) as a yellow oil. LCMS: ESI m / z 282.2 [M+H]+.

[0413] Step 3: To a mixture of 2-bromo-6-fluoro-4-methyl-3-(trifluoromethyl)benzonitrile (1.2 g, 4.2 mmol), bis[(4-methoxyphenyl)methyl]amine (1.6 g, 6.4 mmol) in DMF (5 mb) was added DIEA (3.7 mb, 21.1 mmol). The reaction mixture was purged with nitrogen three times, then heated to 100 °C under nitrogen for 4 hours. The reaction was monitored by analysis of LC-Patent Application Atty. Docket No. ENTX-035PCTMS. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with brine, and organic layer was collected. The aqueous layer was extracted with EtOAc, then the combined extracts were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash silica gel chromatography, elution with a gradient of 0 to 10% EA in PE. The desired fractions were evaporated to dryness to afford 6-(bis(4- methoxybenzyl)amino)-2-bromo-4-methyl-3-(trifluoromethyl)benzonitrile (1 g, 1.9 mmol, 45%) as a yellow oil. LCMS: ESI m / z 519.1 [M+H]+.

[0414] Step 4: To a solution of 6-(bis(4-methoxybenzyl)amino)-2-bromo-4-methyl-3- (trifhjoromethyl)benzonitrile (1000 mg, 1.93 mmol) and hypodiboric acid (342 mg, 3.85 mmol) in EtOH (10 m ) were added KO Ac (567 mg, 5.78 mmol), Xphos (184 mg, 0.39 mmol) and XantphosPDG2 (170 mg, 0.19 mmol). The reaction was stirred at 80 °C under nitrogen for 3 hours. LCMS showed the reaction was 30% DP. The cooled reaction mixture was concentrated under vacuum to give a crude, which was purified by pre-HPLC to afford compound (3-(bis(4- methoxybenzyl)amino)-2-cyano-5-methyl-6-(trifluoromethyl)phenyl)boronic acid (300 mg, 0.62 mmol, 32%) as a yellow solid. LCMS: ESI m / z 485.2 [M+H]+.Intermediate 49 (3S,5S)-3-allyl-5-methyl-l,4-oxazepane

[0415] Step 1: To a solution of (3S)-3-aminobutan-l-ol (5 g, 56.1 mmol) in MeOH (60 mL) was added benzaldehyde (5.7 mL, 56.1 mmol) and the mixture was stirred at room temperature for 1 hour, then cooled to 0°C NaBIL (2.12 g, 56.1 mmol) was added to the mixturePatent Application Atty. Docket No. ENTX-035PCT and the mixture was stirred at 2 hours. LCMS showed the reaction was completed. The mixture was quenched with water (10 mL), concentrated in vacuo. The residue was diluted with water (50 mL), extracted with EtOAc (50 mL) twice. The combined organic layer was dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give crude (3S)-3- (benzylamino)butan-l-ol (9.8 g, 49.20 mmol, 87%) as a yellow oil.

[0416] Step 2: To a solution of (S)-3-(benzylamino)butan-l-ol (10 g, 55.78 mmol) in Toluene (100 mL) was added cyclobutanone (4.50 g, 64.2 mmol). The mixture was stirred at 105°C for 3 hours. The reaction mixture was cooled to room temperature and (18.8 g, 89.3 mmol) was added. The mixture was stirred at room temperature. The reaction was quenched with 2M Na CCh (120 ml) and stirred at room temperature for 1 hour. The reaction mixture was extracted with Toluene. The organic phase was dried over Na2SO4 and concentrated to give (S)-3-(benzyl(oxetan-3-yl)amino)butan-l-ol (13 g, 55.2 mmol, 99%) as a yellow oil.

[0417] Step 3: To a solution of (3S)-3-[benzyl(oxetan-3-yl)amino]butan-l-ol (7.6 g, 32.3 mmol) in toluene (30 mL) was added bis(2-methylpropan-2-yl) hydroxyphosphonate (2.23 g, 10.61 mmol). The mixture was stirred at 110°C overnight. The reaction mixture was cooled to room temperature and 2M Na2CCL (40 ml) was added. The reaction was stirred at room temperature for Ih. The reaction mixture was diluted water, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified by chromatography (silica gel, 0-6%, EtOAc in PE) to give ((5S)-4-benzyl-5-methyl-l,4-oxazepan- 3-yl)methanol (5 g racemic, 21.3 mmol, 66%) as a yellow oil. The racemic was purified by prep- SFC to give ((3S,5S)-4-benzyl-5-methyl-l,4-oxazepan-3-yl)methanol (3 g isomer, 60%) as a yellow oil.

[0418] Preparative separation method:Instrument: Waters Thar 80 preparative SFC Column: ChiralPak C-IG, 250><30mm I.D., 5pm Mobile phase: A for CO2 and B for ME0H( 0.1% 7mol / L NH3 in MeOH) Gradient: B 25% Flow rate: 60 mL / min Back pressure: 100 bar Column temperature: 35 °CPatent ApplicationAtty. Docket No. ENTX-035PCTWavelength: 220nmRun time: 13minCycle-time: 13minInjection volume: 1 mL Number of injection needles: 18 Eluted time: 2HThel800 mg sample was dissolved in 19 mL MeOH

[0419] Step 4: To a solution of ((3S,5S)-4-benzyl-5-methyl-l,4-oxazepan-3-yl)methanol (4.4 g, 18.7 mmol) in DCM (88 mL) was added PPhs (5.4 g, 20.6 mmol) and imidazole (1.9 g, 20.1 mmol) at 0 °C was stirred for 5 min. Then Iodine (5.7 g, 22.4 mmol) was added portion wise and the mixture was stirred at 0 °C for 1 hour. The mixture was filtered and concentrated. The residue was purified by chromatography (silica gel, 0-6%, EtOAc in PE) to give (3R,5S)-4- benzyl-3-(iodomethyl)-5-methyl-l,4-oxazepane (2 g, 5.79 mmol, 31%) as a pale-yellow oil. 'H NMR (400 MHz, CDCh) 8 7.45 - 7.37 (m, 2H), 7.36 - 7.28 (m, 2H), 7.23 (d, J= 7.5 Hz, 1H), 4.13 (d, J= 13.0 Hz, 1H), 3.99 - 3.85 (m, 2H), 3.77 - 3.58 (m, 3H), 3.40 - 3.25 (m, 1H), 3.05 (s, 3H), 1.99 - 1.83 (m, 1H), 1.82 - 1.70 (m, 1H), 1.25 (d, J= 6.8 Hz, 3H). LCMS: ESI m / z 348.0 [M + H]+.

[0420] Step 5: To a solution of Cui (3.3 g, 17.4 mmol) in THF (20 mL) was added bromo(vinyl)magnesium (7 mL, 6.95 mmol) dropwise at -40 °C under N2 was stirred for 30 min, then allowed to warm to - 10 °C. The black suspension was cooled to - 40 °C and a solution of (3R,5S)-4-benzyl-3-(iodomethyl)-5-methyl-l,4-oxazepane (2 g, 5.79 mmol) in THF (20 mL) was added dropwise over 20 min. The thick suspension was stirred for an additional 1 hour with slow warming to 15 °C. EtOAc (100 mL) and saturated NH4CI (200 mL) were added. The mixture was stirred at room temperature for 5 min. Then, 28 % aqueous NH3 (15 mL) was added. The mixture was extracted with EtOAc (3 x 300 mL). The combined organic layers were dried with Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (40 g column) using a gradient from 0 % to 8 % EtOAc in heptane which gave (3S,5S)-3-allyl-4-benzyl-5-methyl-l,4-oxazepane (1.0 g, 4.08 mmol, 70%) as a colorless oil. LCMS: ESI m / z 346.1 [M + H]+.

[0421] Step 6: To a solution of (3S,5S)-3-allyl-4-benzyl-5-methyl-l,4-oxazepane (410 mg, 1.67 mmol) in THF (5 mL) and H2O (1 mL) was added CAN (1.8 g, 3.34 mmol) and the mixturePatent ApplicationAtty. Docket No. ENTX-035PCT was stirred at room temperature for 2 hours. The mixture was diluted with water, extracted with EtOAc. The aqueous layer was adjusted to PH >7 with saturated NaHCO . The following mixture was filtered. The filtrate was extracted with EtOAc. The organic phase was dried with Na2SO4, filtered and concentrated to give (3S,5S)-3-allyl-5-methyl-l,4-oxazepane (160 mg, 1.07 mmol, 61%) as a colorless oil, which was used in next step without further purification. LCMS: ESI m / z 156.1 [M + H]+.Intermediate 50(5aS,10S)-2-chloro-l-fluoro-10-methyl-4-methylene-12-(methylsulfonyl)-4,5,5a,6,9,10- hexahydro-8H-7-oxa-3,10a,ll,13-tetraazanaphtho[l,8-ab]heptalene

[0422] Step 1: To a solution of (3S,5S)-3-allyl-5-methyl-l,4-oxazepane (200 mg, 1.29 mmol) in DCM (5 mL) was added DIEA (500 mg, 3.86 mmol) and 4,5,7-trichloro-8-fluoro-2- (methylthio)pyrido[4,3-d]pyrimidine (385 mg, 1.29 mmol) was stirred at 0 °C for 1 hour. The mixture was concentrated, and the residue was purified by chromatography (silica gel, 0-9%, EtOAc in PE) to give (3S,5S)-3-allyl-4-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-Patent ApplicationAtty. Docket No. ENTX-035PCT d]pyrimidin-4-yl)-5-methyl-l,4-oxazepane (390 mg, 1.51 mmol, 72%) as a yellow oil. LCMS: ESI m / z 417.1 [M + H]+.

[0423] Step 2: To a solution of (3S,5S)-3-allyl-4-(5,7-dichloro-8-fluoro-2- (methylthio)pyrido[4,3-d]pyrimidin-4-yl)-5-methyl-l,4-oxazepane (390 mg, 0.93 mmol) in DMA (15 mL) was added Pd(OAc)2 (42 mg, 0.18 mmol), PPh? (98 mg, 0.37 mmol) and KOAc (275 mg, 2.80 mmol). The mixture was stirred at 100 °C under N2 for 4 hours. The cooled mixture was poured into saturated NaCl (150 mL) and extracted with EtOAc (200 mL). The combined organic phase was washed with brine, dried with Na2SC>4, fdtered and concentrated. The residue was purified by chromatography (silica gel, 0-13%, EtOAc in PE) to give (5aS,10S)-2-chloro-l-fhioro-10-methyl-4-methylene-12-(methylthio)-4,5,5a,6,9,10- hexahydro-8H-7-oxa-3,10a,l l,13-tetraazanaphtho[l,8-ab]heptalene (185 mg, 0.49 mmol, 92%) as a yellow solid. 'H NMR (400 MHz, DMSO-e76): 8 6.33 (s, 1H), 5.46 (s, 1H), 5.07 - 4.92 (m, 1H), 4.27 (t, J= 6.5 Hz, 1H), 3.81 - 3.69 (m, 2H), 3.22 - 3.13 (m, 3H), 2.73 (d, J= 14.7 Hz, 1H), 2.55 (s, 3H), 2.25 - 2.16 (m, 1H), 1.93 - 1.82 (m, 1H), 1.34 (d, J = 6.2 Hz, 3H). LCMS: ESI m / z 381.1 [M + H]+.

