Tricyclic derivatives, compositions and methods thereof

Abstract

The invention provides novel tricyclic 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-034PCTTRICYCLIC DERIVATIVES, COMPOSITIONS AND METHODS THEREOFPriority Claims and Related Applications

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 704,793, filed October 8, 2024, the entire content 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 tricyclic 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 mutation and are referred to as G12D, G12V, G12C, G12R and others, depending on which amino acidPatent ApplicationAtty. Docket No. ENTX-034PCT 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 are 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 Transl Lung Cancer Res . 12(5): 940-943; McCormick2015 Clin Cancer Res. 21 (8): 1797-1801 ; Sun et al. 2012 Agnew Chem Int Ed Engl.5 l(25):6140-6143; Ostrem et al. 2013 Nature 503:548-551; Fell et al. 2018 ACS Med. 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 (e.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 KRas inhibitors, in particular KRasG12D and KRasG12V 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-034PCTor a pharmaceutically acceptable form or an isotope derivative thereof, whereinX is CRX1RX2, wherein each of RX1and RX2is independently selected from H, halo and unsubstituted or substituted C1-3 alkyl;Y is a single bond; orCRY 1RY 2, wherein each of R'1 1and RY2is independently selected from H, halo, OR, unsubstituted or substituted C1-3 alkyl; or RY1and RY2, along with the carbon atom they are bonded to, form an unsubstituted or substituted 3- to 6-membered carbocyclic or heterocyclic group;W isW1: an unsubstituted or substituted 5- or 6-membered carbocyclic, heterocyclic, aryl or heteroaryl group, or unsubstituted or substituted C1.3 alkyl or alkoxyl; orW2: a fused bicyclic of Ring C, which is bonded to Y or N where Y is a single bond, fused with Ring D, wherein each of Ring C and Ring D is independently a substituted 5- or 6-membered carbocyclic, heterocyclic, aryl or heteroaryl group;Z is CR6or N;R2is (CH2)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-034PCTR6is 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 10-membered unsaturated monocyclic or bicyclic ring, comprising 0-5 heteroatoms selected from N, O and S;R8is H, halo, unsubstituted or substituted Ci-6 alkyl, OR or NRR’; each of R10a, R10b, Rl laand Rl lbis independently H, halo, CN, R or OR; or two of R10a, RWb j^iiaanj iib tOgether with the carbon atom(s) they are bonded to respectively, form an unsubstituted or substituted 3- to 6-membered carbocyclic or heterocyclic group; and each of R and R’ is independently selected from H, 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 6-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.

[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.Patent ApplicationAtty. Docket No. ENTX-034PCT

[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, “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.Patent ApplicationAtty. Docket No. ENTX-034PCT

[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 amelioration 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 forPatent ApplicationAtty. Docket No. ENTX-034PCT 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 P01116: Variantp.Gly 12Asp.

[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 moieties 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 having KRas G12#, 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 io inhibit undesired cellular proliferation resulting from enhanced KRas G12# 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 G 12#. 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.Patent ApplicationAtty. Docket No. ENTX-034PCT

[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 derivatives 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 anPatent ApplicationAtty. Docket No. ENTX-034PCT 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 compound 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.Patent ApplicationAtty. Docket No. ENTX-034PCT

[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, sulfmic acids, sulfonic acids and boronic acids. Examples of esters include formates, acetates, propionates, butyrates, acrylates and ethyl succinates. 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.g., 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.

[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.Patent ApplicationAtty. Docket No. ENTX-034PCT

[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 fdler, 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; 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 (e.g., a mammal), including, but not limited to humans, non-human primates, rodents, and the like, which is to be the recipientPatent ApplicationAtty. Docket No. ENTX-034PCT 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 io 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, 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.Patent ApplicationAtty. Docket No. ENTX-034PCT

[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 molecules 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% orPatent ApplicationAtty. Docket No. ENTX-034PCT 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-methylpentyl, 3 -methylpentyl, 4-methylpentyl, 2-methylhexyl, 3 -methylhexyl, 4- methylhexyl, 5-methylhexyl, 2,3 -dimethylbutyl, and the like. The alkyl is attached to the parent 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)2 wherein 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 aPatent Application Atty. Docket No. ENTX-034PCT 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).

[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 acridinyl, azoc-inyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benziniidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, 6,7-dihydro-5H-pyrrolo[l,2- a]imidazole, furanyl, furazanyl, imidazolinyl, imidazolyl, 1H- indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolmyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1 ,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl,Patent ApplicationAtty. Docket No. ENTX-034PCT phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyL pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrirnidinyl, pyrrol! ny I, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5- thiadiazinyl, 1 ,2,3 -thiadi azolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thi enoimidazolyl, thiophenyl, triazinyl, 1,2,3- triazolyl, 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, hydroxyalkyl, mercapto, nitro, -NZ1Z2, and (NZ1Z2 [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 and Zj are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, and formyl. Representative examples of NZ1Z2 include, but are not limited io, 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-ringPatent ApplicationAtty. Docket No. ENTX-034PCT 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, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(Ra)3 , -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 includePatent ApplicationAtty. Docket No. ENTX-034PCT 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, pyrroli di nonyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, quinuclidinyl, thiomorphohnyl, thiomorpholinyl 1,1 dioxide, morpholinyh azepanyl, oxazepanyl, azabicyclohexanyis, azabicycloheptanyl, azabi cyclooctanyis, azabicyclononanyls (e.g., octahydroindoKzinyl), azaspiroheptanyls, dihydro-lH,3H,5H- oxazolo[3,4-c]oxazolyl, tetrahydro-rH,3'H- spiro[cyclopropane-l,2J-pyrrolizine], hexahydro- lH-pyrrolizinyl, hexahydro- 1H-pyrrolo[2,1 - c][l,4]oxazinyl, octahydroindolizinyl, oxaazaspirononanyls, oxaazaspirooctanyls, diazaspirononanyls, oxaazabiocydoheptanyls, hexahydropyrrolizinyl 4(lH)-oxide, and tetrahydro- 2H-thiopyranyl 1 -oxide and tetrahydro-2H- thiopyrany I 1 , 1 -dioxide.Detailed Description of the Invention

[0059] The invention is based in part on the discovery of KRas inhibitors, in particular KRas (G12D) 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 profilesPatent ApplicationAtty. Docket No. ENTX-034PCT 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, whereinX is CRX1RX2, wherein each of RX1and RX2is independently selected from H, halo and unsubstituted or substituted C1-3 alkyl;Y is a single bond; orCRY1RY2, wherein each of RY1and RY2is independently selected from H, halo, OR, unsubstituted or substituted C1-3 alkyl; or RY1and RY2, along with the carbon atom they are bonded to, form an unsubstituted or substituted 3- to 6-membered carbocyclic or heterocyclic group;W isW1: an unsubstituted or substituted 5- or 6-membered carbocyclic, heterocyclic, aryl or heteroaryl group, or unsubstituted or substituted C1.3 alkyl or alkoxyl; orW2: a fused bicyclic of Ring C, which is bonded to Y or N where Y is a single bond, fused with Ring D, wherein each of Ring C and Ring D is independently a substituted 5- or 6-membered carbocyclic, heterocyclic, aryl or heteroaryl group;Z is CR6or N;R2is (CH2)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,Patent ApplicationAtty. Docket No. ENTX-034PCTC(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 10-membered unsaturated monocyclic or bicyclic ring, comprising 0-5 heteroatoms selected from N, O and S;R8is H, halo, unsubstituted or substituted Ci-6 alkyl, OR or NRR’; each of R10a, R10b, Rl laand Rl lbis independently H, halo, CN, R or OR; or two of R10a, R10b, Rllaand Rllbtogether with the carbon atom(s) they are bonded to respectively, form an unsubstituted or substituted 3- to 6-membered carbocyclic or heterocyclic group; and each of R and R’ is independently selected from H, 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 6-membered heterocyclic ring.

[0061] In certain embodiments of (I), Y is CRY1RY2, having the structural formula (II):

[0062] In certain embodiments of (II), Z is CR6, having the structural formula (IIA):Patent ApplicationAtty. Docket No. ENTX-034PCT

[0063] In certain embodiments of (II), Z is N, having the structural formula (IIB):

[0064] In certain embodiments of (IIA) or (IIB), R'1is H and RY2is not H.

[0065] In certain embodiments of (IIA) or (IIB), RY1is H and R'12is C1-3 alkyl.

[0066] In certain embodiments of (IIA) or (IIB), the compound is characterized by the following stereochemistry:

[0067] In certain embodiments of (I), Y is a single bond, having the structural formula (III):Patent ApplicationAtty. Docket No. ENTX-034PCT

[0068] In certain embodiments of (III), Z is CR6, having the structural formula (IIIA):

[0069] In certain embodiments of (III), Z is N, having the structural formula (IIIB):

[0070] In certain embodiments

[0071] In certain embodiments, W1is a substituted 5-membered heteroaryl group.

[0072] In certain embodiments, W1is a substituted 6-membered heteroaryl group.

[0073] In certain embodiments, W1is a substituted or unsubstituted C1-3 alkyl.

[0074] In certain embodiments, W1is a substituted or unsubstituted C1-3 alkoxy.

[0075] In certain embodiments, W1has the structural formula:whereinRW1is NRR';J is N, NRb, CRa, O or S;K is N, NRb, CRa, O or S;Patent ApplicationAtty. Docket No. ENTX-034PCTL is N, NRb, CRa, O or S; each Rais independently R, halo, CN or OR; and each Rbis independently R.

[0076] In certain embodiments, W1has the structural formula:whereinRW1is NRR';T is N or CRa;U is N or CRa;V is N or CRa; and each Rais independently R, halo, CN or OR.

[0077] In certain embodiments (V), one of T, U and V is N and each of the other two is CH.

[0078] In certain embodiments (V), T is N and each of U and V is CH.

[0079] In certain embodiments (V), Rais H.

[0080] In certain embodiments (V), RW1is NH2.

[0081] In certain embodiments of (I)-(IIIB), W is W2.

[0082] In certain embodiments, W2is a 5 : 5 fused bicyclic.

[0083] In certain embodiments, W2is a 5 : 6 fused bicyclic.

[0084] In certain embodiments, W2is a 6 : 5 fused bicyclic.

[0085] In certain embodiments, W2is a 6 : 6 fused bicyclic.

[0086] In certain embodiments of (I)-(IIIB), Y is a single bond and W2has the structural formula:Patent ApplicationAtty. Docket No. ENTX-034PCT(VI) whereinRW2is N R'; m is 0, 1, 2, 3 or 4;J is N, NRb, CRa, O or S;K is N, NRb, CRa, O or S;L is N, NRb, CRa, O or S; each Rais independently R, halo, CN or OR; and each Rbis independently R.

[0087] In certain embodiments of (I)-(IIIB), Y is a single bond and W2has the structural formula:whereinRW2is NRR'; m is 0, 1, 2, 3 or 4;T is N or CRa;U is N or CRa;V is N or CRa; and each Rais independently R, halo, CN or OR.

[0088] In certain embodiments of (I)-(IIIB), each of RX1and RX2is independently selected from H, F and Cl.

[0089] In certain embodiments of (I)-(IIIB), each of RX1and RX2is H.

[0090] In certain embodiments of (I)-(IIIB), one of RX1and RX2is H and the other is F or Cl.

[0091] In certain embodiments of (I)-(IIIB), each of RX1and RX2is F or Cl.

[0092] In certain embodiments of (I)-(IIIB), at least one of RX1and RX2is an unsubstituted or substituted C1-3 alkyl.Patent ApplicationAtty. Docket No. ENTX-034PCT

[0093] In certain embodiments of (I)-(IIIB), each of R10a, R10b, Rllaand Rllbis H.

[0094] In certain embodiments of (I)-(IIIB), each of R10a, R10band Rllais H, and Rl lbis R,OR or halo.

[0095] In certain embodiments of (I)-(IIIB), each of R10a, Rl laand Rllbis H, and R10bis R, OR or halo.

[0096] In certain embodiments of (I)-(IIIB), if present R6is H.

[0097] In certain embodiments of (I)-(IIIB), if present R6is F.

[0098] In certain embodiments of (I)-(IIIB), if present R6is Cl.

[0099] In certain embodiments of (I)-(IIIB), if present R6is C1-3 alkyl or C3-4 cycloalkyl.

[0100] In certain embodiments of (I)-(IIIB), if present R6is CH2F, CHF2 or CF3.

[0101] In certain embodiments of (I)-(IIIB), if present R6is CN, S(O)2R, NRR’, OR orC(O)NRR’.

[0102] In certain embodiments of (I)-(IIIB), z is 1.

[0103] 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’.

[0104] In certain embodiments of (I)-(IIIB), R2is C3-5 carbocyclic ring substituted with 0-5 R2A.

[0105] In certain embodiments of (I)-(IIIB), R2is selected from:

[0106] In certain embodiments of (I)-(IIIB), R2is C3-5 heterocyclic ring substituted with 0-5 R2A.

[0107] In certain embodiments of (I)-(IIIB), R2is selected from:Patent ApplicationAtty. Docket No. ENTX-034PCT

[0108] In certain embodiments of (I)-(IIIB), R2is a bicyclic, unsubstituted or substituted Ce- io heterocyclic ring.

[0109] In certain embodiments of (I)-(IIIB), R2is selected from:Patent ApplicationAtty. Docket No. ENTX-034PCTPatent ApplicationAtty. Docket No. ENTX-034PCT

[0111] 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.

[0112] 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.

[0113] In certain embodiments has the structural formula:(VIIIA)

[0114] In certain embodiments has the structural formula:Patent ApplicationAtty. Docket No. ENTX-034PCT(VIIIB)

[0115] In certain embodiments of (VIII)-(VIIIB), Q is N.

[0116] In certain embodiments of (VIII)-(VIIIB), R7has the structural formula:(VIIIC)

[0117] In certain embodiments of (VIII)-(VIIIB), R7has the structural formula:(VIIID)

[0118] In certain embodiments of (VIII)-(VIIIB), Q is CR7E.

[0119] In certain embodiments of (VIII)-(VIIIB), R7Eis H.

[0120] In certain embodiments of (VIII)-(VIIIB), R7Eis F.

[0121] In certain embodiments of (VIII)-(VIIIB), R7Eis CN.

[0122] In certain embodiments of (VIII)-(VIIIB), R7Dis NH2.

[0123] In certain embodiments of (VIII)-(VIIIB), R7Dis OR.

[0124] In certain embodiments of (VIII)-(VIIIB), R7Ais CF3.

[0125] In certain embodiments of (VUI)-(VHIB), R7Ais cyclopropyl.

[0126] In certain embodiments of (VIII)-(VIIIB), R7Bis C1-3 alkyl.

[0127] In certain embodiments of (VIII)-(VIIIB), R7Bis methyl

[0128] In certain embodiments of (VIII)-(VIIIB), R7C, if present, is F.

[0129] In certain embodiments of (VIII)-(VIIIB), R7C, if present, is H.

[0130] In certain embodiments of (I)-(IIIB), R7is selected from:Patent ApplicationAtty. Docket No. ENTX-034PCT

[0131] In certain embodiments of (I)-(IIIB), R7is selected from:

[0132] In certain embodiments of (I)-(IIIB), R7is an unsubstituted or substituted 9- or 10- membered bicyclic aryl or heteroaryl ring, comprising 0-5 heteroatoms selected from N, O and S.

[0133] In certain embodiments of (I)-(IIIB), R7has the structure formula (V):Patent ApplicationAtty. Docket No. ENTX-034PCT(IX) 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; each of p and q is independently 0, 1, 2 or 3; and each k is independently 0, 1 or 2.

[0134] In certain embodiments of (IX), Ring A is a 6-membered aryl ring.

[0135] In certain embodiments of (IX), Ring A is a 6-membered heteroaryl ring.

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

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

[0138] In certain embodiments of (IX), Ring B is a 5-membered heteroaryl ring.

[0139] In certain embodiments of (IX), Ring B is a 6-membered heteroaryl ring.

[0140] In certain embodiments of (IX), Ring B is a 6-membered aryl ring.

[0141] In certain embodiments of (I)-(IIIB), R7is selected from:Patent ApplicationAtty. Docket No. ENTX-034PCT

[0142] In certain embodiments of (I)-(IIIB), R7is selected from:

[0143] In certain embodiments of (I)-(IIIB), R7is selected from:

[0144] In certain embodiments of (I)-(IIIB), R8is F.

[0145] In certain embodiments of (I), the compound has the structural formula:Patent ApplicationAtty. Docket No. ENTX-034PCTwhereinRW1is NRR';T is N or CRa;U is N or CRa;V is N or CRa; and each Rais independently R, halo, CN or OR.

[0146] In certain embodiments of (I), the compound has the structural formula:whereinRW1is NRR';J is N, NRb, CRa, O or S;K is N, NRb, CRa, O or S;L is N, NRb, CRa, O or S; each Rais independently R, halo, CN or OR; and each Rbis independently R.

[0147] In certain embodiments of (I), the compound has the structural formula:Patent ApplicationAtty. Docket No. ENTX-034PCTwhereinRW2is NRR';T is N or CRa;U is N or CRa;V is N or CRa; and each Rais independently R, halo, CN or OR.

[0148] In certain embodiments of (I), the compound has the structural formula:whereinRW2is NRR';J is N, NRb, CRa, O or S;K is N, NRb, CRa, O or S;L is N, NRb, CRa, O or S; each Rais independently R, halo, CN or OR; and each Rbis independently R.

[0149] In certain embodiments of (I), the compound has the structural formula:Patent ApplicationAtty. Docket No. ENTX-034PCTwhereinRW1is NRR';T is N or CRa;U is N or CRa;V is N or CRa; and each Rais independently R, halo, CN or OR

[0150] In certain embodiments of (I), the compound has the structural formula:whereinRW1is NRR';J is N, NRb, CRa, O or S;K is N, NRb, CRa, O or S;L is N, NRb, CRa, O or S; each Rais independently R, halo, CN or OR; and each Rbis independently R.

[0151] In certain embodiments of (I), the compound has the structural formula:Patent ApplicationAtty. Docket No. ENTX-034PCTwhereinRW2is NRR';T is N or CRa;U is N or CRa;V is N or CRa; and each Rais independently R, halo, CN or OR.

[0152] In certain embodiments of (I), the compound has the structural formula:whereinRW2is NRR';J is N, NRb, CRa, O or S;K is N, NRb, CRa, O or S;L is N, NRb, CRa, O or S; each Rais independently R, halo, CN or OR; and each Rbis independently R.

[0153] In certain embodiments of (IIa)-(IId), R6is F.Patent ApplicationAtty. Docket No. ENTX-034PCT

[0154] In certain embodiments of (IIa)-(IId), R6is Cl.

[0155] In certain embodiments of (IIa)-(IIId), R8is F.

[0156] In certain embodiments of (IIa)-(IHd), each of R10a, R10band Rl lais H.

[0157] In certain embodiments of (I)-(IIIB), the compound is selected from Table 1.

[0158] In certain embodiments of (I)-(IIIB), the compound is selected from Table 2.

[0159] In certain embodiments of (I)-(IIIB), the compound is selected from Table 3.

[0160] In certain embodiments of (I)-(IIIB), the compound is selected from Table 4.

[0161] In certain embodiments of (I)-(IIIB), the compound has one or more deuterium atoms in place of hydrogen.

[0162] In certain embodiments of (I)-(IIIB), the compound has one deuterium atom in place of a hydrogen atom.

[0163] In another aspect, the invention generally relates to a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, or diluent.

[0164] In certain embodiments, the pharmaceutical composition is suitable for oral administration.

[0165] In yet another aspect, the invention generally relates to a unit dosage form comprising a pharmaceutical composition of the invention.

[0166] In certain embodiments, the unit dosage form is a tablet.

[0167] In certain embodiments, the unit dosage form is a capsule.

[0168] In certain embodiments, the unit dosage form is a liquid emulsion of suspension.

[0169] 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.

[0170] 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.

[0171] 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.