[0424] Step 3: To a solution of (5aS,10S)-2-chloro-l-fluoro-10-methyl-4-methylene-12- (methylthio)-4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,l l,13-tetraazanaphtho[l,8-ab]heptalene (185 mg, 0.49 mmol) in DCM (5 mL) was added m-CPBA (211 mg, 1.22 mmol) was stirred at 20 °C for 2 hours. The mixture was concentrated and the residue was purified by chromatography (silica gel, 0-85%, EA in PE) to give (5aS, 10S)-2-chloro-l -fluoro- 10-methyl -4- methylene- 12-(methylsulfonyl)-4, 5 , 5 a, 6, 9, 10-hexahy dro-8H-7-oxa-3 ,10 a, 11,13- tetraazanaphtho [1, 8 -ab] heptal ene (140 mg, 0.34 mmol, 69%) as a yellow oil. LCMS: ESI m / z 413.1 [M + H]-.Intermediate 51 (5aS,10S)-2-chloro-l-fluoro-12-(((2R)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)-10-methyI-4-methylene-4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,ll,13- tetraazanaphtho[l,8-ab]heptalenePatent ApplicationAtty. Docket No. ENTX-035PCT

[0425] Step 1: To a solution of (5aS,10S)-2-chloro-l-fluoro-10-methyl-4-methylene-12- (methylsulfonyl)-4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,l l,13-tetraazanaphtho[l,8- ab]heptalene (100 mg, 0.24 mmol) and ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methanol (116 mg, 0.73 mmol) in THF (3 mL) was added sodium 2-methylpropan-2-olate(70 mg, 0.73 mmol) at -40 °C and the mixture was stirred warmed to room temperature under Nz for 1 hour. The mixture was concentrated and the residue was purified by chromatography (silica gel, 0-4%, MeOH in DCM) to give (5aS,10S)-2-chloro-l-fluoro-12-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-4-methylene-4,5,5a,6,9,10- hexahydro-8H-7-oxa-3,10a,l l,13-tetraazanaphtho[l,8-ab]heptalene (75 mg, 0.15 mmol, 62%) as a yellow solid. LCMS: ESI m / z 492.2 [M + H]+.Intermediate 52(5aS,10S)-2-chloro-12-(((S)-2-(difluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)-l-fluoro-10-methyl-4-methylene-4,5,5a,6,9,10-hexahydro-8H-7-oxa- 3,10a,ll,13-tetraazanaphtho[l,8-ab]heptalenePatent ApplicationAtty. Docket No. ENTX-035PCT

[0426] Step 1: To a solution of (5aS,10S)-2-chloro-l-fluoro-10-methyl-4-methylene-12- (methylsulfonyl)-4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,l l,13-tetraazanaphtho[l,8- ab]heptalene (40 mg, 0.10 mmol) and (S)-(2-(difluoromethylene)tetrahydro-lH-pyrrolizin- 7a(5H)-yl)methanol (36 mg, 0.20 mmol) in THF (3 mL) was added sodium 2-methylpropan-2- olate (28 mg, 0.29 mmol) at -40 °C and the mixture was stirred warmed to room temperature under N2 for 1 hour. The mixture was concentrated and the residue was purified by chromatography (silica gel, 0-4%, MeOH in DCM) to give (5aS,10S)-2-chloro-12-(((S)-2- (difluoromethylene)tetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy)-l -fluoro- 10-methyl-4- methylene-4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,l l,13-tetraazanaphtho[l,8-ab]heptalene (35 mg, 0.07 mmol, 69%) as a yellow oil. LCMS: ESI m / z 522.2 [M + H]+.Intermediate 53 2-amino-6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5- (trifluoromethyl)nicotinonitrilePatent ApplicationAtty. Docket No. ENTX-035PCT

[0427] Step 1: To a solution of 4-bromo-6-methylpyridin-2-amine (500 mg, 2.67 mmol) in DMF (3 mL) and AcOH (3 mL) was added NIS (1.8 g, 8.02 mmol). The reaction mixture was stirred at RT for 1.5 hours. The reaction was monitored by analysis of LC-MS. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SO4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 16%] to afford 4-bromo-5-iodo-6- methylpyridin-2-amine (500 mg, 1.60 mmol, 59%) as a white solid. LCMS: ESI m / z 312.1 [M+H]+.

[0428] Step 2: To a suspension of NaH (0.46 g, 19.1 mmol, 60% in mineral oil) in anhydrous DMF (30 mL) was added ethyl 4-bromo-5-iodo-6-methylpyridin-2-amine (2 g, 6.39 mmol) dropwise under nitrogen at 0 °C. The white suspension was stirred at 0 °C for 0.5 hour, then 4-(chloromethyl)-l -methoxybenzene (3.00 g, 19.1 mmol) was slowly added. The resulting solution was stirred at 0 °C and allowed to warm to room temperature. The reaction mixture was stirred at RT for 1 .5 hours. The reaction was monitored by analysis of LC-MS. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine,Patent ApplicationAtty. Docket No. ENTX-035PCT dried by Na2SO4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 7%] to afford 4-bromo-5-iodo-N,N-bis(4- methoxybenzyl)-6-methylpyridin-2-amine (3.2 g, 5.78 mmol, 90%) as a white solid. LCMS: ESI m / z 553.1 [M+H]+.

[0429] Step 3: To a solution of 4-bromo-5-iodo-N,N-bis(4-methoxybenzyl)-6- methylpyridin-2-amine (2.7 g, 4.88 mmol) in DMA (30 mL) was added Cui (1.86 g, 9.76 mmol) and methyl 2,2-difluoro-2-(fluorodioxo-X6-sulfanyl)acetate (5.63 g, 29.2 mmol). The reaction mixture was purged with nitrogen three times, then heated to 90 °C for 8 hours under nitrogen. The reaction was monitored by analysis of LC-MS. The cooled reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by ISfeSCU, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 5%] to afford 4-bromo-N,N-bis(4-methoxybenzyl)-6-methyl-5- (trifluoromethyl)pyridin-2-amine (2.2 g, 4.44 mmol, 91%) as a white solid. LCMS: ESI m / z 495.3 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 8 7.25 - 7.10 (m, 4H), 6.94 - 6.86 (m, 4H), 6.83 (d, J= 16.0 Hz, 1H), 4.83 (s, 2H), 4.75 (s, 2H), 3.73 (s, 6H), 2.56 (d, J= 14.8, 3.2 Hz, 3H).

[0430] Step 4: To a solution of 4-bromo-N,N-bis(4-methoxybenzyl)-6-methyl-5- (trifluoromethyl)pyridin-2-amine (2.7 g, 5.45 mmol) in TFA (6 mL, 78.4 mmol). The reaction mixture was stirred at 60 °C for 3 h. The reaction was monitored by analysis of LC-MS. The cooled reaction mixture was concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 15%] to afford 4-bromo-6-methyl-5- (trifluoromethyl)pyridin-2-amine (1.2 g, 4.71 mmol, 86%) as a white solid. LCMS: ESI m / z 256.9 [M+H]+.

[0431] Step 5: To a solution of 4-bromo-6-methyl-5-(trifluoromethyl)pyridin-2-amine (1.2 g, 5.10 mmol) in DMF (5 mL) and AcOH (5 mL) was added NIS (3.44 g, 15.2 mmol). The reaction mixture was stirred at rt overnight. The reaction was monitored by analysis of LC-MS. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SO4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 30%] to afford 4-bromo-3-iodo-6- methyl-5-(trifluoromethyl)pyridin-2-amine (1.2 g, 3.15 mmol, 61%) as a white solid. LCMS: ESI m / z 381.1 [M+H]+. ’H NMR (400 MHz, DMSO-d6) 8 7.07 (s, 2H), 2.44 (d, J= 4.4 Hz, 3H).

[0432] Step 6: To a solution of 4-bromo-3-iodo-6-methyl-5-(trifluoromethyl)pyridin-2-Patent ApplicationAtty. Docket No. ENTX-035PCT amine (1 g, 2.63 mmol) in DMA (10 mL)) was added Zn(CN)2 (0.37 g, 3.15 mmol) and Pd3(PPh)4 (0.61 g, 0.53 mmol). The reaction mixture was purged with nitrogen three times, then heated to 130 °C under nitrogen for 5 hours. The reaction was monitored by analysis of LC-MS. The cooled reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SC>4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 30%] to afford 2-amino-4- bromo-6-methyl-5-(trifluoromethyl)nicotinonitrile (515 mg, 1.84 mmol, 70%) as a white solid. LCMS: ESI m / z 281.3 [M+H]+.

[0433] Step 7: To a solution of 2-amino-4-bromo-6-methyl-5-(trifluoromethyl)nicotinonitrile (200 mg, 0.71 mmol) in dioxane (5 mL) was added KOAc (210 mg, 2.14 mmol), 4, 4, 5, 5- tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (362 mg, 1.43 mmol)and Pd(dppf)Ch (104 mg, 0.14 mmol). The reaction mixture was purged with nitrogen three times, then heated to 90 °C under nitrogen overnight. The reaction was monitored by analysis of LC-MS. The cooled reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SO4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 20%] to afford 2-amino-6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5- (trifluoromethyl)nicotinonitrile (150 mg, 0.46 mmol, 64%) as a white solid. LCMS: ESI m / z 328.2 [M+H]+.Intermediate 54 (S)-(2-(difluoromethylene)tetrahydro-LH-pyrrolizin-7a(5 / 7)-yI)methan-672-ol

[0434] Step 1: To a solution of methyl (S)-2-(difluoromethylene)tetrahydro-lH-pyrrolizine-Patent ApplicationAtty. Docket No. ENTX-035PCT 7a(5H)-carboxylate (1 g, 4.60 mmol) in THF (10 mL) was added UAID4 (230 mg, 5.52 mmol) at 0 °C. The reaction was stirred at 0 °C for 2 hours. The reaction was monitored by analysis of LC- MS. The reaction mixture was quenched with Na2SC>4. IOH2O, filtered, and the filter cake was washed with THF. The filtrate was concentrated in vacuo to dryness. The residue was purified by chromatography (silica gel, 0-100%, EA in PE) to give (S)-(2-(difluoromethylene)tetrahydro- lH-pyrrolizin-7a(5H)-yl)methan-d2-ol (700 mg, 3.7 mmol, 79%) as yellow oil. LCMS: 192.1 [M+H]+.Intermediate 55 (lS)-2-chloro-12-(((1S)-2-(difluoromethylene)tetrahydro-l / 7-pyrrolizin-7a(5Z / )-yl)methoxy- <72)-l-fluoro-4-methylene-4,5,5a,6,9,10-hexahydro-8 / / -7-oxa-3,10a,ll,13- tetraazanaphtho [l,8-a / >] heptalene

[0435] Step 1: To a solution of (S)-2-chloro-l-fluoro-4-methylene-12-(methylsulfonyl)- 4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,l l,13-tetraazanaphtho[l,8-ab]heptalene (100 mg, 0.25 mmol) in THF (5 mL) was added (S)-(2-(difluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)- yl)methan-d2-ol (96 mg, 0.50 mmol) and Sodium tert-butoxide (70 mg, 0.75 mmol) at -40°C. The reaction was stirred at -40°C for 1 hour. The reaction mixture was quenched with H2O, extracted with EA. The combined organic phase was washed with brine, dried with Na2SO4,Patent ApplicationAtty. Docket No. ENTX-035PCT filtered and concentrated. The residue was purified by chromatography (silica gel, 0-80% EA in PE) to give (S)-2-chloro-12-(((S)-2-(difluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy-d2)- 1 -fluoro-4-methylene-4, 5 , 5 a, 6, 9, 10-hexahy dro-8H-7-oxa- 3 , 10a, 11 , 13 - tetraazanaphtho[l,8-ab]heptalene (100 mg, 0.2 mmol, 78%) as yellow oil. LCMS: 510.2 [M+H]+.Intermediate 56 (5)-2-chloro-l-fluoro-12-(((27?,7a5)-2-fluorotetrahydro-177-pyrroIizin-7a(5 / 7)-yI)methoxy- t / 2)-4-methylene-4,5,5a,6,9,10-hexahydro-877-7-oxa-3,10a,ll,13-tetraazanaphtho[l,8- rzZi]heptalene

[0436] Step 1: To a solution of (S)-2-chloro-l-fluoro-4-methylene-12-(methylsulfonyl)- 4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,l l,13-tetraazanaphtho[l,8-ab]heptalene (100 mg, 0.25 mmol) in THF (5 mL) was added (S)-(2-(difluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)- yl)methan-d2-ol (96 mg, 0.50 mmol) and Sodium tert-butoxide (70 mg, 0.75 mmol) at -40°C. The reaction was stirred at -40°C for 1 hour. The reaction mixture was quenched with H2O, extracted with EA. The combined organic phase was washed with brine, dried with ISfeSCU, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-80% EA in PE) to give (S)-2-chloro-12-(((S)-2-(difluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy-d2)- 1 -fluoro-4-methylene-4, 5 , 5 a, 6, 9, 10-hexahy dro-8H-7-oxa-3 , 10a, 11 , 13 -Patent ApplicationAtty. Docket No. ENTX-035PCT tetraazanaphthofl, 8-ab]heptalene (100 mg, 0.2 mmol, 78%) as yellow oil. LCMS: 510.2 [M+H]+.Intermediate 577-aIlyl-l,4-dioxa-8-azaspiro[4.6]undecane

[0437] Step 1: A flask containing l,4-dioxaspiro[4.5]decan-8-one (10 g, 64 mmol) and THF (100 mL) was purged with nitrogen for three times. Anhydrous LHMDS (10.7 g, 64 mmol) was added by syringe at -78 °C under nitrogen, the reaction was stirred at -78 °C for 30 minutes. 3- bromoprop-l-ene (8.5 g, 70.4 mmol) was added over a period of 5 min, and the reaction was stirred at room temperature for 18 hours. The reaction was monitored by analysis of TLC. The reaction mixture was diluted with EtOAc, washed with NaHCCh, and organic layer was separated. The aqueous layer was extracted with EtOAc, then the combined extracts were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient of 0-30% EtOAc in petroleum ether to afford 7-allyl- l,4-dioxaspiro[4.5]decan-8-one (5000 mg, 25.5 mmol, 39%) as a colorless oil. LCMS (ESI): m / z 197.1 [M+H]+

[0438] Step 2: To a stirred mixture of 7-allyl-l,4-dioxaspiro[4.5]decan-8-one (6000 mg, 30.6 mmol) and hydroxyamino hydrochloride (3.19 g, 45.8 mmol) in EtOH (70 mL) and H2O (14.00Patent ApplicationAtty. Docket No. ENTX-035PCT mL), was added K2CO3 (8.45 g, 61.15 mmol). The reaction was stirred at 60 °C for 2 hours, then diluted with EtOAc, washed with brine, and organic layer was separated. The aqueous layer was extracted with EtOAc, then the combined organic layer was dried over anhydrous Na2SO4, fdtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient of 0-50% EtOAc in petroleum ether to afford (Z)-7-allyl-l,4-dioxaspiro[4.5] decan-8-one oxime (5 g, 23.67 mmol, 77%) as a white solid. LCMS (ESI): m / z 212.0 [M+H]+

[0439] Step 3: To a stirred mixture of (Z)-7-allyl-l,4-dioxaspiro[4.5]decan-8-one oxime (2000 mg, 9.47 mmol) and TsCl (2707 mg, 14.2 mmol) in DCE (20 mL), was added Na2COs (3010 mg, 28.4 mmol). The reaction was stirred at 90 °C for 2 hours. The reaction was monitored by analysis of TLC. The reaction mixture was diluted with EtOAc, washed with brine, and organic layer was separated. The aqueous layer was extracted with EtOAc, then the combined extracts were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient of 0-50% EtOAc in petroleum ether to afford 7-allyl-l,4-dioxa-8-azaspiro[4.6]undecan-9-one (800 mg, 3.79 mmol, 40%) as a yellow solid. LCMS (ESI): m / z 212.1 [M+H]+

[0440] Step 4: A flask containing 7-(prop-2-enyl)-8-aza-l,4-dioxaspiro[4.6]undecan-9-one (3 g, 14.2 mmol) and THF (3 mL) was purged with nitrogen for three times. Anhydrous LAH (18 mL, 1 mol / L in THF) was added by syringe at -60 °C under nitrogen, the reaction was stirred at 60 °C for 1 hours. The reaction was monitored by analysis of LCMS. After cooling to room temperature, the reaction mixture was quenched with Na2SO4.10H2O at 0 °C. The reaction mixture was filtered to afford crude 7-(prop-2-enyl)-8-aza-l,4-dioxaspiro[4.6]undecane (3.2 g, 12.6 mmol, 89%), which was used directly without further purification. LCMS (ESI): m / z 198 [M+H]+Intermediate 582'-chloro-l'-fluoro-12'-(((2A,7a5)-2-fluorotetrahydro-l / / -pyrrolizin-7a(5 / 7)-yl)methoxy)-4'- iiiethylene-4'.5',5a'.6'.9',l ()'-hexahydro-87 / -3'.l Oa'.l l',13'-tetraazaspiro[[ l,3]dioxolane- 2,7'-naphtho[l,8-czZ>]heptalen]-l'(13a'),2',3a',10b',12'-pentaenePatent ApplicationAtty. Docket No. ENTX-035PCT

[0441] Step 1: To a stirred mixture of 7-(prop-2-enyl)-8-aza-l,4-dioxaspiro[4.6]undecane (3.2 g, 16.1 mmol) in DCM (50 mL) was added DIEA (7 mL, 40.2 mmol) and crude 7-(prop-2- enyl)-8-aza-l,4-dioxaspiro[4.6]undecane (3.2 g, 12.6 mmol) slowly at 0 °C . After stirred at 0 °C for Ih, the mixture was quenched with ice-water and extracted with DCM. The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (0- 20 %, EtOAc in PE) to give 8-[5,7-dichloro-8- fluoro-2-(methylsulfanyl)pyrido[4,3-d]pyrimidin-4-yl]-7-(prop-2-enyl)-8-aza-l,4-dioxaspiro[4.6] undecane (3.2 g, 6.9 mmol, 43%) as a yellow solid. LCMS: ESI m / z 459 [M+H]+.

[0442] Step 2: To a solution of 8-[5,7-dichloro-8-fluoro-2-(methylsulfanyl)pyrido[4,3- d]pyrimidin-4-yl]-7-(prop-2-enyl)-8-aza-l,4-dioxaspiro[4.6]undecane (3.2 g, 6.9 mmol) in DMA (35 mL) was added Pd(OAc)2 (310 mg, 1.4 mmol), PPM (0.73 g, 2.8 mmol) and KO Ac (2.1 g, 20.9 mmol) at room temperature under nitrogen atmosphere. The mixture was stirred at 100 °CPatent ApplicationAtty. Docket No. ENTX-035PCT for 4 h under N2. The mixture was quenched with ice-water and extracted with EtOAc (3 x 10 mL). The combined organic phase was washed with brine, dried with Na2SC>4, filtered and concentrated. The residue was purified by silica gel chromatography (0- 60 %, EtOAc in PE) to give 17'-chloro-18'-fluoro-14'-methylidene-3'-(methylsulfanyl)spiro[l,3-dioxolane-2,10'- 2,4,6,16-tetrazatetracyclo[13.3.1.05 19.06 12]nonadeca-l(2),3,5(19),15(16),17-pentaene] (1.6 g, 3.8 mmol, 54 %) as a brown solid. LCMS: ESI m / z 367 [M+H]+.

[0443] Step 3: To a solution of 2'-chloro-l'-fluoro-4'-methylene-12'-(methylthio)- 4',5',5a',6',9',10'-hexahydro-8'H-3',10a',l r,13'-tetraazaspiro[[l,3]dioxolane-2,7'-naphtho[l,8- ab]heptalen]-r(13a'),2',3a',10b',12'-pentaene (100 mg, 0.24 mmol) in DCM (5 mL) was added m-CPBA (122 mg, 0.71 mmol) was stirred at 0 °C for 2 hours. The mixture was concentrated and the residue was purified by silica gel chromatography (0-50%, EtOAc in PE) to give 2'-chloro-l'-fluoro-4'-methylene-12'-(methylsulfonyl)-4',5',5a',6',9',10'-hexahydro- 8'H-3',10a',l l',13'-tetraazaspiro[[l,3]dioxolane-2,7'-naphtho[l,8-ab]heptalen]- l'(13a'),2',3a',10b',12'-pentaene (70 mg, 0.15 mmol, 65%) as a brown oil. LCMS: ESI m / z 455.1 [M+H]+.

[0444] Step 4: To a solution of 2'-chloro-l'-fluoro-4'-methylene-12'-(methylsulfonyl)- 4',5',5a',6',9',10'-hexahydro-8'H-3',10a',l r,13'-tetraazaspiro[[l,3]dioxolane-2,7'-naphtho[l,8- ab]heptalen]-l'(13a'),2',3a',10b',12'-pentaene (73 mg, 0.16 mmol) and [(2R,7aS)-2-fluoro- 2,3,5,6,7,7a-hexahydro-lH-pyrrolizin-7a-yl]methanol (51.1 mg, 0.32 mmol) in THF (3 mL) was added Na / OBu (18.5 mg, 0.19 mmol) at -40 °C, then was warmed to room temperature for 2 hours. The mixture was concentrated and the residue was purified by silica gel chromatography (0-5%, MeOH in DCM) to give 2'-chloro-l'-fluoro-12'-(((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-4'-methylene-4',5',5a',6',9',10'-hexahydro-8'H-3',10a',l l',13'- tetraazaspiro[[l, 3]di oxolane-2, 7'-naphtho[l,8-ab]heptalen]-l '(13a1), 2', 3a', 1 Ob', 12'-pentaene (60 mg, 0.11 mmol, 70%) as a brown oil. LCMS: ESI m / z 534.3 [M + H]+.Intermediate 592-chloro-l-fluoro-12-(((2A,7a5)-2-fluorotetrahydro-17 / -pyrrolizin-7a(5 / 7)-yl)methoxy)-4- methylene-5,5a,7,8,9,10-hexahydro-3,7,10a,ll,13-pentaazanaphtho[l,8-rz / >]heptalen-6(4Z / )- onePatent ApplicationAtty. Docket No. ENTX-035PCT

[0445] Step 1: To a solution of ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methanol (657 mg, 4.13 mmol) and sodium tert-butoxide (594 mg, 6.19 mmol) in THF (9 mL) were added 2-chloro-l-fluoro-4-methylene-12-(methylsulfonyl)-5,5a,7,8,9,10-hexahydro-3,7, 10a, 1 l,13-pentaazanaphtho[l,8-ab]heptalen-6(4H)-one (850 mg, 2.06 mmol) at -50 °C under nitrogen atmosphere. The mixture was stirred at room temperature for 2 hours. LCMS showed 53% completion. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluted with MeOH in DCM (gradient: 0-10%) to afford 2-chloro-l -fluoro- 12-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)- 4-methylene-5,5a,7,8,9,10-hexahydro-3,7,10a,l l,13-pentaazanaphtho[l,8-ab]heptalen-6(4H)-one (450 mg, 0.92 mmol, 44%) as a yellow solid. LCMS: ESI m / z: 491.3 [M+H]+.Intermediate 60 2-allyl-l,4-diazepan-5-oneSynthetic Scheme:Patent ApplicationAtty. Docket No. ENTX-035PCT

[0446] Step 1: To a solution of methyl (S)-2-((tert-butoxycarbonyl)amino)pent-4-enoate (20 g, 87.3 mmol) in MeOH (20 mL) was added ammonia (100 mL, 700.00 mmol). The reaction mixture was stirred at rt for 18h. The mixture was poured into brine (150 mL) and extracted with EtOAc (200 mL). The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-50%, EtOAc in PE) to give tert-butyl (S)-(l-amino-l-oxopent-4-en-2-yl)carbamate (11.8 g, 55.1 mmol, 63%) as a white solid. LCMS: ESI m / z 215.1 [M + H]+.

[0447] Step 2: To a solution of tert-butyl (S)-(l-amino-l-oxopent-4-en-2-yl)carbamate (11 .8 g, 55.1 mmol) in THF (120 mL) was added LiAlIL (4.60 g, 121.2 mmol) at 0 °C. The reaction mixture was stirred at 30 °C for 18h. Sodium sulfate decahydrate was added to quench the reaction until no bubbles were generated, then the mixture was filtered through diatomaceous earth and washed the filter cake three times with DCM / MeOH (100 mL, v / v=10 / l). Then the resulted filtrate was concentrated to yield the crude product, which was purified by silica gel flash chromatography, eluted with MeOH in DCM [Gradient: 0~10%] to give tert-butyl (S)-(l- aminopent-4-en-2-yl)carbamate (2.5 g, 12.5 mmol, 23%) as a yellow oil. LCMS: ESI m / z 201.1 [M+H]+.

[0448] Step 3: To a solution of 2-methylpropan-2-yl {[(2S)-l-aminopent-4-en-2- yl]amino}methanoate (2.5 g, 12.5 mmol) in THF (25 mL) was added TEA (4.2 mL, 29.9 mmol) and benzyl chi orom ethanoate (1.9 mL, 13.7 mmol) at 0 °C. The reaction mixture was stirred at rt for Ih. The reaction mixture was quenched with water and EA were added for extraction 3 times. The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated to yield the crude product, which was purified by silica gel flash chromatography,Patent ApplicationAtty. Docket No. ENTX-035PCT eluted with EA in PE to give benzyl tert-butyl pent-4-ene-l,2-diyl(S)-dicarbamate (2.7 g, 8.07 mmol, 65%) as a white solid. LCMS: ESI m / z 335.1 [M+H]+.

[0449] Step 4: To a solution of benzyl tert-butyl pent-4-ene-l,2-diyl(S)-dicarbamate (2.7 g, 8.07 mmol) in 1,4-dioxane (5 mL) was added HC1 (4 M, 20.0 mL, 80.7 mmol) at 0 °C. The reaction mixture was stirred at rt for Ih. After completion, the reaction mixture was cooled to ambient temperature. The reaction mixture was concentrated to give benzyl (S)-(2-aminopent-4- en-l-yl)carbamate (1.8 g, 7.68 mmol, 95%) as a yellow oil. LCMS: ESI m / z 235.0 [M+H]+.

[0450] Step 5: To a solution of benzyl (S)-(2-aminopent-4-en-l-yl)carbamate (1.8 g, 7.68 mmol) in MeCN (30 mL) was added Na2COs (4.07 g, 38.41 mmol) and ethyl 3-bromopropanoate (1.29 mL, 9.98 mmol). The reaction mixture was stirred at 90 °C for 18h. The solution was cooled to room temperature and fdtered through a pad of celite and the celite was thoroughly washed with EA. Then the resulted filtrate was concentrated to yield the crude product, which was purified by silica gel flash column chromatography to afford ethyl (S)-3-(( 1 - (((benzyloxy)carbonyl)amino)pent-4-en-2-yl)amino)propanoate (800 mg, 2.39 mmol, 31%) as a yellow oil. LCMS: ESI m / z 335.1 [M+H]+.