[0172] In certain embodiments, the KRas mutant is selected from mutants of G12C, G12D and G12V.Patent ApplicationAtty. Docket No. ENTX-034PCT

[0173] 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.

[0174] In certain embodiments, the cancer is selected from the group consisting of carcinoma, squamous carcinoma, adenocarcinoma, sarcoma, leukemia, neuroma, melanoma, and lymphoma.

[0175] 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.

[0176] In certain embodiments, the subject has a mutation of KRAS, HRAS and / or NRAS.

[0177] In certain embodiments, the subject being treated is further administered one or more of chemotherapy, radiotherapy, targeted therapy, immunotherapy, and hormonal therapy.

[0178] 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.

[0179] In certain embodiments of the use, the disease or disorder is cancer.

[0180] 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.

[0181] 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.

[0182] Non-limiting examples of compounds of the invention include those listed in Table 1.Table 1. Exemplary CompoundsPatent ApplicationAtty. Docket No. ENTX-034PCTPatent ApplicationAtty. Docket No. ENTX-034PCTPatent ApplicationAtty. Docket No. ENTX-034PCTPatent ApplicationAtty. Docket No. ENTX-034PCTPatent ApplicationAtty. Docket No. ENTX-034PCTPatent ApplicationAtty. Docket No. ENTX-034PCTPatent ApplicationAtty. Docket No. ENTX-034PCTPatent ApplicationAtty. Docket No. ENTX-034PCTPatent ApplicationAtty. Docket No. ENTX-034PCTPatent ApplicationAtty. Docket No. ENTX-034PCT

[0183] Non-limiting examples of compounds of the invention also include those listed inTable 2.Patent ApplicationAtty. Docket No. ENTX-034PCTTable 2. Exemplary CompoundsPatent ApplicationAtty. Docket No. ENTX-034PCTPatent ApplicationAtty. Docket No. ENTX-034PCTPatent ApplicationAtty. Docket No. ENTX-034PCTPatent ApplicationAtty. Docket No. ENTX-034PCTPatent ApplicationAtty. Docket No. ENTX-034PCTPatent ApplicationAtty. Docket No. ENTX-034PCTPatent ApplicationAtty. Docket No. ENTX-034PCT

[0184] In certain embodiments, compounds of the invention are selected from Table 3.Table 3. Exemplary CompoundsPatent ApplicationAtty. Docket No. ENTX-034PCTPatent ApplicationAtty. Docket No. ENTX-034PCTPatent ApplicationAtty. Docket No. ENTX-034PCT

[0185] In certain embodiments, compounds of the invention are selected from Table 4.Table 4. Exemplary CompoundsPatent ApplicationAtty. Docket No. ENTX-034PCTPatent ApplicationAtty. Docket No. ENTX-034PCTPatent ApplicationAtty. Docket No. ENTX-034PCTPatent ApplicationAtty. Docket No. ENTX-034PCT

[0186] In certain embodiments, compounds of the invention have one or more deuterium atoms in place of hydrogen atoms.

[0187] In certain embodiments, compounds of the invention have 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.Patent Application Atty. Docket No. ENTX-034PCT

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

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

[0191] In certain embodiments, the unit dosage form is in the form of a tablet or capsule.

[0192] 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.

[0193] In yet another aspect, the invention generally relates to a method for modulating (e.g., inhibiting or reducing) KRas(G12D) activity in a cell, comprising contacting the cell with a compound disclosed herein.

[0194] 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.

[0195] 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.

[0196] 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.

[0197] 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.

[0198] In certain embodiments, the cancer is selected from the group consisting of carcinoma, squamous carcinoma, adenocarcinoma, sarcoma, leukemia, neuroma, melanoma, and lymphoma.

[0199] Examples of cancers targeted in the present invention include, but are not particularly limited to, head 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.), hmg cancer (e g., nonsmall-cell lung cancer, small-cell lung cancer, and mesothelioma), breast cancer, genital cancerPatent ApplicationAtty. Docket No. ENTX-034PCT(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, 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.

[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, a subject suffering from any of the disease selected from the above does not have to have KRAS G12D mutant protein. In certain embodiments, a subject suffering from any of the disease selected from the above has KRAS G12D mutant protein.

[0202] In certain embodiments, the subject has a mutation of KRAS, HR AS and / or NRAS.

[0203] 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.

[0204] 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 ofPatent Application Atty. Docket No. ENTX-034PCT the disease or condition being treated or the nature of the therapy being used and on the nature of the active compound.

[0205] 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 predetermined 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.

[0206] 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.

[0207] 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.Patent ApplicationAtty. Docket No. ENTX-034PCT

[0208] 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.

[0209] Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes 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.

[0210] 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.

[0211] 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,Patent ApplicationAtty. Docket No. ENTX-034PCT 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.

[0212] 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.

[0213] 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.

[0214] 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.

[0215] 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 furtherPatent Application Atty. Docket No. ENTX-034PCT administered one or more of chemotherapy, radiotherapy, targeted therapy, immunotherapy, and hormonal therapy.

[0216] 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. Food 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.

[0217] 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.

[0218] 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.

[0219] 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.

[0220] In certain embodiments, the method further comprises administering a chemotherapeutic agent to the subject.

[0221] 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.

[0222] 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),Patent ApplicationAtty. Docket No. ENTX-034PCTOxaliplatin (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® 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; pancrati statin; 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 deoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone,Patent ApplicationAtty. Docket No. ENTX-034PCT 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; an 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; capeci tabine (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.

[0223] 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 andPatent ApplicationAtty. Docket No. ENTX-034PCT the like), immunotherapic agents (e.g., interleukin, interferon and the like) and antihormonal agents (e.g., tamoxifen, raloxifene and the like).

[0224] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and Zra / rs-i somers, R- and 5-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.

[0225] 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.

[0226] 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.

[0227] 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,lyN,18O,170,31P,32P,35S,18F, and36C1, respectively.

[0228] 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)Patent ApplicationAtty. Docket No. ENTX-034PCT 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. Isotopically labeled compounds presently disclosed, including pharmaceutical salts, esters, and prodrugs thereof, can be prepared by any means known in the art.

[0229] 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.)

[0230] 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.

[0231] 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.

[0232] 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.

[0233] 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.

[0234] 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),Patent ApplicationAtty. Docket No. ENTX-034PCT 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.

[0235] 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.

[0236] 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.

[0237] 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.

[0238] 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 andPatent ApplicationAtty. Docket No. ENTX-034PCT 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 and 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

[0239] The following examples are given for the purpose of illustrating the invention, but not for limiting the scope or spirit of the invention.

[0240] 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,T-binaphthylBMS = Borane-methylsulphide complex Bn = BenzylBoc = tert-Butoxy carbonylBOP = Bis(2-oxo-3-oxazolidinyl)phosphinePatent ApplicationAtty. Docket No. ENTX-034PCTBu or n-Bu = n-Butyl s-Bu or sBu = sec-Butyl t-Bu or tBu = tert-Butyl t-BuOH = tert-ButanolBz = BenzoylBzl = 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 azodi carb oxy lateDIBAL = 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 = l,2-bis(diphenylphosphino)ferrocene dppp = l,3-bis(diphenylphosphino)propaneDtbbpy = 4, 4’-di-tert-butyl-2,2’-dipyridylEDC = l-Ethyl-3-(3-dimethylaminopropy)carbodiimidePatent ApplicationAtty. Docket No. ENTX-034PCTEDCI = l-Ethyl-3-(3-dimethylaminopropy)carbodiimide hydrochlorideEq = equivalentESI or ES = Electrospray ionizationEt = ethylEt O = Diethyl etherEtOAc = 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 -Hydroxy benzotri 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]dichloropalladiumPatent ApplicationAtty. Docket No. ENTX-034PCTPd(PPh3)4 = tetrakis(triphenylphosphine)palladium PCC = Pyridinium chlorochromatePE = Petroleum etherPh = PhenylPiv = Pivaloyl, 2,2-dimethylacetylPMB = 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 chromatographySEM = 2-(Trimethylsilyl)ethoxymethyl TBAF = Tetrabutylammonium fluoride TBDMS = tert-Butyldimethylsilyl TBDPS = tert-Butyldiphenylsilyl TBHP = tert-Butylhydroperoxyde TBS = tert-ButyldimethylsilylTEA = 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 = Trimethylsilyl Tol = p-ToluylTPAP = Tetra-n-propylammonium perruthenatePatent ApplicationAtty. Docket No. ENTX-034PCTTPS = TripropylsilylTr = Trityl, triphenylmethylTroc = 2,2,2-TrichloroethoxycarbonylTrt = Trityl, triphenylmethylTs = p-Toluenesulphonyl p-TsOH = p-Toluenesulphonic acidUV = ultravioletZ = BenzyloxycarbonyGeneral Synthetic Schemes

[0241] Scheme 1 illustrates a procedure for preparing the compounds of disclosure to prepare tricyclic quinazoline derivative IX. 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 a substituted homoallylic amine provides 4-amine- substituted quinazoline intermediate VI. Relacing 2-chloro with alcohol provided 2-substituted ether VII. Palladium-catalyzed intramolecular Heck reaction provided the tricyclic core compound VIII. After deprotonation and zincate formation, Pd-catalyzed Negishi coupling with a suitable aryl halide followed by necessary deprotection affords the aryl-aryl coupling product IX. The axial chiral mixture can be submitted to SFC separation if the single diastereomer is the desired product.Scheme 1:Patent ApplicationAtty. Docket No. ENTX-034PCT1. Pd(ll),Pd(H) Nigeshi coupling Intramolecular 2. Deprotection Heck reaction

[0242] Scheme 2 illustrates another procedure for preparing the tricyclic aza-quinazoline derivates X from 2,6-dichloro-5-fluoronicotinic acid I. Selective deprotonation and quenching with l,2-dichloro-l,l,2,2-tetrafluoroethane afforded fully substituted nicotinic acid intermediate II. After generation of acid chloride and 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 a substituted homoallylic amine provides 4-amine-substituted aza-quinazoline intermediate VI. Palladium-catalyzed intramolecular Heck reaction provided the tricyclic core compound VII. Oxidation of thiomethyl group by oxidation gave methyl sulfone VIII, which can be replaced by alcohol to afford the chloro- intermediate IX. Suzuki coupling and necessary deprotection provided the desired target compound X.Patent ApplicationAty. Docket No. ENTX-034PCTScheme 2:Intermediate Syntheses:Intermediate 1:(R)-3-(l-(but-3-en-l-ylamino)ethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amineSynthetic scheme:Patent ApplicationAtty. Docket No. ENTX-034PCT

[0243] Step 1: To a stirred mixture of 3-bromopyridin-2-amine (15 g, 86.7 mmol) in DMF (60 mL) was added NaH (10.4 g, 260 mmol) slowly at 0 °C. After stirred at 0 °C for Ih, 4- (chl orom ethyl)- 1 -methoxybenzene (35 mL, 260 mmol) was added. After stirred at 50 °C for Ih, the mixture was quenched with ice-water and extracted with EtOAc (50 mL*3). The combined organic phase was washed with brine, dried with Na2SC>4, filtered and concentrated. The residue was purified by silica gel chromatography (0-6 %, EtOAc in PE) to give 2-{bis[(4- methoxyphenyl) methyl]amino}-3-bromopyridine (30 g, 72.6 mmol, 84%) as a colorless oil. LCMS: m / z 413 [M+H]+.

[0244] Step 2: To a solution of 2-{bis[(4-methoxyphenyl)methyl]amino}-3-bromopyridine (20 g, 48.4 mmol) in toluene (200 mL) was added tributyl( 1 -ethoxy vinyl )-Z4-stannane (26.2 g, 72.6 mmol) and Pd(PPha)C12 (3.4 g, 4.84 mmol). The mixture was stirred at 100 °C overnight. The cooled mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 10 mL). The organic layers were washed with water (2 x 20 mL), brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude 2-{bis[(4- methoxyphenyl)methyl]amino}-3-(l-ethoxyvinyl)pyridine (15 g, 37.1 mmol, 77%) as a brown liquid. LCMS: m / z 405 [M+H]+.

[0245] Step 3: A mixture of 2-{bis[(4-methoxyphenyl)methyl]amino}-3-(l- ethoxyvinyl)pyridine (8 g, 19.7 mmol) in HCl / dioxane (20 mL, IN, 20 mmol) was stirred at rt for 2h. The reaction mixture was adjusted the pH to 6~ 7 with aqueous NaHCOa solution. The mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 20 mL). The organicPatent ApplicationAtty. Docket No. ENTX-034PCT layers were washed with brine (30 mL), dried over Na2SC>4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0- 10 %, EtOAc in PE) to give l-(2-{bis[(4- methoxyphenyl)methyl]amino}pyridin-3-yl)ethan-l-one (5.5 g, 14.6 mmol, 74%) as a yellow oil. LCMS: m / z 377 [M+H]+.

[0246] Step 4: To a solution of l-(2-{bis[(4-methoxyphenyl)methyl]amino}pyridin-3- yl)ethan-l-one (5.5 g, 13.7 mmol) in THF (50 mL) was added (S)-(2-methylprop-2-yl)(oxo)-X4- sulfanamine (1.93 g, 15.9 mmol) and titanium(4+) tetrakis(ethanolate) (9.1 g, 39.8 mmol). The mixture was stirred at 120 °C to neat 3 times. The mixture was diluted with water, and filtered and extracted with EtOAc (3 x 10 mL). The organic layers were washed with water (2 x 20 mL), brine (30 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-60 %, EtOAc in PE) to give (lE)-l-(2-{bis[(4- methoxyphenyl)methyl]amino}pyridin-3-yl)-N-[(S)-(2-methylprop-2-yl)(oxo)-X4- sulfanyl]ethanimine (4.6 g, 4.79 mmol, 70%) as a yellow oil. LCMS: m / z 480 [M+H]+.1H NMR (400 MHz, DMSO) 8 8.24 (d, J= 3.4 Hz, 1H), 7.63 (d, J = 6.2 Hz, 1H), 7.04 (d, J = 8.4 Hz, 4H), 6.95 (dd, J= 1A, 4.8 Hz, 1H), 6.84 (d, J= 8.5 Hz, 4H), 4.41 (d, J= 14.8 Hz, 2H), 4.28 (d, J= 14.9 Hz, 2H), 3.71 (s, 6H), 2.62 (s, 3H), 1.19 (S, 9H).

[0247] Step 5: To a solution of (lE)-l-(2-{bis[(4-methoxyphenyl)methyl]amino}pyridin-3- yl)-N-[(S)-(2-methylprop-2-yl)(oxo)-L4-sulfanyl]ethanimine (4.6 g, 4.79 mmol) in THF (20 mL) was added L-SELECTRIDE(R) (7.2 mL, 7.19 mmol) slowly at -65 °C. After stirred at 0 °C for 1 h, the mixture was diluted with water and extracted with EtOAc (3 x 10 mL). The organic layers were washed with water (2 x 20 mL), brine (30 mL), dried overNa2SO4, filtered. The residue was purified by chromatography (silica gel, 0-80 %, EtOAc in PE) to give 2-{bis[(4-methoxyphenyl)methyl]amino}-3-[(lR)-l-{[(S)-(2-methylprop-2-yl)(oxo)-X4- sulfanyl]amino} ethyl]pyridine (4 g, 4.15 mmol, 86%) as a yellow oil. LCMS: ESI m / z 482 [M + H]+. 'H NMR (400 MHz, DMSO) 8 8.20 (dd, J= 4.6, 1.7 Hz, 1H), 7.88 (dd, J= 7.6, 1.6 Hz, 1H), 7.15 (d, J = 8.5 Hz, 4H), 7.09 (dd, J= 7.6, 4.7 Hz, 1H), 6.83 (d, J= 8.5 Hz, 4H), 5.44 (d, J= 7.1 Hz, 1H), 4.96 (t, J= 6.8 Hz, 1H), 4.16 - 4.04 (m, 4H), 3.70 (s, 6H), 1.23 (d, J= 6.6 Hz, 4H), 1.09 (s, 9H).

[0248] Step 6: To a stirred solution of 2-{bis[(4-methoxyphenyl)methyl]amino}-3-[(lR)-l- {[(S)-(2-methylprop-2-yl)(oxo)-X4-sulfanyl]amino}ethyl]pyridine (3.5 g, 7.1 mmol) in MeOH (8 mL) was added HC1 / EA (1 mL, 4.0 mmol, 4 N) at rt. After stirred at rt for 2h, the mixturePatent ApplicationAtty. Docket No. ENTX-034PCT was quenched with NaHCCh (aq) and extracted with EtOAc (20 mL*2). The combined organic phase was washed with brine, dried with NazSCh, fdtered and concentrated. The residue was purified by chromatography (silica gel, 0- 50 %, EtOAc in PE) to give (lR)-l-(2-{bis[(4- methoxyphenyl)methyl]amino}pyridin-3-yl)ethan-l-amine (1.9 g, 5.1 mmol, 66%) as a yellow oil. LCMS: m / z 378 [M+H]+. ’H NMR (400 MHz, DMSO) 5 8.16 (dd, J= 4.7, 1.8 Hz, 1H), 7.86 (dd, J= 7.6, 1.8 Hz, 1H), 7.15 (d, J = 8.6 Hz, 4H), 7.05 (dd, J= 7.6, 4.7 Hz, 1H), 6.83 (d, J= 8.7 Hz, 4H), 4.56 (d, J= 6.6 Hz, 1H), 4.13 (dd, J= 29.2, 14.0 Hz, 4H), 3.71 (d, J= 7.4 Hz, 7H), 1.17 (d, J = 6.5 Hz, 4H).

[0249] Step 7: To a stirred mixture of (lR)-l-(2-{bis[(4- methoxyphenyl)methyl]amino}pyridin-3-yl)ethan-l-amine (1.7 g, 4.5 mmol) in DMA (20 mb) was added NaH (0.22 g, 9.0 mmol, 60% in mineral oil) slowly at 0 °C. After stirred at 0 °C for 30 min, 4-bromobut-l-ene (1.8 g, 13.5 mmol) was poured into the mixture. After stirred at 50 °C for Ih, the mixture was quenched with ice-water and extracted with EtOAc (3 x 20 mb). The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0- 60 %, EtOAc in PE) to give 2-{bis[(4-methoxyphenyl)methyl]amino}-3-[(lR)-l-(but-3-enylamino)ethyl]pyridine (1.6 g, 3.7 mmol, 82%) as a colorless oil. LCMS: 432 [M+H+], 'H NMR (400 MHz, DMSO) 5 8.17 (d, J= 3.2 Hz, IH), 7.80 (dd, J= 7.6, 1.7 Hz, IH), 7.16 (d, J= 8.6 Hz, 4H), 7.06 (dd, J= 7.6, 4.7 Hz, IH), 6.82 (d, J= 8.6 Hz, 4H), 5.76 - 5.61 (m, IH), 4.96 - 4.87 (m, 2H), 4.33 - 4.22 (m, IH), 4.13 - 4.03 (m, 4H), 3.70 (s, 6H), 3.36 (s, IH), 2.27 (s, IH), 2.07 - 1.99 (m, 3H), 1.15 (d, J= 6.4 Hz, 3H).Intermediate 2:5-bromo-2,4,6-trichloro-8-fluoroquinazolineSynthetic scheme:Patent ApplicationAtty. Docket No. ENTX-034PCT

[0250] Step 1: To a solution of 5-bromo-4-chloro-2-fluoroaniline (24.5 g, 109.15 mmol, 1.0 eq) in EtOH (490 mL) was added iodine (30.47 g, 120.07 mmol, 1.1 eq), silver sulfate (30.03 g, 109.15 mmol, 1.0 eq). The mixture was stirred at 25 °C for 2 h. The mixture was filtered, and the filtrate was concentrated to give a crude product, which was purified by silica gel column chromatography (petroleum ether) to afford 3-bromo-4-chloro-6-fluoro-2-iodoaniline (33 g, 86.3%) as a red solid. Tf NMR (400 MHz, DMSO ): 3 7.54 (d, J= 10.8 Hz, 1H), 5.66 (s, 2H).