[0451] Step 6: A solution of ethyl (S)-3-((l-(((benzyloxy)carbonyl)amino)pent-4-en-2- yl)amino)propanoate (800 mg, 2.39 mmol) in TFA (10 mL) was stirred at 70 °C for 18h. The reaction mixture was concentrated to give ethyl 3-((l-aminopent-4-en-2-yl)amino)propanoate (450 mg, 2.25 mmol, 94%) as a yellow oil. LCMS: 201.1 [M+H]+.

[0452] Step 7: To a solution of ethyl 3-((l-aminopent-4-en-2-yl)amino)propanoate (450 mg, 2.25 mmol) in MeOH (5 mL) was added CS2CO3 (2.93 g, 8.99 mmol). The reaction mixture was stirred at 70 °C for 18h. The reaction mixture was concentrated to yield the crude product, which was purified by silica gel flash chromatography to give 2-allyl-l,4-diazepan-5-one (250 mg, 1.62 mmol, 72%) as a yellow oil. LCMS: ESI m / z 155.1 [M+H]+.Intermediate 612-chloro-l-fluoro-12-(((27?,7aS)-2-fluorotetrahydro-l / / -pyrrolizin-7a(5J7)-yl)methoxy)-4- methylene-5,5a,6,7,9,10-hexahydro-3,7,10a,ll,13-pentaazanaphtho[l,8-o7>]heptalen-8(4 / 7)- onePatent ApplicationAtty. Docket No. ENTX-035PCT

[0453] Step 1: To a solution of (S)-2-chloro-l-fluoro-4-methylene-12-(methylsulfonyl)- 4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,l l,13-tetraazanaphtho[l,8-ab]heptalene (100 mg, 0.25 mmol) in THF (5 mL) was added (S)-(2-(difluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)- yl)methan-d2-ol (96 mg, 0.50 mmol) and Sodium tert-butoxide (70 mg, 0.75 mmol) at -40°C. The reaction was stirred at -40°C for 1 hour. The reaction mixture was quenched with H2O, extracted with EA. The combined organic phase was washed with brine, dried with Na2SC>4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-80% EA in PE) to give (S)-2-chloro-12-(((S)-2-(difluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy-d2)- 1 -fluoro-4-methylene-4, 5 , 5 a, 6, 9, 10-hexahy dro-8H-7-oxa-3 , 10a, 11 , 13 - tetraazanaphtho[l,8-ab]heptalene (100 mg, 0.2 mmol, 78%) as yellow oil. LCMS: 510.2 [M+H]+.

[0454] To a solution of 2-allyl-l,4-diazepan-5-one (240 mg, 1.56 mmol) in DCM (30 mL) was added DIEA (0.81 mL, 4.67 mmol) and 4,5,7-trichloro-8-fluoro-2-Patent ApplicationAtty. Docket No. ENTX-035PCT(methylthio)pyrido[4,3-d]pyrimidine (511 mg, 1.71 mmol) was stirred at 0 °C for 1 hour. The mixture was concentrated and the residue was purified by chromatography (silica gel, 0-10%, EtOAc in PE) to give 2-allyl-l-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4- yl)-l,4-diazepan-5-one (300 mg, 0.72 mmol, 46%) as a yellow oil. LCMS: ESI m / z 415.9 [M+H]+.

[0455] Step 2: To a solution of 2-allyl-l-(5,7-dichloro-8-fhioro-2-(methylthio)pyrido[4,3- d]pyrimidin-4-yl)-l,4-diazepan-5-one (300 mg, 0.72 mmol) in DMA (6 mL) was added potassium acetate (212 mg, 2.16 mmol), PPhs (38 mg, 0.14 mmol) and Pd(OAc)2 (16 mg, 0.07 mmol). The mixture was stirred at 100 °C under N2 for 3 hours. The cooled mixture was poured into brine (10 mL) and extracted with EtOAc (20 mL). The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-30%, EtOAc in PE) to give (2-chloro-l-fluoro-4-methylene-12- (methylthio)-5,5a,6,7,9,10-hexahydro-3,7,10a,l l,13-pentaazanaphtho[l,8-ab]heptalen-8(4H)-one (140 mg, 0.37 mmol, 51%) as a yellow solid. LCMS: ESI m / z 380.0 [M + H]+.

[0456] Step 3: To a solution of 2-chloro-l-fluoro-4-methylene-12-(methylthio)- 5,5a,6,7,9,10-hexahydro-3,7,10a,l l,13-pentaazanaphtho[l,8-ab]heptalen-8(4H)-one (200 mg, 0.53 mmol) in DCM (6 mL) was added m-CPBA (227 mg, 1.32 mmol) was stirred at 20 °C for 2 hours. The mixture was concentrated and the residue was purified by chromatography (silica gel, 0-5%, MeOH in DCM) to give 2-chloro-l-fluoro-4-methylene-12-(methylsulfonyl)- 5,5a,6,7,9,10-hexahydro-3,7,10a,l l,13-pentaazanaphtho[l ,8-ab]heptalen-8(4H)-one (120 mg, 0.29 mmol, 55%) as a brown oil. LCMS: ESI m / z 411.9 [M + H]+.

[0457] Step 4: To a solution of 2-chloro-l-fluoro-4-methylene-12-(methylsulfonyl)- 5,5a,6,7,9,10-hexahydro-3,7,10a,l l,13-pentaazanaphtho[l,8-ab]heptalen-8(4H)-one (70 mg, 0.44 mmol) in THF (2 mL) was added sodium 2-methylpropan-2-olate (34 mg, 0.35 mmol) at - 60 °C and the mixture was stirred -60 °C for 5 mins. Then ((2R,7aS)-2-fluorotetrahydro- lH- pyrrolizin-7a(5H)-yl)methanol (120 mg, 0.29 mmol) was added and the mixture was stirred - 60 °C for 1 h. The mixture was concentrated and the residue was purified by chromatography (silica gel, 0-5%, MeOH in DCM) to give 2-chloro-l-fluoro-12-(((2R,7aS)-2-fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy)-4-methylene-5,5a,6,7,9,10-hexahydro-3,7,10a,l 1,13- pentaazanaphtho[l,8-ab]heptalen-8(4H)-one (20 mg, 0.04 mmol, 14%) as a yellow solid. LCMS: ESI m / z 491.1 [M + H]+.Patent ApplicationAtty. Docket No. ENTX-035PCTIntermediate 62 (6-chloro-5-(l-methylcycIopropyl)-l-(tetrahydro-2 / / -pyran-2-yl)-LH-indazol-4-yl)boronic acid

[0458] Step 1: To a stirred mixture of 5-bromo-4-chloro-2-fluoroaniline (1.0 g, 4.46 mmol) and 4,4,5,5-tetramethyl-2-(prop-l-en-2-yl)-l,3,2-dioxaborolane (1.12 g, 6.68 mmol) in dioxane (10.0 m ) and H2O (1.00 m ), were added K3PO4 (2.84 g, 13.3 mmol) and Pd(dppf)C12 (325 mg, 0.45 mmol). The reaction was stirred at 80 °C for 18 hours. The reaction was monitored by analysis of LCMS. The reaction mixture was diluted with EtOAc, washed with brine, and organic layer was separated. The aqueous layer was extracted with EtOAc, then the combined extracts were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient of 0-30% EtOAc in petroleum ether to afford 4-chloro-2-fluoro-5-(prop-l-en-2- yl)aniline (750 mg, 4.04 mmol, 90%) as a yellow oil. LCMS: EST m / z 186.1 [M+H]+

[0459] Step 2: To a stirred mixture of 4-chloro-2-fluoro-5-(prop-l-en-2-yl)aniline (750 mg, 4.04 mmol) and acetic anhydride (0.53 mL, 5.66 mmol) in dioxane (10 mL), was added DIEAPatent ApplicationAtty. Docket No. ENTX-035PCT (522 mg, 4.04 mmol). The reaction was stirred at 50 °C for 18 hours. The reaction was monitored by analysis of LCMS. The reaction mixture was diluted with EtOAc, washed with brine, and organic layer was separated. The aqueous layer was extracted with EtOAc, then the combined extracts were dried over anhydrous Na2SO4, fdtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient of 0-30% EtOAc in petroleum ether to afford N-[4-chloro-2-fluoro-5-(prop-l-en-2-yl)phenyl]acetamide (800 mg, 3.51 mmol, 86%) as a yellow oil. LCMS: ESI m / z 228.1 [M+H]+

[0460] Step 3: A flask containing diethylzinc (3.90 g, 31.6 mmol) and DCE (20.0 mL) was purged with nitrogen for three times. Anhydrous TFA (2.42 mL, 31.6 mmol) in DCE (10 mL) was added by syringe at 0 °C under nitrogen. After 30 minutes, diiodomethane (8.47 g, 31.6 mmol) in DCE (5 mL) was added to the mixture and stirred for 30 minutes. Then N-[4-chloro-2- fluoro-5-(prop-l-en-2-yl)phenyl]acetamide (800 mg, 3.51 mmol) in DCE (10 mL) was added to the mixture. The reaction was stirred at 25 °C for 4 hours. The reaction was monitored by analysis of LCMS. The reaction mixture was diluted with DCM, washed with brine, and organic layer was separated. The aqueous layer was extracted with EtOAc, then the combined extracts were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient of 0-30% EtOAc in petroleum ether to afford N-[4-chloro-2-fluoro-5-(methylcyclopropyl)phenyl]acetamide (600 mg, 2.48 mmol, 70%) as a yellow oil. LCMS: ESI m / z 242.1 [M+H]+

[0461] Step 4: To a stirred mixture of N-[4-chloro-2-fluoro-5- (methylcyclopropyl)phenyl]acetamide (600 mg, 2.48 mmol) in EtOH (10 mL), was added NaOH (3.67 g, 91.8 mmol). The reaction was stirred at 75 °C for 18 hours. The reaction was monitored by analysis of LCMS. The mixture was neutralized with HC1 solution (2 N, 15.2 mL) to pH 5, extracted with EtOAc twice. The combined extracts were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient of 0-30% EtOAc in petroleum ether to afford 4-bromo-6-methyl-l-(3,4,5,6-tetrahydro- 2H-pyran-2-yl)-5-(trifluoromethyl)indazole-3-carbonitrile (5 mg, 0.01 mmol, 13%) as a yellow oil. LCMS: ESI m / z 200.0 [M+H]+

[0462] Step 5: To a stirred mixture of 4-chloro-2-fluoro-5-(methylcyclopropyl)aniline (200 mg, 1.00 mmol) in DMF (3 mL), was added NBS (178 mg, 1.00 mmol). The reaction was stirred at room temperature for 18 hours. The reaction was monitored by analysis of LCMS. ThePatent ApplicationAtty. Docket No. ENTX-035PCT reaction mixture was diluted with EtOAc, washed with brine, and organic layer was separated. The aqueous layer was extracted with EtOAc, then the combined extracts were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient of 0-30% EtOAc in petroleum ether to afford 2-bromo- 4-chloro-6-fluoro-3-(methylcyclopropyl)aniline (230 mg, 0.83 mmol, 82%) as a yellow oil. LCMS: ESI m / z 280.0 [M+H+2]+

[0463] Step 6: To a flask containing ACN (5 mL) were added Cui (102 mg, 0.54 mmol) and 2-methyl-2-(nitrosooxidanyl)propane (55.5 mg, 0.54 mmol). The mixture was stirred at room temperature for 30 minutes. Then 2-bromo-4-chloro-6-fluoro-3- (methylcyclopropyl)aniline (100 mg, 0.36 mmol) in ACN (5 mL) was added drop-wise, which was stirred at 5 °C for 20 minutes and then warmed to room temperature for 48 hours. The reaction was monitored by analysis of TLC. The reaction mixture was diluted with EtOAc, washed with brine, and organic layer was separated. The aqueous layer was extracted with EtOAc, then the combined extracts were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient of 0-30% EtOAc in petroleum ether to afford 3-bromo-5-chloro-l-fluoro-2-iodo-4- (methylcyclopropyl)benzene (100 mg, 0.26 mmol, 71%) as a yellow oil. No MS.1H NMR (400 MHz, Chloroform-d) 5 7.11 (d, J= 7.4 Hz, 1H), 1.31 (s, 3H), 0.98 - 0.86 (m, 4H)

[0464] Step 7: To a flask containing THF (5 mL) were added 3-bromo-5-chloro-l-fluoro-2- iodo-4-(methylcyclopropyl)benzene (100 mg, 0.26 mmol) was added n-BuLi (0.13 mL, 0.33 mmol) at -78 °C under nitrogen atmosphere. The mixture was stirred at that temperature for 10 minutes. Then dry DMF (0.04 mL, 0.51 mmol) was added dropwise, and the mixture was stirred at -78 °C for 1 hour. The reaction was monitored by analysis of TLC. The mixture was quenched with IN HC1 and slowly warmed to room temperature. Then the reaction mixture was diluted with EtOAc, washed with brine, and organic layer was separated. The aqueous layer was extracted with EtOAc, then the combined extracts were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient of 0-30% EtOAc in petroleum ether to afford 2-bromo-4-chloro-6-fluoro-3- (methylcyclopropyl)benzene-l-carbaldehyde (50 mg, 0.14 mmol, 53%) as a yellow oil. No Ms.

[0465] Step 8: To a stirred mixture of 2-bromo-4-chloro-6-fluoro-3- (methylcyclopropyl)benzene-l-carbaldehyde (50 mg, 0.17 mmol) in dioxane (2 mL), wasPatent ApplicationAtty. Docket No. ENTX-035PCT added N2H4.H2O (32.2 mg, 0.51 mmol). The reaction was stirred at 95 °C for 48 hours. The reaction was monitored by analysis of LCMS. The mixture was cooled to room temperature, then the reaction mixture was diluted with MTBE, washed with brine, and organic layer was separated. The aqueous layer was extracted with MTBE, then the combined extracts were dried over anhydrous ISfeSC , fdtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient of 0-10% EtOAc in petroleum ether to afford 4-bromo- 6-chloro-5-(methylcyclopropyl)-lH-indazole (30 mg, 0.11 mmol, 61%) as a yellow solid. LCMS: ESI m / z 287.0 [M+H+2]+

[0466] Step 9: To a stirred mixture of 4-bromo-6-chloro-5-(methylcyclopropyl)-lH-indazole (30 mg, 0.11 mmol) in DCM (3 mL), were added 3,4-dihydro-2H-pyran (0.01 mL, 0.16 mmol) and 4-methylbenzenesulfonic acid (1.81 mg, 0.01 mmol). The reaction was stirred at 30 °C for 2 hours. The reaction was monitored by analysis of TLC. The reaction mixture was diluted with DCM, washed with brine, and organic layer was separated. The aqueous layer was extracted with DCM, then the combined extracts were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient of 0-30% EtOAc in petroleum ether to afford 4-bromo-6-chloro-5-(methylcyclopropyl)- l-(3,4,5,6-tetrahydro-2H-pyran-2-yl)indazole (30 mg, 0.08 mmol, 77%) as a yellow oil. No Ms.

[0467] 1H NMR (400 MHz, CDC13) 8 7.98 (s, 1H), 7.65 - 7.57 (m, 1H), 5.66 - 5.58 (m, 1H),4.04 - 3.96 (m, 1H), 3.78 - 3.70 (m, 1H), 2.54 - 2.42 (m, 1H), 2.19 - 2.05 (m, 2H), 1.78 - 1.66 (m, 3H), 1.36 (s, 3H), 1.29 - 1.24 (m, 1H), 1.08 - 1.00 (m, 1H), 0.97 - 0.82 (m, 2H).

[0468] Step 10: To a stirred mixture of 4-bromo-6-chloro-5-(methylcyclopropyl)-l-(3, 4,5,6- tetrahydro-2H-pyran-2-yl)indazole (30 mg, 0.08 mmol) and tetrahydroxydiboron (14.5 mg, 0.16 mmol) in MeOH (1 mL), were added TEA (0.03 mL, 0.24 mmol) and CataCXium A Pd G3 (11.8 mg, 0.02 mmol). The reaction was stirred at room temperature for 6 hours. The reaction was monitored by analysis of LCMS. The reaction mixture was diluted with EtOAc, washed with brine, and organic layer was separated. The aqueous layer was extracted with EtOAc, then the combined extracts were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient of 0-30% EtOAc in petroleum ether to afford [6-chloro-5-(methylcyclopropyl)-l-(3,4,5,6-tetrahydro-2H-pyran-2- yl)indazol-4-yl]boranediol (15 mg, 0.03 mmol, 38%) as a yellow solid. LCMS: ESI m / z 335.0 [M+H]+Patent ApplicationAty. Docket No. ENTX-035PCTIntermediate 63(S)-7-allyl-l,4-diazepan-5-one

[0469] Step 1: To a solution of (S)-3-((tert-butoxycarbonyl)amino)hex-5-enoic acid (3.0 g, 13.08 mmol) in THF (30 mb) was added K2CO3 (3.6 g, 26.17 mmol) and lodomethane (2.1 mb, 26.17 mmol) at 0 °C. The mixture was stirred at 70 °C for 16 hours. LCMS showed the reaction was 90% DP. The reaction mixture was diluted water, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluted with EA in PE (gradient: 0-30%) to afford methyl (S)-3-((tert- butoxycarbonyl)amino)hex-5-enoate (3.0 g, 12.33 mmol, 94%) as a white solid. LCMS: ESI m / z: 244.1 [M+H]+.

[0470] Step 2: To a solution of methyl (S)-3-((tert-butoxycarbonyl)amino)hex-5-enoate (3.0 g, 12.33 mmol) in Hydrogen chloride 1,4-dioxane solution (20 mb, 4M) at 0 °C. The mixture was stirred at 30 °C for 3 hours. LCMS showed the reaction was 95% DP. The reaction mixture was removed most of solvent under vacuum to afford methyl (S)-3-aminohex-5-enoate hydrochloride (1.7 g, 11.87 mmol, 78%) as a HC1 salt. LCMS: ESI m / z: 144.1 [M+H]+.

[0471] Step 3: To a solution of methyl (S)-3-aminohex-5-enoate hydrochloride (1.7 g, 9.55 mmol) in MeOH (20 mL) was added tert-butyl (2-oxoethyl)carbamate (1.36 g, 8.59 mmol) TEA (0.06 mL, 0.48 mmol), HOAc (177 mg, 0.95 mmol) at 0 °C, and the mixture was stirred at 25 °C for 1 hour under nitrogen, then followed by sodium cyanoboranuide (1.2 g, 19.10 mmol). ThePatent ApplicationAtty. Docket No. ENTX-035PCT mixture was stirred at 25 °C for 2 hours. LCMS showed the reaction was 60% DP. The reaction mixture was diluted water, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluted with MeOH in DCM (gradient: 0-5%) to afford methyl (S)-3-((2-((tert- butoxycarbonyl)amino)ethyl)amino)hex-5-enoate (1.6 g, 5.59 mmol, 58%) as a yellow oil. LCMS: ESI m / z: 287.2 [M+H]+.

[0472] Step 4: To a solution of methyl (S)-3-((2-((tert- butoxycarbonyl)amino)ethyl)amino)hex-5-enoate (1.6 g, 5.57 mmol) in Hydrogen chloride 1,4- dioxane solution (15 mL, 4M) at 0 °C. The mixture was stirred at 30 °C for 2 hours. LCMS showed the reaction was 80% DP. The reaction mixture was removed most of solvent under vacuum to afford methyl (S)-3-((2-aminoethyl)amino)hex-5 -enoate hydrochloride (1.0 g, 4.52 mmol, 81%) as a HCl salt. LCMS: ESI m / z: 187.1 [M+H]+.

[0473] Step 5: To a solution of methyl (S)-3-((2-aminoethyl)amino)hex-5-enoate hydrochloride (1.0 g, 4.44 mmol) in MeOH (20 mL) was added CS2CO3 (5.9 g, 17.76 mmol) at 0 °C. The mixture was stirred at 70 °C for 16 hours. LCMS showed the reaction was 70% DP. The reaction mixture was diluted water, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated to afford (S)-7-allyl-l,4-diazepan-5-one (310 mg, 2.00 mmol, 44%) as a yellow oil. LCMS: ESI m / z: 155.2 [M+H]+.Intermediate 64(A)-2-chloro-l-fluoro-12-(((27?,7aS)-2-fluorotetrahydro-l / / -pyrrolizin-7a(5 / / )-yl)methoxy)- 4-methylene-4,5,5a,6,9,10-hexahydro-3,8,10a,l l,13-pentaazanaphtho[ l,8-a£>]heptalen- 7(87 / )-oneSynthetic Scheme:Patent ApplicationAtty. Docket No. ENTX-035PCT

[0474] Step 1: To a solution of (S)-7-allyl-l,4-diazepan-5-one (310 mg, 2.00 mmol) in DCM (6 mL) was added DIEA (774 mg, 6.00 mmol) and 4,5,7-trichloro-8-fluoro-2- (methylthio)pyrido[4,3-d]pyrimidine (596 mg, 2.00 mmol) at 0 °C, and the mixture was allowed to warm to rt and was stirred 1 hour under nitrogen. LCMS showed the reaction was 65% DP. The reaction mixture was diluted water, extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluted with EA in PE (gradient: 10-60%) to afford (S)-7-allyl-l-(5,7-dichloro-8- fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-l,4-diazepan-5-one (410 mg, 0.99 mmol, 49%) as a brown solid. LCMS: ESI m / z: 416.2 [M+H]+.

[0475] Step 2: To a solution of (S)-7-allyl-l-(5,7-dichloro-8-fhioro-2- (methylthio)pyrido[4,3-d]pyrimidin-4-yl)-l,4-diazepan-5-one (360 mg, 0.86 mmol) in DMA (7.2 mL) were added Pd(OAc)2 (38 mg, 0.17 mmol), PPha (68 mg, 0.26 mmol), and KO Ac (170 mg, 1.73 mmol). The reaction was stirred at 100 °C under nitrogen for 6 hours. LCMS showed the reaction was complete. The cooled reaction mixture was diluted water, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluted with MeOH in DCM (gradient: 0-8%) to afford (S)-2-chloro- 1 -fluoro-4-methylene- 12-(methylthio)-4, 5 , 5 a, 6, 9, 10-hexahy dro- 3,8, 10a, 1 l,13-pentaazanaphtho[l,8-ab]heptalen-7(8H)-one (100 mg, 0.26 mmol, 30%) as a yellow solid. LCMS: ESI m / z: 380.1 [M+H]+.

[0476] Step 3: To a solution of (S)-2-chloro-l-fluoro-4-methylene-12-(methylthio)-Patent Application Atty. Docket No. ENTX-035PCT4,5,5a,6,9,10-hexahydro-3,8,10a,l l,13-pentaazanaphtho[l ,8-ab]heptalen-7(8H)-one (100 mg, 0.26 mmol) in DCM (2 mL) was added m-CPBA (113 mg, 0.65 mmol) at 0 °C under nitrogen atmosphere. The mixture was stirred at room temperature for 2 hours. LCMS showed the reaction was complete. The reaction mixture was quenched with sat. aq. NaHCCh solution and extracted with DCM. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluted with MeOH in DCM (gradient: 0-10%) to afford (S)-2-chloro-l-fluoro-4-methylene-12- (methylsulfonyl)-4,5,5a,6,9,10-hexahydro-3,8,10a,l l,13-pentaazanaphtho[l,8-ab]heptalen- 7(8H)-one (60 mg, 0.15 mmol, 55%) as a yellow solid. LCMS: ESI m / z: 412.1 [M+H]+.

[0477] Step 4: To a solution of ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methanol (28 mg, 0.17 mmol) and sodium tert-butoxide (28 mg, 0.29 mmol) in THF (1 mL) were added (S)-2-chloro-l-fluoro-4-methylene-12-(methylsulfonyl)-4,5,5a,6,9,10-hexahydro- 3,8, 10a, 1 l,13-pentaazanaphtho[l,8-ab]heptalen-7(8H)-one (60 mg, 0.15 mmol) at -50 °C under nitrogen atmosphere. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with EA. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluted with MeOH in DCM (gradient: 0-10%) to afford (S)-2-chloro-l-fluoro- 12-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-4-methylene-4,5,5a,6,9,10- hexahydro-3,8, 10a, 1 l,13-pentaazanaphtho[l,8-ab]heptalen-7(8H)-one (30 mg, 0.06 mmol, 42%) as a yellow solid. LCMS: ESI m / z: 491 .1 [M+H]+.Intermediate 65(R)-7-allyl-l,4-diazepan-5-oneSynthetic Scheme:Patent ApplicationAtty. Docket No. ENTX-035PCT

[0478] Step 1: To a solution of (R)-3-((tert-butoxycarbonyl)amino)hex-5-enoic acid (4.5 g, 19.63 mmol) in MeOH (45 mL) was added SOCh (4.6 g, 39.25 mmol) at 0 °C. The mixture was stirred at 30 °C for 16 hours. LCMS showed 90% completion. Most of solvent was removed under vacuum to afford methyl (R)-3 -aminohex-5 -enoate (2.8 g, 19.55 mmol, 99%) as a white solid. LCMS: ESI m / z: 144.2 [M+H]+.

[0479] Step 2: To a solution of methyl (R)-3-aminohex-5-enoate hydrochloride (2.8 g, 15.59 mmol) in MeOH (30 mL) was added tert-butyl (2-oxoethyl)carbamate (2.0 g, 12.47 mmol), TEA (0.10 mL, 0.77 mmol), HO Ac (90 mg, 1.56 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 hour under nitrogen, then followed by the addition of sodium cyanoborohydride (2.0 g, 31.17 mmol). The mixture was stirred at 25 °C for 2 hours. LCMS showed 50% completion. The reaction mixture was diluted water, extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluted with MeOH in DCM (gradient: 0-5%) to afford methyl (R)-3-((2-((tert- butoxycarbonyl) amino)ethyl)amino)hex-5-enoate (2.2 g, 7.68 mmol, 49%) as a yellow oil. LCMS: ESI m / z: 287.2 [M+H]+.