[0251] Step 2: To a solution of 3-bromo-4-chloro-6-fhtoro-2-iodoaniline (20.0 g, 57.09 mmol, 1.0 eq) in MeOH (90 mL) was added DMF (135 mL), TEA (17.33 g, 171.26 mmol, 3.0 eq), Pd(OAc)2 (641 mg, 2.85 mmol, 0.05 eq) and dppf (791 mg, 1.43 mmol, 0.025 eq). The mixture was stirred at 75 °C for 15 h under 0.4 MPa CO. The mixture was concentrated, diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The organic layers were washed with water (100 mL x 2), brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether: EtOAc = 80: 1) to afford methyl 2-amino-6-bromo-5-chloro-3-fluorobenzoate (9.0 g, 55.8%) as a red liquid. Ti NMR (300 MHz, DMSO-tL): d 7.52 (d, J= 11.1 Hz, 1H), 5.80 (s, 2H), 3.86 (s, 3H).

[0252] Step 3: To a solution of methyl 2-amino-6-bromo-5-chloro-3-fluorobenzoate (8.95 g, 31.68 mmol, 1.0 eq) in MeOH (160 mL) was added NaOH (3.8 g, 95.05 mmol, 3.0 eq) in water (160 mL). The mixture was stirred at 45 °C for 18 h. The reaction mixture was concentrated under reduced pressure to remove MeOH. The resulting mixture was adjusted the pH to ~ 1 with aqueous HC1 solution. Then the mixture was filtered, dried to give 2-amino-6-bromo-5-chloro-3- fluorobenzoic acid (7.6 g, 89.4%) as a white solid. LCMS: 265.8 (M-H ).Patent ApplicationAtty. Docket No. ENTX-034PCT

[0253] Step 4: To a solution of 2-amino-6-bromo-5-chloro-3-fluorobenzoic acid (2 g, 7.45 mmol, 1.0 eq) in DCM (10 mL)-was added chlorosulfonyl isocyanate (2.64 g, 18.63 mmol, 2.5 eq) under N2 at 0 °C. The mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure to give a crude product, which was added 6N HC1 (600 mb) and stirred 2 h at 100 °C. Then the mixture was cooled to room temperature slowly, solid was precipitated, the mixture was fdtered, dried to give 5-bromo-6-chloro-8-fluoroquinazoline- 2,4-diol (1.56 g, 71.4%) as a yellow solid. LCMS: 290.8 (M-H‘).

[0254] Step 5: To a solution of 5-bromo-6-chloro-8-fluoroquinazoline-2,4-diol (3.0 g, 10.22 mmol, 1.0 eq) in POCI3 (30 mL) was added DIEA (3.0 mL). The mixture was stirred at 110 °C for 5 h under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to give 5-bromo-2,4,6-trichloro-8-fluoroquinazoline (4.2 g, crude) as a brown oil.Intermediate 3:(R)-N-(l-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-5-bromo-N-(but-3-en-l-yl)-2,6-dichloro-8-fluoroquinazolin-4-amineSynthetic scheme:

[0255] Step 1: To a stirred mixture of 5-bromo-2,4,6-trichloro-8-fluoroquinazoline (459 mg, 1 .3 mmol) in dioxane (6 mL) was added DIEA (6 mL, 0.232 mmol) and 2-{bis[(4- methoxyphenyl)methyl]amino}-3-[(lR)-l-(but-3-enylamino)ethyl]pyridine (500 mg, 1.1Patent ApplicationAtty. Docket No. ENTX-034PCT mmol) slowly at rt. After stirred at 60 °C for 2h, the mixture was quenched with ice-water and extracted with EtOAc (20 mL*3). 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 5-bromo-2,6-dichloro-8-fluoro-4-{[(lR)-l-(2-{bis[(4- methoxyphenyl)methyl]amino}pyridin-3-yl)ethyl](but-3-enyl)amino}quinazoline (470 mg, 0.64 mmol, 56%) as a yellow oil. LCMS: 724 [M+H+],Intermediate 4:3-((R)-l-(8-chloro-10-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)-7-methylene-6,7-dihydroazepino[2,3?4-de]quinazolin-4(5H)-yl)ethyl)-N,N- bis(4-methoxybenzyl)pyridin-2-aminePatent ApplicationAtty. Docket No. ENTX-034PCT

[0256] Step 1: To a stirred mixture of 5-bromo-2,6-dichloro-8-fluoro-4-{[(lR)-l-(2-{bis[(4- methoxyphenyl)methyl]amino}pyridin-3-yl)ethyl](but-3-enyl)amino}quinazoline (420 mg, 0.58 mmol) in THF (5 mL) was added DIEA (448 mg, 3.5 mmol) and [(2R,7aS)-2-fluoro- 2,3,5,6,7,7a-hexahydro-lH-pyrrolizin-7a-yl]methanol (460 mg, 2.9 mmol) slowly at rt. The reaction was stirred at 130 °C for 30 min (neat). This procedure was repeated 3 times. The residue was purified by chromatography (silica gel, 0- 10 %, MeOH in DCM) to give 5-bromo- 6-chloro-8-fluoro-2-({[(2R,7aS)-2-fluoro-2,3,5,6,7,7a-hexahydro-lH-pyrrolizin-7a- yl]methyl}oxy)-4-{[(lR)-l-(2-{bis[(4-methoxyphenyl)methyl]amino}pyridin-3-yl)ethyl](but-3- enyl)amino}quinazoline (380 mg, 0.45 mmol, 77%) as a brown solid. LCMS: m / z 847 [M+H]+.

[0257] Step 2: To a solution of 5-bromo-6-chloro-8-fluoro-2-({[(2R,7aS)-2-fluoro- 2,3,5,6,7,7a-hexahydro-lH-pyrrolizin-7a-yl]methyl}oxy)-4-{[(lR)-l-(2-{bis[(4- methoxyphenyl)methyl]amino}pyridin-3-yl)ethyl](but-3-enyl)amino}quinazoline (180 mg, 0.2 mmol) in DMA (2 mL) was added Pd(OAc)2 (10 mg, 0.04 mmol), PPhs (20 mg, 0.06 mmol) and CS2CO3 (77 mg, 0.23 mmol) at room temperature under nitrogen atmosphere. The mixture was stirred at 100 °C for 1 h under N2. The mixture was quenched with ice-water and extracted with EtOAc (3x10 mL). The combined organic phase was washed with brine, dried with Na2SO4, filtered. The residue was purified by chromatography (silica gel, 0- 80 %, EtOAc in PE) to give 4-[(lR)-l-(2-{bis[(4-methoxyphenyl)methyl]amino}pyridin-3-yl)ethyl]-8- chloro- 10-fluoro-2-( { [(2R,7aS)-2-fluoro-2, 3 , 5 , 6,7, 7 a-hexahy dro- 1 H-pyrrolizin-7a- yl]methyl}oxy)-7-methylidene-4,5,6,7-tetrahydroazepino[2,3,4-de]quinazoline (80 mg, 0.06 mmol, 55%) as a brown solid. LCMS: m / z 767 [M+H]+.Intermediate 56-bromo-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amineSynthetic scheme:Patent ApplicationAtty. Docket No. ENTX-034PCT

[0258] Step 1: To a solution of 2,6-dichloro-4-methylpyridine (145 g, 895 mmol, 1.0 eq) in PMBNH2 (725 mL) was stirred at 120 °C for 16 h. The mixture was added dropwise water / isopropanol = 2 / 1 (2 L) at 85 °C. Then the mixture was cooled to rt and stirred at rt for 1 h. The mixture was filtrated to afford 6-chloro-N-(4-methoxybenzyl)-4-methylpyridin-2-amine (217 g, 92.3%) as a gray solid. LCMS: m / z 263.1 (M+H+).

[0259] Step 2: To a solution of 6-chloro-N-(4-methoxybenzyl)-4-methylpyridin-2-amine (124 g, 472 mmol, 1.0 eq) in THF (1 L) was added PMBC1 (88.7 g, 566 mmol, 1.2 eq) and t- BuOK (79.4 g, 708 mmol, 1.5 eq) at 0 °C. The mixture was stirred at rt for 6 h. The mixture was added H2O, filtrated, and washed the cake with H2O. Then the cake was stirred in H2O: isopropanol (2:1) (1 L) at rt for overnight. Centrifuged again and washed cake with H2O: isopropanol =2:1 for two times. The cake was collected, and the solids dried at least 16 h at 45 °C. The cake is 6-chloro-N,N-bis(4-methoxybenzyl)-4-methylpyridin-2-amine (162 g, 90%) as a white solid. LCMS: m / z 383.0 (M+H+).

[0260] Step 3: To a solution of 6-chloro-N,N-bis(4-methoxybenzyl)-4-methylpyridin-2- amine (229 g, 598 mmol, 1.0 eq) in DMF (1 L) was added NIS (161.5 g, 718 mmol, 1.2 eq). The solution was stirred at rt overnight. The mixture was cooled to 0±5°C before adding dropwise 5 wt% aq. Na2SOs (1 L) at -5~25°C. After being stirred for at least 30 min at 5±5°C. the solution was centrifuged and washed the cake with soften water for two times. Collected the figure cake and triturated with soften water / isopropanol = 2 / 1 (1 L) for at least 30 min at 70±5°C. Cooled to 20±5°C, stirred for at least 1 hour at 20±5°C. Centrifuged again and washed the cake with water / isopropanol = 2 / 1 for two times. Collected the solids and dried at least 16 hours at 45±5°C.Patent ApplicationAtty. Docket No. ENTX-034PCTThe solid was 6-chloro-5-iodo-N,N-bis(4-methoxybenzyl)-4-methylpyridin-2-amine (190 g, 62.4%) as a white solid. LCMS: m / z 509.0 (M+H+).

[0261] Step 4: To a solution of 6-chloro-5-iodo-N,N-bis(4-methoxybenzyl)-4- methylpyridin-2-amine (229 g, 450 mmol, 1.0 eq) in DMF (1 L) was added hexamethylphosphoramide (403 g, 2250 mmol, 5.0 eq) and Cui (214 g, 1125 mmol, 2.5 eq). The mixture was stirred at rt for 2 h. Then the mixture was heated 90 °C and added methyl 2,2- difluoro-2-(fluorosulfonyl)acetate (259 g, 1350 mmol, 3.0 eq). The mixture was stirred at 90 °C for 2 h. Cooled down and filtered through diatomite. Washed with EtOAc (1 L). Evaporated to 1-1.5 L in vacuum. Cooled to 5+5°C before adding dropwise soften water (1 L) to reactor at 0~25°C. Stirred for at least 30 min at 20+5°C. Centrifuged and washed cake with water for two times. The cake was collected and EtOAc (1 L) added. Stirred for at least 30 min at 25+5°C and filtered through diatomite before washing with EtOAc (1 L). Held, separated, collected the organic phases and concentrated to 2-4 V. Charged isopropanol (0.5 L) to reactor and concentrated to 2-4 V. Repeated charging isopropanol (0.5 L), and concentrating to 2-4 V . Heated to 60+5°C and added dropwise water (1 L) to the vessel and stirred for at least 0.5 hour at 60+5°C. Cooled to 20+5°C and stirred for at least 1 hour at 25+5°C. Centrifuged and washed cake with water / isopropanol = 2 / 1 for two times. Collected and dried the solid at least 16 hours at 50+5°C. The solid was 6-chloro-N,N-bis(4-methoxybenzyl)-4-methyl-5- (trifluoromethyl)pyridin-2-amine (190 g, 93.6%) as a white solid. LCMS: m / z 451.0 (M+H+).

[0262] Step 5: To a solution of 6-chloro-N,N-bis(4-methoxybenzyl)-4-methyl-5- (trifhioromethyl)pyridin-2-amine (41 g, 91 mmol, 1.0 eq) in ACN (100 mL) was added HBr (100 m ). Then the mixture was stirred at 80 °C for overnight, cooled and added EA (50 mL). After cooling to 0±5°C, the solution was neutralized with 15 wt.% aq. NaOH to pH = 7-8 at T < 25°C. , then extracted the aqueous layer with EA (20 mL) for three times and collected. The combined organic layer was concentrated at T < 45°C. to give the desired product, 6-chloro-4- methyl-5-(trifhioromethyl)pyridin-2-amine (19 g, 99.2%) as a yellow solid. LCMS: m / z 211.0 (M+H+).

[0263] Step 6: To a solution of 6-chloro-4-methyl-5-(trifluoromethyl)pyridin-2-amine (19 g, 90 mmol, 1.0 eq) in ACN (80 mL) was added acetyl bromide (166 g, 1353 mmol, 15.0 eq). Then the mixture was stirred at 70 °C for overnight. Cool to 0±5°C and quenched by EtOH (25 mL) at T < 25°C. Cooled to 0±5°C and neutralized with 15 wt% aq. NaOH to pH = 7-8 at T < 25°C.Patent ApplicationAtty. Docket No. ENTX-034PCTExtracted with EtOAc (100 mL) for three times and collected and concentrated the organic layers to 2-4 V at T < 45°C. Cooled to 5-10 °C and stirred for 1 -2 hours at 5-10 °C. Centrifuged and washed the cake with EtOAc twice and collected the cake to give N-(6-bromo-4-methyl-5- (trifluoromethyl)pyridin-2-yl)acetamide (16.7 g, 62.3%) as a white solid. LCMS: m / z 296.9 (M+H+).

[0264] Step 7: To a solution of N-(6-bromo-4-methyl-5-(trifluoromethyl)pyridin-2- yl)acetamide (16.7 g, 56 mmol, 1.0 eq) in ACN (17 mL) was added HBr (17 mL) and EtOH (8 mL). Then the mixture was stirred at 70 °C for overnight. Cooled to 0±5°C and neutralized with 15 wt.% aq. NaOH to pH = 7-8 at T < 25°C. Centrifuged and washed the cake with soften water. The cake was 6-bromo-4-methyl-5-(trifluoromethyl)pyridin-2-amine (11 g, 76.73%) as a white solid. LCMS: m / z 255.0 (M+H+).

[0265] Step 8: To a solution of N-(6-bromo-4-methyl-5-(trifluoromethyl)pyridin-2- yl)acetamide (11 g, 43 mmol, 1.0 eq) in THF (150 mL) was added PMBC1 (17 g, 109 mmol, 2.4 eq) and t-BuOH (12.7 g, 113 mmol, 2.5 eq). Then the mixture was stirred at 45 °C for overnight. The mixture was filtered. After concentrated to 10 mL below 40 °C, EtOH and water was added into the residue at 15 - 25 °C. The mixture was cooled to 5 - 15 °C and stirred for 0.5 h. The solid was filtered and washed with water twice. The wet cake was stirred with EtOH at 15-25 °C for 1 h. The solid was filtered and washed with EtOH (15 mL) twice. The wet cake was dried under vacuum at 45 - 55 °C for 2 h to give 6-bromo-N,N-bis(4-methoxybenzyl)-4-methyl-5- (trifluoromethyl)pyridin-2-amine (13 g, 57.85%) as a yellow solid. LCMS: m / z 495.0 (M+H+).Intermediate 68-chloro-10-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-4- isopropyl-7-methylene-4,5,6,7-tetrahydroazepino[2,3,4-de]quinazolineSynthetic scheme:Patent ApplicationAtty. Docket No. ENTX-034PCT

[0266] Step 1: To a solution of (but-l-en-4-yl) prop-2-yl) amine (300 mg, 2.64 mmol) and 5- bromo-2,4,6-trichloro-8-fluoroquinazoline (918 mg, 2.79 mmol) in DCM (5 mL) was added DIEA (1026 mg, 7.95 mmol), the mixture was stirred at 25°C for 2 hours. LCMS showed the desired mass was detected. The mixture was diluted with water, then extracted with DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE in EA, 4%EA) to afford 5-bromo-4-[(but-3-enyl) (prop-2-yl) amino]-2,6-dichloro-8- fluoroquinazoline (660 mg, 1.55 mmol, 58%) as a yellow solid. LCMS: ESI m / z 408.1 [M + H]+.

[0267] Step 2: To a solution of 5-bromo-4-[(but-3-enyl)(prop-2-yl)amino]-2,6-dichloro-8- fluoroquinazoline (660 mg, 1.55 mmol) and [(2R,7aS)-2-fluoro-2,3,5,6,7,7a-hexahydro-lH- pyrrolizin-7a-yl]methanol (1548 mg, 9.73 mmol) in dioxane (10 mL) was added CS2CO3 (1584 mg, 4.86 mmol), the mixture was stirred at 80 °C for 16 hours. LCMS showed the desired mass was detected. The cooled mixture was diluted with water, then extracted with EA. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH, 5% MeOH) to afford 5-bromo-4-[(but-3-enyl)(prop-2-yl)amino]-6-chloro-8- fluoro-2-( { [(2R,7aS)-2-fluoro-2, 3 , 5 , 6,7, 7 a-hexahy dro- 1 H-pyrrolizin-7a- yl]methyl}oxy)quinazoline (550 mg, 0.83 mmol, 53%) as a yellow oil. LCMS: ESI m / z 529.1 [M + H]+.

[0268] Step 3: To a solution of 5-bromo-4-[(but-3-enyl)(prop-2-yl)amino]-6-chloro-8- fluoro-2-( { [(2R,7aS)-2-fluoro-2, 3 , 5 , 6,7, 7 a-hexahy dro- 1 H-pyrrolizin-7a-Patent ApplicationAtty. Docket No. ENTX-034PCT yl]methyl}oxy)quinazoline (550 mg, 1 .04 mmol) and PPI13 (677 mg, 2.58 mmol) in DMA (10 mL) was added KO Ac (305 mg, 3.12 mmol) and Pd(OAc)2 (69.6 mg, 0.3 mmol), the mixture was degassed and purged with nitrogen for several times, then stirred at 130 °C for 3 hours under nitrogen atmosphere. The cooled mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM in MeOH, 5% MeOH) to afford 8-chloro-10-fhioro-2-({[(2R,7aS)-2-fluoro-2,3,5,6,7,7a-hexahydro-114-pyrrolizin-7a- yl]methyl}oxy)-7-methylidene-4-(prop-2-yl)-4,5,6,7-tetrahydroazepino[2,3,4-de]quinazoline (180 mg, 0.4 mmol, 38%) as a yellow oil. LC-MS (ESI) found: 449.2 [M+H]+.Intermediate 7:(R)-3-(l-(but-3-en-l-ylamino)ethyl)-N-(4-methoxybenzyl)-N-methylpyridin-2-amineSynthetic scheme:

[0269] Step 1: To a mixture of l-(2-chloropyridin-3-yl)ethan-l-one (5 g, 32.14 mmol) and 1- (4-methoxyphenyl)-N-methylmethanamine (9.7 g, 64.3 mmol) in DMA (70 mL) was added K2CO3 (13.3 g, 96.5 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. After cooling to room temperature, 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 MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution with a gradient of 0 to 20% acetone in petroleum ether. The desired fractions were evaporated to dryness to afford l-(2-{[(4-Patent ApplicationAtty. Docket No. ENTX-034PCT methoxyphenyl)methyl](methyl)amino}pyridin-3-yl)ethan-l-one (6 g, 22.2 mmol, 69%) as a yellow solid. LCMS: (ESI) m / z 271.0 [M+H]+.

[0270] Step 2: To a flask containing l-(2-{[(4- methoxyphenyl)methyl](methyl)amino}pyridin-3-yl)ethan-l-one (5 g, 18.5 mmol) and tert- butanesulfmamide (2.7 g, 22.6 mmol) in THF (60 mL) was added and titanium ethoxide (21.1 g, 92.5 mmol). The reaction mixture was purged with nitrogen for three times, then heated to 80 °C under nitrogen overnight. After cooling to room temperature, the reaction mixture was quenched with HjO (70 mL) and extracted with EtOAc three times The combined extracts were washed with brine and dried over anhydrous Na2S0.4. Solvent was evaporated. The resulting mixture was extracted with EtOAc twice, then the combined extracts were dried over anhydrous MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient of 3-30% EtOAc in petroleum ether to afford (lE)-l-(2-{[(4- methoxyphenyl)methyl](methyl)amino}pyridin-3-yl)-N-[(2-methylprop-2-yl)(oxo)-X4- sulfanyl]ethanimine (4 g, 10.7 mmol, 58%) as a white solid. LCMS: (ESI) m / z 374.3 [M+H]+.

[0271] Step 3: To a solution of (lE)-l-(2-{[(4- methoxyphenyl)methyl](methyl)amino}pyridin-3-yl)-N-[(2-methylprop-2-yl)(oxo)-X4- sulfanyl]ethanimine (100 mg, 0.3 mmol) in THF (5 mL) was added L-SELECTRIDE(R) (0.40 mL, 0.4 mmol). The mixture was stirred at -78 °C for 2 hours under N2. The reaction was monitored by analysis of LC-MS. The reaction solvent was evaporated under reduced pressure and the crude product was purified by flash silica chromatography, eluting with a gradient of 10-30% EtOAc in petroleum ether to afford 2-{[(4-methoxyphenyl)methyl](methyl)amino}-3- [(lR)-l-{ [(2-methylprop-2-yl)(oxo)- -sulfanyl]amino}ethyl]pyridine (60 mg, 0.2 mmol, 60%) as a yellow solid. LCMS: (ESI) m / z 376.2 [M+H]+.

[0272] Step 4: To a solution of 2-{[(4-methoxyphenyl)methyl](methyl)amino}-3-[(lR)-l- {[(2-methylprop-2-yl)(oxo)-X4-sulfanyl]amino}ethyl]pyridine (50 mg, 0.2 mmol) in HC1 (2 mL, 0.5 mmol) at 0 °C. The reaction was stirred at room temperature for 30 mins. 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 NaHCOs 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 (1R)-1-Patent ApplicationAtty. Docket No. ENTX-034PCT(2-{[(4-methoxyphenyl)methyl](methyl)amino}pyridin-3-yl)ethan-l -amine (20 mg, 0.1 mmol, 55%) as a yellow oil. LCMS: (ESI) m / z 272.1 [M+H]+.

[0273] Step 5: To a mixture of (lR)-l-(2-{[(4- methoxyphenyl)methyl](methyl)amino}pyridin-3-yl)ethan-l-amine (100 mg, 0.4 mmol) in MeCN (5 mL) were add 4-Bromo-l -butene (75 mg, 0.5 mmol) and followed by K2CO3 (153 mg, 1.1 mmol). The reaction resulting mixture was purged with nitrogen three times, then heated to 90 °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 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 flash silica chromatography, elution with a gradient of 0-20% ethyl acetate in petroleum ether to afford (R)-3-(l-(but-3-en-l-ylamino)ethyl)-N-(4-methoxybenzyl)- N-methylpyridin-2-amine (50 mg, 0.2 mmol, 42%) as a colorless oil. LCMS: (ESI) m / z 326.3 [M+H]+.Intermediate 8:3-((R)-l-(8-chloro-10-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)-7-methylene-6,7-dihydroazepino[2,3,4-de]quinazolin-4(5H)-yl)ethyl)-N-(4- methoxybenzyl)-N-methylpyridin-2-amineSynthetic scheme:Patent ApplicationAtty. Docket No. ENTX-034PCT

[0274] Step 1: To a solution of 3-[(lR)-l-(but-l-en-4-ylamino)ethyl]-2-{[(4- methoxyphenyl)methyl](methyl)amino]pyridine (300 mg, 0.92 mmol) in DCM (5 mL) were added 5-bromo-2,4,6-trichloro-8-fluoroquinazoline (308 mg, 0.93 mmol) and DIEA (357 mg, 2.77 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: 0-20%) to afford 5- bromo-2,6-dichloro-4-[(but-3-enyl)[(lR)-l-(2-{[(4- methoxyphenyl)methyl](methyl)amino}pyridin-3-yl)ethyl]amino]-8-fluoroquinazoline (300 mg, 0.48 mmol, 53%) as a yellow oil. LCMS: (ESI) m / z 620.1 [M+H]+.

[0275] Step 2: To a solution of 5-bromo-2,6-dichloro-4-[(but-3-enyl)[(lR)-l-(2-{[(4- methoxyphenyl)methyl](methyl)amino}pyridin-3-yl)ethyl]amino]-8-fluoroquinazoline (400 mg, 0.65 mmol) in dioxane (2 mL) were added [(7aS)-2-(difluoromethylidene)-2,3,5,6,7,7a- hexahydro-lH-pyrrolizin-7a-yl]methanol (3.13 g, 16.6 mmol) and CS2CO3 (631 mg, 1.94 mmol). The mixture was stirred at 100 °C under N2 atmosphere ON with sealed tube. 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 methanol in dichloromethane (gradient: 0-10%) to afford 5-bromo-Patent ApplicationAtty. Docket No. ENTX-034PCT6-chloro-4-[(but-3-enyl)[(lR)-l-(2-{[(4-methoxyphenyl)methyl](methyl)amino}pyridin-3- yl)ethyl]amino]-8-fluoro-2-({[(2R,7aS)-2-fluoro-2,3,5,6,7,7a-hexahydro-lH-pyrrolizin-7a- yl]methyl }oxy)quinazoline (300 mg, 0.40 mmol, 63%) as a yellow solid. LCMS: (ESI) m / z 743.3 [M+H]+.

[0276] Step 3: To a solution of 5-bromo-6-chloro-4-[(but-3-enyl)[(lR)-l-(2-{[(4- methoxyphenyl)methyl](methyl)amino}pyridin-3-yl)ethyl]amino]-8-fluoro-2-({[(2R,7aS)-2- fluoro-2,3,5,6,7,7a-hexahydro-lH-pyrrolizin-7a-yl]methyl}oxy)quinazoline (300 mg, 0.40 mmol) in DMA (5 mL) were added Pd(OAc)2 (18.2 mg, 0.08 mmol), PPhs (42.4 mg, 0.16 mmol) and KOAc (119 mg, 1.21 mmol). The mixture was stirred at 100 °C under N2 atmosphere for 4h. 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 methanol in di chloromethane (gradient: 0-10%) to afford 8- chloro- 10-fluoro-2-({ [(2R,7aS)-2-fluoro-2, 3 , 5 , 6,7, 7 a-hexahy dro- 1 H-pyrrolizin-7a- yl]methyl }oxy)-4-[(lR)-l-(2-{[(4-methoxyphenyl)methyl](methyl)amino}pyridin-3-yl)ethyl]-7- methylidene-4,5,6,7-tetrahydroazepino[2,3,4-de]quinazoline (50 mg, 0.08 mmol, 19%) as a yellow solid.

[0277] LCMS: (ESI) m / z 661.3 [M+H]+.Intermediate 9:3-[(1R)-l-(but-3-enylamino)ethyl]pyridine / V, / V-bis(4-methoxybenzyl)-3-((1 R)-1 -((2-methylbut-3-en-1 -yl)amino)ethyl)pyridin-2-amineSynthetic scheme:

[0278] Step 1. To a stirred mixture of (lR)-l-(pyridin-3-yl)ethan-l-amine (4.5 g, 36.8 mmol) in THF (50 mL) was added NaH (1.9 g, 47.9 mmol, 60% in mineral oil) at 0 °C. The reaction mixture was stirred for 1 hour. 4-bromobut- 1 -ene (4.9 g, 36.8 mmol) was added at 0 °CPatent Application Atty. Docket No. ENTX-034PCT and the mixture was stirred at room temperature for 16 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 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% MeOH in DCM. The desired fractions were evaporated to dryness to afford 3-[(lR)-l-(but-3-enylamino)ethyl]pyridine (2.8 g, 15.9 mmol, 43 %) as a yellow oil. LCMS: ESI m / z 177 [M I N 7Intermediate 10:8-chloro-10-fluoro-2-({[(2R,7aS)-2-fluoro-2,3,5,6,7,7a-hexahydro-lH-pyrrolizin-7a- yl]methyl}oxy)-7-methylidene-4-[(lR)-l-(pyridin-3-yl)ethyl]-4, 5,6,7- tetrahydr oazepino [2,3,4-de] quinazolineSynthetic scheme:Patent ApplicationAtty. Docket No. ENTX-034PCT

[0279] Step 1. To a solution of 3-[(lR)-l-(but-3-enylamino)ethyl]pyridine (1 g, 5.6 mmol) in THF (20 mL) was added 5-bromo-2,4,6-trichloro-8-fluoroquinazoline (2.2 g, 6.8 mmol) at rt under nitrogen atmosphere. The mixture was stirred at 0 °C for 2 h under N2. The mixture was quenched with ice-water and extracted with EtOAc (20 mL*3). The combined organic phase was washed with brine, dried with Na2SC>4, filtered. The residue was purified by chromatography (silica gel, 0- 40 %, EtOAc in PE) to give crude 5-bromo-2,6-dichloro-4- [(but-3-enyl)[(lR)-l-(pyridin-3-yl)ethyl]amino]-8-fluoroquinazoline (280 mg, 0.39 mmol, 7 %) as a brown solid. LCMS: m / z 470 [M+H]+.

[0280] Step 2. To a stirred mixture of 5-bromo-2,6-dichloro-4-[(but-3-enyl)[(lR)-l-(pyridin- 3-yl)ethyl]amino]-8-fluoroquinazoline (250 mg, 0.53 mmol) in THF (3 mL) was added DIEA (206 mg, 1.6 mmol) and [(2R,7aS)-2-fluoro-2,3,5,6,7,7a-hexahydro-lH-pyrrolizin-7a- yl]methanol (169 mg, 1.06 mmol) slowly at rt. After stirred at 120 °C for 30 min, the solvent was dried. This procedure was repeated 3 times. The residue was purified by chromatography (silica gel, 0- 10 %, MeOH in DCM) to give 5-bromo-6-chloro-4-[(but-3-enyl)[(lR)-l-(pyridin-3- yl)ethyl]amino]-8-fluoro-2-({[(2R,7aS)-2-fluoro-2,3,5,6,7,7a-hexahydro-lH-pyrrolizin-7a- yl]methyl}oxy)quinazoline (160 mg, 0.27 mmol, 50 %) as a brown solid. LCMS: m / z 592 [M+H]+.

[0281] Step 3. To a solution of 5-bromo-6-chloro-4-[(but-3-enyl)[(lR)-l-(pyridin-3- yl)ethyl]amino]-8-fluoro-2-({[(2R,7aS)-2-fluoro-2,3,5,6,7,7a-hexahydro-lH-pyrrolizin-7a-Patent ApplicationAty. Docket No. ENTX-034PCT yl]methyl}oxy) quinazoline (130 mg, 0.22 mmol) in DMA (10 mL) was added Pd(OAc)2 (10 mg, 0.04 mmol), PPh (69 mg, 0.26 mmol) and K2CO3 (91 mg, 0.66 mmol) at room temperature. The mixture was stirred at 100 °C under N2 for 2 h. The mixture was quenched with ice-water and extracted with EtOAc (10 mL*3). The combined organic phase was washed with brine, dried with Na2SC>4 and concentrated. The residue was purified by chromatography (silica gel, 0- 10 %, MeOH in DCM) to give 8-chloro-10-fluoro-2-({[(2R,7aS)-2-fluoro-2,3,5,6,7,7a- hexahydro-lH-pyrrolizin-7a-yl]methyl}oxy)-7-methylidene-4-[(lR)-l-(pyridin-3-yl)ethyl]- 4,5,6,7-tetrahydroazepino[2,3,4-de]quinazoline (40 mg, 0.08 mmol, 35 %) as a brown solid. LCMS: m / z 512 [M+H]+.Intermediate 11N,N-bis(4-methoxybenzyl)-3-((lR)-l-((2-methylbut-3-en-l-yl)amino)ethyl)pyridin-2-amineSynthetic scheme:

[0282] Step 1: To a solution of 2-methylbut-3-en-l-yl 4-methylbenzenesulfonate (1 g, 4.16 mmol) in THF (10 mL) was added (lR)-l-(2-{bis[(4-methoxyphenyl)methyl]amino}pyridin-3- yl)ethan-l -amine (1.5 g, 4.16 mmol) and DIEA (806 mg, 6.24 mmol). After stirred at 130 °C for 30 min, the residue was dried. This procedure was repeated 3 times. The mixture was diluted with water and extracted with EtOAc. The organic layers were washed with water, brine (30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-60 %, EtOAc in PE) to give crude 2-{bis[(4-methoxyphenyl)methyl]amino}-3- [(lR)-l-[(3-methylbut-l-en-4-yl)amino]ethyl]pyridine (330 mg, 0.74 mmol, 35%) as a yellow oil. LCMS: m / z 446 [M+H]+.Intermediate 12Patent ApplicationAty. Docket No. ENTX-034PCT3-((lR)-l-(8-chloro-10-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)-6-methyl-7-methylene-6,7-dihydroazepino[2,3,4-de]quinazoIin-4(5H)-yl)ethyl)- N,N-bis(4-methoxybenzyl)pyridin-2-amineSynthetic scheme:

[0283] Step 1. To a stirred mixture of 2-{bis[(4-methoxyphenyl)methyl]amino}-3-[(lR)-l- [(3-methylbut-l-en-4-yl)amino]ethyl]pyridine (300 mg, 0.67 mmol) in dioxane (3 mL) was added DIEA (3 mL, 0.04 mmol) and 5-bromo-2,4,6-trichloro-8-fluoroquinazoline (289 mg, 0.88 mmol) at rt. After stirred at 60 °C for 2h, the mixture was diluted with water and extracted with EtOAc. The organic layers were washed with water (20 mL x 2), brine (30 mL), dried over Na2SC>4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0- 30 %, EtOAc in PE) to give 5-bromo-2,6-dichloro-8-fluoro-4-{[(lR)-l-(2-{bis[(4-Patent ApplicationAtty. Docket No. ENTX-034PCT methoxyphenyl)methyl]amino}pyridin-3-yl)ethyl](3-methylbut-l-en-4-yl)amino}quinazoline (280 mg, 0.38 mmol, 56%) as a yellow oil. LCMS: m / z 740 [M+H]+.

[0284] Step 2 To a stirred mixture of 5-bromo-2,6-dichloro-8-fluoro-4-{[(lR)-l-(2-{bis[(4- methoxyphenyl)methyl]amino}pyridin-3-yl)ethyl](3-methylbut-l-en-4-yl)amino}quinazoline (260 mg, 0.35 mmol) in THF (5 mL) was added DIEA (136 mg, 1.05 mmol) and [(2R,7aS)-2- fluoro-2,3,5,6,7,7a-hexahydro-lH-pyrrolizin-7a-yl]methanol (112 mg, 0.7 mmol) slowly at rt. After stirred at 130 °C for 30 min, the residue was dried. This procedure was repeated 3 times. The residue was purified by chromatography (silica gel, 0- 10 %, MeOH in DCM) to give 5-bromo-6-chloro-8-fluoro-2-({[(2R,7aS)-2-fluoro-2,3,5,6,7,7a-hexahydro-lH-pyrrolizin- 7a-yl]methyl}oxy)-4-{ [(lR)-l-(2-{bis[(4-methoxyphenyl)methyl]amino}pyridin-3-yl)ethyl](3- methylbut-l-en-4-yl)amino}quinazoline (170 mg, 0.2 mmol, 56%) as a brown oil. LCMS: m / z 861 [M+H]+.

[0285] Step 3. To a solution of 5-bromo-6-chloro-8-fluoro-2-({[(2R,7aS)-2-fluoro- 2,3,5,6,7,7a-hexahydro-lH-pyrrolizin-7a-yl]methyl }oxy)-4-{[(lR)-l-(2-{bis[(4- methoxyphenyl)methyl]amino}pyridin-3-yl)ethyl](3-methylbut-l-en-4-yl)amino}quinazoline (170 mg, 0.2 mmol) in DMA (10 mL) was added Pd(OAc)2 (16 mg, 0.072 mmol), PPhi (189 mg, 0.72 mmol) and K2CO3 (82 mg, 0.59 mmol) at room temperature under nitrogen atmosphere. The mixture was stirred at 100 °C under N2 for 2 h. The mixture was quenched with icewater and extracted with EtOAc. The combined organic phase was washed with brine, dried with Na2SO4, filtered. The residue was purified by chromatography (silica gel, 0- 80 %, EtOAc in PE) to give 4-[(lR)-l-(2-{bis[(4-methoxyphenyl)methyl]amino}pyridin-3-yl)ethyl]-8- chloro-10-fhioro-2-({[(2R,7aS)-2-fhioro-2,3,5,6,7,7a-hexahydro-lH-pyrrolizin-7a- yl]methyl}oxy)-6-methyl-7-methylidene-4,5,6,7-tetrahydroazepino[2,3,4-de]quinazoline (100 mg, 0.13 mmol, 65%) as a brown solid. LCMS: m / z 781 [M+H]+.Intermediate 13N-(but-3-en-l-yl)-l-chloro-5,6,7,8-tetrahydroisoquinolin-8-amineSynthetic scheme:Patent ApplicationAtty. Docket No. ENTX-034PCT

[0286] Step 1: To a solution of ethyl 2-bromo-4-methylpyridine-3-carboxylate (10 g, 40.9 mmol) in THF (150 mb) was added LDA (22.53 mL, 45.1 mmol, 2 M) at -78 °C was stirred for 20 minutes. Then methyl prop-2-enoate (8.82 g, 102.4 mmol) in THF (50 mL) was added into the mixture was stirred for 1.5 hours. The mixture was warmed to 0 °C and AcOH (50 mL, 10% purity in water) was added into the mixture dropwise. The mixture was stirred for 2 hours. The mixture was concentrated and poured into saturated NaHCCh, extracted with EtOAc. The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated to give methyl l-bromo-8-oxo-5,6,7,8-tetrahydroisoquinoline-7-carboxylate (11.6 g, 40.8 mmol, 99%) as an orange oil. LCMS: ESI m / z 284.0 [M + H]+.

[0287] Step 2: To a solution of methyl l-bromo-8-oxo-5,6,7,8-tetrahydroisoquinoline-7- carboxylate (11.6 g, 40.8 mmol) in HC1 (110 mL, 6 M) was stirred at 100 °C for 30 min. Then the mixture was warmed to room temperature was stirred for 12 hours. The acidic solution was concentrated in vacuo, suspended in water (ca. 300 mL), cooled in ice, and basified with 6.0 M KOH. The aqueous solution was washed with EA, the combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica with petrol ether / ethyl acetate (7:3) to give l-chloro-5,6,7,8-tetrahydroisoquinolin-8-one (2.8 g, 15.4 mmol, 37 %) as a white solid. LCMS: ESI m / z 182. 1 [M + H]+. ’H NMR (400 MHz, DMSO-d6) 8 8.40 (d, J = 5.2 Hz, 1H), 7.43 (d, J = 5.2 Hz, 1H), 3.01 (t, J = 6.0 Hz, 2H), 2.70 - 2.65 (m, 2H), 2.08 - 2.00 (m, 2H).