[0480] Step 3: To a solution of (R)-3-((2-((tert-butoxycarbonyl)amino)ethyl)amino)hex-5- enoate (2.2 g, 7.68 mmol) in Hydrogen chloride 1,4-di oxane solution (20 mL, 4M) at 0 °C. The mixture was stirred at 30 °C for 2 hours. LCMS showed the reaction was 80% COMPLETION. The reaction mixture was removed most of solvent under vacuum to afford methyl (R)-3-((2- aminoethyl) amino)hex-5-enoate (1.3 g, 6.98 mmol, 90%) as a HC1 salt. LCMS: ESI m / z: 187.1 [M+H]+.

[0481] Step 4: To a solution of methyl (R)-3-((2-aminoethyl)amino)hex-5 -enoate hydrochloride (1.3 g, 6.98 mmol) in MeOH (26 mL) was added CS2CO3 (4.7 g, 20.9 mmol) at 0Patent ApplicationAtty. Docket No. ENTX-035PCT°C. The mixture was stirred at 70 °C for 16 hours. LCMS showed the reaction was 65% COMPLETION. The reaction mixture was diluted water, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated to afford (R)-7-allyl-l,4-diazepan- 5-one (550 mg, 3.57 mmol, 51%) as a yellow oil. LCMS: ESI m / z: 155.2 [M+H]+.Intermediate 66(7?)-2-chloro-l-fluoro-12-(((2A,7a5)-2-fluorotetrahydro-l / / -pyrrolizin-7a(57 / )-yl)methoxy)-4-methylene-4,5,5a,6,9,10-hexahydro-3,8,10a,l l,13-pentaazanaphtho[ 1.8-< / A|heptalen- 7(81 / )-one

[0482] Step 1: To a solution of (R)-7-allyl-l,4-diazepan-5-one (550 mg, 3.57 mmol) inDCM (10 mL) was added DIEA (1380 mg, 10.70 mmol) and 4,5,7-trichloro-8-fluoro-2- (methylthio)pyrido[4,3-d]pyrimidine (1064 mg, 3.57 mmol) at 0 °C, and the mixture was allowed to warm to rt and was stirred 1 hour under nitrogen. LCMS showed 78% completion. The reaction mixture was fdtered and evaporated to dryness to afford (R)-7-allyl-l-(5,7-dichloro-8-Patent ApplicationAtty. Docket No. ENTX-035PCT fluoro-2-(methylthio)pyrido [4,3-d]pyrimidin-4-yl)-l ,4-diazepan-5-one (950 mg, 2.28 mmol, 64%) as a brown solid. LCMS: ESI m / z: 416.2 [M+H]+.

[0483] Step 2: To a solution of (R)-7-allyl-l-(5,7-dichloro-8-fhroro-2- (methylthio)pyrido[4,3-d]pyrimidin-4-yl)-l,4-diazepan-5-one (950 mg, 2.28 mmol) in DMA (20 mb) were added Pd(OAc)2 (447 mg, 4.56 mmol), PPhs (179 mg, 0.68 mmol), and KOAc (447 mg, 4.56 mmol). The reaction was stirred at 100 °C under nitrogen for 10 hours. LCMS showed the reaction was 55% COMPLETION. The cooled reaction mixture was diluted water, extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluted with MeOH in DCM (gradient: 0-8%) to afford (R)-2-chloro-l-fluoro-4-methylene-12-(methylthio)-4,5,5a,6,9,10- hexahydro-3,8,10a,l l,13-pentaazanaphtho[l,8-ab]heptalen-7(8H)-one (320 mg, 0.84 mmol, 36%) as a yellow solid. LCMS: ESI m / z: 380.1 [M+H]+.

[0484] Step 3: To a solution of (R)-2-chloro-l-fluoro-4-methylene-12-(methylthio)- 4,5,5a,6,9,10-hexahydro-3,8,10a,l l,13-pentaazanaphtho[l,8-ab]heptalen-7(8H)-one (300 mg, 0.79 mmol) in DCM (6 mL) was added zw-CPBA (340 mg, 1.97 mmol) at 0 °C under nitrogen atmosphere. The mixture was stirred at room temperature for 2 hours. LCMS showed 70% completion. The reaction mixture was quenched with sat. aq. NaHCCh solution and extracted with DCM. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluted with MeOH in DCM (gradient: 0-10%) to afford (R)-2-chloro-l-fluoro-4-methylene-12-(methylsulfonyl)- 4,5,5a,6,9,10-hexahydro-3,8,10a,l l,13-pentaazanaphtho[l,8-ab]heptalen-7(8H)-one (203 mg, 0.49 mmol, 62%) as a yellow solid. LCMS: ESI m / z: 412.1 [M+H]+.

[0485] Step 4: To a solution of ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methanol (77 mg, 0.49 mmol) and sodium tert-butoxide (70 mg, 0.73 mmol) in THF (2 mL) were added (R)-2-chloro-l-fluoro-4-methylene-12-(methylsulfonyl)-4,5,5a,6,9, 10-hexahydro- 3,8, 10a, 1 l,13-pentaazanaphtho[l,8-ab]heptalen-7(8H)-one (100 mg, 0.24 mmol) at -50 °C under nitrogen atmosphere. The mixture was stirred at room temperature for 2 hours. LCMS showed 60% completion. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried over 2SO4 and concentrated. The residue was purified using silica gel column chromatography eluted with MeOH in DCM (gradient: 0-10%) to afford (R)-2-chl oro-1 -fluoro- 12-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-Patent ApplicationAtty. Docket No. ENTX-035PCT yl)methoxy)-4-methylene-4,5,5a,6,9,10-hexahydro-3,8,10a,l l ,13-pentaazanaphtho[l,8- ab]heptalen-7(8H)-one (75 mg, 0.15 mmol, 63%) as a yellow solid. LCMS: ESI m / z: 491.1 [M+H]1.Intermediate 67(l-(((d i-ter / -butoxyphosphoryl)oxy)methyl)-6-methyl-5-(trifluoromethyl)-lJ / -indazol-4- yl)boronic acid

[0486] Step 1: To a stirred mixture of 2-bromo-6-fluoro-4-methyl-3- (trifluoromethyl)benzene-l-carbaldehyde (13.0 g, 45.6 mmol) in dioxane (130 m ) was added N2H4.H2O (9.13 g, 182.43 mmol). The reaction was stirred at 100 °C for 18 hours. The reaction was monitored by analysis of LCMS. The cooled reaction mixture was diluted with EtOAc, washed with brine, and organic layer was separated. The aqueous layer was extracted with EtOAc, then the combined extracts were dried over anhydrous Na2SO4, fdtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient of 0~30% EtOAc in petroleum ether to afford 4-bromo-6-methyl-5-(trifluoromethyl)- IH-indazole (11.0 g, 39.4 mmol, 86%) as a white solid. LCMS: ESI m / z 281.0 [M+H+2]+

[0487] Step 2: To a stirred mixture of 4-bromo-6-methyl-5-(trifluoromethyl)-lH-indazole (10.0 g, 35.8 mmol) and bis(2-methylpropan-2-yl) chloromethyl phosphate (18.5 g, 71.6Patent Application Atty. Docket No. ENTX-035PCT mmol) in DMF (3 mL) were added CS2CO3 (35.0 g, 107 mmol) and Nal (6.44 g, 43.0 mmol). The reaction was stirred at room temperature for 3 hours, then diluted with EtOAc, washed with brine. The organic layer was separated. The aqueous layer was extracted with EtOAc, and the combined organic layer was dried over anhydrous Na2SO4, fdtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient of 0-50% EtOAc in petroleum ether to afford (4-bromo-6-methyl-5-(trifluoromethyl)- lH-indazol-l-yl)methyl di-tert-butyl phosphate (7.0 g, 13.9 mmol, 33%) as a colorless oil. LCMS: ESI m / z 503.0 [M+H+2]+

[0488] Step 3: To a stirred mixture of (4-bromo-6-methyl-5-(trifluoromethyl)-lH-indazol-l- yl)methyl di-tert-butyl phosphate (7.0 g, 13.9 mmol) and tetrahydoxydiboron (2.52 g, 28.1 mmol) in MeOH (70 mL) were added TEA (4.27 g, 42.2 mmol) and cataCXium A Pd G3 (2.05 g, 2.81 mmol). The reaction was stirred at room temperature for 18 hours. The reaction mixture was filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient of 0-10% MeOH in DCM ether to afford ( 1 -(((di-tert- butoxyphosphoryl)oxy)methyl)-6-methyl-5-(trifluoromethyl)-lH-indazol-4-yl)boronic acid (5.0 g, 10.7 mmol, 76%) as a yellow oil. LCMS: ESI m / z 467.3 [M+H]+Intermediate 68 (7-fluoro-6-methyl-l-(tetrahydro-2 / / -pyran-2-yl)-5-(trifluoromethyl)-l / 7-indazol-4- yl)boronic acidSynthetic Scheme:Patent ApplicationAtty. Docket No. ENTX-035PCT

[0489] Step 1: To a solution of 3,4-difluorophenol (10 g, 76.8 mmol) in H2O (400 mL) was added potassium iodide (12.7 g, 76.8 mmol) and iodine (19.5 g, 76.8 mmol) at 0 °C. The reaction was stirred at rt until all material fully dissolved. After the KOH (10 g, 76.87 mmol) was dissolved in H2O (400 mL). Then the KOH solution was cooled down to RT and was dropwise about Ih into the reaction mixture at 0 °C. The reaction was stirred for 3h at rt and monitored by LCMS. The reaction mixture was acidified to pH<3 with saturated ammonium chloride aqueous solution and 0. IN HO, extracted with EtOAc. The organic phase was washed with brine, dried by Na2SO4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 5%] to afford 4,5-difluoro-2-iodophenol (13 g, 50.7 mmol, 66%) as a white solid. LCMS: ESI m / z 255 [M+H]'

[0490] Step 2: To a solution of 4,5-difluoro-2-iodophenol (12 g, 46.8 mmol) in DMF (200Patent ApplicationAtty. Docket No. ENTX-035PCT mL) was added K2CO3 (12.9 g, 93.7 mmol), potassium iodide (7.7 g, 46.8 mmol) and (bromomethyl)benzene (7 mL, 56.2 mmol) was added. The reaction was stirred at rt for overnight under nitrogen. The reaction was monitored by analysis of LC-MS. The cooled reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SO4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 2%] to afford l-(benzyloxy)-4,5- difluoro-2-iodobenzene (12 g, 34.6 mmol, 73%) as a white solid. LCMS: ESI m / z 346 [M+H]+.

[0491] Step 3: To a solution of l-(benzyloxy)-4,5-difluoro-2-iodobenzene (5 g, 14.4 mmol) in DMF (500 mL) was added Cui (11g, 57.8 mmol) and methyl 2,2-difluoro-2-(fluorodioxo-X6- sulfanyl)acetate (27.7 g, 144 mmol). The reaction was purged with nitrogen three times and stirred at 60 °C for overnight under nitrogen. The cooled reaction mixture was diluted with H2O, extracted with tert-butyl methyl ether. The organic phase was washed with brine, dried by Na2SO4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 1%] to afford 1 -(benzyloxy )-4,5-difluoro-2- (trifluoromethyl)benzene (5 g crude, 17.36 mmol, 100%) as a white solid.

[0492] Step 4: To a solution of l-(benzyloxy)-4,5-difluoro-2-(trifluoromethyl)benzene (5 g, 17.3 mmol) and ethyl formate (3.86 g, 52 mmol) in THF (50 mL) was added LDA (26 mL, 52 mmol) at -78 °C under nitrogen. The reaction stirred at -78 °C for 30 min under nitrogen, then diluted with H2O, and extracted with EtOAc. The organic phase was washed with brine, dried by Na2SC>4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 1%] to afford 2-(benzyloxy)-5,6-difluoro-3- (trifluoromethyl)benzaldehyde (1 g, 3.27 mmol, 18%) as a white solid.!H NMR (400 MHz, CDCI3) 8 10.25 (s, 1H), 7.77 - 7.69 (m, 1H), 7.49 - 7.45 (m, 2H), 7.44 - 7.39 (m, 3H), 5.05 (s, 2H).

[0493] Step 5: To a solution of 2-(benzyloxy)-5,6-difluoro-3-(trifluoromethyl)benzene-l- carbaldehyde (2 g, 6.32 mmol) in MeOH (10 mL)was added NaBH4 (0.29 g, 7.59 mmol) at 0 °C. The reaction stirred at rt for 2h under nitrogen. The reaction was monitored by analysis of LC. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by IS^SCL, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [Gradient: 10%] to afford [2-(benzyloxy)- 5,6-difluoro-3-(trifluoromethyl)phenyl]methanol (1.5 g, 4.71 mmol, 74%) as a white solid.Patent ApplicationAtty. Docket No. ENTX-035PCT

[0494] Step 6: To a solution of [2-(benzyloxy)-5,6-difluoro-3- (trifluoromethyl)phenyl]methanol (2.5 g, 7.86 mmol) in DMF (20 mL) was added IH-imidazole (1.07 g, 15.7 mmol) and TBSC1 (1.78 g, 11.7 mmol). The reaction stirred at rt for 2h under nitrogen, then diluted with H2O and extracted with EtOAc. The organic phase was washed with brine, dried by Na2SO4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with PE in EA [Gradient: 4%] to afford l-[2-(benzyloxy)-5,6- difluoro-3-(trifluoromethyl)phenyl]-3,3,4,4-tetramethyl-2-oxa-3-silapentane (2.5 g, 5.78 mmol, 73%) as a white solid.

[0495] Step 7: To a solution of l-[2-(benzyloxy)-5,6-difluoro-3-(trifluoromethyl)phenyl]- 3, 3, 4, 4-tetramethyl-2-oxa-3 -silapentane (2 g, 4.62 mmol) and Mel (0.75 mL, 9.25 mmol) in THF (10 mL)was added LDA (0.74 g, 6.94 mmol) at -78 °C under nitrogen. The reaction stirred at - 78 °C for 2h under nitrogen. The reaction was monitored by analysis of LC. The reaction mixture was diluted with H2O and extracted with EA. The organic phase was washed with brine, dried by Na2SO4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 1%] to afford l-[2-(benzyloxy)-5,6-difluoro- 4-methyl-3-(trifluoromethyl)phenyl]-3, 3, 4, 4-tetramethyl-2-oxa-3 -silapentane (2 g, 4.48 mmol, 96%) as a white solid. 'H NMR (400 MHz, CDCh) 8 7.51 - 7.45 (m, 2H), 7.45 - 7.35 (m, 3H), 5.06 (d, J= 2.8 Hz, 2H), 4.75 (d, J= 2.0 Hz, 2H), 2.45 - 2.41 (m, 3H), 0.89 (s, 9H), 0.11 (d, J = 1.6 Hz, 6H).

[0496] Step 8: To a solution of l-[2-(benzyloxy)-5,6-difluoro-4-methyl-3- (trifluoromethyl)phenyl]-3,3,4,4-tetramethyl-2-oxa-3-silapentane (2.5 g, 5.60 mmol) in DCM (10 mL) was added TBAF (1.9 g, 7.28 mmol). The reaction stirred at rt for Ih under nitrogen. The reaction was monitored by analysis of LC. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SC>4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with PE in EA [Gradient: 10%] to afford [2-(benzyloxy)-5,6-difluoro-4-methyl-3- (trifluoromethyl)phenyl]methanol (1.8 g, 5.42 mmol, 96%) as a white solid.

[0497] Step 9: To a solution of [2-(benzyloxy)-5,6-difluoro-4-methyl-3-(trifluoromethyl) phenyl]methanol (2 g, 6.02 mmol) in DCM (10 mL) was added l,l,l-triacetoxy-l,3-dihydro- lX5-benzo[d][l,2]iodoxol-3-one (5.11 g, 12.04 mmol). The reaction stirred at rt for 2h under nitrogen. The reaction was monitored by analysis of LC-MS. The reaction mixture was dilutedPatent ApplicationAtty. Docket No. ENTX-035PCT with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SC>4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with PE in EA [Gradient: 4%] to afford 2-(benzyloxy)-5,6-difluoro-4-methyl-3- (trifluoromethyl)benzene-l-carbaldehyde (1.5 g, 4.54 mmol, 75%) as a white solid.

[0498] Step 10: To a solution of 2-(benzyloxy)-5,6-difluoro-4-methyl-3- (trifluoromethyl)benzene-l-carbaldehyde (1.5 g, 4.54 mmol) in dioxane (10 mL) was added hydrazine (1.5 mL, 45.4 mmol). The reaction stirred at 100 °C overnight under nitrogen. The reaction was monitored by analysis of LCMS. The cooled reaction mixture was diluted with H2O, extracted with EtOAc. The organic phase was washed with brine, dried by Na2SO4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [Gradient: 4%] to afford 4-(benzyloxy)-7-fluoro-6-methyl-5-(trifluoromethyl)- IH-indazole (1 g, 3.08 mmol, 68%) as a white solid. LCMS: ESI m / z 325 [M+H]+.

[0499] Step 11: To a solution of 4-(benzyloxy)-7-fluoro-6-methyl-5-(trifluoromethyl)-lH- indazole (1 g, 3.08 mmol) in DCM (10 mL) was added 4-methylbenzenesulfonic acid (0.53 g, 3.08 mmol) and 3,4-dihydro-2H-pyran (0.5 mL, 6.17 mmol). The reaction stirred at rt for 2h under nitrogen. The reaction was monitored by analysis of LCMS. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by Na2SO4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with PE in EtOAc [Gradient: 6%] to afford 4-(benzyloxy)-7-fluoro-6- methyl-l-(3,4,5,6-tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)indazole (1.1 g, 2.69 mmol, 87%) as a white solid. LCMS: ESI m / z 409 [M+H]+.

[0500] Step 12: To a solution of 4-(benzyloxy)-7-fluoro-6-methyl-l-(3,4,5,6-tetrahydro-2H- pyran-2-yl)-5-(trifluoromethyl)indazole (800 mg, 1.96 mmol) in DCM (10 mL) was added trichloroborane (4.90 mL, 4.90 mmol) at -78 °C under nitrogen. The reaction was stirred at -78 °C for Ih under nitrogen. The reaction was monitored by analysis of LCMS. The reaction mixture was diluted with H2O, extracted with EtOAc. The organic phase was washed with brine, dried by Na2SO4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 20%] to afford 7-fluoro-6-methyl-l-(3, 4,5,6- tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)indazol-4-ol (420 mg, 1.32 mmol, 67%) as a white solid. LCMS: ESI m / z 319 [M+H]+. 'H NMR (400 MHz, CDCh) 5 8.14 (d, J= 1.2 Hz, IH), 6.79 - 6.58 (m, IH), 5.96 - 5.79 (m, IH), 2.65 - 2.52 (m, IH), 2.41 (dd, J= 2.8, 2.0 Hz, 3H), 2.25 -Patent ApplicationAtty. Docket No. ENTX-035PCT 2.02 (tn, 3H), 1 .82 - 1 .69 (m, 3H).

[0501] Step 13: To a solution of 7-fluoro-6-methyl-l-(3,4,5,6-tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)indazol-4-ol (60 mg, 0.19 mmol) in DCM (3 mL) was added TEA (0.5 mL, 0.57 mmol) and trifluoromethanesulfonic anhydride (79 mg, 0.28 mmol) at -78 °C under nitrogen. The reaction stirred at -78 °C for Ih under nitrogen. The reaction was monitored by LCMS. The reaction mixture was diluted with H2O, extracted with EA. The organic phase was washed with brine, dried by NazSCU, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with EtOAc in PE [Gradient: 10%] to afford 7-fluoro-6-methyl- l-(3,4,5,6-tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)indazole-4-yl trifluoromethanesulfonate (80 mg, 0.18 mmol, 94%) as a white solid. LCMS: ESI m / z 451[M+H]+.

[0502] Step 14: To a solution of 7-fluoro-6-methyl-l-(3,4,5,6-tetrahydro-2H-pyran-2...

Claims

1. Patent ApplicationAtty. Docket No. ENTX-035PCTWhat is claimed is:CLAIMS1. A compound having the structural formula (I):or a pharmaceutically acceptable form or an isotope derivative thereof, wherein n is 0, 1 or 2;X is O or CRXIRX2, wherein each of RX1and RX2is independently selected from H, halo and unsubstituted or substituted C1-3 alkyl;Y is O, S, NRY1, C=O, C=N-OR, CRY2RY3or S(O)2, whereinRY1is R, CN, C(O)RY4or C(O)ORY5, and each of R32and RY3is independently selected from halo, CN, R, OR and NRC(O)NR', each of RY4and RY5is H, unsubstituted or substituted C1-6 alkyl or unsubstituted or substituted 3- to 6-membered carbocyclic ring;Z is CR6or N;R2is (CH2)iR2or (CD2)iR2, wherein i is an integer selected from 1-6, and (CH2)i is optionally substituted, wherein R2is selected from the group consisting of H, halogen, CN, OH, C(O)NRR’, unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted 3- to 6-membered carbocyclic ring, unsubstituted or substituted 4- to 6-membered heterocyclic ring and unsubstituted or substituted 7- to 10-membered bicyclic heterocyclic ring;Patent ApplicationAtty. Docket No. ENTX-035PCTR6is selected from the group consisting of H, halogen, CN, OR, unsubstituted or substituted Ci-6 alkyl, unsubstituted or substituted Ci-6 alkoxy, C(O)NRR’, NRR’, S(O)2CH3, unsubstituted or substituted 3- to 6-membered carbocyclic or heterocyclic ring, and unsubstituted or substituted 5- to 6-membered heteroaryl;R7is an unsubstituted or substituted 6- to 14-membered unsaturated monocyclic, bicyclic or multi-cyclic ring, comprising 0-5 heteroatoms selected from N, O and S;R8is H, halo, unsubstituted or substituted Ci-6 alkyl, CN, OR or N R’; each R10aand R10bis independently halo, CN, R or OR; or R10aand R10b, together with the carbon atom they are bonded to, form a cyclopropyl, cyclobutyl or oxetane group; and each R12aand R12bis independently selected from halo, CN, R or OR, or CR12aR12bis C=O; or R12aand R12b, together with the carbon atom they are bonded to, form a cyclopropyl, cyclobutyl or oxetane group; each R14aand R14bis independently selected from halo, CN, R or OR, or CR14aR14bis C=O; or R14aand R14b, together with the carbon atom they are bonded to, form a cyclopropyl, cyclobutyl or oxetane group; each R15aand R15bis independently selected from halo, CN, R or OR, or CR15aR15bis C=O or C=N-OR; or R15aand R15b, together with the carbon atom they are bonded to, form a cyclopropyl, cyclobutyl or oxetane group; each R16aand R16bis independently selected from halo, CN, R or OR; or R16aand R16b, together with the carbon atom they are bonded to, form a cyclopropyl or cyclobutyl group; provided that one of R12aand R12b, together with one of R14aand R14b, one of R15aand R15b, or one of R16aand R16b, may form a 4- to 7-membered carbocyclic or heterocyclic ring; one of R14aand R14b, together with one of R15aand R15b, or one of R16aand R16b, may form a 3- to 7-membered carbocyclic or heterocyclic ring; one of R15aand R15b, together with one of R16aand R16b, may form a 3- to 7-membered carbocyclic or heterocyclic ring; andPatent ApplicationAtty. Docket No. ENTX-035PCT each of R and R’ is independently selected from H, D, unsubstituted or substituted Ci-6 alkyl, or unsubstituted or substituted 3- to 6-membered carbocyclic ring, or where R and R’ are attached to the same N atom, together form an unsubstituted or substituted 4- to 7-membered heterocyclic ring.

2. The compound of claim 1, wherein n is 1, having the having the structural formula (II):

3. The compound of claim 2, wherein Z is CR6, having the structural formula (IIA):

4. The compound of claim 2, wherein Z is N, having the structural formula (IIB):Patent ApplicationAtty. Docket No. ENTX-035PCT(IP)5. The compound of claim 1, wherein n is 0, having the having the structural formula (III):

6. The compound of claim 5, wherein Z is CR6, having the structural formula (IIIA):

7. The compound of claim 5, wherein Z is N, having the structural formula (IIIB):

8. The compound of any one of claims 1-7, wherein each of R and R’ is independently H orCi-6 alkyl optionally substituted with one or more groups selected from halo, CN, OH andPatent ApplicationAtty. Docket No. ENTX-035PCT substituted or unsubstituted Ci-6 alkoxy.

9. The compound of any one of claims 1-8, having the following stereochemistry:

10. The compound of any one of claims 1-8, having the following stereochemistry:

11. The compound of any one of claims 1-10, wherein Y is O.

12. The compound of any one of claims 1-10, wherein Y is C=N-OR.

13. The compound of any one of claims 1-10, wherein Y is C=O.

14. The compound of any one of claims 1-10, wherein Y is S or S(O)2.

15. The compound of any one of claims 1-10, wherein Y is CRY2RY3.

16. The compound of any one of claims 1-10, wherein Y is NR? f17. The compound of claim 16, wherein RY1is R.

18. The compound of claim 16, wherein RY1is C(O)ORY5.

19. The compound of claim 18, wherein RY1comprises:wherein each of R and R’ is selected from H or substituted or unsubstituted Ci- 6 alkyl or substituted or unsubstituted 3- to 6-membered carbocycle.