[0288] Step 3: To a solution of l-chloro-5,6,7,8-tetrahydroisoquinolin-8-one (388 mg, 2.14 mmol) in MeOH (20 mL) was added but-3-en-l -amine hydrochloride (689 mg, 6.41 mmol) and titanium(4+) tetrakis(ethanolate) (1.46 g, 6.41 mmol). The mixture was stirred at 20 °C for 30 min. Then sodium cyanoboranuide (403 mg, 6.41 mmol) was added and the mixture was stirred at 80 °C for 12 hours. The mixture was filtered and concentrated. The residue was purified by chromatography (silica gel, 0-30%, EtOAc in PE) to give 8-(but-3-enylamino)-l- chloro-5,6,7,8-tetrahydroisoquinoline (280 mg, 1.18 mmol, 55 %) as a clear oil. LCMS: ESI m / z 237.2 [M + H]~.Patent ApplicationAtty. Docket No. ENTX-034PCTIntermediate 148-chloro-4-(l-chloro-5,6,7,8-tetrahydroisoquinolin-8-yl)-10-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-7-methylene-4,5,6,7- tetrahydroazepino [2,3,4-de] quinazoline

[0289] Step 1: To a solution of 8-(but-3-enylamino)-l-chloro-5,6,7,8-tetrahydroisoquinoline (260 mg, 1.10 mmol) in DCM (10 mL) was added DIEA (429 mg, 3.29 mmol) and 5-bromo- 2,4,6-trichloro-8-fluoroquinazoline (363 mg, 1.10 mmol). The mixture was stirred at 50 °C for neat. The mixture was concentrated and the residue was purified by chromatography (silica gel, 0-30%, EtOAc in PE) to give 5-bromo-4-[(but-3-enyl)(l-chl oro-5, 6,7, 8-tetrahydroisoquinolin-8-Patent ApplicationAtty. Docket No. ENTX-034PCT yl)amino]-2,6-dichloro-8-fluoroquinazoline (429 mg, 0.81 mmol, 73%) as a yellow solid. LCMS: ESI m / z 531.0 [M + H]+.

[0290] Step 2: To a solution of 5-bromo-4-[(but-3-enyl)(l-chloro-5, 6,7,8- tetrahydroisoquinolin-8-yl)amino]-2,6-dichloro-8-fluoroquinazoline (400 mg, 0.75 mmol) in DMA (10 mL) was added Pd(OAc)2 (20.3 mg, 0.09 mmol), PPh.i (39.5 mg, 0.15 mmol) and KOAc (222 mg, 2.26 mmol). The mixture was stirred at 130 °C under N2 for 30 min. The cooled mixture was poured into H2O and extracted with EtOAc. The combined organic phase was washed with brine, dried with Na2SC>4, fdtered and concentrated. The residue was purified by chromatography (silica gel, 0-50%, EtOAc in PE) to give 2,8-dichloro-4-(l- chl oro-5, 6,7, 8-tetrahydroisoquinolin-8-yl)-10-fluoro-7-methylidene-4, 5,6,7- tetrahydroazepino[2,3,4-de]quinazoline (73 mg, 0.16 mmol, 21%) as yellow oil. LCMS: ESI m / z 451.1 [M + H]-.

[0291] Step 3: To a solution of 2,8-dichloro-4-(l-chloro-5,6,7,8-tetrahydroisoquinolin-8-yl)- 10-fluoro-7-methylidene-4,5,6,7-tetrahydroazepino[2,3,4-de]quinazoline (60 mg, 0.13 mmol) and [(2R,7aS)-2-fluoro-2,3,5,6,7,7a-hexahydro-lH-pyrrolizin-7a-yl]methanol (212 mg, 1.33 mmol) in dioxane (10 mL) was added CS2CO3 (130.4 mg, 0.40 mmol) and the mixture was stirred at 80 °C for 12 hours. The mixture was concentrated and the residue was purified by chromatography (silica gel, 0-10%, MeOH in DCM) to give 8-chloro-4-(l-chloro-5,6,7,8- tetrahydroisoquinolin-8-yl)-10-fluoro-2-({[(2R,7aS)-2-fluoro-2,3,5,6,7,7a-hexahydro-lH- pyrrolizin-7a-yl]methyl}oxy)-7-methylidene-4,5,6,7-tetrahydroazepino[2,3,4-de]quinazoline (40 mg, 0.07 mmol, 52 %) as a yellow oil. LCMS: ESI m / z 572.2 [M + H]+.Intermediate 158-chloro-10-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-7- methylene-4-((R)-l-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazol-7-yl)ethyl)-4, 5,6,7- tetrahydroazepino [2,3,4-de] quinazolineSynthetic scheme:Patent ApplicationAtty. Docket No. ENTX-034PCT

[0292] Step 1: To a stirred mixture of lH-indazole-7-carbaldehyde (25 g, 171 mmol) in THF (250 mL) was added NaH (10.3 g, 257 mmol, 60% in mineral oil) at 0 °C and was stirred for 2 hour. SEM-C1 (33 mL, 188 mmol) was then added at 0 °C and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by analysis of LC-MS. The mixture was quenched by added to water and was extracted with EtOAc (50 mL*3), 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 0-15% EtOAc in petroleum ether to afford l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazole-7-carbaldehyde (25.2 g, 91 mmol, 53%) as a yellow oil. LCMS: m / z 277.2 [M+H]+.

[0293] Step 2: To a flask containing l-(5,5-dimethyl-2-oxa-5-silahex-l-yl)indazole-7- carbaldehyde (25.2 g, 91.2 mmol) in THF (10 mL) was added magnesium monobromide methanide (45.4 mL, 136.8 mmol, 3 mol / L in 2-Methyl-THF) at 0 °C . The reaction mixture was stirred at 0 °C for Ih. The reaction was monitored by analysis of LC-MS. The reaction mixture was quenched with NH4CI solution (200 mL) at 0 °C, partitioned between EtOAc and H2O. The organic extract was washed with brine, dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure to afford l-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-Patent ApplicationAtty. Docket No. ENTX-034PCT indazol-7-yl)ethan-l-ol (24.1 g, 82.5 mmol, 90 %) as a yellow oil, and was used without further purification. LCMS: m / z 293.1 [M+H]+.

[0294] Step 3: To a solution of l-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazol-7- yl)ethan-l-ol (24.1 g, 82.4 mmol) in DCM (100 mL) at 0 °C, was added DESS-MARTIN (52.5 g, 123.4 mmol). The reaction was stirred at room temperature for 1.5 hours. The reaction mixture was filtered, and the filter cake was washed with DCM. The filtrate was washed with Na2SCh and 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 affordl-[l-(5,5-dimethyl-2-oxa-5-silahex-l-yl)indazol-7-yl]ethan-l- one (11.3 g, 39 mmol, 47%) as a yellow oil. LCMS: m / z 291.1 [M+H]+.

[0295] Step 4: To a stirred mixture of l-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazol-7- yl)ethan-l-one (11.3 g, 38.9 mmol) in DMA (20 mL) was added (S)-2-methylpropane-2- sulfinamide (7.1 g, 58.4 mmol) and titanium ethoxide (26.6 g, 116.7 mmol) slowly at r.t. After stirred at 100°C for 18 h, The mixture was quenched with ice-water and extracted with EtOAc (100 mL*3). 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 petroleum ether) to give (R,Z)-2-methyl-N-(l-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazol- 7-yl)ethylidene)propane-2-sulfinamide (9.8 g, 24.9 mmol, 64%) as a yellow oil. LCMS: m / z 394.2 [M+H]+.

[0296] Step 5: To a solution of (R,Z)-2-methyl-N-(l -(l-((2-(trimethylsilyl)ethoxy)methyl)- lH-indazol-7-yl)ethylidene)propane-2-sulfinamide (9.8 g, 24.9 mmol) in THF (40 mL) at -78 °C under N2, was added L-SELECTRIDE(R) (37 mL, 37 mmol Imol / L in THF). The reaction was stirred at -78 °C for 6 hours. The reaction was monitored by analysis of LC-MS. The reaction mixture was diluted with water and extracted with EtOAc (100 mL x 3) and was washed with brine, 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 crude product and was repurified by reverse phase flash chromatography (0%~ 48% ACN in 0.1% NH3COOH) to afford (R)-2-methyl-N-((R)-l-(l-((2- (trimethylsilyl)ethoxy)methyl)-lH-indazol-7-yl)ethyl)propane-2-sulfinamide (1.9 g, 4.8 mmol, 19%). LCMS: m / z 396.2 [M + H]+.Patent Application Atty. Docket No. ENTX-034PCT

[0297] Step 6: To a stirred mixture of (R)-2-methyl-N-((R)-l-(l-((2- (trimethylsilyl)ethoxy)methyl)-lH-indazol-7-yl)ethyl)propane-2-sulfinamide (1.1 g, 2.8 mmol) in DCM (10 mL) was added HC1 in dioxane (20 mL, 5.0 mmol 0.25 mol / L in dioxane) slowly at 0 °C. After stirred at 0 °C for 1 h , the mixture was quenched with saturated sodium bicarbonate solution and extracted with EtOAc (40 mL*3). The combined organic phase was washed with brine, dried with Na2SC>4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0- 60 %, EtOAc in petroleum ether) to give (R)-l-(l-((2- (trimethylsilyl)ethoxy)methyl)-lH-indazol-7-yl)ethan-l-amine (382 mg, 1.31 mmol, 47 %) as a yellow oil. LCMS: m / z 292.3 [M+H]+. 'H NMR (400 MHz, DMSO-D6) 5 8.55 (s, 1H), 7.62 (d, J= 8.4 Hz, 1H), 7.29 (d, J= 6.8 Hz, 1H), 7.18 - 6.89 (m, 1H), 5.79 (s, 2H), 4.56 - 4.42 (m, 1H), 3.71 (t, J= 8.2 Hz, 2H), 1.49 (d, J= 6.6 Hz, 3H), 0.92 ((t, J= 8.2 Hz, 2H), 0.00 (s, 9H).

[0298] Step 7: To a stirred mixture of (R)-l-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH- indazol-7-yl)ethan-l-amine (382 mg, 1.31 mmol) in DMA (3 mL) was added 4-bromobut-l-ene (530.8 mg, 3.93 mmol) and CS2CO3 (1281 mg, 3.93 mmol). After stirred at 80 °C for 16 h, the mixture was quenched with ice-water and extracted with EtOAc (20 mL*3). The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-60 %, EtOAc in petroleum ether) to give (R)-N-(l- (l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazol-7-yl)ethyl)but-3-en-l-amine (300 mg, 0.87 mmol, 66 %) as a yellow oil. LCMS: m / z 346.3 [M + H]+.1H NMR (400 MHz, DMSO-d6) 8 8.56 (s, 1H), 7.65 (d, J= 7.8 Hz, 1H), 7.27 (d, J= 6.8 Hz, 1H), 7.14 - 6.92 (m, 1H), 5.90 - 5.59 (m, 3H), 5.21 - 4.86 (m, 2H), 4.44 - 4.19 (m, 1H), 3.86 - 3.62 (m, 2H), 2.55 - 2.38 (m, 2H), 2.27 - 2.17 (m, 2H), 1.47 (d, J= 6.8 Hz, 3H), 0.99 - 0.89 (m, 2H).Intermediate 16Synthetic scheme:Patent ApplicationAtty. Docket No. ENTX-034PCT

[0299] Step 1. To a stirred mixture of (R)-N-(l-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazol-7- yl)ethyl)but-3-en-l -amine (300 mg, 0.87 mmol) in dioxane (5 mL) was added DIEA (2239 mg, 17.4 mmol) and 5-bromo-2,4,6-trichloro-8-fluoroquinazoline (286 mg, 0.87 mmol) slowly at rt.After stirred at 60 °Cfor 2h, the mixture was quenched with ice-water and extracted with EtOAc (20 mL*3). 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 petroleum ether) to give (R)-5-bromo-N-(but-3-en-l-yl)-2,6-dichloro-8-fluoro-N-(l-(l-((2- (trimethylsilyl)ethoxy)methyl)-lH-indazol-7-yl)ethyl)quinazolin-4-amine (400 mg, 0.63 mmol, 72 %) as a yellow oil. LCMS: m / z 638.2;640.2;642.2 [M + H]+. 'H N.V1R (400 MHz, DMSO-d6) 8 8.34 (s, 1H), 8.14 (d, J= 9.6 Hz, 1H), 7.61 (d, J= 8.2 Hz, 1H), 7.37 (d, J= 6.8 Hz, 1H), 7.09 - 6.90 (m, 1H), 5.98 - 5.78 (m, 1H), 5.51 - 5.30 (m, 2H), 5.24 - 5.10 (m, 1H), 5.10 - 4.90 (m, 2H), 3.56 - 3.46 (m, 2H), 3.29 - 3.18 (m, 2H), 2.43 - 2.32 (m, 2H), 2. 10 (d, J = 6.8 Hz, 3H), 0.83 - 0.60 (m, 2H).

[0300] Step 2. To a stirred mixture of (R)-5-bromo-N-(but-3-en-l-yl)-2,6-dichloro-8-fluoro- N-(l-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazol-7-yl)ethyl)quinazolin-4-amine (400 mg, 0.63 mmol) in THF (5 mL) was added DIEA (161 mg, 1.25 mmol) and ((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (199 mg, 1.26 mmol) slowly at rt. After stirred at 110 °C for 30 min, the residue was dried. The mixture was neated 3 times. The residue was purified by chromatography (silica gel, 0- 50 %, EtOAc in petroleum ether) to give 5-Patent ApplicationAtty. Docket No. ENTX-034PCT bromo-N-(but-3-en-l-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-N-((R)-l-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazol-7- yl)ethyl)quinazolin-4-amine (327 mg, 0.43 mmol, 68 %) as a brown solid. LCMS: 761.3;763.3;765.3 [M + H]+.

[0301] JH NMR (400 MHz, DMSO-d6) 8 8.32 (s, 1H), 8.04 - 7.85 (m, 1H), 7.68 - 7.52 (m, 1H), 7.33 - 7.15 (m, 1H), 7.06 - 6.91 (m, 1H), 5.97 - 5.81 (m, 1H), 5.58 - 5.37 (m, 2H), 5.30 - 5.14 (m, 2H), 5.11 - 4.90 (m, 2H), 3.92 (s, 2H), 3.58 - 3.46 (m, 1H), 3.43 - 3.37 (m, 3H), 3.32 - 3.26 (m, 2H), 2.98 - 2.64 (m, 5H), 2.44 - 2.35 (m, 2H), 2.04 (d, J= 6.8 Hz, 2H), 1.86 - 1.62 (m, 6H), 0.81 - 0.58 (m, 2H), -0.12 (s, 8H).

[0302] Step 3. To a solution of 5-bromo-N-(but-3-en-l-yl)-6-chloro-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy)-N-((R)- 1 -( 1 -((2- (trimethylsilyl)ethoxy)methyl)-lH-indazol-7-yl)ethyl)quinazolin-4-amine (180 mg, 0.24 mmol) in DMA (1 mL) was added Palladium (II) Acetate (16 mg, 0.07 mmol), PPha (37 mg, 0.14 mmol) and potassium acetate (65 mg, 0.48 mmol) at room temperature under nitrogen atmosphere. The mixture was stirred at 100 °C for 4 h under N2. The mixture was quenched with ice-water and extracted with EtOAc (20 mL*3). The combined organic phase was washed with brine, dried with NazSCE, filtered and concentrated. The residue was purified by chromatography (silica gel, 0- 60 %, EtOAc in petroleum ether) to give 8-chloro-10-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-7-methylene-4-((R)-l-(l-((2- (trimethylsilyl)ethoxy)methyl)-lH-indazol-7-yl)ethyl)-4,5,6,7-tetrahydroazepino[2,3,4- de]quinazoline (30 mg, 0.04 mmol, 18%) as a yellow oil. LCMS: 681.2; 683.2 [M + H]+.Intermediate 172-{bis[(4-methoxyphenyl)methyl]amino}-6-bromo-3-fluoro-4-methyl-5- (trifluoromethyl)pyndineSynthetic scheme:Patent ApplicationAtty. Docket No. ENTX-034PCT

[0303] Step 1: To a solution of 6-bromo-4-methyl-5-(trifluoromethyl)pyridin-2-amine (900 mg, 3.53 mmol) in ACN (2 mL) was added 4-(chloromethyl)-l-fluoro-l,4- diazabicyclo[2.2.2]octane-l,4-diium bis(tetrafluoro-X5-boranuide) (1.38 g, 3.88 mmol). The reaction mixture was stirred at rt overnight. 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 ethyl acetate in petroleum ether (gradient: 0-30%) to afford 6-bromo-3-fluoro-4-methyl-5- (trifluoromethyl)pyridin-2-amine (250 mg, 0.92 mmol, 26 %) as a white solid. LCMS: (ESI) m / z 273.0 [M+H]+.

[0304] Step 2: To a solution of 6-bromo-3-fluoro-4-methyl-5-(trifluoromethyl)pyridin-2- amine (290 mg, 1.06 mmol) in DMF (5 mL) was added NaH (127 mg, 3.19 mmol, 60% in mineral oil) at 0 °C for 30 min. Then added 4-(chloromethyl)-l -methoxybenzene (366 mg, 2.34 mmol). The reaction was stirred at 0 °C ON. 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 ethyl acetate in petroleum ether (gradient:0-30%) to afford 2-{bis[(4-methoxyphenyl)methyl]amino}-6-bromo-3- fluoro-4-methyl-5-(trifluoromethyl)pyridine (400 mg, 0.78 mmol, 73%) as a white oil. LCMS: (ESI) m / z 513.2 [M+H]LIntermediate 18:5-bromo-2-fluoro-N,N-bis(4-methoxybenzyl)-3-methyI-4-(trifluoromethyl)anilineSynthetic scheme:Patent ApplicationAtty. Docket No. ENTX-034PCT

[0305] Step 1: To a stirred mixture of 5-bromo-2-fluoro-l-methyl-3-nitrobenzene (5 g, 21.3 mmol) in EtOH / FLO (50 mL) was added in portions Fe (5.97 g, 106 mmol) and NH4CI (5.71 g, 106 mmol). The mixture was stirred at 85 °C for additional 5 hours. The reaction was monitored by analysis of LC-MS. Then water and ethyl acetate were added, filtered, the filtrate was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 15%] to afford 5-bromo-2-fluoro-3-methylaniline (4 g, 19.6 mmol, 91%) as a white solid. LCMS: ESI m / z 206 [M+H]’.

[0306] Step 2: To a solution of 5-bromo-2-fluoro-3-methylaniline (3.7 g, 18.1 mmol) in DMF (20 mL) and AcOH (20 mL) was added NIS (12.2 g, 54.4 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: 10%] to afford 5-bromo-2-fluoro-4-iodo-3- methylaniline (4 g, 12.1 mmol, 66%) as a white solid. LCMS: ESI m / z 330.1 [M+H]+.

[0307] Step 3: To a suspension of NaH (0.81 g, 33.64 mmol, 60% in mineral oil) in anhydrous DMF (30 mL) was added ethyl 5-bromo-2-fluoro-4-iodo-3-methylaniline (3.7 g, 11.2 mmol) dropwise under nitrogen at 0 °C. The white suspension was stirred at 0 °C for 0.5 hour, then 4-(chloromethyl)-l -methoxybenzene (5.27 g, 33.6 mmol) was slowly 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 FEO, 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:Patent Application Atty. Docket No. ENTX-034PCT6%] to afford 5-bromo-2-fluoro-4-iodo-N,N-bis(4-methoxybenzyl)-3-methylaniline (3.5 g, 6.14 mmol, 54%) as a colorless oil. LCMS: ESI m / z 376 [M+H]+.

[0308] Step 4: To a solution of 5-bromo-2-fluoro-4-iodo-N,N-bis(4-methoxybenzyl)-3- methylaniline (1 g, 1.75 mmol) in DMF (10 m ) was added Cui (0.67 g, 3.51 mmol) and methyl 2,2-difluoro-2-(fluorodioxo-X6-sulfanyl)acetate (2.02 g, 10.5 mmol). The Schlenk tube was purged with nitrogen three times and stirred at 90 °C for 2 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, fdtered and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 5%] to afford 5-bromo-2-fluoro-N,N-bis(4-methoxybenzyl)-3-methyl-4- (trifluoromethyl)aniline (680 mg, 1.33 mmol, 75%) as a white solid. LCMS: ESI m / z 512.1 [M+H]+.Intermediate 194-((R)-l-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-10-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-7-methylene-4, 5,6,7- tetrahydroazepino[2,3,4-de]quinazoline-8-carbonitrileSynthetic scheme:Patent ApplicationAtty. Docket No. ENTX-034PCT

[0309] Step 1: To a solution of 3-((R)-l-(8-chloro-10-fluoro-2-(((2R,7aS)-2- fluorotetrahy dro- 1 H-pyrrolizin-7a(5H)-yl)methoxy )-7-methylene-6,7-dihy droazepino[2, 3 ,4- de]quinazolin-4(5H)-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine (100 mg, 0.1 mmol) in NMP (5 mb) was added Zn(CN)2(122 mg, 1.0 mmol) and BIS(TRI-T- BUTYLPHOSPHINE)PALLADIUM(O) (33 mg, 0.07 mmol). The mixture was stirred at 140 °C for 1 h. The reaction was monitored by analysis of LC-MS. The reaction mixture was poured into H2O solution and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient 2% to 5% MeOH in DCM. The desired fractions were evaporated to dryness to afford 4-((R)-l-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-10-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-7-methylene-4, 5,6,7- tetrahydroazepino[2,3,4-de]quinazoline-8-carbonitrile (70 mg, 0.09 mmol, 70%) as a light yellow solid. LCMS(ESI): m / z 758 [M+H]+.Intermediate 202,4-Dichloro-5,6,8-trifluoroquinazoline

[0310] Step 1: Diisopropylamine (26.8 mL, 190 mmol) was dissolved in THF (200 m ) 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 addedPatent ApplicationAtty. Docket No. ENTX-034PCT 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]+.

[0311] 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.

[0312] Step 3: To a solution of methyl carbamimidothioate sulfate (9 g, 44 mmol) in NaHCCL (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]+.

[0313] Step 4: To a solution of methyl (4-bromo-2,6-dichloro-5- fluoronicotinoyl)carbamimidothioate (9 g, 24.9 mmol) in DMF (20 mL) 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]+.

[0314] 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 wasPatent ApplicationAtty. Docket No. ENTX-034PCT 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 216-{bis[(4-methoxyphenyl)methyl]amino}-2-methyl-4-(4,4,5,5-tetramethyl-l,3?2- dioxaborolan-2-yl)-3-(trifluoromethyl)pyridineSynthetic scheme:

[0315] Step 1: To a suspension of 4-bromo-6-methylpyridin-2-amine (1000 mg, 5.35 mmol) in anhydrous THF (20 mL) was added NaH (385 mg, 16.1 mmol, 60% in mineral oil) under nitrogen at room temperature. The white suspension was stirred at room temperature for 30 minutes, then l-(chloromethyl)-4-methoxybenzene (2512 mg, 16.1 mmol) was slowly added. The resulting solution was stirred at 50 °C for 2 hours. The cooled mixture was diluted with water, extracted with EtOAc. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified by flash silica gel chromatography (elution with a gradient of 0 to 30% EtOAc in PE) to afford 4-bromo-N,N-bis(4-methoxybenzyl)-6- methylpyridin-2-amine (1700 mg, 74%) as a colorless oil. LCMS: ESI m / z 427.1 [M + H]+.

[0316] Step 2: To a solution of 2-{bis[(4-methoxyphenyl)methyl]amino}-4-bromo-6- methylpyridine (1200 mg, 2.8 mmol) in AcOH (15 mL) was added NIS (632 mg, 2.8 mmol).Patent ApplicationAtty. Docket No. ENTX-034PCTThe resulting mixture was stirred at room temperature for 30 minutes. The reaction was monitored by analysis of LC-MS. The mixture was diluted with water, extracted with EtOAc. The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified by flash silica gel chromatography (elution with a gradient of 0 to 30% EtOAc in PE) to afford 6-{bis[(4-methoxyphenyl)methyl]amino}-4-bromo-3-iodo-2 -methylpyridine (600 mg, 39%) as a white oil. LCMS: ESI m / z 553.1 [M + H]+.

[0317] Step 3: To a mixture of 6-{bis[(4-methoxyphenyl)methyl]amino}-4-bromo-3-iodo-2- methylpyridine (600 mg, 1.1 mmol), methyl 2,2-difluoro-2-(fluorodioxo-X6-sulfanyl)acetate (1250 mg, 6.5 mmol) in DMF (10 mL) was added Cui (415 mg, 2.2 mmol). The reaction mixture was purged with nitrogen three times, then heated to 100 °C for 2 hours under nitrogen. The reaction was monitored by analysis of LC-MS. The cooled mixture was diluted with water, extracted with EtOAc. The organic phase was washed with brine, dried over Na SO4 and concentrated. The residue was purified by flash silica gel chromatography (elution with a gradient of 0 to 20% EtOAc in PE) to afford 6-{bis[(4-methoxyphenyl)methyl]amino}-4-bromo- 2-methyl-3-(trifluoromethyl)pyridine (400 mg, 74%) as a white oil. LCMS: ESI m / z 495.2 [M + H]+.

[0318] Step 4: To a flask containing 6-{bis[(4-methoxyphenyl)methyl]amino}-4-bromo-2- methyl-3-(trifluoromethyl)pyridine (80 mg, 0.16 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (82 mg, 0.32 mmol) and KOAc (48 mg, 0.48 mmol) in dioxane (3 mL), was added Pd(dppf)C12 (24 mg, 0.032 mmol). The reaction mixture was purged with nitrogen for three times, then heated to 90 °C for 16 hours under nitrogen. The reaction was monitored by analysis of LC-MS. The cooled mixture was diluted with water, extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash silica gel chromatography (elution with a gradient of 0 to 20% EtOAc in PE) to afford 6-{bis[(4-methoxyphenyl)methyl]amino}-2-methyl- 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridine (55 mg, 62%) as an off-white oil. LCMS: ESI m / z 543.3 [M + H]+.Intermediate 226-((4-Methoxybenzyl)amino)-4-methyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3- (trifluoromethyl)benzonitrilePatent ApplicationAtty. Docket No. ENTX-034PCTSynthetic scheme:

[0319] 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 Na2SO4, 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- e) 5 7.77 - 7.67 (m, 1H), 7.45 - 7.36 (m, 1H), 2.52 - 2.50 (m, 3H).

[0320] 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 the mixture was extracted with EtOAc. The organic extract was dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The crude product was purified by flash silicaPatent ApplicationAtty. Docket No. ENTX-034PCT 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-r / ) 8 10.41 - 10.21 (m, 1H), 7.19 - 7.02 (m, 1H), 2.63 - 2.55 (m, 3H).

[0321] 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-l- carbaldehyde (2.2 g, 4.21 mmol, 85%) as a yellow oil. LCMS: ESI m / z 523 [M +H]+

[0322] 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]+.

[0323] 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 was 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 wasPatent ApplicationAtty. Docket No. ENTX-034PCT 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 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 2- bromo-6-{[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)benzene-l- carbonitrile (1.3 g, 3.26 mmol, 87%) as a yellow oil. LCMS: ESI m / z 399.2 [M +H]+.

[0324] Step 6: To a mixture of 2-bromo-6-{[(4-methoxyphenyl)methyl]amino}-4-methyl-3- (trifluoromethyl)benzene-l -carbonitrile (400 mg, 1.00 mmol), 4,4,5,5-tetramethyl-2-(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)C12 (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 6-{[(4-methoxyphenyl)methyl]amino}-4-methyl-2-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)benzene-l-carbonitrile (80 mg, 0.18 mmol, 17%) as a yellow oil . LCMS: ESI m / z 436 [M +H]+.Intermediate 23(2-Cyano-3-((4-methoxybenzyl)amino)-5-methyl-6-(trifluoromethyl)phenyl)boronic acidSynthetic scheme:Patent ApplicationAtty. Docket No. ENTX-034PCT

[0325] Step 1: To a solution of 2-bromo-6-((4-methoxybenzyl)amino)-4-methyl-3- (trifluoromethyl)benzonitrile (1 g, 2.50 mmol) in EtOH (10 mb) 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 (2-cyano-3-((4-methoxybenzyl)amino)-5-methyl-6- (trifluoromethyl)phenyl) boronic acid (600 mg, 1.65 mmol, 65%) as a white solid. LCMS: ESI m / z 365.1 [M+H]+.Intermediate 242,6-Difluoro-3-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline

[0326] 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.Patent ApplicationAtty. Docket No. ENTX-034PCTThe reaction mixture was quenched with saturated ammonium chloride aqueous solution and 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]+

[0327] 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 Na SO4 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]+.

[0328] 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]+.

[0329] 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)C12 (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 252-Fluoro-N,N-bis(4-methoxybenzyl)-5-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)anilinePatent ApplicationAtty. Docket No. ENTX-034PCT

[0330] 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 mb, 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 Na2SO4, 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]+.

[0331] 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 mb, 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 Nal ICO3 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]+.

[0332] Step 3: To a suspension of sodium hydride (1.41 g, 58.8 mmol) in anhydrous DMF (40 mb) was added 3-bromo-2-fluoro-5-methylaniline (4 g, 19.6 mmol) dropwise under nitrogenPatent ApplicationAtty. Docket No. ENTX-034PCT at 0 °C. The white suspension was stirred at 0 °C for 20 min. 4-(chloromethyl)-l- 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 with brine, dried by Na2SC>4, fdtered 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]+.

[0333] 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)C12 (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 Na2SO4, 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]+.. 'H NMR (400 MHz, DMSO-d6) 5 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 26A^V-Bis(4-methoxybenzyl)-4-methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2-amineSynthetic scheme:Patent ApplicationAtty. Docket No. ENTX-034PCT

[0334] 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 for 2 h. The reaction mixture was poured into NH4CI solution and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SC 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]+.

[0335] 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 273-FIuoro-N,N-bis(4-methoxybenzyl)-4-methyl-6-(4,4,5,5-tetramethyl-l,3?2-dioxaborolan-2- yl)pyridin-2-amineSynthetic scheme:Patent ApplicationAtty. Docket No. ENTX-034PCT

[0336] 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(tetrafluoro-X5-boranuide) (7.58 g, 21.4 mmol) in 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>4 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]+.

[0337] Step 2: To a solution of 6-bromo-3-fhioro-4-methylpyridin-2-amine (1.2 g, 5.85 mmol) in DMF (5 mL) 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 Na2SO4 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]+.

[0338] 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-Patent ApplicationAtty. Docket No. ENTX-034PCT dioxaborolan-2-yl)pyridine (500 mg, 1 .02 mmol, 90 %) as a yellow oil. LCMS:(ESI) 492.4 [M+H]+.Intermediate 284-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5-{[tri(prop-2-yl) silyl] ethynyl} quinolineSynthetic scheme:

[0339] Step 1: To a solution of quinolin-4-ol (2 g, 13.8 mmol) in DCE (30 mL) was added (bromoethynyl)[tri(prop-2-yl)] silane (4.32 g, 16.5 mmol), KOAc (1.35 g, 13.8 mmol) and Dichloro(p-cymene) ruthenium (II) dimer (0.42 g, 0.689 mmol). The reaction mixture was stirred at 95 °C under N2 for 16h. The cooled reaction mixture was quenched with water, extracted with DCM (30 mL x 3), washed by water and brine, dried over anhydrous Na2SC>4, filtered and concentrated. The residue was purified by column chromatography on silica gel (EA in PE = 0 ~ 20%) to obtain 5-{[tri(prop-2-yl) silyl] ethynyl} quinolin-4-ol (2.6 g, 7.98 mmol, 58%) as a brown solid. LC / MS (ESI) m / z: 326.1 [M+H]+

[0340] Step 2: To a mixture of 5-{[tri(prop-2-yl) silyl] ethynyl} quinolin-4-ol (1.2 g, 3.69 mmol) in ACN (1 mL) and toluene (10 mL) was added POBr? (1.37 g, 4.79 mmol). The reaction mixture was purged with nitrogen three times, then heated to 70 °C under nitrogen for2 hours. The reaction was monitored by analysis of LC-MS. After cooling toPatent ApplicationAtty. Docket No. ENTX-034PCT room temperature, the reaction mixture was diluted with water, extracted with EtOAc. The organic phase was washed with brine, dried over anhydrous Na2SC>4 and concentrated. 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 4-bromo-5-{[tri(prop-2-yl) silyl] ethynyl} quinoline (1.1 g, 2.83 mmol, 76 %) as a yellow oil. I . ('XIS' ESI m / z 390 [M +H]+

[0341] Step 3: To a mixture of 4-bromo-5-{[tri(prop-2-yl) silyl] ethynyl} quinoline (500 mg, 1.29 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2- dioxaborolane (490 mg, 1.93 mmol), KO Ac (378 mg, 3.86 mmol) in dioxane (10 mL) was added Pd (OAc)2 (58 mg, 0.26 mmol). The reaction mixture was purged with nitrogen three times, then heated to 80 °C under nitrogen for 5 hours. The reaction was monitored by analysis of LC-MS. After cooling to room temperature, the reaction mixture was diluted with water, extracted with EtOAc. The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated. 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 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5-{[tri(prop-2- yl) silyl] ethynyl} quinoline (100 mg, 0.23 mmol, 17%) as a yellow oil. LCMS: ESI m / z 436 [M • H iIntermediate 302-methylpropan-2-yl ({[(2-methylprop-2-yl)oxy]carbonyl}[4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-5-{[tri(prop-2-yl)silyl]ethynyl}quinolin-2-yl]amino)methanoateSynthetic scheme:Patent ApplicationAtty. Docket No. ENTX-034PCT

[0342] Step 1: To a flask containing 2-aminoquinolin-4-ol (1 g, 6.24 mmol) and (Boc)2O (6.81 g, 31 .22 mmol) in DCM (15 mL) was added DMAP (0.23 g, 1 .87 mmol). The reaction mixture was purged with nitrogen for three times, then heated to RT for 18 hours under nitrogen. The reaction was monitored by analysis of LC-MS. The reaction solvent was evaporated under reduced pressure and the crude product was purified by flash silica chromatography, eluting with a gradient of 0-10% EtOAc in petroleum ether to afford 2-methylpropan-2-yl ({[(2-methylprop- 2-yl) oxy] carbonyl} [4-({ [(2-methylprop-2-yl) oxy] carbonyl} oxy) quinolin-2-yl] amino) methanoate (1.3 g, 2.82 mmol, 45%) as a white solid. LCMS: 461.2 [M+H]+.

[0343] Step 2: To a flask containing 2-methylpropan-2-yl ({[(2-methylprop-2-yl) oxy] carbonyl} [4-({[(2-methylprop-2-yl) oxy] carbonyl} oxy) quinolin-2-yl] amino) methanoate (270 mg, 0.59 mmol) in MeOH (5 mL) and H2O (1 mL) was added ISfeCCL (93 mg, 0.88 mmol). The reaction mixture was purged with nitrogen for three times, then heated to RT for 2 hours under nitrogen. The reaction was monitored by analysis of LC-MS. The mixture was poured into a stirred solution of NaHCCh solution, extracted with EtOAc twice. The combined extracts were dried over anhydrous MgSO4, filtered and evaporated to afford crude 2-methylpropan-2-yl [(4- hydroxyquinolin-2-yl) {[(2-methylprop-2-yl) oxy] carbonyl} amino] methanoate (160 mg, 0.44 mmol, 75%) as a white solid, which was used directly without further purification. LCMS: 361.2 [M+H]+.

[0344] Step 3: To a flask containing 2-methylpropan-2-yl [(4-hydroxyquinolin-2-yl) {[(2- methylprop-2-yl) oxy] carbonyl} amino] methanoate (3 g, 8.32 mmol), KOAc (1.63 g, 16.7 mmol) and (bromoethynyl)[tri(prop-2-yl)] silane (2.61 g, 9.99 mmol) in DCE (50 mL), was added Dichloro(p-cymene) ruthenium (II) dimer (0.66 g, 1.08 mmol). The reaction mixture was purged with nitrogen for three times, then heated to RT for 18 hours under nitrogen. The reactionPatent ApplicationAtty. Docket No. ENTX-034PCT was monitored by analysis of LC-MS. The mixture was quenched by added to ice-water and was extracted with EtOAc, 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 ~ 10% EA in PE to afford 2-methylpropan-2-yl [(4-hydroxy-5-{[tri(prop-2-yl) silyl] ethynyl] quinolin-2-yl) { [(2-methylprop-2-yl) oxy] carbonyl] amino] methanoate (4 g, 7.40 mmol, 89%) as a yellow oil. LCMS (ESI): 541.1 [M+H]+.

[0345] Step 4: To a stirred mixture of 7-fluoro-8-{[tri(prop-2-yl) silyl] ethynyl] naphthalene-l,3-diol (1 g, 2.79 mmol) and DIEA (2.15 g, 16.6 mmol) in DCM (10 mL) was added trifluoromethanesulfonic anhydride (2.35 g, 8.32 mmol) at 0 °C. Then heated to RT for 1 hours. The reaction was monitored by analysis of LC-MS. The mixture was quenched by added to ice-water and 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 ~ 2% EA in PE to afford 2-(2,2,8,8-tetramethyl- 4,6-dioxo-5-aza-3,7-dioxanon-5-yl)-5-{[tri(prop-2-yl) silyl] ethynyl ] quinoline-4-yl trifluoromethanesulfonate (3.4 g, 5.05 mmol, 91%) as a yellow oil. LCMS (ESI): 673.3 [M+H]+.

[0346] Step 5: To a mixture of 2-(2,2,8,8-tetramethyl-4,6-dioxo-5-aza-3,7-dioxanon-5-yl)-5- {[tri(prop-2-yl) silyl] ethynyl] quinoline-4-yl trifluoromethanesulfonate (3.5 g, 5.20 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (1.98 g, 7.80 mmol), KO Ac (1.53 g, 15.61 mmol) in dioxane (40 mL) was added Pd(dppf)Ch (0.38 g, 0.52 mmol). The reaction mixture was purged with nitrogen three times, then heated to 80 °C under nitrogen for 15 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 collected. 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 gel chromatography, elution with a gradient of 0 to 5% EA in PE. The desired fractions were evaporated to dryness to afford 2-methylpropan-2-yl ({[(2-methylprop-2- yl)oxy]carbonyl][4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5-{[tri(prop-2- yl)silyl]ethynyl]quinolin-2-yl]amino)methanoate (1.3 g, 2.00 mmol, 38%) as a yellow oil. LCMS: ESI m / z 651 [M +H]+.Examples 1 and 2Patent ApplicationAtty. Docket No. ENTX-034PCTEx. 1 : 6-((S)-4-((R)-l-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-7-methylene-4, 5,6,7- tetrahydroazepino[2,3,4-de]quinazolin-9-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amineEx. 2 : 6-((R)-4-((R)- l-(2-aminopyridin-3-yl)ethyl)-8-chloro- 10-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy )-7-methylene-4, 5,6,7- tetrahydroazepino[2,3,4-de]quinazolin-9-yl)-4-methyI-5-(trifluoromethyl)pyridin-2-amineSynthetic scheme:Patent ApplicationAtty. Docket No. ENTX-034PCT

[0347] Step 1: To a solution of 4-[(lR)-l-(2-{bis[(4-methoxyphenyl)methyl]amino}pyridin- 3-yl)ethyl]-8-chloro-10-fhioro-2-({[(2R,7aS)-2-fluoro-2,3,5,6,7,7a-hexahydro-lH-pyrrolizin-7a- yl]methyl}oxy)-7-methylidene-4,5,6,7-tetrahydroazepino[2,3,4-de]quinazoline (80 mg, 0.1 mmol) in THF (2 mL) was added (TMP)2Zn-2MgC12-2LiCl (1.040 mL) under N2. The mixture was stirred at 50 °C for 2 h. Then LCMS showed the reaction was completed by quenching with D2O (0.4 mL). Then a mixture of 6-{bis[(4-methoxyphenyl)methyl]amino}-2-bromo-4-methyl- 3-(trifluoromethyl)pyridine (67 mg, 0.13 mmol) and CPhos Pd G3 (20 mg, 0.05 mmol, 0.1 eq) in 1,4-dioxane (3 mL) was added to the mixture. The mixture was stirred at 70 °C for 3 h. The reaction mixture was quenched with H2O (15 mL) and extracted with EtOAc (15 mL x 3). The organic layers were washed with brine (15 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by chromatography (silica gel, 0- 10 %, MeOH in DCM) to give 9-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-4-[(lR)-l-(2-{bis[(4-methoxyphenyl)methyl]amino}pyri din-3-Patent ApplicationAtty. Docket No. ENTX-034PCT yl)ethyl]-8-chloro-10-fluoro-2-({[(2R,7aS)-2-fluoro-2,3,5,6,7,7a-hexahydro-lH-pyrrolizin-7a- yl]methyl}oxy)-7-methylidene-4,5,6,7-tetrahydroazepino[2,3,4-de]quinazoline (50 mg, 0.042 mmol, 40%) as a brown solid. LCMS: m / z 1182 [M+H]1.