20. The compound of claim 19, wherein RY1comprises:

21. The compound of any one of claims 1-20, wherein each R10aand R10bis H.

22. The compound of any one of claims 1-20, wherein R10aH and R10bis C1-3 alkyl, OR or halo.Patent ApplicationAtty. Docket No. ENTX-035PCT23. The compound of any one of claims 1 -22, wherein each R12aand R12bis H.

24. The compound of any one of claims 1-23, wherein X is CRX1RX2.

25. The compound of claim 24, wherein each of RX1and RX2is independently selected fromH, F and Cl.

26. The compound of claim 25, wherein each of RX1and RX2is H.

27. The compound of claim 25, wherein one of RX1and RX2is H and the other is F or Cl.

28. The compound of claim 25, wherein each of RX1and RX2is F or Cl.

29. The compound of claim 24, wherein at least one of RX1and RX2is an unsubstituted or substituted C1-3 alkyl.

30. The compound of any one of claims 1-23, wherein X is O.

31. The compound of any one of claims 1-3, 5-6, and 9-30, wherein R6is H.

32. The compound of any one of claims 1-3, 5-6, and 9-30, wherein R6is F.

33. The compound of any one of claims 1-3, 5-6, and 9-30, wherein R6is Cl.

34. The compound of any one of claims 1-3, 5-6, and 9-30, wherein R6is C1-3 alkyl or C3-4 cycloalkyl.

35. The compound of any one of claims 1-3, 5-6, and 9-20, wherein R6is CH2F, CHF2 or CF3.

36. The compound of any one of claims 1-3, 5-6, and 9-20, wherein R6is CN, S(O)2R, NRR’, OR or C(O)NRR’.

37. The compound of any one of claims 1 -36, wherein z is 1 .

38. The compound of any one of claims 1-37, wherein R2is (CH2)iR239. The compound of any one of claims 1-37, wherein R2is (CD2)iR2.

40. The compound of any one of claims 1-37, wherein R2is a C3-6 carbocyclic or heterocyclic ring substituted with 0-5 R2A, wherein each R2Ais independently selected from D, halo, OC1.3 alkyl or C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with one or more of halo, OH, NRR’, CN and CONRR’.

41. The compound of claim 40, wherein R2is C3-5 carbocyclic ring substituted with 0-5 R2A.

42. The compound of claim 41, wherein R2is selected from:Patent ApplicationAtty. Docket No. ENTX-035PCT43. The compound of claim 40, wherein R2is C3-5 heterocyclic ring substituted with 0-5 R2A.

44. The compound of claim 43, wherein R2is selected from:

45. The compound of any one of claims 1-37, wherein R2is a bicyclic, unsubstituted or substituted Ce-io heterocyclic ring.

46. The compound of claim 45, wherein R2is selected from:Patent ApplicationAtty. Docket No. ENTX-035PCT47. The compound of claim 45, wherein R2is selected from:Patent ApplicationAtty. Docket No. ENTX-035PCT48. The compound of claim 45, wherein R2is selected from:Patent ApplicationAtty. Docket No. ENTX-035PCT49. The compound of any one of claims 1-48, wherein R7is an unsubstituted or substituted 6- membered aryl or heteroaryl ring, comprising 0-5 heteroatoms selected from N, O and S.

50. The compound of claim 49, wherein R7has the structural formula:whereinQ is N or CR7E;W is N or CR7C;Patent ApplicationAtty. Docket No. ENTX-035PCTR7Ais H, halo or substituted or unsubstituted C1-3 alkyl;R7Bis H, halo or substituted or unsubstituted C1-3 alkyl;R7Cis H or halo;R7Dis H, NRR’, halo or OR; andR7Eis H, halo, substituted or unsubstituted C1-3 alkyl, OR or CN.

51. The compound of claim 50, wherein W is CR7C, and R7has the structural formula:

52. The compound of claim 50, wherein W is N, and R7has the structural formula:

53. The compound of any one of claims 50-52, wherein Q is N.

54. The compound of claim 53, wherein R7has the structural formula:

55. The compound of claim 53, wherein R7has the structural formula:

56. The compound of any one of claims 50-52, wherein Q is CR7E.

57. The compound of claim 56, wherein R7Eis H.

58. The compound of claim 56, wherein R7Eis F.Patent ApplicationAtty. Docket No. ENTX-035PCT59. The compound of claim 56, wherein R7Eis CN.

60. The compound of any one of claims 50-59, wherein R7Dis NH2.

61. The compound of any one of claims 50-59, wherein R7Dis OR.

62. The compound of any one of claims 59-61, wherein R7Ais CF3.

63. The compound of any one of claims 50-61, wherein R7Ais cyclopropyl.

64. The compound of any one of claims 50-63, wherein R7Bis C1-3 alkyl.

65. The compound of any one of claims 50-63, wherein R7Bis methyl.

66. The compound of any one of claims 50-65, wherein R7C, if present, is F.

67. The compound of any one of claims 50-65, wherein R7C, if present, is H.

68. The compound of claim 50, wherein R7is selected from:

69. The compound of claim 50, wherein R7is selected from:Patent ApplicationAtty. Docket No. ENTX-035PCT70. The compound of any one of claims 1-69, wherein R7is an unsubstituted or substituted 9- to 14-membered bicyclic or multi-cyclic aryl or heteroaryl ring, comprising 0-5 heteroatoms selected from N, O and S.

71. The compound of claim 70, wherein R7has the structure formula (V):whereinRing A is a 6-membered aryl or heteroaryl ring with 0-2 N atoms;Ring B is a 5- or 6-membered carbocyclic, heterocyclic, aryl or heteroaryl ring with 0-3 heteroatoms selected from N, O and S; each of R7Fand R7Gis independently selected from the group consisting of halogen, OH, CN, NRR’, unsubstituted or substituted Ci-6 alkyl, and unsubstituted or substituted Ci-6alkoxy, (CH2)kNRR’, (CH2)kC(=O)NRR’, (CH2)kOC(=O)R, (CH2)kOC(=O)OR; or 2 R7Gs, together with atoms they are bonded to, for a 4- or 7- membered unsubstituted or substituted carbocyclic, heterocyclic, aryl or heteroaryl group; or 2 R7Fs, together with atoms they are bonded to, for a 4- or 7-membered unsubstituted or substituted carbocyclic, heterocyclic, aryl or heteroaryl group;Patent ApplicationAtty. Docket No. ENTX-035PCT each of p and q is independently 0, 1, 2 or 3; and each k is independently 0, 1 or 2.

72. The compound of claim 71, wherein Ring A is a 6-membered aryl ring.

73. The compound of claim 71, wherein Ring A is a 6-membered heteroaryl ring.

74. The compound of claim 72 or 73, wherein Ring B is a 5-membered heterocyclic ring.

75. The compound of claim 72 or 73, wherein Ring B is a 6-membered heterocyclic ring.

76. The compound of claim 72 or 73, wherein Ring B is a 5-membered heteroaryl ring.

77. The compound of claim 72 or 73, wherein Ring B is a 6-membered heteroaryl ring.

78. The compound of claim 72 or 73, wherein Ring B is a 6-membered aryl ring.

79. The compound of claim 71, wherein R7is selected from:The compound of claim 71, wherein R7is selected from:Patent ApplicationAtty. Docket No. ENTX-035PCT81. The compound of claim 71, wherein R7is selected from:Patent ApplicationAtty. Docket No. ENTX-035PCT82. The compound of claim 71, wherein R7has the structure of83. The compound of any one of claims 1-82, wherein R8is F.

84. The compound of claim 1, having the structural formula:

85. The compound of claim 1, having the structural formula:Patent ApplicationAtty. Docket No. ENTX-035PCT86. The compound of claim 1, having the structural formula:

87. The compound of claim 1, having the structural formula:

88. The compound of claim 1, having the structural formula:

89. The compound of claim 1, having the structural formula:Patent ApplicationAtty. Docket No. ENTX-035PCT90. The compound of claim 1, having the structural formula:

91. The compound of claim 1, having the structural formula:

92. The compound of claim 1, having the structural formula:Patent ApplicationAtty. Docket No. ENTX-035PCT93. The compound of claim 1, having the structural formula:

94. The compound of claim 1, having the structural formula:

95. The compound of claim 1, having the structural formula:Patent ApplicationAtty. Docket No. ENTX-035PCT96. The compound of claim 1, having the structural formula:

97. The compound of claim 1, having the structural formula:

98. The compound of claim 1, having the structural formula:Patent ApplicationAtty. Docket No. ENTX-035PCT99. The compound of claim 1, having the structural formula:

100. The compound of claim 1, having the structural formula:

101. The compound of claim 1, having the structural formula:Patent ApplicationAtty. Docket No. ENTX-035PCT102. The compound of claim 1, having the structural formula:

103. The compound of claim 1, having the structural formula:

104. The compound of claim 1, having the structural formula:Patent ApplicationAtty. Docket No. ENTX-035PCT105. The compound of claim 1, having the structural formula:

106. The compound of claim 1, having the structural formula:

107. The compound of claim 1, having the structural formula:Patent ApplicationAtty. Docket No. ENTX-035PCT108. The compound of claim 1, having the structural formula:

109. The compound of claim 1, having the structural formula:

110. The compound of claim 1, having the structural formula:Patent ApplicationAtty. Docket No. ENTX-035PCT111. The compound of claim 1, having the structural formula:

112. The compound of any one of claims 82-111, having the following stereochemistry:

113. The compound of any one of claims 82-111, having the following stereochemistry:

114. The compound of any one of claims 82-86, 92, 94, 96-101, 108 and 109, wherein R6is F.

115. The compound of any one of claims 82-86, 92, 94, 96-101, 108 and 109, wherein R6is Cl.

116. The compound of any one of claims 82-115, wherein R8is F.Patent ApplicationAtty. Docket No. ENTX-035PCT117. The compound of claim 1 , selected from Table 1.

118. The compound of claim 1, selected from Table 2.

119. The compound of claim 1, selected from Table 3.

120. The compound of claim 1, selected from Table 4.

121. The compound of claim 1, selected from Table 5.

122. The compound of claim 1, selected from Table 6.

123. The compound of claim 1, selected from Table 7.

124. The compound of claim 1, selected from Table 8.

125. The compound of claim 1, selected from Table 9.

126. The compound of any of claims 1-125, having one or more deuterium atoms in place of hydrogen.

127. The compound of any of claims 1-125, having one deuterium atom in place of a hydrogen atom.

128. A pharmaceutical composition comprising a compound according to any one of claims 1- 127 and a pharmaceutically acceptable excipient, carrier, or diluent129. The pharmaceutical composition of claim 128, being suitable for oral administration.

130. A unit dosage form comprising a pharmaceutical composition according to claim 128 or 129.

131. The unit dosage form of claim 130, being in the form of a tablet or capsule132. A method for inhibiting cell proliferation in vitro or in vivo, comprising contacting a cell with an effective amount of a compound according to any one of claims 1-127.

133. A method for modulating KRas activity in a cell, comprising contacting the cell with a compound according to any one of claims 1-127.

134. A method for treating a disease or disorder mediated by a Ras mutant protein, comprising administering to a subject in need thereof a therapeutically effective amount of the compound according to any one of claims 1-127.

135. The method of claim 134, wherein the KRas mutant is selected from G12C, G12D and G12V.

136. A method for treating or reducing cancer, or a related disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of the compound according to any one of claims 1-127.Patent ApplicationAtty. Docket No. ENTX-035PCT137. The method of claim 136, wherein the cancer is selected from the group consisting of carcinoma, squamous carcinoma, adenocarcinoma, sarcoma, leukemia, neuroma, melanoma, and lymphoma.

138. The method of claim 136 or 137, wherein the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, lung cancer, endometrial cancer, appendix cancer, cholangiocarcinoma, bladder urothelial cancer, ovarian cancer, gastric cancer, breast cancer, bile duct cancer, and a hematologic malignancy.

139. The method of any one of claims 132-138, wherein the subject has a mutation of KRAS, HRAS and / or NRAS.

140. The method of any one of claims 132-139, wherein the subject being treated is further administered one or more of chemotherapy, radiotherapy, targeted therapy, immunotherapy, and hormonal therapy.

141. Use of the compound according to any one of claims 1-127, and a pharmaceutically acceptable excipient, carrier, or diluent, in preparation of a medicament for treating a disease or disorder.

142. The use of claim 141, wherein the disease or disorder is cancer.

143. The use of claim 142, wherein the cancer is selected from the group consisting of carcinoma, squamous carcinoma, adenocarcinoma, sarcoma, leukemia, neuroma, melanoma, and lymphoma.

144. The use of claim 143, wherein the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, lung cancer, endometrial cancer, appendix cancer, cholangiocarcinoma, bladder urothelial cancer, ovarian cancer, gastric cancer, breast cancer, bile duct cancer, and a hematologic malignancy.

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