[0348] Step 2: A mixture of 9-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-methyl-3- (trifluoromethyl) pyridin-2-yl)-4-[(lR)-l-(2-{bis[(4-methoxyphenyl)methyl]amino}pyridin-3- yl)ethyl]-8-chloro-10-fluoro-2-({ [(2R,7aS)-2-fluoro-2,3,5,6,7,7a-hexahydro-lH-pyrrolizin-7a- yl]methyl}oxy)-7-methylidene-4,5,6,7-tetrahydroazepino[2,3,4-de]quinazoline (50 mg, 0.042 mmol) in TFA (3 mL, 39 mmol) was stirred at 50 °C overnight. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (C18, 20 ~ 90 % MeCN in H2O with 0.1 % TFA) to give 6-{4-[(lR)-l-(2-aminopyridin-3- y 1 ) ethyl ] -8-chloro- 10-fluoro-2-( { [(2R, 7aS)-2-fluoro-2,3 , 5 ,6, 7, 7 a-hexahy dro- 1 H-pyrrolizin-7a- yl]methyl}oxy)-7-methylidene-4,5,6,7-tetrahydroazepino[2,3,4-de]quinazolin-9-yl}-4-methyl-5- (trifluoromethyl)pyridin-2-amine (19 mg, 0.02 mmol, 64%) as a white solid. LCMS: m / z 701 [M+H]+.1H NMR (400 MHz, DMSO) 8 8.00 (d, J= 4.2 Hz, 1H), 7.67 (d, J= 7.3 Hz, 1H), 6.85 (s, 2H), 6.70 - 6.65 (m, 1H), 6.48 (s, 1H), 5.82 - 5.76 (m, 1H), 5.63 - 5.50 (m, 1H), 5.34 - 5.20 (m, 2H), 4.76 (s, 1H), 4.11 (d, J= 10.3 Hz, 1H), 4.01 (d, J= 10.4 Hz, 1H), 3.28 - 3.22 (m, 1H), 3.12 - 3.06 (m, 2H), 3.03 - 3.00 (m, 1H), 2.86 - 2.73 (m, 2H), 2.41 - 2.31 (m, 4H), 2.16 - 2.10 (m, 1H), 2.09 - 1.95 (m, 3H), 1.89 - 1.66 (m, 4H), 1.57 (d, J= 6.7 Hz, 3H).

[0349] Step 3: 6-{4-[(lR)-l-(2-aminopyridin-3-yl)ethyl]-8-chloro-10-fluoro-2-({[(2R,7aS)- 2-fluoro-2,3,5,6,7,7a-hexahydro-lH-pyrrolizin-7a-yl]methyl}oxy)-7-methylidene-4,5,6,7- tetrahydroazepino[2,3,4-de]quinazolin-9-yl}-4-methyl-5-(trifluoromethyl)pyridin-2-amine (50 mg, 0.07 mmol) was purified by prep-SFC to give:Peak 1 : 6-((R)-4-((R)- l-(2-aminopyri din-3 -yl)ethyl)-8-chl oro-10-fluoro-2-(((2R, 7aS)-2- fluorotetrahy dro- 1 H-pyrrolizin-7a(5H)-yl)methoxy )-7-methylene-4, 5 ,6, 7 - tetrahydroazepino[2,3,4-de]quinazolin-9-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (13.3 mg, 0.01 mmol, 26 %) as a white solid. LCMS: m / z 701 [M+H]+. 'H NMR (400 MHz, CD3OD) 8 7.88 (d, J = 4.4 Hz, 1H), 7.68 (d, J = 7.2 Hz, 1H), 6.69 (dd, J = 7.2, 5.3 Hz, 1H), 6.50 (s, 1H), 5.91 - 5.83 (m, 1H), 5.29 - 5.13 (m, 2H), 4.21 - 4.11 (m, 2H), 3.34 - 3.27 (m, 1H), 3.18 - 3.00 (m, 4H), 2.93 - 2.86 (m, 1H), 2.78 - 2.64 (m, 1H), 2.34 (m, 3H), 2.29 - 2.19 (m, 1H), 2.18 - 2.00 (m, 3H), 1.95 - 1.72 (m, 4H), 1.56 (d, J = 6.8 Hz, 3H).Patent ApplicationAtty. Docket No. ENTX-034PCT and 6-((S)-4-((R)-l-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(((2R,7aS)-2- fluorotetrahy dro- 1 H-pyrrolizin-7a(5H)-yl)methoxy )-7-methylene-4, 5 ,6, 7 - tetrahydroazepino[2,3,4-de]quinazolin-9-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (2.8 mg, 0.004 mmol, 6%) as a white solid. LCMS: m / z 701 [M+H]+.Peak 2: 'H NMR (400 MHz, CD3OD) 8 7.92 (d, J= 4.6 Hz, 1H), 7.73 (d, J= 7.2 Hz, 1H), 6.77 - 6.71 (m, 1H), 6.58 (s, 1H), 6.01 - 5.90 (m, 1H), 5.87 - 5.76 (m, 1H), 5.38 - 5.24 (m, 2H), 4.28 (s, 2H), 4.04 (m, 1H), 3.80 (m, 1H), 3.61 (m, 1H), 3.46 (m, 1H), 3.25 - 3.13 (m, 3H), 3.01 (m, 1H), 2.44 (s, 3H), 2.33 - 2.14 (m, 3H), 2.02 - 1.90 (m, 3H), 1.76 (d, J= 6.4 Hz, 3H).

[0350] Preparative SFC separation method:Instrument: SHIMADZU PREP SOLUTION SFCColumn: ChiralPak IB, 250><30mm I.D., 5pmMobile phase: A for CO2and B for MEOH+0.1%NH3H2OGradient: B 25%Flow rate: 60 mL / minBack pressure: 100 barColumn temperature: 35 °CWavelength: 220 nmCycle-time: 15min

[0351] Following similar procedures for preparation of Examples 1 and 2, the following compounds were obtained.Table 5: Example Compound Structures and LCMSPatent ApplicationAtty. Docket No. ENTX-034PCTPatent ApplicationAtty. Docket No. ENTX-034PCTPatent ApplicationAtty. Docket No. ENTX-034PCTPatent ApplicationAtty. Docket No. ENTX-034PCTPatent ApplicationAtty. Docket No. ENTX-034PCTTable 6:1HNMR of Example CompoundsPatent ApplicationAtty. Docket No. ENTX-034PCTPatent ApplicationAtty. Docket No. ENTX-034PCTPatent ApplicationAtty. Docket No. ENTX-034PCTPatent ApplicationAtty. Docket No. ENTX-034PCTPatent ApplicationAtty. Docket No. ENTX-034PCTExamples 22 and 23Ex. 22: (S)-9-(6-amino-4-methyI-3-(trifluoromethyl)pyridin-2-yl)-4-((R)-l-(2-aminopyridin- 3-yl)ethyl)-10-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-7- methylene-4,5,6,7-tetrahydroazepino[2,3,4-de]quinazoline-8-carbonitrileEx. 23: (R)-9-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-4-((R)-l-(2-aininopyridin -3-yl)ethyl)- 10-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)- 7-methylene-4,5,6,7-tetrahydroazepino[2,3,4-de]quinazoline-8-carbonitrilePatent ApplicationAtty. Docket No. ENTX-034PCTSynthetic scheme:

[0352] Step 1: To a solution of 4-((R)-l-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)- 10-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-7-methylene- 4,5,6,7-tetrahydroazepino[2,3,4-de]quinazoline-8-carbonitrile (70 mg, 0.09 mmol) in THF (2 mb) was added (TMP^Zn MgCh LiCl (1.48 mL). The reaction mixture was stirred at 50 °C for Ih and then (TMP^Zn MgCh LiCl (1.48 mL) was added at 50 °C. and stirred at 50 °C for Ih. 6- bromo-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (68.6 mg, 0.14 mmol) and C-Phos Palladacycle Gen 3 (14.8 mg, 0.02 mmol) was dissolved in dioxane (2 mL) and was added to the reaction mixture. The mixture was stirred at 70 °C for 2 h. The reaction was monitored by analysis of LC-MS. The reaction mixture was poured into NH4CI solution and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The crude product was purified by flash silica chromatography, eluting with a gradient 2% to 10% MeOH in DCM. The desired fractions were evaporated to dryness to afford 9-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-4-((R)-l-(2-(bis(4- methoxybenzyl)amino)pyridin-3-yl)ethyl)-10-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-7-methylene-4,5,6,7-tetrahydroazepino[2,3,4-de]quinazoline-8- carbonitrile (32 mg, 0.03 mmol, 30%) as a light yellow solid. LCMS (ESI): m / z 1173 [M+H]+

[0353] Step 2: To a solution of 9-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-4-((R)-l-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-10- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-7-methylene-4, 5,6,7-Patent ApplicationAtty. Docket No. ENTX-034PCT tetrahydroazepino[2,3,4-de]quinazoline-8-carbonitrile (30 mg, 0.03 mmol) in TFA (1 mL) was added TfOH (0.1 mL). The mixture was stirred at 50 °C for 0.5 h. The reaction was monitored by analysis of LC-MS. The reaction mixture was evaporated. The crude product was purified by pre-HPLC to afford:Peak 1 : (S)-9-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-4-((R)-l-(2-aminopyridin-3- yl)ethyl)-10-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-7- methylene-4,5,6,7-tetrahydroazepino[2,3,4-de]quinazoline-8-carbonitrile (1.7 mg, 0.00 mmol, 9%) as a white solid. LCMS (ESI): m / z 692 [M+H]+. 'H NMR (400 MHz, CD3OD) 8 8.00 (d, J = 3.8 Hz, 1H), 7.79 (d, J= 7.1 Hz, 1H), 6.80 (dd, J= 7.4, 5.1 Hz, 1H), 6.62 (s, 1H), 6.01 (d, J = 6.8 Hz, 1H), 5.49 - 5.06 (m, 2H), 4.63 - 4.54 (m, 1H), 4.39 (dd, J= 18.4, 11.0 Hz, 2H), 3.54 - 3.43 (m, 2H), 3.45 - 3.34 (m, 3H), 3.18 - 3.07 (m, 2H), 3.02 - 2.90 (m, 1H), 2.57 - 2.39 (m, 5H), 2.34 - 2.17 (m, 3H), 2.13 - 1.88 (m, 4H), 1.68 (d, J = 6.8 Hz, 3H).Peak 2: (R)-9-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-4-((R)-l-(2-aminopyri din-3- yl)ethyl)-10-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-7- methylene-4,5,6,7-tetrahydroazepino[2,3,4-de]quinazoline-8-carbonitrile (1.5 mg, 0.00 mmol, 8.47%) as a white solid. LCMS (ESI): m / z 692 [M+H]+. ‘HNMR (400 MHz, CD3OD) 8 8.00 (d, J = 4.0 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H), 6.80 (dd, J = 7.4, 5.2 Hz, 1H), 6.63 (s, 1H), 6.05 - 5.95 (m, 1H), 5.51 - 5.13 (m, 2H), 4.62 - 4.56 (m, 2H), 4.53 - 4.44 (m, 2H), 3.67 - 3.47 (m, 4H), 3.25 - 3.13 (m, 2H), 3.05 - 2.90 (m, 1H), 2.58 - 2.35 (m, 6H), 2.31 - 2.23 (m, 1H), 2.21 - 2.10 (m, 2H), 2.09 - 1 .97 (m, 2H), 1 .68 (d, J= 6.8 Hz, 3H). as a white solid.Example 245-ethyl-6-fluoro-4-{6-[(lR)-l-(2-aminopyridin-3-yl)ethyl]-13-fluoro-3-({[(2R,7aS)-2-fluoro-2,3,5,6,7,7a-hexahydro-lH-pyrrolizin-7a-yl]methyl}oxy)-9-methylidene-2,4,6,ll- tetrazatricyclo[8.3.1.05,14]tetradeca-l(2),3,5(14),10(ll),12-pentaen-12-yl}naphthalen-2-olPatent ApplicationAtty. Docket No. ENTX-034PCTSynthetic scheme:

[0354] Step 1: To a solution of 9-[(lR)-l-(2-{bis[(4-methoxyphenyl)methyl]amino]pyridin- 3 -yl)ethy 1] -3 -chloro-2-fluoro- 12-({ [(2R, 7aS)-2-fluoro-2, 3 , 5 , 6,7, 7 a-hexahy dro- 1 H-pyrrolizin-7a- yl]methyl}oxy)-6-methylidene-4,9, 11, 13-tetrazatricyclo[8.3.1.05, 14]tetradeca-1 (13), 2, 4,10(14), 11 -pentaene (50 mg, 0.065 mmol) in methoxycyclopentane (6 mL) and H2O (1 mL) was added K3PO4 (41 mg, 0.195 mmol), cataCXium A Pd G3 (14 mg, 0.020 mmol) and 2- {8-ethyl-7-fluoro-3-[(methoxymethyl)oxy]-l-naphthyl}-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (35 mg, 0.098 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 Na2SC>4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with MeOH in DCM [Gradient: 6%] to afford 9-[(lR)-l-(2- {bis[(4-methoxyphenyl)methyl]amino}pyridin-3-yl)ethyl]-3-{8-ethyl-7-fluoro-3- [(methoxymethyl)oxy]-l-naphthyl}-2-fhioro-12-({[(2R,7aS)-2-fluoro-2,3,5,6,7,7a-hexahydro- lH-pyrrolizin-7a-yl]methyl}oxy)-6-methylidene-4,9,l l,13-tetrazatricyclo[8.3.1.05,14]tetradeca- 1 (13), 2, 4,10(14), 11 -pentaene (50 mg, 0.052 mmol, 79%) as a white solid. LCMS: ESI m / z 966.1 [M+H]+.

[0355] Step 2: To a solution of 9-[(lR)-l-(2-{bis[(4-methoxyphenyl)methyl]amino}pyridin- 3-yl)ethyl]-3-{8-ethyl-7-fluoro-3-[(methoxymethyl)oxy]-l-naphthyl}-2-fluoro-12-({[(2R,7aS)-2-Patent ApplicationAtty. Docket No. ENTX-034PCT fluoro-2,3,5,6,7,7a-hexahydro-lH-pyrrolizin-7a-yl]methyl}oxy)-6-methylidene-4,9,l 1,13- tetrazatricyclo[8.3.1.05, 14]tetradeca-l(13), 2,4,10(14),! 1-pentaene (50 mg, 0.052 mmol) in TFA (4 mL). The reaction mixture was stirred at 60 °C for 2h. The reaction was monitored by analysis of LC-MS. The cooled reaction mixture was filtered and concentrated. The residue was purified using prep-HPLC(Welch XBridge Cl 8, 20% - 95% MeCN in water with 0.1% TFA ) to afford 5- ethyl-6-fluoro-4-{6-[(lR)-l-(2-aminopyridin-3-yl)ethyl]-13-fluoro-3-({ [(2R,7aS)-2-fluoro- 2,3,5,6,7,7a -hexahydro- lH-pyrrolizin-7a-yl]methyl}oxy)-9-methylidene-2, 4, 6, 11 -tetrazatricyclo [8.3.1.05,14] tetradeca-l(2),3,5(14),10(l l),12-pentaen-12-yl}naphthalen-2-ol (8.6 mg, 0.013 mmol, 24%) as a white solid. LCMS: ESI m / z 682.1 [M+H]+. 'H NMR (400 MHz, CD3OD) 5 8.38 - 8.22 (m, 1H), 7.98 (d, J= 6.4 Hz, 1H), 7.68 (dd, J= 9.2, 5.6 Hz, 1H), 7.38 - 7.22 (m, 2H), 7.07 (dd, J= 8.4, 5.2 Hz, 2H), 6.35 - 6.20 (m, 1H), 5.65 - 5.30 (m, 3H), 4.76 - 4.66 (m, 2H), 4.03 - 3.84 (m, 3H), 3.73 - 3.62 (m, 1H), 3.52 - 3.44 (m, 1H), 3.16 - 3.03 (m, 1H), 2.85 (d, J = 5.6 Hz, 1H), 2.70 - 2.57 (m, 2H), 2.50 - 2.16 (m, 6H), 1.80 (d, J= 6.4 Hz, 3H), 0.86 - 0.74 (m, 3H).

[0356] Following similar procedures for preparation of Example 24, the following compounds were obtained.Table 7: Structures and LCMS of Example CompoundsPatent ApplicationAtty. Docket No. ENTX-034PCTPatent ApplicationAtty. Docket No. ENTX-034PCTPatent ApplicationAtty. Docket No. ENTX-034PCTTable 8:1HNMR of Example CompoundsEx. # Target structurePatent ApplicationAtty. Docket No. ENTX-034PCTPatent ApplicationAtty. Docket No. ENTX-034PCTPatent ApplicationAtty. Docket No. ENTX-034PCTPatent ApplicationAty. Docket No. ENTX-034PCTBiological Binding AssaysKRAS / SOS1-RAF1 HTRF Binding Assay

[0357] The test compounds were prepared as 10 mM stock solution in 100% DMSO. The stock solution was then serially diluted 3-fold in 100% DMSO to 10 concentrations. 200nL of each diluted compound solution was transferred to 384-well plate in duplicate. To each well, 5 pL of lOnM enzyme solution containing Biotin-KRAS G12V, G12D or WT protein with final concentration of 2.5 nM for G12D, 3 nM for G12V and WT in the assay buffer (50mM HEPES, pH7.5, 50mM NaCl, 5mM MgCh, ImM DTT, 0.1% BSA, 0.01% Triton X-100). For negative control, 5 pL of assay buffer was added instead. The plate was incubated at room temperature for 20 min. 5 pL of S0S1 and GTP (final concentration at 100 nM and 10 pM, respectively) were subsequently added to each well to initiate the nucleotide exchange. After incubation at room temperature for 2 hours, 5 pL of GST-RAF1 (final concentration at 8 nM) was added. All reactions were incubated at room temperature for 20 min and then 5 pL of lx anti-GST-XL665 and lx Streptavidin-Tb were added for detection. After one-hour incubation at room temperature, all samples were subjected to read the TR-FRET signal on Envision with excitation at 340 nm and emission fluorescence at 615 nm and 665 nm. IC50 values were then calculated by plotting dose-response curves and then using the XLfit application in Excel software.KRAS(GMPPNP)-RAF1 HTRF Binding Assay

[0358] The test compounds were prepared as lOmM stock solution in 100% DMSO. The stock solution was then serially diluted 3 -fold in 100% DMSO to 10 concentrations. 200nL of each diluted compound solution was transferred to 384-well plate in duplicate. To each well, 10 pL of enzyme solution containing Biotin-KRAS G12V, G12D or WT protein with finalPatent ApplicationAtty. Docket No. ENTX-034PCT concentration of 1 nM for G12V, 5 nM for G12D and 2 nM for WT in the assay buffer (50mM HEPES, pH7.5, 50mM NaCl, 5mM MgCl2, ImM DTT, 0.1% BSA, 0.01% Triton X-100), respectively. For negative control, 10 pL of assay buffer was added instead. The plate was incubated at room temperature for 20 min. 5 pL of GST-RAF1 (final concentration at 8 nM) was subsequently added to each well. Then 5 pL of lx anti-GST-XL665 and lx Streptavidin-Tb were added for detection. After one-hour incubation at room temperature, all samples were subjected to read the TR-FRET signal on Envision with excitation at 340nm and emission fluorescence at 615 nm and 665 nm. IC50 values were then calculated by plotting dose-response curves and then using the XLfit application in Excel software.Table 9: Binding Assay Activities*Patent ApplicationAtty. Docket No. ENTX-034PCT*A: < 100 nM; B: 100 nM - 1 uM; C: >1 uM; N: not testedCell Base Assay2D CTG Proliferation Assay

[0359] KRAS G12Vmutant, G12Dmutant or WT cells were grown in culture media according to vendors’ instructions. Cells were plated in clear bottom tissue culture treated 96-well plates at a density of 1000-2000 cells / well in a volume of 100 pL and allowed to recover overnight. The edge wells were filled with cell culture media without cells. The plated cells were treated with a 3-fold 9-point serial dilution doses of test compounds, or DMSO control. Compounds were prepared as 10 mM DMSO stock solution and added to the cells with a HP D300 digital dispenser. The top final concentration varied from 10 to 1 pM depending on the potency of the compounds, with the final concentration of DMSO to be 0.1%. Following 3 days of drug treatment, 100 pL of Cell Titer-Gio (CTG) (Promega, G7570) reagent was added to the cells using a Multidrop Combi instrument. The plates were placed on an orbital shaker for 10 minutes to induce cell lysis, and further incubated at room temperature for 10 minutes to stabilize luminescent signal. The luminescence signal was read on Envision with a measurement time of 0.1 s.Patent ApplicationAtty. Docket No. ENTX-034PCT

[0360] Cell proliferation percent inhibition values were calculated using the following equation:Inhibition% = [l-(T120Compound-T120biank) / (T120DMSo- T120biank)]x100%.T120Compound: the signals from compound-treated wells.T120biank: the signals from blank wells.T 120DMSO: the signals from 0.5%DMSO-treated wells.

[0361] XLfit software (Fit model: Dose response one site / 205 [fit = (A+((B-A) / (I+((C / X)^D))))] ) was used for curve fitting and IC50 calculation.Table 10. Cell Assay Activities*Patent ApplicationAtty. Docket No. ENTX-034PCT*A: < 100 nM; B: 100 nM - 1 uM; C: >1 uM; N: not tested pERK Assay (Western Blot)

[0362] KRAS G12Vmutant, G12Dmutant or WT cells were grown in culture media specified by the vendors. Cells were plated in tissue culture treated 6 well plates at a density of 0.5x10A6 cells / well in 3 mL of culture media and allowed to recover overnight. The plated cells were treated with a 3-fold 9-point serial dilution doses of test compound, or DMSO. Compounds were prepared as 10 mM DMSO stock solution, and 3 pL of the diluted compounds were added to the cells, with a final concentration of 0.1% DMSO. Following 3 hours of drug treatment, cells were lysed on the plate by adding 100 pL of lysis buffer containing protease inhibitor and phosphatase inhibitor. Cells were scraped and transferred to 1.5 mL microcentrifuge tubes. Cell lysates were centrifuged at 13,000 x g for 15 minutes at 4°C. The protein concentrations were determined using the BCA kit. All sample supernatants were transferred to Eppendorf tubes and stored at - 80 °C.

[0363] For Western blot, 15-20 pg of protein was loaded into each well. Following electrophoresis, proteins were transferred to a filter membrane. The membrane was incubated in blocking buffer (LI-COR) for an hour at room temperature with rocking and was incubated overnight at 4 °C in primary antibodies diluted at 1 : 1000. On the second day, the primary antibodies were removed, and the membrane was washed 3 x 10 minutes in TBST and incubated in secondary antibodies for 45 min at room temperature. The membrane was washed again andPatent Application Atty. Docket No. ENTX-034PCT imaged using ODYSSEY (Li-COR) to measure the signal intensity from the IRDye 800CW goat anti-mouse secondary antibodies (LICOR). The data was analyzed for the intensity of each protein band, including total ERK, and phosphorylated ERK (pERK).

[0364] The percentage of pERK was determined by dividing the signal output of pERK by the signal output of total ERK. Percent inhibition of phosphorylation of ERK in compound- treated samples compared to vehicle-treated control samples was determined by subtracting compound-treated pERK signal from vehicle-treated pERK signal then dividing by the vehicle- treated pERK signal and multiplying by 100.

[0365] 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.

[0366] Applicant’s disclosure is described herein in preferred embodiments with reference to the Figures, in which like numbers represent the same or similar elements. Reference throughout this specification to “one embodiment,” “an embodiment,” or similar language means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases “in one embodiment,” “in an embodiment,” and similar language throughout this specification may, but do not necessarily, all refer to the same embodiment.

[0367] The described features, structures, or characteristics of Applicant’s disclosure may be combined in any suitable manner in one or more embodiments. In the description, herein, numerous specific details are recited to provide a thorough understanding of embodiments of the invention. One skilled in the relevant art will recognize, however, that Applicant’s composition and / or method may be practiced without one or more of the specific details, or with other methods, components, materials, and so forth. In other instances, well-known structures, materials, or operations are not shown or described in detail to avoid obscuring aspects of the disclosure.

[0368] In this specification and the appended claims, the singular forms "a," "an," and "the" include plural reference, unless the context clearly dictates otherwise.Patent ApplicationAtty. Docket No. ENTX-034PCT

[0369] 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. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described.Methods recited herein may be carried out in any order that is logically possible, in addition to a particular order disclosed.Incorporation by Reference

[0370] References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, have been made in this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes. Any material, or portion thereof, that is said to be incorporated by reference herein, but which conflicts with existing definitions, statements, or other disclosure material explicitly set forth herein is only incorporated to the extent that no conflict arises between that incorporated material and the present disclosure material. In the event of a conflict, the conflict is to be resolved in favor of the present disclosure as the preferred disclosure.Equivalents

[0371] The representative examples are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples and the references to the scientific and patent literature included herein. The examples contain important additional information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.

Claims

Patent ApplicationAtty. Docket No. ENTX-034PCTWhat is claimed is:CLAIMS1. A compound having the structural formula (I):or a pharmaceutically acceptable form or an isotope derivative thereof, whereinX is CRX1RX2, wherein each of RX1and RX2is independently selected from H, halo and unsubstituted or substituted C1-3 alkyl;Y is a single bond; orCRY1RY2, wherein each of RY1and RY2is independently selected from H, halo, OR, unsubstituted or substituted C1-3 alkyl; or R1 1and RY2, along with the carbon atom they are bonded to, form an unsubstituted or substituted 3- to 6-membered carbocyclic or heterocyclic group;W isW1: an unsubstituted or substituted 5- or 6-membered carbocyclic, heterocyclic, aryl or heteroaryl group, or unsubstituted or substituted C1-3 alkyl or alkoxyl; orW2: a fused bicyclic of Ring C, which is bonded to Y or N where Y is a single bond, fused with Ring D, wherein each of Ring C and Ring D is independently a substituted 5- or 6-membered carbocyclic, heterocyclic, aryl or heteroaryl group;Z is CR6or N;Patent Application Atty. Docket No. ENTX-034PCTR2is (CH2)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 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)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 10-membered unsaturated monocyclic or bicyclic ring, comprising 0-5 heteroatoms selected from N, O and S;R8is H, halo, unsubstituted or substituted Ci-6 alkyl, OR or NRR’; each of R10a, R10b, Rl laand Rl lbis independently H, halo, CN, R or OR; or two of Ri°a, R10b, Rl laand Rl lbtogether with the carbon atom(s) they are bonded to respectively, form an unsubstituted or substituted 3- to 6-membered carbocyclic or heterocyclic group; and each of R and R’ is independently selected from H, 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 6-membered heterocyclic ring.

2. The compound of claim 1, wherein Y is CRY1RY2, having the structural formula (II):

3. The compound of claim 2, wherein Z is CR6, having the structural formula (IIA):Patent ApplicationAtty. Docket No. ENTX-034PCT4. The compound of claim 2, wherein Z is N, having the structural formula (IIB):

5. The compound of claim 3 or 4, wherein RY1is H and RV 2is not H.

6. The compound of claim 3 or 4, wherein RY1is H and RY2is C1-3 alkyl.

7. The compound of claim 5 or 6, with the following stereochemistry:

8. The compound of claim 1, wherein Y is a single bond, having the structural formula(HI)Patent ApplicationAtty. Docket No. ENTX-034PCT9. The compound of claim 8, wherein Z is CR6, having the structural formula (IIIA):

10. The compound of claim 8, wherein Z is N, having the structural formula (IIIB):

11. The compound of any one of claims 1-10, wherein W is W1.

12. The compound of claim 11, wherein W1is a substituted 5-membered heteroaryl group.

13. The compound of claim 11, wherein W1is a substituted 6-membered heteroaryl group.

14. The compound of claim 11, wherein W1is a substituted or unsubstituted C1-3 alkyl or alkoxy group.

15. The compound of claim 11, wherein W1has the structural formula:whereinRW1is NRR';J is N, NRb, CRa, O or S;K is N, NRb, CRa, O or S;Patent ApplicationAtty. Docket No. ENTX-034PCTL is N, NRb, CRa, O or S; each Rais independently R, halo, CN or OR; and each Rbis independently R.

16. The compound of claim 11, wherein W1has the structural formula:whereinRW1is NRR';T is N or CRa;U is N or CRa;V is N or CRa; and each Rais independently R, halo, CN or OR.

17. The compound of claim 16, wherein one of T, U and V is N and each of the other two is CH.

18. The compound of claim 17, wherein T is N and each of U and V is CH.

19. The compound of any one of claims 16-18, wherein Rais H.

20. The compound of any one of claims 15-19, wherein RW1is NH2.

21. The compound of any one of claims 1-10, wherein W is W2.

22. The compound of claim 21, wherein W2is a 5 : 5 fused bicyclic.

23. The compound of claim 21, wherein W2is a 5 : 6 fused bicyclic.

24. The compound of claim 21, wherein W2is a 6 : 5 fused bicyclic.

25. The compound of claim 21, wherein W2is a 6 : 6 fused bicyclic.

26. The compound of claim 21, wherein Y is a single bond and W2has the structural formula:Patent ApplicationAtty. Docket No. ENTX-034PCTwhereinRW2is NRR'; m is 0, 1, 2, 3 or 4;J is N, NRb, CRa, O or S;K is N, NRb, CRa, O or S;L is N, NRb, CRa, O or S; each Rais independently R, halo, CN or OR; and each Rbis independently R.

27. The compound of claim 21, wherein Y is a single bond and W2has the structural formula:whereinRW2is N R’; m is 0, 1, 2, 3 or 4;T is N or CRa;U is N or CRa;V is N or CRa; and each Rais independently R, halo, CN or OR.

28. The compound of any one of claims 1-27, wherein each of RX1and RX2is independently selected from H, F and Cl.Patent ApplicationAtty. Docket No. ENTX-034PCT29. The compound of claim 28, wherein each of RX1and RX2is H.

30. The compound of claim 28, wherein one of RX1and RX2is H and the other is F or Cl.

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

32. The compound of any one of claims 1-27, wherein at least one of RX1and RX2is an unsubstituted or substituted C1-3 alkyl.

33. The compound of any one of claims 1-32, wherein each of R10a, R10b, Rl laand Rllbis H.

34. The compound of any one of claims 1-32, wherein each of R10a, R10band Rl lais H, andRl lbis R, OR or halo.

35. The compound of any one of claims 1-32, wherein each of R10a, Rllaand Rl lbis H, and Riob , QR orhalo36. The compound of any one of claims 1-3, 5-9, and 11-35, wherein R6is H.

37. The compound of any one of claims 1-3, 5-9, and 11-35, wherein R6is F.

38. The compound of any one of claims 1-3, 5-9, and 11-35, wherein R6is Cl.

39. The compound of any one of claims 1-3, 5-6, and 11-35, wherein R6is C1-3 alkyl or C3-4 cycloalkyl.

40. The compound of any one of claims 1-3, 5-6, and 11-35, wherein R6is CH2F, CHF2 or CF3.

41. The compound of any one of claims 1-3, 5-6, and 11-35, wherein R6is CN, S(O)2R, NRR’, OR or C(O)NRR’.

42. The compound of any one of claims 1 -41, wherein z is 1.

43. The compound of any one of claims 1-42, 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’.

44. The compound of claim 43, wherein R2is C3-5 carbocyclic ring substituted with 0-5 R2A.

45. The compound of claim 43, wherein R2is selected from:Patent ApplicationAtty. Docket No. ENTX-034PCT46. The compound of claim 43, wherein R2is C3-5 heterocyclic ring substituted with 0-5 R2A.

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

48. The compound of any one of claims 1-42, wherein R2is a bicyclic, unsubstituted or substituted Ce-io heterocyclic ring.

49. The compound of claim 48, wherein R2is selected from:Patent ApplicationAtty. Docket No. ENTX-034PCT50. The compound of claim 48, wherein R2is selected from:Patent ApplicationAtty. Docket No. ENTX-034PCT51. The compound of any one of claims 1-50, wherein R7is an unsubstituted or substituted 6- membered aryl or heteroaryl ring, comprising 0-5 heteroatoms selected from N, O and S.

52. The compound of claim 51, wherein 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.

53. The compound of claim 52, wherein W is CR7C, and R7has the structural formula:(VIIIA)54. The compound of claim 52, wherein W is N, and R7has the structural formula:Patent ApplicationAtty. Docket No. ENTX-034PCT(VIIIB)55. The compound of any one of claims 52-54, wherein Q is N.

56. The compound of claim 55, wherein R7has the structural formula:(VIIIC)57. The compound of claim 55, wherein R7has the structural formula:(VIIID)58. The compound of any one of claims 52-54, wherein Q is CR7E.

59. The compound of claim 58, wherein R7Eis H.

60. The compound of claim 58, wherein R7Eis F.

61. The compound of claim 58, wherein R7Eis CN.

62. The compound of any one of claims 52-61, wherein R7Dis NH2.

63. The compound of any one of claims 52-61, wherein R7Dis OR.

64. The compound of any one of claims 52-63, wherein R7Ais CF3.

65. The compound of any one of claims 52-63, wherein R7Ais cyclopropyl.

66. The compound of any one of claims 52-65, wherein R7Bis C1-3 alkyl.

67. The compound of any one of claims 52-65, wherein R7Bis methyl.

68. The compound of any one of claims 52-67, wherein R7C, if present, is F.

69. The compound of any one of claims 52-67, wherein R7C, if present, is H.

70. The compound of claim 52, wherein R7is selected from:Patent ApplicationAtty. Docket No. ENTX-034PCT72. The compound of any one of claims 1 -71 , wherein R7is an unsubstituted or substituted 9- or 10-membered bicyclic aryl or heteroaryl ring, comprising 0-5 heteroatoms selected from N, O and S.

73. The compound of claim 72, wherein R7has the structure formula (V):Patent ApplicationAtty. Docket No. ENTX-034PCT(IX) 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; each of p and q is independently 0, 1, 2 or 3; and each k is independently 0, 1 or 2.

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

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

76. The compound of claim 74 or 75, wherein Ring B is a 5-membered heterocyclic ring.

77. The compound of claim 74 or 75, wherein Ring B is a 6-membered heterocyclic ring.

78. The compound of claim 74 or 75, wherein Ring B is a 5-membered heteroaryl ring.

79. The compound of claim 74 or 75, wherein Ring B is a 6-membered heteroaryl ring.

80. The compound of claim 74 or 75, wherein Ring B is a 6-membered aryl ring.

81. The compound of claim 73, wherein R7is selected from:Patent ApplicationAtty. Docket No. ENTX-034PCT82. The compound of claim 73, wherein R7is selected from:

83. The compound of claim 73, wherein R7is selected from:

84. The compound of any one of claims 1-83, wherein R8is F.

85. The compound of claim 1, having the structural formula:Patent ApplicationAtty. Docket No. ENTX-034PCTwhereinRW1is NRR';T is N or CRa;U is N or CRa;V is N or CRa; and each Rais independently R, halo, CN or OR.

86. The compound of claim 1, having the structural formula:whereinRW1is NRR';J is N, NRh, CRa, O or S;K is N, NRb, CRa, O or S;L is N, NRb, CRa, O or S; each Rais independently R, halo, CN or OR; and each Rbis independently R.

87. The compound of claim 1, having the structural formula:Patent ApplicationAtty. Docket No. ENTX-034PCTwhereinRW2is NRR';T is N or CRa;U is N or CRa;V is N or CRa; and each Rais independently R, halo, CN or OR.

88. The compound of claim 1, having the structural formula:whereinRW2is NRR';J is N, NRb, CRa, O or S;K is N, NRb, CRa, O or S;L is N, NRb, CRa, O or S; each Rais independently R, halo, CN or OR; and each Rbis independently R.

89. The compound of claim 1, having the structural formula:Patent ApplicationAtty. Docket No. ENTX-034PCTwhereinRW1is NRR';T is N or CRa;U is N or CRa;V is N or CRa; and each Rais independently R, halo, CN or OR.

90. The compound of claim 1, having the structural formula:whereinRW1is NRR';J is N, NRb, CRa, O or S;K is N, NRb, CRa, O or S;L is N, NRb, CRa, O or S; each Rais independently R, halo, CN or OR; and each Rbis independently R.91 . The compound of claim 1, having the structural formula:Patent ApplicationAtty. Docket No. ENTX-034PCTwhereinRW2is NRR';T is N or CRa;U is N or CRa;V is N or CRa; and each Rais independently R, halo, CN or OR.

92. The compound of claim 1, having the structural formula:whereinRW2is NRR';J is N, NRb, CRa, O or S;K is N, NRb, CRa, O or S;L is N, NRb, CRa, O or S; each Rais independently R, halo, CN or OR; and each Rbis independently R.

93. The compound of any one of claims 85-88, wherein R6is F.Patent ApplicationAtty. Docket No. ENTX-034PCT94. The compound of any one of claims 85-88, wherein R6is Cl.

95. The compound of any one of claims 85-94, wherein R8is F.

96. The compound of any one of claims 85-95, wherein each of R10a, R10band Rl lais H.

97. The compound of claim 1, selected from Table 1.

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

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

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

101. The compound of any of claims 1-100, having one or more deuterium atoms in place of hydrogen.

102. The compound of any of claims 1-100, having one deuterium atom in place of a hydrogen atom.

103. A pharmaceutical composition comprising a compound according to any one of claims 1- 102 and a pharmaceutically acceptable excipient, carrier, or diluent.

104. The pharmaceutical composition of claim 103, being suitable for oral administration.

105. A unit dosage form comprising a pharmaceutical composition according to claim 103 or 104.

106. The unit dosage form of claim 105, being in the form of a tablet or capsule.

107. 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 1-102.

108. A method for modulating KRas activity in a cell, comprising contacting the cell with a compound according to any one of claims 1-102.

109. 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 1-102.

110. The method of claim 109, wherein the KRas mutant is selected from G12C, G12D and G12V.

111. 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 1-102.

112. The method of claim 111, wherein the cancer is selected from the group consisting of carcinoma, squamous carcinoma, adenocarcinoma, sarcoma, leukemia, neuroma,Patent ApplicationAtty. Docket No. ENTX-034PCT melanoma, and lymphoma.

113. The method of claim 111 or 112, 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.

114. The method of any one of claims 107-113, wherein the subject has a mutation of KRAS, HRAS and / or NRAS.

115. The method of any one of claims 107-114, wherein the subject being treated is further administered one or more of chemotherapy, radiotherapy, targeted therapy, immunotherapy, and hormonal therapy.

116. Use of the compound according to any one of claims 1-102, and a pharmaceutically acceptable excipient, carrier, or diluent, in preparation of a medicament for treating a disease or disorder.

117. The use of claim 116, wherein the disease or disorder is cancer.

118. The use of claim 117, wherein the cancer is selected from the group consisting of carcinoma, squamous carcinoma, adenocarcinoma, sarcoma, leukemia, neuroma, melanoma, and lymphoma.

119. The use of claim 118, 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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